US5283256A
Expired / Lapsed
US
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Cholesterol-lowering agents
Assignee: Merck and Co Inc
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Filing: 1992-07-22
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Granted: 1994-02-01
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Expires: 2012-07-22
Abstract
Abstract This invention relates to compounds of structural formula (I): <IMAGE> which are squalene synthase inhibitors and thus useful as cholesterol lowering agents and antifungal agents. These compounds are also inhibitors of farnesyl protein transferase and farnesylation of the oncogene protein Ras and thus useful in treating cancer. This invention also relates to a process for obtaining compounds of structural formula (I).
Inventors
- 👤 Claude Dufresne
- 👤 Josep Guarro
- 👤 Leeyuan Huang
- 👤 Yu L. Kong
- 👤 Russell B. Lingham
- 👤 Maria S. Meinz
- 👤 Keith C. Silverman
- 👤 Sheo B. Singh
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-22 21:59
CPC Classifications
C; C07; C07D; C07D493/00; C07D493/02; C07D493/08; A; A01; A01N; A01N43/00; A01N43/90
Claims Analysis
Total Claims: 20
Claim 1
Independent Claim
66 words
A compound of structural formula (I) ##STR3## wherein R is --(CH 2 ) n CH 3 wherein n is 6 or 8; and Z 1 , Z 2 and Z 3 are each independently a) H; b) C 1-5 alkyl; or c) C 1-5 alkyl substituted with i) phenyl, or ii) phenyl substituted with methyl, or a pharmaceutically acceptable salt of a compound of formula (I).
Claim 2
Dependent Claim
66 words
A compound of structural formula (I) ##STR3## wherein R is --(CH 2 ) n CH 3 wherein n is 6 or 8; and Z 1 , Z 2 and Z 3 are each independently a) H; b) C 1-5 alkyl; or c) C 1-5 alkyl substituted with i) phenyl, or ii) phenyl substituted with methyl, or a pharmaceutically acceptable salt of a compound of formula (I).
Claim 3
Dependent Claim
133 words
A compound of molecular weight 678.290 characterized by: (a) the 13 C NMR chemical shifts as measured in CD 3 OD: δ 14.44, 14.64, 20.12, 21.16, 23.70, 25.86, 30.07, 30.15, 32.68, 32.86, 35.04, 36.31, 37.97, 38.02, 75.67, 76.63, 78.03, 80.99, 82.20, 90.97, 107.21, 127.04 (2), 127.95, 129.51 (2), 129.61, 132.87, 138.12, 168.48, 170.22, 172.52, 173.08, 173.64, and (b) the 1 H NMR chemical shifts as measured in CD 3 OH: δ 0.88 (t, 7.0, 3H), 0.94 (d, 7.0, 3H), 1.3 (m, 8H), 1.59 (m, 4H), 1.69 (m, 2H), 1.89 (m), 1.92 (m, 2H), 2.05 (s, 3H), 2.08 (m), 2.28 (m, 2H), 2.32 (m), 4.02 (d, 2.0), 4.95 (m), 5.23 (s), 6.23 (dt, 16.0, 7.0), 6.24 (d, 2.0), 6.38 (d, 16.0), 7.15 (br t, 7.5), 7.25 (t, 7.5, 2H), 7.34 (br d, 7.5, 2H).
Claim 4
Dependent Claim
133 words
A compound of molecular weight 678.290 characterized by: (a) the 13 C NMR chemical shifts as measured in CD 3 OD: δ 14.44, 14.64, 20.12, 21.16, 23.70, 25.86, 30.07, 30.15, 32.68, 32.86, 35.04, 36.31, 37.97, 38.02, 75.67, 76.63, 78.03, 80.99, 82.20, 90.97, 107.21, 127.04 (2), 127.95, 129.51 (2), 129.61, 132.87, 138.12, 168.48, 170.22, 172.52, 173.08, 173.64, and (b) the 1 H NMR chemical shifts as measured in CD 3 OH: δ 0.88 (t, 7.0, 3H), 0.94 (d, 7.0, 3H), 1.3 (m, 8H), 1.59 (m, 4H), 1.69 (m, 2H), 1.89 (m), 1.92 (m, 2H), 2.05 (s, 3H), 2.08 (m), 2.28 (m, 2H), 2.32 (m), 4.02 (d, 2.0), 4.95 (m), 5.23 (s), 6.23 (dt, 16.0, 7.0), 6.24 (d, 2.0), 6.38 (d, 16.0), 7.15 (br t, 7.5), 7.25 (t, 7.5, 2H), 7.34 (br d, 7.5, 2H).
Claim 5
Dependent Claim
28 words
The compound of claim 1 in which Z 1 , Z 2 and Z 3 are each hydrogen or a pharmaceutically acceptable mono, di or tri salt thereof.
Claim 6
Dependent Claim
18 words
The compound of claim 1 in which Z 1 , Z 2 and Z 3 are each methyl.
Claim 7
Dependent Claim
10 words
The compound of claim 3 in which n is 6.
Claim 8
Dependent Claim
10 words
The compound of claim 3 in which n is 8.
Claim 9
Dependent Claim
20 words
A pharmaceutical composition comprising a nontoxic therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.
Claim 10
Dependent Claim
42 words
A pharmaceutical composition comprising a nontoxic therapeutically effective amount of a compound of claim 1 in combination with a pharmaceutically acceptable non-toxic cationic polymer capable of binding bile acids in a non-resorbable form in the gastrointestinal tract and a pharmaceutically acceptable carrier.
Claim 11
Dependent Claim
59 words
A pharmaceutical composition comprising a nontoxic therapeutically effective amount of a compound of claim 1 in combination with a nontoxic therapeutically effective amount of a cholesterol lowering agent selected from the group consisting of: a) HMG-CoA reductase inhibitor; b) HMG-CoA synthase inhibitor; c) squalene epoxidase inhibitor; d) probucol; e) niacin; f) gemfibrozil; g) clofibrate; and h) LDL-receptor gene inducer.
Claim 12
Dependent Claim
24 words
A pharmaceutical composition comprising a unit dose of a compound of claim 1 and a nontoxic therapeutically effective amount of an HMG-CoA reductase inhibitor.
Claim 13
Dependent Claim
27 words
A method of treating hypercholesterolemia comprising the administration to a subject in need of such treatment a nontoxic therapeutically effective amount of a compound of claim 1.
Claim 14
Dependent Claim
28 words
A method of inhibiting squalene synthase comprising the administration to a subject in need of such treatment a nontoxic therapeutically effective amount of a compound of claim 1.
Claim 15
Dependent Claim
26 words
A method of treating hypercholesterolemia comprising the administration to a subject in need of such treatment 20 to 100 mg of a compound of claim 1.
Claim 16
Dependent Claim
27 words
A method of inhibiting squalene synthase comprising the administration to a subject in need of such treatment 20 to 100 mg of a compound of claim 1.
Claim 17
Dependent Claim
27 words
A method for inhibiting fungal growth comprising applying to the area where growth is to be controlled an antifungally effective amount of a compound of claim 1.
Claim 18
Dependent Claim
38 words
A method for inhibiting fungal growth in a living organism in need of such treatment comprising the oral, systemic, topical or parenteral administration to the living organism of an antifungally effective amount of a compound of claim 1.
Claim 19
Dependent Claim
12 words
The method of claim 16 wherein the living organism is a vertebrate.
Claim 20
Dependent Claim
32 words
The method of claim 16 wherein the living organism is a plant, and the compound is administered by topical application to the plant or to the soil in which the plant grows.
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USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1997-01-31 | 1997-08-02 | 1998-02-01 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 2001-01-31 | 2001-08-02 | 2002-02-01 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 2005-01-31 | 2005-08-02 | 2006-02-01 | $7700.00 | Window Closed / Lapsed |