DE1067438B - Process for the preparation of substituted, analgesic l-phenyl-2,3-dimethyl-4morpholinomethyl - pyrazokm- (5) derivatives - Google Patents

Description

GERMAN

The invention relates to a process for the preparation of substituted, analgesic l-phenyl-2,3-dimethyl - 4 - morpholinomethyl - pyr azolone - (5) - derivatives of the general formula

CHo CHq

C N

H ^ N-CH ₂ -CC

Method of manufacture

of substituted, analgesic l-phenyl ^ S-dimethyl- ^ morpholinomethyl-pyrazolone (5) derivatives

where R is an alkyl radical having 1 to 5 carbon atoms in a straight or branched chain.

The 1 - phenyl - 2,3 - dimethyl - pyrazolone - (5) - 4 - methane compounds are obtained in the process according to the invention obtained in a technically simple manner and in good yields by converting to an alcoholic Solution of the appropriately substituted morpholine, for example 2-phenyl-3-methyl-morpholine, Formaldehyde and an aqueous, hydrochloric acid solution of l-phenyl-2,3-dimethylpyrazolone- (5) is added and preferably Stirred for 2 hours on a water bath at 25 to 30 ° C.

The hydrochlorides of the process products, such as 1-phenyl 2,3 - dimethyl - 4 - (2 '- phenyl - 3' - methyl - morpholinomethyl) pyrazolone (5) hydrochloride fall out of the reaction solution and can optionally be recrystallized from alcohol-acetone. By Adding alkali to the hydrochlorides gives the corresponding ones after known work-up Bases, which are obtained in solid form. The preparation of basic substituted compounds of 1-phenyl-2,3-dimethyl-pyrazolons- (5) with formaldehyde and a heterocyclic base based on the principle of the Mannich reaction is known per se. Here z. B. first piperidine with the formaldehyde to hydroxymethylpiperidine implemented, which then in the presence of anhydrous potassium carbonate with the l-phenyl-2,3-dimethylpyrazolone (5) was implemented. The yields in this two step process were the same as in the carrying out this Mannich reaction in one step is not very satisfactory. About the pharmacological properties of the product obtained in this way nothing has been known so far. For use in medical In practice it does not seem to be suitable.

In the process according to the invention, on the other hand, is not piperidine, but a certain way, namely substituted in the 2-position with a phenyl radical and in the 3-position with a lower alkyl radical Morpholine condensed with the pyrazolone compound in one process stage in the presence of formaldehyde, Applicant:

Ravensberg G.m.b.H. Chemical factory, Constance, Steinstr. 27

Dr. Harm Siemer, Constance,

and Dr. Adolf Doppstadt, Litzelstetten,

have been named as inventors

wherein yields of more / ₀ of theory are obtained as 80 °.

The new compounds are particularly effective analgesic, which results from the pharmacological comparative tests with known compounds, their Results are included in the table below.

Approved preparation

l-phenyl-2,3-dimethyl-4-dimethylamino-

pyrazolone- (5)

Salicylamide

Phenacetin

AD ₅₀ Il

120 540 500

1-phenyl-2,3-dimethyl-4- (2'-phenyl-3'-methyl-morpholinomethyl) -pyrazolone- (5) -HCl 55

In the table above, the mean therapeutic doses found in the pharmacological analgesia test (/1.D ₅₀ II, determined according to the Wolff-Hardy method using dosed heat using a point lamp and magnifying glass) of 1-phenyl-2,3-dimethyl- 4- (2'-phenyl-3'-methyl-morphohnomethyl) -pyrazolone- (5) -hydrochloride compared with 1-phenyl-2,3-dimethyl-4-dimethylamino-pyrazolone- (5), salicylamide and phenacetin . According to this, the new morpholine derivative is twice more effective than the well-known pyrazolone derivative and ten times more potent than salicylamide or phenacetin. If one also takes into account that the analgesic effect of l-phenyl-2,3-dimethyl-pyrazolone- (5) is one third of the effectiveness of 1-phenyl-

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2,3-dimethyl-4-dimethyl-aminopyrazolon- (5), then was compared to the phenyldimethyl-pyrazolon- (5) by introducing the 2-phenyl-3-methylmorpholinomethyl radical achieved a six-fold increase in effectiveness. .

The substituted 1-phenyl ^ S-dimethyl- ^ morpholinomethylpyrazolones prepared by the claimed process - (5) therefore represent new and valuable products in a completely surprising way, especially in the form of their salts Medicinal products. The solutions of the salts are suitable because of the good tolerance of the new analgesic Connection also for injections.

example 1

35.4 g of 2-phenyl-3-methyl-morpholm are dissolved in '50 ml of methanol and 20 ml of 40 ° / ₀ sodium Forinalinlösung added under cooling. Then 37.6 g of 1-phenyl-2,3-dimethylpyrazolon- (5), dissolved in a mixture of 35 ml of water and 20 ml of conc. Hydrochloric acid, was added and at once after the _pH value of the reaction solution to p _H 2 is set to p _H 3, stirred for 2 hours on a water bath at 25 to 3O ⁰ C. The precipitated hydrochloride is recrystallized from methanol-acetone.

Melting point of l-phenyl-2,3-dimethyl-4- (2'-phenyl-3 '- methyl - morpholinomethyl) - pyrazolone - (5) - hydrochloride = 171 to 172 ° C with decomposition. Yield: 81.6 ° / ₀ . The corresponding base, which is obtained from the hydrochloride by alkalization, extraction and to evaporate the extraction agent, melting at 149 to 15O ⁰ C.

Example 2

According to Example 1, 38.2 g of 2-phenyl-3-ethylmorpholine with 37.6 g of l-phenyl-2,3-dimethylpyrazolone (5) implemented. Yield of l-phenyl-2,3-dimethyl-4- (2'-phenyl - 3 '- ethyl - morpholinomethyl) - pyrazolone - (5) - hydrochloride: 82.2%; F. = 174 to 175 ° C with decomposition (recrystallized from acetone-methanol).

Claims (1)

Claim: Process for the preparation of substituted, analgesic l-phenyl ^^ - dimethyl ^ -morpholinomethyl - Pyrazolone - (5) - derivatives of the general formula C-N OH "N-CH ₉ -CC wherein R denotes an alkyl radical with 1 to 5 carbon atoms in a straight or branched chain, characterized in that alcoholic solutions of appropriately substituted morpholines and formanes are mixed with aqueous, acidic solutions of 1-phenyl-2,3-dimethylpyrazolone (5) preferably to 3 in known manner is reacted under mild heating 2 and a _pH value, and optionally the obtained salts of the products according to methods known per se into the free bases converts. Considered publications:
German Auslegeschrift K 20628 IVb / 12p (published on June 28, 1956); Chem. Ber. 89 [1956], pp. 81 to 95. A test report was displayed when the registration was announced. © 909 639/324 10.