DK158227B - METHOD OF ANALOGUE FOR THE PREPARATION OF SUBSTITUTED IMIDAZOOE1,5-AAAPYRIDINES OR 5,6,7,8-TETRAHYDRODE DERIVATIVES OR SALTS THEREOF - Google Patents

Description

in

DK 158227 B

The imidazo [1,5-a] pyridines described in the literature are mainly only functionally substituted in the imidazo portion of the bicyclic ring system. Thus, for example, 1- and 5-aminoalkyl-substituted imidazo [1,5-a] pyridines and their tetrahydro derivatives are described in Journal of Medicinal Chemistry 16, 1272-1276 (1973).

Surprisingly, it has been found that imidazo [1,5-a] pyridine alkanoic acids and their derivatives constitute a new class of highly active and highly specific thromboxane synthetase inhibitors.

These advantages and properties make the disclosed omidazof 1,5-α-pyridine derivatives particularly useful when administered to mammals, e.g. for the treatment or prevention of diseases associated with inhibition of thromboxane synthetase. These diseases also include cardiovascular disorders such as thrombosis, atherosclerosis, cerebral ischemic cases, myocardial infarction, angina pectoris and hypertension, respiratory disorders such as asthma, inflammatory diseases or carcinomas such as tumor metastases and migraine.

The present invention relates to an analogous process for the preparation of novel substituted imidazo- [1,5-a] pyridines of the general formula • AJL * 25 χλ> (I) / 5 3 ch 2 -ab wherein R 2 is hydrogen or lower alkyl, A is alkylene having 1-12 carbon atoms or alkenylene having 2-12 carbon atoms, and B means carboxy, lower alkoxycarbonyl, unsubstituted, mono- or di- (lower alkyl) -

DK 158227 B

2 substituted carbamoyl, cyano or hydroxymethyl, or 5,6,7,8-tetrahydro derivatives thereof or their salts.

Preferred are compounds of general formula I, wherein the group CH 2 -A-B is attached to the 5-position. Very useful are compounds of formula I wherein A represents alkylene having 1-12 C atoms.

Particularly preferred are compounds of the general formula A4i2 γν * (CH) I δ n

R 3 C- (CH 2) m B

B4 10 or their 5,6,7,8-tetrahydro derivatives wherein R 2, R 3 and R 4 each represent hydrogen or alkyl of 1-4 C atoms, n is an integer of 1-7, m is 0 or 1 , and B has the meaning given above and their salts, especially their therapeutically useful salts.

In particular, compounds of the general formula (II) or their 5,6,7,8-tetrahydro derivatives, wherein R 2, R 2 and R 4 are each independently hydrogen, methyl or ethyl, (CH 2> n means propylene, butylene, pentylene or hexylene, m is 0 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.

Furthermore, compounds of formula (II), wherein the group is preferred

DK 158227 B

3 R,

, I

- <CH2) n-C- (CH2) m-B

R4 is bonded at the 5-position and wherein R3, R4, n, m and B have the meanings given above.

Particularly useful are compounds of the general formula

(CH2) p-E

or their 5,6,7,8-tetrahydro derivatives wherein p is an integer of 3-8 and B has the meaning given above, and their salts, especially their therapeutically useful salts.

Particularly valuable are compounds of general formula (IV) 10 yv (CH 2 -COOH 2 q or their 5,6,7,8-tetrahydro derivatives wherein q is 4, 5 or 6, and their salts, especially their therapeutically useful salts.

The general definitions used here have the following meanings.

An alkylene group means alkylene having 1-12 C atoms which may be straight or branched, preferably propylene, butylene, pentylene or hexylene, said groups

DK 158227 B

4 may be unsubstituted or substituted by one or more lower alkyl groups, however, the sum of the carbon atoms 5 is at most 12.

By alkenylene is meant an alkenylene group having 2-12 C atoms which may be straight chain or branched preferably propenylene, 1- or 2-butenylene / 1- or 2-pentenylene, 1-, 2- or 3-hexenylene. These groups may be unsubstituted or substituted by one or more lower alkyl groups, however, the sum of the carbon atoms is at most 12.

The term "low" in the above and subsequent organic groups or compounds shall be understood to mean those having a maximum of 7, preferably 4, especially 1 or 2 C atoms.

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

A lower alkoxycarbonyl group preferably contains 1-4 C atoms in the alkoxy moiety and means e.g. methoxycarbonyl, propoxycarbonyl or isopropoxycarbonyl, especially ethoxycarbonyl. A mono (lower alkyl) carbamoyl group preferably has 1-4 C 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 C atoms in each lower alkyl group and means e.g. N, N-dimethyl-carbamoyl, N-methyl-N-ethylcarbamoyl, and especially N, N-diethylcarbamoyl.

Salts are preferably therapeutically useful salts, e.g. metal salts or ammonium salts of said compounds of formula I wherein B is carboxy, especially alkali metal

DK 158227 B

5 or alkaline earth metal salts, e.g. sodium / potassium / magnesium or calcium salts / primarily light crystallizing ammonium salts. These are derived from ammonia or organic amines, e.g. mono-, di- or tri-low (alkyl, cycloalkyl or hydroxyalkyl) amines, low alkylene diamines or (hydroxy-low alkyl or aryl-low alkyl) -lavalkylammonium bases, e.g. methylamine, diethylamine, triethylamine, dicyclohexylamine, triethanolamine, ethylenediamine, tris- (hydroxymethyl) aminomethane or benzyl trimethylammonium hydroxide. Said compounds of formula I form acid addition salts. These are preferably prepared with such acids which lead to therapeutically useful acid addition salts. Acids which lead to therapeutically useful acid addition salts are e.g. strong mineral acids, such as hydrogen halide acids, e.g. hydrochloric or hydrobromic, sulfuric, phosphoric, nitric or perchloric, or organic acids such as aliphatic or aromatic carboxylic or sulfonic acids, e.g. formic 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, 4 -salicylic 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 of the invention have valuable pharmacological properties, e.g. cardiovascular effects due to selective inhibition of thromboxane secretion in mammals.

This inhibition results from selective diminution of the thromboxane synthetase. The compounds are therefore useful in the treatment of diseases that respond to the thromboxane synthesis inhibition in a mammal, including humans.

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These effects can be demonstrated by in vitro or in vivo animal studies, preferably with mammals, e.g. guinea pigs, mice, rats, cats, dogs or monkeys. Said compounds may be administered to the animals enterally or parenterally, preferably orally or subcutaneously, intravenously or intraperitoneally, e.g. in the form of gelatin capsules or in the form of starchy suspensions or aqueous solutions.

The dose used may be in a range of from about.

0.01 and 100 mg / kg / day, preferably approx. 0.05 to 50 mg / kg / day, especially from ca. 0.1 to 25 mg / kg / day.

The in vitro inhibition of the thromboxane synthetase enzyme can be detected analogously to the method of Sun Biochem. Biophys.

Res. Comm. 7_4> 1432 (1977). The test method is carried out as follows: 14C-Arachidonic acid is incubated with an enzyme blend composition consisting of solubilized and partially purified sheep seminal vesicle prostaglandin cyclooxygenase and a crude microsomal preparation of thromboxane synthetase from lysed human platelets. The test compound (dissolved in a buffer or, if necessary, in a little ethanol) is added to the incubation medium.

At the end of the incubation period (30 minutes), prostaglandin (PGE2) is reduced by the addition of sodium borohydride to a mixture of prostaglandin F2 <x and [PGF2 (α + β)]. The radioactive products and the excess substrate are extracted with ethyl acetate, and the extract is evaporated to dryness. The residue is dissolved in acetone, added dropwise to thin-layer plates and chromatographed with a solvent system consisting of toluene: acetone: glacial acetic acid = 100: 100: 3 (volume). The radioactive zones are located. The zones of thromboxane B2 (TxB2) and PGF2 (a + 0) are transferred to scintillation tubes for liquids and counting is made. The quotient of the numerical values of TXB2 / PGF2 (α + β) is calculated for each concentration of the test compound and the ICsQ values are determined graphically. This value is the concentration of the test compound at which the quotient of TxB2 / PGF2 (α + β) is reduced to 50% of the control value.

7

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The in vitro effect on prostaglandin cyclo-oxygenase is determined by a modification of the method of Takeguchi et al., Described in Biochemistry 10/2372 (1971). The test procedure is carried out as follows: 5 Lyophilized semen bladder microsomes from sheep are used as enzyme preparation for prostaglandin synthesis. 14 determines the conversion of C-arachidonic acid into PGE2. The test compounds (dissolved in a buffer or, 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 to scintillation tubes for liquids and the radioactivity measured. The IC ^ Q value for the inhibition is determined graphically. This value means the concentration of the test compound which reduces the amount of the synthesized PGE2 by 50%.

The in vitro effect on prostacyclin (PGI2) synthetase is determined analogously to the method of Sun et al., Prostaglandins 14, 1055 (1977). The following test procedure is used: 20 µC-Arachidonic acid is incubated with an enzyme mixture consisting of solubilized and partially purified sheep seminal bladder prostaglandin cyclo oxygenase and of raw PG 2 synthetase in the form of a microsomal fraction from bovine aorta.

The test compound (dissolved in a buffer or, if necessary, in a little ethanol) is added to the incubation medium. The reaction mixture is incubated in 100 mM tris (hydroxymethyl) aminomethane hydrochloride Ttris-HCl) (pH 7.5) for 30 minutes at 37 ° C, then adjusted to pH 3 and extracted with ethyl acetate. The extract is evaporated to dryness, the residue is dissolved in acetone and placed on thin-layer chromatography plates, then chromatographed with one of Sun et al. described solvent system. The radioactive zones are located with a detector. The 6-keto-PGFβ (a stable end product of the prostacyclin biotransformation) and PGE2-like zones are transferred to scintillation zones.

DK 158227 B

stir for liquids and counting is done. The quotient of the numerical values of 6-keto-PGF 2 / PGE 1 is calculated for each concentration of the test compound used. The IC ^ Q value for the inhibition is determined graphically. This value is the concentration of the test compound at which the quotient of 6-keto-PGF 2 α / PGE 2 is reduced to 50% of the control value.

The decrease in thromboxane plasma levels is determined in vivo by administering the test compound to guinea pigs as follows: 10 guinea pigs are treated with the test compound or carrier and 2 hours later arachidonic acid (40 mg / kg) is injected intraperitoneally. One hour after administration of the arachidonic acid, blood is drawn from the animals. In a given amount of each plasma sample, thromboxane 3 is determined and from a further 15 amounts 6-keto-PGF 3a, the stable metabolites of thromboxane A2 and prostacyclin (PGI 2) respectively, are determined.

The compounds of formula I are highly effective thromboxane synthetase inhibitors. With effective dose concentrations and above, neither the beneficial prostacyclin synthetase enzyme system nor the prostaglandin cyclooxygenase enzyme system is inhibited.

The IC, -n value of one of the compounds of the present invention, e.g.

-50 µg for 5- (5-carboxypentyl) imidazo [1,5-a] pyridine is 3 x 10 mol for the thromboxane synthetase inhibition, while the IC value for the inhibition of the prostacyclin synthetase and prostacyclin-4 the cyclooxygenase each is greater than 1 x 10 mol.

The compounds of the present invention, e.g. 5- (5-carboxypentyl) imidazo [1,5-a] pyridine also reduces the plasma concentration of thromboxane B2 in guinea pigs at as low an oral dose as 0.25 mg / kg by more than 50%. At this or greater oral doses no significant decrease in prostacyclin is observed.

DK 158227 B

9

Due to the above-mentioned beneficial properties, the compounds of the invention are extremely valuable as specific mammal therapeutic agents, including humans. Thus, e.g. by thromboembolism, this specific inhibition of the thromboxane synthetase enzyme causes the aggregation of platelets induced by arachidonic acid, which plays a role in the formation of solidified blood. Experimentally, prolongation of bleeding time in rats is considered as evidence of beneficial antithrombotic effect. The disclosed imidazo [1,5-a] -10 pyridines prolong bleeding time. Thus, e.g.

5- (5-carboxypentyl) imidazo [1,5-a] pyridine this effect by intraperitoneal administration to rats at a dose of about 1 mg / kg or less.

Regarding the beneficial effects of respiratory distress, reference is made to the fact that the compounds of the present invention provide protection against sudden death due to pulmonary obstruction caused by arachidonic acid.

Thus, e.g. 5- (5-carboxypentyl) -imidazo [1,5-a] -pyridine mice against sudden death by oral administration 20 at a dose of 100 mg / kg.

The process of the invention is characterized in that 1) is reacted with a compound of formula AA wherein M is an alkali metal and R 2 has the meaning given above, with a compound of formula X - A - B '(VII) wherein X is means halogen, A has the meaning given above, and B "means carboxy, trilavalkoxymethyl, unsubstituted, mono- or di- (loweralkyl) -substituted, carbamoyl, cyano, etherified hydroxymethyl or

DK 158227 B

10 halogen methyl, and converting a formed compound of formula XÅ / (Ia) - CEz-AB 'wherein R 2 and A have the above meanings, and (a) wherein B' is trilavalkoxymethyl, by hydrolysis to a compound of formula I, wherein B is carboxy, or (b) wherein B * is halo methyl, by reaction with

10 cyanide ions for a compound of formula X wherein B

means cyan, or (c) wherein B 'is etherified hydroxymethyl, by hydrolysis to a compound of formula I wherein B is hydroxymethyl, or (d) wherein B' is halo methyl, by reaction with an α-phenylthioacetic acid low alkyl ester in the presence of a strong base, oxidation of the thio group to sulfinyl and elimination by heating to a compound of formula I wherein B means lower alkoxycarbonyl and chain A is extended by a terminal -CH = CH group, or (e) wherein B * halogen methyl, by reaction with malonic acid di-lower alkyl ester in the presence of a base in a solvent, hydrolysis and decarboxylation to a compound of formula I wherein B is carb oxy and chain A is extended by a terminal -CH 2 -CH 2 group or (f) wherein B 'is halogenomethyl, to a Grignard compound, it condenses with a haloacetic acid low alkyl ester and hydrolyzes to a compound of formula I wherein B is carboxy and the chain A with a terminal -CH 2 -CH 2 group, or

DK 158227 B

11 (g) wherein B 'is halogenomethyl, to a Grignard compound and condenses it with CO 2 to a compound of formula I wherein B is carboxy, 5 and chain A is extended by a terminal -Cl 2 group, or 2) translates a compound of formula

/ \ JL

j * .Y.A <viii> · L5 wherein M is an alkali metal, R 2 is as defined above, and R 5 is lower alkyl, with a compound of formula X-CH 2 - A - B '(IX) wherein X is halogen A has the meaning given above and B * means carboxy, trilavalkoxymethyl, unsubstituted, mono- or di- (lower alkyl) -substituted carbamoyl, cyano, etherified hydroxymethyl or halo-methyl, whereupon in a formed compound wherein B * means trilavalkoxymethyl, halogenomethyl or etherified hydroxymethyl, converts the group B 'as indicated by process (1) to a group B and desulfurizes the compound formed, or 3) under basic catalysis, a compound of the general formula / = = fc.

i n <«.

wherein R 2 is as defined above and R 8 is lower alkoxycarbonyl or cyano, with a compound of formula X - A - Β · (VII)

DK 158227 B

12 wherein X is halogen, A is as defined above and B 'is carboxy, trilavalkoxymethyl, unsubstituted, mono- or di- (loweralkyl) -substituted carbamoyl, cyano, etherified hydroxymethyl or halo-methyl, the group R a compound formed in which B1 means trilavalkoxymethyl, halo-methyl or etherified hydroxymethyl, as indicated by process (1) for a compound of formula I, or 10 4) cycles a compound of formula A.A- / 'to S> (XI) ).

ch2-ab "fe in which the symbols R2 and R-jj have the meanings given above for R2, A has the meaning given above, and B" means carboxy, lower alkoxycarbonyl, unsubstituted, mono-15 or di- (lower alkyl) -substituted carbamoyl, cyan, hydroxymethyl, etherified hydroxymethyl or halo methyl, to give a compound of formula iA. = fc.

> Å J * (ib> dC-B '··.

wherein R 2, A and B "have the above meanings and convert a formed compound (a) wherein B" means halo methyl, by reaction with cyanide ions to a compound of formula I wherein B means cyan, or (b) wherein B "means etherified hydroxymethyl by hydrolysis to a compound of formula I wherein B represents hydroxymethyl, or 5) hydrogenates a compound of formula .A.Ji.

XÅJ <XIV) ·

C & = CH-A * -B

DK 158227 B

13 wherein A 'means an alkylene, alkenylene or alkynylene group having not more than 11 carbon atoms and R 2 and B have the meanings given above, or 5 6) in a compound of the formula> Å / <XVI>

C 1 -C 4 * wherein R 2 and A have the above meanings, and C means acetyl, carboxycarbonyl, formyl, dilavalkoxymethyl or vinyl, optionally extending chain A within its definition, converts group C to a carboxy group B as follows: method: (a) oxidation of an acetyl group C with sodium hypobromite, followed by cleavage of the resulting intermediate, (b) thermal treatment of a carboxycarbonyl group C, (c) treatment of a vinyl group C with nickel carbonyl and carbon monoxide under high pressure, the chain A or (d) oxidation of a formyl or dilavalkoxymethyl group C, 20 and, if desired, converting a prepared compound of formula I into another compound of formula I and / or, if desired, converting a prepared free compound for a salt or a prepared salt for the free compound or other salt and / or, if desired, a prepared mixture of isomers or racemates in the individual isomers or racemates and / or, if desired, produced racemates in the optical antipodes.

In a particularly advantageous embodiment of the process according to the invention, the 5- (5-carboxypentyl) -30 imidazo [1,5-a] pyridine or the hyarochloride thereof is prepared.

The reactive organometallic compounds of formula VI, wherein M is an alkali metal atom, can be prepared by the metallization of suitable methanol.

14 DK 158227 B

yl-substituted imidazo [1,5-a] pyridines. Thus, e.g. the 5-methylimidazo [1,5-a] pyridine prepared according to the Journal of Organic Chemistry 40, 1210 (1975) with a reactive metallizing agent, e.g. butyllithium 5 or lithium diisopropylamide, in an inert solvent, e.g. tetrahydrofuran, at a temperature below room temperature, preferably at ca. -50 ° C.

The condensation of an intermediate of formula VI with a reactive functional derivative of a compound 10 of formula VII is preferably carried out in a temperature range of from ca. -75 to approx. 50 ° C. When B 'means carb-oxy or mono- (lower-alkyl) -carbamoy], the appropriate metal salt, e.g. the lithium salt of the reactive functional derivative of the corresponding compound of formula VII, upon which it is reacted with the intermediate VI.

The preparation of the organometallic compound VIII used in process 2) and the subsequent condensation is carried out as described above and in Tetrahedron Letters 20 21, 2195-2196 (1980). The desulphurisation is preferably carried out with a desulphurisation catalyst, such as Raney nickel, in a solvent, e.g. ethanol, preferably at elevated temperature.

The starting materials of formula 25 used in process 3) can be prepared by treating the above-described compounds of formula VI, e.g. with carbon dioxide and esterification of the carboxylic acid formed, or by reaction with a di- (lower alkyl) carbonate or with a cyan halide.

In process 4), 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, optionally in an inert solvent, e.g. toluene, in a temperature range of 25 to 150 ° C, preferably 50 to 120 ° C.

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The amides of formula XI are prepared by acylating a compound of formula R2 R1 (XII) CH2 "AB" wherein R4, R5, A and B "have the above meanings, with a carboxylic acid of formula R1 -COOH (XIII ) wherein R 2 has the meaning given above, or with a reactive functional derivative thereof.

Reactive functional derivatives of compounds XIII 10 are preferably acid halides, simple or mixed anhydrides, e.g. the acid chloride, the acid anhydride (R2CO) 20, or a mixed anhydride. This can be prepared from a lower alkoxycarbonyl halide, e.g. chloromyric acid ethyl ester, or from an hindered lower alkanoyl halide, e.g. from 15 pivaloyl chloride, in a manner 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 condensing agents such as disubstituted carbodiimides, e.g. dicyclohexylcarbodiimide.

The acylation of compounds of formula XII with a reactive functional derivative of compounds of formula 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.

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For example, the amines of formula XII can be prepared 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-coal, or by treatment with a chemical reducing agent, e.g. borane or sodium cyanoborohydride.

The reducing agent is selected according to the type of the other functional groups present in the molecule. The compounds of formula XII can also be prepared by aminating the correspondingly substituted and reactively esterified 2- (hydroxymethyl) pyridines.

In process 5) the hydrogenation is carried out in a manner known per se, e.g. preferably in the presence of a catalyst, e.g. palladium.

The starting compounds of formula XIV may be prepared, for example, by condensing a compound of formula R1? 2 (xv)

L; N CHO

manufactured e.g. by reacting a compound of formula VIII with dimethylformamide and subsequently desulfurizing 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.

In process 6), groups which can be converted to a carboxy group, e.g. esterified carboxy groups, anhydritized carboxy groups, including corresponding groups of asymmetric and internal anhydrides, amidated carboxy groups, cyano, amidino groups, including cyclic amidino groups such as 5-tetrazolyl, imino ether groups, including cyclic imino ether groups, such as e.g. with lower alkyl substituted 2-oxazolinyl or 3Q dihydro-2-oxazolinyl groups, further hydroxymethyl, etherated hydroxymethyl, lower alkanoyloxymethyl, trialkoxymethyl, acetyl, trihaloacetyl, halo methyl, carboxycarbonyl.

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17 (COCOOH), methyl, formyl (CHO), di-lower alkoxymethyl, alkylene dioxymethyl, vinyl or diazoacetyl. Upon conversion to the carboxy group, the chain A can be simultaneously extended within the scope of its definition.

The conversion of the carboxy group is carried out in a manner known per se, as described herein or in the examples, e.g. solvolytic, such as hydrolytic or acidolytic, or reductive (esterified carboxy groups). Thus, for example, trichloroethyl or 2-iodoethyl ester can be reduced, e.g. with zinc and a carboxylic acid in the presence of water, is transferred into the carboxylic acid. Benzyl ester or nitro-benzyl ester can by catalytic hydrogenation, the latter also with chemical reducing agents, e.g. sodium dithionite or with zinc and a carboxylic acid are converted to the carboxy group. Furthermore, e.g. tert-butyl ester is also digested with e.g. trifluoroacetic acid.

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

Furthermore, compounds of formula XVI wherein C represents acetyl may be oxidatively cleaved to the corresponding compounds of formula I wherein B represents carboxy. First, the starting compounds are converted to a compound XVI wherein c means trihaloacetyl, e.g. tribromo or triiodoacetyl, e.g. by treatment with sodium hypobromite, after which cleavage, e.g. with an aqueous base such as sodium hydroxide.

Starting compounds of formula XVI wherein C is acetyl can be prepared from compounds of formula Ib wherein B 'is halo methyl by treatment with an acetacetic acid low alkyl ester, e.g. acetic acetic 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.

18

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Starting compounds of formula XVI wherein C means carb-oxycarbonyl (COCOOH) are converted by thermal treatment or by oxidation to the compounds of formula I wherein B means carboxy. The starting compound is heated to a higher temperature, e.g. ca. 200 ° C, in the presence of glass powder or treated, for example, with hydrogen peroxide in the presence of a basic agent, e.g. sodium hydroxide.

The starting compounds of formula XVI wherein C is COCOOH can be prepared e.g. by condensing a compound of formula Ia wherein B 'is halo-methyl, with e.g. 2-ethoxycarbonyl-1,3-dithian and subsequent oxidative hydrolysis, e.g. with bromosuccinimide in aqueous acetone <= and then by treatment with dilute aqueous sodium hydroxide.

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

The carboxaldehydes used as starting compounds, i.e. compounds of formula XVI, wherein c means formyl, are prepared by oxidation of compounds of formula I or Ia, wherein B or B 'means hydroxymethyl or halo-methyl, with e.g. dimethyl sulfoxide and a catalyst, e.g. a mixture of triethylamine and silver tetrafluoroborate.

The carboxaldehydes formed can be converted to the corresponding acetals, ie. for compounds of formula XVI wherein C is di-lower alkoxymethyl or alkylenedioxymethyl, e.g. a dimethyl acetal, by acid-catalyzed condensation with an alcohol, e.g. methanol.

Compounds of formula I wherein B is carboxy can, by the well-known Arndt-Eistert synthesis, be converted to compounds of formula I wherein B is carboxy and the chain further contains a carbon atom. In particular, treatment of a reactive functional derivative of 19 is performed

DK 15 8 2 2 7 B

the starting carboxylic acid / e.g. the acid chloride / with diazomethane, e.g. in diethyl ether to give a compound of formula XVI wherein C is diazoacetyl. In conversion with e.g. silver oxide 5 is obtained the said carboxylic acids of formula I wherein the chain A contains an additional carbon atom.

Compounds of formula XVI wherein C represents vinyl are converted to the compounds of formula I wherein B represents carboxy, first by ozonolysis to the compounds of formula 10 XVI, wherein C represents formyl, whereupon these compounds are oxidized to the compounds of formula I wherein B represents carboxy.

Starting compounds of formula XVI wherein C is vinyl can also be treated with high pressure nickel carbonyl and carbon monoxide 15 to give compounds of formula I wherein B is carboxy and chain A is extended by a carbon atom.

The individual definitions in the processes described above have the following meanings: In a reactive functional derivative of an alcohol of formula VII or IX, the hydroxy group is e.g. esterified with a strong inorganic or organic sulfonic acid, first of all with a hydrogen halide acid, e.g. hydrogen chloride acid, hydrogen bromide or hydrogen iodide acid, an aliphatic or aromatic sulfonic acid, e.g. methanesulfonic acid or p-toluenesulfonic acid. These compounds are prepared in a manner known per se.

Trialkoxymethyl preferably means tri (lower alkoxy) methyl, especially triethoxy or trimethoxy methyl.

Preferably, etherified hydroxymethyl means tertiary low-alkoxymethyl, lower alkoxy-alkoxymethyl, e.g. methoxy-methoxymethyl, 2-oxa or 2-thiacycloalkoxymethyl, especially 2-tetrahydropyranyloxymethyl.

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20

Halo methyl especially means chloromethyl, but also bromomethyl or iodomethyl.

Low alkanoyloxymethyl preferably means acetoxymethyl.

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

The necessary steps for the conversion of a prepared compound wherein B 'or B "is different from B to a compound of formula I or the optional conversions of a manufactured compound of formula I into another of the compounds of the invention are carried out using chemical processes known per se.

The hydrolysis of intermediates wherein B 'is trialkoxymethyl to compounds of formula I wherein B is carboxy is preferably carried out with inorganic acids such as hydrogen halide or sulfuric acid. The hydrolysis of intermediates wherein B 'is etherified hydroxymethyl to compounds of the formula I wherein B is hydroxymethyl is preferably carried out with aqueous solutions of inorganic acids, e.g. a hydrogen halide acid.

Intermediates of the formula Ia or Ib, wherein B 'or B "means halo methyl, can be reacted in a manner known per se, preferably with a metal cyanide, for example potassium cyanide.

. There are thus obtained compounds of formula I wherein the chain is extended by a carbon atom and B is cyano. These can again be converted in a manner known per se into compounds of formula I wherein B is carboxy, alkoxycarbonyl or carbamoyl.

Thus, compounds of formula I wherein B represents cyan (nitriles) can be converted to compounds of formula I, wherein B represents carboxy, by hydrolysis with inorganic acids, e.g. hydrogen halide acid, such as hydrochloric acid, or sulfuric acid, in aqueous solutions or preferably by hydrolysis with aqueous alkali metal hydroxides, e.g. potassium hydroxide, preferably at reflux temperature.

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21

The conversion of said nitriles to the compounds of formula I wherein B is lower alkoxycarbonyl is preferably carried out by treatment with a low alkanol, e.g. anhydrous ethanol, in the presence of a strong acid, e.g. Hydrogen chloride acid, preferably at reflux temperature, and subsequent gentle hydrolysis with water.

Further, the conversion of said nitriles to compounds of formula X wherein B is carbamoyl is preferably carried out by treatment with an alkali metal hydroxide, e.g. dilute sodium hydroxide and hydrogen peroxide, preferably at room temperature.

Furthermore, the intermediates of formula Ia, Ib or XVI wherein B ', B "or C means halogenomethyl, for example chloromethyl, can be converted to the compounds of formula I, wherein B represents carboxy and the chain length is extended by 2 C atoms. , as follows: First, a substituted malonic acid di-lower alkyl ester is prepared by treatment with, for example, a malonic acid di-low alkyl ester, such as with malonic acid diethyl ester, in the presence of a base, e.g., potassium-20 carbonate or sodium ethoxide, in a solvent, for example, dimethylformamide, preferably in a temperature range between 50 and 100 ° C. This is preferably hydrolyzed with an aqueous base, for example diluted sodium hydroxide, to the corresponding malonic acid and decarboxylated using 25 If a cyan acetic acid low alkyl ester is used instead of the malonic acid di-lower alkyl ester, the corresponding compound in which B means cyan is obtained.

Compounds of formulas Ia and Ib, wherein B * and B "are 30 halogenomethyl, can be converted into the corresponding metal-organic intermediates, for example copper or magnesium derivatives, in a manner known per se.

In the condensation of e.g. a prepared organic magnesium (Gr ignard) reagent, e.g. with a compound of formula Ia wherein B "is halogen magnesium, e.g.

CH 2 MgCl and with carbon dioxide a compound of formula I is formed in which B is carboxy and the chain is extended

DK 158227 B

22 with 1 C atom.

By condensing said Grignard reagent with e.g. a haloacetic acid low alkyl ester, e.g. bromoacetic acid ethyl ester, there is obtained a compound of formula I wherein 5 B is lower alkoxycarbonyl and the chain is extended by 2 C atoms.

Said Grignard reagent may be condensed in the presence of a copper I halide, e.g. copper I chloride, with an α ·,,-unsaturated acid or an ester, e.g. with propiolic acid or acrylic acid to give a compound of formula I wherein B is carboxy or lower alkoxycarbonyl and the chain is extended by 3 C atoms.

The present compounds, wherein A represents a straight or branched alkenylene group and contains a terminal double bond, may also be prepared from the intermediates of formula Ia or Ib wherein B 'or B "means halo methyl. Thus, for example, these intermediates are first reacted with for example, an α- (aryl or alkyl) -thioacetic acid-low alkyl ester such as α- (phenylthio) -acetic acid ethyl Ι ester This reaction is carried out in the presence of a strong base, for example, sodium hydroxide. The subsequent oxidation of the resulting α-arylthio or α-alkylthiosubstituted ester to the α-arylsulfinyl or α-alkylsulfinyl ester, with, for example, sodium periodate and subsequent elimination induced by heat application, e.g. refluxing xylene leads to a compound of general formula I (an α, β-unsaturated ester) wherein A is alkenylene and B is, for example, lower alkoxycarbonyl, and

DK 158227 B

The 23 chain is extended by 2 c atoms. Similarly, compounds of formula Ia wherein B 'is halo methyl may first be converted to the corresponding carboxaldehydes, e.g. with dimethyl sulfoxide in the presence of triethylamine 5 and silver tetrafluoroborate. The subsequent Wittig condensation, e.g. with the (triphenylphosphoranylidene) acetic acid ethyl ester also leads to the aforementioned α, β-unsaturated esters.

Compounds of formula I wherein B is lower alkoxycarbonyl may be amidated 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, to compounds of formula I wherein B means unsubstituted mono-15 or di- (lower alkyl) substituted carbamoyl.

Compounds of formula I wherein B is unsubstituted carbamoyl may be dehydrated to the corresponding nitriles in a manner known per se, e.g. by treatment with triphenylphosphine or thionyl chloride in an inert solvent, e.g. toluene.

The conversion of compounds of formula I wherein B is lower alkoxycarbonyl, cyano, unsubstituted, mono- or di- (loweralkyl) substituted carbamoyl, to compounds of formula I wherein B represents carboxy is preferably carried out by hydrolysis with inorganic acids, e.g. .g. with hydrogen halide acids or sulfuric acid, or with aqueous bases, preferably with alkali metal hydroxides, e.g. lithium or sodium hydroxide.

Compounds of formula I wherein B is carboxy or lower alkoxycarbonyl may be reduced by simple or complex light metal hydrides, e.g. with lithium aluminum hydride, alan or diborane, for compounds of formula I wherein B is hydroxymethyl. The alcohols may also be prepared by suitable solvolysis of intermediates of formula Ia 35 or Ib, wherein B "and B" mean halogen methyl, by treatment

DK 158227 B

ling e.g. with an alkali metal hydroxide, e.g. lithium or sodium hydroxide.

The above-mentioned alcohols can, for their part, be converted to compounds of formula I wherein B is 5 carboxy, with conventional oxidizing agents, preferably with pyridine dichromate in dimethylformamide at room temperature. Said alcohols may also be converted to the compounds of formula I wherein B represents carboxy and wherein the chain is extended by 1 C atom by treatment with nickel-10 carbonyl and carbon monoxide under high pressure.

Free carboxylic acids can be esterified with lower alkanols, e.g. ethanol in the presence of a strong acid, e.g. sulfuric acid, preferably at elevated temperature, or with diazo-low alkanes, e.g. diazomethane in a solvent, e.g.

15 ethyl ether, preferably at room temperature, to the corresponding esters, namely to such compounds of formula I wherein B is lava alkoxycarbonyl.

Furthermore, the free carboxylic acids can be converted by treating the reactive intermediates, e.g. an acyl halide, such as an acid chloride, or a mixed anhydride, e.g. one of a halo-carbonic acid lower alkyl ester, e.g. chlormyresyreethylestei; derived mixed anhydride, with ammonia, mono- or di-lower alkyl amines, in an inert solvent, e.g. methylene chloride, preferably in the presence of a basic catalyst, e.g. pyridine, for the compounds of formula I wherein B is unsubstituted, mono- or di- (lower alkyl) substituted carbamoyl.

Compounds of formula I wherein B is monolavalkyl-carbamoyl can be converted to compounds of formula I, wherein B is di-loweralkyl-carbamoyl, 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.

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25

Compounds of formula I can be converted to 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 wherein A represents a straight or branched alkynylene or alkenylene group can be converted by catalytic hydrogenation, preferably under neutral conditions, e.g. with a palladium catalyst at atmospheric pressure in an inert solvent, e.g. ethanol, for the compounds of formula I wherein A means straight or branched alkylene.

Furthermore, compounds of formula I, wherein hydrogen is converted, can be converted to the corresponding halogen derivatives by direct halogenation with chlorine, bromine or iodine.

The above-described reactions are carried out in a manner known per se in the presence or absence of diluents, preferably in those which are inert to the reactants and which dissolve them, catalysts, condensers or other of the above-mentioned agents and / or in a inert atmosphere, under cooling, at room temperature or at elevated temperature, preferably at the boiling point of the solvent used, at normal or elevated pressure.

In the process of the invention, such starting compounds are advantageously used which lead to the above-mentioned compounds which are described as particularly valuable.

26

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Depending on the choice of starting compounds and methods, the compounds of the invention may be in the form of one of the possible isomers or mixtures thereof. Thus, e.g. depending on the presence of a double bond 5 and depending on the number of the asymmetric carbon atoms are present as pure optical isomers, e.g. as antipodes, or as mixtures of the isomers, e.g. such as racemates, mixtures of diastereomers, mixtures of racemates, or mixtures of geometric isomers.

Formed mixtures of diastereomers, mixtures of racemates or geometric isomers can be separated on the basis of differences in the physicochemical properties of the constituents in a manner known per se in the pure isomers, diastereomers, racemates or geometric isomers, e.g. by chromatography and / or fractional crystallization.

Furthermore, formed racemates can be separated into the optical antipodes in a manner known per se, e.g. by recrystallization from optically active solvents, by using microorganisms or by reacting the acidic final product with an optically active base which forms salts with the racemic acid. These salts can in this way, e.g. because of their different solubilities, are separated into the diastereomers. From the latter, the antipodes can be released by the action of suitable agents. Basic racemic compounds can be separated in the antipodes by analogy, such as by separating their diastereomeric salts, e.g. by fractional crystallization of the d or 1 tartrates.

Of the two antipodes, the antipode having the strongest effect is preferably isolated.

Finally, the compounds of the present invention may be prepared in free form or as salts. A prepared free base can be converted to the corresponding acid addition salt, preferably with acids leading to therapeutically useful acid addition salts, or with anion exchangers. Formed salts can be converted

DK 158227 B

27 to the corresponding free bases, e.g. by treatment with a stronger base, such as with a metal hydroxide or ammonium hydroxide, a basic salt, e.g. an alkali metal hydroxide or carbonate, or a cation exchanger. A compound of formula I wherein B is carboxy may also be converted to the corresponding metal or ammonium salts. These or other salts, e.g. The picrates can also be used to clean the free bases. The bases are converted to salts thereof, the salts are isolated and the bases released from the salts.

10 Due to the close relationship between the compounds in question in free form and in salt form, the previous and subsequent compounds and salts may optionally also mean the corresponding salts or free compounds.

The compounds and their salts may also be obtained in the form of hydrates or may contain other solvents used for crystallization.

The pharmaceutical compositions are those suitable for enteral, e.g. oral or rectal, and parenteral administration 20 to mammals, including humans. The compositions are used to treat or prevent diseases that respond to the inhibition of thromboxane synthetase, e.g. peripheral vasculature diseases. These compositions contain an effective dose of a pharmacologically active compound of formula 25 I or a pharmaceutically useful salt thereof, alone or in combination with one or more pharmaceutically acceptable carriers.

The subject pharmacologically useful compounds can be used to prepare pharmaceutical compositions containing an effective amount of compound together with or in admixture with carriers suitable for enteral or parenteral administration. Preferably, tablets or gelatine capsules are used which contain the active compound together with diluents, e.g. lactose, dextrose, cane sugar, mannitol, sorbitol, cellulose and / or

DK 158227B

28 glycine, and lubricants, e.g. silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol. Tablets also contain binders, e.g. magnesium aluminum silicate, starch paste, gelatin tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone, and, if desired, disintegrants, e.g. starches, agar, alginic acid or a salt thereof, such as sodium alginate, and / or effervescent mixtures, or adsorbents, dyes, flavors and sweeteners. Injection preparations are preferably isotonic aqueous solutions or suspensions, and suppositories are primarily fat emulsions or suspensions. The pharmacological compositions may be sterilized and / or contain excipients, e.g. preservatives, stabilizers, wetting agents and / or emulsifiers, solubility promoting agents, salts for regulating the osmotic pressure and / or puffers. eg. by conventional mixing, granulating or coating methods and containing from ca. 0.1 to 75, especially from ca. 1 to approx. 50% effective connection. Single doses for mammals with a body weight of approx. 50-70 kg can contain from approx. 10 to approx. 200 mg of active ingredient.

The process of the invention is further illustrated in the following examples. The parts listed are by weight. Evaporation of the solvents is done under reduced pressure, e.g. between approx. 15 and 100 mm Hg, unless otherwise stated.

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29

Example 1

A solution of 50 g of 5-methylimidazo [1,5-a] pyridine [J. Org.

Chem. 4, 1210 (1975)] in 625 ml of tetrahydrofuran is cooled to -75 ° C and 175 ml of 2.4 N of butyl lithium in hexane are added under nitrogen, keeping the temperature below -53 ° C. The solution of 5- (lithiomethyl) imidazo [1,5-a] pyridine is again cooled to -75 ° C, and a solution of 51.8 g of 5-bromo-1,1,1-triethoxyphenate is rapidly added. pentane in 125 ml of tetrahydrofuran, raising the temperature to -60 ° C.

The reaction mixture is allowed to stand for 45 minutes, raising the temperature to -4 ° C and then evaporating to dryness. The residue is partitioned between 500 ml of ethyl ether and 240 ml of 3 N hydrochloric acid. The ether solution is extracted twice with 60 ml of 3 N hydrochloric acid. The combined aqueous extracts are basified with 100 ml of concentrated ammonium hydroxide solution and extracted with 2x 200 ml of ethyl ether. The ether extract is dried over magnesium sulfate and evaporated to dryness. The resulting oil is distilled in high vacuum. 5- (5-Ethoxycarbonylpentyl) imide-20 azo [1,5-a] pyridirv 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 1 N aqueous sodium hydroxide solution is heated for 2 hours on a steam bath, then 25 ml of ethanol is added and heated for an additional 45 minutes. . The reaction mixture is cooled, washed with ether (300 ml) and 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) -imide-azo [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, then 93 ml of 2.3 N butyllithium solution in hexane is slowly added keeping the temperature below -65 ° C. The suspension is stirred 30

DK 158227 B

for 20 minutes, then a solution of 5- (lithiomethyl) imidazo [1,5-a] pyridine (prepared from 26.9 g of 5-methylimidazo [1,5-a] pyridine and 93 ml of 2.3 N -butyllithium solution of Example 1) at one time 5 at -75 ° C. The reaction mixture is stirred for 2 hours at -75 ° C, then left to warm to room temperature, treated with 15 ml of 12 N hydrochloric acid and evaporated in vacuo.

The residue is partitioned between water and methylene chloride after the pH is adjusted to 10 with sodium carbonate.

The aqueous solution is further washed with chloroform, adjusted to pH 1 with 12N hydrochloric acid and washed again with ether and toluene. The pH is adjusted with sodium bicarbonate of 5.5, and by extraction with chloroform, crude 5- (5-carboxypentyl) imidazo [1,5-a] pyridine is obtained. A solution of the acid in 30 ml of acetonitrile is treated with 20 ml of 5 N 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 neutralizing the methanolic solution with dilute sodium hydroxide solution to pH 5.

b) From 6-bromohexanoic acid, 5- (6-carboxyhexyl) imidazo [1,5-a] pyridine, which melts at 137-139 ° C, is prepared in an analogous manner.

c) Analogously, 5- (7-carboxyheptyl) imidazo [1,5-a] pyridine is prepared from 7-bromoheptanoic acid, m.p. 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-crown-6 in 500 ml of acetonitrile is boiled for 20 hours. reflux. The acetonitrile is evaporated under reduced pressure, the residue partitioned between water and methylene chloride, and the methylene chloride extract evaporated to dryness. By treating a solution of the residue in ether with 31

DK 158227 B

ethanolic hydrochloric acid gives 5- (5-cyanpentyl) imidazo [1,5-a] pyridine hydrochloride, which melts at 178-180 ° C.

The starting compound is prepared as follows:

A solution of 30 g of 1-bromo-4-chlorobutane in 20 ml of dry 5 tetrahydrofuran is added to a solution of 5- (lithiomethyl) imidazo [1,5-a] pyridine (prepared according to Example 1 from 22 g of 5-methyl -imidazo [1,5-a] pyridine and 80 ml of 2.3 N solution of n-butyllithium in hexane) keeping the temperature below -50 ° C. The reaction mixture is stirred for 2-3 hours at -50 ° C, warmed to room temperature, stirred overnight and evaporated to dryness. The solution of the residue in 200 ml of methylene chloride is washed with water, dried over magnesium sulfate and evaporated to dryness. 5- (5-Chloro-pentyl) -imidazo [1,5-a] pyridine is obtained, which is used without further purification.

Example 5

Analogously to the procedure described in Example 4, 5- (4-chlorobutyl) -imidazo [1,5-a] pyridine is converted to 5- (4-cyanbutyl) -imidazo [1,5-a] pyridine, m.p. 72-77 ° C.

Example 6

Analogous to the procedure described in Example 4, 3,5-dimethylimidazo [1,5-a] pyridine (J. Het. Chem.

3, 33 (1966)) to 5- (5-chloropentyl) -3-methyl-imidazo [1,5-a] pyridine, m.p. 98-104 ° C. Using the conditions of Example 4 in the reaction with potassium cyanide, 5- (5-cyanpentyl) -3-methyl-imidazo [1,5-a] pyridine is prepared which is converted to the hydrobromide by dissolving the free base in acetonitrile and acidifying solution containing ethanolic hydrobromic acid. It formed 5- (5-cyanpentyl) -30 3-methylimidazo [1,5-a] pyridine hydrobromide melting at 215-220 ° C.

DK 158227B

32

Example 7

A solution of 36 g of 5- (cyanpentyl) imidazo [1,5-a] pyridine in 100 ml of methanol and 50 ml of 45% aqueous potassium hydroxide solution is refluxed for 48 hours. The methanol is evaporated under reduced pressure and water is added to the residue. The basic solution is washed with ethyl acetate and adjusted to a pH in the range of 5.5-6 with concentrated hydrochloric acid.

The crystallized acid is isolated and recrystallized from ethanol. The product of Example 2 is obtained, namely 5- (5-carboxypentyl) -imidazo [1,5-a] pyridine, which melts at 142-145 ° C. Further recrystallization raises the melting point to 144-147 ° C.

Example 8 By hydrolysis of 5- (4-cyanbutyl) -imidazo [1,5-a] pyridine using the procedure described in Example 7, 5- (4-carboxybutyl) -imidazo [1,5-a] - pyridine, which melts at 161-163 ° C.

Example 9 By hydrolysis of 5- (5-cyanpentyl) -3-methyl-imidazo [1,5-a] pyridine using the procedure described in Example 7, 5- (5-carboxypentyl) -3-methyl- imidazo [1,5-a] pyridine, which melts at 170-173 ° C.

Example 10 To a solution of 3 g of 5- (5-cyanpentyl) -3-methylimidazo [1,5-a] pyridine hydrochloride in a mixture of 20 ml of ethanol and 5 ml of 1 N aqueous sodium hydroxide solution is added 10 ml. 30% hydrogen peroxide solution. To the reaction mixture is then added 5 ml of ethanol and adjusted to pH 10 with 1 N sodium hydroxide solution.

The mixture is stirred overnight at room temperature, the ethanol is evaporated under reduced pressure, water is added to the residue and extracted with methylene chloride.

The resulting product is crystallized from ether and recrystallized.

DK 158227 B

33 is stalled from acetonitrile. 5- (5-carbamoylpentyl) imidazofl, 5-a] pyridine is obtained which melts at 131-132 ° C.

Example 11

A solution of 3.9 g of 5- (5-ethoxycarbonylpentyl) imidazo-5 [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 resulting product is first recrystallized from ether and then from a 1: 1 mixture of ethyl acetate and ether. 10 5- [5- (N-methylcarbamoyl) -pentyl] -imidazo [1,5-a] pyridine is obtained, which melts at 118-122 ° C.

Example 12

To a solution of 2.45 g of 5- [5- (N-methylcarbamoyl) -pentyl] -imidazo [1,5-a] pyridine in 25 ml of dimethylformamide is added 0.011 mole of sodium hydride (prepared by washing 0.53 g of 50 % sodium hydride dispersion in mineral oil with hexane) and brief heating on a steam bath. 1.56 g of methyl iodide are added to the cooled yellow solution.

The mixture is stirred for 2 hours at room temperature, diluted with 100 ml of water and extracted first with 150 ml of 1: 1 mixture of ethyl acetate and ether and then with 100 ml of chloroform. After evaporation of the mixed extracts, a dry residue is obtained, which is dissolved in 100 ml of ether and treated with 20 ml of ethanolic hydrochloric acid. The precipitated salt is filtered off and recrystallized first from 50 ml of a mixture of acetonitrile and ethyl acetate (1: 1) and then from 30 ml of a mixture of ethanol and ether (1: 1). 5- [5- (Ν, Ν-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. To the suspension, stirring at room temperature is first added 2.35 g of trimethylborate and then slowly 1.0 ml (equivalent to 0.01 mole) of borane-methylsulfide complex. The reaction mixture

DK 158227 B

34 is heated for 2 hours at reflux temperature / cooled, then 2.6 ml of methanol, 9.5 ml of water and 2 ml of 50% aqueous sodium hydroxide solution are added. The mixture is refluxed for 1 hour, diluted with 50 ml of water and extracted with 2 times 75 ml of methylene chloride. The methylene chloride extract is evaporated to dryness and the residue is treated with 4 ml of 5 N hydrochloric acid in 30 ml of ether.

5- (6-hydroxyhexyl) -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) imidazo [1,5-a] pyridine (prepared according to Example 1 from 5 g of 5-methylimidazo [1,5-a] pyridine and 17.7 ml of 2.3 N n-butyllithium in hexane). The mixture is stirred for 1 hour at -70 ° C and then overnight without further cooling. The mixture is evaporated to dryness, the residue is dissolved in 50 ml of 4N hydrochloric acid, the solution is washed with 2 times 100 ml of ether, basified with 75 ml of 20 aqueous sodium hydroxide solution and extracted with 2 times 100 ml of methylene chloride. The methylene chloride extract is evaporated to dryness. The residue is converted to the hydrochloride with ethereal hydrochloric acid 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 of concentrated hydrochloric acid is hydrogenated at 3 atmospheres in the presence of 30 of 1 g 10% palladium-on-carbon catalyst for a hydrogen uptake of 2 moles. The catalyst is filtered off and the filtrate is evaporated to dryness. The residue is recrystallized from isopropanol / ether. There is obtained 5- (6-carboxyhexyl) -5,6,7,8-tetrahydroimidazo [1,5-a] pyridine hydrochloride, which melts at 150-154 ° C.

35

DK 158227 B

b) Similarly, by hydrogenation of 5- (5-carboxypentyl) imidazo [1,5-a] pyridine 5- (5-carboxy-pentyl) -5,6,7,8-tetrahydroimidazo [1,5- a] pyridine hydrochloride, which melts at 146-150 ° C.

C) From 5- (4-carboxybutyl) imidazo [1,5-a] pyridine, analogously 5- (4-carboxybutyl) -5,6,7,8-tetrahydroimidazo [1 5-a] pyridine hydrochloride, which melts at 120-123 ° C.

Example 16 A solution of 2.3 g (0.011 mol) of 5-bromo-3,3-dimethyl-pentanoic acid [J. Org. Chem. J44, 1258 (1979)] in 20 ml of dry tetrahydrofuran is cooled in a nitrogen atmosphere to -70 ° C and then 5.05 ml of 2.4 M n-butyllithium in hexane is added dropwise. At the end of the addition, a solution of 5- (lithiomethyl) imidazole 1,5-a] pyridine in hexane (prepared from 1.32 g of 5-methylimidazo [1,5-a] pyridine and 5.05) is added at once. ml of 2.4 N n-butyllithium in hexane).

The mixture is stirred overnight at room temperature.

The reaction mixture is diluted with 50 ml of water, 20 g of sodium carbonate is added and the basic solution is extracted with three times 75 ml of chloroform. The aqueous phase is acidified with 12N hydrochloric acid to pH 2 and extracted with three times 100 ml of ether. Then the aqueous phase with dilute sodium hydroxide solution is adjusted to pH 5 25 and extracted with 200 ml of a mixture of ethyl acetate and ether (1: 1). The extracts are dried and evaporated to give a yellow oil. This is crystallized from 50 ml of a mixture of ethanol and ether (1: 1). 5- (5-carboxy-4,4-dimethylpentyl) -imidazo [1,5-a] pyridine is obtained, which 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 35 most of the iodine solution is added further

DK 158227 B

Add 4 ml of ethanol and the mixture is stirred for 45 minutes. The reaction mixture is diluted with 12 ml of water and extracted with methylene chloride at pH 8 (if necessary, with the addition of sodium bicarbonate). The aqueous phase 5 is concentrated in vacuo, purified with activated charcoal and adjusted to pH 4.5 with 2N hydrochloric acid. The precipitate is isolated, dried and recrystallized from methanol / ether.

There is obtained 1-iodo-5- (5-carboxypentyl) -imidazo [1,5-a] pyridine, which melts at 163-165 ° C.

Example 18

Preparation of 10,000 tablets with a content of 10 mg of active compound according to Example 2 per tablet.

Ingredients 5- (5-Carboxypentyl) -imidazo [1,5-a] pyridine 100 g Milk sugar 1157 g

Corn starch 75 g

Polyethylene Glycol 6000 75 g

Talcum powder 5 g

Magnesium stearate 18 g 20 Purified water q.s.

Course of action; All powdered components are screened through a screen having a mesh width of 0.6 mm. Then, the active compound is mixed with milk sugar, talc, magnesium stearate and half of the starch in a suitable mixing apparatus. The other half of the starch is suspended in 40 ml of water and the suspension is added to a boiling solution of polyethylene glycol in 150 ml of water. The resulting paste is added to the powder mixture and optionally granulated with the addition of additional water. The granulate is dried overnight at 35 ° C, pressed through a screen having a mesh width of 1.2 mm and compressed into tablets with partial grooves and a diameter of 6.4 mm.

Example 19

Preparation of 10,000 capsules with a content of 25 mg of active compound of Example 3b capsule.

37

DK 158227 B

Ingredients 1- (6-Carboxyhexyl) -imidazo [1,5-a] pyridine 250 g Milk sugar 1800 g

Talcum powder 100 g 5 Procedure; All powdered components are screened through a screen having a mesh width of 0.6 mm. Then, the active compound is first homogenized with the talc and then with the milk sugar in a suitable mixing apparatus.

Capsules # 3 are filled with 215 mg of the prepared mixture per ml. capsule using a filling machine.

Similarly, tablets and hard gelatin capsules are also prepared using compounds of other examples.

Example 20 A solution of 5-methylimidazo [1,5-a] pyridine (4.0 g) and tetramethylethylenediamine (4.9 g) in 100 ml of tetrahydrofuran is cooled under nitrogen to 0 ° C and dropwise added. 5 ml of 1.6 N n-butyl lithium in hexane, keeping the temperature below 2 ° C. After 30 minutes, this solution is added in a nitrogen atmosphere over 45 minutes to an ice-cold solution of 4.86 g of 5-bromo-valeronitrile in 80 ml of tetrahydrofuran. The solvent is evaporated after 15 minutes and the residue partitioned between water and ethyl acetate. The organic phase is extracted with three times 15 ml of 2N hydrochloric acid. The aqueous phase is adjusted with 50% sodium hydroxide solution to pH 10. Extract with twice 75 ml of ethyl acetate, dried over magnesium sulfate, evaporated and chromatographed (silica gel, ethyl acetate). 5- (5-Cyanpentyl) imidazo [1,5-a] pyridine is obtained.

Example 21

To a solution of 4 g of 5- (4-ethoxycarbonylbutyl) -3-ethylthio-imidazo [1,5-a] pyridine in 100 ml of ethanol is added approx. 5 g Raney Nickel. The solution is boiled for 18 hours under reflux. Raney nickel is filtered off and washed with

DK 158227 B

38 100 ml of ethyl acetate. The filtrate is evaporated under reduced pressure to dryness. The product is available in the form of a thick oil.

This is purified by column chromatography (silica gel) and eluted with a mixture of ether and hexane (1: 3). The solvent 5 is evaporated under reduced pressure. 5- (4-Ethoxy-carbonyl-butyl) -imidazo [1,5-a] pyridine is obtained as a yellow oil.

NMR (CDCl3) 1/25 (t, 3H), 4.15 (q, 2H), 8.1 (s, 1H).

The starting compound is prepared as follows:

17.8 g of 3-ethylthio-imidazo [1,5-a] pyridine are dissolved in 10 200 ml of dry tetrahydrofuran and the solution is cooled to -70 ° C. Then, dropwise over 80 minutes, stirring 80 ml of 1.6 M n-butyl lithium in hexane is added dropwise.

After the addition is complete, the reaction mixture is stirred for a further 30 minutes at -70 ° C. To the mixture is added dropwise a solution of 20 g of 4-bromopentanoic acid ethyl ester in 75 ml of tetrahydrofuran. The reaction mixture is allowed to warm to -10 ° C, then kept for 30 minutes at this temperature and then for 1 hour at room temperature.

To the reaction mixture is added 400 ml of diethyl ether and 20 400 ml of 4 N hydrochloric acid. The aqueous phase is isolated and the ether layer is washed with water. The mixed aqueous extracts are basified with ammonium hydroxide and extracted with three times 200 ml of ether. The ether extract is dried over anhydrous magnesium sulfate and the solvent is evaporated under reduced pressure. As a crude product a thick oil is obtained. This is chromatographed on a silica gel column and eluted with a mixture of pentane and diethyl ether (4: 1). The solvent is evaporated and the product distilled. 3-Ethylthio-5- (4-ethoxycarbonylbutyl) imidazo [1,5a] pyridine is obtained which boils at 170 ° C / 0.3 mm Hg. NMR (CDCl 3) 1.25 (t, 3H), 1.30 (t, 3H), 3.15 (q, 2H), 4.15 (q, 2H).

Example 22

A solution of 3 g of 5- [5-ethoxycarbonyl-5- (phenylsulfinyl) -pentyl] -imidazo [1,5-a] pyridine in 50 ml of xylene is refluxed for 30 minutes at reflux. The xylene is then evaporated under reduced pressure, the residue dissolved in 39

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15 ml of diethyl ether and chromatographed on silica gel. The product is eluted with a mixture of diethyl ether and ethyl acetate (2: 1). After evaporation of the solvent, 5- (5-ethoxycarbonyl-pent-4-enyl) -imidazo [1,5-a] pyridine 5 is obtained as an oil. NMR (CDCl3) 1.29 (t, 3H), 4.25 (q, 2H), 5.88 (d, 1H).

The starting compound is prepared as follows:

To an ice-cooled magnetically stirred slurry of 0.96 g of sodium hydride in 50 ml of dimethylformamide is added dropwise over 15 minutes 3.92 g of 2- (phenylthio) ethyl acetate.

The suspension is stirred at room temperature for 2 hours, then cooled with an ice bath to 5 ° C. To this suspension, 4.16 g of 5- (4-chlorobutyl) imidazo [1,5-a] pyridine is added dropwise over one hour. Then 3.2 g of sodium iodide is added to the mixture and stirred overnight at room temperature.

The reaction mixture is poured into 150 ml of ice water and extracted with three times 100 ml of a mixture of diethyl ether and ethyl acetate (1: 1). The organic phase is washed with twice 100 ml of saturated aqueous sodium chloride solution and then extracted with three times 50 ml of 1 N hydrochloric acid. The acidic aqueous extracts are combined, basified with ammonium hydroxide, and extracted with three times 150 ml of a mixture of diethyl ether and ethyl acetate (1: 1). The organic extracts are dried over anhydrous magnesium sulfate, 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.

To a solution of 3.8 g of 5- [5-ethoxycarbonyl-5- (phenylthio) -pentyl] -imidazo [1,5-a] pyridine in 100 ml of methanol is added 2.8 g of sodium metaperiodate and the mixture is stirred. 18 hours at room temperature. The solvent is evaporated

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40 under reduced pressure and the residue is taken up in 150 ml of water. Extract with three times 100 ml of ethyl acetate.

The organic phase is extracted twice with 50 ml of 1 N hydrochloric acid, the aqueous extract is basified with ammonium hydroxide and extracted twice with 100 ml of ethyl acetate. The mixed ethyl acetate extracts are dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. An oil is obtained which is purified by column chromatography on silica gel and eluted with a mixture of ethyl acetate and diethyl ether (1: 1). After evaporation, 5- [5-ethoxycarbonyl-5- (phenylsulfinyl) -pentyl] -imidazo [1,5-a] pyridine is obtained as an oil. IR 1720 cm -1, 1040 cm

Example 23

To a solution of 300 mg of 5- (5-ethoxycarbonylpent-4-enyl} -15 imidazo [1,5-a] pyridine in 20 ml of methanol is added 5 ml of 1 N sodium hydroxide solution and the mixture is stirred at room temperature for 18 hours. under reduced pressure, and to the aqueous residue is added an additional 5 ml of water, the mixture is extracted with three times 20 ml of 5 ml of ethyl acetate, the basic aqueous layer is adjusted to pH 5 and extracted with 3x 5 ml of ethyl acetate. anhydrous sodium sulfate, filtered and evaporated under reduced pressure.

There is obtained 5- (5-carboxypent-4-enyl) -imidazo [1,5-a] pyridine, which melts at 142-144 ° C.

Example 24

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 carbethoxymethylene-triphenylphosphorane and the mixture is stirred for 18 hours at room temperature. . Then the solvent is evaporated under reduced pressure. 5- (7-Ethoxycarbonyl-hept-6-enyl) -imidazo [1,5-a] pyridine is obtained as an oil. ir (methylene chloride): 1715 cm ”1 (C = 0).

The starting compound is prepared as follows: To a solution cooled to -60 ° C of 4.9 g of 5- (5-methoxy-carbonyl-pentyl) -imidazo [1,5-a] pyridine (prepared at 41

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esterification of the 5- (5- (carboxymethyl) -imidazo [1,5-a] pyridine with diazomethane in methylene chloride) in 140 ml of methylene chloride is added dropwise over 20 minutes to 40 ml of 1.75 molar solution 5 of di -isobutyl aluminum hydride in hexane. Then, the reaction mixture is stirred for 20 minutes at -60 ° C, then 10 ml of methanol and 100 ml of water are added to quench the reaction. The mixture is stirred for 15 minutes at room temperature, the methylene chloride layer is isolated and the solvent evaporated under reduced pressure.

5- (5-Formylpentyl) -imidazo [1,5-a] pyridine is obtained as an oil. NMR (CDCl3) 9.7 (m, 1H), IR (methylene chloride) 1710 cm -1.

Example 25 To a solution of 2.8 g of 5- (7-ethoxycarbonyl-hept-6-enyl) -imidazo [1,5-a] pyridine in 30 ml of methanol is added 15 ml of 1 M sodium hydroxide solution and the mixture is stirred for 3 minutes. hours at room temperature. The methanol is evaporated under reduced pressure, the residue is diluted with 30 ml of water, 20 and the solution is adjusted to pH 7 with 1 N hydrochloric acid. The solution is extracted twice with 50 ml of ethyl acetate.

The mixed extracts are dried over anhydrous magnesium sulfate, filtered and the solvent evaporated under reduced pressure. There is obtained 5- (7-carboxyhept-6-enyl) -25 imidazo [1,5-a] pyridine, which melts at 110-111 ° C.

Example 26

To a solution of 150 mg of 5- (5-carboxypent-4-enyl) imidazo [1,5-a] pyridine in 7 ml of methanol is added 100 mg of 10% palladium-on-carbon 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. There is obtained 5- (5-carboxypentyl) imidazo [1,5-a] pyridine, which melts at 144-147 ° C and is identical to the compound of Example 2.

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42

Example 27

To a solution of 180 mg of 5- (7-carboxypent-6-enyl) -imide-azo [1,5-a] pyridine in 30 ml of methanol is added 200 mg of 10% palladium-on-carbon catalyst and the mixture is hydrogenated 5 for 3 hours at atmospheric pressure. The catalyst is filtered off and the solvent is evaporated under reduced pressure.

A product is obtained which melts at 69-71 ° C and consists of a mixture of 5- (7-carboxyheptyl) -imidazo [1,5-a] pyridine (compound of Example 3c) and 5- (7 (carboxy-10-heptyl) -5,6,7,8-tetrahydroimidazo [1,5-a] pyridine.

Example 28

A solution of 0.1 g of 2-aminomethyl-3- (4-methoxycarbonyl-butyl) pyridine in 0.6 ml of formic acid is heated at 90 ° C for 18 hours. The mixture is cooled to 0 ° C, basified with saturated aqueous ammonium hydroxide solution and extracted with four times 10 ml of methylene chloride. The extracts are dried, filtered and evaporated. 2- (N-formylaminomethyl) -3- (4-methoxycarbonylbutyl) pyridine is obtained, which melts at 43-45 ° C.

This compound is dissolved again in 1 ml of toluene and heated for 17 hours at 90 ° C with 75 mg of phosphorus oxychloride.

Excess phosphorus oxychloride is evaporated with toluene, the residue is basified at 0 ° C with saturated aqueous ammonium hydroxide solution, extracted with four times 15 ml of methylene chloride and the extracts are dried over sodium sulfate.

After evaporation, an oil is obtained which gives an oil after chromatography (silica gel, ethyl acetate). This is 8- (4-methoxycarbonylbutyl) imidazo [1,5-a] pyridine. Rf = 0.29, NMR (CDCl 3) 3.70 (s, 3H), 6.50 (d, 2H), 7.43 (s, 1H), 7.83 (t, 1H), 8.22 ( s, 1H), IR (methylene chloride) 1725 cm 3 The starting compound is prepared 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 by reflux for 24 hours under argon and the solvent 35 is evaporated. The residue is taken up in 50 ml of methylene chloride and

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43 is washed twice with 40 ml of water. The organic phase is dried and evaporated. 3- (4-methoxycarbonylbut-1-enyl) -pyridine is obtained as a colorless liquid. NMR (CDCl3) 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-carbon 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.

To 3- (4-methoxycarbonylbutyl) -pyridine (10.81 g) was added dropwise 8.3 ml of 40% * peracetic acid, keeping the temperature of the reaction mixture between 80 and 85 ° C. The mixture is then allowed to cool to 30 ° C and the excess 15 of peracetic acid is decomposed with aqueous sodium sulfite solution. The acetic acid is evaporated under reduced pressure, the residue is taken up in 50 ml of methylene chloride, then filtered and evaporated. The residue, which consists of 3- (4-methoxycarbonylbutyl) -pyridine N-oxide, is treated with 7.7 g of dimethyl sulfate in 40 ml of toluene for 1 hour at 90 ° C, after which the solvent is evaporated. The 3- (4-Methoxycarbonylbutyl) -1-methoxypyridinium methyl sulfate salt is dissolved in 16.7 ml of ice-cold water and 8.3 ml of 1 N sodium hydroxide solution, to which is slowly added a solution of 11.21 g of potassium cyanide in 16.7 ml ice cold water, keeping the temperature at 0 ° C. After 24 hours at 0 ° C, the mixture is extracted with three times 30 ml of methylene chloride, the extract is dried over sodium sulfate and the solvent is evaporated. A mixture of the two isomeric cyanopyridines is obtained, of which 2-cyan-3- (4-methoxycarbonylbutyl) -pyridine with Rf value of 0.56 and NMR (CDCl3) 8.82 (m, 1H) and 2-Cyan-5, (<4-methoxycarbonylbutyl) -pyridine having Rf value 0.50 and NMR (CDCl 3) 8.72 (s, 1H) are isolated by chromatography (silica gel, ether-pentane 3: 2).

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44 2-Cyan-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 -carbon catalyst for 3 hours at atmospheric pressure. After filtration, evaporation and recrystallization from ether-methylene chloride, 2-aminomethyl-3- (4-methoxycarbonylbutyl) -pyridine hydrochloride is obtained, which melts at 79-81 ° C.

Example 29

A solution of 8- (4-methoxycarbonylbutyl) imidazo [1,5-a] -10 pyridine (30 mg) in 0.3 ml of ethanol and 0.3 ml of 1 N sodium hydroxide solution is refluxed for 2 hours, then cooled. dilute with 2 ml of water and extract with 5 ml of ethyl acetate once. The aqueous phase is adjusted to pH 6 and extracted with four times 15 ml of methylene chloride. The extracts are dried and evaporated.

8- (4-Carboxybutyl) -imidazo [1,5-a] pyridine is obtained, which melts at 195-197 ° C.

Example 30 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 four times 15 ml of methylene chloride. 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

dissolve in 1 ml of toluene and heat for 18 hours at 90 ° C

with 0.166 g of phosphorus oxychloride. After evaporation of excess phosphorus oxychloride with toluene and addition at 0 ° C of saturated aqueous ammonium hydroxide solution, extraction of the basic solution with four times 15 ml of methylene chloride and drying the extract over sodium sulfate give an oil which is chromatographed (silica gel, ethyl acetate). . There is obtained 6- (4-methoxycarbonylbutyl) imidazo [1,5-a] pyridine. 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

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45

The starting compound is prepared as follows: 2-Cyan-5- (4-methoxycarbonylbutyl) -pyridine (1.48 g, cf. Example 28) is dissolved in 56 ml of methanol containing 1.5 ml of concentrated hydrochloric acid and hydrogenated over 0 75 g of 5% palladium-on-carbon 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 a mixture of methanol and ethyl acetate (1: 1). After recrystallization from a mixture of ether and methylene chloride, 2-aminomethyl-5- (4-methoxycarbonylbutyl) pyridine is obtained in the form of the carbonate, which melts at 79-80 ° C.

NMR (CDCl 3) 3.67 (s, 3H), 4.24 (s, 2H), IR (methylene chloride) 1725 cm

Example 31 A solution of 92 mg of 6- (4-methoxycarbonylbutyl) imidazo [1,5-a] pyridine in 0.3 ml of ethanol and 0.8 ml of 1 N sodium hydroxide solution is gently heated at reflux and then cooled , diluted with 2 ml of water and extracted with 5 ml of ethyl acetate. The aqueous phase 20 is adjusted to pH 6 and extracted with chloroform. The extracts are dried and evaporated. There is obtained 6- (4-carboxybutyl) imidazo [1,5-a] pyridine, which melts at 168-171 ° C.

Example 32 2- (N-Formylaminomethyl) -4- (3-methoxycarbonylpropyl) -pyridine (33 mg) is dissolved in 1 ml of toluene and heated with 44 mg of phosphorus oxychloride under nitrogen for 18 hours at 90 ° C. The solvent is evaporated, the residue is suspended in methylene chloride, then cooled to 0 ° C and basified with saturated aqueous ammonium hydroxide solution. The aqueous phase is extracted with four times 15 ml of methylene chloride. The extracts are dried over sodium sulfate 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, ethyl acetate-methanol 3: 1).

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

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46 chloride) 1730 cm -1

The starting compound is prepared as follows:

Potassium cyanide (11.18 g) and dibenzo-18-crown-6-ether (1.0 g) are added in a nitrogen atmosphere to a solution of 4- (3-5 chloropropyl) -pyridine (6.68 g) (prepared from 4- (3-hydroxypropyl) -pyridine) in 300 ml of dry acetonitrile. The mixture is refluxed for 24 hours, the solvent is evaporated and the residue partitioned between methylene chloride and water. The aqueous phase is extracted with an additional three times 100 ml of methylene chloride. The combined extracts are dried over sodium sulfate, decolorized with activated charcoal and evaporated. 4- (3-cyanopropyl) -pyridine is obtained as a colorless oil.

To a solution of 4- (3-cyanopropyl) -pyridine (5.5 g) in methanol is introduced hydrogen chloride under ice-cooling for 2 hours and to the solution is gently added 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 20 three times 100 ml of methylene chloride. The extract is dried over sodium sulfate and evaporated. The residue is filtered in ether through 50 g of silica gel. 4- (3-methoxycarbonyl-propyl) -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, 2.9 ml of 40% peracetic acid is added to 4- (3-methoxycarbonylpropyl) pyridine (3.20 g). The mixture is heated to 80 ° C for 1 hour and when the peroxide test is negative, the acetic acid is evaporated. The residue is taken up in 50 ml of methylene chloride, filtered and evaporated. The resulting 4- (3-methoxycarbonylpropyl) pyridine N-oxide is treated with 2.8 g (22.2 mmol) of dimethyl sulfate 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 methyl sulfate are added to a solution of 89.75 g of potassium cyanide in 20 ml of water. The reaction mixture is stirred for 1 hour. 47

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1 hour at 0 ° C and for 3 hours at 25 ° C and then extracted with 30 ml of methylene chloride once. The aqueous phase is left for 24 hours, then extracted with 30 ml of methylene chloride once. 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-cyan-4- (3-methoxycarbonylpropyl) -pyridine as an oil. NMR (CDCl3> 3.67 (s, 3H), 7.42 (d, 1H), 7.60 (s, 1H), 8.60 (d, 1H), IR (methylene chloride) 1725 cm -4- (3-methoxycarbonylpropyl) -pyridine (0.83 g) in 9 ml of methanol is hydrogenated over 0.4 g of 10% palladium-on-carbon 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 methanol-ethyl acetate (1: 1) to give 2-amonimethyl-1- (3-methoxycarbonylpropyl) -pyridine Rf = 0.37 (ethyl acetate-methanol 1: 1, 1% ammonium hydroxide), NMR (CDCl 3) 3.67 (s, 3H), 4.15 (s, 2H).

2-Minomomethyl-4- (3-methoxycarbonylpropyl) -pyridine (0.11 g) is heated in 0.5 ml of 97% formic acid for 18 hours at 90 ° C. The reaction mixture is cooled to room temperature, basified with ammonium hydroxide solution and extracted with four times 20 ml of methylene chloride. The organic extracts are dried over sodium sulfate and evaporated. 2- (N-formylaminomethyl) -4- (3-methoxycarbonylpropyl) pyridine is obtained.

IR (methylene chloride) 1735, 1685 cm

Example 33 7- (3-Methoxycarbonylpropyl-3-imidazo [1,5-a] pyridine (Example 32, 8.0 mg) is dissolved in 0.3 ml of methanol and 0.1 ml of 1 N sodium hydroxide solution is added The mixture is stirred for 5 hours at 25 ° C, evaporated and the residue is dissolved in 5 ml of water. The aqueous solution is washed with 2 ml of ethyl acetate, adjusted with 2N sulfuric acid to pH 6 and extracted with 3 times 5 ml of methylene chloride. Organic extracts are dried over sodium sulfate / magnesium sulfate and evaporated to give 7- (3-carboxypropyl) imidazo [1,5-a]

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48 pyridine, IR (CHCl3) 1720 cm ”1.

Example 34

A solution of 7- [4,4- (bis-methoxycarbonyl) -butyl] -imide-azo [1,5-a] pyridine (65 mg) in 0.8 ml of 1N sodium hydroxide solution and 0.5 ml of ethanol heated for 2 hours under reflux. The solvent is evaporated and 0.8 ml of 1 N hydrochloric acid is added to the residue. The water is evaporated, the residue is dissolved in 3 ml of xylene and heated for 4 hours to 137 ° C.

The xylene is evaporated and replaced with 2 ml of 1 N sodium hydroxide solution. The aqueous phase is extracted with 5 ml of ethyl acetate. Acidification to pH 6 and re-extraction with three times 15 ml of chloroform and evaporation gives 7- (4-carboxybuty1) -imidazo [1,5-a] pyridine, which melts at 158-161 ° C.

The starting compound is prepared as follows:

Using the procedures described above (cf. eg Examples 28 and 32), 4- (3-chloropropyl) pyridine is converted to 4- (3-chloropropyl) -2-cyanopyridine.

NMR (CDCl 3) 3.56 (tf 2H) δ 7'40 (d '1H)' 1 · 5Ί <s '1H)' δ 8.60 (d, 1H).

A solution of 0.83 ml (7.7 mmol) of borane-dimethyl sulfide in 7 ml of tetrahydrofuran is added slowly to a refluxing solution of 4- (3-chloropropyl) -2-cyanpyridine (1.24 g 6.9 mmol) in 7 ml of tetrahydrofuran, thereby simultaneously distilling off dimethyl sulfide. After the addition is complete, the mixture is refluxed for 15 minutes, cooled to 30 ° C, then 6N hydrochloric acid is added. After cessation of hydrogen evolution, the mixture is refluxed for 30 minutes, cooled to 30 ° C, saturated with solid sodium carbonate and extracted with four times 50 ml of methylene chloride. The organic extracts are dried over sodium sulfate and evaporated. An oil is obtained which is filtered through 10 g of silica gel (ethyl acetate-methanol 1: 1). 2-aminomethyl-1- (3-chloropropyl) -pyridine is obtained as a yellow oil, NMR (CDCl 3) 3.55 (t, 2H) 4.20 (s, 2H).

49

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A solution of 2-aminomethyl-4- (3-chloropropyl) -pyridine (0.47 g) in 1 ml of formic acid is heated to 90 ° C for 18 hours, then cooled to 0 ° C and basified with saturated aqueous ammonium hydroxide solution. By extraction with four times 10 ml of methylene chloride, drying over magnesium sulfate and evaporation, 2- (N-formylaminomethyl) -4- (3-chloropropyl) -pyridine (IR 1674 cm 2) is obtained. This is heated for 15 hours at 90 ° C in 0.75 g of phosphorus oxychloride. Excess phosphorus oxychloride is evaporated with toluene, the residue is suspended in 15 ml of methylene chloride, then cooled to 0 ° C and basified with saturated ammonium hydroxide solution. Extraction with four times 15 ml of methylene chloride, drying over sodium sulfate and thin layer chromatography (silica gel, ethyl acetate) of the residue gives 7- (3-chloropropyl) imidazo [1,5-a] pyridine (Rf = 0.24, ethyl acetate) as a rubbery material. NMR (CDCl3) 3.58 (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 20 (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 to a temperature between 80 and 90 ° C. The solvent is evaporated, the residue is taken up in 10 ml of water and extracted twice with 10 ml of ethyl acetate. The 25 organic extracts are washed with twice 10 ml of 2N hydrochloric acid. The aqueous extracts are basified with solid sodium hydrogen carbonate, extracted with three times 10 ml of methylene chloride, dried over sodium sulfate and evaporated.

7- [4,4- (bis-methoxycarbonyl) -butyl] -imidazo [1,5-a] pyridine is obtained. NMR (CDCl3) 3.40 (s, 6H), 6.06 (d, 1H), IR (methylene chloride) 1725 cm -1.

Example 35

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 are boiled in 2 hours at reflux. The solvent is evaporated and 6.5 ml is added. 1 N hydrochloric acid. The water is evaporated and the resulting 5- [5.5-

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50 (bis-carboxy) -pentyl] -imidazo [1,5-a] pyridine is heated in 25 ml of xylene for 4 hours at 137 ° C. The xylene is replaced with 16 ml of 1 N sodium hydroxide solution. Extraction of the aqueous phase with 15 ml of ethyl acetate, acidification to pH 5 6, three times extraction with 40 ml of chloroform, drying over magnesium sulfate and evaporation gives 5- (5-carboxypenty1) imidazo [1,5-a] pyridine, which melts at 146-147 ° C. (Compound of Example 2).

The starting compound is prepared 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 are heated under nitrogen for 10 hours to a temperature between 80 and 90 ° C. The solvent is evaporated and the residue is taken up in 50 ml of water. The aqueous phase is extracted with three times 40 ml of ethyl acetate. The extracts are washed three times with 10 ml of 2N hydrochloric acid. The aqueous phase is made basic with solid sodium carbonate, extracted with three times 20 ml of methylene chloride, the extracts are dried over sodium sulfate 20 and evaporated. 5- [5,5-bis-ethoxycarbonyl) -pentyl] -imidazo [1,5-a] pyridine is obtained, which melts at 59-61 ° C.

The 5- (4-chlorobutyl) imidazo [1,5-y] pyridine used as starting material is prepared using the procedure described in Example 4 for the preparation of starting material 25 using 1-bromo-3-chloropropane instead of 1 -bromo-4-chlorobutane.

Example 36 0.94 g of pyridinium dichromate is added in a solid state to a solution of 5- (6-hydroxyhexyl) -imidazo [1,5-a] pyridine 30 (123 mg) in 10 ml of Ν, Ν-dimethylformamide under nitrogen. at 25 ° C. The solution is stirred for 6 hours, then poured into 150 ml of water and extracted with five times 20 ml of methylene chloride. The organic extracts are washed with 1 N sodium hydroxide solution. The aqueous phase is acidified to pH 6, extracted with methylene chloride, the extracts 51

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dried over sodium sulfate / magnesium sulfate and evaporated.

5- (5-carboxypentyl) -imidazo [1,5-a] pyridine is obtained according to Example 2. 145-146 ° C.

Example 37 5-Methylimidazo [1,5-a] pyridine [J. Org. Chem. 0.1210 (1975)] (424.7 g) is added to a 12-liter flask equipped with a mechanical stirrer and thermometer and filled with nitrogen. To the flask is added 3000 ml of dry tetrahydrofuran and the resulting solution is cooled to -65 ° C in a bath of solid carbon dioxide and acetone. To the solution is added n-butyllithium (1.0 mol, 2.4 normal in hexane) in a nitrogen atmosphere in one portion. The temperature rises to -32 ° C. The mixture is again cooled to -50 ° C and similarly an additional 1 mole of N-butyl-lithium is added. The temperature rises again and the mixture is cooled to -50 ° C, then a third mole of n-butyllithium is added. The reaction mixture is stirred for 20 minutes, bringing the temperature to -65 ° C. To the stirred solution is then added as quickly as possible a cold (-67 ° C) solution of 606.9 g of 5-bromo-1,1,1-triethoxypentane in 500 ml of tetrahydrofuran, raising the temperature to -25 ° C. The reaction mixture is then heated to -15 ° C, stirred for 2 hours, then 50 ml of acetic acid is added and most of the solvent is removed in vacuo. The residue is taken up in 2000 ml of ethyl ether, 100 ml of acetic acid and 100 ml of 12 N hydrochloric acid are added and cooled to 0 ° C. After 15-20 minutes, add 1000 ml of ice-cold 7.5 N ammonium hydroxide solution to the mixture. The organic phase 30 is isolated and the aqueous phase is washed with 500 ml of ethyl ether. The pH of the aqueous phase is adjusted with ammonium hydroxide of 9 and extracted again with 500 ml of ethyl ether. The mixed ether extracts are washed with dilute sodium chloride solution and the pH is adjusted with potassium hydroxide of 13-14. The ether extract funnel is treated with activated carbon and magnesium sulfate.

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.

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52

There is obtained 5- (5-ethoxycarbonylpentyl) imidazo [1,5-a] pyridine according to Example 1, which boils at 220 ° C / 0.2 mm Hg.

The 5-bromo-1,1,1-triethoxy-pentane as starting material is prepared as follows: 5 1200 g of 5-bromovaleronitrile are added under nitrogen to a three-necked 5-liter flask. The whole reaction flask is then placed in an ice bath and 287 g of hydrogen chloride gas are slowly added. The reaction mixture is then diluted with 3200 ml of ethyl ether and the mixture is stirred overnight at 4 ° C. The resulting suspension is cooled in a bath of solid carbon dioxide and acetone to -30 ° C. The resulting solid is isolated, washed with ethyl ether and dried for 3 days in a vacuum desiccator over potassium hydroxide and phosphorus pentoxide. There is obtained 5-brcimimido oleic acid-ethyl ester hydrochloride, which is used in the following step without further purification.

5-Bromimidovalerianic acid ethyl ester hydrochloride (556 g) is added under nitrogen to a 12-liter flask equipped with a mechanical stirrer. After adding 20 836 g of anhydrous ethanol, the reaction mixture is stirred for 2 hours at room temperature to form a clear solution. To the flask is added 3700 ml of ethyl ether and the mixture is stirred at room temperature for 3 days. The solution is cooled to -30 ° C and the resulting ammonium chloride 25 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, which distils at approx. 71-82 ° C, collected and redistilled with a column of 30 46 cm. 5-Bromo-1,1-triethoxypentane is obtained which boils at 60-62 ° C / 0.2 mm Hg.

5- (5-Ethoxycarbonylpentyl) imidazo [1,5-a] pyridine can be prepared from 2- (N-formylaminomethyl) -6- (5-ethoxycarbonylpentyl) pyridine analogous to that of Examples 28, 30 and 32 described ring closure method.

53

DK 158227 B

Example 38 5- (5-Ethoxycarbonylpentyl) imidazo [1,5-a] pyridine (1091 g) is added under nitrogen to a 12-liter round bottom flask and with stirring 420 ml of 95% ethyl alcohol is added. With stirring, 2100 ml of 2N sodium hydroxide solution is then added portionwise. After the addition is complete, the mixture is heated to 70 ° C for 20 minutes. A solution is obtained which is heated for a further 2 hours. An additional 21 ml of 50% sodium hydroxide solution is added and heating 10 is continued for 40 minutes. The reaction mixture is cooled and 30 ml of 12N hydrochloric acid is added, after which the ethyl alcohol is partially evaporated under reduced pressure. The resulting solution is washed with 1700 ml of ethyl ether, decolorized with activated carbon, filtered and acidified with acetic acid.

Upon standing overnight at 4 ° C, a product which is isolated is washed, washed with water, then with 1000 ml of ethyl ether, and then dried. There is obtained 5- (5-carboxy-pentyl) -imidazo [1,5-a] pyridine, which melts at 146-148 ° C, which is identical to the compound of Example 2.

Example 39

Analogous to the methods described in the above examples, the following compounds are prepared: a) 5- (4-Ethoxycarbonyl-but-3-enyl) imidazo [1,5-a] pyridine by condensation of 5-methylimidazo [1,5 -a] pyridine with 4-bromocrotonic acid ethyl ester, b) 5- (9-hydroxynon-7-ynyl) -imidazo [1,5-a] pyridine by condensation of 1-tetrahydropyranyloxy-8-bromooct-6-yn with 5 -methyl-imidazo [1,5-a] pyridine and subsequent hydrolysis.

Example 40

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 (if necessary cooling with ice bath).

DK 158227 B

54

After 3 hours, excess sodium hypobromite is dissolved with sodium bisulfite and the solvent is evaporated. The residue is dissolved in 10 ml of 0.5 N sodium hydroxide solution, then extracted with 2 times 5 ml of 5 ether and adjusted to pH 6 with concentrated sulfuric acid. After extraction with three times 10 ml of methylene chloride, drying over sodium sulfate / magnesium sulfate and evaporation give 5- (5-carboxypentyl) -imidazo [1,5-a] pyridine, also prepared according to Example 2.

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

Example 41 In a nitrogen atmosphere, an iodine crystal is added to a mixture of 36.1 mg (1.5 mmol) of magnesium shavings and 5- (4-chlorobutyl) imidazo [1,5-a] pyridine (313 mg) in , 2 ml dry tetrahydrofuran. After dissolving the magnesium chips, an additional 2 ml of anhydrous tetrahydrofuran and 0.43 g of 20-bromoacetic acid ethyl ester are added. The reaction mixture is stirred at room temperature for 1 hour, then refluxed for 30 minutes, cooled to 25 ° C, diluted with 20 ml of ethyl acetate and washed twice with 10 ml of water.

The organic phase is dried, filtered and evaporated. There is obtained 5- (5-ethoxycarbonylpentyl) imidazo [1,5-a] pyridine as an oil. This is boiled in 10 ml of methanol and 5 ml of 1 N sodium hydroxide solution for 3 hours under reflux.

The methanol is evaporated and the residue is dissolved in 10 ml of water. The solution is washed with 10 ml of ethyl acetate and adjusted to pH 6 with concentrated hydrochloric acid. After extraction with five times 10 ml of methylene chloride, drying over sodium sulfate / magnesium sulfate and evaporation to give 5- (5-carboxypentyl) imidazo [1,5-a] pyridine, also prepared according to Example 2.

DK 158227 B

55

Example 42

An iodine crystal is added to a mixture of 36.5 mg of magnesium shavings and 5- (5-chloropentyl) imidazo [1,5-a] pyridine (313 mg) in 0.2 ml of anhydrous tetrahydrofuran under a nitrogen atmosphere.

5 After dissolving the magnesium chips, an additional 2 ml of tetrahydrofuran is added. The solution is cooled to -5 ° C and with vigorous stirring is added dry carbon dioxide gas for 30 minutes. The solvent is evaporated and the residue is dissolved in 10 ml of 25% sulfuric acid. The solution is washed with 10 ml of ether, acidified to pH 6, then extracted with four times 15 ml of methylene chloride. The extracts are dried; over magnesium sulfate and evaporated. There is obtained 5- (5-carboxypentyl) -imidazo [1,5-a] pyridine, which is also prepared according to Example 2.

Example 43

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 gradually heated to 240 ° C. The reaction mixture is kept at 240 ° C for 1 hour, then cooled to room temperature. The residue is taken up in methylene chloride and the solid is filtered off.

Evaporation and recrystallization give 5- (5-carb-oxypentyl) -imidazo [1,5-a] pyridine, which is also prepared according to Example 2.

The starting material is prepared as follows: 5- (5-Chloropentyl) imidazo [1,5-a] pyridine is dissolved in dimethylformamide, reacted with 2-ethoxycarbonyl-1,3-dithian, 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 44

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 35 is evaporated and the residue is dissolved in 15 ml of freshly distilled

DK 158227B

56 dry dioxane. Under cooling at 0 ° C and below, the solution is added to an equimolar ethereal solution of diazomethane. The mixture is allowed to stand overnight at room temperature and the ether is gently evaporated. A solution of 0.14 g of silver oxide in 1 ml of 0.84 molar sodium thiosulfate is added to the solution of the diazo compound formed. The mixture is stirred for 3 hours at room temperature, then a further 0.14 g of silver oxide is added portionwise. The mixture is then stirred for 1 hour at 50 ° C, cooled, filtered and 10% aqueous sodium hydroxide solution is added. Acidification of the aqueous phase with concentrated sulfuric acid, extraction with methylene chloride, drying of the extract over magnesium sulfate and evaporation afforded 5- (5-carboxypentyl) imidazo [1,5-a] pyridine, also prepared according to Example 2 .

Example 45

A mixture of 4.1 g of 5- (5-hydroxypentyl) imidazo [1,5-a] pyridine, 1.5 ml of water, 1.7 g of nickel carbonyl, 0.5 g of nickel chloride hexahydrate and 0, 3 ml of concentrated hydrochloric acid are heated for 10 hours under high pressure carbon monoxide. Then all volatiles are evaporated. The remaining aqueous phase is washed with 5 ml of ether, adjusted to pH 10 with 6 N sodium hydroxide solution, and then extracted with 10 ml of ether. Acidification to pH 25, extraction with methylene chloride, evaporation and recrystallization from a mixture of chloroform and ether give 5- (5-carboxypentyl) imidazo [1,5-a] pyridine, which is also prepared according to Example 2nd

Similarly, treatment of 5- (4-pentenyl) -30 imidazo [1,5-a] pyridine with nickel carbonyl 5- (5-carboxypentyl) imidazo [1,5-aJ pyridine is obtained.

Example 46

A mixture of 0.34 g of silver nitrate in 10 ml of water and 5- (5-formylpentyl) imidazo [1,5-a] pyridine (0.2 g) in 10 ml of dioxane 35 is adjusted to pH 10 with 1N sodium hydroxide solution and gently heated to 70-80 ° C for 1 hour.

57

DK 158227 B

The separated silver is filtered off on diatomaceous earth and the volume of the filtrate is evaporated to 50%. The resulting aqueous base is extracted with ethyl acetate / adjusted with concentrated sulfuric acid at pH 6 and extracted with five times 5 ml of methylene chloride. After drying over sodium sulfate / magnesium sulfate and evaporation, 5- (5-carboxypentyl) imidazo [1,5-a] pyridine is obtained.

The 5- (5-formylpentyl) imidazo [1/5-a] pyridine used as the starting material is prepared as follows: 5- (6-Ghlorhexyl) -imidazo [1,5-a] pyridine is treated with dimethylsulfoxide, triethylamine and silver tetrafluoroborate using the method described in Tetrahedron Letters 1974, 917.

Example 47 Ozone is passed to a solution of 5- (6,6-dimethoxyhexyl) -imidazofl, 5-a] pyridine (0.456 g) in 20 ml of methylene chloride for 4 hours at -50 ° C. Excess ozone is expelled with nitrogen. To the mixture is added 1 ml of dimethyl sulfide at -78 ° C, after which the mixture is allowed to warm slowly to room temperature. The solvent is evaporated, the residue is taken up in 10 ml of methanol and boiled with 10 ml of 1 N sodium hydroxide solution for 2 hours under reflux.

The methanol is evaporated and the residue is washed with 5 ml of ethyl acetate and adjusted with concentrated sulfuric acid to pH 6. By extraction with five times 10 ml of methylene chloride, drying over magnesium sulfate and evaporation give 5- (5-carboxypentyl) imidazo [ 1,5-a] pyridine.

Example 48 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 basified with saturated ammonium hydroxide solution at 0 ° C and extracted with four times 50 ml of methylene chloride. The extracts are dried over sodium sulfate and chromatographed (40 g silica gel,

DK 158227 B

58 ethyl acetate). 5- (5-Ethoxycarbonylpentyl) imidazo [1,5-a] pyridine is obtained.

The starting compound is prepared using the methods described in the above examples over 6- (5-5 ethoxycarbonylpentyl) -2-cyano-pyridine.

Example 49

A solution of 5-methylimidazo [15-a] pyridine (4.0 g, 0.03 mole) and tetramethylenediamine (4.9 g) in 100 ml of tetrahydrofuran is cooled under nitrogen to 0 ° C and added drop 26.5 ml of 1.6 N n-butyllithium, keeping the temperature below 5 ° C. After 40 minutes, this solution is added to an ice-cooled solution of 7.02 g of 4-bromocrotonic acid ethyl ester in 90 ml of tetrahydrofuran.

After 15 minutes, the reaction mixture is partitioned by adding excess saturated ammonium chloride solution and then partitioned between 100 ml of water and 150 ml of ethyl acetate. The organic phase is dried over sodium sulfate, filtered and evaporated. 5- (4-Ethoxy-carbonyl-but-3-enyl) -imidazo [1,5-a] pyridine is obtained. 1¾ (methylene chloride): 1715 cm ^ ((C = O).

Example 50

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

The starting compound is prepared as follows:

To a solution of 18 g of 3-ethylthioimidazo [1,5-a] pyridine [Blatcher and Middlemiss, Tet. Lett. (21), 2195 (1980)] in 200 ml of tetrahydrofuran is added at -50 ° C a solution of 80 ml of 1.6 M n-butyllithium in hexane over 30 minutes.

..... DK 158227 B

59

After the addition, the reaction mixture is stirred for a further 45 minutes at -50 ° C and to the cooled solution 10 ml of dimethyl-formamide is added dropwise over 10 minutes. The reaction mixture is allowed to warm to 5 room temperature and then 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 sulfate, 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 and hexane (1: 2). The solvent is evaporated to give 5-formyl-3-ethylthio-imidazo [1,5-a] pyridine, m.p. 41-43 ° C.

To a solution of 20 g of 5-formyl-3-ethylthioimidazo [1,5-a] pyridine in 200 ml of isopropanol is added approx. 15 g Raney nickel.

The reaction mixture is stirred and refluxed for 16 hours. The catalyst is filtered through silica. The filtrate is evaporated under reduced pressure. The resulting oily residue is purified by column chromatography on silica gel and eluted with a mixture of diethyl ether 20 and ethyl acetate (2: 1). The solvent is evaporated under reduced pressure to give 5-formylimidazo [1,5-a] pyridine which melts at 138-140 ° C.

To a stirred suspension of 150 mg of sodium hydride in 25 ml of toluene is added dropwise 550 mg of triethyl 4-phosphonocrotonate 25 over 10 minutes. The reaction mixture is maintained by cooling with an ice bath of 5 ° C. Then 300 mg of 5-formylimidazo [1,5-a] pyridine is added to the mixture and stirred for 1 hour at room temperature. The reaction mixture is poured into 100 ml of ice water and extracted twice with 100 ml of ethyl acetate. The extracts are combined, dried over magnesium sulfate, filtered and evaporated to dryness.

The resulting oily residue is purified by column chromatography on silica gel and eluted with a mixture of diethyl ether and ethyl acetate. The solvent is evaporated under reduced pressure to give 5- (4-ethoxycarbonyl-buta-1,3-dienyl) -imidazo [1,5-a] pyridine, which melts at 101-103 ° C.

60

DK 158227 B

To a solution of 200 mg of 5- (4-ethoxycarbonylbuta-1,3-dienyl) -imidazo [1,5-a] pyridine in 20 ml of methanol is added 4 ml of 1 N 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 filtered off to give 5- (4-carboxybuta-1,3-dienyl) -imidazo [1,5-a] pyridine, which melts at 243-245 ° C.

Effect on thromboxane synthetase from human platelets

The method is carried out in the manner previously described. This in vitro inhibition of the thromboxane synthetase enzyme is demonstrated analogously to the method of Sun, Biochem. Biophys.

Res. Comm. 74, 1432 (1977).

results;

Compounds of formula -Λ-,

6L H N. CH 2 A-B

are listed in the table below; 61

DK 158227 B

Compound -CH2-AB IC50 according to Example in Cell-free Test No. System_Thromboxane Synthase 8 5- (CH2) 4COOH 41 5 2 5- (CH2) 5COOH 3 3 / b 5- (CH2) 6COOH 5 3 / c 5- (CH2) yCOOH 21 16 5- (CH2) 3C (CH3) 2CH2COOH 18 10 5- (CH2) 5CONH2 77 10 11 5- (CH2) 5CONHCH3 270 12 5- (CH2) 5CON (CH3) 2,550. . 5- (CH2) 4-CN 1,500 4 5- (CH2) 5-CN 630 13 5- (CH2) 5CH2OH 280 15 1 5- (CH2) 5COOC2H5 330 15 / c 5- (CH2) 4COOH 2'90 15 / b 5,6,7,8-tetrahydro-5- (CH2) 5COOH 85 20 / a 5,6f7,8-tetrahydro-5- (CH2) 6COOH 14 23 5 - (CH2) 3CH = CH-COOH 4.8 5- (CH2) 5CH = CH-COOH 40 29 8- (CH2) 4-COOH 390 25 31 6- (CH2) 4-COOH 3.300 34 7- (CH2) ) 4-COOH 4.700 9 (R2 = CH3) 5- (CH2) 5-COOH 25,000

Claims (2)

An analogous process for the preparation of substituted imidazof 1,5-a] pyridines of the general formula • AJL * ί Π (I) XA / ϋίζ-Α-Β wherein R 2 represents hydrogen or lower alkyl, A means alkylene having 1-12 carbon atoms or alkenylene having 2-12 carbon atoms and B means carboxy, lower alkoxycarbonyl, unsubstituted, mono- or di- (lower alkyl) substituted carbamoyl, cyano or hydroxymethyl, or 5,6,7,8-tetrahydro derivatives thereof or their salts , characterized in that 1 is reacted with a compound of formula A in Λ (VI)> χΑβ / ch 2m in which M means an alkali metal and R 2 has the meaning given above, with a compound of formula X - A - B '( VII) wherein X is halogen, A is as defined above, and B 'is carboxy, trilavalkoxy (ethyl, unsubstituted, mono- or di- (lower alkyl) -substituted carbamoyl). cyano, etherified hydroxymethyl or halo-methyl, and converting a formed compound of formula DK 158227 B Ai> A7 CH 2 -A-B 'wherein R 2 and A have the meanings given above, and (a) wherein B' is trilavalkoxymethyl, by hydrolysis to a compound of formula I wherein B is carboxy, or (b) wherein B 'is halo methyl, by reaction with cyanide ions to a compound of formula I wherein B is cyano, or (c) wherein B' is etherified hydroxymethyl , by hydrolysis to a compound of formula I wherein B is hydroxymethyl, or (d) wherein B 'is halogenomethyl, by reaction with an α-phenylthioacetic acid low alkyl ester in the presence of a strong base, oxidation of the thio group to sulfinyl and elimination by heating to a compound of formula I wherein B is lower alkoxycarbonyl and chain A is extended by a terminal -CH = CH group, or (e) wherein B 'is halo methyl, by reaction with malonic acid di-laval cooling ester in the presence of a base in a solvent, hydrolysis and decarboxylation to a compound of formula I wherein B is carboxy and chain A is extended by a terminal 25 -CH 2 -CH 2 group, or (£) wherein B 'is halo methyl , to a Grignard compound, it condenses with a haloacetic acid low alkyl ester and hydrolyzes to a compound of formula I wherein B is carboxy and chain A is extended by a terminal -CH 2 -CH 2 group, or DK 158227 B (g) wherein B 'is halogenomethyl, to a Grignard compound and condenses it with CO 2 to a compound of formula I wherein B is carboxy and chain A is extended by a terminal -CH 2 group, 5 or 2. Converts a compound of formula Ai ϊ π (wine), \ A / * k5 wherein M is an alkali metal, R 2 is as defined above, and R 5 is lower alkyl, with a compound of formula X-CH 2 - A - B '(IX) wherein X is halogen, A is as defined above, and B 'means carboxy, trilavalkoxymethyl, unsubstituted, mono- or di- (lower alkyl) -substituted carbamoyl, cyano, etherified hydroxymethyl or halo gene methyl, then in a formed compound wherein B' means trilavalkoxymethyl, halomethyl or converts the group B 'as set forth in process (1) to a group B and desulfurizes the 20 compound formed, or 3. under basic catalysis, a compound of the general formula Al ί ΓΗ (x), ch2r6 wherein R2 has the meaning given above, and Rg is lower alkoxycarbonyl or cyano, with a compound of formula DK 158227 BX - A - Br (VII) wherein X is halogen, A is as defined above, and B 'is carboxy, trilavalkoxymethyl, unsubstituted, mono- or di- (lower alkyl) -substituted carbamoyl, cyano, etherified hydroxymethyl or halomethyl, leaving the group Rg and converting a formed compound wherein B 'represents trilavalkoxymethyl, halomethyl or etherified hydroxymethyl, as defined by process (1) for a compound of formula I, or 4) terminates a compound of formula A__ / uv ** diz-AB "ice wherein the symbols R means A has the meaning given above and B "means carboxy, lower alkoxycarbonyl, unsubstituted, mono-15 or di- (lower alkyl) -substituted carbamoyl, cyano, hydroxymethyl, etherified hydroxymethyl or halo methyl, to form a compound of formula A f * in JT * (Ib) CH 2 -AB "wherein R 2, A and B" have the above meanings, and convert a formed compound (a) wherein B "represents halo methyl, by reaction with cyanide ions to a compound of formula I, wherein B means cyano, or (b) wherein B "means etherified hydroxymethyl by hydrolysis to a compound of formula I wherein B means hydroxymethyl, or DK 158227 B 5. hydrogenates a compound of formula kA> <XIV) · Cii = CH-A'-B wherein A 'means one alkylene, alkenylene or alkynylene group having not more than 11 carbon atoms and R 2 and B have the above-mentioned meanings, or 6. in a compound of formula S (J (λλ / <XVI) - ch 2 -ac * wherein R 2 and A has the meanings set forth above, and C means acetyl, carboxycarbonyl, formyl, dilavalkoxymethyl 10 or vinyl, optionally extending chain A within its definition, converting group C to a carboxy group B as follows: (a) oxidation (b) thermal treatment of a carboxycarbonyl group C, (c) treating a vinyl group C with nickel carbonyl and carbon monoxide under high pressure, thereby extending chain A with a CH 2 group. , or (d) oxidation of a formyl or dilavalkoxymethyl group 20 C, and, if desired, converting a prepared compound of formula I into another compound of formula 1 and / or, if desired, converting a manufactured free compound into a salt or a prepared salt into the free compound 25 or other salt and / or, if desired, separating a prepared mixture of isomers or racemates into the individual isomers or racemates and / or, if desired, separating manufactured racemates into the optical antipodes. DK 158227B Process according to claim 1, characterized in that the 5- (5-carboxypentyl) imidazo [1,5-a] pyridine or its hydrochloride is prepared.