CA1166259A - Antitumor and immunosuppressive 4-carbamoyl imidazolium-5-olate derivatives, pharmaceutical composition, production and use thereof - Google Patents

Abstract

Abstract of the Disclosure There are provided compounds of the formula:
wherein R is a mono-substituted benzoyl group which is substituted with a phenyl group, an alkanoyl group, a formyl group, a halogeno-alkyl group, an aralkyloxy group, a phenoxy group, an alkoxycarbonyl group, an aral-kyloxycarbonyl group, an alkanoyloxy group, a benzoyl group, a carboxyl group, a hydroxy group, a group of the formula:
(wherein X1 and X2 are a hydrogen atom or u lower alkyl group), an aralkyloxycarbonylamino group, a lower alkoxy-carbonylamino group, a carboxyamino group or a carbamoyl group; a cinnamoyl group which may be substituted at a position or the phenyl ring with an alkyl group, an alkoxy group, an aryl group, a nitro group, a methylene-dioxy group, a formyl group, a halogeno-alkyl group, a halogen atom, a hydroxy group, a carboxyl group, an amino group or a cyano group; or a benzoyl group substi-tuted with from two to five of the same or different substituents selected from the group consisting of alkyl groups, alkoxy groups, aralkyloxy groups, nitro group, halogen atoms, hydroxy group, alkanoyloxy groups, formyl group, carboxy group, alkylthio groups, alkylsulfonyl groups, groups of the formula:
(wherein X1 and X2 are a hydrogen atom or a lower alkyl group), sulfo group and sulfamoyl group; or its non-toxic salt, and a process for producing them.
The compounds are useful as antitumor agents and immunosuppressants.

Description

D ~

The present invention relates to novel 4-carbamoylimidazolium-5-olate derivatives and a process for preparing them. ~ore particularly, the present invention pertains to 4-carbamoylimidazolium-5-olate deriva-tives useful as antitumor agents and immunosup-pressants, a pharmaceutical composition containing at least one of them, and a process for preparing them.
~ he no~el imidazole derivatives of the present invention are those represented b~ the following formula (I), ~ ~ (I) wherein R is a mono-substituted benzoyl group which is substituted with a phenyl group, an alkanoyl group, a formyl group, a halogeno-alkyl group9 an aralk~lox~
group, a phenoxy group, an alkoxycarbonyl group, an aralkyloxycarbonyl group, an alkanoylox~ group, a ben~oyl group, a carboxyl group~ a hydroxy group, a group of the formula:
/X
- N \

(wherein Xl and X2 are a hydrogen atom or lower alkyl group), an aralkylox~carbonylamino group, a lower alkoxy-carbonylamino group, a carboxyamino group or a carbamoyl group; a cinnamoyl group which may be substituted at a positio~ or the phenyl ring with an alkyl group, an alkoxy group, an aryl group, a nitro group, a methylene-dioxy group, a form~l group 3 a halogeno-alkyl group, _ ' a halogen atom, a hydroxy group, a carboxyl group, an amino group or a cyano group; or a benzoyl group substi-tuted with from two to five of the same or dif~erent substituents selected from the group con~isting of alkyl groups, alkoxy groups, aralkyloxy groups, nitro group, halogen atoms, hydroxy group, alkanoyloxy groups, formyl group, carboxyl group, alkylthio groups, alkylsulfonyl groups, groups of the formula:

N~ ~1 ~X2 (wherein Xl and X2 are a hydrogen atom or a lower alkyl group), sulfo group and sulfamoyl group, or its non-toxic salt.
As used herein, the term "alkanoyl" means lower alkanoyl having 2 to 6 carbon atoms (e.g. acetyl, propionyl, pivaloyl hexanoyl), medium alkanoyl having 7 to 12 carbon atoms (e.g. lauroyl) and higher alkanoyl having 13 to ?2 carbon atoms (e.g. octanoyl, palmitoyl).
The term "halogeno-alkyl" mean~ lower alkyl having 1 to 6 carbon atoms substituted with the following halogen atom (e.g. trifluoromethyl, ~-chloroethyl).
~he term "aralkyloxy" means lower alkoxy having 1 to 6 carbon atoms substituted with an aryl group such as benzyloxy, a-methylbenzyloxy, phenethyloxy and the llke.
The term "alkoxycarbonyl" means lower alkoxy carbonyl having 2 to 7 carbon atoms (e.g. methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl), mediwm alkoxycarbonyl having 8 to 13 carbon atom~ (e.g.
octyloxycarbonyl) and higher alkoxycarbonyl having 14 to s~

23 carbon atoms (e.g. octadecyloxycarbonyl, docosyloxy-carbonyl).
The term "aralkyloxycarbonyl" means a carbonyl substituted with the above aralkyloxy group (e.g. ben~yloxy-carbonyl, a-methylbenzyloxycarbonyl, phenethyloxycarbonyl and the like~.
The term "alkanoyloxy" means lower alkanoyloxy having 2 to 6 carbon atoms (e.g. acetoxy, propionyloxy, pivaloyloxy, hexanoyloxy), medium alkanoyloxy having 7 to 12 carbon atoms (e.g. octanoyloxy, lauroyloxy) and higher alkanoyloxy having 13 to 22 carbon atoms (e.g. palmitoyloxy, stearoyloxy).
The term "aralkyloxycarbonylaminol- means an amino group substituted with the above aralkyloxycarbonyl group.
The term 'llower alkoxycarbonylamino" means an amino group substituted with the above lower alkoxycarbonyl group.
The term "alkyl" means lower alkyl having 1 to 6 carbon atoms (e.g. methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl, t-butyl, hexyl), medium alkyl having 7 to 12 carbon atoms (e.g. octyl, decyl, dodecyl) ana higher alkyl having 13 to 22 carbon atoms (e.g. pentadecyl? docosyl).
The term "alkoxy" means lower aIkoxy having 1 to 6 carbon atom (e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy), medium alkoxy having 7 to 12 carbon atoms (e.g. octyloxy, dodecyloxy) and higher alkoxy having 13 to 22 carbon atoms (e.g. octadecyloxy, docosyloxy).
The term "aryl" means ~uch as phenyl, tolyl, naphtyl and the like.

.

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The term "halogen" means fluorine, chlorine, bromine and iodine.
The term "alkylthio" means an alkylthio sub~ti-tuted with the above alkyl group.
The term "alkylsulfonyl" means an alkylsulfonyl substituted with the above alkyl group~
- The term "lower alkyl" in Xl or X2 meanR a lower alkyl having 1 to 6 carbon atoms as stated above.
The term "cinnamoyl" means unsubstituted and subs-tituted at a a position or a phenyl ring with one or moreof the same or different substituents selected from the groups as described,such as p-methylcinnamoyl, p-methoxy-cinnamoyl, a-phenylcinnamoyl, m-nitrocinnamoyl, 3,4-methylenedioxycinnamoyl, p-formylcinnamoyl~ m-trifluorometh~l-cinnamoyl, p-chlorocinnamoyl, p-aminocinnamoyl, p-hydroxy-cinnamoyl, o-carboxycinnamoyl, ~methylcinnamoyl, -fluoro-cinnamoyl, a-cyano-p hydroxycinnamoyl, 2,6 dichlorocinnamoyl 9

2,5-dimethoxycinnamoyl, ~,4-dimethylcinnamoyl, 4-hydroxy-~-methoxycinnamoylj 3,4-dihydroxycinnamoyl, 2,4,5-trimethyoxy-cinnamoyl, 3,5-dimethoxy-4-hydroxycinnamoyl and the like~
The compound of the formula (I) of the preqent invention can be prepared by reacting 4-carbamoyllmidazolium-5-olate (II) - C - ~H
2 .. -~ , ~O '' ~ (II) H

or it~ reactive derivative with a carboxylic acid of the formula (III);
R ~ OH (III) wherein R i~ as defined above or its reactive derivative.

5~

Example~ of preferred reactive derivatives of carboxylic acids of the formula (III) are carboxylic acid halides (e.g. chlorides, bromides, iodides, fluorides), carboxylic acid anhydrides, mixed anhydrides (e.g. mixed anhydrides with ethyl chloroformate, isobutyl chloroformate and the like), activated esters (e.g. p-nitrophenyl e~ter, ester with ~hydroxysuccinimide), imidazolide (e.g. pre-pared by reacting N,N'-carbonyldiimidazole with a carboxylic acid~(III)), activated intermediates prepared by reacting a carboxylic acid (III) with reaction products obtained from N,N-dimethylformamide and oxal~l chloride (or phosgene or thionyl chloride or phosphorus pentachloride) and the .
like.
Examples of preferred reactive derivative~ of 4-carbamoylimidazolium-5-olate of the formula (II) are trimethylsilyl derivatives, trialkyltin derivatives ? mer-cury salts, silver salts and the like.
Typical examples of preferred solvents which may be used in this reaction are methylene chloride, chloroform, pyridine, diethyl ether, tetrahydrofuran, dioxane, benzene, toluene, methanol, ethanol, N,N-dimethylformamide, formamide, N,N-dimethylacetamide, acetonitrile, nitromethane, acetone, ethyl acetate, dimethylsulfoxide, dichloromethane, dichloro-ethane, xylene and water.
~ he reaction can generally be effected at a reaction temperature from -78 to 100C.. preferably from 60 to 60C.
The reaction of 4-carbamoylimidazolium-5-olate with said carboxylic acid halides can usually be carried out in an inert polar solvent or a mixture of water and inert organic solvent, preferably in the presence of an inorganic or organic base, at a tem-perature from -10 to 60C. using one to two mole equiva-lent~ of the acid halide.
Typical examples of said inert polar solvent are tetrahydrofuran, dioxane, pyridine~ N,N-dimethylform-amide, formamide, N,N-dimethylacetamide and dimethylsulfoxide.
Typical examples of said inert organic solvents are tetra-hydrofuran, dioxane, diethyl ether, chloroform, dichloro-methane, dichloroethane, benzene, toluene, and xylene.Examples of preferred inorganic base are sodium hydroxide 9 sodlum carbonate, sodium bicarbonate, potassium carbonate or bicarbonate and potassium hydroxide. Examples of pre-ferred organic base-are pyridine, triethylamine and N,~-dimethylaniline.
The reaction of 4-carbamoylimidazolium-5-olate with the activated intermediates prepared by reacting a car-boxylic acid (III~ with reactlon products obtained from N,N-dimethylformamide and oxalyl chloride (or phosgene or ~0 thlonyl chloride or pho~phorus pentachloride) can usually be carried out in an organic solvent (e.g. acetonitrile, pyridine, N,N-dimethylformamide, ~T,~-dimethylacetamide, chloroform) at a temperature from -78 to 80C.
The compounds of the formula (I) can also be pre-pared by reacting a silylated derivative of 4-carbarnoyl-imidazolium-5-olate with reactive derivatives of a carboxyllc acid (III) (e.g. acid halide~) at a temperature from -78 to 50C. in an inert organic ~olvent (e.g. dimethylformamide, tetrahydrofuran, dioxane, diethyl ether, benzene, toluene).

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The silylated derivatives of 4-carbamoylimida-zolium-5-olate are known and can be prepared by known methods (Hayashi, et al. Japanese Patent Publication (Kokai) No. 50-121276). When -the compounds of the ~ormula ~I) exist in the form of their silylated derivative in the reaction mixture, the compound (I) can be obtained by desilylation reaction with desilylating reagents (e.g.
acetic acid, methanol).
When reactive derivative of acid (III) is the acid halide, the eliminated halide can be neutralized by an organic base (e.g. triethylamine, pyridine).
The compounds of the formula (I) substituted with an amino, hydroxy and carboxyl group can be prepared by the said acylation methods after protecting an amino, hydroxy and carboxyl group with protective groups (e.g.
benzyl, benzyloxycarbonyl, t-butox~carbonyl and the like) and by removing protective groups.
The compounds of the formula (I) can be isolated and purified by known purification methods (e.g. recrystal-lization, column chromatography).
The compounds of the formula (I) may form a salt with an inorganic acid (e.g. hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid) or an organic acid (e.g. p- -toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, tartaric acid, malic acid, lactic acid, maleic acid, fumaric acid.
The imidazole derivatives of the present inven-tion may exist in a mixture of the two tautomers as follows:

o o n - n RO ~ N~ 1~ N - C ~Q N

both of which are within the scope of the present invention~
The cDmpounds of the present invention po3sess potent antitumor activities against Sarcoma 180, ~ewi3 lung carcinoma, ~hrlich carcinoma, P-~88 leukemia and the like~ The compounds of the formula (I) are useful a~ -anti-tumor agents, and they exhibit par-ticularly excellent inhibitory effects against tumor and also exhibit a pro-longing ef~ect on the life span.
~he antitumor activitie~ of the compounds of the present invention were estimated according to the methods described in "Cancer chemotheraphy reports" Part 3, Vol. 3, (~o. 2) p.l3 (1972). The results are given in the following - Table 1.
Table 1 Antitumor effect on mouse experimental tumor~
Inhibition Do~e Ratio ~%) Compound~ (mg/kg)Sche~
Route ~.p. carcinoma (solid~

5-Carbamoyl-lH-imidazole-4-yl p-phenylbenzoate 1005q2d 77.0 5-Carbamoyl-lH-imidazole- d 0 4-yl p-chlorocinnamate .1005q2 9 5-Carbamoyl-l~-imidazole- 10 4-yl m-nitrocinnamate 5q2d 90 -Table 1 (cont7d) 5-Carbamoyl-lH-imidazole-4-yl 3',4'~dimethoxy- 100 5q2d ~3.1 benzoate 5-Carbamoyl-l~-imidazole-4-yl 3'-methoxy-4'- 100 5q2d 89.4 methylbenzoate BDFl male mice, 5 weeks old, weighing between 18 and 22 grams were used. ~ach test group was composed of 6 to 7 mice. ~wo million cells of ~ewis lung carcinoma were injected in the hind leg. The drug was administered intraperitoneally at day 1, 3, 5, 7 and 9 (or 5q2d).
After killing the mice at day 13, tumors were removed and weighed. ~he tumor inhibitory ratio was cal-- culated according -to the following formula.
the mean tumor weights Inhibition ratiO = (1 _ f treated ~roup ) x 100 the mean tumor weights of control group The compounds of the present invention also possess excellent immunosuppressive activity as well as potent antitumor activity.
~ he compounds (I) of the present invention have low toxicity. ~hey do not show any toxic syrnptoms -even whe~
over 1000 mg/kg of the compounds are orally administered to a mouse. Moreover, they do not exhibit the influence of decreasing of peripheral leucocytes, which is one of the most serious side effects of imml~osuppress~nts.
The compounds of the present invention can be administered orally or parenterally to a warm-blood animal at a daily dose of 2 - 200 mg/kg as an antit~nor agent, and 1 - 100 mg/kg as an immunosuppressant agent in a conventional ;2~

dosage unit form.
The compounds of the present invention may be made up alone or together with a conventional pharmaceu-tical carrier or diluent into a conventional solid or liquid pharmaceutical preparation (e.g. powders, granule~, tablets, capsule~,`suspensions, emulsions, solutions) using the conventional methods in the pharmaceuticai field.
For example, tablets or capsules may contain 50 - 500 mg of the compounds (I).
Especially, the compounds (I~ of the present invention can be used for oral administration and are effec-tive for a long period.
The following examples are given to illustrate the present inve~tion more precisely but i-t is not intended to limit the present invention -thereto.

Example To a suspension of 0.636 g. of 4-carbamoylimida-zolium-5-olate in 15 ml of dry pyridine was dropwisely added 1.2 g of 2,6-dimethylbenzoyl chloride at a temperature below 5C. in N2 atmosphere. After being stirred for two hours at 41 - 43C., the reaction mixture was cooled to room temperature and a 0.8 g of triethylamine was added, and separated crystals were filtered off. ~hen the filtrate was concentrated under reduced pressure, and separated crystals were filtered off, washed with toluene and ether and dried to give 0.689 g of 5-carbamoyl-lH-imidazole-4-yl 2',6'-dimethylbenzoate, m.p. 176 - 177C~
Crude material was recrystallized from N,N-dime-thyl-formamide and water. m.p~: 180 - 180.5C.

~nujol ~ max (cm 1): 3425, 3160, 1725, 1670, 1610 Elemental analysis: C(%) H (%) ~(%) Calculated for C13H13N~3 0 3H20 59.00 5.18 15.88 Found 59.1 5.0 15.6 Example 2 Following a procedure similar to that of Example 1 but using 0.636 g of 4 carbamoylimidazolium-5-olate and 1.30 g of 3,4-dimethoxybenzoyl chloride there was obtained 1.353 g of 5-carbamoyl-lH imidazole-4-yl 3',4'-dimethoxy-benzoate. m.p.: 209.5C. (dec~) Crude material was recrystallized ~rom ~,N-di-methylformamide and water. m.p.: 216.5C.

~ max (cm ): 3440, 3330, 3120, 1750, 1650, 1590 Elemental analysis: C(%) H(%) N(~) Calculated for C13H13N305 53.61 4.50 14.43 Found 53.38 4.43 14.30 Example 3 Following a procedure similar to that of Example 1but using 0.636 g of 4-carbamoylimidazolium-5-olate and 2.0 g of 2,4,6-trimethoxybenzoyl chloride there was obtained 0.699 g of 5-carbamoyl-lH-imidazole-4-yl 2',4',6'-trime-thoxy- -benzoate. m.p.: 174C. (charred) Crude material was recrystallized from N,N-dimethyl-formamide and water. m.p.: 184.5C. (charred) ~ max (cm 1): 34109 3330, 1750, 1670, 1610, 1590 Elemental analysis: C(~) H(%) N(~) Calculated for C14~15N~06 52.34 4.71 13.08 Found 52.2 4.8 13.2 -- 1~ --Example 4 Following a procedure similar to that of Example 1but using 0.508 g of 4-carbamoylimidazolium-5-olate and 1.83 g of 3,4-bisbenzyloxybenzoyl chloride there wa~
obtained 1.548 g of 5-carb~noyl-lH-imidazole-4-yl 3'~4'-bisbenzyloxybenzoate. m.p.: 189.5 - 191.5C.
Crude material was recrystallized from N,N-dimethyl-formamide and water. m.p.: 191.5 - 192.5C.
nujol ~ max (cm ): 3460, 3150, 1740, 1670, 1605 Elemental analysis: C(%) H(%) N~%) CalcuIated for C25H2105N~ 67.71 4.77 9.48 Found ~ 67.4 4.9 9.3 5 ~xam~le 5 A suspension of 0.55 g of 5-carbamoyl-lH-imidazole-4-yl 3',4'-bisbenzyloxybenzoate and 0.3 g of 10 % Pd-C in dry tetrahydrofuran was stirred for 6 hours at room tem-perature in H2 atmosphere. Separated precipitates were filtered off and the filtrate was concentrated under reduced pressure to give 0.270 g of 5-carbamoyl-lH-imidazole-4-yl

3',4'-dihydroxybenzoate. m.p.: 156C. -- s Crude material was recrystalli~ed from dimethyl-sulfoxide and water. m.p.: 159 - 161C.
nujol ~ max ~cm~ ): 3480, 3225, 1735, 1675, 1600 Elemental analysis: C(%) H(%) N(~) Calculated fo~ Cll~9N35 1 2~2 46.39 4.03 14.75 Found 46.46 3.81 14.45 Example 6 A mixture of 0.212 g of 3,5-dinitrobenzoic acid, 0.127 g of 4-carbamoylimidazolium-5-olate and 0.206 g of dicyclohexylcarbodiimide in 4 ml of dry pyri-dine was stirred for 21 hours at room temperature.
Separated precipitates were filtered off and were washed with ethyl acetate to give 0.355 g of 5-carbamoyl-lH-imidazole-4-yl 3'~5'-dinitrobenzoate which was recrystallized from dimethylsulfoxide and water. m.p.: 220C. (decomp.) Elemental analysis: C(~0) H~o) N(~) Calculated for CllH7N507 41.13 2.20 21.81 Found 41.5 2.4 20.9 Example 7 Following a procedure similar to that of Example 6 but using 0.83 g of 3-methoxy-4-methylbenzoic acid, 1.03 g of dicyclohexylcarbodiimide and 0.635 g of 4-carb~noyl-imidazolium-5-olate there was obtained 1.45 g of 5-carbamoyl-lH-imidazole-4-yl 3'-methoxy-4'-methylbenzoate.
Crude material was recrystallized from N,N-dimethyl-formamide and water. m.p.: 210C. (decomp.) nujol (cm 1): 3450, 1740, 1655, 1600max ~x~m~le 8 A mixture of 76.26 g of 4-carbamoylimidazolium-5-olate, 174.31 g of 1 J 1,1,3,3,3-hex~nethyldisilazane, 1.59 g of ammonium sulfate and 500 g of dry xylene was refluxed for 4 hours. ~he reaction mixture was concentrated under reduced pressure and a tris-trimethylsilylated deriya-tive of 4-carbamoylimidazolium-5-olate was obtained.

- 15 ~

i2~

m.p.: 83 - 86.5C.
To a stirred solution of 1.718 g of tris-tri-methylsilylated derivative of 4-carbamoyl-imidazolium~5-olate in 15 ml of dry tetrahydrofuran was dropwisely added a solution o~ 0.833 g of cinnamoyl chloride in 5 ml of dry tetrahydrofuran at -50C. under N2 atmosphere. After being stirred for half an hour at -50C., 0.32 g of dry methanol was added to the reaction mixture. After being stirred for 15 minutes at -50C. t 0.51 g of triethylamine was added.
The reaction mixture was heated up to room tempera-ture and then separated crystals were filtered off, washed with tetrahydrofuran and chloroform and dried to give 0.796 g of 5-carbamoyl-lH-imidazole-4-yl cinnamate.
m.p.: 170 - 175C. The filtrate of a tetrahydrofuran solution was concentrated and diethylether was added to the residue and separated crystals were filtered of~, washed with diethyl ether and dried to give 0.427 g of said product.
Crude material was recrystallised from dimethyl-sulfoxide and water. m.p. 197C. (charred~
~nujol ~ max (cm ): 3460, 3160, 3110, 1720, 1670, 1605 Elemental analysis: ~(%) H(%) N(~) Calculated for C13EllN33 O-lH~0 60.27 4.36 16.22 ~ound 60.1. 4.4 16.3 Ex~nple _ ~ ollowing a procedure similar to that of Example 8 but using 0.9 g of p-methylcinnamoyl chloride there was obtained 1.270 g o~ 5-carbamoyl-lH imidazole-4-yl p-methyl-cinnamate. m.p.: 171C. (decomp.) Crude material was recrystallized from dimethyl-sulfoxide and water. m O p. 194C. (charred) nujol (cm~l): 3440, 3150, 1715, 1665, 1600 max ~lemental analysis: C(%) H(~) N(%) Calculated for C14H13~33 2H2 15.29 Found 61.19 4.69 15.49 ~xample 10 Following a procedure similar to that of Example 8 but using 1.01 g of p-chlorocinnamoyl chloride there was obtained 1.408 g of 5-carbamoyl-lH-imidazole-4-yl p-chloro-cinnamate. m.p. 172C. (dec.) Crude material was recrystallized from dimethyl-sulfoxide and water. m.p.: 202C~ (dec~) nu;ol ~ max (cm ): 3440, 3380, 3150, 1725, 1660l 1615 Elemental anlaysis: C(~) H(%) N(%) Calculated for C13HlON303Cl 0 1~20 53.20 3.5 14.32 Found 53.1 3.8 14.1 Example 11 Following a procedure similar to that of Example 8 but using 1.053 g of 3,4-methylenedioxycinnamoyl chloride there was obtained 1.172 g of 5-carbamoyl-lH-imidazole-4-yl 3',4'-methylenedioxycinnamate. m.p.: 165 - 175C.
Crude material was recrystallized from dimethyl sulfoxide and water. m.p.: 189C. (char.) max (cm~l): 3460, 3400, 3125, 1735, 1670, 1630, 1605 ~ 17 -Elemental analysis: C(%) H(/J0) ~(%) Calculated for C14Hl~T35 0 4H20 54.51 3.86 13.62 Found 54.49 3.71 13.48 ExamPle 12 Follwing a procedure similar to that of Example 8 but using 0.98 g of p-methoxyeinnamoyl chloride, there was obtained 1.15 g of 5-carbamoyl-lH-imidazole-4-yl p-methoxy-einnamate. m.p.: 165 - 167C. (dee.) Crude material was reerystallized from dimethyl-sulfoxide and water. m.p.: 185C. (ehar.) nujolmax (em~ ): 3470, 3175, 1725, 1670, 1605 ~lemental analysis: C(%) H(%) ~(%) Caleulated for C14H13N34 6H2 56.41 4.80 14.10 Found 56.75 4.63 13.85 .. . ... . . .
Example 13 Following a procedure similar to that of ~xample 8 but using 0.97 g of p-formyleinnamoyl chloride, there was obtained 1.086 g of 5-carbamoyl-lH-imidazole-4-yl p-formyl-einnamate.
Crude material was recrystallized from dimethyl-sulfoxide and water. m.p.: 233C~ (ehar.) max (em 1): 3100~ 1730, 1680, 1650, 1620, 1590 ~lemental analysis: C(~o) H(%) N(~o) Caleulated for C14HllN34 0'5H2 14.28 Found 57.0 3.9 14.0 3~

Example 14 Following a procedure similar to that of Example 8 but using 1.173 g of m-trifluoromethylcinnamoyl chloride, there was obtained 1.236 g of 5 carbamoyl-lH-imidazole

4-yl m-trifluoromethylcinnamate. m.p.: 167 - 170C. (dec.) Crude material was recrystallized from dimethyl-sulfoxide and water. m.p.: 188C. (char.) nujol ~ max (cm ): 3460, 3175, 1730, 1680, 1610 Elemental analysis: C(~) H(~) N(%) Calculated for C14HloN303F3 2 51.42 3.14 12.85 Found 51.19 2O98 13.09 EY.ample 15 Following a procedure similar to that of Example 8but using 1~058 g of m-nitrocinnamoyl chloride, there was obtained 1.383 g of 5-carbamoyl-lH-imidazole-4-yl m-nitro-cinnamate.
Crude material was recrystallized from dimethyl-sulfoxide and water. m.p.: 197C, ~char.) nujol ~ max (cm ): 3450, 3120, 1740, 1650, 1600 ~lemental analysis: C(%) H(~) N(%3 Calculated for C13HloN405 0-3H2 18.21 Found 50.76 3.30 18.20 Example 16 Following a procedure similar to that of Example 1 but using 1.46 g of a-phenylcinnamoyl chloride, there was obtained 1.186 g of 5-carbamoyl-lH-imidazole-4-yl a-phenyl-cinnamate. m.p.: 208C.

.

Crude material was recrystallized from dimethyl-sulfoxide and water. m.p.: 212C.

~ max (ck 1): 3450, 3125, 1735, 1655, 1605 Elemental analysis: C(~) H(%) Calculated for ClgH15~303 0 3H20 67.37 4.64 12.40 Found 67.48 4.51 12.41 xample 17 . Following a procedure similar to that of ~xample 1 but using 2.544 g of 4-carbamoylimidazolium-5-olate and

5.922 g of p-benzyloxybenzoyl chloride, there was obtained 5-carbamoyl-lH-imidazole-4-yl p-benz~loxybenzoate.
Crude material was recrystallized from dimethyl-sulfoxide and water. m.p.: 215 - 218C. (dec.) ~ nu~ol ( -1) 1730 16~0 Elemental analysis: C(~)H(%) N(%) Calculated for C18H1504~3 64.09 4.48 12.46 Found 63.5 4.5 12.3 Exam~le 18 Following a procedure similar to that of ~xample 1 but using m-trifluoromethylbenzoyl chloride, there was obtained 5-carbamoyl-lH-imidazole-4-yl m-trifluoromethyl-benzoate. m.p. 208 - 211C. (dec.) ~ nu a ol ( cm~l): 1730 1670 Elemental analysi~: C(~)H(%) N(~) Calculated for C12H80~N3F3 48.17 2.7 14.04 Found 48.0 2.9 14.0 -- ~0 --5~

~xam~le 19 Following a procedure similar to that of Example 1 but using p-N-benzyloxycarbonylaminobenzoyl chloride, there was obtained 5-carbamoyl-lH-imidazole-4-yl p-N-benzyloxycarbonylaminobenzoate. m.p.: 187 - 190C. (dec.) nujol ~ max (cm ): 1730, 1680, 1660 Elemental Analysis: C(%) ~(%) N(~) Calculated for cl9Hl6o5N4 59.99 4.24 14.73 Found 59.6 4.3 14.5 Example 20 Eollowing a procedure similar to that of Example 1 but using 1.41 g of 4-biphenylcarbonyl chloride, there was obtained 1.33 g of 5-carbamoyl-lH-imidazole-4-yl p-henyl-benzoate. m.p.: 225C. (char.) Crude material was recrystallized from N,N-dime-thyl-formamide and water. m.p~: 226.5 - 227C. (char~) nujol ~ max (cm 1): 3460, 3160, 1735, 1675, 1605 Elemental analysi~: C(%) H(~
Calculated for C17H1~303 66.44 4.26 13.67 ~ound 66.6 4.3 13.5 ExamPle 21 ~ ollowing a procedure similar to that of Example 8 but using 1.1 g of o-acetylsalicyloyl chloride, there was obtained 1.29 g of 5-carbamoyl~ imidazole-4-yl o-acetoxy-benzoate. m.p.: 143-145C.

nujol max (cm ~ 430, 3190, 1755, 1670, 1605 2S~

Example 22 ~ o a stirred solution of 6.3 ml of N,~T-dimethyl formamide in 14 ml of acetonitrile was added slowly 0.45 ml of oxalyl chloride a-t -20C. and the reaction mixture was heated up to room temperature. ~o the reaction mixture was added 1.33 g of o-benzyloxycarbonylbenzoic acid at -25C. and the reaction mixture was heated up to room tem-perature. lo the reaction mixture were added 0.636 g of 4-carbamoylimidazolium-5-olate and 2.5 ml of dry pyridine over ice bath in ~2 atmosphere and stirring was continued ~or 30 minutes at room temperature.
~ o the residue was added 1.9 ml of triethylamine over ice bath and separated precipitates were filtered off and the filtrate was concentrated under reduced pressure to give 0.78 g of 5-carbamoyl-lH-imidazole-4-yl o-benzyloxy-carbonylbenzoate. m.p.: 122 - 124C.

nujol max (cm~l~: 3460, ~150, 1770, 1725, 1670, 1610 Example 23 Following a procedure similar to that of ~xample 1 but using 1.19 g of p-methoxycarbonylbenzoyl chloride, there was obtained 1.4 g of 5-carbamoyl-lH-imidazole-4-yl p-methoxycarbonylbenzoate 4 Crude material was recrys-tallized from dirnethyl-sulfoxide and water. m.p.: 215C. (dec.) ' nujol max (cm 1): 3475, 3440, 3180, 3120, 1750, 1735, 1680, 1605 ~lemental analysis: C(%) H(%) N(%) Calculated for C13HllN305 53.98 3.83 14.53 ~ound 5~.4~ 3.80 14.46 According to the present invention, there are obtained, for example, the following compounds:
5-carbamoyl-lH-imidazole-4-yl p-aminocinnamate, 5-carbamoyl-lH-imidazole-4-yl p-hydroxycinnamate, 5-carbamoyl-lH-imidazole-4-yl o-carboxycinnamate, 5-carbamoyl-lH-imidazole-4-yl a-cyano-4'-hydroxycinnamate, 5-carbamoyl-lH-imidazole-4-yl 3',4'-dichlorocinnamate, 5-carbamoyl-lH-imldazole-4~yl 3',4'-dimethpxycinnamate, . . 5-carbamoyl-lH-imidazole-4-yl 3',4'-dimethylcinnamate, 5-carbamoyl-lH-imidazole-4-yl 4'-hydroxy-3'-methoxycinnamate, 5-carbamoyl-lH-imidazole-4-yl 3',4',5'-trimethoxycinnamate, 5-carbamoyl-lH-imidazole-4-yl 3',4'-dihydroxycinnamate, 5-carbamoyl-lH-imidazole-4-yl a-~luorocinnamate~
5-carbamoyl-lH-imidazole-4-yl 3',5'-dimethoxy-4'-hydroxycinnamate, 5-carbamoyl-lH-imidazole-4-yl a-methylcinnamate, 5-carbamoyl-lH-imidazole-4-yl p-octylcinnamate, 5-carbamoyl-lH-imidazole-4-yl p-dodecylcinnamate, 5-carbamoyl-lH-imidazole-4-yl p-doco~ylcinnamate, 5-carbamoyl-lH-imidazole-4-yl p-ootyloxycinnamate, 5-carbamoyl-lH-imidazole-4-yl p-octadecyloxycinnamate, ~ .
5-carbamoyl-lH-imidazole-4-yl pentafluorobenzoate, 5-carbamoyl-lH-imidazole-4-yl 2',4'-dicarboxybenzoate, 5-carbamoyl-lH-imidazole-4-yl ~'-amino-4'-mbthylbenzoate, 5-carbamoyl-lH-imidazole-4-yl 3'-acetyloxy-4'-methylbenzoate, 5-carbamoyl-lH-imidazole-4-yl 2'-benzyloxy-5'-methylthiobenzoate, 5-carbamoyl-lH-imidazole-4-yl 4'-methylsulfonyl-3'-nitrobenzoate, z~

5-carbamoyl-lH-imidazole-4-yl 4'-chloro-3'-sulfamoylbenzoate, 5-carbamoyl-lH~imidazole-4-yl 2'-hydroxy-5'-methylthiobenzoate, 5-carbamoyl-lH-imidazole-4-yl 51-~ormyl-2'-hydroxybenzoate, 5-carbamoyl-lH-imidazole-4-yl 2 7 -hydroxy-5'-sulfobenzoate, 5-carbamoyl-lH-imidazole-4-yl 4'-diethylamino-2'-hydroxybenzoate, 5-carbamoyl-lH-imidazole-4-yl 4'-methyl-3'-octyloxybenzoate 9 5-carbamoyl-lH-imîdazole-4-yl 4'-methyl-3'-octodecyloxybenzoate, 5-carbamoyl-lH-imidazole-4-yl 3'-methoxy-4'-lauroyloxybenzoate, 5-carbamoyl-lH-imidazole-4-yl ~1-methoxy-4'-stearoyloxybenzoate, 5-carbamoyl-lH-imidazole-4-yl 4'-hexadecyl-2i-methylbenzoate, 5-carbamoyl-lH-imidazole-4-yl 2'-dodecyl-4'-methoxybenzoate, 5-carbamoyl-lH-imidazole-4-yl p-aminobenzoate, 5-carbamoyl-lH-imidazole-4-yl p-hydroxybenzoate, 5-carbamoyl-lH-imidazole-4-yl o-benzoylbenzoate, 5-carbamoyl-lH-imidazole-4-yl o-carboxybenzoate, 5-carbamoyl-lH-imidazole-4-yl o-phenoxybenzoate, 5-carbamoyl-lH-imidazole-4-yl p-formylbenzoate, 5~carbamoyl-lH-imidazole-4-yl p-acetylbenzoate, 5-carbamoyl-lH-imidazole-4-yl p-carbamoylbenzoate, 5-carbamoyl-lE-imidazole-4-yl p-octanoylbenzoate, 5-carbamoyl-lH-imidazole-4-yl p-palmitoylbenzoate, 5-carbamoyl-lH-imidazole-~ yl p-octyloxycarbonylbenzoate, 5-carbamoyl-1~-imidazole-4-yl p-octadecyloxycarbonylbenzoate,~
5-carbamoyl-lE-imidazole-4-yl p-octanoyloxybenzoate, 5-carbamoyl-lH-imidazole-4-yl p-palmitoyloxybenzoate.

Claims (54)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for producing a compound of formula I:
wherein R is a mono-substituted benzoyl group which is substituted with a phenyl group, an alkanoyl group, a formyl group, a halogeno-alkyl group, an aralkyloxy group, a phenoxy group, an alkoxycarbonyl group, an aralkyloxy-carbonyl group, an alkanoyloxy group, a benzoyl group, a carboxyl group, a hydroxy group, a group of the formula:
(wherein X1 and X2 are a hydrogen atom or a lower alkyl group), an aralkyloxycarbonylamino group, a lower alkoxy-carbonylamino group, a carboxyamino group or a carbamoyl group; a cinnamoyl group which may be substituted at a position or the phenyl ring with an alkyl group, an alkoxy group, an aryl group, a nitro group, a methylene-dioxy group, a formyl group, a halogeno-alkyl group, a halogen atom, a hydroxy group, a carboxyl group, an amino group or a cyano group; or a benzoyl group substituted with from two to five of the same or different substituents selected from the group consisting of alkyl groups, alkoxy groups, aralkyloxy groups, nitro group, halogen atoms, hydroxy group, alkanoyloxy groups, formyl group, carboxyl group, alkylthio groups, alkylsulfonyl groups, groups of the formula:
(wherein X1 and X2 are a hydrogen atom or a lower alkyl group), sulfo group and sulfamoyl group; or its non-toxic salt, which process comprises reacting 4-carbamoylimidazolium-5-olate of the formula, or its obvious chemical equivalent with a carboxylic acid or its obvious chemical equivalent of the formula, R - OH
wherein R is as defined above.

2. A process according to Claim 1, wherein R is a mono-substituted benzoyl group which is substituted with a phenyl group, an alkanoyl group, a formyl group, a halogeno-alkyl group, an aralkyloxy group, a phenoxy group, an alkoxycarbonyl group, aralkyloxycarbonyl group, an alkanoyl-oxy group, a benzoyl group, a carboxyl group, a hydroxy group, a group of the formula:
(wherein X1 and X2 are a hydrogen atom or a lower alkyl group), an aralkyloxycarbonylamino group, a lower alkoxy-carbonylamino group, a carboxyamino group or a carbamoyl group.

3. A process according to Claim 1, wherein R is a cinnamoyl group which may be substituted at an a position or phenyl ring with an alkyl group, an alkoxy group, an aryl group, a nitro group, a methylenedioxy group, a formyl group, a halogeno-alkyl group, a halogen atom, a hydroxy group, a carboxyl group, an amino group or a cyano group.

4. A process according to Claim 1, wherein R is a benzoyl group substituted with from two to five of the same or different substituents selected from the group consisting of alkyl groups, alkoxy groups, aralkyloxy groups, nitro group, halogen atoms, hydroxy group, alkanoyloxy groups, formyl group, carboxyl group, alkylthio groups, alkylsul-fonyl groups, groups of the formula:
(wherein X1 and X2 are a halogen atom or a lower alkyl group), sulfo group and sulfamoyl group.

5. A process according to Claim 2, wherein R is p-benzyloxybenzoyl.

6. A process according to Claim 2, wherein R is m-trifluoromethylbenzoyl.

7. A process according to Claim 2, wherein R is p-N-benzyloxycarbonylaminobenzoyl.

8. A process according to Claim 2, wherein R is 4-biphenylylcarbonyl.

9. A process according to Claim 2, wherein R is o-acetylsalicyloyl.

10. A process according to Claim 2, wherein R is o-benzyloxycarbonylbenzoyl.

11. A process according to Claim 2, wherein R is p-methoxycarbonylbenzoyl.

12. A process according to Claim 3, wherein R is cinnamoyl.

13. A process according to Claim 3, wherein R is p-methylcinnamoyl.

14. A process according to Claim 3, wherein R is p-chlorocinnamoyl.

15. A process according to Claim 3, wherein R is 3,4-methylenedioxycinnamoyl.

16. A process according to Claim 3, wherein R is p-methoxycinnamoyl.

17. A process according to Claim 3, wherein R is p-formylcinnamoyl.

18. A process according to Claim 3, wherein R is m-trifluoromethylcinnamoyl.

19. A process according to Claim 3, wherein R is m-nitrocinnamoyl.

20. A process according to Claim 3, wherein R is a-phenylcinnamoyl.

21. A process according to Claim 4, wherein R is 2,6-dimethylbenzoyl.

22. A process according to Claim 4, wherein R is 3,4-dimethoxybenzoyl.

23. A process according to Claim 4, wherein R is 2,4,6-trimethoxybenzoyl.

24. A process according to Claim 4, wherein R is 3,4-bisbenzyloxybenzoyl.

25. A process according to Claim 4, wherein R is 3,4-dihydroxybenzoyl.

26. A process according to Claim 4, wherein R is 3,5-dinitrobenzoyl.

27. A process according to Claim 4, wherein R is 3-methoxy-4-methylbenzoyl.

28. A compound of formula I:
wherein R is a mono-substituted benzoyl group which is substituted with a phenyl group, an alkanoyl group, a formyl group, a halogeno-alkyl group, an aralkyloxy group, a phenoxy group, an alkoxycarbonyl group, an aralkyloxycarbonyl group, an alkanoyloxy group, a benzoyl group, a carboxyl group, a hydroxy group, a group of the formula:
(wherein X1 and X2 are a hydrogen atom or a lower alkyl group), an aralkyloxycarbonylamino group, a lower alkoxy-carbonylamino group, a carboxyamino group or a carbamoyl group; a cinnamoyl group which may be substituted at a position or the phenyl ring with an alkyl group, an alkoxy group, an aryl group, a nitro group, a methylenedioxy group, a formyl group, a halogeno-alkyl group, a halogen atom, a hydroxy group, a carboxyl group, an amino group or a cyano group; or a benzoyl group substituted with from two to five of the same or different substituents selected from the group consisting of alkyl groups, alkoxy groups, aralkyloxy groups, nitro group, halogen atoms, hydroxy group, alkanoy-loxy groups, formyl group, carboxyl group, alkylthio groups, alkylsulfonyl groups, groups of the formula:
(wherein X1 and X2 are a hydrogen atom or a lower alkyl group), sulfo group and sulfamoyl group; or its non-toxic salt, when produced by the process of claim 1 or by its obvious chemical equivalents.

29. A compound of formula I, wherein R is a mono-substituted benzoyl group which is substituted with a phenyl group, an alkanoyl group, a formyl group, a halogeno-alkyl group, an aralkyloxy group, a phenoxy group, an alk-oxycarbonyl group, aralkyloxycarbonyl group, an alkanoyloxy group, a benzoyl group, a carboxyl group, a hydroxy group, a group of the formula:
(wherein X1 and X2 are hydrogen atom or a lower alkyl group), an aralkyloxycarbonylamino group, a lower alkoxy-carbonylamino group, a carboxyamino group or a carbamoyl group, when produced by the process of claim 2 or by its obvious chemical equivalents.

30. A compound of formula I, wherein R is a cinnamoyl group which may be substituted at a .alpha. position or phenyl ring with an alkyl group, an alkoxy group, an aryl group, a nitro group, a methylenedioxy group, a formyl group, a halogeno-alkyl group, a halogen atom, a hydroxy group, a carboxyl group, an amino group or a cyano group, when pro-duced by the process of claim 3 or by its obvious chemical equivalents.

31. A compound of formula I, wherein R is a benzoyl group substituted with from two to five of the same or different substituents selected from the group consisting of alkyl groups, alkoxy groups, aralkyloxy groups, nitro group, halogen atoms, hydroxy group, alkanoyloxy groups, formyl group, carboxyl group, alkylthio groups, alkylsul-fonyl groups, groups of the formula:
(wherein X1 and X2 are a halogen atom or a lower alkyl group), sulfo group and sulfamoyl group, when produced by the process of claim 4 or by its obvious chemical equivalents.

32. A compound of formula I, wherein R is p-benzyloxy-benzoyl, when produced by the process of claim 5 or by its obvious chemical equivalents.

33. A compound of formula I, wherein R is m-trifluoro-methylbenzoyl, when produced by the process of claim 6 or by its obvious chemical equivalents.

34. A compound of formula I, wherein R is p-N-benzyl-oxycarbonylaminobenzoyl, when produced by the process of claim 7 or by its obvious chemical equivalents.

35. A compound of formula I, wherein R is 4-biphenyl-ylcarbonyl, when produced by the process of claim 8 or by its obvious chemical equivalents.

36. A compound of formula I, wherein R is o-acetyl-salicyloyl, when produced by the process of claim 9 or by its obvious chemical equivalents.

37. A compound of formula I, wherein R is o-benzyl-oxycarbonylbenzoyl, when produced by the process of claim 10 or by its obvious chemical equivalents.

38. A compound of formula I, wherein R is p-methoxy-carbonylbenzoyl, when produced by the process of claim 11 or by its obvious chemical equivalents.

39. A compound of formula I, wherein R is cinnamoyl, when produced by the process of claim 12 or by its obvious chemical equivalents.

40. A compound of formula I, wherein R is p-methyl-cinnamoyl, when produced by the process of claim 13 or by its obvious chemical equivalents.

41. A compound of formula I, wherein R is p-chloro-cinnamoyl, when produced by the process of claim 14 or by its obvious chemical equivalents.

42. A compound of formula I, wherein R is 3,4-methy-lenedioxycinnamoyl, when produced by the process of claim 15 or by its obvious chemical equivalents.

43. A compound of formula I, wherein R is p-methoxy-cinnamoyl, when produced by the process of claim 16 or by its obvious chemical equivalents.

44. A compound of formula I, wherein R is p-formyl-cinnamoyl, when produced by the process of claim 17 or by its obvious chemical equivalents.

45. A compound of formula I, wherein R is m-trifluoro-methylcinnamoyl, when produced by the process of claim 18 or by its obvious chemical equivalents.

46. A compound of formula I, wherein R is m -nitro-cinnamoyl, when produced by the process of claim 19 or by its obvious chemical equivalents.

47. A compound of formula I, wherein R is a-phenyl-cinnamoyl, when produced by the process of claim 20 or by its obvious chemical equivalents.

48. A compound of formula I, wherein R is 2,6-dimethyl-benzoyl, when produced by the process of claim 21 or by its obvious chemical equivalents.

49. A compound of formula I, wherein R is 3,4-dimeth-oxybenzoyl, when produced by the process of claim 22 or by its obvious chemical equivalents.

50. A compound of formula I, wherein R is 2,4,6-tri-methoxybenzoyl, when produced by the process of claim 23 or by its obvious chemical equivalents.

51. A compound of formula I, wherein R is 3,4-bis-benzyloxybenzoyl, when produced by the process of claim 24 or by its obvious chemical equivalents.

52. A compound of formula I, wherein R is 3,4-dihydro-xybenzoyl, when produced by the process of claim 25 or by its obvious chemical equivalents.

53. A compound of formula I, wherein R is 3,5-dinitro-benzoyl, when produced by the process of claim 26 or by its obvious chemical equivalents.

54. A compound of formula I, wherein R is 3-methoxy-4-methylbenzoyl, when produced by the process of claim 27 or by its obvious chemical equivalents.