CZ291419B6 - Pyridine derivatives - Google Patents

Abstract

In the present invention there are disclosed pyridine derivatives of the general formulae A, B, C and D, in which Ri1 represents hydrogen; CHi2Riy wherein Riy denotes alkyl containing 1 to 10 carbon atoms or cycloalkyl having 3 to 10 carbon atoms, alkenyl containing 2 to 10 carbon atoms, or hydroxyalkyl containing 1 to 6 carbon atoms, alkoxyalkyl having 1 to 4 carbon atoms v in the alkoxyl moiety and 1 to 6 carbon atoms in the alkyl moiety or phenylethyl; or -CH=CrizRiz wherein Riz represents alkyl containing 1 to 6 C carbon atoms or cycloalkyl having 3 to 6 carbon atoms; Ri2 represents hydrogen, alkyl containing 1 to 8 carbon atoms, hydroxyalkyl having 1 to 6 carbon atoms, alkoxyalkyl containing 1 to 4 carbon atoms in the alkoxyl moiety and 1 to 6 carbon atoms in the alkyl moiety, benzyl, (phenyl)ethyl or phenyl, whereby the benzyl, (phenyl)ethyl or phenyl substituent can be optionally substituted in the benzene ring with a radical being selected from the group comprising methyl, methoxy and halogen; or morpholinoalkyl containing 1 to 4 carbon atoms in the alkyl moiety; Ri6 and Ri7 represents independently on each other hydrogen or alkyl containing 1 to 5 carbon atoms wherein: Ri6 and Ri7 together do not contain more than 6 carbon atoms; and when Ri7 denotes hydrogen, Ri6 is not hydrogen; R' represents alkyl containing 1 to 4 carbon atoms, perfluoroalkyl containing 1 to 4 carbon atoms, alkylphenyl having 1 to 4 carbon atoms in the alkyl moiety or halophenyl; X denotes nitro or amino; and Bn represents a hydrolysable substituent of an amino group being selected from the group comprising phenylmethyl, (4-methylphenyl)methyl and furylmethyl.

Description

The invention relates to certain pyridine derivatives which are particularly useful as intermediates for the preparation of imidazo [4,5-c] pyridin-4-amines. The latter compounds have an immunomodulatory and antiviral effect.

BACKGROUND OF THE INVENTION

Some 1H-imidazo [4,5-c] quinolin-4-amines and methods for their preparation are known and are described, for example, in U.S. Pat. Nos. 4,689,338, 5,037,985 and 5,175,296, EP-A 90,301766.3, PCT. US91 / 06682, PCT / US92 / 01305 and PCT / US92 / 07226 (Gerster) and US Patent 4,988,815 (Andre et al.). These compounds have been reported to exhibit antiviral activity and some induce cytokine biosynthesis, such as interferon. Certain 6'-C-alkyl-3-diazaneplanocin derivatives, some of which are imidazo [4,5-c] pyridin-4-amines, are known and are described in EP-A 0510260 A2 (Obara et al.). These compounds reportedly exhibit antiviral activity.

Other compounds with antiviral or immunomodulatory activity may be a source of progress in the field of antiviral and immunomodulatory therapy.

SUMMARY OF THE INVENTION

The present invention provides pyridine derivatives selected from compounds of the formula

where

R ₆ and R ₇ are each independently hydrogen or C 1 -C 5 alkyl, wherein: R ₆ and R ₇ taken together contain no more than 6 carbon atoms; wherein further when R ₇ represents a hydrogen atom, then R 6 does not represent a hydrogen atom; and

R 'is C 1 -C 4 alkyl, C 1 -C 4 perfluoroalkyl, C 1 -C 4 alkylphenyl or halophenyl;

compounds of formula

- 1 GB 291419 B6

OSO ₂ R '

JL.no ₂

* 7 where

R 1 represents a hydrogen atom; CH ₂ R _y , where R _y is straight or branched chain alkyl of 1 to 10 carbon atoms or cycloalkyl of 3 to 10 carbon atoms, straight chained or branched alkenyl of 2 to 10 carbon atoms, or hydroxyalkyl of straight chain or branched (C 1 -C 6), (C 1 -C 4) alkoxyalkyl and (C 1 -C 6) alkyl or phenylethyl; or CH = CR _Z R _Z , wherein R _z at each occurrence independently represents a straight or branched chain alkyl group having 1 to 6 carbon atoms or a cycloalkyl group having 3 to 6 carbon atoms;

and R ', R ₆ and R ₇ are as defined above

NCBn) j

NHR 1 wherein X is nitro or amino, R 1, R 1, R 6 and R ₇ are as defined above and Bn is a hydrogenolyzable amino substituent selected from the group consisting of phenylmethyl, (4-methylphenyl) methyl; and furylmethyl;

and compounds of formula

^η ^ where

N.

R ₂ represents hydrogen, alkyl with straight or branched chain containing 1 to 8 carbon atoms, hydroxyalkyl having straight or branched chain containing one to six carbon atoms, alkoxyalkyl having 1 to 4 carbon atoms in alkoxy and 1 to 6 carbon atoms in the alkyl radical benzyl, (phenyl) ethyl or phenyl, wherein the benzyl, (phenyl) ethyl or phenyl substituent is optionally substituted in the benzene ring by a radical selected from the group consisting of methyl, methoxy and halogen; or morpholinoalkyl of 1 to 4 carbon atoms in the alkyl radical;

and R 1, R ₆ , R ₇ and Bn are as defined above.

A common feature of the above compounds is that they are useful as intermediates for the preparation of imidazo [4,5-c] pyridin-4-amines of Formula I

NH where

Ri and R ₂ are as defined above;

R ₇ and R ₇ are each independently hydrogen or C 1 -C 5 alkyl, wherein:

R ₆ and R ₇ taken together contain no more than 6 carbon atoms; wherein further when R ₇ represents a hydrogen atom, then R ₆ does not represent a hydrogen atom and R ₂ does not represent a hydrogen atom or a morpholinoalkyl group; and wherein further when R ₆ represents a hydrogen atom, then none of R ₂ and R ₇ represents a hydrogen atom.

In the above compounds of formula I, R 1 is preferably 2-methylpropyl, n-butyl, 2-methyl-1-propenyl, ethoxyethyl, 2-hydroxy-

2-methylpropyl and 2-phenylethyl.

When R ₂ is alkyl it is preferably methyl, ethyl, propyl or butyl. When R ₂ is hydroxyalkyl, it is preferably a hydroxymethyl group. When R ₂ is alkoxyalkyl, it is preferably ethoxymethyl.

The substituents R ₆ and R _{7 are} preferably alkyl of 1 to about 4 carbon atoms, preferably methyl. Preferably both R ₆ and R ₇ are methyl.

Compounds of formula I may be prepared according to the reaction scheme wherein R 1, R ₂ , R ₆ and R ₇ are as defined above. The reaction scheme is particularly suitable for the preparation of compounds wherein R _b R ₂ , R ₆ and R ₇ are selected from the group of preferred substituents mentioned above and R 'is alkyl (e.g. lower alkyl, i.e. alkyl of 1 to about 4 carbon atoms) , perfluoroalkyl (e.g. perfluoro (lower alkyl) such as trifluoromethyl), aryl (e.g. phenyl), alkylaryl (e.g. (lower)

(C1-4 alkyl) phenyl (such as 4-methylphenyl) or haloaryl (for example, halophenyl such as 4-bromophenyl).

The starting material used in the reaction scheme is 4-hydroxy-2 (1H) -pyridone of formula II. Some of these compounds are known and others can be readily prepared by methods known to those skilled in the art, for example, by the general procedures described in J. Org. Chem. 1941, 6, 54, Tracy et al., J. Chem. Soč. 1962, 3638, Davis et al., Rel. Trav. Chim. 1944, 63, 231, Wibout et al., And Rec., 1961, 80, 545, Salemink. The above and the following citations represent a substitute for bringing their entire contents into the description of the invention.

In step (1) of the reaction scheme, the compound of formula II is nitrated under conventional nitration conditions such as heating (e.g. at 100 ° C) in the presence of nitric acid, preferably in a solvent such as acetic acid or as described, for example, in J Heterocyclic Chem. 1970, 7, 389, Wang. Some of the compounds of formula III can be prepared directly (thus, no nitration of the compound of formula II is necessary) by catalytic condensation of a β-amino ester such as ethyl 3-aminocrotonate with a nitromalonic acid ester such as diethylnitromalonate in the presence of a base as a catalyst See, e.g., J. Org. Chem. 1981, 46, 3040, Seeman et al.).

In step (2), the 3-nitropyridine-2,4-disulfonate of formula IV is obtained by reacting a compound of formula III with a sulfonyl halide or preferably sulfonic anhydride. Suitable sulfonyl halides are alkylsulfonyl halides such as methanesulfonyl chloride and trifluoromethanesulfonyl chloride, and arylsulfonyl halides such as benzenesulfonyl chloride, p-bromobenzenesulfonyl chloride and p-toluenesulfonyl chloride. Suitable sulfonic anhydrides are those corresponding to the above sulfonyl halides. A particularly preferred sulfonic anhydride is trifluoromethanesulfonic anhydride. The sulfonic anhydrides are preferred because the sulfonate anion formed as a by-product of the reaction is relatively weakly nucleophilic and as such does not induce the formation of undesirable by-products in which the nitro group is displaced.

The reaction is preferably carried out by first mixing the compound of formula III with a base, preferably with an excess of a tertiary amine base (e.g. a trialkylamine base such as triethylamine), preferably in a suitable solvent such as dichloromethane, followed by sulfonyl halide or sulfonic anhydride. acid. The addition is preferably carried out in a controlled manner (e.g. dropwise) and at a reduced temperature (e.g. at about 0 ° C). The product can be isolated by conventional methods or used without further isolation as described below in connection with step (3).

In step (3) of the reaction scheme, 3-nitro-4- (substituted amino) pyridine-2-sulfonates are obtained as products. Due to the presence of two sulfonate groups, which can in principle be replaced, the reaction yields a mixture of products that can be readily separated, for example by conventional chromatographic techniques. The compound of formula IV is reacted with an amine, preferably in the presence of an excess of a tertiary amine base, in a solvent such as dichloromethane. Suitable amines include primary amines which provide 4-substituted amino compounds of formula V wherein the amine substituent is R1. Preferred amines include the amines containing the groups described above in relation to the preferred substituents R1.

The reaction can be carried out by adding the tertiary amine base to the reaction mixture obtained in step (2), cooling the resulting mixture (e.g. to 0 ° C) and then adding the amine in a controlled manner (e.g. dropwise). The reaction can also be carried out by adding the amine to a solution of a compound of formula IV and a tertiary amine base in a solvent such as dichloromethane. Since the sulfonate group is a relatively readily cleavable group, the reaction can be carried out at relatively low temperatures, such as about 0 ° C and in relatively non-polar solvents (such as toluene), to reduce the amount of unwanted 2-aminated and 2,4-diaminated by-product. Sometimes it is necessary or appropriate to heat the reaction mixture after the addition to complete the reaction. The product can be isolated from the reaction mixture by conventional means.

-5GB 291419 B6

In step 4, the compound of formula V is reacted with a hydrogenolyzable amine to form a compound of formula VI. The term "hydrogenolyzable amine" as used herein refers to any amine that is sufficiently nucleophilic to displace the sulfonate group in step 4, wherein the resulting substituent (s) can be removed by hydrogenolysis. Those skilled in the art will recognize that such amines include arylmethylamines and di (arylmethyl) amines, i.e., amines wherein the aromatic ring in the substituent or substituents (which are the same or different) is one carbon atom away from the amine nitrogen. The term "hydrogenolyzable amine substituent" as used herein refers to a substituent obtained using a hydrogenolyzable amine in step (4) and which corresponds to a hydrogenolyzable amine depleted of one hydrogen atom. The primary hydrogenolyzable amines are less preferred since their use provides an alternative cyclization site in step (6), (6a) or (6b) below. Secondary hydrogenolyzable amines are preferred. Suitable secondary hydrogenolyzable amines include dibenzylamine (i.e., di (phenylmethyl) amine) and substituted derivatives thereof, such as di [4-methyl (phenylmethyl)] amine, di (2-fluoromethyl) amine, and the like. illustrated the procedure using dibenzylamine. However, the reaction may be carried out using any suitable hydrogenolyzable amine.

Reaction step (4) may be carried out by introducing the starting material and the hydrogenolyzable amine into an inert solvent such as benzene, toluene or xylene and heating the resulting mixture to a temperature and for a time sufficient to replace the sulfonate group with a hydrogenolyzable amine. . The choice of temperature and reaction time is easy for those skilled in the art. Isolation of the product from the reaction mixture may be accomplished by conventional procedures.

In step (5), the nitro group in the compound of formula VI is reduced to an amino group. Methods for this reduction are well known to those skilled in the art. In a preferred method, Ni ₂ B nickel boride is formed in situ from sodium borohydride and nickel chloride in the presence of methanol, and a compound of formula VI is added to the resulting reducing agent solution to reduce the nitro group. The product can be isolated by conventional methods.

In step (6), a compound of formula (VII) is reacted with a carboxylic acid or equivalent to give a cyclized compound of formula (VIII). Suitable carboxylic acid equivalents include acid halides and orthoesters such as orthoformate, orthoesters, acid halides, and carboxylic acids other than formic acid to give the 2-substituted products wherein the 2-substituent is represented by R _2nd The reactions can be carried out in the absence of a solvent, or preferably in an inert solvent such as xylene or toluene, in the presence of a carboxylic acid or equivalent (if necessary, in the presence of an acid catalyst such as p-toluenesulfonic acid) with sufficient heating (e.g. to about 80 ° C to about 150 ° C, depending on the solvent (if present) to drive off any alcohol or water formed as by-products in the reaction.

The compound of formula VIII can also be prepared in two steps from the compound of formula VII. In the first step (step 6a) of the reaction scheme, a compound of formula VII is reacted with an acyl halide of formula R ₂ C (O) X wherein X is chlorine or bromine and R ₂ is as defined above. The reaction product of formula (IX) can be isolated and then cyclized in step (6b) by treatment with methanolic ammonia.

In step (7), the cyclic compound of formula (VIII) is hydrogenolysed to give the 4-amino compound. Conveniently, conventional well-known catalytic hydrogenation processes are employed. Preferably, the hydrogenolysis is carried out with heating in formic acid and in the presence of palladium hydroxide on carbon.

-6GB 291419 B6

The invention is illustrated by the following examples. All reactions were performed under stirring under a dry nitrogen atmosphere unless otherwise noted. The structure of the compounds was confirmed by nuclear magnetic resonance spectroscopy. The examples given, in particular the substances used and the amounts thereof, as well as other conditions and details, are intended to be illustrative only and are not intended to limit the scope of the invention in any way.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

6-Methyl-3-nitropyridine-2,4-bis (trifluoromethanesulfonate)

Triethylamine (24.5 mL, 0.176 mol) was added to a mixture of 4-hydroxy-6-methyl-3-nitro-2 (1H) pyridinone (15 g, 0.088 mol) in methylene chloride (700 mL). The reaction mixture was cooled to 5 ° C and trifluoromethanesulfonic anhydride (50 g, 0.176 mol) was added slowly while maintaining the temperature below 15 ° C. After the addition was complete, the reaction mixture was stirred at 5 ° C for 15 minutes. The ice bath was removed and the reaction stirred for an additional 2 hours and diluted with water. The organic phase was separated, dried over magnesium sulfate and filtered through a pad of silica gel. The filtrate was concentrated under a stream of nitrogen. 32.4 g of solid are obtained. A portion (1.4 g) was recrystallized from petroleum ether. The desired product is obtained in the form of a solid, m.p. 50-52 ° C.

H, 0.93; N, 6.45 Found: C, 22.08; H, 0.84; N, 6.49%.

Example 2

6-Methyl-3-nitro-4 - [(phenylethyl) amino] -2-pyridyltrifluoromethanesulfonate

Triethylamine (10 mL) was added to a mixture of 6-methyl-3-nitropyridine-2,4-bis (trifluoromethanesulfonate) (31 g, 0.071 mol) in methylene chloride (300 mL). The reaction mixture was cooled in an ice bath. Phenylethylamine (9 mL) was diluted with methylene chloride (50 mL) and added slowly to the reaction mixture. After the addition was complete, the reaction mixture was stirred for about 1 hour with cooling and then overnight at room temperature. The reaction mixture was diluted with additional methylene chloride, washed twice with water, twice with aqueous sodium bicarbonate solution, dried over magnesium sulfate and then concentrated under reduced pressure. The orange liquid obtained was eluted from the silica gel layer using methylene chloride and then suspended in petroleum ether. 16 g of a yellow solid are obtained. A small portion (1 g) of this material was recrystallized twice from cyclohexane to give the desired product as a solid, mp 78-79 ° C.

H, 3.48; N, 10.37. Found: C, 44.81; H, 3.42; N, 10.28.

Example 3

6-Methyl-4 - [(2-methylpropyl) amino] -3-nitro-2-pyridyltrifluoromethanesulfonate

Triethylamine (8.34 mL, 0.06 mol) was added to a cooled (0 ° C) solution of 4-hydroxy-6-methyl-3-nitro-2 (1H) -pyridinone (5.0 g, 0.03 mol) in methylene chloride (300 mL). Trifluoromethanesulfonic anhydride (10.1 mL, 0.06 mol) was added to the mixture, which was stirred for about

Isobutylamine (8.94 mL, 0.09 mol) was added and the reaction mixture was stirred overnight at 0 ° C. The reaction mixture was stirred for about 30 minutes and quenched with water (500 mL). The resulting mixture was extracted with methylene chloride (3 x 50 mL). The extracts were combined, dried (MgSO 4) and concentrated in vacuo. The orange oil obtained was purified by column chromatography on silica gel (hexane / ethyl acetate 70/30). 3.4 g of the expected product are obtained in the form of a yellow solid.

Example 4

4 - [(2-Hydroxy-2-methylpropyl) amino] -5,6-dimethyl-3-nitro-2-pyridyltrifluoromethanesulfonate

Triethylamine (1.2 mL, 8.69 mmol) was added to a suspension of 4-hydroxy-5,6-dimethyl-3-nitro-2 (1H) pyridinone (0.8 g, 4.3 mmol) in methylene chloride (25 mL). ml). The solution was cooled in an ice bath and trifluoromethanesulfonic anhydride (1.46 mL, 8.69 mmol) was added dropwise. After the addition was complete, the ice bath was removed and the reaction was allowed to warm to ambient temperature over 30 minutes, filtered through a pad of silica gel and washed with additional methylene chloride. The filtrate was concentrated under reduced pressure to give 1.6 g (3.57 mmol) of 5,6-dimethyl-3-nitropyridine-2,4-bis (trifluoromethanesulfonate). This material was taken up in methylene chloride (30 mL). The mixture was cooled in an ice bath and 2-hydroxyisobutylamine (0.32 g, 3.57 mmol) and triethylamine (0.5 mL, 3.57 mmol) were added. The reaction mixture was then allowed to warm to ambient temperature and diluted with methylene chloride. The diluted mixture was washed with water, dried (MgSO4) and concentrated in vacuo. The yellow oil obtained was purified by silica gel column chromatography (25:75 ethyl acetate / hexane). 0.7 g of the expected product is obtained in the form of a solid, m.p. 79-80 ° C.

N, 10.85. Found: C, 37.21; H, 4.16; C 37.47, H 4.13, N 10.89.

Examples 5 to 9

Following the general procedure described in Example 3, the reaction of 4-hydroxy-3-nitro-2 (1H-pyridinone of formula II with trifluoromethanesulfonic acid anhydride) followed by reaction with an amine of formula R1 NH2 is carried out to produce the intermediates of formula IV 1.

Table 1

Example Intermediate of formula (II) Intermediate of formula (IV) ## STR11 ## R @ 7 R @ 6 R @ 7 R @ 7

5 methyl H methyl H n-butyl 6 methyl methyl methyl methyl 2-phenylethyl 7 methyl methyl methyl methyl 2-methylpropyl 8 chlorine methyl chlorine methyl 2-methylpropyl 9 chlorine methyl chlorine methyl 1,1-dimethylethyl

Example 10

N ⁴ -Butyl-6-methyl-3-nitro-N ² , N ² -bis (phenylmethyl) pyridine-2,4-diamine

Dibenzylamine (1.04 g, 5.28 mmol), triethylamine (0.53 g, 5.28 mmol), 4-butylamino-6-methyl-

3-Nitro-2-pyridyltrifluoromethanesulfonate (1.72 g, 5.28 mmol) and toluene (45 mL) were combined and the mixture was

291419 B6 is heated to reflux for 18 hours. The reaction mixture was cooled to ambient temperature and then filtered through a pad of silica gel. The silica gel was washed with methylene chloride. The combined organic filtrates were evaporated to give 2.08 g of an oily semi-solid.

Examples 11 to 17

Using the general procedure described in Example 10, the intermediates of formula IV are reacted with dibenzylamine to produce intermediates of formula V as shown in Table 2.

Table 2

Example number Intermediate of formula IV from example Rč Intermediate of formula r ₇ Ri 11 2 methyl H 2-phenylethyl 12 3 methyl H 2-methylpropyl 13 4 methyl methyl 2-hydroxy-2-methylpropyl 14 6 methyl methyl 2-phenylethyl 15 Dec 7 methyl methyl 2-methylpropyl 16 8 chlorine methyl 2-methylpropyl 17 9 chlorine methyl 1,1-dimethylethyl

Example 18

6-Methyl-N ⁴ - (2-methylpropyl) -N ² , N ² -bis (phenylmethyl) pyridine-2,3,4-triamine

Sodium borohydride (585 mg, 16 mmol) was added to a solution of nickel chloride hydrate (1.02 g, 4.3 mmol) in methanol (100 mL). The addition induces the formation of a black solid with simultaneous gas evolution. The resulting heterogeneous mixture was stirred at ambient temperature for 30 minutes, then a solution containing 6-methyl-N ⁴ - (2-methylpropyl) -3-nitro-N ² , N ² -bis (phenylmethyl) pyridine-2,4 was added. -diamine (3.47 g, 8.6 mmol) in methylene chloride (20 mL) followed by sodium borohydride (1.37 g, 36 mmol). The reaction mixture was stirred at ambient temperature for about 30 minutes and eluted from the silica gel layer using methanol / methylene chloride. The filtrate was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The ethyl acetate layer was separated, dried over magnesium sulfate and concentrated in vacuo. 2.74 g of the expected product are obtained in the form of a green foam.

Examples 19 to 25

Using the general procedure described in Example 18, the intermediates of formula VI listed in Table 3 are prepared by reducing said intermediates of formula (V).

Table 3

Example number Intermediate of formula V from example Intermediate of formula VI Rí r ₇ R> 19 Dec 10 methyl H n-butyl 20 May 11 methyl H 2-phenylethyl 21 13 methyl methyl 2-hydroxy-2-methylpropyl 22nd 14 methyl methyl 2-phenylethyl 23 15 Dec methyl methyl 2-methylpropyl 24 16 chlorine methyl 2-methylpropyl 25 17 chlorine methyl 1,1-dimethylethyl

-9EN 291419 B6

Example 26

N ³ -Acetyl-6-methyl-N ⁴ - (2-phenylethyl) -N ² , N ² -bis (phenylmethyl) -pyridine-2,3,4-triamine

Triethylamine (2 mL) was added to a solution of 6-methyl-N ⁴ - (2-phenylethyl) -N ² , N ² -bis (phenylmethyl) pyridine-2,3,4-triamine (6 g, 14.2 mmol) in methylene chloride (50 mL). Acetyl chloride (1.1 mL, 15.5 mmol) was slowly added to the reaction mixture and the resulting mixture was heated on a steam bath for about 1 hour. The reaction mixture was stirred overnight at room temperature and then diluted with water and methylene chloride. The organic phase was separated, washed with water, dried over magnesium sulphate and then concentrated under reduced pressure. The light green solid obtained was suspended in ethyl acetate / hexane and then recrystallized from ethyl acetate / hexane to give 4.1 g of a white solid. A small portion (0.8 g) of this material was purified by silica gel column chromatography. 152-153 ° C.

H, 6.94; N, 12.06. Found: C, 77.61; H, 6.89; N, 12.05%.

Examples 27 to 28

Using the general procedure described in Example 26, but not using triethylamine, the intermediates of formula VII shown in Table 4 are prepared by reacting the above intermediates of formula VI with an acid chloride of formula R ₂ C (O) Cl.

Table 4

Intermediate Example of intermediate formula VII compound No. VI Example ₇ _______R _______Rj___________________________R ₂ __________

18 methyl H 2-methylpropyl methyl

21 methyl methyl 2-hydroxy-2-methylpropyl ethoxymethyl

Example 29

2,6-Dimethyl-1- (2-phenylethyl) -N ⁴ , N ⁴ -bis (phenylmethyl) -1H-imidazo [4,5-c] pyridin-4-amine

N ³ -Acetyl-6-methyl-N ⁴ - (2-phenylethyl) -N ² , N ² -bis- (phenylmethyl) pyridine-2,3,4-triamine (3.9 g, 8.39 mmol) treated with 12% (w / w) ammonia in methanol (40 ml). The mixture was placed in a Parr pressure vessel where it was heated to 150 ° C for 5 hours. The resulting solid was collected and purified by silica gel column chromatography (20:80 ethyl acetate / hexane). 2.56 g of the desired product are obtained in the form of a solid, m.p. 124 DEG-126 DEG.

Analysis for C30H30N4:

H, 6.77; N, 12.55. Found: C, 80.24; H, 6.68; N, 12.42.

Examples 30 to 31

Using the general procedure described in Example 29, cyclization of said intermediates of formula (VII) affords intermediates of formula (VIII) in Table 5.

-10GB 291419 B6

Table 5

Example Intermediate of general formula Intermediate of general formula VIII number of formula VII from example ________R ₇ ________Rj____________________________R ₂ ______________

27 methyl H 2-methylpropyl methyl

28 methyl methyl 2-hydroxy-2-methylpropyl ethoxylethyl

Example 32

6-Chloro-2,7-dimethyl-1- (1,1-dimethylethyl) -N ⁴ , N ⁴ -bis- (phenylmethyl) -1H-imidazo [4,5-c] pyridin-4-amine

6-Chloro-5-methyl-N ⁴ - (1,1-dimethylethyl) -N ² , N ² -bis (phenylmethyl) pyridine-2,3,4-triamine is mixed with an excess of triethyl orthoacetate. The resulting mixture was first heated in a steam bath for 16 hours and then at 130 ° C in an oil bath for 2 hours. The excess triethyl orthoacetate was distilled off under reduced pressure. The residue was diluted with methylene chloride, washed with water and sodium bicarbonate solution, dried over magnesium sulfate and then filtered through a pad of silica gel using additional methylene chloride as eluent. The filtrate was concentrated under reduced pressure to give a mixture that was used in the next step.

Example 33

6-Chloro-2,7-dimethyl- N ^4, N ⁴ -bis (phenylmethyl) -lH-imidazo [4,5-c] pyridin-4-amine

The compound of Example 32 was diluted with toluene and treated with phosphorus oxychloride. The reaction mixture was heated at reflux overnight and then concentrated under reduced pressure. The residue was diluted with water and basified with ammonium hydroxide. The mixture was extracted several times with methylene chloride. The methylene chloride extracts were combined, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 10 to 40% ethyl acetate in hexane as eluent. The desired product is obtained.

Example 34

6-Chloro-1- (2-ethoxyethyl) -2,7-dimethyl-N, N-bis (phenylmethyl) -1H-imidazo [4,5-c] pyridin-4-amine

Sodium iodide (1.5 g) and potassium carbonate (1 g) were added to a solution of 6-chloro-2,7-dimethyl-N ⁴ , Nbis (phenyl methyl) -1H-imidazo [4,5-c] pyridine- Of 4-amine (1.0 g, 2.7 mmol) in acetone (250 mL). To the mixture was added 2-bromoethyl ether (0.5 mL, 4.4 mmol). The reaction mixture was heated to reflux overnight, filtered, and the filtrate was concentrated under reduced pressure. The residue was partitioned between methylene chloride and water. The methylene chloride phase was separated, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 10 to 30% ethyl acetate in hexane. 0.7 g of the expected product is obtained.

Example 35 1n-Butyl-2,6-dimethyl-N ⁴ , N ⁴ -bis (phenylmethyl) -1 H -imidazo [4,5- c] pyridin-4-amine

-11 GB 291419 B6

N ⁴ -n-Butyl-6-methyl-N ² , N ² -bis (phenylmethyl) pyridine-2,3,4-triamine (0.65 g, 1.7 mmol) was treated with toluene (10 mL) and acetyl chloride ( 0.12 mL, 1.7 mmol). The mixture was stirred at ambient temperature for 15 minutes, then phosphorus oxychloride (0.31 mL) was added. The reaction mixture was heated to reflux overnight and evaporated. The residue was purified by column chromatography on silica gel (hexane / ethyl acetate 70/30). 0.18 g of the expected product is obtained.

Example 36

6,7-Dimethyl-1- (2-phenylethyl) -2, N ⁴ , N ⁴ -tris (phenylmethyl) -1 H -imidazo [4,5- c] pyridin-4-amine

Phenylacetyl chloride (0.6 mL, 4.5 mmol) was added to a solution of 5,6-dimethyl-N ⁴ - (2-phenylethyl) N ² , N ² -bis (phenylmethyl) pyridine-2,3,4-triamine ( 1.96 g, 4.5 mmol) in methylene chloride (100 mL). The resulting mixture was stirred overnight at room temperature, a catalytic amount of p-toluenesulfonic acid was added and stirring was continued at ambient temperature over the weekend. The reaction mixture was washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and then concentrated under reduced pressure. The oil obtained is purified by silica gel column chromatography using 5 to 10% ethyl acetate in hexane. 1.8 g of the expected product are obtained in the form of a white solid, m.p. 139-141 ° C.

Analysis for C ₃₇ H ₃₆ N 4: C 82.80, H 6.76, N 10.44 Found: C 82.86, H 6.78, N 10.36.

Examples 37 to 43

Using the general procedure described in Example 36, reacting said intermediates of formula (VI) with an acid chloride of formula R ₂ C (O) Cl produces the intermediates of formula (VIII) in Table 6.

Table 6

EXAMPLE Intermediate of formula (VIII) ## STR6 ## from Example R6 R @ ₇ R @ R @ ₂

37 18 methyl H 2-methylpropyl phenylmethoxymethyl 38 21 methyl methyl 2-hydroxy-2-methylpropyl methyl 39 21 methyl methyl 2-hydroxy-2-methylpropyl n-butyl 40 22nd methyl methyl 2-phenylethyl methyl 41 22nd methyl methyl 2-phenylethyl n-butyl 42 23 methyl methyl 2-methylpropyl methyl 43 24 chlorine methyl 2-methylpropyl methyl

Example 44

2-Ethyl-6,7-dimethyl-l- (2-methylpropyl) -N ^4, N ⁴ -bis (phenylmethyl) -lH-imidazo [4,5-c] pyridin-4-amine

Butyllithium (0.5 mL of a 2.5M solution in hexanes) was added to the cooled (-78 ° C) solution

2,6,7-trimethyl-1- (2-methylpropyl) -N ⁴ , N ⁴ -bis (phenylmethyl) -1H-imidazo [4,5-c] pyridin-4

Amine (0.5 g, 1.2 mmol) in tetrahydrofuran (30 mL). The reaction mixture was allowed to warm to -10 ° C, then cooled to -78 ° C and treated with methyl iodide (0.23 mL, 3.6 mmol). The reaction mixture was allowed to warm to ambient temperature and then diluted with water and diethyl ether. The ether layer was separated, washed with ammonium chloride solution, dried over magnesium sulfate and then concentrated. 0.5 g of the expected product is obtained.

Example 45

2,6-Dimethyl-1- (2-phenylethyl) -1H-imidazo [4,5-c] pyridin-4-amine

Palladium hydroxide on carbon (0.5 g, Pearlman's catalyst) was added to a mixture of 2,6-dimethyll- (2-phenylethyl) -N ^4, N ⁴ -bis (phenylmethyl) -lH-imidazo [4,5-c] pyridin-4-amine (2.3 g, 5.15 mmol) in formic acid (10 mL).

The reaction mixture was heated to reflux overnight, an additional 0.5 g of catalyst was added and refluxing was continued overnight. The reaction mixture was neutralized with saturated sodium bicarbonate solution and diluted with methanol. The resulting mixture was filtered through a pad of celite to remove the catalyst. The celite layer was washed with methylene chloride and methanol. The filtrates were combined and concentrated under reduced pressure. A mixture of water and solid was obtained. This mixture was extracted with methylene chloride. The extract was washed with water, dried over magnesium sulfate and concentrated in vacuo. 1.2 g of a tan solid are obtained. This material is recrystallized from ethanol to give 0.24 g of the desired product as a solid, m.p. 185-187 ° C.

Analysis for C ₆ H | ₈ N4: Calculated: C, 72.15; H, 6.81; N, 21.04% Found: C 71.51, H 6.88, N 20.61.

Examples 46 to 56

Using the general procedure described in Example 45, hydrogenolysis of the intermediates of formula (VIII) indicated above gives the compounds of formula (I) shown in Table 7. Melting points and elemental analyzes are given in Table 8.

Table 7

Example number Intermediate of formula VIII from example Re r ₇ Product of formula I Ri r ₂ 46 30 methyl H 2-methylpropyl methyl 47 31 methyl methyl 2-hydroxy-2-methylpropyl ethoxymethyl 48 35 methyl H n-butyl methyl 49 36 methyl methyl 2-phenylethyl phenylmethyl 50 37 methyl H 2-methylpropyl hydroxymethyl 51 38 methyl methyl 2-hydroxy-2-methylpropyl methyl 52 39 methyl methyl 2-hydroxy-2-methylpropyl n-butyl 53 40 methyl methyl 2-phenylethyl methyl 54 41 methyl methyl 2-phenylethyl n-butyl 55 42 methyl methyl 2-methylpropyl methyl 56 44 methyl methyl 2-methylpropyl ethyl

-13GB 291419 B6

Table 8

Example number m.p. (° C) Elementary analysis Formula calculated found %C % H % N %C % H % N 46 153-155 C ₁₂ H ₁₈ N ₄ + 0.15H ₂ O 65.21 8.35 25.35 65.38 8.41 25.37 47 178-181 C ₅ H ₂₄ N ₄ O ₂ 60.68 0.32 18.87 60.55 8.13 19.11 48 130-132 C ₁₂ H ₁₈ K ₄ + 0.2 H ₂ O 64.95 8.36 25.25 65.01 8.10 24.9 49 170-173 C ₂₃ H ₃₄ N ₄ + 0.5 H ₂ O 75.59 6.89 15.33 75.56 6.99 15.36 50 180-181 C ₁₂ H ₁₈ N ₄ O + 0.33 H ₂ O 59.99 7.83 23.32 59.87 7.7 23.39 51 249-250 C ₃ H ₂ O ₄ O ₄ 62.88 8.12 22.56 62.67 8.02 22.19 52 167-170 C ₁₆ H ₂₆ N ₄ O + 0.75 H ₂ O 63.07 9.10 18.39 63.40 8.75 18.33 53 142-145 C ₇ H ₂₀ N ₄ + 0.5 H ₂ O 70.56 7.31 19.36 70.90 7.38 19.43 54 134-135 C ₂₀ H ₂₆ N ₄ + 0.2H ₂ O 73.67 8.16 17.18 73.92 8.21 17.32 55 157-159 C ₁₃ H ₂₀ N ₄ + 0.2 CH ₂ Cl ₂ 63.59 8.25 22.47 63.37 8.18 22.27 56 163-165 C ₁₄ H ₂₂ N ₄ 68.26 9.00 22.74 68.36 9.03 22.73

Example 57 1- (2-Ethoxyethyl) -2,7-dimethyl-1H-imidazo [4,5-c] pyridin-4-amine

6-Chloro-l- (2-ethoxyethyl) -2,7-dimethyl- N ^4, N ⁴ -bis-phenylmethyl) -lH-imidazo [4,5-c] pyridine

The 4-amine (0.7 g, 1.56 mmol) was taken up in a saturated solution of anhydrous hydrogen chloride in methanol (100 mL). Palladium hydroxide on carbon was added and the resulting mixture was hydrogenated in a Parr apparatus for 4 hours. The reaction mixture was filtered to remove the catalyst and then concentrated under reduced pressure. The residue was partitioned between methylene chloride and water and sodium bicarbonate. The methylene chloride layer was separated, dried over magnesium sulfate and concentrated in vacuo. The obtained off-white solid was recrystallized from ethyl acetate-hexane. 0.18 g of the expected product is obtained in the form of a solid, m.p. 129-130 ° C.

Analysis for C ₂ Hi ₈ N ₄ .0.25 H ₂ O: Calculated: C 60.35, H 7.81, N 23.46% Found: C 60.64, H 7.50, N 23.39% .

Example 58

2,7-Dimethyl-1- (2-methylpropyl) -1H-imidazo [4,5-c] pyridin-4-amine

Using the general procedure described in Example 57 from 6-chloro-2,7-dimethyl-l- (2-methylpropyl) -N ^4, N ⁴ -bis-phenylmethyl} -lH-imidazo [4,5-c] pyridine 4-amine (1 g, 2.3 mmol) by hydrogenolysis produces 0.07 g of the desired product as a solid, m.p. 178-180 ° C.

Analysis for C ₁₂ H ₁₈ N ₄ :

calculated: C 66.02, H 8.31, N 25.66%. Found: C 65.58, H 8.34, N 25.30%.

Example 59

6-Methyl-1- (2-methylpropyl) -2-morpholinomethyl-1H-imidazo [4,5-c] pyridin-4-amine

-14GB 291419 B6

Part A

6-Methyl-N ⁴ - (2-methylpropyl) -N ² , N ² -bis (phenylmethyl) pyridine-2,3,4-triamine (2.27 g,

6.1 mmol), ethoxyacetyl chloride (0.74 g, 6.1 mmol) and acetonitrile (100 mL) were mixed and the resulting mixture was stirred at ambient temperature for about 15 minutes. To the heterogeneous reaction mixture was added p-toluenesulfonic acid (0.1 g). The reaction mixture was heated to reflux for 48 hours, cooled to room temperature, and concentrated in vacuo. The residue was partitioned between methylene chloride and 10% ammonium hydroxide. The organic phase was dried over magnesium sulfate and then concentrated to give 2.8 g of an oil. This oil was dissolved in toluene (100 mL) and treated with phosphorus oxychloride (1 mL). The mixture was heated to reflux for 48 hours. The reaction mixture was cooled to ambient temperature, concentrated and the residue partitioned between methylene chloride and 10% ammonium hydroxide. The organic phase was dried over magnesium sulfate and then concentrated to a yellow oil. Analysis by nuclear magnetic resonance spectrum shows that the substance is 2-chloromethyl-6-methyl-l- (2-methylpropyl) -N ^4, N ⁴ -bis (phenylmethyl) -l H-imidazo [4,5-c] pyridine 4-amine and 2-ethoxymethyl6-methyl-l- (2-methylpropyl) -N ^4, N ⁴ -bis (phenyl-methyl) -lH-imidazo [4,5-c] pyridin-4-amine.

PartB

The mixture obtained in Part A was dissolved in methylene chloride (5 mL) and treated with morpholine (2 mL). The resulting mixture was stirred at ambient temperature for 48 hours and quenched with saturated sodium bicarbonate solution. The diluted mixture was partitioned between methylene chloride and water. The organic phase was dried (MgSO4) and concentrated. 1.2 g of an oil are obtained. The oil was chromatographed on silica gel using hexane / ethyl acetate (80:20) as eluent. 0.6 g of 6-methyl-1- (2-methylpropyl) -2-morpholinomethyl-N ⁴ , N ⁴ bis (phenylmethyl) -1H-imidazo [4,5-c] pyridin-4-amine is obtained, and 4 g of 2-ethoxymethyl-6-methyl-l- (2-methylpropyl) -N ^4, N ⁴ -bis (phenylmethyl) -lH-imidazo [4,5-c] pyridin-4-amine.

Part C

Using the general procedure described in Example 45, hydrogenolysis of 6-methyl-1- (2-methylpropyl) -2-morpholinomethyl-N, N-bis (phenylmethyl) -1H-imidazo [4,5-c] pyridin-4-amine (0 6 g (B) gave 0.31 g of the desired product as a white solid, m.p. 188-190 ° C.

Analysis for C ₁₆ H ₂₅ N ₃ O. 1/3 H ₂ O: Calculated: C, 62.11; H, 8.36; N, 22.63% Found: C 62.19, H 8.18, N 22.62%.

Example 60

2-Ethoxymethyl-6-methyl-1- (2-methylpropyl) -1H-imidazo [4,5-c] pyridin-4-amine

Using the general procedure described in Example 45, hydrogenolysis of 2-ethoxymethyl-6-methyl-1- (2-methylpropyl) -N, N-bis (phenylmethyl) -1H-imidazo [4,5-c] pyridin-4-amine (0 4 g, from Example 73 part B), 0.08 g of the desired product is obtained as an off-white solid, m.p. 72-74 ° C.

Analysis for C ₁₄ H ₂₂ N ₄ O. 0.5 _CH3 OH: C, 62.56; H, 8.69; N, 20.13% Found: C, 62.93; H, 8.37; N, 19.8%.

-15GB 291419 B6

Example 61

2-Butyl-6,7-dimethyl-1- (2-methyl-1-propenyl) -1H-imidazo [4,5-c] pyridin-4-amine hydrochloride

4-Amino-2-butyl-α, α, 6,7-tetramethyl-1H-imidazo [4,5-c] pyridine-1-ethanol (about 200 mg) was treated with concentrated hydrobromic acid (50 mL). The resulting mixture was heated to reflux overnight. The reaction mixture was concentrated under reduced pressure. The residue was taken up in methanol and diluted with ether. The resulting precipitate was collected and partitioned between methylene chloride and 10% sodium hydroxide. The organic layer was separated, dried over magnesium sulfate and then concentrated. The oil obtained is taken up in methanol and treated with 0.05 ml of concentrated hydrochloric acid. The resulting mixture was diluted with ether. The resulting precipitate was collected, washed with ether and dried. 60 mg of the expected product is obtained in the form of a white solid, m.p. 205 DEG C. (dec.).

Analysis for C ₁₆ H ₂₄ N ₄ + 1/6 HCl: Calculated: C 58.10, Η 7.80, N 16.94% Found: C 57.95, Η 7.87, N 16.89%.

Example 62

2-Butyl-7-ethyl-6-methyl-1- (2-methylpropyl) -1H-imidazo [4,5-c] pyridin-4amine hydrochloride

Part A

Following the general procedure described in Example 3, 5-ethyl-4-hydroxy-6-methyl-3-nitro-2 (1H) -pyridinone (1.0 g, 5 mmol) was first treated with trifluoromethanesulfonic anhydride (1.7 mL, 10 mL). mmol). The product was then treated with isobutylamine (0.55 mL, 5.5 mmol) to give 1.0 g of 5-ethyl-6-methyl-4 - [(2-methylpropyl) amino] -3-nitro- 2-pyridyltrifluoromethanesulfonate.

PartB

Following the general procedure described in Example 10, Part A was reacted with dibenzylamine (0.52 mL) to give 1.0 g of 5-ethyl-6-methyl-N ⁴ - (2-methylpropyl) -3-nitro-N ² N ² -bis (phenylmethyl) pyridine-2,4-diamine.

Part C

Using the general procedure described in Example 18, the compound obtained under Part B was reduced to give 0.85 g of 5-ethyl-6-methyl-N ⁴ - (2-methylpropyl) -N ² , N ² -bis (phenylmethyl) pyridine -2,3,4-triamine as a light brown oil.

PartD

The material obtained under Part C was dissolved in acetonitrile (20 mL) and then treated with valeryl chloride (0.28 mL). The mixture was stirred at room temperature overnight, then at reflux for 3 hours and then at room temperature over the weekend. The reaction mixture was concentrated under reduced pressure. The residue was taken up in methylene chloride, washed with 10% sodium hydroxide, dried over magnesium sulfate and filtered through a pad of silica gel using 30% ethyl acetate in hexane as eluent. The filtrate was concentrated under reduced pressure to give 0.65 g of 2-butyl-7-ethyl-6-methyl-1- (2-methylpropyl) -N ⁴ , N ⁴ -bis (phenylmethyl) -1H-imidazo [4,5] -c] pyridin-4amine in the form of a gold oil.

-16GB 291419 B6

PartE

Dissolve the substance obtained in Part D in formic acid (20 ml). The solution was treated with palladium hydroxide on carbon (0.5 g, Pearlman's catalyst) and the resulting mixture was then heated to reflux. The reaction mixture was filtered through a pad of celite using methanol as eluent to remove the catalyst. The filtrate was concentrated under reduced pressure and the residue partitioned between methylene chloride and aqueous sodium bicarbonate. The methylene chloride layer was dried over magnesium sulfate and concentrated in vacuo. The residue was recrystallized from ethyl acetate / hexane to give a product which, according to nuclear resonance spectroscopy, contained some formic acid salt. This material was taken up in methanol and 10% sodium hydroxide added. The resulting mixture was heated in a steam bath for 1 hour and concentrated to remove methanol. The residue was extracted with methylene chloride. The methylene chloride extract was dried over magnesium sulfate and concentrated under reduced pressure. The oily residue was taken up in ethyl ether and 1 equivalent of 1M hydrochloric acid in ether was added. The resulting precipitate was collected by filtration and dried. 0.15 g of the desired product is obtained in the form of a solid, m.p. 217-219 ° C.

H, 9.00; N, 17.24. Found: C, 62.39; H, 8.70; N, 16.76.

PATENT CLAIMS

Claims (1)

A pyridine derivative selected from the group consisting of compounds of the formula wherein R ₆ and R ₇ are each independently hydrogen or C 1 -C 5 alkyl, wherein: R 6 and R ₇ together do not contain more than 6 carbon atoms; wherein further when R ₇ represents a hydrogen atom, then R ₆ does not represent a hydrogen atom; and R 'is C 1 -C 4 alkyl, C 1 -C 4 perfluoroalkyl, C 1 -C 4 alkylphenyl or halophenyl; compounds of formula -17GB 291419 B6 where R 1 represents a hydrogen atom; CH ₂ R _y , where R _y is straight or branched 5-chain alkyl of 1 to 10 carbon atoms or cycloalkyl of 3 to 10 carbon atoms, straight-chain or branched alkenyl of 2 to 10 carbon atoms, or hydroxyalkyl of straight chain or branched (C 1 -C 6), (C 1 -C 4) alkoxyalkyl and (C 1 -C 6) alkyl or phenylethyl; or 10 CH = CR _Z R _Z , wherein R _z at each occurrence independently represents a straight or branched alkyl group having 1 to 6 carbon atoms or a cycloalkyl group having 3 to 6 carbon atoms; and R ', R ₆ and R ₇ are as defined above; compound of the formula wherein X is nitro or amino, R |, R ', R and _R7 are as defined above and Bn is a hydrogenolyzable amino substituent selected from the group consisting of 20 phenylmethyl, (4-methylphenyl) methyl; and furylmethyl and compounds of the formula wherein -18GB 291419 B6 R ₂ represents hydrogen, alkyl with straight or branched chain containing 1 to 8 carbon atoms, hydroxyalkyl having straight or branched chain containing one to six carbon atoms, alkoxyalkyl having 1 to 4 carbon atoms in alkoxy and 1 to 6 carbon atoms in the alkyl radical benzyl, (phenyl) ethyl or phenyl, wherein the 5 benzyl, (phenyl) ethyl or phenyl substituent is optionally substituted in the benzene ring with a radical selected from the group consisting of methyl, methoxy and halogen; or morpholinoalkyl having 1 to 4 carbon atoms in the alkyl radical: and R 1 R ₆ , R ₇ and Bn are as defined above. End of document