CN101426496A - Treatment of nonalcoholic fatty liver disease using cholesterol lowering agents and H3 receptor antagonist/inverse agonist - Google Patents
Treatment of nonalcoholic fatty liver disease using cholesterol lowering agents and H3 receptor antagonist/inverse agonist Download PDFInfo
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- CN101426496A CN101426496A CNA2006800516127A CN200680051612A CN101426496A CN 101426496 A CN101426496 A CN 101426496A CN A2006800516127 A CNA2006800516127 A CN A2006800516127A CN 200680051612 A CN200680051612 A CN 200680051612A CN 101426496 A CN101426496 A CN 101426496A
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Abstract
This invention provides for method for the treatment, prevention or ameliorating the symptoms of nonalcoholic fatty liver disease (NAFLD) in a mammal in need thereof comprising the step of administering an effective amount of a composition comprising a therapeutic combination of at least one cholesterol lowering agent and/or at least one H3 antagonist/inverse agonist.
Description
Technical field
The present invention relates to a kind ofly by using the method for effective dose therapeutic combination treatment mammal non-alcoholic fatty liver disease disease, this therapeutic combination comprises at least a cholesterol reducing agent and/or at least a H
3Receptor antagonist/inverse agonist.
Related application
The present invention requires in the provisional application USSN 60/855 of submission on October 30th, 2006,178, in the provisional application USSN 60/752 of December in 2005 submission on the 21st, 710, the provisional application USSN 60/787 that submits on March 29th, 2006,048 and the provisional application USSN 60/836 that submits on August 9th, 2006,642 rights and interests, it incorporates this paper by reference into.
Background technology
Non-alcoholic fatty liver disease disease (NAFLD) be describe a series of with the progressive fibrosis of liver and liver failure from the hepatopathy of simple fatty liver (steatosis) to non-alcoholic stellato-hepatitis (NASH) scope.The hyperglycemia that has or do not have the hyperlipidemia sign is relevant with NAFLD usually.This disease presents the histologic characteristics of the inductive hepatopathy of ethanol in the patient who does not drink a large amount of ethanol.The something in common that all stages of NAFLD all have fat to gather in hepatocyte.Farrell and Larter be at Hepatology, among the 243:S99-S112 (2006) NASH is described as " important diseases " between liver fat degeneration and cirrhosis in the NAFLD scope.Also referring to people's such as Palekar LiverInt., 26 (2): 151-6 (2006).In NASH, fat generation and inflammation and Fibrotic relevant in various degree.The relevant the most common patient's condition with NAFLD is obesity, type 2 diabetes mellitus and metabolic syndrome.
Open No. 2004/29805 announcement of case of the U.S. is a kind of by using the method that a kind of medicament that resists the glucose-dependent-insulinotropic polypeptide receptor prevented or treated NAFLD.People such as Yamagishi propose a kind of hypothesis, and promptly ezetimibe (ezetimibe) may be the new treatment (Medical Hypotheses, 66, the 844 pages to 846 pages (2006)) (in JIUYUE, 2005 can in online acquisition) of a kind of NAFLD of treatment.
The treatment of NASH comprises diet and motion and/or uses probacol (probuco1), clofibrate (clofibrate), gemfibrozil (gemfibrozil), betanin, vitamin e and/or C, metformin, Tuo Gelie hydrazone (toglitaxone), rosiglitazone or sieve guitar hydrazone (plogitazone) and vitamin e.The Clinical Gastroenterology and Hepatology of M.Charlton, 2 (12), 1048-56 (2004); People's such as P.Portincaso Clinical Biochemistry, 38,203-17 (2005).The open case of the U.S. is set forth the treatment of a kind of NASH for 2004/105870A1 number, and it comprises uses a composite that comprises alimentary egg phospholipid complementary goods, vitamin B complex or antioxidant.Open case of U.S. 2005/0032823A1 number and 2004/0102466A1 number elaboration are used for the treatment of NASH with pyrimidine derivatives (it is selective COX-2-inhibitor 2).Other chemical compound that is used for the treatment of the fatty liver disease is set forth in the open case of U.S. 2005/0004115A1 number.But not mentioned cholesterol absorption inhibitor or H
3Receptor antagonist/inverse agonist is used for the treatment of NAFLD or NASH.
People such as Beltroy (Abstract, American College of Gastroenterology Meeting, 2004) discuss the effect of ezetimibe treatment to Niemann-Pick C type mice.Described mice has liver ferment raise (ACT and AST) and steatosis, and thereby has fat hepatitis.People such as Beltroy show that the cholesterol of ezetimibe treatment reduction liver gathers and improve tissue abnormalities regulating liver-QI ferment.
Suppressing chemical compound that cholesterol absorbs in small intestinal has known in this area and for example has been set forth in United States Patent (USP) RE 37, No. 721; United States Patent (USP) the 5th, 631, No. 356; United States Patent (USP) the 5th, 767, No. 115; United States Patent (USP) the 5th, 846, No. 966; United States Patent (USP) the 5th, 698, No. 548; United States Patent (USP) the 5th, 633, No. 246; United States Patent (USP) the 5th, 656, No. 624; United States Patent (USP) the 5th, 624, No. 920; United States Patent (USP) the 5th, 688, No. 787; United States Patent (USP) the 5th, 756, No. 470; No. the 2002/0137689th, the open case of the U.S.; WO 02/066464; Among WO 95/08522 and the WO 96/19450.Each of described aforementioned open case is all incorporated into way of reference.This technology shows, described chemical compound is to use separately or with second chemical compound (for example cholesteral biosynthesis inhibitor) by described chemical compound to be used for the treatment of (for example) coronary atherosclerosis disease.Described file does not show that described inhibitor is used for treating NAFLD.
United States Patent (USP) the 5th, 846, No. 966 and the 5th, 661, disclose to use for No. 145 this type of through the treatment that the azetidinone compounds of hydroxyl-replacements or the 'beta '-lactam compounds that is substituted suppress atherosclerosis and reduce blood plasma cholesterol level in conjunction with the HMG-CoA reductase inhibiter compounds respectively, it is to work by blocking-up hydroxy-methyl-glutaryl coenzyme A (HMG-CoA) reductase (speed Restriction enzyme in liver cholesterol synthesizes).HMG-CoA reductase inhibitor (for example statins, for example lovastatin, simvastatin and pravastatin) slows down the development of coronary artery and the atherosis infringement of carotid artery medium-sized artery.Simvastatin and pravastatin have also shown can reduce the risk of suffering from hypercholesterolemia and/or coronary atherosclerotic heart disease (CHD) patient coronary event.
Simvastatin is with trade (brand) name ZOCOR in whole world sale and in the U.S.
Sell.The method for preparing simvastatin is set forth in United States Patent (USP) the 4th, 444, No. 784; The 4th, 916, No. 239; The 4th, 820, No. 850; And in other patent and the open case of document.
H
3Receptor antagonist/inverse agonist is known in this area.H
3Acceptor site is found on the sympathetic nerve, and wherein it is regulated sympathetic nerve transmission and weakens various terminal organ's responses under sympathetic nervous system control.Particularly, by the activatory H of histamine
3Receptor can reduce the norepinephrine that flows out to resistance vessel and capacitance vessel, and this causes vasodilation.Known H
3Receptor antagonist/inverse agonist can be treated the following disease of patient (for example mammal): anaphylaxis, irritated inductive air flue (for example going up air flue) reaction, congested (for example nasal congestion), hypotension, cardiovascular disease, gastroenteropathy, gastrointestinal motion and acid were secreted low and too high, obesity, sleep disease (hypersomnia for example, drowsiness and Gelineau's syndrome), central nervous system disorder, the damaged many moving obstacles (ADHD) of attention, central nervous system activities crosses weak and strong excessively (for example anxiety neurosis and depression) and/or other CNS disease (alzheimer's disease for example, schizophrenia and migraine).Described chemical compound especially is used for treating anaphylaxis, irritated inductive air flue reaction and/or congested.
Announce and disclose the H of imidazoles May 26 nineteen ninety-five with the WO 95/14007 that way of reference is incorporated into
3Receptor antagonist.
Announced and disclose the H of imidazoles on May 20th, 1999 with the WO 99/24405 that way of reference is incorporated into
3Receptors ligand.
In on April 13rd, 2004 promulgation and the United States Patent (USP) the 6th, 720 incorporated into way of reference, disclose non-imidazoles H 328B1 number
3Receptor antagonist.Disclosed H No. 2004/0019099 in announcement on January 29th, 2004 and with the open case of the U.S. that way of reference is incorporated into
3The indole derivatives of receptor antagonist.Announce and the open case of U.S. 2004/0048843A1 number incorporated into way of reference and announce and disclose as H for 2004/0097483A1 number on March 11st, 2004 with the open case of the U.S. that way of reference is incorporated on May 20th, 2004
3The benzimidizole derivatives of antagonist.Be H
3The hexahydropyridine chemical compound of antagonist is disclosed in United States Patent (USP) the 6th, 849, in No. 621; This document is to incorporate in promulgation on February 1st, 2005 and with way of reference.
WO 2004/110375 sets forth a kind of combination treatment that is used for the treatment of diabetes, and wherein this combination comprises antiobesity agent (H for example
3Receptor antagonist/inverse agonist) and antidiabetic.The disclosure case shows can include other medicament that comprises anti-defat blood agent (anti-dislipidemic agent) (for example bile acid chelating agent) and cholesterol absorption inhibitor (for example aza cyclo-butanone) in.
United States Patent (USP) the 5th, 869, at least a histamine H is used in No. 479 announcements
1Receptor antagonist and at least a histamine H
3The combination of receptor antagonist is used for the treatment of the compositions of allergic rhinitis symptom.
WO 2004/110368 sets forth and is used for the treatment of hypertensive combination treatment, and it comprises the combination of antiobesity agent and hypotensive agent.
WO 2005/000217 sets forth the combination treatment that is used for the treatment of lipidosis, and it comprises the combination of using antiobesity agent and the agent of lipotropism matter dysbolismus.
WO 2004/110375 sets forth the combination treatment that is used for the treatment of diabetes, and it comprises the combination of using antiobesity agent and antidiabetic.
United States Patent (USP) discloses the combination treatment that is used for the treatment of obesity No. 2004/0122033, and it comprises the combination of using appetite suppressant and/or metabolic rate reinforcing agent and/or alimentation inhibitor.No. 2004/0229844 elaboration of United States Patent (USP) is used for the treatment of atherosclerotic combination treatment, and it comprises the combination of using nicotinic acid or another nicotinic acid receptor agonists and DP receptor antagonist.
United States Patent (USP) the 6th, 437, No. 147, the 6th, 756, No. 384 and No. 2003/0135056 are set forth and are bonded to H
3The combination of the imidazole heterocyclic compounds of receptor and antiobesity agent or appetite stimulator, it comprises sibutramine, phentermine (phentermine), topiramate, lovastatin, pravastatin and simvastatin.
Summary of the invention
The invention provides and a kind ofly be used for the treatment of, prevent or improve the method for the symptom that the mammal of needs non-alcoholic fatty liver disease disease (NAFLD) is arranged by the compositions of using effective dose, said composition comprises at least a cholesterol reducing agent (Gu for example sterin absorption inhibitor, 5-α-alkanol absorption inhibitor or HMG-CoA reductase inhibitor) and/or at least a H
3Antagonist/inverse agonist.
The symptom or the development that provide the present invention one alternative embodiment to be used to prevent or improve the mammiferous liver fat degeneration that needs are arranged, it is by using at least a cholesterol reducing agent (Gu for example sterin absorption inhibitor, 5-α-alkanol absorption inhibitor or HMG-CoA reductase inhibitor) and/or at least a H
3Receptor antagonist/inverse agonist.
Also provide another embodiment of the present invention to be used for prevention or improve the development of mammal non-alcoholic stellato-hepatitis (NASH), it is to comprise at least a cholesterol reducing agent (Gu for example sterin absorption inhibitor, 5-α-alkanol absorption inhibitor or HMG-CoA reductase inhibitor) and/or at least a H by using effective dose
3The therapeutic combination of receptor antagonist/inverse agonist.
Provide other embodiment of the present invention to be used for preventing or improve the development of mammal sclerosis and hepatocarcinoma, it is by comprising at least a cholesterol reducing agent (Gu for example sterin absorption inhibitor, 5-α-alkanol absorption inhibitor or HMG-CoA reductase inhibitor) and/or at least a H
3The effective dose therapeutic combination of receptor antagonist/inverse agonist uses that this is mammiferous.
It is a kind of by using the method that effective dose combination treatment, prevention or improvement have NAFLD in the mammal that needs or NASH symptom that another embodiment of the present invention provides, and said composition is removed at least cholesterol reducing agent (Gu for example sterin absorption inhibitor, 5-α-alkanol absorption inhibitor or HMG-CoA reductase inhibitor) and/or at least a H
3Also comprise antiobesity agent beyond antagonist/inverse agonist.
The invention still further relates to the medicine box (kit) that is used for the treatment of, prevents or improve the NAFLD symptom, it comprises at least a cholesterol reducing agent and/or at least a H that is independent form
3Receptor/inverse agonist.
Description of drawings
Fig. 1 shows the H of ezetimibe and formula XIIIA
3Receptor antagonist/inverse agonist is to the influence of Mouse Liver and body weight ratio.
Fig. 2 shows the H of ezetimibe and formula XIIIA
3Receptor antagonist/inverse agonist is to the influence of Mouse Liver triglyceride level.
Fig. 3 shows the H of ezetimibe and formula XIIIA
3Receptor antagonist/inverse agonist is to the influence of mice cholesteryl ester level.
Fig. 4 shows the H of ezetimibe and formula XIIIA
3Receptor antagonist/inverse agonist is to the influence of mice free cholesterol level.
Fig. 5 shows the H of ezetimibe and formula XIIID
3Receptor antagonist/inverse agonist is to the influence of mice plasma alanine aminotransferase (ALT) enzyme activity.
Fig. 6 shows the influence of ezetimibe to Mouse Liver and body weight ratio.
Fig. 7 shows the influence of ezetimibe to the Mouse Liver triglyceride level.
Fig. 8 shows the influence of ezetimibe to mice cholesteryl ester level.
Fig. 9 shows the influence of ezetimibe to mice free cholesterol level.
Describe in detail
The implication that term used herein has its its ordinary meaning and this type of term when it occurs at every turn is Independently. However and except as otherwise noted, otherwise following definition is applicable to whole specification and Shen Please claim: chemical name, common first names and chemical constitution be used interchangeably to describe same structure. Except as otherwise noted, otherwise no matter a term is to use separately or be used in combination institute with other term Stating definition all is suitable for. Thereby the definition of " alkyl " is applicable to " alkyl " and " hydroxyalkyl ", " halogen Alkyl ", " alkyl " part of " alkoxyl " etc.
Should be appreciated that except as otherwise noted, otherwise above all have following implication with the used described following term of whole specification:
" patient " comprises the human and animal.
" mammal " refers to human and other mammal.
" alkyl " refers to can be straight or branched and comprise about 1 aliphatic hydrocarbon group to about 20 carbon atoms in this chain, and it can be chosen wantonly through (for example) following groups and replace: hydroxyl, cyano group, halogen, alkoxyl, aryloxy group, heteroaryl, hetero-oxy (heteroxy) ,-C (O) OH ,-C (O) O alkyl, N3, amino, dialkyl amido, alkyl amino, NO2, sulfydryl, alkylthio group, cycloalkyl etc. Excellent The alkyl group of choosing in chain, comprise about 1 to about 12 carbon atoms. Preferred alkyl group in Comprise in the chain about 1 to about 6 carbon atoms. Side chain refers to one or more low-grade alkyl group (examples Such as methyl, ethyl or propyl group) be connected on the linear alkyl chain. " low alkyl group " refers to can be straight chain Or has about 1 group to about 6 carbon atoms in the chain of side chain. The unrestricted of alkyl group suits The property example comprises methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, the tert-butyl group, n-pentyl, heptan Base, nonyl and decyl. The limiting examples of the suitable alkyl group that is substituted comprises methyl fluoride, three Methyl fluoride and cyclopropyl methyl.
" thiazolinyl " refers to comprise at least one carbon-to-carbon double bond and can be straight or branched and in this chain Comprise about 2 aliphatic hydrocarbon groups to about 15 carbon atoms. Preferred alkenyl group has in chain About 2 to about 12 carbon atoms; And more preferably in this chain, have about 2 to about 6 carbon atoms. Side chain refers to that one or more low alkyl groups (for example methyl, ethyl or propyl group) are connected in the straight-chain alkenyl chain On. " low-grade alkenyl " refers to have about 2 in can be the chain of straight or branched extremely about 6 carbon are former Son. The limiting examples of suitable alkenyl group comprises vinyl, acrylic, n-butene base, 3-first Base but-2-ene base, positive pentenyl, octenyl and decene base.
" alkynyl " is meant and comprises at least one carbon-to-carbon triple bond and can be straight or branched and comprise about 2 aliphatic hydrocarbon groups to about 15 carbon atoms in this chain.Preferred alkynyl group in chain, have about 2 to about 12 carbon atoms; And more preferably in this chain, have about 2 to about 4 carbon atoms.Side chain is meant that one or more low-grade alkyl groups (for example methyl, ethyl or propyl group) are connected on the straight-chain alkynyl chain." low-grade alkynyl " be meant in can be the chain of straight or branched, have about 2 to about 6 carbon atoms.The limiting examples of suitable alkynyl group comprises acetenyl, propinyl, 2-butyne base, 3-methyl butynyl, positive pentynyl and decynyl.
" aryl " be meant comprise about 6 to about 14 carbon atoms, preferred about 6 aromatic series monocycle or multi-ring loop systems to about 10 carbon atoms.This aromatic yl group can choose wantonly through one or more identical or different and as herein defined substituent group replace, perhaps the substituent group on two adjacent carbonses can be joined together to form
Or
The limiting examples of suitable aromatic yl group comprises phenyl and naphthyl.
" heteroaryl " be meant comprise about 5 to about 14 annular atomses, preferred about 5 aromatic series monocycle or multi-ring loop systems to about 10 annular atomses, one to four is alone or in combination element beyond the de-carbon, for example nitrogen, oxygen or sulfur in the wherein said annular atoms.Preferred heteroaryl comprise about 5 to about 6 annular atomses.Should " heteroaryl " can choose wantonly through one or more identical or different and substituent group replacements as herein defined.Prefix azepine, oxa-or sulphur content are not meant and exist at least one nitrogen, oxygen or sulphur atom as an annular atoms before this heteroaryl root name.The nitrogen-atoms of heteroaryl can be chosen wantonly and be oxidized to corresponding N-oxide.The limiting examples of suitable heteroaryl comprises pyridine radicals, pyrazinyl, furyl, thienyl, pyrimidine radicals isoxazolyl, isothiazolyl oxazolyl, thiazolyl, pyrazolyl, furan Xanthones base, pyrrole radicals, pyrazolyl, triazolyl, 1,2, the 4-thiadiazolyl group, pyrazinyl, pyridazinyl quinoxalinyl, dai piperazine base, imidazoles [1,2-a] pyridine radicals, imidazoles [2,1-b] thiazolyl, benzo furan Xanthones base, indyl, azaindolyl, benzimidazolyl, benzothienyl, quinolyl, imidazole radicals, the thienopyridine base, quinazolyl, the Thienopyrimidine base, pyrrolopyridinyl, imidazole pyridyl, isoquinolyl, the benzo-aza indyl, 1,2, the 4-triazine radical, benzothiazolyl etc.
" cycloalkyl " be meant comprise about 3 to about 10 carbon atoms, preferred about 5 non-fragrance to about 10 carbon atoms single-or multi-ring loop systems.Preferred cycloalkyl ring comprise about 5 to about 7 annular atomses.This cycloalkyl can be chosen wantonly through one or more identical or different and substituent group replacements as herein defined.The limiting examples of suitable monocyclic cycloalkyl comprises cyclopropyl, cyclopenta, cyclohexyl, suberyl etc.The limiting examples of suitable polycyclic naphthene base comprises 1-naphthalane, norcamphane base, golden steel alkyl etc.Other limiting examples of cycloalkyl comprises following:
" cycloalkyl ethers " is meant and comprises 1 oxygen atom and 23 Yuans to 7 Yuans non-aromatic rings to 7 carbon atoms.Available ring carbon atom is substituted, and does not comprise halogen or is connected to the substituent group of this ring via oxygen, nitrogen or sulphur atom but condition is the substituent group of adjoining this epoxy.
" cycloalkenyl group " be meant comprise about 3 to about 10 carbon atoms, preferred about 5 to about 10 carbon atoms and comprise the non-fragrant monocycle or the multi-ring loop systems of at least one carbon-to-carbon double bond.This cyclenes basic ring can be chosen wantonly through one or more identical or different and substituent group replacements as herein defined.Preferred cyclenes basic ring comprise about 5 to about 7 annular atomses.The limiting examples of suitable monocycle cycloalkenyl group comprises cyclopentenyl, cyclohexenyl group, cycloheptenyl etc.The limiting examples of suitable multi-ring cycloalkenyl group is the norcamphane base.
" heterocycloalkenyl " (" Heterocyclenyl " or " heterocycloalkeneyl ") be meant comprise about 3 to about 10 annular atomses, preferred about 5 to about 10 annular atomses and comprise at least one carbon-to-carbon double bond or the non-aromatic monocycle or the multi-ring loop systems of the two keys of carbon-nitrogen, wherein one or more described atoms are alone or in combination element beyond the de-carbon, for example nitrogen, oxygen or sulphur atom in this loop systems.In this loop systems, do not exist and adjoin oxygen and/or sulphur atom.Preferred heterocycloalkenyl ring comprise about 5 to about 6 annular atomses.Prefix azepine, oxa-or sulphur content before this heterocycloalkenyl root name is not meant and exists at least one nitrogen, oxygen or sulphur atom as an annular atoms.This heterocycloalkenyl can be chosen wantonly through one or more substituent groups and replace.The nitrogen of this heterocycloalkenyl or sulphur atom can be chosen wantonly and be oxidized to corresponding N-oxide, S-oxide or S, the S-dioxide.The limiting examples of suitable monocycle azepine heterocycloalkenyl group comprises 1,2,3,4-tetrahydro pyridyl, 1,2-dihydropyridine base, 1,4-dihydropyridine base, 1,2,3,6-tetrahydro pyridyl, 1,4,5,6-tetrahydro-pyrimidine base, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl etc.The limiting examples of suitable oxa-heterocycloalkenyl group comprises 3,4-dihydro-2H-pyrans, dihydrofuran base, fluorine dihydrofuran base etc.The limiting examples of suitable multi-ring oxa-heterocycloalkenyl group is 7-oxabicyclo [2.2.1] heptenyl.The limiting examples of suitable monocycle thia cyclenes basic ring comprises dihydro sulfur phenenyl, dihydro sulfur pyranose etc.
" halogen " is meant fluorine, chlorine, bromine or iodine group.Preferably fluorine, chlorine or bromine, and be more preferably fluorine and chlorine.
" alkylhalide group " is meant as hereinbefore defined the alkyl that one or more hydrogen atoms on the alkyl are wherein replaced by defined halogen group above.
" heterocyclic radical " (or Heterocyclylalkyl) be meant comprise about 3 to about 10 annular atomses, preferred about 5 saturated monocycle of non-aromatic or multi-ring loop systems to about 10 annular atomses, wherein 1 to 3, preferred 1 or 2 described atoms are alone or in combination element beyond the de-carbon, for example nitrogen, oxygen or sulfur in this loop systems.In this loop systems, there are not the oxygen and/or the sulphur atom that adjoin.Preferred heterocyclic radical comprise about 5 to about 6 annular atomses.Prefix azepine, oxa-or sulphur content before this heterocyclic radical root name is not meant and exists at least one nitrogen, oxygen or sulphur atom as an annular atoms.This heterocyclic radical can be chosen wantonly through one or more identical or different and substituent group replacements as herein defined.The nitrogen of this heterocyclic radical or sulphur atom can be chosen wantonly and be oxidized to corresponding N-oxide, S-oxide or S, the S-dioxide.The limiting examples of suitable monocyclic heterocycles basic ring comprises piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, tetrahydro-1,4-thiazine base, thiazole pyridine base, 1,3-dioxolanyl, 1,4-alkyl dioxin, tetrahydrofuran base, tetrahydrochysene sulfur phenenyl, tetrahydrochysene sulfur pyranose etc.
" aryl alkyl " is meant that wherein this aryl and alkyl are foregoing aryl-alkyl-groups.Preferred aralkyl comprises low-grade alkyl group.The limiting examples of suitable aromatic alkyl group comprises benzyl, 2-phenethyl and naphthyl methyl.With the bond of parent fraction be to reach by this alkyl.
" cycloalkyl aryl " is meant derived from the group of fused-aryl and cycloalkyl as herein defined.The preferred aryl groups cycloalkyl is such, aryl wherein be phenyl and cycloalkyl by about 5 to about 6 annular atoms makers-ups.This cycloalkyl aryl can be chosen wantonly through one or more substituent groups and replace.The limiting examples of suitable cycloalkyl aryl comprises dihydro indenyl and 1,2,3,4-tetralyl etc.With the bond of parent fraction be to reach by the non-aromatic carbon atom.
" aryl-heterocyclic alkyl " is meant derived from the group of fused-aryl and Heterocyclylalkyl as herein defined.The preferred aryl groups cycloalkyl is such, aryl wherein be phenyl and Heterocyclylalkyl by about 5 to about 6 annular atoms makers-ups.This aryl-heterocyclic alkyl can be chosen wantonly through one or more substituent groups and replace.The limiting examples of suitable aryl-heterocyclic alkyl comprises
With
With the bond of parent fraction be to reach by the non-aromatic carbon atom.
" acyl group " be meant one wherein carboxylic group-organic group that OH is replaced by some other substituent group.Suitable limiting examples comprise H-C (O)-, alkyl-C (O)-, thiazolinyl-C (O)-, alkynyl-C (O)-, aryl-C (O)-or cycloalkyl-C (O)-group, wherein said each group is all as indicated above.With the bond of parent fraction be to reach by carbonyl.Preferred acyl group comprises low alkyl group.The limiting examples of suitable carboxyl groups comprises formoxyl, acetyl group, propiono, 2-methylpropionyl, bytyry and hexamethylene acyl group.
" alkoxyl " is meant that wherein this alkyl is aforesaid alkyl-O-group.The limiting examples of suitable alkoxy grp comprise methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy and heptan the oxygen base.With the bond of parent fraction be to reach by ether oxygen.
" alkoxyalkyl " is meant derived from the group of alkoxyl and alkyl as herein defined.With the bond of parent fraction be to reach by this alkyl.
" aryl alkenyl " is meant derived from the group of aryl and thiazolinyl as herein defined.The preferred aryl groups thiazolinyl is such, aryl wherein be phenyl and this thiazolinyl by about 3 to about 6 atom makers-ups.This aryl alkenyl can be chosen wantonly through one or more substituent groups and replace.With the bond of parent fraction be to reach by a non-aromatic carbon atom.
" aromatic yl polysulfide yl " is meant derived from the group of aryl and thiazolinyl as herein defined.The preferred aryl groups alkynyl is such, aryl wherein be phenyl and this alkynyl by about 3 to about 6 atom makers-ups.This aromatic yl polysulfide yl can be chosen wantonly through one or more substituent groups and replace.With the bond of parent fraction be to reach by the non-aromatic carbon atom.
Suffix " ene " expression divalent moiety on alkyl, aryl, the Heterocyclylalkyl etc., for example-CH
2CH
2-be ethylidene, and
It is right-phenylene.
Term " optional be substituted " be meant can utilize have special groups in the position, base or optional replacement partly.
Aryl mentioned above, heteroaryl, cycloalkyl, cycloalkyl ethers, cycloalkenyl group, heterocycloalkenyl, heterocyclic radical, cycloalkyl aryl, the aryl-heterocyclic alkyl, the substituent group of aryl alkenyl and aromatic yl polysulfide yl group (" ring substituents ") comprises (for example) alkyl, cycloalkyl, aryl, heteroaryl, aryloxy group, heteroaryloxy, cycloalkyl ethers, cycloalkenyl group, heterocycloalkenyl, heterocyclic radical, cycloalkyl aryl, the aryl alkyl of mixing, aryl alkenyl and aromatic yl polysulfide yl, described group can replace through ring substituents and following groups again: halogen, the halogen alkyl, hydroxyl, alkoxyl, the halogen alkoxyl, amino, alkyl amino, dialkyl amido, NO
2, sulfydryl, alkylthio group ,-N
3,-COOH and-C (O) O-alkyl.
Replacement on cycloalkyl-alkyl, Heterocyclylalkyl alkyl, aryl alkyl or the heteroaryl alkyl part comprises on this loop section and/or the replacement on this group moieties.
More than a variable occurs once in group or a variable in the formula structure, occur when once above, described variable can be identical or different.
Mention the quantity of part (for example substituent group, group or ring) in the chemical compound, unless otherwise defined, otherwise phrase " one or more " and " at least one " are meant and can exist and institute's as many part of the quantity that allows chemically, and the definite of this type of part maximum quantity should be in those skilled in the art's ken.Mention being included in and use phrase " at least a " for example " at least a cholesterol reducing agent " or " at least a H in the phrase
3Antagonist/inverse agonist " compositions and method, be meant 1 to 3 kind of cholesterol reducing agent and 1 to 3 kind of H independently
3Receptor antagonist/inverse agonist can be used simultaneously, wherein preferably uses each.
The product that term used herein " compositions " is intended to contain the specific composition that comprises specified quantitative with any product of the combination of the specific composition that directly or indirectly derives from specified quantitative.
Wave-like line as a key
Ordinary representation (for example) comprises mixture that (R)-and (S)-stereochemical may isomers or described one of in may isomers.For example,
Be drawn into the line in the described loop systems, for example:
Expression institute's timberline (key) can be connected in arbitrary ring carbon atom that replaces.
The carbon atom that should note formula I can replace through 1 to 3 silicon atom, as long as satisfy all quantivalence requirements.
For example in the following formula structure
Expression one is positioned at the nitrogen-atoms of arbitrary position (promptly hereinafter represented position 4,5,6 or 7) of these 4 non-condensed positions of ring:
Similarly,
Be meant two nitrogen that are arranged in any two positions, 4 non-condensed positions of this ring (for example 4 and 6,4 and 7 or 5 and 6).
Know as this area, wherein do not indicate that at the key end key table that the specific atoms of part is drawn shows via the methyl of that key bond to this atom, except as otherwise noted from one.For example:
Also it should be noted that having unsaturated valent any hetero atom in this paper literal or structural formula all supposes to have hydrogen atom or satisfy valent atom.
It will be understood by a person skilled in the art that some chemical compound is that tautomer and all this type of tautomeric forms all are covered by herein as a part of the present invention in the structural formula disclosed herein.
Term used herein " cholesterol reducing agent " is meant any medicament that can reduce cholesterol levels in the mammal (for example human).
Limiting examples as lipid depressant chemical compound comprises, for example, Gu the agonist of sterin absorption inhibitor, 5-α-alkanol absorption inhibitor, HMG-CoA reductase inhibitor, bile acid chelating agent, nicotinic acid and/or nicotinic acid receptor agonists, peroxisome proliferation activated receptor (PPAR) or activator etc.Term " H
3The receptor antagonist inverse agonist " be at H
3Receptor is as any chemical compound of antagonist or inverse agonist.
Term " combination treatment " or " therapeutic combination " are meant uses two or more therapeutic agents (for example sterin absorption inhibitor and H
3Receptor antagonist/inverse agonist) with prevention, treat or improve NAFLD or NASH.Combination of the present invention can be used with any suitable way that (for example in experimenter's (mammal or human or other animal) blood plasma, liver or the small intestinal) action site in the health contacts by making described chemical compound with treatment.This uses and comprises in simultaneously mode (for example with single tablet with fixing active ingredient ratio or capsule or with the plurality of single capsule of various therapeutic agents) substantially and use described therapeutic agent altogether.Equally, this uses and comprises and use every type therapeutic agent in a sequential manner.In either case, use the treatment of this combination treatment in the treatment patient's condition, to provide beneficial effect.The possible advantage of combination treatment disclosed herein is can reduce the quantity of required individualized treatment chemical compound or reduce the effectively whole total amount of the treatment chemical compound of this patient's condition of treatment.Compare with the single current system method, can reduce the side effect of described individual compound by the combination of using therapeutic agent, this can improve patient's compliance.Equally, therapeutic agent can be through selecting so that the more complementary effect or the complimentary modes of action of wide region to be provided.
As above discuss, therapeutic combination of the present invention and method can comprise one or more hereinafter go through be substituted aza cyclo-butanone or be substituted beta-lactam sterin absorption inhibitor." sterin absorption inhibitor " used herein is meant a kind of when using mammal or can suppress the chemical compound that one or more sterin absorb when human to treat effectively (solid suppress sterin and/or 5 α-alkanol absorbs) amount, and described sterin includes, but is not limited to that cholesterol, phytosterol (for example sitoesterol, Brassica campestris L sterin, stigmasterol and Herba bromi japonici sterin (avenosterol)) are solid, 5 α-alkanol (for example cholestanol, 5 alpha-oil dishes alkanol, 5 α-paddy alkanol admittedly) admittedly and/or its mixture.
The suitable limiting examples that is substituted aza cyclo-butanone and the method for preparing it comprises following disclosed: United States Patent (USP) RE 37; No. 721; the 5th; 306; No. 817; the 5th; 561; No. 227; the 5th; 618; No. 707; the 5th; 624; No. 920; the 5th; 631; No. 365; the 5th; 656; No. 624; the 5th; 627; No. 176; the 5th; 633; No. 246; the 5th; 661; No. 145; the 5th; 688; No. 785; the 5th; 688; No. 787; the 5th; 688; No. 990; the 5th; 698; No. 548; the 5th; 728; No. 827; the 5th; 739; No. 321; the 5th; 744; No. 467; the 5th; 756; No. 470; the 5th; 767; No. 115; the 5th; 846; No. 966; the 5th; 856; No. 473; the 5th; 886; No. 171; the 5th; 919; No. 672; the 6th; 093, No. 812; the 6th, 096; No. 883; the 6th; 133, No. 001; the 6th, 207; No. 822; the 6th; 627, No. 757; the 6th, 632; No. 933; No. the 2003/0105028th, U.S. Patent Publication case; No. 2004/0180860; No. 2004/0180861 and No. 2004/0198700; N-sulfonyl-2-aza cyclo-butanone (for example be disclosed in United States Patent (USP) the 4th, 983, No. 597 in); 4-(2-oxo-azetidin-4-yl) phenoxy group-alkanoic acid ethyl ester (for example is disclosed in people's such as Ram Indian J.Chem.Sect.B.29B; 12 (1990); in the 1134th page to 1137 pages); with the Diphenylazetidinone and the derivant that are disclosed in following: No. the 2002/0039774th, U.S. Patent Publication case; No. 2002/0128252; No. 2002/0128253; No. 2002/0137689; the open application case of No. 2004/0082561 and PCT WO2002/066464 number; No. 04/000805, WO; No. 04/005247, WO; WO04/000804 number; No. 04/000803, WO; No. 04/014947, WO; No. 04/087655, WO; No. 05/009955, WO; No. 05/023305, WO; No. 05/021495, WO; No. 05/021497, WO; No. 05/044256, WO; No. 05/042692, WO; WO05/033100 number; No. 05/030225, WO; No. 05/047248, WO; No. 05/046662, WO; No. 05/061451, WO; No. 05/061452, WO; No. 05/062824, WO; No. 05/02897, WO; No. 05/000353, WO, and be disclosed in the U.S. Patent Publication case No. 2004/0077623; No. 2002/0137689; acetyl diketone in No. 2004/0067913, each document all is incorporated herein with way of reference.
What in one embodiment, be used for the present composition, therapeutic combination and method is substituted aza cyclo-butanone by representing with following formula (I):
Or the acceptable salt of pharmacy or the solvate of formula (I) chemical compound, wherein, in following formula (I):
Ar
1And Ar
2Be independently selected from aryl and through R
4The aryl that replaces;
Ar
3It is aryl or through R
5The aryl that replaces;
X, Y and Z are independently selected from-CH
2-,-CH (low alkyl group)-and-C (two low alkyl groups)-;
R and R
2Be independently selected from-OR
6,-O (CO) R
6,-O (CO) OR
9With-O (CO) NR
6R
7
R
1And R
3Be independently selected from hydrogen, low alkyl group and aryl;
Q is 0 or 1; R is 0 or 1; M, n and p are independently selected from 0,1,2,3 or 4; But condition is that at least one is 1 among q and the r, and m, n, p, q and r sum are 1,2,3,4,5 or 6; And condition be when p be 0 and r when being 1, m, q and n sum are 1,2,3,4 or 5;
R
4Be 1-5 and be independently selected from following substituent 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 and be independently selected from following substituent 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
8The low alkyl group that is independently selected from hydrogen, low alkyl group, aryl and replaces through aryl; With
R
9Be low alkyl group, aryl or the low alkyl group that replaces through aryl.
Preferably, R
4Be 1-3 the independent substituent group of selecting, and R
51-3 independent substituent group of selecting preferably.
Preferred formula (I) chemical compound is Ar wherein
1It is phenyl or through R
4The phenyl that replaces, more preferably through (4-R
4) those of the phenyl that replaces.Ar
2Preferably phenyl or R
4-be substituted phenyl, more preferably through (4-R
4) phenyl that replaces.Ar
3Preferably through R
5The phenyl that replaces, more preferably through (4-R
5) phenyl that replaces.Work as Ar
1Be through (4-R
4) replace phenyl the time, R
4Halogen preferably.Work as Ar
2And Ar
3Be respectively through R
4-and R
5-replace phenyl the time, R
4Preferably halogen or-OR
6And R
5Preferably-OR
6, R wherein
6Be low alkyl group or hydrogen.Ar wherein especially preferably
1And Ar
2Each is 4-fluorophenyl and Ar naturally
3It is the chemical compound of 4-hydroxy phenyl or 4-methoxyphenyl.
X, Y and Z preferred each naturally-CH
2-.R
1And R
3Preferred each hydrogen naturally.R and R
2Preferably-OR
6(R wherein
6Be hydrogen) or a metabolism easily be hydroxyl group (for example-O (CO) R
6,-O (CO) OR
9With-O (CO) NR
6R
7, above define).
M, n, p, q and r sum are preferably 2,3 or 4, and more preferably 3.Preferably wherein m, n and r respectively do for oneself 0, q be 1 and p be 2 chemical compound.
Also preferably wherein p, q and n respectively do for oneself 0, r be 1 and m be 2 or 3 formula (I) chemical compound.Be more preferably wherein that m, n and r respectively do for oneself 0, q is 1, p is 2, Z is-CH
2-and R be-OR
6(especially work as R
6When being hydrogen) chemical compound.
Also be more preferably wherein that p, q and n respectively do for oneself 0, r is 1, m is 2, X is-CH
2-and R
2Be-OR
6(especially work as R
6When being hydrogen) formula (I) chemical compound.
Another is organized preferred formula (I) chemical compound and is Ar wherein
1It is phenyl or through R
4The phenyl, the Ar that replace
2It is phenyl or through R
4The phenyl and the Ar that replace
3Be through R
5The phenyl person who replaces.Also Ar wherein preferably
1It is phenyl or through R
4The phenyl, the Ar that replace
2It is phenyl or through R
4The phenyl, the Ar that replace
3Be through R
5The phenyl that replaces and m, n, p, q and r sum are 2,3 or 4, more preferably 3 chemical compound.Be more preferably wherein Ar
1It is phenyl or through R
4The phenyl, the Ar that replace
2It is phenyl or through R
4The phenyl, the Ar that replace
3Be through R
5The phenyl that replaces and wherein m, n and r respectively do for oneself 0, q be 1 and p be 2 or wherein p, q and n respectively do for oneself 0, r be 1 and m be 2 or 3 chemical compound.
In preferred embodiments, to be substituted aza cyclo-butanone be to be represented by following formula (II) (ezetimibe) to the formula (I) that is used for the present composition, therapeutic combination and method:
Or the acceptable salt of pharmacy or the solvate of formula (II) chemical compound.Formula (II) chemical compound can be anhydrous or hydrated form.The product that comprises the ezetimibe chemical compound is passable
The ezetimibe composite is available from MSP Pharmaceuticals.
Formula I chemical compound can be by the prepared in various methods that is well known to those skilled in the art, and for example, described method is disclosed in United States Patent (USP) RE 37, No. 721, the 5th, 631, No. 365, the 5th, 767, No. 115, the 5th, 846, No. 966, the 6th, 207, among No. 822, No. the 02/079174th, PCT patent application case and the PCT patent application case WO 93/02048, each document all is incorporated herein with way of reference.
Another that is used for the present composition, therapeutic combination and method is substituted aza cyclo-butanone and represented by following formula (III):
Or the acceptable salt of its pharmacy or its solvate, wherein, in following formula (III):
Ar
1Be through R
3The aryl that replaces;
Ar
2Be through R
4The aryl that replaces;
Ar
3Be through R
5The aryl that replaces;
Y and Z are independently 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
1With R
2Be together=O;
Q is 1,2 or 3;
P is 0,1,2,3 or 4;
R
5Be 1-3 and be independently selected from following substituent 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-halogen ,-halogen, neighbour-low alkyl group ,-low alkyl group ,-(low-grade alkylidene)-COOR
6With-CH=CH-COOR
6
R
3And R
4Be 1-3 independently and be independently selected from R
5, hydrogen, right-low alkyl group, aryl ,-NO
2,-CF
3Substituent group with right-halogen;
R
6, R
7And R
8Be independently selected from the low alkyl group of hydrogen, low alkyl group, aryl and aryl-be substituted; And R
9Be low alkyl group, aryl or the low alkyl group that replaces through aryl.
Preferred formula III chemical compound comprises wherein Ar
1Be through R
3The phenyl that replaces, especially through (4-R
3) those of the phenyl that replaces.Ar
2Preferably through R
4The phenyl that replaces, especially warp (4-R
4) phenyl that replaces.Ar
3Preferably through R
5The phenyl that replaces, especially warp (4-R
5) phenyl that replaces.Preferred Ar
1, Ar
2And Ar
3All single separately the replacement.
Y and Z preferred each naturally-CH
2-.R
2Hydrogen preferably.R
1Preferably-OR
6(R wherein
6Be hydrogen) or a metabolism easily be hydroxyl group (for example-O (CO) R
6,-O (CO) OR
9With-O (CO) NR
6R
7, above define).Also R wherein preferably
1With R
2Be together=chemical compound of O.
Q and p sum preferably 1 or 2, more preferably 1.Preferably wherein p be 0 and q be 1 chemical compound.Be more preferably wherein p and be 0, q is 1, Y is-CH
2-and R
1Be-OR
6(especially work as R
6When being hydrogen) chemical compound.
Another organizes preferred chemical compound is Ar wherein
1Be through R
3The phenyl, the Ar that replace
2Be through R
4The phenyl and the Ar that replace
3Be through R
5The phenyl person who replaces.
Also Ar wherein preferably
1Be through R
3The phenyl, the Ar that replace
2Be through R
4The phenyl, the Ar that replace
3Be through R
5Phenyl that replaces and p and q sum be 1 or 2, especially be 1 chemical compound.Be more preferably wherein Ar
1Be through R
3The phenyl, the Ar that replace
2Be through R
4The phenyl, the Ar that replace
3Be through R
5Phenyl, the p that replaces be 0 and q be 1 chemical compound.
A preferably-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 halogen.R
3More preferred definition is a halogen, especially 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 halogen, wherein R
6And R
7Preferred independently is hydrogen or low alkyl group, and R
9Low alkyl group preferably.R
4More preferred definition is a hydrogen or halogen, especially 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, and R
9Low alkyl group preferably.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 to those skilled in the art.The limiting examples of proper method is disclosed in United States Patent (USP) the 5th, 688, and in No. 990, it is to be incorporated herein with way of reference.
In another embodiment, the aza cyclo-butanone that is substituted that is used for the present composition, therapeutic combination and method is to be represented by following formula (IV):
Or the acceptable salt of its pharmacy or its solvate, wherein, in following formula (IV):
A is selected from through R
2The Heterocyclylalkyl that replaces, through R
2The heteroaryl that replaces, through R
2The benzo-fused heterocycle alkyl that replaces and through R
2The benzo-fused heteroaryl that replaces;
Ar
1It is aryl or through R
3The aryl that replaces;
Ar
2It is aryl or through R
4The aryl that replaces;
Q is a key or forms the volution group with the 3-position of this aza cyclo-butanone ring carbon
With
R
1Be selected from:
-(CH
2)
q-, wherein q is 2 to 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
8-or-S (O)
0-2-, e be 0 to 5 and r be 0 to 5, condition is that e and r sum are 1 to 6;
-(C
2-C
6Alkenylene)-; With
-(CH
2)
f-V-(CH
2)
g-, wherein V is C
3-C
6Cycloalkylidene, f be 1 to 5 and g be 0 to 5, condition is that f and g sum are 1 to 6;
R
5Be selected from:
R
6And R
7Be independently 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
5With adjacent R
6Together or R
5With adjacent R
7Together formation-CH=CH-or-CH=C (C
1-C
6Alkyl)-group;
A and b are 0,1,2 or 3 independently, and condition is that the two is not 0 simultaneously; 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, described R
6Can be identical or different; And condition is when b is 2 or 3, described R
7Can be identical or different;
And when Q is a key, R
1Also can be selected from:
Wherein M be-O-,-S-,-S (O)-or-S (O)
2-;
X, Y and Z are independently selected from-CH
2-,-CH (C
1-C
6Alkyl)-and-C (two-(C
1-C
6) alkyl);
R
10And R
12Be independently selected from-OR
14,-O (CO) R
14,-O (CO) OR
16With-O (CO) NR
14R
15
R
11And R
13Be independently selected from hydrogen, (C
1-C
6) alkyl and aryl; Perhaps R
10With R
11Be together=O, perhaps R
12With 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 to 4; Condition is that at least one is 1 among s and the t, and m, n, p, s and t sum are 1 to 6; Condition be when p be 0 and t when being 1, m, s and n sum are 1 to 5; And condition be when p be 0 and s when being 1, m, t and n sum are 1 to 5;
V is 0 or 1;
J and k independently are 1 to 5, and condition is that j, k and v sum are 1 to 5;
R
2Be that 1-3 is selected from following substituent group on the described ring carbon atom: hydrogen, (C
1-C
10) alkyl, (C
2-C
10) thiazolinyl, (C
2-C
10) alkynyl, (C
3-C
6) cycloalkyl, (C
3-C
6) cycloalkenyl group, through R
17The aryl that replaces, through R
17The benzyl that replaces, through R
17The benzyloxy that replaces, through R
17The aryloxy group that replaces, halogen ,-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 the heterocycloalkyl ring, R
2Be as hereinbefore defined or for=O or
And work as R
2But when being the substituent group on the substituted ring nitrogen, 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
4Be independently selected from 1-3 substituent group, a described 1-3 substituent group is independently selected from: (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
14SO2R
16,-COOR
14,-CONR
14R
15,-COR
14,-SO2NR
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
17Be 1-3 independently and be independently selected from hydrogen, (C
1-C
6) alkyl, (C
1-C
6) alkoxyl ,-COOH, NO
2,-NR
14R
15, OH and halogen group;
R
14And R
15Be independently selected from hydrogen, (C
1-C
6) alkyl, aryl and the (C that replaces through aryl
1-C
6) alkyl;
R
16Be (C
1-C
6) alkyl, aryl or through 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.
The method of preparation formula IV chemical compound is well known to those skilled in the art.The limiting examples of proper method is disclosed in United States Patent (USP) the 5th, 656, and in No. 624, it is incorporated herein with way of reference.
Above used " A " preferably comprises 1 or 2 nitrogen-atoms through R in the formula (IV)
2The 6-element heterocycle alkyl ring of-replacement.Preferred heterocycloalkyl ring is piperidyl, piperazinyl and morpholinyl.This ring " A " preferably is connected to benzyl ring via ring nitrogen.Preferred R
2Substituent group is hydrogen and low alkyl group.R
19Hydrogen preferably.
Ar
2Preferably phenyl or R
4-phenyl is especially through (4-R
4The phenyl of)-replace.R
4Preferred definition is lower alkoxy (especially methoxyl group) and halogen (especially fluorine).
Ar
1Phenyl or preferably through R
3The phenyl of-replacement is especially through (4-R
3The phenyl of)-replace.
For-R
1-Q-union variable has several preferred definitions:
Q is a key and R
1Be low-grade alkylidene, propylidene preferably;
Q is as above defined volution group, wherein a R
6And R
7Preferred each ethylidene and R naturally
5Be
Or
Q is a key and R
1Be
Wherein select described variable so that R
1For-O-CH
2-CH (OH)-;
Q is a key and R
1Be
Wherein select described variable so that R
1For-CH (OH)-(CH
2)
2-; With
Q is a key and R
1Be
Wherein select described variable so that R
1Be-CH (OH)-CH
2-S (O)
0-2-.
In another embodiment, the aza cyclo-butanone that is substituted that is used for the present composition, therapeutic combination and method is to be represented by following formula V:
Or the acceptable salt of its pharmacy or its solvate, wherein, in last formula V:
Ar
1Be aryl, through R
10The aryl that replaces, heteroaryl or through R
10The heteroaryl that replaces;
Ar
2It is aryl or through R
4The aryl that replaces;
Ar
3It is aryl or through R
5The aryl that replaces;
X and Y are independently 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 are 0,1,2,3,4 or 5 independently; Condition is that m, n and q sum are 1,2,3,4 or 5;
R
4Be 1-5 and be independently selected from following substituent 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 and be independently selected from following substituent 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,-CF
3,-CN ,-NO
2, halogen ,-(low-grade alkylidene) COOR
6With-CH=CH-COOR
6
R
6, R
7And R
8The low alkyl group that is independently selected from hydrogen, low alkyl group, aryl and replaces through aryl;
R
9Be low alkyl group, aryl or the low alkyl group that replaces through aryl; With
R
10Be 1-5 and be independently selected from following substituent 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,-CF
3,-CN ,-NO
2And halogen.
In formula V scope, it comprises two kinds of preferred structures.In formula VA, q be 0 and remaining variables as defined above, and in formula VB, q be 1 and remaining variables as defined above:
R
4, R
5And R
10Preferred each 1-3 independent substituent group naturally through selection, as mentioned above.Ar wherein preferably
1Be phenyl, through R
10Phenyl that replaces or thienyl, especially warp (4-R
10) phenyl that replaces or the formula V chemical compound of thienyl.Ar
2Preferably through R
4The phenyl that replaces is especially through (4-R
4) phenyl that replaces.Ar
3Phenyl or preferably through R
5The phenyl that replaces is especially through (4-R
5) phenyl that replaces.Work as Ar
1Be through R
10During the phenyl that replaces, R
10Preferably halogen, especially fluorine.Work as Ar
2Be through R
4During the phenyl that replaces, R
4Preferably-OR
6, R especially wherein
6Be hydrogen or low alkyl group.Work as Ar
3Be through R
5During the phenyl that replaces, R
5Preferably halogen, especially fluorine.Ar wherein especially preferably
1Be phenyl, 4-fluorophenyl or thienyl, Ar
2Be 4-(alkoxyl or hydroxyl) phenyl and Ar
3It is the formula V chemical compound of phenyl or 4-fluorophenyl.
X and Y preferred each naturally-CH
2-.M, n and q sum are preferably 2,3 or 4, and more preferably 2.When q was 1, n was preferably 1 to 5.
In formula (VA) and (VB) each, X, Y, Ar
1, Ar
2And Ar
3Parameter select identical.
In formula (VA) chemical compound, m and n sum preferably 2,3 or 4, more preferably 2.Also preferably wherein m and n sum be 2 and r be 0 or 1 chemical compound.
In formula (VB) chemical compound, m and n sum are preferably 1,2 or 3, and more preferably 1.Special preferably wherein m be 0 and n be 1 chemical compound.R
1Preferably hydrogen and R preferably-OR
6(R wherein
6Be hydrogen) or a metabolism easily be hydroxyl group (for example-O (CO) R
6,-O (CO) OR
9With-O (CO) NR
6R
7, above define), perhaps R and R
1Formation=O group together.
The method of preparation formula V chemical compound is well known to those skilled in the art.The limiting examples of proper method is disclosed in United States Patent (USP) the 5th, 624, and in No. 920, it is incorporated herein with way of reference.
In another embodiment, the aza cyclo-butanone that is substituted that is used for the present composition, therapeutic combination and method is to be represented by following formula (VI):
Or the acceptable salt of its pharmacy or its solvate, wherein:
R
1Be
Or
R
2And R
3Be independently selected from:
-CH
2-,-CH (low alkyl group)-,-C (two-low alkyl group)-,-CH=CH-and-C (low alkyl group)=CH-; Perhaps 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 that the two is not 0 simultaneously; 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, described R
2Can be identical or different; And condition is when u is 2 or 3, described R
3Can be identical or different;
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 e and r sum are 0,1,2,3,4,5 or 6; B-(C
2-C
6Alkenylene)-; B-(C
4-C
6Alkadienylene)-; B-(CH
2)
t-Z-(C
2-C
6Alkenylene)-, wherein Z is as defined above, and wherein t is 0,1,2 or 3, condition is that the carbon number sum is 2,3,4,5 or 6 in t and this alkenylene chain; B-(CH
2)
f-V-(CH
2)
g-, wherein V is C
3-C
6Cycloalkylidene, f be 1,2,3,4 or 5 and g be 0,1,2,3,4 or 5, condition is that f and g sum are 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 all as defined above, condition is that the carbon number sum is 2,3,4,5 or 6 in t and this alkenylene chain;
B-(CH
2)
a-Z-(CH
2)
b-V-(CH
2)
d-, wherein Z and V all as defined above and a, b and d independently be 0,1,2,3,4,5 or 6, condition is that a, b and d sum are 0,1,2,3,4,5 or 6; Or T-(CH
2)
s-, wherein T is that the cycloalkyl and the s of 3 to 6 carbon atoms are 0,1,2,3,4,5 or 6; Or
R
1With R
4Form group together
The heteroaryl that B is selected from dihydro indenyl, indenyl, naphthyl, tetralyl, heteroaryl or replaces through W, wherein heteroaryl is selected from: pyrrole radicals, pyridine radicals, pyrimidine radicals, pyrazinyl, triazine radical, imidazole radicals, thiazolyl, pyrazolyl, thienyl, oxazolyl and furyl, and for nitrogenous heteroaryl, comprise its N-oxide, or
W is that 1-3 is independently selected from the following substituent group that is used for replacing on the ring carbon atom: low alkyl group, hydroxyl low-grade alkyl, lower alkoxy, alkoxyalkyl, alkoxyl alkoxyl, alkoxy carbonyl alkoxyl, (lower alkoxy imido grpup)-low alkyl group, lower alkyl diacyl, low alkyl group lower alkyl 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, halogen ,-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-silanyloxy ylmethyl ,-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 described substituent group on the heteroaryl ring nitrogen-atoms (if existence) that is substituted is 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-(TMS)-ethoxyl methyl;
R
7Be 1-3 be independently selected from low alkyl group, lower alkoxy ,-COOH, NO
2,-N (R
8) (R
9), the group of OH and halogen;
R
8And R
9Be independently 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
17Be independently selected from H and at the defined group of W; Perhaps R
15Be hydrogen and R
16And R
17Form the dioxolanes basic ring together with connected adjacent carbon atom;
R
19Be H, low alkyl group, phenyl or phenyl lower alkyl; With
R
20And R
21Be independently selected from: dioxy cyclopentenyl between phenyl, the phenyl through W replaces, naphthyl, the naphthyl through W replaces, dihydro indenyl, indenyl, tetralyl, benzo, heteroaryl, the heteroaryl that replaces through W, benzo-fused heteroaryl, through benzo-fused heteroaryl and cyclopropyl that W replaces, wherein heteroaryl is as defined above.
One group of preferred formula VI chemical compound is R wherein
21Be selected from the chemical compound of dioxy cyclopentenyl, tetralyl, pyridine radicals, pyrazinyl, pyrimidine radicals, quinolyl or cyclopropyl between phenyl, phenyl, dihydro indenyl, benzofuranyl, benzo through W replaces,
Wherein W be low alkyl group, lower alkoxy, OH, halogen ,-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 tert-butyl group dimethylsilyl oxygen base, wherein R
8, R
9, R
10, R
12And R
19All as definition to formula IV.When W was 2 or 3 substituent groups, described substituent group can be identical or different.
Another organizes preferred formula VI chemical compound is R wherein
20Be the chemical compound of phenyl or the phenyl that replaces through W, wherein the preferred meaning of W is as mentioned at R
21Preferred meaning defines.
Be more preferably wherein R
20Be phenyl or the phenyl and the R that replace through W
21It is the formula VI chemical compound of dioxy cyclopentenyl, tetralyl, pyridine radicals, pyrazinyl, pyrimidine radicals, quinolyl or cyclopropyl between phenyl, phenyl, dihydro indenyl, benzofuranyl, benzo through W replaces; W be low alkyl group, lower alkoxy, OH, halogen ,-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
3Or the tert-butyl group-dimethyl-silanyloxy base, wherein when W was 2 or 3 substituent groups, described substituent group can be identical or different, and R wherein
8, R
9, R
10, R
12And R
19All suc as formula defining among the VI.
Also R wherein preferably
1Be
-or
Formula VI chemical compound.
Another organizes preferred formula VI chemical compound is R wherein
2And R
3Respectively naturally-CH
2-and u and v sum be 2,3 or 4, wherein u=v=2 is preferred chemical compound.
R
4B-(CH preferably
2)
q-or B-(CH
2)
e-Z-(CH
2)
r-, wherein B, Z, q, e and r are all as defined above.B preferably
R wherein
16And R
17Each hydrogen and wherein R naturally
15Preferably H, OH, lower alkoxy, especially methoxyl group or halogen (especially chlorine).
Preferably, Z is-O-that e is 0, and r is 0.
Preferably, q is 0-2.
R
20Preferably phenyl or the phenyl that replaces through W.
R
20Preferred W substituent group be lower alkoxy (especially methoxyl group and ethyoxyl), OH and-C (O) R
12, R wherein
12Lower alkoxy preferably.
R
21The phenyl and the F-phenyl that are preferably selected from phenyl, replace through lower alkoxy.
R wherein especially preferably
1Be
Or
R
2And R
3Respectively naturally-CH
2-, u=v=2, R
4Be B-(CH
2)
q-(wherein B is phenyl or the phenyl that replaces through lower alkoxy or chlorine, and q is 0 to 2), R
20Phenyl that is phenyl, OH-phenyl, replaces through lower alkoxy or phenyl and the R that replaces through elementary alkoxy carbonyl
21The phenyl that is phenyl, replaces through lower alkoxy or the formula VI chemical compound of F-phenyl.
Another useful formula VI examples for compounds is shown among the following formula VIa:
The method of preparation formula VI chemical compound is well known to those skilled in the art.The limiting examples of proper method is disclosed in United States Patent (USP) the 5th, 698, and in No. 548, it is incorporated herein with way of reference.
In another embodiment, be used for the present composition, therapeutic combination and method be substituted aza cyclo-butanone be by following formula (VIIA) and (VIIB) expression:
With
Or acceptable salt of its pharmacy or solvate,
Wherein:
A is-CH=CH-,-C ≡ C-or-(CH
2)
P-, wherein p is 0,1 or 2;
B is
B ' is
D is-(CH
2)
mC (O)-or-(CH
2)
q-, wherein m be 1,2,3 or 4 and q be 2,3 or 4;
E is C
10To C
20Alkyl or-C (O)-(C
9To C
19)-alkyl, wherein this alkyl is a straight or branched, saturated or comprise one or more pairs of keys;
R is that hydrogen, straight or branched are saturated or comprise the C of one or more pairs of keys
1-C
15Alkyl or B-(CH
2)
r-, wherein r is 0,1,2 or 3;
R
1, R
2, R
3, R
1 ', R
2 'And R
3 'Be independently selected from: hydrogen, low alkyl group, lower alkoxy, carboxyl, NO
2, NH
2, OH, halogen, 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 OH, low alkyl group, phenyl, benzyl or the phenyl that is substituted, wherein said substituent group is 1-3 and is independently selected from following group: low alkyl group, lower alkoxy, carboxyl, NO
2, NH
2, OH, halogen, low-grade alkyl amino and two elementary alkyl amido; Or the acceptable salt of its pharmacy or its solvate.
In another embodiment, the sterin absorption inhibitor that is used for the present composition, therapeutic combination and method is to be represented by following formula (VIII):
Or the acceptable salt of its pharmacy or its solvate, wherein, in following formula (VIII),
R
26Be H or OG
1
G and G
1Be independently selected from: H,
With
Condition is to work as R
26When being H or OH, G is not H;
R, R
aAnd R
bBe independently selected from H ,-OH, halogen ,-NH
2, azido, (C
1-C
6) alkoxyl (C
1-C
6)-alkoxyl or-W-R
30
W is independently 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
6Be independently 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
4aBe independently 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: through R
32The T that replaces, through R
32Replace-T-(C
1-C
6) alkyl, through R
32Replace-(C
2-C
4) thiazolinyl, through R
32Replace-(C
1-C
6) alkyl, through R
32Replace-(C
3-C
7) cycloalkyl and through R
32Replace-(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
32Be to be independently selected from 1-3 substituent group, a described 1-3 substituent group is independently selected from: halogen, (C
1-C
4) alkyl ,-OH, phenoxy group ,-CF
3,-NO
2, (C
1-C
4) alkoxyl, methylene dioxy base, oxo, (C
1-C
4) alkyl sulfenyl, (C
1-C
4) alkyl sulphinyl, (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 a covalent bond and R
31, connected nitrogen and R
32Form pyrrolidinyl, piperidyl, N-methyl-piperazinyl, indolinyl or morpholinyl group, perhaps through (C
1-C
4) the alkoxy carbonyl pyrrolidinyl, piperidyl, N methyl piperazine base, indolinyl or the morpholinyl group that replace;
Ar
1It is aryl or through R
10The aryl that replaces;
Ar
2It is aryl or through R
11The aryl that replaces;
Q is a key or forms the volution group with the 3-position of this aza cyclo-butanone ring carbon
With
R
1Be selected from:
-(CH
2)
q-, wherein q is 2 to 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 be 0 to 5 and r be 0 to 5, condition is that e and r sum are 1 to 6;
-(C
2-C
6) alkenylene-; With
-(CH
2)
f-V-(CH
2)
g-, wherein V is C
3-C
6Cycloalkylidene, f be 1 to 5 and g be 0 to 5, condition is that f and g sum are 1 to 6;
R
12Be
Alkyl
Or
R
13And R
14Be independently 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 adjoin R
13Together or R
12With adjoin R
14Together formation-CH=CH-or-CH=C (C
1-C
6Alkyl)-group;
A and b are 0,1,2 or 3 independently, and condition is that the two is not 0 simultaneously;
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, described R
13Can be identical or different; With
Condition is when b is 2 or 3, described R
14Can be identical or different;
And when Q is a key, R
1Also can be:
M is-O-,-S-,-S (O)-or-S (O)
2-;
X, Y and Z are independently selected from-CH
2-,-CH (C
1-C
6) alkyl-and-C (two-(C
1-C
6) alkyl);
R
10And R
11Be independently selected from 1-3 substituent group, a described 1-3 substituent group is to be independently selected from: (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)
1-10-COOR
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
17Be independently selected from-OR
19,-O (CO) R
19,-O (CO) OR
21With-O (CO) NR
19R
20
R
16And R
18Be independently selected from H, (C
1-C
6) alkyl and aryl; Perhaps R
15With R
16Be together=O, perhaps R
17With R
18Be 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 to 4;
Condition is that at least one is 1 among s and the t, and m, n, p, s and t sum are 1 to 6;
Condition be when p be 0 and t when being 1, m, s and n sum are 1 to 5; And condition be when p be 0 and s when being 1, m, t and n sum are 1 to 5;
V is 0 or 1;
J and k independently are 1 to 5, and condition is that j, k and v sum are 1 to 5;
And when Q is a key and R
1Be
The time, Ar
1But pyridine radicals, isoxazolyl, furyl, pyrrole radicals, thienyl, imidazole radicals, pyrazolyl, thiazolyl, pyrazinyl, pyrimidine radicals or pyridazinyl;
R
19And R
20Be independently selected from H, (C
1-C
6) alkyl, aryl and the (C that replaces through aryl
1-C
6) alkyl;
R
21Be (C
1-C
6) alkyl, aryl or through R
24The aryl that replaces;
R
22Be H, (C
1-C
6) alkyl, aryl (C
1-C
6) alkyl ,-C (O) R
19Or-COOR
19
R
23And R
24Be 1-3 independently and be independently selected from H, (C
1-C
6) alkyl, (C
1-C
6) alkoxyl ,-COOH, NO
2,-NR
19R
20The group of ,-OH and halogen; With
R
25Be H, OH or (C
1-C
6) alkoxyl.
The method of preparation formula VIII chemical compound is well known to those skilled in the art.The limiting examples of proper method is disclosed in United States Patent (USP) the 5th, 756, and in No. 470, it is incorporated herein with way of reference.
In another embodiment, the aza cyclo-butanone that is substituted that is used for the present composition, therapeutic combination and method is to be represented by following formula (IX):
Or acceptable salt of its pharmacy or solvate, wherein in formula (IX):
R
1Be selected from H, G, G
1, G
2,-SO
3H and-PO
3H;
G is selected from: H,
(sugar derivatives)
Wherein R, R
aAnd R
bBe selected from independently of one another H ,-OH, halogen ,-NH
2, azido, (C
1-C
6) alkoxyl (C
1-C
6) alkoxyl or-W-R
30
W be independently 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
6Be selected from H, (C independently of one another
1-C
6) alkyl, acetyl group, aryl and aryl (C
1-C
6) alkyl;
R
3, R
4, R
5, R
7, R
3aAnd R
4aBe selected from H, (C independently of one another
1-C
6) alkyl, acetyl group, aryl (C
1-C
6) alkyl ,-C (O) (C
1-C
6) alkyl and-C (O) aryl;
R
30Be to be independently selected from: through R
32The T that replaces, through R
32Replace-T-(C
1-C
6) alkyl, through R
32Replace-(C
2-C
4) thiazolinyl, through R
32Replace-(C
1-C
6) alkyl, through R
32Replace-(C
3-C
7) cycloalkyl and through R
32Replace-(C
3-C
7) cycloalkyl (C
1-C
6) alkyl;
R
31Be independently selected from H and (C
1-C
4) alkyl;
T is independently selected from phenyl, furyl, thienyl, pyrrole radicals, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, benzothiazolyl, thiadiazolyl group, pyrazolyl, imidazole radicals and pyridine radicals;
R
32Be to be independently selected from 1-3 substituent group, a described 1-3 substituent group is selected from independently of one another: H, halogen, (C
1-C
4) alkyl ,-OH, phenoxy group ,-CF
3,-NO
2, (C
1-C
4) alkoxyl, methylene dioxy base, oxo, (C
1-C
4) alkyl sulfenyl, (C
1-C
4) alkyl sulphinyl, (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 a covalent bond and R
31, connected nitrogen and R
32Form pyrrolidinyl, piperidyl, N-methyl-piperazinyl, indolinyl or morpholinyl group, or (C
1-C
4) pyrrolidinyl, piperidyl, N methyl piperazine base, indolinyl or the morpholinyl group of alkoxy carbonyl-be substituted;
G
1Represent by following structure:
R wherein
33It is to be independently selected from: the alkyl that is unsubstituted, through R
34The alkyl, (R that replace
35) (R
36) alkyl-,
R
34Be 1 to 3 substituent group, each R
34Be independently selected from HOOC-, HO-, HS-, (CH
3) S-, H
2N-, (NH
2) (NH) C (NH)-, (NH
2) C (O)-and HOOCCH (NH
3 +) CH
2SS-;
R
35Be independently selected from H and NH
2-;
R
36Be independently selected from H, the alkyl that is unsubstituted, through R
34The alkyl that replaces, the cycloalkyl that is unsubstituted and through R
34The cycloalkyl that replaces;
G
2Represent by following structure:
R wherein
37And R
38Be selected from (C independently of one another
1-C
6) alkyl and aryl;
R
26Be 1 to 5 substituent group, each R
26Be independently selected from:
a)H；
b)-OH；
c)-OCH
3；
D) fluorine;
E) chlorine;
f)-O-G；
g)-O-G
1；
h)-O-G
2；
I)-SO
3H; With
j)-PO
3H；
Condition is to work as R
1When being H, R
26Be not H ,-OH ,-OCH
3Or-O-G;
Ar
1Be aryl, through R
10The aryl that replaces, heteroaryl or through R
10The heteroaryl that replaces;
Ar
2Be aryl, through R
11The aryl that replaces, heteroaryl or through R
11The heteroaryl that replaces;
L is selected from:
A) covalent bond;
B)-(CH
2)
q-, wherein q is 1 to 6;
C)-(CH
2)
e-E-(CH
2)
r-, wherein E be-O-,-C (O)-, phenylene ,-NR
22-or-S (O)
0-2-, e be 0 to 5 and r be 0 to 5, condition is that e and r sum are 1 to 6;
D)-(C
2-C
6) alkenylene-;
E)-(CH
2)
f-V-(CH
2)
g-, wherein V is C
3-C
6Cycloalkylidene, f be 1 to 5 and g be 0 to 5, condition is that f and g sum are 1 to 6; With
f)
Wherein M be-O-,-S-,-S (O)-or-S (O)
2-;
X, Y and Z are selected from-CH independently of one another
2-,-CH (C
1-C
6) alkyl-and-C (two-(C
1-C
6) alkyl)-;
R
8Be selected from H and alkyl;
R
10And R
11Be selected from 1-3 substituent group independently of one another, a described 1-3 substituent group is selected from independently of one another: (C
1-C
6) alkyl ,-OR
19,-O (CO) R
19,-O (CO) OR
21,-O (CH2)
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)
1-10-COOR
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
17Be selected from independently of one another-OR
19,-OC (O) R
19,-OC (O) OR
21,-OC (O) NR
19R
20
R
16And R
18Be selected from H, (C independently of one another
1-C
6) alkyl and aryl;
Perhaps R
15With R
16Be together=O, perhaps R
17With R
18Be 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 are selected from 0 to 4 independently of one another;
Condition is that at least one is 1 among s and the t, and m, n, p, s and t sum are 1 to 6; Condition be when p be 0 and t when being 1, m, n and p sum are 1 to 5; And condition be when p be 0 and s when being 1, m, t and n sum are 1 to 5;
V is 0 or 1;
J and k independently are 1 to 5 separately, and condition is that j, k and v sum are 1 to 5;
Q be a key ,-(CH
2)
q-(wherein q is 1 to 6), perhaps the 3-position ring carbon with this aza cyclo-butanone forms the volution group
R wherein
12Be
R
13And R
14Be selected from independently of one another-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 adjoin R
13Together or R
12With adjoin R
14Together formation-CH=CH-or-CH=C (C
1-C
6Alkyl)-group;
A and b independently are 0,1,2 or 3 separately, and condition is that the two is not 0 simultaneously; 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, described R
13Can be identical or different; And condition is when b is 2 or 3, described R
14Can be identical or different;
And when Q is that a key and L are
The time,
Ar then
1Also pyridine radicals, isoxazolyl, furyl, pyrrole radicals, thienyl, imidazole radicals, pyrazolyl, thiazolyl, pyrazinyl, pyrimidine radicals or pyridazinyl;
R
19And R
20Be selected from H, (C independently of one another
1-C
6) alkyl, aryl and the (C that replaces through aryl
1-C
6) alkyl;
R
21Be (C
1-C
6) alkyl, aryl or through R
24The aryl that replaces;
R
22Be H, (C
1-C
6) alkyl, aryl (C
1-C
6) alkyl ,-C (O) R
19Or COOR
19
R
23And R
24Be selected from 1-3 substituent group independently of one another, a described 1-3 substituent group is selected from H, (C independently of one another
1-C
6) alkyl, (C
1-C
6) alkoxyl ,-COOH, NO
2,-NR
19R
20,-OH and halogen; With
R
25Be H ,-OH or (C
1-C
6) alkoxyl.
The example that is used for formula (IX) chemical compound of the present composition, therapeutic combination and method and combination and prepares this compounds method is disclosed in the U.S. Patent Publication case of filing an application on June 11st, 2002 2003/0105028A1 number, and it is incorporated herein with way of reference.
The useful examples for compounds of the present invention is represented by following formula X:
R wherein
1Be as defined above.
Preferred chemical compound is represented by following formula XI:
Another useful chemical compound is represented by following formula XII:
Other useful azetidinone compounds that is substituted comprises that N-sulfonyl-2-aza cyclo-butanone (for example is disclosed in United States Patent (USP) the 4th; 983; in No. 597); 4-(2-oxo-azetidin-4-yl) phenoxy group-alkanoic acid ethyl ester (for example is disclosed in people's such as Ram Indian J.Chem.Sect.B.29B; 12 (1990); in the 1134th page to 1137 pages) and Diphenylazetidinone and derivant (be disclosed in the U.S. Patent Publication case No. 2002/0039774; No. 2002/0128252; among No. 2002/0128253 and No. 2002/0137689 and the WO 2002/066464), each document all is incorporated herein with way of reference.
Formula I-XII chemical compound can be by comprising the known method preparation of institute's discussion method above, and (for example) WO 93/02048 sets forth wherein-R
1-Q-is the preparation of the chemical compound of alkylidene, alkenylene or the alkylidene, phenylene or the cycloalkylidene that are interrupted by a hetero atom; WO 94/17038 sets forth wherein, and Q is the preparation of the chemical compound of volution group; WO 95/08532 sets forth wherein-R
1-Q-is the preparation through the chemical compound of the alkylidene group of hydroxyl replacement; PCT/US95/03196 sets forth wherein-R
1-Q-be via-O-or S (O)
0-2-group is connected in Ar
1Part is through the chemical compound of the alkylidene of hydroxyl-replacement; And United States Patent (USP) the 5th, 633 is set forth wherein-R for No. 246
1-Q-is via-S (O)
0-2-group connects the preparation of this aza cyclo-butanone ring through the chemical compound of hydroxyl-substituted alkylene group.Each aforementioned document all is incorporated herein with way of reference.
Other kind cholesterol reducing agent comprises following non-limiting class medicament: the HMG-CoA reductase inhibitor; bile acid chelating agent; PPAR agonist or activator; ileal bile acid is carried (" IBAT ") inhibitor (or the living sodium in top (apical sodium) relies on bile acid conveying (" ASBT ") inhibitor altogether); nicotinic acid (niacin usp (niacin)) and/or nicotinic acid receptor agonists; acyl-CoA: cholesterol O-acyltransferase (" ACAT ") inhibitor; cholesterol ester transfer protein (" CETP ") inhibitor; the probacol or derivatives thereof; low density lipoprotein (" LDL ") receptor activator; omega-3 fatty acid (" 3-PUFA "); water-soluble fiber; phytosterol; the fatty acid ester of solid alkanol of plant and/or the solid alkanol of plant.
The limiting examples of suitable cholesteral biosynthesis inhibitor comprises competitive inhibitor (speed conditioning step in the cholesterol biosynthesis), squalene synthase inhibitor, squalene epoxidase inhibitor of HMG-CoA reductase and composition thereof.The limiting examples of suitable HMG-CoA reductase inhibitor comprises statins, and for example lovastatin is (for example, available from Merck ﹠amp; Co.
Pravastatin is (for example, available from Bristol Meyers Squibb's
Fluvastatin (fluvastatin), simvastatin are (for example, available from Merck ﹠amp; Co.
Atorvastatin (atorvastatin), cerivastatin (cerivastatin), CI-981, Rosuvastatin (resuvastatin), auspicious his spit of fland (rivastatin) and Pitavastatin (pitavastatin) (NK-104 of for example Japanese Negma Kowa), the rosuvastatin (rosuvastatin) of cutting down; HMG-CoA reductase inhibitor class, L-659 for example, 699 ((E, E)-11-[3 ' R-(hydroxyl-methyl)-4 '-oxo-2 ' R-oxa-fourth cyclic group]-3,5,7R-trimethyl-2,4-undecandienoic acid); Squalene synthetic inhibitor class, for example squalestatin 1; With squalene epoxidase inhibitor class, for example NB-598 (hydrochloric acid (E)-N-ethyl-N-(6,6-dimethyl-2-heptan-4-thiazolinyl)-3-[(3,3 '-bithiophene-5-yl) methoxyl group] benzene-methane amine) and other sterin biosynthesis inhibitor, for example DMP-565.Preferred HMG-CoA reductase inhibitor comprises lovastatin, pravastatin and simvastatin.Most preferred HMG-CoA reductase inhibitor is a simvastatin.
Generally speaking, the total daily dose of cholesteral biosynthesis inhibitor can be between about 0.1mg/ days to about 160mg/ days and preferably about 0.2mg/ days to about 80mg/ days, and it is single dose or 2 to 3 separate doses.
Other lipid depressant that the present invention is contained comprises a bile acid chelating agent.Bile acid chelating agent can be in conjunction with the bile acid in the intestinal, and this interrupts the enterohepatic circulation of bile acid and causes sterin increase in the excrement.
The limiting examples of suitable bile acid chelating agent comprises colestyramine (cholestyramine), and (a kind of styrene diethylene benzene copoly mer that contains level Four ammonium cation group that can conjugated bile acid is for example as available from Bristol-Myers Squibb
Or
Colestyramine), (diethylenetriamines and 1-chloro-2, the copolymer of 3-expoxy propane is for example available from Pharmacia's for colestipol (colestipol)
Tablet), hydrochloric acid colesevelam (colesevelam hydrochioride) is (for example available from S ankyo's
Tablet (poly-(allyl amine hydrogen chlorate), its with epoxychloropropane crosslinked and with 1-bromo-decane and (6-bromine hexyl)-trimethylammonium bromide alkylation)), soluble derivative (for example 3,3-ionene, N-(cycloalkyl) alkylamine and polyamine glucose), insoluble level Four ammonium polystyrene, Saponin and its mixture.Suitable inorganic cholesterol sequestering agent comprises that bismuth salicylate adds montorillonite clay, aluminium hydroxide and calcium carbonate antacid.
Another embodiment of the present invention comprises activator or the agonist of PPAR.Described activator is the agonist as peroxisome proliferation-activated receptor.Three kinds of hypotype PPAR of alleged occurrence, and described by name peroxisome proliferation-activated receptor α (PPAR α), peroxisome proliferation-activated receptor γ (PPAR γ) and peroxisome proliferation-activated receptor δ (PPAR δ).Should notice that PPAR δ also is called PPAR β and NUC1 in the literature, and each described title all is meant same receptor.
PPAR α regulates lipid metabolism.PPAR α is by the special class (fibrates) of shellfish and multiple medium and long-chain fat acid activation, and it comprises the beta oxidation that stimulates fatty acid.Described PPAR γ receptor subclass relates to the program of activation adipose cell differentiation, does not stimulate peroxisome hypertrophy in the liver but do not relate to.Confirmed that PPAR δ can be used to increase human high density lipoprotein (HDL) level.Referring to, WO97/28149 for example.
PPAR α activator compound especially can be used to reduce triglyceride, appropriateness reduces the LDL level and increases the HDL level.The useful example of PPAR α activator comprises the special class of shellfish.
The limiting examples of suitable fiber acid derivative (" the special class of shellfish ") comprises clofibrate, and (2-(right-chlorophenoxy)-2-methyl-ethyl propionate for example is for example available from Wyeth-Ayerst's
Capsule), (5-(2, the 5-dimethyl phenoxy)-2 for example, 2-dimethyl valeric acid is for example available from Pfizer's for gemfibrozil
Tablet), ciprofibrate (C.A.S. registration number 52214-84-3 number, referring to the United States Patent (USP) the 3rd that is incorporated herein with way of reference, 948, No. 973), bezafibrate (C.A.S. registration number 41859-67-0 number, referring to the United States Patent (USP) the 3rd that is incorporated herein with way of reference, 781, No. 328), clinofibrate (C.A.S. registration number 30299-08-2 number, referring to the United States Patent (USP) the 3rd that is incorporated herein with way of reference, 716, No. 583), binifibrate (C.A.S. registration number 69047-39-8 number is referring to the BE 88472 that is incorporated herein with way of reference), lifibrol (C.A.S. registration number 96609-16-4 number), fenofibrate is (for example available from Abbott Laboratories's
Lipantil (2-[4-(4-chlorobenzene formacyl) phenoxy group]-2-methyl-propanoic acid 1-Methylethyl ester) or available from Labortoire Founier, France's
Lipantil) and composition thereof.Described chemical compound can include, but is not limited to sour form, salt form, racemic isomer, enantiomer, amphion and tautomer and be used in interior various ways.
Other example that is used for the PPAR α activator of the invention process comprises suitable fluorine phenyl compounds, as is disclosed in No. the 6th, 028,109, the United States Patent (USP) that is incorporated herein with way of reference; Some is substituted the phenylpropionic acid chemical compound, as is disclosed among the WO00/75103 that is incorporated herein with way of reference; With PPAR α activator compound, as be disclosed among the WO 98/43081 that is incorporated herein with way of reference.
The limiting examples of suitable PPAR γ activator comprises glitazone or thiazole pyridine diketone derivative, and for example troglitazone, rosiglitazone are (for example available from SmithKline Beecham's
The rosiglitazone maleate (5-[[4-[2-(methyl-2-pyridinylamino) ethyoxyl] phenyl] methyl]-2,4-thiazole pyridine diketone-2-butylene diacid salt)) and pioglitazone (for example available from the ACTOS of TakedaPharmaceuticals
TMThe pioglitazone hydrochlorate (5-[[4-[2-(5-ethyl-2-pyridine radicals) ethyoxyl] phenyl] methyl]-2,4-] thiazole pyridine diketone mono-hydrochloric salts)).Other useful thiazole pyridine diketone comprises ciglitazone, englitazone, darglitazone and BRL49653, as is disclosed among the WO 98/05331 that is incorporated herein with way of reference; PPAR γ activator compound, as be disclosed among the WO 00/76488 that is incorporated herein with way of reference; With PPAR γ activator compound, as be disclosed in No. the 5th, 994,554, the United States Patent (USP) that is incorporated herein with way of reference.
Other useful PPAR γ activator compound comprises some acetophenol, as is disclosed in No. the 5th, 859,051, the United States Patent (USP) that is incorporated herein with way of reference; Some quinoline phenyl compound, as be disclosed among the WO 99/20275 that is incorporated herein with way of reference; Aryl compound, as be disclosed among the WO 99/38845 that is incorporated herein with way of reference; Some 1,4-is through the disubstituted benzenes based compound, as is disclosed among the WO 00/63161; Some aryl compound, as be disclosed among the WO 01/00579 that is incorporated herein with way of reference; Benzoic acid compounds, as be disclosed among the WO 01/12612 that is incorporated herein with way of reference and the WO01/12187; Be substituted 4-hydroxyl-phenyl hydroxy acid compound, as be disclosed among the WO 97/31907 that is incorporated herein with way of reference.
PPAR δ chemical compound especially can be used for reducing triglyceride level or rising HDL level.The limiting examples of PPAR delta activators comprises suitable thiazole with the oxazole derivant, and for example the C.A.S. registration number is 317318-32-4 number, as is disclosed among the WO01/00603 that is incorporated herein with way of reference; Some fluorine, chlorine or sulfur Phenoxyphenylacetic acid, as be disclosed among the WO 97/28149 that is incorporated herein with way of reference; Suitable non--β-oxidizable fatty acid analog, as be disclosed in No. the 5th, 093,365, the United States Patent (USP) that is incorporated herein with way of reference; With PPAR δ chemical compound, as be disclosed among the WO 99/04815 that is incorporated herein with way of reference.
In addition, have the chemical compound that polyfunctionality is used to activate PPAR α, PPAR γ and the various combinations of PPAR δ and also can be used for the invention process.Limiting examples comprises that some is substituted aryl compound, as be disclosed in United States Patent (USP) the 6th, 248, No. 781; WO 00/23416; WO 00/23415; WO00/23425, WO 00/23445; WO 00/23451; With among the WO 00/63153 (all are incorporated herein with way of reference), it is described as useful PPAR α and/or PPAR γ activator compound.Other limiting examples of useful PPAR α and/or PPAR γ activator compound comprises activator compound, as is disclosed among the WO 97/25042 that is incorporated herein with way of reference; Activator compound, as be disclosed among the WO 00/63190 that is incorporated herein with way of reference; Activator compound, as be disclosed among the WO 01/21181 that is incorporated herein with way of reference; Diaryl-Evil (thiophene) azole compounds, as be disclosed among the WO 01/16120 that is incorporated herein with way of reference; Chemical compound, as be disclosed among the WO 00/63196 that is incorporated herein with way of reference and the WO 00/63209; Be substituted 5-aryl-2,4-thiazole pyridine dione compounds, as be disclosed in No. the 6th, 008,237, the United States Patent (USP) that is incorporated herein with way of reference; Aryl thiazole pyridine diketone and Fang Ji oxazole pyridine dione compounds, as be disclosed among the WO 00/78312 that is incorporated herein with way of reference and the WO00/78313G; GW2331 or (2-(4-[difluorophenyl]-1-heptyl urea groups) ethyl] phenoxy group)-2-Methyl Butyric Acid chemical compound, as be disclosed among the WO 98/05331 that is incorporated herein with way of reference; Aryl compound, as be disclosed in No. the 6th, 166,049, the United States Patent (USP) that is incorporated herein with way of reference; The oxazole chemical compound, as be disclosed among the WO 01/17994 that is incorporated herein with way of reference; And dithiolane (dithiolane) chemical compound, as be disclosed among the WO 01/25225 that is incorporated herein with way of reference and the WO 01/25226.
Other useful PPAR activator compound comprises and is substituted the pyridine-2 of benzyl thiazole, the 4-dione compounds, as be disclosed among the WO 01/14349, the WO 01/14350 that are incorporated herein with way of reference and the WO/01/04351; Mercaptan carboxylic acid's chemical compound, as be disclosed among the WO 00/50392 that is incorporated herein with way of reference; The Ascofuranone. chemical compound, as be disclosed among the WO 00/53563 that is incorporated herein with way of reference; Carboxylic acid compound, as be disclosed among the WO 99/46232 that is incorporated herein with way of reference; Chemical compound, as be disclosed among the WO99/12534 that is incorporated herein with way of reference; Benzene compound, as be disclosed among the WO99/15520 that is incorporated herein with way of reference; Neighbour-methoxy benzamide chemical compound, as be disclosed among the WO 01/21578 that is incorporated herein with way of reference; With the PPAR activator compound, as be disclosed among the WO 01/40192 that is incorporated herein with way of reference.
Use described peroxisome proliferation-activated receptor activator with the treatment particular condition with the treatment effective dose, for example, daily dose is preferably between about 50mg/ days to about 3000mg/ days and more preferably from about between 50mg/ days to about 2000mg/ days, its can single dose or 2-4 separate doses give with.Yet actual dose should be determined and depends on factors such as usefulness, patient age, body weight, the patient's condition and reaction such as institute's administered compound by curing mainly the clinicist.
In an alternative embodiment, the present invention includes and use one or more ibat inhibitors or ASBT inhibitor.Described ibat inhibitor can suppress bile acid and carry to reduce the LDL cholesterol levels.The limiting examples of suitable ibat inhibitor comprises that the benzo thiophene exhales, and for example comprises 2,3,4,5-tetrahydrochysene-1-benzo thiophene exhales 1, and the treatment chemical compound of 1-dioxide structure for example is disclosed among the PCT patent application case WO 00/38727 that is incorporated herein with way of reference.
Generally speaking, total daily dose of ibat inhibitor can be between about 0.01mg/ days to about 1000mg/ days and preferably about 0.1mg/ days to about 50mg/ days, its with single dose or 2-4 separate doses give with.
In another alternative embodiment, the inventive method can comprise further that nicotinic acid (niacin usp) and/or niacin receptor (" NAR ") agonist are as the lipid depressant.
" nicotinic acid receptor agonists " used herein is meant any chemical compound that this niacin receptor is worked with as agonist that comprises.Chemical compound comprises those with Nicotinicum Acidum ester structure or pyrazine-2-formic acid esters structure, and it comprises sour form, salt, ester, amphion and tautomer (if available).The example of nicotinic acid receptor agonists comprises niceritrol, nicofuranose (nicofuranose) and acipimox (5-methylpyrazine-2-formic acid 4-oxide).Generation and increase HDL and the apo A-1 level of VLDL and its metabolite LDL in nicotinic acid and the NAR agonist inhibition liver.The example of suitable nicotinic acid product is the NIASPAN available from Kos
(niacin usp delayed-release tablet).
Generally speaking, total daily dose of nicotinic acid can between about 500mg/ days to about 10,000mg/ days, preferably about 1000mg/ days to about 8000mg/ days and more preferably from about between 3000mg/ days to about 6000mg/ days, it can be single dose or separate doses.Generally speaking, total daily dose of NAR agonist can be between about 1mg/ days to about 100mg/ days.
In another alternative embodiment, the inventive method can comprise further that one or more ACAT inhibitor are as the lipid depressant.The ACAT inhibitor reduces LDL and VLDL level.ACAT is the excessive production of synthesizing and comprise the lipoprotein of apo B-100-of being responsible for the ferment of the excessive cell inner cholesterol of esterification and can reducing VLDL (it is a cholesterol esterification product).
The limiting examples of useful ACAT inhibitor comprises avasimibe (avasimibe) ([[2; 4; 6-three (1-Methylethyl) phenyl] acetyl group] sulfamic acid, 2; two (1-Methylethyl) phenylesters of 6-; it before had been called CI-1011), (N-(2 for HL-004, lecimibide (DuP-128) and CL-277082; the 4-difluorophenyl)-and N-[[4-(2, the 2-dimethyl propyl) phenyl] methyl]-N-heptyl urea).Referring to people's such as P.Chang
" Current, New and Future Treatments in Dyslipidaemia andAtherosclerosis ",
Drugs2000 Jul; 60 (1); 55-93, it is incorporated herein with way of reference.
Generally speaking, total daily dose of ACAT inhibitor can be between about 0.1mg/ days to about 1000mg/ days, and it can be single dose or 2-4 separate doses.
In another alternative embodiment, in the inventive method compositions for use can comprise further that one or more and the formula I-X chemical compound of above being discussed are used altogether or with cholesterol ester transfer protein (" the CETP ") inhibitor of its combination.CETP is responsible for exchange or shifts cholesteryl ester that HDL carries and the triglyceride among the VLDL.
The limiting examples of suitable CETP inhibitor is disclosed in No. the 6th, 147,090, PCT patent application case WO00/38721 number and the United States Patent (USP), and it is incorporated herein with way of reference.Pancreas cholesterol ester hydrolase (pCEH) inhibitor (for example WAY-121898) also can with the described fiber acid derivative of above being discussed and the sterin absorption inhibitor is used altogether or with its combination.
Generally speaking, total daily dose of CETP inhibitor can be between about 0.01mg/ days to about 1000mg/ days and preferably about 0.5mg/kg body weight/day between about 20mg/kg body weight/day, and it can be single dose or separate doses.
In another alternative embodiment, the inventive method can comprise further that the probacol or derivatives thereof (for example is disclosed in United States Patent (USP) the 6th, 121, No. 319 and the 6th, AGI-1067 in 147, No. 250 and other derivant), it can be used as cholesterol reducing agent and reduces LDL and HDL level.
Generally speaking, total daily dose of probacol or derivatives thereof can be between about 10mg/ days to about 2000mg/ days and preferably about 500mg/ days to about 1500mg/ days, and it can be single dose or 2-4 separate doses.
In another alternative embodiment, the inventive method can comprise further that one or more low density lipoproteins (LDL) receptor activator is as the lipid depressant.The limiting examples of suitable LDL-receptor activator comprises HOE-402, and it is the active imidazolidine base-pyrimidine derivatives of a kind of direct stimulation ldl receptor.Referring to people's such as M.Huettinger " Hypolipidemic activity of HOE-402is Mediated by Stimulation of the LDL Receptor Pathway ", Arterioscler.Thromb.1993; 13:1005-12.
Generally speaking, total daily dose of ldl receptor activator can be between about 1mg/ days to about 1000mg/ days, and it can be single dose or 2-4 separate doses.
In another alternative embodiment, the inventive method can further comprise fish oil, and it comprises omega-3 fatty acid (3-PUFA), and it can reduce VLDL and triglyceride level as the lipid depressant.Generally speaking, total daily dose of fish oil or omega-3 fatty acid can be between about 1g/ days to about 30g/ days, and it can be single dose or 2-4 separate doses.
In another alternative embodiment, the inventive method can further comprise water-soluble fiber (for example Psyllium (psyllium), guar gum, Herba bromi japonici and pectin), but its cholesterol reducing level.Generally speaking, total daily dose of water-soluble fiber can be between about 0.1 to about 10g/ day, and it can be single dose or 2-4 separate doses.
In another alternative embodiment, the inventive method can further comprise the fatty acid ester (BENECOL for example of solid alkanol of phytosterol, plant and/or the solid alkanol of plant
Employed paddy solid alkane alcohol ester in the margarine), but its cholesterol reducing level.Generally speaking, total daily dose of the fatty acid ester of phytosterol, the solid alkanol of plant and/or the solid alkanol of plant can be between about 0.5g/ days to about 20g/ days, and it can be single dose or 2-4 separate doses.
As mentioned above, the present composition, therapeutic combination and method can comprise at least a H
3Receptor antagonist/inverse agonist.In one embodiment, this H
3But any for example is set forth among WO 95/14007 and the WO 99/21405 (each document all is incorporated herein with way of reference) those in the receptor antagonist inverse agonist imidazoles.
In another embodiment of the present invention, provide the present composition, therapeutic combination and method, wherein at least a H
3Receptor antagonist/inverse agonist is the chemical compound of following formula:
Or acceptable salt of its pharmacy or solvate, wherein:
(1) R
1Be selected from:
(a) aryl;
(b) heteroaryl;
(c) Heterocyclylalkyl
(d) alkyl;
(e) cycloalkyl; Or
(f) alkylaryl;
Wherein said R
1Group can be chosen wantonly through 1 to 4 and be independently selected from following substituent group replacement:
(1) halogen (for example, Br, F or Cl, preferably F or Cl);
(2) hydroxyl (promptly-OH);
(3) lower alkoxy (for example, C
1To C
6Alkoxyl, preferably C
1To C
4Alkoxyl most preferably is C
1To C
2Alkoxyl is more preferably methoxyl group);
(4)-CF
3；
(5)CF
3O-；
(6)-NR
4R
5；
(7) phenyl;
(8)-NO
2，
(9)-CO
2R
4；
(10)-CON (R
4)
2, each R wherein
4Identical or different;
(11)-S (O)
M 'N (R
20)
2, each R wherein
20Be identical or different, it can be H or alkyl group, preferably C
1To C
4Alkyl most preferably is C
1-C
2Alkyl, and be more preferably methyl;
(12)-CN; Or
(13) alkyl; Or
(2) R
1Be selected from following group with X ' formation:
(3) X ' is selected from :=C (O) ,=C (NOR
3) ,=C (NNR
4R
5),
(4) M
1Be carbon;
(5) M
2Be selected from C or N;
(6) M
3And M
4Be independently selected from C or N;
(7) Y ' is selected from :-CH
2-,=C (O) ,=C (NOR
20) (R wherein
20Be as defined above) or=C (S);
(8) Z ' is C
1-C
6Alkyl group;
(9) R
2Be five or six-member's heteroaryl ring, this six-member heteroaryl ring comprises that 1 or 2 nitrogen-atoms and all the other annular atomses are carbon, and this five-member heteroaryl ring to comprise 1 or 2 hetero atom and all the other annular atoms that is selected from nitrogen, oxygen or sulfur be carbon; These five Yuans or six Yuans heteroaryl rings can be chosen wantonly and be independently selected from following substituent group through 1 to 3 and replace: halogen, hydroxyl, low alkyl group, lower alkoxy ,-CF
3, CF
3O-,-NR
4R
5, phenyl ,-NO
2,-CO
2R
4,-CON (R
4)
2, each R wherein
4Identical or different, it can be-CH
2NR
4R
5The C of ,-(N) (NR
4R
5)
2Or-CN;
(10) R
3Be selected from:
(a) hydrogen;
(b) C
1-C
6Alkyl;
(c) aryl;
(d) heteroaryl;
(e) Heterocyclylalkyl;
(f) aryl alkyl (aryl (C for example
1To C
4) alkyl, for example-(CH
2)
W 'Aryl, wherein w ' is 1 to 4, is preferably 1 or 2 and most preferably be 1, for example-CH
2Phenyl or-CH
2Be substituted phenyl);
(g)-(CH
2)
E '-C (O) N (R
4)
2, each R wherein
4It is all identical or different,
(h)-(CH
2)
e′-C(O)OR
4；
(i)-(CH
2)
E '-C (O) R
30, R wherein
30Be heterocycloalkyl, for example, morpholinyl, piperidyl, piperazinyl or pyrrolidinyl, and comprise
(j)-CF
3Or
(k)-CH
2CF
3；
Wherein the aryl moiety of this aryl, heteroaryl, Heterocyclylalkyl and this aryl alkyl all can be chosen wantonly through 1 to 3 (preferred 1) and be selected from following substituent group replacement: halogen (for example F or Cl) ,-OH ,-OCF
3,-CF
3,-CN ,-N (R
45)
2,-CO
2R
45, or-C (O) N (R
45)
2, each R wherein
45Be independently selected from: H, alkyl, alkylaryl or wherein this aryl moiety be independently selected from-CF through 1 to 3
3,-OH, halogen, alkyl ,-NO
2Or-alkylaryl that the substituent group of CN replaces;
(11) R
4Be selected from: hydrogen, C
1-C
6Alkyl, aryl, alkylaryl, described aryl and kiki fang alkyl group can be chosen wantonly through 1 to 3 and be selected from following substituent group replacement: halogen ,-CF
3,-OCF
3,-OH ,-N (R
45)
2,-CO
2R
45,-C (O) N (R
45)
2Or-CN; R wherein
45Be as defined above;
(12) R
5Be selected from: hydrogen, C
1-C
6Alkyl ,-C (O) R
4,-C (O)
2R
4Or-C (O) N (R
4)
2, each R wherein
4All be independent through selecting and R
4Be as defined above;
(13) or R
4And R
5Nitrogen-atoms with its bond forms five Yuans or six element heterocycle alkyl rings (for example morpholine);
(14) R
6Be selected from: alkyl, aryl, alkylaryl, halogen, hydroxyl, lower alkoxy ,-CF
3, CF
3O-,-NR
4R
5, phenyl ,-NO
2,-CO
2R
5,-CON (R
4)
2(each R wherein
4Identical or different) or-CN;
(15) R
12Be selected from: alkyl, hydroxyl, alkoxyl or fluorine;
(16) R
13Be selected from: alkyl, hydroxyl, alkoxyl or fluorine;
(17) a ' (R
12Subscript) be 0 to 2;
(18) b ' (R
12Subscript) be 0 to 2;
(19) c ' (R
6Subscript) be 0 to 2;
(20) e ' is 0 to 5;
(21) m ' is 1 or 2;
(22) n ' is 1,2 or 3; With
(23) p ' is 1,2 or 3, but restrictive condition is to work as M
3And M
4When the two all was nitrogen, then p ' 2 or 3 (that is, worked as M
3And M
2P ' was not 1 when the two was nitrogen)
It is present in the described therapeutic combination.
The more preferably definition of formula XIII chemical compound is as follows:
R
1Be preferably selected from:
(A) aryl (most preferably phenyl);
(B) be substituted aryl (for example being substituted phenyl), wherein this substituent group that is substituted on the aryl most preferably is selected from: (1) halogen (for example, single halogen or two halogens) is more preferably chlorine or fluorine even is more preferably monochloro, dichloro, single fluorine or difluoro; Or (2) alkyl, more preferably be that non-side chain (is a straight chain, methyl for example) alkyl even be more preferably is substituted alkyl, still is more preferably alkyl that replaces through halogen (for example 1,2 or 3 halogen atom, for example Cl or F) even the alkyl that still more preferably replaces through fluorine atom, more preferably trifluoromethyl still;
(C) heteroaryl, most preferably be five Yuans or six Yuans heteroaryl rings, be more preferably six Yuans heteroaryl rings and still be more preferably pyridine radicals, the example of heteroaryl ring comprises pyridine radicals, thienyl, pyrimidine radicals, thiazolyl or pyridine radicals N-oxide, and most preferred heteroaryl ring is by following illustration:
(D) be substituted heteroaryl, most preferably be the heteroaryl that replaces through halogen or alkyl (for example, halogenated pyridyl (for example fluorine pyridine radicals) and alkyl thiazolyl), be more preferably and be substituted heteroaryl, wherein said substituent group is independently selected from an identical or different alkyl group (even more preferably straight chained alkyl group, methyl for example), the thiazolyl that more preferably replaces still through alkyl, and even be more preferably (alkyl)
And still even be more preferably
Or
(E) work as R
1With X ' in conjunction with the time, then this part is
Wherein c ' most preferably is 0 or 1, and when c ' is 1, then R
6Most preferably be halogen, and when c ' is 1, R then
6Be more preferably fluorine.
X ' preferably=C (NOR
3), R wherein
3The alkyl that is preferably selected from H, alkyl or replaces through halogen (alkyl that replaces through fluorine for example, for example-CH
2CF
3), most preferably alkyl, more preferably methyl or ethyl and more preferably methyl still.
M
2Nitrogen preferably.
N ' is preferably 2.
A ' is preferably 0 or 1, and most preferably is 0.
B ' is preferably 0 or 1, and most preferably is 0.
C ' is preferably 0 or 1, and most preferably is 0, and when c is 1, then R
6Halogen preferably, and when c is 1, R
6It most preferably is fluorine.
E ' is preferably 1 to 5.
Y ' preferably=C (O) (promptly=C=O).
M
3And M
4Preferably through selecting so that: (1) one is that carbon and other are nitrogen, or (2) the two be nitrogen, and M
3Most preferably be carbon.
P ' is preferably 2.
Z ' is C preferably
1To C
3Alkyl, and most preferably be
-CH
2-or
R
2Preferably six Yuans heteroaryl rings most preferably are pyridine radicals, are substituted pyridine radicals, pyrimidine radicals or are substituted pyrimidine radicals, are more preferably pyridine radicals, warp-NR
4R
5The pyridine radicals, pyrimidine radicals or the warp-NR that replace
4R
5The pyrimidine radicals that replaces still is more preferably pyridine radicals, warp-NH
2The pyridine radicals that replaces (is R
4And R
5Be H), pyrimidine radicals or warp-NH
2The pyrimidine radicals that replaces (is R
4And R
5Be H), and even be more preferably
And still even be more preferably
R
3Preferably H or alkyl most preferably are H or methyl.
R
4Preferably H or low alkyl group most preferably are H or methyl and be more preferably H.
R
5Preferably H, C
1To C
6Alkyl or-C (O) R
4, most preferably be H or methyl, and be more preferably H.
R
12Preferably alkyl, hydroxyl or fluorine, and most preferably be H.
R
13Preferably alkyl, hydroxyl or fluorine, and most preferably be H.
The method of preparation formula XIII chemical compound is well known to those skilled in the art.The limiting examples of proper method is disclosed in United States Patent (USP) the 6th, 720,328 B1 numbers that are incorporated herein with way of reference.
Being used for formula XIII examples for compounds of the present invention is expressed from the next:
With
In another embodiment, the invention provides the present composition, therapeutic combination and method, wherein at least a H
3Receptor antagonist/inverse agonist is a following formula: compound:
Or acceptable salt of its pharmacy or solvate, wherein:
Dotted line is represented optional pair of key;
A ' is 0 to 2;
B ' is 0 to 2;
N ' is 1,2 or 3;
P ' is 1,2 or 3;
R ' is 0,1,2 or 3;
Condition is to work as M
2When being N, p ' is not 1; And when r ' is 0, M
2Be C (R
3); And p ' is 1 to 4 with r ' sum;
M
1Be C (R
3) or N;
M
2Be C (R
3) or N;
X ' is a key or C
1-C
6Alkylidene;
Y ' is-C (O)-,-C (S)-,-(CH
2)
Q '-,-NR
4C (O)-,-C (O) NR
4-,-C (O) CH
2-,-SO
2-,-N (R
4)-,-NH-C (=N-CN)-or-C (=N-CN)-NH-; Condition is to work as M
1When being N, Y ' is not-NR
4C (O)-or-NH-C (=N-CN)-; Work as M
2When being N, Y ' is not-C (O) NR
4-or-C (=N-CN)-NH-; And when Y ' is-N (R
4)-time, M
1Be CH and M
2Be C (R
3);
Q ' is 1 to 5, and condition is to work as M
1And M
2When the two was N, q ' was 2 to 5;
Z ' is a key, C
1-C
6Alkylidene, C
1-C
6Alkenylene ,-C (O)-,-CH (CN)-,-SO
2-or-CH
2C (O) NR
4-;
R
1Be
Q ' is-N (R
8)-,-S-or-O-;
K ' is 0,1,2,3 or 4;
K1 is 0,1,2 or 3;
K2 is 0,1 or 2;
R is H, C
1-C
6Alkyl, halogen (C
1-C
6) alkyl-, C
1-C
6Alkoxyl, (C
1-C
6) alkoxyl-(C
1-C
6) alkyl-, (C
1-C
6)-alkoxyl-(C
1-C
6) alkoxyl, (C
1-C
6) alkoxyl-(C
1-C
6) alkyl-SO
0-2, R
32-aryl (C
1-C
6) alkoxyl-, R
32-aryl (C
1-C
6) alkyl-, R
32-aryl, R
32-aryloxy group, R
32-heteroaryl, (C
3-C
6) cycloalkyl, (C
3-C
6) cycloalkyl-(C
1-C
6) alkyl, (C
3-C
6) cycloalkyl-(C
1-C
6) alkoxyl, (C
3-C
6) cycloalkyl-oxygen base-, R
37-Heterocyclylalkyl, R
37-Heterocyclylalkyl-oxygen base-, R
37-Heterocyclylalkyl-(C
1-C
6) alkoxyl, N (R
30) (R
31)-(C
1-C
6) alkyl-,-N (R
30) (R
31) ,-NH-(C
1-C
6) alkyl-O-(C
1-C
6) alkyl ,-NHC (O) NH (R
29), R
29-S (O)
0-2-, halogen (C
1-C
6) alkyl-S (O)
0-2-, N (R
30) (R
31)-(C
1-C
6) alkyl-S (O)
0-2-or benzoyl;
R
8Be H, C
1-C
6Alkyl, halogen (C
1-C
6) alkyl-, (C
1-C
6) alkoxyl-(C
1-C
6) alkyl-, R
32-aryl (C
1-C
6) alkyl-, R
32-aryl, R
32-heteroaryl, (C
3-C
6) cycloalkyl, (C
3-C
6) cycloalkyl-(C
1-C
6) alkyl, R
37-Heterocyclylalkyl, N (R
30) (R
31)-(C
1-C
6) alkyl-, R
29-S (O)
2-, halogen (C
1-C
6) alkyl-S (O)
2-, R
29-S (O)
0-1-(C
2-C
6) alkyl-, halogen (C
1-C
6) alkyl-S (O)
0-1-(C
2-C
6) alkyl-;
R
3Be that to have 1 or 2 hetero atom and all the other annular atoms that is independently selected from N or N-O be six of carbon-member's heteroaryl ring; Having 1,2,3 or 4 hetero atom and all the other annular atoms that is independently selected from N, O or S is five of carbon-member's heteroaryl ring; R
32-quinolyl; R
32-aryl; Heterocyclylalkyl; (C
3-C
6) cycloalkyl; C
1-C
6Alkyl; Hydrogen; Thianaphthenyl;
Wherein this six-member heteroaryl ring or this five-member heteroaryl ring are optional through R
6Replace;
R
3Be H, halogen, C
1-C
6Alkyl ,-OH, (C
1-C
6) alkoxyl or-NHSO
2-(C
1-C
6) alkyl;
R
4Be independently selected from: hydrogen, C
1-C
6Alkyl, C
3-C
6Cycloalkyl, (C
3-C
6) cycloalkyl (C
1-C
6) alkyl, R
33-aryl, R
33-aryl (C
1-C
6) alkyl and R
32-heteroaryl;
R
5Be hydrogen, C
1-C
6Alkyl ,-C (O) R
20,-C (O)
2R
20,-C (O) N (R
20)
2, (C
1-C
6) alkyl-SO
2-or (C
1-C
6) alkyl-SO
2-NH-;
Perhaps R
4And R
5Form azetidinyl, pyrrolidinyl, piperidyl, piperazinyl or morpholine basic ring with the nitrogen that it connected;
R
6Be 1 to 3 and be independently selected from following substituent group :-OH, halogen, C
1-C
6Alkyl-, C
1-C
6Alkoxyl, C
1-C
6Alkylthio group ,-CF
3,-NR
4R
5,-CH
2-NR
4R
5,-NHSO
2R
22,-N (SO
2R
22)
2, phenyl, R
33-phenyl, NO
2,-CO
2R
4,-CON (R
4)
2,
R
7Be-N (R
29)-,-O-or-S (O)
0-2-;
R
12Be independently selected from C
1-C
6Alkyl, hydroxyl, C
1-C
6Alkoxyl or fluorine, condition are to work as R
12When being hydroxyl or fluorine, R then
12Bond is not to the carbon that adjoins nitrogen; Perhaps two R
12Substituent group forms the C to another non-adjacent annulus carbon from a ring carbon
1To C
2The alkyl bridge; Perhaps R
12Be=O;
R
13Be independently selected from C
1-C
6Alkyl, hydroxyl, C
1-C
6Alkoxyl or fluorine, condition are to work as R
13When being hydroxyl or fluorine, R then
13Be not binding on the carbon of adjacent nitrogen; Perhaps two R
13Substituent group forms the C to another non-adjacent annulus carbon from a ring carbon
1To C
2The alkyl bridge; Perhaps R
13Be=O;
R
2Be independently selected from hydrogen, C
1-C
6Alkyl or aryl, wherein this aromatic yl group can choose wantonly through 1 to 3 be independently selected from halogen ,-CF
3,-OCF
3, hydroxyl or methoxyl group group replace; Perhaps when there being two R
20During group, described two R
20Group can form five Yuans or six element heterocycle rings with the nitrogen of its bond;
R
22Be C
1-C
6Alkyl, R
34-aryl or Heterocyclylalkyl;
R
24Be H, C
1-C
6Alkyl ,-SO
2R
2Or R
34-aryl;
R
25Be independently selected from: C
1-C
6Alkyl, halogen ,-CN ,-NO
2,-CF
3,-OH, C
1-C
6Alkoxyl, (C
1-C
6) alkyl-C (O)-, aryl-C (O)-,-C (O) OR
29,-N (R
4) (R
5), N (R
4) (R
5)-C (O)-, N (R
4) (R
5)-S (O)
1-2-, R
22-S (O)
0-2-, halogen-(C
1-C
6) alkyl-or halogen-(C
1-C
6) alkoxyl-(C
1-C
6) alkyl-;
R
29Be H, C
1-C
6Alkyl, C
3-C
6Cycloalkyl, R
35-aryl or R
35-aryl (C
1-C
6) alkyl-;
R
30Be H, C
1-C
6Alkyl-, R
35-aryl or R
35-aryl (C
1-C
6) alkyl-;
R
31Be H, C
1-C
6Alkyl-, R
35-aryl, R
35-aryl (C
1-C
6) alkyl-, R
35-heteroaryl, (C
1-C
6) alkyl-C (O)-, R
35-aryl-C (O)-, N (R
4) (R
5)-C (O)-, (C
1-C
6) alkyl-S (O)
2-or R
35-aryl-S (O)
2-;
Perhaps R
30With R
31Be together-(CH
2)
4-5-,-(CH
2)
2-O-(CH
2)
2-or-(CH
2)
2-N (R
38)-(CH
2)
2-and form a ring with its nitrogen that is connected;
R
32Be 1 to 3 be independently selected from following substituent group: H ,-OH, halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl, R
35-aryl-O-,-SR
22,-CF
3,-OCF
3,-OCHF
2,-NR
39R
40, phenyl, R
33-phenyl, NO
2,-CO
2R
39,-CON (R
39)
2,-S (O)
2R
22,-S (O)
2N (R
20)
2,-N (R
24) S (O)
2R
22,-CN, hydroxyl-(C
1-C
6) alkyl-,-OCH
2CH
2OR
22And R
35-aryl (C
1-C
6) alkyl-O-, perhaps adjoin two R on the carbon atom
32Group forms-OCH together
2O-or-O (CH
2)
2The O-group;
R
33Be 1 to 3 and be independently selected from following substituent group: C
1-C
6Alkyl, halogen ,-CN ,-NO
2,-CF
3,-OCF
3,-OCHF
2With-O-(C
1-C
6) alkyl;
R
34Be 1 to 3 be independently selected from following substituent group: H, halogen ,-CF
3,-OCF
3,-OH and-OCH
3
R
35Be 1 to 3 and be independently selected from hydrogen, halogen, C
1-C
6Alkyl, hydroxyl, C
1-C
6Alkoxyl, phenoxy group ,-CF
3,-N (R
36)
2,-COOR
20With-NO
2Substituent group;
R
36Be independently selected from H and C
1-C
6Alkyl;
R
37Be 1 to 3 and be independently selected from hydrogen, halogen, C
1-C
6Alkyl, hydroxyl, C
1-C
6Alkoxyl, phenoxy group ,-CF
3,-N (R
36)
2,-COOR
20,-C (O) N (R
29)
2With-NO
2Substituent group, perhaps R
37Be one or two=the O group;
R
38Be H, C
1-C
6Alkyl, R
35-aryl, R
35-aryl (C
1-C
6) alkyl-, (C
1-C
6) alkyl-SO
2Or halogen (C
1-C
6) alkyl-SO
2-;
R
39Be independently selected from: hydrogen, C
1-C
6Alkyl, C
3-C
6Cycloalkyl, (C
3-C
6) cycloalkyl (C
1-C
6) alkyl, R
33-aryl, R
33-aryl (C
1-C
6) alkyl and R
32-heteroaryl; With
R
40Be hydrogen, C
1-C
6Alkyl ,-C (O) R
20,-C (O)
2R
20,-C (O) N (R
20)
2, (C
1-C
6) alkyl-SO
2-or (C
1-C
6) alkyl-SO
2-NH-;
Perhaps R
39And R
40Form azetidinyl, pyrrolidinyl, piperidyl, piperazinyl or morpholine basic ring with the nitrogen that it connected.
The method of preparation formula XIV chemical compound is well known to those skilled in the art.The limiting examples of proper method is disclosed in the open case of U.S. of being incorporated herein with way of reference US2004/0097483A1 number.
In another embodiment, the invention provides the present composition, therapeutic combination and method, wherein this H
3Receptor antagonist/inverse agonist is a following formula: compound:
Or acceptable salt of its pharmacy or solvate, wherein:
A ' is 0 to 3;
B ' is 0 to 3;
N ' is 1,2 or 3;
P ' is 1,2 or 3;
R ' is 0,1,2 or 3;
X ' is a key or C
1-C
6Alkylidene;
M
1Be CH or N;
M
2Be C (R
3) or N;
Condition is to work as M
2When being N, p ' is not 1; And when r ' is 0, M
2Be C (R
3); And p ' is 1 to 4 with r ' sum;
Y ' is-C (=O)-,-C (=S)-,-(CH
2)
Q '-,-NR
4C (=O)-,-C (=O) NR
4-,-C (=O) CH
2-,-SO
1-2-,-C (=N-CN)-NH-or-NH-C (=N-CN)-; Condition is to work as M
1When being N, Y ' is not-NR
4C (=O)-or-NH-C (=N-CN)-; And work as M
2When being N, Y ' is not-C (=O) NR
4-or-C (=N-CN)-NH-;
Q ' is 1 to 5, and condition is to work as M
1And M
2When the two was N, q ' was not 1;
Z ' is a key, C
1-C
6Alkylidene, C
2-C
6Alkenylene ,-C (=O)-,-CH (CN)-or-CH
2C (=O) NR
4-;
R
1Be
Q ' is-N (R
8)-,-S-or-O-;
K ' is 0,1,2,3 or 4;
K1 is 0,1,2 or 3;
K2 is 0,1 or 2;
Optional pair of key of dotted line representative;
R and R
7Be independently selected from: H, C
1-C
6Alkyl, halogen (C
1-C
6) alkyl-, C
1-C
6Alkoxyl, (C
1-C
6) alkoxyl-(C
1-C
6) alkyl-, (C
1-C
6)-alkoxyl-(C
1-C
6) alkoxyl, (C
1-C
6) alkoxyl-(C
1-C
6) alkyl-SO
0-2, R
32-aryl (C
1-C
6) alkoxyl-, R
32-aryl-(C
1-C
6) alkyl-, R
32-aryl, R
32-aryloxy group, R
32-heteroaryl, (C
3-C
6) cycloalkyl, (C
3-C
6) cycloalkyl-(C
1-C
6) alkyl, (C
3-C
6) cycloalkyl-(C
1-C
6) alkoxyl, (C
3-C
6) cycloalkyl-oxygen base-, R
37-heterocycle-alkyl, N (R
30) (R
31)-(C
1-C
6) alkyl-,-N (R
30) (R
31) ,-NH-(C
1-C
6) alkyl-O-(C
1-C
6) alkyl ,-NHC (O) NH (R
29), R
29-S (O)
0-2-, halogen (C
1-C
6) alkyl-S (O)
0-2-, N (R
30) (R
31)-(C
1-C
6) alkyl-S (O)
0-2-, benzoyl, (C
1-C
6) alkoxyl-carbonyl, R
37-Heterocyclylalkyl-N (R
29)-C (O)-, (C
1-C
6) alkyl-N (R
29)-C (O)-, (C
1-C
6) alkyl-N (C
1-C
6Alkoxyl)-C (O)-and-C (=NOR
36) R
36And when this optional pair of key do not exist, R
7But OH;
R
8Be H, C
1-C
6Alkyl, halogen (C
1-C
6) alkyl-, (C
1-C
6) alkoxyl-(C
2-C
6) alkyl-, R
32-aryl (C
1-C
6) alkyl-, R
32-aryl, R
32-heteroaryl, R
32-heteroaryl (C
1-C
6) alkyl-, (C
3-C
6) cycloalkyl, (C
3-C
6) cycloalkyl-(C
1-C
6) alkyl, R
37-Heterocyclylalkyl, R
37-Heterocyclylalkyl (C
1-C
6) alkyl, N (R
30) (R
31)-(C
2-C
6) alkyl-, R
29-S (O)
2-, halogen (C
1-C
6) alkyl-S (O)
2-, R
29-S (O)
0-1-(C
2-C
6) alkyl-, halogen (C
1-C
6) alkyl-S (O)
0-1-(C
2-C
6) alkyl-, (C
1-C
6) alkyl-N (R
29)-SO
2-or R
32-heteroaryl-SO
2
R
2Be that to have 1 or 2 hetero atom and all the other annular atoms that is independently selected from N or N-O be six of carbon-member's heteroaryl ring; Having 1,2 or 3 hetero atom and all the other annular atoms that is independently selected from N, O or S is five of carbon-member's heteroaryl ring; R
32-quinolyl; R
32-aryl;
Or Heterocyclylalkyl; Wherein this six-member heteroaryl ring or this five-member heteroaryl ring are chosen wantonly and are replaced through R6;
R
3Be H, halogen, C
1-C
6Alkyl ,-OH or (C
1-C
6) alkoxyl;
R
4Be independently selected from: hydrogen, C
1-C
6Alkyl, C
3-C
6Cycloalkyl, (C
3-C
6) cycloalkyl (C
1-C
6) alkyl, R
33-aryl, R
33-aryl (C
1-C
6) alkyl and R
33-heteroaryl;
R
5Be hydrogen, C
1-C
6Alkyl ,-C (O) R
20,-C (O)
2R
20,-C (O) N (R
20)
2, R
33-aryl (C
1-C
6) alkyl or (C
1-C
6) alkyl-SO
2-;
R
6Be 1 to 3 and be independently selected from following substituent group :-OH, halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl ,-CF
3,-NR
4R
5,-(C
1-C
6) alkyl-NR
4R
5, phenyl, R
33-phenyl, NO
2,-CO
2R
4,-CON (R
4)
2,-NHC (O) N (R
4)
2, R
32-heteroaryl-SO
2-NH-, R
32-aryl-(C
1-C
6) alkyl-NH-, R
32-heteroaryl-(C
1-C
6) alkyl-NH-, R
32-heteroaryl-NH-C (O)-NH-and R
37-heterocycle-alkyl-N (R
29)-C (O)-;
R
12Be independently selected from C
1-C
6Alkyl, hydroxyl, C
1-C
6Alkoxyl or fluorine, condition are to work as R
12When being hydroxyl or fluorine, R then
12Be not binding on the carbon that adjoins nitrogen; Perhaps R
12Formation is the C to another ring carbon from a ring carbon
1To C
2The alkyl bridge;
R
13Be independently selected from C
1-C
6Alkyl, hydroxyl, C
1-C
6Alkoxyl or fluorine, condition are to work as R
13When being hydroxyl or fluorine, R then
13Be not binding on the carbon that adjoins nitrogen; Perhaps form the C to another ring carbon from a ring carbon
1To C
2The alkyl bridge; Perhaps R
13Be=O;
R
20On the spot be selected from hydrogen, C
1-C
6Alkyl or aryl, wherein this aromatic yl group can choose wantonly through 1 to 3 be independently selected from halogen ,-CF
3,-OCF
3, hydroxyl or methoxyl group group replace; Perhaps when there being two R
20During group, described two R
20Group can form five Yuans or six element heterocycle rings with the nitrogen of its bond;
R
22Be C
1-C
6Alkyl, R
34-aryl or Heterocyclylalkyl;
R
24Be H, C
1-C
6Alkyl ,-SO
2R
22Or R
34-aryl;
R
25Be independently selected from: C
1-C
6Alkyl, halogen ,-CF
3,-OH, C
1-C
6Alkoxyl, (C
1-C
6) alkyl-C (O)-, aryl-C (O)-, N (R
4) (R
5)-C (O)-, N (R
4) (R
5)-S (O)
1-2-, halogen-(C
1-C
6) alkyl-or halogen-(C
1-C
6) alkoxyl-(C
1-C
6) alkyl-;
R
29Be H, C
1-C
6Alkyl, R
35-aryl or R
35-aryl (C
1-C
6) alkyl-;
R
30Be H, C
1-C
6Alkyl-, R
35-aryl or R
35-aryl (C
1-C
6) alkyl-;
R
31Be H, C
1-C
6Alkyl-, R
35-aryl, R
35-aryl (C
1-C
6) alkyl-, (C
1-C
6) alkyl-C (O)-, R
35-aryl-C (O)-, N (R
4) (R
5)-C (O)-, (C
1-C
6) alkyl-S (O)
2-or R
35-aryl-S (O)
2-;
Perhaps R
30With R
31Be together-(CH
2)
4-5-,-(CH
2)
2-O-(CH
2)
2-or-(CH
2)
2-N (R
29)-(CH
2)
2-and form ring with its nitrogen that is connected;
R
32Be 1 to 3 be independently selected from following substituent group: H ,-OH, halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl, R
35-aryl-O-,-SR
22,-CF
3,-OCF
3,-OCHF
2,-NR
4R
5, phenyl, R
33-phenyl, NO
2,-CO
2R
4,-CON (R
4)
2,-S (O)
2R
22,-S (O)
2N (R
20)
2,-N (R
24) S (O)
2R
22,-CN, hydroxyl-(C
1-C
6) alkyl-,-OCH
2CH
2OR
22And R
35-aryl (C
1-C
6) alkyl-O-, wherein this aromatic yl group can be chosen wantonly through the halogen of 1 to 3 independence through selecting and replace;
R
33Be 1 to 3 and be independently selected from C
1-C
6Alkyl, halogen ,-CN ,-NO
2,-OCHF
2With-O-(C
1-C
6) substituent group of alkyl;
R
34Be 1 to 3 be independently selected from H, halogen ,-CF
3,-OCF
3,-OH and-OCH
3Substituent group;
R
35Be 1 to 3 and be independently selected from hydrogen, halogen, C
1-C
6Alkyl, hydroxyl, C
1-C
6Alkoxyl, phenoxy group ,-CF
3,-N (R
36)
2,-COOR
20With-NO
2Substituent group;
R
36Be independently selected from H and C
1-C
6Alkyl; With
R
37Be independently selected from H, C
1-C
6Alkyl and (C
1-C
6) alkoxy carbonyl.
Preferred formula XV chemical compound comprises following compounds, wherein:
R
1Preferably 3-indyl or 1-indyl.This R
1The preferred pair keys that exist in the substituent group.
R is H, alkyl, R preferably
32-aryl, R
32-heteroaryl, (C
1-C
6) alkoxyl-carbonyl or (C
1-C
6) alkyl-N (R
29)-C (O)-.When R is (C
1-C
6) alkyl-N (R
29)-C (O)-time, R
29Preferably H or C
1-C
6Alkyl.More preferably, R is R
32-aryl or R
32-heteroaryl.R especially preferably
32-phenyl and R
32-pyridine radicals.R
7H preferably.
R
8Preferably H, R
32-aryl (C
1-C
6) alkyl-, R
32-heteroaryl (C
1-C
6) alkyl-, R
32-aryl, R
32-heteroaryl, (C
1-C
6) alkyl-N (R
29)-SO
2-or R
37-Heterocyclylalkyl (C
1-C
6) alkyl-.Especially preferably H, R
31-benzyl, R
32-pyridylmethyl, (C
1-C
6) alkyl-N (R
29)-SO
2-(R wherein
29Be H or C
1-C
6Alkyl) and the piperidyl ethyl.
R
25Preferably H, halogen or-CF
3And k ' is 0 or 1.Work as R
1Be the azepine-or during diaza derivatives of indole, R preferably as defined above, and k1 and k2 all are preferably 0.
X ' is a key preferably.
R
2The preferably optional six-member heteroaryl ring that replaces through 1 substituent group.More preferably, R
2Be optional warp-NH
2The pyridine radicals, pyrimidine radicals or the pyridazinyl that replace.
Y ' preferably-C (O)-.
Z ' is preferably straight or branched C
1-C
3Alkyl.Methylene is especially preferred Z group.
M
1N preferably; A ' is preferably 0; And n ' is preferably 2; Contain M
1Ring in preferably do not have optional pair of key (that is, having singly-bound).
M
2C (R preferably
3), R wherein
3Be hydrogen or fluorine; B ' is preferably 0; R ' is preferably 1; And p ' is preferably 2.
The method of preparation formula XV chemical compound is well known to those skilled in the art.The limiting examples of proper method is disclosed in the open case of U.S. of being incorporated herein with way of reference US2004/0019099A1 number.
In another embodiment, the invention provides compositions, therapeutic combination and method, wherein at least a H
3Receptor antagonist/inverse agonist is a formula XVI chemical compound:
Or acceptable salt of its pharmacy or solvate, wherein:
(A) R
1Be selected from:
(1) aryl;
(2) heteroaryl;
(3) Heterocyclylalkyl
(4) alkyl;
(5)-C(O)N(R
4B)
2；
(6) cycloalkyl;
(7) aryl alkyl;
(8) heteroaryl heteroaryl (for example ， isoxazolyl thienyl or pyridine radicals thienyl); Or
(9) one are selected from following group:
Or
The benzyl ring of the benzyl ring of the benzyl ring of the benzyl ring of the aryl moiety of this aryl (referring to (A) (1) above), heteroaryl (referring to (A) (2) above), aryl alkyl (referring to (A) (7) above), formula II (referring to (A) (9) above), formula III (referring to (A) (9) above), formula IVB (referring to (A) (9) above) or formula IVD (referring to (A) (9) above) can be chosen wantonly and be independently selected from following substituent group through 1 to 3 and replace:
(1) halogen (for example, Br, F or Cl, preferably F or Cl);
(2) hydroxyl (promptly-OH);
(3) lower alkoxy (for example, C
1To C
6Alkoxyl, preferred C
1To C
4Alkoxyl, more preferably C
1To C
2Alkoxyl, most preferably methoxyl group);
(4)-O aryl (that is aryloxy group);
(5)-SR
22；
(6)-CF
3；
(7)-OCF
3；
(8)-OCHF
2；
(9)-NR
4R
5；
(10) phenyl;
(11)NO
2，
(12)-CO
2R
4；
(13)-CON (R
4)
2, each R wherein
4All identical or different;
(14)-S(O)
2R
22；
(15)-S (O)
2N (R
20)
2, each R wherein
20All identical or different;
(16)-N(R
24)S(O)
2R
22；
(17)-CN；
(18)-CH
2OH；
(19)-OCH
2CH
2OR
22；
(20) alkyl (for example, C
1To C
4, methyl for example);
(21) be substituted phenyl, wherein this phenyl have 1 to 3 be independently selected from alkyl, halogen ,-CN ,-NO
2,-OCHF
2The substituent group of ,-O alkyl;
(22)-the O alkylaryl (preferably-the O alkyl phenyl or-O alkyl-be substituted phenyl, for example-OCH
2Dichlorobenzene base, for example-OCH
2-2, the 6-Dichlorobenzene base or-OCH
2-2-chloro-6-fluorophenyl), wherein this aromatic yl group can be chosen wantonly through the halogen replacement of 1 to 3 independence through selecting; Or
(23) phenyl;
(B) X ' be selected from alkyl (for example ,-(CH
2)
Q '-or branched alkyl) or-S (O)
2-;
(C) Y ' expression
(that is, Y ' expression is from M for (1) one singly-bound
1To M
2Direct key); Or
(2) Y ' be selected from-C (O)-,-C (S)-,-(CH
2)
Q '-or-NR
4C (O)-; Condition is:
(a) work as M
1When being N, then Y ' is not-NR
4C (O)-; And
(b) when Y ' is a key, M then
1And M
2The two is carbon;
(D) M
1And M
2Be independently selected from C or N;
(E) Z ' is selected from: C
1-C
6Alkyl ,-SO
2-,-C (O)-or-C (O) NR
4-;
(F) R
2Be selected from:
(1) having 1 or 2 hetero atom and all the other annular atoms that is independently selected from N or N-O (being the N-oxide) is six of carbon-member's heteroaryl ring;
(2) having 1 to 3 hetero atom and all the other annular atoms that is selected from nitrogen, oxygen or sulfur is five of carbon-member's heteroaryl ring; Or
(3) alkyl group, preferably C
1To C
4Alkyl group is more preferably methyl;
(4) aromatic yl group, phenyl or be substituted phenyl (preferably phenyl) for example, wherein this to be substituted phenyl be to be independently selected from following substituent group through 1 to 3 to replace: halogen ,-the O alkyl ,-OCF
3,-CF
3,-CN ,-NO
2,-NHC (O) CH
3Or-O (CH
2)
Q 'N (R
10A)
2
(5)-N (R
11A)
2, each R wherein
11ABe independently selected from: H, alkyl (for example isopropyl) or aryl (for example phenyl), a preferred R
11ABe that H and another are phenyl or alkyl (for example isopropyl);
(6) one have the group of following formula:
(7) heteroaryl heteroaryl groups, for example,
Described five Yuans heteroaryl rings (above (F) (2)) or six-member's heteroaryl ring (above (F) (1)) is optional to be selected from following substituent group replacement through 1 to 3:
(a) halogen;
(b) hydroxyl;
(c) low alkyl group;
(d) lower alkoxy;
(e)-CF
3；
(f)-NR
4R
5；
(g) phenyl;
(h)-NO
2；
(i)-C (O) N (R
4)
2(each R wherein
4All identical or different);
(j)-C (O)
2R
4Or
(k) phenyl, it is independently selected from following substituent group through 1 to 3 and replaces: halogen ,-the O alkyl ,-OCF
3,-CF
3,-CN ,-NO
2Or-O (CH
2)
qN (R
10A)
2
(G) R
3Be selected from:
(1) aryl;
(2) heteroaryl;
(3) Heterocyclylalkyl
(4) alkyl; Or
(5) cycloalkyl;
Wherein said aryl or heteroaryl R
3Group can be chosen wantonly through 1 to 3 and be independently selected from following substituent group replacement:
(a) halogen (for example, Br, F or Cl, preferred F or Cl);
(b) hydroxyl (promptly-OH);
(c) lower alkoxy (for example, C
1To C
6Alkoxyl, preferably C
1To C
4Alkoxyl is more preferably C
1To C
2Alkoxyl most preferably is a methoxyl group);
(d)-O aryl (being aryloxy group);
(e)-SR
22；
(f)-CF
3；
(g)-OCF
3；
(h)-OCHF
2；
(i)-NR
4R
5；
(j) phenyl;
(k)-NO
2，
(1)-CO
2R
4；
(m)-CON (R
4)
2, each R wherein
4All identical or different;
(n)-S(O)
2R
22；
(o)-S (O)
2N (R
20)
2, each R wherein
20All identical or different;
(p)-N(R
24)S(O)
2R
22；
(q)-CN；
(r)-CH
2OH；
(s)-OCH
2CH
2OR
22Or
(t) alkyl;
(H) R
4Be selected from:
(1) hydrogen;
(2) C
1-C
6Alkyl;
(3) cycloalkyl;
(4) cycloalkyl-alkyl (cyclopropyl-CH for example
2-or cyclohexyl-CH
2-);
(5) Heterocyclylalkyl alkyl (for example, tetrahydrofuran base-CH
2-);
(6) bridge joint bicyclo-cycloalkyl ring, for example:
(7) aryl, it has an annelated heterocycles alkyl ring that is binding on this aryl rings, and the hetero atom in this heterocycloalkyl ring is two oxygen atoms preferably, for example have a phenyl that is binding on the heterocycloalkyl ring of this benzyl ring, for example
(8) aryl;
(9) aryl alkyl;
(10) alkylaryl;
(11)-(CH
2)
D 'CH (R
12A)
2, wherein d is 1 to 3 (being preferably 1), and each R
12ABe independently selected from phenyl or be substituted phenyl, this is substituted phenyl is to be independently selected from through 1 to 3: halogen ,-the O alkyl ,-OCF
3,-CF
3,-CN or-NO
2Substituent group replace, for example
(12) Heterocyclylalkyl heteroaryl, for example
Or
(13)-(C
1To C
6) alkylidene-O-R
22(for example-C
3H
6OCH
3);
This aryl R wherein
4Group, this aryl alkyl R
4The aryl moiety of group or this alkylaryl R
4The aryl moiety of group can be chosen wantonly through 1 to 3 and be independently selected from following substituent group replacement:
(a) halogen;
(b) hydroxyl;
(c) low alkyl group;
(d) lower alkoxy;
(e)-CF
3；
(f)-N(R
20)(R
24)，
(g) phenyl;
(h)-NO
2；
(i)-C (O) N (R
20)
2(each R wherein
20All identical or different),
(j)-C(O)R
22；
(i)-(CH
2)
K '-cycloalkyl;
(j)-(CH
2)
Q '-aryl; Or
(k)-(CH
2)
m′-OR
22；
(I) each R
4BBe independently selected from: the group of H, heteroaryl (for example pyridine radicals), alkyl, thiazolinyl (for example pi-allyl), a following formula
Aryl alkyl (for example benzyl) or wherein the aryl alkyl that replaces through 1 to 3 substituent group that is independently selected from halogen of this aryl moiety (for example-CH
2-right-Cl-phenyl); A preferred R
4BBe H;
(J) R
5Be selected from: hydrogen, C
1-C
6Alkyl ,-C (O)
20(for example-C (O) alkyl, for example-C (O) CH
3) ,-C (O)
2R
20,-C (O) N (R
20)
2(each R wherein
20All identical or different);
(K) each R
10ABe independently selected from H or C
1To C
6Alkyl (for example methyl), perhaps each R
10ANitrogen-atoms with its bond forms 4 to 7 element heterocycle alkyl rings;
(L) R
12Be
(1) be selected from alkyl, hydroxyl, alkoxyl or fluorine, condition is to work as R
12When being hydroxyl or fluorine, R then
12Be not binding on the carbon that adjoins nitrogen; Or
(2) R
12Formation is the alkyl bridge to another ring carbon from a ring carbon, and the example of this bridge joint loop systems is:
(M) R
13Be
(1) be selected from alkyl, hydroxyl, alkoxyl or fluorine, condition is to work as R
13When being hydroxyl or fluorine, R then
13Be not binding on the carbon that adjoins nitrogen; Or
(2) R
13Formation is the alkyl bridge to another ring carbon from a ring carbon, and the example of this bridge joint loop systems is:
(N) R
20Be selected from hydrogen, alkyl or aryl, wherein this aromatic yl group can be chosen wantonly through being independently selected from following group from 1 to 3 and replace: halogen ,-CF
3,-OCF
3, hydroxyl or methoxyl group; Perhaps when there being two R
20During group, described two R
20Group forms five Yuans or six element heterocycle shape rings with the nitrogen of its bond;
(O) R
22Be selected from: Heterocyclylalkyl (for example, morpholinyl or pyrrolidinyl), alkyl or aryl, wherein this aromatic yl group can choose wantonly through 1 to 3 be independently selected from halogen ,-CF
3,-OCF
3, hydroxyl or methoxyl group group replace;
(P) R
24Be selected from: hydrogen, alkyl ,-SO
2R
22Or aryl, wherein this aromatic yl group can choose wantonly through 1 to 3 be independently selected from halogen ,-CF
3,-OCF
3, hydroxyl or methoxyl group group replace;
(Q) a ' is 0 to 2;
(R) b ' is 0 to 2;
(S) k ' is 1 to 5;
(T) m ' is 2 to 5;
(U) n ' is 1,2 or 3, and condition is to work as M
1When being N, then n ' is not 1;
(V) p ' is 1,2 or 3, and condition is to work as M
2When being N, then p ' is not 1;
(W) q ' is 1 to 5; With
(X) r ' is 1,2 or 3, and condition is when r ' is 2 or 3, then M
2Be that C and p ' are 1.
The method of preparation formula XVI chemical compound is well known to those skilled in the art.The limiting examples of proper method is disclosed in United States Patent (USP) the 6th, 849,621 B2 numbers that are incorporated herein with way of reference.
In another embodiment, the invention provides the present composition, therapeutic combination and method, wherein at least a H
3Receptor antagonist/inverse agonist is a formula XVII chemical compound:
Or acceptable salt of its pharmacy or solvate, wherein:
Dotted line is represented optional pair of key;
A ' is 0 to 3;
B ' is 0 to 3;
N ' is 1,2 or 3;
P ' is 1,2 or 3;
R ' is 0,1,2 or 3;
Condition is to work as M
2When being N, p ' is not 1; And when r ' is 0, M
2Be C; And p ' is 1 to 4 with r ' sum;
A ' is a key or C
1-C
6Alkylidene;
M
1Be CH or N;
M
2Be C (R
3) or N;
Y ' is-C (=O)-,-C (=S)-,-(CH
2)
Q '-,-NR
4C (=O)-,-C (=O) NR
4-,-C (=O) CH
2-,-SO
1-2-,-NH-C (=N-CN)-or-C (=N-CN)-NH-; Condition is to work as M
1When being N, Y ' is not-NR
4C (=O)-or-NH-C (=N-CN)-; And work as M
2When being N, Y ' is not-C (=O) NR
4-or-C (=N-CN)-NH-;
Q ' is 1 to 5, and condition is to work as M
1And M
2When the two was N, q ' was not 1;
Z ' is a key, C
1-C
6Alkylidene, C
1-C
6Alkenylene ,-C (=O)-,-CH (CN)-or-CH
2C (=O) NR
4-;
R
1Be
K ' is 0,1,2,3 or 4;
K1 is 0,1,2 or 3;
K2 is 0,1 or 2;
R is H, C
1-C
6Alkyl, hydroxyl-(C
2-C
6) alkyl-, halogen-(C
1-C
6) alkyl-, halogen-(C
1-C
6) alkoxyl-(C
1-C
6) alkyl-, R
29-O-C (O)-(C
1-C
6) alkyl-, (C
1-C
6) alkoxyl-(C
1-C
6) alkyl-, N (R
30) (R
31)-(C
1-C
6) alkyl-, (C
1-C
6) alkoxyl-(C
1-C
6) alkoxyl-(C
1-C
6) alkyl-, R
32-aryl, R
32-aryl (C
1-C
6) alkyl-, R
32-aryloxy group (C
1-C
6) alkyl-, R
32-heteroaryl, R
32-heteroaryl (C
1-C
6) alkyl-, (C
3-C
6) cycloalkyl, (C
3-C
6) cycloalkyl (C
1-C
6) alkyl-, N (R
30) (R
31)-C (O)-(C
1-C
6) alkyl-or Heterocyclylalkyl (C
1-C
6) alkyl-;
R
2Be that to have 1 or 2 hetero atom and all the other annular atoms that is independently selected from N or N-O be six of carbon-member's heteroaryl ring; Having 1,2 or 3 hetero atom and all the other annular atoms that is independently selected from N, O or S is five of carbon-member's heteroaryl ring; R
32-quinolyl; R
32-aryl; Heterocyclylalkyl;
Wherein said six-member heteroaryl ring or this five-member heteroaryl ring are optional through R
6Replace;
X ' is C or N;
Q ' is a key or C
1-C
6Alkylidene;
Q
1 'Be a key, C
1-C
6Alkylidene or-N (R
4)-;
R
3Be H, halogen, C
1-C
6Alkyl ,-OH or (C
1-C
6) alkoxyl;
R
4Be independently selected from: hydrogen, C
1-C
6Alkyl, C
3-C
6Cycloalkyl, (C
3-C
6) cycloalkyl (C
1-C
6) alkyl, R
33-aryl, R
33-aryl (C
1-C
6) alkyl and R
32-heteroaryl;
R
5Be hydrogen, C
1-C
6Alkyl ,-C (O) R
20,-C (O)
2R
20,-C (O) N (R
20)
2Or (C
1-C
6) alkyl-SO
2-;
R
6Be 1 to 3 and be independently selected from following substituent group :-OH, halogen, C
1-C
6Alkyl-, C
1-C
6Alkoxyl, C
1-C
6Alkylthio group ,-CF
3,-NR
4R
5, phenyl, R
33-phenyl, NO
2,-CO
2R
4,-CON (R
4)
2,
R
12Be independently selected from C
1-C
6Alkyl, hydroxyl, C
1-C
6Alkoxyl or fluorine, condition are to work as R
12When being hydroxyl or fluorine, R then
12Be not binding on the carbon that adjoins nitrogen; Perhaps R
12Formation is the C to another ring carbon from a ring carbon
1To C
2The alkyl bridge;
R
13Be independently selected from C
1-C
6Alkyl, hydroxyl, C
1-C
6Alkoxyl or fluorine, condition are to work as R
13When being hydroxyl or fluorine, R then
13Be not binding on the carbon that adjoins nitrogen; Perhaps form the C to another ring carbon from a ring carbon
1To C
2The alkyl bridge; Perhaps R
13Be=O;
R
20Be independently selected from hydrogen, C
1-C
6Alkyl or aryl, wherein this aromatic yl group optional through from 1 to 3 be independently selected from halogen ,-CF
3,-OCF
3, hydroxyl or methoxyl group group replace; Maybe when there being two R
20During group, described two R
20Group forms five Yuans or six element heterocycle rings with the nitrogen of its bond;
R
22Be C
1-C
6Alkyl, R
34-aryl or Heterocyclylalkyl;
R
24Be H, C
1-C
6Alkyl ,-SO
2R
22Or R
34-aryl;
R
25Be independently selected from: C
1-C
6Alkyl, halogen ,-CF
3,-OH, C
1-C
6Alkoxyl, (C
1-C
6) alkyl-C (O)-, aryl-C (O)-, N (R
4) (R
5)-C (O)-, N (R
4) (R
5)-S (O)
1-2-, halogen-(C
1-C
6) alkyl-or halogen-(C
1-C
6) alkoxyl-(C
1-C
6) alkyl-;
R
29Be H, C
1-C
6Alkyl, R
35-aryl or R
35-aryl (C
1-C
6) alkyl-;
R
30Be H, C
1-C
6Alkyl-, R
35-aryl or R
35-aryl (C
1-C
6) alkyl-;
R
31Be H, C
1-C
6Alkyl-, R
35-aryl, R
35-aryl (C
1-C
6) alkyl-, (C
1-C
6) alkyl-C (O)-, R
35-aryl-C (O)-, N (R
4) (R
5)-C (O)-, (C
1-C
6) alkyl-S (O)
2-or R
35-aryl-S (O)
2-;
Perhaps R
30With R
31 is-(CH together
2)
4-5-,-(CH
2)
2-O-(CH
2)
2-or-(CH
2)
2-N (R
29)-(CH
2)
2-and form a ring with its nitrogen that is connected;
R
32Be 1 to 3 be independently selected from following substituent group: H ,-OH, halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl, R
35-aryl-O-,-SR
22,-CF
3,-OCF
3,-OCHF
2,-NR
4R
5, phenyl, R
33-phenyl, NO
2,-CO
2R
4,-CON (R
4)
2,-S (O)
2R
22,-S (O)
2N (R
20)
2,-N (R
24) S (O)
2R
22,-CN, hydroxyl-(C
1-C
6) alkyl-,-OCH
2CH
2OR
22And R
35-aryl (C
1-C
6) alkyl-O-, wherein this aromatic yl group can be chosen wantonly through the halogen of 1 to 3 independence through selecting and replace;
R
33Be 1 to 3 and be independently selected from following substituent group: C
1-C
6Alkyl, halogen ,-CN ,-NO
2,-OCHF
2With-O-(C
1-C
6) alkyl;
R
34Be 1 to 3 be independently selected from H, halogen ,-CF
3,-OCF
3,-OH and-OCH
3Substituent group.
R
35Be 1 to 3 and be independently selected from hydrogen, halogen, C
1-C
6Alkyl, hydroxyl, C
1-C
6Alkoxyl, phenoxy group ,-CF
3,-N (R
36)
2,-COOR
20With-NO
2Substituent group; With
R
36Be independently selected from H and C
1-C
6Alkyl.
Preferred formula XVII chemical compound comprises following chemical compound:
R
1The benzimidazolone that replaces through R preferably, wherein preferably H, alkyl, alkoxyalkyl, R of R
32-aryl, R
32-heteroaryl or Heterocyclylalkyl alkyl.More preferably, R is-CH
3, phenyl, 4-fluorophenyl, CH
3-O-(CH
2)
2-,
R
25Preferably halogen or-CF
3And k is 0 or 1.Work as R
1Be the azepine-or during diaza derivatives of benzimidazolone, R preferably as benzimidazolone is defined, and k
1And k
2All be preferably 0.
R
2The preferably optional six-member heteroaryl ring that replaces through a substituent group.More preferably, R
2Be pyridine radicals, pyrimidine radicals or pyridazinyl, each group all can choose wantonly through halogen or-NR
4R
5Replace, wherein R
4And R
5Be independently selected from H and (C
1-C
6) alkyl, perhaps R
4And R
5Form pyrrolidinyl, piperidyl or morpholine basic ring with the nitrogen that it connected.
A ' is a key preferably.
Y ' preferably-C (O)-.
Z ' is preferably straight or branched C
1-C
3Alkyl.
M
1N preferably; A ' is preferably 0; And n ' is preferably 2; Preferably there be not optional pair of key (promptly having singly-bound).
M
2C (R preferably
3), R wherein
3Be hydrogen or halogen, especially fluorine; B ' is preferably 0; R ' is preferably 1; And p ' is preferably 2.
The method of preparation formula XVII chemical compound is well known to those skilled in the art.The limiting examples of proper method is disclosed in the open case of U.S. of being incorporated herein with way of reference US2004/0097483A1 number.
Other non-limiting H
3Receptor antagonist/inverse agonist is disclosed in the following document: No. the 60/692nd, 110, U.S. Provisional Application case and the 60/692nd, No. 175 (the two is all filed an application on June 20th, 2005), No. the 2002/183309th, United States Patent (USP), No. 2002/177589, No. 2002/111340, No. 2004/0122033, No. 2003/0186963, No. 2003/0130253, No. 2004/0248938, No. 2002/0058659, No. 2003/0135056, No. 2003/134835, No. 2003/153548, No. 2004/0019099, No. 2004/0097483, No. 2004/0048843, No. 2004/087573, No. 2004/092521, No. 2004/214856, No. 2004/248899, No. 2004/224953, No. 2004/224952, No. 2005/222151, No. 2005/222129, No. 2005/182045, No. 2005/171181, the 6th, 620, No. 839, the 6th, 515, No. 013, the 6th, 559, No. 140, the 6th, 316, No. 475, the 6th, 166, No. 060, the 6th, 448, No. 282, the 6th, 008, No. 240, the 5th, 652, No. 258, the 6th, 417, No. 218, the 6th, 673, No. 829, the 6th, 756, No. 384, the 6th, 437, No. 147, the 6th, 720, No. 328, the 5th, 869, No. 479, the 6th, 849, No. 621, the 6th, 908, No. 929, the 6th, 908, No. 926, the 6th, 906, No. 060, the 6th, 884, No. 809, the 6th, 884, No. 803, the 6th, 878, No. 736, the 6th, 638, No. 967, the 6th, 610, No. 721, the 6th, 528, No. 522, the 6th, 518, No. 287, the 6th, 506, No. 756, the 6th, 489, No. 337, the 6th, 436, No. 939, the 6th, 448, No. 282, the 6th, 407, No. 132, the 6th, 355, No. 665, the 6th, 248, No. 765, the 6th, 133, No. 291, the 6th, 103, No. 735, the 6th, 080, No. 871, the 5th, 932, No. 596, the 5th, 929, No. 089, the 5th, 837, No. 718, the 5th, 821, No. 259, the 5th, 807, No. 872, the 5th, 639, No. 775, the 5th, 708, No. 171, the 5th, 578, No. 616, the 5th, 990, No. 147, the 6th, 906, No. 081, No. 95/14007, WO, WO 99/24405 (each document all is incorporated herein with way of reference).H
3Other limiting examples of receptor antagonist/inverse agonist is disclosed in U.S. Provisional Application case the 60/752nd, No. 636 (act on behalf of file number CV06410L01US, title is " Phenoxypiperidines and Analogues Thereof Usefulas Histamine H
3Antagonists ") and the interim case of the U.S. No. 60/752637 (act on behalf of file number CV06411L01US, title is " Substituted Aniline Derivatices Useful as HistamineH
3Antagonists ") in, the two is all filed an application same date with the application's case.
The present composition, therapeutic combination or method can further comprise one or more obesity control medicines.Useful obesity control medicine includes but not limited to reduce the medicine of caloric intake or appetite-suppressing, the medicine and the nutrient distribution agent of increase energy expenditure.Suitable obesity control medicine comprises (but being not limited to) norepinephrine energy agent (for example amfepramone, Mazindol, phenylpropanolamine, phentermine, phendimetrazine, tartaric acid amphetamines (phendamine tartrate), metamfetamine (methamphetamine), phendimetrazine and tartrate); CB1 receptor antagonist (for example Rimonabant (rimonabant)); Topiramate; The agent (for example (paroxtine) stung in sibutramine, fenfluramine, dexfenfluramine, fluoxetine, fluvoxamine and Paro west) of 5-hydroxy tryptamine energy; Heat generating agent (for example ephedrine, caffeine, theophylline (theophylline) and selectivity β 3-2-adrenergic agonist components); α-sealer; Kainite or ampa receptor antagonist; Leptin-steatolysis costimulatory receptor; The phosphodiesterase enzyme inhibitor; Chemical compound with nucleotide sequence of horse sky gal (mahogany) gene; Fibroblast growth factor-10 polypeptide; Oxidase inhibitor (for example befloxatone, moclobemide, brofaromine, phenoxthine (phenoxathine), esuprone, than Fu Er (befol), Toloxatone (toloxatone), pirlindole, amiflamine, match Cray bright (sercloremine), bazinaprine, lazabemide, milacemide and caroxazone); Increase the chemical compound (for example evodiamine chemical compound) of lipid metabolism; And lipase inhibitor (for example orlistat (orlistat)).The combination of spendable preferred therapeutic comprises and contains at least a cholesterol reducing agent (Gu for example the sterin of formula I-IV or 5-α-alkanol) and/or a HMG-CoA reductase inhibitor and at least a H in the inventive method
3The combination of receptor antagonist/inverse agonist (for example those of formula XIII to XVII).Especially preferred combination comprises as the ezetimibe of cholesterol reducing agent and/or simvastatin, formula XIIIA-XIIIC chemical compound and orlistat.
Generally speaking, the accumulated dose of above-mentioned obesity control medicine can between 1mg/ days to 3,000mg/ days, expectation from about 1mg/ days to 1,000mg/ days and more expectation oneself between about 1mg/ days to 200mg/ days, it can be single dose or 2-4 separate doses.
Another embodiment of the present invention is to comprise two kinds of cholesterol reducing agents and a H
3The therapeutic combination of receptor antagonist/inverse agonist.Preferred combination comprises cholesterol absorption inhibitor (for example those of being set forth among the formula I to XII) and HMG-CoA reductase inhibitor, PPAR activator, nicotinic acid (niacin usp) and/or nicotinic acid receptor agonists or bile acid chelating agent.Preferred HMG-CoA reductase inhibitor comprises lovastatin, pravastatin, fluvastatin, simvastatin, atorvastatin, cerivastatin, CI-981, Pitavastatin and rosuvastatin.Other the preferred cholesterol reducing agent that uses with a cholesterol absorption inhibitor (for example those of being set forth among the formula I-XII) comprises colestyramine, colestipol, clofibrate, gemfibrozil and fenofibrate.Desire to include in the preferred H in the described therapeutic combination
3Receptor antagonist/inverse agonist comprises and is set forth among the formula XIII-XVII those that chemical compound of its Chinese style XIIIA-XIIIC is especially preferred.
Especially preferred therapeutic combination is VYTORIN, and it is that ezetimibe and simvastatin (referring to United States Patent (USP) the 5th, 846, No. 946, it is incorporated herein with way of reference) are together with formula XIIIA, XVIIIB or XIIIC combination of compounds.
Another embodiment of the present invention contains aforesaid medicine box and Therapeutic Method, and it comprises: (a) at least a cholesterol reducing agent, Gu for example sterin or 5-α-alkanol absorption inhibitor; (b) at least a H
3Receptor antagonist/inverse agonist.Suitable cholesterol reducing agent comprises arbitrary chemical compound and the suitable H among the discussion I-XII of institute above
3Receptor antagonist/inverse agonist comprises the arbitrary chemical compound among the discussion XIII-XVII of institute above.One medicine box contain when two independent unit in conjunction with the time situation: one comprises the medical composition of at least a cholesterol absorption inhibitor and comprises at least a H
3The independent medical composition of receptor antagonist/inverse agonist.This medicine box will preferably include the description of using described independent component.
When described independent component must be used or use at interval with various dose with various dose form (for example, oral and non-through intestinal), especially preferred this kit form.
Another embodiment of the present invention is treatment, prevention or improves symptom or the development that the mammal metabolic syndrome that needs is arranged, it comprises uses this mammiferous step with the effective dose therapeutic combination, and this therapeutic combination comprises at least a cholesterol reducing agent and optional at least a H
3Receptor antagonist/inverse agonist.Metabolic syndrome is trooping of atherosclerosis CHD risk factor, and it comprises obesity, HDL-C reduces and fasting plasma glucose level, triglyceride level and blood pressure increase.More preferably, this therapeutic combination comprises two or three different types of cholesterol reducing agent, for example aza cyclo-butanone (for example, ezetimibe), the activator of PPAR or agonist (the special class of shellfish for example, fenofibrate for example) or HMG-CoA reductase inhibitor (for example, simvastatin or atorvastatin).
The prodrug and the solvate of The compounds of this invention also contained in this paper.Term that this paper uses " prodrug " expression is the chemical compound of prodrug, and it stands chemical transformation by metabolic process or chemical process after using the experimenter, thereby obtains formula I compound or its salt and/or solvate.Be provided in Pro-drugs as Novel Delivery Systems (1987) A.C.S.Symposium Series the 14th volume of T.Higuchi and V.Stella about the argumentation of prodrug and Bioreversible Carriers in DrugDesign (1987), Edward B.Roche edits, among the American Pharmaceutical Associationand Pergamon Press, the two all is incorporated herein with way of reference.
For example, if the acceptable salt of pharmacy, hydrate or the solvate of formula I-XVII chemical compound or this chemical compound comprise carboxylic acid functional, then prodrug can comprise by using such as following groups and replaces the ester that the hydrogen atom of this acid groups forms: (C
1-C
8) alkyl, (C
2-C
12) alkanoyl oxygen ylmethyl; has from 4 the 1-to 9 carbon atoms (alkanoyl oxygen base) ethyl; has from 5 the 1-methyl isophthalic acid to 10 carbon atoms-(alkanoyl oxygen base)-ethyl; has the alkoxy-carbonyl oxy methyl to 6 carbon atoms from 3; has from 4 the 1-to 7 carbon atoms (alkoxy-carbonyl oxy) ethyl; has the 1-methyl isophthalic acid to 8 carbon atoms-(alkoxy-carbonyl oxy) ethyl from 5; has from 3 the N-to 9 carbon atoms (alkoxy carbonyl) amino methyl; has from 4 the 1-to 10 carbon atoms (N-(alkoxy carbonyl) amino) ethyl; the 3-phthalidyl; 4-crotonolactone base; beta-butyrolactone-4-base; two-N, N-(C
1-C
2) alkyl amino (C
2-C
3) alkyl (for example beta-dimethyl-amino-ethyl), carbamyl-(C
1-C
2) alkyl, N, N-two (C
1-C
2) alkylcarbamoyl group-(C
1-C
2) alkyl and piperidyl-, pyrrolidinyl-or morpholinyl (C
2-C
3) alkyl etc.
Equally, if formula I-XVII chemical compound comprises alcohol functional group, then prodrug can form by using the hydrogen atom that replaces this alcohol groups such as following groups: (C
1-C
6) alkanoyl oxygen ylmethyl, 1-((C
1-C
6) alkanoyl oxygen base) ethyl, 1-methyl isophthalic acid-((C
1-C
6) alkanoyl oxygen base) ethyl, (C
1-C
6) alkoxy-carbonyl oxy methyl, N-(C
1-C
6) alkoxycarbonyl amino methyl, succinyl group, (C
1-C
6) alkanoyl ,-amino (C
1-C
4) alkyl, aryl-acyl and alpha-amido acyl group or alpha-amido acyl-alpha--aminoacyl, wherein each alpha-amido carboxyl groups is independently selected from naturally occurring L-aminoacid, P (O) (OH)
2,-P (O) (O (C
1-C
6) alkyl)
2Or glycosyl (this group is to be produced by the oh group of removing a hemiacetal form carbohydrate) etc.
If formula I-XVII chemical compound includes the amino-functional group in, then prodrug can replace such as following groups that a hydrogen atom forms in this amino group by using: (wherein R and R ' are (C independently of one another for R-carbonyl, RO-carbonyl, NRR '-carbonyl
1-C
10) alkyl, (C
3-C
7) cycloalkyl, benzyl, perhaps the R-carbonyl is natural alpha-amido acyl group or natural alpha-amido acyl group) ,-C (OH) C (O) OY
1(Y wherein
1Be H, (C
1-C
6) alkyl or benzyl) ,-C (OY
2) Y
3(Y wherein
2Be (C
1-C
4) alkyl and Y
3Be (C
1-C
6) alkyl, carboxyl (C
1-C
6) alkyl, amino (C
1-C
4) alkyl or list-N-or two-N, N-(C
1-C
6) the alkyl amino alkyl) ,-C (Y
4) Y
5(Y wherein
4Be H or methyl and Y
5Be list-N-or two-N, N-(C
1-C
6) alkyl amino morpholinyl, hexahydropyridine-1-base or Pyrrolizidine-1-yl) etc.
Formula I-XVII chemical compound can be non-fused to exist with fused form." solvate " is meant that the physics of The compounds of this invention and one or more solvent molecules associates.This physics association comprises ion bond and covalency bond (comprising the hydrogen bond knot) in various degree.In some cases, for example when in the lattice of one or more solvent molecule crystalline solids, this solvate can separate." solvate " not only comprises the solution phase but also comprises separable solvate.The limiting examples of suitable solvent compound comprises ethanol compound, methanol compound etc." hydrate " is that wherein this solvent molecule is H
2The solvate of O.
" effective dose " or " treatment effective dose " is to be used for describing The compounds of this invention or the effective treatment of compositions just treating morbid state and thereby producing the amount of expectation therapeutic effect in suitable patient.
Formula I-XVII compound formation salt, it also belongs to the scope of the invention.This paper mentions that formula I-XVII chemical compound is understood to include and mentions its salt, except as otherwise noted.Ackd salt that term used herein " salt " expression and mineral acid and/or organic acid form and the basic salt that forms with inorganic base and/or organic base.In addition, when formula I-XVII chemical compound not only comprises basic moiety (such as but not limited to pyridine or imidazoles) but also comprises acidic moiety (such as but not limited to carboxylic acid), can form amphion (" inner salt ") and include in the term used herein " salt ".The salt of pharmacy acceptable (that is, can accept on avirulence, the physiology) is preferred, but also can use other salt.The salt of formula I-XVII chemical compound can by (for example) such as in the sedimentary medium of this salt wherein or in aqueous medium, make formula I-XVII chemical compound and a certain amount of acid or alkali (for example equivalent) react subsequently lyophilizing forms.For example, it has been generally acknowledged that being fit to form the pharmaceutically acid of useful salt (and alkali) from alkalescence (or acid) pharmaceutical compound is by people such as S.Berge, Journal ofPharmaceutical Sciences (1977) 66 (1) 1-19; P.Gould, International J.ofPharmaceutics (1986) 33 201-217; People such as Anderson, The Practice of MedicinalChemistry (1996), Academic Press, New York; (Food﹠amp in The Orange Book; Drug Administration, Washington, D.C. is on its network); With P.Heinrich Stahl, Camille G.Wermuth (editor), Handbook of Pharmaceutical Salts:Properties, Selection, and Use, (2002) Int ' l.Union of Pure and Applied Chemistry discusses in the 330th page to 331 pages.Described disclosure is incorporated herein by reference.
Exemplary acid-addition salts comprises acetate, adipate, alginate, anti-bad blood salt, aspartate, benzoate, benzene sulfonate, disulfate, borate, butyrate, citrate, camphorate, camsilate, cyclopentane propionate, digluconate, lauryl sulfate, ethane sulfonate, fumarate, the glucose enanthate, glycerophosphate, Hemisulphate, enanthate, caproate, hydrochlorate, hydrobromate, hydriodate, 2-hydroxyethanesulfonic acid salt, lactate, maleate, methane sulfonates, Methylsulfate, the 2-naphthalene sulfonate, nicotinate, nitrate, oxalates, pamoate, pectate, persulfate, 3-phenylpropionic acid salt, phosphate, picrate, pivalate, propionate, Salicylate, succinate, sulfate, sulfonate (for example as herein described those), tartrate, rhodanate, toluene fulfonate (toluenesulfonate also is called tosylate), hendecoic acid salt etc.
Exemplary basic salt comprises ammonium salt, alkali metal salt (for example sodium, lithium and potassium salt), alkali salt (for example calcium salt and magnesium salt, aluminum salt, zinc salt), contains the salt of organic base (for example organic amine) (for example benzyl star (benzathine), diethylamine, hexanamine, Kazakhstan amine (by N, two (dehydrogenation rosin-base) ethylene diamines of N-form), N-methyl D-glucamine, N-methyl D-glucose amide, tert-butylamine, hexahydropyrazine, benzyl ring hexylamine, choline, trometamol) and contains amino acid whose salt (for example arginine, lysine) etc.The alkalescence nitrogen-containing group can be used such as following reagent level Four ammoniumization: low alkyl group halogen (for example methyl, ethyl, propyl group and butyl chloride, bromide and iodide), sulphuric acid dialkyl (vitriolic dimethyl esters, diethyl ester, dibutyl ester and diamyl ester), long-chain halogenide (for example chloride of decyl, lauryl, myristyl and stearyl, bromide and iodide), aralkyl halide (for example benzyl and phenethyl bromination thing) and other.
For purposes of the present invention, all these type of hydrochlorates and alkali salt all are intended to the interior acceptable salt of pharmacy of the scope of the invention and think that all bronsted lowry acids and bases bronsted lowry salt all are equivalent to the free form of respective compound.
All stereoisomers of containing The compounds of this invention (comprising those salt, solvate and the prodrug of described chemical compound and the salt and the solvate of described prodrug) in the scope of the invention (for example, geometric isomer, optical isomer etc.), those that exist because of asymmetric carbon on each substituent group for example, it comprises enantiomerism form (it also can exist even there is not asymmetric carbon), rotational isomeric form, lag switch isomer and diastereo-isomerism form.For example, if formula I-XVII chemical compound includes a pair of key or fused rings in, then suitable-and anti--form the two and mixture all be contained in the scope of the invention.Indivedual stereoisomers of The compounds of this invention can (for example) do not contain substantially other isomers or can with (for example) as the racemic isomer blending or with all other or other through selecting the stereoisomer blending.
The present invention can have as by defined S of IUPAC 1974 Recommendations or R configuration chiral centre.The use of term " salt ", " solvate ", " prodrug " etc. all is intended to be applied to equally salt, solvate and the prodrug of enantiomer, stereoisomer, rotamer, tautomer, racemic isomer or the prodrug of The compounds of this invention.
Non-enantiomer mixture can be separated into its indivedual diastereomers by the method (for example by chromatography and/or fractional crystallization) that is well known to those skilled in the art according to its physical chemistry difference.Enantiomer can be separated by following enforcement: by making this enantiomeric mixture and suitable optically active compound (for example to chiral auxiliary, for example to chiral alcohol or Mosher ' s acid chloride) reaction and make it be converted into non-enantiomer mixture, separate described diastereomer and described independent diastereomer is transformed the corresponding pure enantiomer of (for example, hydrolysis) one-tenth.Equally, but some chemical compound lag switch isomer (for example, being substituted diaryl) of formula I-XVII and think a part of the present invention.Enantiomer also can be separated chirality HPLC tubing string by using.
The polymorphic of salt, solvate and the prodrug of formula I-XVII chemical compound and formula-XVII chemical compound all is intended to include among the present invention.
The present invention is also contained identical the present invention with they described herein through isotope-labeled chemical compound, but one or more atom is different from except the situation that the atom of common atomic weight of occurring in nature or mass number replaces by atomic weight or mass number.Can be contained in isotopic example in the The compounds of this invention comprises and the isotope of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine for example is respectively
2H,
3H,
13C,
14C,
15N,
18O,
17O,
31P,
32P,
35S,
18F and
36Cl.
Some of formula I-XVII (for example used through isotope-labeled chemical compound
3H and
14Those of C labelling) be to be used for chemical compound and/or matrix organization's distributional analysis.Tritium (promptly
3H) and carbon-14 (promptly
14C) isotope is especially preferred because it is easy to prepare and detects.In addition, use (promptly such as deuterium
2H) etc. the replacement of higher isotope can obtain by than some treatment benefit that greater metabolic stability produced (for example, in vivo the half-life increases or required dosage reduces) and therefore can be preferred in some cases.Formula I-XVII usually can be by the following program that discloses this area of being similar to by preparing without isotope-labeled reagent with suitable the replacement through isotope-labeled reagent through isotope-labeled chemical compound.
It should be noted that whole description and thereafter in the appended claims, have unsaturated valent any formula, chemical compound, part or chemical illustration and all suppose described quantivalence to be reached capacity, unless context is marked as a key with hydrogen atom.
Term " treatment effective dose " is meant that therapeutic agent of the present invention (for example is substituted aza cyclo-butanone and H
3Receptor antagonist/inverse agonist and other medicine or the healing potion that can exist) will cause experimenter, tissue, system, animal or mammalian biological that user (for example research worker, doctor or veterinarian) is just being sought or the amount of medical response, this reaction comprises sx, prevents, slows down or stops the development of one or more patient's condition relevant with NAFLD.
The daily dose of using this mammiferous formula I-XVII chemical compound can be between about 1mg/ days to about 1000mg/ days, preferably about 1mg/ days to about mg/ days and more preferably from about 100mg/ days, its be with single dose or 2-4 separate doses give with.Yet actual dose is by curing mainly usefulness, patient's age, body weight, the patient's condition and the reaction that the clinicist determines and depend on institute's administered compound.
With regard to the using of the acceptable salt of pharmacy of above-claimed cpd, above pointed weight is meant derived from the acid equivalent of the treatment chemical compound of this salt or the normal weight of alkali.
For from compound medical composition of the present invention, inertia, pharmaceutically acceptable carrier can be solid or liquid.The solid form preparation comprises powder, tablet, discrete particles, capsule, pill and suppository.Powder and tablet can be formed to about 7.5% active ingredient by about 0.1%.Suitable solid carrier is known in this area, for example, and magnesium carbonate, magnesium stearate, Pulvis Talci, sugar or lactose.Tablet, powder, pill and capsule can be used as and be suitable for Orally administered solid dosage forms.The example of pharmaceutically acceptable carrier and the various method for compositions of manufacturing can be A.Gennaro (editor), the Pharmaceutical Sciences of Remington, the 18th edition, (1990), Mack Publishing Co., Easton finds among the Pennsylvania.
Liquid form preparation comprises solution, suspension and emulsion.As an example, can mention to be that water or water-propylene glycol solution are used for non-through enteral administration or add sweeting agent and opacifier is used for oral administration solution, suspension and emulsion.Liquid form preparation also can comprise the solution of nasal administration.
The aerosol preparations that is suitable for sucking can comprise solution, suspension and be the solid of powder type that it can be used in combination with pharmaceutically acceptable carrier (for example, Compressed Gas, for example HFA).
What also comprise is just to be intended to be converted into the solid form preparation that is used for the oral or non-liquid form preparation of using through intestinal before it be about to use.This type of liquid form comprises solution, suspension and emulsion.
But The compounds of this invention is dermal delivery also.Transdermal composition can adopt the form of cream, emulsion, aerosol and/or emulsion and can be contained in this area for reaching in normally used substrate of this purpose or the reservoir type percutaneous patch.
The preferred dosage forms for oral administration of this chemical compound.
Preferably, this pharmaceutical preparation is unit dosage forms.When this form, said preparation is subdivided into the suitable size unit dosage that comprises an amount of (for example, reaching the effective dose of expectation purpose) active constituent.
The amount of reactive compound in a unit dose formulations according to special-purpose can different or about certainly 1mg to about 500mg, preferably from about 1mg to about 250mg, more preferably certainly about 1mg extremely about 100mg regulated.
The order of severity that the actual dose that uses is looked closely patient demand and just treated the patient's condition can change to some extent.The suitable dosage that is used for concrete condition fixes in this technical scope really.For simplicity, total daily dose can separate and use by part in this sky as required.
Consider to be regulated the amount of application and the frequency of The compounds of this invention and/or the acceptable salt of its pharmacy according to curing mainly the clinicist such as the judgement of the factors such as the order of severity of patient age, the patient's condition and body weight and symptom to be treated.Being used for Orally administered typical recommended scheme can be between about 1mg/ day to about 500mg/ days, preferred 1mg/ days to 100mg/ days, and it is a 2-4 separate doses.
Hereinafter set forth some useful terms:
Capsule-be meant that one makes special container or the cover that is used to hold or comprise the compositions that comprises active ingredient by methylcellulose, polyvinyl alcohol or metagelatin or starch.Hard-shell capsule is made by the admixture of relative high-gel strength bone and pigskin gelatin usually.Itself can comprise a small amount of dyestuff, opacifier, plasticizer and antiseptic this capsule.
Tablet-be meant the compacting or the molded solid dosage form that comprise active ingredient and suitable diluents.This tablet can prepare by mixture or the pelletize that compacting is obtained by wet granulation, non-slurry pelletizing or dry method fusion.
Oral gel-be meant that active ingredient is dispersed or dissolved in the hydrophilic semisolid matrix.
Make up a prescription and use powder-be meant that comprising active ingredient and suitable diluents can suspend or be dissolved in powder admixture in water or the juice.
Diluent-be meant the material of the major part of common composition compositions or dosage form.Suitable diluents comprises sugar, for example lactose, sucrose, mannitol and sorbitol; Starch derived from Semen Tritici aestivi, corn, Oryza sativa L. and Rhizoma Solani tuber osi; And cellulose, for example microcrystalline Cellulose.In the said composition amount of diluent can between about 10 weight % of this total composition to about 90 weight %, preferably from about 25% to about 75%, more preferably from about 30% to about 60 weight % even more preferably between about 12% to about 60%.
Disintegrating agent-be meant to be added in the compositions to help it to break (disintegrate) and to discharge the material of described medicine.Suitable disintegrants comprises starch; " cold water solubles " modified starch, for example carboxymethyl starch sodium; Natural and rubber polymer, for example locust bean gum, karaya, guar gum, sulphur Millefolium glue and agar; Cellulose derivative, for example methylcellulose and sodium carboxymethyl cellulose; Microcrystalline Cellulose and crosslinked microcrystalline Cellulose, for example this sodium of cross-linked carboxymethyl cellulose sodium Ke Sika Metro; Alginate, for example alginic acid and sodium alginate; Clay, for example bentonite and effervescent mixture mixture.In the said composition amount of disintegrating agent can between about 2 weight % of said composition to about 15 weight %, more preferably from about 4 weight % between about 10 weight %.
Binding agent-be meant powder-stuck or " gummed " thus make it have cohesion plays " sticker " effect in composite material together and by forming granule.Binding agent increases already present cohesive strength in diluent or the raising agent.Suitable binders comprises sugar, for example sucrose; Starch derived from Semen Tritici aestivi, corn, Oryza sativa L. and Rhizoma Solani tuber osi; Natural gum, for example arabic gum, gelatin and sulphur Millefolium glue; Sargassum derivant, for example alginic acid, sodium alginate and ammonium alginate calcium; Cellulosic material, for example methylcellulose and sodium carboxy methyl cellulose and HYDROXY PROPYL METHYLCELLULOSE; Polyethylene Pyrrolizidine ketone; And inorganic matter, for example aluminium-magnesium silicate.In the said composition amount of binding agent can between about 2 weight % of said composition to about 20 weight %, more preferably from about 3 weight % to about 10 weight % in addition more preferably from about 3 weight % between about 6 weight %.
Lubricant-be meant be added in this dosage form by reduce friction or abrasion so that the material that tablet, granule etc. can discharge in mould or punch die after its compacting.Suitable lubricant comprises Metallic stearates, for example magnesium stearate, calcium stearate or potassium stearate; Stearic acid; High melting-point wax; And soluble oil, for example sodium chloride, sodium benzoate, sodium acetate, enuatrol, Polyethylene Glycol and d ' l-leucine.Lubricant adds in the final step before compacting usually, and this is must be present on the described particle surface and between described granule and tablet press parts because of it.In the said composition amount of lubricant can between about 0.2 weight % of said composition to about 5 weight %, preferably from about 0.5% to about 2%, more preferably between about 0.3% to about 1.5 weight %.
Fluidizer-prevent to lump and improve the flow behavior of pelletize so that flow level and smooth and uniform material.Suitable fluidizer comprises silicon dioxide and Pulvis Talci.In the said composition amount of fluidizer can between this total composition about 0.1% to about 5 weight %, preferably from about 0.5 weight % between about 2 weight %.
Coloring agent-excipient of color is provided for said composition or dosage form.This type of excipient can comprise food grade dyes and the food grade dyes that is adsorbed on the suitable adsorbent (for example clay or aluminium oxide).The amount of this coloring agent can be in extremely about 5 weight %, preferably variation between about 0.1% to about 1% of about certainly 0.1 weight % of compositions.
Bioavailability-be meant with standard sample or to compare this active pharmaceutical ingredients or treatment part in the same old way to be absorbed in speed and degree in the body circulation from institute's form of administration.
Embodiment
Following limiting examples is set forth the present invention.
Embodiment 1
Made it suffer from obesity, liver fat degeneration and lipidosis in 6 months by comprise 45% fat and the western diet of 0.12% cholesterol to mouse feeding, obesity (DIO) mice of described diet induced is divided into four groups and with around the combined therapy of not treating (contrast), usefulness ezetimibe (formula II) (5mg/kg/ days), formula XIIIA chemical compound (12mg/kg/ days) or ezetimibe (5mg/kg/ days) and formula XIIIA chemical compound (12mg/kg/ days).Liver weight, the liver triglyceride level regulating liver-QI free cholesterol content of each group are put to death and measured to described mice, and be summarized among Fig. 1 to 4.
Fig. 1 shows the liver and the weight ratio of described four groups of each groups.The mice performance liver weight of accepting ezetimibe and/or formula XIIIA chemical compound descends, and the group of wherein accepting this combination shows weight and farthest descends.
Fig. 2 shows the triglyceride level of described four groups of each groups.Accept ezetimibe and/or formula XIIIA chemical compound mice all show that all the liver triglyceride level descends, the group of wherein accepting this combination shows farthest and descends.
Fig. 3 shows the liver cholesterol ester content of described four groups of each groups.Again, all groups of accepting ezetimibe and/or XIIIA chemical compound are compared with matched group and to be shown that all the liver cholesterol ester content descends, and the group of wherein accepting described combination shows farthest and descends.
Fig. 4 shows the liver free cholesterol content of described four groups of each groups.All groups of accepting ezetimibe and/or formula XIIIA chemical compound are compared with matched group and to be shown that all liver cholesterol content descends, and the group of wherein accepting this combination shows farthest and descends.
These data show, the H of ezetimibe, formula XIIIA
3Being combined among the treatment NAFLD of antagonist/inverse agonist and two kinds of therapeutic agents is effective, wherein should combination show a cooperative effect.
Example 2
Comprise 45% fat and the western diet of 0.12% cholesterol made it suffer from obesity, lipidosis, liver fat degeneration and fibrosis in 7 months by the feeding mice, obesity (DIO) mice of described diet induced is divided into four groups and not treat 4 weeks of combined therapy of (contrast), usefulness ezetimibe (formula II) (2mg/kg/ days), formula XIIID chemical compound (9mg/kg/ days) or ezetimibe (2mg/kg/ days) and formula XIIID chemical compound (9mg/kg/ days).With described mice put to death and measure blood plasma alanine aminotransferase (ALT) enzyme activity of each group, with the blood plasma biomarker of the hepatic injury of fat hepatitis, it is summarized among Fig. 5.
Fig. 5 shows blood plasma alanine aminotransferase (ALT) enzyme activity of described four groups of each groups.The mice of accepting formula XIIID chemical compound shows that plasma A LT descends.
These data show, the H of formula XIIID
3The two the combination of antagonist/inverse agonist and formula XIIID chemical compound and ezetimibe can improve hepatic injury biomarker ALT, and therefore can effectively treat NASH.
Example 3
C57BL/6J mice wean back give its feeding higher fatty acid/cholesterol diet (Research Diets contains 45% kilocalorie of fat and 0.12% w/w cholesterol) 7 months.After 4 weeks, there is not significant difference with body weight and the control mice of the DIO mice of ezetimibe (in higher fatty acid/cholesterol diet 0,0.5,1.6 and 5.3mg/kg/ days) treatment.Yet, to compare with control mice, the ratio of liver weight in wet base regulating liver-QI and body weight obviously reduces in the DIO mice of ezetimibe treatment.Liver from the mice of ezetimibe treatment has obviously lower cholesteryl ester free cholesterol and triglyceride.Described data are summarized among Fig. 6 to 9.
Fig. 6 shows the liver and the weight ratio of described four groups of each groups.The mice of accepting ezetimibe shows that the liver and the dose dependent of weight ratio descend, and group demonstration liver and the weight ratio of accepting ezetimibe (53.mg/kg/ days) farthest descend.
Fig. 7 shows the triglyceride level of described four groups of each groups.All groups of accepting ezetimibe show that all the dose dependent of liver triglyceride level descends.
Fig. 8 shows the liver cholesterol ester content of described four groups of each groups.The mice of accepting ezetimibe (1.6 with 5.3mg/kg/ days) is compared with matched group and shows that the liver cholesterol ester content obviously descends.
Fig. 9 shows the liver cholesterol content of described four groups of each groups.The mice of accepting ezetimibe (1.6 with 5.3mg/kg/ days) is compared with matched group and shows that liver cholesterol content obviously descends.
After ezetimibe treated for 4 weeks, total plasma cholesterol and triglyceride obviously reduced 30% and 15% respectively.Also there are obvious decline in VLDL-C and LDL-C, and at HDL-C no change in ezetimibe treatment group.Although this VLDL-C obviously reduces after the ezetimibe treatment, it is suitable to produce speed at VLDL-TG between ezetimibe treatment mice and contrast DIO mice.According to this result, can conclude that ezetimibe can be used for liver fat degeneration in prevention or the treatment mammal.
It will be understood by a person skilled in the art that under the situation that does not deviate from broad sense inventive concept of the present invention and can make change above-mentioned embodiment.Therefore should be appreciated that the present invention is not limited to the particular that is disclosed, and it is intended to be covered by the modification in the spirit and scope of the invention that is defined by the request item of enclosing.
Claims (48)
1. treatment, prevention or improvement have the method for the symptom of the mammal non-alcoholic fatty liver disease disease (NAFLD) that needs, and it comprises the step of the compositions of using effective dose, and described compositions comprises at least a cholesterol reducing agent and at least a H
3The therapeutic combination of antagonist/inverse agonist.
2. the method for claim 1 is Gu wherein said cholesterol reducing agent is sterin or 5-α-alkanol absorption inhibitor.
3. method as claimed in claim 2, Gu wherein said sterin or 5-α-alkanol absorption inhibitor are the chemical compounds of formula (I):
Or acceptable salt of its pharmacy or solvate,
Wherein, in formula (I):
Ar
1And Ar
2Be independently selected from aryl and through R
4The aryl that replaces;
Ar
3It is aryl or through R
5The aryl that replaces;
X, Y and Z are independently selected from-CH
2-,-CH (low alkyl group)-and-C (two low alkyl groups)-;
R and R
2Be independently selected from-OR
6,-O (CO) R
6,-O (CO) OR
9With-O (CO) NR
6R
7
R
1And R
3Be independently selected from hydrogen, low alkyl group and aryl;
Q is 0 or 1; R is 0 or 1; M, n and p are independently selected from 0,1,2,3 or 4; Condition is that at least one is 1 among q and the r, and m, n, p, q and r sum are 1,2,3,4,5 or 6; And condition be when p be 0 and r when being 1, m, q and n sum are 1,2,3,4 or 5;
R
4Be 1-5 and be independently selected from following substituent 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 and be independently selected from following substituent 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
8The low alkyl group that is independently selected from hydrogen, low alkyl group, aryl and replaces through aryl; With
R
9Be low alkyl group, aryl or the low alkyl group that replaces through aryl.
4. method as claimed in claim 3, Gu wherein said sterin or 5-α-alkanol absorption inhibitor are the chemical compounds of formula (II):
Or acceptable salt of its pharmacy or solvate.
5. method as claimed in claim 2, Gu wherein said sterin or 5-α-alkanol absorption inhibitor are the chemical compounds of formula (III):
Or the acceptable salt of its pharmacy or its solvate,
Wherein, in following formula (III):
Ar
1Be through R
3The aryl that replaces;
Ar
2Be through R
4The aryl that replaces;
Ar
3Be through R
5The aryl that replaces;
Y and Z are independently 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 and be independently selected from following substituent 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-halogen ,-halogen, neighbour-low alkyl group ,-low alkyl group ,-(low-grade alkylidene)-COOR
6With-CH=CH-COOR
6
R
3And R
4Be 1-3 independently and be independently selected from R
5, hydrogen, right-low alkyl group, aryl ,-NO
2,-CF
3Substituent group with right-halogen;
R
6, R
7And R
8The low alkyl group that is independently selected from hydrogen, low alkyl group, aryl and replaces through aryl; And R
9Be low alkyl group, aryl or the low alkyl group that replaces through aryl.
6. method as claimed in claim 2, Gu wherein said sterin or 5-α-alkanol absorption inhibitor are the chemical compounds of formula (IV):
Or the acceptable salt of its pharmacy or its solvate,
Wherein, in formula (IV):
A is selected from through R
2The Heterocyclylalkyl that replaces, through R
2The heteroaryl that replaces, through R
2The benzo-fused heterocycle alkyl that replaces and through R
2The benzo-fused heteroaryl that replaces;
Ar
1It is aryl or through R
3The aryl that replaces;
Ar
2It is aryl or through R
4The aryl that replaces;
Q is a key or forms the volution group with the 3-position of this aza cyclo-butanone ring carbon
With
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
8-, or-S (O)
0-2-, e is that 0-5 and r are 0-5, condition is that e and r sum are 1-6;
-(C
2-C
6Alkenylene)-; 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 f and g sum are 1-6;
R
5Be selected from:
R
6And R
7Be independently 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
5With adjacent R
6Together or R
5With adjacent R
7Together formation-CH=CH-or-CH=C (C
1-C
6Alkyl)-group;
A and b are 0,1,2 or 3 independently, and condition is that the two is not 0 simultaneously; 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, described R
6Can be identical or different; And condition is when b is 2 or 3, described R
7Can be identical or different;
And when Q is a key, R
1Also can be selected from:
Wherein M be-O-,-S-,-S (O)-or-S (O)
2-;
X, Y and Z are independently selected from-CH
2-,-CH (C
1-C
6Alkyl)-and-C (two-(C
1-C
6) alkyl);
R
10And R
12Be independently selected from-OR
14,-O (CO) R
14,-O (CO) OR
16With-O (CO) NR
14R
15
R
11And R
13Be independently selected from hydrogen, (C
1-C
6) alkyl and aryl; Perhaps R
10With R
11Be together=O, perhaps R
12With 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 are 0-4 independently; Condition is that at least one is 1 among s and the t, and m, n, p, s and t sum are 1-6; Condition be when p be 0 and t when being 1, m, s and n sum are 1-5; And condition be when p be 0 and s when being 1, m, t and n sum are 1-5;
V is 0 or 1;
J and k are 1-5 independently, and condition is that j, k and v sum are 1-5;
R
2Be 1-3 the substituent group on the described ring carbon atom, it is selected from: hydrogen, (C
1-C
10) alkyl, (C
2-C
10) thiazolinyl, (C
2-C
10) alkynyl, (C
3-C
6) cycloalkyl, (C
3-C
6) cycloalkenyl group, through R
17The aryl that replaces, through R
17The benzyl that replaces, through R
17The benzyloxy that replaces, through R
17The aryloxy group that replaces, halogen ,-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
2For one of on the heterocycloalkyl ring during substituent group, R
2Such as definition, or be=O or
And, work as R
2But during for substituent group on the substituted ring nitrogen, 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,
Wherein J be-O-,-NH-,-NR
18-or-CH
2-;
R
3And R
4Be independently selected from 1-3 substituent group, described substituent group is independently selected from: (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
14SO2R
16,-COOR
14,-CONR
14R
15,-COR
14,-SO2NR
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
17Be 1-3 independently and be independently selected from following group: hydrogen, (C
1-C
6) alkyl, (C
1-C
6) alkoxyl ,-COOH, NO
2,-NR
14R
15, OH and halogen;
R
14And R
15Be independently selected from hydrogen, (C
1-C
6) alkyl, aryl and the (C that replaces through aryl
1-C
6) alkyl;
R
16Be (C
1-C
6) alkyl, aryl or through 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.
7. method as claimed in claim 2, Gu wherein said sterin or 5-α-alkanol absorption inhibitor are the chemical compounds of formula V:
Or the acceptable salt of its pharmacy or its solvate,
Wherein, in formula V:
Ar
1Be aryl, through R
10The aryl that replaces, heteroaryl or through R
10The heteroaryl that replaces;
Ar
2It is aryl or through R
4The aryl that replaces;
Ar
3It is aryl or through R
5The aryl that replaces;
X and Y are independently 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; Perhaps R and R
1Be together=O;
Q is 0 or 1;
R is 0,1 or 2;
M and n are 0,1,2,3,4 or 5 independently; Condition is that m, n and q sum are 1,2,3,4 or 5;
R
4Be 1-5 and be independently selected from following substituent 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 and be independently selected from following substituent 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,-CF
3,-CN ,-NO
2, halogen ,-(low-grade alkylidene) COOR
6With-CH=CH-COOR
6
R
6, R
7And R
8The low alkyl group that is independently selected from hydrogen, low alkyl group, aryl and replaces through aryl;
R
9Be low alkyl group, aryl or the low alkyl group that replaces through aryl; With
R
10Be 1-5 and be independently selected from following substituent 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,-CF
3,-CN ,-NO
2And halogen.
8. method as claimed in claim 2, Gu wherein said sterin or 5-α-alkanol absorption inhibitor are the chemical compounds of following formula:
Or the acceptable salt of its pharmacy or its solvate,
Wherein, in formula (VI):
R
1Be
R
2And R
3Be independently selected from :-CH
2-,-CH (low alkyl group)-,-C (two-low alkyl group)-,-CH=CH-and-C (low alkyl group)=CH-; Perhaps R
1With adjacent R
2Together or R
1With adjacent R
3Together formation-CH=CH-or-CH=C (low alkyl group)-group;
U and v are 0,1,2 or 3 independently, and condition is that the two is not 0 simultaneously; 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
3For-CH=CH-or-during C (low alkyl group)=CH-, u is 1; Condition is when v is 2 or 3, described R
2Can be identical or different; And condition is when u is 2 or 3, described R
3Can be identical or different;
R
4Be selected from following: 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 e and r sum are 0,1,2,3,4,5 or 6; B-(C
2-C
6Alkenylene)-; B-(C
4-C
6Alkadienylene)-; B-(CH
2)
t-Z-(C
2-C
6Alkenylene)-, wherein Z as defined above, and wherein t is 0,1,2 or 3, condition is that the carbon number sum is 2,3,4,5 or 6 in t and this alkenylene chain; B-(CH
2)
f-V-(CH
2)
g-, wherein V is C
2-C
6Cycloalkylidene, f be 1,2,3,4 or 5 and g be 0,1,2,3,4 or 5, condition is that f and g sum are 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 all as defined above, condition is that the carbon number sum is 2,3,4,5 or 6 in t and this alkenylene chain; B-(CH
2)
a-Z-(CH
2)
b-V-(CH
2)
d-, wherein Z and V all as defined above and a, b and d be 0,1,2,3,4,5 or 6 independently, condition is that a, b and d sum are 0,1,2,3,4,5 or 6; Or T-(CH
2)
s-, wherein T is that the cycloalkyl and the s of 3-6 carbon atom are 0,1,2,3,4,5 or 6; Or
R
1And R
4Form group together
The heteroaryl that B is selected from dihydro indenyl, indenyl, naphthyl, tetralyl, heteroaryl or replaces through W, wherein heteroaryl is selected from: pyrrole radicals, pyridine radicals, pyrimidine radicals, pyrazinyl, triazine radical, imidazole radicals, thiazolyl, pyrazolyl, thienyl, oxazolyl and furyl, and for nitrogenous heteroaryl, its N-oxide, or
W is that 1-3 is independently selected from the following substituent group that is used for replacing on the ring carbon atom: low alkyl group, hydroxyl low-grade alkyl, lower alkoxy, alkoxyalkyl, alkoxyl alkoxyl, alkoxy carbonyl alkoxyl, (lower alkoxy imido grpup)-low alkyl group, lower alkyl diacyl, low alkyl group lower alkyl 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, halogen ,-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-silanyloxy ylmethyl ,-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 describedly be substituted the described substituent group on the heteroaryl ring nitrogen-atoms and then be selected from if exist: 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-(TMS)-ethoxyl methyl;
R
7Be 1-3 be independently selected from low alkyl group, lower alkoxy ,-COOH, NO
2,-N (R
8) (R
9), the group of OH and halogen;
R
8And R
9Be independently 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
7Phenyl;
R
13Be selected from-O-,-CH
2-,-NH-,-N (low alkyl group)-or-NC (O) R
19
R
15, R
16And R
17Be independently selected from H and at the defined group of W; Perhaps R
15Be hydrogen and R
16And R
17Form the dioxolanes basic ring with the adjacent carbon atom that it connected;
R
19Be H, low alkyl group, phenyl or phenyl lower alkyl; With
R
20And R
21Be independently selected from: dioxy cyclopentenyl between phenyl, the phenyl through W replaces, naphthyl, the naphthyl through W replaces, dihydro indenyl, indenyl, tetralyl, benzo, heteroaryl, the heteroaryl that replaces through W, benzo-fused heteroaryl, through benzo-fused heteroaryl and cyclopropyl that W replaces, wherein heteroaryl is as defined above.
9. method as claimed in claim 2, Gu wherein said sterin or 5-α-alkanol absorption inhibitor are formula (VIIA) and chemical compound (VIIB):
Or acceptable salt of its pharmacy or solvate,
Wherein in formula (VIIA) or (VIIB):
A is-CH=CH-,-C ≡ C-or-(CH
2)
p-, wherein p is 0,1 or 2;
B is
B ' is
D is-(CH
2)
mC (O)-or-(CH
2)
q-, wherein m be 1,2,3 or 4 and q be 2,3 or 4;
E is C
10To C
20Alkyl or-C (O)-(C
9To C
19)-alkyl, wherein this alkyl is a straight or branched, saturated or comprise one or more pairs of keys;
R is hydrogen, straight or branched, saturated or comprise the C of one or more pairs of keys
1-C
15Alkyl or B-(CH
2) r-, wherein r is 0,1,2 or 3;
R
1, R
2, R
3, R
1 ', R
2 'And R
3 'Be independently selected from: hydrogen, low alkyl group, lower alkoxy, carboxyl, NO
2, NH
2, OH, halogen, 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 OH, low alkyl group, phenyl, benzyl or the phenyl that is substituted, wherein said substituent group is 1-3 and is independently selected from following group: low alkyl group, lower alkoxy, carboxyl, NO
2, NH
2, OH, halogen, low-grade alkyl amino and two elementary alkyl amido.
10. method as claimed in claim 2, Gu wherein said sterin or 5-α-alkanol absorption inhibitor are the chemical compounds of formula (VIII):
Or the acceptable salt of its pharmacy or its solvate,
Wherein, in following formula (VIII),
R
26Be H or OG
1
G and G
1Be independently selected from: H,
With
Condition is to work as R
26When being H or OH, G is not H;
R, R
aAnd R
bBe independently selected from H ,-OH, halogen ,-NH
2, azido, (C
1-C
6) alkoxyl (C
1-C
6)-alkoxyl or-W-R
30
W is independently 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
6Be independently 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
4aBe independently 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: through R
32The T that replaces, through R
32Replace-T-(C
1-C
6) alkyl, through R
32Replace-(C
2-C
4) thiazolinyl, through R
32Replace-(C
1-C
6) alkyl, through R
32Replace-(C
3-C
7) cycloalkyl and through R
32Replace-(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
32Be independently selected from 1-3 substituent group, described substituent group is independently selected from: halogen, (C
1-C
4) alkyl ,-OH, phenoxy group ,-CF
3,-NO
2, (C
1-C
4) alkoxyl, methylene dioxy base, oxo, (C
1-C
4) alkyl sulfenyl, (C
1-C
4) alkyl sulphinyl, (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, and R
31, with its nitrogen that is connected and R
32Form pyrrolidinyl, piperidyl, N-methyl-piperazinyl, indolinyl or morpholinyl or warp (C
1-C
4) the alkoxy carbonyl pyrrolidinyl, piperidyl, N methyl piperazine base, indolinyl or the morpholinyl that replace;
Ar
1It is aryl or through R
10The aryl that replaces;
Ar
2It is aryl or through R
11The aryl that replaces;
Q is a key or forms the volution group with the 3-position of this aza cyclo-butanone ring carbon
With
R
1Be selected from:
-(CH2)
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 that 0-5 and r are 0-5, condition is that e and r sum are 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 f and g sum are 1-6;
R
12Be
R
13And R
14Be independently 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 are 0,1,2 or 3 independently, and condition is that the two is not 0 simultaneously;
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, described R
13Can be identical or different; With
Condition is when b is 2 or 3, described R
14Can be identical or different;
And when Q is a key, R
1Also:
Or
M is-O-,-S-,-S (O)-or-S (O)
2-;
X, Y and Z are independently selected from-CH
2-,-CH (C
1-C
6) alkyl-and-C (two-(C
1-C
6) alkyl);
R
10And R
11Be independently selected from 1-3 substituent group, described substituent group is independently selected from: (C
1-C
6) alkyl ,-OR
19,-O (CO) R
19,-O (CO) OR
21,-O (CH2)
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)
1-10-COOR
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
17Be independently selected from-OR
19,-O (CO) R
19,-O (CO) OR
21With-O (CO) NR
19R
20
R
16And R
18Be independently 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;
S is 0 or 1; T is 0 or 1; M, n and p are 0-4 independently;
Condition is that at least one is 1 among s and the t, and m, n, p, s and t sum are 1-6;
Condition be when p be 0 and t when being 1, m, s and n sum are 1-5; And condition be when p be 0 and s when being 1, m, t and n sum are 1-5;
V is 0 or 1;
J and k are 1-5 independently, and condition is that j, k and v sum are 1-5;
And when Q is a key and R
1Be
The time, Ar
1Also pyridine radicals, isoxazolyl, furyl, pyrrole radicals, thienyl, imidazole radicals, pyrazolyl, thiazolyl, pyrazinyl, pyrimidine radicals or pyridazinyl;
R
19And R
20Be independently selected from H, (C
1-C
6) alkyl, aryl and the (C that replaces through aryl
1-C
6) alkyl;
R
21Be (C
1-C
6) alkyl, aryl or through R
24The aryl that replaces;
R
22Be H, (C
1-C
6) alkyl, aryl (C
1-C
6) alkyl ,-C (O) R
19Or-COOR
19
R
23And R
24Be 1-3 independently and be independently selected from H, (C
1-C
6) alkyl, (C
1-C
6) alkoxyl ,-COOH, NO
2,-NR
19R
20The group of ,-OH and halogen; With
R
25Be H ,-OH or (C
1-C
6) alkoxyl.
11. method as claimed in claim 2, Gu wherein said sterin or 5-α-alkanol absorption inhibitor are the chemical compounds of formula (IX):
Or acceptable salt of its pharmacy or solvate,
Wherein in formula (IX):
R
1Be selected from H, G, G
1, G
2,-SO
3H and-PO
3H;
G is selected from: H,
Wherein R, R
aAnd R
bBe selected from independently of one another H ,-OH, halogen ,-NH
2, azido, (C
1-C
6) alkoxyl (C
1-C
6) alkoxyl or-W-R
30
W is independently 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
6Be selected from H, (C independently of one another
1-C
6) alkyl, acetyl group, aryl and aryl (C
1-C
6) alkyl;
R
3, R
4, R
5, R
7, R
3aAnd R
4aBe selected from H, (C independently of one another
1-C
6) alkyl, acetyl group, aryl (C
1-C
6) alkyl ,-C (O) (C
1-C
6) alkyl and-C (O) aryl;
R
30Be independently selected from: through R
32The T that replaces, through R
32Replace-T-(C
1-C
6) alkyl, through R
32Replace-(C
2-C
4) thiazolinyl, through R
32Replace-(C
1-C
6) alkyl, through R
32Replace-(C
3-C
7) cycloalkyl and through R
32Replace-(C
3-C
7) cycloalkyl (C
1-C
6) alkyl;
R
31Be independently selected from H and (C
1-C
4) alkyl;
T is independently selected from: phenyl, furyl, thienyl, pyrrole radicals, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, benzothiazolyl, thiadiazolyl group, pyrazolyl, imidazole radicals and pyridine radicals;
R
32Be independently selected from 1-3 substituent group, described substituent group is selected from independently of one another: H, halogen, (C
1-C
4) alkyl ,-OH, phenoxy group ,-CF
3,-NO
2, (C
1-C
4) alkoxyl, methylene dioxy base, oxo, (C
1-C
4) alkyl sulfenyl, (C
1-C
4) alkyl sulphinyl, (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 a covalent bond and R
31, with its nitrogen that is connected and R
32Form pyrrolidinyl, piperidyl, N-methyl-piperazinyl, indolinyl or morpholinyl, or pyrrolidinyl, piperidyl, N methyl piperazine base, indolinyl or the morpholinyl of the replacement of warp (C1-C4) alkoxy carbonyl;
G
1Represent by following structure:
R wherein
33Be independently selected from the alkyl that is unsubstituted, through R
34The alkyl, (R that replace
35) (R
36) alkyl-,
With
R
34Be 1 to 3 substituent group, each R
34Be independently selected from HOOC-, HO-, HS-, (CH
3) S-, H
2N-, (NH
2) (NH) C (NH)-, (NH
2) C (O)-and HOOCCH (NH
3 +) CH
2SS-;
R
35Be independently selected from H and NH
2-;
R
36Be independently selected from H, the alkyl that is unsubstituted, through R
34The alkyl that replaces, the cycloalkyl that is unsubstituted and through R
34The cycloalkyl that replaces;
G
2Represent by following structure:
R wherein
37And R
38Be selected from (C independently of one another
1-C
6) alkyl and aryl;
R
26Be 1-5 substituent group, each R
26Be independently selected from:
a)H；
d)-OH；
e)-OCH
3；
D) fluorine;
E) chlorine;
f)-O-G；
k)-O-G
1；
I)-O-G
2；
M)-SO
3H; With
n)-PO
3H；
Condition is to work as R
1When being H, R
26Be not H ,-OH ,-OCH
3Or-O-G;
Ar
1Be aryl, through R
10The aryl that replaces, heteroaryl or through R
10The heteroaryl that replaces;
Ar
2Be aryl, through R
11The aryl that replaces, heteroaryl or through R
11The heteroaryl that replaces;
L is selected from:
F) covalent bond;
G)-(CH
2)
q-, wherein q is 1-6;
H)-(CH
2)
e-E-(CH
2)
r-, wherein E be-O-,-C (O)-, phenylene ,-NR
22-or-S (O)
0-2-, e is that 0-5 and r are 0-5, condition is that e and r sum are 1-6;
I)-(C
2-C
6) alkenylene-;
J)-(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 f and g sum are 1-6; With
f)
Wherein M be-O-,-S-,-S (O)-or-S (O)
2-;
X, Y and Z are selected from-CH independently of one another
2-,-CH (C
1-C
6) alkyl-and-C (two-(C
1-C
6) alkyl)-;
R
8Be selected from H and alkyl;
R
10And R
11Be selected from 1-3 substituent group independently of one another, described substituent group is selected from independently of one another: (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 (CH2)
1-10-COOR
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
17Be selected from independently of one another-OR
19,-OC (O) R
19,-OC (O) OR
21,-OC (O) NR
19R
20
R
16And R
18Be selected from H, (C independently of one another
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;
S is 0 or 1;
T is 0 or 1;
M, n and p are selected from 0-4 independently of one another;
Condition is that at least one is 1 among s and the t, and m, n, p, s and t sum are 1-6; Condition be when p be 0 and t when being 1, m, n and p sum are 1-5; And condition be when p be 0 and s when being 1, m, t and n sum are 1-5;
V is 0 or 1;
J and k are 1-5 independently of one another, and condition is that j, k and v sum are 1-5;
Q be a key ,-(CH
2)
q-, wherein q is 1-6, perhaps the 3-position ring carbon with this aza cyclo-butanone forms the volution group
R wherein
12Be
R
13And R
14Be selected from independently of one another-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 are 0,1,2 or 3 independently of one another, and condition is that the two is not 0 simultaneously; 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, described R
13Can be identical or different; And condition is when b is 2 or 3, described R
14Can be identical or different;
And when Q is that a key and L are
The time,
Ar then
1Also pyridine radicals, isoxazolyl, furyl, pyrrole radicals, thienyl, imidazole radicals, pyrazolyl, thiazolyl, pyrazinyl, pyrimidine radicals or pyridazinyl;
R
19And R
20Be selected from H, (C independently of one another
1-C
6) alkyl, aryl and the (C that replaces through aryl
1-C
6) alkyl;
R
21Be (C
1-C
6) alkyl, aryl or through R
24The aryl that replaces;
R
22Be H, (C
1-C
6) alkyl, aryl (C
1-C
6) alkyl ,-C (O) R
19Or-COOR
19
R
23And R
24Be selected from 1-3 substituent group independently of one another, described substituent group is selected from H, (C independently of one another
1-C
6) alkyl, (C
1-C
6) alkoxyl ,-COOH, NO
2,-NR
19R
20,-OH and halogen; With
R
25Be H ,-OH or (C
1-C
6) alkoxyl.
12. method as claimed in claim 2, wherein said H
3Receptor antagonist/inverse agonist is an imidazole type.
13. method as claimed in claim 2, wherein said H
3Receptor antagonist/agonist is the chemical compound of formula (XIII):
Or acceptable salt of its pharmacy or solvate,
Wherein in formula (XIII):
(1) R
1Be selected from:
(a) aryl;
(b) heteroaryl;
(c) Heterocyclylalkyl
(d) alkyl;
(e) cycloalkyl; Or
(f) alkylaryl;
Wherein said R
1Group can be chosen wantonly through 1 to 4 and be independently selected from following substituent group replacement:
(1) halogen;
(2) hydroxyl;
(3) lower alkoxy;
(4)-CF
3；
(5)CF
3O-；
(6)-NR
4R
5；
(7) phenyl;
(8)-NO
2，
(9)-CO
2R
4；
(10)-CON (R
4)
2, each R wherein
4Identical or different;
(11)-S (O)
M 'N (R
20)
2, each R wherein
20Identical or different, it can be H or alkyl;
(12)-CN; Or
(13) alkyl; Or
(2) R
1And X ' forms together and is selected from following group:
(3) X ' is selected from :=C (O) ,=C (NOR
3) ,=C (NNR
4R
5),
(4) M
1Be carbon;
(5) M
2Be selected from C or N;
(6) M
3And M
4Be independently selected from C or N;
(7) Y ' is selected from :-CH
2-,=C (O) ,=C (NOR
20) (R wherein
20As defined above), or=C (S);
(8) Z ' is C
1-C
6Alkyl group;
(9) R
2Be five Yuans or six-member heteroaryl rings, this six-member heteroaryl ring comprises that 1 or 2 nitrogen-atoms and all the other annular atomses are carbon, and this five-member heteroaryl ring to comprise 1 or 2 hetero atom and all the other annular atoms that is selected from nitrogen, oxygen or sulfur be carbon; Described five Yuans or six Yuans heteroaryl rings can be chosen wantonly and be independently selected from following substituent group through 1-3 and replace: halogen, hydroxyl, low alkyl group, lower alkoxy ,-CF
3, CF
3O-,-NR
4R
5, phenyl ,-NO
2,-CO
2R
4,-CON (R
4)
2(each R wherein
4All identical or different) ,-CH
2NR
4R
5The C of ,-(N) (NR
4R
5)
2Or-CN;
(10) R
3Be selected from:
(a) hydrogen;
(b) C
1-C
6Alkyl;
(c) aryl;
(d) heteroaryl;
(e) Heterocyclylalkyl;
(f) aryl alkyl;
(g)-(CH
2)
E '-C (O) N (R
4)
2, each R wherein
4It is all identical or different,
(h)-(CH
2)
e′-C(O)OR
4；
(i)-(CH
2)
E '-C (O) R
30, R wherein
30It is heterocycloalkyl;
(j)-CF
3Or
(k)-CH
2CF
3；
Wherein the aryl moiety of this aryl, heteroaryl, Heterocyclylalkyl and this aryl alkyl can be chosen wantonly through 1 to 3 and be selected from following substituent group replacement: halogen ,-OH ,-OCF
3,-CF
3,-CN ,-N (R
45)
2,-CO
2R
45Or-C (O) N (R
45)
2, each R wherein
45Be independently selected from: H, alkyl, alkylaryl or wherein this aryl moiety can be independently selected from-CF through 1 to 3
3,-OH, halogen, alkyl ,-NO
2Or-alkylaryl that the substituent group of CN replaces;
(11) R
4Be selected from: hydrogen, C
1-C
6Alkyl, aryl, alkylaryl, described aryl and alkylaryl can be chosen wantonly through 1 to 3 and be selected from following substituent group replacement: halogen ,-CF
3,-OCF
3,-OH ,-N (R
45)
2,-CO
2R
45,-C (O) N (R
45)
2Or-CN; R wherein
45Be as defined above;
(12) R
5Be selected from: hydrogen, C
1-C
6Alkyl ,-C (O) R
4,-C (O)
2R
4Or-C (O) N (R
4)
2, each R wherein
4All independent of selection, and R
4As defined above;
(13) or R
4And R
5Nitrogen-atoms with its bond forms five Yuans or six element heterocycle alkyl rings;
(14) R
6Be selected from: alkyl, aryl, alkylaryl, halogen, hydroxyl, lower alkoxy ,-CF
3, CF
3O-,-NR
4R
5, phenyl ,-NO
2,-CO
2R
5,-CON (R
4)
2(each R wherein
4All identical or different) or-CN;
(15) R
12Be selected from: alkyl, hydroxyl, alkoxyl or fluorine;
(16) R
13Be selected from: alkyl, hydroxyl, alkoxyl or fluorine;
(17) a ' (R
12Subscript) be 0 to 2;
(18) b ' (R
12Subscript) be 0 to 2;
(19) c ' (R
6Subscript) be 0 to 2;
(20) e ' is 0 to 5;
(21) m ' is 1 or 2;
(22) n ' is 1,2 or 3; With
(23) p ' is 1,2 or 3, and condition is to work as M
3And M
4When the two was nitrogen, then p ' 2 or 3 (that is, worked as M
3And M
2P was not 1 when the two was nitrogen).
14. method as claimed in claim 13, wherein said H
3Receptor antagonist/agonist is a kind of being selected from:
With
15. method as claimed in claim 13, Gu wherein said sterin or 5-α-alkanol absorption inhibitor are the chemical compounds of formula (I):
Or acceptable salt of its pharmacy or solvate,
Wherein in formula (I):
Ar
1And Ar
2Be independently selected from aryl and through R
4The aryl that replaces;
Ar
3It is aryl or through R
5The aryl that replaces;
X, Y and Z are independently selected from-CH
2-,-CH (low alkyl group)-and-C (two low alkyl groups)-;
R and R
2Be independently selected from-OR
6,-O (CO) R
6,-O (CO) OR
9With-O (CO) NR
6R
7
R
1And R
3Be independently selected from hydrogen, low alkyl group and aryl;
Q is 0 or 1; R is 0 or 1; M, n and p are independently selected from 0,1,2,3 or 4; Condition is that at least one is 1 among q and the r, and m, n, p, q and r sum are 1,2,3,4,5 or 6; And condition be when p be 0 and r when being 1, m, q and n sum are 1,2,3,4 or 5;
R
4Be 1-5 and be independently selected from following substituent 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 and be independently selected from following substituent 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
8The low alkyl group that is independently selected from hydrogen, low alkyl group, aryl and replaces through aryl; With
R
9Be low alkyl group, aryl or the low alkyl group that replaces through aryl.
16. method as claimed in claim 14, Gu wherein said sterin or 5-α-alkanol absorption inhibitor are the chemical compounds of formula (VIA)
Or acceptable salt of its pharmacy or solvate.
17. method as claimed in claim 14, Gu wherein said sterin or 5-α-alkanol absorption inhibitor are the chemical compounds of formula (II):
Or acceptable salt of its pharmacy or solvate.
18. method as claimed in claim 15, it further comprises the HMG-CoA reductase inhibitor of effective dose.
19. method as claimed in claim 18, wherein said HMG-CoA reductase inhibitor is selected from: lovastatin, pravastatin, fluvastatin, simvastatin, atorvastatin, cerivastatin, Pitavastatin and rosuvastatin.
20. method as claimed in claim 17, it further comprises the HMG-CoA reductase inhibitor of effective dose, and wherein this inhibitor is a simvastatin.
21. method as claimed in claim 15, it further comprises PPAR activator, nicotinic acid and/or nicotinic acid receptor agonists or bile acid chelating agent as the 3rd active constituent.
22. method as claimed in claim 21, wherein said the 3rd active constituent is colestyramine, colestipol, clofibrate, gemfibrozil, fenofibrate or nicotinic acid.
23. method as claimed in claim 2, wherein said H
3Receptor antagonist/agonist is the chemical compound of formula (XIV)
Or acceptable salt of its pharmacy or solvate,
Wherein, in formula (XIV):
Dotted line is represented optional pair of key;
A ' is 0 to 2;
B ' is 0 to 2;
N ' is 1,2 or 3;
P ' is 1,2 or 3;
R ' is 0,1,2 or 3;
Condition is to work as M
2When being N, p ' is not 1; And when r ' is 0, M
2Be C (R
3); And p ' is 1 to 4 with r ' sum;
M
1Be C (R
3) or N;
M
2Be C (R
3) or N;
X ' is a key or C
1-C
6Alkylidene;
Y ' is-C (O)-,-C (S)-,-(CH
2)
Q '-,-NR
4C (O)-,-C (O) NR
4-,-C (O) CH
2-,-SO
2-,-N (R
4)-,-NH-C (=N-CN)-or-C (=N-CN)-NH-; Condition is to work as M
1When being N, Y ' is not-NR
4C (O)-or-NH-C (=N-CN)-; Work as M
2When being N, Y ' is not-C (O) NR
4-or-C (=N-CN)-NH-; And when Y ' is-N (R
4)-time, M
1Be CH and M
2Be C (R
3);
Q ' is 1 to 5, and condition is to work as M
1And M
2When the two was N, q ' was 2 to 5;
Z ' is a key, C
1-C
6Alkylidene, C
1-C
6Alkenylene ,-C (O)-,-CH (CN)-,-SO
2-or-CH
2C (O) NR
4-;
R
1Be
Q ' is-N (R
8)-,-S-or-O-;
K ' is 0,1,2,3 or 4;
K1 is 0,1,2 or 3;
K2 is 0,1 or 2;
R is H, C
1-C
6Alkyl, halogen (C
1-C
6) alkyl-, C
1-C
6Alkoxyl, (C
1-C
6) alkoxyl-(C
1-C
6) alkyl-, (C
1-C
6)-alkoxyl-(C
1-C
6) alkoxyl, (C
1-C
6) alkoxyl-(C
1-C
6) alkyl-SO
0-2, R
32-aryl (C
1-C
6) alkoxyl-, R
32-aryl (C
1-C
6) alkyl-, R
32-aryl, R
32-aryloxy group, R
32-heteroaryl, (C
3-C
6) cycloalkyl, (C
3-C
6) cycloalkyl-(C
1-C
6) alkyl, (C
3-C
6) cycloalkyl-(C
1-C
6) alkoxyl, (C
3-C
6) cycloalkyl-oxygen base-, R
37-Heterocyclylalkyl, R
37-Heterocyclylalkyl-oxygen base-, R
37-Heterocyclylalkyl-(C
1-C
6) alkoxyl, N (R
30) (R
31)-(C
1-C
6) alkyl-,-N (R
30) (R
31) ,-NH-(C
1-C
6) alkyl-O-(C
1-C
6) alkyl ,-NHC (O) NH (R
29), R
29-S (O)
0-2-, halogen (C
1-C
6) alkyl-S (O)
0-2-, N (R
30) (R
31)-(C
1-C
6) alkyl-S (O)
0-2-or benzoyl;
R
8Be H, C
1-C
6Alkyl, halogen (C
1-C
6) alkyl-, (C
1-C
6) alkoxyl-(C
1-C
6) alkyl-, R
32-aryl (C
1-C
6) alkyl-, R
32-aryl, R
32-heteroaryl, (C
3-C
6) cycloalkyl, (C
3-C
6) cycloalkyl-(C
1-C
6) alkyl, R
37-Heterocyclylalkyl, N (R
30) (R
31)-(C
1-C
6) alkyl-, R
29-S (O)
2-, halogen (C
1-C
6) alkyl-S (O)
2-, R
29-S (O)
0-1-(C
2-C
6) alkyl-, halogen (C
1-C
6) alkyl-S (O)
0-1-(C
2-C
6)-;
R
3Be that to have 1 or 2 hetero atom and all the other annular atoms that is independently selected from N or N-O be six of carbon-member's heteroaryl ring; Having 1,2,3 or 4 hetero atom and all the other annular atoms that is independently selected from N, O or S is five of carbon-member's heteroaryl ring; R
32-quinolyl; R
32-aryl; Heterocyclylalkyl; (C
3-C
6) cycloalkyl; C
1-C
6Alkyl; Hydrogen; Thianaphthenyl;
Wherein this six-member heteroaryl ring or this five-member heteroaryl ring can be chosen wantonly through R
6Replace;
R
3Be H, halogen, C
1-C
6Alkyl ,-OH, (C
1-C
6) alkoxyl or-NHSO
2-(C
1-C
6) alkyl;
R
4Be independently selected from: hydrogen, C
1-C
6Alkyl, C
3-C
6Cycloalkyl, (C
3-C
6) cycloalkyl (C
1-C
6) alkyl, R
33-aryl, R
33-aryl (C
1-C
6) alkyl and R
32-heteroaryl;
R
5Be hydrogen, C
1-C
6Alkyl ,-C (O) R
20,-C (O)
2R
20,-C (O) N (R
20)
2, (C
1-C
6) alkyl-SO
2-or (C
1-C
6) alkyl-SO
2-NH-;
Perhaps R
4And R
5Form azetidinyl, pyrrolidinyl, piperidyl, piperazinyl or morpholine basic ring with the nitrogen that it connected;
R
6Be 1 to 3 and be independently selected from following substituent group :-OH, halogen, C
1-C
6Alkyl-, C
1-C
6Alkoxyl, C
1-C
6Alkylthio group ,-CF
3,-NR
4R
5,-CH
2-NR
4R
5,-NHSO
2R
22,-N (SO
2R
22)
2, phenyl, R
33-phenyl, NO
2,-CO
2R
4,-CON (R
4)
2,
R
7Be-N (R
29)-,-O-or-S (O)
0-2-;
R
12Be independently selected from C
1-C
6Alkyl, hydroxyl, C
1-C
6Alkoxyl or fluorine, condition are to work as R
12When being hydroxyl or fluorine, R then
12Be not binding on the carbon of adjacent nitrogen; Or two R
12Substituent group forms the C to another non-adjacent ring carbon from a ring carbon
1To C
2The alkyl bridge; Perhaps R
12For=O;
R
13Be independently selected from C
1-C
6Alkyl, hydroxyl, C
1-C
6Alkoxyl or fluorine, condition are to work as R
13During for hydroxyl or fluorine, R then
13 'Be not binding on the carbon of adjacent nitrogen; Perhaps two R
13Substituent group forms the C to another non-adjacent ring carbon from a ring carbon
1To C
2The alkyl bridge; Perhaps R
13For=O;
R
2Be independently selected from hydrogen, C
1-C
6Alkyl or aryl, wherein this aryl can choose wantonly through from 1 to 3 be independently selected from halogen ,-CF
3,-OCF
3, hydroxyl or methoxyl group group replace; Maybe when there being two R
20During group, described two R
20Group can form five Yuans or six element heterocycles with the nitrogen of its bond;
R
22Be C
1-C
6Alkyl, R
34-aryl or Heterocyclylalkyl;
R
24Be H, C
1-C
6Alkyl ,-SO
2R
2Or R
34-aryl;
R
25Be independently selected from: C
1-C
6Alkyl, halogen ,-CN ,-NO
2,-CF
3,-OH, C
1-C
6Alkoxyl, (C
1-C
6) alkyl-C (O)-, aryl-C (O)-,-C (O) OR
29,-N (R
4) (R
5), N (R
4) (R
5)-C (O)-, N (R
4) (R
5)-S (O)
1-2-, R
22-S (O)
0-2-, halogen-(C
1-C
6) alkyl-or halogen-(C
1-C
6) alkoxyl-(C
1-C
6) alkyl-;
R
29Be H, C
1-C
6Alkyl, C
3-C
6Cycloalkyl, R
35-aryl or R
35-aryl (C
1-C
6) alkyl-;
R
30Be H, C
1-C
6Alkyl-, R
35-aryl or R
35-aryl (C
1-C
6) alkyl-;
R
31Be H, C
1-C
6Alkyl-, R
35-aryl, R
35-aryl (C
1-C
6) alkyl-, R
35-heteroaryl, (C
1-C
6) alkyl-C (O)-, R
35-aryl-C (O)-, N (R
4) (R
5)-C (O)-, (C
1-C
6) alkyl-S (O)
2-or R
35-aryl-S (O)
2-;
Perhaps R
30And R
31Be together-(CH
2)
4-5-,-(CH
2)
2-O-(CH
2)
2-or-(CH
2)
2-N (R
38)-(CH
2)
2-and form ring with its nitrogen that is connected;
R
32Be 1 to 3 be independently selected from following substituent group: H ,-OH, halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl, R
35-aryl-O-,-SR
22,-CF
3,-OCF
3,-OCHF
2,-NR
39R
40, phenyl, R
33-phenyl, NO
2,-CO
2R
39,-CON (R
39)
2,-S (O)
2R
22,-S (O)
2N (R
20)
2,-N (R
24) S (O)
2R
22,-CN, hydroxyl-(C
1-C
6) alkyl-,-OCH
2CH
2OR
22And R
35-aryl (C
1-C
6) alkyl-O-, perhaps two R on the adjacent carbon atom
32Group forms-OCH together
2O-or-O (CH
2)
2The O-group;
R
33Be 1 to 3 and be independently selected from following substituent group: C
1-C
6Alkyl, halogen ,-CN ,-NO
2,-CF
3,-OCF
3,-OCHF
2With-O-(C
1-C
6) alkyl;
R
34Be 1 to 3 be independently selected from H, halogen ,-CF
3,-OCF
3,-OH and-OCH
3Substituent group;
R
35Be 1 to 3 and be independently selected from hydrogen, halogen, C
1-C
6Alkyl, hydroxyl, C
1-C
6Alkoxyl, phenoxy group ,-CF
3,-N (R
36)
2,-COOR
20With-NO
2Substituent group;
R
36Be independently selected from H and C
1-C
6Alkyl;
R
37Be 1 to 3 and be independently selected from following substituent group: hydrogen, halogen, C
1-C
6Alkyl, hydroxyl, C
1-C
6Alkoxyl, phenoxy group ,-CF
3,-N (R
36)
2,-COOR
20,-C (O) N (R
29)
2With-NO
2, perhaps R
37Be one or two=the O group;
R
38Be H, C
1-C
6Alkyl, R
35-aryl, R
35-aryl (C
1-C
6) alkyl-, (C
1-C
6) alkyl-SO
2Or halogen (C
1-C
6) alkyl-SO
2-;
R
39Be independently selected from: hydrogen, C
1-C
6Alkyl, C
3-C
6Cycloalkyl, (C
3-C
6) cycloalkyl (C
1-C
6) alkyl, R
33-aryl, R
33-aryl (C
1-C
6) alkyl and R
32-heteroaryl; With
R
40Be hydrogen, C
1-C
6Alkyl ,-C (O) R
20,-C (O)
2R
20,-C (O) N (R
20)
2, (C
1-C
6) alkyl-SO
2-or (C
1-C
6) alkyl-SO
2-NH-;
Perhaps R
39And R
40Form azetidinyl, pyrrolidinyl, piperidyl, piperazinyl or morpholine basic ring with the nitrogen that it connected.
24. method as claimed in claim 2, wherein said H
3Receptor antagonist/agonist is the chemical compound of formula (XV)
Or acceptable salt of its pharmacy or solvate,
Wherein, in formula (XV):
A ' is 0 to 3;
B ' is 0 to 3;
N ' is 1,2 or 3;
P ' is 1,2 or 3;
R ' is 0,1,2 or 3;
X ' is a key or C
1-C
6Alkylidene;
M
1Be CH or N;
M
2Be C (R
3) or N;
Condition is to work as M
2When being N, p ' is not 1; And when r ' is 0, M
2Be C (R
3); And p ' is 1 to 4 with r ' sum;
Y ' is-C (=O)-,-C (=S)-,-(CH
2)
Q '-,-NR
4C (=O)-,-C (=O) NR
4-,-C (=O) CH
2-,-SO
1-2-,-C (=N-CN)-NH-or-NH-C (=N-CN)-; Condition is to work as M
1When being N, Y ' is not-NR
4C (=O)-or-NH-C (=N-CN)-; And work as M
2When being N, Y ' is not-C (=O) NR
4-or-C (=N-CN)-NH-;
Q ' is 1 to 5, and condition is to work as M
1And M
2When the two was N, q ' was not 1;
Z ' is a key, C
1-C
6Alkylidene, C
2-C
6Alkenylene ,-C (=O)-,-CH (CN)-or-CH
2C (=O) NR
4-;
R
1Be
Q ' is-N (R
8)-,-S-or-O-;
K ' is 0,1,2,3 or 4;
K1 is 0,1,2 or 3;
K2 is 0,1 or 2;
Dotted line is represented optional pair of key;
R and R
7Be independently selected from: H, C
1-C
6Alkyl, halogen (C
1-C
6) alkyl-, C
1-C
6Alkoxyl, (C
1-C
6) alkoxyl-(C
1-C
6) alkyl-, (C
1-C
6)-alkoxyl-(C
1-C
6) alkoxyl, (C
1-C
6) alkoxyl-(C
1-C
6) alkyl-SO
0-2, R
32-aryl (C
1-C
6) alkoxyl-, R
32-aryl-(C
1-C
6) alkyl-, R
32-aryl, R
32-aryloxy group, R
32-heteroaryl, (C
3-C
6) cycloalkyl, (C
3-C
6) cycloalkyl-(C
1-C
6) alkyl, (C
3-C
6) cycloalkyl-(C
1-C
6) alkoxyl, (C
3-C
6) cycloalkyl-oxygen base-, R
37-heterocycle-alkyl, N (R
30) (R
31)-(C
1-C
6) alkyl-,-N (R
30) (R
31) ,-NH-(C
1-C
6) alkyl-O-(C
1-C
6) alkyl ,-NHC (O) NH (R
29), R
29-S (O)
0-2-, halogen (C
1-C
6) alkyl-S (O)
0-2-, N (R
30) (R
31)-(C
1-C
6) alkyl-S (O)
0-2-, benzoyl, (C
1-C
6) alkoxyl-carbonyl, R
37-Heterocyclylalkyl-N (R
29)-C (O)-, (C
1-C
6) alkyl-N (R
29)-C (O)-, (C
1-C
6) alkyl-N (C
1-C
6Alkoxyl)-C (O)-and-C (=NOR
36) R
36And when this optional pair of key do not exist, R
7But OH;
R
8Be H, C
1-C
6Alkyl, halogen (C
1-C
6) alkyl-, (C
1-C
6) alkoxyl-(C
2-C
6) alkyl-, R
32-aryl (C
1-C
6) alkyl-, R
32-aryl, R
32-heteroaryl, R
32-heteroaryl (C
1-C
6) alkyl-, (C
3-C
6) cycloalkyl, (C
3-C
6) cycloalkyl-(C
1-C
6) alkyl, R
37-Heterocyclylalkyl, R
37-Heterocyclylalkyl (C
1-C
6) alkyl, N (R
30) (R
31)-(C
2-C
6) alkyl-, R
29-S (O)
2-, halogen (C
1-C
6) alkyl-S (O)
2-, R
29-S (O)
0-1-(C
2-C
6) alkyl-, halogen (C
1-C
6) alkyl-S (O)
0-1-(C
2-C
6) alkyl-, (C
1-C
6) alkyl-N (R
29)-SO
2-or R
32-heteroaryl-SO
2
R
2Be that to have 1 or 2 hetero atom and all the other annular atoms that is independently selected from N or N-O be six of carbon-member's heteroaryl ring; Having 1,2 or 3 hetero atom and all the other annular atoms that is independently selected from N, O or S is five of carbon-member's heteroaryl ring; R
32-quinolyl; R
32-aryl;
Or Heterocyclylalkyl; Wherein this six-member heteroaryl ring or this five-member heteroaryl ring can be chosen wantonly through R
6Replace;
R
3Be H, halogen, C
1-C
6Alkyl ,-OH or (C
1-C
6) alkoxyl;
R
4Be independently selected from: hydrogen, C
1-C
6Alkyl, C
3-C
6Cycloalkyl, (C
3-C
6) cycloalkyl (C
1-C
6) alkyl, R
33-aryl, R
33-aryl (C
1-C
6) alkyl and R
33-heteroaryl;
R
5Be hydrogen, C
1-C
6Alkyl ,-C (O) R
20,-C (O)
2R
20,-C (O) N (R
20)
2, R
33-aryl (C
1-C
6) alkyl or (C
1-C
6) alkyl-SO
2-;
R
6Be 1 to 3 and be independently selected from following substituent group :-OH, halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl ,-CF
3,-NR
4R
5,-(C
1-C
6) alkyl-NR
4R
5, phenyl, R
33-phenyl, NO
2,-CO
2R
4,-CON (R
4)
2,-NHC (O) N (R
4)
2, R
32-heteroaryl-SO
2-NH-, R
32-aryl-(C
1-C
6) alkyl-NH-, R
32-heteroaryl-(C
1-C
6) alkyl-NH-, R
32-heteroaryl-NH-C (O)-NH-and R
37-heterocycle-alkyl-N (R
29)-C (O)-;
R
12Be independently selected from C
1-C
6Alkyl, hydroxyl, C
1-C
6Alkoxyl or fluorine, condition are to work as R
12When being hydroxyl or fluorine, R then
12Be not binding on the carbon of adjacent nitrogen; Perhaps R
12Formation is the C to another ring carbon from a ring carbon
1To C
2The alkyl bridge;
R
13Be independently selected from C
1-C
6Alkyl, hydroxyl, C
1-C
6Alkoxyl or fluorine, condition are to work as R
13When being hydroxyl or fluorine, R then
13Be not binding on the carbon of adjacent nitrogen; Perhaps form the C to another ring carbon from a ring carbon
1To C
2The alkyl bridge; Perhaps R
13For=O;
R
20Be independently selected from hydrogen, C
1-C
6Alkyl or aryl, wherein this aryl can choose wantonly through from 1 to 3 be independently selected from halogen ,-CF
3,-OCF
3, hydroxyl or methoxyl group group replace; Perhaps when there being two R
20During group, described two R
20Group can form five Yuans or six element heterocycles with the nitrogen of its bond;
R
22Be C
1-C
6Alkyl, R
34-aryl or Heterocyclylalkyl;
R
24Be H, C
1-C
6Alkyl ,-SO
2R
22Or R
34-aryl;
R
25Be independently selected from: C
1-C
6Alkyl, halogen ,-CF
3,-OH, C
1-C
6Alkoxyl, (C
1-C
6) alkyl-C (O)-, aryl-C (O)-, N (R
4) (R
5)-C (O)-, N (R
4) (R
5)-S (O)
1-2-, halogen-(C
1-C
6) alkyl-or halogen-(C
1-C
6) alkoxyl-(C
1-C
6) alkyl-;
R
29Be H, C
1-C
6Alkyl, R
35-aryl or R
35-aryl (C
1-C
6) alkyl-;
R
30Be H, C
1-C
6Alkyl-, R
35-aryl or R
35-aryl (C
1-C
6) alkyl-;
R
31Be H, C
1-C
6Alkyl-, R
35-aryl, R
35-aryl (C
1-C
6) alkyl-, (C
1-C
6) alkyl-C (O)-, R
35-aryl-C (O)-, N (R
4) (R
5)-C (O)-, (C
1-C
6) alkyl-S (O)
2-or R
35-aryl-S (O)
2-;
Perhaps R
30And R
31Be together-(CH
2)
4-5-,-(CH
2)
2-O-(CH
2)
2-or-(CH
2)
2-N (R
29)-(CH
2)
2-and form ring with its nitrogen that is connected;
R
32Be 1 to 3 be independently selected from following substituent group: H ,-OH, halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl, R
35-aryl-O-,-SR
22,-CF
3,-OCF
3,-OCHF
2,-NR
4R
5, phenyl, R
33-phenyl, NO
2,-CO
2R
4,-CON (R
4)
2,-S (O)
2R
22,-S (O)
2N (R
20)
2,-N (R
24) S (O)
2R
22,-CN, hydroxyl-(C
1-C
6) alkyl-,-OCH
2CH
2OR
22And R
35-aryl (C
1-C
6) alkyl-O-, wherein this aromatic yl group can be chosen wantonly through the halogen of 1 to 3 independence through selecting and replace;
R
33Be 1 to 3 and be independently selected from C
1-C
6Alkyl, halogen ,-CN ,-NO
2,-OCHF
2With-O-(C
1-C
6) substituent group of alkyl;
R
34Be 1 to 3 be independently selected from H, halogen ,-CF
3,-OCF
3,-OH and-OCH
3Substituent group;
R
35Be 1 to 3 and be independently selected from hydrogen, halogen, C
1-C
6Alkyl, hydroxyl, C
1-C
6Alkoxyl, phenoxy group ,-CF
3,-N (R
36)
2,-COOR
20With-NO
2Substituent group;
R
36Be independently selected from H and C
1-C
6Alkyl; With
R
37Be independently selected from H, C
1-C
6Alkyl and (C
1-C
6) alkoxy carbonyl.
25. method as claimed in claim 2, wherein said H
3Receptor antagonist/agonist is the chemical compound of formula (XVI)
Or acceptable salt of its pharmacy or solvate,
Wherein, in formula (XVI):
(A) R
1Be selected from:
(1) aryl;
(2) heteroaryl;
(3) Heterocyclylalkyl
(4) alkyl;
(5)-C(O)N(R
4B)
2；
(6) cycloalkyl;
(7) aryl alkyl;
(8) heteroaryl heteroaryl; Or
(9) one are selected from following group:
The benzyl ring of the benzyl ring of the benzyl ring of the benzyl ring of the aryl moiety of described aryl (referring to (A) (1) above), heteroaryl (referring to (A) (2) above), aryl alkyl (referring to (A) (7) above), formula II (referring to (A) (9) above), formula III (referring to (A) (9) above), formula IVB (referring to (A) (9) above) or formula IVD (referring to (A) (9) above) can be chosen wantonly and be independently selected from following substituent group through 1 to 3 and replace:
(1) halogen;
(2) hydroxyl;
(3) lower alkoxy;
(4)-the O aryl;
(5)-SR
22；
(6)-CF
3；
(7)-OCF
3；
(8)-OCHF
2；
(9)-NR
4R
5；
(10) phenyl;
(11)NO
2，
(12)-CO
2R
4；
(13)-CON (R
4)
2, each R wherein
4Can be identical or different;
(14)-S(O)
2R
22；
(15)-S (O)
2N (R
20)
2, each R wherein
20Can be identical or different;
(16)-N(R
24)S(O)
2R
22；
(17)-CN；
(18)-CH
2OH；
(19)-OCH
2CH
2OR
22；
(20) alkyl;
(21) phenyl that is substituted, wherein this phenyl have 1 to 3 be independently selected from alkyl, halogen ,-CN ,-NO
2,-OCHF
2The substituent group of ,-O alkyl;
(22)-the O alkylaryl (preferably-the O alkyl phenyl or-phenyl of O alkyl-be substituted, for example-OCH
2Dichlorobenzene base, for example-OCH
2-2, the 6-Dichlorobenzene base or-OCH
2-2-chloro-6-fluorophenyl), wherein this aromatic yl group can be chosen wantonly through the halogen replacement of 1 to 3 independence through selecting; Or
(23) phenyl;
(B) X ' be selected from alkyl (for example ,-(CH
2)
Q '-or branched alkyl) or-S (O)
2-;
(C) Y ' expression
(that is, Y ' expression one is from M for (1) one singly-bound
1To M
2Direct key); Or
(2) Y ' be selected from-C (O)-,-C (S)-,-(CH
2)
Q '-or-NR
4C (O)-; Condition is:
(a) work as M
1When being N, then Y ' is not-NR
4C (O)-; With
(b) when Y ' is a key, M then
1And M
2The two is carbon;
(D) M
1And M
2Be independently selected from C or N;
(E) Z ' is selected from: C
1-C
6Alkyl ,-SO
2-,-C (O)-or-C (O) NR
4-;
(F) R
2Be selected from:
(1) having 1 or 2 hetero atom and all the other annular atoms that is independently selected from N or N-O (that is N-oxide) is six of carbon-member's heteroaryl ring;
(2) having 1 to 3 hetero atom and all the other annular atoms that is selected from nitrogen, oxygen or sulfur is five of carbon-member's heteroaryl ring; Or
(3) one alkyl groups;
(4) one aryl or be independently selected from the aryl that following substituent group replaces once 1 to 3: halogen ,-the O alkyl ,-OCF
3,-CF
3,-CN ,-NO
2,-NHC (O) CH
3Or-O (CH
2)
Q 'N (R
10A)
2
(5)-N (R
11A)
2, each R wherein
11ABe independently selected from: H, alkyl or aryl;
(6) one have the group of following formula:
Or
(7) one heteroaryl heteroaryl groups,?
These five Yuans heteroaryl rings (above (F) (2)) or six-member's heteroaryl ring (above (F) (1)) can be chosen wantonly through 1-3 and be selected from following substituent group replacement:
(a) halogen;
(b) hydroxyl;
(c) low alkyl group;
(d) lower alkoxy;
(e)-CF
3；
(f)-NR
4R
5；
(g) phenyl;
(h)-NO
2；
(i)-C (O) N (R
4)
2(each R wherein
4All identical or different);
(j)-C (O)
2R
4Or
(k) phenyl, it can be independently selected from following substituent group through 1-3 and replace: halogen ,-the O alkyl ,-OCF
3,-CF
3,-CN ,-NO
2Or-O (CH
2)
qN (R
10A)
2
(G) R
3Be selected from:
(1) aryl;
(2) heteroaryl;
(3) Heterocyclylalkyl
(4) alkyl; Or
(5) cycloalkyl;
Wherein this aryl or heteroaryl R
3Group can be chosen wantonly through 1-3 and be independently selected from following substituent group replacement:
(a) halogen;
(b) hydroxyl;
(c) lower alkoxy;
(d)-the O aryl;
(e)-SR
22；
(f)-CF
3；
(g)-OCF
3；
(h)-OCHF
2；
(i)-NR
4R
5；
(j) phenyl;
(k)-NO
2；
(l)-CO
2R
4；
(m)-CON (R
4)
2, each R wherein
4All identical or different;
(n)-S(O)
2R
22；
(o)-S (O)
2N (R
20)
2, each R wherein
20All identical or different;
(p)-N(R
24)S(O)
2R
22；
(q)-CN；
(r)-CH
2OH；
(s)-OCH
2CH
2OR
22Or
(t) alkyl;
(H) R
4Be selected from:
(1) hydrogen;
(2) C
1-C
6Alkyl;
(3) cycloalkyl;
(4) cycloalkyl-alkyl;
(5) Heterocyclylalkyl alkyl;
(6) bridge joint bicyclo-cycloalkyl ring;
(7) has the aryl of the annelated heterocycles alkyl ring that is binding on this aryl rings;
(8) aryl;
(9) aryl alkyl;
(10) alkylaryl;
(11)-(CH
2)
D 'CH (R
12A)
2, wherein d is 1 to 3, and each R
12AThe phenyl that is independently selected from phenyl or is substituted, this phenyl that is substituted can be independently selected from following substituent group through 1-3 and replace: halogen ,-the O alkyl ,-OCF
3,-CF
3,-CN or-NO
2
(12) Heterocyclylalkyl heteroaryl; Or
(13)-(C
1To C
6) alkylidene-O-R
22
This aryl R wherein
4Group, this aryl alkyl R
4The aryl moiety of group or this alkylaryl R
4The aryl moiety of group can be chosen wantonly through 1-3 and be independently selected from following substituent group replacement:
(a) halogen;
(b) hydroxyl;
(c) low alkyl group;
(d) lower alkoxy;
(e)-CF
3；
(f)-N(R
20)(R
24)，
(g) phenyl;
(h)-NO
2；
(i)-C (O) N (R
20)
2(each R wherein
20All identical or different),
(j)-C(O)R
22；
(i)-(CH
2)
K '-cycloalkyl;
(j)-(CH
2)
Q '-aryl; Or
(k)-(CH
2)
m′-OR
22；
(I) each R
4BBe independently selected from: H, heteroaryl, alkyl, thiazolinyl, have the group of following formula
Aryl alkyl or wherein this aryl moiety can be independently selected from the aryl alkyl that the substituent group of halogen replaces through 1-3;
(J) R
5Be selected from: hydrogen, C
1-C
6Alkyl ,-C (O) R
20,-C (O)
2R
20,-C (O) N (R
20)
2(each R wherein
20Can be identical or different);
(K) each R
10ABe independently selected from H or C
1To C
6Alkyl or each R
10ANitrogen-atoms with its bond forms 4 to 7 element heterocycle alkyl rings;
(L) R
12Be
(1) be selected from alkyl, hydroxyl, alkoxyl or fluorine, condition is to work as R
12When being hydroxyl or fluorine, R then
12Be not binding on the carbon of adjacent nitrogen; Or
(2) R
12Formation is the alkyl bridge to another ring carbon from a ring carbon;
(M) R
13Be
(1) be selected from alkyl, hydroxyl, alkoxyl or fluorine, condition is to work as R
13When being hydroxyl or fluorine, R then
13Be not binding on the carbon of adjacent nitrogen; Or
(2) R
13Formation is the alkyl bridge to another ring carbon from a ring carbon;
(N) R
20Be selected from hydrogen, alkyl or aryl, wherein this aromatic yl group can be chosen wantonly through being independently selected from following group from 1 to 3 and replace: halogen ,-CF
3,-OCF
3, hydroxyl or methoxyl group; Maybe when there being two R
20During group, described two R
20Group forms five Yuans or six element heterocycles with the nitrogen of its bond;
(O) R
22Be selected from: Heterocyclylalkyl, alkyl or aryl, wherein this aromatic yl group can choose wantonly through 1-3 be independently selected from halogen ,-CF
3,-OCF
3, hydroxyl or methoxyl group group replace;
(P) R
24Be selected from: hydrogen, alkyl ,-SO
2R
22Or aryl, wherein this aromatic yl group can choose wantonly through 1-3 be independently selected from halogen ,-CF
3,-OCF
3, hydroxyl or methoxyl group group replace;
(Q) a ' is 0 to 2;
(R) b ' is 0 to 2;
(S) k ' is 1 to 5;
(T) m ' is 2 to 5;
(U) n ' is 1,2 or 3, and condition is when M1 is N, and then n ' is not 1;
(V) p ' is 1,2 or 3, and condition is to work as M
2When being N, then p ' is not 1;
(W) q ' is 1 to 5; With
(X) r ' is 1,2 or 3, and condition is when r ' is 2 or 3, then M
2Be C and ' p is 1.
26. method as claimed in claim 2, wherein said H
3Receptor antagonist/agonist is the chemical compound of formula (XVII)
Or acceptable salt of its pharmacy or solvate,
Wherein, in formula XVII:
Dotted line is represented optional pair of key;
A ' is 0 to 3;
B ' is 0 to 3;
N ' is 1,2 or 3;
P ' is 1,2 or 3;
R ' is 0,1,2 or 3;
Condition is to work as M
2When being N, p ' is not 1; And when r ' is 0, M
2Be C; And p ' is 1 to 4 with r ' sum;
A ' is a key or C
1-C
6Alkylidene;
M
1Be CH or N;
M
2Be C (R
3) or N;
Y ' is-C (=O)-,-C (=S)-,-(CH
2)
Q '-,-NR
4C (=O)-,-C (=O) NR
4-,-C (=O) CH
2-,-SO
1-2-,-NH-C (=N-CN)-or-C (=N-CN)-NH-; Condition is to work as M
1When being N, Y ' is not-NR
4C (=O)-or-NH-C (=N-CN)-; And work as M
2When being N, Y ' is not-C (=O) NR
4-or-C (=N-CN)-NH-;
Q ' is 1 to 5, and condition is to work as M
1And M
2When the two was N, q ' was not 1;
Z ' is a key, C
1-C
6Alkylidene, C
1-C
6Alkenylene ,-C (=O)-,-CH (CN)-or-CH
2C (=O) NR
4-;
R
1Be
K ' is 0,1,2,3 or 4;
K1 is 0,1,2 or 3;
K2 is 0,1 or 2;
R is H, C
1-C alkyl, hydroxyl-(C
2-C
6) alkyl-, halogen-(C
1-C
6) alkyl-, halogen-(C
1-C
6) alkoxyl-(C
1-C
6) alkyl-, R
29-O-C (O)-(C
1-C
6) alkyl-, (C
1-C
6) alkoxyl-(C
1-C
6) alkyl-, N (R
30) (R
31)-(C
1-C
6) alkyl-, (C
1-C
6) alkoxyl-(C
1-C
6) alkoxyl-(C
1-C
6) alkyl-, R
32-aryl, R
32-aryl (C
1-C
6) alkyl-, R
32-aryloxy group (C
1-C
6) alkyl-, R
32-heteroaryl, R
32-heteroaryl (C
1-C
6) alkyl-, (C
3-C
6) cycloalkyl, (C
3-C
6) cycloalkyl (C
1-C
6) alkyl-, N (R
30) (R
31)-C (O)-(C
1-C
6) alkyl-or Heterocyclylalkyl (C
1-C
6) alkyl-;
R
2Be that to have 1 or 2 hetero atom and all the other annular atoms that is independently selected from N or N-O be six of carbon-member's heteroaryl ring; Having 1,2 or 3 hetero atom and all the other annular atoms that is independently selected from N, O or S is five of carbon-member's heteroaryl ring; R
32-quinolyl; R
32-aryl; Heterocyclylalkyl;
Wherein this six-member heteroaryl ring or this five-member heteroaryl ring are optional by R
6Replace;
X ' is C or N;
Q ' is a key or C
1-C
6Alkylidene;
Q
1 'Be a key, C
1-C
6Alkylidene or-N (R
4)-;
R
3Be H, halogen, C
1-C
6Alkyl ,-OH or (C
1-C
6) alkoxyl;
R
4Be independently selected from: hydrogen, C
1-C
6Alkyl, C
3-C
6Cycloalkyl, (C
3-C
6) cycloalkyl (C
1-C
6) alkyl, R
33-aryl, R
33-aryl (C
1-C
6) alkyl and R
32-heteroaryl;
R
5Be hydrogen, C
1-C
6Alkyl ,-C (O) R
20,-C (O)
2R
20,-C (O) N (R
20)
2Or (C
1-C
6) alkyl-SO
2-;
R
6Be 1-3 and be independently selected from following substituent group :-OH, halogen, C
1-C
6Alkyl-, C
1-C
6Alkoxyl, C
1-C
6Alkylthio group ,-CF
3,-NR
4R
5, phenyl, R
33-phenyl, NO
2,-CO
2R
4,-CON (R
4)
2,
R
12Be independently selected from C
1-C
6Alkyl, hydroxyl, C
1-C
6Alkoxyl or fluorine, condition are to work as R
12When being hydroxyl or fluorine, R then
12Be not binding on the carbon of adjacent nitrogen; Perhaps R
12Formation is the C to another ring carbon from a ring carbon
1To C
2The alkyl bridge;
R
13Be independently selected from C
1-C
6Alkyl, hydroxyl, C
1-C
6Alkoxyl or fluorine, condition are to work as R
13When being hydroxyl or fluorine, R then
13Be not binding on the carbon of adjacent nitrogen; Perhaps form the C to another ring carbon from a ring carbon
1To C
2The alkyl bridge; Perhaps R
13For=O;
R
20Be independently selected from hydrogen, C
1-C
6Alkyl or aryl, wherein this aromatic yl group can choose wantonly through from 1 to 3 be independently selected from halogen ,-CF
3,-OCF
3, hydroxyl or methoxyl group group replace; Perhaps when there being two R
20During group, described two R
20Group forms five Yuans or six element heterocycles with the nitrogen of its bond;
R
22Be C
1-C
6Alkyl, R
34-aryl or Heterocyclylalkyl;
R
24Be H, C
1-C
6Alkyl ,-SO
2R
22Or R
34-aryl;
R
25Be independently selected from: C
1-C
6Alkyl, halogen ,-CF
3,-OH, C
1-C
6Alkoxyl, (C
1-C
6) alkyl-C (O)-, aryl-C (O)-, N (R
4) (R
5)-C (O)-, N (R
4) (R
5)-S (O)
1-2-, halogen-(C
1-C
6) alkyl-or halogen-(C
1-C
6) alkoxyl-(C
1-C
6) alkyl-;
R
29Be H, C
1-C
6Alkyl, R
35-aryl or R
35-aryl (C
1-C
6) alkyl-;
R
30Be H, C
1-C
6Alkyl-, R
35-aryl or R
35-aryl (C
1-C
6) alkyl-;
R
31Be H, C
1-C
6Alkyl-, R
35-aryl, R
35-aryl (C
1-C
6) alkyl-, (C
1-C
6) alkyl-C (O)-, R
35-aryl-C (O)-, N (R
4) (R
5)-C (O)-, (C
1-C
6) alkyl-S (O)
2-or R
35-aryl-S (O)
2-;
Perhaps R
30And R
31Be together-(CH
2)
4-5-,-(CH
2)
2-O-(CH
2)
2-or-(CH
2)
2-N (R
29)-(CH
2)
2-and form ring with its nitrogen that is connected;
R
32Be 1-3 be independently selected from following substituent group: H ,-OH, halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl, R
35-aryl-O-,-SR
22,-CF
3,-OCF
3,-OCHF
2,-NR
4R
5, phenyl, R
33-phenyl, NO
2,-CO
2R
4,-CON (R
4)
2,-S (O)
2R
22,-S (O)
2N (R
20)
2,-N (R
24) S (O)
2R
22,-CN, hydroxyl-(C
1-C
6) alkyl-,-OCH
2CH
2OR
22And R
35-aryl (C
1-C
6) alkyl-O-, wherein this aromatic yl group can be chosen wantonly through 1-3 independent halogen through selecting and replace;
R
33Be 1-3 and be independently selected from C
1-C
6Alkyl, halogen ,-CN ,-NO
2,-OCHF
2With-O-(C
1-C
6) substituent group of alkyl;
R
34Be 1-3 be independently selected from H, halogen ,-CF
3,-OCF
3,-OH and-OCH
3Substituent group;
R
35Be 1-3 and be independently selected from following substituent group: hydrogen, halogen, C
1-C
6Alkyl, hydroxyl, C
1-C
6Alkoxyl, phenoxy group ,-CF
3,-N (R
36)
2,-COOR
20With-NO
2With
R
36Be independently selected from H and C
1-C
6Alkyl.
27. the method for claim 1, wherein said cholesterol reducing agent is a bile acid chelating agent.
28. method as claimed in claim 27, wherein said bile acid chelating agent is a colestyramine.
29. the method for claim 1, wherein said cholesterol reducing agent are the HMG-CoA reductase inhibitors.
30. method as claimed in claim 29, wherein said HMG-CoA reductase inhibitor is selected from: lovastatin, pravastatin, simvastatin, atorvastatin, fluvastatin, cerivastatin, CI-981, auspicious his spit of fland (rivastatin), rosuvastatin and the Pitavastatin of cutting down.
31. the method for claim 1, wherein said cholesterol reducing agent are nicotinic acid (niacin usp) and/or nicotinic acid agonist.
32. the method for claim 1, wherein said cholesterol reducing agent are the activators of peroxisome proliferation-activated receptor.
33. method as claimed in claim 32, wherein said activator are Bei Te (fibrate).
34. method as claimed in claim 33, wherein said Bei Te is clofibrate, gemfibrozil, ciprofibrate, bezafibrate, clinofibrate, binifibrate, lifibrol or fenofibrate.
35. method as claimed in claim 2, it further comprises the HMG-CoA reductase inhibitor of effective dose.
36. method as claimed in claim 35, wherein said HMG-CoA reductase inhibitor is selected from: lovastatin, pravastatin, fluvastatin, simvastatin, atorvastatin, cerivastatin, Pitavastatin and rosuvastatin.
37. method as claimed in claim 2, it further comprises PPAR activator, nicotinic acid and/or nicotinic acid receptor agonists or bile acid chelating agent as the 3rd active constituent.
38. the method for claim 1, it further comprises obesity controller.
39. method as claimed in claim 2, it further comprises obesity controller.
40. method as claimed in claim 38, wherein said obesity controller is selected from: amfepramone, Mazindol, phenylpropanolamine, phentermine, phendimetrazine, tartaric acid amphetamines (phendaminetartrate), metamfetamine, phendimetrazine tartrate, sibutramine, fenfluramine, dexfenfluramine, fluoxetine, fluvoxamine, (paroxtine) stung in the Paro west, befloxatone, moclobemide, brofaromine phenoxthine (phenoxathine), esuprone, than Fu Er (befol), Toloxatone, pirlindole, amiflamine, match Cray bright (sercloremine), bazinaprine, lazabemide, milacemide, caroxazone and orlistat.
41. method as claimed in claim 40, it further comprises the HMG-CoA reductase inhibitor.
42. treatment, prevention or improve the method for the symptom that the mammal non-alcoholic fatty liver disease disease (NAFLD) that needs is arranged, Gu it comprises at least a sterin of using effective dose or the step of 5-α-alkanol absorption inhibitor or the acceptable salt of its pharmacy or its solvate.
43. treatment, prevention or improvement have the method for the symptom of the mammal non-alcoholic fatty liver disease disease (NAFLD) that needs, it comprises at least a H that uses effective dose
3The step of receptor antagonist/inverse agonist or the acceptable salt of its pharmacy or its solvate.
44. prevention or improvement have the symptom of the mammalian liver steatosis that needs or the method for development, it comprises the step to the therapeutic combination of described administration effective dose, and described therapeutic combination comprises at least a cholesterol reducing agent and/or at least a H
3Receptor antagonist/inverse agonist.
45. method as claimed in claim 44, it further comprises the HMG-CoA reductase inhibitor.
46, prevention or improvement have the method for mammal non-alcoholic stellato-hepatitis (NASH) development that needs, and it is by giving the therapeutic combination of described administration effective dose, and described therapeutic combination comprises at least a H
3Receptor antagonist/inverse agonist and optional at least a cholesterol reducing agent.
47. method as claimed in claim 46, it further comprises the HMG-CoA reductase inhibitor.
48. prevention or improve has the method for the development of the mammal cirrhosis that needs or hepatocarcinoma, it comprises the step to the therapeutic combination of described administration effective dose, and described therapeutic combination comprises at least a cholesterol reducing agent and/or at least a H
3Receptor antagonist/inverse agonist.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US75271005P | 2005-12-21 | 2005-12-21 | |
| US60/752,710 | 2005-12-21 | ||
| US60/787,048 | 2006-03-29 | ||
| US60/836,642 | 2006-08-09 | ||
| US60/855,178 | 2006-10-30 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101426496A true CN101426496A (en) | 2009-05-06 |
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ID=40616640
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2006800516127A Pending CN101426496A (en) | 2005-12-21 | 2006-12-19 | Treatment of nonalcoholic fatty liver disease using cholesterol lowering agents and H3 receptor antagonist/inverse agonist |
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| Country | Link |
|---|---|
| CN (1) | CN101426496A (en) |
| ZA (1) | ZA200805764B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104780918A (en) * | 2013-03-01 | 2015-07-15 | 浙江海正药业股份有限公司 | Azetidinone compound used for prevention and/or treatment of hepatitis c, and composition of compound |
-
2006
- 2006-12-19 CN CNA2006800516127A patent/CN101426496A/en active Pending
-
2008
- 2008-07-01 ZA ZA200805764A patent/ZA200805764B/en unknown
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104780918A (en) * | 2013-03-01 | 2015-07-15 | 浙江海正药业股份有限公司 | Azetidinone compound used for prevention and/or treatment of hepatitis c, and composition of compound |
| CN104780918B (en) * | 2013-03-01 | 2017-03-08 | 浙江海正药业股份有限公司 | For preventing and/or treating azetidinone compounds of hepatitis C and combinations thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| ZA200805764B (en) | 2009-08-26 |
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