CA1065326A - Hexahydro-4-phenyl-4-hydroxy-indoline - Google Patents
Hexahydro-4-phenyl-4-hydroxy-indolineInfo
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- CA1065326A CA1065326A CA241,104A CA241104A CA1065326A CA 1065326 A CA1065326 A CA 1065326A CA 241104 A CA241104 A CA 241104A CA 1065326 A CA1065326 A CA 1065326A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Abstract of the Disclosure This invention provides new compounds of formula I, I
wherein R1 is hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, fluorine, chlorine or hydroxy, and R2 is i) alkyl of 1 to 4 carbon atoms, ii) alkenyl or alkynyl of 3 to 7 carbon atoms, wherein the multiple bond is located in a position other than .alpha. to the nitrogen atom to which R2 is bound, iii) cycloalkyl of 5 to 7 carbon atoms, iv) alkyl of 1 to 4 carbon atoms mono-substituted by cycloalkyl of 3 to 7 carbon atoms, v) hydroxyalkyl of 2 to 4 carbon atoms, wherein the hydroxy moiety is attached to a carbon atom other than a carbon atom a to the nitrogen atomo to which R2 is bound, vi) a group -(CH2)p-CO-A, wherein p is a whole number from 1 to 3 and A is alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms, or vii) a group
wherein R1 is hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, fluorine, chlorine or hydroxy, and R2 is i) alkyl of 1 to 4 carbon atoms, ii) alkenyl or alkynyl of 3 to 7 carbon atoms, wherein the multiple bond is located in a position other than .alpha. to the nitrogen atom to which R2 is bound, iii) cycloalkyl of 5 to 7 carbon atoms, iv) alkyl of 1 to 4 carbon atoms mono-substituted by cycloalkyl of 3 to 7 carbon atoms, v) hydroxyalkyl of 2 to 4 carbon atoms, wherein the hydroxy moiety is attached to a carbon atom other than a carbon atom a to the nitrogen atomo to which R2 is bound, vi) a group -(CH2)p-CO-A, wherein p is a whole number from 1 to 3 and A is alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms, or vii) a group
Description
Case 100-4263 10653~6 HEXAHYDRO-4-PHENYL- 4-HYDROXY-I~DOLINE
The present invention relates to hexahydro-indolinols.
The present invention provides compounds of formula I, ~ R
HO ~ H
~:`
N
~3 X2 wherein R1 is hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, fluorine, chlorine or hydroxy, and R2 is i) alkyl of 1 to 4 carbon atoms, ii) alkenyl or alkynyl of 3 to 7 carbon atoms, wherein the multiple bond is located in a position other than a to the nitrogen atom to which R2 is bound, iii) cycloalkyl of 5 to 7 carbon atoms, iv) alkyl of 1 to 4 carbon atoms mono-substituted by cycloalkyl of 3 to 7 carbon atoms, ~, .
v) hydroxyalkyl of 2 to 4 carbon atoms, wherein the hydroxy moiety is attached to a carbon atom other than a carbon atom a to the nitrogen atom to which ~2 is bound, vi) a group -(CH2)p-C0-A, wherein p is a whole number from 1 to 3 and A is alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms, or vii) a group -(CH2)n-X ~ 3 wherein R3 and R4, independently, are hydrogen, alk~l of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or halogen, and either X is a direct bond, vinylene or carbonyl and n is a whole number from 1 to 5 or X is -0-, -S-, -S0-, -S02- or -~R5-, wherein R5 is hydrogen, phenyl, alkyl of 1 to 4 carbon atoms or alkanoyl of 2 to 4 carbon atoms, and n is a whole number from 2 to 5, and pharmaceutically acceptable acid addition salt forms thereof.
The alkyl and alkoxy moieties preferably have 1 to 2 carbon atoms, especially 1. Rl preferably is hydrogen, alkyl, alkoxy, fl~orine or chlorine. R2 is ~0653Z6 l00-4263 preferably alkyl, alkenyl, hydroxyalkyl, -(CH2)p-CO-A
( 2)n X ~ 3 . When R2 is hydroxyalkyl, this preferably has 2 or 3 carbon atoms. The significance p is preferably 2 or 3. When R2 is cycloalkylalkyl, S this is preferably cyclopropylmethyl.
A is preferably alkyl.
~ 3 is preferably hydrogen, halogen or alkyl.
R4 is preferably hydrogen. ~Ihen R3 and/or R4 is halogen, this is fluorine, chlorine or bromine, preferably fluorine or chlorine.
When X is a direct bond or vinylene, n is preferably a whole number from 1 to 4. When X is -O-, -S-, -SO-, -S02-, -CO- or -NR5-, n is preferably 2 or 3. ~hen R5 is alkanoyl, this preferably has 2 or 3 carbon atoms.
X is preferably a direct bond, -CO-, -O-, -S-, -S02-, especially a direct bond or -CO-.
The present invention provides a process a) for the production of a compound of formula I, as 2C defined above, which comprises introducing by N-alkylation a group R2, as defined above, into the l-position of a compound of formula II, ~,sil ~065326 100-4 2 6 3 ~---RL
~l N J
wherein Rl is as defined above, or b) for the production of a compound of formula Ia, ~ Rl ~ -_ ~ H Ia wherein R1 is hydrogen, alkyl or alkoxy of 1 to 4 carbon atoms, fluorine or chlorine, S and E is hydrogen, alkyl of 1 to 3 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, alkyl of 1 to 3 carbon atoms mono-substituted by cycloalkyl of 3 to 7 carbon atoms, or a group -(CH2)m ~ R4 wherein m is a whole number from O to 4 and R3 and R4 are as defined above, which comprises reducing the -C03 group to a -CH2E
group in a compound of formula III, ~ R
f~O ~
,Y~ III
- COD
S wherein Rl is as defined above, and D is alkoxy of 1 to 4 carbon atoms or E, as defined above, and isolating the resulting compound of formula I in free form or in acid addition salt form.
-- , Processes a) and b) may be effected in analogous manner to known methods.
Process a) may be effected in conventional manner, e.g. for the alkylation of a secondary amir.e. For example as alkylating agent a compound of formula V, R2_Y V
wherein R2 is as defined above, and Y is a group capable of leaving under SN2 conditions, may be used. Other known alkylating agents ma~ be used, for example those mentioned hereinafter.
Y is conveniently an acid radical of a reactive ester, e.g. a halide such as a chloride, bromide or iodide, _ 5 _ .
10653Z6 100-~263 preferably a chloride or bromide, or an acid radical of an organic sulphonic acid, e.g. alkylsulphonyl-OXy~ such as methylsulphonyloxy,or arylsulphonyloxy such as phenylsulphonyloxy or p-tolylsulphonyloxy.
The alkylation is conveniently effected in an organic solvent, for example in a solvent which is an amide of an aliphatic carboxylic acid, such as dimethyl formamide or in an aromatic hydrocarbon solvent, such as toluene. Preferably a basic condensation agent, e.g. an alkaline metal carbonate, such as potassium carbonate is present. The reaction temperature may be from room temperature to about 120C; preferably it is the reflux temperature.
Alternatively other known alkylating agents may be used,e.g. a compound obtainable from a compound of formula V, as defined above, by splitting off HY.
For the production of compounds of formula I wherein R2 is -(CH2)2~CO~A or -~CH2)2-C0 ~ , wherein A, R3 and R4 are as defined above, a,~ unsaturated carbonyl compounds may be used. For example methyl vinyl ketone or an appropriate alkyl ester of acrylic acid may be used. Conveniently a suitable organic solvent is present, e.g. ethyl acetate or a lower alcohol such as methanol, ethanol. Conveniently the 1065326 1 oo--4263 reaction mixture is stirred. The reaction temperature may vary from room temperature to the reflux temperature;
preferably it is from 20 to 80C.
Alternatively a 1,2-alkylene oxide may be used to produce a compound of formula I, wherein R2 is
The present invention relates to hexahydro-indolinols.
The present invention provides compounds of formula I, ~ R
HO ~ H
~:`
N
~3 X2 wherein R1 is hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, fluorine, chlorine or hydroxy, and R2 is i) alkyl of 1 to 4 carbon atoms, ii) alkenyl or alkynyl of 3 to 7 carbon atoms, wherein the multiple bond is located in a position other than a to the nitrogen atom to which R2 is bound, iii) cycloalkyl of 5 to 7 carbon atoms, iv) alkyl of 1 to 4 carbon atoms mono-substituted by cycloalkyl of 3 to 7 carbon atoms, ~, .
v) hydroxyalkyl of 2 to 4 carbon atoms, wherein the hydroxy moiety is attached to a carbon atom other than a carbon atom a to the nitrogen atom to which ~2 is bound, vi) a group -(CH2)p-C0-A, wherein p is a whole number from 1 to 3 and A is alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms, or vii) a group -(CH2)n-X ~ 3 wherein R3 and R4, independently, are hydrogen, alk~l of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or halogen, and either X is a direct bond, vinylene or carbonyl and n is a whole number from 1 to 5 or X is -0-, -S-, -S0-, -S02- or -~R5-, wherein R5 is hydrogen, phenyl, alkyl of 1 to 4 carbon atoms or alkanoyl of 2 to 4 carbon atoms, and n is a whole number from 2 to 5, and pharmaceutically acceptable acid addition salt forms thereof.
The alkyl and alkoxy moieties preferably have 1 to 2 carbon atoms, especially 1. Rl preferably is hydrogen, alkyl, alkoxy, fl~orine or chlorine. R2 is ~0653Z6 l00-4263 preferably alkyl, alkenyl, hydroxyalkyl, -(CH2)p-CO-A
( 2)n X ~ 3 . When R2 is hydroxyalkyl, this preferably has 2 or 3 carbon atoms. The significance p is preferably 2 or 3. When R2 is cycloalkylalkyl, S this is preferably cyclopropylmethyl.
A is preferably alkyl.
~ 3 is preferably hydrogen, halogen or alkyl.
R4 is preferably hydrogen. ~Ihen R3 and/or R4 is halogen, this is fluorine, chlorine or bromine, preferably fluorine or chlorine.
When X is a direct bond or vinylene, n is preferably a whole number from 1 to 4. When X is -O-, -S-, -SO-, -S02-, -CO- or -NR5-, n is preferably 2 or 3. ~hen R5 is alkanoyl, this preferably has 2 or 3 carbon atoms.
X is preferably a direct bond, -CO-, -O-, -S-, -S02-, especially a direct bond or -CO-.
The present invention provides a process a) for the production of a compound of formula I, as 2C defined above, which comprises introducing by N-alkylation a group R2, as defined above, into the l-position of a compound of formula II, ~,sil ~065326 100-4 2 6 3 ~---RL
~l N J
wherein Rl is as defined above, or b) for the production of a compound of formula Ia, ~ Rl ~ -_ ~ H Ia wherein R1 is hydrogen, alkyl or alkoxy of 1 to 4 carbon atoms, fluorine or chlorine, S and E is hydrogen, alkyl of 1 to 3 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, alkyl of 1 to 3 carbon atoms mono-substituted by cycloalkyl of 3 to 7 carbon atoms, or a group -(CH2)m ~ R4 wherein m is a whole number from O to 4 and R3 and R4 are as defined above, which comprises reducing the -C03 group to a -CH2E
group in a compound of formula III, ~ R
f~O ~
,Y~ III
- COD
S wherein Rl is as defined above, and D is alkoxy of 1 to 4 carbon atoms or E, as defined above, and isolating the resulting compound of formula I in free form or in acid addition salt form.
-- , Processes a) and b) may be effected in analogous manner to known methods.
Process a) may be effected in conventional manner, e.g. for the alkylation of a secondary amir.e. For example as alkylating agent a compound of formula V, R2_Y V
wherein R2 is as defined above, and Y is a group capable of leaving under SN2 conditions, may be used. Other known alkylating agents ma~ be used, for example those mentioned hereinafter.
Y is conveniently an acid radical of a reactive ester, e.g. a halide such as a chloride, bromide or iodide, _ 5 _ .
10653Z6 100-~263 preferably a chloride or bromide, or an acid radical of an organic sulphonic acid, e.g. alkylsulphonyl-OXy~ such as methylsulphonyloxy,or arylsulphonyloxy such as phenylsulphonyloxy or p-tolylsulphonyloxy.
The alkylation is conveniently effected in an organic solvent, for example in a solvent which is an amide of an aliphatic carboxylic acid, such as dimethyl formamide or in an aromatic hydrocarbon solvent, such as toluene. Preferably a basic condensation agent, e.g. an alkaline metal carbonate, such as potassium carbonate is present. The reaction temperature may be from room temperature to about 120C; preferably it is the reflux temperature.
Alternatively other known alkylating agents may be used,e.g. a compound obtainable from a compound of formula V, as defined above, by splitting off HY.
For the production of compounds of formula I wherein R2 is -(CH2)2~CO~A or -~CH2)2-C0 ~ , wherein A, R3 and R4 are as defined above, a,~ unsaturated carbonyl compounds may be used. For example methyl vinyl ketone or an appropriate alkyl ester of acrylic acid may be used. Conveniently a suitable organic solvent is present, e.g. ethyl acetate or a lower alcohol such as methanol, ethanol. Conveniently the 1065326 1 oo--4263 reaction mixture is stirred. The reaction temperature may vary from room temperature to the reflux temperature;
preferably it is from 20 to 80C.
Alternatively a 1,2-alkylene oxide may be used to produce a compound of formula I, wherein R2 is
2-hydroxyalkyl. The reaction may be carried out under conventional conditions, e.g. a reaction temperature of from -10 to 100C may be used.
It will be appreciated that those significances of R2 which contain a moiety which is not completely inert under the conditions of process a) may be introduced using an alkylating agent having the moiety in protected form and then the protecting group is split off. Thus one can produce particularly conveniently compounds of formula Ib, - R
Ib (C~2)r-co ~ R3 wherein Rl, R3 and R4 are as defined above, and r is a whole number from 1 to 5l by using in the above described alkylation processes alkylating agents capable of introducing a moiety of formula - - (CH2) r~co~R3 wherein R3, R4 and r are as defined above, wherein the carbonyl group is in ketal protected form to produce a compound with the carbonyl group in ketal S protected form, e.g the compound of formula VI, ~1 ~0~
-- VI
(Cil ) --C ~R~3 wherein Rl, R3, R4 and r are as defined above, and Rk and Rk are independently alkyl of 1 to 4 carbon atoms, or together an alkyl chain of 2 to 4 carbon atoms, and then removing the protecting group or groups present to produce the compound of formula Ib with the carbonyl group in free form.
In an alternative variant, a reductive alkylation using the appropriate aldehyde or ketone may be used to produce compounds of formula I, wherein R2 has an a-carbon atom carrying a hydrogen atom and wherein the moieties attached tv tne a-carbon are suitably inert under the conditions of a reductive alkylation. This variant may be effected in conventional manner, e.g. hvdrogenolytically or according to the Leuckart-Wallach method.
Process b) may be effected in conventional manner for such reductions, e.g. for the reduction of a tert. amide or an N,N-disubstituted-urethane to a tert. amine. As reducing agent a metal or metalloid hydride, conveniently in complexed form may be used, for example diborane or the aluminium hydrides, such as aluminium hydride, dialkylaluminium hydride, lithium-aluminium hydride or a mixture of lithium aluminium hydride and aluminium chloride.
Conveniently an inert solvent is used, e.g.
cyclic or open-chain ethers, such as diethyl ether and tetrahydrofuran.
The reaction temperature may be from about room temperature to about 100C, for example from about 30C up to the reflux temperature. Reduction of tert.-amides is conveniently effected at from 40 to 60C; whereas the reduction of urethanes is conveniently effected at the reflux temperature.
It will be appreciated that when a chlorine or a bromine substituent is present in the compound of formula III aluminium hydride, dialkyl aluminium hydride, or diborane is conveniently used.
_ g _ Preferred variants of process b) include the reduction of a compound of formula III wherein -COD is alkyloxycarbonyl~ to produce a corresPonding compound of formula Ia, wherein -CEI2E is methyl. Process b) is also particularly suitable for the production of compounds of formula Ia, wherein -CH2E is cyclopropylmethyl.
Free base forms of compounds of formula I may be converted into acid addition salt forms in conventional manner and vice versa. Suitable acids include naphthalene-1,5-disulphonic acid, malonic acid, fumaric acid, hydrochloric acid and maleic acid.
The compounds of formulae II and III are new and may be produced in analogous manner to known methods.
For example compounds of formula IXa, ~I
~0 ~ IIa wherein Rl is as defined above, mav be produced by splitting off the alkoxvcarbonyl group present in the l-position of a compound of formula IIIa, RI
~~
~Q IIIa COOB
wherein R1 is as defined above, and B is alkyl of 1 to 4 carbon atoms.
A compound of formula II, wherein Rl is hydroxy may be produced by splitting the ether group of a compound of formula IIa, wherein Rl- is alkoxy of 1 to 4 carbon atoms. A suitable agent for splitting the ether group is a Lewis acid or a mixtl~re of an alkali metal hydride and a mercaptan such as sodium hydride/methyl mercapian.
A compound of formula IIIa as defined above may be produced by means of a Grignard Synthesis from a comPound of formula IV, H
IV
~NJ
COOB
10653Z6 oo-~ 2~)3 wherein B is as defined above, which proceeds in general stereospecifically.
Compounds of formula IV, wherein B ia ethyl are known. Other compounds of formula IV may be ?repared in analogous manner to known processes.
Compounds of formula III, wherein D ~s E as defined above, may be produced by N-acylatirg or N-formylating the corresponding compounds of formula II
as defined above.
Insofar as the production of any sta~ting material is not particu'arly described thece compo~lds are knownr or may be produced and pu~ified in accordance with known processes, or in a manner analogcis to processes described herein, e.g. in the E~am~les, or to kncwn processes.
In the following Examples all temperG'ures are in degrees Centigrade, and are uncorrected.
EXP~IPLE 1: (3aRS 4SR, 7aRS)-~exahydro~ henethyl-__ _ __L___ __ _________ __ _ ___ __ _ _ __ __ _ ___ 4-~henyl-4-indolinol [process variant a)]
_ _ _~ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 14.8 g-of (3aRS, 4SR, 7aRS)-hexahydro-4-phenyl-4-indolinol, 18.9 g of phenethyl bromide and 18 g of potassium carbonate in 170 ml of dimethylformamide were heated at reflux for 15 hours. After cooling, the reaction mixture was concentrated by evaporation and the concentrate was partitioned between water and ethyl acetate. The organic extract was dried over sodium sulphate, filtered, and concentrated to afford the title compound (M.P. of the hydrogen malonate from ethanol/ethyl acetate 133 - 135).
The starting material was produced as follows:-a) Pnenylmagnesium bromide (produced from 40 g of bromobenzene and 5 g of magnesium) was reacted with 30 g of cis-hexahydro-4-oxo-1-indoline carboxylic acid ethyl ester in tetrahydrofuran. After the reaction mixture had been stirred for 4 hours at room temperature,100 ml of 2N hydrochloric acid and 200 ml diethyl ether were added. The organic phase was separated off, washed with water and dried over sodium sulphate. (3aRS, 4SR, 7aRS)-hexa-hydrG-4-hydroxy-4-phenyl-1-indoline carboxylic acid ethyl ester remained as an oil after concentration by evaporation.
~0653~6 b) To 30 g of (3aRS, 4SR, 7aRS)-hexahydro-~-hydroxy-4-phenyl-1-indoline carboxylic acid ethyl ester in 300 ml of methanol, 300 ml of 2N sodium hydroxide was added and the mixture was stirred overnight under reflux. After cooling the mixture was exhaustively extracted with methylene chloride. The organic extracts were extracted with 2N tartaric acid solution.
The tartaric acid extract was made alkaline and extracted with methylene chloride. After working up the organic phase in conventional manner, (3aRS, 4SR, 7aRS)-hexahydro-4-phenyl-4-indolinol - was obtained (M.P. of the hydrogen naphthalene-1,5-disulphonate from ethanol 228 - 230).
EX~PLE 2: (3aRS, 4SR, 7aRS~-~-fluoro-4-[hexahydro-__________________ ______ _________ ____ 4-hydroxy-4-m-methoxy~henyl-1-indolinyl]
butyro~henone tprocess variant a) ) 6 g of (3aRS, 4SR, 7aRS)-hexahydro-4-m-methoxy-phenyl-4-indolinol and 3 g of 2-(3-choropropyl)-2-~-fluorophenyl-1,3-dioxolanewere heated at 150 for 1 hour. After cooling, the solidified residue containing {(3aRS, 4SR, 7aRS)-1-[3-(2-~-fluorophenyl-1,3-dioxolan-2-yl~propyl~-4-m-methoxyphenyl-4-indolinol}
was made alkaline with 2N sodium hydroxide and the mixture was exhaustively extracted with methylene chloride. After working up in conventional manner, 1065~Z6 100-4263 an oily residue was obtained which was dissolved in 165 ml of acetone. 16.5 ml of 2N hydrochloric acid was added and the mixture was maintained at room temperature for 48 hours. After concentration to dryness, the title compound was obtained as the hydrochloride (M.P. 168 - 170 from acetone/diethyl ether).
_ ~PLE 3: (3aRSL 4SRL 7aP~S)-4-~-chloro~henyl-hexa-hydro-l-methyl-4-indolinol _ _ _ _ _ __ _ _ _ _ _ _ _ _ _ _ _ _ _ _ [process variant b)~
15 g of (3aRS, 4SR, 7aRS)-4-~-chlorophenyl-hexahydro-4-hydroxy-1-indoline carboxylic acid ethyl ester and 4 g of lithium aluminium hydride in 100 ml of tetrahydrofuran were heated at reflux for 15 hours.
Any remaining lithium aluminium hydride was destroyed by the addition of water. Partition between water and diethyl ether afforded after separation and working up of the organic phase the title compound a5 an oil (M.P. of the free ba.se fxom diethyl ether/
petroleum ether 98 - 101).
10~53Z6 100-4263 EXAMPIE 4: ~3aRS, 4SR~ 7aRS)-4-~-chloro~henyl-1-_________ ______ _ ___________ ____ cyclopro~ylmethyl-hexahydro~4-indolin [process variant b)]
A solution of 5 2 g (3aRS, 4SR, 7aRS)-4-p-chloro-phenyl-l-cyclopropylcarbonyl -hexahydro-4-indolinol in 300 ml of tetrahydrofuran was produced by warming, and was added to a suspension of 1.3 g of lithium aluminium hydride in 30 ml of tetrahydrofuran. The mixture was stirred at 50 for 30 minutes. A saturated solution ofamonium sulphate was added. The mixture was filtered. The filtrate was concentrated and reacted with a concentrated solution of naphthalene~l,5-disulphonic acid. Diethyl ether was added, and bis-[(3aRS, 4SR, 7aRS)-4-~-chloro-phenyl-l-cyclopropylmethyl-hexahydro-4-in~olinol~-naphthalene-1,5-disulphonate (M.P. 240-242).
The starting material was produced as follows:-2.74 g of Cyclopropanecarboxylic acid chloride was added dropwise to a solution of 7.2 g of (3aRS, 4SR, 7aRS)-4-p-chlorophenylhexahydro-4-indolinol and 2.5 ml of pyridine in 30 ml of methylene chloride at 0 to 10. ~he mixture was stirred at room temperature for 1 hour, and then was washed first with a 10% tartaric acid solution, then with a sodium bicarbonate solution, t~len with a saturated salt solution.
The orsanic phase was dried over sodi U.T, C ~lphate and concentrated to afford (3aP~S, 4SR, 7zRS)-4-_-chlorophenyl-l-cyclopropylcarbonylhe~ahy~.o-4-indolinol. (M.P. 167 - 169).
The compounds of formula I listed in the Table below are also obtained.
__ _ _ Example ¦ 1 j R2 M . P .
~) Usin~ process a) analo~ous to Example 1_ S m-OCH3 -CH2-CH=CH2 ns140-144 6 p-F - (CH2) 2 ~~~ h f162 -163 7 m-OCH3 ~ (CH2) 3-S~ C1 ns210-212 8 m-OCH 3 - ( CH2) 3-S02 ~C 1 n s139 -141 9 m-OCH 3 - (CH2) 2 -CH--CH~F b102 -103 p-Cl -CH2-CH=CH2 ns120-122 11 p-C1 -CH2-C - CH b92 - 94 12 p-Cl - (CH2) 2-OH ns233-235 13 m-OCH3 ~ (CH2) 3 ~ ns236-237 14 m-OCH3 ( 2) 3 3 ns 130 p-Cl -CH2COCH3 b 90-92~
16 m-OCH3 - (CH2) 3-CO~F hcl 168-170 17 p-Cl -CH2~ ns 240-242 18 p-Cl -CH2-CH-CH~ b 80-82 ~ (CH2) 2 ~~
10653Z6 loO-~1 263 .
Example Rl ¦ R2 ~I.P.
l .
~) Using process a) analogous to Ex. 1 and 2:
m-OCH3 -(CH2)3-CO ~ Cl b 97-99 21 m-OCH3 -(CH2)3-CO ~ ns 237-239 22 p-Cl -(CH2)3-CO ~ F hcl 224-226 23 m-OCH3 -CH -CO ~ b 125-126 24 m-OCH3 -(CH2)3-CO ~ C 3 ns 196-198 m-OCH3 -(CH2)3-CO ~ OC 3 ns 206-208 26 H -(CH2)3-Co ~ OC 3 ~) Usina process a)~ laloaous to Ex. 1 and process b) analoqous I to Example 4ii):
27 m-OCH3 -(CH2)2 ~ b 102-104 28 p-Cl -CH3 b 98-101 29 m-OCH3 -CH2 ~ hf 173 H -(CH2)3 ~ ns 211-213 31 m-OCH3 ( 2)3 ~ ns 240-241 32 p-Cl -(CH2)2 ~ b 105-107 33 m-OCH3 -(CH2)4 ~ hme 142-144 34 p-Cl -CH2 ~ b 92-94 10653Z6 loo-~ 263 . _ ExNOm,ple Rl OCH~ M.P. .
H -(CH2)2 ~ OCH3 36 p-OCH3 -(C~2)2 ~
g) Using process a) ar alogous to Example 1 and p~ ~ocess b) analoqous to Examples 3 ) and 4 ):
37 m-OCH3 -CH3 hf 156-158 38 H -CH3 ns 229-231 39 p-F -CH3 nf 159-161 p-CH3 -CH3 hf 130 41 o-CH3 -CH3 hf 121-123 42 p-OCH3 -CH3 43 o-Cl -CH3 ~) Using process b) analogous to Example 4 :
. 44 ¦ H ¦ ( 2)2 ~ hmo 133-135 In the table:
= decomposition.
ns = bis [base] naphthalene-1,5-disulphonate nf = hydrogen fumarate b = base hmo = hydrogen malonate hcl = hydrochloride hme = hydrogen maleate i) from corresponding compounds of formula III wherein D is ethoY.y ii) from corresponding compounds of formula III wherein D is E as~defined above.
Compounds of formula I exhibit interesting pharmacological activity. In particular they exhibit antiarrhythmic activity as indicated in standard tests, for example by a prolongation of the functional refractory period of the isolated albino guinea pig left atria according to the method of N. Reuter, E. Heeg and U. Haller [Arch. Pharmacol., 268, 323-333, (1971)].
The compounds are therefore indicated for use as anti-arrhythmic agents. For this use an indicated daily dose is from about 1 to about 100 mgr conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from about 0.25 to about 50 mg, or in sustained release form.
Preferred compounds have Rl hydrogen, 3~methoxy, 4-methyl, 4-fluorine or 4-chlorine. Preferably R2 is methyl, allyl, a group -(CH2)p CO CH3, wherein p is as defined above, phenylalkyl of 7 to 10 carbon atoms, phenoxyalkyl with 8 - 9 carbon atoms, 3-~-chlorophenyl-thiopropyl, 3-~-chlorophenylthiopropyl, 3-~-chloro-phenylsulphonylpropyl or a group ~ (CH2 ) r~CO~Rx3 10653~6 100-4263 wherein r is as defined above, RX3 is hydrogen, fluorine, chlorine or methyl, and R4x is hydrogen or methyl.
The Example 1 compound is the most interesting compound.
Compounds of formula I additional7y exhibit anti-depressant activity as indicated in standard tests.
For example in one standard test in accordance with the method of G~ Stille [Arz. Forsch. 14, 534-7 (19641 an antasonism of the ptosis and catalepsy induced in rats by tetrabenazine is observed.
The compounds of formula I are therefore indicated for use as anti-depressants. An indicated suitable daily dosage is from 5 mg to 300 mg, prefera~ly administered in divided dosages of from 1.5 mg to 150 mg, or in sustained release form.
For the anti-depressant use Rl preferably is 4-chlorine. Preferably R2 is methyl, allyl or 2-hydroxyalkyl.
- ~0653Z6 "~ 3 The compounds of formula I may be adsinistered in pharmaceutically acceptable acid addition salt form.
Such acid addition salt forms exhibit the sa.e order of activity as the free base forms and are readily prepared in conventional manner. The present invention also prc,vides a pharmaceutical composition cc,~prising a compound o' formula I, in free base form or in pharmaceutically accep~able acid addition salt form, in association with a pharmaceutical carrier or diluent.
Such compositions may be in the form of, for exa~ple, a solution or a tablet.
It will be appreciated that those significances of R2 which contain a moiety which is not completely inert under the conditions of process a) may be introduced using an alkylating agent having the moiety in protected form and then the protecting group is split off. Thus one can produce particularly conveniently compounds of formula Ib, - R
Ib (C~2)r-co ~ R3 wherein Rl, R3 and R4 are as defined above, and r is a whole number from 1 to 5l by using in the above described alkylation processes alkylating agents capable of introducing a moiety of formula - - (CH2) r~co~R3 wherein R3, R4 and r are as defined above, wherein the carbonyl group is in ketal protected form to produce a compound with the carbonyl group in ketal S protected form, e.g the compound of formula VI, ~1 ~0~
-- VI
(Cil ) --C ~R~3 wherein Rl, R3, R4 and r are as defined above, and Rk and Rk are independently alkyl of 1 to 4 carbon atoms, or together an alkyl chain of 2 to 4 carbon atoms, and then removing the protecting group or groups present to produce the compound of formula Ib with the carbonyl group in free form.
In an alternative variant, a reductive alkylation using the appropriate aldehyde or ketone may be used to produce compounds of formula I, wherein R2 has an a-carbon atom carrying a hydrogen atom and wherein the moieties attached tv tne a-carbon are suitably inert under the conditions of a reductive alkylation. This variant may be effected in conventional manner, e.g. hvdrogenolytically or according to the Leuckart-Wallach method.
Process b) may be effected in conventional manner for such reductions, e.g. for the reduction of a tert. amide or an N,N-disubstituted-urethane to a tert. amine. As reducing agent a metal or metalloid hydride, conveniently in complexed form may be used, for example diborane or the aluminium hydrides, such as aluminium hydride, dialkylaluminium hydride, lithium-aluminium hydride or a mixture of lithium aluminium hydride and aluminium chloride.
Conveniently an inert solvent is used, e.g.
cyclic or open-chain ethers, such as diethyl ether and tetrahydrofuran.
The reaction temperature may be from about room temperature to about 100C, for example from about 30C up to the reflux temperature. Reduction of tert.-amides is conveniently effected at from 40 to 60C; whereas the reduction of urethanes is conveniently effected at the reflux temperature.
It will be appreciated that when a chlorine or a bromine substituent is present in the compound of formula III aluminium hydride, dialkyl aluminium hydride, or diborane is conveniently used.
_ g _ Preferred variants of process b) include the reduction of a compound of formula III wherein -COD is alkyloxycarbonyl~ to produce a corresPonding compound of formula Ia, wherein -CEI2E is methyl. Process b) is also particularly suitable for the production of compounds of formula Ia, wherein -CH2E is cyclopropylmethyl.
Free base forms of compounds of formula I may be converted into acid addition salt forms in conventional manner and vice versa. Suitable acids include naphthalene-1,5-disulphonic acid, malonic acid, fumaric acid, hydrochloric acid and maleic acid.
The compounds of formulae II and III are new and may be produced in analogous manner to known methods.
For example compounds of formula IXa, ~I
~0 ~ IIa wherein Rl is as defined above, mav be produced by splitting off the alkoxvcarbonyl group present in the l-position of a compound of formula IIIa, RI
~~
~Q IIIa COOB
wherein R1 is as defined above, and B is alkyl of 1 to 4 carbon atoms.
A compound of formula II, wherein Rl is hydroxy may be produced by splitting the ether group of a compound of formula IIa, wherein Rl- is alkoxy of 1 to 4 carbon atoms. A suitable agent for splitting the ether group is a Lewis acid or a mixtl~re of an alkali metal hydride and a mercaptan such as sodium hydride/methyl mercapian.
A compound of formula IIIa as defined above may be produced by means of a Grignard Synthesis from a comPound of formula IV, H
IV
~NJ
COOB
10653Z6 oo-~ 2~)3 wherein B is as defined above, which proceeds in general stereospecifically.
Compounds of formula IV, wherein B ia ethyl are known. Other compounds of formula IV may be ?repared in analogous manner to known processes.
Compounds of formula III, wherein D ~s E as defined above, may be produced by N-acylatirg or N-formylating the corresponding compounds of formula II
as defined above.
Insofar as the production of any sta~ting material is not particu'arly described thece compo~lds are knownr or may be produced and pu~ified in accordance with known processes, or in a manner analogcis to processes described herein, e.g. in the E~am~les, or to kncwn processes.
In the following Examples all temperG'ures are in degrees Centigrade, and are uncorrected.
EXP~IPLE 1: (3aRS 4SR, 7aRS)-~exahydro~ henethyl-__ _ __L___ __ _________ __ _ ___ __ _ _ __ __ _ ___ 4-~henyl-4-indolinol [process variant a)]
_ _ _~ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 14.8 g-of (3aRS, 4SR, 7aRS)-hexahydro-4-phenyl-4-indolinol, 18.9 g of phenethyl bromide and 18 g of potassium carbonate in 170 ml of dimethylformamide were heated at reflux for 15 hours. After cooling, the reaction mixture was concentrated by evaporation and the concentrate was partitioned between water and ethyl acetate. The organic extract was dried over sodium sulphate, filtered, and concentrated to afford the title compound (M.P. of the hydrogen malonate from ethanol/ethyl acetate 133 - 135).
The starting material was produced as follows:-a) Pnenylmagnesium bromide (produced from 40 g of bromobenzene and 5 g of magnesium) was reacted with 30 g of cis-hexahydro-4-oxo-1-indoline carboxylic acid ethyl ester in tetrahydrofuran. After the reaction mixture had been stirred for 4 hours at room temperature,100 ml of 2N hydrochloric acid and 200 ml diethyl ether were added. The organic phase was separated off, washed with water and dried over sodium sulphate. (3aRS, 4SR, 7aRS)-hexa-hydrG-4-hydroxy-4-phenyl-1-indoline carboxylic acid ethyl ester remained as an oil after concentration by evaporation.
~0653~6 b) To 30 g of (3aRS, 4SR, 7aRS)-hexahydro-~-hydroxy-4-phenyl-1-indoline carboxylic acid ethyl ester in 300 ml of methanol, 300 ml of 2N sodium hydroxide was added and the mixture was stirred overnight under reflux. After cooling the mixture was exhaustively extracted with methylene chloride. The organic extracts were extracted with 2N tartaric acid solution.
The tartaric acid extract was made alkaline and extracted with methylene chloride. After working up the organic phase in conventional manner, (3aRS, 4SR, 7aRS)-hexahydro-4-phenyl-4-indolinol - was obtained (M.P. of the hydrogen naphthalene-1,5-disulphonate from ethanol 228 - 230).
EX~PLE 2: (3aRS, 4SR, 7aRS~-~-fluoro-4-[hexahydro-__________________ ______ _________ ____ 4-hydroxy-4-m-methoxy~henyl-1-indolinyl]
butyro~henone tprocess variant a) ) 6 g of (3aRS, 4SR, 7aRS)-hexahydro-4-m-methoxy-phenyl-4-indolinol and 3 g of 2-(3-choropropyl)-2-~-fluorophenyl-1,3-dioxolanewere heated at 150 for 1 hour. After cooling, the solidified residue containing {(3aRS, 4SR, 7aRS)-1-[3-(2-~-fluorophenyl-1,3-dioxolan-2-yl~propyl~-4-m-methoxyphenyl-4-indolinol}
was made alkaline with 2N sodium hydroxide and the mixture was exhaustively extracted with methylene chloride. After working up in conventional manner, 1065~Z6 100-4263 an oily residue was obtained which was dissolved in 165 ml of acetone. 16.5 ml of 2N hydrochloric acid was added and the mixture was maintained at room temperature for 48 hours. After concentration to dryness, the title compound was obtained as the hydrochloride (M.P. 168 - 170 from acetone/diethyl ether).
_ ~PLE 3: (3aRSL 4SRL 7aP~S)-4-~-chloro~henyl-hexa-hydro-l-methyl-4-indolinol _ _ _ _ _ __ _ _ _ _ _ _ _ _ _ _ _ _ _ _ [process variant b)~
15 g of (3aRS, 4SR, 7aRS)-4-~-chlorophenyl-hexahydro-4-hydroxy-1-indoline carboxylic acid ethyl ester and 4 g of lithium aluminium hydride in 100 ml of tetrahydrofuran were heated at reflux for 15 hours.
Any remaining lithium aluminium hydride was destroyed by the addition of water. Partition between water and diethyl ether afforded after separation and working up of the organic phase the title compound a5 an oil (M.P. of the free ba.se fxom diethyl ether/
petroleum ether 98 - 101).
10~53Z6 100-4263 EXAMPIE 4: ~3aRS, 4SR~ 7aRS)-4-~-chloro~henyl-1-_________ ______ _ ___________ ____ cyclopro~ylmethyl-hexahydro~4-indolin [process variant b)]
A solution of 5 2 g (3aRS, 4SR, 7aRS)-4-p-chloro-phenyl-l-cyclopropylcarbonyl -hexahydro-4-indolinol in 300 ml of tetrahydrofuran was produced by warming, and was added to a suspension of 1.3 g of lithium aluminium hydride in 30 ml of tetrahydrofuran. The mixture was stirred at 50 for 30 minutes. A saturated solution ofamonium sulphate was added. The mixture was filtered. The filtrate was concentrated and reacted with a concentrated solution of naphthalene~l,5-disulphonic acid. Diethyl ether was added, and bis-[(3aRS, 4SR, 7aRS)-4-~-chloro-phenyl-l-cyclopropylmethyl-hexahydro-4-in~olinol~-naphthalene-1,5-disulphonate (M.P. 240-242).
The starting material was produced as follows:-2.74 g of Cyclopropanecarboxylic acid chloride was added dropwise to a solution of 7.2 g of (3aRS, 4SR, 7aRS)-4-p-chlorophenylhexahydro-4-indolinol and 2.5 ml of pyridine in 30 ml of methylene chloride at 0 to 10. ~he mixture was stirred at room temperature for 1 hour, and then was washed first with a 10% tartaric acid solution, then with a sodium bicarbonate solution, t~len with a saturated salt solution.
The orsanic phase was dried over sodi U.T, C ~lphate and concentrated to afford (3aP~S, 4SR, 7zRS)-4-_-chlorophenyl-l-cyclopropylcarbonylhe~ahy~.o-4-indolinol. (M.P. 167 - 169).
The compounds of formula I listed in the Table below are also obtained.
__ _ _ Example ¦ 1 j R2 M . P .
~) Usin~ process a) analo~ous to Example 1_ S m-OCH3 -CH2-CH=CH2 ns140-144 6 p-F - (CH2) 2 ~~~ h f162 -163 7 m-OCH3 ~ (CH2) 3-S~ C1 ns210-212 8 m-OCH 3 - ( CH2) 3-S02 ~C 1 n s139 -141 9 m-OCH 3 - (CH2) 2 -CH--CH~F b102 -103 p-Cl -CH2-CH=CH2 ns120-122 11 p-C1 -CH2-C - CH b92 - 94 12 p-Cl - (CH2) 2-OH ns233-235 13 m-OCH3 ~ (CH2) 3 ~ ns236-237 14 m-OCH3 ( 2) 3 3 ns 130 p-Cl -CH2COCH3 b 90-92~
16 m-OCH3 - (CH2) 3-CO~F hcl 168-170 17 p-Cl -CH2~ ns 240-242 18 p-Cl -CH2-CH-CH~ b 80-82 ~ (CH2) 2 ~~
10653Z6 loO-~1 263 .
Example Rl ¦ R2 ~I.P.
l .
~) Using process a) analogous to Ex. 1 and 2:
m-OCH3 -(CH2)3-CO ~ Cl b 97-99 21 m-OCH3 -(CH2)3-CO ~ ns 237-239 22 p-Cl -(CH2)3-CO ~ F hcl 224-226 23 m-OCH3 -CH -CO ~ b 125-126 24 m-OCH3 -(CH2)3-CO ~ C 3 ns 196-198 m-OCH3 -(CH2)3-CO ~ OC 3 ns 206-208 26 H -(CH2)3-Co ~ OC 3 ~) Usina process a)~ laloaous to Ex. 1 and process b) analoqous I to Example 4ii):
27 m-OCH3 -(CH2)2 ~ b 102-104 28 p-Cl -CH3 b 98-101 29 m-OCH3 -CH2 ~ hf 173 H -(CH2)3 ~ ns 211-213 31 m-OCH3 ( 2)3 ~ ns 240-241 32 p-Cl -(CH2)2 ~ b 105-107 33 m-OCH3 -(CH2)4 ~ hme 142-144 34 p-Cl -CH2 ~ b 92-94 10653Z6 loo-~ 263 . _ ExNOm,ple Rl OCH~ M.P. .
H -(CH2)2 ~ OCH3 36 p-OCH3 -(C~2)2 ~
g) Using process a) ar alogous to Example 1 and p~ ~ocess b) analoqous to Examples 3 ) and 4 ):
37 m-OCH3 -CH3 hf 156-158 38 H -CH3 ns 229-231 39 p-F -CH3 nf 159-161 p-CH3 -CH3 hf 130 41 o-CH3 -CH3 hf 121-123 42 p-OCH3 -CH3 43 o-Cl -CH3 ~) Using process b) analogous to Example 4 :
. 44 ¦ H ¦ ( 2)2 ~ hmo 133-135 In the table:
= decomposition.
ns = bis [base] naphthalene-1,5-disulphonate nf = hydrogen fumarate b = base hmo = hydrogen malonate hcl = hydrochloride hme = hydrogen maleate i) from corresponding compounds of formula III wherein D is ethoY.y ii) from corresponding compounds of formula III wherein D is E as~defined above.
Compounds of formula I exhibit interesting pharmacological activity. In particular they exhibit antiarrhythmic activity as indicated in standard tests, for example by a prolongation of the functional refractory period of the isolated albino guinea pig left atria according to the method of N. Reuter, E. Heeg and U. Haller [Arch. Pharmacol., 268, 323-333, (1971)].
The compounds are therefore indicated for use as anti-arrhythmic agents. For this use an indicated daily dose is from about 1 to about 100 mgr conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from about 0.25 to about 50 mg, or in sustained release form.
Preferred compounds have Rl hydrogen, 3~methoxy, 4-methyl, 4-fluorine or 4-chlorine. Preferably R2 is methyl, allyl, a group -(CH2)p CO CH3, wherein p is as defined above, phenylalkyl of 7 to 10 carbon atoms, phenoxyalkyl with 8 - 9 carbon atoms, 3-~-chlorophenyl-thiopropyl, 3-~-chlorophenylthiopropyl, 3-~-chloro-phenylsulphonylpropyl or a group ~ (CH2 ) r~CO~Rx3 10653~6 100-4263 wherein r is as defined above, RX3 is hydrogen, fluorine, chlorine or methyl, and R4x is hydrogen or methyl.
The Example 1 compound is the most interesting compound.
Compounds of formula I additional7y exhibit anti-depressant activity as indicated in standard tests.
For example in one standard test in accordance with the method of G~ Stille [Arz. Forsch. 14, 534-7 (19641 an antasonism of the ptosis and catalepsy induced in rats by tetrabenazine is observed.
The compounds of formula I are therefore indicated for use as anti-depressants. An indicated suitable daily dosage is from 5 mg to 300 mg, prefera~ly administered in divided dosages of from 1.5 mg to 150 mg, or in sustained release form.
For the anti-depressant use Rl preferably is 4-chlorine. Preferably R2 is methyl, allyl or 2-hydroxyalkyl.
- ~0653Z6 "~ 3 The compounds of formula I may be adsinistered in pharmaceutically acceptable acid addition salt form.
Such acid addition salt forms exhibit the sa.e order of activity as the free base forms and are readily prepared in conventional manner. The present invention also prc,vides a pharmaceutical composition cc,~prising a compound o' formula I, in free base form or in pharmaceutically accep~able acid addition salt form, in association with a pharmaceutical carrier or diluent.
Such compositions may be in the form of, for exa~ple, a solution or a tablet.
Claims (5)
1. A process for the production of a compound of formula I, I
wherein R1 is hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, fluorine, chlorine or hydroxy, and R2 is i) alkyl of 1 to 4 carbon atoms, ii) alkenyl or alkynyl of 3 to 7 carbon atoms, wherein the multiple bond is located in a position other than .alpha. to the nitrogen atom to which R2 is bound, iii) cycloalkyl of 5 to 7 carbon atoms, iv) alkyl of 1 to 4 carbon atoms mono-substituted by cycloalkyl of 3 to 7 carbon atoms, v) hydroxyalkyl of 2 to 4 carbon atoms, wherein the hydroxy moiety is attached to a carbon atom other than a carbon atom .alpha. to the nitrogen atom to which R2 is bound, vi) a group -(CH2)p-CO-A, wherein p is a whole number from 1 to 3 and A is alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms, or vii) a group , wherein R3 and R4, independently, are hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or halogen, and either X is a direct bond, vinylene or carbonyl and n is a whole number from 1 to 5 or X is -O-, -S-, -SO-, -SO2- or -NR5-, wherein R5 is hydro-gen, phenyl, alkyl of 1 to 4 carbon atoms or alkanoyl of 2 to 4 carbon atoms, and n is a whole number from 2 to 5, or a pharmaceutically acceptable acid addition salt form thereof, which comprises a) introducing by N-alkylation a group R2, as defined above, into the 1-position of a compound of formula II, II
wherein R1 is as defined above, or b) for the production of a compound of formula Ia, Ia wherein R? is hydrogen, alkyl or alkoxy of 1 to 4 carbon atoms, fluorine or chlorine, and E is hydrogen, alkyl of 1 to 3 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, alkyl of 1 to 3 carbon atoms mono-substituted by cycloalkyl of 3 to 7 carbon atoms, or a group wherein m is a whole number from 0 to 4 and R3 and R4 are as defined above, reducing the -COD group to a -CH2-E group in a compound of formula III, III
wherein R? is as defined above, and D is alkoxy of 1 to 4 carbon atoms or E, as defined above, and isolating the resulting compound of formula I in free form or in acid addition salt form, or an obvious chemical equivalent thereof.
wherein R1 is hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, fluorine, chlorine or hydroxy, and R2 is i) alkyl of 1 to 4 carbon atoms, ii) alkenyl or alkynyl of 3 to 7 carbon atoms, wherein the multiple bond is located in a position other than .alpha. to the nitrogen atom to which R2 is bound, iii) cycloalkyl of 5 to 7 carbon atoms, iv) alkyl of 1 to 4 carbon atoms mono-substituted by cycloalkyl of 3 to 7 carbon atoms, v) hydroxyalkyl of 2 to 4 carbon atoms, wherein the hydroxy moiety is attached to a carbon atom other than a carbon atom .alpha. to the nitrogen atom to which R2 is bound, vi) a group -(CH2)p-CO-A, wherein p is a whole number from 1 to 3 and A is alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms, or vii) a group , wherein R3 and R4, independently, are hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or halogen, and either X is a direct bond, vinylene or carbonyl and n is a whole number from 1 to 5 or X is -O-, -S-, -SO-, -SO2- or -NR5-, wherein R5 is hydro-gen, phenyl, alkyl of 1 to 4 carbon atoms or alkanoyl of 2 to 4 carbon atoms, and n is a whole number from 2 to 5, or a pharmaceutically acceptable acid addition salt form thereof, which comprises a) introducing by N-alkylation a group R2, as defined above, into the 1-position of a compound of formula II, II
wherein R1 is as defined above, or b) for the production of a compound of formula Ia, Ia wherein R? is hydrogen, alkyl or alkoxy of 1 to 4 carbon atoms, fluorine or chlorine, and E is hydrogen, alkyl of 1 to 3 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, alkyl of 1 to 3 carbon atoms mono-substituted by cycloalkyl of 3 to 7 carbon atoms, or a group wherein m is a whole number from 0 to 4 and R3 and R4 are as defined above, reducing the -COD group to a -CH2-E group in a compound of formula III, III
wherein R? is as defined above, and D is alkoxy of 1 to 4 carbon atoms or E, as defined above, and isolating the resulting compound of formula I in free form or in acid addition salt form, or an obvious chemical equivalent thereof.
2. A compound of formula I in free form or in acid addition salt form, whenever produced by a process accord-ing to claim 1, or by an obvious chemical equivalent thereof.
3. A process according to claim 1 for the production of (3aRS,4SR,7aRS)-hexahydro-1-phenethyl-4-phenyl-4-indo-linol , which comprises a) N-phenethylating (3aRS,4SR,7aRS)-hexahydro-4-phenyl-4-indolinol or b) reducing (3aRS,4SR,7aRS)1-benzylcarbonyl-hexahydro-4-phenyl-4-indolinol, or an obvious chemical equivalent thereof.
4. A process according to claim 1 for the production of (3aRS,4SR,7aRS)-hexahydro-4-p-methoxyphenyl-1-phenethyl-4-indolinol, which comprises a) N-phenethylating(3aRS,4SR,7aRS)-hexahydro-4-p-methoxy-phenyl-4-indolinol or b) reducing (3aRS,4SR,7aRS)-1-benzylcarbonyl-hexahydro-4-p-methoxyphenyl-4-indolinol, or an obvious chemical equivalent thereof.
5. (3aRS,4SR,7aRS)-hexahydro-1-phenethyl-4-phenyl-4-indolinol, whenever produced by the process of clalm 3, or by an obvious chemical equivalent thereof.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1623674A CH601226A5 (en) | 1974-12-06 | 1974-12-06 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1065326A true CA1065326A (en) | 1979-10-30 |
Family
ID=4415551
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA241,104A Expired CA1065326A (en) | 1974-12-06 | 1975-12-04 | Hexahydro-4-phenyl-4-hydroxy-indoline |
Country Status (20)
| Country | Link |
|---|---|
| JP (1) | JPS5182262A (en) |
| AT (1) | AT357147B (en) |
| AU (1) | AU504180B2 (en) |
| BE (1) | BE836290A (en) |
| CA (1) | CA1065326A (en) |
| CH (1) | CH601226A5 (en) |
| DD (1) | DD123458A5 (en) |
| DE (1) | DE2552563A1 (en) |
| DK (1) | DK140723B (en) |
| ES (1) | ES443200A1 (en) |
| FI (1) | FI753351A (en) |
| FR (2) | FR2313048A1 (en) |
| GB (1) | GB1526309A (en) |
| IL (1) | IL48603A (en) |
| NL (1) | NL7514007A (en) |
| NO (1) | NO754028L (en) |
| NZ (1) | NZ179445A (en) |
| SE (1) | SE408895B (en) |
| SU (2) | SU625603A3 (en) |
| ZA (1) | ZA757653B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4124719A (en) * | 1974-12-06 | 1978-11-07 | Sandoz Ltd. | -4-Phenylhexahydro-4-indolinol derivatives |
| DE2741009A1 (en) | 1976-09-22 | 1978-03-23 | Sandoz Ag | 4-STYRYL-4-INDOLINOL DERIVATIVES, THEIR USE AND PRODUCTION |
-
1974
- 1974-12-06 CH CH1623674A patent/CH601226A5/xx not_active IP Right Cessation
-
1975
- 1975-11-24 DE DE19752552563 patent/DE2552563A1/en not_active Withdrawn
- 1975-11-27 DK DK537175AA patent/DK140723B/en unknown
- 1975-11-27 FI FI753351A patent/FI753351A/fi not_active Application Discontinuation
- 1975-11-28 SE SE7513457A patent/SE408895B/en unknown
- 1975-11-28 NO NO754028A patent/NO754028L/no unknown
- 1975-12-02 NL NL7514007A patent/NL7514007A/en not_active Application Discontinuation
- 1975-12-03 GB GB49614/75A patent/GB1526309A/en not_active Expired
- 1975-12-03 FR FR7537014A patent/FR2313048A1/en active Granted
- 1975-12-04 NZ NZ179445A patent/NZ179445A/en unknown
- 1975-12-04 DD DD189887A patent/DD123458A5/xx unknown
- 1975-12-04 IL IL48603A patent/IL48603A/en unknown
- 1975-12-04 CA CA241,104A patent/CA1065326A/en not_active Expired
- 1975-12-04 SU SU752194153A patent/SU625603A3/en active
- 1975-12-04 AU AU87277/75A patent/AU504180B2/en not_active Expired
- 1975-12-04 BE BE162462A patent/BE836290A/en unknown
- 1975-12-04 ES ES443200A patent/ES443200A1/en not_active Expired
- 1975-12-05 JP JP50144080A patent/JPS5182262A/ja active Pending
- 1975-12-05 ZA ZA757653A patent/ZA757653B/en unknown
- 1975-12-05 AT AT924775A patent/AT357147B/en not_active IP Right Cessation
-
1976
- 1976-08-12 FR FR7624662A patent/FR2308622A1/en not_active Withdrawn
-
1977
- 1977-02-07 SU SU772448706A patent/SU613720A3/en active
Also Published As
| Publication number | Publication date |
|---|---|
| IL48603A (en) | 1978-08-31 |
| AU504180B2 (en) | 1979-10-04 |
| ATA924775A (en) | 1979-11-15 |
| FI753351A (en) | 1976-06-07 |
| CH601226A5 (en) | 1978-06-30 |
| JPS5182262A (en) | 1976-07-19 |
| SU625603A3 (en) | 1978-09-25 |
| FR2313048B1 (en) | 1979-09-21 |
| DE2552563A1 (en) | 1976-06-10 |
| DK140723B (en) | 1979-11-05 |
| DK140723C (en) | 1980-03-31 |
| NO754028L (en) | 1976-06-09 |
| SU613720A3 (en) | 1978-06-30 |
| IL48603A0 (en) | 1976-02-29 |
| BE836290A (en) | 1976-06-04 |
| AU8727775A (en) | 1977-06-09 |
| NZ179445A (en) | 1978-03-06 |
| DD123458A5 (en) | 1976-12-20 |
| DK537175A (en) | 1976-06-07 |
| NL7514007A (en) | 1976-06-09 |
| FR2313048A1 (en) | 1976-12-31 |
| ZA757653B (en) | 1977-07-27 |
| FR2308622A1 (en) | 1976-11-19 |
| ES443200A1 (en) | 1978-03-01 |
| SE7513457L (en) | 1976-06-08 |
| GB1526309A (en) | 1978-09-27 |
| AT357147B (en) | 1980-06-25 |
| SE408895B (en) | 1979-07-16 |
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