CA1134370A - Indoline derivatives, their production and pharmaceutical composition containing them - Google Patents
Indoline derivatives, their production and pharmaceutical composition containing themInfo
- Publication number
- CA1134370A CA1134370A CA000354967A CA354967A CA1134370A CA 1134370 A CA1134370 A CA 1134370A CA 000354967 A CA000354967 A CA 000354967A CA 354967 A CA354967 A CA 354967A CA 1134370 A CA1134370 A CA 1134370A
- Authority
- CA
- Canada
- Prior art keywords
- acceptable acid
- acid addition
- addition salt
- pharmaceutically acceptable
- alkoxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
Abstract
INDOLINE DERIVATIVES, THEIR PRODUCTION ANO PHARMA-CEUTICAL COMPOSITIONS CONTAINING THEM
Abstract of the Disclosure A l-aminoethyl-indoline substituted in the 3 position by a slngle phenyl group and either un-substituted or having a mono-valent substituent in the 2 position is an anti-depressant agent.
Abstract of the Disclosure A l-aminoethyl-indoline substituted in the 3 position by a slngle phenyl group and either un-substituted or having a mono-valent substituent in the 2 position is an anti-depressant agent.
Description
\ ~
~3~3`~i~
100-5214 ~ -INDOLINE DERIVATIVES, THEIR PRODUCTIO~ AND P.~ ~A-CEUTICAL COMPOSITIO~S CO~fTAINING THEM
This invention relates to indoline derivati-ves, their production and pharmaceutical compositions containing them.
~ .S.P. 4,080/330 discloses a class of 2-unsubstituted-3-ohenylindolines ~Iherein the indoline nucleus may be substituted in the phenyl ring in the 5, 6 or 7 position. The ~henyl ring of the in- ~
10 doline nucleus and the exocyclic phenyl ring in the '!;
3 uosition may be monosubs~ituted by halogen, I lower alkoxy or lower alkyl~ The indoline nitrogen ; atom may be unsubstituted or substituted hy a wide . variety of substituents, including acyl and ootio-nally substituted aminoalkyl radicals. Some of thecompounds are indicated to have local anesthetic activity, platelet aggregation inhibiting activity ~nd hvDoglycemic activity. Some of the compounds, _ although it is not clearly s~ecified in the patent which,are said to have central nervous system activity, e.g. anti-depressant activityO
, A ,,~, .
3~37~ -: - 2 - lO0-52 . All the examples of aminoalkyl comnounds specifically named in this U.S.Patent are characte-rised by a substituted amino group and~or a propy- ~-lene or tetramethvlene al~yl chain. The only example fully characterised has a 2-piperidinoethyl side chain~ and this is indicated to be an anti-de-pressant. The substituted amino and~or prooylene or tetramethylene alkyl_c ain compounds do not ~ _ _ _ _ _ _ _ _ _ _ _ _ _ _ - ~ossess in *act a satisfactor~ ~harmacolo-gical profile of a well tolerated antidepressant, e.g. they exhibit weak activity in at least one of ~he standard anti-depressant animal tests, e.g.
,the tetrabenazine ca~ale~sy and ptosis test, and/or are not very active noradrenaline, dopamine or 5-hydro~ytryptam_ne uptake inhibitors. hTe have now found that unsubstituted amino ethylene phenyl-indolines which are nowhere specifically disclosed or suggest~d in the above U.S. Patent have parti-cularly desirable properties as well tolerated .. 20 anti-depressant agents.
In particular the presen~ invention pro-vides a compound of formula I
.~
~, ~
.
., ;.
- , "~. .. , -: .
:, . . .
, ~ , .
, .
::
~3~3`7~1 - 3 ~ 100-5214 Rl ¦ R~
C~2CH;~ 2 wherein Rl and R2 independently are hydrogen, halogen of atomic number from 9 to 35, (Cl_4)alkyll (Cl_4) alkoxy, hydroxy, or trifluoromethyl, Rl' and R2' independently are hydrogen, halogen of atomic number from 9 to 35, (Cl_4)alkyl, ~ (Cl 4)alkoxy, or hydroxy, R2" is hydro~en or (Cl ~)alkoxy, with the proviso that, when R2" is alkoxy, then R2 and R2' are alkoxy, and ; R3 is hydrogen or (Cl 4)alkyl, and pharmaceutically acceptable acid a~.ition sal.ts thereof.
In formula I, alkvl and alkoxy contain pre-ferably 1 or ~, and especially 1, carbon atom.
Halogen is preferably chlorine or 1uorine, espe-cially chl.orine~ R3 is preferably hy~rogen~ Rl is ..
preferably in the 5 or 6 position of the in~oline '~ :
~ "
- .
.: . . - , ~ : . . j . .;: : :
::. :: . : : : . .:
~3~3~
- 4 ~ 100-5~14 nucleus. Rl and Rl' are conveniently other than chlorine in the 5 position of the indoline nucleus.
R2 is preferably in ~he meta or ~ara position~
The present invention provides additionally 5 a process for the production of a compound ~ for-mula I -w-h~c_ comD~r1ses~r ~ nd of fo~r-~ula II
n Il C~12CH2NH2 wherein Rl, Rl', R2, R2', R2" and R3 are as defined above, and where necessary converting the re~ulting comp-ound of foxmula I lnto a pharmaceutically acceptable acid additlon salt thereof.
The process may be effected in conventional manner or the reduction of an indole to an indoline.
For example the process may be effected with nascent hydrogen, e.g. with lithium, sodium, or potassium, in liquid ammorlia. Rreferably for halogen-containing compounds an alternative reduction using diborane or a complex borohydride, e~ g. NaBH4~BF3 or a borane/
dimethylsulphide com~lex ls effected.
. . . _ . .
,~ ~
. ~ :
, , , ~L3~L3~7~
~ 5 ~ 100-5214 The reduction in liquid ammonia may be ef ec-ted in the presence of an inert or~anic solvent such as an ethert e.g. tetrahydrofuran. Suitable temperatures may be fxom about -70~ C to about 30 C, preferably -40 to -30 C0 The reduction with boron compounds is conveniently effected like-wise in an organic solvent. Suitable reaction tem-peratures may be from about 0 C to the reflux temperature of the reac~ion mixture. Any resul~ant boron complex may be conveniently decomposed with acidt e.g. 4N-5N HCl.
The compounds may be isolated fxom the ,l ~reaction mixture and purified in conventional manner.
,) The compounds of fGr~la ~L~_~ may exist in the form of optical isomers or racemates. t~en R3 is alkyl, ~he compounds may exist ln diastereoisomeric forms.
~ The individual optical isomers and diastereoisomers ; may be obtained in conv~ntional manner, e.g. by fractional crystallization of salt forms with appro-; 20 priate acids.
Free base forms of the comDounds of =
ormula I may be converted into acid addition salt forms in conventional manner~ and vice versa. Sui-table acids for salt formation irclude the hydro .
, - -. -3~3 ~ ;
- 6 - ~00-5~14 chloric, maleic, f~aric, cyclohexylsul~nic, an~
naphthalen-1,5-disulphonic acids.
The starting material of foxmula II may be produced in conventional manner, e.g. from ~he S compound of formula III, ~2 H
wherein - ---R~, Rl', R2, R2', R2~ and R3 are as defined above~
~y introducing the ~roup--CH2CONH2 or -CH2C~.~ into a compound of formula III (e.g. with Hal-CH2CO~H2 or Hal-CH2CN) and reducing the resultant amide or nitrile to the amineO
Insofar as the production of any startin~
material is not particularly describea these are known or may be produced in analogous manner to known compounds or to processes described herein.
In the following examples all temperatures ;are in degrees Centigrade and are uncorrected.
In the tables the mel~ing 2oin~ refers to the hydrogen maleate salt form exceDt wnen _ther--wl-se s~ated, e.g~
, ~ . .. . _ . ..
l.,~, ' ,,, . - I .
~. .
- ~3~7~
_ 7 _ 1oo-s2l4 ~ -~ ' .
1) hydrogen fumarate
~3~3`~i~
100-5214 ~ -INDOLINE DERIVATIVES, THEIR PRODUCTIO~ AND P.~ ~A-CEUTICAL COMPOSITIO~S CO~fTAINING THEM
This invention relates to indoline derivati-ves, their production and pharmaceutical compositions containing them.
~ .S.P. 4,080/330 discloses a class of 2-unsubstituted-3-ohenylindolines ~Iherein the indoline nucleus may be substituted in the phenyl ring in the 5, 6 or 7 position. The ~henyl ring of the in- ~
10 doline nucleus and the exocyclic phenyl ring in the '!;
3 uosition may be monosubs~ituted by halogen, I lower alkoxy or lower alkyl~ The indoline nitrogen ; atom may be unsubstituted or substituted hy a wide . variety of substituents, including acyl and ootio-nally substituted aminoalkyl radicals. Some of thecompounds are indicated to have local anesthetic activity, platelet aggregation inhibiting activity ~nd hvDoglycemic activity. Some of the compounds, _ although it is not clearly s~ecified in the patent which,are said to have central nervous system activity, e.g. anti-depressant activityO
, A ,,~, .
3~37~ -: - 2 - lO0-52 . All the examples of aminoalkyl comnounds specifically named in this U.S.Patent are characte-rised by a substituted amino group and~or a propy- ~-lene or tetramethvlene al~yl chain. The only example fully characterised has a 2-piperidinoethyl side chain~ and this is indicated to be an anti-de-pressant. The substituted amino and~or prooylene or tetramethylene alkyl_c ain compounds do not ~ _ _ _ _ _ _ _ _ _ _ _ _ _ _ - ~ossess in *act a satisfactor~ ~harmacolo-gical profile of a well tolerated antidepressant, e.g. they exhibit weak activity in at least one of ~he standard anti-depressant animal tests, e.g.
,the tetrabenazine ca~ale~sy and ptosis test, and/or are not very active noradrenaline, dopamine or 5-hydro~ytryptam_ne uptake inhibitors. hTe have now found that unsubstituted amino ethylene phenyl-indolines which are nowhere specifically disclosed or suggest~d in the above U.S. Patent have parti-cularly desirable properties as well tolerated .. 20 anti-depressant agents.
In particular the presen~ invention pro-vides a compound of formula I
.~
~, ~
.
., ;.
- , "~. .. , -: .
:, . . .
, ~ , .
, .
::
~3~3`7~1 - 3 ~ 100-5214 Rl ¦ R~
C~2CH;~ 2 wherein Rl and R2 independently are hydrogen, halogen of atomic number from 9 to 35, (Cl_4)alkyll (Cl_4) alkoxy, hydroxy, or trifluoromethyl, Rl' and R2' independently are hydrogen, halogen of atomic number from 9 to 35, (Cl_4)alkyl, ~ (Cl 4)alkoxy, or hydroxy, R2" is hydro~en or (Cl ~)alkoxy, with the proviso that, when R2" is alkoxy, then R2 and R2' are alkoxy, and ; R3 is hydrogen or (Cl 4)alkyl, and pharmaceutically acceptable acid a~.ition sal.ts thereof.
In formula I, alkvl and alkoxy contain pre-ferably 1 or ~, and especially 1, carbon atom.
Halogen is preferably chlorine or 1uorine, espe-cially chl.orine~ R3 is preferably hy~rogen~ Rl is ..
preferably in the 5 or 6 position of the in~oline '~ :
~ "
- .
.: . . - , ~ : . . j . .;: : :
::. :: . : : : . .:
~3~3~
- 4 ~ 100-5~14 nucleus. Rl and Rl' are conveniently other than chlorine in the 5 position of the indoline nucleus.
R2 is preferably in ~he meta or ~ara position~
The present invention provides additionally 5 a process for the production of a compound ~ for-mula I -w-h~c_ comD~r1ses~r ~ nd of fo~r-~ula II
n Il C~12CH2NH2 wherein Rl, Rl', R2, R2', R2" and R3 are as defined above, and where necessary converting the re~ulting comp-ound of foxmula I lnto a pharmaceutically acceptable acid additlon salt thereof.
The process may be effected in conventional manner or the reduction of an indole to an indoline.
For example the process may be effected with nascent hydrogen, e.g. with lithium, sodium, or potassium, in liquid ammorlia. Rreferably for halogen-containing compounds an alternative reduction using diborane or a complex borohydride, e~ g. NaBH4~BF3 or a borane/
dimethylsulphide com~lex ls effected.
. . . _ . .
,~ ~
. ~ :
, , , ~L3~L3~7~
~ 5 ~ 100-5214 The reduction in liquid ammonia may be ef ec-ted in the presence of an inert or~anic solvent such as an ethert e.g. tetrahydrofuran. Suitable temperatures may be fxom about -70~ C to about 30 C, preferably -40 to -30 C0 The reduction with boron compounds is conveniently effected like-wise in an organic solvent. Suitable reaction tem-peratures may be from about 0 C to the reflux temperature of the reac~ion mixture. Any resul~ant boron complex may be conveniently decomposed with acidt e.g. 4N-5N HCl.
The compounds may be isolated fxom the ,l ~reaction mixture and purified in conventional manner.
,) The compounds of fGr~la ~L~_~ may exist in the form of optical isomers or racemates. t~en R3 is alkyl, ~he compounds may exist ln diastereoisomeric forms.
~ The individual optical isomers and diastereoisomers ; may be obtained in conv~ntional manner, e.g. by fractional crystallization of salt forms with appro-; 20 priate acids.
Free base forms of the comDounds of =
ormula I may be converted into acid addition salt forms in conventional manner~ and vice versa. Sui-table acids for salt formation irclude the hydro .
, - -. -3~3 ~ ;
- 6 - ~00-5~14 chloric, maleic, f~aric, cyclohexylsul~nic, an~
naphthalen-1,5-disulphonic acids.
The starting material of foxmula II may be produced in conventional manner, e.g. from ~he S compound of formula III, ~2 H
wherein - ---R~, Rl', R2, R2', R2~ and R3 are as defined above~
~y introducing the ~roup--CH2CONH2 or -CH2C~.~ into a compound of formula III (e.g. with Hal-CH2CO~H2 or Hal-CH2CN) and reducing the resultant amide or nitrile to the amineO
Insofar as the production of any startin~
material is not particularly describea these are known or may be produced in analogous manner to known compounds or to processes described herein.
In the following examples all temperatures ;are in degrees Centigrade and are uncorrected.
In the tables the mel~ing 2oin~ refers to the hydrogen maleate salt form exceDt wnen _ther--wl-se s~ated, e.g~
, ~ . .. . _ . ..
l.,~, ' ,,, . - I .
~. .
- ~3~7~
_ 7 _ 1oo-s2l4 ~ -~ ' .
1) hydrogen fumarate
2) bis [base~ fumarate
3~ base
4) hydrochlorlde ; Other ab~reviations:~
5) Decomposi~ion point starting at a~out temperature gi~en Diastereoisomeric isomer ', ~
'' ' "~ , " ";,,- ,~ , -:: : : : , ~3~3~ I
~ ~ ~ 100-5214 EXAMPLE 1: 1--(2-aminoe~hvl~-3-ohenYlindolil~e A solution of 34.7 g 1-(2-~minoethyl)-3-phenylindole in 300 ml ~etrahydrofuran is dropDed into a solution of 17 g sodium in li~ui2 am~onia.
After a further 30 minutes the sodium excess is decomposed by the addition of solid ammonium chlo-rideO The ammonia is e~a~orat~d off to give the title com~ound. M.pt. (hydrogen maleate) 169 170, (from ethanolj.
. The starting material is produced as follows:-a~ A solution of 100 g 3-ohenylindole in 350 ml dimethylfonmamide is dropPed into a suspension of 22.7 g sodium hydride (55 ~ hy weight in oil) in 350 ml dimethylformami2e. After hydrogen for-mation has finished, 73 g solid chloroacetamide are added. The mixtuxe is stirred for 17 hours at room temDerature, and poured onto ice-water causing 3-Phenylindolyl-l-acetamide t~ preci-pita~e (M.pt. 20~202 from CH2C12).
~0 b) A solution of 1~.4 ml conc. H2SO~ in 200 ml ketrahydrofuran is added dropwise to 5d~ 6 g lithium aluminium hydride in 1 litre tetra-hydrofuran at -30. The mixture is allo~e2 to warm to 0, then treated drop~lise with a sus-" ~
, 'L, . .
... . , . _ . . . _ . , . ... . . _ . . _ . . _ _ _ . _ _ : : -- _ _ _ _ _, . _ ;. ' ' . ' :
t ' ` - : . ' : : ~:
. ,' ' ' ' ~L~3~3~
9 - 100~5214 pension of 90.2 g 3-phenylindolyl-1-acetamide in 700 ml tetrahydrofuran and s~irred thereafter for 2 hours at room tem~era~ure. The resultant 1-(2-aminoethyl) 3-phenylindole melts at 268 ~o 270~
'~~- t~ydrochloride~salt for~m)~ -In analogous manner compounds wherein Rl' ~ :
~2' = R2~ = P3 = H may bs made as folLows:-;-, .
;~
~ .
.:
~ ~3~
- 10 - 1S~5214 -~
, .
. - .. , _.... . ,.............. ~_ ~ .. .... - -Ex Rl R2 M~pt No .. .~ __~
~ ' 5~F ~ 1~3--144 - . . , 7-F H 180-183~
. ~, 7-Cl ~ 177-180 . 7-CH3 ~ 188--190
'' ' "~ , " ";,,- ,~ , -:: : : : , ~3~3~ I
~ ~ ~ 100-5214 EXAMPLE 1: 1--(2-aminoe~hvl~-3-ohenYlindolil~e A solution of 34.7 g 1-(2-~minoethyl)-3-phenylindole in 300 ml ~etrahydrofuran is dropDed into a solution of 17 g sodium in li~ui2 am~onia.
After a further 30 minutes the sodium excess is decomposed by the addition of solid ammonium chlo-rideO The ammonia is e~a~orat~d off to give the title com~ound. M.pt. (hydrogen maleate) 169 170, (from ethanolj.
. The starting material is produced as follows:-a~ A solution of 100 g 3-ohenylindole in 350 ml dimethylfonmamide is dropPed into a suspension of 22.7 g sodium hydride (55 ~ hy weight in oil) in 350 ml dimethylformami2e. After hydrogen for-mation has finished, 73 g solid chloroacetamide are added. The mixtuxe is stirred for 17 hours at room temDerature, and poured onto ice-water causing 3-Phenylindolyl-l-acetamide t~ preci-pita~e (M.pt. 20~202 from CH2C12).
~0 b) A solution of 1~.4 ml conc. H2SO~ in 200 ml ketrahydrofuran is added dropwise to 5d~ 6 g lithium aluminium hydride in 1 litre tetra-hydrofuran at -30. The mixture is allo~e2 to warm to 0, then treated drop~lise with a sus-" ~
, 'L, . .
... . , . _ . . . _ . , . ... . . _ . . _ . . _ _ _ . _ _ : : -- _ _ _ _ _, . _ ;. ' ' . ' :
t ' ` - : . ' : : ~:
. ,' ' ' ' ~L~3~3~
9 - 100~5214 pension of 90.2 g 3-phenylindolyl-1-acetamide in 700 ml tetrahydrofuran and s~irred thereafter for 2 hours at room tem~era~ure. The resultant 1-(2-aminoethyl) 3-phenylindole melts at 268 ~o 270~
'~~- t~ydrochloride~salt for~m)~ -In analogous manner compounds wherein Rl' ~ :
~2' = R2~ = P3 = H may bs made as folLows:-;-, .
;~
~ .
.:
~ ~3~
- 10 - 1S~5214 -~
, .
. - .. , _.... . ,.............. ~_ ~ .. .... - -Ex Rl R2 M~pt No .. .~ __~
~ ' 5~F ~ 1~3--144 - . . , 7-F H 180-183~
. ~, 7-Cl ~ 177-180 . 7-CH3 ~ 188--190
6 H o-Cl 172--176 ~
7, H m-Cl 175-178~
10 E ' H - p-Cl 1~ 8-170 ~: ~ ~ 4-Cl H 171 173 6--Cl H - ~ 6 2--16 4 1i 1 H Jn-CF3 172--177 . . .. .. .. _~... . . .
.12, R o-F ~ 5g--163 15 13 ~ m-F 154-157 p_~ ~54-159 1,5, 5-C~1 ~ 154-156 16 ~ S-OCH3 H 156--158 17 , 6-F ~ 1 30-134 ;!018 4~F H . 170--172 19 S-OH }I 16 B-170 2~ 6 Cl m-Cl 155-158 21 6-Cl p-F 28004 ~ 5) . ~ 2 2 6-F p-F 16 6--16 7 ~
25 23 5_07~ m-Cl 182-185 2 ~ S-OH p--F lg 3--19 7 . J`~
... .... . .
. . . :; ; ~, :: : . -3~3`~0 ~ 11 -- - 10C)--5214 . .
. __ .. _ _ , _ .
Ex R R2 M . pk .
- ~CI 1 :25 G-F m-Cl . 208-210'' ~ J
. 26 ' ~-O~I ~ . 172-1753) 2J, H m-OH .135-139 2 . ~I p-OH 182--185 . , . ~ p-CF3 16 4--16 7 : 30 . 6--CF3 H . 176-179 31, 4 -t^F H . ~ .19 5 _ 19 8 4 ) . 32 1 5-Br H 168-170 ' 33 ~ ~ 3 ~1 ~60-1~54) 3~. . ~ p~OCH3 7 ~ 0 3 ) 35 t ~ m OC~3 '~75-177 36, 5-OCH3 p-F 130-13~ -7: m-C I _ ~_ ~ 4 - ... , ;.
' .
` ' . ~
,~ . ~;.
,~, , .
` , . , , ' ' '- :~
.3~3 ~
- 12 - 100-5214 _ - :
.q'ABLE 2 _ In analogous rnanner t:he ~ollowing com~oun~s wherein R ' and R " = H may be maaeO
: ~ ~
Ex Rl R2 R2 ' R3 M . ~t .
3 8 H . H CH3 19 4 -19 7 ) 39 H E~ H CH3 17~-181 - . . 40 _ _ ~Cl p-Cl - H 12 B- 132 -.
_ ', ., ' , :
- ' _ .` ~:
i~ ' ' , '''~
'':'' : ~
' ~3~3~7~
~ 13 - 100-5214 The compounds o~ f~rmula I exhibit pharma-cological activity in animals, in particular an-ti-depressant activity, as indicated by an inhibition of ptosis and catalepsy induced by tetrabenazine in rats o~ i.p. administration of 1 to 50 mg/kg of the compounds.
Furthermore the comoounds lnhibit the in vitro uptake of noradrenaline and serotonin into rat cortical slices and of dopamine into rat striatal lC slices, as indicated in standard tests. These tests have been carried out according to the princi~les of A~ I o Salama et al., JO Pharmacol. Exp. Ther. 178, 474-481, 1971. The in vitro noradrenaline and sero-~onin uptake was tested as follows:
~lale ra~s were killed by decapitation and the brains quickly removed. The cortices were re-moved and 0~4 mm slices were cut from the parietal ~ area. These were the~ placed in incubation flasks, ; wi~h slices from one hal~ of a brain as control and slices from the other half being used ~or treatment. Both flasks contained 2.975 ml oxycarb-,~ saturated Krebs-~Eenseleit solution pH 7.4, with the test drug (initially 5 ~g/mlj bëing added to one. Arter pre-incubation for 10 minutes at 37 C--25 ~l_of a solution~of_3~-noradrenaline or ,.
.
, ~
,.; - . ~
.~. :;:. : :.:
~iO 3~370!
14 - 1~0-5214 25 ~1 of 3H-serotonin was added to ~ive a fina~
concentration of 3H-noradrenaline of 11.3 nMI or ; - 6.6 nM 3H-serotonin. After incubation for a further lS minutes the solutions were replaced with fresh Rrebs-Henseleit solution and post~incubation con~
tinued for a further 10 minutes. After centrifuga ;~
~tion the slices were washed with 1 ml 0~9 ~ sodium chloride, dissolved in 1 ml ~5 % formic a~id at 60 C and the retained 3H-noradrenaline or 3H-serotonin estimated by scintillation counting.
The in vitro dopamine uptake into rat stria-tum was examîned as follo~s:-Male rats were killed by decapitation andthe striata guickly dissected out on an ice-cold surface. The two striata were chopped into 0~4 ~m slices. ~Xe sllces ~~x-o-m~each~s-t~rlatum ~ere then i~mer-sed in 2.975 ml oxycarbsaturated Krebs-Henseleit solution. The test subs~ance(initially 10 ~s~ml) was added to one incubation tube, the other served as control~ After pre-incubation for 10 minutes at 37 ~5 ~1 of 3H dopamine were then added to give a final 3H dopamine concentration of 1.68 nM. After incubation for a further 15 minutes the excess dopamine was removed with fresh Krebs-Henseleit solution and ~he mixture pos~-incubated ~or a fux ~, .. .
, . .: :
..
~L3~3~
- 15 - 100~5214 ther 10 minutes. After centrifugation the super-nates were discarded~ the residual slices washed with 1 ml 0.9 % sodium chloride and then dissolved in 1 ml ~5 ~ formic acid. The retained radioactivity was determined by scintillation counting.
The compounds of formula I inhibit noradre-naline, serotonin and dopamine u~take at rom about 5 to about 20,000 nM.
The compounds are therefore indicated for use as anti-depressant agents. For this indication an indicated daily dose is from 1 to 300 mg, convenien~
tly administered in divided doses 2 to 4 times a day in unit dosage form containing from 0.25 to 150 mg ; (e.y. 1.5 to 75 mg), or in susta~ned release form.
I'he compounds of formula I may be administered in pharmaceutically acceptable acid addition salt Eorm. Such acid addition salt forms exhibit 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 pharmaceutically acceptable acid addition salt form, in association with a pharmaceutical carrier or diluent.
The compound of Examples 1 and 2q exhibits part- ;
icularly interestina properties.
::
~3~3'~
In one group o compounds of formula I R2 is hydrogen, halogen, alko~y, hydroxy or trifluoro-- methyl, Rl' and ~2" are each hydrogen, and R2' is hydrogen ox halogen.
In another gxoup of compounds o formula I
~2' and R2 n are each hydrogen~
.
.
~ ' ~
. .
,. ~.
.. . .
.,. ~ , : :
.. ~ :
:
10 E ' H - p-Cl 1~ 8-170 ~: ~ ~ 4-Cl H 171 173 6--Cl H - ~ 6 2--16 4 1i 1 H Jn-CF3 172--177 . . .. .. .. _~... . . .
.12, R o-F ~ 5g--163 15 13 ~ m-F 154-157 p_~ ~54-159 1,5, 5-C~1 ~ 154-156 16 ~ S-OCH3 H 156--158 17 , 6-F ~ 1 30-134 ;!018 4~F H . 170--172 19 S-OH }I 16 B-170 2~ 6 Cl m-Cl 155-158 21 6-Cl p-F 28004 ~ 5) . ~ 2 2 6-F p-F 16 6--16 7 ~
25 23 5_07~ m-Cl 182-185 2 ~ S-OH p--F lg 3--19 7 . J`~
... .... . .
. . . :; ; ~, :: : . -3~3`~0 ~ 11 -- - 10C)--5214 . .
. __ .. _ _ , _ .
Ex R R2 M . pk .
- ~CI 1 :25 G-F m-Cl . 208-210'' ~ J
. 26 ' ~-O~I ~ . 172-1753) 2J, H m-OH .135-139 2 . ~I p-OH 182--185 . , . ~ p-CF3 16 4--16 7 : 30 . 6--CF3 H . 176-179 31, 4 -t^F H . ~ .19 5 _ 19 8 4 ) . 32 1 5-Br H 168-170 ' 33 ~ ~ 3 ~1 ~60-1~54) 3~. . ~ p~OCH3 7 ~ 0 3 ) 35 t ~ m OC~3 '~75-177 36, 5-OCH3 p-F 130-13~ -7: m-C I _ ~_ ~ 4 - ... , ;.
' .
` ' . ~
,~ . ~;.
,~, , .
` , . , , ' ' '- :~
.3~3 ~
- 12 - 100-5214 _ - :
.q'ABLE 2 _ In analogous rnanner t:he ~ollowing com~oun~s wherein R ' and R " = H may be maaeO
: ~ ~
Ex Rl R2 R2 ' R3 M . ~t .
3 8 H . H CH3 19 4 -19 7 ) 39 H E~ H CH3 17~-181 - . . 40 _ _ ~Cl p-Cl - H 12 B- 132 -.
_ ', ., ' , :
- ' _ .` ~:
i~ ' ' , '''~
'':'' : ~
' ~3~3~7~
~ 13 - 100-5214 The compounds o~ f~rmula I exhibit pharma-cological activity in animals, in particular an-ti-depressant activity, as indicated by an inhibition of ptosis and catalepsy induced by tetrabenazine in rats o~ i.p. administration of 1 to 50 mg/kg of the compounds.
Furthermore the comoounds lnhibit the in vitro uptake of noradrenaline and serotonin into rat cortical slices and of dopamine into rat striatal lC slices, as indicated in standard tests. These tests have been carried out according to the princi~les of A~ I o Salama et al., JO Pharmacol. Exp. Ther. 178, 474-481, 1971. The in vitro noradrenaline and sero-~onin uptake was tested as follows:
~lale ra~s were killed by decapitation and the brains quickly removed. The cortices were re-moved and 0~4 mm slices were cut from the parietal ~ area. These were the~ placed in incubation flasks, ; wi~h slices from one hal~ of a brain as control and slices from the other half being used ~or treatment. Both flasks contained 2.975 ml oxycarb-,~ saturated Krebs-~Eenseleit solution pH 7.4, with the test drug (initially 5 ~g/mlj bëing added to one. Arter pre-incubation for 10 minutes at 37 C--25 ~l_of a solution~of_3~-noradrenaline or ,.
.
, ~
,.; - . ~
.~. :;:. : :.:
~iO 3~370!
14 - 1~0-5214 25 ~1 of 3H-serotonin was added to ~ive a fina~
concentration of 3H-noradrenaline of 11.3 nMI or ; - 6.6 nM 3H-serotonin. After incubation for a further lS minutes the solutions were replaced with fresh Rrebs-Henseleit solution and post~incubation con~
tinued for a further 10 minutes. After centrifuga ;~
~tion the slices were washed with 1 ml 0~9 ~ sodium chloride, dissolved in 1 ml ~5 % formic a~id at 60 C and the retained 3H-noradrenaline or 3H-serotonin estimated by scintillation counting.
The in vitro dopamine uptake into rat stria-tum was examîned as follo~s:-Male rats were killed by decapitation andthe striata guickly dissected out on an ice-cold surface. The two striata were chopped into 0~4 ~m slices. ~Xe sllces ~~x-o-m~each~s-t~rlatum ~ere then i~mer-sed in 2.975 ml oxycarbsaturated Krebs-Henseleit solution. The test subs~ance(initially 10 ~s~ml) was added to one incubation tube, the other served as control~ After pre-incubation for 10 minutes at 37 ~5 ~1 of 3H dopamine were then added to give a final 3H dopamine concentration of 1.68 nM. After incubation for a further 15 minutes the excess dopamine was removed with fresh Krebs-Henseleit solution and ~he mixture pos~-incubated ~or a fux ~, .. .
, . .: :
..
~L3~3~
- 15 - 100~5214 ther 10 minutes. After centrifugation the super-nates were discarded~ the residual slices washed with 1 ml 0.9 % sodium chloride and then dissolved in 1 ml ~5 ~ formic acid. The retained radioactivity was determined by scintillation counting.
The compounds of formula I inhibit noradre-naline, serotonin and dopamine u~take at rom about 5 to about 20,000 nM.
The compounds are therefore indicated for use as anti-depressant agents. For this indication an indicated daily dose is from 1 to 300 mg, convenien~
tly administered in divided doses 2 to 4 times a day in unit dosage form containing from 0.25 to 150 mg ; (e.y. 1.5 to 75 mg), or in susta~ned release form.
I'he compounds of formula I may be administered in pharmaceutically acceptable acid addition salt Eorm. Such acid addition salt forms exhibit 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 pharmaceutically acceptable acid addition salt form, in association with a pharmaceutical carrier or diluent.
The compound of Examples 1 and 2q exhibits part- ;
icularly interestina properties.
::
~3~3'~
In one group o compounds of formula I R2 is hydrogen, halogen, alko~y, hydroxy or trifluoro-- methyl, Rl' and ~2" are each hydrogen, and R2' is hydrogen ox halogen.
In another gxoup of compounds o formula I
~2' and R2 n are each hydrogen~
.
.
~ ' ~
. .
,. ~.
.. . .
.,. ~ , : :
.. ~ :
:
Claims (6)
1. A process for the production of a compound of formula I
I
wherein R1 and R2 independently are hydrogen, halogen of atomic number from g to 35, (C1-4)alkyl, (C1-4) alkoxy, hydroxy, or trifluoromethyl, R1' and R2' independently are hydrogen, halogen of atomic number from 9 to 35, (C1-4)alkyl, (C1-4)alkoxy, or hydroxy, R2" is hydrogen or (C1-4)alkoxy, with the proviso that, when R2" is alkoxy, then R2 and R2' are alkoxy, and R3 is hydrogen or (C1-4)alkyl or a pharmaceutically acceptable acid addition salt thereof, which comprises reducing a compound of formula II
II
wherein R1, R1', R2, R2', R2" and R3 are as defined above, and where necessary converting the resulting compound of formula I into a pharmaceutically acceptable acid addition salt thereof.
I
wherein R1 and R2 independently are hydrogen, halogen of atomic number from g to 35, (C1-4)alkyl, (C1-4) alkoxy, hydroxy, or trifluoromethyl, R1' and R2' independently are hydrogen, halogen of atomic number from 9 to 35, (C1-4)alkyl, (C1-4)alkoxy, or hydroxy, R2" is hydrogen or (C1-4)alkoxy, with the proviso that, when R2" is alkoxy, then R2 and R2' are alkoxy, and R3 is hydrogen or (C1-4)alkyl or a pharmaceutically acceptable acid addition salt thereof, which comprises reducing a compound of formula II
II
wherein R1, R1', R2, R2', R2" and R3 are as defined above, and where necessary converting the resulting compound of formula I into a pharmaceutically acceptable acid addition salt thereof.
2. A compound of formula I, or a pharmaceuti-cally acceptable acid addition salt thereof, whenever produced by a process according to claim 1, or an obvious chemical equivalent thereof.
3. A process according to claim 1 for the produc-tion of 1-(2-aminoethyl)-3-phenylincloline or a pharma-ceutically acceptable acid addition salt thereof, which comprises reducing l-(2-aminoethyl)-3-phenylindole, and where necessary converting the resulting compound into a pharmaceutically acceptable acid addition salt thereof.
4. l-(2-Aminoethyl)-3-phenylindoline, or a phar-maceutically acceptable acid addition salt thereof, whenever produced by a process according to claim 3, or an obvious chemical equivalent thereof.
5. A process according to claim 1 for the produc-tion of 1-(2 aminoethyl)-3-(p-trifluoromethylphenyl) indoline or a pharmaceutically acceptable acid addi-tion salt thereof, which comprises reducing 1-(2-amino-ethyl)-3-(p-trifluoromethylphenyl)indole, and where necessary converting the resulting compound into a pharmaceutically acceptable acid addition salt thereof.
6. 1-(2-Aminoethyl)-3-(p-trifluoromethylphenyl) indoline, or a pharmaceutically acceptable acid addi-tion salt thereof, whenever produced by a process according to claim 5, or an obvious chemical eaui-valent thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH609879 | 1979-06-29 | ||
| CH6098/79 | 1979-06-29 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1134370A true CA1134370A (en) | 1982-10-26 |
Family
ID=4304237
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000354967A Expired CA1134370A (en) | 1979-06-29 | 1980-06-27 | Indoline derivatives, their production and pharmaceutical composition containing them |
Country Status (16)
| Country | Link |
|---|---|
| JP (1) | JPS568363A (en) |
| AU (1) | AU5973980A (en) |
| BE (1) | BE884013A (en) |
| CA (1) | CA1134370A (en) |
| DE (1) | DE3022648A1 (en) |
| DK (1) | DK280380A (en) |
| ES (1) | ES492884A0 (en) |
| FI (1) | FI802002A (en) |
| FR (2) | FR2460296A1 (en) |
| GB (1) | GB2051811B (en) |
| IL (1) | IL60420A (en) |
| IT (1) | IT8049093A0 (en) |
| NL (1) | NL8003674A (en) |
| PT (1) | PT71465B (en) |
| SE (1) | SE8004757L (en) |
| ZA (1) | ZA803888B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW270114B (en) * | 1993-10-22 | 1996-02-11 | Hoffmann La Roche | |
| US6265403B1 (en) * | 1999-01-20 | 2001-07-24 | Merck & Co., Inc. | Angiogenesis inhibitors |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK96884C (en) * | 1959-09-14 | 1963-09-16 | Dumex Ltd As | Process for the preparation of indole derivatives or their salts. |
| US4080330A (en) * | 1975-06-23 | 1978-03-21 | Delmar Chemicals Limited | Phenylindolines and process for their production |
-
1980
- 1980-06-18 DE DE19803022648 patent/DE3022648A1/en not_active Withdrawn
- 1980-06-23 FI FI802002A patent/FI802002A/en not_active Application Discontinuation
- 1980-06-25 GB GB8020753A patent/GB2051811B/en not_active Expired
- 1980-06-25 NL NL8003674A patent/NL8003674A/en not_active Application Discontinuation
- 1980-06-26 BE BE1/9865A patent/BE884013A/en not_active IP Right Cessation
- 1980-06-27 ZA ZA00803888A patent/ZA803888B/en unknown
- 1980-06-27 AU AU59739/80A patent/AU5973980A/en not_active Abandoned
- 1980-06-27 PT PT71465A patent/PT71465B/en unknown
- 1980-06-27 FR FR8014348A patent/FR2460296A1/en active Granted
- 1980-06-27 IT IT8049093A patent/IT8049093A0/en unknown
- 1980-06-27 DK DK280380A patent/DK280380A/en not_active Application Discontinuation
- 1980-06-27 IL IL60420A patent/IL60420A/en unknown
- 1980-06-27 CA CA000354967A patent/CA1134370A/en not_active Expired
- 1980-06-27 SE SE8004757A patent/SE8004757L/en not_active Application Discontinuation
- 1980-06-27 ES ES492884A patent/ES492884A0/en active Granted
- 1980-06-28 JP JP8845180A patent/JPS568363A/en active Pending
-
1982
- 1982-11-08 FR FR8218841A patent/FR2514352A1/fr not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| FI802002A (en) | 1980-12-30 |
| BE884013A (en) | 1980-12-29 |
| ES8105284A1 (en) | 1981-06-01 |
| GB2051811B (en) | 1983-11-23 |
| ES492884A0 (en) | 1981-06-01 |
| NL8003674A (en) | 1980-12-31 |
| JPS568363A (en) | 1981-01-28 |
| PT71465A (en) | 1980-07-01 |
| SE8004757L (en) | 1980-12-30 |
| AU5973980A (en) | 1981-01-08 |
| FR2514352A1 (en) | 1983-04-15 |
| GB2051811A (en) | 1981-01-21 |
| FR2460296A1 (en) | 1981-01-23 |
| DK280380A (en) | 1980-12-30 |
| IT8049093A0 (en) | 1980-06-27 |
| IL60420A (en) | 1983-10-31 |
| IL60420A0 (en) | 1980-09-16 |
| FR2460296B1 (en) | 1983-08-05 |
| DE3022648A1 (en) | 1981-01-15 |
| PT71465B (en) | 1981-07-03 |
| ZA803888B (en) | 1982-02-24 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Sugiura et al. | Syntheses and antiinflammatory and hypnotic activity of 5-alkoxy-3-(N-substituted carbamoyl)-1-phenylpyrazoles. 4 | |
| SU1482522A3 (en) | Method of producing substituted 1-(1-phenylcyclobutyl)-alkylamines or their pharmaceutically acceptable salts | |
| US5494928A (en) | Indole derivatives | |
| GB2124210A (en) | Indoles | |
| CA2110574A1 (en) | Tryptamine analogues, their synthesis and their use as 5-ht1-like or 5-ht2 receptor agonists | |
| CA1161047A (en) | Process for preparing 2(3h)-indolones | |
| US4217349A (en) | Benzisoxazole derivatives | |
| CA1098909A (en) | Indolyloxy-aminopropanol derivatives | |
| US4086353A (en) | Certain azolinylamino (azolidinylimino) indazoles | |
| CA1125657A (en) | Derivatives of 1,2,3,3a,8,8a-hexadydropyrrolo ¬2,3-b| indole | |
| EP0028381B1 (en) | Azepinoindoles, process for their production and pharmaceutical compositions containing them | |
| CA1134370A (en) | Indoline derivatives, their production and pharmaceutical composition containing them | |
| GB2120662A (en) | New azepinoindoles, their production and pharmaceutical compositions containing them | |
| CA1086315A (en) | Morphanthridine derivatives | |
| EP0000355B1 (en) | New indole derivatives, processes for their preparation, and pharmaceutical compositions containing them. | |
| US4258059A (en) | Amino-benzamides | |
| IE61511B1 (en) | Beta-alkylmelatonins | |
| US4057560A (en) | 1,2,2A,3,4,5 Hexahydrobenz[c,d]indol-1-yl-2-guanidines | |
| US3420823A (en) | Dibenzothiazines | |
| IE913005A1 (en) | Indolonaphthyridines | |
| Lunsford et al. | Preparation of 4-Amino-1-butanols and Some Derivatives of Pharmacological Interest | |
| US4208410A (en) | Dibenzo[d,g][1,3,6]dioxazocine derivatives | |
| AU9446898A (en) | 8-azabicyclo (3.2.1) octane-3-methanamine derivatives as ligands of D2 and D3 dopamine and 5HT1A and 5HT2 serotonin receptors | |
| GB1562825A (en) | N-(2-(5-methoxa-6-halo-indol-3-yl)-ethyl)-amides methods for their preparation and their use | |
| CA1137489A (en) | Derivatives of 1,2,3,3a,8,8a-hexadydropyrrolo (2,3-b) indole |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |