IE46381B1 - 1,2,3,4,4a,10b-hexahydro-benz(f)isoquinolines - Google Patents

1,2,3,4,4a,10b-hexahydro-benz(f)isoquinolines

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Publication number
IE46381B1
IE46381B1 IE151/78A IE15178A IE46381B1 IE 46381 B1 IE46381 B1 IE 46381B1 IE 151/78 A IE151/78 A IE 151/78A IE 15178 A IE15178 A IE 15178A IE 46381 B1 IE46381 B1 IE 46381B1
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IE
Ireland
Prior art keywords
carbon atoms
formula
alkyl
compounds
hydrogen
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IE151/78A
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IE780151L (en
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Sandoz Ltd
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Publication of IE46381B1 publication Critical patent/IE46381B1/en

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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

Abstract

The invention relates to a process for preparing compounds of the formula I, in which R1, R2 and R3 have the meaning given in the description, by the elimination of water from the corresponding octahydro-6-ol derivatives. The compounds of the formula I possess the properties of inhibiting aggression and depressing the central nervous system.

Description

The present invention relates to 1,2,3,4,4a,10bhexahydro-benz[f ]isoquinolines.
More particularly, the present invention provides compounds of formula I, wherein R^ 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 10 . atoms, phenyl or phenyl mono- or disubstituted with halogen of atomic number from 9 to 35, alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atans, and R3 is hydrogen; alkyl of 1 to 4 carbon 15 atoms; alkenyl of 3 to 6 carbon atoms or 6381 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- 5 alkyl of 3 to 7 carbon atoms; phenyl- alkyl of 7 to 10 carbon atoms , the phenyl ring of which may be mono- or disubstituted 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 alkanoylalkyl of 3 to carbon atoms.
Insofar as the compounds of formula I are substituted by an alkyl or alkoxy group as previously IS 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.
R^ is preferably hydrogen. When R^ is halogen 20 alkyl or alkoxy, this is preferably in position 8. 6 3 81 Rg Is preferably hydrogen, methyl or phenyl.
I?2 may also be phenyl mono- or di-substituted with halogen of atomic number from 9 to 35. In a further group of compounds, Rg is phenyl mono- or di-substituted with alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms.
Rg can be alkyl of 1 to 4 carbon atoms and is preferably methyl. Rg may also be hydrogen. When Rg is spkenyl or alkynyl of 3 to fa' carbon atoms, these prefer10 ably contain 3 or 4 carbon atoms. Rg may be cycloalkylalkyl of 4 to 10 carbon atoms, for example, cycloalkylalkyl of 4 to 6 carbon atoms. Rg may also be cyoloalkyl of 3 to 7 carbon atoms, for example, cyolohexyl. When Rg is phenylalkyl of 7 to Ϊ0 carbon atoms, this is pref15 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 Rg 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 - 4 46381 the production of a compound of formula I, comprising a) producing a compound of formula la, wherein R^ and Rg are as previously defined, and Rg 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 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 Rg is hydrogen, R^ can also be hydrogen, by removing water from a compound of formula II, compound of formula Ib, b) producing a wherein and R2 are as previously defined, ny removing the group R^1 from a compound of formula Ic, wherein R^ and R2 areas previously defined and R*1 is methyl or benzyl, 6 3 81 or c) producing a compound of formula Id, wherein and R3 are as previously defined and III R3 has the same significance as R3 with the exception of hydrogen, III by introducing a group R3 in a compound of formula Ib as previously defined.
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 appropriate splitting agent, conveniently in the presence of an inert organic solvent. Suitable materials for removing water include strong acids, acid anhydrides and acyl halides.
When R* in the compounds of formula II is alkenyl, the reaction is preferably effected in the presence of an acyl halide. 6 3 81 The removal of the group R^ from the compounds of formula Ic according to process variant b) can be effected in known manner. The reaction is preferablycarried out by reacting the appropriate compound of formula Io with a chlorcfoimic acid ester and converting the urethane so obtained by acid or alkaline hydrolysis to a compound of formula Ib.
The introduction of the group into compounds of formula Ib according to process variant c) can be effected by known methods for the hydrocarbylation of secondary amines, for example, by reaction with a compound of formula-III, wherein R^ is as previously defined and X is the acid residue of a reactive ester.
X is preferably halogen or an organic sulphonic 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 vice - 8 46381 versa in conventional manner. Suitable acids for producing acid addition salt forms include hydrochloric and maleic acids.
The compounds of formula I possess two asym5 metric carbon atoms in the tricyclic system at positions 4a and 10b. Accordingly, two isomer groups may exist, namely compounds wherein rings B and C are linked in the cis configuration and compounds wherein rings B and C are linked in the trans configuration. The configura10 tion of the tricyclic system of the starting materials remains unchanged by the process variants of the invention.
The starting materials can be prepared as follows: a') The compounds of formula II can be produced by known methods from compounds of formula IV, wherein is as previously defined and Rg is alkyl of 1 to 4 carbon atoms. The compounds of formula II wherein 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 5 Chalky! group nay be replaced by the desired group according to knpwn methods. The compounds of formula II wherein R2 is hydrogen may, for example, be produced in the manner hereinafter described in Example 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, wherein and R^ are as previously defined and is alkyl of 1 to 4 carbon atoms. The reduction can, for example, be effected with.a complex metal hydride, such as lithium aluminium hydride, according to known methods. c') The compounds of formula V can, for example, be produced by reacting a compound of formula VI, .COOR, N R VI IV IV wherein R3 and R^ are as previously defined, with a Grignard compound of formula VII, „1 Mg-X VII wherein R^ is as previously defined and X1 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 10 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 15 are in degrees Celsius. 6 381 EXAMPLE 1; Trans-1,2,3,4,4a,lOb-hexahydro-3,6dimethylbenz[£]isoquinoline A mixture of 14.6 g of trans-1,2,3,4,4a,5,6,10boctahydro-3,6-dimethylbenz[f]isoquinoline-6-ol in 20 ml of isopropanol and 30 ml of 5 N isopropanolic hydrochloric acid solution is heated to boiling under nitrogen for 30 minutes. The resulting suspension is cooled to 10° and the hydrochloride of the title compound which crystallises out is filtered, wished with ether and recrystallised from ethanol/isopropanol. M.P. 302-303° (decanp.) 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 0-5° to a solution of 82 g of l-methyl-4-phenylpiperidine-3-ylmethanol in 1500 ml of anhydrous chloroform. The reaction mixture is stirred for one hour at room temperature, one hour at 40° and subsequently for 3 hours at the boiling temperature.
After evaporating to dryness, the residue is triturated with a large amount of ether. The solid 3-chloromethyl-l-methyl-4-phenylpiperidine hydro- 12 46381 chloride is filtered by suction and dried in 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 evaporated to dryness. 51 g of the evaporated residue and 13.4 g of sodium cyanide are suspended in 40 ml of dimethyl formamide and are heated to boiling for 2 hours with vigorous stirring. On cooling to room temperature, the reaction mixture is diluted with 200 ml of water, extracted with chloroform and the chloroform phase is washed with water, dried over sodium sulphate and concentrated. The l-methyl-4-phenyl15 piperidin-3-ylacetonitrile (M.P. of the naphthalene1,5-disulphonic acid salt form; 292-296°, decomp.) remaining as 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 hydrogen chloride. The dark reaction solution is then stirred for 24 hours at the boiling temperature, 6 3 81 thoroughly concentrated by evaporation, 200 ml of anhydrous benzene are added and the solution is evaporated to dryness. The residue is taken up in 290 ml of absolute ethanol, 7.2 ml of water added and the residue is heated 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 again shaken out with chloroform, the extracts are washed with 10% sodium bicarbonate and with water, dried over sodium sulphate and evaporated to dryness. The residue is distilled under high vacuum to yield l-methyl-4-phenylpiper15 idin-3-ylacetic acid ethyl ester. B.P. 118-123°/ 0.08 Torr. n£ s 1.5220. d) A solution of 16.8 g of l-methyl-4-phenylpiperidin3-ylacefcic acid ethyl ester in 10 ml of anhydrous xylene is added dropwise over a period of 15 min20 utes to a mixture of 85 g Of polyphosphoric acid and ml of anhydrous xylene, preheated tt: 90°, with vigorous stirring. The reaction mixture is stirred -•14 46381 for a further 2 hours at 120-125°, cooled to approximately 80° and poured onto 300 ml of vzater. The resulting aqueous solution is washed with ether, made alkaline with 20% caustic soda solution and extracted with chloroform. The chloroform 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 l,2,3,4,4a,10b-hexahydro-3-methylbenz[f3isoquinoline-6-(5H)-one (isomeric mixture) remaining 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 cis-form is isolated as the hydrogen fumarate form from the mother liquor. M.P. 175177°, sint. 172° (from ethanol/ether). e) To a solution of 115 ml of 2 M methyllithium in ether and 400 ml of anhydrous ether, there is added dropwise, in a nitrogen atmosphere and with 6 3 81 stirring, a solution of 20.0 g of trans-1,2,3,4,4a, 10bhexahydro-3-methylbenz[f]isoquinoline-6(5H)-one in 400 ml of anhydrous benzene over a period of 45 minutes at room temperature. The reaction mixture is stirred for 2 hours at room temperature, poured onto 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 water, dried over sodium sulphate, combined and evaporated. The remaining trans-1,2,3,4,4a,5,6,10b-octahydro-3,6dimethylbenztf)isoquinoline-6-ol is recrystallised from benzene/hexane. Sint. 130°, M.P. 148-153°.
The following compounds of formula Ia can be obtained in manner analogous to-that described in Example 1, employing appropriate starting materials in approximately equivalent amounts.
O s-*. O 0 0 • 0 0 υ 0 O 0 0 0 in » If) co O & in CO CO k0 00 oo KT r- Ok Q, k0 r* co O g k0 Γ- cn r· ro k0 r- CM G CM CM CM O o CM CM CM CM CM CM t— 1 CI o Cm 1 ! I O υ 1 J 1 I I 1 ι g o cm r* co ro (1) m* 10 r* in 10 io CM in 0. Φ • co c • c* u kP r» cn Γ- CO 10 Γ** P Q g CM CM CM CM CM CM CI CM CM r~ 1 CM IH — Φ Φ Π3 Ό ‘H Ή P ε 0 0 J-| rH C rH 0 Λ = Q) φ a s h 0 tPP u 0 C (tf o J- Φ P H Ό ntf rH »o (tf & >1 Ii >( CO a a ε a ιΛι CM rH ί 0* U c\ a S’*. in υ Ci £ co a a CO a CM ffi υ US H ro U C υ o υ - £ ε ε s - 04 1 j 1 1 ro ro ti in u Ί ffi ni 04 ro ffi U S 1 = = = = ffi CM U I ro ti U Φ = 9 O o Φ fO co a a H rH u u υ υ 1 1 1 1 ti a ra a ffi a CO w co a a a ffi 00 ci ω (0 iw β β β W (tf £ s 5 5 s ε a wj rtf £ 5 0 •rt U •rt It υ O| +1 ol -Pt # M 0 O H CM ro W B • Cl rO in 10 CO cn H rH rH rH rH EXAMPLE 15: Trans-1,2,3,4,4a,10b-hexahydro-3-methylbenz[f ]isoquinoline In manner analogous to Example 1, the title compound is produced from 10.0 g of trans--l,2,3,4,4a,5, 6,10b-octahydro-3-methylbenz[f]isoquinoline-6-ol in 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 12.0 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-l,2,3,4,4a,10bhexahydro-3-methylbenz(f]isoquinolin-6(5H)-one in 300 ml of anhydrous ether over a period of 30 minutes. The resulting suspension is stirred for one hour at room temperature, 100 ml of water are added dropwise at 0-5° and the insoluble material filtered off and washed several times with methylene chloride. The organic phase is separated from the filtrate, washed with water, dried over sodium sulphate and concentrated by evaporation. The solid residue is recrystallised from ether/ -18 46381 petroleum ether. M.P. 118-128°.
The following compounds of formula Ia can be obtained in manner analogous to that described in Example 15, using appropriate starting materials in approximately equiv5 alent amounts.
EX. No. Confn.R1R2 Salt Form M.P. 16 cis 11 H -GH3 Hydro- chloride 225-226° 17 trans 8-C1 II -ch3 It > 265° (Decomp.) 18 11 8-CH3 H -ch3 II 224-225° 19 II H II -ch2-0 II 252-253° 20 tl H HC1X rr 240-241° EXAMPLE 21: Trans-1,2,3,4,4a,lOb-hexahydro-6-methyl15 benz[f1 isoquinoline To a solution of 7.0 g of trans-1,2,3,4,4a,10bhexahydro-3,6-dimethylbenz[f]isoquinoline in 70 ml of anhydrous benzene is added dropwise a solution of 12.2 g of 12.2 g of chloroformic acid ethyl ester in 50 ml of benzene at room 6 3 81 temperature 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, 1 N hydrochloric acid and again with water, dried over magnesium sulphate and evaporated to dryness. The resulting crude trans-3-ethoxycarbonyll,2,3,4,4a,10b-hexahydro-6‘-methylben2[f]isoquinoline is taken up in 34 ml of n-butanol, 4.5 g of potassium hydroxide are added and stirring is effected for 18 hours at 100°. After cooling, the reaction mixture is diluted with 300 ml of benzene, washed neutral with water and extracted with 2 N tartaric acid. The tartaric acid extract is made alkaline with caustic soda solution and shaken out with methylene chloride. The 15 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 dnd converted into the hydrogen maleate salt form. M.P. 169-170° (from ethanol/ether).
EXAMPLE 22: In manner analogous to that of Example 21, trans-1,2,3,4,4a,10b-hexahydro-8-methylbenzif]isoquino- 20 6 3 8 I line can be produced using an equivalent quantity of the appropriate starting material. M.P. of the hydrochloride salt form: over 310° (decomp.).
EXAMPLE 23: Trans-1,2,3,4,4a,10b-hexahydro-3~isopropyl5 6-methylbenz[f)isoquinoline [Process variant c)] A mixture of 7.0 g of trans-1,2,3,4,4a,10bhexahydro-6-methylben2[f]isoquinoline and 8.0 g of anhydrous sodium carbonate in 70 ml of dimethyl form10 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 reaction mixture is stirred for 6 hours at the same temperature, 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 of farmula Id can be obtained in manner analogous to that of Example 23 using appropriate starting materials in approximately equivalent amounts.
Ex. NO. Confn.R1 *2 RTI1 Salt Form M.P. 24 trans H -CH,. -CH,C=CH Hydrochloride 242-243° 25 It H -ch3 -ch2coch3 « 215-216° The compounds of formula I exhibit pharmacological activity. 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 to TOO mg, suitably from 5 to 50 mg, conveniently administered in divided doses 2 to times a day in unit dosage form containing from 0.25 to 50 mg, suitably from 1 to 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 climbing test in mice.
The compounds are therefore indicated for use as neuroleptics and sedatives.
For these uses, an indicated daily dose is from 5 to 200 mg, conveniently from 5 to 50 mg, and suitably from 10 to 50 mg, conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing 6 3 81 from 1 to 100 rag, conveniently from 1 to 25 mg and suitably from 2.5 to 25 rag, or in sustained release form.
The compounds of formula I may be administered in pharmaceutically acceptable acid addition salt form.
Such acid addition salt forms exhibit the same order of activity as the free base forms and are readily prepared In conventional manner. Suitable acids for salt formation include inorganic acids such as hydrochloric acid and organic acids such as maleic acid.
The present invention also provides a pharmaceutical composition comprising a compound of formula I in free base form or in pharmaceutically acceptable acid addition salt form, in association with a pharmaceuti-. cally acceptable diluent or carrier. Such compositions may be formulated in conventional manner and may, for example, be a solution or a capsule.

Claims (1)

1. A process for the production of a compound of formula I, wherein is hydrogen, halogen of atomic number 5 from 9 to 35, alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms, R 2 is hydrogen, alkyl of 1 to 4 carbon atoms, phenyl or phenyl mono- or disubstituted with halogen of atomic ιθ number from 9 to 35, alkyl of 1 to 4 car bon atoms or alkoxy of 1 to 4 carbon atans, and Rg 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; cycloalkyl if 3 to 7 carbon atoms; phenylalkyl of 7 to 10 carbon atoms, the phenyl ring of which may be mono- or disubstituted 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 aikanoyiaikyi of 3 to 5 carbon atoms, comprising, a) producing a compound of formula la, la wherein R^ and Rg are as previously defined, and -.26 10 I is alkyl of 1 to 4 carbon atans; 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 Rg is hydrogen, Rj can also be hydrogen, by removing water from a compound of formula II,
IE151/78A 1977-01-24 1978-01-23 1,2,3,4,4a,10b-hexahydro-benz(f)isoquinolines IE46381B1 (en)

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CH82077A CH630902A5 (en) 1977-01-24 1977-01-24 Process for preparing novel derivatives of 1,2,3,4,4a,10b-hexahydrobenzo(f)isoquinoline.

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IE780151L IE780151L (en) 1978-07-24
IE46381B1 true IE46381B1 (en) 1983-05-18

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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
WO1993008166A1 (en) * 1991-10-24 1993-04-29 The Upjohn Company Benzo-isoquinoline derivatives and analogs and their use in therapeutics
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

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PH14194A (en) 1981-03-26
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CH630902A5 (en) 1982-07-15
FI780130A (en) 1978-07-25
ZA78430B (en) 1979-09-26
JPS5392778A (en) 1978-08-15
FR2378015B1 (en) 1980-08-22
CH630904A5 (en) 1982-07-15
SU852172A3 (en) 1981-07-30
NL7800719A (en) 1978-07-26
GB1596170A (en) 1981-08-19
DE2801576A1 (en) 1978-07-27
FR2378015A1 (en) 1978-08-18
PT67562A (en) 1978-02-01
NZ186279A (en) 1980-05-27
ES466245A1 (en) 1980-12-16
SE7800452L (en) 1978-07-25
DK19278A (en) 1978-07-25
IL53869A (en) 1981-05-20
ATA45478A (en) 1981-11-15
ES475587A1 (en) 1980-02-16
AU3265478A (en) 1979-08-02
IE780151L (en) 1978-07-24
CA1105468A (en) 1981-07-21
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PT67562B (en) 1980-11-03

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