US2008255109A1PendingUtilityA1
Non-peptide GnRH antagonists
Est. expiryMar 15, 2022(expired)· nominal 20-yr term from priority
Inventors:Michael Bryan RoeAndrzej Roman BattDavid Michael EvansGary Robert William PittDavid Philip Rooker
A61P 5/04A61P 35/00C07D 409/06A61P 13/08C07D 417/06C07D 405/06C07D 403/06C07D 413/06A61P 15/08A61P 15/18A61P 15/00C07D 413/14C07D 401/06C07D 217/02C07D 241/44
51
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Claims
Abstract
Compounds according to general formula 1, wherein A 1 -A 3 are selected from A 5 and A 6 where A 5 is either ═CR 13 — or ═N— and A 6 is —NR 14 —, —O— or —S—; A 4 is either a covalent bond or A 5 , provided that when A 4 is a covalent bond one of A 1 -A 3 must be A 6 and the other two must be A 5 and when A 4 is A 5 then all of A 1 -A 3 must be A 5 ; R 1 is selected from H, NHY′ and COY 2 , in which case R 2 is H, or R 1 and R 2 may both be methyl or together represent ═O; R 3 , R 4 and R 5 are each independently selected from H and lower alkyl groups; R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are each independently selected from H, lower alkyl groups, NH 2 , halogens (F, Cl and Br) O-alkyl, CH 2 NM 2 and CF 3 ; R 13 is selected from H, F, Cl, Br, NO 2 , NH 2 , OH, Me, Et, OMe, NMe 2 and CF 3 ; R 14 is selected from H, methyl and ethyl; W is selected from ═CH— and ═N—; X is selected from CH 2 , O, S, SO 2 , NH and N-lower alkyl; Y 1 is selected from CO-lower alkyl, CO(CH 2 ) b Y 3 , CO(CH 2 ) b COY 3 and CO(CH 2 ) b NHCOY 3 , where b is 1-3; Y 2 is selected from OR 15 , NR 16 R 17 and NH(CH 2 ) c COY3, where c is 1-3; Y 3 is selected from OR 15 and NR 16 R 17 ; R 15 is selected from H, lower alkyl and (CH 2 ) a R 16 , where a is 0-4; R 16 and R 17 are each independently selected from H, lower alkyl and (CH 2 ) a R 16 or together are —(CH 2 ) 2 -Z-(CH 2 ) 2 —; R 18 is OH, a phenyl group or an aromatic heterocycle selected from pyridyl, pyrimidinyl, pyrazinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl and thiadiazolyl, each of which may optionally have a lower alkyl group substituent; and Z is selected from O, CH 2 , S, SO 2 , NH and N-lower alkyl, are new. They are useful in the treatment of breast and prostate cancer, endometriosis and benign prostate hyperplasia, in the regulation of fertility, and in in vitro fertilisation.
Claims
exact text as granted — not AI-modified1 . A compound which is a derivative of general formula 1, or a pharmaceutically acceptable salt thereof,
wherein:
A 1 , A 2 and A 3 are each independently selected from A 5 and A 6 ; and
A 4 is either a covalent bond or A 5 ; provided that
when A 4 is a covalent bond then one of A 1 -A 3 is A 6 and the other two are A 5 and that
when A 4 is A 5 then all of A 1 -A 3 are A 5 ;
A 5 is selected from C—R 13 and N;
A 6 is selected from N—R 14 , S and O;
R 1 is selected from H, NHY 1 and COY 2 and R 2 is H; or R 1 and R 2 are both methyl or together are ═O;
R 3 , R 4 and R 5 are each independently H, lower alkyl or lower alkenyl;
R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are each independently selected from H, lower alkyl, lower alkenyl, NH 2 , F, Cl, Br, O-alkyl, O-lower alkenyl, CH 2 NMe 2 and CF 3 ;
R 13 is selected from H, F, Cl, Br, NO 2 , NH 2 , OH, Me, Et, OMe, NMe 2 and CF 3 ;
R 14 is selected from H, methyl and ethyl;
W is selected from CH and N;
X is selected from CH 2 , O, S, SO 2 , NH, N-lower alkyl and N-lower alkenyl;
Y 1 is selected from CO-lower alkyl, CO-lower alkenyl, CO(CH 2 ) b Y 3 , CO(CH 2 ) b COY 3 and CO(CH 2 ) b NHCOY 3 ;
Y 2 is selected from OR 15 , NR 16 R 17 and NH(CH 2 ) c COY 3 ;
Y 3 is selected from alkyl, lower alkenyl, OR 15 and NR 16 R 17 ;
R 15 is selected from H, lower alkyl, lower alkenyl and (CH 2 ) a R 18
R 16 and R 17 are each independently selected from H, lower alkyl, lower alkenyl and (CH 2 ) a R 8 , or together are —(CH 2 ) 2 -Z-(CH 2 ) 2 —;
R 18 is selected from OH and phenyl, pyridyl, pyrimidinyl, pyrazinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl and thiadiazolyl, each of which may optionally have a lower alkyl, lower alkenyl group substituent;
Z is selected from O, CH 2 , S, SO 2 , NH, N-lower alkyl and N-lower alkenyl;
a is 0-4; and
b and c are 1-3.
2 . A compound according to claim 1 wherein R 3 and R 4 are both H.
3 . A compound according to claim 1 wherein R 5 is lower alkyl or lower alkenyl.
4 . A compound according to claim 3 wherein R 5 is methyl.
5 . A compound according to claim 1 wherein A 1 , A 2 , A 3 and A 4 are all A 5 .
6 . A compound according to claim 5 wherein at least three of A 1 , A 2 , A 3 and A 4 are ═CR 13 —.
7 . A compound according to claim 6 wherein A 1 , A 3 and A 4 are ═CH— and A 2 is ═CR 13 —.
8 . A compound according to claim 7 wherein A 2 is ═CF— or ═CCl—.
9 . A compound according to claim 6 wherein one of A 1 , A 2 , A 3 and A 4 is ═N— and the others are ═CH—.
10 . A compound according to claim 9 wherein A 1 is ═N— and A 2 , A 3 and A 4 are ═CH—.
11 . A compound according to claim 1 wherein A 4 is a covalent bond.
12 . A compound according to claim 11 wherein A 1 is A 5 .
13 . A compound according to claim 12 wherein one of A 2 and A 3 is ═CH— and the other is —S—.
14 . A compound according to claim 1 wherein at least three of R 6 to R 10 are H.
15 . A compound according to claim 14 wherein four of R 6 to R 10 are H and the other is F, Cl, Br or CF 3 .
16 . A compound according to claim 15 wherein R 6 , R 7 , R 9 and R 10 are H and R 8 is F, Cl, Br or CF 3 .
17 . A compound according to claim 1 wherein R 1 is COY 2 and R 2 is H.
18 . A compound according to claim 17 wherein Y 2 is NR 16 R 17 or NHCH 2 COY 3 .
19 . A compound according to claim 18 wherein Y 2 is NHCH 2 R 18 or NHCH 2 CONHCH 3 , and R 18 is pyridyl or 3-methyl-1,2,4-oxadiazol-5-yl.
20 . A compound according to claim 1 selected from
4-(3-Chloro-4-{{(4-chloro-benzenesulfonyl)-methyl-amino]-methyl}-thiophene-2-carbonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-2carboxylic acid (3-methyl-[1,2,4]oxadiazol-5-ylmethyl)-amide
4-(3-Chloro-4 {[(4-chloro-benzenesulfonyl)-methyl-amino]-methyl}-thiophene-2-carbonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic acid (2-hydroxy-ethyl)-amide
4-Chloro-N-[4-chloro-5-(2,3-dihydro-benzo[1,4]oxazine-4-carbonyl)-thiophen-3-ylmethyl]-N-methyl-3-nitro-benzenesulfonamide
ylmethyl]-N-methyl-3-nitro-benzenesulfonamide
3-Amino-4-chloro-N-[4-chloro-5-(2,3-dihydro-benzo[1,4]oxazine-4-carbonyl)-thiophen-3-ylmethyl]-N-methyl-benzenesulfonamide
4-Bromo-N-[4-(3,4-dihydro-2H-quinoline-1-carbonyl)-thiazol-2-ylmethyl]-N-methyl-benzenesulfonamide
N-[1-(2-{[(4-Bromo-benzenesulfonyl)-methyl-amino]-methyl}-thiazole-4-carbonyl)-1,2,3,4-tetrahydro-quinolin-3-yl]-acetamide
4-Bromo-N-[4-chloro-5-(3,4-dihydro-2H-quinoline-1-carbonyl)-thiophen-3-ylmethyl]-N-methyl-benzenesulfonamide
4-Bromo-N-[4-chloro-5-(2,3-dihydro-pyrido[3,2-b][1,4]oxazine-4-carbonyl)-thiophen-3-ylmethyl]-N-methyl-benzenesulfonamide
4-Chloro-N-[4-chloro-5-(7-fluoro-2,3-dihydro-benzo[1,4]oxazine-4-carbonyl)-thiophen-3-ylmethyl]-N-methyl-benzenesulfonamide
4-Bromo-N-[4-chloro-5-(3-oxo-3,4-dihydro-2H-quinoxaline-1-carbonyl)-thiophen-3-ylmethyl]-N-methyl-benzenesulfonamide
4-(4-{[(4-Bromo-benzenesulfonyl)-methyl-amino]-methyl}-3-chloro-thiophene-2-carbonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic acid methylamide
4-(5-{[(4-Bromo-benzenesulfonyl)-methyl-amino]-methyl}-4-chloro-thiophene-3-carbonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic acid (2-hydroxy-ethyl)-amide
4-(3-Chloro-4-{[(4-chloro-benzenesulfonyl)-methyl-amino]-methyl}-thiophene-2-carbonyl)-6-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic acid (2-hydroxy-ethyl)-amide
4-(3-Chloro-4-{[(4-chloro-benzenesulfonyl)-methyl-amino]-methyl}-thiophene-2-carbonyl)-7-fluoro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic acid (2-hydroxy-ethyl-amide
{[4-5{[(4-Bromo-benzenesulfonyl)-methyl-amino]-methyl}-4-chloro-thiophene-3-carbonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl]-amino}-acetic acid methyl ester
4-(3-Chloro-4-{[(4-chloro-benzenesulfonyl)-methyl-amino]-methyl}-thiophene-2-carbonyl)-3,4-dihydro-2H-benzo[1,3]oxazine-2-carboxylic and methylcarbamoylmethyl-amide
4-(3-Chloro-4-{[(4-chloro-benzenesulfonyl)-methyl-amino]-methyl}-thiophene-2-carbonyl)-6-methoxy-3,4-dihydro-2H=benzo[1,4]oxazine=2=carboxylic acid methyl carbamoylmethyl-amide
4-(5-{[(4-Bromo=benzenesulfonyl)-methyl-amino]-methyl}-4-chloro-thiophene-3-carbonyl)-3,4-dihydro=2H-benzo[1,4]axazine-2-carboxylic acid (pyridine-4-ylmethyl)-amide
4-(3-Chloro-4-{[(4-chloro-benzenesulfonyl)-methyl-amino]-methyl}-thiophene-2-carbonyl)-3,4-dihydro=2H-benzo[1,4]oxazine-2-carboxylic acid (pyridine-3-ylmethyl)-amide
4-(3-Chloro-4-{[(4-chloro-benzenesulfonyl)-methyl-amino]-methyl}-thiophene-2-carbonyl)-6-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic acid (pyridine-3-ylmethyl)-amide
4-(3-Chloro-4-{[(4-chloro-benzenesulfonyl)-methyl-amino]-methyl}-thiophene-2-carbonyl)-6-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic acid (pyrazin-2-ylmethyl)-amide
4-(3-Chloro-4-{[(4-chloro-benzenesulfonyl)-methyl-amino]-methyl}-thiophene-2-carbonyl)-6-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic acid (3-methyl-[1,2,4]oxadiazol-5-ylmethyl)-amide
N-[1-(4-{[(4-Bromo-benzenesulfonyl)-methyl-amonio]-methyl}-3-chloro-thiophene-2-carbonyl)-1,2,3,4-tetrahydro-quinolin-3-yl]-acetamide
3-Amino-N-[1-(4-{[(4-bromo-benzenesulfonyl)-methyl-amino]-methyl}-3-chloro=thiophene-2-carbonyl)-1,2,3,4-tetrahydro=quinolin-3-yl]-propionamide
4-(4-{[(4-Bromo-benzenesulfonyl)-methyl-amino]-methyl}-3-chloro=thiophene-2-carbonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic acid (2-amino-ethyl)-amide
4-(3-Chloro-4-{[(4-chloro-benzenesulfonyl)-methyl-amino]-methyl}-thiophene-2-carbonyl)-6-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic acid (2-amino-ethyl)-amide
3-Acetylamino-N-[1-(4-{[(4-bromo benzenesulfonyl)-methyl-amino]-methyl}-3-chloro=thiophene-2-carbonyl)-1,2,3,4-tetrahydro quinolin-3-yl]-propionamide
4-Acetylamino-N-[1-(4-{[(4-bromo benzenesulfonyl)-methyl-amino]-methyl}-3-chloro=thiophene-2-carbonyl)-1,2,3,4-tetrahydro quinolin-3-yl]-butyramide
N-[1-(4-{[(4-Bromo-benzenesulfonyl)-methyl-amonio]-methyl}-3-chloro-thiophene-2-carbonyl)-1,2,3,4-tetrahydro-quinolin-3-yl]-4-(3-ethyl-ureido)-butyramide
4-Bromo-N-[5-(3,4-dihydro-2H-quinoline-1-carbonyl)-thiophen-3-ylmethyl]-N-methyl-benzenesulfonamide
4-Bromo-N-[5-(3,4-dihydro-2H-quinoline-1-carbonyl)-furan-2-yl]-N-methyl-benzenesulfonamide
4-Bromo-N-[6-(3,4-dihydro-2H-quinoline-1-carbonyl)-pyridin-2-ylmethyl]-N-methyl-benzenesulfonamide
4-Bromo-N-[4-chloro-3-(3,4-dihydro-2H-quinoline-1-carbonyl)-benzyl]-N-methyl-benzenesulfonamide
4-Bromo-N-[3-(3,4-dihydro-2H-quinoline-1-carbonyl)-4-fluoro-benzyl]-N-methyl-benzenesulfonamide
4-Bromo-N-[5-(3,4-dihydro-2H-quinoline-1-carbonyl)-4-nitro-benzyl]-N-methyl-benzenesulfonamide
4-Bromo-N-[4-bromo-3-(3,4-dihydro-2H-quinoline-1-carbonyl)-N-methyl-benzenesulfonamide; or pharmaceutically accepted salts thereof.
21 . A use for a compound according to claim 1 which use is as a therapeutic agent in human or animal medicine.
22 . A use according to claim 21 , wherein the compound is used to treat hormone-dependent cancer, endometriosis or benign prostate hyperplasia, as a contraceptive agent, as an adjunct to an assisted fertilization program, or as a behavior-modifying agent.
23 . A use according to claim 21 wherein the compound is used in human medicine.
24 . A pharmaceutical composition comprising a compound according to claim 1 .
25 . A composition according to claim 24 , which is a tablet or capsule for oral administration.
26 . A composition according to claim 24 , which is used to treat hormone-dependent cancer, endometriosis/or benign prostate hyperplasia, as a contraceptive agent, as an adjunct to an assist fertilization program, or as a behaviour-modifying agent.
27 . A use for a compound according to claim 1 , which use is as a component in a pharmaceutical composition.
28 . A method of treatment in human or animal medicine, which method is characterized in that a therapeutically effective amount of a compound according to claim 1 is administered to the subject.
29 . A method according to claim 28 wherein the subject is a human.
30 . A method according to claim 28 , wherein the condition being treated is a hormone-dependent cancer.
31 . A method according to claim 30 , wherein the condition being treated is breast or prostate cancer.
32 . A method according to claim 28 , wherein the condition being treated in endometriosis.
33 . A method according to claim 28 , wherein the condition being treated is benign prostate hyperplasia.
34 . A method according to claim 27 , wherein the condition being treated is infertility.
35 . A method according to claim 28 , wherein the therapeutic aim is contraception.
36 . A method according to claim 28 , wherein the subject is a sex offender.
37 . A composition according to claim 1 having one or more stereogenic centres.
38 . A method of treatment, in a human or animal subject, of hormone dependent cancer, endometriosis, benign prostate hyperplasia or infertility, a method of contraception in a human or animal subject, or a method of behavior modification in a human or animal subject, comprising administration to the subject of a therapeutic amount of a composition which is a derivative according to general formula 1, or a pharmaceutically acceptable salt thereof,
wherein:
A 1 , A 2 and A 3 are each independently selected from A 5 and A 6 ; and
A 4 is either a covalent bond or A 5 ; provided that
when A 4 is a covalent bond then one of A 1 -A 3 is A 6 and the other two are A 5 and that
when A 4 is A 5 then all of A 1 -A 3 are A 5 ;
A 5 is selected from C—R 13 and N;
A 6 is selected from N—R 14 , S and O;
R 1 is selected from H, NHY 1 and COY 2 and R 2 is H; or R 1 and R 2 are both methyl or together are ═O;
R 3 , R 4 and R 5 are each independently H, lower alkyl or lower alkenyl;
R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are each independently selected from H, lower alkyl, lower alkenyl, NH 2 , F, Cl, Br, O-alkyl, O-lower alkenyl, CH 2 NMe 2 and CF 3 ;
R 13 is selected from H, F, Cl, Br, NO 2 , NH 2 , OH, Me, Et, OMe, NMe 2 and CF 3 ;
R 14 is selected from H, methyl and ethyl;
W is selected from CH and N;
X is selected from CH 2 , O, S, SO 2 , NH, N-lower alkyl and N-lower alkenyl;
Y 1 is selected from CO-lower alkyl, CO-lower alkenyl, CO(CH 2 ) b Y 3 , CO(CH 2 ) b COY 3 and CO(CH 2 ) b NHCOY 3 ;
Y 2 is selected from OR 15 , NR 16 R 17 and NH(CH 2 ) c COY 3 ;
Y 3 is selected from alkyl, lower alkenyl, OR 15 and NR 16 R 16 R 17 ;
R 15 is selected from H, lower alkyl, lower alkenyl and (CH 2 ) a R 18
R 16 and R 17 are each independently selected from H, lower alkyl, lower alkenyl and (CH 2 ) a R 8 , or together are —(CH 2 ) 2 -Z-(CH 2 ) 2 —;
R 18 is selected from OH and phenyl, pyridyl, pyrimidinyl, pyrazinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl and thiadiazolyl, each of which may optionally have a lower alkyl, lower alkenyl group substituent;
Z is selected from O, CH 2 , S, SO 2 , NH, N-lower alkyl and N-lower alkenyl;
a is 0-4; and
b and c are 1-3.
39 . A method of treatment, in a human or animal subject, of hormone dependent cancer, endometriosis, benign prostate hyperplasia or infertility, a method of contraception in a human or animal subject, or a method of behavior modification in a human or animal subject, comprising administration to the subject of a therapeutic amount of a composition which is a derivative according to general formula 1, or a pharmaceutically acceptable salt thereof,
wherein:
A 1 , A 2 and A 3 are each independently selected from A and A 6 ; and
A 4 is either a covalent bond or A 5 ; provided that
when A 4 is a covalent bond then one of A 1 -A 3 is A 6 and the other two are A 5 and that
when A 4 is A 5 then all of A 1 -A 3 are A 5 ;
A 5 is selected from C—R 13 and N;
A 6 is selected from N—R 14 , S and O;
R 1 is selected from H, NHY 1 and COY 2 and R 2 is H; or R 1 and R 2 are both methyl or together are ═O;
R 3 , R 4 and R 5 are each independently H, lower alkyl or lower alkenyl;
R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are each independently selected from H, lower alkyl, lower alkenyl, NH 2 , F, Cl, Br, O-alkyl, O-lower alkenyl, CH 2 NMe 2 and CF 3 ;
R 13 is selected from H, F, Cl, Br, NO 2 , NH 2 , OH, Me, Et, OMe, NMe 2 and CF 3 ;
R 14 is selected from H, methyl and ethyl;
W is selected from CH and N;
X is selected from CH 2 , O, S, SO 2 , NH, N-lower alkyl and N-lower alkenyl;
Y 1 is selected from CO-lower alkyl, CO-lower alkenyl, CO(CH 2 ) b Y 3 , CO(CH 2 ) b COY 3 and CO(CH 2 ) b NHCOY 3 ;
Y 2 is selected from OR 15 , NR 16 R 17 and NH(CH 2 ) c COY 3 ;
Y 3 is selected from alkyl, lower alkenyl, OR 15 and NR 16 R 17 ;
R 15 is selected from H, lower alkyl, lower alkenyl and (CH 2 ) a R 18
R 16 and R 17 are each independently selected from H, lower alkyl, lower alkenyl and (CH 2 ) a R 18 , or together are —(CH 2 ) 2 -Z-(CH 2 ) 2 —;
R 18 is selected from OH and phenyl, pyridyl, pyrimidinyl, pyrazinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl and thiadiazolyl, each of which may optionally have a lower alkyl, lower alkenyl group substituent;
Z is selected from O, CH 2 , S, SO 2 , NH, N-lower alkyl and N-lower alkenyl;
a is 0-4; and
b and c are 1-3;
which comprises the steps of:
a) formation of an amide from a carboxylic acid and a cyclic amine; and
b) formation of a sulphonamide from a sulphonyl chloride and an amine.
40 . A process according to claim 38 in which step a) is reaction of a composition of formula 7 and a composition of formula 6 to obtain the composition of formula 9; and step b) is reaction of the composition of formula 9 with a composition of formula 8 to form the composition of formula 1, wherein formulae 6, 7, 8 and 9 are as defined in the specification.
41 . A process according to claim 38 in which step a) is reaction of a composition of formula 10 and a composition of formula 6 to obtain the composition of formula 1; and step b) is reaction of the composition of formula 7 with a composition of formula 8 to form the composition of formula 10, wherein formulae 6, 7, 8 and 10 are as defined in the specification.Cited by (0)
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