Process for preparing octahydropyrrolo-(2,3-g)-isoquionolines in the form of their racemic mixture,

专利摘要:
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, (
公开号:SU1014474A3
申请号:SU812819251K
申请日:1979-10-08
公开日:1983-04-23
发明作者:Бергер Лео；Ли Олсн Гэри
申请人:Ф.Хоффманн-Ля Рош Унд Ко,Аг (Фирма)；
IPC主号:

专利说明:

Priority signs: 13.10.78 with RI-hydrogen, (C-C-alkyl, propenyl, benzyl,
R3 is hydrogen, (C — C alkyl cyclopropyl;
R4- () -alkyl, hydroxy-C-C) -I-alkyl, phenyl, L-chlorophenyl. Y) - ((-alkylphenoxy, and -chlorophenoxy-Csz. C hydroxyalkyl, 1-fluorobenzoyl- (C / | -C) -al kil, (Cd-C / -alkoxycarbonylalkyl, feiyl-I-methoxyphenyl-1G-chlorophenyl , diphenyl- (.) alkyl, propenyl- (C4 .-%) - cycloalkylalkyl; X - o;
09/10/199 with RJ-acetyl; phenyl;
 fluorophenylcarboxamideethyl, (Cs) -alkanoylalkyl, tricyclo-3, 1 (3, 7) -decan-1-yl-2-oxoethyl- (C4) -alkenyloxyalkyl, phenylpropenyl, phenoxypropyl, N-methylpyrrolidinyl, ethylmethyl, phenylpropenyl, phenoxypropyl, N-methylpyrrolidinyl, ethylmethyl, phenylpropenyl, phenoxypropyl, N-methylpyrrolidinyl, ethylmethyl, phenylpropenyl, phenoxypropyl, N-methylpyrrolidinyl, ethylmethyl, phenylpropenyl, phenoxypropyl, N-methylpyrrolidinyl, ethylmethyl, phenylpropenyl, phenoxypropyl, N-methylpyrrolidinyl, ethylmethyl, phenylpropenyl, phenoxypropyl, N-methylpyrrolidinyl, ethylmethyl, phenylpropyl, phenoxypropyl, and , dioxypropyl and- (2,2-dimethyl-1,3 disalon - yl) -methyl, X 5
This invention relates to a process for the preparation of new biologically active compounds, octahydro-1H-pyrrolo | 2, 3-qJoxoxynolines, which can be used in medicine. There is a known method for the alkylation of secondary amines by halogen derivatives of alkyls flj. The purpose of the invention is a method of obtaining new compounds - octahydro-1H-pyrrolo 2, 3 3isoquinolines, possessing pharmacological properties. This goal is achieved by the method of obtaining octahydroH-pyrrolo | 2, 3 isoquinolines of the general formula where R is hydrogen; R is hydrogen, () -alkyl,; propenyl, acetyl, or benzyl; R, is hydrogen, () -alkyl, cyclopropyl or phenyl, fj (, hydroxy - ((- alkyl, phenyl, K1-chloropheny, Vi- (Cj-alkylphenoxy- or I-chlorophenoxy- () hydroxyalkyl, and i-fluorobenzoyl- (C - C h) -alkyl, () -alkoxycarbonylalkyl, phenyl-p-methoxyphenyl-p-chloro-phenyl- or diphenyl (,) aakyl, pryupenyl, (C4-C) -cyloalkylalkyl, And -fluorophenylcarboxam1 ethyl, (C) -alkanoylalkyl, (tricyclo) -3,3,1.1 (3,7) -decan-1-yl (2-oxoethyl) - (C) -alkenyloxyalkyl, phenylpropenyl, phenoxypropyl, N-methylpyrrolidineethyl, dimethylaminoethyl, ((-morpholinyl) ethyl, dioxypropyl or (2,2-dimethyl-1,3-dioxolan- | -yl) methyl; X - oxygen or sulfur, in the form their racemic mixture, the cisi trans isomer, either in free form or as a salt, consisting in that a compound of the general formula "where R, R, Rj and X have the indicated meanings, is reacted with a compound of the formula R4 - Y where Y is chlorine or bromine, El- has the indicated meanings, and the desired product is isolated as a racemic mixture, cis and trans isomers, in free form or as a salt. Example 1. Preparation of Z-ethyl-2-methyl-6- (2-g1ropenyl) - 5,6,7, 8,8a, 9 octahydro, 8a-trans-1H-pyoro 2, 3 93 isoquinoline -one.
3101
A mixture of 0.470 g (2.03 mol) of 3-ethyl-2-methyl-4, a, 5i6.7i8,8a, 9 OKTa-hydro-1H-pyrroloi2, 3 - isoquinoline-it, 0.5 g (", 13 mmol) of zllyl bromide and 0.85 g (6.16 mmol) of potassium carbonate in 35 ml of acetone are stirred at room temperature for 2 hours and filtered. The filtrate is concentrated and the residue (0.53 g) is chromatographed on a column of alumina HI of activity to give 0.0 g of product, which is treated with an ethereal solution of hydrogen chloride and hydrochloride is obtained. The latter is recrystallized from ethanol-ethyl acetate to obtain the hydrochloride of the title compound as a white substance with mp. 214-217C,
Elemental analysis:
Calculated, I: C 6j, 2t; H 8.25, N 8.81; C1 11.15.
 H24N20-HC1-0,5 HzO
Found: C b, 50, H 8.8; N 8.96, C1 11.37.
Examples 1a-22. According to the method described in Example 1, from the above 4, ta, 5,6,7,8, 8a, 9 octahydro-1H-pyrrolo 2,3-isoquinolin-4-one and halide, the compounds shown in Table 2 are obtained. 1. The spectral analysis data obtained from each compound corresponds to their structure. Melting points correspond to the free base or the "indicated hydrochloride. The isolated compounds are 4a, 8a: trans isomers.
PRI me R 2. Preparation of 3 ethyl-2-methyl-6- (2-hydroxy-2-phenylethyl) -, a, 5,6,7,8, Over ,, E octahydro, 8a-trans-1 H-pyrrolo | 2,3-0 (isoquinoline-f-OHa.
0.83 .g (3.58 mmol) of the mixture of ethyl 2-methyl-, ia, 5, 6,7,8,8a, 9-octahydro-1H-pyrrolo 2, (isoquinolin-4-one and 0.51 g of C , 22 mmol) of styrene oxide in 25 ml of methanol is heated to reflux for 2.5 hours, cooled and filtered. The filtrate is concentrated and the residue is chromatographed on a column of Al-ominia III to give 0.69 g of crude product. By recrystallization from ethyl acetate-ethanol, 0.195 g of the title product is obtained as a white solid with mp. 218.5-220C.
Elemental analysis:
Calculated: C 7.97; H 8.01; N 7.95
Found, /: C 7.87v H 7.92; M 7.35
Examples 2a-e. According to
The method described by om with Example 2, from the indicated 3-ethyl-2-methyl-4, 5, 6,7,8, 8a, 9 octahydro-1H-pyrrolo 2, 3- Zizohinolin-4-one and epoxide, is obtained compounds listed in
tab. 2. The spectral analysis data obtained from each compound corresponds to their structure. Melting points correspond to the free base or to the indicated hydro5 chloride. The isolated compounds are la, 8a-trans-isomers. PRI m e R 3. Separation of racemic 3-ethyl-2,6-dimethyl-C .la, 5.6,7,8,8a, 9-octahydro, 8a-trans0 -1H-pyrrolo2, isoquinOlin -one.
1.20 g of the racemic free base obtained in Example k is dissolved in methanol and 0 g of the d - (- f) -vinous solution is added.
5 acids in methanol. Then the solution is concentrated and recrystallized twice from methanol. Then the crystalline d- (+) -TapTDaT is treated with i-ammonium hydroxide to release the free base, which is then treated with anhydrous ether hydrogen chloride to obtain the hydrochloride. After double recrystallization from ethanol and drying at 80 ° C and under a pressure of 0.005 mm, 0.15 g of the (-) - enantiomer is obtained in the form of a white crystalline substance with mp. 2kQ-2kS ° C.
Rotation: 120.78 (with 0.8U, water).
Elemental Analysis: Calculated.: C 62.70; H 8, -: 9,7S.
. „C), R.C1-0.25 H, 0 Found 7;: C 62, H 8.33 P 9.67.
After crystallization of the 11- (+) -tartrate, the mother liquors are treated with ammonium hydroxide to release the free base, which is then treated with 0 g of a solution of - (-) - tartaric acid in methanol. The solution is then concentrated and recrystallized twice from methanol, converted into the free base and the hydrochloride acid reactant in the manner described to produce O, South. (-f-enantiomer as a white crystalline substance with mp. 7kQ2f k ° L. Rotation: 12t, 38 ° (c 0, water). Elemental analysis: Calculated: C 62.70 {H 8, N 9.75 .C ,, O.HCl-0.25 HfcO Found,%: C 63.02; H 8.20, J 9.88. Example: Preparation of N- (2,3-ethyl-, "a, 5.6 , 7,8, 8а, 9-octahydro-2-methyl-o-oxo, 8a-trans-1H-pyrrolo 2, 3) isoquinolin-6-yl (ethyl) -fluorobenzamide. The named product is obtained by two-hour heating of 3-ethyl- 2-methyl-, "a, 5,6,7,8,8а, 9-octahydro-1H-pyrrolo 2,3 9 isoquinolin-4-one and 1- (α-fluorobenzoyl-aziridine in a mixture of benzene and methanol Crude crisp product from ethanol to produce white solid About substances with a melting point of 252 253С, the starting aziridine is obtained and aziridine and chlorofluorobenzoate and sodium bicarbonate in water. Example 5: Ingredients for making capsules are given in Table 3. Acceptance of manufacturing. Active ingredients, lactose and starch mix In a suitable mixer, grind in a suitable mill, mix with talc and magnesium stearate and feed into a capsule making machine. PRI me R 6. Ingredients for the manufacture of tablets (direct compression) are given in tal. 4. Reception of manufacture. The active chalo, lactose, avicelle and modified starch mix for 10-15 minutes in the same mixer, add a preliminarily mixed magnesium stearate and mix for another k min and compress in a press .. Example 7. The ingredients for making tablets (wet granulation) are listed in Table. 5. Reception of manufacture. The active principle, lactose, modified starch and pregelatinized starch are mixed in a suitable mixer, granulated with water, dried and crushed, mixed with magnesium stearate and pressed in a suitable press. Biological tests of the octahydro-1H-pyrrolo f2, 3-0,1 isoquinolines obtained were carried out. For example, trained rats are placed in an experimental chamber. 7 ″ 6 equipped with a counter arm, a steel grate bottom for electric shocks and a loudspeaker for transmitting auditory stimuli. Each test consists of a 15 second warning signal (conditional stimulus) followed by a signal of the same duration as an electrical shock (unconditioned stimulus: 1.0 mA 350 V.A.C). Rats can stop the test at any time by clicking on the response lever. The receipt of a response during the initial 15 second warning signal completes the test before an electrical shock and is considered a avoidance response, while the response received during the strike is considered an escape response. The tests are repeated every 2 minutes for a 1-hour test session (30 tests per session). Trained rats reliably retain their original behavior to avoid electrical shocks (0–3 misses in the hay). Compounds were administered to rats at a certain time before the test, and it was at least three injections for each dose of the whole series of doses. During the test sessions, only the indifferent basis of the preparation was administered to rats. The test and test sessions alternate during each week, with each animal serving as a control for itself. A session is divided into three consecutive 20-minute sections (10 tests each). In each segment, calculate the sum of the responses received from all animals at a given dose. For each segment, the number of tests in which the rats did not show a avoidance reaction (blocking the avoidance reaction — BRI or flight response (blocking the escape response — BRB) with the maximum number of each dose response is determined. This number is expressed as a percentage of one dose. The dose required for a 50% blocking of the avoidance reaction (BRI 507, is determined by the dose regression line of the least squares action. The lowest dose that is obtained by blocking the reaction b egstva
710
1BRB 20, read from the dose-action diagram. Using the obtained values, a chart is made, determining the percentage effect versus the logarithmic dose value.
The proposed antipsychotic substances can be distinguished from other types of drugs acting on the behavior of rats in the tests described, over a wider distance between the doses blocking the avoidance reaction and the doses blocking the escape response. There is a significant and very significant relationship between the clinical efficacy of antipsychotic drugs with known therapeutic prescriptions and properties and their efficacy in these trials. Consequently. The proposed compounds of formula (1) can be used for therapeutic purposes with doses within the limits of their efficacy in the indicated tests.
If Z-ethyl-2,6-dimethyl-, 5.6,7,8,8a, 9-octahydro hydrochloride is used as the test substance; a, 8a-trans-1H-pyrrolo 2, 3-% isoquinoline- it shows OLA, for example, in mice at a dose of 350 mg / kg oral neuroleptic activity is observed 0.7 microns / kg oral and 0.095 mg / kg subcutaneously. At the (-) -enantiome of the title compound, neuroleptic activity is observed with BRI. in Q, B mg / kg orally.
Similarly, if hydrochloride 2,3. Lb-trimethyl-, ta, 5,6,7,8, 8a, 9 octahydro, 8a-trans-1H-pyrrro 2, 3 zizoquinolin-it is used as the test substance, Neuroleptic activity is observed at BRID-O, 8 mg / kg orally.
f,
Similarly, if H- (2), 3-ethyl-, a, 5.6,7,8, 8a, 9-octa hydro-2-methyl-4-oxo-a, 8a-trans-1 is used as the test substance H-Pyrrolo 2, 3-Zizoquinolin-6-yl (ethyl) - + - fluorine benzamide, antipsychotic activity is observed at 3.5 mg / kg orally.
Similarly, if 3-ethyl-2-methyl-6- () 4-fluorophenyl- (4-oxobutythyl) -4.6a, 5,, B, 8a, 9-octahydro-, 8a trans-1H-pyrrolo 2,3-9 isoquinoline - "- it is neuroleptic active" ltT 8
Efficiency is observed at 0.19 mg / kg oral.
Similarly, if 3 ethyl 2, 6-dimethyl-4, 4a, 5.6,7,8,8a, 9-octag, idro-4a, 8a-trans-1H-pyrrolo 2 are used as the test substance. isoquinolin-C-thion, neuroleptic activity is observed at ARI of 0.9 mg / kg orally.
The compounds of formula (I) and their headlights / acologically compatible salts have an antipsychotic effect, which in its quality corresponds to the action of haloperidol, trifluoroperacine and molindone, known for their therapeutic purposes and properties. Thus, compounds of formula (I, in combination with antipsychotic drugs of known efficacy and reliability, exhibit a specific type of activity.
The compounds of formula () and their pharmacologically compatible salts can be used in the form of conventional pharmaceutical preparations. Suitable oral unit doses range from 0.05 to 50 mg and suitable daily oral doses for warm-blooded animals, 0.001 to 10 mg / kg per day. For each warm-blooded animal, however, the specific doses and frequency of their administration may be different and are determined depending on the individual need and on the professional experience of the person using formula (1) or its pharmacologically compatible salt or following their application. In addition, the frequency of taking any dosage form will vary depending on the amount of the active substance contained in the drug and the requirements of the pharmacological situation.
For the proposed use, the compounds of formula (1) and their pharmacologically compatible salts are processed into preparations suitable for oral or parenteral administration, and conventional inert adjuvants are used, for example, tablets, suspensions, solutions, and the like. In addition, the compounds of the formula (.1U may be processed and administered in the form of suitable hard or soft capsules. Inert
auxiliary medicinal substances used to process compounds of formula I 1 and their pharmacologically compatible salts s
preparations suitable for oral and parenteral administration are known. Such auxiliary drugs of inorganic or organic origin include, for example, water, gelatin, lactose, starch, magnesium, talc.
vegetable oils, gums, polyalkylene glycols, etc.
In addition, preservatives, bilisers, wetting agents, emulsifiers can also be included in the preparations. salts, osmotic pressure alters, buffers, etc.
L I I CD 1U
(About JO I
I
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Zethyl-2,6-dimethyl-4,4a, 5,6,7,8, 8a hydrochloride, Eoctagidro-La, 8a-trans-1H-pyrrolo,
T a b l and c a 5

权利要求:
Claims (1)
[1]
METHOD FOR OBTAINING OCTAHYDRO-1H-PYRROLO [2.3 - ^] - IZ) $ INOLINS IN THE FORM OF THEIR RACEMIC MIXTURE, NUMBER OF TRANS-ISOMERS, FREE OR AS THE SALT.
(57) Method for producing octahydro-1H-pyrrolo ^ 2,3 ^] isoquinolines of general formula
X
I R1 where is hydrogen;
. R1 is hydrogen; (C, -C ^ alkyl, propenyl, acetyl. Or benzyl ';
R3 is hydrogen, (C ^ -C _e ) -alkyl, cyclopropyl or phenyl;
R4 '"(C<-C4) alkyl, hydroxy (C, -C ₆₎ alkyl, phenyl and chlorophenyl, u (Sd) and -alkilfenoksi--hlorfenoksi- or (Cp-C ^ hydroxyalkyl, and -fluorobenzoyl- (C ^ -C ^) - alkyl, (Cd-C ₅ ) -alkoxycarbonylal. Kil, phenyl-M-methoxyphenyl-and-chlorophenyl- or diphenyl- (C "- (C) -alkyl, propenyl, Sd- C ₆ cycloalkylalkyl,; n-ftorfenilkarboksamidetil, C3'-alkanoilalkil, tricyclo-3,3,1,1- (3.7) decan-1-yl- (2-oxoethyl) - Sd-alkeniloksialkil, phenylpropenyl , phenoxypropyl, N-methylpyrrolidinethyl, dimethylaminoethyl, (4-morpholinyl) ethyl, dioxipropyl or (2,2 “dimethyl-1,3 ~ dioxolan-4-yl) methyl /
X - oxygen, or sulfur, in the form of a racemic mixture of cis isomers and .trans-, in free form or in the form of q soli.otlichayuschiysya in that a compound of general formula ^{D E} R ^, R. _v R3 and X are as defined values are reacted with a compound of the general formula
R4-
where is chlorine or bromine;
R4 - has the indicated meanings, and the target product is isolated in the form of their racemic mixture, cis and trans isomers, in free form or in the form of a salt.
1014474 Priority by attribute:
10/13/78 at R.J. -hydrogen, (C ^ -C ^) - alkyl, propenyl, benzyl, ’
R3 is hydrogen, (C <-Salkyl, cyclopropyl;
yd- (Sd-Cq) alkyl, okch- (C _v - C ₆₎ alkyl, phenyl, h-chlorophenyl, and - ((d) -alkilfenoksi, h -hlorfenoksy CCr-C ^) · oksilalkil and -fluorobenzoyl- (C>, - C ^) - alkyl, (Cd-C ^ alkoxycarbonylalkyl, phenyl-P * methoxyphenyl-P-chlorophenyl, diphenyl- (C <-Cd.) - alkyl, propenyl- (Cd- Cj) -cycloalkylalkyl)
X is about;
09.09-79 when R _a is acetyl;
R} is phenyl;
Poison-fluorophenylcarboxamideethyl, (Ce) -alkanoylalkyl, tricyclo-3.3 "1" 1- (3, 7) -decan-1-yl-2-oxoethyl- (Cd) -alkenyloxyalkyl, phenylpropenyl, phenoxy propyl, N-methylpyrrolidinylethyl dimethylaminoethyl (; 4 ~ morpholinyl) ethyl dihydroxypropyl u (2,2-dimethyl-D, 3 ^_ diok salon-4-yl) methyl '
X = 9

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引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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JPS51118799A|1975-04-10|1976-10-18|Sankyo Co Ltd|Method for preparing pyridindole derivatives|MC1377A1|1980-02-28|1982-01-19|Hoffmann La Roche|ISOQUINOLEIN DERIVATIVES|

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US4732902A|1986-05-23|1988-03-22|Hoffmann-La Roche Inc.|Pyrroloisoquinolinyl-dimethyloxoalkyl alkonoates and their use as antipsychotic agents|

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EP1131284A1|1998-11-20|2001-09-12|Basf Aktiengesellschaft|Method and intermediate products for producing bismonoethers|

法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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US95094778A| true| 1978-10-13|1978-10-13|

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US06/073,813|US4260762A|1979-09-10|1979-09-10|Octahydro-1H-pyrrolo[2,3-g]isoquinolines|

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