CN101297969A

CN101297969A - Combinations of the peroxisome proliferator-activated receptor (PPAR) activator fenofibrate with sterol absorption inhibitor ezetimibe for vascular indications

Info

Publication number: CN101297969A
Application number: CNA2008100956414A
Authority: CN
Inventors: T·科索格劳; H·R·戴维斯; G·J·B·皮卡德; W·-K·P·曹
Original assignee: Schering Corp
Current assignee: Okanon LLC
Priority date: 2001-01-26
Filing date: 2002-01-25
Publication date: 2008-11-05
Anticipated expiration: 2022-01-25
Also published as: ZA200305692B; CN1915429B; CN1915429A; ECSP034703A; ECSP034702A; CN101297969B; ECSP034704A; ZA200305694B

Abstract

The present invention provides compositions, therapeutic combinations and methods including: (a) at least one peroxisome proliferator-activated receptor activator; and (b) at least one substituted azetidinone or substituted beta-lactam sterol absorption inhibitor which can be useful for treating vascular conditions, diabetes, obesity and lowering plasma levels of sterols.

Description

The combination medicine of peroxisome proliferation-activated receptors (PPAR) activator and sterol absorption inhibitor and for the treatment of blood vessel indication

The application is dividing an application of following application: application number: 02807208.1 (PCT/US02/02009); The applying date: on January 25th, 2002; Denomination of invention: " the combination medicine of peroxisome proliferation-activated receptors (PPAR) activator and sterol absorption inhibitor and for the treatment of blood vessel indication ".

The mutual reference of related application

The application requires the U.S. Provisional Patent Application serial number 60/264 of submission on January 26 calendar year 2001,396 and calendar year 2001 the U.S. Provisional Patent Application serial number 60/323 submitted to of JIUYUE 21 days, 839 priority, and by reference it is attached among the application as a reference.

Invention field

The present invention relates to be used for the treatment of compositions mammal blood vessel angiopathy for example relevant and lipidemia disease, that contain peroxisome proliferation-activated receptors (PPAR) activator and some sterol absorption inhibitor and therapeutic combination medicine (combination) with atherosclerosis, hypercholesterolemia and other angiopathy with the lipidemia disease.

Background of invention

In the Western countries, coronary atherosclerotic heart disease (CHD) is to cause main cause dead and the angiopathy morbidity.Risk factor for coronary atherosclerotic heart disease comprises hypertension, diabetes, family history, male gender, smoking and serum cholesterol.Total cholesterol level surpasses the then dangerous obviously increase of CHD of 225-250mg/dl.

Cholesteryl ester is the main component and the main storage form of cholesterol in arterial wall cell of atheromatous plaque.The formation of cholesteryl ester also is the step that dietary cholesterol absorbs at enteral.Therefore, suppress the formation of cholesteryl ester and reduce the progress that serum cholesterol can suppress atheromatous plaque formation, reduce the gathering of cholesteryl ester in arterial wall and the intestinal absorption of blocking-up dietary cholesterol.

The catabolism that the adjusting of whole body cholesterol stable state relates to the adjusting of dietary cholesterol and cholesterol biosynthesis, the biosynthetic adjusting of bile acid and contains the plasma lipoprotein of cholesterol in mammal and animal body.Liver is to be responsible for cholesterol biosynthesis and catabolic major organs, and therefore, blood plasma cholesterol level is a main decisive.Liver is place synthetic and secretion very low density lipoprotein (VLDL) (VLDL), and very low density lipoprotein (VLDL) metabolism in circulation subsequently is low density lipoprotein, LDL (LDL).LDL is that mainly to have the raising of the lipoprotein of cholesterol and its concentration in the blood plasma relevant with atherosclerotic increase.In any case when the intestinal cholesterol absorption reduced, less cholesterol was transported to liver.The result of described effect is the liver removing that reduces the generation of liver lipoprotein (VLDL) and increase plasma cholesterol (most of LDL of being).Therefore, the net effect of inhibition intestinal cholesterol absorption is to reduce cholesterol levels in the blood plasma.

Shellfish acid (fibric acid) derivant (" shellfish special class (fibrates) ") has been used for triglyceride reducing, has moderately reduced LDL level and increase the HDL level as fenofibrate, gemfibrozil and clofibrate.Known that also the shellfish acid derivative is the peroxisome proliferator-activated receptor alpha activator.

U.S. Patent number 5,767,115,5,624,920,5,668,990,5,656,624 and 5,688,787 disclose the azetidinone chemical compound of hydroxyl replacement and the 'beta '-lactam compounds of replacement respectively, and these chemical compounds are used for cholesterol reducing and/or suppress the formation that the mammal arterial wall contains the speckle of cholesterol.U.S. Patent number 5,846,966 and 5,661,145 'beta '-lactam compounds that disclose azetidinone chemical compound that hydroxyl replaces or replacement respectively combine with HMG CoA reductase inhibitor and to prevent or to treat atherosclerosis and reduction blood plasma sterol levels.

PCT number of patent application WO 00/38725 discloses various cardiovascular treatment combination medicines, comprises with shellfish acid derivative, nicotinic acid derivates, microsomal triglyceride transfer protein inhibitor, sterol absorbing antagonist, plant sterol, stanol (stanol), hypotensive agent or bonded ileal bile acid transfer inhibitor of bile acid intercalating agent or cetp inhibitors.

U.S. Patent number 5,698,527 disclose the lumistane ketone derivatives by the disaccharide replacement as cholesterol absorption inhibitor uses separately or other pravastatin that is used for the treatment of hypercholesterolemia and relevant disease is used in combination with some.

Although obtaining progress in treatment aspect the angiopathy at present, still exist in this area to improved chemical compound with for the demand of the Therapeutic Method of hyperlipemia, atherosclerosis and other angiopathy.

Summary of the invention

In one embodiment, the invention provides the compositions that contains following composition: (a) at least a peroxisome proliferation-activated receptors activator; (b) at least a sterol absorption inhibitor by formula (I) representative:

Or its isomer, or the pharmaceutically acceptable salt or the solvate of formula (I) chemical compound or its isomer, or the prodrug of formula (I) chemical compound or its isomer, salt or solvate,

Wherein in following formula (I):

Ar ¹And Ar ²Independently be selected from aryl and R ⁴The aryl of-replacement;

Ar ³Be aryl or R ⁵The aryl of-replacement;

X, Y and Z independently are selected from-CH ₂-,-CH (low alkyl group)-and-C (two low alkyl groups)-;

R and R ²Independently be selected from-OR ⁶,-O (CO) R ⁶,-O (CO) OR ⁹With-O (CO) NR ⁶R ⁷

R ¹And R ³Independently be selected from hydrogen, low alkyl group and aryl;

Q is 0 or 1;

R is 0 or 1;

M, n and p independently are selected from 0,1,2,3 or 4; Condition is that one of q and r are 1 at least, and the summation of m, n, p, q and r is 1,2,3,4,5 or 6; With condition be when p be 0 and r when being 1, the summation of m, q and n is 1,2,3,4 or 5;

R ⁴Be 1-5 substituent group that independently is selected from following group: low alkyl group ,-OR ⁶,-O (CO) R ⁶,-O (CO) OR ⁹,-O (CH ₂) _1-5OR ⁶,-O (CO) NR ⁶R ⁷,-NR ⁶R ⁷,-NR ⁶(CO) R ⁷,-NR ⁶(CO) OR ⁹,-NR ⁶(CO) NR ⁷R ⁸,-NR ⁶SO ₂R ⁹,-COOR ⁶,-CONR ⁶R ⁷,-COR ⁶,-SO ₂NR ⁶R ⁷, S (O) _0-2R ⁹,-O (CH ₂) _1-10-COOR ⁶,-O (CH ₂) _1-10CONR ⁶R ⁷,-(low-grade alkylidene) COOR ⁶,-CH=CH-COOR ⁶,-CF ₃,-CN ,-NO ₂And halogen;

R ⁵Be 1-5 the substituent group that independently is selected from following group :-OR ⁶,-O (CO) R ⁶,-O (CO) OR ⁹,-O (CH ₂) _1-5OR ⁶,-O (CO) NR ⁶R ⁷,-NR ⁶R ⁷,-NR ⁶(CO) R ⁷,-NR ⁶(CO) OR ⁹,-NR ⁶(CO) NR ⁷R ⁸,-NR ⁶SO ₂R ⁹,-COOR ⁶,-CONR ⁶R ⁷,-COR ⁶,-SO ₂NR ⁶R ⁷, S (O) _0-2R ⁹,-O (CH ₂) _1-10-COOR ⁶,-O (CH ₂) _1-10CONR ⁶R ⁷,-(low-grade alkylidene) COOR ⁶With-CH=CH-COOR ⁶

R ⁶, R ⁷And R ⁸Independently be selected from the low alkyl group that hydrogen, low alkyl group, aryl and aryl replace; With

R ⁹It is the low alkyl group that low alkyl group, aryl or aryl replace.

In another embodiment, the invention provides the compositions that contains following composition: (a) at least a shellfish acid derivative; (b) by chemical compound with following formula (II) representative:

Or its pharmaceutically acceptable salt or solvate, or the prodrug of formula (II) compound or its salt or solvate.

In another embodiment, the invention provides the compositions that contains following composition: (a) at least a peroxisome proliferation-activated receptors activator; (b) at least a sterol absorption inhibitor by formula (III) representative:

Or its isomer, or the pharmaceutically acceptable salt or the solvate of formula (III) chemical compound or its isomer, or the prodrug of formula (III) chemical compound or its isomer, salt or solvate, wherein in following formula (III):

Ar ¹Be R ³The aryl of-replacement; Ar ²Be R ⁴The aryl of-replacement; Ar ³Be R ⁵The aryl of-replacement;

Y and Z independently are selected from-CH ₂-,-CH (low alkyl group)-and-C (two low alkyl groups)-;

A is selected from-O-,-S-,-S (O)-or-S (O) ₂-;

R ¹Be selected from-OR ⁶,-O (CO) R ⁶,-O (CO) OR ⁹With-O (CO) NR ⁶R ⁷R ²Be selected from hydrogen, low alkyl group and aryl; Perhaps R ¹And R ²Be together=O;

Q is 1,2 or 3;

P is 0,1,2,3 or 4;

R ⁵Be 1-3 the substituent group that independently is selected from following group :-OR ⁶,-O (CO) R ⁶,-O (CO) OR ⁹,-O (CH ₂) _1-5OR ⁹,-O (CO) NR ⁶R ⁷,-NR ⁶R ⁷,-NR ⁶(CO) R ⁷,-NR ⁶(CO) OR ⁹,-NR ⁶(CO) NR ⁷R ⁸,-NR ⁶SO ₂-low alkyl group ,-NR ⁶SO ₂-aryl ,-CONR ⁶R ⁷,-COR ⁶,-SO ₂NR ⁶R ⁷, S (O) _0-2-alkyl, S (O) _0-2-aryl ,-O (CH ₂) _1-10-COOR ⁶,-O (CH ₂) _1-10-CONR ⁶R ⁷, neighbour-halogeno-group ,-halogeno-group, neighbour-low alkyl group ,-low alkyl group ,-(low-grade alkylidene)-COOR ⁶With-CH=CH-COOR ⁶

R ³And R ⁴Independent is 1-3 the substituent group that independently is selected from following group: R ⁵, hydrogen, right-low alkyl group, aryl ,-NO ₂,-CF ₃With right-halogeno-group;

R ⁹It is the low alkyl group that low alkyl group, aryl or aryl replace.

In another embodiment, the invention provides the compositions that contains following composition: (a) at least a peroxisome proliferation-activated receptors activator; (b) at least a sterol absorption inhibitor by formula (IV) representative:

Or its isomer, or the pharmaceutically acceptable salt or the solvate of formula (IV) chemical compound or its isomer, or the prodrug of formula (IV) chemical compound or its isomer, salt or solvate, wherein in following formula (IV):

A is selected from R ²The Heterocyclylalkyl, the R that replace ²The heteroaryl, the R that replace ²The benzo-fused Heterocyclylalkyl and the R that replace ²The benzo-fused heteroaryl that replaces;

Ar ¹Be aryl or R ³The aryl of-replacement;

Ar ²Be aryl or R ⁴The aryl of-replacement;

Q is a key, or forms the volution group with the 3-position ring carbon atom of azetidinone

With

R ¹Be selected from following group :-(CH ₂) _q-, wherein q is 2-6, condition is that q also can be 0 or 1 when Q forms volution;

-(CH ₂) _e-G-(CH ₂) _r-, wherein G is-O-,-C (O)-, phenylene ,-NR ⁸-or-S (O) _0-2-, e is that 0-5 and r are 0-5, condition is that the summation of e and r is 1-6;

-(C ₂-C ₆Alkenylene)-; With

-(CH ₂) _f-V-(CH ₂) _g-, wherein V is C ₃-C ₆Be cycloalkylidene, f is that 1-5 and g are 0-5, and condition is that the summation of f and g is 1-6;

R ⁵Be selected from:

Or

R ⁶And R ⁷Independently be selected from-CH ₂-,-CH (C ₁-C ₆Alkyl)-,-C (two-(C ₁-C ₆) alkyl) ,-CH=CH-and-C (C ₁-C ₆Alkyl)=CH-; Or R ⁵With adjacent R ⁶Together or R ⁵With adjacent R ⁷Together formation-CH=CH-or-CH=C (C ₁-C ₆Alkyl)-group;

A and b independently are 0,1,2 or 3, and condition is both and not all is 0; Condition is to work as R ⁶Be-CH=CH-or-C (C ₁-C ₆Alkyl)=during CH-, a is 1; Condition is to work as R ⁷Be-CH=CH-or-C (C ₁-C ₆Alkyl)=during CH-, b is 1; Condition is when a is 2 or 3, R ⁶Can be identical or different; And condition is when b is 2 or 3, R ⁷Can be identical or inequality;

And when Q is a key, R ¹Also can be selected from:

Or

Wherein M be-O-,-S-,-S (O)-or-S (O) ₂-;

X, Y and Z independently are selected from-CH ₂-,-CH (C ₁-C ₆Alkyl)-and-C (two-(C ₁-C ₆) alkyl);

R ¹⁰And R ¹²Independently be selected from-OR ¹⁴,-O (CO) R ¹⁴,-O (CO) OR ¹⁶With-O (CO) NR ¹⁴R ¹⁵

R ¹¹And R ¹³Independently be selected from hydrogen, (C ₁-C ₆) alkyl and aryl; Or R ¹⁰And R ¹¹Be together=O, or R ¹²And R ¹³Be together=O;

D is 1,2 or 3;

H is 0,1,2,3 or 4;

S is 0 or 1; T is 0 or 1; M, n and p independently are 0-4; Condition be s and t at least one be 1, the summation of m, n, p, s and t is 1-6; Condition be when p be 0 and t when being 1, the summation of m, s and n is 1-5; Condition be when p be 0 and s when being 1, the summation of m, t and n is 1-5;

V is 0 or 1;

J and k independently are 1-5, and condition is that the summation of j, k and v is 1-5;

R ²Be 1-3 the substituent group on ring carbon atom that is selected from following group: hydrogen, (C ₁-C ₁₀) alkyl, (C ₂-C ₁₀) alkenyl, (C ₂-C ₁₀) alkynyl, (C ₃-C ₆) cycloalkyl, (C ₃-C ₆) cycloalkenyl group, R ¹⁷Aryl, the R of-replacement ¹⁷Benzyl, the R of-replacement ¹⁷Benzyloxy, the R of-replacement ¹⁷-replace aryloxy group, halogeno-group ,-NR ¹⁴R ¹⁵, NR ¹⁴R ¹⁵(C ₁-C ₆Alkylidene)-, NR ¹⁴R ¹⁵C (O) (C ₁-C ₆Alkylidene)-,-NHC (O) R ¹⁶, OH, C ₁-C ₆Alkoxyl ,-OC (O) R ¹⁶,-COR ¹⁴, hydroxyl (C ₁-C ₆) alkyl, (C ₁-C ₆) alkoxyl (C ₁-C ₆) alkyl, NO ₂,-S (O) _0-2R ¹⁶,-SO ₂NR ¹⁴R ¹⁵With-(C ₁-C ₆Alkylidene) COOR ¹⁴Work as R ²When being the substituent group on heterocycloalkyl ring, R ²As defined above, or=O or

Work as R ²When being the substituent group on commutable theheterocyclic nitrogen atom, it is hydrogen, (C ₁-C ₆) alkyl, aryl, (C ₁-C ₆) alkoxyl, aryloxy group, (C ₁-C ₆) alkyl-carbonyl, aryl carbonyl, hydroxyl ,-(CH ₂) _1-6CONR ¹⁸R ¹⁸,

Or

Wherein J be-O-,-NH-, NR ¹⁸-or-CH ₂-;

R ³And R ⁴Independently be selected from 1-3 substituent group that independently is selected from following group: (C ₁-C ₆) alkyl ,-OR ¹⁴,-O (CO) R ¹⁴,-O (CO) OR ¹⁶,-O (CH ₂) _1-5OR ¹⁴,-O (CO) NR ¹⁴R ¹⁵,-NR ¹⁴R ¹⁵,-NR ¹⁴(CO) R ¹⁵,-NR ¹⁴(CO) OR ¹⁶,-NR ¹⁴(CO) NR ¹⁵R ¹⁹,-NR ¹⁴SO ₂R ¹⁶,-COOR ¹⁴,-CONR ¹⁴R ¹⁵,-COR ¹⁴,-SO ₂NR ¹⁴R ¹⁵, S (O) _0-2R ¹⁶,-O (CH ₂) _1-10-COOR ¹⁴,-O (CH ₂) _1-10CONR ¹⁴R ¹⁵,-(C ₁-C ₆Alkylidene) COOR ¹⁴,-CH=CH-COOR ¹⁴,-CF ₃,-CN ,-NO ₂And halogen;

R ⁸Be hydrogen, (C ₁-C ₆) alkyl, aryl (C ₁-C ₆) alkyl ,-C (O) R ¹⁴Or-COOR ¹⁴

R ⁹And R ¹⁷Independent is 1-3 group that independently is selected from following group: hydrogen, (C ₁-C ₆) alkyl, (C ₁-C ₆) alkoxyl ,-COOH, NO ₂,-NR ¹⁴R ¹⁵, OH and halogeno-group;

R ¹⁴And R ¹⁵Independently be selected from hydrogen, (C ₁-C ₆) (the C that replaces of alkyl, aryl and aryl ₁-C ₆) alkyl;

R ¹⁶Be (C ₁-C ₆) alkyl, aryl or R ¹⁷The aryl that replaces;

R ¹⁸Be hydrogen or (C ₁-C ₆) alkyl; With

R ¹⁹Be hydrogen, hydroxyl or (C ₁-C ₆) alkoxyl.

In another embodiment, the invention provides the compositions that contains following composition: (a) at least a peroxisome proliferation-activated receptors activator; (b) at least a sterol absorption inhibitor by the formula V representative:

Or its isomer, or the pharmaceutically acceptable salt of formula V chemical compound or its isomer or solvate, or the prodrug of formula V chemical compound or its isomer, salt or solvate, wherein in above formula V:

Ar ¹Be aryl, R ¹⁰The aryl or the heteroaryl of-replacement;

Ar ²Be aryl or R ⁴The aryl of-replacement;

Ar ³Be aryl or R ⁵The aryl of-replacement;

X and Y independently are selected from-CH ₂-,-CH (low alkyl group)-and-C (two low alkyl groups)-;

R is-OR ⁶-,-O (CO) R ⁶,-O (CO) OR ⁹Or-O (CO) NR ⁶R ⁷R ¹Be hydrogen, low alkyl group or aryl; Or R and R ¹Be together=O;

Q is 0 or 1;

R is 0,1 or 2;

M and n independently are 0,1,2,3,4 or 5; Condition is that the summation of m, n and q is 1,2,3,4 or 5;

R ⁴Be 1-5 substituent group that independently is selected from following group: low alkyl group ,-OR ⁶,-O (CO) R ⁶,-O (CO) OR ⁹,-O (CH ₂) _1-5OR ⁶,-O (CO) NR ⁶R ⁷,-NR ⁶R ⁷,-NR ⁶(CO) R ⁷,-NR ⁶(CO) OR ⁹,-NR ⁶(CO) NR ⁷R ⁸,-NR ⁶SO ₂R ⁹,-COOR ⁶,-CONR ⁶R ⁷,-COR ⁶,-SO ₂NR ⁶R ⁷, S (O) _0-2R ⁹,-O (CH ₂) _1-10-COOR ⁶,-O (CH ₂) _1-10CONR ⁶R ⁷-(low-grade alkylidene) COOR ⁶With-CH=CH-COOR ⁶

R ⁵Be 1-5 the substituent group that independently is selected from following group :-OR ⁶,-O (CO) R ⁶,-O (CO) OR ⁹,-O (CH ₂) _1-5OR ⁶,-O (CO) NR ⁶R ⁷,-NR ⁶R ⁷,-NR ⁶(CO) R ⁷,-NR ⁶(CO) OR ⁹,-NR ⁶(CO) NR ⁷R ⁸,-NR ⁶SO ₂R ⁹,-COOR ⁶,-CONR ⁶R ⁷,-COR ⁶,-SO ₂NR ⁶R ⁷, S (O) _0-2R ⁹,-O (CH ₂) _1-10-COOR ⁶-O (CH ₂) _1-10-CONR ⁶R ⁷,-CF ₃,-CN ,-NO ₂, halogen ,-(low-grade alkylidene) COOR ⁶With-CH=CH-COOR ⁶

R ⁶, R ⁷And R ⁸Independently be selected from the low alkyl group that hydrogen, low alkyl group, aryl and aryl replace;

R ⁹It is the low alkyl group that low alkyl group, aryl or aryl replace; With

R ¹⁰Be 1-5 substituent group that independently is selected from following group: low alkyl group ,-OR ⁶,-O (CO) R ⁶,-O (CO) OR ⁹,-O (CH ₂) _1-5OR ⁶,-O (CO) NR ⁶R ⁷,-NR ⁶R ⁷,-NR ⁶(CO) R ⁷,-NR ⁶(CO) OR ⁹,-NR ⁶(CO) NR ⁷R ⁸,-NR ⁶SO ₂R ⁹,-COOR ⁶,-CONR ⁶R ⁷,-COR ⁶,-SO ₂NR ⁶R ⁷,-S (O) _0-2R ⁹,-O (CH ₂) _1-10-COOR ⁶,-O (CH ₂) _1-10-CONR ⁶R ⁷,-CF ₃,-CN ,-NO ₂And halogen.

In another embodiment, the invention provides the compositions that contains following composition: (a) at least a peroxisome proliferation-activated receptors activator; (b) at least a sterol absorption inhibitor by formula (VI) representative:

Or its isomer, or the pharmaceutically acceptable salt or the solvate of formula (VI) chemical compound or its isomer, or the prodrug of formula (VI) chemical compound or its isomer, salt or solvate, wherein in following formula (VI):

R ₁Be

Or

R ₂And R ₃Independently be selected from :-CH ₂-,-CH (low alkyl group)-,-C (two-low alkyl group)-,-CH=CH-and-C (low alkyl group)=CH-; Or R ₁With adjacent R ₂Together or R ₁With adjacent R ₃Together formation-CH=CH-or-CH=C (low alkyl group)-group;

U and v independently are 0,1,2 or 3, and condition is both and not all is 0; Condition is to work as R ₂Be-CH=CH-or-during C (low alkyl group)=CH-, v is 1; Condition is to work as R ₃Be-CH=CH-or-during C (low alkyl group)=CH-, u is 1; Condition is when v is 2 or 3, R ₂Can be identical or different; And condition is when u is 2 or 3, R ₃Can be identical or inequality;

R ₄Be selected from B-(CH ₂) _mC (O)-, wherein m is 0,1,2,3,4 or 5; B-(CH ₂) _q-, wherein q is 0,1,2,3,4,5 or 6; B-(CH ₂) _e-Z-(CH ₂) _r-, wherein Z be-O-,-C (O)-, phenylene ,-N (R ₈)-or-S (O) _0-2-, e be 0,1,2,3,4 or 5 and r be 0,1,2,3,4 or 5, condition is that the summation of e and r is 0,1,2,3,4,5 or 6; B-(C ₂-C ₆Alkenylene)-; B-(C ₄-C ₆Inferior alkadienyl)-; B-(CH ₂) _t-Z-(C ₂-C ₆Alkenylene)-, wherein Z as defined above, wherein t is 0,1,2 or 3, condition is that the summation of t and carbon number is 2,3,4,5 or 6 in the alkenylene chain; B-(CH ₂) _f-V-(CH ₂) _g-, wherein V is C ₃-C ₆The ring cycloalkylidene, f be 1,2,3,4 or 5 and g be 0,1,2,3,4 or 5, condition is that the summation of f and g is 1,2,3,4,5 or 6; B-(CH ₂) _t-V-(C ₂-C ₆Alkenylene)-or B-(C ₂-C ₆Alkenylene)-V-(CH ₂) _t-, wherein V and t as defined above, condition is that the summation of t and carbon number is 2,3,4,5 or 6 in the alkenylene chain;

B-(CH ₂) _a-Z-(CH ₂) _b-V-(CH ₂) _d-, wherein Z and V as defined above, a, b and d independently are 0,1,2,3,4,5 or 6, condition is that the summation of a, b and d is 0,1,2,3,4,5 or 6; Or T-(CH ₂) _s-, wherein T is that cycloalkyl and the s with 3-6 carbon atom is 0,1,2,3,4,5 or 6; Perhaps

R ₁And R ₄Form group together

B is selected from 2, the heteroaryl that 3-indanyl, indenyl, naphthyl, tetralyl, heteroaryl or W-replace, wherein heteroaryl be selected from pyrrole radicals, pyridine radicals, pyrimidine radicals, pyrazinyl, triazine radical, imidazole radicals, thiazolyl, pyrazolyl, thienyl, oxazolyl and furyl with and nitrogenous heteroaryl, N-oxide, or

W is a 1-3 substituent group that independently is selected from following groups: the low alkyl group that is used on ring carbon atom, replacing, hydroxyl low-grade alkyl, lower alkoxy, alkoxyalkyl, alkoxyl alkoxyl, alkoxy carbonyl alkoxyl, (lower alkoxy imino group)-low alkyl group, lower alkane diacyl, low alkyl group lower alkane diacyl, allyloxy ,-CF ₃,-OCF ₃, benzyl, R ₇-benzyl, benzyloxy, R ₇-benzyloxy, phenoxy group, R ₇-phenoxy group, dioxolanyl, NO ₂,-N (R ₈) (R ₉), N (R ₈) (R ₉)-low-grade alkylidene, N (R ₈) (R ₉)-low-grade alkylidene oxygen base, OH, halogeno-group ,-CN ,-N ₃,-NHC (O) OR ₁₀,-NHC (O) R ₁₀, R ₁₁O ₂SNH-, (R ₁₁O ₂S) ₂N-,-S (O) ₂NH ₂,-S (O) _0-2R ₈, tert-butyl group dimethyl-siloxy methyl ,-C (O) R ₁₂,-COOR ₁₉,-CON (R ₈) (R ₉) ,-CH=CHC (O) R ₁₂,-low-grade alkylidene-C (O) R ₁₂, R ₁₀C (O) (low-grade alkylidene oxygen base)-, N (R ₈) (R ₉) C (O) (low-grade alkylidene oxygen base)-and

And the substituent group (when having substituent group) on the substituted hetero-aromatic ring nitrogen-atoms, they be selected from low alkyl group, lower alkoxy ,-C (O) OR ₁₀,-C (O) R ₁₀, OH, N (R ₈) (R ₉)-low-grade alkylidene, N (R ₈) (R ₉)-low-grade alkylidene oxygen base ,-S (O) ₂NH ₂And 2-(trimethyl silyl)-ethoxyl methyl;

R ₇Be 1-3 independently be selected from low alkyl group, lower alkoxy ,-COOH, NO ₂,-N (R ₈) (R ₉), the group of OH and halogeno-group;

R ₈And R ₉Independently be selected from H or low alkyl group;

R ₁₀Be selected from low alkyl group, phenyl, R ₇-phenyl, benzyl or R ₇-benzyl;

R ₁₁Be selected from OH, low alkyl group, phenyl, benzyl, R ₇-phenyl or R ₇-benzyl;

R ₁₂Be selected from H, OH, alkoxyl, phenoxy group, benzyloxy,

-N (R ₈) (R ₉), low alkyl group, phenyl or R ₇-phenyl;

R ₁₃Be selected from-O-,-CH ₂-,-NH-,-N (low alkyl group)-or-NC (O) R ₁₉

R ₁₅, R ₁₆And R ₁₇The group that independently is selected from H and defines for W; Perhaps R ₁₅Be hydrogen, R ₁₆And R ₁₇Form dioxolanyl with the adjacent carbon atom that they connected;

R ₁₉Be H, low alkyl group, phenyl or phenyl lower alkyl; With

R ₂₀And R ₂₁Independently be selected from the naphthyl, 2 that phenyl, naphthyl, W-that phenyl, W replace replace, 3-indanyl, indenyl, tetralyl, benzo dioxolyl, heteroaryl, the heteroaryl that W-replaces, benzo-fused heteroaryl, benzo-fused heteroaryl and the cyclopropyl that W-replaces, wherein heteroaryl as defined above.

In another embodiment, the invention provides the compositions that contains following composition: (a) at least a peroxisome proliferation-activated receptors activator; (b) at least a sterol absorption inhibitor by formula (VII) representative:

Or its isomer, or the pharmaceutically acceptable salt or the solvate of formula (VII) chemical compound or its isomer, or the prodrug of formula (VII) chemical compound or its isomer, salt or solvate, wherein in following formula (VII):

A is-CH=CH-,-C ≡ C-or-(CH ₂) _P-wherein P is 0,1 or 2;

B is

E is C ₁₀-C ₂₀Alkyl or-C (O)-(C ₉-C ₁₉)-alkyl, wherein said alkyl are straight or branched, saturated or contain one or more pairs of keys;

R is hydrogen, straight or branched, saturated or contain the C of one or more pairs of keys ₁-C ₁₅Alkyl, or B-is (CH ₂) _r, wherein r is 0,1,2 or 3;

R ₁, R ₂And R ₃Independently be selected from hydrogen, low alkyl group, lower alkoxy, carboxyl, NO ₂, NH ₂, OH, halogeno-group, low-grade alkyl amino, two elementary alkyl amido ,-NHC (O) OR ₅, R ₆O ₂SNH-and-S (O) ₂NH ₂

R ₄Be

Wherein n is 0,1,2 or 3;

R ₅It is low alkyl group; With

R ₆Be the phenyl of OH, low alkyl group, phenyl, benzyl or replacement, wherein said substituent group is 1-3 and independently is selected from low alkyl group, lower alkoxy, carboxyl, NO ₂, NH ₂, OH, halogeno-group, low-grade alkyl amino and two elementary alkyl amido group.

In another embodiment, the invention provides the compositions that contains following composition: (a) at least a peroxisome proliferation-activated receptors activator; (b) at least a sterol absorption inhibitor by formula (VIII) representative:

Or its isomer, or the pharmaceutically acceptable salt or the solvate of formula (VIII) chemical compound or its isomer, or the prodrug of formula (VIII) chemical compound or its isomer, salt or solvate, wherein in following formula (VIII):

R ²⁶Be H or OG ¹

G and G ¹Independently be selected from

With

Condition is to work as R ²⁶When being H or OH, G is not H;

R, R ^aAnd R ^bIndependently be selected from H ,-OH, halogeno-group ,-NH ₂, azido, (C ₁-C ₆) alkoxyl (C ₁-C ₆)-alkoxyl or-W-R ³⁰

W independently is selected from-NH-C (O)-,-O-C (O)-,-O-C (O)-N (R ³¹)-,-NH-C (O)-N (R ³¹)-and-O-C (S)-N (R ³¹)-;

R ²And R ⁶Independently be selected from H, (C ₁-C ₆) alkyl, aryl and aryl (C ₁-C ₆) alkyl;

R ³, R ⁴, R ⁵, R ⁷, R ^3aAnd R ^4aIndependently be selected from H, (C ₁-C ₆) alkyl, aryl (C ₁-C ₆) alkyl ,-C (O)-(C ₁-C ₆) alkyl and-C (O) aryl;

R ³⁰Be selected from R ³²T, the R of-replacement ³²-replace-T-(C ₁-C ₆) alkyl, R ³²-replace-(C ₂-C ₄) alkenyl, R ³²-replace-(C ₁-C ₆) alkyl, R ³²-replace-(C ₃-C ₇) cycloalkyl and R ³²-replace-(C ₃-C ₇) cycloalkyl (C ₁-C ₆) alkyl;

R ³¹Be selected from H and (C ₁-C ₄) alkyl;

T is selected from phenyl, furyl, thienyl, pyrrole radicals, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, benzothiazolyl, thiadiazolyl group, pyrazolyl, imidazole radicals and pyridine radicals;

R ³²Independently be selected from 1-3 and independently be selected from following substituent group: halogeno-group, (C ₁-C ₄) alkyl ,-OH, phenoxy group ,-CF ₃,-NO ₂, (C ₁-C ₄) alkoxyl, methylene-dioxy, oxo base, (C ₁-C ₄) alkyl alkylthio base, (C ₁-C ₄) alkyl sulfinyl, (C ₁-C ₄) alkyl sulphonyl ,-N (CH ₃) ₂-,-C (O)-NH (C ₁-C ₄) alkyl ,-C (O)-N ((C ₁-C ₄) alkyl) ₂,-C (O)-(C ₁-C ₄) alkyl ,-C (O)-(C ₁-C ₄) group of alkoxyl and pyrrolidinyl carbonyl; Perhaps R ³²Be covalent bond, R ³¹With its nitrogen-atoms that is connected and R ³²Form pyrrolidinyl, piperidyl, N-methyl-piperazinyl, indolinyl or morpholinyl, or (C ₁-C ₄) pyrrolidinyl, piperidyl, N-methyl-piperazinyl, indolinyl or the morpholinyl of alkoxy carbonyl-replacement;

Ar ¹Be aryl or R ¹⁰The aryl of-replacement;

Ar ²Be aryl or R ¹¹The aryl of-replacement;

Q is a key, and perhaps the 3-position ring carbon atom with azetidinone forms the spiral group

R ¹Be selected from-(CH ₂) _q-, wherein q is 2-6, condition is that q also can be 0 or 1 when Q forms volution;

-(CH ₂) _e-E-(CH ₂) _r-, wherein E be-O-,-C (O)-, phenylene ,-NR ²²-or-S (O) _0-2, e is 0-5, and r is 0-5, and condition is that the summation of e and r is 1-6;

-(C ₂-C ₆) alkenylene-; With

-(CH ₂) _f-V-(CH ₂) _g-, wherein V is C ₃-C ₆Cycloalkylidene, f are 1-5, and g is 0-5, and condition is that the summation of f and g is 1-6;

R ¹²Be

Or

R ¹³And R ¹⁴Independently be selected from-CH ₂-,-CH (C ₁-C ₆Alkyl)-,-C (two-(C ₁-C ₆) alkyl) ,-CH=CH-and C (C ₁-C ₆Alkyl)=CH-; Perhaps R ¹²With adjacent R ¹³Together or R ¹²With adjacent R ¹⁴Together formation-CH=CH-or-CH=C (C ₁-C ₆Alkyl)-group;

A and b independently are 0,1,2 or 3, and condition is both and not all is 0;

Condition is to work as R ¹³Be-CH=CH-or C (C ₁-C ₆Alkyl)=during CH-, a is 1;

Condition is to work as R ¹⁴Be-CH=CH-or C (C ₁-C ₆Alkyl)=during CH-, b is 1;

Condition is when a is 2 or 3, R ¹³Can be identical or inequality; With

Condition is when b is 2 or 3, R ¹⁴Can be identical or inequality;

And when Q is key, R ¹Also can be

Or

M is-O-,-S-,-S (O)-or-S (O) ₂-;

X, Y and Z independently are selected from-CH ₂-,-CH (C ₁-C ₆) alkyl-and C (two-(C ₁-C ₆) alkyl);

R ¹⁰And R ¹¹Independently be selected from 1-3 and independently be selected from following group: (C ₁-C ₆) alkyl ,-OR ¹⁹,-O (CO) R ¹⁹,-O (CO) OR ²¹,-O (CH ₂) _1-5OR ¹⁹,-O (CO) NR ¹⁹R ²⁰,-NR ¹⁹R ²⁰,-NR ¹⁹(CO) R ²⁰,-NR ¹⁹(CO) OR ²¹,-NR ¹⁹(CO) NR ²⁰R ²⁵,-NR ¹⁹SO ₂R ²¹,-COOR ¹⁹,-CONR ¹⁹R ²⁰,-COR ¹⁹,-SO ₂NR ¹⁹R ²⁰, S (O) _0-2R ²¹,-O (CH ₂) _1-10COOR ¹⁹,-O (CH ₂) _1-10CONR ¹⁹R ²⁰,-(C ₁-C ₆Alkylidene)-COOR ¹⁹,-CH=CH-COOR ¹⁹,-CF ₃,-CN ,-NO ₂And halogen;

R ¹⁵And R ¹⁷Independently be selected from-OR ¹⁹,-O (CO) R ¹⁹,-O (CO) OR ²¹And O (CO) NR ¹⁹R ²⁰

R ¹⁶And R ¹⁸Independently be selected from H, (C ₁-C ₆) alkyl and aryl; Perhaps R ¹⁵And R ¹⁶Be together=O, perhaps R ¹⁷And R ¹⁸Be together=O;

D is 1,2 or 3;

H is 0,1,2,3 or 4;

V is 0 or 1;

And when Q be key and R ¹Be The time, Ar ¹Also can be pyridine radicals, isoxazolyl, furyl, pyrrole radicals, thienyl, imidazole radicals, pyrazolyl, thiazolyl, pyrazinyl, pyrimidine radicals or pyridazinyl;

R ¹⁹And R ²⁰Independently be selected from H, (C ₁-C ₆) (the C of alkyl, aryl and aryl-replacement ₁-C ₆) alkyl;

R ²¹Be (C ₁-C ₆) alkyl, aryl or R ²⁴The aryl of-replacement;

R ²²Be H, (C ₁-C ₆) alkyl, aryl (C ₁-C ₆) alkyl ,-C (O) R ¹⁹Or-COOR ¹⁹

R ²³And R ²⁴Independently be 1-3 and independently be selected from H, (C ₁-C ₆) alkyl, (C ₁-C ₆) alkoxyl ,-COOH, NO ₂,-NR ¹⁹R ²⁰The group of ,-OH and halogeno-group; With

R ²⁵Be H ,-OH or (C ₁-C ₆) alkoxyl.

In another embodiment, the invention provides the compositions that contains following composition: (a) at least a peroxisome proliferation-activated receptors activator; (b) at least a sterol absorption inhibitor by formula (IX) representative:

Or its isomer, or the pharmaceutically acceptable salt or the solvate of formula (IX) chemical compound or its isomer, or the prodrug of formula (IX) chemical compound or its isomer, salt or solvate, wherein in following formula (IX):

R ²⁶Be selected from:

a)OH；

b)OCH ₃；

C) fluorine and

D) chlorine;

R ¹Be selected from following group

,-SO ₃H; Natural and alpha-non-natural amino acid;

R, R ^aAnd R ^bIndependently be selected from H ,-OH, halogeno-group ,-NH ₂, azido, (C ₁-C ₆) alkoxyl (C ₁-C ₆)-alkoxyl and-W-R ³⁰

R ³, R ⁴, R ⁵, R ⁷, R ^3aAnd R ^4aIndependently be selected from H, (C ₁-C ₆) alkyl, aryl (C ₁-C ₆) alkyl ,-C (O) (C ₁-C ₆) alkyl and-C (O) aryl;

R ³⁰Independently be selected from R ³²T, the R of-replacement ³²-replace-T-(C ₁-C ₆) alkyl, R ³²-replace-(C ₂-C ₄) alkenyl, R ³²-replace-(C ₁-C ₆) alkyl, R ³²-replace-(C ₃-C ₇) cycloalkyl and R ³²-replace-(C ₃-C ₇) cycloalkyl (C ₁-C ₆) alkyl;

R ³¹Independently be selected from H and (C ₁-C ₄) alkyl;

R ³²Independently be selected from 1-3 and independently be selected from following substituent group: H, halogeno-group, (C ₁-C ₄) alkyl ,-OH, phenoxy group ,-CF ₃,-NO ₂, (C ₁-C ₄) alkoxyl, methylene-dioxy, oxo base, (C ₁-C ₄) alkyl alkylthio base, (C ₁-C ₄) alkyl sulfinyl, (C ₁-C ₄) alkyl sulphonyl ,-N (CH ₃) ₂-,-C (O)-NH (C ₁-C ₄) alkyl ,-C (O)-N ((C ₁-C ₄) alkyl) ₂,-C (O)-(C ₁-C ₄) alkyl ,-C (O)-(C ₁-C ₄) group of alkoxyl and pyrrolidinyl carbonyl; Perhaps R ³²Be covalent bond and, R ³¹With its nitrogen-atoms that is connected and R ³²Form pyrrolidinyl, piperidyl, N-methyl-piperazinyl, indolinyl or morpholinyl, or (C ₁-C ₄) pyrrolidinyl, piperidyl, N-methyl-piperazinyl, indolinyl or the morpholinyl of alkoxy carbonyl-replacement;

Ar ¹Be aryl or R ¹⁰The aryl of-replacement;

Ar ²Be aryl or R ¹¹The aryl of-replacement;

Q is-(CH ₂) _q-, wherein q is 2-6, perhaps the 3-position ring carbon atom with azetidinone forms the volution group

R ¹²Be

Or

R ¹³And R ¹⁴Independently be selected from-CH ₂-,-CH (C ₁-C ₆Alkyl)-,-C (two-(C ₁-C ₆) alkyl) ,-CH=CH-and C (C ₁-C ₆Alkyl)=CH-; Perhaps R ¹²With adjacent R ¹³Together or R ¹²With adjacent R ¹⁴Together formation-CH=CH-or-CH=C (C ₁-C ₆Alkyl)-;

A and b independently are 0,1,2 or 3, and condition is both and not all is 0; Condition is to work as R ¹³Be-CH=CH-or C (C ₁-C ₆Alkyl)=during CH-, a is 1; Condition is to work as R ¹⁴Be-CH=CH-or C (C ₁-C ₆Alkyl)=during CH-, b is 1; Condition is when a is 2 or 3, R ¹³Can be identical or inequality; With condition be when b is 2 or 3, R ¹⁴Can be identical or inequality;

Ar ¹Also can be pyridine radicals, isoxazolyl, furyl, pyrrole radicals, thienyl, imidazole radicals, pyrazolyl, thiazolyl, pyrazinyl, pyrimidine radicals or pyridazinyl;

R ²¹Be (C ₁-C ₆) alkyl, aryl or R ²⁴The aryl of-replacement;

R ²³And R ²⁴Independently be selected from 1-3 and independently be selected from following group: H, (C ₁-C ₆) alkyl, (C ₁-C ₆) alkoxyl ,-COOH, NO ₂,-NR ¹⁹R ²⁰,-OH and halogeno-group; With

R ²⁵Be H ,-OH or (C ₁-C ₆) alkoxyl.

Therapeutic combination medicine also is provided, and described administration form comprises: (a) the peroxisome proliferation-activated receptors activator of at least a first dosage; (b) at least a second dosage by sterol absorption inhibitor or its isomer with following formula (1-IX) representative, or the pharmaceutically acceptable salt or the solvate of formula (I-IX) chemical compound or its isomer, or the prodrug of formula (I-IX) chemical compound or its isomer, salt or solvate, wherein said first dosage and second dosage are formed treatment or prevention angiopathy, diabetes, obesity together or are reduced the treatment effective dose of mammalian plasma sterol concentration.

The pharmaceutical composition that also can be provided for treating or prevent angiopathy, diabetes, obesity or reduce sterol concentration in the mammalian plasma comprises above-mentioned composition or the therapeutic combination medicine and the pharmaceutically acceptable carrier for the treatment of effective dose.

The method of sterol concentration in treatment or prevention angiopathy, diabetes, obesity or the reduction mammalian plasma also can be provided, comprise the above-mentioned composition or the therapeutic combination medicine of the mammal treatment effective dose that needs this treatment.

Be appreciated that except in operation embodiment, or when pointing out in addition that all are expressed as the data that component, reaction condition etc. use and are modified by term " approximately " in all instances in description and claim.

Detailed Description Of The Invention

Compositions of the present invention and therapeutic combination medicated bag are drawn together the activator of at least a (one or more) peroxisome proliferation-activated receptors (PPAR).These activators are as the agonist of peroxisome proliferation-activated receptors.Determined the hypotype of three kinds of PPAR, they are called peroxisome proliferator-activated receptor alpha (PPAR α), oxide enzyme body proliferin activation receptor γ (PPAR γ) and oxide enzyme body proliferin activation receptor δ (PPAR δ).Should be noted that PPAR δ is also referred to as PPAR β and NUC1 in the literature, these titles all refer to same receptor.

PPAR α regulates lipid metabolism.PPAR α is by the special class of shellfish and some media and long-chain fat acid active, and it relates to the beta oxidation that stimulates fatty acid.Described PPAR γ receptor subtype relates to activation adipose cell differentiation program but does not relate to the peroxisome proliferation that stimulates in the liver.Determined that PPAR δ is useful to improving mammiferous high density lipoprotein (HDL) level.Reference example such as WO 97/28149.

PPAR α activator compound particularly can be used for triglyceride reducing, appropriateness reduces the LDL level and improves the HDL level.The example that can be used for the PPAR α activator of the present composition comprises the special class of shellfish.

The non-limiting example of suitable shellfish acid derivative (" shellfish special class ") comprise clofibrate (2-(right-the chloro phenoxy group)-2-methyl-ethyl propionate for example, for example

Capsule, it can be bought from Wyeth-Ayerst and obtain); Gemfibrozil (5-(2, the 5-dimethyl phenoxy)-2 for example, 2-dimethyl valeric acid, for example

Tablet, it can be bought from Parke Davis and obtain); Ciprofibrate (C.A.S.Registry 52214-84-3 number, referring to the U.S. patent No. 3,948,973, it is attached to herein as a reference); Bezafibrate (C.A.S.Registry 41859-67-0 number, referring to the U.S. patent No. 3,781,328, it is attached to herein as a reference); Clinofibrate (C.A.S.Registry 30299-08-2 number, referring to the U.S. patent No. 3,716,583, it is attached to herein as a reference); Binifibrate (C.A.S.Registry 69047-39-8 number, referring to BE 884722, it is attached to herein as a reference); Lifibrol (C.A.S.Registry 96609-16-4 number); Fenofibrate (for example

The micronization fenofibrate (2-[4-(4-chlorobenzene formoxyl) phenoxy group]-2 Methylpropionic acid, 1-methyl ethyl ester), it can be buied from AbbottLaboratories, or

The micronization fenofibrate, it can be bought from French Labortoire Founirr and obtain) and composition thereof.These chemical compounds can be different form use, include but not limited to sour form, salt form, racemate, enantiomer, amphion and tautomeride.

Other example that is used for PPAR α activator of the present invention comprises as at U.S. Patent number 6,028, the disclosed fluorobenzene based compound of 109 (they are attached to herein as a reference); The phenylpropionic acid chemical compound of disclosed some replacement in WO00/75103 (it is attached to herein as a reference); And in WO 98/43081 (it is attached to herein as a reference) disclosed PPAR α activator compound.

The non-limiting example that is used for the suitable PPAR γ activator of the present composition comprises the derivant of suitable glitazone or thiazolidinedione, for example troglitazone (

Troglitazone (5-[[4-[3,4-dihydro-6-hydroxyl-2,5,7,8-tetramethyl-2H-1-benzofuran-2-yl] methoxyl group] phenyl] methyl)-2, the 4-thiazolidinedione), can obtain from the Parke-Davis purchase); Rosiglitazone (for example

The rosiglitazone maleate (5-[[4-[2-(methyl-2-pyridinylamino) ethyoxyl] phenyl] methyl]-2,4-thiazolidinedione, (Z)-2-butylene two acid esters (1: 1), buy from SmithKline Beecham obtain) and pioglitazone (ACTOS for example ^TMThe pioglitazone hydrochlorate (5-[[4-[2-(5-ethyl-2-pyridine radicals) ethyoxyl] phenyl] methyl]-2,4-thiazolidinedione one hydrochlorate obtains from Takeda Pharmaceuticals purchase).Other useful thiazolidinediones comprise ciglitazone, englitazone, darglitazone and as in WO98/05331 (it is attached to herein as a reference) disclosed BRL 49653; Disclosed PPAR γ activator compound in WO00/76488 (it is attached to herein as a reference); With at U.S. Patent number 5,994, disclosed PPAR γ activator compound in 554 (they are attached to herein as a reference).

Other useful PPAR γ activator compound comprises some as at U.S. Patent number 5,859, disclosed acetophenone phenols in 051 (it is attached to herein as a reference); Some are disclosed quinoline phenyl compound in WO 99/20275 (it is attached to herein as a reference); Disclosed aryl compound in WO 99/38845 (it is attached to herein as a reference); Some are disclosed 1 in WO 00/63161 (it is attached to herein as a reference), the dibasic phenyl compound of 4-; Some are disclosed aryl compound in WO 01/00579 (it is attached to herein as a reference); Some are disclosed benzoic acid compounds in WO 01/12612 and WO 01/12187 (it is attached to herein as a reference); And in WO97/31907 (it is attached to herein as a reference) disclosed substituted 4-hydroxyl-phenyl alconic acid chemical compound.

PPAR δ chemical compound especially can be used for the triglyceride reducing level or improves the HDL level.The non-limiting example that is used for the suitable PPAR delta activators of the present composition comprises suitable thiazole with oxazole derivant such as C.A.S.Registry 317318-32-4 number, as disclosed in WO01/00603 (it is attached to herein as a reference); Some are as disclosed fluoro in WO97/28149 (it is attached to herein as a reference), chloro or sulfo-phenoxy group phenylacetic acid class; As at U.S. Patent number 5,093, disclosed suitable non--β-oxidizable fatty acid analogues in 365 (they are attached to herein as a reference); And in WO 99/04815 (it is attached to herein as a reference) disclosed PPAR delta activators chemical compound.

In addition, the chemical compound with multiple function that is used for activating the combination medicine of various PPAR α, PPAR γ, PPAR δ also is used for compositions of the present invention.Non--limited example comprises that some are as at U.S. Patent number 6,248,781, the aryl compound of disclosed replacement among WO 00/23416, WO 00/23415, WO 00/23425, WO 00/23445, WO 00/23451 and the WO 00/63153 (all these is attached to herein as a reference), described chemical compound is considered to can be used as PPAR α and/or PPAR γ activator compound.Other non-limiting example of available PPAR α and/or PPAR γ activator compound comprises as disclosed activator compound in WO 97/25042 (it is attached to herein as a reference); As disclosed activator compound in WO 00/63190 (it is attached to herein as a reference); As disclosed activator compound in WO 01/21181 (it is attached to herein as a reference); As disclosed biaryl-Evil (thiophene) azole compounds in WO 01/16120 (it is attached to herein as a reference); As disclosed activator compound in WO 00/63196 and WO 00/63209 (it is attached to herein as a reference); As at U.S. Patent number 6,008, disclosed substituted 5-aryl-2 in 237 (they are attached to herein as a reference), 4-thiazolidinedione compound; As disclosed Arylthiazolidinedionderivatives and Fang Ji oxazolidinedione chemical compound in WO 00/78312 and WO00/78313G (it is attached to herein as a reference); As disclosed GW2331 in WO 98/05331 (it is attached to herein as a reference) or (2-(4-[difluorophenyl]-1-heptyl urea groups) ethyl) phenoxy group)-the 2-Methyl Butyric Acid chemical compound; As at U.S. Patent number 6,166, disclosed aryl compound in 049 (it is attached to herein as a reference); As Gong Kai De oxazole chemical compound in WO 01/17994 (it is attached to herein as a reference); As disclosed dithiacyclopentane compound in WO 01/25225 and WO 01/25226 (it is attached to herein as a reference).

Other available PPAR activator compound comprises the benzyl thiazolidine-2 as disclosed replacement in WO 01/14349, WO01/14350 and WO 01/04351 (it is attached to herein as a reference), 4-dione compounds; As disclosed mercaptan carboxylic acid's chemical compound in WO 00/50392 (it is attached to herein as a reference); As disclosed Ascofuranone. chemical compound in WO 00/53563 (it is attached to herein as a reference); As disclosed carboxylic acid compound in WO 99/46232 (it is attached to herein as a reference); As disclosed chemical compound in WO 99/12534 (it is attached to herein as a reference); As disclosed benzene compound in WO 99/15520 (it is attached to herein as a reference); As disclosed neighbour-anisamide chemical compound in WO 01/21578 (it is attached to herein as a reference); And as disclosed PPAR activator compound in WO 01/40192 (it is attached to herein as a reference).

Giving the special disease of the activator treatment of peroxisome proliferation-activated receptors such as daily dose with the treatment effective dose can be in every day about 0.1-1000mg scope, be preferably about 0.25-50mg/ days, more preferably every day about 10mg, give with single dose or 2-4 divided dose.Yet accurate dose is determined and the usefulness of the chemical compound that gives, these factors of age, body weight, state and reaction of patient determine according to clinical.

Term " treatment effective dose " refers to the amount of the therapeutic agent of described compositions, activator as peroxisome proliferation-activated receptors, sterol absorption inhibitor and other the following stated medicine or therapeutic agent, it can cause thinks the tissue that give, system, animal or mammal (research worker for example, doctor or veterinary) biology or medical response, this reaction comprises alleviating of the disease of being treated or disease symptoms and prevents, slow down or stop for example hyperlipemia (atherosclerosis for example of one or more diseases such as angiopathy, hypercholesterolemia or sitosterolemia), vascular inflammation, apoplexy, diabetes, the level of sterol (for example cholesterol) in fat progress and/or the reduction blood plasma.

" therapeutic alliance " used herein or " therapeutic combination medicine " shows the activator that gives two or more therapeutic agents such as peroxisome proliferation-activated receptors and sterol absorption inhibitor so that prevention or treatment disease such as angiopathy such as hyperlipemia (for example atherosclerosis, hypercholesterolemia or sitosterolemia), vascular inflammation, apoplexy, diabetes, obesity and/or reduce the level of sterol (for example cholesterol) in the blood plasma." blood vessel " used herein comprises cardiovascular, cerebrovascular and has both concurrently.Compositions of the present invention, combination medicine and therapeutic agent can give by any suitable manner, and this mode can make the interior site of action of these chemical compounds and body contact as producing in mammal or people's blood plasma, liver or small intestinal.Described administering mode comprises these therapeutic agents in simultaneous in fact mode as single tablet or capsular mode co-administered to have the fixed ratio active component, or with the mode administration of the single capsule multiple dosing of each therapeutic agent.These administering modes also comprise the therapeutic agent that uses each type in a continuous manner.In both cases, use the therapy of therapeutic alliance will provide to the favourable effect of treatment disease.The benefit of the maximum of therapeutic alliance disclosed herein is to reduce the required amount of single therapy chemical compound or reduce chemical compound is effectively treated in treatment to disease whole total amounts.Owing to use the combination medicine of therapeutic agent, can reduce the side effect of unification compound with respect to monotherapy, it can increase patient's adaptability.Also therapeutic agent can be selected so that provide than the promising result of broad range or the satisfactory way that works.

Just as described above, described compositions of the present invention, Pharmaceutical composition and therapeutic combination medicated bag are drawn together the substituted beta-lactam sterol absorption inhibitor of one or more suitable azetidinones or following detailed description.This paper employed " sterol absorption inhibitor " refers to when giving mammal or man-hour with the amount for the treatment of effectively (sterol absorbs and suppresses), can suppress the chemical compound that one or more sterols absorb, described sterol includes but not limited to cholesterol, plant sterol (for example sitosterol, campesterol, stigmasterol and avenasterol (avenosterol)), 5 α-stanol (for example Dihydrocholesterol, 5 α-campestanol, 5 α-sitostamol) and their mixture.

In preferred embodiments, the sterol absorption inhibitor that is used for the present composition, therapeutic combination medicine and method is by representing with following formula (I):

Or the isomer of formula (I) chemical compound, or the pharmaceutically acceptable salt or the solvate of formula (I) chemical compound or formula (I) compound isomers, or the prodrug of isomer, salt or the solvate of formula (I) chemical compound or formula (I) chemical compound, wherein in following formula (I):

Ar ³Be aryl or R ⁵The aryl of-replacement;

R and R ²Independently be selected from-OR ⁶-,-O (CO) R ⁶,-O (CO) OR ⁹With-O (CO) NR ⁶R ⁷

R ¹And R ³Independently be selected from hydrogen, low alkyl group and aryl;

Q is 0 or 1; R is 0 or 1; M, n and p independently are selected from 0,1,2,3 or 4; Condition is that at least one q and r are 1; And the summation of m, n, p, q and r is 1,2,3,4,5 or 6; And condition be when p be 0 and r when being 1, the summation of m, q and n is 1,2,3,4 or 5;

R ⁵Be 1-5 the substituent group that independently is selected from following group :-OR ⁶,-O (CO) R ⁶,-O (CO) OR ⁹,-O (CH ₂) _1-5OR ⁶,-O (CO) NR ⁶R ⁷,-NR ⁶R ⁷,-NR ⁶(CO) R ⁷,-NR ⁶(CO) OR ⁹,-NR ⁶(CO) NR ⁷R ⁸,-NR ⁶SO ₂R ⁹,-COOR ⁶,-CONR ⁶R ⁷,-COR ⁶,-SO ₂NR ⁶R ⁷, S (O) _0-2R ⁹,-O (CH ₂) _1-10-COOR ⁶,-O (CH ₂) _1-10-CONR ⁶R ⁷,-(low-grade alkylidene) COOR ⁶With-CH=CH-COOR ⁶

R ⁹It is the low alkyl group that low alkyl group, aryl or aryl replace;

R ⁴1-3 independent substituent group of selecting preferably, R ⁵1-3 independent substituent group of selecting preferably.

Term used herein " alkyl " or " low alkyl group " refer to that straight or branched has the alkyl chain of 1-6 carbon atom, and " alkoxyl " refers to have the alkoxyl of 1-6 carbon atom.The non-limiting example of low alkyl group comprises for example methyl, ethyl, propyl group and butyl.

" alkenyl " refers to straight or branched, has one or more pair key, conjugation or unconjugated carbochain in described chain.Equally, " alkynyl " refers to straight or branched, has one or more triple-linked carbochain in described chain.When alkyl, alkenyl or alkynyl chain engaged two other variablees and therefore become bivalence, the term that uses was alkylidene, alkenylene and alkynylene.

" cycloalkyl " refers to the saturated carbocyclic ring of 3-6 carbon atom, and same " cycloalkylidene " refers to corresponding bivalence ring, and wherein the junction point with other group comprises all position isomers.

" halogeno-group " refers to fluorine, chlorine, bromine or iodine free radical.

" aryl " refers to phenyl, naphthyl, indenyl, tetralyl or 2,3-indanyl.

" phenylene " refers to the bivalence phenyl, comprises ortho position, a position and para-orientation.

Wherein in narration, for example said by replacing the basis set R that independently selects, R ¹, R ²And R ³Refer to R, R ¹, R ²And R ³For independently selecting, and at this R, R ¹, R ²And R ³More than conversion occurs once repeatedly in molecule, appear as independent selection each time (if for example R is-OR ⁶, R wherein ⁶Be hydrogen, R then ²Can be-OR ⁶, R wherein ⁶Be low alkyl group).Those those skilled in the art should be realized that described substituent size and character will influence and can have the replacement radix.

Chemical compound of the present invention has at least one asymmetric carbon atom and its all isomers, comprises enantiomer, stereoisomer, rotamer, tautomer and the racemate (when they exist) of formula (I-XI) chemical compound that is considered to a part of the present invention.The present invention includes d and l isomer (both are with pure form with the form of mixture), comprise racemic mixture.Use routine techniques can prepare isomer, by optional raw material pure or optional enrichment or the isomer preparation by separate type I-XI chemical compound.For example when two keys existed, isomer also can comprise geometric isomer.

Those it should be appreciated by those skilled in the art that for the chemical compound of some formula I-XI, an isomer should demonstrate the pharmacologically active stronger than other isomer.

Have amino chemical compound of the present invention and can form pharmaceutically acceptable salt with mineral acid with organic.The known hydrochloric acid of the capable field technique personnel of example, sulphuric acid, phosphoric acid, acetic acid, citric acid, oxalic acid, malonic acid, salicylic acid, malic acid, fumaric acid, succinic acid, ascorbic acid, maleic acid, methanesulfonic acid and other mineral acid and the carboxylic acid of the salifiable suitable acid of shape.By the salifiable sour contact preparation salt of required shape that makes free alkali form and q.s.By handling salt with suitable dilute alkaline aqueous solution such as dilute aqueous solution of sodium bicarbonate, free alkali form can be regenerated.Sometimes described free alkali form is different with some physical characteristic of its corresponding salt form, the dissolubility in polar solvent for example, but for the object of the invention, these salt and its free alkali form are suitable.

Chemical compounds more of the present invention are tart (for example those have the chemical compound of carboxyl).These chemical compounds and inorganic and organic base formation pharmaceutically acceptable salt.The example of these salt is sodium salt, potassium salt, calcium salt, aluminum salt, gold and silver salt.Also comprise the salt that forms with pharmaceutically acceptable amine such as ammonia, alkylamine, hydroxy alkyl amine, N-methylglucosamine etc.

This paper employed " solvate " refers to the molecule or the ionic complex of solvent molecule or ion and these solutes (for example the chemical compound of one or more formulas I-XI, the prodrug of the isomer of formula I-XI chemical compound or formula I-XI chemical compound).Non-limiting example as solvent comprises polarity, proton solvent such as water and/or alcohol (for example methanol).

This paper employed " prodrug " refers to it is the chemical compound of prodrug, this chemical compound give behind the patient in vivo by some chemistry or physiological process discharge medicine (for example make prodrug become physiological pH or change required medicine form into) by enzyme reaction.

The chemical compound of preferred formula (I) is those chemical compounds, wherein Ar ¹Be phenyl or R ⁴The phenyl of-replacement, more preferably (4-R ⁴The phenyl of)-replace.Ar ²Preferred phenyl or R ⁴The phenyl of-replacement, more preferably (4-R ⁴The phenyl of)-replace.Ar ³Preferred R ⁵The phenyl of-replacement, more preferably (4-R ⁵The phenyl of)-replace.Work as Ar ¹Be (4-R ⁴During the phenyl of)-replace, R ⁴Halogen preferably.Work as Ar ²And Ar ³Be respectively R ⁴-and R ⁵-replace phenyl the time, R ⁴Preferably halogen or-OR ⁶, R ⁵Preferably-OR ⁶, R wherein ⁶Be low alkyl group or hydrogen.Particularly preferred chemical compound is each Ar wherein ¹And Ar ²Be 4-fluoro phenyl, Ar ³Be 4-hydroxy phenyl or 4-methoxyphenyl.

Each preferred-CH of X, Y and Z ₂-.R ¹And R ³Each preferred hydrogen.R and R ²Preferably-OR ⁶, R wherein ⁶Be hydrogen, or easily metabolism be hydroxyl group (for example as defined above-O (CO) R ⁶,-O (CO) OR ⁹With-O (CO) NR ⁶R ⁷).

The summation of m, n, p, q and r preferably 2,3 or 4 is more preferably 3.Preferably wherein m, n and r are respectively 0, and q is 1, and p is 2 chemical compound.

Also preferably wherein p, q and n respectively be 0, r is 1, m is the chemical compound of 2 or 3 formula (I).More preferably wherein m, n and r respectively are 0, and q is 1, and p is 2, and Z is-CH ₂-, R is-OR ⁶Chemical compound, particularly work as R ⁶Chemical compound when being hydrogen.

Also more preferably wherein p, q and n respectively be 0, r is 1, m is 2, X is-CH ₂-, R ²Be-OR ⁶Formula (I) chemical compound, particularly work as R ⁶When being hydrogen.

Ar in preferred formula (I) chemical compound ¹Be phenyl or R ⁴The phenyl of-replacement, Ar ²Be phenyl or R ⁴The phenyl of-replacement, Ar ³Be R ⁵The chemical compound of the phenyl of-replacement.Also preferred Ar wherein ¹Be phenyl or R ⁴The phenyl of-replacement, Ar ²Be phenyl or R ⁴The phenyl of-replacement, Ar ³Be R ⁵-the phenyl that replaces, and the summation of m, n, p, q and r is 2,3 or 4, more preferably 3 chemical compound.Preferred chemical compound is Ar wherein ¹Be phenyl or R ⁴The phenyl of-replacement, Ar ²Be phenyl or R ⁴The phenyl of-replacement, Ar ³Be R ⁵-the phenyl that replaces, and m, n and r respectively be 0, q is 1, and p is 2, and perhaps p, q and n respectively are 0, and r is 1, m is 2 or 3.

In preferred embodiments, the sterol inhibitor that can be used for the formula (I) in compositions of the present invention, therapeutic combination medicine and the method is by with following formula (II) representative (ezetimibe):

Or the pharmaceutically acceptable salt or the solvate of formula (II) chemical compound, or the prodrug of formula (II) chemical compound, or the salt of formula (II) chemical compound or the prodrug of solvate.

Can be by the whole bag of tricks known in the art as at U.S. Patent number 5,631,365,5,767,115,5,846,966,6,207,822, the chemical compound of the interim patent No. 60/279,288 of the U.S. of March 28 calendar year 2001 application and PCT patent application WO 93/02048 (above each be attached to herein as a reference) and the disclosed method preparation formula of following embodiment I.For example, can prepare suitable formula I chemical compound by the method for forming by following steps:

(a) handle the lactone of formula A or B with highly basic:

Or

Wherein R ' and R ²' be respectively R and R ², or by the hydroxyl of due care; Ar ¹⁰Be Ar ¹, by the aryl of the hydroxyl-replacement of due care or by the aryl of the amino-replacement of due care; As above to the definition of formula I, condition is in the lactone of formula B with remaining parameter, and when n and r respectively were 0, p was 1-4;

(b) make the product of step (a) and the imine reaction of following formula

Ar wherein ²⁰Be Ar ², by the aryl of the hydroxyl-replacement of due care or by the aryl of the amino-replacement of due care; Ar ³⁰Be Ar ³, by the aryl of the hydroxyl-replacement of due care or by the aryl of the amino-replacement of due care;

(c) with the described reaction of sour quencher;

(d) when existing, optional from R ', R ²', Ar ¹⁰, Ar ²⁰And Ar ³⁰Remove protecting group; With

(e) choose wantonly at R, R ², Ar ¹, Ar ²And Ar ³Functionalized hydroxyl or amino substituent group.

Lactone shown in more than using obtains the chemical compound as shown in the formula IA and IB:

Wherein parameter as defined above; With

Wherein parameter as defined above.

Employed other sterol absorption inhibitor is by representing with following formula (III) in chemical compound of the present invention, therapeutic combination medicine and method:

Or the isomer of formula (III) chemical compound, or the pharmaceutically acceptable salt or the solvate of the isomer of formula (III) chemical compound or formula (III) chemical compound, or the prodrug of isomer, salt or the solvate of formula (III) chemical compound or formula (III) chemical compound, wherein in formula (III):

Ar ¹Be R ³The aryl of-replacement;

Ar ²Be R ⁴The aryl of-replacement;

Ar ³Be R ⁵The aryl of-replacement;

A is selected from-O-,-S-,-S (O)-or-S (O) ₂-;

R ¹Be selected from-OR ⁶-,-O (CO) R ⁶,-O (CO) OR ⁹With-O (CO) NR ⁶R ⁷R ²Be selected from hydrogen, low alkyl group and aryl; Or R ¹And R ²Be together=O;

Q is 1,2 or 3;

P is 0,1,2,3 or 4;

R ⁵Be 1-3 the substituent group that independently is selected from following group :-OR ⁶,-O (CO) R ⁶,-O (CO) OR ⁹,-O (CH ₂) _1-5OR ⁹,-O (CO) NR ⁶R ⁷,-NR ⁶R ⁷,-NR ⁶(CO) R ⁷,-NR ⁶(CO) OR ⁹,-NR ⁶(CO) NR ⁷R ⁸,-NR ⁶SO ₂-low alkyl group ,-NR ⁶SO ₂-aryl ,-CONR ⁶R ⁷,-COR ⁶,-SO ₂NR ⁶R ⁷, S (O) _0-2-alkyl, S (O) _0-2-aryl, O (CH ₂) _1-10-COOR ⁶,-O (CH ₂) _1-10CONR ⁶R ⁷, neighbour-halogeno-group ,-halogeno-group, neighbour-low alkyl group ,-low alkyl group ,-(low-grade alkylidene) COOR ⁶With-CH=CH-COOR ⁶

R ⁶, R ⁷And R ⁸Independently be selected from the low alkyl group that hydrogen, low alkyl group, aryl and aryl replace; R ⁹It is the low alkyl group that low alkyl group, aryl or aryl replace;

Preferred formula I chemical compound comprises those wherein Ar ¹Be R ³The phenyl, particularly (4-R of-replacement ³The phenyl of)-replace; Ar ²R preferably ⁴The phenyl, particularly (4-R of-replacement ⁴The phenyl of)-replace; Ar ³R preferably ⁵The phenyl, particularly (4-R of-replacement ⁵The chemical compound of the phenyl of)-replace.Preferred each Ar ¹, Ar ², Ar ³It is single replacement.

Y and Z each preferably-CH ₂-.R ²Hydrogen preferably.R ¹Preferably-OR ⁶, R wherein ⁶Be hydrogen, or easily metabolism be hydroxyl group (for example as defined above-O (CO) R ⁶,-O (CO) OR ⁹With-O (CO) NR ⁶R ⁷).Also preferred R wherein ¹And R ²Be together=chemical compound of O.

The summation of q and p preferably 1 or 2 is more preferably 1.Preferred chemical compound be wherein p be 0 and q be 1 chemical compound.Preferred chemical compound is that wherein p is 0, and q is 1, and Y is-CH ₂-and R ¹Be-OR ⁶, particularly work as R ⁶Chemical compound when being hydrogen.

Another group preferred compound is Ar wherein ¹Be R ³The phenyl of-replacement, Ar ²Be R ⁴The phenyl and the Ar of-replacement ³Be R ⁵The chemical compound of the phenyl of-replacement.

Also preferred Ar wherein ¹Be R ³The phenyl of-replacement, Ar ²Be R ⁴The phenyl of-replacement, Ar ³Be R ⁵-the phenyl that replaces, and the summation of p and q is 1 or 2, is more preferably 1 chemical compound.Preferred chemical compound is Ar wherein ¹Be R ³The phenyl of-replacement, Ar ²Be R ⁴The phenyl of-replacement, Ar ³Be R ⁵-the phenyl that replaces, p be 0 and q be 1 chemical compound.

A is preferred-O-.

R ³Preferably-COOR ⁶,-CONR ⁶R ⁷,-COR ⁶,-SO ₂NR ⁶R ⁷, S (O) _0-2-alkyl, S (O) _0-2-aryl, NO ₂Or halogeno-group.For R ³More preferred definition is a halogeno-group, particularly fluorine or chlorine.

R ⁴Preferably hydrogen, low alkyl group ,-OR ⁶,-O (CO) R ⁶,-O (CO) OR ⁹,-O (CO) NR ⁶R ⁷,-NR ⁶R ⁷, COR ⁶Or halogeno-group, wherein R ⁶And R ⁷Preferred independently is hydrogen or low alkyl group, and R ⁹Low alkyl group preferably.For R ⁴More preferred definition is hydrogen or halogeno-group, particularly fluorine or chlorine.

R ⁵Preferably-OR ⁶,-O (CO) R ⁶,-O (CO) OR ⁹,-O (CO) NR ⁶R ⁷,-NR ⁶R ⁷,-(low-grade alkylidene)-COOR ⁶Or-CH=CH-COOR ⁶, R wherein ⁶And R ⁷Preferred independently is hydrogen or low alkyl group, R ⁹Low alkyl group preferably.For R ⁵More preferred definition is-OR ⁶,-(low-grade alkylidene)-COOR ⁶Or-CH=CH-COOR ⁶, R wherein ⁶Preferably hydrogen or low alkyl group.

The method for preparing the formula III chemical compound is well known by persons skilled in the art.The non-limiting example of appropriate method is at U.S. Patent number 5,688, and open in 990, this patent is combined in herein as a reference.

In another embodiment, the sterol absorption inhibitor that is used for the present composition, therapeutic combination medicine and method is represented by formula (IV):

Or the isomer of formula (IV) chemical compound, or the pharmaceutically acceptable salt or the solvate of the isomer of formula (IV) chemical compound or formula (IV) chemical compound, or the prodrug of isomer, salt or the solvate of formula (IV) chemical compound or formula (IV) chemical compound, wherein in following formula (IV):

A is selected from R ²The Heterocyclylalkyl of-replacement, R ²The heteroaryl of-replacement, R ²The benzo-fused Heterocyclylalkyl and the R of-replacement ²The benzo-fused heteroaryl of-replacement;

Ar ¹Be aryl or R ³The aryl of-replacement;

Ar ²Be aryl or R ⁴The aryl of-replacement;

Q is key or forms the volution group with the 3-position ring carbon atom of azetidinone

R ¹Be selected from:

-(CH ₂) _q-, wherein q is 2-6, condition is that q also can be 0 or 1 when Q forms volution;

-(CH ₂) _e-G-(CH ₂) _r-, wherein G be-O-,-C (O)-, phenylene ,-NR ⁸Or-S (O) _0-2, e is that 0-5 and r are 0-5, condition is that the summation of e and r is 1-6;

-(C ₂-C ₆Alkenylene)-; With

R ⁵Be selected from:

Or

R ⁶And R ⁷Independently be selected from-CH ₂-,-CH (C ₁-C ₆Alkyl)-,-C (two-(C ₁-C ₆) alkyl) ,-CH=CH-and-C (C ₁-C ₆Alkyl)=CH-; Or R ⁵With adjacent R ⁶Together, or R ⁵With adjacent R ⁷Together formation-CH=CH-or-CH=C (C ₁-C ₆Alkyl)-group;

A and b independently are 0,1,2 or 3, and condition is both and not all is 0; Condition is to work as R ⁶Be-CH=CH-or-C (C ₁-C ₆Alkyl)=during CH-, a is 1; Condition is to work as R ₇Be-CH=CH-or-C (C ₁-C ₆Alkyl)=during CH-, b is 1; Condition is when a is 2 or 3, R ⁶Can be identical or inequality; And condition is when b is 2 or 3, R ⁷Can be identical or inequality;

And when Q is a key, R ¹Also can be selected from:

Or

Wherein M be-O-,-S-,-S (O)-or-S (O) ₂-;

D is 1,2 or 3;

H is 0,1,2,3 or 4;

V is 0 or 1;

R ²Be 1-3 substituent group on ring carbon atom, that be selected from following group: hydrogen, (C ₁-C ₁₀) alkyl, (C ₂-C ₁₀) alkenyl, (C ₂-C ₁₀) alkynyl, (C ₃-C ₆) cycloalkyl, (C ₃-C ₆) cycloalkenyl group, R ¹⁷Aryl, the R of-replacement ¹⁷Benzyl, the R of-replacement ¹⁷Benzyloxy, the R of-replacement ¹⁷-replace aryloxy group, halogeno-group ,-NR ¹⁴R ¹⁵, NR ¹⁴R ¹⁵(C ₁-C ₆Alkylidene)-, NR ¹⁴R ¹⁵C (O) (C ₁-C ₆Alkylidene)-,-NHC (O) R ¹⁶, OH, C ₁-C ₆Alkoxyl ,-OC (O) R ¹⁶,-COR ¹⁴, hydroxyl (C ₁-C ₆) alkyl, (C ₁-C ₆) alkoxyl (C ₁-C ₆) alkyl, NO ₂,-S (O) _0-2R ¹⁶,-SO ₂NR ¹⁴R ¹⁵With-(C ₁-C ₆Alkylidene) COOR ¹⁴Work as R ²When being the substituent group on heterocycloalkyl ring, R ²As defined above, or=O or

Or

Wherein J be-O-,-NH-, NR ¹⁸-or-CH ₂-;

R ⁹And R ¹⁷Independently be 1-3 group that independently is selected from following group: hydrogen, (C ₁-C ₆) alkyl, (C ₁-C ₆) alkoxyl ,-COOH, NO ₂,-NR ¹⁴R ¹⁵, OH and halogeno-group;

R ¹⁶Be (C ₁-C ₆) alkyl, aryl or R ¹⁷The aryl that replaces;

R ¹⁸Be hydrogen or (C ₁-C ₆) alkyl; With

R ¹⁹Be hydrogen, hydroxyl or (C ₁-C ₆) alkoxyl.

When being used for following formula (IV), " A " be R preferably ²The first heterocycloalkyl ring of-6-that replace, that contain 1 or 2 nitrogen-atoms.The preferred heterocycloalkyl ring is piperidyl, piperazinyl and morpholinyl.Described ring " A " preferably is connected on the phenyl ring by theheterocyclic nitrogen atom.Preferred R ²Substituent group is hydrogen and low alkyl group.R ¹⁹Preferred hydrogen.

Ar ²Preferred phenyl or R ⁴-phenyl, particularly (4-R ⁴The phenyl of)-replace.For R ⁴Preferred definition be lower alkoxy, methoxyl group and halogeno-group fluorine particularly particularly.

Ar ¹Preferred phenyl or R ³The phenyl, particularly (4-R of-replacement ³The phenyl of)-replace.

But for parameter-R ¹The bonded several preferred definitions of-Q-are:

Q is key and R ¹Be low-grade alkylidene, propylidene particularly;

Q is a volution group as defined above, wherein preferred R ⁶And R ⁷Respectively be ethylidene and R ⁵Be

Or

Q is key and R ¹Be But wherein said parameter is chosen as R ¹Be-O-CH ₂-CH (OH)-;

Q is key and R ¹Be But wherein said parameter is selected R ¹Be-CH (OH)-(CH ₂) ₂-;

Q is key and R ¹Be But wherein said parameter is selected R ¹Be-CH (OH)-CH ₂-S (O) _0-2-.

The method of preparation formula IV chemical compound is well known by persons skilled in the art.The non-limiting example of appropriate method is at U.S. Patent number 5,656, and open in 624, this patent is combined in herein as a reference.

In another embodiment, the sterol absorption inhibitor that is used for the present composition, therapeutic combination medicine and method is represented by formula V:

Or the isomer of formula V chemical compound, or the pharmaceutically acceptable salt or the solvate of the isomer of formula V chemical compound or formula V chemical compound, or the prodrug of the isomer of formula V chemical compound or formula V chemical compound or salt or solvate, wherein in last formula V:

Ar ¹Be aryl, R ¹⁰The aryl or the heteroaryl of-replacement;

Ar ²Be aryl or R ⁴The aryl of-replacement;

Ar ³Be aryl or R ⁵The aryl of-replacement;

Q is 0 or 1;

R is 0,1 or 2;

R ⁴Be 1-5 substituent group that independently is selected from following group: low alkyl group ,-OR ⁶,-O (CO) R ⁶,-O (CO) OR ⁹,-O (CH ₂) _1-5OR ⁶,-O (CO) NR ⁶R ⁷,-NR ⁶R ⁷,-NR ⁶(CO) R ⁷,-NR ⁶(CO) OR ⁹,-NR ⁶(CO) NR ⁷R ⁸,-NR ⁶SO ₂R ⁹,-COOR ⁶,-CONR ⁶R ⁷,-COR ⁶,-SO ₂NR ⁶R ⁷, S (O) _0-2R ⁹,-O (CH ₂) _1-10-COOR ⁶,-O (CH ₂) _1-10CONR ⁶R ⁷,-(low-grade alkylidene) COOR ⁶With-CH=CH-COOR ⁶

R ⁵Be 1-5 the substituent group that independently is selected from following group :-OR ⁶,-O (CO) R ⁶,-O (CO) OR ⁹,-O (CH ₂) _1-5OR ⁶,-O (CO) NR ⁶R ⁷,-NR ⁶R ⁷,-NR ⁶(CO) R ⁷,-NR ⁶(CO) OR ⁹,-NR ⁶(CO) NR ⁷R ⁸,-NR ⁶SO ₂R ⁹,-COOR ⁶,-CONR ⁶R ⁷,-COR ⁶,-SO ₂NR ⁶R ⁷, S (O) _0-2R ⁹,-O (CH ₂) _1-10-COOR ⁶,-O (CH ₂) _1-10-CONR ⁶R ⁷,-CF ₃,-CN ,-NO ₂, halogen ,-(low-grade alkylidene) COOR ⁶With-CH=CH-COOR ⁶

R ⁹It is the low alkyl group that low alkyl group, aryl or aryl replace; With

In formula V scope, comprise two preferred construction.In formula VA, q is 0, but remaining parameter as defined above, and in formula VB, q is 1, but remaining parameter as defined above.

R ⁴, R ⁵And R ¹⁰Each preferred 1-3 independently is selected from above listed substituent group.The chemical compound of preferred formula V, wherein Ar ¹Be phenyl, R ¹⁰The phenyl or the thienyl, particularly (4-R of-replacement ¹⁰Phenyl or the thienyl of)-replace.Ar ²Preferred R ⁴The phenyl, particularly (4-R of-replacement ⁴The phenyl of)-replace.Ar ³Preferred phenyl or R ⁵The phenyl, particularly (4-R of-replacement ⁵The phenyl of)-replace.Work as Ar ¹Be R ¹⁰-replace phenyl the time, R ¹⁰Preferably halogeno-group, particularly fluorine.Work as Ar ²Be R ⁴-replace phenyl the time, R ⁴Preferably-OR ⁶, R wherein particularly ⁶Be hydrogen or low alkyl group.Ar ³Be R ⁵-replace phenyl the time, R ⁵Preferably halogeno-group, particularly fluorine.The chemical compound of preferred especially formula V, wherein Ar ¹Be phenyl, 4-fluoro phenyl or thienyl, Ar ²Be 4-(alkoxyl or hydroxyl) phenyl and Ar ³Be phenyl or 4-fluoro phenyl.

Each preferred-CH of X and Y ₂-.The summation of m, n and q preferably 2,3 or 4 is more preferably 2.When q was 1, n is 1-5 preferably.

In each formula (VA) and (VB) for X, Y, Ar ¹, Ar ²And Ar ³Preferably identical.

In the chemical compound of formula (VA), the summation of m and n preferably 2,3 or 4 is more preferably 2.The summation of also preferred wherein m and n be 2 and r be 0 or 1 chemical compound.

In the chemical compound of formula (VB), the summation of m and n preferably 1,2 or 3 is more preferably 1.Preferred especially wherein m be 0 and n be 1 chemical compound.R ¹Preferred hydrogen and R ²Preferably-OR ⁶, R wherein ⁶Be that hydrogen or easy metabolism are group ((CO) for example defined above-O R of hydroxyl ⁶,-O (CO) OR ⁹With-O (CO) NR ⁶R ⁷), or R and R ¹Formation=O group together.

The method of preparation formula V chemical compound is well known by persons skilled in the art.The non-limiting example of appropriate method is at U.S. Patent number 5,624, and open in 920, this patent is combined in herein as a reference.

In another embodiment, the sterol absorption inhibitor that is used for the present composition, therapeutic combination medicine and method is represented by formula (VI):

Or the isomer of formula (VI) chemical compound, or the pharmaceutically acceptable salt or the solvate of the isomer of formula (VI) chemical compound or formula (VI) chemical compound, or the prodrug of isomer, salt or the solvate of formula (VI) chemical compound or formula (VI) chemical compound, wherein in following formula (VI):

R ¹Be

Or

U and v independently are 0,1,2 or 3, and condition is both and not all is 0; Condition is to work as R ₂Be-CH=CH-or-during C (low alkyl group)=CH-, v is 1; Condition is to work as R ₃Be-CH=CH-or-during C (low alkyl group)=CH-, u is 1; Condition is when v is 2 or 3, R ₂Can be identical or inequality; And condition is when u is 2 or 3, R ₃Can be identical or inequality;

R ₄Be selected from B-(CH ₂) _mC (O)-, wherein m is 0,1,2,3,4 or 5; B-(CH ₂) _q-, wherein q is 0,1,2,3,4,5 or 6; B-(CH ₂) _e-Z-(CH ₂) _r-, wherein Z be-O-,-C (O)-, phenylene ,-N (R ₈)-or-S (O) _0-2-, e is 0,1,2,3,4 or 5, and r is 0,1,2,3,4 or 5, and condition is that the summation of e and r is 0,1,2,3,4,5 or 6; B-(C ₂-C ₆Alkenylene)-; B-(C ₄-C ₆Inferior alkadienyl)-; B-(CH ₂) _t-Z-(C ₂-C ₆Alkenylene)-, wherein Z as defined above, wherein t is 0,1,2 or 3, condition is that the summation of t and carbon number is 2,3,4,5 or 6 in the alkenylene chain; B-(CH ₂) _f-V-(CH ₂) _g-, wherein V is C ₃-C ₆Cycloalkylidene, f are 1,2,3,4 or 5, and g is 0,1,2,3,4 or 5, and condition is that the summation of f and g is 1,2,3,4,5 or 6; B-(CH ₂) _t-V-(C ₂-C ₆Alkenylene)-or B-(C ₂-C ₆Alkenylene)-V-(CH ₂) _t-, wherein V and t as defined above, condition is that the summation of t and carbon number is 2,3,4,5 or 6 in the alkenylene chain; B-(CH ₂) _a-Z-(CH ₂) _b-V-(CH ₂) _d-, wherein Z and V as defined above, a, b and d independently are 0,1,2,3,4,5 or 6, condition is that the summation of a, b and d is 0,1,2,3,4,5 or 6; Or T-(CH ₂) _s-, wherein T is the cycloalkyl with 3-6 carbon atom, s is 0,1,2,3,4,5 or 6; Perhaps

R ₁And R ₄Form group together

W is a 1-3 substituent group that independently is selected from following groups: the low alkyl group that is used on ring carbon atom, replacing, hydroxyl low-grade alkyl, lower alkoxy, alkoxyalkyl, alkoxyl alkoxyl, alkoxy carbonyl alkoxyl, (lower alkoxy imino group)-low alkyl group, lower alkane diacyl, low alkyl group lower alkane diacyl, allyloxy ,-CF ₃,-OCF ₃, benzyl, R ₇-benzyl, benzyloxy, R ₇-benzyloxy, phenoxy group, R ₇-phenoxy group, dioxolanyl, NO ₂,-N (R ₈) (R ₉), N (R ₈) (R ₉)-low-grade alkylidene, N (R ₈) (R ₉)-low-grade alkylidene oxygen base, OH, halogeno-group ,-CN ,-N ₃,-NHC (O) OR ₁₀, NHC (O) R ₁₀, R ₁₁O ₂SNH-, (R ₁₁O ₂S) ₂N-,-S (O) ₂NH ₂,-S (O) _0-2R ₈, tert-butyl group dimethyl-silyloxy methyl ,-C (O) R ₁₂,-COOR ₁₉,-CON (R ₈) (R ₉) ,-CH=CHC (O) R ₁₂,-low-grade alkylidene-C (O) R ₁₂, R ₁₀C (O) (low-grade alkylidene oxygen base)-, N (R ₈) (R ₉) C (O) (low-grade alkylidene oxygen base)-and

And the substituent group (when having substituent group) on substituted hetero-aromatic ring nitrogen-atoms, they be selected from low alkyl group, lower alkoxy ,-C (O) OR ₁₀,-C (O) R ₁₀, OH, N (R ₈) (R ₉)-low-grade alkylidene, N (R ₈) (R ₉)-low-grade alkylidene oxygen base ,-S (O) ₂NH ₂And 2-(trimethyl silyl)-ethoxyl methyl;

R ₈And R ₉Independently be selected from H or low alkyl group;

R ₁₂Be selected from H, OH, alkoxyl, phenoxy group, benzyloxy,

-N (R ₈) (R ₉), low alkyl group, phenyl or R ₇-phenyl;

R ₁₅, R ₁₆And R ₁₇The group that independently is selected from H and defines for W; Perhaps R ₁₅Be hydrogen, R ₁₆And R ₁₇Form the ring of dioxolanyl with the adjacent carbon atom that they connected;

R ₁₉Be H, low alkyl group, phenyl or phenyl lower alkyl; With

One group of preferred formula VI chemical compound is R wherein ₂₁Be selected from the chemical compound of following group: the phenyl, 2 that phenyl, W-replace, 3-indanyl, benzofuranyl, benzo dioxolyl, tetralyl, pyridine radicals, pyrazinyl, pyrimidine radicals, quinolyl or cyclopropyl,

Wherein W is low alkyl group, lower alkoxy, OH, halogeno-group, N (R ₈) (R ₉) ,-NHC (O) OR ₁₀,-NHC (O) R ₁₀, NO ₂,-CN ,-N ₃,-SH ,-S (O) _0-2(low alkyl group) ,-COOR ₁₉,-CON (R ₈) (R ₉) ,-COR ₁₂, phenoxy group, benzyloxy, OCF ₃,-CH=C (O) R ₁₂Or t-butyldimethylsilyl oxygen base, wherein R ₈, R ₉, R ₁₀, R ₁₂And R ₁₉As formula IV is defined.When W was 2 or 3 substituent groups, described substituent group can be identical or inequality.

Another organizes preferred formula V chemical compound is R wherein ₂₀The chemical compound of the phenyl that replaces for phenyl or W-, the wherein preferred meaning of W such as above for R ₂₁Preferred definition.

Be more preferably the chemical compound of formula VI, wherein R ₂₀Be the phenyl that phenyl or W-replace, R ₂₁Be the phenyl, 2 that phenyl, W-replace, 3-indanyl, benzofuranyl, benzo dioxolyl, tetralyl, pyridine radicals, pyrazinyl, pyrimidine radicals, quinolyl or cyclopropyl; W is low alkyl group, lower alkoxy, OH, halogeno-group, N (R ₈) (R ₉) ,-NHC (O) OR ₁₀,-NHC (O) R ₁₀, NO ₂,-CN ,-N ₃,-SH ,-S (O) _0-2(low alkyl group) ,-COOR ₁₉,-CON (R ₈) (R ₉) ,-COR ₁₂, phenoxy group, benzyloxy ,-CH=CHC (O) R ₁₂, OCF ₃, or t-butyldimethylsilyloxy base, wherein when W was 2 or 3 substituent groups, described substituent group can be identical or inequality, wherein R ₈, R ₉, R ₁₀, R ₁₂And R ₁₉As formula VI is defined.

The also preferably chemical compound of formula VI, wherein R ₁Be

Or

Another organizes preferred formula VI chemical compound is R wherein ₂And R ₃Respectively be-CH ₂-, the summation of u and v is 2,3 or 4 chemical compound, simultaneously u=v=2 is for more preferably.

R ₄B-(CH preferably ₂) _q-or B-(CH ₂) _e-Z-(CH ₂) _r-, wherein B, Z, q, e and r are as defined above.B preferably

R wherein ₁₆And R ₁₇Respectively be hydrogen and R wherein ₁₅Preferably H, OH, lower alkoxy, particularly methoxyl group or halogeno-group, particularly chlorine.

Preferably Z is-O-, and e is 0, and r is 0.

Preferred q is 0-2.

R ₂₀The phenyl that replaces of phenyl or W-preferably.

For R ₂₀Preferred W-substituent group be lower alkoxy, particularly methoxyl group and ethyoxyl, OH and-C (O) R ₁₂, R wherein ₁₂Preferred lower alkoxy.

Preferred R ₂₁Be selected from the phenyl and the F-phenyl of phenyl, lower alkoxy-replacement.

The special preferably chemical compound of formula VI, wherein R ₁Be

Or

R ₂And R ₃Respectively be-CH ₂-, u=v=2, R ₄Be B-(CH ₂) _q-, wherein B is phenyl or the phenyl that replaced by lower alkoxy or chlorine, q is 0-2, R ₂₀Be the phenyl of phenyl, OH-phenyl, lower alkoxy-replacement or the phenyl of elementary alkoxy carbonyl-replacement, R ₂₁Be the phenyl or the F-phenyl of phenyl, lower alkoxy-replacement.

The method of preparation formula VI chemical compound is well known by persons skilled in the art.The non-limiting example of appropriate method is at U.S. Patent number 5,698, and open in 548, this patent is combined in herein as a reference.

In another embodiment, the sterol absorption inhibitor that is used for the present composition, therapeutic combination medicine and method is represented by formula (VII):

Or the isomer of formula (VII) chemical compound, or the pharmaceutically acceptable salt or the solvate of the isomer of formula (VII) chemical compound or formula (VII) chemical compound, or the prodrug of isomer, salt or the solvate of formula (VII) chemical compound or formula (VII) chemical compound, wherein in following formula (VII):

A is-CH=CH ,-C ≡ C-or-(CH ₂) _p, wherein p is 0,1 or 2;

B is

E is C ₁₀-C ₂₀Alkyl or-C (O)-(C ₉-C ₁₉)-alkyl, wherein said alkyl are straight or branched, saturated or contain one or more pair key;

R is hydrogen, C ₁-C ₁₅Alkyl, straight or branched, saturated or contain one or more pair key, or B-(CH ₂) _r, wherein r is 0,1,2 or 3;

R ₄Be

Wherein n is 0,1,2 or 3;

R ₅It is low alkyl group; With

Preferred formula (VII) chemical compound be those wherein R be the chemical compound of hydrogen, methyl, ethyl, phenyl or phenyl propyl.Another organizes preferred formula (VII) chemical compound is R wherein ₄Be right-methoxyphenyl or 2,4, the chemical compound of 6-trimethoxyphenyl.Again another to organize preferred formula (VII) chemical compound be that wherein A is the chemical compound of ethylidene or key.Also having one group of preferred formula (VII) chemical compound again is that wherein E is the chemical compound of decyl, oleoyl or 7-Z-hexadecene base.Preferred R ₁, R ₂And R ₃Respectively be hydrogen.

Preferred formula (VII) chemical compound be those wherein R be the chemical compound of hydrogen, methyl, ethyl, phenyl or phenyl propyl.R ₄Be right-methoxyphenyl or 2,4, the 6-trimethoxyphenyl; A is ethylidene or key; E is decyl, oleoyl or 7-Z-hexadecene base.Preferred R ₁, R ₂And R ₃Respectively be hydrogen.

A kind of preferred formula (VII) chemical compound is that wherein E is that decyl, R are that hydrogen, B-A are phenyl and R ₄It is the chemical compound of right-methoxyphenyl.

In another embodiment, employed sterol absorption inhibitor is represented by formula (VIII) in the present composition and method:

Or the isomer of formula (VIII) chemical compound, or pharmaceutically acceptable salt or solvate formula (VIII) chemical compound or formula (VIII) compound isomers, or the prodrug of formula (VIII) chemical compound or its isomer, salt or solvate, wherein in following formula (VIII):

R ²⁶Be H or OG ¹

G and G ¹Independently be selected from

With

Condition is to work as R ²⁶When being H or OH, G is not H;

W independently is selected from-NH-C (O)-,-O-C (O)-,-O-C (O)-(R ³¹)-,-NH-C (O)-N (R ³¹)-and-O-C (S)-N (R ³¹)-;

R ³¹Be selected from H and (C ₁-C ₄) alkyl;

R ³²Independently be selected from 1-3 and independently be selected from following group: halogeno-group, (C ₁-C ₄) alkyl ,-OH, phenoxy group ,-CF ₃,-NO ₂, (C ₁-C ₄) alkoxyl, methylene-dioxy, oxo base, (C ₁-C ₄) alkyl alkylthio base, (C ₁-C ₄) alkyl sulfinyl, (C ₁-C ₄) alkyl sulphonyl ,-N (CH ₃) ₂-,-C (O)-NH (C ₁-C ₄) alkyl ,-C (O)-N ((C ₁-C ₄) alkyl) ₂,-C (O)-(C ₁-C ₄) alkyl ,-C (O)-(C ₁-C ₄) alkoxyl and pyrrolidinyl carbonyl; Perhaps R ³²Be covalent bond, R ³¹With its nitrogen-atoms that is connected and R ³²Form pyrrolidinyl, piperidyl, N-methyl-piperazinyl, indolinyl or morpholinyl, or (C ₁-C ₄) pyrrolidinyl, piperidyl, N-methyl-piperazinyl, indolinyl or the morpholinyl of alkoxy carbonyl-replacement;

Ar ¹Be aryl or R ¹⁰The aryl of-replacement;

Ar ²Be aryl or R ¹¹The aryl of-replacement;

Q is a key, perhaps forms the volution group with azetidinone 3-position ring carbon atom

R ¹Be selected from

-(CH ₂) _e-E-(CH ₂) _r-, wherein E be-O-,-C (O)-, phenylene ,-NR ²²Or-S (O) _0-2, e is that 0-5 and r are 0-5, condition is that the summation of e and r is 1-6;

-(C ₂-C ₆) alkenylene-; With

-(CH ₂) _f-V-(CH ₂) _g-, wherein V is C ₃-C ₆Cycloalkylidene, f are that 1-5 and g are 0-5, and condition is that the summation of f and g is 1-6;

R ¹²Be

R ¹³And R ¹⁴Independently be selected from-CH ₂-,-CH (C ₁-C ₆Alkyl)-,-C (two-(C ₁-C ₆) alkyl) ,-CH=CH-and C (C ₁-C ₆Alkyl)=CH-; Perhaps R ¹²With adjacent R ¹³With or R ¹²With adjacent R ¹⁴Together formation-CH=CH-or-CH=C (C ₁-C ₆Alkyl)-group;

A and b independently are 0,1,2 or 3, and condition is both and not all is 0;

Condition is when a is 2 or 3, R ¹³Can be identical or inequality; With

Condition is when b is 2 or 3, R ¹⁴Can be identical or inequality;

And when Q is key, R ¹Also can be

Or

M is-O-,-S-,-S (O)-or-S (O) ₂-;

D is 1,2 or 3;

H is 0,1,2,3 or 4;

S is 0 or 1; T is 0 or 1; M, n and p independently are 0-4; Condition be s and t at least one be 1, the summation of m, n, p, s and t is 1-6; Condition be when p be 0, t is 1 o'clock, the summation of m, s and n is 1-5; Condition be when p be 0, s is 1 o'clock, the summation of m, t and n is 1-5;

V is 0 or 1;

And when Q be key, R ¹Be

The time, Ar ¹Also can be pyridine radicals, isoxazolyl, furyl, pyrrole radicals, thienyl, imidazole radicals, pyrazolyl, thiazolyl, pyrazinyl, pyrimidine radicals or pyridazinyl;

R ²¹Be (C ₁-C ₆) alkyl, aryl or R ²⁴The aryl of-replacement;

R ²⁵Be H ,-OH or (C ₁-C ₆) alkoxyl.

Ar ²Preferred phenyl or R ¹¹-phenyl, particularly (4-R ¹¹The phenyl of)-replace.For R ¹¹Preferred definition be lower alkoxy, particularly methoxyl group and halogeno-group, particularly fluorine.

Ar ¹Preferred phenyl or R ¹⁰The phenyl, particularly (4-R of-replacement ¹⁰The phenyl of)-replace.Preferred R ¹⁰Be halogeno-group, more preferably fluorine.

Below be for variable-R ¹The more bonded preferred definitions of-Q-:

Q is key and R ¹Be low-grade alkylidene, preferred propylidene;

Q is a volution group as defined above, wherein preferred R ¹³And R ¹⁴Respectively be ethylidene, R ¹²Be

Or

R ¹Be-(CH ₂) _q, wherein q is 0-6;

Q is a key, R ¹Be

Wherein variable is elected R as ¹Be-O-CH ₂-CH (OH)-;

Q is a key, R ¹Be

Wherein variable is elected R as ¹Be-CH (OH)-(CH ₂) ₂-; With

Q is a key, R ¹Be

Wherein variable is elected R as ¹Be-CH (OH)-CH ₂-S (O) _0-2-

Therefore, the preferred chemical compound of formula (VIII) is wherein G and G ¹As defined above and all the other variables have with undefined chemical compound:

Ar ¹Be phenyl or R ¹⁰The phenyl of-replacement, wherein R ¹⁰It is halogeno-group;

Ar ²Be phenyl or R ¹¹-phenyl, wherein R ¹¹Be 1-3 and independently be selected from C ₁-C ₆The substituent group of alkoxyl and halogeno-group;

Q is a key, R ¹It is low-grade alkylidene; The 3-position ring carbon atom of Q and azetidinone forms

Wherein preferred R ¹³And R ¹⁴Respectively be that ethylidene and a and b respectively are 1, R wherein ¹²Be

Or Q is key and R ¹Be-O-CH ₂-CH (OH)-; Q is key and R ¹Be-CH (OH)-(CH ₂) ₂-; Or Q is key and R ¹Be-CH (OH)-CH ₂-S (O) _0-2-.

G and G for following formula ¹The preferred variable of group is as follows:

With

R ², R ³, R ⁴, R ⁵, R ⁶And R ⁷Independently be selected from H, (C ₁-C ₆) alkyl, benzyl and acetyl group.

G and G for following formula ¹The preferred variable of group is as follows:

R ³, R ^3a, R ⁴And R ^4aBe selected from H, (C ₁-C ₆) alkyl, benzyl and acetyl group.

R, R ^aAnd R ^bIndependently be selected from H ,-OH, halogeno-group ,-NH ₂, azido, (C ₁-C ₆) alkoxyl (C ₁-C ₆) alkoxyl and-W-R ³⁰,

Wherein W be-O-C (O)-or-O-C (O)-NR ³¹-, R ³¹Be H, R ³⁰Be (C ₁-C ₆) alkyl ,-C (O)-(C ₁-C ₄) alkoxyl-(C ₁-C ₆) alkyl, T, T-(C ₁-C ₆) alkyl, or T or T-(C ₁-C ₆) alkyl, wherein T is by one or two halogeno-group or (C ₁-C ₆) the alkyl replacement.

Preferred R ³⁰Substituent group is selected from: 2-fluoro phenyl, 2,4 difluorobenzene base, 2,6-Dichlorobenzene base, 2-aminomethyl phenyl, 2-thienyl methyl, 2-methoxyl group-carbonyl ethyl, thiazol-2-yl-methyl, 2-furyl, 2-methoxycarbonyl butyl and phenyl.

For R, R ^aAnd R ^bPreferred compositions is as follows:

1) R, R ^aAnd R ^bIndependently be-OH or-O-C (O)-NH-R ³⁰, R wherein particularly ^aBe-OH and R and R ^bBe-O-C (O)-NH-R ³⁰, R ³⁰Be selected from preferred substituted defined above, perhaps wherein R and R ^aRespectively be-OH R ^bBe-O-C (O)-NH-R ³⁰, R wherein ³⁰Be 2-fluoro phenyl, 2,4 difluorobenzene base, 2, the 6-Dichlorobenzene base;

2) R ^aBe-OH, halogeno-group, azido or (C ₁-C ₆) alkoxyl (C ₁-C ₆) alkoxyl, R ^bBe H, halogeno-group, azido or (C ₁-C ₆) alkoxyl (C ₁-C ₆) alkoxyl, R is-O-C (O)-NH-R ³⁰, R wherein particularly ^aBe-OH R ^bBe H, R ³⁰It is the chemical compound of 2-fluoro phenyl;

3) R, R ^aAnd R ^bIndependently be-OH or-O-C (O)-NH-R ³⁰, R ³⁰Be (C ₁-C ₆) alkyl, T or by one or two halogeno-group or (C ₁-C ₆) T that alkyl replaces, particularly wherein R is-OH and R ^aAnd R ^bBe-O-C (O)-R ³⁰Chemical compound, R wherein ³⁰It is the 2-furyl; With

4) R, R ^aAnd R ^bIndependently be-OH or halogeno-group.Other preferred compound of three classes is those wherein C ¹' end oxygen base is β, C wherein ²' end oxygen base is β, and wherein the R group is the chemical compound of α.G and G ¹Be preferably selected from:

With

Wherein Ac is an acetyl group, and Ph is a phenyl.

Preferred R ²⁶Be H or OH, be more preferably H.-O-G substituent group preferably connects the 4-position of phenyl ring at it.

In another embodiment, in the present composition and method employed sterol absorption inhibitor by representing with following formula (IX):

Or the isomer of formula (IX) chemical compound, or pharmaceutically acceptable salt or solvate formula (IX) chemical compound or formula (IX) compound isomers, or the prodrug of isomer, salt or the solvate of formula (IX) chemical compound or formula (IX) chemical compound, wherein in following formula (IX):

R ²⁶Be selected from following group:

a)OH；

b)OCH ₃；

C) fluorine;

D) chlorine;

R ¹Be selected from

-SO ₃H; Natural and alpha-non-natural amino acid;

R ³¹Independently be selected from H and (C ₁-C ₄) alkyl;

T independently is selected from phenyl, furyl, thienyl, pyrrole radicals, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, benzothiazolyl, thiadiazolyl group, pyrazolyl, imidazole radicals and pyridine radicals;

R ³²Independently be selected from 1-3 and independently be selected from following substituent group: H, halogeno-group, (C ₁-C ₄) alkyl ,-OH, phenoxy group ,-CF ₃,-NO ₂, (C ₁-C ₄) alkoxyl, methylene-dioxy, oxo base, (C ₁-C ₄) alkyl alkylthio base, (C ₁-C ₄) alkyl sulfinyl, (C ₁-C ₄) alkyl sulphonyl ,-N (CH ₃) ₂-,-C (O)-NH (C ₁-C ₄) alkyl ,-C (O)-N ((C ₁-C ₄) alkyl) ₂,-C (O)-(C ₁-C ₄) alkyl ,-C (O)-(C ₁-C ₄) group of alkoxyl and pyrrolidinyl carbonyl; Perhaps R ³²Be covalent bond, R ³¹With its nitrogen-atoms that is connected and R ³²Form pyrrolidinyl, piperidyl, N-methyl-piperazinyl, indolinyl or morpholinyl, or (C ₁-C ₄) pyrrolidinyl, piperidyl, N-methyl-piperazinyl, indolinyl or the morpholinyl of alkoxy carbonyl-replacement;

Ar ¹Be aryl or R ¹⁰The aryl of-replacement;

Ar ²Be aryl or R ¹¹The aryl of-replacement;

R ¹²Be

Or

R ¹⁰And R ¹¹Independently be selected from 1-3 substituent group that independently is selected from following group: (C ₁-C ₆) alkyl ,-OR ¹⁹,-O (CO) R ¹⁹,-O (CO) OR ²¹,-O (CH ₂) _1-5OR ¹⁹,-O (CO) NR ¹⁹R ²⁰,-NR ¹⁹R ²⁰,-NR ¹⁹(CO) R ²⁰,-NR ¹⁹(CO) OR ²¹,-NR ¹⁹(CO) NR ²⁰R ²⁵,-NR ¹⁹SO ₂R ²¹,-COOR ¹⁹,-CONR ¹⁹R ²⁰,-COR ¹⁹,-SO ₂NR ¹⁹R ²⁰, S (O) _0-2R ²¹,-O (CH ₂) _1-10COOR ¹⁹,-O (CH ₂) _1-10CONR ¹⁹R ²⁰,-(C ₁-C ₆Alkylidene)-COOR ¹⁹,-CH=CH-COOR ¹⁹,-CF ₃,-CN ,-NO ₂And halogen;

R ²¹Be (C ₁-C ₆) alkyl, aryl or R ²⁴The aryl of-replacement;

R ²³And R ²⁴Independently independently be selected from H, (C for 1-3 ₁-C ₆) alkyl, (C ₁-C ₆) alkoxyl ,-COOH, NO ₂,-NR ¹⁹R ²⁰The group of ,-OH and halogeno-group; With

R ²⁵Be H ,-OH or (C ₁-C ₆) alkoxyl.

Ar ¹Preferred phenyl or R ¹⁰The phenyl, particularly (4-R of-replacement ¹⁰The phenyl of)-replace.To R ¹⁰Preferred definition is a halogeno-group, particularly fluorine.

Preferred Q is low alkyl group or volution group as defined above, wherein preferred R ¹³And R ¹⁴Respectively be ethylidene, R ¹²Be

Or

Therefore the preferred compound of formula IX is R wherein ¹Be to remain variable as defined above and wherein to have with undefined chemical compound:

Q is low alkyl group (being that C-1 is to C-2), simultaneously preferred Q=C-2, or the 3-position ring carbon atom of Q and azetidinone forms group

Or

R for following formula ¹The preferred variable of group is as follows:

With

R for following formula ¹The preferred variable of group is as follows:

R, R ^aAnd R ^bIndependently be selected from H ,-OH, halogeno-group ,-NH ₂, azido, (C ₁-C ₆) alkoxyl (C ₁-C ₆) alkoxyl and-W-R ³⁰, wherein W be-O-C (O)-or-O-C (O)-NR ³¹-, R ³¹Be H, R ³⁰Be (C ₁-C ₆) alkyl ,-C (O)-(C ₁-C ₄) alkoxyl-(C ₁-C ₆) alkyl, T, T-(C ₁-C ₆) alkyl, or T or T-(C ₁-C ₆) alkyl, wherein T is by one or two halogeno-group or (C ₁-C ₆) the alkyl replacement.

Preferred R ³⁰Substituent group is 2-fluoro phenyl, 2,4 difluorobenzene base, 2,6-Dichlorobenzene base, 2-aminomethyl phenyl, 2-thienyl methyl, 2-methoxyl group-carbonyl ethyl, thiazol-2-yl-methyl, 2-furyl, 2-methoxycarbonyl butyl and phenyl.

For R, R ^aAnd R ^bPreferred compositions is as follows:

1) R, R ^aAnd R ^bIndependently be-OH or-O-C (O)-NH-R ³⁰, R wherein particularly ^aBe-OH and R and R ^bBe-O-C (O)-NH-R ³⁰, R ³⁰Be selected from preferred substituted defined above, perhaps wherein R and R ^aBe-OH R ^bBe-O-C (O)-NH-R ³⁰, R wherein ³⁰Be 2-fluoro phenyl, 2,4 difluorobenzene base, 2, the 6-Dichlorobenzene base;

2) R ^aBe-OH, halogeno-group, azido or (C ₁-C ₆) alkoxyl (C ₁-C ₆) alkoxyl, R ^bBe H, halogeno-group, azido or (C ₁-C ₆) alkoxyl (C ₁-C ₆) alkoxyl, R is-O-C (O)-NH-R ₃₀, R wherein particularly ^aBe-OH R ^bBe H, R ³⁰It is the chemical compound of 2-fluoro phenyl;

3) R, R ^aAnd R ^bIndependently be-OH or-O-C (O)-R ³⁰, R ³⁰Be (C ₁-C ₆) alkyl, T or by one or two halogeno-group or (C ₁-C ₆) T that alkyl replaces, particularly wherein R is-OH and R ^aAnd R ^bBe-O-C (O)-R ³⁰Chemical compound, R wherein ³⁰It is the 2-furyl; With

4) R, R ^aAnd R ^bIndependently be-OH or halogeno-group.The other preferred compound of three classes is those wherein C ¹' end oxygen base is β, C wherein ²' end oxygen base is β, and the R group chemical compound that is wherein.

Preferred R1 is selected from:

With

Wherein Ac is an acetyl group, and Ph is a phenyl.

The examples for compounds that the present invention uses is the chemical compound by formula X representative:

R wherein ¹As defined above, or the pharmaceutically acceptable salt or the solvate of formula (X) chemical compound, or the prodrug of formula (X) chemical compound or the pharmaceutically acceptable salt of formula (X) chemical compound or the prodrug of solvate.

Preferred chemical compound is the chemical compound by formula XI representative:

Or the pharmaceutically acceptable salt or the solvate of formula (XI) chemical compound, or the prodrug of formula (XI) chemical compound or the pharmaceutically acceptable salt of formula (XI) chemical compound or the prodrug of solvate.

In another embodiment, the aforesaid compositions that is provided, Pharmaceutical composition, therapeutic combination medicine, kit and Therapeutic Method comprise: (a) at least a peroxisome proliferation-activated receptors activator; (b) at least a substituted azetidinone chemical compound or at least a substituted 'beta '-lactam compounds, or the isomer of at least a substituted azetidinone chemical compound or at least a substituted 'beta '-lactam compounds, or the pharmaceutically acceptable salt of at least a substituted azetidinone chemical compound or at least a substituted 'beta '-lactam compounds or solvate, or the pharmaceutically acceptable salt of the isomer of at least a substituted azetidinone chemical compound or at least a substituted 'beta '-lactam compounds or solvate, or the isomer of the prodrug of at least a substituted azetidinone chemical compound or at least a substituted 'beta '-lactam compounds or at least a substituted azetidinone chemical compound or at least a substituted 'beta '-lactam compounds, the prodrug of salt or solvate, wherein the total amount of first dosage and second dosage (no matter being administration simultaneously or successive administration) is formed for treatment or prevention angiopathy, diabetes, the treatment effective dose of sterol concentration in obesity or the reduction mammalian plasma.

The azetidinone chemical compound of suitable replacement or the 'beta '-lactam compounds of replacement can be selected from the chemical compound among any above-mentioned formula I-XI.The azetidinone chemical compound of the replacement that other is useful is included in U.S. Patent number 4; 983; disclosed N-sulfonyl-2-azetidinone and at Indian J.Chem.Sect.B.29B such as Ram in 597; 12 (1990); disclosed 4-in the 1134-7 page or leaf (2-oxo aza ring butylene-4-yl) phenoxy group-alkanoic acid ethyl ester, the above document is combined in herein as a reference.

The chemical compound of formula I-XI can be by the preparation of known method, comprise above-described method and for example WO 93/02048 described preparation wherein-R ¹-Q-is the chemical compound of alkylidene, alkenylene or the alkylidene, phenylene or the cycloalkylidene that are interrupted by hetero atom; WO 94/17038 described preparation wherein Q is the chemical compound of volution group; WO 95/08532 described preparation wherein-R ¹-Q-is the chemical compound of the alkylidene of hydroxyl-replacement; PCT/US95/03196 is wherein described-R ¹-Q-be by-O-or S (O) _0-2Group is connected to Ar ¹The chemical compound of the alkylidene of the hydroxyl-replacement of part; And United States Patent (USP) serial number 08/463, the 619 described preparation that submit to June 5 nineteen ninety-five wherein-R ¹-Q-is by-S (O) _0-2Group is connected to the chemical compound of the alkylidene that the hydroxyl of azetidinone ring replaces.

The daily dose of sterol absorption inhibitor can be about 0.1-1000mg every day, preferably approximately 0.25-50mg/ days, more preferably every day about 10mg, give with single dose or with the 2-4 divided dose.Yet definite dosage is decided by clinical treatment doctor decision and according to the character of giving chemical compound, patient's age, body weight, state and reaction.

For the pharmaceutically acceptable salt that gives the above chemical compound, the weight of above indication is described acid equivalent or the normal weight of alkali by the deutero-treatment chemical compound of described salt.

In one embodiment of the invention, described chemical compound or therapeutic combination medicine can also comprise reagent on one or more pharmacology or curative or medicine cholesteral biosynthesis inhibitor and/or lipid-depressant as described below.

In another embodiment, described compositions or treatment can also comprise and the above peroxisome proliferation-activated receptors activator and sterol absorption inhibitor one or more cholesteral biosynthesis inhibitors in company with administration or administering drug combinations.

The non-limiting example of employed cholesteral biosynthesis inhibitor comprises competitive inhibitor (being the biosynthetic rate-limiting step of cholesterol), Squalene synthetic inhibitor, squalene epoxidase inhibitor and their mixture of HMG CoA reductase in the present composition, therapeutic combination medicine and method.The non-limiting example of appropriate H MG CoA reductase inhibitor (for example comprises Statins such as lovastatin

It is from Merck﹠amp; Co buys and to obtain), pravastatin (for example

It is bought from Bristol Meyers Squibb and obtains), fluvastatin, simvastatin (for example It is from Merck ﹠amp; Co buys and to obtain), atorvastatin, cerivastatin, CI-981, rivastatin (7-(4-fluoro phenyl)-2,6-diisopropyl-5-methoxy pyridin-3-yl)-3,5-dihydroxy-6-enanthic acid sodium, rosuvastatin, Pitavastatin (NK-104 of for example Japanese Negma Kowa); HMG CoA synthetic inhibitor is L-659 for example, 699 ((E, E)-11-[3 ' R-(hydroxyl-methyl)-4 '-oxo-2 ' R-oxetanyl]-3,5,7R-trimethyl-2,4-undecandienoic acid); The Squalene synthetic inhibitor is squalestatin 1 for example; The squalene epoxidase inhibitor is NB-598 ((E)-N-ethyl-N-(6 for example, 6-dimethyl-2-heptene-4-base alkynyl (nyl))-and 3-[(3,3 '-two thiophene-5-yl) methoxyl group]-benzene-methylamine hydrochloride) and other sterol biosynthesis inhibitor such as DMP-565.Preferred HMG CoA reductase inhibitor comprises lovastatin, pravastatin and simvastatin.Most preferred HMG CoA reductase inhibitor is a simvastatin.

In general, total daily dose of cholesteral biosynthesis inhibitor can be about 0.1-160mg every day, preferably approximately 0.2-80mg/ days, and with single dose or the administration of 2-3 divided dose.

In another preferred embodiment, described compositions or treatment comprise formula (II) chemical compound with one or more peroxisome proliferation-activated receptors activators and one or more cholesteral biosynthesis inhibitors and usefulness.In described embodiment, preferred peroxisome proliferation-activated receptors activator is the shellfish acid derivative that is selected from gemfibrozil, clofibrate and/or fenofibrate.Preferred cholesteral biosynthesis inhibitor comprises one or more HMG CoA reductase inhibitor, for example lovastatin, pravastatin and/or simvastatins.More preferably described compositions or treatment comprise formula (II) chemical compound with simvastatin and gemfibrozil or fenofibrate and usefulness.

In another alternative embodiment, compositions of the present invention, therapeutic combination medicine or method can also comprise and the above PPAR activator and sterol absorption inhibitor one or more bile acid intercalating agents (undissolved anion exchange resin) in company with administration or administering drug combinations.

Bile acid intercalating agent conjugated bile acid in intestinal is blocked the enterohepatic circulation of bile acid and is caused the steroid in the feces ejection to increase.It is because the non--system mode of their effects that the use of bile acid intercalating agent meets the requirements.The bile acid intercalating agent can reduce the liver inner cholesterol and promote the synthetic of apoenzyme B/E (LDL) receptor, and described receptor further reduces the level of blood cholesterol in conjunction with LDL from blood plasma.

The non-limiting example of suitable bile acid intercalating agent comprise colestyramine (but contain the styrene-divinylbenzene copolymer of the quaternary ammonium cation group of conjugated bile acid, for example

Or QUESTRAN

Colestyramine, it can be bought from Bristol-Myers Squibb and obtain), colestipol (diethylenetriamines and 1-chloro-2, the copolymer of 3-expoxy propane, for example Tablet, it can be bought from Pharmacia and obtain), the hydrochloric acid colesevelam (for example

Tablet, (with epichlorohydrin cross-linked and by 1-bromodecane alkylating (poly-(allylamine hydrochloride) and (6-bromo hexyl)-trimethylammonium bromide), it can be bought from Sankyo and obtain), soluble derivative for example 3,3-ioene, N-(cycloalkyl) alkylamine and poliglusam, the quaternized polystyrene of non-dissolubility, ZAOCAO glycoside and their mixture.Other useful bile acid intercalating agent is as disclosed material in PCT number of patent application WO 97/11345 and WO 98/57652 and U.S. Patent number 3,692,895 and 5,703,188, and the above document is combined in herein as a reference.Suitable inorganic cholesterol intercalating agent comprises that basic bismuth salicylate adds montmorillonitic clay, aluminium hydroxide and calcium carbonate antacid.

Usually, total daily dose of bile acid intercalating agent can be about every day of 1-50g, and be approximately 2-16g preferred every day, with single dose or the administration of 2-4 divided dose.

In another alternative embodiment, compositions of the present invention or treatment can also comprise with the above peroxisome proliferation-activated receptors activator and sterol absorption inhibitor in company with one or more ileal bile acid transfers (" IBAT ") inhibitor of administration or administering drug combinations (or apical sodium-altogether-rely on bile acid transport (" ASBT ") inhibitor).Described ibat inhibitor can suppress bile acid transport to reduce the LDL cholesterol levels.The non-limiting example of suitable ibat inhibitor comprises benzothiazepine

Class (benzothiepine) is for example disclosed in PCT patent application WO00/38727 (it is combined in herein as a reference) to contain 2,3,4,5-tetrahydrochysene-1-benzothiazepine

1, the treatment chemical compound of 1-dioxide structure.

Usually, total daily dose of ibat inhibitor can be about every day of 0.01-1000mg, and be approximately 0.1-50mg preferred every day, with single dose or 2-4 divided dose administration administration.

In another alternative embodiment, compositions of the present invention or treatment can also comprise and the above peroxisome proliferation-activated receptors activator and sterol absorption inhibitor nicotinic acid (vitamin PP) and/or its derivant in company with administration or administering drug combinations.

This literary composition employed " nicotinic acid derivates " refers to contain the chemical compound of pyridine-3-carboxylic acid ester structure or pyrazine-2-carboxylate structure, comprises sour form, salt, ester, amphion and tautomeride, can buy to obtain.The example of nicotinic acid derivates comprises niceritrol, nicofuranose and acipimox (5-methylpyrazine-2-carboxylic acid 4-oxide).The liver that nicotinic acid and derivant thereof suppress VLDL and metabolite LDL thereof produces and increase HDL and apoenzyme A-1 level.The example of suitable nicotinic acid product is

(nicotinic acid prolongation release tablet), it can be bought from Kos and obtain.

Usually, total daily dose of nicotinic acid or derivatives thereof can be about every day of 500-10,000mg, and preferably approximately 1000-8000mg/ days, more preferably approximately 3000-6000mg/ days, with single dose or divided dose administration.

In another alternative embodiment; compositions of the present invention or treatment can also comprise and the above peroxisome proliferation-activated receptors activator and sterol absorption inhibitor one or more acyl-CoAs in company with administration or administering drug combinations: adjacent acyltransferase (" the ACAT ") inhibitor of cholesterol, this inhibitor can reduce LDL and VLDL level.ACAT is a kind of enzyme of responsible esterification cells,extra inner cholesterol, can reduce the excessive generation of synthesizing and contain the lipoprotein of apoenzyme B-100 of cholesterol esterification product VLDL.

Effectively the non-limiting example of ACAT inhibitor comprises avasimibe ([[2; 4; 6-three (1-Methylethyl) phenyl] acetyl group] sulfamic acid; 2; two (1-Methylethyl) phenylesters of 6-; be called CI-1011 in the past), HL-004, lecimibide (DuP-128) and CL-277082 (N-(2,4 difluorobenzene base)-N-[[4-(2, the 2-dimethyl propyl) phenyl] methyl]-N-heptyl urea).Referring to P.Chang etc., " Curreent, New and Future Treatments in Dyslipidaemia andAtherosclerosis " Drugs 2000 Jul; 60 (1); 55-93, it is attached to herein as a reference.

Usually, total daily dose of ACAT inhibitor can be for approximately 0.1-1000mg/ days, with single dose or the administration of 2-4 divided dose.

In another alternative embodiment, compositions of the present invention or treatment can also comprise and the above peroxisome proliferation-activated receptors activator and sterol absorption inhibitor one or more cholesterol ester transfer protein (" the CETP ") inhibitor in company with administration or administering drug combinations.Exchange or transfer that CETP is responsible for having HDL and is present in the cholesteryl ester of the triglyceride among the VLDL.

The non-limiting example of appropriate C ETP inhibitor has disclosed inhibitor in PCT number of patent application WO00/38721 and U.S. Patent number 6,147,090, and described document is combined in herein as a reference.Pancreas cholesterol ester hydrolase (pCEH) inhibitor such as WAY-121898 also can with the above peroxisome proliferation-activated receptors activator and sterol absorption inhibitor in company with administration or administering drug combinations.

Usually, total daily dose of CETP inhibitor can be preferably about 0.5-20mg/kg body weight/day, with single dose or divided dose administration for approximately 0.01-1000mg/ days.

In another alternative embodiment, compositions of the present invention or treatment can also comprise that (for example U.S. Patent number 6 in company with the probucol or derivatives thereof of administration or administering drug combinations with the above peroxisome proliferation-activated receptors activator and sterol absorption inhibitor, 121,319 and 6,147, open AGI-1067 and its derivant in 250), described medicine can reduce the LDL level.

Usually, total daily dose of probucol or derivatives thereof can be preferably 500-1500mg/ days, with single dose or the administration of 2-4 divided dose for approximately 10-2000mg/ days.

In another alternative embodiment, compositions of the present invention or treatment can also comprise and the above peroxisome proliferation-activated receptors activator and sterol absorption inhibitor low density lipoprotein, LDL (LDL) receptor activator in company with administration or administering drug combinations.The non-limiting example of suitable LDL-receptor activator comprises HOE-402, the active imidazolidinyl-pyrimidine derivatives of a kind of direct stimulation ldl receptor.Referring to M.Huettinger etc., " reducing active ", Arterioscler.Thromb.1993 by the short serum lipids of the HOE-402 of ldl receptor stimulation approach mediation; 13:1005-12.

Usually, total daily dose of LDL-receptor activator can be for approximately 1-1000mg/ days, with single dose or the administration of 2-4 divided dose.

In another alternative embodiment, compositions of the present invention or treatment can also comprise and the above peroxisome proliferation-activated receptors activator and the sterol absorption inhibitor fish oil in company with administration or administering drug combinations, described fish oil contains omega-fatty acid (3-PUFA), and it can reduce VLDL and triglyceride levels.Usually, total daily dose of fish oil or omega-fatty acid can be for about 1-30 gram/sky, with single dose or the administration of 2-4 divided dose.

In another alternative embodiment, compositions of the present invention or treatment can also comprise and the above peroxisome proliferation-activated receptors activator and the sterol absorption inhibitor water-soluble fiber in company with administration or administering drug combinations, for example Psyllium, Guar beans, Herba bromi japonici and pectin, they can the cholesterol reducing level.Usually, total daily dose of water-soluble fiber can be for about 0.1-10 gram/sky, with single dose or the administration of 2-4 divided dose.

In another alternative embodiment, compositions of the present invention or treatment can also comprise with the above peroxisome proliferation-activated receptors activator and sterol absorption inhibitor in company with the fatty acid ester of plant sterol, phytostanol and/or the phytostanol of administration or administering drug combinations, for example exist

The sitostanol ester that uses in the margarine, it can the cholesterol reducing level.Usually, total daily dose of the fatty acid ester of plant sterol, phytostanol and/or phytostanol can be for about 0.5-20 gram/sky, with single dose or the administration of 2-4 divided dose.

In another alternative embodiment, compositions of the present invention or treatment can also comprise and the above peroxisome proliferation-activated receptors activator and the sterol absorption inhibitor antioxidant in company with administration or administering drug combinations, for example probacol, tocopherol, ascorbic acid, beta-carotene and selenium, or vitamin such as vitamin B ₆Or vitamin B ₁₂Usually, total daily dose of antioxidant or vitamin can be for about 0.05-10 gram/sky, with single dose or the administration of 2-4 divided dose.

In another alternative embodiment, compositions of the present invention or treatment can also comprise with the above peroxisome proliferation-activated receptors activator and sterol absorption inhibitor in company with the mononuclear cell of administration or administering drug combinations with hugely bite strong born of the same parents' inhibitor, for example polyunsaturated fatty acid (PUFA), the thyroxin that comprises thyroxine analogues such as CGS-26214 (a kind of have the thyroxine compounds of fluoridizing ring), recombinant protein are as gene therapy and the use of reorganization apoenzyme E.Usually, total daily dose of these medicines can be for approximately 0.01-1000mg/ days, with single dose or the administration of 2-4 divided dose.

The present invention also can adopt compositions or therapeutic combination medicine, and described compositions or therapeutic combination medicine also comprise hormone replacement agent and compositions.The hormone preparation and the compositions that can be used for Hormone Replacement Therapy of the present invention comprise androgen, estrogen, progesterone, their pharmaceutically acceptable salt and derivant thereof.It also is effective that these medicines and compositions combine.

The dosage of androgen and estrogen combination medicine can approximately change in 1-4mg androgen and the about 1-3mg estrogen scope ideally.Example includes but not limited to the combination medicine of the estrogen (estrone sodium sulfate and equilin sodium sulfate) of androgen and estrogenic combination medicine such as esterification and methyltestosterone (17-hydroxyl-17-methyl-, (17B)-hero-4-alkene-3-ketone), can be from SolvayPharmaceuticals, Inc., Marieta, GA buys and obtains trade name Estratest (Estratest).

The dosage of estrogen and estrogen combination medicine can change between the highest 8mg at about 0.01m, is desirably about 0.3-3.0mg.The example of available estrogen and estrogen combination medicine comprises:

(a) mixture of nine (9) synthetic estrogen substances, comprise estrone sodium sulfate, equilin sodium sulfate, 17 α-dihydroequilin sodium sulfate, 17 alpha-estradiol sodium sulfate, 17 β-dihydroequilin sodium sulfate, 17 'alpha '-dihydroequilenin sodium sulfate, 17 β-dihydroequilenin sodium sulfate, (.+-.)-Equilenin. sodium sulfate and 17 beta estradiol sodium sulfate, can be from DuramedPharmaceuticals, Inc., Cincinnati, OH buys and obtains, and trade name is Cenestin;

(b) ethinyl estradiol (19-loses carbon-17 α-pregnant steroid-1,3,5-(10)-triolefin-20-alkynes-3,17-glycol); From Schering Plough Corporation, Kenilworth, NJ buys and obtains, and trade name is ethinylestradiol (Estinyl);

(c) esterified estriol combination medicine is as estrone sodium sulfate and equilin sodium sulfate; Can obtain from the Solvay purchase, trade name is Estratab (Estratab), also can be from Monarch Pharmaceuticals, and Bristol, TN buys and obtains, and trade name is esterified estrogen preparation (Menest);

(d) piperazine estrone sulfate (piperazine female-1,3,5 (10)-triolefins-17-ketone, 3-(sulfo-oxygen base)-estrone sulfate); From Pharmacia ﹠amp; Upjohn, Peapack, NJ buys and obtains, and trade name is piperazine estrone sulfate (Ogen), and from Women First Health Care, Inc., San Diego, CA buys and obtains, and trade name is Ortho-Est (Ortho-Est); With

(e) conjugated estrogens (17 α-dihydroequilin, 17 alpha-estradiols and 17 β-dihydroequilin); From Wyeth-Ayerst Pharmaceuticals, Philadelphia, PA buys and obtains, and trade name is premarin (Premarin).

Progestational hormone also can be typically about 0.05-2.0mg progesterone and about 0.001-2mg estrogen with different dosed administrations with estrogens, is desirably about 0.1-1mg progesterone and about 0.01-0.5mg estrogen.The example of transformable progesterone of dosage and administration and estrogen combination medicine comprises:

(a) the combination medicine of estradiol (female-1,3,5-(10)-triolefin-3,17 beta-diketon semihydrate) and norethindrone (17 β-acetate-19-loses carbon-17 α-pregnant steroid-4-alkene-20-alkynes-3-ketone); It is from Pharmacia ﹠amp; Upjohn, Peapack, NJ buys and obtains, and trade name is Activella;

(b) the combination medicine of levonorgestrel (d (-)-13 β-ethyl-17 α-acetenyl-17 beta-hydroxy gland steroid-4-alkene-3-ketone) and acetenyl estradial; Obtain from the Wyeth-Ayerst purchase, trade name is Alesse, from Watson Laboratories, and Inc., Corona, CA buys and obtains, and trade name is Levora (Levora) and Trivora, from Monarch

Pharmaceuticals buys and obtains, and trade name is Levora (Nordette), and obtains from the Wyeth-Ayerst purchase, and trade name is Triphasil;

(c) the combination medicine of ethynodiol diacetate (19-loses carbon-17 α-pregnant steroid-4-alkene-20-alkynes-3 β, 17-glycol diacetate) and ethinyl estradiol; From G.D.Searle ﹠amp; Co., Chicago, IL buy and to obtain, and trade name is that Nelulen (Demulen) and buy from Watson obtains, and trade name is Zovia;

(d) the combination medicine of desogestrel (13-ethyl-11-methylene-18, the two carbon-17 α-pregnant steroid-4-alkene-20-alkynes-17-alcohol that lose of 19-) and ethinylestradiol; Obtain from Organon, commodity Desogen by name and Mircette, and from Ortho-McNeil Pharmaceutical, Raritan, NJ buys and obtains, and trade name is Ortho-Cept;

(e) the combination medicine of norethindrone and ethinyl estradiol; From Parke-Davis, MorrisPlains, NJ buys and obtains, and trade name is Estrostep and femhrt, obtain from the Watson purchase, trade name is Microgestin, Necon and Tri-Norinyl, buys from Ortho-McNeil to obtain, and trade name is Modicon and Ortho-Novum, and from Warner ChilcottLaboratories, Rockaway, NJ buys and obtains, and trade name is Ovcon;

(f) the combination medicine of norgestrel ((±)-13-ethyl-17-hydroxyl-18, two decarburization-17 α of 19--pregnant steroid-4-alkene-20-alkynes-3-ketone) and ethinyl estradiol; Obtain from the Wyeth-Ayerst purchase, trade name is Ovral and Lo/Ovral, buys from Watson to obtain, and trade name is Ogestrel and Low-Ogestrel;

(g) the combination medicine of norethindrone, ethinyl estradiol and mestranol (3-methoxyl group-19-decarburization-17 α-pregnant steroid-1,3,5 (10)-triolefins-20 alkynes-17-alcohol); Obtain from the Watson purchase, trade name is Brevicon and Norinyl;

(h) the combination medicine of 17 beta estradiols (female-1,3,5 (10)-triolefins-3,17-isoallopregnane-3) and micronization norgestimate (17 α-17-(acetyl group oxygen base)-13-ethyl-18, the two pregnant steroids of decarburization of 19--4-alkene-20-alkynes-3-ketone-3-oxime); Obtain from the Ortho-McNeil purchase, trade name is Ortho-Prefest;

(i) norgestimate (18, the two pregnant steroids of decarburization-17-of 19--4-alkene-20-alkynes-3-ketone-, 17-(acetyl group oxygen base)-13-ethyl-, oxime, the combination medicine of (17 (α)-(+)-) and ethinyl estradiol; Obtain from the Ortho-McNeil purchase, trade name is Ortho Cyclen and Orho Tri-Cyclen; With

(j) conjugated estrogens (estrone sodium sulfate and equilin sodium sulfate) and medroxyprogesterone acetate (the 20-diketone, 17-(acetyl group oxygen base)-6-methyl-, (6 (α))-pregnant steroid-4-alkene-3) the combination medicine; Obtain from the Wyeth-Ayerst purchase, trade name is Premphase and Prempro.

In general, the dosage of progestational hormone can be approximately changing in the 0.05-10mg scope, if perhaps give the micronization progesterone, then dosage can arrive at most approximately 200mg.The example of progesterone comprises norethindrone, can be from ESI Lederle, and Inc., Philadelphia, PA buy and to obtain, and trade name is Aygestin, buys from Ortho-McNeil to obtain, and trade name is that Micronor and buy from Watson obtains, and trade name is Nor-QD; Norgestrel obtains from the Wyeth-Ayerst purchase, and trade name is Ovrette; Micronize progesterone (pregnant steroid-4-alkene-3,20-diketone) obtains from the Solvay purchase, and trade name is Prometrium; And medroxyprogesterone acetate, from Pharmacia ﹠amp; Upjohn buys and obtains, and trade name is Provera.

Compositions of the present invention, therapeutic combination medicine or method can also comprise one or more obesity control medicines.Available obesity control medicine includes but not limited to reduce the medicine of caloric intake or appetite-suppressing, the medicine and the nutrient distribution medicine of increase energy expenditure.Suitable obesity control medicine includes but not limited to norepinephrine energy medicament (for example amfepramone, Mazindol, phenylpropanolamine, phentermine, phendimetrazine, tartaric acid phendamine, metamfetamine, phendimetrazine and Tartaric acid salt); Serotonin activator (for example sibutramine, fenfluramine, dexfenfluramine, fluoxetine, fluvoxamine and paroxetine); Thermogenic agent (for example ephedrine, caffeine, theophylline and selectivity β 3-2-adrenergic agonist components); The alpha block agent; Kainite or ampa receptor antagonist; Receptor is excited in leptin-steatolysis; The phosphodiesterase enzyme inhibitor; Chemical compound with nucleotide sequence of mahogany gene; Fibroblast growth factor-10 polypeptide class; Oxidase inhibitor (for example befloxatone, moclobemide, brofaromine, phenoxathine, esuprone, befol, Toloxatone, pirlindole, amiflamine, sercloremine, bazinaprine, lazabemide, milacemide and caroxazone); Improve the chemical compound (as the rutaecarpin chemical compound) of lipid metabolism; And lipase inhibitor (for example orlistat).Usually, the accumulated dose of the above obesity control medicine can be 1-3,000mg/ days, be desirably about 1-1, and 000mg/ days, better was about 1-200mg/ days, with single dose or the administration of 2-4 divided dose.

Compositions of the present invention, therapeutic combination medicine or method can also comprise one or more Hemoregulatories, this regulator is different from the azetidinone of replacement and 'beta '-lactam compounds of replacement (for example the above I-XI chemical compound) and above-mentioned PPAR receptor activator aspect chemical property, for example, they contain one or more different atoms, have the atomic arrangement that is different from above-mentioned sterol absorption inhibitor or PPAR receptor activator or one or more atoms of different numbers.Employed Hemoregulatory includes but not limited to anticoagulant (argatroban, bivalirudin, dalteparin sodium, desirudin, dicoumarol, lyapolate sodium, nafamostat mesilate, phenprocoumon, tinzaparin sodium, warfarin sodium); Antithrombotic drug (anagrelide hydrochloride, bivalirudin, cilostazol, dalteparin sodium, Danaparoid sodium, dazoxiben hydrochloride, efegatran sulfate, Enoxaparin Sodium, fluretofen, ifetroban, ifetroban sodium, lamifiban, hydrochloric acid lotrafiban, Napsagatran, orbofiban acetate, acetic acid roxifiban, sibrafiban, tinzaparin sodium, trifenagrel, abciximab, zolimomab aritox); Fibrinogen deceptor antagonists (acetic acid roxifiban, fradafiban, orbofiban, hydrochloric acid lotrafiban, tirofiban, xemilofiban, 7E3-monoclonal antibody, sibrafiban); Platelet suppressant drug (cilostazol, clopidogrel hydrogenesulphate, epoprostenol, Cycloprostin, ticlopidine hydrochloride, aspirin, cloth Lip river phenol, naproxen, sulindac, idomethacin, mefenamic acid salt (mefenamate), drogelor, diclofenac, sulfinpyrazone, piroxicam, persantin); Anticoagulant (acadesine, Beraprost, beraprost sodium, ciprostene calcium, itazigrel, lifarizine, hydrochloric acid lotrafiban, orbofiban acetate, oxagrelate, fradafiban, orbofiban, tirofiban, xemilofiban); Hemorheology medicine (pentoxifylline); Lipoprotein association blood coagulation inhibitor; VIIa factor inhibitors (4H-31-benzoxazinyl-4-ketone, 4H-3,1-benzoxazinyl-4-thioketone class, the quinazoline-4-one class, quinazoline-4-thioketone class, benzothiazine-4-ketone, imidazole radicals-boric acid-deutero-peptide analogues TFPI-derived peptide class, naphthalene-2-sulfonic acid 1-[3-(amino imino methyl)-benzyl]-2-oxo-pyrrolidine-3-(S)-yl } amide trifluoroacetate, dibenzofurans-2-sulfonic acid 1-[3-(amino methyl)-benzyl]-5-oxo-pyrrolidine-3-yl }-amide, toluene-4-sulfonic acid 1-[3-(amino imino methyl)-benzyl]-2-oxo-pyrrolidine-3-(S)-yl }-amide trifluoroacetate, 3,4-dihydro-1H-isoquinolin-2-sulfonic acid 1-[3-(amino imino methyl)-benzyl]-2-oxo-pyrrolin-3-(S)-yl }-amide trifluoroacetate); Xa factor inhibitor (disubstituted pyrazoline; disubstituted triazoline; just-[(amino imino methyl) phenyl] the propyl amides class that replaces; just-[(amino methyl) phenyl] the propyl amides class that replaces; tissue factor approach restrainer (TFPI); low molecular weight heparin; heparinoid; benzimidazoline benzoxazolinone; benzo piperazine ketone; 2, the 3-bihydrogen-1-indenone; binary (amidino groups aryl) propanoic derivatives class; amidino groups phenyl-pyrrolidines; amidino groups phenyl-pyrrolin class; amidino groups phenyl-isoxazole alkanes; the amidino groups indoles; the amidino groups pyroles; two-arlysulfonylamino heterocyclic carbamate derivatives class; Xa peptide factor inhibitor).

Compositions of the present invention, therapeutic combination medicine or method can also comprise one or more cardiovascular drugses, this medicine is different from the azetidinone of replacement and 'beta '-lactam compounds of replacement (for example the above I-XI chemical compound) and above-mentioned PPAR receptor activator aspect chemical property, for example they contain one or more different atoms, have the atomic arrangement that is different from above-mentioned sterol absorption inhibitor or PPAR receptor activator or one or more atoms of different numbers.Employed cardiovascular drugs includes but not limited to calcium channel blocker (maleic acid clentiazem

Amlodipine Besylate Tablet, isradipine, nimodipine, felodipine, nilvadipine, nifedipine, teludipine hydrochloride, diltiazem hydrochloride

Belfosdil, verapamil hydrochloride, fostedil); Adrenergic blocking drug (fenspiride hydrochloride, labetalol hydrochloride, proroxan, alfuzosin hydrochloride, acebutolol, Acebutolol, alprenolol hydrochloride, atenolol, Bunolol Hydrochloride, carteolol hydrochloride, Celectol (Rorer), cetamolol hydrochloride, the hydrochloric acid cicloprolol, dexpropranolol hydrochloride, diacetolol hydrochloride, dilevalol hydrochloride, esmolol hydrochloride, exaprolol hydrochloride, flestolol sulfate, labetalol hydrochloride, the hydrochloric acid levobetaxolol, Levobunolol Hydrochorid, metalol hydrochloride, metoprolol, spectinomycin hydrochloride, nadolol, pamatolol sulfate, penbutolol sulfate, practolol, propranolol hydrochloride, sotalol hydrochloride, timolol, timolol maleate, tiprenolol hydrochloride, tolamolol, bisoprolol, the bisoprolol fumarate, nebivolol); The Adrenergic agonists class; Angiotensin converting enzyme (ACE) inhibitor (benazepril hydrochloride, benazeprilat, captopril, delapril hydrochloride, fosinopril sodium, libenzapril, CI-925, pentopril, perindopril, quinapril hydrochloride, quinaprilat, ramipril, spirapril hydrochloride, spiral shell pula profit, teprotide, enalapril maleate, lisinopril, zofenopril calcium, perindopril elbumin); Antihypertensive (althiazide, benzthiazide, captopril, carvedilol, 6-chloro-7-sulfamoyl-2H-1,2,4-benzothiadiazin-2-ylsodium 1,1-dioxide, clonidine hydrochloride, cyclothiazide, delapril hydrochloride, dilevalol hydrochloride, Carclura, fosinopril sodium, Guanfacine Hydrochloride, methyldopa, metroprolol succinate, CI-925, monatepil maleate, pelanserin hydrochloride, the fragrant benzyl of hydrochloric acid is bright, minipress, primidolol, quinapril hydrochloride, quinaprilat, ramipril, terazosin hydrochloride, Candesartan, Candesartan Cilexetil, telmisartan, Amlodipine Besylate Tablet, amlodipine maleate, bevantolol hydrochloride); Angiotensin ii receptor antagonist (Candesartan, irbesartan, Losartan Potassium, Candesartan Cilexetil, telmisartan); Anti-anginal drug (Amlodipine Besylate Tablet, amlodipine maleate, betaxolol hydrochloride, bevantolol hydrochloride, butoprozine hydrochloride, carvedilol, cinepazic acid ethyl ester maleate, metroprolol succinate, molsidomine, monatepil maleate, primidolol, ranolazine hydrochloride, tosifen, verapamil hydrochloride); Coronary vasodilator (fostedil, azaclorzine hydrochloride, Cassella 4489, clonitrate, diltiazem hydrochloride

Persantin, droprenilamine, erythrityl tetranitrate, sorbide nitrate, isosorbide mononitrate, lidoflazine, mioflazine hydrochloride, mixidine, molsidomine, nicorandil, nifedipine, nisoldipine, nitroglycerin, oxprenolol hydrochloride, pentrinitrol, perhexiline maleate, prenylamine, propatylnitrate, Bicor (Recip), tolamolol, verapamil); Diuretic (compound artifact of the compound artifact of hydrochlorothiazide and spironolactone and hydrochlorothiazide and triamterene).

Compositions of the present invention, therapeutic combination medicine or method can comprise also that one or more are used to reduce the antidiabetic medicine of blood in human body in glucose level.Employed antidiabetic medicine includes but not limited to reduce the medicine of energy absorption or appetite-suppressing, the medicine and the nutrient distribution medicine of increase energy expenditure.Suitable antidiabetic medicine includes but not limited to sulfacarbamide (acetohexamide for example, chlorpropamide, gliamilide, gliclazide, glimepiride, glipizide, glibenclamide, glibenclamide, tolazamide and tolbutamide), meglitinide (for example repaglinide and Nateglinide), biguanide (for example metformin and buformin), alpha-glucosidase inhibitor (acarbose for example, miglitol, camiglibose and voglibose), some peptide class (amlinitide for example, Pramlintide, exendin and GLP-1 antagonism peptide class) and the analgesic composition of peroral administration insulin or its intestinal delivery, usually, the accumulated dose of the above antidiabetic medicine can be 0.1-1,000mg/ days, with single dose or the administration of 2-4 divided dose.

The above any mixture of medicine pharmacological or treatment may be used in compositions of the present invention and the therapeutic combination medicine.

In another embodiment, the invention provides a kind of compositions or therapeutic combination medicine that comprises following component: (a) at least a acyl-CoA: cholesterol neighbour-inhibitors; (b) at least a substituted azetidinone chemical compound or at least a substituted 'beta '-lactam compounds, the isomer of perhaps at least a substituted azetidinone chemical compound or at least a substituted 'beta '-lactam compounds, the pharmaceutically acceptable salt of perhaps at least a substituted azetidinone chemical compound or at least a substituted 'beta '-lactam compounds or solvate, the pharmaceutically acceptable salt of the isomer of perhaps at least a substituted azetidinone chemical compound or at least a substituted 'beta '-lactam compounds or solvate, the prodrug of perhaps at least a substituted azetidinone chemical compound or at least a substituted 'beta '-lactam compounds, the isomer of perhaps at least a substituted azetidinone chemical compound or at least a substituted 'beta '-lactam compounds, the prodrug of salt or solvate.

In another embodiment, the invention provides a kind of compositions or therapeutic combination medicine that comprises following component: (a) probucol or derivatives thereof; (b) at least a substituted azetidinone chemical compound or at least a substituted 'beta '-lactam compounds, the isomer of perhaps at least a substituted azetidinone chemical compound or at least a substituted 'beta '-lactam compounds, the pharmaceutically acceptable salt of perhaps at least a substituted azetidinone chemical compound or at least a substituted 'beta '-lactam compounds or solvate, the pharmaceutically acceptable salt of the isomer of perhaps at least a substituted azetidinone chemical compound or at least a substituted 'beta '-lactam compounds or solvate, the prodrug of perhaps at least a substituted azetidinone chemical compound or at least a substituted 'beta '-lactam compounds, the isomer of perhaps at least a substituted azetidinone chemical compound or at least a substituted 'beta '-lactam compounds, the prodrug of salt or solvate.

In another embodiment, the invention provides a kind of compositions or therapeutic combination medicine that comprises following component: (a) at least a low density lipoprotein receptor activator; (b) at least a substituted azetidinone chemical compound or at least a substituted 'beta '-lactam compounds, the isomer of perhaps at least a substituted azetidinone chemical compound or at least a substituted 'beta '-lactam compounds, the pharmaceutically acceptable salt of perhaps at least a substituted azetidinone chemical compound or at least a substituted 'beta '-lactam compounds or solvate, the pharmaceutically acceptable salt of the isomer of perhaps at least a substituted azetidinone chemical compound or at least a substituted 'beta '-lactam compounds or solvate, the prodrug of perhaps at least a substituted azetidinone chemical compound or at least a substituted 'beta '-lactam compounds, the isomer of perhaps at least a substituted azetidinone chemical compound or at least a substituted 'beta '-lactam compounds, the prodrug of salt or solvate.

In another embodiment, the invention provides a kind of compositions or therapeutic combination medicine that comprises following component: (a) at least a omega-fatty acid; (b) at least a substituted azetidinone chemical compound or at least a substituted 'beta '-lactam compounds, the isomer of perhaps at least a substituted azetidinone chemical compound or at least a substituted 'beta '-lactam compounds, the pharmaceutically acceptable salt of perhaps at least a substituted azetidinone chemical compound or at least a substituted 'beta '-lactam compounds or solvate, the pharmaceutically acceptable salt of the isomer of perhaps at least a substituted azetidinone chemical compound or at least a substituted 'beta '-lactam compounds or solvate, the prodrug of perhaps at least a substituted azetidinone chemical compound or at least a substituted 'beta '-lactam compounds, the isomer of perhaps at least a substituted azetidinone chemical compound or at least a substituted 'beta '-lactam compounds, the prodrug of salt or solvate.

In another embodiment, the invention provides a kind of compositions or therapeutic combination medicine that comprises following component: (a) at least a water-soluble fiber; (b) at least a substituted azetidinone chemical compound or at least a substituted 'beta '-lactam compounds, the isomer of perhaps at least a substituted azetidinone chemical compound or at least a substituted 'beta '-lactam compounds, the pharmaceutically acceptable salt of perhaps at least a substituted azetidinone chemical compound or at least a substituted 'beta '-lactam compounds or solvate, the pharmaceutically acceptable salt of the isomer of perhaps at least a substituted azetidinone chemical compound or at least a substituted 'beta '-lactam compounds or solvate, the prodrug of perhaps at least a substituted azetidinone chemical compound or at least a substituted 'beta '-lactam compounds, the isomer of perhaps at least a substituted azetidinone chemical compound or at least a substituted 'beta '-lactam compounds, the prodrug of salt or solvate.

In another embodiment, the invention provides a kind of compositions or therapeutic combination medicine that comprises following component: (a) fatty acid ester of at least a plant sterol, phytostanol or phytostanol; (b) at least a substituted azetidinone chemical compound or at least a substituted 'beta '-lactam compounds, the isomer of perhaps at least a substituted azetidinone chemical compound or at least a substituted 'beta '-lactam compounds, the pharmaceutically acceptable salt of perhaps at least a substituted azetidinone chemical compound or at least a substituted 'beta '-lactam compounds or solvate, the pharmaceutically acceptable salt of the isomer of perhaps at least a substituted azetidinone chemical compound or at least a substituted 'beta '-lactam compounds or solvate, the prodrug of perhaps at least a substituted azetidinone chemical compound or at least a substituted 'beta '-lactam compounds, the isomer of perhaps at least a substituted azetidinone chemical compound or at least a substituted 'beta '-lactam compounds, the prodrug of salt or solvate.

In another embodiment, the invention provides a kind of compositions or therapeutic combination medicine that comprises following component: (a) at least a antioxidant or vitamin; (b) or at least a substituted azetidinone chemical compound or at least a substituted 'beta '-lactam compounds, the isomer of perhaps at least a substituted azetidinone chemical compound or at least a substituted 'beta '-lactam compounds, the pharmaceutically acceptable salt of perhaps at least a substituted azetidinone chemical compound or at least a substituted 'beta '-lactam compounds or solvate, the pharmaceutically acceptable salt of the isomer of perhaps at least a substituted azetidinone chemical compound or at least a substituted 'beta '-lactam compounds or solvate, the prodrug of perhaps at least a substituted azetidinone chemical compound or at least a substituted 'beta '-lactam compounds, the isomer of perhaps at least a substituted azetidinone chemical compound or at least a substituted 'beta '-lactam compounds, the prodrug of salt or solvate.

The above any mixture pharmacological or curative drug may be used in the compositions and therapeutic combination medicine of these other embodiments of the present invention.

The mammal that compositions of the present invention and therapeutic combination medicine can need this treatment with the treatment effective dose is to treat one or more diseases for example angiopathy such as atherosclerosis, hyperlipidemia (including but not limited to hypercholesterolemia, hypertriglyceridemia, β-sitosterolemia), vascular inflammation, apoplexy, diabetes, obesity and/or reduce the level of sterol in the blood plasma.Can give described compositions and treatment by any suitable manner, described mode make the position that acted in these chemical compounds and the body for example in mammal or human plasma, produce in liver or the small intestinal and contact.

The daily dose of the above compositions and therapeutic combination medicine can with single or as required repeatedly the branch dosage form give patient.For example divided dose can 2-6 administration every day.Can use suitable sustained-release dosage.When the form with divided dose gives peroxisome proliferation-activated receptors activator and sterol absorption inhibitor, each the dose of components number that gives every day needn't be identical, for example a kind of composition can have very long active duration, therefore need be with less frequency administration.

Medicinal therapeutic combination of the present invention and therapeutic combination medicine can also comprise one or more pharmaceutically acceptable carriers, one or more excipient and/or one or more additives.The non-limiting example of pharmaceutically acceptable carrier comprises solid and/or liquid such as ethanol, glycerol, water etc.The amount of carrier can be about 5-99% weight of described therapeutic combination or therapeutic combination medicine gross weight in the described therapeutic combination.The suitable pharmaceutically acceptable excipient and the non-limiting example of additive comprise nontoxic compatibility filler, binding agent such as starch, disintegrating agent, buffer agent, antiseptic, antioxidant, lubricant, flavoring agent, thickening agent, coloring agent, emulsifying agent etc.The amount of excipient or additive can be about 0.1-90% weight of described therapeutic combination and therapeutic combination medicine gross weight.Those skilled in the art should understand that the amount of carrier, excipient and additive (if existence) can change.

Therapeutic combination of the present invention can be with any regular dosage form administration, and the preferred oral dosage form is capsule, tablet, powder, cachet, suspending agent or solution for example.Can use technology acceptable and conventional on the conventional pharmaceutical to prepare preparation and Pharmaceutical composition.The example of some preparation dosage particles below is provided.

Below the prescription example illustrates dosage forms more of the present invention.In each prescription, the substituted azetidinone chemical compound of term " reactive compound I " expression, the chemical compound of 'beta '-lactam compounds or any above formula I-XI described herein, the isomer of the chemical compound of perhaps at least a substituted azetidinone chemical compound or at least a substituted 'beta '-lactam compounds or any formula I-XI, the pharmaceutically acceptable salt or the solvate of the chemical compound of perhaps at least a substituted azetidinone chemical compound or at least a substituted 'beta '-lactam compounds or any formula I-XI, the pharmaceutically acceptable salt or the solvate of the isomer of the chemical compound of perhaps at least a substituted azetidinone chemical compound or at least a substituted 'beta '-lactam compounds or any formula I-XI, the prodrug of the chemical compound of perhaps at least a substituted azetidinone chemical compound or at least a substituted 'beta '-lactam compounds or any formula I-XI, the isomer of the chemical compound of perhaps at least a substituted azetidinone chemical compound or at least a substituted 'beta '-lactam compounds or any formula I-XI, the prodrug of salt or solvate.The above-mentioned PPAR activator of term " reactive compound II " expression.

Embodiment

Tablet

Sequence number ingredient m g/ sheet

1 reactive compound 110

2 lactose monohydrate NF 55

3 microcrystalline Cellulose NF 20

4 polyvinylpyrrolidones 4

(K29-32)USP

5 cross-linking sodium carboxymethyl cellulose NF 8

6 sodium lauryl sulfates 2

7 magnesium stearate NF 1

Total amount 100

In the present invention, the above tablet can with the tablet that contains reactive compound II, capsule etc. for example the above

Capsule is administering drug combinations together.

Preparation method

In suitable blender, mix the formation binder solution with the 4th with pure water.Then in the fluid bed processing unit (plant), go up the described binder solution of spray to the 1st, 2,6 and the 5th of part, shower water then is so that make described composition granulating.Continue fluidisation and make wet particle drying.Screen described dried granules body and with the 3rd and remaining the 5th fusion.Add the 7th and mixing.Described mixture is pressed into suitable size and weight on suitable tablet machine.

For with single tablet or capsule in company with administration, the preparation that typically contains aforesaid cholesterol absorption inhibitor is well known by persons skilled in the art, and the preparation that typically contains aforesaid peroxisome proliferation-activated receptors activator is that those skilled in the art are known.Expect described two kinds of active component as single compositions administration, more than can easily utilize those skilled in the art's knowledge to improve for substituted azetidinone or the disclosed dosage form of 'beta '-lactam compounds.

Owing to the present invention relates to treat the above disease, for example reduce sterol in the blood plasma (particularly cholesterol) concentration or level by the treatment of using active component combination medicine, wherein said active component can be distinguished administration, the present invention also relates to the kit form isolating Pharmaceutical composition combination.That is, attempt to obtain the kit that wherein two isolating unit combined: the Pharmaceutical composition that contains at least a peroxisome proliferation-activated receptors activator; With the independent Pharmaceutical composition that contains at least a aforesaid sterol absorption inhibitor.Described kit preferably includes the directions for use that is used for each independent compositions administration.When each independent compositions must be with different dosage form (for example oral with parenteral) administration or with different spacing of doses administration, described kit form was convenient especially.

Therapeutic combination of the present invention and therapeutic combination medicine can suppress the cholesterol absorption of suckling enteral, shown in following examples, and can be used for the treatment of and/or prevent mammal, particularly mammiferous disease is angiopathy such as atherosclerosis, hypercholesterolemia and β-sitosterolemia, apoplexy, obesity and reduction blood plasma cholesterol level for example.

In another embodiment of the present invention, compositions of the present invention and therapeutic combination medicine can suppress the sterol absorption or reduce at least a plasma concentration that is selected from following sterol: plant sterol (for example sitosterol, campesterol, stigmasterol and avenosterol), 5 α-stanol (for example Dihydrocholesterol, 5 α-campestanol (campestanol), 5 α-sitostamol), cholesterol and their mixture.At least a therapeutic combination that contains at least a the above PPAR activator and at least a sterol absorption inhibitor or the therapeutic combination medicine of mammal effective dose that also can be by needing this treatment reduce plasma concentration.The reduction scope of sterol plasma concentration can be about 1-70%, preferably approximately 10-50%.The method of measuring the total cholesterolemia of serum and total LDL cholesterol is well known by persons skilled in the art, for example comprises that those in the method described in the 11st page of the PCT WO99/38498, are combined in it herein as a reference.The method of measuring other sterol levels in the serum is disclosed among " Serum Sterols DuringStanol Eser Feeding in a Mildly Hypercholesterolemic Population " J.Lipid Res.40:593-600 (1999) such as H.Gylling, and it is combined in herein as a reference.

Following examples illustrate the present invention, yet do not think as the restriction to details of the present invention.Unless stated otherwise, all calculate by weight in all parts of following examples and percent and the whole description.

Embodiment

The preparation of formula (II) chemical compound

Step 1): to (S)-4-phenyl-2-oxazolidone (41g, CH 0.25mol) ₂Cl ₂(200ml) add in the solution 4-dimethylaminopyridine (2.5g, 0.02mol) and triethylamine (84.7ml 0.61mol) and with described reactant mixture is cooled to 0 ℃.With being added dropwise to 4-(chloroformyl) methyl butyrate (50g, CH 0.3mol) in 1 hour ₂Cl ₂(375ml) solution heats this reaction to 22 ℃.After 17 hours, add entry and H ₂SO ₄(2N 100ml), separates each layer and order NaOH (10%), NaCl (saturated) and water washing organic layer.Use MgSO ₄Dry organic layer and the concentrated hypocrystalline product that obtains.

Step 2): under 0 ℃, to TiCl4 (18.2ml, CH 0.165mol) ₂Cl ₂(600ml) add in the solution titanium isopropoxide (16.5ml, 0.055mol).After 15 minutes, add step 1 product (49.0g, CH 0.17mol) ₂Cl ₂(100ml) solution.After 5 minutes, (65.2ml 0.37mol) and with this reactant stirred 1 hour down at 0 ℃, and described reactant mixture is cooled to-20 ℃ to add diisopropylethylamine (DIPEA), 4-benzyloxy benzylidine (4-fluoro) aniline of adding solid, shaped (114.3g, 0.37mol).With reactant mixture-20 ℃ of following vigorous stirring 4 hours, then with the CH that was added dropwise to acetic acid in 15 minutes ₂Cl ₂Solution is heated this reactant mixture to 0 ℃ and is added H ₂SO ₄(2N).With this reactant mixture restir 1 hour, separate each layer, wash with water, separate and dry organic layer.Raw product crystallization from ethanol/water is obtained pure intermediate.

Step 3): under 50 ℃, to the product of step 2 (8.9g adds N in toluene 14.9mmol) (100ml) solution, O-two (trimethyl silyl) acetamide (BSA) (7.50ml, 30.3mmol).0.5 after hour, add solid TBAF (0.39g, 1.5mmol) and with this reactant mixture 50 ℃ of following restir 3 hours.This mixture is cooled to 22 ℃, adds CH ₃OH (10ml).With reactant mixture HCl (1N), NaHCO ₃(1N) and NaCl (saturated) washing, and use MgSO ₄Dry organic layer.

Step 4): to product (0.94g, CH 2.2mmol) of step 3 ₃Add entry (1ml) and LiOHH in OH (3ml) solution ₂O (102mg, 2.4mmol).This reactant mixture was stirred 1 hour down at 22 ℃, and then add LiOHH ₂O (54mg, 1.3mmol).Amount to and add HCl (1N) and EtOAc after 2 hours, separate each layer, dry organic layer also concentrates in a vacuum.At 22 ℃, to products therefrom (0.91g, CH 2.2mmol) ₂Cl ₂(0.29ml 3.3mmol), stirs this mixture 16 hours to add ClCOCOCl in the solution.Remove in a vacuum and desolvate.

Step 5): under 4 ℃, to by 4-fluoro phenyl-magnesium-bromide (1M in THF, 4.4ml, 4.4mmol) and ZnCl ₂(0.6g 4.4mmol) adds four (triphenylphosphines) and closes palladium (0.25g 0.21mmol), adds step 4 product (0.94g, THF 2.2mmol) (2ml) solution subsequently in the well-beaten suspension of Zhi Bei 4-fluoro phenyl zinc chloride (4.4mmol).This reactant was stirred 1 hour down at 0 ℃, stirred 0.5 hour at 22 ℃ then.(1N 5ml) and with mixture extracts with EtOAc to add HCl.Organic layer is condensed into grease and obtains 1-(4-fluoro phenyl)-4 (S)-(4-hydroxy phenyl)-3 (R)-(3-oxo-3-phenyl propyl)-2-azetidinone through the silica gel column chromatography purification:

HRMS is for C ₂₄H ₁₉F ₂NO ₃Value of calculation=408.1429, measured value 408.1411.

Step 6): to product (0.95g, adding (R)-tetrahydrochysene-1-methyl-3 in THF 1.91mmol) (3ml) solution, the 3-diphenyl-1H of step 5,3H-pyrrolo--[1,2-c] [1,3,2] (120mg 0.43mmol) also is cooled to-20 ℃ with this mixture to oxazaborole.After 5 minutes, be added dropwise in 0.5 hour borohydrides-methyl sulfide complex (2M, in THF, 0.85ml, 1.7mmol).Amount to after 1.5 hours, add CH ₃OH, add HCl (1N) subsequently, this reactant mixture is extracted with EtOAc, obtain 1-(4-fluoro phenyl)-3 (R)-[3 (S)-(4-fluoro phenyl)-3-hydroxypropyl]-4 (S)-[4-(phenyl methoxyl group) phenyl]-2-azetidinone (chemical compound 6A-1), be grease. ¹H is at CDCl ₃Middle d H3=4.68.J＝2.3Hz。Cl(M ⁺H)500。

Use (S)-four-hydrogen-1-methyl-3,3-diphenyl-1H, 3H-pyrrolo--[1,2-c] [1,3,2] oxazaborole obtains corresponding 3 (R)-hydroxypropyl-azetidinones (chemical compound 6B-1). ¹H is at CDCl ₃Middle d H3=4.69.J＝2.3Hz。Cl(M ⁺H)500。

To chemical compound 6A-1 (0.4g, add 10%Pd/C (0.03g) in ethanol 0.8mmol) (2ml) solution and with reactant mixture at H ₂(60psi) pressure of gas stirred 16 hours down.This reactant mixture is filtered, and concentrated solvent obtains chemical compound 6A.Mp?164-166℃；Cl(M ⁺H)410。[α] ²⁵ _D＝-28.1°(c3，CH ₃OH)。For C ₂₄H ₂₁F ₂NO ₃Elementary analysis: value of calculation C 70.41; H 5.17; N 3.42; Measured value C 70.25; H 5.19; N 3.54.

The same chemical compound 6B-1 that handles obtains chemical compound 6B.

Mp?129.5-132.5℃；Cl(M ⁺H)410。For C ₂₄H ₂₁F ₂NO ₃Elementary analysis: value of calculation C 70.41; H 5.17; N 3.42; Measured value C 70.30; H 5.14; N 3.52.

Step 6 ' (alternative): to step 5 products therefrom (0.14g, add in ethanol 0.3mmol) (2ml) solution 10%Pd/C (0.03g) and with this reactant at H ₂(60psi) pressure of gas stirred 16 hours down.Reactant mixture filtered and concentrated solvent obtains 1: 1 mixture of chemical compound 6A and 6B.

Assessment in the body

One at random, in the parallel group of research of the region between the heart and the diaphragm point assessment, placebo, with stable and keep NCEP step 1 diet 32 health hypercholesterolemia the people (screening LDL-C 〉=130mg/dL) is divided into one of following four therapeutic schemes at random:

The placebo of 1 dosage of therapeutic scheme A-orally give every day.

The 10mg Compound I I of 1 dosage of therapeutic scheme B-orally give every day.

The 200mg of 1 dosage of therapeutic scheme C-orally give every day

Micronization fenofibrate (obtaining) from the Labortoire Fournier purchase of France.

The 200mg's of 1 dosage of therapeutic scheme D-orally give every morning

The micronization fenofibrate adds 10mg Compound I I, totally 14 days.

(minimum fasting is after 10 hours) the 1st day (baseline), the 7th day and the 14th day evaluation serum lipids before administration.

The result: 14 days averages (S.E) of changing of percentage ratio (%) that provided in the following table 1 that serum lipids begins from baseline (n=8):

Table 1

Therapeutic scheme LDL-C total amount-C HDL-C TG

A -10.1(4.9) -8.38(4.0) -14.1(2.2) 19.1(13.9)

B -22.3(5.7) -19.6(4.0) -13.3(4.4) -4.57(12.8)

C -13.5(3.1) -13.0(2.4) -6.1(3.6) 0.28(11.4)

D -36.3(3.5) -27.8(1.7) -1.97(4.7) -32.4(4.5)

With respect to independent medication or placebo, the having good toleration and cause that LDL-C remarkable (p≤0.03) reduces of 10mg Compound I I and 200mg fenofibrate in company with administration (therapeutic scheme D).In this research to the inpatient, wherein subjects's body movement is restricted, and HDL-C concentration is tending towards reducing usually, and triglyceride is tending towards increasing.The treatment group of the scheme of receiving treatment C demonstrates the minimizing of the triglyceride levels of minimum HDL-C minimizing and maximum.

It should be appreciated by those skilled in the art, under the prerequisite that does not deviate from wide inventive concept of the present invention, can make change above-described embodiment.Therefore, should be appreciated that, the invention is not restricted to disclosed specific embodiment, and be intended to comprise improvement that limit, in spirit and scope of the invention as incidental claim.

Claims

1. compositions, it comprises:

(a) at least a peroxisome proliferation-activated receptors activator; With

(b) at least a sterol absorption inhibitor by formula (I) representative:

Or its pharmaceutically acceptable salt or solvate, wherein in following formula (I):

Ar ³Be aryl or R ⁵The aryl of-replacement;

R ¹And R ³Independently be selected from hydrogen, low alkyl group and aryl;

Q is 0 or 1;

R is 0 or 1;

M, n and p independently are selected from 0,1,2,3 or 4; Condition is that one of q and r are 1 at least, and the summation of m, n, p, q and r is 1,2,3,4,5 or 6; And condition be when p be 0 and r when being 1, the summation of m, q and n is 1,2,3,4 or 5;

R ⁹It is the low alkyl group that low alkyl group, aryl or aryl replace.

2. therapeutic combination medicine, it comprises:

(a) at least a peroxisome proliferation-activated receptors activator of first dosage; With

(b) at least a sterol absorption inhibitor of second dosage by formula (I) representative:

Or its pharmaceutically acceptable salt, wherein:

Ar ³Be aryl or R ⁵The aryl of-replacement;

R ¹And R ³Independently be selected from hydrogen, low alkyl group and aryl;

Q is 0 or 1;

R is 0 or 1;

R ⁹It is the low alkyl group that low alkyl group, aryl or aryl replace;

Wherein first dosage and second dosage are formed the treatment effective dose for sterol concentration in treatment or prevention angiopathy, diabetes, obesity or the reduction mammalian plasma together.

3. compositions, it comprises:

(a) at least a peroxisome proliferation-activated receptors activator; With

(b) at least aly be selected from following sterol absorption inhibitor:

(1) sterol absorption inhibitor of representing by formula (III):

Or its pharmaceutically acceptable salt or solvate, wherein in following formula (III):

Ar ¹Be R ³The aryl of-replacement;

Ar ²Be R ⁴The aryl of-replacement;

Ar ³Be R ⁵The aryl of-replacement;

A is selected from-O-,-S-,-S (O)-or-S (O) ₂-;

R ¹Be selected from-OR ⁶,-O (CO) R ⁶,-O (CO) OR ⁹With-O (CO) NR ⁶R ⁷

R ²Be selected from hydrogen, low alkyl group and aryl; Or R ¹And R ²Be together=O;

Q is 1,2 or 3;

P is 0,1,2,3 or 4;

R ⁵Be 1-3 the substituent group that independently is selected from following group :-OR ⁶,-O (CO) R ⁶,-O (CO) OR ⁹,-O (CH ₂) _1-5OR ⁹,-O (CO) NR ⁶R ⁷,-NR ⁶R ⁷,-NR ⁶(CO) R ⁷,-NR ⁶(CO) OR ⁹,-NR ⁶(CO) NR ⁷R ⁸,-NR ⁶SO ₂-low alkyl group ,-NR ⁶SO ₂-aryl ,-CONR ⁶R ⁷,-COR ⁶,-SO ₂NR ⁶R ⁷, S (O) _0-2-alkyl, S (O) _0-2-aryl ,-O (CH ₂) _1-10-COOR ⁶,-O (CH ₂) _1-10CONR ⁶R ⁷, neighbour-halogeno-group ,-halogeno-group, neighbour-low alkyl group ,-low alkyl group ,-(low-grade alkylidene)-COOR ⁶With-CH=CH-COOR ⁶

R ⁹It is the low alkyl group that low alkyl group, aryl or aryl replace;

(2) sterol absorption inhibitor of representing by formula (IV):

Or its pharmaceutically acceptable salt or solvate, wherein in following formula (IV):

Ar ¹Be aryl or R ³The aryl of-replacement;

Ar ²Be aryl or R ⁴The aryl of-replacement;

R ¹Be selected from following group:

-(CH ₂) _e-G-(CH ₂) _r-, wherein G is-O-,-C (O)-, phenylene ,-NR ⁸-or-S (O) _0-2-, e is 0-5, and r is 0-5, and condition is that the summation of e and r is 1-6;

-(C ₂-C ₆Alkenylene)-; With

-(CH ₂) _f-V-(CH ₂) _g-, wherein V is C ₃-C ₆Be cycloalkylidene, f is 1-5, and g is 0-5, and condition is that the summation of f and g is 1-6;

R ⁵Be selected from:

Or

And when Q is a key, R ¹Also can be selected from:

Or

Wherein M be-O-,-S-,-S (O)-or-S (O) ₂-;

D is 1,2 or 3;

H is 0,1,2,3 or 4;

V is 0 or 1;

Or

Wherein J be-O-,-NH-, NR ¹⁸-or-CH ₂-;

R ⁹And R ¹⁷Independently be 1-3 substituent group that independently is selected from following group: hydrogen, (C ₁-C ₆) alkyl, (C ₁-C ₆) alkoxyl ,-COOH, NO ₂,-NR ¹⁴R ¹⁵, OH and halogeno-group;

R ¹⁶Be (C ₁-C ₆) alkyl, aryl or R ¹⁷The aryl that replaces;

R ¹⁸Be hydrogen or (C ₁-C ₆) alkyl; With

R ¹⁹Be hydrogen, hydroxyl or (C ₁-C ₆) alkoxyl;

(3) sterol absorption inhibitor of representing by formula V:

Or its pharmaceutically acceptable salt or solvate, wherein in above formula V:

Ar ¹Be aryl, R ¹⁰The aryl or the heteroaryl of-replacement;

Ar ²Be aryl or R ⁴The aryl of-replacement;

Ar ³Be aryl or R ⁵The aryl of-replacement;

Q is 0 or 1;

R is 0,1 or 2;

R ⁹It is the low alkyl group that low alkyl group, aryl or aryl replace; With

R ¹⁰Be 1-5 substituent group that independently is selected from following group: low alkyl group ,-OR ⁶,-O (CO) R ⁶,-O (CO) OR ⁹,-O (CH ₂) _1-5OR ⁶,-O (CO) NR ⁶R ⁷,-NR ⁶R ⁷,-NR ⁶(CO) R ⁷,-NR ⁶(CO) OR ⁹,-NR ⁶(CO) NR ⁷R ⁸,-NR ⁶SO ₂R ⁹,-COOR ⁶,-CONR ⁶R ⁷,-COR ⁶,-SO ₂NR ⁶R ⁷,-S (O) _0-2R ⁹,-O (CH ₂) _1-10-COOR ⁶,-O (CH ₂) _1-10-CONR ⁶R ⁷,-CF ₃,-CN ,-NO ₂And halogen;

(4) sterol absorption inhibitor of representing by formula (VI):

Or its pharmaceutically acceptable salt or solvate, wherein in following formula (VI):

R ₁Be

Or

R ₄Be selected from B-(CH ₂) _mC (O)-, wherein m is 0,1,2,3,4 or 5;

B-(CH ₂) _q-, wherein q is 0,1,2,3,4,5 or 6;

B-(CH ₂) _e-Z-(CH ₂) _r-, wherein Z be-O-,-C (O)-, phenylene ,-N (R ₈)-or-S (O) _0-2-, e is 0,1,2,3,4 or 5, and r is 0,1,2,3,4 or 5, and condition is that the summation of e and r is 0,1,2,3,4,5 or 6;

B-(C ₂-C ₆Alkenylene)-;

B-(C ₄-C ₆Inferior alkadienyl)-;

B-(CH ₂) _t-Z-(C ₂-C ₆Alkenylene)-, wherein Z as defined above, wherein t is 0,1,2 or 3, condition is that the summation of carbon number in t and the alkenylene chain is 2,3,4,5 or 6;

B-(CH ₂) _f-V-(CH ₂) _g-, wherein V is C ₃-C ₆Cycloalkylidene, f are 1,2,3,4 or 5, and g is 0,1,2,3,4 or 5, and condition is that the summation of f and g is 1,2,3,4,5 or 6;

B-(CH ₂) _t-V-(C ₂-C ₆Alkenylene)-or

B-(C ₂-C ₆Alkenylene)-V-(CH ₂) _t-, wherein V and t as defined above, condition is that the summation of carbon number in t and the alkenylene chain is 2,3,4,5 or 6;

B-(CH ₂) _a-Z-(CH ₂) _b-V-(CH ₂) _d-, wherein Z and V as defined above, a, b and d independently are 0,1,2,3,4,5 or 6, condition is that the summation of a, b and d is 0,1,2,3,4,5 or 6; Or T-(CH ₂) _s-, wherein T is the cycloalkyl with 3-6 carbon atom, s is 0,1,2,3,4,5 or 6; Perhaps

R ₁And R ₄Form group together

R ₈And R ₉Independently be selected from H or low alkyl group;

R ₁₂Be selected from H, OH, alkoxyl, phenoxy group, benzyloxy,

-N (R ₈) (R ₉), low alkyl group, phenyl or R ₇-phenyl;

R ₁₉Be H, low alkyl group, phenyl or phenyl lower alkyl; With

R ₂₀And R ₂₁Independently be selected from the naphthyl, 2 that phenyl, naphthyl, W-that phenyl, W replace replace, 3-indanyl, indenyl, tetralyl, benzo dioxolyl, heteroaryl, the heteroaryl that W-replaces, benzo-fused heteroaryl, benzo-fused heteroaryl and the cyclopropyl that W-replaces, wherein heteroaryl is as defined above;

(5) sterol absorption inhibitor of representing by formula (VII):

Or its pharmaceutically acceptable salt or solvate, wherein in following formula (VII):

A is-CH=CH-,-C ≡ C-or-(CH ₂) _P-, wherein P is 0,1 or 2;

B is

R ₄Be

Wherein n is 0,1,2 or 3;

R ₅It is low alkyl group; With

R ₆Be the phenyl of OH, low alkyl group, phenyl, benzyl or replacement, wherein said substituent group is 1-3 and independently is selected from low alkyl group, lower alkoxy, carboxyl, NO ₂, NH ₂, OH, halogeno-group, low-grade alkyl amino and two elementary alkyl amido group;

(6) sterol absorption inhibitor of representing by formula (VIII):

Or its pharmaceutically acceptable salt or solvate, wherein in following formula (VIII):

R ²⁶Be H or OG ¹

G and G ¹Independently be selected from

With

Condition is to work as R ²⁶When being H or OH, G is not H;

R ³¹Be selected from H and (C ₁-C ₄) alkyl;

R ³²Independently be selected from 1-3 substituent group that independently is selected from following group: halogeno-group, (C ₁-C ₄) alkyl ,-OH, phenoxy group ,-CF ₃,-NO ₂, (C ₁-C ₄) alkoxyl, methylene-dioxy, oxo base, (C ₁-C ₄) alkyl alkylthio base, (C ₁-C ₄) alkyl sulfinyl, (C ₁-C ₄) alkyl sulphonyl ,-N (CH ₃) ₂-,-C (O)-NH (C ₁-C ₄) alkyl ,-C (O)-N ((C ₁-C ₄) alkyl) ₂,-C (O)-(C ₁-C ₄) alkyl ,-C (O)-(C ₁-C ₄) alkoxyl and pyrrolidinyl carbonyl; Perhaps R ³²Be covalent bond, R ³¹With its nitrogen-atoms that is connected and R ³²Form pyrrolidinyl, piperidyl, N-methyl-piperazinyl, indolinyl or morpholinyl, or (C ₁-C ₄) pyrrolidinyl, piperidyl, N-methyl-piperazinyl, indolinyl or the morpholinyl of alkoxy carbonyl-replacement;

Ar ¹Be aryl or R ¹⁰The aryl of-replacement;

Ar ²Be aryl or R ¹¹The aryl of-replacement;

R ¹Be selected from

-(CH ₂) _e-E-(CH ₂) _r-, wherein E be-O-,-C (O)-, phenylene ,-NR ²²Or-S (O) _0-2, e is 0-5, and r is 0-5, and condition is that the summation of e and r is 1-6;

-(C ₂-C ₆) alkenylene-; With

R ¹²Be

Or

A and b independently are 0,1,2 or 3, and condition is both and not all is 0;

Condition is when a is 2 or 3, R ¹³Can be identical or inequality; With

Condition is when b is 2 or 3, R ¹⁴Can be identical or inequality;

And when Q is key, R ¹Also can be

Or

M is-O-,-S-,-S (O)-or-S (O) ₂-

D is 1,2 or 3;

H is 0,1,2,3 or 4;

V is 0 or 1;

R ²¹Be (C ₁-C ₆) alkyl, aryl or R ²⁴The aryl of-replacement;

R ²⁵Be H ,-OH or (C ₁-C ₆) alkoxyl; With

(7) sterol absorption inhibitor of representing by formula (IX):

Or its pharmaceutically acceptable salt or solvate, wherein in following formula (IX):

R ²⁶Be selected from:

a)OH；

b)OCH ₃；

C) fluorine and

D) chlorine;

R ¹Be selected from

,-SO ₃H; Natural and alpha-non-natural amino acid;

R ³¹Independently be selected from H and (C ₁-C ₄) alkyl;

R ³²Independently be selected from 1-3 the substituent group that independently is selected from following group: H, halogeno-group, (C ₁-C ₄) alkyl ,-OH, phenoxy group ,-CF ₃,-NO ₂, (C ₁-C ₄) alkoxyl, methylene-dioxy, oxo base, (C ₁-C ₄) alkyl alkylthio base, (C ₁-C ₄) alkyl sulfinyl, (C ₁-C ₄) alkyl sulphonyl ,-N (CH ₃) ₂-,-C (O)-NH (C ₁-C ₄) alkyl ,-C (O)-N ((C ₁-C ₄) alkyl) ₂,-C (O)-(C ₁-C ₄) alkyl ,-C (O)-(C ₁-C ₄) alkoxyl and pyrrolidinyl carbonyl; Perhaps R ³²Be covalent bond, R ³¹With its nitrogen-atoms that is connected and R ³²Form pyrrolidinyl, piperidyl, N-methyl-piperazinyl, indolinyl or morpholinyl, or (C ₁-C ₄) pyrrolidinyl, piperidyl, N-methyl-piperazinyl, indolinyl or the morpholinyl of alkoxy carbonyl-replacement;

Ar ¹Be aryl, R ¹⁰Aryl, pyridine radicals, isoxazolyl, furyl, pyrrole radicals, thienyl, imidazole radicals, pyrazolyl, thiazolyl, pyrazinyl, pyrimidine radicals or the pyridazinyl of-replacement;

Ar ²Be aryl or R ¹¹The aryl of-replacement;

R ¹²Be

Or

A and b independently are 0,1,2 or 3, and condition is both and not all is 0; Condition is to work as R ¹³Be-CH=CH-or C (C ₁-C ₆Alkyl)=during CH-, a is 1; Condition is to work as R ¹⁴Be-CH=CH-or C (C ₁-C ₆Alkyl)=during CH-, b is 1; Condition is when a is 2 or 3, R ¹³Can be identical or inequality; And condition is when b is 2 or 3, R ¹⁴Can be identical or inequality;

R ²¹Be (C ₁-C ₆) alkyl, aryl or R ²⁴The aryl of-replacement;

R ²⁵Be H ,-OH or (C ₁-C ₆) alkoxyl.