IE53396B1 - Substituted imidazo(1,5-a)pyridines,process for their manufacture,pharmaceutical preparations containing these compounds and their therapeutic application - Google Patents

Abstract

The invention concerns compounds with thromboxane synthetase inhibitory effects of the formula I or 5,6,7,8-tetrahydro derivatives thereof, wherein each of R1 and R2 is hydrogen, halogen or lower alkyl; A is alkylene of 1 to 12 carbon atoms, alkynylene or alkenylene of 2 to 12 carbon atoms; B represents carboxy, lower alkoxycarbonyl, unsubstituted, mono- or di-(lower alkyl) substituted carbamoyl, cyano or hydroxymethyl; or salts thereof; and a process for the production of these compounds.

Description

Imidazol1,5-a] pyridines reported in the literature are for the most part only functionally substituted on the imidazole portion of the bicyclic ring system. For example 1- and 3-aminoalkyl substituted imidazo[1,5-a]pyridines and tetrahydro derivatives are described in Journal of Medicinal Chemistry 16, 1272-6 (1973).

Surprisingly it vas found, that imidazo [1,5-a] pyridine alkanoic acids and derivatives represent a novel class of outstanding potent and highly specific thromboxane synthetase inhibitors.

The foregoing advantages and attributes render the imidazo [1,5-a] pyridine derivatives of this invention particularly useful when administered, alone or in combination, to mammals, e.g. for the treatment or prevention of diseases responsive to the inhibition of throaboxane synthetase comprising cardiovascular disorders such as thrombosis, atherosclerosis, cerebral ischaemic attacks, myocardial infarction, angina pectoris and hypertension; respiratory disorders, such as asthma; inflammatory disorders; carcinoma, such as tumor metastasis; and migraine headache.

This invention concerns therefore imidazo[l,5-a]pyridines of formula I or 5,6,7,8-tecrahydro derivatives thereof, wherein each cf R^ and R^ is hydrogen, halogen or lower alkyl; A is alkylene of 1 to 12 carbon atoms, alkynylene or alkenylene of 2 to 12 carbon atoms; 5 represents carboxy, lower alkoxycarbonyl, unsubstituted, mono- or di-(lower alkyl) substituted carbamoyl, cyano or hydroxymethyl; or salts, r especially pharmaceutically acceptable salts thereof, process for their manufacture, pharmaceutical preparations containing these compounds and their therapeutic application.

Preferred embodiments of this invention relate to compounds of formula I wherein the group CH^-A-S is attached at the 5 position. Very useful are compounds of formula I wherein A is alkylene of 1 to 12 carbon atoms.

Particularly useful are compounds of formula II s -C-(CH ) -E Ο , X B or 5,6,7,β-tetrahydroderivatives thereof, wherein R^, R^, and are hydrogen cr lower alkyl of 1 to 4 carbon atoms, n is 1 to 7, m is or 1; B represents carboxy, lower alkoxycarbonyl, unsubstituted or mono- or di-(lower alkyl) substituted carbamoyl, cyano or hydroxy53396 methyl; or salts, especially pharmaceutically acceptable salts thereof.

Especially useful are compounds of formula II or 5,6,7,8-tetrahydro derivatives thereof, «herein R.^, R^, R^ and R^ are hydrogen, methyl or ethyl; (CK ) is propylene, butylene, pentylene or hexylene; m is 4 TL 0 or 1; B represents carboxy, methoxycarbonyl or ethoxycarbonyl, unsubstituted carbamoyl, monomethyl or conoethylcarbamoyl, dimethyl or diethylcarbaaoyl, cyano or hydroxymethyl; or salts, especially pharmaceutically acceptable salts thereof.

IO Preferred in turn, are the compounds of formula II «herein the group (CH ) -C-(CE,) -B 2 n 1 2 m is attached at the 5-position.

Exceedingly useful are compounds of formula III (III) <0h,} -B 2 P or 5,6,7,8-tetraydro derivatives thereof, «herein p is 3 to 8; B represents carboxy, lower alkoxycarbonyl, unsubstituted, mono- or di(lower alkyl) substituted carbamoyl; cyano or hydroxymethyl; or salts, especially pharmaceutically acceptable salts thereof.

Especially valuable are compounds of formula IV __ (CH,) COOH 2 q (IV) - 5 or 5,6,7,8-tetrahydro derivatives thereof, wherein q is 4, 5 or 6; or salts, especially pharmaceutically acceptable acid or base addition salts thereof.

The general definitions used herein have the following meanings within the scope of the present invention.

An alkylene represents C^^-alkylene, may have a straight chain or branched chain, and is preferably propylene, butylene, pentylene or hexylene, said radicals being unsubstituted or substituted by one or more lower alkyl groups, with the proviso that the total number of carbon atoms equals no more than 12.

The term alkenylene represents alkenylene, which may have a straight cr branched chain, and is preferably propenylene, 1- or 2-butenylene, 1- or 2-pentenylene, 1-, 2- or 3-hexenylene, said radicals being unsubstituted or substituted by one or more lower alkyl groups, with the proviso that the total number of carbon atoms equals no more than 12.

The term alkynylene represents C^-C^ alkynylene, which may have a straight or branched chain, and is preferably propynylene, 1- or 2- butynylene, 1- or 2-pentynylene, 1-, 2- or 3-hexynylene, said radicals being unsubstituted or substituted by one or more lover alkyl groups,vith the proviso that the total number of carbon atoms equals no more than 12.

The term lower" referred to above and hereinafter in connection vith organic radicals or compounds respectively defines such with up to and including 7, preferably up and including 4 and advantageously one or tvo carbon atoms. 53336 - 6 A lower alkyl group preferably contains 1-4 carbon atoms and represents for example ethyl, propyl, butyl or advantageously methyl.

A lover alkoxycarbonyl group preferably contains 1-4 carbon atoms in the alkoxy portion and represents for example methoxycarbonyl, propoxycarbonyl, iscpropoxycarbonyl or advantageously ethoxycarbonyl.

A mono-(lover alkyl)carbamoyl group preferably contains 1-4 carbon atoms in the alkyl portion and is for example N-methylcarbamoyl, N-propylcarbamoyl or advantageously N-ethylcarbamoyl. A di-(lower alkyl)carbamoyl group preferably contains 1-4 carbon atoms in each lower alkyl portion and represents for example Ν,Ν-dimethylcarbamoyl, H-methyl-N-ethylcarbamoyl and advantageously K,N-diethylcarbamoyl.

Salts are preferably pharmaceutically acceptable salts, e.g. metal or ammonium salts of said compounds of formula I when S represents carboxy, more particularly alkali or alkaline earth metal salts, e.g., the sodium, potassium, magnesium or calcium salt; or advantageously easily crystallizing ammonium salts derived from ammonia or organic amines, such as mono-, di- or tri-lower (alkyl, cycloalkyl or hydroxyalkyD-amines, lower alkylenediamines or (hydroxy-lower alkyl or aryl-lower alkyl)-lower-alkylamoonium bases, e.g., methylamine, diethylamine, triethylamine, dicyclohexylamine, triethanolamine, ethylenediamine, tris-(hydroxyroeChyl)-aminomethaEe or benzyl-trims thyl ammonium hydroxide. Said compounds of formula 1 form acid addition salts, which are preferably such of therapeutically acceptable inorganic or organic acids, such as strong mineral acids, for example hydrohalic, e.g. hydrochloric or hydrobromic acid; sulfuric, phosphoric, nitric or perchloric acid; aliphatic or aromatic carboxylic or sulfonic acids, e.g. formic, acetic, propionic, succinic, glycollie, lactic, malic, tartaric, gluconic, citric, maleic, fumaric, hydroxymaleic, pyruvic, phenylacetic, benzoic, 4-aminobenzoic, anthranilic, 4-hydroxybenzoic, salicylic, 4-aminnsalicylic, pamoic, nicotinic; methanesulfonic, ethanesulfonic, * - 7 hydroxyethanesulfonic, benzenesulfonic, p-toluenesulfonic, naphthalenesulfonic, sulfanilic or cyclohexylsulfamic acid, or ascorbic acid.

The compounds of this invention exhibit valuable pharmacological properties, e.g. cardiovascular effects, by selectively inhibiting the release of thromboxane through selective inhibition of thromboxane synthetase in mammals. The compounds are thus useful for treating diseases responsive to thromboxane synthetase inhibition in mammals including man.

These effects are demonstrable in vitro assay tests or in vivo animal tests using advantageously mammals, e.g. guinea pigs, mice, rats, cats, dogs or monkeys. Said compounds can be administered to them enterally or parenterally, advantageously orally, or subcutaneously, intravenously or intraperitoneally, for example, within gelatin capsules, or in the form of starchy suspensions or aqueous solutions respectively. The applied dosage may range between about 0.01 and 100 mg/kg. day, preferably between about 0.05 and 50 mg/kg/day, advantageously between about 0.1 and 25 mg/kg/day.

The in vitro inhibition of the thromboxane synthetase enzyme can be demonstrated, analogous to the method of Sun, Biochem. Biophys. Res. Comm. 74, 1432 (1977); the testing procedure is as follows: ...

C-arachidomc acid is incubated with an enzyme mixture preparation consisting of solubilized and partially purified prostaglandin cyclo-oxygenase from sheep seminal vesicles and a crude microsomal preparation of thromboxane synthetase from lysed hynan platelets. The test compound (dissolved in buffer, or if necessary, in a small amount of ethanol) is added to the incubation medium. At the end of tbe incubation period (30 minutes) Prcetaglandin E^ (PGE,) 53336 - 8 is reduced to a mixture of Prostaglandin P^o and Ρ^β (PGF^Ca * ¢)) by addition of sodium borohydride. The radioactive products and excess substrate are extracted into ethyl acetate and the extract is evaporated to dryness. The residue is dissolved in acetone, spatted on thin-layer plates and chromatographed in the solvent system toluene: acetone: glacial acetic acid (100 volumes: 100 volumes: volumes). The radioactive zones are located; those corresponding to Thromboxane (TxB^) and PGP^ a + β are transferred to liquid scintillation vials and counted. The ratio of counts for TxB2/PGF2 a + β is calculated for each concentration of test compound and values are determined graphically as the concentration of test compound at which the ratio of TxBj/PGPj a + β is reduced to 50 X of the cor.trol value.

The in-vitro effect on prostaglandin cyclooxygenase is measured by a modification of the method of Tekeguchi et al described in Biochemistry 10, 2372 (1971); the testing procedure is as follows: Lyophilized sheep seminal vesicle microsomes are utilized as the prostaglandin-synthesizing enzyme preparation. The conversion of 14 C-arachidoaic acid to PGE^ is measured. Test compounds (dissolved 20 in buffer, or if necessary, in small amount of ethanol) are added to the incubation mixture. The prostaglandins are extracted and separated by thin-layer chromatography; the plates are scanned, the radioactive zones corresponding to PGEj are transferred to liquid scintillation vials and counted for radioactivity. values for inhibition are determined graphically as the concentration of test compound causing a 50 2 reduction in the amount of PGE2 synthesized.

The in-vitro effect on prostacyclin (PGI^) synthetase is measured analogous to the method of Sun et al. ,Frostaglandins 14, 1055 (1977).

The testing procedure is as follows: - 9 B3306 ....

C-Arachidonic acid is incubated with an enzyme mixture consisting of solubilized and partially purified prostaglandin cyclo-oxygenase from sheep seminal vesicles and crude PGI^ synthetase in the form of a microsomal fraction of bovine aorta.

Test compound (dissolved in buffer, or if necessary, in a small amount of ethanol) is placed in the incubation medium.

The reaction mixture is incubated in 100 nil Tris HCl (pH 7.5) for 30 minutes at 37, acidified to pH 3 and extracted into ethyl acetate. The extract is evaporated to dryness, the residue is dissolved in acetone, spotted on thin-layer plates and chromatographed in a solvent system described by Sun et al. The radioactive zones are located with a scanner; those corresponding to 6-keto-PGF^o ( a stable end product of prostacyclin biotrasformation) and PGE^ are transferred to liquid scintillation vials and counted. The ratio of counts for 6-keto-PGF^a/PGE2 is calculated for each concentration of test compound used. values for inhibition are determined graphically as the concentration of test compound at which Che ratio of 6-keco-PGF^a/PGE2 is reduced to 50 Z of the control value.

The reduction of plasma levels of thromboxane is determined in vivo on administration of the test compound to guinea pigs in the following manner; Guinea pigs are dosed with vehicle or test drug and injected intraperitoneally with arachidonic acid (40 mg/kg) 2 hours later.

Blood is collected for analysis 1 hour after the arachidonic acid challenge. A single aliquot of each plasma sample is assayed for thromboxane and another aliquot for 6-keto-PGF^a, the stable metabolites of thromboxane A2 and prostacyclin (PGI^) respectively. - 10 53386 The compounds cf the formula I are very potent thromboxane synthetase inhibitors. At effective dose levels and greater, the beneficial prostacyclin synthetase enzyme system is not inhibited, nor is the prostaglandin cyclooxygenese enzyme system.

The IC for a compound of the invention, e.g. 5-(5~carboxypentyl). . 30 9 imidazo[l,5-£jpyridine, is about 3X10 M for thromboxane synthetase inhibition whereas che IC.Q for both inhibition of prostacyclin synthetase and cyclooxygenase is greater than 1X10 M.

A compound of the invention, e.g. 5-(5-carhoxypentyl)-imidazo[l,5-a]10 pyridine, also reduces the plasma levels of thromboxane B^ by over Σ in the guinea pig at an oral dose as low as 0.25 mg/kg; no significant decrease with respect to prostacyclin is observed at the said oral dose or at higher doses.

The aforementioned advantageous properties render the compounds of 15 this invention of great value as specific therapeutic agents for mammals including man. For example, in thromboembolism specific inhibition of the enzyme thromboxane synthetase reduces arachidonic acid induced platelet aggregation involved in clot formation. Experimentally, prolongation of bleeding time in the rat is indicative of a beneficial antithrombotic effect. The imidazo[1,5-a]pyridines of this invention prolong bleeding time, e.g. 5-(5-carboxypeatyl)-imidazo[l,5-a]pyridine prolongs bleeding time when administered to rats at a dose of about 1 mg/kg i.p. or lover.

Indicative or the beneficial effect in respiratory disorders is the fact, that the compounds of this invention afford protection against sudden death due eo arachidonic acid induced pulmonary obstruction. Thus, for example, 5-(5-carboxypentyl)-iaidazo[l,5-alpyridiae protects against sudden death when administered orally to mice at a dose of ICO mg/kg. - 11 The compounds ol this invention are prepared according to conventional methods, advantageously by 1) condensing a compound of the formula VI wherein M is an alkali metal; R^ and R^ represent hydrogen or lower alkyl, with a reactive functional derivative of a compound of Che formula VII BO - A - Β' (VII) wherein A has the meaning given above, B' represents carboxy, trialkoxymethyl, unsubstituted, mono- or di-(lower alkyl) substituted carbamoyl, cyano, etherified hydroxymethyl or halomethyl, to yield a compound of formula la converting any resulting compound wherein B* differs from B, into a 15 compound of formula I; and, if desired, converting any resulting compound of formula .1 into another compound of this invention.

Reactive organometallic compounds of formula VI wherein M is an alkali metal are obtained by metallization of the appropriate methyl substituted imidazo[l,5-a]pyridine, e.g. 5-methyliaidazo[l,5-a]20 pyridine, prepared as described in the Journal of Organic Chemistry 40, 1210 (1975), with a reactive metallizing agent, e.g. butyl - 12 lithium or lithium diisopropylamide in an inert solvent such as tetrahydrofuran st a temperature below room temperature, preferably at about -50*.

Condensation of the intermediate of fonaila VI uith reactive 5 functional derivatives of a compound of formula VII proceeds at a temperature range preferably from about -75* to + 50°. In the case where B' represents carboxy or mono(lower-alkyl)carbamoyl, the appropriate metal salt, e.g. the lithium salt, of the reactive functional derivative of the corresponding compound of formula VII is first prepared for the condensation with intermediate VI.

Another process for the preparation of compounds of formula I consists in 2) condensing a compound of formula VIII wherein M is an alkali metal, R^ and R^ represent hydrogen or lower alkyl, and R$ is lower alkyl, with a reactive functional derivative of a compound of the formula IX HOCHj-A-B’ (IX) wherein A has the meaning given above, B1 represents carboxy, trialkoxymethyl, unsubstituted, mono- or di-(lower alkyl) substituted carbamoyl, cyano, etherified hydroxymethyl or halomethyl; converting in any resulting compound wherein Bf differs from Β, B1 into a group B; desulfurizing the resulting compound; and if desired converting any resulting compound into another compound of this invention. 5333G - 13 Preparation of the organometallic intermediate VIII and subsequent condensations are carried out as described under process 1 supra and in Tetrahedron Lecters 21, 2195—6 (1980). Desulfurization is preferably performed with a desulfurization catalyst such as Raney nickel in a solvent such as ethanol, preferably at elevated temperature.

A further process for the manufacture of compounds of formula I consists in 3) condensing under basic catalysis a compound of the formula X wherein R and R, represents hydrogen or lower alkyl and R, Z b represents lower alkoxycarb'onyl or cyano; with a reactive functional derivative of a compound of the formula VII HO-A-B' (VII) wherein A has the meaning given above, B' represents carboxy, trialkoxyoethyl, unsubstituted, mono- or di-(lower alkyl) substituted carbamoyl, cyano, etherified hydroxymethyl or halomethyl; splitting off Rfi, converting any resulting compound wherein B* differs from B into a compound of formula I; and, if desired, converting any resulting compound of formula I into another compound of the invention.

Ihe intermediates of formula X are prepared from the compound of formula VI supra on treatment with e.g. carbon dioxide and esterifying the resulting carboxylic acid, or with a di-(lower)alkyl carbonate or with a cyanogen halide. - 14 Another process for the preparation of compounds of formula I consists in 4) cycliting a compound of formula XI wherein each of the symbols R^, R' , and R" represents hydrogen or lower alkyl; A has meaning given above; and B represents carboxy, lower alkoxycarbonyl, unsubstituted, mono- or di-(lower alkyl) substituted carbamoyl, cyano, hydroxymethyl, lower alkanovloxymethyl, etherified hydroxymethyl or halomethyl; to yield a compound of formula lb converting any resulting compound wherein B differs from B into a compound of formula I; and if desired converting any resulting compound of formula I into another compound of the invention.

The cyclization of the amide of formula XI is advantageously carried out with a Lewis acid, such as polyphosphoric acid, phosphorous oxychloride or polyphosphate ester, optionally in an inert solvent such as toluene, at a tenperature range of 25' to 150°, preferably 50' to 120’.

The amides of formula XI are prepared by acylating a compound of formula XII 53306 (XII) wherein R^, R^, A and B have meaning given above, with a carboxylic acid of the formula XXII R'^COOH (XIII) wherein R(J has meaning given above, or with a reactive functional derivative thereof.

Reactive functional derivatives of compounds XIII are preferably acid halides, simple or mixed anhydrides, such as the acid chloride, the acid anhydride (R^'CO^O, or a mixed anhydride derived from a lower alkoxvcarbonyl halide, such as ethyl chloroformate, or from a hindered lower alkanoyl halide, e.g., from pivaloyl chloride, by methods well-known to the art.

Said condensation of compounds XII and XIII (the acylation of XII) occurs either spontaneously by e.g. heeting vith formic acid, or in the presence of condensing agents, e.g. disubstituted carbodiimidef, such as dicyclohexylcarbodiimide.

The acylation of compounds of formula XII with a reactive functional derivative of XIII, e.g. acetyl chloride or acetic anhydride, occurs advantageously in the presence of an organic or inorganic base, e.g., potassium carbonate, or triethylamine.

The amines of formula XII may be obtained, e.g. from the correspondingly substituted 2-(cyano or lower hydroxyiminoalkyl) pyridines by reduction, e.g. by hydrogenation in the presence of a catalyst such as palladium on charcoal or by treatment with a chemical reducing agent such as borane or sodium cvanoborohydride, the reducing agent being chosen according to the type of other functional groups present in the molecule. The compounds of formula XII may also be obtained by amination of the correspondingly substituted and reactively esterified 2-(hydroxymethyl)-pyridines.

A further process for the preparation of compounds of formula I where A represents alkylene consists in ) hydrogenating a compound of formula XIV R, '2 (XIV) wherein A' represents alkylene, alkenylene or alkynylene having up to 11 carbon atoms, and, if desired, converting any resulting compound of formula I into another compound of the invention.

The reaction is carried out according to methods known per se, e.g. preferably with hydrogen in the presence of a catalyst, preferably palladium.

The starting materials of formula XIV may be prepared by e.g. condensing a compound of formula XV R.

(XV) ’2 - 17 (obtained e.g. by reacting a compound of formula VIII with dimethylformamide followed by desulfurization with Raney nickel) in a Wittig reaction, for example, with a tri(lower)alkyl 4-phosphonocrotonate in the presence of a strong base, e.g. sodium hydride.

A further process for the preparation of compounds of formula 1, advantageously said compounds wherein A represents alkylene, comprises 6) in a compound of formula XVI R.

(XVI) zz as previously defined and C is a group convertible into a carboxy group, converting said group C into carboxy, optionally by extending . the chain A within its definition, and, if desired, converting any resulting compound of formula I into another compound of the invention.

Groups convertible into a carboxy group are, for example, esterified carboxy groups, carboxy groups in form of their anhydrides, including corresponding groups of asymmetrical and inner anhydrides, amidated carboxy groups, cyano, amidino groups, including cyclic amidino groups such as 5-tetrazolyl, iminoether groups, including cyclic iminoether groups, e.g. 2-oxazolinyl or dihydro-2-oxazolinyl groups, substituted by lower alkyl, and also hydroxymethyl, etherified hydroxymethyl, lower alkanoyloxymethyl, trialkoxymethyl, acetyl, trihaloacetyl, halomethyl, carboxycarbonyl (COCOOH), methyl, formyl (CHO), di(lover)alkoxymethyl, alkylenedioxymetbyl, vinyl, or diazoacetyl. Simultaneously with conversion of C into the carboxy group, the chain A can be extended within its definition. 53395 - 18 The conversion into the carboxy group is accoaplished by methods which are known per se, and as described herein and in the Examples, e.g. by solvolysis such as hydrolysis or aeidolysis, or by reduction (esterified carboxy groups). For example trichloroethyl or 2-iodoechyl ester may be converted into the carboxylic acid by reduction, e.g. with zinc and a carboxylic acid in the presence of water. Benzyl esters or nitrobenzyl esters may be converted into the carboxy group by catalytic hydrogenation, the latter also with chemical reducing agents, e.g. sodium dithionite or with zinc and a carboxylic acid. In addition, cert—butyl ester may also be cleaved with trifluoroacetic acid.

In the reduction of the group C, an alkenylene or alkynylene chain A may be converted into the corresponding alkylene chain.

Furthermore compounds of formula XVI wherein C represents acetyl may be oxidatively cleaved to the corresponding compounds of formula I wherein B represents carboxy by conversion first to a compound of formula XVI wherein C represents trihaloacetyl, e.g. tribroao or triiodoacetyl, by treatment e.g. with sodium hypobromite followed by cleavage vith e.g. an aqueous base, such as sodium hydroxide.

The starting material of formula XVI wherein C represents acetyl is in turn prepared from a compound of formula 1(b) wherein B* represents halosethyl by treatment with an alkyl ester of acetocetic acid, e.g. ethyl acetoacetate, in the presence of a base, e.g. sodium hydride, followed by hydrolysis with a strong base, e.g. aqueous sodium hydroxide. 33396 - 19 Compounds of formula XVI wherein C represents carboxycarbonyl (COCOOH) are converted thermally or by oxidation to compounds of formula I wherein B represents carboxy by heating at elevated temperature e.g. at about 200°, in the presence of glass powder, or by treating e.g. with hydrogen peroxide in the presence of a basic agent, e.g. sodium hydroxide.

The starting materials of formula XVI wherein C represents COCOOH are prepared by e.g. condensation of a compound of formula la wherein B' represents halomethyl with e.g. 2-ethoxyearboayl-l,ΒΙΟ dithiane, and subsequent oxidative hydrolysis, e.g. with N-bromosuccinimide in aqueous acetone followed by treatment with dilute aqueous sodium hydroxide.

Compounds of formula XVI wherein C represents formyl, di(lower) alkoxymethyl or alkylenedioxymethyl (formyl protected in the form of an acetal), e.g. the dimethyl acetal, are oxidized with e.g. silver nitrate or ozone to the corresponding compound of formula I wherein B represents carboxy.

The starting carboxaldehydes, the compounds of formula XVI wherein C represents methyl or formyl, may be prepared by oxidizing compounds of formula I or Ia wherein B or B* represents respectively hydroxymethyl or halomethyl with e.g. dimethylsulfoxide and a catalyst, such as a mixture of triethylamine and silver - 20 tetrafluoroborace. Said carboxaldehvdes are converted to the corresponding acetals, the compounds of formula XVI wherein C represents di(lower) alkoxymethyl, or alkylenedioxymethyl e.g. a dimethylacecal, by acid-catalyzed condensation with an alcohol, e.g. methanol.

Compounds of formula I wherein B represents carboxy may be converted by the well-known Axndt-Eistert synthesis to compounds of formula I wherein B represents carboxy and the chain has been extended by 1 carbon atom. More particularly, a reactive functional derivative of the starting carboxylic acid, e.g. the acid chloride, is treated with diazomethane in e.g. diethyl ether to yield a compound of formula XVI wherein C represents diazoacetyl. Rearrangement with e.g. silver oxide yields said carboxylic acid of formula I wherein the chain A has been extended by 1 carbon atom.

Compounds of formula XVI wherein C represents vinyl may be converted to compounds of formula I wherein B represents carboxy by first ozonolysis to compounds of formula XVI wherein C represents formyl, which axe in turn oxidized to compounds of formula I wherein B represents carboxy.

Compounds of formula XVI wherein C represents vinyl may also be treated with nickel carbonyl and carbon monoxide under high pressure conditions to give compounds of formula I wherein B represents carboxy and the chain length of A has been extended by 1 carbon atom.

Certain terms used in Che foregoing processes have the meanings as defined below.

Reactive functional derivative of alcohols of formula VII and IX are e.g. such esterified by a strong inorganic or organic sulfonic 53336 - 21 acid above all a hydrohalic acid, e.g. hydrochloric, hydrobromic or hydriodic acid, an aliphatic or aromatic sulfonic acid, e.g. methanesulfonic acid or p-toluenesulfonic acid, and are prepared by methods known in the art.

Ttialkoxymethyl represents preferably tri(lower alkoxy)-methyl, particularly triethoxy- or trimethoxymethyl.

Etherified hydroxymethyl represents preferably tertiary lower alkoxymethyl, lower alkoxyalkoxymethyl such as aethoxymethoxymethyl, 2-oxaor 2-thiacycloalkoxymethyl, particularly 2-tetrahydropyranyloxymethyl.

Halomethyl represents especially chloromethyl but may also be bromomethyl or iodomethyl.

Louer alkanoyloxymethyl represents preferably acetoxymethyl.

As alkali metal represents preferably lithium but may also be potassium or sodium.

The indispensable steps of converting in a resulting compound of aforesaid processes, in which compound B' or B differs from B, into a compound of formula I, and the optional conversion of che resulting product of formula I into another compound of this invention are performed by chemical methodology known in the art.

Hydrolysis of intermediates wherein S’ represents trialkoxymetbyl to compounds of formula I wherein B is carboxy is advantageously carried out with inorganic acids such as hydrohalic or sulfuric acid. Hydrolysis of intermediates wherein B’ represents etherified hydroxymethyl to compounds of formula I wherein B represents hydroxymethyl is preferably carried out with aqueous solutions of 53336 - 22 inorganic acids such as ahydrohalic acid.

Intermediates of formula Ia or lb wherein B' or B is halomethyl may be reacted preferably with a metal cyanide such as potassium cyanide in a conventional manner to yield the compounds of formula I wherein the chain is extended by 1 carbon atom and B is cyano. These in turn are converted to compounds of formula I wherein B is carboxy, alkoxycarbonyl or carbamoyl using methods known in the art.

Thus, the compounds of formula I wherein B represents cyano (nitriles) are convertedto compounds of formula I wherein B is IO carboxy by hydrolysis with inorganic acids e.g. a hydrohalic acid such as hydrochloric acid or sulfuric acid in aqueous solution, or advantageously by hydrolysis with aqeous alkali metal hydroxide e.g. potassium hydroxide, preferably at reflux temperature.

The conversion of said nitriles to compounds of formula I wherein B represents lower alkoxycarbonyl is advantageously carried out by treatment first with a lower alkanol, e.g. anhydrous ethanol, in the presence of a strong acid, e.g. hydrochloric acid preferably at reflux temperature, followed by careful hydrolysis with water.

Furthermore the conversion of the said nitriles to compounds of formula I wherein B represents carbamoyl is preferably carried out by treatment with an alkali metal hydroxide ε·8· dilute sodium hydroxide, and hydrogen peroxide, preferably at room temperature.

Furthermore, the intermediates of formula la or lb wherein B' or B is halomethyl, such as chloromethyl, are converted to compounds of formula I, wherein E is carboxy and the chain length is extended by two carbons, by first treating with e.g. a di-(lower)alkyl malonate, such as dietbyl malonate, in the presence of a base such as potassium carbonate or sodium ethoxide, in a solvent such as - 23 dimethylformamide, preferably at a temperature range from 50 to 100*. The resulting substituted di(lower)alkyl malonate is hydrolyzed, advantageously with aqueous base, such as dilute sodium hydroxide, to the corresponding malonic acid which is decarboxylated under standard conditions, e.g. by heating in xylene solution, to give a compound of formula I wherein B is carboxy. Substitution of the di-(lower)alkyl malonate vith a lower alkyl cyanoacetate yields the corresponding compounds of formula I wherein B is cyano.

Compounds of formula Ia or Ib wherein B' or B represents halomethyl may be converted to a corresponding organometallic intermediate, e.g. a cuprous cr magnesium derivative, under conditions well known in the art.

Condensation of e.g. the resulting organo magnesium (Grignard) reagent, e.g. a compound of formula Ia wherein B’ representing halomethyl is transformed to e.g. CH^MgCl, vith carbon dioxide yields the compound of formula I wherein B represents carboxy and the chain has been extended by 1 carbon atom.

Condensation of said Grignard reagent vith e.g. a lover alkyl haloacetate or e.g. ethyl bromoacetate, yields a compound of formula I wherein B represents lower alkoxycarbonyl and wherein the chain has been extended by 2 carbon atoms.

Said Grignard reagent may be condensed in the presence of a cuprous halide, e.g. cuprous chloride, vith an β,β-unsaturated acid or ester, e.g. propiolic or acrylic acid, co yield a compound of formula I wherein B represents carboxy or lover alkoxycarbonyl and wherein the chain has been extended by 3 carbon atoms. - 24 Furthermore, compounds of formula Ia or lb wherein B' anc B represent halomethyl may be condensed with e.g. the 3-lithio derivative of propiolic acid (prepared in situ from propiolic acid with e.g. lithium diisopropylamide) to yield a compound of formula I wherein A represents a terminal alkynylene, B represents carboxy and the chain length has been extended by 3 carbon atoms.

Compounds of the invention, wherein A represents straight chain or branched alkenylene with a terminal double bond, may also be prepared from intermediates of formula Ia or lb wherein B1 or Bis halomethyl. lor instance, said intermediates are first treated with e.g. a lower alkyl ester of an cc-(aryl- or alkyl)-thioacetic acid such as ethyl a-(phenylthic)-acetate, in the presence of a strong base such as sodium hydride. Subsequent oxidation of the resulting σ-arylthio or o-alkylthio substituted ester to the α-arylsulfinyl or o-alkylsulfinyl ester with e.g. sodium periodate, followed by heat-induced elimination, by e.g. refluxing in xylene, yields a compound of general formula I (an α,β-unsaturated ester) wherein A represents alkenylene and B represents e.g. lower alkoxycarbonyl, and the chain length has been extended by two carbon atoms. Similarly, the compounds of formula la wherein B’ represents halomethyl may first be converted to the corresponding carboxaldehydes with e.g. dimethylsulfoxide in the presence of triethylamine and silver tetrafluoroborate. Subsequent Hittig condensation e.g. with ethyl (triphenylphosphoranylidene)-acetate also yields the above-cited a,ρ-unsaturated esters.

Compounds of formula 1 wherein B is lower alkoxycarbonyl may be amidized with asznonia, mono- or di-(lower)alkylamines e.g. methylamine, dimathylamine in an inert solvent, e.g. a lover alkanol, such as butanol, optionally at elevated temperatures, to yield compounds of formula I wherein B represents unsubstituted, mono- or di-(lower) alkyicarbamoyl. - 25 The compounds of formula 1 wherein B represents unsubstituted carbamoyl may be dehydrated to the corresponding nitrile by treatment with e.g. triphenylphosphine or Chionyl chloride in an inert solvent such as toluene.

Conversion of compounds of formula 1 wherein B is lower alkoxycarbonvl, cyano; unsubstituted, mono- or di-(louer alkyl lcarbamoyl to compounds of formula 1 wherein B represents carboxy is advantageously carried out by hydrolysis with inorganic acids such as hydrohalic or sulfuric acid or with aqueous alkalies, preferably alkali metal hydroxides such as lithium or sodium hydroxide.

Compounds of formula I wherein B represents carboxy or lower alkoxycarbonyl may be reduced with simple or complex light metal hydrides such as lithium aluminium hydride, alane or diborane tc compounds of formula I wherein B is hydroxymethyl. Said alcohols are also obtained by appropriate salvolysis of compounds of formula la or lb wherein B' or B is halomethyl by treatment with e.g. an alkali metal hydroxide such as lithium or sodium hydroxide.

Said alcohols may in turn be transformed to the compounds of formula I wherein B is carboxy with conventional oxidizing agents, advantageously wich pyridinum dichromate in dimethylformamide at room temperature.

Said alcohols may also be transformed to the compounds of formula I wherein B is carboxy and Che chain has been extended by 1 carbon atom, by treatment with nickel carbonyl and carbon monoxide under high pressure conditions.

Free carboxylic acids may be esterified with lower alkanols such as ethanol in the presence of a strong acid e.g. sulfuric acid - 26 advantageously at elevated temperature or with diazo (lower) alkanes, e.g. diazomethane in a solvent such as ethyl ether, advantageously at room temperature, to give the corresponding esters, namely compounds of formula I wherein B is lower alkoxycarbonyl.

Furthermore, the free carboxylic acids may be converted via treatment of a reactive intermediate thereof, e.g. an acyl halide such as the acid chloride, or a mixed anhydride, e.g. such derived from a lower alkyl halocarbonate such as ethyl chloroformate, with ammonia, mono- or di-(lower) alkylamines, in an inert solvent such as methylene chloride, preferably in the presence of a basic catalyst such as pyridine, to compounds of formula I wherein B represents unsubstituted, mono or di-(lower)alkylcarbamoyl.

Compounds of formula X wherein B represents mono(lower) alkylcarbamoyl are converted to compounds of formula I wherein B is di-(lower)alkyl15 carbamoyl by treatment of the former with a strong base e.g. sodium hydride followed by an alkylating agent, e.g. a lower alkyl halide in an inert solvent, e.g. dimethylformamide.

Compounds of formula I are converted to the corresponding 5,6,7,8tetrahydroimidazo[l,5-a]pyridine compounds by reduction with hydrogen io Che presence of a hydrogenation catalyst, e.g. palladium, and an acid e.g. a mineral acid, for instance hydrochloric acid in an inert solvent, e.g. ethanol.

Furthermore compounds of formula I wherein A represents a straight chain or branched alkynylene or alkenylene may be converted by catalytic hydrogenation, advantageously under neutral conditions e.g. with palladium catalyst at atmospheric pressure in an inerc solvent, e.g. ethanol, to compounds of formula I wherein A represents straight chain or branched alkylene. - 27 Furthermore compounds of formula I wherein R^ and represent hydrogen can be converted to the corresponding halo derivatives by direct halogenation with chlorine, bromine or iodine.

The above-mentioned reactions are carried out according to standard methods, in the presence or absence of diluents, preferably such as are inert to the reagents and are solvents thereof, of catalysts, condensing or said other agents respectively and/or inert atmospheres, at low temperatures, room temperature or elevated temperatures, preferably at the boiling point of the solvents used, at atmospheric or superataospheric pressure.

The invention further includes any variant of the present processes, in which an intermediate product obtainable at any stage thereof is used as starting material and the remaining steps are carried out, or the process is discontinued at any stage thereof, or in which the starting materials are formed under the reaction conditions, or in which the reaction component; are used in the form of their salts or optically pure antipodes always provided that the end product of the process variant is a compound of formula I. Mainly those starting materials should be used in said reactions, that lead to the formation of those compounds indicated above as being especially useful.

The invention also relates to novel starting materials and processes for their manufacture.

Depending on the choice of starting materials and methods, the new compounds may be in the form of one of the possible isomers or mixtures thereof, for example, depending on the presence of a double bond and the number of asyametrical carbon atoms, as pure optical isomers, such as antipodes, or as mixtures of isomers, such as racemates, mixtures of diastereoisomers, mixtures of racemates or mixtures of geometrical isomers. 339 6 - 28 Resulting mixtures of diastereoisomers, mixtures of racemates and geometric isomers can be separated on the basis of the physicochemical differences of the constituents, in knows manner, into the pure isaoers, diastereoisomers, racemates, or geometric isomers for example by chromatography andZor fractional crystallisation.

Resulting racemates can furthermore be resolved into the optical antipodes by known methods, for example by recrystallisation from an optically active solvent, by means of microorganisms or by reacting an acidic end product with an optically active base that forms salts with the racemic acid, and separating the salts obtained in this manner, for example on the basis of their different solubilities, into the diastereoisomers, from which the antipodes can be liberated by che action of suitable agents. Basic racemic products can likewise be resolved into the antipodes, for example, hy separation of diastereomeric salts thereof, e.g. by the fractional crystallization of d- or 1-tartrates.

Advantageously, the more active of the two antipodes is isolated.

Finally, the confounds of the invention are either obtained in the free form, or as a salt thereof. Any resulting base can be converted into a corresponding acid addition salt, preferably with the use of a therapeutically useful acid or anion exchange preparation, or resulting salts can be converted into the corresponding free bases, for example, with the use of a stronger base, such as a metal or ammonium hydroxide or a basic salt, e.g. an alkali metal hydroxide or carbonate, or a cation exchange preparation. A compound of formula I wherein B represents carboxy can thus also be converted into che corresponding metal or anmonium salts. These or other salts, for example, che picrates, can also be used for purification of the bases obtained; the bases are converted into salts, the salts are 53336 - 29 separated and the bases are liberated from the salts. In view of the close relationship between the free compounds and the compounds in the form of their salts, whenever a compound is referred to in this context, a corresponding salt is also intended, provided such is possible or appropriate under the circumstances.

The compounds, including their salts, can also be obtained in tbe form of their hydrates, or include other solvents used for the crystallisation.

The pharmaceutical compositions according to the invention are those suitable for enteral, such as oral or rectal, and parenteral administration to mammals, including man, for the treatment or prevention of diseases responsive to inhibition of thromboxane synthetase, such as peripheral vascular diseases, comprising an effective amount of a pharmacologically active compound of formula I, or pharmaceutically acceptable salts thereof, alone or in combination with one or nore pharmaceutically acceptable carriers.

The pharmacologically active compounds of the invention are useful in the manufacture of pharmaceutical compositions comprising an effective amount thereof in conjunction or admixture with excipients or carriers suitable for either enteral or parenteral administration. Preferred are tablets and gelatin capsules comprising the active ingredient together with a) diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine, b) lubricants, e.g. silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol, for tablets also c) binders, e.g. magnesium alutinium silicate,starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, if desired, d) disintegrants, e.g. starches, agar, alginic acid or - 53396 - 30 its sodium salt, or effervescent mixtures and/or e) absorbents, colorants, flavors and sweeteners. Injectable compositions are preferably aqueous isotonic solutions or suspensions, and suppositories are advantageously fatty emulsions or suspensions. Said compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers.

In addition, they may also contain other therapeutically valuable substances. Said compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1 to 75 Z, preferably about 1 to 50Z, of the active ingredient. A unit dosage for a mammal of about 50 to 70 kg may contain between about 10 to 200 mg of the active ingredient.

The following Examples are intended to illustrate the invention and are net to be .construed as being limitations thereon. Temperatures are given in degrees Centigrade, and all parts wherever given are parts by weight. If not mentioned otherwise, all evaporations are performed under reduced pressure, preferably between about 15 and 100 naaHg. - 31 Example 1: To a solution of 50 g of 5-methylimidazo[l,5-a]pyridine [J. Org. Chen. 40, 1210 (1975)] in 625 ml of tetrahydrofuran precooled to -75' is added under nitrogen atmosphere 175 ml of 2.4 N n-butyllithium in hexane while maintaining tenperature below -53*.

The solution of 5-(lithiomethyl)-imidazo[l,5-a)pyridine, is cooled back to -75' and a solution of 121.8 g of 5-bromo-l,l,l-triethoxypentane in 125 ml of tetrahydrofuran is added rapidly at which time the tenperature rises to -60°. The reaction mixture is allowed to warm co -4' over a 45 minute period and evaporated practically to dryness. The residue is partitioned between 500 ml of ethyl ether and 240 ml of 3N hydrochloric acid. The ether solution is further extracted twice with 60 ml of 3N hydrochloric acid; the combined aqueous extract is basified with 100 ml of concentrated ammonia hydroxide and reextracted twice with 200 ml of ethyl ether. The ether extract is dried over magnesium sulfate and evaporated to dryness to give an oil which is distilled under high vacuum to give 5-(5-ethoxycarbonylpentyl)-imidazo[l,5-a]pyridine boiling at 180-185'/ 0.12 mm Bg.

Example 2: A suspension of 26 g of 5-(5-ethoxycarbonylpentyl)imidazo[l,5-a]pyridine in 100 ml of IN aqueous sodium hydroxide solution is heated on a steam bath for two hours; 10 ml of ethanol is added and heating is continued for 45 minutes. Tbe reaction mixture is cooled, washed wich 300 ml of ether and the solution is adjusted to pH 5.5 with concentrated hydrochloric acid. The crystallized product is collected by filtration and washed with 50 ml of water to yield 5-(5-carboxypentyl)-imidazo[l,S-a]pyridine melting at 144-147'.

Example 3: a) To a solution of 39.6 g of 5-bromovaleric acid in 400 ml of tetrahydrofuran cooled to -78' is added slowly 93 ml of 2.3N n-butyl lithium solution in hexane so as to maintain the temperature below 53336 - 32 -65°. The suspension is stirred for 20 minutes. Then a solution of 5-(lithiomet'nyl)-imidazo[l,5-a]pyridine, prepared from 26.9 g of 5methylimidazo[l,5-a]pyridine and 93 ml of 2.3N n-butyl lithium solution as described in Example 1, is added all ac once at -75". The reaction mixture is stirred at -75° for two hours, allowed to warm to room temperature, treated with 15 ml of 12S hydrochloric acid, and evaporated under vacuum.

The residue is partitioned between uacer and methylene chloride after pH is adjusted to 10 vith sodium carbonate. The aqueous solution is further washed with chloroform, acidified to pH 1 with 12N hydrochloric acid and again washed with ether and toluene. After pH is adjusted to 5.5 with sodium bicarbonate, extraction with chloroform gives crude 5-(5-carboxypentyl)-imxdazo-[l,5-a]pyridine. A solution of the acid in 30 ml of acetonitrile is treated with 20 ml of 5N ethanolic hydrochloric acid. After addition of 25 ml of ethyl ether, 5-(5-carboxypentyl)-imidazo[l,5-a]pyridine hydrochloride, melting at 201-204°, crystallizes. 5-(5-Carboxypentyl)-imidazo[l,5-a]pyridine (Example 2) is obtained on neutralization of a methanolic solution of the salt to pH 5 with dilute sodium hydroxide solution. b) Similarly prepared from 6-bromohexanoic acid is 5-(6-carboxyhexyl) imidazo[l,5-a]pyridine melting at 137-139°. c) 5-(7-carbcxyheptyl)-imidazoIl,5-a]pyridine melting at 97-101* is similarly prepared from 7-bramoheptannic acid.

Example 4; A solution of 37 g of 5-(5-chloropeatyl)-imidazo[l,5-a]25 pyridine, 21.7 g of potassium cyanide and 3 g of dibenzo-18-crown-6 in 500 ml of acetonitrile is heated under reflux for 20 hours. The acetonitrile is evaporated under reduced pressure, the residue is partitioned between water and methylene chloride, and the methylene - 33 chloride extract is evaporated to dryness. Treatment of a solution of the residue in ether with ethanolic hydrochloric acid yields 5-(5cyanopentyl)-ioidazo(l,5-a]pyridine hydrochloride melting at 178-180*.

The starting material is prepared as follows: A solution of 30 g of l-brcmo-4-chlorobutane in 20 ml of dry tetrahydrofuran is added to a solution of 5-(lithiomethyl)-imidazo(l,5-a]pyridine (prepared from 22 g of 5-methylimidazoIl,5-a]pyridine and 80 ml of 2.3K solution of.n-butyl lithium in hexane according to Example 1) while maintaining the temperature below -50*. The reaction mixture is stirred for 2 to 3 hours at -50*. allowed to warm to room temperature, stirred overnight, and evaporated to dryness.

The solution of the residue in 200 ml of methylene chloride is washed with water, dried over magnesium sulfate and evaporated to dryness to give the 5-(5-chloropentyl)-imidazo[l,5-a]pyridine which is used without further purification.

Example 5: 5-(4-chlorobutyl)-imidazo(l,5-a]pyridine is converted in a manner analogous to that described for Example 4, to 5-(4-cyanobutyl)imidazo[l,5-a)pyridine melting at 72-77*.

Example 6: By a procedure analogous to that described for Example 4, 3,5-dimethylimidazo[l,5-a]pyridine [J. Het. Chem. 3, 33 (1966)] is converted to 5-(5-chloropentyl)-3-methyl-imidazo[l,5-a]pyridine, melting ac 98-104*. Reaction with potassium cyanide, under the conditions of Example 4, yields the 5-(5-cyanopentyl)-3-raethylimidazo(1,5-aJ-pyridine which is converted into its hydrobromide salt by dissolving the free base in acetonitrile and acidification of the solution with ethanolic hydrogen bromide whereupon the 5-{5-cyanopentyl)-3-methyl-imidazo[l,5-a]pyridine hydrobromide crystallizes 53306 - 34 and has a melting point of 215-220°.

Example 7: A solution of 36 g of 5-(cyanopentyl)-imidazo[l,5-a] pyridine in 100 ml of methanol and 50 ml of 45 2 aqueous potassium hydroxide solution is heated under reflux for 48 hours. The methanol is removed by evaporation under reduced pressure, and water is added.

The basic solution is washed with ethyl acetate and acidified to pH 5.5-6 with concentrated hydrochlorid acid.

The crystallized acid is collected, and recrystallized from ethanol to yield the product of Example 2, namely the 5-(5-carboxypentyl)10 imidazo[l,5-a]pyridine melting at 142-145°, further recrystallization raises the melting point to 144-147°.

Example 8: Hydrolysis of 5-(4-cyanobutyl)-imidazo[l,5-a]pyridine as described for Example 7 yields 5-(4-carboxybutyl)-imidazo[l,5-a]pyridine melting at 161-163°.

Example 9: Hydrolysis as described for Example 7, of 5-(5-cyanopentyl)-3-methyl-imidazo[l,5-a]pyridine yields 5-(5-carboxypentyl)3-methyl-imidazo[l,5-a]pyridine melting at 170-173°.

Example 10: To a solution of 3g of 5-(5-cyanopentyl)-3-methyl-imidazo[l,5-a]pyridine hydrochloride in a mixture of 20 ml of ethanol and ml of IN aqueous sodium hydroxide solution is added 10 ml of 30 Σ hydrogen peroxide solution; 5 ml of ethanol and a sufficient volume of IN sodium hydroxide solution to reach pH 10 are then added.

After stirring at room temperature overnight, the ethanol is evaporated under reduced pressure, water is added and the mixture is extracted with methylene chloride. The resulting product is crystallized from ether and recrystallized from acetonitrile to yield - 35 5-(5-carbamovlpentyl)-imidazo[l,5-a]pyridine melting at 131-132*.

Example 11: A solution of 3.9 g of 5-(5-ethoxycarbonylpentyl)-imidazo[1,5-a]pyridine in 40 ml of n-butanol is saturated with methylamine and heated on a steam bath for 56 hours in a pressure bottle. The reaction mixture is evaporated to dryness; the resulting product is first crystallized from ether and then recrystallized from 1:1 ethyl acetate-ether to yield the 5-[5-(H-methylcarbamoyl)-pentyl]-imidazo[l,5-a]pyridine melting at 118-122*.

Example 12: A solution of 2.45 g of 5-[5-(H-methylcarbamoyl)-pentyl]icidazo]1,5-a]pyridine in 25 ml of dimethylformamide is treated with 0.011 mole of sodium hydride (obtained by washing 0.53 g of 50 Z sodium hydride dispersion in mineral oil with hexane) and warmed briefly on a steam bath. Methyl iodide (1.56 g) is added to the cooled yellow solution. The mixture is stirred at room temperature for 2 hours, diluted vith 100 ml of water and extracted first vith 150 ml of a 1:1 mixture of ethyl acetate and ether and subsequently with 100 ml of chloroform. The residue obtained on evaporation of the combined extracts to dryness is dissolved is 100 ml of ether and created with 20 ml of ethanolic hydrochloric acid. The precipitated salt is collected, recrystallized first from 50 ml of 1:1 acetonitrile/ethyl acetate and then from 30 ml of 1:1 ethanol/ether to yield 5-[5-(N,N-dimethylcarbamoyl)-pentyl]-imidazo[l,5-a]pyridine hydrochloride melting at 166-171*.

Example 13: 5-(5-Carboxypentyl)-imidazo[l,5-a]pyridine (1,0 g) is suspended in 5 ml of tetrahydrofuran. While stirring at room temperature, 2.35 g of trimethyl borate is added, followed by the slow addition of 1.0 ml (equivalent to 0.01 mole) of boranemethyl sulfide complex. The reaction mixture is heated at reflux temperature for 2 hours, cooled and quenched by the addition of 2.6 ml of methanol, 5339θ - 36 9.5 ml of water and 2 ml of 50 2 sodium hydroxide solution. After heating under reflux for 1 hour, the mixture is diluted uith 50 ml of water and extracted twice with 75 ml aliquots of methylene chloride. The methylene chloride extract is evaporated to dryness.

The residue is treated uith 4 ml of 5N ethanolic hydrochloric acid in 30 ml of ether to yield the 5-(6-hydroxyhexyl)-imidazo[i,5-a]pyridine hydrochloride melting at 174-179.

Example 14: A solution of 11.1 g of l-tetrahydropyranyloxy-8-bromooctane in 15 ml of tetrahydrofuran is added at -70 to a solution of -(lithiomethyl)-imidazo[l,5-a]pyridine (prepared from 5 g of 5methylimidazo[l,5-a]pyridine and 17.7 ml of 2.3N n-butyl lithium in hexane according to Example 1). The mixture was stirred at -70* for 1 hour and then stirred overnight without additional cooling. A solution of the residue (after evaporation to dryness) in 50 ml of 4N hydrochlorid acid is washed with 2 x 100 ml aliquots of ether, basified with 75 ml of aqueous sodium hydroxide solution and extracted twice with 100 ml aliquots of methylene chloride. The methylene chloride extract is evaporated to dryness. Conversion to the hydrochloride salt with etheral hydrogen chloride aad recrystallization from ethanol/ether yields 5-(9-hydroxynonyl)-iaidazo[l,5-a]pycidine hydrochloride melting at 150-153.

Example 15: a) A solution of 2.7 g of 5-(6-carboxyhexyl)-ixidazo[l, 5-a]-pyridine in a mixture of 120 ml of ethanol and 30 ml of concentrated hydro25 chloric acid is hydrogenated at 3 atmospheres in the presence of 1 g of -10 X palladium on charcoal catalyst until 2 moles of hydrogen are consumed. The mixture is filtered free of catalyst and evaporated to dryness. The residue is recrystallized from isopropanol-ether to yield the 5-( 6-carboxyhexyl) -5,6,7,8-tetrahydroimidazo! 1,5-a]pyridine hydrochloride melting at 150-154. - 37 b) Sinilar hydrogenation of 5-(5-carboxypentyl)-imidazo[l,5-a]pyridine yields 5-(5-carboxypencyl)-5,6,7,8-tetrahydroimidazo[l,5-a]pyridine hydrochloride melting at 146-150*. c) Similar hydrogenation of 5-(4-carboxybutyl)-imidazo[l,5-a]pyridine yieIds 5-(4-carboxybuty1)-5,6,7,S-tetrahydroimidazo[1,5-a Jpyridine hydrochloride melting at 120-123°.

Example 16: A solution of 2.3 g (0.011 mole) of 5-bromo-3,3-dimethylpentanoic acid [J. Org. Chem. 44, 1258 (1979)] in 20 ml of dry tetrahydrofuran is cooled to -70° under nitrogen, 5.05 ml of 2.4N n-butyllithium in hexane is added dropwise. After addition is complete the solution of 5-(lithiomethyl)-imidazo[l,5-a]pyridine in hexane (prepared from 1.32 g of 5-methylimidazo-[l,5-a]pyridine and 5.05 ml of 2.4N n-butyllithium in hexane) is added all at once. The mixture is stirred at room temperature overnight.

The reaction mixture is diluted with 50 ml of water, 10 g of sodium carbonate is added and the basic solution is then extracted 3 times with 75 ml aliquots of chloroform. The aqueous phase is washed 3 times with 100 ml of ether after acidification to pH 2 with 12N hydrochloric acid. Finally the aqueous phase is adjusted to pH 5 with dilute sodium hydroxide solution and extracted with 200 ml of 1:1 ethyl acetate/ether. The extracts are dried and evaporated to give a yellow oil. Material is crystallized from 50 ml of 1:1 ethanol/ ether to give 5-(5-carboxy-4,4-dimethylpentyl)-imidazo(l,5-a]pyridine, melting at 124-129*.

Example 17: Iodine crystals (1.9 g) are added to a well-stirred solution of 1.16 g of 5-(5-carboxypentyl)-imidazo[l,5-a]pyridine and 1.68 g of sodium bicarbonate in 10 ml of water and 1 ml of ethanol.

Additional 4 ml of ethanol are added to dissolve the bulk of the 53386 - 38 iodine and stirring is continued for 45 minutes. The reaction mixture is diluted with 125 ml of water and extracted twice with methylene chloride at pH 8 (NaHCOj added if necessary). The aqueous phase is concentrated in vacuo, charcoaled and adjusted to pH 4.5 with 2H hydrochloric acid. The precipitate is collected, dried and recrystailized from methanolZether to give l-iodo-5-(5-carboxy— pentyl)-imicazo[l,5-a]pyridine melting at 163-165°.

Example 18·. Preparation of 10,000 tablets each containing 10 ml of the active ingredient of Example 2: Formula: -(5-carboxypentyl)-imidazo[l,5-a]pyridine 100.00 g Lactose 1,157.00 g Corn starch 75.00 g Polyethylene glycol 6,000 75.00 g Talcum powder 75.00 g Magnesium stearate 18.00 g Purified water q.s.

Procedure: All the powders are passed through a screen with openings of 0.6 nsn.

Then the drug substance, lactose, talcum, magnesium stearate and half of the starch are mixed in a suitable mixer. The other half of the starch is suspended in 40 ml of water and the suspension added to the boiling solution of the polyethylene glycol in 150 ml of water. The paste formed is added to the powders which are granulated, if necessary, wich an additional amount of water. The granulate is dried overnight at 35°, broken on a screen with 1.2 am openings and compressed into tablets using concave punches with 6.4 am diameter, uppers bisected. - 39 Example 19: Preparation of 10,000 capsules each containing 25 og of the active ingredient of Example 3b: Formula: -(6-carboxyhexy1)-imidazo[1,5-a)pyr id ine Lactose Talcum powder 250.00 g 1.800.00 g 100.00 g Procedure: All the powders are passed through a screen with openings of 0.6 cm. Then the drug substance is placed in a suitable mixer and mixed first vith the talcum, then vith the lactose until homogenous. No. 3 capsules are filled vith 215 mg, using a capsule filling machine.

Example 20: A solution of 5-methylimidazo[l,5-a]pyridine (4.0 g) and tetramethylethylene diamine (4.9 g) in 100 ml of tetrahydrofuran is cooled to 0° under nitrogen and 26.5 ml of 1.6H n-butyllithium in hexane is added dropwise maintaining the temperature below 2*. After 30 minutes this solution is transferred under nitrogen over 45 minutes to an ice-cold solution of 5-bromovaleronitrile (4.86 g) in 80 ml of tetrahydrofuran. After 15 minutes the solvent is evaporated and the residue is partitioned between water and ethyl acetate. The organic phase is reextracted with 2S hydrochloric acid (3x15 ml). Basification of the aqueous phase to pH»10 with 50 Z sodium hydroxide, extraction with ethyl acetate (2x75 ml), drying over magnesium sulfate, evaporation and chromatography (SiO^, ethyl acetate) yields 5-(5-cyanopentyl)-imidazo[l,5-a]pyridine.

Example 21: To a solution of 4 g of 5-(4-ethoxycarbonylbutyl)-3ethylthio-imidazo[l,5-a]pyridine in 100 ml of ethanol is added approximately 5 g of Raney nickel. The solution is heated under reflux for 18 hours. The Raney nickel is renoved by filtration and the filter 52306 - 40 cake washed with 100 ml of ethyl acetate. The filtrate is evaporated to dryness under reduced pressure to yield the product as a heavy oil. This material is purified by column chromatography on silica gel using an ether-hexane mixture (1:3) as eluent. Evaporation of the solvent under reduced pressure yields 5-(4-ethoxycarbonylbutyl)imidazo[l,5-a]pyridine as a yellow oil; NMR (CDCl^) 1.25 (t, 3H), 4.15 (q, 2R), 8.1 (s, IH).

The starting material is prepared as follows: F 17.8 g of 3-ethylthio-imidato[I,5-a]pyridine is dissolved in 200 ml of tetrahydrofuran (dried) and cooled to -70°. 80 ml of 1.6M n-butyl lithium in hexane is added dropwise to the stirred solution over a period of 15 minutes . On completion of the addition, the reaction mixture is allowed to stir at -70’ for a further 30 minutes. To the reaction mixture is added dropwise a solution of 20 g of ethyl 4-bromo15 pentanoate in 75 ml of tetrahydrofuxan. The reaction mixture is allowed to warm up to -10’ where it is maintained for 30 minutes and subsequently is allowed to stand for 1 hour at room temperature. To the reaction mixture is added 400 al of diethyl ether and 400 ml of 4N hydrochloric acid. The aqueous layer is separated and the ethereal 2o layer is washed with water. The combined aqueous extracts are rendered basic with ammonium hydroxide and extracted with 3x200 ml of ether. The ethereal extract is dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure to yield the crude product as a heavy oil. This material is purified by column chromato25 graphy on silica gel using a 4:1 mixture of pentane-diethyl ether as eluent. On evaporation of the solvent the product was distilled to give 3-ethylthio-5-(5-ethoxycarbonylbutyl)-imidaxo[l,5-a]pyridine, boiling at 170°/0.3 mo Hg; NMR (CDCl.) 1.25(t,3E), 1.30 (t,3H), 3.15 (q,2H), 4.15 (q,2H). - 41 Exapple 22: A solution of 3 g of 5-[5-ethoxycarbonyl-5-(phenyl-sulfinyl)-pencyl]-imidazo[l,5-a]pyridine in 50 ol xylene is heated at reflux temperature for 30 minutes under an atmosphere of nitrogen.

The xylene is then removed by distillation under reduced pressure, the residue is dissolved in 15 ml of diethyl ether and purified by column chromatography on silica gel. The product is eluted using a 2:1 mixture of diethyl ether and ethyl acetate as eluent. Evaporation of the solvent yields 5-(5-ethoxycarbcnylpent-4-enyl)-imidazo[l,5-a]pyridine as an oil; NMR (CDCip 1.29 (t,3H), 4.25 (q,2H), 5.88 (d,lH).

The starting material is prepared as follows: To an ice-cooled, magnetically stirred slurry of 0.96 g of sodium hydride in 50 ml dimethylformamide is added 3.92 g of ethyl 2-(phenylthio)acetate in a dropwise manner over a period of 15 minutes. The suspension is stirred at room temperature for 2 hours and then cooled to 5* by. means cf an ice-bath. To this suspension is added 4.16 g of 5-(4-chlorobutyl)-imidazo[l,5-a]pyridine in a dropwise manner over a period of 1 hour. On completion of the addition, 3.2 g of sodium iodide is added to the reaction mixture which is then allowed to stir overnight at room temperature.

The reaction mixture is poured into 150 ml of ice water and extracted with 3x100 ml aliquots of a 1:1 mixture of diethyl ether and ethyl acetate. The organic phase is washed vith 2x100 ml of saturated aqueous sodium chloride solution and then extracted vith 3x50 ml portions of IN hydrochloric acid. The acidic aqueous extracts are combined, basified with ammonium hydroxide and extracted vith 3x150 ml portions of a 1:1 mixture of diethyl ether and ethyl acetate. These organic extracts are dried over anhydrous magnesium sulfate, filtered and the solvent concentrated under reduced pressure to yield the product as an oil, which is purified by column chromatography on 53336 - 42 silica gel using diethyl ether as eluent. Evaporation of the solvent yields 5-[ 5-ethoxycarbony 1-5-(phenylthio)pentyl)-imidazo[l,5-a]pyridine as a heavy oil; NMR (CDCip 3.3-3.8 (IH); IR 1720 cm To a solution of 3.8 g of 5-(5-ethoxycarbonyl-5-(phenylthio)-pentyll5 imidazo[l,5-a]pyridine in 100 ml of methanol is added 2.8 g of sodium metaperiodate. The reaction mixture is allowed to stir at room temperature for 18 hours. The solvent is evaporated under reduced pressure and 150 ml of water is added to the residue, which is extracted with 3x100 ml of ethyl acetate. The organic phase is extracted with 2x50 ml portions of IN hydrochloric acid followed by hasification of the aqueous extract with ammonium hydroxide and reextraction into 2x100 ml portions of ethyl acetate. These combined ethyl acetate extracts are dried over anhydrous magnesium sulfate, filtered and che solvent concentrated under reduced pressure to yield an oil which is purified by column chromatography on silica gel using ethyl acetate, diethyl ether (1:1) as eluent. Evaporation of the solvent yields 5-[ 5-ethoxycarbony l-5-(pheny Isulf iny l)-pentyl]-imidazo[l,5-a]pyridine as an oil; IR 1720 cm \ 1040 cm \ Example 23: To a solution of 300 mg of 5-(5-ethoxycarbonylpent-420 enyl)-imidazo[l,5-a]py-idine in 20 ml methanol is added 5 ml of IN sodium hydroxide. The reaction mixture is stirred at room temperature for 18 hours. The methanol is evaporated under reduced pressure and an additional 5 ml of water is added to the aqueous residue, which is then extracted with 3x5 ml aliquots of ethyl acetate. The basic aqueous layer is then adjusted to pH 5 and extracted with 3x5 ml portions of ethyl acetate. These extracts are dried over anhydrous magnesium sulfate, filtered and the solvent evaporated under reduced pressure to yield 5-(5-carboxypent-4-enyl)-imidazol[l,5-a]pyridine melting at 142-144". - 43 Example 24: To a solution of 2.75 g of 5-(5-formylpentyl)-imidazo[l,5ajpyridine in 180 ml of chloroform is added 6.5 g of carbethoxymethylene-triphenylphosphorane. The reaction mixture is stirred at room temperature for'18 hours. The solvent is then evaporated under reduced pressure to yield 5-(7-ethoxycarbonyl-hept-6-enyl-imidazo[l,5-a]pyridine as an oil.

The starting material is prepared as follows: To a cooled (-60°) solution of 4.9 g of 5-(5-methoxycarbonylpentyl)imidazo[l,5-a]pyridine (obtained by esterification of 5-(5-carboxypentyl)-imidazo[l,5-a]pyridine of Example 2 with diazomethane in methylene chloride) in 140 ml of methylene chloride is added 40 ml of a 1.75 M solution of di-isobutyl aluminium hydride in hexane in a dropwise manner over a 20 minute period. On completion of the addition, the reaction mixture is allowed to stir at -60* for a further 20 minutes. Then, 10 ml of methanol, followed by 100 ml of water, are added to quench the reaction. The reaction mixture is stirred at room temperature for 15 minutes, the methylene chloride layer is separated and the solvent evaporated under reduced pressure to yield 5-(5-fonnylpentyl)-imidazo[l,5-a]pyridine as an oil; NMR (CDC13) 9.7 (m.lH); IR (CEjCl^ 1710 cm1.

Example 25: To a solution of 2.8 g of 5-(7-ethoxycarbonyl-hept-6enyl)—- imidazo [1,5-a] pyridine in 30 ml of methanol is added 15 ml of IN sodium hydroxide. The reaction is stirred at room temperature for 3 hours. The methanol is evaporated under reduced pressure and the residue diluted with 30 ml of water and the solution adjusted to pH 7 with IN hydrochloric acid. The solution is extracted with 2x50 ml of ethyl acetate. The combined ethyl acetate extracts are dried over anhydrous magnesium sulfate, filtered and the solvent evaporated under reduced pressure to yield 5-(7-carboxyhept-6-enyl)-imidazo[l,5-a]pyridine melting at 110-111*. 533θδ - 44 Example 26: To a solution of 150 mg of 5-(5-carboxypent-4-enyl)imidazo[l,5-a]pyridine in 7 ml methanol is added 100 ml of 10 Z palladium on carbon as catalyst. The reaction nixture is hydrogenated at atmospheric pressure for 3 hours. The catalyst'is removed by filtration and the solvent evaporated under reduced pressure to yield 5-(5-carboxypentyl)-iaidazo[l,5-a)pyridine melting at 144-147", and identical to the product of Example 2.

Example 27: To a solution of 180 mg of 5-(7-earboxyhept-6-enyl)imidazo[l,5-a]pyridine in 30 ml of methanol is added 200 mg of 10 2 palladium on carbon as catalyst. The reaction mixture is subjected to hydrogenation at atmospheric pressure for 3 hours. The catalyst is removed by filtration and the solvent evaporated under reduced pressure to yield the product melting at 69-71", consisting of a mixture of 5-(7-carboxyheptyl)-imidazo[l,5-a]pyridine (the compound of example 3c) and 5-(7-carboxyheptyl)-5,6,7,8-tetrahydroimidazo[l,5-a]pyridine.

Example 28: A solution of 0.1 g of 2-aminomethyl-3-(4-methoxycarbonylbutyl)-pyridine in 0.6 ml of formic acid is heated at 90° for 18 hours. The mixture is cooled co 0°, made basic with saturated aqueous ammonium hydroxide solution and extracted with methylene chloride (4x10 ml). Drying, filtration and evaporation of extracts yields 2-(N-£ormylaminomethyl)-3-(4-methoxycarbonylbutyl)-pyridine, melting at 43-45° which is redissolved in 1 ml of toluene and heated at 90° for 17 hours with 75 ag of phosphorus oxychloride. Evaporation of excess phosphorus oxychloride with toluene, basification at 0* with saturated aqueous ammonium hydroxide solution, extraction with methylene chloride (4x15 ml), drying of the extract over sodium sulfate and evaporation yields an oil, which is chromatographed (silica gel, ethyl acetate) to yield as an oil, 8-(4-mechoxycarhonylbutyl)-imidazo[l,5-a]pyridine; Rf 0.29; NMR (CDCl^) 3.70 (s, 3H), 6.50 (d, ZH), 7.43 (s, IH), 7.S3 (t, IH), 8.22 (s, IH); IR (CE^Cl^ 1725 cm1. - 45 The starting material is prepared as follows: A solution of 3-bromopyridine (7.9 g), methyl 4-pentenoate (7.15 g), palladium acetate (0.11 g) and tri-o-tolylphosphine (0.6 g) in 50 ml of triethylamine is refluxed for 24 hours under argon and the solvent evaporated. The residue is taken up in methylene chloride (50 ml) and washed with water (2x40 ml). The organic phase is dried and evaporated to yield 3-(4-methoxycarbonylbut-l-enyl)-pyridine as a colorless liquid; NMR (CDClj) 3.72 (s, 3H), 6.40 (S, IH); IR (film) 1725 cm1. 3~(4-:iethoxycarbonylbut-l-eayl)-pyridine (9.5 g) is hydrogenated in 100 ml of methanol at 3 atmospheres for 3.5 hours with 0.5 g of 5 X palladium on charcoal to yield, after filtration and evaporation, 3-(4-methoxycarbonylbutyl)-pyridine as an oil; NMR (CDCl^) 3.80 (s, 3H); IR (CK2C12) 1730 cm1.

Peracetic acid (40 X, 8.3 ml) is added dropwise to 3-(4-methoxycarbonylbutyl)-pyridine (10.81 g) so as to maintain the reaction temperature between 80 and 85°. After the addition is complete, the temperature is allowed to fall to 30* and excess peracid is destroyed with aqueous sodium sulfite. The acetic acid is distilled at reduced pressure, and the residue is taken up in methylene chloride (50 ml), filtered and evaporated. The residue consisting of 3-(4-methoxycarbonylbutyl)-pyridine-N-oxide is treated with dimethyl sulfate (7.7 g) in 40 ml of toluene at 90* for 1 hour and the solvent is evaporated. The 3-(4-methoxycarbonylbutyl)-l-methoxypyridinium methyl sulfate salt is dissolved in 16.7 ml of ice-cold water and 8.3 ml of IN sodium hydroxide, and a solution of potassium cyanide (11.21 g) in 16.7 ml of ice-cold water is added slowly so as to keep the reaction temperature below 0*. After 24 hours at 0°, extraction with methylene chloride (3x30 ml), drying over sodium sulfate and evaporation of solvent yields a mixture of isomeric cyanopyridines from which - 46 2-cvano-3-(i-methoxycarbonylbutyl)-pyridine having Rf » 0.56 and HMR (CDClj) 8.52 (a, IH), and 2-cyano-5-(4-methoxycarbonylbutyl)-pyridine having Rf * 0.50 and KMR (CDClj) 8.72 (s, IH) were separated by chromatography (silica gel, ether-pentane 3:2). 2-Cyano-3-(4-methoxycarbor.ylbutyl)-pyridine (2.40 g) is dissolved in 92 mi of methanol containing 2.4 al of cone.hydrochloric acid and hydrogenated at atmospheric pressure with 1.2 g of 10 " palladium on charcoal for 3 hours'. Filtration, evaporation and recrystallisation from ether-methylene chloride yields 2-aminomethy l-3-(4-methoxy10 carbonylbutyil-pyridine hydrochloride, m.p. 79-81°.

Example 29: A solution of 8-(4-methoxycarbonylbutyl)-imidazo[l,5-ajpyridine (30 mg) in 0.3 ml of ethanol and 0.3 ml of IN sodium hydroxide is refluxed for 2 hours, cooled, diluted with 2 ml of water and extracted with ethyl acetate (1x5 ml). The aqueous phase is brought to pH-6 and is extracted with methylene chloride (4x10 ml). The extracts are dried and evaporated to yield 8-(4-carboxybutyl)-imidaze[l,5-a]pyridine, melting at 195-197°.

Example 30: 2-Aminomethyl-5-(4-methoxycarbonylbutyl)-pyridine (0.20 g) is heated at 90* in 0.6 ml of formic acid for 18 hours. The mixture is cooled to 0°, made basic with saturated aqueous ammonium hydroxide solution and extracted with methylene chloride (4x15 ml). Drying, filtration and evaporation of the extracts yields 2-(N-formylaminometbyl)-5-(4-methoxycarbonylbutyl)-pyridine as an oil (IR 1720, 1675 ca ) which is redissolved in 1 ml of toluene and heated at 90° for 18 hours with phosphorus oxychloride (0.166 g). Evaporation of excess phosphorus oxychloride with toluene, basification ac 0* vith saturated ammonium hydroxide solution, extraction vith methylene chloride (4x15 ml) and drying of the extract over sodium sulfate yields an oil which is chromatographed (silica gel, ethyl acetate) tc - 47 yield (6-(4-methoxycarbonylbutyl)-imidazo[l,5-a]pyridine; Rf · 0,26; NMR (CDC13) 3.58 (s, 3H), 6.45 (d, IH), 7.25 (d, IH), 7.38 (s. IH), 7.62 (s, IH), 7.94 (s, IH); IR (CH,C12) 1730 cm1.

The starting material is prepared as follows: 2-Cyano-5-(4-methoxycarbonylbutyl)-pyridine (1.48 g, see Example 28) is dissolved in 56 ml of methanol containing 1.5 ml of concentrated hydrochloric acid and hydrogenated at atmospheric pressure with 0.75 g of 10 Z palladium on charcoal for 18 hours. Filtration, evaporation, chromatography on 20 g of silica gel with 1:1 methanol-ethyl acetate, and crystallization from ether-nethylene chloride yields 2-aminomethyl-5-(4-methoxycarbonylbutyl)-pyridine as its carbonate melting at 79-80’; NMR (CDC13) 3.67 (ε, 3H), 4.24 (s, 2H); IR (C^Clj) 1725 cm"1.

Example 31: A solution of 92 mg oi 6-(4-methoxyearbonylbutyl)-imidazo[l,5a]pyridine in 0.3 ml of ethanol and 0.8 ml of IK sodium hydroxide, is refluxed gently for 2 hours, cooled, diluted vith 2 ml of water and extracted vith ethyl acetate (5 ml). The aqueous phase is brought to pH * 6 and is extracted with chloroform. The extracts are dried and evaporated to yield 6-(4-carboxybutyl)-imidazo[l,5-a]pyridine, melting at 168-171+.

Example 32: 2-(N-formylaminomethyl)-4-(3-methoxycarbonylpropyl)pyridine (33 mg) is dissolved in 1 ml of toluene and heated at 90* with phosphorus oxychloride (44 mg) for 18 hours under nitrogen. The solvent is evaporated and the residue is suspended in methylene chloride, cooled to 0‘ and made basic with saturated aamonium hydroxide solution. The aqueous phase is extracted vith methylene chloride (4x15 ml) which is dried over sodium sulfate and evaporated to yield 7-(3-methoxycarbonylpropyl)-imidazo[l,5-a]pyridine as an oil, after purification by preparative thin layer chromatography (silica - 48 gel, 3:1 ethyl acetate-methanol); NKR (CDCip 3.70 Cs, 3 Η), 6.45 (q, 1 H), 7.3 (s, 1 Η), 7.32 (s, 1 H), 7.90 (d, 1 H), 8.08 (s, 1 H); IR 2CI2) 1730 cm'1.

The starting material is prepared as follows: Potassium cyanide (11.18 g) and dibenzo-18-crown-6 (1.0 g) are added to a solution of 4-(3-chloropropyl)-pyridine (6.68 g) (prepared from 4-(3-hydroxypropyl)-pyridine), in 300 al of dry acetonitrile under nitrogen. The mixture is refluxed for 24 hours, the solvent evaporated and the residue partitioned between methylene chloride and water. The aqueous phase is further extracted with methylene chloride (3x100 ml) and the combined extracts are dried over sodium sulfate, decolorized with charcoal and evaporated to yield 4-(3-cyanopropyl)-pyridine as a colorless oil.

Hydrogen chloride is bubbled slowly into an ice-cooled methanolic solution of 4-(3-cyanopropyl)-pyridine (5.5 g) for 2 hours and 100 ml of water is added carefully. The solution is stirred for 15 minutes and the solvent is evaporated. The residue is made basic with saturated aqueous sodium bicarbonate solution and extracted with methylene chloride (3x100 ml) which is dried over sodium sulfate.

Evaporation of the solvent and filtration through 50 g of silica gel in ether yields 4-(3-methoxycarbonylpropyl)-pyridine as an oil; NMR (CI>C13) 3.68 (s, 3 H), 7.05-7.25 (m, 2 H), 8.45-8.65 (a, 2H); IR: 1725 cm1.

Peracetic acid (40 2, 2.9 ml) is added to 4-(3-methcxycarbonylpropyl)25 pyridine (3.20 g) at room temperature. The mixture is heated at 80’ for 1 hour and the acetic acid is evaporated after a test for peroxide Is negative. The residue is taken up in methylene chloride (50 ml), filtered, and the solvent evaporated. The resulting 4-(3-mechoxy53396 - 49 carbonylpropyl)-pyridine-.\’-oxide is treated with dimethylsulfate (2.8 g, 22.2 mmol) in 12 ml of toluene at 80* for 1 hour. The solvent is evaporated to yield 5.45 g of the 4-(3-methoxycarbonylpropyl)-lnethoxypyridinium methyl sulfate salt which is added at 0° co a solution of 89.75 g potassium cyanide in 20 ml of water. The reaction mixture is stirred at 0° for 1 hour and 25° for 3 hours and Chen extracted with methylene chloride (1x30 ml). The aqueous phase is reextracted after standing for 24 hours, with methylene chloride (1x30 ml) and the combined extracts are dried over sodium sulfate and evaporated to yield a red oil. Chromatography on 70 g of silica gel with ether as the eluent yields 2-cyano-4-(3-oethoxycarbonylpropyl)-pyridine as an oil; NMR (CDClj) 3.67 (s, 3 H), 7.42 (d, 1 H), 7.60 (s, 1 H), 8.60 (d, 1 H); IR (CHjCip 1725 cm1. 2-Cyano-4-(3-methoxycarbonylpropyl)-pyridine (0.83 g) is hydrogenated at 3 atmospheres for 3 hours in 9 ml of methanol with 0.4 g of 10 Z palladium on charcoal. Filtration, evaporation, and preparative thin layer chromatography on silica gel with 1:1 methanol-ethyl acetate yields 2-aminomethyl-4-(3-methoxycarbonylpropyl)-pyridine; Rf · 0.37 (EtOAe-MeOH 1:1, 1 X NH^OH); NMR (CDClj) 3.67 (s, 3 H), 4.15 (s, 2 H). 2-Aminomethyl-4-(3-methoxycarbonylpropyl)-pyridine (0.11 g) is heated at 90* in 0.5 ml of 97 Z formic acid for 18 hours. The reaction mixture is cooled to room temperature, made basic with amonium hydroxide solution and extracted with methylene chloride (4 χ 20 ml). The organic extracts are dried over sodium sulfate and evaporated to yield 2- (N-formylaminomethyl)-4- (3-methoxycarbonylpropy1) -pyridine; IR (C^Cip 1735, 1685 cm1.

Example 33: 7-(3-methoxycarbonylpropy1)-imidazo[ 1,5-a ]pyridine (Example 32, 8.0 mg) is dissolved in 0.3 ml of methanol and 0.1 ml of IN sodium hydroxide is added. The mixture is stirred at 25’ for - 50 53336 hours, evaporated, and the residue is redissolved in 5 al of water.

The aqueous solution is washed uith 2 ml of ethyl acetate, brought to pH«6 with 2N sulfuric acid and extracted with methylene chloride (3x5 ml). Tne organic extracts are dried over sodium sulfateXmagnesium sulfate and evaporated to yield 7-(3-carboxypropyl)-imidazo[l,5-a]pyridine, IR (CHCip 1720 cm'1.

Example 34: A solution of 7-:[4,4-(bis-methoxyearbonyl)-bucylJ-imidazo[l,5-a]pyridine (65 mg) in 0,8 ml of IN sodium hydroxide and 0.5 ml of ethanol is heated at reflux for 2 hours. The solvent is evaporated and θ·® ml cf IN hydrochloric acid is added. After the water is evaporated, the residue is redissolved in 3 ml cf xylene and heated at 137' for 4 hours. The xylene is evaporated and replaced with 2 ml of IN sodium hydroxide. Extraction of the aqueous phase with ethyl acetate (5 ml), acidification to pB»6, reextraccion with chloroform (3x15 ml) ana evaporation yields 7-(4-carboxybutyl)-imicazotl,5-a]pvridine, melting at 158-161'.

The starting material is prepared as follows: According to procedures previously described (e.g., Examples 28, 32), 4-(3-chloropropyl)-pyridine is converted to 4-(3-chloropropyl)-220 cyanopyridine; NMR (CDC13) 3.36 (c, 2 H), 7.40 (d, 1 H), 7.57 (s, 1 E), 8.60 (d, IE).

A solution of borane-dimethylsulfide (0.83 ml, 7.7 nmol) in 7 ml of tetrahydrofuran is added slowly to a refluxing solution of 4-(3chloropropyl)-2-cyanopyridine (1.24 g, 6.9 mmol) in 7 ml of tetrahydro25 furan while dimethylsulfide simultaneously distills off. The mixture is refluxed for 15 minutes after Che addition is complete, cooled to ’ and 6 ml of 6N hydrochloric acid is added. After hydrogen evolution ceases, the mixture is refluxed for 30 minutes, cooled co 0' and saturated with solid sodium carbonate before extracting with methylene - 51 chloride (4x50 ml). The organic extracts are dried over sodium sulfate and evaporated to yield an oil which is filtered through 10 g of silica gel (1:1 EtOAc-MeOH) to yield 2-aminomethyl-4-(3-chloropropyl)pyridine as a yellow oil; NMR (CDCl^) 3.SS (t, 2 H), 4.20 (s, 2 H).

A solution of 2-aminomethyl-4-(3-chloropropyl)-pyridine (0.47 g) in 1 ml of formic acid is heated at 90* for IB hours, cooled to 0* and made basic by the addition of saturated aqueous asmonium hydroxide solution. Extraction with methylene chloride (4x10 ml), drying over sodium sulfate and evaporation yields 2-(N-formylaminomethyl)-4-(310 chloropropyl)-pyridine (IR 1674 cm 1) which is heated at 90’ in phospnorus oxychloride (0.75 g) for 15 hours. Excess phosphorus oxychloride is evaporated with toluene and the residue is suspended in methylene chloride (15 ml), cooled to 0° and made basic with saturated ammonium hydroxide. Extraction with methylene chloride (4x15 ml), drying over sodium sulfate and preparative Chin layer chromatography (silica gel, EtOAc) of the residue yields 7-(3-chloropropyl)-imidaao(l,5-a]pyridine (Rf · 0.24, EtOAc) as a gum; NMR (CDCl^) 3.58 (t, 2 H), 6,42 (q, 1 H), 7.21 (s, 1 H), 7.32 (s, 1 E), 7.88 (d, 1 H). 8.07 (s, 1 H).

A solution of 7-(3-ehloropropyl)-imidazo[l,5-a]pyridine (50 mg), dimethyl malonate (0.14 g) and potassium carbonate (144 mg) in 2 ml of dimethylformamide is heated between 80’ and 90’ under nitrogen for 9 hours. The solvent is evaporated and the residue taken up in 10 ml of water and extracted with ethyl acetate (2x10 ml). The organic extracts are washed with 2N hydrochloric acid (2x10 ml). Basification of the aqueous extracts with solid sodium bicarbonate, extraction with methylene chloride (3x10 ml), drying over sodium sulfate and evaporation yields 7-(4,4-(bis-methoxycarbonyl)-butyl]-imidazo[l,5-a]pyridine; KMR (CDCip 3.40 (s, 6 H), 6.06 (d, 1 B); IR (CEjCip 1725 cm1. - 52 Example 35: A solution of 5-(5,5-(bis-ethoxycarbonyl)-pentyl]-imidazo(l,5-a]pyridine (0.60 g) in 6.5 ml of 1 N sodium hydroxide and 4 ml of ethanol is refluxed for 2 hours. The solvent is evaporated and 6.5 ml of IS hydrochloric acid is added. The water is then evaporated and the resulting 5-(5,5-(bis-carboxy)-pentyl]-imidazotl,5-a]pyridine is heated at 137’ for 4 hours in 25 ml of xylene. The xylene is replaced with 16 ml of IK sodium hydroxide. Extraction of the aqueous phase with ethyl acetate (15 ml), acidification to pH*6, reextraction with chloroform (3x40 ml), drying over magnesium sulfate and evapor10 ation yields 5-(5-carboxypentyl)-imidazo[l,5-a]pyridine melting at 146-147" (compound of Example 2).

The starting material is prepared as follows: A solution of 5-(4-chlorobutyl)-imidazo[l,5-a]pyridiae (0.42 g), diethyl malonate (1.34 g) and potassium carbonate (1.15 g) in 20 ml of dimethylformamide is heated between 80* aid 90* under nitrogen for 10 hours. The solvent is evaporated and the residue taken up in 50 ml of water. The aqueous phase is extracted with ethyl acetate (3x40 ml). The extracts are washed vith cold 2H hydrochloric acid (3x10 ml). Basification of the aqueous phase with solid sodium bicarbonate, extraction with methylene chloride (3x20 ml), drying over sodium sulfate and evaporation yields the 5-(5,5-(bis-ethoxycarbonyl)-pentyl]imidazo[l,5-a]pyridine, melting at 59-61*.

The starting material, 5-(4-chlorobutyl)-imidazo[l,5-a3pyridine, is prepared by the procedure described for the starting material in Example 4, using l-hromo-3-chloropropane as the reagent instead of l-bromo-4-chlorobutane therein.

Example 36: Pyridinium dichromate (0.94 g) is added as a solid to a solution of 5-(6-hydroxyhexyl)-imida2o[l,5-a]pyridine (123 mg) in - 53 10 ml of Ν,Ν-dimechylformamide at 25° under nitrogen. The solution is stirred for 6 hours, poured into 150 ml of water and extracted vith methylene chloride (5x20 ml). The organic extracts are washed with IN sodium hydroxide. Acidification of the aqueous phase to pH«6, extrac5 tion with methylene chloride, drying over sodium sulfate/magnesium sulfate and evaporation yields 5-(5-carboxypentyl)-imidazo[l,5-a)pyridine of Example 2 melting at 145-146*.

Example 37: 5-Methylimidazo[l,5-a]pyridine [J. Org. Chem. 40, 1210 (1975), 424.7 g] is charged into a 12 liter flask equipped vith mechanical stirrer, thermometer and nitrogen atmosphere. Dry tetrahydrofuran (3,000 ml) is charged into the flask and the resulting solution is cooled to -65' in a dry ice/acetone bath. N-Butyllithium (1.0 mole, 2.4N in hexane) is poured into the flask all at once under a nitrogen atmosphere. The temperature rises to -32*. The mixture is recooled to -50° and a second mole of n-butyllithium is charged in the same manner. A second temperature rise occurs and after again cooling to -50°, a third mole of the n-butyl-lithium is charged into the reactor. The reaction mixture is then stirred for twenty minutes, the temperature drops to -65°. To this stirring solution a cold (-67°) 2o solution of 5-bromo-l,l,l-triethoxypentane (606.9 g) in 500 ml of tetrahydrofuran is added as repidly as possible, raising the temperature to -25°. The reaction mixture is then warmed to -15° and stirred for 2 hours. Acetic acid (50 al) is added and most of the solvent is removed under vacuum. The residue is taken up in 2,000 ml of ethyl ether; acetic acid (100 ml) and 12N hydrochloric acid (100 ml) are added while the reaction mixture is cooled to 0*. After 15 to 20 minutes, ice-cold 7.5N ammonium hydroxide (1000 ml) is added. The organic phase is separated and the aqueous is washed with ethyl ether (500 ml). The pH of the aqueous layer is adjusted to 9 with anmonium hydroxide and extracted again with ethyl ether (500 ml). The combined ether extracts are washed vith a dilute sodium chloride solution and - 54 53336 basified to pH 13-14 with potassium hydroxide. The ether extract is treated with charcoal and magnesium sulfate. The mixture is filtered and evaporated to give a dark oil which is dried at 2mm Hg. The oil is distilled under high vacuum to give 5-(5-ethoxycarbonylpentyl)~ imidazo(l,5-a]pyridine of Example 1, boiling at 220’/0.2 mm Hg.

The starting 5-bromo-l,l,l-triethoxypentane is prepared as follows: -Bromovaleronitrile (1,200 g) is charged into a 5 liter 3 neck flask under nitrogen atmosphere. The complete reaction vessel is then placed in an ice bath. Then hydrogen chloride gas (287 g) is slowly bubbled into the reaction vessel. The reaction mixture is then diluted with ethyl ether (3,200 ml) and stirred at 4 overnight. The resulting suspension Is cooled to -30‘ in a dry ice/acetone bath. The solid is collected, washed with ethyl ether and dried in a vacuum dessi'cator over potassium hydroxide and phosphorous pentoxide for 3 days to give ethyl 5-broooimidovalerate hydrochloride which is used in the next step without further purification.

Ethyl 5-bromoimidovalerate hydrochloride (556 g) is charged into a 12 liter flask equipped with a mechanical stirrer under a nitrogen atmosphere. Anhydrous ethanol (836 g) is added and the reaction mixture is stirred at room temperature for 2 hours, at which time a clear solution is obtained. Ethyl ether (3700 ml) is charged into the flask and stirring is continued for 5 days at room temperature.

The solution is cooled to -30’ and filtered to remove asconium chloride. The filtrate is evaporated to dryness in a rotary evaporator under vacuum. The residue is distilled under high vacuum (0.2 nm Hg), using a 12 cm fractionation column. The main fraction distilling at ca 71-82* is collected, and redistilled with a 46 cm column to yield 5-bramo-l,l,l-triethoxypentane, b.p. 60-2’/0.2 mm Hg. - 55 33336 -(5-Ethoxycarbonylpentyl)-imidazo[l,5-a]pyridine can also be prepared from 2-(N-formylaminomethy 1)-6-(5-ethoxycarbonylpentyl)-pyridine essentially according to the cyclization procedure described in Examples 28, 30 and 32.

Example 38: 5-(5-Ethoxycarbonylpentyl)-imidazo[1,5-a]pyridine (1091 g) is charged into a 12 liter round bottom flask under a nitrogen atmosphere. Ethyl alcohol (95 Z, 420 ml) is added while stirring. With continued stirring, 2N sodium hydroxide (2100 ml) is added in portions. After complete addition the mixture is warmed at 70° for 20 minutes, at which time a solution is obtained, and heating is continued for 2 hours. Additional sodium hydroxide (50 Z solution, 21 ml) is added and heating is continued for 40 more minutes. The reaction mixture is cooled, 12 H hydrochloric acid (30 ml) is added, and the ethyl alcohol is partially removed by evaporation under reduced pressure. The resulting solution is washed vith ethyl ether (1700 ml), decolorized vith charcoal, filtered, and acidified vith acetic acid (300 ml). The product that crystallizes at 4’ overnight is collected, washed first vith water, then with ethyl ether (1000 ml), and dried to give 5-(5-carboxypentyl)-imidazo[l,5-a]pyridine, melting at 146-148°, and identical to the product of Example 2.

Example 39: The following compounds are prepared analogously to the procedures described in the previous Examples. a) 5-(4-ethoxycarbonyl-but-3-enyl)-imidazo[l,5-a]pyridine by condensation of 5-methylimidazol[l,5-a]pyridine with ethyl 4-bramocrotonate; b) 5-(9-hydroxynon-7-ynyl)-imidazo[l,5-a]pyridine by condensation of l-tetrahydropyranyloxy-8-bro«nooct-6-yne with 5-aethy 1 imidazo [1,5-a ]pyridine and subsequent hydrolysis. - 56 Example 40: A solution of 5-(6-oxoheptyl)-imidazo[1,5-aJpyridine (0.35 g) in 10 ml of dioxane is added slowly to a vigorously stirred aqueous solution (3 ml) of sodium hypobromite (5.2 mmol) at 22-25* (ice-bath cooling, if necessary). After 3 hours the unreacted sodium hypobromite is destroyed with sodium bisulfite and the solvent is evaporated. The residue is redissolved in 10 ml of 0.5N sodium hydroxide, extracted with ether (2x5 ml) and brought to pH"6 with concentrated sulfuric acid. Extraction with methylene chloride (3x10 ml), drying over sodium sulfateZmagnesium sulfate and evapora10 tion yields 5-(5-carboxypentyl)-imidazo[l,5-a]pyridine of Example 2.

T The starting material is prepared by treatment of 5-(4-chlorobutyl)imidazo[l,5-a]pyridine with ethyl acetoacetate in the presence of sodium hydride, followed by hydrolysis with dilute sodium hydroxide.

Example 41: A single crystal of iodine is added to a mixture of 15 magnesium turnings (36.1 mg, 1.5 nmol) and 5-(4-chlorobutyl)-imidazo[1,5-a]pyridine (313 mg) in 0.2 ml of dry tetrahydrofuran tinder nitrogen. When the magnesium turnings have dissolved, an additional 2 mi of anhydrous tetrahydrofuran are added, followed by ethyl bromoacetate (0.43 g). The reaction mixture is stirred at room temperature for 1 hour, refluxed for 30 minutes, cooled to 25*, diluted with 20 ml i I of ethyl acetate and washed with water (2x10 ml). Drying, filtration | and evaporation of the organic phase yields 5-(5-ethoxycarbonylpentyl)imidazo[l,5-a]pyridine as an oil which is refluxed for 3 hours in 10 ml ί of methanol and 5 ml of IN sodium hydroxide. The methanol is evaporated ! and the residue is redissolved in 10 ml of water, washed with 10 ml of ethyl acetace and brought to pH»6 with concentrated hydrochloric acid. Extraction with methylene chloride (5x10 ml), drying over sodium sulfateZmagnesium sulfate and evaporation yields 5-(5-carboxypentyl)imidazo{l,5-a]pyridine of Example 2. „ 53396 - 57 Example 42: A single crystal of iodine is added to a mixture of magnesium turnings (36.5 mg) and 5-(5-chloropentyl)-imidazo[l,5-a]pyridine (313 mg) in 0.2 ml of anhydrous tetrahydrofuran under nitrogen. lihen the magnesium turnings have dissolved, an additional 2 ml of tetrahydrofuran is added. The solution is cooled to -5°, and dry carbon dioxide is bubbled through the solution with vigorous stirring for 30 minutes. The solvent is evaporated and the residue is dissolved in 10 ml of 25 2 sulfuric acid, washed with 5 ml of ether. Acidification to pH«6, extraction with methylene chloride (4x15 ml), drying of the extract over magnesium sulfate and evaporation of the solvent yields 5-(5-carboxypentyl)-imidazo[l,5-a]pyridine of Example 2.

Example 43: A mixture of 5-(6-carboxy—6-oxohexyl)-imidazo[l,5-a]pyridine (0.52 g) and C.5 g of glass powder is heated gradually to 240°. The reaction mixture is maintained at 240° for 1 hour and cooled to room temperature. The residue is taken up in methylene chloride and tbe solid filtered. Evaporation and recrystallization yields 5-(5-carboxypentyl)-imidazo[l,5-a]-pyridine of Example 2.

The starting material may be prepared as follows: -(5-chloropentyl)-imidazo[l,5-a]pyridine is dissolved in dimethyl20 formats:de and reacted with 2-ethoxycarbonyl-l,3-dithiane and sodium hydride followed by treatment with N-bromo-succinimide in aqueous acetone and hydrolysis with dilute sodium hydroxide yields the 5-(6carboxy-6-oxohexy D-imidazo [ 1,5-a ]pyr id ine.

Example 44: A solution of 5-(4-carboxybutyl)-imidazo[l,5-a]pyridine (0.22 g) and oxalyl chloride (0.2 g) in 10 ml of chloroform is refluxed for 1.5 hours. The solvent is evaporated, che residue is redissolved in 15 ml of freshly distilled dry dioxane, and the solution is added to an equimolar ethereal solution of diazomethane with external cooling to keep the reaction at or below 0*. The mixture is allowed - 58 to stand at room temperature overnight and Che ether is evaporated carefully. A solution of silver oxide (0.14 g) in 1 ml of 0,84 M sodium thiosulfate is added to the dioxane solution of the resulting diazo compound. The mixture is stirred for 3 hours at room tewpera5 ture while additional silver oxide (0.14 g) is added portionwise, then stirred for 1 hour at 50°, cooled, filtered and extracted with 1 Z aqueous sodium hydroxide solution. Acidification of the aqueous phase with concentrated sulfuric acid, extracting with methylene chloride, drying of the extract over magnesium sulfate and evaporation yields -(5-carboxypentyl)-iaidazo[l,5-a]pyridine of Example 2.

Example 45: A mixture of 4.1 g of 5-(5-hydroxypentyl)-imidazo[l,5-a]pyridine, 1.5 ml of water, 1.7 g of nickel carbonyl, 0.5 g of nickel chloride hexahydrate and 0.3 ml of concentrated hydrochloric acid is heated under a high pressure of carbon monoxide for 10 hours. All volatile material is evaporated. The remaining aqueous phase is washed with ether (5 ml), made basic (ρΗ·10) with 6N sodium hydroxide and reextracted with ether (10 ml). Acidification to pBa6, extraction with methylene chloride, evaporation and recrystallization from chloroformXether yields 5-(5-carboxypentyl)-imidazo[l,5-a]pyridine of Example 2.

Similar treatment of 5-(4-pentenyl)-imidazo[l,5-a]pyridine with nickel carbonyl also yields 5-(5-carboxypentyl)-imidazo[l,5-a]pyridine.

Example 46: A mixture of silver nitrate (0.34 g) in 10 ml of water and 5-(5-formylpentyl)-imidazo[l,5-a]pyridine (0.2 g in 10 ml of dioxane is brought to pH"10 with IN sodium hydroxide and warmed gently between 70 and 80* for 1 hour. The precipitated silver is filtered through Celite (trade mark) and the volume reduced by 50%. The remaining aqueous base is extracted with ethyl acetate, brought to pH«6 with concentrated sulfuric acid aad extracted with methylene chloride (5x10 ml). Drying - 59 over sodium sulface/magnesium sulfate and evaporation yields 5-(5carboxypenty1)-imidazo(1,5-a]pyridine.

The starting material 5-(5-formylpentyl)-imidazo[l,5-a]pyridine is prepared as follows: -(6-Chlorohexyl)-imidazo[l,5-a]pyridine is treated with dimethylsulfoxide, triethylamine and silver tetrafluoroborate according to the method described in Tetrahedron Letters 1974, 917.

Example 47: Ozone is bubbled through a solution of 5-(6,6-dimethoxyhexyl)-imidazo[l,5-a]pyridine (0.456 g) in 20 ml of methylene chloride at -50’ for 4 hours. Excess ozone is driven off with nitrogen and 1 ml of dimethyl sulfide is added at 78* and the reaction mixture is allowed to warm slowly to room temperature. The solvent is evaporated, the residue is taken up in 10 ml of methanol and refluxed with 10 ml of IN sodium hydroxide for 2 hours. The methanol is evaporated and the residue is washed with ethyl acetate (5 ml) and brought to pR"6 with concentrated sulfuric acid. Extraction with methylene chloride (5x10 ml), drying over magnesium sulfate and evaporation yields 5(5-carboxypentyl)-imidazo[l,5-a]pyr idine.

Example 48: 2-(N-Formylaminomethyl)-6-(5-ethoxycarbonylpentyl)2U pyridine (1.0 g) is heated at 90’ for 15 hours with 0.25 ml of phosphorus oxychloride in 10 ml of toluene. Evaporation of excess phosphorus oxychloride with toluene, basification at 0* with saturated ammonium hydroxide solution, extraction with methylene chloride (4x50 ml), drying over sodium sulfate and chromatography (40 g silica gel, EtOAc) yields 5-(5-ethoxycarbonylpentyl)-imidazo[l,5-a]pyridine.

The starting material is prepared via 6(5-ethoxycarbonylpenty1)-2cyano-pyridine according to procedures described in the previous Examples. - 60 Example 49: A solution of lithium diisopropylamide (from 1.0 g of diisopropylamine and 6.9 ml of 1.6N n-butyllithium) and hexamethylphosphoramide (1.8 g) in 50 ml of tetrahydrofuran, is cooled co -50’, and propiolic acid (0.35 g) is added dropwise. The reaction mixture is allowed to warm slowly (2 hours) to -15* and 5-(chlorobutyl)imidazo[l,5-a]pyridine (1.04 g) in 10 ml of tetrahydrofuran is added dropwise over 15 minutes. External cooling is removed and the reaction mixture is stirred for 90 minutes at room temperature before pouring into 100 g of ice. The aqueous phase is separated, washed with ethyl acetate (20 ml), brought of pH»2 with concentrated sulfuric acid and washed again with ethyl acetate (20 ml). The aqueous phase is adjusted to pH"6 and extracted with methylene chloride (5x30 ml). Drying of the extracts over Na^SO^/MgSO^, filtration and evaporation yields 5-(6-carboxyhex-5-ynyl)-imidazo[l,5-a3pyridine.

Example 50: A solution of 5-methylimidazo[l,5-a]pyridine (4.0 g, 0.03 smile) and tetramethylethylene diamine (4.9 g) in 100 ml of tetrahydrofuran is cooled to 0’ under nitrogen and 26.5 ml of 1.6N n-butyllithium is added dropwise so as to maintain the temperature below 5*. After 40 minutes this solution is added to an ice-cold solution of ethyl 4-bromocrotonate (7.02 g) in 90 ml of tetrahydrofuran. After 15 minutes the reaction mixture is quenched with excess saturated aamonium chloride solution and partitioned between water (100 ml) and ethyl acetate (150 ml). The organic phase is dried over sodium sulfate, filtered and evaporated to yield 5-(4-ethoxycarbonyl-but-3-enyl)25 imidazo[l,5-a]pyridine.

Example 51: A solution of 5-methylimidazo[l,5-a]pyridine (4.0 g) and tetramethylethylene diamine (4.9 g) in 100 ml of tetrahydrofuran is cooled to 0’ under nitrogen and 26.5 ml of 1.6K n-butyl-lithium is added dropwise so as to maintain the temperature below 5*. After 40 minutes this solution is added to an ice-cold solution of 1-tetrahydro53336 - 61 pyranyloxy-8-bromo-oct-6-yne (10.4 g) in 80 ml of tetrahydrofuran. After 30 minutes the reaction is quenched with 50 ml of 2N hydrochloric acid and stirred an additional 2 hours at room temperature. The layers are separated and the aqueous phase is brought to pH*10 with 50 X of sodium hydroxide solution. Extraction with methylene chloride (3x30 ml), drying over sodium sulfate, filtration, evaporation, and chromatography (silica gel, EtOAc) yields 5-(9-hydroxynon-7-ynyl)imidazo[l,5-a]pyridine.

Example 52: To a solutiop of 150 mg of 5-(4-carboxybuta-l,3-dienyl)10 imidazol1,5-aJpyridine in 9 ml of methanol is added 100 mg of 10 2 palladium on carbon as catalyst. The reaction mixture is hydrogenated at atmospheric pressure for 2 hours. The catalyst is removed by filtration and the solvent evaporated under reduced pressure to yield 5-(4-carboxybutyl)-imidazo[l,5-a]pyridine identical to the compound of Example 8.

The starting material is prepared as follows.

To a solution of 18 g of 3-ethylthioimidazo[l,5-a]pyridine [Blatcher and Middlemiss, Tet.Lett. (21) 2195 (1980)] in 200 ml of tetrahydrofuran at -50* is added a solution of 80 ml of 1.6 M n-butyl lithium in hexane in a dropwise manner over a period of 30 minutes. On completion of the addition, the reaction mixture is allowed to stir at -50* for a further 45 minutes and 10 ml of dimethylformamide is added dropwise to the cooled solution over a period of 10 minutes.

On completion of the addition, the reaction mixture is alloved to warm to room temperature and is poured into 500 ml of ice water.

The mixture is extracted with 500 ml of diethyl ether and the ethereal extract is dried over anhydrous magnesium sulfate, filtered and the solvent evaporated under reduced pressure to yield an oily residue.

This is purified by column chromatography on silica gel using a - 62 mixture of diethyl ether and hexane (1:2) as eluent. Evaporation of che solvent yields 5-fcrmyl-3-ethylthioimidazo[l,5-s]pyridine melting at 41-42’.

To a solution of 20 g of 5-formyl-3-ethylthioimidazo[l,5-a]pyridine in 200 ml of isopropanol is added approximately 15 g of Raney nickel.

The reaction mixture is stirred and heated at reflux temperature for 16 hours. The catalyst is removed by filtration through celite. The filtrate is evaporated under reduced pressure to yield an oily residue. This is purified hy column chromatography on silica gel using a mixture of diethyl ether and ethyl acetate (2:1) as eluent. Evaporation of the solvent under reduced pressure yields 5-formylimidazo[l,5-a]" pyridine melting at 138-140’.

Io a stirred suspension of 150 ml of sodium hydride in 25 ml of toluene is added 550 mg of triethyl 4-phosphonccrotonate in a drop15 wise manner over a 10-minute period. The reaction mixture is maintained at 5’ by cooling in an ice-vater bath. On completion of the addition, 300 mg of 5-formylimidazoI l,5-a]pyridine is added co the reaction mixture which is then allowed to stir at room temperature for 1 hour. The reaction mixture is poured into 100 ml of ice water and extracted with 2x100 ml of ethyl acetate. The ethyl acetate extracts are combined and dried over magnesium sulfate, filtered and evaporated to dryness to yield an oily residue. This is purified by column chromatography on silica gel using 'a mixture of diethyl ether and ethyl acetate as eluent. Evaporation of the solvent under reduced pressure yields 5-(425 ethoxycarbonylbuta-l,3-dienyl)-imidazo(l,5-a]pyridine melting at 101-103’.

To a solution of 200 mg Of 5-(4-ethoxycarbonylbuta-l,3-dienyl)imidazo[l,5-a]pyridine in 20 ml of methanol is added 4 ml of IN sodium hydroxide. The reaction mixture is stirred at room temperature for - 63 18 hours. The methanol is evaporated under reduced pressure and the residue diluted with 20 ml of water and the solution adjusted to pH 5 with hydrochloric acid. The precipitate is collected to give 5-(4carboxybuta-l,3-dienyl)-imidatoll,5-a)pyridine, melting at 243-245*. 53336 - 64 Effect on thromboxane synthetase from human platelets The method is carried out according to the description given above, i.e. the in vitro inhibition of the thromboxane synthetase enzyme is demonstrated analogous to the method of Sun, Biochem. Biophys. Res.

Com. 74, 1432 (1977).

Results: Compounds of the formula are represented in the table given below: 1 10 Compound of Example No. -ch2-a-s IC.O (nM) in cell-free test system Thromboxane Synthetase 8 -(CH ) COOH 41 2 -(CH.)icOOH 3 15 3/b -(cho’cooe 5 3/c -(CHO °COOH -(CH,)iC(CH ) CH COOH 21 16 18 10 11 -«πφ'οοκις z 2 -(CH2)"cONHCH 77 270 20 12 '(f^5C™(CH3)2 -(CE.).-CN 550 5 l'5OO 4 -(CHj),-CN 630 13 1 -(CHj)eCH,OH -(ch2kcooc2h5 280 330 25 15/c 5,6,7,8-Tetrahydro-(ch,)4cooh 290 15/b 5., 6,7, -Tetrahydro-(ch2)5cooh 85 15/a 5,6,7,8-Te trahydro- 14 30 - -(CHjjgCOOB i '

Claims (8)

1. A compound of che general formula I or 5,6,7,8-tetrahydro derivatives thereof, wherein each of R^ and 5 is hydrogen, halogen or lower alkyl; A is alkylene of 1 to 12 carbon atoms, alkynylene or alkenylene of 2 to 12 carbon atoms; B represents carboxy, lower alkoxycarbonyl, unsubstituted, mono- or di-(louer alkyl) substituted carbamoyl, cyano or hydroxymethyl.

2. A compound of the formula I shown in claim 1, wherein the group 10 CH^-A-B is attached at the 5-position.

3., A compound of the formula II (II) or 5,6,7,8-tetrahydroderivatives thereof, wherein R^, R^, R^ and R^ are hydrogen or lower alkyl of 1 to 4 carbon atoms, n is 1 to 7, m is 15 0 or 1; B represents carboxy, lower alkoxycarbonyl, unsubstituted or mono- or di-(lowar alkyl) substituted carbamoyl, cyano or hydroxymethyl. - 66 33336

4. A compound of the formula II shown in claim 3, wherein the group of the formula R. q is attached at the 5-position. 5 5. A compound of the formula III Z\_. • · (ia,) -B - P or 5,6,7,8-tetraydro derivatives thereof, wherein p is 3 to 8} B represents carboxy, lower alkoxycarbonyl, unsubstituted, mono- nr didower alkyl) substituted carbamoyl; cyano or hydroxymethyl. (IV) 10 6. A compound of the formula IV • * (kj COOH 2 <1 or 5,6,7,8-tetrahydro derivatives thereof, wherein q is 4, 5 or 6. 7 - 5-(5-ethoxycarbonylpentyl)-imidazo[ 1,5-a]pyridine. 8. 5-(5-carboxypentyl)-imidazo[l,5-a]pyridine. 15 9. 5-(6-carboxyhexyl)-imida2o[l,5-a]pyridine. 10. 5-(7-carboxyheptyl)-imidazo[l,5-a]pyridine. 53336 - 67 11. 5-(5-cyanopenty1)-imidazo[1,5-a]pyridine. 12. 5-(4-cyanobutyl)-imidazo[l,5-a]pyridine. 13. 5- (5-cyanopentyl)-3-methy1-imidazo[1,5-a]pyridine. 14. 5-(4-carboxybutyl)-imidazo[l,5-a]pyridine. 5 15. 5-(5-carboxypentyl )-3-methy1-imidazo[1,5-a] pyridine. 15. • 5-(5-carbamoylpentyl)-imidazo[1,5-a]pyridine. 17. 5-[5-(N-methylcarbamoyl)-pentyl]-imidazo[l f 5-a]pyridine. 18. 5-[5-(N,N-dimethylcarbamoyl)-pentyl]-imidazo[l,5-a]pyridine. 19. 5-(6-hvdroxyhexy1)-imidazo[1,5-a]-pyridine. 10 20. 5-(9-hydroxynonyl)-imidazo[1,5-a]pyridine. 21. 5-(6-carboxyhexy1)-5,6,7,8-tetrahvdroimidazo [ 1,5-a ] pyridine. 22. 5- (5-earboxypentyl)-5,6,7,8-tetrahydroimidazo[ 1,5-a]pyridine. 23. 5- (4-carboxybuty1)-5,6,7,8-tetrahydroimidazo [ 1,5-a J pyridine. 24. 5- (5-carboxy-4,4-dime thy lpenty 1 )-imidazo [ 1,5-a] pyr id ine. 15 25. l-iodo-5-(5-carboxypentyl)-imidazo (1,5-a] pyr idine. 26. 5-(4-ethoxycarbonylbutyl)-imidazo [ 1,5-a] pyridine. 27. 5-(5-ethoxycarbonylpent-4-enyl)-imidazo[l,5-a]pyridine. - 68 53396 28. 5-(5-carboxypent-4-enyl)-imidazol[1,5-alpyridine. 29. 5- (7-ethaxycarbony l-hept-6-eny 1)-imidazo] 1,5-a]pyrid ί ne. 30. 5-(7-carboxyhepcy 1)-5,6,7,8-tetrahydro imidazo] 1,5-a] pyr idine. 31. 8-(4-mechoxyc3rbonylbucyl)-imidazoIl,5-a]pyrLdine. 32. 8-(4-carboxybutyl)-imidazo[ 1,5-a]pyridine. 33. 6-(4-aethoxycarbonylbutyl)-imidazo[1,5-aJpyridine. 34. 6-(4-earboxybuty1)-imidazo]1,5-a]pyridine. 35. 7-(3-methoxycarbony lpropy l)-imidazo[l,5-a]pyridine. 36. 7-(3-carboxypropyl)-imidazo]1,5-a]pyridine. 3 7. 7-(4-carboxybuty1)-imidazo[1,5-a Jpyr idine. 38. 5-(4-ethoxycarbonyl-but-3-enyl)-imidazo[l,5-a]pyridine. 39. 5-(9-hydroxynon-7-ynyl)-imidazo [1,5-aJpyridine. 40. 5-(6-carboxyhax-5-ynyl)-imidazo[ 1,5-aJpyridine. 41. A salt of a compound having a salt forming group, as claimed in any one of claims 1—25. 83396 42. A sale of a compound having a sale forming group, as claimed in any one of claims 26- 40. 43. A pharmaceutically acceptable salt of a compound having a sale forming group, as claimed in any one of claims 1-25. 5 44. A pharmaceutical acceptable salt of a compound having a salt forming group, as claimed in any one of claims 26-40. 45. A pharmaceutical preparation comprising a compound claimed in any one of claims 1-25 and 43, in admixture or conjuction uith a pharmaceutically suitable carrier. 10 46. A pharmaceutical preparation comprising a compound claimed in any one of claims 26-40 and 44, in admixture or conjuction with a pharmaceutically suitable carrier. 47. Process for che manufacture of a compound of the formula I given in claim 1, or salts thereof, which consists in 15 1) condensing a compound of che formula VI wherein M is an alkali metal; R^ and R^ represent hydrogen or lower alkyl, with a reactive functional derivative of a compound of Che formula VII HO - A - B' (VII) - 70 wherein A is as defined in claim I, B’ represents carboxy, trialkoxymethyl, unsubstituted, mono- or di-(lower alkyl) substituted carbamoyl, cyano, etherified hydroxymethyl or halomethyl, to yield a compound of formula Ia and converting any resulting compound wherein B' differs from B, into a compound of formula I, or 2. ) condensing a compound of formula VIII (VIII) 10 wherein M is an alkali metal, R^ and R^ represent hydrogen or lover alkyl, and R^ is lower alkyl, with a reactive functional derivative of a compound of the formula IX HOCH 2 -A-B' (EC) wherein A is as defined in claim 1, B' represents carboxy, 15 trialkoxymethyl, unsubstituted, mono- or di-(lower alkyl) substituted carbamoyl, cyano, etherified hydroxymethyl or halomethyl; converting in any resulting compound wherein B' differs from Β, B' into a group B; and desulfurizing the resulting compound, or 53306 —R·/ - 71 3. ) condensing under basic catalysis a compound of the formula X (X) wherein R^ represents derivative and R. represent hydrogen or lower alkyl and R, 2 0 lower alkoxycarbonyl or cyano; with a reactive functional of a compound of the formula VII HO-A-B' (VII) wherein A is as defined in claim 1, B' represents carboxy, trialkoxymethyl, unsubstituted, mono- or di-(lower alkyl) substituted carbamoyl, cyano, etherified hydroxymethyl or halomethyl; splitting off R^, and converting any resulting compound wherein B' differs from B into a compound of formula I, or 4. ) cycliting a compound of formula XI wherein each of the symbols R^, R^ , and R^ represents hydrogen or lower alkyl; A is as defined in claim I,and B represents carboxy, lower alkoxycarbonyl, unsubstituted, mono- or di-(lower alkyl) substituted carbamoyl, cyano, hydroxymethyl, lower alkanoyloxymethy1, etherified hydroxymethyl or halomethyl; to yield a compound of formula lb (lb) 72 and converting any resulting compound wherein 6 differs from B into a ccnpound of formula X, or

5. ) hydrogenating a ccnpound of formula XIV 5 wherein A' represents alkylene, alkenylene or alkylene having rp to 11 carbon atcms, or

6. ) in a conpound of formula XVI R. ,R. wherein R^, Rj and A are as defined in claim 1; and C is a group con10 vertible into a carboxy group, converting said group C into carboxy, optionally by extending the group A within its definition, and, if desired, converting any resulting ccnpound of formula I into another conpound of the invention, and/or, if desired, converting a resulting free ccnpound into a salt or a resulting salt into the free ccnpound or 15 into another salt, and, if required, resolving a mixture of iscmers or racemates obtained into the single iscmers or raoenates, and, if required, resolving a racemate obtained into the optical antipodes. 48. The process for the preparation of oonpounds according to claim 1 substantially as described in any of Exanples 1 to 1

7. 20 49. The process for the preparation of compounds according to claim 1 substantially as described in any of Exanples 20 to 52. S3396 - 73 50. The compounds prepared according co either of claims 47 and 49. 51. The compounds prepared according co claim 4

8. 52. A compound of formula I substantially as described in any of Examples 1 to 17. 5 53. A compound of formula I substantially as described in any of Examples 20 to 52.