CA2129831A1 - Heteroaryl substituted phenylethenyl compounds having retinoid-like biological activity - Google Patents

Abstract

Compounds of formula (I) where R1, R2, R3 and R4 independently are hydrogen, lower alkyl of 1 to 6 carbons, halogen or lower alkoxy of 1 to 6 carbons; R5 and R5' independently are hydrogen or lower alkyl of 1 to 6 carbons; Y is oxygen or sulfur; Z
is n-alkyl having 1 to 10 carbons, cyclo or branched chain alkyl of 3 to 10 carbons, and straight chain alkenyl having 2 to 10 carbons, or cyclo or branched chain alkenyl of 3 to 10 carbons; X is a heteroaryl group selected from a group consisting of thienyl, pyridyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl and oxazolyl; A is (CH2)n where n is 0-5, lower branched chain alkyl having 3 to 6 carbons, cycloalkyl having 3 to 6 carbons, alkenyl having 2 to 6 carbons and 1 or 2 double bonds, alkynyl having 2 to 6 carbons and 1 or 2 triple bonds; B is hydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR8, CONR9R10, -CH2OH, CH2OR11, CH2OCOR11, CHO, CH(OR12)2, CHOR13O, -COR7, CR7(OR12)2, or CR7OR13O, where R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R8 is an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R8 is phenyl or lower alkylphenyl, R9 and R10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or phenyl or lower alkylphenyl, R11 is alkyl of 1 to 10 carbons, phenyl or lower alkylphenyl, R12 is lower alkyl, and R13 is divalent alkyl radical of 2 - 5 carbons, have retinoic acid like biological activity.

Description

WO 93/16067 PCr/US93/01119 IIETEROA~YL 8UBST~TIJTED PH~:NYLEq~ENY~ COMPOUND8 ~IAVING RETINOID-LIlOE BIOLOGICAL ACTIVITY
BACRGROUN~ OF T}IE IN~ENTION
1. Field of th _Invention -The present invention is directed to novel compounds which have retinoic acid-like biological activity. More specifically, the present invention relates to compounds having a phenyl substituted ethenyl portion, and a heteroaryl portion. The present invention also relates to pharmaceutical compositions comprising these compounds and to methods of using the compounds and compositions.

2. Related Art United States Patent No. 4,326,055 discloses ethene derivatives which have a substituted phenyl ring and a substituted indane or tetrahydronapht~lene group.
The compounds are described as tumor i~hibiting agents, and useful for treating dermatological conditions and rheumatic illnesses~
United States Patent No. 4,723,028 discloses l,2-diphenylethene (stilbene) derivataves which have retinoic acid-like activity.
United States Patent No. 4,740l519 discloses certain aromatic het~rorycl~ derivatives which have retinoic acid-like activity.
Published European Patent Application 0130795 discloses ethene derivatives, where the ethene moiety is substituted by a substituted phenyl group and by a substituted chroman, thiochroman or ~uinoline group.
s The compounds are useful for inhibiting the degradation of cartilage in mammals.
European Patent Application 176034A ~published April 2, 1986) discloses tetrahydronaphtalene compounds WO93/1~K7 PCT/US93/0111 having an ethynylbenzoic group. United states Patent No. 4,739,098 discloses compounds wherein three olefinic units from the acid-containing moiety of - retinoic acid are replaced by an ethynylphenyl functionality. These compound have retinoic acid-like biological activity.
United States Patent No. 4,810,804 (issued on March 7, 1989) based on an application of the same inventor and assigned to the same assignee as the present application, discloses such disubstituted a~etylene compounds wherein one of the substituents of the acetylene (ethyne) group is a substituted phenyl group, and the second substituent is a substituted or unsubstituted 6-chromanyl, 6-thiochromanyl or 6-tetrahydroquinolinyl group. The compounds disclosed and claimed in United States Patent No. 4,810,804 have retinoic acid-like biological activity.
Se~eral co-pending applications and recently iæsued patents of the present inventor, which are assigned to the assignee of the present application, are directed to further co~pounds having retinoic acid-like activity. r A published European patent application of the present applicant (Publication No. 0284288, published on September 28, 1988) describes compounds having retinoic acid-like activity which are 4,4 disubstituted chroman-6-yl, 4,4 disubstituted - thiochroman-6-yl acetylenes also substituted by a substituted heteroaryl group.
Retinoic acid-like activity has been generally recognized in the art to be associated with useful biological activity. Specifically, compounds having retinoic acid-like activity are useful as regulators of W093/1~K7 PCT/USg3/01119 cell proliferation and differentiation, and particularly as agents for treating dermatoses, such as acne, Darier's disease, psoriasis, icthyosis, eczema and atopic dermatitis, and for treating and preventing malignant hyperproliferative diseases such as epithelial cancer, breast cancer, prostatic cancer, head and neck cancer and myelorid leukemias, for rever~ing and preventing atherosclerosis and restenosis resulting from neointiural hyperproliferation, for treating and preventing other non-malignant - -hyperproliferative diseases such as endometrial hyperplasia, benign prostatic hypertrophy, proliferative vitreal retirropalhy and dysplasias, for treating autoimmune diseases and immunological disorders (e.g. lupus erythematosus, for treating chronic inflammatory diseases such as pulmonary fibrosis, for treating and preventing diseases a~sociated with lipid metabolism and transport such as dyslipidemias, for promoting wound healing, for treating dry eye syndrome and for reversing and preventing the effects of sun damage to skin.
Ssm~ary_cf the Invention -- This invention covers~compounds of For~ula 1 :, .

A-B

~ or~ul~ 1 wherein Rl, R2, R3 and R~ independently are hydrogen, lower alkyl of 1 to 6 carbons, halogen or lower alkoxy 21298:~1 WO93/16067 ~ - PC~/US93/01119 of l to 6 carbons;
R5 smf R5~ independently are hydrogen or lower alkyl of l to 6 carbons or halogen;
Y is oxygen or sulfur;
Z is n-alkyl having l to l0 carbons, cyclo or branch-chained alkyl of 3 to l0 carbons, and straight chain alkenyl having 2 to l0 carbons, or cyclo or branched chained alkenyl of 3 to l0 carbons;
X is a heteroaryl group selected from a group consisting of thienyl, pyridyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl and oxazolyl:
A is (CH2)n where n is 0-5, lower branched chain alkyl having 3 to 6 carbons, cycloalkyl having 3 to 6 carbons, alkenyl having 2 to 6 carbons and l or 2 double bonds, alkynyl hàving 2 to 6 carbons and 1 or 2 triple bonds;
~ is hydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR8, C~N~g~lo~ -CH2OH~
CH2ORll, CH2OCORll, CHO, CH(ORl2)2~ CH0~13 ~ 7 CR7(Ri2)2~ or CR70R130, where R7 is an alkyl, cycloalkyl or alkenyl group containing l to 5 carbons, i~ an alkyl group of l to l0 carbons~ or a cycloalkyl group of 5 to lO carbons, or R8 is phenyl or lower alkylphenyl, ~9 and Rlo independently are hydrogen, an alkyl group of 1 to l0 carbons, or a cycloalkyl group of S to l0 carbons, or phenyl or lower alkylphenyl, Rl~ is alkyl of l to l0 carbons, phenyl or lower alkylphenyl, Rl2 is lower alkyl, and Rl3 is divalent alkyl radical of 2 - S carbons.
In a second aspect, this invention relates to the use of the compounds of FO~U1A 1 as regulators of cell proliferation and differentiation, and particularly as agents for treating dermatoses, such as acne, Darier's _ s3/l~K7 PCT/US93/01119 disease, psoriasis, iethyosis, eezema and atopic dermatitis, and for treating and preventing malignant hyperproliferative dlseases such as epithelial eaneer, breast eaneer, prostatie eaneer, head and neek eaneer and myelorid leukemias, for reversing and preventing atherosclerosis and restenosis resulting from neointiural hyperproliferation, for treating and preventing other non-malignant hyperproliferative diseases sueh as endometrial hyperplasia, benign prostatie hypertrophy, proliferative vitreal retirropalhy and dysplasias, for treating autoimmune diseases and immunologieal disorders (e.g. lupuæ
erythematosus, for treating chronie inflammatory di~eases sueh as pulmonary fibrosis, for treating and preventing diseases assoeiated with lipid metabolism and transport sueh as dyslipidemias, for promoting wound healing, for treating dry eye syndrome and for reversing and preventing the effeets of ~un damage to ~kin.
This invention also relates to a pharmaeeutieal for~ulation eomprising a eompound of For~ul~ 1 in ad~ixture with a pharmaeeutieally aeeeptable exeipient.
In-another a~peet, this invention relates to the proee~s for making a eompound of For~ula 1 whieh proeess eomprises reaeting a eompound of Formula 2 with a compound of Yormul~ 3 R2j~ (alkylO)zP(O)Cl lR's-X-A-B' \~ R4 For~ul- 2 . Formul~ 3 212~831 WO93/1~K7 PCT/US93/01115.

in which Rl through R5, R~5, A, X, Y and Z are defined as in connection with For~ula ~, and B' is defined as B
in Formula 1 above, or as such a precursor of B which can be readily converted into B by a chemial reaction or reactions well known in the art and within the skill of the practicing organic chemist. The reaction between compounds of Formula 2 and of Formul~ 3 is conducted under conditions of the Horner-Emmons modification of the Wittig reaction, and the present invention also relates to reactions between the compounds of these formulas and of analogous form~llas under ~orner-Emmons, Wittig or modified Wittig type conditions to provide the compounds of Fox~
Furthermore, the present invention also relates to reactions performed on compounds o~ Formula 1 (or on its precursors) to obtain still further Gompounds of Formula 1, such reaction~ including:
homologating a compound of the Fo~mula 1 where A
is (CH2)n and n is 0-4 to give an acid of Fon~ul~ ~; or conv~rting an acid of Fo~mula 1 to a salt; or forming an acid addition salt;
converting an acid of For~ula 1 to an ester; or converting an acid of Fo~wla 1 ~o an amide; or reducing an acid of Formul~ 1 to an alcohol or aldehyde; or converting an alcohol of Formul~ 1 to an ether or ester; or oxidizing an alcohol of Formula 1 to an aldehyde;
or converting an aldehyde of For~ula l to an acetal;
o~
converting a ketone of Formul~ 1 to a ketal.
General Embodiments W093/l~K7 2 1 2 9 8 3 1 PCT/US93/01119 Definitions The term alkyl refers to and covers any and all groups which are known as normal alkyl, branch-chain ~ alkyl and cycloalkyl. The term alkenyl re-fers to and covers normal alkenyl, branch chain alkenyl and cycloalkenyl groups having one or more sites of unsaturation. Lower alkyl means the above-defined broad definition of alkyl groups having 1 to 6 carbons, , and as applicable, 3 to 6 carbons for branch chained and cyclo-alkyl groups. Lower alkenyl is defined similarly having 2 to 6 carbons for normal alkenyl, and 3 to 6 carbons for branch chained and cycloalkenyl groups.
The term "ester" as used here refers to and covers any compound falling within the definition of that term as classically used in organic chemistry. Where B ~of For~ul~ 1) is -COOH, this term covers the products derived from treatment of this function with alcohols, preferably with aliphatic alcohols having 1-6 carbons.
Where the ester is derived from compounds where B is -CH20H, this term covers compounds of the formula -CH200CR11 where Rll is any substituted or unsubsti*uted aliphatic, aromatic or aliphatic-aromatic group, preferably with 1-6 carbons in the aliphatic portions.
Preferred esters are derived from the saturated aliphatic alcohols or acids of ten or fewer carbon atoms or the cyclic or sàturated aliphatic cyclic alcohols and acids of 5 to 10 carbon atoms.
Particularly preferred aliphatic esters are those derived from lower alkyl acids or alcohols. Also preferred are the phenyl or lower alkylphenyl esters.
Amide has the meaning classically accorded that , i WO 93/16067 PCI`/VS93/01115 term in organic chemistry. In this instance it includes the unsubstituted amides and all aliphatic and aromatic mono-and di-substituted amides. Preferred amides are the mono- and di-substituted amides derived from the saturated aliphatic radicals of ten or fewer carbon atoms or the cyclic or saturated aliphatic-cyclic radicals of 5 to 10 carbon atoms. Particularly preferred amides are those derived from lower alkyl amines. Also preferred are mono- and di-substituted - amides derived from the phenyl or lower alkylphenyl amines. Unsubstituted amides are also preferred.
Acetals and ketals includ~ the radicals of the formula -CK where K is (-OR)2. Here, R is lower alkyl.
Also, K may be -OR10- where Rl is lower alkyl of 2-5 carbon atoms, straight chain or branched.
A pharmaceutically acceptable salt may be prepared for any compound of this invention having a functionality capable of forming such salt, for example an acid or an amine functionality. A pharmaceutically acceptable salt may be any salt which retains the activity of the parent compound and does not impart any deleterious or ~ntoward effect on the subject to which it i8 administered and in ~he context in which it is administered. - -Such a salt may be derived ~rom any organic orinorganic acid or base. The salt may be a mono or polyvalent ion. Of particular interest where the acid function is concerned are the inor~anic ions, sodium, potassium, calcium, and magnesium. Organic amine salts may be made with amines, particularly ammonium salts such as mono-, di- and trialkyl amines or ethanol amines. Salts may also be formed with caffeine, tromethamine and similar molecules. Where there is a ,I WO93/1~K7 2 1 2 9 ~ 3 1 PCT/US93/01119 nitrogen sufficiently basic as to be capable of forming acid addition salts, such may be formed with any inorganic or organic acids or alkylating agent such as methyl iodide. ~referred salts are those formed with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid. Any of a number of simple organic acids such as m~no-, di- or tri-acid may also be used.
The compounds of the present invention contain at least one double bond and therefore may have trans and cis (E and Z) isomers. In addition, some of the compounds of the present invention may contain one or more chiral centers and therefore exist in enantiomeric and diastereomeric forms. The scope of the present invention is intended to cover all such isomers per se, as well as mixtures of cis and trans isomers, mixtures of diastereomers and racemic mixtures of enantiomers (optical isomers) as well.
With reference to the symbols Rl through R~ in Formula 1, in the preferred compounds of the present invention these symbols preferably represent hydrogen or lower alkyl,groups. Particularly preferred are those compounds where ~l through R~ are all hydrogen and those where the three out of the four of the above-mentioned groups is hydrogen, and one is lower alkyl.
Still further preferred among these are compounds where, the lower alkyl group is methyl.
With regard to,the groups R5 and R5' in the compounds of For~ula l, compounds are preferred where ' R5 and RS~ are independently hydrogen or methyl.
The symbol Y represents either oxygen or sulfur in accordance with the present invention.
With regard to the symbol Z in Formula 1, -2123~31 WO93/l~K7 PCT/US93/01119 .

compounds of the invention are preferred where Z
represents a branched chain alkyl or branced chain alkenyl group having one double bond. Particularly preferred are compounds where Z represents 3-methyl-2-butenyl.
With regard to the substitution pattern on the phenyl moiety of the compounds of the present invention, compounds are preferred where the Z-Y and ethenyl groups respectively occupy the 1 and 4 or 1 and 3 positions on the phenyl ring (the substitution is para or meta), and where the Rl through R4 groups are hydrogen. Alternatively, compounds are preferred where the Z-Y and ethenyl groups occupy the 1 and 4 or 1 and 3 (Dara or meta) positions, Rl through ~3 are hydrogen, and R~ is methyl and occupies the 6 position (ortho to the etheneyl group).
The symbol S of Formula 1 represents an aromatic heterocylic group which is substituted in the aromatic nucleus by the phenyletheneyl portion and by the A-B
moiety of the molecule. The preferred compounds of the in~ention are those where ~ represents thiophene, pyridine and furan.
With regard to the side chain (substituent a) on -the heteroaryl group ~, compounds are preferred where A
is (CH2)n, and still more preferred where ~ is 0.
With respect to the symbol B, the compounds of the invention are preferred where B is -COOH, or an alkali metal salt or organic amine salt thereof.
Alternatively, compounds are preferred where B is respresented by COOR8 (ester where R8 is lower alkyl) , CONRgRlo (amide) -CH2OH (alcohol), CH2OCORll, CH2OR
(Rll is lower alkyl; lower alkyl esters and ethers formed with a lower alkanol) or B is -CHO or CH(O~12)2, i W093tl~K7 2 1 2 9 8 3 1 PCT/US93/01119 CHOR130 (acetal derivatives~, where R12 and ~13 are defined as in connection with Formul~ 1. The most preferred compounds of the invention are shown in Formul~ ~: -_~CO2R-~
Z~-S

Formula 4 Compoun~ 1 Z~=(CH3)2C=CH-CH2-; ~*-~ is in the 3 posit ion: ~5 - H and R8 Z ethyl;
Co~pound 2 Z (CH3)2CeCH-CH2-; Z -8 is in the 3 position; R5 = H and R8 ~ H;
Co~pou~ 3 Z G(CH3)zG~CH-CH2-; 5 -B is in the 4 position: R~=CH3 and R8z ethyl;
Compoun~ ~ Z~-(CH3)2C=CH-CH2-; Z -8 is in the 4 position; R5~CH3 and R8= H;
Compound 5 Z~=(CH3)2C=CH-CH2-; Z~-8 is in the 3 position; R5SCH3 and R8- ethyl;
The compounds o~ this invention may be administered ~ystemically or topically, depending on ~uch considerations as the condition to be treated, need for site-specific treat~ent, quantity of drug to be administered, and similar considerations.
In the treatment of dermatcses, it will generally be preferred to administer the drug topically, though in certain cases such as treatment of cevere cystic acne, oral administration may also bQ used. Any common topical formulation such as a solution, suspension, gel, ointment, or salve and the like may be used.

W093/16067 PCT/US93/0111'~

Preparation of such topical formulations are well described in the art of pharmaceutical formulations as exemplified, for example, by Reminqton's PharmaceutLcal - Science, Edition 17, Mack Publishing Company-, Easton, Pennsylvania. For topical application, these compounds could also be administered as a powder or spray, particularly in aerosol form.
If the drug is to be administered systemically, it may be confected as a powder, pill, tablet or the like, or as a syrup or elixir for oral administration. For intravenous or intraperitonea1 administration, the compound will be prepared as a solution or suspension capable of being administered by injection. In certain cases, it may be useful to formulate these compounds in suppository form or as an extended release formulation for deposit under the skin or intermuscular injection.
Other medicaments can be added to such topical formulation for such secondary purposes as treating skin dryness, providing protection against light; other medications for treating dermatoses, preventing infection, reducing irritation, inflammation and the like.
Treatment of dermatoses or any other indications known or discovered to be susceptible to treatment by retinoic acid-like compounds will be effected by administration of the therapeutically effective dose of one or ~ore compounds of the instant invention. A
therapeutic concentration will be that concentration - which effects reduction of the particular condition, or retards its expansion. In certain instances, the drug ~ potentially could be used in a prophylactic manner to I prevent onset of a particular condition. A given therapeutic concentration will vary from condition to W093/1 ~ 7 2 1 2 9 8 3 1 PCT/USg3/01119 condition and in certain instances may vary with the severity of the condition being treated and the patient's susceptibility to treatment. Accordingly, a given therapeutic concentration will be best~determined at the time and place through routine experimentation.~
However, it is anticipated that in the treatment of, for example, acne, or other such dermatoses, that a formulation containing between 0.001 and 5 percent by weight, preferably about 0.01 to 1% will usually constitute a therapeutically effective concentration.
If administered systemically, an amount between 0.01 and 100 mg per kg body weight per day, but preferably about o.l to lo mg/kg, will effect a therapeutic result in most instances.
The retionic acid-like activity of these compounds was confirmed through the classic measure of retionic acid activity involving the effects of retionic acid on ornithine decarboxylase. The original work on the correlation between retinoic acid and decrease in cell proliferation was done by Verma & Boutwell, Cancer Research, 1977, 37, 2196-2201. That reference di wloses that ornithine decarboxylase (ODC) activity increased precedent-to polyamine biosynthesis. It has been e~tablished elsewhere that increases in polyamine synthe~is can be correlated or associated with cellular proliferation. Thus, if ODC activity could be inhibited, cell hyperproliferation could be modulated.
Although all causes for ODC activity increaæe are unknown, it is known that 12-0-tetradecanoyl-phorbol-13-acetate (TPA) induces ODC
activity. Retinoic acid inhibits this induction of ODC
activity by TPA. The compounds of this invention also inhibit TPA induction of ODC as demonstrated by an 2129~31 WO93/1~K7 ~ ;~ PCT/US93/0111`

assay essentially following the procedure set out in Cancer Res., 35: 1662-1670, 1975.
By way of example of retinoic acid-like activity it is noted that in the assay conducted essentially in accordance with the method of Verma & Boutwell, ibid, the following examples of the preferred compounds of the present invention (Compouna~ 1, 2 ~nd 3) attained an 80% inhibition of TPA induced ODC activity at the following concentrations (IC80):
Compound IC80 conc (nmols) Specific Embod~Lments The compounds of this invention can be made by a number of different synthetic chemical pathways. To illustrate this invention, there is here outlined a series of steps which have been proven to provide the compounds of Formula 1 when such synthesis is followed in fact and in ~pirit. The synthetic chemist will readily appreci~te that the conditions set out here are ~pecific embodiments which can be generalized to any and all of the compounds represented by Formula 1.
Furthermore, the synthetic chemist will readily ap~reciate that the herein described synthetic steps may be varied and or adjusted by those skilled in ~he art without departing from the scope and spirit of the invention.
Generally speaking the compounds of the present in~ention can be prepared by a Wittig or analogous ~modified Wittig) reaction between the compounds of ` W093/16067 PCT/VS93/Olllg ~ormul~ 2 and ~ormul~ 3, as described abov~. In this reaction, shown in ~eactio~ Bcheme 1, the appropriately substituted phenyl aldehyde or ketone of Formula 2 reacts with the dialkyl (preferably dieth~l) phosphonate of Formul~ 3 derived from the desired heteroaromatic compound, to form an ethene linkage between the substituted phenyl and the ~ubstituted heterocyclic moieties of the compounds of the invention. Generally speaking, the Horner Emmons (modified Wittig) reaction is conducted in the presence of a strong base, such as sodium hydride (NaH) or dimsyl sodium (NaCH2SOCH3) in a polar solvent sùch as dimethylsulfoxide. The coupling of the reagents of Formul~ 2 and ~ormul~ 3 provides the compounds of For~ula 1 or of For~ul~ S.

R Rs ,. . R2~
~\ R4 (alkylO)2P(O)CHR's-X-A-B' Formula 2 Formula 3 ¦Strong B~

z ~X-A-13' Fonnula 1, B'~ B
Formub S
ON ~ClIBMI~ 1 WO93/1~67 2 PCT/US93/01119 ~ 16 The compounds of Formula S differ from the compounds of Formula 1 only in that the the symbol B' represents such a group which may be readily converted by reactions well known in the art to a group represented by the symbol B. Compounds of Formula 1 may also be converted to still other compounds represented by Formula 1 with reactions which are known in the art. The ~-B and or A-B' functionality of the compounds of Formula 3 can be prepared by well known and published methods of synthetic organic chemistry.
By way of example, carboxylic acids are typically esterified by refluxing the acid in a solution of the appropriate alcohol in the presence of an acid catalyst such as hydrogen chloride or thionyl chloride.
Alternatively, the carboxylic acid can be condensed with the appropriate alcohol in the presence of dicyclohexylcarbodiimide and dimethylaminopyridine.
The ester is recovered and purified by conventional ~~
means. Acetals and ketals are readily made by the method described in March, "Advanced Organic Chemistry," 2nd Edition, McGraw-Hill Book Company, p 810). Alcohols, aldehydes and ketones all may be protected by forming respectively, ethers and ester acetals or ketals by known methods such as those described in NcOmie, Plenum Publishing Press, 1973 and Protectina GrouDs, Ed. Greene, John Wiley ~ Sons, 1981.
To increase the value of n-before effecting the Wittig (or analogous) coupling reaction of Roaction 8cheme 1 (where such compounds are not available from a commercial source) the heteroaromatic derivatives where B is -COOH are subjected to homologation by successive treatment under Arndt-Eistert conditions or other homologation procedures. Alternatively, derivatives ! wo 93~1~K7 PCT~US93/01119 where B is different from COOH, may also be homologated by appropriate procedures. The homologated acids can then be esteri~ied by the general procedure outlined in the preceding paragraph.
An alternative means for making compounds where A
is (CH2)n (n is 1 - 5) is to subject the compounds of Formula 1, where B is an acid or other function, to h~mologation, using the Arndt-Eistert method referred to above, or other homologation procedures.
Compounds of Formula 1 where A is an alkenyl group having one or more double bonds can be made for example, by having the requisite number of double bonds incorporated into the intermediate of Formula 3.
Generally speaking, the compounds of Formula 3 where A
is an unsaturated carbon chain can be obtained by synthetic ~chemes well known to the practicing organic chemist; for example by Wittig and like reactions, or by introduction of a double bond by-elimination of halogen from an alpha-halo-heteroarylalkyl-carboxylic acid, ester or like carboxaldehyde. Compounds of Formula 1 where the A group has a triple (acetylenic) bond can be made by using the corresponding intermediate of For~ul~ 3. Such intermediate can be obtainea by reactions well known in the art, for ex~mple, by reaction of a corresponding heteroaromatic-methyl ketone with strong base, such as lithium diisopropyl amide.
The~acids and salts derived from Formula 1 are readily obtainable from the corresponding esters.
Basic saponification with an alkali metal base will provide the acid. For example, an ester of Formula ~
may be dissolved in a polar solvent such as an alkanol, preferably under an inert atmosphere at room 2129~31 temperature, with about a three molar excess o~ base, for example, potassium hydroxide. The solution is stirred for an extended period of time, between 15 and 20 hours, cooled, acidified and the hydrolysate recovered by conventional means. ~ ~
The amide may be formed by any appropriate amidation means known in the art from the corresponding esters or carboxylic acids. One way to prepare such compounds is to convert an acid to an acid chloride and then treat that compound with ammonium hydroxide or an appropriate amine. For example, the acid is treated with an alcoholic base solution such as ethanolic KOH
(in approximately a lO~ molar excess) at room temperature for about 30 minutes. The solvent is removed and the residue taken up in an organic solvent such as diethyl ether, treated with a dialkyl formamide and then a lO-fold excess of oxalyl chloride~ ~his is all effected at a moderately reduced temperature between about -lO degrees and +lO degrees C. The last mentioned solution is then stirred at the reduced temperature for 1-4 hours, preferably 2 hours. Solvent removal provides a residue which is taken up in an inert organic solvent such as benzene, cooled to about O degrees C and treated with concentrated a~monium hydroxide. The resulting mixture is stirred at a reduced temperature for l - 4 hours. The product is recovered by conventional means.
Alcohols are made by converting the corresponding acids to the acid chloride with thionyl chloride or other means (J. March, "Advanced Organic Chemistry", 2nd Edition, NcGraw-Hill Book Company), then reducing the acid chloride with sodium borohydride (March, Ibid, pg. 1124), which gives the corresponding alcohols.

....

W093~16067 PCI~/US93/01119 lg Alternatively, esters may be reduced with lithium aluminum hydride at reduced temperatures. Alkylating these alcohols with appropriate alky halides under Williamson reaction conditions (March, Ibidj pg. 357) gives the corresponding ethers. These alcohols can be converted to esters by reacting them with appropriate acids in the presence of acid catalysts or dicyclohexylcarbodiimide and dimethlaminopyridine.
Aldehydes can be prepared from the corresponding primary alcohols using mild oxidizing agents such as pyridinium dichromate in methylene chloride (Corey, E.
J., Schmidt, G., Tet. Lett., 399, 1979), or dimethyl sulfoxide/oxalyl chloride in methylene chloride (Omura, K., Swern, D., Tetrahedron. 1978. 34, 1651).
Ketones can be prepared from an appropriate aldehyde by treating the aldehyde with an alkyl Grignard reagent or similar reagent followed by oxidation.
Acetals or ketals can be prepared from the corresponding aldehyde or ketone by the method described in March, Ibid, p 810.
C~mpounds where B is H can be prepared from the ~orresponding halogenated heteroaromatic compounds, preferably where the halogen is I.
The intermediate compounds of general Foxmul~
are prepared in accordance with the generalized reactian steps outlined in Reaction 8ch~a 2.

2129~31 WO 93/16067 PCr/US93/0111S~

R1 B ~- R R1 + Z-L r- z ~r Formula 6 Formula 7 Formula 8 ~MgBr(orLi) ~0 R3 Formtlls 10 Formuls 2 Formuls ~

. RE~C~ION 8C~g~ 2 In acaordance with this ~cheme, a halogenated phenol or thiophenol of ~or~ul~ 6 which has the desir~.d Rl through R~ substituents i~ the ~tarting material.
The general formula indicates a bromo phenol or thiopenol, however instead of bromine another halogen may be used. Examples ~or the starting material of For~ula 6 which are either available commercially, or can be prepaxed in accordance with reactions well known in the art, are 4-bromothiophenol, 2-methyl-4-bromothiophenol, 4-bromophenol, 2-methyl-4-bromophenol, 3-bromothiophenol and 3-bromophenol.

i W093/16067 2 12 9 8 31 PCT/US93/01119 The compound of Formula 6 is reacted under basic conditions with a compound of the formula Z-~ (For~ula 7) ~here Z is defined as in connection with Formul~ 1, and L symbolizes a leaving group, such as halogen, mesyl, tosyl or the like. Generally speaking, the reaction between the compounds of Formul~ 6 and Formula 7 is performed under alkylating conditions. The ether or thioether obtained in the foregoing reaction, which is shown by Formula 8, is thereafter converted to a Grignard or like reagent, shown by ~or~ula 9.
Specifically, ~ormula 9 shows a Grignard reagent deri~ed from a bromophenyl alkyl ether or from the bromophenyl alkyl thioether of Formula 8, which is obtained under conditions known in the art ~or forming Gri~nard reagents of this type. Alternatively, Formul~ 9 shows a lithium reagent derived from the bromophenyl alkyl ether or from the bromophenyl alkyl thioether of Formula 8 under conditionæ of a metal halogen oxchange reaction, such as treatment with n-butyllithium. The Grignard or lithium reagent of Formula 9 is thereafter reacted with dimethylformamide to provide the substituted benzaldehyde ~Formul~ ~
where R5 is H), or with a reagent comprising a source for the ~5-CO- group, ~uch as the acyl-thiopyridine of ~or~ul~ 10. An alternative ~ource for the R5-CO group where ~ is methyl, is the reagent N,O-dimethylhydroxylacetamide.
... ...
The intermediate compounds of general Formula 3 are prepared in accordance with the qeneralized reaction steps outlined in Rea¢tio~ schems 3.

,, , i, . ..

WO93/1~67 ; PCT/US93/0111 CH2R'5-X-A-B' ~ BrCHP~'s-X-A-B' Formula ll Formula 12 (alkylC))3P _ talkYI0)2P~O)GHR~-X-A-B~
h~at Formula 3 REA~TION 8C~B~ 3 In accordance with R~ctio~ 8~h~ 3, the heteroaromatic compound of ~o~mula ll serves as a ~tarting material. This co~pound bears e~her ~he A-B
subst~tuenk (as the ~ymbol~ a and ~ are defin~d in connection with Fonmula ~, or the ~ 8ub tituent, wherein B' is defined as in conne~tion with For~la 3.
The compound of For~ul~ ll also bears a methyl group in the position on the heterocycle where th~ ethen~ moiety of the compounds o the invention ~For~ula l) is attached. $he starting matexials of Formula ll are either commercially available or can be obtainad in accordance with synthetic procedures known in the art.
Commercially a~ailable 5-methyl-2-thiophenecarboxylic 21~9831 iW093/1 ~ 7 PCT/US93/01119 acid (Aldrich), 2-methylnicotinic acid (Aldrich), 6-methylnicotinic acid (Aldrich), 5-methyl-furan-2-carboxylic acid and 5-methyl-furan-3-carboxylic acid can serve as examples of suitable starting materials for Re~ction 8cheme 3. The just mentioned starting~
materials are esterified by any suitable known procedure (such as reaction with ethyl alcohol in the presence of dicyclohexylcarbodiimide (DCC)) and the resulting ester or other intermediate corresponding to Formula ll is reacted with N-bromosuccinimide and benzoyl peroxide to provide the bromo compound of Formul~ ~2. The compound of Formula l~ is thereafter reacted with a trialkylphosphite (preferably triethylphosphite) to provide the phosphonate of For~ula 3.
An alternate synthetic route for making compounds of For~ula 1 i5 the reaction between the phosphonium ~alt of Formul~ 13 and the heteroaromatic aldehyde or ketone of Formula l~, as is indicated in ~eactio~
8¢he~e ~. Still another synthetic route leading to the compounds of Formul~ 1 is the reaction between the aldehyde or ketone of For~ula ~5 and the phosphonium ~alt of Formula 16, as indicated in Re~otion 8che~e 5.
In these formulas and reaction schemes the symbols Rl -R5, R5~, Z - Y, S, A and B~ are defined as above.
Several other synthetic routes and methods for the preparatisn of the compounds of the present invention may be~ome readily apparent to those skilled in the art in light of the present disclosure.

, ~, , ,i .

2129 8~1 -wos3~1~K7 PCT/US93/01119 ~4 s.

~ ~ PPh3Br + R'sC()~X~A~B' Formula l(B'=B) Z-Y

Formula 13Formula 14 Reaction Scheme 4 + BrPh3PCHR'5-X-A-B' ~ Formula 1 (B'aB) ~ ~R R4 Formula 15Formula 16 - Reaction Scheme S

- ~=8pecific ~xa~pl~

4-(3-Methyl-2-_hiQbuten-l-yl~bromobenzene (Co~pound 10) A mixture of 12.8 g (67.7 mmol) of 4-bromothiophenol and 2.7 g (67.7 mmol) sodium hydroxide in 50 mL acetone was heated to reflux under argon for 2.5 hours. The refluxing mixture was then treated dropwise with a solution of 10.0 g (67.1 mmol) of 4-~W093/1~K7 PCT/US93/01119 bromo-2-methyl-2-~utene in 10 mL acetone and the mixture heated to reflux for an additional 24 hours.
The mixture was then cooled to room temperature and the solvent remo~ed in-vacuo. The residue was.treated with 50 mL of watsr and extracted with 3 X 75 mL ether.
The ether extracts were combined and washed successively with 3 X 30 mL of 5% NaOH, 50 mL of water and 50 mL saturated aqueous NaCl and then dried (MgS04). The solvent was removed in-vacuo and the residual oil purified by Kugelrohr distillation ~70C, O.1 mm Hg) to give the title compound as a clear, colorless oil.
PMR (CDC13): ~ 1.58 (3H, s), 1.70 (3H, s), 3.50 (2H, d, J = 8.3 Hz), 7.36 (2H, d, J = 8~3 Hz).
2-Bromo-5-(3-methyl-2-thio~uten-1-Yl)toluene (Compou~
~1) A mix*ure of 5.0 g (24.6 mmol) of 4-bromo-2-methylthiophenol (Fairfield Chemical Co.) and 1.08 g (27.1 mmol) sodium hydroxide in 25 mL acetone was heated to reflux under argon for 2.5 hours. The refluxing mixture was then treated dropwise with a solution of 3.12 mL (27.1 mmol) of 4-bromo ~-methyl-2-butene in 5 mL aceton~ and the mixture heat~.d to reflux for an additional 24 hours. The mixture was then cooled to room temperature and the solvent removed in-vacuo. The residue was treated with 25 mL of water and extracted with 3 X 40 mL ether.
The ether extracts were ~ombined and washed successively with 3 X 15 mL of 5~ NaOH, 25 mL of water and 25 mL saturated aqueous NaCl and then dried (MgS04).. The solvent was removed in-vacuo and the residual oil purified by Kugelrohr distillation ~125 C, 1.5 mm Hg) to give the title compound as a clear, W093/16067 2i2~ 83 I PCT/US93/01119 colorless oil.
PMR (CDC13): ~ 1.60 (3H, s), 1.71 (3H, s), 2.35 (3H, s), 3.51 (2H, d, J = 7.8 Hz), 5.27 (lH, t, J - 7.8 Hz), 7.02 (lH, dd, J = 2.4, 8.3 Hz), 7.18 (lH, d, J =
2.4 Hz), 7.40 ~lH, d, J = 8.3 Hz)~
3-r3-Methyl-2-thiobuten l-vlLbromoben~ene (Compou~ 12) A mixture of 5.0 g (24.6 mmol) of 3 bromothiophenol and 1.08 g (27.1 mmol) sodium hydroxide in 25 mL acetone was heated to reflux under argon for 2.5 hours. The refluxing mixture was then treated dropwise with a solution of 3.12 mL (27.1 mmol) of 4-bromo-2-methyl-2-butene in 5 mL acetone and the mixture heated to reflux for an additional 24 hours. The mixture was then cooled to room temperature and the solvent removed in-vacuo. The residue was treated with 2S mL of water and extracted with 3 X 40 mL ether.
The ether extracts were combined and washed successively with 3 X 15 mL of 5% NaOH, 25 mL of water and 25 mL saturated aqueous NaCl and then dried (MgSO4). The solvent was removed in-vacuo and the residual oil purified by Kugelrohr distillation (125C, j 1.5 mm Hg) to give the title compound as a clear, - colorless oil.
PNR (CDC13): ~ 1.62 (3H, s), 1.73 (3H, s), 3.54 (2H, d, J = 7.8 Hz), 5.28 (lH, t, J = 7.8 Hz), 7.12 (lH, dd, J = 7.1, 7.1 Hz), 7.23 (lH, ddd, J = 0.7, 1.7, 7.1 Hz), 7.29 (lH, dd, J = 0.7, 1.7, 7.1 Hz), 7.44 (lH, dd, J = 0.7, 1.7 Hz).
4-(3-Methvl-2-thiobuten-1-vl)benzaldehvde (Compound 13) To a solution of 1.9517 g (7.5886 mmol) of 4-(3-methyl-2-thiobuten-1-yl)bromobenzene (Compou~ 10) in 25 ml dry ether at -78C. under argon, was added dropwise 9.0 ml of 1.7 M (15.3 mmol) tert-butyllithium .
i, , , ., `- W093/16067 2 1 2 9 8 3 1 PCT/US93/Olllg in pentane. The reaction mixture was stirred at -78C.
for 3 hours and then treated dropwise with a solution of 885.7 mg ~12.12 mmol) of dimethylformamide in 6 ml dry ether. The cooling bath was then remoYed and the mixture stirred at room temperature for 26 hours, then cooled to 0C and treated with 75 ml of saturated NH4Cl. This mixtura was then extracted with 3 X 75 ml ether. The ether extracts were combined and washed successively with saturated NaHC03 and saturated NaCl solutions and then dried (MgS04). The solvent was then removed in-vacuo and residue purified ~y flash chromatography (silica; 10% ethyl acetate in hexanes) followed by Kugelrohr distillation (90 C.~ 0.25 mm) to give the title compound as a colorless oil.
PMR (CDC13: ~ 1.74 (3H, s), 1.76 (3H, s), 3.66 (2H, d, J - 6.9 Hz), 5.33 (lH, t, J - 6.9 Hz), 7.35 (2H, d, J - 8.8 Hz), 7.76 (2H, d J - 8.8 Hz), 9.92 (lH, s).
~-Methvl-4-(3-methyl-2-thiobuten-1-vl)benzaldehyde (Compoun~
To a -78C solution of 0.5 ~ (1.84 mmol) of 2-bromo-5-(3-methyl-2-thiobuten-1-yl)toluene (Co~pou~d 11) and-8 mL THF under argon was added dropwise 0.81 mL
of a 2.5 M solution of n-~utyllithium and hexane (2.02 m~ol~. After 15 minutes, 2.2 mL (15.4 mmol) of ~,N-dimethylformamide was added dropwise and the solution was allowed to warm to 0C in an ice-water bath and stirred for an additional hour. The solution was treated with 5 mL of water and extracted with 3 X 25 mL
ether.
The ether extracts were combined and washed with 25 mL saturated aqueous NaCl and then dried (Mg504~.
The solvent was remo~ed in-vacuo and the residual oil ~129831 WO93/16~ ~ PCT/US93/01119 purified by flash chromatography (SiO2, 95:5, hexane:ethyl acetate) to give the title compound as a clear, colorless oil.
PMR (CDC13): ~ 1.73 (3H, s), 1.75 (3H, s) 2-63 (3H, s), 3.63 (2H, d, J = 7.8 Hz), 5.31 (lH, t, J = ~7.8 Hz), 7.09 (lH, d, J = 1.7 Hz), 7.19 (lH, dd, J = 1.7, 8.2 Hz), 7.68 (lH, dd, J = 8.2 Hz), 10.16 (lH, s).
3-(3-methyl-2-thiobuten-1-yl)benzaldehvde (Compoun~ 15) To a -78C solution of 1.5 g (5.83 ~mol) of 3-(3-methyl-2-thio~uten-1-yl)~romobenzene (Co~pou~ 12~ and 25 mL THF under argon was added dropwise 2.56 mL of a 2.5 M solution of n-butyllithium and hexane (5.83 mmol). After 15 minutes, 7.0 mL (87.8 mmol) of N,N-dimethylformamide was added dropwise and the solution was allowed to warm to 0C in an ice-water bath and stirred for an additional hour. The ~olution was treated with 15 mL of water and extracted with 3 X 75 Ml ether.
The ether extracts were combined and washed with 75 mL saturated aqueous NaCl and then dried (MgS04).
The solvent was removed in-vacuo and the residual oil purified by flash chromatography (Sio2, 95:5, hexane:ethyl acetate) to give the title compound as a clear, colorless oil.
PNR (CDC13): ~ 1.63 (3H, s), 1.73 (3H, s), 3~60 (2H, d, J = 7.7 Hz), 5.30 ~lH, t, J = 7.7 Hz), 7.43 (lH, dd, J = 7.6, 7.6 Hz), 7.56 (lH, dd, J = 2.0, 3.3 Hz), 7.65 (lH, dd, J = 1.5, 7.6 Hz), 7.80 (lH, d, J =
1.5 Hz), 9.97 ~lH, s).
~PYxidylthioacetate tCo~pou~d 16) A solution of 12.5 mL (90 mmol) of triethylamine, 27 mg dimethylaminopyridine and 13 mL dichloromethane was added dropwise to a solution of 5 g (44.5 mmol) of 2129~31 WO93/16~7 ` PCT/US93/01119 2-pyridinethiol and dichloromethane (130 mL) at 0C
under argon. After 5 minutes, 4.16 mL (58.5 mmol) of acetyl chloride was added dropwise and the solution was stirred at oQc for 30 minutes and then at room temperature for 3 hours. The solution was treated with 10 mL of 10~ aqueous HCl and the layers were separated.
The organic layer was washed with 100 mL water, 100 mL saturated aqueous NaHC03, 100 mL saturated aqueous NaCl and then dried (MgS04). The solvent was removed in-vacuo and the residual oil purified by bulb-to bulb distillation (bp = 90C, 2 mm Hg)) to give the title compound as a clear, yellow oil.
PMR (CDC13): ~ 2.50 (3H, s), 7.30 (lH, dd, J =
4.9, 7.4 Hz), 7.62 (lH, d, J = 8.3 Hz), 7.75 (lH, dd, J
= S.9, 7.8 Hz), 8.62 (lH, dd, J = 2, 4.9 Hz).
4-(3-methvl-2-thiobuten-1-vl)aceto~henone (Compoun~ 17) A solution of 1.29 g (S.0 mmol) of 4-(3-methyl-2-thiobuten-l-yl)bromobenzene (Compound 10) and 2.5 mL
THF was added to 0.134 g of magnesium turnings under argon. The solution was heated to initiate the reaction and then 2.5 mL of THF was added and the suspension stirred at reflux for an hour. The resulting æolution was cooled to room temperature ~nd -tran~ferred via cannula to an ice-cold solution of 0.77 g (S.O mmol) of 2-pyridylthioacetate (Compound 16) and 5 mL THF. After 30 minutes, the solution was treated with 1.0 mL of water and concentrated under reduced pressure. The residue was extracted with 3 X 10 mL
ether.
The ether extracts were combined and washed with 10 mL saturated aqueous NaCl and then dried (NgS04).
The solvent was removed in-vacuo and the residual oil purified by flash chromatography (SiO2, 95:5, 2129~31 WO93l1~K7 . ~. PCT/US93/01119~' J

hexane:ethyl acetate~ to give the title compound as a white solid.
PMR (CDC13): ~ 1.71 (3H, s), 1.74 t3H, s~, 2.57 ~ (3H, s), 3.63 (2H, d, J - 7.4 Hz), 5.31 (lH,-t, J = 7.4 Hz), 7.31 (2H, d, J = 8.5 Hz), 7.86 (2H, d, J = 8.5 Hz).
2-MethYl-4-(3-methvl-2-thiobuten-1-Yl)acetophenone (Co~pouna 18) A solution of 1.36 g (5.O ~mol) of 2-bromo-5-(3-methyl-2-thiobuten-1-yl)to].uene (Compound ~1) and 2.5 mL THF was added to 0.134 g of magnesium turnings under argon. The solution was heated to initiate the reaction and then 2.5 mL of THF was added and the suspension stirred at reflllx f or an hour. The resulting solution was coo]Led to room temperature and transferred via cannula to an ice-cold soluti~n of 0~77 g (5.0 mmol~ of 2-pyridyl~lioacetat~ (Co~pou~ 16~ and 5 mL T~F. After 30 minute~;, the solution was treated with 1.0 mL of water and concentrated under reduced pressure. The residue was extracted with 3 X 10 mL
ether.
The ether ~xtracts were aombined and washed with 10 mL ~aturated agueous NaCl and then dried (MgS04).
The solvent was removed in--vacuo and th~ residual oil purified by flas~ chromatos~raphy SiO2, 95:5, hexane:ethyl acetate) to giLve the title compound as a cl~ar, pale yellow oil.
PMR (CDC13): ~ 1.70 (3H, s), 1.74 (3H, ~), 2.53 (3~, ~), 2.56 (3H, s), 3.6:L ~2H, d, J = 7.8 Hz), 5.31 (lH, t, J = 7.8 Hz), 7.11 I(lH, s3, 7.13 (lH, d~ J = 8.0 Hz), 7.65 (lH, d, J - 8.0 Hz).
3-l3-methYl-2-thiobuten-1-yl~acetophenone (Compou~ 19 To a -78C solution oi. 1.5 g ~5.83 mmol) of 3-(3-~ W093/16067 2 1 2 9 8 3 1 PCT/USg3/01119 methyl-2-thiobuten-1-yl)bromobenzene (Compound 12) and 25 mL THF under argon was added dropwise 2.s6 mL of a 2.~ M solution 5.83 mmol) of n-butyllithium and hexane.
After 15 minutes, 0.57 g (5.52 mmol) of N,0-dimethylhydroxylacetamide was added dropwise and the solution was allowed to warm to 0C in an ice-water bath and stirred for an additional hour. The solution was treated with 15 mL of dilute HCl and extracted with 3 X 75 mL ether.
- The ether extracts were combined and washed with 75 mL saturated aqueous NaCl and then dried (MgS04).
The solvent was removed in-vacuo and the residual oil purified by flash chromatography (SiO2, 95:5, hexane:ethyl acetate) to give the title compound as a clear, pale yellow oil.
PMR (CDC13): ~ 1.61 (3H, 8), 1.72 (3H, s), 2.S9 ¦ (3H, s), 3.58 (2H, d, J = 7.7 Hz), 5.30 (lH, t, J = 7.7 Hz), 7~36 (lH, dd, J = 7.7, 7.7 Hz), 7.50 (lH, d, J =
7.7 Hz), 7.74 (lH, d, J = 7.7 Hz), 7.89 (lH, s).
Ethyl S-methvl-2-thiophenecarboxvlate (Compoun~ 20) To a stirred solution of 15.9 g (77.4 mmol) of 1,3-dicyclohexylcarbodiimide in 40 mL dichloromethane was added 10 g (70.3 mmol) of 5-methyl-2-thiophenecaboxvlic acid and 4.85 g (105.5 mmol) of anhydrous ethanol. 0.86 g of dimethylaminopyridine was then added and the suspension stirred at room temperature for 20 hours. The resulting white precipitate was removed by filtration. The filtrate was washed with water, dried (MgS04), filtered and concentrated under reduced pressure. The residue was purified by bulb-to-bulb distillation (bp = 95C, 3 mm Hg) to give the title compound as a clear, pale yellow oil.

~ . ..

WO 93/16067 PCl'/US93/01119 PMR (CDC133: ~i 1.36 (3H, t, J = 7.1 Hz), 2.52 (3H, s~, 4.32 (2H, q, J = 7.1 HZ), 6.76 (lH, d, J = 3.8 Hz), 7 . 61 (lH, d, J = 3 . 8 Hz) .
Ethyl S-bromomethyl-2-thiophenecarboxylate.(~o~pou~
21) N-Bromosuccinimide (23.5 g~ 132 mmol), benzoyl peroxide (0.26 g~ and 90 mL of benzene were brought to reflux under argon. Ethyl 5-methyl-2-thiophenecarboxylate (Compoun~ 20, 22.5 g, 132 mmol) was added dropwise through an addition funnel and the resulting mixture was refluxed for 6 hours and then cooled to room temperature and stirred for 16 hours.
The mixture was treated with 50 mL of water and extracted with 3 X 75 mL ether.
The ether extracts were combined and washed with 75 mL saturated aqueous NaCl and then dried (MgS04).
The solvent was removed in-vacuo and the residual oil purified by flash chromatography tS~02, 99:1, hexane:ethyl acetate) to give the title compound as a clear, yellow oil.
PMR (CDC13): ~ 1.37 (3H, t, J = 7.3 Hz), 4.35 (2H, g, J = 7.3 Hz~, 4.68 ~3H, s~, 7.09 (lH, d, J = 4.0 Hz), 7.64 (lH, d, J = 4.0 Hz).
Diethyl (~-carboethoxy-5-thioPhenyl?methyl~hospbonate (Compou~d 22) A mixture of 4.99 g (20.0 mmol) of ethyl 5-bromomethyl-2-thiophenecarboxylate (Co~pound 21) and 5.17 mL (30.O mmol) of triethylphophite was heated to 120C under argon for 6 hours and the excess triethylphosphite removed by distillation.
The product was purified by vacuum distillation (bp = 175, 3 mm Hg) to give the title compound as a clear, pale yellow oil.

~ ! W093/16~7 212 9 8 31 PCT/US93/01119 PMR (CDC13): ~ 1.30 (6H, t, J = 7~1 Hz), 1.37 (3H, t, J = 7.2 Hz), 3.38 (2H, d, J = 20.9 H2), 4O05 - 4.15 (4H,m), 4.33 (2H, q, J = 7.1 Hz), 6.99 (lH, dd, J =
3.6, 3.6 Hz), 7.66 (lH, d, J = 1.1, 3.6 Hz).
5-(E-2-(3-(3-methvl-2-thiobuten-l-vl2~henyl~ethenyl~-2-thioPhenecarboxYl~te (Compoun~ 1) 400 mg of 60~ NaH in mineral oil was washed successively with three ~-mL portions of hexane. The residual hexane was removed under vacuum and the vacuum was broken with dry argon. 10 ml of dimethyl sulfoxide (DMS0) was added and the resulting suspension ~as heated to 60C for 1 hour to produce a 1 M solut~on of dimsyl sodium. 2.0 mL of 1 M dimsyl sodium was added to 0.674 g (~.2 mmol) of diethyl 2-carboethoxy-5-~hiophenylmethylphosphonate (Compoun~ 22) and the resulting rust-colored solution was stirred for 30 ~inutes at room temperature under argon. This solution was added to 0.220 g (1.0 mmol) of 3-(3-methyl-2-~hiobuten-l-yl)benzaldehyde (Co~pou~ 15) and 3.5 mL
DNSO and this solution wa~ stirred for an additional 2.5 hours. The mixture was treated with 10 mL of water and extracted w$th 3 X 25 mL ether.
The ether extracts were combined and wash~d with 25 mL ~aturated aqueous NaCl and then dried (~gSo4).
The 501~ent was removed in vacuo and the residual oil purified by fla~h chromatography (SiO~, 95:5, hexane:ethyl acetate) to give the title compound ac a light yellow solid. A small portion was recrystallized from ethanol).
PMR (CDC13): ~ 1.38 (3H, t, J = 7.2 Hz), 1.61 (3H, s), 1.73 (3H, s), 3.57 (~H, d, J = 7.7 Hz), 4.35 (2H, q, J = 702 HZ), 5.31 (lH, t, J = 7.7 Hz), 6.98 (lH, d, J = 16.1 Hz), 7.04 (lH, d, J = 3.9 Hz), 7.15 (lH, d, J

2129~31 `; `~
W093/1~K7 PCT/US93/01119 = 16.1 Hz), 7.26 (3H, m), 7.42 (lH, s), 7.68 (lH, d, J
= 3.9 Hz)-Ethyl 5-(E-2-(4-(3-methyl-2-thiobuten-1-yl)phenyl) ~ro~en-l-yl)-2-thio~hencarboxYlate (Compound 3) 400 mg of 60% NaH in mineral oil was washed successively with three 5-mL portions of hexane. The residual hexane was removed under vacuum and the vacuum was broken with dry argon. 10 ml of dimethyl sulfoxide ~DMSO~ was added and the resulting suspension was heated to 60C for 1 hour to produce a 1 M solution of dimsyl sodium. 1.36 mL of dimsyl sodium was added to O.46 g (1.5 mmol) of diethyl 2-carboethoxy-5-thiophenylmethylphosphonate (Compoun~ 22) and the resulting rust-colored solution was stirred for 30 minutes at room temperatur~ under argon. This solution was added to O.15 g (O.68 mmol) of 4-(3-methyl-2-thiobutenyl)acetophenone (Compoun~ 17) and 2.4 mL ~MSO
and this solution was stirred for an additional 2.0 --hours. The solution was treated with O.41 mL of a 2.0 M solution of NaO~t and EtOH and the solution stirred an additional 2 hours at room temperature. The mixture was poured into 40 mL of 5% aq. NaHC03 and extracted with S X 25 mL ether.
The ether extracts were combined and washed with 25 mL saturated aqueous NaCl and then dried (N~SQ4).
The solvent was removed in-Yacuo and the residual oil purified by flash chromatography (SiO2, 98:2, hexane:ethyl acetate) to give the title compound as a light yellow solid.
PMR (CDC13): ~ 1.36 (3H, t, J = 7.1 Hz), 1.63 (3H, ~), 1.73 (3H, s), 2.41 (3H, s), 3.57 (2H, d, J = 7.3 Hz), 4~36 (2H, q, J = 7.1 Hz), 5.31 (lH, t, J = 7.3 --Hz), 6.92 (lH, s), 7.04 ~lH, d, J = 4.0), 7.32 (2H, d, -W093/~6067 2 1 2 ~ 8 3 1 : pCT~US93/01119 J = 8.6 Hz), 7.40 (2H, d, J = 8.6 Hz), 7.73 (lH, d, J =
4.0 Hz)-Ethyl 5-fE-2-l3-(3-methYl-2-thiobuten-1-vl)~henvl~Dro~en-l-yl~-2-thioPhencarboxylat~-(Compou~
5) 400 mg of 60% NaH in mineral oil was washed successively with three 5-mL portions of hexane. The residual hexane was removed under vacuum and the vacuum was broken with dry argon. 10 ml of dimethyl sulfoxide (DMSO) was added and the resulting suspension was heated to 60~C for 1 hour to produce a 1 M solution of dimsyl sodium. 2.0 mL of dimsyl sodium was added to 0.674 g (2.2 mmol) of diethyl 2-carboethoxy-5-thiophenmethylphosphonate (Compou~d 22) and the re~ulting rust-colored solution was ~tirred for 30 minutes at a room empera~ure under argon. This solution was added to 0.220 g (1.0 mmol) of 3-(3-methyl-2-thiobu~en-1-yl)acetophenone (Co~pou~ 19) and 3.5 mL DMSO and this solution was stirred for an additional 2.0 hours. The solution was treated with 0~60 mL of a 2.0 M ~olution of NaOEt and EtOH and the solution stirred an additional 12 hours at room temperature. The mixture was poured into 10 mL of 1%
aq. ~Cl and extracted with 5 X 25 mL e~hyl acetate.
The ethyl acetate extracts were combined and washed with 25 mL saturated aqueous NaCl and then dried (MgS04). The solvent was removed in-vacuo and the residual oil purified by flash chromatography (SiO2, 95:5, hexane:ethyl acetate) to give the E- and Z-isomers as an inseparable mixture in a ratio of 85:15, respectively. The isomers were separated by HPLC (3%
ethyl acetate in hexane) to give the title compound.
PMR (CDC13): ~ 1.39 (3H, t, J = 7.1 Hz), 1.60 (3H, 2129~1 s), 1.72 (3H, s), 2.41 (3H, s), 3.57 (2H, d, J = 7.7 Hz), 4.35 (2H, q, J = 7.1 Hz), 5.31 (lH, t, J = 7.7 Hz), 6.89 (lH, s), 7.04 (lH, d, J = 4.0 Hz), 7.25 -7.43 (3H, m), 7.43 (lH, s), 7.73 (lH, d, J = 4.0 Hz).
5-tE-2-~ 3-(3 -methyl-2-thiobuten-1-vl)~henvl?ethenyl~-2-thiophenecarboxvlic acid (Compoun~ 2) To a solution of 141 mg of ethyl 5-(E-2-(3-~3-methyl-2-thiobuten-1-yl)phenyl)ethenyl)-2-thiophenecarboxylate (Compound 1) in 4 mL of ethanol under argon was added dropwise 1 mL of a 2N solution of aqueous potassium hydroxide. The solution was stirred at room temperature for 18 hours, cooled in an ice-water bath and acidified with 3 N aqueous hydrochloric acid. The resulting precipitate was extracted into ether, the layers separated and the ether layer washed with saturated aqueous sodium chloride, dried (~gSo4), and concentrated under reduced pressure. The resulting solid was recrystallized from ethanol to give the title compound.
PMR (CDC13): ~ 1.61 (3H, s), 1.73 (3H, s), 3.57 (2H, d, J z 7.7 Hz), 5.31 (lH, t, J - 7.~ Hz), 7.02 (lH, d, 7 = 15.9 Hz), 7.08 (lH, d, J = 3.7 Hz), 7.17 (lH, d, J = 15.9 ~z), 7.78 (lH, d, J z 3.7 Hz).~
S-(E-2-(4-(3-meth~1-2-thiQbuten-l-vl)Phenyl~propen-l-yl~-2-thiophencarboxylic acid (Compoun~ 4) To a solution of 40 mg of ethyl 5-(E-2-(4-(3-methyl-2-thiobuten-1-yl)phenyl)propen-1-yl)-2-thiophencarboxylate (Compoun~ 3) in 3 mL of ethanol under argon was added dropwise 1 mL of a 2N solution of aqueous potassium hydroxide. The solution was stirred at room temperature for 18 hours, cooled in an ice-I water bath and acidified with 3 N aqueous hydrochloric I acid. The resulting precipitate was extracted into ) W093/1~67 2 1 2 9 8 3 1 PCT/US93/01119 ether, the layers separated and the ether layer washedwith saturated aqeous sodium chloride~ dried tMgS04), and concentrated under reduced pressure. The resulting solid was recrystallized from ethanol to gi~e the title compound.
PMR (D6-acetone): ~ 1.64 (3H, s), 1.70 (3H, s), 2.41 (3H, s~, 3.63 (2H, d, J = 7.4 Hz), 5.30 (lH, t, J
= 7.4 Hz), 7.13 (lH, s), 7.25 (lH, d, J = 3.9 Hz), 7~35 (2H, d, J = 8.5 Hz), 7.53 (2H, d, J = 8.5 Hz), 7.75 (lH, d, J = 3.9 Hz).
The following further examplary compounds of the invention ~an be prepared in an analogous manner by the Wittig reaction (coupling) of the following intermediates:
E and Z ethyl 2-(4-(3-methyl-2-thiobuten-1-yl)phenyl)ethenyl)-3-pyridinecarboxylate from 4-(3-methyl-2-thiobuten-1-yl)benzaldehyde and diethyl (3-carboethoxy-2-pyridyl)methylphosphonate;
~ and Z ethyl 2-(3-(3-methyl-2-thiobuten-1-yl)phenyl)ethenyl)-3-pyridinecarboxylate from 3-(3-~ethyl-2-thiobuten-1-yl)benzaldehyde and diethyl (3-c~rboethoxy-2-pyridyl)methylphosphonate;
~ and Z ethyl 2-(4-(3-methyl 2-thiobuten-1-yl)-2-methylphenyl)ethenyl)-3-pyridinecarboxylate from 4-(3-methyl-2-thiobuten-1 yl)-2-methylbenzaldehyde and diethyl (3-carboethoxy-2-pyridyl)methylphosphonate;
_ E.and Z ethyl 2-(3-(3-methyl-2-thiobuten-1-yl)-2-methylphenyl)ethenyl)-3-pyridinecar~oxylate from 3-(3 méthyl-2-thiobuten-1-yl)-2-methylbenzaldehyde and diethyl (3~carboethoxy-2-pyridyl)methylphosphonate;
E and Z ethyl 2-(4-(3-methyl-2-thiobuten-1-yl)-phenyl)propen-l-yl)-3-pyridinecarboxylate from 4-(3-methyl-2-thiobuten-1-yl)acetophenone and diethyl (3-WO 93,-6~i1 2 9 8 3 1 PCr/US93/01119`. i ~, ` ..`

carboethoxy-2-pyridyl)methylphosphonate;
~ and Z ethyl 2-(3-(3-methyl-2-thiobuten-1-yl)phenyl)propen-l-yl)-3-pyridinecarboxylate from 3-(3-methyl-2-thiobuten-1-yl)acetophenone and diethyl (3-carboethoxy-2-pyridyl)methylphosphonate;
~ and Z ethyl 2-(4-(3-methyl-2-thiobuten-1-yl)-2-methylphenyl)propen-l-yl)-3-pyridinecarboxylate from 4-(3-methyl-2-thiobuten-1-yl)-2-methylacetophenone and diethyl (3-carboethoxy-2-pyridyl)methylphosphonate;
E and Z ethyl 2-(3-(3-methyl-2-thiobuten-1-yl)-2-methylphenyl)propen-l-yl)-3-pyridinecarboxylate from 3-(3-methyl-2-thiobuten-1-yl)-2-methylacetophenone-and diethyl (3-carboethoxy-2-pyridyl)methylphosphonate;
B and Z ethyl 2-(4-(3-methyl-2-thiobutenyl)phenyl)ethenyl)-5-pyridinecarboxylate from 4-(3-methyl 2-thiobuten-1-yl)benzaldehyde and diethyl (5-carboethoxy-2-pyridyl)methylphosphonate;
~ and Z ethyl 2-(3-(3-methyl-2-thiobutenyl)phenyl)ethenyl)-5-pyridinecarboxylate from 3-(3-methyl-2-thiobuten-1-yl)benzaldehyde and diethyl (5-carboethoxy-2-pyridyl)methylphosphonate;
~ and Z ethyl 2-(4-(3-methyl-2-thiobuten-1-yl)-2-methylphenyl)ethenyl)-5-pyridinecarboxylate from 4-(3-- -methyl-2-thiobuten-1-yl)-2-methylbenzaldehyde and diethyl (5-carboethoxy-2-pyridyl)methylphosphonate;
B and Z ethyl 2-(3-(3-methyl-2-thiobuten-1-yl)-2-methylphenyl)ethenyl)-5-pyridinecarboxylate from 3-(3-methyl-2-thiobuten-1-yl)-2-methylbenzaldehyde and diethyl (5-carboethoxy-2-pyridyl)methylphosphonate;
~ and Z ethyl 2-(4-(3-methyl-2-thiobuten-1-yl)-phenyl)propen-l-yl)-5-pyridinecarboxylate from 4-(3-~ethyl-2-thiobuten-1-yl)acetophenone and diethyl (5-carboethoxy-2-pyridyl)methylphosphonate;

:~ W093/1 ~ 7 2 1 2 9 8 3 1 PCT/US~3/01119 B and g ethyl 2-t3-(3-methyl-2-thiobuten-1-yl)-phenyl)propen-l-yl)-5-pyridinecarboxylate from 3-(3-methyl-2-thiobuten-1-yl)acetophenone and diethyl (5-carboethoxy-2-pyridyl)methylphosphonate; .-E and Z ethyl 2-(4-(3-methyl-2-thiobuten-1-yl)-2-methylphenyl)propen-l-yl)-5-pyridinecarboxylate from 4-(3-methyl-2-thiobuten-1-yl)-2-methylacetophenone and diethyl (5-carboethoxy-2-pyridyl)methylphosphonate;
B and Z ethyl 2-(3-(3-methyl-2-thiobuten-1-yl)-2-methylphenyl)propen-l-yl)-5-pyridinecarboxylate from 3-(3-methyl-2-thiobuten-1-yl)-2-methylacetophenone and diethyl (5-carboethoxy-2-pyridyl)methylphosphonate:
~ and Z ethyl 2-(4-(3-methyl-2-thiobuten-1-yl)phenyl)ethenyl)-5-furancarboxylate from 4-(3-methyl-2-thiobuten-1-yl)benzaldehyde and diethyl (5-carboethoxy-2-furyl)methylphosphonate;
B and Z ethyl 2-(3-(3-methyl-2-thicbuten~
yl) p enyl)ethenyl~-5-furancarboxylate from 3-(3-methyl-2-thiobuten-1-yl)benzaldehyde and diethyl (5-carboethoxy-2-furyl)methylphosphonate;
B and Z ethyl 2-(4-(3-methyl-2-thiobuten-1-yl)-2-methylphenyl)ethenyl)-$-furancarboxylate from 4-(3-methyl-2-thiobuten-2-yl)-2-methylbenzaldehyde and diethyl (5-carboethoxy-2-furyl)methylphosphonate;
~ and ~ ethyl 2-(3-(3-methyl-2-thiobuten-1-yl)-2-methylphenyl)ethenyl)-5-furancarboxylate from 3-(3-methyl-2-thiobuten-1-yl)-2-methylbenzaldehyde and diethyl~(5-carboethoxy-2-furyl)methylphosphonate;
B and ~ ethyl 2-(A-(3-methyl-2-thiobuten-1-yl)-phenyl)propen-l-yl)-5-furancarboxylate from 4-(3-methyl-2-thiobuten-1-yl)acetophenone and diethyl (5-carboethoxy-2-furyl)methylphosphonate;
B and ethyl 2-(3-(3-methyl-2-thiobuten-1-yl)-. .

212g~31 W093/16~7 PCT/US93/01119 phenyl)propen-l-yl)-S-furancarboxylate from 3-(3-methyl-2-thiobuten-1-yl)acetophenone and diethyl (S-carboethoxy-2-furyl)methylphosphonate;
~ E and Z ethyl 2-(4-(3-methyl-2-thiobuten-1-yl)-2-methylphenyl)propen-l-yl)-5-furancarboxylate from 4-(3-methyl-2-thiobuten-1-yl)-2-methylacetophenone and diethyl (5-carboethoxy-2-furyl)methylphosphonate;
E and Z ethyl 2-t3-(3-methyl-2-thiobuten-1-yl)-2-methylphenyl)propen-l-yl)-S-furancarboxylate from 3-(3-methyl-2-thiobuten-1-yl)-2-methylacetophenone and diethyl (S-carboethoxy-2-furyl)methylphosphonate;
B and Z ethyl 2-(4-(3-methyl-2-thiobuten-1-yl)phenyl)ethenyl)-4-furancarboxylate from 4-(3-methyl-2-thiobuten-1-yl)benzaldehyde and diethyl (4-carboethoxy-2-furyl)methylphosphonate;
E and Z ethyl 2-(3-(3-methyl-2-thiobutenyl)phenyl)ethenyl)-4-furancarboxylate from 3-(3-methyl-2-thiobuten-1-yl)benzaldehyde and diethyl (4-carboethoxy-2-furyl)methylphosphonate;
~ and Z ethyl 2-(4-(3-methyl-2-thiobuten-1-yl)-2-methylphenyl~ethenyl)-4-furancarboxylate from 4-(3-methyl-2-thiobuten-1-yl)-2-methylbenzaldehyde and diethyl (4-carboethoxy-2-furyl)methylphosphonate;
E and g ethyl 2-(3-(3-methyl-2-thiobuten-1-yl)-2-methylphenyl)ethenyl~-4-furancarboxylate from 3-(3-methyl-2-thiobuten-1-yl)-2-methylbenzaldehyde and diethyl (4-carboethoxy-2-furyl)methylphosphonate;
E and Z ethyl 2-(4-(3-methyl-2-thiobuten-1-yl~-phenyl)propen-l-yl)-4-furancarboxylate from 4-(3-methyl-2-thiobuten-1-yl)acetophenone and diethyl (4-carboethoxy-2-furyl)methylphcsphonate;
E and Z ethyl 2-(3-(3-methyl-2-thiobuten-1-yl)-phenyl)propen-l-yl)-4-furancarboxylate from W093/1~K7 . '`~ 2129831 PCT/US93/01119 3-(3-methyl-2-thiobuten-1-yl)acetophenone and diethyl (4-carboethoxy-2-furyl)methylphosphonate:
~ and Z ethyl 2-(4-(3-methyl-~-thiobutenyl)-2-methylphenyl)propen-l-yl)-4-furancarboxylate from 4-(3-methyl-2-thiobuten-1-yl)-2-methylacetophenone and ~ -diethyl (4-carboethoxy-2-furyl)methylphosphonate;
~ and Z ethyl 2-(3-(3-methyl-2-thiobutenyl)-2-methylphenyl)propen-1-yl)-4-furancarboxylate from 3-(3-methyl-2-thiobuten-1-yl)-2-methylacetophenone and diethyl (4-carboethoxy-2-furyl)methylphosphonate.
Substituting respectively, diethyl (3-carboethoxy-6-pyridazyl)methylphosphonate, diethyl (5-carboethoxy-6-pyrimidyl)methylphosphonate, diethyl ~5-carboethoxy-2-pyrazyl)methylphosphonate, diethyl ~2-carboethoxy-4-thiazolyl)methylphosphonate and diethyl (2-carboethoxy-4-oxazolyl)methylphosphonate for diethyl (3-car~oethoxy-2-pyridyl)methylphosphonate in the above-listed reactions the corresponding pyridazinyl, pyrimidyl, parazinyl, thiazolyl and oxazolyl derivatives are obtained.

Claims (28)

CLAIM REPLACEMENT SHEET
WHAT IS CLAIMED IS:

1. (Amend) A compound of the formula wherein R1, R2, R3 and R4 independently are hydro-gen, lower alkyl of 1 to 6 carbons, halogen or lower alkoxy of 1 to 6 carbons:
R5 and R5' independently are hydrogen or lower alkyl of 1 to 6 carbons;
Y is oxygen or sulfur;
Z is n-alkyl having 2 to 10 carbons, cyclo or branch-chained alkyl of 3 to 10 carbons, and straight chain alkenyl having 2 to 10 carbons, or cyclo or branched chained alkenyl of 3 to 10 carbons;
X is a heteroaryl group selected from a group consisting of thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, and oxazolyl;
A is (CH2)n where n is 0-5, lower branched chain alkyl having 3 to 6 carbons, cycloalkyl having 3 to 6 carbons, alkenyl having 2 to 6 carbons and 1 or 2 double bonds, alkynyl having 2 to 6 carbons and 1 or 2 triple bonds;
B is COOH of a pharmaceutically acceptable salt thereof, COOR8, CONR9R10, -CH2OH, CH2OR11, CH2OCOR11, CH(OR12)2, CHOR13O, -COR7, CR7(OR12)2, or CR7OR13O, where R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R8 is an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R8 is phenyl or lower alkylphenyl, R9 and R10 inde-pendently are hydrogen, an alkyl group of 1 to lo carbons, or a cycloalkyl group of 5 to 10 carbons, or phenyl or lower alkylphenyl, R11 is alkyl of 1 to 10 carbons, phenyl or lower alkylphenyl, R12 is lower alkyl, and R13 is divalent alkyl radical of 2 - 5 carbons.

2. A compound of Claim 1 wherein R1 through R4 are hydrogen.

3. A compound of Claim 1 wherein one of R1 through R4 is lower alkyl and the others are hydrogen.

4. A compound of Claim 3 wherein the lower alkyl group is in the 2-position of the phenyl ring.

5.A compound of the formula wherein R1, R2, R3 and R4 independently are hydro-gen, lower alkyl of 1 to 6 carbons, halogen or lower alkoxy of 1 to 6 carbons;
R5 and R5' independently are hydrogen or lower alkyl of 1 to 6 carbons;
Y is oxygen or sulfur;
Z is a branched chain alkenyl group, X is a heteroaryl group selected from a group consisting of thienyl, pyridyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl and oxazolyl;
A is (CH2)n where n is 0-5, lower branched chain alkyl having 3 to 6 carbons, cycloalkyl having 3 to 6 carbons, alkenyl having 2 to 6 carbons and 1 or 2 double-bonds, alkynyl having 2 to 6 carbons and 1 or 2 triple bonds:
B is hydrogen, COOH or a pharmaceutically accept-able salt thereof, COOR8, CONR9R10, -CH2OH, CH2OR11, CH2OCOR11, CHO, CH(OR12)2, CHOR13O, -COR7, CR7(OR12)2, or CR7OR13O, where R7 is an alkyl, cycloal-kyl or alkenyl group containing 1 to 5 carbons, R8 is an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R8 is phenyl or lower alkylphenyl, R9 and R10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or phenyl or lower alkylphe-nyl, R11 is alkyl of 1 to 10 carbons, phenyl or lower alkylphenyl, R12 is lower alkyl, and R13 is divalent alkyl radical of 2 - 5 carbons.

6. (Amended) A compound of Claim 5 wherein the Z-Y- substituent is in the 4 position of the phenyl group.

7. (Amended) A compound of Claim 5 wherein the Z-Y- substituent is in the 3 position of the phenyl group.

8. (Amended) A compound of Claim 5 wherein B is COOH or a pharmaceutically acceptably salt thereof, or where b is COOR8, or CONR9R10.

9. A compound of Claim 8 where A is (CH2)n and is o to 3.

10. (Amended) A compound of the formula wherein R1, R2, R3 and R4 independently are hydro-gen, lower alkyl of l to 6 carbons, halogen or lower alkoxy of l to 6 carbons;
R5 and R5' independently are hydrogen or lower alkyl of 1 to 6 carbons;
Y is sulfur;
Z is n-alkyl having 1 to 10 carbons; cyclo or branch-chained alkyl of 3 to 10 carbons, and straight chain alkenyl having 2 to 10 carbons, or cyclo or branched chained alkenyl of 3 to 10 carbons;
X is a heteroaryl group selected from a group consisting of thienyl, pyridyl, and furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl and oxazolyl;
A is (CH2)n wherein is 0-5, lower branched chain alkyl having 3 to 6 carbons, cycloalkyl having 3 to 6 carbons, alkenyl having 2 to 6 carbons and 1 or 2 double bonds, alkynyl having 2 to 6 carbons and 1 or 2 triple bonds;
B is hydrogen, COOH or a pharmaceutically accept-able salt thereof, COOR8, CONR9R10, -CH2OH, CH2OR11, CH2OCOR11, CHO, CH(OR12)2, CHOR13O, -COR7, CR7(OR12)2, or CR7OR13O, where R7 is an alkyl, cycloal-kyl or alkenyl group containing 1 to 5 carbons, R8 is an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R8 is phenyl or lower alkylphenyl, R9 and R10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or phenyl or lower alkylphe-nyl, R11 is alkyl of 1 to 10 carbons, phenyl or lower alkylphenyl, R12 is lower alkyl, and R13 is divalent alkyl radical of 2 - 5 carbons.

11. CANCELLED

12. A compound of the formula wherein R4 is hydrogen or lower alkyl;
R5 and R'5 independently are hydrogen or lower alkyl of 1 to 6 carbons;
Z is n-alkyl having 1 to 13 carbons, cyclo or branch-chained alkyl of 3 to 10 carbons, and straight chain alkenyl having 2 to 10 carbons, or cyclo or branched chained alkenyl of 3 to 10 carbons;
X is a heteroaryl group selected from a group consisting of thienyl, pyridyl and furyl;
n is an integer between 0 to 5, and B is H, COOH or a pharmaceutically acceptable salt thereof, COOR8, CONR9R10, -CH2OH, CH2OR11,, CH2OCOR11, CHO, CH(OR12)2, CHOR13O, -COR7, CR7(OR12)2, or CR7OR13O, where R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R8 is an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R8 is phenyl or lower alkylphenyl, R9 and R10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons or phenyl or lower alkylphenyl, R11 is alkyl 1 to 10 carbons, phenyl or lower alkylphenyl, R12 is lower alkyl, and R13 is divalent alkyl radical of 2 - 5 carbons.

13. A compound of Claim 12 where n is 0.

14. A compound of Claim 13 wherein Z-S is either in the 3 or 4 position of the phenyl ring, and R4 is in the 2 position of the phenyl ring.

15. A compound of Claim 14 wherein X is thienyl.

16. A compound of the formula wherein R4 is hydrogen or lower alkyl;
R5 is hydrogen or lower alkyl, and R8 is hydrogen or lower alkyl.

17. A compound of Claim 16 wherein R4 is hydrogen.

18. A compound of Claim 17 wherein the phenyl ring is 1,3 substituted.

19. A compound of Claim 18 wherein R5 is hydro-gen.

20. The compound of Claim 19 wherein R8 is ethyl.

21. The compound of Claim 19 wherein R8 is hydrogen.

22. A compound of Claim 18 wherein R5 is CH3.

23. The compound of Claim 22 wherein R8 is ethyl.

24. The compound of Claim 22 wherein R8 is hydrogen.

25. A compound of Claim 17 wherein the phenyl ring is 1,4 substituted.

26. A compound of Claim wherein R5 is CH3.

27. The compound of Claim 26 wherein R8 is ethyl.

28. The compound of Claim 26 wherein R8 is hydrogen.