FI61879C - ANALOGIFICATE FARMS FOR FRAMSTAELLNING AV NYA THERAPEUTIC EFFECTIVE AMINOPYRROLDERIVAT - Google Patents

Description

Ι -. ^ "· Π Γβ1 .... AD PUBLICATIONS slants

Vttg ^ <11> UTLÄGGNINGSSKRIFT 61879 c <4S> Patent granted 11 10 1902 itfiätSfJ Patent mcddelat v T ^ (51) Kv.ii ^ / Int.ci.3 C O? D 207/34 FINLAND - FINLAND (21) P »t« nttlhik # mu «- P» tenun * «knlng 2162/71 (22) Htkimlsptlvl - Antöknlngtdag 21.08.7l (Fiy (23) Alkuptlvl— Glltlgh« t * dag 21.08 .7l (41) Has become public - Bllvlt offentlig 23-02.75

National Board of Patents and Registration Nlhtivlk.lp «on j. month »no» date. - 06 82

Patent and registration authorities Aniökin utlagd och utl.skriften publlcerid 3 (32) (33) (31) Requested privilege —Begird priorltet 22.08.7 3

English-England (GB) 39790/73 (71) Gruppo Lepetit SpA, Via Durando, 38, 20158 Milan, Italian-Italian (lT) (72) Giorgio Tarzia, Roma, Gianbattista Panzone, Cornaredo (Milan), Italian-Italian ( The present invention relates to a process for the preparation of novel aminopyrrole derivatives having the general formula.

H2Nx__S K

U)

Rl x n

R

and salts thereof with pharmaceutically acceptable acids, wherein R is hydrogen, (C 1-4) alkyl, benzyl or halogen-substituted benzyl, is hydrogen, (C 1-4) alkyl, phenyl or substituted phenyl, is (C 2-4) aliphatic acyl, benzoyl, substituted benzoyl, (C 1-4) alkoxycarbonyl, carboxy, carbamyl or methylcarbamyl, R 1 is hydrogen, (C 1-4) alkyl, (C 1-4) alkoxycarbonyl, R (C 1-4) alkoxycarbonyl [methyl, trifluoromethyl , carboxy, carbamyl or carbazoyl.

In the specification and claims, the term "(C 1-6) alkyl" means an alkyl radical having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl; "halogen-substituted benzyl" means a benzyl radical substituted on the aromatic ring mainly by fluorine, chlorine or bromine, such as, for example, p-chlorobenzyl, o-chlorobenzyl, p-fluorobenzyl, o-bromobenzyl and m-bromobenzyl; "substituted phenyl" means phenyl radicals substituted with 1 to 3 groups independently selected from () alkyl, () alkoxy, benzyloxy, fluoro, chloro and hydroxy; "(C 2-4) aliphatic acyl" means an aliphatic acyl radical having 2 to 4 carbon atoms, such as acetyl, propionyl, butyryl and isobutyryl ·, "(C 1-4) alkoxy" means alkoxy groups having 1 to 4 carbon atoms, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy and "substituted benzoyl" means a benzoyl radical having 1 to 3 substituents independently of one another chlorine and (C 1-4) alkoxy.

A preferred group of compounds of formula I are those compounds wherein R is hydrogen, methyl, benzyl or chlorine substituted benzyl, R 1 represents hydrogen, phenyl, phenyl substituted by methyl, nitroxy, fluorine or chlorine, is acetyl, propionyl, butyryl, isobutyryl, methoxycarbyl , ethoxycarbonyl, carboxy, carbamyl or benzoyl, Rj. is hydrogen, methyl, methoxycarbonyl, carbamyl or carboxy, and salts thereof with pharmaceutically acceptable acids.

A process for the preparation of the compounds of the invention comprises the preparation of o (-aminonitrile of the general formula

CN

i

CH ^ II

R 1 NH 2 or an acid addition salt thereof, in which the formula has the same meaning as above, is reacted with a compound represented by the general formula 1 wherein R 1 and R 1. have the same meaning as above and X represents a group -C = C- or a group -CH2-C- in which the -CH2 moiety is attached to the substituent 0 * 5 3 61879

R ^ _. It will be apparent to those skilled in the art that compounds having similar chemical properties to dicarbonyl compounds or acetylene carbonyl compounds may be advantageously used as, for example, compounds of formula III wherein X is I

-CH = C-hal, where shark represents a halogen atom, preferably chlorine, and the carbon atom containing the halogen atom is attached to the radical.

The aminonitriles used as starting materials are prepared mainly using the method described by Steiger in Organic Synthesis 22, 13, 19 * + 2 and 22, 23, 19 ^ 2.

The compounds of formula III are either commercially available products or can be prepared from commercially available products with obvious modifications.

The reaction generally proceeds to form, as an intermediate, an open-chain compound of the following general formula IV or its tautomeric imine form CN R 2 /

V \ J ^ r5 IV

Nir

R

which, if desired, can be isolated, purified and characterized according to standard analytical methods before being cyclized to the final compounds of formula I. However, it can also be used as a raw material in the next cyclization step without affecting the final yields.

Reagents II and III are contacted using substantially equimolar amounts in the presence of an anhydrous organic solvent, which is preferably benzene, dioxane, tetrahydrofuran, lower alkanol or the like. A small amount of p-toluenesulfonic acid can be added as a catalyst and the mixture is refluxed for 2-28 hours. The intermediate compound of formula IV may, if desired, be isolated and characterized or used as such in the next cyclization step carried out in the presence of basic catalysts such as carbonates, hydroxides, alkoxides, hydrides or amides of Group I and Group II metals. Also in this case, the reaction is carried out in the presence of a solvent, 1,61879, which is preferably an anhydrous lower alkanol having up to if carbon atoms. The cyclization can take place at room temperature, but in some cases it is necessary to heat or reflux the reaction mixture to accelerate the cyclization reaction, which is completed in 1 to 30 hours.

In some cases, it has been found that when X represents -C = C-, the formation of aminopyrrole derivatives of formula I can take place in one reaction step. In this case, an aminonitrile of formula II or an acid addition salt thereof and a compound of formula III wherein X is -C = C- mainly in equimolar amounts in the presence of an organic solvent such as anhydrous (C 1-4) alkanol, chloroform, tetrahydrofuran, benzene and the like using an alkali or alkaline earth metal carbonate or hydroxide as a catalyst and then boiling the resulting reaction mixture under reflux for about 3 hours. -5 hours.

The final products of formula I are collected from the reaction mixture as free bases or in the form of salts with pharmaceutically acceptable acids using methods fully known to those skilled in the art.

These methods include removing the solvent from the reaction mixture by evaporation, dissolving the residue in the solvent, re-evaporating the solvent, and purifying the resulting solid, liquid, or oily substance by recrystallization, fractional distillation, or distillation under reduced pressure. If a crystalline solid forms directly in the reaction, this is simply isolated by filtration and, if necessary, purified by recrystallization. The recrystallization solvents are preferably C 1 -C 4 lower alkanols, diethyl ether or mixtures thereof.

The aforementioned salts of the compounds of formula I with pharmaceutically acceptable acids are generally hydrochlorides, hydrobromides, hydroiodides, sulphates, phosphates, benzoates, oxalates, acetates, methanesulphonates, cyclohexyl sulphonates and the like and are therefore part of the invention. They are readily prepared by treating a compound of formula I in free base form with a specified pharmaceutically acceptable acid. Conversely, it is possible to liberate the free base from the corresponding acid salt by reaction with at least one equimolar amount of a basic substance.

5,61879

According to the above-mentioned methods, compounds of the formula I in which R is a hydrogen atom or their acid addition salts are obtained.

A suitable method of attaching the desired substituents of formula I to a ring nitrogen atom of a pyrrole ring comprises reacting a predetermined compound of formula I wherein R is hydrogen with a selected (C 1-6) alkyl, benzyl or halogen-substituted benzyl halide with a strong basic substance. , preferably in the presence of an alkali metal or alkali metal hydride in an inert organic solvent such as dimethylformamide under a nitrogen atmosphere. The reaction is carried out at room temperature. The desired aminopyrrole substituted at position 1 is then isolated in good yield from the reaction mixture. It will be appreciated that in the compound of formula I obtained under these reaction conditions, the amino group in the 3-position may also be substituted, for example by one or two) alkyl groups. Thus, the amino group at the 3-position must be protected, e.g., by reaction with a carbonyl compound or an alkylsulfonyl or benzenesulfonyl halide to produce the corresponding Schiff's base or alkylsulfonyl, respectively, benzenesulfonylamino derivatives. Substitution is then performed at the 1-position as mentioned above and acid hydrolytic cleavage of the protecting group affords the desired compounds having an amino group at the 3-position.

The radicals R 1 and R 2 can also be converted, according to known chemical reactions, into other groups which fall within the general definition of said substituents. For example, when a compound of formula I is desired, wherein either R 1 or R 2. or both represent a carboxy group, the desired compound is obtained by hydrolysis under temporal or acidic conditions of the corresponding mono- or di () alkoxycarbonyl derivative.

Compounds of formula I in which either R 1 or R 2 or both represent carbamyl groups are obtained by impregnation with ammonia of an alcoholic solution of the corresponding mono- or di-C 1-4 alkoxycarbonyl compound, while compounds in which carbazoyl is prepared are prepared by reacting compounds of formula I, wherein R 1 is (C 1-6 alkoxycarbonyl, in contact with hydrazine at room temperature. Other obvious methods useful for attaching suitable substituents at the desired positions or converting an already present radical to another radical of the definition are within the scope of the invention.

The compounds of the invention have very interesting pharmacological properties; more specifically, they have significant anti-inflammatory and CNS depressant properties.

Anti-inflammatory activity was determined in the rat by examining carrageenan-induced edema, which was performed in C.A. According to the methodology presented by Winter et al., Cf. Proc. Soc. Exptl.Biol.Med., 111. 5 * + ^, 1962. In typical experiments, Examples 1, 2, 3, 6, 13, 1> +, 15, 17, 19, 20, 22, 26, 33, * + The compounds of 6, 2a, k2b provide a percentage reduction in induced edema of from about 0% to about 80% at doses ranging from 1/50 to 1/5 of the LD50 values. Under the same experimental conditions, a much-used anti-inflammatory agent such as phenylbutazone (t-butyl-1,2-diphenyl-pyrazolidine-3,5-dione) had a reduction in induced edema of about 5%, but only at doses greater than 1 / b of the LD ^ Q value. It should also be noted that the toxicity of the aminopyrrole derivatives of this invention is very low; in fact, with some exceptions, their LD50 values are always greater than about 1000 mg / kg p.o. in mice, while the corresponding LD50 of phenylbutazone is about 390 mg / kg p.o. Toxicity was determined in Lichtfield and Wilcoxon, J. Pharm. Exp. Ther., £ 6, 99, 19 * + 9.

The following table shows the above anti-inflammatory effect in more detail.

Table

Compound LD ^ 0 mg / kg dose mg / kg Example 5% of induced edema p.o. mouse p.o. rat thinning 2> 1000 100 36.5 200 M +, 3 61 879 7

Compound LD <o m & / kg dose mg / kg Example of induced edema percentage of population p.o. mouse p.o. rat thinning 1> 1000 5 23.1+ 10 32.5 20 39.0 50 ^ 3.8 100 58.9 200 76.6 3> 1000 100 * + 0.6 200 53.9 13> 1000 5 23, 2 10 31.9 20 If3.5 50 50.7 100 69.6 200 75, ^ ib> 1000 5 23.0 10 31.1 20 35.1 50 * + 1.9 loo 55Λ 200 67.6 15> 1000 50 29.6 100 1 + 0.8 200 58.3 17> 1000 loo 35.1+ 200 1 + 7.9 19 500 50 21 +, 3 100 1 + 5.9 20> 1000 50 21 +, 2 loo 37.3 200 1 + 1 +, 9 26> 1000 20 29.2 50 1 + 3.1 loo 58.5 200 71.0 1 + 6> 1000 50 27.1 100 1 + 1.1 + 200 56 , 3 8 61 879

Compound LD ^ q mg / kg dose mg / kg Example of induced edema% p.o. mouse p.o. rat thinning k2 a)> 1000 100 31.0 200 53.1 M-2 b)> 1000 50 11.0

100 3M

200 52.7 phenylbutazone 390 50 33 100 M-5

The compounds of the invention also have other biological properties which are very advantageous in effective anti-inflammatory agents. In fact, they have considerable antipyretic and analgesic activity, which is 2, 10 times, respectively, about M times more potent than acetylsalicylic acid. In addition, the compounds according to the invention have a very low exogenous activity, which is about 5 to 10 times lower than that observed with other known and therapeutically used anti-inflammatory agents, such as, for example, acetylsalicylic acid and phenylbutazone. Analgesic, activity was determined at L.0. Randall and J.J. According to the explanation, Arch. Int. Pharmacodyn., No. * f, CXI, p. ^ 09, 1957 ·

Antipyretic activity was studied by R.H. According to Buller et al., J. Pharm. Pharmacol., £, 128, 1957, while exogenous activity was determined according to Thuilliet et al., Chim. Therap., I, 53, 1968.

As mentioned above, the aminopyrrole derivatives of the present invention are also active in the central nervous system; this property was studied according to the general method described by S. Irwin in Psychopharmacologia (Berl.), li, 222, 1968. It was found that 9 61879 compounds with particularly clear anti-inflammatory properties, such as the compounds of Examples 1 and 1 ^, also had significant sedative and muscle relaxant activity; this is undoubtedly a particularly advantageous property of the compounds according to the invention, since a certain sedative and muscle-relaxing effect is advantageous in patients with severe inflammatory diseases. Some of the compounds of the invention also have very interesting meritolytic properties.

These properties were tested in a "pole climbing avoidance test" in rats, which was performed as described by G. Maffii in J. Pharm. Pharmacol., 11, 129, 1959. Typical experiments showed that the compound of Example 29 was particularly effective in inhibiting secondary conditioned response in rats (CRp) at doses that did not affect the primary conditioned response (CR) and unconditioned response (UR). It is known that secondary conditioned response is associated with an animal's pain state and its inhibition can be directly affected by the administration of analgesics.

The result is shown in the following table, which also indicates the toxicity of the test compound. It can be seen from the table that meprobamate (2-methyl-2-propyl-1,3-propanediol dicarbamate) also has significantly lower analgesic properties than the test compound.

Table

Compound LD ^ n mg / kg Dose mg / kg Inhibition

e.g., 5 CRp CR UR

kista i.p. mice i.p. mice deconditioned rats & treated rats 29,800 30 V10 0/10 0/10 60 8/10 0/10 0/10 meprobamate 500 30 3/10 0/10 0/10 60 6/10 2/10 0/10

Although the compounds are preferably administered orally and rectally, parenteral administration may also be used. For oral administration, the compounds are formulated into pharmaceutical dosage forms such as tablets, capsules, elixirs, solutions, and the like. The dosage unit may contain conventional carriers, e.g. starch, gum, fatty acids, alcohols, sugar, etc. For rectal administration, the compounds are administered in the form of suppositories, mixed with conventional carriers such as cocoa butter, wax, whale fat or polyoxyethylene glycols and derivatives thereof. The dose range is from about 0.05 to about 2.00 g / day, and is preferably administered in divided doses.

This invention also relates to a therapeutic composition comprising a compound of the invention as an active ingredient in association with a pharmaceutically acceptable carrier.

The following examples further illustrate the invention, method and method for carrying it out and using it.

Example 1 1+ -Acetyl-3-amino-5-methyl-2-phenyl-pyrrole hydrochloride a) A solution of 2 g (0.015 mol) of 2-amino-2-phenylacetonitrile and 1.3 * g ( 0.01 * + moles) of acetylacetone in 30 ml of anhydrous benzene, refluxed for two hours in an oil bath using 100 mg of p-toluenesulfonic acid. After cooling, the reaction mixture is filtered, then the solvent is evaporated off to form an oily residue which is distilled under reduced pressure. The intermediate open-chain compound boils at 150 ° C / 0.1 mmHg.

b) Dissolve 0-0.0 g of sodium in 15 ml of anhydrous ethanol, then add dropwise a solution of 2.5 g of the compound prepared in a) in anhydrous ethanol and allow the mixture to stand at room temperature for four hours. Dry hydrogen chloride is bubbled into the ethanol solution to form a precipitate which is isolated by filtration and recrystallized from ethanol / diethyl ether. Yield 2.0 g of the title product. Mp 2 * + 2 ° 0 (dispersed). The free base is obtained by extraction with ethyl acetate of an aqueous hydrochloride solution made alkaline with 5% sodium hydroxide. Mp 220 ° C (from methanol).

3-Amino-1-ethoxycarbonyl-5'-ethyl-2-phenyl-pyrride hydrochloride a) A solution of 6 g (0.02 mol) of 2-amino-2-phenyl-acetonitrile and 5 g (0.0 * + 2 moles) of ethyl acetoacetate in 30 ml of 61879 benzene-free benzene, refluxed for four hours in an oil bath using 100 mg of p-toluenesulfonic acid. After cooling, the reaction mixture is filtered, then the solvent is evaporated off to give an oily residue which is distilled under reduced pressure. The k.p. of the intermediate of the open-chain compound obtained is 140 ° C / 0.05 mmHg.

b) 0.80 g of sodium is dissolved in 15 ml of anhydrous ethanol, then a solution of 5 g of the above compound in 35 ml of anhydrous ethanol is added dropwise and the mixture is allowed to stand at room temperature for four hours. Dry hydrogen chloride is bubbled into the ethanol solution to form a precipitate which is filtered and recrystallized from a mixture of ethanol and diethyl ether; yield 4 g, m.p. 249-252 ° C (from ethanol / ethyl ether).

Examples 3 - UI

The following compounds are prepared according to the two-step process described in Example 1, starting from the appropriate compounds of formulas II and III and using alkali metal alkoxides or carbonates as basic cyclization catalysts. If the open-chain compounds obtained as intermediates are isolated and their chemical-physical properties are given, otherwise these intermediates are cyclized directly to the final products.

3 3-Amino-4-benzoyl-5-methyl-2-phenyl-pyrrole hydrochloride Starting from 2-amino-2-phenyl-acetonitrile and benzoyl-acetone, the intermediate is obtained as an intermediate, melting at 134-135 ° C (diethyl ether). / hexane). The title compound is obtained in a total yield of 60%. Mp 285-290 ° C (from methanol / diethyl ether). The free base melts at 203-205 ° C (from methanol).

4 3-Amino-4-benzoyl-2-phenyl-pyrrole hydrochloride An open-chain intermediate melting at 88-90 ° C (from hexane) is prepared from 2-amino-2-phenyl-acetonitrile and benzoyl-acetaldehyde. The title compound is obtained in a total yield of 47%. Mp 272-274 ° C (from ethanol).

4-Acetyl-3-amino-2-ethyl-5-methyl-pyrrole hydrochloride Starting from 2-amino-butyronitrile and acetylacetone, an open-chain intermediate boiling at 100 ° C / 0.02 mmHg is obtained. The title compound is obtained in a total yield of b9%. Sulp. 2-5 + 8 ° C (from ethanol / diethyl ether). The free base melts at 219-221 ° C (from methanol).

6 3-Amino-ethoxycarbonyl-2-phenyl-pyrrole hydrochloride

The title compound is obtained in a total yield of bS% from 2-amino-2-phenylacetonitrile and ethyl propionate. Mp 2U-h -2 ** 5 ° C (from ethanol / diethyl ether).

7 3-Amino-1 * -benzoyl-5-ethoxycarbonyl-2-phenyl-pyrrolo-hydrochloride

The title compound is obtained in a total yield of b8% from 2-amino-2-phenyl-acetonitrile and benzoyl-pyruvic acid ethyl ester. Mp 218-219 ° C (from ethanol / diethyl ether).

3-Acetyl-3-amino-2-phenyl-pyrrole hydrochloride Starting from 2-amino-2-phenyl-acetonitrile and acetylacetaldehyde, an open-chain intermediate is obtained which boils at 1 + + 0 ° C / 0.05 mmHg. The title compound is obtained in a total yield of 56- $. It does not melt up to 335 ° C.

9 * -acetyl-3-amino-2- (p-methoxyphenyl) pyrrole Starting from 2-amino-2- (p-methoxyphenyl) -acetonitrile and acetylacetaldehyde, an open-chain intermediate boiling at 180 ° C is prepared, 03 mmHg. The total yield of the title compound is M *%. Mp 198-200 ° C (from diethyl ether).

3-Amino-1-benzoyl-5-methyl-pyrrole hydrochloride Starting from aminoacetonitrile and benzoylacetone, an open-chain intermediate is prepared which melts at 111-112 ° O (from diethyl ether). The total yield of the title compound is 52%. Mp 225-270 ° C (from ethanol / diethyl ether).

11 1+ -acetyl-3-amino-5-methyl-pyrrole hydrochloride Starting from aminoacetonitrile and acetylacetone, an open-chain intermediate is obtained which melts at 106-108 ° C (from diethyl ether). The title compound is obtained in a total yield of 6k%. Mp 211-212 ° C (from ethanol).

12 3-Amino-1 + -ethoxycarbonyl-5-ethoxycarbonylmethyl-2-phenyl-pyrrole hydrochloride

The title compound is obtained in total yield of β-2-2 from 2-amino-2-phenylacetonitrile and 1,3-dicarbethoxyacetone. Sul. mp 232-2360 ° C (from diethyl ether / ethanol).

13β-Acetyl-3-amino-5-methyl-2- (p-tolyl) pyrrole The title compound is obtained in a total yield of 9b% from 13-61,879 2-amino-2- (p-tolyl) acetonitrile and acetyl acetone. Mp

232-23 ° C (from ethanol / diethyl ether).

lk 1 + -acetyl-3-amino-2- (p-methoxyphenyl) -5-diethylpyrrole

The title compound is prepared in a total yield of 92- $ from 2-amino-2- (p-methoxyphenyl) acetonitrile and acetylacetone. Mp 222-223 ° C (from ethanol).

15 3-Amino-1 + -ethoxycarbonyl-5-methyl-2- (p-tolyl) -pyrrole hydrochloride Starting from 2-amino-2- (p-tolyl) -acetonitrile and ethyl acetoacetate, an open-chain intermediate boiling in the range of 16 ° C is obtained. ° C / 0.05 mmHg. Total yield of the title product: 88%. Mp

266-268 ° C (from methanol).

16 3-Amino-1 + -ethoxycarbonyl-2-phenyl-5-trifluoromethyl-pyrrole hydrochloride

The title compound is obtained in 52% overall yield from 2-amino-2-phenylacetonitrile and trifluoroacetyl ethyl acetate. Mp 203-205 ° C (from ethanol).

17β-Acetyl-3-amino-2- (p-fluorophenyl) -5-methylpyrrole Starting from 2-amino-2- (p-fluorophenyl) acetonitrile and acetylacetone, an open-chain intermediate is obtained. Bp 150 ° C / 0.3 mmHg. Total yield of the title compound: k-7%. Mp 211-212 ° C

(Ethanol).

18 S-Amino-N-ethoxycarbonyl-2- (p-fluorophenyl) -5-methylpyrrole hydrochloride

The open chain intermediate is obtained from 2-amino-2- (p-fluorophenyl) acetonitrile and ethyl acetoacetate. Bp 220 ° C / 0.2 mmHg. The title compound is obtained in a total yield of 53%. Mp

258-26 ° C (from ethanol / diethyl ether).

19 3-Amino-1H-ethoxycarbonyl-5-methyl-pyrrole hydrochloride

The open chain intermediate is obtained from aminoacetonitrile and ethyl acetoacetate. Mp 90-98 ° C (from methanol). The title compound is obtained in a total yield of k-k%. Mp 211-21 ° C (from methanol).

3-Amino-1 + -isobutyryl-5-methyl-2-phenyl-pyrrole The open-chain intermediate is obtained from 2-amino-2-phenyl-acetonitrile and 5-methyl-hexane-2,2-dione. Bp 150 ° C / 0.3 mmHg. Total yield of the title compound: 6%. Mp 180-1830 ° C (from methanol / diethyl ether).

21 3-Amino-5-methyl-2-phenylpropionyl-pyrrole 61879 Starting from 2-amino-2-phenyl-acetonitrile and hexane-2,3-dione, the open chain intermediate is obtained. Bp 160 ° C / 0.3 mmHg. The title compound is obtained in a total yield of 53- $ sn. Mp 166-168 ° C (from methanol).

22 1H-Acetyl-3-amino-5-methyl-2- (m-tolyl) pyrrole Starting from 2-amino-2- (m-tolyl) -acetonitrile and acetylacetone, an open-chain intermediate is obtained. Bp I7O0 C / 0.02 mmHg. The title compound is obtained in a total yield of 59- $. Mp

195-197 ° C (from ethanol).

23 1+ -acetyl-3-amino-2-ethyl-5-methyl-pyrrole hydrochloride The title compound is obtained in a total yield of 73- $ from 2-amino-butyronitrile and acetylacetone. Mp 2b7-2-2 ° C (from methanol).

2b 3-Amino-N- (p-methoxybenzoyl) -5-methyl-2-phenylpyrrole

The title compound is obtained in a total yield of 2% of 2-amino-2-phenylacetonitrile and (p-methoxybenzoyl) acetone. Mp 219-221 ° C (from ethanol).

25 b-Acetyl-3-amino-2- (p-benzyloxyphenyl) -5-methylpyrrole

The title compound is obtained in a total yield of 5 - # from 2-amino-2- (p-benzyloxyphenyl) acetonitrile and acetylacetone. Mp 2b5-250 ° C (from ethanol).

26 1+ -acetyl-3-amino-2- (p-chlorophenyl) -5-methylpyrrole The title compound is obtained in a total yield of 67% xn starting from 2-amino-2- (p-chlorophenyl) acetonitrile and acetylacetone . Mp 205-208 ° C (from ethanol).

27 3-Amino-1 + -ethoxycarbonyl-2- (p-methoxyphenyl) -5-methyl-pyrrole hydrochloride

The title compound is obtained in a total yield of Mf - from 2-amino-2- (p-methoxyphenyl) acetonitrile and ethyl acetoacetate. Mp 23 DEG-2360 DEG C. (from methanol).

28 3-Amino-1 + -benzoyl-2- (p-fluorophenyl) -5-methylpyrrole Starting from 2-amino-2- (p-fluorophenylD-acetonitrile and benzoylacetone, an open-chain intermediate is obtained, KP 120 ° C / 0, 2 mmHg The title compound is obtained in a total yield of 66- $ M.p., mp 209-210 ° C (from ethanol / diethyl ether).

29 * + - Acetyl-3-amino-2- (o-tolyl) -5-methyl-pyrrole Starting from 2-amino-2- (o-tolyl) -acetonitrile and acetylacetone gives the zipper intermediate. Bp 120 ° C / 0.2 mmHg. The title compound is obtained in a yield of 77%. The total yield. Mp 258 ° C 15 61 879 (from methanol).

30 3 "Amino-1 + -methoxycarbonyl-5" -ethoxycarbonylmethyl-2-phenyl-pyrrole hydrochloride

The title product is obtained in a total yield of k-8 - # starting from 2-amino-2-phenylacetonitrile and 1,3- (N-ethoxycarbonylacetone), mp 210-213 ° C (methanol).

31 3-Amino-5-methyl-N-methylcarbamyl-2-phenyl-pyrrole hydrochloride

The title compound is obtained in a total yield of 55- $ sn starting from 2-amino-2-phenylacetonitrile and o (acetyl-N-methylacetamide), mp 2 * +7-250 ° C (from ethanol).

32 3-Amino-α- (o-chlorobenzoyl) -5-methyl-2-phenylpyrrole The title product is obtained in a total yield of 5-1- $ starting from 2-amino-2-phenylacetonitrile and o-chlorobenzoylacetone. . Mp 21 DEG-216 DEG C. (from ethanol).

3 3 3-Amino-carbamyl-5-methyl-2-phenyl-pyrrole hydrochloride Starting from 2-amino-2-phenyl-acetonitrile and β-acetylacetamide, the open-chain intermediate is obtained, mp 128-130 ° C (from diethyl ether) The title compound is obtained in a total yield of b9%, mp 307-309 ° C (from methanol).

3- (3-Amino-tert-butyryl-2-phenyl-5-propyl-pyrrole hydrochloride)

The title compound is obtained in a total yield of 60- $ starting from 2-amino-2-phenylacetonitrile and nonane - * +, 6-dione. Mp 228-230 ° C with decomposition (from methanol / diethyl ether).

35 3-Amino-1-butyryl over -5-methyl-2-phenylpyrrole hydrochloride The title compound is obtained in 10% yield from 2-amino-2-phenylacetonitrile and heptane-2, dione. Mp 20 DEG-2 DEG-4-5 DEG C. with decomposition (from methanol / diethyl ether).

36 3-Amino-1 +, 5-dimethoxycarbonyl-2- (p-chlorophenyl) pyrrole hydrochloride Starting from 2-amino-2- (p-chlorophenyl) acetonitrile and dimethoxycarbonylacetylene gives the open chain intermediate. Mp 7 * + -760 ° C (from diethyl ether). The title compound is obtained in a total yield of * + 8- / 6. Mp 216-218 ° C (from methanol / diethyl ether).

37 3-Amino-1 *, 5-dimethoxycarbonyl-2- (p-tolyl) pyrrolidide Starting from 2-amino-2- (p-tolyl) acetonitrile and dimethoxyxarbonylacetylene gives the open-chain intermediate. Mp 76-77 ° C (from diethyl ether / hexane). The title compound is obtained in a total yield of 70- $. Mp 193-196 ° C (from methanol / diethyl ether).

»61879 38 3-Amino-4,5-diethoxycarbonyl-2-phenyl-pyrrole hydrochloride Starting from 2-amino-2-phenyl-acetonitrile and diethoxycarbonyl-acetylene, an open-chain intermediate is obtained. Bp 140 ° C / 0.03 mmHg. The title compound is obtained in a total yield of 78%. Mp 193-196 ° C (from ethanol / diethyl ether).

39 3-Amino-4,5-dimethoxycarbonyl-2- (p-methoxyphenyl) pyrrole hydrochloride Starting from 2-amino-2- (p-methoxyphenyl) acetonitrile and dimethoxycarbonylacetylene, an open-chain intermediate is obtained. Mp 86-88 ° C (from hexane). The title compound is obtained in a total yield of 63%. Mp 195-197 ° C (from methanol / diethyl ether).

40 3-Amino-4,5-dimethoxycarbonyl-2-ethyl-pyrrole hydrochloride The title compound is obtained in a total yield of 66% from 2-aminobutyronitrile and dimethoxycarbonylacetylene. Mp 209-210 ° C (from diethyl ether / methanol).

41 3-Amino-4,5-dimethoxycarbonyl-2-phenyl-pyrrole hydrochloride The title compound is obtained in a total yield of 39% from 2-amino-2-phenyl-acetonitrile and dimethoxycarbonylacetylene. Mp 205-207 ° C (from methanol / diethyl ether). The free base melts at 142-143 ° C (from diethyl ether).

Example 42 4-Acetyl-3-amino-1,5-dimethyl-2-phenyl-pyrrole a) Solution of 1.4 g (0.00467 mol) of 4-acetyl-3-benzylideneamino-5-methyl 2-Phenyl-pyrrole (prepared from the compound of Example 1 and benzaldehyde, m.p. 173-176 ° C (methanol)) in 25 ml of dimethylformamide is added dropwise to a cold suspension of sodium hydride in 10 ml of dimethylformamide. The resulting mixture is stirred at about 0-5 ° C for 15 minutes, then 1 ml of methyl iodide (0.0161 mol) is added. Stirring is continued for 30 minutes at about 0 ° C and for 30 minutes at room temperature, then 150 ml of water are added to the reaction mixture, which is then extracted with diethyl ether. The organic phase is separated and the solvent is evaporated off. The residue obtained (1.2 g) is recrystallized from isopropanol / water. Mp 136-138 ° C. The product is 4-acetyl-3-benzylideneamino-1,5-dimethyl-2-phenyl-pyrrole.

b) 1.0 g (0.00316 mol) of the compound prepared in a) are dissolved in 30 ml of a 10% aqueous solution of hydrogen chloride and the resulting solution is heated at 80-90 ° C for about 2 hours. Cool and neutralize with sodium hydroxide to form a precipitate which is recrystallized from ethanol / water. Yield 0.8 g of the title compound. Mp 124-126 ° C. The corresponding hydrochloride melts at 208-209 ° C (from ethanol / diethyl ether).

Example 43 4-Acetyl-3-amino-1-ethyl-5-methyl-2-phenyl-pyrrole Working as in Example 42 a) starting from 4-acetyl-3-benzylideneamino-5-methyl-2-phenyl-pyrrole and ethyl iodide 4-acetyl-3-benzylideneamino-1-ethyl-5-methyl-2-phenylpyrrole is obtained. Mp 139-141 ° C (isopropanol / water).

This compound is hydrolyzed as in Example 42 (b). Total yield of the title compound: 54%. Mp 107-108 ° C (from ethanol).

Example 44 4-Acetyl-3-amino-5-methyl-2-phenyl-1-propyl-pyrrole Starting from 4-acetyl-3-benzylideneamino-5-methyl-2-phenyl-pyrrole and propyl iodide and working as in Example 42 a), 4-acetyl-3-benzylideneamino-5-methyl-2-phenyl-1-propylpyrrole is obtained as an oily product. This compound is hydrolyzed as in Example 42 (b). Yield of the title compound: 50%. Mp 113-115 ° C (from ethanol).

Example 45 4-Acetyl-3-amino-1- (p-chlorobenzyl) -5-methyl-2-phenylpyrrole 4-Acetyl-3-benzylideneamino-1- (p-chlorobenzyl) -5-methyl- 2-Phenyl-pyrrole is prepared from 4-acetyl-3-benzylideneamino-5-methyl-2-phenyl-pyrrole and p-chlorobenzyl chloride by working as in Example 42 (a). Mp 136-137 ° C (ethanol / water). This compound is hydrolyzed as in Example 42 (b). Yield of the title compound: 58%. Mp 164-166 ° C (ethanol / water).

Example 46 3-Amino-5-carbamyl-4-methoxycarbonyl-2-phenylpyrrole A solution of 5 g (0.0161 mol) of the compound of Example 41 is saturated with gaseous ammonia and then allowed to stand for two days. The product crystallizes, which is collected by filtration. Yield 2.8 g. Mp 177-179 ° C (methanol / water).

61879 18

Example 47 3-Amino-4,5-dicarboxy-2-phenyl-pyrrole

To a solution of 15 g (0.0545 moles) of the compound of Example 41 in 200 ml of methanol is added 90 ml of a 10% aqueous solution of lithium hydroxide and refluxed for 20 minutes with stirring. The solution is then poured into water and the mixture is acidified with 10% aqueous hydrogen chloride. The title compound precipitates and is collected by filtration and recrystallized from dimethylformamide / ethyl ether. Yield 12.5 g. Mp 191-194 ° C (compound contains one molecule of water of crystallization).

Example 48 3-Amino-5-carboxy-4-methoxycarbonyl-2-phenylpyrrole A solution of 10 g (0.0322 moles) of the compound of Example 41 in 150 ml of methanol and 30 ml of 10% aqueous sodium hydroxide solution is boiled. at reflux for 3 hours. The methanol is evaporated off and the remaining solution is adjusted to pH 7 with 10% aqueous hydrogen chloride. The product separates and is filtered, dissolved in aqueous sodium bicarbonate and then neutralized with 10% aqueous hydrogen chloride. Yield 5 g. Mp 206-207 ° C.

Example 49 3-Amino-4-carboxy-5-methoxycarbonyl-2-phenyl-pyrrole 2 g (0.00644 mol) of the compound from Example 41 are dissolved in 20 ml of concentrated sulfuric acid and the solution is allowed to stand at room temperature for about 35 minutes. It is then poured into ice-water and the resulting mixture is neutralized with 10% aqueous sodium hydroxide solution. The product separates, is collected by filtration and recrystallized from aqueous methanol. Yield 0.5 g. Mp 218-219 ° C.

Example 50 3-Amino-5-carbazoyl-4-methoxycarbonyl-2-phenyl-pyrrole 5 g (0.0161 mol) of the compound from Example 41 are dissolved in 60 ml of methanol and 1.3 g of pyridine are added. To the solution is then added 25 ml of hydrazine in 20 ml of water and kept at room temperature for 15 minutes. The crystallized product is collected on a filter and recrystallized from methanol. Yield 3 g, m.p. 166-167 ° C.

Example 51 4-Acetyl-3-amino-5-methyl-2- (p-hydroxyphenyl) pyrrole 61,879 19

The title compound is prepared starting from the compound of Example 14, using essentially R.L. In Burwell, Chem. Rev., 5J +, 628, 1954 for the hydrolysis of O-alkylphenols. Yield 71%. Mp 273-274 ° C (ethanol / water).

Example 52 3-Amino-5-methyl-2-phenyl-4-phenylcarbamyl-pyrrole This compound was prepared according to the procedure described in Examples 1-41 starting from 2-amino-2-phenyl-acetonitrile and acyl-N-phenylacetamide , and is obtained in a total yield of 73%. Mp 271-273 ° C (from ethanol).

Example 53 3-Amino-4,5-dimethoxycarbonyl-2-phenyl-pyrrole hydrochloride To a solution of 9.5 g (0.0565 mol) of 2-amino-2-phenyl-acetonitrile hydrochloride in 90 ml of anhydrous methanol, 9.0 g of potassium carbonate are added and the resulting mixture is stirred for 15 minutes. 8.0 g (0.0630 mol) of 1,2-dimethoxycarbonylacetylene are then added and the mixture is refluxed for 3 1/2 hours. The solvent is evaporated off and the residue is dissolved in ethyl acetate and extracted three times with 10% aqueous hydrogen chloride solution. The hydrogen chloride solution is neutralized with 10% aqueous sodium hydroxide solution and re-extracted with ethyl acetate. After evaporation of the solvent, a solid is obtained which is recrystallized from a mixture of methanol and diethyl ether saturated with hydrogen chloride. Yield 5 g of the title product. Mp 205-207 ° C. The free base melts at 142-143 ° C (from diethyl ether).

Using the procedure described in this example, the compounds of Examples 6, 36, 37, 38, 39 and 40 are also prepared.

Example 54 3-Acetylamino-4-benzoyl-5-methyl-2-phenyl-pyrrole Starting from the compound of Example 3 and acetyl chloride, the title compound is obtained in 87% yield. Mp 140-142 ° C (ethanol / water).

Claims (5)

1. Analog method for novel anti-inflammatory and central nervous system-financing aminopyrrole derivatives of general formula (I) Ηϊ \ _ / ** rf «> R 1 R 5 wherein R is hydrogen,) alkyl, benzyl or halogen-substituted benzyl; is hydrogen, (C 1-6) alkyl, phenyl or substituted phenyl, the substituents of which, independently of one another, are (C 1-6) alkyl, (C 1-4 alkoxy, benzyloxy, chlorine, fluorine or hydroxy; C2-1) aliphatic acyl, benzoyl, substituted benzoyl, the substituents of which are, independently of one another, (C1-4) alkoxy or chlorine, (C1-1) alkoxycarbonyl, carboxy, carbamyl or methylcarbamyl, R1 is hydrogen, (C1-4) alkyl, (C 1-4) alkoxycarbonyl, [(C 1-6) alkoxycarbonylmethyl, trifluoromethyl, carboxy, carbamyl or carbazoyl; and salts thereof with pharmaceutically acceptable acids, characterized in that substantially equimolar amounts of aminonitrile are obtained, of the general formula (II) is CN CH 1 R 2 NH 2 (II) or an acid addition salt thereof, wherein R 1 is as defined above, and a compound of the general formula (III) is X (III) 1 R 5 wherein R 1 and R 6 are as defined above. same as above and X represents -C = C- or -CH 2 -C, wherein the -C 1-4 moiety is attached to the substituent R f, to react with each other in an inert organic solvent at a temperature between room temperature and the reflux temperature of the reaction mixture, for 1-60 hours, and when a compound of formula (I) is desired, wherein R is (C 1-4) alkyl, benzyl or halogen-substituted benzyl, the resulting compound is further reacted with (C 1-4) alkyl, benzyl- or halogen-substituted benzyl halide in the presence of a strong base, followed by removal of the (C 1 -C 4) alkyl group. an alkylidene, benzylidene or halogen-substituted benzylidene group in the amine function in the 3-position by acid hydrolysis; and if desired a) subjecting a compound of formula (I) wherein or R 9 or both are (C 1-4 alkoxycarbonyl) to basic or acidic hydrolysis to prepare a compound of formula (I) wherein R 1 or R 8 or both are carboxy; reacting a compound of formula (I) wherein R 1 or R 8 or both are (C 1-6) alkoxycarbonyl with ammonia to produce a compound of formula (I) wherein R 1 or R 8 or both are carbamyl; or c) reacting a compound of formula (I) a compound of formula (I) wherein Rg is alkoxycarbonyl to react with hydrazine to produce a compound of formula (I) wherein Rg is carbazoyl. A process for the preparation of compounds of formula (I) according to claim 1, wherein R is hydrogen or (C 1-4 alkyl), R 1 is phenyl or substituted phenyl, the substituents of which, independently of one another, are (C 1-4) alkyl, N, C 1-4 alkoxy, benzyloxy, chloro, fluoro or hydroxy, is (C 1-4 aliphatic acyl, (C 1-4) alkoxycarbonyl or methylcarbamyl, and R 9 is (C 1-4 alkyl) or carbamyl. A process according to claim 1 for the preparation of 3-amino-U-iso-butyl-5-methyl-2-phenylpyrrole. 22 61 879 1. An analogous compound for the preparation of an inflammation of the central nervous system and of the central nervous system by the preparation of aminopyrrole derivatives with the formula (I) Η / χ_ I (n Rx An / \ r? R i vilken R är väte, (C ^ _ ^) alkyl, benzyl or halogen-substituted benzyl, hydrogen, (C 1-4) alkyl, phenyl or substituent phenyl, a substituent, a variety of radicals, (C 1-4) alkyl, (C 1-4) alkoxy, benzyloxy, chloro, fluoro or hydroxyl; R 1? (C 1-4) aliphatic acyl, benzoyl, substituents benzoyl, a substituent, other than varium, C 1-4 alkoxy or chloro, (C 1-4) alkoxycarbonyl, carboxy, carbamyl or methylcarbamyl, (C 1-4) alkyl, (C 1-4 alkoxycarbonyl, C 1-4 alkoxycarbonyl) methyl, trifluoromethyl, carboxy, carbamyl or carbazoyl, and a pharmaceutically acceptable salt; syror, kännetecknat därav, att man omsätter i huvudsak ekvi-molära mängder av en ° (-aminonitrile med den allmänna formuleln (II) CN CH / \ R ^ NH2 (II) eller ett syra-additionssalt därav, i vilken forme In the case of R 1, the deck number of each of the groups (III) X "X i is R 1 and R 2 of the group number of the group C = C- or -CH 2 -C- , and the -CH2-delen is attached to subs- 0