Claims
- 1. A method for the prophylaxis or treatment of a clinical condition in a mammal for which an ACAT inhibitor is indicated, which comprises the administration to the mammal of a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof ##STR5## wherein: W is hydrogen, or a C--.sub.1-12 hydrocarbyl group optionally substituted by one or more groups independently selected from halo, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, hydroxy, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy, and RC(O)-- (wherein R is selected from hydrogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, hydroxy, C.sub.1-4 haloalkyl, and C.sub.1-4 haloalkoxy);
- X is a --NR.sup.1 --C(O)NR.sup.2 --, --NR.sup.1 C(O)--, --NR.sup.1 --C(O)O--, --C(O)NR.sup.2 --, or --OC(O)NR.sup.2 -- (wherein R.sup.1 and R.sup.2 are independently selected from hydrogen, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl);
- Y is a bond, C.sub.2-4 alkynylene, C.sub.2-4 alkenylene (cis or trans), C.sub.1-4 alkylene, --(CH.sub.2).sub.n --O--(CH.sub.2).sub.p --, or --(CH.sub.2).sub.n --S(O).sub.q --(CH.sub.2).sub.p --, (wherein n and p are integers independently selected from 0, 1, 2, 3, and 4; providing that n+p is not greater than 4; and q is an integer selected from 0, 1, and 2),
- and Y is optionally substituted by one or more groups independently selected from halo, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl;
- E is a bond, C.sub.1-4 alkylene, --(CH.sub.2).sub.r --O--(CH.sub.2).sub.s --, --(CH.sub.2),.sub.r --S(O).sub.t --(CH.sub.2).sub.s --, --(CH.sub.2).sub.r --C(O)--(CH.sub.2).sub.s -- (wherein r and s are integers independently selected from 0, 1, 2, 3 and 4; providing that r+s is not greater than 4; and t is an integer selected from 0, 1, and 2), --OC(O)--, --C(O)O--, --S(O).sub.2 N(R.sup.3)--, --(R.sup.3)NS(O).sub.2 --, --C(O)N(R.sup.3)--, --(R.sup.3)NC(O)N(R.sup.4)--, or --(R.sup.3)NC(O)-- (wherein R.sup.3 and R.sup.4 are independently selected from hydrogen, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl);
- Z is an aliphatic non-heterocyclic ring system, C.sub.1-8 alkyl, C.sub.1-8 alkoxy, hydroxy, halo, or non-heterocyclic aryl,
- and Z is optionally substituted by one or more groups independently selected from halo, cyano, --CO.sub.2 R.sup.6, --C(O)NR.sup.6 R.sup.7, --NR.sup.6 R.sup.7 (wherein R.sup.6 and R.sup.7 are independently selected from hydrogen, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl), C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkoxy, hydroxy, and C.sub.2-8 polyether;
- phenyl rings A and B are optionally substituted by one or more groups independently selected from halo, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkoxy, hydroxy, cyano, R.sup.8 R.sup.9 NC(O)--, R.sup.8 C(O)N(R.sup.9)--, R.sup.8 C(O)O--, and R.sup.8 C(O)-- (wherein R.sup.8 and R.sup.9 are independently selected from hydrogen, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl);
- provided that if Y is methylene, ethylene, or n-propylene, or --CH.dbd.CH-- (cis or trans), then group --E--Z is not C.sub.1-6 alkyl optionally substituted by one or more independently selected polar groups.
- 2. A method for the prophylaxis or treatment of a clinical condition in a mammal for which an ACAT inhibitor is indicated, which comprises the administration to the mammal of a therapeutically effective amount of a compound of formula (I) ##STR6## wherein: W is hydrogen, or a C.sub.1-12 hydrocarbyl group optionally substituted by one or more groups independently selected from halo, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, hydroxy, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy, and RC(O)-- (wherein R is selected from hydrogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, hydroxy, C.sub.1-4 haloalkyl, and C.sub.1-4 haloalkoxy);
- X is a --NR.sup.1 --C(O)NR.sup.2 --, --NR.sup.1 C(O)--, --NR.sup.1 --C(O)O--, --C(O)NR.sup.2 --, or --OC(O)NR.sup.2 -- (wherein R.sup.1 and R.sup.2 are independently selected from hydrogen, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl);
- Y is a bond, C.sub.2-4 alkynylene, C.sub.2-4 alkenylene (cis or trans), C.sub.1-4 alkylene, --(CH.sub.2).sub.n --O--(CH.sub.2).sub.p --, or --(CH.sub.2).sub.n --S(O).sub.q --(CH.sub.2).sub.p --, (wherein n and p are integers independently selected from 0, 1, 2, 3, and 4; providing that n+p is not greater than 4; and q is an integer selected from 0, 1, and 2),
- and Y is optionally substituted by one or more groups independently selected from halo, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl;
- E is a bond, C.sub.1-4 alkylene, --(CH.sub.2).sub.r --O--(CH.sub.2).sub.s --, --(CH.sub.2).sub.r --S(O).sub.t --(CH.sub.2).sub.s --, --(CH.sub.2).sub.r --C(O)--(CH.sub.2).sub.s -- (wherein r and s are integers independently selected from 0, 1, 2, 3 and 4; providing that r+s is not greater than 4; and t is an integer selected from 0,
- 1, and 2), --OC(O)--, --C(O)O--, --S(O).sub.2 N(R.sup.3)--, --(R.sup.3)NS(O).sub.2 --, --C(O)N(R.sup.3)--, --(R.sup.3)NC(O)N(R.sup.4)--, or --(R.sup.3)NC(O)-- (wherein R.sup.3 and R.sup.4 are independently selected from hydrogen, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl);
- Z is an aliphatic non-heterocyclic ring system, C.sub.1-8 alkyl, C.sub.1-8 alkoxy, hydroxy, halo, or non-heterocyclic aryl,
- and Z is optionally substituted by one or more groups independently selected from halo, cyano, --CO.sub.2 R.sup.6, --C(O)NR.sup.6 R.sup.7, --NR.sup.6 R.sup.7 (wherein R.sup.6 and R.sup.7 are independently selected from hydrogen, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl), C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkoxy, hydroxy, and C.sub.2-8 polyether;
- phenyl rings A and B are optionally substituted by one or more groups independently selected from halo, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkoxy, hydroxy, cyano, R.sup.8 R.sup.9 NC(O)--, R.sup.8 C(O)N(R.sup.9)--, R.sup.8 C(O)O--, and R.sup.8 C(O)-- (wherein R.sup.8 and R.sup.9 are independently selected from hydrogen, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl);
- provided that if Y is methylene, ethylene, or n-propylene, or --CH.dbd.CH-- (cis or trans), then group --E--Z is not C.sub.1-6 alkyl optionally substituted by one or more independently selected polar groups;
- or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, with the provisoes that:
- (i) when Y is --S--, X is --NR.sup.1 C(O)-- (wherein R.sup.1 is hydrogen or C.sub.1-3 alkyl), and W is hydrogen or C.sub.1-3 alkyl, then --E--Z is not methoxy;
- (ii) when Y is --S-- or --O--, X is --C(O)NH--, W is hydrogen, ring A is unsubstituted or has one substituent selected from C.sub.1-4 alkyl or C.sub.1-4 alkoxy, and ring B is unsubstituted or has one to three substituents selected from halogen and alkyl, then --E--Z is not optionally substituted cycloalkyl, halogen, or alkylmercapto;
- (iii) the compound of formula (I) is not:
- N,N-diethyl-2-[2-(4-methoxyphenyl)ethenyl]benzamide,
- Bis[2-(N-isopropylcarbamoyl)phenyl]sulphide,
- Bis[2-(N-isopropylcarbamoyl)phenyl]sulphoxide,
- Bis[2-(N-isopropylcarbamoyl)phenyl]sulphone,
- 2,2'-thiobis[N,N-bis(1-methylpropyl)benzamide], or
- 2,2'-thiobis(N-butylbenzamide).
- 3. A method for the prophyl axis or treatment of a clinical condition in a mammal for which an ACAT inhibitor is indicated, which comprises the administration to the mammal of a therapeutically effective amount of a compound of formula (I) according to claim 2 wherein:
- W is a C.sub.3-7 alkyl optionally substituted as described in claim 2;
- X is a --C(O)NR.sup.2 --, --NR.sup.1 C(O)--, or --NR.sup.1 C(O)NR.sup.2 -- (wherein R.sup.1 and R.sup.2 are as defined in claim 2);
- Y is ethylene, ethenylene, ethenylene, --O--, --S--, --CH.sub.2 O--, or --OCH.sub.2 --;
- E is --O--, --OCH.sub.2 --, --CH.sub.2 O--, a bond, --C(O)N(R.sup.3)--, --(R.sup.3)NC(O)--, --S--, --S(O)--, --S(O).sub.2 --, --(R.sup.3)NS(O).sub.2 --, --S(O).sub.2 N(R.sup.3)--, --(R.sup.3)NC(O)N(R.sup.4)--, or --C(O)-- (wherein R.sup.3 and R.sup.4 are defined in claim 2); and
- Z is a 5- or 6-membered saturated non-heterocyclic ring or Z is C.sub.1-4 alkyl, C.sub.1-4 alkoxy, hydroxy, or aryl and Z is optionally substituted as described in claim 2;
- or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.
- 4. A method for the prophylaxis or treatment of a clinical condition in a mammal for which an ACAT inhibitor is indicated, which comprises the administration to the mammal of a therapeutically effective amount of a compound of formula (I) according to claim 2 wherein:
- W is C.sub.3-5 alkyl;
- X is --C(O)NH--;
- Y is ethenylene or --O--;
- E is --O--, or a bond;
- Z is a 5- or 6-membered saturated non-heterocyclic ring;
- or Z is C.sub.1-4 alkyl or C.sub.1-4 alkoxy and Z is optionally substituted by one or more groups independently selected from the group consisting of halo, cyano, --CO.sub.2 R.sup.6, --C(O)NR.sup.6 R.sup.7, --NR.sup.6 R.sup.7 wherein R.sup.6 and R.sup.7 are independently hydrogen, C.sub.1-4 alkyl or C.sub.1-4 halo alkyl, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkoxy, hydroxy and C.sub.2-8 polyether.
- 5. A method for the prophylaxis or treatment of a clinical condition in a mammal for which an ACAT inhibitor is indicated, which comprises the administration to the mammal of a therapeutically effective amount of a compound of formula (I) according to claim 3 wherein:
- W is C.sub.3-5 alkyl;
- X is --C(O)NH--;
- Y is ethenylene or --O--;
- E is --O--, or a bond;
- Z is a 5- or 6-membered saturated non-heterocyclic ring;
- or Z is C.sub.1-4 alkyl or C.sub.1-4 alkoxy and Z is optionally substituted by one or more groups independently selected from the group consisting of halo, cyano, --CO.sub.2 R.sup.6, --C(O)NR.sup.6 R.sup.7, --NR.sup.6 R.sup.7 wherein R.sup.6 and R.sup.7 are independently hydrogen, C.sub.1-4 alkyl or C.sub.1-4 haloalkyl, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkoxy, hydroxy and C.sub.2-8 polyether; or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof of formula (I) according to claim 3 wherein:
- W is C.sub.3-5 alkyl;
- X is --C(O)NH--;
- Y is ethenylene or --O--;
- E is --O--, or a bond;
- Z is a 5- or 6-membered saturated non-heterocyclic ring;
- or Z is C.sub.1-4 alkyl or C.sub.1-4 alkoxy and Z is optionally substituted by one or more groups independently selected from the group consisting of halo, cyano, --CO.sub.2 R.sup.6, --C(O)NR.sup.6 R.sup.7, --NR.sup.6 R.sup.7 wherein R.sup.6 and R7are independently hydrogen, C.sub.1-4 alkyl or C.sub.1-4 haloalkyl, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkoxy, hydroxy and C.sub.2-8 polyether.
- 6. A method for the prophylaxis or treatment of a clinical condition in a mammal for which an ACAT inhibitor is indicated, which comprises the administration to the mammal of a therapeutically effective amount of a compound of formula (I) according to claim 2 selected from:
- N-{2,4-Difluoro-6-[4-(1-carbamoyl-1-methylethyl)phenoxy]phenyl}pivalamide;
- N-[2-Fluoro-6-[4-trifluoromethoxyphenoxy)phenyl]pivalamide;
- N-{6-[4-(1-Carbamoyl-1-methylethoxy)phenylethynyl]-2,4-difluorophenyl}pivalamide;
- N-{6-[4-(1-Carbamoyl-1-methylethyl)phenylethynyl]-2,4-difluorophenyl}pivalamide;
- 1-[4-(3-Fluoro-2-pivalamidophenoxy)phenyl]cyclopentane-1-carboxylic acid; and
- 1-[4-(3-Fluoro-2-pivalamidophenoxy)phenyl]cyclopentane-1-carboxamide;
- or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.
- 7. A pharmaceutical formulation comprising a compound of formula (I) ##STR7## wherein: W is hydrogen, or a C--.sub.1-12 hydrocarbyl group optionally substituted by one or more groups independently selected from halo, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, hydroxy, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy, and RC(O)-- (wherein R is selected from hydrogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, hydroxy, C.sub.1-4 haloalkyl, and C.sub.1-4 haloalkoxy);
- X is a --NR.sup.1 --C(O)NR.sup.2 --, --NR.sup.1 C(O)--, --NR.sup.1 --C(O)O--, --C(O)NR.sup.2 --, or --OC(O)NR.sub.2 -- (wherein R.sup.1 and R.sup.2 are independently selected from hydrogen, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl);
- Y is a bond, C.sub.2-4 alkynylene, C.sub.2-4 alkenylene (cis or trans), C.sub.1-4 alkylene, --(CH.sub.2).sub.n --O--(CH.sub.2).sub.p --, or --(CH.sub.2).sub.n --S(O).sub.q --(CH.sub.2).sub.p --, (wherein n and p are integers independently selected from 0, 1, 2, 3, and 4; providing that n+p is not greater than 4; and q is an integer selected from 0, 1, and 2),
- and Y is optionally substituted by one or more groups independently selected from halo, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl;
- E is a bond, C.sub.1-4 alkylene, --(CH.sub.2).sub.r --O--(CH.sub.2).sub.s --, --(CH.sub.2).sub.r --S(O).sub.t --(CH).sub.s --, --(CH.sub.2).sub.r --C(O)--(CH.sub.2).sub.s -- (wherein r and s are integers independently selected from 0, 1, 2, 3 and 4; providing that r+s is not greater than 4; and t is an integer selected from 0, 1, and 2), --OC(O)--, --C(O)O--, --S(O).sub.2 N(R.sup.3)--, --(R.sup.3)NS(O).sub.2 --, --C(O)N(R.sup.3)--, --(R.sup.3)NC(O)N(R.sup.4)--, or --(R.sup.3)NC(O)-- (wherein R.sup.3 and R.sup.4 are independently selected from hydrogen, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl);
- Z is an aliphatic non-heterocyclic ring system, C.sub.1-8 alkyl, C.sub.1-8 alkoxy, hydroxy, halo, or non-heterocyclic aryl,
- and Z is optionally substituted by one or more groups independently selected from halo, cyano, --CO.sub.2 R.sup.6, --C(O)NR.sub.6 R.sup.7, --NR.sup.6 R.sup.7 (wherein R.sup.6 and R.sup.7 are independently selected from hydrogen, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl), C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkoxy, hydroxy, and C.sub.2-8 polyether;
- phenyl rings A and B are optionally substituted by one or more groups independently selected from halo, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkoxy, hydroxy, cyano, R.sup.8 R.sup.9 NC(O)--, R.sup.8 C(O)N(R.sup.9)--, R.sup.8 C(O)O--, and R.sup.8 C(O)-- (wherein R.sup.8 and R.sup.9 are independently selected from hydrogen, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl);
- provided that if Y is methylene, ethylene, or n-propylene, or --CH.dbd.CH-- (cis or trans), then group --E--Z is not C.sub.1-6 alkyl optionally substituted by one or more independently selected polar groups;
- or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof,
- and a pharmaceutically acceptable carrier or excipient.
- 8. A pharmaceutical formulation comprising a compound according to claim 2, or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, and a pharmaceutically acceptable carrier or excipient.
- 9. A pharmaceutical formulation comprising a compound according to claim 3, or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, and a pharmaceutically acceptable carrier or excipient.
- 10. A pharmaceutical formulation comprising a compound according to claim 4, or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, and a pharmaceutically acceptable carrier or excipient.
- 11. A pharmaceutical formulation comprising a compound according to claim 5, or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, and a pharmaceutically acceptable carrier or excipient.
- 12. A pharmaceutical formulation comprising a compound according to claim 6, or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, and a pharmaceutically acceptable carrier or excipient.
- 13. A process for preparing a compound of formula (I) according to claim 2 or a salt, solvate, or physiologically functional derivative thereof; which comprises coupling a compound of formula (II) with a compound of formula (III); ##STR8## wherein; Y' and Y" are groups capable of reacting together to form the desired linkage Y (as defined for formula (I));
- (WX)'-- is either the group W--X-- (wherein W and X are as defined for formula (I)), a protected form thereof, or a precursor for the said group W--X--;
- --(EZ)' is either the group --E--Z (wherein E and Z are as defined for formula (I)), a protected form thereof, or a precursor for the said group --E--Z;
- and rings A and B are optionally substituted as described for formula (I);
- to give either a compound of formula (I) or a compound of formula (IV): ##STR9## wherein Y is as defined for formula (I), (WX)'-- and --(EZ)' are as defined for formulae (II) and (III) respectively (excluding combinations of (WX)'-- and --(EZ)' which give a compound of formula (I)), and rings A and B are optionally substituted as described for formula (I);
- followed by,
- (i) When (WX)'-- in the compound of formula (II) is a precursor for the group W--X--, formation of the group W--X--; and/or
- (ii) When --(EZ)' in the compound of formula (III) is a precursor for the group --E--Z; formation of the group --E--Z; and/or
- (iii) Removal of any protecting groups; and/or
- (iv) Optional formation of a salt, solvate, or physiologically functional derivative of the resulting compound of formula (I), as discussed below or conversion to a different compound of formula (I).
- 14. A compound of formula (I) according to claim 2 wherein:
- W is a C.sub.1-12 hydrocarbyl group;
- X is C(O)NR.sup.2, wherein R.sup.2 is hydrogen;
- Y is (CH.sub.2).sub.n --O--(CH.sub.2).sub.p, wherein n and p are both 0;
- E is a bond;
- Z is C.sub.1-8 alkyl, wherein Z is optionally substituted by --C(O)NR.sup.6 R.sup.7, and R.sup.6 and R.sup.7 are both hydrogen; and
- wherein phenyl rings A and B are optionally substituted by one or more halo groups.
- 15. A compound according to claim 14 which is N-{2,4-difluoro-6-[4-(1-carbomyl-1-methylethyl)phenoxy]phenyl}pivalamide.
- 16. A method according to claim 1 wherein the mammal is a human.
- 17. A method according to claim 2 wherein the mammal is a human.
- 18. A method according to claim 3 wherein the mammal is a human.
- 19. A method according to claim 4 wherein the mammal is a human.
- 20. A method according to claim 5 wherein the mammal is a human.
- 21. A method according to claim 6 wherein the mammal is a human.
Priority Claims (2)
Number |
Date |
Country |
Kind |
9313459 |
Jun 1993 |
GBX |
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9406005 |
Mar 1994 |
GBX |
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Parent Case Info
This application is a divisional application Ser. No. 08/564,281, filed Apr. 11, 1996, now U.S. Pat. No. 5,776,951 which is a 371 of PCT/GB94/01409, filed Jun. 29, 1994.
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Divisions (1)
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564281 |
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