FUSED IMIDAZOHETEROCYCLIC COMPOUNDS

Abstract: Imidazoheterocyclic compounds having the formula: wherein A is a pyridine ring in any of its four positions; B is carbonyl, thioxomethyl or hydroxymethylene; Z is hydrogen, halogen, loweralkyl, hydroxy, loweralkoxy, di­ loweralkylamino or nitro; Ar is phenyl, pyrido, thienyl or furanyl; and W forms a wide combination of groups with B, including acids, esters, alcohols, amides and ketones. The compounds have CNS activity and find use as muscle relaxants, anticonvulsants and antianxiety agents.

Description: The present invention relates to novel fused imidazoheterocyclics which have one substituted imidazo nitrogen and an aryl substitution on the carbon atom between the two imidazo nitrogens, a novel process therefor and novel intermediates in the preparation thereof. The imidazoheterocyclic compounds have CNS activity. The preparation of 2-aryl-substituted imidazo [4,5-b]pyridines has been described by Garmaise, D. L. and Komlossy, J. in J. ORG. CHEM. 29(1) 3403-5 (1964). Unlike the present invention, the compounds have no substitution on the imidazo nitrogen. Preparation of imidazopyridines having alkylaminoalkyl substitution on one imidazo nitrogen and benzyl substitution on the carbon between the two imidazo nitrogens (position 2) has been described in U. S. Patent 2,987,518. The compounds of the present invention do not have alkylaminoalkyl substitution on an imidazo nitrogen. 2-Phenyl-imidazopyridines have been disclosed in U. S. Patents 4,327,100, 4,353,909 and 3,985,891 as cardiotonics and blood pressure altering drugs. In U. S. 3,985,891, one compound is substituted in the 3-position by methyl. The compounds of the present invention are substituted in the 3-position by other radicals. Benzimidazoles substituted on nitrogen by, for example, N,N-diethylacetamide, and in the two position by an ethoxybenzyl radical, are disclosed in Chemical Abstracts Vol. 66, 65425g. Benzimidazoles substituted on nitrogen by carboxylic acid ethyl ester and in the two position by a 2-pyridinyl radical are disclosed in J. Med. Chem. 1980, 23(7), 734-8 as having anti-inflammatory activity. (2-Phenyl-1 benzimidazolyl)propionic acid having growth-stimulating activity in the cotton plant is disclosed in Chemical Abstracts 100 , 81244r (1984). Imidazo[4,5-b]pyridines substituted in the 2-position by have been disclosed in Monatsh. Chem. (1975) 106(5), pp 1059-69 (C.A. 84 , 59315u) as having no significant biological activity as compared to 2-(α-hydroxybenzyl)benzimidazole. N,N-6-Trimethyl-2-(4-methylphenyl)imidazo[1,2a]pyridine-3-acetamide has been disclosed in NAUNYN-SCHMIEDBERG's ARCH. PHARMACOL (1985), Vol 330, pp 248-251. In contrast to the compounds of the present invention, the compound has a nitrogen shared by both the imidazo moiety and the pyridine moiety and the acetamide radical is on a carbon of the imidazo moiety rather than on an imidazo nitrogen. The novel imidazoheterocyclic compounds of the present invention have the formula: wherein; A represents a heterocyclic ring having two of its carbon atoms held mutually with the imidazo moiety selected from the group consisting of pyridine in any of its four positions wherein nitrogen is unshared by the imidazo moiety and substituted by one or two Z radicals on a carbon not shared by the imidazo moiety selected from hydrogen, halogen, loweralkyl, hydroxy, loweralkoxy, diloweralkylamino or nitro; n is 1 to 3; R⁶ is hydrogen or loweralkyl; Ar is selected from: B is selected from carbonyl, i.e. thioxomethyl, i.e. or hydroxymethylene, i.e. W is selected from: hydrogen, loweralkyl, (Y) 1-3 -phenyl, (Y) 1-3 -phenyl-loweralkyl, -OR¹, -OM, -O(CH₂) p -OH, -NR²(CH₂) p COOR¹, -NR²(CH₂) p OR¹, -NR²(CH₂) p COOM, -NR²[(CH₂) p NHC(O)R¹], -NR²(CH₂) p Q, -NR²(CH₂) p Ar¹ wherein Ar¹ is selected from the same group as Ar, -NR³R⁴, or -NR²(CH₂) p NR³R⁴, wherein R¹ and R² are selected from: hydrogen, loweralkyl, (Y) 1-3 -phenyl, or (Y) 1-3 -phenyl-loweralkyl, R³ and R⁴ are selected from: hydrogen, loweralkyl, loweralkenyl, cycloalkyl, cycloalkyl-loweralkyl, (Y) 1-3 -phenyl, (Y) 1-3 -phenyl-loweralkyl, (Y) 1-2 -pyridin-2, 3 or 4-yl, or R³ and R⁴ when taken together with the adjacent nitrogen atom may form a heterocyclic amino radical selected from: azetidin-1-yl, piperidin-1-yl, loweralkyl-piperidin-1-yl, morpholin-4-yl, 4-R⁵-piperazin-1-yl, thiazolidin-3-yl, with the proviso that when B is hydroxymethylene, W is always limited to hydrogen, loweralkyl, (Y) 1-3 -phenyl or (Y) 1-3 -phenyl-loweralkyl wherein Y is as defined below and a further proviso that when B is thioxomethyl, W is other than (Y) 1-3 -phenyl, (Y) 1-3 -phenyl-loweralkyl, loweralkyl, -OR¹, -OM, -O(CH₂) p OR¹, or hydrogen; p is 0-3; R⁵ is selected from loweralkyl, or (Y) 1-3 -phenyl; Q is selected from: wherein all of the above Y is selected from hydrogen, halo, loweralkoxy, loweralkyl, trifluoromethyl, cyano, nitro or diloweralkylamino; M is a pharmaceutically acceptable metal; the optical isomers, the oxides represented by →O, and the pharmaceutically acceptable acid addition salts including hydrates and quaternary salts thereof. The 3H-imidazo[4,5-b]pyridine derivatives encompassed by Formula I have the formula: The 1H-imidazo[4,5-b]pyridine derivatives encompassed by Formula I have the formula: The 3H-imidazo[4,5-c] pyridine derivatives encompassed by Formula I have the formula: The 1H-imidazo[4,5-c]pyridine derivatives encompassed by Formula I have the formula: In the further definitions of symbols in the formulas hereof and where they appear elsewhere throughout this specification and the claims, the terms have the following significance. The term "loweralkyl" as used herein, unless otherwise specified, includes straight and branched chain radicals of up to eight carbons inclusive and is exemplified by such groups as methyl, ethyl, propyl, isopropyl, butyl, sec. butyl, tert. butyl, amyl, isoamyl, hexyl, heptyl and octyl radicals and the like. The term "loweralkoxy" has the formula -O-loweralkyl. The term "cycloalkyl" as used herein includes primarily cyclic alkyl radicals containing 3-9 carbon atoms inclusive and includes such groups as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclohexyl, cycloheptyl and the like. The terms "halo" or "halogen" when referred to herein include fluorine, chlorine, bromine and iodine unless otherwise stated. "Pharmaceutically acceptable salts" include acid addition salts, hydrates, alcoholates and quaternary salts of the compounds of Formula I, which are physiologically compatible in warm-blooded animals. The acid addition salts may be formed by either strong or weak acids. Representative of strong acids are hydrochloric, sulfuric, and phosphoric acids. Representative of weak acids are fumaric, maleic, succinic, oxalic, citric, tartaric, hexamic and the like. Suitable quaternary salts include the loweralkyl halides and loweralkyl sulfates. Formulas Iw, Ix, Iy, and Iz illustrate what is meant by the term, "a pyridine ring in any of its four positions." By the term "sulfurizing" is meant any agent or mixture of agents which will convert an amide to a thioamide such as phosphorus pentasulfide or phosphorus pentasulfide plus alkali-metal sulfide. The compounds of Formula I are useful in the pharmaceutical method of this invention because of their pharmacological action on the central nervous system. This method employs the compounds of Formula I to treat a living animal body including humans for muscle tension and spasticity (i.e., to relax muscles), anxiety and convulsions. Compounds of Formula I wherein B-W forms an acid radical, i.e., -COOH or -COOM, may have weaker CNS activity; however, these compounds are also chemical intermediates in the preparation of other more active compounds. The procedure for testing compounds for muscle relaxant activity is the Morphine-Induced-Straub-Tail-In-Mice Test. The procedure for indicating anti-anxiety response of the compounds is the Vogel Conflict Test based on shock-suppressed drinking behaviour of rats and reaction to subcutaneous administration of metrazole in mice. The procedure for testing compounds for their anticonvulsant activity is based on evaluation of protective activity against seizures caused by electrical or chemical challenge. All of these evaluation techniques are described in greater detail under Pharmacological Test Procedures hereinbelow. It is therefore an object of the present invention to provide certain novel imidazoheterocyclic compounds as described hereinabove and as defined by Formula I, which may have CNS activity and a process for the preparation thereof. Another object is to provide certain novel derivatives of diaminopyridines as intermediates in the preparation of the imidazoheterocyclic compounds . Other objects are to provide methods of treatment for epilepsy, anxiety and spastic muscles. Additional objects and advantages of the present invention will be apparent to one skilled in the art and others will become apparent from the following description of the best mode of carrying out the present invention and from the appended claims. Preferred compounds of the invention include those having any or all of the following characteristics: A represents a [4, 5-b] pyridine-3H ring; Z represents hydrogen; Ar represents phenyl; Y₆ represents halo; R represents hydrogen or methyl; and/or B represents carbonyl. A schematic preparation of compounds of Formula I is given in Chart I. Footnotes to Chart I a) B is -C(O)- or -CHOH-. When B is -C(O)-, W is any radical capable of forming an amide with B given under the definition of W in Formula I including preferably, -NH₂ or W is -OR¹ wherein R¹ is as defined under Formula I except hydrogen. When B is -CHOH-, W is limited to R¹. b) B is -C(O)- or -CHOH-. When B is W is R¹ or -OR¹ wherein R¹ is as defined under Formula I including hydrogen , or any radical capable of forming an amide with B given under the definition of W in Formula I, including -NH₂. When B is -CHOH, W is limited to R¹. c) W′ is any amine radical under the definition of W in Formula I, including -NH₂. d) R¹ is loweralkyl, phenyl or phenyl-loweralkyl wherein phenyl may be substituted. e) Ig or If compounds may be reduced to compounds: wherein BW is -CH₂OH, The free base of acid addition salts of Formula I compounds may be regenerated by commonly recognized procedures of partitioning between dilute aqueous base and a suitable solvent, separating the free base in the solvent layer, drying and evaporating the solvent. The following process Options 1-a, 1-b, and 2-6 each illustrate preparation of various compounds within the definition of Formula I, some of which preparations may depend on the stepwise progression. Option 1-b of the process represents a novel method of obtaining a predominant isomer from a tautomeric starting material. Option 1-a, heating a compound of the formula wherein x and y are alternatively either carbon or nitrogen; Ar, n, Z and R⁶ are as defined under Formula I; B is selected from W is any radical capable of forming an amide with B or an -OR¹ group as defined under Formula I, except wherein R¹ is H, and when B is W is limited to R¹; without solvent (neat) or in a suitable solvent such as ethylene glycol to give a compound of the formula: wherein x, y, B, W, Ar, Z, R⁶ and n have the starting values, compounds of Formula Ia being encompassed by Formula I; or option 1-b, reacting a compound of the formula or its tautomer wherein x and y are alternately either carbon or nitrogen, and Ar and Z are as defined under Formula I in sequence with the following agents a) and b): a) base, e.g. sodium hydride or potassium carbonate in a suitable solvent such as dimethylformamide; and b) a compound having the formula wherein B is selected from or and W, R⁶ and n are as defined under Formula I to give a compound of the formula wherein x and y are alternately carbon or nitrogen and W, R⁶, Z and n are as defined under Formula I, compounds of Formula Ic being encompassed by Formula I; or option 2, oxidizing a compound having the formula wherein A is a pyridine ring in any of its 4 positions; Ar, Z, n and R⁶ are as defined above and W is loweralkyl, phenyl or phenylloweralkyl, i.e. R¹ except hydrogen, with pyridinium chlorochromate to give a compound having the formula: wherein A, Ar, Z, R⁶, n and W have the starting values in this step, compounds of Formula Id being encompassed by Formula I; or Option 3, reacting a compound having the formula wherein A is a pyridine in any of its 4 positions; B is and W forms an ester with B consistent with the above definition of W, or a similarly prepared compound wherein W is any feasible esterifying radical; Ar, Z, R⁶ and n are as defined above; with an (alkali-)metal base in the presence of water in a suitable solvent such as ethylene glycol (de-esterifying) to give a compound of the formula: wherein A, Ar, Z, R⁶ and n are the same as in the starting compound in this step, and M is an alkali-metal, Formula Ie being encompassed by Formula I and thereafter optionally neutralizing the compound of Formula Ie with an acid to obtain a compound having the formula wherein A, Ar, Z, R⁶ and n are unchanged; or Step 4, reacting an acid compound of Formula If with one of the following a), b), or c): a) 1,1′-carbonyldiimidazole, b) oxalyl chloride, c) ethyl chloroformate, followed by reacting an amine having the formula: W′H wherein W′ is selected from -NR²(CH₂) p COOR¹, -NR²(CH₂) p OR¹, -NR²(CH₂) p COOM, -NR² [ (CH₂) p NHC(O)R¹ ] , -NR₂(CH₂) p Q, -NR²(CH₂) p -Ar¹, -NR³R⁴, or -NR²(CH₂) p NR³R⁴, and wherein R¹, R², R³, R⁴, Q, Ar¹, p and M are as defined under Formula I above to give a compound having the formula: wherein A is a pyridine ring in any of its four positions; Ar, n, Z and R⁶ are as defined above and W′ has the same value as in the starting W′H compound, compounds of Formula Ih being encompassed by Formula I; or Option 5, sulfurizing an amide of Formula Ia, Ic or Ih wherein B is and B-W or BW′ forms an amide to give a thioamide of the formula: wherein A is a pyridine in any of its four positions; Ar, Z, R⁶ and n are as defined above, W encompasses W′ and may have any of the amine values as defined under Formula I, compounds of Formula I i being encompassed by Formula I; or Option 6, oxidizing a compound of Formula Ia, Ic, Id, Ie, If, Ih or Ii with m-chloroperbenzoic acid in a anhydrous medium such as glacial acetic acid to obtain an oxide compound having the formula wherein A, Ar, R⁶, Z, n, B and W have the values given under Formula I above, compounds of Formula Ij being encompassed by Formula I. In reference to the process steps summarized above as they apply to the preparation of compounds of Formula I, the following description is applicable. In Step 1-a, starting compounds of Formula II (see Chart I) wherein B is W is OR¹ (except R¹ is never hydrogen), or W is NH₂ or any amino radical given under the definition of Formula I and when B is W is limited to R¹ wherein phenyl may be substituted are heated to cyclize to the imidazoheterocyclic compound. Heating (and consequently the cyclization) may be done with or without solvent, the temperature range encompassed thereby for all the conditions being approximately 100-240°C. Water is given off during cyclization and usual methods for dehydration and collecting water may be incorporated if desired. When the cyclization is conducted without solvent (i.e. neat) temperatures of about 180-240°C. may be employed to bring about cyclization in about 5-30 minutes time. When a refluxing solvent such as toluene is used, the water is advantageously collected in a Dean-Stark apparatus and the solvent is returned to the reaction vessel. In the instance at the boiling point of toluene of about 110°C., the cyclization is slower and may require as long as 24 hr. Strong acid catalysts including toluene sulfonic acid are advantageously added to the solvent to shorten the cyclization time. Ethylene glycol may also be used as solvent at higher temperatures to aid in cyclization. In this instance the water tends to be absorbed by the ethylene glycol and does not have to be driven off. In certain cyclizations, ethylene glycol may be the preferred solvent, since the mix can be used directly in Step 3 without separating the product. Thus, from the foregoing description, it may be seen that the temperature used will depend on whether the reaction is conducted neat or with solvent and the type of solvent employed. The extent of reaction may be determined by employing TLC using a low boiling solvent such as methylene chloride on silica base and using Mass Spectrometer readings of the molecular weight. In Step 1-b, 2-aryl-imidazopyridine compounds in which one of the imidazo nitrogens carries a hydrogen radical is added slowly to a slurry of sodium hydride or a suitable base such as anhydrous potassium carbonate in a suitable carrier, preferably dimethylformamide, and the mixture is heated at about 60-90°C. for 1-2 hr. The compound is added and the mixture is stirred at ambient temperature for a period of time, usually 12-24 hr. Water is added to decompose any unreacted sodium hydride and the product is isolated by conventional crystallizing procedures, utilizing, if necessary, evaporation of solvent, additional solvents and charcoal or converting to acid addition salts. The [4,5-b] and [4,5-c]-1H isomers are generally the predominant isomers formed in this step. The isomers may be separated by crystallizing out the major component first. In Step 2, an imidazopyridine having a secondary or tertiary alkanol side chain is oxidized by contacting it with excess pyridinium chlorochromate in a suitable carrier such as methylene chloride at about room temperature until oxidation is complete. The product is isolated by decanting the solution, evaporation and recrystallizing from a suitable solvent such as isopropyl alcohol. In Step 3, imidazopyridines having a side chain terminated by an ester moiety on the imidazo nitrogen are hydrolyzed by heating with water and alkali-metal base in a suitable solvent such as ethylene glycol or an alkanol such as ethanol to give a solution of alkali-metal acid salt of the resulting acid. The acid salt may be neutralized with any suitable acid to give the free acid which may be separated by precipitation. In Step 4, the imidazopyridine obtained in Step 3 bearing a side chain terminated by a carboxy radical on one of the imidazo nitrogens is reacted with one of 3 reagents: 1,1′-carbonyldiimidazole, oxalyl chloride, or ethyl chloroformate, followed by the desired amine. When the reagent is 1,1′-carbonyldiimidazole, reaction with the acid is carried out in a suitable carrier, preferably tetrahydrofuran, at about room temperature with a stream of nitrogen gas bubbling through the mixture, usually in about 2-4 hr time. The nitrogen sweeps out carbon dioxide. The amine, W′H, is added and stirring is continued at room temperature, usually for several hours. The resulting amide is isolated by evaporation and redissolving the residue in an appropriate solvent such as methylene chloride followed by common crystallization methods as the free base or an acid addition salt. When oxalyl chloride is the reagent used, it and the carboxylic acid derivative are mixed in a suitable solvent, preferably dimethylformamide, at about 5-30°C. and the mixture is heated at about 50-70°C. for 3-5 hr and then added to a cold solution of the W′H amine in dimethylformamide and triethylamine. The product amide is also isolated by usual techniques as the free base or acid addition salt. When ethyl chloroformate is the reagent (see Example 29), it and acid derivative are reacted in a suitable solvent, preferably methylene chloride usually in about 1-3 hr time at room temperature. The W′H amine in solvent is added slowly and the mixture is allowed to stir several hours at ambient temperature. The product amide is separated by conventional means such as evaporation, partitioning between dilute acid and solvent such as diethyl ether followed by column chromatography, if necessary. In Step 5, a compound prepared in Steps 1-a, 1-b, or 4 wherein B-W forms an amide function is optionally converted to a thioamide by sulfurizing, preferably with phosphorus pentasulfide. Acetonitrile is a suitable and preferred carrier during sulfurization. Product thioamides are isolated by conventional methods which may include chromatography (see Example 53). In Step 6, the imidazopyridine compounds prepared in Steps 1-5 may be reacted with m-chloroperbenzoic acid, preferably in glacial acetic acid at a temperature of about 40-70°C. for several hours (see Examples 120 and 121) to produce imidazopyrido-nitrogen oxides. The reaction mixture is diluted with water to precipitate organic acid residue of the spent m-chloroperbenzoic acid and any peroxides are destroyed, preferably with a sulfite reagent. Product oxides are separated and purified by usual methods. Starting compounds of Formula II: wherein x and y are alternately either carbon or nitrogen, Z, Ar, R⁶ and n are as defined under Formula I and B and W are as defined in footnote (a) of Chart I are prepared by reactions illustrated by equations A, B and C in Chart II. Compounds of Formulas IIa, IIb, and IIc are encompassed by Formula II. Procedure B) above in Chart II represents a novel process for the preparation of compounds of Formula IIb. Early attempts to prepare IIb compounds stepwise by this route gave cyclized intermediates after the reduction step. The discovery that addition of ArC(O)Cl immediately after reduction or cooling during the reduction and/or acylation steps prevents the cyclization is the basis of novelty of this novel process. The method B) has application for any compound wherein R¹ is an esterifying radical of any kind, such compounds being usable to prepare compounds of Formula I as the end product independent of what the esterifying radical is. Starting compounds of Formula III: wherein A, Z and Ar are as defined under Formula I are prepared by reactions represented by the equation in Chart III. The following preparations and examples serve to illustrate methods of preparing the compounds. The scope of the invention is not limited by the preparations and examples; however, structures of the compounds of the examples are given for reference in Table 1. Preparation 1 N-(3-Nitro-2-pyridinyl)glycine ethyl ester . A solution of 2-chloro-3-nitropyridine (50 g, 0.315 mole), glycine ethyl ester hydrochloride (220 g, 1.58 mole), and triethylamine, (155 g, 1.53 mole) in 1 liter of absolute ethanol was stirred and heated to reflux overnight. The reaction mixture was evaporated to a solid mass, which was partitioned between water and ethyl acetate. The aqueous layer was separated and extracted with ethyl acetate (3x). The combined ethyl acetate layer was evaporated to an oil, which was dried by azeotropic distillation with benzene. The residue was purified by silica gel chromatography (8 cm x 27 cm column) by elution with 5% methanol/95% benzene. The appropriate fractions totaled 59.2 g of the title product, m.p. 38-9°C. Analysis: Calculated for C₉H₁₁N₃O₄ : C, 48.00; H, 4.92; N, 18.66 Found : C, 48.01; H, 4.94; N, 18.55 Preparation 2 N-[3-(Benzoylamino)-2-pyridinyl]glycine ethyl ester . A solution of N-(3-nitro-2-pyridinyl)glycine ethyl ester (1.0 g, 0.0044 mole) in 140 ml of tetrahydrofuran was hydrogenated over 5% palladium on carbon (0.2 g) at room temperature for 4 hr. The reaction mixture was dried over magnesium sulfate and filtered through a Celite pad. To this stirred solution was added triethylamine (0.6 g 0.0059 mole) and benzoyl chloride (0.62 g, 0.0044 mole). The reaction mixture was allowed to stir at room temperature overnight. The triethylamine hydrochloride was filtered off and the filtrate was evaporated to dryness. The residue was taken up in ether-methylene chloride solution. Sodium sulfate was added to adsorb an immiscible dark oil. The filtrate was evaporated to dryness to give a residue which was recrystallized from ether. The precipitate was collected, washed with a solution of 75% hexanes/25% ether, and dried at room temperature under high vacuum to yield 1.1 g, of title compound, m.p. 115-16°C. Analysis: Calculated for C₁₆H₁₇N₃O₃ : C, 64.20; H, 5.72; N, 14.04 Found : C, 64.05; H, 5.77; N, 14.00 Preparation 3 2-[(3-Nitro-2-pyridinyl)amino]acetamide . A mixture of 2-chloro-3-nitropyridine (1.0 g, 0.0063 mole), glycinamide hydrochloride (3.11 g, 0.028 mole), triethylamine (3.1 g, 0.031 mole) in 35 ml of acetonitrile was heated at reflux for 16½ hrs. The yellow precipitate was filtered off. The precipitate was slurried and filtered successively with water, absolute alcohol and acetone. The yellow solid was dried under high vacuum at room temperature to give 0.9 g (73.2%), of title compound, m.p. 250-51°C with decomposition. Analysis: Calculated for C₉H₈N₄O₃ : C, 42.86; H, 4.11; N, 28.56 Found : C, 42.84; H, 4.08; N, 28.43 Preparation 4 N-[2-[[(Aminocarbonyl)methyl]amino]-3-pyridinyl]benzamide . A mixture of 2-[(3-nitro-2-pyridinyl)amino]acetamide (2.0 g, 0.01 mole) in 160 ml of tetrahydrofuran was hydrogenated over 5% palladium on carbon (0.3 g) at ∼55°C overnight. The reaction mixture was diluted with hot acetonitrile and dried over magnesium sulfate. The mixture was filtered through a Celite pad. To the stirred filtrate under nitrogen atmosphere was added triethylamine (1.21 g, 0.012 mole) and benzoyl chloride (1.41 g, 0.01 mole). The reaction mixture was allowed to stir at ambient temperature overnight. The reaction mixture was evaporated to a solid residue. The solid was washed with methylene chloride, filtered and the filter cake washed with methylene chloride. The solid was added to water and broken up well with a glass rod, and the solid was again collected by filtration. The solid was dried under high vacuum at room temperature overnight to give 0.7 g (26%) of title compound, m.p. 194-95°C with decomposition. Analysis: Calculated for C₁₄H₁₄N₄O₂ : C, 62.21; H, 5.22; N, 20.73 Found : C, 61.87; H, 5.17; N, 20.50 Preparation 5 2-[(3-Amino-2-pyridinyl)amino]acetamide . A mixture of 2-[(3-nitro-2-pyridinyl)amino]acetamide (19.6 g, 0.1 mole) in 160 ml of ethyl acetate was hydrogenated over 5% palladium on carbon (2.0 g) at ∼55°C overnight. The reaction mixture was warmed with acetonitrile and filtered through a Celite pad. The pad was washed with hot acetonitrile and the filtrate was evaporated to a solid. A 1.2-g sample of this solid was recrystallized from methanol-acetonitrile to give a light yellow solid, which was dried under high vacuum at room temperature to give 0.4 g, of title compound, m.p. 153-55°C with decomposition. Analysis: Calculated for C₇H₁₀N₄O : C, 50.59; H, 6.06; N, 33.71 Found : C, 50.62; H, 6.09; N, 33.40 Preparation 6 N-[3-[(2-Pyridinylcarbonyl)amino]1-2-pyridinyl]glycine ethyl ester . A solution of N-(3-nitro-2-pyridinyl)glycine ethyl ester (2.25 g, 0.01 mole) was hydrogenated over 5% palladium on carbon (0.3 g) at room temperature for 4 hours. The reaction mixture was dried over magnesium sulfate and the mixture was filtered through a Celite pad. The filtrate was added at room temperature over 3/4 hour to the imidazolide, which was prepared by adding 1,1′-carbonyldiimidazole (1.69 g, 0.01 mole) in portions to a solution of picolinic acid (1.23 g, 0.01 mole) in 100 ml of tetrahydrofuran while stirring at room temperature for 4 hours. The reaction mixture was filtered and the filtrate was evaporated to a solid. The solid was dissolved in tetrahydrofuran and diluted with ether. The supernatant liquid was decanted from the dark oil which had formed and was evaporated. The reside was dissolved in boiling water, and the solution was filtered, and allowed to crystallize with seeding to give 0.68 g, of title compound, mp 95-6°C. Analysis: Calculated for C₁₅H₁₆N₄O₄ : C, 59.99; H, 5.37; N, 18.66 Found : C, 59.97; H, 5.35; N, 18.58 Preparation 7 N-[2-[(2-Amino-2-oxoethyl)amino]-3-pyridinyl]-2-pyridinecarboxamide . While bubbling nitrogen through a solution of picolinic acid (1.23 g, 0.01 mole) in 100 ml of tetrahydrofuran, solid 1,1′-carbonyldiimidazole (1.62 g, 0.01 mole) was added in portions. The reaction mixture was allowed to stir at room temperature for 5 hours. Then, a solution of 2-[(3-amino-2-pyridinyl)amino] acetamide (1.66 g, 0.01 mole) in acetonitrile was added in portions to the imidazolide solution and the reaction mixture was allowed to stir at room temperature overnight. The solvents were evaporated. The residue completely solidified upon standing. The solid was washed with methylene chloride and the solid was filtered off. The solid was recrystallized from ethyl acetate to give several crops of crystals, which were combined and recrystallized from ethyl acetate to give 0.52 g of title compound, mp 188-90°C with decomposition. Analysis: Calculated for C₁₃H₁₃N₅O₂ : C, 57.26; H, 4.83; N, 25.81 Found : C, 57.41; H, 4.76; N, 25.66 Preparation 8 N-[3-[[(4-Chloro-2-pyridinyl)carbonyl]amino]-2-pyridinyl]glycine ethyl ester . A mixture of 4-chloro picolinic acid (7.38 g, 0.06 mole) and thionyl chloride (29 ml) in 50 ml of benzene was heated at reflux for 3 to 4 hrs, then evaporated to remove solvent and excess thionyl chloride. The residue was azeotroped with benzene (2x). The crude liquid was used without purification. Meanwhile, N-(3-nitro-2-pyridinyl)glycine ethyl ester (11.25 g, 0.05 mole) dissolved in 160 ml of tetrahydrofuran was hydrogenated at room temperature over 5% palladium on carbon for 1 hr. The reaction mixture was dried over sodium sulfate and filtered through a Celite pad. The crude 4-chloro picolinoyl chloride and triethylamine (5.55 g, 0.055 mole) were added dropwise simultaneously to the above stirred filtrate of N-(3-amino-2-pyridinyl)glycine ethyl ester at room temperature and allowed to stir overnight. The reaction mixture was filtered. The tetrahydrofuran filtrate was treated with 50 g of Florisil®, filtered, and the filtrate evaporated to dryness. A 4 g sample of the dark oil was dissolved in 500 ml of hexane and seeded to initiate crystallization. The hexane was decanted and the solid residue was dissolved in methylene chloride and hexane, and the solution was treated with Florisil®, and evaporated to an oil, which was crystallized from hexane. The solid was filtered off and dried under high vacuum at room temperature to give 0.9 g of title compound, mp 78-80°C. Analysis: Calculated for C₁₅H₁₅N₄O₃Cl : C, 53.82; H, 4.52; N, 16.74 Found : C, 53.81; H, 4.51; N, 16.90 Preparation 9 N-[3-[(4-Methoxybenzoyl)amino]-2-pyridinyl]glycine ethyl ester . A solution of N-(3-nitro-2-pyridinyl)glycine ethyl ester (64.4 g, 0.286 mole) in 900 ml of tetrahydrofuran was hydrogenated in a 2-liter Parr bottle over 5% palladium on carbon (6.5 g) at room temperature for 1 hr. The reaction mixture was dried over magnesium sulfate and filtered through a Celite pad. A 235-ml portion of the filtrate was used in this reaction. Under nitrogen atmosphere, p -anisoyl chloride (9.72 g, 0.057 mole) and triethylamine (6.33 g, 0.063 mole) were added dropwise simultaneously to the above-stirred filtrate at room temerature. The reaction mixture was allowed to stir overnight. The reaction mixture was filtered and the filtrate was treated with Florisil® (30 g), and evaporated to a solid The solid (∼1/2 sample) was dissolved in tetrahydrofuran and diluted with water. The tetrahydrofuran was boiled off and a light green solid was collected. The solid was dissolved in tetrahydrofuran, and the solution was decolorized with charcoal, and filtered through a Celite pad. The tetrahydrofuran solution was diluted with petroleum ether to produce a crystalline crop. The solid was filtered off, washed with petroleum ether, and dried under high vacuum at room temperature to give 2.8 g of title compound, mp 130-31°C. Analysis: Calculated for C₁₇H₁₉N₃O₄ : C, 62,00; H, 5.81; N, 12.76 Found : C, 62.14; H, 5.89; N, 12.61 Preparation 10 N-[3-[(2-Chlorobenzoyl)amino]-2-pyridinyl]glycine ethyl ester . A solution of N-(3-nitro-2-pyridinyl)glycine ethyl ester (64.4 g, 0.286 mole) in 900 ml of tetrahydrofuran was hydrogenated in a 2-liter Parr bottle over 5% palladium on carbon (6.5 g) at room temperature for 1 hr. The reaction mixture was dried over magnesium sulfate and filtered through a Celite pad. A 235-ml portion of the filtrate was used in this reaction. Under nitrogen atmosphere, o -chlorobenzoyl chloride (9.97 g, 0.057 mole) and triethylamine (6.33 g, 0.063 mole) were added dropwise simultaneously to the above-stirred filtrate at room temperature. The reaction mixture was allowed to stir overnight, filtered, and the filtrate was treated with Florisil® (30 g), and evaporated to a solid. A 2-g portion was recrystallized from tetrahydrofuran/petroleum ether. The solid was collected, washed with 3:1 petroleum ether/tetrahydrofuran, and dried under high vacuum at room temperature to give 1.45 g of title compound, mp 111-12°C. Analysis: Calculated for C₁₆H₁₆N₃O₃Cl : C, 57.58; H, 4.83; N, 12.59 Found : C, 57.62; H, 4.86; N, 12.67 Preparation 11 N-[3-[(2-Methoxybenzoyl)amino]-2-pyridinyl]glycine ethyl ester . A solution of N-(3-nitro-2-pyridinyl]glycine ethyl ester (64.4 g, 0.286 mole) in 900 ml of tetrahydrofuran was hydrogenated in a 2-liter Parr bottle over 5% palladium on carbon (6.5 g) at room temperature for 1 hour. The reaction mixture was dried over magnesium sulfate and filtered through a Celite pad. A 235-ml portion of the filtrate was used in this reaction. Under nitrogen atmosphere, o -anisoyl chloride (9.72 g, 0.057 mole) and triethylamine (6.33 g, 0.063 mole) were added dropwise simultaneously to the above-stirred filtrate at room temperature. The reaction mixture was allowed to stir overnight. The reaction mixture was filtered, and the filtrate was treated with Florisil® (30 g), and evaporated to a solid. The solid was recrystallized from hot tetrahydrofuran (minimum). The solid was filtered off, washed with cold tetrahydrofuran, and dried under high vacuum at room temperature to give 5.7 g of title compound, mp 111-12°C. Analysis: Calculated for C₁₇H₁₉N₃O₄ : C, 62.00; H, 5.81; N, 12.76 Found : C, 62.00; H, 5.81; N, 12.85 Preparation 12 N-[3-[(3-Chlorobenzoyl)amino]-2-pyridinyl]glycine ethyl ester . A solution of N-(3-nitro-2-pyridinyl)glycine ethyl ester (64.4 g, 0.286 mole) in 900 ml of tetrahydrofuran was hydrogenated in a 2-liter Parr bottle over 5% palladium on carbon (6.5 g) at room temperature for 1 hr. The reaction mixture was dried over magnesium sulfate and filtered through a Celite pad. A 235-ml portion of the filtrate was used in this reaction. Under nitrogen atmosphere, m -chlorobenzoyl chloride (9.97 g, 0.057 mole) and triethylamine (6.33 g, 0.063 mole) were added dropwise simultaneously to the above-stirred filtrate at room temperature. The reaction mixture was allowed to stir overnight, filtered, and the filtrate was treated with Florisil® (30 g), and evaporated to a solid. A 2-g portion was recrystallized from tetrahydrofuran/petroleum ether. The solid was collected, washed with 3:1 petroleum ether/tetrahydrofuran, and dried under high vacuum at room temperature to give 1.4 g of title compound, mp 143-44°C. Analysis: Calculated for C₁₆H₁₆N₃O₃Cl : C, 57;58; H, 4.83; N, 12.59 Found : C, 57.57; H, 4.83; N, 12.60 Preparation 13 N-[3-[(4-Chlorobenzoyl)amino]-2-pyridinyl]glycine ethyl ester . A solution of N-(3-nitro-2-pyridinyl)glycine ethyl ester (64.4 g, 0.286 mole) in 900 ml of tetrahydrofuran was hydrogenated in a 2-liter Parr bottle over 5% palladium on carbon (6.5 g) at room temperature for 1 hour. The reaction mixture was dried over magnesium sulfate and filtered through a Celite pad. A 235-ml portion of the filtrate was used in this reaction. Under nitrogen atmosphere, p -chlorobenzoyl chloride (9.97 g, 0.057 mole) and triethylamine (6.33 g, 0.063 mole) were added dropwise simultaneously to the above stirred filtrate at room temperature. The reaction mixture was allowed to stir overnight. The reaction mixture was filtered, and the filtrate was treated with Florisil® (30 g), and evaporated to a solid. The solid was recrystallized from tetrahydrofuran-water. The product was collected, washed with water, and dried under high vacuum first at 50°C overnight, then at 65°C overnight to give 16.5 g of title compound, mp 133-4°C. Analysis: Calculated for C₁₆H₁₆N₃O₃Cl : C, 57.58; H, 4.83; N, 12.59 Found : C, 57.35; H, 4.80; N, 12.44 Preparation 14 N-[2-[(2-Amino-2-oxoethyl)amino]-3-pyridinyl]-4-chlorobenzamide hydrate [2:1] . A mixture of 2-[(3-nitro-2-pyridinyl)amino]acetamide (26.0 g, 0.133 mole) in 200 ml of ethyl acetate was hydrogenated over 5% palladium on carbon (3.0 g) at 55-60°C for 2 hr. The reaction mixture was diluted with hot methanol and filtered through a Celite pad. The pad was washed several times with hot methanol until the filtrate was clear and colorless. The filtrate was evaporated and dried by azeotropic evaporation of benzene (3x). The solid residue was placed under high vacuum overnight at room temperature. To a stirred mixture of the above solid in 1 liter of acetone was added dropwise simultaneously p -chlorobenzoyl chloride (23.28 g, 0.133 mole) and triethylamine (14.75 g, 0.146 mole). The reaction mixture was allowed to stir overnight at room temperature. The precipitate was filtered off, washed with acetone, and allowed to dry under ambient conditions. The solid was dissolved in hot methanol, filtered, and the filtrate was concentrated to produce a crystalline crop. The solid was filtered, washed with cold methanol and water, then dried under high vacuum at room temperature over the weekend. The sample was redried under high vacuum at 60°C overnight to give 18.36 g of title compound, mp 194-5°C with decomposition. Analysis: Calculated for C₁₄H₁₃N₄O₂Cl·1/2 H₂O : C, 53.60; H, 4.50; N, 17.86 Found : C, 53.89; H, 4.59; N, 17.75 Preparation 15 N-[2-[(2-Amino-2-oxoethyl)amino]-3-pyridinyl]-2-chlorobenzamide hydrochloride [1:1] . A mixture of 2-[(3-nitro-2-pyridinyl)amino]acetamide (26.0 g, 0.133 mole) in 200 ml of ethyl acetate was hydrogenated over 5% palladium on carbon (3.0 g) at 55-60°C for 2 hr. The reaction mixture was diluted with hot methanol and filtered through a Celite pad. The pad was washed several times with hot methanol until the filtrate was clear and colorless. The filtrate was evaporated and dried by azeotropic evaporation of benzene (3x). The solid residue was placed under high vacuum overnight at room temperature. To a stirred mixture of the above solid in 1 liter of acetone was added dropwise simultaneously o -chlorobenzoyl chloride, (23.28 g, 0.133 mole) and triethylamine (14.75 g, 0.146 mole). The reaction mixture was allowed to stir overnight at room temperature. The reaction mixture was filtered and the filter cake washed with acetone and discarded. The filtrate and wash were evaporated to a foamy solid, which was dried under high vacuum at room temperature. A 5-g sample was dissolved in methanol and the solution was acidified with methanolic hydrogen chloride to slowly produce a crystalline solid. The solid was filtered, washed with cold methanol, and dried under high vacuum at room tempeature over 3 days to give 4.33 g of title compound, mp 198-200°C with decomposition. Analysis: Calculated for C₁₄H₁₃N₄O₂Cl·HCl : C, 49.28; H, 4.14; N, 16.42 Found : C, 48.94; H, 4.34; N, 16.22 Preparation 16 N-[3-[(3-Fluorobenzoyl)amino]-2-pyridinyl]glycine ethyl ester. Under a nitrogen atmosphere, 3-fluorobenzoyl chloride (12.9 g, 0.0816 mole) was added dropwise to a stirred and chilled (10-15°C) mixture of N-(3-amino-2-pyridinyl)glycine ethyl ester (0.0816 mole) [freshly prepared by the hydrogenation of a solution of N-(3-nitro-2-pyridinyl)glycine ethyl ester in tetrahydrofuran over 5% palladium on carbon at room temperature], triethylamine (8.3 g, 0.0816 mole), anhydrous tetrahydrofuran (200 ml), and powdered molecular sieves. The reaction mixture was stirred at room temperature for 1 hour and was filtered. The filtrate was concentrated in vacuo and the residual solid triturated in isopropyl ether-isopropyl alcohol, giving 24.2 g (94%). Recrystallization of a 2.0-g sample gave 1.72 g of a white powder, mp 134-135°C. Analysis: Calculated for C₁₆H₁₆N₃O₃F : C, 60.56; H, 5.08; N, 13.24 Found : C, 60.45; H, 5.07; N, 13.20 Preparation 17 3-[(3-Nitro-2-pyridinyl)amino]propanoic acid ethyl ester hydrochloride [1:1] . The mixture of 2-chloro-3-nitropyridine (25.8 g, 0.16 mole), β-alanine ethyl ester hydrochloride (50 g, 0.33 mole), triethylamine (49.4 g, 0.49 mole), and 300 ml of absolute ethanol was warmed at 50-55°C for 4 hr with mechanical stirring. The reaction mixture was evaporated and the residue was partitioned between water and methylene chloride. The water layer was separated and extracted with methylene chloride (2x). The combined methylene chloride extracts were washed with water (2x) and dried over anhydrous sodium sulfate. The filtrate was evaporated to an orange oil (39.2 g). A 2-g sample of the oil was dissolved in acetonitrile acidified with ethereal hydrogen chloride (excess), and scratched to initiate crystallization. The yellow solid was filtered off, washed with ether, and dried under high vacuum at room temperature overnight to give 1.62 g of the title compound, mp 137-40°C (sealed tube). Analysis: Calculated for C₁₀H₁₃N₃O₄·HCl : C, 43.57; H, 5.12; N, 15.24 Found : C, 43.53; H, 5.14; N, 15.27 Preparation 18 3-[(3-Nitro-2-pyridinyl)amino]propanoic acid ethyl ester . A mixture of 2-chloro-3-nitropyridine (68.6 g, 0.434 mole), β-alanine ethyl ester hydrochloride (100 g, 0.651 mole), triethylamine (103.7 g, 1.03 mole) and 95% ethanol (675 ml) was refluxed for 5 hr and then stirred at room temperature overnight. The solvent was evaporated at reduced pressure and the residue was triturated in ethyl acetate (700 ml). The solid was filtered and washed with ethyl acetate. The filtrate was washed three times with water, dried over anhydrous sodium sulfate, filtered and evaporated at reduced pressure to give 113.4 g of an oil. The oil was eluted through a silica gel column (400 g) with ethyl acetate. The eluent was evaporated at reduced pressure to give 106.2 g of an oil (100% yield). A small portion of the oil was crystallized from petroleum ether to give 0.7 g of yellow solid of the title compound, mp. 32.5-33.5°C. Analysis: Calculated for C₁₀H₁₃N₃O₄ : C, 50.21; H, 5.48; N, 17.56 Found : C, 50.22; H, 5.49; N, 17.65 Preparation 19 N-[3-[(4-Bromobenzoyl)amino]-2-pyridinyl]glycine ethyl ester : To a stirred and chilled (10-20°C) solution of N-(3-amino-2-pyridinyl)glycine ethyl ester (14.7 g, 0.075 mole) [freshly prepared by the hydrogenation of a solution of N-(3-nitro-2-pyridinyl) glycine ethyl ester in tetrahydrofuran over 5% palladium on carbon at room temperature], triethylamine 8.1 g, 0.080 mole), and tetrahydrofuran (150 ml) was added (rapid drop) 4-bromobenzoyl chloride (6.9 g, 0.077 mole), followed by 100 ml of methylene chloride. The reaction mixture was stirred at room temperature for 2 hr and was filtered. The filtrate was concentrated in vacuo and the residue combined with the filter cake. The combined mixture was twice suspended in water and filtered. The filter cake was recrystallized from ethanol, giving 22.7 g of crystals (80%). Recrystallization of a 1.6-g samples from ethanol gave 1.5 g of white flocculent solid, mp 153-154°C. Analysis: Calculated for C₁₆H₁₆N₃O₃Br : C, 50.81; H, 4.26; N, 11.11 Found : C, 50.47; H, 4.27; N, 11.09 Preparation 20 3-[[3-(4-Chlorobenzoyl)amino]-2-pyridinyl]amino]propanoic acid ethyl ester . A solution of the free base of 3-[(3-nitro-2-pyridinyl)amino]propanoic acid ethyl ester monohydrochloride, (73.2 g, 0.31 mole) in 900 ml of tetrahydrofuran was hydrogenated over 5% palladium on carbon (7.3 g) at room temperature for 1 hr. The reaction mixture was dried over magnesium sulfate, filtered, and the filtrate was divided into 3 equal volumes. To this stirred filtrate (1/3 volume, 0.102 mole) was added simultaneously triethylamine (11.33 g, 0.11 mole) and p -chlorobenzoyl chloride (17.85 g, 0.102 mole). The reaction mixture was allowed to stir at room temperature overnight and filtered to remove triethylamine hydrochloride. The filtrate was treated with Florisil® (50 g), then filtered. The filtrate was treated with charcoal (6 g) overnight, filtered through Celite, and evaporated to a solid. A 3-g sample was dissolved in tetrahydrofuran (minimum) and diluted with petroleum ether (bp 50-110°C) until crystallization was initiated. The solid was collected and recrystallized twice from tetrahydrofuran/petroleum ether to give a light tan solid which was dried under high vacuum at 55-60°C to give 1.6 g of title compound, mp 124-25°C. Analysis: Calculated for C₁₇H₁₈N₃O₃Cl : C, 58.71; H, 5.22; N, 12.08 Found : C, 58.63; H, 5.24; N, 12.00 Preparation 21 3-[[3-[(3-Chlorobenzoyl)amino]-2-pyridinyl]amino]propanoic acid ethyl ester . A solution of 3-[(3-nitro-2-pyridinyl)amino]propanoic acid ethyl ester (73.2 g, 0.31 mole) in 900 ml of tetrahydrofuran was hydrogenated over 5% palladium on carbon (7.3 g) at room temperature for 1 hr. The reaction mixture was dried over magnesium sulfate, filtered, and the filtrate was divided into 3 equal volumes. To this stirred filtrate (1/3 volume, 0.102 mole) was added simultaneously triethylamine (11.33 g, 0.11 mole) and m -chlorobenzoyl chloride (17.85 g, 0.102 mole). The reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was filtered to remove triethylamine hydrochloride. The filtrate was treated with Florisil® (50 g), then refiltered. The filtrate was treated with charcoal (6 g) overnight, filtered through Celite, and evaporated to dryness. A portion of the solid residue (∼3-4 g) was treated with ∼50 ml of tetrahydrofuran, filtered, and the filtrate was diluted with petroleum ether (bp 50-110°C) until crystallization was inititated. The solid was collected and dried under high vacuum at 55°C overnight. The solid was recrystallized using tetrahydrofuran-water (with methanol to eliminate phasing) with filtering to remove insoluble dark oil. The crystalline solid was collected, washed with water, and dried under high vacuum (50-55°C) overnight to give 0.55 g of title compound, mp 111-12°C. Analysis: Calculated for C₁₇H₁₈N₃O₃Cl : C, 58.71; H, 5.22; N, 12.08 Found : C, 58.64; H, 5.26; N, 12.07 Preparation 22 3-[[3-[(2-Chlorobenzoyl)amino]-2-pyridinyl]amino]propanoic acid ethyl ester . A mixture of 3-[(3-nitro-2-pyridinyl)amino]propanoic acid ethyl ester (73.2 g, 0.306 mole) in 900 ml of tetrahydrofuran was hydrogenated over 5% palladium on carbon (7.3 g) at room temperature for 1 hour. The reaction mixture was dried over magnesium sulfate and filtered. The filtrate was divided into 3 equal parts. To the above stirred filtrate (1/3 volume, 0.102 mole) was added dropwise simultaneously o -chlorobenzoyl chloride (17.85 g, 0.102 mole) and triethylamine (11.33 g, 0.11 mole). The reaction mixture was allowed to stir overnight at room temperature. The reaction mixture was filtered to remove triethylamine hydrochloride. The filtrate was treated with Florisil® (50 g), filtered, and evaporated to dryness. The dark residue was dissolved in ethanol, diluted with water, and refrigerated overnight with seed crystals. The dark crystalline precipitate was filtered off and dried under high vacuum at room temperature overnight. A ∼9 g sample was heated to boiling in ∼600 ml of water and the mixture was filtered hot through a Celite pad to remove an insoluble dark oil. The crystalline precipitate, which formed upon cooling, was filtered off and dried under high vacuum at room temperature overnight (∼1.6 g). The solid was recrystallized from methanol-water. The crystalline precipitate was filtered and dried under high vacuum at 50°C overnight to give 0.95 g of title compound, mp 90-92°C. Analysis: Calculated for C₁₇H₁₈N₃O₃Cl: C, 58.71; H, 5.22; N, 12.08 Found C, 58.80; H, 5.20; N, 12.05 Preparation 23 N-[2-[(2-Amino-2-oxoethyl)amino]-3-pyridinyl]-3-chlorobenzamide . A mixture of 2-[(3-nitro-2-pyridinyl)amino]acetamide (26.0 g, 0.133 mole) in 200 ml of ethyl acetate was hydrogenated over 5% palladium on carbon (3.0 g) at 55-60°C for 2 hours. The reaction mixture was diluted with hot methanol and filtered through Celite. The Celite pad was washed with hot methanol until the filtrate was colorless. The filtrate was evaporated to dryness and azeotropically dried with benzene. The solid was dried under high vacuum overnight. To a stirred mixture of the above solid in 1 liter of acetone was added dropwise simultaneously m -chlorobenzoyl chloride (23.28 g, 0.133 mole) and triethylamine (14.75 g, 0.146 mole). The reaction mixture was allowed to stir overnight. The precipitate was filtered off and the filter cake was washed with acetone. The filter cake was dried under high vacuum overnight. The solid was dissolved in methanol (∼25 g in 1.4 liter) and filtered. The clear filtrate was concentrated to ∼700 ml to produce a crystalline precipitate; which was filtered, washed with cold methanol and water, and dried under high vacuum at 50°C overnight to give 11.6 g of title compound, mp 210-11°C. Analysis: Calculated for C₁₄H₁₃N₄O₂Cl : C, 55.18; H, 4.30; N, 18.38 Found : C, 55.15; H, 4.33; N, 18.77 Two additional concentrations gave 18.6 g additional crystals for a total yield of 30.2 g of product. Preparation 24 N-[3-[[3-(Trifluoromethyl)benzoyl]amino]-2-pyridinyl]glycine ethyl ester . Under a nitrogen atmosphere, 3-trifluoromethylbenzoyl chloride (15.2 g, 0.073 mole) and triethylamine (7.4 g, 0.073 mole) were added dropwise and simultaneously to a stirred and chilled (10-15°C) solution of freshly prepared N-[(3-amino)-2-pyridinyl]glycine ethyl ester (0.070 mole), obtained by 5% palladium on carbon hydrogenation of N-(3-nitro-2-pyridinyl)glycine ethyl ester at room temperature, in dry tetrahydrofuran (200 ml). The reaction mixture was stirred overnight at room temperature and filtered. The filtrate was concentrated in vacuo and the residue dissolved in ethyl acetate (150 ml). The ethyl acetate solution was extracted with saturated sodium bicarbonate (3 x 50 ml), water (2 x 50 ml), dried over anhydrous sodium sulfate and concentrated to give a crude yield of 25.5 g (99%). A 3.5-g portion was recrystallized from tetrahydrofuran-isopropyl ether to give 2.7 g of off-white needles, mp 129-130°C. Analysis: Calculated for C₁₇H₁₆N₃O₃F₃ : C, 55.59; H, 4.39; N, 11.44 Found : C, 55.61; H, 4.41; N, 11.42 Preparation 25 N-[3-[(3-Bromobenzoyl)amino]-2-pyridinyl]glycine . Under a nitrogen atmosphere, 3-bromobenzoyl chloride (0.10 mole) (freshly prepared) and triethylamine (10.1 g, 0.010 mole) were added dropwise and simultaneously to a stirred and chilled (10-15°C) solution of freshly prepared N-[(3-amino)-2-pyridinyl]glycine ethyl ester (0.07 mole), obtained by 5% palladium on carbon hydrogenation of N-(3-nitro-2-pyridinyl) glycine ethyl ester at room temperature, in dry tetrahydrofuran (200 ml). The reaction mixture was stirred overnight at room temperature and then was filtered. The filtrate was concentrated and the residue dissolved in ethyl acetate (150 ml) and washed with saturated sodium bicarbonate (3 x 50 ml), water (2 x 50 ml), saturated sodium chloride brine (30 ml), dried over anhydrous sodium sulfate, and concentrated. The residue was recrystallized from isopropyl alcohol-isopropyl ether giving 22 g (83%) of crystals. A 1.7-g portion was recrystallized from isopropyl alcohol/isopropyl ether to give 1.2 g of white solid, mp 139-140°C. Analysis: Calculated for C₁₆H₁₆N₃O₃Br : C, 50.81; H, 4.26; N, 11.11 Found : C, 50.76; H, 4.28; N, 11.02 Preparation 26 N-[3-[(2-Pyridinylcarbonyl)amino]-2-pyridinyl]glycine ethyl ester . Under a nitrogen atmosphere, triethylamine (0.30 mole) and a solution of freshly prepared acid chloride of 2-pyridine carboxylic acid (0.150 mole), obtained by heating at reflux 2-pyridine carboxic acid and excess thionyl chloride in benzene and then azeotropic distillation with benzene, in dry tetrahydrofuran (50 ml) were added simultaneously (dropwise) to a stirred and chilled (10-20°C) solution of freshly prepared N-(3-amino-2-pyridinyl)glycine ethyl ester prepared by reducing N-(3-nitro-2-pyridinyl)glycine ethyl ester (0.106 mole) in 200 ml of dry tetrahydrofuran. The reaction mixture was stirred overnight at room temperature and was filtered. The filtrate was concentrated in vacuo and dissolved in ethyl acetate (250 ml). The solution was washed with saturated sodium bicarbonate solution (3 x 75 ml), water (2 x 75 ml), dried over anhydrous sodium sulfate, and concentrated in vacuo . The residue was crystallized from isopropyl ether-tetrahydrofuran giving 26.5 g (83%). A 3.0-g sample was twice recrystallized from isopropyl ether-tetrahydrofuran to give 2.4 g of a white needles, mp 98-100°C. Analysis: Calculated for C₁₅H₁₆N₄O₃: C, 59.99; H, 5.37; N, 18.66 Found C, 59.86; H, 5.40; N, 18.62 Preparation 27 N-[3-[[4-(Trifluoromethyl)benzoyl]amino]-2-pyridinyl]glycine ethyl ester . Under a nitrogen atmosphere, triethylamine (7.4 g, 0.073 mole) and 4-trifluoromethylbenzoyl chloride (15.2 g, 0.073 mole) were added simultaneously (dropwise) to a stirred and chilled (10-15°C) solution of freshly prepared N-(3-amino-2-pyridinyl)glycine ethyl ester (0.073 mole), obtained by 5% palladium on carbon hydrogenation of N-(3-nitro-2-pyridinyl)glycine ethyl ester at room temperature, in dry tetrahydrofuran (200 ml). The reaction mixture was stirred at room temperature for 2½ hr and filtered. The filtrate was evaporated to dryness and the residue dissolved in methylene chloride (500 ml). The solution was washed with saturated sodium bicarbonate solution (2 x 100 ml), water (100 ml), dried over anhydrous sodium sulfate, and concentrated in vacuo , giving 24.9 g (93%) of solid. A 2.0-g sample was recrystallized form isopropyl alcohol-isopropyl ether to give white solid, mp 155-156°C. Analysis: Calculated for C₁₇H₁₆N₃O₃F₃: C, 55.59; H, 4.39; N, 11.44 Found C, 55.52; H, 4.40; N, 11.38 Preparation 28 N-[3-[(3,4-Dichlorobenzoyl)amino]-2-pyridinyl]glycine ethyl ester . A solution of N-(3-nitro-2-pyridinyl)glycine ethyl ester (22.5 g, 0.1 mole) in 250 ml of tetrahydrofuran was hydrogenated in a small Parr bottle over 5% palladium on carbon (2.5 g) at room temperature for 1 hr. The reaction mixture was dried over magnesium sulfate and filtered through a Celite pad. Under nitrogen atmosphere, 3,4-dichlorobenzoyl chloride (20.95 g, 0.1 mole) and triethylamine (11.1 g, 0.11 mole) were added dropwise simultaneously to the above stirred filtrate at room temperature. After stirring overnight, the reaction mixture was filtered and the filtrate was evaporated to dryness. The residue was treated with acetone and water to obtain a crystalline solid, which was refrigerated overnight. The solid was collected by filtration, washed with water, and dried under high vacuum at 50°C overnight (37.1 g). A 4-g sample was recrystallized from acetone/water and dried under high vacuum at 50°C for 2 days to give 2.66 g of title compound, mp 137-38°C. Analysis: Calculated for C₁₆H₁₅N₃O₃Cl₂ : C, 52.19; H, 4.11; N, 11.41 Found : C, 52.09; H, 4.13; N, 11.44 Preparation 29 N-[3-[(4-Nitrobenzoyl)amino]-2-pyridinyl]glycine ethyl ester . Under a nitrogen atmosphere, triethylamine (14.9 g, 0.148 mole) and 4-nitrobenzoyl chloride (27.5 g, 0.148 mole) in tetrahydrofuran (25 ml) were added simultaneously (dropwise) to a stirred and chilled (5-10°C) solution of freshly prepared N-(3-amino-2-pyridinyl)glycine ethyl ester (0.14 mole), obtained by 5% palladium on carbon hydrogenation of N-(3-nitro-2-pyridinyl)glycine ethyl ester at room temperature, in dry tetrahydrofuran (140 ml). The reaction mixture was stirred at room temperature under nitrogen overnight and the solvent was evaporated under reduced pressure. The resulting solid was triturated in water (200 ml) and saturated sodium bicarbonate solution (200 ml). The solid was filtered off, rinsed with water and dried under vacuum at 50°C to give 50.5 g (95%) of yellow solid. A 2.0-g sample was recrystallized from isopropyl alcohol to give 1.5 g of yellow solid, mp. 151-154°C. Analysis: Calculated for C₁₆H₁₆N₄O₅ : C, 55.81; H, 4.68; N, 16.27 Found : C, 55.81; H, 4.67; N, 16.28 Preparation 30 (S)-N-(3-Nitro-2-pyridinyl)alanine hydrochloride [1:1] . A suspension of 2-chloro-3-nitropyridine (68.6 g, 0.434 mole), ( S )-alanine ethyl ester hydrochloride (100 g, 0.651 mole) and triethylamine (103.7 g, 1.03 mole) in 95% ethanol was heated at reflux for 4.5 hours, during which time a dark yellow solution formed. The reaction mixture was stirred at room temperature overnight and then refluxed for an additional 2 hours. The solvents were evaporated under reduced pressure, and the resulting solid was triturated in ethyl acetate, filtered, and rinsed with additional ethyl acetate. The filtrate and washings were combined and washed three times with water, dried over sodium sulfate, filtered, and evaporated to an oil weighing 107 g (quantitative yield). The oil was eluted through 600 g of silica gel, using ethyl acetate as the eluent, and evaporated to an oil. A 3.5-g portion of the oil was dissolved in isopropyl alcohol and acidified with ethereal hydrogen chloride. The mixture was evaporated and redissolved in acetonitrile. Addition of isopropyl ether caused a solid to precipitate. The solid was collected by filtration and its mother liquor was evaporated and the residue was triturated in ethereal hydrogen chloride. A yellow solid formed which was collected by filtration. Upon standing, more solid formed in the mother liquor. This solid was collected by filtration, rinsed with diethyl ether and dried under high vacuum to give 0.14 g of title compound, mp >260°C (darkens 178-185°C). Analysis: Calculated for C₈H₁₀N₃O₄Cl : C, 38.80; H, 4.07; N, 16.97 Found : C, 39.14; H, 4.19; N, 16.74 Preparation 31 (S)-N-[3-[(4-Chlorobenzoyl)amino]-2-pyridinyl]alanine ethyl ester hydrochloride[1:1] . A solution of ( S )-N-(3-nitro-2-pyridinyl)alanine ethyl ester (5.0 g, 0.0209 mole) in tetrahydrofuran (60 ml) was hydrogenated over 5% palladium on carbon (0.5 g) keeping the temperature of the solution at approximately room temperature to give (S ) -N-(3-amino-2-pyridinyl) alanine ethyl ester. The solution of the reduction product was cooled in an ice bath and dried over magnesium sulfate under nitrogen. The solution was filtered and 4-chlorobenzoyl chloride (3.84 g, 0.022 mole) and triethylamine (2.22 g, 0.022 mole) were added simultaneously, dropwise, to the cooled and stirred solution. The reaction mixture was stirred at room temperature overnight under nitrogen and the solvents were removed under reduced pressure. The residue was partitioned between water (50 ml) and ethyl acetate (50 ml). The layers were separated and the aqueous layer was extracted again with ethyl acetate. The combined organic layers were washed twice with water, dried over magnesium sulfate, treated with charcoal, filtered and evaporated to an oil weighing 6.2 g (85% yield). A 2.2-g portion of the oil was dissolved in isopropyl alcohol and the solution was acidified wtih ethereal hydrogen chloride. The resulting solid was filtered and dried under high vacuum to give 1.70 g of title compound, mp 172-177°C with decomposition. Analysis: Calculated for C₁₇H₁₉N₃O₃Cl₂ : C, 53.14; H, 4.98; N, 10.94 Found : C, 53.11; H, 5.02; N, 10.91 Preparation 32 N,N,N′-Trimethyl-1,4-benzenediamine hydrochloride[1:2] . Formic acid (95-97%, 15 g, 0.326 mole) was added dropwise to acetic anhydride (27 g, 0.264 mole) at 0°C under a nitrogen atmosphere. The resulting solution was heated at 55°C for 3 hours under a nitrogen atmosphere, then cooled to -20°C and a solution of N,N-dimethyl-1,4-phenylenediamine (13.6 g, 0.100 mole) in dry tetrahydrofuran (40 ml) was added. After stirring at -20°C for 30 minutes, the solvents were removed under reduced pressure. The dark residue was dissolved in dry tetrahydrofuran (50 ml) and the solution was cooled in an ice bath. Over 30 minutes, a solution of borane-methyl sulfide in tetrahydrofuran (2.0M, 125 ml, 0.25 mole) was added dropwise. The ice bath was removed, and upon warming, a vigorous reaction commenced. Upon its cessation, the solution was heated at reflux for 3 hours, stirred at room temperature overnight and cooled in ice. Methanol (40 ml) was added. After the mixture was stirred at 0°C for one hour, 200 ml of methanolic hydrogen chloride solution was added to pH ≦2. The reaction mixture was refluxed for one hour and cooled to room temperature. Evaporation of the solvents under reduced pressure gave a dark solid residue. Water (200 ml) and sodium hydroxide pellets were added to pH ≧ 12 and the product was extracted into 3 (200-ml) portions of diethyl ether. The combined ether layers were washed with water (200 ml (3x)), dried over magnesium sulfate, charcoaled, and filtered. Evaporation of the solvents under reduced pressure gave an oily liquid (12.1 g, 80.7% yield). A 7.9-g sample of the oil was dissolved in absolute ethanol and the solution was acidified with hydrogen chloride in methanol and hydrogen chloride in isopropyl alcohol. A solid precipitated and was collected by filtration, rinsed with isopropyl alcohol-isopropyl ether and then isopropyl ether. Drying under high vacuum gave 8.92 g of title compound, mp 207-210°C. Analysis: Calculated for C₉H₁₆N₂Cl₂ : C, 48.44; H, 7.23; N, 12.55 Found : C, 48.44; H, 7.41; N, 12.38 Preparation 33 2-(4-Chlorophenyl)-3H-imidazo[4,5-b]pyridine . A mixture of 2,3-diaminopyridine (10.9 g, 0.1 mole), p -chlorobenzoic acid (16.0 g, 0.102 mole), and 150 g of polyphosphoric acid was heated at 180°C in an oil bath for 3 1/2 hr. The reaction mixture was neutralized with concentrated ammonium hydroxide and basified with sodium hydroxide. The precipitate was filtered and washed with water. The solid was treated with dilute sodium hydroxide, filtered, washed with water, and dried under high vacuum at 60°C overnight. A 3-g sample was dissolved in hot methanol, and the solution was treated with 3 g of charcoal, and filtered through a Celite pad. The product crystallized from the filtrate upon cooling. The precipitate was filtered, washed with methanol-water (2:1), and dried under high vacuum at 70°C to give 1.0 g of the title compound, mp 305-8°C with sublimation. Analysis: Calculated for C₁₂N₈N₃Cl : C, 62.76; H, 3.51; N, 18.30 Found : C, 62.34; H, 3.48; N, 18.25 Preparation 34 (S)-N-(3-Nitro-2-pyridinyl)alanine ethyl ester . Under a nitrogen atmosphere, triethylamine (82.1 g, 0.813 mole) was added to a stirred suspension of 2-chloro-3-nitropyridine (51.4 g, 0.325 mole) and ( S )-alanine ethyl ester hydrochloride (75 g, 0.488 mole) in absolute ethanol (500 ml). After refluxing for 10.5 hr. and stirring at room temperature overnight, the solvents were evaporated under reduced pressure. The residue was triturated in 500 ml of ethyl acetate, filtered, and the filter cake was rinsed with ethyl acetate. The filtrate was washed three times with water, dried over sodium sulfate, filtered and evaporated to an oil weighing 85.6 g. A 1.25-g sample of the oil was eluted through 20 g of silica gel with isopropyl ether as the eluting solvent to give a pure fraction. The solvent was evaporated and the residual oil was dissolved in methylene chloride, filtered, and evaporated to an oil which was dried under high vacuum at 50°C overnight to give 0.9 g of title compound. Analysis: Calculated for C₁₀H₁₃N₃O₄ : C, 50.21; H, 5.48; N, 17.56 Found : C, 49.91; H, 5.45; N, 17.34 Preparation 35 1-[(3-Nitro-2-pyridinyl)amino]-2-propanol . A mixture of 2-chloro-3-nitropyridine (10.0 g, 0.063 mole), DL-1-amino-2-propanol (7.1 g, 0.095 mole), and triethylamine (8.75 ml, 0.063 mole) in absolute ethanol was heated at reflux for 1 1/2 hours. The reaction mixture was evaporated to dryness and the residue was partitioned between water and methylene chloride. The water layer was separated and extracted with methylene chloride (2x). The combined methylene chloride layers were extracted with water and dried over sodium sulfate. The filtrate was evaporated to a yellow oil. The oil was purified on a silica gel column (200 g) eluting first with methylene chloride, followed by 5%, 10%, 25% (500 ml each), and finally 50% ethyl acetate/methylene chloride. The appropriate fractions (TLC using ethyl acetate) were combined and evaporated to an oil. A sample of the oil was dried at 50-60°C, then at 70°C for 6 hours to give 11.9 g (96%) of a yellow oil. Analysis: Calculated for C₈H₁₁N₃O₃ : C, 48.73; H, 5.62; N, 21.31 Found : C, 48.48; H, 5.63; N, 21.31 Preparation 36 4-Chlorobenzoic acid ester with 4-chloro-N-[2-[(2-hydroxypropyl)amino]3-pyridinyl]benzamide . A mixture of 1-[(3-nitro-2-pyridinyl)amino]-2-propanol (9.9 g, 0.05 mole) and 5% palladium on carbon (1.0 g) in 150 ml of tetrahydrofuran was hydrogenated in a glass Parr apparatus for 1/2 hour. The mixture was dried over magnesium sulfate and filtered through a Celite pad to give a colorless filtrate. p -Chlorobenzoyl chloride (8.79 g, 0.05 mole) and triethylamine (6.98 ml, 0.05 mole) were added dropwise to the stirred filtrate at 10-15°C (ice bath). The reaction mixture was allowed to warm to ambient temperature overnight. The reaction mixture was filtered, and the filtrate was evaporated to dryness. The residue was recrystallized from isopropyl alcohol and water. The solid was collected by filtration, then treated with boiling methanol. The insoluble solid was collected by filtration, washed with methanol, and dried under high vacuum overnight to give 1.4 g of solid, mp. 186-188°C. Analysis: Calculated for C₂₂H₁₉N₃O₃Cl₂ : C, 59.47; H, 4.31; N, 9.46 Found : C, 59.11; H, 4.70; N, 9.36 Preparation 37 N-[2-[(2-Hydroxypropyl)amino]-3-pyridinyl]-4-chlorobenzamide hydrochloride[1:1] . A mixture of 1-[(3-nitro-2-pyridinyl)amino]-2-propanol (9.9 g, 0.05 mole) and 5% palladium on carbon (1.0 g) in 150 ml of tetrahydrofuran was hydrogenated in a glass Parr apparatus for 1/2 hour. The mixture was dried over magnesium sulfate and filtered through a Celite pad to give a colorless filtrate. The p -chlorobenzoyl chloride (8.79 g, 0.05 mole) and triethylamine (6.98 ml, 0.05 mole) were added dropwise to the stirred filtrate at 12-15°C (ice bath). The reaction mixture was allowed to warm to ambient temperature overnight. The reaction mixture was filtered, and the filtrate was evaporated to dryness. The residue was recrystallized from isopropyl alcohol and water. The solid was collected by filtration, then treated with boiling methanol. The insoluble solid was collected by filtration, and the filtrate was evaporated to dryness, azeotroped with benzene, and dried under high vacuum. The residue was partitioned between water and methylene chloride. The methylene chloride was extracted with 5% potassium hydroxide and water. The methylene chloride layer was dried, filtered, and evaporated to a foam. A 1.5-g sample was dissolved in ethyl acetate, acidified with ethereal and methanolic hydrogen chloride, and seeded. The crystalline solid was collected by filtration, washed with ethyl acetate, and dried under high vacuum to give 1.2 g of solid, mp 178-180°C. Analysis: Calculated for C₁₅H₁₆N₃O₂Cl·HCl : C, 52.65; H, 5.01; N, 12.28 Found : C, 52.45; H, 5.24; N, 12.19 Preparation 38 α-[(3-Nitro-2-pyridinylamino)methyl]benzenemethanol . A mixture of 2-chloro-3-nitropyridine (20.0 g, 0.13 mole), 2-amino-1-phenylethanol (20.74 g, 0.15 mole), and triethylamine (17.5 ml, 0.13 mole) in 200 ml of absolute ethanol was heated to reflux for 1 1/2 hours. The reaction mixture was filtered and evaporated to dryness. The residue was partitioned between water and methylene chloride (2x). The methylene chloride layers were combined and extracted with water. The methylene chloride layers were dried, filtered, and evaporated to a solid (30.8 g, 94.5%). A 2.4-g sample was recrystallized from methanol and water to give a yellow solid, which was collected by filtration, washed with water, and dried under high vacuum overnight to give 1.8 g of the compound, mp 101-103°C. Analysis: Calculated for C₁₃H₁₃N₃O₃ : C, 60.23; H, 5.05; N, 16.21 Found : C, 59.99; H, 5.26; N, 16.18 Preparation 39 N-[3-[(5-Bromo-2-furanylcarbonyl)amino]-2-pyridinyl]glycine ethyl ester hydrate[1:1] . Under a nitrogen atmosphere, triethylamine (32.12 g, 0.32 mole) and 5-bromofuranoyl chloride (70.0 g, 0.33 mole) in tetrahydrofuran (200 ml) were added simultaneously, dropwise, to a stirred and chilled solution of freshly prepared N-[[3-amino]-2-pyridinyl]glycine ethyl ester (0.318 mole) in dry tetrahydrofuran (∼1 liter), obtained by 5% palladium on carbon reduction of N-[[3-nitro]-2-pyridinyl]glycine ethyl ester (71.95 g, 0.318 mole) at room temperature. The reaction mixture was stirred at room temperature under nitrogen overnight and the solvent was evaporated under reduced pressure. The residue was partitioned between water and ethyl acetate, the layers separated and the aqueous layer was again extracted with ethyl acetate. The combined organic layers were washed with a saturated sodium chloride solution and with water. It was dried over magnesium sulfate, charcoaled, filtered, and the solvent was evaporated under reduced pressure to give a residue weighing 115.5 g (99%). A 5.0-g sample was recrystallized twice from isopropyl alcohol/water and dried under high vacuum overnight to give 3.14 g of title compound, mp 78-81°C. Analysis: Calculated for C₁₄H₁₆N₃O₅Br : C, 43.54; H, 4.18; N, 10.88 Foun d : C, 43.47; H, 4.18; N, 10.62 Preparation 40 (R)-N-(3-Nitro-2-pyridinyl)alanine methyl ester. A suspension of 2-chloro-3-nitropyridine (37.76 g, 0.239 mole), ( R )-alanine methyl ester hydrochloride (50 g, 0.358 mole) and triethylamine (60.3 g, 0.597 mole) in methanol (370 ml) was refluxed overnight under nitrogen. The solvents were removed under reduced pressure and the resulting solid was triturated in ethyl acetate (300 ml), filtered, and rinsed with additional ethyl acetate. The filtrate and washings were combined and washed once with water. The aqueous wash was extracted with ethyl acetate and the combined organic layers were washed several times with water, dried over sodium sulfate, filtered and evaporated under reduced pressure to give an oil weighing 45.6 g (85%). Elution of a portion of the oil with 1:6 tetrahydrofuran/hexane through a silica gel column gave 3.2 g of product after evaporation of solvent. Drying of a portion of the solid under high vacuum at room temperature gave 0.98 g of title compound, mp 39-40°C. Analysis: Calculated for C₉H₁₁N₃O₄ : C, 48.00; H, 4.92; N, 18.66 Found : C, 47.90; H, 4.90; N, 18.54 Preparation 41 N-(3-Nitro-4-pyridinyl)glycine ethyl ester. Under a nitrogen atmosphere, a mixture of 4-chloro-3-nitropyridine (5.3 g, 0.033 mole) and ethyl glycinate hydrochloride (4.67 g, 0.033 mole) in 50 ml of tetrahydrofuran was treated with triethylamine (4.6 ml, 0.033 mole). The reaction mixture was allowed to stir at room temperature for 1 1/2 hours before treating with additional triethylamine (4.6 ml, 0.033 mole). The tetrahydrofuran was evaporated and the residue was partitioned between water and methylene chloride. The aqueous layer was separated and extracted with methylene chloride. The combined methylene chloride extracts were dried over magnesium sulfate and evaporated to dryness. NMR indicated only 26% product, and the remainder starting material. The residue was dissolved in 50 ml of dioxane and treated with triethylamine (9.2 ml, 0.066 mole) and ethyl glycinate hydrochloride (4.67 g, 0.033 mole). The reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was partitioned between water and methylene chloride. The aqueous layer was separated and extracted with methylene chloride (2x). The combined methylene chloride layers were extracted with water, dried over magnesium sulfate, and evaporated to an oil. A portion of the oil was purified by liquid chromatography (silica gel) and elution with ethyl acetate/hexanes (1:1). The appropriate fraction by TLC (ethyl acetate) was evaporated to an oil, which crystallized. The solid was dried under high vacuum over the weekend to give yellow solid, 1.1 g, mp 81.5-83°C. Total yield by HPLC and silica gel filtration was 69%. Analysis: Calculated for C₉H₁₁N₃O₄ : C, 48.00; H, 4.92; N, 18.66 Found : C, 48.11; H, 4.95; N, 18.90 Preparation 42 N-[3-[(5-Methyl-2-thienylcarbonyl)amino]-2-pyridinyl]glycine ethyl ester . Under a nitrogen atmosphere, triethylamine (31.41 g, 0.311 mole) and 5-methyl-2-thiophenecarbonyl chloride (50 g, 0.311 mole) were added simultaneously, dropwise, to a stirred and chilled solution of freshly prepared N-[[3-amino]-2-pyridinyl]glycine ethyl ester (0.296 mole) by palladium/carbon reduction of N-[[3-nitro]-2-pyridinyl]glycine ethyl ester (66.98 g, 0.296 mole) in dry tetrahydrofuran (∼1 liter). The reaction mixture was stirred at room temperature overnight and the solvent was evaporated under reduced pressure. The residue was partitioned between water and ethyl acetate, the layers separated and the aqueous layer was again extracted with ethyl acetate. The combined organic layers were washed twice with a 5% potassium hydroxide solution, twice with a saturated sodium bicarbonate solution, twice with water, dried over magnesium sulfate, treated with charcoal, filtered, and evaporated under reduced pressure to give 95.3 g of a tan solid in quantitative yield. A 1.5-g portion of the solid was dissolved in hot absolute ethanol, filtered while hot, and brought to its cloud point by addition of water. Cooling to room temperature gave a solid which was collected by filtration, rinsed with water, and dried under high vacuum at room temperature overnight to give 1.11 g of title compound, mp 112-115°C. Analysis: Calculated for C₁₅H₁₇N₃O₃S : C, 56.41; H, 5.36; N, 13.16 Found : C, 56.58; H, 5.36; N, 13.02 Preparation 43 N,N-Dimethyl-2-[(3-nitro-4-pyridinyl)amino]acetamide . Condensed dimethylamine (20 ml) was added in portions to a solution of crude N-(3-nitro-4-pyridinyl)glycine ethyl ester (4.0 g, 0.018 mole) in absolute ethanol (10 ml). The reaction was allowed to stir at ambient temperature over the weekend. The mixture was diluted with petroleum ether and the solid was collected by filtration. The solid 3-g was dissolved in tetrahydrofuran, filtered and diluted with isopropyl ether to produce a dark amorphous solid which was filtered off. The filtrate was further diluted with petroleum ether and placed in the freezer to produce a dark orange crystalline solid. The solid (2.5 g) was dissolved in methylene chloride, treated with Florisil©, and the filtrate was evaporated to a yellow solid, which was dried under high vacuum at 70°C to give 1.8 g (45%), mp 142-143°C. Analysis: Calculated for C₉H₁₂N₄O₃ : C, 48.21; H, 5.39; N, 24.99 Found : C, 48.03; H, 5.36; N, 24.89 Preparation 44 N-[3-[(4-Fluorobenzoyl)amino]-2-pyridinyl]glycine ethyl ester . Under a nitrogen atmosphere, triethylamine (31.8 g, 0.315 mole) and 4-fluorobenzoyl chloride (50 g, 0.315 mole) were added simultaneously, dropwise, to a stirred and chilled solution of freshly prepared N-[[3-amino]-2-pyridinyl]glycine ethyl ester (0.33 mole) by palladium/carbon reduction of N-[[3-nitro]-2-pyridinyl]glycine ethyl ester, (75.3 g, 0.33 mole) in dry tetrahydrofuran (∼800 ml). The reaction mixture was stirred at room temperature overnight and the solvent was evaporated under reduced pressure. The residue was partitioned between ethyl acetate (300 ml) and water (300 ml), the insoluble material was filtered off, the layers were separated and the aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed three times with water, dried over magnesium sulfate, treated with charcoal, filtered and evaporated to give 76.8 g of crude solid (77% yield). A 6.8-g portion of the solid was recrystallized from isopropyl alcohol and water to give 5.63 g of title compound, mp 127-128.5°C. Analysis: Calculated for C₁₆H₁₆N₃O₃F : C, 60.56; H, 5.08; N, 13.24 Found : C, 60.19; H, 5.10; N, 13.09 Preparation 45 Following the procedure of preparation 33 but substituting the following for 2,3-diaminopyridine: a. 2,3-diamino-4-chloropyridine (C.A. 72 , 12687d), b. 2,3-diamino-5-chloropyridine (C.A. 72 , 78970x), c. 2,3-diamino-4,6-dichloropyridine (C.A. 72 , 12687d), d. 2,3-diamino-5-nitropyridine (C.A. 72 , 3431p), e. 2,3-diamino-6-methoxypyridine (C.A. 72 , 61408x), f. 2,3-diamino-5,6-dichloropyridine (C.A. 54 , 5683d), g. 2,3-diamino-5-bromopyridine (C.A. 61 , 651a), h. 2,3-diamino-6-chloropyridine (C.A. 61 , 7763d), i. 2,3-pyridinediamine-4-methylpyridine (US patent 3,985,891), j. 2,3-pyridinediamine-5-methylpyridine (US patent 3,985,891) and k. 2,3-pyridinediamine-6-methylpyridine (US patent 3,985,891). there are obtained: a. 2-(4-chlorophenyl)-7-chloro-3H-imidazo[4,5-b]pyridine, b. 2-(4-chlorophenyl)-6-chloro-3H-imidazo[4,5-b]pyridine, c. 2-(4-chlorophenyl)-5,7-dichloro-3H-imidazo[4,5-b]pyridine, d. 2-(4-chlorophenyl)-6-nitro-3H-imidazo[4,5-b]pyridine, e. 2-(4-chlorophenyl)-5-methoxy-3H-imidazo[4,5-b]pyridine, f. 2-(4-chlorophenyl)-5,6-dichloro-3H-imidazo[4,5-b]pyridine, g. 2-(4-chlorophenyl)-6-bromo-3H-imidazo[4,5-b]pyridine, h. 2-(4-chlorophenyl)-5-chloro-3H-imidazo[4,5-b]pyridine, i. 2-(4-chlorophenyl)-7-methyl-3H-imidazo[4,5-b]pyridine, j. 2-(4-chlorophenyl)-6-methyl-3H-imidazo[4,5-b]pyridine and k. 2-(4-chlorophenyl)-5-methyl-3H-imidazo[4,5-b]pyridine. Preparation 46 Following the procedure of preparation 33 but substituting the following for 2,3-diaminopyridine: a. 3,4-diamino-2-methoxypyridine (C.A. 75 , 62924m), b. 3,4-diamino-5-bromo-6-chloropyridine (C.A. 58 , 5676a), c. 3,4-diaminopyridine (C.A. 66 , 75975t), d. 3,4-diamino-2-chloropyridine (C.A. 63 , 5628e), e. 3,4-diamino-2,6-dichloropyridine (C.A. 63 , 5628e), f. 3,4-diamino-5-nitropyridine (C.A. 62 , 16231h), g. 3,4-diamino-6-bromo-2-chloropyridine (C.A. 58 , 5676a), h. 3,4-diamino-5-bromopyridine (C.A. 58 , 5675h) and i. 4,5-diamino-2-chloropyridine (C.A. 63 , 5628e). there are obtained: a. 2-(4-chlorophenyl)-4-methoxy-3H-imidazo[4,5-c]pyridine, b. 2-(4-chlorophenyl)-6-chloro-7-bromo-3H-imidazo[4,5-c]pyridine, c. 2-(4-chlorophenyl)-3H-imidazo[4,5-c]pyridine, d. 2-(4-chlorophenyl)-4-chloro-3H-imidazo[4,5-c]pyridine, e. 2-(4-chlorophenyl)-4,6-dichloro-3H-imidazo[4,5-c]pyridine, f. 2-(4-chlorophenyl)-7-nitro-3H-imidazo[4,5-c]pyridine, g. 2-(4-chlorophenyl)-4-chloro-6-bromo-3H-imidazo[4,5-c]pyridine, h. 2-(4-chlorophenyl)-7-bromo-3H-imidazo[4,5-c]pyridine and i. 2-(4-chlorophenyl)-6-chloro-1H-imidazo[4,5-c]pyridine. Preparation 47 Following the procedure of preparation 1 but substituting the following for 2-chloro-3-nitropyridine: a. 2-chloro-3-nitro-4-methylpyridine (C.A. 94 , 15636b), b. 2-chloro-3-nitro-5-methylpyridine (C.A. 89 , 6192y), c. 2-chloro-3-nitro-6-methylpyridine (C.A. 89 , 43036w), d. 2-chloro-3-nitro-5,6-dimethylpyridine (C.A. 90 , 121359r), e. 4-chloro-6-diethylamino-2-methyl-5-nitropyridine (C.A. 88 , 6799f), f. 4-chloro-2-methyl-3-nitropyridine (C.A. 91 , 20266y) and g. 2-chloro-6-methoxy-3-nitropyridine (C.A. 77 , 148422g). there are obtained: a. N-(4-methyl-3-nitro-2-pyridinyl)glycine ethyl ester, b. N-(5-methyl-3-nitro-2-pyridinyl)glycine ethyl ester, c. N-(6-methyl-3-nitro-2-pyridinyl)glycine ethyl ester, d. N-(5,6-dimethyl-3-nitro-2-pyridinyl)glycine ethyl ester, e. N-(6-diethylamino-2-methyl-5-nitro-4-pyridinyl)glycine ethyl ester, f. N-(2-methyl-3-nitro-4-pyridinyl)glycine ethyl ester and g. N-(6-methoxy-3-nitro-2-pyridinyl)glycine ethyl ester. Preparation 48 a-g Following the procedure of preparation 13 but substituting the following for N-(3-nitro-2-pyridinyl) glycine ethyl ester: a. N-(4-methyl-3-nitro-2-pyridinyl)glycine ethyl ester, b. N-(5-methyl-3-nitro-2-pyridinyl)glycine ethyl ester, c. N-(6-methyl-3-nitro-2-pyridinyl)glycine ethyl ester, d. N-(5,6-dimethyl-3-nitro-2-pyridinyl)glycine ethyl ester, e. N-(6-diethylamino-2-methyl-5-nitro-4-pyridinyl)glycine ethyl ester, f. N-(2-methyl-3-nitro-4-pyridinyl)glycine ethyl ester and g. N-(6-methoxy-3-nitro-2-pyridinyl)glycine ethyl ester. there are obtained: a. N-[3-(4-chlorobenzoylamino)-4-methyl-2-pyridinyl]glycine ethyl ester, b. N-[3-(4-chlorobenzoylamino)-5-methyl-2-pyridinyl]glycine ethyl ester, c. N-[3-(4-chlorobenzoylamino)-6-methyl-2-pyridinyl]glycine ethyl ester, d. N-[3-(4-chlorobenzoylamino)-5,6-dimethyl-2-pyridinyl]glycine ethyl ester, e. N-[5-(4-chlorobenzoylamino)-6-diethylamino-2-methyl-4-pyridinyl]glycine ethyl ester, f. N-[3-(4-chlorobenzoylamino)-2-methyl-4-pyridinyl]glycine ethyl ester and g. N-[3-(4-chlorobenzoylamino)-6-methoxy-2-pyridinyl]glycine ethyl ester. Preparation 49 (R)-N-[3-[(4-Chlorobenzoyl)amino]-2-pyridinyl]alanine methyl ester . A solution of ( R )-N-(3-nitro-2-pyridinyl)alanine methyl ester (21.0 g, 0.0933 mole) in tetrahydrofuran (300 ml) was hydrogenated over 5% palladium on carbon (2.1 g) keeping the temperature of the solution at approximately room temperature. The solution of the reduction product was cooled in an ice-bath and dried over magnesium sulfate under nitrogen. The solution was filtered and 4-chlorobenzoyl chloride (17.2 g, 0.0982 mole) and triethylamine (9.9 g, 0.0982 mole) were added simultaneously, dropwise, to the cooled and stirred solution. After stirring at room temperature overnight, the solvents were removed under reduced pressure and the residue was partitioned between ethyl acetate (200 ml) and water (200 ml). The layers were separated and the aqueous layer was extracted again with ethyl acetate (100 ml). The combined organic layers were washed three times with water, dried over magnesium sulfate, treated with charcoal, filtered and evaporated to give 30.9 g (99%) of product. A 3.5-g portion of the product was dissolved in hot isopropyl alcohol, treated with charcoal and filtered while hot. Petroleum ether was added to the cool solution and upon stirring, solid precipitated, which was collected by filtration and dried under high vacuum to give 0.68 g of title compound, mp 125-134°C. Analysis: Calculated for C₁₆H₁₆N₃O₃Cl : C, 57.58; H, 4.83; N, 12.59 Found : C, 57.52; H, 4.85; N, 12.52 Preparation 50 4-Chloro-N-(4-chlorobenzoyl)-N-[4-[[2-(dimethylamino)-2-oxoethyl]amino]-3-pyridinyl]benzamide hydrate [1:1] . A mixture of N,N-dimethyl-2-[(3-nitro-4-pyridinyl)amino]acetamide (11.0 g, 0.05 mole) and 5% palladium on carbon catalyst (1.1 g) in 250 ml of tetrahydrofuran was hydrogenated in a small Parr apparatus while heating at 50°C. The reaction mixture was heated with methanol and filtered through a Celite pad. The pad was washed with boiling methanol. The filtrate was evaporated to a solid. The solid was dissolved in acetonitrile (500 ml) and treated with p -chlorobenzoyl chloride (5.97 ml, 0.047 mole) and triethylamine (6.52 ml, 0.047 mole). The reaction mixture was stirred at ambient temperature overnight. The reaction mixture was filtered and the filtrate was evaporated. The solid residue was partitioned between methylene chloride and water (2x). The methylene chloride layer was dried and evaporated to dryness. The residue was dissolved in ethyl acetate, treated with charcoal, filtered through Celite, and concentrated. A crystalline precipitate was collected by filtration, washed with isopropyl ether and dried at 50°C under high vacuum to give 4.65 g of solids (40%), mp 175-176°C. Analysis: Calculated for C₂₃H₂₀N₄O₃Cl₂·H₂O : C, 56.45; H, 4.53; N, 11.45 Found : C, 56.03; H, 4.47; N, 11.55 The filtrate was evaporated to dryness to give 9.24 g of crude title compound. Preparation 51 4-Chloro-N-[2-[(2-hydroxy-2-phenylethyl)amino]-3-pyridinyl]benzamide . A mixture of α-[(3-nitro-2-pyridinylamino)methyl]benzene methanol (30.8 g, 0.12 mole) and 5% palladium on carbon catalyst in 450 ml of tetrahydrofuran was hydrogenated in a large glass Parr bottle at room temperature. The reaction mixture was dried over magnesium sulfate and filtered through a Celite pad. p -Chlorobenzoyl chloride (15.1 ml, 0.12 mole) and triethylamine (16.5 ml, 0.12 mole) were added simultaneously dropwise to the stirred filtrate at 12-15°C (ice-water bath) and the mixture was allowed to stir at ambient temperature overnight. The reaction mixture was filtered and the filtrate was evaporated to dryness. The residue was partitioned between methylene chloride and water. The methylene chloride layer was separated and extracted with water (1x), 5% potassium hydroxide (2x), and water (2x). The methylene chloride layer was separated, dried, and evaporated to dryness. The residue was purified on a silica gel column (400 g) by eluting with 50% ethyl acetate/50% hexanes. Total recovery: 18.2 g (41.6% yield). A 5-g sample was recrystallized from ethyl acetate/hexanes to give 2.71 g of solid, mp. 157-159°C. Analysis: Calculated for C₂₀H₁₈N₃O₂Cl : C, 65.31; H, 4.93; N, 11.42 Found : C, 65.19; H, 4.95; N, 11.41 Preparation 52 N-(6-Chloro-3-nitro-2-pyridinyl)glycine ethyl ester . To a suspenson of 2,6-dichloro-3-nitropyridine (1.0 g, 0.00518 mole) and glycine ethyl ester hydrochloride (0.725 g, 0.00518 mole) in absolute ethanol (10 ml) was added triethylamine (1.05 g, 0.0104 mole). The resulting solution was stirred overnight at room temperature under nitrogen. An additional portion of absolute ethanol (10 ml) was added and the suspension was filtered and the solid was washed with 3-10 ml portions of absolute ethanol. The combined filtrate and washings were evaporated under reduced pressure at room temperature to give a yellow solid which was triturated in water (30 ml) collected by filtration, and rinsed with additional water. The solid was recrystallized from isopropyl ether/light petroleum ether, and the resulting solid was purified by column chromatography (10 g of silica gel) with 1:1 isopropyl ether/light petroleum ether as the eluting solvent. The appropriate fraction was recrystallized from isopropyl ether and dried under high vacuum to give the title compound, mp 77.5-80°C. Analysis: Calculated for C₉H₁₀N₃O₄Cl : C, 41.63; H, 3.88, N, 16.18 Found : C, 41.61; H, 3.85; N, 16.10 Preparation 53 N-[6-Chloro-3-[(4-chlorobenzoyl)amino]-2-pyridinyl]glycine ethyl ester . A solution of N-(6-chloro-3-nitro-2-pyridinyl) glycine ethyl ester (5.0 g, 0.0193 mole) in tetrahydrofuran (100 ml) was hydrogenated over platinum dioxide (0.5 g) at room temperature. After 2/3 of the theoretical amount of hydrogen had been absorbed, the mixture was filtered and a fresh portion of platinum dioxide (0.5 g) was added. The hydrogenation was continued until the theoretical amount of hydrogen was absorbed. The reaction mixture was cooled in ice, dried over magnesium sulfate and filtered. Triethylamine (2.05 g, 0.0203 mole) and 4-chlorobenzoyl chloride (3.55 g, 0.0203 mole) were added simultaneously, dropwise, to the cooled and stirred solution. After stirring at room temperature for 1.75 hours, the mixture was evaporated under reduced pressure and partitioned between water (100 ml) and ethyl acetate (100 ml). The layers were separated and the aqueous layer was re-extracted with ethyl acetate. The combined ethyl acetate layers were washed three times with saturated sodium chloride solution, dried over magnesium sulfate, charcoaled, filtered, and evaporated under reduced pressure. The resulting solid was dissolved in hot isopropyl alcohol, filtered hot and cooled to room temperature to give a solid which was collected by filtration and rinsed with isopropyl ether to give 2.2 g of title compound (31% yield). A 0.5 g portion was dissolved in hot isopropyl alcohol, filtered hot, isopropyl ether was added, and the mixture was cooled. The resulting suspension was filtered, the filtrate was evaporated under reduced pressure, and the residue was recrystallized from isopropyl alcohol/water and dried under high vacuum at 60°C to give 0.37 g of the title compound, mp 157-158.5°C. Analysis: Calculated for C₁₆H₁₅N₃O₃Cl₂ : C, 52.19; H, 4.11, N, 11.41 Found : C, 52.28; H, 4.05; N, 11.09 Example 1 2-(4-Chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid. A mixture of 14.6 g (0.04 mole) of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid ethyl ester, 2.9 g (0.073 mole) of sodium hydroxide pellets, and 150 ml of ethanol/water (1:1) was refluxed for 45 min. The reaction mixture was poured into a 250-ml of water, acidified with concentrated hydrochloric acid; and filtered, giving 12.8 g (97%) of a white solid. A 2-g portion was recrystallized from methanol-water to give 1.2 g of white needles, mp 271-273°C with decomposition. Analysis: Calculated for C₁₄H₁₀N₃O₂Cl : C, 58.45; H, 3.50; N, 14.61 Found : C, 58.30; H, 3.50; N, 14.57 Example 2 2-(4-Bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid. A mixture of 2-(4-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid ethyl ester (7.00 g, 0.0194 mole) sodium hydroxide pellets (0.88 g, 0.0220 mole), and 95% ethanol (100 ml) was refluxed for 1 hr. The reaction mixture was cooled and filtered. The filter cake (7.3 g) was dissolved in warm water, acidified with concentrated hydrochloric acid, and chilled. The precipitated solid was collected by filtration and the filter cake was rinsed with water, giving 5.6 g (87%) of crystals. Recrystallization from tetrahydrofuran-methanol gave 5.4 g of white needles, mp 264-267°C. Analysis: Calculated for C₁₄H₁₀N₃O₂Br : C, 50.63; H, 3.03; N, 12.65 Found : C, 50.38; H, 2.97; N, 12.70 Example 3 2-[4-(Trifluoromethyl)phenyl]-3H-imidazo[4,5-b]pyridine-3-acetic acid. A solution of 2-[4-(trifluoromethyl)phenyl]-3H-imidazo[4,5-b] pyridine-3-acetic acid ethyl ester (17.7 g, 0.051 mole), potassium hydroxide pellets (4.5 g, 0.080 mole), 95% ethanol (150 ml), and water (10 ml) was refluxed for 2-1/2 hrs. The ethanol was evaporated in vacuo , the residue acidified with glacial acetic acid, and the mixture filtered. The filter coke was suspended in water (300 ml) and filtered. The filter cake was air dried (17 g) and recrystallized from ethanol-water to give 12.21 g (75%) of a white solid, mp 240-241°C. Analysis: Calculated for C₁₅H₁₀N₃O₂F₃ : C, 56.08; H, 3.14; N, 13.08 Found : C, 56.02; H, 3.11; N, 13.07 Example 4 2-(4-Nitrophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid hydrate [1:1]. Under a nitrogen atmosphere, a suspension of N-[3-[(4-nitrobenzoyl)amino]-2-pyridinyl]glycine ethyl ester (47.4 g, 0.138 mole) in ethylene glycol (235 ml) was refluxed, with stirring, for 1.5 hr. A solution was formed during heating. The solution was cooled and water (41.5 ml) and potassium hydroxide pellets (10.6 g, 0.189 mole) were added. Solid precipitated, but upon heating, a solution was again formed. The solution was refluxed for 2 hr, cooled, and poured into 750 ml of ice water. Upon acidification with a 3 N hydrochloric acid solution, a yellow solid precipitated. The solid was collected by filtration and rinsed with water. The solid was dissolved in hot methanol, filtered hot and cooled to room temperature. Addition of water caused solid to precipitate. The solid was collected by filtration and dried under high vacuum to give 16.4 g of orange solid (40% yield). 1.0 g of the solid was dissolved in hot methanol, and the solution was treated with charcoal, filtered hot, and cooled to room temperature, causing a solid to precipitate. The solid was collected by filtration, rinsed with water and dried under high vacuum at room temperature overnight to give 0.61 g of title compound, mp. 249-251°C. Analysis: Calculated for C₁₄H₁₂N₄O₅ : C, 53.17; H, 3.82; N, 17.71 Found : C, 52.86; H, 3.64; N, 17.49 Example 5 2-(4-Chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetamide. A mixture of N-[2-[(2-amino-2-oxoethyl)amino]-3-pyridinyl]-4-cblorobenzamide (6.0 g, 0.02 mole) in 150 ml of ethylene glycol was heated at 190°C for 40 minutes. The precipitate, which formed, was filtered off and washed with water. The filtrate was diluted with water to produce a second crop. The first crop was heated to boiling in 300 ml of methanol, filtered through a Celite pad, seeded, and refrigerated overnight. The crystalline precipitate was filtered, washed with cold methanol, and dried under high vacuum at 60°C overnight to give 1.42 g (25%) of title compound, mp 270-1°C. Analysis: Calculated for C₁₄H₁₁N₄OCl : C, 58.65; H, 3.87; N, 19.54 Found : C, 58.38; H, 3.86; N, 19.56 Example 6 2-(4-Chlorophenyl)-3-[2-(4-morpholinyl)-2-oxoethyl]-3H-imidazo[4,5-b]pyridine . A stream of nitrogen gas was bubbled through a stirred suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.96 g, 0.0208 mole), 1,1'-carbonyldiimidazole (3.37 g, 0.0208 mole), and anhydrous tetrahydrofuran (100 ml) at room temperature for 3 hrs. To the resulting solution was added dropwise a solution of morpholine (1.81 g, 0.0208 mole) in tetrahydrofuran (10 ml). The reaction mixture was stirred overnight at room temperature. The tetrahydrofuran was evaporated and the crystalline residue suspended in water and filtered, giving 5.35 g (72%). Recrystallization from 95% ethanol gave 4.9 g of white flakes, mp 213-216°C. Analysis: Calculated for C₁₈H₁₇N₄O₂Cl : C, 60.59; H, 4.80; N, 15.70 Found : C, 60.84; H, 4.84; N, 15.94 Example 7 2-(4-Chlorophenyl)-N-[2-(dimethylamino)ethyl]-3H-imidazo[4,5-b]pyridine-3-acetamide. A stream of nitrogen was bubbled through a stirred suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (4.50 g, 0.0157 mole), 1,1'-carbonyldiimidazole (2.54 g, 0.0157 mole) and anhydrous methylene chloride (100 ml) for 2 hrs at room temperature. A solution of N,N-dimethylethylenediamine (1.50 g, 0.0170 mole) in 10 ml of methylene chloride was added dropwise and the reaction mixture was stirred overnight at room temperature. The methylene chloride was washed with water (2 x 30 ml), 5% sodium hydroxide (2 x 30 ml), water (30 ml), dried over sodium sulfate and concentrated. The residue (4.5 g) was recrystallized from isopropyl alcohol to give 3.5 g (62%) of white flakes, mp 195-196.5°C. Analysis: Calculated for C₁₈H₂₀N₅OCl : C, 60.42; H, 5.63; N, 19.57 Found : C, 60.57; H, 5.68; N, 19.87 Example 8 2-(4-Chlorophenyl)-N-[2-(dimethylamino)ethyl]-3H-imidazo[4,5-b] pyridine-3-acetamide hydrochloride [1:2] . 2-(4-Chlorophenyl)-N-[2-(dimethylamino)ethyl]-3H-imidazo[4,5-b]pyridine-3-acetamide (0.5 g, 0.0014 mole) was dissolved in acetone, acidified with ethanolic hydrogen chloride, and seeded to initiate crystallization. The solid was collected by filtration, washed with diethyl ether, and dried under high vacuum at room temperature overnight to give 0.60 g (quantitative yield), m.p. 222-25°C. Analysis: Calculated for C₁₈H₂₂N₅OCl₃ : C, 50.19; H, 5.15; N, 16.26 Found : C, 50.00; H, 5.25; N, 16.16 Example 9 2-(4-Chlorophenyl)-N-methyl-3H-imidazo[4,5-b]pyridine-3-acetamide . Under a nitrogen atmosphere, a suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid, 6.0 g (0.021 mole) and 1,1'-carbonyldiimidazole (3.39 g, 0.021 mole) in tetrahydrofuran (150 ml) was refluxed, with stirring, for 2.5 hrs. The mixture was cooled to room temperature and a solution of 3.6 g (0.116 mole) of monomethylamine in tetrahydrofuran (60 ml) was added dropwise and the reaction mixture was stirred at room temperature overnight. The tetrahydrofuran was evaporated and the residue was triturated in water (150 ml). The solid was filtered and rinsed with water. The solid was dissolved in hot isopropyl alcohol, treated with charcoal, filtered, and allowed to cool. Solid formed, and water was added to precipitate more. The solid was filtered and dried under vacuum to give 3.0 g (47.5%) of title compound, mp 238-238.5°C. Analysis: Calculated for C₁₅H₁₃N₄OCl : C, 59.91; H, 4.36; N, 18.63 Found : C, 59.76; H, 4.37; N, 18.43 Example 10 2-(4-Chlorophenyl)-N,N-dimethyl-3H-imidazo[4,5-b]pyridine-3-acetamide. A suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (3.0 g, 0.010 mole) 1,1'-carbonyldiimidazole (1.7 g, 0.010 mole) and dry tetrahydrofuran (150 ml) was stirred for 3 hrs. at room temperature with a stream of nitrogen bubbling through it. A solution of 1.0 g of dimethylamine in 25 ml of tetrahydrofuran was added and the reaction container was stoppered and the mixture was stirred overnight at room temperature. The tetrahydrofuran was evaporated and the residue triturated in water (50 ml) and filtered. The filter cake was recrystallized from isopropyl alcohol and then from ethanol, giving 2.4 g (32%) of white needles, mp 212-213°C. Analysis: Calculated for C₁₆H₁₅N₄OCl : C, 61.05; H, 4.80; N, 17.80 Found : C, 60.78; H, 4.76; N, 17.67 Example 11 2-(4-Chlorophenyl)-N,N-dimethyl-3H-imidazo[4,5-b]pyridine-3-acetamide hydrochloride[1:1] . A mixture of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (6.0 g, 0.021 mole) and 1,1'-carbonyldiimidazole (3.39 g, 0.021 mole) in 150 ml of tetrahydrofuran was stirred at room temperature for 3 hours with nitrogen bubbling through it. A solution of dimethylamine in tetrahydrofuran (84 ml of 1 M solution, 0.042 mole) was added dropwise at room temperature to the stirred solution and the reaction mixture was allowed to stir at room temperature overnight. The tetrahydrofuran was evaporated and the solid was triturated with water. The solid was collected and dried under high vacuum overnight. The solid was dissolved in tetrahydrofuran and acidified with ethereal hydrogen chloride to produce a crystalline precipitate, which was collected, washed with tetrahydrofuran, and dried under high vacuum overnight at room temperature to give 5.3 g (73%), mp 216-219.5°C. Analysis: Calculated for C₁₆H₁₆N₄OCl₂ : C, 54.71; H, 4.59; N, 15.95 Found : C, 54.58; H, 4.64; N, 15.88 Example 12 2-(4-Chlorophenyl)-3H-imidazol[4,5-b]pyridine-3-acetic acid 1-methylethyl ester . A solution of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (3.1 g, 0.0108 mole), isopropanol (50 ml), benzene (50 ml), and concentrated sulfuric acid (5 ml) was refluxed under a Dean-Stark trap for 24 hrs. The reaction mixture was concentrated and the residue partitioned between 5% potassium hydroxide solution (50 ml) and ethyl acetate (50 ml). The layers were separated and the aqueous portion extracted with ethyl acetate (2 x 25 ml). The organic layers were combined and washed with 5% potassium hydroxide (25 ml), water (25 ml), dried over sodium sulfate, and concentrated in vacuo to give 2.0 g (56%) of a solid, mp 118-120°C. Recrystallization from isopropyl ether gave 1.7 g of off-white needles, mp 117.5-119°C. Analysis: Calculated for C₁₇H₁₆N₃O₂Cl : C, 61.92; H, 4.89; N, 12.74 Found : C, 61.87; H, 4.84; N, 12.67 Example 13 N,N-Dimethyl-2-[4(trifluoromethyl)phenyl]-3H-imidazo [4,5-b]pyridine-3-acetamide . A suspension of 2-(4-trifluoromethylphenyl)-3H-imidazo [4,5-b]pyridine-3-acetic acid (10.0 g, 0.031 mole), 1,1'-carbonyldiimidazole (6.0 g, 0.037 mole), and dry tetrahydrofuran (200 ml) was stirred at room temperature for 2 hr. with a stream of nitrogen bubbling through it. The suspension was heated at 59°C under nitrogen for 2 hr, cooled in ice and treated with a solution of dimethylamine in tetrahydrofuran (4.22 g of dimethylamine in 40 ml of tetrahydrofuran.) The solution was stirred at room temperature overnight, more dimethylamine (0.071 mole in 30 ml of tetrahydrofuran) was added, and the reaction mixture was heated at 45°C for 3 hr. The reaction mixture was concentrated under reduced pressure; the resulting solid was triturated in water, filtered, rinsed twice with water, twice with 5% potassium hydroxide solution and then twice again with water. The solid was dissolved in hot isopropyl alcohol, filtered hot, and cooled. Water was added and the solid filtered and dried it 80°C under vacuum to yield 3.55 g (33%) of white solid, mp. 181-183°C. Analysis: Calculated for C₁₇H₁₅N₄OF₃ : C, 58.62; H, 4.32; N, 16.08 Found : C, 58.76; H, 4.37; N, 16.07 Example 14 2-(4-Chlorophenyl)-N,N-dipropyl-3H-imidazo[4,5-b]pyridine-3-acetamide . A mixture of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (6.0 g, 0.021 mole) and 1,1'-carbonyldiimidazole (3.39 g, 0.021 mole) in 150 ml of tetrahydrofuran was stirred at room temperature for 2 hours with a stream of nitrogen bubbling through it. A solution of di-n-propylamine (1.94 g, 0.063 mole) in tetrahydrofuran was added dropwise at room temperature to the stirred solution and the reaction mixture was allowed to stir at room temperature overnight. The tetrahydrofuran was evaporated and the solid residue was triturated with water. The solid was collected by filtration and dried under high vacuum overnight. The solid was recrystallized from isopropyl alcohol-water, collected by filtration, washed with water, and dried under high vacuum at room temperature over the weekend to give 3.79 g (59%) in 2 crops, mp 156-57°C. Analysis: Calculated for C₂₀H₂₃N₄OCl : C, 64.77; H, 6.25; N, 15.11 Found : C, 64.60; H, 6.26; N, 15.08. Example 15 2-(4-Chlorophenyl)-N,N-diethyl-3H-imidazo[4,5-b]pyridine-3-acetamide hydrate[1:0.5] . A mixture of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.64 g, 0.020 mole) and 1,1'-carbonyldiimidazole (3.18 g, 0.02 mole) in 150 ml of tetrahydrofuran was stirred at room temperature for 2 hours with a stream of nitrogen bubbling through it. A solution of diethylamine (2.87 g, 0.04 mole) in tetrahydrofuran was added dropwise at room temperature to the stirred solution and the mixture was allowed to stir overnight. The tetrahydrofuran was evaporated and the solid residue was triturated with water. The solid was collected by filtration and dried under high vacuum overnight. The solid was recrystallized from isopropyl alcohol-water, collected by filtration, washed with water, and dried under high vacuum it room temperature over the weekend to give 3.83 g (57%) mp 155-56°C. Analysis: Caculated for C₁₈H₁₉N₄OCl·½H₂O : C, 61.45; H, 5.73; N, 15.92 Found : C, 61.34; H, 5.46; N, 15.96 Example 16 2-(4-Chlorophenyl)-N-[3-(dimethylamino)propyl]-3H-imidazo [4,5-b]pyridine-3-acetamide hydrochloride hydrate [1:2:1] . Under nitrogen bubbling, a mixture of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0174 mole) and 1,1'-carbonyldiimidazole (2.82 g, 0.0174 mole) in 150 ml of tetrahydrofuran was stirred at room temperature for 3 hrs. Under a nitrogen atmosphere, N,N-dimethylaminopropylamine (1.94 g, 0.019 mole) was added dropwise and the reaction was allowed to stir at room temperature overnight. The tetrahydrofuran was evaporated to dryness and the residue was treated with ice water. The solid was collected by filtration and dried under high vacuum. The solid was dissolved in isopropyl alcohol, acidified with ethereal hydrogen chloride, and seeded. The crystalline material was collected by filtration, washed with cold isopropyl alcohol, and dried under high vacuum at 50°C over the weekend to give 2.78 g (34.5%), mp. 188-90°C. Analysis: Calculated for C₁₉H₂₂N₅OCl·2HCl·H₂O : C, 49.31; H, 5.66; N, 15.13 Found : C, 49.34; H, 5,69; N, 15.20 Example 17 2-(4-Bromophenyl)-N,N-dimethyl-3H-imidazo[4,5-b]pyridine-3-acetamide . A suspension of 2-(4-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.5 g, 0.0166 mole), 1,1'-carbonyldiimidazole (2.7 g, 0.0166 mole), and anhydrous tetrahydrofuran (100 ml) was stirred at room temperature with a stream of nitrogen bubbling through it for 2½ hours. The nitrogen flow was stopped and a solution of dimethylamine (0.5 M in tetrahydrofuran) (66 ml) was added. The solution was stirred at room temperature, stoppered, for 16 hours. The reaction mixture was concentrated in vacuo and the residue triturated in water (100 ml) and filtered. The filter cake was recrystallized from ethanol to give 3.78 g (63%) of white needles, mp 224-225°C. Analysis: Calculated for C₁₆H₁₅N₄OBr : C, 53.50; H, 4.21; N, 15.60 Found : C, 53.55; H, 4.19; N, 15.68 Example 18 2-(4-Chlorophenyl)-N-(2-propenyl)-3H-imidazo[4,5-b]pyridine-3-acetamide . Under nitrogen bubbling, a mixture of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (4.0 g, 0.014 mole) and 1,1'-carbonyldiimidazole (2.27 g, 0.014 mole) 130 ml tetrahydrofuran was stirred at room temperature for 3 hours. Under a nitrogen atmosphere, N-allylamine (1.60 g, 0.028 mole) was added and the reaction mixture was allowed to stir at room temperature overnight. The tetrahydrofuran was evaporated to a solid, which was placed under high vacuum over the weekend. The solid residue was dissolved in isopropyl alcohol, filtered, and diluted with water to initiate crystallization, then refrigerated overnight. The solid was collected by filtration, washed with water, and dried under high vacuum at 50°C overnight to give 3.0 g (66%) of title compound, mp 208-9°C. Analysis: Calculated for C₁₇H₁₅N₄OCl : C, 62.48; H, 4.63; N, 17.14 Found : C, 62.53; H, 4.64; N, 17.18 Example 19 2-(4-Bromophenyl)-N-methyl-3H-imidazo[4,5-b]pyridine-3-acetamide . A solution of 2-(4-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.5 g, 0.0166 mole) and 1,1'-carbonyldiimidazole (2.7 g, 0.0166 mole) in anhydrous tetrahydrofuran (100 ml) was stirred at room temperature with a stream of nitrogen bubbling through it for 2½ hours. The nitrogen flow was stopped and a solution of monomethylamine (1 M in tetrahydrofuran) (33 ml) was added. The solution was stoppered and stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo and the residue triturated in water (100 ml) and filtered. The filter cake (5.5 g, 96%) was recrystallized from tetrahydrofuran-ethanol to give 3.0 g of a white flocculent solid, mp 258-259°C after forming a polymorph from 250-255°C. Analysis: Calculated for C₁₅H₁₃N₄OBr : C, 52.19; H, 3.80; N, 16.23 Found : C, 52.22; H, 3.78; N, 16.28 Example 20 2-(4-Bromophenyl)-N-methyl-3H-imidazo[4,5-b]pyridine-3-acetamide hydrochloride [1:1] . A suspension of 2-(4-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.5 g, 0.0166 mole) 1,1'-carbonyldiimidazole (2.7 g, 0.0166 mole) and anhydrous tetrahydrofuran (100 ml) was stirred at room temperature with a stream of nitrogen bubbling through for 2½ hours. The nitrogen flow was stopped and a solution of methylamine (1 M in tetrahydrofuran) (33 ml, 0.0332 mole) was added. The solution was stirred at room temperature under nitrogen for 2 hours. The reaction mixture was concentrated in vacuo and the residue triturated in water (100 ml) and filtered. The filter cake (5.5 g) was recrystallized from tetrahydrofuran-ethanol to give 3.0 g (52%) of the free base of the title compound. The free base was converted to the hydrochloride salt in isopropyl alcohol-isopropyl ether and the salt was recrystallized from isopropyl alcohol-isopropyl ether to give white solid, mp 230-232°C. Analysis: Calculated for C₁₅H₁₄N₄OBrCl : C, 47.20; H, 3.70; N, 14.68 Found : C, 47.27; H, 3.76; N, 14.52 Example 21 N,N-Dipropyl-2-[4-(trifluoromethyl)phenyl]-3H-imidazo[4,5-b]pyridine-3-acetamide . A suspension of 2-(4-trifluoromethylphenyl)-3H-imidazo[4,5-b] pyridine-3-acetic acid (3.21 g, 0.010 mole), and 1,1'-carbonyldiimidazole (1.62 g, 0.010 mole), in anhydrous tetrahydrofuran (75 ml) was stirred at room temperature with a stream of nitrogen bubbling through for 3 hours. The nitrogen flow was stopped and a solution of dipropylamine (1.31 g, 0.013 mole) in dry tetrahydrofuran (25 ml) was added. The solution was stirred at room temperature under temperature for 16 hours. The reaction mixture was concentrated in vacuo and the residue triturated in water (100 ml) and filtered. The filter cake (5.5 g, 96%) was recrystallized from tetrahydrofuran-ethanol to give 3.0 g of a white flocculent solid, mp 258-259°C after forming a polymorph from 250-255°C. Analysis: Calculated for C₁₅H₁₃N₄OBr : C, 52.19; H, 3.80; N, 16.23 Found : C, 52.22; H, 3.78; N, 16.28 Example 22 N,N-Diethyl-2-[4(trifluoromethyl)phenyl]-3H-imidazo[4,5-b] pyridine-3-acetamide . A suspension of 2-(4-trifluoromethylphenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (10.0 g, 0.0312 mole), 1,1'-carbonyldiimidazole (6.1 g, 0.0374 mole), and dry tetrahydrofuran (250 ml) was stirred at room temperature for 3 hr with a stream of nitrogen bubbling through it. An additional 6.1 g (0.0374 mole) of 1,1'-carbonyldiimidazole was added, and the suspension was stirred at room temperature under nitrogen overnight. The suspension was heated at 50°C for 2 hours and then treated with diethylamine (7.07 g, 0.097 mole) in dry tetrahydrofuran (10 ml). The reaction mixture was heated at 50°C for 5 hr and allowed to stand at room temperature over the weekend. The solvent was evaporated under reduced pressure, the resulting solid was triturated in water (200 ml) and filtered. The solid was dissolved in hot isopropyl alcohol, treated with charcoal and filtered while hot. Upon cooling, a solid precipitated. The solid was filtered and rinsed with isopropyl ether to give 6.4 g (55%) of white solid, mp. 140.5-142.5°C. Analysis: Calculated for C₁₉H₁₉N₄OF₃ : C, 60.63; H, 5.09; N, 14.88 Found : C, 60.77; H, 5.09; N, 14.88 Example 23 2-(4-Nitrophenyl)-N,N-dipropyl-3H-imidazo[4,5-b]pyridine-3-acetamide. A suspension of crude 2-(4-nitrophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (3.0 g, 0.0101 mole), 1,1'-carbonyldiimidazole (1.63 g, 0.0101 mole) and dry tetrahydrofuran (100 ml) was stirred at room temperature for three hours with nitrogen bubbling through it and then refluxed under nitrogen overnight. The mixture was cooled to room temperature and a solution of dipropylamine (3.06 g, 0.0302 mole) in tetrahydrofuran (5 ml) was added. The suspension was refluxed over the weekend under nitrogen. The solvents were removed under reduced pressure and the solid residue was triturated in water (100 ml) overnight. The solid was collected by filtration, rinsed twice with water, twice with 5% potassium hydroxide solution and then twice more with water. The solid was dissolved in hot isopropyl alcohol, filtered while hot, and cooled to room temperature to precipitate a solid. Water was added and the solid was collected by filtration, rinsed with water and dried under high vacuum at 70°C to give 1.23 g (32%) of title compound, mp. 205-208°C. Analysis: Calculated for C₂₀H₂₃N₅O₃ : C, 62.98; H, 6.08; N, 18.36 Found : C, 62.63; H, 6.02; N, 18.34 Example 24 N-Methyl-2-(4-nitrophenyl)-3H-imidazo[4,5-b]pyridine-3-acetamide . A suspension of crude 2-(4-nitrophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (3.0 g, 0.0101 mole), 1,1'-carbonyldiimidazole (1.63 g, 0.0101 mole) and dry tetrahydrofuran (100 ml) was stirred at room temperature for three hours with a stream of nitrogen bubbling through it and then refluxed overnight under nitrogen. It was cooled to room temperature and a solution of methylamine (0.94 g, 0.0302 mole) in tetrahydrofuran (10 ml) was added and the reaction mixture was stirred at room temperature over the weekend. The solvents were removed under reduced pressure and the resulting solid was triturated in water, collected by filtration, rinsed once with water, once with 5% potassium hydroxide solution and once with water. The solid was dissolved in hot isopropyl alcohol, filtered hot and cooled in the refrigerator to precipitate a solid. Water was added and the solid was collected by filtration and dried under high vacuum at 70°C to give 0.42 g (13%) of title compound, mp. >260°C. Analysis: Calculated for C₁₅H₁₃N₅O₃ : C, 57.88; H, 4.21; N, 22.50 Found : C, 57.66; H, 4.23; N, 22.30 Example 25 N,N-Dimethyl-2-(4-nitrophenyl)-3H-imidazo[4,5-b]pyridine-3-acetamide . A suspension of 2-(4-nitrophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (3.0 g, 0.0101 mole), 1,1'-carbonyldiimidazole (1.6 g, 0.0101 mole), and dry dimethylformamide (10 ml) in tetrahydrofuran (100 ml) was stirred at room temperature for two hours with nitrogen bubbling through it. A solution of dimethylamine in tetrahydrofuran (26.4 ml of a 2.29 M solution, 0.0606 mole) was added. The resulting solution was heated at 45°C overnight under nitrogen. The solvents were evaporated under reduced pressure. The residue was triturated in water (300 ml), and the resulting solid was collected by filtration, rinsed with water, 5% potassium hydroxide solution and again with water. The solid was dissolved in hot isopropyl alcohol, filtered, and allowed to cool to room temperature. A solid precipitated which was collected by filtration and dried under high vacuum to give 1.26 g (38%) of title compound, mp 204-207°C. Analysis: Calculated for C₁₆H₁₅N₅O₃ : C, 59.07; H, 4.65; N, 21.53 Found : C, 58.86; H, 4.85; N, 21.54 Example 26 1-[2-(4-Chlorophenyl)-3H-imidazo[4,5-b]-pyridine-3-yl]propanone . The free base of 2-(4-chlorophenyl)-α-methyl-3H-imidazo[4,5-b]pyridine-3-ethanol (6.3 g, 0.019 mole) was prepared by partitioning its hydrochloride salt between methylene chloride and dilute aqueous base. The methylene chloride layer was separated and the aqueous basic layer was extracted with methylene chloride (2x). The methylene chloride layers were combined, extracted with saturated sodium chloride and dried over anhydrous sodium sulfate. The methylene chloride filtrate was evaporated and dried under high vacuum overnight. Under nitrogen atmosphere, the free base from above in 21 ml of methylene chloride was added in one portion to a magnetically stirred suspension of pyridinium chlorochromate (6.28 g, 0.029 mole) in 50 ml of methylene chloride. After two hours, a 50-ml portion of diethyl ether was added to the reaction mixture and the supernatant liquid was decanted from a black gum. The insoluble residue was triturated with boiling methylene chloride (3x). The combined organic solvents were treated with Florisil®, filtered, and evaporated to a solid (4.4 g). NMR indicated 50% starting material/50% product. Under nitrogen atmosphere, the 4.4 g of solid in 25 ml of methylene chloride was added to a magnetically stirred suspension of pyridinium chlorochromate (5.0 g, 0.023 mole) in 50 ml of methylene chloride. Allowed to stir at ambient temperature overnight. The reaction solvent was decanted and the residue was triturated with hot methylene chloride (3x). The combined organic solvents were treated with Florisil®, filtered, and evaporated to a solid. NMR indicated complete oxidation to ketone. The solid was recrystallized from isopropyl alcohol with refrigeration. The product was collected by filtration, washed with water, and dried under high vacuum first at room temperature overnight, then at 50°C for 1/2 day to give crystalline solid, 2.2 g (40%), mp 172-173.5°C. Analysis: Calculated for C₁₅H₁₂N₃OCl : C, 63.05; H, 4.23; N, 14.71 Found : C, 62.89; H, 4.15; N, 14.63 Example 27 2-(4-Chlorophenyl)-α-methyl-3H-imidazo[4,5-b]pyridine-3 - ethanol hydrochloride [1:1] . The solid 4-chloro-N-[2[(2-hydroxypropyl)amino]-3-pyridinyl] benzamide monohydrochloride (12.3 g, 0.04 mole) was heated in a glass beaker at 180-185°C with a Wood's metal bath under nitrogen flow for twelve minutes. The residue was dissolved in tetrahydrofuran, filtered, and the filtrate was acidified with ethereal hydrogen chloride. The crystalline solid was collected by filtration, washed with tetrahydrofuran and dried under high vacuum overnight. A portion of the solid was recrystallized from methanol and diethyl ether and dried under high vacuum at 50°C overnight to give 1.6 g (total crude yield 8.55 g, 66%), mp 206-212°C. Analysis: Calculated for C₁₅H₁₄N₃OCl·HCl : C, 55.57; H, 4.66; N, 12.96 Found : C, 55.44; H, 4.79; N, 13.10 Example 28 5-Chloro-2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid . A solution of N-[6-chloro-3-[(4-chlorobenzoyl)amino]-2-pyridinyl]glycine ethyl ester (1.7 g, 0.00462 mole) in ethylene glycol (25 ml) was refluxed under nitrogen for two hours. To one-half of the solution (0.0023 mole) was added water (2 ml) and solid potassium hydroxide (0.20 g, 0.003515 mole) and the mixture was refluxed for an additional 15 mintues, poured into ice water (100 ml) and acidified with 3 N hydrochloric acid solution. The resulting solid was collected by filtration, rinsed with water, dissolved in hot methanol and filtered hot. Addition of water to the cloud point and cooling to room temperature gave a solid which was collected by filtration, washed with water, and dried at 60°C under high vacuum to give 0.4 g (54% yield) of title compound, mp > 250°C. Analysis: Calculated for C₁₄H₉N₃O₂Cl₂ : C, 52.20; H, 2.82; N, 13.04 Found : C, 52.22; H, 2.79; N, 13.00 Example 29 5-Chloro-2-(4-chlorophenyl)-N,N-dimethyl-3H-imidazo[4,5-b]pyridine-3-acetamide hydrate [1:0.5] . A suspension of 5-chloro-2-(4-chlorophenyl)-3H-imidazo [4,5-b]pyridine-3-acetic acid (3.1 g, 0.00963 mole) and 1,1'-carbonyldiimidazole (1.56 g, 0.00963 mole) in tetrahydrofuran (100 ml) was refluxed under nitrogen for 3.25 hours, cooled to room temperature and a stream of nitrogen was bubbled through the soluion for 0.75 hours. A solution of dimethylamine in tetrahydrofuran (21.9 ml of a 2.65 M solution, 0.0578 mole) was added and the solution was stirred at 50°C under nitrogen overnight. The solvents were evaporated under reduced pressure, the residue was triturated in water (50 ml), collected by filtration, and rinsed twice with water, twice with a 5% potassium hydroxide solution and twice again with water. The resulting solid was recrystallized from isopropyl alcohol/water to give 1.70 g of solid (50% yield) which was dissolved in hot isopropyl alcohol, treated with charcoal, filtered while hot and brought to the cloud point by addition of water. Cooling to room temperature gave a solid which was collected by filtration and dried under high vacuum at 70°C to give 1.05 g title compound, mp 203-205°C. Analysis: Calculated for C₁₆H₁₅N₄O₁.₅Cl₂ : C, 53.65; H, 4.22; N, 15.64 Found : C, 53.71; H, 3.95; N, 15.62 Example 30 5-Chloro-2-(4-chlorophenyl)-N-methyl-3H-imidazo[4,5-b]pyridine-3-acetamide . A solution of 5-chloro-2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0155 mole) and 1,1'-carbonyldiimidazol (2.52 g, 0.0155 mole) in dry tetrahydrofuran (100 ml) was refluxed under nitrogen for two hours. The solution was cooled to room temperature and a stream of nitrogen was bubbled through it for thirty minutes. A solution of methylamine in tetrahydrofuran (36 ml of a 2.59 M solution, 0.0932 mole) was added and the suspension was stirred at room temperature under nitrogen for three days. The solvents were evaporated under reduced pressure and the resulting solid was triturated in water (100 ml), collected by filtration, and rinsed twice with water, twice with a 5% potassium hydroxide solution and twice again with water. The solid was dissolved in hot isopropyl alcohol, dried over magnesium sulfate, treated with charcoal and filtered while hot. The filtrate was reduced to one-half its original volume and isopropyl ether was added. Upon cooling to room temperature, solid precipitated, which was collected by filtration, rinsed with isopropyl ether ad dried under high vacuum at 60°C to give 3.45 g (66% yield) of title compound, mp >250°C. Analysis: Calculated for C₁₅H₁₂N₄OCl₂ : C, 53.75; H, 3.61; N, 16.71 Found : C, 53.83; H, 3.60; N, 16.76 Example 31 5-Chloro-2-(4-methylphenyl)-N-methyl-3H-imidazo[4,5-b]pyridine-3-acetamide . A slurry of 5-chloro-2-(4-methylphenyl)-3H-imidazo[4,5-b] pyridine-3-acetic acid (2.8 g, 0.0093 mole) in tetrahydrofuran (11.3 ml) and dimethylformamide (0.68 g, 0.0093 mole) was cooled in an ice bath under nitrogen. Thionyl chloride (1.22 g, 0.0102 mole) was added dropwise to the stirred suspension. After stirring at room temperature for twenty minutes, the solution was cooled again in an ice bath and a solution of methylamine in tetrahydrofuran (21.5 ml of a 2.59 M solution, 0.056 mole) was added dropwise. The suspension was stirred at room temperature under nitrogen for one hour and then the solvents were removed under reduced pressure. The residue was triturated in water (100 ml) and the resulting solid was collected by filtration and rinsed three times with water. The solid was dissolved in hot isopropyl alcohol, filtered while hot, and brought to the cloud point with isopropyl ether. Upon cooling, a solid precipitated which was collected by filtration, rinsed with isopropyl ether, and dried under high vacuum at 70°C to give 1.86 g(64% yield) of title compound, mp >250°C. Analysis: Calculated for C₁₆H₁₅N₄OCl : C, 61.05; H, 4.80; N, 17.80 Found : C, 61.01; H, 4.74; N, 17.68 Example 32 5-Chloro-N,N-dimethyl-2-(4-methylphenyl)-3H-imidazo[4,5-b] pyridine-3-acetamide . A slurry of 5-chloro-2-(4-methylphenyl)-3H-imidazo[4,5-b] pyridine-3-acetic acid (2.8 g, 0.0093 mole) in tetrahydrofuran (11.3 ml) and dimethylformamide (0.68 g, 0.0093 mole) was cooled in an ice bath under nitrogen. Thionyl chloride (1.22 g, 0.0102 mole) was added dropwise to the stirred suspension. After stirring at room temperature for twenty minutes, the solution was cooled again in an ice bath and a solution of dimethylamine in tetrahydrofuran (18.9 ml of a 2.95 M solution, 0.056 mole) was added dropwise. The suspension was stirred at room temperature under nitrogen for one hour and then the solvents were removed under reduced pressure. The residue was triturated in water (100 ml) and the resulting solid was collected by filtration and rinsed three times with water. The solid was dissolved in hot isopropyl alcohol, filtered while hot, and brought to the cloud point with water. Upon cooling, a solid precipitated which was collected by filtration, rinsed with water, and dried under high vacuum at 70°C to give 2.17 g (71% yield) of title compound, mp 182-185°C. Analysis: Calculated for C₁₇H₁₇N₄OCl : C, 62.10; H, 5.21; N, 17.04 Found : C, 61.70; H, 5.12; N, 16.80 The following TABLE 1 lists compounds within the scope of the invention including melting points and Example numbers where appropriate: Pharmacological Test Procedures Muscle Relaxant Test The test Procedure relied on to indicate positive muscle relexant activity is the morphine-induced Straub Tail in Mice Test described by G. D. Novak in DRUG DEVELOPMENT RESEARCH (1982) 2 : 383-386, except 8 animals per group were used per test rather than 10. The test is summarized as follows: The test drug, reference drug, and control articles to be administered are prepared in saline, 0.5% aqueous methylcellulose suspension or other, depending on solubility, in such concentration that the volume administered is 10 ml/kg. The initial screening dose of the test drug is usually 100 mg/kg. Groups of 8 mice are given an IP dose of a compound or vehicle prepared as described above. After 15 min, mice are administered morphine sulfate, 60 mg/kg subcutaneously. Fifteen minutes after administration of morphine (i.e., 30 min after test compound administration), mice were scored for presence of Straub Tail defined as an elevation of the tail at least 90 degrees from the horizontal. An ED₅₀ value may be determined from at least three logarithmically spaced doses by the method of Litchfield and Wilcoxon (1949), J. PHARMACOL. EXP. THER. 96 : 99-113. Illustratively, some of more active compounds such as those prepared in Examples 47, 48, 56, 90, 243 and 246 exhibited ED₅₀ values of about 1-10 mg/kg in the foregoing Straub Tail Test. Antianxiety Test The test screening procedure relied on to indicate positive antianxiety response is a modification of the Vogel Conflict Test which is based on shock-suppressed drinking behavior in rats outlined by J. R. Vogel, et al. in PSYCHOPHARMACOLOGY 21 : 1-7 (1971). The procedure used is as follows: The test reference and control articles to be administered intraperitoneally in physiological saline, 0.5% aqueous methylcellulose or other, depending on a solubility in such concentration that the volume administered is 5 mg/kg. The initial screening dose of the test article is usually 100.0 mg/kg initially. Prior to dosing, rats are housed 2 per cage and deprived of water for 48 hr and thereafter randomized into treatment groups of five. Feed is available ad libitum . Thirty minutes after dosing, each rat is placed individually in a plexiglass cage measuring 18 cm in width, 13 cm in height and 29.5 cm in length and equipped with a stainless steel grid floor. The cage is covered with a plastic lid containing holes to facilitate introduction of a water bottle (30 ml plastic centrifuge tube) with a rubber stopper and metal drinking tube. A Drinkometer circuit (Omniteck Electronics, Inc., 3000 Cortona Road, Columbus, Ohio 43204, is connected between the drinking tube and the grid floor of the apparatus so that the rat completes the circuit whenever it licks the tube. The procedure is to allow the rat to find the drinking tube and complete 20 licks (as displayed on the Drinkometer digital readout) prior to the start of the experimental session. Rats not reaching this criterion are discarded. A three minute experimental session is initiated by a 0.25 mA shock at the 20th lick. Rats that continue drinking will experience a shock at each successive 20th lick. The total number of shocks during the experimental session are recorded as follows: Statistical analysis is performed by the Dunn's Multiple Comparison Test described by O. J. Dunn (1964) TECHNOMETRICS 6(3):241-52. The mean number of shocks experienced by the control group is compared with those of each drug-treated group. Significance is considered at P<0.1. The higher the total shocks compared to control, the more active is the compound. Active compounds may then be similarly tested at reduced dosages. Five rats were tested at a given dosage level and 5 rats were used as controls. Illustratively, some of the more active compounds such as those of Examples 47, 65, 74, 82, 86, 88; 246, 247 and 248 have significant activity in the foregoing Vogel test at 10 mg/kg. Anticonvulsant activity was determined for compounds of Formula I as evidenced by using chemical or electrical challenge as follows: Metrazole Chemical Challenge (Swinyard Method) Groups of 8 adult female mice were randomly assigned to dosage groups according to the method of Steel, R.G.D., and Torrie, J. H. (1960) in "Principles and Procedures of Statistics", McGraw-Hill Book Company, Inc., pp 99-100, pp 428-31. Each mouse was identified with a color code on its tail. The test compounds were administered as solutions or suspensions in 10 ml/kg mouse body weight of 0.5% aqueous methyl cellulose within 15 minutes of preparation of the suspension. Metrazole® (pentylenetetrazol) was prepared as a solution in physiological saline. The mice were not fasted prior to the test. Eight mice were tested at each dosage level. Each mouse received one dose of the test drug (usually 100 mg/kg for screening) in the 0.5% aqueous methylcellulose or the control article (0.5% aqueous methylcellulose alone) intraperitoneally. Metrazole (80 mg/kg S.C.) was then given in a loose fold of skin on the back of the neck; i.e., 1/2 hr after the test compound or control article was given. Injections were given with a 1 ml glass tuberculin syringe with appropriate size hypodermic needle (27 gauge for solutions; 23 gauge for suspensions). All injections were given in a volume of 10 ml/kg mouse body weight. Each mouse was observed for 30 minutes following Metrazol injection. Failure of the animals to exhibit a threshold seizure (a single episode of clonic spasms at least 5 seconds in duration) was defined as protection. Anticonvulsant data were tabulated as the percent protection, The ED₅₀, 95% confidence limits and potency ratio may be ascertained by the computer-based probit analysis ascribed to Finney, D. J. (1964) Statistical Method in Biological Assay, 2nd Ed., New York. Hefner Publishing Co. Illustratively, some of the more active compounds such as those of Examples 30, 48, 56, 242, 243, 246, 247 and 248 exhibit ED₅₀ values of about 1-10 mg/kg in the foregoing metrazole test. Electrical challenge Adult female mice in groups of eight were administered the test drug intraperitoneally (usually 100 mg/kg initially for screening) in liquid carrier; usually physiological saline or water. Animals were challenged electrically by placing brass electrodes on the corneas and applying an electrical stimulus (60 Hz, 5 m sec. pulse width, 34 m A intensity) for 0.2 seconds by way of a Grass Stimulator® and constant current unit and a Hunter Timer®. The absence of tonic seizures upon cessation of the stimuli was scored as protection in that animal. The number of animals protected from tonic seizures at a given dose of test drug was determined. The ED₅₀, 95% confidence limits and potency ratio may be ascertained by the method of J. T. Litchfield and F. Wilcoxon (1949) J. PHARMACOL. EXP. THER. 96 , 99-113. Illustratively, some of the more active compounds such as those of Examples 47, 48, 56, 90 and 243 exhibit ED₅₀ values in the range of about 2-15 mg/kg. Pharmaceutical Compositions The methods of treating anxiety, muscle tension, and spasticity in mammals is best carried out by administering as active ingredients in a pharmaceutical composition at least one of the compounds of Formula I in association with a pharmaceutical carrier or excipient. The compounds are thus presented in a therapeutic composition suitable for oral, rectal, parenteral, subcutaneous, intramuscular, intraperitoneal, or intravenous administration. Thus, for example, the composition for oral administration can take the form of elixirs, capsules, tablets, or coated tablets containing carriers conveniently used in the pharmaceutical art. Suitable tableting excipients include lactose, potato, and maize starches, talc, gelatin, stearic and silicic acids, magnesium stearate and polyvinyl pyrrolidone. For parenteral administration the carrier can be comprised of a sterile parenterally acceptable liquid; e.g., water or arachis oil contained in ampoules. In compositions for rectal administration, the carrier can be comprised of a suppository base; e.g., cocoa butter or glyceride. Advantageously, the compositions are formulated as dosage units, each unit being adapted to supply a fixed dose of active ingredients. Tablets, coated tablets, capsules, ampoules and suppositories are examples of preferred dosage forms according to the invention. It is only necessary that the active ingredient constitute an effective amount; i.e., such that a suitable effective dosage will be consistent with the dosage form employed. The exact individual dosages as well as daily dosages will, of course, be determined according to standard medical principles under the direction of a physician or veterinarian. Animal testing suggests that the more active compounds of Formula I will be effective in humans for muscle relaxant effects at about 1 to 20 mg/kg body weight per day. Thus, an active compound such as that of Example 243 may be administered to effectively control muscle spasms in unit dosage form to an adult human at about 75-200 mg once or twice a day. Animal testing suggests that the more active compounds of Formula I such as those cited above in the Vogel test will be effective in humans for the relief from anxiety at about 4 to 40 mg administered once or twice daily. The compounds of Formula I have anticonvulsant property as exhibited by activity against seizures caused by electrical or chemical challenge. The animal data suggest the more active compounds of Formula I, such as those cited above under Electroshock Experiments, have anticonvulsant activity ranging from about 1.5 to 10 times that of phenobarbital. The animal data suggest the more active compounds of Formula I, such as those cited above under Metrazole Chemical Challenge, have anticonvulsant activity ranging from about 10 to 100 times that of valproic acid. The more active compounds of Formula I are projected to be effective in all types of epilepsy, both grand mal and petit mal, seizures. For example, oral daily doses of about 2-75 mg of the active agent 3 times a day are projected for treatment of epilepsy. The active ingredients of the invention may be combined with other pharmacologically active agents as previously indicated, or with buffers, antacids or the like, for administration and the proportion of the active agent in the composition may be varied widely. Capsules Capsules of 5 mg, 25 mg, and 50 mg of active ingredient per capsule are prepared; with higher amounts of ingredient reduction may be made in the amount of lactose. Typical blend for encapsulation Per Capsule. mg. Active ingredient 5.0 Lactose 296.7 Starch 129.0 Magnesium stearate 4.3 Total 435.0 mg. Uniformly blend the selected active ingredient with lactose, starch and magnesium stearate and encapsulate the blend. Additional capsule formulations preferably contain a higher dose of active ingredient and are as follows: Ingredients 100 mg. per Capsule 250 mg. per Capsule 500 mg. per Capsule Active ingredient 100.0 250.0 500.0 Lactose 231.5 126.5 31.1 Starch 99.2 54.2 13.4 Magnesium stearate 4.3 4.3 5.5 Total, mg. 435.0 435.0 550.0 Tablets A typical formulation for a tablet containing 5.0 mg of active ingredient per tablet follows. The formulation may be used for other strengths of active ingredient by adjustment of weight of dicalcium phosphate. Ingredients Per Tablet. mg. (1) Active ingredient 5.0 (2) Corn Starch 13.6 (3) Corn Starch (paste) 3.4 (4) Lactose 79.2 (5) Dicalcium phosphate 68.0 (6) Calcium Stearate 0.9 Total 170.1 mg. Uniformly blend 1, 2, 4 and 5. Prepare 3 as a 10 percent paste in water. Granulate the blend with the starch paste and pass the wet mass through a number eight mesh screen. The wet granulation is dried and passed through a number twelve mesh screen. The dried granules are blended with calcium stearate and compressed. Additional tablet formulations preferably contain a higher dosage of the active ingredient and are as follows: 50 mg. Tablet Ingredients Per Tablet. mg. Active ingredient 50.0 Lactose 90.0 Corn Starch 58.0 Calcium stearate 2.0 Total 200.0 Uniformly blend the active ingredient, lactose, and corn starch. The blend is granulated, using water as a granulating medium. The wet granules are passed through an eight mesh screen and dried at 140 to 160 degrees Fahrenheit overnight. The dried granules are passed through a number ten mesh screen and blended with the proper amount of calcium stearate and this blend is then converted into tablets on a suitable tablet press. Various modifications and eqivalents will be apparent to one skilled in the art and may be made in the compounds, methods, processes and pharmaceutical compositions of the present invention without departing from the spirit and scope thereof; and it is therefore to be understood that the invention is to be limited only by the scope of the appended claims.

Claims: Claims for the following Contracting States : BE, CH, DE, FR, GB, IT, LI, LU, NL, SE A compound having the formula: wherein; A represents a pyridine ring having two of its carbon atoms held mutually with the imidazo moiety in any of its four positions, the pyridine ring being substituted by one or two z radicals on a carbon atom not shared by the imidazo moiety Z representing a hydrogen atom, halogen atom, C₁₋₈ alkyl, hydroxy, C₁₋₈ alkoxy di C₁₋₈ alkylamino or nitro group; n is an integer from 1 to 3; R⁶ represents a hydrogen atom or C₁₋₈ alkyl group; Ar represents: B represents a carbonyl, thioxomethyl or hydroxymethylene group; W represents: hydrogen, C₁₋₈ alkyl, (Y)₁₋₃-phenyl, (Y)₁₋₃-phenyl-C₁₋₈ alkyl, -OR¹, -OM, -O(CH₂) p -OH, -NR²(CH₂) p COOR¹, -NR²(CH₂) p OR¹, -NR²(CH₂) p COOM, -NR²[(CH₂) p NHC(O)R¹], -NR²(CH₂) p Q, -NR²(CH₂) p Ar¹ wherein Ar¹ is chosen from the same group of substituents represented by Ar, -NR³R⁴, or -NR²(CH₂) p NR³R⁴ wherein R¹ and R² each represent a hydrogen atom. C₁₋ ₈alkyl, (Y)₁₋₃-phenyl, or (Y)₁₋₃-phenylC₁₋₈ alkyl group and R³ and R⁴ represent: hydrogen C₁₋₈alkyl, C₁₋₈alkenyl, C₃₋₉cycloalkyl, C₃₋₉cycloalkyl-C₁₋₈alkyl, (Y)₁₋₃-phenyl, (Y)₁₋₃-phenylC₁₋₈alkyl, (Y)₁₋₂-pyridin-2, 3 or 4-yl, or R³ and R⁴ when taken together with the adjacent nitrogen atom may form a heterocyclic amino radical selected from: azetidin-1-yl, piperidin-1-yl C₁₋₈alkyl-piperidin-1-yl, morpholin-4-yl, 4-R⁵piperazin-1-yl, thiazolidin-3-yl with the proviso that when B is hydroxymethylene, W is always limited to hydrogen, C₁₋₈alkyl, (Y)₁₋₃-phenyl or (Y)₁₋₃-phenylC₁₋₈alkyl wherein Y is as defined below and a further proviso that when B is thioxomethyl, W is other than (Y)₁₋₃-phenyl, (Y)₁₋₃-phenylC₁₋₈alkyl, C₁₋₈alkyl, OR¹, -OM, -O(CH₂)pOR¹, or hydrogen; p is an integer from 0 to 3; R⁵ represents a C₁₋₈alkyl, or (Y)₁₋₃-phenyl group; Q represents: Y represents a hydrogen atom, a halo atom, C₁₋C₈ alkoxy, C₁₋₈ alkyl, trifluoromethyl, cyano, nitro or di C₁₋₈ alkyl-amino group; M is a pharmaceutically acceptable metal; or an optical isomer thereof; an oxide thereof represented by -----> O; or a pharmaceutically acceptable acid addition salt, (including a hydrate or quaternary salts) thereof. A compound as defined in Claim 1 which is 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid, 2-(4-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid, 2-[4-(trifluoromethyl)phenyl]-3H-imidazo[4,5-b]pyridine-3-acetic acid, 2-(4-nitrophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid, 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetamide, 2-(4-chlorophenyl)-3-[2(4-morpholinyl)-2-oxoethyl]-3H-imidazo[4,5-b] pyridine, 2-(4-chlorophenyl)-N-[2-(dimethylamino)ethyl]-3H-imidazo[4,5-b]pyridine-3-acetamide, 2-(4-chlorophenyl)-N-methyl-3H-imidazo[4,5-b]pyridine-3-acetamide 2-(4-chlorophenyl)-N,N-dimethyl-3H-imidazo[4,5-b]pyridine-3-acetamide, 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid 1-methylethyl ester, N,N-dimethyl-2-[4-(trifluoromethyl)phenyl]-3H-imidazo[4,5-b]pyridine-3-acetamide, 2-(4-chlorophenyl)-N,N-dipropyl-3H-imidazo[4,5-b]pyridine-3-acetamide, 2-(4-chlorophenyl)-N,N-diethyl-3H-imidazo[4,5-b]pyridine-3-acetamide, 2-(4-chlorophenyl)-N-[3-(dimethylamino)propyl]-3H-imidazo[4,5-b]pyridine-3-acetamide, 2-(4-bromophenyl)-N,N-dimethyl-3H-imidazo[4,5-b]pyridine-3-acetamide, 2-(4-chlorophenyl)-N-(2-propenyl)-3H-imidazo[4,5-b]pyridine-3-acetamide, 2-(4-bromophenyl)-N-methyl-3H-imidazo[4,5-b]pyridine-3-acetamide, N,N-dipropyl-2-[4-(trifluoromethyl)phenyl]-3H-imidazo[4,5-b]pyridine-3-acetamide, N,N-diethyl-2-[4-(trifluoromethyl)phenyl]-3H-imidazo[4, 5-b]pyridine-3-acetamide, 2-(4-nitrophenyl)-N,N-dipropyl-3H-imidazo[4,5-b]pyridine-3-acetamide, N-methyl-2-(4-nitrophenyl)-3H-imidazo[4,5-b]pyridine-3-acetamide, N,N-dimethyl-2-(4-nitrophenyl)-3H-imidazo[4,5-b]pyridine-3-acetamide, (1)-[2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-yl]-propanone, 5-chloro-2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetamide, 5-chloro-2-(4-chlorophenyl)-N, N-dimethyl-3H-imidazo[4,5-b]pyridine-3-acetamide, 5-chloro-2-(4-chlorophenyl)-N-methyl-3H-imidazo[4,5-b]pyridine-3-acetamide, 5-chloro-2-(4-methylphenyl)-N-methyl-3H-imidazo[4,5-b]pyridine-3-acetamide, 5-chloro-N,N-dimethyl-2-(4-methylphenyl)-3H-imidazo[4,5-b]pyridine-3-acetamide, or pharmaceutically acceptable salts thereof, or 2-(4-chlorophenyl) -N,N-dimethyl-3H-imidazo[4,5-b] pyridine-3-acetamide hydrochloride [1:1]. A compound as claimed in claim 1 or 2 for use in medicine. A pharmaceutical composition comprising a compound as claimed in claim 1 or 2 and a pharmaceutically acceptable carrier. The use of a compound as claimed in claim 1 or 2 in the preparation of an agent for use in the treatment of a CNS disorder. The use of a compound as claimed in claim 5 wherein the compound is other than having B-W representing -COOH or -COOM. The use as claimed in claim 5 or 6, wherein the CNS disorder comprises muscle spasms, epilepsy, muscle tension, spasticity, anxiety and/or convulsions. A process for the preparation of a compound of Formula I, as defined in claim 1 the process comprising: option 1-a, heating a compound of the formula wherein x and y are alternately either carbon or nitrogen; Ar represents n is an integer from 1 to 3 Z represents a hydrogen atom, halogen atom, C₁₋₈ alkyl, hydroxy, C₁₋₈ alkoxy, di C₁₋₈ alkylamino or nitro group; R⁶ represents a hydrogen atom or C₁₋₈ alkyl group; B represents and when B represents W is any radical capable of forming on amide with B as defined in Formula I except R¹ is not hydrogen, and when B represents W is limited to R¹, with or without solvent to obtain a compound having the formula wherein x, y, B, W, Ar, R⁶, Z and n have the starting values, or, option 1-b, reacting a compound of the formula or its tautomeric form wherein x, y, Ar and Z are as defined in option 1-a in sequence with the following agents a) and b): a) a base in a suitable solvent, b) a compound having the formula wherein B is selected from and W, R⁶ and n are as defined in Formula I to give a compound having the formula wherein x, y. Ar, B, W, R⁶, Z and n are as defined in Formula I; or option 2, when desired, oxidizing a compound having the formula wherein A, Ar, Z, n and R⁶ are as defined above and W represents a C₁₋₈ alkyl, phenyl, or phenyl C₁₋₈ alkyl group; with pyridinium chlorochromate to give a compound having the formula wherein A, Ar, Z, R⁶, n and W have the starting values in this option; or option 3, reacting a compound of Formula Ia or Ic within an aqueous basic solution and optionally neutralising with an acid to obtain a compound having the formula wherein A, Ar, Z, R⁶ and n are unchanged; or option 4, when desired, reacting an acid compound of Formula If with one of the following compounds a), b) or c): a) 1,1'-carbonyldiimidazole, b) oxalyl chloride, c) ethyl chloroformate, followed by reaction with an amine having the formula W'H wherein W' represents -NR²(CH₂) p COOR¹, -NR²(CH₂) p OR¹, -NR²(CH₂) p COOM, -NR ² [ (CH 2 ) p NHC(O)R ¹ ] , -NR²(CH₂) p -Q, -NR²(CH₂) p -Ar 1 , -NR³R⁴, or -NR²(CH₂) p NR³R⁴ and where R¹, R², R³, R⁴ , Q, Ar¹, p and M are as defined in Formula I to give a compound having the formula: wherein A, Ar, n, Z and R⁶ are as defined above and W' is the same as in the W'H compound; or option 5, when desired, sulfurizing an amide of Formula Ia, Ic or Ih, wherein B is and B-W or BW' forms an amide to give a thioamide having the formula wherein A, Ar, Z, R⁶, n have the starting values and W encompasses W' which is as stated above; option 6, oxidizing a compound of the formula Ia, Ic, Id, Ie, If, Ih or Ii with a suitable oxidising agent. A process for the preparation of a compound having the formula: wherein x and y are alternately either carbon or nitrogen; Ar represents: wherein Y represents a hydrogen atom, halo atom, C₁₋₈ alkoxy, C₁₋₈ alkyl, trifluoromethyl, cyano, nitro or di C₁₋₈ alkylamino group; Z represents a hydrogen atom, halogen atom, C₁₋₈ alkyl, hydroxy, C₁₋₈ alkoxy, di C₁₋₈ alkylamino or nitro group; R⁶ represents a hydrogen atom or C₁₋₈ alkyl group; n is an integer from 1 to 3; and R¹ represents a C₁₋₈ alkyl group; the process comprising reacting a compound having the formula: with a suitable reducing agent for converting a nitro radical to an amino radical and immediately thereafter reacting the amine product with a compound having the formula: in the presence of a tertiary amine wherein x, y, z, n, R⁶ and R' are as defined above in this claim. A process for the preparation of a compound having the formula: wherein x and y are alternately either carbon or nitrogen; Ar represents: Y represents a hydrogen atom, halo atom, C₁₋₈ alkyl, C₁₋₈ alkyl, trifluoromethyl, cyano, nitro or di C₁₋₈ alkylamino group; Z represents a hydrogen atom, halogen atom, C₁₋₈ alkyl, hydroxy, C₁₋₈ alkoxy, di C₁₋₈ alkylamino or nitro group; R⁶ represents a hydrogen atom or C₁₋₈ alkyl group; n is an integer from 1 to 3; B represents -c(0)- or when B represents -C(O)-, then W represents hydrogen, C₁₋₈ alkyl, (Y)₁₋₃-phenyl, (Y)₁₋₃-phenyl- C₁₋₈-alkyl, -OR¹ , -OM, -O(CH₂) p -OH, -NR²(CH₂) p COOR¹, -NR²(CH₂) p OR¹, -NR²(CH₂) p COOM, -NR²[(CH₂) p NHC(O)R¹], -NR²(CH₂) p Q, -NR²(CH₂) p Ar¹ wherein Ar¹ is chosen from the same group of substituents as Ar, -NR³R⁴, or -NR²(CH₂) p NR³R⁴, wherein R¹ and R² each represent a hydrogen atom, C₁₋₈ alkyl, (Y)₁₋₃-phenyl, or (Y)₁₋₃-phenyl- C₁₋₈ alkyl group; R³ and R⁴ each represent: hydrogen, C₁₋₈alkyl, C₁₋₈alkenyl, C₃₋₉cycloalkyl, C₃₋₉cycloalkyl-C₁₋₈alkyl, (Y)₁₋₃-phenyl, (Y)₁₋₂-pyridin-2, 3, or 4-yl, (Y)₁₋₃-phenyl-C-₁₋₈ alkyl, or R³ and R⁴ when taken together with the adjacent nitrogen atom may form a heterocyclic amino radical selected from: azetidin-1-yl, piperidin-1-yl, C₁₋₈ alkyl-piperidin-1-yl, morpholin-4-yl, 4-R⁵-piperazin-1-yl, thiazolidin-3-yl, and when B represents W represents C₁₋₈ alkyl, (Y)₁₋₃-phenyl, hydrogen, or (Y)₁₋₃-phenyl-C₁₋₈ alkyl; p is an integer from 0 to 3; R⁵ represents a C₁₋₈ alkyl, or (Y)₁₋₃-phenyl group; Q represents: M is a pharmaceutically acceptable metal; or an optical isomer thereof; a pharmaceutically acceptable acid addition salt and quaternary salt thereof (including hydrates thereof); the process comprising reacting a compound having the formula: wherein A represents a pyridine ring in any of its four positions as defined in claim 1 and Ar and Z are defined above in this claim with 1) a base in a suitable solvent, 2) a compound wherein B, W, n and R⁶ are as defined above in this claim. A process for the preparation of a pharmaceutical composition comprising admixing a compound as claimed in claim 1 or 2 with a pharmaceutically acceptable carrier. Claims for following Contracting States : AT, ES, GR A process for the preparation of a compound having the formula: wherein; A represents a pyridine ring having two of its carbon atoms held mutually with the imidazo moiety in any of its four positions, the pyridine ring being substituted by one or two Z radicals on a carbon atom not shared by the imidazo moiety Z representing a hydrogen atom, halogen atom, C₁₋₈ alkyl, hydroxy, C₁₋₈ alkoxy, di.C₁₋₈ alkylamino or nitro group; n is an integer from 1 to 3; R⁶ represents a hydrogen atom or C₁₋₈ alkyl group; Ar represents: B represents a carbonyl, thioxomethyl or hydroxymethylene group; W represents: hydrogen, C₁₋₈ alkyl, (Y)₁₋₃-phenyl, (Y)₁₋₃-phenyl- C₁₋₈ alkyl, -OR¹, -OM, -O(CH₂) p -OH, -NR²(CH₂) p COOR¹, -NR²(CH₂) p OR¹, -NR²(CH₂) p COOM, -NR²[(CH₂) p NHC(O)R¹], -NR²(CH₂) p Q, -NR²(CH₂) p Ar¹ wherein Ar¹ is chosen from the same group of substituents represented by Ar, -NR³R⁴, or -NR²(CH₂) p NR³R⁴ wherein R¹ and R² each represent a hydrogen atom. C₁₋ ₈alkyl, (Y)₁₋₃-phenyl, or (Y)₁₋₃-phenylC₁₋₈ alkyl group and R³ and R⁴ represent: hydrogen C₁₋₈alkyl, C₁₋₈alkenyl, C₃₋₉cycloalkyl, C₃₋₉cycloalkyl-C₁₋₈alkyl, (Y)₁₋₃-phenyl, (Y)₁₋₃-phenylC₁₋₈alkyl, (Y)₁₋₂₋pyridin-2, 3 or 4-yl, or R³ and R⁴ when taken together with the adjacent nitrogen atom may form a heterocyclic amino radical selected from: azetidin-1-yl, piperidin-1-yl C₁₋₈alkyl-piperidin-1-yl, morpholin-4-yl, 4-R⁵-piperazin-1-yl, thiazolidin-3-yl with the proviso that when B is hydroxymethylene, W is always limited to hydrogen, C₁₋₈alkyl, (Y)₁₋₃-phenyl or (Y)₁₋₃-phenylC₁₋₈alkyl wherein Y is as defined below and a further proviso that when B is thioxomethyl, W is other than (Y)₁₋₃-phenyl, (Y)₁₋₃-phenyl C₁₋₈ alkyl, C₁₋₈ alkyl, -OR¹, -OM, -O(CH₂) p OR¹, or hydrogen; p is an integer from 0 to 3; R⁵ represents a C₁₋₈ alkyl, or (Y)₁₋₃-phenyl group; Q represents: Y represents a hydrogen atom, halo atom, C₁₋₈ alkoxy, C₁₋₈ alkyl, trifluoromethyl, cyano, nitro or di C₁₋₈ alkylamino group; M is a pharmaceutically acceptable metal; or an optical isomer thereof; an oxide thereof represented by - -→ 0; or a pharmaceutically acceptable acid addition salt (including a hydrate or quaternary salt) thereof; the process comprising: option 1-a, heating a compound of the formula wherein x and y are alternately either carbon or nitrogen; Ar represents n is an integer from 1 to 3 Z represents a hydrogen atom, halogen atom, loweralkyl, hydroxy, loweralkoxy, diloweralkylamino or nitro group; R⁶ represents a hydrogen atom or loweralkyl group; B represents and when B represents W is any radical capable of forming an amide with B as defined in Formula I except R¹ is not hydrogen, and when B represents W is limited to R¹ , with or without solvent to obtain a compound having the formula wherein x, y, B, W, Ar, R⁶ , Z and n have the starting values, or, option 1-b, reacting a compound of the formula or its tautomeric form wherein x, y, Ar and Z are as defined in option 1-a in sequence with the following agents a) and b): a) a base in a suitable solvent, b) a compound having the formula wherein B is selected from and W, R⁶ and n are as defined in Formula I to give a compound having the formula wherein x, y, Ar, B, W, R⁶ , Z and n are as defined in Formula I; or option 2, when desired, oxidizing a compound prepared having the formula wherein A, Ar, Z, n and R⁶ are as defined above and W represents a loweralkyl, phenyl, or phenylloweralkyl group, with pyridinium chlorochromate to give a compound having the formula wherein A, Ar, Z, R⁶, n and W have the starting values in this option; or option 3 reacting a compound of Formula Ia or Ic with an aqueous basic solution and optionally neutralising with an acid to obtain a compound having the formula wherein A, Ar, Z, R⁶ and n are unchanged; or option 4, when desired, reacting an acid compound of Formula If with one of the following compounds a), b) or c): a) 1,1'-carbonyldiimidazole, b) oxalyl chloride, c) ethyl chloroformate, followed by reaction with an amine having the formula W'H wherein W' represents -NR²(CH₂) p COOR¹, -NR²(CH₂) p OR¹, -NR²(CH₂) p COOM, -NR² [ (CH₂) p NHC(O)R¹ ] , -NR²(CH₂) p -Q, -NR²(CH₂) p -Ar¹, -NR³R⁴, or -NR²(CH₂) p NR³R⁴ and where R¹ , R², R³ , R⁴ , Q, Ar¹ , p and M are as defined in Formula I to give a compound having the formula: wherein A, Ar, n, Z and R⁶ are as defined above and W' is the same as in the W'H compound; or option 5, when desired, sulfurizing an amide of Formula Ia, Ic or Ih, wherein B is and B-W or BW' forms an amide to give a thioamide having the formula wherein A, Ar, Z, R⁶ , n and W have the starting values and W encompasses W' which is also as defined above; or option 6, oxidizing a compound of Formula Ia, Ic Id, Ie, If, Ih or Ii with a suitable oxidising agent. A process as claimed in Claim 1 wherein the compound prepared is 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid, 2-(4-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid, 2-[4-(trifluoromethyl)phenyl]-3H-imidazo[4,5-b]pyridine-3-acetic acid, 2-(4-nitrophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid, 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetamide, 2-(4-chlorophenyl)-3-[2-(4-morpholinyl)-2-oxoethyl]-3H-imidazo[4,5-b] pyridine, 2-(4-chlorophenyl)-N-[2-(dimethylaminoethyl]-3H-imidazo[4,5-b]pyridine-3-acetamide, 2-(4-chlorophenyl)-N-methyl-3H-imidazo[4,5-b]pyridine-3-acetamide, 2-(4-chlorophenyl)-N,N-dimethyl-3H-imidazo[4,5-b]pyridine-3-acetamide, 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid 1-methylethyl ester, N,N-dimethyl-2-[4-(trifluoromethyl)phenyl]-3H-imidazo[4,5-b]pyridine-3-acetamide, 2-(4-chlorophenyl)-N,N-dipropyl-3H-imidazo[4,5-b]pyridine-3-acetamide, 2-(4-chlorophenyl)-N,N-diethyl-3H-imidazo[4,5-b]pyridine-3-acetamide, 2-(4-chlorophenyl)-N-[3-(dimethylamino)propyl]-3H-imidazo[4,5-b)pyridine-3-acetamide, 2-(4-bromophenyl)-N,N-dimethyl-3H-imidazo[4,5-b]pyridine-3-acetamide, 2-(4-chlorophenyl)-N-(2-propenyl)-3H-imidazo[4,5-b]pyridine-3-acetamide, 2-(4-bromophenyl)-N-methyl-3H-imidazo[4,5-b]pyridine-3-acetamide, N,N-dipropyl-2-[4-(trifluoromethyl)phenyl]-3H-imidazo[4,5-b]pyridine-3-acetamide, N,N-diethyl-2-[4-(trifluoromethyl)phenyl]-3H-imidazo[4,5-b]pyridine-3-acetamide, 2-(4-nitrophenyl)-N,N-dipropyl-3H-imidazo[4,5-b]pyridine-3-acetamide, N-methyl-2-(4-nitrophenyl)-3H-imidazo[4,5-b]pyridine-3-acetamide, N,N-dimethyl-2-(4-nitrophenyl)-3H-imidazo[4,5-b]pyridine-3-acetamide, (1)-[2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-yl]-propanone, 5-chloro-2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetamide, 5-chloro-2-(4-chlorophenyl)-N, N-dimethyl-3H-imidazo[4,5-b]pyridine-3-acetamide, 5-chloro-2-(4-chlorophenyl)-N-methyl-3H-imidazo[4,5-b]pyridine-3-acetamide, 5-chloro-2-(4-methylphenyl)-N-methyl-3H-imidazo[4,5-b]pyridine-3-acetamide, 5-chloro-N,N-dimethyl-2-(4-methylphenyl)-3H-imidazo[4,5-b]pyridine-3-acetamide, or pharamceutically acceptable salt thereof, or 2-(4-chlorophenyl -N,N-dimethyl-3H-imidazo[4,5-b] pyridine-3-acetamide hydrochloride [1:1]. The use of a compound of Formula I as defined in claim 1 or a compound as specified in claim 2 in the preparation of an agent for use in the treatment of a CNS disorder. A process as claimed in claim 1 or 2 wherein the compound is of Formula I except that B-W is not -COOM or COOH. The use as claimed in claim 3 wherein the CNS disorder is muscle spasms, epilepsy, muscle tension, spasticity, anxiety and/or convulsions. A process for the preparation of a pharmaceutical composition comprising admixing a compound of Formula I as defined in claim 1 or a compound as specified in claim 2 with a pharmaceutically acceptable carrier. A process for the preparation of a compound having the formula: wherein x and y are alternately either carbon or nitrogen; Ar represents: wherein Y represents a hydrogen atom, halo atom, C₁₋₈ alkoxy, C₁₋₈ alkyl, trifluoromethyl, cyano, nitro or di C₁₋₈ alkylamino group; Z represents a hydrogen atom, halogen atom, C₁₋₈ alkyl, hydroxy, C₁₋₈ alkoxy, di C₁₋₈ alkylamino or nitro group; R⁶ represents a hydrogen atom or C₁₋₈ alkyl group; n is an integer from 1 to 3; and R¹ represents a C₁₋₈ alkyl group; the process comprising reacting a compound having the formula: with a suitable reducing agent for converting a nitro radical to an amino radical and immediately thereafter reacting the amine product with a compound having the formula: in the presence of a tertiary amine wherein x,y,z,n,R⁶ and R' are as defined above in this claim. A process for the preparation of a compound having the formula: wherein x and y are alternately either carbon or nitrogen; Ar represents: Y represents a hydrogen atom, halo atom, C₁₋₈ alkoxy, C₁₋₈ alkyl, trifluoromethyl, cyano, nitro or di C₁₋₈ alkylamino group; Z represents a hydrogen atom, halogen atom, C₁₋₈ alkyl, hydroxy, C₁₋₈ alkoxy, di C₁₋₈alkylamino or nitro goup; R⁶ represents a hydrogen atom or C₁₋₈ alkyl group; n is an integer from 1 to 3; B represents -c(0)- or when B represents -C(O)-, then W represents hydrogen, C₁₋₈ alkyl, (Y)₁₋₃-phenyl, (Y)₁₋₃-phenyl-C₁₋₈-alkyl, -OR¹, -OM, -O(CH₂) p -OH, -NR²(CH₂) p COOR¹, -NR²(CH₂) p OR¹, -NR²(CH₂) p COOM, -NR²[(CH₂) p NHC(O)R¹], -NR²(CH₂) p Q, -NR²(CH₂) p Ar¹ wherein Ar¹ is chosen from the same group of substituents as Ar, -NR³R⁴, or -NR²(CH₂) p NR³R⁴, wherein R¹ and R² each represent a hydrogen atom, C₁₋₈ alkyl, (Y)₁₋₃-phenyl, or (Y)₁₋₃-phenyl- C₁₋₈ alkyl group; R³ and R⁴ each represent: hydrogen, C₁₋₈ alkyl, C₁₋₈alkenyl, C₃₋₉cycloalkyl, C₃₋₉cycloalkyl-C₁₋₈alkyl, (Y)₁₋₃-phenyl, (Y)₁₋₂-pyridin-2, 3, or 4-yl, (Y)₁₋₃-phenyl-C₁₋₈alkyl, or R³ and R⁴ when taken together with the adjacent nitrogen atom may form a heterocyclic amino radical selected from: azetidin-1-yl, piperidin-1-yl, C₁₋₈ alkyl-piperidin-1-yl, morpholin-4-yl, 4-R⁵-piperazin-1-yl, thiazolidin-3-yl, and when B represents W represents C₁₋₈alkyl, (Y)₁₋₃-phenyl, hydrogen, or (Y)₁₋₃-phenyl-C₁₋₈ alkyl; p is an integer from 0 to 3; R⁵ represents a C₁₋₈ alkyl, or (Y)₁₋₃-phenyl group; Q represents: M is a pharmaceutically acceptable metal; or an optical isomer thereof; a pharmaceutically acceptable acid addition salt and quaternary salt thereof (including hydrates thereof); the process comprising reacting a compound having the formula: wherein A represents a pyridine ring in any of its four positions as defined in claim 1 and Ar and Z are as defined above in this claim with 1) a base in a suitable solvent, 2) a compound wherein B, W, n and R⁶ are as defined above in this claim. A process for the preparation of a pharmaceutical composition comprising admixing a compound as claimed in claim 1 or 2 with a pharmaceutically acceptable carrier.

Inventors: SUTHERLAND,DEBORAH SHAWN, TOMCZUK,BRUCE EDWARD
Applicants: A.H. ROBINS COMPANY, INCORPORATED (A DELAWARE CORPORATION)
Application year: 1987
Main classification: C07D471
IPC codes: A61K31, C07D471, A61P25