CA1105468A - 1,2,3,4,4a,10b-hexahydro-benz¬f|isoquinoline compounds - Google Patents
1,2,3,4,4a,10b-hexahydro-benz¬f|isoquinoline compoundsInfo
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- CA1105468A CA1105468A CA295,458A CA295458A CA1105468A CA 1105468 A CA1105468 A CA 1105468A CA 295458 A CA295458 A CA 295458A CA 1105468 A CA1105468 A CA 1105468A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/04—Ortho- or peri-condensed ring systems
- C07D221/06—Ring systems of three rings
- C07D221/10—Aza-phenanthrenes
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
Abstract
Case 100-4732 1, 2, 3, 4, 4a, 10b - HEXAHYDRO-BENZ [f] - ISOQUINOLINE COMPOUNDS
Abstract of the Disclosure:
The present invention relates to compounds of formula,
Abstract of the Disclosure:
The present invention relates to compounds of formula,
Description
~ Case 100- a 7 3 2 1, 2, 3, 4, 4a, 10b ~ HE~AHYDRO-BENZ [f] ISOQUINOLINE COMPOUNDS
The present invention relates to 1,2,3,4,4a,10b-hexahydro-benz~f]isoquinolines.
More particularly, the present invention provides compounds of formula I, ¦1 3N-R3 wherein Rl is hydrogen, halogen of atomic number from 9 to 35, alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms, R2 is hydrogen, alkyl of 1 to 4 carbon atoms, phenyl or phenyl mono- or di-substituted with halogen of atomic number from 9 to 35, alkyl of 1 to 4 car-bon atoms or alkoxy of 1 to 4 carbon atoms, and R3 is hydrogen; alkyl of 1 to 4 carbon lS atoms; alkenyl of 3 to 6 carbon atoms or 61~
. .
alkynyl of 3 to 6 carbon atoms, the multiple bond of which is not adjacent to the tricyclic ring system; cycloalXyl-alkyl of 4 to 10 carbon atoms; cyclo-alkyl of 3 to 7 carbon atoms; phenyl-alkyl of 7 to 10 carbon atoms, the phenyl ring of which may be mono- or di-substituted with halogen of atomic numbex from ~ to 35, alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms; a ~ noylalkyl of 3 to 5 carbon atoms, - the oYygen atom of which is separated by at least 2 carbon atoms from the nitro-gen atom in the tricyclic system; and pharmaceutically acceptable acid addition salts thereof.
. ~ ... . .. ... .
Insofar as the compounds of formula I are substituted by an alkyl or alkoxy group as previously defined, these groups preferably contain 1 or 2 carbon atoms and especially signify methyl or methoxy.
When a substituent signifies halogen, this is preferably chlorine.
Rl is pre~erably hydrogen. When Rl is halogen, alkyl or alkoxy, this is preferably in position 8.
., ~, ....
~5~ 100-4732 R2 is preferably hydrogen, methyl or phenyl.
R2 may also be phenyl mono- or di-substituted wi~h halo-gen of atomic number from 9 to 35~ In a further group of compounds, R2 is phenyl mono- or di-substituted with alkyl of l to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms.
R3 can be alkyl of 1 to a carbon atoms and is preferably methyl. R3 may also be hydrogen. When R3 is alkenyl or alkynyl of 3 to 6 carbon atoms, these prefer-ably contain 3 or 4 carbon atoms. R3 may be cycloalkyl-alkyl of 4 to 10 carbon atoms, for example, cycloalkyl-alkyl of 4 to 6 carbon atoms. R3 may also be cycloalkyl of 3 to 7 carbon atoms, for example, cyclohexyl. When R3 is phenylalkyl of 7 to 10 carbon atoms, this is pref-erably phenethyl. The phenylalkyl group may be mono- or di-substituted in the phenyl ring with halogen of atomic number from 9 to 35. Additionally, the phenylalkyl group may be mono- or di-substituted in the phenyl ring with alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms. When R3 is alkanoylalkyl of 3 to 5 carbon atoms, this preferably contains an acetyl residue and is especially acetonyl.
The invention further provides a process for ~.
., .
. .
~ ~,5 ~ ~ ~ 100-~732 the production of a compound of formula I, eomprising a) producing a compound of formula Ia, R~ ~ Ia wherein Rl and R2 are as previously defined, and R3 is alkyl of 1 to 4 carbon ate~s; alkenyl of 3 to 6 carbon atoms, the multiple bond of whlch is not adjacent to the tricyclic ring system; eyeloalkylalkyl of 4 to 10 carbon atoms; cycloalkyl of 3 to 7 earbon atoms; phenylalkyl of 7 to 10 earbon atoms, wherein the phenyl ring may be mono- or di-substituted with halogen of atomic number from 9 to 35; alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 earbon atoms; or, lS when R2 is hydrogen, R3 can also be hydrogen, by removing water from a compound of formula II, 100-~732 ~ N-R3 Rl ~ ~ II
wherein Rl, R2 and R3 are as previously defined, - b) producing a compound of formula Ib, ~ N-H
1 ~ Ib . wherein Rl and R2 are as previously defined, by removing the group R3 from a compound of formula Ic, ~ N-RII
1 ~ ~ Ic wherein Rl and R2 are as previously defined and R3 is methyl or benzyl, or c) producing a compound of formula Id, Id wherein Rl and R2 are as previously defined and R3II has the same si.gnificance as R3 ; with the exception of hydrogen, by introducing a group R3 in a compound of formula I_ as previously defined; and where desired, forming a pharmaceutically acceptable acid addition salt of said compound of formula 1.
The removal of water according to process variant a) can be effected in known manner, for example, by treating the compound of formula II with an appro-priate spiitting agent, conveniently in the presence of an inert organic solvent. Suitable materials for removing water include strong acids, acid anhydrides and acyl halides~
~ 1hen R3 in the compounds of formula II is alkenyl, the reaccion is preferably effected in the presence of an acyl halide.
r ~
~ 5~ 100-4732 The removal of the group RII from the compounds of formula Ic according to process variant b) can be effected in known manner. The reaction is pxeferahly carried out by reacting the appropriate compound of formula Ic with a chloroformic acid ester and convertins the urethane so obtained by acid or alkaline hydrolysis to a compound of formula Ib.
The introduction of the group R3II into com-pounds of formula Ib according to process variant c) can be effected by known methods for the alkylation of secondary amines, for example, by reaction with a com-pound of formula III, RIII X
wherein R3II is as previously defined and X i9 the acid residue of a reactive ester.
X is preferably halogen or an organic sulph-onic acid residue.
The resulting compounds of formula I may be isolated and purified using conventional techniques.
Free base forms of the compounds of formula I
may be converted into acid addition salt forms and vlce :~ - 8 -~ 100-~732 versa in conventional manner. Suitable acids for pro-ducing acid addition salt forms include hydrochloric and maleic acids.
The compounds of formula I possess two asym-metric carbon atoms in the tricyclic system at positions4a and 10b. Accordingly, two isomer groups may exist, namely compounds wherein rings B and C are linked in the cis configuration and cornpounds wherein rin~s B and C
are linked in the trans configuration. The configura-tion of the tricyclic system of ~he starting materials remains unchanged by the process variants of the inven-tion.
The starting materials can be prepared as follows:
a') The compounds of formula II can be produced by kno~n methods from compounds of formula IV, ~ N-R3 1 ~ OH IV
wherein Rl is as previously defined and R3V is lower alkyl. The compounds of formula II wherein _ g _ .
S~6~1 l00-~732 R2 is as previously defined with the exception of hydrogen may, for example, be produced in the manner hereafter described in Example la) to le) whereby, after cyclisation, the 3-methyl group may be substituted by the desired group R3 according to known methods. The compounds of formula II wherein R2 is hydrogen may, for example, be produced in the manner hereinafter described in Exampl~ la) to ld) and then as described in Example 15 (production of the starting materials).
b') The compounds of formula IV may, for example, be produced by reducing a compound of formula V, I~ N-RIV
Rl ~3/I~R4 V
wherein Rl and R3 are as previously defined and R~ is lower alkyl. The reduction can, for example, be effected with a complex metal hydride, such as lithium aluminium hydride, according to known methods.
~ 100-4732 :
c') The compounds of formula V can, for example, be produced by reacting a compound of formula VI, VI
'IV
wherein R3 and R4 are as previously defined, with a Grignard compound of formula VII, Mg-X
VII
~Rl wherein Rl is as previously defined and XI is - chlorine, bromine or iodine. The reaction can, for example, be effected according to the methods described in J. Org. Chem. 22, 261 ~1957).
Insofar as the production of the starting materials has not been described herein, these compounds are either known or can be produced by known methods or by methods analogous to those described herein or by methods analogous to known methods.
In the following Examples, all temperatures are in degrees Celsius~
~ 5~ 0-4732 , EXAMPI.E 1: Trans-1,2,3,4,4a,10b-hexahydro-3,6-dime ~ n~[f]iso~uinoline A mixture of 1~.6 g of trans-1,2,3,4,4a,5,6,10b-octahydro-3,6-dimethylbenz[f]isoquinoline-6-ol in 20 ml of isopropanol and 30 ml of 5 N isopropanolic hydro-chloric acid solution is heated to boiling under nitro-gen for 30 minutes~ The resulting suspension is cooled to 10 and the hydrochloride of the title compound which crystallises out is filtered, washed with ether and recrystallised from ethanol/isopropanol. M.P. 302-303 (deccmp.) The starting material may be produced as follows:
a) A solution of 39 g of thionyl chloride in 300 ml of anhydrous chloroform is slowly added dropwise at lS 0-5 to a solution of 82 g of 1-methyl-4-phenyl~
piperidine-3-ylmethanol in 1500 ml of anhydrous chloroform. The reaction mixture is stirred for one hour at room temperature, one hour at 40 and sub-sequently for 3 hours a~ the boiling temperature.
After evaporating to dryness, the residue is tri-turated with a large amount of ether. The solid 3-chloromethyl-1-methyl-4-phenylpiperidine hydro-chloride is filtered by suction and dried ln vacuo.
M.P. 203-211~
b) The above product is converted with caustic soda solution to the base, which is extracted with methylene chloride. After drying over sodium sulphate, the organic phase is evaporatsd to dry-ness. 51 g of the evaporated residue and 13.4 g of sodium cyanide are suspended in 40 ml o dimethyl formamide and are heated to boiling for 2 hours with vigorous stirring. On cooling to room temper-ature, the reaction mi.xture is diluted with 200 ml of water, extracted with chloroform and the chloro-form phase is washed with water, dried over sodium sulphate and concentrated. The l-methyl-4-phenyl-piperidin-3-ylacetonitrile (M.P. of the naphthalene-l,S-disulphonic acid salt form: 292-296, decomp.) remaining as a viscous oil is used without further purification.
c) A solution of 85 g of the above product in 150 ml of absolute ethanol is saturated at 10 with hydro-gen ~hloride. The dar~ reaction solution is then stirred for 24 hours at the boiling temperature~
thoroughly concentrated by evaporation, 200 ml of anhydrous benzene are added and the solution is evaporated to dryness. The res.idue is taken up in 290 ml of absolute ethanol, 7.2 ml of water added and the residue is hea~ed to the boil for 2 hours.
On concentration by evaporation, the residue is dissolved in chloroform, water is added and the ; residue is made alkaline with sodium bicarbonate.
After separating the chloroform solution, the aqueous solution is ayain shaken out with chloro-form, the extracts are washed with 10% sodium bicar-bonate and with water, dried over sodium sulphate and evaporated to dryness. The residue is distilled under high vacuum to yield l-methyl~4-phenylpiper-idin-3-ylacetic acid ethyl ester. B.P. 118-123/
0.08 Torr. n20: 1.5220.
d~ A solution of 16.8 g of 1-methyl-4-phenylpiperidin-3-ylaGetic acid ethyl ester in 10 ml of anhydrous xylene is added dropwise over a period of 15 min-20 . utes to a mixture of 85 g o polyphosphoric acid and 25 ml of anhydrous xylene, preheated to 90, with vigorous stirring. The reaction mixture is stirred - ~4 -.':
100-~73~
~ ' .
for a further 2 hours at 120-125, cooled to approx~
imately 80 and poured onto 300 ml of water. The resulting aqueous solution is washed with ether, made alkaline with 20~ caustic soda solution and extracted with chloroform. The ch]oroform solution is washed neutral with water, dried over sodium sulphate, evaporated, the residue is dissolved in a mixture of methylene chloride/methanol 9:1 (v/v), filtered through aluminium oxide and evaporated to dryness. The 1,2,3,4,4a,10b-hexahydro-3-methyl-benz[f]iso~uinoline-6-(5H)-one (isomeric mixture) remainin~ as an oil distills at 106-110/0.08-0.1 Torr.
Isomer separation: The trans-form crystallises from the isomeric mixture from ether/petroleum ether. M.P. 84-85 (ether/petroleum ether).
(Hydrochloride form, M.P. 300-302 decomp., from methanol.) The c1s-form is isolated as ~the hydro~
~en fumarate form from the mother liquor. M.P. 175-177, sint. 172 (from ethanol/ether).
e) To a solution of 115 ml of 2 M methyllithium in ether and ~00 ml of anhydrous ether, there is added dropwise, in a nitro~en atmosphere and with 5~ oo 4732 stirring, a solution of 20.0 g of trans-1,2,3,4,4a,10b-hexahydro-3-methylbenz[f]isoquinoline-6(5H)-one in 400 ml of anhydrous benzene over a period of 45 min-utes at room temperature. The reaction mixture is stirred for 2 hours at room temperature, poured onto 1 litre of 20~ ammonium chloride solution, the organic phase separated and the aqueous solution extracted with methylene chloride. The separate organic solutions are washed with wa~er, dried over sodium sulphate, combined and evaporated. The remaining trans-1,2,3,4,4a,5,6,10b-octahydro-3,6-dimethylbenz[flisoquinoline-6-ol is recrystallised from benæene/hexane. Sint. 130, M.P. 148-153.
The following compounds can be obtained in a manner analogous to that described in Example 1, employ-ing appropriate starting materials in approximately equivalent amounts~
54~6~ 100-4732 ._ . oo~ ooooOoO oLn^
L~ O ~I Ln 0~ 0~~D 0~Ct) ~Dr` CO O ~ N ~
Nt'`l t~l O O t~ 1 0 4 N I I ~ Ll ~ ~ N n~ a . ~ ~ a ~ Q
t~J N N '-- N t~l N N ` NN ~_1 N
__ ~ , . . . _____ _ . _ ., O
~ O
`'~ h 3 ~ o _ . ._ . . . . .
.~
H r~) U - U ~ U
. .. __ _ _ _ P;~ ~ 3 0 ~
_ _ _ ___ ~.. __ _ . _ __ . . .
U~ U U U
P~ ~
- . - . . - - ~ -~ h ~ h ¦
~1 Z; (~ ~ ~ Ln ~ o 'I
---~
~ 100-4732 EX~1P1E 15: Trans~1,2,3 r 4 r 4a,10b-hexahydro-3-methyl-benz~f]isoquinoline In a manner analogous to Example 1, the title compound is produced from 10.0 g of trans-1,2,3,4,4a,5, S 6,10b-octahydro-3-methylbenz[f]isoquinoline-6-ol in 25 ml of isopropanol and 30 ml of 5 N isopropanolic hydrochloric acid solution after boiling for 2 hours.
The title compound is isolated as the hydrochloride salt form. M.P. from 285 (decomp.).
The starting material is produced as follows:
To a suspension of 1~.0 g of lithium aluminium hydride in 800 ml of anhydrous ether, is added dropwise at 0-5, a solution of 15.0 g of trans-1,2,3,4,4a,10b-hexahydro-3-methylbenz[f]iso~uinolin-6(5H)-one in 300 ml of anhydrous ether over a period of 30 minutes. The resulting suspension is stirred for one hour a~ room temperature, 100 ml of water are added dropwlse at 0-5 and the insoluble material filtered off and washed several times ~ith methylene chloride. The organic phase is separated from the filtrate, washed with water, dried over sodium sulphate and concentrated by evapoxa-tion. The solid residue is recrystallised from ether/
. ..~ ;.
'54~ 0 0--G 732 petroleum ether. i~l.P. 118-128.
The following compounds can be obtained in a manner analogous ~o that described in Exam~le 15, using appropriate starting materials in approximately equiv-5alent amounts.
_ _ _ . .
Ex Confn. Rl R2 R3 Form M.P.
_ _ _ __ 16 cis H H -CH3 Hydro- 225-226 chloride 17 trans 8-Cl H -CH ll > 265 3 (Decc~p.) 18 ll 8-CH3 H -CH3 ~ 224-225 19 . H H -CH2 ~ ll 252-253 .
~, L ~ 2 ~ ~ L
EXAMPLE 21: Trans-1,2,3,4,4a,10b-hexahydro~6-methyl-__ _ _ ~
benzEf]isoquinoline To a solution of 7.0 g of trans-1,2,3,4,4a,10b-hexahydro-3,6-dimethylbenz[]isoquinoline in 70 ml of anhydrous benzene is added dropwise a solution of 12.2 g of chloroformic acid ethyl ester in S0 ml of benzene at room temperature ,1, : _ 5fl~
over a period of one hour. The reaction mixture is stirred for one hour at room temperature and for 3 hours at the boiling temperature, cooled to room temperature and washed with water, l N hydrochloric acid and again with water, dried over magnesium sulphate and evaporated ; to dryness. The resulting crude trans-3-ethoxycarbonyl-1,2,3,4,4a,10b-hexahydro-6-methylbenz[f]isoquinoline is ta~en up in 34 ml of n-~utanol, 4.5 g of potassium hydroxide are added and stirring is effected for 18 hours at 100. After cooling, the reac~ion mixture is diluted with 300 ml of benzene, washed neutral with water and extracted with 2 N tartaric aci.d. The tar-taric acid extract is made alkaline with caustic soda solution and shaken out with methylene chloride. The lS methylene chloride solutions are washed with water, dried over sodium sulphate and evaporated. The title compound, remaining as an oily residue, is taken up in ethanol and converted into the hydrogen maleate salt form. M.P. 169-170 tfrom ethanol/ether).
EXAMPLE 22:
In a manner analogous to that of Example 21, trans-1,2,3,4,4a,10b-hexahydro-8-methylbenz[f]isoquino-~ 6 8 line can be produced using an equivalent quantity of the appropriate starting material. M.P. of the hydro-chloride salt form: over 310 (decomp.).
EXAMPLE 23: Trans-1,2,3,4,4a,10b-hexahydro-3-isopropyl-_ 6~methylbenz[f~isoquinoline [Process variant c)]
A mixture of 7.0 g of trans-1,2,3,~,4a,10b-hexahydro-6-methylbenz[f]isoquinoline and 8.0 g of anhydrous sodium carbonate in 70 ml of dimethyl form-amide is preheated to 50. At this temperature, a solution of 6.5 g of isopropyl bromide in 20 ml of dimethyl formamide is slowly added dropwise, the reac-tion mixture is stirred for 6 hours at the same tempera-ture, cooled to 20 and poured onto 300 ml of water and 200 ml of chloroform. The organic solution is separated and the aqueous phase extracted with chloroform. The combined organic solutions are washed with water, dried over sodium sulphate and evaporated. The title compound is isolated as the hydrochloride salt form from methanol/
ethanol. M.P. over 300 (decomp.).
The following compounds can be obtained in a ~ . .
~ `s~
manner analogous to that of Example 23 using appropriate starting materials in approximately equivalent amounts.
_ ~ _ ~ .. , _ Ex Confn. R1 R2 3 Salt Form M.P.
~ _ 24 trans H -CH3 -CH2C--CH Hydrochloride 242-243 25 H -CH3 -CH2COC~3 L _ 215-216 ~5~6~
The compounds of formula I exhibit pharmaco-logical ac~ivity. In particular, the compounds exhibit anti-aggression activity, as indicated in standard tests, for example, in the sedation of aggressive behaviour in mice caused by isolation.
The compounds are therefore indicated for use in the treatment of aggression.
For this use, an indicated daily dose is from about 1 to about 100 mg, suitably from about 5 to about 50 mg, conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from about 0.25 to about 50 mg, suitably from about 1 to about 25 mg, or in sustained release form.
The compounds also exhibit sedative and neuroleptic effects on the central nervous system as indicated in standard tests, for example, in the climb-ing test in mice.
The compounds are therefore indicated for use as neuroleptics and sedatives.
For these uses, an indicated daily dose is from about S to about 200 mg, conveniently from about 5 to about 50 mg, and suitably from about 10 to about 50 mg, conveniently administered in divided doses 2 to 4 times 5 ~ ~ ~
100-~732 a day in unit dosage form containing from about 1 to about 100 m~, conveniently from about 1 to about 25 mg, and suitably from about 2.5 to about 25 mg, or in sus-tained release form.
The eompounds of formula I may be administered in pharmaceutieally aeceptable acid addition salt form.
Sueh acid addition salt orms exhibit the same order of aetivity as the free base forms and are readily prepared in eonventional manner. Suitable acids for salt forma-tion inelude inorganic acids such as hydroehlorie aeid and organie aeids sueh as maleie acidO
The present invention also provides a pharma-eeutical eomposition eomprising a eompound of formula I
in free base form or in pharmaeeutieally aceeptable aeid addition salt form, in assoeiation with a pharmaeeuti-eally aeceptable diluent or earrier. Sueh eompositions may be formulated in eonventional manner and may, for ~xample, be a solution or a eapsule.
The present invention relates to 1,2,3,4,4a,10b-hexahydro-benz~f]isoquinolines.
More particularly, the present invention provides compounds of formula I, ¦1 3N-R3 wherein Rl is hydrogen, halogen of atomic number from 9 to 35, alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms, R2 is hydrogen, alkyl of 1 to 4 carbon atoms, phenyl or phenyl mono- or di-substituted with halogen of atomic number from 9 to 35, alkyl of 1 to 4 car-bon atoms or alkoxy of 1 to 4 carbon atoms, and R3 is hydrogen; alkyl of 1 to 4 carbon lS atoms; alkenyl of 3 to 6 carbon atoms or 61~
. .
alkynyl of 3 to 6 carbon atoms, the multiple bond of which is not adjacent to the tricyclic ring system; cycloalXyl-alkyl of 4 to 10 carbon atoms; cyclo-alkyl of 3 to 7 carbon atoms; phenyl-alkyl of 7 to 10 carbon atoms, the phenyl ring of which may be mono- or di-substituted with halogen of atomic numbex from ~ to 35, alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms; a ~ noylalkyl of 3 to 5 carbon atoms, - the oYygen atom of which is separated by at least 2 carbon atoms from the nitro-gen atom in the tricyclic system; and pharmaceutically acceptable acid addition salts thereof.
. ~ ... . .. ... .
Insofar as the compounds of formula I are substituted by an alkyl or alkoxy group as previously defined, these groups preferably contain 1 or 2 carbon atoms and especially signify methyl or methoxy.
When a substituent signifies halogen, this is preferably chlorine.
Rl is pre~erably hydrogen. When Rl is halogen, alkyl or alkoxy, this is preferably in position 8.
., ~, ....
~5~ 100-4732 R2 is preferably hydrogen, methyl or phenyl.
R2 may also be phenyl mono- or di-substituted wi~h halo-gen of atomic number from 9 to 35~ In a further group of compounds, R2 is phenyl mono- or di-substituted with alkyl of l to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms.
R3 can be alkyl of 1 to a carbon atoms and is preferably methyl. R3 may also be hydrogen. When R3 is alkenyl or alkynyl of 3 to 6 carbon atoms, these prefer-ably contain 3 or 4 carbon atoms. R3 may be cycloalkyl-alkyl of 4 to 10 carbon atoms, for example, cycloalkyl-alkyl of 4 to 6 carbon atoms. R3 may also be cycloalkyl of 3 to 7 carbon atoms, for example, cyclohexyl. When R3 is phenylalkyl of 7 to 10 carbon atoms, this is pref-erably phenethyl. The phenylalkyl group may be mono- or di-substituted in the phenyl ring with halogen of atomic number from 9 to 35. Additionally, the phenylalkyl group may be mono- or di-substituted in the phenyl ring with alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms. When R3 is alkanoylalkyl of 3 to 5 carbon atoms, this preferably contains an acetyl residue and is especially acetonyl.
The invention further provides a process for ~.
., .
. .
~ ~,5 ~ ~ ~ 100-~732 the production of a compound of formula I, eomprising a) producing a compound of formula Ia, R~ ~ Ia wherein Rl and R2 are as previously defined, and R3 is alkyl of 1 to 4 carbon ate~s; alkenyl of 3 to 6 carbon atoms, the multiple bond of whlch is not adjacent to the tricyclic ring system; eyeloalkylalkyl of 4 to 10 carbon atoms; cycloalkyl of 3 to 7 earbon atoms; phenylalkyl of 7 to 10 earbon atoms, wherein the phenyl ring may be mono- or di-substituted with halogen of atomic number from 9 to 35; alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 earbon atoms; or, lS when R2 is hydrogen, R3 can also be hydrogen, by removing water from a compound of formula II, 100-~732 ~ N-R3 Rl ~ ~ II
wherein Rl, R2 and R3 are as previously defined, - b) producing a compound of formula Ib, ~ N-H
1 ~ Ib . wherein Rl and R2 are as previously defined, by removing the group R3 from a compound of formula Ic, ~ N-RII
1 ~ ~ Ic wherein Rl and R2 are as previously defined and R3 is methyl or benzyl, or c) producing a compound of formula Id, Id wherein Rl and R2 are as previously defined and R3II has the same si.gnificance as R3 ; with the exception of hydrogen, by introducing a group R3 in a compound of formula I_ as previously defined; and where desired, forming a pharmaceutically acceptable acid addition salt of said compound of formula 1.
The removal of water according to process variant a) can be effected in known manner, for example, by treating the compound of formula II with an appro-priate spiitting agent, conveniently in the presence of an inert organic solvent. Suitable materials for removing water include strong acids, acid anhydrides and acyl halides~
~ 1hen R3 in the compounds of formula II is alkenyl, the reaccion is preferably effected in the presence of an acyl halide.
r ~
~ 5~ 100-4732 The removal of the group RII from the compounds of formula Ic according to process variant b) can be effected in known manner. The reaction is pxeferahly carried out by reacting the appropriate compound of formula Ic with a chloroformic acid ester and convertins the urethane so obtained by acid or alkaline hydrolysis to a compound of formula Ib.
The introduction of the group R3II into com-pounds of formula Ib according to process variant c) can be effected by known methods for the alkylation of secondary amines, for example, by reaction with a com-pound of formula III, RIII X
wherein R3II is as previously defined and X i9 the acid residue of a reactive ester.
X is preferably halogen or an organic sulph-onic acid residue.
The resulting compounds of formula I may be isolated and purified using conventional techniques.
Free base forms of the compounds of formula I
may be converted into acid addition salt forms and vlce :~ - 8 -~ 100-~732 versa in conventional manner. Suitable acids for pro-ducing acid addition salt forms include hydrochloric and maleic acids.
The compounds of formula I possess two asym-metric carbon atoms in the tricyclic system at positions4a and 10b. Accordingly, two isomer groups may exist, namely compounds wherein rings B and C are linked in the cis configuration and cornpounds wherein rin~s B and C
are linked in the trans configuration. The configura-tion of the tricyclic system of ~he starting materials remains unchanged by the process variants of the inven-tion.
The starting materials can be prepared as follows:
a') The compounds of formula II can be produced by kno~n methods from compounds of formula IV, ~ N-R3 1 ~ OH IV
wherein Rl is as previously defined and R3V is lower alkyl. The compounds of formula II wherein _ g _ .
S~6~1 l00-~732 R2 is as previously defined with the exception of hydrogen may, for example, be produced in the manner hereafter described in Example la) to le) whereby, after cyclisation, the 3-methyl group may be substituted by the desired group R3 according to known methods. The compounds of formula II wherein R2 is hydrogen may, for example, be produced in the manner hereinafter described in Exampl~ la) to ld) and then as described in Example 15 (production of the starting materials).
b') The compounds of formula IV may, for example, be produced by reducing a compound of formula V, I~ N-RIV
Rl ~3/I~R4 V
wherein Rl and R3 are as previously defined and R~ is lower alkyl. The reduction can, for example, be effected with a complex metal hydride, such as lithium aluminium hydride, according to known methods.
~ 100-4732 :
c') The compounds of formula V can, for example, be produced by reacting a compound of formula VI, VI
'IV
wherein R3 and R4 are as previously defined, with a Grignard compound of formula VII, Mg-X
VII
~Rl wherein Rl is as previously defined and XI is - chlorine, bromine or iodine. The reaction can, for example, be effected according to the methods described in J. Org. Chem. 22, 261 ~1957).
Insofar as the production of the starting materials has not been described herein, these compounds are either known or can be produced by known methods or by methods analogous to those described herein or by methods analogous to known methods.
In the following Examples, all temperatures are in degrees Celsius~
~ 5~ 0-4732 , EXAMPI.E 1: Trans-1,2,3,4,4a,10b-hexahydro-3,6-dime ~ n~[f]iso~uinoline A mixture of 1~.6 g of trans-1,2,3,4,4a,5,6,10b-octahydro-3,6-dimethylbenz[f]isoquinoline-6-ol in 20 ml of isopropanol and 30 ml of 5 N isopropanolic hydro-chloric acid solution is heated to boiling under nitro-gen for 30 minutes~ The resulting suspension is cooled to 10 and the hydrochloride of the title compound which crystallises out is filtered, washed with ether and recrystallised from ethanol/isopropanol. M.P. 302-303 (deccmp.) The starting material may be produced as follows:
a) A solution of 39 g of thionyl chloride in 300 ml of anhydrous chloroform is slowly added dropwise at lS 0-5 to a solution of 82 g of 1-methyl-4-phenyl~
piperidine-3-ylmethanol in 1500 ml of anhydrous chloroform. The reaction mixture is stirred for one hour at room temperature, one hour at 40 and sub-sequently for 3 hours a~ the boiling temperature.
After evaporating to dryness, the residue is tri-turated with a large amount of ether. The solid 3-chloromethyl-1-methyl-4-phenylpiperidine hydro-chloride is filtered by suction and dried ln vacuo.
M.P. 203-211~
b) The above product is converted with caustic soda solution to the base, which is extracted with methylene chloride. After drying over sodium sulphate, the organic phase is evaporatsd to dry-ness. 51 g of the evaporated residue and 13.4 g of sodium cyanide are suspended in 40 ml o dimethyl formamide and are heated to boiling for 2 hours with vigorous stirring. On cooling to room temper-ature, the reaction mi.xture is diluted with 200 ml of water, extracted with chloroform and the chloro-form phase is washed with water, dried over sodium sulphate and concentrated. The l-methyl-4-phenyl-piperidin-3-ylacetonitrile (M.P. of the naphthalene-l,S-disulphonic acid salt form: 292-296, decomp.) remaining as a viscous oil is used without further purification.
c) A solution of 85 g of the above product in 150 ml of absolute ethanol is saturated at 10 with hydro-gen ~hloride. The dar~ reaction solution is then stirred for 24 hours at the boiling temperature~
thoroughly concentrated by evaporation, 200 ml of anhydrous benzene are added and the solution is evaporated to dryness. The res.idue is taken up in 290 ml of absolute ethanol, 7.2 ml of water added and the residue is hea~ed to the boil for 2 hours.
On concentration by evaporation, the residue is dissolved in chloroform, water is added and the ; residue is made alkaline with sodium bicarbonate.
After separating the chloroform solution, the aqueous solution is ayain shaken out with chloro-form, the extracts are washed with 10% sodium bicar-bonate and with water, dried over sodium sulphate and evaporated to dryness. The residue is distilled under high vacuum to yield l-methyl~4-phenylpiper-idin-3-ylacetic acid ethyl ester. B.P. 118-123/
0.08 Torr. n20: 1.5220.
d~ A solution of 16.8 g of 1-methyl-4-phenylpiperidin-3-ylaGetic acid ethyl ester in 10 ml of anhydrous xylene is added dropwise over a period of 15 min-20 . utes to a mixture of 85 g o polyphosphoric acid and 25 ml of anhydrous xylene, preheated to 90, with vigorous stirring. The reaction mixture is stirred - ~4 -.':
100-~73~
~ ' .
for a further 2 hours at 120-125, cooled to approx~
imately 80 and poured onto 300 ml of water. The resulting aqueous solution is washed with ether, made alkaline with 20~ caustic soda solution and extracted with chloroform. The ch]oroform solution is washed neutral with water, dried over sodium sulphate, evaporated, the residue is dissolved in a mixture of methylene chloride/methanol 9:1 (v/v), filtered through aluminium oxide and evaporated to dryness. The 1,2,3,4,4a,10b-hexahydro-3-methyl-benz[f]iso~uinoline-6-(5H)-one (isomeric mixture) remainin~ as an oil distills at 106-110/0.08-0.1 Torr.
Isomer separation: The trans-form crystallises from the isomeric mixture from ether/petroleum ether. M.P. 84-85 (ether/petroleum ether).
(Hydrochloride form, M.P. 300-302 decomp., from methanol.) The c1s-form is isolated as ~the hydro~
~en fumarate form from the mother liquor. M.P. 175-177, sint. 172 (from ethanol/ether).
e) To a solution of 115 ml of 2 M methyllithium in ether and ~00 ml of anhydrous ether, there is added dropwise, in a nitro~en atmosphere and with 5~ oo 4732 stirring, a solution of 20.0 g of trans-1,2,3,4,4a,10b-hexahydro-3-methylbenz[f]isoquinoline-6(5H)-one in 400 ml of anhydrous benzene over a period of 45 min-utes at room temperature. The reaction mixture is stirred for 2 hours at room temperature, poured onto 1 litre of 20~ ammonium chloride solution, the organic phase separated and the aqueous solution extracted with methylene chloride. The separate organic solutions are washed with wa~er, dried over sodium sulphate, combined and evaporated. The remaining trans-1,2,3,4,4a,5,6,10b-octahydro-3,6-dimethylbenz[flisoquinoline-6-ol is recrystallised from benæene/hexane. Sint. 130, M.P. 148-153.
The following compounds can be obtained in a manner analogous to that described in Example 1, employ-ing appropriate starting materials in approximately equivalent amounts~
54~6~ 100-4732 ._ . oo~ ooooOoO oLn^
L~ O ~I Ln 0~ 0~~D 0~Ct) ~Dr` CO O ~ N ~
Nt'`l t~l O O t~ 1 0 4 N I I ~ Ll ~ ~ N n~ a . ~ ~ a ~ Q
t~J N N '-- N t~l N N ` NN ~_1 N
__ ~ , . . . _____ _ . _ ., O
~ O
`'~ h 3 ~ o _ . ._ . . . . .
.~
H r~) U - U ~ U
. .. __ _ _ _ P;~ ~ 3 0 ~
_ _ _ ___ ~.. __ _ . _ __ . . .
U~ U U U
P~ ~
- . - . . - - ~ -~ h ~ h ¦
~1 Z; (~ ~ ~ Ln ~ o 'I
---~
~ 100-4732 EX~1P1E 15: Trans~1,2,3 r 4 r 4a,10b-hexahydro-3-methyl-benz~f]isoquinoline In a manner analogous to Example 1, the title compound is produced from 10.0 g of trans-1,2,3,4,4a,5, S 6,10b-octahydro-3-methylbenz[f]isoquinoline-6-ol in 25 ml of isopropanol and 30 ml of 5 N isopropanolic hydrochloric acid solution after boiling for 2 hours.
The title compound is isolated as the hydrochloride salt form. M.P. from 285 (decomp.).
The starting material is produced as follows:
To a suspension of 1~.0 g of lithium aluminium hydride in 800 ml of anhydrous ether, is added dropwise at 0-5, a solution of 15.0 g of trans-1,2,3,4,4a,10b-hexahydro-3-methylbenz[f]iso~uinolin-6(5H)-one in 300 ml of anhydrous ether over a period of 30 minutes. The resulting suspension is stirred for one hour a~ room temperature, 100 ml of water are added dropwlse at 0-5 and the insoluble material filtered off and washed several times ~ith methylene chloride. The organic phase is separated from the filtrate, washed with water, dried over sodium sulphate and concentrated by evapoxa-tion. The solid residue is recrystallised from ether/
. ..~ ;.
'54~ 0 0--G 732 petroleum ether. i~l.P. 118-128.
The following compounds can be obtained in a manner analogous ~o that described in Exam~le 15, using appropriate starting materials in approximately equiv-5alent amounts.
_ _ _ . .
Ex Confn. Rl R2 R3 Form M.P.
_ _ _ __ 16 cis H H -CH3 Hydro- 225-226 chloride 17 trans 8-Cl H -CH ll > 265 3 (Decc~p.) 18 ll 8-CH3 H -CH3 ~ 224-225 19 . H H -CH2 ~ ll 252-253 .
~, L ~ 2 ~ ~ L
EXAMPLE 21: Trans-1,2,3,4,4a,10b-hexahydro~6-methyl-__ _ _ ~
benzEf]isoquinoline To a solution of 7.0 g of trans-1,2,3,4,4a,10b-hexahydro-3,6-dimethylbenz[]isoquinoline in 70 ml of anhydrous benzene is added dropwise a solution of 12.2 g of chloroformic acid ethyl ester in S0 ml of benzene at room temperature ,1, : _ 5fl~
over a period of one hour. The reaction mixture is stirred for one hour at room temperature and for 3 hours at the boiling temperature, cooled to room temperature and washed with water, l N hydrochloric acid and again with water, dried over magnesium sulphate and evaporated ; to dryness. The resulting crude trans-3-ethoxycarbonyl-1,2,3,4,4a,10b-hexahydro-6-methylbenz[f]isoquinoline is ta~en up in 34 ml of n-~utanol, 4.5 g of potassium hydroxide are added and stirring is effected for 18 hours at 100. After cooling, the reac~ion mixture is diluted with 300 ml of benzene, washed neutral with water and extracted with 2 N tartaric aci.d. The tar-taric acid extract is made alkaline with caustic soda solution and shaken out with methylene chloride. The lS methylene chloride solutions are washed with water, dried over sodium sulphate and evaporated. The title compound, remaining as an oily residue, is taken up in ethanol and converted into the hydrogen maleate salt form. M.P. 169-170 tfrom ethanol/ether).
EXAMPLE 22:
In a manner analogous to that of Example 21, trans-1,2,3,4,4a,10b-hexahydro-8-methylbenz[f]isoquino-~ 6 8 line can be produced using an equivalent quantity of the appropriate starting material. M.P. of the hydro-chloride salt form: over 310 (decomp.).
EXAMPLE 23: Trans-1,2,3,4,4a,10b-hexahydro-3-isopropyl-_ 6~methylbenz[f~isoquinoline [Process variant c)]
A mixture of 7.0 g of trans-1,2,3,~,4a,10b-hexahydro-6-methylbenz[f]isoquinoline and 8.0 g of anhydrous sodium carbonate in 70 ml of dimethyl form-amide is preheated to 50. At this temperature, a solution of 6.5 g of isopropyl bromide in 20 ml of dimethyl formamide is slowly added dropwise, the reac-tion mixture is stirred for 6 hours at the same tempera-ture, cooled to 20 and poured onto 300 ml of water and 200 ml of chloroform. The organic solution is separated and the aqueous phase extracted with chloroform. The combined organic solutions are washed with water, dried over sodium sulphate and evaporated. The title compound is isolated as the hydrochloride salt form from methanol/
ethanol. M.P. over 300 (decomp.).
The following compounds can be obtained in a ~ . .
~ `s~
manner analogous to that of Example 23 using appropriate starting materials in approximately equivalent amounts.
_ ~ _ ~ .. , _ Ex Confn. R1 R2 3 Salt Form M.P.
~ _ 24 trans H -CH3 -CH2C--CH Hydrochloride 242-243 25 H -CH3 -CH2COC~3 L _ 215-216 ~5~6~
The compounds of formula I exhibit pharmaco-logical ac~ivity. In particular, the compounds exhibit anti-aggression activity, as indicated in standard tests, for example, in the sedation of aggressive behaviour in mice caused by isolation.
The compounds are therefore indicated for use in the treatment of aggression.
For this use, an indicated daily dose is from about 1 to about 100 mg, suitably from about 5 to about 50 mg, conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from about 0.25 to about 50 mg, suitably from about 1 to about 25 mg, or in sustained release form.
The compounds also exhibit sedative and neuroleptic effects on the central nervous system as indicated in standard tests, for example, in the climb-ing test in mice.
The compounds are therefore indicated for use as neuroleptics and sedatives.
For these uses, an indicated daily dose is from about S to about 200 mg, conveniently from about 5 to about 50 mg, and suitably from about 10 to about 50 mg, conveniently administered in divided doses 2 to 4 times 5 ~ ~ ~
100-~732 a day in unit dosage form containing from about 1 to about 100 m~, conveniently from about 1 to about 25 mg, and suitably from about 2.5 to about 25 mg, or in sus-tained release form.
The eompounds of formula I may be administered in pharmaceutieally aeceptable acid addition salt form.
Sueh acid addition salt orms exhibit the same order of aetivity as the free base forms and are readily prepared in eonventional manner. Suitable acids for salt forma-tion inelude inorganic acids such as hydroehlorie aeid and organie aeids sueh as maleie acidO
The present invention also provides a pharma-eeutical eomposition eomprising a eompound of formula I
in free base form or in pharmaeeutieally aceeptable aeid addition salt form, in assoeiation with a pharmaeeuti-eally aeceptable diluent or earrier. Sueh eompositions may be formulated in eonventional manner and may, for ~xample, be a solution or a eapsule.
Claims (4)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the production of a compound of formula I, I
wherein R1 is hydrogen, halogen of atomic number from 9 to 35, alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms, R2 is hydrogen, alkyl of 1 to 4 carbon atoms, phenyl or phenyl mono- or di-substituted with halogen of atomic number from 9 to 35, alkyl of 1 to 4 car-bon atoms or alkoxy of 1 to 4 carbon atoms, and R3 is hydrogen; alkyl of 1 to 4 carbon atoms; alkenyl of 3 to 6 carbon atoms or alkynyl of 3 to 6 carbon atoms, the multiple bond of which is not adjacent to the tricyclic ring system; cycloalkyl-alkyl of 4 to 10 carbon atoms; cyclo-alkyl of 3 to 7 carbon atoms; phenyl-alkyl or 7 to 10 carbon atoms, the phenyl ring of which may be mono- or di-substituted with halogen of atomic number from 9 to 35, alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms; alkanoylalkyl of 3 to 5 carbon atoms, the oxygen atom of which is separated by at least 2 carbon atoms from the nitro-gen atom in the tricyclic system, and pharmaceutically acceptable acid addition salts thereof, which comprises a) producing a compound of formula Ia, Ia wherein R1 and R2 are as previously defined, and R? is alkyl of 1 to 4 carbon atoms; alkenyl of 3 to 6 carbon atoms, the multiple bond of which is not adjacent to the tricyclic ring system; cycloalkylalkyl of 4 to 10 carbon atoms; cycloalkyl of 3 to 7 carbon atoms; phenylalkyl of 7 to 10 carbon atoms, wherein the phenyl ring may be mono- or di-substituted with halogen of atomic number from 9 to 35; alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms; or, when R2 is hydrogen, R3 can also be hydrogen, by removing water from a compound of formula II, II
wherein R1, R2 and R3 are as previously defined, b) producing a compound of formula Ib, Ib wherein R1 and R2 are as previously defined, by removing the group R?I from a compound of formula Ic, Ic wherein R1 and R2 are as previously defined and R?I is methyl or benzyl, or c) producing a compound of formula Id, Id wherein R1 and R2 are as previously defined and R?II has the same significance as R3 with the exception of hydrogen, by introducing a group R?II in a compound of formula Ib as previously defined; and where desired, forming a pharmaceutically acceptable acid addition salt of said compound of formula I.
wherein R1 is hydrogen, halogen of atomic number from 9 to 35, alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms, R2 is hydrogen, alkyl of 1 to 4 carbon atoms, phenyl or phenyl mono- or di-substituted with halogen of atomic number from 9 to 35, alkyl of 1 to 4 car-bon atoms or alkoxy of 1 to 4 carbon atoms, and R3 is hydrogen; alkyl of 1 to 4 carbon atoms; alkenyl of 3 to 6 carbon atoms or alkynyl of 3 to 6 carbon atoms, the multiple bond of which is not adjacent to the tricyclic ring system; cycloalkyl-alkyl of 4 to 10 carbon atoms; cyclo-alkyl of 3 to 7 carbon atoms; phenyl-alkyl or 7 to 10 carbon atoms, the phenyl ring of which may be mono- or di-substituted with halogen of atomic number from 9 to 35, alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms; alkanoylalkyl of 3 to 5 carbon atoms, the oxygen atom of which is separated by at least 2 carbon atoms from the nitro-gen atom in the tricyclic system, and pharmaceutically acceptable acid addition salts thereof, which comprises a) producing a compound of formula Ia, Ia wherein R1 and R2 are as previously defined, and R? is alkyl of 1 to 4 carbon atoms; alkenyl of 3 to 6 carbon atoms, the multiple bond of which is not adjacent to the tricyclic ring system; cycloalkylalkyl of 4 to 10 carbon atoms; cycloalkyl of 3 to 7 carbon atoms; phenylalkyl of 7 to 10 carbon atoms, wherein the phenyl ring may be mono- or di-substituted with halogen of atomic number from 9 to 35; alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms; or, when R2 is hydrogen, R3 can also be hydrogen, by removing water from a compound of formula II, II
wherein R1, R2 and R3 are as previously defined, b) producing a compound of formula Ib, Ib wherein R1 and R2 are as previously defined, by removing the group R?I from a compound of formula Ic, Ic wherein R1 and R2 are as previously defined and R?I is methyl or benzyl, or c) producing a compound of formula Id, Id wherein R1 and R2 are as previously defined and R?II has the same significance as R3 with the exception of hydrogen, by introducing a group R?II in a compound of formula Ib as previously defined; and where desired, forming a pharmaceutically acceptable acid addition salt of said compound of formula I.
2. A compound of formula I, as defined in claim 1, or a pharmaceutically acceptable acid addition salt thereof, when produced by the process of claim 1 or by an obvious chemical equivalent thereof.
3. A process for preparing the compound trans -1, 2, 3, 4, 4a, 10b - hexahydro-3,6-dimethylbenz [f]
isoquinoline, and pharmaceutically acceptable acid addition salts thereof, which comprises reacting trans -1, 2, 3, 4, 4a, 5, 6, 10b - octahydro -3, 6-dimethylbenz [f] isoquinoline-6-ol with a strong acid in the presence of an inert organic solvent, and where desired, forming a pharmaceutically acceptable acid addition salt of the compound trans -1, 2, 3, 4, 4a, 10b-hexahydro-3,6-dimethylbenz [f] -isoquinoline so produced.
isoquinoline, and pharmaceutically acceptable acid addition salts thereof, which comprises reacting trans -1, 2, 3, 4, 4a, 5, 6, 10b - octahydro -3, 6-dimethylbenz [f] isoquinoline-6-ol with a strong acid in the presence of an inert organic solvent, and where desired, forming a pharmaceutically acceptable acid addition salt of the compound trans -1, 2, 3, 4, 4a, 10b-hexahydro-3,6-dimethylbenz [f] -isoquinoline so produced.
4. Trans -1, 2, 3, 4, 4a, 10b-hexahydro-3,6-dimethylbenz [f] isoquinoline, or a pharmaceutically acceptable acid addition salt thereof, when produced by the process of claim 3 or by an obvious chemical equivalent thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH820/77 | 1977-01-24 | ||
| CH82077A CH630902A5 (en) | 1977-01-24 | 1977-01-24 | Process for preparing novel derivatives of 1,2,3,4,4a,10b-hexahydrobenzo(f)isoquinoline. |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1105468A true CA1105468A (en) | 1981-07-21 |
Family
ID=4195950
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA295,458A Expired CA1105468A (en) | 1977-01-24 | 1978-01-23 | 1,2,3,4,4a,10b-hexahydro-benz¬f|isoquinoline compounds |
Country Status (21)
| Country | Link |
|---|---|
| JP (1) | JPS5392778A (en) |
| AT (1) | AT367405B (en) |
| BE (1) | BE863215A (en) |
| CA (1) | CA1105468A (en) |
| CH (3) | CH630902A5 (en) |
| DE (1) | DE2801576A1 (en) |
| DK (1) | DK19278A (en) |
| ES (2) | ES466245A1 (en) |
| FI (1) | FI780130A (en) |
| FR (1) | FR2378015A1 (en) |
| GB (1) | GB1596170A (en) |
| IE (1) | IE46381B1 (en) |
| IL (1) | IL53869A (en) |
| IT (1) | IT7847687A0 (en) |
| NL (1) | NL7800719A (en) |
| NZ (1) | NZ186279A (en) |
| PH (1) | PH14194A (en) |
| PT (1) | PT67562B (en) |
| SE (1) | SE7800452L (en) |
| SU (1) | SU852172A3 (en) |
| ZA (1) | ZA78430B (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE8302361D0 (en) * | 1983-04-27 | 1983-04-27 | Astra Laekemedel Ab | NEW TRICYCLIC AMINES |
| US5294618A (en) * | 1989-07-28 | 1994-03-15 | Merck Sharp & Dohme Limited | Octahydrobenzisoquinoline derivatives as antipsychotic agents |
| GB8917333D0 (en) * | 1989-07-28 | 1989-09-13 | Merck Sharp & Dohme | Therapeutic agents |
| JPH07500333A (en) * | 1991-10-24 | 1995-01-12 | ジ・アップジョン・カンパニー | Benzo-isoquinoline derivatives |
| EP0539209A1 (en) * | 1991-10-24 | 1993-04-28 | The Upjohn Company | Benzo-isoquinoline derivatives and analogs and their use in therapeutics |
| AT407636B (en) * | 1999-07-09 | 2001-05-25 | Martin Dr Kratzel | Diels-Alder products of tetrahydropyridinedienes with naphthoquinones and their oxidation products, process for their preparation and their use for producing medicaments |
-
1977
- 1977-01-24 CH CH82077A patent/CH630902A5/en not_active IP Right Cessation
-
1978
- 1978-01-14 DE DE19782801576 patent/DE2801576A1/en not_active Withdrawn
- 1978-01-16 DK DK19278A patent/DK19278A/en not_active Application Discontinuation
- 1978-01-16 SE SE7800452A patent/SE7800452L/en unknown
- 1978-01-16 FI FI780130A patent/FI780130A/en not_active Application Discontinuation
- 1978-01-18 IT IT7847687A patent/IT7847687A0/en unknown
- 1978-01-20 NZ NZ186279A patent/NZ186279A/en unknown
- 1978-01-20 NL NL7800719A patent/NL7800719A/en not_active Application Discontinuation
- 1978-01-23 IL IL53869A patent/IL53869A/en unknown
- 1978-01-23 IE IE151/78A patent/IE46381B1/en unknown
- 1978-01-23 AT AT0045478A patent/AT367405B/en not_active IP Right Cessation
- 1978-01-23 CA CA295,458A patent/CA1105468A/en not_active Expired
- 1978-01-23 BE BE184555A patent/BE863215A/en not_active IP Right Cessation
- 1978-01-23 PT PT67562A patent/PT67562B/en unknown
- 1978-01-23 SU SU782571448A patent/SU852172A3/en active
- 1978-01-23 JP JP534678A patent/JPS5392778A/en active Pending
- 1978-01-23 ES ES466245A patent/ES466245A1/en not_active Expired
- 1978-01-23 PH PH20696A patent/PH14194A/en unknown
- 1978-01-23 GB GB2603/78A patent/GB1596170A/en not_active Expired
- 1978-01-24 ZA ZA00780430A patent/ZA78430B/en unknown
- 1978-01-24 FR FR7801860A patent/FR2378015A1/en active Granted
- 1978-11-30 ES ES475587A patent/ES475587A1/en not_active Expired
-
1981
- 1981-03-20 CH CH190981A patent/CH630904A5/en not_active IP Right Cessation
- 1981-03-20 CH CH190881A patent/CH630903A5/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| FR2378015B1 (en) | 1980-08-22 |
| ES475587A1 (en) | 1980-02-16 |
| CH630902A5 (en) | 1982-07-15 |
| ATA45478A (en) | 1981-11-15 |
| PT67562A (en) | 1978-02-01 |
| FR2378015A1 (en) | 1978-08-18 |
| BE863215A (en) | 1978-07-24 |
| PT67562B (en) | 1980-11-03 |
| DE2801576A1 (en) | 1978-07-27 |
| NL7800719A (en) | 1978-07-26 |
| ES466245A1 (en) | 1980-12-16 |
| FI780130A (en) | 1978-07-25 |
| IE780151L (en) | 1978-07-24 |
| DK19278A (en) | 1978-07-25 |
| SE7800452L (en) | 1978-07-25 |
| PH14194A (en) | 1981-03-26 |
| AU3265478A (en) | 1979-08-02 |
| SU852172A3 (en) | 1981-07-30 |
| NZ186279A (en) | 1980-05-27 |
| IE46381B1 (en) | 1983-05-18 |
| IL53869A (en) | 1981-05-20 |
| CH630903A5 (en) | 1982-07-15 |
| GB1596170A (en) | 1981-08-19 |
| IL53869A0 (en) | 1978-04-30 |
| AT367405B (en) | 1982-07-12 |
| IT7847687A0 (en) | 1978-01-18 |
| ZA78430B (en) | 1979-09-26 |
| CH630904A5 (en) | 1982-07-15 |
| JPS5392778A (en) | 1978-08-15 |
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