IE44438B1

IE44438B1 - Improvements in or relating to thienopyridines

Info

Publication number: IE44438B1
Application number: IE254/77A
Authority: IE
Original assignee: Sandoz Ltd
Priority date: 1976-02-09
Filing date: 1977-02-07
Publication date: 1981-12-02
Also published as: PT66166A; BE851180A; ZA77742B; AU512534B2; IL51396A; NZ183267A; SE7700962L; DK42077A; FR2340320A1; NL7701179A; IE44438L; CA1078844A; CH622796A5; DE2703888A1; ES455701A1; FI770320A; AU2213677A; AT363088B; JPS5297995A; GB1570328A

Abstract

The compounds of the formula I in which the substituents have the meanings given in the patent claims, are novel. They have beta -adrenoreceptor-blocking, antiarrhythmic and metabolic actions and are therefore suitable for use as medicines. They are obtained by esterification.

Description

The present invention relates to thieno(3,2c)pyri dine derivatives.

In accordance with the Invention there are provided compounds of formula I, wherein Rj is Ci) hydrogen or alkyl of 1 to 4 carbon atoms,- 1 --- or (ii) chlorine or bromine, in the 2,3 or 7 position, or (ill) fluorine, cyano or COOB, wherein B is alkyl of 1 to 4 carbon atoms, in the 2 or 3 position, Rj is Ci) 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 -COR^, wherein 4 ύ 3 8 R^ 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 atcms, or a group D-COOH, wherein D is ethylene or trimethylene, and R is phenylalkyl of 8 to 10 carbon atoms, phenyl10 alkyl of 8 to 10 carbon atoms monosubstituted in the phenyl radical by alkyl of 1 to 4 carbon 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 disubsti15 tuted ln the phenyl radical by alkoxy of 1 to carbon atoms,the phenyl ring of each of the phenylalkyl radicals being separated by at least 2 carbon at?ms from the nitrogen atom to which R is bound and, when R^ is a group -CORj, R alternatively is alkyl of 3 to 7 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, cycloalkyl of 3 to 7 carbon atoms monosubstituted by alkyl of 1 tc 4 carbon atoms, a-dialkylpropinyl of 5 to 9 carbon atoms, a-dialkyl25 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. 4443® with the general proviso that, when R^ ls cyano or COOB, R2 Is other than fluorine, chlorino or bronlne. In the 2 or 3 position.

Rj Is preferably hydrogen, alkyl, chlorine, bro5 mine or cyano. Rj Is preferably hydrogen or alkyl.

Rj Is preferably a group -CORj. Rj ls preferably alkyl, phenyl, phenyl substituted by halogen or alkoxy, or a group D-COOH. R is preferably alkyl,alkylcycloalkyl, phenylalkyl or phenylalkyl substituted by alkoxy, especially alkyl.

Alkoxy preferably contains 1 or 2, especially 1 carbon atom. When Rj and/or R2 is alkyl or when Η* Is phenyl substituted by alkyl or when R is phenylalkyl substituted in the phenyl radical by alkyl or cycloalkyi substituted by alkyl, or when B is alkyl,these alkyl radicals preferably contain 1 or 2, especially 1 carbon atom. When Rj and/or R2 is fluorine, chlorine or bromine, these radicals are preferably chlorine or bromine, especially bromine. When R is alkyl, this radical preferably Ib branched, especially in an α-positlon to the nitrogen atom to which it is bound. Especially preferred alkyl radicals R are isopropyl, tert.butyl, 3-pentyl and tert, pentyl.

When Rj ls alkyl, this radical preferably contains 1 to 10, especially 4 to 9 carbon atoms. Especially i ·Μ' Η •5' , preferred alkyl, radicals R A are tertk butyl,3• l i ί Ϊ , ; j 4 . ; · ·. i · · · · pentyl,ϊtert. pentyl and n-octyl, especially tert., ' ! · · i ί ) ’ i butyl and n-octy,l. Halogen of atomic number from/ 1 • . · · » ,» . · . ι /1 V i. '» to 35 preferably signifies fluorine 6r\chlbrifne J' , '.‘, ! · · Γ; · , , ·. · ' 1 ' Phenylalkyl preferably signifies phenethyl, sub* s'. · · ··.·.' : stltuted phenylalkyl preferably signifies substituted phenethyl. Cycloalkyl preferably ;is of 3>5 ' I ι or 6, especially of 3 carbon‘atoms. In cycloalkyl substituted, by alkyl# the alkyl radical preferably is attached to the 1 position of the cycloalkyl radical. In o-dialkylpropinyl and a-dialkylallyl, the alkyl radicals preferably are identical and preferably are of 1 or 2, especially of 1 cart bon atom. Phenoxyalkyl preferably signifies phenoxyethyl, D is preferably ethylene. and/or R^ preferably is in the 2 or 3 position. When R is monosubstituted phenylalkyl and/or R^ is monosubstituted phenyl, the phenyl radical preferably is substituted in the >4 posΙΣΟ tion. When R is polysubstituted phenylalkyl and/or is polysubstituted phenyl, the substituents of the phenyl radical may have Independent significances, are however preferably identical, and preferably 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 4443» a) for the production of a compound of formula Ia wherein R, Rj, R^ and R^ are as defined above, esterifying a compound of formula lb wherein R, R^ and are as defined above, or b) for the production of a compound of formula Ib, substituting a compound of formula II II wherein R^ and R? are as defined above and X is a leaving group, with a group of formula III OH I "OCH-CHCII-NII-R 2 2 III 44430 wherein R is as defined above.

Process variant a) may be effected in a manner analogous to methods known for the acyl&tion of secondary alkohols.

To a compound of formula Ib there may, for example, be added an excess of an anhydride corresponding to the acid of formula RjCOOH,as well as an acid. The added acid may be the acid RjCOOH, but may however be different. The process may be effected from about 0 to about 100°C, preferably 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 worked 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 signifies an anionic leaving group, e.g. chlorine, bromine or methylthio}--:-—_____ X especially signi25 fies chlorine. The substitution is readily effected, e.g. by allowing to stand a solution of a compound - 7 44438 of formula II and a compound of formula Η'Κχ» wherein R* le the group of formula III. This may be effected ln 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 alkali metal aleoholate such as potassium tert.butylate. The reaction temperature may vary frcm about 0° to about 80®C, and Is preferably room temperature.

The carbon atom of the side chain carrying the -ORj group ln the compounds of formula I Is asymmetric} the compounds may therefore appear in the form of the corresponding enantiomers.

The individual optical Isomers of the compounds of formula I may be obtained in conventional manner, e.g. by effecting the processes according to the invention starting from the corresponding optical inn mere of the starting materials, which may be obtained ln conventional manner starting from opti20 cally pure (R)-or(S)rglyceraldehyde.

The compounds of formula I may be present ln the free form, or in the form of acid addition salts.

Acid addition salts, for example, the hydrogen maleate may be produced from the free compounds ln known manner, and vice versa.

Insofar as the production of the starting materials is not described, these are known or may be produced in accordance with known processes, or in a manner analogous to the processes described herein or to known processes.

In the following non-limitative Examples all temperatures are indicated in degrees Centigrade and are uncorrected. - 9 EXAMPLE 1: 4-(3-tert.butylamino-2-nonanoyloxypropoxy)thienot3,2-c)pyrldlne-3-carbonltrlle [process variant a] 2.7 g of pelargonic acid and 1.3 g 4-(3-tert.butylamino- 2-hydroxypropoxy)thieno[3,2-c]pyridine-3-carbonitrile ln 12 ml of chloroform are reacted dropwise at 0° with 1.5 g pelargonic anhydride ln 3 ml of chloroform. After 15 hours at roan temperature, 50 ml of a 2M soda solution are added and the reaction mixture ls extracted thrice with methylene chloride, dried over MgSO* , filtered and concentrated. The title compound ls formed (M.P. of the hydrogen maleate form 105-107* - from tetrahydro15 furan).

EXAMPLE 2t fl-tert.butylamino-3- (3-cyano-thieno [3,2-c)pyridlne-4-yloxy)-2-propy1^ hydro gen succinate [process variant a) 1 g of 4-(3-tert.butylamino-2-hydroxypropoxy)thieno [3,2-c]pyridine-3-carbonitrile hydrogen maleate are dissolved in 15 ml acetic acid and reacted at room temperature with 0.48 g of succinic--anhydride. After 15 hours 50 ml of ether aro added.

The hydrogen maleate of the title compound is obtained (M.P. 134-137°).

The following compounds of formula Ia are obtained according to process variant a) in a manner analogous to Example 1, using the corresponding starting materials of formula Ib: EX. nr. R «1R2R4 M.P. 5 3 tert-butyl 3-bromo H phenyl hml 198-201° 4 tert-butyl 3-bromo H tert-butyl hml 185-187° 5 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 R tert-butyl hml 188-190’ 10 8 tert-butyl 3-bromo 2-me- thyl tert-butyl hml 160-163° 9 tert-butyl 3-bromo 2-me- thyl 3,4,5-trimethoxyphenyl 15 10 tert-butyl 3-cyano H tert-butyl hml 158-160° 11* tert-butyl 3-cyano H 4-fluorophenyl hml 172-174° 12 tert-butyl 3-bromo 2-me- thyl phenyl hml 197-200° 20 13 tert-butyl 3-cyhno B 3,4,5-tri- methoxy- phenyl hml 207-210° * using as solvent a 1:1 mixture chloroform /hexamethylphosphoric acid triamide in place of chloroform hml = hydrogen maleate 4443» EXAMPLE 14; 4-(3-(3,4-dimethoxy-phenethylamino)2-hydroxypropoxy)thleno(3,2-c) pyrldlne-2-carbonltrile [process variant b] To a solution of 1.0 cr of potassium in 60 ml of tert butanol produced at 35° is added a solution of 6.4 g of l,2-dihydroxy-3-[3,4-diroethoxyphenethylamino) propane in 50 ml of tert*.butanol} then 5.0 g of 4-chloro-thieno[3,2-c)pyridine-2-carbonltrile is added to the mixture. After 4 hours at 30° the reaction mixture is worked up in the usual manner.

The title compound is obtained (M.P. of the hydrogen maleate : 150-153°). - 12 The compounds of formula I exhibit pharmacological activity. In particular these compounds inhibit lipolysis and glycogenolysis induced by isoproterenol as indicated by standard tests.For example the inhibition of lipolysis may be observed in vitro in isolated fat cells taken from the epidldymal fat tissue of rats, the cells having been isolated in accordance with the method of M.Rodbell [J.Biol. Chem. 239/1964) 375-380).

The compounds are therefore indicated for use as 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 administered in 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 β-blocking activity. In particular the compounds inhibit the positive inotropic adrenaline effect in the spontaneously beating isolated guinea pig atrium .

The compounds are therefore further indicated for use as adrenergic β-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. ln the treatment of heart rhythm disorders.

Por these usee an Indicated daily dose is from 5 about 1 to about 100 mg, conveniently administered ln divided doses 2 to 4 times a day in unit dosage form containing from about 0.25 to about 50 mg, or in sustained release form.

Especially interesting is the adrenergic p-blocking 10 activity of these compounds.

The S enantiomers of the compounds of formula I are pharmacologically more active than the corresponding R enantiomers.

Preferred compounds of formula Ia are compounds 15 of formula Iaa I wherein R* is hydrogen or alkyl of 1 to 4 carbon atoms, bromine or cyano, in the 2 or 3 position, rJ is alkyl of 4 to 9 carbon atoms, phenyl, phenyl monosubstituted by halogen of atomic number from - 14 iSS.aBOT: to 35, phenyl mono-,di-or trisubstituted by alkoxy of 1 to 4 carbon atoms, or a group DI-COOH, wherein D1 is ethylene, and R1 ls alkyl of 3 to 5 carbon atoms or cycloalkyi of 3,5 or 6 carbon atoms monosubstituted by alkyl of 1 or 2 carbon atoms.

Especially preferred are those compounds of formula laa, which are substituted by cyano in the 2-or 3-position, those,which have a tert.butyl radical attached to the nitrogen atom of the side chain and those,wherein R* ls alkyl of 4 to 8 carbon atoms, preferably tert, butyl or n-octyl, or R* is phenyl or phenyl monosubstituted by fluorine, preferably in the 4 position.

Most especially preferred are 4-(3-tert.butylamino-2-piva15 loyloxypropoxy)thieno(3,2-c)pyridine-2-carbonitrlle, 4- (3-?tert.butylamino-2-nonanoyloxypropoxy) thieno(3,2-c)pyridine-3-carbonitrile,fcl-tert. butylamino-3- (3-cyano-thieno [3,2-c]pyridln2-4-yloxy)-2propy4 hydrogen succinate and 4-(3-tert.butylamino20 2~(p-fluorobenzoyloxy) propoxythieno[3,2-c)pyridine3-carbonitrile.

Preferred compounds of formula Ib are compounds of formula Ibb, Oil Ibb wherein R| is as defined above and R11 is alkyl of 3 to 5 carbon atoms, cycloaikyl of to 5 carbon atoms monosubstituted by alkyl of 1 or 2 carbon atoms, phenylalkyl of 8 to 10 carbon atoms or phenylalkyl of 8 to 10 carbon atoms monoor disubstituted in the phenyl radical by alkoxy of 1 or 2 carbon atoms.

Especially preferred are those comsounds of formula Ibb, which axe 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 di15 substituted in the 3 and 4 position&Most especially preferred is 4-[3-(3,4-dimethoxyphenethylamino)-2-hydroxypropoxy ] thieno(3,2- c)pyridine-2-carbon!trile.

The compounds of formula I may be administered ln free form or in pharmaceutically acceptable acid addition salt 2o form. Such salt forms exhibit the same order of activity as the free forms and are readily prepared in conventional manner. The present invention also provides a pharmaceutical composition comprising a compound of formula I, in free form or in pharmaceutically acceptable acid addition salt form,in association with a pharmaceutical carrier or diluent. Such compositions may be in the form of, for example, a solution or a tablet.

Claims

1. A process for the production of a compound of formula ’I wherein R 1 ls (1) hydrogen or alkyl of 1 to 4 carbon atoms, - qj. (11) chlorine or bromine, in the

2. ,3 or 7 position, or (iii) fluorine, cyno or COOB, wherein B is alkyl of 1 to 4 carbon atoms, in the 2 or 3 position. R 2 is (i) hydrogen or alkyl of 1 to 4 carbon Atoms t — or (ii) chlorine or bromine, in the 2,3 or 7 position, or (ill) fluorine, in the 2 or 3 position, R 3 1s hydrogen or a group -COR., wherein 4443» 17 R^ 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 5 number of 9 to 35, phenyl mono-, di- or trisubstituted by alkoxy of 1 to 4 carbon atoms, or a group D-COOIl, wherein D is ethylene or trimethylene, and R is phenylalkyl of 8 to 10 carbon atoms, phenyl10 alkyl of 8 to 10 carbon atoms monosubstituted in the phenyl radical by alkyl of 1 to 4 carbon 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 disubsti15 tuted 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 Rj is a group 20 -COR^, R alternatively is alkyl of 3 to 7 carbon atoms, cycloalkyl of 3 to 7 carbon atcms, cycloalkyl of 3 to 7 carbon atoms monosubstltutcd by alkyl of 1 to 4 carbon atoms, r»-d.lalky lpropinyl of 5 to 9 carbon atoms, a-dialkyl25 allyl of 5 to 9 carbon atoms, or pbenoxyalkyl , 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, - 18 with the general proviso that, when R^ is cyano or COOD, R 2 is other than fluorine, chlorine or bromine, in the 2- pr 3-position, which comprises a) for· the production of a coinpound of formula la wherein R, R^, R^ mid R^ ate as defined above, esterifying a compound of formula lb OH 10 wherein R, R^ and R^ are as defined above, or b) for the production of a compound of formula lb, substituting a compound of formula II II - 19 wherein R^ and Rj are aa defined above and X ls a leaving group, with a group of formula III OH I -OCH,CHCII,N||-R 2 2 III wherein R is as defined above. 5 2. A process for the production of a compound of formula I, as stated in claim 1, substantially as hereinbefore deacrlbed with reference to any one of the Examples.

3. A compound of formula I, whenever produced by 10 a process according to claim 1 or 2.

4. A compound of formula I, as defined in claim 1.

5. A compound of claim 4, wherein R is tert.butyl.

6. A canpound of claim 4, wherein R is 3,4-dimethoxyphenethyl. 15

7. A canpound of claim 5, wherein R x , Rj and Rj are,respectively, 3-cyano, hydrogen and nonanoyl.

8. A canpound of claim 5, wherein R x , Rj and R 3 are,respectively, 3-cyano, hydrogen and 20 -COCHjCHjCOOH . *4438

9. A compound of claim 5, wherein Rp R 2 and R 3 are,respectively, 3-bromo, hydrogen and benzoyl.

10. A compound of claim 5, wherein R 1# r 2 and R 3 are,respectively, 3-bromo, hydrogen and 5 pivaloyl.

11. A compound of claim 5, wherein R x , R 2 and R 3 are«respectively, 2-cyano, hydrogen and pivaloyl.

12. A compound of claim 5, wherein R and R 3 10 are,respectively, 3-cyano, hydrogen and benzoyl.

13. A compound of claim 5, wherein Rp R 2 and Rj are.respectively, 6-methyl, hydrogen and pivaloyl.

14. A compound of claim 5, wherein R 3 , R 2 and R 3 15. Are, respectively, 3-bromo, 2-methyl and pivaloyl.

15. A compound of claim 5, wherein R 1# R 2 and R 3 are. respectively, 3-bromo, 2-methyl and 3,4,5trimethoxybenzoyl. 20

16. A compound of claim 5, wherein Rp R 2 and R 3 are,respectively, 3-cyano, hydrogen and pivaloyl. 21

17. A compound of claim 5, wherein Rj, R 2 and R 3 are,respectively, 3-cyano, hydrogen and 4fluorobenzoyl.

18. A compound of claim 5, wherein Rj, R 2 and R 3 5 are,respectively, 3-brcmo, 2-methyl and benzoyl

19. A compound of claim 5, wherein Rj, R 2 and R 3 are,respectively, 3-cyano, hydrogen and 3,4,5trimethoxybenzoy1.

20. A compound of claim 6, wherein Rj, R^ and R^ 10 are, respectively, 2-cyano, hydrogen and hydrogen.

21. A compound of claim 4, wherein Rj is hydrogen, chlorine, bromine, cyano or alkyl and R 2 is hydrogen or alkyl. 15

22. A compound of claim 21, wherein R. is -CH 2 -CH 2 -C00H. .

23. A compound of claim 21, wherein Rj and R are, independently, alkyl.

24. A compound according to any one of claims 3 to 20 23, in free form.

25. A compound according to any one of claims 3 to 23, in acid addition salt form. <4438

26. A pharmaceutical composition comprising a compound according to any one of claims 3 to 20 ln free form or in pharmaceutically acceptable add addition salt form, ln association with a 5 pharmaceutical carrier or diluent.