GB2072187A

GB2072187A - ImidazoÄ4,5-bÜpyridine Derivatives Useful as Cardiotonics and Preparation

Info

Publication number: GB2072187A
Application number: GB8109250A
Authority: GB
Original assignee: Sterling Drug Inc
Current assignee: STWB Inc
Priority date: 1980-03-24
Filing date: 1981-03-24
Publication date: 1981-09-30
Also published as: ES500605A0; IT8120658A0; LU83251A1; NO810989L; SE8101841L; IL62402A0; AU6868381A; ES8202006A1; IT1167724B; FI810878L; DK130381A; FR2478637A1; PT72710B; PT72710A; NL8101454A; DE3111563A1; FI810878A7

Abstract

ImidazoÄ4,5-bÜpyridin-2-ones or -2-thiones or acid-addition salts thereof, which are useful as cardiotonic agents have the Formula I where Z is O or S, Q% is PY and Q is hydrogen or lower-alkyl or Q is PY and Q% is hydrogen, R1 and R3 each are hydrogen, lower-alkyl, lower- hydroxyalkyl, 2,3-dihydroxypropyl, lower-alkoxyalkyl or Y-NB where Y is lower-alkylene having at least two carbon atoms between its connecting linkages and NB is di-(lower- alkyl)amino or 4-morpholinyl, at least one of R1 and R3 being hydrogen, but in the event that Q is PY, R1 is only hydrogen, and PY is 4- or 3-pyridinyl or 4- or 3-pyridinyl having one or two lower-alkyl substituents. They are prepared by reacting 2-R3NH-3-R1NH- 5-Q%-6-Q-pyridine with urea or carbonyldiimidazole to produce the compound where Z is O or with an alkali metal xanthate, thiourea or thiocarbonyldiimidazole to produce the compound where Z is S.

Description

SPECIFICATION Imidazo [4,5-b]Pyridine Derivatives Useful as Cardiotonics and Preparation This invention relates to imidazo[4,5-b]pyridine derivatives, their preparation and their use as cardiotonics.

Baldwin et al [J. Med. Chem. 20, 1189-1193 (1977)] prepared 2-(3-pyridinyl)-1 H-imidazo[4,5b]pyridine and 2-(4-pyridinyl)-1 H-imidazo[4,5-b]pyridine by heating respectively, a mixture of 2,3diaminopyridine and nicotinic acid or a mixture of 2,3-diaminopyridine and nicotinic acid or a mixture of 2,3-diaminopyridine and isonicotinic acid. Both of these compounds were found by Baldwin et alto be inactive when tested as inhibitors of xanthine oxidase. U.K. Patent 1,322,318 and U.S. Patents 3,838,156 and 4,072,746 disclose related chemical intermediates.

The invention relates to a 1,3-dihydro-1-R,-3-R3-6-Q'-5-Q-2H-imidazo[4,5-b]pyridin-2-one or 2-thione having Formula I

where Z is O or S, Q' is PY and Q is hydrogen or lower-alkyl or Q is PY and Q' is hydrogen, R1 and R3 each are hydrogen, lower-alkyl, lower-hydroxyalkyl, 2,3-dihydroxypropyl, lower-alkoxyalkyl or Y-NB where Y is lower-alkylene having at least two carbon atoms between its connecting linkages and NB is di-(lower-alkyl)amino or 4-morpholinyl, at least one of R, or R3 being hydrogen but in the event the Q is PY, R1 is, only hydrogen, and PY is 4- or 3-pyridinyl or 4- or 3-pyridinyl having one or two lower-alkyl substituents, or an acid-addition salt thereof.The compounds of Formula I are useful as cardiotonic agents, as determined by standard pharmacological evaluation procedures. Preferred embodiments are those of Formula I where 0' is PY, PY is 4-pyridinyl or 3-pyridinyl, Z is 0, R1 is hydrogen when R3 is methyl, ethyl or 2-hydroxyethyl, and R3 is hydrogen when R, is methyl, ethyl or 2-hydroxyethyl, and Q is hydrogen, methyl or ethyl. Particularly preferred embodiments where 0' is PY are the compounds of Formula IA where Z is O, R1 is hydrogen, R3 is 2-hydroxyethyl, PY is 4-pyridinyl and 0 is hydrogen, methyl or ethyl. Preferred embodiments when 0 is PY are where PY is 4-pyridinyl or 3-pyridinyl, Z is, O or S and R3 is hydrogen, methyl, ethyl or 2-hydroxyethyl.

The compound of Formula I may exist in tautomeric forms, that is, when R1 is hydrogen as 1,3 dihydro-3-R3-6-Q'-5-Q-2 H-im idazo[4,5-b] pyridin-2-one or -2-thione of Formula I and/or 3-R3-6-Q'- 3 H-imidazo[4,5-b] pyridine-2-ol or -2-thiol of Formulattitiustratedasfollows

or when R3 is hydrogen as 1,3-dihydro-1-R,-6-Q'-5-Q-2H-imidazo[4,5-b]pyridin-2-one or -2-thione of Formula I and/or 1 -R,-6-Q'-5-Q-1 H-imidazo[4,5-b]pyridine-2-ol or 2-thiol of Formula IB, illustrated as follows

Structural preferences for other known imidazo[4,5-bjpyridin-2-ones or -2-thiones would indicate the above Formula I to be the preferred tautomeric structure; thus, we have preferred to use the names based on structure I, although it is understood that in either above instance where R, or R3 is hydrogen that either or both structures are comprehended herein.

A process for producing the 1,3-dihydro-1-R1-3-R3-6-Q'-5-Q-2H-imidazo[4,5-b]pyridin-2-one or -2-thione of Formula I comprises reacting 2-R3NH-3-R,NH-5-Q'-6-Q-pyridine (II) with urea or carbonyldiimidazole to produce the 2-one (I where Z is O) or with an alkali metal xanthate thiourea or thiocarbonyldiimidazole to produce the 2-thione (I where Z is S), where PY, Rr, R3, Z, Q' and Q have the meanings given above for the compound of Formula I.

Another aspect of the present invention resides in the novel 3-amino-2-R3NH-6-PY-pyridine (IIA: II, Q is PY) or acid-addition salt thereof, where R3 is hydrogen, lower-alkyl, lower-hydroxyalkyl, 2,3dihydroxypropyl, lower-alkaxyalkyl or Y-NB where Y is lower-alkylene having at least two carbon atoms between its connecting linkages and NB is di-(lower-alkyl)amino or 4-morpholinyl, and PY is 4or 3-pyridinyl or 4- or 3-pyridinyG having one or two lower-alkyl substituents. These compounds (IIA) are useful as intermediates in the preparation of the compounds having Formula I where Q is PY.

Preferred embodiments are those where PY is 4-pyridinyl or 3-pyridinyl, and R is hydrogen, methyl, ethyl or 2-hydroxyethyl.

The novel intermediate 2-R3NH-3-RrNH-5-PY-6-Q-pyridines (II) for preparing the compounds of Formula I where Q' is PY are disclosed and claimed in ourcopending Application Serial No.8109260 filed today, 24 March, 1981.

One can react 2-halo-3-nitro-6-0'-pyridine (X) with ammonia or an amine of the formula R3NH2 to produce 2-R3NH-3-nitro-6-PY-pyridine (Xl) and reduce the 3-nitro compound (XII) to produce 3 amino-2-P3NH-6-0'-pyridine (I IA) where halo is chloro or bromo, and R and PY are defined as hereinabove for the compounds of Formula I where Q is PY. Preferred embodiments of this process are those where halo is chloro and which produce the above-said preferred embodiments of 3-amino-2 R3HN- 6-PY-pyridine (I IA).

A cardiotonic composition for increasing cardiac contractility comprises a pharmaceuticallyacceptable carrier and, as the active component thereof, an effective amount of a cardiotonic 1,3 dihydro-1-R,-3-R3-6-Q'-s-Q-2H-imidazo[4,5-b]pyridin-2-one (I where Z is O) or 2-thione (i where Z is S) of Formula I, where Z, R1, R3, PY, 8' and Q are each defined as in formula I, or pharmaceuticallyacceptable acid-addition salt thereof. Preferred embodiments are those having as active components the above-said preferred embodiments of Formula i.

A method for increasing cardiac contractility in a patient requiring such treatment comprises administering orally or parenterally in a solid or liquid dosage form to such patient an effective amount of a cardiotonic 1,3-dihydro-1-R,-3-R3-6-Q'-5-a-2H-imidazo[4,5-b]pyridin-2-one (I where Z isO) or 2-thione (I where Z is S) of Formula I where PY, P1, R3 and Z are defined as in Formula I, or pharmaceuticaliy-acceptable acid-addition salts thereof. Preferred embodiments of this method aspect are those using the preferred cardiotonics of Formula 1 noted above.

The term "lower-alkyl" as used herein, e.g., as one of the meanings for R1, R3 or O or as a substituent for PY in Formula I, means alkyl radicals having from 1 to 6 carbon atoms which can be arranged as straight or branched chains, illustrated by methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.butyl, tert.-butyl, isobutyl, n-amyl, n-hexyl, and the like.

Illustrative of PY in Formula I where PY is 4-, 3- or 2-pyridinyl having 1 or 2 lower-alkyl substituents are the following: 2-methyl-4-pyridinyl, 2-6-dimethyl-4-pyridinyl, 3-methyl-4-pyridinyl, 2- methyl-3-pyridinyl, 6-methyl-3-pyrid inyl (alternative!y named 2-methyl-5-pyridinyl), 2,3-dimethyl-4- pyridinyl. 2,6-dimethyl-4-pyridir?yl, 2-ethyl-4-pyridinyl, 2-isopropyl-4-pyridiriyl, 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, and the like.

The term "lower-hydroxyalkyl" as used herein e.g, for one of the meanings for R, or R3 in Formula I, means hydroxy-alkyl radicals having from two to six carbon atoms which can be arranged as straight or branched chains and at least two carbon atoms of which separate hydroxy and the 1-ring or 3-ring nitrogen atom of the imidazo[4,5b] pyridine ring. illustrated by 2-hydroxyethyl, 3-hydroxy-propyl, 2 hydroxypropyl, 4-hydroxybutyl, 3-hydrnxybutyl, 5-hydroxyamyl, 6-hydroxyhexyl and the like.

The term "lower-alkoxyaikyl'' as used herein, e.g., for one of the meanings for R, or R3 in Formula I, means alkoxyalkyl radicals having from three to six carbon atoms which can be arranged as straight or branched chains and at least two carbon atoms of which separate the oxygen atom of alkoxyalkyl and the 1-ring or 3-ring nitrogen atom of the imidazo[4,5-bpyridine ring, illustrated by 2methoxyethyl, 2-ethoxyethyl, 3-methoxypropyl, 2-methoxypropyl, 2-methoxybutyl, 4-ethoxybutyl, 3- ethoxypropyl, 3-n-propoxypropyl, and the like.

The term lower-alkylene designated as Y as part of R, or R3 herein means lower-alkylene radicals having at least two carbon atoms between its connecting linkages and having from two to six carbon atoms which can be arranged as branched or straight chains, illustrated by

and the like.

The compounds of Formula I are useful both in the free base form and in the form of acid-addition salts, and, both forms are within the purview of the invention. The acid-addition salts are simply a more convenient form for use; and in practice, use of the salt form inherently amounts to use of the base form. The acids which can be used to prepare the acid-addition salts include preferably those which produce, when combined with the free base, pharmaceutically-acceptable salts, that is, salt whose anions are relatively innocuous to the animal organism in pharmaceutical doses of the salts, so that the beneficial cardiotonic properties inherent in the free base (I) are not vitiated by side effects ascribable to the anions.In practicing the invention, it is convenient to use the free base form or the hydrochloride salt: however, appropriate 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 organic acids such as acetic acid, citric acid, lactic acid, tartaric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, quinic acid, and the like, giving the hydrobromide, sulfate, phosphate, sulfamate, acetate, citrate, lactate, ta rtrate, methanesulfonate, ethanesulfonate, benzenesulfonate, cyclohexylsulfamate and quinate, respectively.

The acid-addition salts of said basic compound (I) are prepared either by dissolving the free base in aqueous or aqueous-alcohol solution or other suitable solvents containing the appropriate acid and isolating the salt by evaporating the solution, or by reacting the free base and acid in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution.

Although pharmaceutically-acceptable salts of said basic compound (I) are preferred, all acidaddition salts are within the scope of our invention. All acid-addition salts are useful as sources of the free base form even if the particular salt per se is desired only as an intermediate product as for example when the salt is formed only for purposes of purification or identification, or when it is used as an intermediate in preparing a pharmaceutically-acceptable salt by ion exchange procedures.

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

The manner of making and using the instant invention will now be generally described so as to enable a person skilled in the art of pharmaceutical chemistry to make and use the same, as follows.

The preparation of 1 ,3-dihydro-1 -R1-3-R3-6-Q'-5-Q-2H-imidazo[4,5-b]pyridin-2-one (I, Z is O) by reacting 2-R3NH-3-R1NH-5-Q'-6-Q-pyridine (Il) with urea is conveniently and preferably carried out by heating the reactants in refluxing dimethylformamide. Alternatively, other suitable inert solvents can be used, e.g., dioxane, nitrobenzene, etc. The reaction using carbonyldiimidazole instead of urea is conveniently carried out in dimethylformamide at about 350C. for about one to three hours and then at about 700C. to 800C. for about two to sixteen hours. This preparation is illustrated further hereinbelow in Examples G-1 through G-37.

The preparation of 1,3-dihydro-1-R,-3-R3-6-Q'-5-Q-211-imidazo[4,5-b]pyridin-2-thione (I, Z, is S) is carried out by reacting 2-R3NH-3-R1NH-5-PY-6-Q-pyridine (II) with an alkali metal xanthate, thiourea or thiocarbonyldiimidazole. The reaction with an alkali metal xanthate or thiourea is carried out by heating the reactants in a suitable solvent at about 600C. to 1600C., preferably about 750C. to 850C. The reaction using an alkali metal xanthate, preferably the sodium or potassium salt, is conveniently run by refluxing the reactants in a mixture of water and a lower-alkanol, preferably aqueous ethanol. The reaction using thiourea is conveniently run by heating the reactants in refluxing dimethylformamide.The reaction using thiocarbonyldiimidazole is conveniently run at room temperature or up to about 40-600C. in dimethylformamide. This preparation is further illustrated hereinbelow in Examples H-1 through H-i 1.

Our above-mentioned application describes, int al., the process for preparing the compounds of Formula II where Q' is PY. The reaction of a 3-nitro-5-PY- 6-Q-2(1 H)-pyridinone or of a 5-PY-6-Q-2(1 H) pyridinone with an inorganic halogenating agent to produce a 2-halo-3-nitro-5PY-6-Q-pyridine (III) or 2-halo-5-PY-6-Q-pyridine (VII) is preferably carried out by refluxing the 2(1 H)-pyridinone with excess phosphorus oxychloride containing a catalytic amount of dimethylformamide to obtain the 2-chloro compound. Other suitable inorganic halogenating agents include PCI3, POBr3, PBr3, PAL5, and the like.

The reaction of the 2-halo compound (III or VII) with ammonia or an amine of the Formula R3RNH to obtain V or VIII respectively, is run by heating the reactants, preferably under pressure using ammonia or source thereof and monomethylamine and at atmospheric pressure using the other higher primary amines, R3NH2 or secondary amines, R3RNH. The reaction of Ill or VII with hydrazine is similarly run to obtain the corresponding 2-hydrazino derivatives, which are readily converted by reduction to the corresponding 2-amines. The reaction of V to obtain II where P1 is hydrogen is preferably carried out by catalytic hydrogenation of V using a suitable catalyst, e.g., 10% palladium-on-charcoal, Raney nickel, and the like.The reaction of VIII with a halogenating agent to produce the corresponding 3-halo compound (IX) is preferably carried out using bromine to obtain the 3-bromo compound or phenylphosphoric dichloride to obtain the 3-chloro compound. Optionally, the 3chloro compound (IX) can be obtained in two steps by first reacting 3-nitro-5-PY-6-Q-2(1 H)-pyridinone with phenylphosphoric dichloride to produce 2,3-dichloro-5-PY-6-Q-pyridine and then selectively reacting the latter at the more reactive 2-chloro with PPNH to produce IX. The reaction of IX with ammonia or an amine of the formula RXR'NH to produce II is carried out by heating the reactants as described above in the conversion of III to V or VII to VIII.

The preparation of the known 1 ,2-dihydro-2-oxo-5-PY-nicotinic acids by hydrolysis of the corresponding 1,2-dihydro-2-oxo-5-PY-nicotinonitrile is shown in U.S. Patent 4,004,012.

The hydrolysis of 1 ,2-dihydro-6-(lower-alkyl)-2.-oxo-5-PY-nicotinonitrile to produce 1,2-dihydro6-(lower-alkyl)-2-oxo-5-PY-nicotinic acid is conveniently run by heating the nitrile on a steam bath with an aqueous mineral acid, e.g., 50% sulfuric acid.

The preparation of 1-PY-2-(dimethylamino)ethenyl lower-alkyl ketone by reacting PY-methyl lower-alkyl ketone with dimethylformamide di-(lower-alkyl) acetal is carried out by mixing the reactants in the presence or absence of a suitable solvent. The reaction is conveniently run at room temperature, i.e., about 20-250C., or by warming the reactants up to about 1 000C., preferably in a aprotic solvent, conveniently hexamethylphosphoramide because of the method used to prepare the PY-methyl lower-alkyl ketone, as noted below in Example C-1. Other suitable solvents include tetrahydrofuran, dimethylformamide, acetonitrile, ether, benzene, dioxane, and the like. Also the reaction can be run using no solvent, preferably using an excess of dimethylformamide di-(loweralkyl)acetal.

The intermediate PY-methyl lower-alkyl ketones are generally known compounds which are prepared by known methods [e.g., as given in Rec. trav. chim 72, 522 (1953); U.S. Pat. 3,133,077 (5 12-64); Bull. Soc. Chim. France 1968,4132; Chem. Abstrs. 79, 8539h (1973); Chem. Abstrs. 81, 120,401 a (1974); J. Org. Chem. 39, 3834 (1974); Chem. Abstrs. 87, 6594q (1977); J. Org. Chem.

43,2286(1978)].

The reaction of 1-PY-2-(dimethylamino)ethenyl lower-alkyl ketone with a-cyanoacetamide to produce 1 ,2-dihydrn-2-oxo-5-PY-6-R-nicotinonitrile is carried out preferably by heating the reactants in a suitable solvent in the presence of a basic condensing agent. The reaction is conveniently run using an alkali lower-alkoxide, preferably sodium methoxide or ethoxide, in dimethylformamide. In practicing the invention, the reaction was carried out in refluxing dimethylformamide using sodium methoxide.

Alternatively, methanol and sodium methoxide or ethanol and sodium ethoxide can be used as solvent and basic condensing agent, respectively, however, a longer heating period is required. Other basic condensing agents and solvents include sodium hydride, lithium diethylamide, lithium diisopropylamide, and the like, in an aprotic solvent, e.g., tetrahydrofuran, acetonitrile, ethenyl, benzene dioxane, and the like.

The preparation of the intermediate 6-(lower-alkyl-3-nitro-5-PY-2(1 H)-pyridinones is carried out following the procedure described in Example C-1 of U.S. Patent 4,072,746 using in place of 1,2 dihydro-2-oxo-5-(4-pyrindinyl)nicotinic acid a molar equivalent quantity of the appropriate 1,2dihydro-2-oxo-5-PY-6-(lower-alkyl)nicotinic to produce instead of 3-nitro-5-(4-pyridinyl)-2-( 1 H)pyridinone the corresponding 6-(lower-a Ikyl)-3-nitro-5-PY-2-( 1 H)pyridinone.

The reaction of the 2-halo-3-nitro-6-PY-pyridine (X) with ammonia or an amine of the formula RNH2 to obtain 2-RNH-3-nitro-6-PY-pyridine (XI) is run by heating the reactants, preferably under pressure using ammonia or source thereof and monomethylamine and at atmospheric pressure using 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 carried out by catalytic hydrogenation of XI using a suitable catalyst, e.g., 1 0% palladiumon-charcoal, Raney nickel, and the like, in a suitable solvent. A preferred solvent was the combination of dimethylformamide and ethanol.

The preparation of the intermediate 2-halo-3-nitro-6-PY-pyridine (X) is conveniently carried out in two steps by first nitrating the known 6-PY-2(1H)-pyridine (XII) to produce 3-nitro-6-PY-2(1 H)pyridinone (XIII) and then reacting XIII with an inorganic halogenating agent, preferably by refluxing the 2(1 H)-pyridinone (XIII) with phosphorus oxychloride in dimethylformamide. This two step preparation of X is further illustrated hereinbelow in Examples A-i through A-8 and B-1 through B-9.

The following examples will further illustrate the invention without, however, limiting it thereto.

A. 3-Nitro-6-PY-2(1 H)-Pyridinones A-1. 3-Nitro-6-(4-pyridinyl)-2(1 H)-pyridinone-To a solution warmed to 780C. and containing 413 g. of 6-(4-pyridinyl)-2-(1 H)-pyridinone in 1600 ml. of concentrated sulfuric acid was added dropwise with stirring over a period of about three hours a mixture containing 320 ml. of 90% nitric acid and 1 60 ml. of concentrated sulfuric acid the addition of sulfuric acid was at such a rate as to keep the reaction temperature at about 75-900C. One hour after the sulfuric acid addition had been completed, the reaction temperature had dropped to 400C. and stirring was continued at this temperature for one hour. The reaction mixture was then poured into ice.To the mixture was added concentrated ammonium hydroxide to a pH of about 6, together with more ice. The mixture was then cooled in a refrigerator and allowed to stand overnight. The separated solid was collected, washed successively with water, a little ethanol and ether, and then dried in vacuo at 550C. overnight to yield 277 g. of 3-nitro-4-(pyridinyl)-2(1 H)-pyridinone, m.p. > 3000C.

Following the procedure described in Example A-i but using in place of 6-(4-pyridinyl)-2(1 H)pyridinone a molar equivalent quantity of the appropriate 6-PY-2(1 H)-pyridinone, it is contemplated that the corresponding 3-nitro-6-PY-2(1 H)-pyridinones of Examples A-2 through A--8 can be obtained.

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

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

A-4.6-(3-Methyl-4-pyridinyl)-3-nitro-2(1H)-pyridinone.

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

A-6.6-(3-Ethyl-4-pyridinyl)-3-nitro-2(1H)-pyridinone.

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

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

B. 2-Halo-3-Nitro-6-PY-Pyridines B-1.2-Chloro-3-nitro-6-(4-pyridinyl)pyridine-A mixture containing 277 g. of 3-nitro-6-(4pyridinyl)-2(1 H)-pyridinone, 4400 ml. of dimethylformamide and 470 ml. of phosphorus oxychloride was heated with stirring on a steam bath for about forty minutes, during which time dissolution resulted. The reaction mixture was allowed to cool and then was poured into 15 liters of a mixture of ice and water. The resulting clear solution was neutralized with concentrated ammonium hydroxide.

The solid that precipitated was collected, washed with water, air-dried, and then triturated with six three-liter portions of boiiing cyclohexane, recycling the solvent after collected by filtration the yellow crystalline product from each cooled extract. There was thus obtained 120 g. of 2-chloro-3-nitro-6-(4pyridinyl)pyridine, m.p. 107-1 i00C.

Following the procedure of Example B-i but using in place of phosphorus oxychloride a molar equivalent quantity of phosphorus oxybromide or phosphorus tribromide, it is contemplated that the corresponding 2-bromo compound of Example B-2 can be obtained.

B-2.2-Chloro-3-nitro-6-(4-pyridinyl)pyridine.

Following the procedure described in Example B-1 but using in place of 3-nitro-6-(4-pyridinyl)2(1 H)-pyridinone a molar equivalent quantity of the appropriate 3-nitro-6-PY-2(1 H)-pyridinone, it is contemplated that there can be obtained the corresponding 2-chloro-3-nitro-6-PY-pyridines of Examples B-3 through B-9.

B-3.2-Chloro-3-nitro-6-(3-pyridinyl)pyridine.

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

B-5.2-Chloro-6-(3-methyl-4-pyridinyl)-3-nitropyridine.

B-6. 2-Chloro-6-(2-ethyl-4-pyridinyl)-3-nitropyrid ine.

B-7. 2-Ch loro-6-(3-ethyl-4-pyridinyl)-3-nitropyridine.

B-8.2-Chloro-6-(2,6-dimethyl-4-pyridinyl)-3-nitropyridine.

B-9.2-Chloro-6-(3,5-dimethyl-4-pyridinyl)-3-nitropyridine.

C. 2-RNH-3-NO2-6-PY-Pyridines C-i. 2-Amino-3-nitro-6-(4-pyridinyl)pyridine-A mixture containing 120 g. of 2-chloro-3-nitro6-(4-pyridinyl)-pyridine, 900 ml. of 95% ethanol and 510 ml. of concentrated ammonium hydroxide was autoclaved at 600 C. for twenty hours. The reaction mixture was cooled and the separated solid was collected, washed successively with ethanol and ether, and dried to yield 102 g. of 2-amino-3 nitro-6-(4-pyridinyl)pyridine, m.p. 21 6-218 0C.

Following the procedure described in Example C-i but using in place of 2-chloro-3-nitro-6-(4pyridinyl)pyridine a molar equivalent quantity of 2-chloro-3-nitro-6-PY-pyridine, it is contemplated that there can be obtained the corresponding 2-amino-3-nitro-6-PY-pyridines of Examples C-2 through C-8.

C-2.2-Amino-3-nitro-6-(3-pyridinyl)pyridine.

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

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

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

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

C-7.2-Amino-6-(2,6-dimethyl-4-pyridinyl)-3-nitropyridine.

C-8.2-Amino-6-(3,5-dimethyl-4-pyridinyl)-3-nitropyridine.

Following the procedure described in Example C-i but using in place of ammonia a molar equivalent quantity of the appropriate amine of the formula RN H2, it is contemplated that there can be obtained the corresponding 2-RNH-3-nitro-6-(4-pyridinyl)pyridines of Examples C-9 through C-i 8.

C-9.2-Methylamino-3-nitro-6-(4-pyridinyl)-pyridine.

C-i 0. 2-Ethyl am ino-3-n itro-6-(4-pyridinyl)-pyridine.

C-11.2-Isopropylamino-3-nitro-6-(4-pyridinyl)-pyridine.

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

C-13.2-n-Hexylamino-3-nitro-6-(4-pyridinyl)-pyridine.

C-14.2-(2-Hydroxyethylamino)-3-nitro-6-(4-pyridinyl)pyridine.

C-15.2-(2,3-Dihydroxypropylamino)-3-nitro-6-(4-pyridinyl)pyridine.

C--l 6. 2-(2-Dimethylethylamino)-3-nitro-6-(4-pyridinyl)pyridine.

C--l 7. 2-(2-methoxyethylamino)-3-nitro-6-(4-pyridinyl)pyridine.

C-i 8. 2-[2-(4-Morpholinyl)ethylamino]-3-nitro- D. 3-Amino-2-RNH-6-PY-Pyridines D-1,2,3-Diamino-6-(4-pyridinyl)pyridine-A mixture containing 43.2 g. of 2-amino-3-nitro-6 (4-pyridinyl)pyridine, 360 ml. of dimethylformamide, 220 ml. of ethanol and 1 g. of 10% pailadium-oncharcoal was shaken in a Parr apparatus under catalytic hydrogenation conditions for about one hour.

The reaction mixture was filtered and the filtrate concentrated in vacuo to a volume of about 150 ml.

and cooled. The separated solid was collected and dried to produce 20 g. of 2,3-diamino-6-(4pyridinyl)pyridine which can be used directly in the next step without further purification. In another run, a sample was recrystallized from ethanol using decolorizing charcoal to produce the product, 2,3diamino-6-(4-pyridinyl)pyridine, melting at 252-2540C.

Following the procedure described in Example D-1 using in place of 2-amino-3-nitro-6-(4pyridinyl)pyridine a molar equivalent quantity of the appropriate 2-amino-3-nitro-6-PY-pyridine, it is contemplated that there can be obtained the corresponding 2,3-diamino-6-PY-pyridines of Examples D-2 through D-8.

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

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.

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-(3m5-dimethyl-4-pyridinyl)pyridine.

Following the procedure described in Example D-1 but using in place of 2-amino-3-nitro-6-(4pyridinyl)pyridine a molar equivaient quantity of the appropriate 2-RNH-3-nitro-6-PY-pyridine, it is contemplated that there can be obtained the corresponding 3-amino-2-RNH-6-(4-pyridinyl)pyridines of Examples D-9 through 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.

D-11.3-Amino-2-isopropylamino-6-(-4-pyridinyl)pyridine.

D-12.3-Amino-2-n-butylamino-6-(-4-pyridinyl)pyridine.

D-13.3-Amino-2-n-hexylamino-6-(-4-pyridinyl)pyridine.

D-14.3-Amino-2-(2-hydroxyethylamino)-6-(-4-pyridinyl)pyridine m.p. 208-210 C.

D-15.3-Amino-2-(2,3-dihydroxypropylamino)-6-(-4-pyridinyl)pyridine.

D-16.3-Amino-2-(2-dimethylaminoethylamino)-6-(-4-pyridinyl)pyridine.

D-17.3-Amino-2-(3-methoxyethylamino)-6-(-4-pyridinyl)pyridine.

D-18.3-Amino-2-[2-(4-morpholinyl)ethylamino)-6-(-4-pyridinyl)pyridine.

E. 1,3-Dihydro-3-R-5-PY-2H-Imidazo[4,5b]Pyridin-2-ones E-1.1,3-Dihydro-5-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one-To a warm (45 C.) solution of 11.2 g. of 2,3-diamino-6-[4-pyridinyl)pyridine in 100 ml. of dimethylformamide was added with stirring 10.5 g. of 1.1'-dicarbonyl-diimidazole. Solid began to separate within a few minutes. The reaction mixture was stirred with no external heating for about 40 minutes (temperature of 450C. with no change in appearance after the first ten minutes) and then heated to 80 C. (no change in appearance). The separated solid was collected, washed and triturated with ethanol and dried at 70 C.

in vacuo to yield 11.3 g. of 1,3-dihydro-5-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one, m.p. > 300 C.

Following the procedure described in Example E-1 but using in place of 2,3-diamino-6-(4pyridinyl)pyridine a molar equivalent quantity of the appropriate 2,3-diamino-6-PY-pyridine, it is contemplated that there can be obtained the corresponding 1,3-dihydro-5-PY2H-imidazo[4,5-b]pyridin 2-ones of Examples E-2 through E-8.

E-2.1,3-Dihydro-5-(3-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one.

E-3.1,3-Dihydro-5-(2-methyl--4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one.

E-4.1,3-Dihydro-5-(3-methyl-4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one.

E-5.1,3-Dihydro-5-(2-ethyl-4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one.

E-6.1,3-Dihydro-5-(3-ethyl-4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one.

E-7.1,3-Dihydro-5-(2,6-dimethyl-4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one.

E-8.1,3-Dihydro-5-(3,5-dimethyl-4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one.

Following the procedure described in Example E-1 but using in place of 2,3-diamino-6-(4- pyridinyl)pyridine a molar equivalent quantity of the appropriate 2-RNH-3-amino-6-(4pyridinyl)pyridine, it is contemplated that there can be obtained the corresponding 1,3-dihydro-3-R-5 (4-pyridinyl-2H-imidazo[4,5-b]pyridin-2-ones of Examples E-9 through E-18.

E-9.1,3-Dihydro-3-methyl-5-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one, m.p. 284-286 C. E-10.1,3-Ethyl-1,3-dihydro-5-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one.

E-11.1,3-Dihydro-3-isopropyl-5-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one.

E-12.1,3-n-Butyl-1,3-dihydro-5-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one.

E-13.1,3-n-Hexyl-1,3-dihydro-5-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one.

E-14.1,3-Dihydro-3-(2-hydroxyethyl)-5-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one.

m.p. > 300 C.

E-15.1,3-Dihydro-3-(2,3-dihydroxypropyl)-5-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one.

E-16.1,3-Dihydro-3-(2-dimethylaminoethyl)-5-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one.

E-17.1,3-Dihydro-3-(2-methoxyethyl)-5-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one.

E-i 8. 1 ,3-Dihydro-3-[2-(4-morpholinyl)ethylj-S(4-pyridinyl)-2H-imidazo[4,S-b]pyridin-2-one.

F. 1,3-Dihydro-3-R-5-PY-2H-1 midazo [4,5-b] Pyridine-2-Thiones F-1.1,3-Dihydro-5-(4-pyridinyl)-2H-imidazo[4,5-b]pyridine-2-thione-to-a warm (43 C.) solution containing 9.0 g. of 2,3-diamino-6-(4-pyridinyl)pyridine in 80 ml. of dimethylformamide was added with stirring 10.3 g. of 90% 1,1 '-thiocarbonyldiimidazole, whereupon the temperature rose to 630C. On allowing the reaction solution to cool to about 400C., a solid began to separate. The mixture was chilled and the separated solid collected, washed with ether, triturated with cold ethanol-ether washed again with ether and dried. The resulting solid was ground to a powder and boiled with ethanol to remove dimethylformamide. The solid was then collected and dried in vacuo at 1000C to yield 9.7 g.

of 1,3-dihydro-5-(4-pyridinyl)-2H-imidazo[4,5-b]pyridine-2-thione, m.p. > 300 C.

Following the procedure described in Example F-i but using in place of 2,3-diamino-6-(4pyridinyl)pyridine a molar equivalent quantity of the appropriate 2,3-diamino-6-PY-pyridine, it is contemplated that there can be obtained the 1,3-dihydro--5-PY-2H-imidazo[4,5-b] pyridine-2-thiones of Examples F-2 through F-8.

F-2.1,3-Dihydro-5-(2-methyl-4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-thione.

F-3.1,3-Dihydro-5-(3-methyl-4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-thione.

F-4.1,3-Dihydro-5-(2-ethyl-4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-thione.

F-5.1,3-Dihydro-5-(3-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-thione.

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

F-7.1,3-Dihydro-5-(2,6-dimethyl-4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-thione.

F-8.1,3-Dihydro-5-(3,5-dimethyl-4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-thione.

Following the procedure described in Example F-i but using in place of 2,3-diamino-6-(4pyridinyl)pyridine a molar equivalent quantity of the appropriate 3-amino-2-RNH-6-(4pyridinyl)pyridine, it is contemplated that there can be obtained the corresponding 1,3-dihydro-3-R-5 (4-pyridinyl)-2H-imidazo[4,5-b] pyridine-2-thiones of Examples F-9 through F-i 8.

F-9.1,3-Dihydro-3-methyl-5-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-thione.

F-i 0. 3-Ethyl-i ,3-d i hyd ro-5-(4-pyrid inyl)-2 H-i midazo[4,5-b] pyridine-2-thione.

F-i 1. 1 ,3-Dihydro-3-isopropyl-S- (4-pyridinyl)-2H-imidazo[4,S-bjpyridine-2-thione.

F-12.1,3-n-Butyl-1,3-dihydro-5-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-thione.

F-13.1,3-n-Hexyl-1,3-dihydro-5-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-thione.

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

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

F-16.1,3-Dihydro-3-(2-Dimethylaminoethyl)-5-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2 thione.

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

F-i 8. 1 ,3-Dihydro-3-[2-(4-morpholinyl)ethyl]-5-(4-pyridinyl)-2H-imidazo[4,5-b]pyridine-2- thione.

G. I -R,-3-R3-6-PY-5-Q-2H-I midazo[4,5-b] Pyridin=3-ones G-1.1,3-Dihydro-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one-A mixture containing 20 g.

of 2,3-diamino-5-(4-pyridinyl)pyridine dihydrochloride, 28 g. of urea and 200 ml. of dimethylformamide was refluxed for two hours and then allowed to stand at room temperature overnight. The reaction mixture was poured into a mixture of ice and water and the resulting solid was collected, washed with water and dried. The solid was dissolved in 200 ml. of hot 6N hydrochloric acid, the solution treated with decolorizing charcoal and filtered, and the filtrate poured into a rapidly stirred liter of ethanol. The resulting mixture was cooled. The separated solid was collected, washed successively with ethanol and ether, and then dried. The solid was then recrystallized from water using decolorizing charcoal, washed successively with ethanol and ether and dried in vacuo at 700C to yield 6.5 g. of 1,3-dihydro-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one hydrochloride, m.p. > 3000C.

G-2.1,3-Dihydro-3-methyl-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-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 was refluxed for two hours, cooled and then poured into a mixture of ice and water.

The separated solid was collected, washed with water and dried. THe solid was recrystallized twice from dimethylformamide, washed successively with ethanol and ether and dried in vacuo at 700C. to yield 5g. of 1,3-dihydro-3-methyl-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one, m.p. > 300 C.

G-3,3-Ethyl-1,3-dihydro-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one-A mixture containing 8.57 g. of 3-amino-2-ethylamino-5-(4-pyridinyl)pyridine,9.73 g. of carbonyldiimidazole and 200 ml. of dimethylformamide was stirred in a water bath at 35 C. for over ninety minutes, at room temperature overnight and then heated to 800C. for thirty minutes. To the mixture was added 1 5 ml. of water and the solution was treated with decolorizing charcoal and filtered. The filtrate was concentrated in vacuo to remove the liquid and the residue was recrystallized from acetonitrile (final volume of 140 ml.) and dried at 900 C. in a vacuum oven for sixteen hours to yield 5.15 g. of dark green solid. Another 2.56 g. of green solid had not dissolved in the acetonitrile.The 5.15 g. portion of green solid was recrystallized from ethyl acetate (350 ml.) and dried at 900C. in a vacuum oven for twenty hours to yield, as pale gree prisms, 4.01 g. of 3-ethyl-i ,3-dihydro-6-(4-pyridinyl)-2H-imidazo[4,S- b]pyridin-2-one, m.p. 244-2460C. Also the original 2.56 g. of insoluble green solid was recrystallized from ethyl acetate (150 ml.) and dried at 900C. in vacuo to yield another 1.5 g. of product. The 4.01 g.

and 1.51 g. portions of product were combined and dried in a vacuum oven at 1000C. for over sixty hours to yield 5.38 q. of said product m.p. 244--2460C.

G-4. 1 ,3-Dihydro-3-(2-hydroxyethyl)-6-(4-pyridinyl)-2 H-imidazo[4,S-bjpyridin-2-one-A mixture containing 9.04 g. of 3-amino-2-(2-hydroxyethylamino)-5-(4-pyridinyl)pyridine,14.61 g. of urea and 300 ml. of dimethylformamide was refluxed with stirring for over twenty hours and the dimethylformamide was distilled off in vacuo. The resulting residue was suspended in water and the solid was collected, recrystallized from isopropyl alcohol (final volume 600 ml.), and dried at 900C. in a vacuum oven for over sixteen hours to yield 7,84 g. of product and a second portion of 2.18 g. after concentrating the filtrate to a volume of 100 ml.The combined 7.84 g. and 2.18 g. portions of the product were combined and recrystallized from methanol (final volume of 250 ml.) and dried in a vacuum oven at 900C. for over sixteen hours to yield 6.54 g. of product. A 6.50 g. portion of this product was mixed with 200 ml. of an equimolar mixture of diphenyl and diphenyl ether and the mixture was stirred under reflux for ninety minutes and partially cooled.The resulting suspension was diluted with n-hexane and the tan solid was collected and combined with another 0.95 g. portion of the product prepared in another run by the same procedure and the combined solids were recrystallized from methanol (final volume of 100 ml.) and dried at 900C. in a vacuum oven for over sixty hours to yield, as Iightbrown prisms, 4.26 g. of 1 ,3-dihydrn-3-(2-hydrnxyethyl)-6-(4-pyridinyl)2H-imidazo[4,5- b]pyridin-2-one, m.p. 283-2840C. The product was then dissolved in 1 50 ml. of dimethylformamide and the solution was treated with a slight excess of hydrogen chloride in ethanol, the mixture was diluted with ether, and the resulting solid was collected, dried in a vacuum oven at 850C. for over sixty hours to yield, as a tan solid, 4.44 g. of 1 ,3-dihydro-3-(2-hydroxyethyl)-6-(4-pyridinyl)-2H-imidazo [4,5-b]pyridin-2-one monohydrochloride hemihydrate, m.p. 29 7--299 OC. with decomposition.

G-5. 1 ,3-Dihydro-3-(2-dimethylaminoethyl)-6-(4-pyridinyl)- 2H-im idazo[4,5-bjpyridin-2-one-A mixture containing 6.67 g. of 3-amino-2-(2-dimethylaminoethylamino)-5-(4-pyridinyl)pyridine, 6.30 g.

of carbonyldiimidazole and 1 50 ml. of dimethylformamide was stirred in a water bath at 35-400C. for over two hours and then at 70-750C. for over two hours. To the reaction mixture was added 10 ml. of water and the solvents were distilled off in vacuo. The residual brown oil was crystallized from acetonitrile (final volume of 50 ml.) and dried in a vacuum oven at 930C. for sixteen hours to yield 6.41 g. of product.This product was recrystallized a second time from acetonitrile (final volume of 125 ml.) and dried as above to yield 5.72 g. of white solid, 1 ,3-dihydro-3-(2-dimethylaminoethyl)-6-(4 pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one, m.p. 182-i 840C. in its free base form and 220.5- 2220C. as its dihydrochloride.

G-6. 1 ,3-Dihydro-3-(3-dimethylaminopropyl)-6- (4-pyridinyl)-2 H-imidazo[4,5-b]pyridin-2-one, m.p. 188-i 91 or., 7.53 g., was obtained following the procedure described in Example G-5 using 14.72 g. of 3-amino-2-(3-dimethylaminopropylamino)-5-(4-pyridinyl)pyridine, 13.13 g. of carbonyldiimidazole and 300 ml. of dimethylformamide.

G-7.1,3-Dihydro-3-[2-(4-morpholiny)ethyl]-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one-A mixture containing 15.11 g. of 3-amino-2-[2-(4-morpholinyl)ethylamino]-5-(4-pyridinyl)pyridine, 12.28 g. of carbonyldiimidazole and 300 ml. of dimethylformamide was stirred at 350C. for over one hour and then stirred at room temperature for sixteen hours. The resulting suspension was stirred with heating at 750C. for over seventy-five minutes. To the cooled solution was added another 8.1 1 g.

portion of carbonyldiimidazole and the resulting mixture was stirred at about 35 C. for two and onehalf hours, heated at about 750C. for forty-five minutes, and to the reaction mixture was added 15 ml.

of water. The water and dimethylformamide was distilled off in vacuo and the resulting oily material was washed with n-hexane whereupon crystallization resulted. The crystalline material was then recrystallized from acetonitrile (160 ml.) and dried at 900 C. in a vacuum oven for eighteen hours to yield 11.55 g. of 1,3-dihydro-3-[2-(4-morpholinyl)ethyl]-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2- one, m.p. 1 86-i 900C.

G-8.1,3-Dihydro-1-methyl-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one-A mixture containing 4 g. of 2-amino-3-methylamino-5-(4-pyridinyl)pyridine, 3.25 g. of carbonyldiimidazole and 100 ml. of dimethylformamide was stirred at room temperature for ninety minutes, with no apparent reaction taking place. The reaction mixture was then heated with stirring on a steam bath for four hours and allowed to stand overnight at room temperature. The solvent was distilled off in vacuo and the residual solid was treated with water, collected by filtration, washed with water and dried. The solid was dissolved in 6N hydrochloric acid and the excess aqueous acid distilled off in vacuo. THe remaining residue was recrystallized twice from methanol using decolorizing charcoal, washed successively with ethanol and ether and dried in vacuo at 700C. The resulting hydrochloride salt of the product was dissolved in water, the aqueous solution made the weakly basic with 1 0% aqueous potassium bicarbonate solution and the mixture cooled. The solid was collected, washed with water and dried in vacuo at 700C., recrystallized from 50% ethanolicacetonitrile, and the mixture cooled overnight in ice.

The solid was collected, washed with ether and dried in vacuo at 70 C. to yield 2 g. of 1,3-dihydro-1 methyl-6-(4-pyridlnyl)-2H-imidazo[4,5-b]pyridin-2-one, m.p. 195-198 C.

Following the procedure described in Example G-2 but using in place of 3-amino-2 methylamino-5-(4-pyridinyl)-pyridine a molar equivalent quantity of the appropriate 3-amino-2-R3NH 5-PY-6-Q-pyridine, it is contemplated that the 1,3-dihydro-3-R3-6-PY-5-Q-2H-imidazo[4,5-b]pyridin-2 ones of Examples G-9 thru G-26 can be obtained.

G-9.1,3-Dihydro-3-n-propyl-6-(3-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one.

G-10.1,3-Dihydro-3-isopropyl-6-(2-methyl-5-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one.

G-11.1,3-n-Butyl-1,3-dihydro-6-(5-methyl-3-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one.

G-12.1,3-n-Amyl-1,3-dihydro-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one.

G-13.1,3-Dihydro-3-n-hexyl-6-(3-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one.

G-14.1,3-Dihydro-5-methyl-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one.

G-15.1,3-Dihydro-5-n-propyl-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one.

G-16.1,3-Dihydro-5-isopropyl-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one.

G-17.1,3-Dihydro-5-n-butyl-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one.

G-18.1,3-Dihydro-5-isobutyl-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one.

G-19.1,3-Dihydro-6-(4-pyridinyl)-5-tert. butyl-2H-imidazo[4,5-b]pyridin-2-one.

G-20.1,3-Dihydro-5-n-pentyl-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one.

G-21.1,3-Dihydro-3-(2-ethoxyethyl)-5-ethyl-6-(2-methyl-4-pyridin)-2H-imidazo[4,5 b]pyridin-2-one.

G-22.5-Ethyl-1,3-dihydro-3-(2-methoxyethyl)-6-(3-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one.

G-23.1,3-Dihydro-3-(3-methoxypropyl)-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one.

G-24.1,3-Dihydro-3-(2-hydroxyethyl-5-methyl-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2 one.

G-25.1,3-Dihydro-3-(3-hydroxypropyl)-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one, m.p.

235-238 C.

G-26.1,3-Dihydro-3-(2,3-dihydroxypropyl)-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one.

Following the procedure described in Example G-8 but using in place methylamino-5-(4-pyridinyl)pyridine a molar equivalent quantity of the appropriate 2-amino-3-R,-NH 5-PY-6-Q-pyridine, it is contemplated that there can be obtained the corresponding 1 ,3-dihydro-i -R1- 6-PY-5-Q-2H-i midazo[4,5-b] pyridin-2-ones of Examples G-27 thru G-40.

G-27.1-Ethyl-1,3-dihydro-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one.

G-28.1,3-Dihydro-1-n-propyl-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one.

G-29.1,3-Dihydro-1-isopropyl-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one.

G-30.1-n-Butyl-1,3-dihydro-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one.

G-31.1,3-Dihydro-1-(2-hydroxyethyl)-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one.

G-32.1,3-Dihydro-1-(2,3-dihydroxypropyl)-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one.

G-33.1,3-Dihydro-1-(3-methoxypropyl)-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one.

G-34.1,3-Dihydro-1-(2-ethoxyethyl)-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one.

G-35.1,3-Dihydro-1-(2-dimethylaminoethyl)-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one.

G-36.1,3-Dihydro-1-(3-diethylaminopropyl)-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one.

G-37.1,3-Dihydro-1-[2-(4-morpholinyl)ethyl]-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one.

G-38.1,3-Dihydro-3-(2-methoxyethyl)-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one, m.p.

203-2060C.

G-39.1,3-Dihydro-3-(4-hydroxybutyl)-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one, m.p.

222-223 C.

G-40. 1 ,3-Dihydro-3-(2-hydroxypropyl)-6-(4-pyridinyl)-2H-i midazo[4,5-b]pyridin-2-one, m.p.

300-3050C. as its monohydrochloride hemihydrate.

H. 1 ,3-Dihydro-1 -R 1-3-R3-6-PY-5-Q-.2H-l midazo[4,5-b] Pyridine-3-Thiones H-1.1,3-Dihydro-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-thione-To a mixture containing 18 g. of 2,3-diamino-5-(4-pyridinyl)pyridine dihydrochloride, 180 ml. of ethanol and 80 ml. of water was added 25 ml. of 2N aqueous potassium hydroxide solution and to this mixture was added 18 g. of potassium ethyl xanthate. The resulting reaction mixture was refluxed for five hours and cooled. The excess solvents were distilled off in vacuo and the residue was dissolved in water. The aqueous solution was neutralized with acetic acid and the resulting precipitate was collected and dried in vacuo at 700C.This material was combined with another 1 g. portion obtained in another smaller run and the combined material was dissolved in 6N hydrochloric acid and the acidic solution was treated with methanol and the resulting mixture cooled. The solid that separated was collected, washed with methanol and dried in vacuo at 700 C. This solid was recrystallized twice from 50% aqueous methanol, the second time using decolorizing charcoal, washed successively with methanol and ether and dried in vacuo at 70 C. to yield 7.5 g. of 1,3-dihydro-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridine-2-thione hydrochloride, m.p. > 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 was refluxed for twelve hours and then allowed to stand ovemight at room temperature. Another 13 g. of potassium ethyl xanthate was added and refluxing was continued for an addition fourteen hours. The solvent and excess reactants were distilled off in vacuo and the residue was dissolved in water and the aqueous solution was neutralized with acetic acid. The resulting solid was collected, recrystallized twice from dimethylformamide, washed successively with ethanol and ether and dried in vacuo at 700C.The partially hydrated product was dissolved in 1N aqueous potassium hydroxide solution and the mixture filtered through diatomaceous earth. The filtrate was neutralized with acetic acid, the solid collected, washed with water and dried in a vacuum oven at 80 C. over the weekend (three days) to yield 8.5 g. of 1,3-dihydro-3-methyl-6-(4 pyridinyl)-2H-imidazo[4,5-b] pyridine-2-thione hydrate (3:1), m.p. > 300 C.

In the following run, the same compound was obtained as its hemihydrate: 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 was refluxed with stirring overnight (about fifteen hours). An additional 90 g. of potassium ethyl xanthate was added and the reaction mixture was refluxed with stirring for another fifteen hours, and then concentrated to dryness. The residue was dissolved in water and the aqueous solution was neutralized with acetic acid. The solid was collected, washed with water, recrystallized twice from dimethylformamide, dried in a vacuum oven at 600C. overnight to yield 50 g.

of yellow powder. The yellow powder was slurried with 400 ml. of water and the aqueous mixture was made basic with 35% aqueous sodium hydroxide solution. The resulting solution was made acid with acetic acid, the precipitate was collected, washed with water and dried in a vacuum oven at 60 C.

overnight to yield, as a pale yellow powder, 47 g. of 1,3-dihydro-3-methyl-6-(4-pyridinyl)-2Himidazo[4,5-b]pyridine-2-thione hemihydrate, m.p. > 300 C.

Following the procedure described in Example H-2 but using in place of 3-amino-2methylamino-5-(4-pyridinyl)pyridine a molar equivalent quantity of the corresponding 2-R3NH-3-R,NH5-PY-6-Q-pyridine, it is contemplated that there can be obtained the 1,3-dihydro-1-R1-3-R3-6-PY-5Q- 2H-imidazo[4,5-b]pyridine-3-thiones of Examples H-3 through H-i 1.

H-3. 1 ,3-Dihydro- 1 -methyl-6-(4-pyridinyl)-2 H-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.

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)-2 H-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.

H-11.1,3-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 salts thereof as cardiotonic agents is demonstrated by their effectiveness in standard pharmacological test procedures, for example, in causing a significant increase in contractile force of the isolated cat atria and papillary muscle and/or in causing a significant increase in the cardiac contractile force in the anesthetized dog with low or minimal changes in heart rate and blood pressure. Detailed descriptions of these test procedures appear in U.S. Patent 4,072,746.

When tested by said isolated cat atria and papillary muscle procedure, the compounds of Formula I or pharmaceutically-acceptable acid-addition salts thereof at doses of 1, 3, 10, 30, 100 and/or 300 g./ml. were found to cause significant increases, that is, greater than 25% in papillary muscle force and significant increases, that is, greater than 25%, in right atrial force, while causing a lower percentage increase (about one-third or less than the percentage increase in right atrial for or papillary muscle force) in right atrial rate.For example, when tested at said dose levels by this procedure, the following preferred compounds of Formula I where Q' is PY were found to cause increases of 70% and greater in papillary muscle force and/or right atrial force : the compounds of Examples G-1, G-2, G-3, G-4, G-5, G-6, G-7, G-8, G-40, H-1 and H-2.

When tested by said anesthetized dog procedure, the compounds of Formula I where Q' is PY or pharmaceutically-acceptable acid-addition salts thereof at doses of 0.1,0.3, 1.0, 3.0, and/or 10 mg./kg. administered intravenously were found to cause significant increases, that is, 25% or greater, in cardiac contractile force or cardiac contractility with lower changes in heart rate and blood pressure.

For example, when tested at said dose levels by this procedure, the following preferred compounds were found to cause increases of 70% and greater in contractile force and lower changes in heart rate and blood pressure: the compounds of Examples G--l, G--2, G--3, G 4, G--5, H-i and H-2.

When tested orally in the unanesthetized dog at 1.0, 3.0 and 10.0 mg.Ag. the compound of Example G--4 was found to cause cardiac contractile force increases of 30, 54 and 104%, respectively, while causing respective heart rate increases of 9, 1 9 and 31%, and respective diastolic blood pressure changes of +4%, -6% and -i %.

When tested by said isolated cat atria and papillary muscle procedure, the compounds of Formula I where Q is PY or salts thereof when tested at doses of 10 and 30 ygiml., were found to cause significant increase, that is, greater than 25% in papillary muscle force and a significant increase, that is, greater than 25%, in right atrial force, while causing a lower percentage increase (about one-third or less than the percentage increase in right atrial force or papillary muscle force) in right atrial rate.For example, when tested at 10 and 30 Mg./ml. by this procedu re, 1 ,3-dihydro-5-(4-pyridinyl)-2 H- imidazo[4,5-b]pyridin-2-one was found to cause respective percentages increases in papillary muscle force, right atrial force and right atrial rate of: 45%, 65% and 14%; and 66%, 153% and 26% respectively.Similarly, when tested at 3, 1 0 and 30 Mg./ml. by this procedure, 1 ,3-dihydro-5-(4- pyridinyl)-2H-imidazo[4,5-b]pyridine-2-thione was found to cause respective increases in papillary muscle force, right atrial force and right atrial rate of: 27%, 16% and 0%; 66%, 40% and 1 6%; and 174%, 73% and 29%.

When screened by other standard pharmacological test procedures, some embodiments of the compounds of Formula I where Q' is PY or salts were found to have anti-hypertensive and/or bronchodilator activities. For example, the compounds of Examples G-1 and G-2 were found to have oral AHD, values of 40 and 30 mg./kg. when tested in the spontaneously hypertensive rat; similarly, the compounds of Examples G-4 and G--5 were found to have low antihypertensive activities (AHA, values of 50 mg./kg. p.o.) when tested by this procedure.When tested orally at 100 mg./kg., the compounds of Examples G-i, G-2, and G-3 were each found to have bnonchodilator activity by inhibiting bronchoconstriction induced by histamine, acetylcholine or immune complex in guinea pigs.

The cardiotonic composition for increasing cardiac contractility comprises a pharmaceuticallyacceptable carrier and, as the active component thereof, the cardiotonic compound of Formula I or pharmaceutically-acceptable acid-addition salt thereof. One can increase cardiac contractility in a patient requiring such treatment by administering to such patient an effective amount of cardiotonic compound of Formula I or pharmaceutically-acceptable acid-addition salt thereof. In clinical practice said compound or salt thereof will normally be administered orally or parentally in a wide variety of dosage forms.

Solid compositions for oral administration include compressed tablets, pills, powders and granules. In such solid compositions, at least one of the active compounds is admixed 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, e.g. lubricating agents, such asmagnesium stearate, talc and the like.

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 inert diluents such compositions can also contain adjuvants, such as wetting and suspending agents, and sweetening, flavoring, perfuming and preserving agents.

According to the invention, the compound for oral administration also include capsules of absorbable material, such as gelatin, containing said active component with or without the addition of diluents or excipients.

Preparations according to the invention for parenteral administration include sterile aqueous, aqueous-organic, and organic solutions, suspensions and emulsions. Examples of organic solvents or suspending media are propylene glycoi, polyethylene glycol, vegetable oils such as olive oil and injectable organic esters such as ethyl oleate. These compositions can also contain adjuvants such as stabilizing, preserving, wetting, emulsifying and dispersing agents.

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

The percentages of active component in the said composition and method for increasing cardiac contractility can be varied so that a suitable dosage is obtained. The dosage administered to a particular patient is variable, depending upon the clinician's judgement using as the criteria: the route of administration, the duration of treatment, the size and condition of the patient, the potency of the active component and the patient's response thereto. An effective dosage amount of active component can thus only be determined by the clinician considering all criteria and utilizing the best judgement on the patient's behalf.

Claims

1. A compound having the Formula I (herein) where Z is O or S, O' is PY and 0 is hydrogen or lower-alkyl or Q is PY and Q' is hydrogen, R1 and R3 each are hydrogen, lower-alkyl, lower-hydroxyalkyl, 2,3-dihydroxypropyl, lower-alkoxyalkyl or Y-NB where Y is lower-alkylene having at least two carbon atoms between its connecting linkages and NB is di-(lower-alkyl)amino or 4-morpholinyl, at least one of R, and R3 being hydrogen, but in the event that Q is PY, R1 is only hydrogen, and PY is 4- or 3pyridinyl or 4- or 3-pyridinyl having one or two lower-alkyl substituents, or an acid-addition salt thereof.

2. A compound according to claim 1, where Q' is PY.

3. A compound according to claim 2, where Q is hydrogen, methyl or ethyl.

4. A compound according to claim 2 or 3, where R3 is hydrogen when R1 is methyl, ethyl or 2hydroxyethyl.

5. A compound according to claim 2 or 3, where R1 is hydrogen when R3 is methyl, ethyl or 2hydroxyethyl.

6. A compound according to claim 2 or 3, where R, is hydrogen, R3 is 2-hydroxyethyl, PY is 4pyridinyl and Q is hydrogen, methyl or ethyl.

7.1,3-Dihydro-3-(2-hydroxyethyl)-6-(4-pyridinyl)-2H-imidazo[4,5-b] pyridin-2-one or a pharmaceutically-acceptable acid-addition salt thereof.

8. A compound according to claim 1, where Q is PY.

9. A compound according to claim 8, where R3 is hydrogen, methyl, ethyl or 2-hydroxyethyl.

10. A compound according to claim 8, where R3 is hydrogen, PY is 4-pyridinyl and Z is S.

11. A compound according to claim 8, where R3 is hydrogen, PY is 4-pyridinyl and Z is O.

12. A process for preparing a compound according to any one of claims 1,2 and 8, which comprises reacting 2-R3NH-3-R,NH-5-Q'-6-pyridine with urea or carbonyldiimidazole to produce the compound where Z is O or with an alkali metal xanthate, thiourea or thiocarbonyldiimidazole to produce the compound where Z is S, and, if desired, converting a free base obtained into an acid addition salt thereof.

13. A process for preparing a compound according to claim 2, substantially as herein described with reference to Examples G-1 to G--37 and H-i to H-i 1.

14. A process for preparing a compound according to claim 2, substantially as herein described with reference to Examples G-38 to G-40.

1 5. A process for preparing a compound according to claim 8, substantially as herein described with reference to Examples A-i to A-8, B-i to B-9, C-i to C-i 8, D-1 to D18. E-1 to E-i 8, and F-i to F-i 8.

16. A compound when produced by the process according to any one of claims 12-15.

17. A compound according to claim 2, or a cardiotonic composition comprising same, substantially as herein described with reference to Examples G-1 to G-37 and H-i to H-i 1.

18. A compound according to claim 2, or a cardiotonic composition comprising same, substantially as herein described with reference to Examples G-38 to G. G-40.

19. A compound according to claim 8, or a cardiotonic composition comprising same, substantially as herein described with refeerence to Examples A-1 to A-8, B-1 to B-9, C-1 to C-18, D-1 to D-18, E-1 to E-18, and F-1 to F-18.

20. A cardiotonic composition for increasing cardiac contractility, said composition comprising a pharmaceutically-acceptable inert carrier and, as the active component thereof, an effective amount of a cardiotonic compound according to any one of claims 1-11 1 and 16-19.

21. A compound according to any one of claims 1-11 1 and 16-19, for increasing cardiac contractility in a patient requiring such treatment.