IE44438L

IE44438L - THIENO [3,2-c] PYRIDINES

Info

Publication number: IE44438L
Application number: IE770254A
Authority: IE
Original assignee: Sandoz Ltd
Priority date: 1976-02-09
Filing date: 1977-02-07
Publication date: 1977-08-09
Also published as: AU2213677A; SE7700962L; DE2703888A1; NL7701179A; ES455701A1; PH13659A; NZ183267A; SU683624A3; CA1078844A; IE44438B1; GB1570328A; IL51396A; IL51396A0; ZA77742B; FR2340320A1; PT66166B; CH622796A5; CH619956A5; DK42077A; BE851180A

Abstract

The compounds of the formula I <IMAGE> 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. [GB1570328A]

Description

4 4 13 8 - 1 - The present invention relates to thienol3,2c)pyrl-dine derivatives.

In accordance with the invention there are pro-5 vlded compounds of formula I, OR- I 3 :ii2chch2nh-r wherein Is (i) hydrogen or alkyl of 1 to 4 carbon atoms, — .— or 10 (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, 15 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 (ill) fluorine, in the 2 or 3 position, 20 R3 is hydrogen or a group -COR^, wherein 4 44 3 - 2 - Rj is alkyl of 1 to 17 carbon atoms, phenyl, phenyl monosubstituted by nltro, 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 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 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 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 atrms from the nitrogen atom to which R is bound and, when R^ is a group -C0R4, 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 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 separated by at least two carbon atoms from the nitrogen atom to which R is bound. 44438 - 3 - with the general proviso that, when R^ is cyano or COOB, R2 Is other than fluorine, chlorino or bromine. In the 2 or 3 position.

R^ is preferably hydrogen, alkyl, chlorine, bro-5 mine or cyano. R2 is preferably hydrogen or alkyl.

Rj Is preferably a group -COR^. R4 is preferably alkyl, phenyl, phenyl substituted by halogen or alkoxy, or a group D-COOH. R Is preferably alky 1, alky Icy do-alkyl, phenylalkyl or phenylalkyl substituted by 10 alkoxy, especially alkyl.

Alkoxy preferably contains 1 or 2, especially 1 carbon atom. When R^ and/or R2 is alkyl or when Rj is phenyl substituted by alkyl or when R is phenylalkyl substituted in the phenyl radical by 15 alkyl or cycloalkyl substituted by alkyl, or when B is alky1#these alkyl radicals preferably contain 1 or 2, especially 1 carbon atom. When R^ and/or R2 is fluorine, chlorine or bromine, these radicals are preferably chlorine or bromine, especially 20 bromine. When R is alkyl, this radical preferably 1b branched, especially in an a-positlon to the nitrogen atom to which it is bound. Especially preferred alkyl radicals R are isopropyl, tert.butyl, 3-pentyl and tert. pentyl. 25 When R^ is alkyl, this radical preferably contains 1 to 10, especially 4 to 9 carbon atoms. Especially - 4 - !.-'l n •'flr.tJ .Mi: .;jl' :i 'Ili * i i.

V 10 15 , preferred alkyl. radicals R^'- axe tertibutyl, 3-pentyl,iert. p6ntyl and n-octyl, especially tert.. butyl and n-octyl. Halogen of atomic number front/ \ 9 to 35 preferably signifies fluorine 6r* chlbrilne.' ' ! • • • ' F; 1 ' Phenylalkyl preferably signifies pheneth^l, sub* • i l. • • : stituted phenylalkyl preferably signifies substituted phenethyl. Cycloalkyl preferably ;is of 3*5 > | or 6, especially of 3 carbon1 atoms. In cycloalkyl substituted,by alkyl, the alkyl radical preferably is attached to the 1 position of the cycloalkyl radical. In a-dialkylpropinyl and a-dialkylallyl, the alkyl radicals preferably are identical and preferably are of 1 or 2, especially of 1 car-?- f bon atom. Phenoxyalkyl preferably signifies phenoxy-ethyl, D is preferably ethylene.

; I .

■ I R^ and/or R^ preferably is in the 2 or 3 position. When R is monosubstituted phenylalkyl and/or is monosubstituted phenyl, the phenyl radical preferably is substituted in the >4 posi-20 tion. When R is polysubstituted phenylalkyl aiid/or R^ 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 25 or 3,4,5 positions.

In accordance with the invention, a compound of formula I may be obtained by a process comprising 443« - 5 - a) for the production of a compound of formula la ocor.

I 4 ocii2chch2hu-r la wherein R, R^, R2 and R^ are as defined above, esterifying a compound of formula lb :h2chch2nii-r lb wherein R, R^ and R2 are as defined above, or b) for the production of a compound of formula lb, substituting a compound of formula II II wherein R^ and R2 are as defined above and X is a leaving group, with a group of formula III OH I -ocii2chci?2nh-r hi 4.4438 - 6 - < 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. 5 To a compound of formula lb there may, for example, be added an excess of an anhydride corresponding to the acid of formula R-jCOOH, as well as an acid. The added acid may be the acid R3COOH, ?jut may however be different. The process 10 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 15 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 20 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 methylthioj : ——-—.—- X especially signi- 25 fies chlorine. The substitution is readily effected, e.g. by allowing to stand a solution of a compound 44438 of formula II and a compound of formula H-R^, wherein 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 5 is preferably effected in the presence of a base, e.g. an alkali metal alcoholate such as potassium tert.butylate. The reaction temperature may vary frcm about 0° to about 80°C, and is preferably room temperature. 10 The carbon atom of the side chain carrying the -OR^ group in 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 15 formula I may be obtained in conventional manner, e.g. by effecting the processes according to the invention starting from the corresponding optical i»r>-mers of the starting materials, which may be obtained in conventional manner starting front optl-20 cally pure (R)-or(S)rglyceraldehyde.

The compounds of formula I may be present in 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 25 in known manner, and vice versa. - 8 - 4 4 4 Insofar as the production of the starting materials is not described, these are known or nay 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. 4 4 3 8 EXAMPLE li 4- (3-tert.butylamino-2-nonanoyloxy-propoxy)thleno[3,2-c]pyridine-3-car-bonitrile [process variant a] 2.7 9 of pelargonic acid and 1.3 9 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 9 pelargonic anhydride in 3 ml of chloroform. After 15 hours at roan temperature/ 50 ml of a 2N soda solution are added and the reaction mixture is extracted thrice with methylene ' chloride, dried over MgSO^ , filtered and concentrated. The title compound is formed (M.P. of the hydrogen maleate form 105-107° - from tetrahydro-furan).

EXAMPLE 2i fl-tert.butylamlno-3-(3-cyano-thieno [3,2-c]pyridine-4-yloxy)-2-propy]| hydrogen succinate [process variant a] 1 9 of 4-(3-tert.butylamino-2-hydroxypropoxy)thieno t3,2-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 arc added. The hydrogen maleate of the title compound is obtained (M.P. 134-137°). 44438 10 - The following compounds of formula la are obtained according to process variant a) in a manner analogous to Example 1, using the corresponding startinq materials of formula lb: Ex. nr.

R *1 R2 R4 M.P • 5 3 tert-butyl 3-bromo B phenyl hml 198- 201° 4 tert-butyl 3-brcrao H tert-butyl hml 185- 187® 5 tert-butyl 2-cyano H tert-butyl hml 169- 172° 6 tert-butyl 3-cyano B phenyl hml 202- 204° 7 tert-butyl 6-methyl B 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-thyi 3,4,5-tri- methoxy- phenyl 15 10 tert-butyl 3-cyano B tert-butyl hml 158- 160° 11* tert-butyl 3-cyano H 4-fluoro-phenyl hml 172- 174° 12 tert-butyl 3-bromo 2-me-thyl phenyl hml 197- 200° 20 13 tert-butyl 3-cyhno H 3,4,5-tri- methoxy- phenyl hml 207- 210° * using as solvent a 1:1 mixture chloroform /hexamethyl-phosphoric acid triamide in place of chloroform 25 hml = hydrogen maleate 4 4 ^3 8 - 11 - EXAMPLE 14: 4- [3- (3,4-dlmethoxy-phenethylamlno)-2-hydroxvpropoxy]thieno[3,2-c] pyridine-* 2-carbonltrlle (process variant b] 5 To a solution of 1.0 cr of potassium in 60 znl of tert. butanol produced at 35° is ad<*etf a solution of 6.4 g of l,2-dlhydroxy-3-(3,4-dlmethoxyphenethyl-amlno) propane in 50 ml of tert-.but?mol» then 5.0 g of 4-chloro-thieno(3,2-c]pyridine-2-carbonitrile 10 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°). 44438 - 12 - The compounds of formula I exhibit pharmacological activity. In particular these compounds inhibit llpoly-sis and glycogenolysis Induced by isoproterenol as indicated by standard tests.For example the inhibition of 5 lipolysis may be observed in vitro in isolated fat cells taken from the epididymal fat tissue of rats, the cells having been isolated in accordance with the method of M.Rodbell [J.Biol. Chem. 239(1964) 375-380]. lO The compounds are therefor** inrtieatM 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 15 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 2o p-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 25 as adrenergic p—blocking agents, e.g. for the prophylaxis and therapy of coronary diseases, 4 4^38 - 13 - particularly in the treatment of Angina pectoris, and also as antiarrhythmic agents, e.g. in the treatment of heart rhythm disorders.

For these uses an indicated daily dose is from 5 about 1 to about 100 mg, conveniently administered in 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 la are compounds 15 of formula Iaa I ocor 4 ocm cum Nii-n I Iaa wherein R* is hydrogen or alkyl of 1 to 4 carbon atoms, bromine or cyano, in the 2 or 3 position, 20 rJ is alkyl of 4 to 9 carbon atoms, phenyl, phenyl monosubstituted by halogen of atomic number from 44438 - 14 - 9 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 is alkyl of 3 to 5 carbon atoms or cycloalkyl of 5 3,5 or 6 carbon atoms monosubstituted by alkyl of 1 or 2 carbon atoms.

Especially preferred are those compounds of fornnila Iaa, which are substituted by cyano in the 2-or 3-posit*r>n, those,which have a tert.butyl radical attached to the 10 nitrogen atom of the side chain and those ,wh*»r«in R1. 4 is alkyl of 4 to 8 carbon atoms, preferably tert. butyl or n-octyl, or R^ is phenyl or phenyl mono-substituted by fluorine, preferably in the 4 position.

Most especially preferred are 4-(3-tert.butylamino-2-piva-15 loyloxypropoxy)thieno [3,2-c]pyrldine-2-carboni-trile, 4-(3Ttert.butylamlno-2-nonanoyloxypropoxy) thieno[3,2-c]pyridine-3-carbonitrile,\l-tert.buty1-amino-3-(3-cyano-thieno[3,2-c)pyridln2-4-yloxy) -2-propyli hydrogen succinate and 4-(3-tert.butylamino-20 2- (p-fluoroben20yloxy)propoxythieno[3,2-cJpyridine-3-carbonitrile.

Preferred compounds of formula lb arc compounds of formula Ibb, OU I 0CH2CHCH2nh-r II Ibb ..-y \ i L VlFi 44 4 38 - 15 - wherein R^ is as defined above and R is alkyl of 3 to 5 carbon stoma, cycloalkyl of 3 to 5 carbon atoms monosubstituted by alkyl of 1 5 or 2 carbon atoms, phenylalkyl of 8 to 10 carbon atoms or phenylalkyl of 8 to 10 carbon atoms mor.o-or disubstituted in the phenyl radical by alkoxy of 1 or 2 carbon atoms* Especially preferred are those comoounds of formula Ibb# 10 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 atoius disubstituted in the phenyl radical by alkoxy of 1 or 2 carbon atoms, preferably di-15 substituted in the 3 and 4 position&Most especially preferred 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 pharmaceutlcally 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 J, in free form or 25 in pharmaceutlcally 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. 4 4 4 38 - 16 -

Claims

claims

1. A process for the production of a compound of formula 'I or, I 3 ochjchciijnll-r wherein 5 R^ 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, cy'no or COOB, wherein B is 10 alkyl of 1 to 4 carbon atoms, in the 2 or 3 position, Rj is (i) hydrogen or alkyl of 1 to 4 carbon atoms, ——— or (ii) chlorine or bromine, in the 2,3 or 7 15 position, or (iii) fluorine, in the 2 or 3 position# Rj is hydrogen or a group -COR^, wherein Rj 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 atonic 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 is phenylalkyl of 8 to 10 carbon atoms, phenylalkyl 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 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 front the nitrogen atom, to which R is bound and, when is a group -COR^, R alternativeV 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 to 4 carbon atoms, n-dialky lpropinyl of 5 to 9 carbon atoms, o-dialkyl-allyl of 5 to 9 carbon *toms, 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, 4 4 438 - 18 - with the general proviso that, when R^ is cyano or COOB, R2 is other thai , in the 2- qx 3-position, or COOB, R2 is other than fluorine, chlorine or bromine. la which comprises a) for* the production of a compound of formula Za OCOH. 1 4 OCH2CHCH2NH-R Qm*r- wherein H, R^, H2 ond aio as defined abovn, esterifying a compound of formula lb OH I OCH-CHCH-Nn-R 2 2 lb 10 wherein R, R^ and R2 are as defined above, or b) for the production of a compound of formula lb, substituting a compound of formula XI II 4438 - 19 - wherein R^ and are a's defined above and X Is a leaving group, with a group of formula III Oil i -och-ciicii-nh-r

2. 2 111 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 deiicribed with refAr^n^ to »ry ere 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 compound of claim 4, wherein R is 3,4-di-methoxyphenethyl. 15

7. A compound of claim 5, wherein R^, R2 and R3 are,respectively, 3-cyano, hydrogen and non-anoyl. 20

8. A compound of claim 5, wherein R^, R2 and R3 are,respectively, 3-cyano, hydrogen and -coch2ch2cooh . •£4438 - 20 -

9. A compound of claim 5, wherein R.^ R2 and R3 are,respectively, 3-bromo, hydrogen and benzoyl.

10. A compound of claim 5, wherein Rl# r2 and R3 are,respectively, 3-bromo, hydrogen and 5 pivaloyl.

11. A compound of claim 5, wherein R^, R2 and R3 are,respectively, 2-cyano, hydrogen and pivaloyl.

12. A compound of claim 5, wherein R^, R^ and R3 10 are,respectively, 3-cyano, hydrogen and benzoyl.

13. A compound of claim 5, wherein R^, R2 and R3 are,respectively, 6-methyl, hydrogen and pivaloyl.

14. A compound of claim 5, wherein R^, R2 and R3 15 are, respectively, 3-bromo, 2-methyl and pivaloyl.

15. A compound of claim 5, wherein R^, R2 and R3 are. respectively, 3-bromo, 2-methyl and 3,4,5-trimethoxybenzoy1. 20

16. A compound of claim 5, wherein R^, R2 and R^ are,respectively, 3-cyano, hydrogen and pivaloyl. 44438 - 21 -

17. A compound of claim 5, wherein , R2 and R^ are/respectively# 3-cyano, hydrogen and 4-fluorobenzoyl.

18. A compound of claim 5, wherein R^, R2 and R^ 5 are/respectively, 3-bromo, 2-methyl and benzoyl.

19. A compound of claim 5, wherein R^, R2 and R^ are,respectively, 3-cyano, hydrogen and 3,4,5-trimethoxybenzoyl.

20. A compound of claim 6, wherein R^, R2 and R^ 10 are, respectively, 2-cyano, hydrogen and hydrogen.

21. A compound of claim 4, wherein R^ is hydrogen, chlorine, bromine, cyano or alkyl and R2 is hydrogen or alkyl. 15

22. A compound of claim 21, wherein R^ is -ch2-ch2-cooh. .

23. A compound of claim 21, wherein R^ 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 22 - . A pharmaceutical composition comprising a compound according to any one of claims 3 to 20 in free form or in pharmaceutlcally acceptable acid addition salt form, in association with a pharmaceutical carrier or diluent. 3700/VA/DK Dated this 7th day of February, 1977. BY: TOMKINS & CO., Applicants' Agents, (Signed) ^ , 5, Oartmouth Road, DUBLIN 6.