CN1930121A - Substituted heteroaryl- and phenylsulfamoyl compounds - Google Patents
Substituted heteroaryl- and phenylsulfamoyl compounds Download PDFInfo
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- CN1930121A CN1930121A CN 200580007622 CN200580007622A CN1930121A CN 1930121 A CN1930121 A CN 1930121A CN 200580007622 CN200580007622 CN 200580007622 CN 200580007622 A CN200580007622 A CN 200580007622A CN 1930121 A CN1930121 A CN 1930121A
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- phenyl
- methyl
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- phenylformic acid
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
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Abstract
The present invention is directed at substituted heteroaryl- and phenylsulfamoyl compounds, pharmaceutical compositions containing such compounds and the use of such compounds as peroxisome proliferator activator receptor (PPAR) agonists. PPAR alpha activators, pharmaceutical compositions containing such compounds and the use of such compounds to elevate certain plasma lipid levels, including high density lipoprotein-cholesterol and to lower certain other plasma lipid levels, such as LDL-cholesterol and triglycerides and accordingly to treat diseases which are exacerbated by low levels of HDL cholesterol and/or high levels of LDL-cholesterol and triglycerides, such as atherosclerosis and cardiovascular diseases, in mammals, including humans. The compounds are also useful for the treatment of negative energy balance (NEB) and associated diseases in ruminants.
Description
Background of invention
The heteroaryl that the present invention relates to replace-with phenyl-sulfamoyl compounds, the pharmaceutical composition that contains this compounds and this compounds purposes as peroxisome proliferation activated receptor (PPAR) agonist.These compounds can be used as the PPAR alfa agonists especially, are used for the treatment of Mammals, comprise human atherosclerosis, hypercholesteremia, hypertriglyceridaemia, diabetes, obesity, osteoporosis and X syndrome (also claiming metabolism syndrome).These compounds also can be used for treating ruminating animal negative energy balance (NEB) and diseases related.
Atherosclerosis is a kind of artery disease, is considered to the U.S. and West Europe human mortality's leading reason.Cause that the cardiopathic pathology of atherosclerosis and obstructive knows in proper order.The commitment of this order is the formation of " fatty streak " in carotid artery, coronary artery and cerebral arteries and the aorta.These damages are because existence of lipid deposits are yellow, are mainly seen in the smooth muscle cell of artery and aortic tunica intima layer and in the scavenger cell.And then, suppose that great majority see the formation that the interior cholesterol of fatty streak causes " fibrous plaque " then, it is made up of the intimal smooth muscle cells of being accumulated, and is loaded with lipid, and is surrounded by extracellular lipid, collagen, elastin and proteoglycan.These cells add matrix and form fibrous cap, cover darker cell debris settling and more extracellular lipid.Lipid mainly is the cholesterol of free and esterification.Fibrous plaque slowly forms, might in time become calcification with necrosis, make progress and be " concurrent damage ", this is the reason of obstruction of artery and vessel wall thrombosis and artery muscle spasm trend, these are that late arterial is atherosis peculiar.
The epidemiology evidence is verified, because atherosclerosis, hyperlipemia is the primary hazard factor that causes cardiovascular disorder (CVD).In recent years, the world of medicine reemphasizes and reduces the steps necessary that blood plasma cholesterol level, particularly low density lipoprotein cholesterol are prevention CVD.The present known level of being approved in the past that significantly is lower than of the upper limit of " normally ".Consequently, most of westerner is considered to face extra high danger now.Other independent hazard factor comprises glucose intolerance, left ventricular hypertrophy, hypertension and male gender.Cardiovascular disorder is especially general in the diabetic subject, and at least a portion reason is to have multiple independent hazard factor in this group people.Therefore successfully treat hyperlipemia among common people, the particularly diabetic subject and have especially medical importance.
Although found Regular Insulin very early, be widely used in the treatment diabetes subsequently, and found and used sulfonylurea, biguanides and thiazolidinediones as oral Hypoylycemic agents afterwards, for example troglitazone, rosiglitazone or pioglitazone, but treatment of diabetes still remains to be improved.The use of Regular Insulin requires repeatedly dosage every day usually.Appropriate insulin dose provisioning request is frequently estimated to urinate really or blood in sugar.The administration of crossing multiple doses Regular Insulin causes hypoglycemia, its consequence from the blood-glucose slight abnormality to stupor, perhaps even dead.(type ii diabetes, treatment NIDDM) be usually by diet, exercise, oral Hypoylycemic agents, and thiazolidinediones for example is that the combination of Regular Insulin is formed under serious situation more for non insulin dependent diabetes.But, the available Hypoylycemic agents may have side effect clinically, limits their application.Under the situation of insulin-dependent diabetes mellitus (I type), the therapeutic process that Regular Insulin is normally main.
Thereby although have multiple atherosclerosis and diabetotherapy, but this area still needs and seeks alternative medicine.
And, negative energy balance (NEB) be ruminating animal, particularly cow the frequent problem that meets with.NEB can show any period of cow life, but general especially in the transitional period.The ruminating animal transitional period is defined as crossing over third trimester of pregnancy to the early stage stage of lactation.Sometimes be defined as still having expanded to antenatal 30 days to 70 days postpartum (J N Spain and W A Scheer, Tri-State Dairy NutritionConference, 2001,13) from giving a birth first three three week of thoughtful minute puerperium.
Energy balance is defined as the energy absorption and deducts energy output, if the energy insufficiency of intake is to satisfy life and to produce the needs of (for example giving milk), animal is described to be in negative energy balance.The cow that is in NEB has to seek energy and satisfies shortage from its body deposit.Thereby the cow that is in NEB is tending towards losing body health and body weight, and the more cow of energy deficiency is tending towards losing quickly health and body weight.
It is very important controlling the mineral substance of cow and energy balance and general health in the transitional period well, because this stage all is vital for cow health, production and income subsequently.
Longer chain fatty acid (or non-esterified fatty acid, NEFAs) also from body fat, transfer.NEFAs began from antenatal about 7 days to raise, be cow at early stage main energy derive in postpartum, energy deficiency is big more, NEFA concentration is high more in the blood.Some people's suggestion (Bell and reference wherein are on seeing), early stage in lactation, it is some butterfat synthetic reasons that the breast of NEFAs is taken in.NEFAs in the circulation is absorbed by liver, is oxidized to carbonic acid gas or ketoboidies by plastosome, comprises 3-hydroxybutyric acid salt, perhaps is converted into triglyceride level and storage again via esterification.In the Nonruminantia Mammals, it is believed that NEFAs enters the control that plastosome is subjected to carnitine palmitoyltransferase (CPT-1), but, some studies show that in ruminating animal, CPT-1 is at transitional activity seldom change (G.N.Douglas, J.K.Drackley, T.R.Overton, H.G.Bateman, J.Dairy Science, 1998, Supp 1,81,295).In addition, the synthetic vldl of ruminating animal liver also is restricted with the ability of output triglyceride level from liver.
Obviously, if cattle liver becomes excessive to the absorption of NEFA, accumulating of ketoboidies may cause ketosis, and the excessive storage of triglyceride level can cause fatty liver.Fatty liver can cause the decubation of other diseases prolong, the incidence of health problem increases and the development of dead " downer cow ".
Thereby, fatty liver is the metabolic trouble of transitional period ruminating animal, particularly high-yielding dairy, and it all has adverse influence to disease resistance (abomasum displacement, walk lamely), immunologic function (mazoitis, metritis), fecundity (oestrus, farrowing internal, tire ox viability, ovarian cysts, metritis, placenta keep) and give milk (peak milk yield, milk yield on the 305th).Fatty liver formed day by day in a minute puerperium, made progress to be inducibility (Secondary cases) ketosis.The esterification of the NEFA that its reason normally absorbs from blood increases, and is low as the ability of vldl with ruminating animal hepatic secretion triglyceride level.
By improving energy balance,, the passive degree of sequela will be reduced perhaps by the treatment negative energy balance.The compounds of this invention is devoted to this just.
Summary of the invention
The present invention relates to formula I compound
Formula I
The perhaps prodrug of described compound, the pharmacy acceptable salt of perhaps described compound or prodrug, wherein
Q is a carbon;
Each R
1Be hydrogen, halogeno-group, optional independently by one or more halogeno-groups or (C
1-C
3) (the C that replaces of alkoxyl group
1-C
5) alkyl, optional by the (C of one to 11 halogeno-group replacement
1-C
5) alkoxyl group, the optional (C that is replaced by one or more halogeno-groups
1-C
5) alkylthio, perhaps R
1Unite formation C with two adjacent carbon atoms
5-C
6Condensed, saturated fully, part is unsaturated or fully undersaturated five or six-membered carbon ring, wherein each carbon in this carbochain can be replaced by a heteroatoms that is selected from oxygen and sulphur alternatively;
R
2Be hydrogen or optional quilt (C
1-C
3) (the C that replaces of alkoxyl group
1-C
5) alkyl;
X is-COOR
4,-O-(CR
3 2)-COOR
4,-S-(CR
3 2)-COOR
4,-CH
2-(CR
5 w)-COOR
4, 1H-tetrazolium-5-base-E-or thiazolidinedione-5-base-G-; Wherein w is 0,1 or 2; E is (CH
2)
r, r is 0,1,2 or 3; G is (CH
2)
sOr methylene radical, s is 0 or 1;
Each R
3Be hydrogen, optional independently by one to nine halogeno-group or by the optional (C that is replaced by one or more halogeno-groups
1-C
3) (the C that replaces of alkoxyl group
1-C
4) alkyl, perhaps R
3The carbon that is connected with it constitutes 3,4,5 or 6 yuan of carbocyclic rings;
R
4Be H, (C
1-C
4) alkyl, benzyl or right-nitrobenzyl;
Each R
5Be hydrogen, optional independently by one to nine halogeno-group or by (C
1-C
3) (the C that replaces of alkoxyl group
1-C
4) alkyl, optional by the (C of one to nine halogeno-group replacement
1-C
4) alkoxyl group, optional by one to nine halogeno-group or by (C
1-C
3) (the C that replaces of alkoxyl group
1-C
4) alkylthio, perhaps R
5The carbon that is connected with it constitutes 3,4,5 or 6 yuan of carbocyclic rings, and wherein any carbon of 5-or 6-unit ring can be replaced by Sauerstoffatom;
Ar
1Be phenyl or be selected from following member's condensed phenyl: thiazolyl, furyl, azoles base, pyridine, pyrimidine, phenyl or thienyl, wherein Ar
1Alternatively by following groups single independently-, two-or three-replace: halogeno-group, the optional (C that is replaced by one to nine halogeno-group
1-C
3) alkyl, optional by the (C of one to nine halogeno-group replacement
1-C
3) alkoxyl group or the optional (C that is replaced by one to nine halogeno-group
1-C
3) alkylthio;
B is a key, CO, (CY
2)
n, CYOH, CY=CY ,-L-(CY
2)
n-,-(CY
2)
n-L-,-L-(CY
2)
2-L-, NY-OC-,-CONY-,-SO
2NY-,-NY-SO
2-, wherein each L is O, S, SO or SO independently
2, each Y is hydrogen or (C independently
1-C
3) alkyl, n is 0,1,2 or 3;
Ar
2Be a key, phenyl, phenoxy benzyl, Phenoxyphenyl, benzyloxy phenyl, benzyloxy benzyl, pyrimidyl, pyridyl, pyrazolyl, imidazolyl, thiazolyl, thiadiazolyl group, azoles base, di azoly or be selected from following ring condensed phenyl: phenyl, pyrimidyl, thienyl, furyl, pyrryl, thiazolyl, azoles base, pyrazolyl and imidazolyl;
Each J is hydrogen, hydroxyl, halogeno-group, the optional (C that is replaced by one to 11 halogeno-group independently
1-C
8) alkyl, optional by the (C of one to 11 halogeno-group replacement
1-C
8) alkoxyl group, optional by the (C of one to 11 halogeno-group replacement
1-C
8) alkylthio, (C
3-C
7) cycloalkyl, (C
3-C
7) cycloalkyloxy, (C
3-C
7) cycloalkylthio or optional by one to four phenyl that is selected from following substituting group replacement: halogeno-group, the optional (C that is replaced by one to five halogeno-group
1-C
3) alkyl, optional by the (C of one to five halogeno-group replacement
1-C
3) alkoxyl group, optional by the (C of one to five halogeno-group replacement
1-C
3) alkylthio;
P and q are 0,1,2 or 3 independently of one another;
Its condition is:
If a) Ar
1Be phenyl, B is a key, Ar
2Be a key or phenyl, X is-COOH, and q is not 0 so, and J is not hydrogen, halogeno-group, (C
1-C
8) alkyl or unsubstituted phenyl;
B) if Ar
1Be phenyl, B is not a key, Ar
2Be phenyl, X is-COOR
4, B is connected Ar so
1Last NR
2Contraposition;
C) if B is O, S, SO, NH, CO, CH
2Or SO
2, R so
1Not H.
The application also relates to treatment Mammals dyslipidaemia, fat, overweight, hypertriglyceridaemia, hyperlipemia, low alpha-lipoprotein blood, metabolism syndrome, diabetes (I type and/or II type), hyperinsulinemia, glucose tolerance lowers, insulin resistant, diabetic complication, atherosclerosis, hypertension, coronary heart disease, hypercholesteremia, inflammation, osteoporosis, thrombosis, peripheral vascular disease, the method of cognition dysfunction or congestive heart failure, compound or the prodrug of described compound or the pharmacy acceptable salt of described compound or prodrug that this method is treated any claim 1-18 of significant quantity to the Mammals of this class treatment of needs.
The application also relates to pharmaceutical composition, and it comprises formula I compound or the prodrug of described compound or pharmacy acceptable salt and pharmaceutically acceptable carrier, vehicle or the thinner of described compound or prodrug for the treatment of significant quantity.
In addition, the application relates to pharmaceutical combination composition, comprises: the composition of treatment significant quantity wherein comprises
First compound, the prodrug that described first compound is formula I compound or described compound or the pharmacy acceptable salt of described compound or prodrug;
Second compound, described second compound is a lipase inhibitor, the HMG-CoA reductase inhibitor, the HMG-CoA synthetase inhibitors, HMG-CoA reductase gene expression inhibitor, HMG-CoA synthase gene expression inhibitor, MTP/Apo B secretion inhibitor, the CETP inhibitor, the bile acide absorption inhibitor, cholesterol absorption inhibitor, cholesterol synthesis inhibitor, inhibitor for squalene synthetic enzyme, cyclooxygenase inhibitors of squalene, the squalene cyclase inhibitor, squalene cyclooxygenase/squalene cyclase the inhibitor of associating, the special class of shellfish, nicotinic acid, the combination of nicotinic acid and lovastatin, ion exchange resin, antioxidant, the ACAT inhibitor, the pharmacy acceptable salt of the prodrug of bile acid chelating agent or described compound or described compound or prodrug; With
Pharmaceutically acceptable carrier, vehicle or thinner.
And, the present invention relates to treat the atherosclerotic method of Mammals, the Mammals that this method comprises this class treatment of needs gives:
First compound, the prodrug that described first compound is formula I compound or described compound or the pharmacy acceptable salt of described compound or prodrug; With
Second compound, described second compound is a lipase inhibitor, the HMG-CoA reductase inhibitor, the HMG-CoA synthetase inhibitors, HMG-CoA reductase gene expression inhibitor, HMG-CoA synthase gene expression inhibitor, MTP/Apo B secretion inhibitor, the CETP inhibitor, the bile acide absorption inhibitor, cholesterol absorption inhibitor, cholesterol synthesis inhibitor, inhibitor for squalene synthetic enzyme, cyclooxygenase inhibitors of squalene, the squalene cyclase inhibitor, squalene cyclooxygenase/squalene cyclase the inhibitor of associating, the special class of shellfish, nicotinic acid, the combination of nicotinic acid and lovastatin, ion exchange resin, antioxidant, ACAT inhibitor or bile acid chelating agent;
Wherein the amount of first and second compounds causes result of treatment.
In addition, the application also relates to the medicine box that reaches result of treatment in Mammals, first therapeutical agent that comprises packaged in combination, second therapeutical agent and pharmaceutically acceptable carrier, with give described first and second therapeutical agents to reach the specification sheets of result of treatment, described first therapeutical agent comprises formula I compound or the prodrug of described compound or the pharmacy acceptable salt and the pharmaceutically acceptable carrier of described compound or prodrug for the treatment of significant quantity, and described second therapeutical agent comprises the HMG CoA reductase inhibitor for the treatment of significant quantity, the CETP inhibitor, cholesterol absorption inhibitor, cholesterol synthesis inhibitor, the special class of shellfish, nicotinic acid, slowly-releasing nicotinic acid, the combination of nicotinic acid and lovastatin, ion exchange resin, antioxidant, ACAT inhibitor or bile acid chelating agent and pharmaceutically acceptable carrier.
Another aspect of the present invention is the purposes that formula I compound is made medicine, and this medicine is used to alleviate, prevention or curative therapy ruminating animal negative energy balance.
Another aspect of the present invention is the purposes that formula I compound is made medicine, this medicine is used to alleviate, prevention or curative therapy ruminating animal negative energy balance or the ruminant disease relevant with negative energy balance, wherein prevents or alleviate the excessive excessive rising of accumulating and/or preventing or alleviating non-esterified fatty acid level in the serum of triglyceride level in the liver organization.
Another aspect of the present invention is to comprise that in the ruminating animal ruminant disease relevant with negative energy balance that each side of the present invention is mentioned one or more independently are selected from following disease: fatty liver syndrome, difficult labour, immune dysfunction, immunologic function lowers, poison, primary and Secondary cases ketosis, downer cow syndrome, maldigestion, poor appetite, placenta keeps, the abomasum displacement, mazoitis, uterus (inner membrance) inflammation, Infertility, fertility is low and walk lamely preferred fat liver syndrome, the primary ketosis, downer cow syndrome, uterus (inner membrance) is scorching and fertility is low.
Another aspect of the present invention is the purposes that formula I compound improves fertility, comprises the service recovery rate that reduces, normal oestrus cycle, improves pregnancy rate and improves tire ox viability.
Another aspect of the present invention is the purposes that formula I compound is made medicine, and this medicine is used to control useful physiological process constant (homeorhesis), to be in harmonious proportion childbirth and lactogenesis.
Another aspect of the present invention is the purposes that formula I compound is made medicine, and this medicine is used for improving or keeping transition period ruminating animal liver function and homeostasis signal.
In one aspect of the invention, giving construction I compound during antenatal 30 days to 70 days postpartum.
In another aspect of this invention, antenatal, alternatively also at when childbirth giving construction I compound.
In another aspect of this invention, at giving construction I compound in postpartum.
In another aspect of this invention, giving construction I compound when childbirth.
More preferably, giving construction I compound during antenatal 3 thoughtful 3 weeks of postpartum.
In another aspect of this invention, three giving construction I compounds at the most during the first seven day in postpartum.
Preferably, during preceding 24 hours of postpartum, gave expression of first degree I compound.
In another aspect of this invention, at four giving construction I compounds at the most in antenatal and postpartum.
In another aspect of this invention, when childbirth, then postpartum four giving construction I compounds at the most.
Another aspect of the present invention is the purposes that formula I compound is made medicine, and this medicine is used to alleviate, prevention or curative therapy ruminating animal negative energy balance, increases ruminating animal breast quality and/or milk production.Of the present invention preferred aspect, newborn quality increase is reflected in ruminating animal Ruzhong ketoboidies level and reduces.
In another aspect of this invention, increased the peak milk production.
Preferably, this ruminating animal is cow or sheep.
In another aspect of this invention, obtain the overall increase of ruminating animal milk production between lactation 305 longicorns.
In another aspect of this invention, during preceding 60 days of ox lactation, obtain the overall increase of ruminating animal milk production.
Preferably, from cow, obtain overall increase or the increase of peak milk production or the increase of newborn quality of ruminating animal milk production.
In another aspect of this invention, after formula I compound is to healthy ruminating animal administration, obtain the increase of ruminating animal breast quality and/or milk production.
In another aspect of this invention, provide the formula I compound that is used in the veterinary science.
The application also relates to the compound with formula II
Formula II
Perhaps its pharmacy acceptable salt, wherein
R
2Be hydrogen or (C
1-C
4) alkyl;
Ar
1Be optional by following groups single independently-, two-or the three-phenyl that replaces: halogeno-group, the optional (C that is replaced by one to five halogeno-group
1-C
3) alkyl, optional by the (C of one to five halogeno-group replacement
1-C
3) alkoxyl group or the optional (C that is replaced by one to five halogeno-group
1-C
3) alkylthio;
B is (CY
2)
n, O, S ,-CH
2S-or-CH
2O, n are 1 or 2;
Ar
2Be phenyl or be selected from following ring condensed phenyl: phenyl, pyrimidyl, thienyl, furyl, pyrryl, thiazolyl, azoles base, pyrazolyl and imidazolyl;
Each J is hydrogen, hydroxyl, halogeno-group, the optional (C that is replaced by one to 11 halogeno-group independently
1-C
8) alkyl, optional by the (C of one to 11 halogeno-group replacement
1-C
8) alkoxyl group, optional by the (C of one to 11 halogeno-group replacement
1-C
8) alkylthio, (C
3-C
7) cycloalkyl, (C
3-C
7) cycloalkyloxy, (C
3-C
7) cycloalkylthio or the optional phenyl that is replaced by one or more following groups: halogeno-group, the optional (C that is replaced by one to five halogeno-group
1-C
3) alkyl, optional by the (C of one to five halogeno-group replacement
1-C
3) alkoxyl group or the optional (C that is replaced by one to five halogeno-group
1-C
3) alkylthio;
Q is 0,1,2 or 3.
Self-evident is that above-mentioned general remark and following detailed description all only are exemplary with indicative, is not the restriction of invention required for protection.
Brief description of drawings
Fig. 1 show give compound Z:2-methyl-5-(4 '-trifluoromethoxy-biphenyl-4-base sulphonamide)-phenylformic acid (embodiment 193) transitional period cow serum N EFA level, and compare.
Detailed description of the invention
The present invention can be more easily understood in the detailed description of the embodiment that the following exemplary invention embodiment of reference and this paper are included.
Before disclosure and description The compounds of this invention, composition and method, self-evident is to the invention is not restricted to concrete synthetic method, and they certainly have nothing in common with each other.Also self-evident is that term used herein only is for the purpose of describing specific implementations, does not plan to limit.
The present invention also relates to the pharmaceutically-acceptable acid addition of The compounds of this invention.The acid that is used to prepare the pharmaceutically-acceptable acid addition of the invention described above alkali cpd is to generate those of non-toxic acid addition salt, just contain acceptable anionic salt on the pharmacology, hydrochloride for example, hydrobromate, hydriodate, nitrate, vitriol, hydrosulfate, phosphoric acid salt, acid phosphate, acetate, lactic acid salt, Citrate trianion, the acid Citrate trianion, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, mesylate, esilate, benzene sulfonate, right-tosylate and pamoate (promptly 1,1 '-methylene radical-two-(2-hydroxyl-3-naphthoate)).
The present invention also relates to the base addition salt of The compounds of this invention.Can be to generate those of nontoxicity alkali salt as the chemical bases of the pharmaceutically acceptable alkali salt of the acid The compounds of this invention of reagent preparation with this compounds.This class nontoxicity alkali salt include but not limited to from the pharmacology acceptable positively charged ion deutero-those, for example alkali metal cation (for example potassium and sodium) and alkaline earth metal cation (for example calcium and magnesium), ammonium or water-soluble amine additive salt, the alkali salt of N-methylglucosamine (meglumine) and low-grade alkane alcohol ammonium and other pharmaceutically acceptable organic amines for example.
General chemistry personnel will recognize that it can be the atom of specific stereochemistry or geometric configuration that some The compounds of this invention will contain one or more, form steric isomer and configurational isomer.Comprise all these class isomer and composition thereof in the present invention.The hydrate and the solvate that also comprise The compounds of this invention.
If The compounds of this invention possesses two or more three-dimensional centers, and in title, provide absolute or relative stereochemistry, according to the digital flow process of conventional IUPAC about each molecule, name R and S represent each three-dimensional center with rising numerical order (1,2,3 etc.) respectively.If The compounds of this invention possesses one or more three-dimensional centers, and do not provide stereochemistry in title or structure card, self-evident is that this title or structure plan to contain all compound forms, comprises racemic form.
The compounds of this invention can contain the two keys of alkene sample.When having this generic key, The compounds of this invention exists cis and transconfiguration and composition thereof.Two substituting groups of term " cis " expression about each other with the orientation (all " make progress " or equal " downwards ") of plane of a loop.Similarly, two substituting groups of term " trans " expression about each other with the orientation (substituting group is positioned at the offside of ring) of plane of a loop.
α and β represent the orientation of substituting group about plane of a loop.β is positioned at the top of plane of a loop, and α is positioned at the below of plane of a loop.
The present invention also comprises isotope-labeled compound, they be equal to formula I and II described those, unless such fact, that is, one or more atom that one or more atoms are had special atomic mass or total mass number replaces.Can be combined in isotopic example in the The compounds of this invention and comprise the isotropic substance of hydrogen, carbon, nitrogen, oxygen, sulphur, fluorine and chlorine, respectively for example
2H,
3H,
13C,
14C,
15N,
18O,
17O,
18F and
36Cl.The pharmacy acceptable salt that contains other isotopic The compounds of this invention, its prodrug, described compound or the described prodrug of above-mentioned isotropic substance and/or other atoms belongs to scope of the present invention.Some isotope-labeled The compounds of this invention (for example is combined with radio isotope
3H and
14Those of C) can be used for medicine and/or substrate tissue distribution assay method.Tritium (promptly
3H) and carbon-14 (promptly
14C) isotropic substance is particularly preferred, because their preparation and detections easily.And then, replaced by heavier isotropic substance, for example deuterium is (promptly
2H), can provide the benefit in some treatment (for example transformation period or minimizing dosage demand in the extension body) because metabolic stability is higher, thereby may be preferred in some cases.Isotope-labeled The compounds of this invention and prodrug thereof generally can prepare like this, carry out in the flow process and/or hereinafter embodiment and the disclosed technology of preparation example, replace nonisotopically labelled reagent with the isotope-labeled reagent that obtains easily.
In this specification sheets and the following claims, with reference to a large amount of terms, they should be restricted to has following meanings:
Term used herein " treatment " comprises preventing property (for example preventative) and the treatment of alleviating property.
When " the treatment significant quantity of compound " used herein is illustrated in and uses in mode of the present invention, with regard to effective amount with regard to performance treatment of mammalian subject reactive site or biological activity, do not have undue adverse side effect (for example undue toxicity, pungency or transformation reactions), match with rational interests/risk ratio.
Term used herein " cerebrovascular disease " is selected from but is not limited to that neurological after ischemic episode (for example cross property), ishemic stroke (crosses property), acute apoplexy, cerebral apoplexy, hemorrhagic stroke, the apoplexy is damaged, shorten and the preparation of apoplexy thrombolytic therapy time of recovery after apoplexy, recurrent apoplexy, the apoplexy first.Preferred patient group comprise with or the apoplexy of not depositing earlier or the patient of coronary heart disease.
Term used herein " coronary heart disease " is selected from but is not limited to atherosclerotic plaque and (for example prevents, disappear, stabilization), the rapid wear spot (for example prevents, disappear, stabilization), rapid wear spot area (minimizing), arteriosteogenesis (for example calcification aortic stenosis), the coronary artery calcium scoring increases, the dysfunction vascular reactivity, the vasorelaxation obstacle, coronary vasospasm, myocardial infarction first, myocardium resurgent block, ischemic cardiomyopathy, Si Tanteshi die restenosis, the PTCA restenosis, arterial restenosis, crown bypass graft restenosis, the blood vessel bypass restenosis, the exercise treadmill time reduces, stenocardia/pectoralgia, unstable angina pectoris, the work expiratory dyspnea, exercising ability reduces, local asphyxia (reduce time to), asymptomatic local asphyxia (reducetime to), the seriousness of ischemia symptom and frequency increase, perfusion again after the Thrombolytic Therapy of Acute Myocardial Infarction therapy.
Term used herein " hypertension " is selected from but is not limited to hypertensive lipid obstacle, systolic hypertension and diastolic hypertension.
Term used herein " ventricular dysfunction " is selected from but is not limited to contractile dysfunction, diastolic dysfunction, heart failure, congestive heart failure, DCM (dilated cardiomyopathy), spontaneous DCM (dilated cardiomyopathy) and non-expansion myocardosis.
Term used herein " irregular pulse " is selected from but is not limited to atrial arrhythmia, supraventricular arrhythmia, ventricular arrhythmia and sudden-death syndrome.
Term used herein " pulmonary vascular disease " is selected from but is not limited to pulmonary hypertension, peripheral arterial retardance and pulmonary infarction.
Term used herein " peripheral vascular disease " is selected from but is not limited to peripheral vascular disease and limping.
Term used herein " blood vessel hemostasis disease " is selected from but is not limited to venous thrombosis, the angiemphraxis complication of sicklemia, varix, pulmonary infarction, transient ischemic attack, have the embolism incident (comprising apoplexy) among the patient of mechanical heart valve, have the embolism incident (comprising apoplexy) among the patient of the right side or left ventricular assist device, have the embolism incident (comprising apoplexy) among the patient of pump carrier in the aorta air bag, have the embolism incident (comprising apoplexy) among the patient of artificial heart, embolism incident (comprising apoplexy) among the myocardosis patient, embolism incident (comprising apoplexy) among auricular fibrillation or the auricular flutter patient.
Term used herein " diabetes " expression causes diabetic disease states arbitrarily in a large number, comprises type i diabetes, type ii diabetes, X syndrome, metabolism syndrome, the lipid obstacle relevant with insulin resistant, glucose tolerance lowers, non insulin dependent diabetes, the capillary blood vessel diabetic complication, nerve conduction velocity reduces, vision reduces or loses, diabetic retinopathy, amputation is dangerous to be increased, renal function reduces, renal failure, insulin resistance syndrome, many metabolism syndromes, central obesity (internal organ) (upper torso), the diabetic dyslipidaemia, the insulin sensitivity reduction, diabetic retinopathy/neuropathy, diabetic nephropathy/little and macroangiopathic and little/large protein urine, diabetic cardiomyopathy, diabetic gastroparesis, fat, the oxyphorase saccharification increases (comprising HbA1C), glucose control improves, renal function lowers (dialysis, late period) and liver function (slight, moderate, seriously).
Term used herein " inflammatory diseases, autoimmunity obstacle and other system disease " is selected from but is not limited to multiple sclerosis, rheumatoid arthritis, osteoarthritis, irritable bowel syndrome, intestines and easily swashs disease, Crohn disease, colitis, nodular vasculitis, lupus erythematosus, sarcoidosis, amyloidosis, apoptosis and complement system obstacle.
Term used herein " cognition dysfunction " is selected from but the delay that is not limited to be secondary to atherosclerotic dementia, transient cerebral ischemic attack, neurodegeneration (comprising Parkinson's disease, Huntington's disease, starch deposition and amyotrophic lateral sclerosis), neurone defective and Alzheimer takes place or progress.
" transitional period " represents antenatal 30 days to 70 days postpartum.
That term used herein " treatment " comprises is preventative, alleviating property and curative therapy.
" negative energy balance " used herein means the needs that do not satisfy life and production (breast) from the energy of food.
Term used herein " cow " comprises heifer, primiparity and cow fecund.
" healthy ruminating animal " means that this ruminating animal does not show the sign of following indication: fatty liver syndrome, difficult labour, immune dysfunction, immunologic function attenuating, poisoning, primary and Secondary cases ketosis, downer cow syndrome, maldigestion, poor appetite, placenta reservation, abomasum displacement, mazoitis, uterus (inner membrance) inflammation, Infertility, fertility is low and/or walk lamely.
The level of breast used herein " quality " expression Ruzhong protein, fat, lactose, somatocyte and ketoboidies.Along with the increase of fat, protein or lactose-content, the perhaps reduction of somatocyte level or ketoboidies level, newborn quality also increases.
The increase of milk production can be represented the increase of milk solids or dairy fats or milk protein content, and or replaces the increase of galactopoiesis volume.
Content of triglyceride is greater than the physiological level of 10%w/w in " the excessive of triglyceride level accumulated " used herein expression liver organization.
The non-esterified fatty acid level is greater than 800 μ mol/L in " the excessive rising of non-esterified fatty acid level in the serum " used herein expression serum.
Unless otherwise specified, " antenatal " expression preceding 3 weeks of farrowing are until farrowing the same day.
Unless otherwise specified, " postpartum " expression from uterus is discharged afterwards 6 weeks to newborn cowboy from newborn cowboy from the uterus in " discharges ".
" when childbirth " the newborn cowboy of expression discharged from the uterus back 24 hours.
" before and after the childbirth " expression begins to the stage of end post-natal period from antenatal period.
" metabolism syndrome " also claims " X syndrome ", represent a kind of common clinical obstacle, it is defined as the increase of insulin concentration, and this is relevant with other obstacles, comprises internal organ obesity, hyperlipemia, dyslipidaemia, hyperglycemia, hypertension, potentiality antihyperuricemic and renal tubal dysfunction.
" pharmaceutically acceptable " expression carrier, thinner, vehicle and/or salt must be compatible with other compositions of preparation, and harmless to its recipient.
" compound " used herein comprises pharmaceutically acceptable derivates or variant, comprise conformer (for example cis and trans-isomer(ide)) and all optically active isomers (for example enantiomorph and diastereomer), the racemize of this class isomer, diastereomer and other mixtures, and solvate, hydrate, isomorph, polycrystal, tautomer, ester, salt form and prodrug." tautomer " expression can exist two or more to be in the compound (isomer) of the different structure form in the balance, and the difference of these forms is the position of hydrogen atom usually.May there be various types of tautomerisms, comprise keto-enol, ring-chain and ring-ring tautomerism.Wording " prodrug " expression medicine precursor compound, they are in administration after by discharging medicine (for example prodrug is converted into required medicament forms under physiological pH or enzyme effect) in some chemistry or the physiological processes body.This class hydrolyzable that discharges the exemplary prodrug of corresponding free acid and The compounds of this invention after the cracking becomes the ester residue to include but not limited to have those of carboxy moiety, and wherein free hydrogen is replaced by following groups: (C
1-C
4) alkyl, (C
2-C
7) alkanoyloxymethyl, 1-(alkanoyloxy) ethyl with 4 to 9 carbon atoms, 1-methyl isophthalic acid-(alkanoyloxy) ethyl with 5 to 10 carbon atoms, alkoxy carbonyl oxygen ylmethyl with 3 to 6 carbon atoms, 1-(alkoxy carbonyl oxygen base) ethyl with 4 to 7 carbon atoms, 1-methyl isophthalic acid-(alkoxy carbonyl oxygen base) ethyl with 5 to 8 carbon atoms, N-(alkoxy carbonyl) amino methyl with 3 to 9 carbon atoms, 1-(N-(alkoxy carbonyl) amino) ethyl with 4 to 10 carbon atoms, the 3-phthalidyl, 4-crotons lactone group, gamma-butyrolactone-4-base, two-N, N-(C
1-C
2) alkylamino (C
2-C
3) alkyl (for example β-dimethylaminoethyl), carbamyl-(C
1-C
2) alkyl, N, N-two (C
1-C
2) alkylcarbamoyl group-(C
1-C
2) alkyl and piperidino-(1-position only)-, pyrrolidino-or morpholino base-(C
2-C
3) alkyl.
The following passage is described the exemplary ring about the general ring explanation of this paper.
Optional have one or two and independently be selected from heteroatomic exemplary five of oxygen, nitrogen and sulphur and comprise phenyl, furyl, thienyl, pyrryl, azoles base, thiazolyl, imidazolyl, pyrazolyl, different azoles base, isothiazolyl, pyridyl, pyridazinyl, pyrimidyl and pyrazinyl to hexa-atomic aromatic ring.
Optional have one to four a heteroatomic exemplary fractional saturation that independently is selected from oxygen, sulphur and nitrogen, saturated fully or undersaturated five comprise cyclopentyl, cyclohexyl, suberyl, ring octyl group and phenyl to carbocyclic eight-membered ring fully.
Further exemplary five yuan of carbocyclic rings comprise the 2H-pyrryl, the 3H-pyrryl, the 2-pyrrolinyl, the 3-pyrrolinyl, pyrrolidyl, 1,3-dioxolane base, azoles base, thiazolyl, imidazolyl, the 2H-imidazolyl, the 2-imidazolinyl, imidazolidyl, pyrazolyl, the 2-pyrazolinyl, pyrazolidyl, different azoles base, isothiazolyl, 1,2-dithiolane base, 1,3-dithiolane base, 3H-1,2-oxathiolane base, 1,2,3- di azoly, 1,2,4- di azoly, 1,2,5- di azoly, 1,3,4- di azoly, the 1,2,3-triazoles base, 1,2, the 4-triazolyl, 1,3, the 4-thiadiazolyl group, 1,2,3,4- triazolyl, 1,2,3,5- triazolyl, 3H-1,2,3-two azoles bases, 1,2,4-two azoles bases, 1,3,2-two azoles bases, 1,3,4-two azoles bases, 5H-1,2,5- thiazolyl and 1,3-oxathiolane base.
Further exemplary six-membered carbon ring comprises the 2H-pyranyl, the 4H-pyranyl, pyridyl, piperidyl, 1,2-two thiazolinyls, 1,3-two thiazolinyls, 1,4-two alkyl, morpholinyl, 1,4-dithiane base, the parathiazan base, pyridazinyl, pyrimidyl, pyrazinyl, piperazinyl, 1,3, the 5-triazinyl, 1,2, the 4-triazinyl, 1,2, the 3-triazinyl, 1,3,5-trithian base, 4H-1,2- piperazine base, 2H-1,3- piperazine base, 6H-1,3- piperazine base, 6H-1,2- piperazine base, 1,4- piperazine base, 2H-1,2- piperazine base, 4H-1,4- piperazine base, 1,2,5- plug piperazine base, 1,4- piperazine base, neighbour-different piperazine base, right-different piperazine base, 1,2,5- thiazinyl, 1,2,6- thiazinyl, 1,4,2- diazine and 1,3,5,2- diazine.
Further exemplary seven-element carbon ring comprises azepine base, oxa- base and thia base.
Further exemplary carbocyclic eight-membered ring comprises ring octyl group, cyclooctene base and cyclooctadiene base.
Optionally independently have one to four and independently be selected from nitrogen by two, sulphur and oxygen heteroatomic, condensed, fractional saturation, fully saturated or fully undersaturated five or exemplary two rings formed of six-ring comprise the indolizine base, indyl, pseudoindoyl, the 3H-indyl, the 1H-pseudoindoyl, indolinyl, cyclopenta (b) pyridine, pyrans also (3,4-b) pyrryl, benzofuryl, isobenzofuran-base, benzo (b) thienyl, benzo (c) thienyl, the 1H-indazolyl, indoles and piperazine base, the benzoxazol base, benzimidazolyl-, benzothiazolyl, purine radicals, the 4H-quinolizinyl, quinolyl, isoquinolyl, the cinnolines base, phthalazinyl, quinazolyl, quinoxalinyl, 1, the 8-naphthyridinyl, pteridyl, indenyl, different indenyl, naphthyl, tetralyl, the decahydro naphthyl, the 2H-1-benzopyranyl, pyrido (3,4-b) pyridyl, pyrido (3,2-b) pyridyl, pyrido (4,3-b) pyridyl, 2H-1, the 3-Benzoxazinyl, 2H-1, the 4-Benzoxazinyl, 1H-2, the 3-Benzoxazinyl, 4H-3, the 1-Benzoxazinyl, 2H-1,2-Benzoxazinyl and 4H-1, the 4-Benzoxazinyl.
The carbonatoms of various hydrocarbonaceous parts is with prefix designates, and it specifies minimum and maximum carbonatoms in this part, that is to say prefix C
i-C
jThe individual part to the individual carbon atom of integer " j " of expression integer " i " contains end value.Thereby for example, C
1-C
3Alkyl is represented an alkyl to three carbon atoms, contains end value, perhaps methyl, ethyl, propyl group and sec.-propyl and its all isomeric form and straight chain and side chain form.
The optional substituted hexa-atomic aromatic ring of " aryl " expression comprises many aromatic rings.The example of aryl comprises phenyl, naphthyl and biphenyl.
" heteroaryl " used herein expression optional substituted five or hexa-atomic aromatic ring comprise many aromatic rings, and wherein suitable carbon atom is replaced by nitrogen, sulphur or oxygen.The example of heteroaryl comprises pyridine, pyrimidine, thiazole, azoles, quinoline, quinazoline, benzothiazole and benzoxazol.
" halogeno-group " or " halogen " expression chlorine, bromine, iodine or fluorine.
" alkyl " expression straight chain saturation alkane or branched-chain saturated hydrocarbon.The example of this class alkyl (supposing that specified length contains specific example) has methyl, ethyl, propyl group, sec.-propyl, butyl, sec-butyl, the tertiary butyl, amyl group, isopentyl, neo-pentyl, tert-pentyl, 1-methyl butyl, 2-methyl butyl, 3-methyl butyl, hexyl, isohexyl, heptyl and octyl group.This term also comprises such stable hydrocarbon (straight or branched), wherein removes a hydrogen atom from each end carbon.
" thiazolinyl " mentioned in this article can be straight or branched, and they also can be ring-type (for example cyclobutene base, cyclopentenyl, cyclohexenyl) or bicyclic, perhaps contain cyclic group.They contain 1-3 bar carbon-to-carbon double bond, and these keys can be cis or trans.
" alkoxyl group " expression is by the straight chain saturated alkyl or the side chain saturated alkyl of oxygen bonding.The example of this class alkoxyl group (supposing that specified length contains specific example) has methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, tert.-butoxy, pentyloxy, isopentyloxy, neopentyl oxygen, uncle's pentyloxy, hexyloxy, different hexyloxy, heptan oxygen base and octyloxy.
Self-evident is if carbocyclic ring or heterocyclic moiety can or otherwise be connected in specified substrate and do not indicate concrete tie point by different annular atoms bondings, plan comprises all possible point so, no matter still passes through for example trivalent nitrogen atom by carbon atom.For example, term " pyridyl " expression 2-, 3-or 4-pyridyl, term " thienyl " expression 2-or 3-thienyl or the like.
Term " HMG CoA reductase inhibitor " is selected from but is not limited to lovastatin, Simvastatin, Pravastatin, fluindostatin, velostatin, dihydrocompactin, compactin, fluvastatin, atorvastatin, glenvastatin, Dalvastatin, card and cuts down his spit of fland, Kui and cut down his spit of fland, shellfish and cut down his spit of fland, simvastatin, rosuvastatin, pitavastatin, mevastatin or rivastatin, perhaps its pharmacy acceptable salt.
Term " hypotensive agent " is selected from but is not limited to calcium channel blocker and (includes but not limited to verapamil, diltiazem , mibefradil, isradipine, lacidipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, avanidpine, amlodipine, amlodipine besylate, Manidipine, cilinidipine, lercanidipine and felodipine), ACE inhibitor (includes but not limited to benazepril, captopril, enalapril, fosinopril, lisinopril, perindopril, quinapril, Trolapril, Ramipril, zestril, zofenopril, cilaapril, temocapril, spirapril, moexipril, moral is drawn Puli, imidapril, Ramipril, terazosin, urapidin, Indoramine, amolsulalol and alfuzosin), the A-II antagonist (includes but not limited to losartan, Yi Bishatan, telmisartan and valsartan), diuretic(s) (including but not limited to guanamprazine and Hydrex), β-adrenergic receptor blocker (for example carvedilol) or α-adrenergic receptor blocker (include but not limited to doxazosin, Prazosin and trimazosin), the perhaps pharmacy acceptable salt of this compounds.
In one embodiment of the invention, p is 1 or 2, R
1With the Q bonding.
In another embodiment of the invention, Ar
1Be:
In another embodiment of the invention, Ar
2Be:
In another embodiment of the invention,
Ar
1Be phenyl or with azoles base or thiazolyl condensed phenyl;
Ar
2Be phenyl or be selected from following ring condensed phenyl: phenyl, pyridyl, thienyl, thiazolyl, azoles base and imidazolyl.
In another embodiment of the invention, halogeno-group is a fluorine.
In another embodiment of the invention, B be a key or-L-(CY
2)
n-or-(CY
2)
n-L-, L are O or S, and n is 0,1 or 2.
In another embodiment of the invention,
X is-COOR
4
B is a key;
Ar
1Be phenyl or with azoles base or thiazolyl condensed phenyl;
Ar
2Be phenyl or be selected from following ring condensed phenyl: phenyl, pyridyl, thienyl, thiazolyl, azoles base and imidazolyl.
In another embodiment of the invention,
X is-COOR
4
B is-L-(CY
2)
n-or-(CY
2)
n-L-, L are O or S, and n is 0,1 or 2;
Ar
1Be phenyl or with azoles base or thiazolyl condensed phenyl;
Ar
2Be phenyl or be selected from following ring condensed phenyl: phenyl, pyridyl, thienyl, thiazolyl, azoles base and imidazolyl.
In another embodiment of the invention,
Ar
1Be
Ar
2Be
In another embodiment of the invention, q is 1 or 2, and each J is halogeno-group, the optional (C that is replaced by one to three halogeno-group independently
1-C
3) alkyl or the optional (C that is replaced by one to three halogeno-group
1-C
3) alkoxyl group.
In another embodiment of the invention, p is 1, R
4Be H or (C
1-C
3) alkyl.
In another embodiment of the invention, L is S, and n is 1.
In another embodiment of the invention, formula I compound is selected from:
2-methyl-5-[4-(5-methyl-benzoxazol-2-yl)-phenyl sulfamoyl] phenylformic acid;
5-[4-(5-chloro-benzoxazol-2-yl)-phenyl sulfamoyl]-2-methyl-phenylformic acid;
2-methyl-5-[4-(4-trifluoromethyl-benzylthio-)-phenyl sulfamoyl]-phenylformic acid;
5-[4-(the 4-tertiary butyl-benzylthio-)-phenyl sulfamoyl]-2-methyl-phenylformic acid;
2-ethyl-5-[4-(5-methyl-benzoxazol-2-yl)-phenyl sulfamoyl]-phenylformic acid;
5-[4-(4-ethyl-benzylthio-)-phenyl sulfamoyl]-2-methyl-phenylformic acid;
5-[4-(3,4-two fluoro-benzylthio-s)-phenyl sulfamoyl]-2-methyl-phenylformic acid;
5-[4-(3,4-dimethyl-benzylthio-)-phenyl sulfamoyl]-2-methyl-phenylformic acid;
5-[4-(5,7-two fluoro-benzothiazole-2-methylthiol)-phenyl sulfamoyl]-2-methyl-phenylformic acid;
2,3-dimethyl-5-(4 '-trifluoromethoxy-biphenyl-4-base sulphonamide)-phenylformic acid;
2-ethyl-5-[4-(4-trifluoromethoxy-benzylthio-)-phenyl sulfamoyl]-phenylformic acid;
2-ethyl-5-(4 '-trifluoromethoxy-biphenyl-4-base sulphonamide)-phenylformic acid;
2-sec.-propyl-5-[2-(4-trifluoromethoxy-phenyl)-benzoxazoles-5-base sulphonamide]-phenylformic acid; With
2-methyl-5-(4 '-trifluoromethoxy-biphenyl-4-base sulphonamide)-phenylformic acid;
The perhaps pharmacy acceptable salt of the prodrug of described compound or described compound or prodrug.
In another embodiment of the invention, formula I compound is selected from:
2-ethyl-5-[4-(6-methyl-benzothiazole-2-yl)-phenyl sulfamoyl]-phenylformic acid;
2-methyl-5-(4 '-trifluoromethyl-biphenyl-4-base sulphonamide)-phenylformic acid;
2-sec.-propyl-5-[propyl group-(4 '-trifluoromethoxy-biphenyl-4-yl)-sulphonamide]-phenylformic acid;
2-methyl-5-[(4 '-propoxy--biphenyl-4-yl)-propyl group-sulphonamide]-phenylformic acid;
2-methyl-5-(4 '-propoxy--biphenyl-4-base sulphonamide)-phenylformic acid;
2-ethyl-5-[4-(4-trifluoromethoxy-benzylthio-)-phenyl sulfamoyl]-phenylformic acid;
5-(4 '-tertiary butyl-biphenyl-4-base sulphonamide)-2-methyl-phenylformic acid;
5-[4-(4-chloro-benzylthio-)-phenyl sulfamoyl]-2-methyl-phenylformic acid;
2-methyl-5-[4-(3-trifluoromethoxy-benzylthio-)-phenyl sulfamoyl]-phenylformic acid;
2-methyl-5-[2-(4-trifluoromethyl-phenyl)-benzoxazol-5-base sulphonamide]-phenylformic acid;
2-methyl-5-[4-(5-phenyl-benzoxazol-2-yl)-phenyl sulfamoyl]-phenylformic acid; With
2-sec.-propyl-5-[4-(5-methyl-benzoxazol-2-yl)-phenyl sulfamoyl]-phenylformic acid;
The perhaps pharmacy acceptable salt of the prodrug of described compound or described compound or prodrug.
In a kind of embodiment of the inventive method, the treatment atherosclerosis.
In a kind of embodiment of the inventive method, the treatment peripheral vascular disease.
In a kind of embodiment of the inventive method, the treatment dyslipidaemia.
In a kind of embodiment of the inventive method, the treatment diabetes.
In a kind of embodiment of the inventive method, the low alpha-lipoprotein blood of treatment.
In a kind of embodiment of the inventive method, the treatment hypercholesteremia.
In a kind of embodiment of the inventive method, the treatment hypertriglyceridaemia.
In a kind of embodiment of the inventive method, treatment is fat.
In a kind of embodiment of the inventive method, the treatment osteoporosis.
In a kind of embodiment of the inventive method, the treatment metabolism syndrome.
In another embodiment of the invention, pharmaceutical composition is used for the treatment of the Mammals atherosclerosis, and it comprises formula I compound or the prodrug of described compound or pharmacy acceptable salt and pharmaceutically acceptable carrier, vehicle or the thinner of described compound or prodrug of treatment of atherosclerosis amount.
In a kind of embodiment of pharmaceutical combination composition of the present invention, method and medicine box, second compound is HMG-CoA reductase inhibitor or CETP inhibitor.
In a kind of embodiment of pharmaceutical combination composition of the present invention, method and medicine box, second compound is the prodrug of rosuvastatin, rivastatin, pitavastatin, lovastatin, Simvastatin, Pravastatin, fluvastatin, atorvastatin or simvastatin or described compound or the pharmacy acceptable salt of described compound or prodrug.
In a kind of embodiment of pharmaceutical combination composition of the present invention, method and medicine box, second compound is [2R, 4S] 4-[(3,5-pair-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester.
In a kind of embodiment of pharmaceutical combination composition of the present invention, method and medicine box, said composition further comprises cholesterol absorption inhibitor.
In a kind of embodiment of pharmaceutical combination composition of the present invention, method and medicine box, this cholesterol absorption inhibitor is ezetimibe.
In a kind of embodiment of pharmaceutical combination composition of the present invention, method and medicine box, said composition further comprises hypotensive agent.
In a kind of embodiment of pharmaceutical combination composition of the present invention, method and medicine box, described hypotensive agent is calcium channel blocker, ACE inhibitor, A-II antagonist, diuretic(s), β-adrenergic receptor blocker or α-adrenergic receptor blocker.
In pharmaceutical combination composition of the present invention, in a kind of embodiment of method and medicine box, this hypotensive agent is a calcium channel blocker, and described calcium channel blocker is a verapamil, diltiazem , mibefradil, isradipine, lacidipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, avanidpine, amlodipine, amlodipine besylate, Manidipine, cilinidipine, the pharmacy acceptable salt of the prodrug of lercanidipine or felodipine or described compound or described compound or prodrug.
In another embodiment of the invention, formula II compound is:
4-(5-chloro-benzoxazol-2-yl)-phenyl amine;
4-(4-trifluoromethyl-benzylthio-)-phenyl amine;
4-(the 4-tertiary butyl-benzylthio-)-phenyl amine;
4-(4-ethyl-benzylthio-)-phenyl amine;
4-(3,4-two fluoro-benzylthio-s)-phenyl amine;
4-(3,4-dimethyl-benzylthio-)-phenyl amine;
4-(5,7-two fluoro-benzothiazole-2-methylthiol)-phenyl amine;
4 '-trifluoromethoxy-biphenyl-4-base amine;
4-(4-trifluoromethoxy-benzylthio-)-phenyl amine; Or
4-(trifluoromethoxy-phenyl)-benzoxazol-5-base amine;
Perhaps its pharmacy acceptable salt.
Generally speaking, the process of preparation The compounds of this invention can be similar to chemical field known those, particularly in view of the explanation of this paper.Provide some process of making The compounds of this invention as further inventive features, following reaction process is described.Experiment one joint is described other processes.
Reaction process described herein plans to be provided for to prepare the general remark of the method for a lot of embodiment.But, will find out that obviously the preparation method that is adopted exceeds general technology as herein described from the detailed description of testing a joint.Definite, it should be noted that according to the prepared compound of these flow processs and modify through further, the new embodiment in the scope of the invention can be provided.For example, utilize technology well known to those skilled in the art that the ester functionality is further reacted, obtain another kind of ester, acid amides, acid, methyl alcohol or ketone.
At first note, in the preparation of The compounds of this invention, some preparation method who is used for preparing compound described herein distally functional group (for example primary amine of intermediate, secondary amine, carboxyl) that may need protection.Will be different to the needs of this class provide protection because of the attribute of distally functional group and preparation method's condition, those of ordinary skills determine it easily.This class protects/goes the use of guard method also in the common skill scope of this area.About the general remark of blocking group and their purposes, referring to T.W.Greene, Protective Groups in OrganicSynthesis.John Wiley ﹠amp; Sons, New York, 1991.
For example, in following reaction process, some compound contains primary amine or carboxylic functionality, if do not add protection, and the reaction at their other positions of possibility disturbing molecule.Therefore, this class functionality can be protected by suitable blocking group, and blocking group can be removed in step subsequently.The blocking group that is suitable for the protection of amine and carboxylic acid comprises and is usually used in those blocking groups of peptide synthetic (the N-tertbutyloxycarbonyl, carbobenzoxy-(Cbz) and the 9-fluorenyl methylene oxygen carbonyl that for example are used for amine; the low alkyl group or the benzyl ester that are used for carboxylic acid); they generally do not have chemical reactivity under described reaction conditions; usually can remove, and not in other functionality that chemically change in the compound.
Flow process 1
According to reaction process 1, by prepared formula 1d compound well known in the art, they are such formula I compounds, and wherein X is-COOR
4, R
2Be H, (optional existence) R is halogeno-group, alkyl, alkoxyl group or alkylthio, R
1, B, Ar
2, J, p and q be aforesaid.For example; under temperature preferred 100 ℃ between about 90 and 110 ℃; with phenylformic acid or ester 1a (they be commercially available or document in the known or method preparation that can be familiar with according to those skilled in the art) with about 15 minutes to 3 hours of chlorsulfonic acid (halogeno-group is a chlorine) processing; preferred 2.5 hours of acid; the preferred 15min of ester obtains halogenation alkylsulfonyl 1b.
SULPHURYL CHLORIDE 1b and the aniline 1e that suitably replaces (preparation of aniline 1e as flow process 4,5,6,7 and 8 as described in) reaction generates sulfonanilide 1c, and this can carry out under reaction conditions well known to those skilled in the art.For example, the reaction of SULPHURYL CHLORIDE 1b and aniline 1e can be carried out like this, in inert solvent, the mixture of tetrahydrofuran (THF), dimethyl formamide or acetone and water for example, in the presence of alkali, for example pyridine, salt of wormwood or yellow soda ash, under the temperature between 20 ℃ and 65 ℃, preferred room temperature, about 10 to 36 hours of time, preferred about 20 hours.If 1b is chlorosulfonyl benzoic ether (R
4=CH
3), reaction can preferably be carried out like this, in organic solvent, and tetrahydrofuran (THF) for example, in the presence of amine alkali, for example pyridine and triethylamine.
Ester products 1c can be converted into phenylformic acid 1d with alkali metal hydroxide, preferred sodium hydroxide hydrolysis like this, in the mixture of alcohol, particular methanol and water, and under about 50 to 100 ℃ temperature, preferred reflux temperature, about 2 to 30 hours of time.
Flow process 2
According to reaction process 2, required formula I compound is preparation like this, and wherein X is-COOR
4, R
2Be H, B is a key, Ar
2Be phenyl, (optional existence) R is halogeno-group, alkyl, alkoxyl group or alkylthio, R
1, J, p and q be aforesaid, in inert solvent, tetrahydrofuran (THF) for example; perhaps solvent mixture; for example acetone and water, in the presence of amine alkali, pyridine/triethylamine for example; perhaps mineral alkali; for example salt of wormwood or yellow soda ash, under about 20 ℃ to 50 ℃ temperature, preferred room temperature; make about 20 hours of halogenation alkylsulfonyl (wherein halogeno-group is a chlorine) 1b and 4-halo aniline 2a (wherein halogeno-group is a bromine or iodine) reaction, generate halogenation sulfonanilide 2b.
Utilize technology well known by persons skilled in the art, in solvent, for example tetrahydrofuran (THF), two alkane, glycol dimethyl ether or two alkane/water are under palladium catalysis, in the presence of alkali, for example salt of wormwood, cesium carbonate or yellow soda ash, under the temperature between 80 ℃ and 110 ℃, preferably under refluxing, halogenation sulfonanilide 2b reacted 6-30 hour for boric acid derivatives 2c with the benzene that suitably replaces, preferred 20 hours, obtain biphenyl sulfonanilide 2d.Other operable palladium catalysts, phosphine part, solvent, alkali and temperature of reaction in Chemical Reviews 102,1359 (2002), have been exemplified.For example, at catalytic amount dichloro [1,1 '-two (diphenyl phosphine) ferrocene] palladium (II) methylene dichloride adducts and 1, under the existence of 1 '-two (diphenyl phosphine) ferrocene, the bromo sulfonanilide reacts for boric acid 2c as halogenation sulfonanilide 2b and aryl, as alkali, moisture two alkane obtain biphenyl sulfonanilide 2d as solvent with salt of wormwood.Shown in flow process 1, the ester group of compound 2d (X ,-COOR
4) can be converted into acid groups by alkaline hydrolysis.
Flow process 3
According to reaction process 3, required formula I compound is preparation like this, and wherein X is-COOR
4, R
2Be alkyl, (optional existence) R is halogeno-group, alkyl, alkoxyl group or alkylthio, R
1, R
2, B, Ar
2, J, p and q be aforesaid, in the presence of alkaline carbonate, the carbonate of potassium, sodium or caesium for example, in inert solvent, for example acetone or dimethyl formamide, under the temperature between 60 ℃ and 80 ℃, preferred acetone is under reflux temperature, sulfonanilide 1c is handled with suitable halogenated alkyl (wherein halogeno-group is a bromine or iodine) 3a or with alkyl sulfonic ester, obtain n-alkyl sulfonyl diboronic ester 3b.
N-alkyl sulfonyl diboronic ester 3b can be converted into sour 3c by alkaline hydrolysis, for example the reaction conditions that exemplified of front flow process 1.
Flow process 4,5,6,7 and 8 is described the preparation that is used in the aniline 1e in synthesizing shown in the flow process 1.Select as an alternative, the aniline 1e in the flow process 1 be commercially available or document in known or can be according to prepared well known in the art.
Flow process 4
Can prepare required formula 1e compound, wherein R by 4a with 4b (flow process 4) or by the similar route of synthesis that those skilled in the art are familiar with
2Be hydrogen, (optional existence) R is halogeno-group, alkyl, alkoxyl group or alkylthio, and B is a key, Ar
2Be and imidazoles, azoles or thiazole ring condensed benzyl ring (D is N, O or S), J and q are aforesaid.
Among the flow process 4a, with 2-amino-phenol, 2-aminothiophenol or 2-amino aniline derivative 4a and the 4-benzaminic acid 4b that suitably replaces in Tripyrophosphoric acid, in about 170 ℃ to 200 ℃ heating 4-10 hour down, preferred 190 ℃ and 6 hours, obtain corresponding 4-benzoxazol-2-base-phenyl amine, 4-benzothiazole-2-base-phenyl amine or 4-benzimidazolyl-2 radicals-Ji-phenyl amine derivative 1e4.
Select as an alternative; as described in flow process 4b; in inert solvent; METHYLENE CHLORIDE for example, in the presence of amine alkali, 4-Dimethylamino pyridine for example; under 20 ℃ to 50 ℃ temperature; with 4-nitrobenzoyl chloride or 4-nitrobenzoyl acylbromide 4c acidylate 10-30 hour, preferred room temperature 20 hours obtained corresponding benzamide 4d with 2-amino-phenol, 2-aminothiophenol or 2-amino aniline derivative 4a.
Under the acylation reaction condition, thiophenol derivative 4d (D=S) spontaneously cyclisation is benzothiazole derivant 4e (D=S).Can be benzoxazol derivative 4e (D=O) with phenol derivatives 4d (D=O) cyclisation like this, in solvent, for example tetrahydrofuran (THF), dimethyl formamide, METHYLENE CHLORIDE or two alkane, preferred tetrahydrofuran (THF), at 15 ℃ under 35 ℃, with diethylazodicarboxylate (DEAD) and triphenyl phosphine (Ph
3P) handled 10-30 hour preferred ambient temperature overnight.
Nitro among the 4e can generate aniline 1e4 by the technology reduction that those skilled in the art are familiar with.For example, nitro-compound 4e and iron powder and calcium chloride in aqueous alcohol, for example ethanol, in about 60 ℃ to 100 ℃ heating 4 to 10 hours down, preferably under refluxing 5 hours, are obtained aniline 1e4.At Richard Larock, Comprehensive OrganicTransformations.VCH Publishers, New York has exemplified other reductive agents in 1989,412, for example iron and acetate, zinc and aqueous hydrochloric acid and catalytic hydrogenation.
Flow process 5
Can prepare required formula 1e5 compound, wherein R by flow process 5 or by the similar route of synthesis that those skilled in the art are familiar with
2Be hydrogen, B is a key, Ar
2Be diazole ring, J is aforesaid.
In pyridine, at room temperature, commercially available 5-(4-nitrophenyl)-1H-tetrazolium 5a with acyl chlorides 5b acidylate, succeeded by 60 ℃ of heating 1 hour down, 100 ℃ of heating 2 hours down, is obtained 2-(4-nitrophenyl)-1,3,4- diazole 5c.
Nitro is reduced to amine by method known to those skilled in the art, obtains aniline 1e5.For example, reductive action can be carried out as described in the flow process 4b of front, uses iron powder and calcium chloride in aqueous ethanol.
Flow process 6
Described synthetic or can prepare required formula 1e6 compound, wherein R by 6a, the 6b of flow process 6 and 6c by the similar route of synthesis that those skilled in the art are familiar with
2Be hydrogen, (optional existence) R is halogeno-group, alkyl, alkoxyl group or alkylthio, and B is-L-CH
2-or-CH
2-L-, Ar
2Be phenyl, J and q are as mentioned above.
Benzyloxy oil of mirbane or benzylthio-nitrobenzene derivative (6c) can be by the Mitsunobu prepared in reaction, for example at diethylazodicarboxylate (DEAD) and triphenyl phosphine (Ph
3P) under the existence, in solvent, for example tetrahydrofuran (THF), dimethyl formamide, METHYLENE CHLORIDE or two alkane, under about 15 ℃ to 35 ℃, make 4-nitrophenols or 4-nitro thiophenol 6b and suitable benzylalcohol 6a reaction 10 to 30 hours, preferably in tetrahydrofuran (THF), (flow process 6a) at room temperature spends the night.At Organic Reactions, Vol 42,1992,335, and John Wiley has discussed reaction conditions, solvent, temperature and the reaction times of Mitsunobu reaction in 2002.Nitro by method known to those skilled in the art reduction 6c is included in those that exemplify among the flow process 4b, obtains corresponding aniline 1e6.
For example, in flow process 6b, benzylthio-aniline 1e6-1 can be synthetic like this, in the presence of alkali, and for example sodium hydride, cesium carbonate or sodium tert-butoxide, in solvent, for example tetrahydrofuran (THF), dimethyl formamide or glycol dimethyl ether, preferred tetrahydrofuran (THF) is under about 20 ℃ to 70 ℃ temperature, 4-aminothiophenol 6d was handled 8 to 30 hours with the benzyl chloride 6e that suitably replaces, preferably at room temperature spend the night.
4-benzyloxy-aniline 1e6-2 can be by Mitsunobu prepared in reaction (flow process 6c), wherein as 6c exemplified, by diethylazodicarboxylate (DEAD) and triphenyl phosphine (Ph
3P) mediation 4-amino-phenol 6f and the suitable reaction of benzylalcohol 6a in solvent, for example tetrahydrofuran (THF) are at room temperature spent the night.
Flow process 7
Described synthetic or can prepare required formula 1e compound, wherein R by flow process 7 by the similar route of synthesis that those skilled in the art are familiar with
2Be hydrogen, (optional existence) R is halogeno-group, alkyl, alkoxyl group or alkylthio, and B is a key, Ar
2Be phenyl, J and q are aforesaid.
Exemplified as flow process 2c, utilize technology well known by persons skilled in the art, benzidine derivative 1e7 can be prepared with the Suzuki coupled action of the benzene that suitably replaces for boric acid derivatives 2c by 4-halo aniline 2a (wherein halogeno-group is a bromine or iodine).Benzene is commercially available for boric acid derivatives 2c, is perhaps exemplified as flow process 2c, can easily be prepared by literature method well known by persons skilled in the art.For example, at catalytic amount dichloro [1,1 '-two (diphenyl phosphine) ferrocene] palladium (II) methylene dichloride adducts and 1, under the existence of 1 '-two (diphenyl phosphine) ferrocene, make 4-bromaniline and aryl for boric acid 2c reaction, as alkali, moisture two alkane are as solvent with salt of wormwood, under reflux temperature, spend the night, obtain benzidine derivative 1e7.
Flow process 8
Described synthetic or can prepare required formula 1e compound, wherein R by flow process 8 by the similar route of synthesis that those skilled in the art are familiar with
2Be hydrogen, (optional existence) R is halogeno-group, alkyl, alkoxyl group or alkylthio, and B is L, Ar
2Be phenyl, J and q are aforesaid.
Phenoxybenzamine and thiophenyl anils 1e8 (flow process 8) can prepare like this, in the presence of alkali, for example sodium hydride, sodium tert-butoxide or cesium carbonate, in inert solvent, for example dimethyl formamide, tetrahydrofuran (THF) or glycol dimethyl ether under about 60 ℃ to 90 ℃, reacted 4-halogenated nitrobenzene 8b (wherein halogeno-group is chlorine, bromine or iodine) and suitable phenol or thiophenol 8a about 10 to 30 hours, preferred 80 ℃ are spent the night, obtain nitro-derivative 8c.Utilize technology well known by persons skilled in the art, for example the front in flow process 4b, exemplify those, nitro-derivative 8c can obtain aniline 1e8 by reduction.
Flow process 9
As J.Med.Chem., 29,773 (1986) and Chem.Pharm.Bull., 30,3601 (1982) are instructed, can preparation I compound by flow process 9 described synthetic orders, and wherein X is thiazolidinedione-5-base-G-, G is (CH
2)
s, s is 0, R
2Be H, (optional existence) R is halogeno-group, alkyl, alkoxyl group or alkylthio, R
1, B, Ar
2, J, p and q be aforesaid.In anhydrous methylene chlorine or chloroform, under about 20 ℃ to 30 ℃, the phenyl aldehyde 9a that suitably replaces was handled about 15 to 30 hours with the zinc iodide of trimethyl silyl cyanogen and catalytic amount, preferably in METHYLENE CHLORIDE, at room temperature spend the night, obtain cyanalcohol 9b (Z=OH).
In chloroform or METHYLENE CHLORIDE, under about 30 ℃ to 65 ℃, about 30 to 60 minutes of time, preferably in chloroform, under reflux temperature 45 minutes, cyanalcohol 9b (Z=OH) is converted into chloro-cyanide 9b (Z=Cl).In alcoholic solvent, ethanol for example, under about 60 ℃ to 80 ℃, chloro-cyanide 9b (Z=Cl) and thiocarbamide were reacted about 4 to 10 hours, preferably in ethanol, under reflux temperature 5 hours, succeeded by under about 95 ℃ to 120 ℃, with intermediate imino-thiazolidone with about 4 to 10 hours of aqueous acids hydrolysis, preferred 6N aqueous hydrochloric acid under reflux temperature 5 hours obtains thiazolidinedione 9c.
Select as an alternative, in the mixture of water, acetate and methyl glycol, at room temperature, suitable phenyl aldehyde 9a was handled 1.5 hours with sodium cyanide, succeeded by adding thiocarbamide and concentrated hydrochloric acid, heated 18 hours down at about 100 ℃, obtain thiazolidinedione 9c (Chem.Pharm.Bull., 45,1984 (1997)).
With thiazolidinedione 9c in clean chlorsulfonic acid, in about 90 ℃ to 110 ℃ about 15 to 30 minutes of heating down, preferably 100 ℃ following 15 minutes, obtain SULPHURYL CHLORIDE 9d.Utilize technology well known by persons skilled in the art, for example flow process 1 described reaction makes SULPHURYL CHLORIDE 9d and the aniline 1e reaction that suitably replaces, and obtains required thiazolidine diketone derivative 9e.
Flow process 10
As Chem.Pharm.Bull., 45,1984 (1997) are instructed, can preparation I compound by flow process 10 described reaction sequence, and wherein X is thiazolidinedione-5-base-G-, G is methylene radical or (CH
2)
s, s is 1, R
2Be H, (optional existence) R is halogeno-group, alkyl, alkoxyl group or alkylthio, R
1, B, Ar
2, J, p and q be aforesaid.Under the mediation of the acetic acid solution of the acetate of piperidines or ethanolic soln or acetate ammonia, under about 110 ℃ to 120 ℃, make about 8 to 30 hours of the phenyl aldehyde 9a of suitable replacement and thiazolidinedione condensation, the acetic acid solution of preferred piperidines under refluxing about 20 hours, perhaps piperidines and benzoic toluene solution are under refluxing about 3 to 10 hours, obtain benzylidene thiazolidinedione 10b.
Thiazolidinedione 10b in clean chlorsulfonic acid, about 15 to 25 minutes of about 90 ℃ to 110 ℃ following heating, preferred about 100 ℃, 15 minutes, is obtained SULPHURYL CHLORIDE 10c.
Utilize technology well known by persons skilled in the art, for example flow process 1 described process makes SULPHURYL CHLORIDE 10c and the aniline 1e reaction that suitably replaces, and obtains benzylidene thiazolidine diketone derivative 10d.
Utilize the ethylene linkage of the method reduction 10d that those skilled in the art are familiar with, for example lithium borohydride is in pyridine/tetrahydrofuran (THF), under about 65 ℃ to 90 ℃, about 2 to 6 hours of time, perhaps sodium borohydride/lithium chloride, in pyridine/tetrahydrofuran (THF), under about 65 ℃ to 90 ℃, about 3 to 6 hours of time, the perhaps catalytic hydrogenation of 10%Pd-C, 1, in 4-two alkane or the methyl alcohol, under about 50 to 60psi, about 36 to 60 hours of time, preferred lithium borohydride in pyridine/tetrahydrofuran (THF), under refluxing 3 hours obtains required thiazolidine diketone derivative 10e.
Flow process 11
As Monat.Chem.99,2048 (1968) are instructed, can preparation I compound by flow process 11 described route of synthesis, and wherein X is-O-(CR
3 2)-COOR
4, R
3Be CH
3, R
1Be alkyl, R
2Be H, (optional existence) R is halogeno-group, alkyl, alkoxyl group or alkylthio, B, Ar
2, J and q be aforesaid.Phenol 11a that replaces and lead tetraacetate preferably at room temperature 3 hours, obtain acetate chinol 11b in acetate, about 3 to 6 hours of about 20 ℃ to 30 ℃ following reactions.
Handled about 3 to 6 hours with S-WAT in water, under about 20 ℃ to 30 ℃, preferred room temperature 3 hours makes acetate chinol 11b be converted into sulfonic acid 11c.
With sulfonic acid 11c and phosphorus pentachloride in about 110 ℃ to 130 ℃ about 25 to 55 minutes of heating down, preferred about 120 ℃ about 30 minutes, preparation SULPHURYL CHLORIDE 11d.
Utilize technology well known by persons skilled in the art, for example flow process 1 described process makes SULPHURYL CHLORIDE 11d and the aniline 1e reaction that suitably replaces, and succeeded by the alkaline hydrolysis of acetate, obtains sulphonamide 11e.
In dimethyl formamide or ethanol, under about 80 ℃ to 100 ℃, with sulphonamide 11e with about 12 to 24 hours of 2-isobutyl ethyl bromide and salt of wormwood alkylation, preferred dimethyl formamide about 95 ℃ about 18 hours down, succeeded by the basic hydrolysis of product, obtain required sour 11f.
Flow process 12
Can preparation I compound by flow process 12 described reaction sequence, wherein X is-CH
2(CR
5 w)-COOR
4, R
5Be CH
3CH
2, w is 1, R
2Be H, (optional existence) R is halogeno-group, alkyl, alkoxyl group or alkylthio, R
1, B, Ar
2, J, p and q be aforesaid.In tetrahydrofuran (THF) or glycol dimethyl ether, under about 20 ℃ to 30 ℃, the phenyl aldehyde 9a that makes suitable replacement reacted about 2 to 5 hours with the carbanion that generates from triethyl-2-phosphono butyric ester and potassium tert.-butoxide or sodium hydride, preferably at room temperature 3 hours, obtained alkene ester 12b.
In chlorsulfonic acid, about 55 ℃ to 70 ℃ following heating about 15-25 minute, preferably descended about 15 minutes at about 60 ℃, ester 12b is converted into SULPHURYL CHLORIDE 12c.
Utilize method known to those skilled in the art, for example flow process 1 described process makes SULPHURYL CHLORIDE 12c and the aniline 1e reaction that suitably replaces, and obtains sulphonamide 12d.
Utilize the ethylene linkage of technology well known by persons skilled in the art reduction 12c, magnesium for example is in methyl alcohol or ethanol, under about 60 ℃ to 85 ℃, be consumed until magnesium, perhaps the catalytic hydrogenation of 10%Pd-C, 1, in 4-two alkane or the methyl alcohol, under about 50 to 60psi, about 36 to 60 hours of time, preferably magnesium is in methyl alcohol, under about 65 ℃, succeeded by the alkaline hydrolysis of product, obtain required sour 12e.
Flow process 13
Can preparation I compound, wherein Ar by flow process 1 described reaction sequence
1It or not phenyl, replace aniline 1e as long as use and be selected from following member's condensed aniline: thiazolyl, furyl, azoles base, pyridine, pyrimidine, phenyl or thienyl, their known intermediates from commercially available or document prepare by method known to those skilled in the art.
For example, flow process 13 is described a kind of like this process, wherein Ar
1Be benzoxazol or benzothiazole, B is a key, Ar
2Be phenyl, J and q are as defined above.In the first step of flow process 13, as what in flow process 4a, exemplified, make 2-amino-phenol or 2-aminothiophenol (wherein D is O or S) 13a and suitable phenylformic acid in Tripyrophosphoric acid,, obtain benzoxazol or benzothiazole 13b in about 190 ℃ of about 6 hours of reactions down.With 13b with concentrated nitric acid and sulfuric acid about 75 ℃ nitrated about 30 minutes down, about 100 ℃ nitrated about 1 hour down, obtain nitro-derivative 13c, utilize technology shown in the flow process 4b to be reduced to required amino benzoxazol or aminobenzothiazole 13d again.
Flow process 14
Ar wherein
1Be that quinoline, B are a key, Ar
2Be that phenyl, J and q are that compound can prepare so as defined above, for example known chloroquinoline 14a begins [J.Amer.Chem.Soc. from document, 60,2104 (1938)], utilize the method in flow process 2, exemplify and suitable aryl-or alkyl-Dai acid reaction.
Flow process 15
Ar wherein
1Be quinazoline, B, Ar
2, J and q be that compound can prepare so as defined above, for example by Synlett, (1999) described method p.1993.In acetonitrile, in the presence of salt of wormwood and molecular sieve, under reflux temperature, suitable amidine 15b and nitrobenzaldehyde 15a were reacted about 5 to 10 hours, obtain nitro-quinazoline 15c.Can carry out the reductive action of 15c by the described method of flow process 4b to required amine 15d.
Flow process 16
Ar wherein
1Be that thionaphthene, B are-L-CH
2-, L is O or S, Ar
2, J and q be that compound can prepare so as defined above, for example known methylol thionaphthene 16a begins (J.Heterocycl.Chem., 20,129 (1983)) from document.As J.Med.Chem., 35,457 (1992) are instructed, make 16a and methylsulfonyl chloride and pyridine in METHYLENE CHLORIDE, reaction at room temperature spends the night, and obtains chloromethylbenzene thiophthene 16b.In the presence of alkali, for example sodium hydride or sodium tert-butoxide are in inert solvent, for example tetrahydrofuran (THF), glycol dimethyl ether or dimethyl formamide, under about 20 ℃ to 60 ℃, with 16b with about 6 to 30 hours of suitable alcohol or thiol treatment, preferably at room temperature spend the night, obtain nitro-derivative 16c.Can carry out the reductive action of 16c by the described method of flow process 4b to required amine 16d.
Flow process 17
Ar wherein
1Be that cumarone, B are CH
2, Ar
2, J and q be that compound can prepare so as defined above, as J.Med.Chem., 39,3897 (1996) are instructed, for example in solvent, for example dimethyl formamide, ethanol or acetone are under about 75 to 95 ℃ temperature, 5-nitrosalicylaldehyde 17a and suitable brooethyl aryl ketones and alkali, for example diisopropylethylamine, Potassium monofluoride or salt of wormwood were reacted about 3 to 24 hours, preferred diisopropylethylamine in dimethyl formamide, following 4 hours at 92 ℃.Ketone 17c is reduced to corresponding alcohol with sodium borohydride in methyl alcohol, in trifluoroacetic acid, is converted into nitro-compound 17d with triethyl silicane again.Can carry out the reductive action of 17d by the described method of flow process 4b to required amine.
The compounds of this invention also can be united with other drug composition (for example LDL-cholesterol reducing agent, triglyceride lowering agent) and is used for the treatment of disease/illness described herein.For example, they can with following medication combined use: HMG-CoA reductase inhibitor, cholesterol synthesis inhibitor, cholesterol absorption inhibitor, CETP inhibitor, MTP/Apo B secretion inhibitor, another kind of PPAR adjusting control agent and other cholesterol reducing agents, for example special class of shellfish, nicotinic acid, ion exchange resin, antioxidant, ACAT inhibitor and bile acid chelating agent.The other drug composition also will comprise as follows: bile acide reuptake inhibitor, ileal bile acid transfer inhibitor, ACC inhibitor, hypotensive agent (for example NORVASC ), selective estrogen receptor adjusting control agent, selective androgen receptor adjusting control agent, microbiotic, antidiabetic (for example metformin, PPAR γ activator, sulfonylurea, Regular Insulin, aldose reduction magnesium inhibitor (ARI) and SODH inhibitor (SDI)) and acetylsalicylic acid (acetylsalicylic acid).Available niacin sustained release form is known Niaspan.Nicotinic acid also can with combination with other therapeutic agents, Statins for example, i.e. lovastatin, it is a kind of HMG-CoA reductase inhibitor, hereinafter further describes.This conjoint therapy is called as ADVICOR (Kos Pharmaceuticals Inc.).In conjoint therapy treatment, The compounds of this invention and other drug therapy all are to Mammals (for example people, sex) administration by ordinary method.
Term HMG-CoA reductase inhibitor represents to suppress to be subjected to that the HMG-CoA reductase enzyme is catalytic, hydroxymethyl glutaryl-coenzyme A is to the compound of mevalonic acid bio-transformation.According to the standard test method, those skilled in the art measure this class restraining effect (Meth.Enzymol.1981 for example easily; 71:455-509 and the reference of wherein quoting).Hereinafter describe and multiple these compounds of reference, but other HMG-CoA reductase inhibitors also will be well known by persons skilled in the art.
Atorvastatincalcuim (being atorvastatin hemi-calcium) is disclosed in U.S. Patent No. 5,273, in 995, quotes at this as a reference, at present as Lipitor
Sell, have following formula
Atorvastatincalcuim is a kind of selectivity, competitive HMG-CoA inhibitor.Therefore, atorvastatincalcuim is the compound that reduces lipid effectively.Can mainly there be the lactone of following formula in free carboxy acid's form of atorvastatin
It is disclosed in U.S. Patent No. 4,681, in 893, quotes at this as a reference.
Statins also comprises such compound, and for example rosuvastatin is disclosed in U.S.RE37, among the 314E; Pitavastatin is disclosed in EP 304063B1 and U.S.5, in 011,930; Simvastatin is disclosed in U.S.4, in 444,784, quotes at this as a reference; Pravastatin is disclosed in U.S.4, in 346,227, quotes at this as a reference; Simvastatin is disclosed in U.S.5, in 502,199, quotes at this as a reference; Mevastatin is disclosed in U.S.3, in 983,140, quotes at this as a reference; Velostatin is disclosed in U.S.4, in 448,784 and U.S.4,450,171, all quotes at this as a reference; Fluvastatin is disclosed in U.S.4, in 739,073, quotes at this as a reference; Compactin is disclosed in U.S.4, in 804,770, quotes at this as a reference; Lovastatin is disclosed in U.S.4, in 231,938, quotes at this as a reference; Dalvastatin is disclosed among the european patent application communique No.738510A2; Fluindostatin is disclosed among the european patent application communique No.363934A1; Dihydrocompactin is disclosed in U.S.4, in 450,171, quotes at this as a reference.
The compound that any reduction HMG-CoA reductase gene is expressed can be used in combined aspects of the present invention.These compositions can be HMG-CoA reductase enzyme transcription inhibitors, and retardance the transcribing of DNA, or change inhibitor prevents or the mRNA that reduces coding HMG-CoA reductase enzyme is translated as protein.This compounds can directly influence to be transcribed or translates, and perhaps can be had accumulating of above-mentioned active isoprene meta-bolites for having above-mentioned active compound, perhaps can causing by one or more enzyme bio-transformations in the cholesterol biosynthesizing cascade.This compounds can cause this effect by reducing SREBP (sterol receptor binding protein), inhibition site-1 proteolytic enzyme (S1P) activity or exciting oxzgenal acceptor or SCAP.According to the standard test method, those skilled in the art measure this class regulating effect (Meth.Enzymol.1985 easily; 110:9-19).Hereinafter describe and the some compounds of reference, but other HMG-CoA reductase gene expression inhibitor also will be well known by persons skilled in the art.U.S. Patent No. 5,041,432 (its disclosure is quoted at this as a reference) disclose the lanosterol derivative that some 15-replaces.E.I.Mercer (Prog.Lip.Res.1993; 32:357-416) other have been discussed and have suppressed the oxygenate steroid of HMG-CoA reductase enzyme.
The compound of any CETP of having inhibitor activity can serve as second compound of conjoint therapy of the present invention aspect.Term CETP inhibitor represents to suppress the compound of the various cholesteryl esters of cholesteryl ester transfer protein (CETP) mediation and triglyceride level (from HDL to LDL and VLDL) transhipment.According to the standard test method, those skilled in the art measure this class CETP easily and suppress active (for example U.S. Patent No. 6,140,343).Multiple CETP inhibitor all will be well known by persons skilled in the art, for example be disclosed in U.S. Patent No. of generally transferring the possession of 6,140,343 and the U.S. Patent No. of generally transferring the possession of 6,197,786 those.Disclosed CETP inhibitor comprises such compound in these patents, [2R, 4S] 4-[(3 for example, 5-is two-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester also claims torcetrapib.U.S. Patent No. 5,512,548 disclose some has the polypeptide derivative of CETP inhibitor activity, at J.Antibiot., 49 (8): 815-816 (1996) and Bioorg.Med.Chem.Lett.; The phosphoric acid analogue of some CETP-inhibition rosenonlactone derivative and cholesteryl ester is disclosed respectively among the 6:1951-1954 (1996).
Any other PPAR adjusting control agent can be used in combined aspects of the present invention.Definite, PPAR β and/or PPAR can be used for for gamma regulated dose making up with The compounds of this invention.
Any MTP/Apo B (microsomal triglyceride transfer protein and/or apolipoprotein B) secretion inhibitor can be used in combined aspects of the present invention.Term MTP/Apo B secretion inhibitor represents to suppress triglyceride level, cholesteryl ester and phosphatide excretory compound.According to the standard test method, those skilled in the art measure this class restraining effect (Wetterau, J.R.1992 easily; Science 258:999).Hereinafter describe and multiple these compounds of reference, but other MTP/Apo B secretion inhibitors also will be well known by persons skilled in the art, comprise imputapride (Bayer) and additional compounds, for example those disclosed (two parts of exemplary publications) in WO 96/40640 and WO98/23593.
For example, following MTP/Apo B secretion inhibitor is useful especially:
4 '-trifluoromethyl-diphenyl-2-carboxylic acid [2-(1H-[1,2,4] triazole-3-ylmethyl)-1,2,3,4-tetrahydrochysene-isoquinoline 99.9-6-yl]-acid amides;
4 '-trifluoromethyl-diphenyl-2-carboxylic acid [2-(2-acetylaminohydroxyphenylarsonic acid ethyl)-1,2,3,4-tetrahydrochysene-isoquinoline 99.9-6-yl]-acid amides;
(2-{6-[(4 '-trifluoromethyl-biphenyl-2-carbonyl)-amino]-3,4-dihydro-1H-isoquinoline 99.9-2-yl }-ethyl)-the carboxylamine methyl ester;
4 '-trifluoromethyl-diphenyl-2-carboxylic acid [2-(1H-imidazoles-2-ylmethyl)-1,2,3,4-tetrahydrochysene-isoquinoline 99.9-6-yl]-acid amides;
4 '-trifluoromethyl-diphenyl-2-carboxylic acid [2-(2,2-phenylbenzene-ethyl)-1,2,3,4-tetrahydrochysene-isoquinoline 99.9-6-yl]-acid amides;
4 '-trifluoromethyl-diphenyl-2-carboxylic acid [2-(2-oxyethyl group-ethyl)-1,2,3,4-tetrahydrochysene-isoquinoline 99.9-6-yl]-acid amides;
(S)-N-{2-[benzyl (methyl) amino]-2-oxo-1-phenylethyl }-1-methyl-5-[4 '-(trifluoromethyl) [1,1 '-biphenyl]-the 2-amido]-1H-indoles-2-acid amides;
(S)-2-[(4 '-trifluoromethyl-biphenyl-2-carbonyl)-amino]-QUINOLINE-6-CARBOXYLIC ACID (amyl group carbamyl-phenyl-methyl)-acid amides;
1H-indoles-2-acid amides, the 1-methyl-N-[(1S)-2-[methyl (phenyl methyl) amino]-2-oxo-1-phenylethyl]-5-[[[4 '-(trifluoromethyl) [1,1 '-biphenyl]-the 2-yl] carbonyl] amino]; With
N-[(1S)-2-(benzyl methylamino)-2-oxo-1-phenylethyl]-1-methyl-5-[[[4 '-(trifluoromethyl) biphenyl-2-yl] carbonyl] amino]-1H-indoles-2-acid amides.
Any cholesterol absorption inhibitor can be used in combined aspects of the present invention.Term cholesterol absorption restraining effect represents that compound prevents the ability that the enteric cavity inner cholesterol enters intestinal cells and/or enters lymphsystem and/or blood flow in the intestinal cells.According to the standard test method, those skilled in the art measure this class cholesterol absorption restraining effect (J.Lipid Res. (1993) 34:377-395) easily.Cholesterol absorption inhibitor is well known by persons skilled in the art, for example is described among the PCT WO 94/00480.The example of cholesterol absorption inhibitor has ZETIA
TM(ezetimibe) (Schering-Plough/Merck).
To suffer from diabetes (especially II type), insulin resistant, glucose tolerance attenuating, metabolism syndrome etc. or arbitrarily diabetic complication, for example neuropathy, ephrosis, retinopathy or cataractous patient treat the The compounds of this invention and other combinations that can be used in the composition (for example Regular Insulin) for the treatment of diabetes of significant quantity, can treat diabetes.This comprises the antidiabetic (with concrete composition) of kind described herein.
Any glycogen phosphorylase inhibitors can be as second composition in the The compounds of this invention combination.The term glycogen phosphorylase inhibitors represents to suppress to be subjected to that glycogen phosphorylase is catalytic, glycogen is to the compound of Cori ester bio-transformation.According to the standard test method, those skilled in the art measure this class glycogen phosphorylase inhibitory activity (J.Med.Chem.41 (1998) 2934-2938) easily.Multiple glycogen phosphorylase inhibitors all is well known by persons skilled in the art, is included in those that describe among WO 96/39384 and the WO 96/39385.
Any aldose reductase inhibitor can be used in the combination with The compounds of this invention.The term aldose reductase inhibitor represents to suppress to be subjected to that aldose reductase is catalytic, glucose is to the compound of Sorbitol Powder bio-transformation.According to the standard test method, those skilled in the art measure easily the aldose reductase restraining effect (J.Malone, Diabetes, 29:861-864 (1980). " RedCell Sorbitol, an Indicator of Diabetic Control ").Multiple aldose reductase inhibitor all is well known by persons skilled in the art, and for example in U.S. Patent No. 6,579, those that describe in 879 comprise 6-(5-chloro-3-methyl-cumarone-2-alkylsulfonyl)-2H-pyridazin-3-one.
Any SODH inhibitor can be used in the combination with The compounds of this invention.Term SODH inhibitor represents to suppress to be subjected to that SODH is catalytic, Sorbitol Powder is to the compound of fructose bio-transformation.According to the standard test method, those skilled in the art measure this class SODH inhibitor activity (Analyt.Biochem (2000) 280:329-331) easily.Multiple SODH inhibitor all is known, for example, U.S. Patent No. 5,728,704 and 5,866,578 disclose by suppressing the Compounds and methods for of SODH treatment or prevent diabetes complication.
Any glycosidase inhibitor can be used in the composition with The compounds of this invention.Glycosidase inhibitor suppresses complex carbohydrates and is hydrolyzed to biological available simple carbohydrate, for example glucose by glycoside hydrolase, for example amylase or maltin.The rapid metabolism of Glycosylase, particularly after the absorption of high-level carbohydrate, cause diet hyperglycemia state, cause that in obesity or diabetic subject insulin secretion strengthens, lipogenesis increases and fat acid decomposition reduces.After this class hyperglycemia, because insulin level increases, hypoglycemia appears frequently.In addition, remaining chyme promotes the generation of gastric juice in the known stomach, this initiation or help gastritis or the formation of duodenal ulcer.Therefore, known glycosidase inhibitor can be used for quickening carbohydrate by stomach, suppresses glucose and absorbs from intestines.In addition, correspondingly reduce or postponed carbohydrate to the fatty tissue lipid transform and subsequently dietary fat be combined in the deposit of adipose tissue, with reduce or prevent thus due to harmful unusual benefit.According to the standard test method, those skilled in the art measure this class glucoside inhibiting activity (Biochemistry (1969) 8:4214) easily.
General preferred glycosidase inhibitor comprises amylase inhibitor.Amylase inhibitor is that inhibition starch or glycogen are the glycosidase inhibitor of maltose by enzyme liberating.According to the standard test method, those skilled in the art measure this kind of starch enzyme inhibition activity (Methods Enzymol. (1955) 1:149) easily.Suppressing this class enzyme degradation is of value to and reduces biological available sugar amount, comprise glucose and maltose and thus due to deleterious illness.
Multiple glycosidase inhibitor all is that those of ordinary skills are known, and example is provided below.Preferred glycosidase inhibitor is to be selected from those following inhibitor: acarbose, fat rhzomorph, voglibose, miglitol, emiglitate, Camiglibose, tendamistat, trestatin, pradimicin-Q and salbostatin.Glycosidase inhibitor acarbose and various associated amino sugar derivative are disclosed in U.S. Patent No. 4,062 respectively, in 950 and 4,174,439.The fat rhzomorph of glycosidase inhibitor is disclosed in U.S. Patent No. 4,254, in 256.Glycosidase inhibitor voglibose, promptly 3,4-dideoxy-4-[[2-hydroxyl-1-(methylol) ethyl) amino]-2-C-(methylol)-D-table-inositol and various associated N-replace pseudo-aminosugar and be disclosed in U.S. Patent No. 4,701, in 559.The glycosidase inhibitor miglitol, promptly (2R, 3R, 4R, 5S)-1-(2-hydroxyethyl)-2-(methylol)-3,4,5-piperidines three is pure and mild various associated 3,4,5-trihydroxy-piperidines is disclosed in U.S. Patent No. 4,639, in 436.Glycosidase inhibitor emiglitate, i.e. right-[2-[(2R, 3R, 4R, 5S)-3,4,5-trihydroxy--2-(methylol) piperidino-(1-position only)] oxyethyl group]-phenylformic acid ethyl ester, various associated derivative and its pharmaceutically-acceptable acid addition be disclosed in U.S. Patent No. 5, in 192,772.Glycosidase inhibitor MDL-25637, promptly 2,6-dideoxy-7-O-β-D-glucopyranosyl-2,6-imino--D-glycerine-L-glucoheptose alcohol, various associated equal disaccharides and its pharmaceutically-acceptable acid addition are disclosed in U.S. Patent No. 4,634, in 765.The glycosidase inhibitor Camiglibose, be methyl 6-deoxidation-6-[(2R, 3R, 4R, 5S)-3,4,5-trihydroxy--2-(methylol) piperidino-(1-position only)]-α-D-glycopyranoside sesquialter hydrate, associated deoxidization nojirimycin derivative, various its pharmacy acceptable salt and its preparation synthetic method be disclosed in U.S. Patent No. 5,157, in 116 and 5,504,078.Glycosidase inhibitor salbostatin and various associated pseudo-sugar are disclosed in U.S. Patent No. 5,091, in 524.
Multiple amylase inhibitor all is that those of ordinary skills are known.Amylase inhibitor tendamistat and various associated cyclic peptide are disclosed in U.S. Patent No. 4,451, in 455.Amylase inhibitor AI-3688 and various associated ring type polypeptide are disclosed in U.S. Patent No. 4,623, in 714.Amylase inhibitor trestatin is made up of the mixture of trestatin A, trestatin B and trestatin C, and it and the various associated trehalose aminosugars that contain are disclosed in U.S. Patent No. 4,273, in 765.
Can for example comprise as follows as the antidiabetic compound of second composition in the The compounds of this invention combination in addition: biguanides (for example metformin), Regular Insulin secretagogues (for example sulfonylurea and meglitinide), glitazone, Fei Gelie ketone PPAR gamma agonist, PPAR beta-agonists, DPP-IV inhibitor, PDE5 inhibitor, GSK-3 inhibitor, glucagon antagonists, f-1,6-BP enzyme inhibitors (Metabasis/Sankyo), GLP-1/ analogue (AC 2993, also claim exendin-4), Regular Insulin and insulin-mimickers (Merck natural product).Other examples will comprise PKC-beta inhibitor and AGE decomposition agent.
The compounds of this invention can be used for and other antiobesity agent combinations.Any antiobesity agent can be as second composition in this class combination, and this paper provides example.According to standard test method known in the art, those skilled in the art measure this class anti-obesity activity easily.
The antiobesity agent that is fit to comprises Phenylpropanolamine, ephedrine, pseudoephedrine, phentermine, β
3Adrenoceptor agonists, apo-B secretion/microsomal triglyceride transfer protein (apo-B/MTP) inhibitor, MCR-4 agonist, pancreozymin-A (CCK-A) agonist, monoamine re-uptake inhibitor (for example sibutramine), parasympathomimetic agent, serotonergic agent, class cannabin(e)-1 (CB-1) receptor antagonist (for example rimonabant (SR-141,716A)), dopamine agonist (for example bromocriptine), melanophore-stimulation hormone receptor analogue, 5HT
2cAgonist, melanocyte enrichment hormone antagonist, RMETHU LEPTIN (OB albumen), the RMETHU LEPTIN analogue, the RMETHU LEPTIN receptor stimulant, the galanin antagonist, lipase inhibitor (for example tetrahydrochysene lipstatin, i.e. orlistat), the bombesin agonist, anoretics (for example bombesin agonist), neuropeptide-Y receptor antagonist, thyroxine, intend thyroid, trans-dehydroandrosterone or its analogue, glucocorticoid receptor agonist or antagonist, orexin receptor antagonists, the conjugated protein antagonist of Urocortin, glucagon-like peptide-1 receptor stimulant, ciliary neurotrophic factor (Axokine for example
TM), people agouti associated protein (AGRP), ghrelin receptor antagonist, histamine 3 receptor antagonists or inverse agonist, neuromedin U receptor stimulant etc.
(SR141716A also claims Acomplia to Rimonabant
TM, can obtain from Sanofi-Synthelabo) can be as U.S. Patent No. 5,624,941 described preparations.Other CB-1 antagonists that are fit to comprise following those: U.S. Patent No. 5,747,524,6,432,984 and 6,518,264; U.S. Patent bulletin No.US 2004/0092520, US2004/0157839, US 2004/0214855 and US 2004/0214838; The U.S. Patent application No.10/971599 that on October 22nd, 2004 submitted to; With PCT patent gazette No.WO02/076949, WO 03/075660, WO 04/048317, WO 04/013120 and WO04/012671.
Apo-B secretion/microsomal triglyceride transfer protein (apo-B/MTP) inhibitor that is preferably used as antiobesity agent is an intestines selectivity MTP inhibitor, dirlotapide for example, and as U.S. Patent No. 6,720,351 is described; 4-(4-(4-(4-((2-((4-methyl-4H-1,2,4-triazole-3-base sulfenyl) methyl)-and 2-(4-chloro-phenyl-)-1,3-dioxolane-4-yl) methoxyl group) phenyl) piperazine-1-yl) phenyl)-2-sec-butyl-2H-1,2,4-triazole-3 (4H)-ketone (R103757), as U.S. Patent No. 5,521,186 and 5,929,075 is described; And implitapide (BAY 13-9952), as U.S. Patent No. 6,265,431 is described.Term used herein " intestines selectivity " means that this MTP inhibitor has higher gastrointestinal tissue at systemic exposure and exposes.
Any plan thyroid can be as second composition in the The compounds of this invention combination.According to the standard test method, those skilled in the art measure this comparison Tiroidina activity (Atherosclerosis (1996) 126:53-63) easily.Multiple plan thyroid is well known by persons skilled in the art, for example those disclosed in following document: U.S. Patent No. 4,766,121,4,826,876,4,910,305,5,061,798,5,284,971,5,401,772,5,654,468 and 5,569,674.Other antiobesity agents comprise sibutramine, and it can be as U.S. Patent No. 4,929,629 described preparations, and bromocriptine, and it can be as U.S. Patent No. 3,752,814 and 3,752,888 described preparations.
The compounds of this invention also can be united use with other hypotensive agents.Any hypotensive agent can be as second composition in this class combination, and this paper provides example.According to the standard test method, those skilled in the art measure this class antihypertensive active (for example blood pressure measurement) easily.
In U.S. Patent No. 4,572, amlodipine and relevant dihydropyridine compound are disclosed in 909, to quote as a reference at this, they are strong ischemia resisting and hypotensive agents.U.S. Patent No. 4,879,303 disclose amlodipine benzenesulphonate (also claiming amlodipine besylate), quote at this as a reference.Amlodipine and amlodipine besylate are strong long-acting calcium channel blockers.Therefore, other pharmaceutically-acceptable acid addition of amlodipine, amlodipine besylate, Amlodipine mesylate and amlodipine can be used as hypotensive agent and antiischemic agents.The present commercially available Norvasc that has of amlodipine besylate
Amlodipine has following formula
The raw material of the invention described above compound and combined composition and reagent also be obtain easily or utilize conventional methodology of organic synthesis to be synthesized by those skilled in the art easily.For example, the compound that much is used for this paper relates to or derives from and has the more compound of big science interest and commercial needs, therefore a lot of such compounds are commercially available, or bibliographical information is arranged, or easily from other materials that generally obtain, by the method preparation that bibliographical information is arranged.
Intermediate during synthesize some The compounds of this invention or they has asymmetric carbon atoms, is enantiomorph or diastereomer therefore.On their basis of physical chemistry difference, non-enantiomer mixture can be separated into their discrete diastereomers, for example chromatogram and/or fractional crystallization by known method itself.Enantiomorph can separate by for example chirality HPLC method, perhaps by mixture of enantiomers being converted into non-enantiomer mixture with suitable activity of optically active compounds (for example alcohol) reaction, separate diastereomer, the discrete diastereomer being transformed (for example hydrolysis) again is corresponding pure enantiomorph.And, the mixture of enantiomers that contains the compound of acidity or basic moiety or they intermediate in synthetic can be separated into the pure enantiomorph of their correspondences like this, generate diastereoisomeric salt with optically pure chiral base or acid (for example 1-phenyl-ethylamine or tartrate), separate diastereomer by fractional crystallization, succeeded by neutralization with salt decomposition, thereby obtain corresponding pure enantiomorph.All such isomer, comprise that diastereomer, enantiomorph and its mixture all are regarded as a part of the present invention.And some The compounds of this invention is atropisomer (for example dibenzyl of Qu Daiing), also is regarded as a part of the present invention.
More specifically, The compounds of this invention can obtain like this, makes alkaline intermediate and optically pure chiral acid fractional crystallization, generates diastereoisomeric salt.In the utilization and technology remove and to desalt, obtain the compound of enantiomer-pure.Select as an alternative, can obtain the The compounds of this invention of enantiomorph enriched form like this, adopt asymmetric resin (preferred Chiralcel
TMAD or OD are (from ChiralTechnologies, Exton, Pennsylvania obtains)) chromatogram (preferred high performance liquid chromatography [HPLC]) splits the acetate of final compound or its intermediate in synthetic, mobile phase is made up of hydrocarbon (preferred heptane or hexane), wherein contains 0 to 50% Virahol (preferred 2 to 20%) and 0 to 5% alkylamine (preferred 0.1% diethylamine).Concentrate the fraction that contains product, obtain required product.
Some The compounds of this invention is a tart, and they and pharmaceutically acceptable positively charged ion generate salt.Some The compounds of this invention is alkaline, and they and pharmaceutically acceptable negatively charged ion generate salt.All these class salt all belong to scope of the present invention, and they can prepare by ordinary method, for example, merge acid and alkaline entity, usually according to stoichiometric ratio, in the medium of aqueous, water-free or partially aqueous, depend on the circumstances.The recovery of salt is taked to filter, is precipitated succeeded by filtration, evaporating solvent or lyophilize under the situation of the aqueous solution with non-solvent, depends on the circumstances.Be dissolved in the appropriate solvent, for example ethanol, hexane or water/alcohol mixture can obtain the compound of crystallized form.
The salt of The compounds of this invention, their prodrug and this compounds and prodrug all is suitable for therapeutic as activation Mammals, the particularly active medicine of human peroxisome proliferation activated receptor (PPAR).Thereby, believe that The compounds of this invention is by activating the PPAR acceptor, stimulate transcribe (for example apolipoprotein AI genetic transcription) that participates in Fatty Acid Oxidation and the key gene that participates in high-density lipoprotein (HDL) (HDL) assembling, correspondingly reduce all body fat and increase the HDL cholesterol.In view of their activity, these compositions also reduce the blood plasma level of Mammals, particularly people's quasi-glycerol three-ester, VLDL cholesterol, LDL cholesterol and its relevant component, and increase HDL cholesterol and apolipoprotein AI.Therefore, these compounds can be used for treating with the formation of correcting various and atherosclerosis and cardiovascular disorder and relevant dyslipidaemia take place, and comprise low alpha-lipoprotein blood and hypertriglyceridaemia.
The compounds of this invention also can be used for regulating and control blood plasma and/or serum or organizes lipid or lipoprotein, for example HDL hypotype (for example comprising preceding β-HDL, HDL-1 ,-2 and-3 particles) becomes to assign to measure with number of ions and its by the precipitator method or by taking off auxilliary protein content, size, density, NMR collection of illustrative plates, FPLC and electric charge; With LDL hypotype (comprise the LDL hypotype, for example reduce LDL, VLDL, apo (a) and the Lp (a) of little density LDL, oxidation), measure by the precipitator method or by taking off auxilliary protein content, size, density, NMR collection of illustrative plates, FPLC and electric charge; IDL and residue (reduction); Phosphatide (for example increasing HDL phosphatide); Lipophorin (increase A-I, A-II, A-IV, reduces total and LDL B-100, reduce B-48, regulate and control C-II, C-III, E, J); Paraoxonase (increasing antioxidant effect, antiphlogistic effects); Reduce piarhemia (too high) after the meal; Triglyceride reducing, the non--HDL of reduction; Rising low HDL patient's HDL, the ratio (for example greater than 0.25) of optimization and increase HDL and LDL.
Because the positivity between the formation of the relevant lipophorin with it of triglyceride in blood, LDL cholesterol and cardiovascular, the cerebrovascular and peripheral vascular disease is relevant, the salt of The compounds of this invention, their prodrug and this compounds and prodrug can be used for preventing, stopping and/or disappear atherosclerosis and its diseases related state in view of their pharmacological action.Complication and cognition dysfunction (including but not limited to that the delay that is secondary to atherosclerotic dementia, transient cerebral ischemic attack, neurodegeneration, neurone defective and Alzheimer takes place or progress) that these morbid states comprise cardiovascular disorder (for example cerebrovascular disease, coronary artery disease, ventricular dysfunction, irregular pulse, pulmonary vascular disease, blood vessel hemostasis disease, myocardial ischemia and myocardial infarction), caused by cardiovascular disorder.
Thereby, because the salt of The compounds of this invention, their prodrug and this compounds and prodrug reduces the ability of plasma triglyceride and total plasma cholesterol and blood plasma high density lipoprotein increasing cholesterol, they are used for the treatment of diabetes, comprise glucose tolerance attenuating, diabetic complication, insulin resistant and metabolism syndrome, as noted earlier, in addition, these compounds can be used for treating polycystic ovary syndrome.And it is fat that these compounds can be used for treatment, because the salt of The compounds of this invention, their prodrug and this compounds and prodrug can increase the oxidation of liver fat acid.
The salt of The compounds of this invention, their prodrug and this compounds and prodrug obtains The compounds of this invention active proof in the assay method in following one or more conventional determining methods and body as the practicality of medicinal ingredients in the above-mentioned disease/treatment for diseases of Mammals (for example people, sex).Assay method in the body (suitably adjusting in the skill of this area) can be used to measure the activity of other lipids or triglyceride level control agent and The compounds of this invention.Thereby, following proposal also can be used to prove the practicality of the combination of composition described herein (being The compounds of this invention), in addition, this class assay method provides salt (other compositions perhaps described herein) activity each other and the active means of other known compounds of comparison The compounds of this invention, their prodrug and this compounds and prodrug.These results relatively can be used for being determined at Mammals, comprise the dosage level of this class disease of treatment among the mankind.Those skilled in the art certainly change following scheme.
PPAR FRET assay method
Raising by nuclear receptor-auxilliary activator of part association measurement is a kind of part produces functional ability of replying by nuclear receptor method of estimating.Part-dependency that PPAR FRET (FRET (fluorescence resonance energy transfer)) assay method is measured between nuclear receptor and the auxilliary activator interacts.With the anti--GST antibody labeling of GST/PPAR (α, β and γ) ligand binding domains (LBD), will contain allophycocyanin (APC) mark of the synthetic peptide of SRC-1 (the sterol acceptor is assisted activator-1) of N-terminal long-chain biotin molecule with streptavidin-connection with europium-mark.Part and combining of PPAR LBD cause the variation on the conformation, allow the SRC-1 combination.In case SRC-1 combination, donor FRET molecule (europium) near acceptor molecule (APC), cause fluorescent energy to shift between donor (337nm excites, the 620nm emission) and acceptor (620nm excites, the 665nm emission).The increase of 665nm emission and the ratio of 620nm emission is measuring of part-PPAR LBD ability of raising the synthetic peptide of SRC-1, therefore is part measuring by the PPAR acceptor functional ability of replying of generation.
[1] GST/PPAR LBD expresses.PGEX-6P-1 (Pfizer, Inc.) in, the C-terminal of people PPAR α LBD (amino acid 235-507) and glutathione S-transferase (GST) is merged.At room temperature, utilize the inducing action of 50 μ m IPTG, make GST/PPAR α LBD fusion rotein at BL21[DE3] express 16 hours (A in the pLysS cell～0.6
600Following inducing cell).With fusion rotein purifying on glutathione agarose 4B bead, wash-out in the 10mM reduced glutathione is dialysed to 1xPBS under 4 ℃.Quantize fusion rotein (M.M.Bradford, Analst.Biochem.72:248-254 by the Bradford assay method; 1976), be stored among-20 ℃ of 1xPBS that contain 40% glycerine and 5mM dithiothreitol (DTT).
[2] FRET measures.FRET assaying reaction mixture is formed (50mMTris-Cl pH 8.0 by the 1xFRET damping fluid, 50mM KCl, 0.1mg/ml BSA, 1mM EDTA and 2mM dithiothreitol (DTT)), wherein contain 20nM GST/PPAR α LBD, 40nM SRC-1 peptide (amino acid 676-700,5 '-long-chain vitamin H-CPSSHSSLTERHKILHRLLQEGSPS-NH
2, available from American Peptide Co., Sunnyvale, CA), the 2nM europium-anti--GST antibody of puting together (Wallac, Gaithersburg, MD), the 40nM streptavidin-APC (Wallac), reference substance and the test compound puted together.Water adds to 100 μ l final volumes, is transferred to black 96-hole flat board (Microfuor B, Dynex (Chantilly, VA)).Reaction mixture 4 ℃ of following incubations 1 hour, is read fluorescence in Victor 2 plate readers (Wallac).Data are represented with the ratio of 615nm emission with the 665nm emission.
The assessment of mouse lipid-regulation activity
[1] triglyceride reducing.Can prove the reducing blood-fat therapeutic activity of The compounds of this invention by method based on standard technology.For example, in hybridization B6CBAF1/J mouse, can measure the activity in vivo that these compounds reduce the plasma triglyceride level.
Obtain male B6CVAF1/J mouse (8-11 week age) from The Jackson Laboratory, every cage 4-5 only supports according to 12hr daytime/12hr cycle at night.Animal can be arbitrarily near Purina rodent and water.Give carrier (water or 0.5% methylcellulose gum 0.05% tween 80) or contain the carrier of desired concn test compound to animal by oral gavage every day (9AM).Last administration (the 3rd day) was measured the plasma triglyceride level in back 24 hours, gathered blood with heparinization hematocrit test tube behind eye socket.Utilization commercial can (Osaka, Japan) the triglyceride level E medicine box of Huo Deing carries out triglyceride determination from Wako.
[2] rising HDL cholesterol.In the transgenic mice of expressing human apoAI and CETP transgenosis (HuAICETPTg), can prove the activity of The compounds of this invention rising mammalian plasma high-density lipoprotein (HDL) (HDL) level.Be used in transgenic mice such as forefathers Walsh et al. in this research, J.Lipid Res.1993,34:617-623, Agellon et al., J.Biol.Chem.1991,266:10796-10801 is described.Mouse and CETP mouse (HuCETPTg) pairing with expressing human apoAI transgenosis (HuAITg) obtain the genetically modified mouse of expressing human apoAI and CETP.
People apoAI level according to them is divided into groups male HuAICETPTg mouse (8-11 age in week), can be arbitrarily near Purina rodent and water.The carrier that give carrier (water or 0.5% methylcellulose gum 0.05% tween 80) or contain required dosage test compound to animal by oral gavage every day reaches 5 days.Utilization is measured HDL-cholesterol and people apoAI based on the method 90 minutes (the 5th day) after initial (the 0th day) and administration of standard technology.Separate mouse HDL by the T 500 precipitator method from the lipoprotein that contains apoB, as described in the document (Francone et al., J.Lipid.Res.1996,37:1268-1277).(IND), enzyme process is measured cholesterol for Boehringer MannHeim, Indianapolis, and spectrophotometric quantizes on micro-plate reader to utilize commercially available cholesterol/HP reagent kit.Measure people apoAI by sandwich enzyme-linked immunosorbent assay method, as described in the forefathers (Francone et al., J.Lipid.Res.1996,37:1268-1277).
Reduce the measurement of ob/ob mouse glucose
For the carrier that does not have test compound, reduce the amount of the glucose level of male ob/ob mouse by test compound, can measure the hypoglycemic activity of The compounds of this invention.This test also allows to measure the approximate minimum effective dose (MED) that reduces this class mice plasma glucose concn in this class test compound body.
According to the practice of standard animal care, every cage is fed five five to eight male C57BL/6J-ob/ob mouse in age in week (from Jackson Laboratory, Bar Harbor, ME acquisition).After one adaptive phase in week, animal is weighed, gather 25 microliters of blood from the eye retro-orbital sinus before in office where the managing.Blood sample immediately with the salt solution dilution that contains 0.025% heparin sodium 1: 5, is kept at and supplies the meta-bolites analysis on ice.With the animal grouping, so that every group has similar average blood plasma glucose concn.After the grouping, reach four day to the oral carrier of giving of animal every day, the consisting of of described carrier: the aqueous solution of (1) 0.25%w/v methylcellulose gum, adjust without pH; Perhaps (2) 0.1%Pluronic
The P105 block copolymer surfactant (adjust without pH for BASF Corporation, Parsippany by 0.1% salt brine solution NJ).The 5th day, animal is weighed once more oral then test compound or the independent carrier given.The all administrations in carrier of all compounds, it consists of: the aqueous solution of (1) 0.25%w/v methylcellulose gum; (2) 10%DMSO/0.1%Pluronic
0.1% salt brine solution, adjust without pH; Perhaps (3) clean PEG 400 adjusts without pH.Hole bloodletting behind the animal eye socket after three hours, the level determination of blood supply liquid meta-bolites.At room temperature, with the sample of fresh collection 10, under the 000xg centrifugal 2 minutes.Analytically the glucose of clear liquid for example utilizes Abbott VP
TM(Irving is TX) with VP SuperSystem for AbbottLaboratories, Diagnostics Division
Automatic analyser (Abbott Laboratories, Irving, TX) or AbbottSpectrum CCX
TM(Abbott Laboratories, Irving, TX) and A-Gent
TMGlucose-UV reagent system (Abbott Laboratories, Irving, TX) (Richterich andDauwalder, Schweizerische Medizinische Wochenschrift, the improvement of the method for 101:860 (1971)) (hexokinase method) uses the 100mg/dl standard substance.Calculate plasma glucose by following equation then: plasma glucose (mg/dl)=sample value * 8.14, wherein 8.14 is dilution factor, adjusts (the supposition hematocrit is 44%) according to the blood plasma hematocrit.
Give the animal of carrier and keep hyperglycemic glucose level constant substantially (for example more than or equal to 250mg/dl), have the remarkable glucose level that has suppressed with being fit to animal that dosage has the compound treatment of hypoglycemic activity.By the statistical analysis (t-check in pairs) of average blood plasma glucose concn between the 5th day test compound group and the vehicle treated group, measure the hypoglycemic activity of test compound.Utilize the test compound of certain limit dosage to carry out said determination, can measure the approximate minimum effective dose (MED) that reduces plasma glucose concentration in the body.
The measurement of ob/ob mouse islets element, triglyceride level and cholesterol levels
The compounds of this invention is fit to clinical in hyperinsulinemia reversing agent, triglyceride lowering agent and hypocholesterolemic agents easily.For the control vector that does not have test compound, reduce the amount of male ob/ob mouse islets element, triglyceride level or cholesterol levels by test compound, can measure this class activity.
Because the formation of the concentration of cholesterol and cardiovascular, the cerebrovascular or peripheral blood vessel obstacle is closely related in the blood, The compounds of this invention is in view of their hypercholesterolemia effect, the atherosclerosis of can preventing, stop and/or disappear.
(also have other effects in addition because concentration of insulin is relevant with the reservation of increase kidney sodium with the promotion vascular cell growth in the blood, for example promote glucose utilization), and these functions are known hypertension reasons, The compounds of this invention is in view of their the blood insulin effect of falling, the hypertension of can preventing, stop and/or disappear.
Because the concentration of triglyceride level helps the aggregate level of blood lipid in the blood, The compounds of this invention reduces and/or lipid acid reduction activity in view of their triglyceride level, and hyperlipemia can prevent, stops and/or disappear.
Free fatty acids helps the aggregate level of blood lipid, and to be negativity relevant with insulin sensitivity independently in multiple physiology and pathological state.
According to the practice of standard animal care, every cage is fed five five to eight male C57BL/6J-ob/ob mouse in age in week (from Jackson Laboratory, Bar Harbor, ME acquisition), arbitrarily feeding standard rodent.After one adaptive phase in week, animal is weighed, gather 25 microliters of blood from the eye retro-orbital sinus before in office where the managing.Blood sample immediately with the salt solution dilution that contains 0.025% heparin sodium 1: 5, is kept at and supplies the meta-bolites analysis on ice.With the animal grouping, so that every group has similar average blood plasma glucose concn.Give about 0.02% to 2.0% solution (weight/volume (w/v)) of test compound by oral gavage, solvent is (1) 10%DMSO/0.1%Pluronic
The P105 block copolymer surfactant (adjust without pH for BASF Corporation, Parsippany, and perhaps the aqueous solution of (2) 0.25%w/v methylcellulose gum is adjusted without pH by 0.1% salt brine solution NJ).Select as an alternative, can be dissolved or suspended in test compound among the clean PEG 400 by oral gavage.Administration once a day (s.i.d.) or twice administration every day (b.i.d.) were kept 1 to for example 15 days.Control mice is accepted 10%DMSO/0.1%Pluronic
0.1% salt brine solution of P105 is adjusted without pH, and perhaps the aqueous solution of 0.25%w/v methylcellulose gum is adjusted without pH, and perhaps clean PEG 400 adjusts without pH.
After the last administration three hours, with sacrifice of animal, gather blood to 0.5ml serum and separate test tube, wherein contain 1: 1 w/w Sodium Fluoride of 3.6mg: the potassium oxalate mixture.At room temperature, with the sample of fresh collection 10, under the 000xg centrifugal 2 minutes, shift the serum supernatant liquor, with 1: 1 volume/volume of 0.1% salt brine solution dilution of 1TIU/ml Trypsin inhibitor,Trasylol, adjust without pH.
Under-80 ℃, store the serum samples of process dilution then until analysis.Regular Insulin, triglyceride level, free fatty acids and cholesterol levels that analysis has been melted through the serum sample of dilution.Utilization can be from Binax, South Portland, the Equate that ME obtains
RIA INSULIN medicine box is measured serum insulin concentration (double antibody method; As described in manufacturer).The variation coefficient between mensuration≤10%.Utilize Abbott VP
TMWith VP Super System
Automatic analyser (AbbottLaboratories, Irving, TX) or Abbott Spectrum CCX
TM(AbbottLaboratories, Irving, TX) and A-Gent
TM(Irving TX) measures serum triglyceride (lipase-coupling enzyme process to the triglyceride level reagent system for AbbottLaboratories, Diagnostics Division; Sampson, et al., the improvement of the method for Clinical Chemistry 21:1983 (1975)).Utilize Abbott VP
TMWith VP Super System
Automatic analyser (Abbott Laboratories, Irving, TX) and A-Gent
TMCholesterol reagent systems measurement serum total cholesterol level (Sterol esterase-coupling enzyme process; Allain, et al., the improvement of the method for Clinical Chemistry 20:470 (1974)), use 100 and 300mg/dl standard substance.Be used to from WAKO (Osaka, Japan) medicine box is measured the free serum fatty acid concentration, this medicine box is applicable to Abbott VP
TMWith VP Super System
Automatic analyser (Abbott Laboratories, Irving, TX) or Abbott SpectrumCCX
TM(Abbott Laboratories, Irving, TX).Calculate serum insulin, triglyceride level, free fatty acids and total cholesterol level by following equation then: serum insulin (μ U/ml)=sample value * 2; Serum triglyceride (mg/dl)=sample value * 2; Serum total cholesterol (mg/dl)=sample value * 2; Free serum lipid acid (μ Eq/l)=sample value * 2; Wherein 2 is dilution factor.
It is constant substantially that the animal of giving carrier is kept the serum insulin of rising (for example 275 μ U/ml), serum triglyceride (for example 235mg/dl), free serum lipid acid (1500mEq/ml) and serum total cholesterol (for example 190mg/dl) level.By the statistical analysis (not t-check in pairs) of average serum Regular Insulin, triglyceride level or total cholesterol concentration between test compound group and the vehicle treated control group, serum insulin, triglyceride level, free fatty acids and the total cholesterol of measuring test compound reduce active.
The measurement of rat energy expenditure
As with for relevant those skilled in the art understanded, during increasing the energy expenditure, animal generally consumes more oxygen, and in addition, metabolism fuel, for example glucose and lipid acid are oxidized to CO
2And H
2O, with emitting of heat, this area generally is referred to as calorigenic action.Thereby, measure animal, comprise that the oxygen-consumption of people and pet is the indirect measurement of calorigenic action.Relevant those skilled in the art generally utilize indirect calorimetry to measure this class energy expenditure in animal, for example mankind.
It will be appreciated by those skilled in the art that increases the energy expenditure and follows burning metabolism fuel to cause the generation of heat, and this may be effective about for example fat treatment.
Can prove that according to following scheme The compounds of this invention generates the ability that heat production is replied: screening is designed to estimate the effect of PPAR agonist compound in this body, and the measurement of using whole body oxygen-consumption is as the effect terminal point.This scheme relates to: (a) to about 6 days of fat Zucker rat administration and (b) measure oxygen-consumption.Before research beginning, under standard laboratory conditions, in independent cage, feed the extremely male fat Zucker rat about 3-7 days of about 500g of the about 400g of body weight.Give The compounds of this invention and carrier by oral gavage, once a day at about 3p.m. between about 6p.m., reach about 6 days.The compounds of this invention is dissolved in the carrier that contains 0.25% methylcellulose gum of having an appointment.The administration volume is about 1ml.
Give behind the compound about 1 day for the last time, (Columbus OH43204) measures oxygen-consumption for Oxymax, Columbus Instruments to utilize the indirect calorimeter of open loop formula.Before each experiment, with Oxymax gas sensor N
2Gas and gaseous mixture (about 0.5%CO
2, about 20.5%O
2, about 79%N
2) proofread and correct.From cage, take out and tried rat, write down their body weight.Rat is placed in the sealed cabin of Oxymax (43 * 43 * 10cm), sealed cabin is placed activity monitor, the air velocity that passes sealed cabin is set then is about 1.6L/min about 1.7L/min extremely.Based on the air velocity that passes sealed cabin and inlet and the difference that exports oxygen level, utilize Oxymax computed in software oxygen-consumption (mL/kg/h) then.Every of activity monitor has 15 infrared beams, and about one inch at interval, when two continuous light beams interrupted, it is movable that note is done once, and the result shows with frequency table.
Approximately oxygen-consumption of measurement in per 10 minutes and activity last about 5 hours to about 6.5 hours.Average and calculate the static oxygen-consumption of indivedual rats, get rid of preceding 5 numerical value and resulting numerical value during activity surpasses 100 times.
Atherosclerosis assay method in the body
By the amount that reduces rabbit aorta lipidosis required compound, can measure the atherosclerosis effect of The compounds of this invention.Reach 4 days (feed once every day) to the male New Zealand rabbit feed that contains 0.2% cholesterol and 10% Oleum Cocois of feeding.From the venesection of rabbit ear edge, measure the total plasma cholesterol value of these samples.Then with the rabbit grouping, so that every group total plasma cholesterol concentration, HDL cholesterol concentration and triglyceride concentration have similar average ± SD.After the grouping, give to contain the fodder mixtures or a small pieces gelatin class massecuite of compound every day to rabbit.The contrast rabbit is only accepted carrier, i.e. feed or gelatin massecuite.Cholesterol/Oleum Cocois feed and compound administration continue to spread all over whole research.Random time point during studying is got blood from auricular vein, can measure plasma cholesterol, HDL-cholesterol, LDL-cholesterol and triglyceride level value.After 3-5 month, rabbit is put to death, bend to the iliac artery branch from thorax and draw aorta.Remove aortic tunica adventitia, vertically open, then with sudan dyeing, as described in the Holman etc. (Lab.Invest.1958,7,42-47).Utilize Optimas image analysis system (ImageProcessing Solutions; North Reading MA), quantize painted percentage of surface area by density measurement.Compare with the contrast rabbit, the minimizing of lipidosis has been indicated in the minimizing of the painted percentage of surface area of compound acceptance group.
The activity of The compounds of this invention in following assay method proved the salt that can be used for formula I compound of the present invention, their prodrug and this compounds and the prodrug practicality as above-mentioned ruminant disease/treatment for diseases agent in addition.
Negative energy balance
In order to measure negative energy balance, measure the triglyceride levels in serum N EFA or ketoboidies concentration or the liver organization.Being higher than the NEFA of " normally " level and/or triglyceride level and/or ketoboidies is the index of negative energy balance.Being regarded as " being higher than normal " or the level of " too high " is:
NEFA in the serum＞800 μ mol/L;
Triglyceride level＞10%w/w in the liver organization;
Ketoboidies in the serum＞1.2 μ mol/L.
The mensuration of the variation of blood non-esterified fatty acid (NEFA) concentration and liver tg level
Give compound once or several times in the transitional period, dosage level is predicted as effectively by comparative experiments chamber extracorporeal receptor compatibility test result and the evaluation of ox pharmacokinetics.Measure the NEFA level via the standard laboratory method, for example utilize commercial WAKO NEFA medicine box (Wako ChemicalCo., USA, Dallas, TX 994-75409), utilizes the described method of document to measure liver tg content (J.K.Drackley, J.J.Veenhuizen, M.J.Richard andJ.W.Young, J Dairy Sci, 1991,74,4254).
Can be before expection farrowing day about 30 days, obtain all animals from commercial dairy farm.Before their expection farrowing day, approximately cow migrated in the independent building in 10-14 days, be converted to the dry feed of TMR-Close-Up.Animal enters the about 7 days before expection farrowing day that research starts from them.Can weigh with animal migration to " waiting to try " fence, each AM is locked on the feed pillar.At this moment, give suitable dosage, obtain suitable blood sample (see table the data about the PPAR alfa agonists, compound Z is 2-methyl-5-(4 '-trifluoromethoxy-biphenyl-4-base sulphonamide)-phenylformic acid (embodiment 193)).
Every other day (eod) animal that will be registered as T01 is handled with vehicle Control, starts from estimating before the farrowing days-7, handles once during farrowing again.The animal that every other day will be registered as T02 with compound Z, be that 2-methyl-5-(4 '-trifluoromethoxy-biphenyl-4-base sulphonamide)-phenylformic acid (embodiment 193) is handled, started from estimating day-farrowing 7 days before, handle once again during farrowing.
| Handle | Dosage | Each animal of handling | Antenatal administration (every other day=eod-begin target day-7) | Handle during farrowing |
| The T01 vehicle Control | - | 11 | X | X |
| T02 compound Z | 0.5mg/kg | 9 | X | X |
(～30 minutes) are transferred to the freestall storehouse for next predetermined galactopoiesis (6:00hrs and 19:00hrs) with cow as quickly as possible after farrowing.Every other day give animal processing in postpartum until the 8th day.Utilize WAKO NEFA-C test medicine box (#994-75409) to analyze farrowing front and back NEFA sample.After farrowing the 5th, 10 and 14 day to all cows farrow the back liver biopsy.Organize refrigerated storage under-70 in transhipment on ice.Studying latter stage, utilize Drackley, the described methods analyst liver tg of J.K. level (1991, J DairySci (74): 4254-4264).
At 1-8 days compared with the control, the useful trial-product animal (T02) of handling all show significantly (p＜0.10) lower serum N EFA level, the 5th day T02 make an exception (p=0.17).In all measured time points (farrowing back the 5th, 10 and 14 day), to compare with placebo, all processing systems all significantly reduce the liver tg level.
Ketoboidies
Can measure ketoboidies level in the serum by standard method well known to those skilled in the art, for example utilize the commercial medicine box that can be used for this purpose, comprise Sigma BHBA medicine box, rank numbering 310-A.
Milk content
The machinery of measuring milk-protein, fat or lactose-content be commercially available (MilkoScanTM 50, and MilkoScanTM 4000, MilkoScanTM FT6000, FossGroup).The machinery of measuring somatocyte content also is commercially available (FossomaticTMFC, Fossomatic TM Minor, Foss Group).
Compound used in this invention can be individually dosed or with one or more other The compounds of this invention or with one or more other drugs (perhaps its arbitrary combination) Combined Preparation.
For example, The compounds of this invention also can be selected from following bioactive compounds with one or more or composition mixes: tranquilizer, pain killer, anti-inflammatory agent, stimulant, antibacterial agent, diarrhea, antiendotoxin, anti-mycotic agent, respiratory irritant, reflunomide, diuretic(s), parasiticide, preparation of electrolyte thing and nutritional additive, growth stimulant, hormone and treatment of metabolic diseases agent produce wideer animal doctor or agricultural application scope.
The active compound that is fit to or the example of composition be as follows:
Amylase inhibitor: acarbose;
Glycosidase inhibitor: acarbose;
Tranquilizer: xylazine;
Pain killer and anti-inflammatory agent: lignocaine, PROCAINE HCL, PHARMA GRADE, flunixin, oxytetracycline, Ketoprofen, meloxicam and carprofen;
Stimulant: millophyline, doxapram, Diprenorphine, Scopolamine, Ketoprofen, meloxicam, Pethidine, xylazine and butorphanol;
Antibacterial agent: golden toxin, Tylosin, amoxycilline Trihydrate bp, Ampicillin Trihydrate, Aproamycin, cefquinome, Cephalexin Monohydrate Micro/Compacted, clavulanic acid, florfenicol, danofloxacin, Enrofloxacin, Marbofloxacin, Soframycin, procaine penicillin, procaine penicillin, dibenzylethylenediamine dipenicillin G, Sulphadoxine, trimethoprim, sulphamethazine, baquiloprim, Streptomycin sulphate, Vibriomycin, sulfamethoxypyridazine, sulphamethoxypuridazine, terramycin, flunixin, tilmicosin, cloxacillin, ethyromycin, Xin Meisu, NAFCILLIN, duomycin, lineomycin, cefoperazone, Cephalonium, terramycin, formosulphathiazole, Sulphadiazine Sodium and zinc;
Diarrhea: Scopolamine, Sulpyrine, charcoal, attapulgite, white bole, Isphaghula husk;
Antiendotoxin: flunixin, Ketoprofen;
Anti-mycotic agent: enilconazole, natamycin;
Respiratory irritant: florfenicol;
Reflunomide: dexamethasone, Betamethasone Valerate;
Diuretic(s): Furosemide;
Parasiticide: amitraz, Deltamethrin, Moxidectin, doramectin, α-Cypermethrin, fenvalerate, Eprinomectin, permethrin, ivermectin, abamectin, ricobendazole, LEVAMISOLE HCL, febantel, triclabendazole, fenbendazole, albendazole, Netobimin, oxfenazole, oxyclozanide, nitroxinil, Morantel;
Preparation of electrolyte thing and nutritional additive: glucose, lactose, propylene glycol, whey, glucose, glycine, calcium, cobalt, copper, iodine, iron, magnesium, manganese, phosphorus, selenium, zinc, vitamin H, vitamin B12, vitamin-E and other VITAMIN;
Growth stimulant: monensin, moenomycin, Moenomycin. Flavophospholopol, Salinomycin, Tylosin;
Hormone: chorionic gonadotrophin, Serum Gonadotrophin, coromegine, melatonin, oxytocin, Prostaglin F2, cloprostenol, Rheumon, luprostiol, buserelin, estradiol, Progesterone and Trobest; With
Treatment of metabolic diseases agent: calglucon, boric acid calglucon, propylene glycol, sal epsom.
The compounds of this invention also can be selected from following bioactive compounds with one or more or composition mixes: antiprotozoal, imidocarb for example, flatulence therapy, for example dimethicone and poloxalene, and probiotic bacterium, for example Bacterium lacticum and suis.
The administration of The compounds of this invention can be via the method for any system and/or local delivery The compounds of this invention.These methods comprise oral route, parenteral, intraduodenal route etc.Generally speaking, The compounds of this invention is an oral administration, but also can adopt administered parenterally (for example in intravenously, intramuscular, the subcutaneous or marrow), and for example inappropriate or patient can not swallow under the situation of medicine at oral administration.
Generally speaking, the consumption of The compounds of this invention is enough to the result of treatment (for example reducing lipid) that reaches required.
Generally speaking, the effective dose of the salt of The compounds of this invention, their prodrug and this compounds and prodrug in about 0.001 to about 100mg/kg/ day scope, preferred about 0.005 to about 5mg/kg/ day.
The dosage that medicinal composition composition and PPAR agonist are united use is effective with regard to the indication of being treated.Can determine this class dosage by the standard test method, for example above mention with provided herein those.Combined composition can be according to random order while or administration successively.
For example, the effective dose of HMG-CoA reductase inhibitor is usually in about 0.01 to about 100mg/kg/ day scope.
The compounds of this invention generally is with the form administration of pharmaceutical composition, wherein comprises at least a The compounds of this invention and pharmaceutically acceptable vehicle, diluent or carrier.Thereby The compounds of this invention can be separately or administration in oral, parenteral, rectum or the transdermal formulation of any conventional together.
With regard to oral administration, pharmaceutical composition can be taked forms such as solution, suspension, tablet, pill, capsule, pulvis.Tablet contains various vehicle, for example Trisodium Citrate, lime carbonate and calcium phosphate, and adopt various disintegrating agents, starch for example, preferred potato or tapioca (flour) and some composition silicate, and tackiness agent, for example polyvinylpyrrolidone, sucrose, gelatin and gum arabic.In addition, lubricant is often very useful to the compressing tablet purpose, for example Magnesium Stearate, Sodium Lauryl Sulphate BP/USP and talcum.The solids composition that also adopts similar type is as the weighting agent in the gelatine capsule agent of soft or hard filling; Preferable material also comprises lactose or toffee and high molecular weight polyethylene glycol in this.Preferred preparation is oil solution or the suspension in soft gelatin capsule, for example sweet oil, Miglyol
TMOr Capmul
TMCan add antioxidant as one sees fit, to prevent long-term degradation.When oral administration needs aqueous suspensions and/or elixir, The compounds of this invention and various sweeting agent, correctives, tinting material, emulsifying agent and/or suspension agent can be combined, and thinner, for example water, ethanol, propylene glycol, glycerine and various similar combinations.
For the purpose of administered parenterally, can adopt the solution in sesame or peanut oil or aqueous propylene glycol, and the aseptic aqueous solution of corresponding water-soluble salt.If necessary, this class aqueous solution can suitably be cushioned, and at first gives liquid diluent with isotonicity with capacity salt solution or glucose.These aqueous solution are particularly suitable for intravenously, intramuscular, subcutaneous and peritoneal injection purpose.In this, the sterile aqueous media that is adopted all is to obtain with standard technique well known to those skilled in the art easily.
For the purpose of transdermal (for example local) administration, prepare the solution (concentration common about 0.1% to 5%) of rare, aseptic, moisture or partially aqueous, perhaps similar to above-mentioned parenteral solution.
The method of various pharmaceutical compositions that preparation contains a certain amount of activeconstituents is known, perhaps in view of this paper openly will be apparent for those skilled in the art institute.About the example of the method for pharmaceutical compositions, referring to Remington ' s Pharmaceutical Sciences, Mack Publishing Company, Easter, Pa., 19th Edition (1995).
Can contain the The compounds of this invention of 0.1%-95% according to pharmaceutical composition of the present invention, preferred 1%-70%.In any case, composition to be administered or preparation all will contain effective treatment curee's disease or illness, for example atherosclerosis amount according to compound of the present invention.
Relate to the aspect of using activeconstituents combined therapy disease/illness described herein that can be individually dosed because the present invention has, the present invention also relates to merge independent pharmaceutical composition is kit form.Medicine box comprises two kinds of independent pharmaceutical compositions: the salt of The compounds of this invention, its prodrug or this compounds or prodrug and above-mentioned second compound.Medicine box for example comprises the device that contains independent composition, for example container, the bottle that separates or the paper tinsel bag that separates.Usually, medicine box comprises the administration guidance of independent component.In kit form under the following situation is particularly advantageous: independent component is in different formulations (for example oral and parenteral) of administration preferably, is according to different spacing of doses administrations, perhaps needs the individual components of this combination of attending doctor's titration.
A kind of like this example of medicine box is so-called blister.Blister is known in packaging industry, is widely used in the packing of drug unit formulation, for example tablet, capsule etc.Blister generally is made up of hard relatively material sheet, is coated with one deck paper tinsel on it, is preferably transparent plastic material.During wrapping process, in plastic foil, form depression.The size of depression is consistent with the tablet that will pack or capsule with shape.Next step places tablet or capsule in the depression, in the direction opposite with forming depression relative hard material sheet is sealed with plastic foil.As a result, tablet or capsule are sealed in the depression between plastic foil and the thin slice.Preferably, the intensity of thin slice is that tablet or capsule can be taken out from blister like this, exerts pressure to depression by hand, and the thin slice that is positioned at recess forms opening.Can take out tablet or capsule via described opening then.
May on medicine box, provide aid prompting, the numeral on tablet or capsule next door for example, these numerals date that should be ingested according to dosage regimen thus corresponding to specified tablet or capsule.Another example of a kind of like this aid prompting is the calendar that is imprinted on the card, for example " first week, Monday, Tuesday ... " etc.. " second week, Monday, Tuesday ... " etc.Other variations of aid prompting will be conspicuous." dosage every day " can be single tablet or capsule, or some tablets or capsule, takes in given one day.And dosage every day of The compounds of this invention can be made up of a tablet or capsule, and dosage every day of second compound can be made up of some tablets or capsule, and vice versa.Aid prompting should reflect this point.
In the concrete invention embodiment of another kind, divider is designed to according to each portion dosage every day that distributes of their expection use order.Preferably, divider has aid prompting, so that further help complying with dosage regimen.An a kind of like this example of aid prompting is a mechanical counter, dosage number every day that its indication has been assigned with.Another example of a kind of like this aid prompting is battery-driven microchip storer, be connected with the liquid crystal reader, or the sound prompting signal, for example read taken last every day dosage date and/or when being about to take next time dosage, remind the user.
Generally will in suitable preparation, give The compounds of this invention separately or with each other or other combination of compounds.Following example of formulations only is illustrative, does not plan to limit the scope of the invention.
In following series preparation, " activeconstituents " represents compound of the present invention.
Preparation 1: gelatine capsule agent
Use following ingredients to prepare hard-gelatin capsules:
Become component (mg/ grain)
Activeconstituents 0.25-100
Starch NF 0-650
But starch flowing powder 0-50
Silicone fluid 350 centistoke 0-15
Use following ingredients to prepare tablet:
Preparation 2: tablet
Become component (mg/ sheet)
Activeconstituents 0.25-100
Microcrystalline Cellulose 200-650
Pyrogenic silica 10-650
Stearic acid 5-15
Each component of fusion, compacting are in flakes.
Select as an alternative, be prepared as follows tablet, every contains the 0.25-100mg activeconstituents:
Preparation 3: tablet
Become component (mg/ sheet)
Activeconstituents 0.25-100
Starch 45
Microcrystalline Cellulose 35
Polyvinylpyrrolidone (10% aqueous solution) 4
Xylo-Mucine 4.5
Magnesium Stearate 0.5
Talcum 1
Activeconstituents, starch and Mierocrystalline cellulose are sieved thorough mixing by No.45 order U.S..With polyvinylpyrrolidonesolution solution and gained powder mixes, then by No.14 order U.S. sieve.Formed particle is dry under 50-60 ℃, sieve by No.18 order U.S..Add sodium starch glycolate, Magnesium Stearate and the talcum that sieves by No.60U.S. in advance to particle then, mix the back and on tabletting machine, suppress in flakes.
Be prepared as follows suspension, every 5ml dosage contains the 0.25-100mg activeconstituents:
Preparation 4: suspension
Become component (mg/5ml)
Activeconstituents 0.25-100mg
Xylo-Mucine 50mg
Syrup 1.25mg
Benzoic acid solution 0.10mL
Correctives is an amount of
Pigment is an amount of
Purified water is to 5mL
Activeconstituents by No.45 order U.S. sieve, is mixed the level and smooth mashed prod of formation with Xylo-Mucine and syrup.Benzoic acid solution, correctives and pigment with some water dilutions, are added when stirring.Add enough water then to volume required.
The preparation aerosol solution, contain following ingredients:
Preparation 5: aerosol
Become component (weight %)
Activeconstituents 0.25
Ethanol 25.75
Propelling agent 22 (chlorodifluoromethane) 70.00
Activeconstituents is mixed with ethanol, mixture is joined in a part of propelling agent 22, be cooled to 30 ℃, be transferred to tamping unit.Then to the stainless steel vessel aequum of packing into, with all the other propelling agents dilutions.Then to container mounted valve unit.
Be prepared as follows suppository:
Preparation 6: suppository
Become component (mg/ bolt)
Activeconstituents 250
Saturated fatty acid glyceride 2,000
Activeconstituents by No.60 order U.S. sieve, is suspended in the saturated fatty acid glyceride of using a small amount of necessary heating and melting in advance.Then mixture is poured in the suppository mould of nominal 2g capacity into cooling.
Be prepared as follows iv formulation:
Preparation 7: intravenous solution
Become component
Activeconstituents is dissolved in ethanol 1% 20mg
Intralipid
TMEmulsion 1,000mL
Give the solution of mentioned component to patient's intravenously, speed is about 1mL per minute.
Use following ingredients to prepare Gelseal:
Preparation 8: oil formula Gelseal
Become component (mg/ grain)
Activeconstituents 10-500
Sweet oil or Miglyol
TMOil 500-1000
Mentioned component also can be the combination of therapeutical agent.
General experimental technique
The following example provides the open and explanation that how to prepare and estimate this paper claimed compounds, composition and method for those of ordinary skills, and they are the illustration of invention purely, do not plan to limit the invention scope that the contriver thinks.Unless indication is arranged in addition, per-cent be shown in composition weight with respect to the per-cent of composition total weight, temperature is ℃ or at ambient temperature, pressure be normal atmosphere or near.Commercial reagent need not to be further purified in use.Room temperature or envrionment temperature are represented 20-25 ℃.All non-aqueous reactions are all carried out under nitrogen atmosphere, for convenience and make the yield maximization.Concentrated in a vacuum meaning utilized rotatory evaporator.The title of The compounds of this invention is generated by the Autonom 2.0PC-batch version (ISBN 3-89536-976-4) from Beilstein Informations systeme GmbH." DMSO " represents dimethyl sulfoxide (DMSO).
At ambient temperature, at Varian Unity 400 (Varian Co., Palo Alto, CA) record NMR spectrum on the NMR spectrometer.Chemical drifting is with 1,000,000/umber (δ) expression with respect to external standard (tetramethylsilane).Peak shape is as follows: s is unimodal, and d is bimodal, the t triplet, and the q quartet, m multiplet, prefix br are represented the signal widened.Given coupling constant (J) has the error of maximum ± 0.41Hz, is caused by the spectrographic digitizing that is obtained.Mass spectrum obtains like this: (1) atmospheric pressure chemical ionization (APCI), and mutual positively charged ion and negatively charged ion pattern, Fisons Platform II spectrometer or Micromass MZD spectrometer (Micromass, Manchester, UK); Perhaps (2) electrospray ionization, mutual positively charged ion and negatively charged ion pattern, have Gilson LC-MC interface (Gilson Instrument, Middleton, Micromass MZD spectrometer WI) (Micromass, Manchester, UK); Perhaps (Japan), positive or cloudy single ionic monitoring pattern adopts electrospray ionization or atmospheric pressure chemical ionization to (3) QP-8000 mass spectrograph for Shimadzu Corporation, Kyoto.When describing the intensity of chloride or bromine ion-containing, observe desired strength ratio (contain
35Cl/
37The Cl ion is about 3: 1, contains
79Br/
81The Br ion is about 1: 1), only provide than inferior quality ionic position.
Utilize Baker silica gel (40 μ m) (J.T.Baker, Phillipsburg, N.J.) or silica gel 60 (40-63 μ m) (EM Sciences, Gibbstown N.J.) carry out column chromatography.(Charlottesville VA) carries out flash chromatography for Biotage, Dyar Corp. to utilize Flash 12 or Flash 40 posts.(ShimadzuCorporation, Kyoto carry out the preparation HPLC purifying on Japan), use SIL-10A type automatic sampler and 8A type HPLC pump in Shimadzu 10A preparation HPLC system.In identical system, carry out preparation HPLC-MS, use the QP-8000 mass spectrograph instead,, adopt electrospray ionization or atmospheric pressure chemical ionization by sun or the operation of cloudy single ionic monitoring pattern.Make water/acetonitrile gradient carry out wash-out, wherein contain 0.1% formic acid or ammonium hydroxide as properties-correcting agent.In acid pattern, used typical pillar comprises Waters Symmetry C8,5 μ m, 19 * 50mm or 30 * 50mm, Waters XTerraC18,5 μ m, 50 * 50 (Waters Corp, Milford, MA) or PhenomenexSynergi Max-RP 4 μ m, 50 * 50mm (Phenomenex Inc., Torrance, CA).In alkaline pattern, use Phenomenex Synergi Max RP 4 μ m, 21.2 * 50mm or 30 * 50mm post (Phenomenex Inc., Torrance, CA).
(Jasco Inc., Easton MD) measure specific rotation to utilize Jasco P-1020 polariscope.
Dimethyl formamide, tetrahydrofuran (THF), toluene and methylene dichloride are anhydrous levels, by AldrichChemical Company (Milwaukee, WI) supply.Unless otherwise specified, use the reagent that obtains from commercial source.Term " concentrates " and " evaporation " is illustrated on the rotatory evaporator, depresses to remove at 1-200mm mercury and desolvate, and bathes temperature less than 45 ℃.Abbreviation " min " representative " minute ", " h " or " hr " representative " hour ".Abbreviation " gm " or " g " representative gram.Microlitre is represented in abbreviation " μ l " or " μ L ".
Embodiment 1:5-(4-benzyloxy-phenyl sulfamoyl)-2-methyl-phenylformic acid
(200mg, 0.85mmol) (187mg, 6ml acetone 0.94mmol) and 3ml dimethyl formamide solution add sodium bicarbonate (215mg, 2ml aqueous solution 0.56mmol) with right-benzyloxy-aniline to 5-chlorine sulphonyl-2-tolyl acid.The gained mixture at room temperature stirred spend the night.Under reduced pressure remove acetone then, residual mixture is distributed between 25ml 1N aqueous hydrochloric acid and 25ml ethyl acetate.Water phase separated is with 2 * 25ml ethyl acetate extraction.The combined ethyl acetate extraction liquid, dry (anhydrous sodium sulphate) under reduced pressure concentrates.(silica gel 15gm), with 9: 1 chloroform/methanol wash-outs, obtains white solid (154mg) to resistates through the flash column chromatography purifying.Solid is developed with methylene dichloride, obtained title compound (93mg, 28% yield), be white solid.
MS：395.6(M-1)；
1H NMR(400MHz，CD
3OD)：δ2.57(s，3H)，4.96(s，2H)，6.81(m，2H)，6.93(m，2H)，7.30(m，6H)，7.60(m，1H)，8.20(m，1H).
From suitable raw material, utilize the prepared embodiment 2-26 title compound that is similar to embodiment 1.
Embodiment 2:2-methyl-5-[4-(6-methyl-benzothiazole-2-yl)-phenyl sulfamoyl] phenylformic acid
8% yield .MS:439.4 (M+1);
1H NMR (400MHz, CD
3OD): δ 2.44 (s, 3H), 2.53 (s, 3H), 7.23 (m, 2H), 7.29 (m, 1H), 7.34 (m, 1H), 7.72 (m, 1H), 7.75 (m, 1H), 7.80 (m, 1H), 7.88 (m, 2H), 8.19 (m, 1H).
Embodiment 3:2-methyl-5-[4-(5-methyl-benzoxazol-2-yl)-phenyl sulfamoyl] phenylformic acid
4% yield .MS:423.4 (M+1):
1H NMR (400MHz, CD
3OD): δ 2.42 (s, 3H), 2.51 (s, 3H), 7.17 (m, 1H), 7.26 (m, 2H), 7.35 (m, 1H), 7.44 (m, 2H), 7.56 (m, 1H), 8.0 (m, 2H), 8.15 (m, 1H).
Embodiment 4:5-(4-benzoxazol-2-base-phenyl sulfamoyl)-2-methyl-phenylformic acid
10% yield .MS:407.1 (M-1);
1H NMR (400MHz, CD
3OD): δ 2.48 (s, 3H), 7.38 (m, 3H), 7.65 (m, 1H), 7.7 (m, 1H), 7.92 (m, 3H), 8.22 (m, 1H).
Embodiment 5:2-methyl-5-[4-(5-phenyl-benzoxazol-2-yl)-phenyl sulfamoyl]-phenylformic acid
7% yield .MS:483.2 (M-1);
1H NMR (400MHz, CD
3OD): δ 2.48 (s, 3H), 7.35 (m, 2H), 7.44 (m, 2H), 7.64 (m, 3H), 7.71 (d, 1H), 7.82 (m, 1H), 7.92 (m, 4H), 8.23 (m, 2H).
Embodiment 6:5-[4-(5-chloro-benzoxazol-2-yl)-phenyl sulfamoyl]-2-methyl-phenylformic acid
10% yield .MS:441.1 (M-1);
1H NMR (400MHz, CD
3OD): δ 2.47 (s, 3H), 7.37 (m, 2H), 7.63 (d, 1H), 7.7 (b, 1H), 7.81 (m, 1H), 7.92 (m, 3H), 8.21 (m, 2H).
Embodiment 7:5-(4-benzothiazole-2-base-phenyl sulfamoyl)-2-methyl-phenylformic acid
7% yield .MS:425.1 (M+1);
1H NMR (400MHz, CD
3OD): δ 246 (s, 3H), 7.26 (m, 3H), 7.37 (t, 1H), 7.47 (t, 1H), 7.62 (d, 1H), 7.91 (m 4H), 7.98 (b, 1H).
Embodiment 8:2-methyl-5-[4-(4-trifluoromethyl-benzylthio-)-phenyl sulfamoyl]-phenylformic acid
33% yield .MS:480.2 (M-1);
1H NMR (400MHz, CD
3OD): δ 2.49 (s, 3H), 4.04 (s, 2H), 6.96 (d, 2H), 7.1 (d, 2H), 7.23 (d, 1H), 7.29 (m, 2H), 7.47 (m, 3H), 7.94 (b, 1H).
Embodiment 9:2-methyl-5-[4-(4-trifluoromethyl-benzyloxy)-phenyl sulfamoyl]-phenylformic acid
28% yield .MS:464.1 (M-1);
1H NMR (400MHz, CD
3OD): δ 2.56 (s, 3H), 5.07 (s, 2H), 6.83 (m, 2H), 6.95 (m, 2H), 7.30 (d, 1H), 7.57 (m, 3H), 7.63 (d, 2H), 8.13 (s, 1H).
Embodiment 10:2-methyl-5-(4-styryl-phenyl sulfamoyl)-phenylformic acid
33% yield .MS:392.2 (M-1);
1H NMR (400MHz, CD
3OD): δ 2.54 (s, 3H), 7.05 (m, 4H), 7.18 (t, 1H), 7.26-7.4 (m, 5H), 7.46 (m, 2H), 7.67 (m, 1H), 8.18 (s, 1H).
Embodiment 11:2-methyl-5-[4-(3-trifluoromethyl-benzylthio-)-phenyl sulfamoyl]-phenylformic acid
21% yield .MS:480.1 (M-1);
1H NMR (400MHz, CD
3OD): δ 2.59 (s, 3H), 4.06 (s, 2H), 6.98 (m, 2H), 7.13 (m, 2H), 7.34 (m, 3H), 7.44 (m, 2H), 7.68 (m, 2H), 8.26 (d, 1H).
Embodiment 12:5-[4-(the 4-tertiary butyl-benzylthio-)-phenyl sulfamoyl]-2-methyl-phenylformic acid
31% yield .MS:468.2 (M-1);
1H NMR (400MHz, CD
3OD): δ 1.24 (s, 9H), 2.57 (s, 3H), 3.95 (s, 2H), 6.95 (m, 2H), 7.05 (d, 1H), 7.11 (m, 1H), 7.21 (d, 1H), 734 (d, 1H), 7.66 (m, 1H), 8.22 (d, 1H).
Embodiment 13:5-(4-benzothiazole-2-base-phenyl sulfamoyl)-2-ethyl-phenylformic acid
6% yield .MS:439.1 (M+1);
1H NMR (400MHz, CD
3OD): δ 1.18 (t, 3H), 2.96 (q, 2H), 7.27 (d, 2H), 7.39 (t, 2H), 7.49 (t, 1H), 7.79 (d, 1H), 7.94 (m, 4H), 8.15 (d, 1H).
Embodiment 14:2-ethyl-5-[4-(5-methyl-benzoxazol-2-yl)-phenyl sulfamoyl]-phenylformic acid
9% yield .MS:437.1 (M+1);
1H NMR (400MHz, CD
3OD): δ 1.18 (t, 3H), 2.45 (s, 3H), 2.95 (q, 2H), 7.19 (m, 1H), 7.29 (m, 2H), 7.38 (d, 1H), 7.47 (d, 2H), 7.78 (m, 1H), 8.04 (d, 2H), 8.2 (d, 1H).
Embodiment 15:2-ethyl-5-[4-(4-trifluoromethyl-benzylthio-)-phenyl sulfamoyl]-phenylformic acid
32% yield .MS:495.2 (M-1);
1H NMR (400MHz, CD
3OD): δ 1.17 (t, 3H), 2.93 (q, 2H), 4.04 (s, 2H), 6.97 (m, 2H), 7.11 (m, 2H), 7.3 (m, 3H), 7.46 (d, 2H), 7.59 (m, 1H), 8.0 (d, 1H).
Embodiment 16:5-[4-(4-sec.-propyl-benzylthio-)-phenyl sulfamoyl]-2-methyl-phenylformic acid
10% yield .MS:454.2 (M-1);
1H NMR (400MHz, CD
3OD): δ 1.17 (d, 6H), 2.8 (m, 1H), 3.94 (s, 2H), 6.95 (d, 2H), 7.04 (s, 4H), 7.1 (m, 2H), 7.31 (d, 1H), 7.61 (d, 1H), 8.16 (s, 1H).
Embodiment 17:2-methyl-5-[4-(4-trifluoromethoxy-benzylthio-) phenyl sulfamoyl]-phenylformic acid
29% yield .MS:496.1 (M-1);
1H NMR (400MHz, CD
3OD): δ 2.59 (s, 3H), 4.01 (s, 2H), 6.98 (m, 2H), 7.06 (d, 2H), 7.14 (m, 2H), 7.20 (d, 2H), 7.36 (d, 1H), 7.67 (d, 1H), 8.22 (s, 1H).
Embodiment 18:5-[4-(4-chloro-benzylthio-)-phenyl sulfamoyl]-2-methyl-phenylformic acid
7% yield .MS:448.1 (M+1);
1H NMR (400MHz, CD
3OD): 2.53 (s, 3H), 3.95 (s, 2H), 6.95 (d, 2H), 7.09 (t, 4H), 7.14 (d, 2H), 7.28 (d, 1H), 7.55 (m, 1H), 8.07 (d, 1H).
Embodiment 19:2-methyl-5-[4-(3-phenoxy group-benzylthio-)-phenyl sulfamoyl]-phenylformic acid
25% yield .MS:504.2 (M+1);
1H NMR (400MHz, CD
3OD): δ 2.54 (s, 3H), 3.94 (s, 2H), 6.77 (m, 4H), 6.89 (d, 1H), 6.95 (d, 2H), 7.09 (m, 4H), 7.28 (m, 3H), 7.63 (m, 1H), 8.24 (d, 1H).
Embodiment 20:2-methyl-5-(4-{2-[2-(4-trifluoromethyl-phenyl)-thiazole-4-yl]-oxyethyl group } phenyl sulfamoyl)-phenylformic acid
72% yield .MS:563.1 (M+1);
1H NMR (400MHz, CD
3OD): δ 2.54 (s, 3H), 3.22 (t, 2H), 4.27 (t, 2H), 6.77 (m, 2H), 6.93 (m, 2H), 7.29 (d, 1H), 7.34 (s, 1H), 7.55 (m, 1H), 7.74 (d, 2H), 8.09 (d, 3H).
Embodiment 21:2-methyl-5-(4-{2-[2-(4-trifluoromethoxy-phenyl)-thiazole-4-yl]-oxyethyl group } phenyl sulfamoyl)-phenylformic acid
31% yield .MS:579.1 (M+1);
1H NMR (400MHz, CD
3OD): δ 2.48 (s, 3H), 3.20 (t, 2H), 4.25 (t, 2H), 6.75 (d, 2H), 6.94 (d, 2H), 7.22 (m, 1H), 7.29 (s, 1H), 7.35 (m, 2H), 7.44 (m, 1H), 7.89 (s, 1H), 8.00 (d, 2H).
Embodiment 22:2,3-dimethyl-5-[4-(5-methyl-benzoxazol-2-yl)-phenyl sulfamoyl]-phenylformic acid
7% yield .MS:437.3 (M+1);
1H NMR (400MHz, CD
3OD): δ 2.38 (s, 3H), 2.39 (s, 3H), 2.48 (s, 3H), 7.23 (d, 1H), 7.53 (m, 2H), 7.74 (s, 2H), 7.94 (d, 2H), 8.21 (d, 2H).
Embodiment 23:2,6-dimethyl-3-[4-(6-methyl-benzothiazole-2-yl)-phenyl sulfamoyl]-phenylformic acid
16% yield .MS:453.1 (M+1);
1H NMR (400MHz, CD
3OD): δ 2.33 (s, 3H), 2.46 (s, 3H), 2.63 (s, 3H), 7.2-7.3 (c, 3H), 7.32 (d, 1H), 7.73 (s, 1H), 7.8 (d, 1H), 7.88 (m, 2H), 8.0 (d, 1H).
Embodiment 24:2,6-dimethyl-3-[4-(3-trifluoromethoxy-benzylthio-)-phenyl sulfamoyl]-phenylformic acid
6% yield .MS:510.1 (M-1);
1H NMR (400MHz, CD
3OD): δ 2.34 (s, 3H), 2.57 (s, 3H), 4.02 (s, 2H), 6.95 (m, 2H), 7.07 (d, 1H) 7.12 (m, 4H), 7.22 (m, 2H), 7.85 (d, 1H).
Embodiment 25:2,6-dimethyl-3-[4-(4-trifluoromethoxy-benzylthio-) phenyl sulfamoyl]-phenylformic acid
32% yield .MS:510.3 (M-1);
1H NMR (400MHz, CD
3OD): δ 2.35 (s, 3H), 2.62 (s, 3H), 4.01 (s, 2H), 6.97 (m, 2H), 7.12 (m, 5H), 7.24 (d, 2H), 7.77 (d, 1H).
Embodiment 26:2,6-dimethyl-3-(4 '-trifluoromethoxy-biphenyl-4-base sulphonamide)-phenylformic acid
13% yield.
1H NMR (400MHz, CD
3OD): δ 2.33 (s, 3H), 2.62 (s, 3H), 7.17 (m, 2H), 7.22 (d, 1H), 7.28 (d, 2H), 7.47 (m, 2H), 7.60 (m, 2H), 7.93 (d, 1H).
Embodiment 27:5-[4-(the 4-tertiary butyl-phenoxy group)-phenyl sulfamoyl]-2-methyl-phenylformic acid
With 4-(the 4-tertiary butyl-phenoxy group)-phenyl amine (0.1g, 0.41mmol), (0.097g, 0.41mmol) (0.1ml, 2ml anhydrous tetrahydrofuran solution 1.24mmol) is at 60 ℃ of following heating 2hr with pyridine for 5-chlorosulfonyl-2-tolyl acid.Reaction mixture is cooled to room temperature, with the dilution of 30ml ethyl acetate.Ethyl acetate solution is successively used 25ml 1N aqueous hydrochloric acid and the water washing of 25ml salt, and dry (anhydrous sodium sulphate) under reduced pressure is concentrated into dried.Crude product with 9: 1 chloroform/methanol wash-outs, obtains title compound through preparation type thick layer chromatography purifying (silica gel).
82% yield .MS:438.3 (M-1);
1H NMR (400MHz, CD
3OD): δ 1.30 (s, 9H), 2.58 (s, 3H), 6.82 (m, 4H), 7.02 (d, 2H), 7.36 (d, 3H), 7.63 (d, 1H), 8.1 (b, 1H).
From suitable raw material, utilize the prepared embodiment 28-40 title compound that is similar to embodiment 27.
Embodiment 28:5-[4-(4-ethyl-benzylthio-)-phenyl sulfamoyl]-2-methyl-phenylformic acid
78% yield .MS:442.1 (M+1);
1H NMR (400MHz, CD
3OD): δ 1.15 (t, 3H), 2.54 (q, 2H), 2.57 (s, 3H), 3.94 (s, 2H), 6.94 (m, 3H), 7.01 (m, 3H), 7.10 (d, 2H) .7.33 (d, 1H), 7.64 (m, 1H), 8.20 (d, 1H).
Embodiment 29:2-methyl-5-[3-methyl-4-(4-trifluoromethyl-benzyloxy)-phenyl sulfamoyl]-phenylformic acid
6% yield .MS:478.2 (M-1);
1H NMR (400MHz, CD
3OD): δ 2.17 (s, 3H), 2.60 (s, 3H), 5.11 (s, 2H), 6.80 (m, 2H), 6.88 (s, 1H), 7.36 (d, 1H), 7.63 (m, 5H), 8.20 (d, 1H).
Embodiment 30:2-methyl-5-[2-methyl-4-(4-trifluoromethyl-benzyloxy)-phenyl sulfamoyl]-phenylformic acid
65% yield.
1H NMR (400MHz, CD
3OD): δ 2.00 (s, 3H), 2.62 (s, 3H), 5.10 (s, 2H), 6.71 (m, 1H), 6.79 (d, 1), 6.87 (d, 1H), 7.36 (d, 1H), 7.59 (m, 3H), 7.66 (d, 2H).
Embodiment 31:5-(4-{2-[5-(3,5-dimethyl-phenyl)-[1,3,4] diazole-2-base sulfenyl]-ethyl }-phenyl sulfamoyl)-2-methyl-phenylformic acid
49% yield .MS:524.4 (M+1);
1H NMR (400MHz, CDCl
3): δ 2.36 (s, 3H), 2.59 (s, 3H), 3.03 (t, 2H), 3.41 (t, 2H), 7.05 (d, 2H), 7.13 (d, 3H), 7.27, (b, 1H), 7.61 (s, 2H), 7.75 (b, 1H), 8.14 (b, 1H).
Embodiment 32:5-(4-{2-[5-(3,5-two chloro-phenyl)-[1,3,4] diazole-2-base sulfenyl]-ethyl } phenyl sulfamoyl)-2-methyl-phenylformic acid
90% yield .MS:566.3 (M+1);
1H NMR (400MHz, CDCl
3): δ 2.55 (s, 3H), 2.97 (t, 2H), 3.38 (t, 2H), 7.03 (m, 5H), 7.18 (d, 1H), 7.53 (d, 1H), 7.63 (m, 1H), 7.77 (m, 1H), 8.02 (d, 1H).
Embodiment 33:5-[4-(3-difluoro-methoxy-benzylthio-)-phenyl sulfamoyl]-2-methyl-phenylformic acid
40% yield .MS:478.2 (M-1);
1H NMR (400MHz, CD
3OD): δ 2.58 (s, 3H), 4.01 (s, 2H), 6.98 (c, 5H), 7.14 (m, 2H), 7.20 (t, 1H), 7.33 (d, 1H), 7.63 (m, 1H), 7.87 (s, 1H), 8.19 (d, 1H).
Embodiment 34:2-methyl-5-[4-(2-trifluoromethoxy-benzylthio-)-phenyl sulfamoyl]-phenylformic acid
27% yield .MS:498.3 (M+1);
1H NMR (400MHz, CDCl
3): δ 2.60 (s, 3H), 3.98 (s, 2H), 7.01 (d, 2H), 7.10 (c, 5H), 7.23 (c, 2H), 7.68 (m, 1H), 8.41 (d, 1H).
Embodiment 35:2-methyl-5-[4-(4-trifluoromethyl-phenyl sulfamoyl)-phenyl sulfamoyl]-phenylformic acid
6% yield .MS:512.9 (M-1);
1H NMR (400MHz, CD
3OD): δ 2.55 (s, 3H), 7.20 (m, 3H), 7.30 (d, 1H), 7.48 (d, 2H), 7.66 (m, 3H), 7.90 (s, 1H), 8.20 (d, 1H).
Embodiment 36:5-{4-[5-(4-ethyl-phenyl)-[1,3,4] diazole-2-yl]-phenyl sulfamoyl }-the 2-tolyl acid
34% yield.
1H NMR (400MHz, CD
3OD): δ 1.28 (t, 3H), 2.60 (s, 3H), 2.74 (q, 2H), 7.34 (m, 2H), 7.43 (m, 3H), 7.87 (m, 2H), 8.03 (m, 3H), 8.38 (d, 1H).
Embodiment 37:5-[4-(the 5-tertiary butyl-[1,3,4] diazole-2-yl)-phenyl sulfamoyl]-2-methyl-phenylformic acid
51% yield .MS:416.7 (M+1);
1H NMR (400MHz, CD
3OD): δ 1.46 (s, 9H), 2.60 (s, 3H), 7.30 (m, 2H), 7.42 (d, 1H), 7.84 (m, 1H), 7.89 (m, 2H), 8.35 (d, 1H).
Embodiment 38:2-methyl-5-{4-[5-(4-trifluoromethoxy-phenyl)-[1,3,4] diazole-2-yl] phenyl sulfamoyl }-phenylformic acid
6% yield .MS:518.0 (M+1);
1H NMR (400MHz, CD
3OD): δ 2.47 (s, 3H), 7.2-7.34 (m, 4H), 7.50 (d, 1H), 7.67 (m, 1H), 7.92-8.04 (m, 4H), 8.22 (d, 1H).
Embodiment 39:2-methyl-5-[4-(5-trifluoromethyl-pyridine-2-base carbamyl)-phenyl sulfamoyl]-benzoic acid methyl ester
60% yield.MS：492.0(M-1)
Embodiment 40:5-[4-(5-cyclohexyl-[1,3,4] diazole-2-yl)-phenyl sulfamoyl]-2-methyl-benzoic acid methyl ester
32% yield.MS：454.1(M-1)
From suitable raw material, utilize the prepared embodiment 41-82 title compound that is similar to embodiment 1.
Embodiment 83:2-methyl-5-[4-(4-trifluoromethyl-benzylthio-)-phenyl sulfamoyl]-benzoic acid methyl ester
With sodium bicarbonate (667mg; 7.94mmol) the 4.5ml aqueous solution join 4-(4-trifluoromethyl-benzylthio-)-phenyl amine (750mg; 2.65mmol) and 5-chlorosulfonyl-2-methyl-benzoic acid methyl ester (855mg; 3.44mmol) the 14ml acetone soln in, the gained mixture at room temperature stirred spends the night.Then with reaction mixture with the dilution of 60ml chloroform, successively use the 1N aqueous hydrochloric acid (2 * 50ml), water (50ml) and salt solution (40ml) washs.With chloroformic solution drying (anhydrous sodium sulphate), under reduced pressure be concentrated into the oil (1.59g) of brown.(silica gel 40g), with 8: 2 hexane/ethyl acetate wash-outs, obtains xanchromatic oil (1.3g) to crude product through the flash column chromatography purifying.Should in the 5ml mixture of 98: 2 hexane/diethyl ether, develop by oil, filter the gained solid, obtain title compound, be white solid (1.13g, 86% yield).MS：480.2(M-1)
From suitable raw material, utilize the prepared embodiment 84-153 title compound that is similar to embodiment 83, as shown in the table.
Embodiment 152:2,3-dimethyl-5-[4-(4-trifluoromethoxy-benzylthio-)-phenyl sulfamoyl base] benzoic acid methyl ester
41% yield.
1H NMR (400MHz, CD
3Cl): δ 2.31 (s, 3H), 2.48 (s, 3H), 3.88 (s, 3H), 4.01 (s, 2H), 6.95 (d, 2H), 7.08 (d, 2H), 7.16 (d, 2H), 7.21 (d, 2H), 7.61 (s, 1H), 8.04 (s, 1H).
Embodiment 153:5-[4-(the 1H-benzimidazolyl-2 radicals-yl)-phenyl sulfamoyl]-2-sec.-propyl-benzoic acid methyl ester
41% yield.
1H NMR (400MHz, CD
3Cl): δ 1.16 (d, 6H), 3.67 (m, 1H), 3.83 (s, 3H), 7.11 (d, 2H), 7.23 (c, 2H), 7.42 (d, 1H), 7.61 (c, 2H), 7.85 (c, 3H), 8.23 (d, 1H).
Embodiment 154:5-(4 '-butyl-biphenyl-4-base sulphonamide)-2-methyl-benzoic acid methyl ester
Under nitrogen, with the 4-butylbenzene for boric acid (174mg, 0.975mmol), 5-(4-bromo-phenyl sulfamoyl)-2-tolyl acid methyl ester (150mg, 0.39mmol), dichloro [1,1 '-two (diphenyl phosphine) ferrocene] palladium (II) methylene dichloride adducts (16mg, 0.019mmol), 1,1 '-two (diphenyl phosphine) ferrocene (11mg, 0.019mmol) (the 0.39ml 2M aqueous solution, 0.78mmol) at 15ml 1, the mixture in the 4-two alkane heats 20hr under refluxing with salt of wormwood.Reaction mixture is cooled to room temperature, with the dilution of 80ml water, with 2 * 70ml ethyl acetate extraction.The combined ethyl acetate extraction liquid with the water washing of 60ml salt, through anhydrous sodium sulfate drying, under reduced pressure concentrates.(silica gel 15g), with 6: 1 hexane/ethyl acetate wash-outs, obtains title compound to crude product, is white solid (109mg, 64% yield) through the flash column chromatography purifying.MS：422.1(M-1)
From suitable raw material, utilize the prepared embodiment 155-173 title compound that is similar to embodiment 154, below the results are shown in.
Embodiment 174:2-methyl-5-[4-(4-trifluoromethyl-benzylthio-)-phenyl sulfamoyl]-phenylformic acid
With 1.0N aqueous sodium hydroxide solution (9.1ml, 9.16mmol) join 2-methyl-5-[4-(4-trifluoromethyl-benzylthio-)-phenyl sulfamoyl]-benzoic acid methyl ester (1.13g, 2.29mmol) the 100ml methanol solution in, under nitrogen with gained solution heated overnight under refluxing.Then reaction soln is cooled to room temperature, under reduced pressure concentrates.Resistates is stirred in 1.0N aqueous hydrochloric acid (25ml), filter, obtain title compound, be white solid (1.03g, 94% yield).
MS：480.2(M-1)；
1H NMR(400MHz，CD
3OD)：δ2.49(s，3H)，4.04(s，2H)，6.96(d，2H)，7.1(d，2H)，7.29(m，2H)，7.33(d，1H)，7.47(m，3H)，7.94(b，1H).
From suitable raw material, utilize the prepared embodiment 175-258 title compound that is similar to embodiment 174.
Embodiment 175:5-[4-(biphenyl-4-methylthiol)-phenyl sulfamoyl]-2-methyl-phenylformic acid
30% yield .MS:488.2 (M-1);
1H NMR (400MHz, CD
3OD): δ 2.48 (s, 3H), 4.15 (s, 2H), 6.99 (d, 2H), 7.22 (m, 2H), 7.32 (m, 3H), 7,43 (m, 3H), 7.52 (m, 2H), 7.61 (m, 2H), 7.70 (m, 1H), 8.18 (d, 1H).
Embodiment 176:5-{4-[2-(4-chloro-phenyl)-thiazol-5-methylthiol]-phenyl sulfamoyl }-2 methyl-phenylformic acid
99% yield .MS:529.0 (M-1);
1H NMR (400MHz, CD
3OD): δ 2.60 (s, 3H), 4.15 (s, 2H), 6.99 (m, 2H), 7.19 (m, 2H), 7.3-7.5 (c, 5H), 7.87 (d, 2H), 8.27 (d, 1H).
Embodiment 177:2-methyl-5-[4-(quinoline-2-methylthiol)-phenyl sulfamoyl]-phenylformic acid
56% yield .MS:465.2 (M+1);
1H NMR (400MHz, CD
3OD): δ 2.59 (s, 3H), 4.29 (s, 2H), 6.95 (d, 2H), 7.18 (d, 2H), 7.29 (d, 1H), 7.41 (d, 1H), 7.56 (m, 1H), 7.64 (d, 1H), 7.73 (m, 1H), 7.88 (c, 2H), 8.19 (d, 1H), 8.26 (s, 1H).
Embodiment 178:2-methyl-5-[4-(5-phenyl-[1,2,4] diazole-3-methylthiol)-phenyl sulfamoyl] phenylformic acid
85% yield .MS:481.0 (M-1);
1H NMR (400MHz, DMSO-D
6): δ 2.51 (s, 3H), 4.28 (s, 2H), 7.02 (d, 2H), 7.31 (d, 2H), 7.43 (d, 1H), 7.61 (m, 2H), 7.70 (m, 2H), 8.04 (m, 2H), 8.19 (s, 1H).
Embodiment 179:5-[4-(4-fluoro-benzylthio-)-phenyl sulfamoyl]-2-methyl-phenylformic acid
85% yield .MS:430.0 (M-1);
1H NMR (400MHz, DMSO-D
6): δ 2.53 (s, 3H), 4.08 (s, 2H), 7.01 (m, 4H), 7.17 (m, 2H), 7.23 (m, 2H), 7.46 (d, 1H), 7.71 (m, 1H), 8.17 (d, 1H).
Embodiment 180:2-methyl-5-[4-(naphthalene-2-methylthiol)-phenyl sulfamoyl]-phenylformic acid
82% yield .MS:462.0 (M-1);
1H NMR (400MHz, DMSO-D
6): δ 2.49 (s, 3H), 4.27 (s, 2H), 6.97 (d, 2H), 7.21 (m, 2H), 7.39 (m, 2H), 7.46 (m, 2H), 7.68 (m, 1H), 7.72-7.87 (m, 4H), 8.18 (d, 1H).
Embodiment 181:2-methyl-5-[4-(3-trifluoromethoxy-benzylthio-)-phenyl sulfamoyl]-phenylformic acid
74% yield .MS:496.3 (M-1);
1H NMR (400MHz, DMSO-D
6): δ 2.49 (s, 3H), 4.15 (s, 2H), 6.97 (m, 2H), 7.19 (c, 5H), 7.33 (m, 1H), 7.44 (d, 1H), 7.71 (m, 1H), 8.17 (d, 1H).
Embodiment 182:2-methyl-5-(4-naphthalene-1-base-phenyl sulfamoyl)-phenylformic acid
69% yield .MS:416.0 (M-1);
1H NMR (400MHz, DMSO-D
6): δ 2.49 (s, 3H), 7.22 (d, 2H), 7.34 (m, 3H), 7.48 (m, 4H), 7.67 (d, 1H), 7.91 (m, 3H), 8.23 (d, 1H).
Embodiment 183:5-(3 ', 5 '-two-trifluoromethyl-biphenyl-4-base sulphonamide)-2-methyl-phenylformic acid
81% yield .MS:501.9 (M-1);
1H NMR (400MHz, CD
3OD): δ 2.59 (s, 3H), 7.27 (m, 2H), 7.40 (d, 1H), 7.59 (m, 2H), 7.80 (d, 1H), 7.82 (d, 1H), 8.08 (s, 2H), 8.35 (d, 1H).
Embodiment 184:2-methyl-5-(4-naphthalene-2-base-phenyl sulfamoyl)-phenylformic acid
65% yield .MS:416.0 (M-1);
1H NMR (400MHz, DMSO-D
6): δ 2.53 (s, 3H), 7.21 (d, 2H), 7.49 (m, 3H), 7.70 (d, 2H), 7.75 (m, 1H), 7.81 (m, 1H), 7.92 (m, 2H), 8.11 (s, 1H), 8.24 (d, 1H).
Embodiment 185:2-methyl-5-(4 '-trifluoromethyl-biphenyl-4-base sulphonamide)-phenylformic acid
81% yield .MS:434.0 (M-1);
1H NMR (400MHz, DMSO-D
6): δ 2.53 (s, 3H), 7.20 (m, 2H), 7.49 (d, 1H), 7.63 (d, 2H), 7.72-7.84 (m, 5H), 8.24 (d, 1H).
Embodiment 186:5-(4 '-ethylmercapto group-biphenyl-4-base sulphonamide)-2-methyl-phenylformic acid
79% yield .MS:426.0 (M-1);
1H NMR (400MHz, DMSO-D
6): δ 1.22 (t, 3H), 2.53 (s, 3H), 2.98 (q, 2H), 7.15 (d, 2H), 7.32 (d, 2H), 7.51 (m, 5H), 7.79 (m, 1H), 8.22 (d, 1H).
Embodiment 187:5-[4-(the 1H-benzimidazolyl-2 radicals-yl)-phenyl sulfamoyl]-2-methyl-phenylformic acid
94% yield .MS:408.2 (M+1);
1H NMR (400MHz, CD
3OD): δ 2.60 (s, 3H), 7.46 (m, 3H), 7.59 (m, 2H), 7.76 (m, 2H), 7.92 (m, 1H), 8.00 (m, 2H), 8.40 (d, 1H).
Embodiment 188:2-methyl-5-(3 '-trifluoromethyl-biphenyl-4-base sulphonamide)-phenylformic acid
43% yield .MS:434.0 (M-1);
1H NMR (400MHz, DMSO-D
6): δ 2.53 (s, 3H), 7.19 (d, 2H), 7.48 (d, 1H), 7.64 (c, 4H), 7.81 (m, 1H), 7.88 (c, 2H), 8.23 (d, 1H).
Embodiment 189:5-(4-benzo [b] thiophene-2-base-phenyl sulfamoyl)-2-methyl-phenylformic acid
80% yield .MS:422.0 (M-1);
1H NMR (400MHz, DMSO-D
6): δ 2.53 (s, 3H), 7.18 (d, 2H), 7.33 (m, 2H), 7.49 (d, 1H), 7.65 (m, 2H), 7.73 (s, 1H), 7.80 (m, 2H), 7.92 (m, 1H), 8.23 (d, 1H).
Embodiment 190:5-(4 '-benzyloxy-biphenyl-4-base sulphonamide)-2-methyl-phenylformic acid
74% yield .MS:472.3 (M-1);
1H NMR (400MHz, DMSO-D
6): δ 2.52 (s, 3H), 5.11 (s, 2H), 7.03 (m, 2H), 7.12 (d, 2H), 7.28-7.52 (c, 10H), 7.78 (m, 1H), 8.21 (d, 1H).
Embodiment 191:2-methyl-5-(4 '-propoxy--biphenyl-4-base sulphonamide)-phenylformic acid
61% yield.
1H NMR (400MHz, DMSO-D
6): δ 0.95 (t, 3H), 1.7 (m, 2H), 2.52 (s, 3H), 3.91 (t, 2H), 6.93 (d, 2H), 7.11 (d, 2H), 7.47 (d, 5H), 7.77 (d, 1H), 8.31 (s, 1H).
Embodiment 192:2-methyl-5-(2 '-methylthio group-biphenyl-4-base sulphonamide)-phenylformic acid
87% yield .MS:412.3 (M-1);
1H NMR (400MHz, DMSO-D
6): δ 2.48 (s 3H), 2.54 (s, 3H), 7.06-7.17 (c, 4H), 7.17-7.34 (c, 4H), 7.49 (d, 1H), 7.81 (m, 1H), 8.22 (d, 1H).
Embodiment 193:2-methyl-5-(4 '-trifluoromethoxy-biphenyl-4-base sulphonamide)-phenylformic acid
69% yield .MS:450.2 (M-1);
1H NMR (400MHz, DMSO-D
6): δ 2.48 (s, 3H), 7.17 (d, 2H), 7.38 (d, 2H), 7.48 (d, 1H), 7.56 (d, 2H), 7.68 (d, 2H), 7.80 (m, 1H), 8.22 (d, 1H).
Embodiment 194:2-methyl-5-(2 '-trifluoromethyl-biphenyl-4-base sulphonamide)-phenylformic acid
64% yield .MS:434.3 (M-1);
1H NMR (400MHz, DMSO-D
6): δ (s, 3H), 7.11 (d, 2H), 7.17 (d, 2H), 7.30 (d, 1H), 7.48 (d, 1H), 7.55 (m, 1H), 7.65 (m, 1H), 7.78 (m, 2H), 8.20 (d, 1H), 7.78 (d, 2H).
Embodiment 195:2-ethyl-5-(4 '-trifluoromethyl-biphenyl-4-base sulphonamide)-phenylformic acid
90% yield .MS:448.3 (M-1);
1H NMR (400MHz, CD
3OD): δ 1.19 (t, 3H), 3.01 (q, 2H), 7.23 (d, 2H), 7.43 (d, 1H), 7.56 (d, 2H), 7.68 (d, 2H), 7.73 (d, 2H), 7.82 (m, 1H), 8.28 (d, 1H).
Embodiment 196:2-methyl-5-(2-phenyl-benzoxazol-6-base sulphonamide)-phenylformic acid
85% yield .MS:409.3 (M+1);
1H NMR (400MHz, CD
3OD): δ 2.58 (s, 3H), 7.07 (m, 1H), 7.38 (d, 1H), 7.5-7.6 (c, 5H), 7.75 (m, 1H), 8.18 (m, 2H), 8.29 (d, 1H).
Embodiment 197:2-methyl-5-(2-phenyl-benzothiazole-6-base sulphonamide)-phenylformic acid
93% yield .MS:425.3 (M+1);
1H NMR (400MHz, CD
3OD): δ 2.58 (s, 3H), 7.23 (m, 1H), 7.38 (d, 1H), 7.51 (c, 3H), 7.76 (c, 2H), 7.85 (d, 1H), 8.04 (c, 2H), 8.30 (d, 1H).
Embodiment 198:5-[4-(the 5-tertiary butyl-benzoxazol-2-yl)-phenyl sulfamoyl]-2-methyl-phenylformic acid
62% yield .MS:465.4 (M+1);
1H NMR (400MHz, CD
3OD): δ 1.38 (s, 9H), 2.59 (s, 3H), 7.31 (m, 2H), 7.42 (d, 1H), 7.46 (d, 1H), 7.49d, 1H), 7.53 (d, 1H), 7.69 (d, 1H), 7.85 (m, 1H).
Embodiment 199:5-[4-(3,4-two fluoro-benzylthio-s)-phenyl sulfamoyl]-2-methyl-phenylformic acid
77% yield .MS:448.2 (M-1);
1H NMR (400MHz, CD
3OD): δ 2.61 (s, 3H), 3.98 (s, 2H), 6.89 (c, 1H), 6.97-7.12 (c, 3H), 7.18 (m, 2H), 7.38 (d, 1H), 7.69 (m, 1H), 8.27 (d, 1H).
Embodiment 200:5-[4-(3,5-couple-trifluoromethyl-benzylthio-)-phenyl sulfamoyl]-the 2-tolyl acid
80% yield .MS:548.2 (M-1):
1H NMR (400MHz, CD
3OD): δ 2.61 (s, 3H), 7.02 (m, 2H), 7.16 (m, 2H), 7.37 (d, 1H), 7.71 (m, 2H), 8.30 (d, 1H).
Embodiment 201:2-methyl-5-[4-(2-trifluoromethyl-benzylthio-)-phenyl sulfamoyl]-phenylformic acid
86% yield .MS:480.2 (M-1);
1H NMR (400MHz, CD
3OD): δ 2.62 (s, 3H), 4.15 (s, 2H), 7.02 (m, 2H), 7.14-7.25 (c, 3H), 7.34-7.42 (c, 3H), 7.61 (m, 1H), 7.73 (m, 1H), 8.29 (d, 1H).
Embodiment 202:5-[4-(3,4-dimethyl-benzylthio-)-phenyl sulfamoyl]-2-methyl-phenylformic acid
85% yield .MS:439.9 (M-1);
1H NMR (400MHz, CD
3OD): δ 2.15 (s, 3H), 2.19 (3,3H), 2.61 (s, 3H), 3.94 (s, 2H), 6.83 (d, 1H), 6.95 (c, 2H), 6.98 (m, 2H), 7.14 (m, 2H), 7.38 (d, 1H), 7.70 (m, 1H), 8.28 (d, 1H).
Embodiment 203:5-[4-(2,4-couple-trifluoromethyl-benzylthio-)-phenyl sulfamoyl]-2-methyl-phenylformic acid
80% yield .MS:548.1 (M-1);
1H NMR (400MHz, CD
3OD): δ 2.61 (s, 3H), 4.21 (s, 2H), 7.04 (m, 2H), 7.19 (m, 2H), 7.39 (m, 2H), 7.67 (d, 1H), 7.74 (m, 1H), 7.87 (s, 1H), 828 (d, 1H).
Embodiment 204:5-[4-(2-chloro-4-fluoro-benzylthio-)-phenyl sulfamoyl]-2-methyl-phenylformic acid
84% yield.MS：464.0(M-1)
Embodiment 205:5-[4-(5,6-two fluoro-benzothiazole-2-methylthiol)-phenyl sulfamoyl]-2-methyl-phenylformic acid
49% yield MS:507.0 (M-1);
1H NMR (400MHz, CD
3OD): δ 2.58 (s, 3H), 4.46 (s, 2H), 7.01 (d, 2H), 7.29 (m, 3H), 7.70 (m, 2H), 7.85 (m, 1H), 8.26 (d, 1H).
Embodiment 206:5-[4-(5-fluoro-benzothiazole-2-methylthiol)-phenyl sulfamoyl]-the 2-tolyl acid
80% yield .MS:489.1 (M+1);
1H NMR (400MHz, CD
3OD): δ 2.58 (s, 3H), 4.4-7 (s, 2H), 7.02 (m, 2H), 7.21 (m, 1H), 7.28 (c, 3H), 7.55 (m, 1H), 7.65 (m, 1H), 7.89 (m, 1H), 8.27 (d, 1H).
Embodiment 207:5-[4-(3,5-dimethyl-benzyloxy)-phenyl sulfamoyl]-2-methyl-phenylformic acid
87% yield .MS:424.2 (M-1);
1H NMR (400MHz, CD
3OD): δ 2.28 (s, 6H), 2.60 (s, 3H), 4.90 (s, 2H), 6.83 (m, 2H), 6.95 (c, 5H), 7.35 (d, 1H), 7.62 (m, 1H), 8.22 (d, 1H).
Embodiment 208:5-[4-(4-butoxy-benzyloxy)-phenyl sulfamoyl]-2-methyl-phenylformic acid
88% yield .MS:468.1 (M-1);
1H NMR (400MHz, CD
3OD): δ 0.98 (s, 3H), 1.50 (m, 2H), 1.73 (m, 2H), 2.60 (s, 3H), 3.96 (t, 2H), 4.90 (s, 2H), 6.83 (d, 2H), 6.88 (d, 2H), 6.95 (d, 2H), 7.28 (d, 2H), 7.35 (d, 1H), 7.62 (m, 1H), 8.21 (d, 1H).
Embodiment 209:5-[4-(2-chloro-4-fluoro-benzyloxy)-phenyl sulfamoyl]-2-methyl-phenylformic acid
84% yield; MS:448.0 (M-1);
1H NMR (400MHz, CD
3OD): δ 2.60 (s, 3H), 5.05 (s, 2H), 6.86 (m, 2H), 6.98 (m, 2H), 7.08 (m, 1H), 7.25 (m, 1H), 7.36 (d, 1H), 7.53 (m, 1H), 7.64 (m, 1H), 8.21 (d, 1H).
Embodiment 210:5-[4-(2,3-two fluoro-benzyloxies)-phenyl sulfamoyl]-2-methyl-phenylformic acid
82% yield .MS:432.2 (M-1);
1H NMR (400MHz, CD
3OD): δ 2.60 (s, 3H), 5.08 (s, 2H), 6.87 (m, 2H), 6.99 (m, 2H), 7.17 (c, 1H), 7.24 (c, 2H), 7.36 (d, 1H), 7.64 (m, 1H), 8.22 (d, 1H).
Embodiment 211:5-[4-(3,5-two fluoro-benzyloxies)-phenyl sulfamoyl]-2-methyl-phenylformic acid
56% yield .MS:432.2 (M-1);
1H NMR (400MHz, CD
3OD): δ 2.60 (s, 3H), 5.02 (s, 2H), 6.86 (c, 3H), 6.99 (c, 4H), 7.36 (d, 1H), 7.63 (m, 1H), 8.22 (d, 1H).
Embodiment 212:5-[4-(3,4-two fluoro-benzyloxies)-phenyl sulfamoyl]-2-methyl-phenylformic acid
66% yield .MS:432.2 (M-1);
1H NMR (400MHz, CD
3OD): δ 2.60 (s, 3H), 4.97 (s, 2H), 6.85 (c, 2H), 6.97 (c, 2H), 7.17-7.38 (c, 4H), 7.63 (m, 1H), 8.21 (d, 1H).
Embodiment 213:5-[4-(5,7-two fluoro-benzothiazole-2-methylthiol)-phenyl sulfamoyl]-2-methyl-phenylformic acid
19% yield .MS:507.0 (M+1);
1H NMR (400MHz, CD
3OD): δ 2.47 (s, 3H), 4.49 (s, 2H), 7.02 (m, 2H), 7.12 (m, 2H), 7.26 (m, 2H), 7.46 (c, 2H), 7.97 (d, 1H).
Embodiment 214:2-sec.-propyl-5-[4-(6-methyl-benzothiazole-2-yl)-phenyl sulfamoyl]-phenylformic acid
84% yield .MS:467.1 (M+1);
1H NMR (400MHz, CD
3OD): δ 1.21 (d, 6H), 2.47 (s, 3H), 3.81 (m, 1H), 7.28 (m, 2H), 7.32 (m, 1H), 7.60 (d, 1H), 7.75 (s, 1H), 7.82 (d, 1H), 7.92 (c, 3H), 8.20 (d, 1H).
Embodiment 215:2-methyl-5-[4-(5-trifluoromethyl-benzothiazole-2-methylthiol)-phenyl sulfamoyl]-phenylformic acid
17% yield .MS:539.0 (M+1);
1H NMR (400MHz, CD
3OD): δ 2.55 (s, 3H), 4.52 (s, 2H), 7.01 (d, 2H), 7.27 (c, 4H), 7.64 (m, 2H), 8.12 (d, 1H), 8.22 (b, 1H).
Embodiment 216:2-ethyl-5-[4-(6-methyl-benzothiazole-2-yl)-phenyl sulfamoyl]-phenylformic acid
83% yield .MS:453.0 (M+1);
1H NMR (400MHz, CD
3OD): δ 1.18 (t, 3H), 2.47 (s, 3H), 3.01 (q, 2H), 7.27 (m, 2H), 7.32 (m, 1H), 7.45 (d, 1H), 7.84 (m, 2H), 7.93 (m, 2H), 8.32 (d, 1H).
Embodiment 217:2,3-dimethyl-5-[4-(6-methyl-benzothiazole-2-yl)-phenyl sulfamoyl]-phenylformic acid
75% yield .MS:453.0 (M+1);
1H NMR (400MHz, DMSO-D
6): δ 2.30 (s, 3H), 2.38 (s, 3H), 2.42 (s, 3H), 7.26 (m, 2H), 7.31 (m, 1H), 7.76 (s, 1H).
Embodiment 218:2,3-dimethyl-5-[4-(3-trifluoromethyl-benzylthio-)-phenyl sulfamoyl]-phenylformic acid
75% yield .MS:494.2 (M-1);
1H NMR (400MHz, CD
3OD): δ 2.32 (s, 3H), 2.48 (s, 3H), 4.07 (s, 2H), 7.0 (m, 2H), 7.14 (d, 2H), 7.34 (c, 2H), 7.46 (c, 2H), 7.63 (s, 1H), 8.0 (s, 1H).
Embodiment 219:5-[4-(4-ethyl-benzylthio-)-phenyl sulfamoyl]-2,3-dimethyl-phenylformic acid
80% yield .MS:456.3 (M+1);
1H NMR (400MHz, CD
3OD): δ 1.17 (t, 3H), 2.33 (s, 3H), 2.49 (s, 3H), 2.57 (q, 2H), 3.97 (s, 2H), 6.96-7.06 (c, 6H), 7.13 (c, 1H), 7.63 (d, 1H), 8.00 (d, 1H).
Embodiment 220:2-sec.-propyl-5-(4 '-trifluoromethoxy-biphenyl-4-base sulphonamide)-phenylformic acid
37% yield .MS:480.0 (M+1);
1H NMR (400MHz, CD
3OD): δ 1.22 (d, 6H), 3.81 (m, 1H), 7.20 (m, 2H), 7.29 (d, 2H), 7.51 (m, 2H), 7.58 (d, 1H), 7.63 (m, 2H), 7.84 (m, 1H), 8.14 (d, 1H).
Embodiment 221:5-[2-(the 4-tertiary butyl-phenyl)-benzoxazol-5-base sulphonamide]-2-methyl-phenylformic acid
90% yield .MS:465.3 (M+1);
1H NMR (400MHz, CD
3OD): δ 1.37 (s, 9H), 2.58 (s, 3H), 7.13 (m, 1H), 7.37 (d, 1H), 7.43 (d, 1H), 7.53 (d, 1H), 7.61 (m, 2H), 7.72 (m, 1H), 8.11 (m, 2H), 8.27 (d, 1H).
Embodiment 222:5-[4-(3,5-dimethyl-benzylthio-)-phenyl sulfamoyl]-2-methyl-phenylformic acid
74% yield .MS:440.2 (M+1);
1H NMR (400MHz, CD
3OD): δ 2.19 (s, 6H), 2.56 (s, 3H), 3.93 (s, 2H), 6.78 (s, 2H), 6.82 (s, 1H), 6.98 (d, 2H), 7.12 (d, 2H), 7.30 (d, 1H), 7.58 (d, 1H), 8.08 (b, 1H).
Embodiment 223:5-[4-(4-butoxy-benzylthio-)-phenyl sulfamoyl]-2-methyl-phenylformic acid
82% yield .MS:484.2 (M-1);
1H NMR (400MHz, CD
3OD): δ 0.97 (t, 3H), 1.49 (m, 2H), 1.72 (m, 2H), 2.61 (s, 3H), 3.91 (t, 2H), 3.95 (s, 2H), 6.72 (m, 2H), 6.97 (m, 2H), 7.03 (m, 2H), 7.13 (m, 2H), 7.38 (d, 1H), 7.68 (m, 1H), 8.28 (d, 1H).
Embodiment 224:5-[4-(2,3-two fluoro-benzylthio-s)-phenyl sulfamoyl]-2-methyl-phenylformic acid
81% yield .MS:448.2 (M-1);
1H NMR (400MHz, CD
3OD): δ 2.57 (s, 3H), 4.03 (s, 2H), 6.81 (c, 1H), 6.92 (c, 1H), 7.00 (d, 2H), 7.07 (m, 1H), 7.16 (d, 1H), 7.34 (d, 1H), 7.61 (d, 1H), 8.14 (b, 1H).
Embodiment 225:5-[4-(3,5-two fluoro-benzylthio-s)-phenyl sulfamoyl]-2-methyl-phenylformic acid
84% yield .MS:448.2 (M-1);
1H NMR (400MHz, CD
3OD): δ 2.60 (s, 3H), 4.01 (s, 2H), 6.74 (c, 3H), 7.00 (c, 2H), 7.17 (c, 2H), 7.37, (d, 1H), 7.68 (m, 1H), 8.28 (d, 1H).
Embodiment 226:2-methyl-5-[4-(4-trifluoromethylthio-benzylthio-)-phenyl sulfamoyl]-phenylformic acid
84% yield .MS:512.2 (M-1);
1H NMR (400MHz, CD
3OD): δ 2.63 (s, 3H), 4.78 (s, 2H), 6.98 (m, 2H), 7.13 (m, 2H), 7.21 (d, 2H), 7.40 (d, 1H), 7.47 (d, 2H), 7.72 (m, 1H), 8,28 (d, 1H).
Embodiment 227:2,3-dimethyl-5-[4-(3-trifluoromethoxy-benzylthio-)-phenyl sulfamoyl]-phenylformic acid
77% yield .MS:510.2 (M-1);
1H NMR (400MHz, CD
3OD): δ 2.32 (s, 3H), 2.48 (s, 3H), 4.04 (s, 2H), 6.98 (d, 2H), 7.08 (c, 3H), 7.15 (d, 2H), 7.24 (t, 1H), 7.62 (s, 1H), 7.99 (s, 1H).
Embodiment 228:2,3-dimethyl-5-(4 '-trifluoromethoxy-biphenyl-4-base sulphonamide)-phenylformic acid
77% yield .MS:464.2 (M-1);
1H NMR (400MHz, CD
3OD): δ 2.33 (s, 3H), 2.47 (s, 3H), 7.18 (d, 2H), 7.29 (d, 2H), 7.50 (m, 2H), 7.62 (m, 2H), 7.68 (s, 1H), 8.03 (s, 1H).
Embodiment 229:5-[2-(the 4-tertiary butyl-phenyl)-benzoxazol-5-base sulphonamide]-2-ethyl-phenylformic acid
84% yield .MS:479.4 (M+1);
1H NMR (400MHz, CD
3OD): δ 1.17 (t, 3H), 1.37 (s, 9H), 3.00 (q, 2H), 7.13 (m, 1H), 7.42 (m, 2H), 7.53 (d, 1H), 7.61 (m, 2H), 7.75 (m, 1H), 8.11 (m, 2H), 8.23 (d, 1H).
Embodiment 230:2-ethyl-5-[4-(4-trifluoromethoxy-benzylthio-)-phenyl sulfamoyl]-phenylformic acid
67% yield .MS:510.3 (M-1);
1H NMR (400MHz, CD
3OD): δ 1.20 (t, 3H), 2.97 (q, 2H), 4.03 (s, 2H), 7.01 (m, 2H), 7.09 (d, 2H), 7.14 (m, 2H), 7.23 (m, 2H), 7.34 (d, 1H), 7.63 (m, 1H), 8.06 (d, 1H).
Embodiment 231:2,3-dimethyl-5-[4-(4-trifluoromethoxy-benzylthio-)-phenyl sulfamoyl]-phenylformic acid
49% yield .MS:510.2 (M-1);
1H NMR (400MHz, CD
3OD): δ 2.32 (s, 3H), 2.48 (s, 3H), 4.02 (s, 2H), 6.99 (m, 2H), 7.06 (d, 2H), 7.14 (m, 2H), 7.21 (m, 2H), 7.62 (t, 1H), 7.96 (d, 1H).
Embodiment 232:2-ethyl-5-[2-(4-trifluoromethoxy-phenyl)-benzoxazol-5-base sulphonamide]-phenylformic acid
77% yield .MS:507.3 (M+1);
1H NMR (400MHz, CD
3OD): δ 117 (t, 3H), 2.97 (q, 2H), 7.16 (m, 1H), 7.38 (d, 1H), 7.48 (m, 3H), 7.54 (d, 1H), 7.71 (m, 1H), 8.14 (d, 1H), 8.29 (m, 2H).
Embodiment 233:2-ethyl-5-(4 '-trifluoromethoxy-biphenyl-4-base sulphonamide)-phenylformic acid
82% yield .MS:464.2 (M-1);
1H NMR (400MHz, CD
3OD): δ 1.19 (t, 3H), 3.0 (q, 2H), 7.20 (m, 2H), 7.29 (d, 2H), 7.43 (d, 1H), 7.50 (m, 2H), 7.62 (m, 2H), 7.81 (m, 1H), 8.27 (d, 1H).
Embodiment 234:2-sec.-propyl-5-[4-(4-trifluoromethoxy-benzylthio-)-phenyl sulfamoyl]-phenylformic acid
71% yield .MS:524.2 (M-1);
1H NMR (400MHz, CD
3OD): δ 1.23 (d, 6H), 3.75 (m, 1H), 7.02 (m, 2H), 7.09 (d, 2H), 7.15 (m, 2H), 7.23 (m, 2H), 7.51 (d, 1H), 7.71 (m, 1H), 8.01 (d, 1H).
Embodiment 235:2-methyl-5-[2-(4-trifluoromethoxy-phenyl)-benzoxazol-5-base sulphonamide]-phenylformic acid
71% yield .MS:493.2 (M+1);
1H NMR (400MHz, CD
3OD): δ 2.56 (s, 3H), 7.15 (m, 1H), 7.35 (d, 1H), 7.48 (c, 3H), 7.54 (c, 1H), 7.68 (m, 1H), 8.19 (d, 1H), 8.31 (d, 2H).
Embodiment 236:2-ethyl-5-[4-(quinoline-2-methylthiol)-phenyl sulfamoyl]-phenylformic acid
100% yield .MS:479.4 (M+1);
1H NMR (400MHz, CD
3OD): δ 1.20 (t, 3H), 3.03 (q, 2H), 4.5 (d, 2H), 7.01 (m, 2H), 7.20 (m, 2H), 7.42 (d, 1H), 7.78 (c, 2H), 7.93 (m, 1H), 7.99 (d, 1H), 8.12 (m, 1H), 8.23 (d, 1H), 8.26 (d, 1H), 8.94 (d, 1H).
Embodiment 237:2-sec.-propyl-5-[4-(quinoline-2-methylthiol)-phenyl sulfamoyl]-phenylformic acid
96% yield .MS:493.3 (M+1);
1H NMR (400MHz, CD
3OD): δ 1.23 (d, 6H), 3.82 (m, 1H), 4.49 (s, 2H), 7.02 (m, 2H), 7.2 (m, 2H), 7.58 (d, 1H), 7.76 (d, 1H), 7.82 (m, 1H), 7.95 (m, 1H), 8.04 (m, 1H), 8.11, (c 2H), 8.25 (d, 1H), 8.92 (d, 1H).
Embodiment 238:2-ethyl-5-[2-(4-trifluoromethyl-phenyl)-benzoxazol-5-base sulphonamide]-phenylformic acid
85% yield .MS:491.3 (M+1);
1H NMR (400MHz, CD
3OD): δ 1.17 (t, 3H), 3.00 (q, 2H), 7.19 (m, 1H), 7.41 (d, 1H), 7.51 (d, 1H), 7.58 (d, 1H), 7.76 (m, 1H), 7.87 (d, 2H), 8.23 (d, 1H), 8.37 (d, 2H).
Embodiment 239:2-methyl-5-[2-(4-trifluoromethyl-phenyl)-benzoxazol-5-base sulphonamide]-phenylformic acid
92% yield .MS:477.3 (M+1);
1H NMR (400MHz, CD
3OD): δ 2.58 (s, 3H), 7.18 (m, 1H), 7.38 (d, 1H), 7.50 (d, 1H), 7.38 (d, 1H), 7.50 (d, 1H), 7.58 (d, 1H), 7.73 (m, 1H), 7.88 (d, 2H), 8.27 (d, 1H), 8.38 (d, 2H).
Embodiment 240:5-(4-cyclohexyl methylthio group-phenyl sulfamoyl)-2-methyl-phenylformic acid
74% yield .MS:418.0 (M-1);
1H NMR (400MHz, CD
3OD): δ 0.95 (c, 2H), 1.19 (c, 3H), 1.40 (c, 1H), 1.67 (c, 3H), 1.83 (c, 2H), 2.60 (s, 3H), 2.72 (d, 2H), 7.00 (m, 2H), 7.17 (m, 2H), 7.38 (d, 1H), 7.70 (m, 1H), 8.27 (d, 1H).
Embodiment 241:5-(4-cyclobutylmethyl sulfenyl-phenyl sulfamoyl)-2-methyl-phenylformic acid
83% yield .MS:390 (M-1);
1H NMR (400MHz, CDCl
3): δ 1.70 (c, 2H), 1.85 (c, 2H), 2.06 (c, 2H), 2.47 (m, 1H), 2.68 (s, 3H), 2.93 (d, 2H), 6.99 (m, 2), 7.20 (m, 2H), 7.34 (d, 1H), 7.75 (m, 1H), 8.47 (d, 1H).
Embodiment 242:2-sec.-propyl-5-[4-(5-methyl-benzoxazol-2-yl)-phenyl sulfamoyl]-phenylformic acid
89% yield .MS:451.3 (M+1);
1H NMR (400MHz, CD
3OD): δ 1.21 (d, 6H), 2.45 (s, 3H), 3.81 (m, 1H), 7.20 (d, 1H), 7.32 (d, 2H), 7.48 (d, 2H), 7.61 (d, 1H), 7.91 (m, 1H), 8.07 (d, 2H), 8.21 (d, 1H).
Embodiment 243:5-[4-(the 1H-benzimidazolyl-2 radicals-yl)-phenyl sulfamoyl]-2-sec.-propyl-phenylformic acid
94% yield .MS:436.3 (M+1);
1H NMR (400MHz, CD
3OD): δ 1.22 (d, 6H), 3.81 (m, 1H), 7.48 (m, 2H), 7.61 (c, 3H), 7.77 (c, 2H), 8.00 (c, 3H), 8.23 (d, 1H).
Embodiment 244:2-sec.-propyl-5-[4-(3-trifluoromethoxy-benzylthio-)-phenyl sulfamoyl]-phenylformic acid
91% yield .MS:524.3 (M-1);
1H NMR (400MHz, CD
3OD): δ 1.23 (d, 6H), 3.82 (m, 1H), 7.00 (m, 2H), 7.08 (c, 3H), 7.16 (m, 2H), 7.25 (m, 1H), 7.55 (d, 1H), 7.76 (m, 1H), 8.11 (d, 1H).
Embodiment 245:2-ethyl-5-[4-(3-trifluoromethoxy-benzylthio-)-phenyl sulfamoyl]-phenylformic acid
72% yield .MS:510.1 (M-1);
1H NMR (400MHz, CD
3OD): δ 1.20 (t, 3H), 3.03 (q, 2H), 4.04 (s, 2H), 6.99 (m, 2H), 7.08 (c, 3H), 7.16 (m, 2H), 7.25 (m, 1H), 7.40 (d, 1H), 7.73 (m, 1H), 8.24 (d, 1H).
Embodiment 246:2-ethyl-5-(4 '-propoxy--biphenyl-4-base sulphonamide)-phenylformic acid
92% yield .MS:438.3 (M-1);
1H NMR (400MHz, CD
3OD): δ 1.04 (t, 3H), 1.19 (t, 3H), 1.79 (m, 2H), 3.02 (q, 2H), 3.94 (t, 2H), 6.92 (m, 2H), 7.13 (m, 2H), 7.43 (c, 5H), 7.78 (m, 1H), 8.26 (d, 1H).
Embodiment 247:2-sec.-propyl-5-(4 '-propoxy--biphenyl-4-base sulphonamide)-phenylformic acid
93% yield .MS:452.3 (M-1);
1H NMR (400MHz, CD
3OD): δ 1.04 (t, 3H), 1.22 (d, 6H), 1.79 (m, 2H), 3.81 (m, 1H), 3.94 (m, 2H), 6.93 (m, 2H), 7.14 (m, 2H), 7.44 (c, 4H), 7.57 (d, 1H), 7.80 (m, 1H), 8.13 (d, 1H).
Embodiment 248:5-[2-(the 4-tertiary butyl-phenyl)-benzoxazol-5-base sulphonamide]-2-sec.-propyl-phenylformic acid
93% yield .MS:493.4 (M+1);
1H NMR (400MHz, CD
3OD): δ 1.20 (d, 6H), 1.37 (s, 9H), 3.80 (c, 1H), 7.13 (m, 1H), 7.45 (d, 1H), 7.54 (t, 2H), 7.62 (d, 2H), 7.78 (m, 1H), 8.11 (m, 3H).
Embodiment 249:2-methyl-5-[4-(5-trifluoromethyl-pyridine-2-base carbamyl)-phenyl sulfamoyl]-phenylformic acid
2% yield (material lost) .MS:478.0 (M-1);
1H NMR (400MHz, CD
3OD): δ 2.49 (s, 3H), 7.19 (d, 1H), 7.28 (m, 4H), 7.67 (m, 1H), 7.85 (m, 2H), 8.05 (m, 2H).
Embodiment 250:5-[4-(5-cyclohexyl-[1,3,4] diazole-2-yl)-phenyl sulfamoyl]-2-methyl-phenylformic acid
86% yield MS:442.0 (M+1);
1H NMR (400MHz, CDCl
3): δ 1.15-1.4 (c, 3H), 1.49-1.7 (c, 3H), 1.76 (c, 2H), 2.02 (c, 2H), 2.53 (s, 3H), 2.86 (c, 1H), 7.20 (m, 3H), 7.73 (m, 3H), 8.39 (d, 1H).
Embodiment 259:2-methyl-5-[(4 '-propoxy--biphenyl-4-yl)-propyl group-sulphonamide]-benzoic acid methyl ester
Under nitrogen, with 5-[(4 '-hydroxyl-biphenyl-4-yl)-propyl group-sulphonamide]-2-methyl-benzoic acid methyl ester (100mg, 0.25mmol), (36.7 μ l, 0.38mmol) (52mg, 38mmol) mixture in 5ml acetone is 56 ℃ of following heated overnight with salt of wormwood for propyl iodide.Add other propyl iodide (35.7 μ l, 0.38mmol), under nitrogen with mixture 56 ℃ of following heated overnight.Then reaction mixture is cooled to room temperature, with the dilution of 40ml ethyl acetate.Ethyl acetate solution is successively used 30ml water and the water washing of 30ml salt, and dry (anhydrous sodium sulphate) under reduced pressure concentrates.Resistates is through preparation type thick layer chromatography purifying (silica gel), with 3: 1 toluene/ethyl acetate wash-outs, obtain title compound, be pale solid (21mg, 17% yield), and 5-[(4 '-hydroxyl-biphenyl-4-yl)-propyl group-sulphonamide]-2-methyl-benzoic acid methyl ester (64mg, 58% yield).
MS:482.2 (M+1) 2-methyl-5-[(4 '-propoxy--biphenyl-4-yl)-propyl group-sulphonamide]-benzoic acid methyl ester
MS:440.1 (M+1) 5-[(4 '-hydroxyl-biphenyl-4-yl)-propyl group-sulphonamide]-2-methyl-benzoic acid methyl ester
Embodiment 260:2-sec.-propyl-5-[propyl group-(4 '-trifluoromethoxy-biphenyl-4-yl)-sulphonamide]-benzoic acid methyl ester
Utilization is similar to the prepared title compound of embodiment 257, but is to use 2-sec.-propyl-5-(4 '-trifluoromethoxy-biphenyl-4-base sulphonamide)-benzoic acid methyl ester to replace 5-[(4 '-hydroxyl-biphenyl-4-yl)-propyl group-sulphonamide]-2-methyl-benzoic acid methyl ester.80% yield.MS：564.2(M+1).
Embodiment 261:4-(5-methyl-benzoxazol-2-yl)-phenyl amine
Under nitrogen, with 2-amino-p-Cresol (1.5g, 12mmol), the 4-benzaminic acid (1.67g, 12mmol) with the mixture of 40g Tripyrophosphoric acid 190 ℃ of heating 6 hours down.Reaction mixture is cooled to room temperature, adds 300ml water to viscous liquid.Filter and collect institute's precipitated solid, be dissolved in the 200ml ethyl acetate.Ethyl acetate solution is successively used 100ml saturated sodium bicarbonate aqueous solution, 100ml water and the water washing of 100ml salt, and dry (anhydrous sodium sulphate) under reduced pressure concentrates, and obtains title compound, is pale solid (2.43g, 89% yield).MS：225.0(M+1)
From suitable raw material, utilize the prepared embodiment 262-268 title compound that is similar to embodiment 261.
| Ex. | Chemical name | Data |
| 262 | 4-benzoxazol-2-base-phenyl amine | 85% yield. MS:211.1 (M+1) |
| 263 | 4-(5-phenyl-benzoxazol-2-yl)-phenyl amine | 92% yield. MS:287.2 (M+1) |
| 264 | 4-(5-chloro-benzoxazol-2-yl)-phenyl amine | 77% yield. MS:245.1 (M+1) |
| 265 | 4-benzothiazole-2-base-phenyl amine | 59% yield. MS:227.2 (M+1) |
| 266 | 4-(the 1H-benzimidazolyl-2 radicals-yl)-phenyl amine | 79% yield. MS:210.2 (M+1) |
| 267 | 3-(5-methyl-benzoxazol-2-yl)-phenyl amine | 83% yield. MS:225.1 (M+1) |
| 268 | 3-benzothiazole-2-base-phenyl amine | 39% yield. MS:227.1 (M+1) |
Embodiment 269:4-(4-trifluoromethyl-benzyloxy)-phenyl amine
To para-aminophenol (0.200g, 1.83mmol), the 4-trifluoromethyl-benzyl-alcohol (0.25ml, 1.83mmol) with triphenyl phosphine (0.529g, 2.02mmol) 5ml anhydrous tetrahydrofuran solution add the diethylazodicarboxylate (0.318ml, 2.02mmol).Under nitrogen, reaction mixture at room temperature stirred and spend the night.With the dilution of 70ml ethyl acetate, gained solution is successively used 50ml saturated sodium bicarbonate aqueous solution, 50ml water and the water washing of 50ml salt then, dry (anhydrous sodium sulphate) under reduced pressure concentrates.(silica gel 15g), with 8: 2 hexane/ethyl acetate wash-outs, obtains title compound to solid residue, is pale solid (0.272g, 55% yield) through the flash column chromatography purifying.MS：284.1(M+1)
From suitable raw material, utilize the prepared embodiment 270-276 title compound that is similar to embodiment 269.
| Ex. | Chemical name | Data |
| 270 | 4-(3,5-dimethyl-benzyloxy)-phenyl amine | 21% yield. MS:228.3 (M+1) |
| 271 | 4-(4-butoxy-benzyloxy)-phenyl amine | 19% yield. MS:272.4 (M+1) |
| 272 | 4-(2-chloro-4-fluoro-benzyloxy)-phenyl amine | 27% yield. MS:252.2 (M+1) |
| 273 | 4-(2,3-two fluoro-benzyloxies)-phenyl amine | 29% yield. MS:236.2 (M+1) |
| 274 | 4-(3,5-two fluoro-benzyloxies)-phenyl amine | 19% yield. MS:236.2 (M+1) |
| 275 | 4-(3,4-two fluoro-benzyloxies)-phenyl amine | 29% yield. MS:236.2 (M+1) |
| 276 | 4-(4-trifluoromethoxy-benzyloxy)-phenyl amine | 26% yield. MS:284.2 (M+1) |
Embodiment 277:4-(4-trifluoromethyl-benzylthio-)-phenyl amine
Sodium hydride [0.153g (50% mineral oil dispersion), 3.2mmol] is joined the 4-aminothiophenol, and (0.20g is in 5ml anhydrous tetrahydrofuran solution 1.6mmol).Under nitrogen, the gained mixture was at room temperature stirred 15 minutes, add then the 4-trifluoromethyl benzyl chloride (0.236ml, 1.6mmol).Under nitrogen, reaction mixture at room temperature stirred and spend the night.Add entry (50ml) then, the gained mixture is with 2 * 50ml ethyl acetate extraction.The combined ethyl acetate extraction liquid is successively used 60ml saturated sodium bicarbonate aqueous solution, 60ml water and the water washing of 60ml salt, and dry (anhydrous sodium sulphate) under reduced pressure concentrates.(silica gel 15g), with 85: 15 hexane/ethyl acetate wash-outs, obtains title compound to solid residue, is pale solid (0.318g, 70% yield) through the flash column chromatography purifying.MS：284.1(M+1)
From suitable raw material, utilize the prepared embodiment 278-304 title compound that is similar to embodiment 277.
| Ex. | Chemical name | Data |
| 277 | 3-(4-trifluoromethyl-benzylthio-)-phenyl amine | 66% yield. MS:284.1 (M+1) |
| 278 | 4-(3-trifluoromethyl-benzylthio-)-phenyl amine | 58% yield. MS:284.1 (M+1) |
| 279 | 4-(the 4-tertiary butyl-benzylthio-)-phenyl amine | 42% yield. MS:272.2 (M+1) |
| 280 | 4-(4-sec.-propyl-benzylthio-)-phenyl amine | 56% yield. MS:258.2 (M+1) |
| 281 | 4-(4-trifluoromethoxy-benzylthio-)-phenyl amine | 46% yield. MS:300.1 (M+1) |
| 282 | 4-(4-chloro-benzylthio-)-phenyl amine | 45% yield. 250.1 (M+1) |
| 283 | 4-(4-ethyl-benzylthio-)-phenyl amine | 45% yield. MS:244.1 (M+1) |
| 284 | 4-(4-phenyl-benzylthio-)-phenyl amine | 21% yield. MS:292.1 (M+1) |
| 285 | 4-(3-phenoxy group-benzylthio-)-phenyl amine | 50% yield. MS:308.1 (M+1) |
| 286 | 4-[2-(4-chloro-phenyl)-thiazole-4-methylthiol]-phenyl amine | 25% yield. MS:333.1 (M+1) |
| 287 | 4-(quinoline-2-methylthiol)-phenyl amine | 53% yield. MS:267.1 (M+1) |
| 288 | 4-(5-phenyl-[1,2,4] azoles-3-methylthiol)-phenyl amine | 46% yield. MS:284.2 (M+1) |
| 289 | 4-(naphthalene-2-methylthiol)-phenyl amine | 53% yield. MS:266.3 (M+1) |
| 290 | 4-(4-fluoro-benzylthio-)-phenyl amine | 41% yield. MS:234.3 (M+1) |
| 291 | 4-(3,4-two fluoro-benzylthio-s)-phenyl amine | 66% yield. MS:252.2 (M+1) |
| 292 | 4-(3,5-couple-trifluoromethyl-benzylthio-)-phenyl amine | 45% yield. MS:352.2 (M+1) |
| 293 | 4-(3-trifluoromethyl-benzylthio-)-phenyl amine | 22% yield. MS:284.3 (M+1) |
| 294 | 4-(3,4-dimethyl-benzylthio-)-phenyl amine | 84% yield. MS:244.3 (M+1) |
| 295 | 4-(2,4-couple-trifluoromethyl-benzylthio-)-phenyl amine | 39% yield. MS:251.3 (M+1) |
| 296 | 4-(2-chloro-4-fluoro-benzylthio-)-phenyl amine | 65% yield. MS:268.2 (M+1) |
| 297 | 4-(5,6-two fluoro-benzothiazole-2-methylthiol)-phenyl amine | 22% yield. MS:309.2 (M+1) |
| 298 | 4-(5-fluoro-benzothiazole-2-methylthiol)-phenyl amine | 38% yield. MS:291.1 (M+1) |
| 299 | 4-(5,7-two fluoro-benzothiazole-2-methylthiol)-phenyl amine | 36% yield. MS:309.0 (M+1) |
| 300 | 4-(5-trifluoromethyl-benzothiazole-2-methylthiol)-phenyl amine | 17% yield. MS:341.2 (M+1) |
| 301 | 4-(3-trifluoromethoxy-benzylthio-)-phenyl amine | 39% yield. MS:300.1 (M+1) |
| 302 | 4-(4-cyclohexyl methylthio group)-phenyl amine | 49% yield. MS:222.1 (M+1) |
| 303 | 4-(2-trifluoromethoxy-benzylthio-)-phenyl amine | 43% yield. MS:300.3 (M+1) |
Embodiment 305:4-(3,5-dimethyl-benzylthio-)-oil of mirbane
To the 4-nitro thiophenol (0.400g, 2.57mmol), 3, the 5-dimethyl benzyl alcohol (0.38ml, 2.57mmol) with triphenyl phosphine (0.743g, 10ml anhydrous tetrahydrofuran solution 2.84mmol) add the diethylazodicarboxylate (0.446ml, 2.84mmol).Under nitrogen, reaction mixture at room temperature stirred and spend the night.With the dilution of 90ml ethyl acetate, gained solution is successively used 70ml saturated sodium bicarbonate aqueous solution, 70ml water and the water washing of 70ml salt then, dry (anhydrous sodium sulphate) under reduced pressure concentrates.Solid residue with the development of 95: 5 hexane/ethyl acetate (20ml), is filtered.Concentrated filtrate under reduced pressure, (silica gel 15g), with 95: 5 hexane/ethyl acetate wash-outs, obtains title compound to resistates, is yellow solid (0.35g, 50% yield) through the column chromatography purifying.
1H NMR(400MHz，CD
3Cl)：δ2.30(s，6H)，4.18(s，2H)，6.92(s，1H)，7.0(s，2H)，7.33(d，2H)，8.10(d，2H).
From suitable raw material, utilize the prepared embodiment 306-309 title compound that is similar to embodiment 305.
Embodiment 306:4-(4-butoxy-benzylthio-)-oil of mirbane
26% yield
1H NMR (400MHz, CD
3Cl): δ 0.97 (t, 3H), 1.4-1.53 (c, 2H), 1.7-1.8 (c, 2H), 3.95 (m, 2H), 4.2 (s, 2H), 6.85 (d, 2H), 7.27 (d, 2H), 7.33 (d, 2H), 8.1 (d, 2H).
Embodiment 307:4-(2,3-two fluoro-benzylthio-s)-oil of mirbane
55% yield.
1H NMR (400MHz, CD
3Cl): δ 4.28 (s, 2H), 7.0-7.16 (c, 3H), 7.37 (d, 2H), 8.13 (d, 2H).
Embodiment 308:4-(3,5-two fluoro-benzylthio-s)-oil of mirbane
33% yield.
1H NMR (400MHz, CD
3Cl): δ 4.20 (s, 2H), 6.73 (m, 2H), 6.92 (m, 2H), 7.32 (m, 2H), 8.12 (m, 2H).
Embodiment 309:4-(4-trifluoromethylthio-benzylthio-)-oil of mirbane
55% yield.MS：344.1(M-1).
From suitable raw material, but be to use 4-nitrophenols or 3-nitrophenols to replace the 4-nitro thiophenol, utilize the prepared embodiment 310-312 title compound that is similar to embodiment 305.
Embodiment 310:4-[2-(4-nitro-phenoxy group)-ethyl]-2-(4-trifluoromethoxy-phenyl)-thiazole
78% yield.MS：411.1(M+1)
Embodiment 311:4-[2-(4-nitro-phenoxy group)-ethyl]-2-(4-trifluoromethyl-phenyl)-thiazole
70% yield.MS：395.1(M+1)
Embodiment 312:3-(4-trifluoromethyl-benzyloxy)-oil of mirbane
22% yield.MS：296.1(M-1)
Embodiment 313:4-(4-tertiary butyl phenoxy group) oil of mirbane
At room temperature, (0.5g is in 5ml dimethyl formamide solution 3.33mmol) sodium hydride [0.16g (50% mineral oil dispersion), 3.33mmol] to be joined the 4-tert.-butyl phenol.Add after 15 minutes 1-chloro-4-oil of mirbane (0.262g, 1.66mmol), with reaction mixture 80 ℃ of following heated overnight.Reaction mixture is cooled to room temperature, with the dilution of 50ml ethyl acetate.Ethyl acetate solution is successively used 3 * 40ml water and the water washing of 40ml salt, and dry (anhydrous sodium sulphate) under reduced pressure concentrates.Crude product (0.9g) with 98: 2 hexane/ethyl acetate wash-outs, obtains title compound through flash column chromatography purifying (15g silica gel), is yellow solid (0.499g, quantitative yield).
1H NMR(400MHz，CD
3Cl)：δ1.35(s，9H)，7.0(d，2H)，7.43(d，2H)，8.19(d，2H).
Embodiment 314:4-(3,5-dimethyl-benzylthio-)-phenyl amine
Under nitrogen, with 4-(3,5-dimethyl-benzylthio-)-oil of mirbane (0.35g, 1.28mmol), calcium chloride (0.071g, 0.64mmol) (0.573g, 10.3mmol) mixture in 4ml water and 17ml ethanol heated 4.5 hours under refluxing with iron powder (～325 order).Then reaction mixture is cooled to room temperature, filters by C salt, under reduced pressure concentrated filtrate.Remaining oil with 9: 1 hexane/ethyl acetate wash-outs, obtains title compound through the column chromatography purifying, is xanchromatic oil (0.29g, 91% yield).MS：244.3(M+1)
From suitable raw material, utilize the prepared embodiment 315-327 title compound that is similar to embodiment 314.
Embodiment 315:4-(4-butoxy-benzylthio-)-phenyl amine
80% yield.
1H NMR (400MHz, CD
3Cl): δ 0.96 (m, 3H), 1.4-1.52 (c, 2H), 1.7-1.8 (c, 2H), 3.85-3.96 (m, 4H), 6.57 (d, 2H), 6.77 (d, 2H), 7.07 (d, 2H), 7.13 (d, 2H).
| Ex. | Chemical name | Data |
| 304 | 4-(2,3-two fluoro-benzylthio-s)-phenyl amine | 91% yield. MS:252.2 (M+1) |
| 305 | 4-(3,5-two fluoro-benzylthio-s)-phenyl amine | 84％yield. MS：252.2(M+1) |
| 306 | 4-(4-trifluoromethylthio-benzylthio-)-phenyl amine | 88% yield. MS:316.1 (M+1) |
| 307 | 4 '-propoxy--biphenyl-4-base amine | 55% yield. MS:228.3 (M+1) |
| 308 | 4-(5-cyclohexyl-[1,3,4] diazole-2-yl)-phenyl amine | 29% yield. MS:244.2 (M+1) |
| 309 | 2-(the 4-tertiary butyl-phenyl)-benzoxazol-5-base amine | 97% yield. MS:267.3 (M+1) |
| 310 | 2-(4-trifluoromethoxy-phenyl)-benzoxazol-5-base amine | 99% yield. MS:295.3 (M+1) |
| 311 | 2-(4-trifluoromethyl-phenyl)-benzoxazol-5-base amine | 90% yield. MS (279.3 (M+1) |
| 312 | 4-{2-[2-(4-trifluoromethoxy-phenyl)-thiazole-4-yl]-oxyethyl group }-phenyl amine | 90% yield. MS:381.2 (M+1) |
| 313 | 4-{2-[2-(4-trifluoromethyl-phenyl)-thiazole-4-yl]-oxyethyl group }-phenyl amine | 70% yield. MS:365.2 (M+1) |
| 314 | 4-(the 4-tertiary butyl-phenoxy group)-phenyl amine | 80% yield. MS:242.4 (M+1) |
| 315 | 3-(4-trifluoromethyl-benzyloxy)-phenyl amine | 77% yield. MS:268.1 (M+1) |
Embodiment 328:4 '-trifluoromethoxy-biphenyl-4-base amine
Under nitrogen, with the 4-Trifluoromethyl phenyl ether for boric acid (300mg, 1.45mmol), right-bromaniline (100mg, 0.58mmol), dichloro [1,1 '-two (diphenyl phosphine) ferrocene] palladium (II) methylene dichloride adducts (24mg, 0.029mmol), 1,1 '-two (diphenyl phosphine) ferrocene (16mg, 0.029mmol) (the 0.58ml 2M aqueous solution, 1.16mmol) at 5ml 1, the mixture in the 4-two alkane heats 20hr under refluxing with salt of wormwood.Reaction mixture is cooled to room temperature, with the dilution of 40ml water, with 2 * 40ml ethyl acetate extraction.The combined ethyl acetate extraction liquid with the water washing of 40ml salt, through anhydrous sodium sulfate drying, under reduced pressure concentrates.(silica gel 15g), with 10: 1 hexane/ethyl acetate wash-outs, obtains title compound to crude product, is tawny solid (70mg, 48% yield) through the flash column chromatography purifying.MS：254.1(M+1)
Embodiment 329:2-cyclohexyl-5-(4-nitro-phenyl)-[1,3,4] diazole
Under nitrogen, with 5-(4-nitro-phenyl)-1H-tetrazolium (0.5g, 2.62mmol) with the hexanaphthene carbonyl chloride (0.35ml, 2.62mmol) mixture in the 3ml anhydrous pyridine at room temperature stirs 20min, be heated to 60 ℃ then and reach 1 hour, be heated to 100 ℃ at last and reach 2 hours.Reaction mixture is cooled to room temperature, is poured on the ice (30g) aqueous mixture 30ml ethyl acetate extraction then.Ethyl acetate solution is successively used 30ml water, 30ml 1N aqueous hydrochloric acid and the water washing of 30ml salt, and dry (anhydrous sodium sulphate) under reduced pressure concentrates.(silica gel 40g), with 4: 1 hexane/ethyl acetate wash-outs, obtains title compound to crude product, is yellow solid (0.5g, 100% yield) through the flash column chromatography purifying.MS：274.2(M+1)
Embodiment 330:4-nitro-4 '-propoxy-biphenyl
To the 5ml of 4-hydroxyl-4 '-nitrobiphenyl acetone soln add salt of wormwood (240mg, 1.74mmol) and propyl iodide (0.17ml, 1.74mmol).Reaction mixture was heated 24 hours under refluxing.Add other salt of wormwood (240mg, 1.74mmol) and propyl iodide (0.17ml, 1.74mmol), with reaction mixture heating 24 hours under refluxing.Reaction mixture is cooled to room temperature, with the dilution of 30ml ethyl acetate.Ethyl acetate solution is successively used 25ml water and the water washing of 25ml salt, and dry (anhydrous sodium sulphate) under reduced pressure concentrates.Crude product with 14: 1 hexane/ethyl acetate wash-outs, obtains title compound (0.267g, 89% yield) through column chromatography purifying (silica gel).MS 258.3(M-1)
Embodiment 331:2-(the 4-tertiary butyl-phenyl)-5-nitro-benzoxazol
The 4-tertiary butyl-N-(2-hydroxyl-5-nitro-phenyl)-benzamide
When stirring, (2.62g, 21.4mmol) join 4-tert.-butylbenzene formyl chloride (3.8ml, 19.5mmol) (3.0g is in 60ml METHYLENE CHLORIDE solution 19.5mmol) with 2-amino-4-nitrophenols in batches with the 4-Dimethylamino pyridine.Gained solution at room temperature stirred spend the night.Reaction soln is diluted with the 60ml METHYLENE CHLORIDE, with 3 * 50ml water washing.Separate METHYLENE CHLORIDE solution, remove by filter institute's precipitated solid, dry (anhydrous sodium sulphate) under reduced pressure is concentrated into driedly, obtains title compound, is brown solid (5.01g, 82% yield).
2-(the 4-tertiary butyl-phenyl)-5-nitro-benzoxazol
When stirring, with diethylazodicarboxylate (0.275ml, 1.75mmol) (0.5g, 1.59mmol) (0.458g is in 15ml anhydrous tetrahydrofuran solution 1.75mmol) with triphenyl phosphine to be added drop-wise to the 4-tertiary butyl-N-(2-hydroxyl-5-nitro-phenyl)-benzamide.Reaction mixture at room temperature stirred spend the night, then with the dilution of 75ml ethyl acetate.Ethyl acetate solution is successively used 50ml water and the water washing of 50ml salt, and dry (anhydrous sodium sulphate) under reduced pressure is concentrated into dried.Resistates is through flash column chromatography purifying (40g silica gel), with 9: 1 hexane/ethyl acetate wash-outs, obtain yellow solid (0.305g), further pass through column chromatography purifying (15g silica gel), with 95: 5 hexane/ethyl acetate wash-outs, obtain title compound, be yellow solid (0.125g, 27% yield).MS：297.3(M+1)
From suitable raw material, utilize the prepared embodiment 332-333 title compound that is similar to embodiment 331.
Embodiment 332:2-(4-trifluoromethoxy-phenyl)-5-nitro-benzoxazol
4-trifluoromethoxy-N-(2-hydroxyl-5-nitro-phenyl)-benzamide
100% yield
2-(4-trifluoromethoxy-phenyl)-5-nitro-benzoxazol
66% yield.MS：325.2(M+1)
Embodiment 333:2-(4-trifluoromethoxy-phenyl)-5-nitro-benzoxazol
4-trifluoromethyl-N-(2-hydroxyl-5-nitro-phenyl)-benzamide
83% yield
2-(4-trifluoromethyl-phenyl)-5-nitro-benzoxazol
93% yield.MS：309.3(M+1).
Embodiment 334:5-chlorosulfonyl-2-methyl-phenylformic acid
Under nitrogen, (15g, 0.11mol) mixture with chlorsulfonic acid (30ml) heats 2.5h down at 100 ℃ with neighbour-toluic acid.Then reaction mixture is poured on the ice (500ml), filters the gained precipitation, obtain title compound, be pale solid (20g, 78% yield).MP151-155℃。
From suitable raw material, utilize the prepared embodiment 335-337 title compound that is similar to embodiment 334.
Embodiment 335:3-chlorosulfonyl-2,6-dimethyl-phenylformic acid
28% yield.
1H NMR (400MHz, CD
3OD) δ 2.44 (s, 3H), 2.72 (s, 3H), 7.41 (d, 1H), 8.02 (d, 1H),
Embodiment 336:5-chlorosulfonyl-2,3-dimethyl-phenylformic acid
77% yield.
1H NMR (400MHz, CDCl
3) δ 2.49 (s, 3H), 2.66 (s, 3H), 7.98 (s, 1H), 8.47 (s, 1H).
Embodiment 337:5-chlorosulfonyl-2-ethyl-phenylformic acid
76% yield.MS：247.0(M-1).
Embodiment 338:5-chlorosulfonyl-2-methyl-benzoic acid methyl ester
Under nitrogen, when stirring, with chlorsulfonic acid (106.2ml) go through 1min join carefully 2-methyl-benzoic acid methyl ester (55.9ml, 0.4mol) in.Place the oil bath that preheats to 100 ℃ to reach 15min reaction mixture, be poured on then on the ice (1000ml).Filtration gained precipitation is dissolved in ethyl acetate (400ml).Ethyl acetate solution is successively used 10 * 300ml saturated sodium bicarbonate aqueous solution, 300ml water and the water washing of 300ml salt, and dry (anhydrous sodium sulphate) under reduced pressure concentrates, and obtains title compound, is xanchromatic oil (37.3g, 37% yield).
1H NMR(400MHz，CDCl
3)δ，2.74(s，3H)，3.96(s，3H)，7.52(d，1H)，8.04(m，1H)，8.58(d，1H).
From suitable raw material, utilize the prepared embodiment 339-343 title compound that is similar to embodiment 338.
Embodiment 339:5-chlorosulfonyl-2-ethyl-benzoic acid methyl ester
42% yield.
1H NMR (400MHz, CDCl
3) δ 1.29 (t, 3H), 3.11 (q, 2H), 3.96 (s, 3H), 7.54 (d, 1H), 8.06 (m, 1H), 8.53 (d, 1H).
Embodiment 340:5-chlorosulfonyl-2-sec.-propyl-benzoic acid methyl ester
47% yield.
1H NMR (400MHz, CDCl
3) δ 1.3 (d, 6H), 3.87 (m, 1H), 3.96 (s, 3H), 7.67 (d, 1H), 8.08 (m, 1H), 8.41 (d, 1H).
Embodiment 341:5-chlorosulfonyl-2,3-dimethyl-benzoic acid methyl ester
41% yield.
1H NMR (400MHz, CDCl
3) δ 2.45 (s, 3H), 2.58 (s, 3H), 3.95 (s, 3H), 7.92 (d, 1H), 8.31 (d, 1H).
Embodiment 342:5-chlorosulfonyl-2-oxyethyl group-phenylformic acid ethyl ester
10% yield.
1H NMR (400MHz, CDCl
3) d 1.43 (t, 3H), 1.52 (t, 3H), 4.24 (q, 2H), 4.40 (q, 2H), 7.10 (d, 1H), 8.09 (m, 1H), 8.43 (d, 1H).
Embodiment 343:5-chlorosulfonyl-2-methylthio group-benzoic acid methyl ester
58% yield.
1H NMR (400MHz, CDCl
3) d 2.55 (s, 3H), 3.98 (s, 3H), 7.47 (d, 1H), 8.05 (m, 1H), 8.64 (d, 1H).
The application is with reference to many parts of publications.For the open full text of any these publications of purpose in conjunction with in this application as a reference.
To be it is evident that by those skilled in the art, and can carry out various modifications and variations in the present invention, and not deviate from scope of the present invention or spirit.In view of invention disclosed herein explanation and enforcement, other invention embodiments also will be apparent for those skilled in the art institute.It only is exemplary that these explanations and embodiment should be regarded as, and true scope of the present invention and spirit are indicated by following claim.
Claims (15)
1, formula I compound
Formula 1
The perhaps prodrug of described compound, the pharmacy acceptable salt of perhaps described compound or prodrug, wherein
Q is a carbon;
Each R
1Be hydrogen, halogeno-group, optional independently by one or more halogeno-groups or (C
1-C
3) (the C that replaces of alkoxyl group
1-C
5) alkyl, optional by the (C of one to 11 halogeno-group replacement
1-C
5) alkoxyl group, the optional (C that is replaced by one or more halogeno-groups
1-C
5) alkylthio, perhaps R
1Unite formation C with two adjacent carbon atoms
5-C
6Condensed, saturated fully, part is unsaturated or fully undersaturated five or six-membered carbon ring, wherein each carbon in this carbochain can be replaced by a heteroatoms that is selected from oxygen and sulphur alternatively;
R
2Be hydrogen or optional quilt (C
1-C
3) (the C that replaces of alkoxyl group
1-C
5) alkyl;
X is-COOR
4,-O-(CR
3 2)-COOR
4,-S-(CR
3 2)-COOR
4,-CH
2-(CR
5 w)-COOR
4, 1H-tetrazolium-5-base-E-or thiazolidinedione-5-base-G-; Wherein w is 0,1 or 2; E is (CH
2)
r, r is 0,1,2 or 3; G is (CH
2)
sOr methylene radical, s is 0 or 1;
Each R
3Be hydrogen, optional independently by one to nine halogeno-group or by the optional (C that is replaced by one or more halogeno-groups
1-C
3) (the C that replaces of alkoxyl group
1-C
4) alkyl, perhaps R
3The carbon that is connected with it constitutes 3,4,5 or 6 yuan of carbocyclic rings;
R
4Be H, (C
1-C
4) alkyl, benzyl or to nitrobenzyl;
Each R
5Be hydrogen, optional independently by one to nine halogeno-group or by (C
1-C
3) (the C that replaces of alkoxyl group
1-C
4) alkyl, optional by the (C of one to nine halogeno-group replacement
1-C
4) alkoxyl group, optional by one to nine halogeno-group or by (C
1-C
3) (the C that replaces of alkoxyl group
1-C
4) alkylthio, perhaps R
5The carbon that is connected with it constitutes 3,4,5 or 6 yuan of carbocyclic rings, and wherein any carbon of 5-or 6-unit ring can be replaced by Sauerstoffatom;
Ar
1Be phenyl or be selected from following member's condensed phenyl: thiazolyl, furyl, azoles base, pyridine, pyrimidine, phenyl or thienyl, wherein Ar
1Alternatively by following groups single independently-, two-or three-replace: halogeno-group, the optional (C that is replaced by one to nine halogeno-group
1-C
3) alkyl, optional by the (C of one to nine halogeno-group replacement
1-C
3) alkoxyl group or the optional (C that is replaced by one to nine halogeno-group
1-C
3) alkylthio;
B is a key, CO, (CY
2)
n, CYOH, CY=CY ,-L-(CY
2)
n-,-(CY
2)
n-L-,-L-(CY
2)
2-L-, NY-OC-,-CONY-,-SO
2NY-,-NY-SO
2-, wherein each L is O, S, SO or SO independently
2, each Y is hydrogen or (C independently
1-C
3) alkyl, n is 0,1,2 or 3;
Ar
2Be a key, phenyl, phenoxy benzyl, Phenoxyphenyl, benzyloxy phenyl, benzyloxy benzyl, pyrimidyl, pyridyl, pyrazolyl, imidazolyl, thiazolyl, thiadiazolyl group, azoles base, di azoly or be selected from following ring condensed phenyl: phenyl, pyrimidyl, thienyl, furyl, pyrryl, thiazolyl, azoles base, pyrazolyl and imidazolyl;
Each J is hydrogen, hydroxyl, halogeno-group, the optional (C that is replaced by one to 11 halogeno-group independently
1-C
8) alkyl, optional by the (C of one to 11 halogeno-group replacement
1-C
8) alkoxyl group, optional by the (C of one to 11 halogeno-group replacement
1-C
8) alkylthio, (C
3-C
7) cycloalkyl, (C
3-C
7) cycloalkyloxy, (C
3-C
7) cycloalkylthio or optional by one to four phenyl that is selected from following substituting group replacement: halogeno-group, the optional (C that is replaced by one to five halogeno-group
1-C
3) alkyl, optional by the (C of one to five halogeno-group replacement
1-C
3) alkoxyl group, optional by the (C of one to five halogeno-group replacement
1-C
3) alkylthio;
P and q are 0,1,2 or 3 independently of one another;
Its condition is:
If a) Ar
1Be phenyl, B is a key, Ar
2Be a key or phenyl, X is-COOH, and q is not 0 so, and J is not hydrogen, halogeno-group, (C
1-C
8) alkyl or unsubstituted phenyl;
B) if Ar
1Be phenyl, B is not a key, Ar
2Be phenyl, X is-COOR
4, B is connected Ar so
1Last NR
2Contraposition;
C) if B is O, S, SO, NH, CO, CH
2Or SO
2, R so
1Not H.
2, according to the compound of claim 1, wherein p is 1 or 2, R
1With the Q bonding.
3, according to the compound of claim 1 or 2, Ar wherein
1Be:
Ar wherein
1Be singly alternatively-or two-replace.
4, according to any claim 1,2 or 3 compound, wherein Ar
2Be:
5, according to the compound of claim 1 or 2, wherein:
Ar
1Be phenyl or with azoles base or thiazolyl condensed phenyl;
Ar
2Be phenyl or be selected from following ring condensed phenyl: phenyl, pyridyl, thienyl, thiazolyl, azoles base and imidazolyl.
6, according to the compound of claim 1 or 2, wherein:
X is-COOR
4
B be a key ,-L-(CY
2)
n-or-(CY
2)
n-L-, L are O or S, and n is 0,1 or 2;
Ar
1Be phenyl or with azoles base or thiazolyl condensed phenyl;
Ar
2Be phenyl or be selected from following ring condensed phenyl: phenyl, pyridyl, thienyl, thiazolyl, azoles base and imidazolyl.
7, according to the compound of claim 6, wherein:
Ar
1Be
Ar
2Be
8, according to the compound of claim 7, wherein q is 1 or 2, and each J is halogeno-group, the optional (C that is replaced by one to three halogeno-group independently
1-C
3) alkyl or the optional (C that is replaced by one to three halogeno-group
1-C
3) alkoxyl group.
9, compound according to Claim 8, wherein p is 1, R
4Be H or (C
1-C
3) alkyl.
10, according to the compound of any claim 6-9, wherein L is S, and n is 1, and halogeno-group is a fluorine.
11, be selected from down the compound of group:
2-methyl-5-[4-(5-methyl-benzoxazol-2-yl)-phenyl sulfamoyl] phenylformic acid;
5-[4-(5-chloro-benzoxazol-2-yl)-phenyl sulfamoyl]-2-methyl-phenylformic acid;
2-methyl-5-[4-(4-trifluoromethyl-benzylthio-)-phenyl sulfamoyl]-phenylformic acid;
5-[4-(the 4-tertiary butyl-benzylthio-)-phenyl sulfamoyl]-2-methyl-phenylformic acid;
2-ethyl-5-[4-(5-methyl-benzoxazol-2-yl)-phenyl sulfamoyl]-phenylformic acid;
5-[4-(4-ethyl-benzylthio-)-phenyl sulfamoyl]-2-methyl-phenylformic acid;
5-[4-(3,4-two fluoro-benzylthio-s)-phenyl sulfamoyl]-2-methyl-phenylformic acid;
5-[4-(3,4-dimethyl-benzylthio-)-phenyl sulfamoyl]-2-methyl-phenylformic acid;
5-[4-(5,7-two fluoro-benzothiazole-2-methylthiol)-phenyl sulfamoyl]-2-methyl-phenylformic acid;
2,3-dimethyl-5-(4 '-trifluoromethoxy-biphenyl-4-base sulphonamide)-phenylformic acid;
2-ethyl-5-[4-(4-trifluoromethoxy-benzylthio-)-phenyl sulfamoyl]-phenylformic acid;
2-ethyl-5-(4 '-trifluoromethoxy-biphenyl-4-base sulphonamide)-phenylformic acid;
2-sec.-propyl-5-[2-(4-trifluoromethoxy-phenyl)-benzoxazol-5-base sulphonamide]-phenylformic acid;
2-methyl-5-(4 '-trifluoromethoxy-biphenyl-4-base sulphonamide)-phenylformic acid;
2-methyl-5-(4 '-trifluoromethoxy-biphenyl-4-base sulphonamide)-phenylformic acid;
2-ethyl-5-[4-(6-methyl-benzothiazole-2-yl)-phenyl sulfamoyl]-phenylformic acid;
2-methyl-5-(4 '-trifluoromethyl-biphenyl-4-base sulphonamide)-phenylformic acid;
2-sec.-propyl-5-[propyl group-(4 '-trifluoromethoxy-biphenyl-4-yl)-sulphonamide]-phenylformic acid;
2-methyl-5-[(4 '-propoxy--biphenyl-4-yl)-propyl group-sulphonamide]-phenylformic acid;
2-methyl-5-(4 '-propoxy--biphenyl-4-base sulphonamide)-phenylformic acid;
5-(4 '-tertiary butyl-biphenyl-4-base sulphonamide)-2-methyl-phenylformic acid;
5-[4-(4-chloro-benzylthio-)-phenyl sulfamoyl]-2-methyl-phenylformic acid;
2-methyl-5-[4-(3-trifluoromethoxy-benzylthio-)-phenyl sulfamoyl]-phenylformic acid;
2-methyl-5-[2-(4-trifluoromethyl-phenyl)-benzoxazol-5-base sulphonamide]-phenylformic acid;
2-methyl-5-[4-(5-phenyl-benzoxazol-2-yl)-phenyl sulfamoyl]-phenylformic acid; With
2-sec.-propyl-5-[4-(5-methyl-benzoxazol-2-yl)-phenyl sulfamoyl]-phenylformic acid;
The perhaps pharmacy acceptable salt of the prodrug of described compound or described compound or prodrug.
12, treatment Mammals dyslipidaemia, fat, overweight, hypertriglyceridaemia, hyperlipemia, low alpha-lipoprotein blood, metabolism syndrome, diabetes (I type and/or II type), hyperinsulinemia, glucose tolerance lowers, insulin resistant, diabetic complication, atherosclerosis, hypertension, coronary heart disease, hypercholesteremia, inflammation, osteoporosis, thrombosis, peripheral vascular disease, the method of cognition dysfunction or congestive heart failure, compound or the prodrug of described compound or the pharmacy acceptable salt of described compound or prodrug that this method is treated any claim 1-11 of significant quantity to the Mammals of this class treatment of needs.
13, the method for treatment ruminating animal negative energy balance, compound or the prodrug of described compound or the pharmacy acceptable salt of described compound or prodrug that this method is treated any claim 1-11 of significant quantity to the ruminating animal of this class treatment of needs.
14, pharmaceutical combination composition comprises: the composition of treatment significant quantity wherein comprises
First compound, the pharmacy acceptable salt of the compound that described first compound is any claim 1-11 or the prodrug of described compound or described compound or prodrug;
Second compound, described second compound is a lipase inhibitor, the HMG-CoA reductase inhibitor, the HMG-CoA synthetase inhibitors, HMG-CoA reductase gene expression inhibitor, HMG-CoA synthase gene expression inhibitor, MTP/Apo B secretion inhibitor, the CETP inhibitor, the bile acide absorption inhibitor, cholesterol absorption inhibitor, cholesterol synthesis inhibitor, inhibitor for squalene synthetic enzyme, cyclooxygenase inhibitors of squalene, the squalene cyclase inhibitor, squalene cyclooxygenase/squalene cyclase the inhibitor of associating, the special class of shellfish, nicotinic acid, the combination of nicotinic acid and lovastatin, ion exchange resin, antioxidant, the ACAT inhibitor, the pharmacy acceptable salt of the prodrug of bile acid chelating agent or described compound or described compound or prodrug; With
Pharmaceutically acceptable carrier, vehicle or thinner.
15, the associating composition of claim 14, wherein this second compound is rosuvastatin, rivastatin, pitavastatin, lovastatin, Simvastatin, Pravastatin, fluvastatin, atorvastatin, simvastatin or [2R, 4S] 4-[(3,5-pair-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3, the prodrug of 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester or described compound or the pharmacy acceptable salt of described compound or prodrug.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US55211404P | 2004-03-10 | 2004-03-10 | |
| US60/552,114 | 2004-03-10 | ||
| US11/012,139 | 2004-12-16 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1930121A true CN1930121A (en) | 2007-03-14 |
Family
ID=37859499
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200580007622 Pending CN1930121A (en) | 2004-03-10 | 2005-02-28 | Substituted heteroaryl- and phenylsulfamoyl compounds |
Country Status (5)
| Country | Link |
|---|---|
| CN (1) | CN1930121A (en) |
| CR (1) | CR8567A (en) |
| GT (1) | GT200500042A (en) |
| TN (1) | TNSN06269A1 (en) |
| ZA (1) | ZA200606597B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019029211A1 (en) * | 2017-08-10 | 2019-02-14 | 上海交通大学医学院 | Compound used as sirt6 small-molecule allosteric activator and pharmaceutical composition thereof |
| CN109384694A (en) * | 2017-08-10 | 2019-02-26 | 上海交通大学医学院 | SIRT6 small molecule agonist and its application |
-
2005
- 2005-02-28 CN CN 200580007622 patent/CN1930121A/en active Pending
- 2005-03-09 GT GT200500042A patent/GT200500042A/en unknown
-
2006
- 2006-08-08 ZA ZA200606597A patent/ZA200606597B/en unknown
- 2006-08-24 CR CR8567A patent/CR8567A/en not_active Application Discontinuation
- 2006-09-08 TN TNP2006000269A patent/TNSN06269A1/en unknown
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019029211A1 (en) * | 2017-08-10 | 2019-02-14 | 上海交通大学医学院 | Compound used as sirt6 small-molecule allosteric activator and pharmaceutical composition thereof |
| CN109384694A (en) * | 2017-08-10 | 2019-02-26 | 上海交通大学医学院 | SIRT6 small molecule agonist and its application |
| CN109384694B (en) * | 2017-08-10 | 2022-04-05 | 上海爱乐维生物科技有限公司 | SIRT6 small-molecule agonist and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| ZA200606597B (en) | 2007-10-31 |
| CR8567A (en) | 2006-10-17 |
| TNSN06269A1 (en) | 2007-12-03 |
| GT200500042A (en) | 2005-10-24 |
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