CA1118775A - 6-azido-decohydro-4a phenyl-cis-isoquinoline compounds - Google Patents
6-azido-decohydro-4a phenyl-cis-isoquinoline compoundsInfo
- Publication number
- CA1118775A CA1118775A CA000323128A CA323128A CA1118775A CA 1118775 A CA1118775 A CA 1118775A CA 000323128 A CA000323128 A CA 000323128A CA 323128 A CA323128 A CA 323128A CA 1118775 A CA1118775 A CA 1118775A
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- hydrogen
- alkyl
- cis
- alkoxy
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
- C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
- C07D217/16—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals substituted by oxygen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
- C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
- C07D217/06—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Pain & Pain Management (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
Abstract
Abstract of the Disclosure The present invention provides compounds of formula I
I
Wherein R1, R2 and R3 are chosen from the following signi-ficances (1), (11) and (111):-(1) R1 and R2, independently, are hydrogen (C1-6)alkyl, trifluoromathyl, halogen, or (C1-4)alkoxym, and R3 is hydrogen, or (11) (a) R1 and R2, independently, are hydrogen, (C1-6)alkyl, trifuloromethyl or halogen, or (b) R1 is (C1-4)alkoxy and R2 is (C1-6)alkyl, trifluoromethyl, halogen or (C1-4)alkoxy, and R3 is (C1-6) alkyl, a radical of formula II, -CH2.CH=CR4R5 II
wherein R4 and R5,independently, are hydrogen or (C1-4)alkyl, a radical of formula III, m wherein m is 2,3 or 4, a radical of formula IV
IV
wherein n is 1or 2, or a radical of formula V
wherein p is 1 or 2 and R6 is hydrogen, halogen, trifluoromathyl, (C1-4)alkoxy, (C1-4)alkyl, amino, di[(C1-4)alkyl] amino (C1-4)alkylamino, or (III) the amino group is cis to the phenyl group, R1 is (C1-4)alkoxy in the meta position R2 is hydrogen, and R3 is methyl.
are useful analgesic agents.
I
Wherein R1, R2 and R3 are chosen from the following signi-ficances (1), (11) and (111):-(1) R1 and R2, independently, are hydrogen (C1-6)alkyl, trifluoromathyl, halogen, or (C1-4)alkoxym, and R3 is hydrogen, or (11) (a) R1 and R2, independently, are hydrogen, (C1-6)alkyl, trifuloromethyl or halogen, or (b) R1 is (C1-4)alkoxy and R2 is (C1-6)alkyl, trifluoromethyl, halogen or (C1-4)alkoxy, and R3 is (C1-6) alkyl, a radical of formula II, -CH2.CH=CR4R5 II
wherein R4 and R5,independently, are hydrogen or (C1-4)alkyl, a radical of formula III, m wherein m is 2,3 or 4, a radical of formula IV
IV
wherein n is 1or 2, or a radical of formula V
wherein p is 1 or 2 and R6 is hydrogen, halogen, trifluoromathyl, (C1-4)alkoxy, (C1-4)alkyl, amino, di[(C1-4)alkyl] amino (C1-4)alkylamino, or (III) the amino group is cis to the phenyl group, R1 is (C1-4)alkoxy in the meta position R2 is hydrogen, and R3 is methyl.
are useful analgesic agents.
Description
77 ~
~ ~ R P~EPARATION AND PHA~'ACEU-This invention relates to iso~uinoline derivatives, their preparation and pharmaceutical compositions con-taining them.
The present inven~ion provides compounds of formula I
. ~ N-R3 wherein R , R2 and R3 are chosen from the following stgni-ficc~nces (i), (ii) and (iii):-(i) Rl imd R2, independently, are hydrogen J (Cl 6)alkyl, trifluoromethyl, halogen, or (Cl 4)alkoxy, and R3 is hydrogen, or (ii) (a) Rl i~nd R2, independently, are hydrogen, (Cl 6)alkyl, trifluoromethyl or halogen, or (b) Rl :is (Cl_4)alkoxy and .. .... ~ . ~ .. - -8'775
~ ~ R P~EPARATION AND PHA~'ACEU-This invention relates to iso~uinoline derivatives, their preparation and pharmaceutical compositions con-taining them.
The present inven~ion provides compounds of formula I
. ~ N-R3 wherein R , R2 and R3 are chosen from the following stgni-ficc~nces (i), (ii) and (iii):-(i) Rl imd R2, independently, are hydrogen J (Cl 6)alkyl, trifluoromethyl, halogen, or (Cl 4)alkoxy, and R3 is hydrogen, or (ii) (a) Rl i~nd R2, independently, are hydrogen, (Cl 6)alkyl, trifluoromethyl or halogen, or (b) Rl :is (Cl_4)alkoxy and .. .... ~ . ~ .. - -8'775
- 2 - 100-4997 R2 is (Cl ~)alkyl, trifluoromethyl, halogen or (Cl 4)alkoxy, and R3 is (Cl_6)alkyl, a radical of formula II, -CH2.CH=CR4R5 II
wherein R4 and R5,independently, are hydrogen or - (Cl_4)alkyl, a radical of formula III, ~ CH -CH (CH2)m - wherein m is 2, 3 or 4/
a radical of formula IV
~ 2)n ~ IV
wherein n is 1 or 2/ or a radical of formula V
-(CH2)p ~ 6 wherein p is 1 or 2 and R~ is hydrogen, halogen, trifluoromethyl, (Cl_4)alkoxy, (Cl_4)alkyl, amino, di~(Cl 4)alXyl]amino (Cl ~)alkylamino, or (iii) th~ azido group is cis to the phenyl group, Rl is (Cl 4)alkoxy in the meta position R2 is hydrogen, and R3 is methyl.
8~75
wherein R4 and R5,independently, are hydrogen or - (Cl_4)alkyl, a radical of formula III, ~ CH -CH (CH2)m - wherein m is 2, 3 or 4/
a radical of formula IV
~ 2)n ~ IV
wherein n is 1 or 2/ or a radical of formula V
-(CH2)p ~ 6 wherein p is 1 or 2 and R~ is hydrogen, halogen, trifluoromethyl, (Cl_4)alkoxy, (Cl_4)alkyl, amino, di~(Cl 4)alXyl]amino (Cl ~)alkylamino, or (iii) th~ azido group is cis to the phenyl group, Rl is (Cl 4)alkoxy in the meta position R2 is hydrogen, and R3 is methyl.
8~75
- 3 - 100-4997 Any alkyl or alkoxy moiety has preferably 1 or 2 carbon atoms, and especially one carbon atom. Halogen means fluorine, chlorine or bromine. The azido grou~ in the for-mula I may be cis or trans to the phenyl group. -~
Rl and R2 are preferably other than halogen. Rl ~s preferably alkoxy or hydrogen. Rl`is preferably in the meta position. R2 is preferably hydrogen. R3 is pYeferably alkyl.
R4 and R5 are preferably identical. m is preferably 2 or 3.
n is preferably 1. p is preferably 2.
~he preferred compounds are those under group tiii) above which have the formula Ia ~ 1 N3~ ~ Ia ~ N~
wherein Rl is ~Cl_4)alkoxy.
These compounds fall under the scope of DOS 2655150 but are not specifically described therein. They exhibit especially interesting properties.
The present invention also provides a process for the production of a compound of formula I which is defined above, which comprises, - ~ - 100-~997 a) splitting off a group R7 from a compound of formula VI
1 ' ~ - VI
N
. ~ N~
_ H R7 .
wherein Rl and R2 are as defined above un~er slgnificance i) R7 is an amino protecting ~roup~
to produce a compound of formula I wherein R3 is hydrogen,or 5 b) alkylating a compound of formula VII
R
1 ~ _ 3 ~ VII
NH
H . . .
wherein Rl and R2 are as defined above under significance ii) or iii)l `
to produce a compound of formula I wherein R3 is other than hydrogen.
The splitting off of an amino protecting group according to process a) may be effected in conventional manner. Preferably the amino protecting group is capable of being split off hydrolytically, especially under acidic conditions.
- . : :
.
R7 may ba for example (C2_11~ acyl, x e-g- benzcyl, or aoetyl. Alternatively R7 may (C;2 6)a~o~ycarbonyl or phenoxycarbonyl.
A suitable acid is hydrochloric acid. An inert solvent such as butanol may be present. Sui~able temperatures are from about 50 to about lOGC.
me alkylation of process b) may be effected in conventional manner for the alkylation of a secondary amine.
A suitable alkylating agent is an appropriate alkyl iodide, bromide, mesylate or tosylate. Alternatively when R3 has an hydrogen atom attached to the -carbon atom thereof, and preferably when R3 is methyl, reductive alkylation with the appropriate aldehyde or ketone in the presence of so-dium borohydride or sodium dihydro-bis-(2-methoxyethoxy-ethoxy) al~inate may be used.
The starting materials of formula VI may be ob-.. ..
tained as follows (In the flow sheet Rl and R2 are R
and R2 as defined above with the proviso that they are other than chlorine or bromine):-~11877~
R'J
R~ ~ -Li ~R2'1 7 Cu ~ 7 -60~ to 0C H
Rl and R2 are preferably other than halogen. Rl ~s preferably alkoxy or hydrogen. Rl`is preferably in the meta position. R2 is preferably hydrogen. R3 is pYeferably alkyl.
R4 and R5 are preferably identical. m is preferably 2 or 3.
n is preferably 1. p is preferably 2.
~he preferred compounds are those under group tiii) above which have the formula Ia ~ 1 N3~ ~ Ia ~ N~
wherein Rl is ~Cl_4)alkoxy.
These compounds fall under the scope of DOS 2655150 but are not specifically described therein. They exhibit especially interesting properties.
The present invention also provides a process for the production of a compound of formula I which is defined above, which comprises, - ~ - 100-~997 a) splitting off a group R7 from a compound of formula VI
1 ' ~ - VI
N
. ~ N~
_ H R7 .
wherein Rl and R2 are as defined above un~er slgnificance i) R7 is an amino protecting ~roup~
to produce a compound of formula I wherein R3 is hydrogen,or 5 b) alkylating a compound of formula VII
R
1 ~ _ 3 ~ VII
NH
H . . .
wherein Rl and R2 are as defined above under significance ii) or iii)l `
to produce a compound of formula I wherein R3 is other than hydrogen.
The splitting off of an amino protecting group according to process a) may be effected in conventional manner. Preferably the amino protecting group is capable of being split off hydrolytically, especially under acidic conditions.
- . : :
.
R7 may ba for example (C2_11~ acyl, x e-g- benzcyl, or aoetyl. Alternatively R7 may (C;2 6)a~o~ycarbonyl or phenoxycarbonyl.
A suitable acid is hydrochloric acid. An inert solvent such as butanol may be present. Sui~able temperatures are from about 50 to about lOGC.
me alkylation of process b) may be effected in conventional manner for the alkylation of a secondary amine.
A suitable alkylating agent is an appropriate alkyl iodide, bromide, mesylate or tosylate. Alternatively when R3 has an hydrogen atom attached to the -carbon atom thereof, and preferably when R3 is methyl, reductive alkylation with the appropriate aldehyde or ketone in the presence of so-dium borohydride or sodium dihydro-bis-(2-methoxyethoxy-ethoxy) al~inate may be used.
The starting materials of formula VI may be ob-.. ..
tained as follows (In the flow sheet Rl and R2 are R
and R2 as defined above with the proviso that they are other than chlorine or bromine):-~11877~
R'J
R~ ~ -Li ~R2'1 7 Cu ~ 7 -60~ to 0C H
4 ~ i)NaBH4 thenii)(CH300)20 sePara- iii)separa.tiGn of ~ epimers \ epimers R ~ R2 RlJI R2"
C~3S ~ lj CH3S02Cl no I ~ - ~ ~ ~\ .
~_,N ~ ii) optionally 1 7 brominate or ~" N~R
yTI~ H chlorinate ~ 7 The mesyloxy group of a compound of formula VIII may be displaced by an azide group from an appropriate azide with re-versal of the configuration at C6 to yield a compound of formula VI.
Compounds of ormula VIII or VI wherein Rl and/or R2 are chlorine or bromine may be conveniently made by chlorina-ting or brominating selectively the 4a phenyl ring using con-veniently aromatic chlorinating or brominating agen~s, e.g.
pyridinium tri.bromide.
Compouncls of formula VII are compounds of formula I where-' .
' ~ 7 - 100-4997 in R3 is hydrogen or else are known or may be made in analo-gous manner to compounds of formula I wherein R3 is hydro~en.
The configuration of the compounds may be determined on the basis that when the 6-substituen~ e.g azido and hy-droxy is cis to the phenyl ring the compound is more polaron silicagel chromatography, e.g. using CH2C12/CH30H as eluant, than the corresponding 6~epimer.
In so far as the production of any startin~ material is not particularly described, this is known or may be produ-10ced or purified by known processes or in a manner an~logous to known processes or to processes herein described.
Free base forms of the compounds of formula I may be converted into acid addition salt forms in conventional manner and vice versa. Suitable acids include hydrochloric acid, maleic acid, oxalic acid, hydrobromic acid~ tartaric acia ,malonic acid and di-0,0'-p-toluoyl-tartaric acid.
Thè compounds of formula I may exist in racemic form or in individual optically active form. ~he optically active forms may be obtained by fractional crystallization of dia-stereoisomeric salts, e.g. their salts with (+) or (-) di-0,0'-p-toluoyl-tartaric acid.
In the following Examples all temperatures are in degrees Centigrade and are uncorrected. All ratios are by volume except where otherwise stated.
377~i -8- 1~0-4997 EXP~LE 1: (4aRS,_6RS, 8_RS)-6-a~ido-decah~dro-4a-(3-methoxy~henyl)-cis-iso~uinollne (process a) (4aRS, 6RS, 8aRS)-6-azido-2-henzoyl-decahydro-4a-(3-methoxyphenyl)-cis-isoquinoline in 40 ml n-butanol are eated with 40 ml 4N HCl. The mixture is stirred at 90C
for 72 hours~ cooled and extracted with hexane. The aqueous phases are made alkaline with 10% (by weight) Na2C03 and extracted with CH2C12/C2H50H (8:2). The extracts are evapo-rated and chromatographed on silicagel -using as eluant CH2C12: CH30H: conc. NH40H (95:4.5:0.5). The title compound is obtained, M.pt. (HCl salt) 113-115 (from acetone/ether)~
The starting material is obtained as follows:-a) A mixture of 600 ml absolute tetrahydrofuran, 112.2 g 3-bromoanisole and 661 mg hydroquinone are treated under n~trogen at -65 with 278 ml 2.2N butyl lithium, maintained at -50 for 30 minutes and then treated with 57.13 .g copper (I) iodide, stirred at -43C for 30 minutes and then treated with 1, 3, 4, 7, ~t 8a-hexahydro-2-benzoyl-6(2H)-isoquinolinone. The mixture is warmed to 0 over 2 hours,malntained at 0 for 16 hours and then worked up to give 2-benzoyl-octahydro-4a-(3-methoxyphenyl)-cis-6(2H)-isoqui-nolone. M.pt:. 78 (from methanol)0 b) 72.6 g of 2-benzoyl-octahydro-4a-(3-methoxyphenyl~ cis-6(2H)-iso~uinolone in 200 ml CH30H is reduced at 0 with 2,84 g NaBH~ over 2 hours. 20 ml acetone and 200 ml H20 are ' ~ ' :
~ 9 ~ 100-~997 added and the mixture continuou31y extracted with methylene chloride to give,after ~orking up, a mixture of the 6-hydroxy deri-vatives as an oil. These were acetylated by 19~ ml acetic anhydride in 100 ml pyridine. The mixture is carefully worked up to give an oil. The oil ~s treated with 80 ml acetone and 50 ml ether and (4aRS, 6SR, 8aRS) -6-acetoxy-2-benzoyl-decahydro-4a-(3-methoxyphenyl)-cis-isoquinoline (M.pt. 133-135) crystal7izes out.
Chromatography of the mother liquor on silicagel and elution with CH2C12 + 0.5 -1~ CH30H yields (4aRS, 6RS, 8aRS) -6-acetoxy-2-benzoyl-decahydro-4a-(3-methoxyphenyl)-cis-isoquinoline ~M.pt. 124-125~after crystallization from ethyl acetate/ether).
c) A suspension of 40.8 g (4aRS, 6SR, 8aRS) -6-acetoxy-2-benzoyl-decahydro-4a-(3-methoxyphenyl)-cis~isoquinoline in 200 ml CH30H and 50 ml CH2C12 is stirred and treated with 100 ml 2N K0~ - ln CH30H/H20 (9:1). After 90 minutes the re-action mixture is evaporated , taken up in CH2C12/C2H50H
~9:1), washed with water, dried and evaporated to yield~
(4aRS, 6SR, 8aRS) -2-benzoyl-decahydro-6-hydroxy-4a-(3-me~
~hoxyphenyl)-cis-isoquinoline as a colourless fam.
d) 44.3 g of (4aRS, 6SR, 8aRS) -2-benzoyl-decahydro-6-hydroxy-4a-~3-methoxyphenyl)-cis-isoquinoline in 300 ml absolute tetrahydrofuran and 60 ml triethylamine are stirred and cooled and treated with 11.4 ml me~hanesulphonyl chloride in 100 ml absolute telrahydrofuran. After 1 hour the reaction mixture 7~
is poured onto ice and extracted with CH2C12.
Concentrat~on under a vacuum yields (4aRS, 6SR, 8a RS) 2-benzoyl-decahydro-6-mesyloxy-4a-(3-methoxyphenyl)-cis-isoquinoline. M.pt. 142-143 (from petroleum ether).
e) 3.8 g of sodIum azide, 12.8 g (4aRS, 6SR, 8aRS) 2-ben-zoyl-decahydro-6-mesyloxy-4a-(3-methoxyphenyl)-cis-isoqui-noline, and 60 ml DMS0 are stirred for 6 hours at 80 under nitrogen. The mixture is partitioned between toluene and water. The organic phase is evaporated to yield (4a RS, 6RS, 8aRS)-6-azido-2-~enzoyl-decahydro-4a-(3-methoxy-phenyl)-cis-isoquinoline.
EX~PLE 2: (4aRS, 6RS, 8aR~)-6-azi_o-decah~dro-2-methyl-4a-(3-meth_x~phenyl)-cis-iso~uinoline (process b) 28.6 g of 14aRS, 6RS, 8aRS)-6-a2ido-2-benzoyl-deca-hydro-4a-(3-methoxyphenyl)-cis-isoquinoline and 100 ml 35%
aqueous formaldehyde solution in 300 ml C2H50H are stirred with 19 g NaBH4. After 30 minutes ice-water is added and }he mixture is extracted with CH2C12. The extracts yield the tit~e-compo~tnd. M.pt. (hydrogen maleate) 155 from acetone/
ether; (HCl salt) from 190 (decomp).
11.88 g of the title compound and 15.96 g di-0,0?-p-toluoyl-L(~)-tartaric acid are dissolved in warm methanol, filtered an~ allowed to afford crystals at room temperature.
2S The cxystals are collected, washed with cold methanol and dried. The crystals are recrystallized four times from me-37~5 ~ 100-4997 thanol. Treatment with 2N NaOH and CH2C12 yields the free base of the title compound (-) isomer, [a]D = - 24.3 (c = 0.5 in pyridine) which is converted into the hydro-chloride M.pt. 170-172 []20 = _50.3o (c = 0.5 in H20~.
In analogous manner the (+) isomer of the title compound is obtained by ~ractional crystallization of the di-O,O`-toluoyl-D(-)-tartaric acid salt. [a]D (free base) - ~ 24.1 (c = 0.5 in pyridine); (hydrochloride) = ~ 48.6 ~c = 0.5 in H20).
0 EX~MPLE 3: (4aRS, 6RS, 8aRS)-6-azido-deca_ydro-2-meth~l-4a-(3-metho~y~henyl)-cis-iso~uinoline (process b) 1.43 g (4aRS, 6RS, 8aRS)-6-azido-decahydro-4a-(3-methoxyphenyl)-cis-isoquinoline in 25 ml acetone and 25 ml 15 CH30H as solvent are ~reated with 0.95 ml N-ethyl-diisoprop-ylamine as condensation agent, 0.91 g potassium iodide and O.1 ~1 methyl iodide. The mixture is warmed to 50 under nitrogen. After 20 hours the mixture is worked up to give the title compound, M.pt. (HC1 salt) 190 (decomp).
:
~18775 - 12 - l00-49g7 In analogous manner to that described above the following compounds of form.ula I are produced:-Ex R R2 R3 ~nfigul) M.pt2? Production ration analogous to Ex~le 4 3~13 H H 6-SR 138-41 ) 1 4-OCH3 H H 6-RS 5) 6 4-OCH3 H H 6~R 5) 7 3 OCH3 4-Br H 6-F6 8 3 OCH3 >24003) ~ 3 lo 3 2 5 H CH3 6--RS ~184 1 2,3.
12 3--o--isoC3H~ c~3 6-RS 188--9 2 ,3 3--CH3 H CB3 6--RS ~180 ) 2 ~3 16 3`~CH3 H CH3 6-SR 185 ) 2,3 l? H H H 6-RS
18 H H CH3 6-RS 190 2 ,3 , 1) 6-BS = (4aRS, 6RS, 8aRS) isomer 6-SR = (4aRS, 6SR, 8aRS) iscmer 2) HCl salt unless otherwise stated 3) decomposition 4) hydrogen ~.alonate
C~3S ~ lj CH3S02Cl no I ~ - ~ ~ ~\ .
~_,N ~ ii) optionally 1 7 brominate or ~" N~R
yTI~ H chlorinate ~ 7 The mesyloxy group of a compound of formula VIII may be displaced by an azide group from an appropriate azide with re-versal of the configuration at C6 to yield a compound of formula VI.
Compounds of ormula VIII or VI wherein Rl and/or R2 are chlorine or bromine may be conveniently made by chlorina-ting or brominating selectively the 4a phenyl ring using con-veniently aromatic chlorinating or brominating agen~s, e.g.
pyridinium tri.bromide.
Compouncls of formula VII are compounds of formula I where-' .
' ~ 7 - 100-4997 in R3 is hydrogen or else are known or may be made in analo-gous manner to compounds of formula I wherein R3 is hydro~en.
The configuration of the compounds may be determined on the basis that when the 6-substituen~ e.g azido and hy-droxy is cis to the phenyl ring the compound is more polaron silicagel chromatography, e.g. using CH2C12/CH30H as eluant, than the corresponding 6~epimer.
In so far as the production of any startin~ material is not particularly described, this is known or may be produ-10ced or purified by known processes or in a manner an~logous to known processes or to processes herein described.
Free base forms of the compounds of formula I may be converted into acid addition salt forms in conventional manner and vice versa. Suitable acids include hydrochloric acid, maleic acid, oxalic acid, hydrobromic acid~ tartaric acia ,malonic acid and di-0,0'-p-toluoyl-tartaric acid.
Thè compounds of formula I may exist in racemic form or in individual optically active form. ~he optically active forms may be obtained by fractional crystallization of dia-stereoisomeric salts, e.g. their salts with (+) or (-) di-0,0'-p-toluoyl-tartaric acid.
In the following Examples all temperatures are in degrees Centigrade and are uncorrected. All ratios are by volume except where otherwise stated.
377~i -8- 1~0-4997 EXP~LE 1: (4aRS,_6RS, 8_RS)-6-a~ido-decah~dro-4a-(3-methoxy~henyl)-cis-iso~uinollne (process a) (4aRS, 6RS, 8aRS)-6-azido-2-henzoyl-decahydro-4a-(3-methoxyphenyl)-cis-isoquinoline in 40 ml n-butanol are eated with 40 ml 4N HCl. The mixture is stirred at 90C
for 72 hours~ cooled and extracted with hexane. The aqueous phases are made alkaline with 10% (by weight) Na2C03 and extracted with CH2C12/C2H50H (8:2). The extracts are evapo-rated and chromatographed on silicagel -using as eluant CH2C12: CH30H: conc. NH40H (95:4.5:0.5). The title compound is obtained, M.pt. (HCl salt) 113-115 (from acetone/ether)~
The starting material is obtained as follows:-a) A mixture of 600 ml absolute tetrahydrofuran, 112.2 g 3-bromoanisole and 661 mg hydroquinone are treated under n~trogen at -65 with 278 ml 2.2N butyl lithium, maintained at -50 for 30 minutes and then treated with 57.13 .g copper (I) iodide, stirred at -43C for 30 minutes and then treated with 1, 3, 4, 7, ~t 8a-hexahydro-2-benzoyl-6(2H)-isoquinolinone. The mixture is warmed to 0 over 2 hours,malntained at 0 for 16 hours and then worked up to give 2-benzoyl-octahydro-4a-(3-methoxyphenyl)-cis-6(2H)-isoqui-nolone. M.pt:. 78 (from methanol)0 b) 72.6 g of 2-benzoyl-octahydro-4a-(3-methoxyphenyl~ cis-6(2H)-iso~uinolone in 200 ml CH30H is reduced at 0 with 2,84 g NaBH~ over 2 hours. 20 ml acetone and 200 ml H20 are ' ~ ' :
~ 9 ~ 100-~997 added and the mixture continuou31y extracted with methylene chloride to give,after ~orking up, a mixture of the 6-hydroxy deri-vatives as an oil. These were acetylated by 19~ ml acetic anhydride in 100 ml pyridine. The mixture is carefully worked up to give an oil. The oil ~s treated with 80 ml acetone and 50 ml ether and (4aRS, 6SR, 8aRS) -6-acetoxy-2-benzoyl-decahydro-4a-(3-methoxyphenyl)-cis-isoquinoline (M.pt. 133-135) crystal7izes out.
Chromatography of the mother liquor on silicagel and elution with CH2C12 + 0.5 -1~ CH30H yields (4aRS, 6RS, 8aRS) -6-acetoxy-2-benzoyl-decahydro-4a-(3-methoxyphenyl)-cis-isoquinoline ~M.pt. 124-125~after crystallization from ethyl acetate/ether).
c) A suspension of 40.8 g (4aRS, 6SR, 8aRS) -6-acetoxy-2-benzoyl-decahydro-4a-(3-methoxyphenyl)-cis~isoquinoline in 200 ml CH30H and 50 ml CH2C12 is stirred and treated with 100 ml 2N K0~ - ln CH30H/H20 (9:1). After 90 minutes the re-action mixture is evaporated , taken up in CH2C12/C2H50H
~9:1), washed with water, dried and evaporated to yield~
(4aRS, 6SR, 8aRS) -2-benzoyl-decahydro-6-hydroxy-4a-(3-me~
~hoxyphenyl)-cis-isoquinoline as a colourless fam.
d) 44.3 g of (4aRS, 6SR, 8aRS) -2-benzoyl-decahydro-6-hydroxy-4a-~3-methoxyphenyl)-cis-isoquinoline in 300 ml absolute tetrahydrofuran and 60 ml triethylamine are stirred and cooled and treated with 11.4 ml me~hanesulphonyl chloride in 100 ml absolute telrahydrofuran. After 1 hour the reaction mixture 7~
is poured onto ice and extracted with CH2C12.
Concentrat~on under a vacuum yields (4aRS, 6SR, 8a RS) 2-benzoyl-decahydro-6-mesyloxy-4a-(3-methoxyphenyl)-cis-isoquinoline. M.pt. 142-143 (from petroleum ether).
e) 3.8 g of sodIum azide, 12.8 g (4aRS, 6SR, 8aRS) 2-ben-zoyl-decahydro-6-mesyloxy-4a-(3-methoxyphenyl)-cis-isoqui-noline, and 60 ml DMS0 are stirred for 6 hours at 80 under nitrogen. The mixture is partitioned between toluene and water. The organic phase is evaporated to yield (4a RS, 6RS, 8aRS)-6-azido-2-~enzoyl-decahydro-4a-(3-methoxy-phenyl)-cis-isoquinoline.
EX~PLE 2: (4aRS, 6RS, 8aR~)-6-azi_o-decah~dro-2-methyl-4a-(3-meth_x~phenyl)-cis-iso~uinoline (process b) 28.6 g of 14aRS, 6RS, 8aRS)-6-a2ido-2-benzoyl-deca-hydro-4a-(3-methoxyphenyl)-cis-isoquinoline and 100 ml 35%
aqueous formaldehyde solution in 300 ml C2H50H are stirred with 19 g NaBH4. After 30 minutes ice-water is added and }he mixture is extracted with CH2C12. The extracts yield the tit~e-compo~tnd. M.pt. (hydrogen maleate) 155 from acetone/
ether; (HCl salt) from 190 (decomp).
11.88 g of the title compound and 15.96 g di-0,0?-p-toluoyl-L(~)-tartaric acid are dissolved in warm methanol, filtered an~ allowed to afford crystals at room temperature.
2S The cxystals are collected, washed with cold methanol and dried. The crystals are recrystallized four times from me-37~5 ~ 100-4997 thanol. Treatment with 2N NaOH and CH2C12 yields the free base of the title compound (-) isomer, [a]D = - 24.3 (c = 0.5 in pyridine) which is converted into the hydro-chloride M.pt. 170-172 []20 = _50.3o (c = 0.5 in H20~.
In analogous manner the (+) isomer of the title compound is obtained by ~ractional crystallization of the di-O,O`-toluoyl-D(-)-tartaric acid salt. [a]D (free base) - ~ 24.1 (c = 0.5 in pyridine); (hydrochloride) = ~ 48.6 ~c = 0.5 in H20).
0 EX~MPLE 3: (4aRS, 6RS, 8aRS)-6-azido-deca_ydro-2-meth~l-4a-(3-metho~y~henyl)-cis-iso~uinoline (process b) 1.43 g (4aRS, 6RS, 8aRS)-6-azido-decahydro-4a-(3-methoxyphenyl)-cis-isoquinoline in 25 ml acetone and 25 ml 15 CH30H as solvent are ~reated with 0.95 ml N-ethyl-diisoprop-ylamine as condensation agent, 0.91 g potassium iodide and O.1 ~1 methyl iodide. The mixture is warmed to 50 under nitrogen. After 20 hours the mixture is worked up to give the title compound, M.pt. (HC1 salt) 190 (decomp).
:
~18775 - 12 - l00-49g7 In analogous manner to that described above the following compounds of form.ula I are produced:-Ex R R2 R3 ~nfigul) M.pt2? Production ration analogous to Ex~le 4 3~13 H H 6-SR 138-41 ) 1 4-OCH3 H H 6-RS 5) 6 4-OCH3 H H 6~R 5) 7 3 OCH3 4-Br H 6-F6 8 3 OCH3 >24003) ~ 3 lo 3 2 5 H CH3 6--RS ~184 1 2,3.
12 3--o--isoC3H~ c~3 6-RS 188--9 2 ,3 3--CH3 H CB3 6--RS ~180 ) 2 ~3 16 3`~CH3 H CH3 6-SR 185 ) 2,3 l? H H H 6-RS
18 H H CH3 6-RS 190 2 ,3 , 1) 6-BS = (4aRS, 6RS, 8aRS) isomer 6-SR = (4aRS, 6SR, 8aRS) iscmer 2) HCl salt unless otherwise stated 3) decomposition 4) hydrogen ~.alonate
5) Hydrogen fumarate mixture of 6RS/SR isomers 188 (decomp) `
,:
- 14 - lOo-4997 The compounds of formula I are eY~ibit analgesic activity ` as indicated in standard tests, e.g. ln the phenylbenzoquinone writhing test in mice on p.o. ac~ministration of from 0.5 to ~0 mg/kg of the co~-pounds, and in the tail flick test in mice on s.c. and p.o.administration from 0.5 to 100 mg/kg of the compc)unds.
The compounds of formula I~ exhibit nota~le analge-sic activity in the above tests as well as notable activity on oral administration in e.g. the arthritlc pain test - 10 in the rat over 1 to 5 hours on administratlon of fro~ 1 to 10 mg/kg p.o. These compounds also appear to be well tolera-ted in the mouse and rat at doses of from 50 to 100 mg/kg.
Furthermore thes~ compounds appear to be exhibit less mor-phine dependent efects ~han expected for such compounds as 15 indicated by the following properties:-i) These compounds do not appear to bind selectively to rat brain opiate receptors. In standard tests for indicating the inhibition of specific 3H-naloxone binding to rat brain membrane~, e.g. according to the princlples of PertC.~,and 20 Synder S.H.~Science 1~79, 1011-1014 (1973) and Molec~Pharmac.
10, 868-869 (1971)~a high concentration of compound, e.g.
1000 to 100,000 nM, was required to lnhiblt the specific binding of 3H naloxone (1 nM) both in the presence of 100 nM
sodium chlorlde and in the absence of sodium chloride.
25 ii) These compounds do not appear to be lnduce si~nificant dose-dependent jumping hehavour in morphine-c'ependent mice on . ^ ~
7~
_15 _ 100-4997 administration of from 30 to 100 mg/kg i.p. In one standard test male mice ~OFI) strain weighing about 25 a were implanted under llght ether anaesthesiawith a pellet containing 75 mg morphine base. After recovering, the ani~als were maintained in groups of 10 with free access to ~ood and water. 6 days after the implantation the mice were judged to be morphine dependent. The compound was then administered and the number of jumps recorded in a 5~ ~inute period thereafter recorded.
10 (iii) These compounds do not appear to markedly inhibit the withdr~al syndrome in morphine dependent monkeys at a dose of from 1 to 10 mg/kg i.v. One standard test is car~ed out as follows:-Male rhesus monkéys (2.5 - 3.4 kg) were kept, each in a metal harness (weight 600 g), ln separate, open-fronted 15 cubicles (70 x 70 x 90 cm) with free access to food and water, and a 12 hour light-dark cycle (6 a.m. - 6 p.m. light) main-tained. After 7 days acclimatisation to their harnesses and to the cages, the monkeys were anaPsthetized w1th pentothal i.v. and halothane and implanted with a single-lumen silastic 20 catheter into the left jugular vein. l`he free end of the ca'heter was then led subcutaneously over the shoulder of each animal cmd out through a small stab wound made in the skin between the shoulder blades. The monkeys were refltted lnto their harnesses and connected to a saline-filled cannula 25 coming from the injecticn pumps. During the 7 day recovery period, all anlmals received 0.8 ml physiological saline 7~
every 30 minutes in order to keept the tip o thè cannula free of clots.
Each monkey received programmed injeclions of mor-phine (5.6 mg/kg i.v.) at intervals of 4 hours. After several days the morphine injections are stopped and two hours after the last morphine injection the compound is admini-stered to the animal. The nature and intensity of the withdrawal syndrome is then recorded.
In the above tests the Example 2 title compound showed especially interesting activity. The (-) form of the Example 2 compound exhibits more interesting activity than the (+) form. This indicates that all optical isomers having the same absolute configuration as the (-) form of the Example 2 compound are the preferred optical isomers.
The compounds are therefore indicated for use as analgesic agents. For this use an indicated daily dose is from about 10 to about 300 mg, conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from about 5 to about 150 mg, or in sustained release form.
s ~ 17 - 100-4997 The compounds of formula I may be ad~lnistered in pharmaceutically acceptable acid addition salt for~.
Such acid addition salt fo~ms exhbit the same order of activity as the free base forms and are readily prepared in conventional manner. The present invention also provides a pharmaceutical composition comprising a compound of formula I, in free base form or in pharmaceutlcally acceptable acid addition salt form, ~n association with a pharmaceutical carrier or diluent.
Such compositions may be in the form of, for example, a solution or a tablet.
Example 2 is the preferred compound.
,:
- 14 - lOo-4997 The compounds of formula I are eY~ibit analgesic activity ` as indicated in standard tests, e.g. ln the phenylbenzoquinone writhing test in mice on p.o. ac~ministration of from 0.5 to ~0 mg/kg of the co~-pounds, and in the tail flick test in mice on s.c. and p.o.administration from 0.5 to 100 mg/kg of the compc)unds.
The compounds of formula I~ exhibit nota~le analge-sic activity in the above tests as well as notable activity on oral administration in e.g. the arthritlc pain test - 10 in the rat over 1 to 5 hours on administratlon of fro~ 1 to 10 mg/kg p.o. These compounds also appear to be well tolera-ted in the mouse and rat at doses of from 50 to 100 mg/kg.
Furthermore thes~ compounds appear to be exhibit less mor-phine dependent efects ~han expected for such compounds as 15 indicated by the following properties:-i) These compounds do not appear to bind selectively to rat brain opiate receptors. In standard tests for indicating the inhibition of specific 3H-naloxone binding to rat brain membrane~, e.g. according to the princlples of PertC.~,and 20 Synder S.H.~Science 1~79, 1011-1014 (1973) and Molec~Pharmac.
10, 868-869 (1971)~a high concentration of compound, e.g.
1000 to 100,000 nM, was required to lnhiblt the specific binding of 3H naloxone (1 nM) both in the presence of 100 nM
sodium chlorlde and in the absence of sodium chloride.
25 ii) These compounds do not appear to be lnduce si~nificant dose-dependent jumping hehavour in morphine-c'ependent mice on . ^ ~
7~
_15 _ 100-4997 administration of from 30 to 100 mg/kg i.p. In one standard test male mice ~OFI) strain weighing about 25 a were implanted under llght ether anaesthesiawith a pellet containing 75 mg morphine base. After recovering, the ani~als were maintained in groups of 10 with free access to ~ood and water. 6 days after the implantation the mice were judged to be morphine dependent. The compound was then administered and the number of jumps recorded in a 5~ ~inute period thereafter recorded.
10 (iii) These compounds do not appear to markedly inhibit the withdr~al syndrome in morphine dependent monkeys at a dose of from 1 to 10 mg/kg i.v. One standard test is car~ed out as follows:-Male rhesus monkéys (2.5 - 3.4 kg) were kept, each in a metal harness (weight 600 g), ln separate, open-fronted 15 cubicles (70 x 70 x 90 cm) with free access to food and water, and a 12 hour light-dark cycle (6 a.m. - 6 p.m. light) main-tained. After 7 days acclimatisation to their harnesses and to the cages, the monkeys were anaPsthetized w1th pentothal i.v. and halothane and implanted with a single-lumen silastic 20 catheter into the left jugular vein. l`he free end of the ca'heter was then led subcutaneously over the shoulder of each animal cmd out through a small stab wound made in the skin between the shoulder blades. The monkeys were refltted lnto their harnesses and connected to a saline-filled cannula 25 coming from the injecticn pumps. During the 7 day recovery period, all anlmals received 0.8 ml physiological saline 7~
every 30 minutes in order to keept the tip o thè cannula free of clots.
Each monkey received programmed injeclions of mor-phine (5.6 mg/kg i.v.) at intervals of 4 hours. After several days the morphine injections are stopped and two hours after the last morphine injection the compound is admini-stered to the animal. The nature and intensity of the withdrawal syndrome is then recorded.
In the above tests the Example 2 title compound showed especially interesting activity. The (-) form of the Example 2 compound exhibits more interesting activity than the (+) form. This indicates that all optical isomers having the same absolute configuration as the (-) form of the Example 2 compound are the preferred optical isomers.
The compounds are therefore indicated for use as analgesic agents. For this use an indicated daily dose is from about 10 to about 300 mg, conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from about 5 to about 150 mg, or in sustained release form.
s ~ 17 - 100-4997 The compounds of formula I may be ad~lnistered in pharmaceutically acceptable acid addition salt for~.
Such acid addition salt fo~ms exhbit the same order of activity as the free base forms and are readily prepared in conventional manner. The present invention also provides a pharmaceutical composition comprising a compound of formula I, in free base form or in pharmaceutlcally acceptable acid addition salt form, ~n association with a pharmaceutical carrier or diluent.
Such compositions may be in the form of, for example, a solution or a tablet.
Example 2 is the preferred compound.
Claims (6)
1. A process for the production of a compound of formula I
wherein R1, R2 and R3 chosen from the followlnq signi-ficances (1) (11) and (111):-(1) R1 and R2, independently, are hydrogen (C1-6)alkyl, trifluoromethyl, halogen, or (C1-4)alkoxy, and R3 is hydrogen, or (11) (a) R1 and R2, independently, are hydrogen, (C1-6)alkyl, trifluoromethyl or halogen, or (b) R1 is (C1-4)alkoxy and R2 is (C1-6)alkyl, trifluoromethyl, halogen or (C1-4)alkoxy, and R3 is (C1-6) alkyl, a radical of formula II, -CH2.CH=CR4R5 II
wherein R4 and R5, independently, are hydrogen or (C1-4)alkyl, a radical of formula III, - 19 -. 100-4997 wherein m is 2, 3 or 4, a radlcal of formula IV
IV
whereln n is 1 or 2, or a radical of formula V
wherein p is 1 or 2 and R6 is hydrogen, halogen, trifluoromethyl, (C1-4)alkoxy, (C1-4)alkyl, amino, di[C1-4)alkyl]amino (C1-4)alkylamino, or (111) the azido group is cis to the phenyl group, R1 is (C1-4)alkoxy in the meta positlon R2 is hydrogen, and R3 is methyl, which comprises a) splitting off a group R7 from a compound of formula VI
VI
wherein R1 and R2 are as defined above under significance 1) R7 is an amino protecting group, to produce a compound of formula I wherein R3 is hydrogen,or b) alkylating a compound of formula VII
VII
wherein R1 and R2 are as defined above under significance 11) or 111), to produce a compound of formula I whereln R3 is other than hydrogen.
wherein R1, R2 and R3 chosen from the followlnq signi-ficances (1) (11) and (111):-(1) R1 and R2, independently, are hydrogen (C1-6)alkyl, trifluoromethyl, halogen, or (C1-4)alkoxy, and R3 is hydrogen, or (11) (a) R1 and R2, independently, are hydrogen, (C1-6)alkyl, trifluoromethyl or halogen, or (b) R1 is (C1-4)alkoxy and R2 is (C1-6)alkyl, trifluoromethyl, halogen or (C1-4)alkoxy, and R3 is (C1-6) alkyl, a radical of formula II, -CH2.CH=CR4R5 II
wherein R4 and R5, independently, are hydrogen or (C1-4)alkyl, a radical of formula III, - 19 -. 100-4997 wherein m is 2, 3 or 4, a radlcal of formula IV
IV
whereln n is 1 or 2, or a radical of formula V
wherein p is 1 or 2 and R6 is hydrogen, halogen, trifluoromethyl, (C1-4)alkoxy, (C1-4)alkyl, amino, di[C1-4)alkyl]amino (C1-4)alkylamino, or (111) the azido group is cis to the phenyl group, R1 is (C1-4)alkoxy in the meta positlon R2 is hydrogen, and R3 is methyl, which comprises a) splitting off a group R7 from a compound of formula VI
VI
wherein R1 and R2 are as defined above under significance 1) R7 is an amino protecting group, to produce a compound of formula I wherein R3 is hydrogen,or b) alkylating a compound of formula VII
VII
wherein R1 and R2 are as defined above under significance 11) or 111), to produce a compound of formula I whereln R3 is other than hydrogen.
2. Process according to Claim 1 which com-prises methylating (4aRS,6RS,8aRS)-6-azido-decahydro-4a-(3-methoxyphenyl)-cis-isoquinoline to produce (4aRS,6RS, 8aRS)-6-azido-decahydro-2-methyl-4a-(3-methoxyphennyl)-cis-isoquinoline.
3. Process according to Claim 2 wherein the methylation is effected by reaction with formaldehyde in the presence of sodium borohydride.
4. Process according to Claim 2 wherein the methylation is effected by reaction with a methyl halide in the presence of a condensation agent.
5. A compound of formula I as defined in Claim 1 whenever prepared by a process as claimed in Claim 1 or by an obvious chemical equivalent thereof.
6. (4aRS,6RS,8aRS)-6-azido-decahydro-2-methyl-4a-(3-methoxyphenyl)-cis-isoquinoline whenever prepared by a process as claimed in any one of Claims 2 to 4 or by an obvious chemical equivalent thereof.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH2643/78 | 1978-03-10 | ||
| CH264378A CH636859A5 (en) | 1978-03-10 | 1978-03-10 | Substituted cis-4a-phenyldecahydroisoquinolines, their preparation and drugs containing them |
| CH628378 | 1978-06-08 | ||
| CH6283/78 | 1978-06-08 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1118775A true CA1118775A (en) | 1982-02-23 |
Family
ID=25691019
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000323128A Expired CA1118775A (en) | 1978-03-10 | 1979-03-08 | 6-azido-decohydro-4a phenyl-cis-isoquinoline compounds |
Country Status (15)
| Country | Link |
|---|---|
| JP (1) | JPS54128585A (en) |
| AU (1) | AU529350B2 (en) |
| CA (1) | CA1118775A (en) |
| DE (1) | DE2907461A1 (en) |
| DK (1) | DK88279A (en) |
| ES (1) | ES478430A1 (en) |
| FI (1) | FI790701A (en) |
| FR (1) | FR2419286A2 (en) |
| GB (1) | GB2016012B (en) |
| IL (1) | IL56823A0 (en) |
| IT (1) | IT7948220A0 (en) |
| NL (1) | NL7901764A (en) |
| NZ (1) | NZ189856A (en) |
| PH (1) | PH14162A (en) |
| SE (1) | SE7901848L (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2600649B1 (en) * | 1986-06-26 | 1989-02-24 | Rhone Poulenc Sante | PROCESS FOR THE PREPARATION OF LEVOMEPROMAZINE ACID MALEATE |
| JP3858273B2 (en) * | 1995-07-20 | 2006-12-13 | 東レ株式会社 | “4a-Aryldecahydroisoquinoline compounds and pharmaceutical uses thereof” |
| WO2015006280A1 (en) * | 2013-07-10 | 2015-01-15 | Vertex Pharmaceuticals Incorporated | Fused piperidine amides as modulators of ion channels |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2655150A1 (en) * | 1975-12-16 | 1977-06-23 | Sandoz Ag | NEW ORGANIC COMPOUNDS, THEIR PRODUCTION AND USE |
-
1979
- 1979-02-26 DE DE19792907461 patent/DE2907461A1/en not_active Withdrawn
- 1979-03-01 DK DK88279A patent/DK88279A/en not_active Application Discontinuation
- 1979-03-01 FI FI790701A patent/FI790701A/en not_active Application Discontinuation
- 1979-03-01 SE SE7901848A patent/SE7901848L/en not_active Application Discontinuation
- 1979-03-06 GB GB7907868A patent/GB2016012B/en not_active Expired
- 1979-03-06 NL NL7901764A patent/NL7901764A/en not_active Application Discontinuation
- 1979-03-06 IT IT7948220A patent/IT7948220A0/en unknown
- 1979-03-06 FR FR7905753A patent/FR2419286A2/en active Granted
- 1979-03-08 AU AU44956/79A patent/AU529350B2/en not_active Ceased
- 1979-03-08 ES ES478430A patent/ES478430A1/en not_active Expired
- 1979-03-08 NZ NZ189856A patent/NZ189856A/en unknown
- 1979-03-08 IL IL56823A patent/IL56823A0/en unknown
- 1979-03-08 CA CA000323128A patent/CA1118775A/en not_active Expired
- 1979-03-09 PH PH22274A patent/PH14162A/en unknown
- 1979-03-10 JP JP2818379A patent/JPS54128585A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| FR2419286B1 (en) | 1982-03-05 |
| GB2016012B (en) | 1982-07-21 |
| JPS54128585A (en) | 1979-10-05 |
| GB2016012A (en) | 1979-09-19 |
| FI790701A (en) | 1979-09-11 |
| FR2419286A2 (en) | 1979-10-05 |
| IT7948220A0 (en) | 1979-03-06 |
| IL56823A0 (en) | 1979-05-31 |
| ES478430A1 (en) | 1979-05-16 |
| PH14162A (en) | 1981-03-19 |
| DE2907461A1 (en) | 1979-09-20 |
| NL7901764A (en) | 1979-09-12 |
| AU529350B2 (en) | 1983-06-02 |
| DK88279A (en) | 1979-09-11 |
| AU4495679A (en) | 1979-09-13 |
| SE7901848L (en) | 1979-09-11 |
| NZ189856A (en) | 1981-12-15 |
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