CN1379776A - Pharmaceutical compositions containing thiazolidinedione derivatives and process for their preparation - Google Patents

Pharmaceutical compositions containing thiazolidinedione derivatives and process for their preparation Download PDF

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Publication number
CN1379776A
CN1379776A CN00814298A CN00814298A CN1379776A CN 1379776 A CN1379776 A CN 1379776A CN 00814298 A CN00814298 A CN 00814298A CN 00814298 A CN00814298 A CN 00814298A CN 1379776 A CN1379776 A CN 1379776A
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formula
compound
acceptable salt
solvent thing
tautomeric forms
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R·E·布金哈姆
M·厄克特
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SmithKline Beecham Ltd
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SmithKline Beecham Ltd
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Priority claimed from GBGB9919465.6A external-priority patent/GB9919465D0/en
Priority claimed from GBGB9919842.6A external-priority patent/GB9919842D0/en
Priority claimed from GBGB9920149.3A external-priority patent/GB9920149D0/en
Application filed by SmithKline Beecham Ltd filed Critical SmithKline Beecham Ltd
Publication of CN1379776A publication Critical patent/CN1379776A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
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    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

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Abstract

A pharmaceutical composition which composition comprises an effective non-toxic amount of a compound of formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof, and/or a pharmaceutically acceptable solvate thereof, wherein: A<1> represents OH or -OSO2OH; R<1> represents a hydrogen atom or a C1-6 alkyl group; and R<2> and R<3> each represent hydrogen or R<2> and R<3> together represent a bond; and a pharmaceutically acceptable carrier therefor; certain novel compounds used in such a composition and the use of such compounds and composition in medicine.

Description

Comprise pharmaceutical composition of thiazolidine diketone derivative and preparation method thereof
The present invention relates to new pharmaceutical composition and some new compound, the method and described composition and the application of compound in medical science that prepare these compositions and compound.
Publication number is to have described some formula (A) thiazolidine diketone derivative in 0306228 the european patent application:
Figure A0081429800051
Or its tautomeric forms and/or its pharmacologically acceptable salt, and/or its acceptable solvent thing, wherein:
A aReplace or the unsubstituted aromatic heterocyclic radical of representative;
R aRepresent hydrogen atom, alkyl, acyl group, aralkyl, wherein, aryl moiety can be that replace or unsubstituted, perhaps that replace or unsubstituted aryl base;
R bAnd R cEach represents hydrogen or R bAnd R cRepresent key together;
R bRepresentative has maximum 5 substituent phenyl ring; With
N ' represents the integer of 2-6.
A disclosed specific thiazole alkane diketone is 5-[4-[2-N-methyl-N-(2-pyridyl) amino among the EP0306228) oxyethyl group] benzyl] thiazolidine-2,4-diketone (hereinafter claim compound (I) ').Some salt that discloses compound (I) among the WO94/05659 comprises maleate.
Xenobiotica, 26,6,627-636,1996 and J.Clin.Pharmacol, 48 (3), 424-432 discloses some metabolite of compound (I) in 1999.
Now show, these compounds have good hypoglycemic activity and therefore can be used for the treatment of 2-type diabetes effectively or with the relevant illness of 2-type diabetes.
Therefore, the invention provides a kind of effective nontoxic amount formula (I) compound that comprises:
Figure A0081429800061
Or its tautomeric forms and/or its pharmacologically acceptable salt, and/or the pharmaceutical composition of its acceptable solvent thing and pharmaceutically acceptable carrier, wherein:
A 1Represent OH or-OSO 2OH;
R 1Represent hydrogen atom or C 1-6Alkyl; And
R 2And R 3Each represents hydrogen or R 2And R 3Represent key together.
In one aspect, A 1Represent OH.
Preferably, A 1Representative-OSO 2OH.
Preferably, R 1Represent C 1-6Alkyl, particularly methyl.
Preferably, R 2And R 3Each represents hydrogen.
Preferably, A 1-(C 5H 3N)-NR 1-part representative formula (a) group:
Figure A0081429800062
A wherein 1And R 1Define suc as formula (I).
The present invention also provides formula (I) compound or its tautomeric forms and/or its pharmacologically acceptable salt and/or its acceptable solvent thing of solid form.
The present invention also provides formula (I) compound or its tautomeric forms and/or its pharmacologically acceptable salt and/or its acceptable solvent thing of purification form.
The present invention also provides formula (I) compound or its tautomeric forms and/or its pharmacologically acceptable salt and/or its acceptable solvent thing of crystallized form.
The present invention also provides formula (I) compound or its tautomeric forms and/or its pharmacologically acceptable salt and/or its acceptable solvent thing of pharmaceutically acceptable form.
In addition, some formula (I) compound is new, so the present invention also provides formula (I) compound or its tautomeric forms and/or its pharmacologically acceptable salt and/or its acceptable solvent thing; Precondition is that formula (I) does not comprise 5-(4-{2-[(5-pyridone-2-yl)-methyl-amino]-oxyethyl group }-benzyl)-thiazolidine-2,4-diketone and/or formula (I) do not comprise sulfuric acid-[6-({ 2-[4-(2,4-dioxy-thiazolidine-5-ylmethyl)-phenoxy group]-ethyl }-methyl-amino)-pyridin-3-yl one ester.
Suitable pharmacologically acceptable salt includes pharmaceutically acceptable acid or alkali deutero-salt.Suitable alkali deutero-pharmacologically acceptable salt comprises metal-salt such as aluminium salt, an alkali metal salt such as lithium, sodium or sylvite, the ammonium salt of alkaline earth salt such as calcium or magnesium salts and ammonium or replacement, for example, by rudimentary alkanamine such as triethylamine, hydroxyl alkanamine such as 2 hydroxy ethylamine, two-(2-hydroxyethyl)-amine or three-(2-hydroxyethyl)-amine, cycloalkanes amine such as dicyclohexyl amine, or by PROCAINE HCL, PHARMA GRADE, the dibenzyl piperidines, N-benzyl-β-phenylethylamine, the dehydrogenation rosin Amine D, N, N '-two dehydrogenation rosin Amine D, glutamine, N-methyl glutamine or pyridines alkali such as pyridine, collidine, the salt of quinine or quinoline derivatives.
Suitable alkali deutero-pharmaceutically acceptable acid comprises acid salt.
Suitable acid salt comprises pharmaceutically acceptable inorganic salt such as vitriol, nitrate, phosphoric acid salt, borate, hydrochloride and hydrobromate and pharmaceutically acceptable organic acid addition salt such as acetate, tartrate, maleate, citrate, succinate, benzoate, ascorbate salt, mesylate, alpha-ketoglutarate and α-glycerophosphate.
Suitable acceptable solvent thing comprises hydrate.
As mentioned above, a kind of form of formula (I) compound in can several tautomers exists, and wherein form of ownership all is included in the scope of the present invention.Be appreciated that also formula (I) compound can have at least one chiral carbon atom and therefore can form two or more steric isomers.The present invention comprises all isomeric forms of formula (I) compound, comprises that its any stereoisomer forms, and no matter is single isomer or isomer mixture.
Unless otherwise indicated, this paper term " alkyl " independent or that use as other group part is the straight or branched alkyl that comprises up to 12 carbon atoms as alkoxyl group or aralkyl.Suitable alkyl is C 1-6Alkyl, for example methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-or the tertiary butyl.
Term as used herein " illness relevant " with diabetes comprise the illness relevant, the illness relevant with diabetes itself with pre-diabetes and with the diabetes complications associated with arterial system.
Term as used herein " illness relevant with pre-diabetes " comprises illness such as insulin resistance, fasting glucose deficiency, glucose tolerance weakening and hyperinsulinemia.
" illness relevant with diabetes itself " comprises hyperglycemia, insulin resistance and obesity.Other illness relevant with diabetes itself comprises hypertension and cardiovascular disorder, particularly atherosclerosis and the illness relevant with insulin resistance.The illness relevant with insulin resistance comprises polycystic ovarian syndrome and steroide inductive insulin resistance and gestational diabetes.
" with the diabetes complications associated with arterial system " comprises kidney disease, particularly relevant with diabetes B kidney disease, neuropathy and retinopathy.
The kidney disease relevant with diabetes B comprise ephrosis, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis and late period kidney disease.
Term as used herein " pharmaceutically useful " comprises that human and animal doctor use compound, composition and component: for example, term " pharmacologically acceptable salt " comprises that the animal doctor uses salt.
The compounds of this invention also provides the method for preparation formula (I) compound, and this method comprises formula (II) compound:
Figure A0081429800081
R wherein 2And R 3Suc as formula definition of (I) compound and L 1Represent leavings group, particularly halogen atom such as fluorine atom,
With formula (III) compound:
Figure A0081429800082
R wherein 1Suc as formula (I) definition and A 1Suc as formula (I) definition,
Or its protection form reaction, if desired, carry out one or more following optional step:
(i), formula (I) compound is converted into another formula (I) compound;
(ii), remove the essential protecting group of people;
(iii), the pharmacologically acceptable salt of preparation formula (I) compound and/or its acceptable solvent thing.
Suitable A 1 'For OH or be preferably its protectiveness form such as benzyl form.
Preferably, formula (III) compound uses with its activation form, and described activation form is on-site preparation in the corresponding reaction normally.
Formula (III) compound of suitable activation form is anionic form such as salt form and particularly alkali metal form, for example sylvite.
The formula of activation form (III) compound can be by any suitable ordinary method preparation.For example, the formula of anionic form (III) compound can be by using alkali such as metal alcoholate, and for example potassium tert.-butoxide is handled formula (III) compound.
Formula (II) and the reaction conditions that (III) reacts between the compound are generally suitable normal condition.For example, the reaction between formula (II) compound and salt form formula (III) compound can be in aprotic solvent such as dimethyl formamide, provide required product the suitable temperature that forms speed any, for example carries out under 60 ℃ in the temperature that raises usually.
Formula (II) and (III) compound be that known compound or they can be by the employed similar methods of preparation compound known, for example disclosed method preparation among the EP0306228.L wherein 1Represent F and R 2With R 3Represent the compound (II) of key also can utilize disclosed method preparation among the people (Fiziol.Akt.Veshchestva, 11,97-101,1979) such as Steblyuk together.
Above-mentioned formula (I) compound comprising to the conversion of another formula (I):
(a), with A 1Base is converted into another A 1Base;
(b), incite somebody to action wherein R 2With R 3Represent the compound of key to be converted into wherein R together 2With R 3Each represents the compound of hydrogen.
Formula (I) compound can be undertaken by suitable ordinary method to the conversion of another formula (I).
Suitable conversion (a) comprises wherein A 1For the compound of OH to A wherein 1For-OSO 2The compound of OH transforms, and this conversion can provide required product the suitable temperature that forms speed any by in solvent such as pyridine, for example carries out with pyridine/sulphur trioxide mixture under the room temperature.
Suitable conversion (b) can be by using suitable conventional reduction method, for example by in alkanol solvent such as ethanol, carrying out with 10% palladium on carbon catalyst catalytic reduction, this method can be by using metal/solvent systems such as Tet.Lett.1986,27, magnesium metal/methyl alcohol described in 2409 or in aprotic solvent such as tetrahydrofuran (THF) and pyridine, typically as international patent application, described in the publication number WO98/37073, at elevated temperatures, use metal borohydride, carry out as lithium borohydride (use usually stoichiometric calculation excessive).
Above-mentioned conversion can be taken the circumstances into consideration to carry out at any midbody compound described herein.
Be appreciated that any reactive group of substrate molecule can be protected according to the chemical process of routine in any above-mentioned reaction and transforming.Suitable protecting group is normally used those protecting groups in this area.Therefore, for example, suitable hydroxyl protecting group comprises benzyl or trialkylsilkl.The method that forms or remove described protecting group is those ordinary methods suitable to institute's protecting group molecule.Therefore, for example, benzyloxy can prepare by suitable compounds is handled with benzyl halide such as bromotoluene, and then, if desired, described benzyl can be by using diluted acid, and for example the HCl/ acetolysis is removed aptly.
As mentioned above, The compounds of this invention has effective treatment characteristic.Therefore, the invention provides formula (I) compound or its tautomeric forms and/or its pharmacologically acceptable salt and/or its acceptable solvent thing as the active treatment thing.
Therefore, the invention provides and be used for the treatment of diabetes B or formula (I) compound or its tautomeric forms and/or its pharmacologically acceptable salt and/or its acceptable solvent thing of related disorders arranged with diabetes B.
In described application, formula (I) compound or its tautomeric forms and/or its pharmacologically acceptable salt and/or its acceptable solvent thing give with the pharmaceutical compositions of the present invention that it also contains pharmaceutically acceptable carrier.
Preferably, the present composition can prepare by formula (I) compound of effective nontoxic amount or its tautomeric forms and/or its pharmacologically acceptable salt and/or its acceptable solvent thing are mixed with pharmaceutically acceptable carrier.
If desired, the present composition can be to exist with the packaged form of writing or print working instructions.
Although also as the composition by injection and Transdermal absorption administration, usually, pharmaceutical composition of the present invention is applicable to oral administration to imagination by other approach.
Shi Yi composition for oral administration is unit dosage such as tablet and capsule especially.Other fixedly the formulation of unit also can use as the pulvis that is contained in the deck.
According to conventional pharmacy convention, described carrier can comprise thinner, weighting agent, disintegrating agent, wetting agent, lubricant, tinting material, correctives or other conventional excipients.
For example, typical carrier comprises Microcrystalline Cellulose, starch, sodium starch glycollate, polyvinylpyrrolidone, polyvinylpolypyrrolidone, Magnesium Stearate or sodium lauryl sulphate.
Ground preferably is mixed with unit dosage form with described composition.Described unit dosage form comprises 0.1-1000mg usually, more preferably the active ingredient of 0.1-500mg and preferred especially 0.1-250mg scope amount.
The present invention further provides treatment people or non-human mammal diabetes B or have the method for related disorders, this method to comprise to need the people who treats with diabetes B or non-human mammal is effective, the formula of nontoxic amount (I) compound or its tautomeric forms and/or its pharmacologically acceptable salt and/or its acceptable solvent thing.
In diabetes B or relevant treatment of conditions with diabetes B, Mammals can give every day 1-6 time as mentioned above the formula of dosage (I) compound or its tautomeric forms and/or its pharmacologically acceptable salt and/or its acceptable solvent thing make 70kg grownup's total dose every day usually at 0.1-6000mg, and more preferably usually greatly about the 1-1500mg scope.Particularly in the treatment of dog, active ingredient can be passed through orally give at non-human mammal, and every day 1-2 time and dosage range are approximately 0.025mg/kg-25mg/kg usually, for example 0.1mg/kg-20mg/kg.Similarly dosage is applicable to and treats and/or prevents non-human mammal hyperlipoidemia.
On the other hand, the invention provides and utilize formula (I) compound or its tautomeric forms and/or its pharmacologically acceptable salt and/or its acceptable solvent thing to generate to be used for the treatment of diabetes B or the medicine of related disorders is arranged with diabetes B.
Definite, formula (I) compound no toxicology effect under above-mentioned dosage.
The hypoglycemic activity of The compounds of this invention can be by using standard test, as carry out oral glucose tolerance test (Oral Glucose ToleranceTest) with C57b11/6 obesity (ob/ob) mouse, for example use disclosed methodology mensuration among the EP0306228.
Following method and embodiment are used for explanation but do not limit the present invention in any way.Method 1:2-[(5-bromopyridine-2-yl)-methylamino-]-ethanol
Figure A0081429800111
Under agitation, with 2,5-dibromo pyridine (27.93g) and 2-(methylamino-) ethanol (36.15g) heated 5 hours under 150 ℃ of nitrogen environments.Reaction mixture is cooled to room temperature and is added in the salt solution (490ml), use ethyl acetate (245 * 3) to extract then.Dried over sodium sulfate is washed and used to the organic phase that merges with salt solution (245ml).
Mixture is filtered and removal of solvent under reduced pressure.Add the ethyl acetate that final trace is removed in toluene (100ml * 2) and evaporation.Remaining oily matter is dry under high vacuum, so crystallization occurs.
Output 27.23g, 117.89mmol.m.p.38-43℃。Infrared (nujol): ν Max1589,1540,1501,1435,1417,1365,1322,1274,1257,1226,1203,1154,1143,1095,1079,1065,983,954,944,911,856,811,806,754,735,722,633,585,538 and 514cm -1.PNMR (in dimethyl sulfoxide (DMSO), DMSO): δ H3.00 (3H, s, NCH 3), 3.53 (4H, t, NCH 2, OCH 2), 4.66 (1H, bs, OH), 6.60 (1H, d, ArH), 7.59 (2H, dd, ArH), 8.10 (1H, d, ArH) .CNMR (DMSO): δ C36.9,51.9,58.3,104.8,107.7,139.1,147.5,157.0.MS (EI.70eV) .m/z:230 (33.8) [M.+], 199 (100), 156 (15.0). method 2:(5-bromo-pyridine-2-yl)-[2-(tertiary butyl-dimethyl-siloxy-)-ethyl] methylamine
Under agitation, the monoethanolamine that method 1 is obtained (27.23g) under nitrogen environment, be dissolved in tetrahydrofuran (THF) (THF) (326ml) in.Add tertiary butyl dimethylsilane chlorine (21.40g) and imidazoles (9.67g), mixture at room temperature stirred 18 hours.Removal of solvent under reduced pressure, resistates water (768ml) and ethyl acetate (192ml) are extracted.Be separated two, water layer extracts with ethyl acetate (192ml * 2) again.Organic phase water (384ml * 2) washing that merges, with dried over sodium sulfate and reduction vaporization obtain yellow oil (weight 42,04g).
This crude product is used ethyl acetate: 60-80 ℃ of sherwood oil, 3: 7 (volume ratio) wash-outs by chromatogram chromatographic separation on silica gel.Merge the cut and the reduction vaporization that are rich in product and obtain almost colourless oily matter.Be dissolved in the toluene (100ml) again it and evaporation.This method repeats once.At last, product is obtained crystalline oily matter when placing in drying under the high vacuum.
Output 39.53g, 114.51mmol, 96.8%.Infrared (nujol): ν Max1588,1550,1498,1436,1393,1361,1313,1256,1205,1142,1102,995,922,836,803,776 and 757cm -1.PNMR (DMSO): δ H-0.03 (6H, s, Si (CH 3) 2), 0.81 (9H, s, t-BuSi), 3.00 (3H, s, NCH 3), 3.59 (2H, t, NCH 2), 3.72 (3H, t, OCH 2), 6.60 (1H, d, ArH), 7.59 (2H, dd, ArH), 8.09 (1H, d, ArH) .CNMR (DMSO): δ C-5.5,17.8,25.7,37.2,51.6,60.2,104.9,107.8,139.1,147.5,156.9.MS (EI, 70eV), m/z:344 (26.0) [M.+], 331 (7.0), 287 (85.4), 213 (34.8), 199 (100), 186 (28.0). method 3:3,6-{[2-(tertiary butyl-dimethyl-siloxy-)-ethyl] methylamino }-pyridine-3-alcohol
Under magnetic stirs, the product (39.53g) that method 2 is obtained is dissolved in tetrahydrofuran (THF) (THF under nitrogen environment, 336ml), be cooled to＜-70 ℃ and with about 25 minutes time dropping 2.7M n-butyllithium solution (52ml), and guarantee that the temperature of reaction mixture is no more than-68 ℃.When adding, with reaction mixture-70 ℃ of following restir 20 minutes.Then, trimethylammonium borine (48.3ml) is added in this reaction mixture with about 30 minutes time, and guarantee that temperature of reaction is no more than-65 ℃.Continuously stirring 20 minutes again under approximately-70 ℃ stirs reaction mixture then and spends the night (at least 15 hours) and be warming up to room temperature under nitrogen environment.
Reaction mixture is cooled to 10 ℃ more also adds 2M aqueous sodium hydroxide solution (27ml) as quickly as possible, maintain the temperature at about 10 ℃ (about 1 minutes) simultaneously, the hydrogen peroxide (27ml) that adds 27.5% w/w then with time of 2-3 minute keeps temperature＜25 ℃ simultaneously.After adding, remove cooling bath and reaction mixture was at room temperature stirred 2 hours.
To extract in the reaction mixture impouring dilute hydrochloric acid (54ml 1M hydrochloric acid+1625ml water) and with ethyl acetate (670ml * 3).The organic solution water (670ml * 2) that merges washs and uses dried over sodium sulfate.After the filtration, removal of solvent under reduced pressure obtains dark yellow oily thing (35.47g).
With oily matter chromatography on silica gel, with 3: 7 (volume ratio) ethyl acetate/60-80 ℃ of sherwood oil wash-out.Merge the cut be rich in product, reduction vaporization and with residue with toluene (100ml * 2) azeotropic drying, drying obtains heavy-gravity xanchromatic oily matter under high vacuum then.
Output 29.57g, 104.78mmol, 91.5%.Infrared (nujol): ν Max2954,2928,2884,2856,1620,1570,1506,1472,1463,1439,1416,1388,1360,1318,1256,1205,1135,1102,1071,1018,1006,993,974,938,926,900,836,809,777,741,713,695,662 and 650cm -1.PNMR (DMSO): δ H0.03 (6H, s, SiCH 3) 2), 0.83 (9H, s, t-BuSi), 2.94 (3H, s, NCH 3), 3.51 (2H, t, J6Hz, NCH 2), 3.69 (3H, t, J6Hz, OCH 2), 6.46 (1H, d, J8Hz, ArH), 7.01 (2H, dd, J8,4Hz, ArH), 7.67 (1H, d, J4Hz, ArH), 8.67 (1H, s, OH) .CNMR (DMSO): δ C-5.5,17.8,25.7,37.5,52.1,60.5,106,125.5,134.1,144.7, and 152.6.MS (EI, 70eV), m/z 283 (14) [M+], 151 (100%), 136 (6), 123 (5), 110 (6). method 4:[2-(5-benzyloxy-pyridine-2-yl)-methyl-amino]-ethanol
Figure A0081429800151
Under agitation, be added in the mixture of sodium hydride (4.62g) and bromotoluene (12ml) with time of 35 minutes THF (20ml) solution method 3 products.[the N.B. sodium hydride provides with 60% oil dispersion form and washs with sherwood oil and THF before use].After adding, reaction mixture at room temperature stirred spend the night.
Add (2ml), add tetrabutylammonium hydrate (40.0g) then and reaction mixture was at room temperature stirred 5 hours.
Add entry (70ml) then and reduce pressure and remove THF.Residue is separated with ethyl acetate (200ml) and water (660ml) jolting and with two.Water extracts with ethyl acetate (250ml * 2) again, and the organic phase of merging is used dried over sodium sulfate then with weak brine (432ml * 2) washing.After the filtration, the solution decompression evaporation is obtained darkorange oily matter (32.37g).
With product chromatography on silica gel, earlier with 1: 1 (volume ratio) ethyl acetate/60-80 ℃ of sherwood oil, (volume ratio) ethyl acetate/60-80 ℃ of sherwood oil wash-out of using 7: 3 again.Merge the cut and the reduction vaporization that are rich in product and obtain yellow oil.By adding toluene (100ml * 2) and revaporization drying, dry under high vacuum at last.Product crystallization such as creamy solid.
Output 18.29g, 70.89mmol, 67.7%, m.p.61-63 ℃.Infrared (nujol): ν Max1614,1566,1508,1405,1366,1319,1277,1236,1202,1151,1133,1087,1051,1009,972,913,898,860,824,754,710,694,643 and 541cm -1.PNMR (DMSO): δ H2.96 (3H, s, NCH 3), 3.50 (4H, m, NCH 2, OCH 2), 4.61 (1H, t, OH), 5.03 (2H, s, OCH 2Ph), 6.56 (1H, dd, ArH), 7.28 (2H, dd, ArH), 7.31 (2H, tt, ArH), 7.38 (2H, tt, ArH), 7.42 (2H, dd, ArH), 7.86 (1H, d, ArH) .CNMR (DMSO): δ C37.2,52.3,58.6,70.5,105.9,126.1,127.6,127.7,128.3,134.6,137.3,146.2,153.9.MS (EI, 70eV), m/z 258 (26.8) [M.+], 227 (28.8), 167 (100), 91 (100). method 5:5-(4-{2-[(5-benzyloxy-pyridine-2-yl)-methyl-amino]-oxyethyl group }-Ben Yajiaji)-thiazolidine-2, the 4-diketone
Figure A0081429800161
Under nitrogen environment and magnetic stir, with the 5-[(4-fluorophenyl) methylene radical-2, people (Fiziol.Akt.Veshchestva, 11,97-101,1979) such as 4-thiazolidinedione (15.82g) Steblyuk be added to dimethyl formamide (DMF, 159ml).Adding method 4 products (18.29g) divide 3-4 time then and add potassium tert.-butoxide (17.38g).Resulting orange solution heated 4 hours in 60 ℃ of oil baths, and TLC shows that reaction finishes.
After being cooled to room temperature, reaction mixture is under agitation obtained faint yellow suspension in the mixture of impouring 1M HCl (72ml) and water (1160ml).PH is 6.5.Continuously stirring 30 minutes, then with solid filtering, water (100ml) washing is also aspirated on filter and is done.
The pasty state moist solids is suspended in the Denatured alcohol (100ml) and reflux under agitation.Reflux after 30 minutes, reaction mixture is slowly cooled to 30 ℃, continue to be cooled to 10 ℃ of outlet temperatures.(25ml 10ml) washs, then dried overnight in 50 ℃ of blowing-type baking boxs with Denatured alcohol with solid filtering and on filter.
Output 27.46g, 59.54mmol, 84.0%, m.p.186-187 ℃.Infrared (nujol): ν Max1730,1695,1601,1564,1545,1508,1406,1336,1312,1287,1251,1230,1208,1188,1163,1075,1028,973,896,862,848,823,813,804,796,741,716,697,686,651,631,606,552,542,520cm -1.PNMR (DMSO): δ H3.02 (3H, s, NCH 3), 3.86 (2H, t, NCH 2), 4.19 (2H, t, OCH 2), 5.04 (2H, s, OCH 2Ph), 6.62 (1H, dd, ArH), 7.07 (2H, d, ArH), 7.31 (2H, m, ArH), 7.38 (2H, d, ArH), 7.43 (2H, t, ArH), 7.52 (2H, d, ArH), 7.67 (1H, s, ArH), 7.91 (1H, d, ArH), 12.4 (1H, bs, NH) .CNMR (DMSO): δ C36.8,48.8,65.8,70.5,106.1,115.2,122.1,125.9,126.1,127.6,127.7,128.4,130.4,131.9,134.7,137.2,146.5,153.5,159.9,168.9,169.5.MS (EI, 70eV), m/z 461 (0.7) [M.+], 370 (1.3), 311 (43.4), 150 (55.6), 91 (100). method 6:5-(4-{2-[(5-benzyloxy-pyridine-2-yl)-methyl-amino]-oxyethyl group }-benzyl)-thiazolidine-2, the 4-diketone
At nitrogen environment with under stirring, be added in the pyridine (47ml) and THF (43ml) mixture of method 5 thiazolidinediones (26.79g) with the THF solution (61ml) of 25 minutes times with the 2M lithium borohydride.After being cooled to room temperature, with reaction mixture under agitation in the mixture of impouring concentrated hydrochloric acid (27ml) and ice (181g), keep temperature＜25 ℃.Resulting suspension at room temperature stirred 30 minutes and checked pH.PH is approximately 6.5.Solid filtering and thorough washing is colourless until filtrate.With solid with toluene (100ml) azeotropic drying and reduction vaporization.This process is repeated once.The exsiccant residue is by being heated to reflux temperature with ethyl acetate (500ml) and filtering resulting hot mixt and extract.For insoluble substance, (500ml) repeats this process with more ethyl acetate.
The filtrate evaporation that merges obtains as above with toluene (100ml * 2) exsiccant white solid, and is dry under high vacuum then.
Output 24.70g, 53.32mmol, 91.8%, m.p.152-155 ℃.Infrared (nujol): ν Max1740,1696,1613,1586,1561,1509,1406,1328,1310,1290,1268,1247,1208,1180,1163,1110,1075,1037,1014,975,907,847,832,810,803,734,717,695,663,602,573,548,539, and 502cm -1.PNMR (DMSO): δ H3.01 (4H, s, NCH 3, ArCH 2CH), 3.29 (1H, dd, ArCH 2CH), 3.82 (2H, t, NCH 2), 4.08 (2H, t, OCH 2), 4.83 (1H, dd, ArCH 2CH), 5.04 (2H, s, OCH 2Ph), 6.61 (1H, d, ArH), 6.86 (2H, d, ArH), 7.13 (2H, d, ArH), 7.31 (2H, t, ArH), 7.38 (2H, t, ArH), 7.42 (2H, d, ArH), 7.90 (1H, d, ArH), 11.80 (1H, bs, NH) .CNMR (DMSO): δ C36.3,37.3,48.9,53.1,65.4,70.5.106.1,114.3,126.1,127.6,127.7,128.3,128.6.130.3,134.7,137.2,146.5,153.6,157.5,171.8.175.9.MS (EI, 70eV), m/z 463 (63.5) [M.+], 372 (100), 227 (95.4), 107 (96.1), 91 (42.7). embodiment 1:5-(4-{2-[(5-hydroxyl-pyridine-2-yl)-methyl-amino]-oxyethyl group }-benzyl)-thiazolidine-2, the 4-diketone
Method 6 thiazolidinediones (24.26g) are dissolved in the Glacial acetic acid (183ml) and under agitation add concentrated hydrochloric acid (91ml), this mixture was stirred 2 hours down at 90 ℃.
After being cooled to room temperature, acetate is removed in decompression.Residue fully stirs with ethyl acetate (535ml) and water (535ml), and pH transfers to 0.81-6.0 with solid sodium bicarbonate.When obtaining constant pH, separate two-phase, (150ml) extract again, remains on the solid of interface and aqueous phase separation by 250ml * 2 with ethyl acetate for water.The organic phase dried over sodium sulfate that merges.
After the filtration, remove ethyl acetate by the rotatory evaporator decompression and obtain the weak yellow foam thing.By under scraping, grinding with Denatured alcohol (25ml), described foam thing is converted into the milk yellow solid, filter and wash with IMS (total amount 10ml).Spend the night 50 ℃ of blowing-type oven dried.
Output 13.91g, 37.28mmol, 71.2%, m.p.160-162 ℃.Infrared (nujol): ν Max3452,1774,1733,1682,1635,1614,1584,1569,1512,1391,1348,1327,1312,1302,1246,1217,1204,1179,1159,1142,1112,1073,1038,1016,976,942,929,920,892,851,835,828,808,733,728,710,668,605,575,551,537,526 and 505cm -1.PNMR (DMSO): δ H2.98 (3H, s, NCH 3), 3.05 (1H, dd, ArCH 2CH), 3.29 (1H, dd, ArCH 2CH), 3.79 (2H, t, NCH 2), 4.07 (2H, t, OCH 2), 4.85 (1H, dd, ArCH 2CH), 6.53 (1H, d, ArH), 6.86 (2H, d, ArH), 7.04 (1H, dd, ArH), 7.13 (2H, d, ArH), 7.71 (1H, d, ArH), 8.74 (1H, brs, OH), 11.97 (1H, bs, NH) .CNMR (DMSO): δ C36.3,37.5,49.0,53.0,65.4,106.2,114.3,125.7,128.6,130.3,134.1,145.0,152.5,157.5,171.6,175.7.MS (EI, 70eV), m/z 373 (3.6) [M+H], 223 (1.4), 151 (12.9), 137 (100), 107 (40.6). embodiment 2: sulfonic acid one-[6-(2-[4-(2,4-dioxy-thiazolidine-5-ylmethyl) phenoxy group]-ethyl }-methyl-amino)-pyridine)-3-base ester
Figure A0081429800191
With embodiment 1 product (3.40g) with pyridine-sulphur trioxide mixture (4.53g) is dissolved in the pyridine (230ml) and stirred under the room temperature nitrogen environment 26 hours.Acetate is removed in decompression, is added in the residue toluene (70ml) and revaporization.(10ml) repeats this process with more toluene.Then residue is handled with methyl alcohol (140ml) and under agitation reflux until dissolving the solution of heat is filtered.After at room temperature cooling off 16 hours, precipitation forms.Mixture was cooled off 26 hours in refrigerator (4-5 ℃) again, obtain crude product by solid collected by filtration and with methyl alcohol (20ml) washing then.
Output 3.14g, 6.93mmol, 76.1%.
Crude product (3.14g) is suspended in the mixture of water (250ml) and methyl alcohol (50ml) and reflux under agitation.With resulting yellow solution heating solid dissolving all until when filtered while hot time the at least 30 minutes.Filtrate is cooled to room temperature and placed at least 20 hours.With resulting cream-colored solid filtering, water (30ml * 2) washing is also aspirated dry down again.
Output 2.74g, 6.05mmol, 87.3% (recrystallization, the rate of recovery), m.p.198-201 ℃.Infrared(nujol)：ν max3185，3142，3074，3046，1759，1701，1659，1613，1552，1513，1409，1362，1345，1331，1306，1279，1228，1214，1186，1143，1083，1050，1013，1003，974，970，927，848，816，789，738，708，686，636，618，606，573cm -1.PNMR(DMSO)：δ H3.23(3H，s，NCH 3)，3.06(1H，dd，ArCH 2CH)，3.26(1H，dd，ArCH 2CH)，3.99(2H，t，NCH 2)，4.21(2H，t，OCH 2)，4.84(1H，dd，ArCH 2CH)，6.84(2H，d，ArH)，7.14(2H，d，ArH)，7.32(1H，dd，ArH)，7.81(1H，d，ArH)，7.91(1H，dd，ArH)，11.95(1H，bs，NH).CNMR(DMSO)：δ C?36.2，38.0，50.5，52.9，64.9，112.5，114.3，127.8，129.0，130.4，138.9，140.9，150.0，157.0，171.6，175.6.MS(EI，70eV)，m/z?452(56.3)[M-H]，372(37.6)，229(14.0)，222(50.5)，116(100).

Claims (11)

1. one kind comprises effective nontoxic amount formula (I) compound: Or its tautomeric forms and/or its pharmacologically acceptable salt, and/or the pharmaceutical composition of its acceptable solvent thing and pharmaceutically acceptable carrier, wherein:
A 1Represent OH or-OSO 2OH;
R 1Represent hydrogen atom or C 1-6Alkyl; And
R 2And R 3Each represents hydrogen or R 2And R 3Represent key together.
2. the composition of claim 1, wherein in formula (I) compound, A 1Representative-OSO 2OH.
3. claim 1 or 2 composition, wherein in formula (I) compound, R 1Represent methylidene.
4. arbitrary composition of claim 1-3, wherein in formula (I) compound, R 2And R 3Each represents hydrogen.
5. arbitrary composition of claim 1-4, wherein in formula (I) compound, A 1-(C 5H 3N)-NR 1-part representative formula (a) group:
Figure A0081429800022
A wherein 1And R 1Define suc as formula (I).
6. the composition of claim 1, its Chinese style (I) compound is 5-(4-{2-[(5-hydroxyl-pyridine-2-yl)-methyl-amino]-oxyethyl group }-benzyl)-thiazolidine-2,4-diketone or sulfuric acid-[6-(2-[4-(2,4-dioxy-thiazolidine-5-ylmethyl)-phenoxy group]-ethyl }-methyl-amino)-pyridin-3-yl one ester; Or its tautomeric forms and/or its pharmacologically acceptable salt and/or its acceptable solvent thing.
7. the method for preparation formula (I) compound and/or its acceptable solvent thing, this method comprises formula (II) compound:
Figure A0081429800031
R wherein 2And R 3Suc as formula definition of (I) compound and L 1Represent leavings group,
With formula (III) compound:
Figure A0081429800032
R wherein 1Suc as formula (I) definition and A 1Suc as formula (I) definition,
Or its protection form reaction, if desired, carry out one or more following dispensable steps:
(i), formula (I) compound is converted into another formula (I) compound;
(ii), remove the essential protecting group of people;
(iii), the pharmacologically acceptable salt of preparation formula (I) compound and/or its acceptable solvent thing.
8. as preparing the method for claim 1 pharmaceutical composition, this method comprises with claim 1 when defined that (I) compound or its tautomeric forms and/or its pharmacologically acceptable salt and/or its acceptable solvent thing mix with pharmaceutically acceptable carrier.
9. be used as the defined formula of claim 1 (I) compound or its tautomeric forms and/or its pharmacologically acceptable salt and/or its acceptable solvent thing of therapeutical agent material.
10. be used for the treatment of diabetes B or the defined formula of claim 1 (I) compound or its tautomeric forms and/or its pharmacologically acceptable salt and/or its acceptable solvent thing of related disorders arranged with diabetes B.
11. treat people or non-human mammal diabetes B or with diabetes B the method for related disorders is arranged for one kind, this method comprises the people who needs treatment or non-human mammal is effective, the formula of nontoxic amount (I) compound or its tautomeric forms and/or its pharmacologically acceptable salt and/or its acceptable solvent thing.
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