Substituted 2-azetidinones useful as hypocholesterolemic agents
First Claim
Patent Images
1. A compound represented by the Formula (IA):
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or a pharmaceutically acceptable salt or solvate thereof, wherein in Formula (IA);
R1 is selected from the group consisting of H, G, G1, G2, —
SO3H and —
PO3H;
G is selected from the group consisting of;
H, wherein R, Ra and Rb are each independently selected from the group consisting of H, —
OH, halo, —
NH2, azido, (C1-C6)alkoxy(C1-C6)alkoxy or —
W—
R30;
W is independently selected from the group consisting of —
NH—
C(O)—
, —
O—
C(O)—
, —
O—
C(O)—
N(R31)—
, —
NH—
C(O)—
N(R31)— and
—
O—
C(S)—
N(R31)—
;
R2 and R6 are each independently selected from the group consisting of H, (C1-C6)alkyl, acetyl, aryl and aryl(C1-C6)alkyl;
R3, R4, R5, R7, R3a and R4a are each independently selected from the group consisting of H, (C1-C6)alkyl, acetyl, aryl(C1-C6)alkyl, —
C(O)(C1-C6)alkyl and —
C(O)aryl;
R30 is independently selected from the group consisting of R32-substituted T, R32-substituted-T-(C1-C6)alkyl, R32-substituted-(C2-C4)alkenyl, R32-substituted-(C1-C6)alkyl, R32-substituted-(C3-C7)cycloalkyl and R32-substituted-(C3-C7)cycloalkyl(C1-C6)alkyl;
R31 is independently selected from the group consisting of H and (C1-C4)alkyl;
T is independently selected from the group consisting of phenyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, benzothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl and pyridyl;
R32 is independently selected from 1-3 substituents which are each independently selected from the group consisting of H, halo, (C1-C4)alkyl, —
OH, phenoxy, —
CF3, —
NO2, (C1-C4)alkoxy, methylenedioxy, oxo, (C1-C4)alkylsulfanyl, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonyl, —
N(CH3)2, —
C(O)—
NH(C1-C4)alkyl, —
C(O)—
N((C1-C4)alkyl)2, —
C(O)—
(C1-C4)alkyl, —
C(O)—
(C1-C4)alkoxy and pyrrolidinylcarbonyl;
or R32 is a covalent bond and R31, the nitrogen to which it is attached and R32 form a pyrrolidinyl, piperidinyl, N-methyl-piperazinyl, indolinyl or morpholinyl group, or a (C1-C4)alkoxycarbonyl-substituted pyrrolidinyl, piperidinyl, N-methylpiperazinyl, indolinyl or morpholinyl group;
G1 is represented by the structure;
wherein R33 is independently selected from the group consisting of R34-substituted alkyl, (R35)(R36)alkyl-, R34 is one to three substituents, each R34 being independently selected from the group consisting of HOOC—
, HS—
, (CH3)S—
, H2N—
, (NH2)(NH)C(NH)—
, (NH2)C(O)—
, HOOCCH(NH3+)CH2SS—
;
R35 is independently selected from the group consisting of H and NH2—
;
R36 is independently selected from the group consisting of H, unsubstituted alkyl, R34-substituted alkyl, unsubstituted cycloalkyl, R34-substituted cycloalkyl, HOOCCH2CH2—
, HSCH2—
, HOOCCH2—
, (CH3)SCH2CH2—
, HOCH2—
, H2N(CH2)4—
, H2NCH2CHOH(CH2)2—
, CH3(OH)CH—
, (NH2)(NH)CNH(CH2)3—
, H2NC(O)CH2—
, HOOCCH(NH3+)CH2SSCH2— and
H2NCO(CH2)2—
wherein when R35 is H, R36 is not H or unsubstituted alkyl;
G2 is represented by the structure;
wherein R37 and R38 are each independently selected from the group consisting of (C1-C6)alkyl and aryl;
R26 is one to five substituents, each R26 being independently selected from the group consisting of;
a) H;
b) —
OH;
c) —
OCH3;
d) fluorine;
e) chlorine;
f) —
O-G;
g) —
O-G1;
h) —
O-G2;
i) —
SO3H; and
j) —
PO3H;
provided that when R1 is H, R26 is not H, —
OH, —
OCH3 or —
O-G;
Ar1 is aryl, R10-substituted aryl, heteroaryl or R10-substituted heteroaryl;
Ar2 is aryl, R11-substituted aryl, heteroaryl or R11-substituted heteroaryl;
L is selected from the group consisting of;
a) a covalent bond;
b) —
(CH2)q—
, wherein q is 1-6;
c) —
(CH2)e-E-(CH2)r—
, wherein E is —
O—
, —
C(O)—
, phenylene, —
NR22—
or d) —
S(O)0-2—
, e is 0-5 and r is 0-5, provided that the sum of e and r is 1-6;
e) —
(C2-C6)alkenylene-;
f) —
(CH2)f—
V—
(CH2)g—
, wherein V is C3-C6cycloalkylene, f is 1-5 and g) g is 0-5, provided that the sum of f and g is 1-6; and
h) wherein M is —
O—
, —
S—
, —
S(O)—
or —
S(O)2—
;
X, Y and Z are each independently selected from the group consisting of —
CH2—
, —
CH(C1-C6)alkyl- and —
C(di-(C1-C6)alkyl)-;
R8 is selected from the group consisting of H and alkyl;
R10 and R11 are each independently selected from the group consisting of 1-3 substituents which are each independently selected from the group consisting of (C1-C6)alkyl, —
OR19, —
O(CO)R19, —
O(CO)OR21, —
O(CH2)1-5OR19, —
O(CO)NR19R20, —
NR19R20, —
NR19(CO)R20, —
NR19(CO)OR21, —
NR19(CO)NR20R25, —
NR19SO2R21, —
COOR19, —
CONR19R20, —
COR19, —
SO2NR19R20, S(O)0-2R21, —
O(CH2)1-10—
COOR19, —
O(CH2)1-10CONR19R20, —
(C1-C6 alkylene)—
COOR19, —
CH═
CH—
COOR19, —
CF3, —
CN, —
NO2 and halo;
R15 and R17 are each independently selected from the group consisting of —
OR19, —
OC(O)R19, —
OC(O)OR21, —
OC(O)NR19R20;
R16 and R18 are each independently selected from the group consisting of H, (C1-C6)alkyl and aryl;
or R15 and R16 together are ═
O, or R17 and R18 together are ═
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, —
(CH2)q—
, wherein q is 1-6, or, with the 3-position ring carbon of the azetidinone, forms the spiro group wherein R12 is R13 and R14 are each independently selected from the group consisting of —
CH2—
, —
CH(C1-C6 alkyl)-, —
C(di-(C1-C6) alkyl), —
CH═
CH— and
—
C(C1-C6 alkyl)=CH—
;
or R12 together with an adjacent R13, or R12 together with an adjacent R14, form a —
CH═
CH—
or a —
CH═
C(C1-C6 alkyl)- group;
a and b are each independently 0, 1, 2 or 3, provided both are not zero;
provided that when R13 is —
CH═
CH—
or —
C(C1-C6 alkyl)=CH—
, a is 1;
provided that when R14 is —
CH═
CH—
or —
C(C1-C6 alkyl)=CH—
, b is 1;
provided that when a is 2 or 3, the R13'"'"'s can be the same or different; and
provided that when b is 2 or 3, the R14'"'"'s can be the same or different;
and when Q is a bond and L is then Ar1 can also be pyridyl, isoxazolyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, pyrazinyl, pyrimidinyl or pyridazinyl;
R19 and R20 are each independently selected from the group consisting of H, (C1-C6)alkyl, aryl and aryl-substituted (C1-C6)alkyl;
R21 is (C1-C6)alkyl, aryl or R24-substituted aryl;
R22 is H, (C1-C6)alkyl, aryl (C1-C6)alkyl, —
C(O)R19 or —
COOR19;
R23 and R24 are each independently selected from the group consisting of 1-3 substituents which are each independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkoxy, —
COOH, NO2, —
NR19R20, —
OH and halo; and
R25 is H, —
OH or (C1-C6)alkoxy.
1 Assignment
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Accused Products
Abstract
Hypocholesterolemic substituted 2-azetidinone compounds of the formula:
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.
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Citations
27 Claims
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1. A compound represented by the Formula (IA):
-
or a pharmaceutically acceptable salt or solvate thereof, wherein in Formula (IA); R1 is selected from the group consisting of H, G, G1, G2, —
SO3H and —
PO3H;
G is selected from the group consisting of;
H,wherein R, Ra and Rb are each independently selected from the group consisting of H, —
OH, halo, —
NH2, azido, (C1-C6)alkoxy(C1-C6)alkoxy or —
W—
R30;
W is independently selected from the group consisting of —
NH—
C(O)—
, —
O—
C(O)—
, —
O—
C(O)—
N(R31)—
, —
NH—
C(O)—
N(R31)— and
—
O—
C(S)—
N(R31)—
;
R2 and R6 are each independently selected from the group consisting of H, (C1-C6)alkyl, acetyl, aryl and aryl(C1-C6)alkyl;
R3, R4, R5, R7, R3a and R4a are each independently selected from the group consisting of H, (C1-C6)alkyl, acetyl, aryl(C1-C6)alkyl, —
C(O)(C1-C6)alkyl and —
C(O)aryl;
R30 is independently selected from the group consisting of R32-substituted T, R32-substituted-T-(C1-C6)alkyl, R32-substituted-(C2-C4)alkenyl, R32-substituted-(C1-C6)alkyl, R32-substituted-(C3-C7)cycloalkyl and R32-substituted-(C3-C7)cycloalkyl(C1-C6)alkyl;
R31 is independently selected from the group consisting of H and (C1-C4)alkyl;
T is independently selected from the group consisting of phenyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, benzothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl and pyridyl;
R32 is independently selected from 1-3 substituents which are each independently selected from the group consisting of H, halo, (C1-C4)alkyl, —
OH, phenoxy, —
CF3, —
NO2, (C1-C4)alkoxy, methylenedioxy, oxo, (C1-C4)alkylsulfanyl, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonyl, —
N(CH3)2, —
C(O)—
NH(C1-C4)alkyl, —
C(O)—
N((C1-C4)alkyl)2, —
C(O)—
(C1-C4)alkyl, —
C(O)—
(C1-C4)alkoxy and pyrrolidinylcarbonyl;
or R32 is a covalent bond and R31, the nitrogen to which it is attached and R32 form a pyrrolidinyl, piperidinyl, N-methyl-piperazinyl, indolinyl or morpholinyl group, or a (C1-C4)alkoxycarbonyl-substituted pyrrolidinyl, piperidinyl, N-methylpiperazinyl, indolinyl or morpholinyl group;
G1 is represented by the structure;
wherein R33 is independently selected from the group consisting of R34-substituted alkyl, (R35)(R36)alkyl-, R34 is one to three substituents, each R34 being independently selected from the group consisting of HOOC—
, HS—
, (CH3)S—
, H2N—
, (NH2)(NH)C(NH)—
, (NH2)C(O)—
, HOOCCH(NH3+)CH2SS—
;
R35 is independently selected from the group consisting of H and NH2—
;
R36 is independently selected from the group consisting of H, unsubstituted alkyl, R34-substituted alkyl, unsubstituted cycloalkyl, R34-substituted cycloalkyl, HOOCCH2CH2—
, HSCH2—
, HOOCCH2—
, (CH3)SCH2CH2—
, HOCH2—
, H2N(CH2)4—
, H2NCH2CHOH(CH2)2—
, CH3(OH)CH—
, (NH2)(NH)CNH(CH2)3—
, H2NC(O)CH2—
, HOOCCH(NH3+)CH2SSCH2— and
H2NCO(CH2)2—
wherein when R35 is H, R36 is not H or unsubstituted alkyl;
G2 is represented by the structure;
wherein R37 and R38 are each independently selected from the group consisting of (C1-C6)alkyl and aryl; R26 is one to five substituents, each R26 being independently selected from the group consisting of;
a) H;
b) —
OH;
c) —
OCH3;
d) fluorine;
e) chlorine;
f) —
O-G;
g) —
O-G1;
h) —
O-G2;
i) —
SO3H; and
j) —
PO3H;
provided that when R1 is H, R26 is not H, —
OH, —
OCH3 or —
O-G;Ar1 is aryl, R10-substituted aryl, heteroaryl or R10-substituted heteroaryl;
Ar2 is aryl, R11-substituted aryl, heteroaryl or R11-substituted heteroaryl;
L is selected from the group consisting of;
a) a covalent bond;
b) —
(CH2)q—
, wherein q is 1-6;
c) —
(CH2)e-E-(CH2)r—
, wherein E is —
O—
, —
C(O)—
, phenylene, —
NR22—
ord) —
S(O)0-2—
, e is 0-5 and r is 0-5, provided that the sum of e and r is 1-6;
e) —
(C2-C6)alkenylene-;
f) —
(CH2)f—
V—
(CH2)g—
, wherein V is C3-C6cycloalkylene, f is 1-5 andg) g is 0-5, provided that the sum of f and g is 1-6; and
h) wherein M is —
O—
, —
S—
, —
S(O)—
or —
S(O)2—
;X, Y and Z are each independently selected from the group consisting of —
CH2—
, —
CH(C1-C6)alkyl- and —
C(di-(C1-C6)alkyl)-;
R8 is selected from the group consisting of H and alkyl;
R10 and R11 are each independently selected from the group consisting of 1-3 substituents which are each independently selected from the group consisting of (C1-C6)alkyl, —
OR19, —
O(CO)R19, —
O(CO)OR21, —
O(CH2)1-5OR19, —
O(CO)NR19R20, —
NR19R20, —
NR19(CO)R20, —
NR19(CO)OR21, —
NR19(CO)NR20R25, —
NR19SO2R21, —
COOR19, —
CONR19R20, —
COR19, —
SO2NR19R20, S(O)0-2R21, —
O(CH2)1-10—
COOR19, —
O(CH2)1-10CONR19R20, —
(C1-C6 alkylene)—
COOR19, —
CH═
CH—
COOR19, —
CF3, —
CN, —
NO2 and halo;
R15 and R17 are each independently selected from the group consisting of —
OR19, —
OC(O)R19, —
OC(O)OR21, —
OC(O)NR19R20;
R16 and R18 are each independently selected from the group consisting of H, (C1-C6)alkyl and aryl;
or R15 and R16 together are ═
O, or R17 and R18 together are ═
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, —
(CH2)q—
, wherein q is 1-6, or, with the 3-position ring carbon of the azetidinone, forms the spiro groupwherein R12 is R13 and R14 are each independently selected from the group consisting of —
CH2—
, —
CH(C1-C6 alkyl)-, —
C(di-(C1-C6) alkyl), —
CH═
CH— and
—
C(C1-C6 alkyl)=CH—
;
or R12 together with an adjacent R13, or R12 together with an adjacent R14, form a —
CH═
CH—
or a —
CH═
C(C1-C6 alkyl)- group;
a and b are each independently 0, 1, 2 or 3, provided both are not zero;
provided that when R13 is —
CH═
CH—
or —
C(C1-C6 alkyl)=CH—
, a is 1;
provided that when R14 is —
CH═
CH—
or —
C(C1-C6 alkyl)=CH—
, b is 1;
provided that when a is 2 or 3, the R13'"'"'s can be the same or different; and
provided that when b is 2 or 3, the R14'"'"'s can be the same or different;
and when Q is a bond and L is then Ar1 can also be pyridyl, isoxazolyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, pyrazinyl, pyrimidinyl or pyridazinyl; R19 and R20 are each independently selected from the group consisting of H, (C1-C6)alkyl, aryl and aryl-substituted (C1-C6)alkyl;
R21 is (C1-C6)alkyl, aryl or R24-substituted aryl;
R22 is H, (C1-C6)alkyl, aryl (C1-C6)alkyl, —
C(O)R19 or —
COOR19;
R23 and R24 are each independently selected from the group consisting of 1-3 substituents which are each independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkoxy, —
COOH, NO2, —
NR19R20, —
OH and halo; and
R25 is H, —
OH or (C1-C6)alkoxy.- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 17, 18, 19, 20, 21, 22)
wherein; R2, R3, R4, R5, R6 and R7 are each independently selected from the group consisting of H, (C1-C6)alkyl, benzyl and acetyl.
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6. The compound according to claim 5, wherein G is:
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7. The compound according to claim 3, wherein G is:
-
8. The compound according to claim 7, wherein G is:
-
wherein; R3, R3a, R4 and R4a are selected from the group consisting of H, (C1-C6)alkyl, benzyl and acetyl;
R, Ra and Rb are independently selected from the group consisting of H, —
OH, halogeno, —
NH2, azido, (C1-C6)alkoxy(C1-C6)alkoxy and —
W—
R30, wherein W is —
O—
C(O)—
or —
O—
C(O)—
NR31—
, R31 is H and R30 is (C1-C6)alkyl, —
C(O)—
(C1-C4)alkoxy-(C1-C6)alkyl, T, T-(C1-C6)alkyl, or T or T-(C1-C6)alkyl wherein T is substituted by one or two halogeno or (C1-C6)alkyl groups.
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9. The compound according to claim 8, wherein R30 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
R30 is (C1-C6)alkyl, T, or T substituted by one or two halo or (C1-C6)alkyl groups.
- O—
-
10. The compound according to claim 1, wherein R1 is G1 which is represented by the structure:
-
wherein R33 is (R35)(R36)HC—
, wherein R35 is NH2 and R36 is selected from the group consisting of;H, —
CH3, CH3CH2—
, CH3CH2CH2—
, (CH3)2CH—
, (CH3)2CHCH2—
, CH3CH2(CH3)CH—
, CH3CH2(CH3)CH—
, HOOCCH2CH2—
, HSCH2—
, HOOCCH2—
, (CH3)SCH2CH2—
, HOCH2—
, H2N(CH2)4—
, H2NCH2CHOH(CH2)2—
, CH3(OH)CH—
, (NH2)(NH)CNH(CH2)3—
, H2NC(O)CH2—
, HOOCCH(NH3+)CH2SSCH2—
, H2NCO(CH2)2—
.
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11. The compound according to claim 1, wherein Ar1 is phenyl or R10-substituted phenyl and Ar2 is phenyl or R11-substituted phenyl.
-
12. The compound according to claim 11, wherein R10 is halo and R11 is lower alkoxy or halo.
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13. The compound according to claim 1, wherein:
-
Ar1 is phenyl or R10-substituted phenyl;
Ar2 is phenyl or R11-phenyl;
R10 is halo;
R11 is lower alkoxy or halo;
Q is —
(CH2)q—
, wherein q is 2-6;
or Q, with the 3-position ring carbon of the azetidinone, forms the group
wherein R13 and R14 are each ethylene and a and b are each 1, and wherein R12 isR1 is selected from the group consisting of wherein R2, R3, R4, R5, R6 and R7 are each independently selected from the group consisting of H, (C1-C6)alkyl, benzyl and acetyl;
or R1 iswherein R3, R3a, R4 and R4a are each independently selected from the group consisting of H, (C1-C6)alkyl, benzyl and acetyl; and
R, Ra and Rb are each independently selected from the group consisting of H, —
OH, halo, —
NH2, azido, (C1-C6)alkoxy(C1-C6)alkoxy and —
W—
R30, wherein W is —
O—
C(O)—
or —
O—
C(O)—
NR31—
, R31 is H and R30 is (C1-C6)alkyl, —
C(O)—
(C1-C4)alkoxy-(C1-C6)alkyl, T, T-(C1-C6)alkyl, or T or T-(C1-C6)alkyl wherein T is substituted by one or two halo or (C1-C6)alkyl groups.
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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.
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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.
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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)methoxy]benzene-methanamine hydrochloride), pitavastatin and rosuvastatin.
- R-(hydroxy-methyl)-4′
-
21. The pharmaceutical composition according to claim 20, wherein the cholesterol biosynthesis inhibitor is simvastatin.
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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.
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14. A compound represented by the Formula II:
-
or a pharmaceutically acceptable salt or solvate thereof, wherein in Formula II; R1 is selected from the group consisting of G, G1, G2, —
SO3H and —
PO3H,G is selected from the group consisting of;
wherein R, Ra and Rb are each independently selected from the group consisting of H, —
OH, halo, —
NH2, azido, (C1-C6)alkoxy(C1-C6)alkoxy or —
W—
R30;
W is independently selected from the group consisting of —
NH—
C(O)—
, —
O—
C(O)—
, —
O—
C(O)—
N(R31)—
, —
NH—
C(O)—
N(R31)— and
—
O—
C(S)—
N(R31)—
;
R2 and R6 are each independently selected from the group consisting of H, (C1-C6)alkyl, acetyl, aryl and aryl(C1-C6)alkyl;
R3, R4, R5, R7, R3a and R4a are each independently selected from the group consisting of H, (C1-C6)alkyl, acetyl, aryl(C1-C6)alkyl, —
C(O)(C1-C6)alkyl and —
C(O)aryl;
R30 is independently selected from the group consisting of R32-substituted T, R32-substituted-T-(C1-C6)alkyl, R32-substituted-(C2-C4)alkenyl, R32-substituted-(C1-C6)alkyl, R32-substituted-(C3-C7)cycloalkyl and R32-substituted-(C3-C7)cycloalkyl(C1-C6)alkyl;
R31 is independently selected from the group consisting of H and (C1-C4)alkyl;
T is independently selected from the group consisting of phenyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, benzothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl and pyridyl;
R32 is independently selected from 1-3 substituents which are each independently selected from the group consisting of H, halo, (C1-C4)alkyl, —
OH, phenoxy, —
CF3, —
NO2, (C1-C4)alkoxy, methylenedioxy, oxo, (C1-C4)alkylsulfanyl, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonyl, —
N(CH3)2, —
C(O)—
NH(C1-C4)alkyl, —
C(O)—
N((C1-C4)alkyl)2, —
C(O)—
(C1-C4)alkyl, —
C(O)—
(C1-C4)alkoxy and pyrrolidinylcarbonyl;
or R32 is a covalent bond and R31, the nitrogen to which it is attached and R32 form a pyrrolidinyl, piperidinyl, N-methyl-piperazinyl, indolinyl or morpholinyl group, or a (C1-C4)alkoxycarbonyl-substituted pyrrolidinyl, piperidinyl, N-methylpiperazinyl, indolinyl or morpholinyl group;
G1 is represented by the structure;
wherein R33 is independently selected from the group consisting of R34-substituted alkyl, (R35)(R36)alkyl-, R34 is one to three substituents, each R34 being independently selected from the group consisting of HOOC—
, HS—
, (CH3)S—
, H2N—
, (NH2)(NH)C(NH)—
, (NH2)C(O)—
, and HOOCCH(NH3+)CH2SS—
R35 is independently selected from the group consisting of H and NH2—
;
R36 is independently selected from the group consisting of H, unsubstituted alkyl, R34-substituted alkyl, unsubstituted cycloalkyl, R34-substituted cycloalkyl, HOOCCH2CH2—
, HSCH2—
, HOOCCH2—
, (CH3)SCH2CH2—
, HOCH2—
, H2N(CH2)4—
, H2NCH2CHOH(CH2)2—
, CH3(OH)CH—
, (NH2)(NH)CNH(CH2)3—
, H2NC(O)CH2—
, HOOCCH(NH3+)CH2SSCH2— and
H2NCO(CH2)2—
wherein when R35 is H, R36 is not H or unsubstituted alkykl;
G2 is represented by the structure;
wherein R37 and R38 are each independently selected from the group consisting of (C1-C6)alkyl and aryl.
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- 15. A compound represented by the Formula III:
-
16. A compound represented by the structural formula I
or a pharmaceutically acceptable salt or solvate thereof, wherein R26 is selected from the group consisting of: -
a) OH;
b) OCH3;
c) fluorine and d) chlorine, provided that when R1 is H, R26 is not —
OH,R1 is selected from the group consisting of wherein G1 is represented by the structure;
wherein R33 is independently selected from the group consisting of R34-substituted alkyl, (R35)(R36)alkyl-, R34 is one to three substituents, each R34 being independently selected from the group consisting of HOOC—
, HS—
, (CH3)S—
, H2N—
, (NH2)(NH)C(NH)—
, (NH2)C(O)—
, HOOCCH(NH3+)CH2SS—R35 is independently selected from the group consisting of H and NH2—
;
R36 is independently selected from the group consisting of H, unsubstituted alkyl, R34-substituted alkyl, unsubstituted cycloalkyl, R34-substituted cycloalkyl, HOOCCH2CH2—
, HSCH2—
, HOOCCH2—
, (CH3)SCH2CH2—
, HOCH2—
, H2NC(CH2)4—
, H2NCH2CHOH(CH2)2—
, CH3(OH)CH—
, (NH2)(NH)CNH(CH2)3—
, H2NC(O)CH2—
, HOOCCH(NH3+)CH2SSCH2— and
H2NCO(CH2)2—
wherein when R35 is H, R36 is not H or unsubstituted alkykl;
R, Ra and Rb are each independently selected from the group consisting of H, —
OH, halogeno, —
NH2, azido, (C1-C6)alkoxy(C1-C6)-alkoxy or —
W—
R30;
W is independently selected from the group consisting of —
NH—
C(O)—
, —
O—
C(O)—
, —
O—
C(O)—
N(R31)—
, —
NH—
C(O)—
N(R31)— and
—
O—
C(S)—
N(R31)—
;
R2 and R6 are each independently selected from the group consisting of H, (C1-C6)alkyl, aryl and aryl(C1-C6)alkyl;
R3, R4, R5, R7, R3a and R4a are each independently selected from the group consisting of H, (C1-C6)alkyl, aryl(C1-C6)alkyl, —
C(O)(C1-C6)alkyl and —
C(O)aryl;
R30 is independently selected form the group consisting of R32-substituted T, R32-substituted-T-(C1-C6)alkyl, R32-substituted-(C2-C4)alkenyl, R32-substituted-(C1-C6)alkyl, R32-substituted-(C3-C7)cycloalkyl and R32-substituted-(C3-C7)cycloalkyl(C1-C6)alkyl;
R31 is independently selected from the group consisting of H and (C1-C4)alkyl;
T is independently selected from the group consisting of phenyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, benzothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl and pyridyl;
R32 is independently selected from 1-3 substituents which are each independently selected from the group consisting of H, halogeno, (C1-C4)alkyl, —
OH, phenoxy, —
CF3, —
NO2, (C1-C4)alkoxy, methylenedioxy, oxo, (C1-C4)alkylsulfanyl, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonyl, —
N(CH3)2, —
C(O)—
NH(C1-C4)alkyl, —
C(O)—
N((C1-C4)alkyl)2, —
C(O)—
(C1-C4)alkyl, —
C(O)—
(C1-C4)alkoxy and pyrrolidinylcarbonyl;
or R32 is a covalent bond and R31, the nitrogen to which it is attached and R32 form a pyrrolidinyl, piperidinyl, N-methyl-piperazinyl, indolinyl or morpholinyl group, or a (C1-C4)alkoxycarbonyl-substituted pyrrolidinyl, piperidinyl, N-methylpiperazinyl, indolinyl or morpholinyl group;
Ar1 is aryl, R10-substituted aryl, heteroaryl, R10-substituted heteroaryl;
Ar2 is aryl, R11-substituted aryl, heteroaryl, R11-substituted heteroaryl;
Q is —
(CH2)q—
, wherein q is 2-6, or, with the 3-position ring carbon of the azetidinone, forms the spiro groupR12 is R13 and R14 are each independently selected from the group consisting of —
CH2—
, —
CH(C1-C6 alkyl)-, —
C(di-(C1-C6) alkyl), —
CH═
CH— and
—
C(C1-C6 alkyl)=CH—
;
or R12 together with an adjacent R13, or R12 together with an adjacent R14, form a —
CH═
CH—
or a —
CH═
C(C1-C6 alkyl)- group;
a and b are each independently 0, 1, 2 or 3, provided both are not zero;
provided that when R13 is —
CH═
CH—
or —
C(C1-C6 alkyl)=CH—
, a is 1;
provided that when R14 is —
CH═
CH—
or —
C(C1-C6 alkyl)=CH—
, b is 1;
provided that when a is 2 or 3, the R13'"'"'s can be the same or different; and
provided that when b is 2 or 3, the R14'"'"'s can be the same or different;
R10 and R11 are each independently selected from the group consisting of 1-3 substituents independently selected from the group consisting of (C1-C6)alkyl, —
OR19, —
O(CO)R19, —
O(CO)OR21, —
O(CH2)1-5OR19, —
O(CO)NR19R20, —
NR19R20, —
NR19(CO)R20, —
NR19(CO)OR21, —
NR19(CO)NR20R25, —
NR19SO2R21, —
COOR19, —
CONR19R20, —
COR19, —
SO2NR19R20, S(O)0-2R21, —
O(CH2)1-10—
COOR19, —
O(CH2)1-10CONR19R20, —
(C1-C6 alkylene)-COOR19, —
CH═
CH—
COOR19, —
CF3, —
CN, —
NO2 and halogen;
R19 and R20 are each independently selected from the group consisting of H, (C1-C6)alkyl, aryl and aryl-substituted (C1-C6)alkyl;
R21 is (C1-C6)alkyl, aryl or R24-substituted aryl;
R22 is H, (C1-C6)alkyl, aryl (C1-C6)alkyl, —
C(O)R19 or —
COOR19;
R23 and R24 are each independently 1-3 groups which are each independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkoxy, —
COOH, NO2, —
NR19R20, —
OH and halo; and
R25 is H, —
OH or (C1-C6)alkoxy.
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Specification