CA2015114A1 - 4-/4'-halophenyl/-2-methyl-1,2,3,4-tetrahydroisoquinolines and a method for their preparation - Google Patents
4-/4'-halophenyl/-2-methyl-1,2,3,4-tetrahydroisoquinolines and a method for their preparationInfo
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- CA2015114A1 CA2015114A1 CA 2015114 CA2015114A CA2015114A1 CA 2015114 A1 CA2015114 A1 CA 2015114A1 CA 2015114 CA2015114 CA 2015114 CA 2015114 A CA2015114 A CA 2015114A CA 2015114 A1 CA2015114 A1 CA 2015114A1
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- Prior art keywords
- methyl
- halophenyl
- product
- optically active
- preparation
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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
Abstract
ABSTRACT OF THE DISCLOSURE:
4-/4'-halophenyl/2-methyl-1,2,3,4-tetrahydroiso-quinoline racemate or optically active isomer having the formula: wherein R is a member selected from brome or fluor, and their physiologically acceptable salts. These have high inhibitory effect towards dopamine noradrenaline or serotonin uptake, as well as high antiulcer activity. A
method for the preparation, is characterised in that benzylmethylamine is alkylated with at least one .alpha.-halogenated aryl aliphatic ketone to 2-/N-methyl-N-benzylamin/-4-haloacetophenone, and then reduced to N-benzyl-2-methylamine-1-/4-halophenyl/-1-ethanol with sodium borhydrate. The latter is cyclodehydrated with concentrated sulphuric acid.
4-/4'-halophenyl/2-methyl-1,2,3,4-tetrahydroiso-quinoline racemate or optically active isomer having the formula: wherein R is a member selected from brome or fluor, and their physiologically acceptable salts. These have high inhibitory effect towards dopamine noradrenaline or serotonin uptake, as well as high antiulcer activity. A
method for the preparation, is characterised in that benzylmethylamine is alkylated with at least one .alpha.-halogenated aryl aliphatic ketone to 2-/N-methyl-N-benzylamin/-4-haloacetophenone, and then reduced to N-benzyl-2-methylamine-1-/4-halophenyl/-1-ethanol with sodium borhydrate. The latter is cyclodehydrated with concentrated sulphuric acid.
Description
The invention concerns 4-/4'-halophenyl/-2-methyl-1,2,3,4,-tetrahydroisoquinolines racemates or optically active antipodes and a method for their preparation.
It is known from R. Kunstmen, H. Gerhards, H.
Kruse, M. Leven, E. Paulus, U. Schacht, K. Schmitt, J. Med.
Chem. 1987, 30, 7988-804 that racemic or optically active 4-phenyl-8-amino-2-methyl-1,2,3,4,-tetrahydroisoquinolines, possess inhibitory effect on the uptake of dopamine/DA/, noradrenaline/NA/ and serotonin/5-HT/ from synaptozomes of rats' cerebral cortex.
It is also known from M. Bickel, Arzneim-Torsch;
Drug Res., 30(1), No 1, 69, 1980, that the racemic 4-phenyl-8-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline possesses moderate inhibitory effect towards stress inducing stomach ulcers in rats.
The object of the invention is to create new 4-/4'-halophenyl/-2-methyl-1,2,3,4,-tetrahydroisoquinolines having general formula (1):
R
1~1 ,, ~ ,, -CH3 la R = Br lb R = F
where R means brome or fluor, and their physiologically acceptable salts, which have high inhibitory effect towards dopamine, noradrenaline or serotonin uptake, as well as a high antiulcer activity.
The essence of the invention comprises in the fact that the racemic compounds with general formula 1 are ; obtained according to the following three-stage reaction scheme:
It is known from R. Kunstmen, H. Gerhards, H.
Kruse, M. Leven, E. Paulus, U. Schacht, K. Schmitt, J. Med.
Chem. 1987, 30, 7988-804 that racemic or optically active 4-phenyl-8-amino-2-methyl-1,2,3,4,-tetrahydroisoquinolines, possess inhibitory effect on the uptake of dopamine/DA/, noradrenaline/NA/ and serotonin/5-HT/ from synaptozomes of rats' cerebral cortex.
It is also known from M. Bickel, Arzneim-Torsch;
Drug Res., 30(1), No 1, 69, 1980, that the racemic 4-phenyl-8-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline possesses moderate inhibitory effect towards stress inducing stomach ulcers in rats.
The object of the invention is to create new 4-/4'-halophenyl/-2-methyl-1,2,3,4,-tetrahydroisoquinolines having general formula (1):
R
1~1 ,, ~ ,, -CH3 la R = Br lb R = F
where R means brome or fluor, and their physiologically acceptable salts, which have high inhibitory effect towards dopamine, noradrenaline or serotonin uptake, as well as a high antiulcer activity.
The essence of the invention comprises in the fact that the racemic compounds with general formula 1 are ; obtained according to the following three-stage reaction scheme:
X - C ,i~,"- o ~ /~>_ ~ . .s R
_;
~3 c~ J C~Z - C~ R ` - " J ~
, _, Oh~ .
ai ALkyldti..~n of bt=n~-ylt=thy].~;l~.ine ~'. free ~a5~ aik~1l ir~
twi._e m~llar e~GSS wit~ C-h~lo~en~ e~- ar~;l aliF~hat:i.c.
ket:~n~s _~ in a boil:ir~ ~n_ol c~ a~ ~t~nt~ m2~iium til.l tha F.~ arati.orl c~f c.--"'N-m2thyl-N-~en~ylan~ir{~f--4-hal~a~ ~to-ph~ rlc~ t, wher~ 1~ has th~ showr, ~bov~ ~anin~. Kr~lones ~
~}~: i9~ t.;~ ~Crrll ot h~td~ .h~ori~ 3~,t~, pr~areiJ 3-'y ~i-cOtmenr ~i- ~`aJ ~ SF'5 with ~;tly di~thYl ~th2r ~satura~e,~ wit h~
t,) .-~edu~_tii;,r. cf ket~n~s ~ tc~ N--~n, y].--~-fm~thylamir~ ~.f-l-~-ha:l~_r.~h~n~,lf-l.-ethar-,o~s ~ u~ing ;~ thr~e-l:inl~ molar ~,~c--sg c~f si~dium ~c~rhYdr~t~ Ths: r~a~-.ti~ ,arrl,=d c~u t in l.-~wer ali ~ ~h.~ls medium at a tt---m~!erature ir-ter~Ja 1 f rc,m 10 t-o , .~i.: : . :: : : : . .: :
2 ~
Thc pre~;1r-d .:-J,,iinols 5 ~re s~ rate-l in th~ ic,Jm --,f well.
cr~st~ i~irl~ tree t~ses. wr.ictl ar-.- clear enou~h /~ccording t~ ~7-2 Ol- TL~ for the l-ext ~t-~e o~~ c~/cli~.ati(~n c) cyclizaci-~nl ot- Gart~in~ s 5 tc .4-aryl-t~tr~hy~rois~-Jqu~ ines 1 i~ ~arrie~ out in a dichlormethane or dichl~re~lane medi~lm in the ~reser.ce ~f ~oncentrated sulph~ri-_ ~ciA at a tempeI~ture interval from O to 30~~
pr~erar,l-~ from ~ o ;5~ f-~. 1 t~ ~', hours, p~e~er3bly 1 t~
hours R~ ba~es 1 ~re is~lat~d l-r-om ~he ..eacliorl mixtures by c~3tir,~ -h~ l~rter in ice cold water f~llowÆd t~y neu-~.raliza tiOIl ~al -th~ prepare~ so~u~.ons i~ ~5 per cent aquec,L~s sc~iu._~r:.-.. amm~ni.ull ~nd extr3ction with ~ .c.uitable ~rgar,i,- soivent.
The hydroct.ic,~ide ~alt~ of 1 are prepared .~rom raw bases ~y dlssoluti~n ~f the lart_r in absolute ethan~l and treatment of ttle prepared solutiQns with dry diethyl ether.
satl-ra-~d ~ith HCl ~as.
The structure or the compounds with general. ~rmula 1 is proved by data Erom IR, lH-NMi~ and ~ass spectroscopy. as weil as from data of the elemental analysis.
The optic~lly~ aGtive forms of la, /~=Br/ are obtained by treatment of ~ la free base with /+~-O.O-dibenzoyl-D-tartariG acid or ,~-f-O.~-di~2n oyl-L-tar~aric acid in 98 per c,ent alcch2. med,u~.
The compouncls with a veneral formula 1 are studied Eor influenc~ on dopamine ~DA/~ r,oraclrenalin~ ~NA~ and serotonin j5HT/ uptake from synaptozomes. isolated from cerebral cortex o~ rats. Thes~ bioc~lemical tes~s, a~ it is known, are reg~rded as basic criterià for presence of antidepressant activity As it is seen fro~l the pres~nted result.s on ~ge10 itabLe 1~, the racemiG ~a and 1~ p2ssess not 2nly,high inhi~it.~ry efl'ec,t in reg,3ri to ~A ancl NA u~tai~e. but the~e are also str~n~ inhihitors oE 5HT uptak2 for ~iffeI-ence t~
the ~.nown antidepre~ant Noinifenzine, which is a wea~.
serotonin inhibitor r~ - arlti~ ,ti~ ~ t ~l ' r~ d dl~ or~ dn .:L?~l-im~l~t,~1 m~-"3~i -). w~r-inlm~T~ . ~tr~ uc~-:~ C,t~m~
~llcers in ra~s is d,L~o .,~ ie-i ~t~ , As a pr-pdrarion f~r c.o~palis.ori 13 used H~-~ntd~ni.~ Rar.it~
The re~ults ~rc,m th-se stu.lies show that the compound 1~ a~plie~-1 oraliy ~s~esses hi~h antiulcer activity ever. at se :J 05(-l m~k~, with a suppressi~r of the u~cer index perGentage o-f 2~. l'he av~rage effective do~.e i~ O.~CIO m~,~k~
a, which the inh~bi.ion per-~l.t~Ee i~ ~,' With ,he incre~
.-.f the d._,se als~ ncrea~es re~;.l.arlY the ,~nhit~itorY ~ffect ~n~ t.he maximum is aohieved at ~o~e ~ m~k~.
The results ot the c~-~mparalive stud~es ~it.h Raniti~ir-sh~ J that la h~c several time~ higher ~ntiulcer ef.eGt T~u~-.
~c.r,example at c~05e 0 1~0 mg,f'~ the p~rc~entage of ~hi~ition of ~h~ ul~e-~- inclex i~ 'or la. while at five times hi~her ~aniti~iir ~ose ~I ',00 m~.~k~) the percenta~e of inhibiti~n is onl~; ~7 At dc~s~ Cl 500 m~k~ of la the per~er.ta~e o~ inhibit}~n is ~ while L~e same p~rcentage is achieved at Ranitidin d~se o~ lu mgJkg This rasult shows that la possesses ~ times stronger antiul._er effect than the taken for co~parison Ranitidin Similar result~ are ~bt~i~ed for comp~un~ lb. too.
I'he following examples illustrate the inventic~n without lim~.ting i~
Example 1. Pr~paration o~ N-methyl-N-benzylaminQ/-4-brom-ace-topherlone ~a ~R-Br~
To a sol.utlon of 6 ~5 g ~50 mmol~ ben~ylmethyla~nin free base in lS ml acetone at temperature 35-4~C i3 added a solution of 6 ~5 ~ J~5 mmolf w-brom-4-~rc~macetoph2none in ~,5 ml acetone The reaction ~i~ture is boilin~ f~r 8 hours, and aft~r that it is left tc, stay for c,ne ni~ht in a refrigerator The crystalli~ed hydrobromide of the initial ben~ylmethylam~ne is filtered The fil-tr~te is evaporated under vacuo to give an oil re.siclue The latter i~ d:iss~lved in 5 ml absolut2 ethanc.l and tc. the prepared ~olution is added ,iry diethyl ether ~aturated with H~l gas For the `:~ :.. . : : : :
~ ~ ~, r '~
complete ~edimentation o~ the produced hydrochloride t~ 4,a are further added SO ml diethyl et~er. The raw hydrochloride is recrystallized from ethanol, and after that are isolated 6 09 g /70 per cent/ from 4a hydrochloride with M.P. 133-138C ~:.
IR spectre ~K8r/ cm~ 90 /COf.
Elemental analysis: calculated per cent C 54 ~8, N 3 93~ Cl 9 96, Br 22 46, C16H18NOClBr, found per cent C 54 20. H 4 98, N 4 01, Cl 9.80, Br 22 30 In a similar way i~ prepared 2-/N-methyl-N-benzylamino/-4-fluoracetophenone 4b fR=F~ with a yield of 79 per Gent Elemental analysis: calculated per cent C 65 19, H 6 15, N 4.75-, Cl 12.03. C16H18NOClF, found per cent C 65 ~2, H 6 10, N 4 80, Cl 12 10 :, E,x,am,~le_2,, Preparation of N-benzyl-2-/methylamino/-1-/4-bromphen~ 1-ethanol 5 ~R=Br~
12 30 g /37 mmol/ 2-/N-methyl-N-benzylamino/-4-b~omacetophenone hydroch~oride are dissolved in 1?0 ml methanol and to the prepared solution are added 5 32 g /139 mmol~ sodium bo~hydrate at temperature about ~0C and stirring for 30 minutes The stirring continues at room temperature for 30 minutes more, and after that the reaction mixture is boiling ror 6 hours The solvent is removed under vacuo and 150 ml water are added to the residue and the separated oil is extracted four time~ with dichlormethane The extract is dried with Na2S04 and evaporated in vacuo to dive ~.5 g /82 per cent~ TLC pure 5,a free base with M P . 60-61.5C.
IR spectre /KBr/ cm~l: 3200 /OH/
In a-similar way is prepared N-benzyl-2-~methylamino/-1-/fluorphenyl/-1-ethanol 5b f~=F~ with a yield of 94 per .
cent ~ lemental ~nalysis for Sa: calculated per cent C ~9.02, ~
H 5 66. N 4 37, Br 24 qS, C~6H18NOBr~ found per cent ~-C ~0 ~0, H 5 40~ N 4 20, Br 24 85 :;
.. ; .
..; ~
2 ~
Elemental analysi~ for 5~: calculated per cent C 74 19 H ~ 9g N 5 40 C16H18NBr fo~nd per cent C 74 30 H 7 10 Exampl~ 3 Preparation of 4-/4 -bromphenyl/-2-methyl-1 2 3 4-tetrahydroisoquinoline hydrochloride la /~=Br/
To 11 7 ml concentrated sulphuric acid cooled to 5C i~
added drop by drop at intense stirrin~ for 45 minutes a sQlution of 2 ~8 ~ /9 3 mmol/ N-~e~zyl-~-Jmethylamino~ 4 bromphenyl~-1-ethanol in 25 ml dichlorm~thane The stirring continues for 1 hour more at the ~ame temperature and after that the r~eaction-mixture i-~ poured on 50 ~ ground ice and 50 ml water The organic layer i~ ~eparated and the aqueous phase is basified w~th 5 per cent aqueous solution o~
ammonium and the prepared oil is extr~cted with dichlormethane After drying of the extr~ct with sodi~l~
~ulphat~ and re~oval of the Qolv~nt under vacuo is ot~ined la fr~e base in the form of oil. The latter i3 di3301ved in a minimum quantity methanol and is changed to hydrochloc~ide bly treatment with dry diethyl ether saturated with HCl ~as ~he raw hydrochloride is recrystallized from methanol-diethyl ether and 2.5 g ~82 per cent/ la hydrochlorid~ are obtained with M.P ~20-224C
1H-NMR ~ppm ~DMS0-d6~:2 65 (s 3H)-N-C~3 ~ 32-3 76 lm 2H) and 4.53 (m lH)-~H2f3/-~ ~ 4.24 and ~ 36 ~m 2H
J=8.~ Hz)-1-CH2 6.65-7.40 ~two m 9H Ar)- o-C6H4 ~nd p--C6H4-MS /70 eV/: m~z = 303/~301 ~1:1/ for 81Brf79Br ~base) Elemental analysis: ~alculated per cent C 56 74 H 5 06 N ~ 13 C16H17NClBr found per .-ent C 56 64 H 5 20 -~
In a similar way is obtained 4-/4 -fluorphenyl/-~- -methyl-1 2 3 4-tetrahydroi~oquinoline hydrochloride lb ~R=F~
with a yield of 86 per cent M P 136-140C ;;~
`' ~
.
' 2 ~
H-NMR, ~ ppm (DMS0-d6):2 52 (s,~H)-t~C~3, 3,20-3 Oo ~m~,H~ and 4 40 (m,lH)-C~2/3~-CH/1/, ~ i2 and ~ ~5 '~1,2H
J=10 Hz)-1-CH2, 6 78-7 36 (two m, 8H Ar~- o-C6H4 and p-C~H4 ~S /70 e'v',': m/7- - ?J~ M+~
~ lemental analysis: calculated per ?,ent C 5g.1~, H 6 17, N 5 ~4, C16H17NC~F, ~ound per cent C 6~ ~-0. H 6 3S, E,xa,m~,1~,, Preparation of optica~ly ~ctive ~o~ms o~
/4'-bromphenyl~2-methyl-1,2,~,4-tetrahydroisoquir.oline ,la 9 g ~0 ~3 mol,' racemic 1a free base are dis~clved at boil.n~ in 90 ml ethanol 10 75 ~ fO 03 mol~ -O,O-diben~ovl-n-tartaric acid in ~0 ml ethanol are ad~ed tc the prepared qolution After ~taying for one day at temperature 8-lO~C 9 5 g /96 4 per cent ~rom the 'theoretical yield/
diben~cyl-D-~+f- tartarate of la crystallize with ~ P 115-ll9~C and ~C ~ = +68 0~ ~c=0 2~. CH30H~, t~]~ of the ~ree base is t31 3~ ~c=0 ~S, C~Cl3; Af~ar one recrystalli~,ation of the raw tartarate from ethanol ~ 2 ~
/87 per cFnt from the theoretical yield/ la tartara~e are j obtained with [~]~ = 3~ 38 and ~ P il~-121~ A'ter treatment of the tartarate with an aquéous ~olution of ammonium and following extrac-tion with chlorophor.~ is obtained a free base /+~ ,~a with [~3~ = ~3~ 7~- fc-~ ~5, i cHcl3/-The mother li~ors of the raw tartarate and these of the first cr~rstallizatiQn are combined and are evaporated ~nder vacuo to dryness The produced residue i~ dissolvsd in water, basified ~ith an aque~u~ ~olution of ~mmonium and the obtained oil i8 extracted from chlorof~rm After drying of --the ~xtract with sodium ~ulphate and following distillation ' ' of the solvent under ~acuo are obtained 7 5 g J-~ la raw ', base The latter is di~olved in 37 ~ ml ~oilir.g ethanol and ~-8 96 g /0 02~ mol/ /-/-0,9-~ibenzoyl-L-tartaric acid are added to the prepared solution After ~tayin~ at temperature B-10C S ~ g raw tartarate o~ /-/ la are obtained with C d]~ = -~8 08 /c=0 25, C~3~f After one recrystallization 2 ~
of the raw tartarate from ethanol are prepared 4.8 g/92 per cent from the theoretical yield/ /-/ la tartarate with ~D -~
= -74.89/c=0.25, CH30H/ and M.P~ 120-124 C /-/'a free base:
~1D = -30.64/c=0.25, CHCl3/.
Example 5: Determination of the inhibitory effect of 4-/4'-halophenyl/-2-methyl-1,2,3,4,-tetrahydroisoquinolines la and lb on DA, NA and 5HT uptake from the synaptozomes isolated from cerebral cortex of rats.
Synaptozomes are isolated from cerebral cortex of white male rats "Wister" species by method from E.C. Gray, V.R. Whittaker, J. Anatomy, 96, 79, 1962. The tissue is homogenized in 10 volumes 0.32 M saccharose. The homogenite is centrifuged at 3000 g for 10 minutes at 0C. The prepared supernatant is centrifuged at 17 000 g for 60 min.
The fraction enriched with synaptozomes, P-2 fraction, is flushed only once with 0.32 M saccharose and is separated at 11 000 g for 20 minutes. The synaptozome fraction is resuspended in buffer containing 134 mM sodium chloride;
4.1 mM potassium chloride; 1.1 mM acide calcium phosphate;
1.2 mM magnesium chloride; 5.5 mM /+/ gl~cose; 23.6 mM tris base 1.3 mM calcium dichloride; 0.3 mM EDTA-Na; 0.1 mM
ascorbic acid; 0.01 mM nialamid. The buffer pH is maintained to 7.4 with sulphuric acid at 37C. The ~`
synaptozomes are resuspended in concentration about 500 ug protein per 0.1 ml.
The reaction is carried out in glass tubes. The incubation mixture volume is 1.0 ml. Each test consists of a blind smaple/incubation is carried out in an ice bath/, a control sample/ without inhibitors of the uptake/ and a test sample/ containing the studied substances/. The studied substances are dissolved in Tween 80 and in the operating buffer in three concentrations. The samples are reincubated for 10 minutes at 37C and the reaction starts with the addition of 100-300 nM /-/ 3H-noradrenaline, 50-300nM/3H/-.... .
,'j: . `::
2 ~
dopamine or 200-250 nM/3H/-serotonin to each sample. The incubation continues 3 min for dopamine and 6 min for noradrenaline and serotonin and stops with the addition of 4 ml glacial solution of sodium chloride 0.9%. The synaptozome material is separated from the incubation mixture by filtering through Millipore filter /0.45 ,u/ and is flushed only once with 4 ml 0.9 per cent solution of sodium chloride. Each filter is placed in a scintillation flask containing standard scintillation solution. The radioactivity is read on liquid scintillation counter.
Example 6: Determination of the inhibitory effect of 4-aryl tetrahydroisoguinolines la and lb on water immersion stress induced stomach ulcers in rats.
The tests are carried out on 280 white male rats "Wister" species with weight between 150 and 200 g by the method described in K. Takadi, Y. Ischil, Arzneim-Torsch/
Drug Res., 17, 1544, 1967. Eighteen hours prior the test the animals starve with free access to water. The studied substance is applied by mouth and the animals are tied still on their backs on separated stands immersed in water, termostated to 17-18C. Five hours later the rats are killed, their stomachs are taken out and the destructive changes are read by microscope.
; :;
.
2 ~ L. ,~"
.T. n h i ~ . n g r~ F F~ L-. c, ~ . a l _, E t. . =~ ?e ~ , 3, ', -t~tr~-lh~rA~.,7.~cf31 ir~c,~-.T.. ~ n ~ L~r.~', rloradrf n.~~ *
_;
~3 c~ J C~Z - C~ R ` - " J ~
, _, Oh~ .
ai ALkyldti..~n of bt=n~-ylt=thy].~;l~.ine ~'. free ~a5~ aik~1l ir~
twi._e m~llar e~GSS wit~ C-h~lo~en~ e~- ar~;l aliF~hat:i.c.
ket:~n~s _~ in a boil:ir~ ~n_ol c~ a~ ~t~nt~ m2~iium til.l tha F.~ arati.orl c~f c.--"'N-m2thyl-N-~en~ylan~ir{~f--4-hal~a~ ~to-ph~ rlc~ t, wher~ 1~ has th~ showr, ~bov~ ~anin~. Kr~lones ~
~}~: i9~ t.;~ ~Crrll ot h~td~ .h~ori~ 3~,t~, pr~areiJ 3-'y ~i-cOtmenr ~i- ~`aJ ~ SF'5 with ~;tly di~thYl ~th2r ~satura~e,~ wit h~
t,) .-~edu~_tii;,r. cf ket~n~s ~ tc~ N--~n, y].--~-fm~thylamir~ ~.f-l-~-ha:l~_r.~h~n~,lf-l.-ethar-,o~s ~ u~ing ;~ thr~e-l:inl~ molar ~,~c--sg c~f si~dium ~c~rhYdr~t~ Ths: r~a~-.ti~ ,arrl,=d c~u t in l.-~wer ali ~ ~h.~ls medium at a tt---m~!erature ir-ter~Ja 1 f rc,m 10 t-o , .~i.: : . :: : : : . .: :
2 ~
Thc pre~;1r-d .:-J,,iinols 5 ~re s~ rate-l in th~ ic,Jm --,f well.
cr~st~ i~irl~ tree t~ses. wr.ictl ar-.- clear enou~h /~ccording t~ ~7-2 Ol- TL~ for the l-ext ~t-~e o~~ c~/cli~.ati(~n c) cyclizaci-~nl ot- Gart~in~ s 5 tc .4-aryl-t~tr~hy~rois~-Jqu~ ines 1 i~ ~arrie~ out in a dichlormethane or dichl~re~lane medi~lm in the ~reser.ce ~f ~oncentrated sulph~ri-_ ~ciA at a tempeI~ture interval from O to 30~~
pr~erar,l-~ from ~ o ;5~ f-~. 1 t~ ~', hours, p~e~er3bly 1 t~
hours R~ ba~es 1 ~re is~lat~d l-r-om ~he ..eacliorl mixtures by c~3tir,~ -h~ l~rter in ice cold water f~llowÆd t~y neu-~.raliza tiOIl ~al -th~ prepare~ so~u~.ons i~ ~5 per cent aquec,L~s sc~iu._~r:.-.. amm~ni.ull ~nd extr3ction with ~ .c.uitable ~rgar,i,- soivent.
The hydroct.ic,~ide ~alt~ of 1 are prepared .~rom raw bases ~y dlssoluti~n ~f the lart_r in absolute ethan~l and treatment of ttle prepared solutiQns with dry diethyl ether.
satl-ra-~d ~ith HCl ~as.
The structure or the compounds with general. ~rmula 1 is proved by data Erom IR, lH-NMi~ and ~ass spectroscopy. as weil as from data of the elemental analysis.
The optic~lly~ aGtive forms of la, /~=Br/ are obtained by treatment of ~ la free base with /+~-O.O-dibenzoyl-D-tartariG acid or ,~-f-O.~-di~2n oyl-L-tar~aric acid in 98 per c,ent alcch2. med,u~.
The compouncls with a veneral formula 1 are studied Eor influenc~ on dopamine ~DA/~ r,oraclrenalin~ ~NA~ and serotonin j5HT/ uptake from synaptozomes. isolated from cerebral cortex o~ rats. Thes~ bioc~lemical tes~s, a~ it is known, are reg~rded as basic criterià for presence of antidepressant activity As it is seen fro~l the pres~nted result.s on ~ge10 itabLe 1~, the racemiG ~a and 1~ p2ssess not 2nly,high inhi~it.~ry efl'ec,t in reg,3ri to ~A ancl NA u~tai~e. but the~e are also str~n~ inhihitors oE 5HT uptak2 for ~iffeI-ence t~
the ~.nown antidepre~ant Noinifenzine, which is a wea~.
serotonin inhibitor r~ - arlti~ ,ti~ ~ t ~l ' r~ d dl~ or~ dn .:L?~l-im~l~t,~1 m~-"3~i -). w~r-inlm~T~ . ~tr~ uc~-:~ C,t~m~
~llcers in ra~s is d,L~o .,~ ie-i ~t~ , As a pr-pdrarion f~r c.o~palis.ori 13 used H~-~ntd~ni.~ Rar.it~
The re~ults ~rc,m th-se stu.lies show that the compound 1~ a~plie~-1 oraliy ~s~esses hi~h antiulcer activity ever. at se :J 05(-l m~k~, with a suppressi~r of the u~cer index perGentage o-f 2~. l'he av~rage effective do~.e i~ O.~CIO m~,~k~
a, which the inh~bi.ion per-~l.t~Ee i~ ~,' With ,he incre~
.-.f the d._,se als~ ncrea~es re~;.l.arlY the ,~nhit~itorY ~ffect ~n~ t.he maximum is aohieved at ~o~e ~ m~k~.
The results ot the c~-~mparalive stud~es ~it.h Raniti~ir-sh~ J that la h~c several time~ higher ~ntiulcer ef.eGt T~u~-.
~c.r,example at c~05e 0 1~0 mg,f'~ the p~rc~entage of ~hi~ition of ~h~ ul~e-~- inclex i~ 'or la. while at five times hi~her ~aniti~iir ~ose ~I ',00 m~.~k~) the percenta~e of inhibiti~n is onl~; ~7 At dc~s~ Cl 500 m~k~ of la the per~er.ta~e o~ inhibit}~n is ~ while L~e same p~rcentage is achieved at Ranitidin d~se o~ lu mgJkg This rasult shows that la possesses ~ times stronger antiul._er effect than the taken for co~parison Ranitidin Similar result~ are ~bt~i~ed for comp~un~ lb. too.
I'he following examples illustrate the inventic~n without lim~.ting i~
Example 1. Pr~paration o~ N-methyl-N-benzylaminQ/-4-brom-ace-topherlone ~a ~R-Br~
To a sol.utlon of 6 ~5 g ~50 mmol~ ben~ylmethyla~nin free base in lS ml acetone at temperature 35-4~C i3 added a solution of 6 ~5 ~ J~5 mmolf w-brom-4-~rc~macetoph2none in ~,5 ml acetone The reaction ~i~ture is boilin~ f~r 8 hours, and aft~r that it is left tc, stay for c,ne ni~ht in a refrigerator The crystalli~ed hydrobromide of the initial ben~ylmethylam~ne is filtered The fil-tr~te is evaporated under vacuo to give an oil re.siclue The latter i~ d:iss~lved in 5 ml absolut2 ethanc.l and tc. the prepared ~olution is added ,iry diethyl ether ~aturated with H~l gas For the `:~ :.. . : : : :
~ ~ ~, r '~
complete ~edimentation o~ the produced hydrochloride t~ 4,a are further added SO ml diethyl et~er. The raw hydrochloride is recrystallized from ethanol, and after that are isolated 6 09 g /70 per cent/ from 4a hydrochloride with M.P. 133-138C ~:.
IR spectre ~K8r/ cm~ 90 /COf.
Elemental analysis: calculated per cent C 54 ~8, N 3 93~ Cl 9 96, Br 22 46, C16H18NOClBr, found per cent C 54 20. H 4 98, N 4 01, Cl 9.80, Br 22 30 In a similar way i~ prepared 2-/N-methyl-N-benzylamino/-4-fluoracetophenone 4b fR=F~ with a yield of 79 per Gent Elemental analysis: calculated per cent C 65 19, H 6 15, N 4.75-, Cl 12.03. C16H18NOClF, found per cent C 65 ~2, H 6 10, N 4 80, Cl 12 10 :, E,x,am,~le_2,, Preparation of N-benzyl-2-/methylamino/-1-/4-bromphen~ 1-ethanol 5 ~R=Br~
12 30 g /37 mmol/ 2-/N-methyl-N-benzylamino/-4-b~omacetophenone hydroch~oride are dissolved in 1?0 ml methanol and to the prepared solution are added 5 32 g /139 mmol~ sodium bo~hydrate at temperature about ~0C and stirring for 30 minutes The stirring continues at room temperature for 30 minutes more, and after that the reaction mixture is boiling ror 6 hours The solvent is removed under vacuo and 150 ml water are added to the residue and the separated oil is extracted four time~ with dichlormethane The extract is dried with Na2S04 and evaporated in vacuo to dive ~.5 g /82 per cent~ TLC pure 5,a free base with M P . 60-61.5C.
IR spectre /KBr/ cm~l: 3200 /OH/
In a-similar way is prepared N-benzyl-2-~methylamino/-1-/fluorphenyl/-1-ethanol 5b f~=F~ with a yield of 94 per .
cent ~ lemental ~nalysis for Sa: calculated per cent C ~9.02, ~
H 5 66. N 4 37, Br 24 qS, C~6H18NOBr~ found per cent ~-C ~0 ~0, H 5 40~ N 4 20, Br 24 85 :;
.. ; .
..; ~
2 ~
Elemental analysi~ for 5~: calculated per cent C 74 19 H ~ 9g N 5 40 C16H18NBr fo~nd per cent C 74 30 H 7 10 Exampl~ 3 Preparation of 4-/4 -bromphenyl/-2-methyl-1 2 3 4-tetrahydroisoquinoline hydrochloride la /~=Br/
To 11 7 ml concentrated sulphuric acid cooled to 5C i~
added drop by drop at intense stirrin~ for 45 minutes a sQlution of 2 ~8 ~ /9 3 mmol/ N-~e~zyl-~-Jmethylamino~ 4 bromphenyl~-1-ethanol in 25 ml dichlorm~thane The stirring continues for 1 hour more at the ~ame temperature and after that the r~eaction-mixture i-~ poured on 50 ~ ground ice and 50 ml water The organic layer i~ ~eparated and the aqueous phase is basified w~th 5 per cent aqueous solution o~
ammonium and the prepared oil is extr~cted with dichlormethane After drying of the extr~ct with sodi~l~
~ulphat~ and re~oval of the Qolv~nt under vacuo is ot~ined la fr~e base in the form of oil. The latter i3 di3301ved in a minimum quantity methanol and is changed to hydrochloc~ide bly treatment with dry diethyl ether saturated with HCl ~as ~he raw hydrochloride is recrystallized from methanol-diethyl ether and 2.5 g ~82 per cent/ la hydrochlorid~ are obtained with M.P ~20-224C
1H-NMR ~ppm ~DMS0-d6~:2 65 (s 3H)-N-C~3 ~ 32-3 76 lm 2H) and 4.53 (m lH)-~H2f3/-~ ~ 4.24 and ~ 36 ~m 2H
J=8.~ Hz)-1-CH2 6.65-7.40 ~two m 9H Ar)- o-C6H4 ~nd p--C6H4-MS /70 eV/: m~z = 303/~301 ~1:1/ for 81Brf79Br ~base) Elemental analysis: ~alculated per cent C 56 74 H 5 06 N ~ 13 C16H17NClBr found per .-ent C 56 64 H 5 20 -~
In a similar way is obtained 4-/4 -fluorphenyl/-~- -methyl-1 2 3 4-tetrahydroi~oquinoline hydrochloride lb ~R=F~
with a yield of 86 per cent M P 136-140C ;;~
`' ~
.
' 2 ~
H-NMR, ~ ppm (DMS0-d6):2 52 (s,~H)-t~C~3, 3,20-3 Oo ~m~,H~ and 4 40 (m,lH)-C~2/3~-CH/1/, ~ i2 and ~ ~5 '~1,2H
J=10 Hz)-1-CH2, 6 78-7 36 (two m, 8H Ar~- o-C6H4 and p-C~H4 ~S /70 e'v',': m/7- - ?J~ M+~
~ lemental analysis: calculated per ?,ent C 5g.1~, H 6 17, N 5 ~4, C16H17NC~F, ~ound per cent C 6~ ~-0. H 6 3S, E,xa,m~,1~,, Preparation of optica~ly ~ctive ~o~ms o~
/4'-bromphenyl~2-methyl-1,2,~,4-tetrahydroisoquir.oline ,la 9 g ~0 ~3 mol,' racemic 1a free base are dis~clved at boil.n~ in 90 ml ethanol 10 75 ~ fO 03 mol~ -O,O-diben~ovl-n-tartaric acid in ~0 ml ethanol are ad~ed tc the prepared qolution After ~taying for one day at temperature 8-lO~C 9 5 g /96 4 per cent ~rom the 'theoretical yield/
diben~cyl-D-~+f- tartarate of la crystallize with ~ P 115-ll9~C and ~C ~ = +68 0~ ~c=0 2~. CH30H~, t~]~ of the ~ree base is t31 3~ ~c=0 ~S, C~Cl3; Af~ar one recrystalli~,ation of the raw tartarate from ethanol ~ 2 ~
/87 per cFnt from the theoretical yield/ la tartara~e are j obtained with [~]~ = 3~ 38 and ~ P il~-121~ A'ter treatment of the tartarate with an aquéous ~olution of ammonium and following extrac-tion with chlorophor.~ is obtained a free base /+~ ,~a with [~3~ = ~3~ 7~- fc-~ ~5, i cHcl3/-The mother li~ors of the raw tartarate and these of the first cr~rstallizatiQn are combined and are evaporated ~nder vacuo to dryness The produced residue i~ dissolvsd in water, basified ~ith an aque~u~ ~olution of ~mmonium and the obtained oil i8 extracted from chlorof~rm After drying of --the ~xtract with sodium ~ulphate and following distillation ' ' of the solvent under ~acuo are obtained 7 5 g J-~ la raw ', base The latter is di~olved in 37 ~ ml ~oilir.g ethanol and ~-8 96 g /0 02~ mol/ /-/-0,9-~ibenzoyl-L-tartaric acid are added to the prepared solution After ~tayin~ at temperature B-10C S ~ g raw tartarate o~ /-/ la are obtained with C d]~ = -~8 08 /c=0 25, C~3~f After one recrystallization 2 ~
of the raw tartarate from ethanol are prepared 4.8 g/92 per cent from the theoretical yield/ /-/ la tartarate with ~D -~
= -74.89/c=0.25, CH30H/ and M.P~ 120-124 C /-/'a free base:
~1D = -30.64/c=0.25, CHCl3/.
Example 5: Determination of the inhibitory effect of 4-/4'-halophenyl/-2-methyl-1,2,3,4,-tetrahydroisoquinolines la and lb on DA, NA and 5HT uptake from the synaptozomes isolated from cerebral cortex of rats.
Synaptozomes are isolated from cerebral cortex of white male rats "Wister" species by method from E.C. Gray, V.R. Whittaker, J. Anatomy, 96, 79, 1962. The tissue is homogenized in 10 volumes 0.32 M saccharose. The homogenite is centrifuged at 3000 g for 10 minutes at 0C. The prepared supernatant is centrifuged at 17 000 g for 60 min.
The fraction enriched with synaptozomes, P-2 fraction, is flushed only once with 0.32 M saccharose and is separated at 11 000 g for 20 minutes. The synaptozome fraction is resuspended in buffer containing 134 mM sodium chloride;
4.1 mM potassium chloride; 1.1 mM acide calcium phosphate;
1.2 mM magnesium chloride; 5.5 mM /+/ gl~cose; 23.6 mM tris base 1.3 mM calcium dichloride; 0.3 mM EDTA-Na; 0.1 mM
ascorbic acid; 0.01 mM nialamid. The buffer pH is maintained to 7.4 with sulphuric acid at 37C. The ~`
synaptozomes are resuspended in concentration about 500 ug protein per 0.1 ml.
The reaction is carried out in glass tubes. The incubation mixture volume is 1.0 ml. Each test consists of a blind smaple/incubation is carried out in an ice bath/, a control sample/ without inhibitors of the uptake/ and a test sample/ containing the studied substances/. The studied substances are dissolved in Tween 80 and in the operating buffer in three concentrations. The samples are reincubated for 10 minutes at 37C and the reaction starts with the addition of 100-300 nM /-/ 3H-noradrenaline, 50-300nM/3H/-.... .
,'j: . `::
2 ~
dopamine or 200-250 nM/3H/-serotonin to each sample. The incubation continues 3 min for dopamine and 6 min for noradrenaline and serotonin and stops with the addition of 4 ml glacial solution of sodium chloride 0.9%. The synaptozome material is separated from the incubation mixture by filtering through Millipore filter /0.45 ,u/ and is flushed only once with 4 ml 0.9 per cent solution of sodium chloride. Each filter is placed in a scintillation flask containing standard scintillation solution. The radioactivity is read on liquid scintillation counter.
Example 6: Determination of the inhibitory effect of 4-aryl tetrahydroisoguinolines la and lb on water immersion stress induced stomach ulcers in rats.
The tests are carried out on 280 white male rats "Wister" species with weight between 150 and 200 g by the method described in K. Takadi, Y. Ischil, Arzneim-Torsch/
Drug Res., 17, 1544, 1967. Eighteen hours prior the test the animals starve with free access to water. The studied substance is applied by mouth and the animals are tied still on their backs on separated stands immersed in water, termostated to 17-18C. Five hours later the rats are killed, their stomachs are taken out and the destructive changes are read by microscope.
; :;
.
2 ~ L. ,~"
.T. n h i ~ . n g r~ F F~ L-. c, ~ . a l _, E t. . =~ ?e ~ , 3, ', -t~tr~-lh~rA~.,7.~cf31 ir~c,~-.T.. ~ n ~ L~r.~', rloradrf n.~~ *
3,-~ r--.-ot.~ ir~ T~
r~C~iVi ty /~1,' PC~lr.f~ _ F~ T
la E3r 1~-7 1.~-8 lC-7 lb ':~ 10-7 ~ -8 10-7 n-?ir~if en,7ine ----- -,, -- - -- -- _",1 J-7 _ _ l0 .8 _ 1v ~ f l ur-nr,~ ~ f 4 - ~ l opl~~e ~ h~ ~ f~
t ~l: T -- ~ yr~l- c~ ? r~ ? i T~s ~ ?~P~n~r ~ ~ 1 ~C ~ 'f.--s~r 3 i ci ~ g ~ ],-,~:,3 S ~ nd~ t: ?!n a,f, ~ i ç ,* ~ y m~
a~:,p ~ ~ ~ 3 ~ 1 ~?
~;
=Br Per~f-nt~;~e 3f ~ -- N~ - of suppressl~ f Df.~G, mg~k~ ~ni~.?3~s Ulcer index _ _ the ul~r indGx :~: ;
1,,,,,, , ........ __ , ,:2, ,,_,, _ , , ,,, " ", , "", " " , , ,, ,.~, , _ "., ".. .. .. . .. . ... .
~, con'~rol 15 74 . f~6 '~ B~g . ~4 -5C~ q + 1c~ . ~ f~ . 6 o 1~2 ., ', . 4 * ~ S~ 4D, 3 O.50~ 10 ~0.Z + 1.-. 7 5~
'' ~ . 000' ~ 5 . 7 + 1 ~ . f~ ~a . ~
3 . 0 00 1 ~ _ l CI = 5 + ~ g . 3 ~ ~ ~
.' -. ; ~.
.
2~3.~
~ 4 _ont~-ol 1 ~ ~5 . a_ + 3~2, 19 --. 0~0 8 ~i . 5 ~ 7 . 75 ~1 .
,, , ,, 3 , . . .
c-~ntrol lC~ ~4 . ~ -Q . S O O1 ~ 3 ~ '7 1 . OO~.J 1~
3 ~ 1 ~2 ~ 5 ,~ ;
U ~ ~ 4
r~C~iVi ty /~1,' PC~lr.f~ _ F~ T
la E3r 1~-7 1.~-8 lC-7 lb ':~ 10-7 ~ -8 10-7 n-?ir~if en,7ine ----- -,, -- - -- -- _",1 J-7 _ _ l0 .8 _ 1v ~ f l ur-nr,~ ~ f 4 - ~ l opl~~e ~ h~ ~ f~
t ~l: T -- ~ yr~l- c~ ? r~ ? i T~s ~ ?~P~n~r ~ ~ 1 ~C ~ 'f.--s~r 3 i ci ~ g ~ ],-,~:,3 S ~ nd~ t: ?!n a,f, ~ i ç ,* ~ y m~
a~:,p ~ ~ ~ 3 ~ 1 ~?
~;
=Br Per~f-nt~;~e 3f ~ -- N~ - of suppressl~ f Df.~G, mg~k~ ~ni~.?3~s Ulcer index _ _ the ul~r indGx :~: ;
1,,,,,, , ........ __ , ,:2, ,,_,, _ , , ,,, " ", , "", " " , , ,, ,.~, , _ "., ".. .. .. . .. . ... .
~, con'~rol 15 74 . f~6 '~ B~g . ~4 -5C~ q + 1c~ . ~ f~ . 6 o 1~2 ., ', . 4 * ~ S~ 4D, 3 O.50~ 10 ~0.Z + 1.-. 7 5~
'' ~ . 000' ~ 5 . 7 + 1 ~ . f~ ~a . ~
3 . 0 00 1 ~ _ l CI = 5 + ~ g . 3 ~ ~ ~
.' -. ; ~.
.
2~3.~
~ 4 _ont~-ol 1 ~ ~5 . a_ + 3~2, 19 --. 0~0 8 ~i . 5 ~ 7 . 75 ~1 .
,, , ,, 3 , . . .
c-~ntrol lC~ ~4 . ~ -Q . S O O1 ~ 3 ~ '7 1 . OO~.J 1~
3 ~ 1 ~2 ~ 5 ,~ ;
U ~ ~ 4
Claims (11)
1. At least one 4-/4'-halophenyl/-2-methyl-1,2,3,4,-tetrahydroisoquinoline racemate or optically active isomer having the formula:
wherein R is a member selected from brome or fluor, and their physiologically acceptable salts.
wherein R is a member selected from brome or fluor, and their physiologically acceptable salts.
2. The product of claim 1, wherein R is brome.
3. The product of claim 1, wherein R is fluor.
4. The product of claim 1, being a racemate.
5. The product of claim 1, being an optically active isomer.
6. The product of claim 1, being a physiological active salt.
7. A method for the preparation, of at least one racemic tetrahydroisoquinoline as defined in claim 1, characterized that benzylmethylamine is alkylated with at least one .alpha.-halogenated aryl aliphatic ketone to 2-/N-methyl-N-benzylamin/-4-haloacetophenone, and then reduced to N-benzyl-2-methylamine-1-/4-halophenyl/-1-ethanol with sodium borhydrate, and the latter is cyclodehydrated with concentrated sulphuric acid.
8. A Method for the preparation of optically active tetrahydroisoquinolones as defined in claim 1, characterized that a racemic tetrahydroisoquinolone is treated with at least one optically active acid.
9. The method as defined in 7, characterized that the alkylating of said benzylmethylamine is carried out in acetone or benzol medium at twice molar excess of the latter per mole of the ketone.
10. The method as defined claim 7, characterized that said reduction of said acetophenone is carried out in a medium of lower alcohols at a temperature interval from 10 to 80°C.
11. The method as defined in claim 7, characterized in that the cyclization of said ethanol is carried out in dichloromethane or dichloroethane medium at a temperature ranging from 0 to 30°C.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| BG88220 | 1989-04-24 | ||
| BG8822089A BG49761A1 (en) | 1989-04-24 | 1989-04-24 | 4- (4'- chalophenyl)- 2- methyl- 1, 2, 3, 4- tetrahydroisohinolines and method for its preparation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2015114A1 true CA2015114A1 (en) | 1990-10-24 |
Family
ID=3921819
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2015114 Abandoned CA2015114A1 (en) | 1989-04-24 | 1990-04-23 | 4-/4'-halophenyl/-2-methyl-1,2,3,4-tetrahydroisoquinolines and a method for their preparation |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0400319A1 (en) |
| AU (1) | AU5381090A (en) |
| BG (1) | BG49761A1 (en) |
| CA (1) | CA2015114A1 (en) |
| PL (1) | PL284911A1 (en) |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6579885B2 (en) | 1999-11-03 | 2003-06-17 | Albany Molecular Research, Inc. | Aryl and heteroaryl substituted tetrahydroisoquinolines and use thereof |
| US7084152B2 (en) | 2000-07-11 | 2006-08-01 | Amr Technology, Inc. | 4-phenyl substituted tetrahydroisoquinolines therapeutic use thereof |
| US7163949B1 (en) | 1999-11-03 | 2007-01-16 | Amr Technology, Inc. | 4-phenyl substituted tetrahydroisoquinolines and use thereof |
| US7541357B2 (en) | 2004-07-15 | 2009-06-02 | Amr Technology, Inc. | Aryl- and heteroaryl-substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin |
| US7956050B2 (en) | 2005-07-15 | 2011-06-07 | Albany Molecular Research, Inc. | Aryl- and heteroaryl-substituted tetrahydrobenzazepines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin |
| US8420811B2 (en) | 2008-06-04 | 2013-04-16 | Bristol-Myers Squibb Company | Tetrahydroisoquinolines and intermediates therefor |
| US8802696B2 (en) | 2009-05-12 | 2014-08-12 | Albany Molecular Research, Inc. | 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoqu inoli and use thereof |
| US8815894B2 (en) | 2009-05-12 | 2014-08-26 | Bristol-Myers Squibb Company | Crystalline forms of (S)-7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline and use thereof |
| US9034899B2 (en) | 2009-05-12 | 2015-05-19 | Albany Molecular Research, Inc. | Aryl, heteroaryl, and heterocycle substituted tetrahydroisoquinolines and use thereof |
| US9156812B2 (en) | 2008-06-04 | 2015-10-13 | Bristol-Myers Squibb Company | Crystalline form of 6-[(4S)-2-methyl-4-(2-naphthyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]pyridazin-3-amine |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2293728C2 (en) * | 1999-11-03 | 2007-02-20 | Эймр Текнолоджи, Инк. | Derivatives of tetrahydroisoquinoline, pharmaceutical composition containing thereof, method for inhibition of synaptic uptake of dopamine and treatment method |
| CA2592353A1 (en) * | 2004-12-17 | 2006-06-22 | Janssen Pharmaceutica, N.V. | Tetrahydroisoquinoline compounds for treatment of cns disorders |
-
1989
- 1989-04-24 BG BG8822089A patent/BG49761A1/en unknown
-
1990
- 1990-04-20 EP EP90107538A patent/EP0400319A1/en not_active Withdrawn
- 1990-04-23 CA CA 2015114 patent/CA2015114A1/en not_active Abandoned
- 1990-04-24 PL PL28491190A patent/PL284911A1/en unknown
- 1990-04-24 AU AU53810/90A patent/AU5381090A/en not_active Abandoned
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| US7612090B2 (en) | 1999-11-03 | 2009-11-03 | Albany Molecular Research, Inc. | Aryl and heteroaryl substituted tetrahydroisoquinolines and use thereof |
| US7163949B1 (en) | 1999-11-03 | 2007-01-16 | Amr Technology, Inc. | 4-phenyl substituted tetrahydroisoquinolines and use thereof |
| US7265116B2 (en) | 1999-11-03 | 2007-09-04 | Arm Technology, Inc. | Aryl and heteroaryl substituted tetrahydroisoquinolines and use thereof |
| US6579885B2 (en) | 1999-11-03 | 2003-06-17 | Albany Molecular Research, Inc. | Aryl and heteroaryl substituted tetrahydroisoquinolines and use thereof |
| US7084152B2 (en) | 2000-07-11 | 2006-08-01 | Amr Technology, Inc. | 4-phenyl substituted tetrahydroisoquinolines therapeutic use thereof |
| US7309789B2 (en) | 2000-07-11 | 2007-12-18 | Amr Technology, Inc. | 4-phenyl substituted tetrahydroisoquinolines and therapeutic use thereof |
| US7419985B2 (en) | 2000-07-11 | 2008-09-02 | Amr Technology, Inc. | 4-Phenyl substituted tetrahydroisoquinolines and therapeutic use thereof |
| US9085531B2 (en) | 2004-07-15 | 2015-07-21 | Albany Molecular Research, Inc. | Aryl- and heteroaryl-substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin |
| US8227486B2 (en) | 2004-07-15 | 2012-07-24 | Albany Molecular Research, Inc. | Aryl- and heteroaryl-substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin |
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| US8791101B2 (en) | 2005-07-15 | 2014-07-29 | Albany Molecular Research, Inc. | Aryl- and heteroaryl-substituted tetrahydrobenzazepines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin |
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| US8420811B2 (en) | 2008-06-04 | 2013-04-16 | Bristol-Myers Squibb Company | Tetrahydroisoquinolines and intermediates therefor |
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| US9498476B2 (en) | 2008-06-04 | 2016-11-22 | Albany Molecular Research, Inc. | Crystalline form of 6-[(4S)-2-methyl-4-(2-naphthyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]pyridazin-3-amine |
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| US8815894B2 (en) | 2009-05-12 | 2014-08-26 | Bristol-Myers Squibb Company | Crystalline forms of (S)-7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline and use thereof |
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| US9034899B2 (en) | 2009-05-12 | 2015-05-19 | Albany Molecular Research, Inc. | Aryl, heteroaryl, and heterocycle substituted tetrahydroisoquinolines and use thereof |
| US8802696B2 (en) | 2009-05-12 | 2014-08-12 | Albany Molecular Research, Inc. | 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoqu inoli and use thereof |
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Also Published As
| Publication number | Publication date |
|---|---|
| EP0400319A1 (en) | 1990-12-05 |
| PL284911A1 (en) | 1991-11-04 |
| BG49761A1 (en) | 1992-02-14 |
| AU5381090A (en) | 1990-10-25 |
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