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Details for Patent: 6,982,251

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Details for Patent: 6,982,251

Title:Substituted 2-azetidinones useful as hypocholesterolemic agents
Abstract: Hypocholesterolemic substituted 2-azetidinone compounds of the formula: ##STR00001## are disclosed, as well as a methods of lowering cholesterol by administering said compounds, pharmaceutical compositions containing them, and the combination of a substituted 2-azetidinone cholesterol-lowering agent and a cholesterol biosynthesis inhibitor for the treatment and prevention of atherosclerosis.
Inventor(s): Ghosal; Anima (Edison, NJ), Zbaida; Shmuel (East Brunswick, NJ), Chowdhury; Swapan K. (Warren, NJ), Iannucci; Robert M. (Hampton, NJ), Feng; Wenqing (Chatham, NJ), Alton; Kevin B. (Cedar Knolls, NJ), Patrick; James E. (Belle Mead, NJ), Davis; Harry R. (Berkeley Heights, NJ)
Assignee: Schering Corporation (Kenilworth, NJ)
Filing Date:Jun 11, 2002
Application Number:10/166,942
Claims:1. A compound represented by the Formula (IA): ##STR00044## or a pharmaceutically acceptable salt or solvate thereof, wherein in Formula (IA): R.sup.1 is selected from the group consisting of H, G, G.sup.1, G.sup.2, --SO.sub.3H and --PO.sub.3H; G is selected from the group consisting of: H, ##STR00045## wherein R, R.sup.a and R.sup.b are each independently selected from the group consisting of H, --OH, halo, --NH.sub.2, azido, (C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkoxy or --W--R.sup.30; W is independently selected from the group consisting of --NH--C(O)--, --O--C(O)--, --O--C(O)--N(R.sup.31)--, --NH--C(O)--N(R.sup.31)-- and --O--C(S)--N(R.sup.31)--; R.sup.2 and R.sup.6 are each independently selected from the group consisting of H, (C.sub.1-C.sub.6)alkyl, acetyl, aryl and aryl(C.sub.1-C.sub.6)alkyl; R.sup.3, R.sup.4, R.sup.5, R.sup.7, R.sup.3a and R.sup.4a are each independently selected from the group consisting of H, (C.sub.1-C.sub.6)alkyl, acetyl, aryl(C.sub.1-C.sub.6)alkyl, --C(O)(C.sub.1-C.sub.6)alkyl and --C(O)aryl; R.sup.30 is independently selected from the group consisting of R.sup.32-substituted T, R.sup.32-substituted-T-(C.sub.1-C.sub.6)alkyl, R.sup.32-substituted-(C.sub.2-C.sub.4)alkenyl, R.sup.32-substituted-(C.sub.1-C.sub.6)alkyl, R.sup.32-substituted-(C.sub.3-C7)cycloalkyl and R.sup.32-substituted-(C.sub.3-C7)cycloalkyl(C.sub.1-C.sub.6)alkyl; R.sup.31 is independently selected from the group consisting of H and (C.sub.1-C.sub.4)alkyl; T is independently selected from the group consisting of phenyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, benzothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl and pyridyl; R.sup.32 is independently selected from 1-3 substituents which are each independently selected from the group consisting of H, halo, (C.sub.1-C.sub.4)alkyl, --OH, phenoxy, --CF.sub.3, --NO.sub.2, (C.sub.1-C.sub.4)alkoxy, methylenedioxy, oxo, (C.sub.1-C.sub.4)alkylsulfanyl, (C.sub.1-C.sub.4)alkylsulfinyl, (C.sub.1-C.sub.4)alkylsulfonyl, --N(CH.sub.3).sub.2, --C(O)--NH(C.sub.1-C.sub.4)alkyl, --C(O)--N((C.sub.1-C.sub.4)alkyl).sub.2, --C(O)--(C.sub.1-C.sub.4)alkyl, --C(O)--(C.sub.1-C.sub.4)alkoxy and pyrrolidinylcarbonyl; or R.sup.32 is a covalent bond and R.sup.31, the nitrogen to which it is attached and R.sup.32 form a pyrrolidinyl, piperidinyl, N-methyl-piperazinyl, indolinyl or morpholinyl group, or a (C.sub.1-C.sub.4)alkoxycarbonyl-substituted pyrrolidinyl, piperidinyl, N-methylpiperazinyl, indolinyl or morpholinyl group; G.sup.1 is represented by the structure: ##STR00046## wherein R.sup.33 is independently selected from the group consisting of R.sup.34-substituted alkyl, (R.sup.35)(R.sup.36)alkyl-, ##STR00047## R.sup.34 is one to three substituents, each R.sup.34 being independently selected from the group consisting of HOOC--, HS--, (CH.sub.3)S--, H.sub.2N--, (NH.sub.2)(NH)C(NH)--, (NH.sub.2)C(O)--, HOOCCH(NH.sub.3.sup.+)CH.sub.2SS--; ##STR00048## R.sup.35 is independently selected from the group consisting of H and NH.sub.2--; R.sup.36 is independently selected from the group consisting of H, unsubstituted alkyl, R.sup.34-substituted alkyl, unsubstituted cycloalkyl, R.sup.34-substituted cycloalkyl, HOOCCH.sub.2CH.sub.2--, HSCH.sub.2--, HOOCCH.sub.2--, (CH.sub.3)SCH.sub.2CH.sub.2--, HOCH.sub.2--, H.sub.2N(CH.sub.2).sub.4--, H.sub.2NCH.sub.2CHOH(CH.sub.2).sub.2--, CH.sub.3(OH)CH--, (NH.sub.2)(NH)CNH(CH.sub.2).sub.3--, H.sub.2NC(O)CH.sub.2--, HOOCCH(NH.sub.3.sup.+)CH.sub.2SSCH.sub.2-- and H.sub.2NCO(CH.sub.2).sub.2-- wherein when R.sup.35 is H, R.sup.36 is not H or unsubstituted alkyl; G.sup.2 is represented by the structure: ##STR00049## wherein R.sup.37 and R.sup.38 are each independently selected from the group consisting of (C.sub.1-C.sub.6)alkyl and aryl; R.sup.26 is one to five substituents, each R.sup.26 being independently selected from the group consisting of: a) H; b) --OH; c) --OCH.sub.3; d) fluorine; e) chlorine; f) --O-G; g) --O-G.sup.1; h) --O-G.sup.2; i) --SO.sub.3H; and j) --PO.sub.3H; provided that when R.sup.1 is H, R.sup.26 is not H, --OH, --OCH.sub.3 or --O-G; Ar.sup.1 is aryl, R.sup.10-substituted aryl, heteroaryl or R.sup.10-substituted heteroaryl; Ar.sup.2 is aryl, R.sup.11-substituted aryl, heteroaryl or R.sup.11-substituted heteroaryl; L is selected from the group consisting of: a) a covalent bond; b) --(CH.sub.2).sub.q--, wherein q is 1-6; c) --(CH.sub.2).sub.e-E-(CH.sub.2).sub.r--, wherein E is --O--, --C(O)--, phenylene, --NR.sup.22-- or d) --S(O).sub.0-2--, e is 0-5 and r is 0-5, provided that the sum of e and r is 1-6; e) --(C.sub.2-C.sub.6)alkenylene-; f) --(CH.sub.2).sub.f--V--(CH.sub.2).sub.g--, wherein V is C.sub.3-C.sub.6cycloalkylene, f is 1-5 and g) g is 0-5, provided that the sum of f and g is 1-6; and h) ##STR00050## wherein M is --O--, --S--, --S(O)-- or --S(O).sub.2--; X, Y and Z are each independently selected from the group consisting of --CH.sub.2--, --CH(C.sub.1-C.sub.6)alkyl- and --C(di-(C.sub.1-C.sub.6)alkyl)-; R.sup.8 is selected from the group consisting of H and alkyl; R.sup.10 and R.sup.11 are each independently selected from the group consisting of 1-3 substituents which are each independently selected from the group consisting of (C.sub.1-C.sub.6)alkyl, --OR.sup.19, --O(CO)R.sup.19, --O(CO)OR.sup.21, --O(CH.sub.2).sub.1-5OR.sup.19, --O(CO)NR.sup.19R.sup.20, --NR.sup.19R.sup.20, --NR.sup.19(CO)R.sup.20, --NR.sup.19(CO)OR.sup.21, --NR.sup.19(CO)NR.sup.20R.sup.25, --NR.sup.19SO.sub.2R.sup.21, --COOR.sup.19, --CONR.sup.19R.sup.20, --COR.sup.19, --SO.sub.2NR.sup.19R.sup.20, S(O).sub.0-2R.sup.21, --O(CH.sub.2).sub.1-10--COOR.sup.19, --O(CH.sub.2).sub.1-10CONR.sup.19R.sup.20, --(C.sub.1-C.sub.6 alkylene)--COOR.sup.19, --CH.dbd.CH--COOR.sup.19, --CF.sub.3, --CN, --NO.sub.2 and halo; R.sup.15 and R.sup.17 are each independently selected from the group consisting of --OR.sup.19, --OC(O)R.sup.19, --OC(O)OR.sup.21, --OC(O)NR.sup.19R.sup.20; R.sup.16 and R.sup.18 are each independently selected from the group consisting of H, (C.sub.1-C.sub.6)alkyl and aryl; or R.sup.15 and R.sup.16 together are .dbd.O, or R.sup.17 and R.sup.18 together are .dbd.O; d is 1, 2 or 3; h is 0, 1, 2, 3 or 4; s is 0 or 1; t is 0 or 1; m, n and p are each independently selected from 0-4; provided that at least one of s and t is 1, and the sum of m, n, p, s and t is 1-6; provided that when p is 0 and t is 1, the sum of m, n and p is 1-5; and provided that when p is 0 and s is 1, the sum of m, t and n is 1-5; v is 0 or 1; j and k are each independently 1-5, provided that the sum of j, k and v is 1-5; Q is a bond, --(CH.sub.2).sub.q--, wherein q is 1-6, or, with the 3-position ring carbon of the azetidinone, forms the spiro group ##STR00051## wherein R.sup.12 is ##STR00052## R.sup.13 and R.sup.14 are each independently selected from the group consisting of --CH.sub.2--, --CH(C.sub.1-C.sub.6 alkyl)-, --C(di-(C.sub.1-C.sub.6) alkyl), --CH.dbd.CH-- and --C(C.sub.1-C.sub.6 alkyl)=CH--; or R.sup.12 together with an adjacent R.sup.13, or R.sup.12 together with an adjacent R.sup.14, form a --CH.dbd.CH-- or a --CH.dbd.C(C.sub.1-C.sub.6 alkyl)- group; a and b are each independently 0, 1, 2 or 3, provided both are not zero; provided that when R.sup.13 is --CH.dbd.CH-- or --C(C.sub.1-C.sub.6 alkyl)=CH--, a is 1; provided that when R.sup.14 is --CH.dbd.CH-- or --C(C.sub.1-C.sub.6 alkyl)=CH--, b is 1; provided that when a is 2 or 3, the R.sup.13's can be the same or different; and provided that when b is 2 or 3, the R.sup.14's can be the same or different; and when Q is a bond and L is ##STR00053## then Ar.sup.1 can also be pyridyl, isoxazolyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, pyrazinyl, pyrimidinyl or pyridazinyl; R.sup.19 and R.sup.20 are each independently selected from the group consisting of H, (C.sub.1-C.sub.6)alkyl, aryl and aryl-substituted (C.sub.1-C.sub.6)alkyl; R.sup.21 is (C.sub.1-C.sub.6)alkyl, aryl or R.sup.24-substituted aryl; R.sup.22 is H, (C.sub.1-C.sub.6)alkyl, aryl (C.sub.1-C.sub.6)alkyl, --C(O)R.sup.19 or --COOR.sup.19; R.sup.23 and R.sup.24 are each independently selected from the group consisting of 1-3 substituents which are each independently selected from the group consisting of H, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, --COOH, NO.sub.2, --NR.sup.19R.sup.20, --OH and halo; and R.sup.25 is H, --OH or (C.sub.1-C.sub.6)alkoxy.

2. The compound according to claim 1, wherein R.sup.1 is G.

3. The compound according to claim 2, wherein G is selected from the group consisting of ##STR00054##

4. The compound according to claim 3, wherein G is selected from the group consisting of ##STR00055##

5. The compound according to claim 4, wherein G is selected from the group consisting of: ##STR00056## wherein: R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6 and R.sup.7 are each independently selected from the group consisting of H, (C.sub.1-C.sub.6)alkyl, benzyl and acetyl.

6. The compound according to claim 5, wherein G is: ##STR00057##

7. The compound according to claim 3, wherein G is: ##STR00058##

8. The compound according to claim 7, wherein G is: ##STR00059## wherein: R.sup.3, R.sup.3a, R.sup.4 and R.sup.4a are selected from the group consisting of H, (C.sub.1-C.sub.6)alkyl, benzyl and acetyl; R, R.sup.a and R.sup.b are independently selected from the group consisting of H, --OH, halogeno, --NH.sub.2, azido, (C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkoxy and --W--R.sup.30, wherein W is --O--C(O)-- or --O--C(O)--NR.sup.31--, R.sup.31 is H and R.sup.30 is (C.sub.1-C.sub.6)alkyl, --C(O)--(C.sub.1-C.sub.4)alkoxy-(C.sub.1-C.sub.6)alkyl, T, T-(C.sub.1-C.sub.6)alkyl, or T or T-(C.sub.1-C.sub.6)alkyl wherein T is substituted by one or two halogeno or (C.sub.1-C.sub.6)alkyl groups.

9. The compound according to claim 8, wherein R.sup.30 is 2-fluorophenyl, 2,4-difluorophenyl, 2-methylphenyl, 2-thienylmethyl, 2-methoxycarbonyl-ethyl, thiazol-2-yl-methyl, 2-methoxycarbonylbutyl or phenyl, or W is --O--C(O)-- and R.sup.30 is (C.sub.1-C.sub.6)alkyl, T, or T substituted by one or two halo or (C.sub.1-C.sub.6)alkyl groups.

10. The compound according to claim 1, wherein R.sup.1 is G.sup.1 which is represented by the structure: ##STR00060## wherein R.sup.33 is (R.sup.35)(R.sup.36)HC--, wherein R.sup.35 is NH.sub.2 and R.sup.36 is selected from the group consisting of: H, --CH.sub.3, CH.sub.3CH.sub.2--, CH.sub.3CH.sub.2CH.sub.2--, (CH.sub.3).sub.2CH--, (CH.sub.3).sub.2CHCH.sub.2--, CH.sub.3CH.sub.2(CH.sub.3)CH--, CH.sub.3CH.sub.2(CH.sub.3)CH--, HOOCCH.sub.2CH.sub.2--, HSCH.sub.2--, HOOCCH.sub.2--, (CH.sub.3)SCH.sub.2CH.sub.2--, HOCH.sub.2--, H.sub.2N(CH.sub.2).sub.4--, H.sub.2NCH.sub.2CHOH(CH.sub.2).sub.2--, CH.sub.3(OH)CH--, (NH.sub.2)(NH)CNH(CH.sub.2).sub.3--, H.sub.2NC(O)CH.sub.2--, HOOCCH(NH.sub.3.sup.+)CH.sub.2SSCH.sub.2--, H.sub.2NCO(CH.sub.2).sub.2--.

11. The compound according to claim 1, wherein Ar.sup.1 is phenyl or R.sup.10-substituted phenyl and Ar.sup.2 is phenyl or R.sup.11-substituted phenyl.

12. The compound according to claim 11, wherein R.sup.10 is halo and R.sup.11 is lower alkoxy or halo.

13. The compound according to claim 1, wherein: Ar.sup.1 is phenyl or R.sup.10-substituted phenyl; Ar.sup.2 is phenyl or R.sup.11-phenyl: R.sup.10 is halo; R.sup.11 is lower alkoxy or halo; Q is --(CH.sub.2).sub.q--, wherein q is 2-6; or Q, with the 3-position ring carbon of the azetidinone, forms the group ##STR00061## wherein R.sup.13 and R.sup.14 are each ethylene and a and b are each 1, and wherein R.sup.12 is ##STR00062## R.sup.1 is selected from the group consisting of ##STR00063## wherein R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6 and R.sup.7 are each independently selected from the group consisting of H, (C.sub.1-C.sub.6)alkyl, benzyl and acetyl; or R.sup.1 is ##STR00064## wherein R.sup.3, R.sup.3a, R.sup.4 and R.sup.4a are each independently selected from the group consisting of H, (C.sub.1-C.sub.6)alkyl, benzyl and acetyl; and R, R.sup.a and R.sup.b are each independently selected from the group consisting of H, --OH, halo, --NH.sub.2, azido, (C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkoxy and --W--R.sup.30, wherein W is --O--C(O)-- or --O--C(O)--NR.sup.31--, R.sup.31 is H and R.sup.30 is (C.sub.1-C.sub.6)alkyl, --C(O)--(C.sub.1-C.sub.4)alkoxy-(C.sub.1-C.sub.6)alkyl, T, T-(C.sub.1-C.sub.6)alkyl, or T or T-(C.sub.1-C.sub.6)alkyl wherein T is substituted by one or two halo or (C.sub.1-C.sub.6)alkyl groups.

14. A compound represented by the Formula II: ##STR00065## or a pharmaceutically acceptable salt or solvate thereof, wherein in Formula II: R.sup.1 is selected from the group consisting of G, G.sup.1, G.sup.2, --SO.sub.3H and --PO.sub.3H, G is selected from the group consisting of: ##STR00066## wherein R, R.sup.a and R.sup.b are each independently selected from the group consisting of H, --OH, halo, --NH.sub.2, azido, (C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkoxy or --W--R.sup.30; W is independently selected from the group consisting of --NH--C(O)--, --O--C(O)--, --O--C(O)--N(R.sup.31)--, --NH--C(O)--N(R.sup.31)-- and --O--C(S)--N(R.sup.31)--; R.sup.2 and R.sup.6 are each independently selected from the group consisting of H, (C.sub.1-C.sub.6)alkyl, acetyl, aryl and aryl(C.sub.1-C.sub.6)alkyl; R.sup.3, R.sup.4, R.sup.5, R.sup.7, R.sup.3a and R.sup.4a are each independently selected from the group consisting of H, (C.sub.1-C.sub.6)alkyl, acetyl, aryl(C.sub.1-C.sub.6)alkyl, --C(O)(C.sub.1-C.sub.6)alkyl and --C(O)aryl; R.sup.30 is independently selected from the group consisting of R.sup.32-substituted T, R.sup.32-substituted-T-(C.sub.1-C.sub.6)alkyl, R.sup.32-substituted-(C.sub.2-C.sub.4)alkenyl, R.sup.32-substituted-(C.sub.1-C.sub.6)alkyl, R.sup.32-substituted-(C.sub.3-C.sub.7)cycloalkyl and R.sup.32-substituted-(C.sub.3-C.sub.7)cycloalkyl(C.sub.1-C.sub.6)alkyl; R.sup.31 is independently selected from the group consisting of H and (C.sub.1-C.sub.4)alkyl; T is independently selected from the group consisting of phenyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, benzothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl and pyridyl; R.sup.32 is independently selected from 1-3 substituents which are each independently selected from the group consisting of H, halo, (C.sub.1-C.sub.4)alkyl, --OH, phenoxy, --CF.sub.3, --NO.sub.2, (C.sub.1-C.sub.4)alkoxy, methylenedioxy, oxo, (C.sub.1-C.sub.4)alkylsulfanyl, (C.sub.1-C.sub.4)alkylsulfinyl, (C.sub.1-C.sub.4)alkylsulfonyl, --N(CH.sub.3).sub.2, --C(O)--NH(C.sub.1-C.sub.4)alkyl, --C(O)--N((C.sub.1-C.sub.4)alkyl).sub.2, --C(O)--(C.sub.1-C.sub.4)alkyl, --C(O)--(C.sub.1-C.sub.4)alkoxy and pyrrolidinylcarbonyl; or R.sup.32 is a covalent bond and R.sup.31, the nitrogen to which it is attached and R.sup.32 form a pyrrolidinyl, piperidinyl, N-methyl-piperazinyl, indolinyl or morpholinyl group, or a (C.sub.1-C.sub.4)alkoxycarbonyl-substituted pyrrolidinyl, piperidinyl, N-methylpiperazinyl, indolinyl or morpholinyl group; G.sup.1 is represented by the structure: ##STR00067## wherein R.sup.33 is independently selected from the group consisting of R.sup.34-substituted alkyl, (R.sup.35)(R.sup.36)alkyl-, ##STR00068## R.sup.34 is one to three substituents, each R.sup.34 being independently selected from the group consisting of HOOC--, HS--, (CH.sub.3)S--, H.sub.2N--, (NH.sub.2)(NH)C(NH)--, (NH.sub.2)C(O)--, and HOOCCH(NH.sub.3.sup.+)CH.sub.2SS-- ##STR00069## R.sup.35 is independently selected from the group consisting of H and NH.sub.2--; R.sup.36 is independently selected from the group consisting of H, unsubstituted alkyl, R.sup.34-substituted alkyl, unsubstituted cycloalkyl, R.sup.34-substituted cycloalkyl, HOOCCH.sub.2CH.sub.2--, HSCH.sub.2--, HOOCCH.sub.2--, (CH.sub.3)SCH.sub.2CH.sub.2--, HOCH.sub.2--, H.sub.2N(CH.sub.2).sub.4--, H.sub.2NCH.sub.2CHOH(CH.sub.2).sub.2--, CH.sub.3(OH)CH--, (NH.sub.2)(NH)CNH(CH.sub.2).sub.3--, H.sub.2NC(O)CH.sub.2--, HOOCCH(NH.sub.3.sup.+)CH.sub.2SSCH.sub.2-- and H.sub.2NCO(CH.sub.2).sub.2-- wherein when R.sup.35 is H, R.sup.36 is not H or unsubstituted alkykl; G.sup.2 is represented by the structure: ##STR00070## wherein R.sup.37 and R.sup.38 are each independently selected from the group consisting of (C.sub.1-C.sub.6)alkyl and aryl.

15. A compound represented by the Formula III: ##STR00071##

16. A compound represented by the structural formula I ##STR00072## or a pharmaceutically acceptable salt or solvate thereof, wherein R.sup.26 is selected from the group consisting of: a) OH; b) OCH.sub.3; c) fluorine and d) chlorine, provided that when R.sup.1 is H, R.sup.26 is not --OH, R.sup.1 is selected from the group consisting of ##STR00073## wherein G.sup.1 is represented by the structure: ##STR00074## wherein R.sup.33 is independently selected from the group consisting of R.sup.34-substituted alkyl, (R.sup.35)(R.sup.36)alkyl-, ##STR00075## R.sup.34 is one to three substituents, each R.sup.34 being independently selected from the group consisting of HOOC--, HS--, (CH.sub.3)S--, H.sub.2N--, (NH.sub.2)(NH)C(NH)--, (NH.sub.2)C(O)--, HOOCCH(NH.sub.3.sup.+)CH.sub.2SS-- ##STR00076## R.sup.35 is independently selected from the group consisting of H and NH.sub.2--; R.sup.36 is independently selected from the group consisting of H, unsubstituted alkyl, R.sup.34-substituted alkyl, unsubstituted cycloalkyl, R.sup.34-substituted cycloalkyl, HOOCCH.sub.2CH.sub.2--, HSCH.sub.2--, HOOCCH.sub.2--, (CH.sub.3)SCH.sub.2CH.sub.2--, HOCH.sub.2--, H.sub.2NC(CH.sub.2).sub.4--, H.sub.2NCH.sub.2CHOH(CH.sub.2).sub.2--, CH.sub.3(OH)CH--, (NH.sub.2)(NH)CNH(CH.sub.2).sub.3--, H.sub.2NC(O)CH.sub.2--, HOOCCH(NH.sub.3.sup.+)CH.sub.2SSCH.sub.2-- and H.sub.2NCO(CH.sub.2).sub.2-- wherein when R.sup.35 is H, R.sup.36 is not H or unsubstituted alkykl; R, R.sup.a and R.sup.b are each independently selected from the group consisting of H, --OH, halogeno, --NH.sub.2, azido, (C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)-alkoxy or --W--R.sup.30; W is independently selected from the group consisting of --NH--C(O)--, --O--C(O)--, --O--C(O)--N(R.sup.31)--, --NH--C(O)--N(R.sup.31)-- and --O--C(S)--N(R.sup.31)--; R.sup.2 and R.sup.6 are each independently selected from the group consisting of H, (C.sub.1-C.sub.6)alkyl, aryl and aryl(C.sub.1-C.sub.6)alkyl; R.sup.3, R.sup.4, R.sup.5, R.sup.7, R.sup.3a and R.sup.4a are each independently selected from the group consisting of H, (C.sub.1-C.sub.6)alkyl, aryl(C.sub.1-C.sub.6)alkyl, --C(O)(C.sub.1-C.sub.6)alkyl and --C(O)aryl; R.sup.30 is independently selected form the group consisting of R.sup.32-substituted T, R.sup.32-substituted-T-(C.sub.1-C.sub.6)alkyl, R.sup.32-substituted-(C.sub.2-C.sub.4)alkenyl, R.sup.32-substituted-(C.sub.1-C.sub.6)alkyl, R.sup.32-substituted-(C.sub.3-C7)cycloalkyl and R.sup.32-substituted-(C.sub.3-C7)cycloalkyl(C.sub.1-C.sub.6)alkyl; R.sup.31 is independently selected from the group consisting of H and (C.sub.1-C.sub.4)alkyl; T is independently selected from the group consisting of phenyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, benzothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl and pyridyl; R.sup.32 is independently selected from 1-3 substituents which are each independently selected from the group consisting of H, halogeno, (C.sub.1-C.sub.4)alkyl, --OH, phenoxy, --CF.sub.3, --NO.sub.2, (C.sub.1-C.sub.4)alkoxy, methylenedioxy, oxo, (C.sub.1-C.sub.4)alkylsulfanyl, (C.sub.1-C.sub.4)alkylsulfinyl, (C.sub.1-C.sub.4)alkylsulfonyl, --N(CH.sub.3).sub.2, --C(O)--NH(C.sub.1-C.sub.4)alkyl, --C(O)--N((C.sub.1-C.sub.4)alkyl).sub.2, --C(O)--(C.sub.1-C.sub.4)alkyl, --C(O)--(C.sub.1-C.sub.4)alkoxy and pyrrolidinylcarbonyl; or R.sup.32 is a covalent bond and R.sup.31, the nitrogen to which it is attached and R.sup.32 form a pyrrolidinyl, piperidinyl, N-methyl-piperazinyl, indolinyl or morpholinyl group, or a (C.sub.1-C.sub.4)alkoxycarbonyl-substituted pyrrolidinyl, piperidinyl, N-methylpiperazinyl, indolinyl or morpholinyl group; Ar.sup.1 is aryl, R.sup.10-substituted aryl, heteroaryl, R.sup.10-substituted heteroaryl; Ar.sup.2 is aryl, R.sup.11-substituted aryl, heteroaryl, R.sup.11-substituted heteroaryl; Q is --(CH.sub.2).sub.q--, wherein q is 2-6, or, with the 3-position ring carbon of the azetidinone, forms the spiro group ##STR00077## R.sup.12 is ##STR00078## R.sup.13 and R.sup.14 are each independently selected from the group consisting of --CH.sub.2--, --CH(C.sub.1-C.sub.6 alkyl)-, --C(di-(C.sub.1-C.sub.6) alkyl), --CH.dbd.CH-- and --C(C.sub.1-C.sub.6 alkyl)=CH--; or R.sup.12 together with an adjacent R.sup.13, or R.sup.12 together with an adjacent R.sup.14, form a --CH.dbd.CH-- or a --CH.dbd.C(C.sub.1-C.sub.6 alkyl)- group; a and b are each independently 0, 1, 2 or 3, provided both are not zero; provided that when R.sup.13 is --CH.dbd.CH-- or --C(C.sub.1-C.sub.6 alkyl)=CH--, a is 1; provided that when R.sup.14 is --CH.dbd.CH-- or --C(C.sub.1-C.sub.6 alkyl)=CH--, b is 1; provided that when a is 2 or 3, the R.sup.13's can be the same or different; and provided that when b is 2 or 3, the R.sup.14's can be the same or different; R.sup.10 and R.sup.11 are each independently selected from the group consisting of 1-3 substituents independently selected from the group consisting of (C.sub.1-C.sub.6)alkyl, --OR.sup.19, --O(CO)R.sup.19, --O(CO)OR.sup.21, --O(CH.sub.2).sub.1-5OR.sup.19, --O(CO)NR.sup.19R.sup.20, --NR.sup.19R.sup.20, --NR.sup.19(CO)R.sup.20, --NR.sup.19(CO)OR.sup.21, --NR.sup.19(CO)NR.sup.20R.sup.25, --NR.sup.19SO.sub.2R.sup.21, --COOR.sup.19, --CONR.sup.19R.sup.20, --COR.sup.19, --SO.sub.2NR.sup.19R.sup.20, S(O).sub.0-2R.sup.21, --O(CH.sub.2).sub.1-10--COOR.sup.19, --O(CH.sub.2).sub.1-10CONR.sup.19R.sup.20, --(C.sub.1-C.sub.6 alkylene)-COOR.sup.19, --CH.dbd.CH--COOR.sup.19, --CF.sub.3, --CN, --NO.sub.2 and halogen; R.sup.19 and R.sup.20 are each independently selected from the group consisting of H, (C.sub.1-C.sub.6)alkyl, aryl and aryl-substituted (C.sub.1-C.sub.6)alkyl; R.sup.21 is (C.sub.1-C.sub.6)alkyl, aryl or R.sup.24-substituted aryl; R.sup.22 is H, (C.sub.1-C.sub.6)alkyl, aryl (C.sub.1-C.sub.6)alkyl, --C(O)R.sup.19 or --COOR.sup.19; R.sup.23 and R.sup.24 are each independently 1-3 groups which are each independently selected from the group consisting of H, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, --COOH, NO.sub.2, --NR.sup.19R.sup.20, --OH and halo; and R.sup.25 is H, --OH or (C.sub.1-C.sub.6)alkoxy.

17. A pharmaceutical composition for the treatment of atherosclerosis, hypercholesterolemia, sitosterolemia, diabetes, obesity or lowering concentration of a sterol in plasma of a mammal, comprising an effective amount of a compound of claim 1 in a pharmaceutically acceptable carrier.

18. A pharmaceutical composition comprising a cholesterol-lowering effective amount of a compound of claim 1 in a pharmaceutically acceptable carrier.

19. A pharmaceutical composition for the treatment of atherosclerosis, hypercholesterolemia, sitosterolemia, diabetes, obesity or lowering concentration of a sterol in plasma of a mammal, comprising an effective amount of a combination of a compound of claim 1, a cholesterol biosynthesis inhibitor and a pharmaceutically acceptable carrier.

20. The pharmaceutical composition according to claim 19, wherein the cholesterol biosynthesis inhibitor is selected from the group consisting of lovastatin, pravastatin, fluvastatin, simvastatin, atorvastatin, ((E,E)-11-[3'R-(hydroxy-methyl)-4'-oxo-2'R-oxetanyl]-3,5,7R-trimethyl-2,4- -undecadienoic acid), squalestatin 1, ((E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-[(3,3'-bithiophen-5-yl)me- thoxy]benzene-methanamine hydrochloride), pitavastatin and rosuvastatin.

21. The pharmaceutical composition according to claim 20, wherein the cholesterol biosynthesis inhibitor is simvastatin.

22. A kit comprising in separate containers in a single package pharmaceutical compositions for use in combination to treat atherosclerosis, hypercholesterolemia, sitosterolemia, diabetes, obesity or lowering concentration of a sterol in plasma of a mammal which comprises in one container an effective amount of a cholesterol biosynthesis inhibitor in a pharmaceutically acceptable carrier, and in a second container, an effective amount of a compound of claim 1 in a pharmaceutically acceptable carrier.

23. A pharmaceutical composition comprising a cholesterol-lowering effective amount of the compound of claim 15 and a pharmaceutically acceptable carrier.

24. A pharmaceutical composition for the treatment of atherosclerosis, or for the reduction of cholesterol levels, comprising an effective amount of a combination of the compound of claim 15, a cholesterol biosynthesis inhibitor and a pharmaceutically acceptable carrier.

25. The pharmaceutical composition according to claim 24, wherein the cholesterol biosynthesis inhibitor is selected from the group consisting of lovastatin, pravastatin, fluvastatin, simvastatin, atorvastatin, ((E,E)-11-[3'R-(hydroxy-methyl)-4'-oxo-2'R-oxetanyl]-3,5,7R-trimethyl-2,4- -undecadienoic acid), squalestatin 1, ((E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-[(3,3'-bithiophen-5-yl)me- thoxy]benzene-methanamine hydrochloride), pitavastatin and rosuvastatin.

26. The pharmaceutical composition according to claim 25, wherein the cholesterol biosynthesis inhibitor is simvastatin.

27. A kit comprising in separate containers in a single package pharmaceutical compositions for use in combination to treat atherosclerosis or to reduce cholesterol levels which comprises in one container an effective amount of a cholesterol biosynthesis inhibitor in a pharmaceutically acceptable carrier, and in a second container, an effective amount of the compound of claim 15 in a pharmaceutically acceptable carrier.
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