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Hydroxy-substituted azetidinone compounds useful as hypocholesterolemic agents

a technology of azetidinone and hydroxysubstituted azetidinone, which is applied in the field of hydroxysubstituted azetidinone compounds useful as hypocholesterolemic agents, can solve the problems of significant elevation of the risk of chd, achieve the effects of reducing plasma cholesterol, preventing atherosclerosis, and lowering serum cholesterol levels

Inactive Publication Date: 2011-06-14
MERCK SHARP & DOHME CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

A total cholesterol level in excess of 225-250 mg / dl is associated with significant elevation of risk of CHD.

Method used

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  • Hydroxy-substituted azetidinone compounds useful as hypocholesterolemic agents
  • Hydroxy-substituted azetidinone compounds useful as hypocholesterolemic agents
  • Hydroxy-substituted azetidinone compounds useful as hypocholesterolemic agents

Examples

Experimental program
Comparison scheme
Effect test

example 2

[0109]

[0110]To a solution of compound A from Example 1 (0.5 g, 1.3 mmol) in anhydrous pyridine (2.7 ml), add acetic anhydride (0.63 ml, 6.7 mmol). Stir for 16 h, dilute with CH2Cl2 and wash 3× with 1N HCl 1× with NaCl (sat'd) and 1× with water. Concentrate the organic layer to dryness and crystallize the residue from EtOAc to obtain the title compound (0.46 g), mp 167°-169° C.; IR 1745 cm-1; EI (M+) 415; J=5.9 Hz.

example 3

[0111]

[0112]Freshly prepare a solution of lithium isopropylcyclohexylamide (LICA) by adding n-butyllithium (2.84 mL of a 1.6M solution) to 5 a solution of isopropylcyclohexylamine (0.75 mL) in THF (100 mL) at −78° C. Dissolve N-phenyl-4-(4-methoxyphenyl)-2-azetidinone (1.0 g) in THF (8 mL) and slowly add to the LICA solution at −78° C. After stirring for 20 min, add hydrocinnamaldehyde (0.54 g) and stir the reaction mixture at −78° C. for 4 h. Quench the reaction with 10% KHSO4 and extract the product with EtOAc. Separate the organic layer, wash with water and NaCl (sat'd). Concentrate the extract and purify the resultant residue on a silica gel 60 column, eluting with EtOAc:hexane (15:85) to obtain 1.15 g of product as a mixture of diastereomers. Separate the diastereomers by HPLC on a silica gel column to give three diastereomers 3A, 3B and 3C:

[0113]

3A1H in CDCl3: 7.32-7.18(m, 11H); 708-6.99 (m, 1H); 6.89(d, J = 9 Hz, 2H); 4.80(d, J = 2.4 Hz, 1H); 4.10-4.00(m, 1H); 3.79(s. 3H); 3....

example 4

[0129]

Method 1:

[0130]Step 1) To a refluxing solution of of 4-methoxyberizylidene anisidine (10.0 g, 41.5 mmol) and tributylamine (20.8 ml. 87 mmol) in toluene (100 ml), add 5-bromovaleroyl chloride (8.5 g, 43, mmol) in toluene (20 ml) dropwise over 2 h. Stir the reaction mixture at 80° C. for 12 h, cool to room temperature, wash 3× with 1 N HCl, 1× with water and dry the organic layer over MgSO4. Purify by silica gel chromatography, eluting with ethyl acetate:hexane (4:1) to obtain 5.1 g of (3R, 4S)-1,4-bis(4-methoxyphenyl)-3-(3-bromoproyl)-2-azetidinone (relative stereochemistry), mp 70°-73° C., E1 (M+) 404; J=2.3 Hz.

[0131]Step 2) To a solution of the product of step 1 (5.1 g, 12.6 mmol) in (CH3)2SO (20 ml), add (CH3)3N(O) (2.39 g, 31.9 mmol). Heat the mixture at 60° C. for 3 h, cool to room temperature, dilute with EtOAc, and wash 3× with water. Combine the aqueous fractions and extract with EtOAc. Combine the organic fractions and concentrate. Purify the crude product by silica g...

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Abstract

Hydroxy-substituted azetidinone hypocholesterolemic agents of the formulaor a pharmaceutically acceptable salt thereof, wherein:Ar1 and Ar2 are aryl or R4-substituted aryl;Ar3 is aryl or R5-substituted aryl;X, Y and Z are —CH2—, —CH(lower alkyl)— or —C(dilower alkyl)—;R and R2 are —OR6, —O(CO)R6, —O(CO)OR9 or —O(CO)NR6R7;R1 and R3 are H or lower alkyl;q is 0 or 1; r is 0 or 1; m, n and p are 0-4; provided that at least one of q and r is 1, and the sum of m, n, p, q and r is 1-6; and provided that when p is O and r is 1, the sum of m, q and n is 1-5;R4 is selected from lower alkyl, R5, —CF3, —CN, —NO2 and halogen R5 is selected from —OR6, —O(CO)R6, —O(CO)OR9, —O(CH2)1-5OR6, —O(CO)NR6R7, —NR6R7, —NR6(CO)R7, —NR6(CO)OR9, —NR6(CO)NR7R8, —NR6SO2R9, —COOR6, —CONR6R7, —COR6, —SO2NR6R7, S(O)0-2R9, —O(CH2)1-10—COOR6, —O(CH2)1-10CON6R7, —(lower alkylene)COOR6 and —CH═CH—COOR6;R6, R7 and R8 are H, lower alkyl or aryl-substituted IcR9 is lower alkyl, aryl or aryl-substituted lower alkyl;are disclosed, as well as a method of lowering serum cholesterol by administering said compounds, alone or in combination with a cholesterol biosynthesis inhibitor, pharmaceutical compositions containing them; and a process for preparing them.

Description

[0001]The present application is the United States national application corresponding to International Application No. PCT / US94 / 10099, filed Sep. 14, 1994 and designating the United States, which PCT application is in turn a continuation-in-part of U.S. application Ser. No. 08 / 257593, filed Jun. 9, 1994, U.S. Pat. No. 5,631,365, which is a continuation-in-part of U.S. application Ser. No. 08 / 102,440, filed Sep. 21, 1993, abandoned.BACKGROUND OF THE INVENTION[0002]The present invention rotates to hydroxy-substituted azetidinones useful as hypocholesterolemic agents in the treatment prevention of atherosclerosis, and to the combination of a hydroxy-substituted azetidinone of this invention and a cholesterol bioxynthesis inhibitor for the treatment and prevention of atherosclerosis. The invention also relates to a process for preparing hydroxy-substituted azetidinones.[0003]Atherosclerotic coronary heart disease (CHD) represents the major cause for death and cardiovascular morbidity in...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): C07D205/08A61P9/10A61P3/06A61K31/395A61K31/21A61K31/35A61K31/397A61K31/40A61P7/00
CPCC07D205/08Y02P20/55A61K45/06A61K9/2018A61K9/4858A61K31/21A61K31/35A61K31/395A61K31/40A61P3/06A61P7/00A61P9/10A61K2300/00
Inventor ROSENBLUM, STUART B.DUGAR, SUNDEEPBURNETT, DUANE A.CLADER, JOHN W.MCKITTRICK, BRIAN A.
Owner MERCK SHARP & DOHME CORP
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