CN101284810A - Cyano-pyrrolidine and cyano-tetrahydrothiazole derivates - Google Patents

Cyano-pyrrolidine and cyano-tetrahydrothiazole derivates Download PDF

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CN101284810A
CN101284810A CNA2008101237362A CN200810123736A CN101284810A CN 101284810 A CN101284810 A CN 101284810A CN A2008101237362 A CNA2008101237362 A CN A2008101237362A CN 200810123736 A CN200810123736 A CN 200810123736A CN 101284810 A CN101284810 A CN 101284810A
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amino
methyl
ethanoyl
cyano group
phenyl
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秦引林
朱崇泉
曹庆先
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JIANGSU WUZHONG PHARMACEUTICAL DEVELOPMENT Co Ltd
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Abstract

The invention provides novel medicine possibly provided with multiple action mechanisms of insulin sensitization and DPP-IV inhibition, by connecting a pharmacophore of sulfonylurea and PPAR excitant medicine and a basic pharmacophore of DPP-IV inhibitor in an appropriate mode according to a combination principle of medicine design, which can improve the control ability of blood sugar and decrease possible side effects. The structural formula of the derivative is as above. The invention also proposes that the derivative, along with pharmaceutically accepted halomorphic salt, is suitable for being prepared and convenient for clinical application. The experiment proves that the derivative plays better medicine effect than single pharmacophore.

Description

Cyanopyrolidine and cyano-tetrahydrothiazole derivates
Technical field
The present invention relates to the derivative and the acceptable salt of pharmacy meaning thereof of dipeptidyl peptidase-IV (DPP-IV) inhibitor, reach their application in the medicine of preparation carbohydrate metabolism disturbance disease, be particularly related to novel 2-cyanopyrrole alkanes and 4-cyano thiazole alkane derivative and the acceptable salt of pharmacy meaning thereof, reach their application in the medicine of preparation carbohydrate metabolism disturbance disease.Belong to the pharmaceutical chemistry field.
Background technology
Diabetes have a strong impact on HUMAN HEALTH and with various complication.Diabetes mainly can be divided into two kinds: I-type Diabetes mellitus is that islet cells is downright bad and cause seldom or normal excreting insulin, and II-type diabetes are to cause insulin deficit or insulin resistant owing to other reasons.Nearly diabetics more than 90% belongs to II-type diabetes.The complication of diabetes comprises hyperlipidemia, hypertension, retinal diseases and renal insufficiency.Sulfonylurea (stimulating the islet cells excreting insulin), biguanides (it is synthetic to suppress liver starch), alpha-glucosidase inhibitor (glucose absorption that suppresses enteron aisle) all are effective Remedies for diabetes.Recently, peroxisome proliferation activated receptor agonist γ (PPAR γ) agonist (insulin sensitivity enhancing is as thiazolidinediones) is subjected to more and more many attentions as Remedies for diabetes.Yet all there is certain side effect in these medicines, as hypoglycemia and weight increase etc.Therefore, the clinical littler Remedies for diabetes of side effect that presses for.
Dipeptidyl peptidase-IV (DPP-IV) lacks activity and the high insulin levels can keep glucagon-like peptide 1 (GLP-1), lowering blood glucose level consequently, and therefore, this just may be the new target spot for the treatment of diabetes.GLP-1 has vital role in the carbohydrate metabolism process, for example, (1), GLP-1 strengthen secretion of insulin; (2), expression of insulin is secreted necessary gene; (3), stimulate the differentiation of inducing pancreatic; (4), suppress the glucagon secretion; (5), suppress Alimentary secreting function and wriggling; (6), depress appetite.Therefore, GLP-1 has restricted food intake, has postponed the digestion and the absorption process of food, has improved the blood sugar utilization.DPP-IV loses activity it by the terminal dipeptides of the glucagon-like peptide that dissociates-1 (GLP-1) (His-Ala), therefore, the DPP-IV inhibitor can be kept the GLP-1 activity by the inactivation mechanism of blocking-up GLP-1, thereby can become treatment and prevent various and carbohydrate metabolism diseases associated, particularly non insulin dependent diabetes (II-type diabetes).
The DPP-IV inhibitor also can be used as slimming medicine, because the DPP-IV inhibitor can produce feeling of repletion and reduce the digestion of enteron aisle to food.And a large amount of studies show that, the DPP-IV inhibitor can controlling blood sugar and blood lipid level.These studies have shown that the DPP-IV inhibitor has the effect of potential treating diabetes.
Up to the present, the development research of a large amount of DPP-IV inhibitor concentrates on 2-cyanopyrrole alkane derivative, and for example, the 2-cyanopyrrole hydride compounds of WO0034241 report has following structure:
Figure A20081012373600081
R is an adamantyl, and n equals 0～3.(R=3-hydroxyadamantane base n=0) has entered clinical study to its representation compound LAF-237.
The 4-cyano thiazole alkyl compound of US6110949 report,
Figure A20081012373600082
With WO03074500 report (2S 4S)-4-fluoro-2-Cyanopyrolidine compounds compound, all has good DPP-IV equally and suppresses active.
Figure A20081012373600083
The DPP-IV inhibitor is as Remedies for diabetes, its advantage is can be in the unsuitable time, between two meal, increase plasma insulin level, therefore, the DPP-IV inhibitor can avoid occurring the Remedies for diabetes such as the sulfonylurea of present clinical use, biguanides, occurred when alpha-glucosidase inhibitor and peroxisome hyperplasia activated receptor γ (PPAR γ) agonist as side effects such as hypoglycemia and weight increase, yet, because there is multiple dipeptidyl peptidase in human body, the DPP-IV inhibitor suppresses the selectivity of dipeptidyl peptidase-IV, illustrate the DPP-IV inhibitor to the inhibition ability of other enzymes extremely a little less than, relatively may reach several magnitude with DPP-IV.However, since individual difference, the issuable side effect after extensive clinical application of DPP-IV inhibitor, still unpredictable at present.
So the DPP-IV inhibitor is studied, find out better derivative applying clinical, promote the well-being of mankind.
Summary of the invention
Technical problem: the objective of the invention is to principle of hybridization according to medicinal design, the pharmacophoric group of sulfonylurea and PPAR stimulant medicine is connected by suitable mode with the basic pharmacophoric group of DPP-IV inhibitor, provide a class the new medicine that may not only have the multiple action mechanism that insulin sensitivity enhancing but also tool DPP-IV suppress, improve glycemic control ability, the side effect that reduction may occur with expectation.Another object of the present invention is to propose this derivative can with the acceptable sour salify of pharmacy meaning, and their application in the medicine of preparation carbohydrate metabolism disturbance disease.
Technical scheme:, Cyanopyrolidine and cyano-tetrahydrothiazole derivates, its structural formula is as follows:
Figure A20081012373600091
Wherein, X is CH 2, CHF, CF 2Or S; L is a linking group, is C 1-8Straight chained alkyl, C 1-8Branched-chain alkyl or C 3-6Cycloalkyl; R 1Be the pharmacophoric group of sulfonylurea hypoglycemic hypoglycemic drug or the pharmacophoric group of peroxisome proliferation activated receptor agonist agonist class ofhypoglycemic medicine; R 2Be R 1, hydrogen ,-CH 2CO 2H or CH 2CO-R 7, R 7Be 2-cyanopyrrole alkyl or 4-cyano thiazole alkyl; Work as R 2Be R 1Or during carboxymethyl, R 2---R 1For connecting or not connecting; Work as R 2Be hydrogen or CH 2CO-R 7The time, R 2---R 1For not connecting.
This derivant structure can be as follows:
Figure A20081012373600092
Wherein, X is CH 2, CHF, CF 2Or S; R 3Be C 1-8Straight chained alkyl, C 1-8Branched-chain alkyl or C 3-6Cycloalkyl, C 3-6Cycloalkyl is not substituted or by C 1-6Alkane replace; M is 0～2; R 5Be hydrogen, C 1～6Alkyl or C 3～6Cycloalkyl.
This derivant structure can also be as follows:
Figure A20081012373600101
Wherein, X is CH 2, CHF, CF 2Or S;
Figure A20081012373600102
Be singly-bound or two key; R 9Be C 1-6Alkyl or C 3-6Cycloalkyl; R 6Be hydrogen, C 1-6Alkyl or C 3-6Cycloalkyl; R 6---N is for connecting or not connecting.
This derivant structure is as follows:
Figure A20081012373600103
Wherein, X is CH 2, CHF, CF 2Or S; U is 0～1; R 8Be hydrogen, C 1～6Alkyl or C 3～6Cycloalkyl; V is 1～3; R 10For hydrogen ,-CH 2CO 2H or CH 2CO-R 11, R 11Be 2-cyanopyrrole alkyl or 4-cyano thiazole alkyl.
This derivative is preferably especially:
(R)-and N-[4-[[[(cyclohexyl amino) formyl radical] amino] alkylsulfonyl] phenyl] glycyl-4-cyano-tetrahydrothiazole
(S)-and N-[4-[[[(cyclohexyl amino) formyl radical] amino] alkylsulfonyl] phenyl] glycyl-2-Cyanopyrolidine
(S)-and N-[4-[[[(4-methylcyclohexyl amino) formyl radical] amino] alkylsulfonyl] phenyl] glycyl-2-Cyanopyrolidine
(R)-and N-[4-[[[(4-methylcyclohexyl amino) formyl radical] amino] alkylsulfonyl] phenyl] glycyl-4-cyano-tetrahydrothiazole
(S)-and N-[4-[[[(cyclohexyl amino) formyl radical] amino] alkylsulfonyl] phenmethyl] glycyl-2-Cyanopyrolidine
(R)-and N-[4-[[[(cyclohexyl amino) formyl radical] amino] alkylsulfonyl] phenmethyl] glycyl-4-cyano-tetrahydrothiazole
(S)-and 1-[[4-[[-4 methyl-(hexamethylene amino) formyl radical] amino-sulfonyl]-phenmethyl] amino]-ethanoyl]-2-cyano group-tetramethyleneimine
(R)-and 1-[[4-[[-4 methyl-(hexamethylene amino) formyl radical] amino-sulfonyl]-phenmethyl amino]-ethanoyl]-4-cyano group-thiazolidine
(S)-and 1-[[4-[[(hexamethylene amino) formyl radical] amino-sulfonyl]-phenylethyl amino]-ethanoyl]-2-cyano group-tetramethyleneimine
(R)-and 1-[[4-[[(hexamethylene amino) formyl radical] amino-sulfonyl]-phenylethyl amino]-ethanoyl]-4-cyano group-thiazolidine
(S)-and 1-[[4-[[-4 methyl-(hexamethylene amino) formyl radical] amino-sulfonyl]-phenylethyl amino]-ethanoyl]-2-cyano group-tetramethyleneimine
(R)-and 1-[[4-[[-4 methyl-(hexamethylene amino) formyl radical] amino-sulfonyl]-phenylethyl amino]-ethanoyl]-4-cyano group-thiazolidine
(S)-and 1-[[4-[[(hexamethylene amino) formyl radical] amino-sulfonyl]-a-methyl-phenmethyl amino]-ethanoyl]-2-cyano group-tetramethyleneimine
(R)-and 1-[[4-[[(hexamethylene amino) formyl radical] amino-sulfonyl]-a-methyl-phenmethyl amino]-ethanoyl]-4-cyano group-thiazolidine
(S)-and 1-[[4-[[-4 methyl-(hexamethylene amino) formyl radical] amino-sulfonyl]-a-methyl-phenmethyl amino]-ethanoyl]-2-cyano group-tetramethyleneimine
(R)-and 1-[[4-[[-4 methyl-(hexamethylene amino) formyl radical] amino-sulfonyl]-a-methyl-phenmethyl amino]-ethanoyl]-4-cyano group-thiazolidine
(S)-and 1-[[4-[[-4 methyl-(hexamethylene amino) formyl radical] amino-sulfonyl]-α-ethyl-phenmethyl amino]-ethanoyl]-2-cyano group-tetramethyleneimine
(R)-and 1-[[4-[[(hexamethylene amino) formyl radical] amino-sulfonyl]-α-ethyl-phenmethyl amino]-ethanoyl]-4-cyano group-thiazolidine
(S)-and 1-[[4-[[-4 methyl-(hexamethylene amino) formyl radical] amino-sulfonyl]-a-ethyl-phenmethyl amino]-ethanoyl]-2-cyano group-tetramethyleneimine
(R)-and 1-[[4-[[-4 methyl-(hexamethylene amino) formyl radical] amino-sulfonyl]-a-ethyl-phenmethyl amino]-ethanoyl]-4-cyano group-thiazolidine
(R)-and 1-[[4-[[(hexamethylene amino) formyl radical] amino-sulfonyl]-a-cyclohexyl-phenmethyl amino]-ethanoyl]-4-cyano group-thiazolidine
(R)-and 1-[[4-[[4 methyl-(hexamethylene amino) formyl radical] amino-sulfonyl]-a-cyclohexyl-phenmethyl amino]-ethanoyl]-4-cyano group-thiazolidine
(S)-and 1-[[4-[[(hexamethylene amino) formyl radical] amino-sulfonyl]-a-cyclohexyl-phenmethyl amino]-ethanoyl]-2-cyano group-tetramethyleneimine
(S)-and 1-[[4-[[4 methyl-(hexamethylene amino) formyl radical] amino-sulfonyl]-a-cyclohexyl-phenmethyl amino]-ethanoyl]-2-cyano group-tetramethyleneimine
(S)-and 1-[[4-[4-[(2,4-thiazolidinedione-5-yl) methyl] phenoxy group] piperidines-1-yl]-ethanoyl]-2-cyano group-tetramethyleneimine
(R)-and 1-[[4-[4-[(2,4-thiazolidinedione-5-yl) methyl] phenoxy group] piperidines-1-yl]-ethanoyl]-4-cyano group-thiazolidine
(R)-and 1-[[4-[4-[(2,4-thiazolidinedione-5-yl) methyl] phenoxy group] hexamethylene amino]-ethanoyl]-4-cyano group-thiazolidine
(S)-and 1-[[4-[4-[(2,4-thiazolidinedione-5-yl) methyl] phenoxy group] hexamethylene amino]-ethanoyl]-2-cyano group-tetramethyleneimine
(S)-and 1-[[2-[4-[(2,4-thiazolidinedione-5-yl) methyl] phenoxy group] ethylamino]-ethanoyl]-2-cyano group-tetramethyleneimine
(S)-and 1-[[2-[4-[(2,4-thiazolidinedione-5-yl) methyl] phenoxy group]-2-methylethyl amino]-ethanoyl]-2-cyano group-tetramethyleneimine
(R)-and 1-[[2-[4-[(2,4-thiazolidinedione-5-yl) methyl] phenoxy group] ethylamino]-ethanoyl]-4-cyano group-thiazolidine
(R)-and 1-[[2-[4-[(2,4-thiazolidinedione-5-yl) methyl] phenoxy group]-2-methylethyl amino]-ethanoyl]-4-cyano group-thiazolidine
(S)-and 1-[[4-[4-[(2,4-thiazolidinedione-5-yl) methylene radical] phenoxy group] piperidines-1-yl]-ethanoyl]-2-cyano group-tetramethyleneimine
(R)-and N-[[4-[4-[(2,4-thiazolidinedione-5-yl) methylene radical] phenoxy group] piperidines-1-yl]-ethanoyl]-4-cyano group-thiazolidine
(S)-and 1-[N-carboxymethyl-N-[4-[(2-phenyl-1,3-oxazole-4-yl) oxyethyl group] phenyl methyl] amino]-ethanoyl]-2-cyano group-tetramethyleneimine
(R)-and 1-[N-carboxymethyl-N-[4-[(2-phenyl-1,3-oxazole-4-yl) oxyethyl group] phenyl methyl] amino]-ethanoyl]-4-cyano group-thiazolidine
(S)-and 1-[[4-[(2-phenyl-1,3-oxazole-4-yl) oxyethyl group] phenyl methyl] amino]-ethanoyl]-2-cyano group-tetramethyleneimine
(S)-1-[N-[(2-cyano group-tetramethyleneimine-1-yl)-the formyl methyl]-N-[4-[(2-phenyl-1,3-oxazole-4-yl) oxyethyl group] phenyl methyl] amino]-ethanoyl]-2-cyano group-tetramethyleneimine
(R)-and 1-[[4-[(2-phenyl-1,3-oxazole-4-yl) oxyethyl group] phenyl methyl] amino]-ethanoyl]-4-cyano group-thiazolidine
(R)-1-[N-[(4-cyano group-thiazolidine-1-yl)-the formyl methyl]-N-[4-[(2-phenyl-1,3-oxazole-4-yl) oxyethyl group] phenyl methyl] amino]-ethanoyl]-4-cyano group-thiazolidine
(S)-and 1-[N-carboxymethyl-N-[4-[(2-phenyl-5-methyl isophthalic acid, 3-oxazole-4-yl) oxyethyl group] phenyl methyl] amino]-ethanoyl]-2-cyano group-tetramethyleneimine
(R)-and 1-[N-carboxymethyl-N-[4-[(2-phenyl-5-methyl isophthalic acid, 3-oxazole-4-yl) oxyethyl group] phenyl methyl] amino]-ethanoyl]-4-cyano group-thiazolidine
(S)-and 1-[[4-[(2-phenyl-5-methyl isophthalic acid, 3-oxazole-4-yl) oxyethyl group] phenyl methyl] amino]-ethanoyl]-2-cyano group-tetramethyleneimine
(R)-and 1-[[4-[(2-phenyl-5-methyl isophthalic acid, 3-oxazole-4-yl) oxyethyl group] phenyl methyl] amino]-ethanoyl]-4-cyano group-thiazolidine
Cyanopyrolidine and cyano-tetrahydrothiazole derivates can also with the sour salify of any pharmacy meaning.
Cyanopyrolidine that the present invention proposes and the salt on cyano-tetrahydrothiazole derivates and Cyanopyrolidine and the cyano-tetrahydrothiazole derivates pharmacy meaning can be used to prepare the medicine of treatment carbohydrate metabolism disturbance disease.
The synthetic method of compound of the present invention is to obtain with compound V and compound VI, VII or VIII reaction;
Figure A20081012373600131
Beneficial effect:
The present invention is synthetic by a large amount of medicines according to the principle of hybridization of medicinal design, effect experiment research, the pharmacophoric group of sulfonylurea and PPAR stimulant medicine is connected by suitable mode with the basic pharmacophoric group of DPP-IV inhibitor, the derivative that may not only have the multiple action mechanism that insulin sensitivity enhancing but also tool DPP-IV suppress is provided, the drug effect that experimental results show that derivative in this than single pharmacophoric group performance will be good many, the present invention also propose this derivative can with the pharmacologically acceptable salts salify, make things convenient for preparation, the salt that has also proposed this derivative and derivative is used to prepare the medicine of treatment carbohydrate metabolism disturbance disease, applying clinical.
Specific implementation method:
Embodiment 1 (2S)-N-(acetyl bromide)-2-itrile group tetramethyleneimine (V 1) preparation
Figure A20081012373600142
(1), the preparation of (2S)-N-(bromotrifluoromethane carbonyl)-2-formamyl tetramethyleneimine
43.6g (0.22mol) bromoacetyl bromide and 200ml methylene dichloride are placed reaction flask; add the drying tube that calcium chloride is housed; the ice bath cooling; more than 0 ℃ of following 60min, drip 22.37g (0.20mol) (S)-mixed solution of the methylene dichloride of 2-formamyl tetramethyleneimine, 22.5g (0.22mol) triethylamine, 30.0mg dimethyl aminopyridine (DMAP) and 200ml; stirred 2 hours under this condition; pour into then in 3.5 liters the ethyl acetate; filter; filter cake washs with ethyl acetate, filtrate concentrate the dark semi-solid oil of 38g (yield 82.5%).
(2), (2S)-N-(acetyl bromide)-2-itrile group tetramethyleneimine (V 1) preparation
With above-mentioned 38g product, 500ml methylene dichloride and 39g (0.26mol) POCl 3Place the 100ml round-bottomed flask, reflux disappears until raw material point, about 6 hours.Successively with after saturated nacl aqueous solution, saturated sodium bicarbonate solution, each each minute of 600ml three extraction of water, anhydrous sodium sulfate drying filters reaction solution, and evaporated under reduced pressure gets 15g (yield 42.6%) deep yellow liquid, ESI-MS:215: 217=1: 1[M-H] -
Embodiment 2 (4R)-N-(acetyl bromide)-4-nitrile-base thiazole alkane (V 2) preparation
Figure A20081012373600151
The preparation of (1), (4R)-thiazolidine-4-carboxylic acid (X)
Take by weighing L-cysteine hydrochloride monohydrate 80 grams (0.46mol), place the 1000ml three-necked bottle that is connected to the thermometer electric mixing device, add 228mlH 2O stirs and makes its dissolving.Treat that its complete molten back keeps temperature slowly to drip 37-40% formalin 91ml below 20 ℃, dropwise stirring at room, react after 20 hours 228ml ethanol adding three-necked bottle, slowly drip pyridine 228ml again under the ice bath cooling, the adularescent solid is separated out, and continues to stir 30 minutes, room temperature left standstill 2 hours, suction filtration, absolute ethanol washing, oven dry, get (4R)-thiazolidine-4-carboxylic acid (X), white solid, and 46g (productive rate: 76.7%), mp:192-194 ℃ (decomposition).
(2), the preparation of (4R) thiazolidine-4-carboxylate methyl ester hydrochloride (XI)
With above-mentioned experiment (1) gained (4R)-thiazolidine-4-carboxylic acid 46g (0.35mol), place the three-necked bottle of the 1L that is connected to drying tube, thermometer, add 460ml methyl alcohol, after stirring, maintain the temperature at 25 ℃ and slowly drip SOCl down 292ml (1.24mol) drips off back stirring at room 22 hours, and the adularescent solid is separated out, suction filtration, the benzene washing, oven dry gets (4R) thiazolidine-4-carboxylate methyl ester hydrochloride (XI), white solid, 35g (productive rate: 55.5%), mp:161-163 ℃, ESI-MS:147[M-Cl+H] +
(3), the preparation of (4R)-4-amine formyl thiazolidine (XII)
The 35g (0.19mol) that the last step was made (R)-thiazolidine-4-carboxylate methyl ester hydrochloride drops in the 1000ml flask; add the about 500ml of methanol ammonia solution (350ml methyl alcohol feeds about 70g ammonia); airtight stirring is 40 hours under the room temperature; evaporated under reduced pressure; add the 300ml Virahol; stirring makes it fully to dissolve after-filtration and removes insolubles; evaporate to dryness; gained solid methanol/toluene recrystallization; get the white powdery crystallization of (4R)-4-amine formyl thiazolidine (XII) 8.5g (productive rate 33.9%); m.p.96-98.5 ℃, ESI-MS:132[M-H] -
(4), the preparation of (4R) N-(bromotrifluoromethane carbonyl)-4-formamyl thiazolidine (XIII)
With the 8.5g (0.064mol) of above-mentioned experiment gained (R)-4-amine formyl thiazolidine and 220ml tetrahydrofuran (THF) mix, dissolving adds 5.0g (0.064mol) pyridine, and is standby.
14.1g (0.070mol) bromoacetyl bromide and 100ml tetrahydrofuran (THF) are placed reaction flask, add calcium chloride tube, bathe with cryosel and be cooled to-5 ℃, stir down and drip above-mentioned stock solution, drip off more than 1.5 hours.Reaction is 3 hours under this temperature, filters, and filtrate is the tetrahydrofuran solution of (4R) N-(acetyl bromide)-4-formamyl thiazolidine (XIII), is directly used in next step reaction.
(5), (4R)-N-(bromotrifluoromethane carbonyl)-4-nitrile-base thiazole alkane (V 2) preparation
Above-mentioned experiment gained filtrate is placed reaction flask, stir adding phosphorus oxychloride 15.7g (0.102mol) down, temperature is controlled at about 10 ℃; finish room temperature reaction 8 hours, pressure reducing and steaming tetrahydrofuran (THF); raffinate adds frozen water; use dichloromethane extraction, each washs once water with being full of salt solution, anhydrous magnesium sulfate drying; filter; evaporated under reduced pressure with ether and tetrahydrofuran (THF) crystallization, gets (4R)-N-(acetyl bromide)-4-nitrile-base thiazole alkane (V 2), white solid, 5.8g (two step yields add up to: 38.6%), mp:133-138 ℃, MS (ESI): 233: 235=1: 1[M-H] -
Embodiment 3 4-[[[(hexamethylene amino) carbonyl] amino] alkylsulfonyl] aniline (VI 1) preparation
Figure A20081012373600161
(1) preparation of cyclohexyl isocyanate
Take by weighing hexahydroaniline 43g (0.43mol), triethylamine 87.7g (0.86mol), standby with placement refrigerator behind the 100ml toluene mixing.Trichloromethylchloroformate 50g (0.25mol) inserts in the 1000ml four-necked bottle that is connected to thermometer, drying tube and electronic stirring, add 300ml toluene, stirring down, ice bath is cooled to 0 ℃, the hexahydroaniline toluene solution that slow dropping has been got ready keeps the interior temperature of reaction flask to be no more than 15 ℃, drips off in about 3 hours, remove ice bath, room temperature reaction 2 hours refluxed 2 hours, put cold back suction filtration, filter cake washes with toluene 100ml, filtrate decompression is removed toluene, and 8KPa is collected in underpressure distillation, 88-90 ℃ cut, get colourless liquid 32g, productive rate 59.5%, standby.
(2), N-ethanoyl aniline (XIV 1) preparation
Take by weighing aniline 18.6g (0.20mol) and place the 100ml three-necked flask, add the 50ml methylene dichloride, the ice-water bath cooling slowly drips aceticanhydride 22.5g (0.22mol) down, and stirring at room 1.5 hours is poured reaction solution in the 100ml water into, tell organic layer, water layer extracts the back at twice with the 50ml methylene dichloride and merges, and organic layer washs with saturated sodium bicarbonate solution, anhydrous magnesium sulfate drying, methylene dichloride is removed in decompression, gets Acetanilide (XIV 1), colourless particulate state crystal 2 6g (productive rate: 96.3%), mp:111-113 ℃.
(3), 4-acetylamino benzsulfamide (XV 1) preparation
Take by weighing 20g Acetanilide (XIV 1), place the 100ml three-necked bottle, place on the ice bath, slowly drip chlorsulfonic acid 50ml, keep temperature to be no more than 20 ℃.Drip off the recession deicing and bathe, slowly be warming up to 50 ℃, till no longer including hydrogenchloride and emitting (about 1h).Under constantly stirring reaction solution is poured in an amount of trash ice, the adularescent solid is separated out, suction filtration, and the filter cake concentrating under reduced pressure, purifying is not directly used in the next step.
To go up the step reaction product and join in the 40ml strong aqua, stirring at room 20 minutes, unnecessary ammonia is removed in decompression, place refrigerator (2 ℃) to spend the night, suction filtration, gained get white solid with 50% ethanol/water recrystallization, activated carbon decolorizing gets 4-acetylaminohydroxyphenylarsonic acid benzsulfamide (XV 1), white, needle-shaped crystals, and 11g (productive rate: 35%), mp:213-215 ℃.
(4), carbonyl 4-[[[(hexamethylene amino)] amino] alkylsulfonyl] Acetanilide (XVI 1) preparation
Get 2.1g (0.01mol) compounds X V 1, K 2CO 33g and 30ml acetone place the 50ml three-necked bottle, and reflux is 6 hours under stirring, and puts to room temperature; the cyclohexyl isocyanate 1.4g (0.011mol) that dropwise reaction (1) is prepared, stirring at room 1 hour refluxed 8 hours; the ice bath cooling, suction filtration, gained white solid add in the 100ml distilled water; suction filtration is removed insolubles; filtrate transfers to crowd H=5-6 with concentrated hydrochloric acid, separates out white solid, suction filtration; drying gets 4-[[[(hexamethylene amino) carbonyl] amino] alkylsulfonyl] Acetanilide (XVI 1), 2g (productive rate: 59%), mp:214-216 ℃, ESI-MS:338.4[M-H] -
(5), carbonyl 4-[[[(hexamethylene amino)] amino] alkylsulfonyl] aniline (VI 1) preparation
Previous step is tested prepared compounds X VI 11.7g (0.005mol), NaOH 0.6g (0.015mol), 3ml water places the 10ml flask, reflux 10 hours, reaction solution is transferred pH=5-6, separates out white solid, the suction filtration oven dry gets 4-[[[(hexamethylene amino) carbonyl] amino] alkylsulfonyl] aniline (VI 1), the white powder solid, and 1.4g (productive rate: 94.5%), mp:157-159 ℃.ESI-MS：297.3[M-H] -。
Embodiment 4 4-[[[(4-methyl cyclohexane amino) carbonyl] amino] alkylsulfonyl] aniline (VI 2) preparation
Figure A20081012373600171
(1), trans-4-isocyanatomethyl
With reference to the preparation method of embodiment 3 they (1), make trans-4-isocyanatomethyl by trans-4-methyl cyclohexylamine.Colourless liquid, yield 69.9%.
(2), carbonyl 4-[[[(4-methyl cyclohexane amino)] amino] alkylsulfonyl] Acetanilide (XVI 2)
According to embodiment 3 (4) methods, use prepared 4-isocyanatomethyl of single step reaction and compounds X V 1The synthetic 4-[[[(4-methyl cyclohexane amino of reaction) carbonyl] amino] alkylsulfonyl] Acetanilide (XVI 2), be white solid, productive rate: 61.2%, mp:213-215 ℃, ESI-MS:353.4[M-H] -
(4), carbonyl 4-[[[(4-methyl cyclohexane amino)] amino] alkylsulfonyl] aniline (VI 2)
According to reference to 3 (5) methods, synthesize 4-[[[(4-methyl cyclohexane amino) carbonyl] amino] alkylsulfonyl] aniline (VI 2), productive rate: 92.5%.mp：148-150℃，ESI-MS：311.4[M-H] -。
Embodiment 5 4-[[[(hexamethylene amino) carbonyl] amino] alkylsulfonyl] benzene methanamine (VI 3) preparation
Figure A20081012373600181
(1), N-formyl radical benzylamine
Get benzylamine 50g (0.47mol), formic acid 32g (0.70mol) and 150ml toluene and place the 250ml three-necked bottle that is connected to water trap, about 8 hours of reflux, till anhydrous telling, reaction solution saturated sodium carbonate solution 200ml and three washings of each minute of water 200ml, anhydrous magnesium sulfate drying, pressure reducing and steaming toluene gets light yellow oil, add an amount of isopropyl ether, place in the refrigerator and spend the night, separate out white solid, suction filtration, vacuum-drying, get white powder solid 60g (productive rate 94.6%), mp:50-52 ℃.
(2), 4-(formamido group) methyl benzenesulfonamide (XV 2)
According to embodiment 3 (3) methods, make 4-formamido group methyl-benzsulfamide (XV with N-formyl radical benzylamine and chlorsulfonic acid, ammoniacal liquor elder generation afterreaction 2), productive rate: 30.2%, mp:141-143 ℃, ESI-MS:214.2[M-H] -
(3), carbonyl 4-[[[(hexamethylene amino)] amino] alkylsulfonyl]-N-formyl radical benzene methanamine (XVI 3)
According to embodiment 3 (4) methods, synthetic 4-[[[(hexamethylene amino) carbonyl] amino] alkylsulfonyl]-N-acetylbenzene methylamine (XVI 3), productive rate: 62.1%, mp:157-159 ℃, ESI-MS:338.4[M-H] -
(4), carbonyl 4-[[[(hexamethylene amino)] amino] alkylsulfonyl]-N-formyl radical benzene methanamine (VI 3)
According to embodiment 3 (5) methods, synthetic compound VI 3, productive rate: 90.5%, ESI-MS:310.3[M-H] -
Embodiment 6 4-[[[(4-methyl cyclohexane amino) carbonyl] amino] alkylsulfonyl] benzene methanamine (VI 4) preparation
Figure A20081012373600182
(1), carbonyl 4-[[[(4-methyl cyclohexane amino)] amino] alkylsulfonyl]-N-formyl radical benzene methanamine (XVI 4)
According to embodiment 3 (4) methods, with 4-isocyanatomethyl and compounds X V 2Synthetic 4-[[[(4-methyl cyclohexane amino) carbonyl] amino] alkylsulfonyl]-N-formyl radical benzene methanamine (XVI 4), productive rate: 64.7%, mp:165-167 ℃, ESI-MS:352.4[M-H] -
(2), carbonyl 4-[[[(4-methyl cyclohexane amino)] amino] alkylsulfonyl]-N-formyl radical benzene methanamine (VI 3)
According to embodiment 3 (5) methods, synthetic compound VI 4, productive rate: 94.7%, ESI-MS:324.4[M-H] -
Embodiment 7 4-[[[(hexamethylene amino) carbonyl] amino] alkylsulfonyl]-phenylethylamine (VI 5) preparation
(1), N-ethanoyl-styroyl amine (XIV 3)
According to embodiment 3 (2) methods, synthetic N-ethanoyl-styroyl amine (XIV 3), productive rate: 92.1%, fusing point: 50-52 ℃.
(2), 4-kharophen ethyl-benzsulfamide (XV 3)
According to embodiment 3 (3) methods, synthetic 4-kharophen ethyl-benzsulfamide (XV 5), productive rate: 37.8%, mp:177-178 ℃.
(3), carbonyl 4-[[[(hexamethylene amino)] amino] alkylsulfonyl]-N-acetylbenzene ethamine (XVI 5)
According to reference example 3 (4) methods, synthetic 4-[[[(hexamethylene amino) carbonyl] amino] alkylsulfonyl]-N-acetylbenzene ethamine (XVI 5), productive rate: 63.6%, mp:191-195 ℃.
(4), carbonyl 4-[[[(hexamethylene amino)] amino] alkylsulfonyl]-phenylethylamine (VI 5)
According to embodiment 3 (5) methods, synthetic 4-[[[(hexamethylene amino) carbonyl] amino] alkylsulfonyl]-phenylethylamine (VI 5), productive rate: 92.5%, begin to decompose carbonization more than mp:100 ℃.
Embodiment 8 4-[[[(4-methyl cyclohexane amino) carbonyl] amino] alkylsulfonyl]-phenylethylamine (VI 6) preparation
Figure A20081012373600192
(1), carbonyl 4-[[[(4-methyl cyclohexane amino)] amino] alkylsulfonyl]-N-acetylbenzene ethamine (XVI 6)
According to embodiment 3 (4) methods, use 4-methylcyclohexyl isocyanic acid at ester and compounds X V 3Synthetic 4-[[[(4-methyl cyclohexane amino) carbonyl] amino] alkylsulfonyl]-N-acetylbenzene ethamine (XVI 6), productive rate: 63.6%, mp:179-180 ℃.
(2), carbonyl 4-[[[(4-methyl cyclohexane amino)] amino] alkylsulfonyl]-phenylethylamine (VI 6)
According to embodiment 3 (5) methods, synthetic compound VI 6, productive rate: 91.7%, begin to decompose carbonization more than mp:100 ℃.
Embodiment 9 4-[[[(hexamethylene amino) carbonyl] amino] alkylsulfonyl]-Alpha-Methyl benzene methanamine (VI 7) preparation
Figure A20081012373600201
(1), N-formyl radical-Alpha-Methyl benzene methanamine (XIV 4),
According to embodiment 3 (2) methods, make the white powder solid, yield 94.3%, mp:43-45 ℃ by Alpha-Methyl benzylamine and formic acid reaction.
(2), 4-(α-formamido group ethyl)-benzsulfamide (XV 4)
According to embodiment 3 (3) methods, synthetic 4-(α-formamido group ethyl)-benzsulfamide (XV that obtains 4), productive rate: 37.8%, mp:143-145 ℃, ESI-MS:227.2[M-H] -
(3), carbonyl 4-[[[(hexamethylene amino)] amino] alkylsulfonyl]-Alpha-Methyl-N-formyl radical benzene methanamine (XVI 7)
According to ginseng example 3 (4) methods, the synthetic 4-[[[(hexamethylene amino that obtains) carbonyl] amino] alkylsulfonyl]-Alpha-Methyl-N-formyl radical benzene methanamine (XVI 7), productive rate: 63.3%, mp:165-167 ℃, ESI-MS:352.4[M-H] -
(4), carbonyl 4-[[[(hexamethylene amino)] amino] alkylsulfonyl]-Alpha-Methyl phenmethyl amine (VI 7)
According to ginseng example 3 (5) methods, synthetic 4-[[[(hexamethylene amino) carbonyl] amino] alkylsulfonyl]-Alpha-Methyl phenmethyl amine (VI 7), get the white powder solid, yield 94.6%, ESI-MS:324.4[M-H] -
Embodiment 10 4-[[[(4-methyl cyclohexane amino) carbonyl] amino] alkylsulfonyl]-Alpha-Methyl phenmethyl amine (VI 8) preparation
Figure A20081012373600202
(1), carbonyl 4-[[[(4-methyl cyclohexane amino)] amino] alkylsulfonyl]-Alpha-Methyl-N-formyl radical benzene methanamine (XVI 8),
According to embodiment 3 (4) methods, obtain 4-[[[(4-methyl cyclohexane amino) carbonyl] amino] alkylsulfonyl]-Alpha-Methyl-N-formyl radical benzene methanamine (XVI 8), get the white powder crystallization, productive rate: yield 64.3%, mp:168-170 ℃, ESI-MS:366.5[M-H] -
(2), according to embodiment 3 (5) methods, obtain 4-[[[(4-methyl cyclohexane amino) carbonyl] amino] alkylsulfonyl]-Alpha-Methyl-benzene methanamine (VI 8), productive rate: 94.3%, ESI-MS:338.3[M-H] -
Embodiment 11 4-[[[(hexamethylene amino) carbonyl] amino] alkylsulfonyl]-α-ethyl-benzene methanamine (XVI 9) preparation
Figure A20081012373600211
(1), propionyl chloride
Propionic acid 50g (0.68mol) and 100ml benzene are placed the 250ml flask, the ice-cooled 124gSOCl that slowly drips down 2(1.02ml), keep temperature to be no more than 10 ℃, after dripping off, remove ice bath, stirring at room 1 hour, backflow 2h, benzene is removed in decompression, gets propionyl chloride, and light yellow oil is directly used in next step reaction.
(2), Propiophenone
The anhydrous AlCl of 109g (0.82mol) 3150ml benzene places the 500ml three-necked bottle, the ice bath cooling, under the vigorous stirring that previous step is oily with slowly splashing in the flask after the dilution of 50ml benzene, keep temperature of reaction to be no more than 5 ℃, drip off the recession deicing and bathe stirring at room 1 hour, temperature rising reflux is till no longer include HCl and emit, constantly stir down reaction solution is poured in an amount of trash ice, ethyl acetate 300ml divides three extractions, the extraction liquid anhydrous magnesium sulfate drying, activated carbon decolorizing, evaporate to dryness gets Propiophenone, colourless oil liquid, 55g (yield: 60.4%), be directly used in next step reaction.
(3), N-formyl radical-α-ethylbenzene methylamine (XIV 5)
Get Propiophenone 20g (0.15mol); ammonium formiate 38g (0.60mol) places the 100ml three-necked bottle; stir slowly heating down; all melt at 120 ℃ of ammonium formiates; there are water and Propiophenone to steam when continuing to be warming up to 150 ℃, continue to be warming up to 180 ℃, stop heating; the Propiophenone that distills out is refunded in the reaction flask; reheat is to 180-185 ℃, and insulation reaction 3 hours is poured in the water; ethyl acetate 200ml extraction; the extraction liquid anhydrous magnesium sulfate drying, evaporated under reduced pressure, isopropyl ether crystallization; get the white granular crystallization; filter, vacuum-drying obtains N-formyl radical-α-ethylbenzene methylamine (XIV 5) 22g (92.3%), mp:51-52 ℃, ESI-MS:164.1[M+H] +
(4), 4-(α-ethyl-formamido group methyl)-benzene sulfonyl (XV 5)
According to embodiment 3 (3) methods, synthetic 4-(α-ethyl-acetylamino methyl)-benzsulfamide (XV 5), productive rate: 34.2%, fusing point: 164-166 ℃, ESI-MS:241.3[M-H] -
(5), carbonyl 4-[[[(hexamethylene amino)] amino] alkylsulfonyl]-α-ethyl-N-formyl radical benzene methanamine (XVI 9)
According to ginseng example 3 (4) methods, synthetic 4-[[[(hexamethylene amino) carbonyl] amino] alkylsulfonyl]-α-ethyl-N-formyl radical benzene methanamine (XVI 9), productive rate: 68.8%, mp:166-168 ℃, ESI-MS:366.2[M-H] -
(6), carbonyl 4-[[[(hexamethylene amino)] amino] alkylsulfonyl]-α-ethyl-benzene methanamine (VI 9)
According to ginseng example 3 (5) methods, synthetic 4-[[[(hexamethylene amino) carbonyl] amino] alkylsulfonyl]-α-ethyl-benzene methanamine (VI 9), productive rate: 93.3%, ESI-MS:338.6[M-H]] -
Embodiment 12 4-[[[(4-methyl cyclohexane amino) carbonyl] amino] alkylsulfonyl]-α-ethyl-benzene methanamine (VI 10) preparation
Figure A20081012373600221
(1), carbonyl 4-[[[(4-methyl cyclohexane amino)] amino] alkylsulfonyl]-α-ethyl-N-formyl radical phenylethylamine (XVI 10)
According to ginseng example 3 (4) methods, synthetic 4-[[[(4-methyl cyclohexane amino) carbonyl] amino] alkylsulfonyl]-α-ethyl-N-formyl radical phenylethylamine (XVI 10), productive rate: 64.3%, mp:150-152 ℃.
(2), carbonyl 4-[[[(4-methyl cyclohexane amino)] amino] alkylsulfonyl]-α-ethyl-benzene methanamine (VI 10)
According to ginseng example 3 (5) methods, synthetic 4-[[[(4-methyl cyclohexane amino) carbonyl] amino] alkylsulfonyl]-α-ethyl-benzene methanamine (VI 10), the white powder solid, productive rate: 91.7%, ESI-MS:352.0[M-H] -
Embodiment 13 4-[[[(hexamethylene amino) carbonyl] amino] alkylsulfonyl]-α-cyclohexyl-benzene methanamine (XVI 11) preparation
Figure A20081012373600222
(1), phenylcyclohexane ketone
With reference to embodiment 11 methods, heptanaphthenic acid is prepared the phenylcyclohexane ketone, prism-shaped crystallization, two step yields 61.7%, mp:55-57 ℃.
(2), N-formyl radical-α-phenylcyclohexane methylamine (XIV 6)
With reference to embodiment 11 (3) methods, prepare and obtain N-formyl radical-α-phenylcyclohexane methylamine (XIV 6), white powder, yield: 87.6%, mp:127-129 ℃, ESI-MS:216.0[M+H] +
(3), 4-(α-cyclohexyl-formamido group methyl)-benzene sulfonyl (XV 6)
According to embodiment 3 (3) methods, synthetic 4-(α-ethyl-acetylamino methyl)-benzsulfamide (XV 6), white powder, productive rate: 57.8%, mp:215-217 ℃, ESI-MS:295.2[M-H] -
(4), carbonyl 4-[[[(hexamethylene amino)] amino] alkylsulfonyl]-α-cyclohexyl-N-formyl radical benzene methanamine (XVI 11)
According to ginseng example 3 (4) methods, synthetic 4-[[[(hexamethylene amino) carbonyl] amino] alkylsulfonyl]-α-cyclohexyl-N-formyl radical benzene methanamine (XVI 11), white solid, productive rate: 62.8%, mp:150-152 ℃, ESI-MS:420.0[M-H] -
(5), carbonyl 4-[[[(hexamethylene amino)] amino] alkylsulfonyl]-α-cyclohexyl-benzene methanamine (VI 11)
According to ginseng example 3 (5) methods, synthetic 4-[[[(hexamethylene amino) carbonyl] amino] alkylsulfonyl]-α-cyclohexyl-benzene methanamine (VI 11), white solid, productive rate: 94.6%, ESI-MS:392.3[M-H] -
Embodiment 14 4-[[[(4-methyl cyclohexane amino) carbonyl] amino] alkylsulfonyl]-α-cyclohexyl-benzene methanamine (VI 12) preparation
Figure A20081012373600231
(1), carbonyl 4-[[[(4-methyl cyclohexane amino)] amino] alkylsulfonyl]-α-cyclohexyl-N-formyl radical benzene methanamine (XVI 12)
According to ginseng example 3 (4) methods, synthetic 4-[[[(4-methyl cyclohexane amino) carbonyl] amino] alkylsulfonyl]-α-cyclohexyl-N-formyl radical benzene methanamine (XVI 12), productive rate: 59.4%, mp:157-159 ℃.ESI-MS：434.1[M-H] -。
(2), carbonyl 4-[[[(4-methyl cyclohexane amino)] amino] alkylsulfonyl]-Alpha-Methyl-phenylethylamine (VI 12)
According to ginseng example 3 (5) methods, synthetic 4-[[[(4-methyl cyclohexane amino) carbonyl] amino] alkylsulfonyl]-Alpha-Methyl-phenylethylamine (VI 12), the white powder solid, productive rate: 91.4%, ESI-MS:406.5[M-H] -
Embodiment 15 5-[[(4-piperidyl oxygen bases) phenyl] methyl]-2,4-thiazolidinedione hydrochloride (VII 1) preparation
Figure A20081012373600232
(1), 4-hydroxy-n-Te Ding oxygen formyl piperidine (XVII 1)
Taking by weighing 10.1g (0.1mol) 4-hydroxy piperidine places the three-necked bottle of 500ml (to have thermometer, drying tube and dropping funnel) methylene dichloride of adding 190ml under electronic stirring, stir not molten entirely, a small amount of insoluble oily matter is arranged, the cooling of external application ice bath, equitemperature is reduced to and is slowly dripped the solution that 24g (0.11mol) Boc acid anhydrides is dissolved in the methylene dichloride of 100ml below 0 ℃ again, drips off the back ice bath and stirs half an hour down, the deicing of dropping back half an hour is bathed, stirred overnight at room temperature.Respectively use saturated sodium bicarbonate solution with reaction solution next day; adding anhydrous magnesium sulfate drying again after saturated nacl aqueous solution and water are respectively given a baby a bath on the third day after its birth time spends the night; next day suction filtration; filtrate decompression obtains colorless oil after being concentrated into and doing; put the refrigerator crystallization after the normal hexane of adding 50ml shakes up, next day, the adularescent solid was separated out, suction filtration; put oven dry under the infrared lamp after the normal hexane washing of filter cake with ice, get 4-hydroxy-n-Te Ding oxygen formyl piperidine (XVII 1), 9.4g, yield 50%.mp：79-81℃，ESI-MS；230.1[M+H] +。
(2), the special fourth oxygen of 4-mesyloxy-N-formyl piperidine (XVIII 1)
5g (0.025mol) compounds X VII 1Place the three-necked bottle (having thermometer, drying tube and dropping funnel) of 250ml, under magnetic agitation, add the methylene dichloride of 150ml, be stirred to complete molten back and feed nitrogen, and then disposable adding 2.8g (0.03mol) triethylamine.Stir, the cooling of external application ice bath slowly drips 3.6g (0.03mol) methane sulfonyl chloride again when equitemperature is reduced to below 0 ℃, and after dripping off, ice bath stirs half hour down, and the deicing of dropping back half an hour is bathed stirred overnight at room temperature.Respectively use saturated sodium bicarbonate solution with reaction solution next day; saturated nacl aqueous solution and water respectively wash three times (3X100ml) back adding anhydrous magnesium sulfate drying and spend the night; next day suction filtration; filtrate decompression obtains white solid after being concentrated into and doing; put oven dry infrared lamp under again after solid ground the washing that rubs with isopropyl ether, 4-mesyloxy-N-spy fourth oxygen formyl piperidine (XVIII 1), 6.3g, yield 91%.mp：68-70℃，ESI-MS：308.2[M+H] +。
(3), 4-(the special fourth oxygen of 1-formyl piperidine-4-yl) oxygen base] phenyl aldehyde (XIX 1),
5g (0.018mol) compounds X VIII 1And 1.8g (0.01mol) p-Hydroxybenzaldehyde places the four-hole bottle of 250ml (to have thermometer, drying tube and prolong) DMF of adding 200ml under electronic stirring, be stirred to complete molten after property adding 5g (0.036mol) salt of wormwood again, slowly be warming up to 80 ℃ of reactions 48 hours then, reaction is poured into reaction solution in the frozen water of 650ml after finishing, stirring does not have solid to separate out, with ethyl acetate extraction three times (3X200ml), extracting solution is used saturated nacl aqueous solution and water washing three times (3X150ML) more respectively, washes back adding anhydrous magnesium sulfate drying and spends the night.Next day suction filtration, filtrate decompression is concentrated into the dried brown oily matter 4.8g (XIX that obtains 1), yield 87%.Be directly used in next step reaction.
(4), 5-[[[4-(tertbutyloxycarbonyl piperidin-4-yl) oxygen base] phenyl] the methylene base] thiazolidine-2,4-diketone (XX 1)
4.8g compounds X IX 1Place the there-necked flask of 500ml (to have thermometer, drying tube, prolong and water trap), the toluene that under magnetic agitation, adds 100ml, be stirred to and complete add 1.84g 2.4-thiazolidone and 0.24g acetyl piperidine more successively after molten, slowly be heated to backflow then, reflux water-dividing reaction 20 hours, after finishing, reaction have yellow solid to generate, cooling back suction filtration, filter cake is put oven dry under the infrared lamp after with methanol wash, compound 5-[[[4-(tertbutyloxycarbonyl piperidin-4-yl) oxygen base] phenyl] the methylene base] thiazolidine-2,4-diketone (XX 1), 2.7g, yield 42%, mp:199-201 ℃, ESI-MS:433.0[M+H] +
(5), 5-[[[4-(tertbutyloxycarbonyl piperidin-4-yl) oxygen base] phenyl] methyl] thiazolidine-2,4-diketone (XXI 1)
2.2g compounds X XI 1Place the beaker of 500ML, adding 300ml methyl alcohol and 1.4-dioxane mixing solutions (1: 1) is stirred to and adds 3.4g10% palladium carbon again after molten entirely. again this solution is poured in the autoclave after stirring evenly, the hydrogen pressure that adds 8MPa, keep 40 ℃ of reactions 18 hours. after reaction finishes, suction filtration, filtrate decompression obtains oily matter after being concentrated to and doing, add and put the refrigerator crystallization after an amount of anhydrous diethyl ether shakes up and spend the night, next day, the adularescent solid was separated out, suction filtration, filter cake is put infrared oven dry down, gets 5-[[[4-(tertbutyloxycarbonyl piperidin-4-yl) oxygen base] phenyl] methyl] thiazolidine-2,4-diketone (XXI 1) 1.5g, yield 62.2%, mp:128-130 ℃, ESI-MS:435.3[M+H] +
(6), 5-[[(4-piperidyl oxygen base) phenyl] methyl]-2,4-thiazolidinedione hydrochloride (VII 1)
1.5g compound 6 places the eggplant type bottle of 250ml, the hydrogenchloride anhydrous diethyl ether that under magnetic agitation, adds 100ml, sealing back stirring reaction 24 hours, reaction finishes back adularescent solid and generates, suction filtration, filter cake is put oven dry under the infrared lamp, obtains dry product 5-[[(4-piperidyl oxygen base) phenyl] methyl]-2,4-thiazolidinedione hydrochloride (VII 1), 1g, yield 80%.
Embodiment 16 5-[[[(4-aminocyclohexyl) oxygen base] phenyl] methyl]-2,4-thiazolidinedione hydrochloride (VII 2) preparation
Figure A20081012373600251
(1), the special butyloxy formylamido hexalin of 4-(XVII 2)
According to embodiment 15 (1) methods, (0.2mol) 4-Trans-4-Amino Cyclohexanol replacement 4-hydroxy piperidine with 23g obtains the special butyloxy formylamido hexalin of 4-(XVII 2), get white solid, 38g (yield: 88%), mp:95-96 ℃, ESI-MS:216.2[M+H] +
(2), the methanesulfonates (XVIII of the special butyloxy formylamido hexalin of 4- 2)
According to embodiment 15 (2) methods, with 30g (0.14mol) compounds X VII 2Synthetic methanesulfonates (the XVIII that obtains the special butyloxy formylamido hexalin of 4- 2) 39.5g (productive rate: 97%), mp:76-78 ℃, ESI-MS:294.0[M+H] +
(3), the cyclohexyl special butyloxy formylamido of 4-[[(4-)] the oxygen base] phenyl aldehyde (XIX 2)
According to embodiment 15 (3) methods, with 32g (0.1mol) compounds X VIII 2The synthetic special butyloxy formylamido of 4-[[(4-that obtains) cyclohexyl] the oxygen base] phenyl aldehyde (XIX 2) 18.8g (productive rate: 54%), mp:121-123 ℃, ESI-MS:320.2[M+H] +
(4), the special butyloxy formylamido of 5-[[4-[[(4-) cyclohexyl] the oxygen base] phenyl] methylene radical]-2,4-thiazolidinedione (XX 2)
According to embodiment 15 (4) methods, with 18g (0.056mol) compounds X IX 2The synthetic special butyloxy formylamido of 5-[[4-[[(4-that obtains) cyclohexyl] the oxygen base] phenyl] methylene radical]-2,4-thiazolidinedione (XX 2) 7g (productive rate: 30%), mp:214-216 ℃, ESI-MS:419.2[M+H] +
(5), the special butyloxy formylamido of 5-[[4-[[(4-) cyclohexyl] the oxygen base] phenyl] methyl]-2,4-thiazolidinedione (XXI 2)
According to embodiment 15 (5) methods, with 7g compounds X X 2The synthetic special butyloxy formylamido of 5-[[4-[[(4-that obtains) cyclohexyl] the oxygen base] phenyl] methyl]-2,4-thiazolidinedione (XXI 2) 6.9g (productive rate: 97%), mp:149-151 ℃, ESI-MS:421.1[M+H] +
(6), the 5-[[[(4-aminocyclohexyl) the oxygen base] phenyl] methyl]-2,4-thiazolidinedione (VII 2)
According to embodiment 15 (6) methods, with 6.9g (0.017mol) compounds X XI 2The synthetic 5-[[[(4-aminocyclohexyl that obtains) oxygen base] phenyl] methyl]-2,4-thiazolidinedione (VII 2) 6.5g (productive rate: 98%), mp:242-246 ℃.
Embodiment 17 5-[[[(2-amino-ethyls) oxygen base] phenyl] methyl]-2,4-thiazolidinedione (VII 3) preparation
Figure A20081012373600261
(1), the special butyloxy formylamido ethanol of 2-(XVII 3)
According to embodiment 15 (1) methods, replace the 4-hydroxy piperidine with 18.8g (0.3M) thanomin, obtain the special butyloxy formylamido ethanol of 2-(XVII 3) 28.8g (productive rate: 60%), oily matter.Be not further purified and be directly used in next step reaction.
(2), the special butyloxy formylamido alcoholic acid of 2-methanesulfonates (XVIII 3),
According to embodiment 15 (2) methods, with 28.8g compounds X VII 3The synthetic special butyloxy formylamido alcoholic acid of the 2-methanesulfonates (XVIII that obtains 3), oily matter is directly used in the next step.
(3), the oxyethyl group special butyloxy formylamido of 4-[(2-)] phenyl aldehyde (XIX 3)
According to embodiment 15 (3) methods, the synthetic special butyloxy formylamido of 4-[(2-that obtains) oxyethyl group] phenyl aldehyde (XIX 3) 14.5g (two step yields: 46%), faint yellow solid, mp:65-66 ℃, ESI-MS:266.1[M+H] +
(4), the special butyloxy formylamido of 5-[[4-[(2-) oxyethyl group] phenyl] methylene radical]-2,4-thiazolidinedione (XX 3)
According to embodiment 15 (4) methods, with 8.1g compounds X IX 3The synthetic special butyloxy formylamido of 5-[[4-[(2-that obtains) oxyethyl group] phenyl] methylene radical]-2,4-thiazolidinedione (XX 3) 10g (productive rate: 89%), mp:269-270 ℃, ESI-MS:365.0[M+H] +
(5), the special butyloxy formylamido of 5-[[4-[(2-) oxyethyl group] phenyl] methyl]-2,4-thiazolidinedione (XXI 3)
According to embodiment 15 (5) methods, with 7g compounds X X 3The synthetic special butyloxy formylamido of 5-[[4-[(2-that obtains) oxyethyl group] phenyl] methyl]-2,4-thiazolidinedione (XXI 3) 4.7g (productive rate: 67%), mp:242-245 ℃, ESI-MS:367.1[M+H] +
(6), the 5-[[(2-amino ethoxy) phenyl] methyl]-2,4-thiazolidinedione (VII 3)
According to embodiment 15 (6) methods, with 4.7g compounds X XI 3The synthetic 5-[[(2-amino ethoxy that obtains) phenyl] methyl]-2,4-thiazolidinedione (VII 3) 3.8g (productive rate: 98%), mp:169.5-170 ℃.
Embodiment 18 5-[[[(Alpha-Methyl-beta-aminoethyls) oxygen base] phenyl] methyl]-2,4-thiazolidinedione (VII 4) preparation
Figure A20081012373600271
(1), the special butyloxy formylamido of 2--1-methyl ethanol (XVII 4)
According to embodiment 15 (1) methods, replace the 4-hydroxy piperidine with the 16g Yi Bingchunan, obtain the special butyloxy formylamido of 2--1-methyl ethanol (XVII 4) 39g (99%), water white oil is not further purified and directly carries out next step reaction.
(2), the methanesulfonates (XVIII of the special butyloxy formylamido of 2--1-methyl ethanol 4)
According to embodiment 15 (2) methods, with the synthetic methanesulfonates (XVIII that obtains the special butyloxy formylamido of 2--1-methyl ethanol of above-mentioned reaction product 39g 4) 32g (productive rate: 57%), Liquid Paraffin.
(3), phenyl aldehyde (the XIX special butyloxy formylamido of 2--1-methyl ethoxy) 4)
According to embodiment 15 (3) methods, with 15.2g compounds X VIII 4Synthetic obtaining (the special butyloxy formylamido of 2--1-methyl ethoxy) phenyl aldehyde (XIX 4), 9.8g (productive rate: 58%), light green oil.
(4), the special butyloxy formylamido of 5-[4-[(2--1-methyl ethoxy) phenyl] methylene radical]-2,4-thiazolidinedione (XX 4)
According to embodiment 15 (4) methods, with 9.8g compounds X IX 4The synthetic special butyloxy formylamido of the 5-[4-[(2--1-methyl ethoxy that obtains) phenyl] methylene radical]-2,4-thiazolidinedione (XX 4) 4.7g (productive rate: 35%), mp:190-192 ℃, ESI-MS:379.0[M+H] +
(5), the special butyloxy formylamido of 5-[4-[(2--1-methyl ethoxy) phenyl] methyl]-2,4-thiazolidinedione (XXI 4)
According to embodiment 15 (5) methods, with 4.7g compounds X X 4The synthetic special butyloxy formylamido of the 5-[4-[(2--1-methyl ethoxy that obtains) phenyl] methyl]-2,4-thiazolidinedione (XXI 4) 3g (productive rate: 65%), mp:122-124 ℃, ESI-MS:381.1[M+H] +
(6), 5-[[[(Alpha-Methyl-beta-aminoethyl) the oxygen base] phenyl] methyl]-2,4-thiazolidinedione (VII 4)
According to embodiment 15 (6) methods, with 3g compounds X XI 4The synthetic 5-[[[(Alpha-Methyl-beta-aminoethyl that obtains) oxygen base] phenyl] methyl]-2,4-thiazolidinedione (VII 4), 2.4g (productive rate: 97%), mp:199-201 ℃.
Embodiment 19 4-[(2-Ben Ji oxazole-4-yls) oxyethyl group] phenyl methylamine (VIII 1) preparation
(1), (2-Ben Ji oxazole-4-yl) ethyl acetate
147g (1.21mol) benzamide and the heating of 200g (1.21mol) 4-ethyl chloroacetate mixed solution, steam the water of producing in the reaction, when treating that temperature rises to 120 ℃, be incubated 2 hours, cooling, stir the saturated sodium bicarbonate aqueous solution that adds 1580ml down, add the 500ml ethyl acetate, have solid to separate out, filter, the solid ethyl acetate is washed, and the filtrate ethyl acetate extraction is washed to neutrality with saturated common salt, anhydrous magnesium sulfate drying, filter evaporate to dryness, first product column chromatography (ether: normal hexane=1: 9), get (2-Ben Ji oxazole-4-yl) ethyl acetate, white solid 52g, mp:48-50 ℃, MS (+) 231.
(2), (2-Ben Ji oxazole-4-yl) ethanol (XXII 1)
3.8g (0.1mol) tetrahydrochysene lithium aluminium and 300ml anhydrous diethyl ether mix, ice bath is cooled to 0 ℃, and stirring down, gradation adds 23.1g (0.1mol) (2-Ben Ji oxazole-4-yl) ethyl acetate, temperature is controlled at 0-5 ℃, finishes stirring reaction 1.5 hours, drip the 9ml ethyl acetate, 22ml water has precipitation to separate out, filter, filtrate adds anhydrous magnesium sulfate drying, filters, and concentrates, post separates (ether: normal hexane=1: 9), get orange-yellow oily thing (2-benzene base oxazole-4-yl) ethanol (XXII 1), 16.2g.
(3), (2-Ben Ji oxazole-4-yl) ethanol methanesulfonates (XXII 2),
18.9g (0.1mol) (2-Ben Ji oxazole-4-yl) ethanol and 100ml methylene dichloride mix, cryosel is bathed and is cooled to-5 ℃, disposable adding 12.5g (0.11mol) methane sulfonyl chloride, the back drips 11.1g (0.11mol) triethylamine, finish, remove cryosel and bathe, rise to room temperature naturally, thin layer is followed the tracks of reaction, finish the back and wash reaction mixture with the hydrochloric acid (50ml * 2) of 3N, combining water layer is used dichloromethane extraction, water and salt water washing successively, anhydrous slufuric acid is U.S. dry, filters, and concentrates, use the normal heptane crystallization, get (2-Ben Ji oxazole-4-yl) ethanol methanesulfonates (XXII 2), yellow solid 13.8g.
(4), oxyethyl group 4-[(2-Ben Ji oxazole-4-yl)] phenyl aldehyde (XXIII 1)
13.4g compound 19 and 7.38g (0.06mol) 4-hydroxy benzaldehyde, 10.35g (0.75mol) salt of wormwood and 120mlDMF mix, slowly be added to 100 ℃ under the electronic stirring, insulation reaction 2 hours is chilled to room temperature naturally, stir down and pour in the frozen water of 1L, there is the khaki color solid to separate out, filters drying, use the methyl tertiary butyl ether recrystallization, get 4-[(2-Ben Ji oxazole-4-yl) oxyethyl group] phenyl aldehyde (XXIII 1), 10.5g, light yellow solid, mp:108-110 ℃.
(5), oxyethyl group 4-[(2-Ben Ji oxazole-4-yl)] phenyl methylamine (VIII 1),
4-[(2-Ben Ji oxazole-4-yl) oxyethyl group] phenyl aldehyde 5g (0.017mol) and 1.25g oxammonium hydrochloride, the ethanol mixed dissolution of 200ml95% adds 1.25g yellow soda ash, stirring at room 12 hours is filtered, and filtrate decompression concentrates, solid of separating out and filter cake acetic acid ethyl dissolution, filter washing, anhydrous magnesium sulfate drying, filter, concentrate, crystallization gets white solid 4.8g aldoxime, mp:182-188 ℃.
The 250g dehydrated alcohol, logical ammonia is made saturated ethanol ammonia solution, and 5g (0.016mol) 4-[(2-Ben Ji oxazole-4-yl) oxyethyl group] benzaldoxime, 1.2g10% palladium carbon places autoclave, be forced into 20kg, stirring at room 14 hours is filtered, filtrate concentrates, and gets 4-[(2-Ben Ji oxazole-4-yl) oxyethyl group] phenyl methylamine (VIII 1), white solid 1.2g, mp:132-138 ℃.
Embodiment 20 4-[(5-methyl-2-Ben Ji oxazole-4-yl) methoxyl group] phenyl methylamine (VIII 2) preparation
Figure A20081012373600291
(1), 2,3-dimethyl diketone monoxime
62g Sodium Nitrite and 21g ethanol, 220ml water mixes, and is (I) solution; 44g sulfuric acid and 21g ethanol, 220ml water mixes, and is (II) solution.
The 62g butanone feeds hydrogen chloride gas after about 10 minutes, will splash into the ethyl nitrite gas feeding that (I) solution produces under (II) solution stirring, the water-bath cooling, finishes by controlled temperature 40-55 ℃, boil off ethanol and unnecessary butanone, add the dilution of 40ml water, regulate the about 7-8 of pH with ammoniacal liquor, wet distillation, add solid sodium chloride make saturated, the refrigerator freezing and crystallizing, filter, dry 2,3-dimethyl diketone monoxime, 18g (yield: 21%), white solid, mp:82-88 ℃.
(2), N-oxygen-2-phenyl-4,5-Er Jia Ji oxazole
2.8g 2,3-dimethyl diketone monoxime and 2.9g benzaldehyde solution, the saturated ethyl acetate solution of 17ml hydrogen fluoride mixes, stirring at room 12 hours has solid to separate out, and filters, filtrate decompression concentrates, drying is filtered in crystallization, get N-oxygen-2-phenyl-4,5-Er Jia Ji oxazole, and 2.5g (yield: 50.7%), mp:188-193 ℃.
(3), 2-phenyl-5-methyl-4-chloromethyl-oxazole (XXII 3)
10.2g N-oxygen-2-phenyl-4,5-Er Jia Ji oxazole and 80ml chloroform mix, stir adding 11.7g phosphorus oxychloride down, 50 ℃ were reacted the pressure reducing and steaming solvent 14 hours, add entry and ethyl acetate, transfer pH to 7-8, divide water-yielding stratum with the 1N sodium hydroxide solution, use ethyl acetate extraction, the saturated common salt water washing, anhydrous magnesium sulfate drying filters, concentrating under reduced pressure gets 2-phenyl-5-methyl-4-chloromethyl-oxazole (XXII 3), white solid 8.2g (yield: 73%), mp:80-93 ℃.
(4), methoxyl group 4-[(2-phenyl-5-methyl-4-oxazolyl)] phenyl aldehyde (XXIII 2)
8.2g 2-phenyl-5-methyl-4-chloromethyl-oxazoles and 4.8g4-hydroxy benzaldehyde, 10.9g salt of wormwood and 100ml acetonitrile mix, and reflux concentrating under reduced pressure 8 hours, add entry and ethyl acetate, divide water-yielding stratum, use ethyl acetate extraction, the saturated common salt water washing, anhydrous magnesium sulfate is done, filter, concentrating under reduced pressure gets 4-[(2-phenyl-5-methyl-4-oxazolyl) methoxyl group] phenyl aldehyde (XXIII 2), white solid, and 8.6g (yield: 75%), mp:134-140 ℃.
(5), methoxyl group 4-[(5-methyl-2-Ben Ji oxazole-4-yl)] phenyl methylamine (VIII 2)
According to the method for embodiment 17 (5), the synthetic 4-[(5-methyl-2-Ben Ji oxazole-4-yl that obtains) methoxyl group] phenyl methylamine (VIII 2), 3.5g (yield: 40%), mp:141-146 ℃.
Embodiment 21 (R)-N-[4-[[[(cyclohexyl amino) formyl radical] amino] alkylsulfonyl] phenyl amino] ethanoyl-4-cyano-tetrahydrothiazole (I 21) preparation
1.20g carbonyl (0.004mol) 4-[[[(hexamethylene amino)] amino] alkylsulfonyl] aniline (VI 1), 0.90g (0.0038mol) is N-(acetyl bromide)-4-nitrile-base thiazole alkane (V (4R) 2), triethylamine 0.39g (0.0038mol), DMF 20ml places the 25ml flask, stirring at room reaction 8 hours is being poured reaction solution in the 100ml distilled water under constantly stirring then, regulates pH=4-5, separates out white solid, suction filtration, dry white powder I 211.2g (productive rate: 15.2%), mp:173-175 ℃.ESI-MS：486.0∶488.0＝3∶1[M+Cl] -
1H-NMR(CDCl 3)：1.19-1.38(m，6H， -CH 2 CH 2 CH 2 -)，1.66-1.86(m，4H，NHCH (CH 2 ) 2 )，3.17-3.22(d，2H，S- CH 2 CH-)，3.56-3.58(m，1H，J＝6.6Hz，NH CH(CH 2) 2)，4.28(s，2H，CO CH 2 NH)，4.47(s，2H，Ar NH)，4.55-4.65(dd，2H，S CH 2 N)，5.25-5.26(t，1H， CHCN)，6.66-6.69(d，2H，ArH)，7.07-7.09(d，1H，J＝6.6Hz， NHCH (CH 2 ) 2 )，7.65-7.68(d，2H，ArH)。
Figure A20081012373600301
Embodiment 22 (S)-N-[4-[[[(cyclohexyl amino) formyl radical] amino] alkylsulfonyl] phenyl] glycyl-2-Cyanopyrolidine (I 22) preparation
According to the method for embodiment 21, with (2S)-N-(acetyl bromide)-2-itrile group tetramethyleneimine (V 1) replacement (4R)-N-(acetyl bromide)-4-nitrile-base thiazole alkane (V 2) and 4-[[[(hexamethylene amino) carbonyl] amino] alkylsulfonyl] aniline (VI 1) reaction obtains (S)-N-[4-[[[(cyclohexyl amino) formyl radical] amino] alkylsulfonyl] phenyl] glycyl-2-Cyanopyrolidine (I 22), yield: 16.7%, mp:165～167 ℃.
Embodiment 23 (S)-N-[4-[[[(4-methylcyclohexyl amino) formyl radical] amino] alkylsulfonyl] phenyl] glycyl-2-Cyanopyrolidine (I 23) preparation
According to the method for embodiment 21, with (2S)-N-(acetyl bromide)-2-itrile group tetramethyleneimine (V 1) and 4-[[[(4-methyl cyclohexane amino) carbonyl] amino] alkylsulfonyl] aniline (VI 2) reaction obtains (S)-N-[4-[[[(cyclohexyl amino) formyl radical] amino] alkylsulfonyl] phenyl] glycyl-2-Cyanopyrolidine (I 23), yield: 13.8%, mp:165～167 ℃.
Figure A20081012373600311
Embodiment 24 (R)-N-[4-[[[(4-methylcyclohexyl amino) formyl radical] amino] alkylsulfonyl] phenyl] glycyl-4-cyano-tetrahydrothiazole (I 24) preparation
According to the method for embodiment 21, with 4-[[[(4-methyl cyclohexane amino) carbonyl] amino] alkylsulfonyl] aniline (VI 2), with (4R)-N-(acetyl bromide)-4-nitrile-base thiazole alkane (V 2), reaction obtains (R)-N-[4-[[[(4-methylcyclohexyl amino) formyl radical] amino] alkylsulfonyl] phenyl] glycyl-4-cyano-tetrahydrothiazole (I 24), yield: 17.1%, mp:175～177 ℃.
Embodiment 25 (S)-N-[4-[[[(cyclohexyl amino) formyl radical] amino] alkylsulfonyl] phenmethyl] glycyl-2-Cyanopyrolidine (I 25) preparation
According to the method for embodiment 21, with 4-[[[(hexamethylene amino) carbonyl] amino] alkylsulfonyl] benzene methanamine (VI 3), with (2S)-N-(acetyl bromide)-2-itrile group tetramethyleneimine (V 1), reaction obtains (S)-N-[4-[[[(cyclohexyl amino) formyl radical] amino] alkylsulfonyl] phenmethyl] glycyl-2-Cyanopyrolidine (I 25), yield: 10.1%, mp:145～147 ℃.
Figure A20081012373600321
Embodiment 26 (R)-N-[4-[[[(cyclohexyl amino) formyl radical] amino] alkylsulfonyl] phenmethyl] glycyl-4-cyano-tetrahydrothiazole (I 26) preparation
According to the method for embodiment 21, with (4R)-N-(acetyl bromide)-4-nitrile-base thiazole alkane (V 2) and 4-[[[(hexamethylene amino) carbonyl] amino] alkylsulfonyl] benzene methanamine (VI 3), reaction obtains (R)-N-[4-[[[(cyclohexyl amino) formyl radical] amino] alkylsulfonyl] phenmethyl] glycyl-4-cyano-tetrahydrothiazole (I 26), yield: 11.5%, mp:149～151 ℃, ESI-MS:464.0[M-H] -
Embodiment 27 (S)-1-[[4-[[-4 methyl-(hexamethylene amino) formyl radical] amino-sulfonyl]-phenmethyl] amino]-ethanoyl]-2-cyano group-tetramethyleneimine (I 27) preparation
According to the method for embodiment 21, use compound V 1With compound VI 4Reaction obtains (S)-1-[[4-[[-4 methyl-(hexamethylene amino) formyl radical] amino-sulfonyl]-phenmethyl] amino]-ethanoyl]-2-cyano group-tetramethyleneimine (I 27), yield: 16.9%, mp:150-152 ℃.
Figure A20081012373600322
Embodiment 28 (R)-1-[[4-[[-4 methyl-(hexamethylene amino) formyl radical] amino-sulfonyl]-phenmethyl amino]-ethanoyl]-4-cyano group-thiazolidine (I 28) preparation
With reference to embodiment 21, use compound V 2With compound VI 4Reaction obtains target compound I 28, yield: 13.4%, mp:153-155 ℃, ESI-MS:478.0[M-H] -
Embodiment 29 (S)-1-[[4-[[(hexamethylene amino) formyl radical] amino-sulfonyl]-phenylethyl amino]-ethanoyl]-2-cyano group-tetramethyleneimine (I 29) preparation
With reference to embodiment 21, use compound V 1With compound VI 5Reaction obtains target compound I2 9, yield: 11.2%, mp:144-146 ℃.
Figure A20081012373600331
Embodiment 30 (R)-1-[[4-[[(hexamethylene amino) formyl radical] amino-sulfonyl]-phenylethyl amino]-ethanoyl]-4-cyano group-thiazolidine (I 30) preparation
With reference to embodiment 21, use compound V 2With compound VI 5Reaction obtains target compound I 30, yield: 14.4%, mp:147-149 ℃.
1H-NMR(DMSO-D 6)：1.00～1.31(m，7H)；1.27(d，3H，J＝3.9Hz)；1.45～1.49(m，2H)；1.58～1.60(m，2H)；1.65～1.70(m，2H)；3.76(q，1H，J＝3.9Hz)；4.46(d，2H，J＝5Hz)；4.56(d，1H，J＝5Hz)；4.31～4.37(dd，1H，J＝5.7，10.3Hz)；4.75～4.78(dd，1H，J＝2.7，5.7Hz，)；5.73(br，NH)；7.28(d，2H，J＝4.5Hz)；7.66(d，2H，J＝4.7Hz)；
Embodiment 31 (S)-1-[[4-[[-4 methyl-(hexamethylene amino) formyl radical] amino-sulfonyl]-phenylethyl amino]-ethanoyl]-2-cyano group-tetramethyleneimine (I 31) preparation
With reference to embodiment 21, use compound V 1With compound VI 6Reaction obtains target compound I 31, yield: 16.7%, mp:152-154 ℃.
Figure A20081012373600332
Embodiment 32 (R)-1-[[4-[[-4 methyl-(hexamethylene amino) formyl radical] amino-sulfonyl]-phenylethyl amino]-ethanoyl]-4-cyano group-thiazolidine (I 32) preparation
With reference to embodiment 21, use compound V 2With compound VI 6Reaction obtains target compound I 32, yield: 12.5%, mp:156-158 ℃.
Embodiment 33 (S)-1-[[4-[[(hexamethylene amino) formyl radical] amino-sulfonyl]-a-methyl-phenmethyl amino]-ethanoyl]-2-cyano group-tetramethyleneimine (I 33) preparation
With reference to embodiment 21, use compound V 1With compound VI 7Reaction obtains target compound I 33, yield: 18.6%, mp:147-149 ℃.
Figure A20081012373600341
Embodiment 34 (R)-1-[[4-[[(hexamethylene amino) formyl radical] amino-sulfonyl]-a-methyl-phenmethyl amino]-ethanoyl]-4-cyano group-thiazolidine (I 34) preparation
With reference to embodiment 21, use compound V 2With compound VI 7Reaction obtains target compound I 34, yield: 19.3%, mp:146-148 ℃.
1H-NMR(DMSO-D 6)：1.00～1.31(m，7H)；1.27(d，3H，J＝3.9Hz)；1.45～1.49(m，2H)；1.58～1.60(m，2H)；1.65～1.70(m，2H)；3.76(q，1H，J＝3.9Hz)；4.46(d，2H，J＝5Hz)；4.56(d，1H，J＝5Hz)；5.22(d，1H，J＝2.9Hz)；5.79～5.83(s，NH)；5.27(m，1H)；7.34(d，2H，J＝4.6Hz)；7.69(d，2H，J＝4.7Hz)；
Embodiment 35 (S)-1-[[4-[[-4 methyl-(hexamethylene amino) formyl radical] amino-sulfonyl]-a-methyl-phenmethyl amino]-ethanoyl]-2-cyano group-tetramethyleneimine (I 35) preparation
With reference to embodiment 21, use compound V 1With compound VI 8Reaction obtains target compound I 35, yield: 17.4%, mp:156-158 ℃.
Figure A20081012373600342
Embodiment 36 (R)-1-[[4-[[-4 methyl-(hexamethylene amino) formyl radical] amino-sulfonyl]-a-methyl-phenmethyl amino]-ethanoyl]-4-cyano group-thiazolidine (I 36) preparation
With reference to embodiment 21, use compound V 2With compound VI 8Reaction obtains target compound I 36, yield: 20%, mp:159-161 ℃.
ESI-MS：492.6[M-H] -。
1H-NMR(DMSO-D 6)：0.81～0.83(d，3H，J＝6.3Hz)，0.90～1.15(m，5H)；1.27(d，3H，J＝5.7Hz)；2.08(s，2H)，3.83～3.87(q，1H，J＝5.7Hz)，4.48～4.73(dm，J＝7.8Hz)，5.19～5.24(t，1H，J＝7.8Hz)；5.56～5.66(dbr，NH)；6.25～6.28(d，1H)；7.53～7.55(d，2H，J＝4.6Hz)；7.81～7.84(d，2H，J＝4.7Hz)；
Embodiment 37 (S)-1-[[4-[[-4 methyl-(hexamethylene amino) formyl radical] amino-sulfonyl]-α-ethyl-phenmethyl amino]-ethanoyl]-2-cyano group-tetramethyleneimine (I 37) preparation
With reference to embodiment 21, use compound V 1With compound VI 9Reaction obtains target compound I 37, yield: 12.5%, mp:131-133 ℃.
Figure A20081012373600351
Embodiment 38 (R)-1-[[4-[[(hexamethylene amino) formyl radical] amino-sulfonyl]-α-ethyl-phenmethyl amino]-ethanoyl]-4-cyano group-thiazolidine (I 38) preparation
With reference to embodiment 21, use compound V 2With compound VI 9Reaction obtains target compound I 38, yield: 13.4%, mp:135-137 ℃.ESI-MS：492.0[M-H] -；
1H-NMR(DMSO-D 6)：0.73-0.78(t，3H，J＝6.6Hz)，1.06-1.23(m，6H，)，1.50-1.73(m，6H，)；2.96-3.06(m，1H)；3.58(s2H)；4.41-4.62(ddd，2H)，5.18-5.20(m，1H)，5.56(br，1H)，6.30-6.32(m，1H)；7.47-7.50(d，2H)7.81-7.83(d，2H)。
Embodiment 39 (S)-1-[[4-[[-4 methyl-(hexamethylene amino) formyl radical] amino-sulfonyl]-a-ethyl-phenmethyl amino]-ethanoyl]-2-cyano group-tetramethyleneimine (I 39) preparation
With reference to embodiment 21, use compound V 1With compound VI 10Reaction obtains target compound I 39, yield: 20%, mp:146-148 ℃.
Figure A20081012373600352
Embodiment 40 (R)-1-[[4-[[4 methyl-(hexamethylene amino) formyl radical] amino-sulfonyl]-a-ethyl-phenmethyl amino]-ethanoyl]-4-cyano group-thiazolidine (I 40) preparation
With reference to embodiment 21, use compound V 2With compound VI 10Reaction obtains target compound I 40, yield: 18.8%, mp:151-153 ℃.
Embodiment 41 (R)-1-[[4-[[(hexamethylene amino) formyl radical] amino-sulfonyl]-a-cyclohexyl-phenmethyl amino]-ethanoyl]-4-cyano group-thiazolidine (I 41) preparation
With reference to embodiment 21, use compound V 2With compound VI 11Reaction obtains target compound I 41, yield: 13.4%, mp:158-160 ℃.
Embodiment 42 (R)-1-[[4-[[4 methyl-(hexamethylene amino) formyl radical] amino-sulfonyl]-a-cyclohexyl-phenmethyl amino]-ethanoyl]-4-cyano group-thiazolidine (I 42) preparation
With reference to embodiment 21, use compound V 2With compound VI 12Reaction obtains target compound I 42, yield: 14.6%, mp:162-164 ℃.
Embodiment 43 (S)-1-[[4-[[(hexamethylene amino) formyl radical] amino-sulfonyl]-a-cyclohexyl-phenmethyl amino]-ethanoyl]-2-cyano group-tetramethyleneimine (I 43) preparation
With reference to embodiment 21, use compound V 1With compound VI 11Reaction obtains target compound I 43, yield: 15.4%, mp:148-150 ℃.
Figure A20081012373600362
Embodiment 44 (S)-1-[[4-[[4 methyl-(hexamethylene amino) formyl radical] amino-sulfonyl]-a-cyclohexyl-phenmethyl amino]-ethanoyl]-2-cyano group-tetramethyleneimine (I 44) preparation
With reference to embodiment 21, use compound V 2With compound VI 12Reaction obtains target compound I 44, yield: 14.6%, mp:152-154 ℃.
Embodiment 45 (S)-1-[[4-[4-[(2,4-thiazolidinedione-5-yl) methyl] phenoxy group] piperidines-1-yl]-ethanoyl]-2-cyano group-tetramethyleneimine (I 45) preparation
1.6g (0.005mol) compound VI I 1And 1g (0.005mol) (2S)-N-((bromotrifluoromethane carbonyl)-2-itrile group tetramethyleneimine (V 1) place the three-necked bottle of 100ml (to have thermometer, drying tube and dropping funnel) tetrahydrofuran (THF) of adding 50ml under magnetic agitation, stir not moltenly entirely, slowly be heated to backflow, under refluxad slowly drip the solution that the 1.4ml triethylamine is dissolved in the 10ml tetrahydrofuran (THF), after dripping off, back flow reaction 16 hours, after reaction finished, concentrating under reduced pressure obtained oily mater after removing and desolvating, this oily mater is carried out column chromatography (sherwood oil: ethyl acetate: methyl alcohol=9: 2: 1), obtain target compound I 45, 0.6g, yield: 9%, mp:143-145 ℃.
1H-NMR(DMSO-D 6)：1.57-1.66(m，2H)；1.91-2.01(m，4H)；2.09-2.21(m，2H)；2.33-2.43(m，2H)；2.73-2.77(m，2H)；1.57-1.66(m，2H)；2.99-3.07(m，1H)；3.22(d，1H，J＝3.4Hz)；3.27(d，1H，J＝4.2Hz)；3.36-3.55(m，2H)；3.64-3.70(m，1H)；4.31-4.36(m，1H)；4.72(q，1H，J＝3.9，7.3Hz)；4.85(q，1H，J＝4.3，9.1Hz)；6.88(d，2H，J＝8.6Hz)；7.13(d，2H，J＝8.6Hz)；11.96(s，NH)。
Embodiment 46 (R)-1-[[4-[4-[(2,4-thiazolidinedione-5-yl) methyl] phenoxy group] piperidines-1-yl]-ethanoyl]-4-cyano group-thiazolidine (I 46) preparation;
1.5 (0.004mol) g compound VI I 1Place the three-necked bottle of 100ml (to have thermometer, drying tube and dropping funnel) tetrahydrofuran (THF) of adding 50ml under magnetic agitation, stir not molten entirely, it is still not molten entirely to add the stirring of 1.2ml triethylamine again, and the ice bath cooling drips (4R) N-(bromotrifluoromethane carbonyl)-4-nitrile-base thiazole alkane (V of 1g (0.004mol) down 2) be dissolved in the tetrahydrofuran solution of 20ml, keep 50 ℃ of reactions 12 hours after dripping off, after reaction finishes, concentrating under reduced pressure obtains the semi-solid material after removing and desolvating, this semi-solid material is dissolved in ethyl acetate, a small amount of insolubles is arranged, suction filtration, filtrate is spent the night with adding anhydrous magnesium sulfate drying after saturated sodium bicarbonate and each washed twice of saturated sodium-chloride respectively, next day suction filtration, filter obtains oily matter after being evaporated to and doing, and this oily matter is carried out silica gel column chromatography (sherwood oil: ethyl acetate: methyl alcohol=4: 2: 1), obtain target compound I 46, 0.4g, yield: 17.1%, mp:148-150 ℃.
1H-NMR(DMSO-D 6)：1.62-1.65(m，2H)；1.91-1.95(m，2H)；2.37-2.42(m，2H)；2.72(m，2H)；3.00-3.08(m，1H)；3.27-3.51(m，3H)；4.33-4.4(m，1H)；4.64(d，1H，J＝9.7Hz)；4.71(d，1H，J＝8.8Hz)；4.81(d，1H，J＝8.9Hz)；4.82-4.88(p，1H，J＝4.3，4.8Hz)；5.22-5.24(m，1H)；5.75(d，1H，J＝5.4Hz)；6.89(d，2H，J＝8.4Hz)；7.14(d，2H，J＝8.4Hz)；11.95(s，NH)。
Embodiment 47 (R)-1-[[4-[4-[(2,4-thiazolidinedione-5-yl) methyl] phenoxy group] hexamethylene amino]-ethanoyl]-4-cyano group-thiazolidine (I 47) preparation;
With reference to embodiment 45, with compound VI I 2With compound V 2Reaction gets target compound I 47, yield: 15.8%, mp:154-156 ℃.
1H-NMR(DMSO-D 6)：1.60-1.78(m，8H)；2.99-3.04(m，1H)；3.12-3.14(m，1H)；3.33-3.47(m，3H)；4.47(d，1H，J＝10Hz)；4.56(s，1H)；4.62-4.66(dd，1H，J＝3Hz)；4.71(d，1H，J＝5Hz)；4.92(d，1H，J＝5Hz)；5.06-5.09(m，1H)；5.26-5.28(m，1H)；6.90(d，2H，J＝5Hz)；7.21(d，2H，J＝5Hz)；11.99(s，NH)。
Figure A20081012373600381
Embodiment 48 (S)-1-[[4-[4-[(2,4-thiazolidinedione-5-yl) methyl] phenoxy group] hexamethylene amino]-ethanoyl]-2-cyano group-tetramethyleneimine (I 48) preparation;
With reference to embodiment 45, with compound VI I 2With compound V 1Reaction gets target compound I 48, mp:176-178 ℃.
Embodiment 49 (S)-1-[[2-[4-[(2,4-thiazolidinedione-5-yl) methyl] phenoxy group] ethylamino]-ethanoyl]-2-cyano group-tetramethyleneimine (I 49) preparation;
With reference to embodiment 45, with compound VI I 3With compound V 1Reaction gets target compound I 49, yield: 16.5%, mp:176-178 ℃.
1H-NMR(DMSO-D 6)：1.99-2.07(m，2H)；2.14-2.19(m，2H)；3.01-3.11(m，2H)；3.21-3.22(m，2H)；3.45-3.53(m，1H)；3.53-3.55(m，1H)；3.74-3.75(m，1H)；4.43-4.48(dd，1H，J＝3.4，10Hz)；5.06-5.09(m，1H)；6.94(d，2H，J＝5.1Hz)；7.25(d，2H，J＝5.1Hz)；8.09(s，2H，NH)。
Figure A20081012373600382
Embodiment 50 (S)-1-[[2-[4-[(2,4-thiazolidinedione-5-yl) methyl] phenoxy group]-2-methylethyl amino]-ethanoyl]-2-cyano group-tetramethyleneimine (I 50) preparation;
With reference to embodiment 45, with compound VI I 4With compound V 1Reaction gets target compound I 50, yield: 12.7%, mp:165-167 ℃.
1H-NMR(DMSO-D 6)：1.25(d，3H，J＝3.5Hz)；1.97-2.07(m，2H)；2.14-2.20(m，2H)；2.97-3.11(m，3H)；3.23-3.48(m，1H)；3.53-3.55(m，1H)；3.51-3.61(m，1H)；3.72-3.76(m，1H)；4.33(d，1H，J＝10Hz)；4.44-4.49(qd，1H，J＝1，3.6，10Hz)；4.62-4.67(m，1H)；4.75-4.77(m，1H)；5.06-5.09(m，1H)；6.95(d，2H，J＝4.8Hz)；7.26(d，2H，J＝5.4Hz)；8.0(s，2H，NH)。
Embodiment 51 (R)-1-[[2-[4-[(2,4-thiazolidinedione-5-yl) methyl] phenoxy group] ethylamino]-ethanoyl]-4-cyano group-thiazolidine (I 51) preparation;
With reference to embodiment 45, with compound VI I 3With compound V 2Reaction gets target compound I 51, yield: 13.6%, mp:181-183 ℃.
1H-NMR(DMSO-D 6)：3.01-3.11(m，1H)；3.18(s，2H)；3.28-3.66(m，3H)；3.99-4.30(m，2H)；4.46(d，1H，J＝10Hz)；4.57-4.61(m，1H)；4.68-4.70(m，1H)；4.85-4.91(m，1H)；5.07(m，1H)；5.25(m，1H)；6.92(d，2H，J＝4Hz)；7.22(d，2H，J＝4Hz)；8.25(s，2H，NH)。
Figure A20081012373600391
Embodiment 52 (R)-1-[[2-[4-[(2,4-thiazolidinedione-5-yl) methyl] phenoxy group]-2-methylethyl amino]-ethanoyl]-4-cyano group-thiazolidine (I 52) preparation;
With reference to embodiment 45, with compound VI I 4With compound V 2Reaction gets target compound I 52, yield: 15.9%, mp:170-171 ℃.
1H-NMR(DMSO-D 6)：1.25(d，3H，J＝3.6Hz)；3.00-3.05(m，2H)；3.11(s，1H)；3.33-3.38(m，2H)；3.45-3.53(m，1H)；4.48(d，1H，J＝10Hz)；4.62-4.67(m，2H)；4.93(d，1H，J＝5Hz)；5.08-5.10(m，1H)；5.27(m，1H)；6.95(d，2H，J＝4.9Hz)；7.24(d，2H，J＝4.8Hz)；8.06(s，2H，NH)。
Embodiment 53 (S)-1-[[4-[4-[(2,4-thiazolidinedione-5-yl) methylene radical] phenoxy group] piperidines-1-yl]-ethanoyl]-2-cyano group-tetramethyleneimine (I 53) preparation;
(1), (S)-1-[[4-[4-[(2,4-thiazolidinedione-5-yl) methylene radical] phenoxy group] piperidines (VII 5)
With 1.5g embodiment 15 (4) resulting compounds X X 1Place the eggplant type bottle of 250ml, the hydrogenchloride anhydrous diethyl ether that under magnetic agitation, adds 100ml, sealing back stirring reaction 24 hours, reaction finishes back adularescent solid and generates, and suction filtration, filter cake are put oven dry under the infrared lamp, get 1.2g midbody compound (S)-1-[[4-[4-[(2,4-thiazolidinedione-5-yl) methylene radical] phenoxy group] piperidines (VII 5).
(2), 1.4g (0.005mol) previous step reaction (1) gained compound VI I 5And 1g (0.005mol) (2S)-N-((bromotrifluoromethane carbonyl)-2-itrile group tetramethyleneimine (V 1) place the three-necked bottle of 100ml (to have thermometer, drying tube and dropping funnel) tetrahydrofuran (THF) of adding 50ml under magnetic agitation, stir not moltenly entirely, slowly be heated to backflow, under refluxad slowly drip the solution that the 1.4ml triethylamine is dissolved in the 10ml tetrahydrofuran (THF), after dripping off, back flow reaction 20 hours, after reaction finished, concentrating under reduced pressure obtained oily mater after removing and desolvating, this oily shape material is carried out column chromatography (ethyl acetate: methyl alcohol=5: 2), obtain target compound I 53, 0.25g, mp:182-184 ℃
Embodiment 54 (R)-N-[[4-[4-[(2,4-thiazolidinedione-5-yl) methylene radical] phenoxy group] piperidines-1-yl]-ethanoyl]-4-cyano group-thiazolidine (I 54);
Figure A20081012373600401
With 1.3g (0.004mol) embodiment 33 (1) gained compound VI I 5Place the three-necked bottle of 100ml (to have thermometer, drying tube and dropping funnel) tetrahydrofuran (THF) of adding 50ml under magnetic agitation, stir not molten entirely, add again the 1.2ml triethylamine stir still not molten entirely, the ice bath cooling drip down 1g (0.004mol) (4R)-N-(bromotrifluoromethane carbonyl)-4-nitrile-base thiazole alkane (V 2) be dissolved in the tetrahydrofuran solution of 20ml, keep 10 ℃ of reactions 24 hours after dripping off, after reaction finishes, concentrating under reduced pressure obtains the semi-solid material after removing and desolvating, the adularescent solid is separated out after adding ethyl acetate, and suction filtration, filter cake are inhaled and ridiculed, the solid that this suction is ridiculed carries out silica gel column chromatography (sherwood oil: ethyl acetate: methyl alcohol=4: 2: 1), obtain target compound I 54, 0.3g, mp:188-191 ℃
Embodiment 55 (S)-1-[N-carboxymethyl-N-[4-[(2-phenyl-1,3-oxazole-4-yl) oxyethyl group] phenyl methyl] amino]-ethanoyl]-2-cyano group-tetramethyleneimine (I 55) preparation;
Figure A20081012373600402
(1), oxyethyl group 4-[(2-Ben Ji oxazole-4-yl)] aminotoluene guanidine-acetic acid ethyl ester (VIII 3),
Compounds X XIII with 3.8g (0.013mol) embodiment 19 they (4) gained 1And 2.7g (0.0195mol) glycine ethyl ester hydrochloride, 2g (0.0195mol) triethylamine, 2g anhydrous magnesium sulfate, 40ml tetrahydrofuran (THF) place reaction flask, stirred overnight at room temperature, adding 40g (0.018mol) NaBH (OAc) 3Solid stirred 5 hours, filtered, and filtrate decompression concentrates, and added the 40ml methylene dichloride, wash with water to neutrality, anhydrous magnesium sulfate drying filters, and filtrate concentrates, add an amount of normal hexane, separate out solid, oven dry gets 4-[(2-Ben Ji oxazole-4-yl) oxyethyl group] aminotoluene guanidine-acetic acid ethyl ester (VIII 3), white solid 1.9g, mp:46-52 ℃.
(2), oxyethyl group 4-[(2-Ben Ji oxazole-4-yl)] aminotoluene guanidine-acetic acid (VIII 4)
0.3g (0.007mol) lithium hydroxide is dissolved in the 8ml water, be added in the mixing solutions of 100ml tetrahydrofuran (THF) of the above-mentioned reaction of 1.2g (1) gained compound, stirring at room reaction 12 hours, be acidified to pH about 4 with dilute hydrochloric acid, filter, the filter cake washing, oven dry gets 4-[(2-Ben Ji oxazole-4-yl) oxyethyl group] aminotoluene guanidine-acetic acid (VIII 4), white solid 0.7g, mp:188-192 ℃.
(3), (S)-1-[N-carboxymethyl-N-[4-[(2-phenyl-1,3-oxazole-4-yl) oxyethyl group] phenyl methyl] amino]-ethanoyl]-2-cyano group-tetramethyleneimine (I 55)
0.53g compound VIII (0.0015mol) 4And 1.16g (0.0015mol) triethylamine, 40ml acetone, 50ml methanol mixed, be chilled to 3 ℃, stir and drip 0.44g (2S)-N-(bromotrifluoromethane carbonyl)-2-itrile group tetramethyleneimine (V down 1) be dissolved in the solution of 10ml acetone; reaction is 4 hours under this temperature; remove ice bath; naturally rose to room temperature reaction 24 hours; filter; filtrate decompression concentrates, and adds water and ethyl acetate, and dilute hydrochloric acid is regulated the about 6-7 of pH; tell ethyl acetate; the water layer ethyl acetate extraction merges anhydrous magnesium sulfate drying; filter; concentrate the yellow solid dehydrated alcohol crystallization of separating out, get (S)-1-[N-carboxymethyl-N-[4-[(2-phenyl-1,3-oxazole-4-yl) oxyethyl group] phenyl methyl] amino]-ethanoyl]-2-cyano group-tetramethyleneimine (I 55), white solid 0.2g, mp:104-108 ℃, MS (+)=489.
1H-NMR(DMSO-D 6)：2.03-2.23(m，4H)；3.08(t，2H，J＝10Hz)；3.28-3.43(m，2H)；3.53-3.66(m，4H)；3.97(s，2H，)；4.27(t，2H，J＝6.5Hz)；4.71(d，1H，J＝5.4Hz)；，6.90(d，2H，J＝8.4Hz)；7.27(d，2H，J＝8.4Hz)，7.42-7.48(m，3H)；7.57(s，1H)；7.99-8.03(m，2H)。
Embodiment 56 (R)-1-[N-carboxymethyl-N-[4-[(2-phenyl-1,3-oxazole-4-yl) oxyethyl group] phenyl methyl] amino]-ethanoyl]-4-cyano group-thiazolidine (I 56) preparation;
Figure A20081012373600411
With reference to embodiment 55, with compound VIII 4(4R)-N-(bromotrifluoromethane carbonyl)-4-nitrile-base thiazole alkane (V 2) reaction, obtain target compound I 56, mp:121-108 ℃, MS (+)=507.
Embodiment 57 (S)-1-[[4-[(2-phenyl-1,3-oxazole-4-yl) oxyethyl group] phenyl methyl] amino]-ethanoyl]-2-cyano group-tetramethyleneimine (I 57) preparation;
Figure A20081012373600421
0.338g (1.15mmol) compound VIII 1And 0.72g (7.1mmol) triethylamine, the dissolving of 25ml methanol mixed is cooled to-4 ℃, drips (2S)-N-(bromotrifluoromethane carbonyl)-2-itrile group tetramethyleneimine (V of 0.5g (2.3mmol) 1) be dissolved in the solution of 10ml acetone, stirred 4 hours, remove ice bath; naturally rise to room temperature, stirred concentrating under reduced pressure 24 hours; add water and ethyl acetate is told ethyl acetate, the water layer ethyl acetate extraction merges; anhydrous magnesium sulfate drying; filter, concentrate, residual solidliquid mixture post separates (normal hexane: ethyl acetate: methyl alcohol=7: 7: 1); get (S)-1-[[4-[(2-phenyl-1,3-oxazole-4-yl) oxyethyl group] phenyl methyl] amino]-ethanoyl]-2-cyano group-tetramethyleneimine (I 57), 0.15g, solid, MS (+)=431.
Embodiment 58 (S)-1-[N-[(2-cyano group-tetramethyleneimine-1-yl)-the formyl methyl]-N-[4-[(2-phenyl-1,3-oxazole-4-yl) oxyethyl group] phenyl methyl] amino]-ethanoyl]-2-cyano group-tetramethyleneimine (I 58) preparation;
Figure A20081012373600422
The separation of embodiment 57 posts obtains another Compound I 58, 0.1g, MS (+)=567.
1H-NMR(DMSO-D 6)：2.03～2.20(m，8H，H 14，15)；3.07(t，2H，J＝6.5Hz，H 8)；3.32～3.93(m，10H，H 11，12，13)；4.27(t，2H，H 7)；4.66～4.69(m，2H，H 16)；6.87～6.91(dd，2H，J＝7，1.6Hz，H 10)；7.27～7.29(dd，2H，J＝7，1.6Hz，H 9)；7.42～7.45(m，3H，H 3， 4，5)；7.57(s，1H，H 6)；7.99(m，2H，H 1，5)；
Embodiment 59 (R)-1-[[4-[(2-phenyl-1,3-oxazole-4-yl) oxyethyl group] phenyl methyl] amino]-ethanoyl]-4-cyano group-thiazolidine (I 59) preparation;
Figure A20081012373600431
With reference to embodiment 37, compound VIII 1With compound V 2Reaction obtains target compound I 59, mp:202-208 ℃, MS (+)=449.
1H-NMR(DMSO-D 6)：3.01(t，2H，J＝3.76Hz)；3.66～3.69(m，1H)；4.00(d，1H，J＝10.4Hz)；4.16(d，1H，J＝10.3Hz)；4.30(t，2H，J＝3.86Hz)；4.34(d，1H，J＝5.67Hz)；4.71～4.79(m，2H)；4.85～4.91(m，2H)；7.02(d，2H，J＝5Hz)；7.33(d，2H，J＝5Hz)；7.52～7.53(m，3H)；7.97～7.95(m，2H)；8.03(s，1H)；9.62(s，1H，NH)；
Embodiment 60 (R)-1-[N-[(4-cyano group-thiazolidine-1-yl)-the formyl methyl]-N-[4-[(2-phenyl-1,3-oxazole-4-yl) oxyethyl group] phenyl methyl] amino]-ethanoyl]-4-cyano group-thiazolidine (I 60) preparation;
Figure A20081012373600432
The separation of embodiment 59 posts obtains Compound I 60, mp:256-260 ℃, MS (+)=603.
Embodiment 61 (S)-1-[N-carboxymethyl-N-[4-[(2-phenyl-5-methyl isophthalic acid, 3-oxazole-4-yl) oxyethyl group] phenyl methyl] amino]-ethanoyl]-2-cyano group-tetramethyleneimine (I 61) preparation;
Figure A20081012373600433
(1), methoxyl group 4-[(2-phenyl-5-Jia Ji oxazole-4-yl)] aminotoluene guanidine-acetic acid (VIII 6),
The compound 4-[(2-phenyl-5-methyl-4-oxazolyl of embodiment 20 they (4) gained) methoxyl group] phenyl aldehyde, according to the method for embodiment 55, obtain 4-[(2-phenyl-5-Jia Ji oxazole-4-yl) methoxyl group] aminotoluene guanidine-acetic acid (VIII 6),
(2), (S)-1-[N-carboxymethyl-N-[4-[(2-phenyl-5-methyl isophthalic acid, 3-oxazole-4-yl) oxyethyl group] phenyl methyl] amino]-ethanoyl]-2-cyano group-tetramethyleneimine,
With reference to embodiment 55 they (2) methods, obtain target compound (S)-1-[N-carboxymethyl-N-[4-[(2-phenyl-5-methyl isophthalic acid, 3-oxazole-4-yl) oxyethyl group] phenyl methyl] amino]-ethanoyl]-2-cyano group-tetramethyleneimine (I 61), mp:128-132 ℃.
Embodiment 62 (R)-1-[N-carboxymethyl-N-[4-[(2-phenyl-5-methyl isophthalic acid, 3-oxazole-4-yl) oxyethyl group] phenyl methyl] amino]-ethanoyl]-4-cyano group-thiazolidine (I 62) preparation;
Figure A20081012373600441
With reference to embodiment 61, with compound VIII 6(4R)-and N-(bromotrifluoromethane carbonyl)-4-itrile group-thiazolidine (V2) reaction, obtain target compound I 62, mp:121-124 ℃, MS (+)=507.
1H-NMR(DMSO-D 6)：2.44(s，3H，H 6)；3.22(s，2H，H 10)；3.32～3.86(m，6H，H 14，13，12)；4.42～4.63(m，2H，H 11)；4.99(s，2H，H 7)；5.21(br，s，1H，H 15)；6.01(s，1H，H 16)；7.00(d，2H，H 9)；7.25(d，2H，H 8)；7.42～7.48(m，3H，H 2，3，4)；7.97～8.02(m，2H，H 1，5)。
Embodiment 63 (S)-1-[[4-[(2-phenyl-5-methyl isophthalic acid, 3-oxazole-4-yl) oxyethyl group] phenyl methyl] amino]-ethanoyl]-2-cyano group-tetramethyleneimine (I 63) preparation;
Figure A20081012373600442
With reference to embodiment 53, with compound VIII 2And compound (V 1), obtain target compound (S)-1-[[4-[(2-phenyl-5-methyl isophthalic acid, 3-oxazole-4-yl) oxyethyl group] phenyl methyl] amino]-ethanoyl]-2-cyano group-tetramethyleneimine (I 63), mp:141-144 ℃.
Embodiment 64 (R)-1-[[4-[(2-phenyl-5-methyl isophthalic acid, 3-oxazole-4-yl) oxyethyl group] phenyl methyl] amino]-ethanoyl]-4-cyano group-thiazolidine (I 64) preparation;
Figure A20081012373600443
With reference to embodiment 55, with compound VIII 2And compound (V 2) reaction, obtain target compound I 64, mp:158-160 ℃, MS (+)=603.
Embodiment 65 (S)-1-[[4-[4-[(2,4-thiazolidinedione-5-yl) methyl] phenoxy group] piperidines-1-yl]-ethanoyl]-2-cyano group-tetramethyleneimine fumaric acid synthetic
0.443g (S)-1-[[4-[4-[(2; 4-thiazolidinedione-5-yl) methyl] phenoxy group] piperidines-1-yl]-ethanoyl]-2-cyano group-tetramethyleneimine is dissolved in 50ml methyl alcohol, adds the 0.116g fumaric acid, low-grade fever in batches; after stirring 30min; solvent evaporated under reduced pressure adds anhydrous ethyl acetate to an amount of, produces precipitation; filter; oven dry is (S)-1-[[4-[4-[(2,4-thiazolidinedione-5-yl) methyl] phenoxy group] piperidines-1-yl]-ethanoyl]-2-cyano group-tetramethyleneimine fumaric acid.
Embodiment 66 DPP IV active suppression tests
The blood plasma that contains DPP IV is taken from the healthy normal mouse body, by the centrifugation preparation, carries out in the Tris damping fluid of the pH7.8 of enzyme reaction under 37 ℃.Measure enzymic activity by catalyzed reaction (glycyl prolyl p-Nitroaniline resolves into glycyl proline(Pro) and p-Nitroaniline), under 405nm, detect p-Nitroaniline with optical density for chromogenic substrate.Use the methyl-sulphoxide sample dissolution, and control an amount of concentration, the enzyme digestion reaction time is controlled within the 1h, compares with blank, determines IC50 with nonlinear analysis, parallel test several times, and each sample compound is surveyed 3 times, averages.The result is as follows:
Sample compound IC 50(nM)DPP-IV
I 21 58.3
I 22 45.2
I 28 95.3
I 45 102.6
I 46 12.7
I 49 26.4
I 55 46.1
The above results is represented: The compounds of this invention is effective DPP-IV inhibitor.
Embodiment 67 stimulates the pancreas islet uelralante test of exsomatizing
Get mice pancreatic, remove fat and lymphoglandula, the HBSS damping fluid is washed, and places beaker, shreds into fritter, 37 ℃ of water-bath vibration digestion 60min.Cross 80 order stainless steel sifts rapidly, add 4 ℃ HBSS damping fluid dilution stopped reaction.Supernatant liquor is removed in suction, uses the HBSS buffer solution for cleaning again.Add 4 ℃ of dyeing of dithizone dye liquor 15min, get the circular or rotund particle of dying scarlet.Get 24 well culture plates, add the 0.9mlKRBH Incubating Solution, get in the pancreas islet adding aperture and in 37 ℃ incubator, incubate 1h in advance.Take out the sample compound (100ug/mL1) and the solvent 0.25%DMSO that add 0.1ml, continue to hatch 4h, take out the back and draw supernatant, cryogenic refrigerator is preserved, 0.25%DMSO compares with solvent, adopts the radioimmunoassay medicine box to measure content of insulin in the supernatant liquor, and data are as follows:
Sample compound Regular Insulin (uIU/mL) Active
Contrast 25.1±1.9 1.1
I 21 72.2±5.3 3.1
I 22 65.2±4.2 2.8
I 28 58.6±3.5 2.3
I 32 62.3±4.0 2.6
I 33 45.1±2.9 1.9
The above results is represented: contrast does not influence the secretion of insulin activity of exsomatizing, and The compounds of this invention has the function that stimulates the pancreas islet uelralante that exsomatizes.
Embodiment 68 step-downs experiment
Prepare 63 of spontaneously hypertensive mouse, about body weight 150g, be divided into 7 groups at random, 9 every group, 1. blank group gives clear water; 2. positive drug control group, rosiglitazone (10mg/L adds in the drinking-water); 3. testing drug group (15mg/L add drinking-water in); Adopt the outer blood pressure measuring method indirectly of mouse urosome; Weekly each group rat is measured a blood pressure, average for continuous three times.Testing data is as follows:
Figure A20081012373600461
From table as can be known, The compounds of this invention equally has the identical function that brings high blood pressure down with PPAR agonist rosiglitazone.
Embodiment 69 hypoglycemic tests
Get some 40 of normal mouse; wherein stay 5 as one group of solvent contrast 1 (0.5%CMC); other mouse is all adopted low dose of STZ to add special diet inductive method and deals with Yan Nei Ci venous plexus and get blood and survey fasting plasma glucose; select for use blood sugar＞11.5mmol/L person to be used for test; mouse is divided into solvent contrast 2 (0.5%CMC) at random; the glimepiride group (20mg/kg, ig) and (S)-1-[[4-[[-4 methyl-(hexamethylene amino) formyl radical] amino-sulfonyl]-phenylethyl amino]-ethanoyl]-2-cyano group-tetramethyleneimine (I 31, 20mg/kg, ig) compound group, by test grouping, single gastric infusion and successive administration after 7 days different time Ci venous plexus in Yan get blood, use the determination of glucose oxidase blood glucose value.Data are as follows:
Figure A20081012373600471
By above-mentioned testing data as can be known: compare with contrast 2 (diabetes); add the glimepiride group of about equimolar amount and (S)-1-[[4-[[-4 methyl-(hexamethylene amino) formyl radical] amino-sulfonyl]-phenylethyl amino]-ethanoyl]-2-cyano group-tetramethyleneimine after; mouse all obviously demonstrates blood sugar decline function; but compare with control group 1 (health) group; the blood sugar of glimepiride group is low than normal group behind the 6h; show hypoglycemia, and (S)-1-[[4-[[-4 methyl-(hexamethylene amino) formyl radical] amino-sulfonyl]-phenylethyl amino]-ethanoyl]-2-cyano group-tetramethyleneimine group do not show the hypoglycemia side effect.

Claims (6)

1, Cyanopyrolidine and cyano-tetrahydrothiazole derivates, its structural formula is as follows:
Figure A20081012373600021
Wherein, X is CH 2, CHF, CF 2Or S; L is a linking group, is C 1-8Straight chained alkyl, C 1-8Branched-chain alkyl or C 3-6Cycloalkyl; R 1Be the pharmacophoric group of sulfonylurea hypoglycemic hypoglycemic drug or the pharmacophoric group of peroxisome proliferation activated receptor agonist class ofhypoglycemic medicine; R 2Be R 1, hydrogen ,-CH 2CO 2H or CH 2CO-R 7, R 7Be 2-cyanopyrrole alkyl or 4-cyano thiazole alkyl; Work as R 2Be R 1Or during carboxymethyl, R 2---R 1For connecting or not connecting; Work as R 2Be hydrogen or CH 2CO-R 7The time, R 2---R 1For not connecting.
2, Cyanopyrolidine according to claim 1 and cyano-tetrahydrothiazole derivates are characterised in that this derivant structure is as follows:
Wherein, X is CH 2, CHF, CF 2Or S; R 3Be C 1-8Straight chained alkyl, C 1-8Branched-chain alkyl or C 3-6Cycloalkyl, C 3-6Cycloalkyl is not substituted or by C 1-6Alkane replace; M is 0～2; R 5Be hydrogen, C 1～6Alkyl or C 3～6Cycloalkyl.
3, Cyanopyrolidine according to claim 1 and cyano-tetrahydrothiazole derivates are characterised in that this derivant structure is as follows:
Figure A20081012373600023
Wherein, X is CH 2, CHF, CF 2Or S;
Figure A20081012373600031
Be singly-bound or two key; R 9Be C 1-6Alkyl or C 3-6Cycloalkyl; R 6Be hydrogen, C 1-6Alkyl or C 3-6Cycloalkyl; R 6---N is for connecting or not connecting.
4, Cyanopyrolidine according to claim 1 and cyano-tetrahydrothiazole derivates are characterised in that this derivant structure is as follows:
Wherein, X is CH 2, CHF, CF 2Or S; U is 0～1; R 8Be hydrogen, C 1～6Alkyl or C 3～6Cycloalkyl; V is 1～3; R 10For hydrogen ,-CH 2CO 2H or CH 2CO-R 11, R 11Be 2-cyanopyrrole alkyl or 4-cyano thiazole alkyl.
5,, be characterised in that this derivative is according to the described Cyanopyrolidine and the cyano-tetrahydrothiazole derivates of claim 1:
(R)-and N-[4-[[[(cyclohexyl amino) formyl radical] amino] alkylsulfonyl] phenyl] glycyl-4-cyano-tetrahydrothiazole
(S)-and N-[4-[[[(cyclohexyl amino) formyl radical] amino] alkylsulfonyl] phenyl] glycyl-2-Cyanopyrolidine
(S)-and N-[4-[[[(4-methylcyclohexyl amino) formyl radical] amino] alkylsulfonyl] phenyl] glycyl-2-Cyanopyrolidine
(R)-and N-[4-[[[(4-methylcyclohexyl amino) formyl radical] amino] alkylsulfonyl] phenyl] glycyl-4-cyano-tetrahydrothiazole
(S)-and N-[4-[[[(cyclohexyl amino) formyl radical] amino] alkylsulfonyl] phenmethyl] glycyl-2-Cyanopyrolidine
(R)-and N-[4-[[[(cyclohexyl amino) formyl radical] amino] alkylsulfonyl] phenmethyl] glycyl-4-cyano-tetrahydrothiazole
(S)-and 1-[[4-[[-4 methyl-(hexamethylene amino) formyl radical] amino-sulfonyl]-phenmethyl] amino]-ethanoyl]-2-cyano group-tetramethyleneimine
(R)-and 1-[[4-[[-4 methyl-(hexamethylene amino) formyl radical] amino-sulfonyl]-phenmethyl amino]-ethanoyl]-4-cyano group-thiazolidine
(S)-and 1-[[4-[[(hexamethylene amino) formyl radical] amino-sulfonyl]-phenylethyl amino]-ethanoyl]-2-cyano group-tetramethyleneimine
(R)-and 1-[[4-[[(hexamethylene amino) formyl radical] amino-sulfonyl]-phenylethyl amino]-ethanoyl]-4-cyano group-thiazolidine
(S)-and 1-[[4-[[-4 methyl-(hexamethylene amino) formyl radical] amino-sulfonyl]-phenylethyl amino]-ethanoyl]-2-cyano group-tetramethyleneimine
(R)-and 1-[[4-[[-4 methyl-(hexamethylene amino) formyl radical] amino-sulfonyl]-phenylethyl amino]-ethanoyl]-4-cyano group-thiazolidine
(S)-and 1-[[4-[[(hexamethylene amino) formyl radical] amino-sulfonyl]-a-methyl-phenmethyl amino]-ethanoyl]-2-cyano group-tetramethyleneimine
(R)-and 1-[[4-[[(hexamethylene amino) formyl radical] amino-sulfonyl]-a-methyl-phenmethyl amino]-ethanoyl]-4-cyano group-thiazolidine
(S)-and 1-[[4-[[-4 methyl-(hexamethylene amino) formyl radical] amino-sulfonyl]-a-methyl-phenmethyl amino]-ethanoyl]-2-cyano group-tetramethyleneimine
(R)-and 1-[[4-[[-4 methyl-(hexamethylene amino) formyl radical] amino-sulfonyl]-a-methyl-phenmethyl amino]-ethanoyl]-4-cyano group-thiazolidine
(S)-and 1-[[4-[[-4 methyl-(hexamethylene amino) formyl radical] amino-sulfonyl]-α-ethyl-phenmethyl amino]-ethanoyl]-2-cyano group-tetramethyleneimine
(R)-and 1-[[4-[[(hexamethylene amino) formyl radical] amino-sulfonyl]-α-ethyl-phenmethyl amino]-ethanoyl]-4-cyano group-thiazolidine
(S)-and 1-[[4-[[-4 methyl-(hexamethylene amino) formyl radical] amino-sulfonyl]-a-ethyl-phenmethyl amino]-ethanoyl]-2-cyano group-tetramethyleneimine
(R)-and 1-[[4-[[-4 methyl-(hexamethylene amino) formyl radical] amino-sulfonyl]-a-ethyl-phenmethyl amino]-ethanoyl]-4-cyano group-thiazolidine
(R)-and 1-[[4-[[(hexamethylene amino) formyl radical] amino-sulfonyl]-a-cyclohexyl-phenmethyl amino]-ethanoyl]-4-cyano group-thiazolidine
(R)-and 1-[[4-[[4 methyl-(hexamethylene amino) formyl radical] amino-sulfonyl]-a-cyclohexyl-phenmethyl amino]-ethanoyl]-4-cyano group-thiazolidine
(S)-and 1-[[4-[[(hexamethylene amino) formyl radical] amino-sulfonyl]-a-cyclohexyl-phenmethyl amino]-ethanoyl]-2-cyano group-tetramethyleneimine
(S)-and 1-[[4-[[4 methyl-(hexamethylene amino) formyl radical] amino-sulfonyl]-a-cyclohexyl-phenmethyl amino]-ethanoyl]-2-cyano group-tetramethyleneimine
(S)-and 1-[[4-[4-[(2,4-thiazolidinedione-5-yl) methyl] phenoxy group] piperidines-1-yl]-ethanoyl]-2-cyano group-tetramethyleneimine
(R)-and 1-[[4-[4-[(2,4-thiazolidinedione-5-yl) methyl] phenoxy group] piperidines-1-yl]-ethanoyl]-4-cyano group-thiazolidine
(R)-and 1-[[4-[4-[(2,4-thiazolidinedione-5-yl) methyl] phenoxy group] hexamethylene amino]-ethanoyl]-4-cyano group-thiazolidine
(S)-and 1-[[4-[4-[(2,4-thiazolidinedione-5-yl) methyl] phenoxy group] hexamethylene amino]-ethanoyl]-2-cyano group-tetramethyleneimine
(S)-and 1-[[2-[4-[(2,4-thiazolidinedione-5-yl) methyl] phenoxy group] ethylamino]-ethanoyl]-2-cyano group-tetramethyleneimine
(S)-and 1-[[2-[4-[(2,4-thiazolidinedione-5-yl) methyl] phenoxy group]-2-methylethyl amino]-ethanoyl]-2-cyano group-tetramethyleneimine
(R)-and 1-[[2-[4-[(2,4-thiazolidinedione-5-yl) methyl] phenoxy group] ethylamino]-ethanoyl]-4-cyano group-thiazolidine
(R)-and 1-[[2-[4-[(2,4-thiazolidinedione-5-yl) methyl] phenoxy group]-2-methylethyl amino]-ethanoyl]-4-cyano group-thiazolidine
(S)-and 1-[[4-[4-[(2,4-thiazolidinedione-5-yl) methylene radical] phenoxy group] piperidines-1-yl]-ethanoyl]-2-cyano group-tetramethyleneimine
(R)-and N-[[4-[4-[(2,4-thiazolidinedione-5-yl) methylene radical] phenoxy group] piperidines-1-yl]-ethanoyl]-4-cyano group-thiazolidine
(S)-and 1-[N-carboxymethyl-N-[4-[(2-phenyl-1,3-oxazole-4-yl) oxyethyl group] phenyl methyl] amino]-ethanoyl]-2-cyano group-tetramethyleneimine
(R)-and 1-[N-carboxymethyl-N-[4-[(2-phenyl-1,3-oxazole-4-yl) oxyethyl group] phenyl methyl] amino]-ethanoyl]-4-cyano group-thiazolidine
(S)-and 1-[[4-[(2-phenyl-1,3-oxazole-4-yl) oxyethyl group] phenyl methyl] amino]-ethanoyl]-2-cyano group-tetramethyleneimine
(S)-1-[N-[(2-cyano group-tetramethyleneimine-1-yl)-the formyl methyl]-N-[4-[(2-phenyl-1,3-oxazole-4-yl) oxyethyl group] phenyl methyl] amino]-ethanoyl]-2-cyano group-tetramethyleneimine
(R)-and 1-[[4-[(2-phenyl-1,3-oxazole-4-yl) oxyethyl group] phenyl methyl] amino]-ethanoyl]-4-cyano group-thiazolidine
(R)-1-[N-[(4-cyano group-thiazolidine-1-yl)-the formyl methyl]-N-[4-[(2-phenyl-1,3-oxazole-4-yl) oxyethyl group] phenyl methyl] amino]-ethanoyl]-4-cyano group-thiazolidine
(S)-and 1-[N-carboxymethyl-N-[4-[(2-phenyl-5-methyl isophthalic acid, 3-oxazole-4-yl) oxyethyl group] phenyl methyl] amino]-ethanoyl]-2-cyano group-tetramethyleneimine
(R)-and 1-[N-carboxymethyl-N-[4-[(2-phenyl-5-methyl isophthalic acid, 3-oxazole-4-yl) oxyethyl group] phenyl methyl] amino]-ethanoyl]-4-cyano group-thiazolidine
(S)-and 1-[[4-[(2-phenyl-5-methyl isophthalic acid, 3-oxazole-4-yl) oxyethyl group] phenyl methyl] amino]-ethanoyl]-2-cyano group-tetramethyleneimine
(R)-and 1-[[4-[(2-phenyl-5-methyl isophthalic acid, 3-oxazole-4-yl) oxyethyl group] phenyl methyl] amino]-ethanoyl]-4-cyano group-thiazolidine.
6, the salt of Cyanopyrolidine as claimed in claim 1 and cyano-tetrahydrothiazole derivates, feature are the sour salifies of this derivative and any pharmacy meaning.
CNA2008101237362A 2008-06-02 2008-06-02 Cyano-pyrrolidine and cyano-tetrahydrothiazole derivates Pending CN101284810A (en)

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