NO159276B - ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY EFFECTIVE IMIDAZO (1,5-A) PYRIDINES. - Google Patents

Description

The invention relates to an analogous process for the preparation of imidazo/1,5-a/pyridines with the general formula I,

or 5,6,7,8-tetrahydroderivatives in which means hydrogen, halogen or lower alkyl, A means the alkylene with 1-12 carbon atoms, the alkynylene or the alkenylene with 2-12 carbon atoms,

B means carboxy, lower alkoxycarbonyl, unsubstituted raano- or di-(lower alkyl)-substituted carbamoyl, cyano or hydroxymethyl, as well as their salts.

Preferred are compounds of the general formula I in which the group Cf^-A-B is bound in the 5-style. Very useful are the compounds of formula I, in which A means the alkylene with 1-12 carbon atoms.

Particularly preferred are compounds of the general formula II

or their 5,6,7,8-tetrahydroderivatives in which each of the symbols , R-j and R. means hydrogen or lower alkyl with 1-4 carbon atoms, n means an integer from 1-7, m means zero or 1, B means carboxy , lower alkoxycarbonyl, unsubstituted , mono- or di-(lower alkyl)-substituted

carbamoyl, cyano or hydroxymethyl as well as their salts, especially their therapeutically useful salts.

substituted, mono- or di-(lower alkyl)-substituted carbamoyl. cyan or hydroxymethyl as well as their salts, especially their therapeutically useful salts.

Particularly to be highlighted are compounds of the general formula II or their 5,6,7,8-tetrahydroderivatives in which each of the symbols , R3 and R. means hydrogen,

methyl or ethyl, (CH2^n means propylene, butylene, pentylene or hexylene, m means zero or 1, B means carboxy, methoxycarbonyl or ethoxycarbonyl, unsubstituted carbamoyl, monomethyl- or monoethylcarbamoyl, dimethyl- or diethylcarbamoyl, cyan or hydroxymethyl and their salts, especially their therapeutically useful salts.

Further preferred are compounds of formula II in which the group

is in 5 position.

Extremely useful are compounds of the general formula III

or their 5,6,7,8-tetrahydroderivatives in which p means an integer from 3 - 8, B means carboxy, lower alkoxycarbonyl, unsubstituted, mono- or di-(lower alkyl)-substituted carbamoyl, cyano or hydroxymethyl and their salts , especially their therapeutically useful salts. Particularly valuable are compounds of the general formula IV

or their 5,6,7,8-tetrahydro derivatives in which q is 4,

5 or 6 and their salts, especially their therapeutically useful salts.

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

An alkylene residue means alkylene with 1-12 carbon atoms which may be straight or branched and preferably means propylene, butylene, pentylene or hexylene, the said residues being unsubstituted or substituted with one or more lower alkyl groups with the precaution that the sum of the carbon atoms is not more than 12.

The term alkenylene means an alkenylene residue with 2 - 12 carbon atoms which residue can be straight or branched and preferably means propenylene, 1- or 2-butenyl-ene, 1- or 2-pentenylene, 1-, 2- or 3-hexenylene. The mentioned residues are unsubstituted or substituted with one or more lower alkyl groups with the precaution that the sum of the carbon atoms does not exceed 12.

The term alkynyl denotes an alkynyl residue with 2 - 12 carbon atoms as straight or branched and preferably propynyl means 1- or 2-butynylene, 1- or 2-pentynylene, 1-, 2- or 3-hexynylene. These residues are unsubstituted or substituted with one or more lower alkyl groups, the sum of the carbon atoms not exceeding 12.

The term "lower" defines in the above and following mentioned organic residues or compounds such with a maximum of 7, preferably 4, especially 1 or 2 carbon atoms.

A lower alkyl group preferably contains 1-4 carbon atoms and means e.g. ethyl, propyl or butyl, especially methyl.

A lower alkoxycarbonyl group preferably contains 1-4 carbon atoms in the alkoxy part and means e.g. methoxycarbonyl, propoxycarbonyl or isopropoxycarbonyl, especially ethoxycarbonyl. A mono-)lower alkyl)-carbamoyl group preferably has 1-4 carbon atoms in the alkyl part and is e.g. N-methylcarbamoyl, N-propylcarbamoyl or especially N-ethylcarbamoyl, A di-(lower alkyl)carbamoyl group preferably contains 1-4 carbon atoms in each lower alkyl group and means e.g. N,N-dimethylcarbamoyl, N-methyl-N-ethylcarbamoyl and especially N,N-diethylcarbamoyl.

Salts and preferably therapeutically useful salts, e.g. metal or ammonium salts of the aforementioned compounds of formula I in which B means carboxy, especially alkali metal or alkaline earth metal salts, e.g. sodium, potassium, magnesium or calcium salts, primarily easily crystallising ammonium salts. These are derived from ammonia or organic amines, e.g. mono-, di- or tri-lower (alkyl, cycloalkyl or hydroxyalkyl)amines, lower alkylenediamines or (hydroxy-lower alkyl or aryl-lower alkyl)-lower alkylammonium bases, e.g. methylamine, diethylamine, triethylamine, dicycloethylamine, triethanolamine, ethylenediamine, tris-(hydroxymethyl)aminomethane or benzyltrimethylammonium hydroxide. The aforementioned compounds of formula I form acid addition salts. These are preferably prepared with acids which give therapeutically usable acid addition salts. Acids that give therapeutically useful acid addition salts are e.g. strong mineral acids, such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulphurous, phosphoric, nitric or perchloric acid, or organic acids such as aliphatic or aromatic carboxylic or sulphonic acids, e.g. mayric acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, gluconic acid, citric acid, maleic acid, fumaric acid, hydroxymaleic acid, pyruvic acid, phenylacetic acid, benzoic acid, 4-aminobenzoic acid, anthranilic acid, 4-hydroxybenzoic acid, salicylic acid, 4 -aminosalicylic acid, pamoic acid, nicotinic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, sulfanil or cyclohexylsulfamic acid or ascorbic acid.

The compounds according to the invention show valuable pharmacological properties, e.g. cardiovascular effects by selective inhibition of thromboxane release in mammals. This inhibition is reversed by selective reduction of the thromboxane synthetase. The compounds are therefore useful in the treatment of diseases responsive to thromboxane synthetase inhibition in mammals including humans.

These effects can be demonstrated in in vitro experiments or in vivo animal experiments, preferably on mammals, e.g. guinea pigs, mice, rats, cats, dogs or monkeys. The said compounds can be administered enterally or parenterally, preferably orally or subcutaneously, intravenously or intraperitoneally, e.g. by means of gelatin capsules or in the form of starch-containing suspensions or aqueous solutions. The dose used may range from about 0.01 to 100 mg/kg/day, preferably about 0.05 to 50 mg/kg/day, especially about 0.1 to 25 mg/kg/day.

The in vitro inhibition of the thromboxane synthetase enzyme can be demonstrated according to the method of Sun, Biochem. Biophys. Res. Comm. 74, 1432 (1977). The test procedure is carried out as follows: 14 C-arachidonic acid is incubated with an enzyme mixture preparation consisting of solubilized and partially purified prostaglandin cyclooxygenase from sheep seminal vesicles and a crude microsome preparation of thromboxane synthetase from lysed human platelets. The test compound (dissolved in a buffer or if necessary a little ethanol) is added to the incubation medium. At the end of the incubation period (30 minutes), the prostaglandin E2 (PGE2) is reduced by the addition of sodium borohydride to a mixture of prostaglandin F2a and F2B [PFG^ (ct+3) ] • The radioactive products and the excess substrate are extracted with acetic acid ethyl ester and evaporated to dryness. The residue is dissolved in acetone, applied dropwise to thin-layer plates and chromatographed with a solvent system of toluene:acetone:glacial vinegar [100:100:3 (volume)]. The radioactive zones are located. The zones of thromboxane B2 (TxB2) and PGF2a+6 are transferred into liquid scintillation tubes and counted. The quotient of the numerical values of TxB2/PGF2a+3 is calculated for each concentration of the test compound and the IC5Q value is determined graphically. This value is the concentration of the test compound at which the quotient of TxB^/PGF2a+6 is reduced to 50% of the control value.

The in vitro activity of protaglandin cyclooxygenase is measured according to a modification of the method of Takeguchi et al as discussed in Biochemistry 10, 2372 (1971). The test procedure is as follows: Lyophilized seminal vesicle microsomes from sheep are used as an enzyme preparation for prostaglandin synthesis. The conversion of "<*>"<4>C-arachidonic acid in PGE2» is measured. The test compounds (dissolved in a buffer and if necessary in a little ethanol) are added to the incubation mixture. The prostaglandins are extracted and separated by thin-layer chromatography. The plates are examined, the radioactive zones corresponding to PGE2 are transferred into scintillation tubes for liquids and their radioactivity is counted. The ICj-g value of the inhibition is determined graphically. This value means the concentration of the test compound which reduces the amount of synthesized PGE 2 by around 50%. ;The in vitro effect on prostacyclin-(PGI2) synthetase is obtained analogously to the method of Sun et al, Prostaglandins 14, 10 55 ;(1977). The test procedure is as follows: 14 ;C-arachidonic acid is incubated with an enzyme mixture consisting of solubilized and partially purified prostaglandin cyclooxygenase from sheep seminal vesicles and crude PGI2 synthetase in the form of a microsomal fraction from bovine aortas. ;The test compound (dissolved in a buffer or if necessary a little ethanol) is added to the incubation medium. The reaction mixture is incubated in 100 mmol tris HCl (pH 7.5) for 30 minutes at 37°C, acidified to pH 3 and extracted with ethyl acetate. The extract is evaporated to dryness, the residue is dissolved in acetone and applied to thin-layer plates and chromatographed with a Sun et al. mentioned solvent system. The radioactive zones are located in a detector. The zones corresponding to 6-keto-PGFα (a stable end product of prostacyclin biotransformation) and PGE2 are transferred into liquid scintillation ion tubes and counted. The quotient of the numerical values of 6-keto-PGF 2 a /PGE 2 is calculated for each concentration of the test compound used. The IC^^ value of the inhibition is determined graphically. This value is the concentration of the test compound at which the quotient of 6-keto-PGF.alpha./PGE.sub.2 is reduced to 50% of the control value. The decrease in the thromboxane plasma level is determined in vivo by administering the test compound to guinea pigs as follows: Guinea pigs are treated with the test substance or carrier material and 2 hours later arachidonic acid (40 mg/kg) is injected intraperitoneally. One hour after the administration of the arachidonic acid, blood is taken from the animals. In a specific single amount of each plasma sample, thromboxane B2 is determined and from additional single amounts, 6-keto-PFG1a, the stable metabolites of thromboxane A2 resp. prostacyclin (PGI2). The compounds of formula I are highly effective thromboxane synthetase inhibitors. At effective dose levels and higher, neither the beneficial prostacyclin synthetase nor the prostaglandin cyclooxygenase enzyme system is inhibited. The IC^Q value for a compound according to the invention, e.g. for 5.(5-carboxypentyl)-imidazo[1,5-a]pyridine amounts to 3 x 10 -9 mol for thromboxane synthetase inhibition, while the inhibition for prostacyclin synthetase and prostacyclin cyclooxygenase is each time greater than 1 x 10 -4 mol. ;A compound according to the invention, e.g. 5-(5-Carboxypentyl)-imidazo[1,5-a]pyridine also decreases the plasma level of thromboxane B2 in guinea pigs at an oral dose as low as 0.25 mg/kg by more than 50%. At this or higher oral doses, no clear decrease in prostacyclin is determined. Because of the above beneficial properties, the compounds of the invention are very valuable to mammals including humans as specific therapeutic agents. So reduces e.g. in the case of thromboembolism, this specific inhibitory action of the thromboxane synthetase enzyme, the aggregation of blood platelets produced by arachidonic acid, which plays a role in the formation of blood clots. Experimentally, the prolongation of bleeding times in rats is considered a sign of a favorable antithrombotic effect. The imidazo[1,5-a]pyridines according to the invention prolong the bleeding time. Thus, e.g. 5-(5-carboxypentyl)-imidazo[1,5-a]pyridine this effect when administered intraperitoneally to rats at a dose of about 1 mg/kg or less. Regarding the beneficial effects in respiratory disorders, the fact that the compounds according to the invention ensure protection against the sudden death that occurs due to the lung obstruction produced by arachidonic acid is worth mentioning. Thus protects e.g. 5-(5-Carboxypentyl)-imidazo[1,5-a]pyridine mice against sudden death by an oral administration of a dose of 100 mg/kg. The process according to the invention for producing compounds of formula I is characterized by 1) a compound of formula VI, in which M means an alkali metal and R2 means hydrogen or lower alkyl, is reacted with a compound of formula VII X - A - B ' (VII ) preferably means halogen, A has the above-mentioned meaning, B' means carboxy, trilaverealalkyloxymethyl, cyan, etherified hydroxymethyl or halogenmethyl, and a formed compound of formula Ia; (a) in which B' means trilaverealoxymethyl, is transferred in situ in an acidic environment to a compound of formula I, in which B ;means lower alkoxycarbonyl1, or ;(b) in which B<1> means halomethyl1, is transferred by reaction with cyanide ions to a compound of formula I, in which ;B means cyan or ;(c) in which B' means etherified hydroxymethyl, is hydrolyzed to a compound of formula I, in which B means hydroxymethyl, ;or ;(d) in which B<1> means halomethyl by reaction with an alpha-phenylthioacetic acid lower alkyl ester, oxidation of the thio group to su lfinyl and elimination is transferred to a compound of formula I, in which ;B means lower alkoxycarbonyl and the chain A is extended ;by a terminal -CH=CH- group or, ;(e) in which B<1> means halomethyl, is converted by reaction with malonic acid dilave alkyl ester, hydrolysis and decarboxylation to a compound of formula I, in which B means carboxy and the chain A is an extended with a terminal - CH^-Cr^ group or (f) in which B<1> means halomethyl is converted by conversion to a Grignard compound, condensation of this with a haloacetic acid lower alkyl ester and hydrolysis to a compound of formula I, in which ;B means carboxy and the chain A is extended by a terminal ;-CH2CH2~ group or ;(g) in which B<1> means halomethyl , is converted by conversion to a Grignard compound and condensation of this with C02 to a compound of formula I, in which B means carboxy and the chain A is extended by a terminal ;-CH0 group or, ;(h) in which B' means halomethyl , is converted by reaction with lithium mdiisopropylamide and propionic acid to a compound of formula I, wherein B is carboxy and the chain A is extended by a terminal -CH 2 -C=C group, or ;(2) a compound of formula VIII ;wherein M is an alkali metal, R 2 is hydrogen or lower alkyl, and R,- means lower alkyl, is reacted with a compound of formula IX in which X preferably means halogen, A has the above meaning, B' means carboxy, trilavereal oxymethyl, cyan, etherified hydroxymethyl or halomethyl, in a compound formed, in which B ' means trilavereal oxymethyl, halomethyl or etherified hydroxymethyl, the group B<1> is converted as indicated by method (1) into a residue B, and the compound formed is desulphurised, or 3) a compound of formula XI in which each of the symbols R'2 and R "2 means hydrogen or lower alkyl, A has the above meaning and B" means carboxy, lower alkoxycarbonyl, cyano, hydroxymethyl, lower alkanoyloxymethyl, etherified hydroxymethyl or halomethyl, is ring-closed to a compound with rmel Ib ; and a compound formed, ; (a) in which B" means halomethyl, is transferred by reaction with cyanide ions to a compound of formula I, in which ; B means cyan, or ; (b) in which B" means etherified hydroxymethyl or lower alka- noyloxy, is hydrolyzed to a compound of formula I, in which B means hydroxymethyl, or; 4) a compound of formula XIV; in which A<1> means an alkylene, alkylene or alkynyl residue with a maximum of 11 carbon atoms, is hydrogenated, or 5) in a compound of formula XVI in which Rp and A have the above meaning, and C means acetyl, carboxycarbonyl, formyl or dilavereal oxymethyl, C is transferred to a carboxy group B in the following way: (a) oxidation of an acetyl group C by means of sodium hypobromide, (b ) thermal treatment of C=carboxycarbony1, ; (c) oxidation of a formyl or dilavereal oxymethyl group C, and if desired. (a) for the preparation of 5,6,7,8-tetrahydro derivatives of compounds of formula I, a formed compound of formula I, which is not hydrogenated in the 5-, 6-, 7- and 8-position, is hydrogenated, ;(b) for the preparation of compounds of formula I, in which B is carboxy, a formed compound of formula I, in which B is lower alkoxycarbonyl, ;carbamoyl or cyan, is hydrolyzed; ;(c) for the preparation of compounds of formula I, in which B is carbamoyl, a formed compound of formula I, in which B means cyan, is partially hydrolyzed; (d) to prepare compounds of formula I, in which B means hydroxymethyl, a formed compound of formula I, in which B means carboxy or lower alkyl oxyca is reduced rbony1, (e) for the preparation of compounds of formula I, in which B means carboxy, a formed compound is oxidized; of formula I, in which B means hydroxymethyl, ; (f) for the preparation of compounds of formula I, in which B means carboxy and A is extended by a terminal CC^ group, a formed is transferred compound of formula I, in which B is carboxy, to an acid halide and is reacted with diazomethane, (g) to prepare compounds of formula I, in which B is carboxy and A is extended with a terminal CO, group, a formed is reacted compound of formula I, in which B means hydroxymethyl, with nickel carbonyl, (h) for the preparation of compounds of formula I, in which B means mono- or di-(lower alkyl)-carbamoyl, a formed compound of formula I, in which B means lower alkoxycarbonyl or carboxy, with ethyl lower alkyl- or (i) for the preparation of compounds of formula I, in which B means di-(lower alkyl)-carbamoyl, N-alkylates a resulting compound of formula I, in which B means mono-(lower alkyl)- carbamoyl, (j) for the preparation of compounds of formula I, in which 1*2 means halogen, a compound formed is halogenated

of formula I, wherein is hydrogen,

(k) for the preparation of compounds of formula I, wherein

A means alkylene, a formed compound of formula I is hydrogenated, in which A means alkenylene,

and/or if desired, a formed free compound is transferred to a salt or a formed salt to the free compound or to another salt,

Reactive organometallic compounds of formula VI, in which M represents an alkali metal atom, can be obtained by metallization of suitable methyl-substituted imidazo[1,5-a]pyridines. Thus, e.g. according to Journal of Organic Chemistry 40, 1210 (1975) prepared 5-methylimidazo[1,5-a]-pyridine with a reactive metallizing agent, e.g. with butyllithium or lithium diisopropylamide in an inert solvent, e.g. tetrahydrofuran at a temperature below room temperature, preferably at about -50°C.

The condensation of an intermediate of formula VI with a reactive functional derivative of a compound of formula VII is preferably carried out in a temperature range from approximately -75° - +50°C. When B' means carboxy or mono-(lower alkyl)-carbanoyl, the suitable metal salt is first prepared, e.g. the lithium salt of the reactive functional derivative of the corresponding compound of formula VII and this reacts with the intermediate VI.

The preparation of the organometallic intermediate VIII and the subsequent condensation is carried out as discussed above and in Tetrahedron Letters 21, 2195-6 (1980). Desulphurisation is preferably carried out with a desulphurisation catalyst such as Raney nickel in a solvent, e.g. ethanol, preferably at elevated temperature.

The cyclization of the amide of formula XI is preferably carried out with a Lewis acid, e.g. polyphosphoric acid, phosphorus oxychloride or polyphosphate ester, possibly in an inert solvent, e.g. toluene, in a temperature range between 25 - 150°C, preferably 50 - 120°C.

The amides of formula XI are prepared by acylation of a compound of formula XII in which each of the symbols R-^, R^, A and B" has the above meaning, with a carboxylic acid of formula XIII

where RIJ has the above meaning or with a reactive functional derivative thereof.

Reactive functional derivatives of compounds XIII are preferably acid halides, simple or mixed anhydrides, e.g. the acid chloride, the acid anhydride (RIJCO^O or a mixed anhydride. This can be prepared from a lower alkoxycarbonyl halide, e.g. chloroformate ethyl ester, or from a hindered lower alkanoyl halide, e.g. from pivaloyl chloride, according to methods known per se.

The condensation of compounds XII and XIII (acylation of compounds XII) proceeds either spontaneously, e.g. by heating with formic acid or in the presence of condensation agents such as disubstituted carbodiimides, e.g. dicyclohexyl carbodiimide.

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

The amines of formula XII can e.g. are obtained from correspondingly substituted 2-(cyano- or hydroxyimino-lower alkyl)-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, e.g. borane or sodium cyanoborohydride. The reducing agent is chosen according to the type of functional groups present in the molecule. The compounds of formula XII can also be obtained by amination of the correspondingly substituted and reactive esterified 2-(hydroxymethyl)-pyridines.

The starting substances with formula XIV can e.g. obtained by condensation of a compound of formula XV

(formed e.g. by reacting a compound of formula VIII with dimethylformamide and subsequent desulfurization with Raney nickel) in a Wittig reaction, e.g. with a tri-lower alkyl-4-phosphonocrotonate in the presence of a strong base, e.g. sodium hydride.

Residues transferable to a carboxy group are e.g. esterified carboxy groups, anhydridized carboxy groups, including corresponding groups of asymmetric or internal anhydrides, amidated carboxy groups, cyan, amidino groups including cyclic amidino groups such as 5-tetrazolyl, iminoether groups, including cyclic iminoether groups such as e.g. with lower alkyl substituted 2-oxazolinyl or dihydro-2-oxazolinyl groups, further hydroxymethyl, etherified hydroxymethyl, lower alkanoyloxymethyl, trialkyloxymethyl, acetyl, trihaloacetyl, halomethyl, carboxycarbonyl (COCOOH), methyl, formyl (CHO), di-lower alkoxymethyl , alkylenedioxymethyl, vinyl or diazoacetyl. During the conversion to the carboxy group, the chain A can be extended within its definition at the same time.

The transfer to the carboxy group is carried out according to i

and known methods as discussed here or in the examples, e.g. solvolytic, such as hydrolytic or acidolytic or reductive (esterified carboxy groups). Thus, e.g. trichloroethyl or 2-iodoethyl ester by reduction, e.g. with zinc and a carboxylic acid in the presence of water to the carboxylic acid. Benzyl esters or nitrobenzyl esters can be converted by

catalytic hydrogenation, the latter also with chemical reducing agents, e.g. sodium dithionite or with zinc and a carboxylic acid to the carboxyl group. Furthermore, e.g. tert-butyl ester is also split, e.g. with trifluoroacetic acid.

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

Furthermore, compounds of formula XVI in which C means acetyl can be cleaved oxidatively to the corresponding compounds of formula I in which B means carboxy. First, the starting material is converted into a compound XVI in which C means trihaloacetyl, e.g. tribromo- or triiodoacetyl, e.g. by treatment with sodium hypobromite and then decomposed, e.g. with an aqueous base, e.g. sodium hydroxide.

Starting substances with formula XVI in which C means acetyl can be prepared starting from compounds Ib in which B' means halomethyl by treatment with an acetoacetic acid-lower alkyl ester, e.g. acetoacetic acid ethyl ester in the presence of a base, e.g. sodium hydride and subsequent hydrolysis with a strong base, e.g. with aqueous sodium hydroxide.

Starting substances with formula XVI in which C means carboxycarbonyl (COCOOH) are transferred by thermal treatment or by oxidation in connection with formula I in which B means carboxy. The starting material is thereby heated to an elevated temperature, e.g. approximately 200°C in the presence of glass powder or treated e.g. with hydrogen peroxide in the presence of a basic agent, e.g. sodium hydroxide,

Starting substances with formula XVI in which C means COCOOH can e.g. obtained by condensation of a compound of formula Ia in which B<1> means halomethyl with e.g. 2-ethoxycarbonyl-1,3-dithiane and subsequent oxidative hydrolysis, e.g. with bromosuccinimide in aqueous acetone and then by treatment with dilute aqueous sodium hydroxide.

Compounds of formula XVI in which C means formyl, lower alkoxymethyl or alkylenedioxymethyl (formyl protected in the form of an acetal), e.g. dimethyl acetal, is oxidized e.g. with silver nitrate or ozone to compounds of formula I in which B is carboxy.

The carboxyaldehydes used as starting materials, i.e. compounds of formula XVI in which C means formyl, are produced by oxidation of compounds of formula I or Ia in which B resp. B' means hydroxymethyl or halomethyl, e.g. with dimethylsulfoxide and a catalyst, e.g. a mixture of triethylamine and silver tetrafluoroborate. The carboxyaldehydes formed can be transferred into the corresponding acetals, i.e. compounds of formula XVI in which C means di-lower alkoxymethyl or alkylenedioxymethyl, e.g. a dimethyl acetal by acid catalyzed condensation with an alcohol, e.g. methanol.

Compounds of formula I in which B is carboxy

can be converted by the well-known Arndt-Eistert synthesis into compounds of formula I in which B means carboxy and the chain contains one more carbon atom. In particular, a reactive functional derivative of the carboxylic acid used as starting material is treated, e.g. acid chloride with diazomethane, e.g. in diethyl ether, obtaining a compound of formula XVI in which C is diazoacetyl. Conversion with e.g. silver oxide in said carboxylic acid with formula I in which the chain A contains one more carbon atom.

Compounds of formula XVI in which C means vinyl are converted into compounds of formula I in which B means carboxy first by ozonolysis to compounds of formula XVI in which C means formyl. These are then oxidized to the compounds of formula I in which B means carboxy.

Starting substances of formula XVI in which C can mean

vinyl can also be treated with nickel carbonyl and carbon monoxide under high pressure, obtaining compounds of formula I in which B means carboxy and the chain A is extended by one carbon atom.

The individual definitions in the above-mentioned methods have the following meanings: In a reactive functional derivative of an alcohol of formula VII and IX, the hydroxy group is e.g. esterified with a strong inorganic acid or organic sulphonic acid, above all with a hydrohalic acid, e.g. hydrochloric, hydrobromic or hydroiodic acid or an aliphatic or aromatic sulphonic acid, e.g. methanesulfonic or p-toluenesulfonic acid. These compounds are produced in a manner known per se.

Trialkoxymethyl preferably means tri(lower alkoxy)methyl/ especially triethoxy or trimethoxymethyl.

Ethered hydroxymethyl preferably means tertiary lower alkoxymethyl, lower, alkoxyalkyloxymethyl, e.g. methoxymethoxymethyl, 2-oxa- or 2-thiacycloalkoxymethyl, especially 2-tetrahydropyranyloxymethyl.

Halomethyl means especially chloromethyl, but also bromomethyl or iodomethyl.

Lower alkanoyloxymethyl preferably means acetoxymethyl.

An alkali metal is preferably lithium, but it can also be potassium or sodium.

The inevitable steps for the conversion of a formed compound in which B<1> or B" differs from B into a compound of formula I or the facultative conversion of a formed product of formula I into another compound according to the invention are carried out according to per se known chemical methods.

The hydrolysis of intermediates in which B<1> stands for trialkoxymethyl to compounds of formula I in which B is carboxy is preferably carried out with inorganic acids such as halogen-hydrogen or sulfuric acid. The hydrolysis of intermediates in which B' means etherified hydroxymethyl to compounds of formula I in which B is hydroxymethyl is preferably carried out with aqueous solutions of inorganic acids, e.g. a hydrohalic acid.

The compounds of formula I in which B means lower alkoxycarbonyl can with ammonia, mono- or di-lower alkylamines, e.g. methylamine or dimethylamine in an inert solvent, e.g. lower alkanol such as butanol, optionally at elevated temperatures is amidated to compounds of formula I in which B means unsubstituted mono- or di-(lower alkyl)-substituted carbamoyl.

Compounds of formula I in which B means unsubstituted

carbamoyl can be dehydrated to the corresponding nitriles on

in and of itself known way, e.g. by treatment with triphenylphosphine or thionyl chloride in an inert solvent, e.g. toluene.

The conversion of compounds of formula I in which B means lower alkoxycarbonyl, cyano, unsubstituted, mono- or di-(lower alkyl)-substituted carbamoyl to compounds of formula I in which B means carboxy is preferably carried out by means of hydrolysis with inorganic acids, e.g. with hydrohalic acids or sulfuric acid or with aqueous alkalis, preferably with alkali metal hydroxides, e.g. lithium

or sodium hydroxide.

Compounds of formula I in which B is carboxy or lower alkoxycarbonyl can be reduced with simple or complex light metal hydrides, e.g. with lithium aluminum hydride, alane or diborane to compounds of formula I in which B is hydroxymethyl. The alcohols can also be obtained by suitable solvolysis of intermediates of formula Ia or Ib in which B<1>

and B" means halomethyl, by treatment eg with an alkali metal hydroxide, eg lithium or sodium hydroxide.

The above-mentioned alcohols can in turn be converted

to compounds of formula I in which B is carboxy, with usual oxidizing agents, preferably with pyridine dichromate in dimethylformamide at room temperature. The mentioned alcohols can also be converted to the compounds of formula I in which B means carboxy and the chain is lengthened by one carbon atom by treatment with nickel carbonyl and carbon monoxide under high pressure.

Free carboxylic acids can with lower alkanols, e.g. ethanol in the presence of a strong acid, e.g. sulfuric acid, preferably at elevated temperatures, or with diazo-lower alkanes, e.g. diazomethane in a solvent, e.g. ethyl ethers, preferably at room temperature, are esterified to the corresponding esters, namely to such compounds of formula I in which B means lower alkoxycarbonyl.

Furthermore, they can free carboxylic acids during treatment

of their reactive intermediates, e.g. an acyl halide such as an acid chloride or mixed anhydrides, e.g.

one derived from a halocarbonic acid lower alkyl ester, e.g. chloroformic acid ethyl ester with ammonia, mono- or di-lower alkylamines, in an inert solvent, e.g. methylene chloride, preferably in the presence of a basic catalyst, e.g. pyridine, is converted in the compounds of formula I in which B means unsubstituted, mono- or di-(lower alkyl)-substituted carbamoyl.

The compounds of formula I wherein B is mono-lower alkylcarbamoyl can be converted into compounds of formula I wherein B is di-lower alkylcarbamoyl by treatment with a strong base, e.g. sodium hydride and then with an alkylating agent, e.g. a lower alkyl halide, in an inert solvent, e.g. dimethylformamide.

The compounds of formula I can be converted into the corresponding 5,6,7,8-tetrahydro-imidazo[1,5-a]pyridine compounds by reduction with hydrogen in the presence of hydrogenation catalysts, e.g. palladium and an acid, e.g. a mineral acid such as hydrochloric acid in an inert solvent, e.g. ethanol.

Furthermore, compounds of formula I in which A means a straight-line or branched alkynylene or alkenylene residue can by catalytic hydrogenation preferably under neutral conditions, e.g. with a palladium catalyst at atmospheric pressure in an inert solvent, e.g. ethanol, is converted to compounds of formula I in which A means straight or branched alkylene.

Moreover, the compounds of formula I in which R 2 means hydrogen can be transferred into the corresponding halogen derivatives by direct halogenation with chlorine, bromine or iodine.

The above-mentioned reactions are carried out according to methods known per se in the presence or absence of diluents, preferably in such that are inert towards the reagents and dissolve them, catalysts, condensation or other above-mentioned agents and/or in an inert atmosphere under

> cooling at room temperature or elevated temperature, preferably at the boiling point of the solvent used, at normal or elevated pressure.

In the method according to the invention, such starting materials are preferably used which lead to the compounds mentioned above as particularly valuable.

Finally, the compounds according to the invention can be obtained

in free form or as salts. A formed free base can be transferred into the corresponding acid addition salt, preferably with acids which give therapeutically usable acid addition salts or with anion exchangers. Formed salts can be converted into the corresponding free bases, e.g. by treatment with a strong-er such as a metal hydroxide or ammonium hydroxide, basic salts, e.g. an alkali metal hydroxide or carbonate, or a cation exchanger. A compound of formula I in which B means carboxy can also be transferred in the corresponding metal or ammonium salts. These and other salts, e.g. the picrates, can also be used for the purification of free bases. The bases are transferred in their salts, the salts are separated and the bases are released from the salts.

Due to the narrow relationship between the new compounds in free form and in the form of their salts, in the foregoing and the following, free compounds and salts may also mean the corresponding salts or free connections.

The compounds and their salts can also be obtained in form

of their hydrates or other entrapping solvents used for the crystallization.

The invention will be explained in more detail with the help of some examples. The temperatures are stated in degrees Celsius and the indications above parts relate to parts by weight. If nothing else is specified, evaporation of the solvent is carried out under reduced pressure, e.g. between about 15 and 100 mg/Hg.

Example 1

A solution of 50 g of 5-methylimidazo[1,5-a]pyridine [J. Org. Chem. 40, 1210 (1975)] in 625 ml of tetrahydrofuran is pre-cooled to -75°C and mixed under nitrogen with 175 ml of 2.4N butyllithium in hexane keeping the temperature below -53°C. The solution of 5-(lithiomethyl)-imidazo[1,5-a]pyridine is cooled again to -75°C and mixed rapidly with a solution of 121.8 g of 5-bromo-1,1,1-triethoxypentane in 125 ml of tetrahydrofuran as the temperature rises to -60°C. The reaction mixture is allowed to warm to -4°C within 4-5 minutes and is practically evaporated to dryness. The residue is distributed between 500 ml of ethyl ether and 240 ml of 3N hydrochloric acid. The ether solution is extracted again twice with 60 ml of 3N hydrochloric acid. The combined aqueous extracts are basified with 100 ml of concentrated ammonium hydroxide and extracted twice with 200 ml of ethyl ether. The ether extract is dried over magnesium sulfate and evaporated to dryness. The oil formed is distilled under high vacuum. 5-(5-ethoxycarbonylpentyl)-imidazo[1,5-a]pyridine is obtained which boils at 180-186°C/0.12 mm Hg.

Example 2

A suspension of 26 g of 5-(5-ethoxycarbonylpentyl)-imidazo[1,5-a]pyridine in 100 ml of IN aqueous sodium hydroxide solution is heated for 2 hours on a steam bath, mixed with 10 ml of ethanol and heated again for 45 minutes. The reaction mixture is cooled, washed with 300 ml of ether and the solution is adjusted to pH 5.5 with concentrated hydrochloric acid. The crystallized product is filtered off and washed with 50 ml of water. 5-(5-carboxypentyl)-imidazo[1,5-a]pyridine is obtained which melts at 144-147°C.

Example 3

a) A solution of 39.6 g of 5-bromovaleric acid in 400 ml of tetrahydrofuran is cooled to -78°C and slowly mixed with 93 ml of 2.3N butyllithium solution in hexane, keeping the temperature below -65°C. The suspension is stirred for 20 minutes and then mixed with a solution of 5-(lithio-methyl)-imidazo[1,5-a]pyridine (prepared from 26.9 g of 5-methyl-imidazo[1,5-a]pyridine and 93 ml of 2.3N n-butyllithium solution according to example 1) all at once at -75°C. The reaction mixture is stirred for 2 hours at -75°C, allowed to warm to room temperature, treated with 15 ml of 12N hydrochloric acid and evaporated in vacuo.

The residue is distributed between water and methylene chloride after adjusting the pH value with sodium carbonate to 10. The aqueous solution is further washed with chloroform, adjusted with 12N hydrochloric acid to a pH value of 1 and washed again with ether and toluene. The pH is adjusted with sodium bicarbonate to 5.5, and the extraction with chloroform gives crude 5-(5-carboxypentyl)-imidazo[1,5-a]pyridine. A solution of the acid in 30 ml of acetonitrile is treated with 20 ml of 5N hydrochloric acid. After adding 25 ml of ethyl ether, the crystalline 5-(5-carboxypentyl)-imidazo[1,5-a]pyridine hydrochloride is obtained which melts at 201-204°C. 5-(5-Carboxypentyl)-imidazo[1,5-a]pyridine (Example 2) is obtained after neutralization of the methanolic solution with dilute sodium hydroxide solution to a pH value of 5.

b) Starting from 6-bromohexanoic acid, 5-(6-carboxyhexyl)-imidazo[1,5-a]pyridine is prepared in an analogous way

which melts at 137-139°C.

c) Analogously, 5-(7-carboxyheptyl)-imidazo-[1,5-a]pyridine is also obtained when starting from 7-bromoheptanoic acid. Melting point 97-101°C.

Example 4

A solution of 37 g of 5-(5-chloropentyl)-imidazo-[1,5-a]pyridine, 21.7 g of potassium cyanide and 3 g of dibenzo-18-croneether-6 in 500 ml of acetonitrile is boiled for 20 hours under reflux -run. The acetonitrile is evaporated under reduced pressure, the residue is distributed between water and methylene chloride and the methylene chloride extract is evaporated to dryness. By treating a solution of the residue in ether with ethanolic hydrochloric acid, 5-(5-cyanopentyl)-imidazo[1,5-a]pyridine hydrochloride is obtained which melts at 178-180°C.

The starting material is obtained as follows:

A solution of 30 g of 1-bromo-4-chlorobutane in 20 ml of dry tetrahydrofuran is added to a solution of 5-(lithio-methyl)-imidazo[1,5-a]pyridine (prepared according to example 1

of 22 g of 5-methyl-imidazo[1,5-a]pyridine in 80 ml of a 2.3N solution of n-butyllithium in hexane), keeping the temperature below -50°C. The reaction mixture is stirred for 2-3 hours at -50°C, heated 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 sulphate and evaporated to dryness. 5-(5-chloro-pentyl)-imidazole [1,5-a]pyridine is obtained which is used without further purification.

Example 5

According to the method described in example 4, 5-(chlorobutyl)-imidazo[1,5-a]pyridine is converted to 5-(4-cyanobutyl)-imidazo 1,5-a pyridine, melting point 72-77°C.

Example 6

In an analogous procedure to the one mentioned in example 4,

in manner 3,5-dimethylimidazo[1,5-a]pyridine is converted [J. Hot. Chem.

3, 33 (1966)] to 5-(5-chloropentyl)-3-methyl-imidazo[1,5-a]pyridine. Melting point 98-104°C. The reaction carried out according to the conditions in example 4 with potassium cyanide gives 5-(5-cyan-pentyl)-3-methyl-imidazo[1,5-a]pyridine, which is converted into its hydrobromide by dissolving the free base in acetonitrile and acidifying the solution with ethanolic hydrogen bromide. The 5-(5-cyanopentyl)-3-methylimidazo[1,5-a]pyridine hydrobromide formed melts at 215-220°C.

Example 7

A solution of 36 g of 5-(cyanopentyl)-imidazo[1,5-a]-pyridine in 100 ml of methanol and 50 ml of a 45% aqueous potassium hydroxide solution is refluxed for 48 hours. The methanol is evaporated under reduced pressure and the residue is mixed with water. The basic solution is washed with acetic acid ethyl ester and acidified with concentrated hydrochloric acid to a pH value of 5.5-6. The crystallized acid is separated and recrystallized from ethanol. The product from example 2 is obtained, namely 5-(5-carboxypentyl)-imidazo[1,5-a]pyridine, which melts at 142-145°C. A further recrystallization increases the melting point to 144-147°C.

Example 8

Hydrolysis of 5-(4-cyanobutyl)-imidazo[1,5-a]pyridine according to Example 7 gives 5-(4-carboxybutyl)-imidazo[1,5-a]pyridine which melts at 161-163°C.

Example 9

The hydrolysis of 5-(5-cyanopentyl)-3-methyl-imidazo-[1,5-a]pyridine according to Example 7 gives 5-(5-carboxypentyl)-3-methyl-imidazo[1,5-a]pyridine which melts at 170-173°C.

Example 10

A solution of 3 g of 5-(5-cyanopentyl)-3-methyl-imidazo[1,5-a]pyridine hydrochloride in a mixture of 20 ml of ethanol and 5 ml of IN aqueous sodium hydroxide solution is mixed with 10 ml of a 30% ig hydrogen peroxide solution. The reaction mixture is then mixed with 5 ml of ethanol and adjusted to pH 10 with IN sodium hydroxide solution.

The mixture is stirred overnight at room temperature, ethanol is evaporated under reduced pressure, the residue is mixed with water and extracted with methylene chloride. The product formed is crystallized from ether and recrystallized from acetonitrile. 5-(5-carbamoylpentyl)-imidazo[1,5-a]pyridine is obtained which melts at 131-132°C.

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 in a pressure vessel for 56 hours on a steam bath. The reaction mixture is evaporated to dryness. The product formed is recrystallized first from ether and then from a 1:1 mixture of acetic acid-ethyl ester-ether. 5-[5-(N-methyl-carbamoyl)-pentyl]-imidazo[1,5-a]pyridine is obtained which melts at 118-122°C.

Example 12

A solution of 2.45 g of 5-[5-(N-methylcarbamoyl)-pentyl]-imidazo[1,5-a]pyridine in 25 ml of dimethylformamide is mixed with 0.011 mol of sodium hydride (formed by washing 0.53 g of a 50% sodium hydride dispersion in mineral oil with hexane)

and heated briefly in a steam bath. The cooled yellow solution is mixed with 1.56 g of methyl iodide. The mixture is stirred for 2 hours at room temperature, diluted with 100 ml of water and extracted first with 150 ml of a 1:1 mixture of ethyl acetate and ether and then with 100 ml of chloroform. The dry residue formed after evaporation of the combined extracts is dissolved in 100 ml of ether and treated with 20 ml of ethanolic hydrochloric acid. The salt formed as a precipitate is separated, first recrystallized from 50 ml of a mixture of acetonitrile/acetic acid ethyl ester (1:1) and then from 30 ml of ethanol/ether mixture (1:1). 5-[5-(N,N-dimethylcarbamoyl)-pentyl]-imidazo [1,5-a]pyridine hydrochloride is obtained which melts at 166-171°C.

Example 13

1.0 g of 5-(5-carboxypentyl)-imidazo-[1,5-a]pyridine is suspended in 5 ml of tetrahydrofuran. The suspension is mixed with stirring at room temperature first with 2.35 g of trimethylborate and then slowly with 1.0 ml (equivalent to 0.01 mol) of borane-methylsulphide complex. The reaction mixture is heated for 2 hours at reflux temperature, cooled and stopped by adding 2.6 ml of methanol, 9.5 ml of water and 2 ml of 50% aqueous sodium hydroxide solution. The mixture is refluxed for 1 hour, diluted with 50 ml of water and extracted twice with 75 ml of methylene chloride each time. The methylene chloride extract is evaporated to dryness and the residue is treated with 4 ml of 5N hydrochloric acid in 30 ml of ether. 5-(6-hydroxy-hexyl)-imidazo[1,5-a]pyridine hydrochloride is obtained which melts at 174-179°C.

Example 14

A solution of 11.1 g of 1-tetrahydropyranyloxy-8-bromooctane in 15 ml of tetrahydrofuran is added at -70°C to a solution of 5-(lithiomethyl)-imidazofl,5-a]pyridine (prepared according to example 1 from 5 g 5 -methylimidazo[1,5-a]pyridine and 17.7 ml of 2,3N n-butyllithium in hexane). The mixture is stirred for 1 hour at -70°C and then without additional cooling overnight. The mixture is evaporated to dryness, the residue is dissolved in 50 ml of 4N hydrochloric acid, the solution is washed twice with each time 100 ml of ether, made basic with 75 ml of aqueous sodium hydroxide solution and extracted twice with each time 100 ml of methylene chloride. The methylene chloride extract is evaporated to dryness. The residue is converted with ethereal hydrochloric acid to the hydrochloride and recrystallized from ethanol/ether. 5-(9-hydroxynonyl)-imidazo[1,5-a]pyridine hydrochloride is obtained which melts at 150 - 153°C.

Example 15

a) A solution of 2.7 g of 5-(6-carboxyhexyl)-imidazo [1,5-a]pyridine in a mixture of 120 ml of ethanol and 30 ml

concentrated hydrochloric acid is hydrogenated at 3 atmospheres in the presence of 1 g of 10% palladium-on-charcoal catalyst to absorb 2 mol of hydrogen. The mixture is filtered from the catalyst and evaporated to dryness. The residue is recrystallized from isopropanol/ether. 5-(6-carboxyhexyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine hydrochloride is obtained which melts at 150-154°C. b) In an analogous way, by hydrogenating 5-(5-carboxypentyl)-imidazo[1,5-a]pyridine, 5-(5-carboxypentyl)-5,6,7,8-tetrahydroimidazo[1, 5-a]pyridine hydrochloride melting at 146-150°C. c) Starting from 5-(4-carboxybutyl)-imidazo [1 , 5-a ]pyridine, one obtains in an analogous way 5-(4-carboxybutyl)-

5,6,7,8-tetrahydro-imidazo[1,5-a]pyridine hydrochloride melting at 120-123°C.

Example 16

A solution of 2.3 g (0.011 mol) of 5-bromo-3,3-dimethylpentanoic acid [J.Org.Chem., 44, 1258 (1979)] in 20 ml of dry tetrahydrofuran is cooled in a nitrogen atmosphere to -70° C

and mixed dropwise with 5.05 ml of 2.4-molar n-butyllithium in hexane. After completion of the addition, a solution of 5-(lithomethyl)-imidazo[1,5-a]pyridine in hexane (prepared from 1.32 g of 5-methylimidazo[1,5-a]pyridine and 5.05 ml 2.4N n-butyllithium in hexane). The mixture is stirred overnight at room temperature.

The reaction mixture is diluted with 50 ml of water, mixed with 10 g of sodium carbonate and the basic solution is extracted three times with 75 ml of chloroform each time. The aqueous phase is acidified with 12N hydrochloric acid to a pH value of 2 and extracted three times with 100 ml of ether each time. Finally, the aqueous phase is adjusted to pH 5 with dilute sodium hydroxide solution and extracted with 200 ml of an acetic acid ethyl ester/ether mixture (1:1). The extracts are dried and evaporated to give a yellow oil. This is recrystallized from 50 ml of an ethanol/ether mixture (1:1). 5-(5-carboxy-4,4-dimethylpentyl)-imidazo[1,5-a]pyridine is obtained as

melts at 124-129°C.

Example 17

1.9 g of iodine crystals are added to a vigorously stirred solution of 1.16 g of 5-(5-carboxypentyl)-imidazo[1,5-a]pyridine and 1.68 g of sodium carbonate in 10 ml of water and 1 ml of ethanol. To dissolve most of the iodine, a further 4 ml of ethanol is added and the mixture is stirred for a further 45 minutes. The reaction mixture is diluted with 12 ml of water and extracted twice at pH 8 (if necessary with the addition of sodium bicarbonate) with methylene chloride. The aqueous phase is concentrated in vacuo, cleaned with activated carbon 5 and adjusted to pH 4.5 with 2N hydrochloric acid. The precipitate is separated, dried and recrystallized from methanol/ether. One obtains 1-iodo-5-(5-carboxypentyl)-imidazo[1,5-a]pyridine which melts at 163-165°C.

Example 18

A solution of 5-methylimidazo[1,5-a]pyridine

(4.0 g) and tetramethylethylenediamine (4.9 g) in 100 ml of tetrahydrofuran are cooled under nitrogen at 0°C and mixed dropwise with 26.5 ml of 1.6N n-butyllithium in hexane while keeping the temperature below 2 °C. After 30 minutes in a nitrogen atmosphere, this solution is added over 45 minutes to an ice-cold solution of 5-bromovaleronitrile (4.86 g) in 80 ml of tetrahydrofuran. The solvent is evaporated after 15 minutes and the residue is divided between water and ethyl acetate. The organic phase is extracted with 2N hydrochloric acid (3 x 15 ml). The aqueous phase is adjusted with a 50% sodium hydroxide solution to a pH value of 10. It is extracted with ethyl acetate (2 x 75 ml), dried with magnesium sulfate, evaporated and chromatographed (silica gel, ethyl acetate). 5-(5-cyanopentyl)-imidazole[1,5-a]pyridine is obtained.

Example 19

A solution of 4 g of 5-(4-ethoxycarbonylbutyl)-3-ethylthio-imidazo[1,5-a]pyridine in 100 ml of ethanol is mixed with about 5 g of Raney nickel. The solution is boiled for 18 hours under reflux. Raney nickel is filtered off and washed with 100 ml ethyl acetate. The filtrate is evaporated under reduced pressure to dryness. You get the product as a heavy oil. This is purified by column chromatography (silica gel) and eluted with a (1:3) mixture of ether-hexane. The solvent is evaporated under reduced pressure. 5-(4-Ethoxycarbonylbutyl)-imidazo-[1,5-a]pyridine is obtained as a yellow oil. NMR (CDCl 3 ) 1.25 (t, 3H), 4.15 (q, 2H), 8.1 (s, 1H).

The starting material is produced as follows:

17.8 g of 3-ethylthio-imidazo[1,5-a]pyridine are dissolved in 200 ml of dry tetrahydrofuran and the solution is cooled to

-70°C. Over the course of 15 minutes, 50 ml of 1.6-molar n-butyllithium in hexane is added dropwise with stirring. After the addition is complete, the reaction mixture is stirred for a further 30 minutes at -70°C. The mixture is mixed dropwise with a

solution of 20 g of bromopentanoic acid ethyl ester in 75 ml of tetrahydrofuran. The reaction mixture is allowed to warm to -10°C, kept for 30 minutes at this temperature and then 1 hour at room temperature. The reaction mixture is mixed with 400 ml of diethyl ether and 400 ml of 4N hydrochloric acid. The aqueous phase is separated and the ethereal layer is washed with water. The combined aqueous extracts are basified with ammonium hydroxide and extracted three times each time

200 ml of ether. The ether extract is dried over anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure. A heavy oil is obtained as a raw product. This is chromatographed on

a silica gel column and eluted with a (4:1) mixture of pentane diethyl ether. The solvent is evaporated and the product

is distilled. 3-Ethylthio-5-(4-ethoxycarbonylbutyl)-imidazo[1,5-a]pyridine is obtained which boils at 170°C/0.3 mm Hg. NMR

(CDCl 3 ) 1.25 (5, 3H), 1.30 (5, 3H), 3.15 (q, 2H), 4.15 (q, 2H).

Example 2 0

A solution of 3 g of 5-[5-ethoxycarbonyl-5-(phenyl-sulfinyl)-pentyl]-imidazo[1,5-a]pyridine in 50 ml of xylene is boiled

) under nitrogen 30 minutes under reflux. The xylene is then evaporated under reduced pressure, the residue being dissolved in 15 ml of diethyl ether and chromatographed on silica gel. The product is eluted with a (2:1) mixture of diethyl ether and acetic acid ethyl ester. After evaporation of the solvent, 5-(5-ethoxycarbonyl-5-bonyl-pent-4-enyl)-imidazofl,5-a]pyridine is obtained as an oil. NMR (CDCl 3 ) 1.29 (5, 3H), 4.25 (q, 2H), 5.88 (d, 1H).

The starting material is produced as follows:

An ice-cooled magnetically stirred slurry of 0.96 g of sodium hydride in 50 ml of dimethylformamide is formed dropwise over <5> 15 minutes with 3.92 g of 2-(phenylthio)-acetic acid ethyl ester. The suspension is stirred for 2 hours at room temperature and then cooled with an ice bath to 5°C. This suspension is mixed dropwise over the course of 1 hour with 4.16 g of 5-(4-chlorobutyl)-imidazo-[1,5-α]pyridine. The mixture is then mixed with 3.2 g of sodium <>> umidide and stirred overnight at room temperature.

The reaction mixture is poured into 150 ml of ice water and extracted three times with each time 100 ml of a (1:1) mixture of diethyl ether and acetic acid ethyl ester. The organic phase is washed twice with each time 100 ml of saturated aqueous sodium chloride solution and then extracted three times with each time 50 ml of 1N hydrochloric acid. The acidic aqueous extracts are combined, made basic with ammonium hydroxide and extracted three times with each time 150 ml of a 1:1 mixture of diethyl ether and acetic acid ethyl ester. The organic extracts are dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure. An oil is obtained which is purified by column chromatography on silica gel and eluted with diethyl ether. After evaporation of the solvent, 5-[5-ethoxycarbonyl-5-(phenylthio)-pentyl]-imidazo[1,5-a]pyridine is obtained as a heavy oil. NMR (CDCl 3 ) 3.3-3.8 (1H); IR 1720 cm"<1>.

A solution of 3.8 g of 5-[5-ethoxycarbonyl-5-(phenyl-thio)-pentyl]-imidazo[1,5-a]pyridine in 100 ml of methanol is mixed with 2.8 g of sodium metaperiodate and the mixture is stirred for 18 hours at room temperature. The solvent is evaporated under reduced pressure and the residue is taken up in 150 ml of water. It is extracted three times, each time with 100 ml of acetic acid ethyl ester. The organic phase is extracted twice with 50 ml of 1N hydrochloric acid each time, the aqueous extract is made basic with ammonium hydroxide and extracted again with 2 x 100 ml of acetic acid ethyl ester. The combined acetic acid ethyl ester extracts are dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure. An oil is obtained which is purified by column chromatography on silica gel and eluted with a (1:1) mixture of acetic acid ethyl ester and diethyl ether. After evaporation, 5-[5-ethoxycarbonyl-5-(phenylsulfinyl)-pentyl]-imidazo-[1,5-a]pyridine is obtained as an oil. IR 1720 cm ^, 1040 cm 1.

Example 21

A solution of 300 mg of 5-(5-ethoxycarbonylpent-4-enyl)-imidazo[1,5-a]pyridine in 20 ml of methanol is mixed with 5 ml of IN sodium hydroxide solution and the mixture is stirred for 18 hours at room temperature. The methanol is evaporated under reduced pressure and the aqueous residue is mixed with a further 5 ml of water. The mixture is extracted three times with 5 ml of ethyl acetate each time. The basic aqueous layer is then adjusted to pH 5 and extracted three times with 5 ml ethyl acetate each time. These extracts are dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. 5-(5-carboxypent-4-enyl)-imidazotl,5-a]-pyridine is obtained, which melts at 142-144°C.

Example 2 2

To a solution of 2.75 g of 5-(5-formylpentyl)-imidazo[1,5-a]pyridine in 180 ml of chloroform is added 6.5 g of carbetoxymethylenetriphenylphosphorane and the mixture is stirred for 18 hours at room temperature. The solvent is then evaporated under reduced pressure. 5-(7-Ethoxycarbonyl-hept-6-enyl-imidazo[1,5-a]pyridine is obtained as an oil.

The starting material is produced as follows:

A cooled to -60°C solution of 4.9 g of 5-(5-met-

in oxycarbonyl-pentyl)-imidazo[1,5-a]pyridine (which is obtained by esterification of the 5-{5-carboxy-methyl)-imidazo[1,5-a]pyridine prepared according to example 2 with diazomethane in methylene chloride)

in 140 ml of methylene chloride is mixed dropwise over 20 minutes with 40 ml of a 1.75-molar solution of diisobutyl-

) aluminum hydride in hexane. The reaction mixture is then stirred for 20 minutes at -60°C and then mixed with 10 ml of methanol and 100 ml of water to stop the reaction. The mixture is stirred at room temperature for 5 minutes, the methylene chloride layer is separated and the solvent is evaporated at reduced pressure. 5-(5-formylpentyl)-imidazo[1,5-a]pyridine is obtained as an oil. NMR (CDCl 3 ) 9.7 (m, 1H), IR (methylene chloride) 1710 cm"<1>.

Example 2 3

A solution of 2.8 g of 5-(7-ethoxycarbonyl-hept-6-enyl)-imidazo[1,5-a]pyridine in 30 ml of methanol is mixed with 15 ml of 0 IN sodium hydroxide solution and the mixture is stirred at room temperature for 3 hours. The methanol is evaporated under reduced pressure, the residue is diluted with 30 ml of water and the solution is adjusted with 1N hydrochloric acid to a pH value of 7. The solution is extracted with 2 x 50 ml of acetic acid ethyl ester. The combined extracts are dried over anhydrous magnesium sulfate, filtered

and the solvent is evaporated under reduced pressure. 5-(7-carboxyhept-6-enyl)-imidazo[1,5-a]pyridine is obtained, which melts

at 110-111°C.

Example 24

A solution of 150 mg of 5-(5-carboxypent-4-enyl)-imidazotl,5-a]pyridine in 7 ml of methanol is mixed with 100 mg of 10%-

ig palladium-on-charcoal catalyst. The reaction mixture is hydrogenated for 3 hours at atmospheric pressure. The catalyst is filtered off and the solvent is evaporated under reduced pressure.

5-(5-carboxypentyl)-imidazotl,5-a]pyridine is obtained which melts at 144-147°C and is identical to the product obtained according to example 2.

Example 2 5

A solution of 180 mg of 5-(7-carboxyhept-6-enyl)-imidazo[1,5-a]pyridine in 30 ml of methanol is mixed with 200 mg of 10% palladium-on-charcoal catalyst and the mixture is hydrogenated for 3 hours at atmospheric pressure. The catalyst is filtered off and the solvent is evaporated under reduced pressure.

The product that melts at 69-71°C is obtained and consists of the mixture of 5-(7-carboxyheptyl)-imidazo[1,5-a]pyridine (the compound from example 3c) and of 5-(7-carboxyheptyl)-5 ,6,7,8-tetrahydroimidazo[1,5-a]pyridine.

Example; 2 6

A solution of 0.1 g of 2-aminomethyl-3-(4-methoxycarbonylbutyl)-pyridine in 0.6 ral of formic acid is heated for 18 hours at 90°C. The mixture is cooled to 0°C, basified with saturated aqueous ammonium hydroxide solution and extracted with methylene chloride (4 x 10 mL). The extracts are dried, filtered and evaporated. 2-(N-formylaminomethyl)-3-(4-methoxycarbonylbutyl)-pyridine is obtained which melts at 43-45°C. This is redissolved in 1 ml of toluene and heated for 17 hours at 90°C with 75 mg of phosphorus oxychloride. Excess phorphoroxychloride is evaporated with toluene, the residue is made basic at 0°C with saturated aqueous ammonium hydroxide solution, extracted with methylene chloride (4 x 15

ml) and the extract is dried over sodium sulphate. After evaporation, an oil is obtained which after chromatography (silica gel, ethyl acetate) gives an oil. This is 8-(4-methoxycarbonylbutyl)-imidazo[1,5-a]pyridine. R f = 0.29; NMR (CDCl 3 ) 3.70 (s, 3H), 6.50 (d, 2H), 7.43 (s, 1H), 7.83 (5, 1H), 8.22

(s, 1H); IR (methylene chloride) 1725 cm"<1.>

The starting material is produced as follows:

A solution of 3-bromopyridine (7.9 g), 4-pentenoic acid methyl ester (7.15 g), palladium acetate (0.11 g) and tri-o-tolylphosphine (0.6 g) in 50 ml of triethylamine is boiled for 24 hours under reflux and under argon and the solvent is evaporated. The residue is taken up in methylene chloride (50 ml) and washed with water

(2 x 40 ml). The organic phase is dried and evaporated. 3-(4-Methoxycarbonylbut-1-enyl)-pyridine is obtained as a colorless liquid. NMR (CDCl 3 ) 3.72 (s, 3H), 6.40 (s, 1H); IR (film) 1725 cm"<1>.

3-(4-Methoxycarbonylbut-1-enyl)-pyridine (9.5 g) is hydrogenated in 100 ml of methanol with 0.5 g of 5% palladium-on-charcoal catalyst for 3.5 hours at 3 atmospheres. After filtration and evaporation, 3-(4-methoxycarbonylbutyl)-pyridine is obtained as an oil. NMR (CDCl 3 ) 3.80 (s, 3H); IR (methylene chloride) 1730 cm"<1.>

3-(4-Methoxycarbonylbutyl)-pyridine (10.81 g) is mixed dropwise while maintaining the temperature of the reaction mixture between 80 and 85°C with peracetic acid (40%, 8.3 ml). Gradually, the temperature is allowed to drop to 30°C and excess peracetic acid is split with aqueous sodium sulphite solution. The acetic acid is evaporated under reduced pressure, the residue is taken up in methylene chloride (50 ml), filtered and evaporated. The residue, which consists of 3-(4-methoxycarbonylbutyl)-pyridine-N-oxide, is treated with dimethyl sulfate (7.7 g) in 40 ml of toluene for 1 hour at 90° C. and the solvent is evaporated. 3-(4-Methoxycarbonylbutyl)-1-methoxy-pyridinium methyl sulfate salt is dissolved in 16.7 ml of ice-cold water and 8.3 ml of 1N sodium hydroxide solution and mixed with a solution of potassium cyanide (11.21 g) in 16.7 ml ice cold water slowly while keeping the temperature at 0°C. After 24 hours at 0°C, the mixture is extracted with methylene chloride (3 x 30 ml), the extract is dried over sodium sulphate and the solvent is evaporated. A mixture of isomeric cyanopyridines is obtained from which 2-cyano-3-(4-methoxycarbonylbutyl)-pyridine is separated with an Rf value of 0.56 and NMR (CDC13) 8.82 (m, 1H) and 2- cyano-5-(4-methoxycarbonylbutyl)-pyridine with Rf value 0.50 and NMR

(CDCl-j) 8.72 (s, 1H) by chromatograph (silica gel, ether-pentane 3:2).

2-cyano-3-(4-methoxycarbonylbutyl)-pyridine (2.40 g) is dissolved in 92 ml of methanol containing 2.4 ml of concentrated hydrochloric acid and hydrogenated with 1.2 g of 10% palladium-on-charcoal catalyst for 3 hours at atmospheric pressure. Filtration, evaporation and recrystallization from ether-methylene chloride gives 2-aminomethyl-3-(4-methoxycarbonylbutyl)-pyridine hydrochloride, which melts at 79-81°C.

Example 2 7

A solution of 8-(4-methoxycarbonylbutyl)-imidazol,5-a]pyridine (30 mg) in 0.3 ml of ethanol and 0.3 ml of 1N sodium hydroxide solution is refluxed for 2 minutes, cooled and diluted with 2 ml of water and extracted with acetic acid ethyl ester (1x5 ml). The aqueous phase is adjusted to pH 6 and extracted with methylene chloride (4 x 10 ml). The extracts are dried and evaporated. 8-(4-carboxybutyl)-imidazotl,5-a]pyridine is obtained which melts at 195-197°C.

Example 2 8

2-Aminomethyl-5-(4-methoxycarbonylbutyl)-pyridine (0.20 g) is heated in 0.6 ml of formic acid for 18 hours at 90°C. The mixture is cooled to 0°C, basified with saturated aqueous ammonium hydroxide solution and extracted with methylene chloride (4 x 15 mL). The extracts are dried, filtered and evaporated. 2-(N-formylaminomethyl)-5-(4-methoxycarbonyl-butyl)-pyridine is obtained as an oil (IR 1720 and 1675 cm^) which is dissolved in 1 ml of toluene and heated for 18 hours at 90°C with phosphorus oxychloride (0.166 g). Evaporation of excess phosphorus oxychloride with toluene and addition at 0°C of saturated aqueous ammonium hydroxide solution, extraction of the basic solution with methylene chloride (4 x 15 ml) and drying of the extract over sodium sulphate gives an oil which is chromatographed (silica gel, ethyl acetate). 6-(4-Methoxycarbonylbutyl)-imidazo[1,5-a]pyridine is obtained. R f = 0.26; NMR (CDCl 3 ) 3.58

(s, 3H), 6.45 (d. 1H), 7.25 (d, 1H), 7.38 (s, 1H), 7.62

(s, 1H), 7.94 (s, 1H); IR (methylene chloride) 1730 cm"<1>.

The starting material is produced 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 over 0.75 g of 10% palladium-on-charcoal catalyst for 18 hours at atmospheric pressure. The mixture is filtered, the filtrate is evaporated, the residue is chromatographed on 20 g of silica gel and eluted with 1:1 methanol-acetic acid ethyl ester. After recrystallization from ether-methylene chloride, 2-aminomethyl-5-(4-methoxycarbonylbutyl)-pyridine is obtained as its carbonate which melts at 79-80°C. NMR (CDCl 3 ) 3.67 (s, 3H), 4.24 (s, 2H); IR (methylene chloride) 1725 cm"<1.>

Example 2 9

A solution of 92 mg of 6-(4-methoxycarbonylbutyl)-imidazotl,5-a]pyridine in 0.3 ml of ethanol and 0.8 ml of 1N sodium hydroxide solution is heated slowly for 2 hours under reflux. cool, dilute with 2 ml of water and extract with ethyl acetate (5 ml). The aqueous phase is adjusted to pH 6 and extracted with chloroform. The extracts dry-

kes and evaporated. 6-(4-carboxybutyl)-imidazo[1,5-a]-pyridine is obtained which melts at 168-171°C.

Example 3 0

2-(N-formylaminomethyl)-4-(3-methoxycarbonylpropyl)-pyridine (33 mg) is dissolved in 1 ml of toluene and heated with phosphorus oxychloride (44 mg) under nitrogen for 18 hours at 90°C. The solvent is evaporated, the residue is suspended in methylene chloride, cooled to 0°C and made basic with saturated aqueous ammonium hydroxide solution. The aqueous phase is extracted with methylene chloride (4 x 15 ml), the extracts are dried over sodium sulphate and evaporated. 7-(3-Methoxycarbonylpropyl)-imidazo[1,5-a]pyridine is obtained as an oil which is purified by preparative thin-layer chromatography (silica gel, 3:1 acetic acid ethyl ester-methanol). NMR (CDCl 3 ) 3.70 (s, 3H), 6.45 (q, 1H), 7.2 (s, 1H), 7.32 (s, 1H), 7.90 (d. 1H), 8 .08 (s, 1H); IR (methylene chloride) 1730 cm"<1>.

The starting material is produced as follows:

Potassium cyanide (11.18 g) and dibenzo-18-crown-6-ether

(1.0 g) is added under a nitrogen atmosphere to a solution of 4-(3-chloropropyl)-pyridine (6.68 g) (prepared from 4-(3-hydroxypropyl)-pyridine) in 300 ml of dry acetonitrile. The mixture is boiled for 24 hours under reflux, the solvent is evaporated and the residue is distributed between methylene chloride and water. The aqueous phase is further extracted with methylene chloride (3 x 100 ml).

The combined extracts are dried over sodium sulfate, decolorized with activated charcoal and evaporated. 4-(3-cyanopropyl)-pyridine is obtained as a colorless oil.

Hydrogen chloride is passed through a solution of 4-(3-cyanopropyl)pyridine (5.5 g) in methanol under ice cooling for 2 hours and the solution is carefully mixed with 100 ml of water. The solution is stirred for 15 minutes and the solvent is evaporated. The residue is basified with saturated aqueous sodium hydrogen carbonate solution and extracted with methylene chloride (3 x 100 ml). The extract is dried over sodium sulfate and evaporated. The residue is filtered in ether through 50 g of silica gel. 4-(3-Methoxycarbonylpropyl)pyridine is obtained as an oil. NMR (CDCl 3 ) 3.68 (s, 3H), 7.05-7.25 (m, 2H), 8.45-8.65 (m, 2H); IR

1725 cm <1>.

At room temperature, add peracetic acid

(40%, 2.9 mL) to 4-(3-methoxycarbonylpropyl)-pyridine (3.20

g). The mixture is heated for 1 hour at 80°C and when the test for peroxide is negative, the acetic acid is evaporated. The residue is taken up in

methylene chloride (50 ml), filtered and evaporated. The formed 4-(3-methoxycarbonylpropyl)-pyridine-N-oxide is treated with dimethyl sulfate (2.8 g, 22.2 mmol) in 12 ml of toluene for 1 hour at 80°C. After evaporation of the solvent, 5.45 g of 4-(3-methoxycarbonylpropyl)-1-methoxypyridinium methylsulphate is obtained, which is added to a solution of 89.75 g of potassium cyanide in 20 ml of water. The reaction mixture is stirred for 1 hour at 0°C and 3 hours at 25°C and then extracted with methylene chloride (1

x 30 ml). The aqueous phase is allowed to stand for 24 hours and then extracted with methylene chloride (1 x 30 ml). The combined extracts are dried over sodium sulfate and evaporated. A red oil is obtained which, after chromatography on 70 g of silica gel and elution with ether, gives 2-cyano-4-(3-methoxycarbonylpropyl)-pyridine as a

oil. NMR (CDCl 3 ) 3.67 (s, 3H), 7.42 (d, 1H), 7.60 (s, 1H), 8.60 (d, 1H); IR (methylene chloride) 1725 cm<-1>.

2-cyano-4-(3-methoxycarbonylpropyl)-pyridine (0.83 g)

in 9 ml of methanol is hydrogenated over 0.4 g of 10% palladium-on-charcoal catalyst for 3 hours at 3 atmospheres. The mixture is filtered, the filtrate is evaporated and the residue is purified by preparative thin-layer chromatography on silica gel with 1:1 methanol-acetic acid ethyl ester. 2-Aminomethyl-4-(3-methoxycarbonylpropyl)-pyridine is obtained. Rf = 0.37 (ethyl acetate-methanol 1:1, 1% ammonium hydroxide); NMR (CDCl 3 > 3.67 (s, 3H), 4.15 (s,

2H).

2-Aminomethyl-4-(3-methoxycarbonylpropyl)-pyridine (0.11 g) in 0.5 ml of 97% formic acid is heated for 18 hours at 90°C. The reaction mixture is cooled to room temperature, made basic with ammonium hydroxide solution and extracted

es with methylene chloride (4 x 20 ml). The organic extracts are dried over sodium sulfate and evaporated. 2-(N-formyl-aminomethyl)-4-)3-methoxycarbonylpropyl)-pyridine is obtained. IR (methylene chloride) 1735, 1685 cm"<1>.

Example 31

7-(3-Methoxycarbonylpropyl)-3-imidazo[1,5-a]-pyridine (Example 32, 8.0 mg) is dissolved in 0.3 mL of methanol and mixed with 0.1 mL of 1N sodium hydroxide solution. The mixture is stirred for 5 hours at 25°C, evaporated and the residue dissolved in 5 ml of water. The aqueous solution is washed with 2 ml ethyl acetate, adjusted with 2N sulfuric acid to pH 6 and extracted with methylene chloride (3 x 5 ml). The organic extracts are dried over sodium sulphate/magnesium sulphate and evaporated. 7-(3-carboxypropyl)-imidazo[1,5-a]pyridine is obtained; IR (CHC13) 1720 cm<-1>.

Example 3 2

A solution of 7-[4,4-(bis-methoxycarbonyl)-butyl]-imidazotl,5-a]pyridine (65 mg) in 0.8 ml of IN sodium hydroxide solution and 0.5 ml of ethanol is heated for 2 hours under back-run. The solvent is evaporated and the residue is mixed with 0.8 ml of 1N hydrochloric acid. The water is evaporated, the residue is dissolved in 3 ml of xylene and heated for 4 hours at 137°C. The xylene is evaporated and replaced with 2 ml IN sodium hydroxide solution. The aqueous phase is extracted with ethyl acetate (5 ml). Acidification to pH 6 and re-extraction with chloroform

(3 x 15 ml) and evaporation gives 7-(4-carboxybutyl)-imidazo-1,5-a]pyridine which melts at 158-161°C.

The starting material is produced as follows:

According to the previously mentioned methods (e.g. examples 28 and 32) 4-(3-chloropropyl)-pyridine is converted to 4-(3-chloropropyl)-2-cyano-pyridine. NMR (CDCl 3 ) 3.56 (t, 2H), 7.40 (d, 1H), 7.57 (s, 1H), 8.60 (d, 1H).

A solution of borane dimethyl sulfide (0.83 mL, 7.7 mmol) in 7 mL of tetrahydrofuran is slowly added to a refluxing solution of 4-(3-chloropropyl)-2-cyanopyridine (1.24 g, 6.9 mmol) in 7 ml of tetrahydrofuran while distilling off dimethyl sulphide at the same time. After the addition is complete, the mixture is boiled for 15 minutes under reflux and cooled to 30°C and mixed with 6N hydrochloric acid. After the hydrogen evolution has ceased, the mixture is refluxed for 30 minutes and cooled to 0°C, saturated with solid sodium carbonate and extracted with methylene chloride (4 x 50 ml). The organic extracts are dried over sodium sulfate and evaporated. An oil is obtained which is filtered through 10 g of silica gel (1:1 acetic acid ethyl ester-methanol). 2-Aminomethyl-4-(3-chloropropyl)-pyridine is obtained as a yellow oil, NMR (CDCl 3 ) 3.55 (t, 2H),

4.20 (p, 2H).

A solution of 2-aminomethyl-4-(3-chloropropyl)pyridine (0.47 g) in 1 ml of formic acid is heated for 18 hours at 90°C and cooled to 0°C and made basic with saturated aqueous ammonium hydroxide solution. Extraction with methylene chloride (4

x 10 ml), drying over magnesium sulfate and evaporation gives 2-(N-formylaminomethyl)-4-(3-chloropropyl)-pyridine (IR 1674 cm 1). This is heated in phosphorus oxychloride (0.75 g) for 15 hours at 90°C. Excess phosphorus oxychloride is evaporated with toluene, the residue is suspended in methylene chloride (15 ml), cooled to 0°C and made basic with saturated ammonium hydroxide. Extraction with methylene chloride (4 x 15 ml), drying over sodium sulfate and thin-layer chromatography (silica gel, ethyl acetate

ester) of the residue gives 7-(3-chloropropyl)-imidazot1,5-a]pyridine (Rf = 0.24, acetic acid ethyl ester) as a gummy material. NMR (CDCl 3 ) 3.59 (t, 2H), 6.42 (q, 1H), 7.21 (s, 1H), 7.32

(s, 1H) , 7.88 (d, 1H) , 8.07 (s, 1H) .

A solution of 7-(3-chloropropyl)-imidazo[1,5-a]pyridine (50 mg), malonic acid dimethyl ester (0.14 g) and potassium carbonate (144 mg) in 2 ml of dimethylformamide is heated under nitrogen for 9 hours between 80 and 90°C. The solvent is evaporated, the residue is taken up in 10 ml of water and extracted with acetic acid ethyl ester (2 x 10 ml). The organic extracts are washed with 2N hydrochloric acid (2 x 10 ml). The aqueous extracts are made basic with solid sodium bicarbonate, extracted with methylene chloride (3 x 10 ml), dried over sodium sulfate and evaporated. 7-[4,4-(bis-methoxycarbonyl)-butyl]-imidazotl,5-a]pyridine is obtained. NMR (CDCl - ) 3.40 (s, 6H), 6.06 (d, 1H); IR (methylene chloride) 1725 cm-1.

Example 33

A solution of 5-[5,5-(bis-ethoxycarbonyl)-pentyl]-imidazo[1,5-a]pyridine (0.60 g) in 6.5 ml of 1N sodium hydroxide solution and 4 ml of methanol is boiled 2 hours during the to-back race. The solvent is evaporated and 6.5 is added

ml IN hydrochloric acid. The water is then evaporated and the 5-[5,5-(bis-carboxy)-pentyl]-imidazo[1,5-a]pyridine formed in 25 ml of xylene is heated for 4 hours at 137°C. The xylene is replaced with 16 ml IN sodium hydroxide solution. Extraction

of the aqueous phase with ethyl acetate (15 ml), acidification to pH 6, re-extraction with chloroform (3 x 40

ml), drying over magnesium sulfate and evaporation gives 5-(5-carboxypentyl)-imidazotl,5-a]pyridine which melts at 146-147°C. (The compound according to example 2).

The starting material is produced as follows:

A solution of 5-(4-chlorobutyl)-imidazo[1,5-a]-pyridine (0.42 g), malonic acid diethyl ester (1.34 g) and potassium carbonate (1.15 g) in 20 ml of dimethylformamide is heated under nitrogen in 10 hours between 80 and 90°C. Drain the solvent pes and the residue is taken up in 50 ml of water. The aqueous phase is extracted with ethyl acetate (3 x 40 ml). The extracts are washed with 2N hydrochloric acid (3 x 10 ml). The aqueous phase is made basic with solid sodium carbonate, extracted with methylene chloride (3 x 20 ml), the extracts are dried over sodium sulfate and evaporated. 5-[5,5-bis-ethoxycarbonyl)-pentyl]-imidazol, 5-a]pyridine is obtained which melts at 59-61°C.

The 5-(4-chlorobutyl)-imidazotl,5-a]pyridine used as starting material is prepared according to that in example 4

for the preparation of the starting material mentioned method using l-bromo-3-chloropropane as reagent instead of l-bromo-4-chlorobutane.

Example 3 4

Pyridinium dichromate (0.94 g) is added in the solid state to a solution of 5-(6-hydroxyhexyl)-imidazo[1,5-a]-pyridine (123 mg) in 10 ml of N,N-dimethylformamide under nitrogen at 25° C. The solution is stirred for 6 hours, poured into 150 ml of water and extracted with methylene chloride (5 x 20 ml). The organic extracts are washed with IN sodium hydroxide solution. The aqueous phase is acidified to pH 6, extracted with methylene chloride, the extract is dried over sodium sulphate/magnesium sulphate and evaporated. 5-(5-carboxypentyl)-imidazo[1,5-a]pyridine is obtained according to example 2. Melting point 145-146°C. Example 3 5

5-methylimidazo[1,5-a]pyridine [J. Org. Chem. 40, 1210 (1975), 424.7 g] is placed in a 12-liter flask equipped with a mechanical stirrer and thermometer and filled with nitrogen. Dry tetrahydrofuran (3000 ml) is in the flask and the resulting solution is cooled in a dry ice/acetone bath to -65°C. The solution is mixed with n-butyllithium (1.0 mol, 2,4-normal in hexane) at once under a nitrogen atmosphere. The temperature rises to -32°C. The mixture is cooled again to -50°C and mixed in the same way with one further mole of n-butyllithium. The temperature rises again and the mixture is mixed after cooling to -50°C with a third mole of n-butyllithium. The reaction mixture is stirred for 20 minutes as the temperature falls

-65°C. The stirred solution is then mixed as quickly as possible with a cold (-67°C) solution of 5-bromo-1,1,1-triethoxypentane (606.9 g) in 500 ml of tetrahydrofuran while

temperature increases to -25°C. The reaction mixture is then heated to -15°C, stirred for 2 hours, mixed with acetic acid (50 ml) and the main part of the solvent is removed in vacuo. The residue is taken up in 2000 ml of ethyl ether, mixed with acetic acid (100 ml) and 12N hydrochloric acid (100 ml) and cooled to 0°C. The mixture is mixed after 15-20 minutes with ice and 7.5N ammonium hydroxide (1000 ml). The organic phase is separated and the aqueous phase is washed with ethyl ether (500 ml). The pH of the aqueous layer is adjusted to 9 with ammonium hydroxide and extracted again with ethyl ether (500 ml). The combined ether extracts are washed with dilute sodium chloride solution and the pH is adjusted to 13-14 with potassium hydroxide. The ether extract is treated with activated carbon and magnesium sulphate. The mixture is filtered and evaporated. A dark oil is obtained which is dried at 2 mm Hg. The oil is distilled under high vacuum. 5-(5-ethoxycarbonylpentyl)-imidazo[1,5-a]pyridine is obtained which boils at 220°C/0.2 mm Hg.

The 5-bromo-1,1,1-triethoxypentane used as starting material is prepared as follows: 5-bromovaleronitrile (1200 g) is placed under nitrogen in a 5-liter three-necked flask. The complete reaction flask is then placed in an ice bath and 287 g of hydrogen chloride is slowly introduced. The reaction mixture is then diluted with ethyl ether (3200 ml) and stirred overnight at 4°C. The resulting suspension is cooled in a dry ice/acetone bath at -30°C. The solid material formed is separated, washed with ethyl ether and dried in a vacuum desiccator over potassium hydroxide and phorsphorpentoxide for 3 days. 5-bromidovaleric acid ethyl ester hydrochloride is obtained, which is used in the next step without further purification.

5-bromidovaleric acid ethyl ester hydrochloride

(556 g) is placed under nitrogen in a 12-liter flask that is shaken with a mechanical stirrer. After addition of anhydrous ethanol (836 g), the reaction mixture is stirred for 2 hours at room temperature, obtaining a clear solution. Ethyl ether (3700 ml) is added to the flask and the mixture is stirred at room temperature for 3 days. The solution is cooled to -30°C and

the formed ammonium chloride is filtered off. The filtrate is evaporated to dryness in a rotary evaporator under vacuum. The residue is distilled in high vacuum (0.2 mm Hg) using a 12 cm fractionation column. The main fraction distilling at approximately 71-82°C is collected and redistilled with a 46 cm column. 5-bromo-1,1,1-triethoxypentane is obtained which boils at 60-62°C/0.2 mm Hg.

5-(5-ethoxycarbonylpentyl)-imidazo[1,5-a]pyridine can also be prepared starting from 2-(N-formylamino-methyl)-6-(5-ethoxycarbonylpentyl)-pyridine according to that in example 28, 30 and 32 referred to the looping procedure. Example 3 6

5-(5-Ethoxycarbonylpentyl)-imidazo[1,5-a]pyridine (1091 g) is placed under nitrogen in a 12 liter round bottom flask and mixed with stirring with ethyl alcohol (95%, 4 20 ml). While stirring, 2N sodium hydroxide solution (2100 ml) is then added in portions. After the addition, the mixture is heated for 20 minutes at 70°C. You get a solution that is further heated for 2 hours. A further amount of sodium hydroxide (50% solution, 21 ml) is added and heating is continued for 40 minutes. The reaction mixture is cooled, mixed with 12N hydrochloric acid (30 ml) and the ethyl alcohol is partially evaporated under reduced pressure. The resulting solution is washed with ethyl ether (1700 ml), decolorized with activated carbon, filtered and acidified with acetic acid. The product crystallized overnight at 4°C is separated, washed first with water, then with ethyl ether (1000 ml) and dried. 5-(5-carboxypentyl)-imidazo[1,5-a]pyridine is obtained which melts at 146-148°C and is identical to the product from example 2.

in

Example 3 7

A solution of 5-(6-oxoheptyl)-imidazo[1,5-a]-pyridine (0.35 g) in 10 ml of dioxane is slowly added to a vigorously stirred aqueous solution (3 ml) of sodium hypobromite (5.2 mmol ) at 22-25°C (ice bath cooling if necessary). After 3 hours, excess sodium hypobromite is decomposed with sodium bisulphite and the solvent is evaporated. The residue is dissolved in 10 ml of 0.5N sodium hydroxide solution, extracted with ether (2x5 ml) and adjusted with concentrated sulfuric acid to pH 6. After extraction with methylene chloride (3 x 10 ml), drying over sodium sulphate/magnesium sulphate and evaporation, 5- (5-Carboxypentyl)-imidazo-[1,5-a]-pyridine according to Example 2.

The starting material is prepared by treating 5-(4-chlorobutyl)-imidazo-[1,5-a]pyridine with acetoacetic acid ethyl ester in the presence of sodium hydride and subsequent hydrolysis with dilute sodium hydroxide solution.

Example 3 8

Under a nitrogen atmosphere, a mixture of magnesium shavings (36.1 mg, 1.5 mmol) and 5-(4-chlorobutyl)-imidazo- t , 5-a ]pyridine (313 mg) in 0.2 mL of dry tetrahydrofuran is mixed with one iodine crystal. After dissolving the magnesium shavings, a further 2 ml of anhydrous tetrahydrofuran and bromoacetic acid ethyl ester (0.43 g) are added. The reaction mixture is stirred at room temperature for 1 hour, boiled for 30 minutes under reflux, cooled to 25°C, diluted with 20 ml of ethyl acetate and washed with water (2 x 10 ml). The organic phase is dried, filtered and evaporated. 5-(5-ethoxycarbonyl-pentyl)-imidazo[1,5-a]pyridine is obtained as an oil. This is boiled in 10 ml methanol and 5 ml IN sodium hydroxide solution for 3 hours under reflux. The methanol is evaporated and the residue is dissolved in 10 ml of water. This solution is washed with 10 ml of acetic acid ethyl ester and adjusted with concentrated hydrochloric acid to a pH value of 6. After extraction with methylene chloride (5 x 10 ml), drying over sodium sulfate/magnesium sulfate and evaporation, 5-(5-carboxypentyl)-imidazo[1,5 -a]pyridine according to exem-

pole 2.

Example 3 9

A mixture of magnesium shavings (36.5 mg) and 5-(5-chloropentyl)-imidazo[1,5-a]pyridine (313 mg) in 0.2 ml of anhydrous tetrahydrofuran is mixed under nitrogen with one iodine crystal. After the magnesium shavings have dissolved, a further 2 ml of tetrahydrofuran is added. The solution is cooled to -5°C and, with vigorous stirring, dry carbon dioxide gas is introduced for 30 minutes. The solvent is evaporated and the residue is dissolved in 10 ml of 25% sulfuric acid. The solution is washed with 5 ml of ether, acidified to pH 6, extracted with methylene chloride (4 x 15 ml). The extracts are dried over magnesium sulfate and evaporated. 5-(5-carboxypentyl)-imidazo[1,5-a]-pyridine is obtained according to example 2.

Example 4 0

A mixture of 5-(6-carboxy-6-oxo-hexyl)-imidazo[1,5-a]pyridine (0.52 g) and 0.5 g of glass powder is heated stepwise to 240°C. The reaction mixture is held for 1 hour at 240°C and then cooled to room temperature. The residue is taken up in methylene chloride and the solid material is filtered off. Evaporation and recrystallization gives 5-(5-carboxypentyl)-imidazo[1,5-a]pyridine according to Example 2.

The starting material is prepared as follows: 5-(5-chloro-pentyl)-imidazo[1,5-a]pyridine is dissolved in dimethylformamide, reacted with 2-ethoxycarbonyl-1,3-dithiane and sodium hydride, then treated with N-bromosuccinimide in aqueous acetone and hydrolyzed with dilute sodium hydroxide solution. 5-(6-carboxy-6-oxohexyl)-imidazo[1,5-a]pyridine is obtained.

Example 41

A solution of 5-(4-carboxybutyl)-imidazo[1,5-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, the residue is dissolved in 15 ml of freshly distilled dry dioxane. While cooling at 0°C and below, the solution is added to an equimolar ethereal solution of diazomethane. The mixture is left overnight at room temperature and the ether is carefully evaporated. A solution of silver oxide (0.14 g) in ml of imidazo[1,5-a]pyridine is prepared as follows: 5-(6-chlorohexyl)-imidazo[1,5-a]pyridine is treated with dimethylsulfoxide, triethylamine and silver tetrafluoroborate according to the method described in Tetrahedron Letters 1974, 917.

Example 4 4

Ozone is introduced into a solution of 5-(6-dimethoxyhexyl)-imidazotl,5-a]pyridine (0.456 g) in 20 ml of methylene chloride for 4 hours at -50°C. Excess ozone is expelled with nitrogen. The mixture is mixed with 1 ml of dimethyl sulphide at -78°C and allowed to slowly warm to room temperature. The solvent is evaporated, the residue is taken up in 10 ml of methanol and boiled with 10 ml of IN sodium hydroxide solution for 2 hours under reflux. The methanol is evaporated and the residue is washed with ethyl acetate (5 ml) and brought to pH 6 with concentrated sulfuric acid. Extraction with methylene chloride (5 x 10 ml), drying over magnesium sulphate and evaporation gives 5-(5-carboxypentyl)-imidazotl, 5-a]pyridine.

Example 4 5

2-(N-formylaminomethyl)-6-(5-ethoxycarbonylpentyl)-pyridine (1.0 g) is heated with 0.25 ml of phosphorus oxychloride in 10

ml of toluene for 15 hours at 90°C. Excess phosphorus oxychloride is evaporated with toluene. The residue is made basic with saturated ammonium hydroxide solution at 0°C and extracted with methylene chloride (4 x 50 ml). The extracts are dried over sodium sulfate and chromatographed (40 g silica gel, ethyl acetate). 5-(5-ethoxycarbonylpentyl)-imidazotl,5-a]pyridine is obtained.

The starting material is prepared according to the methods described in previous examples using 6-(5-ethoxycarbonylpentyl)-2-cyano-pyridine.

Example 4 6

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 to -50°C and mixed dropwise with propiolic acid (0 .35 g). The reaction mixture is allowed to warm up slowly (within 2 hours)

to -15°C and mixing it dropwise over 15 minutes with 5-(4-chlorobutyl)-imidazo[1,5-a]pyridine (1.04 g) in 10 ml of tetra-

hydrofuran. The cooling is removed and the reaction mixture is stirred for 90 minutes at room temperature. The mixture is poured into 100 g of ice, the aqueous phase is separated, washed with acetic ester (20 ml), brought to pH 2 with concentrated sulfuric acid and washed again with acetic acid ethyl ester (20 ml). The aqueous phase is adjusted to pH 6 and extracted with methylene chloride (5 x 30 ml). The extracts are dried over sodium sulphate/magnesium sulphate, filtered and evaporated. 5-(6-carboxyhex-5-ynyl)-imidazo[1,5-a]pyridine is obtained.

Example 4 7

A solution of 5-methylimidazo[1,5-a]pyridine

(4.0 g, 0.03 mol) and tetramethylenediamine (4.9 g) in 100 ml of tetrahydrofuran are cooled under nitrogen to 0°C and mixed dropwise with 26.5 ml of 1.6N n-butyllithium, keeping the temperature below 5 °C. After 40 minutes, this solution is added to an ice-cold solution of 5-bromocrotonic acid ethyl ester (7.02 g) in 90 ml of tetrahydrofuran. After 15 minutes, the reaction mixture is quenched with excess saturated ammonium chloride solution and partitioned between water (100 ml) and ethyl acetate (150 ml). The organic phase is dried over sodium sulphate, filtered and evaporated. Mein gets 5-(4-ethoxycarbonyl-but-3-enyl)-imidazo[1,5-a]pyridine.

Example 4 8

A solution of 5-methylimidazo[1,5-a]pyridine (4.0 g) and tetramethylenediamine (4.9 g) in 100 ml of tetrahydrofuran is cooled under nitrogen to 0°C and mixed dropwise with 26.5 ml 1.6N n-butyllithium while keeping the temperature below 5°C. After 40 minutes, this solution is added to an ice-cold solution of 1-tetrahydropyranyloxy-8-bromo-oct-6-yne (10.4 g) in 80 ml of tetrahydrofuran. After 30 minutes, the reaction is interrupted with 50 ml of 2N hydrochloric acid and the mixture is stirred for a further 2 hours at room temperature. The layers are separated and the aqueous phase is brought to pH 10 with 50% sodium hydroxide solution. Extraction with methylene chloride (3 x 30 ml), drying over sodium sulfate, filtration, evaporation and chromatography (silica gel, ethyl acetate) gives 5-(9) -hydroxynon-7-ynyl)-imidazo[1,5-a]pyridine.

Example 4 9

A solution of 150 mg of 5-(4-carboxybuta-1,3-dienyl)-imidazo[1,5-a]pyridine in 9 ml of methanol is mixed with 100 mg of 10% palladium-on-charcoal catalyst. The reaction mixture is hydrogenated at atmospheric pressure for 2 hours. The catalyst is filtered off and the solvent is evaporated under reduced pressure. 5-(4-carboxybutyl)-imidazo[1,5-a]-pyridine is obtained which is identical to the compound according to example 8.

The starting material is produced as follows:

A solution of 18 g of 3-ethylthioimidazo[1,5-a]-pyridine Blatcher and Middlemiss, Tet. Easy. (21), 2195 (1980) in 200 ml of tetrahydrofuran is mixed dropwise at -50°C with a solution of 80 ml of 1.6-molar n-butyllithium in hexane during 30 minutes. After the addition, the reaction mixture is stirred at -50°C for a further 45 minutes and the cooled solution is mixed dropwise with 10 ml of dimethylformamide over the course of 10 minutes. The reaction mixture is then allowed to warm to room temperature and poured into 500 ml of ice water. The mixture is extracted with 500 ml of diethyl ether. The ether extract is dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure. The oily residue is purified by column chromatography on silica gel and eluted with a mixture of diethyl ether-hexane (1:2). The solvent is evaporated. 5-formyl-3-ethylthioimidazo[1,5-a]pyridine is obtained, melting point 41-43°C.

A solution of 20 g of 5-formyl-3-ethylthioimidazo-[1,5-a]pyridine in 200 ml of isopropanol is mixed with about 15 g of Raney nickel. The reaction mixture is stirred and boiled for 16 hours under reflux. The catalyst is filtered off through diatomaceous earth. The filtrate is evaporated under reduced pressure. The oily residue formed is purified by column chromatography on silica gel and eluted with a mixture of diethyl ether-acetic acid ethyl ester (2:1). The solvent is evaporated under reduced pressure. 5-formylimidazo[1,5-a]pyridine is obtained which melts at 138-140°C.

A stirred suspension of 150 mg of sodium hydride in 25 ml of toluene is mixed dropwise over 10 minutes with 550 mg of triethyl-4-phosphonocrotonate. The reaction mixture is kept by cooling with an ice bath at 5°C. The mixture is then mixed with 300 mg of 5-formylimidazo 1,5-a pyridine and stirred at room temperature for 1 hour. The reaction mixture is poured into 100 ml of ice water and extracted with 2 x 100 ml of ethyl acetate. The extracts are combined, dried over magnesium sulphate, filtered and evaporated to dryness. The oily residue formed is purified by column chromatography on silica gel and eluted with a mixture of diethyl ether-acetic acid ethyl ester. The solvent is evaporated under reduced pressure. 5-(4-ethoxycarbonyl-buta-1,3-dienyl)-imidazo 1,5-a pyridine is obtained which melts at 101-103°C.

A solution of 200 mg of 5-(4-ethoxycarbonylbuta-1,3-dienyl)-imidazo 1,5-a pyridine in 20 ml of methanol is mixed with 4 ml of 1N sodium hydroxide solution. The reaction mixture is stirred for 18 hours at room temperature. The methanol is evaporated under reduced pressure, the residue is diluted with 20 ml of water and the solution is adjusted to pH 5 with hydrochloric acid. The precipitate is separated. 5-(4-carboxybuta-1,3-dienyl)-imidazo 1,5-a pyridine is obtained which melts at 243-245°C. Effect on thromboxane synthetase of human platelets

The method is carried out according to the previously stated description. This in vitro inhibition of the thromboxane synthetase enzyme has been shown analogously to the method of Sun, Biochem. Biophys. Res. Comm. 74, 1432 (1977).

Results:

Compounds with formula are in the table below:

Claims (5)

1. Analogy method for the preparation of therapeutically effective imidazo/1,5-a/pyridines with the general formula I or 5,6,7,8-tetrahydro derivatives thereof, in which R^ means hydrogen, halogen or lower alkyl, A means the alkylene with 1-12 carbon atoms, the alkynyl or the alkenylene with 2-12 carbon atoms, B means carboxy, lower alkoxycarbonyl, unsubstituted, mono- or di-(lower alkyl)-substituted carbamoyl, cyano or hydroxymethyl, as well as their salts, characterized in that 1) a compound of formula VI wherein M means an alkali metal, and R 2 means hydrogen or lower alkyl, is reacted with a compound of formula VII wherein X preferably means halogen, A has the above-mentioned meaning, B' means carboxy, trilaverealkyloxymethyl, cyan, etherified hydroxymethyl or halomethyl, and a formed compound of formula Ia (a) in which B' means trilaverealoxymethyl is transferred in situ in an acidic environment to a compound of formula I, in which B means lower alkoxycarbonyl, or (b) in which B" means halomethyl, is transferred by reaction with cyanide ions to a compound of formula I, wherein B is cyan or (c) wherein B<1> is etherified hydroxymethyl, is hydrolyzed to a compound of formula I, wherein B is hydroxymethyl, or (d) wherein B' is halomethyl by reaction with an alpha-phenylthioacetic acid lower alkyl ester, oxidation of the thio group to sulfinyl and elimination is transferred to a compound of formula I, wherein B means lower alkoxycarbonyl and the chain A is extended by a terminal -CH=CH- group or, (e) in which B' means halomethyl, is converted by reaction with malonic acid dilave alkyl ester, hydrolysis and decarboxylation into a compound of formula I<, in which B means carboxy and the chain A is extended by a terminal -Cr^-Cr^ group or (f) in which B<1> means halomethyl is converted by conversion to a Grignard compound, condensation of this with a haloacetic acid lower alkyl ester and hydrolysis to a compound of formula .1, wherein B means carboxy and the chain A is extended by a terminal -Cr^-Cr^ group or (g) in which B<1> means halomethyl, is converted by conversion to a Grignard compound and condensation of this with CC>2 to a compound of formula I, in which B means carboxy and the chain A is extended by a terminal -CH2~ group or, (h) in which B' means halomethyl, is converted by reaction with lithium diisopropylamide and propiolic acid into a compound of formula I, in which B means carboxy and chain A is extended by a terminal -CH 2 -C=C group, or (2) a compound of formula VIII wherein M means an alkali metal, R 2 means hydrogen or lower alkyl, and R(- means lower alkyl, is reacted with a compound of formula IX in which X preferably means halogen, A has the above-mentioned meaning, B' means carboxy, trilavereal oxymethyl, cyan, etherified hydroxymethyl or halomethyl, in the compound formed, in which B' means trilavereal oxymethyl, halomethyl or etherified hydroxymethyl, group B' is converted as indicated by method ( 1) to a residue B, and the compound formed is desulphurised, or 3) a compound of formula XI in which each of the symbols R'2 and R"2 means hydrogen or lower alkyl, A has the above meaning and B" means carboxy, lower alkoxycarbonyl, cyano, hydroxymethyl, lower alkanoyl-oxymethyl, etherified hydroxymethyl or halomethyl, is ring-closed to a compound of formula Ib and a compound formed, (a) wherein B" is halomethyl, is transferred by reaction with cyanide ions to a compound of formula I, wherein B is cyan, or (b) wherein B" is etherified hydroxymethyl or lower alkanoyloxy, is hydrolyzed to a compound of formula I, wherein B is hydroxymethyl, or 4) a compound of formula XIV in which A' means an alkylene, alkylene or alkynyl radical with a maximum of 11 carbon atoms, is hydrogenated, or 5) in a compound with formula XVI wherein and A has the above meaning, and C means acetyl, carboxycarbonyl, formyl or dilavereal oxymethyl, C is transferred to a carboxy group B in the following way: (a) oxidation of an acetyl group C to the carboxy group by means of sodium hypobromide, (b) thermal treatment of C = carboxycarbonyl, (c) oxidation of a formyl or dilavereal oxymethyl group C, and if desired, (a) for the preparation of 5,6,7,8-tetrahydro derivatives of compounds of formula I, a formed compound of formula I is hydrogenated, which is not hydrogenated in the 5-, 6-, 7- or 8-position, (b) for the preparation of compounds of formula I, in which B means carboxy, a formed compound of formula I, in which B means lower alkoxycarbonyl, carbamoyl or cyano, is hydrolysed, ( c) for the preparation of compounds of formula I, wherein B is carbamoyl, a formed compound of formula I, wherein B is cyan, is partially hydrolyzed, (d) for the preparation of compounds of formula I, wherein B is hydroxymethyl, a form is reduced t compound of formula I, in which B means carboxy or lower alkoxycarbonyl 1 , (e) for the preparation of compounds of formula I, in which B means carboxy, a formed compound of formula I, in which B means hydroxymethyl, is oxidized, (f) for the preparation of compounds of formula I, wherein B is carboxy and A is extended with a terminal CG^ group, a compound of formula I formed, wherein B is carboxy, is transferred to an acid halide and reacted with diazomethane, (g) to produce compounds of formula I, in which B is carboxy and A is extended by a terminal CG^ group, a compound formed with formal, in which B is hydroxymethyl, is reacted with nickel carbonyl, (h) to prepare compounds of formula I in which B is mono- or di- (lower alkyl)-carbamoyl- reacts a formed compound of formula I, in which B means lower alkoxycarbonyl or carboxy, with a lower alkyl- or (i) for the preparation of compounds of formula I, in which B means di-(lower alkyl)-carbamoyl, A formed compound of formula I, in which B means mono-(lower alkyl)-carbamoyl, is N-alkylated, (j) to prepare compounds of formula I, in which 1*2 means halogen, a formed compound of formula I, in which means hydrogen , (k) for the preparation of compounds of formula I, wherein A means alkylene, a formed compound of formula I is hydrogenated, in which A means alkenylene, and/or if desired, a formed free compound is transferred to a salt or a formed salt to the free compound or to another salt. 2. Process according to claim 1 for the production of 5-(5-carboxypentyl)-imidazo[1,5-a]pyridine or salts thereof, characterized in that corresponding starting materials are used.