CS242858B2 - Method of octahydro-1h-pyrrolo(2,3-g)-isoquinolines production - Google Patents

Abstract

1. Claims for the Contracting States : BE, CH, DE, FR, GB, IT, LU, NL, SE. An octahydro-1H-pyrrolo[2,3-g]isoquinoline of the general formula see diagramm : EP0010661,P42,F2 wherein R1 is hydrogen, (C1 -C7 )-alkyl, (C1 -C7 )-alkanoyl or benzoyl or phenyl-(C1 -C7 )-alkyl each of which is optionally substituted on the phenyl ring by halogen, trifluoromethyl, (C1 -C7 )-alkyl, (C1 -C7 )-alkoxy, nitro, amino, (C1 -C7 )-alkylamino or di-(C1 -C7 )-alkylamino, R2 and R3 independently of each other are hydrogen, (C1 -C7 )-alkyl, (C3 -C6 )-cycloalkyl, (C2 -C7 -alkenyl, (C1 -C7 )-alkanoyl or benzoyl, phenyl or phenyl-(C1 -C7 )-alkyl each of which is optionally substituted on the phenyl ring by halogen, trifluoromethyl, (C1 -C7 )-alkyl, (C1 -C7 )-alkoxy, nitro, amino, (C1 -C7 )-alkylamino or di-(C1 -C7 )-alkyl-amino and R4 is hydrogen, (C1 -C7 )-alkyl, hydroxy-(C1 -C7 )-alkyl, phenyl-hydroxy-(C1 -C7 )-alkyl, halophenyl-hydroxy-(C1 -C7 )-alkyl, (C1 -C7 )-alkylphenyl-hydroxy-(C1 -C7 )-alkyl, (C1 -C7 )-alkoxyphenyl-hydroxy-(C1 -C7 )-alkyl, (C1 -C7 )-alkoxy-(C1 -C7 )-alkyl, (C1 -C7 )-alkoxy-hydroxy-(C1 -C7 )-alkyl, (C1 -C7 )-alkanoyloxy-(C1 -C7 )-alkyl, (C1 -C7 )-alkoxycarbonyl-(C1 -C7 )-alkyl, (C2 -C7 )-alkenyl, (C3 -C6 )-cycloalkyl-(C1 -C7 )-alkyl, (C2 -C7 )-alkynyl, thienyl-(C1 -C7 )-alkyl, furyl-(C1 -C7 )-alkyl, (C1 -C7 )-alkanoyl-(C1 -C7 )-alkyl, (C3 -C6 )-cycloalkoxy-(C1 -C7 )-alkyl, (C3 -C6 )-cycloalkyl-hydroxy-(C1 -C7 )-alkyl, (C2 -C7 )-alkenyloxy-(C1 -C7 )-alkyl, N-(C1 -C7 )-alkyl-pyrrolidinyl-(C1 -C7 )-alkyl, trifluoroalkyl with 2 to 6 carbon atoms or phenoxy-hydroxy-(C1 -C7 )-alkyl, benzoyloxy-(C1 -C7 )-alkyl benzoyl-(C1 -C7 )-alkyl, phenyl-(C1 -C7 )-alkyl, phenylcarboxamido-(C1 -C7 )-alkyl, phenyl-(C2 -C7 )-alkenyl, phenoxy-(C1 -C7 )-alkyl or phenyl-N-imidazolonyl-(C1 -C7 )-alkyl each of which is optionally substituted on the phenyl ring by halogen, trifluoromethyl, (C1 -C7 )-alkyl, (C1 -C7 )-alkoxy, nitro, amino, (C1 -C7 )-alkylamino or di-(C1 -C7 )-alkylamino, or see diagramm : EP0010661,P43,F2 wherein R6 and R7 independently of each other are hydrogen or (C1 -C7 )-alkyl or together with the nitrogen atom are a 5- or membered saturated heterocyclic ring which can further contain as a ring member an oxygen atom or a nitrogen atom optionally substituted by (C1 -C7 )-alkyl or hydroxy-(C1 -C7 )-alkyl, and X is O or S, an optical or geometric isomer thereof or a pharmaceutically acceptable acid addition salt thereof. 1. Claims for the Contracting State : AT. A process for the manufacture of octahydro-1H-pyrrolo[2,3-g]isoquinolines of the general formula see diagramm : EP0010661,P47,F3 wherein R1 is hydrogen, (C1 -C7 )-alkyl, (C1 -C7 )-alkanoyl or benzoyl or phenyl-(C1 -C7 )-alkyl each of which is optionally substituted on the phenyl ring by halogen, trifluoromethyl, (C1 -C7 )-alkyl, (C1 -C7 )-alkoxy, nitro, amino, (C1 -C7 )-alkylamino or di-(C1 -C7 )-alkylamino, R2 and R3 independently of each other are hydrogen, (C1 -C7 )-alkyl, (C3 -C6 )-cycloalkyl, (C2 -C7 )-alkenyl, (C1 -C7 )-alkanoyl or benzoyl, phenyl or phenyl-(C1 -C7 )-alkyl each of which is optionally substituted on the phenyl ring by halogen, trifluoromethyl, (C1 -C7 )-alkyl, (C1 -C7 )-alkoxy, nitro, amino, (C1 -C7 )-alkylamino or di-(C1 -C7 )-alkylamino and R4 is hydrogen, (C1 -C7 )-alkyl, hydroxy-(C1 -C7 )-alkyl, phenyl-hydroxy-(C1 -C7 )-alkyl, halophenyl-hydroxy-(C1 -C7 )-alkyl, (C1 -C7 )-alkylphenyl-hydroxy-(C1 -C7 )-alkyl, (C1 -C7 )-alkoxyphenyl-hydroxy-(C1 -C7 )-alkyl, (C1 -C7 )-alkoxy-(C1 -C7 )-alkyl, (C1 -C7 )-alkoxy-hydroxy-(C1 -C7 )-alkyl, (C1 -C7 )-alkanoyloxy-(C1 -C7 )-alkyl, (C1 -C7 )-alkoxycarbonyl- (C1 -C7 )-alkyl, (C2 -C7 )-alkenyl, (C3 -C6 )-cycloalkyl-(C1 -C7 )-alkyl, (C2 -C7 )-alkynyl, thienyl-(C1 -C7 )-alkyl, furyl-(C1 -C7 )-alkyl, (C1 -C7 )-alkanoyl-(C1 -C7 )-alkyl, (C3 -C6 )-cycloalkoxy-(C1 -C7 )-alkyl, (C3 -C6)-cycloalkyl-hydroxy-(C1 -C7 )-alkyl, (C2 -C7 )-alkenyloxy-(C1 -C7 )-alkyl, N-(C1 -C7 )-alkyl-pyrrolidinyl-(C1 -C7 )-alkyl, trifluoroalkyl with 2 to 6 carbon atoms or phenoxy-hydroxy-(C1 -C7 )-alkyl, benzoyloxy-(C1 -C7 )-alkyl, benzoyl-(C1 -C7 )-alkyl, phenyl-(C1 -C7 )-alkyl, phenylcarboxamido-(C1 -C7 )-alkyl, phenyl-(C2 -C7 )-alkenyl, phenoxy-(C1 -C7 )-alkyl or phenyl-N-imidazolonyl-(C1 -C7 )-alkyl each of which is optionally substituted on the phenyl ring by halogen, trifluoromethyl, (C1 -C7 )-alkyl, (C1 -C7 )-alkoxy, nitro, amino, (C1 -C7 )-alkylamino or di-(C1 -C7 )-alkylamino, or see diagramm : EP0010661,P47,F2 wherein R6 and R7 independently of each other are hydrogen or (C1 -C7 )-alkyl or together with the nitrogen atom are a 5- or 6-membered saturated heterocyclic ring which can further contain as a ring member an oxygen atom or a nitrogen atom optionally substituted by (C1 -C7 )-alkyl or hydroxy-(C1 -C7 )-alkyl, and X is O or S, the optical and geometric isomers of these compounds and their pharmaceutically acceptable acid addition salts, characterized by a) for the manufacture of a compound of the general formula see diagramm : EP0010661,P47,F4 wherein R"4 is (C1 -C7 )-alkyl, (C1 -C7 )-alkoxy-(C1 -C7 )-alkyl or (C3 -C6 )-cyclo-alkyl-(C1 -C7 )-alkyl and R2 and R3 are as described previously, treating a compound of the general formula see diagramm : EP0010661,P48,F1 wherein R2 , R3 and R"4 are as described previously, with formaldehyde, or b) for the manufacture of a compound of formula Ia above, treating a compound of the general formula see diagramm : EP0010661,P48,F2 wherein R"4 is as described previously, with a compound of the general formula see diagramm : EP0010661,P48,F3 in the presence of a reducing agent, or with a compound of the general formula see diagramm : EP0010661,P48,F5 wherein R2 and R3 are as described previously, or a precursor thereof, or c) for the manufacture of a compound of the general formula see diagramm : EP0010661,P48,F7 wherein R2 and R3 are as described previously, N-demethylating a compound of formula Ia above wherein R"4 is methyl, or d) for the manufacture of a compound of the general formula see diagramm : EP0010661,P48,F8 wherein R'2 and R'3 independently of each other are hydrogen, (C1 -C7 )-alkyl, (C3 -C6 )-cycloalkyl, (C2 -C7 )-alkenyl or phenyl or phenyl-(C1 -C7 )-alkyl each of which is optionally substituted on the phenyl ring by halogen, trifluoromethyl, (C1 -C7 )-alkyl, (C1 -C7 )-alkoxy, nitro, amino, (C1 -C7 )-alkyl-amino or di-(C1 -C7 )-alkylamino, R'"4 is hydrogen, (C1 -C7 )-alkyl, (C1 -C7 )-alkoxy-(C1 -C7 )-alkyl, (C2 -C7 )-alkenyl, (C3 -C6 )-cycloalkyl-(C1 -C7 )-alkyl, (C2 -C7 )-alkynyl, thienyl-(C1 -C7 )-alkyl, furyl-(C1 -C7 )-alkyl, (C2 -C7 )-alkenyloxy-(C1 -C7 )-alkyl or phenyl-(C1 -C7 )-alkyl, phenyl-(C2 -C7 )-alkenyl or phenoxy-(C1 -C7 )-alkyl each of which is optionally substituted on the phenyl ring by halogen, trifluoro-methyl, (C1 -C7 )-alkyl, (C1 -C7 )-alkoxy, nitro, amino, (C1 -C7 )-alkylamino or di-(C1 -C7 )-alkylamino, or trifluoroalkyl with 2 to 6 carbon atoms and R1 is as described previously, treating a compound of the general formula see diagramm : EP0010661,P48,F4 wherein R1 , R'2 , R'3 and R'"4 are as described previously, with phosphorus pentasulphide, or e) for the manufacture of a compound of the general formula see diagramm : EP0010661,P48,F6 wherein R4-IV is hydroxy-(C1 -C7 )-alkyl, phenyl-hydroxy-(C1 -C7 )-alkyl, halophenyl-hydroxy-(C1 -C7 )-alkyl, (C1 -C7 )-alkyl-phenyl-hydroxy-(C1 -C7 )-alkyl, (C1 -C7 )-alkoxyphenyl-hydroxy-(C1 -C7 )-alkyl, (C1 -C7 )-alkoxy-hydroxy-(C1 -C7 )-alkyl, (C1 -C7 )-alkanoyloxy-(C1 -C7 )-alkyl, (C1 -C7 )-alkoxycarbonyl-(C1 -C7 )-alkyl, (C1 -C7 )-alkanoyl-(C1 -C7 )-alkyl, (C3 -C6 )-cycloalkoxy-(C1 -C7 )-alkyl, (C3 -C6 )-cycloalkyl-hydroxy-(C1 -C7 )-alkyl, N-(C1 -C7 )-alkyl-pyrrolidinyl-(C1 -C7 )-alkyl or phenyl-N-imidazolonyl-(C1 -C7 )-alkyl, phenoxy-hydroxy-(C1 -C7 )-alkyl, benzoyloxy-(C1 -C7 )-alkyl, benzoyl-(C1 -C7 )-alkyl or phenylcarboxamido-(C1 -C7 )-alkyl each of which is optionally substituted on the phenyl ring by halogen, trifluoromethyl, (C1 -C7 )-alkyl, (C1 -C7 )-alkoxy, nitro, amino, (C1 -C7 )-alkylamino or di-(C1 -C7 )-alkylamino, or see diagramm : EP0010661,P48,F9 and R1 , R2 , R3 , R6 and R7 are as described previously, cleaving off the protecting group or protecting groups in a compound of the general formula see diagramm : EP0010661,P49,F1 wherein R"2 and R"3 have the same significance as R2 and R3 except when R2 and R3 are (C1 -C7 )-alkanoyl or benzoyl optionally substituted on the phenyl ring by halogen, trifluoromethyl, (C1 -C7 )-alkyl, (C1 -C7 )-alkoxy, nitro, amino, (C1 -C7 )-alkyl-amino or di-(C1 -C7 )-alkylamino, R"2 and R"3 are in protected form, R4-V has the same significance as R4-IV , but in protected form, and R1 is as described previously, or f) for the manufacture of a compound of the general formula see diagramm : EP0010661,P49,F2 wherein R'1 is (C1 -C7 )-alkyl, (C1 -C7 )-alkanoyl or benzoyl or phenyl-(C1 -C7 )-alkyl each of which is optionally substituted on the phenyl ring by halogen, trifluoromethyl, (C1 -C7 )-alkyl, (C1 -C7 )-alkoxy, nitro, amino, (C1 -C7 )-alkylamino or di-(C1 -C7 )-alkylamino and R2 , R3 , R"4 and X are as described previously, substituting a compound of the general formula see diagramm : EP0010661,P49,F5 wherein R2 , R3 , R"4 and X are as described previously, at the pyrrole nitrogen atom, or g) for the manufacture of a compound of the general formula see diagramm : EP0010661,P49,F7 wherein R'4 is (C1 -C7 )-alkyl, hydroxy-(C1 -C7 )-alkyl, phenyl-hydroxy-(C1 -C7 )-alkyl, halophenyl-hydroxy-(C1 -C7 )-alkyl, (C1 -C7 )-alkylphenyl-hydroxy-(C1 -C7 )-alkyl, (C1 -C7 )-alkoxyphenyl-hydroxy-(C1 -C7 )-alkyl, (C1 -C7 )-alkoxy-(C1 -C7 )-alkyl, (C1 -C7 )-alkoxy-hydroxy-(C1 -C7 )-alkyl, (C1 -C7 )-alkanoyloxy-(C1 -C7 )-alkyl, (C1 -C7 )-alkoxycarbonyl-(C1 -C7 )-alkyl, (C2 -C7 )-alkenyl, (C3 -C6 )-cycloalkyl-(C1 -C7 )-alkyl, (C2 -C7 )-alkynyl, thienyl-(C1 -C7 )-alkyl, furyl-(C1 -C7 )-alkyl, (

Description

Present at ^y n ^and falsehood te th of ^{p kl} ůtobu production ^Y octahydro ^y dro-lH-p ^y yrolo ^{[2,3-g gi} tochinolinů formula A

(A) wherein ^R 2 ^{3 R} 3 ^R 4 znammenjí nezáiisle thee hydrogen alkyoovou TKU ^p yne with 1-7 carbon atoms, cycloalkyl te 3-6 carbon atoms, alkenyl te 2-7 carbon 'atoms, acyl ^C 1 -C 7 -alkyl, phenyl or benzyl, and is C 1 -C 7 -alkyl, C 2 -C 14 -alkyl or cyclic alkyl-C 1-6 -alkyl; C 3 -C 6 -cycloalkyl and C 1 -C 7 -alkyls, the optical and geometric isomers of these compounds, and their pharmaceutically acceptable acid addition salts.

The term alkyl, as used herein, denotes a straight or branched, saturated hydrocarbon radical having 1 to 7 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, neopentyl, pennyl, heppyl and the like. The term alkoxy refers to an alkyl ether group in which the alkyl group is preferably a group as hereinbefore defined, such as, for example, methoxy, ethoxy, prop, K, pentoxy, etc. The term alkenyl refers to a straight or branched unsaturated hydrocarbon group of 2 to 7 atoms. The term halogeno refers to halogen atoms, i.e. bromine, chlorine, fluorine and iodine atoms. The term acyl refers to an alkamyl group derived from an aliphatic carboxylic acid having 1 to 7 carbon atoms, for example, a formyl group, an acetyl group, a C 1-6 alkyl group, and the like. , cyclohexyl and cyclohexyl.

Preferred are those compounds of formula (A) wherein R ₂ and R 6 are C 1 -C 7 alkyl and R 1 is C 2 -C 7 alkyl or C 1 -C 7 alkyl. and altoxyl moieties.

The most preferred compounds of formula (A) are the following:

^{3-ethyl-2, 6} ^^ ⁱ ^ ^{y t} mt -4 _l 43,5,6,7,8, 8a, 9-octahydro ^{y l} ur 44.88 ^{and the} H-trans pyrrlll ^[2, 3- q] ^ ocfinoHn-4-one, LJ - ^ethyl-3-yl -2,6-UieetyУ-4,4a, 5,7,7,8,8a, 9 "OktahyУuo-44.88-y-NS-lн- ^RY yгclc [2,3-g] NOJ-in - ^ - one (^ -l- ethyl ^{2 6} · Ήθ1 ^ - ^{4-4 -, 5,6,} 7, ^8, 8a, 9-L ) ktah ^yU rl and ^-4, trans ^ ^ K ^ ym]! ^{[2, 3-g] i i} SCCH nc1Пп 4-! П, hyddoccIooíU 0.25 MDL-hydrate,

2.3.6- trimethyl ^y -4-4a, 5,6,7,8,8a, ^{9-octahydro-yl} Уuoc 4.88 Hp-rannt ^{y y y} c YRC [2-З д} itcchino ^y-4 -cn,

2.3.6- trieet.y ^y -4,4-5,6,7,8,8a, 9-oct-trans- hyduoc44,88a · ^y H řyrrclc [2,3 ^ (^] itcd in ^ (^ lin-4-one hydrolC Ori ^{y, 2-methyl-3} - t ^t -L ⁶ - ⁽² -ttcxyyt ^t l) - ^4, 5? ^{6> 7.8} _<and ^8, 9-octa ^h ydro- ⁴ and, f and trans-lH-p &lt; yclo ^{[2, 3-g]} itcchino ^yl-4-CN,

2- ^yl methyl ^{3-ethyl y} - ^6-J2 ttcxyyt У ^t) - ^{4, 4} and 5, ^{6, 7, 8,} ^, 31 ^ ^^^ 9-0 44 88 -raass ^{y of} Hp YRO ^l of ^{[2, 3} -g] - tc ⁱ ¢ 211 ^ 01 ^ -4-0, and Ori ^y hydrocC

2.6- diueey ^y yУ-e4 ^t t-У, ⁴ a, a ^, 5 ^, 6 ^{, 8.8} a ^, --9 kCa ^th УUr ^l -, ^- a - tt- ^{t н} y yyy ^г c [ ^l , ³ - ^g] isos ^CC nO ^{y i} in 4-one hydr · OCC Ori ^y _of dihydrate.

Examples of compounds of formula A include:

3-Ethyl-2,6-dimethyl-1,4,4,4,5,7,8,8-octahydro-1H- [2,3-^GJ ^ 011001111-4-0, -³tf ^ J ^] .-^2, MimtyL ·⁴,⁴and,⁵,^{3 * * 6}7^{, 8.8}-^{, 9}-cktah^yUrc-⁴-^,4'-trans-1'-p'-yolof^2.3-G]^andtcchino^lin -4-on, (-) -^3-E^ty1-²,⁶-^atieet^yl-⁴⁴4-^{, 5},⁶,⁷,⁸,⁸and, 9-oct-h^yyuгc⁴4^{, 8}8^andtrarlSt⁴H-p^ŘУrolc^[2,3-g]^andtcchino^lin -4-on, h^yУrocC1ociU, 0.25 meo-h,

The third ⁶ - DME those U-2-prop-l-4, and ^{4, 8} ,, 7, ⁸ and ⁹ -ckt ^{y-hydroxy-lH-uo} pyrrc ^l c ^{[2, 3} - ^{g] and} tcchino ⁴ⁱ - ⁴ - cn ^, hyУuocC1ociU,

The third ⁶ - ieet ^{at the} - ² - ⁽² - ^{row RY} RCP) ^{4 4, 4,} and ^{5, 6, 7, 8.8,} and ^{- y} cktahy ur ^C4H -přУrolc ^[2,3 -g] ^and tcchinolin- ⁴ -lH ² .6- ^{u i t} l et] 3- ^ ^- ^ u ^ t ^ ^t У- and ^4,4, 5, ^{6, 7, 8, 8} - ⁹ -ckt-hy ^{y l4H} u O p ^{R 4} c УΓO ^[2,3 -g] itcchinclin- ⁴ -CN,

^2-yl EET У- ³ -TT У ^yl-6- (cyclopropylamino ⁴ cprop ^of Уπmty ^s) - ^{4, 4} and ^{5, 6, 7/8/8} and, 9-octahydro ^yy UOC ⁴ HP ryclc ^{y [2} , ^{3-g] i} in ^{4 l} tcchino

-4-on,

2-methyl-3-ethyl-6- (cyclopropylmethyl) -4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo [2,3-g] isoquinolin-4-one hydrochloride, 0,2 raol-hydrate,

2,6-dimethyl-3-cyclopropyl-4,43,5,6,7,8,83,9-octahydro-1H-pyrrolo [2,3-g] isoquinolin-4-one,

2-benzyl-3,6-dimethyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo [2,3-g] isoquinolin-4-one,

3,6-dimethyl-2- (2-propenyl) -4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo [2,3-g] isoquinolin-4-one,

2,6-dimethyl-3- (2-propyl) -4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo [2,3-g] isoquinolin-4-one,

3,6-diethyl-2-methyl-4,4a, 6,6,7,8,8a, 9-octahydro-1H-pyrrolo [2,3-g] isoquinolin-4-one,

2-methyl-3-ethyl-6-propyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo [2,3-g] isoquinolin-4-one,

2-methyl-3-ethyl-6-butyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo [2,3-g] isoquinolin-4-one,

2-methyl-3-ethyl-6-pentyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo [2,3-g] isoquinolin-4-one,

3,6-dimethyl-4,4a, 5 / 6,7,8,8a, 9-octahydro-1H-pyrrolo [2,3-g] isoquinolin-4-one,

6-methyl-1,4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo [2,3-g] isoquinolin-4-one,

2,6-dimethyl-3-propyl-4,4a, 5,6,7,8a, 9-octahydro-1H-pyrrolo [2,3-g] isoquinolin-4-one,

3-ethyl-2-methyl-6- (2-methylpropyl) -4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo [2,3-g] isoquinolin-4-one,

3-ethyl-2-methyl-6-cyclobutylmethyl-4,4a, 5,6,7,8,8a, 9-octahydro-ΙΗ-pyrrolo [2,3-g] isoquinolin-4-one,

3-ethyl-2-methyl-6-hexyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo [2,3-g] 2-quinolin-4-one,

3-ethyl-2-methyl-6-heptyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H, -pyrrolo [2,3-g] isoquinolin-4-one,

2,6-dimethyl-3-propyl-4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2,3-g] isoquinolin-4-one,

2,6-dimethyl-3-ethyl-4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-cis-1H-pyrrolo [2,3-g] isoquinolin-4-one and

2-acetyl-3,6-dimethyl-4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2,3-g] isoquinolin-4-one.

The compounds produced by the process of the invention may exist as the 4a, 8a-trans or 4a, 8a-cis isomers or as mixtures thereof, the 4a, 8a-trans isomers being preferred.

According to the invention, the compounds of the above general formula (A), their optical and geometric isomers and their pharmaceutically usable addition salts are used. the acid salts are prepared by treating the compound of formula IX

(IX) in which:

R _2, R ^ and R ^ are as defined above, with formaldehyde and, if desired resulting mixture of cis and trans isomers is isomerized to a final ratio which is largely represented by the trans-isomer and / or the obtained mixture optionally separating the trans-isomer, and / or the racemic mixture obtained is optionally resolved into optical antipodes, and / or the compound or pharmaceutically unacceptable acid addition salt obtained is optionally converted into a pharmaceutically usable acid addition salt.

AND

In particular, the compounds of the above general formula (A), their optical and geometric isomers, and their pharmaceutically usable acid addition salts, as well as various intermediates, can be prepared as explained in more detail below.

Reaction Scheme I

(XIV) (III) (IV) (V) wherein R 6 is CH 4

(Ix) (A) wherein R _2, R ^ and R ^ are as defined above.

According to Reaction Scheme I, compounds of formula IV wherein R R is methyl are prepared by reacting a primary amine of formula XIV with ethyl chloroformate to give a urethane of formula III which is reduced with lithium aluminum hydride to the N-methylamine of formula IV.

In a broader aspect, compounds of formula IV can be prepared by reductive alkylation of a compound of formula XIV using the corresponding aldehyde, for example acetaldehyde and the like, and sodium cyanoborohydride under known conditions (cf., for example, R. F. Borch, J. Am. Chem.

Soc., 93, 2897 (1971)).

The Birch reduction of the amine IV with lithium in ammonia-containing tert-butanol provides the dihydroamine V. Other variations of the Birch reduction may also be seen. Thus, an amine of formula IV can be reacted with an alkali metal, such as sodium, lithium, potassium or cesium, in an amine or an amine, such as methylamine or ethylamine, in addition to a lower alkanol, such as ethanol, butanol or tert-butanol.

The reaction is conducted generally at reflux temperature or lower temperature, e.g. ^p s on ^{d 8} -7 to ⁵ ° C. The reaction mixture was refluxed under reflux. Optionally, co-solvents such as diethyl ether or tetrahydrofuran may be added.

Hydrolysis of the dihydroamine of formula V is accomplished readily by conventional methods of hydrolyzing enol ethers, e.g., by treatment with aqueous acid. Examples of suitable acids include hydrochloric acid, hydrobromic acid, formic acid, acetic acid, p-toluene acid and chloric acid.

These acids can be used in aqueous solutions or in mixed solvents. At least two equivalents of water per mole of dihydroamine and more than one equivalent of acid are required. Examples of solvents include tetrahydrofuran, benzene, diethyl ether, acetone, toluene, dioxane or accionitil.

For example, hydrolysis is performed díhydroaminu formula V wherein R represents meeylovou group in 2N hydrochloric acid at artfully or at a temperature ^Yss I in aqueous rivets ^E k ^y Selina ^P s te ^ father ^ between 40 ° C and te ^ Ota boiling ^p o of ^PE sLex ^d ^ Ia ^ what _the fourth

dikztnnj to form the formula VI wherein R is ^p mmeylovou SKU inu.

The diketone of formula (VI) is condensed to a dihydropyridine-ethylamine of formula (IX) by Knor condensation. Knorr condensation is generally known process for the production of pmax jrrolů and this process may be carried out at various permutations of known (see. E.g. Patterson JM, S ^y nthezis, 281, 1976 and references cited therein liieraijrj).

This procedure is carried out, for example, by reacting the isooctone of formula VII in the presence of a reducing agent, e.g. zinc in aqueous acetic acid or hydrochloric acid, and proceeding via the aminocarbonyl compound of formula VII, which is then condensed with diethyl ether of formula VI to dihydropyridine.

Furthermore, the condensation may be carried out using an aminocarbonyl compound of formula VIII or intermediates thereof, such as amino-amino-ammonium ketone or an acetal derivative of aminoketone or aminoaldehyde. The use of aminoketone or aminoaldehyde mesylate is advantageous since such substances are readily prone to spontaneous condensation.

They can best be produced in situ, where the aminocarbonyl builder is released in the di-acid of formula VI. The amnocarbonyl component reacts immediately to form the dihydroindolone ethylamine of formula IX. The dihydroethone of formula VI does not necessarily have to be isolated prior to carrying out the Knorre condensation since the reaction conditions employed are sufficient to hydrolyze the dihydro-. of an amine of formula V to a diketone of formula VI. The Knorr condensation is preferably carried out at a pH of from about 2 to 6. At a pH substantially higher than 6, there is a significant loss in yield due to the formation of products resulting from the self-condensation of the aminocarbonyl compound of formula VII.

Preferably, the compound of formula (VII) and the zinc powder are present in aqueous acetic acid with a di (C ^ eoo <ťť m m) formula of formula (VE) in which R znamená znamená is a methyl group to give the desired β-product. IX in which R ^ represents a methyl group.

The Knorr condensation is carried out at temperatures ranging from about room temperature to the boiling point of the reaction mixture. Isonitoosoketones of formula VII are known compounds (see, e.g., Feerit,

J. Org. Chem., 24, 1726 (1959)) or can be readily prepared by nitrosating the corresponding ketones, such as alkyl nitrite, or, in the case of strongly acidic beta-diketones or beta-ketoesters, with sodium nitrate. *

As ^{an equivalent} of ^{iron pentacarbonyl} ice ^y ^ onitosooketoniJ ^used it.elnýc ^hp s ^K norrov ^sk ondennzai, include ICI follow:

2-isonitosso-3 ^- pentanone,

2, - butandoonmonoxime,

2-Itonitosso-4-methyl-3 ^- pentonone,

2-itonitssso-3-eexanone,

2-itonitosso-3-ee ^- aanone,

--itonίtooso ^4-p meayl22- enatnon,

2- tontoniaooso-lc _C kklp ^p opyllll-poo ^p anon,

--isQniaooso-5-hexen-2-one ^cyclo- loproppl 2-itoniaoosol-l - and prpannon.

3-IsobinoQOSO-4-phenyl-22-lutane.

Examples of aminocarbonyl compound intermediates which are useful in Knorr's condensation include: aminoacetaldehyde dimethylacetal; and

2-Amino-3-pentanedione.

The amine of formula (IX) is converted to the compound of formula (A) by an intratolecular M 1 -n-4-reaction. The reaction is usually carried out using a ketone and a dialkylamine, for example diethylthiohydrochloride and formate (for example in the form of an aqueous solution such as paraformaldehyde or as a throxxane) in an alcoholic solvent such as ethanol at reflux temperature. In an embodiment of the invention, the acid addition salt of the formula (IX) with an acid is reacted with formaldehyde, which is added in the form of paraformaldehyde, tetraoxane, or aqueous formaldehyde in a solvent.

Examples include high boiling solvents containing a hydroxyl group such as thi-alcohol, octanol, ethylene glycol or diethylene glycol dihydroxide, high-boiling polar aprotic solvents such as methylene sorbide, N-methylpyrrolidinone, or diethylene glycol ether, or diethylene glycol. ^ -propanol under pressure or nízkovtQuoí aprotic solvents under pressure, such as dioxane or tetrahydrofuran-n / ^p s te ^ OTE range ^d of about ¹³⁵ ° C ^{d 2} of about 00 DEG C., ^{and prc} what I am zísJcaiií ^ rrolo ^{[ 2,} 3-g] ^{and d} sohhinolin formula A.

This reaction results and especially ^p ^ s te ^{pl rt} c ^{d hp} of ¹⁵⁰ ° C and the ^allowed-to cis- and trans- ooier ^s, i.e. ^P r., When R r is mmeylovou SKU ^P-well, to sl These are represented by formulas I'a and Ia

‘2 trans-isomer cis-isomer

By longer heating the reaction mixture or separately heating the mixture of isomers of the lydrochlorils of formulas 1'a and Ia, e.g. in ethylene glycol for two hours under reflux, the final balance of cis- and trans -isers can be achieved, where the t1 is largely represented. and .alpha.1 -is.multidot.1, which can be easily isolated by crystallization or by chromatographic separation.

Preferred is the reaction hydrocCloridu dihydrsi ^ r ^ dsl ^ s ^ net ^ Yia ^ mi ^ nu formula IX wherein R is mmeylsvsu slcupinu, with ^p araformaldehydem in octanol at 180 ° C over a 2 Lodin ^y přččemž product isolated almost exclusively in the form of the tris and thio-mer of formula Ia.

In the reaction described in Reaction Scheme I, both trans-isomers of Formula I 'may be formed

HIM

(d) in which:

R ₂ , R 3 and R 3 are as defined above,

in which

R _2, R ^ and R ^ are as defined above in this sr0ěi prevails. The pure tris-isomer is a compound of formula (A), wherein the trisorters may be separated by crystallization or crystallization. In addition, this mixture can be isolated by isolation as described for the isomerization of the trans- and cis -isomers of a compound of formula Ia and Ia.

The compounds of formula A form an addition salt with inorganic or organic acids.

Thus, these compounds form pharmaceutically useful addition salts with both pharmaceutically acceptable organic acids and inorganic acids. ₍ eg with hydrohalic acid, such as hydrochloric acid, hydrobromic acid,

nou. , Lalirri rinerTriir acids, such as sulfuric acid, nitric acid,

with phosphoric acid or similar acids, with alkyl and rosin sulphonic acids, such as readsulfonic acid, fatty acids, benzenesulfonic acid or the like, other organic acids such as acetic acid, most acid, maleic acid, ees. The acid (benzoic acid, ialic acid, ascorbic acid and the like) may be used.

The pharmaceutically acceptable acid addition savers of the compounds of formula (A) may be converted to the acid-usable acid addition groups using conventional exchange reactions to replace the non-useful, anionic, non-useful anions of the racemic acids. by anion, or, on the other hand, by non-neutralization of the pharmaceutically acceptable acid addition salts by the pharmacologically inapplicable reaction followed by reaction of the free base thus obtained with a pharmaceutically acceptable acid addition salt. Acid addition salts can also form hydrates.

The compounds of formula A and their pharmaceutically usable acid addition salts show neuroleptic effects. However, these compounds do not exhibit remarkable hypotenitive efficacy and exhibit only weak cataleptic activity. As a result, the compounds of formula A are useful as antipsychotic agents, e.g. in the treatment of schhsophrenia.

The compounds of formula A, on the basis of which they can be used as antipsychotic agents, can be demaonsonated by warm-blooded methods in a known manner.

For example, according to one method, trained rats are placed in experimental cages equipped with a reaction lever, a steel wire bottom to impart an electric shock, and a loudspeaker for acoustic stimulation. Each experiment consists of a warning tone of 15 seconds (conditional reflex) that continues for a further 15 seconds and is accompanied by an electric shock (unconditional reflex; 1.0 mA, 350 V AC napptt). Rats can terminate the experiment at each site by simply pressing the reaction lever. The reaction during the first 15 seconds of the warning tone terminates the attempt before the shock is given and is considered a defensive reaction, while the reaction that occurs during the shock is an escape reaction.

The experiments were performed every 2 minutes during the one-hour duration of the experiment (30 trials per test duration).

Trained rats! a reliable baseline in defensive behavior (0 to 3 non-aggressive defensive reactions over the duration of the experiment). At least 3 to 4 rats are dosed at appropriate time intervals with pretreatment of the compound in each dosed amount over the applied dose range. During the test, only the vehicle alone is administered to control rats. Every week it changes to ^ n ^ la per try and vice versa.

Each experiment time is divided into 3 consecutive 20-minute intervals (10 trials). The number of responses for all exemplifiers are added at a given dose within each time interval.

The number of experiments in which the rats did not show any defensive reaction (defense blocking, VB), or no escape target (blocking effect, FB) was determined for the time interval at which the mmaimmic effect was achieved at each dose.

This number is the percentage of all attempts made during the time period. The dose calculated for the 50% blockade of defense effect (VB 50) is obtained from a regression curve indicating the dose-to-effect ratio determined using the least squares method. The non-linear dose that elicits a 20% blockade of the escape reaction (FB 20) is read from the diagram, which gives the ratio of the effect value in percent versus the logarithm of the dose.

The formulations differ from the other types of active substances which adversely affect the behavior of the rats in this test, by a greater difference between the doses which block the protective reaction and those which block the reaction. escape reaction. The clinical intensity of action of anti-psychotic drugs with known therapeutic applications and properties depends very much on the intensity of their action in this test. Consequently, the compound of formula (A) may be administered therapeutically in doses corresponding to its effects in the test described above.

Jessiiže was tested as ^^^ ι * 3-ethyl -2, 4a, 5,6,7,8 3,9tokaahyart ^ - ^ 'Sa-trans-lH-piyrolo ^[2, 3-g] ^h ISTC intlin- ⁴ -tn- ^h y ^and rtchl (thirty ^mu m ^kt projecting into the cavity width in ^{m s h} o ^d caries note LoGG e.g. 350 mg / kg, can be observed at a neuroleptic jktivitž νΒ θ ^ 0.7 mg / kg and 0.095 mg / kg sc, the (-) - enantiomers of the above compound can then be observed to have neutoleptic activity at νΒ, -θ 0.48 mg / kg po

Similarly, when, as the test substance loužijl 2? G-trimethyl-, 4a, 5,6,7,8 ^Oa-d -oktahy AO- ⁴ 4,88attaan-lH-plrrrto [2,3-GGI-tchizolin -4-tn-hydroechoride, then zeutollptickot jktivitt can be observed at VBj-θ 0.48 mg / kg po

The compounds of formula A and their pharmaceutically usable acid addition salts have antipsychotic effects which are similar to those of halopeeidol, trfnuorperazine and mooindone, which are known for their therapeutic use and properties.

Thus, the compounds of formula A exhibit activity comparable to that of known antipsychotic drugs.

The compounds of formula A and their pharmaceutically acceptable acid addition salts can be used in the form of conventional pharmaceutical preparations. These preparations contain, for example, suitable dosage units for oral administration or contain the active ingredient in a range of from 0.05 to 50 mg. Suitable dosages for oral administration in warm-blooded animals range from about 0.001 mg / kg per day and about 10 mg / kg per day. For each particular warm-blooded animal, however, the specific dose may vary and should be determined according to the individual requirements and expert judgment by the person administering the compound of formula A or the pharmaceutically acceptable addition salt or the end-user. Furthermore, the frequency at which each such dosage form is administered will vary depending upon the amount of direct active drug and the requirements of the pharmacological situation.

mixes with common inertin. pharmaceutical excipients on a dispenser suitable for oral or parenneral administration. Such dosage forms of suspensions, solutions and the like. Furthermore, the compounds of formula A may be formulated as hard or soft capsules and administered in this manner. Type of inert

In order to formulate the compounds of formula A and their pharmaceutically usable acid addition salts in the form of tablets, in the form of suitable excipients which are used for the formulation of the compounds of formula A and their pharmaceuticals of ethically usable acid addition salts for oral and parenteral dosing of the mold is well known to the skilled person. These auxiliary materials are represented by either inorganic or organic substances such as water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, resins, polysilkynglytsly, etc.

In addition, preservatives, stabilizers, emulsifiers, emulsifiers, salts for influencing osmosis pressure, buffers and the like can optionally be added to such mixtures.

Since the compounds of formula (A) and their pharmaceutically acceptable acid addition salts have an allymortic carbon atom, they are usually prepared in the form of a racemate. The resolution of these racemates from the optically active isomers can be carried out by known methods. Many racemates can be obtained in the form of a eutectic and then resolved. However, chemical cleavage is preferred. They are formed from a large salt of the disterterone salt by treatment with an optically active resolving acid such as (+) - tartaric acid.

forms diastereomerically by optically active agents, for example diastereomers can be separated from the optically isomeric base. These isomers of the compounds of formula A and their racemates.

The invention encompasses how they can be converted to α

preparation of optically active

Further, due to possible different spatial arrangements of atoms, it is apparent that the compounds of the invention can be obtained in more than one possible geomeric polymeric form. The compounds of formula (A) as described herein and as formulated in the subject matter of the invention are all such isomeric forms. Thus, the examples herein are to be understood as being either the salt of geomoeric isomes or monolithic geodetic isomers, and the invention is not to be limited in this respect.

The following examples illustrate the process according to the invention. All temperatures, unless otherwise indicated, are in degrees Celsius.

Example 1

Preparation of N-2- (3,5-dimethoxyphenyl) ethylcarbamic acid ethyl ester

To a 5 L 3-neck round bottom flask equipped with a mechanical stirrer and dropping funnel was charged 32.63 g of (3,5-dimethoxyphenyl) ethylamine hydrochloride, 600 mL of water, 600 mL of methylene chloride and 150 mL of 1N sodium hydroxide solution. The mixture was stirred and cooled in an ice bath, 16.28 g of ethyl chloroformate in 60 ml of methylene chloride were added dropwise over 30 minutes. A total of 150 ml of 1N sodium hydroxide solution was added in eight portions to maintain the pH between 8 and 9. After the addition was complete, the mixture was stirred in an ice bath for 1 hour. The mixture was transferred to a separatory funnel and the organic layer was separated. The aqueous solution was extracted with 200 ml of methylene chloride and the organic solutions were combined and washed with 100 ml of water and 100 ml of brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated on a rotary evaporator to 37.1 g of crude N-2- (3,5-dimethoxyphenyl) ethylcarbamic acid ethyl ester as a colorless oil.

Example 1a

Preparation of N-methyl- (3,5-dimethoxyphenyl) ethylamine hydrochloride

A 3-liter, 3-necked round-bottomed flask equipped with a mechanical stirrer, dropping funnel and condenser was charged with 180 ml of 70% sodium dihydro-bis (2-methoxyethoxy) aluminate solution and 700 ml of absolute tetrahydrofuran. The solution is cooled in an ice bath and a solution of 37.1 g of crude N-2- (3,5-dimethoxyphenyl) ethylcarbamic acid ethyl ester in 100 ml of absolute tetrahydrofuran is added over 15 minutes. After the addition, the mixture was heated under reflux for 1 hour and then cooled in an ice bath, the excess hydride was quenched by dropwise addition of 100 ml of 5% sodium hydroxide solution and after all the base had been added, the organic layer was separated and the aqueous layer was extracted. ml of ether. The combined organic solutions were concentrated to an oil on a rotary evaporator and this oil was dissolved in 300 mL of ether. The ethereal solution was washed with 50 ml of water, 50 ml of brine, dried over anhydrous sodium sulfate, and filtered. 70 ml of ethereal hydrogen chloride were added to the filtrate to precipitate the amine hydrochloride. The solid was collected on a Buchner funnel and crystallized from a mixture of 180 mL of absolute ethanol and 270 mL of ether. 28.9 g of N-methyl- (3,5-dimethoxyphenyl) ethylamine hydrochloride are obtained in the form of a white crystalline solid, m.p. 160-164 ° C.

Example 2

Preparation of N-methyl-1,5-dimethoxycyclohexane-1,4-diene-3-ethylamine

185.2 g of N-methyl- (3,5-dimethoxyphenyl) ethylamine hydrochloride were dissolved in 1600 ml of water and basified with 160 ml of ammonium hydroxide. The mixture was extracted three times with 1000 ml of methylene chloride each time, the combined extracts were washed with 1000 ml of brine and dried over anhydrous sodium sulfate. Evaporation of the solvent on a rotary evaporator at 35-40 ° C afforded 156.0 g of the free base.

In a 12-liter three-necked flask equipped with a mechanical stirrer and two solid carbon dioxide coolers, a gas supply tube and another tube (driers) filled with soda lime, 4.0 liters of anhydrous ammonia are condensed. To this ammonia was added a solution of 156.0 g of the free base in 400 ml of tert-butanol and 400 ml of anhydrous ether over 15 minutes.

A total of 33.6 g of a 6.35 cm long lithium wire cut into pieces is added to the stirred solution over 50 minutes. The rate of addition is controlled to add 12.7 cm of wire within a minute. After all the lithium was added, the deep blue mixture was stirred.

for 2 hours at reflux.

Thereafter, 2.8 liters of anhydrous ether was added to dilute the mixture, the drying tubes were removed to allow hydrogen to escape, and a total of 280 g of ammonium chloride powder was slowly added over 30 minutes until the blue color disappeared. The solid carbon dioxide controller was removed and the mixture was stirred while the ammonia was evaporated overnight. 2.8 liters of ice water are added to the residue. The mixture was transferred to a separatory funnel, washed with ether and the layers separated. The aqueous layer was extracted twice with 1.5 liters of meylene chloride extracts were combined, washed with one filter of sodium chloride solution. Evaporation melted on rota-oharce at ⁴ 0 used rinse solution 800 ml and dried over anhydrous ° C and rt ^{p e p} s ⁴⁰ ° C / 13.3 Pa for 1.5 hours to give 150.7 g of crude product as a of yellow oil. the through ^ eHluje ^30.5 cm high ^^ c ^ o ^ loeovu Tolona (smoked ¹⁵⁰ DEG C. ^{EXAMPLE IR} EM ^and the following fractions:

Crude oil back!

Fractions

Boiling point ° C / Pa

Hmmtnost

Purity ^

1 40 and 80 ° C / 5.6 Pa 7.9 G 4 2 80 and ⁸⁵ ° C ^{/ 5.6} and ^{20 p} a 6.2 G 50 3 85 and ⁸⁶ ° C / ²⁰ Pa 21.2 G 92 4 86 ^and 87 ° C / 20 P ^a 99.4 G 100 ALIGN!

%%

according to gas chromaaooraai

Chimney Fractions 3 and 4 combined 120.6 g of N-Inyl-1,5-γ-methoxycarbonyl, 4-chloro-3-quinolone as a colorless oil.

Example 3

Production of 6- ^{(N-Me e ylamino)} eth ^y 1] -2-methyl-y M ^e ejj- ^{6, 7- IH} d y ^d ro ^- (5H) -4 ^(1H, 5H) ^d -in Olona

To a 1 liter round bottom flask equipped with an alcoholic stirrer and condenser was charged a solution of 60.0 g of distilled N-methyl-1,5-dimethoxycyclohexyl-4-diene-3-ethylamine in 700 mL of 70% aqueous acetic acid. kyseeiny. The reaction mixture was refluxed for 15 minutes and 59.5 g of zinc dust was added in 5 portions over 10 minutes and the mixture was boiled for another. 15 minutes under reflux. To the refluxing solution was added a solution of 42.1 g of 2-isoisoquinoline-3-one in 175 ml of 70% aqueous acetic acid over 1 hour. After addition, the mixture was refluxed for 2 1/2 hours and then cooled to room temperature. The precipitated zinc acetate is filtered off and the filter cake is washed with 500 ml of meetyenechoride. Zahnusí filtrate on a rotary evaporator and the residue was heated for 30 minutes at 100 ° C / ^{133.3 P} and to odstraněí ECENT ^{P I} C ^H s ^ ^e ^ op vinegars sslány. ^To be left over was dissolved 'in 500 ml of water and extracted twice with 150 ml meetyennchoridu modes. The methylene chloride extracts were set aside and the aqueous layer was made alkaline with 165 ml of ammonium hydroxide (pH 8-9) and 500 ml of sodium chloride solution were added. The mixture was extracted three times with 200 ml of meeylene chloride and the combined extracts washed with 100 ml of sodium chloride solution. Evaporation of the solvent gave 56.0 g of crude tetrahydroindolone dissolved in 90 mL of a mixture of toluene and ethyl acetate (2: 1).

The solution was stirred with a magnetic stirrer and seeded, then allowed to crystallize with stirring overnight. The first fraction isolated by filtration was 20.8 g of product. The mother liquor is heated and the stirred solution is recrystallized to give a further product of 10.0 g. The mother liquor is dissolved in 75 ml of ethanol and a solution of 15.0 g of oxalic acid in 50 ml of methanol is added. The mixture was heated on a steam bath for 10 minutes and then cooled.

The solid oxalate is filtered off and washed with 10 ml of methanol and dissolved in 50 ml of water. The solution was basified with ammonium hydroxide and extracted twice with 50 ml of methylene chloride. The extracts were washed with 1 x 20 ml of brine and dried over anhydrous sodium sulfate, and then concentrated on a rotary evaporator to give 4.5 g of additional product (crude product). Crystallization from deuterium, toluene and ethyl alcohol (2: 1) gave 2.6 g of additional crystalline product. Both množssví pochhzzjíhí crystals and oxalate were combined and dried Tohei Odin ^{2 hours} at ²⁵ ° C /! And 33.3 ^{p. From} IS ^{ka 33.4 g of} 6-I ² - ^(N-methyl-l amino) e 4- (1 H, 6 H) -4- (1 H, 5 H) -ododiolose as a pale yellow solid. Temperature T ^and the eye ¹¹⁴ to ¹²⁰ ° C. The product is ^p ^ Ahe htoomaao ccording to this layer ^of homogeneous slender.

Example ⁴

Preparation of 3-e eyl- ² 6 56,7,8,8a, O-oltta dro ^ ^ ^A ^ U- Uatrans-rroL · '2,3-g] When n isohh amino - 4 - o-hydrochloride lori du

A 500 ml round-bottomed flask is charged with 17.0 g of O - (-) - meetlamino-2-methyl-2-methyl-3-ethyl-6,7- (1-oxo-5 -) - (1H, 5H) iodine and 170 ml of meeanol. The roztioku was added 20 ml of 4N HCl (ιΐ ^^ ^ ^ ίτ (prepared by introducing HCl gas into dietiléteru an ice bath and the trac). Ro-PP-sat was evaporated on a rotary evaporator and the residue was dried in a ^y s ^{p 50} ° C ^{/ 138} Pa runs 3 ^ m ^ ^^ two hours from EMZ ^{s kA 19.7 g} surová- ^hy ^ droch r.du.

A 3-neck, 3-liter flask, equipped with a mechanical stirrer, a thermometer, and a deesillin adapter, was charged with 19.7 g of hydrocoride, 21.8 g of propylene glycol and 1000 ml. The reaction mixture is heated to reflux of the virus and the released-DA deetiliině d- removed until a state where the temperature of the destination--kyin solution in the flask reaches 175 to ¹⁸ 0 ° C, then ^{d i} ertill alpha о ^^^ removed and replacing the back ^of sLex cdidčem.

The reaction tm ^E is zihř ^{s and 1 Hz} in the IOU to ^{d y} e ^{y L- 175} in Iz ¹⁸ 0 C AB ^E during ⁵ minutes in three portions was added 6.54 g plrlformlldthydu. V-DA as before ždddtSilujt to dosažní te ^{p s} Lot ^175-180 ° C and a mixture ^of the warm up is ^S T ^{E 1h} -diol OA ¹⁷⁵ and ^{≥ 18} 0C. Tmavohn ^of Each solution was cooled and vylijj into 1000 ml of water. The layers were separated and the organic layer was extracted twice with 400 ml of 5% hydrochloric acid solution each time. The combined aqueous extracts were washed twice with 150 ml of chloroform each and the chlorine solutions were discarded.

The aqueous layer was mixed with 120 ml of ammonium hydroxide and 400 ml of chloroform. The layers were separated and the aqueous solution was extracted four times with 200 ml of chloroform each. The combined chloroform extracts were washed with brine (200 ml) and dried over anhydrous sodium sulfate. Evaporating the ^ Ia ^ mouth of ^{í KA 12} 0 sur-v ^ Z ^ RRO ¹ - ^{[2, 3-g]} isoquinoline isžh ^l as smčěi ίιηο ^ -, 4a, 8a-cis (about 8: 1 ) in the form of a dark yellow-brown solid. The crude solid was dissolved in 100 mL of methanol: methanol (9: 1) and then 300 mL of diethyl ether was added. The fine, solid precipitate, predominantly the 4α, 8α-trans-isomer, was collected by filtration and the filtrate was concentrated and crystallized to give further trit of a tan-brown solid (second and third runs).

Materšl combined in dry ^{p y} s ²⁵ ° C / ^133.3 Pa over ^{1 hour} Odio ^PRC wherein the zísU

8.20 g light gray solid, i e., 3-TT ^y 1-2,6 "direeyl-4,4a, 5,6,7,8,8a, ^9-yl okУlh dr - 4 liters, 8 liters Упо-^ -р ^ ^ ^ уг о0 ^2, 3-GJ .socl ioolin ^ ^ -one tepl- ^thee mp ^203-226 ° C. Cásttčn vyči ^STE from the district ^of the gray solid is suspended in 80 ml Mee-Anoto and 12 ml 4N HCl solution in dietylktrrs.

The oily solvent was removed and the residue crystallized from 25 ml of hot, at room temperature.

The first layer is isolated by filtration and the mother liquor is concentrated and crystallized to obtain second and third crystals. The combined solid was dissolved in 120 mL and 2.4 g of active sulfur was added. The mixture is heated for 10 minutes on a steam bath and the active shH is filtered over silica. The filtrate was concentrated and the residue was recrystallized from ethanol (15 ml) to give an additional white crystal.

Evné related ^{e p} l ^l t ^ te ^ ^alkyl dried in va uu ^p s ^{to 80} ° С ^ ^p and ^6.7 l ⁸ Tohei odio ^{y te} 5.4 g of 3-eeyl-2,6-4-lieeeyl 4a, 5,6,7,8,8a, 9 --- octahydro - 4a, 8a-traos-lH-řyrr-l- [2, ³ - ^g] is-Chio-lin-4-onЪ ^lr rlchl -R ^r in the form of a solid Toni temperature between approximately ^196-198 ° C oxw-Semih-sulfate, Toni tepita ^{of 133} and ¹³¹ ° C.

Examples 4a to c

Following the procedures of Examples 3 and 4, they are prepared from a suitable isocyanate ^{to the} above-mentioned compound. Each compound exhibits specular features that are consistent with the structure described. Melting points apply to the v-ln-u base or Уу ^ Тос? CУolir as indicated. Isoitococcal 110 are prepared as described in the literature [Feeris et al., J. Org. Chem. , 24, ketone. The isolated compounds are the .alpha.,. Alpha.-trans-isomers.

726 (1959)], nitration of suitable

and buka

Knono -va reaction

Mannich reaction

Example ^R2

4a

3, .alpha.-methyl-2- (2-pr] pU -4,4a, 5,6,7, ⁸ , ^8a , 9-ketyl-1H-p-2-yl); g] iticyinolin-4-yne

CHteRR

4b

2,6- (Lieyl-3-phthyl-4,4a, 5,6,7,8,8a, 9- '-iktayydro-1H-pyyr-1- [2,3-д] -4-pyrrolidin-4 -in

CH ₃

^R 3

CH ₃

Analysis no. Ni lez. Melting temperature Crystallizes from idlišnoisi mode man. (.hcl) (.Hd) mta- - C 64.74 64.53 &Gt; 280 ° C nolu H 8.49 8.38 (rl ^ k ^ kL) N 9.44 9.36 Cl 11.94 12.16 C 77.23 77.23 Mp > 240 ° C směěi Mannichiva H 7.53 7.50 (rizkk.) etan-lu reaction N 9.52 9.54 and ethyl- in the river ac etate glykolmono ·

ethyl ether

155 ° C 1 hr

4c

2,3.6 ^ 1г ^ У [-4.4a, 5-CR 6,7,8, δa, 9 - ktjУlrrl- ^{C, i} 3 c (.HCl) 62.56 62.19 275-280 ° C from the mixture Knorrova foH ^ yyrilifpfogj iti- H 7.88 7.97 of (ethanol) reaction quinolin-4-in N 10.42 10.20 and ether in butanol cl 13, 19 13.41 at 170 ° C /

/ 0.35 MPa

Example 5

Resolution of racemic 3, 4, 6-dimethyl-4,4a, 5,6,7,8,8a, 9-octahydro-44,88-trans-1H-pyrrolo [2,3-g] isoquinio-4-one

The racemic free base (produced in the same manner as in Example 4) in an amount of 1.20 g was dissolved in meeanol and a solution of 0.74 g of r- (+) - free acid in copper was added. The solution is solidified and recrystallized twice from crystalline d- (+) - tartrate to liberate the free base with hydroxide, and the free base is then treated with anhydrous ethereal hydrogen chloride to give hydrooClolir. After twice REDRAW-t-profiling of tУ-methanol and after drying the v ^ at 80 ° C / ⁰ 6 ⁷ Pa ^s of ^{0.15 g KA} ^ Η-ο οΙη ^ ™ as a white to ^p ^ stalickě evné mp 2 ^{40 and 245} ° C.

Oppic ^ka otečivoss: | p] ^ ⁵ = - ^120.7 8 ° C ^(c = ^0.81%, water)

Pr _Analysis: C ^ H ^^ O.HCl.O, 25 ° H ₂ Calculated: C 62.70% H 8.24% N 9.75% Found: C 62.44% H 8.33% N 9 , 67%.

The mother, alkalis krlsУ lizact-D- (+) Tartrate was added ammonium hydroxide for the purpose ^of release in the ^L ^ n ^{s b} Aze ^to Hero piůsolbí solution ^{of l- (-)} tartaric βΐ ^e ^ ^ (? ^{46 g)} in methanol. The solution is concentrated and the residue is recrystallized twice from methanol and then converted to the free base and hydrochloride as described above. Was obtained 0.10 g of (+) - ^a-f in oУioitru Milky Orme, ^^ ^p taHckté Evoé ^solid te ^ OTE m.p. ^{240 and 244} ° ^C.

^Oop ic ^ka rotation: [ck] θ θ ^- 8 + ^121.3 ° ^{(C - 0.44%,} and in ^d)

Analysis for: СцН ^^ О. H21.0.25 H ₂ O

calculated: C 62.70% H 8.24% N 9.75%, found: C 63.02% H 8.20% N, 9.88%. Example 6 In an analogous way like as described in Example 4, the following compound is obtained:

oioy:

2 ’,⁶'l ^ i.m^you1 -? - iso^p1 ^ (^ f ^^p1-4⁴^,⁵/ 67 8 8 ^^_/9 - ^ (^) <k <^^^^hdrr-^-4J^,8^and: yr ^ -o^col^ -^-^^p1r (.delta^[2, ^ g ^ so chioolin-4-oo, body temperature:²⁴⁴ and^{s 247} ° C (from ethyl acetate);

3^,6 ^ dimt^y11- (2-pi: trans)^and1- <^{, 4}^, 5^,6^,^_Ř88 ^_/^ octa ^ á ^ - ^^, Sa-trans-J H-dyrrolo^12.3-G^] í ^ so chioolio-4-oo, temperature: 22¹ and^with 22nd³ °^C,

3-c lopro ^yk-p p1-2,6 diieey1-4,4a, 5.6, ^7, 8,8a, ^ oct-hydroxy ^ -, 8a-traos-lH-pyrrolo [2,3-g] isoch ioolio-4-oo, melting point: 258 DEG and ²⁵⁹ DEG ^C. Decomposition;

2-beozy1-3,6 IMET ^ ^^ ^ 1-4,4 _l, 5,6,7,8,8a, 9-4- okУah1rro, 8a-transslH-ppirolo [2,3-g] isochioolio- 4-on,

6-methyl-L · * ^4, 4a, 5,6, ^7, Ma, 9-octahydro ⁴ a, 8a-trans-lH ^_ pyrrolo ^{(2,3-g] isoquinolin-4-one,} te ^th the OTA ^pl : ²³⁴ and ²³⁵ ° C t: e ^p lota mp ^{2 08-210} ° C

1 ₂ 0 mol

2-methyl-3-ethyl-6- (cyclopropylmethyl) -4,4a, 5,6,7,8,8,8a, 9-octayl-1H-ppyrrolo [2,3-g] isoquinolin-4-one hydrochloride . 0.2

Analysis:

calculated: C 66.22% found C 66.24%

8,15%

8.35%

8.58%

8.36%

Cl 10.85%,

Cl 10.51%.

Melting point: ²¹⁵ to ²¹⁵ DEG C.

219 ° C (from ethanol / ethyl acetate):

rac. 2-ImtyУ 3 - tyУ-6- (2-ttoxyytyУ) -4,4, 5,6,7,8,8a, 9-oktalydro-4a, 8a-trans-lH-pyrrolo ^[2, 3-g ] ^{i l} Soc inoli.n- ⁴ -one ^LYD Roch ^l or ^id

Analysis:

calculated: C 63.24% H 8.57% N 8.21% Cl 10.40%, found: C 63.13% H 8.71% N 8.17% CL 10.64%.

Mp: ²¹³ and ^{from 215} ° C (from a mixture of ethanol and a ^{m ethyl]} ^ c ^{ethane are} herein):

rac. 3,6- (Г1 у1-2-methyl-ey 1-4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a "trans-lH-p ^y yrolo [2,3-g isoclinolin-4-one

Analysis:

calculated: C found: C

73.81%

73.91%

H, 9.99

H 9), 39% N 107 69%

N 10.49%

Having ^a melting ^point

228 ^and from 230 ° C (from ethanol)

rac. 3-ethyl-2-methyl-6-yrlyyl-4,4a, 5,6,7,8,8a, 9-lktahydro-4a, 8a-rans-1H ^- pyrrolo [2,3-g] isoclinoline- 4-on

Analysis) Calculated: C 74.41%

9.5 59 1

N 10 _r 11 'found: C 74.29%

Hl

9, 09 09

N 1 O 2 19%.

The temperature T ^and 226 and ^from 228 ° C (from ethanol)

rac. 3-Eeyl-4-methyl-2-methylpyridine-4,4a, 5,6,7,8,8a, 9-octa- ^d -4a, 8a-trans-1H-pyrrolo [g] - ⁱ slc ^h inolin- ^4- yn.

Analysis:

calculated: C 74.96%

9 9.719% found: C 75.24%

H 9j _of 99 9 9 9, 5 00

Melting point: 213-215 ° C ethanol

I rac. 6- (cyclobutylmethyl) -3-ethyl-2-methyl-4,4a, 5,6,7,8,8a, 9-octahydro-44,88-trans-1H-pyrrolo [2,1-g] isoquinoline- 4-on.

Analysis:

calculated: C 75.96% H 9, -9% N 9.2%, found: C 75.7.0% H 9, -4% N 9.2-%.

Melting point: ²²² to ²²⁴ ° C (from ethanol):

rac. 6,6-Dimethyl-2- (1D-4,4a, 5,6,7,8,8a, 9-oyahyrro-4a, 8a-trans-1H-ppyrrolo [2,1-g] isoquinolin-4-one .

'Analysis:

N, 10.66%. Found: C, 68.97%; 16.76%, H, 10.76%.

Melting point: 2 ⁷ 3 to ²⁷⁵ ° C:

rac. 2,6-Dimethyl-propil-4a, 5,6,7,8,8a, 9-ocyahydro-4a, 8a-tr-5s-1H-plro-o [2,1-g] quinoline- ^ -on.

Analysis:

calculated: C 73.81% 16 9 96% N 2 10% _R 66, Found: C 73.56% 6 9.06% 6 10.11%.

Melting point: ⁶ 250-251 ° C ^: rac. 2,6-trimethyl-4,4a, 5,6,7,8,8a, 9-ok-hyrr-4a, 8a-yrans-1H-pyrrolo [2,1-g] is-quino-in-4- he.

Analysis:

calculated: C 71,5-% H 8, -1% N 12 8-% found: C 71.44% H 8.44% N 12.98% Melting point: 251 to 250 ° C 21 ° C.

Example 7

Preparation of capsules

Composition of em / capsule

0.5

5.0

10.0

3-ety1-2,6 - ^^ 15 ^ ^ 1-4,4, 56, 88, 7, 9-octahydro-44.88 trans-i ^ ppi H- pyrrolo ^{[2, - /]} iLOC ^h in- ^ln n-4-on- ^hyr r-chloride lactose starch talc magnesium salt lyearic acid total

0.5 5.0 10.0 18-, 5 179.0 218.0 -0.0 -0.0 50.0 5.0 5.0 10.0 1.0 1.0 2,0 20 mg 220 mg 290 mg

Method:

The active ingredient, lactose and starch are mixed in a suitable mixer. The mixture is then ground in a suitable mill. Finally, talc and magnesium stearic acid salt are added and the resulting mixture is machine filled into capsules.

Example 8

Tablet preparation (direct compression)

Ingredients 0.5 mg / tablet 5.0 10.0 3-ethyl-2,6-dimethyl-4,4a, 5,6,7,8,8a, 9- -octahydro-4a, 8a-trans-1H-pyrrolo- [2,3-g] isoquinolin-4-one hydrochloride 0.5 5.0 10.0 lactose 85.5 81.0 103.0 microcrystalline cellulose (Avicel) 30.0 30.0 45.0 modified starch 7.5 7.5 10.0 magnesium salt of stearic acid 1.5; 1/5 2,0 total 125 mg 125 mg 170 mg

Method:

The active ingredient, lactose, microcrystalline cellulose (Avicel) and modified starch are mixed in a suitable blender for 10 to 15 minutes. The magnesium stearate salt is then admixed and the mixture is further stirred for 4 minutes. The tablets are then compressed from a mixture on a suitable press.

Example 9

Tablet preparation (wet granulation)

Ingredients mg / tablet 0.5 5.0 10.0 3-ethyl-2,6-dimethyl-4,4a, 5,6,7,8,8a, 9- -octahydro-4a, 8a-trans-1H-pyrrolo- [2,3-g] isoquinolin-4-one hydrochloride 0.5 5.0 10.0 lactose 103.5 99.0 148.0 modified starch 10.0 10.0 20.0 pregelatinized starch 10.0 10.0 20.0 magnesium salt of stearic acid 1.0 1.0 2,0 total 125 mg 125 mg 200 mg

Method:

The active ingredient, lactose, modified starch and pregelatinized starch are mixed in a suitable blender and granulated using water. The granulate is then dried and ground. Finally, the magnesium salt of stearic acid is admixed and the mixture is compressed into tablets using a suitable press.

Claims (7)

OBJECT OF THE INVENTION A process for the preparation of octahydro-1H-pyrrolo [2,3-g] isoquinolines of the general formula A wherein ^R 2 ^{and R} 3 are each independently hydrogen, C 1 -C 7 alkyl, C 3 -C 6 cycloalkyl, (C 2 -C 7) alkenyl, (C 1 -C 7) acyl, phenyl or benzyl and is C 1 -C 7 alkyl; 2. A process according to claim 1, wherein the corresponding compound of formula (IX) is used as the starting material to form a compound of formula (A) wherein ^R2 and R3 are each independently hydrogen, C1-C7alkyl. ^R ₄ represents a methyl group, its optical and geometric isomers, and its pharmaceutically acceptable acid addition salts. C 2 -C 14 or C 3 -C 6 cycloalkyl having 1 to 7 C atoms in the alkyl moiety, optical and geometric isomers of these compounds, and their pharmaceutically acceptable acid addition salts, characterized in that the compound is of formula IX (IX) wherein ^r 2, ^R 3 and ^r ₄ are as above defined with formaldehyde, the resulting mixture of cis and trans isomers is optionally isomerized to a final ratio in which the trans isomer is predominantly present, and / or the trans-isomer is optionally separated from the obtained mixture, and / or the racemic mixture obtained is optionally resolved into optical antipodes and / or the obtained compound or a pharmaceutically unusable acid addition salt thereof is optionally converted into a pharmaceutically usable acid addition salt. 3. A process as claimed in claim 1 or 2, wherein the corresponding compound of formula (IX) is used as the starting material to form a compound of formula (A) wherein ^R2 is independently C1-C7alkyl, and ^R ₄ is as defined in point 1 or 2. 4. A process as claimed in claim 4, wherein the starting material of the formula IX is obtained in the form of the trans-isomer by the formation of a compound of the formula A by any one of items 1 to 4. 4. A process according to any one of claims 1 to 3, wherein the corresponding compound of formula (IX) is used as the starting material to produce a compound of formula (A) wherein ^R2 and ^R2 are as defined in any of claims 1 to 3. 3 and ^{R 1} represents an alkyl group having 1 to 7 carbon atoms or an alkoxyalkyl group having 2 to 14 carbon atoms in both the alkyl and alkoxy moieties. 5. The process according to any one of items 1 to 1, wherein the compounds of the general formula R ₂ , R ₃ and R ₃ are as defined in 6. Method. The compound of claim 2, wherein the corresponding compound of formula IX is killed as the starting material to give 3-ethyl-2,6-dimethyl-4-sctahydrs-4a, 8a, 8a, 9a, 9a, 9a, 9a, 9a, 9a, 9a, 9a, 9a, 9a, 9a, 9a, 11a, 11a, 11a. [2,3-g] isobutan-4-ol. 7. 2. The process of claim 1, wherein the starting material is reacted with a reagent of a compound of formula (IX) to form ^{7, 8.8, and 9-yl} sktah drs- ⁴ a, 8a-traas-lΗ- rrsls ^{py [2,} 3-g] :! sculpted lin-4-one