DD145536A5 - PROCESS FOR PREPARING TRANS-2-SUBSTITUTED-5-ARYL-2,3,4,4A, 5,9B-HEXAHYDRO-1H-PYRIDO (4,3-B) -INDOLDERIVATE - Google Patents

Description

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Process for the preparation of trans-substituted 5-aryl- 2,3,4-, Aa, 5,9b-, 1H - pyrido (4,3- b) indole derivatives

Field of application of the invention :

The invention relates to starred trans-2-substituted -5-aryl-2,3,4,4a, 5j9fc-hexahydro-1H-pyrido (4,3-b) indole derivatives useful as tranquilizers.

Characteristic of the known technical solutions;

Ira's follow-up to the introduction of reserpine and chlorpromazine in psychotherapeutic medicine in the early 19130-yr have been making great efforts in finding other tranquilizers biivJ. Tranquillanten rat improved biological profiles made more thereof are Ϋ _{-Carbolinderivate} is} the in the art as derivatives of pyrido (A, 3-b) indole are known "

In U.S. Patent 3,668? 961, 8-fluoro-2 ~ / ^ ~ (4-fluorphenyla ~ nilonO) -propyl_ / ~ 1j2,3, ^A-teti> ahydro-y-carboline described as useful for tranquilizers VJamiblüter In US Patent 3 755 are structurally related compounds described fluorine in the 6 "or 8 positions and a specific, p-substituted phenylalkyl moiety in the 2-position as compounds with similar activity *

U.S. Patent 3,983,239 describes hexahydro-1,4-carboline

1 ·· 2

of formula a, wherein R is a methyl or ethyl radical and R 'represents a hydrogen atom, a methyl or ethyl radical. The stereochemical arrangement of the hydrogen atoms bound to the carbon atoms in the 4a and 9b positions is not mentioned in this document. However, it can be assumed that they are in a cis arrangement because of the method of formation of hexahydro ^ -carbolinringes from a 1,2,3,4-tetrahydro ^{~}; w} carboline-precursor compound by catalytic hydrogenation in Anuesenheit of platinum, a well-known in the art ethod for the introduction of hydrogen atoms in a cis configuration to a carbon -carbon double bond. The compounds mentioned are neuroleptic agents which are considered useful for the treatment of schizophrenia »

U.S. Patent 3,991,199 discloses hexahydropyrimido- (4,3-b) indoles and their pharmaceutically acceptable salts, useful as analgesics and sedatives, some of which are of tranquillizers, some of which are muscle relaxants, and many of these compounds hypotensive activity; the compounds described have the formula b, wherein the hydrogen atoms bound to the carbon atoms in the 4a and 9b positions are in a trans arrangement with respect to each other and wherein "when Y = -H ', X = -H, -Cl, -Br, -CH-, -tert «~ C ^ H or -OCH, and when Y ^a = -CF ₃ , X ^a = -H and R has the meaning: hydrogen, 3-chloro-2-butenyl Benzyl, methoxy or chloro; phenethyl, 3-phenylpropyl; 3-phenylpropyl substituted by chlorine, bromine or methoxy on the ring; furfuryl; 2-thenyl; C 1 -C 4 -alkyl; c_-C _r -alkenyl; C ^ -C ₁ -alkynyl; cinnamyl; cinnamyl substituted with chlorine, bromine or methoxy-ara ring; 3-phenyl-2-propynyl; C-C ₁₇ -cycloalkyl; C 1 -Co-c -Cycloalkylmethyl; (methylcyclopropyl) -methyl; (cis-methylmethyl-cyclopropyl) -methyl; Cg-Cg-cyclooalkenylmethyl; Cg-Cg-cyclooalkadienyl-methyl;

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(2,3-DImethylcycloprop-2-en-1-yl) methyl; exo-7-Norcarylmethyl; (cis-1 _f -dimethy.lendo-3-norcaren-7-yl) -raethyl; (4-methylbicyclo /2.2.2._7oct-1-yl) -raethyl (4-methylbicyclo / 2.2.2_Ioct-2-en-1-yl) -methyl "(Bioyclo / 2" .2.2_7hept-2 yl) -raethyl; (bicyclo / 2 \ 2.2j7hept ~ 2 ~ en »5-yi) -methyl; 1-adaraantyl-3-methyl or 2 ~ adaraantylmethyl,

Belgian Patent 845,368 (Derwerst, Hr. 00043Y), recently published, discloses 5-phenyl-hexahydro-carbolines optionally substituted in the 2- and 4-positions by methyl or ethyl ViDd in the 3-position by alkyl 1 to 3 carbon atoms, allyl or propargyl substituted. These compounds are useful as antidepressants.

In more recent unpublished German Offenlegungsschrift 2 631 (Dervjent No. 097.38Y) there are described structurally distributed octahydropyrido / 4 ', 3': 2,3_ / ~ iβdolo / 1,7-ab-1 / benzo-sinepins obtained from can be derived from the formula previously given to ™ in which .Y is an ethylenic bridge between the two benzene . X is a water toffatora and R ^{a is} -CH ₂ CH ₂ COCH or -CH ₂ CH ₂ COCgH ₅ . These compounds are also indicated to be useful as analgesics and tranquilizers. "

U.S. Patent 4,001,263 discloses 5-aryl-1,2,3,4-tetrahydro-jr

carbol-1-n-quaternarymer of the formula σ in which X and Z may be a hydrogen atom or a fluorine atom, and the meanings of the meaning as previously may be for R ^a .

Surprisingly, it has now been found that certain new trans-2,3 ₅ 4. 4a, 5 "9 '^; - Hexahydro ~ ⁱ ~ 1II-pyrido (4 ₅ 3-b) indoles .ausgeprägt over le ge no Tran ™ quilizeralctivität compared to the corresponding 1,2, ^, h have DRO -cai ⁱ bolinon.

tfSSIS

Object of the invention:

The present invention relates to a process for the preparation of intermediates which are valuable for the products of compounds of formula II, as well as the pharmaceutically acceptable salts thereof. These end products are useful as tranquilizers. In formula II, wherein the hydrogens bonded to the carbon atoms in the 4a and 9b positions are in a trans arrangement to each other before X and y, which may be the same or different, represent a hydrogen atom or fluorine atom, η is 3 or 4, M is one of the radicals η _t

-C- or -CII-, and Z is a hydrogen atom, fluorine atom or a Msthoxyrest. The preparation of these end products is described in the priority application AP C 07 D / 205 479.

Other valuable tranquilizers according to the invention are the enantiomers and racemic compounds of formula III, as well as the pharmaceutically acceptable salts thereof, wherein the hydrogen atoms in the 4a and 9b "positions are in the same trans arrangement as before, X. and Y are as defined above, m is the number 2 or 3 is a. fluorine atom and _Z? or a methoxy radical, ''

Explanation of the essence of the invention

According to the invention, for the preparation of intermediates in the form of 4a, 9b ~ trans ~ hexahydrocarboline ~ compounds of formula I is a 4a _s 9b «Hexahydro> - ^/ * '» carbolin ~ compound of formula IV, wherein X. Y is hydrogen and R ₂ Bsnzyl reacted with hydrogen in the presence of a palladium-carbon catalyst, typically -is the reaction untex use of the hydrochloride salt of the compound IV at a temperature of about 50 C to 100 ⁰ C, preferably "

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Example 60 ⁰ C to 75 ° C, and hydrogen pressure of about 1.4 to 7 kg /

2 cm in the presence of an acidic solvent, e.g. Methanol, ethanol, isopropanol, ethyl acetate or mixtures thereof with water. After completion of hydrogen uptake, the catalyst is removed by filtration and the hydrochloride salt of the product of formula X is precipitated by the addition of a nonsolvent such as ethyl ether, benzene or hexane , Alternatively, the free base of formula X can be isolated by evaporating the filtrate from the debenzylation to dryness, partitioning the residue between aqueous alkali, e.g., sodium hydroxide, and a solvent such as chloroform or ethyl ether. The free base is then purified by standard methods, e.g. the methods described above, isolated.

The following describes the preparation of the starting materials. «

The "carboline" is obtained after Fischer's synthesis of T, using N-, N-dipheny- .hydra2in, and N-3snzyl-4-piperidone., The mono- or di-fluoro-substituted starting tetrahydro- ^ -carbolines of _? formula VIII, wherein at least one of X or Y represents a fluorine atom and R is the benzyl radical, are prepared from the corresponding compounds of formula VIII, ν or in R ₂ ^e ^ - ⁿ V / asserstof fatom, by reaction with a Benzylhalogsnid The compounds of the formula VIII, Rp-H, which are required for this purpose, are prepared as described in US Pat. No. 4,001,236. The starting tetrahydro-carbolines V are described in the same document

The other starting materials are either commercially available products, their preparation is described in detail in the chemical literature or they can be prepared by methods known per se to those skilled in the art.

be-made. For example phenylhydrazines are commercially available or they are prepared by reduction of the phenyldiazoniurase salt as described above. Wagner and Zook in Synthetic Organic Chemistry, John Wiley & Sobs, New York, N.Y., 1956 chapter 26. The i-substituted-piperidones are commercial reagents or are prepared by the method of M. McElvain and Rorig, J.Anu. Chem. Soc., O (1948), S * 1826. The required 3-Bensoylpropinsäuren and 4-benzoyl butyric acids are either commercially * available or they are by modification of the procedure according to "Organic Synthesis", Coll. VoI, 2, John Wiley & Sons, Mew York, N.Y., 1943, p. 81.

Exporting rungsbe ispiel: _

dl-trans-5-phenyl-2,3 _J 4,4a, 5 ₉ 9b-hexahydro-1 H -pyrido (4,3-b) -indole

A suspension of 4.17 g of dI-trans-2-benzyl-5-phenyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido (4,3-b) -α-dihydrochloride in 150 ml of absolute ethanol hydrogenated at 3 »5 kp / cm and S0 ~ 70 ° C using 1.0 g of 10 % Ρά / C catalyst for a period of 2 hours. The catalyst was removed by filtration, and sufficient ethyl ether was added to the filtrate to precipitate the hydrochloride of the desired product; Yield = 2, 6 g (8%) 1 F. 235 ~ 237 ° C,

The hydroxochloride salt was converted to the free base by partitioning between ether and dilute sodium hydroxide solution. The ether layer was dried over sodium sulfate and evaporated to give the title compound in 97 % yield; F, 74-76 ⁰ C ₄

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Claims (1)

Invention claim: A process for preparing a 4a, 9b-trans-hexahydro-f-carboline compound of Formal I, wherein X and Y are hydrogen, denotes dadu rc h that a 4a, 9b-hexahydro [^ f -carboline compound of FormellV , viorin implemented X and Y is hydrogen and Rp represents benzene, V / on hydrogen in presence of a palladium-carbon catalyst vjird _o For this purpose .. ^. Sslfen'Formslo