Heterocyclic-substituted alkyl amide acat inhibitors

• US 5,693,657 A
• Filed: 01/21/1997
• Issued: 12/02/1997
• Est. Priority Date: 08/22/1991
• Status: Expired due to Fees

• Current Assignee: Warner-Lambert Company (Pfizer Inc.)
• Original Assignee: Warner-Lambert Company (Pfizer Inc.)
• Inventors: O'Brien, Patrick Michael, Lee, Helen Tsenwhei, Roth, Bruce David, White, Andrew David, Picard, Joseph Armand, Sliskovic, Drago Robert, Purchase, Claude Forsey Jr.
• Primary Examiner(s): Gupta, Yogendra N.
• Application Number:
  US08/786,062
• Time in Patent Office: 315 Days
• Field of Search: 514/340, 514/381, 546/276, 548/253
• US Class Current: 514/340
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 231/12 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 233/56 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 249/04 1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
• CPC Class Codes: C07D 257/04 Five-membered rings
• CPC Class Codes: C07D 261/08 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 271/06 1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
• CPC Class Codes: C07D 271/10 1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
• CPC Class Codes: C07D 277/22 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

Pharmaceutically useful compounds having ACAT inhibitory activity of the formula ##STR1## wherein n is 0, 1, or 2, for X other than tetrazole and n=2 then R₂ ═R₃ ═H; R₁ is phenyl, substituted phenyl, naphthyl, substituted naphthyl, a heteroaromatic group or a hydrocarbon group having from one to 18 carbon atoms; R₂ and R₃ are hydrogen, halo, hydroxy, alkyl, alkenyl, cycloalkyl, phenyl, substituted phenyl, a heteroaryl, or form a spiroalkyl group; X is a heteromonocyclic 5-membered ring containing one to four heteroatoms, said heteroatoms being nitrogen, oxygen or sulfur, and combination thereof; and R₄ is a hydrocarbon group having from one to 20 carbon atoms are described as well as methods of their manufacture.

Claims

1. A compound of the formula

wherein n is 0, 1, or 2;

wherein R₁ is selected from

(a) phenyl which is substituted with from one to three substituents selected from;

alkyl having from one to four carbon atoms and which is straight or branched,

alkoxy having from one to three carbon atoms and which is straight or branched,

alkylthio having from one to three carbon atoms and which is straight or branched,

hydroxy,

phenyl,

fluorine,

chlorine,

bromine,

nitro,

cyano,

trifluoromethyl,

--COOH,

--COOalkyl wherein alkyl has from one to four carbon atoms and which is straight or branched,

--(CH₂)_m NR₅ R₆ wherein m is 0 or 1, and each of R₅ and R₆ is hydrogen or a straight or branched alkyl group having one to four carbon atoms;

(b) 1- or 2-naphthyl which is unsubstituted or substituted with one to three substituents selected from;

alkyl having from one to four carbon atoms and which is straight or branched,

alkoxy having from one to three carbon atoms and which is straight or branched,

hydroxy,

fluorine,

chlorine,

bromine,

nitro,

cyano,

trifluoromethyl,

--COOH,

--COOalkyl wherein alkyl has from one to four carbon atoms and is straight or branched,

--(CH₂)_m NR₅ R₆ wherein m, R₅, and R₆ have the meanings defined above;

(c) a straight or branched hydrocarbon group having from one to 18 carbon atoms which is saturated or is unsaturated containing one double bond or two nonadjacent double bonds;

or

(d) a cycloalkyl group having from three to eight carbon atoms;

R₂ is hydrogen;

R₃ is a heteroaryl selected from a 5- or 6-membered monocyclic or fused bicyclic heterocyclic group containing at least one to four heteroatoms in at least one ring, said heteroatoms being nitrogen, oxygen, or sulfur and combinations thereof, said heterocyclic group being unsubstituted or substituted with an alkyl group having from one to four carbon atoms and the N-oxides thereof;

wherein x is tetrazole;

wherein R₄ is a straight or branched hydrocarbon chain having from 12 to 20 carbon atoms and is saturated or is unsaturated and has one double bond or has two nonadjacent double bonds or is alkyl substituted with trifluoromethyl; and

R₄ is in the two position of the tetrazole ring and the side chain, ##STR14## is attached to the carbon atom of the tetrazole ring or a pharmaceutically acceptable salt or individual enantiomeric isomer thereof.

2. A compound of claim 1 wherein n is 0.

3. A compound of claim 1 wherein n is 1 or 2.

4. A compound of claim 1 wherein R₄ is a saturated hydrocarbon chain and has from 12 to 18 carbon atoms.

5. A compound of claim 4 wherein R₁ is substituted phenyl.

6. A compound of claim 1 wherein R₃ is 2-, 3-, or 4-pyridyl.

7. A compound of claim 1 wherein R₁ is 2,6-(1-methylethyl)phenyl or 2,4,6-trimethoxyphenyl.

8. A compound of claim 1 which is (±

)-2-dodecyl-α

-(2-pyridyl)-N-(2,4,6-trimethoxyphenyl)-2H-tetrazole-5-acetamide, or

(±

)-N- 2,6-Bis(1-methylethyl)phenyl!-2-dodecyl-α

-2-pyridinyl-2H-tetrazole-5-acetamide.

9. A pharmaceutical composition useful for treating hypercholesterolemia or atherosclerosis in a mammal comprising an effective amount of a compound of claim 1 together with a pharmaceutically acceptable carrier.

10. A method of treating hypercholesterolemia or atherosclerosis in a patent in need thereof which comprises administering to said patient a compound according to claim 1.