CARBAZOLE DERIVATIVES AND THEIR USE AS NEUROPEPTIDE Y5 RECEPTOR LIGANDS
CHEMICAL COMPOUNDS
This invention relates to compounds which antagonise the interaction between neuropeptide Y (NPY) and the neuropeptide Y5 (NPY-5) receptor sub-type. This invention also relates to processes for the manufacture of NPY-5 receptor antagonists or agonists, pharmaceutically acceptable salts thereof, and to novel pharmaceutical compositions of NPY-5 receptor antagonists or agonists.
NPY is a 36 amino acid polypeptide which is a member of the pancreatic polypeptide family of regulatory peptides with widespread distribution throughout the mammalian system. NPY is the most abundant neuropeptide in the central and peripheral nervous systems and has been shown to have powerful and complex effects on feeding, anxiety, circadian rhythms, reproduction, pituitary-adrenocortical axis function, memory retention, seizures, thermo-regulation, and cardiovascular and gastrointestinal functions. NPY interacts with a heterogeneous population of at least six receptor subtypes, Y,-Y6 which activate adenylate cyclase via a G-protein. For reviews of NPY see: CRC Critical Reviews in Neurobiology. (1988) 4, 97-135; Regulatory Peptides (1996) 62, 1 -11.
One of the most striking actions of NPY is induction of feeding in a variety of vertebrate species. Direct injection of NPY into the hypothalamus of satiated rats can increase food intake up to 10-fold over a 4 hour period and NPY is the only known peptide which can cause animals to eat until they are obese. Recent studies on NPY have focused on the identification of the NPY receptor responsible for the regulation of feeding. The NPY-5 receptor has been identified as the receptor most closely matching a proposed appetite receptor. The functional role of this receptor was addressed by receptor blockade studies. Intra-cerebro-ventricular injection of NPY-5 receptor antisense oligodeoxynucleotides prevented the increase in hypothalamic NPY levels during food deprivation and inhibited fasting-induced food intake in rats [Schaffhauser et al (1997) Diabetes 46, 1792 - 1798]. Thus the NPY-5 receptor is a potential pharmacological target in the modulation of feeding disorders such as obesity. For reviews on the association between NPY and feeding see: Zimanyi et al (1998) Current Pharm Des 4, 349-66; Heinrichs et al (1998) Vitamins and Hormones 54, 51-66. Obesity is a large and ever expanding problem in affluent societies, which has reached epidemic proportions. According to the US Institute of Medicine, 59% of Americans are
clinically obese or at least 20% above their ideal body weight. Obesity is associated with susceptibility to a number of other conditions e.g. non-insulin-dependent diabetes, hypertension, dyslipidaemia and coronary heart disease. These conditions lead to reduction in life expectancy and decreased quality of life. The overall financial burden of obesity is difficult to quantify but it has been estimated that in the US it may account for 6-8% of total healthcare expenditure.
Thus there is need for pharmaceutical agents which have efficacy in the treatment of eating disorders such as obesity. Modulation of NPY activity through antagonism at the NPY-5 receptor offers one potential target for pharmacological intervention in these conditions.
According to the first feature of the invention there is provided the use of a compound of formula (I) in the manufacture of a medicament for the treatment, in a warm-blooded animal, of disorders mediated by the neuropeptide Y5 receptor:
R, is selected from hydrogen, C,.6alkyl, C,.4alkoxyC|.4alkyl, C,.6alkanoyl, C,.4alkanoylC1.4alkyl, aryl, arylC alkyl, arylC,.4alkoxyC,.4alkyl, arylCι_4alkanoyl, arylcarbonyl, heteroaryl, heteroarylC alkyl, heteroarylC,.4alkoxyC|.4alkyl, heteroarylCι_4alkanoyl, heteroarylcarbonyl, heterocyclyl, heterocyclylC,.4alkyl, heterocyclylC,.4alkoxyC,.4alkyl, heterocyclylC,.4alkanoyl, heterocyclylcarbonyl, carbocyclyl, carbocyclylC,.4alkyl, carbocyclylC,.4alkoxyC,.4alkyl, carbocyclylCMalkanoyl, carbocyclylcarbonyl, C alkylsulphonyl, NN-di-C,.4alkylaminosulphonyl or N-C,_4alkylaminosulphonyl wherein R, may be optionally substituted (on an available carbon atom) by up to three substituents independently selected from C,.4alkyl optionally substituted by up to three fluoro substituents, C,.4alkoxy, C,.4alkanoyl, carboxy, hydroxy, halo, cyano, amino, N-C,.4alkylamino, N,N-di-C,.4alkylamino, C,.4alkanoylamino, mercapto,
C,.4alkylsulphonyl, C,.4alkylsulphinyl, C,.4alkylsulphanyl, nitro, heteroarylC alkanoylamino, or C,.4alkoxycarbonyl;
R2 is selected from hydrogen, C,.4alkyl (optionally substituted by hydroxy), C alkoxy, cyano, nitro, halo, amino, N-C,.4alkylamino, or N,N-di-C alkylamino; A is selected from, -NH-, -CH2NH-, -NHC(O)-, -CH2NHC(O)-, -C(O)NH-,
-NHC(O)NH-, -NHC(O)O-, -NHS(O2)-, -NHC(=N-CN)-, or a direct bond; wherein each nitrogen atom is optionally substituted with C,.4alkyl or hydroxyC2.4alkyl;
B is selected from C Oalkylene, C2.10alkenylene, C2.,0alkynylene, or a direct bond wherein the alkylene, alkenylene and alkynylene chains are optionally substituted by hydroxy, C , _4alkoxy or amino ;
R3 is selected from hydrogen, hydroxy, C,.6alkoxy, C,.6alkanoyl, C,.6alkanoyloxy, C,.6alkanoylamino, C,.6alkoxycarbonyl, aryl, aryloxy, arylcarbonyl, arylC,.4alkyl, arylC,.4alkoxy, arylC,.4alkanoyl, aryloxycarbonyl, aryl ^alkoxycarbonyl, arylamino, diarylamino, arylsulphonyl, heteroaryl, heteroaryloxy, heteroarylC,.4alkoxy, heteroarylcarbonyl, heteroarylC,.4alkanoyl, heteroaryloxycarbonyl, heteroarylCMalkoxycarbonyl, heteroarylC,.4alkyl, heteroarylamino, heteroarylsulphonyl, diheteroarylamino, heterocyclyl, heterocyclyloxy, heterocyclylC,.4alkoxy, heterocyclylcarbonyl, heterocyclylC,.4alkanoyl, heterocyclyloxycarbonyl, heterocyclylC,.4alkoxycarbonyl, heterocyclylC,.4alkyl, heterocyclylamino, diheterocyclylamino, heterocyclylsulphonyl, carbocyclyl, carbocyclyloxy, carbocyclylC,.4alkoxy, carbocyclylcarbonyl, carbocyclylC,.4alkanoyl, carbocyclyloxycarbonyl, carbocyclylC alkoxycarbonyl, carbocyclylC,.4alkyl, carbocyclylamino, carbocyclylsulphonyl, dicarbocyclylamino, cyano, carbamoyl, ureido, amino, N-C,.4alkylamino, N,N-di-C,.4alkylamino, C,.4alkoxycarbonylamino, carbamoyl, V-C alkylcarbamoyl, NN-di-C,.4alkylcarbamoyl, C,.4alkylsulphanyl, C,_4alkylsulphinyl, C,.4alkylsulphonyl, trifluoromethyl or fluoro wherein R3 may be optionally substituted by up to three substituents independently selected from CMalkyl, hydroxyC,_4alkyl, C,.4alkoxy, C,.6alkoxycarbonyl, C2.6alkenyloxycarbonyl, C,.4alkanoyl, C,.4alkanoylamino, C,.4alkanoylthio, oxo, carboxy, hydroxy, halo, cyano, amino, JV-C,_4alkylamino, NN-di-C,.4alkylamino, N-C1.4alkylaminoC).4alkyl, NΛr-di-C,.4alkylaminoCl.4alkyl, carbamoyl, N-C,.4alkylcarbamoyl, NN-di-C,.4alkylcarbamoyl, mercapto, C,.4alkylsulphonyl,
C,.4alkylsulphinyl, C,.4alkylsulphanyl, C,.4alkylsulphonyloxyC1.4alkyl, nitro, trifluoromethyl, trifluoromethylC ,.4alkyl, C , .6alkoxycarbonylamino, C , .6alkoxycarbonyl(N-C , _4alkyl)amino, aryl (optionally substituted by one C,.4alkoxy or sulphamoyl), arylC,.4alkyl, aryloxyC,.4alkyl, arylcarbonyl, heteroaryl, heteroarylC].4alkyl, heteroaryloxyC,.4alkyl, heteroarylcarbonyl, heterocyclyl, heterocyclylC,.4alkyl, heterocyclyloxyC,.4alkyl, heterocyclylcarbonyl, carbocyclyl, carbocyclylC,.4alkyl, carbocyclyloxyC,.4alkyl or carbocyclylcarbonyl; and
R4 is selected from hydrogen, C,.4alkyl, halo or nitro; or a pharmaceutically acceptable salt, prodrug or solvate thereof.
According to a further aspect of the first feature of the invention there is provided a method of treatment, in a warm-blooded animal, of disorders mediated by the neuropeptide Y5 receptor comprising administering a therapeutically effective amount of a compound of formula (I).
According to a further aspect of the first feature of the invention there is provided a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt, prodrug or solvate thereof, in admixture with a pharmaceutically-acceptable diluent or carrier for the treatment of a warm-blooded animal, in need of treatment of disorders mediated by the neuropeptide Y5 receptor.
To treat disorders mediated by the neuropeptide Y5 receptor neuropeptide Y5 receptor agonists or antagonists can be administered. According to a further aspect of the first feature of the invention there is provided the use of a compound of formula (I) in the manufacture of a medicament for the treatment of eating disorders in a warm-blooded animal.
Examples of eating disorders include: obesity, bulimia or anorexia. Further examples of eating disorders include: obesity and related disorders, bulimia or anorexia. Examples of "related disorders" are diabetes, dyslipidaemia, hypertension and sleep disturbances. Preferably "related disorders" refers to diabetes.
According to a further aspect of the first feature of the invention there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt, prodrug or solvate thereof, in the manufacture of a medicament for the treatment of eating disorders in a warm-blooded animal.
According to another feature of the invention there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt, prodrug or solvate thereof, in the manufacture of a medicament for promoting weight loss.
According to a further aspect of the first feature of the invention there is provided a method of treatment, in a warm-blooded animal, of eating disorders, comprising administering a therapeutically effective amount of a compound of formula (I).
According to a further aspect of the first feature of the invention there is provided a method of treatment, in a warm-blooded animal, of eating disorders, comprising administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, prodrug or solvate thereof.
According to a further aspect of the first feature of the invention there is provided a method of promoting weight loss, comprising administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, prodrug or solvate thereof. According to a further aspect of the first feature of the invention there is provided a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt, prodrug or solvate thereof, in admixture with a pharmaceutically acceptable diluent or carrier for the treatment of eating disorders in a warm-blooded animal.
According to a further aspect of the invention there is provided a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt, prodrug or solvate thereof, in admixture with a pharmaceutically acceptable diluent or carrier for use in promoting weight loss.
Preferably promoting weight loss would refer to promoting weight loss in a warm-bloodied animal. Preferably a warm-blooded animal is man.
For the avoidance of doubt the numbering of the positions on the carbazole ring is as follows:
In this specification the generic term "alkyl" includes both straight-chain and branched-chain alkyl groups. However references to individual alkyl groups such as "propyl" are specific for the straight-chain version only and references to individual branched-chain alkyl groups such as "isopropyl" are specific for the branched-chain version only. An analogous convention applies to other generic terms. The term "aryl" refers to phenyl or naphthyl.
The term "heteroaryl" refers to a 4-14 membered aromatic mono, bicyclic or tricyclic ring containing up to 5 heteroatoms independently selected from nitrogen, oxygen or sulphur, linked via ring carbon atoms or ring nitrogen atoms where a bond from a nitrogen is allowed, for example no bond is possible to the nitrogen of a pyridine ring, but a bond is possible through the 1 -nitrogen of a pyrazole ring. The term "heteroaryl" preferably refers to a 4-10 membered aromatic mono or bicyclic ring containing up to 5 heteroatoms independently selected from nitrogen, oxygen or sulphur, linked via ring carbon atoms or ring nitrogen atoms where a bond from a nitrogen is allowed, for example no bond is possible to the nitrogen of a pyridine ring, but a bond is possible through the 1 -nitrogen of a pyrazole ring. The term "heteroaryl" particularly refers to a 5-10 membered aromatic mono or bicyclic ring containing up to 5 heteroatoms independently selected from nitrogen, oxygen or sulphur, linked via ring carbon atoms or ring nitrogen atoms where a bond from a nitrogen is allowed, for example no bond is possible to the nitrogen of a pyridine ring, but a bond is possible through the 1 -nitrogen of a pyrazole ring. More preferably, the term "heteroaryl" refers to a 5 or 6 membered aromatic mono or bicyclic ring containing up to 5 heteroatoms independently selected from nitrogen, oxygen or sulphur, linked via ring carbon atoms or ring nitrogen atoms where a bond from a nitrogen is allowed, for example no bond is possible to the nitrogen of a pyridine ring, but a bond is possible through the 1 -nitrogen of a pyrazole ring. Examples of 5- or 6-membered heteroaryl ring systems include pyrrole, furan, imidazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, pyridine, isoxazole, oxazole, 1 ,2,4 oxadiazole, isothiazole, thiazole, 1,2,4-triazole and thiophene. Particular examples of 5- or 6-membered heteroaryl ring systems include pyrrole, furan, imidazole, triazole, pyrazine, pyrimidine, pyridazine, pyridine, isoxazole, oxazole, 1,2,4 oxadiazole, isothiazole, thiazole and thiophene. More particularly, the term "heteroaryl" refers to a 9 or 10 membered aromatic mono or bicyclic ring containing up to 5 heteroatoms independently selected from
nitrogen, oxygen or sulphur, linked via ring carbon atoms or ring nitrogen atoms where a bond from a nitrogen is allowed, for example no bond is possible to the nitrogen of a pyridine ring, but a bond is possible through the 1-nitrogen of a pyrazole ring. A 9 or 10 membered bicyclic heteroaryl ring system is an aromatic bicyclic ring system comprising a 6-membered ring fused to either a 5 membered ring or another 6 membered ring. Examples of 5/6 and 6/6 bicyclic ring systems include benzofuran, benzimidazole, benzthiophene, benzthiazole, benzisothiazole, benzoxazole, benzisoxazole, 1,3-benzodioxole, indole, pyridoimidazole, pyrimidoimidazole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, cinnoline and naphthyridine. Particular examples of 5/6 and 6/6 bicyclic ring systems include benzofuran, benzimidazole, benzthiophene, benzthiazole, benzisothiazole, benzoxazole, benzisoxazole, indole, pyridoimidazole, pyrimidoimidazole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, cinnoline and naphthyridine.
The term "heterocyclyl" refers to a 5-10 membered saturated or partially saturated mono or bicyclic ring containing up to 5 heteroatoms selected from nitrogen, oxygen or sulphur linked via ring carbon atoms or ring nitrogen atoms. Examples of 'heterocyclyl' include tetrahydrofuranyl, 2,3-dihydro-4H-pyran, pyrrolinyl, pyrrolidinyl, 1,3-thiazolidine, morpholinyl, piperidinyl, piperazinyl, dihydropyridinyl, dihydropyrimidinyl and azepane. Particular examples of 'heterocyclyl' include pyrrolinyl, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, dihydropyridinyl and dihydropyrimidinyl. A "nitrogen linked heteroring" is a 5-10 membered saturated, partially saturated or totally saturated mono or bicyclic ring containing at least one nitrogen atom, the heteroring being linked through this nitrogen, and 0 to 4 further heteroatoms selected from nitrogen, oxygen or sulphur. Note "nitrogen linked heteroring" only includes such heterorings where a bond from a nitrogen is allowed, for example no bond is possible to the nitrogen of a pyridine ring, but a bond is possible through the 1-nitrogen of a pyrazole ring. Examples of "nitrogen linked heteroring" are piperidin-1 -yl, morpholino, piperazin-1-yl, pyrrolidin-1-yl, ρyrazolin-1-yl, thiomorpholino, benzimidazol-1-yl and isoindol-2-yl. Preferably "nitrogen linked heteroring" refers to piperidin-1 -yl, morpholino, piperazin-1-yl or pyrrolidin-1-yl.
The term "carbocyclyl" refers to a totally saturated or partially saturated mono, bi or tri cyclic 3-10 membered carbon ring. Particularly the term "carbocyclyl" refers to a totally saturated or partially saturated mono, bi or tri cyclic carbon ring. Examples of carbocyclic
rings are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo-octane, adamantyl or 2,3-dihydroindene. Particular examples of carbocyclic rings are cyclopentyl, cyclohexyl, bicyclo-octane or adamantyl.
The term "halo" refers to fluoro, chloro, bromo or iodo. Examples of C,.6alkyl include methyl, ethyl, propyl, isopropyl, sec-butyl and tert-butyl; examples of C,_4alkoxy include methoxy, ethoxy and propoxy; examples of Cl.4alkoxyC,.4alkyl include butyloxyethyl and methoxymethyl; examples of C,.4alkoxycarbonyl include methoxycarbonyl, tert-butoxycarbonyl, ethoxycarbonyl and propoxycarbonyl; examples of C,.4alkoxycarbonylamino include methoxycarbonylamino and tert-butoxycarbonylamino; an example of C2.6alkenyloxycarbonyl is
2-propenyloxycarbonyl; examples of C,.6alkanoyl include formyl, acetyl and propionyl; an example of C,.6alkanoyloxy is acetoxy; an example of C,.4alkanoylthio is acetylthio; examples of N-C,.4alkylamino include N-methylamino, N-ethylamino, N-propylamino, N-isopropylamino, N-sec-butylamino and N-tert-butylamino; examples of Λ^N-di-Cj^alkylamino include NN-dimethylamino, NN-diethylamino and N-ethyl-N-methylamino; examples of N-C].4alkylaminoC,.4alkyl include N-methyl aminomethyl and N-ethylaminoethyl; examples of /V,7V-di-C,.4alkyIaminoC1.4alkyl include NN-dimethylaminomethyl and N-methyl-N-ethylaminomethyl; an example of N-alkylaminocarbonyl is N-methylaminocarbonyl; an example of N,N-dialkylaminocarbonyl is NN-dimethylaminocarbonyl; an example of
N-alkylcarbamoyl is N-methylcarbamoyl; an example of N,N-dialkylcarbamoyl is NN-dimethylcarbamoyl; examples of C,.4alkylsulphonyl include mesyl and butylsulphonyl; examples of C,.4alkylsulphanyl include methylsulphanyl and propylsulphanyl; examples of C,.4alkylsulphinyl include methylsulphinyl and butylsulphinyl; an example of N-Cl.4alkylaminosulphonyl is N-methylaminosulphonyl; an example of
N,iV-C1.4alkylaminosulphonyl is NN-dimethylaminosulphonyl; examples of C Oalkylene include methylene and ethylene; examples of C2.10alkenylene include 2-propenylene, 2-butenylene,
?H3 CH2
— C-C=C-CH
H H H 2 „„, — CH2-C-CH2- and
examples of C2.l0alkynylene include:
examples of arylC^alkyl include benzyl and phenethyl; an example of aryloxy is phenoxy; an example of aryIC
Malkoxy is benzyloxy; an example of arylcarbonyl is benzoyl; an example of heteroarylalkanoylamino is 3-pyridin-4-yl-propanamido.
A suitable pharmaceutically-acceptable salt of a compound of formula (I) is, for example, an acid-addition salt of a carbazole derivative of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic, citric or maleic acid. In addition a suitable pharmaceutically-acceptable salt of a carbazole derivative of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a physiologically acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
The compounds of the formula (I) may be administered in the form of a prodrug which is broken down in the human or animal body to give a compound of the formula (I). Examples of prodrugs include in vivo hydrolysable esters of a compound of the formula (I).
Various forms of prodrugs are known in the art. For examples of such prodrug derivatives, see: a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Prodrugs", by H. Bundgaard p. 113-191 (1991); c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); d) H. Bundgaard, et al, Journal of Pharmaceutical Sciences, 77, 285 (1988); and e) N. Kakeya, et al, Chem Pharm Bull, 32, 692 (1984).
An in vivo hydrolysable ester of a compound of the formula (I) containing a carboxy
or a hydroxy group is, for example, a pharmaceutically-acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol. Suitable pharmaceutically-acceptable esters for carboxy include C,.6alkoxymethyl esters for example methoxymethyl, C,.6alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, C3.8cycloalkoxycarbonyloxyC,.6alkyl esters for example
1-cyclohexylcarbonyloxyethyl; l,3-dioxolen-2-onylmethyl esters, for example 5-methyl-l,3-dioxolen-2-onylmethyl; and C,.6alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethyl and may be formed at any carboxy group in the compounds of this invention. An in vivo hydrolysable ester of a compound of the formula (I) containing a hydroxy group includes inorganic esters such as phosphate esters (including phosphoramidic cyclic esters) and α-acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group/s. Examples of α-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxy-methoxy. A selection of in vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl. Examples of substituents on benzoyl include morpholino and piperazino linked from a ring nitrogen atom via a methylene group to the 3- or 4- position of the benzoyl ring.
It is to be understood that, insofar as certain of the compounds of formula (I) defined above may exist in optically active or racemic forms by virtue of one or more asymmetric carbon atoms, the invention includes in its definition any such optically active or racemic form which possesses the property of being an agonist or antagonist at the neuropeptide Y5 receptor. The synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form. Similarly, binding to the neuropeptide Y5 receptor may be evaluated using the standard laboratory techniques referred to hereinafter. The invention also relates to any and all tautomeric forms of the compounds of the formula (I) that possess neuropeptide Y5 receptor agonist or antagonist activity.
- li ¬
lt will also be understood that certain compounds of the present invention may exist in solvated, for example hydrated, as well as unsolvated forms. It is to be understood that the present invention encompasses all such solvated forms which possess the property of interacting with the neuropeptide Y5 receptor. According to another first feature of the invention there is provided the use of a compound of formula (I') in the manufacture of a medicament for the treatment, in a warm-blooded animal, of disorders mediated by the neuropeptide Y5 receptor:
(I') wherein:
R, is selected from hydrogen, C,.
6alkyl, C ,.
4alkoxyC alkyl, C,.
6alkanoyl, C
1.
4alkanoylC,
.4alkyl, aryl, arylC,.
4alkyl, arylC
MalkoxyC
|.
4alkyl, arylC
Malkanoyl, arylcarbonyl, heteroaryl, heteroarylC,.
4alkyl,
heteroarylC,_
4alkanoyl, heteroarylcarbonyl, heterocyclyl, heterocyclylC,.
4alkyl, heterocyclylC,.
4alkoxyC,.
4alkyl, heterocyclylC
Malkanoyl, heterocyclylcarbonyl, carbocyclyl, carbocyclylC,.
4alkyl, carbocyclylC,.
4alkoxyC,.
4alkyl, carbocyclylC,.
4alkanoyl, carbocyclylcarbonyl, cyanoC,.
4alkyl, aminoC
ι.
4alkyl, N-C,.
4alkylaminoCι_
4alkyl, or NN-di-C
1.
4alkylaminoC,.
4alkyl; wherein R, may be optionally substituted (on an available carbon atom) by up to three substituents independently selected from: C
Malkyl, C,.
4alkoxy, C
Malkanoyl, carboxy, hydroxy, halo, cyano, amino, N-C,.
4alkyl amino, NN-di-C alkylamino, C,.
4alkanoylamino, mercapto, C,.
4alkylsulphonyl, C,.
4alkylsulphinyl, C,.
4alkylsulphanyl, nitro, trifluoromethyl-C,.
4alkyl, heteroarylC,.
4alkanoylamino, or C alkoxycarbonyl;
R2 is selected from hydrogen, C,.4alkyl, C,.4alkoxy, cyano, nitro, halo, amino, N-C,.4alkylamino, or NN-di-C,.4alkylamino; A is selected from, -ΝH-, -CH2NH-, -NHC(O)-, -CH2NHC(O)-, -C(O)NH-,
-NHC(O)NH-, -NHC(O)O-, -NHS(O2)-, or a direct bond; wherein each nitrogen atom is optionally substituted with C,.4alkyl;
B is C,.6alkylene, C2.6alkenylene, C2.6alkynylene, or a direct bond; R3 is hydrogen, C,.6alkoxy, C,.6alkanoyl, C,.0alkoxycarbonyl, aryl, aryloxy, arylCMalkoxy, arylcarbonyl, aryl ^alkanoyl, aryloxycarbonyl, arylC,.4 alkoxycarbonyl, heteroaryl, heteroaryloxy, heteroarylC,.4alkoxy, heteroarylcarbonyl, heteroarylC,.4alkanoyl, heteroaryloxycarbonyl, heteroarylC,.4alkoxycarbonyl, heterocyclyl, heterocyclyloxy, heterocyclylC,.4alkoxy, heterocyclylcarbonyl, heterocycιylC alkanoyl, heterocyclyloxycarbonyl, heterocyclylC,.4alkoxycarbonyl, carbocyclyl, carbocyclyloxy, carbocyclylC, ^alkoxy, carbocyclylcarbonyl, carbocyclylC,.4alkanoyl, carbocyclyloxycarbonyl, carbocyclylCι_4alkoxycarbonyl, amino, N-C,.4alkylamino, NN-di-C,.4alkylamino, C,.4alkylthio wherein R3 may be optionally substituted (on an available carbon atom) by up to three substituents independently selected from C,.4alkyl, C alkoxy, C,.4alkanoyl, carboxy, hydroxy, halo, cyano, amino, N-C,.4alkylamino, NN-di-Cι.4alkylamino, CMalkanoylamino, mercapto, C alkylsulphonyl, C,.4alkylsulphinyl, C,.4alkylsulphanyl, nitro, trifluoromethylC,.4alkyl, phenyl, C,.4alkoxyphenyl, heteroaryl, heteroarylC,_4alkyl, aminosulphonylphenyl or CMalkoxycarbonyl; and R4 is hydrogen, C,.4alkyl, or nitro; or a pharmaceutically acceptable salt, prodrug or solvate thereof.
According to an alternative first feature of the invention there is provided the use of a compound of formula (T) (as depicted above) in the manufacture of a medicament for the treatment, in a warm-blooded animal, of disorders mediated by the neuropeptide Y5 receptor wherein:
R, is selected from hydrogen, C,
.6alkyl, C,
.4alkoxyC
Malkyl, C,
.6alkanoyl, C
1.
4alkanoylC,.
4alkyl, aryl, arylC,.
4alkyl, arylC,.
4alkoxyC
].
4alkyl, arylC,.
4 alkanoyl, arylcarbonyl, heteroaryl, heteroarylC,_
4alkyl, heteroarylC|_
4alkoxyC,.
4alkyl, heteroarylC,.
4alkanoyl, heteroarylcarbonyl, heterocyclyl, heterocyclyl C,.
4alkyl, heterocyclylC, ^alkoxy C,.
4alkyl, heterocyclylC,.
4alkanoyl, heterocyclylcarbonyl, carbocyclyl, carbocyclylC,.
4alkyl, carbocyclylC,.
4alkoxyC,.
4alkyl,
carbocyclylcarbonyl, cyanoC,.
4alkyl, aminoC,.
4alkyl, N-C
ι.
4alkylaminoC,
.4alkyl, or NN-di-C
].
4alkylaminoC,.
4alkyl; wherein R, may be optionally substituted (on an available carbon atom) by up to three substituents independently selected from: C alkyl, C,.
4alkoxy, C,.
4alkanoyl, carboxy, hydroxy, halo, cyano, amino, N-C,_
4alkylamino, Λ N-di-C alkylamino,
C,
.4alkanoylamino, mercapto, C
Malkylsulphonyl, C,
.4alkylsulphinyl, C,_
4alkylsulphanyl, nitro, trifluoromethyl-C
1.
4alkyl, heteroarylCι.
4alkanoylamino, or C,_
4alkoxycarbonyl;
R2 is selected from hydrogen, C,_4alkyl, C,.4alkoxy, cyano, nitro, halo, amino, N-C,.4alkylamino, or NN-di-C, .4alkylamino; A is selected from, -ΝH-, -CH2NH-, -NHC(O)-, -CH2NHC(O)-, -C(O)NH-,
-NHC(O)NH-, -NHC(O)O-, -NHS(O2)-, or a direct bond; wherein each nitrogen atom is optionally substituted with C1-4alkyl;
B is C,_6alkylene, C2.fialkenylene, C2.6alkynylene, or a direct bond;
R3 is hydrogen, C,.6alkoxy, C,_6alkanoyl, C,.6alkoxycarbonyl, aryl, aryloxy, arylCMalkoxy, arylcarbonyl, aryl alkanoyl, aryloxycarbonyl, arylCMalkoxycarbonyl, heteroaryl, heteroaryloxy, heteroarylC,.4alkoxy, heteroarylcarbonyl, heteroarylC,.4alkanoyl, heteroaryloxycarbonyl, heteroaryl-C,.4alkoxycarbonyl, heterocyclyl, heterocyclyloxy, heterocyclylC,_4alkoxy, heterocyclylcarbonyl, heterocyclylC,.4alkanoyl, heterocyclyloxycarbonyl, heterocyclylC,.4alkoxycarbonyl, carbocyclyl, carbocyclyloxy, carbocyclylC,.4alkoxy, carbocyclylcarbonyl, carbocyclylC alkanoyl, carbocyclyloxycarbonyl, carbocyclylC,.4alkoxycarbonyl, amino, N-C,.4alkylamino, NN-di-C,.4alkylamino, C,.4alkylthio or fluoro wherein R3 may be optionally substituted on an available carbon atom) by up to three substituents independently selected from C,.4alkyl, C,.4alkoxy, C,.4alkanoyl, carboxy, hydroxy, halo, cyano, amino, N-C,.4alkylamino, NN-di-C,.4alkylamino, C,.4alkanoylamino, mercapto, C,.4alkylsulphonyl, C,.4alkylsulphinyl, C,.4alkylsulphanyl, nitro, trifluoromethylC,_4alkyl, phenyl, C,.4alkoxyphenyl, heteroaryl, heteroarylC,.4alkyl, aminosulphonylphenyl or C,.4alkoxycarbonyl; and
R4 is hydrogen, C,.4alkyl, or nitro; or a pharmaceutically acceptable salt, prodrug or solvate thereof. According to a further alternative first feature of the invention there is provided the use of a compound of formula (I) as depicted above in the manufacture of a medicament for the treatment, in a warm-blooded animal, of disorders mediated by the neuropeptide Y5 receptor wherein:
R, is selected from hydrogen, C,.6alkyl, C,.4alkoxyC,.4alkyl, C,.6alkanoyl, C,.4alkanoylC,.4alkyl, aryl, arylC alkyl, arylC,.4alkoxyC,„4alkyl, arylC,.4alkanoyl, arylcarbonyl, heteroaryl, heteroarylC,_4alkyl, heteroarylC,.4alkoxyC,.4alkyl,
heteroarylC,.4alkanoyl, heteroarylcarbonyl, heterocyclyl, heterocyclylC,.4alkyl, heterocyclylC,.4alkoxyC,.4alkyl, heterocyclylC,.4alkanoyl, heterocyclylcarbonyl, carbocyclyl, carbocyclylC,.4alkyl, carbocyclylC,.4alkoxyC,.4alkyl, carbocyclylC,_4alkanoyl, carbocyclylcarbonyl, CMalkylsulphonyl, NN-di-C Malkylaminosulphonyl or N-C,.4alkylaminosulphonyl wherein R, may be optionally substituted (on an available carbon atom) by up to three substituents independently selected from C,.4alkyl optionally substituted by up to three fluoro substituents, C,.4alkoxy, C,.4alkanoyl, carboxy, hydroxy, halo, cyano, amino, N-C,.4alkylamino, NN-di-C, _4alkylamino, C,.4alkanoylamino, mercapto, CMalkylsulphonyl, C,.4alkylsulphinyl, C,.4alkylsulphanyl, nitro, heteroarylC,.4alkanoylamino, or C,.4alkoxycarbonyl;
A is selected from, -ΝH-, -CH2NH-, -NHC(O)-, -CH2NHC(O)-, -C(O)NH-, -NHC(O)NH-, -NHC(O)O-, -NHS(O2)-, or a direct bond; wherein each nitrogen atom is optionally substituted with C,.4alkyl or hydroxyC2.4alkyl;
B is C,.,0alkylene, C2.10alkenylene, C2.,0alkynylene, or a direct bond wherein the alkylene, alkenylene and alkynylene chains are optionally substituted by hydroxy, C,.4alkoxy or amino;
R3 is hydrogen, hydroxy, C,.6alkoxy, C,.6alkanoyl, C,.6alkanoyloxy, C,.6alkanoylamino, C,.6alkoxycarbonyl, C,.4alkoxycarbonylamino, aryl, aryloxy, arylcarbonyl, arylC,.4alkyl, arylC,.4alkoxy, arylC,.4alkanoyl, aryloxycarbonyl, arylC,„4alkoxycarbonyl, arylamino, heteroaryl, heteroaryloxy, heteroarylC,.4alkoxy, heteroarylcarbonyl, heteroarylC,.4alkanoyl, heteroaryloxycarbonyl, heteroarylC,.4alkoxycarbonyl, heterocyclyl, heterocyclyloxy, heterocyclylC,_4alkoxy, heterocyclylcarbonyl, heterocyclylC,.4alkanoyl, heterocyclyloxycarbonyl, heterocyclylCMalkoxycarbonyl, carbocyclyl, carbocyclyloxy, carbocyclylC,.4alkoxy, carbocyclylcarbonyl, carbocyclylC,.4alkanoyl, carbocyclyloxycarbonyl, carbocyclylC,.4alkoxycarbonyl, cyano, carbamoyl, ureido, amino, N-C,.4alkylamino, NN-di-C,.4alkylamino, C,_4alkoxycarbonylamino, aminocarbonyl, N-C,.4alkylaminocarbonyl, NN-di-C,.4alkylaminocarbonyl, C,.4alkylthio, trifluoromethyl or fluoro wherein R3 may be optionally substituted by up to three substituents independently selected from C,.4alkyl, hydroxy C,.4alkyl, C,.4alkoxy, C,_6alkoxycarbonyl, C,.6alkenyloxycarbonyl, C,.4alkanoyl, C,.4alkanoylamino, C,.4alkanoylthio, oxo, carboxy, hydroxy, halo, cyano, amino, N-C,.4alkylamino, NN-di-C,.4alkylamino,
N-C i _4alkylaminoC , ^alkyl, NN-di-C ,.4alkylaminoC , .4alkyl, aminocarbonyl, N-C,.4alkylaminocarbonyl, NN-di-C,.4alkylaminocarbonyl, mercapto, C,.4alkylsulphonyl, C,.4alkylsulphinyl, C,.4alkylsulphanyl, nitro, trifluoromethyl, trifluoromethylC,.4alkyl, aryl, arylC,.4alkyl, aryloxyC,.4alkyl, C,.4alkoxyphenyl, heteroaryl, heteroarylC,.4alkyl, heterocyclylcarbonyl, or aminosulphonylphenyl; and R4 is hydrogen, C,.4alkyl, halo or nitro; or a pharmaceutically acceptable salt, prodrug or solvate thereof.
Preferred values of R1, R2, R3, R4, A and B are as follows. Such values may be used where appropriate with any of the definitions, claims or embodiments defined hereinbefore or hereinafter.
Preferably R, is C,.6alkyl, C,.4alkylsulphonyl, C,.6alkanoyl, /V,N-di-C,.4alkylaminosulphonyl, N-CMalkylaminosulphonyl or arylcarbonyl.
Most preferably R, is C,.4alkyl, C,.4alkanoyl, C,.2alkylsulρhonyl or NN-di-C, _2alkylaminosulphonyl. In another aspect of the invention, preferably R, is hydrogen, C,.6alkyl, C,.6alkanoyl, aryl, arylC,.4alkyl, arylC,.4alkanoyl, arylcarbonyl, heteroaryl, heteroarylC alkyl, heteroarylC,.4alkanoyl, heteroarylcarbonyl, heterocyclyl, heterocyclylC,.4alkyl, heterocyclylC,.4alkanoyl, or heterocyclylcarbonyl.
In another aspect of the invention, most preferably R, is ethyl or 4-pyridinylpropanoyl. In a further aspect of the invention, preferably R, is selected from hydrogen, C,.6alkyl,
C,.6alkanoyl, aryl, arylcarbonyl, heterocyclylC,.4alkyl, C,.4alkylsulphonyl or NN-di-C, _4alkylaminosulphonyl wherein R, may be optionally substituted (on an available carbon atom) by up to three substituents independently selected from halo or heteroarylC,.4alkanoylamino. In a further aspect of the invention, more preferably R, is selected from hydrogen, methyl, ethyl, «-propyl, t-propyl, acetyl, mesyl, NN-dimethylaminosulphonyl, pyrrolidin-1 -ylmethyl, (2-piperidin-4-ylethylaminocarbonyl)phenyl, benzoyl or 2,2,2-trifluoroethyl.
In a further aspect of the invention, particularly R, is selected from ethyl, -propyl, acetyl, mesyl or 2,2,2-trifluoroethyl.
Preferably R2 is: hydrogen or C,.4alkyl.
Most preferably R2 is hydrogen.
In a further aspect of the invention, preferably R2 is selected from hydrogen, C,.4alkyl (optionally substituted by hydroxy), cyano or halo.
In a further aspect of the invention, more preferably R2 is selected from hydrogen, hydroxymethyl, cyano, fluoro, chloro or bromo.
In a further aspect of the invention, particularly R2 is selected from hydrogen, hydroxymethyl, fluoro, chloro or bromo.
In a further aspect of the invention, particularly R2 is selected from hydrogen, 6-hydroxymethyl, 6-fluoro, 6-chloro or 6-bromo. In a further aspect of the invention, particularly preferred R2 is selected from 6-fluoro.
Preferably A is -NHC(O)-, -NHC(O)NH-, -NHC(O)N(CMalkyl)-, -NHC(O)O-, -NHS(O)2-.
Most preferably A is: -NHC(O)O-, -NHC(O)N(C2H5)-, -NHC(O)N(CH3)-, or -NHC(O)-. In another aspect of the invention most preferably A is: -NHC(O)O-,
-NHC(O)N(C2H5)- or -NHC(O)-.
In another aspect of the invention preferably A is selected from -NH-, -CH2NH-, -CH2NMe-,-NHC(O)-, -NMeC(O)-,-CH2NHC(O)-, -C(O)NH-, -NHC(O)NH-, -NHC(O)NMe-, -NHC(O)O-, -NHS(O2)-, -NHC(=N-CN)-, or a direct bond; wherein each nitrogen atom is optionally substituted with C,.4alkyl or hydroxyC2.4alkyl.
In another aspect of the invention more preferably A is selected from -NH-, -NHC(O)-, -NHC(O)NH-, -NHC(O)NMe- or a direct bond.
Preferably A is linked on the 3-position of the carbazole ring.
It is to be understood that groups listed for A are orientated such that the left side is attached to the carbazole ring and the right side is linked to B. For example for the group of the formula -NHC(O)-, nitrogen is attached to the carbazole ring and the -C(O)-is linked to B.
Preferably B is: C2.10alkylene, C2.,0alkenylene, or a direct bond.
Most preferably B is methylene, ethylene, -CH(CH3)CH2- or a direct bond.
In another aspect of the invention, preferably B is: C,.6alkylene, C,.6alkenylene, or a bond.
In another aspect of the invention, most preferably B is methylene, ethylene, -CH(CH3)CH2-, -CH(CH3)CH2-, or -C(CH3)=CH-.
In another aspect of the invention, preferably B is selected from C,.,0alkylene, C2.,0alkenylene or a direct bond wherein the alkylene, alkenylene chains are optionally substituted by hydroxy, C,.4alkoxy or amino.
Preferably R3 is: hydrogen, C,.6alkyl, C,.6alkoxy, C,.6alkoxycarbonyl, aryl, aryloxy, aryloxycarbonyl, heteroaryl, heteroaryloxy, heteroaryloxycarbonyl, heterocyclyl, heterocyclyloxy, or heterocyclyloxycarbonyl, optionally substituted as above.
Most preferably R3 is: hydrogen, C,.4alkyl, morpholino, pyridin-4-yl, pyrrolidinon-1-yl, N-methylpiperidin-4-yl, triazol-1-yl or imidazol-1 -yl.
In another aspect of the invention, preferably R3 is: hydrogen, C,.6alkyl, C,.6alkoxy, C,.6alkoxy carbonyl, aryl, aryloxy, aryloxycarbonyl, heteroaryl, heteroaryloxy, heteroaryloxycarbonyl, heterocyclyl, heterocyclyloxy, heterocyclyloxycarbonyl.
In another aspect of the invention, most preferably R3 is: hydrogen, 4-pyridinyl or -[l,2,4]-oxadiazolyl 1 -substituted with 2-methoxyphenyl.
As stated above the R3 group may be optionally substituted examples include: C,.4alkyl, halo, pyridinyl, aminosulphonylphenyl, and 2-methoxyphenyl.
Preferably the group -A-B-R3 is selected from N'-propylureido, TV ',N'-diethylureido, N ', N '-dimethylureido, N '-pyrid-4-ylmethylureido, N '-pyrid-4-ylmethyl-N '-ethylureido, 4-methoxyanilinocarbonylamino, N'-benzylureido, N'-methyl-Λ^'-benzylureido, N'-ethylanilinocarbonylamino, N'-(3-hydroxypropyl)-N'-pyrid-4-ylmethylureido, N'-methyl-N'-phenethylureido, N'-methyl-N'-pyrid-4-ylethylureido, N '-(2-N ', N '-dimethylaminoethyl)-N '-methylureido,
N'-(3-N',N'-dimethylaminopropyl)-N'-methylureido, anilinocarbonylamino, 4-fluoroanilinocarbonylamino, N'-phenoxyethylureido, N'-methylanilinocarbonylamino, N '-methyl-N '-pyrid-2-ylethylureido, N '-moφholinoethylureido, N'-ethyl-N'-phenoxyethylureido, N'-methyl-N'-moφholinopropylureido, N '-methyl-N '-morpholinoethylureido, N'-acetamidoethylureido, N'-methylthioethylureido, N'-imidazol-l-ylpropylureido, N'-4-hydroxycyclohexylureido, N'-3,5,5-trimethylcyclohexylureido, N'-l -ethylpyrrolidin-2-ylmethylureido,
N'-fur-2-ylmethylureido, N'-tetrahydrofur-2-ylmethylureido, N '-morpholinopropylureido,
N'-pyrid-2-ylmethylureido, N'-pyrid-2-ylethylureido, N'-methyl-N'-pyrid-2-ylmethylureido, N'-l-benzylpiperidin-4-ylureido, /V'-l-phenyleth-l-ylureido, N'-2-propynylureido, N'-allylureido, 3-N',N'-diethylaminopropylureido, N'-(l,l-di- -butylmethyl)ureido, N '-methyl-N '-(2-N',N'-diethylaminoethyl)ureido, N '-(2-phenoxy- 1 -methylethylaminoindan-2-yl)ureido,
N '- [4-( 1 ,2,3 -thiaziazol-4-yl)benzyl]ureido, N '-methyl-N '-( 1 -methylpiperidin-4-yl)ureido, N '-(2-fluoro-4-trifluoromethylbenzyl)ureido, N '-( 1 -methylpyrrolidin-2-ylethyl)ureido, N'-(5-methylfur-2-ylmethyl)ureido, N'-(4-N',N'-dimethylaminophenethyl)-N'-methylureido, N'-methyl-N'-pyrid-4-ylethylureido, N'-(2-anilino- 1,1 -dimethyl ethyl) ureido, N'-(2-anilinoethyl)ureido, N'-benzthiazol-2-ylureido, N'-(2-oxohomopiperidin-3-yl)ureido, N'-(4-bromobenzoylmethyl)ureido, N'-(benzimidazol-2-ylmethyl)ureido, N'-oxazol-3-ylureido, N'-(2-fluoro-4-chlorobenzyl)ureido, N '-(3 -N'-methylaminopropyl)-N '-methyl ureido, N'-(9-ethylcarbazol-3-yl)ureido, piperidin- 1 -ylcarbonylamino, moφholinocarbonylamino, 4-methylpiperazin- 1 -ylcarbonylamino, 3-methyl-2-phenylmoφholinocarbonylamino,
4-benzylpiperazin- 1 -ylcarbonylamino, 2-pyrrolidin- 1 -ylmethylpyrrohdin- 1 -ylcarbonylamino, pyrrolidin- 1 -ylpiperidin- 1 -ylcarbonylamino, 4-ethoxycarbonylpiperidin- 1 -ylcarbonylamino, 4-hydroxymethylpiperidin- 1 -ylcarbonylamino, 4-carboxypiperidin- 1 -ylcarbonylamino, 4-mesy loxymethylpiperidin- 1 -ylcarbonylamino, 4-NN-dimethylaminomethylpiperidin- 1 -ylcarbonylamino, 4-phenoxymethylpiperidin- 1 -ylcarbonylamino, 4-N-methylcarbamoylpiperidin- 1 -ylcarbonylamino, 4-NN-dimethylcarbamoylpiperidin-l -ylcarbonylamino, 4-fl-butylcarbamoylpiperidin- 1 -ylcarbonylamino, 4-moφholinocarbonylpiperidin- 1 -ylcarbonylamino,
3 -phenoxyethylpyrrolidin- 1 -ylcarbonylamino, 3 -carbamoylpiperidin- 1 -ylcarbonylamino, 4-piperidin- 1 -ylpiperidin- 1 -ylcarbonylamino, 3-t-butoxycarbonyl(N-methyl)aminopyrrolidin-l -ylcarbonylamino, 3-N-methylaminopyrrolidin-l-ylcarbonylamino, 2,6-dimethylmoφholinocarbonylamino, amino, hydrogen, acetamido, benzimidazol-2-yl, 2-(trifluoroacetyl)ethenyl,
4-pyrid-4-ylmethylpthalazin- 1 -ylamino, succinimido, 4-pyrid-2-ylpiperazin- 1 -ylmethyl,
indol-3-ylethylaminomethyl, 3,4-dichlorobenzoylamino, l-methylpiperidin(N-methyl)aminomethyl, pyrid-4-ylethylcarbonyl(N-methyl)amino, pyrid-4-ylpropyl, z'-propylcarbonyl(N-methyl)amino, ethoxycarbonylamino, methoxycarbonylmesylamino, mesylamino, benzylsulphonylamino, 2-phenylethenylsulphonylamino, carbamoyl, t-butoxycarbonylamino, benzyloxycarbonylamino, phenoxycarbonylamino, aminomethyl, t-propylcarbonylaminomethyl, NN-dimethylaminosulphonylamino,
4-nitrophenoxycarbonylamino, pyrid-2-ylamino, Ν2-(cyano)methylthiocarboxamidine
N2-(cyano)moφholinocarboxamidine, 6-methylpyridazin-3-ylamino, NN-di-(6-methylpyridazin-3-yl)amino, 6-methylpyrid-3-ylamino, pyrid-3-ylamino,
6-carbamoylpyridazin-3-ylamino, 6-trifluoromethylpyridazin-3-ylamino,
6-(pyrid-4-yl)pyridazin-3-ylamino, 6-cyanopyridazin-3-ylamino,
6-chloropyridazin-3-ylamino, benzimidazol-2-ylamino, methylcarbonylamino, phenylcarbonylamino, ethoxycarbonylcarbonylamino, isopropylcarbonylamino, 4-methylphenoxymethylcarbonylamino, 2-pyrid-4-ylethylcarbonylamino,
2-pyrid-4-ylethenylcarbonylamino, 2-pyrid-4-yl- 1 -methylethenylcarbonylamino,
2-pyrid-4-yl- 1 -methylethylcarbonylamino,
2-[3-(2-methoxyphenyl)-l,2,4-oxadiazol-5-yl]ethylcarbonylamino, l-t-butoxycarbonylpiperid-4-ylcarbonylamino, t-butoxycarbonylaminomethylcarbonylamino, aminomethylcarbonylamino, 4-methoxyphenethylcarbonylamino,
2-(l,3-benzodioxol-5-yl)ethylcarbonylamino,
2-(3-phenyl-l,2,4-oxadiazol-5-yl)ethylcarbonylamino,
3-(2-phenyl-l,3,4-oxadiazol-5-yl)propylcarbonylamino,
2-(3-benzyl- 1 ,2,4-oxadiazol-5-yl)ethylcarbonylamino, 2-methoxyphenethylcarbonylamino, 3-phenylpropylcarbonylamino, 3-(3-pyrid-4-yl-l,2,4-oxadiazol-5-yl)propylcarbonylamino,
2-phenylcyclopropylcarbonylamino, 2 -phenyl- 1 -methylethylcarbonylamino,
3-methoxyphenethylcarbonylamino, 4-fluorophenethylcarbonylamino, phenethylcarbonylamino, 3 ,4-dimethoxyphenethylcarbonylamino,
3,4,5-trimethoxyphenethylcarbonylamino, 3-(3-pyrid-2-yl-l ,2,4-oxadiazol-5-yl)propylcarbonylamino, 4-mesylphenethylcarbonylamino,
3-trifluorophenethylcarbonylamino, piperid- 1 -ylcarbonylamino,
2-fur-2-ylethylcarbonylamino, methoxycarbonylmethylcarbonylamino, cyclohexylcarbonylamino, t-butylcarbonylamino, 1 -methylbutylcarbonylamino, cyanomethylcarbonylamino, t-butylcarbonylamino, 2-oxopyrrolidin-5-ylcarbonylamino, cyclobutylcarbonylamino, 2-carbamoylethylcarbonylamino, 1 -ethylpropylcarbonylammo, 2-oxotetrahydrofur-5-ylcarbonylamino, 2-oxotetrahydrothiazol-4-ylcarbonylamino, 1 -methyl- 1 -phenylmethylcarbonylamino, 2,2,2-trifluoroethylcarbonylamino, ureidomethylcarbonylamino, methoxycarbonylaminomethylcarbonylamino, triazol- 1 -ylmethylcarbonylamino, 1 -methylpyrrolidin-2-ylcarbonylamino, l-methylpiperid-4-ylcarbonylamino, 2-oxopyrrolidin-l -ylmethylcarbonylamino, 2-methoxycarbonylethylcarbonylamino, 2,3-dihydropyran-2-ylcarbonylamino, 1-acetamidoethylcarbonylamino, NN-dimethylaminomethylcarbonylamino, 2-prop-2-enylcarbonylamino, tetrahydropyran-2-ylcarbonylamino, 2-pyrid-3-ylethenylcarbonylamino, imidazol-4-ylcarbonylamino, methoxyethylcarbonylamino, NN-dimethylcarbamoylethylcarbonylamino, pyrazol-4-ylcarbonylamino, fur-2-ylmethylcarbonylamino,
5-methylisoxazol-3-ylcarbonylamino, imidazol-1-ylethylcarbonylamino,
4-cyanophenylcarbonylamino, NN-dimethylaminoethylcarbonylamino,
1 -hydroxy- 1 -methyl-2,2,2-trifluoroethylcarbonylamino,
1 -methyl- 1 -acetoxyethylcarbonylamino, 1 -methyl- 1 -hydroxy ethylcarbonylamino, 1 -moφholinoprop-2-ylcarbonylamino, thien-2-ylpropylcarbonylamino,
2-(3-bromoisoxazol-5-yl)ethylcarbonylamino, imidazol-4-ylethylcarbonylamino, 2-(pyrid-4-ylcarbonyl)ethylcarbonylamino, cyclopropylcarbonylamino, mesylmethylcarbonylamino, l-t-butoxycarbonylamino-2-methoxyethylcarbonylamino, 1 -methyl-2-(t-butoxycarbonylamino)ethylcarbonylamino, tetrazol- 1 -ylmethylcarbonylamino, 1 ,2,5-thiadiazol-3-ylcarbonylamino, thiazol-4-ylcarbonylamino,
1,2,4-triazol-l-ylethylcarbonylamino, l,2,4-triazol-3-ylcarbonylamino, fur-2-ylcarbonylamino, thien-2-ylmethylcarbonylamino,
4-methy lphenylsulphonylmethylcarbonylamino, 2-methoxy- 1 -aminoethylcarbonylamino, 1 -amino- 1 -methylethylcarbonylamino, 2-chloro-3-methoxy-thien-4-ylcarbonylamino, 3,5-dimethylisoxazol-4-ylcarbonylamino, 1 ,2,3-thiadiazol-4-ylcarbonylamino,
2-methylfur-4-ylcarbonylamino, l,l-dioxotetrahydrothien-3 -ylmethylcarbonylamino, 3-amino-l ,2,4-tetrazol-5-ylcarbonylamino or isothiazol-5-ylcarbonylamino.
More preferably the group -A-B-R3 is selected from N'-(2-N',N'-dimethylaminoethyl)-N'-methylureido, N '-(3-N',N'-dimethylaminopropyl)-N'-methylureido, N '-methyl- '-pyrid-2-ylethylureido, N '-acetamidoethylureido, N '- 1 -phenyleth- 1 -ylureido,
N'-(l-methylpyrrolidin-2-ylethyl)ureido, N '-methyl-N '-pyrid-4-ylethylureido, moφholinocarbonylamino, 4-NN-dimethylaminomethylpiperidin- 1 -ylcarbonylamino, 4-moφholinocarbonylpiperidin-l -ylcarbonylamino, amino, 6-carbamoylpyridazin-3-ylamino, 6-(pyrid-4-yl)pyridazin-3-ylamino, isopropylcarbonylamino,
2-pyrid-4-ylethenylcarbonylamino, 2-oxotetrahydrothiazol-4-ylcarbonylamino, 1,2,4-triazol-l -ylmethylcarbonylamino, 2-oxopyrrolidin-l -ylmethylcarbonylamino, imidazol- 1 -ylethylcarbonylamino, 2-(3-bromoisoxazol-5-yl)ethylcarbonylamino or isothiazol-5-ylcarbonylamino. Preferably R4 is hydrogen or nitro.
Most preferably R4 is hydrogen.
In another aspect of the invention, preferably R4 is selected from hydrogen, C,.4alkyl, or nitro.
In another aspect of the invention, more preferably R4 is selected from hydrogen, methyl, or nitro.
In another aspect of the invention, particularly R4 is selected from hydrogen or methyl.
In another aspect of the invention, preferred compounds of the invention are any one of the Examples or a pharmaceutically acceptable salt, prodrug or solvate thereof.
In a further aspect of the invention, preferred compounds of the invention are: 9-isopropyl-3-(6-carbamoylpyridazin-3-ylamino)carbazole; 9-ethyl-3-(6-carbamoylpyridazin-3-ylamino)carbazole; 9-isopropyl-3-(moφholinocarbonylamino)carbazole; 9-ethyl-3-(moφholinocarbonylamino)carbazole; 9-ethyl-3-(l,2,4-triazil-l-ylmethylcarbonylamino)carbazole; or a pharmaceutically acceptable salt, prodrug or solvate thereof.
According to a second feature of the invention there is provided a compound of the formula (II):
R, is selected from hydrogen, C,.6alkyl, C,.4alkoxyC,.4alkyl, C,.ύalkanoyl, C,.4alkanoylC,.4alkyl, aryl, arylC,.4alkyl, arylCMalkoxyC,.4alkyl, arylC,.4alkanoyl, arylcarbonyl, heteroaryl, heteroarylC,.4alkyl, heteroarylC,.4alkoxyC,.4alkyl, heteroarylC,.4alkanoyl, heteroarylcarbonyl, heterocyclyl, heterocyclylC,.4alkyl, heterocyclylC,.4alkoxyCMalkyl, heterocyclylC,.4alkanoyl, heterocyclylcarbonyl, carbocyclyl, carbocyclylC,.4alkyl, carbocyclylC,.4alkoxyC,.4alkyl, carbocyclylC,.4alkanoyl, carbocyclylcarbonyl, C,.4alkylsulphonyl, NN-di-C, _4alkylaminosulρhonyl or N-C,.4alkylaminosulphonyl wherein R, may be optionally substituted (on an available carbon atom) by up to three substituents independently selected from: C,.4alkyl optionally substituted by up to three fluoro substituents, C,.4alkoxy, C,.4alkanoyl, carboxy, hydroxy, halo, cyano, amino, N-C,.4alkylamino, NN-di-C, .4alkylamino, C,.4alkanoylamino, mercapto, C alkylsulphonyl, C,.4alkylsulphinyl, C,.4alkylsulphanyl, nitro, heteroaryl C,.4alkanoylamino, or C,.4alkoxycarbonyl;
R2 is selected from hydrogen, C,.4alkyl (optionally substituted by hydroxy), C,_4alkoxy, cyano, nitro, halo, amino, N-C,.4alkylamino, or N/V-di-C,_4alkylamino; L, is selected from hydrogen or C,.4alkyl;
B is selected from C,.,0alkylene, C2.,()alkenylene, C2.,0alkynylene, or a direct bond wherein the alkylene, alkenylene and alkynylene chains are optionally substituted by hydroxy, C,.4alkoxy or amino; R3 is selected from hydrogen, hydroxy, C,.6alkoxy, C,.6alkanoyl, C,.6alkanoyloxy,
C,_6alkanoylamino, C,.6alkoxycarbonyl, aryl, aryloxy, arylcarbonyl, arylC,_4alkyl, arylC,.4alkoxy, arylC,.4alkanoyl, aryloxycarbonyl, arylC,.4alkoxycarbonyl, arylamino, diarylamino, arylsulphonyl, heteroaryl, heteroaryloxy, heteroarylC,_4 alkoxy,
heteroarylcarbonyl, heteroarylC,.4alkanoyl, heteroaryloxycarbonyl, heteroarylC,.4alkoxycarbonyl, heteroarylC,.4alkyl, heteroarylamino, heteroarylsulphonyl, diheteroarylamino, heterocyclyl, heterocyclyloxy, heterocyclylC,.4alkoxy, heterocyclylcarbonyl, heterocyclylC,.4alkanoyl, heterocyclyloxycarbonyl, heterocyclylC,.4alkoxycarbonyl, heterocyclylC,.4 alkyl, heterocyclylamino, diheterocyclylamino, heterocyclylsulphonyl, carbocyclyl, carbocyclyloxy, carbocyclylC,.4alkoxy, carbocyclylcarbonyl, carbocyclylC,.4alkanoyl, carbocyclyloxycarbonyl, carbocyclylC,.4alkoxycarbonyl, carbocyclylC,.4alkyl, carbocyclylamino, carbocyclylsulphonyl, dicarbocyclylamino, cyano, carbamoyl, ureido, amino, N-C,.4alkylamino, NN-di-C,.4alkylamino, C,.4alkoxycarbonylamino, carbamoyl, N-C,.4alkylcarbamoyl, NN-di-C, .4alkylcarbamoyl, C,.4alkylsulphanyl, C,.4alkylsulphinyl, C,.4alkyl sulphonyl, trifluoromethyl or fluoro wherein R3 may be optionally substituted by up to three substituents independently selected from CMalkyl, hydroxy C,.4alkyl, C,.4alkoxy, C,.6alkoxycarbonyl, C2.6alkenyloxycarbonyl, C,.4alkanoyl, C,.4alkanoylamino, C,.4alkanoylthio, oxo, carboxy, hydroxy, halo, cyano, amino, N-C,_4aikylamino,
NN-di-C, _4alkylamino, N-C,.4alkylaminoC,.4alkyl, Λ Λ^-di-C,.4alkylaminoC,.4alkyl, carbamoyl, N-C,.4alkylcarbamoyl, NN-di-C, .4alkylcarbamoyl, mercapto, C,.4alkylsulphonyl, C,.4alkylsulphinyl, C,.4alkylsulphanyl, C,.4alkylsulphonyloxyC,.4alkyl, nitro, trifluoromethyl, trifluoromethylC,.4alkyl, C,.6alkoxycarbonyl amino, C,.6alkoxycarbonyl(Ν-C alkyl)amino, aryl (optionally substituted by one C,.4alkoxy or sulphamoyl), arylC,.4alkyl, aryloxy C,.4alkyl, arylcarbonyl, heteroaryl, heteroarylC,.4alkyl, heteroaryloxyC,.4alkyl, heteroarylcarbonyl, heterocyclyl, heterocyclylC,.4alkyl, heterocyclyloxyC,.4alkyl, heterocyclylcarbonyl, carbocyclyl, carbocyclylC,.4alkyl, carbocyclyloxyC,.4alkyl or carbocyclylcarbonyl; and R4 is selected from hydrogen, C,.4alkyl, halo or nitro; or a pharmaceutically acceptable salt, prodrug or solvate thereof; with the proviso that when R, is hydrogen, methyl, ethyl or acetyl, R2 is hydrogen, B is a direct bond or -CH2-, R4 is hydrogen then R3 cannot be phenyl; when -N(L,)C(O)O- is linked on the 3 position of the carbazole ring, R, is methyl or ethyl, R2 is hydrogen, B is -C2H4- and R4 is hydrogen then R3 cannot be hydrogen; and when R, is benzyl or 2-methoxy-4-carboxy-benzyl, R2 is hydrogen, B is a direct bond, R4 is hydrogen then R3 cannot be ethyl or cyclopentyl.
According to an alternative second feature of the invention there is provided a compound of the formula (II) (as depicted above) wherein:
R, is selected from hydrogen, C,.6alkyl, C,.4alkoxyC,.4alkyl, C,.6alkanoyl, C,.4alkanoylC,.4alkyl, aryl, arylC,.4alkyl, arylC,.4alkoxyC,.4alkyl, arylC,.4alkanoyl, arylcarbonyl, heteroaryl, heteroarylC,.4alkyl, heteroarylCl.4alkoxyC,_4alkyl, heteroarylC,.4alkanoyl, heteroarylcarbonyl, heterocyclyl, heterocyclylC,.4alkyl, heterocyclylC|.4alkoxyC,.4alkyl, heterocyclylC,.4alkanoyl, heterocyclylcarbonyl, carbocyclyl, carbocyclylC,.4alkyl, carbocyclylC,.4alkoxyC,.4alkyl, carbocyclylC,_4 alkanoyl, carbocyclylcarbonyl, C,.4alkylsulphonyl, NN-di-C, _4alkylaminosulphonyl or N-C,.4alkylaminosulphonyl wherein R, may be optionally substituted (on an available carbon atom) by up to three substituents independently selected from: C,.4alkyl optionally substituted by upto three fluoro substituents, C,.4alkoxy, C,.4alkanoyl, carboxy, hydroxy, halo, cyano, amino, N-C,.4alkylamino, NN-di-C, _4alkylamino, C,.4alkanoylamino, mercapto, C,.4alkylsulphonyl, C,.4alkylsulphinyl, C,.4alkylsulphanyl, nitro, heteroarylC,.4alkanoylamino, or C,.4alkoxycarbonyl;
L, is hydrogen or CMalkyl;
B is C,.,0alkylene, C2.10alkenylene, C2.,0alkynylene, or a direct bond wherein the alkylene, alkenylene and alkynylene chains are optionally substituted by hydroxy, C,.4alkoxy or amino; R3 is hydrogen, hydroxy, C,.6alkoxy, C,.6alkanoyl, C,.6alkanoyloxy,
C,.6alkanoylamino, C,.6alkoxycarbonyl, C,.4alkoxycarbonylamino, aryl, aryloxy, arylcarbonyl, arylC,.4alkyl, arylCMalkoxy, arylC,.4alkanoyl, aryloxycarbonyl, arylC alkoxycarbonyl, arylamino, heteroaryl, heteroaryloxy, heteroarylC,.4alkoxy, heteroarylcarbonyl, heteroarylC,.4alkanoyl, heteroaryloxycarbonyl, heteroarylC,.4alkoxycarbonyl, heterocyclyl, heterocyclyloxy, heterocyclylC,.4alkoxy, heterocyclylcarbonyl, heterocyclylC,.4alkanoyl, heterocyclyloxycarbonyl, heterocyclylC,.4alkoxycarbonyl, carbocyclyl, carbocyclyloxy, carbocyclylC,_4alkoxy, carbocyclylcarbonyl, carbocyclylC,.4alkanoyl, carbocyclyloxycarbonyl, carbocyclylC,.4alkoxycarbonyl, cyano, carbamoyl, ureido, amino, N-C,.4alkylamino, NN-di-C, .4alkylamino, C,.4alkoxycarbonylamino, aminocarbonyl, N-C,.4alkylaminocarbonyl, NN-di-C, .4alkylaminocarbonyl, C,.4alkylthio, trifluoromethyl or fluoro wherein R3 may be optionally substituted by up to three substituents independently
selected from C alkyl, hydroxyC,.4alkyl, C,.4alkoxy, C,.6alkoxycarbonyl, C,.6alkenyloxycarbonyl, CMalkanoyl, C,.4alkanoylamino, C,.4alkanoylthio, oxo, carboxy, hydroxy, halo, cyano, amino, N-C,.4alkylamino, /V,N-di-C,.4alkylamino, N-C,.4alkylaminoC,.4alkyl, NN-di-C,.4alkylaminoC,.4alkyl, aminocarbonyl, N-C!.4alkylaminocarbonyl, NN-di-C,.4alkylaminocarbonyl, mercapto, C,.4alkylsulphonyl, C,.4alkylsulphinyl, C,.4alkylsulphanyl, nitro, trifluoromethyl, trifluoromethylC,.4alkyl, aryl, arylC alkyl, aryloxy C,.4alkyl, C,.4alkoxyphenyl, heteroaryl, heteroarylC,.4alkyl, heterocyclylcarbonyl, or aminosulphonylphenyl; and R4 is hydrogen, C,.4alkyl, halo or nitro; or a pharmaceutically acceptable salt, prodrug or solvate thereof. with the proviso that when R, is hydrogen, methyl, ethyl or acetyl, R2 is hydrogen, B is a direct bond or -CH2-, R4 is hydrogen then R3 cannot be phenyl; when -Ν(L,)C(O)O- is linked on the 3 position of the carbazole ring, R, is methyl or ethyl, R2 is hydrogen, B is -C2H4- and R4 is hydrogen then R3 cannot be hydrogen; and when R, is benzyl or 2-methoxy-4-carboxy-benzyl, R2 is hydrogen, B is a direct bond, R4 is hydrogen then R3 cannot be ethyl or cyclopentyl.
According to a further second feature of the invention there is provided a compound of the formula (II'):
R, is selected from hydrogen, C,.6alkyl, C,.4alkoxyC,.4alkyl, C,.0alkanoyl, C,.4alkanoylC,.4alkyl, aryl, arylC,.4alkyl, arylC,.4alkoxyC,.4alkyl, arylC,.4alkanoyl, arylcarbonyl, heteroaryl, heteroarylC,.4alkyl, heteroarylC,.4alkoxyC,.4alkyl, heteroarylC,_4alkanoyl, heteroarylcarbonyl, heterocyclyl, heterocyclylC,.4alkyl, heterocyclylC,.4alkoxyC,.4alkyl, heterocyclylC alkanoyl, heterocyclylcarbonyl, carbocyclyl, carbocyclylC,.4alkyl, carbocyclylC,.4alkoxyC,.4alkyl, carbocyclylC,.4alkanoyl, carbocyclylcarbonyl, cyanoC,.4alkyl, aminoC,_4alkyl, N-C,.4alkylaminoC,.4alkyl, or
N,N-di-C,.4alkylaminoC,.4alkyl; wherein R, may be optionally substituted (on an available carbon atom) by up to three substituents independently selected from: CMalkyl, C alkoxy, C,.4alkanoyl, carboxy, hydroxy, halo, cyano, amino, N-C,.4alkylamino, /V,N-di-C,.4alkylamino, C,.4alkanoylamino, mercapto, C,.4alkylsulphonyl, C,.4alkylsulphinyl, C,.4alkylsulphanyl, nitro, trifluoromethyl-CMalkyl, heteroarylC,.4alkanoyl amino, or C,.4 alkoxycarbonyl;
R2 is selected from hydrogen, C,.4alkyl, C,.4alkoxy, cyano, nitro, halo, amino, N-C,.4alkylamino, or NN-di-C, .4alkylamino;
B is C,.5alkylene, C2.6alkenylene, C2.6alkynylene, or a direct bond;
R3 is hydrogen, C,.6alkoxy, C,.6alkanoyl, C,.6 alkoxycarbonyl, aryl, aryloxy, aryl-C,.4alkoxy, arylcarbonyl, aryl,.4alkanoyl, aryloxycarbonyl, arylC,.4alkoxycarbonyl, heteroaryl, heteroaryloxy, heteroarylCι.4alkoxy, heteroarylcarbonyl, heteroaryl-C,_4alkanoyl, heteroaryloxycarbonyl, heteroarylC,.4alkoxycarbonyl, heterocyclyl, heterocyclyloxy, heterocyclylC,.4alkoxy, heterocyclylcarbonyl, heterocyclylC,_4alkanoyl, heterocyclyloxycarbonyl, heterocyclylC,.4alkoxycarbonyl, carbocyclyl, carbocyclyloxy, carbocyclylC,.4alkoxy, carbocyclylcarbonyl, carbocyclylC,.4alkanoyl, carbocyclyloxycarbonyl, carbocyclylC,.4alkoxycarbonyl, amino, N-C,.4alkylamino, NΛ^-di-Cj^alkylamino, C,.4alkylthio wherein R3 may be optionally substituted (on an available carbon atom) by up to three substituents independently selected from C,.4alkyl, C,.4alkoxy, C,.4alkanoyl, carboxy, hydroxy, halo, cyano, amino, N-CMalkylamino, NN-di-C,.4alkylamino, C,_4alkanoyl amino, mercapto, C,.4alkylsulphonyl, C,.4alkylsulphinyl, C,.4alkylsulphanyl, nitro, trifluoromethylCMalkyl, phenyl, C,.4alkoxyphenyl, heteroaryl, heteroarylC,.4alkyl, aminosulphonylphenyl or C,.4alkoxycarbonyl; and
R4 is hydrogen, C,.4alkyl, or nitro; or a pharmaceutically acceptable salt, prodrug or solvate thereof; with the proviso that compound of formula (I) is not selected from: Carbamic acid, (9-ethyl-9H-carbazol-3-yl)-, phenylmethyl ester; Carbamic acid, 9H-carbazol-3-yl-, phenylmethyl ester; Carbamic acid, (9-acetyl-9H-carbazol-3-yl)-, phenylmethyl ester; Carbamic acid, (9-methyl-9H-carbazol-3-yl)-, ethyl ester; Carbamic acid, (9-methyl-9H-carbazol-2-yl)-, phenylmethyl ester; Carbamic acid, (9-ethyl-9H-carbazol-3-yl)-, phenyl ester;
Benzoic acid, 4-[[2-[[(cyclopentyloxy)carbonyl]amino]-9H-carbazol-9-yl]methyl] -3 -methoxy-;
Carbamic acid, [9-(phenylmethyl)-9H-carbazol-3-yl]-, ethyl ester, or Carbamic acid, (9-ethyl-9H-carbazol-3-yl)-, ethyl ester. According to an alternative further second feature of the invention there is provided a compound of the formula (II') (as depicted above) wherein:
R, is selected from hydrogen, C,.6alkyl, C,.4alkoxyC,.4alkyl, C,.6alkanoyl, C,.4alkanoylC1.4alkyl, aryl, arylC,.4alkyl, arylC,.4alkoxyC,.4alkyl, arylC,.4alkanoyl, arylcarbonyl, heteroaryl, heteroarylC,.4alkyl, heteroarylC,.4alkoxyC,.4alkyl, heteroarylC,.4alkanoyl, heteroarylcarbonyl, heterocyclyl, heterocyclylC,.4alkyl, heterocyclylC, _4alkoxyC,.4alkyl, heterocyclylC,_4alkanoyl, heterocyclylcarbonyl, carbocyclyl, carbocyclylC , .4alkyl, carbocyclylC ,.4alkoxyC , .4alkyl , carbocycly IC , _4alkanoyl, carbocyclylcarbonyl, cyanoC,.4alkyl, aminoC,.4alkyl, N-C,.4alkylaminoC,.4alkyl, or NN-di-C, .4alkylaminoC,.4alkyl; wherein R, may be optionally substituted (on an available carbon atom) by up to three substituents independently selected from: C,.4alkyl, C,.4alkoxy, C,.4alkanoyl, carboxy, hydroxy, halo, cyano, amino, N-C,.4alkylamino, NN-di-C, .4alkylamino, C,.4alkanoylamino, mercapto, C,.4alkylsulphonyl, C,.4alkylsulphinyl, C,_4alkylsulphanyl, nitro, trifluoromethyl-C,.4alkyl, heteroarylC,.4alkanoylamino, or C,.4alkoxycarbonyl;
R2 is selected from hydrogen, C,.4alkyl, C,.4alkoxy, cyano, nitro, halo, amino, N-C,.4alkylamino, or NN-di-C, .4alkylamino; L, is hydrogen or C,.4alkyl;
B is C,.6alkylene, C2_6alkenylene, C2.6alkynylene, or a direct bond; R3 is hydrogen, C,.6alkoxy, C,.6alkanoyl, C,.6alkoxycarbonyl, aryl, aryloxy, aryl-C,.4alkoxy, arylcarbonyl, aryl,_4alkanoyl, aryloxycarbonyl, arylC, ^alkoxycarbonyl, heteroaryl, heteroaryloxy, heteroarylC,.4alkoxy, heteroarylcarbonyl, heteroaryl-C,.4alkanoyl, heteroaryloxycarbonyl, heteroarylC,.4alkoxycarbonyl, heterocyclyl, heterocyclyloxy, heterocyclylC , _4 alkoxy, heterocyclylcarbonyl, heterocyclylC , .4alkanoyl , heterocyclyloxycarbonyl, heterocyclylC ,.4alkoxycarbonyl, carbocyclyl, carbocyclyloxy, carbocyclylC,.4alkoxy, carbocyclylcarbonyl, carbocyclylC,.4alkanoyl, carbocyclyloxycarbonyl, carbocyclylC,.4alkoxycarbonyl, amino, N-(C,.4alkyl)amino,
NN-di-(C,.4alkyl)amino, C,.4alkylthio or fluoro wherein R3 may be optionally substituted (on
an available carbon atom) by up to three substituents independently selected from C,.4alkyl, C,.4alkoxy, C, ^alkanoyl, carboxy, hydroxy, halo, cyano, amino, N-C,.4alkylamino, NN-di-C, .4alkylamino, C,.4alkanoylamino, mercapto, C,.4alkylsulphonyl, C,.4alkylsulphinyl, C,.4alkylsulphanyl, nitro, trifluoromethylC,.4alkyl, phenyl, C,.4alkoxyphenyl, heteroaryl, heteroarylC,.4alkyl, aminosulphonylphenyl or C,_4alkoxycarbonyl; and R4 is hydrogen, C,.4alkyl, or nitro; or a pharmaceutically acceptable salt, prodrug or solvate thereof; with the proviso that when R, is hydrogen, methyl, ethyl or acetyl, R2 is hydrogen, B is a direct bond or -CH2-, R4 is hydrogen then R3 cannot be phenyl; when -Ν(L,)C(O)O- is linked on the 3 position of the carbazole ring, R, is methyl or ethyl, R2 is hydrogen, B is -C2H4- and R4 is hydrogen then R3 cannot be hydrogen; and when R, is benzyl or 2-methoxy-4-carboxy-benzyl, R2 is hydrogen, B is a direct bond, R4 is hydrogen then R3 cannot be ethyl or cyclopentyl.
According to a third feature of the invention there is provided a compound of the formula (III):
R, is selected from hydrogen, C,.6alkyl, C,.4alkoxyC,.4alkyl, C,.6alkanoyl, C,.4alkanoylC,.4alkyl, aryl, arylC,.4alkyl, arylC,.4alkoxyC,.4alkyl, arylC,.4alkanoyl, arylcarbonyl, heteroaryl, heteroarylC,.4alkyl, heteroarylC,.4alkoxyC,.4alkyl, heteroarylC,.4alkanoyl, heteroarylcarbonyl, heterocyclyl, heterocyclylC,.4alkyl, heterocyclylC,.4alkoxyCMalkyl, heterocyclylC,.4alkanoyl, heterocyclylcarbonyl, carbocyclyl, carbocyclylC,.4alkyl, carbocyclylC, ^alkoxyCMalkyl, carbocyclylC, .4alkanoyl, carbocyclylcarbonyl, C,.4alkylsulphonyl, NN-di-C,.4alkylaminosulphonyl or
N-C,.4alkylaminosulphonyl wherein R, may be optionally substituted (on an available carbon atom) by up to three substituents independently selected from: C,.4alkyl optionally substituted
by up to three fluoro substituents, C,.4alkoxy, C,.4alkanoyl, carboxy, hydroxy, halo, cyano, amino, N-C,.4alkylamino, NN-di-C, ,4alkylamino, C,_4alkanoylamino, mercapto, C,.4alkylsulphonyl, C,.4alkylsulphinyl, C,.4alkylsulphanyl, nitro, heteroarylC,.4alkanoylamino, or C,_4 alkoxycarbonyl; R2 is selected from hydrogen, C,.4alkyl (optionally substituted by hydroxy),
C,.4alkoxy, cyano, nitro, halo, amino, N-C,.4alkylamino, or NN-di-C, .4alkylamino; L, is selected from hydrogen or C,.4alkyl; L2 is selected from hydrogen or C,.4alkyl; B is selected from C,.,0alkylene, C2.,0alkenylene, C2.,0alkynylene, or a direct bond wherein the alkylene, alkenylene and alkynylene chains are optionally substituted by hydroxy, C,_4alkoxy or amino;
R3 is selected from hydrogen, hydroxy, C,.6alkoxy, C,.6alkanoyl, C,.6alkanoyloxy, C,.6alkanoylamino, C,_6alkoxycarbonyl, aryl, aryloxy, arylcarbonyl, arylC,_4alkyl, arylC,_4alkoxy, arylC,.4alkanoyl, aryloxycarbonyl, arylC,.4alkoxycarbonyl, arylamino, diarylamino, arylsulphonyl, heteroaryl, heteroaryloxy, heteroarylC,_4 alkoxy, heteroarylcarbonyl, heteroarylC,.4alkanoyl, heteroaryloxycarbonyl, heteroarylC,.4alkoxycarbonyl, heteroarylC,.4alkyl, heteroarylamino, heteroarylsulphonyl, diheteroarylamino, heterocyclyl, heterocyclyloxy, heterocyclylC, .4alkoxy, heterocyclylcarbonyl, heterocyclylC,.4alkanoyl, heterocyclyloxycarbonyl, heterocyclylC, .4alkoxycarbonyl, heterocyclylC ,.4alkyl, heterocyclylamino, diheterocyclylamino, heterocyclylsulphonyl, carbocyclyl, carbocyclyloxy, carbocyclylC,.4alkoxy, carbocyclylcarbonyl, carbocyclylC,.4 alkanoyl, carbocyclyloxycarbonyl, carbocyclylC, .4alkoxycarbonyl, carbocyclylC M alkyl, carbocyclylamino, carbocyclylsulphonyl, dicarbocyclylamino, cyano, carbamoyl, ureido, amino, N-C,_4alkylamino, NN-di-C, .4alkylamino, C,_4alkoxycarbonylamino, carbamoyl, N-C,.4alkylcarbamoyl, NN-di-C Malkylcarbamoyl, C,.4alkylsulphanyl, C,.4alkylsulphinyl, C,.4alkylsulphonyl, trifluoromethyl or fluoro wherein R3 may be optionally substituted by up to three substituents independently selected from C,.4alkyl, hydroxyC,.4alkyl, C,.4alkoxy, C,.6alkoxycarbonyl, C2.6alkenyloxycarbonyl, C,.4alkanoyl, C,.4alkanoylamino, C,.4alkanoylthio, oxo, carboxy, hydroxy, halo, cyano, amino, /V-C,.4alkylamino,
NN-di-C, .4alkylamino, N-C,.4alkylaminoC,.4alkyl, NN-di-C, .4alkylaminoC,.4alkyl, carbamoyl,
N-C,.4alkylcarbamoyl, N/V-di-C,_4alkylcarbamoyl, mercapto, C,.4alkylsulphonyl, C,.4alkylsulphinyl, CMalkylsulphanyl, C,.4alkylsulphonyloxyC,.4 alkyl, nitro, trifluoromethyl, trifluoromethylC , .4alkyl, C , .6alkoxycarbonylamino, C , .6alkoxycarbonyl(Ν-C , .4alkyl)amino, aryl (optionally substituted by one C,.4alkoxy or sulphamoyl), arylC,.4alkyl, aryloxyC,.4alkyl, arylcarbonyl, heteroaryl, heteroarylCMalkyl, heteroaryl oxyC,.4alkyl, heteroarylcarbonyl, heterocyclyl, heterocyclylC, .4alkyl, heterocyclyloxyC,.4alkyl, heterocyclylcarbonyl, carbocyclyl, carbocyclylC ,.4alkyl, carbocyclyloxyC,.4alkyl or carbocyclylcarbonyl; and
R4 is selected from hydrogen, C,.4alkyl, halo or nitro; or a pharmaceutically acceptable salt, prodrug or solvate thereof; with the proviso that when -N(L,)- is linked on the 2-position of the carbazole ring, R, is hydrogen, R2 is hydrogen, B is a direct bond, L, is hydrogen, L2 is hydrogen and R4 is hydrogen then R3 cannot be hydrogen; and when -N(L,)- is linked on the 3-position of the carbazole ring, R, is ethyl, R2 is hydrogen, B is a direct bond or -(CH2)3-, L, is hydrogen, L2 is hydrogen and R4 is hydrogen then R3 cannot be hydrogen, amino, NN-diethylamino or naphth-1-yl.
According to an alternative third feature of the invention there is provided a compound of the formula (III) (as depicted above) wherein:
R, is selected from hydrogen, C,.6alkyl, C,.4alkoxyC,.4alkyl, C,.6alkanoyl, C,.4alkanoylC,.4alkyl, aryl, arylC alkyl, arylC,.4alkoxyC,.4alkyl, arylC,.4alkanoyl, arylcarbonyl, heteroaryl, heteroarylC,.4alkyl, heteroarylC,.4alkoxyC,_4alkyl, heteroarylC,.4alkanoyl, heteroarylcarbonyl, heterocyclyl, heterocyclylC, .4alkyl, heterocyclylC, _4alkoxyC,.4alkyl, heterocyclylC,.4alkanoyl, heterocyclylcarbonyl, carbocyclyl, carbocyclylC,.4alkyl, carbocyclylC, _4alkoxyC,_4alkyl, carbocyclylC,.4alkanoyl, carbocyclylcarbonyl, C,.4alkylsulphonyl, NN-di-C, _4alkylaminosulphonyl or N-C,.4alkylaminosulphonyl wherein R, may be optionally substituted (on an available carbon atom) by up to three substituents independently selected from: C,.4alkyl optionally substituted by up to three fluoro substituents, C,.4alkoxy, CMalkanoyl, carboxy, hydroxy, halo, cyano, amino, N-Cl.4alkylamino, NN-di-C,.4alkylamino, C,.4alkanoylamino, mercapto, C,.4alkylsulphonyl, C,.4alkylsulphinyl, C,.4alkylsulphanyl, nitro, heteroarylC,.4alkanoylamino, or C,.4alkoxycarbonyl;
L, is hydrogen or C,.4alkyl;
L2 is hydrogen or C,.4alkyl;
B is C,.,0alkylene, C2.,0alkenylene, C2.,0alkynylene, or a direct bond wherein the alkylene, alkenylene and alkynylene chains are optionally substituted by hydroxy, C,.4alkoxy or amino; R3 is hydrogen, hydroxy, C,.6alkoxy, C,.6alkanoyl, C,.6alkanoyloxy,
C,_6alkanoylamino, C,.6alkoxycarbonyl, C!.4alkoxycarbonylamino, aryl, aryloxy, arylcarbonyl, arylC,.4alkyl, arylC,.4alkoxy, arylC,.4alkanoyl, aryloxycarbonyl, arylCMalkoxycarbonyl, arylamino, heteroaryl, heteroaryloxy, heteroarylC,.4 alkoxy, heteroarylcarbonyl, heteroarylCMalkanoyl, heteroaryloxycarbonyl, heteroarylC,.4alkoxycarbonyl, heterocyclyl, heterocyclyloxy, heterocyclylC ,.4alkoxy, heterocyclylcarbonyl, heterocyclylC, .4alkanoyl, heterocyclyloxycarbonyl, heterocyclylC ,_4alkoxycarbonyl, carbocyclyl, carbocyclyl oxy, carbocyclylC!.4alkoxy, carbocyclylcarbonyl, carbocyclylC, .4alkanoyl, carbocyclyloxycarbonyl, carbocyclylC,.4alkoxycarbonyl, cyano, carbamoyl, ureido, amino, N-C,.4alkylamino, NN-di-C, .4alkylamino, C,.4alkoxycarbonylamino, aminocarbonyl, N-C,.4alkylaminocarbonyl, NN-di-C,.4alkylaminocarbonyl, C,.4alkylthio, trifluoromethyl or fluoro wherein R3 may be optionally substituted by up to three substituents independently selected from C,.4alkyl, hydroxyC,.4alkyl, C,.4alkoxy, C,.6alkoxycarbonyl, C,.6alkenyloxycarbonyl, C,.4alkanoyl, C,.4alkanoyl amino, C,.4alkanoylthio, oxo, carboxy, hydroxy, halo, cyano, amino, N-C,.4alkylamino, N/V-di-C,.4alkylaιnino, N-C,.4alkylaminoC,.4alkyl, NN-di-Cl.4alkylaminoC,_4alkyl, aminocarbonyl,
N-C,.4alkylaminocarbonyl, NN-di-C,.4alkylaminocarbonyl, mercapto, C,.4alkylsulphonyl, C,.4alkylsulphinyl, C,.4alkylsulphanyl, nitro, trifluoromethyl, trifluoromethylC,.4alkyl, aryl, arylC,.4alkyl, aryloxy C,.4alkyl, C,.4alkoxyphenyl, heteroaryl, heteroarylC,.4alkyl, heterocyclylcarbonyl, or aminosulphonylphenyl; and R4 is hydrogen, C,.4alkyl, halo or nitro; or a pharmaceutically acceptable salt, prodrug or solvate thereof; with the proviso that when -Ν(L,)- is linked on the 2-position of the carbazole ring, R, is hydrogen, R2 is hydrogen, B is a direct bond, L, is hydrogen, L2 is hydrogen and R4 is hydrogen then R3 cannot be hydrogen; and when -N(L,)- is linked on the 3-position of the carbazole ring, R, is ethyl, R2 is hydrogen, B is a direct bond or -(CH2)3-, L, is hydrogen, L2 is
hydrogen and R4 is hydrogen then R3 cannot be hydrogen, amino, NN-diethylamino or naphth-1-yl.
According to a further third feature of the invention there is provided a compound of the formula (IIF):
(III') wherein:
R, is selected from hydrogen, C,.6alkyl, C,.4alkoxyC,.4alkyl, C,.0alkanoyl,
C,.4alkanoylC,.4alkyl, aryl, arylC,.4alkyl, arylC,.4alkoxyC,.4alkyl, arylC,.4alkanoyl, arylcarbonyl, heteroaryl, heteroarylC,.4alkyl, heteroarylC,.4alkoxyC,.4alkyl, heteroarylC,.4alkanoyl, heteroarylcarbonyl, heterocyclyl, heterocyclylC, _4alkyl, heterocyclylC, .4alkoxyC,.4alkyl, heterocyclylC ,.4alkanoyl, heterocyclylcarbonyl, carbocyclyl, carbocyclylC ,.4alkyl, carbocyclylC,.4alkoxyC,.4alkyl, carbocyclylC,.4alkanoyl, carbocyclylcarbonyl, cyanoC,.4alkyl, aminoC,.4 alkyl, N-C,.4alkylaminoC,.4alkyl, or NN-di-C,.4alkylaminoC,.4alkyl; wherein R, may be optionally substituted (on an available carbon atom) by up to three substituents independently selected from: C,.4alkyl, C,.4alkoxy, C,_4alkanoyl, carboxy, hydroxy, halo, cyano, amino, N-C,.4alkylamino, N/V-di-C,.4alkylamino, C,.4alkanoylamino, mercapto, C,.4alkylsulphonyl, C,.4alkylsulphinyl, C,.4alkylsulphanyl, nitro, trifluoromethyl-C,.4alkyl, heteroarylCMalkanoylamino, or C,.4alkoxycarbonyl; R2 is selected from hydrogen, C,.4alkyl, C,.4alkoxy, cyano, nitro, halo, amino,
N-C,.4alkylamino, or NN-di-C, .4alkylamino;
L, is selected from hydrogen or C,.4alkyl;
B is C,.6alkylene, C2.6alkenylene, C2.6alkynylene, or a direct bond;
R3 is hydrogen, C,.6alkoxy, C,.6alkanoyl, C,.6alkoxycarbonyl, aryl, aryloxy, arylC,.4alkoxy, arylcarbonyl, aryl,.4alkanoyl, aryloxycarbonyl, arylCMalkoxycarbonyl, heteroaryl, heteroaryloxy, heteroarylC,.4alkoxy, heteroarylcarbonyl, heteroarylC,.4alkanoyl, heteroaryloxycarbonyl, heteroaryl-C,.4alkoxycarbonyl, heterocyclyl, heterocyclyloxy, heterocyclylC , .4alkoxy, heterocyclylcarbonyl, heterocyclylC , .4alkanoyl,
heterocyclyloxycarbonyl, heterocyclylC , ^alkoxycarbonyl, carbocyclyl, carbocyclyloxy, carbocyclylC, .4alkoxy, carbocyclylcarbonyl, carbocyclylC ,.4alkanoyl, carbocyclyloxycarbonyl, carbocyclylC,.4 alkoxycarbonyl, amino, N-C,_4alkylamino, NN-di-C ,.4alkylamino, CM lkylthio wherein R3 may be optionally substituted (on an available carbon atom) by up to three substituents independently selected from C,.4alkyl, C,_4alkoxy, C,.4alkanoyl, carboxy, hydroxy, halo, cyano, amino, /V-C,_4alkylamino, NN-di-C, _4alkylamino, C,.4alkanoylamino, mercapto, C,.4alkylsulphonyl, C,.4alkylsulphinyl, C,.4alkylsulphanyl, nitro, trifluoromethylC,.4alkyl, phenyl, C,.4alkoxyphenyl, heteroaryl, heteroarylC,.4alkyl, aminosulphonylphenyl or C,.4alkoxycarbonyl; and R4 is hydrogen, C,.4alkyl, or nitro; or a pharmaceutically acceptable salt, prodrug or solvate thereof; with the proviso that compound of formula (I) is not selected from: Hydrazinecarboxamide, N-(9-ethyl-9H-carbazol-3-yl)-; Urea, (9-ethyl-9H-carbazol-3-yl)-; Urea, 9H-carbazol-2-yl-;
Urea, N-(9-ethyl-9H-carbazol-3-yl)-Ν'-l-naphthalenyl-, or Urea, N-[3-(diethylamino)propyl]-N'-(9-ethyl-9H-carbazol-3-yl)-.
According to an alternative further third feature of the invention there is provided a compound of the formula (III') (as depicted above) wherein: R, is selected from hydrogen, C,.6alkyl, C,.4alkoxyC,.4alkyl, C,.6alkanoyl,
C,.4alkanoylC,.4alkyl, aryl, arylC,.4alkyl, arylC,.4alkoxyC,.4alkyl, arylC,.4alkanoyl, arylcarbonyl, heteroaryl, heteroarylC,_4 alkyl, heteroarylC,_4alkoxyCl_4alkyl, heteroarylC,.4alkanoyl, heteroarylcarbonyl, heterocyclyl, heterocyclylC,.4alkyl, heterocyclylC, _4alkoxyC,.4alkyl, heterocyclylC ,.4alkanoyl, heterocyclylcarbonyl, carbocyclyl, carbocyclylC, .4alkyl, carbocyclylC, _4alkoxyC,_4alkyl, carbocyclylC,_4alkanoyl, carbocyclylcarbonyl, cyanoC,.4alkyl, aminoC,.4alkyl, N-C,.4alkylaminoC,.4alkyl, or NN-di-C, _4alkylaminoC,.4alkyl; wherein R, may be optionally substituted (on an available carbon atom) by up to three substituents independently selected from: C,.4alkyl, C,.4alkoxy, C,.4alkanoyl, carboxy, hydroxy, halo, cyano, amino, N-C,.4alkylamino, NN-di-C,.4alkylamino, C,.4alkanoylamino, mercapto, C,.4alkylsulphonyl, C,.4alkylsulphinyl, C,.4alkylsulphanyl, nitro, trifluoromethyl-C,.4alkyl, heteroarylC,.4alkanoylamino, or C,.4alkoxycarbonyl;
R2 is selected from hydrogen, C,.4alkyl, C,.4alkoxy, cyano, nitro, halo, amino, N-C,.4alkylamino, or NN-di-C, .4alkylamino;
L, is selected from hydrogen or C,.4alkyl;
L2 is selected from hydrogen or C,.4alkyl; B is C,.6alkylene, C2.6alkenylene, C2.6alkynylene, or a direct bond;
R3 is hydrogen, C,.6alkoxy, C,.6alkanoyl, C,.6alkoxycarbonyl, aryl, aryloxy, arylC,.4alkoxy, arylcarbonyl, aryl,.4alkanoyl, aryloxycarbonyl, arylCMalkoxycarbonyl, heteroaryl, heteroaryloxy, heteroarylC,_4 alkoxy, heteroarylcarbonyl, heteroarylC,.4alkanoyl, heteroaryloxycarbonyl, heteroaryl-C,.4alkoxycarbonyl, heterocyclyl, heterocyclyloxy, heterocyclylC,.4alkoxy, heterocyclylcarbonyl, heterocyclylC,.4alkanoyl, heterocyclyloxycarbonyl, heterocyclylC,.4alkoxycarbonyl, carbocyclyl, carbocyclyloxy, carbocyclylC,.4alkoxy, carbocyclylcarbonyl, carbocyclylC ,.4 alkanoyl, carbocyclyloxycarbonyl, carbocyclylC ,.4alkoxycarbonyl, amino, N-C,.4alkylamino, NN-di-C alkylamino, C,.4alkyl)thio or fluoro wherein R3 may be optionally substituted (on an available carbon atom) by up to three substituents independently selected from C,.4alkyl, C,.4alkoxy, C,.4alkanoyl, carboxy, hydroxy, halo, cyano, amino, N-C,_4alkylamino, NN-di-C,.4alkylamino, C,.4alkanoylamino, mercapto, C,.4alkylsulphonyl, C,.4alkylsulphinyl, C,.4alkylsulphanyl, nitro, trifluoromethylC,.4alkyl, phenyl, C,.4alkoxyphenyl, heteroaryl, heteroarylC,.4alkyl, aminosulphonylphenyl or C,.4alkoxycarbonyl; and R4 is hydrogen, C,.4alkyl, or nitro; or a pharmaceutically acceptable salt, prodrug or solvate thereof; with the proviso that when -Ν(L,)- is linked on the 2-position of the carbazole ring, R, is hydrogen, R2 is hydrogen, B is a direct bond, L, is hydrogen, L2 is hydrogen and R4 is hydrogen then R3 cannot be hydrogen; and when -N(L,)- is linked on the 3-position of the carbazole ring, R, is ethyl, R2 is hydrogen, B is a direct bond or -CH,)3-, L, is hydrogen, L2 is hydrogen and R4 is hydrogen then R3 cannot be hydrogen, amino, NN-diethylamino or naphth-1-yl.
According to a fourth feature of the invention there is provided a compound of the formula (IV):
R, is selected from hydrogen, C,.6alkyl, C,.4alkoxyC,.4alkyl, C,.6alkanoyl, C,.4alkanoylC,.4alkyl, aryl, arylC,.4alkyl, arylC,.4alkoxyC,.4alkyl, arylC,.4alkanoyl, arylcarbonyl, heteroaryl, heteroarylC alkyl, heteroarylC|.4alkoxyC,.4alkyl, heteroarylC,.4alkanoyl, heteroarylcarbonyl, heterocyclyl, heterocyclylC ,.4alkyl, heterocyclylC,.4alkoxyCMalkyl, heterocyclylC,.4alkanoyl, heterocyclylcarbonyl, carbocyclyl, carbocyclylC, .4alkyl, carbocyclylC, _4alkoxyCl.4alkyl, carbocyclyl C,.4alkanoyl, carbocyclylcarbonyl, C,.4alkyl sulphonyl, NN-di-C,.4alkylaminosulphonyl or
N-C,.4alkylaminosulphonyl wherein R, may be optionally substituted (on an available carbon atom) by up to three substituents independently selected from: C,.4alkyl optionally substituted by up to three fluoro substituents, C,.4alkoxy, C,.4alkanoyl, carboxy, hydroxy, halo, cyano, amino, N-C,.4alkylamino, NN-di-C,.4alkylamino, C,.4alkanoylamino, mercapto, C,.4alkylsulphonyl, C,.4alkylsulphinyl, C,.4alkylsulphanyl, nitro, heteroarylC,.4alkanoylamino, or C,.4alkoxycarbonyl;
R2 is selected from hydrogen, C,_4alkyl (optionally substituted by hydroxy), CMalkoxy, cyano, nitro, halo, amino, N-C,.4alkylamino, or NN-di-C ,.4alkylamino; L, is selected from hydrogen or C,.4alkyl; B is selected from C,.,0alkylene, C2.,0alkenylene, C2.,0alkynylene, or a direct bond wherein the alkylene, alkenylene and alkynylene chains are optionally substituted by hydroxy, C,.4alkoxy or amino;
R3 is selected from hydrogen, hydroxy, C,.6alkoxy, C,.6alkanoyl, C,.6alkanoyloxy, C,.6alkanoylamino, C,.6alkoxycarbonyl, aryl, aryloxy, arylcarbonyl, arylC,_4alkyl, arylC,.4alkoxy, arylC,.4alkanoyl, aryloxycarbonyl, arylC,.4alkoxycarbonyl, arylamino, diarylamino, arylsulphonyl, heteroaryl, heteroaryloxy, heteroarylC,.4alkoxy, heteroarylcarbonyl, heteroarylC,.4alkanoyl, heteroaryloxycarbonyl,
heteroarylC,.4alkoxycarbonyl, heteroarylC,.4alkyl, heteroarylamino, heteroarylsulphonyl, diheteroarylamino, heterocyclyl, heterocyclyloxy, heterocyclylC,.4alkoxy, heterocyclylcarbonyl, heterocyclylCMalkanoyl, heterocyclyloxycarbonyl, heterocyclylC, .4alkoxycarbonyl, heterocyclylC, _4alkyl, heterocyclylamino, diheterocyclylamino, heterocyclylsulphonyl, carbocyclyl, carbocyclyloxy, carbocyclylC,.4alkoxy, carbocyclylcarbonyl, carbocyclylC,.4alkanoyl, carbocyclyloxycarbonyl, carbocyclylC,.4alkoxycarbonyl, carbocyclylC ,.4alkyl, carbocyclylamino, carbocyclylsulphonyl, dicarbocyclylamino, cyano, carbamoyl, ureido, amino, N-C,.4alkylamino, NN-di-C,.4alkylamino, C,.4alkoxycarbonylamino, carbamoyl, N-C,.4alkylcarbamoyl, NN-di-C, _4alkylcarbamoyl, C,.4alkylsulphanyl, C,.4alkylsulphinyl, C,.4alkylsulphonyl, trifluoromethyl or fluoro wherein R3 may be optionally substituted by up to three substituents independently selected from C,.4alkyl, hydroxyC,_4alkyl, C,.4alkoxy, C,.6alkoxycarbonyl, C2.6alkenyloxycarbonyl, C,.4alkanoyl, C,.4alkanoylamino, C,_4alkanoylthio, oxo, carboxy, hydroxy, halo, cyano, amino, N-C,_4alkylamino, NN-di-C, .4alkylamino, N-C,.4alkylaminoC,.4alkyl, NN-di-C, .4alkylaminoC,.4alkyl, carbamoyl, N-C,.4alkylcarbamoyl, NN-di-C,.4alkylcarbamoyl, mercapto, C,.4alkyl sulphonyl, C,.4alkylsulphinyl, C,.4alkylsulphanyl, C,.4alkylsulphonyloxyC,.4alkyl, nitro, trifluoromethyl, trifluoromethylC,.4alkyl, C,.6alkoxycarbonylamino, C,.6alkoxycarbonyl(Ν-C,.4alkyl)amino, aryl (optionally substituted by one C,.4alkoxy or sulphamoyl), arylC,.4 alkyl, aryloxyC,.4alkyl, arylcarbonyl, heteroaryl, heteroarylC,.4alkyl, heteroaryloxyC,.4alkyl, heteroarylcarbonyl, heterocyclyl, heterocyclylC,.4alkyl, heterocyclyloxyC,.4alkyl, heterocyclylcarbonyl, carbocyclyl, carbocyclylC,.4alkyl, carbocyclyloxyC,.4alkyl or carbocyclylcarbonyl; and
R4 is selected from hydrogen, C,.4alkyl, halo or nitro; or a pharmaceutically acceptable salt, prodrug or solvate thereof; with the proviso that when -N(L,)- is linked on the 2-position of the carbazole ring, R, is hydrogen, methyl, acetyl, (4-methyl- l-piperazinyl)propyl or 2-methoxy-4-carboxy-benzyl, R2 is hydrogen, 6-ethyl, 6-bromo or 6-nitro, L, is hydrogen, B is a direct bond, -CH2-, -CH(CH3)CH2- or -(CH2)5- and R4 is hydrogen or nitro then R3 cannot be hydrogen or cyclopentyl; when -N(L,)- is linked on the 3-position of the carbazole ring, R, is hydrogen, methyl, ethyl, acetyl, 2-carboxyethyl or benzoyl, R2 is hydrogen, 6-methyl, 6-methoxy,
7-methoxy, 6-nitro or 6-amino, L, is hydrogen or ethyl, B is -CH2- and R4 is hydrogen, methyl
or nitro, then R3 cannot be hydrogen; when -N(L,)- is linked on the 3-position of the carbazole ring, R, is hydrogen, methyl or ethyl, R2 is hydrogen; L, is hydrogen, B is a direct bond, -C2H4-, -CH(CH3)CH2-, -CH=CH- or -C(=CH2)CH2-, R4 is hydrogen then R3 cannot be hydrogen; when -N(L,)- is linked on the 3-position of the carbazole ring, R, is hydrogen or ethyl, R2 is hydrogen, L, is hydrogen or ethyl, B is a direct bond and R4 is hydrogen then R3 cannot be unsubstituted phenyl, 2-carboxyphenyl, 4-nitro-phenyl or
2-hydroxy-5-amino-phenyl; when -N(L,)- is linked on the 3-position of the carbazole ring R, is hydrogen, R2 is hydrogen, L, is hydrogen, B is -CH2- and R4 is hydrogen then R3 cannot be phenoxy; when -N(L,)- is linked on the 3-position of the carbazole ring, R, is hydrogen , methyl or 2-cyanoethyl, R2 is hydrogen, L, is hydrogen, B is a direct bond, and R4 is hydrogen then R3 cannot be 3-hydroxy-2-naphthyl or 2-hydroxy-l-naphthyl; when -N(L,)- is linked on the 3-position of the carbazole ring, R, is ethyl, R2 is hydrogen, L, is hydrogen, B is a bond and R4 is hydrogen then R3 cannot be 4,5,6,7-terahydro-lH-benzimidazol-6-yl or lH-benzo[d][l,2,3]triazol-6-yl; and when R, is hydrogen, methyl, ethyl, carboxymethyl or 2-carboxyethyl, R2 is hydrogen, L, is hydrogen, B is a direct bond, -CH2- or -CH(CH3)- and R4 is hydrogen then R3 cannot be amino, halo or trifluoromethyl.
According to a fourth feature of the invention there is provided a compound of the formula (IV) (as depicted above) wherein:
R, is selected from hydrogen, C,.6alkyl, C,.4alkoxyC,.4alkyl, C,.6alkanoyl, C,.4alkanoylC,.4alkyl, aryl, arylC,_4alkyl, arylC,.4alkoxyC,.4alkyl, arylC,.4alkanoyl, arylcarbonyl, heteroaryl, heteroarylC,.4alkyl, heteroarylC,.4alkoxyC,.4alkyl, heteroarylC,.4alkanoyl, heteroarylcarbonyl, heterocyclyl, heterocyclylC ,.4alkyl, heterocyclylC, .4alkoxyC,.4alkyl, heterocyclylC ,.4alkanoyl, heterocyclylcarbonyl, carbocyclyl, carbocyclylC, .4alkyl, carbocyclylC,.4alkoxyC,.4alkyl, carbocyclylC ,.4 alkanoyl, carbocyclylcarbonyl, C,.4alkylsulphonyl, NN-di-C, _4alkylaminosulphonyl or
N-C,.4alkylaminosulphonyl wherein R, may be optionally substituted (on an available carbon atom) by up to three substituents independently selected from: C,.4alkyl optionally substituted by up to three fluoro substituents, C,.4alkoxy, C,.4alkanoyl, carboxy, hydroxy, halo, cyano, amino, N-C,.4alkylamino, NN-di-C ,.4alkylamino, C,.4alkanoyl amino, mercapto, C,.4alkylsulphonyl, C,.4alkylsulphinyl, C,.4alkylsulphanyl, nitro, heteroarylC,.4alkanoylamino, or C,.4alkoxycarbonyl;
L, is hydrogen or C,.4alkyl;
B is C,.,0alkylene, C2.10alkenylene, C2.,0alkynylene, or a direct bond wherein the alkylene, alkenylene and alkynylene chains are optionally substituted by hydroxy, C,.4alkoxy or amino; R3 is hydrogen, hydroxy, C,.6alkoxy, C,.6alkanoyl, C,.6alkanoyloxy,
C,_6alkanoylamino, C,.6alkoxycarbonyl, C,.4alkoxycarbonylamino; aryl, aryloxy, arylcarbonyl, arylC,.4alkyl; arylC,.4alkoxy, arylC,.4alkanoyl, aryloxycarbonyl, arylCMalkoxycarbonyl, arylamino, heteroaryl, heteroaryloxy, heteroarylC,.4alkoxy, heteroarylcarbonyl, heteroarylC,.4alkanoyl, heteroaryloxycarbonyl, heteroarylC,.4alkoxycarbonyl, heterocyclyl, heterocyclyloxy, heterocyclylC,.4alkoxy, heterocyclylcarbonyl, heterocyclylC,.4alkanoyl, heterocyclyloxycarbonyl, heterocyclylC, _4alkoxycarbonyl, carbocyclyl, carbocyclyloxy, carbocyclylC, .4alkoxy, carbocyclylcarbonyl, carbocyclylC,.4alkanoyl, carbocyclyloxycarbonyl, carbocyclylC,.4alkoxycarbonyl, cyano, carbamoyl, ureido, amino, N-C,.4alkylamino, NN-di-C, .4alkylamino, C,_4alkoxycarbonylamino, aminocarbonyl, N-C,.4alkylaminocarbonyl, NN-di-C, .4alkylaminocarbonyl, C,.4alkylthio, trifluoromethyl or fluoro wherein R3 may be optionally substituted by up to three substituents independently selected from C,.4alkyl, hydroxy C,.4alkyl, C,.4alkoxy, C,.6alkoxycarbonyl, C,.6alkenyloxycarbonyl, C,.4alkanoyl, C,_4alkanoylamino, C,.4alkanoylthio, oxo, carboxy, hydroxy, halo, cyano, amino, N-C,.4alkylamino, NN-di-C,.4alkylamino, N-C,.4alkylaminoC,.4alkyl, NN-di-C, _4alkylaminoCl.4alkyl, aminocarbonyl,
N-C,.4alkylaminocarbonyl, NN-di-C, .4alkylaminocarbonyl, mercapto, C,.4alkylsulphonyl, C,.4alkylsulphinyl, C,.4alkylsulphanyl, nitro, trifluoromethyl, trifluoromethylC,.4alkyl, aryl, arylC,.4alkyl, aryloxyC,.4alkyl, C,.4alkoxyphenyl, heteroaryl, heteroarylC,.4alkyl, heterocyclylcarbonyl, or aminosulphonylphenyl; and R4 is hydrogen, C,.4alkyl, halo or nitro; or a pharmaceutically acceptable salt, prodrug or solvate thereof; with the proviso that when -Ν(L,)- is linked on the 2-position of the carbazole ring, R, is hydrogen, methyl, acetyl, (4-methyl- l-piperazinyl)propyl or 2-methoxy-4-carboxy-benzyl, R2 is hydrogen, 6-ethyl, 6-bromo or 6-nitro, L, is hydrogen, B is a direct bond, -CH2-, -CHCH3)CH2- or -CH2)5- and R4 is hydrogen or nitro then R3 cannot be hydrogen or cyclopentyl; when -N(L,)- is linked on the 3-position of the carbazole ring, R, is hydrogen,
methyl, ethyl, acetyl, 2-carboxyethyl or benzoyl, R2 is hydrogen, 6-methyl, 6-methoxy, 7-methoxy, 6-nitro or 6-amino, L, is hydrogen or ethyl, B is -CH2- and R4 is hydrogen, methyl or nitro, then R3 cannot be hydrogen; when -N(L,)- is linked on the 3-position of the carbazole ring, R, is hydrogen, methyl or ethyl, R2 is hydrogen; L, is hydrogen, B is a direct bond, -C2H4-, -CHCH3)CH2-, -CH=CH- or -C(=CH2)CH2-, R4 is hydrogen then R3 cannot be hydrogen; when -N(L,)- is linked on the 3-position of the carbazole ring, R, is hydrogen or ethyl, R2 is hydrogen, L, is hydrogen or ethyl, B is a direct bond and R4 is hydrogen then R3 cannot be unsubstituted phenyl, 2-carboxyphenyl, 4-nitro-phenyl or 2-hydroxy-5-amino-phenyl; when -N(L,)- is linked on the 3-position of the carbazole ring R, is hydrogen, R2 is hydrogen, L, is hydrogen, B is -CH2- and R4 is hydrogen then R3 cannot be phenoxy; when -N(L,)- is linked on the 3-position of the carbazole ring, R, is hydrogen , methyl or 2-cyanoethyl, R2 is hydrogen, L, is hydrogen, B is a direct bond, and R4 is hydrogen then R3 cannot be 3-hydroxy-2-naphthyl or 2-hydroxy-l-naphthyl; when -N(L,)- is linked on the 3-position of the carbazole ring, R, is ethyl, R2 is hydrogen, L, is hydrogen, B is a bond and R4 is hydrogen then R3 cannot be 4,5,6, 7-terahydro-lH-benzimidazol-6-yl or lH-benzo[d][l,2,3]triazol-6-yl; and when R, is hydrogen, methyl, ethyl, carboxymethyl or 2-carboxyethyl, R2 is hydrogen, L, is hydrogen, B is a direct bond, -CH2- or -CHCH3)- and R4 is hydrogen then R3 cannot be amino, halo or trifluoromethyl.
According to a fourth feature of the invention there is provided a compound of the formula (IV):
R, is selected from hydrogen, C,_6alkyl, C,.4alkoxyC,.4alkyl, C,.6alkanoyl, C|.4alkanoylC,.4alkyl, aryl, arylC,.4alkyl, arylC,.4alkoxyC,.4alkyl, arylC,.4alkanoyl, arylcarbonyl, heteroaryl, heteroarylC,.4alkyl, heteroarylC,.4alkoxyC,.4alkyl, heteroarylC,.4alkanoyl, heteroarylcarbonyl, heterocyclyl, heterocyclylC ,.4alkyl, heterocyclylC,.4alkoxyC,.4alkyl, heterocyclylC ,.4alkanoyl, heterocyclylcarbonyl, carbocyclyl,
carbocyclylC , .4alkyl, carbocyclylC, .4alkoxyC , .4alkyl, carbocyclylC , .4 alkanoyl, carbocyclylcarbonyl, cyanoC,.4alkyl, aminoC,.4alkyl, N-C,_4alkylaminoC,.4alkyl, or NN-di-C,.4alkylaminoC,.4alkyl; wherein R, may be optionally substituted (on an available carbon atom) by up to three substituents independently selected from: C,.4alkyl, C,.4alkoxy, C,.4alkanoyl, carboxy, hydroxy, halo, cyano, amino, N-C,.4alkylamino, N,N-di-C,.4alkylamino, C,.4alkanoylamino, mercapto, C,.4alkylsulphonyl, C,.4alkylsulphinyl, C,.4alkylsulphanyl, nitro, trifluoromethyl-C,.4alkyl, heteroarylC,.4alkanoylamino, or C,.4alkoxycarbonyl;
R2 is selected from hydrogen, C,.4alkyl, C,.4alkoxy, cyano, nitro, halo, amino, N-C,.4alkylamino, or NN-di-CMalkylamino; B is C,.6alkylene, C2.6alkenylene, C2.6alkynylene, or a direct bond;
R3 is hydrogen, C,.6alkoxy, C,.6alkanoyl, C,.6alkoxycarbonyl, aryl, aryloxy, aryl-C,.4alkoxy, arylcarbonyl, aryl,.4alkanoyl, aryloxycarbonyl, arylC,.4alkoxycarbonyl, heteroaryl, heteroaryloxy, heteroarylC,.4alkoxy, heteroarylcarbonyl, heteroaryl-C,.4alkanoyl, heteroaryloxycarbonyl, heteroarylC,.4alkoxycarbonyl, heterocyclyl, heterocyclyloxy, heterocyclylC,.4alkoxy, heterocyclylcarbonyl, heterocyclylC, .4alkanoyl, heterocyclyloxycarbonyl, heterocyclylC,_4alkoxycarbonyl, carbocyclyl, carbocyclyloxy, carbocyclylC,.4alkoxy, carbocyclylcarbonyl, carbocyclylC alkanoyl, carbocyclyloxycarbonyl, carbocyclylC ,.4 alkoxycarbonyl, amino, N-C,_4alkylamino, NN-di-C ,.4alkylamino, C,.4alkyl)thio wherein R3 may be optionally substituted (on an available carbon atom) by up to three substituents independently selected from C,.4alkyl, C,.4alkoxy, C,.4alkanoyl, carboxy, hydroxy, halo, cyano, amino, N-C,.4alkylamino, NN-di-C ,.4alkylamino, C,.4alkanoylamino, mercapto, CMalkylsulphonyl, C,.4alkylsulphinyl, C,.4alkylsulphanyl, nitro, trifluoromethylC,_4alkyl, phenyl, C,.4alkoxyphenyl, heteroaryl, heteroarylC,.4alkyl, aminosulphonylphenyl or C,.4alkoxycarbonyl; and R4 is hydrogen, C,.4alkyl, or nitro; or a pharmaceutically acceptable salt, prodrug or solvate thereof; with the proviso that compound of formula (I) is not selected from:
Acetamide, N-9H-carbazol-3-yl-2-phenoxy-;
Acetamide, N-[9-[3-(4-methyl-l-piperazinyl)propyl]-9H-carbazol-2-yl]-, dihydrochloride; Formamide, N-(9-methyl-9H-carbazol-3-yl)-;
Acetamide, N-(9-acety 1-3 -nitro-9H-carbazol-2-yl)-;
2-Propenamide, N-(9-ethyl-9H-carbazol-3-yl)-2-methyl-, homopolymer;
1-Νaphthamide, 2-hydroxy-N-(9-methylcarbazol-3-yl)-;
Acetamide, 2,2,2-trifluoro-N-(9-methyl-9H-carbazol-3-yl)-;
Acetamide, N-[9-[3-(4-methyl-l-piperazinyl)propyl]-9H-carbazol-2-yl]-; Acetamide, N-ethyl-N-(9-ethyl-9H-carbazol-3-yl)-;
2-Νaphthamide, N-[9-(2-cyanoethyl)carbazol-3-yl]-3-hydroxy-;
Formamide, N-9H-carbazol-3-yl-;
2-Propenamide, N-(9-ethyl-9H-carbazol-3-yl)-, homopolymer;
N-(9-ethyl-9H-carbazol-3-yl)-2-methyl-2-propenamide (9CI); Acetamide, N-(6-bromo-9H-carbazol-2-yl)-;
2-Propenamide, N-(9-ethyl-9H-carbazol-3-yl)-2-methyl-;
Butanamide, N-9H-carbazol-2-yl-;
Acetamide, N-(2-nitro-9H-carbazol-3-yl)-;
2-Proρenamide, N-(9-ethyl-9H-carbazol-3-yl)- (9CI); Benzamide, N-ethyl-N-(9-ethyl-9H-carbazol-3-yl)-4-nitro-;
Formamide, N-9H-carbazol-2-yl-;
Butanamide, N-(5,8-dimethyl-6-nitro-9H-carbazol-3-yl)-;
Acetamide, N-(9-benzoyl-2-nitro-9H-carbazol-3-yl)-;
Propanamide, N-(5,8-dimethyl-6-nitro-9H-carbazol-3-yl)-; Acetamide, N-(9-acetyl-2-nitro-9H-carbazol-3-yl)-;
Benzoic acid, 4-[[6-ethyl-2-[(l-oxohexylamino]-9H-carbazol-9-yl]methyl]-3-methoxy-;
Acetamide, N-(9-benzoyl-9H-carbazol-3-yl)-;
Acetamide, V-(7-methoxy-9H-carbazol-3-yι)-;
Benzoic acid, 4-[[2-[(cyclopentylacetylamino]-9H-carbazol-9-yl]methyl]-3-methoxy-, methyl ester ;
Acetamide, N-(5,8-dimethyl-6-nitro-9H-carbazol-3-yl)-;
Acetamide, N-(9-acetyl-9H-carbazol-3-yl)-;
Benzamide, N-(9-ethyl-9H-carbazol-3-yl)-;
Benzamide, 5-amino-N-9H-carbazol-3-yl-2-hydroxy-; Acetamide, N-9H-carbazol-3-yl-;
Benzenesulfonic acid, 2-[[(9-ethyl-9H-carbazol-3-ylamino]carbonyl]-;
lH-Benzimidazole-5-carboxamide, N-(9-ethyl-9H-carbazol-3-yl)-4,5,6,7-tetrahydro-;
Benzoic acid, 4-[[2-[(cyclopentylcarbonylamino]-9H-carbazol-9-yl]methyl]- 3-methoxy-, methyl ester ;
Acetamide, N-(5,8-dimethyl-9H-carbazol-2-yl)-; Acetamide, N-(9-acetyl-9H-carbazol-2-yl)-;
Benzoic acid, 2-[[(9-ethyl-9H-carbazol-3-ylamino]carbonyl]-;
2-Νaphthalenecarboxamide, N-9H-carbazol-2-yl-3 -hydroxy-; lH-Benzotriazole-5-carboxamide, N-(9-ethyl-9H-carbazol-3-yl)-;
2-Proρenamide, N-9H-carbazol-3-yl-, homopolymer; Acetamide, N-(6-methoxy-9H-carbazol-3-yl)-;
Propiona ide, 2-amino-N-9-ethylcarbazol-2-yl-, hydrochloride;
Propionamide, 2-amino-N-carbazol-3-yl-;
Acetamide, N-(6-amino-9-ethyl-9H-carbazol-3-yl)-;
2-Propenamide, N-9H-carbazol-3-yl-; Propanamide, N-9H-carbazol-3-yl-2-iodo-;
Acetamide, N-(9-ethyl-6-methyl-9H-carbazol-3-yl)-;
Benzamide, N-9H-carbazol-3-yl-;
2-Νaphthamide, N-carbazol-3-yl-3-hydroxy-;
Acetamide, N-(9-ethyl-6-nitro-9H-carbazol-3-yl)-; Acetamide, N-9H-carbazol-3-yl-2-iodo-;
Diphenamic acid, N-(9-ethylcarbazol-3-yl)-;
5-Pyrimidinecarboxamide,
N-(9-ethyl-9H-carbazol-3-yl)-l,2,3,4-tetrahydro-6-methyl-2-oxo-4-thioxo-;
Acetamide, N-(9-methyl-9H-carbazol-3-yl)-; Acetamide, N-(2-methyl-9H-carbazol-3-yl)-;
Acetamide, N-(9-methyl-3,6-dinitro-9H-carbazol-2-yl)-;
Formamide, N-(9-ethyl-9H-carbazol-3-yl)-;
Acetamide, N-(9-methyl-9H-carbazol-3-yl)-, monohydrochloride;
Acetamide, 2-bromo-N-9H-carbazol-3-yl-; 2-Νaphthamide, 3-hydroxy-N-(9-methylcarbazol-3-yl)-;
Acetamide, N-(9-methyl-9H-carbazol-2-yl)-;
Acetamide, N-9H-carbazol-2-yl-; Acetamide, N-9H-carbazol-3-yl-2-fluoro-; Acetamide, N-(9-ethyl-9H-carbazol-3-yl)-, or Acetamide, 2,2,2-trifluoro-N-(9-methyl-9H-carbazol-2-yl)- According to a fourth feature of the invention there is provided a compound of the formula (IV) (as depicted above) wherein:
R, is selected from hydrogen, C,.6alkyl, C,.4alkoxyC,.4alkyl, C,.6alkanoyl, C|.4alkanoylC,.4alkyl, aryl, arylC,.4alkyl, arylC,.4alkoxyC,.4alkyl, arylC,.4alkanoyl, arylcarbonyl, heteroaryl, heteroarylC,.4alkyl, heteroarylC,.4alkoxyC,.4 alkyl, heteroarylC,.4alkanoyl, heteroarylcarbonyl, heterocyclyl, heterocyclylC ,.4alkyl, heterocyclylC, .4alkoxyC,.4alkyl, heterocyclylC ,.4alkanoyl, heterocyclylcarbonyl, carbocyclyl, carbocyclylC , .4alkyl, carbocyclylC , .4alkoxyC , .4alkyl, carbocyclylC , .4alkanoyl, carbocyclylcarbonyl, cyanoC,.4alkyl, aminoC,.4alkyl, N-C,.4alkylaminoC,.4 alkyl, or NN-di-C|.4alkylaminoC,.4alkyl; wherein R, may be optionally substituted (on an available carbon atom) by up to three substituents independently selected from: C,.4alkyl, C,.4alkoxy, C,.4alkanoyl, carboxy, hydroxy, halo, cyano, amino, N-C,.4alkylamino, NN-di-C,.4alkylamino, C,.4alkanoylamino, mercapto, C,.4alkylsulphonyl, C,.4alkylsulphinyl, C,.4alkylsulphanyl, nitro, trifluoromethyl-C,.4alkyl, heteroarylC,.4alkanoylamino, or C,.4alkoxycarbonyl;
R2 is selected from hydrogen, C,.4alkyl, C,.4alkoxy, cyano, nitro, halo, amino, N-C,.4alkylamino, or NN-di-C, .4alkylamino; L, is hydrogen or C,.4alkyl;
B is C,.6alkylene, C2.6alkenylene, C2.6alkynylene, or a direct bond; R3 is hydrogen, C,.6alkoxy, C,.6alkanoyl, C,.6alkoxycarbonyl, aryl, aryloxy, aryl-C,.4 alkoxy, arylcarbonyl, aryl,.4alkanoyl, aryloxycarbonyl, arylCMalkoxycarbonyl, heteroaryl, heteroaryloxy, heteroarylC,.4alkoxy, heteroarylcarbonyl, heteroaryl-C,.4alkanoyl, heteroaryloxycarbonyl, heteroarylC,.4alkoxycarbonyl, heterocyclyl, heterocyclyloxy, heterocyclylC, _4alkoxy, heterocyclylcarbonyl, heterocyclylC ,.4alkanoyl, heterocyclyloxycarbonyl, heterocyclylC, .4alkoxycarbonyl, carbocyclyl, carbocyclyloxy, carbocyclylC, .4alkoxy, carbocyclylcarbonyl, carbocyclylC, .4alkanoyl, carbocyclyloxycarbonyl, carbocyclylC, .4alkoxycarbonyl, amino, N-C,_4alkylamino,
NN-di-C, _4alkylamino, C,.4alkyl)thio or fluoro wherein R3 may be optionally substituted (on
an available carbon atom) by up to three substituents independently selected from C,.4alkyl, C,_4alkoxy, C,.4alkanoyl, carboxy, hydroxy, halo, cyano, amino, N-C,.4alkylamino, NN-di-C ,.4alkylamino, CMalkanoylamino, mercapto, C,.4alkylsulphonyl, C,.4alkylsulphinyl, C,.4alkylsulphanyl, nitro, trifluoromethylC,.4alkyl, phenyl, C,.4alkoxyphenyl, heteroaryl, heteroarylC,.4 alkyl, aminosulphonylphenyl or C,.4alkoxycarbonyl; and R4 is hydrogen, C,.4alkyl, or nitro; or a pharmaceutically acceptable salt, prodrug or solvate thereof; with the proviso that when -Ν(L,)- is linked on the 2-position of the carbazole ring, R, is hydrogen, methyl, acetyl, (4-methyl- l-piperazinyl)propyl or 2-methoxy-4-carboxy-benzyl, R2 is hydrogen, 6-ethyl, 6-bromo or 6-nitro, L, is hydrogen, B is a direct bond, -CH2-, -CHCH3)CH2- or -CH2)5- and R4 is hydrogen or nitro then R3 cannot be hydrogen or cyclopentyl; when -N(L,)- is linked on the 3-position of the carbazole ring, R, is hydrogen, methyl, ethyl, acetyl, 2-carboxyethyl or benzoyl, R2 is hydrogen, 6-methyl, 6-methoxy, 7-methoxy, 6-nitro or 6-amino, L, is hydrogen or ethyl, B is -CH2- and R4 is hydrogen, methyl or nitro, then R3 cannot be hydrogen; when -N(L,)- is linked on the 3-position of the carbazole ring, R, is hydrogen, methyl or ethyl, R2 is hydrogen; L, is hydrogen, B is a direct bond, -C2H4-, -CHCH3)CH2-, -CH=CH- or -C(=CH2)CH2-, R4 is hydrogen then R3 cannot be hydrogen; when -N(L,)- is linked on the 3-position of the carbazole ring, R, is hydrogen or ethyl, R2 is hydrogen, L, is hydrogen or ethyl, B is a direct bond and R4 is hydrogen then R3 cannot be unsubstituted phenyl, 2-carboxyphenyl, 4-nitro-phenyl or
2-hydroxy-5-amino-phenyl; when -N(L,)- is linked on the 3-position of the carbazole ring R, is hydrogen, R2 is hydrogen, L, is hydrogen, B is -CH2- and R4 is hydrogen then R3 cannot be phenoxy; when -N(L,)- is linked on the 3-position of the carbazole ring, R, is hydrogen , methyl or 2-cyanoethyl, R2 is hydrogen, L, is hydrogen, B is a direct bond, and R4 is hydrogen then R3 cannot be 3-hydroxy-2-naphthyl or 2-hydroxy-l-naphthyl; when -N(L,)- is linked on the 3-position of the carbazole ring, R, is ethyl, R2 is hydrogen, L, is hydrogen, B is a bond and R4 is hydrogen then R3 cannot be 4,5,6,7-terahydro-lH-benzimidazol-6-yl or lH-benzo[d][l,2,3]triazol-6-yl; and when R, is hydrogen, methyl, ethyl, carboxymethyl or 2-carboxyethyl, R2 is hydrogen, L, is hydrogen, B is a direct bond, -CH2- or -CHCH3)- and R4 is hydrogen then R3 cannot be amino, halo or trifluoromethyl.
Particular compounds which fall within the above provisos include:
Benzoic acid, 4-[[6-ethyl-2-[(l-oxohexyl)amino]-9H-carbazol-9-yl]methyl]-3- methoxy-benzoic acid,
4-[[2-[(cyclopentylacetyl)amino]-9H-carbazol-9-yl]methyl]-3-methoxy-9H-carbazole-9- propanoic acid, 3-(acetylamino)-5-pyrimidinecarboxamide, N-(9-ethyl-9H-carbazol-3-yl)-l,2,3,4-tetrahydro-6-methyl-2-oxo-4-thioxo-
For the avoidance of doubt compounds of the invention include any tautomeric forms of compounds which occur by virtue of substitution on heteroaryl and heterocyclyl rings. For example, a compound containing 2-hydroxypyrimidine would have 2 tautomers.
According to the fifth feature of the invention there is provided the use of a compound of formula (la), or a pharmaceutically acceptable salt, prodrug or solvate thereof, for use in medical therapy,
(la) wherein:
R, is selected from hydrogen, C,.6alkyl, C,.4alkoxyC,_4alkyl, C,.6alkanoyl, C,.4alkanoylC,.4alkyl, aryl, arylC,.4alkyl, arylC,.4alkoxyC,.4alkyl, arylC,.4 alkanoyl, arylcarbonyl, heteroaryl, heteroarylC,.4alkyl, heteroarylC,.4alkoxyC,.4alkyl, heteroarylC,.4alkanoyl, heteroarylcarbonyl, heterocyclyl, heterocyclylC ,.4alkyl, heterocyclylC, _4alkoxyC,.4alkyl, heterocyclylC, .4alkanoyl, heterocyclylcarbonyl, carbocyclyl, carbocyclylC,.4alkyl, carbocyclylCMalkoxyC,_4alkyl, carbocyclylC, .4alkanoyl, carbocyclylcarbonyl, C,.4alkylsulphonyl, NN-di-C, ,4alkylaminosulphonyl or N-C,.4alkylaminosulphonyl wherein R, may be optionally substituted (on an available carbon atom) by up to three substituents independently selected from: C,.4alkyl optionally substituted by up to three fluoro substituents, C,.4alkoxy, C,.4alkanoyl, carboxy, hydroxy, halo, cyano,
amino, N-CMalkylamino, NN-di-C, .4alkylamino, C,.4alkanoylamino, mercapto, C,.4alkylsulphonyl, C,.4alkylsulphinyl, C,.4alkylsulphanyl, nitro, heteroarylC,.4alkanoylamino, or C,.4alkoxycarbonyl;
R2 is selected from hydrogen, C,.4alkyl (optionally substituted by hydroxy), C,.4alkoxy, cyano, nitro, halo, amino, N-C,.4alkylamino, or NN-di-C,.4alkylamino; A is selected from, -ΝH-, -CH2NH-, -NHC(O)-, -CH2NHC(O)-, -C(O)NH-, -NHC(O)NH-, -NHC(O)O-, -NHS(O2)-, -NHC(=N-CN)-, or a direct bond; wherein each nitrogen atom is optionally substituted with C,.4alkyl or hydroxyC2_4alkyl;
B is selected from C,.,0alkylene, C2.,0alkenylene, C2_,0alkynylene, or a direct bond wherein the alkylene, alkenylene and alkynylene chains are optionally substituted by hydroxy, CMalkoxy or amino;
R3 is selected from hydrogen, hydroxy, C,.6alkoxy, C,.6alkanoyl, C,.6alkanoyloxy, C,.6alkanoylamino, C,.6alkoxycarbonyl, aryl, aryloxy, arylcarbonyl, arylC,.4alkyl, arylC,.4alkoxy, arylC,.4alkanoyl, aryloxycarbonyl, arylC,.4alkoxycarbonyl, arylamino, diarylamino, arylsulphonyl, heteroaryl, heteroaryloxy, heteroarylC,.4alkoxy, heteroarylcarbonyl, heteroarylC,.4alkanoyl, heteroaryloxycarbonyl, heteroarylC,.4alkoxycarbonyl, heteroarylC,.4alkyl, heteroarylamino, heteroarylsulphonyl, diheteroarylamino, heterocyclyl, heterocyclyloxy, heterocyclylC ,.4alkoxy, heterocyclylcarbonyl, heterocyclylC ,.4alkanoyl, heterocyclyloxycarbonyl, heterocyclylC,.4alkoxycarbonyl, heterocyclylC ,.4alkyl, heterocyclylamino, diheterocyclylamino, heterocyclylsulphonyl, carbocyclyl, carbocyclyloxy, carbocyclylC ,.4alkoxy, carbocyclylcarbonyl, carbocyclylC ,_4alkanoyl, carbocyclyloxycarbonyl, carbocyclylC,.4alkoxycarbonyl, carbocyclylC,.4alkyl, carbocyclylamino, carbocyclylsulphonyl, dicarbocyclylamino, cyano, carbamoyl, ureido, amino, N-C,.4alkylamino, NN-di-C, .4alkylamino, C,.4alkoxycarbonylamino, carbamoyl, N-C,_4alkylcarbamoyl, NN-di-C,.4alkylcarbamoyl, C,.4alkylsulphanyl, C,.4alkylsulphinyl, C,.4alkylsulphonyl, trifluoromethyl or fluoro wherein R3 may be optionally substituted by up to three substituents independently selected from C,.4alkyl, hydroxyC,.4alkyl, C,.4alkoxy, C,.6alkoxycarbonyl, C2.6alkenyloxycarbonyl, C,.4alkanoyl, C,.4alkanoylamino, C,.4alkanoylthio, oxo, carboxy, hydroxy, halo, cyano, amino, N-C,.4alkylamino,
N,N-di-C,.4alkylamino, N-C,.4alkylaminoC,.4alkyl, NN-di-C, .4alkylaminoC,.4alkyl, carbamoyl,
N-C,.4alkylcarbamoyl, NN-di-C, .4alkylcarbamoyl, mercapto, C,.4alkylsulphonyl, C,.4alkylsulphinyl, C alkylsulphanyl, C,.4alkylsulphonyloxyC,.4alkyl, nitro, trifluoromethyl, trifluoromethylC,.4alkyl, C,.6alkoxycarbonylamino, C,.6alkoxycarbonyl(Ν-C,.4alkyl)amino, aryl (optionally substituted by one C,.4alkoxy or sulphamoyl), arylC,.4alkyl, aryloxyC,.4alkyl, arylcarbonyl, heteroaryl, heteroarylC,.4alkyl, heteroaryloxyC,.4alkyl, heteroarylcarbonyl, heterocyclyl, heterocyclylC,.4alkyl, heterocyclyloxyC,.4alkyl, heterocyclylcarbonyl, carbocyclyl, carbocyclylC alkyl, carbocyclyloxyC,_4 alkyl or carbocyclylcarbonyl; and
R4 is selected from hydrogen, C,.4alkyl, halo or nitro; or a pharmaceutically acceptable salt, prodrug or solvate thereof; with the proviso that when A is -NHC(O)- and is linked on the 2-position of the carbazole ring, R, is hydrogen, methyl or 3-(4-methylpiperazin-l-yl)propyl, R2 is hydrogen or 6-bromo, B is a direct bond, -CH2-, or -C3H7- and R3 is hydrogen or amino then R4 cannot be hydrogen; when A is -NHC(O)- and is linked on the 3-position of the carbazole ring, R, is hydrogen, R2 is hydrogen or 6-methoxy, B is a direct bond, -CH2- or -CH(CH3)-, R3 is hydrogen, halo, phenyl or phenoxy, then R4 cannot be hydrogen or nitro; when A is -NHC(O)- and is linked on the 3-position of the carbazole ring, R, is ethyl, R2 is hydrogen, B is a direct bond, R3 is amino, 2-(2-carboxyphenyl)phenyl, 4,5,6,7-tetrahydro-lH-Benzimidazol-5-yl, or 6-methyl-4-mercapto-2-hydroxy-pyrimidin-5-yl, then R4 cannot be hydrogen; and when A is -NHC(O)- and is linked on the 3 position of the carbazole ring, R, is acetyl, benzoyl, carboxymethyl or carboxyethyl, R2 is hydrogen, B is -CH2-, R3 is hydrogen, bromo or iodo, then R4 cannot hydrogen or nitro.
According to a further fifth feature of the invention there is provided the use of a compound of formula (la) (as depicted above), or a pharmaceutically acceptable salt, prodrug or solvate thereof, for use in medical therapy, wherein: R, is selected from hydrogen, C,.6alkyl, C,.4alkoxyC,.4alkyl, C,.6alkanoyl,
C,.4alkanoylC,.4alkyl, aryl, arylCMalkyl, arylC,.4alkoxyC,.4alkyl, arylC,.4alkanoyl, arylcarbonyl, heteroaryl, heteroarylC,.4alkyl, heteroarylC,.4alkoxyC,.4alkyl, heteroarylC,.4alkanoyl, heteroarylcarbonyl, heterocyclyl, heterocyclylC ,.4alkyl, heterocyclylC,.4alkoxyC,.4alkyl, heterocyclylC,.4alkanoyl, heterocyclylcarbonyl, carbocyclyl, carbocyclylC,.4alkyl, carbocyclylC,.4alkoxyC,.4alkyl, carbocyclylC,.4alkanoyl, carbocyclylcarbonyl, C,.4alkylsulphonyl, NN-di-C, .4alkylammosulphonyl or
N-C,.4alkylaminosulphonyl wherein R, may be optionally substituted (on an available carbon atom) by up to three substituents independently selected from: C,.4alkyl optionally substituted by upto three fluoro substituents, C,.4alkoxy, C,.4alkanoyl, carboxy, hydroxy, halo, cyano, amino, N-C,.4alkylamino, NN-di-C, .4alkylamino, C,.4alkanoylamino, mercapto, C,.4alkylsulphonyl, C,.4alkylsulphinyl, C,.4alkylsulphanyl, nitro, heteroarylC,.4alkanoylamino, or CMalkoxycarbonyl;
A is selected from, -ΝH-, -CH2NH-, -NHC(O)-, -CH2NHC(O)-, -C(O)NH-, -NHC(O)NH-, -NHC(O)O-, -NHS(O2)-, or a direct bond; wherein each nitrogen atom is optionally substituted with C,.4alkyl or hydroxyC2.4alkyl; B is C,.,0alkylene, C2.,0alkenylene, C2.,0alkynylene, or a direct bond wherein the alkylene, alkenylene and alkynylene chains are optionally substituted by hydroxy, C,.4alkoxy or amino;
R3 is hydrogen, hydroxy, C,.6alkoxy, C,.6alkanoyl, C,.6alkanoyloxy, C,.6alkanoylamino, C,.6alkoxycarbonyl, C,.4alkoxycarbonylamino; aryl, aryloxy, arylcarbonyl, arylC,_4alkyl; arylC,.4alkoxy, arylC,.4alkanoyl, aryloxycarbonyl, arylCMalkoxycarbonyl, arylamino, heteroaryl, heteroaryloxy, heteroarylC,.4alkoxy, heteroarylcarbonyl, heteroarylC,.4alkanoyl, heteroaryloxycarbonyl, heteroarylC,.4alkoxycarbonyl, heterocyclyl, heterocyclyloxy, heterocyclylC ,.4alkoxy, heterocyclylcarbonyl, heterocyclylC ,.4alkanoyl, heterocyclyloxycarbonyl, heterocyclylC ,.4alkoxycarbonyl, carbocyclyl, carbocyclyloxy, carbocyclylC, ^alkoxy, carbocyclylcarbonyl, carbocyclylC,.4alkanoyl, carbocyclyloxycarbonyl, carbocyclylC, .4alkoxycarbonyl, cyano, carbamoyl, ureido, amino, N-C,.4alkylamino, NN-di-C, .4alkylamino, C,.4alkoxycarbonylamino, aminocarbonyl, N-C,.4alkylaminocarbonyl, NN-di-C, .4alkylaminocarbonyl, C,.4alkylthio, trifluoromethyl or fluoro wherein R3 may be optionally substituted by up to three substituents independently selected from C,.4alkyl, hydroxyC,.4alkyl, C,.4alkoxy, C,.ftalkoxycarbonyl,
C,.6alkenyloxycarbonyl, C,.4alkanoyl, C,.4alkanoylamino, C,.4alkanoylthio, oxo, carboxy, hydroxy, halo, cyano, amino, N-CMalkylamino, NN-di-C,.4alkylamino, N-C , .4alkylaminoC , ^alkyl, N N-di-C , .4alky laminoC , .4alky 1 , aminocarbonyl, N-C,.4alkylaminocarbonyl, NN-di-C|.4alkylaminocarbonyl, mercapto, C,.4alkylsulphonyl, C,.4alkylsulphinyl, C,.4alkylsulphanyl, nitro, trifluoromethyl, trifTuoromethylC,_4alkyl, aryl,
arylC,.4alkyl, aryloxyC,.4alkyl, C,.4alkoxyphenyl, heteroaryl, heteroarylC,.4alkyl, heterocyclylcarbonyl, or aminosulphonylphenyl; and
R4 is hydrogen, C,.4alkyl, halo or nitro; or a pharmaceutically acceptable salt, prodrug or solvate thereof; with the proviso that when A is -NHC(O)- and is linked on the 2-position of the carbazole ring, R, is hydrogen, methyl or 3-(4-methylpiperazin-l-yl)propyl, R2 is hydrogen or 6-bromo, B is a direct bond, -CH2-, or -C3H7- and R3 is hydrogen or amino then R4 cannot be hydrogen; when A is -NHC(O)- and is linked on the 3-position of the carbazole ring, R, is hydrogen, R2 is hydrogen or 6-methoxy, B is a direct bond, -CH2- or -CHCH,)-, R3 is hydrogen, halo, phenyl or phenoxy, then R4 cannot be hydrogen or nitro; when A is -NHC(O)- and is linked on the 3-position of the carbazole ring, R, is ethyl, R2 is hydrogen, B is a direct bond, R3 is amino, 2-(2-carboxyphenyl)phenyl, 4,5,6, 7-tetrahydro-lH-Benzimidazol-5-yl, or 6-methyl-4-mercapto-2-hydroxy-pyrimidin-5-yl, then R4 cannot be hydrogen; and when A is -NHC(O)- and is linked on the 3 position of the carbazole ring, R, is acetyl, benzoyl, carboxymethyl or carboxyethyl, R2 is hydrogen, B is -CH2-, R3 is hydrogen, bromo or iodo, then R4 cannot hydrogen or nitro.
According an alternative fifth feature of the invention there is provided the use of a compound of formula (la'), or a pharmaceutically acceptable salt, prodrug or solvate thereof, for use in medical therapy:
(la1) wherein:
R, is selected from hydrogen, C,.6alkyl, C,.4alkoxyC,.4alkyl, C,.6alkanoyl, C,_4alkanoylC,.4alkyl, aryl, arylC,.4alkyl, arylC,.4alkoxyC,.4alkyl, arylC,.4alkanoyl, arylcarbonyl, heteroaryl, heteroarylC,.4alkyl, heteroarylC,.4alkoxyC,_4alkyl, heteroarylC,.4alkanoyl, heteroarylcarbonyl, heterocyclyl, heterocyclylC, .4alkyl, heterocyclylC,.4alkoxyC,.4alkyl, heterocyclylC ,.4alkanoyl, heterocyclylcarbonyl, carbocyclyl, carbocyclylC ,.4alkyl, carbocyclylC , .4alkoxyC , _4alkyl, carbocyclylC , _4alkanoyl,
carbocyclylcarbonyl, cyanoC,.4alkyl, aminoC,.4alkyl, N-C,.4alkylaminoC,.4alkyl, or /V,N-di-C,.4alkylaminoC,.4alkyl; wherein R, may be optionally substituted (on an available carbon atom) by up to three substituents independently selected from: C,.4alkyl, C,.4alkoxy, C,.4alkanoyl, carboxy, hydroxy, halo, cyano, amino, N-C,.4alkylamino, NN-di-C, _4alkylamino, C,.4alkanoylamino, mercapto, C,.4alkylsulphonyl, C,.4alkylsulphinyl, C,.4alkylsulphanyl, nitro, trifluoromethyl-CMalkyl, heteroarylC,.4alkanoylamino, or C,.4alkoxycarbonyl;
R2 is selected from hydrogen, C,.4alkyl, C,.4alkoxy, cyano, nitro, halo, amino, N-C,.4alkylamino, or NN-di-C ,.4alkylamino;
A is selected from -ΝHC(O)-, -NHC(O)NH-, or -NHC(O)O- wherein each nitrogen atom is optionally substituted with C,.4alkyl;
B is C,.6alkylene, C2.6alkenylene, C2.6alkynylene, or a direct bond; R3 is hydrogen, C,.6alkoxy, C,.6alkanoyl, C,.6alkoxycarbonyl, aryl, aryloxy, arylC,.4alkoxy, arylcarbonyl, aryl,.4alkanoyl, aryloxycarbonyl, arylC^alkoxycarbonyl, heteroaryl, heteroaryloxy, heteroarylC,.4alkoxy, heteroarylcarbonyl, heteroarylC,.4alkanoyl, heteroaryloxycarbonyl, heteroaryl-C,.4alkoxycarbonyl, heterocyclyl, heterocyclyloxy, heterocyclylC,.4 alkoxy, heterocyclylcarbonyl, heterocyclylC,.4alkanoyl, heterocyclyloxycarbonyl, heterocyclylC, .4alkoxycarbonyl, carbocyclyl, carbocyclyloxy, carbocyclylC,.4alkoxy, carbocyclylcarbonyl, carbocyclylC,.4alkanoyl, carbocyclyloxycarbonyl, carbocyclylC, _4alkoxycarbonyl, amino, N-C,.4alkylamino, NN-di-C, .4alkylamino, C,.4alkyl)thio, or fluoro wherein R3 may be optionally substituted (on an available carbon atom) by up to three substituents independently selected from C,.4alkyl, C,.4alkoxy, C,.4alkanoyl, carboxy, hydroxy, halo, cyano, amino, N-C,_4alkylamino, NN-di-C, _4alkylamino, C alkanoylamino, mercapto, C,.4alkylsulphonyl, C,.4alkylsulphinyl, CMalkylsulphanyl, nitro, trifluoromethylC,.4alkyl, phenyl, C,.4alkoxyphenyl, heteroaryl, heteroarylC,.4alkyl, aminosulphonylphenyl or C,_4alkoxycarbonyl; and R4 is hydrogen, C,.4alkyl, or nitro; with the proviso that when A is -ΝHC(O)- and is linked on the 2-position of the carbazole ring, R, is hydrogen, methyl or 3 -(4-methy lpiperazin-l-yl)propyl, R2 is hydrogen or 6-bromo, B is a direct bond, -CH2-, or -C3H7- and R3 is hydrogen or amino then R4 cannot be hydrogen; when A is -NHC(O)- and is linked on the 3-position of the carbazole ring, R, is hydrogen, R2 is hydrogen or 6-methoxy, B is a direct bond, -CH2- or -CHCH3)-, R3 is hydrogen, halo,
phenyl or phenoxy, then R4 cannot be hydrogen or nitro; when A is -NHC(O)- and is linked on the 3-position of the carbazole ring, R, is ethyl, R2 is hydrogen, B is a direct bond, R3 is amino, 2-(2-carboxyphenyl)phenyl, 4,5,6,7-tetrahydro-lH-Benzimidazol-5-yl, or 6-methyl-4-mercapto-2-hydroxy-pyrimidin-5-yl, then R4 cannot be hydrogen; and when A is -NHC(O)- and is linked on the 3 position of the carbazole ring, R, is acetyl, benzoyl, carboxymethyl or carboxyethyl, R2 is hydrogen, B is -CH2-, R3 is hydrogen, bromo or iodo, then R4 cannot hydrogen or nitro.
A preferred group of values for the substituents described within each feature of the invention described herein, are: R, is C^alkyl, C,.4alkanoyl, arylC,.4alkanoyl, heteroarylC,.4alkanoyl,
C,.4alkyl sulphonyl, N-CMalkylaminosulphonyl, or NN-C,.4alkylaminosulphonyl, optionally substituted as above;
R2 is hydrogen, hydroxyCMalkyl or halo;
A is -ΝH-C(O)-O-; B is C,.6alkylene or C2.6alkenylene, optionally substituted as above;
R3 is hydrogen, C,.6alkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, or heterocyclyloxy, optionally substituted as above; and
R4 is hydrogen.
A further preferred group of values for the substituents described in the first feature of the invention described herein, are:
R, is C,.4alkyl, C,.4alkanoyl , arylC,.4alkanoyl, heteroarylC,.4alkanoyl, C,.4alkylsulphonyl, N-C alkylaminosulphonyl, or NN-C,.4alkylaminosulphonyl, optionally substituted as above;
R2 is hydrogen, hydroxyC,.4alkyl or halo; A is -ΝH-C(O)-ΝH-, or -NH-C(O)-N(C,.4alkyl)-;
B is C,.6alkylene or C2.6alkenylene, optionally substituted as above;
R3 is hydrogen, C,.6alkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, or heterocyclyloxy, optionally substituted as above; and
R4 is hydrogen. A further preferred group of values for the substituents described in the first feature of the invention described herein, are:
R, is C,.4alkyl, C,.4 alkanoyl , arylC,.4alkanoyl, heteroarylC|.4alkanoyl, C,.4alkylsulphonyl, N-C,.4alkylaminosulphonyl, or N,N-C,.4alkylaminosulphonyl, optionally substituted as above;
R2 is hydrogen, hydroxyC,.4alkyl or halo; A is -ΝH-C(O)-;
B is C,.6alkylene or C2.6alkenylene, optionally substituted as above; R3 is hydrogen, C,.6alkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, or heterocyclyloxy, optionally substituted as above; and R4 is hydrogen. A more preferred group of values for the substituents described the first feature of the invention described herein, are:
R, is C,.4alkylsulphonyl, N-Cι_4alkylaminosulphonyl, or NN-C,.4alkylaminosulphonyl; R2 is hydrogen, hydroxyC,.4alkyl or halo;
A is -ΝH-C(O)-, -NH-C(O)-O-, -NH-C(O)-NH-, or -NH-C(O)-N(C,.4alkyl)-; B is C,_6alkylene or C2.6alkenylene, optionally substituted as above;
R3 is hydrogen, alkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, or heterocyclyloxy; optionally substituted as above; and R4 is hydrogen.
A further preferred group of values for the substituents described in the first feature of the invention described herein, are:
R, is C,.4alkyl, C,.4alkanoyl , arylC,.4alkanoyl, or heteroarylC,.4alkanoyl, C,.4alkyl sulphonyl, N-C,.4alkylaminosulphonyl, or NN-Cl.4alkylaminosulphonyl optionally substituted as above;
R2 is hydrogen, hydroxyC,.4alkyl or halo; A is -ΝH-C(O)-, -NH-C(O)-O-, -NH-C(O)-NH-, or -NH-C(O)-N(C,.4alkyl)-;
B is C,.
6alkylene or C
2.
6alkenylene, optionally substituted as above; R
3 is moφholino, pyridin-4-yl, pyrrolidinon-1-yl, N-methylpiperidin-4-yl, .triazol-1-yl or imidazol-1-yl. optionally substituted as above; and R
4 is hydrogen. According to the sixth feature of the invention there is a compound of formula (lb):
(lb) wherein:
R,b is selected from hydrogen, C,.6alkyl, C,.4alkoxyC,.4alkyl, C,.6alkanoyl, C,.4alkanoylC,.4alkyl, aryl, arylC,.4alkyl, arylC,.4alkoxyC,.4alkyl, arylC,_4 alkanoyl, arylcarbonyl, heteroaryl, heteroarylC,.4 alkyl, heteroarylC,.4alkoxyC,.4alkyl, heteroarylC,.4alkanoyl, heteroarylcarbonyl, heterocyclyl, heterocyclylC, _4alkyl, heterocyclylC, .4alkoxyC,.4alkyl, heterocyclylC ,.4alkanoyl, heterocyclylcarbonyl, carbocyclyl, carbocyclylC,.4alkyl, carbocyclylC, _4alkoxyC,.4alkyl, carbocyclylC ,.4alkanoyl, carbocyclylcarbonyl, C,.4alkylsulphonyl, NN-di-C, .4alkylaminosulphonyl or
N-C,.4alkylaminosulphonyl wherein R,b may be optionally substituted (on an available carbon atom) by up to three substituents independently selected from C,.4alkyl optionally substituted by up to three fluoro substituents, C,.4alkoxy, C,.4alkanoyl, carboxy, hydroxy, halo, cyano, amino, N-C,.4alkylamino, NN-di-C, _4alkylamino, C,.4alkanoylamino, mercapto, C,.4alkylsulphonyl, CMalkylsulphinyl, C,.4alkylsulphanyl, nitro, heteroarylC,.4alkanoylamino, or C,.4alkoxycarbonyl;
R2b is selected from hydrogen, C,.4alkyl (optionally substituted by hydroxy), C,.4alkoxy, cyano, nitro, halo, amino, N-C,.4alkylamino, or NN-di-C,.4alkylamino; R4b is selected from hydrogen, C,.4alkyl, halo or nitro; Rj,, is selected from C,.4alkyl, hydroxyC,.4alkyl, C,.4alkoxy, C,.6alkoxycarbonyl,
C2.6alkenyloxycarbonyl, C,.4alkanoyl, C,.4alkanoylamino, C,.4alkanoylthio, oxo, carboxy, hydroxy, halo, cyano, amino, N-C,.4alkylamino, NN-di-C, _4alkylamino, N-C,.4alkylaminoC,.4alkyl, NN-di-Cι.4alkylaminoC,.4alkyl, carbamoyl, N-C,.4alkylcarbamoyl, NN-di-C,.4alkylcarbamoyl, mercapto, C,.4alkylsulphonyl, C,.4alkylsulphinyl, C,.4alkylsulphanyl, Cι.4alkylsulphonyloxyC,.4alkyl, nitro, trifluoromethyl, trifluoromethylC,.4alkyl, C,.6alkoxycarbonylamino, C,.6alkoxycarbonyl(N-C,.4alkyl)amino, aryl (optionally substituted by one C,.4alkoxy or sulphamoyl), arylC,.4alkyl, aryloxyC,.4alkyl, arylcarbonyl, heteroaryl, heteroarylC,.4alkyl, heteroaryloxyC,.4alkyl, heteroarylcarbonyl,
heterocyclyl, heterocyclylC Malkyl, heterocyclyloxyC,.4alkyl, heterocyclylcarbonyl, carbocyclyl, carbocyclylC, .4alkyl, carbocyclyloxyC,.4alkyl or carbocyclylcarbonyl; and n is 0-3; wherein the values of R5b may be the same or different; or a pharmaceutically acceptable salt, prodrug or solvate thereof. Preferably R,b is selected from C,.6alkyl optionally substituted by up to three halo substituents.
More preferably R,b is selected from C,.3alkyl optionally substituted by up to three halo substituents.
Particularly R,b is selected from ethyl, isopropyl and 2,2,2-trifluoroethyl. More particularly R,b is isopropyl.
Preferably R2b is hydrogen.
Preferably R4b is hydrogen.
Preferably R5b is selected from C,.4alkyl, halo, cyano, carbamoyl, trifluoromethyl or heteroaryl. More preferably R5b is selected from methyl, halo, cyano, carbamoyl, trifluoromethyl or pyridyl.
Particularly R5b is selected from methyl, halo, cyano, carbamoyl, trifluoromethyl or pyrid-4-yl.
More particularly R5b is carbamoyl. Preferably n is i.
Preferred compounds of formula (lb) are: 9-ethyl-3-(6-methylpyridazin-3-ylamino)carbazole; 9-isopropyl-3-(6-methylpyridazin-3-ylamino)carbazole; 9-ethyl-3-(6-carbamoylpyridazin-3-ylamino)carbazole; 9-(2,2,2-trifluoroethyl)-3-(6-methylpyridazin-3-ylamino)carbazole; 9-(2,2,2-trifluoroethyl)-3-(6-carbamoylpyridazin-3-ylamino)carbazole; 9-isopropyl-3-(6-carbamoylpyridazin-3-ylamino)carbazole; 9-ethyl-3-(6-trifluoromethylpyridazin-3-ylamino)carbazole; 9-ethyl-3-[6-(pyrid-4-yl)pyridazin-3-ylamino]carbazole; and 9-ethyl-3-(6-cyanopyridazin-3-ylamino)carbazole; or a pharmaceutically acceptable salt, prodrug or solvate thereof.
According to a further aspect of the invention there is provided the use of a compound of formula (lb), or a pharmaceutically acceptable salt, prodrug or solvate thereof, as a medicament.
According to a further aspect of the invention there is provided a pharmaceutical composition comprising a compound of formula (lb), or a pharmaceutically acceptable salt, prodrug or solvate thereof, in admixture with a pharmaceutically-acceptable diluent or carrier.
According to a further aspect of the invention there is provided a pharmaceutical composition comprising a compound of formula (lb), or a pharmaceutically acceptable salt, prodrug or solvate thereof, in admixture with a pharmaceutically-acceptable diluent or carrier for the treatment of a warm-blooded animal, in need of treatment of disorders mediated by the neuropeptide Y5 receptor.
According to a further aspect of the invention there is provided a pharmaceutical composition comprising a compound of formula (lb), or a pharmaceutically acceptable salt, prodrug or solvate thereof, in admixture with a pharmaceutically-acceptable diluent or carrier for the treatment of eating disorders in a warm-blooded animal, in need of treatment.
According a further aspect of the invention there is provided the use of a compound of formula (lb) in the manufacture of a medicament for the treatment, in a warm-blooded animal, of disorders mediated by the neuropeptide Y5 receptor or a pharmaceutically acceptable salt, prodrug or solvate thereof. According to a further aspect of the invention there is provided the use of a compound of formula (lb) or a pharmaceutically acceptable salt, prodrug or solvate thereof in the manufacture of a medicament for the treatment of eating disorders in a warm-blooded animal.
According to a further aspect of the invention there is provided a method of treatment, in a warm-blooded animal, of disorders mediated by the neuropeptide Y5 receptor comprising administering a therapeutically effective amount of a compound of formula (lb) or a pharmaceutically acceptable salt, prodrug or solvate thereof.
According to a further aspect of the invention there is provided a method of treatment, in a warm-blooded animal, of eating disorders, comprising administering a therapeutically effective amount of a compound of formula (lb) or a pharmaceutically acceptable salt, prodrug or solvate thereof.
According to another feature of the invention there is provided the use of a compound of formula (lb), or a pharmaceutically acceptable salt, prodrug or solvate thereof, in the manufacture of a medicament for promoting weight loss.
According to a further aspect of the first feature of the invention there is provided a method of promoting weight loss, comprising administering a therapeutically effective amount of a compound of formula (lb), or a pharmaceutically acceptable salt, prodrug or solvate thereof.
According to a further aspect of the invention there is provided a pharmaceutical composition comprising a compound of formula (lb), or a pharmaceutically acceptable salt, prodrug or solvate thereof, in admixture with a pharmaceutically acceptable diluent or carrier for use in promoting weight loss.
According to the seventh feature of the invention there is provided a compound of the formula (Ic):
R,c is selected from C,.6alkyl, C,.4alkoxyCl.4alkyl, C,.4alkanoylC,.4alkyl, aryl, arylC alkyl, arylC,.4alkoxyC,.4alkyl, heteroaryl, heteroarylC,.4alkyl, heteroarylC,.4alkoxyC,.4alkyl, heterocyclyl, heterocyclylC, .4alkyl, heterocyclylC,.4alkoxyC,.4alkyl, carbocyclyl, carbocyclylC,.4alkyl, carbocyclylC, .4alkoxyC,.4alkyl, C,.4alkylsulphonyl, NN-di-C,.4alkylaminosulphonyl or N-C,.4alkylaminosulphonyl wherein R,c may be optionally substituted (on an available carbon atom) by up to three substituents independently selected from: C,.4 alkyl optionally substituted by up to three fluoro substituents, C,.4alkoxy, C,.4alkanoyl, carboxy, hydroxy, halo, cyano, amino, N-C,.4alkylamino, NN-di-C, .4alkylamino, C,.4alkanoylamino, mercapto,
C,.4alkylsulphonyl, C,.4alkylsulphinyl, C,.4alkylsulphanyl, nitro, heteroarylC,.4alkanoylamino, or C,.4alkoxycarbonyl;
R2c is selected from hydrogen, C,.4alkyl (optionally substituted by hydroxy), C,.4alkoxy, cyano, nitro, halo, amino, N-C,.4alkylamino, or NN-di-C,.4 alkyl amino;
Xc is a nitrogen linked heteroring optionally substituted by up to three substituents independently selected from Group Ac; or Xc is -Ν(LC)-Bc-R3c; Lc is selected from hydrogen, C,.4alkyl or hydroxyC2.4 alkyl;
Bc is selected from C,.,„alkylene, C2.,0alkenylene, C2.,0alkynylene, or a direct bond wherein the alkylene, alkenylene and alkynylene chains are optionally substituted by hydroxy, C,.4alkoxy or amino;
R3c is selected from hydrogen, hydroxy, C,.6alkoxy, C,.6alkanoyl, C,.6alkanoyloxy, C,_6alkanoylamino, C,.6alkoxycarbonyl, C,.4alkoxycarbonylamino; aryl, aryloxy, arylcarbonyl, arylC,.4alkyl, arylCM lkoxy, arylC,.4alkanoyl, aryloxycarbonyl, arylC,.4alkoxycarbonyl, arylamino, diarylamino, arylsulphonyl, heteroaryl, heteroaryloxy, heteroarylC,.4alkoxy, heteroarylcarbonyl, heteroarylC,.4alkanoyl, heteroaryloxycarbonyl, heteroarylC,.4alkoxycarbonyl, heteroarylC,.4alkyl, heteroarylamino, diheteroarylamino, heteroarylsulphonyl, heterocyclyl, heterocyclyloxy, heterocyclylC ,.4alkoxy, heterocyclylcarbonyl, heterocyclylC, .4alkanoyl, heterocyclyloxycarbonyl, heterocyclylC , .4alkoxycarbonyl, heterocyclylC , .4alkyl , heterocyclylamino, diheterocyclylamino, heterocyclylsulphonyl, carbocyclyl, carbocyclyloxy, carbocyclylC, .4alkoxy, carbocyclylcarbonyl, carbocyclylC,.4alkanoyl, carbocyclyloxycarbonyl, carbocyclylC,.4alkoxycarbonyl, carbocyclylC,.4 alkyl, carbocyclylamino, carbocyclylamino, carbocyclylsulphonyl, cyano, carbamoyl, ureido, amino, N-C,.4alkylamino, NN-di-C, .4alkylamino, carbamoyl, N-C,.4alkylcarbamoyl, NN-di-C,.4alkylcarbamoyl, C,.4alkylsulphanyl, C,.4alkylsulphinyl, C,.4alkylsulphonyl, trifluoromethyl or fluoro wherein R3c may be optionally substituted by up to three substituents independently selected from Group Ac;
R4c is selected from hydrogen, C,.4alkyl, halo or nitro; and Group Ac is C,.4alkyl, hydroxyC,.4alkyl, C,.4alkoxy, C,.6alkoxycarbonyl, C2.6alkenyloxycarbonyl, C,.4alkanoyl, C,.4alkanoyl amino, C,.4alkanoylthio, oxo, carboxy, hydroxy, halo, cyano, amino, N-CMalkylamino, NN-di-C,.4alkylamino, N-C,.4alkylaminoC,_4alkyl, NN-di-C, .4alkylaminoC,.4alkyl, carbamoyl, N-C,.4alkylcarbamoyl, NN-di-C, ,4alkylcarbamoyl, mercapto, C,.4alkylsulphonyl, C,.4alkylsulphinyl,
C,.4alkylsulphanyl, C,.4alkylsulphonyloxyC,.4alkyl, nitro, trifluoromethyl, trifluoromethylC , .4alkyl, C , ^alkoxycarbonylamino, C , _4alkoxycarbonyl(N-C , .4alkyl)amino, aryl (optionally substituted by one C,.4alkoxy or sulphamoyl), arylC,.4alkyl, aryloxyC,.4alkyl, arylcarbonyl, heteroaryl, heteroarylC,.4alkyl, heteroaryloxyC,.4alkyl, heteroarylcarbonyl, heterocyclyl, heterocyclylC, _4alkyl, heterocyclyloxyC,.4alkyl, heterocyclylcarbonyl, carbocyclyl, carbocyclylC,.4alkyl, carbocyclyloxyC,.4alkyl or carbocyclylcarbonyl; or a pharmaceutically acceptable salt, prodrug or solvate thereof; with the proviso that when R,c is ethyl, R2cand R4c are hydrogen and Xc is -Ν(LC)-Bc-R3c, -N(LC)-Bc-R3c is not 5-t-butyloxazol-3-ylamino, 3-methoxynaphtl-2-ylamino, 2-methoxy-5-t-butylaniline, 3-(diethylamino)propylamino, naphthylamino, hydrazino, 9-ethylcarbazol-3-ylamino, amino or benzoylamino.
Preferably R,c is selected from C,.6alkyl, C,.4alkylsulphonyl, N,N-di-C,.4alkylaminosulphonyl wherein R,c may be optionally (on an available carbon) substituted by up to three halo substituents. More preferably R,c is selected from C,.3alkyl, C,.2alkylsulphonyl,
NN-di-C,.2alkylaminosulphonyl wherein R,c may be optionally substituted (on an available carbon) by up to three halo substituents.
Particularly R,c is selected from ethyl, isopropyl, 2,2,2-trifluoroethyl, mesyl and NN-dimethylaminosulphonyl. More particularly R,c is selected from ethyl, isopropyl and mesyl.
Preferably R2c is selected from hydrogen, cyano or halo.
More preferably R2c is selected from hydrogen, cyano, fluoro or bromo.
Particularly R2c is hydrogen or fluoro.
More particularly R2c is hydrogen. In one aspect of the invention preferably Xc is a nitrogen linked heteroring optionally substituted by up to three substituents independently selected from Group Ac.
In another aspect of the invention, preferably Xc is -Ν(LC)-Bc-R3c.
When Xc is a nitrogen linked heteroring optionally substituted by up to three substituents independently selected from Group Ae preferably Xc is piperidin-1 -yl, moφholino, piperazin-1-yl, pyrrolidin-1-yl, optionally substituted by up to three substituents independently selected from C,.4alkyl, hydroxyC,.4alkyl, C,.6alkoxycarbonyl, carboxy,
N-C,.4alkylamino, NN-di-C,.4alkylaminoC,.4alkyl, carbamoyl, N-C,.4alkylcarbamoyl, NN-di-C, .4alkylcarbamoyl, C,.4alkylsulphonyloxyC,.4alkyl,
C,.4alkoxycarbonyl(N-Cl.4alkyl)amino, aryl, arylC,.4alkyl, aryloxyC,.4alkyl, heterocyclyl, heterocyclylC,.4alkyl, or heterocyclylcarbonyl. When Xc is a nitrogen linked heteroring optionally substituted by up to three substituents independently selected from Group Ac more preferably Xc is piperidin-1 -yl, moφholino, piperazin-1-yl, pyrrolidin-1-yl, optionally substituted by one or two substituents independently selected from methyl, hydroxymethyl, ethoxycarbonyl, carboxy, methylamino, NN-dimethylaminomethyl, carbamoyl, N-methylcarbamoyl, π-butylcarbamoyl, NN-dimethylcarbamoyl, mesyloxymethyl, t-butoxycarbonyl(N-methyl)amino, phenyl, benzyl, phenoxymethyl, phenoxyethyl, pyrrolidin-1-yl, piperidin-1 -yl, pyrrolidin-1 -ylmethyl or moφholinocarbonyl.
When Xc is a nitrogen linked heteroring optionally substituted by up to three substituents independently selected from Group Ac particularly Xc is piperidin-1 -yl, moφholino, 4-methylpiperazin-l-yl, 3-methyl-2-phenylmoφholino, 4-benzylpiperazin-l-yl, 2-pyrrolidin- 1 -ylmethylpyrrohdin- 1 -yl, pyrrolidin- 1 -ylpiperidin- 1 -yl, 4-ethoxycarbonylpiperidin- 1 -yl, 4-hydroxymethylpiperidin- 1 -yl, 4-carboxypiperidin- 1 -yl, 4-mesyloxymethylpiperidin-l-yl, 4-NN-dimethylaminomethylpiperidin-l-yl, 4-phenoxymethylpiperidin- 1 -yl, 4-N-methylcarbamoylpiperidin- 1 -yl, 4-N,N-dimethylcarbamoylpiperidin-l-yl, 4-n-butylcarbamoylpiperidin-l-yl, 4-moφholinocarbonylpiperidin-l-yl, 3-phenoxyethylpyrrolidin-l-yl, 3-carbamoylpiperidin-l-yl, 4-piperidin- 1 -ylpiperidin- 1 -yl,
3-t-butoxycarbonyl(N-methyl)aminopyrrolidin- 1 -yl, 3-N-methylaminopyrrolidin- 1 -yl and 2,6-dimethylmoφholino. When Xc is -Ν(LC)-Bc-R3c, preferably Xc is propylamino, NN-diethylamino,
NN-dimethylamino, pyrid-4-ylmethylamino, N-pyrid-4-ylmethyl-N-ethylamino, 4-methoxyanilino, benzylamino, N-methyl-N-benzylamino, N-ethylanilino, N-(3-hydroxypropyl)-N-pyrid-4-ylmethylamino, N-methyl-N-phenethylamino, N-methyl-N-pyrid-4-ylethylamino, N-(2-NN-dimethylaminoethyl)-N-methylamino, N-(3-NN-dimethylaminopropyl)-N-methylamino, anilino, 4-fluoroanilino, phenoxyethylamino, N-methylanilino, N-methyl-N-pyrid-2-ylethylamino,
moφholinoethylamino, N-ethyl-N-phenoxyethylamino, N-methyl-N-moφholinopropylamino,
N-methyl-N-moφholinoethylamino, acetamidoethylamino, methylthioethylamino, imidazol- 1 -ylpropylamino, 4-hydroxycyclohexylamino, 3,5,5-trimethylcyclohexylamino,
1 -ethylpyrrolidin-2-ylmethylamino, fur-2-ylmethylamino, tetrahydrofur-2-ylmethylamino, moφholinopropylamino, pyrid-2-ylmethylamino, pyrid-2-ylethylamino,
N-methyl-N-pyrid-2-ylmethylamino, 1 -benzylpiperidin-4-ylamino, 1 -phenyleth- 1 -ylamino,
2-propynylamino, allylamino, 3-NN-diethylaminopropylamino, 1,1-di-i-butylmethylamino,
N-methyl-N-(2-NN-diethylaminoethyl)amino,
2-phenoxy-l-methylethylaminoindan-2-ylamino, 4-(l,2,3-thiaziazol-4-yl)benzylamino, N-methyl-N-(l-methylpiperidin-4-yl)amino, 2-fluoro-4-trifluoromethylbenzylamino,
1 -methylpyrrolidin-2-ylethylamino, 5-methylfur-2-ylmethylamino,
N-(4-NN-dimethylaminophenethyl)-N-methylamino, N-methyl-N-pyrid-4-ylethylamino,
2-anilino- 1 , 1 -dimethylethylamino, 2-anilinoethylamino, benzthiazol-2-ylamino,
2-oxohomoρiperidin-3 -ylamino, 4-bromobenzoylmethylamino, benzimidazol-2-ylmethylamino, oxazol-3 -ylamino, 2-fluoro-4-chlorobenzylamino,
N-(3-N-methylaminopropyl)-N-methylamino and 9-ethylcarbazol-3-ylamino. Preferably Xc is N-(2-NN-dimethylaminoethyl)-N-methylamino,
N-(3-N,N-dimethylaminopropyl)-N-methylamino, N-methyl-N-pyrid-2-ylethylamino, acetamidoethylamino, 1 -phenyleth- 1 -ylamino, 1 -methylpyrrolidin-2-ylethylamino, N-methyl-N-pyrid-4-ylethylamino, 4-NN-dimethylaminomethylpiperidin- 1 -yl,
4-moφholinocarbonylpiperidin-l-yl or moφholino. Preferably R4c is hydrogen. Preferred compounds of formula (Ic) are:
9-ethyl-3-[N'-methyl-N'-(2-NN-dimethylaminoethyl)ureido]carbazole; 9-ethyl-3-[N'-methyl-N'-(3-NN-dimethylaminopropyl)ureido]carbazole;
9-ethyl-3-[N'-methyl-N'-(2-pyrid-2-ylethyl)ureido]carbazole;
9-ethyl-3-[N'-(2-acetamidoethyl)ureido]carbazole;
9-ethyl-3-[N'-(l-methyl-l-phenylmethyll)ureido]carbazole;
9-ethyl-3-{N'-[2-(l-methylpyrrolidin-2-yl)ethyl]urei do} carbazole; 9-mesyl-3-[N'-methyl-N'-(2-pyrid-4-ylethyl)ureido]carbazole;
9-ethyl-3-[4-(NN-dimethylaminomethyl)piperidin-l-ylcarbonylamino]carbazole;
9-ethyl-3-[4-(moφholinocarbonyl)piperidin-l-ylcarbonylamino]carbazole;
9-isopropyl-3-(moφholinocarbonylamino)carbazole;
6-fluoro-9-isopropyl-3-(moφholinocarbonylamino)carbazole; or a pharmaceutically acceptable salt, prodrug or solvate thereof. According to a further aspect of the invention there is provided the use of a compound of formula (Ic), or a pharmaceutically acceptable salt, prodrug or solvate thereof, as a medicament.
According to a further aspect of the invention there is provided a pharmaceutical composition comprising a compound of formula (Ic), or a pharmaceutically acceptable salt, prodrug or solvate thereof, in admixture with a pharmaceutically-acceptable diluent or carrier. According to a further aspect of the invention there is provided a pharmaceutical composition comprising a compound of formula (Ic), or a pharmaceutically acceptable salt, prodrug or solvate thereof, in admixture with a pharmaceutically-acceptable diluent or carrier for the treatment of a warm-blooded animal, in need of treatment of disorders mediated by the neuropeptide Y5 receptor.
According to a further aspect of the invention there is provided a pharmaceutical composition comprising a compound of formula (Ic), or a pharmaceutically acceptable salt, prodrug or solvate thereof, in admixture with a pharmaceutically-acceptable diluent or carrier for the treatment of eating disorders in a warm-blooded animal, in need of treatment. According a further aspect of the invention there is provided the use of a compound of formula (Ic) in the manufacture of a medicament for the treatment, in a warm-blooded animal, of disorders mediated by the neuropeptide Y5 receptor or a pharmaceutically acceptable salt, prodrug or solvate thereof.
According to a further aspect of the invention there is provided the use of a compound of formula (Ic) or a pharmaceutically acceptable salt, prodrug or solvate thereof in the manufacture of a medicament for the treatment of eating disorders in a warm-blooded animal. According to a further aspect of the invention there is provided a method of treatment, in a warm-blooded animal, of disorders mediated by the neuropeptide Y5 receptor comprising administering a therapeutically effective amount of a compound of formula (Ic) or a pharmaceutically acceptable salt, prodrug or solvate thereof.
According to a further aspect of the invention there is provided a method of treatment, in a warm-blooded animal, of eating disorders, comprising administering a therapeutically effective amount of a compound of formula (Ic) or a pharmaceutically acceptable salt, prodrug or solvate thereof. According to another feature of the invention there is provided the use of a compound of formula (Ic), or a pharmaceutically acceptable salt, prodrug or solvate thereof, in the manufacture of a medicament for promoting weight loss.
According to a further aspect of the first feature of the invention there is provided a method of promoting weight loss, comprising administering a therapeutically effective amount of a compound of formula (Ic), or a pharmaceutically acceptable salt, prodrug or solvate thereof.
According to a further aspect of the invention there is provided a pharmaceutical composition comprising a compound of formula (Ic), or a pharmaceutically acceptable salt, prodrug or solvate thereof, in admixture with a pharmaceutically acceptable diluent or carrier for use in promoting weight loss.
According to the eighth feature of the invention there is provided a compound of formula (Id):
R1U is selected from C,.6alkyl, C,.4alkoxyC,.4alkyl, C,.4alkanoylC,.4alkyl, aryl, arylC,.4alkyl, arylC,.4alkoxyC,.4alkyl, heteroaryl, heteroarylC,.4alkyl, heteroarylC,.4alkoxyC,.4alkyl, heterocyclyl, heterocyclylC ,.4alkyl, heterocyclylC, .4alkoxyC,.4alkyl, carbocyclyl, carbocyclylC,.4alkyl, carbocyclylC ,.4alkoxyC,.4alkyl, C,.4alkylsulphonyl, NN-di-C, _4alkylaminosulphonyl or
N-C,_4alkylaminosulphonyl wherein R,d may be optionally substituted (on an available carbon atom) by up to three substituents independently selected from: C,.4alkyl optionally substituted by up to three fluoro substituents, C,.4alkoxy, C,.4alkanoyl, carboxy, hydroxy, halo, cyano,
amino, N-C,.4alkylamino, NN-di-C,.4alkylamino, C,.4alkanoylamino, mercapto, C,.4alkylsulphonyl, C,.4alkylsulphinyl, C,.4alkylsulphanyl, nitro, heteroarylC,.4alkanoylamino, or C,.4alkoxycarbonyl;
R2ϋ is selected from hydrogen, C,.4alkyl (optionally substituted by hydroxy), C,.4alkoxy, cyano, nitro, halo, amino, N-C,.4alkylamino, or NN-di-C,.4alkylamino;
Bd is selected from C,.,0alkylene, C2.,0alkenylene, C2.,0alkynylene, or a direct bond wherein the alkylene, alkenylene and alkynylene chains are optionally substituted by hydroxy, C,.4alkoxy or amino;
R3d is selected from hydrogen, hydroxy, C,.6alkoxy, C,.fialkanoyl, C,.6alkanoyloxy, C,.6alkanoylamino, C,.6alkoxycarbonyl, aryl, aryloxy, arylcarbonyl, arylC,.4alkyl, arylC,.4alkoxy, arylC,.4alkanoyl, aryloxycarbonyl, arylC,.4 alkoxycarbonyl, arylamino, diarylamino, arylsulphonyl, heteroaryl, heteroaryloxy, heteroarylC,.4alkoxy, heteroarylcarbonyl, heteroarylC,.4 alkanoyl, heteroaryloxycarbonyl, heteroarylC,.4alkoxycarbonyl, heteroarylC,.4alkyl, heteroarylamino, heteroarylsulphonyl, diheteroarylamino, heterocyclyl, heterocyclyloxy, heterocyclylC, .4alkoxy, heterocyclylcarbonyl, heterocyclylC ,.4alkanoyl, heterocyclyloxycarbonyl, heterocyclylC,.4alkoxycarbonyl, heterocyclylC, .4alkyl, heterocyclylamino, diheterocyclylamino, heterocyclylsulphonyl, carbocyclyl, carbocyclyloxy, carbocyclylC,.4alkoxy, carbocyclylcarbonyl, carbocyclylC ,.4alkanoyl, carbocyclyloxycarbonyl, carbocyclylC ,.4alkoxycarbonyl, carbocyclylC,.4alkyl, carbocyclylamino, carbocyclylsulphonyl, dicarbocyclylamino, cyano, carbamoyl, ureido, amino, N-C,.4alkylamino, NN-di-C, .4alkylamino, C,.4alkoxycarbonylamino, carbamoyl, N-C,.4alkylcarbamoyl, NN-di-C,.4alkylcarbamoyl, C,.4alkylsulphanyl, C,_4alkylsulphinyl, C,.4alkylsulphonyl, trifluoromethyl or fluoro wherein R3d may be optionally substituted by up to three substituents independently selected from C,.4alkyl, hydroxyC,.4alkyl, C,.4alkoxy, C,.6alkoxycarbonyl, C2.6alkenyloxycarbonyl, C,.4alkanoyl, C,.4alkanoylamino, C,.4alkanoylthio, oxo, carboxy, hydroxy, halo, cyano, amino, N-C,.4alkylamino, NN-di-C, .4alkylamino, N-CMalkylaminoC,.4alkyl, NN-di-C,.4alkylaminoC,.4alkyl, carbamoyl, N-C,_4alkylcarbamoyl, NN-di-C, .4alkylcarbamoyl, mercapto, C,.4alkylsulphonyl, C,_4alkylsulphinyl, C,.4alkylsulphanyl, C,.4alkylsulphonyloxyC,.4alkyl, nitro, trifluoromethyl, trifluoromethylC,.4alkyl, C,.6alkoxycarbonylamino, C,.6alkoxycarbonyl(Ν-C|.4alkyl)amino,
aryl (optionally substituted by one C,.4alkoxy or sulphamoyl), arylC,.4alkyl, aryloxyC,.4alkyl, arylcarbonyl, heteroaryl, heteroarylC,.4alkyl, heteroaryloxyC,.4alkyl, heteroarylcarbonyl, heterocyclyl, heterocyclylC, ,4alkyl, heterocyclyloxyC,.4alkyl, heterocyclylcarbonyl, carbocyclyl, carbocyclylC ,.4alkyl, carbocyclyloxyC,_4alkyl or carbocyclylcarbonyl; and R4d is selected from hydrogen, C,.4alkyl, halo or nitro; wherein the group "-Bd-R3d" is linked to the carbonyl of the amide moiety via a carbon atom; or a pharmaceutically acceptable salt, prodrug or solvate thereof; with the provisos
1) if R2d and R4d are hydrogen: when R,d is ethyl, the group "-Bd-R3d" is not l-t-butoxycarbonyl-3-hydroxypyrrolidin-5-yl, l-t-butoxycarbonylpyrrolidin-5-yl, 1 -(4-t-butoxybenzoyl)pyrrolidin-5-yl, 1 -(benzo[b]fur-2-yl)pyrrolidin-5-yl, l-benzyl-3-t-butylpyrazol-5-yl, 2-propen-2-yl, 2-carboxyphenyl, l-(naphth-l-yl)ethylaminocarbonylmethyl, 4,5,6, 7-tetrahydrobenzimidazol-6-yl, 5-(benzyloxycarbonylamino)-l-aminopentyl, benztriazol-6-yl, 4-ureido-l-aminobutyl, phenyl, ethenyl, 2-carboxyethenyl or methyl; when Rld is methyl the group "-Bd-R3d" is not methyl, 3-hydroxynaphth-2-yl, 2-hydroxynaphth-l-yl or trifluoromethyl; when R,d is 2-cyanoethyl the group "-Bd-R3d" is not 3-hydroxynaphth-2-yl; and when R,d is 2-carboxyethyl, the group "-Bd-R3d" is not l-(t-butoxycarbonylamino)ethyl or methyl; and
2) when R2d is 6-amino, 6-methyl or 6-nitro, R4d is hydrogen and Rld is ethyl, the group "-Bd-R3d" is not methyl.
For the avoidance of doubt the statement "wherein the group "-Bd-R3d" is linked to the carbonyl of the amide moiety via a carbon atom" is to be inteφreted such that, for example, if R3d is C,.6alkoxy then B could not be a direct bond (in this example the group "-Bd-R3d" would then be linked to the carbonyl of the amide moiety via an oxygen atom). The same applies when R3d is other groups, for example arylamino and C,.4alkylsulphanyl.
Preferably Rld is C,.6alkyl, optionally substituted (on an available carbon atom) by up to three halo substituents.
More preferably R,d is selected from methyl, ethyl, w-propyl, /-propyl and 2,2,2-trifluoroethyl. In one aspect of the invention particularly Rld is /-propyl.
In another aspect of the invention particularly R,d is ethyl or 2,2,2-trifluoroethyl.
Preferably R2d is selected from hydrogen, C,.4alkyl (optionally substituted by hydroxy) or halo.
More preferably R2d is selected from hydrogen, hydroxymethyl or chloro. Particularly R2d is selected from hydrogen, 6-hydroxymethyl or 6-chloro. More particularly R2d is selected from hydrogen.
Preferably the group "-Bd-R3d" forms methyl, phenyl, ethoxycarbonyl, isopropyl, 4-methylphenoxymethyl, 2-pyrid-4-ylethyl, 2-pyrid-4-ylethenyl, 2-pyrid-4-yl- 1 -methylethenyl, 2-pyrid-4-yl- 1 -methylethyl, 2-[3-(2-methoxyphenyl)-l,2,4-oxadiazol-5-yl]ethyl, 1 -t-butoxycarbonylpiperid-4-yl, t-butoxycarbonylaminomethyl, aminomethyl, 4-methoxyphenethyl, 2-(l,3-benzodioxol-5-yl)ethyl, 2-(3-phenyl-l,2,4-oxadiazol-5-yl)ethyl, 3-(2-phenyl-l,3,4-oxadiazol-5-yl)propyl, 2-(3-benzyl-l,2,4-oxadiazol-5-yl)ethyl, 2 -methoxyphenethy 1, 3 -phenylpropy 1, 3 -(3 -pyri d-4-y 1- 1 ,2 ,4-oxadi azo 1- 5 -y l)propyl, 2-phenylcyclopropyl, 2-phenyl-l -methylethyl, 3 -methoxyphenethy 1, 4-fluorophenethyl, phenethyl, 3,4-dimethoxyphenethyl, 3,4,5-trimethoxyphenethyl,
3-(3-pyrid-2-yl-l ,2,4-oxadiazol-5-yl)propyl, 4-mesylphenethyl, 3-trifluorophenethyl, piperid-1-yl, 2-fur-2-ylethyl, methoxycarbonylmethyl, cyclohexyl, t-butyl, 1-methylbutyl, cyanomethyl, /-butyl, 2-oxopyrrolidin-5-yl, cyclobutyl, 2-carbamoylethyl, 1 -ethylpropyl, 2-oxotetrahydrofur-5-yl, 2-oxotetrahydrothiazol-4-yl, 1 -methyl- 1 -phenylmethyl, 2,2,2-trifluoroethyl, ureidomethyl, methoxycarbonylaminomethyl, 1,2,4-triazol-l -ylmethyl, l-methylpyrrolidin-2-yl, l-methylpiperid-4-yl, 2-oxopyrrolidin-l -ylmethyl, 2-methoxycarbonylethyl, 2,3-dihydropyran-2-yl, 1 -acetamidoethyl, NN-dimethylaminomethyl, 2-prop-2-enyl, tetrahydropyran-2-yl, 2-pyrid-3-ylethenyl, imidazol-4-yl, methoxyethyl, NN-dimethylcarbamoylethyl, pyrazol-4-yl, fur-2-ylmethyl, 5-methylisoxazol-3-yl, imidazol-1 -ylethyl, 4-cyanophenyl, NN-dimethylaminoethyl,
1 -hydroxy- 1 -methyl-2,2,2-trifluoroethyl, 1 -methyl- 1 -acetoxyethyl, 1 -methyl- 1 -hydroxyethyl, 1 -moφholinoprop-2-yl, thien-2-ylpropyl, 2-(3-bromoisoxazol-5-yι)ethyl, imidazol-4-ylethyl, 2-(pyrid-4-ylcarbonyl)ethyl, cyclopropyl, mesylmethyl, 1 -t-butoxycarbonylamino-2-methoxyethyl, 1 -methyl-2-(t-butoxycarbonylamino)ethyl, tetrazol- 1 -ylmethyl, l,2,5-thiadiazol-3-yl, thiazol-4-yl, 1,2,4-triazol-l -ylethyl, l,2,4-triazol-3-yl, fur-2-yl, thien-2-ylmethyl, 4-methylphenylsulphonylmethyl,
2-methoxy-l-aminoethyl, 1 -amino- 1 -methylethyl, 2-chloro-3-methoxy-thien-4-yl, 3,5-dimethylisoxazol-4-yl, l,2,3-thiadiazol-4-yl, 2-methylfur-4-yl, l ,l-dioxotetrahydrothien-3-ylmethyl, 3-amino-l,2,4-tetrazol-5-yl or isothiazol-5-yl.
More preferably the group "-Bd-R3d" forms 2-oxotetrahydrothiazol-4-yl, 2-(3-bromoisoxazol-5-yl)ethyl, isothiazol-5-yl, imidazol-1 -ylethyl or 2-oxopynolidin-l -ylmethyl.
Preferably R4d is selected from hydrogen or C,.4alkyl.
More preferably R4d is selected from hydrogen or methyl.
Particularly R4d is selected from hydrogen. Preferred compounds of formula (Id) are:
9-ethyl-3-(2-oxotetrahydrothiazol-4-ylcarbonylamino)carbazole; 9-ethyl-3-[2-(3-bromoisoxazol-5-yl)ethylcarbonylamino]carbazole; 9-ethyl-3-(isothiazol-5-ylcarbonylamino)carbazole; 9-(2,2,2-trifluoroethyl)-3-(imidazol-l-ylethylcarbonylamino)carbazole; 9-(2,2,2-trifluoroethyl)-3-2-oxopyrrolidin-l-ylmethylcarbonylamino)carbazole; or a pharmaceutically acceptable salt, prodrug or solvate thereof.
According to a further aspect of the invention there is provided the use of a compound of formula (Id), or a pharmaceutically acceptable salt, prodrug or solvate thereof, as a medicament. According to a further aspect of the invention there is provided a pharmaceutical composition comprising a compound of formula (Id), or a pharmaceutically acceptable salt, prodrug or solvate thereof, in admixture with a pharmaceutically-acceptable diluent or carrier.
According to a further aspect of the invention there is provided a pharmaceutical composition comprising a compound of formula (Id), or a pharmaceutically acceptable salt, prodrug or solvate thereof, in admixture with a pharmaceutically-acceptable diluent or carrier for the treatment of a warm-blooded animal, in need of treatment of disorders mediated by the neuropeptide Y5 receptor.
According to a further aspect of the invention there is provided a pharmaceutical composition comprising a compound of formula (Id), or a pharmaceutically acceptable salt, prodrug or solvate thereof, in admixture with a pharmaceutically-acceptable diluent or carrier for the treatment of eating disorders in a warm-blooded animal, in need of treatment.
According a further aspect of the invention there is provided the use of a compound of formula (Id) in the manufacture of a medicament for the treatment, in a warm-blooded animal, of disorders mediated by the neuropeptide Y5 receptor or a pharmaceutically acceptable salt, prodrug or solvate thereof. According to a further aspect of the invention there is provided the use of a compound of formula (Id) or a pharmaceutically acceptable salt, prodrug or solvate thereof in the manufacture of a medicament for the treatment of eating disorders in a warm-blooded animal.
According to a further aspect of the invention there is provided a method of treatment, in a warm-blooded animal, of disorders mediated by the neuropeptide Y5 receptor comprising administering a therapeutically effective amount of a compound of formula (Id) or a pharmaceutically acceptable salt, prodrug or solvate thereof.
According to a further aspect of the invention there is provided a method of treatment, in a warm-blooded animal, of eating disorders, comprising administering a therapeutically effective amount of a compound of formula (Id) or a pharmaceutically acceptable salt, prodrug or solvate thereof.
According to another feature of the invention there is provided the use of a compound of formula (Id), or a pharmaceutically acceptable salt, prodrug or solvate thereof, in the manufacture of a medicament for promoting weight loss.
According to a further aspect of the first feature of the invention there is provided a method of promoting weight loss, comprising administering a therapeutically effective amount of a compound of formula (Id), or a pharmaceutically acceptable salt, prodrug or solvate thereof.
According to a further aspect of the invention there is provided a pharmaceutical composition comprising a compound of formula (Id), or a pharmaceutically acceptable salt, prodrug or solvate thereof, in admixture with a pharmaceutically acceptable diluent or carrier for use in promoting weight loss.
A preferred group of values for the substituents described in first feature (and within each feature) of the invention described herein, are:
R, is C,.4alkyl, C, ^alkanoyl, arylC,.4alkanoyl, aryloxy, heteroarylC,.4alkanoyl, or heteroaryloxy, optionally substituted as above;
R2 is hydrogen;
A is -NH-C(O)-O-;
B is C,.6alkylene, C2.6alkenylene
R3 is hydrogen, alkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, or heterocyclyloxy, optionally substituted as above. R4 is nitro or hydrogen.
A further preferred group of values for the substituents described in the first feature of the invention described herein, are:
R, is C,.4alkyl, C,.4alkanoyl, arylC,.4alkanoyl, aryloxy, heteroarylC,.4alkanoyl, or heteroaryloxy, optionally substituted as above; R2 is hydrogen;
A is -NH-C(O)-NH-, or -NH-C(O)-NC,.4alkyl)-,
B is C,.6alkylene, C2.6alkenylene
R3 is hydrogen, alkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, or heterocyclyloxy, optionally substituted as above; and R4 is nitro or hydrogen.
A further preferred group of values for the substituents described in the first feature of the invention described herein, are:
R, is C,.4alkanoyl, arylC, ^alkanoyl, aryloxy, heteroarylC,.4alkanoyl, or heteroaryloxy, optionally substituted as above; R2 is hydrogen;
A is -NH-C(O)-;
B is C,.6alkylene, C2.6alkenylene
R3 is hydrogen, alkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, or heterocyclyloxy, optionally substituted as above; and R4 is nitro or hydrogen.
A more preferred group of values for the substituents described the first feature of the invention described herein, are:
R, is C,.4alkyl;
R2 is hydrogen; A is -NH-C(O)-;
B is C,.6alkylene, C2.6alkenylene
R3 is hydrogen, alkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, or heterocyclyloxy; and
R4 is nitro or hydrogen.
For the avoidance of doubt it should be noted that when these preferred groups of values for R,, R2, A, B, R3 and R4 are applied to each feature of the invention then the respective provisos also apply.
Particular compounds of the invention are: N-(9-ethyl-9H-carbazol-3-yl)-2,2-dimethylpropionamide; N-(9-ethyl-9H-carbazol-3-yl)-2-(2-oxopyrolidine-l-ylacetamide; N-(9-ethyl-9H-carbazol-3-yl)-3-(imidazol-l-yl)propionamide; l-methyl-l-(pyridin-4-ylethyl)-3-(9-ethyl-9H-carbazol-3-yl) urea; 1 -methyl- l-(NN-dimethylaminoethyl)-3-(9-ethyl-9H-carbazol-3-yl) urea; and l-(4-hydroxycyclohex-l-yl)-3-(9-ethyl-9H-carbazol-3-yl) urea.
More particular compounds of the invention are: N-(9-ethyl-9H-carbazol-3-yl)-2-(l ,2,4-triazole- 1 -ylacetamide; N-(9-ethyl-9H-carbazol-3-yl)-4-moφholine carboxamide; l-(9-ethyl-9H-carbazol-3-yl)-3-(N-methylpiperidin-4-yl)-3-methyl urea; and N-(9-methylsulfonyl-9H-carbazol-3-yl)moφholine 4-carboxamide.
Particular compounds of the invention or of the first feature of the invention are: Ν-(9-ethyl-9H-carbazol-3-yl)-3-pyridm-4-ylpropanamide
N-(9-ethyl-9H-carbazol-3-yl)-3-[3-(2-methoxyphenyl)-l,2,4-oxadiazol-5-yl]propanamide N-(9-ethyl-9H-carbazol-3-yl)-2-methyl-3-pyridin-4-ylpropanamide (E)-N-(9-ethyl-9H-carbazol-3-yl)-2-methyl-3-pyridin-4-ylprop-2-enamide N-(9-methyl-9H-carbazol-3-yl)-3-pyridin-4-ylpropanamide N-(9-benzoyl-9H-carbazol-3-yl)-3-pyridin-4-ylpropanamide N-(9-ethyl-9H-carbazol-3-yl)-2-methylpropanamide Isopropyl-Ν-(9-ethyl-9H-carbazol-3-yl)carbamate 1 , 1 -diethyl-3-(9-ethyl-9H-carbazol-3-yl) urea 1 -(9-ethyl-9H-carbazol-3-yl)-3-(2,6-diethylphenyl) urea N-(9-ethyl-9H-carbazol-3-yl)-2-(4-methylphenyloxy) ethanamide N-(9-ethyl-9H-carbazol-3-yl) ethanamide
phenyl-N-(9-ethyl-9H-carbazol-3-yl)carbamate phenylmethyl-N-(9-ethyl-9H-carbazol-3-yl)carbamate
A carbazole derivative of formula (I), or a pharmaceutically-acceptable salt or in vivo hydrolysable ester thereof, may be prepared by any process known to be applicable to the 5 preparation of chemically related compounds. These processes may additionally be used to form a carbazole derivative of formula (I) or a pharmaceutically acceptable salt, prodrug or solvate thereof. Such processes, when used to prepare carbazole derivative of formula (I), or a pharmaceutically-acceptable salt or in vivo hydrolysable ester thereof, or a carbazole derivative of formula (I), or a pharmaceutically acceptable salt, prodrug or solvate thereof, are
10 provided as a further feature of the invention and are illustrated by the following representative examples in which R„ R2, A, B, R3 and R4 have the same meaning as herein before defined. R, or R3 bear the same optional substituents as described herein unless another substituent is drawn thereon (optionally protected as necessary). The reader is referred to Advanced Organic Chemistry, 4* Edition, by Jerry March, published by John Wiley & Sons
15 1992, for general guidance on reaction conditions and reagents. The reader is referred to Protective Groups in Organic Synthesis 2nd Edition, by Green et al, published by John Wiley & Sons for general guidance on protecting groups.
Carbazoles of the invention can be synthesised from the respective R,- and R2-substituted 2- or 3-aminocarbazole derivative or 2- or 3-carboxycarbazole derivative as
20 appropriate.
Many carbazole derivatives which can be used as starting points for synthesis of compounds of formula (I)-(V) are known in the art. For example 3-aminocarbazole (Aldrich Chemical Company), 3-amino-9-ethyl-carbazole (Aldrich Chemical Company), 3-carboxy carbazole [Preston et al (1942) J. Chem. Soc. 500-504, 2-carboxycarbazole [Narashimhan et al
25 (1983) Indian J Chem Sect. B 22B(10), 1004-10], 2-hydroxycarbazole [Haase (1963) J Prakt. Chem. 20, 161], 2-formylcarbazole [Molina et al (1993) Tetrahedron 49, 1223-1236 or 3-nitrocarbazole [Chakrabarty et al (1994) Synthetic Communications 24, 1-10]. In the following processes it is advisable to maintain the 2- or 3- amino group on the carbazole ring as a nitro group until the R, group has been incoφorated and then reducing the nitro group to
30 an amino group. Likewise it is advisable to maintain the 2-carboxy or 3-carboxy group on the carbazole ring as the aldehyde until the R, group has been incoφorated and then oxidising the
aldehyde to the carboxylic acid. The skilled man would be able to adapt processes described herein and processes known in the art to produce other suitable starting materials for the synthesis of compounds of the invention.
Carbazole derivatives of formula (V) wherein R5 is an nitro or formyl group, can be prepared as starting points for synthesis of compounds of the invention as follows:
(V)
(1) 3-amino-6-alkyl-9-ethylcarbazole
6-Alkylcarbazole [Luo (1989) Journal of Heterocyclic Chemistry 26, 1213] can be converted to 3-nitro-6-alkyl-9-ethylcarbazole as follows. Reaction with ethyl iodide or diethyl sulphate in the presence of a base (e.g. sodium hydride, sodium hydroxide or potassium carbonate) in a solvent such as DMF or N-methylpyrrolidinone to give 6-alkyl-9-ethylcarbazole, followed by a standard nitration procedure (nitric acid in a suitable solvent, such as acetic acid, at a temperature of 0 - 25°C). A person skilled in the art could produce alternative R, substitutions as follows.
6-alkylcarbazole could be converted to 3-nitro-6-alkylcarbazole using eerie ammonium nitrate in a suitable solvent, such as chloroform in the presence of SiO2under reflux [Chakrabarty & Batabyal (1994) Synthetic Communications 24, 1-10). R, substituents could then be added as described below. Finally the nitro group could be reduced to the amino using standard conditions.
(2) 3-amino-6-halo-9-aminocarbazole 3-nitro-6-halo-9-aminocarbazole [J. Prakt. Chem. (1996) 338, 731-737.
(3) 3-amino-6-alkoxy-9-alkyl-carbazole
This compound can be produced as follows: 6-methoxy-l,2,3,4-tetrahydrocarbazole is produced by a Fischer indole synthesis as follows, Para-alkoxyphenylhydrazine is reacted with cyclohexanone in cold dilute acid at room temperature followed by heating at a temperature in the range of 80 - 100°C in the presence of glacial acetic acid or dilute sulphuric acid. This can then be dehydrogenated to the 6-alkoxycarbazole in the presence of palladium
on carbon at a temperature of about 280°C. 6-alkoxycarbazole can then be alkylated using an alkyl iodide or an alkyl sulphate in the presence of a base (e.g. potassium carbonate) in a suitable solvent such as DMF, followed by nitration using standard conditions as described above. Alternatively 6-alkoxycarbazole can be derivatised at R2 as described below followed by nitration using eerie ammonium nitrate.
(4) 3-amino-6-cyano-9-ethyl-carbazole
3-Formylcarbazole can be converted into the corresponding oxime using hydroxylamine in a suitable solvent, such as ethanol. The oxime can then be converted to the nitrile by heating at a temperature of 80 - 120°C with acetic anhydride or phoφorous oxychloride in the absence of solvent. 3-cyanocarbazole can then be nitrated under standard conditions using for example eerie ammonium nitrate or nitric acid and acetic acid as described above. An analogous reaction can also be performed using the 1-formylcarbazole
(5) 6-amino carbazole derivatives
3-Amino-9-ethylcarbazole can be reacted with acetic anhydride or acetyl chloride to form the corresponding amide. This can then be nitrated on the 6-position of the carbazole ring using standard nitration conditions as described above, followed by reduction of the nitro group to the amine and hydrolysis of the amide using dilute hydrochloric acid at a temperature of 80 - 100°C to form the 3,6-diaminocarbazole.
The skilled man would be able to use analogous methodology to produce di-aminocarbazole derivatives with substituents at R, other than an alkyl chain.
(6) 7-substituted carbazole derivatives
2-Formylcarbazole can be oxidised using standard conditions (e.g. potassium permanganate in a suitable solvent such as water or aqueous acetone, at 20 - 100°C temperature) to form the carboxylic acid. This can then converted to a amino group by a Curtius reaction using diphenylphosphoryl azide in dioxane in the presence of benzyl alcohol followed by heat to form the isocyanate. This is then reacted with tertiary butyl alcohol, followed by trifluoroacetic acid to form the amine. The amine can then subjected to a diazotisation reaction using nitrous acid in a suitable solvent, such as water at a temperature of -5 - 10°C, to form the 2-diazo-substituted carbazole. The diazo group can then be reacted with a number of compounds to form 2-substituted carbazoles, such as copper chloride to form 2-chlorocarbazole derivative or copper cyanide to form 2-cyanocarbazole. These 2-derivatives
can then be nitrated as described above to produce the corresponding 7-substituted 3-nitrocarbazole.
A number of approaches are available to add substituents at R, on the carbazole ring.
(1) aryl and heteroaryl groups Aryl, substituted aryl, heteroaryl and substituted heteroaryl groups can be added by palladium-catalysed reaction of a carbazole with an aryl halide [Mann et al (1998) Journal of the American Chemical Society 120, 827-828].
(2) aryl groups
Aryl groups and substituted aryl groups can be added using the appropriate triphenylbismuth bis-trifluoroacetate derivative [Barton et al (1988) Tetrahedron Letters 29, 1115-1118].
(3) alkyl group and substituted alkyl groups
An R2 substituted carbazole can be reacted with the appropriate alkyl halide or substituted alkyl halide to form the corresponding 9-alkyl or alkyl-substituted-9-alkyl substituted carbazole. This can be performed in the presence of a base e.g. potassium hydroxide in a suitable solvent such as DMSO or using sodium hydride in a suitable solvent such as DMF. The resulting substituted carbazole can be nitrated using standard conditions e.g. nitric acid in acetic acid at a temperature of 0 - 25°C. This is followed by reduction to the amine using standard conditions such as hydrogen gas in the presence of 10% palladium on carbon in a suitable solvent such as ethyl acetate or ethanol at a temperature of 0 - 30°C. The skilled man would know how to prepare the appropriate protected alkylamino compounds to add alkylamino groups and N-substituted alkylamino groups at R,.
(4) alkanoyl groups or substituted alkanoyl groups, aryl carbonyl or heteroaryl carbonyl groups The appropriate 2- or 3-nitro carbazole or 2- or 3-formylcarbazole can be reacted with the appropriate acid chloride or acid anhydride in a suitable solvent such as chloroform or DMF at a temperature of 0 - 80°C. Alternatively the appropriate 2- or 3-nitro carbazole can be reacted with the appropriate carboxylic acid with a carbodiimide, such as ED AC and DMAP in a suitable solvent, such as DCM or chloroform in the presence of a base such as triethylamine at room temperature.
(5) alkylsulphonyl groups, N-alkylaminosulponyl groups
A compound of formula (V) can be reacted with the appropriate alkylsulponyl halide or substituted alkylsulphonyl halide to form the corresponding alkyl sulphonyl-substituted compound. This can be performed in the presence of a base e.g. sodium hydroxide in a suitable solvent such as THF or DMF or using sodium hydride in a suitable solvent such as DMF.
The skilled man would know how to prepare the appropriate protected alkylaminosulphonyl compounds to add alkylamino groups and N-substituted alkylamino groups at R, .
A number of approaches are available to add groups of the formula R5-R6 to the 2- or 3- position of the carbazole ring of formula (VI) to form compounds of formula (I), wherein R5 is a amino or carboxyl group and R6 is a group of the formula -A'-B-R3, wherein A' is a precursor to the group A producing group A when reacted with the amino or carboxyl group on the carbazole ring. These include (1) Compounds of formula (I) where A is -ΝH-C(O)- These can be prepared by reacting a carbazole of formula (VI)
(VI) with a carboxylic acid of formula HOOCR6 to form an amide. Coupling of amino groups with carboxylic acids are well known in the art and can be facilitated by a number of chemical reactions using an appropriate coupling reagent. For example a carbodiimide coupling reaction can be performed with ED AC in the presence of DMAP in a suitable solvent such as
DCM, chloroform or DMF at room temperature.
(2) Compounds of formula (I) where A is -NH-C(O)-
These can also be prepared by reacting a carbazole of formula (VI) with an acid chloride of formula ClC(O)R6, in the presence of a base, such as triethylamine or pyridine, in a suitable solvent such as chloroform or DCM at a temperature between 0°C and room temperature.
(3) Compounds of formula (I) where A is -NH-S(O2)-.
These can be prepared by reacting a carbazole of formula (VI) with a sulphonyl chloride of formula ClSO2R6 in the presence of a base, such as triethylamine or pyridine, in a suitable solvent such as chloroform or DCM at a temperature between 0°C and room temperature.
(4) Compounds of formula (I) where A is -C(O)-NH-.
These can be prepared by reacting a carbazole of formula (VII)
(VII) with an amine of formula NH2R6. Methodology is identical to processes described in (1) above in this section. Compounds of formula (I) where A is -C(O)-N(C,.4 alkyl)- can also be produced by this method using a secondary amine of formula NH(C,.4alkyl)R6. (5) Compounds of formula (I) where -A-B-R3 is -C(O)-NH2,
These can be prepared by reacting a carbazole of formula (VII) with an alkylchloro formate in a suitable solvent, such as DCM or chloroform, at a temperature between -10°C and 0°C to form the mixed anhydride. This is followed by reacting with the ammonium hydroxide at room temperature in a suitable solvent, such as chloroform. This reaction can also be used to create secondary amides if the ammonium hydroxide is substituted with the appropriate amino compound. (6) Compounds of formula (I) wherein A is -CH2NH-.
These can be prepared by reduction of the compound of formula (VIII)
(VIII)
as prepared using process (4) in this section using lithium aluminium hydride in an inert solvent such as THF at a temperature of 0°C under argon, followed by refluxing. This can be followed by reaction of the amino group with a group of the formula HOOC-R6 as described above. (7) Compounds of formula (I) wherein A is -NHC(O)O-
These can be prepared by reacting a carbazole of formula (VI) with a chloroformate of formula ClC(O)OR6 or a carbonate of formula (R6O)2CO in a suitable solvent, such as DCM or chloroform, in the presence of a base, such as N-methylmoφholine, pyridine or triethylamine, at a temperature between -10°C and 0°C. (8) Alkyl substitution can be introduced onto the nitrogen groups within group A of formula (I) by reacting the corresponding non-alkylated nitrogen carbazole derivative of formula (I) with an alkyl iodide e.g. methyl iodide in the presence of sodium hydride in an inert solvent such as THF at 0°C under argon, followed by heating to 50°C.
Alkyl substitution on one or both nitrogen atoms in group A in formula (I) wherein group A is -ΝHC(O)ΝH- can be facilitated as follows:
A carbazole of formula (VI) is reacted with an aldehyde of formula R7CHO, wherein R7 is C,.4alkyl in the presence of sodium cyanoborohydride in a suitable solvent, such as acetic acid, at a temperature between room temperature and 60°C. The resulting secondary amine or a compound of formula (VI) is reacted with phenylchloro formate, in a suitable solvent, such as DCM or chloroform, in the presence of a base, such as triethylamine at a temperature of -10 - 0°C. This is then reacted with R8NHR6 under the same conditions, wherein R8 is either hydrogen or C,.4alkyl to form the N-substituted urea derivative. Νon-N-substituted urea derivatives of the invention can also be make by this approach.
(9) Compounds of formula (I) wherein A is -ΝHC(O)ΝH- These can be produced by reacting a carbazole of formula (VI) with an isonitrile of formula CNR6, in a suitable solvent, such as chloroform or DCM, in the presence of a base such as triethylamine at a temperature between 0°C and room temperature.
(10) Compounds of formula (I) wherein -A-B-R3 is -N-R3 wherein R3 is a 2-linked heterocycle
These can be produced by reacting a carbazole of formula (V) with a 2-chloroheterocycle in a suitable solvent, such as isopropanol, DMF or DMA in the presence or absence of an acid, such as hydrochloric acid at a temperature of about 85°C.
A person skilled in the art would be able to generate appropriate compounds, of the formula R5-R6, to react with compounds of formula (V) to produce compounds of formula (I) wherein R5 is a amino or carboxyl group and R6 is a group of the formula -A'-B-R3, wherein A' is an appropriate group to produce the group A when reacted with the amino or carboxyl group on the carbazole ring.
It will be appreciated that, in certain steps in the reaction sequence to compounds of the formula (I), it will be necessary to protect certain functional groups in intermediates in order to prevent side reactions. De-protection may be carried out at a convenient stage in the reaction sequence once protection is no longer required. Therefore, another aspect of the present invention provides a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt, prodrag or solvate thereof which process (wherein R1, R2, R3, R4, A and B are, unless otherwise specified, as defined in formula (I)) comprises of: Process a): for compounds of formula (I) wherein the group -A-B-R3 forms a side chain of the formula -NH-C(O)-X or -NH-S(O)2-X; wherein X defines a group such that -NH-C(O)-X or -NH-S(O)2-X falls within the definition of -A-B-R3 above (and with the proviso that X is not linked to the -NH-S(O)2- moiety via an oxygen); reacting an amine of formula (A):
(A) with a compound of formula (B):
M-W-X
(B) wherein W is -C(O)- or -S(O)2-; M is a displaceable group or M may be OH if W is -C(O)-; or
Process b): for compounds of formula (I) wherein the group -A-B-R3 forms a side chain of the formula -NH-C(O)-N(Y)(Z); wherein Y and Z define groups such that -NH-C(O)-N(Y)(Z) falls within the definition of -A-B-R3 above; by reacting a compound of formula (C):
(C) wherein L is a displaceable group; with an amine of formula (D):
HNYZ (D)
Process c): for compounds of formula (I) wherein the group -A-B-R3 forms a side chain of the formula -NH-C(O)-N(Y)(Z) or -NH-C(O)-O-Q; wherein Y, Z and Q define groups such that -NH-C(O)-N(Y)(Z) and -NH-C(O)-O-Q fall within the definition of -A-B-R3 above; reacting an amine of formula (A) with a compound of formula (E):
D
CI
O
(E) wherein D is -N(Y)(Z) or -O-Q;
Process d): for compounds of formula (I) wherein the group -A-B-R3 forms a side chain of the formula -NH-C(O)-NH-Z; wherein Z defines a group such that -NH-C(O)-NH-Z falls within the definition of -A-B-R3 above; reacting an amine of formula (A) with an isocyanate of formula (F):
O=^=N-Z
(F)
Process e): reacting a compound of formula (I) wherein R1 is hydrogen; with a compound of formula (G):
R'-L (G) wherein R1 is not hydrogen and L is a displaceable group;
Process j): for compounds of formula (I) wherein the group -A-B-R3 forms a side chain of the formula -C(O)-NH-V; wherein V defines groups such that -C(O)-NH-V falls within the definition of -A-B-R3 above; by reacting an acid of formula (H):
(H) or an activated derivative thereof; with an amine of formula (J):
V-NH2 (J)
Process g): for compounds of formula (I) wherein the group -A-B-R3 forms a group of the formula -NH-Ring Z wherein Ring Z is a aryl, heteroaryl, heterocyclyl or carbocyclyl ring (optionally substituted as defined above); reacting an amine of formula (A) with a compound of formula (K):
(K) wherein L is a displaceable group;
Process h): for compounds of formula (I) wherein the group R1 is attached to the nitrogen of the carbazole via a -CH- or -CH2- group; by reacting a compound of formula (I) wherein R1 is hydrogen with a compound of formula (L):
( ) wherein E and T are groups such that (E)(T)CH- would form a group of the formula R1; Process i): by oxidation of compounds of formula (M):
(M)
Processj): by oxidation of compounds of formula (N):
(N) Process k): for compounds of formula (I) wherein the group -A-B-R3 forms a side chain of the formula -NH-C(O)-NH-Z; wherein Z defines a group such that -NH-C(O)-NH-Z falls within the definition of -A-B-R3 above; reacting an amine of formula (O):
Z-NH2 (O) with an isocyanate of formula (P):
(P) and thereafter if necessary: i) converting a compound of the formula (I) into another compound of the formula (I); ii) removing any protecting groups; iii) forming a pharmaceutically acceptable salt, prodrug or solvate.
The skilled man will appreciate that where a process is suitable for preparing compounds where A is selected from, -NH- or -NHC(O)-, these reactions would also be suitable for preparing the homologues: -CH2NH- and-CH2NHC(O)-.
L and M are displaceable groups. Suitable values for L or M are halo for example chloro or bromo; or phenols for example »-nitrophenol or pentafluorophenol. Specific reaction conditions for the above reactions are as follows. Process a) The reaction of compounds of formula (A) and (B) where M is a displaceable group is well known in the art, for example they may be reacted in the presence of a base, for example triethylamine, pyridine, or 2,6-di-α/^y/-pyridines such as 2,6-lutidine or
2,6-di-tert-butylpyridine, and in a suitable solvent, such as DMA, DCM, benzene, THF and DMF. The reaction may conveniently be performed at a temperature in the range of -40 to 140°C.
Where M is OH and W is -C(O)-, amines of formula (A) and acids of formula (B) may be coupled together in the presence of a suitable coupling reagent. Standard peptide coupling reagents known in the art can be employed as suitable coupling reagents, or for example carbonyldiimidazole and dicyclohexyl-carbodiimide, optionally in the presence of a catalyst such as dimethylaminopyridine or 4-pyrrolidinopyridine, optionally in the presence of a base such as those described above. Suitable solvents include those described above. The coupling reaction may conveniently be performed at a temperature in the range of -40 to 140°C.
Processes b and c) Compounds of formula (C) and (D) and amines of formula (A) and (E) may be reacted together in the presence of a suitable base, for example triethylamine, pyridine, or 2,6-di-α/Λrμ/-pyridines such as 2,6-lutidine or 2,6-di-tert-butylpyridine, or excess (A) or (D), in a suitable solvent such as dichloromethane, ethyl acetate or tetrahydrofuran. The reaction may conveniently be performed at a temperature in the range of -40 to 50°C.
Process d) Amines of formula (A) and compounds of formula (F) may be reacted in the presence of a suitable solvent, such as toluene, dichloromethane or tetrahydrofuran. Process e) Compounds of formula (I) wherein R1 is hydrogen may be reacted with compounds of formula (G) under standard alkylation, acylation and sulphonylation conditions. For example in the presence of a base, such as an inorganic base for example sodium carbonate or sodium hydroxide, in the presence of an inert solvent for example tetrahydrofuran or toluene and at a temperature in the range of 50-120°C, preferably at or near reflux. Process f) Acids of formula (H) and amines of formula (J) may be reacted together under standard peptide coupling conditions, for example those described in Process a) above.
Suitable activated acid derivatives include acid halides, for example acid chlorides, and active esters, for example pentafluorophenyl esters.
Process g) Amines of formula (A) and compounds of formula (K) may be reacted together either directly in the presence of a suitable high boiling solvent for example toluene or DMF, with or without additional base (suitable examples include those described above), or they
may be reacted together under standard transition metal (for example palladium) cross coupling reaction conditions. Such conditions are well documented in the art. Process h) Compounds of formula (I) wherein R' is hydrogen and compounds of formula (L) may be reacted with amines under standard reductive animation conditions. For example in the presence of a reducing agent such as hydrogen and a hydrogenation catalyst (for example palladium on carbon), or zinc and hydrochloric acid, or sodium cyanoborohydride, or sodium triacetoxyborohydride, or sodium borohydride, iron pentacarbonyl and alcoholic potassium hydroxide, or borane and pyridine or formic acid. The reaction is preferable carried out in the presence of a suitable solvent such as an alcohol, for example methanol or ethanol, and at a temperature in the range of 0-50°C, preferably at or near room temperature.
Processes i) andj) 1,2,3,4-tetrahydrocarbazole may be oxidised under standard conditions, for example in a suitable solvent such as toluene or xylene, using a suitable oxidising agent for example 2,3-dichloro-5,6-dicyano-l,4-benzoquinone and at a temperature at or near reflux. Process k) Amines of formula (O) and isocyanates of formula (P) may be reacted together under conditions such as those described in Process d) above.
Isocyanates of formula (P) may be generated in situ from the corresponding carboxylic acid under standard Curtis re-arrangement conditions.
It will be appreciated that certain of the various ring substituents in the compounds of the present invention may be introduced by standard aromatic substitution reactions or generated by conventional functional group modifications either prior to or immediately following the processes mentioned above, and as such are included in the process aspect of the invention. Such reactions and modifications include, for example, introduction of a substituent by means of an aromatic substitution reaction, reduction of substituents, alkylation of substituents and oxidation of substituents. The reagents and reaction conditions for such procedures are well known in the chemical art. Particular examples of aromatic substitution reactions include the introduction of a nitro group using concentrated nitric acid, the introduction of an acyl group using, for example, an acyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; the introduction of an alkyl group using an alkyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; and the introduction of a halo group. Particular examples of modifications include the reduction of a nitro group to an amino group by for example, catalytic hydrogenation with
a nickel catalyst or treatment with iron or tin in the presence of hydrochloric acid with heating; oxidation of alkylthio to alkylsulphinyl or alkylsulphonyl. The reader is referred to Advanced Organic Chemistry, 4th Edition, by Jerry March, published by John Wiley & Sons 1992, for general guidance on reaction conditions and reagents. It will also be appreciated that in some of the reactions mentioned herein it may be necessary/desirable to protect any sensitive groups in the compounds. The instances where protection is necessary or desirable and suitable methods for protection are known to those skilled in the art. Conventional protecting groups may be used in accordance with standard practice (for illustration see T.W. Green, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991). Thus, if reactants include groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein.
A suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a t-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine. A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with
a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon. The protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art.
In order to use a compound of the formula (I) or formula (II) or formula (III) or formula (IV), or a pharmaceutically-acceptable salt or in vivo cleavable ester thereof, for the therapeutic treatment (including prophylactic treatment) of mammals including humans, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
Furthermore in order to use a compound of the formula (I) or formula (II) or formula (III) or formula (IV), or a pharmaceutically acceptable salt, prodrug or solvate thereof, for the therapeutic treatment (including prophylactic treatment) of mammals including humans, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
According to this aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the formula (I) or formula (II) or formula (III) or formula (IV) or a pharmaceutically-acceptable or in vivo cleavable ester thereof, as defined herein before in association with a pharmaceutically-acceptable diluent or carrier. According to this aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the formula (I) or formula (II) or formula (III) or formula (IV) or a pharmaceutically acceptable salt, prodrug or solvate thereof, as defined herein before in association with a pharmaceutically-acceptable diluent or carrier. The compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible
powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository for rectal dosing).
The compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.
Suitable pharmaceutically-acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl p-hydroxybenzoate, and anti-oxidants, such as ascorbic acid. Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absoφtion of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in either case, using conventional coating agents and procedures well known in the art. Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil.
Aqueous suspensions generally contain the active ingredient in finely powdered form together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or
condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid), colouring agents, flavouring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame).
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil (such as arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin). The oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening, flavouring and colouring agents, may also be present. The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these. Suitable emulsifying agents may be, for example, naturally-occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soya bean, lecithin, an esters or partial esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and condensation products of the said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening, flavouring and preservative agents.
Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavouring and/or colouring agent.
The pharmaceutical compositions may also be in the form of a sterile injectable aqueous or oily suspension, which may be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents, which
have been mentioned above. A sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example a solution in 1,3-butanediol.
Suppository formulations may be prepared by mixing the active ingredient with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Suitable excipients include, for example, cocoa butter and polyethylene glycols.
Topical formulations, such as creams, ointments, gels and aqueous or oily solutions or suspensions, may generally be obtained by formulating an active ingredient with a conventional, topically acceptable, vehicle or diluent using conventional procedures well known in the art.
Compositions for administration by insufflation may be in the form of a finely divided powder containing particles of average diameter of, for example, 30μm or much less, the powder itself comprising either active ingredient alone or diluted with one or more physiologically acceptable carriers such as lactose. The powder for insufflation is then conveniently retained in a capsule containing, for example, 1 to 50mg of active ingredient for use with a turbo-inhaler device, such as is used for insufflation of the known agent sodium cromoglycate.
Compositions for administration by inhalation may be in the form of a conventional pressurised aerosol arranged to dispense the active ingredient either as an aerosol containing finely divided solid or liquid droplets. Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons may be used and the aerosol device is conveniently ananged to dispense a metered quantity of active ingredient.
For further information on formulation the reader is referred to Chapter 25.2 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.
The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 2 g of active agent compounded with an appropriate and convenient amount of excipients which may vary from
about 5 to about 98 percent by weight of the total composition. Dosage unit forms will generally contain about 1 mg to about 500 mg of an active ingredient. For further information on Routes of Administration and Dosage Regimes the reader is referred to Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.
The size of the dose for therapeutic or prophylactic puφoses of a compound of the formula (I) will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine. In using a compound of the formula (1) for therapeutic or prophylactic puφoses it will generally be administered so that a daily dose in the range, for example, 0.5 mg to 75 mg per kg body weight is received, given if required in divided doses. In general lower doses will be administered when a parenteral route is employed. Thus, for example, for intravenous administration, a dose in the range, for example, 0.5 mg to 30 mg per kg body weight will generally be used. Similarly, for administration by inhalation, a dose in the range, for example, 0.5 mg to 25 mg per kg body weight will be used. Oral administration is however preferred, particularly in tablet form. Typically, unit dosage forms will contain about 1 mg to 500 mg of a compound of this invention.
The compounds of this invention may be used in combination with other drugs and therapies used in the treatment of disease states which would benefit from antagonism at the neuropeptide Y5 receptor. For example, the compounds of the formula (I) could be used in combination with drugs and therapies used in the treatment of eating disorders, including, but not limited to, obesity or bulimia. Furthermore, the compounds of the formula (I) could be used in combination with drugs and therapies used in the treatment of eating disorders, including, but not limited to, obesity and related disorders, anorexia or bulimia.
If formulated as a fixed dose such combination products employ the compounds of this invention within the dosage range described herein and the other pharmaceutically-active agent within its approved dosage range. Sequential use is contemplated when a combination formulation is inappropriate. Although the compounds of the formula (1) are primarily of value as therapeutic agents for use in warm-blooded animals (including man), they are also useful whenever it is
required to antagonise binding at the neuropeptide Y5 receptor. Thus, they are useful as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents. Biological Assays The activity of compounds of the invention was measured in a neuropeptide Y5 receptor binding assay as follows. Compounds were also tested in binding assays for the neuropeptide Y, and neuropeptide Y2 receptors. Activity against these 2 receptors is contraindicated for a neuropeptide Y5 antagonist. a) expression of human neuropeptide Y5 receptor in High 5™ insect cells. High 5™ insect cells were obtained from Invitrogen (catalogue N° B855-02) and stored in liquid nitrogen. Cells were revived from liquid nitrogen storage and grown at 28°C in 100 ml ExCell 405 (JRH Biosciences) serum free medium in a 250 ml conical flask (Corning) agitated at 140 φm in an Innova 4330 orbital shaker (New Brunswick Scientific). Cultures were routinely sub-cultured every 3 - 4 days. High 5™ insect cells were transfected with the human NPY5 receptor as follows: PCR primers were designed against huNPY5 receptor sequence, Genbank Accession Number U56079 [Gerald et. al (1996) Nature 382, 168-171], but starting at base 56 through to base 1393, to express the protein 10 amino acid residues shorter at the amino terminal end [see Borowsky et al (1998) Regulatory Peptides 75-76, 45-53]. These primers were used to amplify the huNPY5 receptor from human placenta genomic DNA by PCR. This was then sub-cloned into pZERO2 (obtained from Invitrogen) for sequencing and re-cloned into pFASTB AC 1 (obtained from GIBCO BRL Life Technologies) for expression. Human NPYr was isolated from pZERO2 on BamHI fragment and sub-cloned into pFastbacl on BamHI restriction site. The junctions were sequenced to ensure correct prior to expression. A baculovirus containing the pFASTB AC 1 was then generated using the Bac-to-Bac™ baculovirus expression system [Anderson et al (1996) FASEB Journal 10(6), 727-726] (obtained from GIBCO BRL Life Technologies) following the protocol supplied with this expression system by GIBCO BRL Life Technologies.
High 5™ insect cells were infected with the baculovirus to transfect the cells with the human neuropeptide Y5 receptor as follows: Batches were grown for membrane preparation by inoculating 5 L of ExCell 405™ medium in a 7 L Bioreactor (FT-Applikon) with 1.75 x
109 mid log High 5™ cells. After 2-3 days growth at 28°C the mid log culture was infected with Baculovirus expressing the human NPY5 receptor at a multiplicity of infection (MOI) of 1.0. Cells (typically lxlO10) were harvested 48 hours post infection by centrifugation (Heraeus Omnifuge 2.0RS 30 min, 296g , 4°C) and flash frozen in liquid nitrogen for storage at -80°C. b Membrane preparation procedure
The following buffer was prepared daily and stored at 4°C. 50mM Tris HCl pH 7.4, 5mM EDTA and 10% w.v. sucrose. A protease inhibitor cocktail (Boehringer Mannheim) was added to both buffers according to the manufacturers instruction. Cells were thawed rapidly in three times their packed cell volume of hypotonic buffer (3:1 mix of water and buffer) and lysed routinely on ice using five Vibra Cell Sonicator (Sonics and Materials Inc.) bursts often seconds for the High 5™ insect cells. The cell lysate (typically 10-15 ml) was carefully loaded onto a 10 ml 41% sucrose cushion which was topped off with lysis buffer and spun at 150,000g for 1 hour at 4°C in a Beckman Optima LE-80K Ultracentrifuge. The membrane fraction was carefully removed from the inter-phase and diluted at least four fold with lysis buffer. The membrane pellets were recovered by centrifugation at 150,000g for 20 min at 4°C in a Beckman Optima LE-80K Ultracentrifuge and re-suspended at 5x107 cell equivalents per ml. The re-suspended membranes were divided into working aliquots, routinely 1ml, flash frozen in liquid nitrogen and stored frozen at -80°C until use.
Prior to use the 1ml High 5™ membranes were thawed and resuspended in 8ml binding buffer (see below). Membranes are used at approximately 7μg/ml of protein per incubate. c^ neuropeptide Y5 receptor binding assay The following reagents were used: Binding buffer: 50mM HEPES, 2.5mM CaCl2, ImM MgCl2, 0.5% BSA, pH=7.4 Binding wash buffer: 50mM HEPES, 2.5mM CaCl2, ImM MgCl2, 0.5M NaCl, 0.5% BSA, pH=7.4
Unifilter GFC filter plates: 50μl of 0.5% polyethyleneimine was added to each well and left to equilibrate for four hours before use Incubation plates: 96 well polypropylene plates, siliconised prior to use Test Compounds: Compounds were dissolved in DMSO at a concentration of ImM. Final concentration of DMSO in the assay did not exceed 1%.
Peptide PYY (pancreatic polypeptide Y) - lOμM stock solution in binding buffer. I25I PYY - lOμCi/ml stock solution, diluted 1 :10 dilution, into binding buffer.
Assays were performed in 96 well microtitre plates. lOμl of diluted test compound was added to each well of a plate, followed by 80μl of membranes and lOμl of radiolabelled l25I PYY (O.OlμCi per well). Total and non-specific binding controls were included in each plate. The non-specific binding wells received lOμl of Peptide PYY from the lOμM stock solution, whilst the total binding wells received lOμl of binding buffer. For each assay, a duplicate dose response of peptide PYY was included, top concentration lμM.
The plates were incubated for two hours at room temperature with mixing, and then filtered onto the pre-treated filter plates. The incubation plates were washed twice with 150μl of cold binding wash buffer per well, then the filter plates were further washed with approximately 2.5ml per well. The filter plates were dried overnight at room temperature, the bottoms were sealed, and 20μl of Scintillant (Microscint 40, Canberra Packard) was added to each well. The tops of the plates were sealed and the plates were counted for 1 minute on a protocol set up for 125I on a 96 well plate liquid scintillation counter (Top Count, Canberra Packard).
Compounds were considered to be active if they inhibited the binding by more than 50% at a concentration of lOμM. Dose responses were carried out on all compounds found to be active (8 point curves in duplicate). Although the pharmacological properties of the compounds of the formula (I) vary with structural change as expected, in general compounds of the formula (I) possess an IC50 in the above test in the range, for example, 0.0002 to 200μM. For example N-(9-ethyl-9H-carbazol-3-yl)-(4-methylphenoxy)-acetamide has an IC50 for the Neuropeptide Y5 receptor of 86nM. Examples
The invention will now be illustrated by the following non-limiting Examples in which, unless otherwise stated:
(i) concentrations and evaporations were carried out by rotary evaporation in vacuo; (ii) operations were carried out at room temperature, that is in the range 18-26°C; (iii) yields, when given, are intended for the assistance of the reader only and are not necessarily the maximum attainable by diligent process development;
(iv) the following abbreviations are used:
DMAP 4-dimethyaminopyridine;
DMA dimethylacetamide
ED AC l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide; DMF NN-dimethylformamide;
THF tetrahydrofuran;
DMSO dimethylsulphoxide;
MeOH methanol;
EtOH ethanol DCM dichloromethane; ether diethylether;
EtOAc ethyl acetate; and
RT retention time; v) all procedures were carried out at room temperature unless otherwise stated; vi) all commercially available reagents and solvents were used without further purification unless otherwise stated; vii) Organic solvent extracts were dried over anhydrous magnesium sulphate unless otherwise stated; viii) Η and 13C ΝMR were recorded on Bruker DPX-300, DPX-400 or Varian Gemini 2000 instruments using CDC13 or DMSO-d6 with Me4Si as internal reference and 'H ΝMR is quoted at 300 MHz using DMSO-d6 as a solvent unless otherwise stated; chemical shifts are in δ (ppm) and peak multiplicities are designated as follows: s, singlet; d, doublet; dd, doublet of doublets; t, triplet; dt, doublet of triplets; q, quartet; m, multiplet; br, broad; sept, septuplet; ix) mass spectra were recorded on Micromass Platform positive and negative electrospray spectrometers; m/z values are quoted and unless otherwise stated the positive electrospray is quoted - (MH)+; x) for TLC analysis, Merck precoated TLC plates (silica gel 60 F254, d = 0.25 mm) were used; xi) flash chromatography was performed on silica (Merck Keiselgel: Art.9385) unless otherwise stated; where a "Bond Elut" column is referred to, this means a column containing 10 g or 20 g of silica of 40 micron particle size, the silica being contained in a 60 ml
disposable syringe and supported by a porous disc, obtained from Varian, Harbor City,
California, USA under the name "Mega Bond Elut SI"; where an ISOLUTE column is referred to, this means an "ion exchange" extraction cartridge for adsoφtion of basic or acid material, i.e. a polypropylene tube containing a special grade of ion exchange sorbent, high purity, surface to pH ~7, incoφorating a phase-separation filtering material, used according to the manufacturers instructions, obtained from Varian, Harbor City, California, USA under the name of "Extube, Chem Elut, ISOLUTE"; "Extube" is a registered trademark of International
Sorbent Technology Limited; xii) The following Solvent Systems (v/v/v) were used: Zl EtOAc;
Z2 10% MeOH, 89% DCM, 1% ammonia;
Z3 stepped gradient eluting initially with 20% isohexane, 80% EtOAc, through 100% EtOAc to 20% MeOH, 80% EtOAc;
Z4 DCM; Z5 2% MeOH, 98% DCM;
Z6 20% MeOH, 80% DCM;
Z7 2% NH4OH, 18% MeOH, 80% DCM;
Z8 5% NH4OH, 15% MeOH, 80% DCM;
Z9 20% EtOAc, 80% isohexane; Z10 10% MeOH, 90% EtOAc;
Zl 1 50% isohexane, 50% EtOAc;
Z12 10% EtOAc, 90% isohexane; xiii) HPLC Method A refers to the following system:
Column: 2.1mm x 3cm Waters Symmetry C18 3.5μm Solvent: A = 95 Water, 5 MeOH + 0.1 % Formic acid,
B = 95 Acetonitrile, 5 MeOH + 0.1% Formic acid
Run time: 5 minutes with a 4.5 minute gradient from 0 -100% B
Wavelength: 254nm, bandwidth 1 Onm
Injection 2 μl Gradient:
Salor Sigma Aldrich, Gillingham, Dorset, United Kingdom
Chembridge Chembridge Coφoration, San Diego, USA
Specs Specs, Rijswijk, Netherlands Fanwood Fanwood, New Jersey, USA
Maybridge Maybridge Chemical Company Ltd., Cornwall, United Kingdom
Aldrich Sigma Aldrich, Gillingham, Dorset, United Kingdom; and xv) starting materials for reactions are commercially available unless otherwise indicated.
Example 1
2-Amino-9-ethylcarbazole dihydrochloride
2-Nitro-9-ethylcarbazole (Method 12; 2.00 g, 8.30 mM) in EtOAc (10 ml) and EtOH (20 ml) was hydrogenated over 10% palladium on carbon at ambient temperature under atmospheric pressure of hydrogen. The catalyst was filtered off through diatomaceous earth and the filtrate concentrated. The residue was redissolved in DCM and HCl in ether (1 M) added. Filtration gave the title product as an off-white solid. Yield 1.64 g (94%). Rf (Zl) 0.55; NMR 8.26 (d, IH), 8.18 (d, IH), 7.66 (d, IH), 7.58 (s, IH), 7.50 (dd, IH), 7.25 (d, IH), 7.21 (d, IH), 4.40 (q, 2H), 1.32 (t, 3H); m/z 211.4.
Examples 2-10
The following compounds were prepared by the procedure of Example 1 using the appropriate starting materials.
' MeOH and palladium on carbon 5% were used instead of EtOH and palladium on carbon 10%. Filtration from celite the only purification.
2 Starting Material described in Synth Comm, 1994, 24, 1-10.
3 Product purified by flash chromatography (5% EtOH/DCM)
Example 11
3-Amino-6-cyano-9-ethylcarbazole
6-Cyano-3-nitro-9-N-ethyl carbazole (Method 35; 780 mg) was refluxed with tin (II) chloride dihydrate (4.6 g) in EtOH (6 ml) for 2 hours . After cooling to ambient temperature, water (50 ml) was added, the mixture was basifed with 2M sodium hydroxide and extracted with DCM (3 x 30 ml). The combined organic extracts were washed with brine (2 x 10 ml), dried and evaporated under reduced pressure to give the title compound (403 g). NMR (CDClj) 1.4 (t, 3H), 4.3 (q, 2H), 7.0 (s, IH), 7.2 (d, IH), 7.4 (m, 2H), 7.6 (d, IH), 8.3 (s, IH): m/z 236.
Example 12
3-(4-NitrophenoxycarbonylaminoV9-ethylcarbazole dihydrochloride
To a solution of/?-nitrophenyl chloroformate (9.62 g, 48 mmol) in EtOAc (100 ml) was added potassium carbonate (6.57 g, 48 mmol). To this was added 3-amino-9- ethylcarbazole (Example 1; 10.00 g, 48 mmol) dropwise in EtOAc (100 ml). After the addition was complete the reaction was stirred for lh before washing with water, brine and then dried. The solution was then dry loaded onto silica and chromatographed with DCM / isohexane. A yellow solid was isolated 12.85 g (72%). NMR 1.30 (t, 3H), 4.40 (q, 2H), 6.93 (d, 2H), 7.17 (t, IH), 7.50 (m, 4H), 8.10 (t, 3H), 8.32 (s, IH), 8.60 (s, IH).
Example 13-14
The following compounds were prepared by the procedure of Example 12 using the appropriate starting materials.
Example 15
3-(3-Pyrid-4-ylpropionamido)-9-ethylcarbazole To a solution of 3-pyridin-4-ylpropanoic acid (Method 3; 20 g, 132 mmol), DMAP (27 g, 220 mmol) and ED AC (42 g, 220 mmol) in DMF (100 ml) at room temperature was added 3-amino-9-ethylcarbazole (Ref Ex 15; 23 g, 110 mmol). After 18 hours the reaction was concentrated and water (300 ml) was added followed by MeOH (30 ml). The resulting precipitate was recrystalhzed from EtOAc (100 ml) to give a white solid. Yield 15.4 g (42%). Rf (Zl) 0.13; NMR 9.96 (s, IH), 8.47 (d, 2H), 8.38 (s, IH), 8.04 (d, IH), 7.50 (m, 3H), 7.44 (t, IH), 7.30 (d, 2H), 7.18 (t, IH), 4.40 (q, 2H), 2.98 (t, 2H), 2.70 (t, 2H), 1.30 (t, 3H); MS (ES+) 344.4 [MH+].
Examples 16-128 The following compounds were prepared by the procedure of Example 15 using the appropriate starting materials.
1 Resultant compound was purified by flash column chromatography
2 Double bond of E stereochemistry
Pol J Chem, 1983, 57, 839 - 47
4 Lancelot J.C. et. al, Chem. Pharm. Bull., 1984, 32 (11), 4447-54
5 Starting Material was 9-(4-aminophenyl)carbazole
6 PL 163595
7 Canad. J. Chem, 1970, 48, 1566-73
5 8 J Prakt Chem/Chem Ztg, 1996, 338, 731-737
9 J Org Chem, 1966, 31, 3948-51
10 Org Prep Proced Int, 1999, 31, 693-4
11 J Org Chem, 1981, 46, 2473-6
12 J Chem Soc (C), 1967. 2156-70 10 13 J Chem Soc, 1964, 446-51
14 J Braz Chem Soc, 1993, 4, 84-5
15 HOBT was used instead of DMAP
16 J Org Chem, 1967, 32, 2823-8
17 J Amer Chem Soc, 1955, 77, 2572 15
Example 129 9-Ethy1-3-[(4-N-methylcarbamoylpiperid-l-yl)carbonylamino]carbazole
9-Ethyl-3-[(4-carboxypiperid-l-yl)carbonylamino]carbazole (Example 187; 250 mg, 0.68 mM), HOBT (105 mg, 0.68 mM), EDAC (132 mg, 0.68 mM), DMF (10 ml) and 0 methylamine (8 M in EtOH, 0.17 ml, 1.4 mM) were stirred at room temperature overnight and then evaporated to dryness. The residue was dissolved in DCM (10 ml), washed with water (5 ml), extracted with hydrochloric acid (2 M). The extraction was allowed to stand for 15 mins and the solid precipitate was collected by filtration. ΝMR: 8.45 (s, IH), 8.13 (s, IH), 8.01 (d, IH), 7.71 (m, IH), 7.53 (d, IH), 7.45 (s, 2H), 7.40 (t, IH), 7.13 (t, IH), 4.37 (q, 2H), 4.16 (d, 5 2H), 2.80 (t, 2H), 2.57 (d, 3H), 2.31 (m, IH), 1.69 (m, 2H), 1.51 (m, 2H), 1.28 (t, 3H); m/z 379.
Examples 130-132
The following compounds were prepared by the procedure of Example 129 using 9- 30 ethyl-3-[(4-carboxypiperid-l-yl)carbonylamino]carbazole (Example 187) and the appropriate amine.
Example 133
9-Ethyl-3-(2-methylpropionamido carbazole
To a solution of 3-amino-9-ethylcarbazole (Reference Example 15; 4.20 g, 20 mmol) in DCM (50 ml) was added triethylamine (2.22 g, 22 mmol) and the stirred mixture was cooled in an ice/MeOH bath. A solution of zsø-butyrylchloride (2.13 g, 20 mmol) in DCM (50 ml) was added slowly over 30 minutes and the reaction mixture was allowed to warm to ambient temperature and was stirred for 16 hours. The black mixture was washed with water (2 x 100 ml), brine (50 ml) and finally dried, filtered and reduced in vacuo to give a black residue, this was triturated with a 1 :1 mixture of ether : isohexane (50 ml) then washed with a little ether to give the title product (3.19 g). NMR 1.13 (d, 6H), 1.29 (t, 3H), 2.62 (sept, IH),
4.39 (q, 2H), 7.15 (t, IH), 7.42 (t, IH), 7.53 (m, 3H), 8.03 (d, IH), 8.40 (s, IH), 9.77 (s, IH); MS (ES+) 281 (MH)+.
Examples 134-139 The following compounds were prepared by the procedure of Example 133 using the appropriate starting materials.
Product purified by chromatography - eluent gradient of DCM to EtOAc
Example 140
9-Ethyl-3-fethyloxyoxalylamino)carbazole Ethyl oxalyl chloride (245 μl) was added to a solution of 9-ethyl-3-aminocarbazole
(Reference Example 15; 350 mg) in THF (10 ml) containing calcium carbonate (110 mg). After stirring for 4 hours at ambient temperature the mixture was carefully acidified to pH = 3 using 1 M HCl and then extracted with EtOAc (2 x 20 ml). The combined organic extracts were washed with water (10 ml) and saturated brine (10 ml), dried and the solvents removed under reduced pressure. The resulting greenish solid was recrystalhzed twice from EtOAc to give the title compound (0.31 g). Mp 140-141°C; found : C, 69.8%; H, 5.8%: N, 8.9%; C18H18N2O3 requires C, 69.7%; H, 5.8%; N, 9.0%; NMR: 1.2-1.4 (6H, q), 4.3-4.5 (4H, m), 7.1- 7.2 (IH, t), 7.4-7.5 (IH, t) 7.5-7.6 (2H, d), 7.7-7.8 (IH, d), 8.0-8.1 (IH, d), 8.5 (IH, s), 10.8 (IH, s); m/z 311.
Example 141 9-Ethyl-3-mesylaminocarbazole
A solution of methanesulphonyl chloride (0.33 g, 2.9 mmol) in DCM (2.5 ml) was added over 5 minutes to a solution of 3-amino-9-ethylcarbazole (Reference Example 15; 0.50 g, 2.4 mmol), triethylamine (0.40 ml, 2.9 mmol) and DMAP (ca. 10 mg) in DCM (12 ml) at room temperature. The resulting dark coloured solution was stirred at room temperature for 18 hours. The mixture was diluted with DCM (13 ml) and washed with water (25 ml) and brine (25 ml). The organic phase was dried and evaporated in vacuo to leave a black solid. The crude product was purified by flash chromatography eluting with DCM to give the product as a light brown solid. NMR 9.40 (IH, s), 8.10 (IH, d), 7.98 (IH, s), 7.60 (2H, d), 7.45 (IH, t), 7.36 (IH, dd), 7.19 (IH, t), 4.41 (2H, q), 2.92 (3H, s), 1.32 (3H, t); MS (ES-) 287 (MH-).
Examples 142-146
The following compounds were prepared by the procedure of Example 141 using the appropriate sulphonyl chloride.
1 Syn, 1979, 5, 321-2
2 Double bond of (E)-stereochemistry
Example 147
9-Ethyl-3-[N-(2-pyridin-4-ylethyl)carbamoyl]carbazole
To a solution of 9-ethyl-3-carboxycarbazole (Method 11; 1.96 g, 8.2 mmol), DMAP (1.1 g, 9 mmol) and ED AC (1.72 g, 9 mmol) in DMF (15 ml) at room temperature was added 3-pyridin-4-ylpropylamine (1.05 g, 8.6 mmol). After 18 hours water (100 ml) was added and the mixture extracted with DCM (3 x 100 ml). The organic layers were concentrated to give a brown gum which was purified by flash column chromatography (Z3). Yield 851 mg (30%). ΝMR 8.64 (s, IH), 8.56 (t, IH), 8.44 (d, 2H), 8.15 (d, IH), 7.94 (d, IH), 7.64 (d, 2H), 7.49 (t, IH), 7.27 (m, 3H), 4.43 (q, 2H), 3.58 (q, 2H), 2.90 (t, 2H), 1.31 (t, 3H); MS (ES+) 344.3 [MH+].
Example 148
9-Ethyl-3-carbamoylcarbazole
To a solution of 9-ethyl-3-carboxycarbazole (Method 11; 7.347 g, 30.7 mmol) and triethylamine (4.32 ml, 31 mmol) in dry THF (100 ml) was added ethyl chloroformate (2.96 ml, 31 mmol) slowly at 0°C under an argon atmosphere. 2 hours after warming to room temperature ammonium hydroxide (30 ml) was added slowly. After 3 hours the reaction mixture was concentrated, water (100 ml) was added and the mixture extracted with EtOAc (2 x 100 ml). The organic layer was dried and concentrated to give a yellow solid. Yield 5.76 g (79%). Rf (Zl) 0.33; ΝMR 8.72 (s, IH), 8.17 (d, IH), 8.01 (d, IH), 7.62 (d, 2H), 7.46 (t, IH), 7.22 (t, IH), 6.38 (brs, IH), 4.47 (q, 2H), 1.31 (t, 3H); m/z 239.4.
Example 149
9-Ethyl-3-aminomethylcarbazole To a solution of 9-ethyl-3-carbamoylcarbazole (Example 148; 5.5 g, 23.1 mmol) in dry THF (100 ml) was added lithium aluminium hydride (1 M solution in THF; 25 ml, 25 mmol) slowly at 0°C under an argon atmosphere. After complete addition the mixture was heated to reflux for 72 hours. After cooling to 0°C, water (100 ml) then 15%ι w/v sodium hydroxide solution (100 ml) were added to the orange mixture before stirring for 1 hour. The mixture was filtered under vacuum before the filtrate was concentrated, water (100 ml) was added followed by extraction with DCM (2 x 100 ml). The organic layer was dried over
sodium sulphate and concentrated to give a yellow oil. Chromatography (eluent gradient of Z4 to Z6 then Z7 to Z8) gave a brown oil which solidified on standing. Yield 902 mg (17%). Rf (Z2) 0.5; NMR (CDC13) 8.06 (d, IH), 8.01 (s, IH), 7.45 (m, 4H), 7.23 (m, IH), 4.34 (q, 2H), 4.02 (s, 2H), 1.42 (t, 3H); m/z 208.3 [M - NH3]+.
Example 150
The following compound was prepared by the procedure of Example 149 using the appropriate starting materials.
' Purified on an ISOLUTE column (10 g) (eluent gradient of Z9 to Zl then to Z10)
Example 151
9-Ethyl-3-[(2-methylpropionamido)methyl] carbazole
To a solution of 9-ethyl-3-aminomethylcarbazole (Example 149; 300 mg, 1.34 mmol) and diisopropylethylamine (244 μl, 1.4 mmol) in DCM (5 ml), isobutyryl chloride (155 μl, 1.4 mmol) was slowly added. After stirring at room temperature for 2 hours, water (5 ml) was added before the organic layer was concentrated. Chromatography on a Bond Elut column (eluent gradient of Zl l to Zl) gave a white solid. Yield 158 mg (40%). Rf (Zl) 0.5; NMR (CDCI3) 8.08 (d, IH), 8.00 (s, IH), 7.49 (t, IH), 7.39 (m, 3H), 7.22 (m, IH), 5.73 (brs, IH), 4.60 (d, 2H), 4.37 (q, 2H), 2.40 (m, IH), 1.20 (d, 6H); m/z 295.4.
Example 152
9-Ethyl-3-isopropoxycarbonylaminocarba7,ole
To a solution of 3-amino-9-ethylcarbazole (Reference Example 15; 1.050 g, 5 mmol) in DCM (20 ml) was added triethylamine (0.555 g 5.5 mmol) and the resultant mixture was cooled in an ice bath. A 1.0 M solution of z'so-propylchloro formate in toluene (5 ml, 5 mmol) was added slowly over 30 minutes at ambient temperature and the resultant mixture was stirred for 16 hours. A white precipitate formed which was removed by filtration and the black filtrate was washed with water (2 x 25 ml), brine (25 ml) and finally dried, filtered and reduced in vacuo to give a black residue which was purified by chromatography on a Bond Elut column (20 g) eluting with DCM. The residue thus obtained was crystallised in 1 : 1 ether : isohexane to give the title product as a pale brown solid. NMR 1.27 (9H, m), 4.40 (2H, q), 4.94 (IH, m), 7.16 (IH, t), 7.43 (2H, t), 7.53 (IH, d), 7.58 (IH, d), 8.04 (IH, d), 8.26 (IH, s), 9.48 (IH, s); m/z 297.
Example 153
The following compound was prepared by the procedure of Example 152 using 3- amino-9-ethylcarbazole (Reference Example 15) and the stated starting material.
Example 154
3-(N-Methyl-3-pyrid-4-ylpropionamidoV9-ethylcarbazole
Sodium Hydride (60% dispersion in oil; 65 mg, 1.5 mM) was added to a solution of 3- (3-pyrid-4-ylpropionamido)-9-ethylcarbazole (Example 15; 500 mg, 1.5 mM) in THF (10 ml) at 0°C under an argon atmosphere. After heating to 50°C for 2 hours the mixture was allowed
to cool to room temperature and methyl iodide (0.1 ml, 1.5 mM) was added dropwise. After heating to 50°C for 2 hours the mixture was allowed to cool to room temperature. Water (30 ml) was added and the resulting mixture was extracted with EtOAc (3 x 50 ml). The organic layers were concentrated and then purified by flash column chromatography to give a brown 5 gum. Yield 225 mg (43%). NMR 8.32 (d, 2H), 8.11 (d, IH), 7.88 (s, IH), 7.64-7.56 (m, 2H), 7.45 (t, IH), 7.28 (m, IH), 7.19 (t, IH), 7.05 (d, 2H), 4.42 (q, 2H), 3.25 (s, 3H), 2.78 (t, 2H), 2.35 (t, 2H), 1.30 (t, 3H); m/z 358.4.
Example 155
10 The following compounds were prepared by the procedure of Example 154 using the appropriate starting materials.
Example 156
15 3-(N-Propylureido)-9-ethylcarbazole
To a solution of 3-amino-9-ethylcarbazole (Reference Example 15; 1.00 g, 4.8 mM) and triethylamine (0.8 ml, 4.8 mM) in DMF (20 ml) at 0°C was added N-propylisocyanate (0.42 ml, 4.8 mM). After 90 minutes water (100 ml) was added and the resultant solid filtered off, washed with water (300 ml) then recrystalhzed from EtOAc, as a white powder. Yield
20 700 mg (50%). ΝMR 8.28 (s, IH), 8.16 (s, IH), 8.02 (d, IH), 7.52 (m, IH), 7.38 (m, 3H), 7.12 (t, IH), 6.02 (t, IH), 4.36 (t, 2H), 3.06 (q, 2H), 1.45 (m, 2H), 1.28 (t, 3H), 0.89 (t, 3H); m/z 296.5.
Example 157
3 -(N'. N -Diethylureido)-9-ethylcarbazole
To a solution of 3-amino-9-ethylcarbazole (Reference Example 15; 1.00 g, 4.8 mM) and triethylamine (0.8 ml, 4.8 mM) in DMF (10 ml) at 0°C was added diethylcarbamoyl chloride (0.60 ml, 4.8 mM). After warming to room temperature and stirring for 48 hours, diethylcarbamoyl chloride (0.30 ml, 2.4 mM) was added. After 24 hours a mixture of MeOH water; 1 : 2 (50 ml) was added and the suspension was concentrated to give a white solid. Yield 327 mg (22%). Rf (Zl l) 0.53; NMR 8.12 (d, 2H), 8.03 (d, IH), 7.48 (m, 4H), 7.12 (t, IH), 4.37 (q, 2H), 3.36 (q, 4H), 1.28 (t, 3H), 1.10 (t, 6H); m/z 310.4.
Examples 158 - 161
The following compounds were prepared by the procedure of Example 157 using morpholine chloroformate and the appropriate carbazole.
Example 162
3-[4-(Pyrid-4-ylmethyl)phthalazin- 1 -ylamino]-9-ethylcarbazole l-Chloro-4-(pyrid-4-ylmethyl)phthalazine (Method 15; 100 mg, 0.39 mmol) and 3- amino-9-ethylcarbazole (Reference Example 15; 0.47 mmol) in isopropanol (1 ml) containing 5.5 M HCl in isopropanol (78 μl, 0.43 mmol) was heated at 85°C for 5 min. Further isopropanol (5 ml) was added and heating was continued for 2 days. After cooling , the precipitate was filtered, washed with ether and dried under vacuum to give the title product (121 mg). NMR (500 MHz) 11.5 (IH, brs), 8.95 (IH, m), 8.61 (2H, d), 8.32 (2H, m), 8.24 (2H, m), 8.16 (IH, d), 7.81 (IH, d), 7.68 (IH, d), 7.58 (3H, m), 7.52 (IH, t), 7.24 (IH, t), 4.70 (2H, s), 4.52 (2H, q), 1.36 (3H, t); m/z 429.
Example 163
(EV 3 -(4.4.4-Trifluoro-3-oxo- 1 -buten- 1 -ylV9-ethylcarbazole 3-Formyl-9-ethylcarbazole (1.12 g, 5 mmol) was dissolved in anhydrous THF (30 ml) and piperidine (0.4 g) and acetic acid (0.4 g) were added and the mixture cooled to 0°C under argon. Trifluoroacetone (2 ml) in dry THF (10 ml) was added over 5 minutes and then the reaction mixture was allowed to warm to room temperature and stirred for 16 hours before evaporating to dryness. The residue was dissolved in EtOAc (50 ml), washed with ammonium chloride solution (2 x 50 ml), dried, filtered and concentrated. The crude product was purified by chromatography using 20%> DCM in isohexane as eluent to give the product as a red solid (655 mg, 41%). NMR (CDC13) 8.35 (IH, d), 8.2 (IH, d), 8.12 (IH, d), 7.75 (IH, dd), 7.5 (IH, m), 7.4 (2H, m), 7.3 (IH, m), 7.05 (IH, d), 2.38 (2H, q), 1.45 (3H, t); m/z 318.
Example 164
3-Mo holinocarbonylamino-9-ethylcarhazole
To a solution of 3-(4-nitrophenoxycarbonylamino)-9-ethylcarbazole (Example 12; 250 mg, 0.67 mmol) and DMAP (4 mg, 0.03 mmol), in EtOAc (10 ml) was added morpholine (0.067 ml, 0.73 mmol) at ambient temperature. The mixture was stirred for 18 hours then filtered to give the title product 145 mg (67 %). NMR 1.28 (t, 3H), 3.44 (m, 4H), 3.63 (m, 4H), 4.37 (q, 2H), 7.13 (t, IH), 739 (t, IH), 7.45 (s, 2H), 7.52 (d, IH), 8.00 (d, IH), 8.13 (s, IH), 8.51 (s, IH); m/z 324.
Examples 165 - 238
The following compounds were prepared by the procedure of Example 164 using 3-(4- nitrophenoxycarbonylamino)-9-ethylcarbazole (Example 12) or 3-(4-nitrophenoxycarbonyl- amino)-9-mesylcarbazole (Example 13) or 3-(4-nitrophenoxycarbonylamino)-9-(NN- dimethylsulphamoyl)carbazole (Example 14) and the appropriate amine.
2 Amine: Tetrahedron, 1992, 48(11), 1999.
3 Amine: Method 20
4 Amine: Tetrahedron, 1998, 54(10), 2181-2208 5 Compound of (R) stereochemistry
6 Amine: J Org Chem, 1962, 27, 3251-3
7 Amine: J Am Chem Soc, 1946, 68, 14-18
Example 239
3-[4-(NN-Dimethy1aminomethyDpiperidin-l-ylcarbonylamino]-9-ethylcarbazo1e
To a stirred solution of 3-[4-(NN-mesyloxymethyl)piperidin-l-ylcarbonylamino]-9- ethylcarbazole (Example 145; 250 mg, 0.58 mM) in DCM (10 ml) was added dimethylamine solution (33% in EtOH; 10 ml). The solution was heated at reflux for 18 hours before adding additional dimethylamine solution (33 > in EtOH; 10 ml) and stirring for a further 18 hours. The reaction was then concentrated in vacuo. The crude solids were dissolved in DCM and washed twice with water before drying and concentrating in vacuo. These solids were purified by chromatography eluting with a MeOH/ DCM mixture. The desired product was isolated as a gum, yield 20 mg (9%). ΝMR 8.40 (s, IH), 8.13 (s, IH), 8.01 (d, IH), 7.53 (d, IH), 7.45 (s, 2H), 7.40 (t, IH), 7.13 (t, IH), 4.37 (q, 2H), 4.13 (d, 2H), 2.79 (t, 2H), 2.13 (m, 8H), 1.71 (m, 3H), 1.28 (t, 3H), 1.03 (m, 2H); m/z 379.
Example 240 3-(3-Methoxy-2-aminopropionamidoV9-ethylcarbazole
Trifluoroacetic acid (1.0 ml) was added to a solution of 3-(3-methoxy-2-t- butyloxycarbonylaminopropionamido)-9-ethylcarbazole (Example 52; 0.5 g) in DCM (10 ml) at room temperature. The dark mixture was stirred overnight at room temperature. The mixture was diluted with DCM (25 ml) and washed with aqueous sodium hydroxide (1 M, 20 ml). The organic layer was washed with brine (25 ml), dried and evaporated in vacuo to leave a brown oil. The crude product was purified by flash chromatography eluting with DCM/2%MeOH to leave the product as a brown oil. The amine was dissolved in EtOAc (10 ml) and a solution of HCl (2 M) in EtOAc (5 ml) was added. The solution was evaporated in vacuo and the residue triturated with ether (10 ml) to leave a grey solid. ΝMR 10.75 (s, IH), 8.4 (brs, 4H), 8.05 (d, IH), 7.65-7.55 (m, 3H), 7.45 (t, IH), 7.2 (t, IH), 4.4 (q, 2H), 4.25 (brs, IH), 3.8 (d, 2H), 3.3 (s, 3H), 1.3 (t, 3H); m/z 312.
Examples 241-244
The following compounds were prepared by the procedure of Example 240 using the appropriate starting materials.
Example 245
3-(2-Hydroxy-2-methylpropionamidoV9-ethylcarbazole Sodium hydroxide (0.19 g, 4.8 mmol) was added to a solution of 3-(2-acetoxy-2- methylpropionamido)-9-ethylcarbazole (Example 136; 0.47 g, 1.4 mmol) in MeOH (10 ml) and water (5 ml). The solution was stirred at room temperature overnight. The solvent was removed in vacuo and the residue shaken with HCl (1 M, 4.8 ml, 4.8 mmol) and extracted with DCM (25 ml). The organic layer was separated, washed with brine (25 ml), dried and evaporated in vacuo to leave a light brown solid. The crude product was recrystalhzed from aqueous EtOH to leave the product as a light brown microcrystalline solid. NMR 9.5 (s, IH),
8.5 (d, IH), 8.05 (d, IH), 7.7 (dd, IH), 7.55 (d, IH), 7.5 (d, IH), 7.4 (t, IH), 7.2 (t, IH), 5.7 (s, IH), 4.4 (q, 2H), 1.4 (s, 6H), 1.3 (t, 3H); m/z 297.
Example 246 3-(4-Phenoxymethylpiperidin-l-ylcarbonylamino)-9-ethylcarbazole
To a solution of 3-[4-(mesyloxymethyl)piperidin-l-ylcarbonylamino]-9-ethylcarbazole (Example 145; 250 mg, 0.58 mM) and phenol (120 mg, 1.28 mM) in DMF (10 ml) was added potassium carbonate (176 mg, 1.28 mM). The slurry was stirred for 18 hours before concentrating in vacuo. The residue was dissolved in DCM and washed twice with water, then saturated sodium hydrogen carbonate before drying and concentrating to afford a crude solid. This was chromatographed eluting with EtOAc/ isohexane mixtures. A gum was afforded, yield 50 mg (20%). NMR 8.45 (s, IH), 8.13 (s, IH), 8.01 (d, IH), 7.53 (d, IH), 7.45 (s, 2H), 7.40 (t, IH), 7.27 (t, 2H), 7.13 (t, IH), 6.93 (m, 3H), 4.37 (q, 2H), 4.19 (d, 2H), 3.85 (d, 2H), 2.93 (t, 2H), 1.99 (brs, IH), 1.81 (d, 2H), 1.28 (m, 6H); m/z 428.
Example 247 3-(4-Phenoxyethylpyrrolidin-l-ylcarbonylamino -9-ethylcarbazole
This title compound was produced as a by-product of Example 246 and was purified by flash chromatography from the same reaction mixture. NMR 8.17 (s, IH), 8.07 (s, IH), 8.01 (d, IH), 7.45 (m, 4H), 7.27 (t, 2H), 7.13 (t, IH), 6.93 (m, 3H), 4.37 (q, 2H), 4.03 (t, 2H), 3.68 (m, IH), 3.56 (m, IH), 3.35 (m, IH), 3.05 (t, IH), 2.36 (m, IH), 2.08 (brs, IH), 1.85 (q, 2H), 1.64 (m, IH), 1.28 (m, 6H); m/z 428.
Example 248 3-(Pyrid-2-ylaminoV9-ethylcarbazole
9-Ethyl-3-aminocarbazole (Reference Example 15; 456 mg, 2.17 mM) was dissolved in 2-fluoropyridine (2 ml) and heated to 120°C for 18 hours under an inert atmosphere. On cooling the mixture was diluted with DCM, washed with aqueous potassium carbonate solution, dried over sodium sulphate and concentrated. Chromatography (eluent gradient of hexane to EtOAc) gave the title compound as a pale brown solid (433 mg, 70%). Rf
(MeOH:DCM -1:19) 0.40; NMR 8.87 (IH, m), 8.41 (IH, d), 8.15 (IH, dd), 8.06 (IH, d), 7.63-
7.45 (4H, m), 7.42 (IH, t), 7.15 (IH, t), 6.79 (IH, d), 6.67 (IH, dd), 4.02 (2H, q), 1.32 (3H, t); m/z 288.47.
Example 249 3-(Benzimidazol-2-ylamino)-9-ethylcarbazole
A mixture of 9-ethyl-3-isothiocyanatocarbazole (Method 34; 378 mg, 1.5 mmol), 1,2- phenylenediamine (216 mg, 2.0 mmol) and yellow mercuric oxide (432 mg, 2.0 mmol) in EtOH (10 ml) was stirred for 8 hours under reflux in an argon atmosphere and allowed to cool overnight. The mixture was partitioned between EtOAc and water, and the organic phase was separated and washed with brine, dried and evaporated to dryness. The crude product was chromatographed, eluting with 0-6% EtOH in DCM to yield the title compound (129 mg) as a grey solid. NMR 10.84 (IH, brs), 9.20 (IH, s), 8.44 (IH, d), 8.07 (IH, dd), 7.72 (IH, dd), 7.55 (2H, d), 7.41 (1 H, dd), 7.30 (IH, brd), 7.24 (IH, brd), 7.15 (IH, dd), 6.95 (2H, brdd), 4.40 (2H, q), 1.31 (3H, t); m/z 327.
Example 250 3-(6-Methylpyridazin-3-ylamino)-9-ethylcarbazo1e
Example 251 3-[NN-Di-(6-methylpyridazin-3-yl ammo]-9-ethylcarbazole
9-Ethyl-3-aminocarbazole (Reference Example 15; 4.52 g, 21.48 mM), 3-chloro-6- methylpyridazine (2.76 g, 21.48 mM), S-2,2'-bis(diphenylphosphino)-l,l'-binaphthyl (535 mg, 0.86 mM) and tris(dibenzylideneacetone)dipalladium(0) (394 mg, 0.43 mM) were added to sodium t-butoxide (2.89 g, 30.07 mM) in toluene (10 ml) under an inert atmosphere and heated to 80°C for 18 hours. On cooling, the mixture was diluted with DCM, washed with aqueous potassium carbonate solution, dried over sodium sulphate and concentrated.
Chromatography (eluent gradient of hexane to EtOAc then MeOH) gave a mixture of the title compounds.
3-(6-Methylpyridazin-3-ylamino)-9-ethylcarbazole: Yield 2.20 g (34%); Rf (EtOAc) 0.13; ΝMR (CDC13) 8.04 (IH, d), 8.00 (IH, d), 7.53-7.33 (4H, m), 7.27 (IH, d), 7.22 (IH, t),
7.02 (IH, t), 6.99 (IH, brs), 6.90 (IH, d), 4.39 (2H, q), 2.58 (3H, s), 1.45 (3H, t); m/z 303.30.
3-[NN-Di-(6-methylρyridazin-3-yl)amino]-9-ethylcarbazole: Yield 301 mg (4%); Rf (MeOH:DCM- 1 :9) 0.40; ΝMR 8.13 (IH, d), 8.09 (IH, d), 7.69 (IH, d), 7.63 (IH, d), 7.46 (IH, t), 7.42 (2H, d), 7.28 (IH, d), 7.26 (IH, d), 7.15 (IH, t), 4.48 (2H, q), 2.52 (6H, s), 1.34 (3H, t); m/z 395.34.
Examples 252 - 260
The following compounds were prepared by the procedure of Example 250 using the appropriate starting materials.
1 3-Chloro-6-methylpyridazine
2 3-Bromo-6-methylpyridine
3 3-Bromopyridine
4 3-Chloro-6-trifluoromethylpyridazine (Tetrahedron, 1999, 55, 15067-70)
5 3-Chloro-6-pyrid-4-ylpyridazine (US 4590194)
6 3-Chloro-6-cyanopyridazine (Eur J Med Chem, 1984, 19, 111-117) 7 3,6-dichloropyridazine
Example 261
3-(6-Carbamoylpyridazin-3-ylaminoV9-ethylcarbazole
9-Ethyl-3-aminocarbazole (Reference Example 15; 683 mg, 3.25 mM) and 3-chloro-6- carbamoylpyridazine (512 mg, 3.25 mM) were dissolved in DMF (7 ml) and heated to 110°C for 18 hours. On cooling the mixture was poured onto water and the resultant solid isolated. The solid was chromatographed (eluent gradient of DCM to EtOAc then MeOH) to give the title compound as an off white solid. Yield 184 mg (17%). Rf (EtOAc) 0.20; NMR 9.68 (IH, brs), 8.54 (IH, d), 8.24 (IH, brs), 8.07 (IH, d), 7.92 (IH, d), 7.70-7.50 (4H, m), 7.46 (IH, t), 7.25-7.10 (2H, m), 4.40 (2H, q), 1.30 (3H, t); m/z 332.34.
Examples 262 - 263
The following compounds were prepared by the procedure of Example 261 using the appropriate starting materials.
Example 264
N2-Cyano-N'-(9-ethylcarbazol-3-yl)methylthiocarboxamidine
To a solution of dimethyl N-cyanodithioiminocarbonate (10.42 g, 71.4 mmol) in EtOH 5 (100 ml) at room temperature was slowly added a solution of 3-amino-9-ethylcarbazole (Reference Example 15; 5.0 g, 23.8 mmol) in EtOH (100 ml). After being heated at reflux for 72 hours the reaction mixture was concentrated and absorbed onto silica. Chromatography (eluent 30% EtOAc / isohexane - 10% MeOH/ EtOAc) yielded the title compound as a brown solid (3.822 g, 52%). Rf (50% EtOAc /isohexane) 0.52; ΝMR 10.30 (s, IH), 8.20 (m, 2H), 10 7.60 (m, 2H), 7.45 (m, 2H), 7.20 (t, IH), 4.45 (q, 2H), 2.65 (s, 3H), 1.3 (t, 3H); m/z 309.5.
Example 265
Ν2-Cyano-Ν'-(9-ethylcarbazol-3-yl)morpholinocarboxamidine
A mixture of N2-cyano-N'-(9-ethylcarbazol-3-yl)methylthiocarboxamidine (Example
15 264; 268 mg, 0.87 mmol), silver nitrate (170 mg, 1 mmol), morpholine (0.08 ml, 0.9 mmol) and triethylamine (4 ml) in dry DMF (6 ml) was stirred at room temperature for 20 hours. The reaction mixture was concentrated and azeotroped with toluene before being absorbed onto silica. Chromatography on a Bond Elut column (20 g) (Eluent - EtOAc) yielded the title compound as a brown solid. Rf (EtOAc) 0.33; NMR (CDC13) 8.05 (d, IH), 7.80 (s, IH), 7.55
20 (m, IH), 7.45 (m, IH), 7.40 (m, IH), 7.15 (dd, IH), 7.10 (s, IH), 4.40 (q, 2H), 3.60 (m, 4H), 3.40 (m, 4H), 1.45 (t, 3H); m/z 348.5.
Example 266
3-(Succinimid-l-yl)-9-ethylcarbazole 25 The title compound was isolated as a by-product in the synthesis of Example 66. NMR
8.1 (d, IH), 8.0 (d, IH), 7.7 (d, IH), 7.65 (d, IH), 7.5 (t, IH), 7.25 (dd, IH), 7.2 (t, IH), 4.5 (q, 2H), 2.8 (s, 4H), 1.3 (t, 3H); m/z 293.
Example 267
2-Methyl-3-(t-buty1carbonylamino)-9-ethylcarbazole
Example 268 l-Methyl-3-(t-butylcarbonylamino)-9-ethylcarbazole
A solution of 3-(t-butylcarbonylamino)-9-ethylcarbazole (Example 139; 1.18 g, 4.0 mmol) in dry THF (15 ml) was cooled to -30°C under a stream of argon. 1.7 M tert- butyllithium in pentane (5.15 ml, 8.8 mmol) was added cautiously to the stirred mixture over a period of 10 minutes, the mixture was allowed to warm to 0°C over a period of 30 minutes and then re-cooled to -30°C. lodomethane (596 mg, 4.2 mmol) was added slowly, the mixture stirred for 3 hours at ambient temperature then reduced in vacuo. The residue was chromatographed (eluent 1 : 3 EtOAc in isohexane) to give the title compounds. Example 267: (214 mg). NMR 8.94 (s, IH), 8.05 (d, IH), 7.84 (s, IH), 7.54 (d, IH), 7.43 (s, IH), 7.38 (t, IH), 7.12 (t, IH), 4.38 (q, 2H), 2.31 (s, 3H), 1.27 ( , 12H); m/z 309. Example 268: (8.7 mg). NMR 9.12 (s, IH), 8.19 (s, IH), 7.78 (d, IH), 7.54 (d, IH), 7.39 (t, IH), 7.33 (t, IH), 7.14 (t, IH), 4.55 (q, 2H), 2.73 (s, 3H), 1.29 (t, 3H) 1.23 (s, 9H); m/z 309.
Example 269
6-Fluoro-9-isopropyl-3-(morpholinocarbonylamino carbazole Triethylamine (139 μl, 1 mmol) was added to a stirred suspension of 6-fluoro-9- isopropyl-3-carboxycarbazole (Method 36; 271 mg, 1 mmol) and diphenylphosphorylazide (275 mg, 1.1 mmol) in dry toluene (15 ml) under argon. The resultant solution was stirred at ambient temperature for one hour then heated to reflux for one hour. The heat source was removed and morpholine (200 μl, 3 mmol) was added and the resultant solution stirred overnight at ambient temperature. The mixture was filtered, the filtrate diluted with EtOAc (30 ml) and washed with water (10 ml), IM HCl (10 ml), 0.2M NaOH (10 ml), water (10 ml), saturated brine (10 ml), dried and evaporated to dryness under reduced pressure. The resultant gum was purified using a Bond Elut column (20 g) eluting with 0.5% MeOH/DCM to give the title compound (259 mg) as a white solid. NMR (CDC13) 1.6 (t, 6H), 3.5 (t, 4H), 3.7 (t, 4H), 4.9 (m, IH), 7.1 (t, IH), 7.2-7.4(m, 3H), 7.6 (d, IH), 8.0 (s, IH); m/z 356.
Example 270
The following compound was prepared by the procedure of Example 269 using the appropriate morpholine starting material.
Example 271
6-Fluoro-9-isopropyl-3-ethoxycarbonylcarbazole
6-Fluoro-3-ethoxycarbonylcarbazole (Example 272) was alkylated with 2- bromopropane by the procedure of Method 12. NMR (CDC13) 1.4 (t, 3H), 1.7 (d, 6H), 4.5 (q, 2H), 5.0 (m, IH), 7.2 (t, IH), 7.4 (d, IH), 7.5 (d, IH), 7.8 (d, IH), 8.2 (d, IH), 8.8 (s, IH); m/z 300.
Example 272
6-Fluoro-3-ethoxycarbonylcarbazole 6-Fluoro-3-ethoxycarbonyl-l,2,3,4-tetrahydrocarbazole (Method 37; 3.13 g, 12 mmol) in xylene was treated with 2,3-dichloro-5,6-dicyano-l ,4-benzoquinone (6.45 g, 26 mmol) and the mixture was heated under reflux for 4 hours, cooled to ambient temperature, filtered through diatomaceous and the filtrate loaded on to a Bond Elut column (20 g) and eluted with 5% EtO Ac/toluene then recrystalhzed from EtOAc/hexane to give the title compound (2.35g). NMR (CDCI3) 1.5 (t, 3H), 4.4 (t, 2H), 7.2 (t, IH), 7.3 (m, IH), 7.4 (d, IH), 7.8 (d, IH), 8.2 (d, IH), 8.3 (b, IH), 8.8 (s, IH); m/z 258.
Reference Examples
The following compounds are provided as a further feature of the invention and are known in the art. However, their use as agonists or antagonists at the neuropeptide Y5 receptor is not known in the art. Synthetic procedures to these compounds are included by reference.
Preparation of Starting Materials
The starting materials for the Examples above are either commercially available or are readily prepared by standard methods from known materials. For example the following reactions are illustrations but not limitations of the preparation of some of the starting materials used in the above reactions.
Method 1
Ethyl (E)-3 -pyridin-4-ylprop-2-enoate To a solution of 4-pyridinecarboxaldehyde (67 ml, 700 mmol) and triethyl phosphono acetate (152 ml, 770 mmol) in THF (200 ml) at room temperature was added lithium hydroxide (32.4 g, 770 mmol). After 18 hours ether (500 ml) was added, washed with sodium hydrogen carbonate, brine and concentrated to give a white solid. Yield 102.1 g (83%>). NMR
8.62 (d, 2H), 7.60 (d, IH), 7.35 (d, 2H), 6.59 (d, IH), 4.30 (q, 2H), 1.35 (t, 3H); m/z 178.3.
Method 2
Ethyl 3-pyridin-4-ylpropanoate
Ethyl (E)-3-ρyridin-4-ylprop-2-enoate (Method 1; 102.3 g, 576 mmol) in MeOH (300 ml) was hydrogenated using palladium on carbon 5%> (9.0 g) under atmospheric pressure hydrogen for 72 hours. Catalyst was filtered off through diatomaceous earth and the filtrate concentrated to give a yellow oil. Yield 103.1 g (99%). NMR (CDC13) 8.50 (d, 2H), 7.15 (d,
2H), 4.12 (q, 2H), 2.95 (t, 2H), 2.64 (t, 2H), 1.21 (t, 3H); m/z 180.4.
Method 3
3-Pyridin-4-ylpropanoic acid
To a solution of ethyl 3-pyridin-4-ylpropanoate (Method 2; 103.1 g, 576 mmol) in water (400 ml) and EtOH (20 ml) at room temperature was added potassium hydroxide (60 g, 5 1600 mmol). After 18 hours hydrochloric acid (100 ml) was added to give a white solid. Yield 62.8 g (73%). NMR 8.38 (d, 2H), 7.21 (d, 2H), 2.70 (t, 2H), 2.52 (t, 2H); m/z 152.2.
Method 4
Ethyl (E)-2-methyl-3-pyridin-4-ylprop-2-enoate
10 To a solution of 4-pyridinecarboxaldehyde (9 ml, 93 mmol) and triethyl 2- phosphonopropianoate (22 ml, 102 mmol) in THF (50 ml) at room temperature was added lithium hydroxide (4.3 g, 102 mmol). After 18 hours ether (100 ml) was added, washed with sodium hydrogen carbonate, brine and concentrated to give a white solid. 7.6 g (43%). NMR (CDC13) 8.60 (d, 2H), 7.53 (s, IH), 7.20 (d, 2H), 4.25 (q, 2H), 2.06 (s, 3H), 1.35 (t, 3H); m/z
15 191.7.
Method 5
(EV2-Methyl-3-pyridin-4-ylprop-2-enoic acid
To a solution of ethyl (E) 2-methyl-3-pyridin-4-ylprop-2-enoate (Method 4; 3 g, 15.7 20 mmol) in water (20 ml) at room temperature was added potassium hydroxide (1.7 g, 30.4 mmol). After 18 hours hydrochloric acid (3.5 ml) was added to give a white solid. Yield 1.48 g (56%). NMR 8.60 (d, 2H), 7.49 (s, IH), 7.40 (d, 2H), 1.99 (s, 3H); m/z (ES") 161.6 (MH").
Method 6
25 Ethyl 2-methyl-3-pyridin-4-ylpropanoate
Ethyl (E) 2-methyl-3-ρyridin-4-ylprop-2-enoate (Method 4; 4.8 g, 25 mmol) in MeOH (300 ml) was hydrogenated using palladium on carbon 5% (500 mg) under atmospheric hydrogen at room temperature for 18 hours. The catalyst was filtered through diatomaceous earth and filtrate concentrated to give a yellow oil. Yield 4.2 g (88%). NMR (CDC13) 8.60 (d,
30 2H), 7.10 (d, 2H), 4.09 (q, 2H), 3.01 (m, IH), 2.73 (m, 2H), 1.19 (m, 6H); m/z 193.8.
Method 7
2 -Methyl- 3 -pyridin-4-ylpropanoic aci d
To a solution of ethyl 2-methyl-3-pyridin-4-ylpropanate (Method 6; 3.8 g, 19.7 mmol) in water (20 ml) and EtOH (5 ml) at room temperature was added potassium hydroxide (2.3 g, 39.4 mmol). After 18 hours hydrochloric acid (3.5 ml) was added to give a white solid. Yield 1.84 g (56%). NMR (CDC13) 9.26 (brs, IH), 8.46 (d, 2H), 7.21 (d, 2H), 3.06 (m, IH), 2.76 (m, 2H), 1.24 (s, 3H); m/z 166.3.
Method 8 (E)-3 -pyridin-4-ylprop-2-enoic acid
To a solution of ethyl (E)-3-pyridin-4-ylprop-2-enoate (Method 1; 2 g, 11.3 mmol) in water (20 ml) at room temperature was added potassium hydroxide (1.3 g, 22.6 mmol). After
18 hours hydrochloric acid (2 ml) was added to give a white solid. Yield l .l g (59%). NMR
8.60 (d, 2H), 7.61 (d, 2H), 7.55 (d, IH), 6.75 (d, IH); m/z 150.3.
Method 9
2-Methoxybenzamidoxime
A solution of 1-methoxybenzonitrile (1 g, 7.5 mmol), hydroxylamine hydrochloride
(0.6 g, 8.6 mmol) and sodium carbonate (0.43 g, 4.1 mmol) in water (3 ml) and EtOH (15 ml) were heated at reflux for 22 hours. The mixture was concentrated and sodium carbonate solution added to give a white precipitate. Yield 0.41 g (33%). M. p. 122-123 °C.
Method 10
3-[3-(2-Methoxyphenyl)-1.2.4-oxadiazol-5-yl] propionic acid A solution of 1-methoxybenzamidoxime (Method 9; 19 g, 115 mmol) and succinic anhydride (1 1.5 g, 115 mmol) in xylene (750 ml) were heated at reflux for 5 hours to give a white precipitate. Yield 23.5 g (65%). M. p. 133-133.5 °C; EA calc: Cl2H12N2O3: C. 58.06; H, 4.84; N, 11.29; found; C, 58.5; H, 4.8; N, 11.3.
Method 11
9-Ethyl-3-carboxycarbazole
To a solution of 9-ethyl-3-formylcarbazole (8.3 g, 37.2 mmol) in acetone (25 ml) was added potassium permanganate (12.1 g, 76.6 mmol) in water (50 ml) and the mixture heated at reflux for 18 hours. The mixture was filtered through diatomaceous earth and acidified with hydrochloric acid to give a white solid. Yield 7.7 g (87%). NMR 12.53 (s, IH), 8.78 (s, IH), 8.26 (d, IH), 8.06 (d, IH), 7.68 (d, 2H), 7.50 (t, IH), 7.25 (t, IH), 4.47 (q, 2H), 1.33 (t, 3H); m/z 240.4.
Method 12
2-Nitro-9-ethylcarbazole
2-Nitrocarbazole (Tet, 1984, 40(10), 1857-61; 3.00 g, 14.14 mM) was added to a suspension of sodium hydride (60%) suspension in oil; 623 mg, 15.55 mM) in DMF (70 ml) at 0°C under an argon atmosphere. After 30 minutes ethyl iodide (1.25 ml, 15.55 mM) was added and the mixture allowed to warm to room temperature. After 18 hours water was added and the mixture extracted with EtOAc. The organic was washed with water and brine, dried over sodium sulphate and concentrated to give the title compound as a yellow solid. Rf (Z9) 0.36; NMR 8.34 (s, IH), 8.16 (d, IH), 8.13 (s, 2H), 7.60 (dd, IH), 7.48 (d, IH), 7.30 (d, IH), 4.42 (q, 2H), 1.48 (t, 3H); m/z 241.3.
Methods 13 - 14
The following compounds were prepared by the procedure of Method 12 using 3- nitrocarbazole and the appropriate alkyl iodide.
Method 15 l-Chloro-4-(pyrid-4-ylmethylVphthalazine
A mixture of phthalic anhydride (20 g, 0.135 mol) and 4-methy lpyri dine (26.3 ml, 0.27 mol) was heated at 140°C for 22 hours. After cooling, the reaction mixture had solidified and the solid was ground and triturated with ether followed by acetone. A suspension of the resulting crude solid (30 g) in aqueous hydrazine (135 ml) was heated at 135°C for 14hrs. After cooling a precipitate was formed. The solid was filtered, washed with water and dried under vacuum to give l-oxo-2H-4-(4-pyridylmethyl)-phthalazine (10.4 g). A mixture of this material (4 g, 16.9 mmol), NN-diethylaniline (2.7 ml), tetrabutylammonium chloride (9.4 g, 33.7 mmol) and phosphorous oxychloride (9.4 ml, 101 mmol) in acetonitrile (80 ml) was heated at 98°C for 2 hours. After removal of the volatiles under vacuum, the residue was poured onto a mixture of DCM (300 ml) and water/ice (900 ml). The mixture was maintained cold and the pH was adjusted to 4.7 with 2 M ΝaOH. The organic layer was separated and the aqueous layer was further extracted with DCM. The organic layers were combined, and washed with water, brine, dried and evaporated to dryness. The resulting solid was triturated with ether followed by EtOAc, filtered and dried under vacuum to give 2.6 g of solid. The product was purified by column chromatography eluting with DCM/MeOH 95/5.
Method 16 9-Mesyl-3-nitrocarbazole
To a solution of 3-nitrocarbazole (0.5 g, 2.4 mmol) in DMF (10 ml) at 0° C was added sodium hydride (110 mg, 2.7 mmol; as a 60%> dispersion in mineral oil). After 30 minutes the mixture was added to methane sulphonyl chloride (0.21 ml, 2.7 mmol) in DMF (10 ml) at 0° C. After 4 hours water (50 ml) was added. The resulting precipitate was extracted (EtOAc), washed with sat. potassium carbonate solution, dried over sodium sulphate and evaporated to give a yellow solid. Yield 420 mg (61%). ΝMR 8.90 (s, IH), 8.39 (m, IH), 8.28 (m, IH), 8.17 (d, IH), 8.10 (d, IH), 7.62 (t, IH), 7.50 (m, IH), 3.13 (s, 3H).
Method 17
9-Acetyl-3-nitrocarbazole
To a solution of 3-nitrocarbazole (4.1 g, 19.3 mmol) in DMF (100 ml) and triethylamine (3.4 ml) at 0°C was added acetyl chloride (1.7 ml, 21.2 mmol). After 4 hours 5 water (400 ml) was added. The resulting precipitate was collected by filtration, washed with sat. potassium carbonate solution, dried, to give a yellow solid. Yield 3.7 g (59%>). NMR (CDC13) 8.86 (s, IH), 8.50 (m, IH), 8.38 (m, IH), 8.11 (t, 2H), 7.61 (t, IH), 7.50 (t, IH), 2.95 (s, 3H).
10 Method 18
NN-Dimethylsulphamoyl-3-nitrocarbazole
To a solution of 3-nitrocarbazole (0.5 g, 2.4 mmol) in DMF (10 ml) at 0°C was added sodium hydride (110 mg, 2.7 mmol; as a 60%> dispersion in mineral oil). After 30 minutes dimethyl sulphamoyl chloride (0.29 ml, 2.7 mmol) was added. After 2 hours water (50 ml) 15 was added. The resulting precipitate was extracted (EtOAc), washed with water, dried over sodium sulphate and evaporated to give a yellow solid. Yield 480 mg (63%). ΝMR 8.90 (s, IH), 8.39 (m, IH), 8.28 (m, IH), 8.17 (d, IH), 8.10 (d, IH), 7.62 (t, IH), 7.50 (m, IH), 3.13 (s, 3H).
20 Method 19
3-Formyl-6-nitro-9-ethylcarbazole
Fuming nitric acid (0.9 ml) was added to a cooled (ice-bath) solution of 9-ethyl-3- formylcarbazole (4.0 g, 17.9 mmol) in acetic anhydride (13 ml) and acetic acid (9 ml) maintaining the internal temperature below 10°C. The mixture was stirred in an ice-bath for 25 30 minutes. The mixture was poured onto crushed ice and water (50 ml). The precipitated solid was collected by filtration and washed with water to leave the product as a tan solid (12.7 g). ΝMR (CDC13) 10.1 (s, IH), 9.05 (d, IH), 8.65 (d, IH), 8.4 (dd, IH). 8.1 (d, IH), 7.6 (d, IH), 7.5 (d, IH), 4.45 (q, 2H), 1.5 (t, 3H); m/z 269.
30
Method 20
3-Nitro-6-hydroxymethyl-9-ethylcarbazole
Sodium borohydride (0.071 g, 1.9 mmol) was added to a solution of 3-formyl-6-nitro- 9-ethylcarbazole (Method 19; 0.5 g, 1.9 mmol) and water (1 ml) in THF (20 ml). The mixture was stirred at room temperature for 1 hour. The solvent was removed in vacuo and the residue partitioned between EtOAc and water. The organic layer was removed and washed with HCl (2 M), washed with water and dried. The solvent was removed in vacuo to leave a brown solid. NMR 9.1 (d, IH), 8.35-8.25 (m, 2H), 7.75 (d, 2H), 7.7 (d, IH), 7.5 (dd, IH), 5.2 (brs, IH), 4.7 (brs, 2H), 4.5 (q, 2H), 1.3 (t, 3H); m/z 271.
Method 21
4-(Mesyloxyethyl)-NN-dimethylaniline
The title compound was prepared from 4-(2-hydroxyethyl)dimethylaniline in a similar manner as described for Example 141. ΝMR 7.15 (d, 2H), 6.85 (brs, 2H), 4.45 (t, 2H), 2.88 (m, l lH); m/z 244.
Method 22
4-(Methylaminoethyl)-NN-dimethylaniline To a stirred solution of 4-(mesyloxyethyl)-NN-dimethylaniline (Method 21; 750 mg,
3.1 mM) in chloroform (10 ml) was added methylamine solution (33% in EtOH, 25 ml). The solution was stirred for 18 hours before concentrating in vacuo. The residue was dissolved in DCM and washed with water. The aqueous layer was concentrated in vacuo before chromatographing with MeOH/ DCM. A white solid was isolated, 293 mg (53%). ΝMR 7.05 (d, 2H), 6.68 (d, 2H), 3.29 (brs, IH), 3.03 (t, 2H), 2.84 (s, 6H), 2.75 (t, 2H), 2.55 (s, 3H); m z 179.
Method 23
3 -Morpholino- 1 -(methylamino)propane Methyl amine was bubbled into a solution of 3 -moφholino- 1-chloropropane (20 mmol) in absolute ethanol (30 ml) at ambient temperature for 10 min. The reaction mixture
was stirred during 1 hour and evaporated to give an oil which solidified. The solid was triturated with dry ether, filtered, washed with ether and dried under vacuum to give the title compound as a white solid (1.58g; 50%).
Method 24
1 -Mθφholino-2-carboxypropyl l-Moφholino-2-methoxycarbonylpropyl (2.5 g, 13.4 mmol) and sodium hydroxide (1.0 g, 25 mmol) were dissolved in MeOH (30 ml) and water (15 ml) and the solution was stirred at room temperature for 18 hours. The solvent was removed in vacuo and the residue was dissolved in hydrochloric acid (1 M, 25 ml). The solvent was again removed in vacuo and the residue was triturated with MeOH (10 ml). The solid was removed by filtration and the filtrate was evaporated in vacuo to leave a light brown solid (2.0 g). M/z 174.
Method 25 1 -Carboxymethylpyrrolidin-2-one l-(Methoxycarbonylmethyl)pyrrolidin-2-one (2 g/l.77 ml, 12.73 mmol) was added to potassium hydroxide (87%>, 2.46 g) and EtOH (35 ml) and the reaction was stirred for 3 days at room temperature. A solution of MeOH and hydrochloric acid was added until the pH of the solution was 2 and then the solvent was removed in vacuo. The resulting solid was stirred in EtOAc (150 ml) for 30 mins and then the solid was removed by filtration The solid was the stirred in boiling EtOAc for 1 hour, the suspension was allowed to cool and the solid was removed by filtration. The filtrates were combined and the solvent was removed in vacuo to yield a white solid (1.788 g, 98%). Mp 135-137°C.
Method 26
3-Nitro-9-(2.2.2-trifluoroethyl carbazole
To a solution of 3-nitrocarbazole (4 g, 18.9 mmol) in dimethylacetamide (125 ml) at 0°C was added sodium hydride (0.85 g, 20.8 mmol; as a 60% dispersion in mineral oil). After 1 hour 2,2,2-trifluoroethyl-p-toluenesulfonate (5.03 g, 19.8 mmol) was added and the mixture was heated at reflux. After 18 hours water (300 ml) was added. The resulting precipitate was extracted (EtOAc), washed with water, dried (sodium sulphate), evaporated and purified by
chromatography (eluent 10% EtOAc; 90% isohexane) to give a yellow solid. Yield 2.3 g (41%). NMR 9.16 (s, IH), 8.40 (m, 2H), 7.95 (d, IH), 7.83 (d, IH), 7.60 (t, IH), 7.37 (t, IH), 5.58 (q, 2H); m z 295.4.
5 Method 27
2-Methyl-9-isopropyl-3-nitrocarbazole
To a stirred solution of l,2,3,4-tetrahydro-9-isopropyl-7-methyl-6-nitrocarbazole (Method 28, 1.53 g, 5.62 mmol) in 1,4-dioxane at room temperature was added 2,3-dichloro- 5,6-dicyano-l ,4-benzoquinone (2.56 g, 11.24 mmol) portionwise. The reaction mixture was 10 stirred at 100°C for 20h before being concentrated. Chromatography (eluent 10%)
EtOAc/isohexane) yielded the title compound as a yellow solid (947 mg, 63%). Rf (50% EtOAc/isohexane) 0.62; NMR 8.96 (s, IH), 8.29 (d, IH), 7.77 (d, IH), 7.73 (s, IH), 7.50 (t, IH), 7.26 (t, IH), 5.17 (sept, IH), 2.76 (s, 3H), 1.63 (d, 6H).
15 Method 28
1.2.3.4-Tetrahydro-9-isopropyl-7-methyl-6-nitrocarbazole
Sodium hydride (454 mg, 11.34 mmol) was added slowly to a solution of 1,2,3,4- tetrahydro-7-methyl-6-nitrocarbazole (Aust. J. Chem., 1969, 22, 185-195; 1.74 g) in dry DMF at 0°C under an argon atmosphere. When no more gas was given off 2-bromopropane (1.06
20 ml, 11.34 mmol) was added and the reaction mixture was heated at 60°C for 20 hours before cooling. Further sodium hydride (1.21 g, 30.24 mmol) was added followed by 2- bromopropane (2.84 ml, 30.24 mmol) and the mixture was heated at 60°C for 4 hours. The reaction mixture was concentrated, diluted with water and extracted into EtOAc. The organic layers were separated and washed with water and brine and dried. Chromatography (eluent
25 25%o EtOAc/isohexane) yielded the title compound as a yellow solid (1.53 g, 74%>). Rf (ether) 0.71; NMR 8.13 (s, IH), 7.52 (s, IH), 4.68 (sept, IH), 2.75 (m, 2H), 2.34 (m, 5H), 1.87 (m, 2H), 1.77 (m, 2H), 1.50 (d, 6H).
30
Method 29
2-Phenyl-5-f3-carboxypropylV1.3.4-oxadiazole
5-(N'-Benzoylhydrazino)-5-oxo-pentanoic acid (Method 30, 15.2 g) was added to stirred concentrated sulphuric acid (50 ml) at room temperature and the reaction mixture was stirred overnight. The reaction mixture was poured onto ice (200 g) and the mixture was stirred for 30 minutes. The resulting white precipitate was removed by filtration, washed with water and dried by suction. The residue was purified by recrystallization from 80-100 petrol to yield the title compound as a white solid. Mp 114-115°C.
Method 30
5-(N'-Benzoylhydrazino)-5-oxo-pentanoic acid
Benzoyl hydrazine (13.6 g) in hot EtOAc (100 ml) was added in 10 portions at 30 second intervals to a warm solution of glutaric anhydride (12.4 g) in EtOAc (100 ml). The solution was stirred for 30 minutes whilst cooling to room temperature. The resulting white solid was collected by filtration to give the title compound (20.7 g, 83%).
Method 31
3-Benzyl-5-(2-carboxyethyl)-1.2.4-oxadiazole
N-Hydroxy-2-phenylacetamidine (Method 32, 35 g) and succinic anhydride (23.4 g) were ground together and suspended in xylene (600 ml). The mixture was refluxed for five hours whilst removing water. The charred mixture was then refluxed in ether (500 ml) with decolourising charcoal before filtration. The filtrate was made alkaline by addition of ammonium hydroxide (2 M). The aqueous layer was then separated and acidified with hydrochloric acid (2 M) and extracted with ether. The ether layers were dried and evaporated to dryness to yield the title compound (4.0 g). This was recrystalhzed from toluene. Mp 58- 60°C.
Method 32
N-Hydroxy-2-phenylacetamidine Hydroxylamine hydrochloride (69.5 g) was dissolved in water (150 ml) and was added to sodium carbonate (52.5 g) in water (90 ml). Benzonitrile (100 g) in EtOH (600 ml) was
added and the mixture was refluxed with stirring for 20hours. It was then basified with sodium hydrogen carbonate solution (10%) and extracted with ether. The ether layers were combined and extracted with hydrochloric acid (2 M). The hydrochloric acid layers were basified with sodium carbonate and then extracted with ether. The ether layers were combined, dried and evaporated to dryness to give the title compound (108.0 g). This was recrystalhzed from EtOH. Mp 73-75°C.
Method 33
3-Bromo-5-(2-carboxyethyl)isoxazole 2-(2-Nitrovinyl)furan (13.5 g) in glacial acetic acid (125 ml) and hydrobromic acid
(48%o, 62.5 ml) was heated on a steam bath for 9 hours. The solution was concentrated in vacuo to 60 ml and was then diluted with water (60 ml). The reaction mixture was then boiled, treated with diatomaceous earth and charcoal and filtered hot before allowing to cool. The solution was extracted with chloroform (4x50 ml), dried and evaporated to dryness. The resultant gum was crystallised from benzene/cyclohexane, then carbon tetrachloride (carbon treated and filtered hot) and then toluene to give 2.5 g. Mp 108-110°C.
Method 34
9-Ethyl-3-isothiocyanatocarbazole A solution of 3-amino-9-ethylcarbazole (Reference Example 15; 5.0 g, 23.8 mmol) in
DCM (50 ml) was added over 1 hour to a stirred refluxing solution of thiophosgene (2.57 ml, 33.7 mmol) in DCM (40 ml). The reaction mixture was stirred for a further 18 hours under reflux, cooled and filtered. The filtrate was evaporated to dryness and the black residue was chromatographed, eluting with 10-50% EtOAc in isohexane, to give a yellow solid. Recrystallization from ether gave the title compound (2.74 g). NMR: 8.31 (IH, d), 8.18 (IH, d), 7.66 (IH, dd), 7.63 (IH, d), 7.50 (2H, m), 7.23 (1 H, dd), 4.44 (2H, q), 1.30 (3H, t).
Method 35
6-Cyano-3-nitro-9-ethylcarbazole 3-Formyl-6-nitro-9-ethylcarbazole (Method 19) was treated with hydroxylamine hydrochloride, p-toluene sulphonic acid and magnesium sulphate in xylene in the manner
described by Ganboa and Palomo in Synthetic Communications, 1983, 13, 219-223 to give the title compound. NMR (300 MHz, CDC13) 1.5 (t, 3H), 4.4 (q, 2H), 7.5 (m, 2H), 7.8 (s, IH), 8.4 (m, 2H), 9.0 (s, IH): m/z 266.
Method 36
6-Fluoro-9-isopropyl-3-carboxycarbazole
6-Fluoro-9-isopropyl-3-ethoxycarbonylcarbazole (Example 271; 1.46 g) was dissolved in THF : MeOH (3 : 1, 40 ml) and IM lithium hydroxide (19 ml) was added and the solution was heated at 60°C for 1 hour. After cooling the organic solvents were removed under vacuum and the resultant aqueous solution was acidified to pH 1 with concentrated hydrochloric acid and the resultant precipitate filtered and dried to give the title compound (1.3 g). NMR 1.6 (d, 6H), 5.1 (m, IH), 7.3 (t, IH), 7.7 (m, 2H), 8.0 (d, IH), 8.2 (d, IH), 8.8 (s, IH); m/z 272.
Method 37
6-Fluoro-3-ethoxycarbonyl-1.2.3.4-tetrahydrocarbazole
A stirred mixture of 4-fluorophenylhydrazine hydrochloride (4.4 g, 27 mmol) and ethyl-4-oxocyclohexanecarboxylate in ethanol (100 ml) was heated under reflux overnight. The solution was cooled in an ice bath and the resultant white crystals filtered off and washed with ice cold EtOH to give the title compound. NMR (CDC13) 1.3 (t, 3H), 1.9-2.1 (m, IH), 2.3 (m, IH), 2.7-2.9 (m, 4H), 3.0 (m, IH), 4.2 (t, 2H), 6.8 (t, IH), 7.0-7.2 (m, 2H), 7.7 (s, IH); m z 262.
Example 273 The following illustrate representative pharmaceutical dosage forms containing the compound of formula (I), or a pharmaceutically acceptable salt, prodrug or solvate thereof (hereafter compound X), for therapeutic or prophylactic use in humans :-
Note The above formulations may be obtained by conventional procedures well known in the pharmaceutical art. The tablets (a)-(c) may be enteric coated by conventional means, for example to provide a coating of cellulose acetate phthalate.