EP0010893A1
Expired / Lapsed
EP
⏱️ 0.0 years remaining
Antisecretory branched-chain heterocyclic guanidine derivatives, processes for their manufacture, intermediates, and pharmaceutical compositions containing said derivatives
Assignee: Imperial Chemical Industries Ltd
•
Filing: 1979-10-15
•
Granted: —
•
Expires: 1999-10-15
Abstract
Abstract Heterocyclic guanidine derivatives of the formula: in which D is O, S or NH; E is CH or when D is O or S, E is N; Y is S, O, CH 2 , SO or a direct bond; P is a direct bond or C (1-4) unbranched alkylene optionally substituted by 1 or 2 C (1-4) alkyls and Q is C (1-4) unbranched alkylene optionally substituted by 1 or 2 C( 1 - 4 )alkyls, provided total number of alkyls in P and Q is 1 or 2, that when Y is S, 0 or SO, P is alkylene and that when Y is O or SO, Q is C (2-4) alkylene; R 1 is H or C (1-10) alkyl; A is 3,4-dioxocyclo- buten-1,2-diyl or C=Z where Z is S, O, NCN, NNO 2 , CHNO 2 , NCONH 2 , C(CN) 2 , NCOR 2 , NCO 2 R 2 , NSO 2 R 2 or NR 3 where R 3 is C (1-6) alkyl or C (6-12) aryl and R 3 is H or C (1-6) alkyl; B is C( 1 - 6 )alkoxy, C (1-6) alkylthio or NR 4 R 5 where R 4 and R 5 are H, C (1-10) alkyl, C (3-6) alkenyl, C (3-6) alkynyl, C( 2 - 6 )(primary,OH)alkyl, C (2-6) primary NH 2 )alkyl, C (3-6) cycloalkyl, or R 4 and R 5 together are a 5- or 6-membered saturated ring which may contain an additional O or NH: and the salts thereof. A process for the manufacture of said compounds is described; e.g. 2-guanidino-4-(5-amino-2-methylpentyl)-thiazole gives by reaction with dimethyl(cyanimido)dithio- carbonate and then methylamine 2-guanidino-4-[5-(2-cyano-3-methylguanidino)-2-methylpentyl]thiazole.
Inventors
- 👤 Tobias Oregon Yellin
- 👤 David John Gilman
- 👤 Derrick Fleet Jones
Bibliographic Details
Application Number
—
Jurisdiction
EP
Data Source
google_patents
Last Synchronized
2026-11-07 00:25
CPC Classifications
C; C07; C07D; C07D209/00; C07D209/02; C07D209/44; C07D209/48; A; A61; A61P; A61P1/00; A61P1/04; A61P43/00; C07D277/00; C07D277/02; C07D277/08; C07D277/12; C07D277/14; C07D277/20; C07D277/32; C07D277/38; C07D277/44; C07D277/48
Claims Analysis
Total Claims: 14
Claim 1
Independent Claim
447 words
A heterocyclic derivative of the formula:- in which D is an oxygen or sulphur atom or an NH radical; E is a CH radical or, when D is an oxygen or sulphur atom, E is a nitrogen atom; Y is a sulphur or oxygen atom, a direct bond or a methylene or sulphinyl radical; P isa direct bond, or an unbranched alkylene chain of 1 to 4 carbon atoms optionally substituted by 1 or 2 alkyl radicals of 1 to 4 carbon atoms, and Q is an unbranched alkylene chain of 1 to 4 carbon atoms optionally substituted by 1 or 2 alkyl radicals of 1 to 4 carbon atoms, provided at least one of P and Q is substituted by at least one alkyl radical, that the number of alkyl radical substituents on P and Q together is a maximum of 2, that when Y is a sulphur or oxygen atom or a sulphinyl radical P is an optionally substituted alkylene chain, and that when Y is an oxygen atom or a sulphinyl radical Q is an optionally substituted alkylene chain of 2 to 4 carbon atoms; R 1 is a hydrogen atom or an alkyl radical of 1 to 10 carbon atoms; A is a 3,4-dioxocyclobuten-1,2-diyl radical or a radical of the formula C=Z in which Z is a sulphur or oxygen atom or a radical of the formula NCN, NN0 2 , CHN0 2 , NCONH 2 , C(CN) 2 , NCOR 2 , NCO 2 R 2 , NSO 2 R 2 or NR 3 in which R 2 is an alkyl radical of 1 to 6 carbon atoms or an aryl radical of 6 to 12 carbon atoms and R 3 is a hydrogen atom or an alkyl radical of 1 to 6 carbon atoms; B is an alkoxy or alkylthio radical of 1 to 6 carbon atoms or a radical of the formula NR 4 R 5 in which R 4 and R 5 , which may be the same or different, are hydrogen atoms, alkyl radicals of 1 to 10 carbon atoms, alkenyl or alkynyl radicals of 3 to 6 carbon atoms in which the double or triple bond respectively is separated from the nitrogen atom of NR 4 R 5 by-at least one carbon atom, (primary hydroxy)alkyl or (primary amino)alkyl radicals of 2 to 6 carbon atoms or cycloalkyl radicals of 3 to 6 carbon atoms, or R 4 and R 5 are joined to form, together with the nitrogen atom to which they are attached, a 5- or 6- membered saturated ring which optionally contains an additional oxygen atom or NH radical: and the pharmaceutically-acceptable acid-addition salts thereof.
Claim 2
Dependent Claim
447 words
A heterocyclic derivative of the formula:- in which D is an oxygen or sulphur atom or an NH radical; E is a CH radical or, when D is an oxygen or sulphur atom, E is a nitrogen atom; Y is a sulphur or oxygen atom, a direct bond or a methylene or sulphinyl radical; P isa direct bond, or an unbranched alkylene chain of 1 to 4 carbon atoms optionally substituted by 1 or 2 alkyl radicals of 1 to 4 carbon atoms, and Q is an unbranched alkylene chain of 1 to 4 carbon atoms optionally substituted by 1 or 2 alkyl radicals of 1 to 4 carbon atoms, provided at least one of P and Q is substituted by at least one alkyl radical, that the number of alkyl radical substituents on P and Q together is a maximum of 2, that when Y is a sulphur or oxygen atom or a sulphinyl radical P is an optionally substituted alkylene chain, and that when Y is an oxygen atom or a sulphinyl radical Q is an optionally substituted alkylene chain of 2 to 4 carbon atoms; R 1 is a hydrogen atom or an alkyl radical of 1 to 10 carbon atoms; A is a 3,4-dioxocyclobuten-1,2-diyl radical or a radical of the formula C=Z in which Z is a sulphur or oxygen atom or a radical of the formula NCN, NN0 2 , CHN0 2 , NCONH 2 , C(CN) 2 , NCOR 2 , NCO 2 R 2 , NSO 2 R 2 or NR 3 in which R 2 is an alkyl radical of 1 to 6 carbon atoms or an aryl radical of 6 to 12 carbon atoms and R 3 is a hydrogen atom or an alkyl radical of 1 to 6 carbon atoms; B is an alkoxy or alkylthio radical of 1 to 6 carbon atoms or a radical of the formula NR 4 R 5 in which R 4 and R 5 , which may be the same or different, are hydrogen atoms, alkyl radicals of 1 to 10 carbon atoms, alkenyl or alkynyl radicals of 3 to 6 carbon atoms in which the double or triple bond respectively is separated from the nitrogen atom of NR 4 R 5 by-at least one carbon atom, (primary hydroxy)alkyl or (primary amino)alkyl radicals of 2 to 6 carbon atoms or cycloalkyl radicals of 3 to 6 carbon atoms, or R 4 and R 5 are joined to form, together with the nitrogen atom to which they are attached, a 5- or 6- membered saturated ring which optionally contains an additional oxygen atom or NH radical: and the pharmaceutically-acceptable acid-addition salts thereof.
Claim 3
Dependent Claim
139 words
A heterocyclic derivative as claimed in claim 1 in which R l is a hydrogen atom or a methyl or n-butyl radical; P is optionally substituted by 1 or 2 methyl radicals; Q is optionally substituted by 1 or 2 methyl radicls; R 2 is a methyl, phenyl or p-tolyl radical; R 3 is a hydrogen atom or a methyl radical; B is a methoxy, ethoxy or methylthio radical or a radical of the formula NR 4 R 5 in which R 4 and R 5 , which may be the same or different, are hydrogen atoms or methyl, ethyl, n-propyl, i-propyl, n-hexyl, allyl, propargyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-aminoethyl, cyclopropyl, cyclobutyl or cyclohexyl radicals, or R and R 5 are joined to form, together with the nitrogen atom to which they are attached a pyrrolidine, piperidine, piperazine or morpholine ring.
Claim 4
Dependent Claim
32 words
A heterocyclic derivative as claimed in claim 1 or 2 in which Y is a sulphur atom, P is an optionally substituted methylene radical and Q is an optionally substituted ethylene radical.
Claim 5
Dependent Claim
34 words
A heterocyclic derivative as claimed in claim 1 or 2 in which Y is a direct bond, P is an optionally substituted methylene radical and Q is an optionally substituted propylene or butylene radical.
Claim 6
Dependent Claim
25 words
A heterocyclic derivative as claimed in claim 3 or 4 in which the number of alkyl radical substituents on P and Q together is 1,
Claim 7
Dependent Claim
64 words
A heterocyclic derivative as claimed in any of claims 1 to 5 in which R 1 is a hydrogen atom and B is a radical of the formula NR 4 R 5 in which R 5 is a hydrogen atom and R 4 is a hydrogen atom or a methyl, ethyl, n-propyl, i-propyl, n-hexyl, allyl, propargyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-aminoethyl, cyclopropyl, cyclobutyl or cyclohexyl radical.
Claim 8
Dependent Claim
29 words
A heterocyclic derivative as claimed in any of claims 1 to 6 in which D is a sulphur atom and E is a CH radical or a nitrogen atom.
Claim 9
Dependent Claim
15 words
A compound selected from 2-guanidino-4-[5-(2-cyano-3-methylguanidino)-2-methylpentyl]thiazole, 2-guanidino-4-[2-(2-cyano-3-methylguanidino)-1-methyl- ethylthiomethyl]thiazole and 2-guanidino-4-[2-(2-cyano-3-methylguanidino)-2-methylethylthiomethyl]thiazole, and the pharmaceutically-acceptable acid-addition salts thereof.
Claim 10
Dependent Claim
15 words
A compound selected from 2-guanidino-4-[5-(2-cyano-3-methylguanidino)-2-methylpentyl]thiazole, 2-guanidino-4-[2-(2-cyano-3-methylguanidino)-1-methyl- ethylthiomethyl]thiazole and 2-guanidino-4-[2-(2-cyano-3-methylguanidino)-2-methylethylthiomethyl]thiazole, and the pharmaceutically-acceptable acid-addition salts thereof.
Claim 11
Dependent Claim
343 words
A process for the manufacture of a heterocyclic derivative as claimed in claim 1 characterised by:- (a) reaction of a compound of the formula II:- in which R 6 is a displaceable radical with a compound of the formula B-H; (b) for those compounds in which A is a radical of the formula C=Z in which Z is a sulphur or oxygen atom and B is a radical of the formula NR 4 R 5 in which R5 is a hydrogen atom and R 4 has the value stated in claim 1 other than a hydroxyalkyl or aminoalkyl radical, reaction of a compound of the formula III:- with a compound of the formula R 7- N=C=G in which G is an oxygen or sulphur atom and R 7 is a hydrogen atom or an alkyl, alkenyl, alkynyl or cycloalkyl radical; (c) reaction of a compound of the formula III with a compound of the formula IV:- in which R is a displaceable radical; (d) for those compounds in which A is a radical of the formula C= Z in which Z is a radical of the formula NCONH 2 and B is a radical of the formula NR 4 R 5 , hydrolysis of a compound of the formula I in which A is a radical of the formula C=Z in which Z is a radical of the formula NCN and B is a radical of the formula NR 4 R 5 ; (e) for those compounds in which Y is a sulphinyl radical, oxidation of a compound of the formula I in which Y is a sulphur atom; or (f) for a compound which is an optically-active enantiomer, resolution of the racemic compound of the formula I or use of any of processes (a) to (d) inclusive in which the starting material is itself a resolved isomer: whereafter when the compound of the formula I is obtained in the form of the free base and a salt is required, the free base is reacted with an acid which affords a pharmaceutically-acceptable anion.
Claim 12
Dependent Claim
21 words
A pharmaceutical composition comprising a heterocyclic derivative as claimed in claim 1 in association with a non-toxic pharmaceutically-acceptable diluent or carrier.
Claim 13
Dependent Claim
213 words
A heterocyclic derivative of the following formula (III):- wherein D is an oxygen or sulphur atom or an NH radical; E is a CH radical or, when D is an oxygen or sulphur atom, E is a nitrogen atom; Y is a sulphur or oxygen atom, a direct bond or a methylene or sulphinyl radical; P is a direct bond, or an unbranched alkylene chain of 1 to 4 carbon atoms optionally substituted by 1 or 2 alkyl radicals of 1 to 4 carbon atoms, and Q is an unbranched alkylene chain of 1 to 4 carbon atoms optionally substituted by 1 or 2 alkyl radicals of 1 to 4 carbon atoms, provided at least one of P and Q is substituted by at least one alkyl radical, that the number of alkyl radical substituents on P and Q together is a maximum of 2, that when Y is a sulphur or oxygen atom or a sulphinyl radical P is an optionally substituted alkylene chain, and that when Y is an oxygen atom or a sulphinyl radical Q is an optionally substituted alkylene chain of 2 to 4 carbon atoms; and R 1 is a hydrogen atom or an alkyl radical of 1 to 10 carbon atoms; , and the acid-addition salts thereof.
Claim 14
Dependent Claim
213 words
A heterocyclic derivative of the following formula (III):- wherein D is an oxygen or sulphur atom or an NH radical; E is a CH radical or, when D is an oxygen or sulphur atom, E is a nitrogen atom; Y is a sulphur or oxygen atom, a direct bond or a methylene or sulphinyl radical; P is a direct bond, or an unbranched alkylene chain of 1 to 4 carbon atoms optionally substituted by 1 or 2 alkyl radicals of 1 to 4 carbon atoms, and Q is an unbranched alkylene chain of 1 to 4 carbon atoms optionally substituted by 1 or 2 alkyl radicals of 1 to 4 carbon atoms, provided at least one of P and Q is substituted by at least one alkyl radical, that the number of alkyl radical substituents on P and Q together is a maximum of 2, that when Y is a sulphur or oxygen atom or a sulphinyl radical P is an optionally substituted alkylene chain, and that when Y is an oxygen atom or a sulphinyl radical Q is an optionally substituted alkylene chain of 2 to 4 carbon atoms; and R 1 is a hydrogen atom or an alkyl radical of 1 to 10 carbon atoms; , and the acid-addition salts thereof.
References Cited (Backward Citations)
US4070475A
Cited
US4000302A
Cited
US4104382A
Cited
US3975530A
Cited
FR2276042A1
Cited
GB1533380A
Cited
FR2311536A1
Cited
USPTO Annuity & Maintenance Windows
Maintenance schedule is calculated for granted US utility patents.