US2014221383A1PendingUtilityA1
Cetp inhibitors
Est. expiryJul 2, 2024(expired)· nominal 20-yr term from priority
Inventors:Amjad AliJoann M. NapolitanoQiaolin DengZhijian LuPeter J. SinclairGayle E. HalletChristopher F. ThompsonNazia QuraishiCameron SmithJulianne A. HuntAdrian A. DowstYi-Heng ChenHong Li
A61P 3/10A61P 3/06A61P 9/08A61P 43/00A61P 9/10A61P 9/14A61P 9/12A61P 7/00A61P 9/00A61P 39/02A61P 3/00A61P 3/04C07D 417/10C07D 417/04C07D 263/20A61K 31/4168C07F 7/10C07D 233/32C07D 263/24A61K 31/501A61K 31/433C07D 207/27A61K 31/421C07D 233/52C07D 285/10A61K 31/427A61K 31/497C07D 263/26A61K 31/506C07D 413/10C07D 263/22C07D 207/26A61K 31/422A61K 31/4015C07D 413/04C07D 233/50C07D 401/04C07D 263/04A61K 31/4166C07D 285/06A61K 45/06C07D 233/38A61K 31/4439C07F 7/1804C07D 413/06
60
PatentIndex Score
0
Cited by
0
References
0
Claims
Abstract
Compounds having the structures of Formula I, including pharmaceutically acceptable salts of the compounds, are CETP inhibitors, and are useful for raising HDL-cholesterol, reducing LDL-cholesterol, and for treating or preventing atherosclerosis: In the compounds of Formula I, B or R 2 is a phenyl group which has an ortho aryl, heterocyclic, benzoheterocyclic or benzocycloalkyl substituent, and one other position on the 5-membered ring has an aromatic, heterocyclic, cycloalkyl, benzoheterocyclic or benzocycloalkyl substituent connected directly to the ring or attached to the ring through a —CH 2 —.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound having Formula I, or a pharmaceutically acceptable salt thereof, wherein
Y is selected from the group consisting of —C(═O)— and —(CRR 1 )—;
X is selected from the group consisting of —O—, —NH—, —N(C 1 -C 5 alkyl)-, and —(CRR 6 )—;
Z is selected from the group consisting of —C(═O)—, —S(O) 2 —, and —C(═N—R 9 )—, wherein R 9 is selected from the group consisting of H, —CN, and C 1 -C 5 alkyl optionally substituted with 1-11 halogens;
Each R is independently selected from the group consisting of H, —C 1 -C 5 alkyl, and halogen, wherein —C 1 -C 5 alkyl is optionally substituted with 1-11 halogens;
B is selected from the group consisting of A 1 and A 2 , wherein A 1 has the structure:
R 1 and R 6 are each selected from the group consisting of H, —C 1 -C 5 alkyl, halogen, and —(C(R) 2 ) n A 2 , wherein —C 1 -C 5 alkyl is optionally substituted with 1-11 halogens;
R 2 is selected from the group consisting of H, —C 1 -C 5 alkyl, halogen, A 1 , and —(C(R) 2 ) n A 2 , wherein —C 1 -C 5 alkyl is optionally substituted with 1-11 halogens;
Wherein one of B and R 2 is A 1 ; and one of B, R 1 , R 2 , and R 6 is A 2 or —(C(R) 2 ) n A 2 ; so that the compound of Formula I comprises one group A 1 and one group A 2 ;
A 3 is selected from the group consisting of:
(a) an aromatic ring selected from phenyl and naphthyl;
(b) a phenyl ring fused to a 5-7 membered non-aromatic cycloalkyl ring, which optionally comprises 1-2 double bonds;
(c) a 5-6-membered heterocyclic ring having 1-4 heteroatoms independently selected from N, S, O, and —N(O)—, and optionally also comprising 1-3 double bonds and a carbonyl group, wherein the point of attachment of A 3 to the phenyl ring to which A 3 is attached is a carbon atom; and
(d) a benzoheterocyclic ring comprising a phenyl ring fused to a 5-6-membered heterocyclic ring having 1-2 heteroatoms independently selected from O, N, and —S(O) x — and optionally 1-2 double bonds, wherein the point of attachment of A 3 to the phenyl ring to which A 3 is attached is a carbon atom;
A 2 is selected from the group consisting of:
(a) an aromatic ring selected from phenyl and naphthyl;
(b) a phenyl ring fused to a 5-7 membered non-aromatic cycloalkyl ring, which optionally comprises 1-2 double bonds;
(c) a 5-6-membered heterocyclic ring having 1-4 heteroatoms independently selected from N, S, O, and —N(O)—, and optionally also comprising 1-3 double bonds and a carbonyl group;
(d) a benzoheterocyclic ring comprising a phenyl ring fused to a 5-6-membered heterocyclic ring having 1-2 heteroatoms independently selected from O, N, and S and optionally 1-2 double bonds; and
(e) a —C 3 -C 8 cycloalkyl ring optionally having 1-3 double bonds;
wherein A 3 and A 2 are each optionally substituted with 1-5 substituent groups independently selected from Ra;
Each R a is independently selected from the group consisting of —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, —C 3 -C 8 cycloalkyl optionally having 1-3 double bonds, —OC 1 -C 6 alkyl, —OC 2 -C 6 alkenyl, —OC 2 -C 6 alkynyl, —OC 3 -C 8 cycloalkyl optionally having 1-3 double bonds, —C(═O)C 1 -C 6 alkyl, —C(═O)C 3 -C 8 cycloalkyl, —C(═O)H, —CO 2 H, —CO 2 C 1 -C 6 alkyl, —C(═O)SC 1 -C 6 alkyl, —OH, —NR 3 R 4 , —C(═O)NR 3 R 4 , —NR 3 C(═O)OC 1 -C 6 alkyl, —NR 3 C(═O)NR 3 R 4 , —S(O) x C 1 -C 6 alkyl, —S(O) y NR 3 R 4 , —NR 3 S(O) y NR 3 R 4 , halogen, —CN, —NO 2 , and a 5-6-membered heterocyclic ring having 1-4 heteroatoms independently selected from N, S, and O, said heterocyclic ring optionally also comprising a carbonyl group and optionally also comprising 1-3 double bonds, wherein the point of attachment of said heterocyclic ring to the ring to which R a is attached is a carbon atom, wherein said heterocyclic ring is optionally substituted with 1-5 substituent groups independently selected from halogen, —C 1 -C 3 alkyl, and —OC 1 -C 3 alkyl, wherein —C 1 -C 3 alkyl and —OC 1 -C 3 alkyl are optionally substituted with 1-7 halogens;
wherein for compounds in which R a is selected from the group consisting of —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, —C 3 -C 8 cycloalkyl optionally having 1-3 double bonds, —OC 1 -C 6 alkyl, —OC 2 -C 6 alkenyl, —OC 2 -C 6 alkynyl, —OC 3 -C 8 cycloalkyl optionally having 1-3 double bonds, —C(═O)C 1 -C 6 alkyl, —C(═O)C 3 -C 8 cycloalkyl, —CO 2 C 1 -C 6 alkyl, —C(═O)SC 1 -C 6 alkyl, —NR 3 C(═O)OC 1 -C 6 alkyl, and —S(O) x C 1 -C 6 alkyl, then R a is optionally substituted with 1-15 halogens and is optionally also substituted with 1-3 substituent groups independently selected from (a) —OH, (b) —CN, (c) —NR 3 R 4 , (d) —C 3 -C 8 cycloalkyl optionally having 1-3 double bonds and optionally substituted with 1-15 halogens, (e) —OC 1 -C 4 alkyl optionally substituted with 1-9 halogens and optionally also substituted with 1-2 substituent groups independently selected from —OC 1 -C 2 alkyl and phenyl, (f) —OC 3 -C 8 cycloalkyl optionally having 1-3 double bonds and optionally substituted with 1-15 halogens, (g) —CO 2 H, (h) —C(═O)CH 3 , (i) —CO 2 C 1 -C 4 alkyl which is optionally substituted with 1-9 halogens, and (j) phenyl which is optionally substituted with 1-3 groups independently selected from halogen, —CH 3 , —CF 3 , —OCH 3 , and —OCF 3 ;
with the proviso that when B is A 1 , and X and Y are —CH 2 —, and Z is —C(═O)—, and R 2 is phenyl which has a substituent R a in the 4-position, wherein R a is —OC 1 -C 6 alkyl which is optionally substituted as described above, then there are no other R a substitutents on R 2 in which R a is selected from —OH, —OC 1 -C 6 alkyl, —OC 2 -C 6 alkenyl, —OC 2 -C 6 alkynyl, and —OC 3 -C 8 cycloalkyl optionally having 1-3 double bonds, optionally substituted as described above.
n is 0 or 1;
p is an integer from 0-4;
x is 0, 1, or 2;
y is 1 or 2;
R 3 and R 4 are each independently selected from H, —C 1 -C 5 alkyl, —C(═O)C 1 -C 5 alkyl and —S(O) y C 1 -C 5 alkyl, wherein —C 1 -C 5 alkyl in all instances is optionally substituted with 1-11 halogens; and
R 5 is selected from the group consisting of H, —OH, —C 1 -C 5 alkyl, and halogen, wherein —C 1 -C 5 alkyl is optionally substituted with 1-11 halogens.
2 . The compound of claim 1 , which is selected from the group consisting of compounds having Formula Ia, Ib, and Id, or a pharmaceutically acceptable salt thereof:
3 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
Y is —(CRR 1 )—; R and R 6 are each independently selected from the group consisting of H and —C 1 -C 5 alkyl, wherein —C 1 -C 5 alkyl is optionally substituted with 1-11 halogens; R 1 is selected from the group consisting of H, —C 1 -C 5 alkyl, and —(C(R) 2 ) n A 2 , wherein —C 1 -C 5 alkyl is optionally substituted with 1-11 halogens; Wherein one of B and R 2 is A 1 ; and one of B, R 1 , and R 2 is A 2 or —(C(R) 2 ) n A 2 ; so that the compound of Formula I comprises one group A 1 and one group A 2 ; A 3 is selected from the group consisting of:
(a) an aromatic ring selected from phenyl and naphthyl;
(b) a 5-6-membered heterocyclic ring having 1-4 heteroatoms independently selected from N, S, O, and —N(O)—, and optionally also comprising 1-3 double bonds and a carbonyl group, wherein the point of attachment of A 3 to the phenyl ring to which A 3 is attached is a carbon atom; and
(c) a benzoheterocyclic ring comprising a phenyl ring fused to a 5-6-membered heterocyclic ring having 1-2 heteroatoms independently selected from O, N, and —S(O) x — and optionally 1-2 double bonds, wherein the point of attachment of A 3 to the phenyl ring to which A 3 is attached is a carbon atom;
A 2 is selected from the group consisting of:
(a) an aromatic ring selected from phenyl and naphthyl;
(b) a 5-6-membered heterocyclic ring having 1-4 heteroatoms independently selected from N, S, O, and —N(O)—, and optionally also comprising 1-3 double bonds and a carbonyl group;
(c) a benzoheterocyclic ring comprising a phenyl ring fused to a 5-6-membered heterocyclic ring having 1-2 heteroatoms independently selected from O, N, and S and optionally 1-2 double bonds; and
(d) a —C 3 -C 8 cycloalkyl ring optionally having 1-3 double bonds;
wherein A 3 and A 2 are each optionally substituted with 1-4 substituent groups independently selected from R a ; Each R a is independently selected from the group consisting of —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 3 -C 8 cycloalkyl optionally having 1-3 double bonds, —OC 1 -C 6 alkyl, —C(═O)C 1 -C 6 alkyl, —C(═O)H, —CO 2 H, —CO 2 C 1 -C 6 alkyl, —OH, —NR 3 R 4 , —NR 3 C(═O)OC 1 -C 6 alkyl, —S(O) x C 1 -C 6 alkyl, halogen, —CN, —NO 2 , and a 5-6-membered heterocyclic ring having 1-4 heteroatoms independently selected from N, S, and O, said heterocyclic ring optionally also comprising a carbonyl group and optionally also comprising 1-3 double bonds, wherein the point of attachment of said heterocyclic ring to the ring to which R a is attached is a carbon atom, wherein said heterocyclic ring is optionally substituted with 1-5 substituent groups independently selected from halogen, —C 1 -C 3 alkyl, and —OC 1 -C 3 alkyl, wherein —C 1 -C 3 alkyl and —OC 1 -C 3 alkyl are optionally substituted with 1-7 halogens; wherein for compounds in which R a is selected from the group consisting of —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 3 -C 8 cycloalkyl optionally having 1-3 double bonds, —OC 1 -C 6 alkyl, —C(═O)C 1 -C 6 alkyl, —CO 2 C 1 -C 6 alkyl, —NR 3 C(═O)OC 1 -C 6 alkyl, and —S(O) x C 1 -C 6 alkyl, R a is optionally substituted with 1-15 halogens and is optionally also substituted with one substituent group selected from (a) —OH, (b) —NR 3 R 4 , (c) —OC 1 -C 4 alkyl optionally substituted with 1-9 halogens and optionally also substituted with 1-2 substituent groups independently selected from —OC 1 -C 2 alkyl and phenyl, and (d) phenyl which is optionally substituted with 1-3 groups independently selected from halogen, —CH 3 , —CF 3 , —OCH 3 , and —OCF 3 ; with the proviso that when B is A 1 , and X and Y are —CH 2 —, and Z is —C(═O)—, and R 2 is phenyl which has a substituent R a in the 4-position, wherein R a is —OC 1 -C 6 alkyl which is optionally substituted as described above, then there are no other R a substitutents on R 2 in which R a is —OH or —OC 1 -C 6 alkyl which is optionally substituted as described above; p is an integer from 0-2; R 3 and R 4 are each independently selected from H and —C 1 -C 5 alkyl, wherein —C 1 -C 5 alkyl in all instances is optionally substituted with 1-11 halogens; and R 5 is selected from the group consisting of H, —OH, and —C 1 -C 5 alkyl, wherein —C 1 -C 5 alkyl is optionally substituted with 1-11 halogens.
4 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
Y is —(CRR 1 )—; Z is selected from the group consisting of —C(═O)—, —S(O) 2 —, and —C(═N—R 9 )—, wherein R 9 is selected from the group consisting of H, —CN, and CH 3 ; Each R is independently selected from the group consisting of H and C 1 -C 2 alkyl; R 6 is selected from the group consisting of H and —C 1 -C 3 alkyl, wherein C 1 -C 3 alkyl is optionally substituted with 1-5 halogens; R 1 is selected from the group consisting of H, —C 1 -C 3 alkyl, and —(C(R) 2 ) n A 2 , wherein —C 1 -C 3 alkyl is optionally substituted with 1-5 halogens; R 2 is selected from the group consisting of H, —C 1 -C 3 alkyl, A 1 , and —(C(R) 2 ) n A 2 , wherein —C 1 -C 3 alkyl is optionally substituted with 1-5 halogens; Wherein one of B and R 2 is A 1 ; and one of B, R 1 , and R 2 is A 2 or —(C(R) 2 ) n A 2 ; so that the compound of Formula I comprises one group A 1 and one group A 2 ; A 3 is selected from the group consisting of:
(a) phenyl;
(b) a 5-6-membered aromatic heterocyclic ring having 1-2 heteroatoms independently selected from N, S, O, and —N(O)—, wherein the point of attachment of A 3 to the phenyl ring to which A 3 is attached is a carbon atom; and
(c) a benzoheterocyclic ring comprising a phenyl ring fused to a 5-membered aromatic heterocyclic ring having 1-2 heteroatoms independently selected from O, N, and —S(O) x , wherein the point of attachment of A 3 to the phenyl ring to which A 3 is attached is a carbon atom;
A 2 is selected from the group consisting of:
(a) phenyl;
(b) a 5-6-membered heterocyclic ring having 1-4 heteroatoms independently selected from N, S, O, and —N(O)—, and optionally also comprising 1-3 double bonds;
(c) a benzoheterocyclic ring comprising a phenyl ring fused to a 5-membered heterocyclic ring having 1-2 heteroatoms independently selected from O, N, and S; and
(d) a —C 5 -C 6 cycloalkyl ring;
wherein A 3 and A 2 are each optionally substituted with 1-4 substituent groups independently selected from Ra; Each R a is independently selected from the group consisting of —C 1 -C 4 alkyl, —C 2 -C 4 alkenyl, cyclopropyl, —OC 1 -C 2 alkyl, —C(═O)C 1 -C 2 alkyl, —C(═O)H, —CO 2 C 1 -C 4 alkyl, —OH, —NR 3 R 4 , —NR 3 C(═O)OC 1 -C 4 alkyl, —S(O) x C 1 -C 2 alkyl, halogen, —CN, —NO 2 , and a 5-6-membered heterocyclic ring having 1-2 heteroatoms independently selected from N, S, and O, wherein the point of attachment of said heterocyclic ring to the ring to which R a is attached ring is a carbon atom, wherein said heterocyclic ring is optionally substituted with 1-5 substituent groups independently selected from halogen; wherein for compounds in which R a is selected from the group consisting of —C 1 -C 4 alkyl, —C 2 -C 4 alkenyl, —OC 1 -C 2 alkyl, —C(═O)C 1 -C 2 alkyl, —CO 2 C 1 -C 4 alkyl, —NR 3 C(═O)OC 1 -C 4 alkyl, and —S(O) x C 1 -C 2 alkyl, the alkyl group of R a is optionally substituted with 1-5 halogens and is optionally also substituted with one substituent group selected from (a) —OH, (b) —NR 3 R 4 , (c) —OCH 3 optionally substituted with 1-3 fluorine atoms and optionally also substituted with one phenyl group, and (d) phenyl which is optionally substituted with 1-3 groups independently selected from halogen, —CH 3 , —CF 3 , —OCH 3 , and —OCF 3 ; with the proviso that when B is A 1 , and X and Y are —CH 2 —, and Z is —C(═O)—, and R 2 is phenyl which has a substituent R a in the 4-position, wherein R a is —OC 1 -C 2 alkyl which is optionally substituted as described above, then there are no other R a substitutents on R 2 in which R a is selected from —OH or —OC 1 -C 2 alkyl which is optionally substituted as described above; p is an integer from 0-2; and R 3 , R 4 , and R 5 are each independently selected from H and —C 1 -C 3 alkyl.
5 . The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein
A 3 is selected from the group consisting of phenyl, thienyl, imidazolyl, pyrrolyl, pyrazolyl, pyridyl, N-oxido-pyridyl, thiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzothienyl, benzothienyl-5-oxide, and benzothienyl-5-dioxide; and A 2 is selected from the group consisting of phenyl, thienyl, imidazolyl, thiazolyl, pyrrolyl, pyrazolyl, 1,2,4-triazolyl, tetrazolyl, benzodioxolyl, pyridyl, N-oxido-pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, cyclopentyl, cyclohexyl, and tetrahydropyranyl.
6 . The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein
X is selected from the group consisting of —O—, —NH—, and —N(C 1 -C 3 alkyl)-; and Z is —C(═O)—.
7 . The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein A 2 and A 3 are both phenyl; and
R a is selected from the group consisting of —C 1 -C 4 alkyl which is optionally substituted with 1-5 fluorine atoms and is optionally also substituted with one group selected from —OH and —OCH 3 ; —OC 1 -C 2 alkyl, which is optionally substituted with 1-3 fluorine atoms; —C 2 -C 4 alkenyl; —C 1 -C 2 alkyl which is substituted with one group —NR 3 R 4 ; —C 1 -C 2 alkyl-O—C 1 -C 2 alkyl-phenyl; cyclopropyl; —C(═O)H; —OH; —NR 3 R 4 ; —S(O) x C 1 -C 2 alkyl; halogen; —CN; —NO 2 ; and a 5-6-membered heterocyclic ring comprising 1-2 oxygen atoms which is optionally substituted with C 1 -C 2 alkyl; subject to the same proviso as in claim 4 .
8 . The compound of claim 7 having Formula II, or a pharmaceutically acceptable salt thereof, wherein:
R 7 is selected from the group consisting of Cl and —CF 3 ;
Each R b is independently selected from the group consisting of —C 1 -C 3 alkyl, —OCH 3 , and F;
R 1 is selected from the group consisting of H and —C 1 -C 2 alkyl;
R c is selected from the group consisting of halogen, —CH 3 —CF 3 , and —CN;
q is 2 or 3; and
t is an integer from 0-2.
9 . The compound of claim 7 having Formula Ij, or a pharmaceutically acceptable acceptable salt thereof, wherein:
R 7 is selected from the group consisting of Cl and —CF 3 ;
Each R b is independently selected from the group consisting of —C 1 -C 3 alkyl, —OCH 3 , and F;
R 1 is selected from the group consisting of H and —C 1 -C 2 alkyl;
R c is selected from the group consisting of halogen, —CH 3 —CF 3 , and —CN;
q is 2 or 3; and
t is an integer from 0-2.
10 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
A 3 is phenyl, which is optionally substituted with 1-4 substituent groups R a , wherein R a is independently selected from —C 1 -C 5 alkyl, —OC 1 -C 3 alkyl, —CO 2 C 1 -C 3 alkyl, —CO 2 H, halogen, —NR 3 R 4 , —C(═O)C 1 -C 3 alkyl, —C(═O)H, —C(═O)NR 3 R 4 , —SC 1 -C 3 alkyl, —C 2 -C 3 alkenyl, —CN, —NO 2 , and 1,2,4-oxadiazolyl, wherein —C 1 -C 3 alkyl and —C 1 -C 5 alkyl in all occurrences is optionally substituted with 1-6 substituents independently selected from 1-5 halogens and one —OH group; and —C 2 -C 3 alkenyl is optionally substituted with 1-3 halogens; A 2 is selected from the group consisting of phenyl, cyclohexyl, and a heterocyclic 5-6 membered ring comprising 1-2 heteroatoms independently selected from O, N, S, and —N(O)— and optionally also comprising 1-3 double bonds, wherein A 2 is optionally substituted with 1-2 substituent groups independently selected from —C 1 -C 4 alkyl, —OC 1 -C 3 alkyl, —NO 2 , —CN, —S(O) x C 1 -C 3 alkyl, —NHS(O) 2 C 1 -C 3 alkyl, —NR 3 R 4 , —NR 3 C(═O)R 4 , —C 2 -C 3 alkenyl, —C(═O)NR 3 R 4 , halogen, and pyridyl, wherein C 1 -C 3 alkyl, C 1 -C 4 alkyl, and C 2 -C 3 alkenyl in all instances is optionally substituted with 1-3 halogens, with the proviso that when B is A 1 , and X and Y are —CH 2 —, and Z is —C(═O)—, and R 2 is phenyl which has a substituent R a in the 4-position in which R a is —OC 1 -C 3 alkyl which is optionally substituted as described above, then there are no other R a substitutents on R 2 in which R a is —OC 1 -C 3 alkyl optionally substituted as described above; R 3 and R 4 are each independently selected from H and —C 1 -C 3 alkyl; and p is 0-2.
11 . The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein A 1 is
R 7 and R 8 are each independently selected from the group consisting of H, halogen, —NR 3 R 4 , —C 1 -C 3 alkyl, —OC 1 -C 3 alkyl, —CN, —NO 2 , and pyridyl, wherein C 1 -C 3 alkyl in all instances is optionally substituted with 1-3 halogens; and
A 2 is selected from the group consisting of phenyl, pyridyl, and cyclohexyl, wherein A 2 is optionally substituted with 1-2 substituents independently selected from —C 1 -C 4 alkyl, —OC 1 -C 3 alkyl, —NO 2 , —CN, and halogen, wherein C 1 -C 4 alkyl and C 1 -C 3 alkyl in all uses is optionally substituted with 1-3 halogens, with the proviso that when B is A 1 , and X and Y are —CH 2 —, and Z is —C(═O)—, and R 2 is phenyl which has a substituent R a in the 4-position, wherein R a is —OC 1 -C 3 alkyl which is optionally substituted with 1-3 halogens, then there are no other R a substitutents on R 2 in which R a is selected from —OC 1 -C 3 alkyl which is optionally substituted with 1-3 halogens.
12 . The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein A 1 is
R 7 is selected from the group consisting of H, halogen, —NR 3 R 4 , —C 1 -C 3 alkyl, —OC 1 -C 3 alkyl, —CN, —NO 2 , and pyridyl, wherein C 1 -C 3 alkyl in all instances is optionally substituted with 1-3 halogens; and
R 8 is selected from the group consisting of H, halogen, —CH 3 , —CF 3 , —OCH 3 , and —OCF 3 .
13 . A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
14 . The compound of claim 4 , which is selected from the group consisting of the following compounds, or a pharmaceutically acceptable salt thereof:
15 . The compound of claim 4 , which is selected from the group consisting of compounds with the formula (a) to (c), or a pharmaceutically acceptable salt thereof:
wherein R is selected from the group consisting of
wherein R is selected from the group consisting of
wherein R is selected from the group consisting of
16 . The compound of claim 4 , which is selected from the group consisting of the following compounds, or a pharmaceutically acceptable salt thereof:
17 . The compound of claim 4 , selected from the group consisting of compounds having the formula (a) to (k), or a pharmaceutically acceptable salt thereof:
wherein A 3 , A 2 , and Z for the compounds (1) to (6) are selected from the group consisting of:
A 3
A 2
Z
(1)
CO
(2)
CO
(3)
CO
(4)
CO
(5)
CO and
(6)
SO 2 ;
wherein A 3 is selected from the group consisting of:
wherein A3 and A2 for the compounds (1) to (6) are selected from the group consisting of:
A 3
A 2
(1)
(2)
(3)
(4)
(5)
(6)
wherein R is selected from the group consisting of
wherein R is Et or n-Pr;
wherein R and A3 for the compounds (1) to (4) are selected from the group consisting of
R
A 3
(1)
(2)
(3)
(4)
wherein R is selected from the group consisting of:
wherein A 2 is selected from the group consisting of
wherein R is selected from the group consisting of
wherein A 3 is selected from the group consisting of:
wherein A 3 , R 2 and R 3 for the compounds (1) to (3) are selected from the group consisting of:
A 3
R 2
R 3
(1)
Et
(2)
Et
(3)
Et
18 . A method of treating atherosclerosis in a patient in need of treatment comprising the administration of a therapeutically effective amount of the compound of claim 1 to said patient, or a pharmaceutically acceptable salt thereof.
19 . A method of raising HDL-C in a patient in need of treatment comprising the administration of a therapeutically effective amount of the compound of claim 1 to said patient, or a pharmaceutically acceptable salt thereof.
20 . The use of the compound of claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of atherosclerosis.
21 . A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, and one or more active ingredients selected from the group consisting of:
(i) HMG-CoA reductase inhibitors;
(ii) bile acid sequestrants;
(iii) niacin and related compounds;
(iv) PPARα agonists;
(v) cholesterol absorption inhibitors;
(vi) acyl CoA:cholesterol acyltransferase (ACAT) inhibitors;
(vii) phenolic anti-oxidants;
(viii) microsomal triglyceride transfer protein (MTP)/ApoB secretion inhibitors;
(ix) anti-oxidant vitamins;
(x) thyromimetics;
(xi) LDL (low density lipoprotein) receptor inducers;
(xii) platelet aggregation inhibitors;
(xiii) vitamin B12 (also known as cyanocobalamin);
(xiv) folic acid or a pharmaceutically acceptable salt or ester thereof;
(xv) FXR and LXR ligands;
(xvi) agents that enhance ABCA1 gene expression; and
(xvii) ileal bile acid transporters.Cited by (0)
No later patents cite this yet.
References (0)
No backward citations on record.