CA1078844A - Thieno (2,3-c) pyridine derivatives - Google Patents
Thieno (2,3-c) pyridine derivativesInfo
- Publication number
- CA1078844A CA1078844A CA271,181A CA271181A CA1078844A CA 1078844 A CA1078844 A CA 1078844A CA 271181 A CA271181 A CA 271181A CA 1078844 A CA1078844 A CA 1078844A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
-
- 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
- A61P9/06—Antiarrhythmics
-
- 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
- A61P9/08—Vasodilators for multiple indications
-
- 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
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Abstract
IMPROVEMENTS IN OR RELATING TO THIENO[3,2-c]PYRIDINE
DERIVATIVES
Abstract of the disclosure This invention provides compounds of formula I
I
wherein R1 is (i) hydrogen or alkyl of 1 to 4 carbon atoms, or (ii) chlorine or bromine, in the 2,3 or 7 position, or (iii) fluorine, cyano or COOB, wherein B is alkyl of 1 to 4 carbon atoms, in the 2 or 3 position, R2 is (i) hydrogen or alkyl of 1 to 4 carbon atoms, or (ii) chlorine or bromine, in the 2,3 or 7 position, or (iii) fluorine, in the 2 or 3 position, R3 is hydrogen or a group -COR4, wherein R4 is alkyl of 1 to 17 carbon atoms, phenyl, phenyl monosubstituted by nitro, phenyl mono- or disubstituted by alkyl of 1 to 4 carbon atoms or halogen with an atomic number of 9 to 35, phenyl mono-, di- or trisubstituted by alkoxy of 1 to 4 carbon atoms, or a group D-COOH, wherein D is ethylene or trimethylene, and R is phenylalkyl of 8 to 10 carbon atoms, phenyl-alkyl of 8 to 10 carbon atoms monosubstituted in the phenyl radical by alkyl of 1 to 4 car-bon atoms, alkoxy of 1 to 4 carbon atoms or halogen with an atomic number of 9 to 35, or phenylalkyl of 8 to 10 carbon atoms disubsti-tuted in the phenyl radical by alkoxy of 1 to 4 carbon atoms, the phenyl ring of each of the phe-nylalkyl radicals being separated by at least 2 carbon atoms from the nitrogen atom to which R is bound and, when R3 is a group -COR4, R alternatively is alkyl of 3 to 7 car-bon atoms, cycloalkyl of 3 to 7 carbon atoms, cycloalkyl of 3 to 7 carbon atoms monosubsti-tuted by alkyl of 1 to 4 carbon atoms, .alpha.-dial-kylpropinyl of 5 to 9 carbon atoms, .alpha.-dialkyl-allyl of 5 to 9 carbon atoms, or phenoxyalkyl of 8 to 11 carbon atoms, the oxygen atom of the phenoxyalkyl radical being separated by at least two carbon atoms from the nitrogen atom to which R is bound, with the general proviso that, when R1 is cyano or COOB, R2 is other than fluorine, chlorine or bromine, in the 2 or 3 position, useful in the treatment of heart diseases, hyper-lipoidemia and hyperglycemia
DERIVATIVES
Abstract of the disclosure This invention provides compounds of formula I
I
wherein R1 is (i) hydrogen or alkyl of 1 to 4 carbon atoms, or (ii) chlorine or bromine, in the 2,3 or 7 position, or (iii) fluorine, cyano or COOB, wherein B is alkyl of 1 to 4 carbon atoms, in the 2 or 3 position, R2 is (i) hydrogen or alkyl of 1 to 4 carbon atoms, or (ii) chlorine or bromine, in the 2,3 or 7 position, or (iii) fluorine, in the 2 or 3 position, R3 is hydrogen or a group -COR4, wherein R4 is alkyl of 1 to 17 carbon atoms, phenyl, phenyl monosubstituted by nitro, phenyl mono- or disubstituted by alkyl of 1 to 4 carbon atoms or halogen with an atomic number of 9 to 35, phenyl mono-, di- or trisubstituted by alkoxy of 1 to 4 carbon atoms, or a group D-COOH, wherein D is ethylene or trimethylene, and R is phenylalkyl of 8 to 10 carbon atoms, phenyl-alkyl of 8 to 10 carbon atoms monosubstituted in the phenyl radical by alkyl of 1 to 4 car-bon atoms, alkoxy of 1 to 4 carbon atoms or halogen with an atomic number of 9 to 35, or phenylalkyl of 8 to 10 carbon atoms disubsti-tuted in the phenyl radical by alkoxy of 1 to 4 carbon atoms, the phenyl ring of each of the phe-nylalkyl radicals being separated by at least 2 carbon atoms from the nitrogen atom to which R is bound and, when R3 is a group -COR4, R alternatively is alkyl of 3 to 7 car-bon atoms, cycloalkyl of 3 to 7 carbon atoms, cycloalkyl of 3 to 7 carbon atoms monosubsti-tuted by alkyl of 1 to 4 carbon atoms, .alpha.-dial-kylpropinyl of 5 to 9 carbon atoms, .alpha.-dialkyl-allyl of 5 to 9 carbon atoms, or phenoxyalkyl of 8 to 11 carbon atoms, the oxygen atom of the phenoxyalkyl radical being separated by at least two carbon atoms from the nitrogen atom to which R is bound, with the general proviso that, when R1 is cyano or COOB, R2 is other than fluorine, chlorine or bromine, in the 2 or 3 position, useful in the treatment of heart diseases, hyper-lipoidemia and hyperglycemia
Description
Case 100-4513 IMPROVEMENTS IN OR RELATING TO THIENO [3, 2--c]PYRIDINE
DERIVATIVES
The present invention relates to thienot3,2c~pyri-dine derivatives.
In accor~ance with the inventi~n there are pro-vided compounds of formula I, ~R3 Olcfl2cl~cH2NH - R .:
~ 3 6 ~ ~ R 1 wherein Rl is (i) hydrogen or alkyl of 1 to 4 carbon atoms/ . or :
(ii) chlorine or bromine, in ~he 2,3 or 7 positlon, or :
tiii) fluorine, cyano or COOB, wherein B is alkyl of 1 to 4 carbon atoms, in the ~
DERIVATIVES
The present invention relates to thienot3,2c~pyri-dine derivatives.
In accor~ance with the inventi~n there are pro-vided compounds of formula I, ~R3 Olcfl2cl~cH2NH - R .:
~ 3 6 ~ ~ R 1 wherein Rl is (i) hydrogen or alkyl of 1 to 4 carbon atoms/ . or :
(ii) chlorine or bromine, in ~he 2,3 or 7 positlon, or :
tiii) fluorine, cyano or COOB, wherein B is alkyl of 1 to 4 carbon atoms, in the ~
2 or 3 position, :
~ .
5 R2 is (i) hydrogen or alkyl of 1 to 4 carbon atoms, - - - or (ii) chlorine or bromine, in the 2,3 or 7 position, or (iii) fluorine, in the 2 or 3 position, R3 ls hydrogen or a group -C0~4, wherein ~ ` 1 "~ ~
- ~ - 100-4513 R4 is alkyl of 1 to 17 carbon atoms, phenyl, phenyl monosubstituted by nitro, phenyl mono- or disubstituted by alkyl of 1 to 4 carbon atoms or halogen with an atomic numher of 9 to 35, phenyl mono-, di- or trisubstituted by alkoxy of 1 to 4 carbon atoms, or a group D-COOH, whereln D is ethylene or trimethylene, and R is phenylalkyl of 8 to 10 carbon atoms, phenyl~
alkyl of 8 to 10 carbon atoms monosubstituted ln the phenyl radical by alkyl of 1 to 4 car-bon atoms, alkoxy of 1 to 4 carbon atoms or halogen with an atomic number of 9 to 35, or phenylalkyl of 8 to 10 carbon atoms disubsti-tuted in the phenyl radical by alkoxy of 1 to 4 carbon atoms,~he phenyl ring of each o~ ~he phenylaikyl radicals being separated by at least 2 carbon atoms from the nitrogen atom to which R is bound and, when R3 is a group -COR4, R alterne.tlve~is alkyl of 3 to 7 car-bon atoms, cycloalkyl of 3 to 7 carbon atoms, cycloalkyl of 3 to 7 carbon atoms monosubsti-tuted by alkyl of 1 to 4 carbon atoms, a-dial-kylpropinyl of 5 to 9 carbon atoms, a-dialkyl-allyl of 5 to 9 carbon atoms, or phenoxyalkyl of 8 to 11 carbon atoms, the oxygen atom of the phenoxyalkyl radical being separate~ by at least two carbon atoms from the nitrogen atom ~:
to which R is bound, ~17~8~
.
~ .
5 R2 is (i) hydrogen or alkyl of 1 to 4 carbon atoms, - - - or (ii) chlorine or bromine, in the 2,3 or 7 position, or (iii) fluorine, in the 2 or 3 position, R3 ls hydrogen or a group -C0~4, wherein ~ ` 1 "~ ~
- ~ - 100-4513 R4 is alkyl of 1 to 17 carbon atoms, phenyl, phenyl monosubstituted by nitro, phenyl mono- or disubstituted by alkyl of 1 to 4 carbon atoms or halogen with an atomic numher of 9 to 35, phenyl mono-, di- or trisubstituted by alkoxy of 1 to 4 carbon atoms, or a group D-COOH, whereln D is ethylene or trimethylene, and R is phenylalkyl of 8 to 10 carbon atoms, phenyl~
alkyl of 8 to 10 carbon atoms monosubstituted ln the phenyl radical by alkyl of 1 to 4 car-bon atoms, alkoxy of 1 to 4 carbon atoms or halogen with an atomic number of 9 to 35, or phenylalkyl of 8 to 10 carbon atoms disubsti-tuted in the phenyl radical by alkoxy of 1 to 4 carbon atoms,~he phenyl ring of each o~ ~he phenylaikyl radicals being separated by at least 2 carbon atoms from the nitrogen atom to which R is bound and, when R3 is a group -COR4, R alterne.tlve~is alkyl of 3 to 7 car-bon atoms, cycloalkyl of 3 to 7 carbon atoms, cycloalkyl of 3 to 7 carbon atoms monosubsti-tuted by alkyl of 1 to 4 carbon atoms, a-dial-kylpropinyl of 5 to 9 carbon atoms, a-dialkyl-allyl of 5 to 9 carbon atoms, or phenoxyalkyl of 8 to 11 carbon atoms, the oxygen atom of the phenoxyalkyl radical being separate~ by at least two carbon atoms from the nitrogen atom ~:
to which R is bound, ~17~8~
.
- 3 - 100-4513 with the general proviso that, when Rl is cyano or COOB, Rz is other than fluorlne, chlorine or bromine, in the 2 or 3 position.
Rl is preferably hydrogen, alkyl, chlorlne, bro-mine or cyano. R2 is preferably hydrogen or alkyl.
R3 is preferably a ~roup -CQR~. R~ is preferably al]syl, phenyl, phenyl substituted by halogen or alkoxy, or a group D-COOH. R is preferably alkyl,alkylcyclo-alkyl, phenylalkyl or phenylalkyl substituted by - 10 alkoxy, especially alkyl.
Alkoxy preferably contains 1 or 2, especially 1 carbon atom. When Rl and/or R2 is alkyl or when R4 is phenyl substituted by alkyl or when R is phenylalkyl substituted in the phenyl radical by alkyl or cycloalkyl substituted by alkyl, or when B is alkyl,these alkyl radicals preferabIy contain 1 or 2, especially 1 carbon`a~om. When Rl and/or R2 is fluorine, chlorine or bromine, these radi-cals are preferably chlorin~ or bromine, especially bromine. When R is alkyl, this radical preferably is branched, especially in an a-position to the nitrogen atom to which it is bound. Especially pre-ferred alkyl radicals R are isopropyl, tert.butyl, 3-pentyl and tert. pentyl~
When R4 is alkyl, this radical preferably contains 1 to 10, especially 4 to 9 carbon atoms. Especially ~7~15 4~
- ~ - 100-4513 preferred alkyl radicals R4 are tert.butyl, 3-pentyl, tert. pentyl and n-octyl, especially terk.
butyl and n-octyl. Halogen of atomic number from 9 to 35 preferably signifies fluorine or chlorine.
Phenylalkyl preferably signifies phenethyl, sub-stltuted phenylalkyl preferably signlfies substi-tuted phenethyl. Cycloalkyl preferably is of 3,5 or 6, especially of 3 carbon atoms. In cycloalkyl ~ubstituted by alkyl, the alkyl radical preferably is attached to the 1 position of the cycloalkyl radical. In ~-dialkylpropinyl and ~-dialkylallyl, the alkyl radicals preferably are ident.ical and preferably are of 1 or 2, especially of 1 car- -bon atom. Phenoxyalkyl preferably s1gnifies phenoxy-ethyl, D is prefer~bly ethylene.
:Rl and/or R2 preferably is in the 2 or 3 position. When R is monosubstituted phenylalkyl and/or R4 is monosubstituted phenyl, the phenyl radical preferably is substituted in the 4 posi-tion. When R is polysubstituted phenylalkyl and/orR4 is polysubstituted phenyl, the substituents of the phenyl radical may have independent signifi-cances, are however preferably identical, and pre-ferably are alkoxy groups, especially in the 3,4 or 3,4,5 positions.
In accordance with the invention, a compound of formula I may be obtained by a process comprising a) for the production of a compound of foxmula Ia fCOR4 oC~12CHClI
~ - R~ ~a wherein R, Rl, R2 and R4 are as deflned above, esterifylng a compound of formula Ib OH
ocH2c~IcH2N~l-R Ib ~ ~ ~ Rl wherein R, Rl and R2 are as defined abo~e, or b~ for the production o a compound of ormula Ib, substituting a compound of formula II
~ Rl II
wherein Rl and R2 are as defined above and X
is a leaving group, with a group of formula III
OH
-OCH2CIlCH2NH-R III
8~
-wherein R is as defined above.
Process variant a~ may be effected in a manner analogous to methods known for the acylation of secondary alkohols.
To a compound of formula ~b there may, for example, be added an excess of an anhydride corresponding to the acid of ~ormula R3COCH, as well as an acid. The added acid may be the acid R3COOH, hut may however be different. The process may be effected from about 0 to about 100C, pre-ferably from about room temperature to about 40~C. The process is optionally effected in the presence of an inert organic solvent. The reaction mixture may be woxked up in known manner,conveniently under mild conditions, as otherwise the ester group may be split off.
Process variant b) is a substitution reaction on an aromatic, nitrogen-containing heterocycle which contains a leaving group on a carbon atom adjacent to the nitrogen. It may be effected in a manner analogous to known methods.x preferably sig-nifies an anionic leaVing group, e.g. chlorine, bromine or methylthio; -` -X especially signi-fies chlorine. The substitution is readily effected, e.g. by allowing to stand a solution of a compound ~37~84~
of formula II and a compound of formula H-RX~
wherein Rx is the group of formula III. This may be effected in an inert organic solvent, e.g. a lower alkanol such as tert.butanol. The reaction is preferably effected in the presence of a base, e.g. an alkal~ metal alcoholate such as potassium tert.~utylate. The reaction temperature may vary from a~out 0 to about 80C, and is preferably room temperature.
The carbon atom of the side chain carrying the - -OR3 group in the compounds of formula- I is as~mmetric; the compounds may there~ore appear in the form of the corresponding enantiomers.
The individual optical isomers of the compounds of formula I may be ob~ained in conventional manner, e.g. by effecting the processes according to the invention starting from the corresponding optical i~o-~ mers of the starting materials, whlch may be ob- -- tained in conventional manner starting from opti-cally pure (R)-or(s).glyceraldehyde.
,, . . ., ~ ;
The compounds of formula I may be pxesent in the free form, or in the form of acid addition salts.
Acid addition salts, for example, the hydrogen maleinate, may be produced from the free compounds in known manner, and vice versa.
~L~)7~
- 8 - 100-~513 Insofar as the produc~ion of the starting ma-terials is not described, these are known or may be producPd in accordance with known processes, or in a manner analogous to the processe.s des-crlbed herein or to known processes.
In the follow~ng non-limitative Examples all tempera~ures are indicated in degrees Centigrade and are uncorrected.
:
..:
iV~8~
' -~
EXAMPLE 1: 4-(3 tert.butylamino-2-nonanoyloxy-_xy)thieno~3,2~c~pyridine-3-car-bon~trile ~process variant a]
2.7 g of pelargonic acid and 1.3 g 4-(3-tert.butyl-- amino-2-hydroxypropoxy)thieno[3,2-c]pyridine-3-car-bonitrile in 12 ml of chloroform are reacted drop-wise at 0 with 1.5 g pel~rgonic anhydride in 3 ml of chloro~orm. After 15 hours at room temperature, 50 ml of a 2N soda solution are added and the reaction mixture is extracted thrice ~ith methylene chloride, drled over MgS04, filtered and concen-trated, The title compound is formed (M.P. of the hydrogen malein,ate form 105-107 - from tetrahydro-~uran).
EXAMPLE 2:
~3,2-c]pyridine-4-y gen succinate [process variant a]
1 g of 4-~3-tert.butylamino-2-hydroxypropoxy)thieno E3 ,2-c]pyridine-3-carbonitrile hydrog~n maleinate are dissolved ln 15 ml acetic acid and reacted at room temperature with 0.48 g ofsuccinic - - anhy-dride~ After 15 hours 50 ml of ether are added.
The hydrogen maleinate of the titel compound is obtained (M.P. 134-137).
~ 10 - 100-4513 .
The following compounds of formula Ia are obtained according to process variant a~in a manner analogous to Example 1, us~ng the ~orresponding starting ma-terials of formula Ib:
_ _ . _ ~ .~ .
Enr R Rl R2 4 M.P.
. . _ _____ _ _ 3 tert-butyl 3-bromo H phenyl ~ml 198-201
Rl is preferably hydrogen, alkyl, chlorlne, bro-mine or cyano. R2 is preferably hydrogen or alkyl.
R3 is preferably a ~roup -CQR~. R~ is preferably al]syl, phenyl, phenyl substituted by halogen or alkoxy, or a group D-COOH. R is preferably alkyl,alkylcyclo-alkyl, phenylalkyl or phenylalkyl substituted by - 10 alkoxy, especially alkyl.
Alkoxy preferably contains 1 or 2, especially 1 carbon atom. When Rl and/or R2 is alkyl or when R4 is phenyl substituted by alkyl or when R is phenylalkyl substituted in the phenyl radical by alkyl or cycloalkyl substituted by alkyl, or when B is alkyl,these alkyl radicals preferabIy contain 1 or 2, especially 1 carbon`a~om. When Rl and/or R2 is fluorine, chlorine or bromine, these radi-cals are preferably chlorin~ or bromine, especially bromine. When R is alkyl, this radical preferably is branched, especially in an a-position to the nitrogen atom to which it is bound. Especially pre-ferred alkyl radicals R are isopropyl, tert.butyl, 3-pentyl and tert. pentyl~
When R4 is alkyl, this radical preferably contains 1 to 10, especially 4 to 9 carbon atoms. Especially ~7~15 4~
- ~ - 100-4513 preferred alkyl radicals R4 are tert.butyl, 3-pentyl, tert. pentyl and n-octyl, especially terk.
butyl and n-octyl. Halogen of atomic number from 9 to 35 preferably signifies fluorine or chlorine.
Phenylalkyl preferably signifies phenethyl, sub-stltuted phenylalkyl preferably signlfies substi-tuted phenethyl. Cycloalkyl preferably is of 3,5 or 6, especially of 3 carbon atoms. In cycloalkyl ~ubstituted by alkyl, the alkyl radical preferably is attached to the 1 position of the cycloalkyl radical. In ~-dialkylpropinyl and ~-dialkylallyl, the alkyl radicals preferably are ident.ical and preferably are of 1 or 2, especially of 1 car- -bon atom. Phenoxyalkyl preferably s1gnifies phenoxy-ethyl, D is prefer~bly ethylene.
:Rl and/or R2 preferably is in the 2 or 3 position. When R is monosubstituted phenylalkyl and/or R4 is monosubstituted phenyl, the phenyl radical preferably is substituted in the 4 posi-tion. When R is polysubstituted phenylalkyl and/orR4 is polysubstituted phenyl, the substituents of the phenyl radical may have independent signifi-cances, are however preferably identical, and pre-ferably are alkoxy groups, especially in the 3,4 or 3,4,5 positions.
In accordance with the invention, a compound of formula I may be obtained by a process comprising a) for the production of a compound of foxmula Ia fCOR4 oC~12CHClI
~ - R~ ~a wherein R, Rl, R2 and R4 are as deflned above, esterifylng a compound of formula Ib OH
ocH2c~IcH2N~l-R Ib ~ ~ ~ Rl wherein R, Rl and R2 are as defined abo~e, or b~ for the production o a compound of ormula Ib, substituting a compound of formula II
~ Rl II
wherein Rl and R2 are as defined above and X
is a leaving group, with a group of formula III
OH
-OCH2CIlCH2NH-R III
8~
-wherein R is as defined above.
Process variant a~ may be effected in a manner analogous to methods known for the acylation of secondary alkohols.
To a compound of formula ~b there may, for example, be added an excess of an anhydride corresponding to the acid of ~ormula R3COCH, as well as an acid. The added acid may be the acid R3COOH, hut may however be different. The process may be effected from about 0 to about 100C, pre-ferably from about room temperature to about 40~C. The process is optionally effected in the presence of an inert organic solvent. The reaction mixture may be woxked up in known manner,conveniently under mild conditions, as otherwise the ester group may be split off.
Process variant b) is a substitution reaction on an aromatic, nitrogen-containing heterocycle which contains a leaving group on a carbon atom adjacent to the nitrogen. It may be effected in a manner analogous to known methods.x preferably sig-nifies an anionic leaVing group, e.g. chlorine, bromine or methylthio; -` -X especially signi-fies chlorine. The substitution is readily effected, e.g. by allowing to stand a solution of a compound ~37~84~
of formula II and a compound of formula H-RX~
wherein Rx is the group of formula III. This may be effected in an inert organic solvent, e.g. a lower alkanol such as tert.butanol. The reaction is preferably effected in the presence of a base, e.g. an alkal~ metal alcoholate such as potassium tert.~utylate. The reaction temperature may vary from a~out 0 to about 80C, and is preferably room temperature.
The carbon atom of the side chain carrying the - -OR3 group in the compounds of formula- I is as~mmetric; the compounds may there~ore appear in the form of the corresponding enantiomers.
The individual optical isomers of the compounds of formula I may be ob~ained in conventional manner, e.g. by effecting the processes according to the invention starting from the corresponding optical i~o-~ mers of the starting materials, whlch may be ob- -- tained in conventional manner starting from opti-cally pure (R)-or(s).glyceraldehyde.
,, . . ., ~ ;
The compounds of formula I may be pxesent in the free form, or in the form of acid addition salts.
Acid addition salts, for example, the hydrogen maleinate, may be produced from the free compounds in known manner, and vice versa.
~L~)7~
- 8 - 100-~513 Insofar as the produc~ion of the starting ma-terials is not described, these are known or may be producPd in accordance with known processes, or in a manner analogous to the processe.s des-crlbed herein or to known processes.
In the follow~ng non-limitative Examples all tempera~ures are indicated in degrees Centigrade and are uncorrected.
:
..:
iV~8~
' -~
EXAMPLE 1: 4-(3 tert.butylamino-2-nonanoyloxy-_xy)thieno~3,2~c~pyridine-3-car-bon~trile ~process variant a]
2.7 g of pelargonic acid and 1.3 g 4-(3-tert.butyl-- amino-2-hydroxypropoxy)thieno[3,2-c]pyridine-3-car-bonitrile in 12 ml of chloroform are reacted drop-wise at 0 with 1.5 g pel~rgonic anhydride in 3 ml of chloro~orm. After 15 hours at room temperature, 50 ml of a 2N soda solution are added and the reaction mixture is extracted thrice ~ith methylene chloride, drled over MgS04, filtered and concen-trated, The title compound is formed (M.P. of the hydrogen malein,ate form 105-107 - from tetrahydro-~uran).
EXAMPLE 2:
~3,2-c]pyridine-4-y gen succinate [process variant a]
1 g of 4-~3-tert.butylamino-2-hydroxypropoxy)thieno E3 ,2-c]pyridine-3-carbonitrile hydrog~n maleinate are dissolved ln 15 ml acetic acid and reacted at room temperature with 0.48 g ofsuccinic - - anhy-dride~ After 15 hours 50 ml of ether are added.
The hydrogen maleinate of the titel compound is obtained (M.P. 134-137).
~ 10 - 100-4513 .
The following compounds of formula Ia are obtained according to process variant a~in a manner analogous to Example 1, us~ng the ~orresponding starting ma-terials of formula Ib:
_ _ . _ ~ .~ .
Enr R Rl R2 4 M.P.
. . _ _____ _ _ 3 tert-butyl 3-bromo H phenyl ~ml 198-201
4 tert-butyl 3-bromo H tert-butyl hml 185-187 tert-butyl 2-cyano H tert-butyl hml 169-172 6 tert-butyl 3~cyano H phenyl hml 202-204 7 tert-butyl 6-methyl H tert-butyl hml 188-190 8 tert-butyl 3-bromo 2-me- tert~butyl hml 160-163 thyl 9 tert-butyl 3-bromo 2-me- 3,4,5-tri-thyl methoxy-phenyl tert-butyl 3-cyano H tert-butyl hml 158-160 11* tert-butyl 3-cyano E 4-fluoro- hml 172-174 phenyl 12 tert-butyl 3-bromo 2-me- phenyl hml 197-200 thyl 13 tert-butyl3-cyano H 3,4,5-tri~ hml 207-210 methoxy-phenyl . :
. ~ _ _ _ _ __ 1, * using as solvent a 1:1 mixture chloroform /hexamethyl-phosphoric acid triamide in place of chloroform hml = hydrogen maleinat.e ~ 97~
.
~ 100-4513 EX~MPI.E 14: 4-[3-(3,4-dimethoxy-phene.hylamino)-~ ~ -- .
~vrldine-2-carbonitrile ~ _ ___ tprocess variant b]
To a solution of 1.0 ~ of po~assium in 60 ml of tert.
butanol ~rc~duced at 35 is ac~cl a solutlon of 6.4 g of 1,2-dihydroxy-3-(3,4-dimethoxyphenethyl-amino)propana in 50 ml of ter~;butanol; then 5.0 g of 4-chloro--thieno[3,2 c]pyridine-2-carbonitrile is added to the mixtu~e. After 4 hours at 30 the reaction mixture is worked up in the usual manner.
The title compound is obtained (M.P. of the hydro-gen maleinate: 150-153~).
, 38~
The compounds of formula I exhibit pharmacological activity. In particular these compounds inhibit lipoly-sis and glycogenolysis induced by isoproterenol as in-dicated bY standard tests.For example the inhibition of lipolysis may be observed in vltro in isolated fat cells taken from the epididymal fat tissue of rats,~
the cells ha~ing been isolated in accordance with the method of M.Rodbell ~J.Biol. Chem. 239(1964) 375-38~.
.. . . . .. ...
The compounds~ are therefox~ inAicateA for u~e ~s inhibitors of the increase in free fatty acid and glucose concentration in blood~induced by emotional stress. -For this use an indicated daily dose is from about 1 to about 200 mg, conveniently administeredin divided doses 2 to 4 times a day in unit dosage form containing from about 0.25 to about 100 mg, or in sustained release form.
Additionally, the compounds exhibit adrenergic ~-blocking activity. In particular the compounds inhibit the positive inotropic adrenaline efect in the spontaneously beating isolated guinea pig atrium.
. ' - .
The compounds are therefore further inaicated for US2 as adreneryic ~-blocking agents, e.g. for the prophylaxis and therapy of coronary diseases, . .
particularly in the treatment of Angina pectoris, and also as antiarrhythmic agents, e.g. in the tr~atment of heart rhythm disorders.
For these usé~ an indicated daily dose is from abo~t 1 to about 100 mg, convenienLly administered in divided ~oses 2 to 4 times a day in unit dosage form containing from about 0.25 to about 50 mg, or -in sustained release form.
.. .. . . . .
Especlally lnteresting is the adrenergic ~-blocking activity of these compounds.
The S enantiomers of the compounds of formula I
are pharmacologically more active than the corres-ponding R enantiomers.
Preferred compounds of formula Ia are compounds of formula Iaa I
OCH2CHCH2NH-RI Iaa ~ ~ I -wherein Rl is hydrogen or alkyl of 1 to 4 carbon atoms, bromine or cyano, in the 2 or 3 position, R4 is alkyl of 4 to 9 carbon atoms, phenyl, phenyl monosubstituted by halogen of atomic number from . . , ~.
.. . .
~)7~
. ~
9 to 35, phenyl mono-,di-or trisubstituted by al-koxy of 1 to 4 carbon atoms, sr a gxoup D -COOH, wherein D is ethylene, and RI is alkyl of 3 to 5 carbon atoms or cycloalkyl of 3,5 or 6 carbon atoms monosubstitu~ed by alkyl of 1 or 2 carbon atoms.
Especially preferred are those compounds of formula Iaa, which are substituted by cyano in the 2-or 3-posit.i.on, those,which have a tert.butyl radical attached to the nitrogen atom of the side chain and those,wherein R4 is alkyl of 4 to 8 carbon atoms, preferably tert.
butyl c~r n octyl, or R4 is phenyl or phenyl mono-substituted by fluorine, preferably in the 4 psition.
Most especially preferred are 4-(3-tert.butylamino-2-piva- -loy~oxypropoxy)thieno[3,2-c]pyridine-2-carboni-trlle, 4-(3.tert.butylamino-2-~onanoyloxypropoxy) thieno[3,2-c]pyridine-3-carbonitrile,~l-tert.butyl-amino-3-(3-cyano-thienoE3,2-c]pyridine-4-yloxy)-2-propyl~hydrogen succinate and 4-(3-tert.butylamino-2-(p-fluorobenæoyloxy)propoxy~hieno~3~2-c]pyridine 3-carbonitrile.
Preferred compounds of formula Ib are compounds of formula Ibb, 0~
OCH2CHC112NH-R Ibb U ~ ~ R
.
. -~o~
- 15 ~ 100-4513 wherein RI is as defined above and :I T
R is alkyl of 3 to 5 carbon atoms, cycloalkyl of 3 to 5 carbon atoms monosuhstituted by alkyl of 1 or 2 carbon atoms, phenylallcyl of 8 to 10 carbon atoms or phenylalkyl of 8 to 10 carbon atoms moro-or disubstituted in the phenyl radical by alkoxy of 1 or 2 carbon atoms.
Es ecially ~referred are those compounds of formula Ibb, which are substituted by cyano in the 2-or 3-position, those, which have attached to the nitrogen atom .
of the side chain a phenylalkyl group of 8 to 10 carbon atoms disubstituted in the phenyl radical by alkoxy of 1 or 2 carbon atoms, preferably di-substituted in the 3 and 4 positions,Most especially pre-~erred is 4-[3-~3,4-dimethoxyphenethylamino)-2-hydroxy-propoxy]thieno[3,2-c]pyridine-2-carbonitrile.
The compounds of formula I may be administered in free form or in pharmaceutically acceptable acid addition salt form. Such salt orms exhibit the same order of activity as the free forms and are readily pre-pared ln conventional manner, The present inven-tion also provides a pharmaceutical composition com-prising a compound of formula I, in free form or in pharmaceutically acceptable acid addItion salt form,in association with a pharmaceutical carrier or di-luent. Such compositions may be in the form of, for example, a solution or a tablet.
. ~ _ _ _ _ __ 1, * using as solvent a 1:1 mixture chloroform /hexamethyl-phosphoric acid triamide in place of chloroform hml = hydrogen maleinat.e ~ 97~
.
~ 100-4513 EX~MPI.E 14: 4-[3-(3,4-dimethoxy-phene.hylamino)-~ ~ -- .
~vrldine-2-carbonitrile ~ _ ___ tprocess variant b]
To a solution of 1.0 ~ of po~assium in 60 ml of tert.
butanol ~rc~duced at 35 is ac~cl a solutlon of 6.4 g of 1,2-dihydroxy-3-(3,4-dimethoxyphenethyl-amino)propana in 50 ml of ter~;butanol; then 5.0 g of 4-chloro--thieno[3,2 c]pyridine-2-carbonitrile is added to the mixtu~e. After 4 hours at 30 the reaction mixture is worked up in the usual manner.
The title compound is obtained (M.P. of the hydro-gen maleinate: 150-153~).
, 38~
The compounds of formula I exhibit pharmacological activity. In particular these compounds inhibit lipoly-sis and glycogenolysis induced by isoproterenol as in-dicated bY standard tests.For example the inhibition of lipolysis may be observed in vltro in isolated fat cells taken from the epididymal fat tissue of rats,~
the cells ha~ing been isolated in accordance with the method of M.Rodbell ~J.Biol. Chem. 239(1964) 375-38~.
.. . . . .. ...
The compounds~ are therefox~ inAicateA for u~e ~s inhibitors of the increase in free fatty acid and glucose concentration in blood~induced by emotional stress. -For this use an indicated daily dose is from about 1 to about 200 mg, conveniently administeredin divided doses 2 to 4 times a day in unit dosage form containing from about 0.25 to about 100 mg, or in sustained release form.
Additionally, the compounds exhibit adrenergic ~-blocking activity. In particular the compounds inhibit the positive inotropic adrenaline efect in the spontaneously beating isolated guinea pig atrium.
. ' - .
The compounds are therefore further inaicated for US2 as adreneryic ~-blocking agents, e.g. for the prophylaxis and therapy of coronary diseases, . .
particularly in the treatment of Angina pectoris, and also as antiarrhythmic agents, e.g. in the tr~atment of heart rhythm disorders.
For these usé~ an indicated daily dose is from abo~t 1 to about 100 mg, convenienLly administered in divided ~oses 2 to 4 times a day in unit dosage form containing from about 0.25 to about 50 mg, or -in sustained release form.
.. .. . . . .
Especlally lnteresting is the adrenergic ~-blocking activity of these compounds.
The S enantiomers of the compounds of formula I
are pharmacologically more active than the corres-ponding R enantiomers.
Preferred compounds of formula Ia are compounds of formula Iaa I
OCH2CHCH2NH-RI Iaa ~ ~ I -wherein Rl is hydrogen or alkyl of 1 to 4 carbon atoms, bromine or cyano, in the 2 or 3 position, R4 is alkyl of 4 to 9 carbon atoms, phenyl, phenyl monosubstituted by halogen of atomic number from . . , ~.
.. . .
~)7~
. ~
9 to 35, phenyl mono-,di-or trisubstituted by al-koxy of 1 to 4 carbon atoms, sr a gxoup D -COOH, wherein D is ethylene, and RI is alkyl of 3 to 5 carbon atoms or cycloalkyl of 3,5 or 6 carbon atoms monosubstitu~ed by alkyl of 1 or 2 carbon atoms.
Especially preferred are those compounds of formula Iaa, which are substituted by cyano in the 2-or 3-posit.i.on, those,which have a tert.butyl radical attached to the nitrogen atom of the side chain and those,wherein R4 is alkyl of 4 to 8 carbon atoms, preferably tert.
butyl c~r n octyl, or R4 is phenyl or phenyl mono-substituted by fluorine, preferably in the 4 psition.
Most especially preferred are 4-(3-tert.butylamino-2-piva- -loy~oxypropoxy)thieno[3,2-c]pyridine-2-carboni-trlle, 4-(3.tert.butylamino-2-~onanoyloxypropoxy) thieno[3,2-c]pyridine-3-carbonitrile,~l-tert.butyl-amino-3-(3-cyano-thienoE3,2-c]pyridine-4-yloxy)-2-propyl~hydrogen succinate and 4-(3-tert.butylamino-2-(p-fluorobenæoyloxy)propoxy~hieno~3~2-c]pyridine 3-carbonitrile.
Preferred compounds of formula Ib are compounds of formula Ibb, 0~
OCH2CHC112NH-R Ibb U ~ ~ R
.
. -~o~
- 15 ~ 100-4513 wherein RI is as defined above and :I T
R is alkyl of 3 to 5 carbon atoms, cycloalkyl of 3 to 5 carbon atoms monosuhstituted by alkyl of 1 or 2 carbon atoms, phenylallcyl of 8 to 10 carbon atoms or phenylalkyl of 8 to 10 carbon atoms moro-or disubstituted in the phenyl radical by alkoxy of 1 or 2 carbon atoms.
Es ecially ~referred are those compounds of formula Ibb, which are substituted by cyano in the 2-or 3-position, those, which have attached to the nitrogen atom .
of the side chain a phenylalkyl group of 8 to 10 carbon atoms disubstituted in the phenyl radical by alkoxy of 1 or 2 carbon atoms, preferably di-substituted in the 3 and 4 positions,Most especially pre-~erred is 4-[3-~3,4-dimethoxyphenethylamino)-2-hydroxy-propoxy]thieno[3,2-c]pyridine-2-carbonitrile.
The compounds of formula I may be administered in free form or in pharmaceutically acceptable acid addition salt form. Such salt orms exhibit the same order of activity as the free forms and are readily pre-pared ln conventional manner, The present inven-tion also provides a pharmaceutical composition com-prising a compound of formula I, in free form or in pharmaceutically acceptable acid addItion salt form,in association with a pharmaceutical carrier or di-luent. Such compositions may be in the form of, for example, a solution or a tablet.
Claims (12)
1. A process for the production of a compound of formula I
I
wherein R1 is (i) hydrogen or alkyl of 1 to 4 carbon atoms (ii) chlorine or bromine, in the 2,3 or 7 position, or (iii) cyano, in the 2 or 3 position, R2 is (i) hydrogen or alkyl of 1 to 4 carbon atoms, or (ii) chlorine or bromine, in the 2,3 or 7 position, or R3 is hydrogen or a group -COR4, wherein R4 is alkyl of 1 to 10 carbon atoms,phenyl mono- or disubstituted by halogen with an atomic number of 9 to 35, phenyl mono-, di- or trisubstituted by alkoxy of 1 to 4 carbon atoms, or a group D-COOH, wherein D is ethylene or trimethylene, and R is phenylalkyl of 8 to 10 carbon atoms or phenyl-alkyl of 8 to 10 carbon atoms mono- or disubstituted in the phenyl radical by alkoxy of 1 to 4 carbon atoms, the phenyl ring of each of the phenylalkyl radicals being separated by at least 2 carbon atoms from the nitrogen atom to which R is bound and, when R3 is a group -COR4, R alternatively is alkyl of 3 to 5 carbon atoms, with the general proviso that, when R1 is cyano, R2 is other than chlorine or bromine, in the 2 or 3 po-sition, or a pharmaceutically acceptable acid addition salt thereof, which comprises a) for the production of a compound of formula Ia Ia wherein R, R1, R2 and R4 are as defined above, esterifying a compound of formula Ib Ib wherein R; R1 ana R2 are as defined above, or b) for the production of a compound of formula Ib, substituting a compound of formula II
II
wherein R1 and R2 are as defined above and X
is a leaving group, with a compound of formula III
III
wherein R is as defined above, and where necessary converting the resulting compound of formula I into a pharmaceutically acceptable acid addition salt thereof.
I
wherein R1 is (i) hydrogen or alkyl of 1 to 4 carbon atoms (ii) chlorine or bromine, in the 2,3 or 7 position, or (iii) cyano, in the 2 or 3 position, R2 is (i) hydrogen or alkyl of 1 to 4 carbon atoms, or (ii) chlorine or bromine, in the 2,3 or 7 position, or R3 is hydrogen or a group -COR4, wherein R4 is alkyl of 1 to 10 carbon atoms,phenyl mono- or disubstituted by halogen with an atomic number of 9 to 35, phenyl mono-, di- or trisubstituted by alkoxy of 1 to 4 carbon atoms, or a group D-COOH, wherein D is ethylene or trimethylene, and R is phenylalkyl of 8 to 10 carbon atoms or phenyl-alkyl of 8 to 10 carbon atoms mono- or disubstituted in the phenyl radical by alkoxy of 1 to 4 carbon atoms, the phenyl ring of each of the phenylalkyl radicals being separated by at least 2 carbon atoms from the nitrogen atom to which R is bound and, when R3 is a group -COR4, R alternatively is alkyl of 3 to 5 carbon atoms, with the general proviso that, when R1 is cyano, R2 is other than chlorine or bromine, in the 2 or 3 po-sition, or a pharmaceutically acceptable acid addition salt thereof, which comprises a) for the production of a compound of formula Ia Ia wherein R, R1, R2 and R4 are as defined above, esterifying a compound of formula Ib Ib wherein R; R1 ana R2 are as defined above, or b) for the production of a compound of formula Ib, substituting a compound of formula II
II
wherein R1 and R2 are as defined above and X
is a leaving group, with a compound of formula III
III
wherein R is 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 pharmaceutically acceptable acid addition salt thereof, whenever pro-duced by a process according to claim 1 or by an obvious chemical equivalent thereof.
3. A process according to claim 1 for the production of a compound of formula I, wherein R1 is cyano.
4. A process according to claim 1 for the production of a compound of formula I, wherein R is tert-butyl.
5. A process according to claim 1 for the production of a compound of formula I, wherein R2 is hydrogen.
6. A process according to claim 1 for the production of a compound of formula I, wherein R4 is phenyl or phenyl substituted by halogen.
7. A process according to claim 3 for the production of a compound of formula I, wherein R1 is cyano in the 2 or 3 position.
8. A compound according to claim 2, wherein, in formula I
R1 is cyano, whenever produced by the process of claim 3, or by an obvious chemical equivalent thereof.
R1 is cyano, whenever produced by the process of claim 3, or by an obvious chemical equivalent thereof.
9. A compound according to claim 2 wherein, in formula I, R is tert-butyl, whenever produced by the process of claim 4, or by an obvious chemical equivalent thereof.
10. A compound according to claim 2 wherein, in formula I, R2 is hydrogen, whenever produced by the process of claim 5, or by an obvious chemical equivalent thereof.
11. A compound according to claim 2 wherein, in formula I, R4 is phenyl or halogen-substituted phenyl, whenever produced by the process of claim 6 or by an obvious chemical equivalent thereof.
12. A compound according to claim 2, wherein R1 is cyano in the 2 or 3 position, whenever prepared by the process of claim 7 or by an obvious chemical equivalent thereof.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH153076A CH619956A5 (en) | 1976-02-09 | 1976-02-09 | Process for the preparation of novel thieno[3,2-c]pyridine derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1078844A true CA1078844A (en) | 1980-06-03 |
Family
ID=4212597
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA271,181A Expired CA1078844A (en) | 1976-02-09 | 1977-02-07 | Thieno (2,3-c) pyridine derivatives |
Country Status (21)
| Country | Link |
|---|---|
| JP (1) | JPS5297995A (en) |
| AT (1) | AT363088B (en) |
| AU (1) | AU512534B2 (en) |
| BE (1) | BE851180A (en) |
| CA (1) | CA1078844A (en) |
| CH (2) | CH619956A5 (en) |
| DE (1) | DE2703888A1 (en) |
| DK (1) | DK42077A (en) |
| ES (1) | ES455701A1 (en) |
| FI (1) | FI770320A (en) |
| FR (1) | FR2340320A1 (en) |
| GB (1) | GB1570328A (en) |
| IE (1) | IE44438B1 (en) |
| IL (1) | IL51396A (en) |
| NL (1) | NL7701179A (en) |
| NZ (1) | NZ183267A (en) |
| PH (1) | PH13659A (en) |
| PT (1) | PT66166B (en) |
| SE (1) | SE7700962L (en) |
| SU (1) | SU683624A3 (en) |
| ZA (1) | ZA77742B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS53153946U (en) * | 1977-05-10 | 1978-12-04 | ||
| FR2452490A1 (en) * | 1979-03-30 | 1980-10-24 | Sanofi Sa | 2-Hydroxy-3-aminopropoxy thieno-pyridine derivs. - useful as antiinflammatories, beta blockers and antiarrhythmics for human and veterinary medicine |
| GB0525164D0 (en) | 2005-12-09 | 2006-01-18 | Xention Discovery Ltd | Compounds |
-
1976
- 1976-02-09 CH CH153076A patent/CH619956A5/en not_active IP Right Cessation
-
1977
- 1977-01-31 DE DE19772703888 patent/DE2703888A1/en not_active Withdrawn
- 1977-01-31 SE SE7700962A patent/SE7700962L/en not_active Application Discontinuation
- 1977-01-31 FI FI770320A patent/FI770320A/fi not_active Application Discontinuation
- 1977-02-01 DK DK42077A patent/DK42077A/en unknown
- 1977-02-04 NL NL7701179A patent/NL7701179A/en not_active Application Discontinuation
- 1977-02-07 PH PH19422A patent/PH13659A/en unknown
- 1977-02-07 IL IL51396A patent/IL51396A/en unknown
- 1977-02-07 NZ NZ183267A patent/NZ183267A/en unknown
- 1977-02-07 CA CA271,181A patent/CA1078844A/en not_active Expired
- 1977-02-07 PT PT66166A patent/PT66166B/en unknown
- 1977-02-07 BE BE174734A patent/BE851180A/en unknown
- 1977-02-07 ES ES455701A patent/ES455701A1/en not_active Expired
- 1977-02-07 IE IE254/77A patent/IE44438B1/en unknown
- 1977-02-08 FR FR7703432A patent/FR2340320A1/en active Granted
- 1977-02-08 GB GB5104/77A patent/GB1570328A/en not_active Expired
- 1977-02-08 AT AT0080977A patent/AT363088B/en not_active IP Right Cessation
- 1977-02-08 JP JP1219677A patent/JPS5297995A/en active Pending
- 1977-02-09 AU AU22136/77A patent/AU512534B2/en not_active Expired
- 1977-02-09 SU SU772451699A patent/SU683624A3/en active
- 1977-02-09 ZA ZA00770742A patent/ZA77742B/en unknown
-
1980
- 1980-01-30 CH CH75580A patent/CH622796A5/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| AU2213677A (en) | 1978-08-17 |
| SE7700962L (en) | 1977-08-10 |
| DE2703888A1 (en) | 1977-08-11 |
| NL7701179A (en) | 1977-08-11 |
| ES455701A1 (en) | 1978-04-16 |
| PH13659A (en) | 1980-08-21 |
| NZ183267A (en) | 1979-04-26 |
| IE44438L (en) | 1977-08-09 |
| SU683624A3 (en) | 1979-08-30 |
| IE44438B1 (en) | 1981-12-02 |
| GB1570328A (en) | 1980-06-25 |
| IL51396A (en) | 1980-02-29 |
| IL51396A0 (en) | 1977-04-29 |
| ZA77742B (en) | 1978-09-27 |
| FR2340320A1 (en) | 1977-09-02 |
| PT66166B (en) | 1978-10-13 |
| CH622796A5 (en) | 1981-04-30 |
| CH619956A5 (en) | 1980-10-31 |
| DK42077A (en) | 1977-08-10 |
| BE851180A (en) | 1977-08-08 |
| ATA80977A (en) | 1980-12-15 |
| AU512534B2 (en) | 1980-10-16 |
| AT363088B (en) | 1981-07-10 |
| FI770320A (en) | 1977-08-10 |
| FR2340320B1 (en) | 1980-03-14 |
| PT66166A (en) | 1977-03-01 |
| JPS5297995A (en) | 1977-08-17 |
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