DE1037455B - Process for the preparation of 1-alkyl-carbamyloxyindolines, their salts and quaternary ammonium compounds - Google Patents

Description

GERMAN

The invention relates to a process for the preparation of 1-alkyl-6-carbamyloxyindolines of the general formula

R ¹

R ² '

- COO— ¹ ,

in which R is an alkyl radical and R ¹ and R ^{2 are} hydrogen atoms, alkyl or aryl radicals, their salts and quaternary ammonium compounds, e.g. B. 1,1-dialkylindolinium salts, especially 1,1-dimethyl-6- (N-methylcarbamyloxy) indolinium salts, such as the bromide of the formula

HoCNHCOO-

Br-

H ₃ C

CH ₃

The compounds obtained according to the process have a pharmacological level comparable to that of physostigmine Effect and should be used as a remedy. In particular, said 1,1-dimethyl-6- (N-methylcarbamyloxy) indolinium bromide is about ten times more effective than physostigmine in the brain cholinesterase inhibition test.

The compounds according to the invention are also more similar to the already known synthetic substances with physostigmines Effect, for example the dimethylcarbamic acid ester of m-hydroxyphenyltrimethylammonium methyl sulfate, superior in vitro and in situ. This is 1,1-dimethyl-6- (N-methyl-carbamyloxy) -indolinium bromide in situ around 7 to 10 times more effective than the dimethylcarbamic acid ester of m-Hydroxy-phenyltrimethyl-ammonium-methyl sulfate, while its toxicity is only twice as great. It has also been shown that the method according to the 6-position Compounds substituted by the carbamyloxy radical are more effective than the corresponding 5-substituted ones. In the literature, compounds with a physostigmine-like effect are l, l, 2,3-tetramethyl-5- (N-dimethyl-carbamyloxy) indolinium iodide [Journal of the American Chemical Society, Vol. 69 (1947), pp. 3086 to 3088] and the Ν, Ν-disubstituted carbamic acid ester des 3-Oxypyridins (Austrian Patent 165 072 and USA Patent 2,489,247). That known 1,1,2,3-tetramethyl-5- (N-dimethyl-carbamyloxy) indolinium iodide was made by reacting 5-0xy-1,2,3-trimethylindoline with dimethylcarbamic acid chloride method of manufacture

of l-alkyl-carbamyloxyindolines,

their salts and quaternary

Ammonium compounds

Applicant:
CIBA Aktiengesellschaft, Basel (Switzerland)

Representative: Dipl.-Ing. E. Splanemann, patent attorney, Hamburg 36, Neuer Wall 10

Claimed priority:
Switzerland from February 8, 1952 and January 6, 1953

Dr. Emil Schüttler, Basel,

and Dr. Johannes Müller, Ariesheim (Switzerland),
have been named as inventors

and treating the base obtained with methyl iodide.

The new indolines are obtained when 1-alkyl-6-oxyindolines are used with a carbamic acid halide the general formula

R ¹ ,

R ² '

N -CO shark

in which Hal is a halogen atom, R ¹ and R ^{2 are} hydrogen atoms, alkyl or aryl radicals, reacts, optionally treating the bases obtained with quaternizing agents and / or acids or, instead of the carbamic acid halide, also a corresponding isocyanic acid ester, which is formed in the course of the reaction can, or phosgene and ammonia or a corresponding primary or secondary amine are used.

The oxyindolines can also be used for the reaction in the form of their salts or quaternary compounds Find. The quaternization to be carried out, if necessary, can be carried out in a manner known per se are, preferably with agents that contain an alkyl radical, e.g. B. are able to introduce a methyl radical. So can the 6-carbamyloxy-l-alkyl-indolines with reactive esters of strong inorganic or organic acids, ζ. B. with esters of

809 599/547

3 4

Hydrohalic acids, sulfuric acid or orga- Shake entered and the mixture last

Nischer sulfonic acids, such as with alkyl halides, alkyl boiled under reflux for 2 hours. Then it will be

Sulfates or toluene sulfonates. the mixture is rinsed with benzene into a separatory funnel,

The procedural reactions can be carried out three times with water, twice with ice-cold 2 n soda

or the absence of diluents with ordinary lye and again washed three times with water. With

Licher or higher temperature in open or in sodium sulfate dried benzene solution is finally

closed vessel under pressure, possibly evaporated in a vacuum; the remaining brown

The presence of condensing agents and / or oil crystallizes after a short time. The sucked off

Catalysts. Crystal cake is subjected to high vacuum sublimation

The starting materials are known or can be thrown after an io and the sublimate from a mixture of ether

known methods can be produced. and hexane recrystallized. After another sub-

Depending on the working method, the new version (0.5 mm / 110 ° C) is obtained, the pure 1-methyl-

bonds in the form of the free bases or their salts. From 6- (N, N-dimethyl-carbamyloxy) -indoline of the formula
these can in the usual way, the free amine or. _x

Ammonium bases are obtained. Of the latter 15 HC Ii

in turn, by reaction with acids that ^ NfOf) i

suitable for the formation of therapeutically useful salts χ ^ '' ^

are to win salts, e.g. B. the hydrohalic acids, H ₃ C

Sulfuric acid, nitric acid, phosphoric acid, rhodanic

hydrogen acid, acetic acid, propionic acid, oxalic acid, 20 CH ₃
Malonic acid, succinic acid, malic acid, methanesulfone - which melts at 63 to 64 ° C. Yield 2.1 weight acid, ethanesulphonic acid, oxyethanesulphonic acid, benzene parts (48% of theory). Analogous to that in Example 1 or toluenesulfonic acid. The process described is used to obtain the 1,1-di-

The invention is illustrated in the following examples methyl-ö-iN.N-dimethyl-carbamyloxyJ-indoliniumbro-

explained. 25 mid, which melts between 158 and 164 ° C.

Example 1 Example 3

1.75 parts by weight of l-methyl-6-oxyindoline are mixed with 3.0 parts by weight of l-methyl-6-oxyindoline in

0.1 part by weight of triethylamine, followed by 4 volumes of 30 Volum- dry benzene dissolved andin 100 parts by volume of methyl isocyanate in portions under cooling 30 parts of a 20 ° / ₀ solution of phosgene in benzene under offset, wherein added gradually all substance in solution agitation. Then the secluded goes. Then the mixture is filtered off with suction for 24 hours at 20.degree. C., crystalline hydrochloride of the base and left to stand, l-methyl-6- (N-methyl-carb-filtrate being freed from excess phosgene by evaporation under reduced pressure amyloxy) indoline of the formula . The oily residue

35 of the chlorocarbonic acid ester obtained in this way - is dissolved in 30 parts by volume of benzene and stirred

_wr , and cooling in 3.0 parts by volume of a 33% aqueous

H ₃ CNHLUU - \ / \ _N / Dimethylamine solution added dropwise, another 1 hour

stirred and left to stand overnight. The benzene solution is then separated off three times with water, twice with ice-cold ³ 2 η sodium hydroxide solution and again three times with water. It melts after recrystallizing from ether wash. After drying over sodium sulfate and sublimation (0.1 mm / 80 ° C.) at 98 ° C. Yield of evaporation of the solvent under reduced pressure 1.30 parts by weight (54% of theory). soon crystallization of the oily residue occurs.

1 part by weight of l-methyl-6- (N-methyl-carbamyloxy) - 45 The crystals are purified as indicated in Example 2, indoline is mixed with 5 parts by weight of methyl bromide and the l-methyl-6- (N, N-di-5 parts by weight of benzene for 12 to 15 hours in methyl-carbamyloxy) indoline. Yield 1.05 weight bomb tube heated to 80 ° C. The 1,1-di-part is obtained in this way (24% of theory).
methyl-6- (N-methyl-carbamyloxy) -indoUniumbromid, das.

after recrystallization from a mixture of methanol 50 Example 4

and ether melts between 158 and -170 ° C. Yield 5.0 parts by weight of l-methyl-6-oxyindoline are in

1.15 parts by weight (98% of theory). 70 parts by volume of dry benzene dissolved and under

The 1-methyl-6-oxy used as starting material stir in 120 parts by volume of a 20% benzene phosgene solution can be added dropwise to indoline (mp 97 ° C.) in a manner known per se. Then the separated be obtained by sucking off m-acetylanisidine with 55 crystalline hydrochloride of the base and that The filtrate is converted from dimethyl sulfate into the N-methyl-m-anisidine by evaporation under reduced pressure and the corresponding N-methyl- freed from excess phosgene with chloroacetyl chloride. The oily residue N-chloroacetyl-m-anisidine produces. The ring closure to the chloroformate obtained in this way 1-methyl-6-oxyoxindole is pre-dissolved in 40 parts by volume of benzene with aluminum chloride and stirring taken and the keto group with lithium aluminum-60 and cooling in a solution of 5.7 parts by weight hydride reduced to the indoline derivative. Diphenylamine added dropwise in 30 parts by volume of benzene,

. . then for 1 hour at room temperature

Example I continued to stir and last for 1 hour on the back

3.0 parts by weight of l-methyl-6-oxyindoline are boiled in a river. Then the cooled solution is used three times

a solution of 0.8 parts by weight of sodium hydroxide 65 with water, twice with ice-cold 2 η sodium hydroxide solution and dissolved in 15 parts by volume of water and then washed under again three times with water, with sodium sulfate evaporated to dryness under reduced pressure. That dried and evaporated in vacuo. From the oily

The solid sodium salt obtained therefrom will separate in portions after adding a little ether into a solution of 2.6 parts by weight of dimethylcarb crystals. The crystals are sucked off and the amyl chloride in 20 parts by volume of absolute benzene under 70 filter residue to remove added di-

phenylamine washed several times with ether. It is then recrystallized from a mixture of benzene and hexane and finally sublimed at 0.5 mm / 160 ° C., the pure l-methyl-6- (N, N-diphenyl-carbamyloxy) indoline the formula

H ₅ C

₅ C _6x

H ₅ C ₆

NCOO-v

10

CH,

obtained, which has a melting point of 158 to 159 ° C. Yield 2.8 parts by weight (24% of theory).

Claims (3)

Patent claims: 1. Process for the preparation of 1-alkyl-carbamyloxyindolines, their salts and quaternary ammonium compounds by reacting 1-alkyloxyindolines with a carbamic acid halide of the general formula N —CO shark, nizing agents and / or acids, characterized in that l-alkyl-6-oxyindolines are added l-alkyl-6-carbamyloxyindolines of the general formula R ¹ . N -COO in which R represents an alkyl radical and R ¹ and R ^{2 have} the meaning given, reacted and, in place of the carbamic acid halide, also used a corresponding isocyanic acid ester, which can be formed in the course of the reaction, or phosgene and ammonia or a corresponding primary or secondary amine . 2. The method according to claim 1, characterized in that 1-methyl-6-oxyindoline is used as the l-alkyl-6-oxyindoline used. 3. The method according to claim 1 and 2, characterized in that l-methyl-6-oxyindoline is added 1-methyl-6- (N-methylcarbamyloxy) indoline converts. R ² Considered publications: Austrian Patent No. 165 072; wherein Hal is halogen, R ¹ and R ^{2 are} hydrogen - U.S. Patent No. 2,489,247; mean atoms, alkyl or aryl radicals, optionally Journal of the American Chemical Society, Vol. 69 Treatment of the bases obtained with Quater 30 (1947), pp. 3086 to 3088. © 809 599/5 + 7 8.58