DE1620438B - Diazabicyclo square bracket to 4,4, 0 square bracket to decane compounds and a process for their preparation - Google Patents

Description

The invention relates to new diazabicyclo [4,4,0] decane derivatives of the general formula

known way a compound of the general formula

R ₁
N- (CH ₂ ) ,, -C-Ar

Z - (CH ₂ ) ,, - C - Ar

II

where R _{1 is} a hydrogen atom or a hydroxy radical, R _{2 is} a hydrogen atom, a phenyl or cyclohexyl radical and Ar is a phenyl radical which can optionally be substituted by a chlorine or fluorine atom, a trifluoromethyl or methyl radical, one or two methoxy radicals or a methylenedioxy group , and η is a number from 0 to 2, their salts with organic acids or mineral acids and a process for their preparation.

The compounds according to the invention have interesting pharmacological and therapeutic properties, especially spasmolytic-musculotropic properties, being on intestinal and Bronchial spasms have an effect, as well as adrenolytic, anticholinergic, antihistamine and antiserotonin properties. .

The compounds according to the invention are particularly advantageous with regard to their spasmolytic effectiveness superior to recognized good and proven commercial products that are effective in the same direction, as the test results listed in the table below show which according to the invention Compare compounds with the well-known papaverine hydrochloride.

40

45 wherein Z represents a chlorine or bromine atom or a benzene or p-toluenesulfonic acid radical, with Diazabicyclo [4,4,0] decane of the formula

example Toxicity DL ₅₀
ma / ka mouse
(Ip.) DA ₅₀ ¹ ) More therapeutic
index
DL ₅₀ DA ₅₀ 1 150 7.4 · ΙΟ " ⁸ 2 ⁹ la 150 1.4 · ΙΟ " ⁶ 1.07 ⁸ Ib 225 1.8 ■ ΙΟ " ⁶ 1.25 ⁸ lc 175 1.4 · ΙΟ " ⁶ 1.25 ■ 10 ^s ld 125 1.4 ■ ΙΟ " ⁶ 9 · 10 ⁷ 2 150 1.5 · ΙΟ " ⁶ 10 ^s 2a 170 3 · 10 ~ ⁷ 5.7 x 10 ^s 2 B 125 1.4 · ΙΟ " ⁶ 9 ⁷ 2c 140 3 · ΙΟ " ⁷ 4.7 ⁸ 2d 125 7 · ΙΟ " ⁷ 1.8 ⁸ 2e 225 1.8 · ΙΟ " ⁶ 1.25 ⁸ 2f 100 10 ~ ⁶ ΙΟ ³ 2g 225 1.8 · ΙΟ " ⁶ 1.25 ⁸ Comparison:
father
verine · HCl 150 1.8 x 10 ~ ⁶ 8.3 ⁷

NH

55

60

') Determined by the method of Magnus on the isolated Rat duodenum as an antagonistic effect against the spasms caused by barium chloride. The results are as active concentration expressed.

The compounds of general formula I are prepared by being-III

condensed.

The process is most conveniently carried out in such a way that a compound of the general formula II with diazabicyclo [4,4,0] decane is in solution in an aromatic hydrocarbon with a high boiling point, such as toluene or xylene, or in a polar hydrocarbon chosen from among the aliphatic amides Solvent, such as dimethylformamide or dimethylacetamide, is reacted. It is advantageous to work at a temperature between 110 and 140 ^° C. in the presence of an acceptor for the hydrohalic acid or arylsulfonic acid formed. The latter is z. B. an alkali or alkaline earth salt of carbonic acid, e.g. B. sodium or potassium bicarbonate or carbonate or calcium carbonate, or a tertiary organic base such as dimethylaniline, pyridine or triethylamine. An excess of diazabicyclo [4,4,0] decane can also be used. The latter variant is advantageously used when, in the compound of the general formula II to be condensed, Z is one of the arylsulfonic acid esters mentioned; but it can also be used just as well when Z represents a chlorine or bromine atom. The excess diazabicyclo- [4,4,0] decane used also serves as a solvent.

The new diazabicyclo [4,4,0] decane derivatives of the general formula I obtained in this way, the weak ones Represent bases can be converted into the salts with organic acids or mineral acids. This Salts can by the action of the new bases on the acids in suitable solvents, such as Water or the water-miscible alcohols. Among those used to make the salts The acids used can be listed in the series of mineral acids: hydrochloric acid, hydrobromic acid, Sulfuric acid or phosphoric acid; in the organic series: acetic acid, propionic acid, maleic acid, Fumaric acid, tartaric acid, citric acid, oxalic acid, benzoic acid and methanesulfonic acid. Possibly can the new compounds through physical methods, such as distillation, crystallization or chromatography, or by chemical methods, such as formation of the salts defined above, Crystallization thereof and decomposition by alkaline agents.

The following examples are intended to explain the process according to the invention further. The specified melting points were determined on the Kofler block under the microscope.

example 1

4- (3 ', 4'-methylenedioxybenzyl) -1,4-diazabicyclo [4,4.0] decane

^ o

A solution of 6 g of 1,4-diazabicyclo [4,4,0] decane and 7.7 g of 3,4-methylenedioxybenzyl chloride in 400 ml of xylene was heated for 10 hours in the presence of 1.24 g dry potassium carbonate to 135 ⁰ C. After the reaction has ended, the salt is filtered off and the xylene solution is extracted several times with 10% hydrochloric acid. The combined acidic solutions are washed with ether and then made alkaline with 10% sodium hydroxide solution. The released oily base is extracted with ether. After drying over dry potassium carbonate, the solvent is evaporated off under reduced pressure and 10 g of the crude, oily base are obtained.

After dissolving in anhydrous ethanol and adding a solution of dry hydrogen chloride in Ether, 7.6 g of white crystals of dichlorohydrate are obtained; F. 239 to 241 ° C. The yield is 52.6%.

Following the procedure given above, the following compounds were made:

a) 4 - (3 ', 4'-methylenedioxyphenethyl) -1,4-diazabicyclo [4,4,0] decane using 1,4-diazabicyclo [4,4,0] decane and 3,4-methylenedioxyphenethyl chloride in a yield of 32.4%. The corresponding dichlorohydrate melts at 210 to 214 ° C with decomposition.

b) 4 - (3 ', 4'-dimethoxybenzyl) -1,4-diazabicyclo- [4,4.0] decane using 1,4-diazabicyclo- [4,4.0] decane and 3,4-dimethoxybenzyl chloride in a yield of 74.1%. The corresponding dichlorohydrate melts at 152 to 154 ° C.

c) 4 - [2 ', 2'-Diphenyl - T- hydroxyethyl - (1')] 1,4-diazabicyclo [4,4,0] decane using 1,4-diazabicyclo [4,4,0] decane and 2 ', 2'-diphenyl-2'-hydroxyethyl chloride in a yield of 47%. The corresponding dichlorohydrate melts at 210 ^° C.

d) 4 - («- Cyclohexylbenzyl) -1, 4-diazabicyclo [4,4,0] decane using 1,4-diazabicyclo [4,4,0] decane and α-cyclohexylbenzyl chloride in a yield of 15 , 2%. The corresponding dichlorohydrate melts at 239 to 24O ⁰ C.

B e i s ρ i e 1 2

4-phenethyl 1-1,4-diazabicyclo [4,4,0] decane

The following compounds were produced according to the above procedure:

a) 4-Benzhydryl-1,4-diazabicyclo [4,4.0] decane using 1,4-diazabicyclo [4,4.0] decane and benzhydryl bromide in a yield of 62.9%. The corresponding dichlorohydrate melts at 195 up to 210 ° C with decomposition.

b) 4- [3 ', 3'-Diphenylpropyl- (l)] - 1,4-diazabicyclo- [4,4,0] decane using 1,4-diazabicyclo- [4,4,0] decane and 3,3-diphenylpropyl bromide in 78.5% yield. The corresponding dichlorohydrate melts at 200 to 207 ⁰ C with decomposition.

c) 4- (p-Chlorobenzhydryl) -1, 4-diazabicyclo [4,4,0] decane using 1,4-diazabicyclo [4,4,0] decane and p-chlorobenzhydryl bromide in 31.2% yield. The corresponding dichlorohydrate melts at 168 to 171 ° C.

d) 4- (p-Fluorobenzhydryl) -1, 4-diazabicyclo [4,4,0] decane using 1,4-diazabicyclo [4,4,0] decane and p-fluorobenzhydryl bromide in a yield of 46 ,8th%. The corresponding dichlorohydrate melts at 190 to 220 ⁰ C with decomposition.

e) 4- (p-Methylbenzhydryl) -1, 4-diazabicyclo [4,4,0] decane using 1,4-diazabicyclo [4,4,0] decane and p-methylbenzhydryl bromide in 50.4% yield. The corresponding dichlorohydrate melts at 227 to 230 ° C.

0 4 - (m-Trifluoromethylbenzhydryl) - 1,4 - diazabicyclo [4,4.0] decane using 1,4-diazabicyclo [4,4.0] decane and m-trifluoromethylbenzhydryl bromide in a yield of 27.9% . The corresponding dichlorohydrate melts at 204 to 230 ^° C. with decomposition.

g) 4 - (p-Methoxybenzhydryl) -1,4-diazabicyclo- [4,4,0] decane using 1,4-diazabicyclo- [4,4,0] decane and p-methoxybenzhydryl bromide in a yield of 59.4%. The corresponding dichlorohydrate melts at 168 to 173 ° C.

CH,

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Claims (7)

Patent claims: 1. DiazabicycloJ ^ / t ^ decane compounds
general formula A solution of 10 g of 1,4-diazabicyclo [4,4,0] decane and 13.3 g Phenäthylbromid in 400 ml of N, N-dimethylacetamide is heated 14 hours in the presence of 20 g of dry potassium carbonate in 13O ⁰ C. When the reaction has ended, the salt is filtered off and the solvent is evaporated off under reduced pressure. The residue is dissolved in excess 10% hydrochloric acid, and the solution obtained is treated as indicated in Example 1. The yield is 44.4%. The corresponding dichlorohydrate melts at 210 to 212 ° C. with decomposition. (CHA-C-Ar I where R ₁ denotes a hydrogen atom or a hydroxyl group, R ₂ denotes a hydrogen atom, a phenyl or cyclohexyl group and Ar denotes a phenyl group which can optionally be substituted by a chlorine or fluorine atom, a trifluoromethyl or methyl group, one or two methoxy groups or a methylenedioxy group, and η is a number from 0 to 2, as well as its salts with organic acids or mineral acids. 2. 4 - (3 ', 4' - methylenedioxybenzyl) -1,4 - diazabicyclo [4,4.0] decane. 3. 4 - (3 ', 4' - dimethoxybenzyl) - 1,4 - diazabicyclo [4,4,0] decane. 4. 4 - Benzhydryl -1,4 - diazabicyclo [4,4,0] decane. 5. 4 - (p-Chlorobenzhydryl) -1,4-diazabicyclo- [4,4,0] decane. 6. 4 - (p-Fluorobenzhydryl) -1,4-diazabicyclo- [4,4,0] decane. 7. A method for the preparation of the compounds according to claim 1, characterized in that a compound of the general formula is used in a manner known per se Z- (CH ₂ ) _n -C-Ar wherein Z represents a chlorine or bromine atom or a benzene or p-toluenesulfonic acid radical, with diazabicyclo [4,4,0] decane of the formula NH condensed.