Compounds affecting cholesterol absorption

Details Compounds affecting cholesterol absorption Compounds affecting cholesterol absorption

2002-11-12

2004-04-27

Owens, Amelia (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C549S214000, C549S384000, C568S633000

Reexamination Certificate

active

06727277

ABSTRACT:

TECHNICAL FIELD
This invention relates to novel organic compound and methods for their synthesis. More particularly, the invention relates to novel compounds affecting lymphatic absorption of cholesterol.
BACKGROUND
Atherosclerosis is a major cause of heart attack, stroke, and gangrene of the extremities and can be attributed directly to having high levels of cholesterol in the body. Cholesterol can enter the body by absorption from foods by the intestinal mucosal cells and the lymphatic system (i.e., exogenous sources). Cholesterol also is produced in the liver by a sequence of enzymatic reactions (i.e., endogenous biosynthesis). Endogenous biosynthesis of cholesterol involves a key enzyme, HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase. HMG-CoA reductase inhibitors can be used to lower total plasma cholesterol in patients with primary hypercholesterolemia. Effective inhibition of HMG-CoA reductase is realized by drugs such as Lovastatin (sold as Mevacor from Merck Co.), Mevalotin (from Sankyo Co., Japan), and analogs thereof (e.g., compounds sold under the trade names Sivastatin, Mevastatin, and Pravastatin). Exogenous sources of cholesterol, however, are not affected by these drugs. Various compounds have been reported to be useful for lowering cholesterol absorption. See, e.g., U.S. Pat. Nos. 5,246,960, 5,175,186, 5,215, 972, 5,495,048, 5,856,503, and 5,637,771. Currently, a lipase inhibitor termed Xenical® has been offered for obesity management. Xenical® has been reported to achieve a slight reduction in cholesterol.
SUMMARY
The invention features a compound of Formula I:
R
1
can be independently hydrido, halo, alkyl, alkenyl, alkylyl, haloalkyl, hydroxyalkyl, hydroxy, alkoxy, alkoxyalkyl, haloalkoxy, haloalkoxyalkyl, aryl, heterocyclic, heteroaryl, alkylsulfonyl, arylsulfonyl, N-alkylsulfamyl, N,N-dialkylsulfamyl, N-arylsulfomyl, N-alkyl-N-arylsulfamyl, carboxy, carboxyalkyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, amido, N-alkylamido, N-N-dialkylamido, N-monoarylamido, N-alkyl-N-arylamido, N-alkyl-N-hydroxyamido, N-alkyl-N-hydroxyamidoalkyl, amidoalkyl, aminoalkyl, alkylaminoalkyl, amidino, cyanoamidino, heterocycloalkyl, aralkyl, cycloalkyl, cycloalkenyl, alkylthio, alkylsulfinyl, N-alkylamino, N,N-dialkylamino, acyl, acyloxy, aryloxy, acylamino, amino, cyano, nitro, sulfonate, alkylsilyl, phenylselenyl, thiol, arylsulfenyl, alkylsulfenyl, arylsulfinyl, or alkylsilyloxy.
R
2
can be independently hydrido, halo, alkyl, alkenyl, alkylyl, haloalkyl, hydroxyalkyl, hydroxy, alkoxy, alkoxyalkyl, haloalkoxy, haloalkoxyalkyl, aryl, heterocyclic, heteroaryl, alkylsulfonyl, arylsulfonyl, N-alkylsulfamyl, N,N-dialkylsulfamyl, N-arylsulfomyl, N-alkyl-N-arylsulfamyl, carboxy, carboxyalkyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, amido, N-alkylamido, N-N-dialkylamido, N-monoarylamido, N-alkyl-N-arylamido, N-alkyl-N-hydroxyamido, N-alkyl-N-hydroxyamidoalkyl, amidoalkyl, aminoalkyl, alkylaminoalkyl, amidino, cyanoamidino, heterocycloalkyl, aralkyl, cycloalkyl, cycloalkenyl, alkylthio, alkylsulfinyl, N-alkylamino, N,N-dialkylamino, acyl, acyloxy, aryloxy, acylamino, amino, cyano, nitro, sulfonate, alkylsilyl, or phenylselenyl, thiol, arylsulfenyl, alkylsulfenyl, arylsulfinyl, or alkylsilyloxy;
R
3
can be independently hydrido, halo, alkyl, alkenyl, alkylyl, haloalkyl, hydroxyalkyl, hydroxy, alkoxy, alkoxyalkyl, haloalkoxy, haloalkoxyalkyl, aryl, heterocyclic, heteroaryl, alkylsulfonyl, arylsulfonyl, N-alkylsulfamyl, N,N-dialkylsulfamyl, N-arylsulfomyl, N-alkyl-N-arylsulfamyl, carboxy, carboxyalkyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, amido, N-alkylamido, N-N-dialkylamido, N-monoarylamido, N-alkyl-N-arylamido, N-alkyl-N-hydroxyamido, N-alkyl-N-hydroxyamidoalkyl, amidoalkyl, aminoalkyl, alkylaminoalkyl, amidino, cyanoamidino, heterocycloalkyl, aralkyl, cycloalkyl, cycloalkenyl, alkylthio, alkylsulfinyl, N-alkylamino, N,N-dialkylamino, acyl, acyloxy, aryloxy, acylamino, amino, cyano, nitro, sulfonate, alkylsilyl, phenylselenyl, thiol, arylsulfenyl, alkylsulfenyl, arylsulfinyl, or alkylsilyloxy.
R
4
can be independently hydrido, alkyl, or hydroxyalkyl.
R
5
can be independently hydrido, alkyl, or hydroxyalkyl.
In some embodiments, R
1
is halo, R
2
and R
3
are hydroxy, and R
4
and R
5
are alkyl in the compound, e.g., R
1
is chloro and R
4
and R
5
are methyl. In other embodiments, R
1
is halo, R
2
and R
3
are alkylsilyloxy, and R
4
and R
5
are alkyl, e.g., R
1
is chloro, R
2
and R
3
are OSi-t-BuMe2, and R
4
and R
5
are methyl. In one embodiment, the compound has Formula (24):
The invention also features a compound of Formula II:
R
1
can be independently any of the groups described above for R
1
of Formula I. R
2
can be independently any of the groups described above for R
2
of Formula I. R
3
can be independently any of the groups described above for R
3
of Formula I. R
4
can be independently hydrido, alkyl, or hydroxyalkyl. R
5
can be independently hydrido, alkyl, or hydroxyalkyl. However, when R
1
is chloro, R
2
and R
3
are not hydroxy and R
4
and R
5
are methyl.
In some embodiments, R
1
is halo, R
2
and R
3
are hydroxy, and R
4
and R
5
are alkyl. In some embodiments, R
1
is halo, R
2
and R
3
are alkylsilyloxy; and R
4
and R
5
are alkyl, e.g., R
1
is chloro, R
2
and R
3
are OSi-t-BuMe
2
, and R
4
and R
5
are methyl.
The invention also features a compound of Formula III:
In these compounds, R
1
can be independently any of the groups described above for R1 of Formula I.
R
2
can be independently any of the groups described above for R
2
of Formula I. R
3
can be independently any of the groups described above for R
3
of Formula I. R
4
can be independently hydrido, alkyl, or hydroxyalkyl. R
5
can be independently hydrido, alkyl, or hydroxyalkyl.
In some embodiments, R
1
is halo, R
2
and R
3
are selected from hydroxy and alkylsilyloxy, and R
4
and R
5
are alkyl, e.g., R
1
is chloro, R
2
and R
3
are hydroxy, and R
4
and R
5
are methyl. In some embodiments, R
1
is halo, R
2
and R
3
are alkylsilyloxy, and R
4
and R
5
are methyl, e.g., R
1
is chloro, R
2
and R
3
are OSi-t-BuMe
2
, and R
4
and R
5
are methyl. In some embodiments the compound has Formula (23):
The invention also features a compound of Formula IV:
R
1
can be independently any of the groups described above for R
1
of Formula I. R
2
can be independently any of the groups described above for R
2
of Formula I. R
3
can be independently any of the groups described above for R
3
of Formula I. R
4
can be independently hydrido, alkyl, or hydroxyalkyl. R
5
can be independently hydrido, alkyl, or hydroxyalkyl. R
6
can be independently hydrido, hydroxy, or acyloxy. R
7
can be independently alkyl, or arylselenylalkyl.
In some embodiments, R
1
is halo, R
2
and R
3
are selected from hydroxy, alkylsilyloxy, or aralkyloxy, R
4
and R
5
are alkyl, R
6
is selected from hydrido, hydroxy, or acyloxy, and R
7
is selected from alkyl or arylselenylalkyl, e.g., R
1
is chloro; R
2
and R
3
are OSi-t-BuMe
2
, R
4
and R
5
are methyl, R
6
is hydrido, and R
7
is methyl. In other embodiments, R
1
is chloro, R
2
and R
3
are hydroxy, R
4
and R
5
are methyl, R
6
is hydrido, and R
7
is methyl. In some embodiments, R
1
is chloro; R
2
and R
3
are arylalkyloxy; R
4
and R
5
are methyl, R
6
is hydroxy, and R
7
is arylselenylalkyl. In some embodiments, R
1
is chloro,; R
2
and R
3
are arylalkyloxy, and R
4
and R
5
are methyl, R
6
is acyloxy, and R
7
is arylselenylalkyl. In some embodiments, R
1
is chloro, R
2
and R
3
are arylalkyloxy; R
4
and R
5
are methyl, R
6
is acyloxy, and R
7
is methyl.
The invention also features a compound of Formula V:
R
1
can be independently any of the groups described above for R
1
of Formula I. R
2
can be independently any of the groups described above for R
2
of Formula I. R
3
can be independently any of the groups described above for R
3
of Formula I. R
4
can be independently hydrido, alkyl, or hyd

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