DIPHENYLHETEROCYCLE CHOLESTEROL ABSORPTION INHIBITORS
Various azetidinone, pyrrolidine, imidazolidine, and oxazolidine derivatives are described, as are pharmaceutical compositions containing these compounds and methods of treatment of diseases using these compounds. Other embodiments are also described.
1 . A compound of formula I or II
wherein
each independently represent an aryl or heteroaryl residue;
Q is chosen from SO 2 and C═S;
U is (C 2 -C 6 )-alkylene in which one or more —CH 2 — may be replaced by a radical chosen from —S—, —S(O)—, —SO 2 —, —O—, —C(═O)—, —CHOH—, —NH—, CHF, CF 2 , —CH(O-loweralkyl)-, —CH(O-loweracyl)-, —CH(OSO 3 H)—, —CH(OPO 3 H 2 )—, —CH(OR 110 )—, or —CH(OSO 2 R 110 )—;
R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 , independently of one another, are chosen from:
H, F, Cl, Br, I, OH, CF 3 , NO 2 , N 3 , CN, COOH, COO(C 1 -C 6 )-alkyl, CONH 2 , CONH(C 1 -C 6 )-alkyl, CON[(C 1 -C 6 )-alkyl] 2 , (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, or O—(C 1 -C 6 )-alkyl, wherein the alkyl radical is unsubstituted or at least one hydrogen in the alkyl radical is replaced by fluorine; or C(═NH)(NH 2 ), PO 3 H 2 , SO 3 H, SO 2 NH 2 , SO 2 NH(C 1 -C 6 )-alkyl, SO 2 N[(C 1 -C 6 )-alkyl] 2 , S—(C 1 -C 6 )-alkyl, S—(CH 2 ) n -phenyl, SO—(C 1 -C 6 )-alkyl, SO—(CH 2 ) n -phenyl, SO 2 —(C 1 -C 6 )-alkyl, or SO 2 —(CH 2 ) n -phenyl, wherein n=0-6, and wherein the phenyl radical is unsubstituted or substituted one or two times, each substituent chosen independently from: F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl, and NH 2 ; and
NH 2 , NH—(C 1 -C 6 )-alkyl, N((C 1 -C 6 )-alkyl) 2 , NH(C 1 -C 7 )-acyl, phenyl, or O—(CH 2 ) n -phenyl, wherein n=0-6, and wherein the phenyl ring is unsubstituted or substituted one, two, or three times, each substituent chosen independently from: F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl, NH 2 , NH(C 1 -C 6 )-alkyl, N((C 1 -C 6 )-alkyl) 2 , SO 2 CH 3 , COOH, COO—(C 1 -C 6 )-alkyl, and CONH 2 ; and R 2 may additionally be chosen from —OSO 2 —R 110 and —SO 2 —R 110 ;
R 104 represents one, two, three or four residues chosen independently from H, halogen, —OH, loweralkyl, —O-loweralkyl, hydroxyloweralkyl, —CN, CF 3 , nitro, —SH, —S-loweralkyl, amino, alkylamino, dialkylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, acyl, carboxy, alkoxycarbonyl, arboxyalkyl, carboxamido, alkylsulfoxide, acylamino, amidino, —PO 3 H 2 , —SO 3 H, —B(OH) 2 , a sugar, a polyol, a glucuronide, a sugar carbamate, —OSO 2 —R 110 and —SO 2 —R 110 ;
R 105 is chosen from H, halogen, —OH, loweralkyl, —O-loweralkyl, methylenedioxy, ethylenedioxy, hydroxyloweralkyl, —CN, CF 3 , nitro, —SH, —S-loweralkyl, amino, alkylamino, dialkylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, acyl, carboxy, alkoxycarbonyl, carboxyalkyl, carboxamido, alkylsulfoxide, acylamino, amidino, —PO 3 H 2 , —SO 3 H, —B(OH) 2 , a sugar, a polyol, a glucuronide, a sugar carbamate, —OSO 2 —R 110 and —SO 2 —R 110 ; and
R 110 is chosen from a sugar, a polyol, a glucuronide and a sugar carbamate;
or a pharmaceutically acceptable salt thereof, in any stereoisomeric form, or a mixture of any such compounds in any ratio.
2 . A compound of formula Ia or IIa according to claim 1 :
3 . A compound according to claim 1 of formula Ib:
4 . A compound according to claim 1 of formula IIb:
5 . A compound according claim 1 wherein Q is SO 2 .
6 . A compound according claim 1 wherein Q is C═S.
7 . A compound of formula III or IV
wherein
each independently represent an aryl or heteroaryl residue;
X is chosen from S and O;
E is chosen from CH 2 , O, S and NR 50 ;
U is (C 2 -C 6 )-alkylene in which one or more —CH 2 — may be replaced by a radical chosen from —S—, —S(O)—, —SO 2 —, —O—, —C(═O)—, —CHOH—, —NH—, CHF, CF 2 , —CH(O-loweralkyl)-, —CH(O-loweracyl)-, —CH(OSO 3 H)—, —CH(OPO 3 H 2 )—, —CH(OR 110 )—, or —CH(OSO 2 R 110 )—;
R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 , independently of one another, are chosen from:
H, F, Cl, Br, I, OH, CF 3 , NO 2 , N 3 , CN, COOH, COO(C 1 -C 6 )-alkyl, CONH 2 , CONH(C 1 -C 6 )-alkyl, CON[(C 1 -C 6 )-alkyl] 2 , (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, or O—(C 1 -C 6 )-alkyl, wherein the alkyl radical is unsubstituted or at least one hydrogen in the alkyl radical is replaced by fluorine; or C(═NH)(NH 2 ), PO 3 H 2 , SO 3 H, SO 2 NH 2 , SO 2 NH(C 1 -C 6 )-alkyl, SO 2 N[(C 1 -C 6 )-alkyl] 2 , S—(C 1 -C 6 )-alkyl, S—(CH 2 ) n -phenyl, SO—(C 1 -C 6 )-alkyl, SO—(CH 2 ) n -phenyl, SO 2 —(C 1 -C 6 )-alkyl, or SO 2 —(CH 2 ) n -phenyl, wherein n=0-6, and wherein the phenyl radical is unsubstituted or substituted one or two times, each substituent chosen independently from: F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl, and NH 2 ; and
NH 2 , NH—(C 1 -C 6 )-alkyl, N((C 1 -C 6 )-alkyl) 2 , NH(C 1 -C 7 )-acyl, phenyl, or O—(CH 2 ) n -phenyl, wherein n=0-6, and wherein the phenyl ring is unsubstituted or substituted one, two, or three times, each substituent chosen independently from: F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl, NH 2 , NH(C 1 -C 6 )-alkyl, N((C 1 -C 6 )-alkyl) 2 , SO 2 CH 3 , COOH, COO—(C 1 -C 6 )-alkyl, and CONH 2 ; and R 2 may additionally be chosen from —OSO 2 —R 110 and —SO 2 —R 110 ;
R 50 is chosen from hydrogen and C 1 to C 6 alkyl;
R 104 represents one, two, three or four residues chosen independently from H, halogen, —OH, loweralkyl, —O-loweralkyl, hydroxyloweralkyl, —CN, CF 3 nitro, —SH, —S-loweralkyl, amino, alkylamino, dialkylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, acyl, carboxy, alkoxycarbonyl, carboxyalkyl, carboxamido, alkylsulfoxide, acylamino, amidino, —PO 3 H 2 , —SO 3 H, —B(OH) 2 , a sugar, a polyol, a glucuronide, a sugar carbamate, —OSO 2 —R 110 and —SO 2 —R 110 ;
R 105 is chosen from H, halogen, —OH, loweralkyl, —O-loweralkyl, methylenedioxy, ethylenedioxy, hydroxyloweralkyl, —CN, CF 3 , nitro, —SH, —S-loweralkyl, amino, alkylamino, dialkylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, acyl, carboxy, alkoxycarbonyl, carboxyalkyl, carboxamido, alkylsulfoxide, acylamino, amidino, —PO 3 H 2 , —SO 3 H, —B(OH) 2 , a sugar, a polyol, a glucuronide, a sugar carbamate, —OSO 2 —R 110 and —SO 2 —R 110 ; and
R 110 is chosen from a sugar, a polyol, a glucuronide and a sugar carbamate;
or a pharmaceutically acceptable salt thereof, in any stereoisomeric form, or a mixture of any such compounds in any ratio.
8 . A compound according to claim 7 of formula IIIa or IVa:
9 . A compound according to claim 7 of formula IIIc or IVc:
10 . A compound according to claim 7 of formula IIIb
11 . A compound according to claim 7 of formula IIId:
12 . A compound according to claim 7 of formula IVb:
13 . A compound according to claim 7 of formula IVd:
14 . A compound according to claim 7 wherein E is CH 2 .
15 . A compound according to claim 7 wherein E is CH 2 .
16 . A compound according to claim 7 wherein E is NH or NCH 3 .
17 . A compound according to claim 7 wherein E is NH or NCH 3 .
18 . A compound according to claim 7 wherein E is O.
19 . A compound according claim 7 wherein E is O.
20 . A compound according claim 7 wherein E is S.
21 . A compound according claim 7 wherein E is S.
22 . A compound according claim 1 wherein R 104 is chosen from —OH, —SH, —PO 3 H 2 , —SO 3 H, —B(OH) 2 , a sugar, a polyol, a glucuronide and a sugar carbamate and R 105 is chosen from H, —OH, —SH, —PO 3 H 2 , —SO 3 H, —B(OH) 2 , a sugar, a polyol, a glucuronide, a sugar carbamate, —OSO 2 —R 10 and —SO 2 —R 110 .
23 . A compound according to claim 22 wherein R 104 is —OH.
24 . A compound of formula V:
wherein
each independently represent an aryl or heteroaryl residue;
R 2 , R 3 , R 4 , R 5 , and R 6 , independently of one another, are chosen from:
H, F, Cl, Br, I, OH, CF 3 , NO 2 , N 3 , CN, COOH, COO(C 1 -C 6 )-alkyl, CONH 2 , CONH(C 1 -C 6 )-alkyl, CON[(C 1 -C 6 )-alkyl] 2 , (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, or O—(C 1 -C 6 )-alkyl, wherein the alkyl radical is unsubstituted or at least one hydrogen in the alkyl radical is replaced by fluorine; or C(═NH)(NH 2 ), PO 3 H 2 , SO 3 H, SO 2 NH 2 , SO 2 NH(C 1 -C 6 )-alkyl, SO 2 N[(C 1 -C 6 )-alkyl] 2 , S—(C 1 -C 6 )-alkyl, S—(CH 2 ) n -phenyl, SO—(C 1 -C 6 )-alkyl, SO—(CH 2 ) n -phenyl, SO 2 —(C 1 -C 6 )-alkyl, or SO 2 —(CH 2 ) n -phenyl, wherein n=0-6, and wherein the phenyl radical is unsubstituted or substituted one or two times, each substituent chosen independently from: F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl, and NH 2 ; and
NH 2 , NH—(C 1 -C 6 )-alkyl, N((C 1 -C 6 )-alkyl) 2 , NH(C 1 -C 7 )-acyl, phenyl, or O—(CH 2 ) n -phenyl, wherein n=0-6, and wherein the phenyl ring is unsubstituted or substituted one, two, or three times, each substituent chosen independently from: F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl, NH 2 , NH(C 1 -C 6 )-alkyl, N((C 1 -C 6 )-alkyl) 2 , SO 2 CH 3 , COOH, COO—(C 1 -C 6 )-alkyl, and CONH 2 ;
R 104a represents one, two, three or four residues chosen independently from H, halogen, loweralkyl, —O-loweralkyl, hydroxyloweralkyl, —CN, —CF 3 , nitro, —S-loweralkyl, amino, alkylamino, dialkylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, acyl, carboxy, alkoxycarbonyl, carboxyalkyl, carboxamido, alkylsulfoxide, acylamino, amidino, —PO 3 H 2 , —SO 3 H, —B(OH) 2 , a sugar, a polyol, a glucuronide, a sugar carbamate, —SO 2 —R 110 , and —OSO 2 —R 110 ;
R 105 is chosen from H, halogen, —OH, loweralkyl, —O-loweralkyl, methylenedioxy, ethylenedioxy, hydroxyloweralkyl, —CN, CF 3 , nitro, —SH, —S-loweralkyl, amino, alkylamino, dialkylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, acyl, carboxy, alkoxycarbonyl, carboxyalkyl, carboxamido, alkylsulfoxide, acylamino, amidino, —PO 3 H 2 , —SO 3 H, —B(OH) 2 , a sugar, a polyol, a glucuronide, a sugar carbamate, —SO 2 —R 110 , and —OSO 2 —R 110 ; and
R 10 is chosen from a sugar, a polyol, a glucuronide and a sugar carbamate;
or a pharmaceutically acceptable salt thereof, in any stereoisomeric form, or a mixture of any such compounds in any ratio.
25 . A compound according to claim 24 wherein R 104a is chosen from —PO 3 H 2 , —SO 3 H, —B(OH) 2 , a sugar, a polyol, a glucuronide and a sugar carbamate and R 105 is chosen from H, —OH, —SH, —PO 3 H 2 , —SO 3 H, —B(OH) 2 , a sugar, a polyol, a glucuronide, a sugar carbamate, —OSO 2 —R 100 and —SO 2 —R 110 .
26 . A compound according claim 1 wherein U is C 3 -alkylene or C 4 -alkylene in which one or more —CH 2 — may be replaced.
27 . A compound according to claim 26 wherein U is —CH 2 CH 2 CH(OH)—.
28 . A compound according to claim 26 wherein U is —CH 2 CH 2 CH 2 CH(OH)—.
29 . A compound according to claim 1 wherein:
R 4 and R 6 are hydrogen; and
R 3 and R 5 are chosen from hydrogen, fluorine, methyl and methoxy; and R 3 and R 5 are in the para position.
30 . A compound according to claim 1 wherein
are both phenyl groups.
31 . A pharmaceutical formulation comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.
32 . A method for treating hypercholesterolemia comprising administering a to a mammal a therapeutically effective amount of a compound according to claim 1 .
33 . A method for treating or preventing vascular inflammation and cholesterol-associated benign and malignant tumors comprising administering a to a mammal a therapeutically effective amount of a compound according claim 1 .
34 . A method for treating, preventing, or ameliorating Alzheimer's Disease comprising administering a to a mammal a therapeutically effective amount of a compound according to claim 1 .
35 . A method for regulating the production or level of amyloid β peptide and ApoE isoform 4 comprising administering a to a mammal a therapeutically effective amount of a compound according to claim 1 .