CN100567276C - The amides that three (rings) replace - Google Patents

Abstract

The compound of general formula (I) or the acceptable salt of its pharmacology, it can be effective to preventative and therapeutic treatment hyperglycemia and diabetes.

Description

The amides that three (rings) replace

Technical field

The present invention relates to the amides that three (rings) replace.Particularly, the present invention relates to the amides of following replacement mode: i) replace at the ethyl/vinyl (ethenyl) that is connected on the carbonyl carbon on phenyl ring or the carbocyclic ring, and ii) on amino, replaced by the thiazole ring that replaces by fluorine, they are conditioning agents of glucokinase and can be used for preventative or therapeutic treatment hyperglycemia and diabetes, especially type ii diabetes.

Background technology

It is very important aspect the health adjusting of plasma glucose levels that glucokinase (" GK ") is considered to.GK mainly is present in liver and the pancreas, and it is one of initial metabolic four kinds of hexokinase of catalysis glucose.The GK approach the glucose level that is higher than other hexokinase approach saturated (referring to R.L.Printz etc., Annu.Rev.Nutr., 13:463-496 (1993)).GK is very crucial for keeping mammiferous glucose balance.The animal of not expressing GK is dead in the near future after suffering from the diabetes birth, and the animal of overexpression GK has the glucose tolerance that increases.The activation of GK can cause hyperinsulinism hypoglycemia (referring to as H.B.T.Christesen etc., Diabetes, 51: 1240-1246 (2002)).In addition, II type among youngster adult's morbidity type diabetes (type IImaturity-onset diabetes) be because of the sudden change of afunction in the GK gene caused, this shows that GK brings into play effect (Y.Liang etc., the Biochem.J. of glucose sensor in the mankind 309: 167-173 (1995)).Therefore, the compound of activation GK can increase GK susceptor system susceptibility and may be used for the treatment of hyperglycemia-especially relevant with type ii diabetes hyperglycemia.Therefore expectation provides and can activate the novel cpd of GK with the treatment diabetes.

Open No.WO2001/044216 of international monopoly and U.S. Patent No. 6,353,111 have been put down in writing (E)-2 as the GK activator, the two replacement-N-heteroaryl acrylamides of 3-.Open No.WO2002/014312 of international monopoly and U.S. Patent No. 6,369,232,6,388,088 and 6,441,180 have been put down in writing tetrazolyl phenyl ethanamide GK activator.International monopoly open No.WO2000/058293, european patent application No.EP 1169312 and U.S. Patent No. 6,320,050 have been put down in writing cycloalkyl aryl propionic acid amide GK activator.Open No.WO2002/008209 of international monopoly and U.S. Patent No. 6,486,184 have been put down in writing as the α-acyl group of antidiabetic medicine and the phenyl-acetamides GK activator of α-heteroatoms-replacement.The open No.WO2001/083478 of international monopoly has put down in writing the GK activator of hydantoin-containing.Open No.WO2001/083465 of international monopoly and U.S. Patent No. 6,388,071 have been put down in writing alkynyl phenyl hetero-aromatic ring GK activator.Open No.WO2001/085707 of international monopoly and U.S. Patent No. 6,489,485 have been put down in writing the benzamide GK activator that contraposition amido (amine) replaces.Open No.WO2002/046173 of international monopoly and U.S. Patent No. 6,433,188,6,441,184 and 6,448,399 have been put down in writing condensed hetero-aromatic ring GK activator.Open No.WO2002/048106 of international monopoly and U.S. Patent No. 6,482,951 have been put down in writing isoindole-1-ketone GK activator.The open No.WO2001/085706 of international monopoly has put down in writing the phenyl-acetamides GK activator of the replacement that is used for the treatment of type ii diabetes.U.S. Patent No. 6,384,220 have put down in writing the phenyl GK activator to aryl or heteroaryl replacement.French Patent No.2,834,295 have put down in writing purification process and the crystalline texture of human GK.The open No.WO2003/095438 of international monopoly has put down in writing N-heteroaryl phenyl-acetamides and the related compound that is used for the treatment of type ii diabetes as the GK activator.U.S. Patent No. 6,610,846 have put down in writing the preparation as the cycloalkyl heteroaryl propionic acid amide of GK activator.The open No.WO2003/000262 of international monopoly has put down in writing ethenylphenyl GK activator.The open No.WO2003/000267 of international monopoly has put down in writing amino-nicotinic acid ester (aminonicotinate) derivative as the GK conditioning agent.The open No.WO2003/015774 of international monopoly has put down in writing the compound as the GK conditioning agent.The open No.WO2003/047626 of international monopoly has put down in writing GK activator and glucagon antagonists and has united application in treating type ii diabetes.The open No.WO2003/055482 of international monopoly has put down in writing the amide derivatives as the GK activator.The open No.WO2003/080585 of international monopoly has put down in writing has the active aminobenzamide derivative that can be used for treating diabetes and obesity of GK.The open No.WO2003/097824 of international monopoly has put down in writing human liver GK crystal and based on the application in the medicinal design of structure.The open No.WO2004/002481 of international monopoly has put down in writing the aryl carbonyl derivatives as the GK activator.Open No.WO2004/072031 of international monopoly and WO2004/072066 (open after the application's priority date) have put down in writing the multiple amides that replaces as three (rings) of modulators of glucokinase.

Summary of the invention

The compound of general formula (I) representative or the acceptable salt of its pharmacology:

Can be used for preventative or therapeutic treatment hyperglycemia (hyperglycemia) and diabetes, especially type ii diabetes.

Embodiment

The present invention relates to the compound or the acceptable salt of its pharmacology of general formula (I):

Wherein:

V is (CH ₂) _k, one of them CH ₂Group can be randomly by CH (OH), C=O, C=NOH, C=NOCH ₃, CHX, CXX ¹, CH (OCH ₃), CH (OCOCH ₃), CH (C _1-4Alkyl) or C (OH) (C _1-4Alkyl) substitutes;

X and X ₁Be independently selected from fluorine and chlorine;

R ¹And R ²Be independently selected from hydrogen, halogen, hydroxyl, amino, cyano group, nitro, SR ³, SOR ³, SO ₂R ³, SO ₂NR ⁴R ⁵, NHSO ₂R ³Or C _1-4Alkyl, C _2-4Thiazolinyl, C _2-4Alkynyl, C _1-4Alkoxyl group or heteroaryl, wherein arbitrary group randomly is independently selected from halogen, cyano group, nitro, hydroxyl, C by 1 to 5 _1-2Alkoxyl group ,-N (C _0-2Alkyl) (C _0-2Alkyl), C _1-2Alkyl, CF _nH _3-n, aryl, heteroaryl ,-CON (C _0-2Alkyl) (C _0-2Alkyl), SCH ₃, SOCH ₃, SO ₂CH ₃And-SO ₂N (C _0-2Alkyl) (C _0-2Alkyl) substituting group replaces;

R ³Be C _1-4Alkyl, C _3-7Cycloalkyl, aryl, heteroaryl or 4 to 7 element heterocycle bases, wherein arbitrary group randomly is independently selected from halogen, cyano group, nitro, hydroxyl, C by 1 to 5 _1-2Alkoxyl group ,-N (C _0-2Alkyl) (C _0-2Alkyl), C _1-2Alkyl, C _3-7Cycloalkyl, 4 to 7 element heterocycles, CF _nH _3-n, aryl, heteroaryl, COC _1-2Alkyl ,-CON (C _0-2Alkyl) (C _0-2Alkyl), SOCH ₃, SO ₂CH ₃And-SO ₂N (C _0-2Alkyl) (C _0-2Alkyl) substituting group replaces;

R ⁴And R ⁵Be hydrogen or C independently _1-4Alkyl, C _3-7Cycloalkyl, aryl, heteroaryl or 4 to 7 element heterocycle bases, wherein arbitrary group randomly is independently selected from halogen, cyano group, nitro, hydroxyl, C by 1 to 5 _1-2Alkoxyl group ,-N (C _0-2Alkyl) (C _0-2Alkyl), C _1-2Alkyl, C _3-7Cycloalkyl, 4 to 7 element heterocycles, CF _nH _3-n, aryl, heteroaryl ,-CON (C _0-2Alkyl) (C _0-2Alkyl), SOCH ₃, SO ₂CH ₃And-SO ₂N (C _0-2Alkyl) (C _0-2Alkyl) substituting group replaces;

Perhaps R ⁴And R ⁵Form together and randomly be independently selected from C by 1 to 2 _1-24 to 8 element heterocycles that the substituting group of alkyl and hydroxyl replaces;

K is the integer of 2-7;

M is 0 or 1;

N is 1,2 or 3; And

Dotted line forms optional two keys with solid line, and on behalf of this pair key, Δ have (E)-configuration.

If dotted line forms singly-bound with solid line, so with aromatic ring and containing-HC＜side chain of V is connected to the carbon atom on the amidocarbonylation carbon, the carbon atom that promptly is marked with " * " is a chiral centre.Therefore, in this center, this compound can be used as racemic modification or as the enantiomorph of single (R)-or (S)-configuration and exist.(R)-enantiomorph is preferred.With " # " marked carbon atoms also can be chirality.Therefore, in the heart, this compound can be used as racemic modification or as the enantiomorph of single (R)-or (S)-configuration and exist in this.When dotted line and solid line are represented singly-bound, (R)-enantiomorph is preferred.When dotted line forms two key with solid line, (S)-enantiomorph is preferred.

On the other hand, the present invention relates to the compound or the acceptable salt of its pharmacology of general formula (Ia) representative:

Wherein V, R ¹, R ², m and Δ such as in general formula (I) definition.

In another embodiment, the present invention relates to the compound or the acceptable salt of its pharmacology of general formula (Ia) representative, wherein by-HC＜and the group that becomes of V-arrangement represents oxygen basic ring alkyl or hydroxyl cycloalkyl, as, the 3-oxocyclopentyl, particularly (R)-3-oxocyclopentyl, 4-oxo cyclohexyl or 3-hydroxycyclopent base, particularly (R)-3-oxocyclopentyl.

Another preferred aspect, the present invention relates to the compound or the acceptable salt of its pharmacology of general formula (Ib) representative:

Wherein V, R ¹, R ², and m such as in general formula (I) definition.

In the specific embodiments aspect this is preferred, the present invention relates to the compound or the acceptable salt of its pharmacology of general formula (Ib) representative, wherein by-HC＜and the group that becomes of V-arrangement represents oxo cycloalkyl or hydroxyl cycloalkyl, as, the 3-oxocyclopentyl, particularly (R)-3-oxocyclopentyl, 4-oxo cyclohexyl or 3-hydroxycyclopent base, particularly (R)-3-oxocyclopentyl.

The molecular weight of the compound of general formula (I) is preferably less than 800, more preferably less than 600, most preferably is less than 500.

In the present invention, R ¹And R ²Be preferably not all is hydrogen.

In the present invention, R ¹CF preferably ₃, SOR ³, SO ₂R ³, SO ₂NR ⁴R ⁵, NHSO ₂R ³Or triazolyl; Be more preferably SOR ³, SO ₂R ³Or SO ₂NR ⁴R ⁵Most preferably be SO ₂R ³Or SO ₂NR ⁴R ⁵, SO particularly ₂R ³

Particularly, R ¹Be SO ₂C _3-4Cycloalkyl, particularly SO ₂Cyclopropyl.

In the present invention, R ²Preferably hydrogen, chlorine, fluorine or trifluoromethyl; Be more preferably hydrogen or chlorine.

In the present invention, R ³C preferably _1-3Alkyl or C _3-4Cycloalkyl is more preferably C _3-4Cycloalkyl, especially cyclopropyl.

In the present invention, R ⁴And R ⁵Preferably be hydrogen or C independently _1-4Alkyl is as R ⁴And R ⁵In one of be hydrogen and another is an ethyl, perhaps form 4 to 8 element heterocycles together.R ⁴And R ⁵Be preferably not all is hydrogen.

In the present invention, m preferably 0.

In the present invention, V (CH preferably ₂) _k, one of them CH ₂Substituted by CH (OH) or C=O.

In the present invention, k preferably 4 or 5.

The specific compound that can mention in the present invention is:

2 (R)-2-(3-chloro-4-methylsulfonyl phenyl)-N-(5-fluorine thiazol-2-yl)-3-((R)-3-oxocyclopentyl) propionic acid amide;

2 (R)-2-(3-chloro-4-methylsulfonyl phenyl)-N-(5-fluorine thiazol-2-yl)-3-(4-oxo cyclohexyl) propionic acid amide;

2 (R)-2-(3-chloro-4-methylsulfonyl phenyl)-N-(5-fluorine thiazol-2-yl)-3-(3-hydroxycyclopent base) propionic acid amide;

(E)-N-(5-fluorine thiazol-2-yl)-2-(4-methylsulfonyl phenyl)-3-((S)-3-oxocyclopentyl) acrylamide;

(E)-N-(5-fluorine thiazol-2-yl)-2-(4-methylsulfonyl phenyl)-3-(4-oxo cyclohexyl) acrylamide;

(E)-N-(5-fluorine thiazol-2-yl)-3-(3-hydroxycyclopent base)-2-(4-methylsulfonyl phenyl) acrylamide;

2 (R)-2-(4-encircles the third alkylsulfonyl phenyl)-N-(5-fluorine thiazol-2-yl)-3-((R)-3-oxocyclopentyl) propionic acid amide;

2 (R)-2-(4-encircles the third alkylsulfonyl phenyl)-N-(5-fluorine thiazol-2-yl)-3-(4-oxo cyclohexyl) propionic acid amide;

2 (R)-2-(4-encircles the third alkylsulfonyl phenyl)-N-(5-fluorine thiazol-2-yl)-3-(3-hydroxycyclopent base) propionic acid amide;

2 (R)-2-(4-ring fourth alkylsulfonyl phenyl)-N-(5-fluorine thiazol-2-yl)-3-(3-oxocyclopentyl) propionic acid amide;

2 (R)-2-(4-ring fourth alkylsulfonyl phenyl)-N-(5-fluorine thiazol-2-yl)-3-(4-oxo cyclohexyl) propionic acid amide;

2 (R)-2-(4-ring fourth alkylsulfonyl phenyl)-N-(5-fluorine thiazol-2-yl)-3-(3-hydroxycyclopent base) propionic acid amide;

2 (R)-2-(3-fluoro-4-methylsulfonyl phenyl)-N-(5-fluorine thiazol-2-yl)-3-((R)-3-oxocyclopentyl) propionic acid amide;

2 (R)-2-(3-fluoro-4-methylsulfonyl phenyl)-N-(5-fluorine thiazol-2-yl)-3-(4-oxo cyclohexyl) propionic acid amide; And

2 (R)-2-(3-fluoro-4-methylsulfonyl phenyl)-N-(5-fluorine thiazol-2-yl)-3-(3-hydroxycyclopent base) propionic acid amide;

Or any acceptable salt of pharmacology wherein.

Although the preferred group for each variable is as above listed separately with regard to each variable usually, it is preferred with regard to each variable, preferred, most preferred, especially or the group of specifically listing that preferred compound of the present invention comprises that several or each variable in those its formula ofs (I) all is selected from.Therefore, the invention is intended to comprise preferred, preferred, most preferred, special all combinations that reach the group of specifically listing.

Except as otherwise noted, as used herein, " alkyl (alkyl) " and other have the group of prefix " alk ", are meant it can is the carbochain of straight or branched or its combination as alkoxyl group, thiazolinyl, alkynyl etc.The specific examples of alkyl comprises methyl, ethyl, propyl group, sec.-propyl, butyl, sec-butyl and the tertiary butyl, amyl group, hexyl, heptyl etc." thiazolinyl ", " alkynyl " and other terms comprise the carbochain that contains at least one unsaturated carbon carbon bond.

As used herein, as " C _0-4Alkyl " be meant and in the straight or branched configuration, contain 0-4 carbon, the i.e. alkyl of 0,1,2,3 or 4 carbon.When alkyl was end group, carbon-free alkyl was a hydrogen.When alkyl was bridging (connection) base, carbon-free alkyl was direct key (direct bond).

Term " cycloalkyl " reaches " carbocyclic ring " and is meant and does not contain heteroatoms and comprise the saturated C of monocycle _3-7The isocyclic carbocyclic ring.Cycloalkyl and isocyclic example comprise cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl etc.

Term " halogen " comprises fluorine, chlorine, bromine and iodine atom.

Term " aryl " comprises, as phenyl and naphthyl, preferably phenyl.

Except as otherwise noted, term " heterocycle " comprises and contains heteroatomic 4 to 8 Yuans saturated rings that one or two is selected from oxygen, sulphur and nitrogen.Heteroatoms does not directly link to each other each other.The heterocyclic example comprises trimethylene oxide, tetrahydrofuran (THF), tetrahydropyrans, oxepane, oxocane, Thietane, tetramethylene sulfide, tetrahydric thiapyran, thia suberane, thia cyclooctane, azetidine, tetramethyleneimine, piperidines, azepan, Azacyclooctane, [1,3] dioxane, oxazolidine, piperazine etc.Other examples of heterocyclic comprise the oxidised form of sulfur-bearing ring.Therefore, tetramethylene sulfide 1-oxide compound, tetramethylene sulfide 1,1-dioxide, tetrahydric thiapyran 1-oxide compound and tetrahydric thiapyran 1, the 1-dioxide also is considered to heterocycle.

Except as otherwise noted, term " heteroaryl " comprises and contains heteroatomic 5 or 6 Yuans hetero-aromatic rings that 1-4 is selected from oxygen, sulphur and nitrogen.The example of this hetero-aromatic ring comprises furyl, thienyl, pyrryl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazole base, thiadiazolyl group, tetrazyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl and triazinyl.

Above general formula is not expressed definite stereochemistry in some position.Except that drawing especially or having in addition the regulation, the present invention includes all steric isomers (as geometrical isomer, optical isomer, diastereomer etc.) and the acceptable salt of pharmacology thereof.In addition, except that drawing especially or having in addition the regulation, also comprise the mixture and the isolating particular stereoisomer of steric isomer.At the synthesis process that is used for preparing these compounds or using in the process of racemization well known by persons skilled in the art or epimerization, the product of these processes can be the mixture of steric isomer.When there is tautomer in above compound,, the present invention includes any possible tautomer and acceptable salt of pharmacology and their mixture except that drawing especially or having in addition the regulation.When the compound of above-mentioned general formula and the acceptable salt of pharmacology thereof exist with the form of solvate or polymorph, the present invention includes any possible solvate and polymorph.As long as this solvent is that pharmacology is acceptable, the type of the solvent that forms solvate is not particularly limited.For example, can answer water, ethanol, propyl alcohol, acetone etc.

Because it is medicinal that the compound of general formula (I) is intended to, they preferably adopt the pure form of essence, and for example at least 60% purity is preferably at least 75% purity, and at least 95% purity also is in particular at least 98% purity (% is a weight percent).

The present invention also comprises the compound that comprises general formula (I) or the pharmaceutical composition of acceptable salt of its pharmacology and pharmacology acceptable carrier.

Preferably, said composition comprises the compound or the acceptable salt of its pharmacology of the general formula (I) of pharmacology acceptable carrier and nontoxic treatment significant quantity.

And, in this specific embodiments, the present invention is contained and is used for preventing or treat hyperglycemia and diabetes by activation GK, especially the pharmaceutical composition of type ii diabetes, said composition comprise the compound or the acceptable salt of its pharmacology of the general formula (I) of pharmacology acceptable carrier and nontoxic treatment significant quantity.

The present invention also provides the application as medicine of the compound of general formula (I) or the acceptable salt of its pharmacology.

Compound of the present invention and composition can be effective to treat the Mammals such as the mankind's hyperglycemia and diabetes, especially type ii diabetes.

The method that the present invention also provides a kind of preventative or therapeutic treatment need activate the illness of GK, this method comprise the compound of general formula (I) of effective dosage or the step of the acceptable salt of its pharmacology.

The present invention also provides a kind of method of preventative or therapeutic treatment hyperglycemia and diabetes, especially type ii diabetes, and this method comprises the compound of general formula (I) of effective dosage or the step of the acceptable salt of its pharmacology.

The present invention also provides a kind of prevention to show preceding diabetic (pre-diabetic) hyperglycemia or glucose tolerance to reduce diabetes among the mankind of (impaired glucose tolerance), especially the method for type ii diabetes, this method comprise the compound of general formula (I) of effective dosage or the step of the acceptable salt of its pharmacology.

The present invention also provides the application as the GK activator of the compound of general formula (I) or the acceptable salt of its pharmacology.

The present invention also provides the compound or the application of the acceptable salt of its pharmacology in preventative or therapeutic treatment hyperglycemia and diabetes, especially type ii diabetes of general formula (I).

The present invention also provides the application in diabetes, the especially type ii diabetes among the compound of general formula (I) or the acceptable salt of its pharmacology mankind that diabetic hyperglycemia or glucose tolerance before prevention shows reduce.

The present invention also provides the compound of general formula (I) or the acceptable salt of its pharmacology to be used for activating the application of the medicine of GK in preparation.

The present invention also provide the compound of general formula (I) or the acceptable salt of its pharmacology preparation be used for preventative or the medicine of therapeutic treatment hyperglycemia and diabetes, especially type ii diabetes in application.

The present invention also provides the application in the compound of general formula (I) or the acceptable salt of its pharmacology mankind's that diabetic hyperglycemia or glucose tolerance before preparation is used for preventing to show reduce the medicine of diabetes, especially type ii diabetes.

Compound of the present invention and composition can be randomly and one or more other antidiabetic medicines or hyperglycemia disease drug combined utilization, and these medicines comprise as sulfonylurea (as Glyburide, glimepiride, glipyride, Glipizide, P-607, gliclazide, glisoxepid, acetohexamide, glibornuride, tolbutamide, tolazamide, carbutamide, gliquidone, glyhexamide, R-131, metahexamide (tolcyclamide) etc.), biguanides is (as N1,N1-Dimethylbiguanide, phenformin, buformin etc.), glucagon antagonists (as peptide or non-peptide class glucagon antagonists), alpha-glucosidase inhibitors is (as acarbose, miglitol etc.), insulinsecetagogues, euglycemic agent is (as troglitazone, rosiglitazone, pioglitazone etc.) etc.; Perhaps anti-obesity medicine (as sibutramine, Ao Lisita etc.) etc.Compound of the present invention and composition and other antidiabetic medicines or anti-hyperglycemia medicine can be simultaneously, successively or individually dosed.

Term " the acceptable salt of pharmacology " is meant by acceptable nontoxic alkali of pharmacology or the sour salt for preparing.When compound of the present invention was acidity, its corresponding salt can comprise that mineral alkali and organic bases prepare easily by the acceptable nontoxic alkali of pharmacology.Comprise aluminium salt, ammonium salt, calcium salt, mantoquita, cuprous salt, molysite, ferrous salt, lithium salts, magnesium salts, manganese salt (manganic salt), manganous salt (manganous salt), sylvite, sodium salt, zinc salt etc. by this mineral alkali deutero-salt.Be preferably ammonium salt, calcium salt, magnesium salts, sylvite and sodium salt especially.By the acceptable non-toxic organic alkali of pharmacology deutero-salt comprise primary, the second month in a season and tertiary amine, and the salt of the amine of cyclammonium and replacement such as natural existence and synthetic amine.Other can comprise by the acceptable non-toxic organic alkali of the salifiable pharmacology of shape, as arginine, trimethyl-glycine, caffeine, choline, N ', N '-dibenzyl-ethylenediamin, diethylamine, 2-DEAE diethylaminoethanol, 2-dimethylaminoethanol, thanomin, quadrol, N-ethylmorpholine, N-ethylpiperidine, grape amine, glucosamine, Histidine, Isopropylamine, Methionin, methyl grape amine, morpholine, piperazine, piperidines, versamid 900, PROCAINE HCL, PHARMA GRADE, purine, Theobromine, triethylamine, Trimethylamine 99, tripropyl amine, Trometamol etc.

When compound of the present invention was alkalescence, its corresponding salt can comprise that mineral acid and organic acid prepare easily by the acceptable nontoxic acid of pharmacology.These acid comprise as acetate, Phenylsulfonic acid, phenylformic acid, camphorsulfonic acid, citric acid, ethyl sulfonic acid, fumaric acid, glyconic acid, L-glutamic acid, Hydrogen bromide, hydrochloric acid, isethionic acid, lactic acid, toxilic acid, oxysuccinic acid, amygdalic acid, methylsulfonic acid, glactaric acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succsinic acid, sulfuric acid, tartrate, tosic acid etc.Be preferably citric acid, Hydrogen bromide, hydrochloric acid, toxilic acid, phosphoric acid, sulfuric acid, methylsulfonic acid and tartrate especially.

Pharmaceutical composition of the present invention comprises compound or the acceptable salt of its pharmacology, pharmacology acceptable carrier and the optional other treatment composition or the assistant agent of the general formula (I) as activeconstituents.Said composition comprises and is suitable for oral, rectum, part and parenteral route (comprising subcutaneous, intramuscular and intravenously) administration and the composition by inhalation, but in any given case, optimum approach will depend on the character and the seriousness of the illness of specific main body and the administration of this activeconstituents institute.This pharmaceutical composition can use the known method of pharmacy field to be prepared as unit dosage easily.

Pharmaceutical composition of the present invention is preferably and is applicable to oral administration.

In fact, according to conventional medicine compatibility technology, the activeconstituents that the compound of general formula (I) or the acceptable salt of its pharmacology can be used as in the intimate mixture combines with pharmaceutical carrier.This carrier can adopt multiple mode according to the required dosage form of administration, as oral or parenteral route carrier (comprising intravenously administrable).Therefore, pharmaceutical composition of the present invention can adopt the form of the discrete unit that is suitable for oral administration, as capsule, cachet or the tablet of the activeconstituents that comprises predetermined amount respectively.In addition, said composition can adopt the form of powder, granule, solution, suspensoid, on-aqueous liquid, oil-in-water emulsion or water-in-oil-type liquid emulsion in liquid, aqueous.Except the above-mentioned general formulation of listing, the compound of general formula (I) or the acceptable salt of its pharmacology also can carry out administration by controlled release mode and/or transfer device.Said composition can use any method of pharmacy to be prepared.Usually, these methods comprise the step of activeconstituents with the carrier combinations that constitutes one or more neccessary compositions.Usually, said composition is by with solid carrier or both homogeneous of activeconstituents and liquid vehicle or segmentation and closely mix and prepare.Product can be shaped to required outward appearance expediently then.

Therefore, pharmaceutical composition of the present invention can comprise the compound or the acceptable salt of its pharmacology of pharmacology acceptable carrier and general formula (I).The compound of general formula (I) or the acceptable salt of its pharmacology can also be planted the other treatment active compound with one or more and together is included in the pharmaceutical composition.

Pharmaceutical composition of the present invention comprises the compound that contains general formula (I) or the acceptable Liposomal formulation of pharmacology of the acceptable salt of its pharmacology.

Applied pharmaceutical carrier can be as solid, liquid or gas.The example of solid carrier comprises lactose, carclazyte (terra alba), sucrose, talcum, gelatin, agar, pectin, gum arabic, Magnesium Stearate and stearic acid.The example of liquid vehicle is syrup, peanut oil, sweet oil and water.The example of carrier gas comprises carbonic acid gas and nitrogen.

Be used for the composition of oral dosage units in preparation, can use any drug media easily.For example, water, glycols, oil, alcohol, seasonings, sanitas, tinting material etc. can be used to form oral liquid such as suspensoid, elixir and solution; And carrier such as starch, sucrose, Microcrystalline Cellulose, thinner, granulation agent, lubricant, tackiness agent, disintegrating agent etc. can be used to form oral solid formulation such as powder, capsule and tablet.Because they are convenient to administration, tablet and capsule are the preferred oral dosage units of applying solid pharmaceutical carrier.Tablet can randomly carry out dressing by the moisture or non-water technology of standard.

Contain the tablet of composition of the present invention can be randomly with one or more supplementary components or assistant agent by compacting or molded the preparation.Compressed tablets can by in suitable machine with activeconstituents with free-pouring form such as powder or particle, randomly forming with tackiness agent, lubricant, inert diluent, tensio-active agent or dispersion agent or the compacting of other vehicle.These vehicle can be for example inert diluent such as lime carbonate, yellow soda ash, lactose, calcium phosphate or sodium phosphate; Granulation agent and disintegrating agent such as W-Gum or Lalgine; Tackiness agent such as starch, gelatin or gum arabic; And lubricant such as Magnesium Stearate, stearic acid or talcum.Tablet not dressing or with known technology coatings delaying disintegration and the absorption in gi tract, thereby lasting effect was provided in the longer time.For example, can use a kind of time dilation material such as glyceryl monostearate or distearin.

In hard gelatin capsule, activeconstituents mixes mutually with inert solid diluent such as lime carbonate, calcium phosphate or kaolin.In soft gelatin capsule, activeconstituents is to mix with water or oily medium such as peanut oil, whiteruss or olive oil phase.Molded tablet can prepare by molded mixture with the moistening powdered compounds of inert liquid diluent in suitable machine.Each tablet preferably contains from about 0.05mg to about 5g activeconstituents, and each cachet or capsule preferably contain about 5g activeconstituents extremely from about 0.05mg.

The preparation that for example is intended to human oral administration may contain the 0.5mg that has an appointment to about 5g activeconstituents, and mixes with about 5% to about 95% the solid support material suitable and that measure easily that accounts for total composition.Unit dosage contains have an appointment the 1mg extremely activeconstituents of about 2g, normally 25mg, 50mg, 100mg, 200mg, 300mg, 400mg, 500mg, 600mg, 800mg or 1000mg usually.

The pharmaceutical composition of the present invention that is suitable for parenteral administration can be prepared into solution or the suspension of active compound in water.Can comprise suitable tensio-active agent such as hydroxypropylcellulose.Can also in glycerine, liquid macrogol and the mixture in oil thereof, prepare dispersion.Can comprise sanitas in addition to prevent the harmful microorganism growth.

The pharmaceutical composition of the present invention that is suitable for drug administration by injection comprises aseptic aqueous solution or dispersion.And said composition can adopt the form of sterilized powder to be used for preparing this injectable sterile solution or dispersion temporarily.In a word, final injectable forms must be aseptic and must be the effective fluid that is easy to inject.This pharmaceutical composition must be stable under production and condition of storage; Therefore, preferably should carry out anticorrosion at the contamination of microorganism such as bacterium and fungi.Carrier can be solvent or the dispersion medium that contains just like water, ethanol, polyvalent alcohol (as glycerine, propylene glycol and liquid macrogol), vegetables oil and suitable mixture thereof.

Pharmaceutical composition of the present invention can adopt and be suitable for the local form of using, as aerosol, emulsifiable paste, ointment, lotion, face powder etc.In addition, said composition can adopt the form that is applicable to transdermal device.These preparations can utilize the compound of general formula (I) or the acceptable salt of its pharmacology to be prepared by conventional working method.For example, emulsifiable paste or ointment can be by hydrophilic material and water and about 5 weight % are had required denseness to the compound of about 10 weight % with preparation emulsifiable paste or ointment.

Pharmaceutical composition of the present invention can adopt wherein, and carrier is the form that solid is suitable for rectal administration.Preferred mixture forms the suppository of unitary dose.Appropriate carriers comprises theobroma oil and this area other materials commonly used.By earlier composition being mixed with softening or melting carrier, cooling and moulding can prepare suppository easily in mould then.

Pharmaceutical composition of the present invention can adopt the form that is suitable for inhalation.This administering mode can adopt and be recorded in Particulate Interactions in Dry Powder Formulations forInhalation, Xian Zeng etc., 2000, Taylor and Francis; PharmaceuticalInhalation Aerosol Technology, Anthony Hickey, 1992, Marcel Dekker; And Respiratory Drug Delivery, 1990, editor: P.R.Byron, the form among the CRC Press also adopts wherein said carrier.

Except that above-mentioned carrier components, when suitable, aforementioned pharmaceutical compositions can comprise carrier components that one or more are other such as thinner, buffer reagent, seasonings, tackiness agent, tensio-active agent, thickening material, lubricant, sanitas (comprising antioxidant) etc.And, also can comprise other assistant agents so that ooze with the blood etc. of the acceptor of expection.Contain the compound of general formula (I) or the composition of the acceptable salt of its pharmacology and also can be prepared as powder or concentrated liquid form.

Usually, every day, about substantially 0.01mg/kg arrived the dosage level of about 150mg/kg body weight, and perhaps the about 0.5mg of every patient every day can be effective to treat above-mentioned illness to the dosage level of about 10g.For example by about 0.01 to 100mg this compound of per kilogram of body weight administration every day, perhaps every day every about 0.5mg of patient's administration extremely this compound of about 7g can effectively treat diabetes.

Yet, the given dose level that should understand for any particular patient will depend on multiple factor, comprise the specific diabetic subject's who receives treatment age, body weight, whole body health, sex, diet, administration time, route of administration, excretion rate, drug regimen and severity of disease.In addition, should understand compound of the present invention and salt thereof can with the expection the hyperglycemia illness in the prophylactically administration of inferior therapeutic dose.

For example described in experiment described herein, compare with known glucokinase activators, the compound of general formula (I) shows favorable properties.Particularly, compare with other known GK activators, compound of the present invention shows the K of improvement _m, V _Max, EC ₅₀(glucose concn=5mM) and/or the maximum blood sugar on basic glucose level basis reduce (as in the C57BL/6J mouse), perhaps other favourable pharmacological properties for value, maximum activation.

According to the present invention, the compound of general formula (Ia) can prepare according to the scheme that following route 1 is set forth:

Route 1

Wherein V, R ¹, R ², m and Δ as mentioned above, and R ¹¹Be C _1-4Alkyl.Aldehyde II and phenylacetate III can buy and obtain or utilize currently known methods to prepare easily.At-78 ℃, the phenylacetate III (R that in as tetrahydrofuran (THF), generates by highly basic such as lithium diisopropylamine ¹¹=C _1-4Alkyl) α-carbanion can with the II condensation obtain alpha, beta-unsaturated esters (T.Severin etc., Chem.Ber.1985,118,4760-4773), it can utilize carries out saponification as sodium hydroxide (W.L.Corbett etc. WO2001/44216) generates IV.If desired, any functional group in the intermediate, as the oxo of the compound of general formula I I or hydroxyl can be protected and this protecting group can utilize ordinary method to remove.For example, oxo can be used as ketal protection, and hydroxyl is protected as methoxymethyl (MOM) ether as ether.

α, beta-unsaturated carboxylic acid IV can with 2-amino-5-fluorine thiazole V or its salt, example hydrochloric acid salt, condensation generates (Ia), and 2-amino-5-fluorine thiazole or its salt can utilize multiple coupling condition at 20 ℃ as described in embodiment, as the polymkeric substance fixed at N, carbodiimide-I-hydroxybenzotriazole in the dinethylformamide prepares that (typical process is referring to http://www.argotech.com/PDF/resins/ps_carbodiimide.pdf, and can be from Argonaut Technologies, Inc., Foster City, California buys).

According to the present invention, the compound of general formula (Ib) can prepare according to the scheme that following route 2 is set forth:

Route 2

Wherein V, R ¹, R ²With m as mentioned above, Y is CO ₂R ¹², R wherein ¹²Be hydrogen, C _1-4Alkyl or benzyl; And X be chlorine, bromine, iodine or-OSO ₂R ¹³, R wherein ¹³Be the C that is randomly replaced by one or more fluorine _1-4Alkyl, or randomly substituted aryl.

Halogenide and sulphonate VI and toluylic acid and ester VII can buy and obtain or utilize the known technology as being put down in writing among international monopoly open No.WO2000/058293, WO2001/044216 and the WO2003/095438 to prepare easily.These alkylating agents can with-78 ℃ in tetrahydrofuran (THF) the dianion reaction by the toluylic acid VII that produced more than or equal to 2 normal highly basic such as lithium diisopropylamines directly generate VIII (F.T.Bizzarro etc., WO2000/58293).Perhaps-78 ℃ in tetrahydrofuran (THF) by highly basic such as two (trimethyl silyl) Lithamide (L.Snyder etc., J.Org.Chem.1994,59, α-carbanion of the phenylacetate VII that 7033-7037) is produced can be generated the ester of alpha-substitution by the VI alkylation.Use as the sodium hydroxide in the aqueous methanol at 20 ℃ of these esters generation carboxylic acids of saponification VIII under the reflux temperature.If desired, any functional group in the intermediate, as the oxo of the compound of general formula VI or hydroxyl can be protected and this protecting group can utilize ordinary method to remove.For example, oxo can be used as ketal protection, and hydroxyl is protected as methoxymethyl (MOM) ether as ether.

Carboxylic acid VIII can with 2-amino-5-fluorine thiazole V or its salt, example hydrochloric acid salt, carry out condensation and generate acid amides (Ib), 2-amino-5-fluorine thiazole or its salt can utilize multiple coupling condition at 20 ℃ as described in embodiment, as the polymkeric substance fixed at N, carbodiimide-I-hydroxybenzotriazole in the dinethylformamide prepares that (typical process is referring to http://www.argotech.com/PDF/resins/ps_carbodiimide.pdf and can be from Argonaut Technologies, Inc., Foster City, California buys).

The compound of general formula (Ib) contains a unsymmetrical carbon, it connecting amidocarbonylation carbon, aryl rings and contain side chain-HC＜V.According to the present invention, this preferred steric configuration in asymmetric center place is (R).

If want to separate pure (R) obtain general formula (Ib) compound-or (S)-steric isomer, racemic mixture that might be by conventional chemical method resolving chiral carboxylic acid precursor VIII utilizes the reagent that causes racemization hardly that the carboxylic acid of enantiomer-pure and 2-amino-5-fluorine thiazole V or its salt are carried out condensation then.For example, racemic VIII can with the condensation of chiral oxazolidinone derivative (referring to, for example F.T.Bizzarro etc. WO2000/58293) generates diastereoisomeric imide mixture, this mixture can separate by ordinary method such as column chromatography.The pure imide of hydrolysis obtains three-dimensional pure (R)-and (S)-carboxylic acid, can utilize afterwards and make the minimized reagent of chiral centre racemization such as benzotriazole-1-base oxygen base tripyrrole alkyl phosphonium hexafluorophosphate (benzotriazol-l-yloxy tris (pyrrolidino) phosphonium hexafluorophosphate) (J.Coste etc., Tetrahedron Lett.1990,31,205-208) it and 2-amino-5-fluorine thiazole V or its salt are carried out condensation and obtain (R) of the general formula (Ib) of enantiomer-pure-or (S)-acid amides.Perhaps, the racemic mixture of the acid amides of general formula (Ib) can utilize chiral stationary phase to separate by chiral high performance liquid chromatography, and chiral stationary phase can be from for example Daicel Chemical Industries, Ltd, and Tokyo, Japan buys.

Compound at general formula (I) can transform generation by functional group well known by persons skilled in the art with the various functional groups that the intermediate that is used for its preparation occurs.For example in the compound of general formula VIII, can generate alkylsulfonyl by utilizing as the corresponding sulfane base of mCPBA oxidation (sulfanyl group).

The details of the compound of preparation general formula (I) are seen embodiment.

The compound of general formula (I) can prepare separately or as comprise at least 2 kinds, as 5 to 1,000 kinds of compounds and more preferably the compound library of the compound of 10 to 100 kinds of general formulas (I) prepare.Compound library can utilize method known to those skilled in the art to pass through combination " cut apart mix (split-mix) " method or by using liquid phase or solid state chemistry to carry out preparing parallel synthesizing of multistep.

In the synthetic process of the compound of general formula (I), can protect unstable functional group such as hydroxyl, oxygen base, carboxyl and the amino of intermediate.Protecting group can any stage in the compound of general formula (I) synthetic be removed, and perhaps can appear in the compound of final general formula (I).At for example Protective Groups in Organic Chemistry; T.W.Greene and P.G.M.Wuts; (1991) Wiley-Interscience; New York has discussed the method for derivative of the protection of the guard method of various unstable functional groups and excision gained comprehensively in the second edition.

Any new intermediate of above-mentioned definition is also included within the scope of the present invention.Therefore the present invention also provides:

A) compound of the general formula I V of above-mentioned definition, wherein R ¹Be SO ₂R ³Or SO ₂NR ⁴R ⁵

R ²Be hydrogen;

R ³Be C _1-3Alkyl, C _3-7Cycloalkyl or 4 to 6 element heterocycle bases;

R ⁴And R ⁵Be hydrogen or C independently _1-4Alkyl, condition are R ⁴And R ⁵Not all be hydrogen;

M is 0; And

Δ represents that two keys have (E)-configuration; And

B) compound of the general formula VIII of above-mentioned definition, wherein R ¹Be SO ₂R ³Or SO ₂NR ⁴R ⁵

R ²Be hydrogen;

R ³Be C _3-7Cycloalkyl or 4 to 6 element heterocycle bases;

R ⁴And R ⁵Be hydrogen or C independently _1-4Alkyl, condition are R ⁴And R ⁵Not all be hydrogen;

M is 0.

All publications include but not limited to that the patent and the patent application of quoting in this specification sheets all incorporate into herein as a reference, just look like concrete and illustrate that respectively each independent publication all incorporates into the same as a reference in full herein.

Embodiment

Material and method:

Except as otherwise noted, column chromatography can be at SiO ₂Carry out on (40-63 order).The LCMS data can use one of two kinds of methods to obtain: method A:Waters Symmetry 3.5 μ C ₁₈Post (2.1 * 30.0mm, flow velocity=0.8mL/min) with containing 0.1%HCO ₂(the H that contains 5%MeCN of H ₂O)-MeCN eluant solution 6min and detect at the UV of 220nm place.Gradient information: the 0.0-1.2min:100% (H that contains 5%MeCN ₂O); 1.2-3.8min: rise to the 10% (H that contains 5%MeCN ₂O)-90%MeCN; 3.8-4min: keep the 10% (H that contains 5%MeCN ₂O)-90%MeCN; 4.4-5.5min: rise to 100%MeCN; 5.5-6.0min: return to the 100% (H that contains 5%MeCN ₂O).Method B:Phenomenex Mercury Luna 3 μ C ₁₈Post (2.0 * 10.0mm, flow velocity=1.5mL/min), with containing 0.1%HCO ₂(the H that contains 5%MeCN of H ₂O)-MeCN solution (4: 1 to 1: 4) wash-out 2.95min and use diode array and detect.The mass spectrum of method A and B can use electric spray ion source with positive ion (ES ⁺) or negative ion (ES ^-) pattern obtain.Atmospheric pressure chemical ionization (APCI) spectrum can obtain on FinniganMatSSQ 7000C instrument.

The synthetic of following compounds reported in the past:

7 (S)-iodomethyls-2 (S), 3 (S)-phenylbenzene-1,4-dioxy spiral shell [4,4] nonane: WO2003/095438.

Abbreviation and acronym: Ac: ethanoyl; ATP:5 '-Triphosaden; N-Bu: normal-butyl; DMF:N, dinethylformamide; DMPU:1,3-dimethyl-3,4,5,6-tetrahydrochysene-2 (1H)-pyrimidone; DMSO: dimethyl sulfoxide (DMSO); EDCI:1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride; Et: ethyl; FA: activate multiple (Fold activation); GK: glucokinase; Glc: glucose; G6P: G-6-P ester; G6PDH: glucose-6-phosphate dehydrogenase (G6PD); GST-GK: glutathione S-transferase-glucokinase enzyme fusion proteins; IH; Isohexane; LHMDS: two trimethyl silyl Lithamides; Me: methyl; NADP (H): β-Triphosphopyridine nucleotide, reduced (reductive); The NBS:N-bromo-succinimide; Ph: phenyl; Rt: room temperature; RT: retention time; TFAA: trifluoroacetic anhydride; THF: tetrahydrofuran (THF).Intermediate

Preparation 1:5-fluorine thiazol-2-yl amine hydrochlorate

With NEt ₃(63.4mL, (102.7g is 379mmol) at CH 455mmol) to join the basic amine hydrobromate of 5-bromo thiazole-2- ₂Cl ₂In the suspension under the stirring (1.5L).Under 0 ℃, in 15min, drip behind the 1h TFAA (64.2mL, 455mmol).Mixture is warming up to 20 ℃ in 1h, afterwards restir 2h.Add H ₂O (600mL) and the precipitation of collecting gained.The water layer of separating filtrate is also used CHCl ₃(3 * 300mL) extractions.With organic extract salt water washing, the drying (Na that merges ₂SO ₄), filter and concentrate.The precipitation and the residual solid of collecting are merged, and use EtOAc-n-C ₆H ₁₄Grinding obtains N-(5-bromo thiazole-2-yl)-2,2,2-trifluoroacetamide: δ _H(CDCl ₃): 7.45 (IH, s), 13.05 (IH, br).(solution of the 1.58M of 253mL in hexane, (50.0g is 183mmol) in the solution under the stirring of anhydrous THF (1.3L) 403mmol) to drop to above-mentioned acid amides in 50min with n-BuLi at-78 ℃.1.5h in 30min, drip N-fluoro two benzsulfamide (86.0g, 275mmol) solution in anhydrous THF (250mL) afterwards.This mixture is stirred 3h, be warming up to-30 ℃ afterwards.Add H ₂O (300mL) also filters this mixture by Celite pad.Collect solid and use Et ₂O (400mL) and H ₂O (400mL) washs diatomite.(2 * 400mL) extractions of the organic layer of separating filtrate and water.With the water layer Et that merges ₂O (400mL) washing is acidified to pH 6.5 with 2M HCl afterwards, and (2 * 400mL) extract with EtOAc.With the organic extract liquid H that merges ₂O (2 * 400mL) and salt water washing, drying (MgSO afterwards ₄), filter and concentrate.Through column chromatography (EtOAc-n-C ₆H ₁₄, 1: 3 to 1: 2) and obtain N-(5-fluorine thiazol-2-yl)-2,2,2-trifluoroacetamide: δ _H(CDCl ₃): 7.13 (IH, d).(12.6mL, (15.7g is 73mmol) in the solution under the stirring in MeOH (300mL) 175mmol) to drop to this acid amides with AcCl at 0 ℃.This mixture is stirred 30min at 20 ℃, reflux 1h, and last vacuum concentration.Residual solids is ground with THF and is obtained target compound: δ _H(D ₂O): 7.00 (1H, d).

The free alkali of target compound is by the preparation of following method: HCl salt is suspended in the ether, uses saturated NaHCO ₃The free alkali that solution washing, dry ether layer and evaporation are used at once.

Preparation 2:(4-methylsulfonyl phenyl) ethyl acetate

At-10 ℃ with SOCl ₂(8.2mL, (20.00g is 93.3mmol) in the suspension under the stirring of EtOH (80mL) 112.0mmol) to join (4-methylsulfonyl phenyl) acetate.This mixture is warming up to 20 ℃ in 16h, under reduced pressure removes afterwards and desolvate.Resistates is dissolved in EtOAc and uses H ₂The solution of O washing gained is neutral until the pH of water.This EtOAc solution is used saturated Na again ₂CO ₃Solution washing, drying (MgSO afterwards ₄).Also evaporating solvent obtains target compound after filtration: m/z (ES ⁺)=284.1[M+MeCN+H] ⁺

3-14:2 (R)-2-(3-chloro-4-methylsulfonyl phenyl)-(3-chloro-4-methylsulfonyl phenyl)-propionic acid can be according to preparing that WO2003/095438 put down in writing for 3-(3-hydroxycyclopent base) for 3-((R)-3-oxocyclopentyl) propionic acid, 2 (R)-2-(3-chloro-4-methylsulfonyl phenyl)-3-(4-oxo cyclohexyl) propionic acid and 2 (R)-2-in preparation.The carboxylic acid intermediate of needed general formula VIII can prepare by identical logical method in embodiment 7-15 synthetic, comprise with 4-iodomethyl-HC＜V carries out alkylation afterwards with the product hydrolysis to suitable ester.

The carboxylic acid intermediate of needed general formula VIII can prepare by following method in embodiment 7 synthetic:

Preparation 6a:(4-cyclopropyl sulfane base phenyl) ethoxyacetic acid

The 2M NaOH aqueous solution (163mL) is joined (4-cyclopropyl sulfane base phenyl) oxo ethyl acetate (40.62g, 162.5mmol) in the solution in EtOH (200mL) and the mixture under will stirring heat 2h at 60 ℃.After the cooling, mixture is concentrated into 150mL and uses ether (2 * 100mL) washings.Adding enough dense HCl afterwards regulates the precipitation that pH to 1 also will produce and is extracted into EtOAc (in 2 * 300mL).With the organic phase water that merges (3 * 100mL), salt solution (200mL) washing and dry (MgSO ₄).Removing desolvates obtains target compound: m/z (ES ^-)=221.0[M-H ⁺] ^-

Preparation 6b:(4-cyclopropyl sulfane base phenyl) acetate

With hydrazine hydrate (14.19g, 283.5mmol) be cooled to-50 ℃ and disposable adding (4-cyclopropyl sulfane base phenyl) oxo acetate (preparation 6a, 12.6g, 56.7mmol).Soup compound under the vigorous stirring is at first risen to room temperature keep 5min at 80 ℃ afterwards.(8.76g 156.5mmol) and with gained solution heats 20h at 100 ℃ to be divided into quarter adding solid KOH.When being cooled to room temperature, adding entry (25mL) and use Et ₂O (20mL) washs water.(2 * 15mL) wash ether phase self water, and transfer pH to 1 to the enough dense HCl of aqueous phase adding that merges.Afterwards the precipitation that will produce be extracted into EtOAc (in 2 * 300mL), and with the organic phase water that merges (3 * 100mL), salt solution (200mL) washing and dry (MgSO ₄).Evaporating solvent obtains target compound: m/z (ES ^-)=207.1[M-H ⁺] ^-

Preparation 6c:2-(4-cyclopropyl sulfane base phenyl)-N-(2 (R)-hydroxyl-1 (R)-methyl-2-styroyl)-N-methylacetamide

Anhydrous propanone (148mL) is joined (4-cyclopropyl sulfane base phenyl)-acetate (preparation 6b, 16.41g, 78.8mmol) and K ₂CO ₃(32.67g, 236.4mmol) in forming soup compound, and it under agitation is cooled to-10 ℃.(10.2mL 82.74mmol), and guarantees that temperature is no more than-10 ℃ in the dropping process dropwise to add pure trimethyl-acetyl chloride.Reaction mixture is stirred 20min at-10 ℃, is warming up to 0 ℃ of 20min, be cooled to afterwards-15 ℃ and disposable adding solid (1 (R), 2 (R))-(-)-pseudoephedrine (19.53g, 118.2mmol).Behind the 10min, reaction mixture is risen to room temperature, continue to stir 1.5h.Add entry (100mL) and extract mixture with EtOAc (500mL).The organic phase water (2 * 100mL) washings, and the water layer that merges is used EtOAc again, and (2 * 250mL) extract.Afterwards the organic layer that merges is washed with salt solution (100mL) and dry (MgSO ₄).Except that desolvating and making yellow solid residue recrystallization from EtOAc-IH obtain target compound: m/z (ES ⁺)=356.1[M+H] ⁺

Preparation 6d:2 (R)-(4-cyclopropyl sulfane base phenyl)-3-(3 (R)-oxocyclopentyl) propionic acid

(162mL, the 1M solution in THF 162mmoL) also under agitation are cooled to-20 ℃ with anhydrous THF (161mL) dilution LHMDS.Add 2-(4-cyclopropyl sulfane base phenyl)-N-(2 (R)-hydroxyl-1 (R)-methyl-2-styroyl)-N-methylacetamide (preparation 6c by sleeve pipe in the 10min, 30g, 84.4mmoL) solution in anhydrous THF (245mL), and guarantee that temperature of reaction remains on below-15 ℃ in the whole adition process.In 30min, reaction is warming up to-7 ℃, be cooled to-12 ℃ afterwards, and in 10min, add 7 (S)-iodomethyls-2 (S) by sleeve pipe, 3 (S)-phenylbenzene-1,4-dioxo spiro [4,4] nonane (27g, the 64.2mmoL) solution in anhydrous THF (111mL) and DMPU (18.9mL) mixture, and guarantee that temperature of reaction remains on below-7 ℃ in the whole process.Reaction is warming up to 2 ℃ and stir 4.5h, pours toluene (770mL) and 20%NH afterwards into ₄In the mixture of the Cl aqueous solution (550mL).After the vigorous stirring, separate organic layer and use 20%NH ₄The Cl aqueous solution (550mL) and salt solution (100mL) washing.Merge water and use EtOAc (500mL) extraction, with salt solution (100mL) washing of its after separating.Organic phase drying (the MgSO that merges ₄), filter, evaporation and by flash chromatography (IH-EtOAc, being increased to 1: 1 at 9: 1) oil of purifying gained obtains 2 (R)-(4-cyclopropyl sulfane base phenyl)-3-(2 (S), 3 (S)-phenylbenzene-1,4-dioxo spiro [4.4] ninth of the ten Heavenly Stems-7 (R)-yl)-N-(2 (R)-hydroxyl-1 (R)-methyl-2-styroyl)-N-methyl propanamide: m/z (ES ⁺)=648.3[M+H] ⁺Use 4.5M H ₂SO ₄The aqueous solution (61.5mL) dilute this acid amides (30.7g, 47.38mmol) 1, the solution under the stirring in the 4-dioxane (62mL), and the gained mixture heated 18h under relax refluxing.After ice-cooled, add entry (162mL) and extract this mixture with EtOAc (250mL).Separate water layer and further use EtOAc that (2 * 150mL) extractions are with (3 * 200mL) washings, and guarantee that last washing lotion is a pH neutrality, and washing with salt solution (100mL) of the organic layer water that merges.Dry (MgSO ₄) and filter after, remove and desolvate, residue is through flash chromatography (CH ₂Cl ₂, be CH afterwards ₂Cl ₂-THF became 3: 1 from 5: 1) purifying obtains target compound: m/z (ES ⁺)=305.1[M+H] ⁺

Preparation 6e:2 (R)-(4-encircles the third alkylsulfonyl phenyl)-3-(3 (R)-oxocyclopentyl) propionic acid

(preparation 6d, 5.0g is 16.43mmol) at CH with 2 (R)-(4-cyclopropyl sulfane base phenyl)-3-(3 (S)-oxocyclopentyl) propionic acid ₂Cl ₂Solution under the stirring (250mL) with ice-cooled to 1 ℃.Add 70%mCPBA (8.099g, 32.85mmol), and holding temperature is lower than 3 ℃ in batches.After the 6h, remove and desolvate, residue is through the flash chromatography (CH that contains 1%AcOH ₂Cl ₂, use THF afterwards) and purifying obtains target compound: m/z (ES ⁺)=337.1[M+H] ⁺

Preparation 15-17:

The intermediate of needed general formula I V can prepare by following logical method in embodiment 4-6 synthetic.When needs, any functional group in the intermediate, as the oxo in the compound of general formula I I or hydroxyl can be protected and this protecting group can utilize ordinary method to remove:

Under method A:-78 ℃, (24mL is at n-C with LDA ₇H ₁₆1.8M solution among the-THF-PhEt, (19mL is 153.0mmol) in the solution under the stirring in anhydrous THF (100mL) 43.3mmol) to be added drop-wise to DMPU.Behind the 30min, drip the suitable solution of phenylacetate III (20.6mmol) in anhydrous THF (42mL).With this mixture restir 1h, use the solution of derivative (20.6mmol) in anhydrous THF (25mL) of aldehyde II or its protection dropwise to handle afterwards.In 16h, be warming up to after 20 ℃, use saturated NH ₄The Cl aqueous solution (210mL) cancellation reaction.THF is removed in decompression, uses EtOAc (3 * 250mL) extraction leftovers then.With the merging of EtOAc extract, dry (MgSO ₄), filter and concentrate.Obtain ethyl propenoate by column chromatography.By for example under reflux state, heating this ester (19.1mmol) at MeOH (30mL) and 1MNaOH (40mL, 40.0mmol) this ester of solution 1h saponification in.Under cooling, wash this mixture with EtOAc.Water layer extracts with EtOAc afterwards with 1M HCl acidifying.Dry (MgSO ₄) organic extract that merges.(E)-vinylformic acid that filtration and evaporating solvent obtain expecting.

Method B: (the 0.5M solution of 0.63mL in EtOH 0.32mmol) drops in the solution of derivative (3.47mmol) in anhydrous DMSO (3mL) of phenylacetate III (3.16mmol) and aldehyde II or its protection with NaOEt.With mixture 80 ℃ the heating 16h, afterwards with AcOH with pH regulator to 7.Add EtOAc (30mL), water H afterwards ₂O (2 * 10mL) and salt solution (10mL) wash this solution, dry then (MgSO ₄).Obtain ethyl propenoate through filtration, evaporating solvent and column chromatography.Obtain desired (E)-vinylformic acid according to this ester of method saponification described in the method A.

Embodiment

Following compounds can utilize the logical method of the following stated to be prepared:

Method C: at 0 ℃ to PPh ₃(3.53g is 13.4mmol) at CH ₂Cl ₂Add in the solution under the stirring (70mL) NBS (882mg, 10.6mmol).After the 10min, add the compound of suitable general formula I V or VIII (9.0mmol), then mixture is stirred 20min at 0 ℃, stir 30min at 20 ℃ afterwards.0 ℃ add 5-fluorine thiazol-2-yl amine hydrochlorate (933mg, 9.3mmol) and pyridine (2.2mL, 18.8mmol), afterwards with mixture at 20 ℃ of stirring 20h.Behind the evaporating solvent, residue is distributed between 5% aqueous citric acid solution (100mL) and EtOAc (500mL).Water layer is further used EtOAc (200mL) extraction, afterwards with the organic layer H that merges ₂O and salt water washing, dry then (Na ₂SO ₄), filter and vacuum concentration.Use Chromatorex

NH-DM1020 (Fuji Silysia Chemical, Ltd., Aichi-ken, Japan; Also referring to http://www.fuji-silysia.co.jp/e-fl100dx.htm) residue is carried out chromatogram purification (CHCl ₃-MeOH, 99: 1) obtain desired compounds.

Method D: EDCI (80mg, 420 μ mol) and HOBt (56mg, 420 μ mol) are joined the compound of suitable general formula I V or VIII (320 μ mol) in the solution of dry DMF (6mL).After the 15min, this solution is handled with 5-fluorine thiazol-2-yl amine hydrochlorate (38mg, 380 μ mol) and pyridine (61 μ L, 760 μ mol).This mixture is stirred 16h at 20 ℃, under reduced pressure concentrate afterwards.With residue at CH ₂Cl ₂With saturated Na ₂CO ₃Distribute between the aqueous solution.Organic layer is washed with 1M HCl and dry (MgSO ₄).Filtration and evaporating solvent obtain desired compound, if this compound is a racemic modification, then can separate by chiral stationary phase HPLC.Method: CHIRAL CEL OJ

(Daicel Chemical Industries, Ltd., Tokyo, Japan), 10cm

* 25cm, MeOH (100%), 189mL/min, UV 285nm, 25 ℃.

Method E: (0.23mL 0.47mmol) joins the compound of suitable general formula I V or VIII (0.42mmol) at anhydrous CH with oxalyl chloride at 0 ℃ ₂Cl ₂In the solution (6mL).Add dry DMF (50 μ L), afterwards mixture is stirred 2h at 0 ℃.Add 5-fluorine thiazol-2-yl amine hydrochlorate (151mg, 1.28mmol; By with this hydrochloride at Et ₂O and saturated Na ₂CO ₃Distribute, separate Et between the aqueous solution ₂O layer, drying (MgSO ₄) and evaporating solvent and obtain) and pyridine (69 μ L 0.85mmol), stir 16h with mixture at 0-5 ℃ afterwards, are warming up to 20 ℃ and with EtOAc (45mL) dilution at last.With this solution with 1M HCl (2 * 20mL) and saturated Na ₂CO ₃The aqueous solution (2 * 20mL) washings, dry afterwards (MgSO ₄), filter, and concentrate.Obtain desired compound through chromatogram purification.

The compound of embodiment 7,2 (R)-2-(4-encircles the third alkylsulfonyl phenyl)-N-(5-fluorine thiazol-2-yl)-3-((R)-3-oxygen basic ring amyl group) propionic acid amide are by following method preparation:

(preparation 6e, 893mg is 2.65mmol) at anhydrous CH with 2 (R)-(4-encircles the third alkylsulfonyl phenyl)-3-(3 (R)-oxocyclopentyl) propionic acid ₂Cl ₂Solution (38mL) is cooled to 0 ℃ and dropwise add oxalyl chloride (0.408g is 3.21mmol) at anhydrous CH ₂Cl ₂Solution (2mL), and during adding holding temperature at 0 ℃.Add dry DMF (0.08mL) and reaction mixture is stirred 2.5h.(preparation 1,345mg is 2.92mmol) at anhydrous CH slowly to introduce 2-amino-5-fluorine thiazole ₂Cl ₂Solution (6mL), (0.53mL 5.31mmol), and stirs 2h with mixture at 0 ℃ and at room temperature stirs then and spend the night to add pyridine afterwards.With this solution CH ₂Cl ₂(150mL) dilution and with the aqueous citric acid solution of 5%w/v (2 * 30mL), saturated NaHCO ₃The aqueous solution (2 * 30mL), the washing of water (50mL) and salt solution (50mL).With organic layer drying (MgSO ₄), evaporation and the residue purifying is obtained target compound by flash chromatography (IH-EtOAc, 3: 2): RT=3.47min; M/z (ES ⁺)=437.1[M+H] ⁺

Measure

External GK activity:

Utilization is similar to the scheme of putting down in writing among the WO2000/58293, can interrelate by the generation that to be contact enzyme (coupling enzyme) with G6PDH generate the process of G6P and NADPH with GST-GK and measure the GK activity.

It is under 30 ℃, carry out in the final incubation volume available from Costar is the flat 96 hole analysis plates of 100 μ L that GK measures.Assay buffer comprises: 25mM Hepes damping fluid (pH7.4), 12.5mM KCl, 5mM D-Glc, 5mM ATP, 6.25mM NADP, 25mMMgCl ₂, 1mM dithiothreitol (DTT) (dithiothreitol), testing compound or 5%DMSO, 3.0 units/mL G6PDH and 0.4 μ L/mL derive from the GST-GK of people liver GK.ATP, G6PDH and NADP can buy from Roche Diagnostics.Other reagent is＞98% purity and can having bought from Kanto Chemicals.Earlier testing compound is dissolved among the DMSO, joins then in the assay buffer that does not contain ATP.(preincubation is 10 minutes in temperature-controlling chamber CA) for Molecular Devices Corporation, Sunnyvale, adds 10 μ L ATP solution afterwards and begins reaction at SPECTRAmax 250 micro-incubation plate spectrophotometers with this mixture.

After the reaction beginning, measure the GK activity by the increase of monitoring 340nm place optical density(OD) (OD) in 10 minutes incubation period.In 10 minutes incubation period, add enough GST-GK containing 5%DMSO but do not contain in the hole of testing compound, so that OD ₃₄₀Increase.Interim GK reaction was linear when trial test showed this section, even also was like this in the presence of the activator that makes 8 times of the active increases of GK.Compare hole and contain GK activity in the hole of GK activator to be measured.The calculating active compound concentration that increases by 50% (being FA1.5) of GK of sening as an envoy to.The GK activator reaches FA1.5 when≤30 μ M.Use the dilution of a series of concentration ranges of testing compound, can calculate the active maximum increase of GK and produce 50% activation (EC ₅₀) the concentration of testing compound.

The compound of embodiment 7 can reach the maximum activation of GK more than four times, its EC ₅₀Be lower than 0.5 μ M.

The activity in vivo of GK:

After the fasting 18 hours, the C57BL/6J its mouse oral is raised the GK activator of 50mg/kg body weight by force.6 hours in-test after administration, measure blood Glc and reached 5 times of original content.

Before oral processing, body weight of mensuration mouse (n=5) and fasting earlier 18 hours.The GK activator is dissolved in the Gelucire carrier (EtOH: Gelucire44/14: PEG400q.s.4: 66: 30v/v/v) that once reported as WO 00/58293 with the concentration of 13.3mg/mL.To the composition administration of mouse, be equivalent to 50mg/kg dosage with per kilogram of body weight 7.5mL.Before the horse back administration, from the afterbody clip sub-fraction (less than 1mm) of animal, and collect 15 μ L blood, thereby record the blood Glc of (0 time) before the administration for analysis.With after the GK Treatment with activating agent, after administration, from the wound of same afterbody, measured blood Glc respectively on the the 1st, 2,4 and 6 hour.Reach a conclusion by comparing 6 hour in-test, 5 mouse and 5 mouse blood Glc mean values with the GK Treatment with activating agent with vehicle treated.If compare with carrier, they 2 successive analysis time point make blood Glc show statistics to reduce significantly, then these compounds are considered to have activity.

Claims (14)

1, the compound of a kind of general formula (I) or the acceptable salt of its pharmacology:

Wherein:

By-HC＜and the group that becomes of V-arrangement represents 3-oxocyclopentyl, 4-oxo cyclohexyl or 3-hydroxycyclopent base,

R ¹Be SOR ³, SO ₂R ³Or SO ₂NR ⁴R ⁵

R ²Be hydrogen, chlorine, fluorine or trifluoromethyl;

R ³Be C _1-4Alkyl or C _3-7Cycloalkyl;

R ⁴And R ⁵Be hydrogen or C independently _1-4Alkyl;

M is 0;

Dotted line forms optional two keys with solid line, and on behalf of this pair key, Δ have (E)-configuration.

2, compound as claimed in claim 1 or the acceptable salt of its pharmacology, wherein dotted line forms two keys with solid line.

3, compound as claimed in claim 1 or the acceptable salt of its pharmacology, wherein dotted line forms singly-bound with solid line.

4, compound as claimed in claim 3 or the acceptable salt of its pharmacology, wherein dotted line forms singly-bound with solid line, and is (R) in the absolute configuration of the asymmetric center of amidocarbonylation carbon α position.

5, as claim 1,2,3 or 4 compound or the acceptable salt of its pharmacology, wherein R ³Be C _3-7Cycloalkyl.

6, as claim 1,2,3 or 4 compound or the acceptable salt of its pharmacology, wherein R ¹Be SO ₂C _3-4Cycloalkyl.

7, as claim 1,2,3 or 4 compound or the acceptable salt of its pharmacology, wherein R ²Be hydrogen, chlorine or fluorine.

8, be selected from following compound or the acceptable salt of its pharmacology:

2 (R)-2-(3-chloro-4-methylsulfonyl phenyl)-N-(5-fluorine thiazol-2-yl)-3-((R)-3-oxocyclopentyl) propionic acid amide;

2 (R)-2-(3-chloro-4-methylsulfonyl phenyl)-N-(5-fluorine thiazol-2-yl)-3-(4-oxo cyclohexyl) propionic acid amide;

2 (R)-2-(3-chloro-4-methylsulfonyl phenyl)-N-(5-fluorine thiazol-2-yl)-3-(3-hydroxycyclopent base) propionic acid amide;

(E)-N-(5-fluorine thiazol-2-yl)-2-(4-methylsulfonyl phenyl)-3-((S)-3-oxocyclopentyl) acrylamide;

(E)-N-(5-fluorine thiazol-2-yl)-2-(4-methylsulfonyl phenyl)-3-(4-oxo cyclohexyl) acrylamide;

(E)-N-(5-fluorine thiazol-2-yl)-3-(3-hydroxycyclopent base)-2-(4-methylsulfonyl phenyl) acrylamide;

2 (R)-2-(4-encircles the third alkylsulfonyl phenyl)-N-(5-fluorine thiazol-2-yl)-3-((R)-3-oxocyclopentyl) propionic acid amide;

2 (R)-2-(4-encircles the third alkylsulfonyl phenyl)-N-(5-fluorine thiazol-2-yl)-3-(4-oxo cyclohexyl) propionic acid amide;

2 (R)-2-(4-encircles the third alkylsulfonyl phenyl)-N-(5-fluorine thiazol-2-yl)-3-(3-hydroxycyclopent base) propionic acid amide;

2 (R)-2-(4-ring fourth alkylsulfonyl phenyl)-N-(5-fluorine thiazol-2-yl)-3-(3-oxocyclopentyl) propionic acid amide;

2 (R)-2-(4-ring fourth alkylsulfonyl phenyl)-N-(5-fluorine thiazol-2-yl)-3-(4-oxo cyclohexyl) propionic acid amide;

2 (R)-2-(4-ring fourth alkylsulfonyl phenyl)-N-(5-fluorine thiazol-2-yl)-3-(3-hydroxycyclopent base) propionic acid amide;

2 (R)-2-(3-fluoro-4-methylsulfonyl phenyl)-N-(5-fluorine thiazol-2-yl)-3-((R)-3-oxocyclopentyl) propionic acid amide;

2 (R)-2-(3-fluoro-4-methylsulfonyl phenyl)-N-(5-fluorine thiazol-2-yl)-3-(4-oxo cyclohexyl) propionic acid amide; And

2 (R)-2-(3-fluoro-4-methylsulfonyl phenyl)-N-(5-fluorine thiazol-2-yl)-3-(3-hydroxycyclopent base) propionic acid amide.

9, a kind of pharmaceutical composition, it comprises as any described compound in the claim 1 to 8 or acceptable salt of its pharmacology and pharmacology acceptable carrier.

10, the purposes that is used for the medicine of preventative or therapeutic treatment hyperglycemia or diabetes as any described compound in the claim 1 to 8 or the acceptable salt of its pharmacology in production.

11, as the purposes of claim 10, wherein said medicine is used for and one or more other hyperglycemia medicine or antidiabetic medicine Combined Preparation.

12, the purposes in the medicine of the people's treatment diabetes that reduce as any described compound in the claim 1 to 8 or the acceptable salt of its pharmacology diabetic hyperglycemia or glucose tolerance before production is used for showing.

13, the compound of preparation general formula (Ia) or the method for the acceptable salt of its pharmacology:

Described method comprises the compound with general formula (IV):

Carry out condensation with the compound or its salt of logical formula V,

Wherein V, R ¹, R ², m and Δ such as claim 1 definition.

14, the method for the compound of preparation general formula (Ib):

Described method comprises the compound with general formula (VIII):

Carry out condensation with the compound or its salt of logical formula V,

Wherein V, R ¹, R ²With m such as claim 1 definition.