DE2309087A1 - AMIDOIMIDAZOLE, THE PROCESS FOR THEIR MANUFACTURING AND MEDICINAL PREPARATIONS CONTAINING THESE COMPOUNDS - Google Patents

Description

"Amidoimidazoles, processes for their preparation and these compounds containing medicinal products "

Priority: 2h. February 1972 - Great Britain - Kr. 8604/72

The invention relates to amidoimidazoles with anti-inflammatory ' Activity.

In Belgian patent specification No. 777 7 ^ 8, imidazoles are the general formula (I) and its salts described,

KH ₂ CO ..

NII-A,

R NII

(D

in the A. an optionally substituted hydrocarbon radical, Ap is hydrogen or acyl. These connections have anti-inflammatory activity.

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Up to now it was assumed that the structural similarity of the compounds of the general formula (I) with intermediates of adenosine biosynthesis is essential for their activity. For this reason, the ^J l-CarboxF.iriido group was not modified, since this would have led to structural deviations in relation to the naturally precorrecting adenosine precursors and thus to a decrease in activity.

It has now been found that with certain changes in the carboxainido group of the compounds of formula (I) the activity
preserved.

The invention thus relates to amidoimidazoles of the general formula (II) and their salts,

R ₄ R N. CO. NH-Rp

^H l

in the R. an optionally substituted aromatic group,

R _{0 is} a hydrogen atom or a lower acyl radical, R, a

-rest ■ '

Hydrogen atom or a hydrocarbon with 1 to 7 "carbon atoms and R _2. Represents a hydrocarbon radical with 1 to 7 carbon atoms.

Suitable lower acyl groups are the acetyl, propionyl,
Butyroyl and Benzoy! Groups.

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Suitable for R. are phenyl, naphthyl, halophenyl, lower alkylphenyl, hydroxyphenyl, lower acyloxyphenyl, lower alkoxyphenyl and trifluoromethylphenyl groups.

Fhenyl and halogen phenyl groups are particularly suitable for R. The phenyl and p-fluorophenyl groups are preferred for R.

The hydrogen atom and the acetyl, propionyl, Butyroyl, benzoyl and chloroacetyl groups.

The acetyl group is preferred for Rp.

For R-, the hydrogen atom and the methyl, ethyl, Hexyl, benzyl and phenyl groups.

/ R-, the hydrogen atom and the methyl group are preferred.

For E ₁ , the methyl, ethyl, benzyl and phenyl groups are suitable, for R ^ the methyl and phenyl groups are preferred.

Amidoimidazoles according to the invention of the general formula (III ) _f

R ₁₁ HN-CO - ^ ^ NHCOCH,

(in)

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in the R. a phenyl or a p-fluorophenyl group and Rj. a Methyl or phenyl are particularly effective.

The amidoinidazoles of the general formula (II) according to the invention, in which R _{p is} a hydrogen atom, conventionally form acid addition salts with organic or inorganic acids. Examples of such salts are hydrochlorides, phosphates, sulfates, acetates, citrates and methanesulfonate.

The invention also relates to a process for the preparation of the amidoimidazoles of the general formula (II), which is characterized is that an imino compound of the general formula (IV),

R ₁ (R ₆ Y) C = MI (IV)

in which Y is an oxygen or sulfur atom, R, - optionally substituted hydrocarbon radical with 1 to 7 carbon atoms and R, as defined in formula (II), with a compound of the general formula (V),

(V)

in which R., and R ^ are defined as in formula (II).

Preferred for RgY are methoxy, ethoxy, methylthio and benzyl thio group. The benzylthio group is particularly preferred.

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The reaction is preferably carried out in an organic solvent, such as an alkanol, e.g. methanol or ethanol. Other suitable solvents are chlorinated hydrocarbons, Ether, aromatic KohienwaaserstofTe and other conventional inert solution rrii ttüi.

The reaction can be carried out at any non-extreme temperature; Room or slightly higher temperatures, 7. .D. 12 to 8O C are preferred.

Compounds of the general formula (II) according to the invention in which Rp is a lower acyl radical can be prepared from the corresponding compounds of the formula (II) in which R _{0 is} a hydrogen atom by reaction with a lower organic carboxylic acid or its acylating derivative. An acid halide, such as the acid chloride or acid bromide, the acid anhydride or mixed anhydride, a reactive intermediate product of the acid and a carbodiimide, an acyl azide or any other conventional derivative which reacts with an amine to form an amide is suitable as the acylating derivative .

This reaction is carried out under the conventional acylation conditions of an aromatic amine.

The invention also relates to medicinal preparations which are characterized by a content of a compound of the general formula (II) as an active ingredient in combination with pharmacologically acceptable carriers and / or diluents.

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The medicinal preparations can be administered orally or parenterally v / ground and in the form of single doses that are 10 to 1000 rng at one Compound of the general formula (II) contain, are present. Irn in general, the medicinal preparations according to the invention are orally ver and contain 50 to 800 ng, preferably 100 to 500 r; .. ^ Active ingredient. These single doses are given 1 to 12 times a day, to maintain a normal daily level of 200 to 2000 mg in a 70 kg patient.

The examples illustrate the invention.

example 1

5- ^Amino-j l- ( N-methylcarboxyido) -2-phynylimidazole hydrochloride

5 * 5 S aminocyano-N-methylacetamide and 13 g of phenylformaminobenzylthioether hydrochloride are refluxed in 50 ml of ethanol for 10 minutes. The resulting solid is filtered off and recrystallized from ethanol. This gives 5 g of 5-A "nino-4- (N-methylcarboxamido) -2-phenylimidazole hydrochloride, mp. 272 ⁰ C (with decomposition).

Example2

5-Amino-2-p-fluorophenyl-4- (N-methylcarboxamido ^ imidazole hydrochloride

5 * 5 g aminocyano-N-methylacetarnide and 14 g p-fluorophenylformatr.ino benzyl thioether hydrochloride are refluxed in 50 ml of ethanol for 20 minutes. The solution is poured into water and

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- Y _

ditched. The resulting solid is crystallized from ethanol and the like; J> g of 5-amino-2-p-fluorophenyl-4- (N-methyl carboxamido) imidazole hydrochloride, melting point 265 ° to 20 ° C., are obtained.

Examples J to 8

According to example 1, the following connections are made:

5-Amino-4- (N-methylcarboxamido) -2-p-nitrophenyliiiidazole hydrochloride j Mp 250 ° C. .

5-Amino-2- (p-chlorophenyl) -4- (N-methylcarboxar'co) -imidazole hydrochloride j Mp. 140 ° C. (with decomposition).

5-amino-4- (N-methylcarboxamido) -2- (m-methylphenyl) imidazole hydrochloride; M.p. 278 ^° C.

5-amino ■ ^{^} ^ -carboxaniljdo-2-phenylimidazole hydrochloride; M.p. 16I C.

5-amino-4-carboxanilido-2- (p-fluorophenyl) iir.idazole hydrochloride; Mp 250 ° C.

5-Aniino-4- (N-ethylcarboxamido) -2-phenyliiT.idazole-hydrochloridj Mp. 117 ° C (with decomposition).

Example 9

5-acetamido- ^J ^ -carboxanilido-2-p-fluorophenylimidazole

2 g of S-amino - ^ - carboxanilido ^ -p-fluorophenylimidazole hydrochloride are dissolved in k ml of pyridine and treated with 2 ml of acetic anhydride. To make it easier to dissolve, the mixture is heated,

in
for 10 minutes allowed to stand and poured ^v 10 ml of water.

The resulting solid is recrystallized from isopropanol,

900 mg of 5-acetamine-4-carboxanilido-2 ~ p-fluorophenyl-

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imidazole m.p.

Examples 10 to

According to example 9, the following compounds are produced:

2- (p-fluorophenyl) - ^ - S-carboxanilido-propionamidoimidazol, Fp..14O ⁰ C, V

- ^ - (N-methylcarboxamido) -2-phenylimidazole,

Mp. 150 ° C., 5-acetamido-4- (N-methylcarboxarnido) -2- (rn-methylphenyl) imidazole, Mp. 204 ° C, 5-acetamido-2- (p-fluorophenyl) -4- (N-methylcarboxarriido) imidazole, Mp. 182 to 184 ° C, 4- (N-methylcarboxamido) -2- (m-methylphenyl) -5-propionaniidoimidazole, Mp. 104 ° C, 2- (p-fluorophenyl) -4- (N-methylcarboxamido) -5-propionamidoimida- _ zol, m.p. 172 ° C, 4- (N-methylcarboxamido) -2-phenyl-5-propionamidoimidazole, Mp. 186 ° C, 5-acetarnido-4- (N-ethylcarboxamido) -2-phenylimidazole, Mp. 166 to 167 ° C, 5-acetamido-4- (N-methylcarboxamido) -2- (p-chlorophenyl) ~ imidazole, Mp. 164 ° C, 5-propionamido-4- (N-ethylcarboxamido) -2-phenylimidazole, Mp. 167 to 168 ° C, 5-chloroacetamido-4- (N-methylcarboxamido) -2-phenylimidazole, Mp. ° 5-Trichloroacetamido-4- (N-methylcarboxamido) -2-phenylimldazole,

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Pp. 212 ° C,

_5 - ^ - ohlorpropionamido) -2-phenylimi dazol, Pp. 202 to 203 ° C,

4-carboxanilido-5-chloracetamido-2-phenylimida; iol,
Pp. 187 ^O C.

Pharmacological experiments

In the mouse ear test according to Brown (cf. Nature 202, 1964, pp. 812-813) the following compounds of the invention were anti-inflammatory. At the doses given in the table, they reduced inflammation by 20 percent or more.

Tabel
Compounds of formula II dose

RTj / n TjN T)

Λ JVq \ l \ -z-n J rlji

PPC ₆ H _{4 H} ^CH 2 ^C 6 ^H 5 ¹⁶ °

y 6 4 η CH ₅ 45

C ₆ H ₅ HC ₆ H ₅ . 150

C ₆ H ₅ H CH ₅ 200

C ₆ H ₅ HC ₂ H ₅ 160

m-CH, -CrHi, C0.C _o H _c CH, 160

I ₅ -C ₆ H ₄ CO. C ₂ H ₅ CH ₅

-C ₆ H ₄ co.CH ₅ CH ₅ 160

P-NO ₉ C ₆ H ₄ CO.CH ₅ CH, 75

PFC ₆ H ₄ CO. C ₂ H ₅ CH ₅ 300

PPC ₆ H ₄ CO.CH ₅ CH ₅ 150

C ₆ H ₅ co.CH ₅ CH ₅ 150

C ₆ H ₅ CO.CH ₅ C ₂ H ₅ 300

P-Ci-C ₆ H ₄ co.CH ₅ CH ₅ 160

C ₆ H ₅ . CO. C ₂ Hc. C ₉ Hc 160

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Claims (12)

Claims amidoimidazoles of the general formula (II) and their salts, in the R .. an optionally substituted aromatic group, Rp a V / water atom or a lower acyl radical, R ^. represents a hydrogen atom or a hydrocarbon radical having 1 to 7 carbon atoms and R _{4 represents} a carbon radical having 1 to 7 carbon atoms. 2. Amidoimidazoles according to claim I, characterized in that Rp and R- are each a hydrogen atom. J5. Amidoimidazoles according to Claim 1, characterized in that "R _{2 is} a lower acyl radical and R ^ is a hydrogen atom. 4. amidoimidazoles according to claim 1 and 3, characterized in that that Rp is an acetyl group. 5. amidoimidazoles according to claim 1 to 4, characterized in that R ^ is a methyl, ethyl, phenyl or benzyl group. 309835/1185 original inspected ■ - Ii - 6. Amidoimidazoles according to claim 1 to 5 * characterized © indicates that R _{1 is} a phenyl, halophenyl, nitrophenyl or methylphenyl group. 7. amidoimidazoles according to claim 1 to 6, characterized in that R. is a p-fluorophenyl group. 8. Process for the preparation of the amidoimidazoles according to Claim 1 and 2, characterized in that one is an imino compound the general formula R ₁ (R ₆ Y) C = NH (IV) in which Y is an oxygen or sulfur atom, R / - optionally substituted hydrocarbon radical having 1 to 7 carbon atoms and R. is defined according to claim 1, with a compound of the general formula (V) R ₅ R ₁ ^ N. CO. CH (CN) NH ₂ (V) in which R- and R ^ are defined according to claim 1. 9. The method according to claim 8, characterized in that a compound of formula (IV) is used in which the radical R ^ Y is a benzylthio group. 10. A process for the preparation of the amidoimidazoles according to claim 1 and 3 # characterized in that a compound of the general formula (II) in der.R _{2 is} a hydrogen atom with 309835/1185 a lower organic carboxylic acid or its acylating derivative implements. 11. The method according to claim 10, characterized in that • the acylating acid derivative is acetic anhydride, acetylochloride or Acetylbroraid used. 12. Medicinal preparations, characterized by a content of a compound according to claim 1 as an active ingredient in combination with pharmacological compatible carriers and / or diluents. 309835/1185