Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-11-28
1999-07-06
Davis, Zinna Northington
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546143, C07D21704, C07D40106, A61K 3147, A61K 31495
Patent
active
059197951
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to compounds which are inhibitors of microsomal triglyceride transfer protein and/or apolipoprotein B (Apo B) secretion, and which are accordingly useful for the prevention and treatment of atherosclerosis and its clinical sequelae, for lowering serum lipids, and related diseases. The invention further relates to compositions comprising the compounds and to methods of treating atherosclerosis, obesity, and related diseases and/or conditions with the compounds.
BACKGROUND OF THE INVENTION
Microsomal triglyceride transfer protein (MTP) catalyzes the transport of triglyceride, cholesteryl ester, and phospholipids. It has been implicated as a probable agent in the assembly of Apo B-containing lipoproteins, biomolecules which contribute to the formation of atherosclerotic lesions. See European Patent application publication no. 0 643 057 A1, European Patent application publication no. 0 584 446 A2, and Wetterau et al., Science, 258, 999-1001, (1992). Compounds which inhibit MTP and/or otherwise inhibit Apo B secretion are accordingly useful in the treatment of atherosclerosis. Such compounds are also useful In the treatment of other diseases or conditions in which, by inhibiting MTP and/or Apo B secretion, serum cholesterol and triglyceride levels can be reduced. Such conditions include hypercholesterolemia, hypertriglyceridemia, pancreatits, and obesity; and hypercholesterolemia, hypertriglyceridemia, and hyperlipidemla associated with pancreatitis, obesity, and diabetes.
Examples of general information and/or documents defining the general state of the art include EP-A-0 635 492, J. Med. Chem. (1975) 18(12), 1227-1231, U.S. Pat. No. 4,022,900, and EP-A-0 106 140.
SUMMARY OF THE INVENTION
This invention provides compounds of formula I ##STR2## wherein X is CH.sub.2, CO, CS, or SO.sub.2 ; radical may be mono-substed by hydroxy, (C.sub.1 -C.sub.10)alkoxy, (C.sub.1 -C.sub.10)acyl, (C.sub.1 -C.sub.10)acyloxy, or (C.sub.6 -C.sub.10)aryl, (C.sub.1 -C.sub.10)acyl, thiophenylcarbonyl, (C.sub.1 -C.sub.10)alkylcarbonyl, (C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.10)alkylamino, provided that Y is not O or NH, -C.sub.8)cycloalkyl and fused benz derivatives thereof, (C.sub.7 -C.sub.10)polycycloalkyl, (C.sub.4 -C.sub.8)cycloalkenyl, (C.sub.7 -C.sub.10)polycycloalkenyl, -C.sub.10)aryl(C.sub.1 -C.sub.10)alkoxy, (C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.10)alkylthio, (C.sub.3 -C.sub.8)cycloalkyloxy, (C.sub.4 -C.sub.8)cycloalkenyloxy, and fused polycyclic radicals, wherein said radicals contain a total of from 5 to 14 ring atoms, wherein said radicals contain a total of from 1 to 4 ring heteroatoms independently selected from oxygen, nitrogen, and sulfur, and wherein the individual rings of said radicals may be independently saturated, partially unsaturated, or aromatic, (6), independently bear 0 to 4 substituents independently selected from halo, hydroxy, cyano, nitro, oxo (O.dbd.), thioxo(S.dbd.), aminosulfonyl, phenyl, phenoxy, phenylthio, halophenylthio, benzyl, benzyloxy, (C.sub.1 -C.sub.10)alkyl, (C.sub.1 -C.sub.10)alkoxy, (C.sub.1 -C.sub.10)alkoxycarbonyl, (C.sub.1 -C.sub.10)alkylthio, (C.sub.1 -C.sub.10)alkylamino, (C.sub.1 -C.sub.10)alkylaminocarbonyl, di(C.sub.1 -C.sub.10)alkylamino, di(C.sub.1 -C.sub.10)alkylaminocarbonyl, di(C.sub.1 -C.sub.10)alkylamino(C.sub.1 -C.sub.10)alkoxy, (C.sub.1 -C.sub.3)perfluoroalkyl, (C.sub.1 -C.sub.3)perfluoroalkoxy, (C.sub.1 -C.sub.10)acyl, (C.sub.1 -C.sub.10)acyloxy, (C.sub.1 -C.sub.10)acyloxy(C.sub.1 -C.sub.10)alkyl, and pyrrolidinyl;
Reference to Z as "heterocyclyl" means any single ring or fused ring system containing at least one ring heteroatom independently selected from O, N, and S. Thus a polycyclic fused ring system containing one or more carbocyclic fused saturated, partially unsaturated, or aromatic rings (usually benz rings) is within the definition of heterocyclyl so long as the system also contains at least one fused ring which contains at least one of the aforementioned heteroatoms. As a substituent, such heterocyclyls may b
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Journal Of Medicinal Chemistry, vol. 18, No. 12, Dec. 1975, pp. 1227-1231.
Chang George
Dorff Peter H.
Quallich George J.
Benson Gregg C.
Davis Zinna Northington
Jones James T.
Pfizer Inc.
Richardson Peter C.
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