FI75569B - ANALOGIFICATION OF FRUIT PROCESSING THERAPEUTIC NETWORK IMIDATION / 1,5-A / PYRIDINER. - Google Patents

Description

75569

Analog method for the preparation of therapeutically active imidazo [1,5-a] pyridines - Analog-free method for the preparation of therapeutically active imidazo [1,5-a] pyridines

The imidazot1f-α-pyridines described in the literature are mainly only functionally substituted in the imidazo portion of the bicyclic ring system. Thus, for example, 1- and 3-aminoalkyl-substituted imdiazo [1,5-a] pyridines and their tetrahydro derivatives have been described in Journal of Medicinal Chemistry 16, 1272-1276 (1973).

It has now surprisingly been found that imidazo [1,5-a] pyridine alkanoic acids and their derivatives constitute a very potent and highly specific class of thromboxane synthetase inhibitors.

Due to the above advantages and properties, the imidazo [1,5-a] pyridine derivatives of this invention are very useful when administered to mammals as such or in combination, e.g., for the treatment or prevention of diseases affected by thromboxane synthetase inhibition. Such diseases also include cardiovascular disorders such as thrombosis, atherosclerosis, seebral anemia, myocardial infarction, angina pectoris, and hypertension; respiratory disorders such as asthma; inflammatory diseases and cancers such as tumor metastases; and migraines.

The present invention therefore relates to an analogous process for the preparation of imidazo [1,5] pyridines of general formula (I) R 2 / L-L .; • s · i 3

CH 2 A-B

2 75569 or 5,6,7,8-tetrahydro derivatives thereof, wherein R 2 represents hydrogen, iodine or lower alkyl, A represents alkylene having 3 to 7 carbon atoms or alkenylene having 4 to 6 carbon atoms, B represents carboxy, Lower pialkoxycarbonyl , carbamoyl or N-lower alkylcarbamoyl, cyano or hydroxymethyl, the "lower" radicals having 1 to 4 carbon atoms, or salts thereof.

The general definitions used herein have the following meanings within the scope of this invention:

Alkylene residue means alkylene having 3 to 7 carbon atoms, which may be straight-chain or branched, and preferably represents propylene, butylene, pentylene or hexylene, said residue being unsubstituted or substituted by one or more lower carbon groups, provided that not more than 7.

The expression alkenylene means an alkenylene residue having 4 to 6 carbon atoms, which residue may be straight-chain or branched and preferably denotes 1- or 2-butenylene, 1- or 2-pentenylene or 1-, 2- or 3-hexenylene. Said residues are unsubstituted or substituted by one or more lower alkyl groups, provided that the number of carbon atoms does not exceed 6.

Alkynylene means an alkynylene residue having 2 to 6 carbon atoms which is straight-chain or branched and preferably means propynylene, 1- or 2-butynylene, 1- or 2-pentynylene or 1-, 2- or 3-hexynylene. These residues are unsubstituted or substituted by one or more lower alkyl groups, the number of carbon atoms not exceeding six.

The term "lower" defines the organic residues or compounds mentioned above or below as containing up to 4, in particular 1 or 2, carbon atoms.

3 75569

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

The lower alkoxycarbonyl group contains 1 to 4 carbon atoms in the alkoxy moiety and means e.g. methoxycarbonyl, propoxycarbonyl or isopropoxycarbonyl, especially ethoxycarbonyl. The N-lower alkylcarbmaoyl group contains 1 to 4 carbon atoms in the alkyl moiety and is, for example, N-methylcarbamoyl, N-propylcarbamoyl or especially N-ethylcarbamoyl.

Salts of said compounds of formula (I) in which B represents carboxy and in particular therapeutically useful salts are, for example, metal or ammonium salts, in particular alkali metal or alkaline earth metal salts, e.g. sodium, potassium, magnesium or calcium salts. ? primarily crystalline ammonium salts. These are derived from ammonia or organic amines, e.g. mono-, di- or trialempi- (alkyl, cycloalkyl or hydroxyalkyl) amines, lower alkylenediamine or (hydroxy-lower alkyl or aryl-lower alkyl) lower alkylammonium bases, e.g. methylamine. , triethylamine, dicyclohexylamine, triethanolamine, ethylenediamine, tris- (hydroxymethyl) aminomethane or benzyltrimethylammonium hydroxide. Said compounds of formula (I) form acid addition salts. These are preferably prepared with acids which form therapeutically useful acid addition salts. Acids with which therapeutically useful acid addition salts are obtained include, for example, strong mineral acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, phosphoric, nitric or perchloric acid; or organic acids, such as aliphatic or aromatic carboxylic or sulfonic acids, e.g. formic, acetic, propionic, succinic, glycolic, lactic, malic, tartaric, gluconic, citric or , maleic, fumaric, hydroxymalein, fire grape, phenylacetic, benzoic, 4-aminobenzoic, anthranilic, 4-hydroxybenzoic, salicylic, 4-aminosalicylic acid, pamoic, nicotine, methanesulfone -, ethanesulfonic, hydroxyethanesulfonic, benzenesulfonic, toluenesulfonic, naphthalenesulfonic, sulfaniline or cyclohexylsulfamic acid; or ascorbic acid.

The compounds of the invention have valuable pharmacological properties, e.g. cardiovascular effects, by selectively inhibiting thromboxane formation in mammals. This inhibition is the result of a selective reduction in thromboxane synthesis-20 again. The compounds are thus useful in the treatment of diseases affected by thromboxane synthetase inhibition in mammals, including humans.

These effects can be demonstrated in in vitro experiments or in vivo animal experiments, preferably in mammals, e.g.

in guinea pigs, mice, rats, cats, dogs or monkeys. Said compounds may be administered to animals enterally or parenterally, preferably orally or subcutaneously, intravenously or intraperitoneally, e.g. in gelatin capsules or in the form of suspensions or aqueous solutions containing starches. The dose used may be in the range of about 0.01 to 100 mg / kg / day, preferably about 0.05 to 50 mg / kg / day, especially about 0.1 to 25 mg / kg / day.

The following results obtained in certain medical experiments demonstrate the advantageous properties of the compounds of formula (I).

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In vitro inhibition of the thromboxane synthetase enzyme can be detected by the method of Sun, Biochem.Biophys.Res.Comm. 74, 1432 (1977). The test method is performed as follows: 1C-arachidonic acid is co-incubated with an enzyme mixture preparation consisting of solubilized and partially purified prostaglandin cyclooxygenase from ovine vesicles and dissolved human platelet thromboxane synthetase microtase synthetase. The test compound (dissolved in buffer or, if necessary, a small amount of ethanol) is added to the incubation medium. At the end of the incubation period (30 minutes), prostaglandin E2 (PFE2) is reduced to a mixture of prostaglandin R2a and F2S [PGF2 (a + B) 1 by the addition of sodium borohydride. The radioactive products and excess substrate are extracted with ethyl acetate and the extract is evaporated to dryness. The residue is dissolved in acetone, transferred dropwise to thin-layer chromatography plates and chromatographed on a solvent system toluene: acetone: glacial acetic acid [100: 100: 3 (v / v)]. Radioactive zones are located. The bands of thromboxane B2 (Txb2> and PGF20t + f3) are transferred to liquid scintillation counting tubes and measured. PGF2α + 3 decreases to 50% of control.

The values according to the following table are obtained for the compounds according to the invention:

Table 7 5 5 6 9

Compound -CH2-AB IC50 (nM) e.g. in cell-free test no. System____thromboxane synthetase 8 - (CH2) 4COOH 41 2 - (CH2> 5COOH 3 3 / b - (CH2) βΟΟΟΗ 5 3 / c - (CH2) 7COOH 21 16 - (CH2) 3C (CH3) 2CH2COOH 18 10 - (CH2) 5CONH2 77 11 - (CH2) 5CONHCH3 270 12 - (CH2) 5CON (CH3) 2 550 5 - (CH2) 4 'CN 1500 4 - (CH2 ) 5 ”CN 630 13 - (CH2> 5CH2OH 280 1 - (CH2) 5COOC2H5 330 15 / c 5,6,7,8-tetrahydro- (CH2) 4COOH 290 15 / b 5,6,7,8-tetrahydro- (CH2) 5COOH 85 15 / a 5/6 / 7,8-tetrahydro- (CH2> 6cOOH 14 21 - (CH2) 3 ~ CH = CH-COOH 4.8 23 - (CH2) 5-CH = CH-COOH 40

The in vitro effect on prostaglandin cyclooxygenase is determined according to a modification of the method of Takeguchi et al., Presented in Biochemistry 10, 2372 (1971). The test method is as follows:

Lyophilized microsomes of the sheep vesicle are used as an enzyme preparation in prostaglandin synthesis. The conversion of 1β-arachidonic acid to PGE2 is measured. Test compounds (dissolved in buffer or, if necessary, a small amount of ethanol) are added to the incubation mixture. Prostaglandins 75569 are extracted and separated by thin layer chromatography. The plates are examined, the radioactive zones corresponding to PGE2 are transferred to liquid scintillation counting tubes and their radioactivity is counted. The IC 50 values of the inhibition are determined graphically. This value refers to the concentration of test compound that reduces the amount of PGE2 synthesized by 50%.

The in vitro effect on prostacyclin (PG 2) synthetase was measured by the method of Sun et al., Prostaglandins JM, 1055 (1977). The test method is as follows: 14 C-arachidonic acid is co-incubated with a mixture of enzymes consisting of solubilized and partially purified prostaglandin cyclooxygenase from the sheep bladder gland and crude PG 2 synthetase in the form of a microsomal fraction of bovine aorta.

The test compound (dissolved in buffer or, if necessary, a small amount of ethanol) is added to the incubation medium. The reaction mixture is incubated in 100 mM Tris-HCl (pH 7.5) for 30 minutes at 37 ° C, acidified to pH 20 and extracted with ethyl acetate. The extract is evaporated to dryness, the residue is dissolved in acetone and transferred to thin-layer plates and chromatographed using a solvent system described by Sun et al. have submitted. Radioactive zones are located with a detector. The bands corresponding to 6-keto-25 PGF1α (a stable end product of prostacyclin biotransformation) and PGE2 are transferred to liquid scintillation counting tubes and counted. The quotient of the numerical values of 6-keto-PGF1α / PGF2 is calculated for each concentration of test compound used. The IC 50 values of the inhibition are calculated graphically. This value is the concentration of test compound at which the quotient of 6-keto-PGF1α / PGF2 decreases to 50% of the control value.

The decrease in thromboxane plasma levels in vivo is determined by administering the test compound to guinea pigs as follows: 8 75569

The guinea pigs are treated with the test substance or vehicle and injected 2 hours later with arachidonic acid (40 mg / kg) intraperitoneally. One hour after the arachidonic acid dose, the animals are bled.

5 From a defined number of units, each plasma sample is assayed for thromboxane ε * 2 and for a second unit amount of 6-keto-PGF 2α, the stable metabolites of thromboxane A2, prostacyclin (PGI2).

The compounds of formula (I) are very potent thromboxane synthetase inhibitors. At and above effective dose levels, the preferred prostacyclin synthetases and prostaglandin cyclooxygenase enzyme systems are not incubated.

IC 50 value of a compound of the invention, e.g.

5- (5-Carboxypentyl) -imidazo (1,5-a) pyridine has 3 x -9 10 moles for inhibition of thromboxane synthetase, while inhibition of prostacyclin synthetase and prostacyclin-cyclooxygenase has an IC is in each case greater than -4 1 x 10 moles.

A compound of the invention, e.g. 5- (5-carboxypentyl) imidazo (1,5-a) pyridine, also reduces the plasma levels of thromboxane B2 by more than 50% in guinea pigs, at oral doses as low as 0.25 mg: O / kg. At this or higher oral doses, no significant reduction in prostacyclin was observed.

Based on the advantageous properties set forth above, the compounds of the invention are of great value to mammals, including humans, as specific therapeutic agents. Thus, for example, in thromboembolism, this specific inhibitory effect of the enzyme tromoxan 30 synthetase reduces the platelet aggregation caused by arachidonic acid, which is a significant factor in the formation of blood clots. Experimentally, prolongation of clotting time in the rat is considered a sign of a beneficial antithrombotic effect. The imidazo (1,5-a) pyridines of this invention prolong the clotting time. This effect is observed, e.g., with 5- (5-carboxypentyl) -imidazo [1,5-a] pyridine, when the compound is administered to rats intraperitoneally at a dose of about 1 mg / kg, or less.

Advantageous effects in the treatment of respiratory disorders are indicated by the fact that the compounds of this invention provide protection against sudden death resulting from pulmonary obstruction caused by arachidonic acid. Thus, for example, 5- (5-carboxypentyl) -imidazo [1,5-a] pyridine protects the mouse from sudden death at an oral dose of 100 mg / kg.

The compounds of this invention are prepared according to methods known per se, preferably such that

1) a compound of formula VI

VI

CH2M

wherein M represents an alkali metal, R 2 is hydrogen or lower alkyl, is reacted with a compound of formula VII

HO - A - B 'VII

with a halide or methane or p-toluenesulphonic acid ester of the compound of formula I, wherein A is as defined above, B 'is carboxy, trialkoxymethyl, carbamoyl or N-lower alkylcarbamoyl, cyano, etherified hydroxymethyl or halomethyl, and the compound of formula I 75569 10 f * i ϊ * NA / ia CH2-AB · (a) in which B 'represents trialkoxymethyl, is converted by partial or complete hydrolysis to a compound of formula I in which B represents lower alkoxycarbonyl or carboxy or (b) in which B' represents halomethyl , by reaction with cyanide ions, is converted to a compound of formula I wherein B is cyano or (c) wherein B 'is etherified hydroxymethyl is hydrolysed to a compound of formula I wherein B is hydroxymethyl.

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

The condensation of an intermediate of formula (VI) with a reactive functional derivative of a compound of formula (VII) preferably takes place at a temperature of about -75 ° C to + 50 ° C. When B 'represents carboxy or N-lower alkylcarbamoyl, a suitable metal salt, e.g. a lithium salt of a reactive functional derivative of a compound of formula (VII), is first prepared and reacted with intermediate 11 of formula (VI). 755 69

Another process for the preparation of compounds of formula (I) is based on the fact that

2) a compound of formula VIII

»A A

s VIII

I f M SR 'M _-y

wherein M represents an alkali metal, R 2 represents hydrogen or lower alkyl and R 5 represents lower alkyl, is reacted with a compound of formula IX

HOCH2 - A - B 'IX

with a halide or methane or p-toluenesulfonic acid ester of the compound of formula wherein A 'is as defined above, B' is carboxy, trialkoxymethyl, carbamoyl or N-lower alkylcarbamoyl, cyano, etherified hydroxymethyl or halomethyl, in the resulting compound wherein B 'represents trialkoxymethyl, halomethyl or etherified hydroxymethyl, group B' is converted to group B as shown in process variant 1), and the resulting compound is desulfurized by reaction with Raney nickel.

The preparation of the organometallic intermediate of formula (VIII) and the subsequent condensation are carried out as described above and as described in Tetrahdron Letters 21, 2195-2196 (1980). The desulfurization is preferably carried out with a desulfurizing catalyst such as Raney nickel in a solvent, e.g. ethanol, preferably at elevated temperature.

Furthermore, the compounds of formula (I) may be prepared by:

3) a compound of formula XI

12 75569 / s __ / '

! V * \. ^ H

| k ch2-ab "wherein R 2 * and R 2" represent hydrogen or lower alkyl, A is as defined above and B "is carboxy, lower alkoxycarbonyl, carbamoyl or N-lower alkylcarbamoyl, cyano, hydroxymethyl, lower alkoxyloxymethyl, etherified hydroxymethyl or halomethyl, ring-capped to give a compound of formula Ib ✓ \ Jti i yi SA / Ib CH2-A-B "and the resulting compound (a) wherein B" represents halomethyl by reaction with cyanide ions is converted to a compound of formula I , wherein B is cyano or (b) wherein B "represents etherified hydroxymethyl or lower alkanoyloxy, is hydrolyzed to a compound of formula I wherein B represents hydroxymethyl.

The ring closure 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 at a temperature between 25-150 ° C, preferably 50-120 ° C.

Amides of formula (XI) are prepared by acylation of a compound of formula (XII) 13 R · 75569 I2 y \ / J I NH2 (XII) m CH0-aB "wherein each of the symbols R2 ', A and B" has the same meaning as above. , a carboxylic acid of formula (XIII) is R 2n - COOH (XIII) wherein R 2 "is as defined above, or a reactive functional derivative thereof.

Reactive functional derivatives of the compounds of formula (XIII) are preferably acid halides, simple or mixed anhydrides, e.g. acid chloride, acid anhydride (R "2CO) 2 O or mixed anhydride. or a hindered lower alkanoyl halide, e.g. pivaloyl chloride, in a manner known per se.

The condensation of compounds of formulas (XII) and (XIII) (acylation of compounds of formula (XII)) takes place either spontaneously, e.g. by heating with formic acid, or in the presence of condensing agents, such as disubstituted carbodiimides, e.g. dicyclohexylcarbodiimide.

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

The amines of formula (XII) can be obtained, for example, from the correspondingly substituted 2- (cyano or hydroxyimino-lower alkyl) pyridines by reduction, e.g. hydrogenation in the presence of a catalyst such as palladium-carbon catalyst, or by treatment with a chemical reducing agent. , e.g. with borane or sodium cyanoborohydride. The reducing agent is always selected according to the other functional groups present in the molecule. Compounds of formula (XII) may also be obtained by amination of correspondingly substituted and reactive esterified 2- (hydroxymethyl) pyridines.

Another process for the preparation of compounds of formula (I) in which A represents a straight-chain or branched alkylene chain is based on the fact that

4) a compound of formula XIV

• IBCSt w

CH = CH-A'-B

wherein A 'represents an alkylene, alkenylene or alkynylene residue having up to 6 carbon atoms, and R 2 and B have the same meaning as above, are hydrogenated.

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

The starting materials of formula (XIV) can be prepared, e.g., by condensing a compound of formula (XV) with / \ J * KJÖ

CHO

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

Another process for the preparation of compounds of formula (II), preferably compounds in which A represents an alkylene residue, is based on the fact that

5) in a compound of formula XVI

✓ \ _ £. t A>

H. / \ / XVI

CH 2 -A-C

wherein R 2 and A are as defined above and C is formyl, lower alkanoyl, halomethyl, dicarboxymethyl, carboxycarbonyl, vinyl or di (lower alkoxy) methyl, C is converted to a carboxy group, optionally by extending chain A as defined, and if desired (a) To prepare 5,6,7,8-tetrahydro derivatives of the compounds of formula I, the obtained compound of formula I which is not hydrogenated at the 5-, 6-, 7-, and 8-positions is hydrogenated,

(b) for the preparation of compounds of formula I wherein B is carboxy, a compound of formula I wherein B is

is lower alkoxycarbonyl, carbamoyl or cyano, hydrolysed, (c) to prepare compounds of formula I wherein B is carbamoyl, a compound of formula I wherein B is cyano is partially hydrolysed, (d) to prepare compounds of formula I wherein B is hydroxymethyl , a compound of formula I wherein B is carboxy or lower alkoxycarbonyl is reduced, 16 755 69

(e) for the preparation of compounds of formula I wherein B is carboxy, a compound of formula I wherein B is

is hydroxymethyl, oxidized, (f) to prepare compounds of formula I wherein B is carboxy and A is extended by a terminal CH 2 group, the resulting compound of formula I wherein B is carboxy is converted to an acid halide and reacted with diazomethane, (g) reacting a compound of formula I wherein B is hydroxymethyl with nickel carbonyl to give compounds of formula I wherein B is carboxy and A is extended by a terminal CH 2 group; (h) preparing compounds of formula I wherein B is N-lower alkylcarbamoyl, a compound of formula I wherein B is lower alkoxycarbonyl or carboxy is reacted with a lower alkylamine, (i) to give compounds of formula I wherein R 2 is iodine, a compound of formula I wherein R 2 is hydrogen is iodinated , (j) for the preparation of compounds of formula I wherein A is alkylene, a compound of formula I wherein A is alkenyl is obtained ene, hydrogenating and / or optionally converting the resulting free compound to a salt or the resulting salt to the free compound or another salt and / or optionally separating the resulting mixture of isomers or racemates into individual isomers or racemates and / or cleaving the resulting racemates into optical antipodes.

Residues that can be converted to a carboxy group include, for example, esterified carboxy groups, anhydrated carboxy groups, including the corresponding groups of asymmetric and internal anhydrides, amidated carboxy groups, cyano, amidino groups, including cyclic amidino groups, such as 5-tetrazole groups. including cyclic iminoether groups such as, for example, lower alkyl-substituted 2-oxazolinyl or dihydro-2-oxazolinyl groups, also hydroxymethyl, etherified hydroxymethyl, lower alkanoyloxymethyl, trialkoxymethyl, acetyl, trihalocarboxyethyl, halogenomethyl, halogenated formyl (CHO), di-lower alkoxymethyl, alkylene dioxymethyl, vinyl or diazoacetyl. Simultaneously with the modification of the carboxy group 10, the chain A can be extended within its definition.

The conversion to the carboxy group takes place by methods known per se, as shown here or in the examples, e.g. solvolytically, such as hydrolytically or acidolytically, or by reduction (esterified carboxy groups).

Thus, for example, trichloroethyl or 2-iodoethyl ester is converted to a carboxylic acid by reduction with, for example, zinc and a carboxylic acid in the presence of water. The benzyl ester or nitro-benzyl ester can be converted to a carboxy group by catalytic hydrogenation, the latter also with chemical reducing agents, e.g. sodium dithionite or zinc and a carboxylic acid. Furthermore, e.g. tert-butyl ester can also be cleaved off with e.g. trifluoroacetic acid.

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

Furthermore, compounds of formula (XVI) wherein C represents acetyl can be oxidatively cleaved to the corresponding compounds of formula (I) wherein B represents carboxy. The starting material is first converted to a compound of formula (XVI) wherein C represents trihaloacetyl, e.g. tribromo or triiodoacetyl, e.g. by treatment with sodium hypobromite and then cleaved off with e.g. an aqueous base, e.g. sodium hydroxide.

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Starting materials of formula (XVI) wherein C is acetyl may be prepared starting from compounds of formula (Ib) wherein B 'is halomethyl by treatment with acetic acid lower alkyl ester, e.g. acetic acid ethyl ester in the presence of a base, e.g. sodium hydride and carrying out this then hydrolysis with a strong base, e.g. aqueous sodium hydroxide.

The starting materials of formula (XVI) in which C represents 10 carboxycarbonyl (COCOOH) are converted to the compounds of formula (I) in which B represents carboxy by heat treatment or oxidation. In this case, the starting material is heated to an elevated temperature, e.g. to about 200 ° in the presence of glass powder, or it is treated, e.g. with hydrogen peroxide, in the presence of a basic substance, e.g. sodium hydroxide.

The starting materials of formula (XVI) in which C represents COCOOH can be obtained, e.g., by condensing a compound of formula (Ia) in which B1 represents halomethyl, e.g. with 2-ethoxycarbonyl-1,3-dithian, followed by oxidative hydrolysis. , e.g., bromo-succinimide in aqueous acetone followed by treatment with dilute aqueous sodium hydroxide.

Compounds of formula (XVI) in which C represents formyl, di-lower alkoxymethyl or alkylenedioxymethyl (formyl protected in the form of an acetal), e.g. dimethyl acetal, are oxidized, e.g. with silver nitrate or ozone, to compounds of formula (I) in which B is 30 try carboxy.

Carboxyaldehydes used as starting materials, i. compounds of formula (XVI) in which C represents formyl are prepared by oxidation of compounds of formula (I) or (Ia) in which B or B 'represents hydroxymethyl or halomethyl, e.g. with dimethyl sulphoxide and a catalyst, e.g. triethylamine and with a mixture of silver tetrafluoroborate. The resulting carboxyaldehydes can be converted to the corresponding acetals, i. to compounds of formula (XVI) wherein C represents di-lower alkoxymethyl or alkylenedioxymethyl, e.g. dimethylacetyl, by acid catalyzed condensation with an alcohol, e.g. methanol.

Compounds of formula (I) in which B represents carboxy can be converted by well known Arndt-Eistert synthesis to compounds of formula (I) in which B is carboxy and the chain contains one more carbon atom. In particular, a reactive functional derivative of the starting carboxylic acid is obtained, e.g. by treatment of the acid chloride with diazomethane, e.g. in diethyl ether, to give a compound of formula (XVI) wherein C is diazoacetyl. Modification, e.g. with silver oxide, results in said carboxylic acid of formula (I) in which chain A contains one more carbon atom.

Compounds of formula (XVI) in which C represents vinyl are converted to compounds of formula (I) in which B is carboxy by first carrying out ozonolysis in compounds of formula (XVI) in which C represents formyl. These are then oxidized to compounds of formula (I) wherein B represents carboxy.

The starting materials of formula (XVI) in which C represents vinyl can also be obtained by treatment with nickel carbonyl and carbon monoxide under high pressure to give compounds of formula (I) in which B represents carboxy and the chain A is extended by one carbon atom.

The individual definitions in the above methods have the following meanings:

In the reactive, functional derivative of the alcohols of the formulas (VII) and (IX), the hydroxy group is esterified with, for example, a strong inorganic acid or an organic sulfonic acid, in particular a hydrohalic acid, e.g. a hydrochloric, hydrobromic or hydroiodic acid, an aliphatic or aromatic. sulfonic acid, e.g. methanesulfonic or p-toluenesulfonic acid. These compounds are prepared in a manner known per se.

Trialkoxymethyl preferably means tri (lower-5-coke) methyl, especially triethoxy or trimethoxymethyl.

Etherified hydroxymethyl preferably means tertiary lower alkoxymethyl, lower alkoxyalkoxymethyl, e.g. methoxymethoxymethyl, 2-oxa- or thiacyclo-10 alkoxymethyl, especially 2-tetrahydropyranyloxymethyl.

Halomethyl means in particular chloromethyl, but also bromomethyl or iodomethyl.

Lower alkanoyloxymethyl preferably means acetoxymethyl.

The alkali metal is preferably lithium, it may also be potassium or sodium.

The necessary steps for converting the obtained compound in which B 'or B "is different from B to the compound of formula (I), or for the possible conversion of the obtained product of formula (I) into another compound of the invention, are carried out according to chemical methods known per se. .

The hydrolysis of intermediates in which B 'represents trialkoxymethyl to the compounds of formula (I) in which B is carboxy is preferably carried out with inorganic acids such as hydrohalic acid or sulfuric acid. The hydrolysis of intermediates in which B 'represents etherified hydroxymethyl to the compounds of formula (I) in which B is hydroxymethyl is preferably carried out with aqueous solutions of inorganic acids, e.g. an aqueous solution of hydrohalic acid.

Intermediates of formula (Ia) or (Ib) in which B 'or B "represents halomethyl may be reacted with a metal cyanide, e.g. potassium cyanide, in a manner known per se. In this case, compounds of formula (I) in which the chain is extended by one carbon atom and B represents cyanide, which in turn can be converted by methods known per se into compounds of formula (I) in which B represents carboxy, alkoxycarbonyl or carbamoyl.

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

Conversion of said nitriles to compounds of formula (I) wherein B represents lower alkoxycarbonyl is carried out preferably by treatment with a lower alkanol, e.g. anhydrous ethanol in the presence of a strong acid, e.g. hydrochloric acid, preferably at reflux temperature and then carrying out a var. rolysis with water.

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

Furthermore, intermediates of formula (Ia), (Ib) or (XVI) in which B ', B "or C are halomethyl, e.g. chloromethyl, can be converted to compounds of formula (I) in which B is carboxy and the chain is elongated with two carbon atoms, as follows:

First, the substituted malonic acid di-Lower alkyl ester is prepared by treating e.g. a malonic acid di-lower alkyl ester such as malonic acid diethyl ester in the presence of a base 35, e.g. potassium carbonate or sodium ethoxide 22 in the presence of a solvent in a solvent, e.g. dimethylformamide, e.g. -100 °. This is preferably hydrolyzed with an aqueous base, e.g. dilute sodium hydroxide, to the corresponding malonic acid and decarboxylated in a conventional manner, e.g. by heating in chloroform. If the malonic acid di-lower alkyl ester is replaced by a cyanoacetic acid lower alkyl ester, the corresponding compound is obtained in which B represents cyano.

Compounds of formula (Ia) and (Ib) in which B 'and 10 B "represent halomethyl may be converted into the corresponding organometallic intermediates, e.g. copper or magnesium derivatives, by methods known per se.

For example, condensation of the obtained organic magnesium (Grignard) reagent with e.g. a compound of formula (Ia) wherein B 'represents halogenmagnesium gives, e.g. CH 2 MgCl 2, and carbon dioxide forms a compound of formula (I), where B represents carboxy and the chain is extended by one carbon atom.

Condensation of said Grignard reagent with e.g. a halo-20-acetic acid lower alkyl ester, e.g. a bromoacetic acid ethyl ester, gives a compound of formula (I) wherein B represents lower alkoxycarbonyl and the chain is extended by two carbon atoms.

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

75569 23

Compounds of the invention in which A represents a straight or branched alkenylene residue and which contain a double bond at the terminal position can also be prepared from intermediates of formula (Ia) or (Ib) in which B 'or B "represent halomethyl. Thus, these intermediates are first treated e.g. - (aryl or alkyl) -thio-acetic acid lower alkyl ester, such as α- (phenylthio) -acetic acid ethyl ester The reaction is carried out in the presence of a strong base, e.g. sodium hydroxide The resulting α-arylthio or α-alkylthio is substituted the ester is oxidized to the α-arylsulfinyl or α-alkylsulfinyl ester, e.g. with sodium periodate, after which the insoluble matter is eliminated by heating, e.g. by boiling in xylene under reflux, to give the compound of general formula (I) (α, β- unsaturated ester) in which A represents alkenylene and B represents e.g. lower alkoxycarbonyl and the chain is extended by 2 carbon atoms. The compounds of formula (Ia) in which B 'represents halomethyl may first be converted to the corresponding carboxyaldehydes, e.g. with dimethyl sulphoxide in the presence of triethylamine and silver tetrafluoroborate. Subsequent Wittig condensation, e.g. with (triphenylphosphorianylene) acetic acid ethyl ester, also yields the already mentioned α, β-unsaturated ester.

Compounds of formula (I) wherein B represents lower alkoxycarbonyl may be amidated with ammonia or lower alkylamines, e.g. methylamine in an inert solvent, e.g. lower alkanol such as butanol, optionally at elevated temperature, to compounds of formula (I) wherein B represents N- lower alkylcarbamoyl;

Compounds of formula (I) in which B represents 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) in which B represents lower alkoxycarbonyl, cyano, carbamoyl or N "lower alkylcarbamoyl to compounds of formula (I) in which B represents carboxy is preferably carried out by hydrolysis using inorganic acids or e.g. hydrohalic acids or hydrogen halides. aqueous alkalis, preferably alkali metal hydroxides, e.g. lithium or sodium hydroxide.

Compounds of formula (I) in which B represents carboxy or lower alkoxycarbonyl may be reduced with simple or complex light metal hydrides, e.g. lithium aluminum hydride, alanine or diborane to compounds of formula (I) in which B represents hydroxymethyl. Alcohols can also be obtained by suitable solvolysis of intermediates of formula (Ia) or (Ib) in which B 'and B "represent halomethyl by treatment with e.g. an alkali metal hydroxide, e.g. lithium or sodium hydroxide.

The aforementioned alcohols can in turn be converted into compounds of formula (I) in which B represents carboxy with conventional oxidizing agents, preferably pyridine-25-dichromate in dimethylformamide at room temperature. Said alcohols can also be converted into compounds of formula (I) in which B represents carboxy and the chain is extended by 1 carbon atom by treatment with nickel carbonyl and carbon monoxide under high pressure.

The free carboxylic acids can be esterified with, for example, lower alkanols, e.g. ethanol in the presence of a strong acid, e.g. sulfuric acid, preferably at elevated temperature, or diazo-lower alkanes, e.g. diazomethane in a solvent, e.g. ethyl ether, preferably at room temperature. (I) 25 7 5 5 6 9, wherein B represents a lower alkoxycarbonyl

Furthermore, the free carboxylic acids can be converted to compounds of formula (I) wherein B represents carbamoyl or N-lower alkylcarbamoyl by treating the reactive intermediates of the compounds, e.g. an acyl halide such as an acid chloride or mixed anhydride, e.g. e.g. a mixed anhydride derived from chloroformic acid ethyl ester with ammonia, mono- or dialkylalkylamines in an inert solvent, e.g. methylene chloride, preferably in the presence of a basic catalyst, e.g. pyridine.

The compounds of formula (I) may be converted into the corresponding 5,6,7,8-tetrahydroimidazo (1,5-a) pyridine compounds by reduction with hydrogen of a hydrogenation catalyst, e.g. palladium and an acid, e.g. a mineral acid, when hydrochloric acid-15 in the presence of an inert solvent, e.g. ethanol.

Compounds of formula (I) in which A represents a straight or branched alkenylene residue may also be converted to compounds of formula (I) in which A represents straight or branched alkylene by catalytic hydrogenation, preferably under neutral conditions, e.g. with a palladium catalyst under atmospheric pressure. in an inert solvent, e.g. ethanol.

Thus, compounds of formula (I) in which hydrogen is meant can be converted into their corresponding halogen compounds by direct halogenation with e.g. chlorine, bromine or iodine.

75569 26

The above reactions are carried out by methods known per se in the presence or absence of diluents, preferably in diluents which are inert to and soluble in the reagents, in the presence or absence of catalysts, condensing agents or other substances mentioned above, and / or in an 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.

The invention also relates to variants of this process in which the intermediate obtained in any process step is used as starting material and the remaining process steps are carried out, or the process is stopped at any stage, or in which the starting material is formed under reaction conditions, or in which the starting material is salt or optically pure antipode. in terms of.

The starting materials used in the process of the present invention are those which give the compounds described above as being particularly valuable.

Depending on the choice of starting materials and process, the new compounds may be in the form of a possible isomer or a mixture of such. Thus, for example, depending on the presence of a double bond and the number of asymmetric carbon atoms, they may exist as pure, optical isomers, e.g. antipodes or mixtures of isomers, e.g. racemates, mixtures of diastereomers, mixtures of racemates or mixtures of geometric isomers.

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

75569 27

The racemates obtained can be further separated into optical antipodes in a manner known per se, e.g. by recrystallization from optically active solvents, by microorganisms or by reacting the acidic end product with an optically active base which forms a salt with the racemic acid. In this way, these salts can be separated into diastereomers, e.g. on the basis of their different solubilities. From the latter, the antipodes can be liberated by the action of suitable substances. The parent racemic products can be separated into the antipodes in the same manner as their diastereomeric salts, e.g., by fractional crystallization of the d- or 1-tartrates.

Preferably, the more potent is isolated from the two antipodes.

In addition, the compounds of this invention may be obtained in free form or as salts. The resulting free base can be converted to the corresponding acid addition salt, preferably with acids which form therapeutically useful acid addition salts or with anion exchangers. The resulting salts can be converted to the corresponding free bases, e.g., by treatment with a strong base such as a metal hydroxide or ammonium hydroxide, a basic salt, e.g., an alkali metal hydroxide or carbonate, or a cation exchanger. The compound of formula (I) wherein B 25 represents carboxy may also be converted to the corresponding metal or ammonium salt. These or other salts, e.g. picrates, can also be used to purify the free bases. The bases are converted to their salts, the salts are separated and the bases are liberated from the salts.

Since the novel compounds are very similar in free form and in the form of their salts, in the foregoing and hereinafter the free compounds and salts are to be understood simultaneously and expediently as meaning the corresponding salts or free compounds.

75569 28

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

The following examples are intended to illustrate the invention.

5 Temperatures are given in degrees Celsius and parts given are parts by weight. Unless otherwise specified, the solvents are evaporated under reduced pressure, e.g. at about 15-100 mg / Hg.

Example 1; A solution of 50 g of 5-methylimidazo (1,5-a) pyridine (Org. Chem. £ 12, 1210 (1975)) in 625 ml of tetrahydrofuran is first cooled to -75 °. and under a nitrogen atmosphere, 175 ml of 2,4-normal butyllithium in hexane are added, keeping the temperature below -63 °. A solution of 5- (lithiomethyl) imidazo (1,5-a) pyridine is again cooled to -75 ° and a solution of 121.8 g of 5-bromo-1,1,1-triethoxypentane is rapidly added. In 125 ml of tetrahydrofuran, bringing the temperature to -60 °. The reaction mixture is allowed to warm to -4 ° 20 within 45 minutes and evaporated to virtually dryness. The residue is partitioned between 500 ml of ethyl ether and 240 ml of 3N hydrochloric acid. The ether solution is extracted again twice with 60 ml of 3N hydrochloric acid. The combined aqueous extracts are basified with 100 ml: 75569 g of conc. Ammonium hydroxide and extracted twice with 200 ml of ethyl ether. The ether extract is dried over magnesium sulfate and evaporated to dryness. The oil obtained is distilled under high vacuum. 5- (5-Ethoxycarbonylpentyl) -imidazo 5 (1,5-a) pyridine is obtained, boiling at 180-186 ° / 0.12 mmHg.

Example 2:

A suspension of 26 g of 5- (5-ethoxycarbonylpentyl) imidazo (1,5-a) pyridine in 100 ml of 1N aqueous sodium hydroxide solution is heated for two hours on a steam bath, 10 ml of ethanol are added and the mixture is further heated. minutes. The reaction mixture is cooled, washed with 300 ml of ether and the pH of the solution is adjusted to conc. with hydrochloric acid to 5.5. The crystallized product is filtered off and washed with 50 ml of water. 5- (5-Carboxypentyl) -imidazo-15β (1,5-a) pyridine is obtained, melting at 144-147 °.

Example 3: a) A solution of 39.6 g of 5-bromovaleric acid in 400 ml of tetrahydrofuran is cooled to -78 ° and 93 ml of a solution of 2,3-normal butyllithium in hexane are slowly added, keeping the temperature below -65 °. The suspension is stirred for 20 minutes, after which 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 according to Example 1). The reaction mixture is stirred at -75 ° for two hours, allowed to warm to room temperature, treated with 15 ml of 12N hydrochloric acid and evaporated in vacuo.

The residue is partitioned between water and methylene chloride, after adjusting the pH to 10 with sodium carbonate. The aqueous solution is further washed with chloroform, the pH is adjusted to 1 with 12N hydrochloric acid and washed again with ether and toluene. The pH is adjusted to 5.5 with sodium hydrogen carbonate and extraction with chloroform gives 75569 30 of crude 5- (5-carboxypentyl) imidazo (1,5-a) pyridine.

A solution of the acid in 30 ml of acetonitrile is treated with 20 ml of 5N hydrochloric acid. 25 ml of ethyl ether are added, followed by crystalline 5- (5-carboxypentyl) -5-imidazo (1,5-a) pyridine hydrochloride, melting at 201-204 °. 5- (5-Carboxypentyl) -imidazo [1,5-a] pyridine (Example 2) is obtained after neutralization of the methanolic solution with dilute sodium hydroxide solution to pH 5.

B) In a similar manner, 5- (6-carboxyhexyl) -imidazo [1,5-a] pyridine is prepared from 6-bromohexanoic acid, melting at 137-139 °.

c) In a similar manner, 5- (7-carboxyhepyl) imidazo [1,5-a] pyridine is obtained starting from 7-bromohepta-15 nitric acid. Mp 97-101 °.

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 ether-6 in 500 ml of acetonitrile is refluxed for 20 hours. The acetonitrile is evaporated off under reduced pressure, the residue is partitioned between water and methylene chloride and the methylene chloride extract is evaporated to dryness. 178-180 ° C.

The starting material is prepared as follows:

A solution of 30 g of 1-bromo-4-chlorobutane in 20 ml of dry tetrahydrofuran is added to a solution of 5- (lithiomethyl) imidazo (1,5-a) pyridine (prepared according to Example 1 from 22 g). 5-methylimidazo (1,5-a) pyridine and 80 ml of a 2,3-n solution of n-butyllithium in hexane) keeping the temperature below -50 [deg.] C. The reaction mixture is stirred for 2-3 hours at -50 [deg.] C. at room temperature, stir overnight and evaporate to dryness. A solution of the residue in 200 ml of methylene chloride 75569 is washed with water, dried over magnesium sulphate and evaporated to dryness. 5- (5-Chloropentyl) -imidazo (1,5-a) pyridine is obtained, which is used without further purification.

5 Example 5:

According to the procedure described in Example 4, 5- (4-chlorobutyl) imidazo (1,5-a) pyridine is converted to 5- (4-cyanobutyl) imidazo [1,5-a] pyridine. Mp 72-77 °. Example 6: In accordance with an analogous procedure to that described in Example 4, 3,5-dimethylimidazo (1,5-a) pyridine (J.Het.Chem. 3, 33 (1966)) is converted into 5- (5-chloropentyl) -3 -methylimidazo (1,5-a] pyridine, mp 98-104 ° C. Conversion with potassium cyanide under the conditions of Example 4 affords 5- (5-cyanopentyl) -3-methylimidazo (1 , 5-a) pyridine which is converted to its hydrobromide by dissolving the free base in acetonitrile and acidifying the solution with ethanolic hydrogen bromide to give 5- (5-cyanopentyl) -3-methylimidazo (1,5-a) pyridine hydrobromide melts at 215-220 °.

20 Example 7:

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

The crystallized acid is separated and recrystallized from ethanol. The product of Example 2 is obtained, namely 5- (5-carboxymethyl) imidazo [1,5-a] pyridine, melting at 142-145 °. Recrystallization still causes the melting point to rise to 144-147 °.

Example 8: Hydrolysis of 5- (4-cyanobutyl) imidazo (1,5-a) pyridine according to Example 7 yields 5- (4-carboxybutyl) imidazo [1,5-a] pyridine, melting 161-163 ° C.

32

Example 9; 75569 Hydrolysis of 5- (5-cyanopentyl) -3-methylimidazo (1,5-a) pyridine according to Example 7 affords 5- (5-carboxypentyl) -3-methylimidazo [1,5-a] pyridine which su-5 at 170-173 °.

Example 10:

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

The mixture is stirred overnight at room temperature, the ethanol is evaporated off under reduced pressure, water is added to the residue and extracted with methylene chloride. The product obtained is crystallized from ether, after which it is recrystallized from acetonitrile. 5- (5-Carbamoylpentyl) -imidazo (1,5-ajpyridine is obtained), melting at 131-132 °.

Example 11;

A solution of 3.9 g of 5- (5-ethoxycarbonylpentyl) imidazo (1,5-a) pyridine in 40 ml of n-butanol is saturated with methylamine and heated in a pressure vessel for 56 hours on a steam bath. The reaction mixture is evaporated to dryness.

The product obtained is recrystallized first from ether and then from a 1: 1 mixture of acetic acid and ether. 5- (5- (N-methylcarbamoyl) pentyl) imidazo [1,5-a] pyridine is obtained, melting at 118-122 °.

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 mol of sodium hydride ( obtained when 0.53 g of a 50% sodium hydride dispersion in mineral oil is washed with hexane) and heated briefly on a steam bath.

To the cooled yellow solution is added 1.56 g of methyl 75569 33 iodide. The mixture is stirred for 2 hours at room temperature, diluted with 100 ml of water and extracted first with 150 ml of a 1: 1 mixture of ethyl acetate and ether and then with 100 ml of chloroform. The combined extracts are evaporated, after which the dry residue obtained is dissolved in 100 ml of ether and treated with 20 ml of ethanolic hydrochloric acid. The salt obtained as a precipitate is separated off, recrystallized first from 50 ml of acetonitrile / acetic acid-ethyl ester (1: 1) and then from 30 ml of ethanol / 10 with ether (1: 1). 5- [5- (Ν, Ν-Dimethylcarbamoyl) pentyl) imidazo (1,5-a) pyridine hydrochloride is obtained, melting at 166-171 °.

Example 13:

1.0 g of 5- (5-carboxypentyl) -imidazo 15 (1,5-a) pyridine are suspended in 5 ml of tetrahydrofuran. 2.35 g of trimethylborate are then added to the suspension, while stirring at room temperature, and then 1.0 ml (equivalent to 0.01 mol) of borane-methyl sulfide complex are slowly added. The reaction mixture is heated at reflux for 2 hours, cooled and dissolved by adding 2.6 ml of methanol, 9.5 ml of water and 2 ml of 50% aqueous sodium hydroxide solution. The mixture is refluxed for 1 hour, diluted with 50 ml of water and extracted twice with 75 ml of methylene chloride each time. The methylene chloride extract is evaporated to dryness and the residue is taken up in 4 ml of 5N hydrochloric acid in 30 ml of ether. 5- (6-Hydroxyhexyl) -imidazo [1,5-a] pyridine hydrochloride is obtained, melting at 174-179 °.

Example 14: A solution of 11.1 g of 1-tetrahydropyranyloxy-8-bromooctane in 15 ml of tetrahydrofuran is added at -70 ° 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 2,3-35 normal n-butyllithium in hexane). The mixture is stirred for 1 hour at -70 ° and then, without further cooling, overnight. The mixture is evaporated to dryness, the residue is dissolved in 50 ml of 4N hydrochloric acid, the solution is washed twice with 100 ml of ether each time, basified with 75 ml of aqueous sodium hydroxide solution and extracted twice with 100 ml each time. of methylene chloride. The methylene chloride extract is evaporated to dryness. The residue is converted into the hydrochloride with ethereal hydrogen chloride and recrystallized from ethanol / ether. 5- (9-Hydroxynonyl) -imidazo [1,5-a] pyridine hydrochloride is obtained, melting at 150-153 °.

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 15 and 30 ml of conc. hydrochloric acid, hydrogenated at 3 atmospheres in the presence of 1 g of 10% palladium-on-carbon catalyst until 2 moles of hydrogen have been consumed. The catalyst is filtered off from the mixture and evaporated to dryness. The residue is recrystallized from isopropanol / ether. 5 - [(20-carboxyhexyl) -5,6,7,8-tetrahydroimidazo [1,5-a] pyridine hydrochloride is obtained, melting at 150-154 °.

b) In a similar manner, hydrogenation of 5- (5-carboxypentyl) imidazo (1,5-a) pyridine gives 5- (5-carboxypentyl) -5,6,7,8-tetrahydroimidazo (1,5-a) pyridine hydrochloride, melting 146-150 ° C.

c) Starting from 5- (4-carboxybutyl) imidazo (1,5-a) pyridine, 5- (4-carboxybutyl) -5,6,7,8-tetrahydroimidazo [1,5-a] pyridine hydrochloride is obtained in a similar manner. melts at 120-123 °.

30 Example 16:

A solution of 2.3 g (0.011 mol) of 5-bromo-3,3-dimethylpentanoic acid (Org. Chem. £ 4, 1258 (1979)) in 20 ml of dry tetrahydrofuran is cooled to -70 ° under a nitrogen atmosphere. and 5.05 ml of 2.4-35 molar n-butyllithium in hexane are added dropwise. When the addition is complete, a solution of 5- (lithiomethyl) imidazo (1,5-a) pyridine in hexane (prepared from 1.32 g of 5-methylimidazo (1,5-a)) is added in one portion. pyridine and 5.05 ml of 2,4-normal n-butyllithium in hexane). Mixture 5 is stirred overnight at room temperature.

The reaction mixture is diluted with 50 ml of water, 10 g of sodium carbonate are added and the basic solution is extracted three times with 75 ml of chloroform each time. The aqueous phase is acidified to pH 2 with 12N hydrochloric acid and extracted three times with 100 ml of ether each time. The pH of the aqueous phase is then adjusted to pH 5 with dilute sodium hydroxide solution and extracted with 200 ml of acetic acid ethyl ester / ether (1: 1). The extracts are dried and evaporated to give a yellow oil.

This is recrystallized from 50 ml of ethanol / ether (1: 1). 5- (5-Carboxy-4,4-dimethylpentyl) -imidazo [1,5-a] pyridine is obtained, melting at 124-129 °.

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-ajpyridine and 1.68 g of sodium carbonate in 10 ml of water and 1 ml of ethanol). To dissolve most of the iodine, an additional 4 mL of ethanol is added and the mixture is further stirred for 45 minutes.The reaction mixture is diluted with 12 mL of water and extracted twice with methylene chloride at pH 8 (sodium bicarbonate is added if necessary). The aqueous phase is concentrated in vacuo, purged with charcoal and adjusted to pH 2. with normal hydrochloric acid to 4.5 The precipitate is separated, dried and recrystallized from methanol / ether to give 1-iodo-5- (5-carboxypentyl) -imidazo [1,5-a] pyridine, melting at 163-165 ° .

75569 36

Example 18 <

A solution of 5-methylimidazo (1,5-a) pyridine (4.0 g) and tetramethylethylenediamine (4.9 g) in 100 ml of tetrahydrofuran is cooled to 0 ° C under a nitrogen atmosphere and 26 is added dropwise. 5 ml of 1,6 N n-butyllithium in hexane, keeping the temperature below 2 °. This solution is added, after 30 minutes under a nitrogen atmosphere over 45 minutes, to an ice-cold solution of 5-bromo-valeronitrile (4.86 g) in 80 ml of tetrahydrofuran. After 15 minutes, the solvent is evaporated and the residue is partitioned between water and ethyl acetate. The organic phase is extracted with 2N hydrochloric acid (3 x 15 ml). The pH of the aqueous phase is adjusted to pH 10 with 50% sodium hydroxide solution. Extract with ethyl acetate (2 x 75 ml), dry over magnesium sulphate, evaporate and chromatograph (silica gel, ethyl acetate). 5- (5-Cyanopentyl) -imidazo (1,5-a) pyridine is obtained. Example 19;

To a solution of 4 g of 5- (4-ethoxycarbonylbutyl) -20 3-ethylthioimidazo (1,5-a) pyridine in 100 ml of ethanol is added about 5 g of Raney nickel. The solution is refluxed for 18 hours. The Raney nickel is filtered off and washed with 100 ml of ethyl acetate. The filtrate is evaporated to dryness under reduced pressure. The product is obtained in the form of a black oil. This is purified by column chromatography (silica gel) and eluted with ether-hexane (1: 3). The solvent is evaporated off under reduced pressure. 5- (4-Ethoxycarbonyl-butyl) -imidazo (1,5-a) pyridine is obtained in the form of a yellow oil. NMR (CDCl 3) 1.25 (t, 3H), 4.15 (q, 2H), 8.1 (s, 1H).

30 The starting material is prepared as follows:

17.8 g of 3-ethylthioimidazo (1,5-a) pyridine are dissolved in 200 ml of dry tetrahydrofuran and the solution is cooled to -70 °. Within 15 minutes, 80 ml of a solution of 1,6 molar n-butyllithium in hexane are added dropwise, with stirring. When the addition is complete, 75569 37 of the reaction mixture are stirred for a further 30 minutes at -70 °. A solution of 20 g of 4-bromopentanoic acid ethyl ester in 75 ml of tetrahydrofuran is added dropwise to the mixture. The reaction mixture is allowed to warm to -10 °, maintained at this temperature for 30 minutes to 5 hours and then for 1 hour at room temperature. To the reaction mixture are added 400 ml of diethyl ether and 400 ml of 4-normal hydrochloric acid. The aqueous phase is separated and the ether layer is washed with water. The combined aqueous extracts are basified with ammonium hydroxide and extracted three times with 200 ml of ether each time. The ether extract is dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The crude product is black oil. This is chromatographed on a silica gel column and eluted with pentane-diethyl ether (4: 1). Solvent 15 is evaporated and the product is distilled. 3-Ethylthio-5- (4-ethoxycarbonylbutyl) imidazo (1,5-a) pyridine is obtained, boiling at 170 ° / 0.3 mmHg. NMR (CDCl 3) 1.25 (t, 3H), 1.30 (t, 3H), 3.15 (q, 2H), 4.15 (q, 2H).

Example 20; A solution of 3 g of 5- (5-ethoxycarbonyl-5- (phenylsulfinyl) -pentyl] imidazo (1,5-a) pyridine in 50 ml of xylene is refluxed under nitrogen for 30 minutes, then the xylene is evaporated under reduced pressure. The residue is dissolved in 15 ml of diethyl ether and chromatographed on silica gel, eluting with a mixture of diethyl ether and ethyl acetate (2: 1) and evaporating the solvent to give 5- (5-ethoxycarbonyl-pent-4-enyl) -imidazo (1, 5-a) pyridine as an oil NMR (CDCl 3) 1.29 (t, 3H), 4.25 (q, 2H), 5.88 (d, 1H).

The starting material 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) acetic acid ethyl ester. The suspension is stirred at room temperature for 2 hours, then cooled to 5 ° in an ice bath. To this suspension is added dropwise over 1 hour 4.16 g of 5- (4-chloro-ethyl) -imidazo (1,5-a) pyridine. 3.2 g of sodium iodide are then added to mixture 5 and the mixture is stirred overnight at room temperature.

The reaction mixture is poured into 150 ml of ice water and extracted three times, each time with 100 ml of a mixture of diethyl ether and ethyl acetate (1: 1). The organic phase is washed twice with 100 ml of saturated aqueous sodium chloride solution each time, followed by extraction three times with 50 ml of 1N hydrochloric acid each time. The acidic aqueous extracts are combined, basified with ammonium hydroxide and extracted three times with 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 di-ethyl ether. Evaporation of the solvent gives 5- (5-ethoxycarbonyl-5- (phenylthio) -pentyl} imidazo (1,5-a) pyridine as a black oil NMR (CDCl 3) 3.3-3.8 (1H); IR 1720 cm -1 'l.

To a solution of 3.8 g of 5- (5-ethoxycarbonyl-5- (phenyl-thio) -pentyl) -imidazo (1,5-a) pyridine in 100 ml of methanol is added 2.8 g of sodium metaperiodate. and the mixture is stirred for 18 hours at room temperature. The solvent is evaporated off under reduced pressure and the residue is dissolved in 150 ml of water. Extract three times, each time with 100 ml of ethyl acetate. The organic phase is extracted twice, each time with 50 ml of 1N hydrochloric acid, the aqueous extract is made basic with ammonium hydroxide and extracted again with 2 x 100 ml of ethyl acetate. The combined acetic acid ethyl ester 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-5-5 (phenylsulfinyl) -pentyl] imidazo (1,5-a) pyridine is obtained in the form of an oil, IR 1720 cm-1040 cm-Example 21:

To a solution of 300 mg of 5- (5-acetoxycarbonylpent-4-enyl) imidazo (1,5-a) pyridine in 20 ml of methanol is added 5 ml of 1N sodium hydroxide solution and the mixture is stirred for 18 hours at room temperature. . The methanol is evaporated off under reduced pressure and a further 5 ml of water are added to the aqueous residue. The mixture is extracted three times with 5 ml of ethyl acetate each time. The pH of the basic aqueous layer is then adjusted to 5 and extracted three times with 5 ml of ethyl acetate each time. These extracts are dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. 5- (5-Carboxypent-4-enyl) -imidazo (1,5-a) pyridine is obtained, melting at 142-144 °.

Example 22:

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. The solvent is then evaporated under reduced pressure to give 5- (7-ethoxycarbonyl-hept-6-enyl-imidazo [1,5-a] pyridine as an oil.

The starting material is prepared as follows:

To a solution cooled to -60 ° containing 4.9 g of 5- (5-methoxycarbonyl-pentyl) -imidazo (1,5-a) pyridine obtained by esterification of the 5- (5- carboxymethyl) imidazo (1,5-a) pyridine with diazomethane in methylene chloride) in 140 ml of methylene chloride, 40 ml of a 1.75 molar solution of diisobu-35 style aluminum hydride in hexane are added dropwise over 20 minutes. you. The reaction mixture is then stirred for 20 minutes at -60 °, after which 10 ml of methanol and 100 ml of water are added to stop the reaction. The mixture is stirred for 15 minutes at room temperature, the methylene chloride layer is separated and the solvent is evaporated off under reduced pressure. 5- (5-Formylpentyl) -imidazo (1,5-a} pyridine is obtained as an oil. NMR (CDCl 3 9.7 (m, 1H); IR (methylene chloride) 1710 -1 cm

Example 23; 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 1N sodium hydroxide solution and the mixture is stirred for 3 hours. at room temperature. The methanol is evaporated off under reduced pressure, the residue is diluted with 15 ml of water and the pH of the solution is adjusted to 7 with 1N hydrochloric acid. The solution is extracted with 2 x 50 ml of ethyl acetate. The combined extracts are dried over anhydrous magnesium sulfate, filtered and the solvent is evaporated off under reduced pressure. 5- (7-Carboxyhept-206-enyl) -imidazo [1,5-a] pyridine is obtained, melting at 110-111 °.

Example 24:

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 off under reduced pressure. 5- (5-Carboxypentyl) -imidazo [1,5-a] pyridine is obtained. which melts at 144-147 ° and is identical to the product of Example 30 2.

Example 25;

To a solution of 180 mg of 5- (7-carboxyhept-6-enyl) -imidazo (1,5-a) pyridine in 30 ml of methanol is added 200 mg of 10% palladium on carbon catalyst and the mixture is hydrogenated for 3 hours under atmospheric pressure. pressure. The catalyst is filtered off and the solvent is evaporated off under reduced pressure. A product is obtained which melts at 69-71 ° and forms 5- (7-carboxyheptyl) imidazo [1,5-a] pyridine (product of Example 3c) and 5- (7-carboxyheptyl) -5,6.7 , 8-tetrahydroimidazo from a mixture of 5 (1,5-a) pyridine.

Example 26:

A solution of 0.1 g of 2-aminomethyl-3- (4-methoxycarbonylbutyl) pyridine in 0.6 ml of formic acid is heated at 90 ° for 18 hours. The mixture is cooled to 0 °, basified with saturated aqueous ammonium hydroxide solution and extracted with methylene chloride (4 x 10 mL). The extracts are dried, filtered and evaporated. 2- (N-Formylaminomethyl) -3- (4-methoxycarbonyl-butyl) -pyridine is obtained, melting at 43-45 °. This in turn is dissolved in 1 ml of toluene and heated at 90 ° for 17 hours with 75 mg of phosphorus oxychloride. The excess phosphorus oxychloride is evaporated off with toluene, the residue is basified at 0 ° with saturated aqueous ammonium hydroxide solution, extracted with methylene chloride (4 x 15 ml) and the extract is dried over sodium sulphate. After evaporation, an oil is obtained which, after chromatography (silica gel, ethyl acetate), gives an oil. This is 8- (4-methoxycarbonylbutyl) imidazo (1,5-a) pyridine. 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.

The starting material 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 in triethylamine, reflux for 24 hours under argon and the solvent is evaporated. The residue is dissolved in methylene chloride (50 mL) and washed with water (2 x 40 mL). The organic phase is dried and evaporated. 3- (4-35 methoxycarbonylbut-1-enyl) pyridine is obtained in the form of a colorless liquid. NMR (CDCl 3) 3.72 (s, 3H), 6.40 (s, 1H); IR (film) 1725 cm.

3- (4-Methoxycarbonylbut-1-enyl) pyridine (9.5 g) in 100 ml of methanol is hydrogenated with 0.5 g of 5% palladium-on-carbon catalyst for 3.5 hours at 3 atmospheres.

Filter and evaporate to give 3- (4-methoxycarbonylbutyl) pyridine as an oil. NMR (CDCl 3)

-1 J

3.80 (s. 3H); IR (methylene chloride) 1730 cm 3- (4-Methoxycarbonylbutyl) pyridine (10.81 g) Li-10 is added dropwise peracetic acid (40%, 8.3 ml), during the addition the temperature of the reaction mixture is kept at 80-85 °. The temperature is then allowed to fall to 30 ° and the excess peracetic acid is destroyed with aqueous sodium sulphite solution. The acetic acid is evaporated off under reduced pressure, the residue is dissolved in methylene chloride (50 ml), filtered and evaporated. The residue formed from 3- (4-methoxycarbonylbutyl) pyridine N-oxide is treated with dimethyl sulfate (7.7 g) in 40 ml of toluene at 90 ° for 1 hour and the solvent is evaporated. The 3- (4-methoxycarbonylbutyl) -1-20 methoxypyridinium methyl sulfate salt is dissolved in 16.7 ml of ice-cold water and 8.3 ml of 1N sodium hydroxide solution and a solution of potassium cyanide (11 , 21 g) in 16.7 ml of ice-cold water, the temperature being kept at 0 ° during the addition. The mixture is kept at 0 ° for 24 hours, then extracted with methylene chloride (3 x 30 ml), the extract is dried over sodium sulphate and the solvent is evaporated. A mixture of isomeric cyanopyridines is obtained, which is chromatographically separated (silica gel, ether-pentane 3: 2) 2-cyano-3- (4-methoxycarbonylbutyl) pyridin-30 with an Rf value of Or56 and NMR (CDCl3). ) 8.82 (m, 1H) and 2-cyano-5- (4-methoxycarbonylbutyl) pyridine with an Rf value of 0.50 and NMR (CDCl 3) 8.72 (s, 1H).

2-Cyano-3- (4-methoxycarbonylbutyl) pyridine (2.40 g) is dissolved in 92 ml of methanol containing 35 ml of conc. hydrochloric acid, and hydrogenated with 1.2 g of 10% 75569 43 palladium on carbon catalyst for 3 hours at atmospheric pressure. Filter, evaporate and recrystallize from ether-methylene chloride to give 2-aminomethyl-3- (4-methoxycarbonylbutyl) pyridine hydrochloride, melting at 79-81 °.

Example 27;

A solution of 8- (4-methoxycarbonylbutyl) imidazo (1,5-a) pyridine (30 mg) in 0.3 ml of ethanol and 0.3 ml of 1N sodium hydroxide solution is boiled for 2 hours. At reflux, cool, dilute with 2 mL of water and extract with ethyl acetate (1 x 5 mL). The pH of the aqueous phase is adjusted to 6 and extracted with methylene chloride (4 x 10 mL). The extracts are dried and evaporated. 8- (4-Carboxybutyl) -imidazo [1,5-a] pyridine is obtained, m.p. 195-197 °.

Example 28:

A mixture of 2-aminomethyl-5- (4-methoxycarbonylbutyl) pyridine (0.20 g) in 0.6 ml of formic acid is heated to 90 ° for 18 hours. The mixture is cooled to 0 °, basified with saturated aqueous ammonium hydroxide solution and extracted with methylene chloride (4 x 15 ml). The extracts are dried, filtered and evaporated. There is obtained 2- (N-formylaminomethyl) -5- (4-methoxycarbonylbutyl) pyridine as an oil (IR 1720 and 1675 cm -1 S) which is dissolved in 1 25 ml of toluene and heated for 18 hours at 90 ° with phosphorus oxychloride (0.166 The excess phosphorus oxychloride is evaporated with toluene and saturated aqueous ammonium hydroxide solution is added at 0 °, the basic solution is extracted with methylene chloride (4 x 15 ml) and the extract is dried over sodium sulphate to give an oil which is chromatographed on ethyl acetate (silica gel). 6- (4-Methoxycarbonylbutyl) -imidazo [1,5-a] pyridine is obtained.

Rf = 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, 1 H); IR (methylene chloride) 35 1730 cm -1.

75569 44 The starting material is prepared as follows: 2-Cyano-5- (4-methoxycarbonylbutyl) pyridine (1.48 g, see Example 28) is dissolved in 56 ml of methanol containing 1.5 ml of conc. hydrochloric acid and hydrogenated with 0.75 g of 10% 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 acetic acid ethyl ester (1: 1). Recrystallize from ether-methylene chloride,

10 followed by 2- (N-formylaminomethyl) -5- (4-methoxycarbonylbutyl) pyridine as its carbonate, melting at 79-80 °. NMR (CDCl 3 J 3.67 (s, 3H), 4.24 (s, 2H);

_i (methylene chloride) 1725 cm Example 29; 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 1N sodium hydroxide solution is slowly heated under reflux for 2 hours, cooled , diluted with 2 ml of water and extracted with ethyl acetate (5 ml). The pH of the aqueous phase is adjusted to 6 and extracted with chloroform. The extracts are dried and evaporated. 6- (4-Carboxybutyl) -imidazo (1,5-a] pyridine is obtained, melting at 168-171 °.

Example 30: 2- (N-Formylaminomethyl) -4- (3-methoxycarbonylpropyl) pyridine (33 mg) is dissolved in 1 ml of toluene and heated with phosphorus oxychloride (44 mg) under nitrogen for 18 hours at 90 °. . The solvent is evaporated, the residue is suspended in methylene chloride, cooled to 0 ° and basified with saturated aqueous ammonium hydroxide solution. The aqueous phase is extracted with methylene chloride (4 x 15 mL). The extracts are dried over sodium sulfate and evaporated. 7- (3-Methoxycarbonylpropyl) -imidazo (1,5-a) pyridine is obtained in the form of an oil which is purified by preparative thin layer chromatography (silica gel, acetic acid 75569 45 acid ethyl ester-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, 1 H); IR (methylene chloride) 1730 cm The starting material is prepared as follows: Potassium cyanide (11.18 g) and dibenzo-18-crown-6-ether (1.0 g) are added under nitrogen to a solution of 4- (3-chloropropyl) -pyridine (6.68 g) (prepared from 4- (3-hydroxypropyl) pyridine) in 300 ml of dry acetonitrile. The mixture is refluxed for 24 hours, the solvent is evaporated and the residue is partitioned between methylene chloride and water. The aqueous phase is extracted again with methylene chloride (3 x 100 ml). The combined extracts are dried over sodium sulfate, decolorized with activated carbon and evaporated. 4- (3-Cyanopropyl) pyridine is obtained as a colorless oil.

4- (3-Cyanopropyl) -pyridine (5.5 g) is dissolved in methanol, hydrogen chloride is introduced for 2 hours while cooling with ice, and 100 ml of water are carefully added to the solution. The solution is stirred for 15 minutes and the solvent is evaporated. The residue is basified with saturated aqueous sodium hydrogen carbonate solution and extracted with methylene chloride (3 x 100 ml). The extract is dried over sodium sulfate and evaporated. The residue is filtered through ether on 50 g of silica gel. 4- (3-Methoxycarbonylpropyl) pyridine is obtained as an oil. NMR (CDCl 3) 3.68 (s, 3H), 7.05-7.25 (m, 2H), 8.45-8.65 J -125 (m, 2H); IR: 1725 cm.

Peracetic acid (40%, 2.9 mL) is added to 4- (3-methoxycarbonylpropyl) pyridine (3.20 g) at room temperature. The mixture is heated at 80 ° for one hour, after a negative peroxide test, the acetic acid is evaporated off. The residue is dissolved in methylene chloride (50 ml), filtered and evaporated. The resulting 4- (3-methoxycarbonylpropyl) -pyridine N-oxide is treated with dimethyl sulfate (2.8 g, 22.2 mmol) in 12 mL of toluene for 1 hour at 80 °. After evaporation of the solvent, 5.45 g of 4- (3-methoxycarbonyl-35-propyl) -1-methoxypyridinium methylsulfate are obtained, which is added to a solution of 89.75 g of potassium cyanide in 20 ml of water. The reaction mixture is stirred for 1 hour at 0 ° and 3 hours at 25 °, after which it is extracted with methylene chloride (1 x 30 ml). The aqueous phase is allowed to stand for 24 hours, after which it is extracted with methylene chloride (1 x 30 ml). The combined extracts are dried over sodium sulfate and evaporated. A red oil is obtained which is chromatographed on 70 g of silica gel and eluted with ether to give 2-cyano-4- (3-methoxycarbonylpropyl) pyridine as an oil.

NMR (CDCl 3) 3.67 (s, 3H), 7.42 (d, 1H), 7.60 (s, 1H), 8.60 (d, J -1 1H); IR (methylene chloride) 1725 cm 2-Cyano-4- (3-methoxycarbonylpropyl) -pyridine (0.83 g) in 9 ml of methanol is hydrogenated with 0.4 g of 10% palladium on carbon catalyst, 3 hours at 3 atmospheres-15 sa. The mixture is filtered, the filtrate is evaporated and the residue is purified by preparative thin layer chromatography on silica gel, eluting with methanol-acetic acid ethyl ester, 1: 1. 2-Aminomethyl-4- (3-methoxycarbonylpropyl) -pyridine is obtained. Rf = 0.37 (acetic acid ethyl ester-methanol, 1: 1, 1% ammonium hydroxide); NMR (CDCl 3) 3.67 (s, 3H), 4.15 (s, 2H).

2-Aminomethyl-4- (3-methoxycarbonylpropyl) -pyridine (0.11 g) in 0.5 ml of 97% formic acid is heated at 90 ° for 18 hours. The reaction mixture is cooled to room temperature, basified with ammonium hydroxide solution and extracted with methylene chloride (4 x 20 ml). 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 31: 30 7- (3-Methoxycarbonylpropyl-3-imidazo (1,5-a) pyridine (Example 32, 8.0 mg) is dissolved in 0.3 ml of methanol and added 0.1 ml of 1N sodium hydroxide solution, the mixture is stirred for 5 hours at 25 [deg.] C., evaporated and the residue is dissolved in 5 ml of water, the aqueous solution is washed with 2 ml of ethyl acetate, adjusted to pH 6 with 75 ml of 2N sulfuric acid. and extracted with methylene chloride (3 x 5 ml) The organic extracts are dried over sodium sulphate / magnesium sulphate and evaporated to give 7- (3-carboxypropyl) imidazo (1,5-a) pyridine, IR (CHCl 3) δ 1720 cm

Example 32i

A solution of 7- (4,4- (bis-methoxycarbonyl) -butyl) -imidazo (1,5-a) pyridine (65 mg) in 0.8 ml of 1N sodium hydroxide solution and in 0.5 ml ethanol, moon-10 is passed at reflux for 2 hours. The solvent is evaporated off and 0.8 ml of 1N hydrochloric acid are added to the residue. The water is evaporated, the residue is dissolved in 3 ml of xylene and heated to 137 ° for 4 hours. The xylene is evaporated off and replaced with 2 ml of 1N sodium hydroxide solution. The aqueous phase is extracted with ethyl acetate (5 ml). The solution is acidified to pH 6 and back-extracted with chloroform (3 x 15 ml) and evaporated to give 7- (4-carboxybutyl) -imidazo (1,5-a) pyridine, melting at 158-161 °.

20 The starting material is prepared as follows:

According to the above procedure (e.g. Examples 28 and 32), 4- (3-chloropropyl) pyridine is converted to 4- (3-chloropropyl) -2-cyanopyridine. NMR (CDCl 3) 3.56 (t, 2H), 7.40 (d, 1H), 7.57 (s, 1H), 8.60 (d, 1H).

A solution of borane dimethyl sulfide (0.83 mL, 7.7 mmol) in 7 mL of tetrahydrofuran is slowly added at reflux to a boiling solution of 4- (3-chloropropyl) -2-cyanopyridine (1.24 g, 6.9 mmol) in 7 ml of tetrahydrofuran, while distilling off di-30 methyl sulfide. After the addition is complete, the mixture is refluxed for 15 minutes, cooled to 30 ° and 6N hydrochloric acid is added.

When the evolution of hydrogen has ceased, the mixture is refluxed for 30 minutes, cooled to 0 °, saturated with solid sodium carbonate and extracted with methylene chloride (4 x 50 ml). The organic extracts are dried over sodium sulfate and evaporated. An oil is obtained which is filtered through 10 g of silicic acid (1: 1, ethyl acetate-methanol). 2-Aminomethyl-4- (3-chloropropyl) -pyridine is obtained as a yellow oil, NMR (CDCl 3) 3.55 (t, 2H), 4.20 (s, 2H).

A solution of 2-aminomethyl-4- (3-chloropropyl) pyridine (0.47 g) in 1 ml of formic acid is heated at 90 ° for 18 hours, cooled to 0 ° and basified with saturated aqueous ammonium hydroxide solution. 10 la. Extract with methylene chloride (4 x 10 ml), dry over magnesium sulphate and evaporate to give 2- (N-formylaminomethyl) -4- (3-chloropropyl) pyridine (IR 1674 cm -1). This is heated in phosphorus oxychloride (0.75 g) for 15 hours at 90 °. Excess phosphorus oxychloride is evaporated off with toluene, the residue is suspended in methylene chloride (15 ml), cooled to 0 ° and basified with saturated ammonium hydroxide. The residue is extracted with methylene chloride (4 x 15 ml), dried over sodium sulphate and purified by thin layer chromatography (silica gel, ethyl acetate) to give 7- (3-chloropropyl) -imidazo (1,5-a) pyridine (Rf = 0.24, ethyl acetate) as a gum. NMR (CDCl 3), 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 (50 mg), malonic acid dimethyl ester (0.14 g) and potassium carbonate (144 mg) in 2 ml of dimethylformamide is heated for 9 hours. -90 ° C. The solvent is evaporated, the residue is dissolved in 10 ml of water and extracted with ethyl acetate-ethyl acetate (2 x 10 ml). The organic extracts are washed

With 2N hydrochloric acid (2 x 10 ml). The aqueous extracts are basified with solid sodium hydrogen carbonate, extracted with methylene chloride (3 x 10 ml), dried over sodium sulphate and evaporated. 7- (4,4- (Bis-mimethoxycarbonyl) -butyl) -imidazo (1,5-a) pyridine is obtained. NMR

75569 49 (CDCl 3) 3.40 (s, 6H), 6.06 (d, 1H); IR (methylene chloride) 1725 cm-1.

Example 33;

A solution of 5- (5,5- (bis-ethoxycarbonyl) -pentyl-5H) -imidazo (1,5-a) pyridine (0.60 g) in 6.5 ml of 1N sodium hydroxide solution and In 4 ml of methanol, heated at reflux for 2 hours. The solvent is evaporated off and 6.5 ml of 1N hydrochloric acid are added.

The water is then evaporated off and the resulting 5- (5,5- (bis-10-carboxy) -pentyl} -imidazo (1,5-a) pyridine is heated in 25 ml of xylene for 4 hours at 137 ° C. The xylene is replaced by 16 ml of The aqueous phase is extracted with ethyl acetate (15 ml), acidified to pH 6 and back-extracted with chloroform 15 (3 x 40 ml), dried over magnesium sulphate and evaporated to give 5- (5-carboxypentyl) -imidazo. 1,5-a) pyridine, melting at 146-147 ° (compound of Example 2).

The starting material is prepared as follows:

A solution of 5- (4-chlorobutyl) imidazo (1,5-a) 2 O (0.42 g), malonic acid diethyl ester (1.34 g) and potassium carbonate (1.15 g) in 20 ml. dimethylformamide, heated under nitrogen at 80-90 ° for 10 hours. The solvent is evaporated and the residue is dissolved in 50 ml of water. The aqueous phase is extracted with ethyl acetate (3 x 40 ml). The extracts are washed with 2N hydrochloric acid (3 x 10 ml). The aqueous phase is basified with solid sodium carbonate, extracted with methylene chloride (3 x 20 ml), the extracts dried over sodium sulphate and evaporated. 5- (5,5-Bis-ethoxycarbonyl) -pentyl) -30 imidazo (1,5-a) pyridine is obtained, melting at 59-61 °.

The starting 5- (4-chlorobutyl) imidazo (1,5-a) pyridine is prepared according to the procedure described in Example 4 for the starting material using 1-bromo-3-chloropropane instead of 1-bromo-4-chlorobutane as the reagent.

75569 50

Example 34;

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

Example 35: 5-Methylimidazo (1,5-a) pyridine (j.Org.Chem. 40, 121010 (1975), 424.7 g) is added to a 12 liter flask equipped with a mechanical stirrer and thermometer and filled nitrogen. Dry tetrahydrofuran (3000 mL) is added to the flask and the resulting solution is cooled to -65 ° in a dry ice / acetone bath. Under a nitrogen atmosphere, n-butyllithium (1.0 mol, 2,4-normal in hexane) is added in one portion to the solution. The temperature rises to -32 °. The mixture is re-cooled to -50 ° and at the same time another mole of n-butyllithium is added. The temperature rises again and the mixture is cooled to -50 °, after which a third mole of 25 n-butyllithium is added. The reaction mixture is stirred for 20 minutes, at which time the temperature drops to -65 °. A cold (-67 °) solution of 5-bromo-1,1,1-triethoxypentane (606.9 g) in 500 ml of tetrahydrofuran is then added to the stirred solution as quickly as possible, at which point the temperature rises to -25 °: C. The reaction mixture is then warmed to -15 °, stirred for 2 hours, acetic acid (50 ml) is added and most of the solvent is evaporated off under vacuum. The residue is dissolved in 2000 ml of ethyl ether, acetic acid (100 ml) and 12N hydrochloric acid (100 ml) are added and the mixture is cooled to 0 °. After 15-20 minutes, ice-cold, 7.5 N ammonium hydroxide (1000 mL) is added to the mixture. The organic phase is separated and the aqueous phase is washed with ethyl ether (500 ml). The pH of the aqueous layer is adjusted to 9 with ammonium hydroxide and extracted again with ethyl ether (500 ml). The combined ether extracts are washed with dilute sodium chloride solution and the pH is adjusted to 13-14 with potassium hydroxide. The ether extract is treated with activated carbon and magnesium sulfate. The mixture is filtered and evaporated. A dark oil is obtained which is dried at 2 mm Hg.

10 The oil is distilled under high vacuum. The compound of Example 1, 5- (5-ethoxycarbonylpentyl) -imidazo (1,5-a) pyridine, boiling at 220 ° / 0.2 mmHg, is obtained.

The starting 5-bromo-1,1,1-triethoxypentane is prepared as follows: 5-Bromovaleronitrile (1200 g) is added to a 5-liter three-necked flask under a nitrogen atmosphere. The entire reaction flask is then placed in an ice bath and 287 g of hydrogen chloride gas are slowly introduced. The reaction mixture is then diluted with ethyl ether (3200 mL) and stirred overnight at 4 °.

The resulting suspension is cooled to -30 ° in a dry ice / acetone bath. The solid obtained is separated, washed with ethyl ether and dried in a vacuum desiccator over potassium hydroxide and phosphorus pentoxide for 3 days. 5-Bromo-imidovaleric acid ethyl ester hydrochloride is obtained, which is used in the next step without further purification.

5-Bromo-imidovaleric acid ethyl ester hydrochloride (556 g) is added under a nitrogen atmosphere to a 12 liter flask equipped with a mechanical stirrer. Anhydrous ethanol (836 g) is added, after which the reaction mixture is stirred for 2 hours at room temperature to give a clear solution. Ethyl ether (3700 ml) is added to the flask and the mixture is stirred at room temperature for 3 days. The solution is cooled to -30 ° and the ammonium chloride obtained is filtered off. The filtrate is evaporated to dryness on a rotary evaporator in vacuo.

The residue is distilled under high vacuum (0.2 mmHg) using a 12 cm fraction column. The main fraction distilling at about 71-82 ° is collected and redistilled on a 46 cm column. 5-Bromo-1,1,1-triethoxypentane boiling at 60-62 ° / 0.2 mm Hg is obtained.

5- (5-Ethoxycarbonylpentyl) imidazo (1,5-a) pyridine can also be prepared starting from 2- (N-formylaminomethyl) -6- (5-ethoxycarbonylpentyl) pyridine according to Examples 28, 30 and 32. according to the ring closure method.

Example 36: 5- (5-Ethoxycarbonylpentyl) -imidazo (1,5-a) pyridine (1091 g) is added under a nitrogen atmosphere to a 12 L round bottom flask to which ethyl alcohol (95%, 420 mL) is added with stirring. 2-N sodium hydroxide solution (2100 ml) is then added portionwise with stirring. After the addition, the mixture is heated to 70 ° within 20 minutes. A solution is obtained which is further heated for 2 hours. Add another portion of sodium hydroxide (50% solution, 21 mL) and continue heating for 40 minutes. The reaction mixture is cooled, 12N hydrochloric acid (30 ml) is added and the ethyl alcohol is evaporated off under reduced pressure.

The resulting solution is washed with ethyl ether (1700 ml), decolorized with activated carbon, filtered and acidified with acetic acid. The product, which crystallizes overnight at 4 °, is separated off, washed first with water, then with ethyl ether (1000 ml) and dried. 5- (5-Carboxypentyl) -imidazo (1,5-a) pyridine is obtained, melting at 146-148 ° and identical to the product of Example 2.

Example 37: The following compounds are prepared analogously to the methods described in the above examples: 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; 35 b) 5- (9-Hydroquinon-7-ynyl) -imidazo [1,5-a] pyridine by condensation of 1-tetrahydropyranyloxy-8-bromooct-6-yne 5-methylimidazo (1,5-a) with pyridine and then hydrolysis.

Example 38; A solution of 5- (6-oxoheptyl) -imidazo (1,5-a) pyridine (0.35 g) in 10 ml of dioxane is added slowly at 22-25 ° (ice bath cooling, if necessary ) to sodium hypo-bromide (5.2 mmol) in a vigorously stirred aqueous solution (3 mL). After 3 hours, the excess sodium hypobromite is destroyed with sodium bisulfite and the solvent is evaporated. The residue is dissolved in 10 ml of 0.5N sodium hydroxide solution, extracted with ether (2 x 5 ml) and the pH is adjusted to 6 with concentrated sulfuric acid. Extracted with methylene chloride (3 x 10 ml), dried over sodium sulphate / 15a / magnesium sulphate and evaporated to give then 5- (5-carboxypentyl) -imidazo [1,5-a] pyridine, which is the compound of Example 2, is obtained.

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

Under a nitrogen atmosphere, iodine crystal is added to a mixture of magnesium turnings (36.1 g, 1.5 mmol) and 5- (4-chlorobut-25-style) -imidazo 1,5-a pyridine (313 mg) in 0.2 mL of dry tetrahydrofuran. . After the magnesium turnings have dissolved, a further 2 ml of anhydrous tetrahydrofuran and bromoacetic acid ethyl ester (0.43 g) are added. The reaction mixture is stirred for 1 hour at room temperature, refluxed for 30 minutes, cooled to 25 °, diluted with 20 ml of ethyl acetate and washed with water (2 x 10 ml). The organic phase is dried, filtered and evaporated. 5- (5-Ethoxycarbonylpentyl) -imidazo (1,5-a] pyridine is obtained in the form of an oil, which is refluxed for 3 hours in 10 ml of methanol and 5 ml of 1N sodium hydroxide solution. the residue is dissolved in 10 ml of water, this solution is washed with 10 ml of ethyl acetate and the pH is adjusted to 6 with conc. hydrochloric acid, extracted with methylene chloride (5 x 5 ml), dried over sodium sulphate / magnesium sulphate and evaporated to give 5- ( 5-carboxypentyl) -imidazo [1,5-a] pyridine, which is the compound of Example 2. Example 40;

To a mixture of magnesium turnings (36.5 mg) and 5-10 (5-chloropentyl) imidazo (1,5-a) pyridine (313 mg) in 0.2 ml of anhydrous tetrahydrofuran is added iodine crystal under a nitrogen atmosphere. After the magnesium turnings have dissolved, a further 2 ml of tetrahydrofuran are added. The solution is cooled to -5 ° and 15 minutes of dry carbon dioxide gas are introduced, stirring vigorously. The solvent is evaporated and the residue is dissolved in 10 ml of 25% sulfuric acid. The solution is washed with 5 ml of ether, acidified to pH 6, extracted with methylene chloride (4 x 15 ml). The extracts are dried over magnesium sulfate and evaporated. The compound of Example 2, which is 5- (5-carboxypentyl) imidazol-1,5-a) pyridine, is obtained.

Example 41;

A mixture of 5- (6-carboxy-6-oxo-hexyl) -imidazo (1,5-a) pyridine (0.52 g) and 0.5 g of glass powder is heated stepwise to 240 °. The reaction mixture is kept at 240 ° for one hour and then cooled to room temperature. The residue is dissolved in methylene chloride and the solid is filtered off. Evaporation and recrystallization give 5- (5-carboxypentyl) -imidazo (1,5-a) pyridine, which is the compound of Example 2.

The starting material is prepared as follows: 5- (5-chloropentyl) -imidazo (1,5-a) pyridine is dissolved in dimethylformamide, 2-ethoxycarbonyl-1,3-dithian and sodium hydride are added, followed by treatment with N-bromosuccin-35 imide in aqueous form. in acetone and hydrolyzed with dilute sodium hydroxide solution. 5- (6-Carboxy-6-oxohexyl) -imidazo (1,5-a) pyridine is obtained.

Example 42:

A solution of 5- (4-carboxybutyl) imidazo 5 (1,5-a) pyridine (0.22 g) and oxalyl chloride (0.2 g) in 10 ml of chloroform is refluxed for 1.5 hours. The solvent is evaporated, the residue is dissolved in 15 ml of freshly distilled dry dioxane. With cooling, at 0 ° and below, the solution is added to an equimolar amount of an ethereal solution of diazomethane. The mixture is allowed to stand at room temperature overnight and the ether is carefully evaporated. A solution of silver oxide (0.14 g) in 1 ml of 0.84 molar sodium thiosulfate is added to a solution of the resulting diazo compound. The mixture is stirred for 3 hours at room temperature and more silver oxide (0.14 g) is added portionwise. The mixture is then stirred for 1 hour at 50 °, cooled, filtered and 1% aqueous sodium hydroxide solution is added. The aqueous phase is acidified with concentrated sulfuric acid, extracted with methylene chloride, the extract dried over magnesium sulphate and evaporated to give 5- (5-carboxypentyl) -imidazo (1,5-a) "pyridine, which is the compound of Example 2.

Example 43:

A mixture of 4.1 g of 5- (5-hydroxypentyl) imidazo-25S (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 g of ml conc. hydrochloric acid, heated for 10 hours in carbon monoxide under high pressure. All volatiles are then evaporated. The remaining aqueous phase is washed with ether (5 ml), the pH is adjusted to 10 with 6N sodium hydroxide solution and re-extracted with ether (10 ml). Acidify to pH 6, extract with methylene chloride, evaporate and recrystallize from chloroform / ether to give 5- (5-carboxypentyl) -35 imidazo [1,5-a] pyridine, which is the compound of Example 2.

75569 56

Similarly, treatment of 5- (4-pentenyl) -imidazo (1,5-a) pyridine with nickel carbonyl also affords 5- (5-carboxypentyl) -imidazo (1,5-a) pyridine.

Example 44: The pH of a mixture of silver nitrate (0.34 g) in 10 ml of water and 5- (5-formylpentyl) imidazo (1,5-a) pyridine (0.2 g) in 10 ml of dioxane is adjusted. With 1N sodium hydroxide solution to 10 and the mixture is slightly heated to 70-80 ° within one hour. The separating silver is filtered off through diatomaceous earth and the volume of the filtrate is evaporated to 50%. The resulting aqueous base is extracted with ethyl acetate, the pH is adjusted to conc. sulfuric acid to 6 and extracted with methylene chloride (5 x 10 mL). Dry over sodium sulfate / magnesium sulfate and evaporate to give 5- (5-carboxypentyl) imidazo [1,5-a] pyridine.

The starting 5- (5-formylpentyl) imidazo (1,5-a) pyridine is prepared as follows: 5- (6-chlorohexyl) imidazo (1,5-ajpyridine is treated with dimethyl sulfoxide, triethylamine and silver tetrafluoroborate by the method , disclosed in Tetrahedron Letters 1974, 917.

Example 45;

To a solution of 5- (6,6-dimethoxyhexyl) -imidazo-25S (1,5-a) pyridine (0.456 g) in 20 ml of methylene chloride is introduced ozone for 4 hours at -50 °. Excess ozone is displaced by nitrogen. 1 ml of dimethyl sulfide is added to the mixture at -78 ° and the mixture is allowed to slowly warm to room temperature. The solvent is evaporated off, the residue is dissolved in 10 ml of methanol and refluxed for 2 hours with 10 ml of 1N sodium hydroxide solution. The methanol is evaporated and the residue is washed with ethyl acetate (5 ml) and the pH is adjusted to 6 with concentrated sulfuric acid. Extracted with methylene chloride (5 x 10 ml), dried over magnesium sulphate and evaporated to give 75569 57 5- (5-carboxybenzyl) imidazo. f1,5-a) pyridine.

Example 46; 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 °. Excess phosphorus oxychloride is evaporated off with toluene. The residue is basified with saturated ammonium hydroxide solution at 0 ° and extracted with methylene chloride (4 x 50 ml). The extracts are dried over sodium sulfate and chromatographed (40 g of silica gel, ethyl acetate). 5- (5-Ethoxycarbonylpentyl) -imidazo (1,5-a) pyridine is obtained.

The starting material is prepared according to the procedure described in the above examples for the preparation of 6- (5-ethoxycarbonylpentyl) -2-cyanopyridine.

Example 47;

A solution of lithium diisopropylamide (1.0 g of diisopropylamine and 6.9 ml of 1.6 N n-butyllithium) and hexamethylphosphoramide (1.8 g) in 50 ml of tetrahydrofuran, is cooled to -50 ° and propiolic acid (0.35 g) is added dropwise. The reaction mixture is allowed to slowly (over 2 hours) warm to -15 ° and 5- (4-chlorobutyl) imidazo (1,5-a) pyridine (1.04 g) in 10 ml is added dropwise over 15 minutes. in tet-25 rahydrofuran. The cooling is removed and the reaction mixture is stirred for 90 minutes at room temperature. The mixture is poured onto 100 g of ice, the aqueous phase is separated off, washed with glacial acetic acid (20 ml), the pH is adjusted to conc. sulfuric acid to 2 and washed again with ethyl acetate (20 mL).

The pH of the aqueous phase is adjusted to pH 6 and extracted with methylene chloride. (5 x 30 mL). The extracts are dried over sodium sulfate / magnesium sulfate, filtered and evaporated. 5- (6-Carboxyhex-5-ynyl) -imidazo (1,5-a] pyridine is obtained.

75569 58

Example 48:

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

Example 49:

A solution of 5-methylimidazo [1,5-a] pyridine (4.0 g) and tetramethylenediamine (4.9 g) in 100 ml of tetrahydrofuran is cooled to 0 ° under a nitrogen atmosphere and 26 is added dropwise. 5 ml of 1,6-n-butyllithium, keeping the temperature below 5 °. After 40 minutes, this solution is added to an ice-cold solution of 1-tetrahydropyranyloxy-8-bromo-oct-6-yne (10.4 g) in 80 ml of tetrahydrofuran. After 30 minutes, the reaction is stopped by adding 50 ml of 2N hydrochloric acid and the mixture is further stirred for 2 hours at room temperature. The layers are separated and the pH of the aqueous phase is adjusted to 10 with 50% sodium hydroxide solution. Extracted with methylene chloride (3 x 30 ml), dried over sodium sulfate, filtered, evaporated and chromatographed (silica gel, ethyl acetate) to give 5- (9-h) -sinon-7-ynyl) -imidazo [1,5-a] pyridine.

Example 50;

To a solution of 150 mg of 5- (4-carboxybut-1,3-di-35-enyl) imidazo (1,5-a) pyridine in 9 ml of methanol was added 100 mg of 10 mg of 10% palladium on carbon. Catalyst as. The reaction mixture is hydrogenated at atmospheric pressure for 2 hours. The catalyst is filtered off and the solvent is evaporated off under reduced pressure. 5- (4-Carboxybutyl) -imidazo (1,5-a) pyridine identical to the compound of Example 8 is obtained. The starting material 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 dropwise at -50 ° 10. within 1 minute a solution of 80 ml of 1,6 molar n-butyllithium in hexane. After the addition, the reaction mixture is further stirred for 45 minutes at -50 ° and 10 ml of dimethylformamide are added dropwise to the cooled solution over 10 minutes. The reaction mixture is then allowed to warm to room temperature and poured into 500 ml of ice water. The mixture is extracted with 500 ml of diethyl ether. The ether extract is dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. the oily residue is purified by column chromatography on silica gel, eluting with a mixture of diethyl ether and hexane (1: 2). The solvent is evaporated. 5-Formyl-3-ethylthioimidazo (1,5-a} pyridine is obtained. Melting point 41-43 °.

To a solution of 20 g of 5-formyl-3-ethylthioimidazo (1,5-a) pyridine in 200 ml of isopropanol is added about 25 g of Raney nickel. The reaction mixture is stirred and refluxed for 16 hours. The catalyst is filtered off with diatomaceous earth. 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 and acetic acid-ethyl ester (2: 1). The solvent is evaporated off under reduced pressure. 5-Formylimidazo (1,5-a) pyridine is obtained, melting at 138-140 °.

To a stirred suspension of 150 mg of sodium hydride in 25 ml of toluene is added dropwise over 10 minutes 550 mg of triethyl 4-phosphono-crotonate. The reaction mixture 75569 60 is cooled to 5 ° with an ice bath. 300 mg of 5-formylimidazo [1,5-a] pyridine are then added and the mixture is stirred for 1 hour at room temperature. The reaction mixture is poured into 100 ml of ice water and extracted with 2 x 100 ml of ethyl acetate. The extracts are combined, dried over magnesium sulphate, filtered and evaporated to dryness. The oily residue obtained is purified by column chromatography on silica gel and eluted with a mixture of diethyl ether and acetic acid. The solvent is evaporated off under reduced pressure. 5- (4-Ethoxycarbonyl-but-1,3-dienyl) -imidazo (1,5-a) pyridine is obtained, melting at 101-103 °.

To a solution of 200 mg of 5- (4-ethoxycarbonylbut-1,3-dienyl) imidazo (1,5-a) pyridine in 20 ml of methanol is added 4 ml of 1N sodium hydroxide solution. The reaction mixture is stirred for 18 hours at room temperature. The methanol is evaporated off under reduced pressure, the residue is diluted with 20 ml of water and the pH of the solution is adjusted to 5 with hydrogen chloride. The precipitate is separated. 5- (4-Carboxybut-1,3-dienyl) -imidazo (1,5-a) pyridine is obtained, melting at 243-245 °.

Claims (4)

75569 Ana log iamene as a batch of therapeutically active imidazo [1,5-a] pyridines of the general formula I R2 ✓ \ I. · To prepare 3 ch2-ab or 5,6,7,8-tetrahydro derivatives thereof, in which R2 represents hydrogen, iodine or lower alkyl, A represents alkylene having 3 to 7 carbon atoms or alkenylene having 4 to 6 carbon atoms, B is carboxy , Lower p-alkoxycarbonyl, carbamoyl or N-lower alkylcarbamoyl, cyano or hydroxymethyl, wherein "the lower radicals may have 1 to 4 carbon atoms, or for the preparation of their salts, characterized in that 1. a compound of formula VI / \ J * i ji S, A / vi CH2M in which M represents an alkali metal, R2 is hydrogen or lower alkyl, is reacted with a halide of a compound of formula VII HO - A - B 'VII or a methane or p-toluenesulphonic acid ester in which A means the same as above, B 'represents carboxy, trialkoxymethyl, carbamoyl or N-lower alkylcarbamoyl, cyano, etherified hydroxymethyl or halomethyl, and the resulting compound of formula Ia 62 7 5 5 6 9 / \ V i il 2 / la '· · jossa CH2-AB' (a) wherein B 'represents trialkoxymethyl, is converted by partial or complete hydrolysis to a compound of formula I wherein B represents lower alkoxycarbonyl or carboxy or (b) wherein B' represents halomethyl, by reacting with cyanide ions, is converted to a compound of formula I wherein B is cyano or (c) wherein B 'is etherified hydroxymethyl is hydrolysed to a compound of formula I wherein B is hydroxymethyl or 2. a compound of formula VIII Jr "i yy VIII M 1 R 5 wherein M represents an alkali metal, R 2 represents hydrogen or lower alkyl and R 5 represents lower alkyl, is reacted with a halide of a compound of formula IX HOCH 2 - A - B 'IX or a methane or p-toluenesulphonic acid ester in which A is as defined above, B 'is carboxy, trialkoxymethyl, carbamoyl or N-lower alkylcarbamoyl, cyano, etherified hydroxymethyl t ai halomethyl, in the obtained compound in which B 'represents trialkoxymethyl, halomethyl or etherified hydroxymethyl, the group B' is converted to group B, 75569 as shown in process variant 1), and the obtained compound is desulfurized by reaction with Raney nickel or 3. a compound of formula XI A __ / * »M v * ·. I h XI ch2-a-bh wherein R2 * and R2 "are hydrogen or lower alkyl, A is as defined above and B" is carboxy, lower alkoxycarbonyl, carbamoyl or N-lower alkylcarbamoyl, cyano, hydroxymethyl, lower alkyl -noyloxymethyl, etherified hydroxymethyl or halomethyl, ring-capped in formula Ib / 4i. And the resulting compound (a) wherein B "represents halomethyl, by reaction with cyanide ions, is converted to a compound of formula I wherein B is cyano or (b) wherein B" represents etherified hydroxymethyl or lower alkanoyloxy, is hydrolyzed to a compound of formula I wherein B represents hydroxymethyl or 4. a compound of formula XIV ✓ \ J *! x1 xiv CH = CH-A'-B wherein A 'represents an alkyl having up to 6 carbon atoms. , an alkenylene or alkynylene radical, and R 2 and B have the same meaning as above, are hydrogenated or 5. in a compound of formula XVI , halomethyl, dicarboxymethyl, carboxycarbonyl, vinyl or di (lower alkoxy) methyl, is converted to the C carboxy group, optionally by extending chain A within its definition, and if desired (a) to prepare 5,6,7,8-tetrahydro derivatives of compounds of formula I, the resulting compound of formula I which is not hydrogenated at the 5-, 6-, 7-, and 8-positions is hydrogenated, (b) the compounds of formula I for the preparation of compounds wherein B is carboxy, the compound of formula I wherein B is lower alkoxycarbonyl, carbamoyl or cyano is hydrolyzed, (c) for the preparation of compounds of formula I wherein B is carbamoyl, the compound of formula I wherein B is cyano is hydrolysed in part, (d) for the preparation of compounds of formula I wherein B is hydroxymethyl, a compound of formula I wherein B is carboxy or lower alkoxycarbonyl is reduced, (e) for the preparation of compounds of formula I wherein B is carboxy, a compound of formula I wherein B is hydroxymethyl is oxidized, (f) to prepare compounds of formula I wherein B is carboxy and A is extended by a terminal CH 2 group, a compound of formula I is obtained, wherein a B is carboxy, 75569 is converted to an acid halide and reacted with diazomethane, (g) to prepare compounds of formula I wherein B is carboxy and A is extended by a terminal CH2 group, a compound of formula I wherein B is hydroxy (methyl) is reacted with nickel carbonyl, (h) to prepare compounds of formula I wherein B is N-lower alkylcarbamoyl, a compound of formula I wherein B is lower alkoxycarbonyl or carboxy is reacted with a lower alkylamine, (i) to prepare compounds of formula I wherein R 2 is iodine, the compound of formula I wherein R 2 is hydrogen is iodinated, (j) for the preparation of compounds of formula I wherein A is alkylene, the compound of formula I wherein A is alkenylene is hydrogenated and / or optionally modified the free compound obtained as a salt or the salt obtained as the free compound or another salt and / or, if desired, the isomeric or racemic the mixture is separated into individual isomers or racemates and / or, if desired, the racemates obtained are cleaved into optical antipodes. Process according to Claim 1, characterized in that 5- (5-carboxypentyl) -imidazo [1,5-a] pyridine or a salt thereof is prepared. Patent krav; 1. An analogous formulation for the therapeutic use of an imidazole 1,5-a] -pyridine in the formulation of the formula I 66 75569 R s \ L ·% Λ * 3 1 CH2-AB or 5,6,7,8-tetrahydroderivatts, i vilken Formula R2 is optionally substituted with iodine or alkyl, A is alkylated with 3-7 cholaters, alkenylen with 4-6 cholatomers, B is carboxy, lagalkoxycarbonyl, carbamoyl or N-lagalkylcarbamoyl, cyan or hydroxymethyl, colors "lag" -resterna kan innehalla 1-4 kolatomer, eller salter därav, kännetecknat därav, att 1. en förening med formuleln VI / \ f * i Π yA / vi CH2M 1 vilken Formula M betecknar en alkalimetal and R2 R2 vä väte eller lägalkyl, omsätts med halogen or methane or p-toluenesulfonyl ester in the form of a compound of formula VII HO - A - B * VII and anhydrous formula A of the same solution, B 'of the carboxy, trialkoxymethyl, carbamoyl or N-lagalkylcarbamoyl, cyano hydroxymethyl or halomethyl, and the corresponding derivatives of formula 67 7 5 5 6 9 / \ J * • «ns; i k k \ A. /; · And CH2-AB '(a) is selected from the group consisting of beta-triacoxymethyl, alternatively part of a process or a total hydrolysis and a mixture of formula I, color B is selected from the group consisting of galkoxycarbonyl or carboxy or (b) having a cyanide ion, a mixture of compounds of formula I, color B of the hydroxymethyl ester (c) and a mixture of hydroxymethyl derivatives of formula B, hydrolysers for the preparation of formula I, color B of the hydroxymethyl mixture Formula VIII / \ ± KJO • VIII 1 is selected from the group consisting of an alkali metal, R2 and an alkyl metal having the halogen alkyl and R5 is an alkyl metal, halogenated or halogenated with methane or p-toluenesulfonyl ester of the formula IX HOCH2 - A - B 'IX In the form of A, the following measures are used, B 'is carboxy, trialkoxymethyl, carbamoyl or N-lagalkylcarbamoyl, cyan, hydroxymethyl or halomethyl, the same as the color of B, trialkoxymethyl, halomethyl hydroxyl yl, Group B 'in Group B, Sasom i förfarandealternativet 1) in particular, and in the case of pure desulfurization of the genome of Raney nickel or 75569 3. in the case of Group XI / • n _ / * »U s J« ii, ch2 -ab "and a symbol R21 and R2" are attached to the group or a "B" means a mixture of carboxyl, a alkoxycarbonyl, a carbamoyl or an N-Igalkylcarbamoyl, cyan, hydroxymethyl, lagalkanoyloxymethyl, halogenated hydroxyl for the formulation Ib / \ J * w, Ib CH2-AB "and for the purposes of (b) halogenated methyl", the genome of which is a cyanide ion, a formulation and a formulation of form I, color B and cyanide (b) in column B "a hydroxymethyl chloride or a lactalkanoylox, hydrolyzed to a compound of formula I, color B a hydroxymethyl or formula 4, and a mixture of formula XIV / \ J * K JO V» r XIV CH = CH-A'- B 2 2 vilken A 'betecknar en alkylen-, alkenylen- ell is alkyny-lenrest med högst 6 kolatom, och R2 and B betecknar det- 75569 samma som ovan, hydreras eller 5. i en förening med formuleln XVI / \ ϋ. λ A / XVI CH2-AC in the form of R2 and A in the form of a mixture of oval and C in the formyl form, lagalkanoyl, halomethyl, dicarboxymethyl, carboxycarbonyl, vinyl or di (lagalkoxy) methyl, inverted C and en carboxy groups in the genome (A) for the purpose of the invention, the 5,6,7,8-tetrahydroderivative of the formulation of Formula I, which differs from the formulation of 5-, 6-, 7- and 8-methylation, as hydrogens, (b) for the preparation of formulations I, color B and carboxy, and especially for formulation I, color B Mr llgalkoxycarbonyl, carbamoyl or cyan, hydrolysers, (c) ) for the preparation of formulations I, or B of carbamoyl, and for the preparation of formulas I, or B of cyan, hydrolysing batches, (d) for the formulation of formulations I, or B of hydroxymethyl, for the formulation of formulas I, vari B Mr carboxy or llgalkoxycarbonyl, reducer, (e) for framstMllni with a mixture of Formula I, vari B Mr carboxy, and a particular formulation of Form I, vari B Mr hydroxymethyl, oxide, (f) for the preparation of Form I, vari B Mr carboxy and A Mr Förlängd med en terminal CH2- a group, preferably in the form of formula I, vari B Mr carboxy, in the form of a cyanogen halide and a mixture of diazomethane, (g) a formulation of the formulation in formula I, vari B Mr carboxy and A A form of the terminal CH2 ~ group, en derived from Form I, vari B Mr hydroxymethyl, om-