US 5,180,717 AGranted

Bivalent ligands effective for blocking ACAT enzyme for lowering plasma triglycerides and for elevating HDL cholesterol

AssigneeThe Upjohn Company

InventorsRonald B. Gammill, Frank P. Bell

Life of this patent

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Abstract

Bivalent ligand compounds synthesized from a tether composition joining two heterocyclic groups comprising furochromones, furobenzoxazinones, and benzobisdifurans. These compounds show pharmacological activity in blocking ACAT enzymes which are major regulators of cholesterol metabolism. The compounds also show activity in lowering plasma triglycerides and elevating HDL cholesterol. They are useful in the prevention or treatment of the constriction or obstruction of arterial vessels, atherosclerosis, hyperlipidemia, hypertriglyceridemia, chylomicronemia, and pancreatitis.

Claims16

Dependent claims

A bivalent ligand .alpha.-.beta.-.alpha. wherein .alpha. is structurally represented by the formula ##STR30## or a pharmaceutically acceptable salt thereof wherein:

R.sup.1 and R.sup.2 are independently:
a) H,
b) halo,
c) C.sub.1-8 alkyl,
d) --(CH.sub.2).sub.p -aryl,
e) --(CH.sub.2).sub.p -heteroaryl,
f) --(CH.sub.2).sub.p --CO.sub.2 R.sup.6,
g) --(CH.sub.2).sub.p --CONR.sup.7 R.sup.8,
h) --Si(R.sup.9),
i) --(CH.sub.2).sub.n --NR.sup.7 R.sup.8,
j) --(CH.sub.2).sub.n --OR.sup.10,
k) --CF.sub.3, or
l) --(CH.sub.2).sub.n --SR.sup.6, --(CH.sub.2).sub.n --SOR.sup.6, --(CH.sub.2).sub.n --SO.sub.2 R.sup.6 ;
R.sup.3 is
a) OH,
b) OCH.sub.2 CH.dbd.CH.sub.2,
c) OCH.sub.2 CH(OH)CH.sub.2 NHR.sup.6,
d) --O--C.sub.1-8 alkyl,
e) --O--(CH.sub.2).sub.n --CO.sub.2 R.sup.6, or
f) --O--(CH.sub.2).sub.n --CONR.sup.7 R.sup.8 ;
R.sup.4 is
a) hydrogen,
b) halo,
c) NO.sub.2,
d) NH.sub.2
e) CF.sub.3,
f) C.sub.1-8 alkyl,
g) aryl,
h) --S--C.sub.1-8 alkyl or aryl,
i) --SO--C.sub.1-8 alkyl or aryl,
j) --SO.sub.2 --C.sub.1-8 alkyl or aryl,
k) R.sup.3, or
l) --CH.sub.2).sub.n --NR.sup.7 R.sup.8 ;
R.sup.6 is H, CF.sub.3, alkyl or aryl, Li.sup.+, Na.sup.+, K.sup.+, Ca.sup.2+ and other pharmaceutically acceptable counter ions for carboxylic acids;
R.sup.7 and R.sup.8 and H, CO-alkyl, CO-aryl, alkyl, cycloalkyl, alkylaryl, aryl, heteroalkyl, aryl, or R.sup.7 and R.sup.8 can be taken together to form a piperidine ring or morpholine ring;
R.sup.9 is an C.sub.1-8 alkyl or aryl;
R.sup.10 is H, CF.sub.3, C.sub.1-8 alkyl, aryl or heteroaryl;
and
n is 0-5 and p is 0-8;
and
.beta. is ##STR31## wherein:
W is --(CH.sub.2).sub.n -- where n is 0-5 and
R.sup.11 is H, C.sub.1-8 alkyl, CO--C.sub.1-8 alkyl or CON--C.sub.1-8 alkyl or -aryl;
where aryl is an aromatic mono or bicyclic, optionally substituted, C.sub.6 -C.sub.12 group;
where heteroaryl is a mono or bicyclic hetero aryl having one N, O, S or two N atoms substituted for one or two carbon atoms;
where heteroalkyl is a 2 to 8 carbon atom alkyl having one N, O, S or two N atoms substituted for one or two carbon atoms.

43 more elements

A method for preventing or treating atherosclerosis comprising:

administering to a patient in need thereof a therapeutically effective amount of bivalent ligand .alpha.-.beta.-.alpha. wherein .alpha. is structurally represented by the formula ##STR32## or a pharmaceutically acceptable salt thereof wherein:
R.sup.1 and R.sup.2 are independently:
a) H,
b) halo,
c) C.sub.1-8 alkyl,
d) --(CH.sub.2).sub.p -aryl,
e) --(CH.sub.2).sub.p -heteroaryl,
f) --(CH.sub.2).sub.p --CO.sub.2 R.sup.6,
g) --(CH.sub.2).sub.p --CONR.sup.7 R.sup.8,
h) --Si(R.sup.9),
i) --(CH.sub.2).sub.n --NR.sup.7 R.sup.8,
j) --(CH.sub.2).sub.n --OR.sup.10,
k) --CF.sub.3, or
l) --(CH.sub.2).sub.n --SR.sup.6, --(CH.sub.2).sub.n --SOR.sup.6, --(CH.sub.2).sub.n --SO.sub.2 R.sup.6 ;
R.sup.3 is
a) OH,
b) OCH.sub.2 CH.dbd.CH.sub.2,
c) OCH.sub.2 CH(OH)CH.sub.2 NHR.sup.6,
d) --O--C.sub.1-8 alkyl,
e) --O--(CH.sub.2).sub.n --CO.sub.2 R.sup.6, or
f) --O--(CH.sub.2).sub.n --CONR.sup.7 R.sup.8 ;
R.sup.4 is
a) hydrogen,
b) halo,
c) NO.sub.2,
d) NH.sub.2
e) CF.sub.3,
f) C.sub.1-8 alkyl,
g) aryl,
h) --S--C.sub.1-8 alkyl or aryl,
i) --SO--C.sub.1-8 alkyl or aryl,
j) --SO.sub.2 --C.sub.1-8 alkyl or aryl,
k) R.sup.3, or
l) --(CH.sub.2).sub.n --NR.sup.7 R.sup.8 ;
R.sup.6 is H, CF.sub.3, alkyl or aryl, Li.sup.+, Na.sup.+, K.sup.+, Ca.sup.2+ and other pharmaceutically acceptable counter ions for carboxylic acids;
R.sup.7 and R.sup.8 are h, CO-alkyl, CO-aryl, alkyl, cycloalkyl, alkylaryl, aryl, heteroalkyl, aryl, or R.sup.7 and R.sup.8 can be taken together to form a piperidine ring or morpholine ring;
R.sup.9 is an C.sub.1-8 alkyl or aryl;
R.sup.10 is H, CF.sub.3, C.sub.1-8 alkyl, aryl or heteroaryl;
n is 0-5 and p is 0-8;
and
.beta. is ##STR33## wherein:
W is --(CH.sub.2).sub.n -- where n is 0-5 and
R.sup.11 H, C.sub.1-8 alkyl, CO--C.sub.1-8 alkyl or CON--C.sub.1-8 alkyl or -aryl;
where aryl is an aromatic mono or bicyclic, optionally substituted, C.sub.6 -C.sub.12 group;
where heteroaryl is a mono or bicyclic hetero aryl having one N, O, S or two N atoms substituted for one or two carbon atoms;
where heteroalkyl is a 2 to 8 carbon atom alkyl having one N, O, S or two N atoms substituted for one or two carbon atoms.

43 more elements

A method for blocking or inhibiting ACAT enzyme comprising:

administering to a patient a therapeutically effective amount of a bivalent ligand .alpha.-.beta.-.alpha. wherein .alpha. is structurally represented by the formula ##STR34## or a pharmaceutically acceptable salt thereof wherein:
R.sup.1 and R.sup.2 are independently:
a) H,
b) halo,
c) C.sub.1-8 alkyl,
d) --(CH.sub.2).sub.p -aryl,
e) --(CH.sub.2).sub.p -heteroaryl,
f) --(CH.sub.2).sub.p --CO.sub.2 R.sup.6,
g) --(CH.sub.2).sub.p --CONR.sup.7 R.sup.8,
h) --Si(R.sup.9),
i) --(CH.sub.2).sub.n --NR.sup.7 R.sup.8,
j) --(CH.sub.2).sub.n --OR.sup.10,
k) --CF.sub.3, or
l) --(CH.sub.2).sub.n --SR.sup.6, --(CH.sub.2).sub.n --SOR.sup.6, --(CH.sub.2).sub.n --SO.sub.2 R.sup.6 ;
R.sup.3 is
a) OH,
b) OCH.sub.2 CH.dbd.CH.sub.2,
c) OCH.sub.2 CH(OH)CH.sub.2 NHR.sup.6,
d) --O--C.sub.1-8 alkyl,
e) --O--(CH.sub.2).sub.n --CO.sub.2 R.sup.6, or
f) --O--(CH.sub.2).sub.n --CONR.sup.7 R.sup.8 ;
R.sup.4 is
a) hydrogen,
b) halo,
c) NO.sub.2,
d) NH.sub.2
e) CF.sub.3,
f) C.sub.1-8 alkyl,
g) aryl,
h) --S--C.sub.1-8 alkyl or aryl,
i) --SO--C.sub.1-8 alkyl or aryl,
j) --SO.sub.2 --C.sub.1-8 alkyl or aryl,
k) R.sup.3, or
l) --(CH.sub.2).sub.n --NR.sup.7 R.sup.8 ;
R.sup.6 is H, CF.sub.3, alkyl or aryl, Li.sup.+, Na.sup.+, K.sup.+, Ca.sup.2+ and other pharmaceutically acceptable counter ions for carboxylic acids;
R.sup.7 and R.sup.8 are H, CO-alkyl, CO-aryl, alkyl, cycloalkyl, alkylaryl, aryl, heteroalkyl, aryl, or R.sup.7 and R.sup.8 can be taken together to form a piperidine ring or morpholine ring;
R.sup.9 is an C.sub.1-8 alkyl or aryl;
R.sup.10 is H, CF.sub.3, C.sub.1-8 alkyl, aryl or heteroaryl;
n is 0-5 and p is 0-8;
and
.beta. is ##STR35## wherein:
W is --(CH.sub.2).sub.n -- where n is 0-5 and
R.sup.11 is H, C.sub.1-8 alkyl, CO--C.sub.1-8 alkyl or CON--C.sub.1-8 alkyl or --aryl;
where aryl is an aromatic mono or bicyclic, optionally substituted, C.sub.6 -C.sub.12 group;
where heteroaryl is a mono or bicyclic hetero aryl having one N, O, S or two N atoms substituted for one or two carbon atoms;
where heteroalkyl is a 2 to 8 carbon atom alkyl having one N, O, S or two N atoms substituted for one or two carbon atoms.

43 more elements

A method for lowering plasma triglycerides comprising:

administering to a patient in need thereof a therapeutically effective amount of a bivalent ligand .alpha.-.beta.-.alpha. wherein .alpha. is structurally represented by the formula ##STR36## or a pharmaceutically acceptable salt thereof wherein:
R.sup.1 and R.sup.2 are independently:
a) H,
b) halo,
c) C.sub.1-8 alkyl,
d) --(CH.sub.2).sub.p -aryl,
e) --(CH.sub.2).sub.p -heteroaryl,
f) --(CH.sub.2).sub.p --CO.sub.2 R.sup.6,
g) --(CH.sub.2).sub.p --CONR.sup.7 R.sup.8,
h) --Si(R.sup.9),
i) --(CH.sub.2).sub.n --NR.sup.7 R.sup.8,
j) --(CH.sub.2).sub.n --OR.sup.10,
k) --CF.sub.3, or
l) --(CH.sub.2).sub.n --SR.sup.6, --(CH.sub.2).sub.n --SOR.sup.6, --(CH.sub.2).sub.n --SO.sub.2 R.sup.6 ;
R.sup.3 is
a) OH,
b) OCH.sub.2 CH.dbd.CH.sub.2,
c) OCH.sub.2 CH(OH)CH.sub.2 NHR.sup.6,
d) --O--C.sub.1-8 alkyl,
e) --O--(CH.sub.2).sub.n --CO.sub.2 R.sup.6, or
f) --O--(CH.sub.2).sub.n --CONR.sup.7 R.sup.8 ;
R.sup.4 is
a) hydrogen,
b) halo,
c) NO.sub.2,
d) NH.sub.2
e) CF.sub.3,
f) C.sub.1-8 alkyl,
g) aryl,
h) --S--C.sub.1-8 alkyl or aryl,
i) --SO--C.sub.1-8 alkyl or aryl,
j) --SO.sub.2 --C.sub.1-8 alkyl or aryl,
k) R.sup.3, or
l) --(CH.sub.2).sub.n --NR.sup.7 R.sup.8 ;
R.sup.6 is H, CF.sub.3, alkyl or aryl, Li.sup.+, Na.sup.+, K.sup.+, Ca.sup.2+ and other pharmaceutically acceptable counter ions for carboxylic acids;
R.sup.7 and R.sup.8 are H, CO-alkyl, CO-aryl, alkyl, cycloalkyl, alkylaryl, aryl, heteroalkyl, aryl, or R.sup.7 and R.sup.8 can be taken together to form a piperidine ring or morpholine ring;
R.sup.9 is an C.sub.1-8 alkyl or aryl;
R.sup.10 is H, CF.sub.3, C.sub.1-8 alkyl, aryl or heteroaryl;
n is 0-5 and p is 0-8;
and
.beta. is ##STR37## wherein:
W is --(CH.sub.2).sub.n -- where n is 0-5 and
R.sup.11 is H, C.sub.1-8 alkyl, CO--C.sub.1-8 alkyl or CON--C.sub.1-8 alkyl or --aryl;
where aryl is an aromatic mono or bicyclic, optionally substituted, C.sub.6 -C.sub.12 group;
where heteroaryl is a mono or bicyclic hetero aryl having one N, O, S or two N atoms substituted for one or two carbon atoms;
where heteroalkyl is a 2 to 8 carbon atom alkyl having one N, O, S or two N atoms substituted for one or two carbon atoms.

43 more elements

A method for elevating HDL cholesterol comprising:

administering to a patient a therapeutically effective amount of a bivalent ligand .alpha.-.beta.-.alpha. wherein .alpha. is structurally represented by the formula ##STR38## or a pharmaceutically acceptable salt thereof wherein:
R.sup.1 and R.sup.2 are independently:
a) H,
b) halo,
c) C.sub.1-8 alkyl,
d) --(CH.sub.2).sub.p --aryl,
e) --(CH.sub.2).sub.p --heteroaryl,
f) --(CH.sub.2).sub.p --CO.sub.2 R.sup.6,
g) --(CH.sub.2).sub.p --CONR.sup.7 R.sup.8,
h) --Si(R.sup.9),
i) --(CH.sub.2).sub.n --NR.sup.7 R.sup.8,
j) --(CH.sub.2).sub.n --OR.sup.10,
k) --CF.sub.3, or
l) --(CH.sub.2).sub.n --SR.sup.6, --(CH.sub.2).sub.n --SOR.sup.6, --(CH.sub.2).sub.n --SO.sub.2 R.sup.6 ;
R.sup.3 is
a) OH,
b) OCH.sub.2 CH=CH.sub.2,
c) OCH.sub.2 CH(OH)CH.sub.2 NHR.sup.6,
d) --O--C.sub.1-8 alkyl,
e) --O--(CH.sub.2).sub.n --CO.sub.2 R.sup.6, or
f) --O--(CH.sub.2).sub.n --CONR.sup.7 R.sup.8 ;
R.sup.4 is
a) hydrogen,
b) halo,
c) NO.sub.2,
d) NH.sub.2
e) CF.sub.3,
f) C.sub.1-8 alkyl,
g) aryl,
h) --S--C.sub.1-8 alkyl or aryl,
i) --SO--C.sub.1-8 alkyl or aryl,
j) --SO.sub.2 --C.sub.1-8 alkyl or aryl,
k) R.sup.3, or
l) --(CH.sub.2).sub.n --NR.sup.7 R.sup.8 ;
R.sup.6 is H, CF.sub.3, alkyl or aryl, Li.sup.+, Na.sup.+, Ca.sup.2+ and other pharmaceutically acceptable counter ions for carboxylic acids;
R.sup.7 and R.sup.8 are H, CO-alkyl, CO-aryl, alkyl, cycloalkyl, alkylaryl, aryl, heteroalkyl, aryl, or R.sup.7 and R.sup.8 can be taken together to form a piperidine ring or morpholine ring;
R.sup.9 is an C.sub.1-8 alkyl or aryl;
R.sup.10 is H, CF.sub.3, C.sub.1-8 alkyl, aryl or heteroaryl;
n is 0-5 and p is 0-8;
and
.beta. is ##STR39## wherein:
W is --(CH.sub.2).sub.n -- where n is 0-5 and
R.sup.11 is H, C.sub.1-8 alkyl, CO-C.sub.1-8 alkyl or CON-C.sub.1-8 alkyl or --aryl;
where aryl is an aromatic mono or bicyclic, optionally substituted, C.sub.6 -C.sub.12 group;
where heteroaryl is a mono or bicyclic hetero aryl having one N, O, S or two N atoms substituted for one or two carbon atoms;
where heteroalkyl is a 2 to 8 carbon atom alkyl having one N, O, S or two N atoms substituted for one or two carbon atoms.

43 more elements

Dependencies are inferred from the claim text.

Facts

Application: 07/697,301Filed 7 May 1991 · continuation in part
Priority: 16 Aug 1988
Granted: 19 Jan 1993
Term ends: Not estimatedThe source records don’t support an estimate.

Classification4 codes

C07D 519/00
Heterocyclic compounds containing more than one system of two or more relevant
C07F 7/0814
Comprising a heterocyclic ring: said ring is substituted at a C ring atom by Si
C07D
Heterocyclic compounds
C07F
Acyclic, carbocyclic or heterocyclic compounds containing elements other than carbon, hydrogen, halogen

Family

Serial232,931Parent of this continuation · filed 16 Aug 1988
Serial2,572Parent of this continuation-in-part · filed 16 Jun 1989
Serial486,648Parent of this continuation-in-part · filed 28 Feb 1990
Serial651,334Parent of this continuation-in-part · filed 8 Feb 1991
US 5,180,717 AThis patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A bivalent ligand .alpha.-.beta.-.alpha. wherein .alpha. is structurally represented by the formula ##STR30## or a pharmaceutically acceptable salt thereof wherein:

R.sup.1 and R.sup.2 are independently:
a) H,
b) halo,
c) C.sub.1-8 alkyl,
d) --(CH.sub.2).sub.p -aryl,
e) --(CH.sub.2).sub.p -heteroaryl,
f) --(CH.sub.2).sub.p --CO.sub.2 R.sup.6,
g) --(CH.sub.2).sub.p --CONR.sup.7 R.sup.8,
h) --Si(R.sup.9),
i) --(CH.sub.2).sub.n --NR.sup.7 R.sup.8,
j) --(CH.sub.2).sub.n --OR.sup.10,
k) --CF.sub.3, or
l) --(CH.sub.2).sub.n --SR.sup.6, --(CH.sub.2).sub.n --SOR.sup.6, --(CH.sub.2).sub.n --SO.sub.2 R.sup.6 ;
R.sup.3 is
a) OH,
b) OCH.sub.2 CH.dbd.CH.sub.2,
c) OCH.sub.2 CH(OH)CH.sub.2 NHR.sup.6,
d) --O--C.sub.1-8 alkyl,
e) --O--(CH.sub.2).sub.n --CO.sub.2 R.sup.6, or
f) --O--(CH.sub.2).sub.n --CONR.sup.7 R.sup.8 ;
R.sup.4 is
a) hydrogen,
b) halo,
c) NO.sub.2,
d) NH.sub.2
e) CF.sub.3,
f) C.sub.1-8 alkyl,
g) aryl,
h) --S--C.sub.1-8 alkyl or aryl,
i) --SO--C.sub.1-8 alkyl or aryl,
j) --SO.sub.2 --C.sub.1-8 alkyl or aryl,
k) R.sup.3, or
l) --CH.sub.2).sub.n --NR.sup.7 R.sup.8 ;
R.sup.6 is H, CF.sub.3, alkyl or aryl, Li.sup.+, Na.sup.+, K.sup.+, Ca.sup.2+ and other pharmaceutically acceptable counter ions for carboxylic acids;
R.sup.7 and R.sup.8 and H, CO-alkyl, CO-aryl, alkyl, cycloalkyl, alkylaryl, aryl, heteroalkyl, aryl, or R.sup.7 and R.sup.8 can be taken together to form a piperidine ring or morpholine ring;
R.sup.9 is an C.sub.1-8 alkyl or aryl;
R.sup.10 is H, CF.sub.3, C.sub.1-8 alkyl, aryl or heteroaryl;
and
n is 0-5 and p is 0-8;
and
.beta. is ##STR31## wherein:
W is --(CH.sub.2).sub.n -- where n is 0-5 and
R.sup.11 is H, C.sub.1-8 alkyl, CO--C.sub.1-8 alkyl or CON--C.sub.1-8 alkyl or -aryl;
where aryl is an aromatic mono or bicyclic, optionally substituted, C.sub.6 -C.sub.12 group;
where heteroaryl is a mono or bicyclic hetero aryl having one N, O, S or two N atoms substituted for one or two carbon atoms;
where heteroalkyl is a 2 to 8 carbon atom alkyl having one N, O, S or two N atoms substituted for one or two carbon atoms.

43 more elements

Facts

Application

07/697,301Filed 7 May 1991 · continuation in part

Priority

16 Aug 1988

Granted

19 Jan 1993

Term ends

Not estimatedThe source records don’t support an estimate.

Classification4 codes

C07D 519/00
Heterocyclic compounds containing more than one system of two or more relevant
C07F 7/0814
Comprising a heterocyclic ring: said ring is substituted at a C ring atom by Si
C07D
Heterocyclic compounds
C07F
Acyclic, carbocyclic or heterocyclic compounds containing elements other than carbon, hydrogen, halogen

Family

Serial232,931Parent of this continuation · filed 16 Aug 1988

Serial2,572Parent of this continuation-in-part · filed 16 Jun 1989

Serial486,648Parent of this continuation-in-part · filed 28 Feb 1990

Serial651,334Parent of this continuation-in-part · filed 8 Feb 1991

US 5,180,717 AThis patent

From the US filing history. Foreign family members aren’t listed.