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CN101151245A - Indan-amide derivatives with glycogen phosphorylase inhibitory activity - Google Patents

Indan-amide derivatives with glycogen phosphorylase inhibitory activity Download PDF

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Publication number
CN101151245A
CN101151245A CNA2006800102259A CN200680010225A CN101151245A CN 101151245 A CN101151245 A CN 101151245A CN A2006800102259 A CNA2006800102259 A CN A2006800102259A CN 200680010225 A CN200680010225 A CN 200680010225A CN 101151245 A CN101151245 A CN 101151245A
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amino
alkyl
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艾伦·M·伯奇
克雷格·约翰斯通
阿莱恩·T·普洛赖特
伊恩·辛普森
保罗·R·O·惠特莫尔
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AstraZeneca AB
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Abstract

A compound of the formula (1) or a pharmaceutically-acceptable salt: (A chemical formula should be inserted here - please see paper copy enclosed herewith) (1) possess glycogen phosphorylase inhibitory activity and accordingly have value in the treatment of disease states associated with increased glycogen phosphorylase activity. Processes for the manufacture of compounds and pharmaceutical compositions containing them are described.

Description

Indan-amide derivatives with glycogen phosphorylase inhibitory activity
Technical field
The present invention relates to indan-amide derivatives (indan amide derivatives), hydrolyzable ester in its pharmacy acceptable salt and the body.These heterocycleamides have glycogen phosphorylase inhibitory activity, thereby having value with active the increasing in the relevant treatment of conditions of glycogen phosphorylase, so can be used for warm-blooded animal such as people's methods of treatment potentially.The invention still further relates to the preparation method of described heterocyclic amide derivative, comprise their pharmaceutical composition, and the purposes in preparation inhibition warm-blooded animal such as people's the active medicine of glycogen phosphorylase.
Background technology
Liver is the major organs of regulating glucemia in the postabsorptive state.In addition, although the contribution of eating the back glucose level is had less effect, liver is the key that keeps the blood sugar normal capacity to the reaction of external source blood sugar.It is believed that, seen at diabetes B, arrive that hepatic glucose output (HGO) is increased in and keeps playing an important role in high fasting plasma glucose (FPG) level; Particularly (Weyeret al, (1999), J Clin Invest 104:787-794 in the diabetes B of those FPG＞140mg/dl (7.8mM); Clore﹠amp; Blackgard (1994), Diabetes 43:256-262; De Fronzo, R.A., et al, (1992) Diabetes Care 15; 318-355; Reaven, G.M. (1995) Diabetologia 38; 3-13).
Because present per os anti-diabetic therapy can not make the FPG level be in normal non-diabetic scope, and since high FPG (and glycHbAlc) level for grand vascular disease (Charles, M.A.et al (1996) Lancet 348,1657-1658; Coutinho, M.et al (1999) Diabetes Care 22; 233-240; Shaw, J.E.et al (2000) Diabetes Care 23,34-39) and microvascular disease (DCCTResearch Group (1993) New.Eng.J.Med.329; 977-986) all be dangerous factor; So the reduction of high FPG level and normalizing remain the therapeutic goal of diabetes B.
It is estimated that after overnight fasting, 74% HGO derives from glycogenolysis, remaining derive from the gluconeogenesis precursor (Hellerstein et al (1997) Am J Physiol, 272:E163).Glycogen phosphorylase is the glycogenolysis glucogenic key enzyme in liver and other tissue such as muscle and nervous tissue by Cori ester.
The liver glycogen phosphorylase activity raises in the diabetes animal model that comprises db/db mouse and fa/fa rat, and (Aiston S et al (2000), Diabetalogia 43,589-597).
Show, adopt chloro-indole class inhibitor (CP91149 and CP320626) that liver glycogen phosphorylase is suppressed, can reduce the promoted glycogenolysis of glucagon and glucose output (Hoover et al (1998) J Med Chem 41,2934-8 in the liver cell; Martin et al (1998) PNAS 95,1776-81).In addition, after db/db and ob/ob mouse were with these compound treatment, blood sugar concentration reduced in the mode relevant with dosage.
Exist and do not exist under the situation of other glycogen phosphorylase inhibitors Bay K 3401, excite conscious dog to study with glucagon, these researchs show that equally this medicament has potential effectiveness in the situation (as at 1 type and diabetes B) that round-robin glucagon level raises.Under the situation that has Bay R 3401, and the reduction significantly after glucagon excites of hepatic glucose output and artery blood sugar (Shiota et al, (1997), Am J Physiol, 273:E868).
Indan-amide of the present invention has glycogen phosphorylase inhibitory activity, expection can be used for treating diabetes B (type 2 diabetes), insulin resistance (insulin resistance), syndrome X (syndromeX), hyperinsulinemia (hyperinsulinaemia), the too much disease of blood glucagon (hyperglucagonaemia), myocardial ischemia (cardiac ischaemia) and obesity (obesity), particularly diabetes B.
Compound of the present invention has good physical properties, as good solubility.
Summary of the invention
According to an aspect of the present invention, provide formula (1) compound or its pharmacy acceptable salt:
Figure A20068001022500071
In the formula:
N is 0,1 or 2;
M is 0,1 or 2;
R 1Be independently selected from halogen, nitro, cyano group, hydroxyl, carboxyl, formamyl, N-C 1-4Alkyl-carbamoyl, N, N-(C 1-4Alkyl) 2Formamyl, sulfamyl, N-C 1-4Alkylsulfamoyl group, N, N-(C 1-4Alkyl) 2Sulfamyl, C 1-4Alkyl S (O) b(wherein b is 0,1 or 2) ,-OS (O) 2C 1-4Alkyl, C 1-4Alkyl, C 2-4Thiazolinyl, C 2-4Alkynyl, C 1-4Alkoxyl group, C 1-4Alkyloyl, C 1-4Alkanoyloxy, hydroxyl C 1-4Alkyl, methyl fluoride, difluoromethyl, trifluoromethyl, trifluoromethoxy, and-NHSO 2C 1-4Alkyl;
Perhaps, when n is 2, two R 1Group can be coupled carbon atom form 4 to 7 yuan of saturated rings together, it is optional to comprise 1 or 2 heteroatoms that independently is selected from O, S or N, and is optionally replaced by one or two methyl;
R 4Be independently selected from halogen, nitro, cyano group, hydroxyl, methyl fluoride, difluoromethyl, trifluoromethyl, trifluoromethoxy, carboxyl, formamyl, C 1-4Alkyl, C 2-4Thiazolinyl, C 2-4Alkynyl, C 1-4Alkoxyl group, and C 1-4Alkyloyl;
Z 1For following a) or b):
A) formula-Y-COOH, wherein Y is C 1-6Alkylidene group or C 3-6Cycloalkylidene; Perhaps
B) formula-Y-COOH, wherein Y is C 1-6Alkylidene group, this C 1-6Alkylidene group:
I) be selected from-N (R 7)-,-O-,-S-,-SO-and-SO 2-in heteroatoms (condition is that this heteroatoms is not adjacent with described carboxyl, and R wherein at interval 7Be hydrogen, C 1-4Alkyl, C 1-4Alkyloyl or C 1-4Alkyl sulphonyl); And/or
Ii) independently being selected from following substituting group by 1 or 2 on carbon replaces: cyano group, oxo, hydroxyl, C 1-3Alkoxyl group, C 1-3Alkyloyl, C 1-3Alkoxy C 2-3Alkoxyl group, hydroxyl C 1-3Alkyl, hydroxyl C 2-3Alkoxyl group, C 3-6Cycloalkyl, C 3-6Cycloalkyl C 1-3Alkyl, C 3-6Cycloalkyloxy, C 3-6Cycloalkyl C 1-3Alkoxyl group, C 1-3Alkyl S (O) c(wherein c is 0,1 or 2) ,-CON (R 2) R 3,-N (R 2) COR 3,-SO 2N (R 2) R 3, and-N (R 2) SO 2R 3, R wherein 2And R 3Be independently selected from hydrogen and C 1-3Alkyl;
Perhaps when described alkylidene group by heteroatoms at interval the time, it also can be chosen wantonly on carbon by two substituting groups and replace, the coupled carbon atom of described two substituting groups forms C together 3-6Cycloalkyl ring.
On the other hand, defined formula (1) compound or its prodrug in the present invention relates to as mentioned.The suitable example of the prodrug of formula (1) compound is the interior hydrolyzable ester of the body of formula (1) compound.Therefore in another aspect, hydrolyzable ester in defined formula (1) compound or its body in the present invention relates to as mentioned.
Should be understood that, as long as some formula defined above (1) compound can exist with optically-active or racemic form owing to one or more unsymmetrical carbon, comprise any this optically-active or racemic form in the definition of the present invention with glycogen phosphorylase inhibitory activity.The synthetic of optically-active form can carry out according to the known standard technique of organic chemistry filed, for example by carrying out from the synthetic of optically-active raw material or by the fractionation of racemic form.Similarly, above-mentioned activity can utilize standard laboratory technology hereinafter described to estimate.
In the present invention, should be appreciated that can there be tautomerism in formula (1) compound or its salt, and the structural formula figure in this specification sheets can only represent a kind of possible tautomeric form.Should be appreciated that to the present invention includes any tautomeric form, be not limited only to any tautomeric form that adopts among the structural formula figure with glycogen phosphorylase inhibitory activity.Structural formula figure in this specification sheets can only represent one of possible tautomeric form, and be to be understood that, this specification sheets comprises all possible tautomeric form of the compound of being described, not those tautomeric forms that just may illustrate herein.
It is also understood that some formula (1) compound and salt thereof can solvations and solvation form such as hydrated form do not exist.Should be appreciated that the solvation form that all these have glycogen phosphorylase inhibitory activity that the present invention includes.
It is also understood that some formula (1) compound may have polymorphism, the present invention includes the form that all these have glycogen phosphorylase inhibitory activity.
Defined formula (1) compound and salt thereof in the present invention relates to as mentioned.The salt that is used for pharmaceutical composition is pharmacy acceptable salt, but other salt also can be used for preparation formula (1) compound and pharmacy acceptable salt thereof.For example, the acid salt of defined formula (1) compound during pharmacy acceptable salt of the present invention comprises as mentioned, described formula (1) compound is abundant tart, thereby forms this salt.This acid salt for example comprises and pharmaceutically acceptable anionic mineral acid or organic acid salt is provided, for example with the salt of hydrogen halide (particularly hydrochloric acid or Hydrogen bromide wherein preferred hydrochloric acid) or with the salt of sulfuric acid or phosphoric acid, perhaps with the salt of trifluoroacetic acid, citric acid or toxilic acid.Suitable salt comprises hydrochloride, hydrobromate, phosphoric acid salt, vitriol, hydrosulfate, alkylsulfonate, arylsulphonate, acetate, benzoate, Citrate trianion, maleate, fumarate, succinate, lactic acid salt and tartrate.In addition, if formula (1) compound is abundant tart, then can form pharmacy acceptable salt with pharmaceutically acceptable cationic mineral alkali or organic bases are provided.For example, the salt that forms with mineral alkali or organic bases comprises an alkali metal salt such as sodium or sylvite, alkaline earth salt such as calcium or magnesium salts, ammonium salt or for example with the salt of methylamine, dimethylamine, Trimethylamine 99, piperidines, morpholine or three-(2-hydroxyethyl) amine.
Compound of the present invention can be with the form administration of prodrug, and described prodrug decomposes in human body or animal body and obtains compound of the present invention.Prodrug can be used for changing or improving the physics and/or the pharmacokinetic properties of parent compound, and can form when parent compound comprises the proper group that can be derivatized to prodrug or substituting group.The example of prodrug comprises the interior hydrolyzable ester of the body of compound of the present invention and pharmacy acceptable salt thereof.
The interior hydrolyzable ester of body that comprises formula (1) compound of carboxyl or hydroxyl is for example pharmaceutically acceptable ester, and it decomposes generation parent acid or alcohol in human body or animal body.
For carboxyl, suitable pharmaceutically acceptable ester comprises C 1-6Alkoxy methyl ester such as methoxymethyl ester, C 1-6Alkanoyloxymethyl ester such as oxy acid methyl neopentyl ester, phthalidyl ester, C 3-8Cycloalkyloxy carbonyl oxygen base C 1-6Alkyl ester such as 1-cyclohexyl carbonyl oxygen base ethyl ester, 1,3-dioxole-2-ketone group methyl ester such as 5-methyl isophthalic acid, 3-dioxole-2-ketone group methyl ester, and C 1-6Alkoxyl group carbonyl oxygen base ethyl ester such as 1-methoxyl group carbonyl oxygen base ethyl ester, and can become ester on any carboxyl in compound of the present invention.
For hydroxyl, suitable pharmaceutically acceptable ester comprises inorganic ester such as phosphoric acid ester (comprising the phosphoramidic acid cyclic ester) and because hydrolysis and obtain the alpha-acyloxy alkyl oxide and relevant compound of parent hydroxy in the body of ester.The example of alpha-acyloxy alkyl oxide comprises acetoxyl group methoxyl group and 2,2-dimethyl propylene acyloxy methoxyl group.For hydroxyl, the selection of hydrolyzable ester comprises C in the organizer 1-10Alkyloyl, for example ethanoyl; Benzoyl; Phenylacetyl; The benzoyl and the phenylacetyl that replace; C 1-10Alkoxy carbonyl (obtaining alkyl carbonate), for example ethoxy carbonyl; Two-(C 1-4) alkyl-carbamoyl and N-(two-(C 1-4) the alkylamino ethyl)-N-(C 1-4) alkyl-carbamoyl (obtaining carbamate); Two-(C 1-4) alkylamino ethanoyl and carboxyl ethanoyl.The example of the ring substituents of phenylacetyl and benzoyl comprises amino methyl, (C 1-4) alkylamino methyl and two-((C 1-4) alkyl) amino methyl, and be connected to the 3-of benzoyl basic ring or morpholino or the Piperazino that the 4-position forms by the methylene radical linking group by theheterocyclic nitrogen atom.Hydrolyzable ester comprises in other interested body, for example, and R AC (O) OC 1-6Alkyl-CO-, wherein R ABe for example benzyloxy-(C 1-4) alkyl, perhaps phenyl).Suitable substituting group on the phenyl of this ester comprises, for example, and 4-(C 1-4Alkyl) Piperazino-C 1-4Alkyl, Piperazino-C 1-4Alkyl and morpholino-(C 1-C 4) alkyl.
In this manual, generic term " alkyl " comprises straight chain and branched-chain alkyl.Yet the independent alkyl of mentioning only refers in particular to straight chain type as " propyl group ", and the independent branched-chain alkyl such as the tertiary butyl mentioned only refer in particular to branched chain type.For example, " C 1-4Alkyl " comprise methyl, ethyl, propyl group, the sec.-propyl and the tertiary butyl, and " C 1-6Alkyl " example comprise " C 1-4Alkyl " example and other amyl group, 2,3-dimethyl propyl, 3-methyl butyl and hexyl.Similarly regulation is applicable to other generic term, for example, and " C 2-4Thiazolinyl " comprise vinyl, allyl group and 1-propenyl, and " C 2-6Thiazolinyl " example comprise " C 2-4Thiazolinyl " example and other 1-butylene base, crotyl, 3-butenyl, 2-methyl-but-2-ene base, 3-methyl-but-1-ene base, 1-pentenyl, 3-pentenyl and 4-hexenyl." C 2-4Alkynyl " example comprise ethynyl, 1-proyl and 2-propynyl, and " C 2-6Alkynyl " example comprise " C 2-4Alkynyl " example and other 3-butynyl, valerylene base and 1-methylpent-2-alkynyl.
Term " hydroxyl C 1-4Alkyl " comprise hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyl sec.-propyl and hydroxybutyl.Term " hydroxyethyl " comprises 1-hydroxyethyl and 2-hydroxyethyl.Term " hydroxypropyl " comprises the 1-hydroxypropyl, 2-hydroxypropyl and 3-hydroxypropyl, and similarly regulation is applicable to other term such as hydroxybutyl.Term " dihydroxyl C 1-4Alkyl " comprise dihydroxy ethyl, dihydroxypropyl, dihydroxyl sec.-propyl and dihydroxyl butyl.Term " dihydroxypropyl " comprises 1,2-dihydroxypropyl and 1,3-dihydroxypropyl.Similarly regulation is applicable to other term such as dihydroxyl sec.-propyl and dihydroxyl butyl.
Term " halo " is meant fluoro, chloro, bromo and iodo.For example, term " dihalo C 1-4Alkyl " comprise difluoromethyl and dichloromethyl.For example, term " three halo C 1-4Alkyl " comprise trifluoromethyl.
" C 1-3Alkoxyl group ", " C 1-4Alkoxyl group " and " OC 1-4Alkyl " example comprise methoxyl group, oxyethyl group, propoxy-and isopropoxy." C 1-6Alkoxyl group " example comprise " C 1-4Alkoxyl group " example and other butoxy, tert.-butoxy, pentyloxy and 1,2-(methyl) 2Propoxy-." hydroxyl C 2-3Alkoxyl group " example comprise the 1-hydroxyl-oxethyl, 1-hydroxyl propoxy-and 2-hydroxyl propoxy-; C 1-3Alkoxy C 2-3The example of alkoxyl group comprises methoxy ethoxy, ethoxy ethoxy and methoxy propoxy; " C 1-3Alkyloyl " and " C 1-4Alkyloyl " example comprise formyl radical, ethanoyl and propionyl." C 1-6Alkyloyl " example comprise " C 1-4Alkyloyl " example and other butyryl radicals, pentanoyl, caproyl and 1,2-(methyl) 2Propionyl." C 1-4Alkanoyloxy " example comprise methanoyl, acetoxyl group and propionyloxy." C 1-6Alkanoyloxy " example comprise " C 1-4Alkanoyloxy " example and other butyryl acyloxy, penta acyloxy, hexylyloxy and 1,2-(methyl) 2Propionyloxy." N-(C 1-4Alkyl) formamyl " example be methylamino formyl radical and ethylamino formyl radical." N, N-(C 1-4Alkyl) 2Formamyl " example be N, N-(methyl) 2Formamyl, N, N-(ethyl) 2Formamyl and N, methyl-N-ethylamino formyl radical." N-(C 1-4Alkyl) sulfamyl " example be N-(methyl) sulfamyl and N-(ethyl) sulfamyl." N, N-(C 1-4Alkyl) 2Sulfamyl " example be N, N-(methyl) 2Sulfamyl, N, N-(ethyl) 2Sulfamyl and N-(methyl)-N-(ethyl) sulfamyl.-NHSO 2C 1-4The example of alkyl is a methyl sulphonyl amino, ethylsulfonyl amino, sulfonyl propyl base amino, sec.-propyl sulfuryl amino and tertiary butyl sulfuryl amino.
" C 1-4Alkyl S (O) b(wherein b is 0,1 or 2) ", " C 1-4Alkyl S (O) c(wherein c is 0～2) ", " C 1-3Alkyl S (O) c(wherein c is 0～2) " and " C 1-4Alkyl S (O) d(wherein d is 0～2) " example comprise methylthio group independently, ethylmercapto group, rosickyite base, methanesulfinyl, second sulfinyl, third sulfinyl, methylsulfonyl, ethylsulfonyl, third alkylsulfonyl and different third alkylsulfonyl." C 1-4Alkyl S (O) bC 1-4Alkyl-(wherein b is 0,1 or 2) " example comprise the sulfonyloxy methyl ylmethyl, methylsulfinyl methyl, methylthiomethyl, ethylsulfonyl methyl, ethyl sulfinyl methyl and ethylmercapto group methyl." C 1-4Alkyl sulphonyl " example comprise methylsulfonyl, ethylsulfonyl, third alkylsulfonyl and different third alkylsulfonyl." OSO 2C 1-4Alkyl " example comprise sulfonyloxy methyl oxygen base, ethyl sulfonyloxy, sulfonyl propyl oxygen base, sec.-propyl sulfonyloxy and tertiary butyl sulfonyloxy.
" C 3-6Cycloalkyl " example comprise cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl." C 3-6Cycloalkyl C 1-3Alkyl " example comprise the cyclopropyl methyl, cyclobutylmethyl, cyclopentyl-methyl and cyclohexyl methyl." C 3-6Cycloalkyloxy " example comprise the ring propoxy-, cyclobutoxy group, cyclopentyloxy and cyclohexyloxy." C 3-6Cycloalkyl C 1-3Alkoxyl group " example comprise cyclo propyl methoxy, cyclobutyl methoxy base, cyclopentyl methoxyl group and cyclohexyl methoxyl group.
Use group that compound term description comprises an above functional group as-C in this manual 1-4Alkyl SO 2C 1-4Alkyl.The implication of each integral part that this class term should be understood according to those skilled in the art is explained.
C 3-6The example of cycloalkylidene comprises ring third-1-subunit, ring fourth-1-subunit and ring penta-1-subunit.
For fear of doubt, should be appreciated that in this manual, if certain group be restricted to ' defining in the preamble ' or ' as in the preamble fixed ", then this group comprises and occurring for the first time and the wideest definition, and the whole of relevant this group specifically define.
Should be appreciated that if substituting group comprises two substituting groups on alkyl chain wherein the two all connects (for example two alkoxy substituents) by heteroatoms, then the substituting group on these two substituting groups same carbon atom that is not alkyl chain.
Should be appreciated that the optional substituting group on all groups can be connected on any suitable available atom, unless otherwise prescribed, comprise heteroatoms, as long as they are not therefore by quaternized.Therefore, the C of hydroxyl replacement 1-6Alkyl comprises hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl and 3-hydroxypropyl.
For fear of doubt, if Z 1=-Y-COOH, wherein Y is by the C of a heteroatoms interval (and optional being substituted) 1-6Alkylidene group, then this C 1-6Alkylidene group can be a side chain, and any optional substituting group can be positioned on the side chain, makes this Z 1Definition comprise structure as follows (wherein Y is the ethylidene that methoxyl group replaces).
Figure A20068001022500121
If optional substituting group is selected from " 0,1 or 2 " individual group, should be appreciated that this definition comprises to be selected from all substituting groups of specifying one of group or to be selected from the regulation group two or more substituting group.
Be selected from the heteroatoms C at interval of nitrogen, oxygen and sulphur 1-6The example of alkylidene group comprises divalence-CH 2XCH 2-,-CH 2XCH 2CH 2-,-CH 2CH 2XCH 2-,-CH (R a) XCH 2-,-CH (R a) XCH 2CH 2-,-CH (R a) CH 2XCH 2-,-CH 2CH (R a) XCH 2-,-CH 2CH 2XCH (R a)-,-CH 2XCH (R a) CH 2-,-CH 2XCH 2CH (R a)-[, wherein X was selected from-O-,-S-,-SO-,-SO 2-and-N (R c) (R among the application cBe selected from methyl, ethyl, formyl radical, ethanoyl and methylsulfonyl) and R aBe selected from methyl and ethyl].The connector on right side and Z 1In the COOH group link to each other.
By heteroatoms C at interval 1-6Other example of alkylidene group comprises-CH 2XCH 2-,-CH 2XCH 2CH 2-,-CH 2CH 2XCH 2,-CH (R f) XCH 2-,-CH (R f) XCH 2CH 2-,-CH (R f) CH 2XCH 2-,-CH 2CH (R f) XCH 2-,-CH 2CH 2XCH (R f)-,-CH 2XCH (R f) CH 2-,-CH 2XCH (R f)-,-CH 2XCR f 2-,-CH 2XCH 2CH 2CH 2-,-CH (CH 2XCH 2CH 3)-,-CH (CH 2XCH 3)-,-CH (CH 2CH 2XCH 3)-,-CH (CH 2CH 2XCH 2CH 3)-,-CH (CH 2CH 2CH 2XCH 3)-,-CH (CH 2XCH 2CH 3) CH 2-,-CH (CH 2XCH 3) CH 2-,-CH (CH 2CH 2XCH 3) CH 2-,-CH (CH 2CH 2XCH 2CH 3) CH 2-, and-CH (CH 2CH 2CH 2XCH 3) CH 2-[wherein X definition as above and particularly be selected from-O-,-S-and-SO 2-, and R fBe selected from methyl and ethyl].The connector on right side and Z 1In the COOH group link to each other.
C 1-6The example of alkylidene group comprises the methylene radical of divalence, ethylidene, and propylidene, butylidene ,-CH (Me)-,-CH (Et)-,-C (Me) 2-,-CH 2CH (Me)-,-CH 2CH (Et)-and-CH 2C (Me) 2-.The connector on right side and Z 1In the COOH group link to each other.
Y, R 1, R 4, the occurrence of n and m is as follows.If suitable, then can use these values to preamble and the definition of hereinafter being established, claim, aspect and embodiment.
Formula (1) compound is provided in one embodiment of the invention, the pharmacy acceptable salt of formula (1) compound is provided in selectable embodiment, hydrolyzable ester in the body of formula (1) compound is provided in further selectable embodiment, and the pharmacy acceptable salt of hydrolyzable ester in the body of formula (1) compound is provided in selectable embodiment further.
In further optionally embodiment, the prodrug of formula (1) compound is provided, further optionally in the embodiment, provide the pharmacy acceptable salt of the prodrug of formula (1) compound.
The occurrence of m
I) in one aspect of the invention, m is 1 or 2.
Ii) in another aspect of the present invention, m is 1.
Iii) in another aspect of the present invention, m is 0.
R 4 Occurrence
I) in one aspect of the invention, R 4Be selected from halogen, cyano group, hydroxyl, methyl fluoride, difluoromethyl and trifluoromethyl.
Ii) in another aspect of the present invention, R 4Be halogen.
Iii) aspect another, R 4Be selected from chlorine and bromine.
Iv) aspect another, R 4Be selected from chlorine, fluorine and methyl.
V) aspect another, R 4Be selected from chlorine and fluorine.
Vi) more specifically, R 4Be chlorine, and if m be 1 then it is positioned at the 5-position.
The occurrence of n
I) in one aspect of the invention, n is 0 or 1.
Ii) one preferred aspect, n is 1.
Iii) in yet another aspect, preferred n is 0.
N is 2 o'clock R 1 Occurrence
I) n is 2, and two R 1Group can be coupled carbon atom form 4 to 7 yuan of saturated rings together, and this ring is optional when comprising 1 or 2 heteroatoms that independently is selected from O, S or N, preferably this ring is 5 or 6 yuan of rings.
Ii) in one embodiment, these 5 or 6 yuan of rings comprise two O atoms (being cyclic acetal).
Iii) on the one hand, as two R 1When group formed such cyclic acetal together, it was unsubstituted.
Iv) more specifically, two R 1Group is group-O-CH together 2-O-.
R 1 Occurrence
I) in another aspect of this invention, R 1Be selected from halogen, nitro, cyano group, hydroxyl, methyl fluoride, difluoromethyl, trifluoromethyl and C 1-4Alkoxyl group.
Ii) aspect another, R 1Be selected from halogen, nitro, cyano group, hydroxyl, methyl fluoride, difluoromethyl, trifluoromethyl ,-S (O) bC 1-4Alkyl (wherein b is 0,1 or 2) ,-OS (O) 2C 1-4Alkyl, C 1-4Alkyl and C 1-4Alkoxyl group.
Iii) aspect another, R 1Be selected from halogen, nitro, cyano group, hydroxyl, methyl fluoride, difluoromethyl, trifluoromethyl ,-S (O) bMe (wherein b is 0,1 or 2) ,-OS (O) 2Me, methyl and methoxyl group.
Iv) aspect another, R 1Be C 1-4Alkyl.
V) particularly, R 1Be selected from halogen and C 1-4Alkoxyl group.
Vi) in another preferred embodiment, R 1Be selected from fluorine, chlorine, methyl, ethyl, methoxyl group and-O-CH 2-O-.
In one aspect, Y is selected from option a).
On the other hand, Y is selected from option b), b particularly) i).
The occurrence of option Y a)
I) in one aspect, Y is C 3-6Cycloalkylidene.
Ii) on the other hand, Y is a cyclopropylidene, methylene basic ring third-1-base, methylene basic ring fourth-1-base or methylene basic ring penta-1-base.
Iii) on the other hand, Y is C 1-6Alkylidene group.
Iv) on the other hand, Y is selected from methylene radical, ethylidene, and propylidene, butylidene ,-CH (Me)-,-CH (Et)-,-C (Me) 2-,-CH 2CH (Me)-,-CH 2CH (Et)-and-CH 2C (Me) 2-.
V) aspect another, Y is selected from methylene radical and ethylidene.
Option b) occurrence of Y
Vi) the occurrence of Y comprises-CH 2XCH 2-,-CH 2XCH 2CH 2-,-CH 2CH 2XCH 2,-CH (R a) XCH 2-,-CH (R a) XCH 2CH 2-,-CH (R a) CH 2XCH 2-,-CH 2CH (R a) XCH 2-,-CH 2CH 2XCH (R a)-,-CH 2XCH (R a) CH 2-,-CH 2XCH 2CH (R b)-[, wherein X was selected from-O-,-S-,-SO-,-SO 2-and-N (R c) (R among the application cBe selected from methyl, ethyl, formyl radical, ethanoyl, methylsulfonyl) and R aBe selected from methyl and ethyl and R bBe selected from methyl, ethyl, methoxyl group and oxyethyl group] ,-CH 2C (Me) 2OCH 2-,-CH 2CH 2OC (Me) 2-,-CH 2OC (Me) 2CH 2-,-CH 2OCH 2C (Me) 2-,-CH (R d)-(be R wherein dBe selected from cyclopropyl, cyclopropyl methyl, methoxyl group, oxyethyl group, methoxy ethyl, cyclo propyl methoxy, methoxy ethoxy and cyano group) ,-CH 2CH (R e)-(be R wherein eBe selected from cyclopropyl, cyclopropyl methyl, methoxyl group, oxyethyl group; cyclo propyl methoxy, methoxy ethoxy, cyano group, methylthio group; methylsulfinyl, methyl sulphonyl, amino-sulfonyl, N-methylamino alkylsulfonyl; N, N-dimethylamino alkylsulfonyl, methanesulfonamido, N-methyl-methanesulfonamido; ethanoyl, kharophen, N-methyl kharophen, formamyl; N-methylamino formyl radical and N, the N-formyl-dimethylamino), methylene basic ring third-1-base oxygen ylmethyl (CH 2C (CH 2CH 2) OCH 2-), ethyleneoxy group ring third-1-base, methylene radical oxygen basic ring third-1-ylmethyl and methylene radical oxygen ylmethyl ring third-1-base.
Vii) the value more specifically of Y comprises-CH 2XCH 2-,-CH 2XCH 2CH 2-,-CH 2CH 2XCH 2,-CH (R f) XCH 2-,-CH (R f) XCH 2CH 2-,-CH (R f) CH 2XCH 2-,-CH 2CH (R f) XCH 2-,-CH 2CH 2XCH (R f)-,-CH 2XCH (R t) CH 2-,-CH 2XCH (R f)-,-CH 2XCR f 2-,-CH 2XCH 2CH 2CH 2-[wherein X is selected from-O-,-S-and-SO 2-, and R fBe selected from methyl and ethyl] ,-CH 2-,-CH 2CH 2-,-CH 2CH 2CH 2-,-CH 2CH (Me)-,-CH (R g)-and-CH (R g) CH 2-[R wherein gBe selected from methoxymethyl, ethoxyethyl group, methoxy ethyl, ethoxyl methyl, methoxy-propyl, cyclopropyl methyl, isopropyl methyl, ethyl and propyl group].
Viii) the value more specifically of Y comprises-CH 2-,-CH (CH 3)-,-CH 2OCH 2-,-CH 2OCH (CH 3)-and-CH (CH 2CH 2OCH 3)-.
Utilize the combination of above-mentioned definition, the specific category of compound of the present invention is disclosed among Table A, B and the C.For example, the table acceptance of the bid is entitled as R 1The hurdle in ' i ' be meant provide above about R 1Definition (i), ' I ' be meant the explanation section start provide about each variable in formula (1) compound first the definition.Should be appreciated that definition about Y, " a) I " be meant the explanation section start option a) under about formula (1) compound in first definition of each variable, and similarly regulation is applicable to " b) i ".
Table A
Classification R 1 n Y R 4 m
1 i I a)I v i
2 ii i i vi ii
3 iii i iii vi ii
4 iv i iv vi ii
5 v i v vi ii
6 - iii v vi ii
Table B
Classification R 1 n Y R 4 m
1 i I b)i v i
2 ii i b)i - iii
3 iii i b)i vi ii
4 iv i vi vi ii
5 v i vi vi ii
6 - iii vi vi ii
Compound more specifically of the present invention is defined compound among the table C:
Table C
Classification R 4 m n Y
1 v i iii vi
2 v i iii vii
3 v i iii viii
In one aspect of the invention, formula (1) compound is the compound of formula (1A):
Figure A20068001022500171
Should be appreciated that above-mentioned occurrence, aspect and embodiment about formula (1) compound is equally applicable to the compound of formula (1A).
Particular compound of the present invention is compound or its pharmacy acceptable salt among each embodiment, its each further independent aspects of the present invention all is provided.In still another aspect of the invention, provide any two or more embodiment or its pharmacy acceptable salt.
Compound more specifically of the present invention comprises any one or a plurality of (perhaps its pharmacy acceptable salts) in following:
[((1R, 2R)-2-{[(5-chloro-1H-indoles-2-yl) carbonyl] amino }-2,3-dihydro-1H-indenes-1-yl) methoxyl group] acetate;
[((1R, 2R)-2-{[(5-fluoro-1H-indoles-2-yl) carbonyl] amino }-2,3-dihydro-1H-indenes-1-yl) methoxyl group] acetate;
(2R/S)-[((1R, 2R)-2-{[(5-chloro-1H-indoles-2-yl) carbonyl] amino }-2,3-dihydro-1H-indenes-1-yl) methoxyl group] propionic acid;
(2R/S)-[((1R, 2R)-2-{[(5-fluoro-1H-indoles-2-yl) carbonyl] amino }-2,3-dihydro-1H-indenes-1-yl) methoxyl group] propionic acid;
((1R, 2R)-2-{[(5-fluoro-1H-indoles-2-yl) carbonyl] amino }-2,3-dihydro-1H-indenes-1-yl) acetate;
((1R, 2R)-2-{[(5-chloro-1H-indoles-2-yl) carbonyl] amino }-2,3-dihydro-1H-indenes-1-yl) acetate;
((1R, 2R)-2-{[(5,6-two fluoro-1H-indoles-2-yls) carbonyl] amino }-2,3-dihydro-1H-indenes-1-yl) acetate;
(1R, 2R)-2-[(5-chloro-7-fluoro-1H-indole-2-carbonyl)-amino]-indane-1-yl }-acetate;
(2R)-2-{ (1R, 2R)-2-[(5-chloro-1H-indole-2-carbonyl)-amino]-indane-1-yl }-4-methoxyl group-butyric acid;
(2S)-2-{ (1R, 2R)-2-[(5-chloro-1H-indole-2-carbonyl)-amino]-indane-1-yl }-4-methoxyl group-butyric acid;
(2R)-2-{ (1R, 2R)-2-[(5-chloro-1H-indole-2-carbonyl)-amino]-indane-1-yl }-propionic acid; And
(2S)-2-{ (1R, 2R)-2-[(5-chloro-1H-indole-2-carbonyl)-amino]-indane-1-yl }-propionic acid.
Another aspect of the present invention provides the method for hydrolyzable ester in preparation formula (1) compound or its pharmacy acceptable salt or its body, this method to comprise (Z wherein 1, Y, R 1, R 4, m, and n is suc as formula defined in (1), unless otherwise indicated):
A) make the acid of formula (2):
Or the amine of its activatory derivative and formula (3) reaction:
Figure A20068001022500182
And thereafter if desired:
I) formula (1) compound is changed into other formula (1) compound;
Ii) remove any protecting group;
Iii) form hydrolyzable ester in pharmacy acceptable salt or the body.
The concrete reaction conditions of above-mentioned reaction is as follows.
Method a) the amine of the acid of formula (2) and formula (3) can be coupled at together in the presence of suitable coupling agent.Can adopt standard peptide coupling agent as known in the art as the coupling agent that should suit, for example, carbonyl dimidazoles, 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride (EDCI) and dicyclohexyl-carbodiimide (DCCI), choose wantonly in the presence of such as catalyzer such as I-hydroxybenzotriazole, Dimethylamino pyridine or 4-pyrrolidino pyridines, choose wantonly at alkali for example triethylamine, two-sec.-propyl ethylamine, pyridine or 2,6-dialkyl group-pyridine is as 2,6-lutidine or 2, the 6-di-tert-butyl pyridine exists down.The suitable solvent comprises N,N-DIMETHYLACETAMIDE, methylene dichloride, benzene, tetrahydrofuran (THF) and dimethyl formamide.Linked reaction can be carried out under-40～40 ℃ the temperature in scope easily.
Suitable activated acid derivatives comprises carboxylic acid halides such as acyl chlorides, and active ester such as pentafluorophenyl group ester.The reaction of the type compound and amine is well known in the art, and for example, they can react in appropriate solvent (as above-mentioned those solvents) in the presence of alkali (as above-mentioned those alkali).This reaction can be carried out under-40～40 ℃ the temperature in scope easily.
The acid of formula (2) can obtain from commercial, and perhaps they are compound known, and perhaps they can prepare according to methods known in the art.
The compound or the compound known of formula (3) perhaps can prepare according to methods known in the art, perhaps according to the method preparation of using in following scheme 1～6 or the specific embodiment:
Scheme 1
Figure A20068001022500191
(R wherein 17=C 1-6Alkyl, R 18Be the variable relevant-for example, when Y is CHCH with Y 3The time, R 18Be CH 3, perhaps working as Y is CH (OCH 3) time, R 18Be OCH 3).
Compd A (R wherein 1Be hydrogen) can from commercial obtaining [(1R, 2R)-(-)-anti-form-1-amino-2-indanol, Cas.Reg.No.:163061-73-2 or [(1S, 2S)-(-)-anti-form-1-amino-2-indanol Cas.Reg.No.:13286-59-4].The compound of type B can be according to known method preparation in the document, the method as shown in above-mentioned scheme 1.The method shown in the scheme 1 that should be appreciated that be equally applicable to those with shown in the opposite enantiomer of compd A, B and C.Then compound (C) is coupled in the suitable acid (2), then removes disacidify protecting group R by methods known in the art (as trifluoroacetic acid or potassium hydroxide) 17
Similarly, can adopt the method for following scheme 2:
Scheme 2
Figure A20068001022500201
(R wherein 9Be C 1-6Alkyl, R 8Be the variable relevant-for example, if Y is CH with Y 2C (O) NHCH 2, R then 8Be CH 2CO 2R 9).Then (C) is coupled in the suitable acid (2), then (as trifluoroacetic acid or potassium hydroxide) removes disacidify protecting group R by means commonly known in the art 8
The compound of formula (3a) can obtain from commercial, and perhaps they are compound known, and perhaps they can be according to method preparation well known in the art.For example, by primary amine (wherein R is H or the suitable protecting group) beginning of formula (4), R 1Can pass through acidylate (for example with acetoxy acid and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDAC) reaction), alkylation, standard reductive alkylation, sulfonation or methods involving and introduce, then under suitable situation, carry out O-and go protection.As selection, R 1Can be before this introducing; combination by means of reduction, oxidation, hydrolysis (for example acetoxyl group being changed into hydroxyl), nucleophilic substitution, amination or methods involving or these methods; obtain by the functional group that changes in the group, then under suitable situation, carry out O-and go protection.Should be appreciated that this change can comprise the change that one of formula (1) compound is changed into another kind of formula (1) compound.
Scheme 3
Figure A20068001022500202
In other words, (wherein W is NH to the compound that the amine of formula (3) can be by being applied to the described method of compound of preparation formula (3a) formula (5) 2Or nitrogen-atoms) obtains with one or two suitable protecting group.
Scheme 4
Figure A20068001022500211
(R wherein 1Be hydrogen or CO 2R 10R 10Be C 1-6The acid of alkyl or due care; And R 11Be the variable relevant-for example, when Y is CH with Y 2CH (OCH 3) time, R 11Be OCH 3).Then (C) is coupled in the suitable acid (2), then (as trifluoroacetic acid or potassium hydroxide) removes disacidify protecting group R by means commonly known in the art 10
Scheme 5
(R wherein 12Be C independently 1-6Alkyl or carboxyl-protecting group, R 13Be the variable relevant-for example, when Y is CH with Y 2CH (CH 2OCH 3) time, R 13Be CH 2OCH 3LG is a leavings group).Then (C) is coupled in the suitable acid (2), then (as trifluoroacetic acid or potassium hydroxide) removes disacidify protecting group R by means commonly known in the art 12
Scheme 6
Figure A20068001022500221
(R wherein 16Be C 1-6Alkyl, R 14And R 15Be the variable relevant-for example, when Y is CH with Y 2OCH (CH 3) CH 2The time, R 14Be CH 3, R 15Be H; LG is a leavings group).Then (C) is coupled in the suitable acid (2), then (as trifluoroacetic acid or potassium hydroxide) removes disacidify protecting group R by means commonly known in the art 16
Should be appreciated that some the different ring substituents in the compound of the present invention, for example R 1And R 4, can the aromatics substitution reaction by standard introduce, also can before the aforesaid method or just aforesaid method after the functional group's change by routine generate, this is included in the method for the present invention aspect equally.This class reaction can change into a kind of formula (1) compound another kind of formula (1) compound.This reaction and change comprise, for example, introduce substituent reduction, substituent alkylation and substituent oxidation by means of the substituting group of aromatics substitution reaction.The reagent of these methods and reaction conditions are well-known at chemical field.The specific examples of aromatics substitution reaction comprises the nitro introducing of adopting concentrated nitric acid; Adopt for example carboxylic acid halides and the acyl group introducing of Lewis acid (Lewis acid) (as aluminum chloride) under Fu Ke (Friedel Crafts) condition; Adopt alkylogen and Lewis acid (as the aluminum chloride) alkyl under the Fu Ke condition to introduce; And the introducing of halogen group.The specific examples that changes comprises that nitro arrives amino reduction, for example, adopts the catalytic hydrogenation of nickel catalyzator, perhaps adopts the processing of iron under hydrochloric acid existence and heating condition; Alkylthio is to the oxidation of alkyl sulphinyl or alkyl sulphonyl.
It is also understood that in some reaction of mentioning in this article, any sensitive group of protection in the compound may be necessary/desirable.Protection is necessary or desirable occasion and suitable guard method is that those skilled in the art is known.Can adopt conventional protecting group according to put into practice (referring to the T.W.Green, ProtectiveGroups in Organic Synthesis, John Wiley and Sons, 1991) of standard.Therefore, if reactant comprises such as groups such as amino, carboxyl or hydroxyls, perhaps this group of protection is desirable in some reaction of then mentioning in this article.
For example, the protecting group that suits amino and alkylamino comprises acyl group, for example alkyloyl such as ethanoyl; Alkoxy carbonyl, methoxycarbonyl for example, ethoxy carbonyl or tert-butoxycarbonyl; Aryl methoxy carbonyl, for example benzyloxycarbonyl; Perhaps aroyl, for example benzoyl.The protective condition that goes of above-mentioned protecting group changes with the selection of protecting group certainly.Therefore, for example, acyl groups such as alkyloyl or alkoxy carbonyl or aroyl can be removed by being hydrolyzed with suitable alkali, and the example of described alkali comprises alkali metal hydroxide such as lithium hydroxide or sodium hydroxide.As selection; also can remove such as acyl groups such as tert-butoxycarbonyls by for example handling with suitable sour example hydrochloric acid, sulfuric acid, phosphoric acid or trifluoroacetic acid, such as aryl methoxy carbonyls such as benzyloxycarbonyl then can be by for example adopting catalyzer such as palladium/carbon hydrogenation or remove by closing the boron processing as three (trifluoroacetic acids) with Lewis acid.The alternative protecting group that is fit to primary amino be for example phthaloyl base, and it can be by removing with alkylamine such as dimethylamino-propyl amine or with the hydrazine processing.
For example, the protecting group that is fit to hydroxyl is an acyl group, for example such as alkyloyls such as ethanoyl; Aroyl, for example benzoyl; Perhaps arylmethyl, for example phenmethyl.The protective condition that goes of above-mentioned protecting group changes with the selection of protecting group certainly.Thereby for example, acyl groups such as alkyloyl or aroyl can be removed by being hydrolyzed with suitable alkali, and the example of described alkali comprises alkali metal hydroxide such as lithium hydroxide or sodium hydroxide.As selection, arylmethyl such as phenmethyl can be removed by the hydrogenation of for example adopting palladium/carbon catalyst.
For example, the protecting group that is suitable for carboxyl is an esterified group, for example methyl or ethyl, and it can be removed by for example using alkali (as sodium hydroxide) to be hydrolyzed; Perhaps be the tertiary butyl, it can be by handling and remove with acid (as organic acids such as trifluoroacetic acids); Perhaps be benzyl, it can be removed by carrying out hydrogenation with catalyzer (as palladium/carbon).
Protecting group can be utilized the known routine techniques of chemical field, makes things convenient for the stage to remove in that synthetic is any.
Some intermediate in the preparation of formula (1) compound is new, and constitutes another aspect of the present invention.
As described in the text, the compound that defines among the present invention has glycogen phosphorylase inhibitory activity.This character can be utilized following method evaluation.
Test
The activity of compound is by measuring compound the restraining effect of glycogen degraded to be measured, produce glucose-1-phosphate by multienzyme coupling test monitoring by glycogen, described in EP 0846464A2, people's such as Pesce general method (Pesce, M A, Bodourian, S H, Harris, R C, and Nicholson, J F (1977) Clinical Chemistry 23,1171-1717).Reaction is 384 hole microtest plate forms, and volume is 50 μ l.In the multi-functional microtest plate reader of Tecan Ultra, with 340nm excitation wavelength and 465nm emission wavelength, measurement is converted into the change in fluorescence that NADH causes because of cofactor NAD.Be reflected at the 50mM HEPES that contains the 0.5mM dithiothreitol (DTT), 3.5mM KH 2PO 4, 2.5mMMgCl 2, 2.5mM ethylene glycol-two (b-amino-ethyl ether N, N, N ', N '-tetraacethyl, 100mM KCl carries out in the test damping fluid of 8mMD-(+)-glucose pH7.2.With human recombination hepatic glycogen phosphorylase a (hrlGPa) 20nM pre-cultivation 30 minutes in the test damping fluid, described damping fluid contains 6.25mM NAD, 1.25mg III type glycogen (1.25mgml -1The reagent damping fluid).In the reagent damping fluid, prepare conjugate enzyme, phosphoglucomutase and G-6-P ester desaturase (Sigma), ultimate density is 0.25 unit/hole.The hrl GPa solution of 20 μ l is added in the compound solution of 10 μ l, and reaction is started by the conjugate enzyme solution that adds 20 μ l.The compound that will test is in 10 μ l 5%DMSO/ test damping fluid, and the ultimate density of DMSO is 1% in the test.In the presence of 10 μ l 5%DMSO/ test damping fluid, the non-inhibition of measuring GPa is active, and at 5mgml -1The N-ethyl maleimide exist down, measure maximum the inhibition.At 30 ℃ after following 6 hours, excite emission wavelength with 340nm with 465nm, measure relative fluorescence unit (RFU).
This test is carried out with the inhibitor experimental concentration of 10 μ M or 100 μ M.Utilize the inhibitor of a series of experimental concentration, estimate the compound that under these two concentration one or both of, presents remarkable inhibition, thereby measure IC 50, estimate that promptly inhibitory enzyme reacts 50% concentration.
Activity is calculated as follows:
% inhibition=(1-(RFU that compound R FU-suppresses fully)/(RFU that the RFU-of non-killer stage suppresses fully)) * 100.
When in above-mentioned test, testing, the typical IC of compound of the present invention 50Value is 100 μ M to 1nM.For example, measure the IC of embodiment 5 50Be 0.161 μ M, measure the IC of embodiment 2 50Be 1.67 μ M.
The inhibition activity of further test compound in the rat primary hepatocyte.Rat hepatocytes is by the collagenase perfusion technology, and promptly the general method of Seglen (P.O.Seglen, Methods Cell Biology (1976) 1329-83) is isolating.Cell was being cultivated 4～6 hours in DMEM (Dulbeco ' sModified Eagle ' s Medium) on Nunclon six well culture plates, described DMEM has high-load glucose, comprise 10% foetal calf serum, NEAA (non-primary amino acid), glutamine, penicillin/streptomycin ((100 units/100 μ g)/ml).Then with liver cell do not contain foetal calf serum but contain 10nM Regular Insulin and the DMEM solution of 10nM dexamethasone in cultivate.After cultivating 18～20 hours, contain 2.5mM CaCl by washed cell and adding 2Begin experiment with the Krebs-Henseleit bicarbonate buffer of 1% gelatin.Add test compound, and after 5 minutes, use 25nM glycogen test cell.At 37 ℃, 95%O 2/ 5%CO 2After middle the cultivation 60 minutes, remove Krebs-Henseleit solution, and measure the glucose concn of Krebs-Henseleit solution.
According to other aspects of the invention, provide pharmaceutical composition, it comprises hydrolyzable ester in the defined formula of preamble (1) compound or its pharmacy acceptable salt or the body, and is combined with pharmaceutically acceptable diluent or carrier.
Composition of the present invention can be following suitable form: orally use (tablet for example, lozenge, hard capsule or soft capsule, water-based or oiliness suspensoid, emulsion, dispersible pulvis or granule, syrup or elixir), the local use (emulsifiable paste for example, ointment, gel, or water-based or oily solution agent or suspensoid), inhalation (for example fine dispersive powder or liquid aerosol), be blown into administration (for example fine dispersive powder) or administered parenterally and (for example be used for intravenously, subcutaneous, the sterile aqueous of administration or oily solution between intramuscular or flesh, or be used for the suppository of rectal administration).
Composition of the present invention can use conventional medicine vehicle well known in the art to obtain by routine operation.Therefore, the purpose composition that is used to orally use can comprise for example one or more tinting materials, sweetener, seasonings and/or sanitas.On the one hand, composition of the present invention is the form that is suitable for oral dosage.
The suitable medicinal vehicle that tablet formulation is used comprises for example inert diluent such as lactose, yellow soda ash, calcium phosphate or lime carbonate, granulating agent and disintegrating agent such as W-Gum or Lalgine (algenic acid); Tackiness agent such as starch; Lubricant such as Magnesium Stearate, stearic acid or talcum; Sanitas such as ethyl p-hydroxybenzoate or propylparaben, and antioxidant such as xitix.Tablet can be dressing or dressing not, with disintegration and the absorption of activeconstituents in intestines and stomach subsequently that changes them, or improves their stability and/or outward appearance, under kind situation arbitrarily, uses conventional Drug coating well known in the art and operation.
The composition that orally uses can be the form of hard gelatin capsule, and wherein for example lime carbonate, calcium phosphate or kaolin mix activeconstituents with inert solid diluent; Perhaps be the form of soft gelatin capsule, wherein activeconstituents and water or oil are as peanut oil, whiteruss or mixed with olive oil.
Aqueous suspension comprises activeconstituents and one or more suspension agents of fine powder form, for example Xylo-Mucine, methylcellulose gum, Vltra tears, sodiun alginate, Polyvinylpyrolidone (PVP), Tragacanth and Sudan Gum-arabic usually; Dispersion agent or wetting agent, condensation product (for example polyoxyethylene stearate) as Yelkin TTS or alkylene oxide and lipid acid, or the condensation product of ethylene oxide and long chain aliphatic alcohol is as 17 oxyethylene group hexadecanols (heptadecaethyleneoxycetanol), or ethylene oxide and derived from the condensation product such as the polyoxyethylene Sorbic Acid sugar alcohol monoleate of the partial ester of lipid acid and hexitol, or the condensation product of ethylene oxide and long chain aliphatic alcohol is as 17 oxyethylene group hexadecanols, or ethylene oxide and derived from the condensation product such as the polyoxyethylene Sorbic Acid sugar alcohol monoleate of the partial ester of lipid acid and hexitol, the perhaps condensation product of ethylene oxide and long chain aliphatic alcohol, as 17 oxyethylene group hexadecanols, perhaps ethylene oxide and condensation product such as polyoxyethylene sorbitol monoleate, or ethylene oxide and derived from the condensation product such as the polyoxyethylene dehydration Sorbic Acid sugar alcohol monoleate of the partial ester of lipid acid and hexitan derived from the partial ester of lipid acid and hexitol.Aqueous suspension also can comprise and contains one or more sanitass (as ethyl p-hydroxybenzoate or propylparaben), antioxidant (as xitix), tinting material, seasonings and/or sweeting agent (as sucrose, asccharin or aspartame).
Can prepare the oiliness suspensoid by activeconstituents is suspended in vegetables oil (as peanut oil, sweet oil, sesame oil or Oleum Cocois) or the mineral oil (for example whiteruss).The oiliness suspensoid also can comprise thickening material such as beeswax, solid paraffin or hexadecanol.Can add sweeting agent such as those sweeting agents listed above and seasonings, so that agreeable to the taste oral preparation to be provided.These compositions can be preserved by adding antioxidant such as xitix.
Usually comprise activeconstituents and dispersion agent or wetting agent, suspension agent and one or more sanitass by adding dispersible powder and the particle that entry is suitable for preparing aqueous suspension.Suitable dispersion agent or wetting agent and suspension agent for example have above-mentioned those.Also can there be other vehicle such as sweeting agent, seasonings and tinting material.
Pharmaceutical composition of the present invention also can be the form of O/w emulsion.Oil phase can be vegetables oil such as sweet oil or peanut oil, or mineral oil whiteruss for example, or the mixture of any of these oil.Suitable emulsifying agent can be for example naturally occurring natural gum such as Sudan Gum-arabic, Tragacanth, naturally occurring phosphatide such as soybean, Yelkin TTS, derived from the ester of lipid acid and hexitol or partial ester (as dehydrating sorbitol monooleate) and as described in the condensation product such as the polyoxyethylene sorbitan monoleate of partial ester and ethylene oxide.This emulsion also can comprise sweetener, seasonings and sanitas.
Syrup and elixir can be prepared with sweetener, and sweetener such as glycerine, propylene glycol, Sorbitol Powder, aspartame or sucrose also can comprise negative catalyst, sanitas, seasonings and/or tinting material.
Pharmaceutical composition also can be the water-based of sterile injectable or the form of oiliness suspensoid, and this suspensoid can be prepared according to known operation, uses one or more above-mentioned suitable dispersion agent or wetting agent and suspension agents.The goods of sterile injectable also can be sterile injectable solution or the suspensoid in nontoxicity parenteral acceptable diluent or solvent, for example solution in 1,3 butylene glycol.
The composition that is used for inhalation can be conventional pressurized aerosol form, and it is arranged to activeconstituents is distributed into aerosol or the drop that comprises fine dispersible solid.Can use conventional aerosol propellants such as volatility fluorinated hydrocarbons or hydrocarbon, and aerosol device is arranged to the activeconstituents of distribution and computation amount usually.
For the more information of preparation, the reader can be with reference to Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), the 25.2nd chapter in the 5th of Pergamon Press 1990 the volume.
The amount that activeconstituents combines with one or more vehicle to prepare single formulation changes with the main body and the concrete route of administration of treatment certainly.For example, the preparation that purpose is used for people's oral administration comprises for example active agent of 0.5mg-2g usually, and is mixed with vehicle suitable, convenient amount, and the amount of vehicle can be about 5～about 98 weight % of whole composition.Dosage unit form comprises the activeconstituents of about 1mg～about 500mg usually.For the more information of route of administration and dosage regimen, the reader can be with reference to Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of EditorialBoard), the 25.3rd chapter in the 5th of Pergamon Press 1990 the volume.
Formula (1) compound is every square metre of animal body area 5～5000mg with scope usually, and promptly the unitary dose of about 0.1～100mg/kg is administered to warm-blooded animal, and this provides treatment effective dosage usually.Unit dosage such as tablet or capsule comprise for example activeconstituents of 1～250mg usually.Preferred employing scope is the per daily dose of 1～50mg/kg.Yet, the inevitable host of per daily dose, concrete route of administration and the severity of disease that will treat and change along with treatment.Therefore, Zui Jia dosage can be determined by the concrete patient's of treatment practitioner.
The active inhibition of glycogen phosphorylase as herein described can be made base therapy and use, and can also comprise one or more other material and/or treatments except theme of the present invention.This combination therapy can be by simultaneously, in succession or respectively administration is respectively treated component and realized.Treatment simultaneously can be the form of single tablet or different tablets.
For example, for prevent, sluggish or treatment diabetes B, compound of the present invention or its pharmacy acceptable salt can with one or more following medicament Combined Preparation:
1) Regular Insulin and insulin analog;
2) comprise the Regular Insulin succagoga (as Glyburide, Glipizide) of sulfonylurea, meals glucose conditioning agent (as repaglinide, nateglinide) and glucokinase activators;
3) medicament (as inhibitors of dipeptidyl IV, the GLP-1 agonist) of raising internal secretion effect;
4) insulin sensitizers comprises PPAR gamma agonist (as pioglitazone and rosiglitazone), and has the medicament of bonded PPAR α and gamma activity;
5) adjust hepatic glucose equilibrated medicament (as N1,N1-Dimethylbiguanide, fructose-1,6 diphosphatase inhibitor, glycogen synthase kinase inhibitor, glucokinase activators);
6) medicament (as acarbose) of reduction glucose intestinal absorption;
7) stop glucose by the resorbent medicament of kidney (SGLT inhibitor);
8) be used for the treatment of the medicament (as aldose reductase inhibitor) of the hyperglycemia complication of delay;
9) anti-obesity medicament (as sibutramine and orlistat);
10) anti-lipid obstacle medicament such as HMG-CoA reductase inhibitor (statins is as general Liprevil); PPAR alfa agonists (the chlorine fibrate is as gemfibrozil); Bile acid multivalent chelator (QUESTRAN); Cholesterol absorption inhibitor (plant stanols, synthetic inhibitor); Bile acide absorption inhibitor (IBATi); And nicotinic acid and analogue (nicotinic acid and slow release formulation);
11) hypotensive agent such as beta-blocker (for example atenolol USP 23, Propranololum); ACE inhibitor (as lisinopril); Calcium antagonist (as nifedipine); Ipertensinu receptor antagonist (as Candesartan), alpha-2 antagonists and diuretic(s) (as Furosemide, benzthiazide);
12) hemostasis conditioning agent such as antithrombotic, Fibrinolytic activator, and anti-platelet agents; The zymoplasm antagonist; Coagulation factor xa inhibitors; Proconvertin a inhibitor); Anti-platelet agents (as Asprin, clopidogrel); Anti-coagulant (heparin and lower molecular weight analogue, r-hirudin) and warfarin;
13) medicament of the effect of antagonism glucagon; And
14) anti-inflammatory agent, for example NSAID (non-steroidal anti-inflammatory drug) (as Asprin) and steroidal anti-inflammatory medicine (as cortisone).
According to another aspect of the invention, provide the purposes of hydrolyzable ester in above defined formula (1) compound or its pharmacy acceptable salt or the body, promptly treat purposes in warm-blooded animal such as people's the method by therapy.
According to a further aspect in the invention, provide the purposes of the interior hydrolyzable ester of above defined formula (1) compound or its pharmacy acceptable salt or body as medicine.
According to a further aspect in the invention, provide the purposes of the interior hydrolyzable ester of above defined formula (1) compound or its pharmacy acceptable salt or body: diabetes B as the medicine of treatment warm-blooded animal such as people's following disease, insulin resistance, syndrome X, hyperinsulinemia, blood glucagon too much disease, myocardial ischemia or obesity.
According to a further aspect in the invention, provide hydrolyzable ester in above defined formula (1) compound or its pharmacy acceptable salt or the body to be used for the treatment of purposes in warm-blooded animal such as people's the medicine of following disease: diabetes B in preparation, insulin resistance, syndrome X, hyperinsulinemia, blood glucagon too much disease, myocardial ischemia or obesity.
According to a further aspect in the invention, provide hydrolyzable ester in above defined formula (1) compound or its pharmacy acceptable salt or the body to be used for the treatment of purposes in warm-blooded animal such as people's the medicine of diabetes B in preparation.
The further feature of this aspect according to the present invention is provided at the warm-blooded animal such as the philtrum that need this treatment and produces the inhibiting method of glycogen phosphorylase, and this method comprises the formula of significant quantity (1) compound administration in described animal.
The further feature of this aspect according to the present invention, the warm-blooded animal of this treatment of treatment needs such as people's diabetes B are provided, insulin resistance, syndrome X, hyperinsulinemia, the too much disease of blood glucagon, the method for myocardial ischemia or obesity, this method comprise the formula of significant quantity (1) compound administration in described animal.
The further feature of this aspect according to the present invention provides the method for warm-blooded animal that treatment needs this treatment such as people's diabetes B, and this method comprises the formula of significant quantity (1) compound administration in described animal.
As mentioned above, the size of treatment or prophylactic treatment specific cells hyperplasia required dosage is inevitable changes with host, the route of administration of treatment and the severity of disease that will treat.The unitary dose scope of drafting is preferably 1～50mg/kg for for example 1～100mg/kg.
Except that being used for the treatment of medicine, formula (1) compound and pharmacy acceptable salt thereof also can be used as pharmacological tool, be used for laboratory animal, as estimating the exploitation and the stdn of the external and body built-in test system of active inhibitor effect of cell cycle in cat, dog, rabbit, monkey, rat and the mouse, as the integral part of seeking novel treatment.
In above-mentioned other medicines composition, process, method, purposes and medicine manufacturing feature, the selectivity of described compound of the present invention and preferred embodiment are suitable equally herein.
Embodiment
Now the present invention is described by the following examples, unless otherwise indicated, wherein:
(i) temperature with degree centigrade (℃) provide; Operate in room temperature or envrionment temperature, promptly under 18～25 ℃ temperature range and inert atmosphere such as argon gas, carry out;
(ii) organic solution is passed through anhydrous magnesium sulfate drying; The evaporation of solvent adopts Rotary Evaporators at decompression (600-4000Pascals; 4.5-30mmHg) and the highest 60 ℃ bath temperature under carry out;
(iii) chromatogram is meant fast silica gel chromatogram; Thin-layer chromatography (TLC) carries out on silica-gel plate; When mentioning Bond Elut post, it is meant that the particle size that comprises 10g or 20g or 50g is the post of 40 microns silicon oxide, this silicon oxide is contained in the disposable syringe of 60ml and by alveolar disk and supports, derive from the Varian of California, USA, Harbor City, name is called " Mega Bond Elut SI "; " MegaBond Elut " is a kind of trade mark; When mentioning the Biotage tube, it is meant and contains KP-SIL TMThe assembly tube of silicon oxide (60 μ, particle size 32-63mM) is provided by the Biotage branch office of the U.S. (VA 22902 for 1500Avon Street Extended, Charlottesville) Dyax company;
(iv) usually, reaction process is followed the tracks of by TLC, and only provides the reaction times in order to illustrate;
(v) only provide yield, and need not to be the yield that those obtain by conscientious technological process in order to illustrate; More if desired material then repeats preparation process;
If (vi) provide, then the NMR data are the δ value form of main diagnosis proton, provide with the millionth umber (ppm) with respect to internal standard substance tetramethylsilane (TMS), utilize full deuterium methyl-sulphoxide (DMSO-δ under 300MHz 6) measure as solvent (unless otherwise noted), other solvent (pointed in the literary composition) comprises deuterate chloroform CDCl 3
(vii) chemical symbol has its common meaning; Use SI units and symbol;
(viii) reduce pressure and provide with pascal (Pa) as absolute pressure; High pressure provides as the gauge pressure Israel and Palestine;
(ix) solvent ratios by volume: volume (v/v) provides;
(x) mass spectrum (MS) data result from the LCMS system, and wherein the HPLC integral part generally comprises Waters Alliance HT (2790﹠amp; 2795) equipment and operate in Phemonenex Gemini C185 μ m, 50 * 2mm chromatographic column (or similar chromatographic column), this chromatographic column with acid elutriant (for example, adopting gradient is water/acetonitrile of 0～95%, and it contains 5% 1% formic acid in 50: 50 water: the solution in acetonitrile (v/v) mixture; Perhaps adopt the solvent system of equal value that replaces acetonitrile with methyl alcohol), perhaps alkaline eluant (for example, adopting gradient is water/acetonitrile of 0～95%, and it contains 5% the solution of 0.1%880 ammonia in the acetonitrile mixture); And the MS integral part generally comprises Waters ZQ spectrograph.Produce the positive and negative base peak intensity of electron spray(ES) color atlas (ESI), reach the UV hypersorption color atlas of 220-300nm, and provide the value of m/z; Usually, only the ion of parent quality is represented in report, and unless otherwise indicated, the numerical value in the bracket is (MH +);
(xi) can use following abbreviation:
The RT retention time;
The EtOAc ethyl acetate;
MeOH methyl alcohol;
EtOH ethanol;
The DCM methylene dichloride;
The HOBT I-hydroxybenzotriazole;
The DIPEA diisopropylethylamine;
EDCI 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride;
Et 2The O ether;
The THF tetrahydrofuran (THF);
DMF N, dinethylformamide;
HATU O-(7-azepine benzo triazol-1-yl)-N, N, N ', N '-tetramethyl- hexafluorophosphate;
EDAC 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride;
The TFA trifluoroacetic acid
DMTMM 4-(4,6-dimethoxy-1,3,5-triazines-2-yl)-4-methylmorpholine  muriate;
The DMA N,N-dimethylacetamide;
NaHCO 3Sodium bicarbonate;
NaHMDS hexamethyldisilazane sodium (Sodium hexamethyldisilazide);
The mCPBA metachloroperbenzoic acid;
DABCO diaza-[2.2.2] two ring-octanes;
AcOH acetate;
The TEA triethylamine
The Boc tert-butoxycarbonyl;
The MeCN acetonitrile.
Embodiment 1:[((1R, 2R)-2-{[5-chloro-1H-indoles-2-yl) carbonyl] amino }-2,3-dihydro-1H-indenes -1-yl) methoxyl group] acetate
Figure A20068001022500321
To [((1R, 2R)-2-{[(5-chloro-1H-indoles-2-yl) carbonyl] amino }-2,3-dihydro-1H-indenes-1-yl) methoxyl group] tert.-butyl acetate (intermediate 1; 0.5g, 1.1mmol) in the solution in DCM (5mL), add trifluoroacetic acid (1mL), and reaction mixture stirred 2 hours in envrionment temperature.Reduction vaporization and vacuum-drying obtain title compound (275mg, 63%), and it is a foam.
1H NMRδ：2.9(dd，1H)，3.25(dd，1H)，3.47(m，lH)，3.7(m，1H)，3.82(m，1H)，4.05(s，2H)，4.55(m，1H)，7.2(m，6H)，7.4(m，2H)，7.7(s，1H)，8.75(d，1H)，11.74(s，1H)MS m/z 397/399。
By the method for embodiment 1, adopt suitable tertiary butyl ester (intermediate 2) as the feedstock production the following examples.
Embodiment 2:[((1R, 2R)-2-{[(5-fluoro-1H-indoles-2-yl) carbonyl] amino }-2,3-dihydro-1H-indenes -1-yl) methoxyl group] acetate
Figure A20068001022500322
Figure A20068001022500323
Embodiment 3:(2R/S)-[((1R, 2R)-2-{[(5-chloro-1H-indoles-2-yl) carbonyl] amino }-2, the 3-dihydro -1H-indenes-1-yl) methoxyl group] propionic acid
Figure A20068001022500324
To (2R/S)-[((1R, 2R)-2-{[(5-chloro-1H-indoles-2-yl) carbonyl] amino }-2,3-dihydro-1H-indenes-1-yl) methoxyl group] propionic acid tertiary butyl ester (intermediate 13; 430mg 0.917mmol) in the solution in DCM (10mL), adds trifluoroacetic acid (1mL) and reaction mixture was stirred 20 hours in envrionment temperature.0 reduction vaporization and vacuum-drying obtain title compound (340mg, 90%), and it is Powdered thing.
1H NMRδ：1.27(dd，3H)，2.9(m，1H)，3.25(m，1H)，3.45(m，1.5H)，3.63(m，0.5H)，3.8(m，0.5H)，3.95(m，1.5H)，4.55(m，1H)，7.2(m，6H)，7.4(m，2H)，7.68(d，1H)，8.75(d，1H)，11.74(s，0.5H)，12.52(s，0.5H)；MS m/z 411/413(M-H)。
By the method for embodiment 3, adopt suitable tertiary butyl ester (intermediate 14) as the feedstock production the following examples.
Embodiment 4:(2R/S)-[((1R, 2R)-2-{[(5-fluoro-1H-indoles-2-yl) carbonyl] amino }-2, the 3-dihydro -1H-indenes-1-yl) methoxyl group] propionic acid
Figure A20068001022500331
Figure A20068001022500332
Embodiment 5:((1R, 2R)-2-{[(5-fluoro-1H-indoles-2-yl) carbonyl] amino }-2,3-dihydro-1H-indenes -1-yl) acetate
Figure A20068001022500333
Will ((1R, 2R)-2-{[(5-fluoro-1H-indoles-2-yl) carbonyl] amino }-2,3-dihydro-1H-indenes-1-yl) methyl acetate (intermediate 18; 100mg 0.27mmol) is dissolved in MeOH (5mL).Adding salt of wormwood (500mg) also stirs this suspension 19 hours at 60 ℃.Volatile matter is removed in decompression, adds EtOAc (25mL) and water (25mL) then.Organic phase is separated, water (2 * 25mL), salt solution (25mL) washing, dry (MgSO 4) also reduce pressure and remove volatile matter.With product vacuum-drying, obtain title compound (34mg, 36%) then, it is a solid.
1H-NMRδ：2.59(dd，1H)，2.69(dd，1H)，2.91(dd，1H)，3.25(dd，1H)，3.61(m，1H)，4.46(m，1H)，7.01(t，1H)，7.19(m，5H)，7.39(m，2H)，8.68(d，1H)，11.64(s，1H)，12.22(s，1H)；MS m/z 353。
Press the method for embodiment 5, adopt ((1R, 2R)-2-{[(5-chloro-1H-indoles-2-yl) carbonyl] ammonia Base }-2,3-dihydro-1H-indenes-1-yl) methyl acetate(intermediate 19) is as the feedstock production the following examples.
Embodiment 6:((1R, 2R)-2-{[(5-chloro-1H-indoles-2-yl) carbonyl] amino }-2,3-dihydro-1H-indenes -1-yl) acetate
1H-NMRδ：2.63(m，2H)，2.91(dd，1H)，3.25(dd，1H)，3.61(m，1H)，4.46(m，1H)，7.19(m，6H)，7.42(d，1H)，7.68(s，1H)，8.72(d，1H)，11.73(s，1H)，12.20(s，1H)；MS m/z 369。
Embodiment 7:((1R, 2R)-2-{[(5,6-two fluoro-1H-indoles-2-yls) carbonyl] amino }-2,3-dihydro-1H- Indenes-1-yl) acetate
Figure A20068001022500342
With ((1R, 2R)-2-{[(5,6-two fluoro-1H-indoles-2-yls) carbonyl] amino }-2,3-dihydro-1H-indenes-1-yl) methyl acetate (intermediate 25,132mg, (1.71mL is in mixture 3.42mmol) 0.34mmol) to be suspended in methyl alcohol (5mL) and 2M sodium hydroxide, and, obtain clear soln 50 ℃ of heating 30 minutes.Then the reaction mixture concentrating under reduced pressure also is acidified to pH2 with dense HCl.The gained throw out is extracted in the ethyl acetate (50mL), and with this ethyl acetate solution water (20mL) and salt solution (20mL) washing, dry (MgSO 4) and evaporation, obtaining title compound, it is white solid (115mg, 91%).
1H NMRδ：2.6(m，2H)，2.9(dd，1H)，3.2(m，1H)，3.6(m，1H)，4.45(m，1H)，7.2(m，5H)，7.3(dd，1H)，7.6(dd，1H)，8.7(d，1H)，11.7(s，1H)，12.2(s，1H)；MS m/z 383，385。
Embodiment 8:{ (1R, 2R)-2-[(5-chloro-7-fluoro-1H-indole-2-carbonyl)-amino]-indane-1-yl }-second Acid
Will (1R, 2R)-2-[(5-chloro-7-fluoro-1H-indole-2-carbonyl)-amino]-indane-1-yl }-(intermediate 28,202mg 0.51mmol) are suspended in the methyl alcohol (10mL) the acetate methyl ester, and handle with 2M sodium hydroxide solution (2.5mL) in envrionment temperature.This mixture 50 ℃ of heating 2 hours, is cooled to envrionment temperature and concentrating under reduced pressure then.With resistates water-soluble (20mL), be acidified to pH3 with 2M HCl, and (3 * 10mL) extract with ethyl acetate.The extraction liquid water that merges (2 * 10mL) washings, dry (MgSO 4) and evaporation, staying title compound, it is white solid (150mg, 76%).
1H NMR(400MHz，DMSO-d 6)δ2.58-2.74(2H，m)，2.89-2.95(1H，m)，3.21-3.34(1H，m)，3.59-3.64(1H，m)，4.45-4.52(1H，m)，7.15-7.26(6H，m)，7.58-7.59(1H，s)，8.76(1H，d)，12.25(2H，s)；MS m/z 387。
Embodiment 9 and 10:(2R)-2-{ (1R, 2R)-2-[(5-chloro-1H-indole-2-carbonyl)-amino]-indane-1- Base }-4-methoxyl group-butyric acid and (2S)-2-{ (1R, 2R)-2-[(5-chloro-1H-indole-2-carbonyl)-amino]-indane -1-yl }-4-methoxyl group-butyric acid
Figure A20068001022500352
Figure A20068001022500353
With ((1S, 2R)-2-{[(2,3-two chloro-4H-thieno-s [3,2-b] pyrroles-5-yl) carbonyl] amino }-2,3-dihydro-1H-indenes-1-yl) (intermediate 31,200mg 0.44mmol) are dissolved in THF (10mL) to (2-methoxy ethyl) dimethyl malonate, add then lithium hydroxide (50mg, 1.2mmol) and water (3mL).By microwave reaction mixture was heated 30 minutes at 130 ℃, add EtOAc (25mL) then, it is washed with 1N citric acid (10mL), water (10ml), salt solution (10mL), dry (MgSO 4) also reduce pressure and remove volatile matter, obtain brown oil.This oily matter carries out purifying by HPLC (acetonitrile/water, TFA damping fluid 0.2%), obtains product (64mg, 0.14mmol, 32%).Then this product is carried out stratographic analysis under following condition, separates two kinds of diastereomers:
Chromatographic column Merck 50mm 16 μ m Kromasil Chirose 2, CT9014 Packed 16-02-04
Elutriant isohexane/EtOAc/AcOH/TEA 50/50/0.2/0.1
Suitable fraction is merged, evaporates, each diastereomer is dissolved in also uses TFA (2mL) acidifying among the EtOAc (50mL), water (2 * 25mL) washings then then.Then with product vacuum-drying, obtain the first wash-out compound (20mg as jelly, 0.047mmol, 33%) and the second wash-out compound (27mg, 0.063mmol, 45%), one is (2R)-2-{ (1R, 2R)-2-[(5-chloro-1H-indole-2-carbonyl)-amino]-indane-1-yl }-4-methoxyl group-butyric acid, its another be (2S)-2-{ (1R, 2R)-2-[(5-chloro-1H-indole-2-carbonyl)-amino]-indane-1-yl }-4-methoxyl group-butyric acid.
First wash-out (embodiment 9): 1H NMR (400MHz, CDCl 3) 1.09-1.21 (1H, m), 1.91 (1H, s), 3.04-3.06 (1H, m), 3.13 (3H, s), 3.35 (2H, t), 3.56 (1H, t), 3.81-3.84 (1H, m), 4.45 (1H, m), 6.89 (1H, s), 7.10 (3H, t), 7.08-7.15 (2H, m), 7.20 (1H, s), 7.29 (1H, d), 7.44 (1H, d); MS m/z 449[M+Na].
Second wash-out (embodiment 10): 1H NMR (400MHz, CDCl 3) δ 1.24 (1H, d), 3.18 (2H, s), 3.36 (2H, q), 3.42 (1H, s), 4.65 (1H, m), 6.83 (1H, s), 7.07-7.09 (2H, m), 7.10 (1H, s), 7.21 (1H, m), 7.46 (1H, s); MS m/z 449[M+Na].
Embodiment 11 and 12:(2R)-2-{ (1R, 2R)-2-[(5-chloro-1H-indole-2-carbonyl)-amino]-indane -1-yl }-propionic acid and (2S)-2-{ (1R, 2R)-2-[(5-chloro-1H-indole-2-carbonyl)-amino]-indane-1-yl }-third Acid
Figure A20068001022500361
With 2-{ (1R, 2R)-2-[(5-chloro-1H-indole-2-carbonyl)-amino]-indane-1-yl }-propionic acid methyl ester (intermediate 36; 120mg 0.3mmol) is dissolved in THF (10mL), adds lithium hydroxide (25mg, water 0.60mmol) (3mL) solution afterwards.This solution was at room temperature stirred 48 hours.Volatile matter is removed in decompression, adds the citric acid solution (10mL) of EtOAc (25mL) and 1N then.Organic phase is separated, water (2 * 10mL), salt solution (10mL) washing, dry (MgSO 4) also reduce pressure and remove volatile matter, obtain oily matter.This oily matter carries out purifying by HPLC (acetonitrile/water, TFA damping fluid 0.2%), obtains product (56mg, 0.15mmol, 50%).
This product (56mg 0.15mmol) carries out stratographic analysis under following condition, separate two kinds of diastereomers:
Chromatographic column 10 μ m Merck 50mm Kromasil 100CHI-TBB No.CT0021
Elutriant isohexane/EtOH/HOAc/TEA 80/20/0.2/0.1
Merge suitable fraction and evaporation, afterwards each diastereomer is dissolved in EtOAc (10mL) also with TFA (1mL) acidifying, water (2 * 10mL) washings then.Then with product vacuum-drying, obtain the gelationus first wash-out compound (27.0mg, 0.07mmol, 46%) and the second wash-out compound (19.8mg, 0.05mmol, 33%), one is (2R)-2-{ (1R, 2R)-2-[(5-chloro-1H-indole-2-carbonyl)-amino]-indane-1-yl }-propionic acid, its another be (2S)-2-{ (1R, 2R)-2-[(5-chloro-1H-indole-2-carbonyl)-amino]-indane-1-yl }-propionic acid.
First wash-out (embodiment 11): 1H NMR (400MHz, CDCl 3) δ 2.15 (1H, s), 2.77 (2H, m), 3.14 (1H, s), 3.63 (1H, d), 3.88 (1H, s), 4.38 (1H, s), 6.88 (1H, s), 7.12 (4H, s), 7.19 (3H, s), 7.29 (1H, d), 7.37-7.42 (1H, m), 8.97 (1H, s), 10.10 (1H, s); MS m/z 405[M+Na].
Second wash-out (embodiment 12): 1H NMR (400MHz, CDCl 3) δ 2.15 (1H, s), 2.63 (1H, s), 2.70-2.75 (1H, m), 3.41-3.44 (1H, m), 3.61 (1H, s), 4.62 (1H, s), 6.80 (1H, s), 7.12 (5H, s), 7.19 (3H, s), 7.25 (2H, s), 7.46 (1H, s), 10.10 (1H, s); MS m/z405[M+Na].
Intermediate 1:[((1R, 2R)-2-{[(5-chloro-1H-indoles-2-yl) carbonyl] amino }-2,3-dihydro-1H-indenes -1-yl) methoxyl group] tert.-butyl acetate
With HOBT (280mg, 2.07mmol), { [(1R, 2R)-2-amino-2,3-dihydro-1H-indenes-1-yl] methoxyl group } tert.-butyl acetate (intermediate 3; 575mg, 2.07mmol) and EDAC (496mg, (404mg is 2.07mmol) in the suspension in DMA (5mL) 2.6mmol) to add to 5-chloro-indole-2-carboxylic acid.Reaction mixture was stirred 20 hours in envrionment temperature.Add entry (25mL) and filtering-depositing, (2 * 20mL) washings are also dry for water.By flash chromatography (SiO 2, isohexane: EtOAc, 1: 1) and carry out purifying, obtain title compound (500mg, 53%), it is a foam.
1H NMRδ：1.48(s，9H)，3.0(dd，1H)，3.55(m，1H)，3.65(dd，1H)，3.8(m，1H)，3.95(m，1H)，4.05(d，2H)，4.61(m，1H)，6.86(s，1H)，7.05(m，1H)，7.47(m，5H)，7.35(d，1H)，7.59(s，1H)，9.63(s，1H)；MS m/z 453/455(M-H)。
Press the method for intermediate 1, adopt { [(1R, 2R)-2-amino-2,3-dihydro-1H-indenes-1-yl] methoxyl group } tert.-butyl acetate (intermediate 3) to prepare following intermediate as amine and suitable carboxylic acid (5-fluoro indole-2-carboxylic acid).
Intermediate 2:[((1R, 2R)-2-{[(5-fluoro-1H-indoles-2-yl) carbonyl] amino }-2,3-dihydro-1H-indenes -1-yl) methoxyl group] tert.-butyl acetate
Figure A20068001022500381
Figure A20068001022500382
Intermediate 3:{[(1R, 2R)-2-amino-2,3-dihydro-1H-indenes-1-yl] methoxyl group } tert.-butyl acetate
Figure A20068001022500383
To ((1R, 2R)-the 2-[({[tertiary butyl (dimethyl) silyl] the oxygen base } carbonyl) amino]-2,3-dihydro-1H-indenes-1-yl } methoxyl group) tert.-butyl acetate (intermediate 4; 3.5g 8.03mmol) in the solution in THF (30mL), (8.8mL, the THF solution of 1M 8.8mmol), and stir reaction mixture 1 hour in envrionment temperature to add the tetra-n-butyl Neutral ammonium fluoride.Add ammonium chloride solution (25mL, saturated aqueous solution), and (2 * 25mL) extract with EtOAc with this mixture.Organic extract liquid water (20mL), salt solution (20mL) washing, dry (MgSO 4) and reduction vaporization remove volatile matter, obtain title compound (2.2g, 100%), it is an oily matter.
MS m/z 278。
Intermediate 4:({ (1R, 2R)-the 2-[({[tertiary butyl (dimethyl) silyl] the oxygen base } carbonyl) ammonia Base]-2,3-dihydro-1H-indenes-1-yl } methoxyl group) tert.-butyl acetate
Figure A20068001022500391
To ((1R, 2R)-the 2-[(tert-butoxycarbonyl) amino]-2,3-dihydro-1H-indenes-1-yl } methoxyl group) tert.-butyl acetate (intermediate 5; 2.8g, 7.42mmol) with 2,6-lutidine (1.73mL, 14.83mmol) in the solution in anhydrous DCM (20mL), (2.6mL 11.1mmol), and stirs reaction mixture 30 minutes in envrionment temperature to add the t-butyldimethylsilyl triflate.Add ammonium chloride solution (20mL, saturated aqueous solution), and (2 * 35mL) extract with EtOAc with this mixture.Organic extract liquid water (20mL), salt solution (20mL) washing, dry (MgSO 4) and reduction vaporization remove volatile matter, obtain title compound (3.2g, 100%), it is an oily matter.MS m/z 458(M+Na)。
Intermediate 5:({ (1R, 2R)-the 2-[(tert-butoxycarbonyl) amino]-2,3-dihydro-1H-indenes-1-yl } methoxy Base) tert.-butyl acetate
Figure A20068001022500392
To [(1R, 2R)-1-(hydroxymethyl)-2,3-dihydro-1H-indenes-2-yl] t-butyl carbamate (intermediate 6; 2.63g, 10.0mmol) in the solution in DCM (35mL), add bromo-acetic acid tert-butyl (2.0mL, 12.5mmol), 4-n-butyl ammonium hydrogen sulfate (850mg, 2.5mmol) and sodium hydroxide (9.6mL, the 50%w/v aqueous solution, 120.0mmol), and reaction mixture stirred 3 hours in envrionment temperature.Add entry (50mL), and (2 * 50mL) extract with DCM with this mixture.Organic extract liquid water (25mL), salt solution (25mL) washing, dry (MgSO 4) also reduce pressure and remove volatile matter.Resistates is by flash chromatography (SiO 2, isohexane: EtOAc, 3: 1) and purifying, obtain title compound (350mg, 93%), it is an oily matter.MS m/z 400(M+Na)。
Intermediate 6:[(1R, 2R)-1-(hydroxymethyl)-2,3-dihydro-1H-indenes-2-yl] t-butyl carbamate
Figure A20068001022500401
(10.0mL, the THF solution of 2.0M 20.0mmol) add to [(1R, 2R)-1-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl)-2,3-dihydro-1H-indenes-2-yl] t-butyl carbamate (intermediate 7 with tetrabutyl ammonium fluoride; 4.1g, 10.9mmol) in the solution in THF (50mL), and envrionment temperature stirring 4 hours.Volatile matter is removed in decompression, and resistates is dissolved in ethyl acetate (100mL), water (2 * 50mL), salt solution (50mL) washing, dry (MgSO 4) also reduce pressure and remove volatile matter.(4: 1, isohexane: ethyl acetate), filter and drying, obtain title compound (1.5g, 54%), it was a white solid with thick resistates grinding.
1H NMR 1.44(s，9H)，2.78(dd，1H)，3.15(m，2H)，3.61(m，1H)，3.75(m，1H)，4.07(m，1H)，4.7(m，1H)，7.19(m，4H)，7.37(m，1H)。
Intermediate 7:[(1R, 2R)-1-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl)-2, the 3-dihydro -1H-indenes-2-yl] t-butyl carbamate
Figure A20068001022500402
Will (1R, 2R)-1-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl)-2,3-dihydro-1H-indenes-2-yl] amine (intermediate 8; 3.1g, 11.2mmol) and triethylamine (3.1mL 22.4mmol) is dissolved in DCM (40mL).Add tert-Butyl dicarbonate (2.9g, the 13.4mmol) solution in DCM (10mL), and this mixture stirred 24 hours in envrionment temperature.Volatile matter is removed in decompression, and resistates is dissolved in ethyl acetate (75mL), water (2 * 50mL), salt solution (50mL) washing, dry (MgSO 4) also reduce pressure and remove volatile matter.Thick resistates by silica gel chromatography (16: 1, isohexane: ethyl acetate) purifying, obtain title compound (4.2g, 100%), it is colourless oily matter.
1H NMR 0.3(d，6H)，0.85(s，9H)，1.42(s，9H)，2.75(dd，1H)，3.15(m，2H)，3.79(m，1H)，3.95(m，1H)，4.05(m，1H)，7.15(m，4H)，7.3(m，1H)。
Intermediate 8:[(1R, 2R)-1-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl)-2, the 3-dihydro -1H-indenes-2-yl] amine
Figure A20068001022500411
Will (1S, 2S)-1-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl)-2,3-dihydro-1H-indenes-2-base methanesulfonates (intermediate 9; 7.2g, 20.2mmol) be dissolved in DMA (50mL), (3.94g 60.6mmol), and stirs this mixture 7 hours at 60 ℃ to add sodiumazide.This mixture is poured in the ethyl acetate (250mL), water (6 * 75mL), salt solution (100mL) washing and dry (MgSO 4).(500mg 10%w/w), stirs this mixture 6 hours under nitrogen atmosphere, filters and reduces pressure by diatomite (Celite) and remove volatile matter, obtains title compound (5.2g, 93%), and it is a light brown oily thing to add palladium/carbon.
1H NMR 0.07 (d, 6H), 0.9 (s, 9H), 2.58 (dd, 1H), 2.89 (m, 1H), 3.1 (dd, 1H), 3.3 (broad peak s, 2H), 3.41 (m, 1H), 3.85 (m, 2H), 7.2 (m, 4H).
Intermediate 9:(1S, 2S)-1-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl)-2, the 3-dihydro -1H-indenes-2-base methanesulfonates
Figure A20068001022500412
At 5 ℃, will (1S, 2S)-1-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl) indane-2-alcohol (intermediate 10; 6.3g, 22.65mmol) and triethylamine (4.7mL 34.0mmol) is dissolved in DCM (90mL).Add methylsulfonyl chloride (2.86g, the 24.9mmol) solution in DCM (10mL), and this mixture stirred 2 hours in envrionment temperature.Volatile matter is removed in decompression, and resistates is dissolved in ethyl acetate (150mL), water (2 * 50mL), salt solution (50mL) washing, dry (MgSO 4) also reduce pressure and remove volatile matter.Thick resistates by silica gel chromatography (6: 1, isohexane: ethyl acetate) purifying, obtain title compound (7.2g, 89%), it is colourless oily matter.
1H NMR 0.03(d，6H)，0.85(s，9H)，3.19(s，3H)，3.21(m，2H)，3.45(m，1H)，3.95(m，2H)，5.45(m，1H)，7.22(m，4H)。
Intermediate 10:(1S, 2S)-1-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl) indane-2-alcohol
Figure A20068001022500421
At 10 ℃, will (1S, 2S)-1-(hydroxymethyl) indane-2-alcohol (intermediate 11; 9.0g, 54.8mmol) and imidazoles (4.5g 65.8mmol) is dissolved in DCM (75mL).(9.1g, the 60.3mmol) solution in DCM (25mL) make this mixture be warming up to envrionment temperature and stirred 2 hours to add TERT-BUTYL DIMETHYL CHLORO SILANE.Volatile matter is removed in decompression, and resistates is dissolved in ethyl acetate (150mL), water (2 * 50mL), salt solution (50mL) washing, dry (MgSO 4) also reduce pressure and remove volatile matter.Thick resistates by silica gel chromatography (16: 1, isohexane: ethyl acetate) purifying, obtain title compound (9.5g, 62%), it is colourless oily matter.
1H NMR 0.03(d，6H)，0.9(s，9H)，2.78(dd，1H)，3.0(dd，1H)，3.1(m，1H)，3.9(m，2H)，4.54(m，1H)，4.68(d，1H)，7.2(m，4H)。
Intermediate 11:(1S, 2S)-1-(hydroxymethyl) indane-2-alcohol
Figure A20068001022500422
Under nitrogen atmosphere and 0 ℃, will (1R, 2S)-2-hydroxy indene-1-carboxylate methyl ester (intermediate 12; 10.56g, 55.0mmol) be dissolved in anhydrous THF (100mL).(55.0mL, the THF solution of 2.0M 110.0mmol), and stir reaction mixture 0.5 hour at 0～5 ℃, make it to be warming up to envrionment temperature and further stir 2 hours to add lithium borohydride.Pour this mixture into saturated NaHCO 3In, and with ethyl acetate (200mL) extraction, the organic phase water (2 * 50mL), salt solution (50mL) washing and dry (MgSO 4).Reduction vaporization is removed volatile matter, obtains title compound (9.1g, 93%), and it is colourless oily matter.
1HNMR 2.7(m，1H)，2.95(m，1H)，3.05(m，1H)，3.55(m，1H)，3.8(m，1H)，4.55(m，3H)，7.2(m，4H)。
Intermediate 12:(1R, 2S)-2-hydroxy indene-1-carboxylate methyl ester
Figure A20068001022500423
(reference: Didier, E et al Tetrahedron 47 (27), 4941-4958,1991)
Deionized water (20L) is warming up to 34 ℃, adds Saccharomyces cerevisiae (3Kg), and this mixture was stirred 0.5 hour.(40g 0.21mmol), stirs this suspension 3 days and uses diatomite filtration to add 2-oxo indane-1-carboxylate methyl ester.(4 * 2.5L) extractions are with organic extract liquid drying (MgSO with ethyl acetate will to contain filter liquor 4), filtration and reduction vaporization are removed volatile matter.With thick resistates by fast silica gel chromatogram (4: 1 isohexanes: ethyl acetate) purifying, evaporating solvent, gained solid obtain title compound (10.8g, 27%) with isohexane/re-crystallizing in ethyl acetate, it is colourless spicule.
Mp＝72.5-73.5℃(lit＝73.2℃)；[∝] D＝+48.7°(C＝1.0，CHCl 3)(lit＝+48.3°)
1H NMR 2.85(dd，1H)，3.04(dd，1H)，3.61(s，3H)，4.1(d，1H)，4.76(m，1H)，5.2(d，1H)，7.2(m，4H)。
Intermediate 13:(2R/S)-[((1R, 2R)-2-{[(5-chloro-1H-indoles-2-yl) carbonyl] amino }-2,3-two Hydrogen-1H-indenes-1-yl) methoxyl group] the propionic acid tert-butyl ester
Figure A20068001022500431
With HOBT (185mg, 1.37mmol), (2R/S)-{ [(1R, 2R)-2-amino-2,3-dihydro-1H-indenes-1-yl] methoxyl group } the propionic acid tert-butyl ester (intermediate 15; 400mg, 1.37mmol) and EDAC (328mg, (267mg is 1.37mmol) in the suspension in DMA (5mL) 1.71mmol) to add to 5-chloro-indole-2-carboxylic acid.Reaction mixture was stirred 20 hours in envrionment temperature.Add entry (25mL), filtering precipitate, (2 * 20mL) washings are also dry for water.By flash chromatography (SiO 2, isohexane: EtOAc, 2: 1) and purifying, obtain title compound (430mg, 67%), it is a foam. 1H NMRδ：1.38(dd，3H)，1.47(d，9H)，3.0(m，1H)，3.65(m，4.5H)，4.1(m，0.5H)，4.56(m，1H)，6.82(dd，1H)，6.84(d，0.5H)，7.22(m，5.5H)，7.37(d，1H)，7.59(s，1H)，9.65(d，1H)；MS m/z 467/469(M-H)。
Press the method for intermediate 13, adopt (2R/S)-{ [(1R, 2R)-2-amino-2,3-dihydro-1H-indenes-1-yl] methoxyl group } propionic acid tert-butyl ester (intermediate 15) prepares following intermediate as amine and suitable carboxylic acid (5-fluoro indole-2-carboxylic acid).
Intermediate 14:(2R/S)-[((1R, 2R)-2-{[(5-fluoro-1H-indoles-2-yl) carbonyl] amino }-2,3-two Hydrogen-1H-indenes-1-yl) methoxyl group] the propionic acid tert-butyl ester
Figure A20068001022500441
Intermediate 15:(2R/S)-[(1R, 2R)-2-amino-2,3-dihydro-1H-indenes-1-yl] methoxyl group } propionic acid The tert-butyl ester
Figure A20068001022500443
To (2R/S)-((1R, 2R)-the 2-[({[tertiary butyl (dimethyl) silyl] the oxygen base carbonyl) amino]-2,3-dihydro-1H-indenes-1-yl } methoxyl group) the propionic acid tert-butyl ester (intermediate 16; 3.1g 7.0mmol) in the solution in THF (50mL), (9.0mL, the THF solution of 1M 9.0mmol) and with reaction mixture stirred 4 hours in envrionment temperature to add tetrabutyl ammonium fluoride.Add ammonium chloride solution (25mL, saturated aqueous solution), and (2 * 25mL) extract with EtOAc with this mixture.Organic extract liquid water (20mL), salt solution (20mL) washing, dry (MgSO 4) and reduction vaporization remove volatile matter, obtain title compound (1.6g, 80%), it is an oily matter.
1H NMRδ(CDCl 3)：1.48(d，9H)，3.0(ddd，1H)，3.32(m，1H)，3.55(m，3H)，3.7(m，1H)，3.9(m，1H)，4.04(m，1H)，7.17(m，4H)；MS m/z 292。
Intermediate 16:(2R/S)-((1R, 2R)-the 2-[({[tertiary butyl (dimethyl) silyl] the oxygen base } carbonyl) Amino]-2,3-dihydro-1H-indenes-1-yl } methoxyl group) the propionic acid tert-butyl ester
Figure A20068001022500444
To (2R/S)-({ (1R, 2R)-2-[(tert-butoxycarbonyl) amino]-2,3-dihydro-1H-indenes-1-yl } methoxyl group) the propionic acid tert-butyl ester (intermediate 17; 2.75g, 7.02mmol) with 2,6-lutidine (1.6mL, 14.0mmol) in the solution in anhydrous DCM (25mL), (2.4mL 10.54mmol), and stirs reaction mixture 30 minutes in envrionment temperature to add the t-butyldimethylsilyl triflate.Add ammonium chloride solution (20mL, saturated aqueous solution), and (2 * 35mL) extract with EtOAc with this mixture.Organic extract liquid water (20mL), salt solution (20mL) washing, dry (MgSO 4) and reduction vaporization remove volatile matter, obtain title compound (3.2g, 100%), it is an oily matter.MS m/z 472(M+Na)。
Intermediate 17:(2R/S)-((1R, 2R)-the 2-[(tert-butoxycarbonyl) amino]-2,3-dihydro-1H-indenes-1- Base } methoxyl group) the propionic acid tert-butyl ester
Figure A20068001022500451
To [(1R, 2R)-1-(hydroxymethyl)-2,3-dihydro-1H-indenes-2-yl] (intermediate 6:2.63g 10.0mmol) in the solution in DCM (30mL), adds (2R/S)-bromo-propionic acid tert-butyl ester (2.6g to t-butyl carbamate, 12.5mmol), 4-butyl ammonium hydrogen sulfate (850mg, 2.5mmol) and sodium hydroxide (9.6mL, the 50%w/v aqueous solution, 120.0mmol), and reaction mixture stirred 3 hours in envrionment temperature.Add entry (50mL), and (2 * 50mL) extract with DCM with this mixture.Organic extract liquid water (25mL), salt solution (25mL) washing, dry (MgSO 4) also reduce pressure and remove volatile matter.Resistates is by flash chromatography (SiO 2, isohexane: EtOAc, 3: 1) and purifying, obtain title compound (2.5g, 64%), it is an oily matter.
1H NMRδ(CDCl 3)：1.42(m，21H)，2.78(ddd，1H)，3.23(m，1H)，3.35(m，1H)，3.57(m，1H)，4.85(m，2H)，4.14(m，1H)，4.9(m，1H)，7.17(m，3H)，7.37(m，1H)；MS m/z 414(M+Na)。
Intermediate 18:((1R, 2R)-2-{[(5-fluoro-1H-indoles-2-yl) carbonyl] amino }-2,3-dihydro-1H-indenes -1-yl) methyl acetate
Figure A20068001022500452
With 5-fluoro indole-2-carboxylic acid (75mg, 0.42mmol), [(1R, 2R)-2-amino-2,3-dihydro-1H-indenes-1-yl] and the methyl acetate hydrochloride (intermediate 20,113mg, 0.42mmol), DIPEA (144 μ L, 0.84mmol) and HOBT (57mg 0.42mmol) is dissolved in DMA (5mL).(102mg 0.53mmol), and stirs reaction mixture 19 hours in envrionment temperature to add EDAC.Volatile matter is removed in decompression, and crude product is dissolved in EtOAc (15mL).The organic phase water (3 * 15mL), salt solution (15mL) washing, dry (MgSO 4) and solvent removed in vacuo.Carry out purifying (SiO by flash column chromatography 2, 1: 5EtOAc: hexane to 3: 2EtOAc: hexane gradient), obtain title compound (100mg, 65%), it is a solid.
1H-NMRδ：2.73(m，2H)，2.93(dd，1H)，3.25(dd，1H)，3.57(s，3H)，3.63(m，1H)，4.48(m，1H)，7.02(t，1H)，7.17(m，5H)，7.4(m，2H)，8.70(d，1H)，11.63(s，1H)；MS m/z 367。
Press the method for intermediate 18, adopt [(1R, 2R)-2-amino-2,3-dihydro-1H-indenes-1-yl] methyl acetate hydrochloride (intermediate 20) and 5-chloro-indole-2-carboxylic acid to make the feedstock production the following examples.
Intermediate 19:((1R, 2R)-2-{[(5-chloro-1H-indoles-2-yl) carbonyl] amino }-2,3-dihydro-1H-indenes -1-yl) methyl acetate
Figure A20068001022500461
1H NMRδ：2.73(d，2H)，2.93(dd，1H)，3.25(dd，1H)，3.57(s，3H)，3.63(m，1H)，4.48(m，1H)，7.17(m，6H)，7.42(d，1H)，7.68(s，1H)，8.72(d，1H)，11.73(s，1H)；MS m/z 383。
Intermediate 20:[(1R, 2R)-2-amino-2,3-dihydro-1H-indenes-1-yl] the methyl acetate hydrochloride
Figure A20068001022500462
Will (1R, 2R)-the 2-[(tert-butoxycarbonyl) amino]-2,3-dihydro-1H-indenes-1-yl } methyl acetate (intermediate 21; 4.09g, 13mmol) be dissolved in DCM (20mL), handle with HCl (20mL, the two  alkane solution of 4M), and stirred 1 hour in envrionment temperature.Reduction vaporization is removed volatile matter then.The gained white solid is stirred with ether (70mL), and, obtain title compound (2.96g, 91%) by filtered and recycled.
1H NMRδ：2.73(m，1H)，2.99(m，2H)，3.31(m，1H)，3.60(m，4H)，3.76(m，1H)，7.18(m，4H)，8.51(s，3H)；MS m/z 206。
Intermediate 21:{ (1R, 2R)-the 2-[(tert-butoxycarbonyl) amino]-2,3-dihydro-1H-indenes-1-yl } acetate Methyl esters
(405mg 6.93mmol) adds to { (1R, 2R)-2-[(tert-butoxycarbonyl) amino]-2,3-dihydro-1H-indenes-1-yl } dimethyl malonate (intermediate 22 with sodium chloride; 630mg, 1.73mmol) in the solution in comprising 4 DMSO that drip (8mL), and with reaction mixture 160 ℃ the heating 46 hours.On the centrifugal evaporimeter of Genevac EZ-2, remove and desolvate, and resistates is absorbed among water (25mL) and the EtOAc (25mL).With organic layer drying (MgSO 4), filter and evaporation.By column chromatography (SiO 2, EtOAc: hexane, 1: 2) and carry out purifying, obtain title compound (360mg, 68%), it is a solid.
1H NMRδ：1.45(s，9H)，2.78(m，2H)，3.38(m，2H)，3.75(s，3H)，4.13(m，1H)，4.87(br。s，1H)，7.17(m，4H)；MS m/z 386[M+Na+MeCN] +。
Intermediate 22:{ (1R, 2R)-2-[(tert-butoxycarbonyl) amino]-2,3-dihydro-1H-indenes-1-yl } the third two Dimethyl phthalate
Figure A20068001022500472
With NaHMDS (6mL, the THF solution of 1M, 6.00mmol) add to (1S that is stirring, 2S)-and the 1-[(tert-butoxycarbonyl) amino]-2,3-dihydro-1H-indenes-2-base methanesulfonates (intermediate 23,1.79g, 5.46mmol) in the solution in THF (24mL), keep internal temperature＜20 ℃ simultaneously.After 30 minutes, add dimethyl malonate (0.69mL, 6.00mmol), then add NaHMDS (6mL, the THF solution of 1M, 6.00mmol), and with reaction mixture 50 ℃ of heating 18.5 hours.Ammonium chloride solution (50mL, saturated aqueous solution) and Et are also used in reaction mixture cooling (envrionment temperature) 2-O (50ml) cancellation, water layer is used Et once more 2O (50mL) extraction.With gained organic extract liquid drying (MgSO 4), filtration and vacuum are removed volatile matter.Carry out purifying (SiO by flash column chromatography 2, the elutriant gradient: 1: 3 to 1: 1EtOAc: hexane), obtain title compound (630mg, 32%), it is a white solid.
1H NMRδ：1.45(s，9H)，2.78(dd，1H)，3.37(dd，1H)，3.72(m，8H)，4.40(m，1H)，4.78(br。s，1H)，7.20(m，4H)；MS m/z 386[M+Na]。
Intermediate 23:(1S, 2S)-the 1-[(tert-butoxycarbonyl) amino]-2,3-dihydro-1H-indenes-2-base methylsulfonic acid Ester
Figure A20068001022500481
With methylsulfonyl chloride (2.24mL, 30.03mmol) add to the [(1S of cooling (0 ℃), 2S)-2-hydroxyl-2,3-dihydro-1H-indenes-1-yl] t-butyl carbamate (intermediate 24,6.80g, 27.3mmol) and triethylamine (4.01mL, 30.03mmol) in the solution in DCM (100mL), and in 0 ℃ of stirring 1 hour.By adding saturated NaHCO 3The aqueous solution (100mL) makes the reaction cancellation, with organic layer drying (MgSO 4), filtration and vacuum are removed volatile matter.The hot Et of crude product 2O (40mL) grinds, and cooling is also filtered, and obtains title compound (8.11g, 91%), and it is a white solid.
1H NMRδ：1.45(s，9H)，3.18(m，4H)，3.47(dd，1H)，4.78(s，1H)5.19(m，2H)，7.28(m，4H)；MS m/z 350[M+Na] +。
Intermediate 24:[(1S, 2S)-2-hydroxyl-2,3-dihydro-1H-indenes-1-yl] t-butyl carbamate
Figure A20068001022500482
Successively THF (100mL) and 1M aqueous sodium hydroxide solution are added to (1S, 2S) (+)-anti-form-1-amino-2-indanol (CAS Reg.No.163061-74-3,5.00g, 33.55mmol) in.Add then tert-Butyl dicarbonate (7.30g, 33.55mmol) and stirred 16 hours.Vacuum is removed THF, and remaining water layer is acidified to pH2 with citric acid (the 5%w/v aqueous solution), and dilutes with EtOAc (150mL).With organic layer drying (MgSO 4), filtration and vacuum are removed volatile matter.With the hot Et of crude product 2O: hexane (1: 1,40mL) grind, with this suspension cooling and filtration, obtain title compound (6.80g, 81%), it is a white solid.
1H NMRδ：1.54(s，9H)，2.92(dd，1H)，3.28(dd，1H)，4.23(s，1H)，4.42(m，1H)，4.93(t，1H)，5.03(s，1H)，7.22(m，4H)；MS m/z 313[M+Na+MeCN] +。
Intermediate 25:((1R, 2R)-2-{[(5,6-two fluoro-1H-indoles-2-yls) carbonyl] amino }-2, the 3-dihydro -1H-indenes-1-yl) methyl acetate
Figure A20068001022500491
With 5,6-two fluoro-1H-Indoline-2-carboxylic acids (intermediate 26,98.5mg, 0.5mmol), [(1R, 2R)-and 2-amino-2,3-dihydro-1H-indenes-1-yl] methyl acetate hydrochloride (intermediate 20,121mg, 0.5mmol), DIPEA (193.5mg, 1.5mmol) and HOBT (81mg 0.6mmol) is dissolved in DMF (2mL).(114.6mg 0.6mmol) and with this mixture stirred 6 hours in envrionment temperature to add EDAC.Add ethyl acetate (50mL), and with this mixture water (2 * 10mL), 2M HCl (10mL), saturated sodium bicarbonate (10mL) and salt solution (10mL) washs.Dry (MgSO 4) afterwards, reduction vaporization is removed volatile matter, resistates carries out purifying by flash column chromatography, adopts 0～20% ethyl acetate/DCM gradient, obtains title compound (132mg, 68%), and it is a white solid.MS m/z 383(m-H) -。
Intermediate 26:5,6-two fluoro-1H-Indoline-2-carboxylic acids
Figure A20068001022500492
With 4, (intermediate 27,1.24g 4.86mmol) are dissolved in dry DMF (15mL) to 5-two fluoro-2-Iodoanilines.Add pyruvic acid (1.32g, 15mmol) and DABCO (1.68g, 15mmol), and by alternately vacuum and purging with nitrogen gas outgas this mixture.Add acid chloride (56mg) then, and this mixture was heated 2 hours at 100 ℃.To be cooled to envrionment temperature, with the reaction mixture diatomite filtration, with ethyl acetate (100mL) dilution, with 2M HCl (2 * 20mL) and water (2 * 20mL) washings, drying (MgSO 4) and evaporation, obtaining title compound, it is dark solid (860mg, 90%).
1H NMRδ：7.0(s，1H)，7.3(dd，1H)，7.6(dd，1H)，11.9(s，1H)；MS m/z 196(m-H) -。
Intermediate 27:4,5-two fluoro-2-Iodoanilines
With 3, (645mg 5mmol) is suspended in the water (25mL) the 4-difluoroaniline.Add sodium bicarbonate (630mg, 7.5mmol), add subsequently iodine (1.65g, 6.5mmol).Reaction mixture envrionment temperature vigorous stirring 30 minutes, is poured in the saturated sodium thiosulfate solution (50mL) then, and with ethyl acetate (2 * 25mL) extractions.The extraction liquid that merges washs with Sulfothiorine (20mL), water (20mL) and salt solution (20mL), dry (MgSO 4) and evaporation, obtaining title compound, it is dark-coloured oily matter (1.24g, 97%).
Intermediate 28:{ (1R, 2R)-2-[(5-chloro-7-fluoro-1H-indole-2-carbonyl)-amino]-indane-1-yl }- The acetate methyl ester
Figure A20068001022500501
With 5-chloro-7-fluoro-1H-Indoline-2-carboxylic acid (intermediate 29,213mg, 1mmol), ((1R, 2R)-2-amino-indane-1-yl)-acetate methyl ester hydrochloride (240mg, 1mmol), DIPEA (347 μ L, 2mmol) and HOBT (135mg 1mmol) is dissolved in DMF (10mL).(238mg 1.25mmol), and stirs this mixture 18 hours in envrionment temperature to add EDCI then.With reaction mixture with ethyl acetate (100mL) dilution, water (3 * 25mL) and salt solution (25mL) washing, drying (MgSO 4) and the evaporation, stay oily matter, this oily matter by silica gel chromatography (EtOAc/DCM, 0-15%) purifying obtains title compound, it is foam (202mg, 50%). 1H NMR(400MHz，DMSO-d 6)δ2.75(2H，d)，2.90-2.96(1H，m)，3.25-3.35(1H，m)，3.57(3H，s)，3.64(1H，t)，4.46-4.53(1H，m)，7.16-7.26(6H，m)，7.59(1H，s)，8.77(1H，d)，12.25(1H，s)；MS m/z401。
Intermediate 29:5-chloro-7-fluoro-1H-Indoline-2-carboxylic acid
Figure A20068001022500502
With 4-chloro-2-fluoro-6-Iodoaniline (intermediate 30,1.35g, 5mmol), pyruvic acid (1.32g, 15mmol) and DABCO (1.68g 15mmol) is dissolved in DMF (15mL).With this solution degassing and adding acid chloride (56mg).Then this mixture was heated 3 hours at 100 ℃, be cooled to envrionment temperature and filtration.With filtrate with EtOAc (100mL) dilution, with 2M HCl (2 * 20mL), water (20mL) and salt solution (20mL) washing, drying (MgSO 4) and evaporation, obtaining title compound, it is dark-coloured solid (0.9g, 85%).
1H NMR(400MHz，DMSO-d 6)δ7.16(1H，t)，7.21-7.24(1H，m)，7.59(1H，d)，12.52(1H，s)，13.27(1H，s)；MS m/z 212(M-H) -。
Intermediate 30:4-chloro-2-fluoro-6-Iodoaniline
Figure A20068001022500511
(2.9g 20mmol) is dissolved in ethanol (200mL) with 4-chloro-2-fluoroaniline.Add Sulfuric acid disilver salt (6.22g, 20mmol), divide then aliquot ground adding iodine (5.08g, 20mmol).After adding, reaction mixture was stirred 90 minutes in envrionment temperature.Reaction mixture by diatomite filtration and evaporation, is obtained dark-coloured oily matter, it is absorbed among the DCM (200mL), with 2M sodium hydroxide (2 * 50mL), saturated sodium thiosulfate (2 * 50mL) and water (2 * 50mL) wash.With this solution drying (MgSO 4) and evaporation, obtaining title compound, it is dark-coloured oily matter (4.73g, 87%).
1H NMR(400MHz，DMSO-d 6)δ5.30(2H，s)，7.25-7.29(1H，m)，7.47(1H，t)。
Intermediate 31:2-{ (1S, 2R)-2-[(5-chloro-1H-indole-2-carbonyl)-amino]-indane-1-yl }-2-(2- Methoxyl group-ethyl)-diethyl malonate
Figure A20068001022500512
With 5-chloro-1H-Indoline-2-carboxylic acid (109mg, 0.55mmol), 2-((1S, 2R)-2-amino-indane-1-yl)-2-(2-methoxyl group-ethyl)-diethyl malonate hydrochloride (intermediate 32,160mg, 0.51mmol), DIPEA (0.11mL, 0.31mmol) and HOBT (99.5mg 0.51mmol) is dissolved in DCM (10mL).(122g 0.64mmol), and stirs reaction mixture 19 hours in envrionment temperature to add EDAC.Reduction vaporization DCM adds entry (10mL), and (2 * 20mL) extract with EtOAc with this mixture then.Merge organic phase, with saturated sodium bicarbonate aqueous solution (10mL), water (10mL) washing, dry (MgSO 4), and solvent removed in vacuo, obtaining title compound (200mg, 75%), it is an oily matter.MS m/z 526。
Intermediate 32:2-((1S, 2R)-2-amino-indane-1-yl)-2-(2-methoxyl group-ethyl)-propanedioic acid diethyl Ester hydrochloride
Figure A20068001022500521
((intermediate 33,383mg 3.89mmol) handle with HCl (20mL, the two  alkane solution of 4M) (1S, 2R)-2-tert-butoxycarbonyl amino-indane-1-yl)-2-(2-methoxyl group-ethyl)-diethyl malonate, and stir 2 hours in envrionment temperature with 2-.Reduction vaporization is removed volatile matter then, and product is further carried out vacuum-drying, obtains title compound, and it is oily matter (300mg, 100%).
Intermediate 33:2-((1S, 2R)-2-tert-butoxycarbonyl amino-indane-1-yl)-2-(2-methoxyl group-second Base)-diethyl malonate
Figure A20068001022500522
(3.3mL, the THF solution of 1M 3.3mmol) add to (1S that is stirring with NaHMDS, 2S)-and the 1-[(tert-butoxycarbonyl) amino]-2,3-dihydro-1H-indenes-2-base methanesulfonates (intermediate 34,1g, 3mmol) in the solution in THF (30mL), keep internal temperature＜5 ℃ simultaneously.After 30 minutes, (720mg, 3.3mmol), (1.65mL, the THF solution of 1M 1.65mmol), are warming up to room temperature with reaction mixture and stirred 18 hours then to add NaHMDS to add (2-methoxy ethyl) diethyl malonate.To react with saturated aqueous ammonium chloride (50mL) and Et 2O (50mL) cancellation, and with water layer Et 2O (50mL) extracts once more.With the organic extract liquid drying (MgSO that merges 4), filter, and vacuum is removed volatile matter.Carry out purifying (SiO by flash column chromatography 2, gradient: 0% to 40% hexane: EtOAc), obtain title compound (546mg, 1.21mmol, 40%), it is an oily matter.MS m/z 450。
Intermediate 34:(1S, 2S)-the 1-[(tert-butoxycarbonyl) amino]-2,3-dihydro-1H-indenes-2-base methylsulfonic acid Ester
Figure A20068001022500531
With methylsulfonyl chloride (2.24mL, 30.03mmol) add to the [(1S of cooling (0 ℃), 2S)-2-hydroxyl-2,3-dihydro-1H-indenes-1-yl] t-butyl carbamate (intermediate 35,6.80g, 27.3mmol) and triethylamine (4.01mL, 30.03mmol) in the solution in DCM (100mL), and 0 ℃ of stirring 1 hour.Reaction is passed through to add saturated sodium bicarbonate (100mL) aqueous solution cancellation, with organic layer drying (MgSO 4), filter, and vacuum is removed volatile matter.The hot Et of crude product 2O (40mL) grinds, and cooling is also filtered, and obtains title compound (8.11g, 91%), and it is a white solid. 1H NMRδ：1.45(s，9H)，3.18(m，4H)，3.47(dd，1H)，4.78(s，1H)5.19(m，2H)，7.28(m，4H)；MS m/z350[M+Na] +。
Intermediate 35:[(1S, 2S)-2-hydroxyl-2,3-dihydro-1H-indenes-1-yl] t-butyl carbamate
Figure A20068001022500532
Successively THF (100mL) and 1M aqueous sodium hydroxide solution are added to (1S, 2S) (+)-anti-form-1-amino-2-indanol (CAS Reg.No.163061-74-3,5.00g, 33.55mmol) in.Add then tert-Butyl dicarbonate (7.30g, 33.55mmol) and stirred 16 hours.Vacuum is removed THF, and remaining water layer is acidified to pH2 with citric acid (the 5%w/v aqueous solution), and dilutes with EtOAc (150mL).With organic layer drying (MgSO 4), filtration and vacuum are removed volatile matter.With the hot Et of crude product solid 2O: hexane (1: 1,40mL) grind, with this suspension cooling and filtration, obtain title compound (6.80g, 81%), it is a white solid.
1H NMRδ：1.54(s，9H)，2.92(dd，1H)，3.28(dd，1H)，4.23(s，1H)，4.42(m，1H)，4.93(t，1H)，5.03(s，1H)，7.22(m，4H)；MS m/z 313[M+Na+MeCN] +。
Intermediate 36:2-{ (1R, 2S)-2-[(5-chloro-1H-indole-2-carbonyl)-amino]-indane-1-yl }-propionic acid Methyl ester
Figure A20068001022500533
With 5-chloro-1H-Indoline-2-carboxylic acid (69mg, 0.35mmol), 2-((1R, 2R)-2-amino-indane-1-yl)-propionic acid methyl ester hydrochloride (intermediate 37,80mg, 0.32mmol), DIPEA (0.07mL, 0.38mmol) and HOBT (43mg 0.32mmol) is dissolved in DCM (10mL).(77mg 0.40mmol), and stirs reaction mixture 19 hours in envrionment temperature to add EDAC.Volatile matter is removed in decompression, then crude product is dissolved in EtOAc (15mL).Organic phase is washed with saturated carbonate aqueous solution (10mL), water (10mL) and salt solution (10mL), dry (MgSO 4), and solvent removed in vacuo, obtaining title compound (120mg, 94%), it is a solid.MS m/z 419[M+Na]。
Intermediate 37:2-((1R, 2R)-2-amino-indane-1-yl)-propionic acid methyl ester hydrochloride
Figure A20068001022500541
With 2-((1R, 2R)-2-tert-butoxycarbonyl amino-indane-1-yl)-propionic acid methyl ester (intermediate 38; 200mg 0.63mmol) handles with HCl (20mL, the two  alkane solution of 4M), and stirs 2 hours in envrionment temperature.Reduction vaporization is removed volatile matter then, obtains title compound (164mg, 100%).MS m/z 220。
Intermediate 38:2-((1R, 2R)-2-tert-butoxycarbonyl amino-indane-1-yl)-the propionic acid methyl ester
Figure A20068001022500542
(251mg 4.4mmol) adds to 2-((1S, 2R)-2-tert-butoxycarbonyl amino-indane-1-yl)-2-methyl-propanedioic acid dimethyl esters (intermediate 39 with sodium chloride; 630mg, 1.73mmol) in the solution in containing 4 DMSO that drip (5mL), and with reaction mixture 160 ℃ the heating 4 hours.Reaction mixture is absorbed among water (25mL) and the EtOAc (25mL).With organic layer water (10mL) washed twice, dry (MgSO 4), filter and reduction vaporization.By column chromatography (SiO 2, gradient: 0% to 30% hexane: EtOAc) carry out purifying, obtain title compound (200mg, 57%), it is a yellow oil.MS m/z 342[M+Na]。
Intermediate 39:2-((1S, 2R)-2-tert-butoxycarbonyl amino-indane-1-yl)-2-methyl-propanedioic acid two Methyl ester
With NaHMDS (1.65mL, the THF solution of 1M, 1.65mmol) add to (1S that is stirring, 2S)-and the 1-[(tert-butoxycarbonyl) amino]-2,3-dihydro-1H-indenes-2-base methanesulfonates (intermediate 40,0.5g, 1.5mmol) in the solution in THF (15mL), keep internal temperature＜5 ℃ simultaneously.After 30 minutes, (0.22mL, 1.65mmol), (0.83mL, the THF solution of 1M 0.83mmol), is warming up to room temperature with reaction mixture, and stirs 18 hours then to add NaHMDS to add (2-methyl) dimethyl malonate.To react water (20mL) and Et 2O (40ml) cancellation, water layer is used Et once more 2O (15mL) extraction.The organic extract that merges is used saturated carbonate aqueous solution (20mL) and salt solution (20mL) washing successively.With organic phase drying (MgSO 4), filtration and vacuum are removed volatile matter.By flash column chromatography (SiO 2, gradient: 0% to 40% hexane: EtOAc) carry out purifying, obtain title compound (424mg, 75%), it is the jelly of white.
MS m/z 400[M+Na]。
Intermediate 40:(1S, 2S)-the 1-[(tert-butoxycarbonyl) amino]-2,3-dihydro-1H-indenes-2-base methylsulfonic acid Ester
Figure A20068001022500552
With methylsulfonyl chloride (2.24mL, 30.03mmol) add to the [(1S of cooling (0 ℃), 2S)-2-hydroxyl-2,3-dihydro-1H-indenes-1-yl] t-butyl carbamate (intermediate 41,6.80g, 27.3mmol) and triethylamine (4.01mL, 30.03mmol) in the solution in DCM (100mL), and 0 ℃ of stirring 1 hour.Make reaction by adding saturated sodium bicarbonate aqueous solution (100mL) cancellation, with organic layer drying (MgSO 4), filter, and vacuum is removed volatile matter.The hot Et of crude product 2O (40mL) grinds, and cooling is also filtered, and obtains title compound (8.11g, 91%), and it is a white solid. 1H NMRδ：1.45(s，9H)，3.18(m，4H)，3.47(dd，1H)，4.78(s，1H)5.19(m，2H)，7.28(m，4H)；MS m/z 350[M+Na] +。
Intermediate 41:[(1S, 2S)-2-hydroxyl-2,3-dihydro-1H-indenes-1-yl] t-butyl carbamate
Figure A20068001022500561
Successively THF (100mL) and 1M sodium hydroxide (aqueous solution) are added to (1S, 2S) (+)-anti-form-1-amino-2-indanol (CAS Reg.No.163061-74-3,5.00g, 33.55mmol) in.Add then tert-Butyl dicarbonate (7.30g, 33.55mmol) and stirred 16 hours.Vacuum is removed THF, and remaining water layer is acidified to pH2 with citric acid (the 5%w/v aqueous solution), and dilutes with EtOAc (150mL).With organic layer drying (MgSO 4), filter, and vacuum is removed volatile matter.With the hot Et of crude product solid 2O: hexane (1: 1,40mL) grind, and, obtain title compound (6.80g, 81%) this suspension cooling and filtration, it is a white solid. 1H NMRδ：1.54(s，9H)，2.92(dd，1H)，3.28(dd，1H)，4.23(s，1H)，4.42(m，1H)，4.93(t，1H)，5.03(s，1H)，7.22(m，4H)；MS m/z 313[M+Na+MeCN] +。

Claims (16)

1. formula (1) compound or its pharmacy acceptable salt:
Figure A2006800102250002C1
In the formula:
N is 0,1 or 2;
M is 0,1 or 2;
R 1Be independently selected from halogen, nitro, cyano group, hydroxyl, carboxyl, formamyl, N-C 1-4Alkyl-carbamoyl, N, N-(C 1-4Alkyl) 2Formamyl, sulfamyl, N-C 1-4Alkylsulfamoyl group, N, N-(C 1-4Alkyl) 2Sulfamyl, C 1-4Alkyl S (O) b(wherein b is 0,1 or 2) ,-OS (O) 2C 1-4Alkyl, C 1-4Alkyl, C 2-4Thiazolinyl, C 2-4Alkynyl, C 1-4Alkoxyl group, C 1-4Alkyloyl, C 1-4Alkanoyloxy, hydroxyl C 1-4Alkyl, methyl fluoride, difluoromethyl, trifluoromethyl, trifluoromethoxy, and-NHSO 2C 1-4Alkyl;
Perhaps, when n is 2, two R 1Group can be coupled carbon atom form 4 to 7 yuan of saturated rings together, it is optional to comprise 1 or 2 heteroatoms that independently is selected from O, S or N, and is optionally replaced by one or two methyl;
R 4Be independently selected from halogen, nitro, cyano group, hydroxyl, methyl fluoride, difluoromethyl, trifluoromethyl, trifluoromethoxy, carboxyl, formamyl, C 1-4Alkyl, C 2-4Thiazolinyl, C 2-4Alkynyl, C 1-4Alkoxyl group, and C 1-4Alkyloyl;
Z 1For following a) or b):
A) formula-Y-COOH, wherein Y is C 1-6Alkylidene group or C 3-6Cycloalkylidene; Perhaps
B) formula-Y-COOH; Wherein Y is C 1-6Alkylidene group, this C 1-6Alkylidene group:
I) be selected from-N (R 7)-,-O-,-S-,-SO-and-SO 2-in heteroatoms (condition is that this heteroatoms is not adjacent with described carboxyl, and R wherein at interval 7Be hydrogen, C 1-4Alkyl, C 1-4Alkyloyl or C 1-4Alkyl sulphonyl); And/or
Ii) independently being selected from following substituting group by 1 or 2 on carbon replaces: cyano group, oxo, hydroxyl, C 1-3Alkoxyl group, C 1-3Alkyloyl, C 1-3Alkoxy C 2-3Alkoxyl group, hydroxyl C 1-3Alkyl, hydroxyl C 2-3Alkoxyl group, C 3-6Cycloalkyl, C 3-6Cycloalkyl C 1-3Alkyl, C 3-6Cycloalkyloxy, C 3-6Cycloalkyl C 1-3Alkoxyl group, C 1-3Alkyl S (O) c(wherein c is 0,1 or 2) ,-CON (R 2) R 3,-N (R 2) COR 3,-SO 2N (R 2) R 3, and-N (R 2) SO 2R 3, R wherein 2And R 3Be independently selected from hydrogen and C 1-3Alkyl;
Perhaps when described alkylidene group by heteroatoms at interval the time, it also can be chosen wantonly on carbon by two substituting groups and replace, the coupled carbon atom of described substituting group forms C together 3-6Cycloalkyl ring.
2. the formula of claim 1 (1) compound or its pharmacy acceptable salt, wherein m is 1 or 2, and each R 4Be Cl or F independently.
3. claim 1 or 2 formula (1) compound or its pharmacy acceptable salt, wherein n=0.
4. each formula (1) compound or its pharmacy acceptable salt in the claim 1～3, wherein Y is selected from option a).
5. each formula (1) compound or its pharmacy acceptable salt in the claim 1～3, wherein Y is selected from option b).
6. the formula of claim 5 (1) compound or its pharmacy acceptable salt, wherein Y is selected from :-CH 2XCH 2-;-CH 2XCH 2CH 2-;-CH 2CH 2XCH 2-CH (R f) XCH 2-;-CH (R f) XCH 2CH 2-;-CH (R f) CH 2XCH 2-;-CH 2CH (R f) XCH 2-;-CH 2CH 2XCH (R f)-;-CH 2XCH (R f) CH 2-;-CH 2XCH (R f)-;-CH 2XCR f 2-;-CH 2XCH 2CH 2CH 2-[wherein X be selected from-O-,-S-and-SO 2-, R fBe selected from methyl and ethyl];-CH 2-;-CH 2CH 2-;-CH 2CH 2CH 2-;-CH 2CH (Me)-;-CH (R g)-; And-CH (R g) CH 2-[R wherein gBe selected from methoxymethyl, ethoxyethyl group, methoxy ethyl, ethoxyl methyl, methoxy-propyl, cyclopropyl methyl, isopropyl methyl, ethyl and propyl group].
7. claim 5 or 6 formula (1) compound or its pharmacy acceptable salt, wherein Y is selected from :-CH 2-,-CH (CH 3)-,-CH 2OCH 2-,-CH 2OCH (CH 3)-; And-CH (CH 2CH 2OCH 3)-.
8. the formula of claim 4 (1) compound or its pharmacy acceptable salt, wherein Y is C 1-6Alkylidene group.
9. the formula of claim 1 (1) compound or its pharmacy acceptable salt, its be in following any one or multiple:
[((1R, 2R)-2-{[(5-chloro-1H-indoles-2-yl) carbonyl] amino }-2,3-dihydro-1H-indenes-1-yl) methoxyl group] acetate;
[((1R, 2R)-2-{[(5-fluoro-1H-indoles-2-yl) carbonyl] amino }-2,3-dihydro-1H-indenes-1-yl) methoxyl group] acetate;
(2R/S)-[((1R, 2R)-2-{[(5-chloro-1H-indoles-2-yl) carbonyl] amino }-2,3-dihydro-1H-indenes-1-yl) methoxyl group] propionic acid;
(2R/S)-[((1R, 2R)-2-{[(5-fluoro-1H-indoles-2-yl) carbonyl] amino }-2,3-dihydro-1H-indenes-1-yl) methoxyl group] propionic acid;
((1R, 2R)-2-{[(5-fluoro-1H-indoles-2-yl) carbonyl] amino }-2,3-dihydro-1H-indenes-1-yl) acetate;
((1R, 2R)-2-{[(5-chloro-1H-indoles-2-yl) carbonyl] amino }-2,3-dihydro-1H-indenes-1-yl) acetate;
((1R, 2R)-2-{[(5,6-two fluoro-1H-indoles-2-yls) carbonyl] amino }-2,3-dihydro-1H-indenes-1-yl) acetate;
(1R, 2R)-2-[(5-chloro-7-fluoro-1H-indole-2-carbonyl)-amino]-indane-1-yl }-acetate;
(2R)-2-{ (1R, 2R)-2-[(5-chloro-1H-indole-2-carbonyl)-amino]-indane-1-yl }-4-methoxyl group-butyric acid;
(2S)-2-{ (1R, 2R)-2-[(5-chloro-1H-indole-2-carbonyl)-amino]-indane-1-yl }-4-methoxyl group-butyric acid;
(2R)-2-{ (1R, 2R)-2-[(5-chloro-1H-indole-2-carbonyl)-amino]-indane-1-yl }-propionic acid; And
(2S)-2-{ (1R, 2R)-2-[(5-chloro-1H-indole-2-carbonyl)-amino]-indane-1-yl }-propionic acid.
10. pharmaceutical composition, it comprises formula (1) compound or its pharmacy acceptable salt of claim 1, and is combined with pharmaceutically acceptable diluent or carrier.
11. the formula of claim 1 (1) compound or its pharmacy acceptable salt, it is used for treating by therapy warm-blooded animal such as people's method.
12. the formula of claim 1 (1) compound or its pharmacy acceptable salt are as medicine.
13. the formula of claim 1 (1) compound or its pharmacy acceptable salt are as the medicine of treatment warm-blooded animal such as people's following disease: diabetes B, insulin resistance, syndrome X, hyperinsulinemia, blood glucagon too much disease, myocardial ischemia or obesity.
14. the formula of claim 1 (1) compound or its pharmacy acceptable salt, be used for the treatment of purposes in warm-blooded animal such as people's the medicine of following disease in preparation: diabetes B, insulin resistance, syndrome X, hyperinsulinemia, blood glucagon too much disease, myocardial ischemia or obesity.
15. the formula of claim 1 (1) compound or its pharmacy acceptable salt are used for the treatment of purposes in warm-blooded animal such as people's the medicine of diabetes B in preparation.
16. the preparation method of the formula of claim (1) compound or its pharmacy acceptable salt, this method (Z wherein 1, Y, R 1, R 4, m, and n, unless otherwise indicated, suc as formula defined in (1)) comprising:
A) make the acid of formula (2) or the amine reaction of its activatory derivative and formula (3)
Figure A2006800102250005C1
And thereafter, when needed:
I) formula (1) compound is changed into other formula (1) compound;
Ii) remove any protecting group;
Iii) form pharmacy acceptable salt.
CNA2006800102259A 2005-02-05 2006-02-02 Indan-amide derivatives with glycogen phosphorylase inhibitory activity Pending CN101151245A (en)

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