WO1999016441A1 - Aporphinoid matrix metalloproteinase inhibitors - Google Patents

Aporphinoid matrix metalloproteinase inhibitors Download PDF

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Publication number
WO1999016441A1
WO1999016441A1 PCT/EP1998/006123 EP9806123W WO9916441A1 WO 1999016441 A1 WO1999016441 A1 WO 1999016441A1 EP 9806123 W EP9806123 W EP 9806123W WO 9916441 A1 WO9916441 A1 WO 9916441A1
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hydroxy
alkyl
halogenyl
mercapto
hydrogen
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PCT/EP1998/006123
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French (fr)
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Hans-Willi Krell
Frank Grams
Alfred Brunner
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Roche Diagnostics Gmbh
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Priority to AU97470/98A priority Critical patent/AU9747098A/en
Publication of WO1999016441A1 publication Critical patent/WO1999016441A1/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D221/00Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04Ortho- or peri-condensed ring systems
    • C07D221/18Ring systems of four or more rings

Definitions

  • proteases belong to at least three groups of matrix metallopro teases. These are the collagenases, gelatinases and stromelysins.
  • MMP-1, HFC interstitial fibroblast coUagenase
  • MMP-8, HNC neutrophil collagenase
  • MMP-9 neutrophil collagenase
  • stromelysins such as HSL-1, MMP-3
  • MMP-7 Matrilysin
  • the uncontrolled excessive degradation of this matrix is a characteristic of many pathological states such as e.g. in the clinical picture of angiogenesis, tumor progression, sun-induced skin-aging, emphysema, cardiovascular diseases like restinosis, arteriosclerosis and platelet aggregation, rheumatoid arthritis, osteoarthritis, periodontal diseases, multiple sclerosis, in the formation of tumour metastases, corneal ulceration, inflamative diseases and diseases, where the presence of bacteria results in the release of MMPs, like bacterial Meningitis. It can be assumed that the pathogenesis of these clinical pictures can be favourably influenced by the administration of matrix metalloprotease inhibitors. A number of compounds are known in the literature (see e.g.
  • Some of these compounds have a high activity as inhibitors of matrix metalloproteases but only have a very low oral availability.
  • Rl represents hydrogen, hydroxy, acyl, halogenyl or Cl-C6-alkyl
  • R2 represents hydrogen, hydroxy, halogenyl, cyano, Cl-C6-alkyl, or acyl
  • R3 and R4 represent independently of each other hydrogen, hydroxy, halogenyl, C1-C7- alkyl, acyl or a monocycle;
  • R5, and R6 represent independently of each other hydrogen, hydroxy, mercapto, C1-C8- alkyl, Cl-C7-alkoxy or acyl;
  • R7 represents hydrogen, hydroxy, halogenyl or amino
  • R8 represents hydrogen, hydroxy, mercapto, Cl-C8-alkyl, acyl or R8 and R9 represent together O-(CH2)n-O with n equals 1 or 2;
  • R9 represents hydroxy, mercapto, Cl-C7-alkoxy or Cl-C7-alkylthio.
  • RIO represents hydrogen, hydroxy, mercapto, halogenyl or amino, Cl-C16-alkyl, acyl, a optionally sustituted mono- or bicyclus; and pharmacologically acceptable salts or prodrugs thereof, to produce pharmaceutical agents for the treatment of diseases where MMP activity is envolved.
  • Rl represents hydrogen, hydroxy, acyl, Cl-C5-alkoxy, Cl-C5-alkenoxy, halogenyl or
  • R2 represents hydrogen, hydroxy, halogenyl, cyano, Cl-C5-alkyl, Cl-C5-alkenyl, Cl-
  • R3 and R4 represent independently of each other hydrogen, hydroxy, halogenyl, C 1 -C7- alkyl, Cl-C7-alkenyl, acyl or a monocycle;
  • R5, and R6 represent independently of each other hydrogen, hydroxy, mercapto, C1-C7- alkyl, Cl-C7-alkoxy, acyl, or Cl-C7-alkylthio, Cl-C7-alkenyl, Cl-C7-alkenoxy, or Cl-
  • R7 represents hydrogen, hydroxy, halogenyl or amino
  • R8 represents hydrogen, hydroxy, mercapto, Cl-C7-alkyl, C 1 -C7-alkoxy, C1-C7- alkylthio, Cl-C7-alkenyl, Cl-C7-alkenoxy, Cl-C7-alkenylthio, acyl or R8 and R9 represent together O-(CH2)n-O with n equals 1 or 2;
  • R9 represents hydroxy, mercapto, Cl-C7-alkoxy or Cl-C7-alkylthio.
  • RIO represents hydrogen, hydroxy, mercapto, halogenyl or amino, Cl-C15-alkyl, Cl- C15-alkoxy, Cl-C15-alkylthio, Cl-C15-alkenyl, Cl-C15-alkenoxy, C1-C15- alkenylthio, acyl, a optionally sustituted mono- or bicyclus; and pharmacologically acceptable salts or prodrugs thereof,
  • Rl is preferably methyl or hydrogen.
  • R2 is preferably hydrogen.
  • R3 is preferably hydrogen.
  • R4 is preferably hydrogen.
  • R5 is preferably hydroxy, Cl-C3-alkoxy, especially methoxy, mercapto, C1-C3- alkylthio, especially methylthio.
  • R6 is preferably Cl-C3-alkoxy, especially methoxy.
  • R7 is preferably hydroxy or hydrogen.
  • R8 is preferably hydroxy, Cl-C12-alkoxy, mercapto, Cl-C12-alkylthio.
  • R9 is preferrably hydroxy or mercapto.
  • the invention concerns new substances of the general formula I, whererin R9 represents mercapto or Cl-C7-alkylthio.
  • new substances of general formula I are such wherein the residues Rl to RIO has the following meanings Rl represents C2-C5-alkyl or halogenyl; R2 represents halogenyl, cyano, C2-C5-alkyl, or C2-C5-alkoxy; R3 represent halogenyl, C 1 -C7-alkyl or a monocycle R4 represent halogenyl, C2-C7-alkyl or a monocycle;
  • R5, R6, R8 and R9 represent independently of each other mercapto, C2-C7-alkyl, C2- C7-alkoxy, or Cl-C7-alkylthio;
  • R7 represents halogenyl or amino;
  • RIO represents mercapto, halogenyl or amino, Cl-C15-alkyl, Cl-C15-alkoxy, C1-C15- alkylthio, a optionally sustituted mono- or bicyclus; and pharmacologically acceptable salts or prodrugs thereof,and pharmacologically acceptable salts or prodrugs thereof.
  • aporphine alkaloids are known. A selection is: Aporphine, Boldine, Apomorphine, Laurotetanine, Norisocorydine, Isocorydine, Glaucine, Nuciferine, Fissoldine, Norglaucin, Xylpine, Actinodaphnine and others like dicentrine.
  • Boldine and Glaucine are well known as ingredients of extracts from Annonaceae, Lauraceae, Magnoliaceae, Monimiaceae and others.
  • Boldine is one of many ingredients of Monimiaceae Peumus boldus, commonly called Boldo.
  • Boldo is used as vermifuge, to treat liver, gall bladder and bowel dysfunctions, or inflammation.
  • Boldine is believed to be responsible for both the choleretic and diuretic activity of the leaves from Boldo.
  • rat aorta (S)-Boldine depressed contractions evoked by noradrenaline in a concentration dependent manner (Ivorra MD et al. Eur. J. Pharmacol. 231: 165-74 (1993)).
  • Boldine and Glaucine show inhibitory effects on TPA induced down regulation of gap junction function (Hu J et al. Biochem. Pharmacol. 50: 1635-43 (1995) and show antioxidative properties (Pharmacol. Res. 31: 103-7 (1995)).
  • the monocycle listed in the case of R3 and RI Q is understood as saturated or unsaturated ring systems with 3 - 8, preferably 5 - 7 carbon atoms which can optionally be interrupted one or several times by heteroatoms such as nitrogen, oxygen or sulphur in particular a cyclopentyl, cyclohexyl, cycloheptyl, mo ⁇ holinyl, thiamo ⁇ holinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, furyl, thiophenyl, imidazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl or 1,2,4-triazolyl residue.
  • Lower alkyl, alkoxy and halogen come above all
  • the bicycle listed under R1 Q is understood to be a condensed bicycle or a bicycle of the type monocycle ⁇ -L-monocycle2, wherein L denotes a valence dash C ⁇ -C4-alkyl group, C2-C4 an alkenyl group, an oxygen or -C(O)-group.
  • the bicycle is preferably a residue such as a naphthyl, tetrahydronaphthyl, dekalinyl, quinolinyl, isoquinolinyl, tetrahydroquino-linyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, indazolyl, oxindolyl, benzofuranyl, benzothiophenyl, benzthiazolyl, benzoxazolyl, purinyl, biphenyl or (4-phenoxy)phenyl residue and in particular a naphthyl, biphenyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, indolyl or benzimidazolyl residue.
  • a residue such as a naphthyl, tetrahydronaphthyl, dekalinyl, quinolinyl, isoquinolin
  • R2, R3, R4, R5, R6, R8, R9 RIO can optionally be substituted once or several times by halogen, hydroxy, thio, alkyl, hydroxyalkyl, alkoxy, alkylthio, alkylsulfinyl, alkyl-sulfonyl, amino, alkylamino, dialkylamino, nitro, carboxyl, carboxamido, alkoxy-carbonyl, amino or aminocarbonyl optionally substituted once or twice by lower alkyl, nitrile, oxo, thiocarboxamido, alkoyxythiocarbonyl, alkmercapto- carbonyl, phosphono, alkylphosphono, dialkylphosphono, alkylsulfonylamido, arylamino, aryl, hetaryl, aryloxy, arylthio, arylsulfmyl, arylsulfonyl
  • halogen hydroxy, oxo, thio, alkoxy, alkylthio, amino, aminocarbonyl, carboxyl and acyl groups are preferred.
  • Lower alkyl denotes C1-C6- Alkyl, preferred methyl, ethyl, propyl, isopropyl or tert- butyl.
  • alkyl residues in general formula I can optionally be interrupted once or several time by heteroatoms (O, S, NH). If heteroatoms are present, the first backbone atom is preferrably O or S.
  • Alkyl in general formula I or in combination with alkoxy, alkylthio, arylsulfonyl, alkylsulfonyl, alkylaminocarbonyl, arylaminocarbonyl, alkylamino, alkoxycarbonyl, aryloxycarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl represent a straight-chained, branched, saturated or unsaturated residue such as e.g.
  • Aryl also in combination with aryloxy, arylthio, arylsulfonyl, arylaminocarbonyl, aryloxycarbonyl, arylaminothiocarbonyl is understood as a phenyl or naphthyl residue which can optionally be substituted in particular by halogen, lower alkyl or alkoxy.
  • Halogen is understood as chlorine, bromine, iodine and preferably chlorine. If compounds of the general formula I contain one or several asymmetric carbon atoms, the optically active compounds of the general formula I are also a subject matter of the present invention.
  • heteroatom in connection with alkyl or acyl groups means preferred oxygen or NH, more preferred oxygen.
  • Substitutions of monocycles or bicycles in Ri, R4 and R5 are halogen, nitro, hydroxy, alkoxy, amino, alkylamino, dialkylamino, halogenmethyl, dihalogenmethyl, trihalogen- methyl, phosphono, alkylphosphono, dialkylphosphono, SO2NH2, SO2NH(alkyl), SO2N(alkyl)2, SO2(alkyl), acetyl, formyl, nitril, COOH, COOalkyl, -OC(O)alkyl, - NHC(O)Oalkyl, OC(O)O-aryl, -NHC(S)NH2, -NHC(S)NHalkyl, -NHC(O)-aryl.
  • Preferred optical isomers of the compounds of the invention are:
  • Example 15 6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo ⁇ de,g>quinoline-l,2-diol
  • Example 16 6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo ⁇ de.g>quinoline-10,l 1-diol
  • Example 17 2-methoxy-5,6,6a,7-tetrahydro-4H-dibenzo ⁇ de,g>quinoline-l,10-diol
  • Example 18 2,ll-dimethoxy-6-methyl-5,6,6a,7-tetrahydro-4H- dibenzo ⁇ de,g>quinolin- 1 -ol
  • Example 19 1 , 10-dimethoxy-5 ,6,6a,7-tetrahydro-4H-dibenzo ⁇ de,g>quinoline-2,9-diol
  • Example 20 1 ,2, 10-trimethoxy-5 ,6,6a,7-tetrahydro-4H-dibenzo ⁇
  • Example 22 l,10-dimethoxy-6-methyl-5,6,6a,7-tetrahydro-4H- dibenzo ⁇ de,g>quinoline-2, 11 -diol
  • Example 25 l-(10-hydroxy-1.2-dimethoxy-4,5,6a,7-tetrahydro- dibenzo ⁇ de,g>quinolin-6-yl)-ethanone
  • Example 26 acetic acid l,2,10-trimethoxy-6-methyl-5,6,6a,7-tetrahydro-4H- dibenzo ⁇ de,g>quinolin-9-yl ester
  • Example 27 l-(l,2,9,10-tetramethoxy-4,5,6a,7-tetrahydro-dibenzo ⁇ de,g>quinolin-6- yl)-ethanone
  • Example 28 l l-hydroxy-l,2,10-trimethoxy-4,5,6a,7-tetrahydro- dibenzo ⁇ de,g>quinoline-6-carbothioic acid phenylamide
  • Dibromboldin or 3-bromopredicentrine by protruding protection of the free hydroxy groups by an ester or allyl or benzyl protecting group.
  • an ester or allyl or benzyl protecting group After Bromide/Lithium exchange that compound can be reacted with an appropriate (substituted) alkylbromide or (substituted) alkenylbromide by standard procedures. Afterwards the protecting groups can be deprotected. This can be done by standard methods for the ester, with Pd for the allyl and by hydrogenolysis for the benzyl protecting group.
  • Compounds having no bromide group can be bromidated by a standard radical reaction with bromine and the different reactions products can be purified by chromatography, prior to the mentioned alkylation procedure.
  • O -> S exchange reagents e.g. potassium thiocyanate (e.g. Snyder, H.R., Stewart, J.M., Ziegler, J.B., J. Am. Chem. Soc. (1947) 69, 2672), thiourea (e.g. Ketcham, R., Shah, V.P., J. Org. Chem. (1963) 28, 229), 3-methylbenzothiazole-2- thione (e.g. Calo, V., Lopez, L., Marchese, L., Pesce, G., J. Chem. Soc. Chem. Commun.
  • O -> S exchange reagents e.g. potassium thiocyanate
  • thiourea e.g. Ketcham, R., Shah, V.P., J. Org. Chem. (1963) 28, 229
  • 3-methylbenzothiazole-2- thione e.g. Calo, V., Lopez, L
  • Example 32 2,9-Diethoxy-l-10-dimethoxyapo ⁇ hine (l,10-dimethoxy-2,9-diethoxy- 6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo ⁇ de,g>quinoline)
  • Example 33 2-Hydroxy-9-n-Propyloxy-l-10-dimethoxyapo ⁇ hine (l,10-dimethoxy-9- propyloxy-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo ⁇ de,g>quinoline-2-ol)
  • Example 34 9-Hydroxy-2-n-Propyloxy- 1 - 10-dimethoxyapo ⁇ hine (1,10-dimethoxy-2- propyloxy-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo ⁇ de,g>quinoline-9-ol)
  • Example 36 2,9-Di- «-propyloxy-6a- «-propyl-l-10-dimethoxyapo ⁇ hine (1,10- dimethoxy-2,9-dipropyloxy-6-methyl-6a-propyl-5,6,7-trihydro-4H- dibenzo ⁇ de,g>quinoline)
  • Example 37 2- «-Butyloxy-9-Hydroxy-l-10-dimethoxyapo ⁇ hine (l,10-dimethoxy-2- butyloxy-6-methyl-5 ,6,6a,7-tetrahydro-4H-dibenzo ⁇ de,g>quinoline-9-ol)
  • Compounds of the general formula I can contain one or several chiral centres and can then be present in a racemic or in an optically active form.
  • the racemates can be separated according to known methods into the enantiomers.
  • diastereomeric salts which can be separated by crystallization are formed from the racemic mixtures by reaction with an optically active acid such as e.g. D- or L-tartaric acid, mandelic acid, malic acid, lactic acid or camphorsulfonic acid or with an optically active amine such as e.g. D- or L- ⁇ -phenyl-ethylamine, ephedrine, quinidine or cinchonidine.
  • an optically active acid such as e.g. D- or L-tartaric acid, mandelic acid, malic acid, lactic acid or camphorsulfonic acid
  • an optically active amine such as e.g. D- or L- ⁇ -phenyl-ethylamine, ephe
  • Alkaline salts, earth alkaline salts like Ca or Mg salts, ammonium salts, acetates or hydrochlorides are mainly used as pharmacologically acceptable salts which are produced in the usual manner e.g. by tritrating the compounds with inorganic or organic bases or inorganic acids such as e.g. sodium hydroxide, potassium hydroxide, aqueous ammonia, Ci-C4-alkyl-amines such as e.g. triethylamine or hydrochloric acid.
  • the salts are usually purified by reprecipitation from water/acetone.
  • the new substances of formula I and salts thereof according to the invention can be administered enterally or parenterally in a liquid or solid form.
  • all the usual forms of administration come into consideration such as for example tablets, capsules, coated tablets, syrups, solutions, suspension etc.
  • Water which contains additives such as stabilizers, solubilizers and buffers that are usual in injection solutions is preferably used as the injection medium.
  • Such additives are e.g. tartrate and citrate buffer, ethanol, complexing agents (such a ethylenediaminetetra-acetic acid and non-toxic salts thereof), high-molecular polymers
  • Liquid carrier substances for injection solutions have to be sterile and are preferably dispensed into ampoules.
  • Solid carrier substances are e.g. starch, lactose, mannitol, methylcellulose, talcum, highly dispersed silicic acids, higher molecular fatty acids (such as stearic acid), gelatins, agar- agar, calcium phosphate, magnesium stearate, animal and vegetable fats, solid high- molecular polymers (such as polyethylene glycols); suitable preparations for oral application can optionally also contain flavourings and sweeteners.
  • the dosage can depend on various factors such as manner of administration, species, age and/or individual state of health.
  • the doses to be administered daily are about 5- 2000 mg/human, preferably 100-500 mg/human and can be taken singly or distributed over several administrations.
  • Prodrugs of the compounds of the invention are such which are converted in vivo to the pharmacological active compound.
  • the most common prodrugs are carboxylic acid esters, e.g. acetats, ethyl esters etc.
  • Example 44 1 ,2-dihydroxy-3-hexyl- 10-methoxy-6-methyl-5 ,6,6a,7-tetrahydro-4H- dibenzo ⁇ de,g>quinoline-9-ol
  • Example 45 l,10-dimethoxy-3,4-dipentyl-2-hydroxy-6-methyl-5,6,6a,7-tetrahydro-4H- dibenzo ⁇ de,g>quinoline-9-ol
  • MMP-8 the catalytic domain (isolation and purification see for example Schnierer, S., Kleine, T., Gote, T., Hillemann, A., Knauper, V., Tschesche, H.,Biochem. Biophys. Res. Commun. (1993) 191, 319-326) is incubated with inhibitors having various concentrations. Subsequently, the initial reaction rate in the conversion of a standard substrate is measured in a manner analogous to Grams F. et al., FEBS 335 (1993) 76-80). Alternatively the percent inhibition will be determined at a distant inhibitor concentration.
  • Enzyme 8 nM catalytic domain (Met80-Gly242) of human neutrophil coUagenase Substrate: 10 microM DNP-Pro-Leu-Gly-Leu-T ⁇ -Ala-D-Arg-NH2 Total assay volume: 1 ml
  • Table 1 shows the inhibition in % at a compound concentration of 100 ng/ml or IC50 values in brackets.

Abstract

Use of a compound of formula (I) wherein R1 represents hydrogen, hydroxy, acyl, halogenyl or C1-C6-alkyl; R2 represents hydrogen, hydroxy, halogenyl, cyano, C1-C6-alkyl, or acyl; R3 and R4 represent independently of each other hydrogen, hydroxy, halogenyl, C1-C7-alkyl, acyl or a monocycle; R5, and R6 represent independently of each other hydrogen, hydroxy, mercapto, C1-C8-alkyl, C1-C7-alkoxy or acyl; R7 represents hydrogen, hydroxy, halogenyl or amino; R8 represents hydrogen, hydroxy, mercapto, C1-C8-alkyl, acyl or R8 and R9 represent together O-(CH2)n-O with n equals 1 or 2; R9 represents hydroxy, mercapto, C1-C7-alkoxy or C1-C7-alkylthio; R10 represents hydrogen, hydroxy, mercapto, halogenyl or amino, C1-C16-alkyl, acyl, an optionally substituted mono- or bicyclus; and pharmacologically acceptable salts or prodrugs thereof, to produce pharmaceutical agents for the treatment of diseases where MMP activity is involved, processes for their production and pharmaceutical agents which contain these compounds having a matrix metalloprotease-inhibitory action.

Description

APORPHINOID MATRIX METALLOPROTEINASE INHIBITORS
In normal tissue there is an equilibrium between synthesis and degradation. Extracellular matrix is degraded by proteases which belong to at least three groups of matrix metallopro teases. These are the collagenases, gelatinases and stromelysins. Normally there are endogenic inhibitors for these catabolic en_ymes such as ct2 macro globulines and TIMP (= tissue inhibitor of metalloproteases (MMP)) so that an excessive degradation of extracellular matrix does not occur.
At least 15 different and yet highly homologous MMP species have been characterized, including the interstitial fibroblast coUagenase (MMP-1, HFC), the neutrophil collagenase (MMP-8, HNC), two gelatinases (gelatinase A or MMP -2 and gelatinase B or MMP-9), stromelysins (such as HSL-1, MMP-3) and Matrilysin (MMP-7). These proteinases share a number of structural and functional features but differ somewhat in their substrate specificity. Only HNC and HFC are capable of cleaving type I, II and III native triple-helical collagens at a single bond with the production of fragments 3/4 and
1/4 of the native chain length. This lowers the collagen melting point and makes them accessible to further attack by other matrix degrading enzymes.
However, the uncontrolled excessive degradation of this matrix is a characteristic of many pathological states such as e.g. in the clinical picture of angiogenesis, tumor progression, sun-induced skin-aging, emphysema, cardiovascular diseases like restinosis, arteriosclerosis and platelet aggregation, rheumatoid arthritis, osteoarthritis, periodontal diseases, multiple sclerosis, in the formation of tumour metastases, corneal ulceration, inflamative diseases and diseases, where the presence of bacteria results in the release of MMPs, like bacterial Meningitis. It can be assumed that the pathogenesis of these clinical pictures can be favourably influenced by the administration of matrix metalloprotease inhibitors. A number of compounds are known in the literature (see e.g. the review article of Beckett RP, Davidson AH, Drummond AH, Huxley P, Whittaker M. Drug Disc. T. (1996)1: 16-26.)) or are described in the patent literature, these mainly being peptides with a hydroxamic acid residue, a thiol or phosphinic group as a zinc binding group (see e.g. WO-A- 9209563 by Glycomed, EP-A-497 192 by Hoffmann-LaRoche, WO-A-9005719 by British Biotechnology, EP-A-489 577 by Celltech, EP-A-320 118 by Beecham, US-A- 459 5700 by Searle among others).
Some of these compounds have a high activity as inhibitors of matrix metalloproteases but only have a very low oral availability.
It has now been found that the claimed Aporphinoidderivatives are very efficacious as matrix metalloprotease inhibitors and are orally availability.
The present invention therefore concerns the use of substances of the general formula I
Figure imgf000004_0001
wherein
Rl represents hydrogen, hydroxy, acyl, halogenyl or Cl-C6-alkyl;
R2 represents hydrogen, hydroxy, halogenyl, cyano, Cl-C6-alkyl, or acyl;
R3 and R4 represent independently of each other hydrogen, hydroxy, halogenyl, C1-C7- alkyl, acyl or a monocycle; R5, and R6 represent independently of each other hydrogen, hydroxy, mercapto, C1-C8- alkyl, Cl-C7-alkoxy or acyl;
R7 represents hydrogen, hydroxy, halogenyl or amino;
R8 represents hydrogen, hydroxy, mercapto, Cl-C8-alkyl, acyl or R8 and R9 represent together O-(CH2)n-O with n equals 1 or 2;
R9 represents hydroxy, mercapto, Cl-C7-alkoxy or Cl-C7-alkylthio. RIO represents hydrogen, hydroxy, mercapto, halogenyl or amino, Cl-C16-alkyl, acyl, a optionally sustituted mono- or bicyclus; and pharmacologically acceptable salts or prodrugs thereof, to produce pharmaceutical agents for the treatment of diseases where MMP activity is envolved.
Preferred is the use of substances of the general formula I to produce pharmaceutical agents for the treatment of diseases where MMP activity is envolved, with the proviso that alkyl represents a saturated carbo-chain wherein
Rl represents hydrogen, hydroxy, acyl, Cl-C5-alkoxy, Cl-C5-alkenoxy, halogenyl or
Cl-C5-alkyl or Cl-C5-alkenyl;
R2 represents hydrogen, hydroxy, halogenyl, cyano, Cl-C5-alkyl, Cl-C5-alkenyl, Cl-
C5-alkenoxy or Cl-C5-alkoxy, acyl; R3 and R4 represent independently of each other hydrogen, hydroxy, halogenyl, C 1 -C7- alkyl, Cl-C7-alkenyl, acyl or a monocycle;
R5, and R6 represent independently of each other hydrogen, hydroxy, mercapto, C1-C7- alkyl, Cl-C7-alkoxy, acyl, or Cl-C7-alkylthio, Cl-C7-alkenyl, Cl-C7-alkenoxy, or Cl-
C7-alkenylthio; R7 represents hydrogen, hydroxy, halogenyl or amino;
R8 represents hydrogen, hydroxy, mercapto, Cl-C7-alkyl, C 1 -C7-alkoxy, C1-C7- alkylthio, Cl-C7-alkenyl, Cl-C7-alkenoxy, Cl-C7-alkenylthio, acyl or R8 and R9 represent together O-(CH2)n-O with n equals 1 or 2;
R9 represents hydroxy, mercapto, Cl-C7-alkoxy or Cl-C7-alkylthio. RIO represents hydrogen, hydroxy, mercapto, halogenyl or amino, Cl-C15-alkyl, Cl- C15-alkoxy, Cl-C15-alkylthio, Cl-C15-alkenyl, Cl-C15-alkenoxy, C1-C15- alkenylthio, acyl, a optionally sustituted mono- or bicyclus; and pharmacologically acceptable salts or prodrugs thereof,
Rl is preferably methyl or hydrogen.
R2 is preferably hydrogen.
R3 is preferably hydrogen.
R4 is preferably hydrogen.
R5 is preferably hydroxy, Cl-C3-alkoxy, especially methoxy, mercapto, C1-C3- alkylthio, especially methylthio.
R6 is preferably Cl-C3-alkoxy, especially methoxy.
R7 is preferably hydroxy or hydrogen.
R8 is preferably hydroxy, Cl-C12-alkoxy, mercapto, Cl-C12-alkylthio.
R9 is preferrably hydroxy or mercapto.
In addition the invention concerns new substances of the general formula I, whererin R9 represents mercapto or Cl-C7-alkylthio. Also new substances of general formula I are such wherein the residues Rl to RIO has the following meanings Rl represents C2-C5-alkyl or halogenyl; R2 represents halogenyl, cyano, C2-C5-alkyl, or C2-C5-alkoxy; R3 represent halogenyl, C 1 -C7-alkyl or a monocycle R4 represent halogenyl, C2-C7-alkyl or a monocycle;
R5, R6, R8 and R9 represent independently of each other mercapto, C2-C7-alkyl, C2- C7-alkoxy, or Cl-C7-alkylthio; R7 represents halogenyl or amino; RIO represents mercapto, halogenyl or amino, Cl-C15-alkyl, Cl-C15-alkoxy, C1-C15- alkylthio, a optionally sustituted mono- or bicyclus; and pharmacologically acceptable salts or prodrugs thereof,and pharmacologically acceptable salts or prodrugs thereof.
Within the scope of the general formula I many aporphine alkaloids are known. A selection is: Aporphine, Boldine, Apomorphine, Laurotetanine, Norisocorydine, Isocorydine, Glaucine, Nuciferine, Fissoldine, Norglaucin, Xylpine, Actinodaphnine and others like dicentrine. Boldine and Glaucine are well known as ingredients of extracts from Annonaceae, Lauraceae, Magnoliaceae, Monimiaceae and others. Boldine is one of many ingredients of Monimiaceae Peumus boldus, commonly called Boldo. Boldo is used as vermifuge, to treat liver, gall bladder and bowel dysfunctions, or inflammation. Boldine is believed to be responsible for both the choleretic and diuretic activity of the leaves from Boldo. In rat aorta (S)-Boldine depressed contractions evoked by noradrenaline in a concentration dependent manner (Ivorra MD et al. Eur. J. Pharmacol. 231: 165-74 (1993)). Boldine and Glaucine show inhibitory effects on TPA induced down regulation of gap junction function (Hu J et al. Biochem. Pharmacol. 50: 1635-43 (1995) and show antioxidative properties (Pharmacol. Res. 31: 103-7 (1995)). Moreno PRH et al. (Int J. Pharmacog. 31: 189-192 (1993)) show anti-tumor activity using a crude extract of Nectandra grandiflora bark. This extract contains less than 0.5% Boldine. Gonzales-Cabello R. et al. J. Invest. Allergol. Clin. Immunol. 4: 139-145
(1994) show effects of Boldine on cellular immune functions in vitro. It is suggested that the immune and antioxidant properties of boldine induce effects on patients with cancer, autoimmune and other diseases. Boldine has been described as effective inhibitor of the prostaglandin biosynthesis which is involved in the carrageenan induced inflammation in guinea pig (Backhouse et al., Agents Actions 42: 114-117 (1994)). Boldine and related compounds have been shown as inhibitors of platelet aggregation, however the mechanism is yet unclear (Chen et al., Planta Medica 62, 133-136 (1996)). None of the references cited above show or assume the effect of compounds of the general formula I as inhibitors of Metalloproteases or especially of MMPs. Compounds of the general formula 1 with R9 = thiol or thiolalkyl has not been published at all.
The monocycle listed in the case of R3 and RI Q is understood as saturated or unsaturated ring systems with 3 - 8, preferably 5 - 7 carbon atoms which can optionally be interrupted one or several times by heteroatoms such as nitrogen, oxygen or sulphur in particular a cyclopentyl, cyclohexyl, cycloheptyl, moφholinyl, thiamoφholinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, furyl, thiophenyl, imidazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl or 1,2,4-triazolyl residue. Lower alkyl, alkoxy and halogen come above all into consideration as substituents.
The bicycle listed under R1 Q is understood to be a condensed bicycle or a bicycle of the type monocycleι-L-monocycle2, wherein L denotes a valence dash Cι-C4-alkyl group, C2-C4 an alkenyl group, an oxygen or -C(O)-group.
The bicycle is preferably a residue such as a naphthyl, tetrahydronaphthyl, dekalinyl, quinolinyl, isoquinolinyl, tetrahydroquino-linyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, indazolyl, oxindolyl, benzofuranyl, benzothiophenyl, benzthiazolyl, benzoxazolyl, purinyl, biphenyl or (4-phenoxy)phenyl residue and in particular a naphthyl, biphenyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, indolyl or benzimidazolyl residue.
The residues listed under R2, R3, R4, R5, R6, R8, R9 RIO can optionally be substituted once or several times by halogen, hydroxy, thio, alkyl, hydroxyalkyl, alkoxy, alkylthio, alkylsulfinyl, alkyl-sulfonyl, amino, alkylamino, dialkylamino, nitro, carboxyl, carboxamido, alkoxy-carbonyl, amino or aminocarbonyl optionally substituted once or twice by lower alkyl, nitrile, oxo, thiocarboxamido, alkoyxythiocarbonyl, alkmercapto- carbonyl, phosphono, alkylphosphono, dialkylphosphono, alkylsulfonylamido, arylamino, aryl, hetaryl, aryloxy, arylthio, arylsulfmyl, arylsulfonyl or acyl.
In this case the halogen, hydroxy, oxo, thio, alkoxy, alkylthio, amino, aminocarbonyl, carboxyl and acyl groups are preferred.
Lower alkyl denotes C1-C6- Alkyl, preferred methyl, ethyl, propyl, isopropyl or tert- butyl.
Acyl in the residues Rl denotes for -C(O)-Ci-C6-alkyl or -C(O)H, preferred for an acetyl group.
If not given differently, the alkyl residues in general formula I can optionally be interrupted once or several time by heteroatoms (O, S, NH). If heteroatoms are present, the first backbone atom is preferrably O or S. Alkyl in general formula I or in combination with alkoxy, alkylthio, arylsulfonyl, alkylsulfonyl, alkylaminocarbonyl, arylaminocarbonyl, alkylamino, alkoxycarbonyl, aryloxycarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl represent a straight-chained, branched, saturated or unsaturated residue such as e.g. a methyl, ethyl, propyl, pentyl, octyl, allyl, propargyl, 2,4-pentadienyl, isopropyl, sec. butyl, 3-methylbutyl, 2-hydroxyhexyl and in particular a methyl, propyl, isopropyl, pentyl, octyl, allyl, 3-methylbutyl, 2- hydroxyhexyl and propargyl residue.
Aryl, also in combination with aryloxy, arylthio, arylsulfonyl, arylaminocarbonyl, aryloxycarbonyl, arylaminothiocarbonyl is understood as a phenyl or naphthyl residue which can optionally be substituted in particular by halogen, lower alkyl or alkoxy.
Halogen is understood as chlorine, bromine, iodine and preferably chlorine. If compounds of the general formula I contain one or several asymmetric carbon atoms, the optically active compounds of the general formula I are also a subject matter of the present invention.
The term "several" means in connection with heteroatoms in monocycles or bicycles preferred one, two or three more preferred one or two, the most preferred heteroatom is nitrogen.
The term "several" means in connection with substituents or substitution preferred one to five, more preferred one, two or three most preferred one or two.
The term "heteroatom" in connection with alkyl or acyl groups means preferred oxygen or NH, more preferred oxygen.
Substitutions of monocycles or bicycles in Ri, R4 and R5 are halogen, nitro, hydroxy, alkoxy, amino, alkylamino, dialkylamino, halogenmethyl, dihalogenmethyl, trihalogen- methyl, phosphono, alkylphosphono, dialkylphosphono, SO2NH2, SO2NH(alkyl), SO2N(alkyl)2, SO2(alkyl), acetyl, formyl, nitril, COOH, COOalkyl, -OC(O)alkyl, - NHC(O)Oalkyl, OC(O)O-aryl, -NHC(S)NH2, -NHC(S)NHalkyl, -NHC(O)-aryl.
Preferred optical isomers of the compounds of the invention are:
Figure imgf000010_0001
The following compounds are commercially available, can be synthesized or isolated in a manner known in the art:
Example Structure Molec Name Weight
333,813 R(-)-2,ll-DIHYDROXY-10- METHOXYAPORPHINE HYDROCHLORIDE
364,237 R(-)-2,10,ll-TRIHYDROXYAPOREH_SE
Figure imgf000011_0001
392,290 R(-)-2,10,l 1-TRfflYDROXY-N-PROPYL- NORAPORPHINE HYDROBROMEDE
364,237 S(+)-2, 10, 11 -TRIHYDROXYAPORPHINE HYDROBROMIDE
469,312 (+)-MAGNOFLORINE IODIDE
341,404 ISOCORYDINE
Figure imgf000011_0002
355,431 (+)-GLAUCINE
483,339 (+)-MENISPERINE IODIDE
341,404 (+)-CORYDINE
327,377 (+)-CORYTUBERINE
311,378 ISOTHEBAINE
327,377 BOLDINE
Figure imgf000012_0001
3 313,351 LAUROLITSTNE
4 497,366 O-METHYLISOCORYDINE IODOMETHYLATE
Figure imgf000013_0001
9">
Many other compounds are known from the literature. The following selection provide an illustration of embodiments of the invention and should not be construed to limit the scope of the invention:
Example 15: 6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo<de,g>quinoline-l,2-diol Example 16: 6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo<de.g>quinoline-10,l 1-diol Example 17: 2-methoxy-5,6,6a,7-tetrahydro-4H-dibenzo<de,g>quinoline-l,10-diol Example 18: 2,ll-dimethoxy-6-methyl-5,6,6a,7-tetrahydro-4H- dibenzo<de,g>quinolin- 1 -ol Example 19 1 , 10-dimethoxy-5 ,6,6a,7-tetrahydro-4H-dibenzo<de,g>quinoline-2,9-diol Example 20 1 ,2, 10-trimethoxy-5 ,6,6a,7-tetrahydro-4H-dibenzo<de,g>quinolin- 11 -ol Example 21 10,ll-dimethoxy-6-methyl-5,6,6a,7-tetrahydro-4H- dibenzo<de,g>quinoline- 1 ,2-diol
Example 22: l,10-dimethoxy-6-methyl-5,6,6a,7-tetrahydro-4H- dibenzo<de,g>quinoline-2, 11 -diol
Example 23: 2,9,10-trimethoxy-6-methyl-5,6,6a,7-tetrahydro-4H- dibenzo<de,g>quinolin- 1 -ol
Example 24: 1 ,2,9, 10-tetramethoxy-5,6,6a,7-tetrahydro-4H-dibenzo<de,g>quinoline
Example 25: l-(10-hydroxy-1.2-dimethoxy-4,5,6a,7-tetrahydro- dibenzo<de,g>quinolin-6-yl)-ethanone Example 26: acetic acid l,2,10-trimethoxy-6-methyl-5,6,6a,7-tetrahydro-4H- dibenzo<de,g>quinolin-9-yl ester
Example 27: l-(l,2,9,10-tetramethoxy-4,5,6a,7-tetrahydro-dibenzo<de,g>quinolin-6- yl)-ethanone Example 28: l l-hydroxy-l,2,10-trimethoxy-4,5,6a,7-tetrahydro- dibenzo<de,g>quinoline-6-carbothioic acid phenylamide
Example 29: 10-methoxy-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo<de,g>quinoline- 2,11-diol
Compounds of the general formula I can be synthesized by well-known processes preferably in that a) an alcoholic group of one of the described compounds (in the literature; e.g. Srilankin or Boldin) is converted to an ether using Alkyliodide in basic solution (see Example 30). Reaction products can be isolated by chromatography. In compounds having a phenolic and an alkylic hydroxy group, the phenolic group has to be protected by ester formation first, before the alkylic hydroxy group can be alkylated, since the phenolic hydroxy group is more reactive (e.g. in the case of Srilankin). b) an alkyl or substitued alkyl or alkenyl or substituted alkenyl group is introduced into one of the bromide substituted compounds described in the literature (e.g. 3,8-
Dibromboldin or 3-bromopredicentrine) by protruding protection of the free hydroxy groups by an ester or allyl or benzyl protecting group. After Bromide/Lithium exchange that compound can be reacted with an appropriate (substituted) alkylbromide or (substituted) alkenylbromide by standard procedures. Afterwards the protecting groups can be deprotected. This can be done by standard methods for the ester, with Pd for the allyl and by hydrogenolysis for the benzyl protecting group. Compounds having no bromide group can be bromidated by a standard radical reaction with bromine and the different reactions products can be purified by chromatography, prior to the mentioned alkylation procedure. c) Compounds with sulfur directly attached to the apoφhine sceleton can be obtained from the corresponding oxygen compounds by oxygen/sulfur exchange, which can be done by using O -> S exchange reagents, e.g. potassium thiocyanate (e.g. Snyder, H.R., Stewart, J.M., Ziegler, J.B., J. Am. Chem. Soc. (1947) 69, 2672), thiourea (e.g. Ketcham, R., Shah, V.P., J. Org. Chem. (1963) 28, 229), 3-methylbenzothiazole-2- thione (e.g. Calo, V., Lopez, L., Marchese, L., Pesce, G., J. Chem. Soc. Chem. Commun.
(1975) 621) and triphenylphosphine sulfide (Chan, T.H., Finkenbine, J.R., J. Am. Chem. Soc. (1972) 94, 2880) or Lowry reagent (Lowry, O.H., Rosebrough, N.J., Faro, A.L., Randall, R.J., JBC (1951) 193, 265-275).
Example 30:
Synthesis of 9-Ethoxy-2-Hydroxy- 1 - 10-dimethoxyapoφhine (1,10-dimethoxy-9- ethoxy-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo<de,g>quinoline-2-ol)
5 nMol of Ethyliodide has been added to a solution of 5 nM 2,9-Dihydroxy-l-10- dimethoxyapoφhine and 30 nMol K2CO3 in 30 ml Dimethylformamide. After stirring one hour at 50°C the solution was filtered and the solute was evaporated. The product has been purified by chromatography.
The following compounds can be prepared in an analogous manner:
Example 31 : 2-Ethoxy-9-Hydroxy- 1 - 10-dimethoxyapoφhine (1,10-dimethoxy-2- ethoxy-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo<de,g>quinoline-9-ol)
Example 32: 2,9-Diethoxy-l-10-dimethoxyapoφhine (l,10-dimethoxy-2,9-diethoxy- 6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo<de,g>quinoline) Example 33: 2-Hydroxy-9-n-Propyloxy-l-10-dimethoxyapoφhine (l,10-dimethoxy-9- propyloxy-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo<de,g>quinoline-2-ol)
Example 34: 9-Hydroxy-2-n-Propyloxy- 1 - 10-dimethoxyapoφhine (1,10-dimethoxy-2- propyloxy-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo<de,g>quinoline-9-ol)
Example 35 : 2,9-Di-w-propyloxy- 1 - 10-dimethoxyapoφhine (1,10-dimethoxy-2,9- dipropyloxy-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo<de,g>quinoline)
Example 36: 2,9-Di-«-propyloxy-6a-«-propyl-l-10-dimethoxyapoφhine (1,10- dimethoxy-2,9-dipropyloxy-6-methyl-6a-propyl-5,6,7-trihydro-4H- dibenzo<de,g>quinoline)
Example 37: 2-«-Butyloxy-9-Hydroxy-l-10-dimethoxyapoφhine (l,10-dimethoxy-2- butyloxy-6-methyl-5 ,6,6a,7-tetrahydro-4H-dibenzo<de,g>quinoline-9-ol)
Example 38: 2,9-Di-n-butyloxy-l-10-dimethoxyapoφhine (l,10-dimethoxy-2,9- dibutyloxy-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo<de,g>quinoline)
Example 39: 9-«-Butyloxy-2-Hydroxy-l-10-dimethoxyapoφhine (l,10-dimethoxy-9- butyloxy-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo<de,g>quinoline-2-ol)
Example 40: 2,9-Di-«-butyloxy-6a-n-butyl-l-10-dimethoxyapoφhine (1,10- dimethoxy-2,9-dibutyloxy-6-methyl-6a-butyl-5,6,7-trihydro-4H- dibenzo<de,g>quinoline)
Compounds of the general formula I can contain one or several chiral centres and can then be present in a racemic or in an optically active form. The racemates can be separated according to known methods into the enantiomers. Preferably diastereomeric salts which can be separated by crystallization are formed from the racemic mixtures by reaction with an optically active acid such as e.g. D- or L-tartaric acid, mandelic acid, malic acid, lactic acid or camphorsulfonic acid or with an optically active amine such as e.g. D- or L-α-phenyl-ethylamine, ephedrine, quinidine or cinchonidine.
Alkaline salts, earth alkaline salts like Ca or Mg salts, ammonium salts, acetates or hydrochlorides are mainly used as pharmacologically acceptable salts which are produced in the usual manner e.g. by tritrating the compounds with inorganic or organic bases or inorganic acids such as e.g. sodium hydroxide, potassium hydroxide, aqueous ammonia, Ci-C4-alkyl-amines such as e.g. triethylamine or hydrochloric acid. The salts are usually purified by reprecipitation from water/acetone.
The new substances of formula I and salts thereof according to the invention can be administered enterally or parenterally in a liquid or solid form. In this connection all the usual forms of administration come into consideration such as for example tablets, capsules, coated tablets, syrups, solutions, suspension etc. Water which contains additives such as stabilizers, solubilizers and buffers that are usual in injection solutions is preferably used as the injection medium.
Such additives are e.g. tartrate and citrate buffer, ethanol, complexing agents (such a ethylenediaminetetra-acetic acid and non-toxic salts thereof), high-molecular polymers
(such as liquid polyethylene oxide) to regulate viscosity. Liquid carrier substances for injection solutions have to be sterile and are preferably dispensed into ampoules. Solid carrier substances are e.g. starch, lactose, mannitol, methylcellulose, talcum, highly dispersed silicic acids, higher molecular fatty acids (such as stearic acid), gelatins, agar- agar, calcium phosphate, magnesium stearate, animal and vegetable fats, solid high- molecular polymers (such as polyethylene glycols); suitable preparations for oral application can optionally also contain flavourings and sweeteners.
The dosage can depend on various factors such as manner of administration, species, age and/or individual state of health. The doses to be administered daily are about 5- 2000 mg/human, preferably 100-500 mg/human and can be taken singly or distributed over several administrations.
Prodrugs of the compounds of the invention are such which are converted in vivo to the pharmacological active compound. The most common prodrugs are carboxylic acid esters, e.g. acetats, ethyl esters etc.
Within the sense of the present invention the following derivatives are preferred in addition to the compounds mentioned in the examples and compounds that can be derived by combining all meanings of substituents mentioned in the claims: Example 41:
2-ethoxy- 10-methoxy-6-methyl- 1 -pentyloxy-5 ,6,6a,7-tetrahydro-4H- dibenzo<de,g>quinoline-9-ol
Example 42: l,10-dimethoxy-2-hydroxy-6-methyl-3-pentyl-5,6,6a,7-tetrahydro-4H- dibenzo<de,g>quinoline-9-ol
Example 43: l,10-dimethoxy-4-hexyl-2-hydroxy-6-methyl-5,6,6a,7-tetrahydro-4H- dibenzo<de,g>quinoline-9-ol
Example 44: 1 ,2-dihydroxy-3-hexyl- 10-methoxy-6-methyl-5 ,6,6a,7-tetrahydro-4H- dibenzo<de,g>quinoline-9-ol Example 45: l,10-dimethoxy-3,4-dipentyl-2-hydroxy-6-methyl-5,6,6a,7-tetrahydro-4H- dibenzo<de,g>quinoline-9-ol Example 46:
10-dimethoxy-2-hydroxy-6-methyl-3-pentyl-l-pentyloxy-5,6,6a,7-tetrahydro-4H- dibenzo<de,g>quinoline-9-ol
Example 47:
1 , 10-dimethoxy-2-hydroxy-6-methyl-3-octyl-5 ,6,6a,7-tetrahydro-4H- dibenzo<de,g>quinoline-9-ol Example 48:
1 , 10-dimethoxy-3-heptyl-2-hydroxy-6-methyl-5,6,6a,7-tetrahydro-4H- dibenzo<de,g>quinoline-9-ol Example 49: 1,10-dimethoxy-2-hydroxy-6-methyl-4-octyl-5 ,6,6a,7-tetrahydro-4H- dibenzo<de,g>quinoline-9-ol Example 50:
1 , 10-dimethoxy-4-heptyl-2-hydroxy-6-methyl-5,6,6a,7-tetrahydro-4H- dibenzo<de,g>quinoline-9-ol Example 51:
3,4-dibutyl-l,10-dimethoxy-2-ethoxy-6-methyl-5,6,6a,7-tetrahydro-4H- dibenzo<de,g>quinoline-9-ol
Example 52
In order to determine the inhibition of MMPs, for example MMP-8, the catalytic domain (isolation and purification see for example Schnierer, S., Kleine, T., Gote, T., Hillemann, A., Knauper, V., Tschesche, H.,Biochem. Biophys. Res. Commun. (1993) 191, 319-326) is incubated with inhibitors having various concentrations. Subsequently, the initial reaction rate in the conversion of a standard substrate is measured in a manner analogous to Grams F. et al., FEBS 335 (1993) 76-80). Alternatively the percent inhibition will be determined at a distant inhibitor concentration.
The assays for other MMPs are performed in a analogous manner.
Assay buffer: 50 inM Tris/HCI pH 7.6 (Tris= Tris-(hydroxymethyl)-aminomethan)
100 mM NaCl/10 mM CaCl2/5 % MeOH (if necessary)
Enzyme: 8 nM catalytic domain (Met80-Gly242) of human neutrophil coUagenase Substrate: 10 microM DNP-Pro-Leu-Gly-Leu-Tφ-Ala-D-Arg-NH2 Total assay volume: 1 ml
Table 1 shows the inhibition in % at a compound concentration of 100 ng/ml or IC50 values in brackets.
Table 1: Inhibition (%) with different MMPs at lOOng/ml
Compound Example MMP 2 MMP 3 MMP 8 MMP 9
Boldin- 12 82% 82% 100% 82%
(44 nM)
Glaucine 7 20% 21% 26% 26%
(121 nM)
2-«-Butyloxy-9- 37 14% 23% 23% 21%
Hydroxy-1-10- dimethoxyapoφh ine

Claims

Claims
Use of a substatially pure compound of formula I
Figure imgf000021_0001
wherein
Rl represents hydrogen, hydroxy, acyl, halogenyl or C l-C6-alkyl;
R2 represents hydrogen, hydroxy, halogenyl, cyano, Cl-C6-alkyl, or acyl;
R3 and R4 represent independently of each other hydrogen, hydroxy, halogenyl,
Cl-C7-alkyl, acyl or a monocycle;
R5, and R6 represent independently of each other hydrogen, hydroxy, mercapto,
Cl-C8-alkyl, Cl-C7-alkoxy or acyl;
R7 represents hydrogen, hydroxy, halogenyl or amino;
R8 represents hydrogen, hydroxy, mercapto, Cl-C8-alkyl, acyl or R8 and R9 represent together O-(CH2)n-O with n equals 1 or 2;
R9 represents hydroxy, mercapto, Cl-C7-alkoxy or Cl-C7-alkylthio.
RIO represents hydrogen, hydroxy, mercapto, halogenyl or amino, Cl-C16-alkyl, acyl, a optionally sustituted mono- or bicyclus; and pharmacologically acceptable salts or prodrugs thereof, to produce pharmaceutical agents for the treatment of diseases where MMP activity is envolved.
2. Use as claimed in claim 1 wherein Rl is methyl or hydrogen or R2 is hydrogen or R3 is hydrogen or R4 is hydrogen.
3. Use as claimed in one of the claims 1 or 2 wherein R5 is hydroxy, C1-C3- alkoxy, mercapto, or Cl-C3-alkylthio or R6 is Cl-C3-alkoxy or R7 is hydroxy or hydrogen.
4. Use as claimed in one of the claims 1 to 3 wherein R8 is hydroxy, C1-C12- alkoxy, mercapto, Cl-C12-alkylthio.
5. Use as claimed in one of the claims 1 to 4 wherein R9 is preferrably hydroxy or mercapto.
6. A compound of formula I as given in one of the claims 1 - 5,wherein Rl represents C2-C5-alkyl or halogenyl;
R2 represents halogenyl, cyano, C2-C5-alkyl, or C2-C5-alkoxy;
R3 represent halogenyl, Cl-C7-alkyl or a monocycle
R4 represent halogenyl, C2-C7-alkyl or a monocycle;
R5, R6, R8 and R9 represent independently of each other mercapto, C2-C7- alkyl, C2-C7-alkoxy, or C 1 -C7-alkylthio;
R7 represents halogenyl or amino;
RIO represents mercapto, halogenyl or amino, Cl-C15-alkyl, Cl-C 15 -alkoxy,
Cl-C15-alkylthio, a optionally sustituted mono- or bicyclus; and pharmacologically acceptable salts or prodrugs thereof.
A compound of formula I as given in one of the claims 1 - 5, wherein R9 represents mercapto or Cl-C7-alkylthio and their pharmacologically acceptable salts, optically active forms thereof or prodrugs thereof. Pharmaceutical composition containing at least one compound of formula I as claimed in one of the claims 6 or 7 in addition to common carrier substances and auxiliary substances.
Use of a compound of formula I as claimed in one of the claims 1 to 6 for the production of pharmaceutical agents for treatment of osteo- and rheumatoid arthritis, periodontal diseases, diseases, where the presence of bacteria results in the release of MMPs, corneal ulceration, metastasis, angiogenesis, multiple sclerosis, sun-induced skin-aging, emphysema, restinosis and arteriosclerosis
10. Use of a compound of formula I as claimed in one of the claims 6 or 7 for the production of pharmaceutical agents for treatment of osteo- and rheumatoid arthritis, periodontal diseases, diseases, where the presence of bacteria results in the release of MMPs, corneal ulceration, metastasis, angiogenesis, tumour progression, multiple sclerosis, sun-induced skin-aging, emphysema, and cardiovascular diseases.
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WO2002066000A2 (en) * 2001-02-21 2002-08-29 Sederma Novel cosmetic slimming compositions containing boldine
WO2002066000A3 (en) * 2001-02-21 2004-03-04 Sederma Sa Novel cosmetic slimming compositions containing boldine
JP2005537332A (en) * 2002-08-30 2005-12-08 セダーマ エス.アー.エス. New noraporphine derivatives
US7354926B2 (en) * 2002-08-30 2008-04-08 Sederma Sas Molecules derived from noraporphine
WO2010026487A1 (en) * 2008-09-08 2010-03-11 University Of Concepcion Therapeutic methods and compositions
CN103483256A (en) * 2013-09-23 2014-01-01 广西师范大学 (-)-4-(2,3-dihydroxypropxyl)-methanamide-6-azabenzanthrone as well as synthesis method and application thereof

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ZA988782B (en) 2000-03-27
AR013524A1 (en) 2000-12-27

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