AP830A

AP830A - Indole derivatives useful in therapy.

Info

Publication number: AP830A
Application number: APAP/P/1997/000982A
Authority: AP
Inventors: David James Rawson; Kevin Neil Dack; Roger Peter Dickinson; Kim James
Original assignee: Pfizer
Priority date: 1996-05-09
Filing date: 1997-05-08
Publication date: 2000-05-03
Also published as: US6306852B1; HN1997000058A; EA001471B1; ZA973963B; IS1856B; CA2253876A1; NO985225L; AU717849B2; GB9609641D0; JPH11508285A; UA50767C2; EP0901470B1; TNSN97078A1; UY24546A1; HUP9901245A3; KR100331217B1; EP0901470A1; US6136843A; CN1216531A; NO985225D0

Abstract

Compounds of formula I, and their pharrnaceutically acceptable derivatives. Rs wherein R1 and R2 are optional substiruents and independently represent C1-6 alkyj, C,^ alkenyl [optionally substituted by CO:H or Co2(C1-6 alkyl)], C,.6 alkynyl, halogen, C,.; perfluoroalkyl, (CH2)raAr', (CHJ^Het1, (CH,)mCONR7R3, (CH3)mC02R3, O(CH,)qCO,R3, CCH,)mCOR3, (CH,)mOR3, 0(CH!)pORi, (CH,)mNR7R3, CO,(CH:),NR7R3, (CH,)mCN, S(0)nR.3, SO;NR7RS, CONfHfCH^-Ar1 or CONH(CHJmHet'; R3 represents H, C^ alk>'l, (CKJjNR'R10, SO2R10, SO,NR9R10, (CHJ^COR10, C,^ alkenyt, C,.5 aUcynyl, (CHJ^CONR^R10, (CH,)raCO,R10, (CH,JPCN, (CH,),Rio or (CH,)POR10; R4 represents H or C,^ alkyl: R3 represents H or OK; R° represents phenyl optionally iHised to a heterocyclic rins, the group as a whole beina optionally substituted; R"'° are fully defined here:.-, and may independently represent Ar: or Het:; Z represents CO:K, CONK(;ecazol-5-yl), CONHSO:0(CM alkyl), CO:.V, CO;(C,.., alkyl). :etrazol-5-yl, CONKSO:.Ar;. CONHSO,(CH,)rV or CONHSO:(C,., aiky!): Ar 'J independently represent :;r.er.y[. naphthyl. or an aromatic heterocvcle. -Ahich ^rou^s are optionally fjsed and op::cnai[y substituted; and Ket' and Ke:" ir.dspeacsr.iiy represent a non-aromatic heterocycie '.vhich is o-tionally substituted; are userul in the :reatrnent ofrester.osis. rsnal failure and Du!rn.onarv hvcer.ension.

Description

Indole derivatives useful in therapy

This invention relates to indole derivatives useful in the treatment of a variety of diseases including restenosis, renal failure and pulmonary hypertension, and to pharmaceutical formulations containing such compounds.

International Patent Application WO 94/14434 discloses indole derivatives which are indicated as endothelin receptor antagonists. European Patent Application 617001 discloses a large number of phenoxyphenylacetic acid derivatives which are also indicated as endothelin receptor antagonists.

Bergman et al, Tetrahedron, Vol 31, N° 17, 1975, pages 2063-2073, disclose a number of indole-3-acetic acids. Similar compounds are disclosed by Rusinova et al, Khim Geterotsikl Soedin, 1974, (2), 211-213 (see also Chemical Abstracts, Vol 81, N° 7, 19 August 1974, abstract N° 37455a), and Yarovenko et al, J Gen Chem USSR (English translation), Vol 39, 1969, page 2039 (see also Beilstein, Registry Number 431619). These compounds are not indicated in any kind of therapy, and proviso (i) below relates to them.

Julian et al, J Chem Soc, Chemical Communications, N° 1, 1973, disclose an N-p-chlorobenzoylindole derivative as a by-product of a photo-addition reaction. The compound is not indicated in any kind of therapy, and proviso (ii) below relates to it.

Yamamoto et al, Japanese Patent N° 70 041 381 (see also Chemical Abstracts, Vol 75, N° 3, 1971, abstract N° 20189v), disclose an N-p-chlorobenzoylindole derivative which is indicated as an anti-inflammatory. Proviso (iii) below relates to it. ' According to the present invention, there is provided a compound of formula I,

wherein R and R“ are optional substituents and independently represent C,_6 alkyl, C2.6 alkenyl [optionally substituted by CO2H or CO^C^g alkyl)], C2_6 alkynyl, halogen, perfluoroalkyl, (CH2)mAr’, (CH2)mHet', (CH2)mCONR7R8, (CH2)mCO2R8, O(CH2)qCO2R8, (CH2)mCOR8, (CH2)mOR8, O(CH2)pOR8, (CH2)mNR7R8, CO2(CH2)qNR7Rs, (CH2)mCN, S(O)nR8, SO2NR7R8, CONH(CH2)mAr‘ or CONH(CH2)mHet1; R3 represents H, C,.6 alkyl, (CH2)pNR9R10, SO2R10, SO2NR9R10, (CH2)mCOR10, C2.6 alkenyl, C2.6 alkynyl, (CH2)mCONR9R10, (CH2)mCO2R10, (CH2)pCN, (CH2)pR10 or (CH2)pOR10; R4 and R9 independently represent H or Ct.6 alkyl; R7 represents H, Cj.6 alkyl or Cj.6 alkoxy; R5 represents H or OH; R6 represents phenyl optionally fused to a saturated or unsaturated 5- or 6-membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, S and O, the group as a whole being optionally substituted by one or more groups selected from Ct.6 alkyl, C[.6 alkoxy and halogen, and wherein any members of the heterocyclic ring which are S may be substituted by one or two oxygen atoms; R and R independently represent H, Cj.6 alkyl, Ar , Het~ or C].6 alkyl substituted by Ar" or Het2; Z represents CO2H, CONH(tetrazol-5-yl), CONHSO2O(CM alkyl), CO2Ar3, CO2(C,.6 alkyl), tetrazol-5-yl, CONHSO2Ar3, CONHSO2 (CH2)qAr3 or CONHSO/Cj.g alkyl); m represents 0, 1, 2 or 3; n represents 0, 1 or 2; p represents 2, 3 or 4; q represents 1, 2 or 3;

Ar1'3 independently represent phenyl, naphthyl, or an aromatic heterocycle having 5 or 6 ring members up to 4 of which are selected from N, S and O, which aromatic heterocycle is optionally fused to a benzene ring, and which phenyl group is optionally fused to an aromatic heterocycle as defined immediately above, the group as a whole being optionally substituted by one or more groups falling within the definition of R1 above; and Het and Het" independently represent a non-aromatic heterocycle having 5 or 6 ring members up to 4 of which are selected from N, S and O, which group is optionally substituted by one or more groups falling within the definition of R1 above, and is further optionally substituted by =0 or =S; provided that: (i) when R1 represents methoxy or is absent. R" is absent, RJ represents H, R4 represents H, methyl or ethyl, and R6 represents unsubstituted phenyl, then Z does not represent CO2H or CO2(Cj.6 alkyl); (ii) when R1 and R2 are absent, RJ represents CO(p-ClC6H4), R4 represents H, and R6 represents unsubstituted phenyl, then Z does not represent CO2(C[.6 alkyl); and (iii) when R1 represents methoxy, R2 is absent, RJ represents CO(p-ClC6H4), R4 represents methyl, and R6 represents unsubstituted phenyl,. then Z does not represent CO2H; or a pharmaceutically acceptable derivative thereof.

Pharmaceutically acceptable derivatives include those compounds in which the functional groups explicitly recited above have been derivatised to provide prodrugs which can be » converted to the parent compound in vivo. Such prodrugs are discussed in Drugs of Today, Vol 19, 499-538 (1983) and Annual Reports in Medicinal Chemistry, Vol 10, Ch 31 p306-326. In addition, pharmaceutically acceptable derivatives include pharmaceutically acceptable salts, such as alkali metal salts (for example sodium salts) of any acidic groups that may be present. “Halogen” includes fluorine, chlorine, bromine and iodine.

Alkyl groups which R1"4, R6’10 and Z represent or comprise may be straight chain, branched or cyclic.

Besides phenyl and naphthyl, specific groups that Ar1_J may represent or comprise include indolvl, pyridinyl, thienyl, oxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolvl, imidazolyl, thiazolinidvl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl and pyrimidinvl. 1

Specific groups that Het and Het' may represent or comprise include oxazolidinyl, triazolethione, triazolone, oxadiazolone, oxadiazolethione, imidazolidinyl, morpholinyl, piperidinyl and piperazinyl.

Preferred groups of compounds which may be mentioned include those in which: (a) R1 represents halogen, (CH2)mCONR7R8, (CH2)mCO2R8, (CH2)mCORs, (CH2)mOR8 or (CH2)mCN. In these groups it is preferred that R and R represent H or alkyl. Preferably, m is 0 or 1. Thus, specific groups which may be mentioned are CONH2, CO2H, CH2OH, F or CH3CO. R1 is preferably attached to the 6-position of the indole ring. (b) R2 is absent (i.e. its place on the indole ring is occupied by H). (c) R3 represents H, C,.6 alkyl or (CH2)pOR10. Preferably, R10 is Cj_6 alkyl and p is 2.

Thus, specific groups which may be mentioned are methyl and (CH2)2OCH3. (d) R4 represents H. (e) R5 represents H. (f) R6 represents phenyl fused to a saturated 5-membered heterocyclic ring, for example 3,4-methylenedioxyphenyl. (g) Z represents CO2H or CONHSO2Ar . Preferably, Ar is phenyl substituted by one or more groups selected from Cb6 alkyl, Cj_6 alkoxy and Cj.6 alkyl substituted by carboxy. Thus, specific groups which may be mentioned are:

There is further provided a process for the production of the compounds of the invention, comprising: (a) when R~ represents H, reaction of a compound of formula IIA,

wherein R1’4 are as defined above, with a compound of formula III,

wherein R6 and Z are as defined above, in the presence of a Lewis acid or trifluoroacetic acid, and a tri(C5.6 alkyl)silane; (b) when R~ represents OH, reaction of a compound of formula IIA, as defined above, with a compound of formula III, as defined above, in the presence of a Lewis acid; (c) when RJ represents H and R3 represents H, treatment of a compound of formula IIB,

wherein R1, R2 and R4 are as defined above, with a Grignard reagent, followed by reaction with a compound of formula III, as defined above, followed by treatment with a Lewis acid or trifluoroacetic acid, and a tri(C(.6 alkyl)silane; (d) when R3 represents H and R5 represents H, treatment of a compound of formula IIB, as defined above, with a Grignard reagent, followed by reaction with a compound of formula IV,

wherein R6 and Z are as defined above, and Hal represents halogen; (e) when R5 represents H, reaction of a compound of formula IIA, as defined above, with a compound of formula IV, as defined above, in the presence of a hindered, non-nucleophilic base; (f) reacting a compound of formula I, in which R1 represents Br, with CO gas in the presence of a palladium catalyst and a reducing agent, to provide the corresponding compound of formula I in which R1 represents CHO; (g) reacting a compound of formula I, in which R1 represents Br, with CO gas in the presence of a palladium catalyst and a Cj_6 alkanol, to provide the corresponding compound of formula I in which R1 represents CO2(C,.6 alkyl); (h) coupling a compound of formula I in which Z represents CO2H with a compound of formula VI,

wherein Ar3 is as defined above, to provide the corresponding compound of formula I in which Z represents CONHSO2ArJ; or (i) reacting a compound of formula I, in which R1 represents Br, with an alkyl lithium reagent and quenching with dimethylformamide or carbon dioxide, to give a corresponding compound in which R1 represents CHO or CO2H respectively; and where desired or necessary converting the resulting compound of formula I into a pharmaceutically acceptable derivative thereof or vice versa.

In process (a), suitable Lewis acids include boron trifluoride diethyletherate. The reaction is preferably carried out in a solvent which does not .adversely affect the reaction, for example dichloromethane, at a temperature below room temperature, for example -40 to -78°C. A preferred tri(Cj_6 alkyl)silane is triethylsilane. Intermediate compounds in which R5 represents OH may be isolated from this process.

In process (b), suitable Lewis acids include boron trifluoride diethyletherate. The reaction is preferably carried out in a solvent which does not adversely affect the reaction, for example dichloromethane, at a temperature below room temperature, for example -40 to -78°C. The reaction is followed by basic work up.

In process (c), suitable Grignard reagents include methylmagnesium iodide. The reaction is preferably carried out in a solvent which does not adversely affect the reaction, for example toluene, below room temperature, for example -70°C. Suitable Lewis acids include boron trifluoride diethyletherate. The acid treatment may be carried out in a solvent which does not adversely affect the reaction, for example dichloromethane, at a temperature of 0°C to room temperature. A preferred tri(C μ6 alkyl)silane is triethylsilane.

In process (d), suitable Grignard reagents include methylmagnesium iodide. The reaction is preferably carried out in a solvent which does not adversely affect the reaction, for example toluene, at or around room temperature. The reaction mixture may be worked up with a weak acid such as aqueous ammonium chloride. Hal is preferably Br.

In process (e), suitable hindered non-nucleophilic bases include 2,6-dimethylpvridine. The reaction is preferably carried out.in a solvent which does not adversely affect the reaction, for example dimethylformamide, at an elevated temperature, for example 80°C.

In process (f), suitable palladium catalysts include dichlorobis(triphenylphosphine)-palladium(II). Suitable reducing agents include sodium formate. The reaction is preferably carried out in a solvent which does not adversely affect the reaction, for example dimethylformamide, at an elevated temperature, for example 110°C.

In process (g), suitable palladium catalysts include dichlorobis(triphenylphosphine)-palladium(II). The reaction is preferably carried out in a,solvent which does not adversely affect the reaction, for example dimethylformamide, at an elevated temperature, for example the reflux temperature of the reaction mixture.

In process (h), the reaction may be facilitated by the use of conventional coupling agents, for example Ν,Ν-carbonyl diimidazole. When using this agent, the acid is first reacted with the agent (for example in dichloromethane at the reflux temperature of the solvent), and then the product of this reaction is reacted with the amine (preferably in the presence of a strong hindered amine base such as l,8-diazabicyclo[5.4.0]undec-7-ene, in a solvent such as dichloromethane at the reflux temperature of the solvent). An alternative agent is l-(3-dimethylaminopropyl)-3-ethylcarbodiimide which reacts at room temperature.

In process (i), suitable alkyl lithium reagents include n-butyl lithium. The reaction is carried out by adding the alkyl lithium reagent to the compound of formula I in a solvent such as tetrahydrofuran, at a temperature below room temperature (for example -40 to -78°C), and stirring for about 2 hours. Dimethylformamide or solid carbon dioxide is then added and the reaction mixture allowed to warm to room temperature.

Compounds of formulae IIA, IIB, III, IV and VI are either known or may be prepared by conventional methods well known to those skilled in the art. For example, compounds of formulae IIA and IIB may be prepared by the Fischer, Reissert and Madelung syntheses. In addition, International Patent Application WO 94/14434 discloses a number of routes to 2-carboxy indole derivatives (see page 8 onwards) which may be decarboxylated readily (using copper and quinoline) to give compounds of formulae IIA or IIB in which R4 is H, or reduced to give compounds of formulae IIA or IIB in which R is alkyl. Other methods for the preparation of indoles are described by Moyer et al, J Org Chem, 1986, 51, 5106-5110; Wender et al, Tetrahedron, 1983, 39 N°22, 3767-3776; Uhle, J Am Chem So.c, 1949, 71, 761; Uhle et al, J Am Chem Soc, 1960, 82, 1200; Nagasaka et al, Heterocycles, 1977, 8, 371; Bowman et al, J Chem Soc, Perkin Trans 1, 1972, 1121; Bowman et al, J Chem Soc, Perkin Trans 1, 1972, 1926; and Clark et al, Heterocycles, 1984, 22, 195.

Compounds of formula III in which R6 is an electron-rich group (for example 1,3-benzodioxole) and Z is CO2CH2CH3 may be prepared by a Friedel-Crafts acylation between a compound of formula R6H and the compound of formula C1COCO2CH2CH3. The reaction is preferably carried out in the presence of a Lewis acid (for example A1C13), in a solvent which does not adversely affect the reaction, for example dichloromethane, below room temperature (for example 0°C).

Compounds of formula III in which R6 is not an electron-rich group (for example groups substituted by halogen or OH) and Z is CO2CH3 may be prepared by reaction of a compound of formula R6Li with a compound of formula CH3OCOCO2CH3. The reaction may be carried out in a solvent which does not adversely affect the reaction, for example tetrahydrofuran, below room temperature (for example -40°C to -78°C).

Compounds of formula R6Li may be prepared by reacting a compound of formula R6Br and butyl lithium. The reaction may be carried out in a solvent which does not adversely affect the reaction, for example tetrahydrofuran, below room temperature (for example -78°C).

Compounds of formula IV may be prepared by halogenating the corresponding alcohol with an agent such as hydrobromic acid. When Z represents CO2(C].6 alkyl), compounds of formula R6CH(OH)Z may be prepared by reacting an aldehyde of formula R6CHO with bromoform under basic conditions, and treating the crude carboxylic acid intermediate with aCw alkanol.

Claims

Original document published without claims.