DD273628A5 - METHOD FOR MANUFACTURING AN AUTOGONIST OF THE PLATE-ACTIVATING FACTOR - Google Patents

Abstract

Anagonists of the platelet activating factor of the formula (I) in which R is, for example, phenyl or a phenyl group which is substituted by one or more substituents, for example nitro, halogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, aryl (C 1 -C 4) alkoxy, is substituted, or is phenyl fused to a dioxole ring, R 1 and R 2 are, for example, independently of one another H or C 1 -C 6 -alkyl or, for example, R 2 is H or C 1 -C 4 -alkyl and R 1 is CN, C 3 -C 7 -cycloalkyl, Aryl is substituted by one or more selected from C3-C7-cycloalkyl, C1-C4-alkoxycarbonyl, aryl or heteroaryl substituent, Z is, for example, C1-C6-alkoxy or aryl (C1-C4) alkoxy, Y is 1.4 Phenylene or pyridine-2,5-diyl, and X is, for example, a 5- or 6-membered aromatic heterocyclic group and pharmaceutically acceptable salts thereof. Formula (I)

Description

Field of application of the invention

This invention relates to dihydropyridines, and more particularly to certain 4-aryl-5-carbamoyl-1,4-dihydropyridines which are of value in the treatment of allergic and inflammatory conditions in humans and animals.

Characteristic of the known state of the art

Several 1,4-Dih ^1, dropyridine have been described as anti-ischemic and antihypertensive agents acting. These compounds are capable of inhibiting the entry of calcium into the cell and are therefore effective in the treatment or prevention of a variety of cardiac conditions or as antihypertensive agents. (See, for example, EP-A-100189.) However, the compounds of the present invention are potent and selective antagonists of platelet activating factor and, as such, have clinical value in a completely different field, namely in the treatment of allergic and inflammatory conditions .as. /. B. Asthma or arthritis.

The platelet activating factor (PAF) 1-OAlkyl-2-acetyl-sn-glyceryl-3-phosphorylcholine) is an ether phospholipid whose structure was elucidated in 1979. It is produced by and released from many proinflammatory cells, platelets and the kidney with which it also interacts. In addition to potent platelet aggregation-promoting activity, PAF exhibits a diverse range of biological activities, either directly or through the release of other strong mediators, such as those shown in U.S. Pat. B. thromboxone A ₂ or the leukotrienes are triggered. In vitro, PAF stimulates the migration and aggregation of neutrophils and the release of tissue-destroying enzymes and oxygen radicals from them. These activities are part of the effects of PAF in vivo, which are consistent with its role in inflammatory and allergic reactions. Thus, it has been demonstrated that in.radermal PAF induces an inflammatory response with associated pain, accumulation of inflammatory cells and increased vascular permeability, comparable to the allergic response of the skin after exposure to an allergen. Similarly, both acute bronchoconstriction and chronic inflammatory responses caused by allergens in asthma can be artificially mimicked by intratracheal administration of PAF. Accordingly, agents that are antagonists to the action of PAF and, as a consequence, also prevent the release of mediators by PAF, have clinical value in the treatment of a variety of allergic, inflammatory and hypersecretory conditions such as asthma, arthritis, rhinitis, bronchitis and urticaria.

Object of the invention

In addition to the above, PAF has been associated with a number of other medical conditions. Thus, the symptoms of circulatory shock characterized by systemic hypotension, over-pressure in the lung, and increased permeability of the pulmonary vessels can be artificially mimicked by infusion of PAF. Dias, coupled with the finding that circulating PAF levels are increased by endotoxin infusions, shows that PAF is a primary mediator in certain forms of shock. Intravenous infusion of PAF at doses of 20-200 pmol kg " ¹ min" ¹ in rats leads to the formation of extensive haemorrhagic erosions in the gastric mucosa, and PAF is accordingly the strongest gastric ulcerogen to date, whose endogenous release is the cause of certain forms The formation can be or contribute to gastric ulcers. Psoriasis is an inflammatory and proliferative disease caused by. Skin lesions is characterized. PAF favors inflammation and has been isolated from damaged dandruff from psoriasis patients, demonstrating that PAF plays a role in psoriatic disease. And finally, new Befur.de support a strong pathophysiological role for PAF in cardiovascular disease. Recent studies in angina patients have shown PAF release in atrial pacing. Intracoronary injection of PAF into pigs induces a longer decrease in coronary flow, and induces in guinea pig hearts: ie regional

Shunt formation and ischemia. In addition, it has been demonstrated that PAF initiates thrombus formation in a mesenteric artery preparation, both when administered exogenously and when released endogenously.

More recently, PAF has been shown to play a role in brain ischemia, as described in Tiermo. Jlen's stroke was induced.

Therefore, it is expected that the compounds of the invention will be of value in the treatment of all of the above-mentioned diseases because of their ability to antagonize the effects of PAF.

Our copending, published patent applications EP-A-258033 and EP-A-266989 disclose 4-aryl-5-carbamoyl 1-1,4-dihydropyridines which are PAF antagonists.

Explanation of the essence of the invention

According to the invention, compounds of the formula (I)

Y-X H

available.,

wherein R is phenyl or nine-phenyl group represented by one or more substituents independently of one another under nitro, halo. C, -C ₄ -Alky !, Ci-C ₄ y -AiKo.- aryl (Ci-C ₄₎ alkoxy, fluoro (dC ₄₎ alkoxy, Ci-C ^ AIkylthio, C, -C ₄ alkylsulfonyl, hydroxy, Trif luormethyl and cyano are selected, substituted, or is fused to a dioxole ring phenyl,

R ¹ and R ^{2 are} each, independently of one another, H or C ₁ -C 20 -alkyl or R ¹ and R ² together form a pyrrolidinyl, piperidino, morpholino, piperazinyl, N-ICHVAIkyO-piperazinyl or N-ICz-d- Alkanoyd-piperazinyl group var complete,

or R ² is H or C | -C ₄ alkyl and R ¹ is CN, Cj-Cy-cycloalkyl, aryl, heteroaryl or a dC ₄ alkyl group. wherein this C ¹ -C ₄ -alkyl group, when it is R ^1, is substituted by one or more substituents each independently selected from C ₁ -C 6 -cycloalkyl, C ₁ -C 6 -alkoxycarbonyl, aryl or heteroaryl, Z is C ₁ - C ₈ alkoxy, aryl (Ci-C ₄ ) alkoxy, hydroxy and NR ⁴ R ^{5 is} selected, wherein R ⁴ and R ^{5 are} each independently H or Ci-Ce-alkyl or R ⁴ and R ⁶ together Complete pyrrolidinyl, piperidino, morpholino, piperazinyl or N-fCt-C 1-4 alkyldiperazinyl group,

Y is 1,4-phenylene or pyridine-2,5-diyl,

and X is a 5- or 6-membered aromatic heterocyclic group containing one or more nitrogen atoms in the ring, which ring is optionally fused with a benzene ring or another 5- or 6-membered aromatic heterocyclic ring containing one or more nitrogen atoms. in, and wherein at least one of these heterocyclic rings optionally also contains an oxygen or sulfur atom and is optionally substituted with one or more substituents independently of one another by C, -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, CF ₃ and CN are selected

and their pharmaceutically acceptable salts.

According to one embodiment of the invention, precursors of the formula (Ia)

(La)

made available,

in which R is phenyl or a phenyl group which is substituted by one or more substituents which are independently of one another nitro, halogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, aryl (C ₁ -C ₄ ) -alkoxy, dC ^ alkylthio, Ci-d-alkylsulfonyl, hydroxy, trifluoromethyl and cynano are selected,

R ¹ and R ^{2 are} each independently H or C, -C _e alkyl, or the two groups are summarized

may form a pyrrolidinyl, piperidino, morpholino, piperazinyl, N- (C 1 -C ₄ alkyl) -piperaL'inyl or N- (C ₂ -C ₄ alkanoyl) piperazinyl group, or R ² H or C ₁ -C ₄ -alkyl and R ¹ CH is'-, CHVCycloalkyl, aryl, heteroaryl or a Cr-C ₄ alkyl group which is substituted by one or more substituents which under Cj-C ^ cycloalkyl, C C ₄ alkoxycarbonyl, aryl or heteroaryl

are selected,

R ^{3 is} C 1 -C 6 -alkyl or AryKC 1-4 -alkyl,

X is a 5- or 6-membered aromatic heterocyclic group containing one or more nitrogen atoms in the ring, which is optionally substituted by a benzene ring or another 6-membered aromatic heterocyclic group containing a

contains or more nitrogen atoms, can be fused and which may be optionally substituted with one or more substituents which are selected from Ci-C ₄ -alkyl ₁ C ₁ -C ₄ -alkoxy, halogen, Lr _3, and CN, and their pharmaceutically acceptable salts.

According to a further embodiment of the invention, compounds of the formula (Ia) are provided above, in which

R is phenyl or a phenyl group, by one or more substituents selected from nitro, halogen, Cv-C ₄ alkyl, C, -C ₄ alkoxy, aryl (Ct-C ₄₎ A! Koxy, C ^ C ^ Alkylthio, C 1 -C 4 -alkylsulfonyl, hydroxy, trifluoromethyl and cyano,

R ¹ and R ^{2 are} each independently H or C ₁ -C ₆ alkyl or these two groups to form a pyrrolidinyl, piperidino, morpholino, piperazinyl, N- {Ci-C ₄ alkyl) piperazinyl or N- (C ₂ -C ₄ alkanoyl) -piperazinyl group may be summarized, or

R ² is H or C, -C ₄ alkyl and R 'CN, Cj-Cy-cycloalkyl, aryl, heteroaryl or C) - C ₄ alkyl group, by one or more under-Cr C7-cycloalkyl, C , C ₄ alkoxycarbonyl, aryl or heteroaryl selected substituent is substituted,

R ³ is C, -C _e alkyl, or aryl (C, -C ₄₎ alkyl,

X is a 5- or 6-membered aromatic heterocyclic group containing one or more nitrogen atoms in the ring, which ring may optionally be fused with a benzene ring or another 5- or 6-membered aromatic heterocyclic ring containing one or more nitrogen atoms, and wherein at least one of said heterocyclic rings optionally also contains an oxygen or sulfur atom and may optionally be substituted with one or more substituents independently selected from C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, CF ₃ and CN, and their pharmaceutically acceptable salts

 According to another embodiment of the invention, compounds of the formula (I b)

CONR ⁴ R ⁵

(Ib)

in which R, R ', R ² and X are as defined above and in which R ⁴ and R ^{5 are} each independently H or C ₁ -C ₆ -alkyl or in which these two groups are substituted by the nitrogen atom, to which they are attached, may be grouped together into a pyrrolidinyl, piperidino, morpholino, piperazinyl or N-fC ^ C 1 alkylpiperazinyl group.

As used herein, the term "halogen" means fluoro, chloro, bromo or iodo, alkyl and alkoxy groups

3 or more carbon atoms and C ₄ alkanoyl groups may be straight or branched chain.

"Aryl" in the definition given for R ¹ and Z means phenyl or a phenyl group represented by one or more (preferably 1 or 2) substituents which are chosen from halogen, trifluoromethyl, C, -O ₄ -alkyl, hydroxy, C ₁ - C ₄ -alkoxy, (C) -C ₄ -

Alkoxyjcarbonyl, sulfamoyl and CN are selected.

"Heteroaryl" in the definition used for R ¹ means a 5- or 6-membered aromatic heterocyclic group which has one or more heteroatoms independently selected from N, O and S and which may be optionally fused to a benzene ring and which may optionally be present in at least one , the rings in the heterocyclic and fused benzene ring by one or more C under | selected substituted -C ₄ alkyl, C ₁ -C ₄ -alkoxy and halogen substituents

can be.

Examples of suitable heteroaryl groups include pyridyl, thiazolyl, thiadiazolyl, oxazolyl and imidazolyl, each of which may be facultatively benzo-fused and optionally substituted in the heterocyclic or fused ring by C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy or halogen , Thus, specific examples of heteroaryls for R ¹ include pyrid-2-yl, 4- and 6-methylpyrid-2-yl, thiazol-2-yl, A- and 5-methylthiazol-2-yl, 5-methylthiadiazol-2-yl , 5-Methyloxadiazol-3-yl, 5-methylisoxazole-3

yl, benzothiazol-2-yl and 5-ethoxybenzothiazol-2-yl and 1-methylimidazol-2-yl.

Preferably, R ^{2 is} H and R 'is H, C ₁ -C ₄ -alkyl, pyridyl (most preferably 2-pyridyl), thiazolyl (most preferred

2-thiazolyl) or 1- (phenyl) ethyl.

In a preferred embodiment of the invention, Z is ethoxy, methoxy or benzyloxy which is substituted by halogen in the ring (ie R ³ is ethyl, methyl or benzyl substituted in the ring by halogen). R is preferably 2-chlorophenyl,

2-trifluoromethoxyphenyl, 2,4-difluorophenyl, 4-cyanophenyl or 1,3-benzodioxol-4-yl.

X may be an optionally substituted by one or two C, -C ₄ alkyl groups 1,2, 'l-triazolyl or an imidazo! / !, which is optionally substituted by up to three C 1 -C ₄ alkyl groups or optionally substituted by a C 1 -C ₄ alkyl or CF ₃ group and fused with a benzene or pyridine or pyrimidine ring which may be substituted with at least one C, -C ₄ alkyl or Cj -CvAlkoxygruppe. Alternatively, X may be optionally substituted by one to three C ₁ -C ₄ alkyl or CF ₃ groups

substituted pyridyl group.

Alternatively, X may be optionally substituted by up to two C, -C ₄ alkyl substituted oxazolyl or thiazolyl group or an imidazolyl group, the optionally substituted ₃ group by a C ₁ -C ₄ -AIkYl- or CF and an oxazolyl or

Thiazolyl ring is condensed.

X is more preferably 2-methylimidazo [4,5-c] pyrid-1-yl, imidazol-1-yl, benzimidazol-1-yl, 2-methylbenzimidazol-1-yl, 3,5-dimethyl-1,2, 4-triazo-4-yl, 2-trifluoromethyl-imidazo [4,5-cl-pyrid-1-yl, 2-butyl-imidazo [4,5-c] pyrid-1-yl _/ 2-methyl-imidazo [4,5-b] pyrid 3-yl, 2-methylimidazo [1,2-a] pyrid-3-yl, 2-ethylimidazo (4,5-c] pyrid-1-yl, 7-methoxy-2-methylimidazo [4,5-d ] pyrimidine-3 ^: yl, 2-methylimidazo / 4,5-c / pyrid-3-yl, 2,4,6-trimethylimidazo [-4,5-c] pyrid-1-yl, 2,4-dimethylimidazole 1-yl, 2-methylimidazol-1-yl,

2,4,5-trimethylimidazol-1-yl, 4-metbylimidazol-1-yl, 2-methylpyrid-3-yl, 2,6-dimethylpyrid-3-yl, 3,5-dimothyl-1,2,4- triazol-1-yl,

4-Methyloxazol-5-yl, 2,4-dimethylthiazol-5-yl, 6-methylimidazo [1,2-b] thiazol-5-yl or 4-methylthiazol-5-yl.

Particularly preferred single compounds are 1- (2-chlorophenyl) -1,4-dihydro-3-ethoxycarbonyl-6-methyl-2- [4- (2-methylimidazo [4,5-cipyrid-1-yl) phenyl] -5- [N- (2-pyridyl) carbamoyl] pyridine, 4- (2-chlorophenyl) -1,4-dihydro-3-ethoxycarbonyl-6-methyl-2-I4- (2-methylimidazo [1,2 -a] pyrid-3-yl) phoiiyl] -5-IN- (2-pyridyl) -carbarnoyl] pyridine, 4- (2-chlorophenyl) -l, 4-dihydro-3-ethoxycarbonyl-6-methyl-2- [4- (2,4,6-trimethylimidazo [4,5-clpyrid-1-yl) phenyl] -5- [N- (2-pyridyl) carbamoyl] pyridine or 4- (2-chlorophenyl) -1,4-dihydro -3-ethoxycarbonyl-6-methyl-2- [2- (2-methylimidazo [4,5-c] pyrid-1-yl) pyrid-5-yl] -5- [N- (2-

pyridyDcarbamoy is pyridine.

Other particularly preferred individual compounds are those whose preparation is also described hereinafter in the

Examples is described.

The compounds of formula (I) contain at least one asymmetric center and therefore exist as one or more pairs of enantiomers, and such pairs of individual isomers can be resolved by physical methods.

z. By fractional crystallization or by chromatography of the parent compounds or a suitable salt or derivative thereof. Alternatively, individual isomers may be prepared using the appropriate optical isomers of the precursors used to prepare compounds of the invention. The invention includes all enantiomers of the compounds of formula (I), whether or not they are separate.

The pharmaceutically acceptable acid addition salts of the compounds of formula (I) are those prepared from non-toxic acid addition salts-forming acids, e.g. Hydrochloric acid, hydrobromide, sulfate or hydrogen sulfate, phosphate or acid phosphate, acetate, citrate, fumarate, gluconate, lactate, maleate, succinate,

Tartrate, the methanesulfonate, benzenesulfonate and p-toluenesulfonate salts.

Compounds according to the invention in which Z is C ₁ -C ₆ -alkoxy or aryl (C ₁ -C ₄ ) -filkoxy can be synthesized via the Hantz synthesis

be prepared according to the following reaction scheme:

^R \ ³

+ RCHO +

0 Y-X

(II) (HD

wherein R, R ¹ , R ² , R ³ , Y and X are as defined above.

In a typical process, the aminocrotonic acid amide (II), the ketoester (III) and the aldehyde are dissolved in a suitable organic solvent, e.g. A C, -C ₄ alkanol, such as ethanol, heated to 60-130 ° C, preferably under reflux, until the reaction is substantially complete, typically 24 hours or shorter. Optional is a small amount of a lower one. Alkanoic acid, for example acetic acid, present to neutralize the solution. The product of formula (I) can then be isolated and purified by conventional means, for example by distribution extraction, recrystallization or by chromatography.

In an alternative method, the ketoester of formula (II) and the aldehyde are reacted together, typically by stirring a slight excess of ketoester with the aldehyde for 48 hours at room temperature in a suitable solvent, e.g. In isopropyl alcohol containing piperidine as a catalyst, whereby an intermediate of formula (IV)

(IV) Y-X

arises.

If desired, the intermediate can be separated, for example, by evaporating the reaction mixture to give an oil, by stirring the oil with water and purifying the product by filtration and recrystallizing from ethyl acetate. The compound of formula (IV) may then be reacted with aminocrotonamide (II), for example by heating the compounds together in an alcoholic solvent at 60-130 ° C and preferably at reflux to give the compound of formula (I) to produce. The compound thus formed can be separated in the usual way. The ketoesters of the formula (III) are either known compounds or they can be prepared by the following methods:

(i) The ketoesters of the formula (III) can be prepared by a slaver reaction based on a modification of the literature method described by SM Hannick, Y. Kishi, J. Org. Chem., (1983), 48, 3833 , according to the following reaction sequence:

.3

CN

Zn

BrCH ₂ CO ₂ R

COCH ₀ CO-R '

I ^{2 2}

The cyano compound is added in an inert solvent such as tetrahydrofuran under nitrogen to a suspension of zinc dust and the corresponding bromoacetic acid ester. Woitero amounts of the corresponding bromoacetic acid ester are added under refluxing, and after cooling followed by the addition of aqueous potassium carbonate. After filtration, the filtrate is hydrolyzed by refluxing with dilute hydrochloric acid for several hours or by stirring in a souvern such as dichloromethane with 20% aqueous trifluoroacetic acid.

The reduction mixture is then neutralized and the ketuester of formula (III) is isolated and purified in the usual way, for example by distribution extraction, recrystallization or chromatography.

The cyano compounds are either known compounds, or they may be analogous to literature references

be prepared as explained here.

(ii) An alternative process for the preparation of certain ketoesters of the formula (III) is carried out with the aid of the Goldberg and

Claisen ester sorting according to the following reaction scheme:

COCH.

f \ .c

Close

COCH.

(R 0) ₂ C0

3 (III)

The p-bromoacetophenone can be replaced by the corresponding fluorine, chlorine, or iodine compound, and in the first stage of this sequence, a copper / copper (I) bromide K? .aly sator be added.

In a typical process, a mixture of a compound XH, p-bromoacetophenone, copper alloy, copper (I) bromide and anhydrous potassium carbonate is heated in a solvent such as dry N-methylpyrrolidinone under an inert atmosphere for up to 8 hours. Then the solvent is removed and the intermediate ketone becomes

isolated and cleaned in the usual way.

The ketone intermediate is added under nitrogen to a suspension of sodium hydride in a dry solvent such as tetrahydrofuran. The appropriate dialkyl carbonate is added and the resulting mixture is heated to reflux for about 18 hours. Alternatively, the dialkyl carbonate itself can be used as a solvent. The ketoester with

of the formula (III) is isolated and purified in the usual way.

The amino-crotonsäureamide (II) are either known compounds, or they can be prepared by conventional methods

For example, from the ketoamide by reaction with ammonia.

Similarly, the aldehydes RCHO are either known compounds, or they can be prepared by known methods in US Pat

Consistent with previously published literature.

In an alternative method of representing the compounds of formula (I) in which Z is C, -C ₆ alkoxy or aryl (C, -C ₄ -) alkoxy, a carboxylic acid of formula (V) with ammonia or an Amine with the formula NHR ¹ R ²

wherein R, R ¹ , R ² , R ³ , X and Y are as defined above:

Y-X

In a typical procedure, the compound of formula (V) in dichloromethane containing 2,4,6-triisopropylbenzenesulfonyl chloride and 4- (N, N-dimethylamino) pyridine is stirred at room temperature and the ammonia or amine is then added. The resulting compound of formula (I) is isolated by evaporation of the solution, extraction with aqueous acid, neutralization of the aqueous phase, extraction of the aqueous phase with dichloromethane and flash chromatography of the extract

 The compound of the formula (V) can be obtained by hydrolysis of a compound of the formula (VI)

NC-CH ₂ -CH ₂ -OC

Y-X

getting produced.

The hydrolysis can be carried out using aqueous sodium hydroxide and a solvent such as dioxane. The compound of the formula (VI) can be prepared by a Hantz synthesis using the corresponding ketoester of the formula (III), an aldehyde having the formula RCHO and 3-aminobut-2-enoic acid 2-cyanoethyl ester. The above-described preparation of the compound of the formula (I) using the compound of the formula (VI) allows the recovery of individual optical isomers of the compounds of the formula (I). The Hantz synthesis produces a mixture of (+) and (-) isomers of compound (VI), but these can be separated by the formation of a salt. In one process, the unseparated cyanoethyl ester of formula (VI) is dissolved in a hot solution of an alcoholic solvent such as methanol and reacted with an optical isomer of 4- (2,4-dichlorophenyl) -5,5-dimethyl-2-hydroxy 1,3,2-dioxaphosphorinan-2-oxide to form a solution of the diastereomeric salts (a method described by W. den Hoeve, H. Wynberg, J. Org. Chem. [1985] 50,4508 ). Fractional recrystallization of the salt yields a diacetate-terecyanoethyl ester salt. The free cyanoethyl ester can be recovered by treating this salt with a base such as sodium carbonate.

The separated cyanoethyl esters can be converted into the separated compounds of the formula (I) by means of the processes described above.

Compounds of formula (I) wherein Z is OH or -NR ⁴ R ⁵ are conveniently obtained by simple chemical conversion reactions. For example, compounds of formula (I) wherein Z is benzyloxy may be subjected to conventional catalytic hydrogenation to recover the corresponding compounds wherein Z is OH. The acid product or a derivative thereof, e.g. An acid chloride, can be converted to the corresponding compound in which Z-NR ⁴ R ⁵ is by reacting it under suitable conditions with ammonia or an amine R ⁴ R ⁶ NH. Reagents and conditions suitable for these conversions will be well known to those skilled in the art.

The activity of the compounds of the invention is demonstrated by their ability to inhibit the platelet aggregating activity of PAF in vitro. One tests as follows:

Rabbits or humans are sampled and placed in 0.1 volume of ethylenediaminetetraacetic acid disodium salt buffer and the samples are centrifuged for 15 minutes to obtain platelet-free plasma. The plasma is further centrifuged to obtain a platelet pellet containing a buffer solution (4 mM KH ₂ PO ₄ , 6 mM Na ₂ NPO ₄ , 10 mM NaCl, 0.1% glucose and 0.1% bovine serum albumin, pH 7, 25) and finally resuspended with buffer solution to a concentration of 2 × 10 ⁸ platelets / ml. A sample (0.5 ml) is pre-incubated with stirring for two minutes at 37 ⁰ C in a Paton aggregometer, either with vehicle or with the carrier containing the compound to be tested in each case. PAF is added in sufficient concentration in the absence of test compound ⁽⁸ to 10 ~ ⁹ ~ 10 molar) to effect maximum aggregation reaction, and the platelet aggregation is measured by following the increase in light transmission of the solution. The experiment is repeated in the presence of test compounds over a concentration range and the concentration of compound needed to lower the response to 50% of its maximum value is recorded as the IC _M value.

The activity of the compounds of formula (I) is further demonstrated in vivo by their ability to protect mice from the lethal effect of PAF injection. A mixture of PAF (50pg / kg) and DL-propanolol (5mg / kg) in 0.9% w / v. Sodium chloride is injected into mice via a tail vein (0.2 ml). The compounds to be tested are either injected into the tail vein immediately before PAF / propranolol injection, or orally administered two hours before by gavage. Compounds are tested at various concentrations on groups of 5 mice and the dose lowering mortality to 50% is recorded as the PD _M value.

The compounds are also being tested for their ability to reduce PAF-induced bronchoconstriction in anesthetized guinea pigs. In this test airway resistance and dynamic lung compliance are calculated from records of airflow and transpleural pressure and the calculation of respiratory volume. The PAF (100ng / kg) induced sronchoconstriction is determined. One hour after the first PAF dose, the compound to be tested is administered and the test is repeated. The ability of the compound to reduce the bronchoconstrictive effect of PAF is recorded as a ratio.

For therapeutic use, the compounds of formula (I) are generally added in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. For example, they may be administered orally in the form of tablets containing such carriers as starch or lactose, or in capsules or ovules, either alone or in admixture with carriers, or in the form of flavoring or coloring elixirs or suspensions. They may be injected parenterally, for example, intravenously, intramuscularly or subcutaneously. For parenteral administration, they are best used in the form of a sterile, aqueous solution which may contain other substances, for example, enough salts or glucose to render the solution isotonic with blood.

For administration to humans in the treatment or prophylaxis of lung allergic conditions and arthritis, oral dosages of the compounds will generally be in the range of 2-1 oocmg daily for an average adult patient (70kg). Thus, for a typical adult patient, individual tablets or capsules contain from 1 to 500 mg of active compound in a suitable pharmaceutical vehicle or carrier. Dosages for intravenous administration should typically be as needed in the range of 1 to 10 mg per single dose

lie. For the treatment of allergic and bronchial hyperreactive conditions, inhalation by means of a nebulizer or an aerosol may be the preferred route of drug administration. The dosages given in this way should be within the range of 0.1 to 50 mg per single dose as needed. In practice, the physician will determine the actual dose that will be most appropriate for the particular patient and this will vary with the age, weight and response of the particular patient. The above dosages are exemplary of the average case, but of course there may be individual circumstances in which higher or lower doses are appropriate, and also these are within the scope of this invention.

Thus, in a further aspect, the invention provides a pharmaceutical composition comprising a compound of formula (I) or one of its pharmaceutically acceptable salts together with a pharmaceutically acceptable diluent or carrier.

The invention si! Also relates to a compound of the formula (I) or one of its pharmaceutically acceptable salts for use in medicine, particularly in the treatment of allergic and inflammatory conditions in a human.

The preparation of the compounds of the formula (I) is further illustrated by the following examples.

Preparation Examples example 1

4- (2-chlorophenyl) - ^, 4-dihydro-3-ethoxycarbonyl-e-methyl-2- [4- (2-methyllmidazo [4,5-c] pyrld-1-yl) phenyl] -5- [ N- (2-pyridyl) carbamoyl-pyridine

A mixture of ethyl 4 '- (2-methylimidazo [4,5-c] pyrid-1-yl-benzoylacetate (475 mg, 1.47 mmol), N- (2-pyridyl) -3-aminocrotonic acid amide (260 mg, 1.47 mmol). and 2-chlorobenzaldehyde (207 mg, 1.47 mmol) in absolute ethanol was refluxed under nitrogen for 8 hours, the solution was allowed to cool and the solvent was removed under reduced pressure, the residue was purified by flash chromatography (gradient elution with 5% diethylamine). Ethyl acetate and methanol) and the product-containing fractions were concentrated, the solid product was further purified by trituration with diethyl ether / ethyl acetate, then the solid was filtered off and dried in vacuo to give the title compound (280mg, 31%), m.p. 226-228 "C.

Analysis%:

Found: C 66.86 H 4.76 N 13.72

Calculated (for the semihydrate):

C 66.50 H 4.92 N 13.68.

Examples 2-28

Further compounds having the general formula (Ia) were prepared in analogy to the process of Example 1, using in each case the corresponding aldehyde, the corresponding 4'-substituted benzoylessigoster and N-substituted crotonic acid amide:

(La)

The compounds are shown in Table I.

TABLE 1

Example tfr.

Cl

Cl

C-Bu

Cl

-L "

He

me

me

tt

et

Mp. ⁰ C

156-159

235-238

(Dec.)

208-211 (Zers.)

Yield%

16

Anslys e X

(Theoretical values in Klarrra.) CHN

67.82 5.80 11.72 (67.86 5.87 11.99)

59.59 4.5 11.83 0 (59.53 U. 65 11.96)

68.39 4.67 11.61 * f68.16 4.88 11.69)

σ> ro oo

TABLE 1 (cont.)

Example no.

Cl

Cl

C-Ru

C-Bu

et

et

_N

CH.

CH.

EC

CH.

Slip. "C.

157-159

188-189

-N

CH

161-162

Yield%

25

43

20

Analysis X

(Theoretical values in gorge.) CHN

69.80 5.97 9.50 (70.03 6.05 9.61)

6A.29 5.00 14.IA * (64.41 5.23 14.54)

64.84 6.07 12.60 * (64.68 6.33 12.57)

IS9 • sj CO

TABLE 1 (cont.)

example

No.

R R

Cl

Cl

10

Cl

EC

He.

CF

3 ·

CH.

Mp.

135-138

202-204

197-199

Yield%

18

10

Analysis Z

(Theoretical values i.i Klainn.) CHN

** (NMR data see below)

67.68 5.56 12.31 //(67.55 5.71 12.52)

66.50 4.89 13.63 * (66.49 4.92 13.69)

TABLE 1 (cont. )

Example no.

11

12 13

Cl

Cl

Cl

? pyridyl

2-pyrldyl

R "

EC

et

OMe

Mp. "C

190-191

255-257

220-222

Yield%

15

13

27

Analysis%

(Theoretical values in Klamm.) C H N

68.00 5.00 11.AO Δ (68.56 5.14 11.34)

67.20 5.00 13.09 (66.92 5.13 13.3) *

* 3.3O 4.74 15.09 (63.29 4.84 15.20) *

α> ro oo

TABLE 1 (cont.)

Example no.

14] 5 16

Cl

OCF.

Cl

2-pyridyl

2-pyrldyl

ec

EC

ec

me

N N

amp. ° c

200-202

235-238

238-240

Yield%

IA

13

Analysis e%

(Theoretical values in Klarrin.) CHN

63.64 h.03 12.41 (63.78 5.16 12.82) +

62.63 4.53 12.29 (62.49 4.65 12.49) +

67.24 4.84 13.78 (67.48 4.83 13.89)!

TABLE 1 (cont.)

Example · κ No.

Cl

18

Cl

2-pyridyl

et

et

et

me

me

me

CH.

Mp. ⁰ C

196-198

115-122

158-160

yield

15

Analysis%

(Theoretical values in gorge.) CHN

66.58 5.15 12.93 (66.40 5.42 12.91) +

13

64.25 5.29 12.45 (64.68 5.43 12.16) i

• »CO

w + j u ο

"5

cn

γη 4->

go

dP

CM

UJ

O CN cn cn CM CN rl CM cn UI U; cn vO vO r- »vO

UI

CN

CM

CN CN

<u

K /

oo

CM

<J \

CM

65

CM

66

-3 Ti U

Q.

α ι

CN

vOcnCN

I CMcnCN

MD

ul

CM

.2}

O CN / 7nc ολ

TABLE 1 (cont.)

Yield%

15

Analysis%

(Theoretical values in Klarrm.) CHN

67.86 5.48 11.99 (68.09 5.54 12.03)

66.68 5.24 12.48 (66.81 5.22 12.25) ++

69.83 5.35 9.96 (70.14 5.17 9.91)

TABLE 1 (cont.) example

Nrf · -

Analysis%

(Theoretical values in gorge.) CHN

69.48 5.32 9.42 (69.44 5.48 9.53) *

65.53 4.30 11.52 (65.92 4.40 11.83) *

66.05 4.89 12.77 (65.98 5.14 13.09)

* Calculated for the semihydrate Calculated for the Vj EtOAc- · V2 HjO solvate

# Calculated for the ¹ A isopropyl alcohol-V2 HjO solvate λ Calculates Wr ³ AH ₂ O + Calculates the hydrate ++ Calculates as 1Λ EtOAc # 1 ¹ H-NMR (CDCl ₃ for the 1: 1 mixture of diastereomers

0 ₍ 96 (3H, t, J7Hz), 0.97 (3H, t, J7Hz), 1.44 (2H, d, J7Hz), 1.45 (2H, d, J7Hz), 2.26 (3H, s), 2.34 (3H, s), 2, ei (6H, s), 3.90 (4H, m),

5.08 (2H, m), 5.45 (1H, s), 5.48 (1H, s), 5.74 (1H, s), 5.76 (1H, s), 6.03 (2 H, m), 7.03-7.69 (32 H, complex), 8.39 (2 H, d, J 7 Hz),

9:09 (2 H, s).

# ₂ ¹ HNMR (CDCI ₃ )

1.00 (3H, t, J 7 Hz), 2.47 (3H, s), 2.61 (3H, s), 3.97 (2H, m), 5.23 (1H, s), 6.42 (2H, s), 7.03 (1H, d, J6Hz), 7.10 (1H, d, J5Hz), 7.42 (2H, d, J7Hz), 7.60 (2H, d , J 7 Hz), 7.66 (4 H, m), 7.90 (1 H, s), 8.19 (1H, d, J 7 Hz), 8.24 (1H, d, J 6 Hz ), 8.29 (1 H, d, J 5 Hz),

9.04 (1 H, s)

" ¹ HNMR (CDCl ₃ ): 1.00 (3H, t, J 7Hz), 2.31 (3H, s), 3.93 (2H, m), 5.63 (1H, s) , 5.99 (1H, s), 7.02 (1H, dd, J6 and 7Hz), 7.21 (2H, m), 7.28-7.37 (3H, m), 7.51 (2 H, d, J 9 Hz), 7.63 1 H, m), 7.66 (2 H, d, J 9 Hz), 8.15 (2 H, m), 8, 28 (1H, m), 8.55 (1H, d, J 6Hz),

9.31 {1 h. Br s)

 The compound was isolated from the Hantz reaction as a covalent hydrate and refluxed in toluene

Presence of para-toluenesulfonic transferred to the dihydropyridine. 0 Calculated as ⁶ AH ₂ O

Example 29

4- (2-Chlorphenvl) -1,4-dihydro-2 [4- (3,5-dimethyl-1,2,4-tr! Azol-l-yl) phenyl] -3-ethoxycarbonyl-6-methyl- 5- [N- (2-pyridyl) -

carbamoyljpyridln

(a) 2- [4 '- (3,5-Dimethyl-1,2,4-triazol-1-yl) benzoyl] -3- (2'-chlorophenyl) propenoate

A mixture of 4 '- (3,5-dimethyl-1,2,4-triazol-1-yl) benzoyl-acetic acid ethyl ester (618 mg, 2.15 mmol), 2-chlorobenzaldehyde (302 mg, 2.15 mmol) and piperidine (2 drops) in isopropanol (10 ml) was stirred at ambient temperature for 72 hours. The volatiles of the mixture were removed by evaporation and the residue was purified by flash chromatography (eluting with ethyl acetate) to give the title compound (6COmg, 68% yield).

(b) 4- (2-chlorophenyl) -1,4-dihydro-2- [4- (3,5-dimethyl-1,2,4-triazol-1-yl) -phenyl] -3-ethoxycarbonyl-6- methyl-fifth [N- (2 'pyrldyl) carbamoyl] pyrldin

A mixture of the product from step (a) (566 mg, 1.38 mmol) and N- (2-pyridyl) -3-aminocrotonic acid amide (245 mg, 1.38 mmol) in ethanol (10 ml) was added under nitrogen for hours Reflux heated. The solvent was removed and the residue was purified by flash chromatography (eluting with 2% diethylamine in ethyl acetate) to give the title compound (50 mg, 6%) as a white solid, m.p. 13O ⁰ C.

Analysis%:

Found: C 63.36 H 5.43 N 13.96 Calculated: C 63.42 H 5.01 N 14.32.

The compound of Example 1 was also prepared by this method using 4 '- (2-methylimidazo | 4,5-c] pyrid-1-y-benzoylacetic acid ethyl ester instead of 4' - (3,5-dimethyl-1,2,4-) triazol-1-yl) benzoylacetic acid ethyl ester The analysis of the product was identical to that given in Example 1.

Example 30

4- (2-chlorophenyl) -1,4-dihydro-3-ethoxycarbonyl-6-methyl-2- [4- (4-methyloxazol-5-yl) phenyl] -5- [l \ l- (2-pyridyl ) carbamoyl] pyridine A mixture of ethyl 4 '- (4-methyloxazo-5-yl) benzoylacetate (260mg, 1.0mmol), N- (2-pyridyl) -3-aminocrotonic acid amide (160mg, 1.1mmol) and 2-Chlorobenzaldehyde (160 mg, 1.1 mmol) in ethanol (10 mL) containing one drop of acetic acid was refluxed under nitrogen for 16 h. The solution was allowed to cool and all of the volatile material was evaporated under reduced pressure. The residue was purified by chromatography on silica gel (elution with ethyl acetate) to give a pale yellow oil. Trituration with anhydrous diethyl ether afforded the title compound as a white solid (24mg, 5%), m.p. 176-179 ° C.

Analysis%:

Found: C66.56 H5.22 N9.29

Calculated (for the semi-etherate): C, 66.90, H, 5.42, N, 9.46.

Examples 31-33

Other compounds having the formula below were prepared in analogy to the procedure of Example 30, wherein

2-Chlorobenzald3hyd and the corresponding "! '- substituted Benzoylessigsäureester were used.

The compounds are shown in Table 2.

R ¹ R ² R ³ • TABLE 2 Sn ₅ J- ⁰ C From prey (%) 6 Analysis% (Theoret. Values in Gorge.) CHN -22- 273 628 α ii ec 215 (out of focus) 8th 6 64.82 4.83 9.30 (64.69 5.01 9.43) (Semihydrate) Example no. C H et X 164-166 64.36 5.21 10.74 (64.80 5.14 10.82) (Semietherat) 31 C H EC "η ^ S ' Ke 193-200 65.02 4.83 9.62 (65.2 4.76 9.81) 32 Me ό 33 1 Me / ^ » J 1

Example 34

a) (±) -4- (2-Chlorophenyl) -5- (2-cyanoethoxycarbonyl) -1,4-dlhydro-3-ethoxycarbonyl-6-methyl-2- [4- (2) methyl imidazo [4,5 -c] pyrid-1-yl) phenyljpyrldln

A mixture of ethyl 4 '- (2-methylimidazo [4,5-c] pyrid-1-yl) benzoylacetate (7.50g, 23.1mmol), 2-chlorobenzaldehyde (3.255g, 23.1mmol) and 3 -Aminobut-2-enoic acid 2-cyanoethyl ester (3.557 g, 23.1 mmol) in ethanol (60 mL) was reacted as described in Example 1. Purification of the crude product by flash chromatography (eluting with ethyl acetate / diethylamine 19: 1) and then trituration with ether gave the title compound as an off-white solid (5.875g, 44%), m.p. 177-179 ° C.

Analysis%:

Found: C 65.59 H 4.81 N 11.89

Calcd. WrC ₃₂ H ₂₈ CIN ₆ O ₄ : C 66.03 H 4.85 N 12.03.

b) Separation via the salt with 4- (2,4-dichlorophenyl) -5,5-dimethyl-2-hydroxy-1,3,2-dioxaphosphorinan-2-oxide

A solution of the (±) -cyanoethyl ester prepared as described above (2.340 g, 4.02 mmol) in 20 ml of hot methanol was treated with (-) - 4- (2,4-dichlorophenyl) -5,5-dimethyl-2- hydroxy-1,3,2-dioxaphosphorinane-2-oxide (W.den Hoeve, H. Wynberg, J. Org.

Chem., [1985], 50, 4508) (1.250 g, 4.02 mmol) to give a solution of the diastereomeric salts. The solvent

was evaporated and the crystallization was induced by stirring with ethyl acetate and cooling.

The pictured salts were recrystallized from methanol / toluene to give the (-) cyanoethyl ester salt (207 mg). The mother liquors were concentrated under reduced pressure and recrystallized from dichloromethane / Etnylacetat, what more

350mg of the (-) cyanoethyl ester salt, m.p. 141-144 ° C, [a) J e = -36.9 ° (c = 0.52, ethanol).

¹ H NMR (500 MHz, CDCl ₃ ) showed that the diastereomer ratio was 92%.

Analysis%:

Found: C 56.91 H 4.70 N 7.72

Calcd WrC ₄₃ H ₄ ICI ₃ N ₆ O ₈ PxH ₂ O:

C, 56.68, H, 4.76, N, 7.69.

Substituting this salt with base (Na ₂ CO ₃ ) and extracting with dichloromethane afforded the free (-) cyanoethyl ester base (271 mg), m.p. 177-179 ° C (EtOAc), Ia] II ₉ = -38.2 "(c = 0.28, ethanol).

Analysis%:

Found: C 65.75 H 4.86 N 12.02

Calcd. WrC ₃₂ H ₂₈ CIN ₆ O ₄ : C 66.03 H 4.85 N 12.03.

Similarly, the (±) -cyanoethyl ester (3.492 g, 6.0 mmol) was treated with (+) - 4- (2,4-dichlorophenyl) -5,5-dimethyl-2-hydroxy-1,3,2-dioxaphosphorinane. 2-oxide (1.866 g, 6.0 mmol) was added and the resulting salts were recrystallized from methanol / toluene and then from dichloromethane / ethyl acetate to give the optically pure (+) - cyanoethyl ester salt (2.30 g). The salt was decomposed as described above, which upon recrystallization from ethyl acetate gave the free (+ 1-cyanoethyl ester base (735m'g), m.p. 177-179 ⁰ C, IaJiI ₉ = + 38.9 ° (c = 0, 27, ethanol).

Analysis%:

Found: C 66.02 H 4.94 N 12.20.

(c) (-) - 4- (2-Chloro-phenyl) -1,4-dihydro-3-ethoxycarbonyl-6-methyl-2- [4- (2-methyl-imidazo [4,5-c] pyrid-1-yl ) phonyl] pyridln-5

carboxylic acid

A mixture of the (-j-cyanoethyl ester from (b) above (271mg, 0.566mmol) and aqueous sodium hydroxide (2.54mL, 0.55M, 1.40mmol) in dioxane (7.5ml) under nitrogen at room temperature Hydrochloric acid (1.40ml, 1M, 1.40mmol) was added dropwise and the mixture was concentrated under reduced pressure, the resulting yellow solid was suspended in water, filtered off and dried in vacuo to afford the

Title link (200mg, 81%).

¹ H NMR (300MHz, DMSO-ds) 0.8 (3H, t, J 7Hz), 2.28 (3H, s), 2.50 (3H, s), 2.71 (2H, q, J 7Hz), 5.37 (1H, s), 7.11 (1H, d, J6Hz), 7.15 (1H, m), 7.28 (2H, m), 7.49 (iH, m) _/ 7.53 (2H, d, J 8 Hz), 7.63 (2H, d, J 8 Hz), 8.34 (1H, d, J 6 Hz), 8.93 (1H, s), 9.09 (1H, s) ,

(H) -4- (2-chlorophenyl) -1,4-dihydro-3-ethoxycarbonyl-6-methyl-2- [4- (2-methylimidazo [4,5-c] pyrid-1-yl] pyridine) 5-Carboxylic acid The (+ (- cyanoethyl ester of (b) above (531 mg, 0.91 mmol) was converted to the (+) - 5-carboxylic acid by the method described above for the (-) - 5-carboxylic acid Product was a yellow solid (340mg, 71%), Ja] II ₉ = 96.9 ° (c = 0, i95,

Ethanol).

pyridine | pyridyl] carbomoyl

The (-) - 5-carboxylic acid (200 mg, 0.378 mmol) prepared as above was suspended under nitrogen at room temperature in dry dichloromethane (10 ml). 4- (N, N-Dimethylamino) -pyridine (115 mg, 0.945 mmol) and subsequently 2,4,6-triisopropylbenzenesulfonyl chloride (286 mg, 0.945 mmol) were added and the resulting mixture was allowed to stand at room temperature for 2 '/ 2 hours stirred for a long time, forming a yellow solution. 2-Aminopyridine (355 mg, 3.78 mmol) was added and the mixture was stirred again for 4 h. The solution was concentrated under reduced pressure, dissolved in 0.1 N aqueous hydrochloric acid, and the solution was washed with ether (30 ml). The aqueous solution was basified by the addition of aqueous saturated bicarbonate and the product was extracted into dichloromethane (4 × 30 ml). The extracts were combined, dried (MgSO ₄ ), concentrated in vacuo and purified by flash chromatography (eluting with ethyl acetate: diethylamine, 19: 1) to give a yellow gum (105 mg).

This material was suspended in ether, ultrasonicated into a powder and this was filtered off and

dried in vacuo, mp 223-225 ° C. [alig = + 62.0 ° (c = 0.25, ethanol).

¹ HNMR (300 MHz, CDCl ₃ ) 1.02 (3 H, t, J 7 Hz), 2.32 (3 H, s), 2.63 (3 H, s), 3.94 (2 H, q, J 7 Hz), 5.65 (1H, s) 5.94 (1H, br's), 7.03 (1H, dd, J 5and 7Hz), 7.15 (1H, d, J 6Hz) , 7.23 (1H, t, J 8Hz), 7.33 (2H, m), 7.45 (2H, d, J8Hz), 7.68 (4H, m), 8.09 (1H, brs), 8,19 (1 H, d, J

8Hz), 8.29 (1H, d, J5Hz), 8.38 (1H, d, J6Hz), 9.09 (1H, s).

Following the same procedure, the (+) - 5-carboxylic acid (250 mg, 0.473 mmol) was converted to the (-) - 5- | N- (2-pyridyl) amide (76 mg),

M.p. 217-219X, Ia) U ₉ = -55.3 ° (c = 0.215, ethanol).

Example 35

4- (2-chlorophenyl) -1,4-dihydro-3-ethoxcyrbonyl-6-methyl-2- [2- (2-methyllmldazo [4,5-c] pyrld-1-yl) pyrld-5-yl] -5- [N- (2-pyrldyl) carbamoyl] pyridine

A solution of 2- (2-methylimidazo [4,5-c] pyrid-1-yl) pyrid-5-o-ethylacetic acid ethyl ester (324 mg, 1.0 mmol), 3-amino-N- (2-pyridyl) -but-2 -eneamine (178mg, 1.0mmol) and 2-chlorobenzaldehyde (140mg, 1.0mmol) in ethanol (4ml) was refluxed under nitrogen for 5 hours. The solution was cooled and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with ethyl acetate: methanol, 6: 1) followed by sonication of a suspension of the eluted product in ether / ethyl acetate (3: 1) for 45 minutes. There? off-white product was filtered off and dried in vacuo to give the title compound, 140mg (23%), mp. 242-243 ⁰ C.

Analysis%:

Found: C 04.11 H 4.56 N 15.52

Calculated for

C ₃₃ H ₂₈ CIN ₇ O ₃ X 3 / 4H ₂ O: C 63.96 H 4.79 N 15.82.

The following preparation examples refer to intermediates suitable for preparing the compounds of formula (I).

Production Example 1

4 '- (2-Methylbenzlmldazol-1-yl) benzoylesslgs8ureethylester

Under nitrogen, a suspension of activated zinc dust (994 mg, 15.2 mmol) in dry THF (10 ml) was sonicated for 10 minutes, then three drops of ethyl bromoacetate were added. The mixture was refluxed for 10 minutes, after which 1 - (4-cyanophenyl) -2-methylbenzimidazole (708 mg, 3.04 mmol) was added at once *. A solution of ethyl bromoacetate (1.35 mL, 12.1 mmol) in dry THF (4 mL) was added dropwise to the refluxing iodide mixture over 1 h, and after a further 10 min, it was cooled to room temperature and washed with THF (19 , 5ml) diluted. 50% aqueous potassium carbonate (4 ml) was added and the mixture was stirred vigorously for 30 minutes. The organic solution was filtered through Arbocel filter aid (trade name), and the inorganic salts and filter cake were washed with THF (90 ml). Dilute hydrochloric acid (10 ml) was added to the combined organic solutions and the biphasic mixture was stirred at room temperature for 14 hours. The mixture was neutralized with saturated aqueous sodium bicarbonate and concentrated under reduced pressure. The residue was partitioned between brine and dichloromethane, and the organic phase was dried (MgSO ₄ ) and concentrated to a yellow oil. Purification of the crude product by flash chromatography (Et ₂ O / EtOAc, 1: 1) afforded the title compound (526 mg) as a pale yellow solid.

¹ HNMR (CDCl ₃ ): 1.33 (3H, t, J 7Hz), 2.59 (3H, s), 4.1 (2H, s), 4.29 (2H, q, J 7Hz), 7 , 15-7.35 (3H, m), 7.56 (2H, d, J 9Hz), 7.79 (1H ₁ d, J 8Hz), 8.20 (2H, d, J 9Hz) ,

Manufacturing bells 2-20

Other ketoesters of the formula (III) were prepared from the corresponding nitriles analogously to the general procedure of Example 1. However, the hydrolysis step required stirring a two-phase mixture of a solution of the crude product in dichloromethane with 20% trifluoroacetic acid at room temperature for 15-20 minutes.

COCH CO R ι 2. 2

(III)

The compounds are shown in Table 3.

υ a υ

I W CQ

PO

ca

cd cr <

CN

sr o

A ·

A "O O ^

CQ A A

• CN N CN vO

ΟΓ- «·

CN CN

he

ao co

A A

N • X X CN OO

PO ON

A N X A * "1 CS ss X X s? N iH PO A • '*' ' TJ CO M ta A • r-i N CN \ ^ X ON A vO ~> N • X A A TJ N X * X CN "^ A co X CN · CO A • «^ ^ or oo Φ CN A PO X • CN

cn cn

U- 2

O)

SI CO Q) -H

A X X CN (O ^v - ' A O X CN • • ^N - ' TJ rh m i-H X • N rh sr X * - < A ΙΛ ON N • X 00 A TJ • _n A N X X U ^^ 00 X i-H CN η • A "^ TJ ON A CN X " N rh X

X CO  -) • O CN • "όο TJ ON A I O m A X O\ • X i-H CM sr N i-H • X rh A • sr e-H A N sr X • N N 00 X <- " -σ vO sr A N ^ "5 A X X U r-t A r- XJ X * CJN »- A CN O X • A cn T3 sr 00 A A CN • X ro N CN X A CN » S CN M. " oo ' X X A CN O* A ^ j X * N A r ^ oo CN X U * CO A X A CN sr • * TJ O X A A CN * sy co O

ro X O

ro

CN

in + j u O

W ►Y .J

α \ · <Ν 00 * νθ • O (N × X • , χ η - C CO vT • • -. fH X CM N • η ή vT N ν- ' CN - ^ - X χ m m U νθ • αο • UI (Ν. • U ^ -N OV CO CO oo <- < • η ^ "S * (O · O · χ (0 «--Ν η οο • oo CO · X N * * νν C m * 4 X ι «. fH · · 3Β ^^ OO CM Ό / - » CO X λ CM ^ N co χ • CNN v ^ Ui η • X 00 -H ^ X CM 00 X • Λ 00 · · O CM <7> χ η O rv T3 ντ ^ν ^ η U sr · · · UI ^ ν νθ · • NiS N β · Τ3 CO · • X CM CM X · X Ν '' • * ™ i νθ '^ CO ^ <Ν | χ * ^ - ^ £ \ «/ N CO CO · »ν. , χ · ν- 'υ -σ ΌΪΝ Γ ". νθ «^^ · • ι-ι · UI X N X CM ^ 00 • f X fH CM N ^ νθ N ^ Λ CO / -S • CM η CM N · N .-. 00 CM SM X ν θ Ό CO νθ «(ν. (Ν. co η ^ η -) ^ -. X ^ υ χ N fH N «« • X W X υ U ifl T3 · U (ν.30 ν · - m • »-> · N • · -> νο η OS X XX χ Σ CO · fH co rv. , Z X <Γ · ν © η vT «/ -C · co χ O CO X N X • CM · · • CM X CN ιΗ V ^ OO TJ , H WVO * - Ml ^ L X! U CO U ω CD to · Cn U Γν UI r- (φ φH at

TABLE 3 (cont.)

Production Example No.

10

^X HNMR (CDCl.)

• J

1.16 (3H, C.J 7Hz), 1.28 (3H, C, J 7Hz). 2.7A (2H, q J 7Hz), 3.98 (2H, s), 4.13 (2H q q J 7Hz), 6.99 (IH, d, J 7Hz), 7.45 (2H, d, J 8Hz), 8.11 ( 2H, d, J 8Hz), 8.23 (IH, d, J 7Hz), 8.9A (IH, s).

1.33 (3H, C, J 7Hz), 2.62 (3H, s), 4.08 (2H, s), A.25 (3H, s), A.28 (2H, q, J 7Hz), 7.61 (2H, d , J 8Hz), 8.22 (2H, i.e. J 8Hz), 8.53 (IH, s).

1.30 (3H, C, J 7Hz), 2.62 (3H, s), A.11 (2H s), A.29 (2H, q, J 7Hz), 7 * 71 (IH, d, J 6Hz), 7.99) 2H. d, J j 8Hz), 8.25 (2H, d, J 8Hz), 8.52 (IH, d, J 6Hz), 8.60 I (IH, 8). -;

TABLE 3 (cont.)

Production Example No.

17

19

et

et

et

^ S ' Μθ

HNMR (CDCl ₃ )

1.32 (3Η, η »), 2.52 and 2.7A (jew .. 3H ε), -4.02 (2Η, s), 4.27 (2Η, m), 7.53 and 8.01 (each 2H, d, J - 8Hz) ,

1.32 (3H, tJ - 7.5 Hz), 2.52 (3H, s), A.03 (2H, s). A.28 (2H, qJ - 7.5 Hz), 6.91 "^ d 7.33 (ih, d, J - AHz), 7.58 and 8.09 (each ₂ H. d, J - 9.5 Hz).

1.32 (3H, t, J - 7.5 Hz), 2.63 (3H, s), A.03 (2H, s), A.27 (2H, q, J - 7.5 Hz), 7.61 and 8.0A (jew. 2H, d, J - 8Hz) and 8.77 (IH, s).

U O tu

ο * Ε CM • CN in Λ in CO

Ό Η

CN

co

U)

• CN

ο ·. oo

CN vT

σ »· η

• M

CN · Ό

• a) «

N «CN

"O CN

• ο r »»

U ·

 * ·

X · N

cn / -ν χ

cn χ. cn

τ) X * § CN ν »^ CM ιθ M X • CN CN CN • _Μ • • • η X co νθ * O X • oo

UOC »τ co r«.

X cn

rl M B

cn X

CJ

 -σ

cn o

(Ij

a:

CN

oo · O ^ n

· MI · ^s S

cn

χ η

u -o

CN

N σ * X CN I · -) χ * CN Vk_ / Ό CN rh ϋ sr 00 X cn co and O cn * X CN

in

(1) tH

Ul Ul

TABLE 3 (cont.)

14 15 16

ec

et

CH,

CH CH.

CH,

HNMR (CDCl ₃ )

1.30 (3H, t, J - 6Hz), 1.97, 2.20 and 2.25 (3H, s respectively), 4.05 (2H, β), 4.25 (2H.q, J - 6Hz) 7.34 and 8.13 (2H, respectively) , J - 9Hz).

1.30 (3H, t _s J - 6Hz), 2.54 (3H, s), 4.06 (2H, s) 4.25 (2H, q, J - 6Hz), 7.25 (lh, m), 7.45 (3H, m), 8.08 (2H, d, J = 9Hz), 8.67 (IH, m).

1.30 (3H, t, J - 6Hz), 2.52 and 2.62 (each 3H, s), 4.05 (2H, s), 4.25 (2H, q, J - 6Hz ;, 7.11 (IH.

d, 6Hz), 7.45 (3H, m), 8.08 (2H, d, J «9Hz).

TABLE 3 (cont.)

Production Example No.

Mp. 80-82 C, not further characterized

The ketoesters are present in CDCl ₃ to 5-30% in the enol form, and the spectroscopic data are given for the keto form.

Production Example 21 4- (4-Methylimidazol-1-yl) benzoylsilsesulfurate

(a) 4 '- (4-Methylimidazol-1-yl) acetophenone

A mixture of 4'-fluoroacetophenone (13.8 g, lOOmmol), 4-methylimidazole (8.2g, lOOmmol) and potassium carbonate (2O, 7g, 150 mmol) in dry dimethylformamide (190ml) was heated at 15O ⁰ C for 23 hours. Under reduced pressure, most of the solvent was evaporated and the residue was partitioned between ethyl acetate and brine. The organic phase was washed with brine (3x), dried (magnesium sulfate) and evaporated to leave a sticky residue which was purified by flash chromatography (eluting with 5% diethylamine in ethyl acetate). Recrystallization from ethyl acetate / hexane afforded the title compound (yield 4g, 20%), m.p. 100 ^° C.

(b) Title ketoester

The product from (a) (2g, 10mmol) was added to a refluxing suspension of sodium hydride (0.44g of a 60% dispersion in mineral oil - washed with dry hexane) in diethyl citrate (12ml). After refluxing for one hour, another portion of sodium hydride (500 mg) was added and heating to reflux continued for two more hours. Excess sodium hydride was destroyed by the addition of ethanol and the mixture was concentrated to dryness. The residue was dissolved in the smallest possible amount of 2 M hydrochloric acid and then partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic extract was dried (magnesium sulfate) and evaporated to a gum. Flash chromatography (eluting with ethyl acetate) afforded the title compound as a white solid (yield 400 mg), 15%.

¹ HNMR (CDCl ₃ ): 1,? C! 3H, t, J = 6Hz), 2.33 (3H, s), 4.05 (2H, s), 4.25 (2H, q, J = 6Hz ), 7.11 (1H, s), 7.52 (2H, d, J = 9riz); 7.90 (1H, s), 8.11 (2H, d, J = 9Hz).

Production Example 22

4 (3,5-Dlmethyl-1,2,4-trlazol-1-yl) -benzoylesslgs8ureethylester

The procedure of Preparation 21 was followed, but instead of 4-methylimidazole the corresponding amount

3,5-dimethyl-1,2,4-triazole. Step (a) provided 4- (3,5-dimethyl-1,2,4-triazol-1-yl) acetophenone in 42% yield.

Step (b) yielded ethyl 4- (3,5-dimethyl-1,2,4-triazol-1-yl) -benzoylacetate in 63% yield.

¹ H-NMR (CDCl ₃ ) of the title ketoester: 1.30 (3 H, t, J = Hz), 2.47 and 2.60 (3 H, s respectively), 4.04 (2 H, s ), 4.25 (2 H, q, J = Hz), 7.66 and

8.11 (each 2H, d, J = 9Hz).

Preparation Example 23 4 '- (1-Benzimidazolyl) benzoylacetic acid ethyl ester

(a) 4 '(1-Benzimidazolyl) acetophenone

A mixture of p-bromoacetophenone (3.98g, 20mmol), benzimidazole (4.72g, 40mmol), copper alloy (1.27g, 20mmol), anhydrous potassium carbonate (5.52g, 40mmol) and copper (I) bromide (290mg, 2 mmol) (in dry N-methylpyrrolidinone 60ml) was heated under nitrogen for 8 hours at 160 ⁰ C. Most of the solvent was removed by distillation under reduced pressure and the residue was diluted with dichloromethane (500 ml) and 2 N sodium hydroxide (200 ml). The organic phase was washed with water (300 ml), dried (MgSO ₄ ) and concentrated to a dark brown oil. Purification by flash chromatography (eluting with ethyl acetate) gave 4 '- (1 -BenzimidazolyO-acetophenone, 3,085g, in the form of a pale yellow solid, mp 133-135 ⁰ C.

¹ H-NMR (CDCl ₃ ): 2.37 (3H, s), 7.46 (2H, m), 7.65 (1H, m), 7.69 (2H, d, J 8Hz), 7 , 94 (1H, m), 8.21 (1H, s), 8.23 (2H, d, J 8Hz).

(b) 4 '(1-Benzimidazolyl) benzoylacetic acid ethyl ester

The title compound was prepared in a modification of the method of U.S. Patent 4,353,905. Sodium hydride (132 mg,

80% dispersion in oil, 4.4mmol) was washed with dry pentane under nitrogen and suspended in dry THF (10ml), and a solution of 4 '- (1-benzimidazolydacetophenone (944mg, 4.0mmol) in dry THF ( The mixture was stirred at room temperature for one hour and diothyl carbonate (1.21 mL, 10 mmol) was added, the mixture was heated to reflux for 18 hours, cooled and filtered The solid was suspended in water with acetic acid The extracts were dried (MgSO ₄ ) and concentrated, and the residue purified by flash chromatography (eluting with ethyl acetate: hexane 4: 1) to give 4 '(1-benzimidazole-benzoyl-acetic acid, 449 mg, as a colorless solid, m.p. 69-71 ⁰ C.

¹ HNMR (CDCl ₃ ) 1.32 (3H, t, J 6Hz), 4.08 (2H, s), 4.28 (2H, q, J 6Hz), 7.41 (2H , m), 7.63 (1H, m), 7.71 (2H, m), 7.94 (1H, m), 8.22 (3H,

4 '(Imidazole-1-yl-benzoylacetic acid ethyl ester was prepared by the method of U.S. Patent 4,353,905.

Preparation 24 1- (4-Cyanophenyl) -2-methylbenzimidazole

(a) N- (4-iodophenyl) -2-nitroaniline

The method of VP Chernetskii, AI Kiprianov, Zh. Obsch. KhIm., 1956, 26, 3465, followed by heating a mixture of 2-fluoronitrobenzene (14.0 g, 100 mmol), p-iodoaniline (10.95 g, 50 mmol) and triethylamine (13.9 mL, 100 mmol) at reflux for 42 hours , The mixture was cooled, diluted with ethyl acetate (300ml) and washed sequentially with water (100ml), 2N sodium hydroxide (100ml) and brine (100ml). The organic phase was dried (MgSO ₄ ) and concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate to give N- (4-iodo-phenyl) -2-nitroaniline, 10.03 g, as light orange needles, m.p. 171-172 ⁰ C.

(b) N- (4-iodophenyl) -1,2-diaminobenzene

Following the procedure of Chem. Abs., 1962, 57, 9840a, a solution of sodium dithionite (85%, 24.74 g, 121 mmol) in water (120 ml) was added to a suspension of (4-iodophenyl) -2-nitroaniline in Ethanol (500ml). The mixture was heated to reflux for 45 minutes, cooled, treated with 300 ml of dilute aqueous ammonia and concentrated under reduced pressure. The resulting white suspension was mixed with 200 ml of dilute aqueous ammonia, and the

The residue was filtered off and washed with water (200 ml). The solid was dried in a vacuum desiccator at room temperature yielding N- (4-iodophenyl) -1,2-diaminobenzene, 8.91 g, which gradually becomes darker on exposure to light, mp 122 -123 ° C

¹ H-NMR (CDCl ₃ ) 3.81 (2H, br s), 5.21 (1H, br s), 6.54 (2H, d, J 8Hz), 6.82 (2H , m), 7.09 (2H, m), 7.48 (2H, d, J 8 Hz).

(c) 1- (4-iodophenyl) -2-methyl-sulfimidazole

Ethyl iminoacetate hydrochloride (6.757 g, 54.9 mmol) was added at room temperature to a suspension of N- (4-iodophenyl) -1,2-diaminobenzene (6.812 g, 22.0 mmol) in absolute ethanol (30 mL). After 2 hours, 50 ml ice-cold 2 N aqueous sodium hydroxide was added and the product was extracted into ethyl acetate (2 x 100 ml). The extracts were washed with water (3 x 100 ml), dried (MgSO ₄ ) and concentrated under reduced pressure, and man

obtained 1- (4-iodophenyl) -2-methylbenzimidazole, 6,695g, in the form of a white solid, mp. 136-137 ⁰ C.

HNMR (CDCl ₃ ): 2.55 (3H, s), 7.14 (1H, d, J 8Hz), 7.17 (2H, d, J 8Hz), 7.25 (1H, J 8Hz), 7.31 (1H, t, J 8Hz), 7.93 (1H, d, J 8Hz), 7.95

(2H, d, J 8 Hz).

(d) 1- (4-cyanophenyl) -2-methylbenzimidazole

Copper (I) cyanide (8.323g, 93mmol) was added to a mixture of 1- (4-iodophenyl) -2-methylbenzimidazole (5.184g, 15.5mmol) and palladium (II) acetate (170mg) in N, N'- Dimethyl 1,4,5,6-tetrahydro-2-pyrimidone (15ml) and the resulting solution was heated at 100 ° C under nitrogen for 15 hours. The mixture was cooled, poured into saturated aqueous ammonia (150 ml) and shaken to dissolve the copper salts. The mixture was extracted with ether (3 x 150 ml) and the combined extracts were washed successively with water (3 x 150 ml) and brine (150 ml) and then dried (MgSO ₄ ) and concentrated under reduced pressure to give 1- (4-cyanophenyl) -2-methylbenzimidazole, 941 mg, as a white solid.

¹ HNMR (CDCI _3): 2.58 (3H, s), 7.17 (1 H, d, J 8 Hz), 7.27 (1 H, t J 8 Hz), 7.34 (1 H, t, J8Mz ), 7.58 (2H, d, J8Hz), 7.79 (1H, d, J8Hz), 7.95 (2H, d, J8Hz).

Production Example 25

4- (4-cyanophenyl) -3,5-dimethyl-1,2,4-trlazol

Hydrazine hydrate (1.64 ml, 34 mmol) was added at room temperature to a solution of p-cyanothioacetanilide prepared according to J. Chem.

Pharm. Soc. Jpn., 1952.72, 739, (5.43 g, 30.9 mmol) in THF (50 ml). After 30 minutes, the solution was concentrated under reduced pressure and to the residue was added triethyl orthoacetate (ethyl acetate) (40 ml).

The mixture was 30 minutes I nuf 80 ⁰ C, cooled, and the excess reagent was removed under reduced pressure. The residue was added with ice-cold dilute aqueous ammonia (100 ml) and the product was filtered off, washed with water and dried in vacuo. The title triazole (4.85g) was a dirty white solid, mp.

¹ H-NMR (CDCl ₃ ): 2.32 (6H, s), 7.42 (2H, d, J 8Hz), 7.92 (2H, d, J 8Hz).

Preparation Bulk 26 1- (4-Cyanophenyl) -2-methyl! Mldazo [4,5 cipyridyl

(a) N- (4-cyanophenyl) -4-amino-3-nitropyridine

According to the procedure of J. C, S. Perkln Trans. 1,1979,135, p-cyanoaniline (6.894 g, 58.4 mmol) was added to a solution of 4-chloro-3-nitropyridine (9.26 g, 58.4 mmol ) in ethanol (200 ml), and the mixture was stirred at room temperature for 18 hours. The resulting yellow suspension was poured into 500 ml of ice-cold dilute ammonia and filtered. The solid was added with 150 ml of boiling ethanol, cooled in ice and filtered to give N- (4-cyanophenyl) -4-amino-3-nitropyridine, 12.15g, as a light yellow powder, m.p. 210-211 ° C , ¹ H-NMR! CDCl ₃ ): 7.15 (1 H, d, J 6Hz), 7.45 (2H, d, J 9Hz), 7.79 (2H, d, J 9Hz), 8.43 ( 1H, d, J 6Hz), 9.36 (1H, s), 9.80 (1H, br s).

(b) 3-Amino-4- (4'-cyanophenyl) aminopyridine

According to a modification of the method of Pharm. HeIv. Acata, 1975, 50, 188, stannous chloride dihydrate (56.4 g, 250 mmol) was added to a suspension of N- (4-cyanophenyl) -4-amino-3-nitropyridine (12.0 g, 50 mmol) in 2 N aqueous hydrochloric acid (35 mL Water (150 ml) and ethanol (75 ml) were added and the resulting mixture was refluxed under nitrogen for 10 minutes. The mixture was cooled in ice, poured into ice-cold 2 N aqueous sodium hydroxide (400 ml) and filtered. The chrominance solid was washed with 2 N aqueous sodium hydroxide and water and then dried in a vacuum desiccator. The product, 3-amino-4- (4'-cyanophenyl) -aminopyridine, 9.31 g, gradually turns reddish-brown when exposed to light and air

¹ HNMR (CDCl ₃ ): 3.52 (2H, br s), 6.04 (1H, br s), 7.03 (2H, d, J 9Hz), 7.59 (2H, d, J 9Hz) , 8.07 (1H, m), 8.20 (1H, s).

(c) 1- (4-Cyanophenyl) -2-methylimidazo [4,5-c] pyridine

A mixture of 3-amino-4- (4'-cyanophenyl) aminopyridine (9.31 g, 44.3 mmol), triethyl orthoacetate

(Ethyl acetate) (40 ml) and acetic anhydride (30 ml) was refluxed for 2 hours under nitrogen, cooled and then concentrated under reduced pressure. The brown residue was dissolved in 1M hydrochloric acid and washed with ethyl acetate (200 ml.) The aqueous phase was basified with saturated aqueous ammonia and extracted with dichloromethane (3 × 200 ml) The combined extracts were washed with water, dried (MgSO ₄ ) and concentrated and, thereby 1- (4-cyanophenyl) -2-meihylimidazo [4,5-c] pyridine, 6.5 g, in the form of a brown solid ¹ H NMR (CDCI _3). 2.61 (3H, s), 7.13 (1H, d, J6Hz), 7.58 (2H, d, J9Hz), 7.98 (2H, d, J9Hz), 8.45 (1H, d, J6Hz), 9 , 11 (1H, s).

Production Example 27

1- (4-cyanophenyl) -2-trlfluormethylimidazo [4,5-c] pyrldin

A mixture of 3-amino-4- (4'-cyanophenyl) aminopyridine (420mp, 2.0mmol) (prepared as described above), trifluoroacetaldehyde hydrate (232mg, 2.0mmol) and sodium metabisulfite (475mg, 2.5mmol) in N, N-dimethylacetamide (10 ml) was heated to reflux for 16 hours. After the mixture was cooled, it was washed with ethyl acetate (200ml).

diluted and saturated:.,! aqueous sodium bicarbonate (50ml) and water (5x50ml). The organic phase was dried (MgSO ₄ ) and taken in under reduced pressure. The residue was purified by flash chromatography (eluting with ethyl acetate) to give 1- (4-cyanophenyl) -2-trifluoromethylimidazo [4,5-c] pyridine, 337mg. ¹ HNMR (CDCl ₃ ): 7.17 (1H, d, J 5Hz), 7.63 (2H, d, J 8Hz), 7.99 (2H, d, J 8Hz), 8.62 (1H, d , J 5Hz), 9.35 (1 H, s).

Production Example 28

2-Butyl-1- (4-cyanophenyl) lmldazo [4,5-c] pyrldln

A mixture of 3-amino-4- (4'-cyanophenyl) aminopyridine (Preparation 26 [b |] (1.26g, 6.0mmol) and valeric anhydride (10ml) was heated to reflux under nitrogen for 16 hours. The mixture was cooled, poured into 2N aqueous sodium hydroxide (100 ml) and allowed to stand for 15 minutes. The solution was extracted with dichloromethane (3x70ml) and the extracts were dried (MgSO ₄ ) and concentrated under reduced pressure. Purification by flash chromatography (eluting with ethyl acetate / methanol 9: 1) afforded the title precursor, 947 mg, as a brown

Solid.

¹ HNMR (CDCl ₃ ): 0.93 (3H, t, J 8Hz), 1.4 (2H, p, J8Hz), 1.86 (2H, p, J 8Hz), 2.84 (2H, t, J8Hz), 7.10 (1H, d, J5Hz), 7.56 (2H, d, J8Hz),

7.97 (2H, d, J 8Hz), 8.46 (1H, d, J 5Hz), 9.13 (1H, s).

Production Example 29

1 - (4-cyanophenyl) -2-ethylimida7.o [4,5-c] pyridine

A mixture of 3-amino-4- (4'-cyanophenyl) aminopyridine (Preparation 26 [b]) (2.00 g, 9.5 mmol) and propionic anhydride (12.2 mL, 95 mmol) was added all under nitrogen Heated to reflux for 17 hours. The resulting solution was treated with an excess of aqueous sodium bicarbonate and the product was extracted into dichloromethane (3 x 150 ml). The combined extracts were dried (MgSO ₄ ) and concentrated under reduced pressure and the residue was purified by flash chromatography (eluting with ethyl acetate / methanol) to give the title compound as a brown solid (510mg, 22%).

¹ HNMR (300MHz, CDCI ₃ ): 1.45 (3H, t, J 7Hz), 2.87 (2H, q, J 7Hz), 7.10 (1H, d,> 5Hz), 7.55 (2H, d , J 8Hz), 7.96 (2H, d, J 8Hz), 8.44 (1H, d, J 5Hz), 9.13 (1H, s).

Preparation Example 30 9- (4-Cyanophenyl) -t> -methoxy-8-methylpurln

(a) 5-Amino-6-chloro-4- (4-cyanophenyl) -aminopyrimidine

A solution of 5-amino-4,6-dichloropyrimidine (7.00g, 42.7mmol) and 4-aminobenzonitrile (5.04g, 42.7mmol) in n-butanol (130ml) was heated at reflux for 16 hours. After allowing the mixture to cool, the precipitated solid was filtered off and partitioned between dichloromethane (500 ml) and saturated aqueous sodium bicarbonate. The organic phase was dried (MgSO ₄ ) and concentrated under reduced pressure to give the title compound (6.31 g, 60%).

'H NMR (300MHz, MeOH-d ₄ ): 7.72 (2H, d, J 8Hz), 7.99 (2H, d, J 8Hz), 8.02 (1H, s).

(b) 4- (acetyl- [4-cyanophenyl] amino) -6-chloro-5-diacetylamino-pyrimidine

A mixture of 5-amino-6-chloro-4- (4-cyanophenyl) aminopyrimidine (6.31 g, 25,7mmoi / and acetic anhydride (105ml) was heated for 6 hours at 120 ⁰ C and then for 16 hours at 20 The excess of reagent was removed under reduced pressure and the residue recrystallised from methanol to afford the title compound (4.62 g, 51%) as a white solid

¹ H NMR (300MHz, DMSO-d _e ): 2.15 (3H, s), 2.38 (6H, s), 7.40 (2H, d, J 8Hz), 7.80 (2H, d, J 8Hz), 8.87 (1H, s).

(c) 6-Chloro-9- (4-cyaiophenyl) -8-methylpurine 4- (N-acetyl-N- [4-cyanophenyl] amino) -6-chloro-5- (N, N'-diacetylamino ) pyrimidine (2.50 g, 6.73 mmol) was at 50 mmHg

Heated to 240 ° C for 2 hours. The reaction melt was cooled and purified by flash chromatography eluting with ethyl acetate: dichloromethane 3: 1 to give the title compound (1.10 g, 61%).

(d) 9- (4-gyanophenyl) 6-methoxy-8-methylpurine

Sodium metal (160 mg, 6.96 mmol) was allowed to react under nitrogen with dry methanol (5 mL) until hydrogen evolution ceased. 6-Chloro-9- (4-cyanophenyl) -8-methylpurine (1.03 g, 3.82 mmol) was added all at once, and the resulting suspension was heated to reflux for 90 minutes. The solvent was removed under reduced pressure and the gummy residue was dissolved in dichloroformethane (50 ml). The solution was washed with brine (20ml), dried (MgSO ₄ ) and concentrated in vacuo to give the title compound (840mg, 83%).

received.

¹ H NMR (300MHz, CDCl ₃ ): 2.63 (3H, s), 4/26 (3H, s), 7.63 (2H, d, J 8Hz), 7.95 (2H, d, J 8Hz ), 8.52 (1H, s).

Preparative Example 31 3- (4-Cyanophenyl) -2-methylimidazo [4,5-c] pyridine

(a) 2-Methylimidazo [4,5-c] pyridine

A mixture of 3,4-diaminopyridine (20.0 g, 183mmol) and acetic anhydride (360ml) was heated at 100 ⁰ C for 16 hours. The excess reagent was removed under reduced pressure and the residue was purified by flash chromatography, eluting with ethyl acetate: methanol, 3: 1. The product was a brown solid (15.5g, 64%)

¹ H NMR (300MHz, MeOH-d ₄ ): 2.68 (3H, s), 7.58 (1H, d, J 6Hz), 8.31 (1H, d, J 6Hz), 8.80 (1H , s).

(b) 2-Methylimidazo [4,5-c] pyridine N-oxide

Following the procedure of Chem. Pharm. Bull., 12, 866 (1964), a solution of 2-methylimidazo [4,5-c] pyridine (5.65g, 42.5mmol) in 30% aqueous hydrogen peroxide (15ml) and glacial acetic acid Stirred at 60 ⁰ C for 6 days. The volatiles were removed under reduced pressure and the residue was dissolved in ethanol and treated with solid, anhydrous potassium carbonate. The solid was filtered off and washed with ethanol and the filtrate was taken

concentrated reduced pressure. The crude product was purified by flash chromatography, eluting with 10-30% water in acetone. The product-containing fractions were concentrated under reduced pressure, redissolved in isopropanol / toluene, 1: 1 (200 ml) and evaporated again to give the title compound as a hygroscopic solid

(2.94g, 46%).

¹ H NMR (300MHz, MeOH-d ₄ ): 2.69 (3H, s), 7.69 (2H, d, J 6Hz), 8.23 (1H, d, J 6Hz), 8.72 (1 H, s).

(c) 3- (4-Cyanophenyl) -2-methylimid8Zo [4, S-c] pyridine

A mixture of 2-methylimidazo [4,5-c] pyridine N-oxide (2.06 g, 13.8 mmol), 4-fluorobenzonitrile (1.67 g, 13.8 mmol) and anhydrous potassium carbonate (13.8 mmol) in dry dimethylformamide (35 ml) was heated at 140 ° C. under nitrogen for 16 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a mixture

of 1- and 3- (4-cyanophenyl) -2-methylimidazo | 4,5-c] pyridine N-oxides.

This mixture was dissolved in glacial acetic acid (40 ml) and iron powder (1.16 g, 20.7 mmol) was added. The mixture was heated for 30 minutes at 100 ⁰ C, cooled and filtered through Arbocel filter aid. The filtrate was concentrated under reduced pressure and the residue was taken up in dichloromethane (150 ml) and washed with saturated aqueous sodium bicarbonate. The organic phase was dried (MgSO ₄ ) and concentrated under reduced pressure

concentrated.

The resulting crude product was purified by flash chromatography eluting with ethyl acetate: methanol, 9: 1, to give three fractions. The first eluate contained 3- (4-cyanophenyl) -2-methylimidazo [4,5-c] pyridine (<* 15 mg, 13%).

¹ H NMR (300MHz, CDCl ₃ ): 2.64 (3H s), 7.62 (2H, d, J 8Hz), 7.70 (1H, d, J 5Hz), 7.98 (2H, d, J8Hz), 8.52 (1H, d, J5Hz), 8.59 (iH, s).

Second, a mixture of 3- and 1- (4-cyanophenyl) -2-methylimidazoI4,5-c] pyridines (410 mg, 13%) was eluted, and

third eluate was pure 1- (4-cyanophenyl) -2-methylimidazo [4,5-clpyridine (350mg, 11%).

Preparation 32 1- (4-cyanophenyl) -2,4,6-trimethylimidazo [4,5-c] pyridine

(a) 2,6-D! methyl-3-nitrc-4-pyridone

2,6-Dimethyl-4-pyridone (Chem. Abs., 84, 4811 x, (1976)) (52.56 g, 0.427 mol) was dissolved in 5 O ⁰ C warm water (100 ml) and was added dropwise fuming nitric acid (40 ml The mixture was cooled in ice for 45 minutes and then the pale brown-yellow crystals were filtered off, washed with a small amount of water and dried by suction to give 2, G-dimethyl-4-pyridone nitrate salt (46 , 79g, 59%) received. this substance was added portionwise at room temperature (in a mixture of fuming sulfuric acid 23ml) and fuming nitric acid (31 ml) was added, and the mixture was heated to 100 ⁰ C and held VIi hours at this temperature. the Mixture was poured onto ice and neutralized with saturated aqueous potassium carbonate The precipitating pale yellow solid was filtered off, filled into a Soxhlet extraction apparatus and extracted with boiling isopropanol The isopropanol was removed under reduced pressure to give the diol e title compound (26.5g, 63%)

¹ H NMR (300MHz, MeOH-d _4): 2.38 (3H, s), 2.45 (3H, s), 6.39 (1 H, s).

(b) 4-Chloro-2, C-diethyl-3-nitropyridine

According to the method of Yakugaku Zssshi, 87, 387 (1967), 2,6-dimethyl-3-nitro-4-pyridone (11.23 g, 66.8 mmol) and phosphorus oxychloride (57 ml) were heated together for four hours at reflux. The excess reagent was removed under reduced pressure and the residue was dissolved in dichloromethane (150 ml). To this solution was added dilute aqueous sodium bicarbonate until the aqueous phase had pH 7 and then the organic phase was separated, dried (MgSO ₄ ) and concentrated under reduced pressure to give a pale yellow solid (9.8 g, 79%) , Caution: This compound is classified as highly irritating to the skin. ¹ H NMR (300MHz, CDCl ₃ ): 2.58 (3H, s), 2.61 (3H, s), 7.22 (1H, s).

(c) 4- (4-Cyanophenyl) -amino-2,6-dimethyl-3-n-tropyridine

A solution of 4-chloro-2,6-dimethyl-3-nitropyridine (9.80g, 52.5mmol) and 4-aminobenzonitrile (6.20g, 52.5mmol) in ethanol (160ml) was allowed to stand at room temperature for 16 hours touched. The solvent was removed under reduced pressure and the residue was dissolved in dichloromethane (200 ml) and washed with saturated aqueous sodium bicarbonate (100 ml). The organic phase was dried (MgSO ₄ ) and concentrated under reduced pressure to a gum which was crystallized by addition of ether (100 ml) and sonication for 5 minutes. The yellow solid (9.80g, 70%) was filtered off and dried in vacuo, m.p. 171-172 ° C

¹ H NMR (300MHz, CDCl ₃ ): 2.49 (3H, s), 2.76 (3H, s), 6.96 (1H, s), 7.35 (2H, d, J 8Hz), 7 , 74 (2H, d, J 8Hz), 8.69 (1H, br s).

(d) 3-Amino-4- (4-cyanophenyl) amino-2,6-dimethylpyridine

A solution of 4- (4-cyanophenyl) amino-2,6-dimethyl-3-nitropyridine (5.00 g, 18.6 mmol) in a mixture of dichloromethane (20 mL) and ethanol (100 mL) was heated at 20 ° C over 10 % palladium on charcoal (500 mg) for 3 hours at 138 kPa (20 psi). The catalyst was filtered off and the solvents were removed under reduced pressure to give

the title compound was obtained as a brown solid (4.20 g, 94%).

Ή NMR (300MHz, MeOH-d ₄ ): 2.39 (3H, s), 2.62 (3H, s), 6.98 (1H, s), 7.11 (2H, d, J 8Hz), 7.62 (2H, d, J 8Hz).

(e) 1- (4-Cyanophenyl) -2,4,6-trimethylimidazo [4,5-c] pyridine

A mixture of 3-amino-4- (4-cyanophenyl) amino-2,6-dimethylpyridine (4,20g, 17,6mmol), acetic anhydride (12,6ml) and acetic acid (12,6ml) was added at 100 hours ⁰ C16 stirred for a long time. The excess reagents were removed under reduced pressure, the gummy residue was dissolved in water, and the solution was basified by the addition of concentrated aqueous ammonia. The precipitated white solid was filtered off and dried in vacuo to give the title compound (4,06g, 88%), mp. 260-262 ⁰ C.

¹ H NMR (300MHz, CDCl ₃ ): 2.60 (3H, s), 2.65 (3H, s), 2.90 (3H, s), 6.81 (1H, s), 7.55 ( 2H, d, J 8Hz), 7.96 (2H, d, J 8Hz).

Analysis%:

Found: C 73.57 H 5.37 N 21.53

Calculated for C ₁₆ Ht ₄ N ₄ :

C 73.26 H 5.38 N 21.36.

Preparative Example 33 (1'S) -N- (1-Phenylethyl) -3-aminobut-2-enamide

(1'S) - N - (1-Phenylethyl) -3-ketobutarrmide (J. Chem. Eng. Data, 1954, 29, 229) (4.20 g, 20.5 mmol) was dissolved at room temperature in ethanol (20 mL). Then ammonia gas was bubbled through the solution for 6 hours. The solvent was under

The title compound was obtained as a golden brown oil (4.00 g, 95%) without

Further purification could be used directly in the Hantz synthesis.

Preparative Example 34 4- (2,4-Dimethylmimidazol-1-yl) benzonitrile

A mixture of 4-fluorobenzonitrile (3g, 25mmol), 2,4-dimethylimidazolium chloride (3g, 25mmol) and potassium carbonate (7.2g, 52mmol) in dimethylformamide (50ml) was heated at 145 ° C for 16 hours. In vacuo, most of the solvent was evaporated and the residue was partitioned between ethyl acetate and brine. The organic phase was dried (magnesium sulfate) and evaporated to a yellow solid. Crystallization from hexane / ether gave one

pale yellow solid (2.6g, 57%).

¹ HNMR, CDCI ₃ (among others): 2.25 and 2.41 (each 3H, s), 6.78 (1H, s). 7.43 and 7.80 (each 2H, d, J = 9H /).

Preparation Example 35 4 - (? - Methylimidazol-1-yl) benzonitrile

The procedure of Example 34 was repeated, but instead of 2,4-Di lethylimidazoliumchlorid 25mmol

2-methylimidazolium chloride. The title nitrile was obtained in 22% yield.

¹ HNMR, CDCI ₃ (among others): 2.44 (3H, s), 7.09 and 7.48 (each 2H, d, J = 9Hz), 7.84 (2H, d, J = 8Hz).

Preparative Example 36 4- (2,4,5-trimethyl-imidazoM-yl) benzonitrile

The procedure was similar to that of Preparation Example 34, but instead of 2,4-dimethylimidazolium chloride, 25 mmoles of 2,4,5-trimethylimidazolium chloride were used. The title nitrile was obtained in 7% yield. 'HNMR, CDCI ₃ (among others): 1.96, 2.18 and 2.23 (3H, s, respectively), 7.34 and 7.84 (each 2H, d, J = 9Hz).

Preparation 37 3- (4-Cyanohenyl) -2-methylpyridine

Under a nitrogen atmosphere, t-butyllithium (1.8 molar in pentane) (18.1 mL, 32.6 mmol) was stirred at -60 ± 5 ° C to a solution of 4-bromobenzonitrile (2.81 g, 15.4 mmol After stirring for 20 minutes at this temperature, a solution of dry zinc chloride (4.62 g, 33.8 mmol) in anhydrous tetrahydrofuran (55 mL) was added via cannula and allowed to stir without stirring Warm the solution to + 10 ° C over 10 minutes, then add tetrakis (triphenylphosphine) palladium (0.5 g, 0.43 mmol) and 3-bromo-2-methylpyridine (3.19 g, 18.5 mmol) red solution was then stirred at reflux for 5.5 hours.

After being cooled to ambient temperature, the crude mixture was concentrated under reduced pressure to about 50 ml and the residue was partitioned between methylene chloride (300 mM) and a solution of the disodium salt of ethylenediaminetetraacetic acid (8 g) and sodium carbonate (10 g) in wasiser (500 ml) , The organic extract was separated, dried over magnesium sulfate and concentrated under reduced pressure to a dark oil.

This oil was chromatographed over Merck 60 silica gel (trade name) eluting with 0% -> 100% ether in hexane.

The product-containing fractions were combined and concentrated under reduced pressure to give the title compound

in the form of an oil (0,6g, 20%), which solidified on standing.

¹ HNMR (CDCI ₃ ), including: 2.52 (3H, s), 7.26 (1H, m), 7.48 (2H, d, J = 9Hz), 7.53 (1H, m), 7.78 (2H, d, J = 9Hz), 8.58 (1H, m).

Preparation Example 38 Synthesis of 3- (4-cyanophenyl) -2,6-dimethylpyridine

A solution of 3-bromo-2,6-dimethylpyridine (5.58 g, 30 mmol) in anhydrous tetrahydrofuran (20 mL) was added to a boiling suspension of magnesium turnings (0.8 g, 33 mmol) and a single iodine crystal under a nitrogen atmosphere with stirring in anhydrous tetrahydrofuran (15 ml). The mixture was refluxed for another hour

stirred for a long time.

After cooling to room temperature, a solution of dry zinc chloride (4.1 g, 30 mmol) in anhydrous tetrahydrofuran (40 mL) was added to the reaction mixture via cannula with stirring, followed by the addition of töträkis (triphenylphous phen) pal! Adiurn (0, 2g, 17mmol) and a solution of 4-3-trichlorobenzene (2.34g, ISrnrnol) in anhydrous tetrahydrofuran (5ml). The reaction mixture was stirred at reflux for 1 hour.

After allowing the reaction mixture to cool to ambient temperature, it was partitioned between methylene chloride (200 ml) and a solution of the disodium salt of ethylenediaminetetraacetic acid (8 g) and sodium carbonate (10 g) in water (500 ml). The organic extract was separated, dried over magnesium sulfate and concentrated under reduced pressure

Compressed pressure to an oil.

This oil was chromatographed over Merck 60 silica gel "b" itz "using ether: hexane: diethylamine (25: 75: 2) as eluent

served.

The product-containing fractions were combined and concentrated to about 10 ml. The precipitated crystalline precipitate was filtered off, washed with ether and dried in air to give the title compound (1.2g, 44%).

¹ HNMR (CDCI ₃ ) among others: 2.50 and 2.62 (3H, s, respectively), 7, 12>, and 7.43 (1H, d, J = 8Hz, respectively), 7.47 and 7.77 (each 2H, d,

Preparation 39 5- (4-Cyanophenyl) -4-methyloxazole

With stirring, a two-phase mixture of formamide (0.6 ml, 15 mmol) and 4- (1-bromo-2-oxopropyl) benzonitrile (0.8 g, 3.4 mmol) was heated to 12O ⁰ C for 2 hours. After cooling, dichloromethane (15 ml) and saturated aqueous sodium bicarbonate (10 ml) were added, the organic phase was separated and dried (magnesium sulfate) and the solvent was removed under reduced pressure to give 0.4 g of an amorphous yellow solid. The product was purified by silica gel chromatography, eluting with dichloromethane, and the title compound (0.29 g, 47%) was obtained in the form of a pale yellow solid, mp. 120-121 ⁰ C.

Production Example 40 5- (4-Cyanophenyl) -6-methylimidazo [2,1-b] thiazole

A solution of 4- (1-bromo-2-oxopropyl) benzonitrile 1 g, 4 mmol) in n-butanol (3 mL) was added all at once to a hot (110X), stirred solution of 2-aminothiazole in n-butanol (3ml). After being boiled for 2 hours, triethylamine (0.5 ml, 4 mmol) was added and heating was continued for a further 2 hours. All volatiles were removed by evaporation and the residue was triturated with ethyl acetate: hexane: diethylamine (5: 14: 1) as eluent

Silica gel chromatographs to give a off-white solid (0.34 g, 35%), m.p. 88-91 ° C.

Preparation Example 415- (4-Cyanophenyl) -2,4-d-methylthiazole

To a solution of 4- (1-bromo-2-oxopropyl) benzonitrile (0.9 g, 3.83 mmol) in toluene (2 mL) was added thioacetamide (0.6 g, 8 mmol) and then pyridine (0.45 mL). The mixture was warmed to 100 ^° C. for 1 hour and then partitioned between ethyl acetate and brine. The organic phase was dried (MgSO ₄ ) and evaporated to a yellow oil.

Chromatography on silica gel eluting with 5% ether in dichloromethane afforded a light yellow oil which crystallized

(0.52 g, 64%), mp. 108-110 ⁰ C.

Production Example 42 5- (4-Cyanophenyl) -4-methylthiazole

(a) 5- (4-Cyanophenyl) -4-methylthiazole-2-thiol

A solution of 4- (1-bromo-2-oxopropyl) benzonitrile (4.65g, 0.02mol) in absolute ethanol (20ml) was added at ambient temperature over 10 minutes with stirring to a suspension of ammonium dithiocarbamate (2.2g , 0.02 mol) in absolute ethanol (20 ml), and the reaction mixture was stirred for a further 24 hours. Then the reaction mixture was diluted with H ₂ O (50 ml), the bulk of the ethanol was removed under reduced pressure and the product was extracted with ethyl acetate. The organic extract was dried (MgSO ₄ ), filtered and the filtrate was concentrated in vacuo. Trituration of the residue with ethanol and filtration gave the title product (1.2 g, 26%).

(b) 5- (4-cyanophenyl) -4-methylthlazole

Was added Raney nickel (1 g) to a solution of the product of (a) (1.2 g, 5 mmol) in absolute ethanol (120 ml) and heated the reactants in an autoclave 18 F-inden heated at 8O ⁰ C . After cooling to ambient temperature the reaction mixture was again Raney nickel (1g) was added and the reactants were heated in an autoclave for 6 hours at 8O ⁰ C. Then, the reaction mixture was filtered through arbocel and the filtrate was concentrated to dryness. The residue was flash chromatographed (Merck 60 silica gel - ethyl acetate: hexane! Diethylamine, 25: 75: 2) to afford the title product as a gum which solidified on standing (0.36 g, 35%) and used directly in Preparation 19 has been.

PREPARATION 43 2- (2-Methylimidazo [4,5-c] pyrid-1-yl) pyrid-5-o-ethylacetic acid ethyl ester

(a) 4-Chloro-1- (5-ethoxycarbonyl-pyrid-2-yl) -2-methyl-imidazo [4,5-c] pyridine

4-chloro-2-methylimidazo [4,5-c] pyridine described in CA. 79.105515f but prepared by the method of Chem. Pharm. Bull, 12 (8) 866-872 (1964), (3.34g, 20mmol) and 6-chloronicotinic acid ethyl ester (3.71g, 26.2mmol) were prepared in Dissolved N, N-dimethylformamide (42 ml). Potassium carbonate (2.76 g, 20 mmol) was added and the reaction mixture was heated at reflux overnight. The reaction mixture was cooled, the solvent was removed under reduced pressure, and the crude product was purified by flash chromatography eluting with ethyl acetate. The product containing fractions were evaporated and the resulting foam was stirred with ether. The solid was filtered off and dried under reduced pressure to give the title precursor as a yellow solid (3.2g, 51%).

¹ H NMR (300MHz, CDCl ₃ ): 1.47 (3H, t, J6Hz), 2.84 (3H,. S), 4, 8 (2H, q, J6Hz), 7.38 (1H, d, J4Hz), 7.59 (1H, d, J6Hz), 8.25 (1H, d, J4Hz), 8.63 (1H, d, J6Hz), 9.36 (1H, s).

(b) i-IB-ethoxycarbonylpyridyl-1-methyl-imidazoH.S-c-pyrrole

A solution of 4-chloro-1- (5-ethoxycarbonylpyrid-2-yl) -2-methylimidazo [4,5-c] pyridine in ethanol (100 ml) was treated with 50 psi (345 kPa) for 30 hours at 30% Palladium hydrogenated on carbon (3g) and magnesium oxide (0.8g). The mixture was filtered through Arbocel filter aid and the filter cake was washed with boiling ethanol (6 x 50 ml). The filtrate was concentrated under reduced pressure to afford the title compound as a white foam (2.75 g, 96%). ¹ H NMR (300MHz, methanol-d "): 1.51 (3H, t, J 6Hz), 2.83 (3H, s), 4.53 (2H, q, J 6Hz), 7.70 (1H , d, J 4Hz), 7.92 (1H, d, J 6Hz), 8.43 (1H, d, J 4Hz), 8.72 (1H, d, J 6Hz), 8.97 (1H , s), 9.32 (1 H, s).

(c) e- (2-Methylimidazo [4,5-c] pyrid-1-yl-pyrryl) -carboxylic acid

1 - (δ-Ethoxycarbonylpyrido) -dD-methylimidazoKö-clpyridine (2.75g, 9.75mmol) was dissolved in ethanol (15ml) and 2N aqueous sodium hydroxide (5.8ml) was added and the mixture was allowed to stand for three days The residue was neutralized with dilute hydrochloric acid (pH 6) and the resulting precipitate was filtered off and dried in vacuo to give the title compound as a white solid (1, 70g, 69%).

^l HNMR (300MHz, DMSO-de): 2.70 (3H, s), 7.58 (1H, d, J4Hz), 7.93 (1H, d, J6Hz), 8.36 (1H, d, J4Hz ), 8.58 (1H, d, J6Hz), 8.96 (1H, s), 9.18 (1H, s).

(d) 2- (2-Methylimidazo [4,5-c] pyrid-1-yl) pyrid-5-oyl-acetic acid, ethyl ester

6- (2-Methylimidazo [4,5-c] pyrid-1-yl) pyridine-3-carboxylic acid (50 mg) was suspended in dry dichloromethane (1 ml) and oxalyl chloride (29 mg) and Ν, Ν-dimethylformamide (1 , 5 mg) were added. The mixture was sonicated for 1 hour at room temperature to yield a suspension of 6- (2-methylimidazo [4,5-c] pyrid-1-yl) pyrid-3-oyl chloride in dichloromethane.

The potassium salt of the malonic monoamine ethyl ester (57 mg) was suspended in dry tetrahydrofuran (1 ml) and 2M isopropylmagnesium chloride in THF (170 μL) was added. The suspension was sonicated for half an hour, yielding a homogeneous solution. This was added with stirring to the suspension of 6- (2-methylimidazo [4,5-c] pyrid-1-yl) pyrid-3-oyl chloride in dichloromethane. The mixture was stirred at room temperature for ^x hr . It was then poured into 1N hydrochloric acid, allowed to stir for 15 minutes and then adjusted to pH 8 with saturated sodium carbonate. The aqueous phase was extracted with dichloromethane (2 × 10 ml), the extracts were combined, dried over magnesium sulfate, and the solvent was removed under reduced pressure to give the title compound as a pale red oil (40 mg, 63%) (as 1: 1 mixture of encl and keto tautomers). ¹ HNMRCDCI ₃ : 1.40 (3H, m), 2.78 and 2.80 (3H, 2 χ s), 4.10 (1H, s), 4.30 (2H, m), 5.80 ('/ 2H, s), 7.40 (1H, m), 7.57 (V2H, d, J = 5Hz), 7.62 (VjH, d, J = 5Hz), 8.37 (V2H, d, J = 5Hz), 8.42 (1H, m), 8.57 (V2H, d, J = 5Hz), 9.10 (IV2H, s), 9.25 (V2H, s), 12.87 (V2H, br).

Preparation Example 44 5- (4-Cyanophenyl) -4-methylimidazo [1,2-a] pyridine

(a) 4- (1-Bronv2-oxopropyl) benzonitrile

Bromine (5.28g) in dichloromethane (80ml) was added dropwise at 25 ° C over one hour to 4- (2-oxopropyl) benzonitrile in dichloromethane (85ml). The reaction mixture was stirred for a further 2h after the addition was complete. The mixture was washed with brine (50 ml) and dried over magnesium sulfate, the solvent was removed under reduced pressure to give the title compound as a pale red oil (7.55 g, 96%). ¹ HNMR (CDCl3): 2.41 (a, 3H), 5.24 (s, 1H), 7.61 (d, J = 4Hz, 2H), 7.73 (d, J = 4Hz, 2H) ,

(b) 5- (4-Cyanophenyl) -4-methylimidazo [1,2-a] pyridine

A mixture of 2-aminopyridine (178mg) and 4- (1-bromo-2-oxopropyl) benzonitrile (450mg) was stirred in refluxing ethanol (2ml) for 5 hours, then the ethanol was removed under reduced pressure deducted. Dichloromethane (15 ml) and saturated aqueous sodium bicarbonate (1 OmI) were added and the organic phase was separated and dried (magnesium sulfate) and the solvent was removed under reduced pressure. The product was purified by flash chromatography on silica gel eluting with ethyl acetate to give the title compound (180mg, 41%) as a white solid.

¹ HNMR (CDCl3): 2.47 (s, 3H), 6.84 (t, J = 4Hz, 1H), 7.25 (d, J = 4Hz, 1H), 7.62 (d, J = 5Hz, 2H), 7.86 (d, J = 4Hz, 2H), 8.17 (d, J = 4Hz, 1H).

Production Example 45

4M2-methylimidazo [4,5-c] pyrid-1-yl) benzoylacetic acid 2-chlorobenzyl ester

A mixture of 4 '- (2-methylimidazo [4,5-c] pyrid-1-yl) benzoylacetic acid ethyl ester (320mg, 1mmol) and 2-chlorobenzyl alcohol (710mg, 5mmol) in toluene (5ml) was refluxed for 20 hours heated. The solution was concentrated, and the residue was purified by flash chromatography (elution with 10% methanol in ethyl acetate) and afforded thereby a colorless foam (300mg, 72%), mp. <40 ^c C. The analysis value is with 0.5 mol H ₂ O calculated.

Analysis%:

Found: C 66.14 H 4.38 N 9.55 Calculated: C 64.41 H 4.47 N 9.80.

Production Example 46

3- {4-Cyanepheny!} - 2-mothy imidazu [4,5-c] pyridine!

(a) N- (4-cyanophenyl) -2-amino-3-nltropyridine

A mixture of p-cyanoaniline (2.36g) and 2-chloro-3-nitropyridine (3.17g) in ethanol (60ml) was heated to reflux for 3 days. The resulting solid was separated by filtration and partitioned between dichloromethane (50ml) and saturated sodium bicarbonate (30ml) The organic phase was dried (MgSO ₄ ) and concentrated to afford a yellow solid,

which was recrystallized from ethyl acetate. Yield 2,70g.

¹ HNMR (CDCI ₃ ): 7.03 (1H, dd, J = 4 and 8Hz), 7.69 (2H, d, J = 9Hz), 7.92 (2H, d, J = 9Hz), 8, 59 (1H, d, J = 4Hz), 8.62 (1H, d,

J = 8Hz), 10.39 (1H, br, s).

This product was prepared by a procedure analogous to that described in Preparation 26, parts (b) and (c), in

3- (4-cyanophenyl) -2-methylimidazo [4,5-b] pyridine.

(b) 3-Amino-2- (4-cyanophenyl) aminopyridine

¹ HNMR (CD ₃ OD): 6.92 (1H, dd, J = 4 and 8Hz), 7.19 (1H, d, J = 8Hz), 7.45 (2H, d, J = 9Hz), 7.58 (2H, d, J = 9Hz), 7.69 (1H, d, J = 4Hz).

(c) 3- (4-Cyano-phenyl) -2-methyl-imidazo [4,5-b] pyridine

'HNMR (CDCl ₃ ): 2.66 (3H, s), 7.31 (1H, dd, J = 5 and 8Hz), 7.66 {2H, d, J = 9Hz), 7.94 (2H , d, J = 9Hz), 8.07 (1H, d, J = 8Hz), 8.34 (1H, d, J = 5Hz).

Claims (17)

in which R is phenyl or a phenyl group which is represented by one or more substituents which are unquestionably selected from nitro, halogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkylthio, C ₁ -C ₄ -alkylsulfonyl, hydroxy, trifluoromethyl and Cyano are selected, or to a dioxole ring R ¹ and R ^{2 are} each independently H or C ₁ -C 6 alkyl, or R ¹ and R ² together are pyrrolidinyl, piperidino, morpholino, piperzinyl, ISMCv-C 1-4 alky-O-piperzinyl or N- (C ₂ Complete C ₄ alkanoyl) piperazinyl group, or R ^{2 is} H or C ¹ -C ₄ -alkyl and R ^{1 is} CN, C ¹ -C ₄ -cycloalkyl, aryl, heteroaryl or a C ¹ -C ₄ -alkyl group, said C ¹ -C ₄ -alkyl group, if it stands for R ¹ , being replaced by one or more a plurality of substituents is substituted, which are each independently selected from C ₃ -C ₇ -CyClOaIkVl ₇ C ₁ -C ₄ -AlkOXy arbonyl, aryl or heteroaryl, Z selected from C ₁ -C ₆ -alkoxy and AryK ^ -CjJ-alkoxy selected Y is 1,4-phenylene or pyridine-2,5-diyl, and X is a 5- or 6-membered aromatic heterocyclic group containing one or more nitrogen atoms in the ring, which ring may be condensed with a benzene ring or another 5- or 6-membered aromatic heterocyclic ring containing one or more nitrogen atoms, and wherein at least one of said heterocyclic rings optionally also contains an oxygen or sulfur atom and is optionally substituted with one or more substituents independently selected from C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, CF ₃ and CN are selected and their pharmaceutically acceptable salts, in which "aryl" denotes phenyl or a phenyl group which is substituted by one or more substituents which are halogen, trifluoromethyl, C ₁ -C ₄ -alkyl, hydroxy, C ₁ -C ₄ -alkoxy, (C ₁ -C ₄ -alkoxy) -carbonyl, sulfamoyl and CN are selected, "heteroaryl" in the definition of R ¹ and 5- or 6-membered aromatic heterocyclic group having one or more independently selected from among N, O and S heteroatoms and which optionally a benzene ring may be condensed and which may optionally be substituted in at least one of the rings, in the heterocyclic and in the fused benzene ring, by one or more substituents selected from C ₁ -C ₄ -alkoxy and halogen, and "halogen" is fluoro, chloro, bromo or iodine means characterized in that A) a compound of the formula RCHO, a compound of the formula (II) and a ketoester, of the formula (III) are reacted together to form the compound of the formula (I) ₍ ^RJ N - Y-X (II) (HI) in which R ^{3 is} C ₁ -C ₆ -alkyl-orthoaryl (C ₁ -C ₄ -alkyl) or B) a compound of the formula (IV) Il, Y-X (IV), wherein R, X and Y are as defined in claim 1 and R ^{3 is} C ₁ -C ₆ -alkyl or aryl (C ₁ -C ₁ -alkylR RyI), reacted with a compound of formula (II) as defined in claim 1 will, or
C) Reacting a compound with the formula (V) HO - (V) with a compound of the formula HNR ¹ R ² wherein R, R ¹ , R ² , X and Y are as defined in claim 1 and R ^{3 is} C ₁ -C ₆ -alkyl or aryl (C ₁ -C ₄ -alkyl) , 2. The method according to claim 1A, characterized in that the compound of the formula RCHO, the compound of the formula (II) and the ketoester (III) and an organic solvent together are heated to 60 to 130 ⁰ C. 3. The method according to claim 1 B, characterized in that the compound of formula (IV) is prepared by reacting a compound of the formula RCHO with a defined as in claim 1 ketoester of the formula (III) and the compound having the formula (IV) is isolated, 4. The method according to claim 3, characterized in that the compound of the formula RCHO and the ketoester of the formula (III) are stirred at room temperature with IsopropylalRohol and piperidine, the ReaRtionsmischung is evaporated and the oil formed solidified with water, filtered off and from Ethyl acetate is recrystallized to form the compound of formula (IV) and that the compound of formula (IV) is heated with the compound of formula (II) in a solvent, the compound of formula (I) formed by filtration, washing and drying in a vacuum. 5. Process according to Claim 1C, characterized in that the compound of the formula (V) is prepared by reacting a compound of the formula (VI) η ^Η NC-CH ₂ -CH ₂ -OC ^, ^ -ζ " _{(ν |)} Y-X Η is hydrolyzed. 6. The method according to claim 5, characterized in that the compound of formula (Vl) is prepared by reacting a compound having the formula R-CHO as defined in claim 1, a ketoester with dor formula (III), such as it is defined in claim 1, and 3-aminobut-2-enoic acid 2-cyanoethyl ester are reacted with each other. 7. The method according to claim 1, 2, 3, 4 or 6, characterized in that the ketoester of the formula (III) is prepared by reacting a compound of the formula NC-Y-X is reacted with zinc and a compound having the formula BrCH ₂ COZ, wherein X, Y and Z are as defined in claim 1. 8. The method of claim 1,2,3,4 or 7, characterized in that the ketoester of the formula (III) is prepared by reacting a compound of the formula XH in the presence of potassium carbonate in an anhydrous solvent with a p-haloacetope ! ienon is reacted, wherein a compound having the formula XY-COCH ₃ which is then reacted in the presence of sodium hydride with a compound of the formula (Z ₂ ) CO, wherein Y is 1,4-phenylene and X, Z and halogen are as defined in claim 1. A process according to any one of claims 1 to 3 or 5 to 8, characterized in that Z is ethoxy, methoxy or optionally halogen substituted benzyloxy. 10. The method according to any one of the preceding claims, characterized in that R is 2-chlorophenyl, 2-trifluoromethoxyphenyl, 2,4-difluorophenyl, 4-cyanophenyl or 1,3-Bθnzodioxol-4-yl. 11. The method according to any one of the preceding claims, characterized in that R ^{1 is} pyrid-2-yl, 4- or 6-methyl-pyrid-2-yl, thiazol-2-yl, 4- or 5-methyl-thiazole 2-yl, 5-methylthiadiazol-2-yl, 5-methyloxadiazol-3-yl, 5-methylisoxazol-3-yl, benzothiazol-2-yl or 5-ethoxybenzothiazol-2-yl or 1-methylimidazol-2-yl , 12. The method according to any one of claims 1 to 10, characterized in that R ^{2 is} H and R ¹ , C ₁ -C ₄ -Alkyl, pyridyl, thiazolyl or 1- (phenyl) ethyl. A process according to any one of the preceding claims characterized in that X is an oxazolyl or thiazolyl group optionally substituted with up to two C ₁ -C ₁ alkyl groups or an imidazolyl group optionally substituted with a C ₁ -C ₄ alkyl group - or CF ₃ group is substituted and condensed with an oxazolyl or thiazolyl ring. 14. A method according to any one of claims 1 to 12, characterized in that X is an optionally substituted by one or two alkyl groups ^ -CJ-1,2,4-triazolyl group or an imidazolyl group which are optionally substituted by up to three Ci-C ₄ Alkyl is substituted or optionally with a C ₁ -C ₄ -AlICyI or CF ₃ substituie.t group and is fused to a benzene, pyridine or pyrimidine ring, which by at least one C ₁ -C ₄ -AlkYl- or C ₁ -C ₄ Alkoxygruppe may be substituted, or is a pyridyl group, which is optionally substituted by a C ₁ -C ₄ -AlkYl- or CF ₃ group. 15. The method according to any one of claims 1 to 12, characterized in that X is 2-methylimidazo / 4,5-c / pyrid-1-yl, imidazol-1-yl, benzimidazol-1-yl, 2-methylbenzimidazole-1 -yl, 3,5-dimethyl-1,2,4-triazol-4-yl, 2-trifluoromethylimidazo / 4,5-c / pyrid-1-yl, 2-butylimidazo / 4,5-c / pyrid-1 -yl, 2-methylimidazo / 4,5-b / pyrid-3-yl, 2-methylimidazo / 1,2-a / pyrid-3-yl, 2-ethylimidazo / 4,5-c / pyrid-i-yl , 7-Methoxy-2-methylimidazo / 4,5-d / pyrimid-3-yl, 2-methylimidazo / 4,5-c / pyrid-3-yl, 2,4,6-trimethylimidazo / 4,5-c / pyrid-1-yl, 2,4-dimethylimidazol-1-yl, 2-methylimidazol-1-yl, 2,4,5-trimethylimidazol-1-yl _/ 4-methylimidazol-1-yl, 2-methylpyri-3-yl, 2,6-dimethylpyrid-3-yl, 3,5-dimethyl- ^1- i ₍ 2, 4-triazol-1-yl, 4-vinylthioxazol-5-yl, 2,4-dimethylthiazol-5-yl, 6-methylimidazo / 1,2-b / thiazol-5-yl or 4-methylthiazol-5-yl , 16. The method according to any one of claims 1 to 4.5 or 6, characterized in that the compound of formula (I) 4- (2-chlorophenyl) -1,4-dihydro-3-ethoxy-carbonyl-6- Methyl 2-4- (2-ethylimidazo / 4,5-c / pyrid-1-yl) -phenyl / -5- / N- (2-pyridyl) -carbamoyl / pyridine, 4- (2-chlorophenyl ) -1,4-dihydro-3-ethoxycarbonyl-6-methyl-2- / 4- (2-methylimidazo / 1,2-a / pyrid-3-yl) phenyl / -5- / N- (2- pyridylj-carbamoyl / pyridine, 4- (2-chlorophenyl) -1,4-dihydro-3-ethoxycarbonyl-6-methyl-2-4- (2,4,6-trimethylimidazo / 4,5-c / pyridine) 1-yl) phenyl / -5- / N- (2-pyridyl) carbamoyl / pyridine or 4- (2-chlorophenyl-1-i-dihydro-S -ethoxycarbonyl-6-methyl) - ^ -methylimidazoM ^ -c / pyrid-iyl) pyrid-5-yl / -5- / N- (2-pyridyl) carbamoyl / pyridinist. 17. The method according to claim 5, characterized in that the compound of formula (Vl) in solution with an optical isomer of 4- (2,4-dichlorophenyl) -5,5-dimethyl-2-hydroxy-1,3, 2-dioxaphosphorinan-2-oxide is added to form a solution of diastereomeric cyanoethyl ester salts, one of the diastereomeric salts is separated from the solution by fractional recrystallization and a separate optical isomer of the compound of formula (VI) therefrom is isolated in salts.