DE2549686A1 - 4-ARYL-1,6-DIHYDRO-TRIMETHYLIMIDAZO-SQUARE CLAMP ON 1.2-ANGLE CLAMP FOR PYRAZOLO SQUARE CLAMP ON 4.3-ANGLE CLAMP FOR ANGULAR CLAMP ON 1.4-ANGLE CLAMP FOR DIAZEPINE CONNECTIONS AND PROCESSES TO CREATE THEM - Google Patents

Description

UR. ING. F. WUKSTHOFF

DR.E.v.PEOIIMANN DK. ING. D. BEJIHKNS DIPL. ING. R. GOKTZ

PATENT LAWYERS

S, MUNICH ÖO SCmVICIGERSTHASSE 2 TELEPHONE (089) 60 20 51 TELEX S 24 070

TKLROIIAMMEI

Munich

1A-47 228

Description of the patent application

Parke, Davis & Company-Joseph Campau at the River Detroit, Michigan, USA

concerning:

"4-Aryl-1,6-dihydro-trimethylimidazo {], 2-a} pyrazolo C4, 3- £) 0, 4) diazepine compounds and process for their preparation"

The invention relates to new diazepine compounds and especially certain. 4-aryl-1,6-dihydro-trimethylimidazo - (/ I »2-a) pyrazolo (4,3-f) (i, 4 ^ diazepine compounds, their salts and methods of making them.

The compounds according to the invention have the formula in the form of the free bases

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in which R ₁ and R ₂ each represent a hydrogen atom or a methyl group, at least one of the radicals being a methyl group and X being a hydrogen, fluorine or chlorine atom.

The compounds according to the invention can be prepared by reacting a 7- (2-propynylamino) pyrazolo / 3,4 ~ i7ZT, 47diazepine compound the formula

NH-CH-C = CH

II

in which Rp is a hydrogen atom or a methyl group and X has the meaning given above, with a strong acid in the presence of a mercury salt catalyst.Für the reaction can be any of a number of strong anhydrous Acids are used such as sulfuric acid and hydrocarbyl sulfonic acids e.g. methanesulfonic acid. One the preferred acid is sulfuric acid. It is not necessary to use a solvent. Usually only one Excess acid used as a solvent. Any mercury salt, the soluble in the acidic medium. Only a catalytic amount of the mercury salt is required although larger amounts can be used without disadvantage. The procedure is carried out by one the reactants 1 to 24 hours at temperatures in

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Range of 0 h? .S 100 ° C - The preferred RfeaAaroÄff conditions are temperatures in the range of 20 to 50 ° C and reaction times of 4 to 16 hours. The product is isolated in the form of the free base or as an acid addition salt, depending on the pH setting.

The 7- (2-propynylamino) pyrazolo / 3,4-e7- / T, 47-diazepines used as starting substances for the above process can be obtained by reacting a 4-aryl-1,6-dihydro-1,3-dimethylpyrazolo / 3 ^ 4-e_7 - Z ~ »ii7" -diazepine-7-thiol with 2-propynylamine or 1-methyl-2-propynylamine. This procedure will be detailed later.

The compounds according to the invention can also be prepared by reacting an aryl (2-hydroxymethyl) imidazol-1-yl-1,3-dimethylpyrazol-4-ylmethanone hydrocarbon sulfonate ester the formula

R ₁ R ₂

CH ₃

jLJT s

III

Or

in which R is a lower alkyl group having 1 to 4 carbon atoms, an aryl or trifluoromethyl group and R ^, Rp and X have the meaning given above with ammonia in the presence of «iodide. The group R is preferably one Methyl group. An aryl group is preferably a phenyl or substituted phenyl such as a halophenyl, Alkylphenyl, alkoxyphenyl or nitrophenyl group. Any soluble metal oodide can be used for the reaction may be employed, particularly an alkali iodide which is preferred or an alkaline earth iodite. It can be catalytic until equivalent amounts of iodide are applied and it is a large excess of ammonia preferred. It can be more liquid (watery

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Ammonia can be used as the solvent or an additional solvent such as a lower alkanol (e.g. methanol or ethanol), a chlorinated hydrocarbon (e.g. dichloromethane or chloroform), an ether (e.g. tetrahydrofuran or dioxane) or mixtures of these solvents can be used. The reaction conditions can be varied within a wide range. The reaction may be carried out to about +80 ⁰ C at temperatures in the range of about 20 and is complete within about 2 to 24 hours. It is preferred to start the reaction at a low temperature and then, after 1 to 2 hours, to warm the reaction mixture to room temperature. The product is isolated in the form of the free base or as an acid addition salt depending on the setting of the pH.

Those in the above process as starting substances used aryl (2-hydroxymethyl) imidazol-1-yl-1,3-dimethylpyrazol-4-ylmethanone hydrocarbon sulfonate ester can be obtained by reacting an aryl- (2-hydroxymethyl) imidazol-1-yl-1,3-dimethylpyrazol-4-ylmethanone with a hydrocarbon sulfonyl chloride in the presence of a tertiary amine. This procedure will described in more detail later.

The free bases of the invention form acid addition salts with any of a variety of organic ones or inorganic acids. Pharmaceutically acceptable acid addition salts are formed with acids such as hydrochloric acid and hydrogen bromide-5 Sulfur, nitric, phosphorus, vinegar, lemon, wine, amber, salicylic, maleic, Malic, lactic, gluconic and pamoic acid. In. Most of the cases are salts with one equivalent of a mineral acid or a strong organic acid stable derivatives. The free bases and their salts are obtained by setting the pH-value convertible into each other. The free bases will be

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made by alkaline machai and the acid addition salts by acidification. They differ in their solubility properties, but are generally otherwise for the purposes of the invention are equivalent.

The compounds of the present invention are new chemical compounds useful as pharmacological agents. They are useful as anticonvulsants and anti-anxiety drugs, while having only a minimal depressive effect on the central nervous system. The anticonvulsant effect is demonstrated by its ability to prevent the occurrence of convulsions in animals after administration of pentamethylenetetrazole. The anti-anxiety effect is demonstrated by their ability to overcome inhibited behavior in animals placed in a fear-inducing situation. The anti-convulsive action of the compounds according to the invention is measured in a standard test in which each of a group of five rats is given a measured oral dose of the compound to be tested dissolved in water or suspended with acacia and 30 minutes later a subcutaneous dose of 93 mg / kg Pentamethylene tetrazole. This amount of pentamethylenetetrazole quickly causes convulsions in 98 to 100% of untreated control rats. The treated animals are then visually observed 30 minutes after the administration of pentamethylenetetrazole and the anti-convulsive effect is assessed by noting the time to onset and the severity of the clonic convulsions and the number of animals which were completely spared from convulsions. The activity of the compound tested at each dose is rated as follows: 4+ = protection of all 5 rats, 3+ = protection of 3 rats or 4 rats, 2+ = protection of 1 or 2 rats, 1+ = delay in onset, 0 = no effect.

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Some results that were obtained for the compounds according to the invention when investigated by the method given above are IR ₁ = methyl and R ₂ and X are each hydrogen, 4+ at 16 to 125 mg / kg; R ₁ = methyl and R ₂ and X hydrogen or fluorine, 4+ at 8 to 125 mg / kg; R ₁ , R ₂ and X are hydrogen, itethyl and fluorine, 4+ at 8 to 64 mg / kg, respectively.

The anti-anxiety effect of the compounds according to the invention is determined in a test in which food intake measured by rats placed in a fearful situation. In this attempt become newly-arrived male Holtzmanalbino rats Accustomed to the laboratory environment at least three days before the start of the experiment. The animals have not yet had any experience with experiments and are not lacking in food.

and weigh about 230 g. Once adjusted to the normal laboratory environment, each of the 8 rats is measured Dose of the compound to be investigated dissolved in water or suspended in 0.2% aqueous methyl cellulose administered by oral intubation and immediately placed the rat in a single metabolic cage given. Allow 30 minutes for the compound under study to be absorbed. Then every animal will allows access to a milk preparation in a calibrated measuring tube. The preparation consists of one part sweetened condensed milk and two parts water. The total milk intake of each animal after 1 and 2 hours is recorded and compared with that of a group of 8 untreated control animals. It is also observed whether any unusual (large) signs in the behavior of the animals occur. If the treated animals have more milk absorb as normal, this is taken as an indication that the test compound is having an effect on the Inhibitory brain system has suppressed the natural tendency of rodents in a new, fear-inducing way Situation not to move, as created in the attempt by isolation in the metabolic cage.

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A certain dose of the tactile connection is considered active, if it leads to an intake of more than 5.0 ml per animal after the first hour of the experiment. During this same time, the untreated control animals usually take between 2.0 and 4.0 ml Milk on.

Some activities of the compounds according to the invention as obtained with the aid of the experimental procedure given above are the following, with the first value indicating the volume of milk that was obtained at the end of the first Hour of the attempt has been recorded.

R ₁ = methyl, R ₂ = methyl, X = hydrogen, 15.3 ml at 40 mg / kg; 7.2 ml at 20 mg / kg; 9.1 ml at 10 mg / kg. R ₁ s methyl, R ₂ = hydrogen, X = chlorine, 12.1 ml at 40 mg / kg; 11.0 ml at 20 mg / kg; 13.4 ml at 10 mg / kg. R ₁ = methyl, R ₂ = hydrogen, X = hydrogen, 8.1 ml at 40 mg / kg; 4.5 ml at 20 mg / kg; 6.3 ml at 10 mg / kg; R ₁ a hydrogen, R ₂ = methyl, X = chlorine, 6.2 ml at 40 mg / kg; 9.9 ml at 20 mg / kg; 8.6 ml at 10 mg / kg; R ₁ = hydrogen, R ₂ = methyl, X = fluorine, 5.8 at 5 mg / kg; 8.0 Bl at 2.5 mg / kg; 6.4 ml at 1.25 mg / kg. The pharmacological agents diazepam and chlordiazepoxide, which are known to be clinically useful for treating anxiety, are also effective in this test method. Evidence of the effectiveness of diazepam and chlordiazepoxide shows the value of the test procedure for determining anti-anxiety activity.

The compounds of the invention are preferably administered orally as noted above, although they can also be administered parenterally. You can use either a solid or liquid carrier or diluent given together and in various amounts in pharmaceutical forms such as tablets, capsules, and powders aqueous and non-aqueous suspensions and solutions are made available.

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The invention is further illustrated by the following examples explained:

example 1

1.3 g of 1,6-dihydro-1,3-dimethyl-7- (1-methyl-2-propynylamino) -4-phenylpyrazolo / 3,4- £ 7Zϊ ^ ί!: 7-diazepine were stirred into a solution of 1 mg of mercury (II) oxide in 5 ml of concentrated sulfuric acid was added. The mixture was heated to 50 ° C. in order to achieve complete solution and then left to stand for 16 hours at room temperature (20 to 30 ^° C.). The resulting solution was poured over crushed ice and neutralized with 30 ml of concentrated aqueous ammonia. The mixture was extracted repeatedly with dichloromethane, the extracts were combined, dried and evaporated under reduced pressure. The residue was triturated with ether and the solid product 1,6-dihydro-1,3, 8,9-tetramethyl-4-phenylimidazo / T, 2-a7-pyrazolo / 4 ", 3- £ 7ΖΤ» £ 7 diazepine was filtered off , mp 168-170 ⁰ C after sublimation at 142 ⁰ C and 0.2 mm Hg. the citrate salt was obtained by reacting the free base with citric acid in methanol.

Example 2

1.4 g of 4- (2-chlorophenyl) -1,6-dihydro-1,3-dimethyl-7- (2-propynylamino) pyrazolo ^ 3,4- £ 7Z ~ »47-diazepine were stirred in a solution of 1 mg of mercury-II-oxide dissolved in 5 ml concentrated sulfuric acid at 50 ⁰ C. The solution was allowed to stand for 16 hours at room temperature (20-30 ⁰ C) and poured over crushed ice and made basic with excess concentrated aqueous ammonia. The mixture was extracted repeatedly with dichlorine than, the extracts were combined, dried and evaporated under reduced pressure. A residue of 4- (2-chlorophenyl) -1,6-dihydro-1,3,9-trimethylimidazo / T, 2-a7-pyrazolo / i, 3-f7Z ~ »it7-diazepine, mp 189-190 was obtained ⁰ C (decomp.) After sublimation at 130 ⁰ C and 0.1 mm Hg.

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Example 3

When using 2.0 g of 1,6-dihydro-1,3-d-imethyl-4-phenyl- 7- (2-propynylamino) pyrazolo / 3,4- £ 7ZT »47diazepine instead of 4- (2-chlorophenyl ) -1,6-dihydro, 1,3-dimethyl-7- (2-propynylamino) pyrazolo / 3,4- £ 7 / T, 47diazepine in Example 2, 1,6-dihydro-1,3> 9- trimethyl-4-phenylimidazo- / T, 2-a7pyrazolo / 4 ^ 3-ί7ZT, 47-diazepine, ^F «P · 224-226 ⁰ C after sublimation at 172 ° C and 0.1 mm Hg. The tartrate and maleate was obtained by reacting the free base with tartaric acid or maleic acid.

Example 4

When using 1.85 g of 4- (2-fluorophenyl) -1,6-dihydro-1,3-dimethyl-7- (2-propynylamino) pyrazolo / 5,4- £ 7ZT »ii: 7-diazepine instead of 4-. (2-Chlorophenyl) -1,6-dihydro-1,3-dimethyl-7- (2-propynylamino) pyrazolo / 3> 4- £ 7Z ~ »47-diazepine in Example 2 gave 4- ( 2-fluorophenyl) -1,6-dihydro-1 '3,9-trimethylimidazo / T, 2-a7pyrazolo / i, 3-F7Z ~ »it7- ^(iiazepin, mp 169-171 ⁰ C after sublimation at 142 ° C and 0.1 mm Hg.

example 5

When using 1.6 g of 4- (2-chlorophenyl) -1,6-dihydro-1,3- <iimethyl-7- (i-methyl-2-propynylamino ) pyrazolo / 3.4- £ 7- / T, 4_7diazepine instead of 1,6-dihydro-1,3-dimethyl-7- (1-methyl-2-propynylamino) -4-phenylpyrazolo / 3,4-e7ZJ »47-diazepine Example 1 gave 4- (2-chlorophenyl) -1,6-dihydro-1,3,8,9-tetramethylimidazo / T, 2-a7pyrazolo / i »3-f7- / T, 47diazepine.

Starting substances

The diazepine Ausgangssubstanzm for Examples 1 to 5 were prepared by de _n the following methods:

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a) A mixture of 2.9 g of 1,6-dihydro-1,3-dimethyl-7- (methylthio) -4-phenylpyrazolo / 3,4- £ 7Z "» it7diazepine (US Pat. No. 3,770,762), 10 ml of ethanol and 2.0 g of 1-methyl-2-propynylamine for four days at room temperature (20-30 ⁰ C) was allowed to stand, heated for 15 minutes under reflux and allowed to stand for another 16 hours at room temperature (20-30 ° C). The resulting crystalline precipitate of 1,6-dihydro-1,3-dimethyl-7- (1-methyl-2-propynylamino) -4-phenylpyrazolo / 3, 4- ^ 7 / T, 4_7diazepine was filtered off, washed with ether and dried, mp 193-195 ⁰ C (dec.)

b) A mixture of 4.65 g of 4- (2-chlorophenyl) -1,6-dihydro-1,3-dimethylpyrazolo / 3,4-e7Z ~ »ii7ciiazepine-7-thiol (US Pat. No. 3,770,762) 250 ml of tetrahydrofuran, 3.0 g of 2-propynylamine and 20 ml of methanol were left to stand for three days at room temperature (20-30 ° C.) and then evaporated under reduced pressure. A residue of 4- (2-chlorophenyl) -1,6-dihydro-1,3-dimethyl-7- (2-propynylamino) pyrazolo / 3,4-e7ZT> 47diazepine, mp 165-167 ° C. was obtained 'Link crystallize from acetonitrile. For further purification, the product was dissolved in 9: 1 toluene: acetonitrile and chromatographed on a column with neutral alumina. The column was eluted with 9: 1 methanol: acetonitrile and the eluate was evaporated under reduced pressure. A residue was obtained, mp 176-178 ⁰ C (dec.)

c) A mixture of 2.9 g of 1,6-dihydro-1,3-dimethyl-7- (methylthio) -4-phenylpyrazolo / _i 5,4-e7 / T, 47diazepine (US Pat. No. 3,770,762), 1.5 g of 2-propynylamine and 50 ml of ethanol were refluxed for 48 hours and then evaporated under reduced pressure. A residue of 1,6-dihydro-1,3-dimethyl-4-phenyl-7- (2-propynylamino) pyrazolo ^ 3,4- £ 7ZT> 47-diazepine was obtained; Mp 193-195 ° C after recrystallization from ether.

d) A mixture of 3.0 g of 4- (2-fluorophenyl) -1,6-dihydro-1,3-dimethylpyrazolo / 5.4- £ 7ZT »ii7d-iazepine-7-thiol (US Pat. No. 3,770,762), 1.8 g of 2-propynylamine and 50 ml of tetrahydrofuran were refluxed for two hours and then under

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evaporated under reduced pressure. A residue was obtained from 4- (2-fluorophenyl) -1,6-dihydro-1,3-dimethyl-7- (2-propinilamino) pyrazolo / 3,4-e_7Z ~> it7diazepin, mp 202-204 ⁰ C ( Decomposition) after trituration with ether, filtration and drying.

e) When using 3.0 g of 4- (2-fluorophenyl) -1,6-dihydro-1,3-dimethyl-7- (methylthio) pyrazolo / 3,4- £ 7Zi "» ii7 " ^ciia2e P ^iri ( US Pat. No. 3,770,762) instead of 1,6-dihydro-1,3-dimethyl-7- (methylthio) -4-phenylpyrazolo / 3 »4 ~ e_7 / T, 47diazepine in a), 4- (2- Chlorophenyl) -1,6-dihydro-1,3-dimethyl-7- (1-methyl-2-propynylamino) pyrazolo / 3,4- £ 7 / J> 47diazepine.

Example 6

A solution of 5.0 g of (2-chlorophenyl) - / 5- / 2 "- (hydroxymethyl) -4-methyl-1H-imidazol-1-yl7-1,3-dimethyl-1H-pyrazol-4-yl7- methanone and 2.5 ml of triethylamine in 75 ml methylene dichloride was cooled to -5 ° C and by dropwise addition of 2 g of methanesulfonyl chloride treated. The reaction mixture was stirred for another hour at -5 ⁰ C and then overnight in a refrigerator (5 ° C The mixture was washed first with water and then with saturated sodium bicarbonate solution, and the solution was dried over magnesium sulfate and evaporated in vacuo to give (2-chlorophenyl) - / 5- / 2- (hydroxymethyl) -4-methyl-1H- imidazol-1-yl7-1,3-dimethyl-1H-pyrazol-4-yl7-niethanone methane sulfonate ester The product was dissolved in 75 ml of tetrahydrofuran and cooled to -20 ° C. The solution was added with 5 g Potassium iodide and approximately 15 ml of liquid ammonia added The mixture was stirred at -20 ° C. for 1 to 2 hours and then warmed to room temperature overnight ndamped. The remaining product was 4- (2-chlorophenyl) -1,6-dihydro-1,3,8-trimethylimidazo / T, 2-a7-pyrazoloZ4 ", 3-f7ZT, 47diazepine, mp 150-153 ° C. after washing (Dichloromethane / water), drying, concentration to dryness, percolation over a column with neutral clay in ethyl acetate, renewed evaporation to dryness and recrystallization from ether.

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To obtain the hydrochloride, the free base was dissolved in tetrahydrofuran and the solution treated with an excess of a saturated hydrogen chloride solution in 2-propanol and diluted with ether until it became cloudy. The resulting mono-hydrochloride which precipitated was collected and dried, m.p. 275 ⁰ C (dec.).

Example 7

Following the procedure of the examples given above, starting from (2-fluorophenyl) - / F- / 2- (hydroxymethyl) -4-methyl-1H-imidazol-1-yl7-1 »3-dimethyl-1H-pyrazole-4- yl7methanone (3> 3 g) and 1.8 g methanesulfonyl chloride were obtained (2-fluorophenyl) - / 5- / 2-4iydroxymethyl) -4-methyl-1H-imidazol-1-yl7-1 »3-dimethyl- 1H-pyrazol-4-yl7-methanone methanesulfonate ester. 4- (2-fluorophenyl) -1,6-dihydro-1,3,8-trimethylimidazo / T, 2-a7-pyrazolo / 5.3 - // T, 47-diazepine, mp 153-154 ⁰ C after recrystallization from ethyl acetate-petroleum ether.

Example 8

Following the procedure of Example 6, but starting from phenyl- / 5- / 2- (hydroxymethyl) -4,5-dimethyl.-1H-imidazol-1-yl7-1, ^ - dimethyl-IH-pyrazol ^ -y ^ Methanone (6.5 g) and 2.5 g of methanesulfonyl chloride gave phenyl- / 5- / 2- (hydroxymethyl) -4,5-dimethyl-1H-imidazol-1-yl7-1 »3-dimethyl-1H -pyrazol-4-yl7-ßi ^e "thanon methanesulfonate ester. The ester was treated with excess liquid ammonia in tetrahydrofuran according to the procedure of Example 6. 1,6-dihydro-1,3,8,9-tetramethyl-4 was obtained -phenylimidazo / T, 2-a7-pyrazolo / 5,3-f7 / ~ »fi; 7diazepine _> mp 167-17O ° C after recrystallization from ethyl acetate-petroleum ether.

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2bA9686

Starting substances

The starting substances for Examples 6 to 8 can be prepared according to Examples f) and g) below will:

Arovl- (5-imidazole-1-vl) -pvrazole-4-vl-methanone

f-1) A mixture of 27 g of 5-chloro-4- (o, -chlorobenzoyl) -1,3-dimethylpyrazole (US Pat. No. 3,558,605) and 10 g of 4-methylimidazole in 150 ml of dimethylformamide was added in individual portions Treated 5 g of sodium hydride (50% dispersion in mineral oil) under nitrogen. The mixture was stirred and heated under nitrogen four hours 90-100 ⁰ C. The mixture was filtered and evaporated in vacuo. The residue was dissolved in ethyl acetate and extracted twice with 150 ml of InHCl. The combined aqueous extract was with conc. NH, OH made alkaline and extracted with dichloromethane. The organic extract was washed with brine, dried over MgSO 4 and evaporated in vacuo. (2-Chlorophenyl) -ß-ß- (methyl) -1 H-imidazol-1-yl-1, 3-dimethyl-1H-pyrazol-4-yl7-methanone, melting point 125-128 ° C., after recrystallization from ether.

f-2) From 25 g of 5-chloro-1,3-dimethyl-4- (£ -fluorobenzoyl) pyrazole (US Pat. No. 3,558,605), 9 g of 4-methylimidazole and 5.5 g of 50% sodium hydride in 200 ml of dimethylformamide were obtained according to method f-1) 18 g of (2-fluorophenyl) - ß-ß- (methyl) -1H-imidazol-1-yl7-1,3-dimethyl-1H-pyrazol-4-yl7 methanone, mp 136-139 ° C from ether.

f-3) From 47 g of 4-benzoyl-5-chloro-1,3-dimethylpyrazole (US Pat. No. 3,558,605) and 20 g of 4,5-dimethylimidazole (Ber. 86, 88 (1953)) and 10 g of 50 % NaH in dimethylformamide was obtained according to f-1) 30 g of phenyl- / 5- / i, 5- (dimethya> 1H-imidazol-1-yl7-1,3-dimethyl-1H-pyrazol-4-yl7methanone, m.p. 95-97 ⁰ C from ether.

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Aroy 1- / 5- / 2 "- (hydroxyme thy 3) imidazol-1 methanone

g-1) A mixture of 20 g of (2-chlorophenyl) - / 5- / ^z i'- (methyl) -1H-imidazol-1-yl7-1,3-dimethyl-1H-pyrazol-4-yl7-methanone and 60 ml of 37% aqueous formaldehyde was refluxed with stirring for 40 hours and evaporated in vacuo. The residue was dissolved in warm ethyl acetate and the solution washed with water and extracted with 300 ml InHCl. The aqueous HCl extract was concentrated with. ΝΗλΟΗ made strongly alkaline and extracted with dichloromethane. The organic extracts were washed with brine, dried over MgSOi and evaporated in vacuo. (2-Chlorophenyl) - / 5 - /, 2- (hydroxymethyl) -4-methyl-1H-imidazol-1-yl7-1, S-dimethyl-1H-pyrazol-1-yl-methanone, m.p. , 195-197 ° C from ethyl acetate.

g-2) From 18 g of (2-fluorophenyl) -5- / i- (methyl) -1H-imidazol-1-yl7-1,3-dimethyl-1H-pyrazol-4-yl7methanone and 50 ml of 37% formalin were obtained according to g-1) (2-fluorophenyl) -5- ^ 2- (hydroxymethyl) -4-methyl-1H-imidazol-1-yl / -1,3-dimethyl-1H- pyrazol-4-yl7-methanone, F.p. 185-187 ° C from ethyl acetate.

g-3) From 20 g of phenyl- / 5- / £, 5- (dimethyl) -1-H-imidazol-1-yl7-1 »3-dimethyl-1H-pyrazol-4-yl7methanone and 50 ml of 37% formalin were obtained according to g-1) Phenyl- £ 5 - / 2 ~ - (hydroxymethyl) -4,5-dimethyl-1H-imidazol-1-yl7-1,3-dimethyl-1H- pyrazol-4-yl7me thanon.

../Patent claims

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Claims (5)

DR. INO. F. WUESTUOFK DR.E.T.PKCJIMANN DR. ING. I). BEURENS DIPI .. ING. R. GOKTZ PATENT LAWYERS JS- 8 MUNICH 9O TKl.EFOK (0R9) βθ 20 51 TELEX 5 2 * 070 TKI.EOHi.MM E: PHOTEOTPATKNT 1A-47 228 Claims 4-Aryl-1, e-dibydro-trimethylimidazo-ZT, 2-a7-pyrazolo-7ZJi ⁿ compounds of the formula "" in which fL and Rp each have a hydrogen atom or a methyl group mean, but at least one of the radicals R ^ and Rp · is a methyl group and X is a hydrogen, fluorine or chlorine atom, and their acid addition salts. 2. Process for the preparation of the compounds according to Claim 1, characterized in that a 7- (2-propynylamino) pyrazolo / 3> 4-e7 / T, 47diazepine is used the formula NH-CH-C = CH II 609820 / 114t) - ■ β-- 1A-47 228 in which R ^ is a hydrogen atom or a methyl group and X has the meaning given in claim 1 with a strong acid in the presence of a mercury salt as Reacts catalyst and the product is isolated in the form of the free base or a salt. 3. The method according to claim 2, characterized in that there is used as strong acid sulfuric acid and at temperatures in the range of 20-50 ⁰ C. 4. Process for the preparation of the compounds according to claim 1, characterized in that one an aryl (2-hydroxymethyl) imidazol-1-yl-1,3-dimethylpyrazol-4-yl-methanone-hydrocarbon-sulfonate ester the formula. III CH ₃ | ^{= 0} -X in which R is a lower alkyl group with 1 to 4 carbon atoms, an aryl or trifluoromethyl group and R ^, R ₂ and X have the meaning given in claim 1 and reacts with ammonia in the presence of iodide. 5. The method according to claim 4, characterized in that that the reaction is carried out with the aid of liquid ammonia and an alkali iodide. 609820/1140