CA1114381A - Process for production of indole derivatives - Google Patents
Process for production of indole derivativesInfo
- Publication number
- CA1114381A CA1114381A CA307,174A CA307174A CA1114381A CA 1114381 A CA1114381 A CA 1114381A CA 307174 A CA307174 A CA 307174A CA 1114381 A CA1114381 A CA 1114381A
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- Prior art keywords
- alkyl
- formula
- compound
- hydrogen
- phenyl
- Prior art date
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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
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- 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
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
- C07D209/16—Tryptamines
-
- 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
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Cardiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Abstract of the Invention The invention provides indole compounds useful for the treatment of hypertension, processes for the preparation of said compounds and pharmaceutical compositions containing these compounds.
The compounds of the invention have the formula
The compounds of the invention have the formula
Description
~ 3~ D~ 100-4838 PROCESS FOR PRODUCTION OF INDOLE DERIVATIVES
The present invention relates to new indole derivates, processes for their preparation, and pharmaceuti~al compositions containing them.
In accordance with the inventionthere are provided ne~ co~pounds of formula I
R2 Rl tI) S wherein n is 2 or 3, either A is trimethylene optionally substituted by (Cl 4) alkyl or 1,4-cyclohexylidene and R is hydrogen or (C 5) alkyl, ; or A together with Rl and the nitrogen atom to which Rl is bound, form a 4-piperidyl radical, R2 is hydrogen or (Cl 5) alkyl, 3 is (Cl 4) alkyl; (C3 6)cycloalkyl; amino;
(Cl 4)alkylamino; ditCl 4~alkylamino; l;
phenylamino wherein the phenyl ring is .
.: -:. : . : :
~ ~ - 100-4838 unsubstituted or mono-, di- or trisubstituted independently by halogen, tCl 4)alkyl, (Cl 4)alkoxy or di(Cl 4)alkylamino; phenyl or benzyl wherein the phenyl rings are unsubstituted or mono-, di- or trisubsti-tuted independently by halogen, hydroxy, (Cl 4)alkyl, (C~ 4)alkoxy or di-(Cl 4)alkyl-amino; 2-,3~ or 4-pyridylmethyl;or an aromatic 5- or 6-membered heterocycle containing one heteroatom chosen from nitrogen, oxygen or sul-phur and optionally additional one or two nitro-gen atoms, R4 is hydrogen, chlorine, bromine or (Cl 4)alkyl, R5 is hydrogen, (Cl_4)alkyl~ (Cl_4)alkxY
or (Cl 4)alkylthio, and X i~ -C0- or -CS-~ and pharma~eutically acceptable acid addition salts thereof.
hny alkyl, alkoxy or alkylthio radical contains preferably two car~on atoms, especially one carbon atom. Halogen means fluorine, chlorine, bromine or iodine, especially chlorine.
When A is 1,4-cyclohexylidene, this may be c~s or trans-1,4-cyclohexylidene. ;
When A is optionally substituted trimethylene, ~ s is preferably either unsubstituted or mono-substituted, conveniently at the middle carbon atom.
When Rl and R2 are chosen from hydrogen or alkyl, these are preferably alkyl.
Conveniently A is optionally substituted trimethy-lene or 1,4-cyclohexylidene. Preferably A is optionally substituted trimethylene.
When R3 ls or contains a dialkylamino radical, the alkyl groups are preferably the same. When R3 is an optionally substituted phenyl or phenylamino radical, the substituents are conveniently identical.
Conveniently these radicals are unsubstituted or mono-substituted preferably in the para position. When R3 is a heterocycle, conveniently this contains one heteroatom chosen from nitrogen, oxygen or sulphur and optionally a second nitrogen atom, e.g. thienyl, furyl, pyrrolyl, pyridyl or pyrazinyl.
Conveniently the heterocycle is bound to X by a ring carbon atom adjacent to a heteroatom.
R3 is preferably unsubstituted phenyl.
R~ and R5 are conveniently hydrogen.
X is conveniently -C0-.
The present invention provides a process for the production of a compound of formula I
as defined above, which comprises a) acylating a compound of formula II
"..~
.
.. . ..... . . . . .
;........... . . .
,. . .
: ~ .
~ 4 ~ ~ P l ~
, ~ ~
(C~ A-NII
R5 _ ~ ~ (II) ~1 4 . .
wherein n, A and Rl to R~ are as defined above, or b) condensing a compound of formula III
5~ ~( (III) wherein n, R4 and R5 are as defined above, and Y is a leaving group, with a compoùnd of formula IV
HN - A - N - X - R (IV) wherein A, Rl to R3 and X are as defined above ; and where necessary or desired, converting the resulting compound of Formula I into a pharmaceutically acceptable acid addition salt thereof.
Process a) may be effected in con~entional ~.
manner for the production of amides or thio-amides from amines. For example there may be used, as acylating agent, a compound of formula V
Z - X - R3 (V) wherein X is as defined above,R3 has the same signification as R3 but is other than amino, alkyl-~1 ' :........ : . . : ::
. . :
: ~ . . . . . .
:~ ' '' . , ' , ; ,' ,: ~ . : ~ . ':' , :, ' , - 5 - 100~-~838 amino and optionally substituted phenylamino and 2 is chlorine or bromine. The reaction may be effected conveniently in a solvent such as pyridine and at temperatures from 0 to 25. Alternatively when R3 is amino, alkylamino or optiona:Lly substituted phenylamino, there may be used a compound of formula VI X - R (VI~
wherein X is asdefined above and R6 is imino, alkylimino or optionally substituted phenylimino.
The reaction may be effected conveniently in a solvent such as dimethylformamide and at temperatures from 5 to 25. A compound of formula VI wherein R6 is imino may be prepared in situ from potassium or sodium cyanate or thiocyanate, by treatment with acid , for example hydrochloric acid.
Process b) may be effected in conventional manner for a condensation reaction to produce a secondary or tertiary amine. Y is conveniently chlorine, bromine, iodine, tosyloxy or mesyloxy.
The reaction may be conveniently effected in acetGne or dimethylformamide. Suitable reaction temperatures are from 20 to 150~.
The compounds of formula I may be isolated from the reaction mixture and purified in known - . , , ' ~ . .: , ' : ' ~ ': , , ', ~ ' :' ' ' ' :
:.:, ' ' ~ " ', ' ~ ' ' - 6 - 100-4~3 manner.The free base forms may be converted`
into acid addition salt forms in the usual manner and vice versa. Suitable acids for salt formation are . .
hydrochloric acid, o~alic acid, fumaric acid~naph~alene-2-sulphonic acid and naphthalene-1,5--disulphonic acid.
The starting material of formula II may be produced from a compound of formula III and a compound of formula VII
~N - A - NH ~VII) ; wherein A, R and R2 are as defined above, in analogous manner to process b).
When the amine of formula VII is unsymmetrical, the conditions should be chosen to avoid the formation of the undesired corresponding compound produced by condensation at the nitrogen atom bearing the R
substituent. For this purpose the amine may be used in protected form of formula VIII
R2 ll (VIII) wherein R7 is a protecting group, such as benzyl or benzyloxy, which may be removed from the ;
resulting product, e.g. by hydrogenolysis.
A starting material of formula IIa , .
: , . . .
.,`, ~ ` : ' - . ' : - .' ' ' '~ ' ': ' ' ;' . , : , ' .
~: ' - : . . :
- 7 ~ 100-4838 l2 I I
5 ~ (C~l2)n-N~A -NH
N ~ (IIa~
. 1 4 wherein A is fH-CH2-CH2- or R~
-CH2-CH -CH2- and wherein R8 is (Cl_4~alkyl and R
n, R2, R4 and R5 are as defined above, may alternatively be produced by reducing a compound of formula IX
R5 ~ (CH2)n-N-B-CN (IX~
wherein B is -CH(R8)-CH2- or -CH2-CH(R~)-and n, ~2~ R4, R5 and R~ are as defined above, e.~.
by hydrogenation in the presence of Raney-nickel.
Any starting material of formula II wherein Rl and/or R2 is hydrogen m~y be converted into a corresponding compound wherein Rl and R2 are both alkyl, or Rl is alkyl and R2 is hydrogen under appropriate selective alkylation conditions~
The starting material of formula IV may be produced by acylating an amine of formula VII in ~ ~ , .: ~
: , ' ' ::
analogous manner to process a). If desired, one nitrogen atom of an unsymmetrical amine may be protected to facilitate production of the desired product.
S A starting material of formula IVa IVa) ~IN A - N - X - R3 wherein X, R2 and R3 are as defined above and A
together with Rl and the nitrogen atom to which Rl is bound, form a 4-piperidyl radical, may alternatively be produced by acylatlng 4-piperidone with a compound of formula V or VI and condensing the resulting compound of formula X
0= ~ -X-R3 (X) wherein X and R3 are as defined above, with a compound of formula XI
R -NH
The present invention relates to new indole derivates, processes for their preparation, and pharmaceuti~al compositions containing them.
In accordance with the inventionthere are provided ne~ co~pounds of formula I
R2 Rl tI) S wherein n is 2 or 3, either A is trimethylene optionally substituted by (Cl 4) alkyl or 1,4-cyclohexylidene and R is hydrogen or (C 5) alkyl, ; or A together with Rl and the nitrogen atom to which Rl is bound, form a 4-piperidyl radical, R2 is hydrogen or (Cl 5) alkyl, 3 is (Cl 4) alkyl; (C3 6)cycloalkyl; amino;
(Cl 4)alkylamino; ditCl 4~alkylamino; l;
phenylamino wherein the phenyl ring is .
.: -:. : . : :
~ ~ - 100-4838 unsubstituted or mono-, di- or trisubstituted independently by halogen, tCl 4)alkyl, (Cl 4)alkoxy or di(Cl 4)alkylamino; phenyl or benzyl wherein the phenyl rings are unsubstituted or mono-, di- or trisubsti-tuted independently by halogen, hydroxy, (Cl 4)alkyl, (C~ 4)alkoxy or di-(Cl 4)alkyl-amino; 2-,3~ or 4-pyridylmethyl;or an aromatic 5- or 6-membered heterocycle containing one heteroatom chosen from nitrogen, oxygen or sul-phur and optionally additional one or two nitro-gen atoms, R4 is hydrogen, chlorine, bromine or (Cl 4)alkyl, R5 is hydrogen, (Cl_4)alkyl~ (Cl_4)alkxY
or (Cl 4)alkylthio, and X i~ -C0- or -CS-~ and pharma~eutically acceptable acid addition salts thereof.
hny alkyl, alkoxy or alkylthio radical contains preferably two car~on atoms, especially one carbon atom. Halogen means fluorine, chlorine, bromine or iodine, especially chlorine.
When A is 1,4-cyclohexylidene, this may be c~s or trans-1,4-cyclohexylidene. ;
When A is optionally substituted trimethylene, ~ s is preferably either unsubstituted or mono-substituted, conveniently at the middle carbon atom.
When Rl and R2 are chosen from hydrogen or alkyl, these are preferably alkyl.
Conveniently A is optionally substituted trimethy-lene or 1,4-cyclohexylidene. Preferably A is optionally substituted trimethylene.
When R3 ls or contains a dialkylamino radical, the alkyl groups are preferably the same. When R3 is an optionally substituted phenyl or phenylamino radical, the substituents are conveniently identical.
Conveniently these radicals are unsubstituted or mono-substituted preferably in the para position. When R3 is a heterocycle, conveniently this contains one heteroatom chosen from nitrogen, oxygen or sulphur and optionally a second nitrogen atom, e.g. thienyl, furyl, pyrrolyl, pyridyl or pyrazinyl.
Conveniently the heterocycle is bound to X by a ring carbon atom adjacent to a heteroatom.
R3 is preferably unsubstituted phenyl.
R~ and R5 are conveniently hydrogen.
X is conveniently -C0-.
The present invention provides a process for the production of a compound of formula I
as defined above, which comprises a) acylating a compound of formula II
"..~
.
.. . ..... . . . . .
;........... . . .
,. . .
: ~ .
~ 4 ~ ~ P l ~
, ~ ~
(C~ A-NII
R5 _ ~ ~ (II) ~1 4 . .
wherein n, A and Rl to R~ are as defined above, or b) condensing a compound of formula III
5~ ~( (III) wherein n, R4 and R5 are as defined above, and Y is a leaving group, with a compoùnd of formula IV
HN - A - N - X - R (IV) wherein A, Rl to R3 and X are as defined above ; and where necessary or desired, converting the resulting compound of Formula I into a pharmaceutically acceptable acid addition salt thereof.
Process a) may be effected in con~entional ~.
manner for the production of amides or thio-amides from amines. For example there may be used, as acylating agent, a compound of formula V
Z - X - R3 (V) wherein X is as defined above,R3 has the same signification as R3 but is other than amino, alkyl-~1 ' :........ : . . : ::
. . :
: ~ . . . . . .
:~ ' '' . , ' , ; ,' ,: ~ . : ~ . ':' , :, ' , - 5 - 100~-~838 amino and optionally substituted phenylamino and 2 is chlorine or bromine. The reaction may be effected conveniently in a solvent such as pyridine and at temperatures from 0 to 25. Alternatively when R3 is amino, alkylamino or optiona:Lly substituted phenylamino, there may be used a compound of formula VI X - R (VI~
wherein X is asdefined above and R6 is imino, alkylimino or optionally substituted phenylimino.
The reaction may be effected conveniently in a solvent such as dimethylformamide and at temperatures from 5 to 25. A compound of formula VI wherein R6 is imino may be prepared in situ from potassium or sodium cyanate or thiocyanate, by treatment with acid , for example hydrochloric acid.
Process b) may be effected in conventional manner for a condensation reaction to produce a secondary or tertiary amine. Y is conveniently chlorine, bromine, iodine, tosyloxy or mesyloxy.
The reaction may be conveniently effected in acetGne or dimethylformamide. Suitable reaction temperatures are from 20 to 150~.
The compounds of formula I may be isolated from the reaction mixture and purified in known - . , , ' ~ . .: , ' : ' ~ ': , , ', ~ ' :' ' ' ' :
:.:, ' ' ~ " ', ' ~ ' ' - 6 - 100-4~3 manner.The free base forms may be converted`
into acid addition salt forms in the usual manner and vice versa. Suitable acids for salt formation are . .
hydrochloric acid, o~alic acid, fumaric acid~naph~alene-2-sulphonic acid and naphthalene-1,5--disulphonic acid.
The starting material of formula II may be produced from a compound of formula III and a compound of formula VII
~N - A - NH ~VII) ; wherein A, R and R2 are as defined above, in analogous manner to process b).
When the amine of formula VII is unsymmetrical, the conditions should be chosen to avoid the formation of the undesired corresponding compound produced by condensation at the nitrogen atom bearing the R
substituent. For this purpose the amine may be used in protected form of formula VIII
R2 ll (VIII) wherein R7 is a protecting group, such as benzyl or benzyloxy, which may be removed from the ;
resulting product, e.g. by hydrogenolysis.
A starting material of formula IIa , .
: , . . .
.,`, ~ ` : ' - . ' : - .' ' ' '~ ' ': ' ' ;' . , : , ' .
~: ' - : . . :
- 7 ~ 100-4838 l2 I I
5 ~ (C~l2)n-N~A -NH
N ~ (IIa~
. 1 4 wherein A is fH-CH2-CH2- or R~
-CH2-CH -CH2- and wherein R8 is (Cl_4~alkyl and R
n, R2, R4 and R5 are as defined above, may alternatively be produced by reducing a compound of formula IX
R5 ~ (CH2)n-N-B-CN (IX~
wherein B is -CH(R8)-CH2- or -CH2-CH(R~)-and n, ~2~ R4, R5 and R~ are as defined above, e.~.
by hydrogenation in the presence of Raney-nickel.
Any starting material of formula II wherein Rl and/or R2 is hydrogen m~y be converted into a corresponding compound wherein Rl and R2 are both alkyl, or Rl is alkyl and R2 is hydrogen under appropriate selective alkylation conditions~
The starting material of formula IV may be produced by acylating an amine of formula VII in ~ ~ , .: ~
: , ' ' ::
analogous manner to process a). If desired, one nitrogen atom of an unsymmetrical amine may be protected to facilitate production of the desired product.
S A starting material of formula IVa IVa) ~IN A - N - X - R3 wherein X, R2 and R3 are as defined above and A
together with Rl and the nitrogen atom to which Rl is bound, form a 4-piperidyl radical, may alternatively be produced by acylatlng 4-piperidone with a compound of formula V or VI and condensing the resulting compound of formula X
0= ~ -X-R3 (X) wherein X and R3 are as defined above, with a compound of formula XI
R -NH
2 2 (XI) wherein R2 is as defined above, under simultaneous reduction, e.g. with hydrogen in presence of a catalyst.
Insofar as the production of any starting material is not particularly described, these are known or may be produced in conventional manner or in a manner analogous to that described above.
In the following non-limitative Examples all temperatures are indicated in degrees Centigrade.
~J
: . . .. .
.
. , - . ~ . -:
. . i . .. .. . :
: , ~ 9 - 100-4838 EX~MPI,E 1 N-benzoyl-N'-[3-(3-indolyl)PrPYl]=N~-.
methyl-l,3-diaminopropane A solution of 10.1 g benzoyl chloride in 15 ml allhydrous methylene chloride is added dropwise with stirring for 25 minutes between 0 and 10 to a solution of 14.5 g N-[3-(3-indolyl)propyl]-N-methyl-1,3-diaminopropane in 150 ml anhydrous pyridine and the reddish clear solution is stirred for 2 hours at 0. The reaction mixture i5 divided between a 2N sodium carbonate solution and methylene chloride, and the organic phase is washed, dried and evaporated. Chromatographic purification of the resinous product on aluminium oxide using methylene chloride with 0.1 to 0 3% of methanol yields the lS title coumpound. The naphthalene-2-sulfonate-dihydrate, obtained by conventional methods, melts at 73-74 after crystallization from methanol/water/ethyl acetate The starting material may be obtained as follows :
a) A mixture of 57 g trifluoroacetic acid and 105 g trifluoroacetic anhydride in 400 ml anhydrous :
acetonitrile are added dropwise to a stirred ~:~
suspension of 95.1 g 3-~3-indoly1)propionic acid in 500 ml anhydrous acetonitrile and maintained with stirring at -15 for 30 minutes.
' .~
~ .......... . .
:- ~ .. : . ' -:.. . .. --: .::~ . : :.
.: ~ . ;. . -, Under good cooling 500 ml anhydrous pyridine are added between -20 and -15 and quickly 238 ml of a 4.2 N solution of anhydrous methylamine in acetonitrile. The mixture is warmed with stirring at 0 for 15 minutes and maintained to 0 for 3 hours.
Insofar as the production of any starting material is not particularly described, these are known or may be produced in conventional manner or in a manner analogous to that described above.
In the following non-limitative Examples all temperatures are indicated in degrees Centigrade.
~J
: . . .. .
.
. , - . ~ . -:
. . i . .. .. . :
: , ~ 9 - 100-4838 EX~MPI,E 1 N-benzoyl-N'-[3-(3-indolyl)PrPYl]=N~-.
methyl-l,3-diaminopropane A solution of 10.1 g benzoyl chloride in 15 ml allhydrous methylene chloride is added dropwise with stirring for 25 minutes between 0 and 10 to a solution of 14.5 g N-[3-(3-indolyl)propyl]-N-methyl-1,3-diaminopropane in 150 ml anhydrous pyridine and the reddish clear solution is stirred for 2 hours at 0. The reaction mixture i5 divided between a 2N sodium carbonate solution and methylene chloride, and the organic phase is washed, dried and evaporated. Chromatographic purification of the resinous product on aluminium oxide using methylene chloride with 0.1 to 0 3% of methanol yields the lS title coumpound. The naphthalene-2-sulfonate-dihydrate, obtained by conventional methods, melts at 73-74 after crystallization from methanol/water/ethyl acetate The starting material may be obtained as follows :
a) A mixture of 57 g trifluoroacetic acid and 105 g trifluoroacetic anhydride in 400 ml anhydrous :
acetonitrile are added dropwise to a stirred ~:~
suspension of 95.1 g 3-~3-indoly1)propionic acid in 500 ml anhydrous acetonitrile and maintained with stirring at -15 for 30 minutes.
' .~
~ .......... . .
:- ~ .. : . ' -:.. . .. --: .::~ . : :.
.: ~ . ;. . -, Under good cooling 500 ml anhydrous pyridine are added between -20 and -15 and quickly 238 ml of a 4.2 N solution of anhydrous methylamine in acetonitrile. The mixture is warmed with stirring at 0 for 15 minutes and maintained to 0 for 3 hours.
3-(3-indolyl)-N-methyl-propionamide ~M.pt 97-98 after crystallization from methylene chloride/ethyl acetate) is obtained after working up.
b) A solution of 60.6 g 3-(3-indolyl)-N-methyl-propiona-mide in 500 ml anhydrous tetrahydrofuran are added dropwise at 25 for 15 minutes under nitrogen ~ . -atmosphere to a suspension of 34.2 g lithium alwL~iurn hydride in 800 ml anhydrous tetrahydrofuran and maintained at 66 for 3 hours. N-methyl-3-(3-indolyl)-propylamine (M.pt 81-82 after crystallization from methylene chloride/ethyl acetate) is obtained after working up.
c~ A mixture of 37.6 g N-methyl-3-(3-indolyl)-propyl-amine and 21,2 g acrylonitrile ln 65 ml anhydrous 1,2-dimethoxyethane are warmed with stirring at 60 for 2 1/2 hours.N-(2-cyanoethyl)-N-methyl-3-(3-indolyl)propylamine (M.pt 48-49 after crystalli-zation from isopropyl ether) is obtained after working up.
d) 36.2 g N~(2-cyanoethyl)-N-methyl-3-(3-indolyl)propyl . .. ... .. . ..
: ' ` ~ ' -~mine are hydrogenated at normal pressure and at room temperature with 20 g Raney-nickel catalyst.
in 400 ml dioxan and 400 ml of a 10% ammonia solution. N-[3-(3-indolyl)propyl]-N-methyl-1,3-diaminopropane is obtained after working up~
M.pt of the neutral fumarate:l80-181 (with decomposition) a~ter crystallization from ethanol.
From the appropriate compounds of formula II the following compounds of formula I wherein X is -C0- may be obtained in analogous manner to Example 1.
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il ~ ~ ~ ~ U~
_ _ ' '. . ' : . ' . ' : , . . ' ~ ' ' ~' '. ' ~~4~s- ~
EXAMPBE 2~ N-~henylcarbdmoyl-Nl-[2-(3-lndolyl)ethyl ]-N'-methyl-lL3-dlaminop,rop~ne 3 ml phenyl isocyanate are added d~p~ise between 5 and 10 and with stirring to a solution of 5.3 g N-[2-(3-indolyl) ethyl]-N-methyl-1,3-diaminopropane in 25 ml anhydrous dimethylformamide. The solution is stirred for an hour between 10 and 15 and evaporated. The residue is dried in high vacuum and chromatographed on silicagel using methylene chloridewith 6 to 10% methanol,to yield the title compound (M.pt. of the hydrogen maleate 153-155 with decomposition after crystalliza~ion from alcohol/acetone).
The starting material may be obtained as follows:
a) Reaction of 3-[2-methylamino)ethyl]indole with acrylo-nitrile in dimethoxy-ethane yields the N-(2-cyano-ethyl)-N-methyl-2-(3-indolyl)ethylamine which is worked up further direc-tly.
b) Reduction of N-(2-cyanoethyl)-N-methyl-2-(3-indolyl)-ethylamine with Raney-Nickel catalyst yields the N-[2-(3-indolyl)ethyl]-N-methyl-1,3-diaminopropane (M.pt. of the fumarate 153-154).
EXAMPLE 3: N-Benzoyl-Nl-[2-(3-in-dolyl)ethyl l-lL3-diamino-~ro~ane _ _ _ _ _ A ~olution of 8 g N-benzoyl-1,3-diaminopro~ane, 6,7 g 3-(2-bromoethyl)indole and 5 ml anhydro~ triethylamine in 15 ml anhydrous dimethylformamlde is m~int ~ ed for 72 hours ~,~
,.
3~
in nitrogen atmosphere. A dilute ammonia solution and methylene chloride are then added to the reaction mixture and the organic phase is dried and evaporated. ~ie residue is chromatographed on silicagel usi~g as eluant methylene chloride+ 5~ methanol ~ 0.3~ ammon.ia, to yield the title compound (M.pt. of the naphthalene-2-sulfonate 203-204 with decomposition after crystallization from ethanol).
The following compounds of formula (cH2)2-N-(cH2)3-NH-CO-R3 may be obtained in analogous manner to Example 3 :
T a b 1 e . . . . ,:
x R2 R3 R4 M.Pt. ~ ~:
. . . . . ___ . ..
a) -n-C3H7 p-tolyl H 181-l830 1) 3) b) -CH3 p-methoxyphenyl H 133-135~ 1~ 3) c3 -CH3 p-chlorophenyl H 161-l630 1) 3) d) -CH3 phenyl H 122-l240 2) 3) e) -CH3 2-furyl H 95-96 f) -C~l3 phenyl Br 148-150o 1~ 3) :
1) hydrogen oxal~ate 2) naphthalene-2-sulfonate 3) with decomp~sition ,, .
~ ~ 1 ~ 100-4~38 EXEMPLE 4:
From the appropriate 4-~nino-piperidines and 2-(3-indolyl)ethyl bromide or 3-~3-indolyl)propyl bromide, the following compounds of formula ~ ~ (C}l2)n-N- ~ C0 R3 may be obtained in analogous manner to Example 3:
T a b 1 e _ ~ .~ . .___ Ex n R2 R3 M.Pt.
. .. _ .
a) 2 -CH3i phenyl 131-133 ) b) 3 CH3 phenyl 201-203o 13 3) c) 2 i~o-C4Hg phenyl 152-l540 2) 3) d) 2 H ~phenyl 151-152 ) ~:
e) 2 -CH3 phenylamino 58-60 f~ 2 dimethylamino 119 -120 1) naphthalene-2-sulfonate 2) hydrochloride ~-3) with decomposition The colnpounds o formula I exhibit pharmacolo-gi:cal activity in animals. In particular, the compounds -.
exhihlt anti-hypertensive activity, as indicated by .: ~
~'' '' "
- l9 - 100-~838 standard ~ests, e.g. in the awake renal hypertonic Grollman rat upon administration of l to 50 m~/kg animal body weight of the compounds~clnd in the awake renal hypertonic Goldblatt dog upon administration of l to lO mg/kg animal body weight of the compounds.
The compounds are therefore indicated for use as anti-hypertensives. For this use an indicated daily dose is from about lO to about 2000 mg, conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from about2,5 to about 1000 mg, or in sustained release form.
A particularly interesting compound is the Example l compound.
The compounds of formula I may be administered in pharmaceutically acceptable acid addition salt form.
Such salts exhibit the same order of activity as the free base forms.
The invention also provides a pharmaceutical composition comprising a compound of formula I, in free base or pharmaceutically acceptable acid addition salt form, in association with a pharmaceutical carrier or diluent. A suitable pharmaceutical form is a capsule~
In one group of compounds n is 3, A is trimethylene, Rl is hydrogen or (Cl 5)alkyl, R2 is ~5 hydrogen or (Cl 5)alky1, R3 is phenyl or benzyl unsubsti-tuted or rono-, dl- or trlslbstituted independently by . . ,,. , '..: . .
.. . . . .
.
halogen, hydroxy, (Cl_4)alkyl~ ~cl_4)al y ~Cl 4)alkylamino; (C3 6)cycloalkyl; or an aromatic 5- or 6-membered heterocycle containing one heteroatom chosen fxom nitrogen, oxygen or sulphur, R4 is hydrogen, chlorine, bromine or (Cl 4)alkyl, R5 is hydrogen, ~:
~Cl_4)alkyl, (C1~4)alkoxy, or (Cl_4)alkylthio, and X is -C0-.
In another group of compounds n is 2~
either A is trimethylene and Rl is hydrogen or ~Cl 5) alkyl, or A together with Rl and the nitrogen atom to which Rl is bound form a 4-piperidyl radical, and R2 is hydrogen or (Cl 5)alkyl, R3 is (Cl_4)alkyl; phenyl unsubstituted or mono-, di- or trisubstituted indepen-dently by halogen, (Cl_4)alkyl or ~Cl 4)alkoxy;
(C3_6)cycloalkyl; or an aromatic 5- or 6 membered heterocycle containing one heteroatom chosen from nitrogen, oxygen or sulphur, R4 is hydrogen, ch1orine, bromine or (Cl 4)alkyl, R5 is hydrogen, (Cl_4)alkyl or (Cl 4)alkoxy, and X is -C0- or -CS.
~^ ' . ,.
.:: , .: : '.
,: ; : . . :
. .: .
.
b) A solution of 60.6 g 3-(3-indolyl)-N-methyl-propiona-mide in 500 ml anhydrous tetrahydrofuran are added dropwise at 25 for 15 minutes under nitrogen ~ . -atmosphere to a suspension of 34.2 g lithium alwL~iurn hydride in 800 ml anhydrous tetrahydrofuran and maintained at 66 for 3 hours. N-methyl-3-(3-indolyl)-propylamine (M.pt 81-82 after crystallization from methylene chloride/ethyl acetate) is obtained after working up.
c~ A mixture of 37.6 g N-methyl-3-(3-indolyl)-propyl-amine and 21,2 g acrylonitrile ln 65 ml anhydrous 1,2-dimethoxyethane are warmed with stirring at 60 for 2 1/2 hours.N-(2-cyanoethyl)-N-methyl-3-(3-indolyl)propylamine (M.pt 48-49 after crystalli-zation from isopropyl ether) is obtained after working up.
d) 36.2 g N~(2-cyanoethyl)-N-methyl-3-(3-indolyl)propyl . .. ... .. . ..
: ' ` ~ ' -~mine are hydrogenated at normal pressure and at room temperature with 20 g Raney-nickel catalyst.
in 400 ml dioxan and 400 ml of a 10% ammonia solution. N-[3-(3-indolyl)propyl]-N-methyl-1,3-diaminopropane is obtained after working up~
M.pt of the neutral fumarate:l80-181 (with decomposition) a~ter crystallization from ethanol.
From the appropriate compounds of formula II the following compounds of formula I wherein X is -C0- may be obtained in analogous manner to Example 1.
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_ _ ' '. . ' : . ' . ' : , . . ' ~ ' ' ~' '. ' ~~4~s- ~
EXAMPBE 2~ N-~henylcarbdmoyl-Nl-[2-(3-lndolyl)ethyl ]-N'-methyl-lL3-dlaminop,rop~ne 3 ml phenyl isocyanate are added d~p~ise between 5 and 10 and with stirring to a solution of 5.3 g N-[2-(3-indolyl) ethyl]-N-methyl-1,3-diaminopropane in 25 ml anhydrous dimethylformamide. The solution is stirred for an hour between 10 and 15 and evaporated. The residue is dried in high vacuum and chromatographed on silicagel using methylene chloridewith 6 to 10% methanol,to yield the title compound (M.pt. of the hydrogen maleate 153-155 with decomposition after crystalliza~ion from alcohol/acetone).
The starting material may be obtained as follows:
a) Reaction of 3-[2-methylamino)ethyl]indole with acrylo-nitrile in dimethoxy-ethane yields the N-(2-cyano-ethyl)-N-methyl-2-(3-indolyl)ethylamine which is worked up further direc-tly.
b) Reduction of N-(2-cyanoethyl)-N-methyl-2-(3-indolyl)-ethylamine with Raney-Nickel catalyst yields the N-[2-(3-indolyl)ethyl]-N-methyl-1,3-diaminopropane (M.pt. of the fumarate 153-154).
EXAMPLE 3: N-Benzoyl-Nl-[2-(3-in-dolyl)ethyl l-lL3-diamino-~ro~ane _ _ _ _ _ A ~olution of 8 g N-benzoyl-1,3-diaminopro~ane, 6,7 g 3-(2-bromoethyl)indole and 5 ml anhydro~ triethylamine in 15 ml anhydrous dimethylformamlde is m~int ~ ed for 72 hours ~,~
,.
3~
in nitrogen atmosphere. A dilute ammonia solution and methylene chloride are then added to the reaction mixture and the organic phase is dried and evaporated. ~ie residue is chromatographed on silicagel usi~g as eluant methylene chloride+ 5~ methanol ~ 0.3~ ammon.ia, to yield the title compound (M.pt. of the naphthalene-2-sulfonate 203-204 with decomposition after crystallization from ethanol).
The following compounds of formula (cH2)2-N-(cH2)3-NH-CO-R3 may be obtained in analogous manner to Example 3 :
T a b 1 e . . . . ,:
x R2 R3 R4 M.Pt. ~ ~:
. . . . . ___ . ..
a) -n-C3H7 p-tolyl H 181-l830 1) 3) b) -CH3 p-methoxyphenyl H 133-135~ 1~ 3) c3 -CH3 p-chlorophenyl H 161-l630 1) 3) d) -CH3 phenyl H 122-l240 2) 3) e) -CH3 2-furyl H 95-96 f) -C~l3 phenyl Br 148-150o 1~ 3) :
1) hydrogen oxal~ate 2) naphthalene-2-sulfonate 3) with decomp~sition ,, .
~ ~ 1 ~ 100-4~38 EXEMPLE 4:
From the appropriate 4-~nino-piperidines and 2-(3-indolyl)ethyl bromide or 3-~3-indolyl)propyl bromide, the following compounds of formula ~ ~ (C}l2)n-N- ~ C0 R3 may be obtained in analogous manner to Example 3:
T a b 1 e _ ~ .~ . .___ Ex n R2 R3 M.Pt.
. .. _ .
a) 2 -CH3i phenyl 131-133 ) b) 3 CH3 phenyl 201-203o 13 3) c) 2 i~o-C4Hg phenyl 152-l540 2) 3) d) 2 H ~phenyl 151-152 ) ~:
e) 2 -CH3 phenylamino 58-60 f~ 2 dimethylamino 119 -120 1) naphthalene-2-sulfonate 2) hydrochloride ~-3) with decomposition The colnpounds o formula I exhibit pharmacolo-gi:cal activity in animals. In particular, the compounds -.
exhihlt anti-hypertensive activity, as indicated by .: ~
~'' '' "
- l9 - 100-~838 standard ~ests, e.g. in the awake renal hypertonic Grollman rat upon administration of l to 50 m~/kg animal body weight of the compounds~clnd in the awake renal hypertonic Goldblatt dog upon administration of l to lO mg/kg animal body weight of the compounds.
The compounds are therefore indicated for use as anti-hypertensives. For this use an indicated daily dose is from about lO to about 2000 mg, conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from about2,5 to about 1000 mg, or in sustained release form.
A particularly interesting compound is the Example l compound.
The compounds of formula I may be administered in pharmaceutically acceptable acid addition salt form.
Such salts exhibit the same order of activity as the free base forms.
The invention also provides a pharmaceutical composition comprising a compound of formula I, in free base or pharmaceutically acceptable acid addition salt form, in association with a pharmaceutical carrier or diluent. A suitable pharmaceutical form is a capsule~
In one group of compounds n is 3, A is trimethylene, Rl is hydrogen or (Cl 5)alkyl, R2 is ~5 hydrogen or (Cl 5)alky1, R3 is phenyl or benzyl unsubsti-tuted or rono-, dl- or trlslbstituted independently by . . ,,. , '..: . .
.. . . . .
.
halogen, hydroxy, (Cl_4)alkyl~ ~cl_4)al y ~Cl 4)alkylamino; (C3 6)cycloalkyl; or an aromatic 5- or 6-membered heterocycle containing one heteroatom chosen fxom nitrogen, oxygen or sulphur, R4 is hydrogen, chlorine, bromine or (Cl 4)alkyl, R5 is hydrogen, ~:
~Cl_4)alkyl, (C1~4)alkoxy, or (Cl_4)alkylthio, and X is -C0-.
In another group of compounds n is 2~
either A is trimethylene and Rl is hydrogen or ~Cl 5) alkyl, or A together with Rl and the nitrogen atom to which Rl is bound form a 4-piperidyl radical, and R2 is hydrogen or (Cl 5)alkyl, R3 is (Cl_4)alkyl; phenyl unsubstituted or mono-, di- or trisubstituted indepen-dently by halogen, (Cl_4)alkyl or ~Cl 4)alkoxy;
(C3_6)cycloalkyl; or an aromatic 5- or 6 membered heterocycle containing one heteroatom chosen from nitrogen, oxygen or sulphur, R4 is hydrogen, ch1orine, bromine or (Cl 4)alkyl, R5 is hydrogen, (Cl_4)alkyl or (Cl 4)alkoxy, and X is -C0- or -CS.
~^ ' . ,.
.:: , .: : '.
,: ; : . . :
. .: .
.
Claims (4)
1) A process for the production of a compound of formula I
(I) wherein n is 2 or 3, either A is trimethylene optionally substituted by (C1-4)alkyl or 1,4-cyclohexylidene and R1 is hydrogen or (C1-5) alkyl, or A together with R1 and the nitrogen atom to which R1 is bound, form a 4-piperidyl radical, R2 is hydrogen or (C1-5)alkyl, R3 is (C1-4) alkyl; (C3-6)cycloalkyl; amino;
(C1-4)alkylamino; di(C1-4)alkylamino;
phenylamino wherein the phenyl ring is unsubstituted or mono-, di- or trisubstituted independently by halogen, (C1-4)alkyl, (C1-4)alkoxy or di(C1-4)alkylamino; phenyl or benzyl wherein the phenyl rings are unsubstituted or mono-, di- or trisubsti-tuted independently by halogen, hydroxy, (C1-4)alkyl, (C1-4)alkoxy ox di-(C1-4)alkyl-amino; 2-,3- or 4-pyridylmethyl;or an aromatic 5- or 6-membered heterocycle containing one heteroatom chosen from nitrogen, oxygen or sul-phur and optionally additional one or two nitro-gen atoms, R4 is hydrogen, chlorine, bromine or (C1-4)alkyl, R5 is hydrogen, (C1-4)alkyl, (C1-4)alkoxy or (C1-4)alkylthio, and X is -CO- or -CS-, or pharmaceutically acceptable acid addition salts thereof, which comprises a) acylating a compound of formula II
(II) wherein n, A and R1 to R5 are as defined above, or b) condensing a compound of formula III
(III) wherein n, R4 and R5 are as defined above, and Y is a leaving group, with a compound of formula IV
(IV) wherein A, R1 to R3 and X are as defined above; and where necessary or desired, converting the resulting compound of Formula I into a pharmaceutically acceptable acid addition salt thereof.
(I) wherein n is 2 or 3, either A is trimethylene optionally substituted by (C1-4)alkyl or 1,4-cyclohexylidene and R1 is hydrogen or (C1-5) alkyl, or A together with R1 and the nitrogen atom to which R1 is bound, form a 4-piperidyl radical, R2 is hydrogen or (C1-5)alkyl, R3 is (C1-4) alkyl; (C3-6)cycloalkyl; amino;
(C1-4)alkylamino; di(C1-4)alkylamino;
phenylamino wherein the phenyl ring is unsubstituted or mono-, di- or trisubstituted independently by halogen, (C1-4)alkyl, (C1-4)alkoxy or di(C1-4)alkylamino; phenyl or benzyl wherein the phenyl rings are unsubstituted or mono-, di- or trisubsti-tuted independently by halogen, hydroxy, (C1-4)alkyl, (C1-4)alkoxy ox di-(C1-4)alkyl-amino; 2-,3- or 4-pyridylmethyl;or an aromatic 5- or 6-membered heterocycle containing one heteroatom chosen from nitrogen, oxygen or sul-phur and optionally additional one or two nitro-gen atoms, R4 is hydrogen, chlorine, bromine or (C1-4)alkyl, R5 is hydrogen, (C1-4)alkyl, (C1-4)alkoxy or (C1-4)alkylthio, and X is -CO- or -CS-, or pharmaceutically acceptable acid addition salts thereof, which comprises a) acylating a compound of formula II
(II) wherein n, A and R1 to R5 are as defined above, or b) condensing a compound of formula III
(III) wherein n, R4 and R5 are as defined above, and Y is a leaving group, with a compound of formula IV
(IV) wherein A, R1 to R3 and X are as defined above; and where necessary or desired, converting the resulting compound of Formula I into a pharmaceutically acceptable acid addition salt thereof.
2. The process of claim 1 wherein n is 2, R1 is CH3, A is CH2-CH (CH3)-CH2, R2 is CH3,R3 is phenyl, R4 and R5 are H, and X is -CO-.
3. A compound of Formula I as defined in claim 1 or a pharmaceutically acceptable acid addition salt thereof, whenever prepared by the process of claim 1 or by an obvious chemical equivalent thereof.
4. N-(3-(N-(2-(1H-indol-3-yl) ethyl (methylamino) -2-methylpropyl)-N-methylbenzamide or a pharmaceutically acceptable acid addition salt thereof, whenever prepared by the process of claim 2 or by an obvious chemical equivalent thereof.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH858977 | 1977-07-12 | ||
| CH8589/77 | 1977-07-12 | ||
| CH300878 | 1978-03-20 | ||
| CH3008/78 | 1978-03-20 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1114381A true CA1114381A (en) | 1981-12-15 |
Family
ID=25691930
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA307,174A Expired CA1114381A (en) | 1977-07-12 | 1978-07-11 | Process for production of indole derivatives |
Country Status (14)
| Country | Link |
|---|---|
| EP (1) | EP0000355B1 (en) |
| JP (1) | JPS5436259A (en) |
| AU (1) | AU521641B2 (en) |
| CA (1) | CA1114381A (en) |
| DE (1) | DE2861502D1 (en) |
| DK (1) | DK300978A (en) |
| ES (1) | ES471593A1 (en) |
| FI (1) | FI782138A (en) |
| IE (1) | IE47209B1 (en) |
| IL (1) | IL55116A (en) |
| IT (1) | IT7850140A0 (en) |
| NZ (1) | NZ187813A (en) |
| PH (1) | PH14993A (en) |
| PT (1) | PT68270A (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0003901B1 (en) * | 1978-02-24 | 1981-08-05 | Pfizer Limited | 3-(imidazol-1-ylalkyl)indoles as selective inhibitors of thromboxane synthetase,pharmaceutical compositions thereof, and methods for preparing them |
| US4634713A (en) * | 1982-05-28 | 1987-01-06 | Ciba-Geigy Corporation | Antihypertensive 3-(ureidocyclohexyleneamino)propane-1,2-diol derivatives |
| JPH0283380A (en) * | 1988-09-21 | 1990-03-23 | Kotobuki Seiyaku Kk | Novel diamine derivative, antiarrhythmic agent and production thereof |
| FR2642422A1 (en) * | 1988-12-22 | 1990-08-03 | Roussel Uclaf | NOVEL ACYLATED POLYAMINES, PROCESS FOR PREPARING THEM AND THEIR APPLICATION AS FUNGICIDES |
| DE69430861T2 (en) * | 1993-04-07 | 2003-01-23 | Otsuka Pharmaceutical Co., Ltd. | N-ACYLATED 4-AMINOPIPERIDINE DERIVATIVES AS ACTIVE INGREDIENTS OF PERIPHERAL VESSEL WIDING AGENTS |
| MY142362A (en) | 2004-01-29 | 2010-11-30 | Otsuka Pharma Co Ltd | Pharmaceutical composition for promoting angiogenesis |
| US11764679B2 (en) | 2020-01-15 | 2023-09-19 | Solaredge Technologies Ltd. | Power device |
| CN115433164B (en) * | 2022-09-14 | 2023-12-12 | 南京师范大学 | Nicotinamide derivative, preparation method thereof and application thereof in resisting aging and prolonging life |
-
1978
- 1978-06-12 PH PH21359A patent/PH14993A/en unknown
- 1978-06-29 DE DE7878100274T patent/DE2861502D1/en not_active Expired
- 1978-06-29 EP EP78100274A patent/EP0000355B1/en not_active Expired
- 1978-07-03 IT IT7850140A patent/IT7850140A0/en unknown
- 1978-07-03 FI FI782138A patent/FI782138A/en not_active Application Discontinuation
- 1978-07-03 DK DK783009A patent/DK300978A/en not_active Application Discontinuation
- 1978-07-10 NZ NZ187813A patent/NZ187813A/en unknown
- 1978-07-10 PT PT68270A patent/PT68270A/en unknown
- 1978-07-10 ES ES471593A patent/ES471593A1/en not_active Expired
- 1978-07-10 IE IE1382/78A patent/IE47209B1/en unknown
- 1978-07-10 IL IL55116A patent/IL55116A/en unknown
- 1978-07-11 AU AU37939/78A patent/AU521641B2/en not_active Expired
- 1978-07-11 JP JP8363778A patent/JPS5436259A/en active Pending
- 1978-07-11 CA CA307,174A patent/CA1114381A/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| AU3793978A (en) | 1980-01-17 |
| EP0000355B1 (en) | 1982-01-06 |
| NZ187813A (en) | 1981-03-16 |
| IE47209B1 (en) | 1984-01-11 |
| AU521641B2 (en) | 1982-04-22 |
| IL55116A0 (en) | 1978-09-29 |
| EP0000355A1 (en) | 1979-01-24 |
| DE2861502D1 (en) | 1982-02-25 |
| ES471593A1 (en) | 1979-10-01 |
| FI782138A (en) | 1979-01-13 |
| IL55116A (en) | 1982-02-28 |
| IT7850140A0 (en) | 1978-07-03 |
| DK300978A (en) | 1979-01-13 |
| IE781382L (en) | 1979-01-12 |
| PH14993A (en) | 1982-03-22 |
| JPS5436259A (en) | 1979-03-16 |
| PT68270A (en) | 1978-08-01 |
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