Anti-atherosclerotic diaryl compounds

• US 5,776,951 A
• Filed: 04/11/1996
• Issued: 07/07/1998
• Est. Priority Date: 06/30/1993
• Status: Expired due to Fees

• Current Assignee: Glaxo Wellcome Incorporated (GlaxoSmithKline PLC)
• Original Assignee: Glaxo Wellcome Incorporated (GlaxoSmithKline PLC)
• Inventors: Hodgson, Simon Teanby, Franzmann, Karl Witold, Arrowsmith, Richard James, Dann, John Gordon, Wates, Peter John
• Primary Examiner(s): Ivy, C. Warren
• Assistant Examiner(s): DAHLEN, GARTH
• Application Number:
  US08/564,281
• Time in Patent Office: 817 Days
• Field of Search: 514/237.5, 514/328, 514/330, 514/399, 514/450, 514/456, 514/459, 544/165, 546/220, 546/225, 548/338.1, 549/23, 549/28, 549/352
• US Class Current: 514/328
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07C 233/25 having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
• CPC Class Codes: C07C 233/33 with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 233/54 having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of a saturated carbon skeleton
• CPC Class Codes: C07C 233/75 with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 235/34 having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
• CPC Class Codes: C07C 237/24 having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
• CPC Class Codes: C07C 255/46 to carbon atoms of non-condensed rings
• CPC Class Codes: C07C 2601/08 the ring being saturated
• CPC Class Codes: C07C 2602/44 the bicyclo ring system containing eight carbon atoms
• CPC Class Codes: C07C 271/28 to a carbon atom of a non-condensed six-membered aromatic ring
• CPC Class Codes: C07C 275/36 with at least one of the oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. N-aryloxyphenylureas
• CPC Class Codes: C07C 311/21 having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 311/29 having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 317/22 with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
• CPC Class Codes: C07C 323/41 Y being a hydrogen or an acyclic carbon atom
• CPC Class Codes: C07D 211/32 by oxygen atoms
• CPC Class Codes: C07D 211/88 attached in positions 2 and 6, e.g. glutarimide
• CPC Class Codes: C07D 231/12 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 233/56 : with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 249/08 : 1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
• CPC Class Codes: C07D 295/192 : from aromatic carboxylic acids
• CPC Class Codes: C07D 309/04 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 309/08 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 309/10 : Oxygen atoms

Abstract

The present invention is concerned with diaryl compounds of formula (l) and their use in medical therapy, particularly in the prophylaxis or treatment of a clinical condition for which an ACAT inhibitor is indicated, such as hyperlipidaema or atherosclerosis. The invention also relates to pharmaceutical compositions and processes for the preparation of compounds according to the invention. ##STR1##

Claims

1. A compound of formula (I) ##STR5## or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, wherein:

W is hydrogen, or a C_1-12 hydrocarbyl group optionally substituted by one or more groups independently selected from halo, C_1-4 alkyl, C_1-4 alkoxy, hydroxy, C_1-4 haloalkyl C_1-4 haloalkoxy, and RC(O)-- (wherein R is selected from hydrogen, C_1-4 alkyl C_1-4 alkoxy, hydroxy, C_1-4 haloalkyl, and C_1-4 haloalkoxy);

X is --NR¹ C(O)NR² --, --NR¹ C(O)--, --NR¹ C(O)O--, --C(O)NR² --, or --OC(O)NR² -- (wherein R¹ and R² are independently selected from hydrogen, C_1-4 alkyl, and

Y is a bond, C_2-4 alkynylene, C_2-4 alkenylene (cis or trans), C_1-4 alkylene, --(CH₂)_n --O--(CH₂)_p --, or --(CH₂)_n S(O)_q --(CH₂)_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_1-4 alkyl, and C_1-4 haloalkyl;

E is a bond, C_1-4 alkylene, --(CH₂)_r O--(CH₂)_s --, --(CH₂)_r --S(O)_t --(CH₂)_s --, --(CH₂)_r C(O)--(CH₂)_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)₂ N(R³)--, --(R³)NS(O)₂ --, --C(O)N(R³)--, --(R³)NC(O)N(R⁴)--, or --(R³)NC(O)-- (wherein R³ and R⁴ are independently selected from hydrogen, C_1-4 alkyl, and C_1-4 haloalkyl);

Z is an aliphatic heterocyclic ring system,

and Z is optionally substituted by one or more groups independently selected from halo, cyano, --CO₂ R⁶, --C(O)NR⁶ R⁷, --NR⁶ R⁷ (wherein R⁶ and R⁷ are independently selected from hydrogen, C_1-4 alkyl, and C_1-4 haloalkyl), C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 alkoxy, C_1-4 haloalkoxy, hydroxy, and C_2-8 polyether,

phenyl rings A and B are optionally substituted by one or more groups independently selected from halo, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 alkoxy, C_1-4 haloalkoxy, hydroxy, cyano, R⁸ R⁹ NC(O)--, R⁸ C(O)N(R⁹)--, R⁸ C(O)O--, and R⁸ C(O)-- (wherein R⁸ and R⁹ are independently selected from hydrogen, C_1-4 alkyl, and C_1-4 haloalkyl).

2. A compound of formula (I) according to claim 1 wherein:

W is C_3-7 alkyl optionally substituted as described in claim 1;

X is --C(O)NR² --, --NR¹ C(O)--, or --NR¹ C(O)NR² -- (wherein R¹ and R² are as defined in claim 1;

Y is ethylene, ethenylene, ethenylene, --O--, --S--, --CH₂ O--, or --OCH₂ --;

E is --O--, --OCH₂ --, --CH₂ O--, a bond, --C(O)N(R³)--, --(R³)NC(O)--, --S--, --S(O)--, --S(O)₂ --, --R³)NS(O)₂ --, --S(O)₂ N(R³)--, --(R³)NC(O)N(R⁴)--, or --C(O)-- (wherein R³ and R⁴ are as defined in claim

     1); and

Z is a 5-- or 6-membered saturated heterocyclic ring and Z is optionally substituted as described in claim 1;

or a salt, solvate, or physiologically functional derivative thereof.

3. A compound of formula (I) according to claim 1 selected from:

N-{2,4-Difluoro-6- 4-(2,6-dioxo-4-piperidinyl)phenylethynyl!phenyl}pivalamide;

N-{2,4-Difluoro-6- 4-(4-methoxytetrahydropyran-4-yl)phenylethynyl!phenyl}- pivalamide;

N-{2,4-Difluoro-6- 4-(2,6-dioxo-4-piperidinyl)phenoxy!phenyl}pivalamide;

or a salt, solvate, or physiologically functional derivative thereof.

4. A pharmaceutical formulation comprising a compound of formula (I) (as defined in claim 1), or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, and a pharmaceutically acceptable carrier or excipient.

5. A process for preparing a compound of formula (I) according to claim 1, or a salt, solvate, or physiologically functional derivative thereof;

which comprises coupling a compound of formula (II) with a compound of formula (III);

##STR6## 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 precusor 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);

##STR7## 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).

6. A compound of formula (I) according to claim 1 wherein:

W is C_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 heterocylic ring and Z is optionally substituted by one or more groups independently selected from the group consisting of halo, cyano, --CO₂ R⁶, --C(O)NR⁶ R⁷, --NR⁶ R⁷ wherein R⁶ and R⁷ are independently hydrogen, --C_1-4 alkyl or C_-4 haloalkyl, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 alkoxy, C_1-4 haloalkoxy, hydroxy and C_2-8 polyether.

7. A compound of formula (I) according to claim 2 wherein:

W is C_3-5 alkyl;

X is --C(O)NH--;

Y is ethenylene or --O--;

E is --)--, or a bond;

Z is a 5- or 6-membered saturated heterocylic ring and Z is optionally substituted by one or more groups independently selected from the group consisting of halo, cyano, --CO₂ R⁶, --C(O)NR⁶ R⁷, --NR⁶ R⁷ wherein R⁶ and R⁷ are independently hydrogen, C_1-4 alkyl or C_1-4 haloalkyl, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 alkoxy, C_1-4 haloalkoxy, hydroxy and C_2-8 polyether.

9. A method for the prophylaxis or treatment of a clinical condition in a mammal, such as a human, for which an ACAT inhibitor is indicated, which comprises the administration to the mammal of a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.

10. A method for the prophylaxis or treatment of a clinical condition in a mammal, such as a human, for which an ACAT inhibitor is indicated, which comprises the administration to the mammal of a therapeutically effective amount of a compound according to claim 2, or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.

11. A method for the prophylaxis or treatment of a clinical condition in a mammal, such as a human, for which an ACAT inhibitor is indicated, which comprises the administration to the mammal of a therapeutically effective amount of a compound according to claim 3, or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.

8. A method for the prophylaxis or treatment of a clinical condition in a mammal, such as a human, 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 ##STR8## wherein:

W is hydrogen, or a C_1-12 hydrocarbyl group optionally substituted by one or more groups independently selected from halo, C_1-4 alkyl, C_1-4 alkoxy, hydroxy, C_1-4 haloalkyl, C_1-4 haloalkoxy, and RC(O)-- (wherein R is selected from hydrogen, C_1-4 alkyl C_1-4 alkoxy, hydroxy, C_1-4 haloalkyl, and C_1-4 haloalkoxy);

X is --NR¹ C(O)NR² --, --NR¹ C(O)--, --NR¹ C(O)O--, --C(O)NR² --, or --OC(O)NR² --(wherein R¹ and R² are independently selected from hydrogen, C_1-4 alkyl, and C_1-4 haloalkyl);

Y is a bond, C_2-4 alkynylene, C_2-4 alkenylene (cis or trans), C_1-4 alkylene, --(CH₂)_n --O--(CH₂)_p --, or --(CH₂)_n --S(O)_q --(CH₂)_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_1-4 alkyl, and C_1-4 haloalkyl;

E is a bond, C_1-4 alkylene, --(CH₂)_r O--(CH₂)_s --, --(CH₂)_r --S(O)_t --(CH₂)_s --, --(CH₂)_r --C(O)--(CH₂)_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)₂ N(R³)--, --(R³)NS(O)₂ --, --C(O)N(R³)--, --(R³)NC(O)N(R⁴)--, or --(R³)NC(O)-- (wherein R³ and R⁴ are independently selected from hydrogen. C_1-4 alkyl, and C _1-4 haloalkyl);

Z is an aliphatic heterocyclic ring system or heteroaromatic,

and Z is optionally substituted by one or more groups independently selected from halo, cyano, --CO₂ R⁶, --C(O)NR⁶ R⁷, --NR⁶ R⁷ (wherein R⁶ and R⁷ are independently selected from hydrogen, C_1-4 alkyl, and C_1-4 haloalkyl), C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 alkoxy, C_1-4 haloalkoxy, hydroxy, and C_2-8 polyether;

phenyl rings A and B are optionally substituted by one or more groups independently selected from halo, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 alkoxy, C_-4 haloalkoxy, hydroxy, cyano, R⁸ R⁹ NC(O)--, R⁸ C(O)N(R⁹)--, R⁸ C(O)O--, and R⁸ C(O)-- (wherein R⁸ and R⁹ are independently selected from hydrogen, C_1-4 alkyl, and C_1-4 haloalkyl);

provided that if Y is methylene, ethylene, or n-propylene, or --CH═

CH--(cis or trans), then group --E--Z is not C_1-6 alkyl optionally substituted by one or more independently selected polar groups.