BE856403A - IMIDAZOLE-4-CARBOXAMIDE 5-0-ACYLES DERIVATIVES, PROCESS FOR THEIR PREPARATION AND MEDICINAL PRODUCTS CONTAINING - Google Patents

Description

       

  Toshio Atsumi, Yoshiaki Takebayashi, Yuzo Tarumi, Hisao Yamamoto.

  
The present invention relates to imidazole4-carboxamide derivatives and the preparation thereof. More particularly, the present invention relates to 5-0-acylated imidazole4-carboxamide derivatives which are useful as anti-mitotic agents.

  
 <EMI ID = 1.1>

  
and the application of these compounds.

  
So far, it is known that bredinin, 4-carbamoyl1 - &#65533; -D-ribofuranosylimidazolium-5-olate exhibits immunosuppressive activity and weak anti-mitotic activity against L1210 / Kimio lymphatic leukemia. Mizuno et al. J. of Antibiotics, 27, 775 (1974) 7.

  
The aglycone derivative of brédinin, 4-carbamoylimidazolium-

  
 <EMI ID = 2.1>

  
 <EMI ID = 3.1>

  
The gics of 4-carbamoylimidazolium-5-olate were not known until recently.

  
Growth inhibitory effects on L5178Y cells and immunosuppressive effects have also been reported to be produced by administration of 4-carbamoylimidazolium5-olate. However, it has been suggested that these effects are not a direct result of the product but are due to the metabolic conversion of 4-carbamoylimidazolium-5-olate to bredinin. &#65533; enzo Sakaguchi et al. J. of Antibiotics, 28, 798 (1975); T. Tsujino et. al. Proceedings of the firts intersectional congress of IAMS Vol. 3,

  
 <EMI ID = 4.1>

  
The 5-0-acylated imidazole-4-carboxamide derivatives according to the present invention are represented by the formula:

  

 <EMI ID = 5.1>


  
 <EMI ID = 6.1>

  
or a phenyl group which is unsubstituted or substituted by a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a halogen atom, a nitro group, a cyano group, a methylene-dioxy group or an acetamido group.

  
 <EMI ID = 7.1>

  
relates to straight or branched alkyl chains comprising

  
1 to 17 carbon atoms (eg methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, iso-butyl, n-pentadecyl, n-hexadecyl, n-heptadecyl). The expression "lower alkyl" is preferably intended for a straight or branched alkyl chain comprising from 1 to 5 carbon atoms (for example methyl, ethyl, n-propyl, isopropyl). The expression “lower alkoxy” preferably applies to straight or branched alkoxy chains comprising from 1 to 5 carbon atoms (for example methoxy, ethoxy, n-propoxy, n-butoxy, isobutoxy). The expression “lower alkylthio” preferably applies to a straight or branched alkylthio chain comprising from 1 to 5 carbon atoms (for example methylthio, ethylthio). The term "halogen" applies to fluorine, chlorine, bromine and iodine.

  
According to the present invention, the 5-0-acylated imidazole-4carboxamide derivatives of formula:

  

 <EMI ID = 8.1>


  
in which R is as defined above, can be prepared by reaction of 4-carbamoylimidazolium-5-olate of formula:

  

 <EMI ID = 9.1>


  
or its: - derivative 'silylated with a: derivative; - reactive'; of carboxylic acids of formula:

  

 <EMI ID = 10.1>


  
where R is as defined above.

  
Examples of preferred reactive carboxylic acid derivatives of formula (III) are the anhydrides and halides of carboxylic acids, preferably the chlorides.

  
The reaction can generally be carried out by cooling a reaction mixture to a temperature of -10 to 30 [deg.] C, preferably.

  
 <EMI ID = 11.1>

  
with the carboxylic acid halides can generally be carried out in an inert polar solvent or a mixture of water and an inert organic solvent, preferably in the presence of an inorganic or tertiary organic base. Typical examples of such

  
 <EMI ID = 12.1> acetonitrile, acetone, nitromethane, ethyl acetate). In this case, the carboxylic acid anhydrides can be used as a solvent.

  
The compounds of formula CI) can also be prepared by reacting a silylated derivative of 4-carbamoylimidazolium-5-olate with the aforementioned carboxylic acid halides in inert organic solvents (for example benzene, toluene, xylene, ethyl acetate, n-hexane, dichloroethane, anhydrous ethyl ether, anhydrous dioxane, anhydrous tetrahydrofuran).

  
The reaction can be carried out by cooling to a

  
 <EMI ID = 13.1>

  
 <EMI ID = 14.1>

  
following tautomeric forms:

  

 <EMI ID = 15.1>


  
and as a result, the position where acylation takes place can be doubtful.

  
The Applicant has found that the acylation takes place in a specifically localized manner in the 5-0- position of the

  
 <EMI ID = 16.1>

  
as well as potent activity against tumors.

  
For example, the compounds exhibit <EMI ID = 17.1> <EMI ID = 18.1> activity

  
reduced toxicity. Symptoms of toxicity are not observed when more than 500 mg / kg of the compound is administered orally to mice. However, the compounds do not show an influence on a reduction in peripheral leukocytes,

  
which is one of the more serious side effects of compounds

  
 <EMI ID = 19.1>

  
invention, azathioprine and 6-mercaptopurine are listed in the following table. After a preparation of blood cells

  
 <EMI ID = 20.1>

  
to mice, the compounds were administered orally once daily from day 0 to day 3. The number of platelet-forming cells (plaque forming cell = PFC) was

  
 <EMI ID = 21.1>

  
et al. Immunol. 14, 599 (1968) 7.

  
Board
 <EMI ID = 22.1>
 The compounds of the present invention were found to also possess potent anti-mitotic activity against Sarcoma 180, Ehrlich carcinoma, MH 134 hepatoma, and P388 leukemia. The inhibitory effects are particularly marked against solid tumors.

  
The methods according to the invention also have an activity

  
 <EMI ID = 23.1>

  
The present invention is particularly useful as an immunosuppressive and anti-mitotic agent.

  
The compounds of the present invention can be administered orally or parenterally, at a daily dose of 0.1 g to 1.0 g / adult person as an immunosuppressant and 3 g to

  
10 g / adult person as an anti-mitotic agent in the forms

  
conventional dosing. For oral or parenteral administration, they are prepared either alone or with conventional pharmaceutical carriers, diluents or excipients to prepare conventional solid or liquid pharmaceutical preparations (e.g. powders, granules, tablets, capsules, suspensions, emulsions, solutions) using the conventional galenic preparation process.

  
The following examples are given by way of illustration of the present invention but should not in any way be. considered limiting the scope.

Example 1

  
To a suspension of 455 mg of 4-imidazolium-5-olate in 5 ml of dry pyridine, 1.02 g of benzoyl chloride is added

  
at a temperature below 5 [deg.] C. When the addition is complete, the mixture is stirred for 2 hours while cooling using

  
of ice. The crystals are then filtered off, washed.

  
with water and ether and dry to obtain 5-0-benzoyl-imidazol- <EMI ID = 24.1> 0

  
 <EMI ID = 25.1>

  
486 mg of triethylamine in 6 ml of anhydrous dimethylformamide, 770 mg of p-chlorobenzoyl chloride in 3 ml of anhydrous dimethylformamide are added at a temperature below 5 [deg.] C.

  
The mixture is stirred for 4 hours while cooling in ice. The insoluble crystals are separated by filtration, then the filtrate is concentrated under reduced pressure to obtain a residue which is dissolved in chloroform. The chloroform solution

  
is washed with water and dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure to give 5-0- (p-chlorobenzoyl) -imidazole-4-carboxamide. The raw solid

  
is washed with ethyl acetate to give 340 mg of pure product, mp 220 [deg.] C (product decomposes on charcoal).

  
The following compounds were obtained essentially by the same procedure as that described above:
5-0-adamantoyl-imidazole-4-carboxamide

  
Pf. 211 [deg.] C (dec.)

  
 <EMI ID = 26.1>

  
5-0- (p-fluorobenzoyl) -imidazole-4-carboxamide

  
Pf. 214 [deg.] C (dec.).

Example 3

  
The mixture of 100 mg of 4-imidazolium-5-olate and

  
1.1 g of acetic anhydride in 50 ml of anhydrous ethanol is stirred for one hour at a temperature below 5 [deg.] C. Then

  
20 mg of insoluble crystals of 4-imidazolium-5-olate are recovered. The filtrate is left to stand in the refrigerator for 2 days.

  
The resulting solution is evaporated in vacuo to obtain a residue to which is added 10 ml of a 50% toluene-ethanol solution. In addition, the organic solvent is evaporated under vacuum to dryness and the residue obtained is washed with a small amount of ethyl acetate and filtered to give 5-0-acetyl-imidazole4-carboxamide, Pf. 190 [deg.] C (decomposition by charcoal).

  
Infrared absorption spectrum

  
 <EMI ID = 27.1>

  
Nuclear magnetic resonance spectrum

  

 <EMI ID = 28.1>


  
The following compound was also obtained in the same way:

  
5-0-butyryl-imidazole-4-carboxamide

  
Pf. 240 [deg.] C (dec. Charcoal).

Example 4

  
A mixture of 10 g of hexamethyldisilazane, a catalytic amount of ammonium sulfate and 745 mg of 4-carbamoylimidazolium-5-olate is subjected to reflux for 1 1/2 hours.

  
The solution is concentrated under reduced pressure to give the silylated derivative of 4-carbamoylimidazolium-5-olate. The resulting solid (345 mg) is dissolved in 30 ml of dry benzene.

  
To the benzene solution, 350 mg of p-chlorobenzyl chloride is added while cooling on ice and then the mixture is stirred for 3 hours and a further 6 hours at room temperature. The solution obtained is evaporated under vacuum to dryness.

  
and the solid result is washed with ethyl acetate to obtain

  
 <EMI ID = 29.1>

  
(decomposition by charcoal).

Example 5

  
 <EMI ID = 30.1>

  
in 42.4 g of a 10% aqueous solution of sodium carbonate, 7.38 g of 3,4-methylenedioxybenzoyl chloride are added in

  
20 ml of toluene at room temperature. After the addition is complete, stirring of the mixture is continued for 4 hours. The crystals are filtered off, washed with water and toluene, dried under vacuum to give 5-0- (3 ', 4'-methylenedioxy-

  
 <EMI ID = 31.1>

  
The following compounds are also obtained by a process similar to that described in Example 5.

  
5-0- (o-methoxybenzoyl) -imidazole-4-carboxamide

  
Pf. 205 [deg.] C (dec. While charcoal)

  
5-0- (m-cyanobenzoyl) -imidazole-4-carboxamide

  
Pf. 195 [deg.] C (dec.)

  
 <EMI ID = 32.1>

  
Pf. 211 [deg.] C (dec.).

  
By the process of the present invention, it is also possible, for example, to obtain the following 5-0-acylated imidazole-4-carboxamides:

  
5-0- (o-chlorobenzoyl) -imidazole-4-carboxamide 5-0- (m-chlorobenzoyl) -imidazole-4-carboxamide 5-0- (p-bromobenzoyl) -imidazole-4-carboxamide .5-0- (p-acetamidobenzoyl) -imidazole-4-carboxamide.

  
 <EMI ID = 33.1>

  
5-0-stearoyl-imidazole-4-carboxamide-

  
 <EMI ID = 34.1> 5-0-pivaloyl-imidazole-4-carboxamide

  
 <EMI ID = 35.1>

CLAIMS

  
1. Compounds of formula

  

 <EMI ID = 36.1>


  
 <EMI ID = 37.1>

  
lower alkyl group, lower alkoxy group, lower alkylthio group, halogen atom, nitro group,

  
 <EMI ID = 38.1>


    

Claims (1)

2. Compounds according to claim 1 characterized in that <EMI ID = 39.1> carbon. 3. Compounds according to claim 1 characterized in that R represents a phenyl group which is unsubstituted or substituted by a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a halogen atom, a nitro group, a cyano group, a methylene-dioxy group or an acetamido group. 4. Compounds according to claim 1 characterized in that <EMI ID = 40.1> carbon, an adamantyl group, a phenyl group or a phenyl group substituted by a halogen atom. 5. Compounds according to claim 1 characterized in that B represents a phenyl group substituted by a lower alkyl group, a lower alkoxy group, a nitro group, a cyano group, a methylenedioxy group, an acetamido group or a lower alkylthio group. <EMI ID = 41.1> <EMI ID = 42.1> 8. 5-0-Acetylimidazole-4-carboxamide. <EMI ID = 43.1> 12. 5-0- (p-nitrobenzoyl) -imidazole-4-carboxamide. 13. 5-0- (p-fluorobenzoyl) -imidazole-4-carboxamide. <EMI ID = 44.1> 18. Process for the preparation of a compound of formula <EMI ID = 45.1> <EMI ID = 46.1> adamantyl, or a phenyl group which is unsubstituted or substituted by a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a halogen atom, a nitro group, a cyano group, a methylene-dioxy group or an acetamido group, characterized in that a 4-carbamoylimidazolium-5olate of formula is reacted <EMI ID = 47.1> <EMI ID = 48.1> <EMI ID = 49.1> <EMI ID = 50.1> 19. Method according to claim 18, characterized in that the reactive derivative of carboxylic acids of formula (III) is a carboxylic acid halide or anhydride. 20. The method of claim 19 characterized in that the reaction is carried out at a temperature of -10 to 30 [deg.] C in the presence or absence of solvent. 21. Pharmaceutical compositions or drugs useful for their anti-mitotic and immunosuppressive effects, characterized: with an effective content of at least one compound according to any one <EMI ID = 51.1> of claims 18 to 20 and optionally a pharmaceutically acceptable carrier, diluent or excipient.