LU83251A1 - IMIDAZO (4,5-B) PYRIDINE DERIVATIVES, THEIR PREPARATION AND THEIR USE AS CARDIOTONIC AGENTS - Google Patents

Description

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This invention relates to imidazo- [4,5-b] pyridine derivatives, their preparation and their use as cardiotonic agents.

Baldwin et al [J. Med. Chem. 120, 1189-11.93 (1977)] 5 prepare 2- (3-pyridinyl) -1H-imidazo [4,5-b] pyridine and 2- (4-pyridinyl) -lH-imidazo [4,5-b ] pyridine by heating respectively a mixture of 2,3-diaminopyridine and nicotinic acid or a mixture of 2,3-diaminopyridine and isonicotinic acid. Baldwin et al have found that these two compounds are inactive when tested as xanthine oxidase inhibitors. British Patent No. 1,322,318 and the patents of E.ü.A. Nos. 3.838.156 and 4.072.746 describe related chemical intermediates.

The invention relates to a 1, S-dihydro-1-R ^ -S-R ^ -ô-15 Q'-5-Q-2H-imidazo [4,5-b] pyridine-2-one or -2-thione of formula I

“YVt1

20. 5 D 3 2 I

R3 in which Z is O or S, Q 'is PY and Q is a hydrogen atom or a lower alkyl group, where Q is PY and Q' is a hydrogen atom, and are each a hydrogen atom or a lower alkyl, lower hydroxyalkyl, 2,3-dihydroxypropyl, lower alkoxyalkyl or Y-NB group where Y is a lower alkylene group having at least two carbon atoms between its connecting bonds and NB is a di- (alkyl lower) amino or 4-morpholinyl, at least one of and being a hydrogen atom but in case Q is PY, R1 is only a hydrogen atom, and PY is a 4- or 3-pyridinyl group or 4-35 or 3-pyridinyl having one or two lower alkyl substituents, or one of its acid addition salts. The compounds of formula I are useful as cardiotonic agents, as shown by conventional pharmacological test procedures 4-2. The preferred compounds are those of formula I where Q ′ is PY, PY is a 4-pyridinyl or 3-pyridinyl group, Z is 0, is a hydrogen atom when is a methyl, ethyl or 2-hydroxyethyl group and is a 5 hydrogen atom when is a methyl, ethyl or 2-hydroxyethyl group, and Q is a hydrogen atom or a methyl or ethyl group. Particularly preferred compounds where Q 'is PY are the compounds of formula IA where Z is 0, R ^ is a hydrogen atom, is a 2-10 hydroxyethyl group, PY is a 4-pyridinyl group and Q is a d atom hydrogen or a methyl or ethyl group. Preferred compounds when Q is PY are those where PY is a 4-pyridinyl or 3-pyridinyl group, Z is 0 or S and R3 is a hydrogen atom or a methyl, ethyl or 2-hydroxyethyl group.

The compound of formula I can exist in tautomeric forms, that is to say when R ^ is a hydrogen atom, such as 1,3-dihydro-3-R3-6-Q'-5-Q-2H -imidazo [4,5-b] pyridine-2-one or 2-thione of formula I and / or 3-R3 ~ 6-Q'-5-Q-3H-20 imidazo [4,5-b] pyridine -2-ol or -2-thiol of formula IA, shown below.

YVr -> γν-Λ s I (R1 = H) IA '3 or when R3 is a hydrogen atom, in the form of 1,3-30 dihydro- * lRL “6-Q'-5-Q-2H -imidazo [4,5-b] pyridine-2-one or 2-thione of formula I and / or l-R1-6-Q'-5-Q-1H-imidazo [4,5-b] pyridine- 2-ol or 2-thiol of formula IB, shown below.

--N-R -> Q1 —- N-R

35 i i i1 ._) li Î

i (R3 = H) IB

day 3

Structure preferences for other known imidazo [4,5-b] -pyridine-2-ones or -2-thiones would indicate that formula I above is the preferred tautomeric structure; we therefore preferred to use the names based on the formula 5 I although it is understood that in the two preceding cases when or is a hydrogen atom, both or one or the other of the structures are envisaged here.

A process for the production of 1, S-dihydro-1R ^ -S-R3 “6-Q'-5-Q-2H-imidazo [4,5-b] pyridine-2-one or -2-thione of 10 formula I consists in reacting 2-R2NH-3-R1NH-5-Q'-6-Q-pyridine (II) with urea or carbonyldiimidazole to obtain 2-one (I where Z is O) or with an alkali metal xanthate, thiourea or thiocarbonyldiimidazole to obtain 2-thione (I where Z is S), where PY, R ^, R ^, Z, Q 'and 15 Q are as defined above for the compound of formula I.

Another aspect of the present invention relates to the novel S-amino ^ -R ^ NH-S-PY-pyridine (IIA: II, Q is PY) or its acid addition salts, where R ^ is a d atom hydrogen or a lower alkyl, lower hydroxyalkyl, 2,3-dihydroxypropyl, lower alkoxyalkyl or Y-NB group where Y is a lower alkylene group having at least two carbon atoms between its connecting bonds and NB is a di- (lower alkyl) amino or 4-morpholinyl, and PY is a 4- or 3-pyridinyl or 4- or 3-pyridinyl group having one or two lower alkyl substituents. These compounds of formula (IIA) can be used as intermediates in the preparation of the compounds of formula I where Q is PY. The preferred compounds are those where PY is a 4-30 pyridinyl or 3-pyridinyl group and R is a hydrogen atom or a methyl, ethyl or 2-hydroxyethyl group.

The new 2-R2NH-3-R ^ NH-5-PY-6-Q ~ intermediate pyridines of formula (II) making it possible to prepare the compounds of formula I where Q ′ is PY are described and claimed in the patent application N ° deposited on $ / '' f

2-halo-3-nitro-6-Q'-pyridine (X) can be reacted with ammonia or an amine of formula R3NH2 to

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4 i produce 2-R3NH-3-nitro-6-PY-pyridine (formula XI) and reduce the 3-nitrë derivative (XII) to produce 3-amino-2-R ^ NH-ô-Q'-pyridine (ΙΙΆ) where halo denotes chlorine or bromine, and R and PY are as defined above for the compounds of formula I where Q is PY. Preferred embodiments of this process are those where halo is a chlorine atom and those which produce the aforementioned preferred compounds of the compounds of formula (IIA).

A cardiotonic composition for increasing cardiac contractility comprises a pharmaceutically acceptable carrier and, as active ingredient, an effective amount of 1/3-dihydro-1-R1-3-R3-6-Q '“5-Q-2H -imidazo [4,5-b] pyridine-2-one cardiotonic (I where Z is O) or 2-thione (I where Z is S) of formula I, where Z, R ^, R3, PY, Q 'and Q are as defined for formula I, or a pharmaceutically acceptable acid addition salt thereof. The preferred compositions are those which contain as active components the above-mentioned clearly preferred compounds of formula I.

The cardiac contractility of a patient in need of such treatment can be increased by administering orally or parenterally, in solid or liquid dosage form, an effective amount of 1, 3-dihydro-1-R1-3-R3 - 6-Q'-5-Q-2H-imidazo [4,5-b] pyridine-2-one (I where Z is O) or -2-thione (I where Z is S) of formula I where PY, R. ^, R3 and Z are as defined in formula I, or one of their pharmaceutically acceptable acid addition salts. It is preferred to use the preferred cardiotonic compounds of formula I indicated above.

The term "lower alkyl" as used herein, for example, as one of a meaning of R ^, R3 or Q or as a substituent of PY in formula I, denotes alkyl radicals having from 1 to 6 carbon atoms, in straight or branched chain, represented by methyl, ethyl, n-propyl, isopropyl n-butyl, s-butyl, t-butyl, isobutyl, n-amyl, n-hexyl, etc. groups.

Examples of PY in formula I where PY is a 4- or 3-pyridinyl group having one or two lower alkyl substituents are as follows: 2-methyl-4-pyridinyl, 5! 2.6- dimethyl-4-pyridinyl, 3-methyl-4-pyridinyl, 2-methyl- 3-pyridinyl, 6-methyl-3-pyridinyl (also called 2-methyl-5-pyridinyl), 2,3-dimethyl-4 -pyridinyl, 2,6-dimethyl-4-pyridinyl, 2-ethyl-4-pyridinyl, 2-isopropyl-4- 5 pyridinyl, 2-n-butyl-4-pyridinyl, 2-n-hexyl-4-pyridinyl, 2.6-diethyl-4-pyridinyl, 2,6-diethyl-3-pyridinyl, 2,6-diisopropyl-4-pyridinyl, 2,6-di-n-hexyl-4-pyridinyl, etc ...

The term "lower hydroxyalkyl" as used herein, for example as one of the definitions of v 10 R ^ or in formula I, denotes hydroxy alkyl radicals having from two to six carbon atoms, in straight chain or branched, and where at least two carbon atoms separate the hydroxy group and the nitrogen atom in position 1 or 3 of the imidazo [4,5-b] pyridine ring, for example the 2-hydroxyethyl, 3-hydroxypropyl groups , 2-hydroxy-propyl, 4-hydroxybutyl, 3-hydroxybutyl, 5-hydroxyamyl, 6-hydroxyhexyl, etc ...

The term "lower alkoxyalkyl" as used herein, for example as one of the definitions for R ^ or in formula I, denotes alkoxyalkyl groups having three to six carbon atoms which can be arranged in a straight chain or branched and in which at least two carbon atoms separate the oxygen atom from the alkoxyalkyl group from the nitrogen atom in position 1 or 3 of the imidazo [4,5-b] pyridine ring, represented by groups 2 -methoxyethyl, 2-ethoxyethyl, l-mdthoxypropyie, 2-methoxy-propyl, 2-methoxybutyl, 4-ethoxybutyl, 3-ethoxypropyl, 3-n-propoxypropyl, etc ...

The expression "lower alkylene" designating Y 30 as part of R ^ or R ^ denotes lower alkylene groups having at least two carbon atoms between their connecting bonds and having from two to six carbon atoms in straight or branched chain, represented by the groups -CH2CH2-, -CH2ÔH (CH3), -CH (CH ^) CH2 ~, -CH (CH3) - 35 ch (ch3), -chchch2ch3, - (ch2) 3-, - (ch2) 4 -, - (ch2) 5-, - (ch2) 6-, -CH (C2H5) CH (CH3), etc ...

The compounds of formula I can be used both in the form of the free base and in the form of the salts

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6 Λ of addition of acids, and these two forms form part of the field of the invention. Acid addition salts are simply a more convenient means for use and, in practice, the use of the salt form inherently corresponds to the use of the base form. The acids which can be used to prepare the acid addition salts preferably include those which produce, when combined with the free base, pharmaceutically acceptable salts, i.e. salts of which the anions are relatively harmless to the animal body at pharmaceutical doses of the salts, so that the attractive cardiotonic properties inherent in the free base (I) are not vitiated by side effects attributable to anions. In practicing the invention, it is convenient to use the free base form or its hydrochloride; however, suitable pharmaceutically acceptable salts within the scope of the invention are those derived from other mineral acids such as hydrobromic acid, sulfuric acid, phosphoric acid and sulfamic acid; and 20 organic acids such as acetic acid, citric acid, lactic acid, tartaric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, l cyclohexylsulfamic acid, quinic acid, etc., giving the hydrobromide, sulfate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methane-sulfonate, ethanesulfonate, benzenesulfonate, -cyclohexyl-sulfamate and quinate respectively.

The acid addition salts of the basic compound of formula I are prepared either by dissolving the free base in an aqueous or aqueous-alcoholic solution or in other suitable solvents containing the appropriate acid and isolating the salt by evaporation of the solution, either by reaction of the free base and the acid in an organic solvent, in which case the salt separates directly or can be obtained by concentrating the solution.

Although the pharmaceutically acceptable salts of the basic compound are preferred, all of the acid addition salts are within the scope of the invention. The acid addition salts * * 7 are all usable as sources of the free base even if the particular salt is sought in itself only as an intermediate product, for example when the salt is formed solely for the purpose of purification or identification or when used as an intermediate in the preparation of a pharmaceutically acceptable salt by ion exchange procedures.

The molecular structure of the compound of formula I was assigned based on the data provided by the nuclear magnetic resonance, mass and infrared spectra, and by the correspondence between the calculated and found values for the elemental analysis.

The preparation of 1,3-dihydro-1R ^ -3-R3-6-Q'-5-Q-2H-imidazo [4,5-b] pyridine-2-one (I, Z is O) by reaction 2-R3NH-3-R3NH-5-Q'-6-Q-pyridine (of formula II) with urea is conveniently and preferably carried out by heating the reagents in dimethylformamide at reflux.

Other suitable inert solvents can also be used, for example dioxane, nitrobenzene, etc.

The reaction using carbonyldiimidazole in place of urea is conveniently carried out in dimethylformamide at about 35 ° C for about 1 to 3 hours and then at about 70 to 80 ° C for about 2 to 16 hours. This preparation is better illustrated below in Examples G-1 to G-37. Preparation of 1,3-dihydro-1R ^ - 3-R3-6-Q'-5-Q-2H-imidazo [4,5-bJpyridine-2-thicme (I, Z is S) is carried out reacting 2-R3NH-3-R3NH-5-PY-6-Q-pyridine (of formula II) with an alkali metal xanthate, thiourea or thiocarbonyldiimidazole. The reaction with an alkali metal xanthate or thiourea is carried out by heating the reagents in an appropriate solvent to about 60 ° C to 100 ° C, preferably about 75 ° C to 85 ° C. The reaction is conveniently carried out using an alkali metal xanthate, preferably the sodium or potassium salt, by heating the reagents to reflux in a mixture of water and a lower alkanol, preferably aqueous ethanol. The reaction using thiourea is conveniently carried out by heating the reagents in dimethylformamide at reflux. The reaction using thiocarbonyldiimidazole is conveniently carried out at room temperature or up to about 40 to 60 ° C in dimethylformamide. This preparation is further illustrated below in Examples H-1 to H-11.

The patent application mentioned on page 3, lines 35-36 describes, inter alia, the process for preparing the compounds of formula II where Q 'is PY. Reacting a 3-nitro-5-PY- 6-Q-2 (1H) pyridinone or a 5-PY-6-Q-2 (1H) pyridinone with a mineral halogenating agent to obtain a 2 -halo-3-10 nitro-5-PY-6-Q-pyridine (III) or a 2-halo-5-PY-6-Q-pyridine (VII) is preferably carried out by refluxing the * 2 ( 1H) pyridinone with an excess of phosphorus oxychloride containing a catalytic amount of dimethylformamide, to obtain the 2-chlorinated compound. Other suitable mineral halogenating agents include PCl ^, POBr ^, PBr ^, PCl ^, etc. The reaction of the 2-halogen compound (III or VII) with ammonia or an amine of formula R ^ RNH to obtain compounds V or VIII respectively, is carried out by heating the reactants, preferably under pressure using ammonia or a source of ammonia and monomethylamine, and at atmospheric pressure using the other primary amines higher or secondary amines R- ^ RNH. The reaction of compounds III or VII with hydrazine is carried out in a similar manner to obtain the corresponding 2-hydrazino derivatives, which are easily converted, by reduction, to corresponding 2-amines. The reaction of compound V to obtain compound II where R ^ is a hydrogen atom is preferably carried out by catalytic hydrogenation of compound V using a suitable catalyst, for example 10% palladium on carbon, nickel by Raney, etc. The reaction of the compound VIII with a halogenating agent to obtain the corresponding 3-halogenated derivative of formula (IX) is preferably carried out using bromine, to obtain the 3-brominated compound or the phenylphosphoric dichloride to obtain the compound 3 -chlorine. Optionally, the 3-chlorinated compound of formula (IX) can be obtained in two stages, by first reacting 3-nitro-5-PY-6-Q-2 (1H) -pyridinone with phenylphosphoric dichloride to obtain 2,3-dichloro- Λ .t 9 5-PY-6-Q-pyridine then by reacting selectively the latter on the more reactive 2-chloro group, with R ^ RNH to obtain compound IX. The reaction of compound IX with ammonia or an amine of formula I ^ R'NH to obtain the compound of formula II is carried out by heating the reagents as described previously in the transformation of III into V or from VII into VIII.

The preparation of known 1,2-dihydro-2-oxo-5-PY-nicotinic acids by hydrolysis of the corresponding 1,2-dihydro-2-oxo-5-PY-10 nicotinonitrile is described in the U.S. Patent. N ° 4.004.012.

Hydrolysis of 1,2-dihydro-6- (lower alkyl) -2-. oxo-5-PY-nicotinonitrile to obtain 1,2-dihydro-6- (lower alkyl) -2-oxo-5-PY-nicotinic acid is conveniently carried out by heating the nitrile in a steam bath with a mineral acid aqueous, for example 50% sulfuric acid.

The preparation of l-PY-2- (dimethylamino) ethenyl (lower alkyl) ketone by reaction of PY-methyl (lower alkyl) ketone with a lower dialkyl acetal of dimethylformamide is carried out by mixing the reactants in the presence or in the presence of absence of a suitable solvent. The reaction is conveniently carried out at room temperature, i.e. about 20 to 25 ° C, or by heating the reagents to about 100 ° C, preferably in an aprotic solvent, conveniently hexamethylphosphoramide in reason · for the process used to prepare PY-methyl (lower alkyl) ketone. Other suitable solvents include tetrahydrofuran, dimethylformamide, acetonitrile, ether, benzene, dioxane, etc. The reaction can also be carried out without solvent, preferably using an excess of the di- (lower alkyl) acetal of dimethylformamide.

PY-methyl (lower alkyl) intermediate ketones are generally known compounds which are prepared by known methods [for example, as described in Rec. trav. chem 72, 522 (1953); the U.S. patent No. 3,133,077; Bull.

Soc. Chim. France 1968, 4132; Chem. Abstrs. 79, 8539h (1973); Chem. Abstrs. 8_1, 120, 401a (1974); J. Org. Chem. 39 ^ 3834 t 10 (1974); Chem. Abstrs. 87, 6594q (1977); J. Org. Chem. 43, 2286 (1978)].

The reaction of l-PY-2- (dimethylamino) ethenyl (lower alkyl) ketone with 11α-cyanoacetamide to produce 1,2-dihydro-2-oxo-5-PY-6-R-nicotinonitrile is preferably carried out by heating the reagents in a suitable solvent in the presence of a basic condensing agent.

The reaction is conveniently carried out using a lower alkaline alcoholate, preferably sodium methylate or ethylate, in dimethylformamide. In the implementation of the invention, the reaction is carried out in dimethylformamide at reflux using sodium methylate. Methanol and sodium methylate or ethanol and sodium ethylate can also be used as the solvent and as the basic condensing agent, respectively, but a longer heating period is then necessary. Other basic condensing agents and other solvents include sodium hydride, lithium diethylamide, lithium diisopropylamide, etc., in an aprotic solvent, for example tetrahydrofuran, acetonitrile, benzene, dioxane , etc ...

The preparation of the 6- (lower alkyl) -3-nitro-5-PY-2 (1H) -pyridinones is carried out by following the procedure described in Example C-1 of the U.S. Patent. No. 4,072,746, using instead of 1,2-dihydro-2-oxo-5- (4-pyridinyl) nicotinic acid an equimolar amount of 1,2-dihydro-2-oxo- acid 5-PY-6- (lower alkyl) nicotinic suitable for obtaining, in place of 3-nitro-5- (4-pyridinyl) -2- (1H) -pyridinone, 6- (lower alkyl) -3 -nitro-5-PY-2- (1H) corresponding pyridinone.

Reaction of 2-halo-3-nitro-6-PY-pyridine of formula (X) with ammonia or with an amine of formula RNH2 to obtain 2-RNH-3-nitro-6-PY-pyridine ( XI) is carried out by heating the reactants, preferably under pressure when using ammonia or a source of ammonia and monomethylamine, and at atmospheric pressure when using the other higher primary amines.

The reaction of 2-RNH-3-nitro-6-PY-pyridine (XI) to obtain 3-amino-2-RNH-6-PY-pyridine is preferably 11

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carried out by catalytic hydrogenation of compound XI using an appropriate catalyst, for example palladium, on 10% carbon, Raney nickel, etc., in an appropriate solvent. A preferred solvent is the combination of dimethylformamide and ethanol.

The preparation of the intermediate 2-halo-3-nitro-6-PY-pyridine of formula (X) is conveniently carried out in two stages, first nitrating the known 6-PY-2 (1H) -pyridine of formula ( XII) to obtain 3-nitro-6-PY-2 (1H) -10 pyridinone (XIII) then by reacting compound XIII with an inorganic halogenating agent, preferably by reflux heating of 2 (1H) -pyridinone (XIII) with phosphorus oxychloride in dimethylformamide. This two-step preparation of compound X is further illustrated below in Examples A-1 to A-8 and B-1 to B-9.

The following examples will better illustrate the invention without however limiting it.

A. 3-NITRO-6-PY-2 (1H) -PYRIDINONES

A-l. 3-Nitro-6- (4-pyridinyl) -2 (1H) -pyridinone 20 A solution heated to 78 ° C and containing 413 g of 6- (4-pyridinyl) -2 (1H) -pyridinone in 1600 ml of 'concentrated sulfuric acid, a mixture containing 320 ml of 90% nitric acid and 160 ml of concentrated sulfuric acid is added dropwise with stirring, in approximately 3 hours; The addition of sulfuric acid takes place at such a rate that the reaction temperature is maintained at about 75-90 ° C. One hour after completing the addition of sulfuric acid, the reaction temperature dropped to 40 ° C and stirring was continued at this temperature for one hour. The reaction mixture is then poured onto ice. To the mixture is added concentrated ammonium hydroxide to a pH of about 6, with more ice. Then the mixture is cooled in the refrigerator and left to stand overnight. The solid which separates is collected, washed successively with water, a little ethanol and ether, then dried under vacuum at 55 ° C. overnight and 277 g are obtained. of 3-nitro-4- (pyridinyl) -2 (1H) -pyridinone, pf > 300 ° C.

12

X

S

Following the procedure described in Example A1 but using instead of 6- (4-pyridinyl) -2 (1H) -pyridinone an equimolar amount of the appropriate 6-PY-2 (1H) -pyridinone, it can be seen that the corresponding 3-5 nitro-6-PY-2 (1H) pyridinones from Examples A-2 to A-8 can be obtained.

A-2. 3-Nitro-6- (3-pyridinyl) -2 (1H) -pyridinone.

A-3. 6- (2-Methyl-4-pyridinyl) -3-nitro-2 (1H) - pyridinone.

10 A-4. 6- (3-Methyl-4-pyridinyl) -3-nitro-2 (1H) - pyridinone.

AT 5. 6- (2-Ethyl-4-pyridinyl) -3-nitro-2 (1H) - pyridinone.

A-6. 6- (3-Ethyl-4-pyridinyl) -3-nitro-2 (1H) - 15 pyridinone.

A-7. 6- (2,6-Dimethyl-4-pyridinyl) -3-nitro-2 (1H) - pyridinone.

AT 8. 6- (3,5-Dimethyl-4-pyridinyl) -3-nitro-2 (1H) - pyridinone.

20 B. 2-HALO-3-NITRO-6-PY-PYRIDINES

B-l. 2-Chloro-3-nitro-6- (4-pyridinyl) pyridine

A mixture containing 277 g of 3-nitro-6- (4-pyridinyl) -2 (1H) -pyridinone, 4400 ml of dimethylformamide and 470 ml of phosphorus oxy-chloride is heated by stirring on a steam bath. for about 40 minutes, period 4 during which dissolution occurs. Leave the reaction mixture to cool and then pour it into 15 l of a mixture of ice and water. The resulting clear solution is neutralized with concentrated ammonium hydroxide. The precipitating solid is collected, washed with water, dried in air and then triturated with six 3 l portions of cyclohexane at the boil, recycling the solvent after collecting the yellow crystalline product of each cooled extract. 120 g of 2-chloro-3-nitro-6- (4-pyridinyl) pyridine are thus obtained, m.p. 107-110 ° C.

Following the procedure of Example B-1, but using an equimolar amount of phosphorus oxybromide or phosphorus tribromide instead of phosphorus oxychloride, it can be seen that 13

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X

corresponding 2-brora derivative of Example B-2.

B-2. 2-Bromo-3-nitro-6- (4-pyridinyl) pyridine.

Following the procedure described in Example B1 but using instead of 3-nitro-6- (4-5 pyridinyl) -2 (1H) -pyridinone, an equimolar amount of 3-nitro-6- PY-2 (1H) -pyridinone suitable, it can be seen that the corresponding 2-chloro-3-nitro-6-PY-pyridines can be obtained from Examples B-3 to B-9.

B-3. 2-Chloro-3-nitro-6- (3-pyridinyl) pyridine.

10 B-4. 2-Chloro-6- (2-methyl-4-pyridinyl) -3 ~ nitropyridine.

B-5. 2-Chloro-6- (3-methyl-4-pyridinyl) -3-nitro-pyridine.

B-6. 2-Chloro-6- (2-ethyl-4-pyridinyl) -3-nitro-pyridine.

B-7. 2-Chloro-6- (3-ethyl-4-pyridinyl) -3-nitro-pyridine.

B-8. 2-Chloro-6- (2,6-dimethyl-4-pyridinyl) -3-nitropyridine.

20 B-9. 2-Chloro-6- (3,5-dimethyl-4-pyridinyl) -3-nitropyridine.

C. 2-RNH-3-N02-6-PYRIDINES

C-l. 2-Amino-3-nitro-6- (4-pyridinyl) pyridine A mixture containing 120 g of 2-chloro-3-nitro-6- (4-pyridinyl) is autoclaved at 60 ° C for 20 hours. ) -pyridine, 900 ml of 95% ethanol and 510 ml of S-concentrated ammonium hydroxide. The reaction mixture is cooled and the solid which separates is collected, washed successively with ethanol and ether and dried to give 102 g of 2-amino-3-nitro-6- (4-pyridinyl) pyridine, pf 216-218 ° C.

Following the procedure described in Example C1 but using instead of 2-chloro-3-nitro-6- (4-pyridinyl) pyridine an equimolar amount of 2-chloro-35 3-nitro-6- PY-pyridine, it can be seen that the corresponding 2-amino-3-nitro-6-PY-pyridines from Examples C-2 to C-8 can be obtained.

C-2. 2-Amino-3-nitro-6- (3-pyridinyl) pyridine.

* 1 14 pyridine.

C-3. 2-Amino-6- (2-methyl-4-pyridinyl) -3-nitro- C-4. 2-Amino-6- (3-methyl-4-pyridinyl) -3-nitro-pyridine.

5 C-5. 2-Amino-6- (2-ethyl-4-pyridinyl) -3-nitro-pyridine.

C-6. 2-Amino-6- (3-ethyl-4-pyridinyl) -3-nitro-pyridine.

C-7. 2-Amino-6- (2,6-dimethyl-4-pyridinyl) -3-nitro-pyridine.

C-8. 2-Amino-6- (3,5-dimethyl-4-pyridinyl) -3-nitro-pyridine.

Following the procedure described in Example C1 but using instead of ammonia an equimolar amount of the appropriate amine of formula RNH2 / it is seen that the 2-RNH-3-nitro can be obtained -6- (4-pyridinyl) -pyridines corresponding to Examples C-9 to C-18.

C-9. 2-Methylamino-3-nitro-6- (4-pyridinyl) - pyridine.

20 C-10. 2-Ethylaraino-3-nitro-6- (4-pyridinyl) - pyridine.

C-ll. 2-Isopropylamino-3-nitro-6- (4-pyridinyl) - pyridine.

C-12. 2-n-Butylamino-3 “nitro-6- (4-pyridinyl) - pyridine.

C-13. 2-n-Hexylamino-3-nitro-6- (4- ^ ridinyl) - pyridine.

C-14. 2- (2-Hydroxyethylamino) -3-nitro-6- (4-pyridinyl) pyridine.

30 C-15. 2- (2,3-Dihydroxypropylamino) -3-nitro-6- (4-pyridinyl) pyridine.

C-16. 2- (2-Dimethylaminoethylamino) -3-nitro-6- (4-pyridinyl) pyridine.

C-17. 2- (2-Methoxyethylamino) -3-nitro-5- (4-pyridinyl) pyridine.

C-18. 2— [2— (4-Morpholinyl) ethylamino] -3-nitro-6- (4-pyridinyl) pyridine.

Ό. 3-AMINO-2-RMH-6-PY-PYRIDINES

15 D-l. 2,3-Diamino-6- (4-pyridlnyl) pyridine

A mixture containing 43.2 g of 2-amino-3-nitro-6- (4-5 pyridinyl) pyridine, 360 ml of dimethylformamide, 220 is stirred in a Parr apparatus under catalytic hydrogenation conditions for approximately one hour. ml of ethanol and 1 g of 10% palladium on carbon. The reaction mixture is filtered and the filtrate is concentrated in vacuo to a volume of about 150 ml and cooled. The separating solid is collected and dried to give 20 g of 2,3-diamino-6- (4-pyridinyl) pyridine which can be used directly in the next step without further purification. In another test, a sample was recrystallized from ethanol using bleaching charcoal to obtain the product, 2,3-diamino-6- (4-pyridinyl) -15 pyridine, melting at 252-254 ° C.

Following the procedure described in Example D1 and using, in place of 2-amino-3-nitro-6- (4-pyridinyl) pyridine, an equimolar amount of 2-amino-3-nitro-6 -PY-pyridine suitable, it can be seen that the 2,3-diamino-6-PY-pyridines of Examples D-2 to D-8 can be obtained.

D-2. 2,3-Diamino-6- (3-pyridinyl) pyridine.

D-3. 2,3-Diamino-6- (2-methyl-4-pyridinyl) pyridine.

D-4. 2,3-Diamino-6- (3-methyl-4-pyridinyl) pyridine.

D-5. 2,3-Diamino-6- (2-ethyl-4-pyridinyl) pyridine.

25 D-6. 2,3-Diamino-6- (3-ethyl-4-pyridinyl) pyridine.

D-7. 2,3-Diamino-6- (2,6-dimethyl-4- ”pyridinyl) - pyridine.

D-8. 2,3-Diamino-6- (3,5-dimethyl-4-pyridinyl) - pyridine.

Following the procedure described in Example D1 but using instead of 2-amino-3-nitro-6- (4-pyridinyl) pyridine an equimolar amount of 2-RNH-3-nitro-6 -PY-pyridine suitable, it is seen that one can obtain the 3-amino-2-RNH-6- (4-pyridinyl) pyridines of Examples D-9 to 35 D-18.

D-9. 3-Amino-2-methylamino-6- (4-pyridinyl) pyridine, m.p. 184-186 ° C.

D-10. 3-Amino-2-ethylamino-6- (4-pyridinyl) pyridine.

pyridine.

* 16 D-ll. 3-Amino-2-isopropylamino ~ 6- (4-pyridinyl) - D-12. 3-Amino-2-n-butylamino-6- (4-pyridinyl) - pyridine.

5 D-13. 3-Amino-2-n-hexylamino-6- (4-pyridinyl) - pyridine.

D-14. 3-Ainino-2- (2-hydroxyethylamino) -6- (4-pyridinyl) pyridine, m.p. 208-210 ° C.

D-15. 3-Amino-2- (2,3-dihydroxypropylamino) -6-10 (4-pyridinyl) pyridine.

D-16. 3-Amino-2- (2-dimethylaminoethylamino) -6- (4-pyridinyl) pyridine.

D-17. 3-Amino-2- (2-methoxyethylamino) -6- (4-pyridinyl) pyridine.

15 D-18. 3-Amino-2- [2- (4-morpholinyl) ethylamino] -6- (4-pyridinyl) pyridine.

E. 1,3-DIHYDRO-3-R-5-PY-2H-IMIDAZO [4,5-b] PYRIDINE-2-ONES

E-l. 1,3-Dihydro-5- (4-pyridinyl) -2H-iinidazo [4,5— b] pyridine-2-one 20 A warm solution (45 ° C) of 11.2 g of 2,3-diamino -6- (4-pyridinyl) pyridine in 100 ml of dimethylformamide, 10.5 g of 1,1'-dicarbonyl-diimidazole are added with stirring. A solid begins to separate after a few minutes. The reaction mixture is stirred without any external heating for about 40 minutes (temperature 45 ° C, no change in appearance after the first ten minutes) and then heated to 80 ° C (no change in appearance). The solid which separates is collected, washed and triturated with ethanol and dried at 70 ° C in vacuo to give 11.3 g of 1,3-dihydro-5- ( 4-pyridinyl) -2H-imidazo [4,5-b] pyridine-2-one, pf > 300 ° C.

Following the procedure described in Example E1 but using instead of 2,3-diamino-6- (4-pyridinyl) pyridine an equimolar amount of 2,3-diamino-35 6-PY-pyridine appropriate, it can be seen that the corresponding 1,3-dihydro-5-PY-2H-imidazo [4,5-b] pyridine-2-ones can be obtained from Examples E-2 to E-8.

E-2. 1,3-Dihydro-5- (3-pyridinyl) -2H-imidazo [4,5- b] pyridine-2-one.

i # 17 t E-3. 1,3-Dihydro-5- (2-methyl-4-pyridinyl) -2H- imidazo [4,5-b] pyridine-2-one.

E-4. 1,3-Dihydro-5- (3-methyl-4-pyridinyl) -2H-5 iraidazo [4,5-b] pyridine-2-one.

E-5. 1,3-Dihydro-5- (2-ethyl-4-pyridinyl) -2H-imidazo [4,5-b] pyridine-2-one. · E-6. 1,3-Dihydro-5- (3-ethyl-4-pyrldinyl) -2H- imidazo [4,5-b] pyridine-2-one.

10 E-7. 1,3-Dihydro-5- (2,6-dimethyl-4-pyridinyl) - 2H-imidazo [4,5-b] pyridine-2-one.

E-8. 1,3-Dihydro-5- (3,5-dimethyl-4-pyridinyl) -2H-imidazo [4,5-b] pyridine-2-one.

Following the procedure described in Example 15 El but using, in place of 2,3-diamino-6- (4-pyridinyl) pyridine, an equimolar amount of 2-RNH-3-amino-6- ( 4 ~ pyridinyl) appropriate pyridine, it can be seen that the corresponding 1,3-dihydro-3-R-5- (4-pyridinyl-2H-imidazo- [4,5-b] pyridine-2-ones can be obtained Examples E-9 to 20 E-18.

E-9. 1,3-Dihydro-3-methyl-5- (4-pyridinyl) -2H- imidazo [4,5-b] pyridine-2-one, m.p. 284-286 ° C.

E-10. 3-Ethyl-1,3-dihydro-5- (4-pyridinyl) -2H-imidazo [4,5-b] pyridine-2-one.

25 E-ll. 1,3-Dihydro-3-isopropyl-5- (4-pyridinyl) -2H- iraidazo [4,5-b] pyridine-2-one. ·.

E.12. 3-n-Butyl-1,3-dihydro-5- (4-pyridinyl) -2H-imidazo [4,5-b] pyridine-2-one.

E-13. 3-n-Hexyl-1,3-dihydro-5- (4-pyridinyl) -2H-30 imidazo [4,5-b] pyridine-2-one.

E-14-. 1,3-Dihydro-3- (2-hydroxyethyl) -5- (4-pyridinyl) -2H-imidazo [4,5-b] pyridine-2-one, m.p. > 300 ° C.

E-15. 1,3-Dihydro-3- (2,3-dihydroxypropyl) -5- (4-pyridinyl) -2H-imidazo [4,5-b] pyridine-2-one.

35 E-16. 1,3-Dihydro-3- (2-dimethylaminoethyl) -5- (4-pyridinyl) -2H-imidazo [4,5-b] pyridine-2-one.

E-17. 1,3-Dihydro-3- (2-methoxyethyl) -5- (4-pyridinyl) -2H-imidazo [4,5-b Jpyridine-2-one.

»18> E-18. 1/3-Dihydro-3- [2- (4-morpholinyl) ethyl] -5- (4-pyridinyl) -2H-imidazo [4,5-b] pyridine-2-one.

F. 1,3-DIHYDRO-3 ~ R-5-PY-2H-IMIDAZO [4,5-b] PYRIDINE-2-THI0NES

F-1. 1,3-Dihydro-5- (4-pyridinyl) -2H-iitiidazo [4 / 5- 5 b] pyridine-2-thione To a hot solution (43 ° C) containing 9.0 g of 2,3-diamino -6- (4-pyridinyl) pyridine in 80 ml of dimethylformamide, 10.3 g of 1,11-thiocarbonyl-diimidazole at 90% are added with stirring, and the temperature rises to 63 ° C. If the reaction solution is allowed to cool to about 40 ° C, a solid begins to separate. The mixture is cooled, the solid which separates is collected, washed with ether, triturated with a cold ethanol-ether mixture, washed again with ether and dried. The resulting solid is ground to a powder and boiled with ethanol to remove dimethylformamide. The solid is then collected and dried under vacuum at 100 ° C., which gives 9.7 g of 1,3-dihydro-5- (4-pyridinyl) -2H-imidazo [4,5-b] -pyridine -2-thione, pf > 330 ° C.

Following the procedure described in Example F1 but using instead of 2,3-diamino-6- (4-pyridinyl) pyridine an equimolar amount of 2,3-diamino-6-PY-pyridine appropriate, it can be seen that the 1,3, dihydro-5-PY-2H-imidazo [4,5-b] pyridine-2-25 thiones from Examples F-2 to F-8 can be obtained.

F-2. 1,3-Dihydro-5- (2-methyl-4-pyrid-inyl) -2H- imidazo [4,5-b] pyridine-2-thione.

“F-3. 1,3-Dihydro-5- (3-methyl-4-pyridinyl) -2h- imidazo [4,5-b] pyridine-2-thione.

30 F-4. 1,3-Dihydro-5- (2-ethyl-4-pyridinyl) -2H- imidazo [4,5-b] pyridine-2-thione.

F-5. 1,3-Dihydro-5- (3-pyridinyl) -2H-imidazo- [4,5-b] pyridine-2-thione.

F-6. 1,3-Dihydro-5- (3-ethyl-4-pyridinyl) -2H-imidazo [4,5-b] pyridine-2-thione.

F-7. 1,3-Dihydro-5- (2,6-dimethyl-4-pyridinyl) -2H- imidazo [4,5-b] pyridine-2-thione.

F-8. 1,3-Dihydro-5- (3,5-dimethyl-4-pyridinyl) -2H-> * 19 imidazo [4,5-b] pyridine-2-thione.

Following the procedure described in Example F1, but using instead of 2,3-diamino-6- (4-pyridinyl) pyridine an equimolar amount of 3-amino-2-5 RNH-6- ( 4-pyridinyl) appropriate pyridine / we can see that we can obtain the 1,3-dihydro-3-R-5- (4-pyridinyl) -2H-imidazo [4,5- b] pyridine-2-thiones Examples F-9 to F-18.

F-9. 1,3-Dihydro-3-methyl-5- (4-pyridinyl) -2H-. imidazo [4,5-b] pyridine-2-thione.

10 F-10. 3-Ethyl-1,3-dihydro-5- (4-pyridinyl) -2H- imidazo [4,5-b] pyridine-2-thione.

F-ll. 1,3-Dihydro-3-isopropyl-5- (4-pyridinyl) -2H-imidazo [4,5-b] pyridine-2-thione.

F-12. 3-n-Butyl-1,3-dihydro-5- (4-pyridinyl) -2H-15 imidazo [4,5-b] pyridine-2-thione.

F-13. 3-n-Hexyl-1,3-dihydro-5- (4-pyridinyl) -2H-imidazo [4,5-b] pyridine-2-thione.

F-14. 1,3-Dihydro-3- (2-hydroxyethyl) -5- (4-pyridinyl) -2H-imidazo [4,5-blpyridine-2-thione.

20 F-15. 1,3-Dihydro-3- (2,3-dihydroxypropyl.) - 5- (4-pyridinyl) -2H-imidazo [4,5-b] pyridine-2-thione.

F-16. 1,3-Dihydro-3- (2-dimethylaminoethyl) -5- (4-pyridinyl) -2H-imidazo [4,5-b] pyridine-2-thione.

F-17. 1,3-Dihydro-3- (2-methoxyethyl) -5- (4-pyridinyl) -25 2H-iraidazo [4,5-b] pyridine-2-thione.

F-18. 1,3-Dihydro-3- [2- (4-morpholinyi) ethyl] -5- (4-pyridinyl) -2H-imidazo [4,5-b] pyridine-2-thione.

G. l-R1-3-R3 »6-PY-5-Q-2H-IMIDAZO [4f5-b] PYRIDINE-3-ONES

30 G-l. 1/3-Dihydro-6- (4-pyridinyl) -2H-imidazo [4,5- b] pyridine-2-one

A mixture containing 20 g of 2,3-diamino-5- (4-pyridinyl) pyridine dihydrochloride, 28 g of urea and 200 ml of dimethyl-formamide is heated at reflux for two hours, then allowed to stand at temperature. ambient overnight, the reaction mixture is poured onto a mixture of ice and water and the resulting solid is collected, washed with water and dried. The solid * 20 is dissolved in 200 ml of hot 6N hydrochloric acid, the solution is treated with bleaching charcoal and filtered, and the filtrate is poured into a liter of rapidly stirred ethanol.

The resulting mixture is cooled. The solid 5 which separates is collected, washed successively with ethanol and ether and then dried. The solid is then recrystallized from water using bleaching charcoal, washed successively with ethanol and ether and dried in vacuo at 70 ° C., which gives 6.5 g of hydrochloride 10 1,3-dihydro-6- (4-pyridinyl) -2H-imidazo [4,5-b] pyridine-2-one, pf > 300 ° C.

G-2. 1,3-Dihydro-3-methyl-6- (4-pyridinyl) -2H- imidazo [4,5-blpyridine-2-one

A mixture containing 7 g of 3-amino-2-methylamino-5- (4-pyridinyl) -pyridine, 6 g of urea and 100 ml of dimethylformamide is heated at reflux for two hours, cooled and then poured on a mixture of ice and water.

The separated solid is collected, washed with water and dried. The solid is recrystallized twice from dimethylformamide, washed successively with ethanol and ether and dried in vacuo at 70 ° C., which gives 5 g of 1,3-dihydro-3- methyl-6- (4-pyridinyl) -2H-imidazo [4,5-b] -pyridine-2-one, pf > 300 ° C.

G-3 · 3-Ethyl-1,3-dihydro-6- (4-pyridinyl) -2H-25 imidazo [4,5-b] pyridine-2-one

A mixture containing 8.57 g of 3-amino-2-ethylamino-5- (4-pyridinyl) pyridine, 9.73 g of carbonyl-diimidazole and 200 ml of dimethylformamide is stirred in a water bath at 35 ° C for more than 90 minutes, at room temperature 30 overnight and then heated to 80 ° C for 30 minutes. To the mixture is added 15 ml of water and the solution is treated with bleaching charcoal and filtered. The filtrate is concentrated in vacuo to remove the liquid and the residue is recrystallized from acetonitrile (final volume of 140 ml) and dried at 90 ° C. in an oven under vacuum for 16 hours, which gives 5.15 g of a dark green solid. An additional 2.56 g of green solid was not dissolved in acetonitrile. The 5.15 g portion of green solid is recrystallized from 350 ml of ethyl acetate and dried at 90 ° C. in a vacuum oven for 20 hours and obtained in the form of pale green prisms , 4.01 g of 3-ethyl-1,3-dihydro-6- (4-pyridinyl) -2H-imidazo [4,5-b] pyridine-2-one, pf 244-246 ° C. The initial 2.56 g of insoluble green solid is also recrystallized from 150 ml of ethyl acetate and dried at 90 ° C. under vacuum and an additional 1.5 g of product is obtained. The 4.01 g and 1.5 g portions of product are combined and dried in a vacuum oven at 100 ° C for more than 60 hours to give 5.38 g of the product, m.p. 244-246 ° C.

G-4. 1,3-Dihydro-3- (2-hydroxyethyl) -6- (4-pyridinyl) -2H-imidazo [4,5-b] pyridine-2-one

The mixture is heated to reflux while stirring for more than 20 hours a mixture containing 9.04 g of 3-amino-2- (2-hydroxy-15 ethylamino) -5- (4-pyridinyl) pyridine, 14.61 g of urea and 300 ml of dimethylformamide and the dimethylformamide is distilled under vacuum. The resulting residue is suspended in water and the solid is collected, recrystallized from isopropyl alcohol (final volume 600 ml) and dried at 90 ° C. in an oven under vacuum for more than 16 hours, which gives 7.84 g of product and a second portion of 2.18 g after concentration of the filtrate to a volume of 100 ml.

The 7.84 g and 2.18 g portions of product are combined and recrystallized from inethanol (final volume of 250 ml) and dried in an oven under vacuum at 90 ° C. for more than 16 hours, which gives 6.54 g of product. 6.50 g of this product are mixed with 200 ml of an equimolar mixture of diphenyl and diphenyl ether and the mixture is stirred at reflux for 90 minutes and partially cooled. .

The resulting suspension is diluted with n-hexane, the yellow-brown solid is collected and combined with 0.95 g of product prepared in another test by the same procedure, and recrystallized from methanol (final volume 100 ml) the solids together and dried at 90 ° C in a vacuum oven for more than 60 hours, to obtain 4.26 g of 1,3-dihydro-3- (as light brown prisms) 2-hydroxyethyl) -6- (4-pyridinyl) -2H-imidazo [4,5-b] pyridine-2-one, pf 283-284 ° C. Then the product is dissolved in 150 ml of dimethylformamide and the solution is treated with a slight * 22 excess of hydrochloric acid in ethanol, the mixture is diluted with ether, the resulting solid is collected, it is dried in an oven under vacuum at 85 ° C. for more than 60 hours and 4.44 g of 1,3-dihydro-3- (2-hydroxyethyl monohydrochloride hemihydrate) are obtained in the form of a yellow-brown solid ) -6- (4-pyridinyl) -2H-imidazo- [4,5-b] pyridine-2-one, pf 297-299 ° C with decomposition.

G-5. 1,3-Dihydro-3- (2-dimethylaminoethyl) -6- (4-pyridinyl) -2H-iroidazo [4,5-b] pyridine-2-one 10 Stir in a water bath at 35-40 ° C for more than two hours then at 70-75 ° C for more than two hours a mixture containing 6.67 g of 3-amino-2- (2-dimethylaminoethyl-amino) -5- (4-pyridinyl) pyridine, 6, 30 g of carbonyldiimidazole and 150 ml of dimethylformamide. To the reaction mixture is added 10 ml of water and the solvents are distilled in vacuo. The residual brown oil is crystallized from acetonitrile (final volume of 50 ml) and dried in an oven under vacuum at 83 ° C for 16 hours, which gives 6.41 g of product. The product is recrystallized a second time from acetonitrile 20 (final volume of 125 ml) and dried as above, which gives 5.72 g of a white solid, 1,3-dihydro-3- (2-dimethylaminoethyl ) -6- (4-pyridinyl) -2H-imidazo [4,5-b] pyridine-2-one, pf 182-184 ° C in the form of the free base and 220.5-222 ° C in the form of its dihydrochloride.

25 G-6. 1,3-Dihydro-3- (3-dimethylaminopropyl) -6- (4-pyridinyl) -2H-imidazo [4,5-b] pyridine-2-one

7.53 g of this product are obtained, m.p. 188-191 ° C, following the procedure described in Example G-5 and using 14.72 g of 3-amino-2- (3-dimethylaminopropyl-30 amino) -5- (4-pyridinyl) pyridine , 13.13 g of carbonyldiimidazole and 300 ml of dimethylformamide.

G-7. 1,3-Dihydro-3- [2- (4-morpholinyl) ethyl] -6- (4-pyridinyl) -2H-iroidazo [4,5-b] pyridine-2-one

A mixture containing 15.11 g of 3-amino-2- [2- (4-morpholinyl) ethylamino] - 5- (4-pyridinyl) pyridine, 12.28 is stirred at 35 ° C. for more than one hour. g of carbonyldiimidazole and 300 ml of dimethylformamide and then stirred at room temperature for 16 hours. The resulting suspension is stirred> 23 * while heating at 75 ° C for more than 75 minutes. To the cooled solution, another 8.11 g portion of carbonyldiimidazole is added and the resulting mixture is stirred at about 35 ° C for two and a half hours, heated to about 75 ° C for 45 minutes and added to the mixture 15 ml of water. The water and dimethylformamide are distilled under vacuum and the resulting oily material is washed with n-hexane, which causes crystallization. Then the crystalline material is recrystallized from 160 ml of 10 aceto-nitrile and dried at 90 ° C. in an oven under vacuum for 18 hours, which gives 11.55 g of 1,3-dihydro-3- [2- (4-morpholinyl) ethyl] -6- (4-pyridinyl) -2H-imidazo [4,5-b] pyridine-2-one, pf 186-190 ° C.

G-8. 1,3-Dihydro-1-methyl-6- (4-pyridinyl) -2H-imidazo [4, 5-b] pyridine-2-one

Stirred at room temperature for 90 minutes, without any apparent reaction taking place, a mixture containing 4 g of 2-amino-3-methylamino-5- (4-pyridinyl) -pyridine, 3.25 g of carbonyldiimidazole and 100 ml of dimethyl-20 formamide. The reaction mixture is then heated by stirring on a steam bath for 4 hours and is left to stand overnight at room temperature. The solvent is distilled in vacuo and the residual solid is treated with water, collected by filtration, washed with water and dried. The solid is dissolved in 6N hydrochloric acid and the excess aqueous acid is distilled under vacuum. The remaining residue is recrystallized twice from methanol using bleaching charcoal, washed successively with ethanol and ether and dried in vacuo at 70 ° C. The hydrochloride resulting from the product is dissolved in water, the aqueous solution is basified slightly with 10% aqueous potassium bicarbonate and the mixture is cooled. The solid was collected, washed with water and dried in vacuo at 70 ° C, recrystallized from 50% ethanolic acetonitrile and the mixture cooled overnight in ice. The solid is collected, washed with ether and dried in vacuo at 70 ° C., which gives 2 g of 1,3-dihydro-1-4 methyl-6- (4-pyridinyl) - 2H-imidazo [4,5-b] pyridine-2-one, pf 195-198 ° C.

Following the procedure described in Example G-2 but using instead of 3-amino-2-methylamino-5 5- (4-pyridinyl) pyridine an equimolar amount of 3-amino ^ -R ^ NH-S-PY-ô-Q-pyridine suitable, we see that we can obtain 1,3-dihydro-3-R3-6-PY-5-Q-2H-imidazo [4,5-b] -pyridine-2-ones of Examples G-9 to G-26.

G-9. 1,3-Dihydro-3-n-propyl-6- (3-pyridinyl) - 2H-imidazo [4,5-b] pyridine-2-one.

/ G-10. 1,3-Dihydro-3-isopropyl-6- (2-methyl-5-pyridinyl) -2H-imidazo [4,5-b] pyridine-2-one.

G-ll. 3-n-Butyl-1,3-dihydro-6- (5-methyl-3-pyridinyl) -2H-imidazo [4,5-b] pyridine-2-one.

15 G-12. 3-n-Amyl-1,3-dihydro-6- (4-pyridinyl) -2H- imidazo [4,5-b] pyridine-2-one.

G-13. 1,3-Dihydro-3-n-hexyl-6- (3-pyridinyl) -2H-imidazo [4,5-b] pyridine-2-one.

G-14. 1,3-Dihydro-5-methyl-6- (4-pyridinyl) -2H-20 imidazo [4,5-b] pyridine-2-one.

G-15. 1,3-Dihydro-5-n-propyl-6- (4-pyridinyl) -2H- imidazo [4,5-b] pyridine-2-one.

G-16. 1,3-Dihydro-5-isopropyl-6- (4-pyridinyl) -2H-imidazo [4,5-b] pyridine-2-one.

25 G-17. 1,3-Dihydro-5-n-butyl-6- (4-pyridinyl) -2H- v imidazo [4,5-b] pyridine-2-one. ..

G-18. 1,3-Dihydro-5-isobutyl-6- (4-pyridinyl) -2H-imidazo [4,5-b] pyridine-2-one.

G-19. 1,3-Dihydro-6- (4-pyridinyl) -5-t-butyl-2H-30 imidazoC4,5-b] pyridine-2-one.

G-20. 1,3-Dihydro-5-n-pentyl-6- (4-pyridinyl) -2H-imidazo f 4,5-b] pyridine-2-one.

G-21. 1,3-Dihydro-3- (2-ethoxyethyl) -5-ethyl-6- (2-methyl-4-pyridinyl) -2H-imidazo [4,5-b] pyridine-2-one.

35 G-22. 5-Ethyl-1,3-dihydro-3- (2-methoxyethyl) -6- (3-pyridinyl) -2H-imidazot4,5-b] pyridine-2-one.

G-23. 1,3-Dihydro-3- (3-methoxypropyl) -6- (4-pyridinyl) -2H-imidazo [4,5-b] pyridine-2-one.

, * 25 ft G-24. 1,3-Dihydro-3- (2-hydroxyethyl) -5-methyl- 6- (4-pyridinyl) -2H-imidazo [4,5-b] pyridine-2-one.

G-25. 1,3-Dihydro-3 “(3-hydroxypropyl) -6- (4-pyridinyl) -2H-imidazo [4,5-b] pyridine-2-one, m.p. 235-238 ° C.

5 G-26. 1,3-Dihydro-3- (2,3-dihydroxypropyl) -6- (4-pyridinyl) -2H-imidazo [4,5-b] pyridine-2-one.

Following the procedure described in Example G-8 but using instead of 2-amino-3-methylamino-, 5- (4-pyridinyl) pyridine an equimolar amount of 2- 10 amino-3- R ^ -NH-5-PY-6-Q-pyridine suitable / we see that we can obtain the 1,3-dihydro-l-R1-6-PY-5-Q-2H-imidazo [4,5 -b] -pyridine-2-ones from Examples G-27 to G-40.

G-27. 1-Ethyl-1/3-dihydro-6- (4-pyridinyl) -2H-imidazo [4,5-b] pyridine-2-one.

15 G-28. 1,3-Dihydro-1-n-propyl-6- (4-pyridinyl) -2H- imidazo [4,5-b] pyridine-2-one.

G-29. 1,3-Dihydro-1-isopropyl-6- (4-pyridinyl) - 2H-imidazo [4,5-b] pyridine-2-one.

G-30. 1-n-Butyl-1,3-dihydro-6- (4-pyridinyl) -2H-20 imidazo [4,5-b] pyridine-2-one.

G-31. 1,3-Dihydro-1- (2-hydroxyethyl) -6- (4-pyridinyl) -2H-imidazo [4,5-b] pyridine-2-one.

G-32. 1,3-Dihydro-1- (2,3-dihydroxypropyl) -6- (4-pyridinyl) -21-I-imidazo |. 4,5-b Jpyridine-2-one.

25 G-33. 1,3-Dihydro-1- (3-methoxypropyl) -6- (4-pyridinyl) -2H-imidazo [4,5-b] pyridine-2-one. ·· G-34. 1/3-Dihydro-1- (2-ethoxyethyl) -6- (4-pyridinyl) -2H-imidazo [4,5-b] pyridine-2-one.

G-35. 1,3-Dihydro-1- (2-dimethylaminoethyl) -6- (4-pyridinyl) -2H-imidazo [4,5-b] pyridine-2-one.

G-36. 1,3-Dihydro-1- (3-diethylaminopropyl) -6- (4-pyridinyl) -2H-imidazo [4,5-b] pyridine-2-one.

G-37. 1,3-Dihydro-1- [2- (4-morpho-linyl) ethyl] -6- (4-pyridinyl) -2H-imidazot4,5-b] pyridine-2-one.

35 G-38. 1/3-Dihydro-3- (2-methoxyethyl) -6- (4-pyridinyl) -2H-imidazo [4,5-b] pyridine-2-one, m.p. 203-206 ° C.

G-39. 1,3-Dihydro-3- (4-hydroxybutyl) -6- (4-pyridinyl) -2H-imidazo [4,5-b] pyridine-2-one, m.p. 222-223 ° C.

5 26 G-40. 1,3-Dihydro-3- (2-hydroxypropyl) -6- (4-pyridinyl) -2H-imidazo [4,5-b] pyridine-2-one, m.p. 300-305 ° C in the form of the hydrochloride hemihydrate.

H. 1,3-DIHYDRO-l-R1-3-R3-6-PY-5-Q-2H-IMIDAZO-

5 [4,5-b] PYRIDINE-3-THIONES

H-l. 1,3-Dihydro-6- (4-pyridinyl) -2H-imidazo [4, 5-b] pyridine-2-thione To a mixture containing 18 g of 2,3-diamino-5- (4-pyridinyl) dihydrochloride ) pyridine, 180 ml of ethanol and 80 ml of water, 25 ml of a 2N "aqueous solution of potassium hydroxide are added and to this mixture is added 18 g of potassium ethylxanthate. the resulting reaction mixture at reflux for 5 hours then cooled, the excess solvents are distilled and the residue is dissolved in water, the aqueous solution is neutralized with acetic acid, the precipitate is collected resulting and dried under vacuum at 70 ° C. This product is combined with another portion of 1 g obtained in a test on a smaller scale and the combined material is dissolved in 6N hydrochloric acid and the acid solution with methanol, before cooling the resulting mixture, the solid which separates is collected, washed with methanol and dried under vacuum at 70 ° C. This solid is recrystallized from both in 50% aqueous methanol, the second time using bleaching charcoal, washed successively with methanol and ether and dried under vacuum at 70 ° C to give 7.5 g 1,3-dihydro-6- (4-pyridinyl) -2H-imidazo [4,5-b] pyridine-2-thione hydrochloride, pf > 300 ° C.

H-2. 1,3-Dihydro-3-methyl-6- (4-pyridinyl) -2H- imidazo [4,5-b] pyridine-2-thione

A mixture containing 10 g of 3-amino-2-methylamino-5- (4-pyridinyl) -pyridine, 13 g of potassium ethyl xanthate, 100 ml of ethanol and 50 ml of water is heated at reflux for 12 hours. then allowed to stand overnight at room temperature. An additional 13 g of potassium ethyl xanthate is added and reflux is continued for an additional 14 hours. The solvent and the excess of reagents are distilled under vacuum and the residue is dissolved in water *! 27 "and the aqueous solution is neutralized with acetic acid. The resulting solid is collected, recrystallized twice from dimethylformamide, washed successively with ethanol and ether and dried in vacuo at 70 ° C. The partially hydrated product is dissolved in a 1N aqueous solution of potassium hydroxide and the mixture is filtered through diatomaceous earth.

The filtrate is neutralized with acetic acid, the solid is collected, washed with water and dried in a vacuum oven at 80 ° C for the weekend (three days) which gives 8.5 g of 1,3-dihydro-3-methyl-6- (4-pyridinyl) -2H-imidazo [4,5-b] pyridine-2-thione hydrate (3: 1), mp > 300 ° C.

In the following test, the same compound is obtained in the form of its hemihydrate: the mixture is heated to reflux while stirring overnight (approximately 15 hours) a mixture containing 58.2 g of 3-amino-2-methylamino-5- (4-pyridinyl) -pyridine, 93.2 g of potassium ethyl xanthate, 580 ml of ethanol and 200 ml of water. An additional 90 g of potassium ethyl xanthate is added and the reaction mixture is heated to reflux with stirring for an additional 15 hours and then concentrated to dryness. The residue is dissolved in water and the aqueous solution is neutralized with acetic acid. The solid is collected, washed with water, recrystallized twice from dimethylformamide, dried in a vacuum oven at 60 ° C overnight and 50 g of a yellow powder. The yellow powder is diluted with 400 ml of water and the aqueous mixture is made alkaline with a 35% aqueous solution of sodium hydroxide. The resulting solution is acidified with acetic acid, the precipitate is collected, washed with water and dried in a vacuum oven at 60 ° G overnight and obtained in the form of '' a pale yellow powder, 47 g of 1,3-dihydro-3-methyl-6- (4-pyridinyl) -2H-imidazo-35 [4,5-b] pyridine-2-thione hemihydrate, mp > 300 ° C.

Following the procedure described in Example H-2 but using instead of 3-amino-2-methylamino- 5- (4-pyridinyl) pyridine an equimolar amount of 2-R3NH- 1 * 28 • 3-R-jNH-5-Py-6-Q-pyridine corresponding, we see that we can obtain the 1, S-dihydro-lR ^ -SR ^ -ô-PY-SQ- ^ H-imidazo [4 , 5-b] -pyridine-3-thiones of Examples H-3 to H-11.

H-3. 1,3-Dihydro-1-methyl-6- (4-pyridinyl) -2H-5 imidazo [4,5-b] pyridine-2-thione.

H-4. 1-Ethyl-1,3-dihydro-6- (4-pyridinyl) -2H-imidazo [4,5-b] pyridine-2-thione.

H-5. 3-Ethyl-1,3-dihydro-6- (4-pyridinyl) -2H-imidazo [4,5-b] pyridine-2-thione.

10 H-6. 1,3-Dihydro-3- (2-hydroxyethyl) - (4-pyridinyl) -2H-imidazo [4,5-b] pyridine-2-thione.

H-7. 1, 3-Dihydro-1- (2-hydroxyethyl) -6- (4-pyridinyl) - 2H-imidazo [4,5-b] pyridine-2-thione.

H-8. 1,3-Dihydro-3- (2,3-dihydroxypropyl) -6- (4-pyridinyl) -2H-imidazo [4,5-b] pyridine-2-thione.

H-9. 1,3-Dihydro-3- (2-methoxyethyl) -6- (4-pyridinyl) -2H-imidazo [4,5-b] pyridine-2-thione.

H-10. 1,3-Dihydro-3,5-dimethyl-6- (4-pyridinyl) -2H-imidazo [4,5-b] pyridine-2-thione.

8:11 p.m. 1,3-Dihydro-3- (2-hydroxyethyl) -5-methyl-6- (4-pyridinyl) -2H-imidazo [4,5-b] pyridine-2-thione.

The usefulness of the compounds of formula I or their salts as cardiotonic agents is demonstrated by their effectiveness in standard pharmacological test procedures, for example in that they cause a significant increase in the force of contraction of the atria and Papillary muscles isolated from cat and / or in that they cause a significant increase in the force of cardiac contraction in the anesthetized dog, with small or minimal changes in heart speed and blood pressure. Detailed descriptions of these test procedures can be found in the U.S. Patent. N ° 4.072.746.

When tested by the above procedure on cat atria and papillary muscles, it is found that the compounds of formula I or their acid addition salts, in doses of 1, 3, 10, 30, 100 and / or 300 pg / ml, cause significant increases, that is to say greater than 25 I, in the strength of the papillary muscles and significant increases, that is to say greater than 25 I, in the strength of the right atrium, while causing a lower percentage increase 5 (about a third or less of the percentage increase in the strength of the right atrium or the strength of the papillary muscle) in the speed of l right atrium. For example, when tested at the doses indicated by this procedure, the following preferred compounds of Formula I where Q 'is PY are found to give 70% and more increases in papillary muscle strength and / or the strength of the right atrium: compounds of Examples Gl, G-2, G-3, G-4, G-5, G-7, G-8, G-40, Hl and H-2.

When tested by the procedure on the anesthetized dog, it is found that the compounds of formula I where Q 'is PY or their pharmaceutically acceptable acid addition salts, in doses of 0.1, 0.3 , 1.0, 3.0 and / or 10 mg / kg administered intravenously, cause significant increases, i.e. 25% or more, in the force of cardiac contraction or cardiac contractility, with lower changes in heart speed and blood pressure. For example, when tested at these doses by this procedure, the following preferred compounds are found to cause increases in.

25 70% or more of the contraction force and lower changes in heart rate and blood prassion: ~ compounds of Examples Gl, G-2, G-3, G-4, G-5, Hl and H -2.

When tested orally in non-anesthetized dogs at doses of 1.0, 3.0 and 10.0 mg / kg, the compound of Example G-4 is found to cause increases in cardiac contraction force of 30, 54 and 104% respectively, while causing corresponding increases in heart speed of 9, 19 and 31% and changes in diastolic blood pressure of 35 + 4%, - 6% and - 1% respectively.

When tested by the procedure on atria and papillary muscles isolated from cats, we find that the compounds of formula I where Q is PY or their salts, at 30 / - '*.

doses of 10 and 30 yg / ml cause a significant increase, that is to say greater than 25%, of the strength of the papillary muscle and a significant increase, that is to say greater than 25%, of the force of the right atrium 5, while causing a lower percentage increase (about one-third or less of the percentage increase of the force of the right atrium or the force of the papillary muscle) in the speed of the right atrium. For example, when tested at 10 and 30 yg / ml per 1 10 this procedure, it is found that 1,3-dihydro-5- (4- 'pyridinyl) -2H-imidazo [4,5-b ] pyridine-2-one gives percentages of increase in papillary muscle strength, right atrium strength and right atrium speed of 45%, 65% and 14%; and 66%, 153% and 15 26% respectively. Similarly, when tested at 3, 10 and 30 yg / ml by this procedure, we find that 1,3-dihydro-5- (4-pyridinyl) -2H-imidazo [4,5-b] pyridine-2-thione causes respective increases in the strength of the papillary muscle, the strength of the right atrium and the speed of the right atrium of: 27%, 16% and 0%; 66%, 40% and 16%; and 174%, 73% and 29%.

When tested by other conventional pharmacological testing procedures, it is found that certain compounds of formula I where Q 'is PY and their salts have antihypertensive and / or bronchodilator activities. For example, the compounds of Examples G-1 and G-2 * were found to have oral AHD ^ q values of 40 and 30 mg / kg * · when tested in spontaneous hypertensive rats; similarly, the compounds of Examples G-4 and G-5 are found to have weak anti-hypertension activities (AHD ^ g of 50 mg / kg orally) when tested by this procedure. When tested orally at 100 mg / kg, the compounds of Examples Gl, G-2 and G-3 are found to have bronchodilator activity in that they inhibit histamine-induced bronchoconstriction. acetylcholine or immunocomplex in guinea pigs.

The cardiotonic composition intended to increase the cardiac contractility comprises a pharmaceutically acceptable carrier and, as active principle, the cardiotonic compound of formula I or one of its pharmaceutically acceptable acid addition salts. Cardiac contractility can be increased in a patient in need of such treatment by administering to that patient an effective amount of a cardiotonic compound of formula I or a pharmaceutically acceptable acid addition salt thereof. In clinical practice, the compound or its salt will normally be administered orally or parenterally in a wide variety of dosage forms.

Solid compositions for oral administration include tablets, pills, powders and granules. In such solid compositions, at least one of the active compounds is mixed with at least one inert diluent such as starch, calcium carbonate, sucrose or lactose. These compositions can also contain additional substances other than inert diluents, for example lubricants, such as magnesium stearate, talc, etc.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art, such as water and liquid paraffin. Besides the inert diluents, such compositions may also contain adjuvants, such as wetting agents and suspending agents, and sweetening, flavoring, flavoring and preserving agents. According to the invention, the compositions for oral administration also include capsules of absorbable material, such as gelatin, containing the active compound with or without the addition of diluents or excipients.

The preparations according to the invention intended for parenteral administration include sterile aqueous, aqueous-organic and organic solutions, suspensions and emulsions. Examples of organic solvents or suspending media are propylene glycol, polyethylene glycol, vegetable oils 32%, such as olive oil, and injectable organic esters such as ethyl oleate. These compositions may also contain adjuvants such as stabilizers, preservatives, wetting agents, emulsifying agents and dispersing agents.

They can be sterilized, for example by filtration on a filter retaining the bacteria, by incorporation of sterilizing agents in the compositions, by irradiation or by heating. They can also be produced in the form of sterile solid compositions which can be dissolved in sterile water or in any other sterile injectable medium, immediately before their use.

The percentages of active compound in said composition intended to increase cardiac contractility can vary so as to allow an appropriate dose to be obtained. The dose administered to a particular patient varies according to the judgment of the physician using as criteria the route of administration, the duration of treatment, the size and condition of the patient, the potency of the active compound and the reaction of the patient. An effective dose of active compound can therefore only be determined by the doctor by considering all these criteria and by using his best judgment on the behavior of the patient.

* · · ·.

Claims (11)

4 1 * jr H 33 1. Compound of formula IQ '' T Ί- · Γ “ι 5 is A 3 2i R3 where Z is 0 or S, Q1 is PY and Q is a hydrogen atom or 10 a lower alkyl group or Q is PY and Q 'is a hydrogen atom, and R ^ are each a hydrogen atom or a lower alkyl, lower hydroxyalkyl, 2,3-dihydroxypropyl, lower alkoxyalkyl or Y-NB group where Y is a lower alkylene group having at least two carbon atoms between its connecting bonds and NB is a di- (lower alkyl) amino or 4-morpholinyl group, at least one of R3 and R3 being a hydrogen atom but, in case Q is PY, is only a hydrogen atom, and PY is a 4- or 3-pyridinyl or 4- or 3-20 pyridinyl group having one or two lower alkyl substituents, or one of its acid addition salts. 2. Compound according to claim 1, characterized in that Q 'is PY and Q is a hydrogen atom or a methyl or ethyl group. 3. Compound according to claim 2, characterized in that R ^ is a hydrogen atom when R ^ .is a - = methyl, ethyl or 2-hydroxyethyl group. ' 4. Compound according to claim 2, characterized in that Rx is a hydrogen atom when R3 is a methyl, ethyl or 2-hydroxyethyl group. 5. Compound according to claim 2, characterized in that R3 is a hydrogen atom, R3 is a 2-hydroxyethyl group, PY is a 4-pyridinyl group and Q is a hydrogen atom or a methyl or ethyl group. 6. 6,3-Dihydro-3- (2-hydroxyethyl) -6- (4-pyridinyl) - 2H-imidazo [4,5-b] pyridine-2-one or one of its addition salts pharmaceutically acceptable acids. 7. A compound according to claim 1, in which Q is PY 34 and is a hydrogen atom or a methyl, ethyl or 2-hydroxyethyl group. 8. A method of preparing a compound according to claim 1, characterized in that a 2- 5 R-jNH-SR ^ NH-S-Q'-6-Q-pyridine with urea or carbonyl-diimidazole to obtain the compound of formula I where Z is 0, or with an alkali metal xanthate, thiourea or thiocarbonyldiimidazole to obtain the compound of formula I where Z is S and, if desired, the free base obtained is converted into one of its acid addition salts. 9. Cardiotonic composition intended to increase the cardiac contractility, characterized in that it comprises an inert carrier which is acceptable from a pharmaceutical point of view and, as active principle, an effective amount of a cardiotonic compound according to any one of claims 1 to 6. 10. A compound according to any one of claims 1 to 6, used to increase the cardiac contractility in a patient in need of such treatment. ”· ♦