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CN101189005A - Combinations of squalene synthase inhibitors and HMG-CoA reductase inhibitors for the treatment of hyperlipidemia - Google Patents

Combinations of squalene synthase inhibitors and HMG-CoA reductase inhibitors for the treatment of hyperlipidemia Download PDF

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CN101189005A
CN101189005A CNA2006800197386A CN200680019738A CN101189005A CN 101189005 A CN101189005 A CN 101189005A CN A2006800197386 A CNA2006800197386 A CN A2006800197386A CN 200680019738 A CN200680019738 A CN 200680019738A CN 101189005 A CN101189005 A CN 101189005A
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西本诚之
兔泽隆一
和田岳夫
石川英一郎
西俊哉
山川弘子
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Takeda Pharmaceutical Co Ltd
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Takeda Chemical Industries Ltd
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Abstract

本发明提供用于预防和/或治疗高脂血症的药物组合物，其包括有效量的角鲨烯合酶抑制剂和HMG－CoA还原酶抑制剂的组合。而且，本发明还提供用于预防和/或治疗由给予HMG－CoA还原酶抑制剂引起的肝毒性的方法，其包括给予有效量的角鲨烯合酶抑制剂。The present invention provides a pharmaceutical composition for preventing and/or treating hyperlipidemia, which comprises a combination of effective doses of squalene synthase inhibitors and HMG-CoA reductase inhibitors. Furthermore, the present invention also provides a method for preventing and/or treating liver toxicity caused by administration of an HMG-CoA reductase inhibitor, which comprises administering an effective amount of a squalene synthase inhibitor.

Description

Be used for the treatment of the combination of the squalene synthase inhibitor and the HMG-CoA reductase inhibitor of hyperlipemia
Technical field
The present invention is based on following discovery; N-[[(3R; 5S)-1-(3-acetoxyl group-2; the 2-dimethyl propyl)-7-chloro-5-(2; the 3-Dimethoxyphenyl)-2-oxo-1; 2; 3; 5-tetrahydrochysene-4; 1-benzo oxygen azepine -3-yl] acetyl group] piperidines-4-acetic acid (hereinafter being abbreviated as compounds X) is squalene synthase inhibitor (hereinafter writing " SSI ") and preventive and/or the therapeutic agent that can be used as hyperlipemia; it can strengthen the effect of HMG-CoA reductase inhibitor; the HMG-CoA reductase inhibitor (for example also claims " inhibin "; atorvastatin; lovastatin; simvastatin; pravastatins etc.), present HMG-CoA reductase inhibitor is widely used as the preventive and/or the therapeutic agent of hyperlipemia clinically.The invention still further relates to by using the method for squalene synthase inhibitor and the mammiferous hyperlipemia of HMG-CoA reductase inhibitor combined therapy etc., described mammal comprises the animal or human.
Background technology
Hyperlipemia is meant the state that the serum lipids concentration abnormality raises.Serum lipids comprises cholesterol, phospholipid, triglyceride (neutral fat) etc.Particularly, clinical problem appears when cholesterol and triglyceride rising.Many epidemiological investigations show that hypercholesterolemia is one of three kinds of risk factors of atheromatosis, and described atheromatosis is as with the myocardial infarction of hypertension and smoking, angina pectoris, cerebral infarction etc.Therefore, suitably controlling blood cholesterol level is very important for the atheromatosis that prevents or treat as ischemic heart desease.Up to now, above-mentioned HMG-CoA reductase inhibitor has been widely used in clinical, as reducing blood cholesterol levels to prevent and/or treat the medicine of hyperlipemia.
Current treatment guide (NCEP-ATP III about blood fat control, USA, the guides of Japan atherosclerosis association etc.) suggestion is for there being high-risk to develop into the patient of ischemic heart desease, and the therapeutic goal concentration of low-density lipoprotein cholesterol (LDL-C) is less than 100mg/dl.And the normal level of triglyceride is less than 150mg/dl, and therefore lipid is controlled in the suggestion strictness.Yet, from showing about effective result of detection on a large scale who reduces the LDL-C therapy recently, reducing the LDL-C level is effectively for the danger that reduction develops into ischemic heart desease, even when LDL-C level during less than 100mg/dl (PROVE-IT detects, TNT detection etc.).
On the other hand, according to the following fact, the HMG-CoA reductase inhibitor has the clinical danger that has side effects, and the described fact is that the HMG-CoA reductase inhibitor is the medicine that suppresses the synthetic of body inner cholesterol and reduction blood cholesterol concentration by HMG-CoA reductase activity in the inhibition cholesterol biosynthesis pathway.Particularly, when the HMG-CoA reductase is suppressed, not only essential composition of the biosynthesis of cholesterol but also some other live bodies such as the biosynthesis of ubiquinone, dolichol and haemachrome A also are suppressed, and make to have caused undesirable side effect (for example, rhabdomyolysis, myalgia etc.).And, reported side effect as gastrointestinal disturbance regulating liver-QI function reduction.Therefore, according to dosage that liver toxicity or musclar toxicity occur and the safety zone in the animal and human, determine to give the HMG-CoA reductase inhibitor maximal dose (for example, atorvastatin and simvastatin: at the most every day 80mg; Pravastatin: at the most every day 40mg; Pitavastatin: at the most every day 2mg).Yet, owing to give the HMG-CoA reductase inhibitor to the maximal dose of people's administration these toxicity are arranged probably, so do not advocate HMG-CoA reductase inhibitor treatment with high dose with approval.Therefore, when in actual administration therapeutic method, giving the HMG-CoA reductase inhibitor and be used for the treatment of hyperlipemia, when initial, give to have only then when when not obtaining enough effects, just giving higher dosage usually than low dosage with low dosage.The general HMG-CoA reductase inhibitor of as far as possible avoiding giving high dose.
In order to meet the requirement of blood fat control in the current therapeutic scheme, desired is that the HMG-CoA reductase inhibitor that gives higher dosage will effectively reduce LDL-C.On the other hand, what be concerned about is that the high-dose therapy method of HMG-CoA reductase inhibitor will increase and toxicity occur, as the danger of liver toxicity etc.And, for HMG-CoA reductase inhibitor and the combination that is used for the fibrate of triglyceride reducing, reported dangerous increase such as musclar toxicity such as rhabdomyolysis.
In the case, consider HMG-CoA reductase inhibitor and novel drugs combined therapy, it can treat independent use HMG-CoA reductase inhibitor can not make the LDL cholesterol reach the patient of therapeutic goal concentration, reduce the toxicity risk of high-dose therapy and further improve the TL that comprises triglyceride, described combined therapy is important selection for preventing and/or treating hyperlipemia.
Summary of the invention
The present invention finds unexpectedly, do the time spent the various of research compounds X, with give the HMG-CoA reductase inhibitor separately and compare, when this chemical compound and the combination of HMG-CoA reductase inhibitor, can cholesterol reducing and triglyceride, and reduced the liver toxicity that the HMG-CoA reductase inhibitor causes, and finished the present invention.
That is, the present invention relates to:
(1) be used to prevent and/or treat the method for hyperlipemia, it comprises the squalene synthase inhibitor and the HMG-CoA reductase inhibitor of the mammal effective dose of suffering from hyperlipemia;
(2) according to the method for above-mentioned (1), wherein the high dose with approval dosage (approved dosage) gives HMG-CoA reductase inhibitor;
(3) according to the method for above-mentioned (2), wherein the maximal dose with approval dosage gives HMG-CoA reductase inhibitor;
(4) be used to prevent and/or treat by giving the hepatotoxic method that the HMG-CoA reductase inhibitor causes, it comprises the squalene synthase inhibitor that the mammal that gives the HMG-CoA reductase inhibitor is given effective dose, to suppress by giving the toxicity that the HMG-CoA reductase inhibitor causes;
(5) according to the method for above-mentioned (4), wherein mammal suffers from hyperlipemia;
(6) according to the method for above-mentioned (1) or (2), wherein squalene synthase inhibitor is the chemical compound that following formula is represented:
Figure S2006800197386D00031
Wherein, R 1Be hydrogen atom or optional substituted alkyl, R 2And R 3Identical or different; and be hydrogen atom, optional substituted alkyl or optional substituted heterocyclic group; X ' but be the group that comprises the heterocycle residue of optional esterified carboxyl, optional substituted carbamoyl, optional substituted hydroxyl, optional substituted amino or the optional substituted hydrogen atom that contains deprotonation; ring A is optional substituted phenyl ring or optional substituted heterocycle; the ring J ' for contain 3 or still less hetero atom as the ring composed atom 7 yuan or 8 yuan of heterocycles, and the ring J ' also can contain except that R 1, R 2, R 3And the outer substituent group of X ';
(7) according to the method for above-mentioned (1) or (2), wherein squalene synthase inhibitor is N-[[(3R, 5S)-1-(3-acetoxyl group-2, the 2-dimethyl propyl)-7-chloro-5-(2, the 3-Dimethoxyphenyl)-and 2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzo oxygen azepine -3-yl] acetyl group] piperidines-4-acetic acid;
(8) according to the method for above-mentioned (1) or (2), wherein the HMG-CoA reductase inhibitor is one or more medicines that are selected from atorvastatin, lovastatin, simvastatin, pravastatin, fluvastatin, rosuvastatin, cerivastatin and Pitavastatin;
(9) according to the method for above-mentioned (1) or (2), the mammal that wherein suffers from hyperlipemia is the patient that the HMG-CoA reduction inhibitor agent does not tolerate;
(10) according to the method for above-mentioned (1) or (2), the mammal that wherein suffers from hyperlipemia is the high risk patient of ischemic heart desease;
(11) according to the method for above-mentioned (1) or (2), the mammal that wherein suffers from hyperlipemia is the patient who suffers from familial hypercholesterolemia;
(12) be used to prevent and/or treat the pharmaceutical composition of hyperlipemia, it comprises the combination of the squalene synthase inhibitor and the HMG-CoA reductase inhibitor of effective dose;
(13) be used to prevent and/or treat the pharmaceutical composition of hyperlipemia, it comprises the squalene synthase inhibitor and the HMG-CoA reductase inhibitor of effective dose, and this pharmaceutical composition is prepared (compounded) or packed (packed) so that suffer from the mammal of hyperlipemia in succession or simultaneously with divided dose;
(14) according to the pharmaceutical composition of above-mentioned (12) or (13), it comprises the high dose combination with the approval dosage of HMG-CoA reductase inhibitor;
(15) according to the pharmaceutical composition of above-mentioned (12) or (13), it comprises the maximal dose combination with the approval dosage of HMG-CoA reductase inhibitor;
(16) be used to strengthen the method for the effect that prevents and/or treats hyperlipemia of HMG-CoA reductase inhibitor, it comprises the mammal of HMG-CoA reductase inhibitor of effective dose that suffered from being given of hyperlipemia, gives the squalene synthase inhibitor of effective dose;
(17) squalene synthase inhibitor is used for preventing and/or treating the purposes of the pharmaceutical composition of hyperlipemia in preparation, and described pharmaceutical composition comprises the combination of the squalene synthase inhibitor and the HMG-CoA reductase inhibitor of effective dose;
(18) squalene synthase inhibitor is used for preventing and/or treating the purposes of the pharmaceutical composition of hyperlipemia in preparation, described pharmaceutical composition comprises the squalene synthase inhibitor and the HMG-CoA reductase inhibitor of effective dose, described pharmaceutical composition is prepared or is packed so that suffer from the mammal of hyperlipemia in succession or simultaneously with divided dose;
(19) according to the method for above-mentioned (1) or (2), wherein also make up the ezetimibe that gives as the 3rd effective amount of drug;
(20) according to the pharmaceutical composition of above-mentioned (12) or (13), it also comprises the ezetimibe of combination as the 3rd effective amount of drug;
(21) be used for preventing and/or treating the purposes of the pharmaceutical composition of hyperlipemia according to the squalene synthase inhibitor of above-mentioned (17) or (18) in preparation, described pharmaceutical composition also comprises the ezetimibe of combination as the 3rd effective amount of drug; Or the like.
Compounds X is disclosed known compound, for example in JP-ANo.9-136880 (embodiment 36).Known this chemical compound has the squalene synthase inhibitory action, and a step of the inhibition cholesterol biosynthesis pathway identical with the effect of the HMG-CoA reductase inhibitor downstream of HMG-CoA reductase inhibitor action site (but be positioned at) is to suppress the biosynthesis of cholesterol, thereby reduce blood cholesterol concentration, and be useful therefore for preventing and/or treating hyperlipemia.
JP-A No.9-136880 discloses the SSI chemical compound of application, this application comprises uses the medicine of the various reduction lipids that are used to prevent and/or treat hyperlipemia of compounds X and other or the drug regimen of cholesterol reducing, wherein also relates to being used in combination the HMG-CoA reductase inhibitor.Yet, do not relate to individually dosed and comparing, the effect of the effect that is used in combination and the enhanced activity of effect (yet not disclosing pharmacology data).
And the known SSI that comprises compounds X has and reduces the musclar toxicity that the HMG-CoA reductase inhibitor causes, as the effect (WO04/064865) of rhabdomyolysis etc.And the known SSI of compounds X that comprises has the effect that increases ubiquinone, so it is effective (WO03/002147) for preventing and/or treating the organ dysfunction and the organ insufficiency that cause owing to atheromatosis and cerebrovascular disease etc.Yet, there is not report to comprise that the SSI of compounds X has for drug-induced organ toxicity, proved that especially the hepatopathy disease as the side effect of HMG-CoA reductase inhibitor has organ protection.
For the effect that is used in combination compounds X and HMG-CoA reductase inhibitor, the inventor finds to compare with individually dosed, and combination medicine-feeding can obviously improve effect and the effect to animal model, the pharmacological tests of face series as follows.From being used in combination compounds X, the effect of SSI and HMG-CoA reductase inhibitor is beyond thought and can not infers from the understanding of routine.
And the present invention finds first that also SSI and HMG-CoA reductase inhibitor can suppress the liver toxicity that the HMG-CoA reductase inhibitor causes, and state the pharmacological experiment result as follows by being used in combination compounds X.
By the discovery in the above-mentioned animal model, the inventor has obtained the present invention, and the present invention can be achieved as follows the medical science effect that prevents and/or treats hyperlipemia by being used in combination SSI and HMG-CoA reductase inhibitor.
1) more effectively realize the improvement of serum lipids, this improvement can not realize by giving HMG-CoA reductase inhibitor or SSI respectively separately.
2) can suppress the side effect of HMG-CoA reductase inhibitor, as musclar toxicity, liver toxicity etc.Therefore, can give patient safely than the routine dose HMG-CoA reductase inhibitor of high dose more.
By these good synergism, compare with independent use HMG-CoA reductase inhibitor, can more effectively control hyperlipemia with the combined therapy of SSI and HMG-CoA reductase inhibitor.Promptly, by giving HMG-CoA reductase inhibitor with the SSI combination, even with the maximal dose of HMG-CoA reductase inhibitor, can realize reducing the effect of lipid and do not have significantly liver toxicity and the musclar toxicity relevant, so the method for novel treatment hyperlipemia is provided in actual therapy with the HMG-CoA reductase inhibitor.And, can expect at present to be used in combination and can start the method that an amount with the maximal dose that surpasses approval gives the HMG-CoA reductase inhibitor with SSI.
Also do not have report and SSI to be used in combination the HMG-CoA reductase inhibitor so far and can realize above-mentioned purposes in human or animal's test.Therefore, the invention provides the novel use of squalene synthase inhibitor.
The specific embodiment of invention
The preferred embodiment of every definition is as described below among the present invention.
" hyperlipemia " is meant the state that the serum lipids concentration abnormality raises.Serum lipids comprises cholesterol, phospholipid, triglyceride (neutral fat) etc.Particularly, clinical problem appears when cholesterol and triglyceride rising." hyperlipemia " comprises hypercholesterolemia, hypertriglyceridemia etc.
As mentioned above, the present invention can obtain to the good prevention of hyperlipemia and or therapeutic effect, therefore, the present invention is fit to be applied to, especially the serious symptom hyperlipemia.For example, the present invention can advantageously be applied to following situation, the patient (mammal) who suffers from hyperlipemia for patient that the ischemic heart medical history is arranged, the high risk patient of multiple ischemic heart desease risk factor (as hypertension, diabetes, obesity and smoking) is arranged or suffers from the patient of familial hypercholesterolemia.
" HMG-CoA reductase inhibitor " among the present invention is meant so-called " inhibin ", as atorvastatin, lovastatin, simvastatin, pravastatin, fluvastatin, rosuvastatin, Pitavastatin, cerivastatin etc.
In the present invention, the term high dose of dosage " approval " that is used for the HMG-CoA reductase inhibitor is meant the higher dosage that comprises maximal dose, and when a lot of approval dosage, this term refers to multiple dosage sometimes.Generally, this dosage surpasses the dosage of HMG-CoA reductase inhibitor, and change according to different mammals, the dosage of above-mentioned HMG-CoA reductase inhibitor be generally by give separately the HMG-CoA reductase inhibitor prevent and/or suppress hyperlipemia give each mammiferous dosage (that is usual amounts).
The approval dosage of commercially available every kind of HMG-CoA reductase inhibitor is as follows at present:
10,20,40,80mg/ people/sky atorvastatin:
5,10,20,40,80mg/ people/sky simvastatin:
10,20,40,80mg/ people/sky pravastatin:
20,40,80mg/ people/sky fluvastatin:
10,20,40mg/ people/sky lovastatin:
5,10,20,40mg/ people/sky rosuvastatin:
Pitavastatin: 1,2mg/ people/sky
The example of the preferred dose of " high dose of approval dosage " includes but not limited to atorvastatin 40,80mg/ people/sky; Simvastatin 20,40,80mg/ people/sky (more preferably 40,80mg/ people/sky); Pravastatin 40,80mg/ people/sky; Fluvastatin 40,80mg/ people/sky; Lovastatin 20,40mg/ people/sky; Rosuvastatin 20,40mg/ people/sky; With Pitavastatin 2mg/ people/sky.
" patient that the HMG-CoA reductase inhibitor does not tolerate " is meant following patient, comprise " patient who the HMG-CoA reductase inhibitor is had hypoergia " that give wherein that the HMG-CoA reductase inhibitor shows and do not have cholesterol reduction effect or do not have enough effects, wherein limit the patient of administration owing to the high incidence of side effect, wherein the patient that can not realize enough preventions and/or inhibition by common treatment (for example, patient (the NCEP-ATP III that in current therapeutic scheme, can not do the trick about blood fat control, USA, Japanese atherosclerosis association guide etc.)).
For " squalene synthase inhibitor " that use among the present invention, can use any inhibiting chemical compound of squalene synthase that has, for example Squalene inhibin (squalenestatins) is (as USP numbers 5506262,5430055,5409950,5369125, JP-A 7-173166,9-124655,9-227566, " AnnualReview of Microbiology ", Vol.49, pp.607-639,1995, " Journal of MedicinalChemistry ", Vol.38, pp.3502-3513,1995, " Journal of Medicinal Chemistry ", Vol.39, pp.207-216,1996, " Journal of Medicinal Chemistry ", Vol.39, pp.1413-1422,1996, Deng), the phosphate of substrate analogue (phosphate) chemical compound and carboxylic acid compound are (as USP numbers 5374628,5441946,5428028, JP-A 7-041554, WO95/04025, " Journal of Medicinal Chemistry ", Vol.38, pp.2596-2605,1995, " Arzniemittel-Forschung Drug Research ", Vol.46, pp.759-762,1996, " Journal ofMedicinal Chemistry ", Vol.31, pp.1869-1871,1988, " Journal of MedicinalChemistry ", Vol.39, pp.657-660,1996, " Journal of Medicinal Chemistry ", Vol.39, pp.661-664,1996), carboxylic acid derivates is (as WO97/40006, WO96/33159, WO95/21834, WO97/48701, EP-A numbers 645377,645378,814080,790235, JP-A 7-173120,10-316634,10-298134,10-298177,10-316617,9-136880, WO2000/00458, WO2001/98282, WO98/29380, " Bioorganic Medicinal Chemistry Letters ", Vol.5, pp.1989-1994,1995, " Bioorganic Medicinal Chemistry Letters ", Vol.6, pp.463-466,1996, " Journal of Medicinal Chemistry ", Vol.40, pp.2123-2125,1997 etc.), based on the chemical compound of amine such as quinuclidine derivant (as USP numbers 5385912,5494918,5395846,5451596, JP-A 8-134067,2000-169474,10-152453,2000-502716, WO94/03541, WO 94/05660, WO95/35295, WO96/26938, WO95/31458, WO95/00146, WO97/25043, WO98/12170 etc.) and the chemical compound represented of Sa Lage acid (Zaragozic acids), especially following formula:
Wherein, R 1Be hydrogen atom or optional substituted alkyl, R 2And R 3Identical or different; and be hydrogen atom, optional substituted alkyl or optional substituted heterocyclic group; X ' but be the group that comprises the heterocycle residue of optional esterified carboxyl, optional substituted carbamoyl, optional substituted hydroxyl, optional substituted amino or the optional substituted hydrogen atom that contains deprotonation; ring A is optional substituted phenyl ring or optional substituted heterocycle; the ring J ' for contain 3 or still less hetero atom as the ring composed atom 7 yuan or 8 yuan of heterocycles, and the ring J ' also can contain except that R 1, R 2, R 3And the outer substituent group of X '; Or
The chemical compound that following formula is represented:
Wherein, R 1Be hydrogen atom or optional substituted alkyl, R 2And R 3Identical or different, and be hydrogen atom, optional substituted alkyl or optional substituted heterocyclic group, X 1Be key or bivalent chain, but Y is the heterocycle residue of the carboxyl of optionally esterify, the optional carbamoyl that replaces, the optional hydroxyl that replaces, the optional amino or optional hydrogen atom that contains deprotonation that replaces that replaces, ring B is the optional phenyl ring that replaces; The chemical compound of formula [II] expression:
Figure S2006800197386D00092
Its medium ring A and the optional substituted phenyl ring of each expression of ring B, ring C represents optional further substituted aromatic rings, R 1The low alkyl group that the optional hydroxyl that is preferably replaced of expression replaces, X 1aExpression key or the optional low-grade alkylidene that replaces, X 1bExpression key or optional substituted low-grade alkylidene, X 2The expression key ,-O-or-S-, X 3Expression key or optional substituted bivalent hydrocarbon radical, and Y represents optional esterified or amidated carboxyl;
Use Deng being preferred.
The example of other squalene synthase inhibitor comprises A-104109 (Abbott Laboratories)
Figure S2006800197386D00101
F-10863-A (Sa Lage acid D3, Sankyo Co., Ltd.)
Diphosphonic acid derivative such as ER-28448, ER-27856 (ER-28448 prodrug) and quinuclidine derivant (Eisai) are as ER-119884 and ER-132781
Figure S2006800197386D00102
RPR-107393 and RPR-101821 (Aventis Pharma Ltd.)
Figure S2006800197386D00103
Thiadiazoles derivative (NovoNordisk)
Figure S2006800197386D00111
2-aminopropane. derivant and quinuclidine derivant (Yamanouchi Pharmaceutical Co., Ltd.)
Figure S2006800197386D00112
Different quinuclidine derivant (Kotobuki pharmaceutical Co., Ltd.)
Figure S2006800197386D00113
Malonate derivative (Nippon Kayaku Co., Ltd.)
Figure S2006800197386D00114
The propionyl derivant (Daiichi Pharmaceutical Co., Ltd.)
Figure S2006800197386D00115
Wherein R is hydrogen atom or methyl,
SQ-34919, SQ-32709, BMS-187745 and BMS-188494 (Bristol-Myers SquibbCompany)
Figure S2006800197386D00121
Wherein R be potassium atom or-CH 2OCOC (CH 3) 3,
J-104118(Merck&Co.，Inc.)
Figure S2006800197386D00122
Quinuclidine spit of fland biology (AstraZeneca)
Figure S2006800197386D00123
SDZ-266-806(Novartis Pharma)
Figure S2006800197386D00124
And these squalene synthase inhibitors can be used for medicine of the present invention.
" have squalene synthase and suppress active chemical compound " of using among the present invention can be used with the form of salt or prodrug.
Have " salt " that squalene synthase suppresses active chemical compound, preferably acceptable salt of pharmacy or an acceptable acid-addition salts of physiology for what the present invention used.For these salt, can use for example inorganic acid salt (example hydrochloric acid salt, phosphate, hydrobromate, sulfate etc.) or acylate (as acetate, formates, propionate, fumarate, maleate, succinate, tartrate, citrate, malate, oxalates, benzoate, mesylate, benzene sulfonate etc.) etc.And, " have squalene synthase and suppress active chemical compound " used as the present invention has acidic-group, during as carboxylic acid etc., " have squalene synthase and suppress active chemical compound " can with for example inorganic base (as alkali metal or alkaline-earth metal, as sodium, potassium, calcium, magnesium or ammonia etc.) or organic base (as three-C 1-3Alkylamine is as triethylamine etc.) form salt.
The present invention uses to have " prodrug " or its salt that squalene synthase suppresses active chemical compound [being called " SSI chemical compound " hereinafter] and is meant the chemical compound that is converted into the SSI chemical compound by the body internal reaction under the physiological condition that contains enzyme, gastric acid etc., and promptly the Oxidation by enzyme, reduction, hydrolysis etc. are converted into the chemical compound of SSI chemical compound; Hydrolysis by gastric acid etc. etc. is converted into the chemical compound of SSI chemical compound; Deng.The example of the prodrug of SSI chemical compound comprises following compounds, wherein the amino of SSI chemical compound by the chemical compound of acidylate, alkylation or phosphorylation (as, wherein the amino of SSI chemical compound by eicosylization, alanylization, amyl group amino carbonylization, (5-methyl-2-oxo-1,3-Dioxol-4-yl) methoxycarbonylization, tetrahydrofuran baseization, pyrrolidinyl methylate, pivaloyl oxygen methylates or the chemical compound of tert-butylation etc.); Wherein the hydroxyl of SSI chemical compound by the chemical compound of acidylate, alkylation, phosphorylation or borylization (borylated) (as, wherein the hydroxyl of SSI chemical compound be acetylation, the chemical compound of palmitoylation, propionylization, pivaloylization, succinylation, fumaroylization, alanylization or dimethylaminomethyl carbonylation etc.); Or wherein esterified the or amidated chemical compound of carboxyl of SSI chemical compound (as, wherein the carboxyl of SSI chemical compound is by ethyl esterization, phenyl esterization, carboxyl methyl-esterified, dimethylamino esterification, the esterification of pivaloyl oxygen, ethoxy carbonyl 2-ethoxyethyl acetateization, phthalidyl esterification, (5-methyl-2-oxo-1,3-Dioxol-4-yl) esterification, cyclohexyl oxygen base carbonyl ethyl esterization or methyl nitrosoureaization etc.); Deng.These chemical compounds can be by known method own from the SSI compound.
In addition, the prodrug of SSI chemical compound can be following chemical compound, its at Hirokawa Publishing Co. at nineteen ninety disclosed " Pharmaceutical Research and Development ", Vol.7 (Molecular Design), the physiological condition described in the pp.163-198 is converted into the SSI chemical compound.
And the SSI chemical compound can be hydration.
When needing the SSI chemical compound of optically active form, it can be by obtaining as the optically active starting material of use or by the method for using conventional optical resolution SSI chemical compound raceme.And, when the SSI chemical compound contains asymmetric carbon atom and the R configuration arranged and during two kinds of stereoisomers of S configuration, any isomer or its mixture are also included within the scope of the present invention in its molecule.
In formula (I) with (Ia), by R 1The example of the alkyl in " optional substituted alkyl " of expression comprises aliphatic chain (acyclic) alkyl, alicyclic hydrocarbon radical and aryl, and preferred aliphat chain alkylene wherein.
The aliphatic chain alkyl of alkyl comprises straight chain or the aliphatic alkyl of side chain is arranged, as alkyl, thiazolinyl and alkynyl.Wherein, preferably have the alkyl of side chain.The example of alkyl comprises C 1-7Alkyl such as methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, n-pentyl, isopentyl, neopentyl, 1-methyl-propyl, n-hexyl, isohesyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 3,3-dimethyl propyl, 2-ethyl-butyl, n-heptyl etc.Especially, be preferably C 3-5Alkyl as, n-pro-pyl, isopropyl, isobutyl group, neopentyl etc., and be preferably isobutyl group, neopentyl etc. especially.The example of thiazolinyl comprises C 2-6Thiazolinyl is as vinyl, pi-allyl, isopropenyl, 2-methacrylic, 1-acrylic, 2-methyl isophthalic acid-acrylic, 2-methyl-2-acrylic, 1-butylene base, crotyl, 3-cyclobutenyl, 2-ethyl-1-butylene base, 2-methyl-2-butene base, 3-methyl-2-butene base, 1-pentenyl, pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl etc.Especially, be preferably especially vinyl, pi-allyl, isopropenyl, 2-methacrylic, 2-methyl isophthalic acid-acrylic, 2-methyl-2-acrylic, 3-methyl-2-butene base etc.The example of alkynyl comprises C 2-6Alkynyl, as acetenyl, 1-propinyl, 2-propynyl, ethyl acetylene base, 2-butyne base, 3-butynyl, 1-pentynyl, valerylene base, 3-pentynyl, 4-pentynyl, 1-hexin base, 2-hexin base, 3-hexin base, 4-hexin base, 5-hexin base etc., be preferably acetenyl, 1-propinyl, 2-propynyl etc. especially especially.
The alicyclic hydrocarbon radical of alkyl comprises saturated or the unsaturated lipid cyclic hydrocarbon radical, as cycloalkyl, cycloalkenyl group, cycloalkadienyl etc.For cycloalkyl, be preferably C 3-9Cycloalkyl, and the example comprises cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, ring octyl group, ring nonyl etc.Wherein, be preferably C 3-6Cycloalkyl such as cyclopropyl, cyclobutyl, cyclopenta and cyclohexyl.The example of cycloalkenyl group comprises C 5-6Cycloalkenyl group is as 2-cyclopentenes-1-base, 3-cyclopentenes-1-base, 2-cyclohexene-1-base, 3-cyclohexene-1-base, 1-cyclobutane-1-base and 1-cycloheptene-1-base.The example of cycloalkadienyl comprises C 5-6Cycloalkadienyl is as 2,4-cyclopentadiene-1-base, 2,4-cyclohexadiene-1-base and 2,5-cyclohexadiene-1-base.
The aryl of alkyl comprises C 6-16Monocycle or fused polycyclic aromatic hydrocarbon base as, phenyl, naphthyl, anthryl, phenanthryl, acenaphthenyl especially are preferably C 6-10Aryl as, phenyl, 1-naphthyl and 2-naphthyl.
R 1The substituent group of " optional substituted alkyl " of expression comprise optional substituted aryl, optional substituted cycloalkyl, optional substituted cycloalkenyl group, optional substituted heterocyclic radical, optional substituted amino, optional substituted hydroxyl, optional substituted sulfydryl, halogen atom (as, fluorine, chlorine, bromine, iodine) and oxo etc.And described alkyl is optional to be replaced on commutable position by individual these substituent groups of any 1～5 (being preferably 1～3).The example of the aryl of optional substituted aryl comprises C 6-16Aryl as phenyl, naphthyl, anthryl, phenanthryl and acenaphthenyl, especially, is preferably C 6-10Aryl such as phenyl, 1-naphthyl and 2-naphthyl.The substituent group of optional substituted aryl comprises C 1-3Alkoxyl (as methoxyl group, ethyoxyl, propoxyl group etc.), halogen atom (as, fluorine, chlorine, bromine, iodine), C 1-3Alkyl (as methyl, ethyl, propyl group etc.) etc., and described aryl is optional by 1～2 these substituent groups replacement arbitrarily.The example of the cycloalkyl of optional substituted cycloalkyl comprises C 3-7Cycloalkyl as, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl and suberyl.For the substituent group and the substituent quantity of optional substituted cycloalkyl, identical kind and quantity are arranged with the substituent group of the optional substituted aryl of above-mentioned example.The example of the cycloalkenyl group of optional substituted cycloalkenyl group comprises C 3-6Cycloalkenyl group, as cyclopropanyl, cyclobutane base, cyclopentenyl and cyclohexenyl group.For the substituent group and the substituent quantity of optional substituted cycloalkyl, identical kind and quantity are arranged with the substituent group of the optional substituted aryl of above-mentioned example.The heterocyclic radical of optional substituted heterocyclic radical comprises fragrant heterocyclic radical and saturated or undersaturated nonaromatic heterocycles base (aliphatic heterocyclic radical), it contains at least one and preferably contains 1～4 hetero atom that is selected from oxygen, sulfur and nitrogen as member ring systems composed atom (annular atoms), is preferably fragrant heterocyclic radical.The example of fragrant heterocyclic radical comprises that 5 to 6 yuan of fragrant monocyclic heterocycles bases are (as furyl, thienyl, pyrrole radicals,  azoles base, different  azoles base, thiazolyl, isothiazolyl, imidazole radicals, pyrazolyl, 1,2,3- di azoly, 1,2,4- di azoly, 1,3,4- di azoly, the furazan base, 1,2, the 3-thiadiazolyl group, 1,2, the 4-thiadiazolyl group, 1,3, the 4-thiadiazolyl group, 1,2, the 3-triazolyl, 1,2, the 4-triazolyl, tetrazole radical, pyridine radicals, pyridazinyl, pyrimidine radicals, pyrazinyl, triazine radical etc.) and wherein the fragrant annelated heterocycles base that condenses 2 to 35 to 6 yuan of rings is (as benzofuranyl, isobenzofuran-base, benzo [b] thienyl, indyl, isoindolyl, the 1H-indazolyl, benzimidazolyl, the benzoxazol base, 1,2-benzisoxa  azoles base, benzothiazolyl, 1,2-benzisothiazole base, 1H-benzotriazole base, quinolyl, isoquinolyl, cinnolines base (cinnolyl), quinazolyl, quinoxalinyl, phthalazinyl, naphthyridinyl (naphthylizinyl), purine radicals, pteridyl, carbazyl, α-carbolinyl, the B-carboline base, the gamma-carbolines base, acridinyl, fen  piperazine base, phenothiazinyl, phenazinyl, dibenzthioxine base (phenoxathinyl), thianthrene group, phenanthridinyl, the phenanthroline base, the indolizine base, pyrrolo-[1,2-b] pyridazinyl, pyrazolo [1,5-a] pyridine radicals, imidazo [1,2-a] pyridine radicals, imidazo [1,5-a] pyridine radicals, imidazo [1,2-b] pyridazinyl, imidazo [1,2-a] pyrimidine radicals, 1,2,4-triazol [4,3-a] pyridine radicals, 1,2,4-triazol [4,3-b] pyridazinyl etc.), especially, be preferably 5 to 6 yuan of fragrant monocyclic heterocycles bases, as furyl, thienyl, indyl, isoindolyl, pyrazinyl, pyridine radicals and pyrimidine radicals.The example of nonaromatic heterocycles base comprises 4 to 8 yuan of nonaromatic heterocycles bases, as Oxyranyle, azetidine base, oxetanyl, Thietane base, pyrrolidinyl, tetrahydrofuran base, tetrahydro-thienyl (thiolanyl), piperidyl, THP trtrahydropyranyl, morpholinyl, tetrahydro-1,4-thiazine base and piperazinyl.Optional substituted heterocyclic radical can have 1～4, be preferably 1～2 substituent group, and these substituent groups comprises C 1-3Alkyl (as methyl, ethyl, propyl group etc.) etc.For the substituent group in optional substituted amino (comprising amino, the single replacement or dibasic amino), optional substituted hydroxyl and the optional substituted sulfydryl, that exemplary is rudimentary (C 1-3) alkyl (as methyl, ethyl, propyl group etc.) etc.And, work as R 1When the alkyl in the optional substituted alkyl of expression was alicyclic alkyl or aryl, substituent group also can be C 1-3Alkyl (as methyl, ethyl, propyl group etc.).
In addition, as mentioned above, R 1Can contain oxo group as substituent group, and be included in R as the carboxylic acyl radical of the alkyl that is replaced by oxo group 1In.The example comprises optional substituted C 1-6Acyl group (as formoxyl, acetyl group, propiono, bytyry, isobutyryl, valeryl, isovaleryl, pivaloyl group, caproyl, dimethyl acetyl group, pivaloyl group etc.) etc.And acyl group can contain 1～5 substituent group in commutable position, and substituent group comprise halogen atom (as, fluorine, chlorine, bromine).
In formula (I) with (Ia), R 2And R 3" optional substituted alkyl " of expression can comprise and be described as R 1The group of " the optional substituted alkyl " of expression.Yet alkyl, aryl and its substituent group can be following radicals.That is, for the alkyl of " optional substituted alkyl ", that exemplary is C 1-6Low alkyl group (as methyl, ethyl, n-pro-pyl, isopropyl, butyl, isobutyl group, sec-butyl, the tert-butyl group, amyl group, isopentyl, neopentyl, hexyl, isohesyl etc.), and exemplary preferred be C 1-4Alkyl is as methyl, ethyl, propyl group, isopropyl, butyl, the tert-butyl group.For example, these optional substituted alkyl can contain 1～4 substituent group, and these substituent groups comprise halogen atom (as fluorine, chlorine, bromine, iodine), C 1-4Lower alkoxy (as methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, tert-butoxy etc.) etc.
" optional substituted aryl " comprises monocycle or fused polycyclic aromatic hydrocarbon base, as phenyl, naphthyl, anthryl, phenanthryl and acenaphthenyl, wherein, is preferably phenyl especially.The substituent group of " optional substituted aryl " comprises halogen atom (as fluorine, chlorine, bromine, iodine etc.), optional substituted low alkyl group, optional substituted lower alkoxy, optional substituted hydroxyl, nitro and cyano group, and can be replaced by individual these the identical or different substituent groups of 1～3 (being preferably 1～2).The example of low alkyl group comprises C 1-4Alkyl as methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, sec-butyl and the tert-butyl group, especially, is preferably methyl and ethyl especially.The example of lower alkoxy comprises C 1-4Alkoxyl as methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, especially, is preferably methoxyl group and ethyoxyl especially.The substituent group of optional substituted low alkyl group and optional substituted lower alkoxy comprises halogen atom (as fluorine, chlorine, bromine, iodine etc.), and can be replaced by 1～5 substituent group in any commutable position.In the substituent example of optional substituted hydroxyl, comprise rudimentary (C 1-4) alkyl (as methyl, ethyl, propyl group, isopropyl, butyl, the tert-butyl group etc.), C 3-6Cycloalkyl (as cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl etc.), C 6-10Aryl (as phenyl, 1-naphthyl, 2-naphthyl etc.) and C 7-12Aralkyl (as benzyl, phenethyl etc.).And these substituent groups can form ring with adjacent substituent group, and work as R 2And R 3When the aryl of " the optional substituted aryl " of expression is phenyl, the group that can use following formula to represent
Figure S2006800197386D00171
And these groups can be by 1～4 rudimentary (C 1-3) alkyl replacements such as (as methyl, ethyl, propyl group, isopropyls etc.).
R 2And R 3The heterocyclic group of " the optional substituted heterocyclic group " of expression is included in R 1The heterocyclic group that provides in the substituent group of " optional substituted alkyl " of expression for the detailed description of " optional substituted heterocyclic group ".Wherein, be preferably 5～6 yuan of fragrant monocyclic heterocycles especially, as furyl, thienyl, indyl, isoindolyl, pyrazinyl, pyridine radicals, pyrimidine radicals and imidazole radicals.The substituent group of heterocyclic group comprises C 1-3Alkyl (as methyl, ethyl, propyl group etc.), its described heterocycle can contain 1～4 such substituent group.
In above-mentioned, for R 2And R 3, be preferably optional substituted phenyl, more preferably substituted phenyl, and, be preferably 1～2 halogen atom particularly by 1～3, as phenyl, the rudimentary (C of chlorine and bromine replacement 1-3) alkoxyl etc. is preferred.And, R 2And R 3Any one is preferably hydrogen atom.
In formula (I), " group that comprises optional esterified carboxyl " of X ' expression comprises optional esterified carboxyl and contains the group of optional esterified carboxyl.Optional esterified carboxyl comprises with following for the identical group of Y definition.
" group that comprises optional substituted carbamoyl " of X ' expression comprises optional substituted carbamoyl and contains the group of optional substituted carbamoyl.Optional substituted carbamoyl comprises with following for the identical group of Y definition.
" group that comprises optional substituted hydroxyl " of X ' expression comprises optional substituted hydroxyl and contains the group of optional substituted hydroxyl.Optional substituted hydroxyl comprises with following for the identical group of Y definition.
" group that comprises optional substituted amino " of X ' expression comprises optional substituted amino and contains the group of optional substituted amino.Optional substituted amino comprises with following for the identical group of Y definition.
The group of the heterocycle residue of optional substituted hydrogen atom with deprotonation " but comprise " of X ' expression comprise have can be by the hydrogen atom of deprotonation (promptly containing active proton) but optional substituted heterocycle residue and containing choose the group of the heterocycle residue of substituted hydrogen atom with deprotonation wantonly.But optional substituted heterocycle residue with hydrogen atom of deprotonation comprises following for the identical group of Y definition.
X ' comprises the group of following formula (a) expression:
Figure S2006800197386D00181
Wherein X is a key; or bivalence or triad chain; Y is optional esterified carboxyl, optional substituted carbamoyl, optional substituted hydroxyl, optional substituted amino, but or optional substituted heterocycle residue and dotted line with hydrogen atom of deprotonation be singly-bound or two key.
In formula (a), " the bivalent chain " that X represents can preferably have 1～7 for any bivalence chain, and more preferably has 1～4 atom of forming linear fraction, and can contain side chain.
The example comprises the group that following formula is represented
Figure S2006800197386D00182
Wherein, m and n represent 0,1,2 or 3 integer independently, E represent key or oxygen atom, sulphur atom, sulfoxide, sulfone ,-N (R 5)-,-NHCO-,-CON (R 6)-or-NHCONH-.At this, R 4And R 6Expression hydrogen atom, optional substituted low alkyl group, optional substituted aralkyl or optional substituted phenyl.And, R 5Expression hydrogen atom, low alkyl group, aralkyl or acyl group.
R 4And R 6Alkyl in " the optional substituted low alkyl group " of expression comprises C 1-6The low alkyl group of straight or branched (as methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, n-pentyl, isopentyl, neopentyl).Should can have 1～4 by optional substituted low alkyl group, be preferably 1～2 substituent group, and these substituent examples comprise aromatic heterocycle group (as 5～6 yuan of heteroatomic aromatic heterocycles that contain 1～4 N, O and S, as furyl, thienyl, indyl, isoindolyl, pyrazinyl, pyridine radicals, pyrimidine radicals and imidazole radicals), optional substituted amino, optional substituted hydroxyl, optional substituted sulfydryl, optional esterified carboxyl and halogen atom (as fluorine, chlorine, bromine, iodine).Substituent group in optional substituted amino (comprising amino, the single replacement or dibasic amino), optional substituted hydroxyl and the optional substituted sulfydryl comprises rudimentary (C 1-3) alkyl (as methyl, ethyl, propyl group etc.).The example of optional esterified carboxyl comprises C 2-5Alkoxy carbonyl, as methoxycarbonyl, ethoxy carbonyl, propoxycarbonyl, phenyloxycarbonyl and 1-naphthoxy carbonyl, and C 7-11Aryloxycarbonyl, and preferred illustrative is methoxycarbonyl, ethoxy carbonyl and propoxycarbonyl.
R 4And R 6Aralkyl in " the optional substituted aralkyl " of expression comprises C 7-C 15Aralkyl is as benzyl, naphthyl methyl, phenyl propyl and phenyl butyl.Optional substituted aralkyl can contain 1～4, be preferably 1～2 substituent group, and these substituent groups comprises halogen atom (as fluorine, chlorine, bromine, iodine), C 1-3Alkoxyl (as methoxyl group, ethyoxyl, propoxyl group), hydroxyl, amino, carboxyl, sulfydryl etc.
R 4And R 6Substituent group in " the optional substituted phenyl " of expression comprises halogen atom (as fluorine, chlorine, bromine, iodine), C 1-3Alkoxyl (as methoxyl group, ethyoxyl, propoxyl group etc.), C 1-3Alkyl (as methyl, ethyl, propyl group).
Condition is R in each methene chain 4Can be different.
In addition, R 5The example of " low alkyl group " and " aralkyl " of expression comprises C respectively 1-4Low alkyl group (as methyl, ethyl, propyl group, butyl, the tert-butyl group etc.), C 7-15Aralkyl (as benzyl, phenethyl, phenyl propyl, phenyl butyl, naphthyl methyl etc.).
R 5The example of " acyl group " of expression comprises rudimentary (C 1-6) alkanoyl (as formoxyl, acetyl group, propiono, bytyry, isobutyryl, valeryl, isovaleryl, pivaloyl group, caproyl etc.), rudimentary (C 3-7) enoyl-(as acryloyl group, methacryl, crotonyl, methacrylyl etc.), C 4-7Carbonyl naphthene (as cyclopropane carbonyl, Tetramethylene. carbonyl, Pentamethylene. carbonyl, cyclohexane extraction carbonyl etc.), rudimentary (C 1-4) alkane sulfonyl (as mesyl, ethylsulfonyl, third sulfonyl etc.), C 7-14Aroyl (as benzoyl, toluoyl base, 1-naphthoyl, 2-naphthoyl etc.), C 6-10Rudimentary (the C of aryl 2-4) alkanoyl (as phenyl acetyl, phenyl propiono, hydratropoyl, phenyl bytyry etc.), C 6-10Rudimentary (the C of aryl 3-5) enoyl-(as Cortex cinnamomi japonici (Ramulus Cinnamomi) acyl group, atropoyl etc.), C 6-10Aromatic hydrocarbons sulfonyl (as benzenesulfonyl, p-toluenesulfonyl etc.).
And, X can be contain two keys or-carbochain of L-CH (OH)-(L represents the alkylidene chain of key or straight or branched).The example of the carbochain of keys " contain two " comprises and contains preferred 1～7, more preferably 1～4 carbochain of forming the carbon atom of linear part, and also can contain side chain.Two keys in the carbochain are comprised among one of linear part or chain part or both, and preferably are comprised in the linear part.And the quantity of the two keys that contain in the carbochain has no particular limits, but optionally, preferred 1～2.
The example that contains the carbochain of two keys comprises methine, ethenylidene, allylidene, butenylidene, Aden's dialkylene, methyl allylidene, ethyl allylidene, propyl group allylidene, methyl butenylidene, ethyl butenylidene, propyl group butenylidene, methyl Aden dialkylene, ethyl Aden dialkylene, propyl group Aden dialkylene, inferior pentenyl, inferior hexenyl, inferior heptenyl, inferior pentadienyl, inferior hexadienyl, inferior heptadiene base etc., and to be preferably methine, ethenylidene, allylidene, butenylidene and Aden's dialkylene be exemplary.At this, when carbochain was trivalent, carbochain and the commutable carbon atom on the ring of ring J ' formed two keys.
The example of " alkylidene chain of straight or branched " that L represents comprises the C of straight or branched 1-6Alkylidene chain, divalent group for example is as methylene, ethylidene, trimethylene, 1,4-butylidene, 1,5-pentylidene, hexamethylene, 1, the inferior heptyl, 1 of 7-, 2-propylidene, ethyl methylene, ethyl ethylidene, propyl group ethylidene, butyl ethylidene, methyl 1,4-butylidene and methyl trimethylene, and be preferably C 1-3Chain is exemplary as methylene, ethylidene, trimethylene and propylene.
Wherein, X ' is preferably the group of following formula (b) expression:
-X 1-Y
X wherein 1Expression key or bivalent chain, but Y represents the esterified carboxyl of choosing wantonly, optional substituted carbamoyl, optional substituted hydroxyl, optional substituted amino or the optional substituted heterocyclic group that contains the hydrogen atom of deprotonation.
In formula (b), for X 1The bivalent chain of expression, exemplary is with identical for the bivalent chain of following X definition.
In formula (a) with (b), X or X 1" the bivalent chain " of expression comprises the alkylidene chain of the straight or branched that contains the carbon atom that is preferably 1～7 (more preferably 1～4) composition linear fraction.The example of alkylidene chain comprises divalent group, as methylene, ethylidene, 1,3-propylidene, tetramethylene, pentamethylene, 1,6-hexylidene, 1, the inferior heptyl of 7-, propylene, ethyl methylene, ethyl ethylidene, propyl group ethylidene, butyl ethylidene, methyl tetramethylene and methyl 1, the 3-propylidene, and be preferably C 1-4Chain is exemplary as methylene, ethylidene, trimethylene and propylene.
In formula (a) with (b), " optional esterified carboxyl " that Y represents comprises C 2-7Elementary alkoxy carbonyl (as methoxycarbonyl, ethoxy carbonyl, propoxycarbonyl, isopropoxy carbonyl, butoxy carbonyl, tert-butoxycarbonyl, sec-butoxy carbonyl, pentyloxy carbonyl, isoamoxy carbonyl, neopentyl oxygen carbonyl etc.), C 7-14Aryloxycarbonyl (as phenyloxycarbonyl, 1-naphthoxy carbonyl) and C 8-12Aralkyl oxy carbonyl (as benzyl oxygen base carbonyl etc.).Wherein, be preferably carboxyl, methoxycarbonyl and ethoxy carbonyl.
The substituent group of " optional substituted carbamoyl " that Y represents comprises optional substituted rudimentary (C 1-6) alkyl (as methyl, ethyl, n-pro-pyl, isopropyl, butyl, isobutyl group, sec-butyl, the tert-butyl group, amyl group, isopentyl, neopentyl, hexyl, isohesyl etc.), optional substituted C 3-6Cycloalkyl (as cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl etc.), optional substituted C 6-14Aryl (as phenyl, 1-naphthyl, 2-naphthyl etc.) and optional substituted C 7-11Aralkyl (as benzyl, phenethyl etc.), and carbamoyl can be replaced by 1～2 identical or different these substituent groups.Optional substituted rudimentary (C 1-6) alkyl and optional substituted C 3-6Substituent group in the cycloalkyl comprises optional by rudimentary (C 1-5) alkyl (as methyl, ethyl, propyl group, isopropyl, butyl, the tert-butyl group, amyl group, isopentyl, neopentyl) esterification carboxyl, contain 1～4 heteroatomic 5～6 membered aromatic heterocycle group (as furyl, thienyl, indyl, isoindolyl, pyrazinyl, pyridine radicals, pyrimidine radicals, imidazole radicals etc.), amino, hydroxyl and phenyl, 1～3 these identical or different group can replace.The substituent group of optional substituted aryl and optional substituted aralkyl comprises halogen atom (as fluorine, chlorine, bromine, iodine) and optional by rudimentary (C 1-4) carboxyl of alkyl (as methyl, ethyl, propyl group, isopropyl, butyl, the tert-butyl group etc.) esterification.In addition, in optional substituted carbamoyl, it is amino that two substituent groups on the nitrogen-atoms can form ring with nitrogen-atoms, and the amino example of these rings comprises 1-azetidine base, 1-pyrrolidinyl, piperidino, morpholino base, 1-piperazinyl etc.And ring amino also can contain substituent group.
Substituent group in " optional substituted hydroxyl " that Y represents comprises, for example, and rudimentary (C 1-4) alkyl (as methyl, ethyl, propyl group, isopropyl, butyl, the tert-butyl group etc.), C 3-6Cycloalkyl (as cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl etc.), optional substituted C 6-10Aryl (as phenyl, 1-naphthyl, 2-naphthyl etc.) and optional substituted C 7-11Aralkyl (as benzyl, phenethyl etc.).The substituent group of optional substituted aryl and optional substituted aralkyl comprises halogen atom (as fluorine, chlorine, bromine, iodine), optional by rudimentary (C 1-4) carboxyl of alkyl (as methyl, ethyl, propyl group, isopropyl, butyl, the tert-butyl group etc.) esterification, etc.
" optional substituted amino " that Y represents comprises single the replacement and dibasic amino, and these substituent examples comprise rudimentary (C 1-4) alkyl (as methyl, ethyl, propyl group, isopropyl, butyl, the tert-butyl group etc.), C 3-6Cycloalkyl (as cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl etc.), optional substituted C 6-10Aryl (as phenyl, 1-naphthyl, 2-naphthyl etc.), optional substituted C 7-11Aralkyl (as benzyl, phenethyl etc.) etc.The substituent group of optional substituted aryl and optional substituted aralkyl comprises halogen atom (as fluorine, chlorine, bromine, iodine), optional by rudimentary (C 1-4) carboxyl etc. of alkyl (as methyl, ethyl, propyl group, isopropyl, butyl, the tert-butyl group etc.) esterification, can contain 1～4, be preferably 1～2 these substituent group.In addition, two substituent groups on the nitrogen-atoms can form ring amino together with nitrogen-atoms, and the amino examples of these rings comprise 1-azetidine base, 1-pyrrolidinyl, piperidino, morpholino base, 1-piperazinyl.And ring amino also can further contain substituent group.
The heterocycle residue of " but optional substituted heterocyclic group that contains the hydrogen atom of deprotonation " that Y represents comprises that 5～7 yuan (being preferably 5 yuan) contain the heteroatomic monocyclic heterocycles residue (being preferably nitrogenous heterocycle residue) that at least one is selected from N, S and O, and it contains can eliminate and form the hydrogen atom of proton.The example comprises the group that tetrazolium-5-base or following formula are represented:
Figure S2006800197386D00221
Wherein i represent-O-or-S-j represents＞C=O,＞C=S or＞S (O) 2, (wherein, being preferably 2,5-dihydro-5-oxo-1,2,4- diazole-3-base, 2,5-dihydro-5-sulfo-(thioxo)-1,2,4- diazole-3-base and 2,5-dihydro-5-oxo-1,2,4-thiadiazoles-3-yl).
Above-mentioned heterocycle residue can (be preferably C by optional substituted low alkyl group 1-4Alkyl) or acyl group protection.Optional substituted low alkyl group example comprises the optional C that is replaced by following radicals 1-4Alkyl: 1) optional by C 1-3Alkyl, nitro or C 1-3The phenyl or 2 that alkoxyl replaces) C 1-3Alkoxyl (as methyl, trityl group, methoxy, ethoxyl methyl, to mehtoxybenzyl, p-nitrophenyl methyl etc.).The example of acyl group comprises rudimentary (C 2-5) alkanoyl, benzoyl etc.
Wherein, X ' is preferably the alkyl that is replaced by following radicals, but described group for optional esterified carboxyl, choose alkyl that the substituted heterocycle residue that contains the hydrogen of deprotonation replaces or by the alkyl of optional substituted carbamoyl replacement.
In formula (I), the heterocycle that ring A represents is included in R 1The heterocyclic radical of describing in detail in the substituent group of alkyl of expression because of.Wherein, be preferably the group that following formula is represented.
Figure S2006800197386D00222
Or
Figure S2006800197386D00223
" the optional substituted phenyl ring " that ring A represents and the substituent group of " optional substituted heterocycle " comprise halogen atom (as fluorine, chlorine, bromine, iodine), optional substituted C 1-4Low alkyl group (as methyl, ethyl, propyl group, butyl, the tert-butyl group etc.), optional substituted C 1-4Lower alkoxy (as methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, tert-butoxy etc.), hydroxyl, nitro and cyano group.Ring A can contain 1～3, is preferably 1～2 these substituent group.And these substituent groups can form ring with adjacent substituent group.The substituent group of optional substituted low alkyl group and optional substituted lower alkoxy comprises halogen atom (as fluorine, chlorine, bromine, iodine) etc., and can have 1～3 substituent group at an arbitrary position.Ring A is preferably replaced by methoxyl group or chlorine atom, and to be preferably especially be that ring A is replaced by the chlorine atom.
In formula (Ia), the substituent group in " optional substituted phenyl ring " that ring B represents comprises halogen atom (as fluorine, chlorine, bromine, iodine), optional substituted C 1-4Low alkyl group (as methyl, ethyl, propyl group, butyl, the tert-butyl group etc.), optional substituted C 1-4Lower alkoxy (as methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, tert-butoxy etc.), hydroxyl, nitro and cyano group.Ring B can contain 1～3, is preferably 1～2 these substituent group.And these substituent groups can form ring with adjacent substituent group.The substituent group of optional substituted low alkyl group and optional substituted lower alkoxy comprises halogen atom (as fluorine, chlorine, bromine, iodine) etc., and can have 1～3 substituent group at an arbitrary position.Ring B can be preferably replaced by methoxyl group or chlorine atom, and is preferably ring B especially and is replaced by the chlorine atom.
In formula (I), comprise in ring J ' expression " containing 3 or still less hetero atom 7～8 yuan of heterocycles " and for example saturated or undersaturatedly to contain at least one and be selected from O, S (O) as the composed atom of ring q7 or 8 yuan of heterocycles of (q represents 0,1 or 2) and N.Yet, to form in the atom (ring composed atom) of described heterocyclic ring, hetero atom is 3 or still less.
And, in commutable position, remove R 1, R 2, R 3And outside the group of X ' expression, ring J ' also can contain 1～2 substituent group.When substituent group linked to each other with the nitrogen-atoms of ring on the J ', substituent example comprised that alkyl is (as C 1-6Alkyl is as methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, n-pentyl, isopentyl, neopentyl etc.), acyl group is (as C 1-4Acyl group as, formoxyl, acetyl group, propiono, bytyry etc.).Alkyl or acyl group also can be replaced by 1～5 halogen atom (as fluorine, chlorine, bromine, iodine).And when substituent group linked to each other with the carbon atom of ring on the J ', substituent example comprised oxo, sulfo-, optional substituted hydroxyl and chooses substituted amino wantonly.For optional substituted hydroxyl and optional substituted amino, exemplary is identical with " optional substituted amino " with above-mentioned " optional substituted hydroxyl " about the Y definition.
In commutable position, remove R 1, R 2, R 3And outside the group of X ' expression, preferably encircle J ' and also replaced by oxo or sulfo-.
The example that contains the fused rings of ring A and ring J ' comprises:
Figure S2006800197386D00241
Figure S2006800197386D00242
Or
Figure S2006800197386D00243
Formula (I) is preferably the group by following formula (I ') expression:
Figure S2006800197386D00244
Wherein, R 1, R 2, R 3, X ' and ring A such as above-mentioned definition, and ring J 1Represent 7 yuan of heterocycles, Z 1Expression-N (R 7)-(R 7Expression hydrogen atom, alkyl or acyl group) ,-S (O) q(q represents 0,1 or 2) ,-CH 2-or-O-, K represents C or N, and G represents O or S.
In following formula (I '), R 7The alkyl of expression comprises C 1-6The low alkyl group of straight or branched (as methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, n-pentyl, isopentyl, neopentyl etc.), it can be replaced by 1～5 halogen atom (as fluorine, chlorine, bromine, iodine).
R 7The example of the acyl group of expression comprises C 1-4Acyl group (as formoxyl, acetyl group, propiono, bytyry etc.), it can be replaced by 1～5 halogen atom (as fluorine, chlorine, bromine, iodine).
In formula (I '), Z1 is preferably S (O) q(q represents 0,1 or 2) or O.And K is preferably C, and G is preferably O.
For formula (I '), (chemical compound of I ") expression is preferred to following formula
Wherein, R 1, R 2, R 3, X 1, Y and ring A as above define, and Z 2Expression S (O) q(q represents 0,1 or 2) or O.
The chemical compound of formula (I) expression is preferably the chemical compound of following formula (Ia) expression
Figure S2006800197386D00252
The chemical compound of formula (Ia) also can be the chemical compound of following formula (Ia ') expression
Figure S2006800197386D00253
Wherein, R 1B as above defines with ring, and Q represents hydrogen atom or metal ion, and ring C represents optional substituted phenyl.In this formula, to represent transly in 3 and 5 s' substituent group, its plane with 7 yuan of rings is relative in the other direction, and (R) represents the R configuration.
In formula (Ia '), the metal ion that Q represents comprises sodium ion, potassium ion, calcium ion, aluminium ion etc., especially is preferably sodium ion and potassium ion.
The substituent group of " optional substituted phenyl " that ring C represents comprises with above-mentioned about R 2And R 3The identical group of substituent group of the example described " optional substituted aryl " of " the optional substituted alkyl " of definition.
The example of the salt of the chemical compound of formula (I) expression comprises the acceptable salt of pharmacology, as inorganic salt, and example hydrochloric acid salt, hydrobromate, sulfate, nitrate and phosphate; Acylate, as acetate, tartrate, citrate, fumarate, maleate, toluene fulfonate and mesylate, slaine such as sodium salt, potassium salt, calcium salt and aluminum salt and the salt that forms with alkali are as triethylamine salt, guanidinesalt, ammonium salt, hydrazonium salt, quinine salt and cinchonine salt.Wherein, be preferably sodium salt.
The instantiation of the chemical compound of formula (I) expression comprises as follows:
(3R, 5S)-7-cyano group-5-(2, the 3-Dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzo oxygen azepine -3-acetic acid,
(3R, 5S)-7-cyano group-5-(2, the 4-Dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzo oxygen azepine -3-acetic acid,
(3R, 5S)-7-cyano group-5-(2,3-methylenedioxyphenyl base)-1-neopentyl-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzo oxygen azepine -3-acetic acid,
(3R, 5S)-7-cyano group-5-(2,3-ethylidene dioxy base phenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzo oxygen azepine -3-acetic acid,
(3R, 5S)-7-cyano group-5-(2, the 3-Dimethoxyphenyl)-1-isobutyl group-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzo oxygen azepine -3-acetic acid,
(3R, 5S)-7-cyano group-5-(2, the 4-Dimethoxyphenyl)-1-isobutyl group-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzo oxygen azepine -3-acetic acid,
(3R, 5S)-7-cyano group-5-(2,3-methylenedioxyphenyl base)-1-isobutyl group-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzo oxygen azepine -3-acetic acid,
(3R, 5S)-7-cyano group-5-(2,3-ethylidene dioxy base phenyl)-1-isobutyl group-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzo oxygen azepine -3-acetic acid,
(3R, 5S)-7-chloro-5-(2, the 3-Dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzo oxygen azepine -3-acetic acid,
(3R, 5S)-7-chloro-5-(2, the 4-Dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzo oxygen azepine -3-acetic acid,
(3R, 5S)-7-chloro-5-(2,3-methylenedioxyphenyl base)-1-neopentyl-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzo oxygen azepine -3-acetic acid,
(3R, 5S)-7-chloro-5-(2,3-ethylidene dioxy base phenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzo oxygen azepine -3-acetic acid,
(3R, 5S)-7-chloro-5-(2, the 3-Dimethoxyphenyl)-1-isobutyl group-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzo oxygen azepine -3-acetic acid,
(3R, 5S)-7-chloro-5-(2, the 4-Dimethoxyphenyl)-1-isobutyl group-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzo oxygen azepine -3-acetic acid,
(3R, 5S)-7-chloro-5-(2,3-methylenedioxyphenyl base)-1-isobutyl group-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzo oxygen azepine -3-acetic acid,
(3R, 5S)-7-chloro-5-(2,3-ethylidene dioxy base phenyl)-1-isobutyl group-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzo oxygen azepine -3-acetic acid,
(3R, 5S)-7-cyano group-5-(2, the 3-Dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzothiazepine -3-acetic acid,
(3R, 5S)-7-cyano group-5-(2, the 4-Dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzothiazepine -3-acetic acid,
(3R, 5S)-7-cyano group-5-(2,3-methylenedioxyphenyl base)-1-neopentyl-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzothiazepine -3-acetic acid,
(3R, 5S)-7-cyano group-5-(2,3-ethylidene dioxy base phenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzothiazepine -3-acetic acid,
(3R, 5S)-7-cyano group-5-(2, the 3-Dimethoxyphenyl)-1-isobutyl group-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzothiazepine -3-acetic acid,
(3R, 5S)-7-cyano group-5-(2, the 4-Dimethoxyphenyl)-1-isobutyl group-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzothiazepine -3-acetic acid,
(3R, 5S)-7-cyano group-5-(2,3-methylenedioxyphenyl base)-1-isobutyl group-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzothiazepine -3-acetic acid,
(3R, 5S)-7-cyano group-5-(2,3-ethylidene dioxy base phenyl)-1-isobutyl group-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzothiazepine -3-acetic acid,
(3R, 5S)-7-chloro-5-(2, the 3-Dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzothiazepine -3-acetic acid,
(3R, 5S)-7-chloro-5-(2, the 4-Dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzothiazepine -3-acetic acid,
(3R, 5S)-7-chloro-5-(2,3-methylenedioxyphenyl base)-1-neopentyl-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzothiazepine -3-acetic acid,
(3R, 5S)-7-chloro-5-(2,3-ethylidene dioxy base phenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzothiazepine -3-acetic acid,
(3R, 5S)-7-chloro-5-(2, the 3-Dimethoxyphenyl)-1-isobutyl group-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzothiazepine -3-acetic acid,
(3R, 5S)-7-chloro-5-(2, the 4-Dimethoxyphenyl)-1-isobutyl group-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzothiazepine -3-acetic acid,
(3R, 5S)-7-chloro-5-(2,3-methylenedioxyphenyl base)-1-isobutyl group-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzothiazepine -3-acetic acid,
(3R, 5S)-7-chloro-5-(2,3-ethylidene dioxy base phenyl)-1-isobutyl group-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzothiazepine -3-acetic acid,
(3R, 5S)-7-cyano group-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzo oxygen azepine -3-acetic acid,
(3R, 5S)-7-cyano group-5-(2-chlorophenyl)-1-isobutyl group-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzo oxygen azepine -3-acetic acid,
(3R, 5S)-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzo oxygen azepine -3-acetic acid,
(3R, 5S)-7-chloro-5-(2-chlorophenyl)-1-isobutyl group-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzo oxygen azepine -3-acetic acid,
(3R, 5S)-7-cyano group-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzothiazepine -3-acetic acid,
(3R, 5S)-7-cyano group-5-(2-chlorophenyl)-1-isobutyl group-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzothiazepine -3-acetic acid,
(3R, 5S)-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzothiazepine -3-acetic acid,
(3R, 5S)-7-chloro-5-(2-chlorophenyl)-1-isobutyl group-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzothiazepine -3-acetic acid,
(3R, 5S)-7-chloro-5-(4-ethyoxyl-2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzo oxygen azepine -3-acetic acid,
(3R)-and 7-chloro-5-(2-chlorophenyl)-2,3-dihydro-1-isobutyl group-2-oxo-1H-1,4-benzodiazepine-3-acetic acid,
(3R, 5S)-7-chloro-5-(2-chlorophenyl)-2,3,4,5-tetrahydrochysene-1-isobutyl group-2-oxo-1H-1,4-benzodiazepine-3-acetic acid,
N-[[(3R, 5S)-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzothiazepine -3-yl]-acetyl group] glycine,
(3R, 5S)-7-chloro-5-(2-chlorophenyl)-3-dimethylamino carbonyl methyl isophthalic acid-neopentyl-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzothiazepine ,
7-chloro-5-(2-chlorophenyl)-1-isobutyl group-2-oxo-2,3,4,5-tetrahydrochysene-1H-[1]-benzazepine-3-acetic acid,
(3R, 5S)-7-chloro-5-(2-chlorophenyl)-1-neopentyl-1,2,3,5-tetrahydrochysene-2-sulfo--4,1-benzo oxygen azepine -3-acetic acid,
(3R, 5S)-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydrochysene-4,1-thieno [2,3-e] oxygen azepine -3-acetic acid,
(3R, 5S)-7-chloro-5-(2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydrochysene-4,1-thieno [2,3-e] oxygen azepine -3-acetic acid,
(3R, 5S)-7-chloro-1-isobutyl group-5-(2-methoxyphenyl)-2-oxo-1,2,3,5-tetrahydrochysene-4,1-thieno [2,3-e] oxygen azepine -3-acetic acid,
(3R, 5S)-7-chloro-5-(3-hydroxyl-2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzothiazepine -3-acetic acid,
(3R, 5S)-7-chloro-5-(4-hydroxyl-2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzothiazepine -3-acetic acid,
(3R, 5S)-7-chloro-5-(3-hydroxyl-2-methoxyphenyl)-1-isobutyl group-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzothiazepine -3-acetic acid,
(3R, 5S)-7-chloro-5-(4-hydroxyl-2-methoxyphenyl)-1-isobutyl group-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzothiazepine -3-acetic acid,
(3R, 5S)-7-chloro-5-(3-ethyoxyl-2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzothiazepine -3-acetic acid,
(3R, 5S)-7-chloro-5-(4-ethyoxyl-2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzothiazepine -3-acetic acid,
(3R, 5S)-7-chloro-5-(3-ethyoxyl-2-methoxyphenyl)-1-isobutyl group-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzothiazepine -3-acetic acid,
(3R, 5S)-7-chloro-5-(4-ethyoxyl-2-methoxyphenyl)-1-isobutyl group-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzothiazepine -3-acetic acid,
(3R, 5S)-7-chloro-5-(2-chloro-3-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzothiazepine -3-acetic acid,
(3R, 5S)-7-chloro-5-(2-chloro-4-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzothiazepine -3-acetic acid,
(3R, 5S)-7-chloro-5-(2-chloro-3-methoxyphenyl)-1-isobutyl group-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzothiazepine -3-acetic acid,
(3R, 5S)-7-chloro-5-(2-chloro-4-methoxyphenyl)-1-isobutyl group-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzothiazepine -3-acetic acid,
(3R, 5S)-7-chloro-5-(2-chloro-3-hydroxy phenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzothiazepine -3-acetic acid,
(3R, 5S)-7-chloro-5-(2-chloro-4-hydroxy phenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzothiazepine -3-acetic acid,
(3R, 5S)-7-chloro-5-(2-chloro-3-hydroxy phenyl)-1-isobutyl group-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzothiazepine -3-acetic acid,
(3R, 5S)-7-chloro-5-(2-chloro-4-hydroxy phenyl)-1-isobutyl group-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzothiazepine -3-acetic acid; And salt.
The chemical compound of formula (I) expression and salt thereof are [hereinafter, sometimes be abbreviated as the chemical compound (I) that comprises salt] be disclosed in, for example, EP-A-567026, WO95/21834 (Japanese patent application No. 6-15531), EP-A-645377 (Japanese patent application No. 6-229159), EP-A-645378 (Japanese patent application No. 6-229160), and can be according to the open preparation of these applications.
The chemical compound of formula (I) expression is preferably the chemical compound of following formula (Ib) expression:
Figure S2006800197386D00301
The preferred embodiment of the chemical compound of formula (Ib) expression comprises:
Chemical compound, wherein R bFor containing 1～3 substituent C that is selected from the amino propionyloxy of hydroxyl, acetoxyl group, propionyloxy, uncle's bytyry oxygen base, Petiolus Trachycarpi acyloxy, dimethylamino acetoxyl group and 2- 1-6Alkyl;
Chemical compound, wherein R bFor containing 1～3 substituent side chain C that is selected from the amino propionyloxy of hydroxyl, acetoxyl group, propionyloxy, uncle's bytyry oxygen base, Petiolus Trachycarpi acyloxy, dimethylamino acetoxyl group and 2- 3-6Alkyl;
Chemical compound, wherein R bBe 2,2-dimethyl-3-hydroxypropyl, 3-hydroxyl-2-hydroxymethyl-2-methyl-propyl, 3-acetoxyl group-2,2-dimethyl propyl, 3-acetoxyl group-2-hydroxymethyl-2-methyl-propyl or 3-acetoxyl group-2-acetoxy-methyl-2-methyl-propyl;
Chemical compound, wherein R 1bBe methyl;
Chemical compound, wherein W is the chlorine atom;
Chemical compound, wherein X bThe group of representing for following formula:
Figure S2006800197386D00311
Wherein, R 2bAnd R 3bBe respectively hydrogen atom, optional substituted alkyl, optional substituted heterocyclic group or acyl group, or R 2bAnd R 3bCan form optional substituted 5 yuan or 6 member heterocyclic ring containing nitrogens with adjacent nitrogen-atoms, described nitrogen heterocyclic ring is optional to contain 1～3 hetero atom that is selected from nitrogen-atoms, sulphur atom and oxygen atom as the ring composed atom;
Chemical compound is wherein for X bThe group of expression:
R 2bBe hydrogen atom or C 1-7Alkyl,
R 3bBe (1) alkyl, it is selected from (a) C 1-7Alkyl, (b) C 3-7Cycloalkyl, (c) C 2-6Thiazolinyl, (d) C 6-10Aryl and (e) C 6-10Aryl-C 1-4Alkyl
[wherein, (a) C 1-7Alkyl, (b) C 3-7Cycloalkyl and (c) C 2-6Thiazolinyl can be replaced by 1～4 substituent group respectively, and it is optional by C that described substituent group is selected from (i) 1-6Alkyl or C 6-10Aryl-C 1-4The carboxyl of alkyl esterification, (ii) optional by C 1-6Alkyl or C 2-7Alkanoyl oxygen base-C 1-6The alkyl list replaces or dibasic phosphate (phosphate group), (iii) sulfonic group (sulfonate group), (iv) optional by C 1-6 alkyl or C 6-10Aryl-C 1-4The sulfamoyl (sulfonamide group) that alkyl replaces, (v) optional by C 1-3The hydroxyl of alkyl-alkylization, (vi) optional by C 1-3The sulfydryl of alkyl-alkylization, (vii) carbamoyl, (viii) optionally be selected from hydroxyl, chlorine atom, fluorine atom, amino-sulfonyl and optional by C by 1～5 1-3The alkyl list replaces or the phenyl that substituent group replaced, (ix) of dibasic amino choose wantonly by C 1-3The alkyl list replaces or dibasic amino, (x) derived from piperidines, pyrrolidine, morpholine, tetrahydro-1,4-thiazine, piperazine, 4-methyl piperazine, 4-benzyl piperazine, 4-phenylpiperazine, 1,2,3, the ring amino of 4-tetrahydroisoquinoline or phthalimide, it can be by C 1-3Alkyl, benzyl or phenyl replace and (xi) derived from 5～6 membered aromatic heterocycle groups of pyridine, imidazoles, indole or tetrazolium; With
(d) C 6-10Aryl and (e) C 6-10Aryl-C 1-4Alkyl can have 1～4 respectively and be selected from following substituent group and replace, and it is optional by C that described substituent group is selected from (i) 1-4The carboxyl of alkyl esterification, (ii) optional by C 1-6Alkyl or C 2-7Alkanoyl oxygen base-C 1-6The alkyl list replaces or dibasic phosphate, (iii) sulfonic group, (iv) C 1-4Alkyl sulphonyl, C 6-10Aryl sulfonyl or C 6-10Aryl-C 1-4Alkyl sulphonyl, (v) optional by C 1-6Alkyl or C 6-10Aryl-C 1-4The sulfamoyl that alkyl replaces, (the vi) optional C that is replaced by following group 1-3Alkyl, described group is: optional by C 1-4The carboxyl of alkyl esterification, optional by C 1-6Alkyl list or dibasic phosphate, sulfonic group, C 1-4Alkyl sulphonyl, C 6-10Aryl sulfonyl or C 6-10Aryl-C 1-4Alkyl sulphonyl, optional by C 1-6Alkyl or C 6-10Aryl-C 1-4The sulfamoyl that alkyl replaces and (vii) halogen atom],
(2) tetrazole radical, 4,5-dihydro-5-oxo-1,2,4- di azoly, 4,5-dihydro-5-sulfo--1,2,4- di azoly, 2,3-dihydro-3-oxo-1,2,4- di azoly, 2,3-dihydro-3-sulfo--1,2,4- di azoly, 3,5-dioxo-1,2,4- two oxazolidinyls (oxadiazolydinyl), 4,5-dihydro-5-oxo-different  azoles base, 4,5-dihydro-5-sulfo--different  azoles base, 2,3-dihydro-2-oxo--1,3,4- di azoly, 2,3-dihydro-3-oxo-1,2,4-tetrazole radical or 2,3-dihydro-3-sulfo--1,2, the 4-tetrazole radical, or
(3) be selected from the C that the acyl group (i) of following radicals can be replaced by 1～2 halogen atom 2-7Alkanoyl and (ii) optionally be selected from C by 1～4 1-3Alkyl, C 1-3Alkoxyl and halogen atom, C 1-4Alkyl sulphonyl or C 6-10Aryl-C 1-4The C that the substituent group of alkyl sulphonyl replaces 6-10Aryl sulfonyl,
Or R 2bAnd R 3bCan form derived from piperidines, piperazine, pyrrolidine, 2-oxo piperazine, 2 with adjacent nitrogen atom, [wherein, described 5 yuan or 6 yuan of rings are optional is selected from following substituent group by 1～4 and replaces: (A) optional by C for 6-dioxo piperazine, morpholine or tetrahydro-1,4-thiazine 5 yuan or 6 yuan of rings 1-3Alkyl or C 2-7The hydroxyl that alkanoyl replaces, (B) choose wantonly by C 1-6Alkyl or C 6-10Aryl-C 1-4The carboxyl of alkyl esterification, (C) choose wantonly by C 1-6Alkyl or C 2-7Alkanoyl oxygen base-C 1-6The replacement of alkyl list or dibasic phosphate, (D) sulfonic group, (E) choose wantonly by C 1-6Alkyl or C 6-10Aryl-C 1-4Sulfamoyl, (F) C that alkyl replaces 1-6Alkyl and C 2-5Thiazolinyl, they each can be replaced by optional following group: by C 1-6Alkyl or C 6-10Aryl-C 1-4The carboxyl of alkyl esterification; Optional by C 1-6Alkyl or C 2-7Alkanoyl oxygen base-C 1-6The alkyl list replaces or dibasic phosphate; Sulfonic group; Optional by C 1-6Alkyl or C 6-10Aryl-C 1-4The sulfamoyl that alkyl replaces; Optional by C 1-3Alkyl or C 2-7The hydroxyl that alkanoyl replaces; Optional by C 1-3The sulfydryl of alkyl-alkylization; Carbamoyl; Choose wantonly by 1～5 and be selected from hydroxyl, halogen atom, amino-sulfonyl and optional by C 1-3The phenyl that the substituent group of the amino that alkyl replaces replaces; Optional by C 1-3The alkyl list replaces or dibasic amino; Or tetrazole radical (G) is optional by C 1-3The alkyl list replaces or dibasic amino, (H) derived from ring amino, (I) cyano group, (J) carbamoyl, (K) oxo base, (L) tetrazole radical or 2 of piperidines, pyrrolidine, morpholine, tetrahydro-1,4-thiazine, 4-methyl piperazine, 4-benzyl piperazine or 4-phenylpiperazine; 5-dihydro-5-oxo-1; 2,4- di azoly, (M) choose wantonly by C 6-10Aryl sulfonyl, C 1-4Alkyl sulphonyl or C 6-10Aryl-C 1-4The carbamoyl that alkyl sulphonyl replaces, (N) choose wantonly by C 1-3The sulfydryl of alkyl-alkylization and (O) can be selected from hydroxyl, halogen atom, amino-sulfonyl and optional by 1～5 by C 1-3The phenyl that the substituent group of the amino that alkyl replaces replaces];
Chemical compound, wherein X b, R 2bAnd R 3bThe group of expression can form derived from piperidines, piperazine, pyrrolidine, 2-oxo piperazine or 2 with the adjacent nitrogen atom of carbamoyl, 5 yuan or 6 yuan of rings of 6-dioxo piperazine, and described 5 yuan or 6 yuan of rings can be contained 1～2 substituent C by optional 1-6Alkyl replaces, and it is optional by C that described substituent group is selected from (i) 1-6Alkyl or C 6-10Aryl-C 1-4The carboxyl of alkyl esterification, (ii) optional by C 1-6Alkyl or C 2-7Alkanoyl-C 1-6The alkyl list replaces or dibasic phosphate, (iii) sulfonic group, (iv) optional by C 1-6Alkyl or C 6-10Aryl-C 1-4The sulfamoyl that alkyl replaces, (v) optional by C 1-3The hydroxyl of alkyl-alkylization, (vi) optional by C 1-3The sulfydryl of alkyl-alkylization, (vii) carbamoyl, (viii) can be selected from hydroxyl, halogen atom, amino-sulfonyl and optional by 1～5 by C 1-3The phenyl that the substituent group of the amino that alkyl replaces replaces, (ix) choose wantonly by C 1-3The alkyl list replaces or dibasic amino and (x) tetrazole radical;
Chemical compound, wherein X b, R 2bThe group of expression is hydrogen atom or C 1-7Alkyl, and R 3bBe C 1-4Alkyl sulphonyl;
Chemical compound, wherein X bThe heterocyclic group of expression is a tetrazole radical, 4,5-dihydro-5-oxo-1,2,4- di azoly, 4,5-dihydro-5-sulfo--1,2,4- di azoly, 2,3-dihydro-3-oxo-1,2,4- di azoly, 2,3-dihydro-3-sulfo--1,2,4- di azoly, 3,5-dioxo-1,2,4- two oxazolidinyls, 4,5-dihydro-5-oxo-different  azoles base, 4,5-dihydro-5-sulfo--different  azoles base, 2,3-dihydro-2-oxo--1,3,4- di azoly, 2,3-dihydro-3-oxo-1,2,4-tetrazole radical or 2,3-dihydro-3-sulfo--1,2, the 4-tetrazole radical;
Chemical compound, wherein R 1bBe methyl, W is the chlorine atom, R bBe the C that is selected from the substituent group replacement of the amino propionyloxy of hydroxyl, acetoxyl group, propionyloxy, tertbutyloxycarbonyl oxygen base, Petiolus Trachycarpi acyloxy, dimethylamino acetoxyl group and 2-by 1～3 3-6Branched alkyl, and X bThe group of representing for following formula:
Figure S2006800197386D00341
Wherein, R 2b 'Expression hydrogen atom or C 1-7Alkyl, and R 3b 'Expression C 1-4Alkyl;
Chemical compound, wherein R 1bBe methyl, W is the chlorine atom, R bBe the C that is selected from the substituent group replacement of the amino propionyloxy of hydroxyl, acetoxyl group, propionyloxy, tertbutyloxycarbonyl oxygen base, Petiolus Trachycarpi acyloxy, dimethylamino acetoxyl group and 2-by 1～3 3-6Branched alkyl, and X bThe group of representing for following formula:
Figure S2006800197386D00342
Wherein, R B 'Expression hydrogen atom or C 1-7Alkyl, and n represents 1～5 integer;
Chemical compound, wherein R 1bBe methyl, W is the chlorine atom, R bBe the C that is selected from the substituent group replacement of the amino propionyloxy of hydroxyl, acetoxyl group, propionyloxy, tertbutyloxycarbonyl oxygen base, Petiolus Trachycarpi acyloxy, dimethylamino acetoxyl group and 2-by 1～3 3-6Branched alkyl, and X bThe group of representing for following formula:
Figure S2006800197386D00343
Wherein, R " expression hydrogen atom or C 1-4Alkyl;
Chemical compound, wherein R 1bBe methyl, W is the chlorine atom, R bBe the C that is selected from the substituent group replacement of the amino propionyloxy of hydroxyl, acetoxyl group, propionyloxy, tertbutyloxycarbonyl oxygen base, Petiolus Trachycarpi acyloxy, dimethylamino acetoxyl group and 2-by 1～3 3-6Branched alkyl, and X bBe tetrazole radical;
Chemical compound, wherein R bBe the optional low alkyl group that is replaced by 1 or 2 hydroxyl, and X bBe selected from carbamoyl (a) C that following alkyl replaces for (1) is optional 1-7Alkyl, (b) C 3-7Cycloalkyl, (c) C 2-6Thiazolinyl, (d) C 6-10Aryl and (e) C 7-14Aryl alkyl [wherein, (a) C 1-7Alkyl, (b) C 3-7Cycloalkyl and (c) C 2-6Thiazolinyl can contain 1～4 respectively, and to be selected from following substituent group (i) optional by C 1-6Alkyl or C 7-10The carboxyl of aryl alkyl esterification, (ii) phosphate, (iii) sulfonic group, (iv) optional by C 1-6Alkyl or C 7-10The sulfamoyl that aryl alkyl replaces, (v) optional by C 1-3The hydroxyl of alkyl-alkylization, (vi) optional by C 1-3The sulfydryl of alkyl-alkylization, (vii) carbamoyl, (viii) optional hydroxyl, chlorine atom, fluorine atom, the amino-sulfonyl and optional of being selected from by C 1-3Phenyl, (ix) that the substituent group of the replacement of alkyl list or dibasic amino replaces choose wantonly by C 1-3The alkyl list replaces or dibasic amino and (x) derived from the ring amino of piperidines, pyrrolidine, morpholine, tetrahydro-1,4-thiazine, piperazine, 4-methyl piperazine, 4-benzyl piperazine or 4-phenylpiperazine, and it can be by C 1-3Alkyl, benzyl or phenyl replace and (xi) derived from 5 yuan or 6 membered aromatic heterocycle groups of pyridine, imidazoles, indole or tetrazolium, and (d) C 6-10Aryl and (e) C 7-14Aryl alkyl can contain 1～4 respectively, and to be selected from following substituent group (i) optional by C 1-4The carboxyl of alkyl esterification, (ii) phosphate, (iii) sulfonic group, (iv) optional by C 1-6Alkyl or C 7-10The sulfamoyl that aryl alkyl replaces, (the v) optional C that is replaced by following group 1-3Alkyl: can be by C 1-4The carboxyl of alkyl carboxyl esterification, phosphate, sulfonic group or optional by C 1-6Alkyl or C 7-10Sulfamoyl that aryl alkyl replaces and (iv) halogen atom],
(2) tetrazole radical, 4,5-dihydro-5-oxo-1,2,4- di azoly, 4,5-dihydro-5-sulfo--1,2,4- di azoly, 2,3-dihydro-3-oxo-1,2,4- di azoly, 2,3-dihydro-3-sulfo--1,2,4- di azoly, 3,5-dioxo-1,2,4- two oxazolidinyls, 4,5-dihydro-5-oxo-different  azoles base, 4,5-dihydro-5-sulfo--different  azoles base, 2,3-dihydro-2-oxo--1,3,4- di azoly, 2,3-dihydro-3-oxo-1,2,4-tetrazole radical or 2,3-dihydro-3-sulfo--1,2, the 4-tetrazole radical
(3) optional by the carbamoyl of acyl substituted, described acyl group is selected from (i) optional C that is replaced by 1～2 halogen atom 2-7Alkanoyl and
(ii) C 6-10Aryl sulfonyl, C 1-4Alkyl sulphonyl or C 7-14Aryl alkylsulfonyl, each can be selected from C by 1～4 1-3Alkyl, C 1-3The substituent group of alkoxyl and halogen atom replaces, or
(4) derived from piperidines, piperazine, pyrrolidine, 2-oxo piperazine, 2, [wherein, the ring amino carbonyl can contain 1～4 to be selected from following substituent group (A) hydroxyl, (B) optional by C the ring amino carbonyl of 6-dioxo piperazine, morpholine and tetrahydro-1,4-thiazine 1-4The carboxyl of alkyl esterification, (C) phosphate, (D) sulfonic group, (E) choose wantonly by C 1-6Alkyl or C 7-10Sulfamoyl, (F) C that aryl alkyl replaces 1-3Alkyl or C 2-5Thiazolinyl, each can be chosen wantonly by C by above-mentioned (A), (B), (C), (D) or (E) replacement, (G) 1-3The alkyl list replaces or dibasic amino, (H) derived from ring amino, (I) cyano group, (J) carbamoyl, (K) oxo base, (L) C of piperidines, pyrrolidine, morpholine, tetrahydro-1,4-thiazine, 4-methyl piperazine, 4-benzyl piperazine or 4-phenylpiperazine 1-3Alkoxyl, (M) be derived from tetrazole radical or 2,5-dihydro-5-oxo-1,2, the heterocyclic group of 4- di azoly and (N) optional by C 6-10Aryl sulfonyl, C 1-4Alkyl sulphonyl or C 7-14The carbamoyl that aryl alkylsulfonyl replaces];
Chemical compound, wherein R bBe 2,2-dimethyl-3-hydroxypropyl; Deng
In above-mentioned formula, R bThe example of the low alkyl group of expression comprises C 1-6Alkyl is as methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, n-pentyl, isopentyl, neopentyl and hexyl.Wherein, be preferably C 3-6Alkyl, and C more preferably 4-5Alkyl.Especially, preferred side chain C 4-5Alkyl is as isobutyl group and neopentyl.
R bThe substituent example of the low alkyl group of expression comprises optional by C 2-20Alkanoyl or C 1-7The hydroxyl that alkyl etc. replace.These substituent examples comprise the amino propionyloxy of hydroxyl, acetoxyl group, propionyloxy, tertbutyloxycarbonyl oxygen base, Petiolus Trachycarpi acyloxy, dimethylamino acetoxyl group and 2-.
On their commutable positions, can there be 1～3 such substituent group.
In addition, R bThe example of the optional substituted low alkyl group of expression comprises 2,2-dimethyl-3-hydroxypropyl, 3-hydroxyl-2-hydroxymethyl-2-methyl-propyl, 3-acetoxyl group-2,2-dimethyl propyl, 3-acetoxyl group-2-hydroxymethyl-2-methyl-propyl group and 3-acetoxyl group-2-acetoxy-methyl-2-methyl-propyl.
X bThe optional substituted carbamoyl of expression comprises the group that following formula is represented:
Figure S2006800197386D00361
R 2bAnd R 3bThe example of " the optional substituted alkyl " of expression comprises optional substituted C 1-7Straight or branched alkyl (as methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, 1,1-dimethyl ethyl, n-pentyl, 3-methyl butyl, 2-methyl butyl, 1-methyl butyl, 1-ethyl propyl, n-hexyl, 4-methyl amyl, 3-methyl amyl, 2-methyl amyl, 2-ethyl-butyl, 1-ethyl-butyl, neopentyl, hexyl, heptyl), optional substituted C 3-7Cycloalkyl (as cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, cyclohexyl methyl etc.), optional substituted C 2-6The straight or branched thiazolinyl is (as vinyl, pi-allyl, isopropenyl, the 2-methacrylic, the 1-acrylic, 2-methyl isophthalic acid-acrylic, 2-methyl-2-acrylic, the 1-butylene base, crotyl, the 3-cyclobutenyl, 2-ethyl-1-butylene base, 2-methyl-2-butene base, 3-methyl-2-butene base, the 1-pentenyl, pentenyl, the 3-pentenyl, the 4-pentenyl, 4-methyl-3-pentenyl, the 1-hexenyl, the 2-hexenyl, the 3-hexenyl, the 4-hexenyl, 5-hexenyl etc.), optional substituted C 6-10Aryl (as phenyl and naphthyl) and optional substituted C 7-14Aryl alkyl (as benzyl, phenethyl and naphthyl methyl).
" optional substituted C 1-7The alkyl of straight or branched, optional substituted C 3-7Cycloalkyl and optional substituted C 2-6The straight or branched thiazolinyl " substituent example comprise optional by C 1-6Alkyl or C 6-10Aryl-C 1-4The carboxyl of alkyl (as methyl, ethyl, propyl group, isopropyl, butyl, the tert-butyl group, phenyl, benzyl etc.) esterification, optional by C 1-6Alkyl (as methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, n-pentyl, isopentyl, neopentyl, hexyl etc.) or C 2-7Alkanoyl oxygen base-C 1-6Alkyl such as acetoxy-methyl or the replacement of pivaloyl oxygen ylmethyl list or dibasic phosphate, sulfonic group, optional by C 1-6Alkyl or C 6-10Aryl-C 1-4Sulfamoyl, hydroxyl and sulfydryl that alkyl (as methyl, ethyl, propyl group, isopropyl, butyl, the tert-butyl group, benzyl etc.) replaces, each is optional by C 1-3Alkyl (as methyl, ethyl, propyl group etc.) alkylation, carbamoyl, optional by 1～5 substituent group [as hydroxyl, chlorine, fluorine, amino-sulfonyl or optional by C 1-3The amino that alkyl (as methyl, ethyl, propyl group etc.) replaces] phenyl, optional that replaces by C 1-3The single replacement of alkyl (as methyl, ethyl, propyl group etc.) or dibasic amino, ring amino are (as 5 yuan or 6 yuan ring amino derived from cyclammonium, described cyclammonium such as piperidines, pyrrolidine, morpholine, tetrahydro-1,4-thiazine, piperazine, 4-methyl piperazine, 4-benzyl piperazine, 4-phenylpiperazine, 1,2,3,4-tetrahydroisoquinoline and phthalimide, it can be by C 1-3Replacements such as alkyl, benzyl, phenyl, and also optional oxygen atom or the sulphur atom of containing is as the ring composed atom) and contain 1～4 heteroatomic 5～6 membered aromatic heterocycle (as pyridine, imidazoles, indole, tetrazolium etc.) that are selected from N, O and S.
In addition, as forming X bThe substituent C of the optional substituted amino of the carbamoyl of " the optional substituted carbamoyl " of expression 6-10Aryl and C 6-10Aryl-C 1-4The substituent example of alkyl comprises optional by C 1-4The carboxyl of alkyl (methyl, ethyl, propyl group, the tert-butyl group etc.) esterification, optional by C 1-6Alkyl (methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, n-pentyl, isopentyl, neopentyl, hexyl) or C 2-7Alkanoyl oxygen base-C 1-6Alkyl such as pivaloyl oxygen ylmethyl and the replacement of acetoxy-methyl list or dibasic phosphate, sulfonic group, C 1-4Alkyl sulphonyl, C 6-10Aryl sulfonyl or C 6-10Aryl-C 1-4Alkyl sulphonyl, optional by C 1-6Alkyl or C 6-10Aryl-C 1-4The sulfamoyl that alkyl (as methyl, ethyl, propyl group, isopropyl, butyl, the tert-butyl group, benzyl etc.) replaces and optional by C 1-4The carboxyl of alkyl esterification, optional by C 1-6Alkyl, as methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, n-pentyl, isopentyl, neopentyl and hexyl, or C 2-7Alkanoyl oxygen base-C 1-6Alkyl such as pivaloyl oxygen ylmethyl, the single replacement or dibasic phosphate, optional by sulfonic group and optional by C 1-6Alkyl or C 6-10Aryl C 1-4The C that the sulfamoyl that alkyl replaces replaces 1-3Alkyl (as methyl, ethyl, propyl group and isopropyl), and halogen atom (as fluorine and chlorine), etc.
Should " alkyl " 1～5 substituent group can be arranged on commutable position.
R 2bAnd R 3b" optional substituted heterocyclic group " of expression can contain 1～2 (preferred 1) substituent group such as oxo base and thio group, and is preferably that contain can be by the heterocyclic group of the hydrogen atom of deprotonation.This heterocyclic group is preferably and contains 1～4, preferred 2～3 heteroatomic 5～6 yuan of heterocyclic groups that are selected from S, O and N.Instantiation comprises tetrazole radical, 4,5-dihydro-5-oxo-1,2,4- di azoly, 4,5-dihydro-5-sulfo--1,2,4- di azoly, 2,3-dihydro-3-oxo-1,2,4- di azoly, 2,3-dihydro-3-sulfo--1,2,4- di azoly, 3,5-dioxo-1,2,4- two oxazolidinyls, 4,5-dihydro-5-oxo-different  azoles base, 4,5-dihydro-5-sulfo--different  azoles base, 2,3-dihydro-2-oxo--1,3,4- di azoly, 2,3-dihydro-3-oxo-1,2,4-tetrazole radical and 2,3-dihydro-3-sulfo--1,2, the 4-tetrazole radical.Wherein, be preferably tetrazole radical.
R 2bAnd R 3bThe example of " acyl group " of expression comprises that the carboxylic acyl radical of derived from carboxylic acid is (as C 2-7Carboxylic acyl radical is as acetyl group, propiono, bytyry, benzoyl etc.) and C 6-10Aryl sulfonyl, C 1-4Alkyl sulphonyl and C 6-10Aryl-C 1-4Alkyl sulphonyl, each in them can contain substituent group (as methyl sulphonyl, ethylsulfonyl, phenyl sulfonyl, naphthyl sulfonyl, phenyl methyl sulfonyl, phenylethyl sulfonyl, naphthyl methyl sulfonyl, naphthyl ethylsulfonyl etc.).The substituent group of aryl, alkyl and aryl alkylsulfonyl comprises C 1-3Alkyl (as methyl, ethyl, propyl group etc.), C 1-3Alkoxyl (as methoxyl group, ethyoxyl, propoxyl group etc.), halogen atom (as chlorine, fluorine, bromine) etc., and on commutable position, can have 1～4, be preferably 1～2 these group.
Above-mentioned carboxylic acyl radical can contain 1～2 halogen atom (as chlorine, fluorine, bromine) as substituent group.
Optional by C 1-3Alkyl, C 2-7Alkanoyl etc. replace by R 2bAnd R 3bBe combined to form the amino example of ring with the nitrogen-atoms of adjacent carbamoyl and comprise group derived from 5 yuan or 6 yuan cyclammonium; described cyclammonium such as piperazine, piperidines, pyrrolidine, piperazine-2-ketone, piperazine-2; 6-diketone, morpholine and tetrahydro-1,4-thiazine, and described cyclammonium also can contain 1～3 hetero atom that is selected from nitrogen-atoms, sulphur atom and oxygen atom as the ring composed atom.This ring amino can contain 1～4, is preferably 1～2 substituent group.These substituent examples comprise optional by C 1-3Alkyl or C 2-7The hydroxyl that alkanoyl replaces, optional by C 1-4Alkyl (methyl, ethyl, propyl group, the tert-butyl group etc.) and C 7-10The carboxyl of aryl alkyl esterification, optional by C 1-6Alkyl or C 2-7Alkanoyl oxygen base-C 1-6Alkyl (acetoxy-methyl, pivaloyl oxygen ylmethyl) is single to be replaced or dibasic phosphate, sulfonic group and optional by C 1-6Alkyl or C 6-10Aryl-C 1-4The sulfamoyl that alkyl (as methyl, ethyl, propyl group, isopropyl, butyl, the tert-butyl group, benzyl etc.) replaces, C 1-6Alkyl and C 2-5Thiazolinyl, each can be by " optional by C 1-6Alkyl or C 6-10Aryl-C 1-4The carboxyl of alkyl esterification, optional by C 1-6Alkyl or C 2-7Alkanoyl oxygen base-C 1-6The single replacement of alkyl (as acetoxy-methyl, pivaloyl oxygen ylmethyl etc.) or dibasic phosphate, sulfonic group, optional by C 1-6Alkyl or C 6-10Aryl-C 1-4The sulfamoyl that alkyl replaces, optional by C 1-3Alkyl or C 2-7The hydroxyl that alkanoyl replaces, optional by C 1-3The sulfydryl of alkyl-alkylization, carbamoyl, optional by 1～5 substituent group (as hydroxyl, halogen atom, amino-sulfonyl, optional by C 1-3The amino that alkyl replaces etc.) phenyl that replaces, optional by C 1-3The alkyl list replaces or dibasic amino, or tetrazole radical " institute replaces, chooses wantonly by C 1-3Alkyl (as methyl, ethyl, propyl group etc.) is single to be replaced or dibasic amino, and ring is amino, and (derived from the group of 5 yuan or 6 yuan cyclammonium, it can contain the other hetero atom that is selected from nitrogen-atoms, sulphur atom and oxygen atom as the ring composed atom, and can be by C 1-3Replacements such as alkyl, benzyl, phenyl, for example piperidines, pyrrolidine, morpholine, tetrahydro-1,4-thiazine, 4-methyl piperazine, 4-benzyl piperazine, 4-phenylpiperazine etc.), cyano group, carbamoyl, oxo base, C 1-3Alkoxyl (as methoxyl group, ethyoxyl, ethylidene dioxy base etc.); but optional by oxo base or thio group containing of replacing as the heterocyclic group of the hydrogen atom of above-mentioned deprotonation (as tetrazole radical, 2; 5-dihydro-5-oxo-1; 2; 4- di azoly etc.), for the C of the substituent group exemplary of the optional substituted amino of the carbamoyl of forming " optional substituted carbamoyl " that X represents 6-10Aryl sulfonyl, C 6-10Aryl-C 1-4Alkyl sulphonyl and C 1-4Alkyl sulphonyl (as methyl sulphonyl, ethylsulfonyl, sulfonyl propyl base, butyl sulfonyl, isopropyl sulfonyl, tert-butyl group sulfonyl, phenyl sulfonyl, benzyl sulfonyl etc.), optional by C 1-3The sulfydryl of alkyl-alkylization, or the carbamoyl that is replaced by phenyl, described phenyl can be by 1～5 substituent group (as hydroxyl, halogen atom, amino-sulfonyl, optional by C 1-3The amino that alkyl replaces) replace.
X bThe example of the optional substituted carbamoyl of expression comprises:
Figure S2006800197386D00391
R 2b 'And R B 'Comprise hydrogen atom and C 1-7Alkyl.Be preferably hydrogen atom especially.
R 2b, R 2b 'And R B 'The C of expression 1-7Alkyl comprise with for the C of above-mentioned " alkyl " 1-7The group that the group of alkyl example is identical.
R " comprises hydrogen atom and C 1-4Alkyl.Be preferably hydrogen atom especially.
R 3b 'And the R " C of expression 1-4Alkyl comprises, for example, and methyl, ethyl, propyl group, isopropyl, normal-butyl, the tert-butyl group etc.
For X bBut the optional substituted heterocyclic group of the hydrogen atom that contains deprotonation of expression, be preferably nitrogenous (be preferably and contain 1～4 nitrogen-atoms) and 5～6 yuan of heterocycles that contain Broensted acid sample active proton, and those contain 1～4, preferred 2～3 nitrogen-atoms, sulphur atom and oxygen atoms be preferred.Its substituent group comprises oxo base and thio group, and can have 1～2, and preferred 1 these substituent group exists.The example of the optional substituted heterocyclic group of the hydrogen atom of deprotonation " but contain " that X represents; by those for substituent " the optional substituted heterocyclic group " of " optional substituted carbamoyl " represented as X and example; as tetrazole radical, 2; 5-dihydro-5-oxo-1; 2,4- di azoly etc.
R 1bThe example of " low alkyl group " of expression comprises C 1-6Alkyl is as methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, the tert-butyl group, amyl group, hexyl etc.Wherein, be preferably C 1-3Alkyl.Consider pharmacological activity, R 1bEspecially preferable methyl.
The example of " halogen atom " that W represents comprises chlorine atom, fluorine atom, bromine atoms, iodine atom.Especially preferred chlorine atom.
The example of the salt of the chemical compound of formula (Ib) expression comprises the acceptable salt of pharmacology, as inorganic salt, and example hydrochloric acid salt, hydrobromate, sulfate, nitrate, phosphate etc.; Acylate is as acetate, tartrate, citrate, fumarate, maleate, toluene fulfonate, mesylate etc.; Slaine is as sodium salt, potassium salt, calcium salt, aluminum salt; With the salt that forms with alkali, as triethylamine salt, guanidinesalt, ammonium salt, hydrazonium salt, quinine salt, cinchonine salt etc.
In addition, the hydrate and the non-hydrate of the chemical compound of formula (Ib) expression are also included within scope of the present invention.
Chemical compound and its salt of formula (Ib) expression contain asymmetric carbon atoms at 3 and 5, preferred herein transisomer, wherein 3 relative in the other direction with 5 substituent groups with respect to the plane of 7 yuan of rings, especially 3 absolute configurations are that the isomer that R configuration and 5 absolute configurations are the S configuration is preferred.
For the compound or its salt of formula (Ib) expression, following chemical compound is particularly preferred.
The N-mesyl-[(3R, 5S)-7-chloro-5-(2, the 3-Dimethoxyphenyl)-1-(3-hydroxyl-2,2-dimethyl propyl)-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzo oxygen azepine -3-yl] acetamide,
The N-mesyl-[(3R, 5S)-7-chloro-5-(2, the 3-Dimethoxyphenyl)-1-(3-hydroxyl-2-hydroxymethyl-2-methyl-propyl)-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzo oxygen azepine -3-yl] acetamide,
N-[2-(pyrrolidine-1-yl) ethyl]-[(3R, 5S)-7-chloro-5-(2, the 3-Dimethoxyphenyl)-1-(3-hydroxyl-2-hydroxymethyl-2-methyl-propyl)-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzo oxygen azepine -3-yl] acetamide,
N-[2-(pyrrolidine-1-yl) ethyl]-[(3R, 5S)-7-chloro-5-(2, the 3-Dimethoxyphenyl)-1-(3-hydroxyl-2,2-dimethyl propyl)-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzo oxygen azepine -3-yl] acetamide,
The N-mesyl-[(3R, 5S)-1-(3-acetoxyl group-2,2-dimethyl propyl)-7-chloro-5-(2, the 3-Dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzo oxygen azepine -3-yl] acetamide,
The N-mesyl-[(3R, 5S)-1-(3-acetoxyl group-2-acetoxy-methyl-2-methyl-propyl)-7-chloro-5-(2, the 3-Dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzo oxygen azepine -3-yl] acetamide,
N-[[(3R, 5S)-1-(3-acetoxyl group-2,2-dimethyl propyl)-7-chloro-5-(2, the 3-Dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzo oxygen azepine -3-yl] acetyl group] piperidines-4-acetic acid,
N-[[(3R, 5S)-1-(3-hydroxyl-2,2-dimethyl propyl)-7-chloro-5-(2, the 3-Dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzo oxygen azepine -3-yl] acetyl group] piperidines-4-acetic acid,
N-[[(3R, 5S)-1-(2, the 2-dimethyl propyl)-7-chloro-5-(2, the 3-Dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzo oxygen azepine -3-yl] acetyl group] piperidines-4-acetic acid,
N-[[(3R, 5S)-1-(3-acetoxyl group-2-acetoxy-methyl-2-methyl-propyl)-7-chloro-5-(2, the 3-Dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzo oxygen azepine -3-yl] acetyl group] piperidines-4-acetic acid,
N-[[(3R, 5 S)-1-(3-acetoxyl group-2,2-dimethyl propyl)-7-chloro-5-(2, the 3-Dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzo oxygen azepine -3-yl] acetyl group] piperidines-4-ethyl acetate,
N-[[(3R, 5S)-1-(3-acetoxyl group-2-acetoxy-methyl-2-methyl-propyl)-7-chloro-5-(2, the 3-Dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzo oxygen azepine -3-yl] acetyl group] piperidines-4-ethyl acetate,
(3R, 5S)-7-chloro-5-(2, the 3-Dimethoxyphenyl)-1-(3-hydroxyl-2,2-dimethyl propyl)-1,2,3,5-tetrahydrochysene-3-[1H (or 3H)-tetrazolium-5-yl] methyl-4,1-benzo oxygen azepine  (benzoxapin)-2-ketone,
(3R, 5S)-7-chloro-5-(2, the 3-Dimethoxyphenyl)-1-(3-hydroxyl-2-hydroxymethyl-2-methyl-propyl)-1,2,3,5-tetrahydrochysene-3-[1H (or 3H)-tetrazolium-5-yl] methyl-4,1-benzo oxygen azepine -2-ketone,
(3R, 5S)-1-(3-acetoxyl group-2,2-dimethyl propyl)-7-chloro-5-(2, the 3-Dimethoxyphenyl)-1,2,3,5-tetrahydrochysene-3-[1H (or 3H)-tetrazolium-5-yl] methyl-4,1-benzo oxygen azepine -2-ketone,
(3R, 5S)-1-(3-acetoxyl group-2-acetoxy-methyl-2-methyl-propyl)-7-chloro-5-(2, the 3-Dimethoxyphenyl)-1,2,3,5-tetrahydrochysene-3-[1H (or 3H)-tetrazolium-5-yl] methyl-4,1-benzo oxygen azepine -2-ketone,
N-[2-(pyrrolidine-1-yl) ethyl]-[(3R, 5S)-7-chloro-5-(2, the 3-Dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzo oxygen azepine -3-yl] acetamide, etc.
Chemical compound and its salt of formula (Ib) expression can be according to following disclosed methods, for example, EP-A-567026, WO95/21834 (based on the PCT application of Japanese patent application No. 6-15531), EP-A-645377 (based on the application of Japanese patent application No. 6-229159), EP-A-645378 (based on the application of Japanese patent application No. 6-229160), WO97/10224 etc., or the preparation of method similarly.
For the chemical compound of formula (I) expression, the chemical compound of above-mentioned formula (Ic) expression is preferred.
Figure S2006800197386D00421
The preferred embodiment of the chemical compound of formula (Ic) expression comprises:
Chemical compound, wherein R 1cBe 3-carboxyl propyl group, 1-carboxy ethyl or C 3-6Straight chained alkyl-sulfonyl, (carboxyl-C 5-7Cycloalkyl)-C 1-3Alkyl, (carboxyl furyl)-alkyl, carboxyl-C 6-10Aryl, (carboxyl-C 2-3Alkyl)-C 6-10Aryl or (carboxyl-C 1-3Alkyl)-C 7-14Aralkyl, each can be chosen wantonly and be substituted;
Chemical compound, wherein R 1cFor containing substituent (carboxyl-C 1-4Alkyl)-C 6-10Aryl;
Chemical compound, wherein R 1cFor containing substituent (carboxyl-C 2-3Alkyl)-C 6-10Aryl;
Chemical compound, wherein R 1cFor containing substituent (carboxyl-C 2-3Alkyl)-phenyl;
Chemical compound, wherein R 1cSubstituent (carboxyl furyl)-alkyl for containing;
Chemical compound, wherein R 2cFor containing the C of alkanoyl oxygen base and/or hydroxyl 3-6Alkyl;
Chemical compound, wherein R 2cFor containing 1～3 substituent C that is selected from hydroxyl, acetoxyl group, propionyloxy, tert-butoxycarbonyl oxygen base and Petiolus Trachycarpi acyloxy 3-6Alkyl;
Chemical compound, wherein R 2cBe 2,2-dimethyl propyl, 3-hydroxyl-2,2-dimethyl propyl or 3-acetoxyl group-2,2-dimethyl propyl;
Chemical compound, wherein R 3cBe methyl;
Chemical compound, wherein W is the chlorine atom;
Chemical compound, 3 is the R configuration, and 5 is the S configuration; Deng.
In above-mentioned formula, R 1cThe optional substituted 1-carboxy ethyl of expression, optional substituted carboxyl-C 3-6Straight chained alkyl, optional substituted C 3-6Straight chained alkyl-sulfonyl, optional substituted (carboxyl-C 5-7Cycloalkyl)-C 1-3Alkyl, or by formula-X 1c-X 2c-Ar-X 3c-X 4cThe group that-COOH represents (X wherein 1cAnd X 4cRepresent key or optional substituted C respectively 1-4Alkylidene, X 2cAnd X 3cRepresent respectively key ,-O-or-S-, and Ar represents optional substituted bivalence fragrance cyclic group.Condition is to work as X 1cDuring for key, X 2cThe expression key, and work as X 4cDuring for key, X 3cThe expression key).
At R 1cThe optional substituted carboxyl-C of expression 3-6C in the straight chained alkyl 3-6The example of straight chained alkyl comprises n-pro-pyl, normal-butyl, n-pentyl, n-hexyl.Wherein, be preferably n-pro-pyl and normal-butyl, and n-pro-pyl more preferably.
At R 1cThe optional substituted C of expression 3-6C in straight chained alkyl-sulfonyl 3-6The example of straight chained alkyl comprises n-pro-pyl, normal-butyl, n-pentyl, n-hexyl.Wherein, be preferably n-pro-pyl and normal-butyl is, and n-pro-pyl more preferably.
At R 1cOptional substituted (carboxyl-the C of expression 5-7Cycloalkyl)-C 1-3C in the alkyl 5-7The example of cycloalkyl comprises cyclopenta, cyclohexyl and suberyl.Wherein, be preferably cyclopenta and cyclohexyl, and cyclohexyl more preferably.
At R 1cOptional substituted (carboxyl-the C of expression 5-7Cycloalkyl)-C 1-3C in the alkyl 1-3The example of alkyl comprises methyl, ethyl, n-pro-pyl and isopropyl.Wherein, be preferably methyl and ethyl, and methyl more preferably.
For R 1cFormula-X 1c-X 2c-Ar-X 3c-X 4cIn the group that-COOH represents, X 1cAnd X 4c" the optional substituted C of expression 1-4Alkylidene " in " C 1-4Alkylidene " example comprise methylene, ethylidene, trimethylene, tetramethylene, and be preferably C 1-3Alkylidene, and wherein preferably use straight chain.
In " optional substituted bivalence aromatic group " that Ar represents, " bivalence aromatic group " example comprises bivalence aryl radical, bivalence aromatic heterocycle group etc.
At this, the example of bivalence aryl radical comprises by from C 6-10Aryl (as phenyl, naphthyl etc.) is removed a hydrogen atom and the group that forms, and phenylene is preferably as the bivalence aryl radical.
The example of bivalence aromatic heterocycle group comprises removes the group that a hydrogen atom forms from aromatic heterocycle group, described aromatic heterocycle group contains at least 1 (being preferably 1～4, more preferably 1～2) and is selected from 1～3 kind of (being preferably 1～2 kind) hetero atom in oxygen atom, sulphur atom and the nitrogen-atoms as member ring systems composed atom (annular atoms).
At this, aromatic heterocycle group comprises 5～6 yuan of fragrant monocyclic heterocycles groups, as furyl, thienyl, pyrrole radicals,  azoles base, different  azoles base, thiazolyl, isothiazolyl, imidazole radicals, pyrazolyl, 1,2,3- di azoly, 1,2,4- di azoly, 1,3,4- di azoly, the furazan base, 1,2, the 3-thiadiazolyl group, 1,2, the 4-thiadiazolyl group, 1,3, the 4-thiadiazolyl group, 1,2, the 3-triazolyl, 1,2, the 4-triazolyl, tetrazole radical, pyridine radicals, pyridazinyl, pyrimidine radicals, pyrazinyl and triazine radical (are preferably, furyl, thienyl, pyrrole radicals, imidazole radicals, thiazolyl, pyridine radicals etc.) and 8～12 yuan of fragrant annelated heterocycles groups, as benzofuranyl, isobenzofuran-base, benzo [b] thienyl, indyl, isoindolyl, the 1H-indazolyl, benzimidazolyl, the benzoxazol base, 1,2-benzisoxa  azoles base, benzothiazolyl, benzopyranyl, 1,2-benzisothiazole base, 1H-benzotriazole base, quinolyl, isoquinolyl, the cinnolines base, quinazolyl, quinoxalinyl, phthalazinyl, naphthyridinyl (naphthyridinyl), purine radicals, pteridyl, carbazyl, α-carbolinyl, the B-carboline base, the gamma-carbolines base, acridinyl, fen  piperazine base, phenothiazinyl, phenazinyl, dibenzthioxine base (phenoxathiinyl), thianthrene group, phenanthridinyl (phenathridinyl), the phenanthroline base, the indolizine base, pyrrolo-[1,2-b] pyridazinyl, pyrazolo [1,5-a] pyridine radicals, imidazo [1,2-a] pyridine radicals, imidazo [1,5-a] pyridine radicals, imidazo [1,2-b] pyridazinyl, imidazo [1,2-a] pyrimidine radicals, 1,2,4-triazol [4,3-a] pyridine radicals and 1,2,4-triazol [4,3-b] pyridazinyl (is preferably, wherein above-mentioned 5～6 yuan of fragrant monocyclic heterocycles groups and phenyl ring condensed heterocycle group, or wherein two identical or different above-mentioned 5～6 yuan of fragrant monocyclic heterocycles groups condense the heterocyclic group of formation, and more preferably, wherein above-mentioned 5～6 yuan of fragrant monocyclic heterocycles groups and phenyl ring condensed heterocycle group).
X 1cAnd X 4c" the optional substituted C of expression 1-4Alkylidene " in " C 1-4Alkylidene " and " optional substituted bivalence fragrance cyclic group " in " bivalence fragrance cyclic group " the substituent example that can contain comprise: (i) optional by C 1-6Alkyl or C 6-10Aryl-C 1-4The carboxyl of alkyl (as methyl, ethyl, propyl group, isopropyl, butyl, the tert-butyl group, phenyl, benzyl etc.) esterification, (ii) optional by C 1-6Alkyl (as methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, n-pentyl, isopentyl, neopentyl, hexyl etc.) or C 2-7Alkanoyl oxygen base-C 1-6Alkyl, as acetoxy-methyl and pivaloyl oxygen ylmethyl, the single replacement or dibasic phosphate, (iii) sulfonic group, (iv) optional by C 1-6Alkyl or C 6-10Aryl-C 1-4The sulfamoyl that alkyl (as methyl, ethyl, propyl group, isopropyl, butyl, the tert-butyl group, benzyl etc.) replaces, (v) hydroxyl and sulfydryl, each can be by C 1-3Alkyl (as methyl, ethyl, propyl group etc.) alkylation, (vi) carbamoyl, (vii) phenyl, its can be replaced by 1～5 substituent group [as, hydroxyl, chlorine, fluorine, amino-sulfonyl and optional by C 1-3The amino that alkyl (as methyl, ethyl, propyl group etc.) replaces], and can connect, (viii) choose wantonly by C by O or S 1-3The single replacement of alkyl (as methyl, ethyl, propyl group etc.) or dibasic amino, (ix) choose wantonly by 1～3 C 1-3Alkyl is (as methyl, ethyl etc.), benzyl, the ring amino that phenyl etc. replace is (amino as 5～6 yuan of rings, it is except that the nitrogen-atoms derived from the ring amino of (by removing a hydrogen atom) cyclammonium, also can contain oxygen atom or sulphur atom as the ring composed atom, described cyclammonium such as piperidines, pyrrolidine, morpholine, tetrahydro-1,4-thiazine, piperazine, the 4-methyl piperazine, 4-benzyl piperazine, the 4-phenylpiperazine, 1,2,3, the 4-tetrahydroisoquinoline, phthalimide etc.), (x) can contain 1～4 and be selected from N, heteroatomic 5～6 membered aromatic heterocycle groups of O and S, and can by O or S be connected (as pyridine radicals, imidazole radicals, indyl, tetrazole radical etc.), (xi) halogen atom is (as chlorine, fluorine, bromine, iodine etc.), (xii) C 1-4Alkyl (as methyl, ethyl, propyl group, isopropyl, butyl, the tert-butyl group etc.), C 1-4Alkoxyl (as methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, tert-butoxy etc.) or C 1-4Alkyl sulfenyl (as methyl sulfenyl, ethyl sulfenyl, propyl group sulfenyl, isopropyl sulfenyl, butyl sulfenyl, tert-butyl group sulfenyl etc.), each can be selected from C 1-4Alkoxyl, C 1-4The substituent group of alkyl sulfenyl, carboxyl and phenyl replaces, (xiii) C 5-7Cycloalkyl (as cyclopenta, cyclohexyl, suberyl etc.) and (xiv) C 1-7Alkanoyl oxygen base (as formyloxy, acetoxyl group, propionyloxy, bytyry oxygen base, tert-butoxycarbonyl oxygen base, isobutyryl oxygen base, penta acyloxy, pivaloyl oxygen base etc.).On commutable position, can there be 1～6, be preferably 1～3 these substituent group.And two substituent groups can be connected to form C 3-6Alkylidene, C 3-6Alkylidene oxygen base, C 3-6Alkylenedioxy groups etc., for example, two adjacent substituent groups on phenyl are connected to form C 4During alkylidene, formed naphthane.
R 1cChinese style-X 1c-X 2c-Ar-X 3c-X 4cThe instantiation of the group that-COOH represents comprises optional substituted (carboxyl-heteroaryl)-C 1-4Alkyl [is preferably optional substituted (carboxyl-furyl)-C 1-4Alkyl], optional substituted (carboxyl-C 6-10Aryl)-C 1-4Alkyl, optional substituted carboxyl-heteroaryl, optional substituted carboxyl-C 6-10Aryl, optional substituted (carboxyl-C 1-4Alkyl)-heteroaryl, optional substituted (carboxyl-C 1-4Alkyl)-C 6-10Aryl [is preferably (carboxyl-C 2-3Alkyl)-C 6-10Aryl], optional substituted (carboxyl-C 1-4Alkyl)-heteroaryl-C 1-4Alkyl, optional substituted (carboxyl-C 1-4Alkyl)-C 7-14Aralkyl [is preferably optional substituted (carboxyl-C 1-3Alkyl)-C 7-14Aralkyl], optional substituted (carboxyl-C 1-4Alkoxyl)-C 6-10Aryl, optional substituted (carboxyl-C 1-4Alkoxyl)-C 6-10Aryl-C 1-4Alkyl, optional substituted (carboxyl-C 1-4Alkyl)-C 6-10Aryloxy group-C 1-4Alkyl, optional substituted (carboxyl-C 6-10Aryloxy group)-C 1-4Alkyl and optional substituted (carboxyl-C 1-4The alkyl sulfenyl)-heteroaryl.
At this, can be example and above-mentioned " aromatic heterocycle group " identical group for heteroaryl, and heteroaryl can contain the identical substituent group of substituent group that can contain with above-mentioned " aromatic heterocycle group ".And, C 6-10The example of aryl comprises phenyl, naphthyl, azulene base, and preferably uses phenyl.C 6-10Aryl can contain the identical substituent group of substituent group that can contain with above-mentioned " aromatic heterocycle group ".
R 1Optional substituted (carboxyl the furyl)-C of expression 1-4The example of the alkyl in the alkyl comprises C 1-4The straight or branched alkyl is as methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, 1,1-dimethyl ethyl etc.Wherein, be preferably C 1-4Alkyl, as methyl, ethyl, n-pro-pyl, isopropyl and normal-butyl, and more preferably methyl, ethyl and n-pro-pyl.The example of carboxyl furyl comprises 3-carboxyl-2-furyl, 4-carboxyl-2-furyl, 2-carboxyl-3-furyl, 2-carboxyl-5-furyl etc.Wherein, be preferably 3-carboxyl-2-furyl and 4-carboxyl-2-furyl, and 3-carboxyl-2-furyl more preferably.
R 1cOptional substituted (carboxyl-the C of expression 2-3Alkyl)-C 6-10C in the aryl 2-3The example of alkyl comprises ethyl, n-pro-pyl and isopropyl, and preferred ethyl and n-pro-pyl.C 6-10The example of aryl comprises phenyl, naphthyl and azulene base, and is preferably phenyl.
R 1cOptional substituted (carboxyl-the C of expression 1-3Alkyl)-C 7-14C in the aralkyl 1-3The example of alkyl comprises methyl, ethyl, n-pro-pyl and isopropyl, and is preferably methyl and ethyl, and is preferably ethyl especially.C 7-14Aralkyl (C 6-10Aryl-C 1-4Alkyl) example comprises phenyl methyl, the 1-phenylethyl, the 2-phenylethyl, the 3-phenyl propyl, the 2-phenyl propyl, the 4-phenyl butyl, (1-naphthyl) methyl, (2-naphthyl) methyl, 1-(1-naphthyl) ethyl, 1-(2-naphthyl) ethyl, 3-(1-naphthyl) propyl group, 3-(1-naphthyl) propyl group, 4-(1-naphthyl) butyl and 4-(2-naphthyl) butyl, and be preferably phenyl methyl, the 1-phenylethyl, the 3-phenyl propyl, (1-naphthyl) methyl, (2-naphthyl) methyl, (1-naphthyl) ethyl and (2-naphthyl) ethyl, and be preferably phenyl methyl and 2-phenylethyl especially.
Work as R 1cWhen each group of expression contains substituent group, for this substituent group, the identical substituent group of substituent group that " bivalence aromatic group " can contain in " optional substituted bivalence aromatic group " that but example and Ar represent, and can there be 1～6 in commutable position, be preferably 1～3 substituent group.In addition, R 1cIn each group of expression, preferably carboxy moiety is not substituted, but and is not that the arbitrary portion of carboxy moiety can contain commutable substituent group at the position of substitution.
For R 1c, be preferably each and can contain substituent 3-carboxyl propyl group, 1-carboxy ethyl or C 3-6Straight chained alkyl-sulfonyl, (carboxyl-C 5-7Cycloalkyl)-C 1-3Alkyl, (carboxyl furyl)-alkyl, carboxyl-C 6-10Aryl, (carboxyl-C 1-4Alkyl)-C 6-10Aryl [is preferably (carboxyl-C 2-3Alkyl)-C 6-10Aryl] and (carboxyl-C 1-3Alkyl)-C 7-14Aralkyl etc. are preferably optional substituted (carboxyl-C 1-4Alkyl)-C 6-10Aryl, and more preferably optional substituted (carboxyl-C 2-3Alkyl)-C 6-10Aryl.Especially, preferably optional substituted (carboxyl-C 2-3Alkyl)-phenyl.
At R 2cChoosing wantonly of expression by the C of alkanoyl oxygen base or hydroxyl replacement 3-6C in the alkyl 3-6The example of alkyl comprises n-pro-pyl, isopropyl, 1,1-dimethyl ethyl, normal-butyl, isobutyl group, n-pentyl, 2,2-dimethyl propyl, isopentyl, n-hexyl, isohesyl etc., wherein, be preferably isopropyl, 1,1-dimethyl ethyl, normal-butyl, isobutyl group, 2,2-dimethyl propyl and isohesyl, and be preferably 2 especially, the 2-dimethyl propyl.
At R 2cChoosing wantonly of expression by the C of alkanoyl oxygen base or hydroxyl replacement 3-6The example of the alkanoyl oxygen base in the alkyl comprises C 1-20Alkanoyl oxygen base (is preferably C as formyloxy, acetoxyl group, propionyloxy, bytyry oxygen base, tert-butoxycarbonyl oxygen base, isobutyryl oxygen base, penta acyloxy, pivaloyl oxygen base, lauroyl oxygen base, Petiolus Trachycarpi acyloxy, stearyl oxygen base 1-7Alkanoyl oxygen base etc.).Wherein, be preferably acetoxyl group, propionyloxy, tert-butoxycarbonyl oxygen base and Petiolus Trachycarpi acyloxy, and be preferably acetoxyl group especially.On commutable position, can be substituted with 1～3 alkanoyl oxygen base or hydroxyl.
R 2cChoosing wantonly of expression by the C of alkanoyl oxygen base or hydroxyl replacement 3-6The preferred embodiment of alkyl comprises 2,2-dimethyl propyl, 3-hydroxyl-2,2-dimethyl propyl, 3-hydroxyl-2-hydroxymethyl-2-methyl-propyl, 3-acetoxyl group-2,2-dimethyl propyl, 3-acetoxyl group-2-hydroxymethyl-2-methyl-propyl and 3-acetoxyl group-2-acetoxy-methyl-2-methyl-propyl.Wherein, be preferably 2 especially, 2-dimethyl propyl, 3-hydroxyl-2,2-dimethyl propyl and 3-acetoxyl group-2,2-dimethyl propyl.
In addition, for R 2c, be preferably the C that contains alkanoyl oxygen base and/or hydroxyl 3-6Alkyl.
R 3cThe example of the low alkyl group of expression comprises C 1-6Alkyl is as methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, the tert-butyl group, amyl group, hexyl.Wherein, be preferably C 1-3Alkyl.Consider pharmacological activity, R 3cBe preferably methyl especially.
The example of the halogen atom that W represents comprises chlorine, fluorine, bromine and iodine atom.Wherein, be preferably the chlorine atom.
The present invention includes chemical compound with formula (Ic) expression of free form or the acceptable salt form of its pharmacology.For salt, the chemical compound of representing when formula (Ic) contains acidic-group, during as carboxyl, its can with inorganic base (as alkali metal, as sodium and potassium, alkaline-earth metal, as calcium and magnesium, transition metal such as zinc, ferrum and copper etc.) or organic base (as organic amine, as trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine and N, N '-benzhydryl ethylenediamine and basic amino acid such as arginine, lysine and ornithine etc.) formation salt.
If when formula of the present invention (Ic) expression chemical compound contains basic group, during as amino, its can with mineral acid or organic acid (example hydrochloric acid, nitric acid, sulphuric acid, phosphoric acid, carbonic acid, heavy carbonic, formic acid, acetic acid, propanoic acid, trifluoroacetic acid, Fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-methyl benzenesulfonic acid etc.), and acidic amino acid, form salt as aspartic acid, glutamic acid etc.
The compound or its salt of formula (Ic) expression contains asymmetric carbon atom at 3 and 5, but it can be the mixture of stereoisomer, and also can pass through conventional method separating isomerism body.Be preferably transisomer, wherein 3 with 5 on substituent group relative in the other direction with respect to 7 yuan of plane of a loops, and especially preferably wherein 3 absolute configurations be R configuration and 5 isomers that absolute configuration is the S configuration.And it can be racemoid or optically active isomer.Can be by known method for optical resolution dissociated optical active isomer from racemoid.
Compound or its salt for formula of the present invention (Ic) expression is preferably following chemical compound especially.
N-third sulfonyl-[(3R, 5S)-7-chloro-5-(2, the 3-Dimethoxyphenyl)-1-(3-hydroxyl-2,2-dimethyl propyl)-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzo oxygen azepine -3-yl] acetamide or its salt;
(2R)-2-[[(3R, 5S)-7-chloro-5-(2, the 3-Dimethoxyphenyl)-1-(2, the 2-dimethyl propyl)-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzo oxygen azepine -3-yl] acetyl group] alanine or its salt;
3-[3-[[(3R, 5S)-7-chloro-5-(2, the 3-Dimethoxyphenyl)-1-(2, the 2-dimethyl propyl)-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzo oxygen azepine -3-yl] acetyl group] aminophenyl] propanoic acid or its salt;
4-[[(3R, 5S)-7-chloro-5-(2, the 3-Dimethoxyphenyl)-1-(2, the 2-dimethyl propyl)-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzo oxygen azepine -3-yl] acetyl group] aminobutyric acid or its salt;
Trans-4-[[(3R, 5S)-1-(3-acetoxyl group-2,2-dimethyl propyl)-7-chloro-5-(2, the 3-Dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzo oxygen azepine -3-yl] acetyl group]-aminomethyl-1,2-cyclohexane-carboxylic acid or its salt;
Trans-4-[[(3R, 5S)-7-chloro-5-(2, the 3-Dimethoxyphenyl)-1-(3-hydroxyl-2,2-dimethyl propyl)-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzo oxygen azepine -3-yl] acetyl group]-aminomethyl-1,2-cyclohexane-carboxylic acid or its salt;
3-[3-[[[(3R, 5S)-1-(3-acetoxyl group-2,2-dimethyl propyl)-7-chloro-5-(2, the 3-Dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzo oxygen azepine -3-yl] acetyl group] amino]-the 4-fluorophenyl] propanoic acid or its salt;
3-[3-[[[(3R, 5S)-7-chloro-5-(2, the 3-Dimethoxyphenyl)-1-(3-hydroxyl-2,2-dimethyl propyl)-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzo oxygen azepine -3-yl] acetyl group] amino]-the 4-aminomethyl phenyl] propanoic acid or its salt;
3-[3-[[[(3R, 5S)-1-(3-acetoxyl group-2,2-dimethyl propyl)-7-chloro-5-(2, the 3-Dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzo oxygen azepine -3-yl] acetyl group] amino]-the 4-aminomethyl phenyl] propanoic acid or its salt;
3-[3-[[[(3R, 5S)-7-chloro-5-(2, the 3-Dimethoxyphenyl)-1-(3-hydroxyl-2,2-dimethyl propyl)-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzo oxygen azepine -3-yl] acetyl group] amino methyl] phenyl] propanoic acid or its salt;
3-[3-[[[(3R, 5S)-1-(3-acetoxyl group-2,2-dimethyl propyl)-7-chloro-5-(2, the 3-Dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzo oxygen azepine -3-yl] acetyl group] amino methyl] phenyl] propanoic acid or its salt;
3-[3-[[[(3R, 5S)-7-chloro-5-(2, the 3-Dimethoxyphenyl)-1-(3-hydroxyl-2,2-dimethyl propyl)-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzo oxygen azepine -3-yl] acetyl group] amino]-the 4-methoxyphenyl] propanoic acid or its salt;
2-[2-[[[(3R, 5S)-7-chloro-5-(2, the 3-Dimethoxyphenyl)-1-(3-hydroxyl-2,2-dimethyl propyl)-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzo oxygen azepine -3-yl] acetyl group] amino] ethyl] furan-3-carboxylic acid or its salt;
3-[3-[[[(3R, 5S)-7-chloro-5-(2, the 3-Dimethoxyphenyl)-1-(3-hydroxyl-2,2-dimethyl propyl)-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzo oxygen azepine -3-yl] acetyl group] amino]-the 4-fluorophenyl] propanoic acid or its salt;
3-[3-[[(3R, 5S)-7-chloro-5-(2, the 3-Dimethoxyphenyl)-1-(3-hydroxyl-2,2-dimethyl propyl)-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzo oxygen azepine -3-yl] acetyl group] aminophenyl] propanoic acid or its salt;
4-[3-[[[(3R, 5S)-7-chloro-5-(2, the 3-Dimethoxyphenyl)-1-(3-hydroxyl-2,2-dimethyl propyl)-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzo oxygen azepine -3-yl] acetyl group] amino]-the 4-methoxyphenyl] butanoic acid or its salt;
5-[3-[[[(3R, 5S)-7-chloro-5-(2, the 3-Dimethoxyphenyl)-1-(3-hydroxyl-2,2-dimethyl propyl)-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzo oxygen azepine -3-yl] acetyl group] amino]-the 4-methoxyphenyl] valeric acid or its salt;
5-[3-[[[(3R, 5S)-7-chloro-5-(2, the 3-Dimethoxyphenyl)-1-(3-hydroxyl-2,2-dimethyl propyl)-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzo oxygen azepine -3-yl] acetyl group] amino]-the 4-fluorophenyl] valeric acid or its salt.
Can prepare the compound or its salt of above-mentioned formula (Ic) expression according to following disclosed method, described method is disclosed in for example EP A 567,026, WO95/21834 (based on the international application of Japanese patent application No. 6-15531), EP A 645,377 (based on the applications of Japanese patent application No. 6-229159), EP A645,378 (based on the applications of Japanese patent application No. 6-229160), WO01/98282 (based on the international application of Japanese patent application No. 2000-190253) etc., or its similar method.
Raw material for the chemical compound of formula of the present invention (I) expression can use and above-mentioned those identical salt, but as long as their disturbance reponses not have no particular limits them.
The preferred embodiment of each definition is as follows in the chemical compound of formula (II) expression.
The substituent group of " optional substituted phenyl ring " that ring A represents comprises halogen (as fluorine, chlorine, bromine, iodine), contain the optional substituted low alkyl group (as methyl, ethyl, propyl group, butyl, the tert-butyl group etc.) of 1～4 carbon atom, contain optional substituted lower alkoxy (as methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, tert-butoxy etc.), hydroxyl, nitro and the cyano group of 1～4 carbon atom.Ring A can contain 1～3, is preferably 1～2 these substituent group.These substituent adjacent substituent groups can form ring together.The substituent group that contains the optional substituted low alkyl group of 1～4 carbon atom or contain the optional substituted lower alkoxy of 1～4 carbon atom comprises halogen (as fluorine, chlorine, bromine, iodine), and in optional commutable position 1～3 substituent group can be arranged.Ring A is preferably by the phenyl ring of replacements such as halogen atom, the more preferably phenyl ring that is replaced by the chlorine atom.Ring A is preferably the phenyl ring that following formula is represented:
Figure S2006800197386D00501
Wherein, W represents halogen atom (as fluorine, chlorine, bromine, iodine), and especially, W is preferably the chlorine atom.
The substituent group of " optional substituted phenyl ring " that ring B represents comprises the identical group of substituent group of " optional substituted phenyl ring " that ring A equal number and above-mentioned example represents.Ring B is preferably the phenyl ring of the lower alkoxy replacement that is contained 1～4 carbon atom, and especially, is preferably the phenyl ring that following formula is represented:
Figure S2006800197386D00502
R wherein 2aAnd R 2bRepresent hydrogen atom independently or contain the low alkyl group (as methyl, ethyl, propyl group, butyl etc.) and the particularly preferred R of 1～4 carbon atom 2aAnd R 2bBe methyl.
The aromatic rings of " optional further substituted aromatic rings " that ring C represents comprises aromatic hydrocarbon ring and aromatic heterocycle.The aromatic hydrocarbon ring comprises, for example phenyl ring, naphthalene nucleus etc., and be preferably phenyl ring.Aromatic heterocycle (aromatic heterocycle of " the optional further substituted aromatic heterocycle " of ring C ' expression) comprises, for example, contain at least 1 (being preferably 1～4, more preferably 1～2) and be selected from the aromatic heterocycle of 1～3 kind of oxygen atom, sulphur atom, nitrogen-atoms etc. (be preferably 1 or 2 kind) hetero atom as the atom (annular atoms) of makeup ring system.
Aromatic heterocycle comprises 5～6 yuan of monocycle aromatic heterocycles, as furan, thiophene, pyrroles,  azoles, different  azoles, thiazole, isothiazole, imidazoles, pyrazoles, 1,2,3- diazole, 1,2,4- diazole, 1,3,4- diazole, furazan, 1,2,3-thiadiazoles, 1,2,4-thiadiazoles, 1,3,4-thiadiazoles, 1,2,3-triazole, 1,2,4-triazole, tetrazolium, pyridine, pyridazine, pyrimidine, pyrazine, triazine etc.; 8～12 yuan condense aromatic heterocycle, as benzofuran, isobenzofuran, benzo [b] thiophene, indole, iso-indoles, the 1H-indazole, benzimidazole, benzoxazol, 1,2-benzisoxa  azoles, benzothiazole, .alpha.-5:6-benzopyran, 1, the 2-benzisothiazole, the 1H-benzotriazole, quinoline, isoquinolin, cinnolines, quinazoline, quinoxaline, phthalazines, naphthyridines (naphthyridine), purine, pteridine, carbazole, α-carboline, B-carboline, gamma-carbolines, acridine, fen  piperazine, phenothiazine, azophenlyene, fen thiophene , thianthrene, phenanthridines, phenanthroline, indolizine, pyrrolo-[1,2-b] pyridazine, pyrazolo [1,5-a] pyridine, imidazo [1,2-a] pyridine, imidazo [1,5-a] pyridine, imidazo [1,2-b] pyridazine, imidazo [1,2-a] pyrimidine, 1,2,4-triazol [4,3-a] pyridine, 1,2,4-triazol [4,3-b] pyridazine etc. (is preferably wherein above-mentioned 5～6 yuan of monocycle aromatic heterocycles and phenyl ring condensed heterocycle, or 2 identical or different above-mentioned 5～6 yuan of monocycle aromatic heterocycle condensed heterocycle wherein, more preferably wherein above-mentioned 5～6 yuan of monocycle aromatic heterocycles and phenyl ring condensed heterocycle) etc.
Ring C is preferably monocycle aromatic heterocycle, phenyl ring etc., and especially, is preferably 5 yuan of monocycle aromatic heterocycles, as pyrazoles, imidazoles, thiazole,  azoles, different  azoles, 1,2, and 4- diazole, 1,3,4- diazole etc.
But though but ring C can or not contain the aromatic rings of the hydrogen atom of deprotonation for the aromatic rings of the hydrogen atom that contains deprotonation, but be preferably the aromatic rings of the hydrogen atom that contains deprotonation.Originally do not contain the aromatic rings of the hydrogen atom of deprotonation but remove (as phenyl ring, thiazole,  azoles, different  azoles, 1,2,4- diazole, 1,3,4- diazole etc.) outside, but the aromatic rings that does not contain the hydrogen atom of deprotonation comprise wherein can be protonated the hydrogen atom substituted aromatic rings (as pyrroles, pyrazoles, imidazoles etc., the hydrogen atom on the nitrogen-atoms of its makeup ring is substituted or its nitrogen-atoms by makeup ring is connected to X 1aOr/and X 1b).
The substituent group that aromatic rings in " optional further substituted aromatic rings " that its medium ring C represents can contain comprises that (i) is optional by optional halogenated C 1-6Alkyl or optional by halogenated C 6-10Aryl-C 1-4The carboxyl of alkyl (as methyl, ethyl, propyl group, isopropyl, butyl, the tert-butyl group, phenyl, benzyl etc.) esterification, (ii) optional by optional halogenated C 1-6Alkyl (as methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, n-pentyl, isopentyl, neopentyl, hexyl etc.) or C 2-7Alkanoyl oxygen base-C 1-6Alkyl replaces or dibasic phosphate, (iii) sulfonic group, (iv) optional by optional halogenated C as acetoxy-methyl or pivaloyl oxygen ylmethyl list 1-6Alkyl or optional halogenated C 6-10Aryl-C 1-4The sulfamoyl that alkyl (as methyl, ethyl, propyl group, isopropyl, butyl, the tert-butyl group, benzyl etc.) replaces, (v) hydroxyl and sulfydryl, it can be chosen wantonly by optional halogenated C 1-3Alkyl (as methyl, ethyl, propyl group etc.) replaces, (vi) carbamoyl, (vii) optional by 1～5 substituent group [as hydroxyl, chlorine, fluorine, amino-sulfonyl, optional by C 1-3The amino that alkyl (as methyl, ethyl, propyl group etc.) replaces] phenyl that replaces, and optional by O or S links to each other with aromatic rings, (viii) optionally chosen wantonly halogenated C 1-3The single replacement of alkyl (as methyl, ethyl, propyl group etc.) or dibasic amino, (ix) choose wantonly by 1～3 C 1-3Alkyl is (as methyl, ethyl etc.), benzyl, the ring amino of replacements such as phenyl (also contains oxygen atom or sulphur atom is amino as 5～6 yuan of rings of the atom of makeup ring as optional except that nitrogen-atoms, as ring amino derived from (by removing a hydrogen atom) cyclammonium, described cyclammonium such as piperidines, pyrrolidine, morpholine, tetrahydro-1,4-thiazine, piperazine, the 4-methyl piperazine, 4-benzyl piperazine, the 4-phenylpiperazine, 1,2,3,4-tetrahydroisoquinoline or phthalimide), (x) contain 1～4 and be selected from N, heteroatomic 5～6 membered aromatic heterocycle groups of O and S, and optional connect aromatic rings (as pyridine radicals by O or S, imidazole radicals, indyl, tetrazole radical etc.), (xi) halogen atom is (as chlorine, fluorine, bromine, iodine etc.), (xii) C 1-4Alkyl (as methyl, ethyl, propyl group, isopropyl, butyl, the tert-butyl group etc.), C 1-4Alkoxyl (as methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, tert-butoxy etc.) or C 1-4Alkyl sulfenyl (as methyl sulfenyl, ethyl sulfenyl, propyl group sulfenyl, isopropyl sulfenyl, butyl sulfenyl, tert-butyl group sulfenyl etc.), each can be chosen wantonly and is selected from halogen atom, C 1-4Alkoxyl, C 1-4The substituent group of alkyl sulfenyl, carboxyl and phenyl replaces, (xiii) C 5-7Cycloalkyl (as cyclopenta, cyclohexyl, suberyl etc.) and (xiv) optional halogenated C 1-7Alkanoyl oxygen base (as formyloxy, acetoxyl group, propionyloxy, bytyry oxygen base, tert-butoxycarbonyl oxygen base, isobutyryl oxygen base, penta acyloxy, pivaloyl oxygen base etc.).In commutable position, " optional further substituted aromatic rings " can be preferably 1～3 these substituent group and replace by 1～6.2 these substituent groups can form C together 3-6Alkylidene, C 3-6Alkylidene oxygen base, C 3-6Alkylenedioxy group etc.For example, the continuous mutually C that forms of 2 adjacent substituent groups on phenyl 4During alkylidene, form tetralyl.
R 1Low alkyl group in " the optional low alkyl group that is replaced by optional substituted hydroxyl " of expression comprises, for example, and C 1-6Alkyl is as methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, n-pentyl, isopentyl, neopentyl, hexyl etc.Wherein, be preferably C 3-6Alkyl, and C more preferably 4-5Alkyl.Especially, be preferably side chain C 4-5Alkyl is as isobutyl group, neopentyl etc.
R 1The substituent group that low alkyl group in " the optional low alkyl group that is replaced by optional substituted hydroxyl " of expression can contain comprises optional by C 2-20Alkanoyl or C 1-7The hydroxyl that alkyl replaces.These substituent groups comprise, for example, and hydroxyl, acetyl group oxygen base (acetyloxy) (acetoxyl group (acetoxy)), propionyloxy, tert-butoxycarbonyl oxygen base, Petiolus Trachycarpi acyloxy, dimethylamino acetoxyl group, the amino propionyloxy of 2-etc.In commutable position, low alkyl group can be replaced by 1～3 such substituent group.
R 1Example comprise 1-propyl group, 1-isopropyl, 1-isobutyl group, 1-neopentyl, 2,2-dimethyl-3-hydroxypropyl, 3-hydroxyl-2-hydroxymethyl-2-methyl-propyl, 3-acetoxyl group-2,2-dimethyl propyl, 3-acetoxyl group-2-hydroxymethyl-2-methyl-propyl group, 3-acetoxyl group-2-acetoxy-methyl-2-methyl-propyl, [1-(hydroxymethyl) cyclobutyl] methyl etc.Wherein, be preferably 2,2-dimethyl-3-hydroxypropyl, 3-hydroxyl-2-hydroxymethyl-2-methyl-propyl, 3-acetoxyl group-2,2-dimethyl propyl, 3-acetoxyl group-2-hydroxymethyl-2-methyl-propyl, 3-acetoxyl group-2-acetoxy-methyl-2-methyl-propyl etc.
X 1aLow-grade alkylidene in " optional substituted low-grade alkylidene " of expression comprises, for example, and C 1-6Alkylidene is as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene etc.Wherein, be preferably straight chain C 1-4Alkylidene, as methylene, ethylene, trimethylene, tetramethylene etc., and straight chain C more preferably 1-3Alkylidene.
X 1aThe substituent group that low-grade alkylidene in " optional substituted low-grade alkylidene " of expression can contain comprises the identical group of substituent group that the aromatic rings of " the optional further substituted aromatic rings " represented with the ring C of above-mentioned example can contain, oxo base etc.In commutable position, " low-grade alkylidene " can be preferably 1～3 such substituent group and replace by 1～6.
X 1aBe preferably key or straight chain C 1-3Alkylidene, and be preferably methylene especially.
X 1bLow-grade alkylidene in " optional substituted low-grade alkylidene " of expression be exemplified as X 1aThe identical group of low-grade alkylidene of " the optional substituted low-grade alkylidene " of expression.X 1bThe substituent group that the low-grade alkylidene of " optional substituted low-grade alkylidene " of expression can contain, comprise equal number be exemplified as X 1aThe identical group of substituent group of the low-grade alkylidene of " the optional substituted low-grade alkylidene " of expression.
X 1bBe preferably key or straight chain C 1-3Alkylidene, and be preferably key especially.
X 2Be preferably key.
X 3" bivalent hydrocarbon radical " in " the optional substituted bivalent hydrocarbon radical " of expression comprises by removing the group that hydrogen atom forms from alkyl.Described alkyl comprises C 1-7Straight or branched alkyl (as methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, 1,1-dimethyl ethyl, n-pentyl, 3-methyl butyl, 2-methyl butyl, 1-methyl butyl, 1-ethyl propyl, n-hexyl, 4-methyl amyl, 3-methyl amyl, 2-methyl amyl, 2-ethyl-butyl, 1-ethyl-butyl, neopentyl, hexyl, heptyl), C 3-7Cycloalkyl (cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, cyclohexyl methyl etc.), straight or branched C 2-6Thiazolinyl (as vinyl, pi-allyl, isopropenyl, 2-methacrylic, 1-acrylic, 2-methyl isophthalic acid-acrylic, 2-methyl-2-acrylic, 1-butylene base, crotyl, 3-cyclobutenyl, 2-ethyl-1-butylene base, 2-methyl-2-butene base, 3-methyl-2-butene base, 1-pentenyl, pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl etc.), C 6-10Aryl (as phenyl, naphthyl), C 7-14Aryl alkyl (as benzyl, phenethyl, naphthyl methyl) etc.
X 3The substituent group that " bivalent hydrocarbon radical " in " the optional substituted bivalent hydrocarbon radical " of expression can contain comprises with above-mentioned as X 1aThe group that the substituent group that the low-grade alkylidene of " the optional substituted low-grade alkylidene " of expression can contain is identical, optional by halogenated C 1-6Alkylidene radical (as methene base, ethidine, propylidene base, isopropylidene, fourth fork base etc.), vinylidene base, cyclohexylidene base, benzene methene base etc.But at the position of substitution, described " bivalent hydrocarbon radical " can be preferably 1～3 such substituent group and replace by 1～6.
X 3" bivalent hydrocarbon radical " in " the optional substituted bivalent hydrocarbon radical " of expression preferably includes (1) straight or branched alkylidene, the carbon number of wherein forming linear fraction is that 1～7 (being preferably 1～4) is (as methylene, 1, the 2-ethylidene, 1, the 3-propylidene, 1, the 4-butylidene, 1, the 5-pentylidene, 1, the 6-hexylidene, 1, the inferior heptyl of 7-, propylidene, the ethyl methylene, the ethyl ethylidene, the propyl group ethylidene, the butyl ethylidene, methyl 1, the 4-butylidene, methyl 1,3-propylidene etc.), (2) contain the carbochain of two keys, the carbon number of wherein forming linear fraction is that 2～7 (being preferably 2～4) are (as ethenylidene, allylidene, butenylidene, Aden's dialkylene, the methyl allylidene, the ethyl allylidene, the propyl group allylidene, the methyl butenylidene, the ethyl butenylidene, the propyl group butenylidene, methyl Aden dialkylene, ethyl Aden dialkylene, propyl group Aden dialkylene, inferior pentenyl, inferior hexenyl, inferior heptenyl, inferior pentadienyl, inferior hexadienyl, inferior heptadiene base etc.), (3) phenylene is (as 1, the 2-phenylene, 1, the 3-phenylene, 1,4-phenylenes etc.) and (4) divalent group, wherein phenylene and alkylidene and/or alkenylene are bonded (as-CH 2-C 6H 4-,-CH 2CH 2-C 6H 4-,-CH 2-C 6H 4-CH 2-etc.).
X 3Be preferably C 1-4Alkylidene is as methylene, ethylidene, trimethylene, tetramethylene etc., ethenylidene, allylidene, phenylene etc.
" the optional esterified or amidated carboxyl " that Y represents comprises carboxyl, contains elementary alkoxy carbonyl (as methoxycarbonyl, ethoxy carbonyl, propoxycarbonyl, isopropoxy carbonyl, butoxy carbonyl, tert-butoxycarbonyl, sec-butoxy carbonyl, pentyloxy carbonyl, isoamoxy carbonyl, neopentyl oxygen carbonyl etc.), the C of 2～7 carbon atoms 7-14Aryloxycarbonyl (as phenyloxycarbonyl, 1-naphthoxy carbonyl), C 8-12Aralkyl oxy carbonyl (as benzyl oxygen base carbonyl etc.), carbamoyl, N-C 1-6Alkyl-carbamoyl, N, N-two C 1-6Alkyl-carbamoyl, N-C 8-12Aryl alkyl amino formoxyl, N, N-two C 8-12Aryl alkyl amino formoxyl, 1-pyrrolidinyl carbonyl, piperidino carbonyl, morpholino base carbonyl etc.Wherein, Y is preferably carboxyl, methoxycarbonyl, ethoxy carbonyl etc., and is preferably carboxyl especially.
The chemical compound of formula (II) expression can be the form of free form or the acceptable salt of pharmacology, and two kinds of forms all are included in the scope of the present invention.The chemical compound of representing when formula (II) has acidic-group to be, as carboxyl etc., this chemical compound can with inorganic base (as, alkali metal, as sodium, potassium etc., alkaline-earth metal, as calcium, magnesium etc., transition metal, as zinc, ferrum, copper etc.) or organic base (as organic amine, as trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, three (hydroxymethyl) methylamine, hexanamine, N, N '-benzhydryl ethylenediamine and tert-butylamine, basic amino acid are as arginine, lysine, ornithine etc.) formation salt.
When the chemical compound of formula of the present invention (II) expression contains basic group, as amino etc., this chemical compound can with mineral acid or organic acid (example hydrochloric acid, nitric acid, sulphuric acid, phosphoric acid, carbonic acid, heavy carbonic, formic acid, acetic acid, propanoic acid, trifluoroacetic acid, Fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-methyl benzenesulfonic acid etc.) or acidic amino acid, form salt as aspartic acid or glutamic acid.
The compound or its salt of formula (II) expression contains asymmetric carbon atom on 3 and 5, and can be the mixture of stereoisomer.Can pass through known method separating isomerism body.Be preferably transly, wherein 3 substituent groups with 5 are relative is relative in the other direction with the plane of 7 yuan of rings, and particularly preferred for containing the chemical compound of the absolute configuration that formula (IIa) represents.And the compound or its salt of formula (II) expression can be the form of raceme, and can be by known method for optical resolution dissociated optical activity form from raceme.
Compound or its salt for formula of the present invention (II) expression is preferably following chemical compound especially.
(1) chemical compound, wherein X 1bBe key, and Y is optional esterified carboxyl;
(2) chemical compound, its medium ring A are the phenyl ring that halogen atom replaces;
(3) chemical compound, its medium ring B are the phenyl ring that lower alkoxy replaces;
(4) chemical compound, its medium ring C is optional further substituted monocycle aromatic heterocycle;
(5) chemical compound, its medium ring C is optional further substituted phenyl ring;
(6) chemical compound, but its medium ring C is the optional further substituted aromatic rings that does not contain the hydrogen atom of deprotonation;
(7) chemical compound, wherein X 1aBe C 1-3Alkylidene;
(8) chemical compound, wherein X 2Be key;
(9) chemical compound, wherein X 3Be C 1-4Alkylidene;
(10) chemical compound, its Chinese style (II) are following formula (IIa):
Wherein each symbol defines suc as formula (II);
(11) 3-(2-{3-[(3R, 5S)-7-chloro-5-(2, the 3-Dimethoxyphenyl)-1-(3-hydroxyl-2, the 2-dimethyl propyl)-and 2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzo oxygen azepine -3-yl] propyl group }-1,3-thiazoles-5-yl) propanoic acid, 3-(2-{2-[(3R, 5S)-7-chloro-5-(2, the 3-Dimethoxyphenyl)-1-(2, the 2-dimethyl propyl)-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzo oxygen azepine -3-yl] ethyl }-1,3-thiazoles-4-yl) propanoic acid, or its salt;
(12) (2-{[(3R, 5S)-7-chloro-5-(2, the 3-Dimethoxyphenyl)-1-(3-hydroxyl-2, the 2-dimethyl propyl)-and 2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzo oxygen azepine -3-yl] methyl }-1,3- azoles-5-yl) propanoic acid, (2-{[(3R, 5S)-7-chloro-5-(2, the 3-Dimethoxyphenyl)-1-isobutyl group-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzo oxygen azepine -3-yl] methyl }-1,3- azoles-5-yl) acetic acid, or its salt;
(13) 5-(3-{[(3R, 5S)-7-chloro-5-(2, the 3-Dimethoxyphenyl)-1-(2, the 2-dimethyl propyl)-and 2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzo oxygen azepine -3-yl] methyl }-1,2,4- diazole-5-yl) valeric acid, 5-(3-{[(3R, 5S)-7-chloro-5-(2, the 3-Dimethoxyphenyl)-1-(3-hydroxyl-2, the 2-dimethyl propyl)-and 2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzo oxygen azepine -3-yl] methyl }-1,2,4- diazole-5-yl) valeric acid, 5-(3-{[(3R, 5S)-1-(3-acetoxyl group-2,2-dimethyl propyl)-7-chloro-5-(2, the 3-Dimethoxyphenyl)-and 2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzo oxygen azepine -3-yl] methyl }-1,2,4- diazole-5-yl) valeric acid, 4-{[(3R, 5S)-7-chloro-5-(2, the 3-Dimethoxyphenyl)-1-(3-hydroxyl-2,2-dimethyl propyl)-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzo oxygen azepine -3-yl] acetyl group } phenyl) acetic acid, or its salt;
Can be by being disclosed in for example chemical compound of the method preparation formula (II) of WO 2005/012272.
In above-mentioned these squalene synthase inhibitors, be preferably following chemical compound:
(1) N-[[(3R, 5S)-1-(3-acetoxyl group-2,2-dimethyl propyl)-7-chloro-5-(2, the 3-Dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzo oxygen azepine -3-yl] acetyl group] piperidines-4-acetic acid,
(2) 3-(2-{3-[(3R, 5S)-7-chloro-5-(2, the 3-Dimethoxyphenyl)-1-(3-hydroxyl-2,2-dimethyl propyl)-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzo oxygen azepine -3-yl] propyl group }-1,3-thiazoles-5-yl) propanoic acid,
(3) 3-(2-{2-[(3R, 5S)-7-chloro-5-(2, the 3-Dimethoxyphenyl)-1-(2, the 2-dimethyl propyl)-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzo oxygen azepine -3-yl] ethyl }-1,3-thiazoles-4-yl) propanoic acid,
(4) (2-{[(3R, 5S)-7-chloro-5-(2, the 3-Dimethoxyphenyl)-1-(3-hydroxyl-2,2-dimethyl propyl)-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzo oxygen azepine -3-yl] methyl }-1,3- azoles-5-yl) propanoic acid,
(5) (2-{[(3R, 5S)-7-chloro-5-(2, the 3-Dimethoxyphenyl)-1-isobutyl group-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzo oxygen azepine -3-yl] methyl }-1,3- azoles-5-yl) acetic acid,
(6) 5-(3-{[(3R, 5S)-7-chloro-5-(2, the 3-Dimethoxyphenyl)-1-(3-hydroxyl-2,2-dimethyl propyl)-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzo oxygen azepine -3-yl] methyl-1,2,4- diazole-5-yl) valeric acid,
(7) 5-(3-{[(3R, 5S)-1-(3-acetoxyl group-2,2-dimethyl propyl)-7-chloro-5-(2, the 3-Dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzo oxygen azepine -3-yl] methyl-1,2,4- diazole-5-yl) valeric acid,
(8) 5-(3-{[(3R, 5S)-7-chloro-5-(2, the 3-Dimethoxyphenyl)-1-(2, the 2-dimethyl propyl)-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzo oxygen azepine -3-yl] methyl-1,2, the valeric acid of 4- diazole-5-yl) and
(9) (4-{[(3R, 5S)-7-chloro-5-(2, the 3-Dimethoxyphenyl)-1-(3-hydroxyl-2,2-dimethyl propyl)-2-oxo-1,2,3,5-tetrahydrochysene-4,1-benzo oxygen azepine -3-yl] acetyl group } phenyl) acetic acid.
Can implement the present invention with following administering mode.
The administering mode (composite reagent) of the combination of squalene synthase inhibitor (SSI) and HMG-CoA reductase inhibitor has no particular limits, and needs only combination S SI and HMG-CoA reductase inhibitor when administration.The example of described administering mode is for example:
(1) gives the unitary agent that obtains by cofabrication SSI and HMG-CoA reductase inhibitor;
(2) give by preparing two kinds of preparations that SSI and HMG-CoA reductase inhibitor obtain respectively by identical route of administration simultaneously;
(3) give by preparing two kinds of preparations that SSI and HMG-CoA reductase inhibitor obtain respectively by identical route of administration at interval respectively;
(4) give by preparing two kinds of preparations that SSI and HMG-CoA reductase inhibitor obtain respectively by different approaches simultaneously;
(5) give by preparing two kinds of preparations that SSI and HMG-CoA reductase inhibitor obtain (for example, give SSI, give the HMG-CoA reductase inhibitor then or with opposite order) respectively at interval respectively by different way of administration.
According to the dosage of clinical practice, can suitably select the dosage of HMG-CoA reductase inhibitor.According to the experimenter of institute's administration, route of administration, target disease, symptom, its combination etc., can suitably select the portfolio ratio of SSI and HMG-CoA reductase inhibitor.For example, if the experimenter of administration is a man-hour, though depend on the kind of HMG-CoA reductase inhibitor, but HMG-CoA reductase inhibitor based on available 1 weight portion, the amount of SSI is that 0.1～100 weight portion (being preferably 0.5～100 weight portion) is (when using atorvastatin as the HMG-CoA reductase inhibitor, the amount of SSI is 0.1～10 weight portion, more preferably 0.5～10 weight portion).
When implementing foregoing invention, can give the pharmaceutical composition of dosage form, described preparation uses the conventional carrier that is used for preparation of appropriate amount to prepare by conventional method, described carrier compatibly is selected from, as excipient (excipients) (calcium carbonate for example, Kaolin, sodium bicarbonate, lactose, starch, crystalline cellulose, Talcum, Saccharum Sinensis Roxb., porous mass etc.), binding agent (for example, dextrin, colloid, alcoholization starch, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, amylopectin etc.), disintegrating agent (for example, carboxymethylcellulose calcium, cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, low-substituted hydroxypropyl cellulose, the starch of part gelation in advance etc.), lubricant (for example, magnesium stearate, calcium stearate, Talcum, starch, sodium benzoate etc.), coloring agent (tar dyestuff for example, caramel, ferric oxide, titanium dioxide, riboflavin etc.), odor mask (sweeting agent for example, flavouring agent etc.), stabilizing agent (for example sodium sulfite etc.), antiseptic (parabens for example, sorbic acid etc.) etc.The pharmaceutical preparation of the present invention that comprises above-mentioned preparation contains SSI and/or the HMG-CoA reductase inhibitor for treatment and prevent disease effective dose.And the preparation that the present invention uses can also contain other medicines composition except that SSI and/or HMG-CoA reductase inhibitor as active component.As long as can realize purpose of the present invention, this composition is not had special restriction, and can use these compositions with the mixed ratio that is fit to.The instantiation of described preparation comprises tablet (tablet, the tablet of film coating, the layering tablet that comprise sweet tablet), pill, capsule, granule, fine grained agent, powder, syrup, Emulsion, suspending agent, injection, suspending injection, inhalant, ointment etc.The preparation that these preparations can be put as the gentle slow release of the preparation of rapid release for controlled release preparation (as the microcapsule of slow release).In these preparations, in some cases, the oral formulations with convenient or compliance advantage is preferred.When these preparations are solid preparation, the indentation that can stamp labelling or character feature in the above or can affix be used to cut apart.
Can prepare these preparations (for example, the method for describing in the Japanese Pharmacopoeia) by conventional method.
In practical application of the present invention, when use contains the solid preparation (so-called fixed dosage combination) of SSI and HMG-CoA reductase inhibitor, according to following preparation method preparation.
1) with SSI and HMG-CoA reductase inhibitor and additive, as mixed with excipients together after, with granulating mixture, use the dispersant or the solvent of additive simultaneously, spray as the binding agent in solvent (as water).With gained granule and additive, as disintegrating agent and mix lubricant, then, optionally tabletting is with the preparation solid preparation.
2),, use the dispersant or the solution spray (as the spraying of the binding agent in solvent (as water)) of HMG-CoA reductase inhibitor and additive simultaneously with granulating mixture with after SSI and additive such as the mixed with excipients.With gained granule and additive, as disintegrating agent and mix lubricant, then, optionally tabletting is with the preparation solid preparation.
3) with after SSI and additive such as the mixed with excipients, with granulating mixture, use the dispersant or the solution spray of additive simultaneously, spray as the binding agent in solvent (as water).
On the other hand,, after mixed with excipients,, use the dispersant or the solution spray of additive simultaneously, spray as the binding agent in solvent (as water) with granulating mixture with HMG-CoA reductase inhibitor and additive.
With granule that contains SSI that obtains thus and granule and additive such as disintegrating agent and the mix lubricant that contains the HMG-CoA reductase inhibitor, then, optionally tabletting is with the preparation solid preparation.
4) with after SSI and additive such as the mixed with excipients, with granulating mixture, use the dispersant or the solution spray of additive simultaneously, spray as the binding agent in solvent (as water).
On the other hand, the dispersant of usefulness HMG-CoA reductase inhibitor and additive (as the binding agent in solvent (as water)) or solution spray additive such as adjuvant are with pelletize.
With granule that contains SSI that obtains thus and granule and the additive that contains the HMG-CoA reductase inhibitor, as disintegrating agent and mix lubricant, then, optionally tabletting is with the preparation solid preparation.
5),, use the dispersant of additive or solution to spray simultaneously as the binding agent in solvent (as water) with granulating mixture with after SSI and additive such as the mixed with excipients.With the granule of gained and additive such as disintegrating agent and mix lubricant to obtain blended powder.
On the other hand, the dispersant of usefulness HMG-CoA reductase inhibitor and additive (as the binding agent in solvent (as water)) or solution spray additive such as adjuvant are with pelletize.With the granule of gained and additive such as disintegrating agent and mix lubricant to obtain blended powder.
Mixed-powder and the mixed-powder layering that contains the HMG-CoA reductase inhibitor with the thus obtained SSI of containing compress then with preparation solid preparation (two-layer tablet).
6),, use the dispersant of additive or solution to spray simultaneously as the binding agent in solvent (as water) with granulating mixture with after SSI and additive such as the mixed with excipients.Granule and additive such as disintegrating agent and mix lubricant with gained are pressed into label then.
On the other hand, the dispersant of usefulness HMG-CoA reductase inhibitor and additive (as the spraying of the binding agent in solvent (as water)) or solution spray additive such as adjuvant are with pelletize.With the granule of gained and additive such as disintegrating agent and mix lubricant to obtain blended powder.
Press skin for above-mentioned label with preparation solid preparation (dried coated tablet) mixed-powder of gained.
7),, use the dispersant of additive or solution to spray simultaneously as the binding agent in solvent (as water) with granulating mixture with after SSI and additive such as the mixed with excipients.Granule and additive such as disintegrating agent and mix lubricant, tablet forming then with gained.With this sheet of film solution coating of HMG-CoA reductase inhibitor, coated substrate and additive (as the lucifuge agent) with preparation solid preparation (film-coated tablet).
According to age of route of administration, symptom and patient or body weight etc., change the dosage of preparation of the present invention.When being administered to the adult patient, preferably give 1～100mg/ days SSI or HMG-CoA reductase inhibitor when oral, once give or give at twice or repeatedly.Route of administration can be by oral or non-oral.
Embodiment
Below, explain the good effect of the combination of use compounds X by concrete pharmacology's testing result as the representative compounds of SSI and HMG-CoA reductase inhibitor.Yet these are examples that SSI of the present invention and HMG-CoA reductase inhibitor are used in combination effect, and therefore effect of Combination is not limited to following concrete pharmacological effect.
Embodiment 1: use the reduction effect of the combination of compounds X and atorvastatin to plasma triglyceride
Detection method:
(in 19 ages in week, female, N=6), the solvent of 10mL/kg dosage (vehicle) is used compounds X (30mg/kg) separately, uses the combination oral administration 8 days of atorvastatin (30mg/kg) or two kinds of medicines separately, once a day for Wistar Fatty rat.In first day morning after the administration the 8th time, gather overnight fasting blood down, the concentration of measurement plasma triglyceride.
The result:
Treatment Plasma triglyceride value (mg/dL)
Solvent 519.7±43.5
Compounds X (30mg/kg) 376.5±22.0
Atorvastatin (30mg/kg) 192.1±15.2
The combination of atorvastatin (30mg/kg)+compounds X (30mg/kg) 142.9±15.3
Mean+/-standard error (N=6)
Conclusion:
By using the combination of compounds X and atorvastatin, observe the effect of extra reduction plasma triglyceride.(P＜0.01, two-factor analysis of variance (ANOVA) (two-wayANOVA) method).
Embodiment 2: use the reduction effect of the combination of compounds X and atorvastatin to plasma cholesterol
Method:
For the Hartley Cavia porcellus (5 the week ages, male, N=12), fed for 3 weeks with the RC-4 food that contains 0.05% cholesterol and 10% Semen Maydis oil, oral administration 14 days, once a day, the solvent of 10-mL/kg dosage, give compounds X (30mg/kg) separately, give atorvastatin (3,10,30mg/kg) separately or give the combination of atorvastatin (3,10,30mg/kg) and compounds X (30mg/kg).First day morning after administration the 14th time, gather blood, measure the T-CHOL in the blood plasma.
Testing result:
Treatment Total cholesterol level (mg/dL)
Solvent 56.3±4.1
Compounds X (30mg/kg) 44.4±4.1
Atorvastatin (3mg/kg) 46.1±3.3
Atorvastatin (10mg/kg) 37.4±4.1
Atorvastatin (30mg/kg) 33.5±2.8
The combination of atorvastatin (3mg/kg)+compounds X (30mg/kg) 39.2±2.3
The combination of atorvastatin (10mg/kg)+compounds X (30mg/kg) 31.0±3.7
The combination of atorvastatin (30mg/kg)+compounds X (30mg/kg) 27.9±1.8
Mean+/-standard error (N=12)
Conclusion:
By using the combination of compounds X and atorvastatin, observe the effect of T-CHOL in the extra reduction blood plasma.(P＜0.01, two-factor analysis of variance (ANOVA) (two-wayANOVA) method).
Embodiment 3: use the reduction effect of the combination of compounds X and simvastatin to plasma cholesterol
Detection method:
For the Hartley Cavia porcellus (5 the week ages, male, N=12), fed for 3 weeks with the RC-4 food that contains 0.05% cholesterol and 10% Semen Maydis oil, oral administration 14 days, once a day, the solvent of 10-mL/kg dosage, give compounds X (30mg/kg) separately, give simvastatin (10,30,100mg/kg) separately or give the combination of simvastatin (10,30,100mg/kg) and compounds X (30mg/kg).First day morning after administration the 14th time, collect blood, measure the T-CHOL in the blood plasma.
Testing result
Treatment Total cholesterol level (mg/dL)
Solvent 56.9±4.8
Compounds X (30mg/kg) 40.2±4.7
Simvastatin (10mg/kg) 41.0±3.6
Simvastatin (30mg/kg) 43.4±2.2
Simvastatin (100mg/kg) 31.7±2.6
Simvastatin (10mg/kg)+compounds X (30mg/kg) 40.0±3.0
Simvastatin (30mg/kg)+compounds X (30mg/kg) 34.8±2.3
Simvastatin (100mg/kg)+compounds X (30mg/kg) 24.2±1.8
Mean+/-standard error (N=12)
Conclusion:
By using the combination of compounds X and simvastatin, observe the effect of T-CHOL in the extra reduction blood plasma.(P＜0.01, two-factor analysis of variance (ANOVA) (two-wayANOVA) method).
Embodiment 4: compounds X and atorvastatin are to the influence of the pathology variation of liver
Detection method:
For the Hartley Cavia porcellus (5 the week ages, male, N=12), fed for 3 weeks with the RC-4 food that contains 0.05% cholesterol and 10% Semen Maydis oil, oral administration 14 days, once a day, the solvent of 10-mL/kg dosage, give compounds X (30mg/kg) separately, give atorvastatin (30mg/kg) separately or give atorvastatin (30mg/kg) and the combination of compounds X (30mg/kg).First day morning after administration the 14th time, gather blood, measure the T-CHOL in the blood plasma.And, take out liver and carry out pathological evaluation.
Testing result:
Treatment T-CHOL (mg/dL) The single hepatic necrosis in lobule center
Solvent 53.6±3.0 0 example is arranged in 12 examples
Compounds X (30mg/kg) 40.1±3.1 0 example is arranged in 12 examples
Atorvastatin (30mg/kg) 32.9±1.5 3 examples are arranged in 12 examples
Atorvastatin (30mg/kg)+compounds X (30mg/kg) 28.3±1.3 0 example is arranged in 12 examples
Mean+/-standard error (N=12)
Conclusion:
In atorvastatin treatment group, observe the image of hepatic necrosis, and in separately with the group of compounds X and in the group that compounds X and atorvastatin make up, do not observe the image of hepatic necrosis.
Embodiment 5: compounds X and atorvastatin are for the influence of hepatic injury (liver-deviated) enzymic change
Detection method:
For the Hartley Cavia porcellus (5 the week ages, male, N=12), fed for 2 weeks with the RC-4 food that contains 0.05% cholesterol and 10% Semen Maydis oil, oral administration 7 days, once a day, the solvent of 5-mL/kg dosage gives atorvastatin (50mg/kg) separately or gives atorvastatin (50mg/kg) and the combination of compounds X (30mg/kg).First day morning after administration the 7th time, collect blood, measure the concentration of the hepatotoxic alanine aminotransferase of representative and aspartate transaminase in the blood plasma.
Testing result:
Treatment Aspartate transaminase (I.U./L) Alanine aminotransferase (I.U./L)
Solvent 43.0±4.5 30.2±1.2
Atorvastatin (50mg/kg) 169.0±39.1 * 48.9±9.7
Atorvastatin (50mg/kg)+compounds X (30mg/kg) 75.2±8.1# 30.7±1.2
Mean+/-standard error (N=12)
*(Student t check) compared in P＜0.05 with the solvent group.(Student t check) compared in #P＜0.05 with atorvastatin treatment group.
Conclusion:
In atorvastatin treatment group, observe the obvious rising of aspartate transaminase in the blood plasma.Yet, in the group of compounds X and atorvastatin combination, do not observe this transaminase's rising.
Embodiment 6: compounds X and cerivastatin are for the influence of muscle injury (muscle-deviated) enzymic change
Detection method:
For the Hartley Cavia porcellus (5 the week ages, male, N=16), the solvent of 5-mL/kg dosage gives cerivastatin (1mg/kg) separately or gives cerivastatin (1mg/kg) and the combination of compounds X (30mg/kg), oral administration 14 days, once a day.First day morning after administration the 14th time, collect blood, measure KPK (CK) and the Myoglobin (Mb) of representing musclar toxicity in the blood plasma.
Testing result:
Treatment TC(mg/dL) CK(mg/dL) Mb(ng/mL)
Solvent 24.2±1.0 389±99 0.3±0.2
Cerivastatin (1mg/kg) 13.2±0.8 ** 4072±800 ** 25.7±2.6 **
Cerivastatin (1mg/kg)+compounds X (30mg/kg) 12.0±0.6 498±62## 1.1±0.4##
Mean+/-standard error (N=16). *P＜0.01 is compared with the solvent group, compares Student t-check with the cerivastatin monotherapy with ##P＜0.01.
Conclusion
In cerivastatin treatment group, observe the obvious rising of KPK and Myoglobin in the blood plasma.Yet compounds X has obviously improved by giving the KPK that cerivastatin causes and the rising of Myoglobin separately, and slight raising the effect of cholesterol reducing.
As above as can be known,, can cover the shortcoming of HMG-CoA reductase inhibitor, obtain the good effect that prevents and/or treats hyperlipemia, can not obtain this effect by individually dosed by being used in combination SSI and HMG-CoA reductase inhibitor.
The present invention finds can obtain the better effect that prevents and/or treats hyperlipemia by further using together as ternary ezetimibe.
Hereinafter, prove the effect of three kinds of drug regimens by testing result.
Embodiment 7: use three joint groups of compounds X, simvastatin and ezetimibe to close, reduce the effect of plasma cholesterol
Detection method:
For the Hartley Cavia porcellus (5 the week ages, male, N=6), fed for 3 weeks with the RC-4 food that contains 0.05% cholesterol and 10% Semen Maydis oil, oral administration 14 days, once a day, the solvent of 6-mL/kg dosage, give compounds X (30mg/kg) separately, the combination of simvastatin (30mg/kg) and ezetimibe (0.15mg/kg), or three joint groups of simvastatin (30mg/kg), ezetimibe (0.15mg/kg) and compounds X (30mg/kg) close.First day morning after administration the 14th time, gather blood, measure the T-CHOL in the blood plasma.
Testing result:
Treatment Total cholesterol level (mg/dL)
Solvent 56.8±4.0
Compounds X (30mg/kg) 43.5±4.1
The combination of simvastatin (30mg/kg)+ezetimibe (0.15 mg/kg) 34.6±2.1
Three joint groups of simvastatin (30mg/kg)+ezetimibe (0.15 mg/kg)+compounds X (30mg/kg) close 29.4±2.5
Mean+/-standard error (N=6)
Conclusion:
Observe, close the effect (P＜0.05, two-factor analysis of variance (ANOVA) (two-wayANOVA) method) that shows T-CHOL in the extra reduction blood plasma by three joint groups that use compounds X, simvastatin and ezetimibe.
Obviously find out from The above results, can more effectively prevent and/or treat high ester hyperlipemia by three drug regimens that are used in combination SSI, HMG-CoA reductase inhibitor and ezetimibe.
In addition, when being used in combination three kinds of medicines, concrete administering mode can use the embodiment of SSI and HMG-CoA reductase inhibitor with reference to combinations thereof as medication and form of administration.
Commercial Application
By being used in combination SSI of the present invention and HMG-CoA reductase inhibitor, can effectively prevent or treat mammiferous hyperlipidemia.

Claims (21)

1.用于预防和/或治疗高脂血症的方法，其包括给予患有高脂血症的哺乳动物有效量的角鲨烯合酶抑制剂和HMG-CoA还原酶抑制剂的组合。CLAIMS 1. A method for preventing and/or treating hyperlipidemia, which comprises administering an effective amount of a combination of a squalene synthase inhibitor and an HMG-CoA reductase inhibitor to a mammal suffering from hyperlipidemia. 2.权利要求1的方法，其中以批准剂量的高剂量给予所述HMG-CoA还原酶抑制剂。2. The method of claim 1, wherein the HMG-CoA reductase inhibitor is administered at a high dose of an approved dose. 3.权利要求2的方法，其中以批准剂量的最大剂量给予所述HMG-CoA还原酶抑制剂。3. The method of claim 2, wherein the HMG-CoA reductase inhibitor is administered at the maximum of the approved dose. 4.用于预防和/或治疗由给予HMG-CoA还原酶抑制剂引起的肝毒性的方法，其包括对给予HMG-CoA还原酶抑制剂的哺乳动物给予有效量的角鲨烯合酶抑制剂，以抑制由给予HMG-CoA还原酶抑制剂引起的毒性。4. A method for preventing and/or treating liver toxicity caused by administration of an HMG-CoA reductase inhibitor, comprising administering an effective amount of a squalene synthase inhibitor to a mammal administered with an HMG-CoA reductase inhibitor , to suppress toxicity caused by administration of HMG-CoA reductase inhibitors. 5.权利要求4的方法，其中哺乳动物患有高脂血症。5. The method of claim 4, wherein the mammal suffers from hyperlipidemia. 6.权利要求1或2的方法，其中所述角鲨烯合酶抑制剂是下式表示的化合物：6. The method of claim 1 or 2, wherein the squalene synthase inhibitor is a compound represented by the formula:
Figure S2006800197386C00011
Figure S2006800197386C00011
 其中，R1为氢原子或任选被取代的烃基，R2和R3相同或不同，且为氢原子、任选被取代的烃基或任选被取代的杂环基团，X’为包括任选被酯化的羧基、任选被取代的氨基甲酰基、任选被取代的羟基、任选被取代的氨基或任选被取代的含有可去质子化的氢原子的杂环残基的基团，环A为任选被取代的苯环或任选被取代的杂环，环J’为含有3个或更少杂原子作为环组成原子的7元或8元杂环，且环J’还可含有除R1、R2、R3和X’外的取代基。Wherein, R 1 is a hydrogen atom or an optionally substituted hydrocarbon group, R 2 and R 3 are the same or different, and are a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, X' is a group comprising Optionally esterified carboxyl, optionally substituted carbamoyl, optionally substituted hydroxyl, optionally substituted amino or optionally substituted heterocyclic residues containing deprotonatable hydrogen atoms Group, ring A is an optionally substituted benzene ring or an optionally substituted heterocyclic ring, ring J' is a 7-membered or 8-membered heterocyclic ring containing 3 or less heteroatoms as ring constituent atoms, and ring J ' may also contain substituents other than R 1 , R 2 , R 3 and X'. 7.权利要求1或2的方法，其中角鲨烯合酶抑制剂为N-[[(3R，5S)-1-(3-乙酰氧基-2，2-二甲基丙基)-7-氯-5-(2，3-二甲氧基苯基)-2-氧代-1，2，3，5-四氢-4，1-苯并氧氮杂-3-基]乙酰基]哌啶-4-乙酸。7. The method of claim 1 or 2, wherein the squalene synthase inhibitor is N-[[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7 -Chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl Base] piperidine-4-acetic acid. 8.权利要求1或2的方法，其中HMG-CoA还原酶抑制剂是一种或多种选自阿伐他汀、洛伐他汀、辛伐他汀、普伐他汀、氟伐他汀、罗苏伐他汀、西立伐他汀和匹伐他汀的药物。8. The method of claim 1 or 2, wherein the HMG-CoA reductase inhibitor is one or more selected from the group consisting of atorvastatin, lovastatin, simvastatin, pravastatin, fluvastatin, rosuvastatin , cerivastatin and pitavastatin drugs. 9.权利要求1或2的方法，其中患有高脂血症的哺乳动物为HMG-CoA还原抑制剂不耐受的病人。9. The method of claim 1 or 2, wherein the mammal suffering from hyperlipidemia is an HMG-CoA reduction inhibitor intolerant patient. 10.权利要求1或2的方法，其中患有高脂血症的哺乳动物为缺血性心脏病的高危病人。10. The method of claim 1 or 2, wherein the mammal suffering from hyperlipidemia is at high risk for ischemic heart disease. 11.权利要求1或2的方法，其中患有高脂血症的哺乳动物为患有家族性高胆固醇血症的病人。11. The method of claim 1 or 2, wherein the mammal suffering from hyperlipidemia is a patient suffering from familial hypercholesterolemia. 12.用于预防和/或治疗高脂血症的药物组合物，其包括有效量的角鲨烯合酶抑制剂和HMG-CoA还原酶抑制剂的组合。12. A pharmaceutical composition for preventing and/or treating hyperlipidemia, comprising an effective amount of a combination of a squalene synthase inhibitor and an HMG-CoA reductase inhibitor. 13.用于预防和/或治疗高脂血症的药物组合物，其包括有效量的角鲨烯合酶抑制剂和HMG-CoA还原酶抑制剂，将该药物组合物进行配制或包装以便以分剂量相继或同时给予患有高脂血症的哺乳动物。13. A pharmaceutical composition for preventing and/or treating hyperlipidemia, comprising effective doses of squalene synthase inhibitors and HMG-CoA reductase inhibitors, the pharmaceutical composition being formulated or packaged so as to Sub-doses are administered sequentially or simultaneously to mammals suffering from hyperlipidemia. 14.权利要求12或13的药物组合物，其包括以HMG-CoA还原酶抑制剂的批准剂量的高剂量组合。14. A pharmaceutical composition according to claim 12 or 13 comprising a high dose combination at an approved dose of an HMG-CoA reductase inhibitor. 15.权利要求12或13的药物组合物，其包括以HMG-CoA还原酶抑制剂的批准剂量的最大剂量组合。15. The pharmaceutical composition according to claim 12 or 13, comprising the maximum dose combination at the approved dose of the HMG-CoA reductase inhibitor. 16.用于增强HMG-CoA还原酶抑制剂的预防和/或治疗高脂血症的效果的方法，其包括对患有高脂血症的被给予了有效量的HMG-CoA还原酶抑制剂的哺乳动物，给予有效量的角鲨烯合酶抑制剂。16. A method for enhancing the effect of an HMG-CoA reductase inhibitor for preventing and/or treating hyperlipidemia, comprising administering an effective amount of an HMG-CoA reductase inhibitor to a person suffering from hyperlipidemia A mammal is given an effective amount of a squalene synthase inhibitor. 17.角鲨烯合酶抑制剂在制备用于预防和/或治疗高脂血症的药物组合物中的用途，所述药物组合物包括有效量的角鲨烯合酶抑制剂和HMG-CoA还原酶抑制剂的组合。17. Use of a squalene synthase inhibitor in the preparation of a pharmaceutical composition for the prevention and/or treatment of hyperlipidemia, the pharmaceutical composition comprising an effective amount of a squalene synthase inhibitor and HMG-CoA Combinations of Reductase Inhibitors. 18.角鲨烯合酶抑制剂在制备用于预防和/或治疗高脂血症的药物组合物中的用途，所述药物组合物包括有效量的角鲨烯合酶抑制剂和HMG-CoA还原酶抑制剂，将所述药物组合物进行配制或包装以便以分剂量相继或同时给予患有高脂血症的哺乳动物。18. Use of a squalene synthase inhibitor in the preparation of a pharmaceutical composition for the prevention and/or treatment of hyperlipidemia, the pharmaceutical composition comprising an effective amount of a squalene synthase inhibitor and HMG-CoA A reductase inhibitor, the pharmaceutical composition being formulated or packaged for sequential or simultaneous administration to a mammal suffering from hyperlipidemia in divided doses. 19.权利要求1或2的方法，其中还组合给予作为第三药物的有效量的依泽替米贝。19. The method of claim 1 or 2, wherein an effective amount of ezetimibe is also administered in combination as a third drug. 20.权利要求12或13的药物组合物，其还包括组合作为第三药物的有效量的依泽替米贝。20. The pharmaceutical composition of claim 12 or 13, further comprising an effective amount of ezetimibe in combination as a third drug. 21.权利要求17或18的角鲨烯合酶抑制剂在制备用于预防和/或治疗高脂血症的药物组合物中的用途，所述药物组合物还包括组合作为第三药物的有效量的依泽替米贝。21. The use of the squalene synthase inhibitor of claim 17 or 18 in the preparation of a pharmaceutical composition for the prevention and/or treatment of hyperlipidemia, said pharmaceutical composition also comprising an effective combination as a third drug dose of ezetimibe.
CNA2006800197386A 2005-06-01 2006-05-31 Combinations of squalene synthase inhibitors and HMG-CoA reductase inhibitors for the treatment of hyperlipidemia Pending CN101189005A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103502820A (en) * 2011-04-08 2014-01-08 佐拉生物科学公司 Biomarkers for sensitive detection of statin-induced muscle toxicity
US9541565B2 (en) 2011-04-08 2017-01-10 Zora Biosciences Oy Biomarkers for sensitive detection of statin-induced muscle toxicity

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103502820A (en) * 2011-04-08 2014-01-08 佐拉生物科学公司 Biomarkers for sensitive detection of statin-induced muscle toxicity
CN103502820B (en) * 2011-04-08 2016-09-07 佐拉生物科学公司 The biomarker of Sensitive Detection for the musclar toxicity that statin causes
US9541565B2 (en) 2011-04-08 2017-01-10 Zora Biosciences Oy Biomarkers for sensitive detection of statin-induced muscle toxicity
US9664698B2 (en) 2011-04-08 2017-05-30 Zora Biosciences Oy Biomarkers for sensitive detection of statin-induced muscle toxicity

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