GB2165235A

GB2165235A - Carbocyclic compounds

Info

Publication number: GB2165235A
Application number: GB08422456A
Authority: GB
Inventors: Eric William Collington; Peter Hallett; Christopher John Wallis; Norman Frank Hayes
Original assignee: Glaxo Group Ltd
Current assignee: Glaxo Group Ltd
Priority date: 1984-09-05
Filing date: 1984-09-05
Publication date: 1986-04-09
Also published as: GB8422456D0

Abstract

Compounds of the general formula (1> <IMAGE> wherein: (a) W is straight or branched C1-7 alkylene; X is cis or trans -CH=CH-, or -CH2CH2-; Y is a saturated heterocyclic amino group; Z is -COOR<1> (where R<1> is a hydrogen atom, or a C1-6 or C7-10 aralkyl group), -CH2OH, -CHO or -CONHR<4> where R<4> is a hydrogen atom or a methyl group; R<2> is (i) straight or branched C1-5 alkyl substituted by (a) phenyl substituted by phenyl C1-3 alkyl thienyl, phenyl substituted by C1-4 alkyl, C1-4 alkoxy or phenyl, (b) optionally substituted thienyl, or (ii) cinnamyl; (b) W is -(CH2)3-; X is cis -CH=CH-; Y is a saturated heterocyclic amino group; Z is -CO2H, -CO2CH3, -CH2OH, -CHO or CONHR<4>; R<2> is C1-3 alkyl substituted by (a) phenyl optionally substituted by C1-6 alkyl, C5-7 cycloalkyl, phenyl, or (b) napththyl optionally substituted by C1-4 alkyl or C1-4 alkoxy; and the physiologically acceptable salts and solvates thereof. These compounds inhibit blood platelet aggregation, bronchoconstriction and vasoconstriction and may be formulated for use as antithrombotic or antiasthmatic agents.

Description

SPECIFICATION Carbocyclic compounds The endoperoxides prostaglandins G2 and H2 and thromboxane A2 are naturally occurring reactive metabolites of arachidonic acid in human platelets. They are not only potent aggregatory agents but are also constrictors of vascular and bronchial smooth muscle, and therefore substances which antagonise their effects are of considerable interest in human medicine.

We have now found a new group of compounds which have shown endoperoxide and thromboxane antagonist activity, and are therefore of interest in the treatment of cardiovascular diseases, asthma and adult respiratory distress syndrome, and for use in renal transplant and dialysis and in the prevention of relapse of healed peptic ulcers.

The invention thus provides compounds of the general formula (1 )

wherein: (a) W is straight or branched C1.7 alkylene; X is cis or trans -CH=CH-, or -CH2CH Y is a saturated heterocyclic amino group (attached to the cyclopentane ring via the nitrogen atom) which has 5-8 ring members and (a) optionally contains in the ring -0-, -S-. -S02-, or -NR3 (where R3 is a hydrogen atom, C17 alkyl or aralkyl having a C1.4 alkyl portion); and/or (b) is optionally substituted by one or more ClA alkyl groups; Z is -COOR1 (where R1 is a hydrogen atom, or a C1.6 alkyl or C7 10 aralkyl group) -CH2OH, -CHO or -CONHR4 where R4 is a hydrogen atom or a methyl group;R2 is (i) straight or branched C1-5 alkyl substituted by (a) phenyl substituted by phenylalkyl having a C1.3 alkyl portion, thienyl, phenyl substituted by C1 4 alkyl, C1.4 alkoxy or phenyl, (b) thienyl [optionally substituted by C5 7 cycloalkyl or phenyl (optionally substituted by C1.3 alkyl, C1.3 alkoxy or halogen)l, or (ii) cinnamyl; (b) W is -(CH2)3-; Xis cis -CH=CH-; Y is a saturated heterocyclic amino group (attached to the cyclopentane ring via the nitrogen atom), which has 5-7 ring members and is optionally substituted by a methyl group; Z is -CO2H, -CO2CH3, -CH2OH, -CHO or CONHR4;; R2 is C1.3 alkyl substituted by (a) phenyl optionally substituted by C1.6 alkyl, C5.7 cycloalkyl, phenyl, or (b) naphthyl optionally substituted by C1.4 alkyl or C1 4 alkoxy; and the physiologically acceptable salts and solvates thereof.

Certain compounds of formula (1) as hereinbefore defined in (b) and the physiologically acceptable salts thereof fall within the scope of the general disclosure in U.K. Patent Specification Publication No. 2028805, but there is no specific disclosure of any compound of the present invention. Moreover the compounds of the present invention unexpectedly possess especially good endoperoxide and thromboxane antagonist activity compared with the corresponding compounds of the same ring type specifically disclosed in U.K.

Patent Specification Publication No. 2028805.

The structural formulae herein are to be understood to include the enantiomers of each of the compounds concerned as well as mixtures of the enantiomers including racemates, even though the precise structure as set out only relates to one enantiomer.

Suitable physiologically acceptable salts of the compounds of general formula (1 ) include acid addition salts derived from inorganic and organic acids, such as hydrochlorides, hydrobromides, sulphates, phosphates, maleates, tartrates, citrates, 2-chlorobenzoates, p-toluenesulphonates, methanesulphonates, salicylates, fumarates, lactates, hydroxy-naphthalenecarboxylates (e.g.) 1 -hydroxy- or 3-hydroxy-2naphthalenecarboxylates) orfuroates. When Z in the compounds of formula (1 ) is -CO2H the compounds may also form salts with suitable bases. Examples of such salts are alkali metal (e.g. sodium and potassium), alkaline earth metal (e.g. calcium or magnesium), ammonium and substituted ammonium (e.g. dimethylammonium, triethylammonium, piperidine, ethylenediamine and choline).

In the compounds of formula 1(a), the heterocyclic amino group Y may for example have a 5,6 or 7-membered ring, e.g. pyrrolidino, piperidino, morpholino, piperazino, thiomorpholino, 1,1dioxothiomorpholino, homomorpholino and hexamethyleneimino. Examples of the optional substituents (R3) which may be present on a second nitrogen atom in the ring are methyl, ethyl, butyl, hexyl, benzyl and phenethyl. The carbon atoms of the heterocyclic rings may for example be substituted by methyl, ethyl or butyl.

In general Y is preferably pyrrolidino, piperidino or hexamethyleneimino optionally substituted by one or two C1.4 alkyl (particularly methyl) groups, e.g. 4-methyl-piperidino. Compounds of formula 1 (a) in which Y is piperidino are particularly preferred.

Examples of the group Z in compounds of formula 1 (a) are COOR1 in which R1 is a hydrogen atom, benzyl or a C1.3 alkyl group e.g. methyl or ethyl. In general, Z is preferably -COOR1, where R1 is a hydrogen atom or a methyl group, particularly a hydrogen atom.

Where R2 in the compounds of formula 1 (a) is a substituted alkyl group of type (i), the alkylene portion may for example contain 1-3 carbon atoms (e.g. methylene, ethylene or propylene) and is preferably a methylene or propylene group.

In R2 groups of the type (i) (a), the phenyl group may be substituted by, for example, benzyl, phenethyl, thienyl or phenyl substituted by methyl, ethyl, methoxy or butoxy groups.

In R2 groups of the type (i) (b), the thienyl group may be substituted by, for example, cyclohexyl or phenyl (optionally substituted by methyl, ethyl, methoxy, ethoxy, chloro or bromo) groups.

In compounds of formula 1 (a) R2 is preferably (1 ) a C1-5 alkyl (particularly methyl, ethyl or propyl) group substituted by thienyl (optionally substituted by phenyl) or phenyl substituted by phenyl (C1.3) alkyl, thienyl or phenyl substituted by C1.4 alkyl or C1.4 alkoxy or (2) cinnamyl. Thus R2 may be, for example, (1 ) methyl, ethyl or propyl (particularly methyl) substituted by thienyl substituted by phenyl or phenyl substituted (preferably in the para position) bythienyl, benzyl or phenyl substituted (preferably in the para position) by methyl or methoxy, or (2) cinnamyl.Examples of such R2 groups are benzyl substituted by phenyl substituted by methyl or methoxy, for example [4'-methoxy(1 ,1 '-biphenyl)-4-yljmethyl or [4'-methyl(1 1 '-biphenyl)-4-yl]methyl.

Xis preferably cis -CH=CH-.

W may contain for example 1-5 carbon atoms in a straight or branched chain, and may be for example -(CH2)2-r -(CH2)3- or -(CH2)4-. Particularly interesting compounds according to the invention are those in which W is -(CH2)3-.

The preferences indicated above apply both separately and in combination with each otherand/orthe general definitions stated for general formula 1(a).

In the compounds of formula 1 (by, Y may be pyrrolidino, piperidino or hexamethyleneimino, optionally substituted by a methyl group, e.g. 4-methylpiperidino.

R2 may be methyl, ethyl or propyl substituted by naphthyl, phenyl or phenyl substituted by methyl, ethyl, t-butyl, cyclohexyl or phenyl. In particular, R2 is methyl or propyl substituted by phenyl substituted (preferably in the para position) by phenyl, e.g. [(1,1 '-biphenyl)-4-yl] methyl.

Z is preferably -CO2H or -CO2CH3.

Preferred compounds according to the present invention, by virtue of their especially favourable endoperoxide and thromboxane antagonist activity, include compounds of formula 1 (b) wherein Y is piperidino, Z is -CO2H or CO2CH3 (particularly -CO2H) and R2 is methyl, ethyl or propyl (particularly methyl or propyl) substituted by phenyl substituted (particularly in the para position) by phenyl, and especially is [(1,1 '-biphenyl)-4-yl]methyl.

Aparticularly preferred compound according to the invention is R-[1(Z),2,5pI]-(+)-7-[2-[[(1,1'-biphenyl)- 4-yl]methoxy]-5-(1 -piperidinyl)cyclopentyl]-5-heptenoic acid.

In general, tha compounds of formula (1 ) in which the carbon atom carrying the -CH2XWZ group is in the R configuration (and mixtures containing this isomer) and/or compounds of formula (1) in which Y is pyrrolidino, piperidino, or hexamethyleneimino, optionally substituted by a methyl group are preferred.

Compounds of formula (1 ) inhibit blood platelet aggregation, bronchoconstriction and vasoconstriction. A test to determine inhibition of blood platelet aggregation is as described by G V Born (Nature 194, 927-929, (1962)) except in that collagen is used instead of ADP as the pro-aggregatory agent.

The ability of the compounds of the invention to inhibitvasoconstriction or bronchoconstriction is determined using the relevant isolated tissue (e.g. spirally cut rat aortic strip or guinea-pig lung parenchymal strip) by measuring the effect of the compound to be tested on the contraction of the tissue to [1R-[1R,4t,5,(Z),6(x(1E,3S*)]]-7-[6-(3-hydroxy-1-octenyl)-2-oxabicyclo[2,2,1]hept-5-yl]-5-heptenoicacid (U46619).

The compounds are thus of interest in the treatment of asthma, and as inhibitors of platelet aggregation and thrombosis for use in renal transplant and dialysis and the treatment and prevention of occlusive vascular diseases such as atherosclerosis, peripheral vascular disease, cerebral vascular disease including transient ischaemic attacks, stroke, pulmonary embolism, diabetic retinopathy, post operative thrombosis, angina and myocardial infarction.

The compounds are also of potential use in the treatment of adult respiratory distress syndrome and the prevention of relapse of healed peptic ulcers.

The compounds may be formulated in a conventional manner four use with one or more pharmaceutical carriers.

For oral administration, the pharmaceutical composition may take the form of for example, tablets, capsules, powders, solutions, syrups or suspensions prepared by conventional means with acceptable excipients.

The compounds may be formulated for parenteral administration by continuous infusion. Formulations for injections may be presented in unit dosage form in ampoules, or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oil or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and xor dispersing agents. Alternatively, the active ingredient may be in powder form for reconstitution before use with a suitable vehicle, e.g. sterile pyrogen-free water.

For administration by inhalation the compounds are conveniently delivered in the form of an aerosol spray presentation from pressurised packs or a nebuliser, or as a cartridge from which the powdered composition may be inhaled with the aid of a suitable device. In the case of a pressurised aerosol the dosage unit may be determined by providing a valve to deliver a metered amount.

For use as antithrombotic agents, the compounds are preferably administered orally, for example in amounts of 0.05 to 1 Omg/kg body weight, 1 to 4 times daily, or intravenously for example in amounts of 0.01 to 25mg/kg body weight, 1 to 4 times daily.

For use in the treatment of asthma, the compounds may also be administered orally in amounts of 0.05 to 1 Omg/kg body weight, 1 to 4 times daily; preferably however they are administered by inhalation at doses varying from 0.02 to 30mg, preferably 0.02 to 3mg, 1 to 4 times daily. The compounds may be used in combination with other antiasthmatic agents.

The precise dose administered will of course depend on the age and condition of the patient.

Suitable methods for preparing the compounds of the invention are described below, the various groups and symbols being as defined above except where otherwise indicated.

(a) Compounds of formula (1 ) in which Z is a CO3H group may be prepared by hydrolysis of the corresponding ester or amide.

The hydrolysis can in general be effected by conventional methods, for example under basic conditions, in a suitable solvent, e.g. an alcohol such as methanol or ethanol at any suitable temperature up to and including reflux. Suitable bases include inorganic bases such as alkali metal hydroxides e.g. NaOH or KOH.

(b) The compounds of the invention in which X is -CH2CH2- may be prepared by catalytic hydrogenation of a corresponding compound in which Xis -CH=CH-, using a catalyst such as palladium oxide. Alcohols such as ethanol are suitable solvents and the reaction may be performed at room temperature.

(c) Compounds of formula (1) in which Xis trans -CH=CH- may be prepared by isomerising the corresponding cis compound. The isomerisation may be effected for example by treatment with p-toluene sulphinic acid in dioxan (e.g. at reflux) or azobisisobutyronitrile and thiophenol, using for example a hydrocar' on solvent (e.g. benzene) and any suitable temperature up to reflux.

(O s Compounds of formula (1 ) may be prepared by dehydroxylation (homolytic cleavage of the arbon--oxygen bond) of a corresponding alcohol offormula (2)

in which Z is C02R1, for example via tri-n-butyltin hydride reduction of a thioester derivative such as the thiocarbonyl imidazolide. The reaction is particularly suitable for the preparation of compounds in which Z is C02R1, where R1 is C16 alkyl or C7.10 aralkyl.

The reduction is preferably carried out in a hydrocarbon solvent (e.g. toluene) at a temperature up to and including reflux in the presence of a radical initiator e.g. azobisisobutyronitrile.

The thioester derivative may be conveniently prepared from the alcohol (2) using a suitable reagent (e.g.

1,1 '-thiocarbonyldiimidazole) in a suitable solvent (e.g. tetrahydrofuran) at room temperature.

Alcohols of formula (2) may be prepared by the methods generally described in UK Patent Specifications 2028805A, 2070591A, 2075503A and 2097397A.

(e) Compounds of formula (1) in which Z is -CH2OH may be prepared by reducing a corresponding compound of formula (1) in which Z is -CO3CH3, for example with LiAIH4.

(f) Compounds of formula (1) in which Z is -CHO may be prepared by oxidising the corresponding compound of formula (1) in which Z is -CH2OH, using for example an activated sulphur reagent, e.g. (i) N-chlorosuccinimide-dimethylsulphide complex in a suitable solvent (e.g. toluene or dichloromethane) at temperatures of for example 25 to 25"C, preferably at 0-5"C, or (ii) pyridine-SO3 complex in dimethylsulphoxide, preferably at 0 C to room temperature.

(g) Compounds of formula (1) in which Z is -CONHR4 may be prepared by amidation of the parent carboxylic acid i.e. the corresponding compound of formula (1) in which Z is -CO2H.

Conventional methods for converting acids into am ides may be used, for example by treating the acid with isobutylchloroformate in the presence of triethylamine and reacting the resulting reactive derivative of the carboxylic acid with ammonia or an amine R4NH2.

(h) Where salts of compounds of the invention are desired such salts may be formed by conventional methods, for example by treatment with an acid or with a base.

Treatment may for example be effected in a suitable solvent such as an ether (e.g. diethylether), acetonitrile, acetone, chloroform, dichloromethane, ethyl acetate, isopropyl acetate or an alcohol, e.g.

methanol, ethanol or isopropanol.

Salts may also be formed by conversion of one salt of a compound of the invention into another, e.g. by ion exchange using conventional methods.

When a specific enantiomer of formula (1) is required, starting materials having the desired stereochemical configuration should be used in the above processes. Such starting materials may be prepared for example from an enantiomeric bicycloheptenone as described in European Patent Specification 74856 using the methods generally described in UK Patent specifications 2028805A, 2070591A, 2075503A and 2097397A.

The following examples illustrate the invention. Temperatures are in C. Chromatography and t.l.c. are using silica unless stated otherwise. Dried refers to drying with MgSO4.

The following abbreviations are used: THF - tetrahydrofuran ER-ether EA - ethyl acetate PE - petroleum ether (b.p. 40-60 ) The preparation of the following Intermediate is described in British Patent Specification 2097397A.

Intermediate 1.

[1 R-(1α,2ss,3α,5α)]-5-[[(1,1 '-Biphenyl)-4-yl] methoxyl-3-hydroxy-2-( 1 - piperidinyl)cyclopentaneacetaldehyde.

Intermediate 2.

[iR-[ la (Z),2ss,3α,5α-(+)-Methyl- 7-[5-[[[1, 1 '-Biphenyl)-4ylymethoxy]-S-hydroxy-2-{1-piperidinyl)cyclopentyl]- 5-heptenoate,hydrochloride.

To a stirred solution of potassium-t-butoxide (5.9g) in dry THF (70ml) was added (4 carboxybutyl)triphenylphosphonium bromide (11.089) with stirring maintained at 20G under dry nitrogen for 0.5h. A solution of Intermediate 1 (39) in dry THF (30ml) was added and stirring continued at 20 for 50min, whereupon water (15ml) was added and excess solvent removed in vacuo. After dilution with water (20ml) the solution was basified with 2N NaOH (30ml) and extracted with ER (3 x 100ml). The aqueous phase was adjusted to pH 7 with 2N HC1 (35ml) and extracted with CH2C12 (2 x 100ml).The solution was then adjusted to pH 6 and extracted with CH2Cl2 (100ml) and finally to pH 5.5 and extracted with CH2Cl2 (100ml). The combined extracts were dried and evaporated to afford a foam (3.71 g). A portion of the foam (0.4969) in methanol (1 Oml) at 20 was treated with concentrated H2SO4 (0.2ml) and the mixture stirred for 2.75h. The solution was then poured into 8% NaHCO3 solution (20ml) and extracted with CH2Cl2 (3 x 20ml). The combined extracts were dried and evaporated, and the residue purified by chromatography using 4:1 EA-methanol as eluantto give an oil (1.4389).

Saturated ethereal hydrogen chloride (ca 1ml) was added to a portion of the oil (300mg) in ER (5ml). The solvent was decanted and the resultant solid triturated with ER (ca 5ml) to give the title compound (311 mg) m.p.96-989.

[α]D23 = +19.6 = +19.6 (CHCl3).

Intermediate 3 [1Rj1a(Z),2,35all-()-Meth 7-[5-[[( 1,1 '-Biph en yl)-4- yIJm eth ox y]-3-[( iH-im idazo I- 1-yl)thioxomethoxyl-2- (1-piperidinyl)cyclopentyl]-5-heptenoate To a solution of Intermediate 2, base, (1.5g) in THF (1 100ml) was added thiocarbonyldi-imidazole (0.83g) and the yellow solution stirred at ambient temperature for 4h. The solvent was evaporated in vacuo and the residue taken up in pH 6.5 phosphate buffer (30ml) and extracted with EA (3x30ml). The combined organic layers were washed with brine (30ml), dried and evaporated in vacuo to afford the title compound as an oil (1.78g).T..c. 100:1 EA-Et3N Rf 0.6.

Example 1 [1R-1[α(Z),2α,5ss]]-(+) Methyl 7-(2-[[[1, I'-Biphenyll-4-yl]methoxy]-5-(l-piperidi A solution of Intermediate 3 (1.859) in toluene (15ml) was treated over a 1 Omin period with a solution of tri-n-butyltin hydride (1.26ml) and azobisisobutyronitrile (58mg) in toluene (8ml) at 1000 under nitrogen.

The solution was heated at 1000 for a further lOmin., cooled, and concentrated in vacuo. The mixture was purified by chromatography using 3:1 PE-ER followed by 50:50:1 PE-ER-Et3N as eluant to give the title compound as an oil (565mg) T.l.c. 49:49: :2 PE-ER-Et3N Rf 0.35 l.r. (Neat) 1735cm-1 [a]301 = + 35.7" (CHCl3) Example 2 [1R-[1α(Z),2α,5ss-(+)-7-I2-lf(i, 1 '-Biohenyl)-4-Wjmethoxyj-5-(ipioeridiny[)cyclopentyll-5-heptenoic acid To a solution of the compound of Example 1 (420mg) in methanol (5ml) was added 5N NaOH (0.5ml) and the mixture stirred at ambient temperature overnight The mixture was neutralised with 5N HCI (0.5ml) and pH 6.5 phosphate buffer (15my), then concentrated in vacuo. The solution was extracted with CH2C12 (3 xl Sm I), the organic extracts dried, and evaporated in vacuo and the residue was purified by chromatography using 17:2:1 CH2Cl2-ethanol-ET3N as eluant. The product was dissolved in CH2CI1 (1 5ml) and washed with pH 6.5 phosphate buffer (20ml), the organic layer separated, and the aqueous portion further extracted with CH2CI1 (5ml). The combined extracts were dried and evaporated in vacuo to afford the title compound as a gum (187mg).

T.l.c. 17:2:1 CH2C12-ethanol-Et3N Rf 0.27.

I.r. (CHBr3) 1710,1600cm~'.

[α]2D20.5= + 50.3 CHCl3).

Claims

CLAIM

1. Compounds of the general formula (1)

wherein: (a) W is straight or branched C17 alkylene; Xis cis or trans -CH=CH-, or -CH2CH2-; Y is a saturated heterocyclic amino group (attached to the cyclopentane ring via the nitrogen atom) which has 5-8 ring members and (a) optionally contains in the ring -0--S-, -SO2-, or -NR3 (where R3 is a hydrogen atom, C1.7 alkyl or aralkyl having a C1.4 alkyl portion); and/or (b) is optionally substituted by one or more C1.4 alkyl groups; Z is -COOR1 (where R1 is a hydrogen atom, or a C16 alkyl or C7.10 aralkyl group) -CH2OH, -CHO or -CONHR4where R4 is a hydrogen atom or a methyl group; R2 is (i) straight or branched C1-5 alkyl substituted by (a) phenyl substituted by phenylalkyl having a Con 3 alkyl portion, thienyl, phenyl substituted by C1.4 alkyl, C1.4 alkoxy or phenyl, (b) thienyl [optionally substituted by C5 7 cycloalkyl or phenyl (optionally substituted by C1.3 alkoxy or halogen)], or (ii) cinnamyl; (b)W is -(CH2)3-; Xis cis -CH=CH-; ; Y is a saturated heterocyclic amino group (attached to the cyclopentane ring via the nitrogen atom), which has 5-7 ring members and is optionally substituted by a methyl group; Z is -CO2H, - CO2CH3, -CH2OH, -CHO or CONHR4; R2 is C1.3 alkyl substituted by (a) phenyl optionally substituted by C1-6 alkyl, C5 7 cycloalkyl, phenyl, or (b) naphthyl optionally substituted by C1-4 alkyl or C1.4 alkoxy; and the physiologically acceptable salts and solvates thereof.