CN103601674B - A kind of suppress dipeptides kininase compound and preparation method and purposes - Google Patents

A kind of suppress dipeptides kininase compound and preparation method and purposes Download PDF

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CN103601674B
CN103601674B CN201310301406.9A CN201310301406A CN103601674B CN 103601674 B CN103601674 B CN 103601674B CN 201310301406 A CN201310301406 A CN 201310301406A CN 103601674 B CN103601674 B CN 103601674B
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methyl
pyridin
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CN103601674A (en
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陈建忠
蒋超意
吴昊姝
何俏军
杨波
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Zhejiang University ZJU
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Abstract

The invention provides compound and pharmacy acceptable salt thereof that a class suppresses dipeptides kininase, reacted by Vilsmeier, Williamson reaction and reductive amination process obtain.Show through preliminary pharmacological evaluation, compound of the present invention has stronger restraining effect to DPP-IV, and has obvious blood sugar reducing function to normal rat, and does not have liver toxicity, can treat the application in type ii diabetes medicine in preparation.The present invention is reasonable in design, and preparation method's synthetic route is brief, and cheaper starting materials is easy to get, and is suitable for practicality.General structure is as follows:

Description

A kind of suppress dipeptides kininase compound and preparation method and purposes
Technical field
This case is the divisional application of application number 201210008855.X.The invention belongs to medical art, relate to a kind of compound and the pharmacy acceptable salt thereof that suppress dipeptides kininase (DPP-IV), also relate to the preparation method of this compounds, and the application of this compounds in preparation treatment type ii diabetes medicine.
Background technology
Diabetes are metabolic diseases of a kind of multi-pathogenesis, are the organism metabolic disorders because the absolute of Regular Insulin or relative deficiency cause blood sugar increasing and cause.Diabetes have a strong impact on human health and with multiple complications.Diabetes mainly can be divided into two kinds: insulin-dependent diabetes mellitus (type i diabetes) and non insulin dependent diabetes (type ii diabetes).Wherein type ii diabetes is the most common, accounts for more than 90% of diabetic.The complication of diabetes comprises hyperlipidemia, hypertension, retinal diseases and renal insufficiency.Mostly the research of current Remedies for diabetes is to launch for type ii diabetes.Traditional ofhypoglycemic medicine is of a great variety, mainly contains three major types: euglycemic agent, comprises biguanides (as N1,N1-Dimethylbiguanide) and thiazolidinediones (as pioglitazone); Insulin secretagogues, comprises sulfonylurea (as than lattice row piperazine); And alpha-glucosidase inhibitor (as acarbose) etc.But these medicines are all with side effects such as such as blood sugar reduction, body weight increases.Therefore, clinically in the urgent need to the ofhypoglycemic medicine of development of new.
Dipeptides kininase-IV(DPP-IV) shortage can maintain activity and the high insulin levels of glucagon-like peptide 1 (GLP-1), consequently reduce glucose level, therefore this may be just the novel targets for the treatment of diabetes.DPP-IV is a kind of glycoprotein be distributed widely in body, and its function class is similar to serine protease, by making its inactivation to the shearing of polypeptide, thus reaches the effect of regulation of physiological functions.GLP-1 plays an important role in carbohydrate metabolism, and such as, (1) GLP-1 strengthens the secretion of Regular Insulin; (2), expression of insulin secretes necessary gene; (3) differentiation of inducing islet beta cell is stimulated; (4) secretion of glucagon suppression; (5) Alimentary secretion and wriggling is suppressed; (6) depress appetite.Therefore, GLP-1 constrains the absorption of food, is delayed the absorption and digestion process of food, improves blood sugar and utilizes.Therefore, the treatment plan based on GLP-1 can control blood sugar effectively, but GLP-1 is as the substrate of DPP-IV, and the transformation period is very short, is just cut off inactivation rapidly by DPP-IV after secretion in 1-2min.Therefore, use DPP-IV inhibitor can be maintained the activity of GLP-1 by the inactivation blocking GLP-1, thus can treat and prevent the various disease relevant with carbohydrate metabolism, particularly non insulin dependent diabetes (type ii diabetes) (E. Matteucci, O. Giampietro, Curr. Med. Chem., 2009,16,2943).
The DPP-IV inhibitor of the treatment type ii diabetes of current listing comprises Sitagliptin, Saxagliptin, Linagliptin, Alogliptin, Vildagliptin.These compounds have good security and tolerance, also do not find that the patient used has body weight to increase or potential to lose weight and the symptom (G. R. Lankas, et al., Diabetes, 2005,54,2988) such as oedema at present.Although but highly active DPP-IV inhibitor is a lot, be still difficult to solve to the problem such as selectivity, specificity of DPP-IV.Therefore, the DPP-IV being badly in need of the how better renewal of exploitation suppresses medicine to meet the needs (S. H. Havale, M. Pal, Bioorg. Med. Chem., 2009,17,1783) of clinical application.
Summary of the invention
First object of the present invention provides a kind of compound and the pharmacy acceptable salt thereof that suppress dipeptides kininase, its general structure following (V):
V
Wherein:
X represents carbon or nitrogen-atoms; Y represents oxygen or nitrogen-atoms
A represents hydrogen atom, or is replaced by 1-4 R or unsubstituted phenyl ring or fragrant heterocycle;
R represents hydrogen atom, halogen atom, carboxyl, and amino, cyano group, by the substituted or unsubstituted low alkyl group of one or more halogen atom or lower alkoxy, containing straight or branched alkyl or the alkoxyl group of 1 to 3 carbon atom;
R 1represent without replacing, monosubstituted, two to replace or trisubstituted aromatic rings, the substituting group on ring can be hydrogen atom, halogen atom, amino, containing the alkyl of the straight or branched of 1 to 3 carbon atom or alkoxyl group;
R 2represent the condensed ring of the naphthenic hydrocarbon of 4 to 7 carbon, aromatic ring, fragrant heterocycle or 4-10 carbon, wherein aromatic ring, fragrant heterocycle, condensed ring can be without replacement, monosubstituted, dibasic aromatic ring, fragrant heterocycle, the substituting group on ring can be hydrogen atom, halogen atom, hydroxyl, carboxyl, amino, containing the alkyl of the straight or branched of 1 to 3 carbon atom or alkoxyl group.
Another object of the present invention is to provide and a kind ofly suppresses the compound of dipeptides kininase and the preparation method of pharmacy acceptable salt thereof, is realized by following concrete steps:
(1) compound of the compound of formula I and the compou nd synthesis formula III of formula II;
Formula I can be carried out Williamson in the basic conditions and be reacted to obtain formula III compound with formula II compound, reactions steps is generally carried out in polar solvent is as dimethyl formamide (DMF), N,N-DIMETHYLACETAMIDE (DMA), dimethyl sulfoxide (DMSO), conventional alkaline matter has salt of wormwood, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride KH etc., conventional catalyzer has the mantoquitas such as cuprous iodide, cuprous bromide, cuprous chloride, temperature of reaction is generally at 80-120 DEG C, and the product obtained can column chromatography purification.
(2) compound of the compound of formula III and the compounds accepted way of doing sth V of formula IV;
formula III compound can carry out reductive amination process with formula IV compound under neutral or basic conditions and obtain formula V compound, reactions steps is generally carried out in protic solvent is as methyl alcohol, ethanol, methyl alcohol ~ water, ethanol ~ water, reduction reagent used comprises various boron hydrogen sodium salt, such as sodium borohydride, sodium cyanoborohydride etc., temperature of reaction is room temperature, and the product obtained is by column chromatography method purifying.
(3) compound of formula V is dissolved in methyl alcohol, adds appropriate acid such as hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, oxalic acid etc., is spin-dried for solvent, obtains the pharmacy acceptable salt of formula V compound.
Wherein A, X, R, R 1, R 2definition identical with front; Hal is selected from chlorine or bromine.
The compound of formula I can reference method (Gangadasu, B. tetrahedron, 2002,62,8398-8403; Bhuyan, P. J. synlett, 2006,2593 – 2596.) to be obtained by reacting by Vilsmeier or to buy commercial compound, formula II and formula IV is commercial compound.
Another object of the present invention is to provide compound and the application of pharmacy acceptable salt in preparation treatment type ii diabetes medicine thereof of described suppression dipeptides kininase.Pharmacological evaluation finds: described compound and pharmacy acceptable salt thereof have good restraining effect to DPP-IV, IC 50value between 0.014 ~ 10.019 μM, and has obvious blood sugar reducing function to diabetic model rats.This compounds of these data declarations has the value of better research and development.
Feature of the present invention: using the activated DPP-IV inhibitor of tool as research object, utilize various medicinal design and synthetic method, obtains the compound with DPP-IV inhibit activities that a class formation is brand-new, and synthetic route is brief, and cheaper starting materials is easy to get, and is suitable for practicality.Preliminary pharmacological activity screening experiment shows that these compounds all have stronger DPP-IV inhibit activities, and has obvious blood sugar reducing function to normal rat, has good DEVELOPMENT PROSPECT.
Embodiment
The present invention is further described in conjunction with the embodiments, instead of limits the present invention by any way.
The bromo-2-of embodiment 1,5-chloro-3-formaldehyde pyridine 2a
With the chloro-3-pyridine carboxylic acid of the bromo-2-of 5-for raw material (32.9g, 0.151mol) be dissolved in 167ml phosphorus trichloride, add the DMF of 10.5ml, reflux 4h, reaction terminates, be cooled to room temperature, the thionyl chloride that reclaim under reduced pressure is unnecessary, under ice-water bath, drip the sodium cyanoborohydride aqueous solution (31.42g, 0.5mol), stirred overnight at room temperature, after reaction terminates, is extracted with ethyl acetate, saturated sodium-chloride washs, anhydrous sodium sulfate drying, decompression and solvent recovery, the intermediate obtained does not carry out purifying and continues to drop into next step reaction.The intermediate 1a(2.01g, the 9.02mmol that obtained) be dissolved in 20ml anhydrous methylene chloride, add PCC(2.35g, 10.8mmol), stirring at room temperature 24h, reaction terminates decompression and solvent recovery, washing, extraction into ethyl acetate, saturated sodium-chloride washs, anhydrous sodium sulfate drying, and decompression and solvent recovery eluent (sherwood oil: methylene dichloride=20:1) carries out column chromatography, obtain white solid 2a 1.65 g, yield: 83%; Fusing point: 112-113 DEG C
1H NMR(δ, CDCl 3): 9.73(s, 1H), 7.84(d, 1H, J = 2.5 Hz), 8.04(d, 1H, J = 2.5 Hz)。
Embodiment 2,5-methyl-2-chloro-3-formaldehyde pyridine 4a
Benzylamine is that raw material (5g, 46mmol) adds in the flask of 50ml, slowly drips propionic aldehyde (2.71g, 46mmol) at 0 DEG C, dropping process maintains 1h, after dropwising, adds LiOH(960mg, 23mmol), continue to stir, until there is obvious demixing phenomenon, get organic layer stand-by.Get above-mentioned organic layer (6g, 40mmol) and put into reaction flask, add acetic anhydride (4.08g, 40mmol) and triethylamine (4.12g, 40mmol) at 0-5 DEG C, stirred overnight at room temperature, obtain intermediate 3a, productive rate 88%.By DMF(13.5g at 0 DEG C, 185mmol) add triphosgene (54.7g, 185mmol), stir 30min, add intermediate 3a(5g, the 26mmol of above-mentioned gained), after adding, remove ice-water bath, at room temperature stir 2h, be heated to 70 DEG C of reaction 4h, after reaction terminates, poured into by mixture in frozen water, dichloromethane extraction, saturated sodium-chloride washs, anhydrous sodium sulfate drying, decompression and solvent recovery eluent (sherwood oil: methylene dichloride=20:1) carries out column chromatography, obtains white solid 4a, yield: 64%; Fusing point: 42-45 DEG C.
1H NMR(δ, CDCl 3): 9.73(s, 1H), 8.04(d, 1H, J = 2.5 Hz), 8.24(d, 1H, J = 2.5 Hz), 2.31(s, 1H)。
Embodiment 3,2-chloro-6-methyl-3-quinolin formaldehyde 5a
Drip phosphorus trichloride (13ml, 98.28mmol) at 0-5 DEG C to DMF(2.7ml, 34.65mmol are housed) reaction flask in, stir 30min, add the first and second anilides (1.54g, 10.37mmol), be warming up to 85 DEG C and stir 8h, after reaction terminates, mixture is poured in frozen water, separate out light yellow solid, filter, washing, vacuum-drying, obtain light yellow solid 5a 1.62g, yield: 80%; Fusing point: 124-125 DEG C.
Embodiment 4,3-chloro-quinoxaline-2-formaldehyde 6a
Operating process, with example 1, just replaces the chloro-3-pyridine carboxylic acid of the bromo-2-of 5-with to 3-chloro-quinoxaline-2-formic acid, obtains faint yellow solid compound 6a, yield: 38%; Fusing point: 63-65 DEG C.
Chloro-1, the 8-naphthyridine-3-formaldehyde 7a of embodiment 5,2-
Operating process, with example 1, just replaces the chloro-3-pyridine carboxylic acid of the bromo-2-of 5-with chloro-1, the 8-naphthyridine-3-carboxylic acid of 2-, obtains faint yellow solid compound 7a, yield: 24%; Fusing point: 143-144 DEG C.
Embodiment 6,2,6-dichloroquinoline-3-formaldehyde 8a
Operating process, with example 1, just replaces the chloro-3-pyridine carboxylic acid of the bromo-2-of 5-with 2,6-dichloroquinoline-3-carboxylic acid, obtains faint yellow solid compound 8a, yield: 65%; Fusing point: 146-148 DEG C.
Chloro-6, the 7-dimethoxy-quinoline-3-formaldehyde 9a of embodiment 7,2-
Operating process, with example 1, just replaces the chloro-3-pyridine carboxylic acid of the bromo-2-of 5-with chloro-6, the 7-dimethoxy-quinoline-3-carboxylic acids of 2-, obtains faint yellow solid compound 9a, yield: 76%; Fusing point: 175-176 DEG C.
Embodiment 8,6-chlorothiophene be [2,3-b] pyridine-5-formaldehyde 10a also
Operating process, with example 1, just with the 6-chlorothiophene also chloro-3-pyridine carboxylic acid of [2,3-b] pyridine-5-carboxylic acid replacement bromo-2-of 5-, obtains faint yellow solid compound 10a, yield: 77%; Fusing point: 157-158 DEG C.
The chloro-6-methylpyrazine of embodiment 9,3--2-formaldehyde 11a
Operating process, with example 1, just replaces the chloro-3-pyridine carboxylic acid of the bromo-2-of 5-with 3-chloro-6-methylpyrazine-2-carboxylic acid, obtains faint yellow solid compound 11a, yield: 45%; Fusing point: 123-124 DEG C.
The chloro-7-of embodiment 10,3-(trifluoromethyl) quinoxaline-2-formaldehyde 12a
Operating process, with example 1, just replaces the chloro-3-pyridine carboxylic acid of the bromo-2-of 5-with the chloro-7-of 3-(trifluoromethyl) quinoxalin-2-carboxylic acid, obtains faint yellow solid compound 12a, yield: 51%; Fusing point: 156-157 DEG C.
Embodiment 11,2-(4-chlorophenoxy) pyridine-3-aldehyde 1b
Chloro-for compound 2-3 pyridylaldehydes (141mg, 1mmol) are dissolved in 5ml DMF, add successively
Potassiumphosphate (424mg, 4mmol), cuprous iodide (19mg, 0.1mmol), para-chlorophenol (121mg, 1mmol), put into the ultrasound reactor of ultrasonic power 600W, reaction 8min, after reaction terminates, washing, is extracted with ethyl acetate, and saturated sodium-chloride washs, anhydrous sodium sulfate drying, decompression and solvent recovery, obtains yellowish crude product 1b, yield: 84%; Fusing point: 93-94 DEG C.
Embodiment 12,2-(2,4 dichloro benzene oxygen base) pyridine-3-aldehyde 2b
Operating process, with example 11, just replaces para-chlorophenol with 2,4 dichloro phenol, obtains yellow solid compound 2b, yield: 79%; Fusing point: 114-115 DEG C.
Embodiment 13,2-(4-methylphenoxy) pyridine-3-aldehyde 3b
Operating process, with example 11, just replaces para-chlorophenol with 4-methylphenol, obtains yellow solid compound 3b, yield: 86%; Fusing point: 126-127 DEG C.
Embodiment 14,2-(2-cyano-benzene oxygen) pyridine-3-aldehyde 4b
Operating process, with example 11, just replaces para-chlorophenol with 2-cyanophenol, obtains yellow solid compound 4b, yield: 76%; Fusing point: 154-156 DEG C.
Embodiment 15,2-(4-methoxyphenoxy) pyridine-3-aldehyde 5b
Operating process, with example 11, just replaces para-chlorophenol with 4-methoxyphenol, obtains yellow solid compound 5b, yield: 84%; Fusing point: 136-137 DEG C.
The bromo-2-of embodiment 16,5-(4-methoxyphenoxy)-3-formaldehyde pyridine 6b
Operating process, with example 11, just replaces chloro-3 pyridylaldehydes of 2-with compound 2a, replaces para-chlorophenol, obtain yellow solid compound 6b, yield: 67% with 4-methoxyphenol; Fusing point: 123-124 DEG C.
Embodiment 17,5-methyl-2-(4-chlorophenoxy)-3-formaldehyde pyridine 7b
Operating process, with example 11, just replaces chloro-3 pyridylaldehydes of 2-with compound 4a, obtains yellow solid compound 7b, yield: 73%; Fusing point: 154-155 DEG C.
Embodiment 18,3-(4-chlorophenoxy)-6-methylpyrazine-2-formaldehyde 8b
Operating process, with example 11, just replaces chloro-3 pyridylaldehydes of 2-with compound 11a, obtains yellow solid compound 8b, yield: 66%; Fusing point: 210-211 DEG C.
Embodiment 19,2-(4-chlorphenylamino) Nicotine aldehyde 9b
Operating process, with example 11, replaces para-chlorophenol with 4-chloroaniline, obtains yellow solid compound 9b, yield: 66%; Fusing point: 154-155 DEG C.
Embodiment 20,3-(3,4-dichlorophenyl is amino) pyrazine-2-formaldehyde 10b
Operating process, with example 11, replaces chloro-3 pyridylaldehydes of 2-with compound 3-chlorin pyrazine-2-formaldehyde, replaces para-chlorophenol, obtain yellow solid compound 10b, yield: 33% with 3,4-DCA; Fusing point: 171-172 DEG C.
Embodiment 21,6-methyl-2-(4-chlorophenoxy)-3-formaldehyde quinoline 11b
Operating process, with example 11, just replaces chloro-3 pyridylaldehydes of 2-with compound 5a, obtains yellow solid compound 11b, yield: 78%; Fusing point: 134-135 DEG C.
Embodiment 22,2-(4-methoxyphenoxy)-6-(trifluoromethyl) quinoline-3-formaldehyde 12b
Operating process, with example 11, just replaces chloro-3 pyridylaldehydes of 2-with compound 12a, replaces para-chlorophenol, obtain yellow solid compound 12b, yield: 43% with 4-methoxyphenol; Fusing point: 123-124 DEG C.
Embodiment 23,2-(p-tolyloxy)-1,8-naphthyridine-3-formaldehyde 13b
Operating process, with example 11, just replaces chloro-3 pyridylaldehydes of 2-with compound 7a, replaces para-chlorophenol, obtain yellow solid compound 13b, yield: 36% with 4-methylphenol; Fusing point: 144-145 DEG C.
Embodiment 24,2-(3,4-dimethyl phenoxy)-6,7-dimethoxy-quinoline-3-formaldehyde 14b
Operating process, with example 11, just replaces chloro-3 pyridylaldehydes of 2-with compound 9a, replaces para-chlorophenol, obtain yellow solid compound 14b, yield: 77% with 3,4-xylenol; Fusing point: 146-147 DEG C.
Embodiment 25,6-(3,4-dichlorophenyl is amino) thieno-[2,3-b] pyridine-5-formaldehyde 15b
Operating process, with example 11, just replaces chloro-3 pyridylaldehydes of 2-with compound 10a, replaces para-chlorophenol, obtain yellow solid compound 15b, yield: 41% with 3,4-DCA; Fusing point: 165-166 DEG C.
Embodiment 26,1-(2-(4-chlorophenoxy) pyridin-3-yl)-N-(pyridin-3-yl methyl) methylamine 1c
By compound 1b(23mg, 0.1mmol) be dissolved in 5ml methyl alcohol, add 3-aminomethyl-pyridine (45ul, 0.4mmol), at 70 DEG C, stir 2h, be cooled to room temperature, add sodium borohydride (15mg, 0.4mmol), stirred at ambient temperature 2h, after reaction terminates, decompression and solvent recovery, washing, extraction into ethyl acetate, saturated sodium-chloride washs, anhydrous sodium sulfate drying, decompression and solvent recovery, carries out column chromatography with eluent (sherwood oil: ethyl acetate: triethylamine=5:1:0.1), obtain colourless transparent liquid 1c, yield: 72%.
1H NMR(δ, CDCl 3): 8.59(s, 1H), 8.50(d, 1H, J = 4.5Hz), 8.04(d, 1H, J = 4.5Hz), 7.70(m, 2H), 7.33(d, 2H, J = 8.5Hz), 7.24(m, 1H), 7.04(d, 2H, J = 8.5Hz), 6.99(m, 1H), 3.91(s, 2H), 3.86(s, 2H)。
Embodiment 27, N-((2-(4-chlorophenoxy) pyridin-3-yl) methyl) cyclopentamine 2c
Operating process, with example 26, just replaces 3-aminomethyl-pyridine by cyclopentamine, obtains colourless transparent liquid 2c, yield: 82%.
1H NMR(δ, CDCl 3): 8.02(d, 1H, J = 5Hz), 7.70(d, 1H, J= 7Hz), 7.34(d, 2H, J= 8.5Hz), 7.05 (d, 2H, J = 8.5Hz), 6.98(m, 1H), 3.88 (s, 2H), 3.10(m, 1H), 1.83(m, 2H), 1.67(m, 2H), 1.50(m, 2H), 1.36(m, 2H)。
Embodiment 28,1-(benzo [d] [1,3] bis-oxazole-5-bases)-N-((2-(4-chlorophenoxy) pyridin-3-yl) methyl) methylamine 3c
Operating process, with example 26, just replaces 3-aminomethyl-pyridine with piperonyl amine, obtains colourless transparent liquid 3c, yield: 64%.
1H NMR(δ, CDCl 3): 8.04(d, 1H, J = 5Hz), 7.73(d, 1H, J= 7Hz), 7.34(d, 2H, J= 9.0Hz), 7.05(d, 2H, J = 8.5Hz), 6.99(m, 1H), 6.88(s, 1H), 6.75(m, 2H), 5.94(d, 2H), 3.90(s, 2H), 3.76(s, 2H)。
Embodiment 29,1-(2-(2,4 dichloro benzene oxygen base) pyridin-3-yl)-N-(4-benzyl) methylamine 4c
Operating process, with example 26, just replaces 1b with compound 2b, replaces 3-aminomethyl-pyridine to obtain colourless transparent liquid 4c, yield: 58% with 4-flunamine.
1H NMR(δ, CDCl 3): 7.99(d, 1H, J = 5Hz), 7.70(d, 1H, J = 7.5Hz), 7.46(d, 1H, J= 2.5Hz), 7.28(m, 3H), 7.17(d, 1H, J= 8.5Hz), 7.00(m, 3H), 3.95(s, 2H), 3.81(s, 2H)。
Embodiment 30,1-(furans-2-base)-N-((2-(p-tolyloxy) pyridin-3-yl) methyl) methylamine 5c
Operating process, with example 26, just replaces 1b with compound 3b, replaces 3-aminomethyl-pyridine to obtain colourless transparent liquid 5c, yield: 87% with chaff amine.
1H NMR(δ, CDCl 3): 8.04(d, 1H, J = 5Hz), 7.68(d, 1H, J = 7.5Hz), 7.36(s, 1H), 7.19(d, 2H, J = 8Hz), 7.00(d, 2H, J = 8.5Hz), 6.94(m, 1H), 6.31(m, 1H), 6.20(d, 1H, J = 3Hz), 3.93(s, 2H), 3.84(s, 2H), 2.36(s, 3H)。
Embodiment 31,2-(3-((4-hydroxyphenylmethyl is amino) methyl) pyridine-2-oxygen base) cyanobenzene 6c
Operating process, with example 26, just replaces 1b with compound 4b, replaces 3-aminomethyl-pyridine to obtain colourless transparent liquid 6c, yield: 58% with 4-hydroxy benzylamine.
1H NMR(δ, CDCl 3): 8.04(d, 1H, J = 5Hz), 7.73(d, 1H, J= 7.5Hz), 7.65(d, 1H, J= 8.0Hz), 7.58(d, 1H, J = 8H), 7.25(m, 2H), 7.11(d, 2H, J = 8.5Hz), 7.01(m, 1H), 6.62(d, 2H, J = 8.5Hz), 3.98(s, 2H), 3.76(s, 2H)。
Embodiment 32, N-(3,4-dimethyl benzyl)-1-(2-(4-methoxyphenoxy) pyridin-3-yl) methylamine 7c
Operating process, with example 26, just replaces 1b with compound 5b, replaces 3-aminomethyl-pyridine, obtain colourless transparent liquid 7c, yield: 74% with 3,4-dimethyl benzylamine.
1H NMR(δ, CDCl 3): 8.01(d, 1H, J = 5Hz), 7.68(d, 1H, J = 7Hz ), 7.23(d, 2H, J = 8Hz), 7.34(d, 1H, J = 7.5Hz), 7.12(d, 1H, J = 8.5Hz), 7.02(s, 1H), 6.93(m, 1H), 6.90(d, 2H, J = 8Hz), 3.92(s, 2H), 3.81(s, 2H), 3.803 (s,3H), 2.33 (s, 6H)。
Embodiment 33,4-(((the bromo-2-of 5-(4-methoxyphenoxy) pyridin-3-yl) methylamino) methyl) phenylformic acid 8c
Operating process, with example 26, just replaces 1b with compound 6b, replaces 3-aminomethyl-pyridine to obtain colourless transparent liquid 8c, yield: 61% with 4-carboxyl benzylamine.
1H NMR(δ, CDCl 3): 8.04(d, 1H, J = 2.5Hz), 7.77(d, 1H, J = 2.5Hz), 7.13(d, 2H, J= 8.5Hz), 7.00(d, 2H, J = 8.5Hz), 6.90 (d, 2H, J = 8.5Hz), 6.67(d, 2H, J = 8.5Hz), 3.90(s, 2H), 3.79(s, 3H), 3.76(s, 2H)。
Embodiment 34,4-(((2-(4-chlorophenoxy)-5-picoline-3-base) methylamino) methyl) aniline 9c
Operating process, with example 26, just replaces 1b with compound 7b, replaces 3-aminomethyl-pyridine to obtain light yellow transparent liquid 9c, yield: 57% with 4-amino-benzylamine.
1H NMR(δ, CDCl 3): 8.04(d, 1H, J = 2.5Hz), 7.81(d, 1H, J = 2.5Hz ), 7.16(t, 4H, J = 7.5Hz, 8Hz), 6.96(d, 2H, J = 9Hz), 6.72(d, 2H, J = 9Hz), 3.90(s, 2H), 3.77(s, 2H), 2.35(s, 3H)。
Embodiment 35,1-(3-(4-chlorophenoxy)-6-methylpyrazine-2-base)-N-(4-methylbenzyl) methylamine 10c
Operating process, with example 26, just replaces 1b with compound 8b, replaces 3-aminomethyl-pyridine to obtain colourless transparent liquid 10c, yield: 72% with 4-methylbenzylamine.
1H NMR(δ, CDCl 3): 8.04(s, 1H), 7.24(d, 2H, J = 7.5Hz ), 7.16(d, 2H, J = 7.5Hz), 6.96(d, 2H, J = 9Hz), 6.72(d, 2H, J = 9Hz), 3.90(s, 2H), 3.77(s, 2H), 2.35(s, 6H)。
Embodiment 36, N-(4-chloro-phenyl-)-3-((4-methylbenzyl is amino) methyl) pyridine-2-amine 11c
Operating process, with example 26, just replaces 1b with compound 9b, replaces 3-aminomethyl-pyridine to obtain colourless transparent liquid 11c, yield: 43% with 4-methylbenzylamine.
1H NMR(δ, CDCl 3): 8.04(d, 1H, J = 5Hz), 7.69(d, 1H, J = 7Hz ), 7.32(d, 2H, J = 9Hz), 7.10(d, 2H, J = 9Hz), 7.02(d, 2H, J = 9H), 6.97(m, 1H), 6.62(d, 2H, J = 9Hz), 3.93(s, 2H), 3.75(s, 2H), 2.36(s, 3H)。
Embodiment 37, N-(3,4-dichlorophenyl)-3-((4-fluorobenzylamino) methyl) pyrazine-2-amine 12c
Operating process, with example 26, just replaces 1b with compound 10b, replaces 3-aminomethyl-pyridine to obtain colourless transparent liquid 12c, yield: 54% with 4-flunamine.
1H NMR(δ, CDCl 3): 8.06(d, 1H, J = 2.5Hz), 7.83(d, 1H, J = 2.5Hz), 7.46(d, 2H, J = 8.5Hz), 7.31(d, 1H, J= 8Hz), 7.26 (s, 1H), 7.19(d, 1H, J = 8Hz), 7.00(d, 2H, J = 8.5Hz), 3.91(s, 2H), 3.87(s, 2H)。
Embodiment 38,1-(2-(4-chlorophenoxy) quinoline-3-base)-N-(4-methylbenzyl) methylamine 13c
Operating process, with example 26, just replaces 1b with compound 11b, replaces 3-aminomethyl-pyridine to obtain colourless transparent liquid 13c, yield: 67% with 4-methylbenzylamine.
1H NMR(δ, CDCl 3): 8.03(s, 1H, J = 2.5Hz), 7.60(d, 1H, J = 8.5Hz), 7.51(s, 1H), 7.38(d, 1H, J = 8.5Hz), 7.35(d, 2H, J =9Hz), 7.25(d, 2H, J =7.5Hz), 7.16(d, 2H, J = 7.5Hz), 7.13(d, 2H, J = 7.5Hz), 4.02(s, 2H), 3.84(s, 2H), 2.35(s, 6H)。
Embodiment 39, N-(4-benzyl)-1-(3-(4-methoxyphenoxy)-7-(trifluoromethyl) quinoxaline-2-base) methylamine 14c
Operating process, with example 26, just replaces 1b with compound 12b, replaces 3-aminomethyl-pyridine, obtain colourless transparent liquid 14c, yield: 42% with 4-flunamine.
1H NMR(δ, CDCl 3): 7.62(d, 1H, J = 8.5Hz), 7.33(m, 4H), 7.23(d, 1H, J = 8.5Hz), 7.16(d, 1H, J = 8.5Hz), 7.06(d, 2H, J= 9Hz), 7.01 (d, 2H, J = 9Hz), 4.03(s, 2H), 3.90(s, 2H), 3.86(s, 3H)。
Embodiment 40, N-((2-(p-tolyloxy)-1,8-naphthyridine-3-base) methyl) cyclopentamine 15c
Operating process, with example 26, just replaces 1b with compound 13b, replaces 3-aminomethyl-pyridine, obtain colourless transparent liquid 15c, yield: 55% by cyclopentamine.
1H NMR(δ, CDCl 3): 8.32(s, 1H), 8.02(d, 1H, J = 5Hz), 7.70(d, 1H, J= 5Hz), 7.34(d, 2H, J= 8.5Hz), 7.05 (d, 2H, J = 8.5Hz), 6.98(m, 1H), 3.88 (s, 2H), 3.10(m, 1H), 2.33(s, 3H), 1.83(m, 2H), 1.67(m, 2H), 1.50(m, 2H), 1.36(m, 2H)。
Embodiment 41, N-((6-(3,4-dichlorophenoxy) thieno-[2,3-b] pyridine-5-base) methyl) cyclopentamine 16c
Operating process, with example 26, just replaces 1b with compound 15b, replaces 3-aminomethyl-pyridine, obtain colourless transparent liquid 16c, yield: 76% by cyclopentamine.
1H NMR(δ, CDCl 3): 8.32(s, 1H), 8.02(d, 1H, J = 7.5Hz), 7.70(d, 1H, J= 7.5Hz), 7.34(s, 1H), 7.05 (d, 1H, J = 5Hz), 6.98(d, 1H, J = 5Hz), 3.88 (s, 2H), 3.10(m, 1H), 1.83(m, 2H), 1.67(m, 2H), 1.50(m, 2H), 1.36(m, 2H)。
Embodiment 42,1-(2-(3,4-dimethyl phenoxy)-6,7-dimethoxy-quinoline-3-base)-N-(pyridin-3-yl methyl) methylamine 17c
Operating process, with example 26, just replaces 1b with compound 14b, obtains yellow transparent liquid 17c, yield: 39%.
1H NMR(δ, CDCl 3): 8.61(s, 1H), 8.51(d, 1H, J= 4.5Hz), 8.02(s, 1H), 7.79(d, 1H, J= 7.5Hz), 7.36 (d, 1H, J= 7.5Hz), 7.27 (m, 1H), 7.15(d, 1H, J= 7.5Hz), 7.06 (s, 1H), 7.03 (s, 1H), 6.90 (s, 1H), 4.05(s, 2H), 3.97(s, 3H), 3.94(s, 3H), 3.92(s, 2H), 2.37 (s, 6H)。
Embodiment 43, N-(4-methylbenzyl)-1-(2-(pyridine-4-oxygen base) pyridin-3-yl) methylamine 18c
Operating process, with example 26, just replaces 1b with compound 2-(pyridine-4-oxygen base) Nicotine aldehyde, replaces 3-aminomethyl-pyridine, obtain colourless transparent liquid 18c, yield: 51% with 4-methylbenzylamine.
1H NMR(δ, CDCl 3): 8.51(d, 2H, J= 9Hz), 7.69(d, 1H, J= 7.5Hz), 7.36 (d, 1H, J= 7.5Hz), 7.15(d, 2H, J= 7.5Hz), 6.98 (m, 1H), 7.06 (d, 2H, J= 9Hz), 7.03 (d, 2H, J= 9Hz), 3.97(s, 2H), 3.92(s, 2H), 2.37 (s, 3H)。
Embodiment 44,1-(2-(4-chlorophenoxy) pyridin-3-yl)-N-(pyridin-3-yl methyl) methylamine hydrochloride 1d
By compound 1c(650mg, 2mmol) be dissolved in 5ml methyl alcohol, drip dilute hydrochloric acid 25ml under ice-water bath, stir 30min, decompression is spin-dried for solvent, obtains white solid 1d, yield 78%; Fusing point: >200 DEG C.
Embodiment 45, N-((2-(4-chlorophenoxy) pyridin-3-yl) methyl) cyclopentamine hydrochloride 2d
Compound 2c, with example 44, is just replaced 1c, obtains white solid 2d, yield 89% by operating process; Fusing point: >200 DEG C.
Embodiment 46,1-(benzo [d] [1,3] bis-oxazole-5-bases)-N-((2-(4-chlorophenoxy) pyridin-3-yl) methyl) methylamine vitriol 3d
Compound 3c, with example 44, is just replaced 1c, substitutes dilute hydrochloric acid and obtain white solid 3d, yield 77% with dilute sulphuric acid by operating process; Fusing point: >200 DEG C.
Embodiment 47,1-(2-(2,4 dichloro benzene oxygen base) pyridin-3-yl)-N-(4-benzyl) methylamine hydrochloride 4d
Compound 4c, with example 44, is just replaced 1c, obtains white solid 4d, yield 87% by operating process; Fusing point: >200 DEG C.
Embodiment 48,1-(furans-2-base)-N-((2-(p-tolyloxy) pyridin-3-yl) methyl) methylamine hydrochloride 5d
Compound 5c, with example 44, is just replaced 1c, obtains white solid 5d, yield 89% by operating process; Fusing point: >200 DEG C.
Embodiment 49,2-(3-((4-hydroxyphenylmethyl is amino) methyl) pyridine-2-oxygen base) benzonitrile hydrochloride 6d
Compound 6c, with example 44, is just replaced 1c, obtains white solid 6d, yield 72% by operating process; Fusing point: >200 DEG C.
Embodiment 50, N-(3,4-dimethyl benzyl)-1-(2-(4-methoxyphenoxy) pyridin-3-yl) acephatemet hydrochlorate 7d
Compound 7c, with example 44, is just replaced 1c by operating process, replaces dilute hydrochloric acid to obtain white solid 7d, yield 88% with phosphoric acid; Fusing point: >200 DEG C.
Embodiment 51,4-(((the bromo-2-of 5-(4-methoxyphenoxy) pyridin-3-yl) methylamino) methyl) benzoate hydrochlorate 8d
Compound 8c, with example 44, is just replaced 1c, obtains white solid 8d, yield 75% by operating process; Fusing point: >200 DEG C.
Embodiment 52,4-(((2-(4-chlorophenoxy)-5-picoline-3-base) methylamino) methyl) anilinechloride 9d
Compound 9c, with example 44, is just replaced 1c, obtains white solid 9d, yield 86% by operating process; Fusing point: >200 DEG C.
Embodiment 53,1-(3-(4-chlorophenoxy)-6-methylpyrazine-2-base)-N-(4-methylbenzyl) methylamine hydrochloride 10d
Compound 10c, with example 44, is just replaced 1c, obtains white solid 10d, yield 70% by operating process; Fusing point: >200 DEG C.
Embodiment 54, N-(4-chloro-phenyl-)-3-((4-methylbenzyl is amino) methyl) pyridine-2-amine hydrochlorate 11d
Compound 11c, with example 44, is just replaced 1c, obtains white solid 11d, yield 78% by operating process; Fusing point: >200 DEG C.
Embodiment 55, N-(3,4-dichlorophenyl)-3-((4-fluorobenzylamino) methyl) pyrazine-2-amine hydrochlorate 12d
Compound 12c, with example 44, is just replaced 1c, obtains white solid 12d, yield 69% by operating process; Fusing point: >200 DEG C.
Embodiment 56,1-(2-(4-chlorophenoxy) quinoline-3-base)-N-(4-methylbenzyl) methylamine hydrochloride 13d
Compound 13c, with example 44, is just replaced 1c, obtains white solid 13d, yield 86% by operating process; Fusing point: >200 DEG C.
Embodiment 57, N-(4-benzyl)-1-(3-(4-methoxyphenoxy)-7-(trifluoromethyl) quinoxaline-2-base) methylamine hydrochloride 14d
Compound 14c, with example 44, is just replaced 1c, obtains white solid 14d, yield 75% by operating process; Fusing point: >200 DEG C.
Embodiment 58, N-((2-(p-tolyloxy)-1,8-naphthyridine-3-base) methyl) cyclopentamine hydrochloride 15d
Compound 15c, with example 44, is just replaced 1c, obtains white solid 15d, yield 67% by operating process; Fusing point: >200 DEG C.
Embodiment 59, N-((6-(3,4-dichlorophenoxy) thieno-[2,3-b] pyridine-5-base) methyl) cyclopentamine hydrochloride 16d
Compound 16c, with example 44, is just replaced 1c, obtains white solid 16d, yield 88% by operating process; Fusing point: >200 DEG C.
Embodiment 60,1-(2-(3,4-dimethyl phenoxy)-6,7-dimethoxy-quinoline-3-base)-N-(pyridin-3-yl methyl) methylamine hydrochloride 17d
Compound 17c, with example 44, is just replaced 1c, obtains white solid 17d, yield 90% by operating process; Fusing point: >200 DEG C.
Embodiment 61, N-(4-methylbenzyl)-1-(2-(pyridine-4-oxygen base) pyridin-3-yl) methylamine hydrochloride 18d
Compound 18c, with example 44, is just replaced 1c, obtains white solid 18d, yield 74% by operating process; Fusing point: >200 DEG C.
Embodiment 62, DPP-IV inhibit activities measure:
Compound provided by the invention can use DPP-IV-Glo to the inhibiting rate of DPP-IV tMhomogeneous luminescent detection system (the DPP-IV-Glo of proteolytic ferment tMprotease Assay, Promega cat#G8350) record.This system contains the Laemmli buffer system Laemmli of the amino luciferin of DPP-IV substrate Gly-Pro-and luciferase activity detection, DPP-IV-Glo tMluciferase reaction can be activated after being cut by DPP-IV, produce " glow-type " type luminous signal, then use Turner Veritas tMmicrowell plate luminometer detects the activity that luminous signal can characterize DPP-IV.
Experimental technique: GP-PNA is released in respective damping fluid, concentration is 100 μm of ol/L, 25 μm, every hole ol; Enzyme gradient dilution, initial concentration is DPP-IV:0.01mU/ μ l, by 5 times of dilutions, every hole 25 μ l, mixing; 37 DEG C, 360/460nm measures the dynamic change of fluorescent value, measures 30 minutes; Linearly rise with absorbancy, the enzyme concn of S/N >=5 is working concentration.
Inhibitor activity measure: all enzymes, inhibitor, all with analysis buffer preparation, arrange without compound control, contrast without enzyme liquid.By the working concentration preparation enzyme liquid of enzyme, every hole 25 μ l; Gradient dilution inhibitor (10 times or 5 times of dilutions), every hole 25 μ l, mixing; Add the GP-AMC solution 50 μ l diluted, mixing; 37 DEG C are reacted 20 minutes, and 360/460nM measures fluorescent value.The inhibiting rate of the vitro inhibition DPP-IV activity of compound and the IC of compound pharmacy acceptable salt vitro inhibition DPP-IV activity 50(μM) value is in table 1.
As can be seen from the above table, 18 1) all compounds all have certain inhibit activities to DPP-IV.2) parent nucleus is the DPP-IV inhibit activities of the compound of 5 pyridines replaced or 6 quinoline replaced, and is high without the activity of the compound of the pyridine replaced than parent nucleus.3) the DPP-IV inhibit activities of the compound of clogP value between 4-5 is greater than the chemical combination object height of 5 than clogP value, such as compound 11d and compound 12d, the wherein IC of compound 11d 50value reaches 0.014 μM.
Example 63, part of compounds are tested the impact of diabetes rat oral glucose tolerance
Adopt intact animal, impaired glucose tolerance or diabetic animal models, giving test-compound, take solvent as negative control, and Xi Gelieting is positive control, carries out oral glucose tolerance test, and under glucose tolerance curve, area trapezoidal method calculates.
In pre-stage test, adopt fasting plasma glucose be less than 7 mmol/L impaired glucose tolerance animal (high lipid food feed within 4 weeks, add low dose of U-9889 again high lipid food feed 3 weeks, cause animal glucose tolerance curve apparently higher than normal control), gavage gives test-compound 11c and 12c of corresponding dosage, after 0.5h, gavage gives glucose 1g/kg, before measuring administration with fast blood glucose meter, after administration and to the blood glucose value of each time point of 20,40,60,120 min after glucose, area AUC under calculating glucose tolerance curve.Result shows, the AUC value of rat model control group than normal rat control group obviously raise ( p<0.001).2 tested materials all can obviously reduce animal pattern AUC value ( p<0.05), positive control drug Xi Gelieting also can obviously reduce animal pattern AUC value ( p<0.01).The AUC value of test-compound compare with Xi Gelieting unknown significance difference ( p>0.05).Each administration group compare with normal rat control group there was no significant difference ( p>0.05).Visible, test-compound is the same with positive drug Xi Gelieting, can improve the oral glucose tolerance of rat model, has blood sugar reducing function in obvious body.In table 3.
tinspection, compares with rat model control group, * p<0.05, * * p<0.01, * * * p<0.001.
To sum up, as can be seen from above biologically active data, this compounds has good hypoglycemic application prospect, the commercial value that thus tool is good.

Claims (6)

1. suppress the compound of dipeptides kininase and a preparation method for pharmacy acceptable salt thereof, it is characterized in that, be specifically related to the preparation of following compound:
1-(2-(4-chlorophenoxy) pyridin-3-yl)-N-(pyridin-3-yl methyl) methylamine,
N-((2-(4-chlorophenoxy) pyridin-3-yl) methyl) cyclopentamine,
1-(benzo [d] [1,3] bis-oxazole-5-bases)-N-((2-(4-chlorophenoxy) pyridin-3-yl) methyl) methylamine,
1-(2-(2,4 dichloro benzene oxygen base) pyridin-3-yl)-N-(4-benzyl) methylamine,
1-(furans-2-base)-N-((2-(p-tolyloxy) pyridin-3-yl) methyl) methylamine,
2-(3-((4-hydroxyphenylmethyl is amino) methyl) pyridine-2-oxygen base) cyanobenzene,
N-(3,4-dimethyl benzyl)-1-(2-(4-methoxyphenoxy) pyridin-3-yl) methylamine,
4-(((the bromo-2-of 5-(4-methoxyphenoxy) pyridin-3-yl) methylamino) methyl) phenylformic acid,
4-(((2-(4-chlorophenoxy)-5-picoline-3-base) methylamino) methyl) aniline,
1-(3-(4-chlorophenoxy)-6-methylpyrazine-2-base)-N-(4-methylbenzyl) methylamine,
N-(4-chloro-phenyl-)-3-((4-methylbenzyl is amino) methyl) pyridine-2-amine,
N-(3,4-dichlorophenyl)-3-((4-fluorobenzylamino) methyl) pyrazine-2-amine;
Realized by following concrete steps:
(1) formula I is carried out Williamson in the basic conditions and is reacted to obtain formula III compound with formula II compound, and react and carry out in polar solvent, temperature of reaction 80-120 DEG C, the product obtained is with column chromatography purification;
(2) formula III compound carries out reductive amination process with formula IV compound under neutral or basic conditions and obtains formula V compound, and react and carry out in protic solvent, temperature of reaction is room temperature, and the product obtained is by column chromatography method purifying;
(3) compound of formula V is dissolved in methyl alcohol, adds appropriate acid, is spin-dried for solvent, obtains the salt of formula V compound;
Wherein A, X, R, R 1, R 2definition identical with particular compound; Hal is selected from chlorine or bromine;
Reaction formula is:
。
2. according to claim 1ly a kind ofly suppress the compound of dipeptides kininase and the preparation method of pharmacy acceptable salt thereof, it is characterized in that, step (1) Semi-polarity solvent selects dimethyl formamide, N,N-DIMETHYLACETAMIDE or dimethyl sulfoxide (DMSO).
3. according to claim 1ly a kind ofly suppress the compound of dipeptides kininase and the preparation method of pharmacy acceptable salt thereof, it is characterized in that, step (1) neutral and alkali material selects salt of wormwood, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride KH; Catalyzer selects cuprous iodide, cuprous bromide or cuprous chloride.
4. according to claim 1ly a kind ofly suppress the compound of dipeptides kininase and the preparation method of pharmacy acceptable salt thereof, it is characterized in that, in step (2), protic solvent selects methyl alcohol, ethanol, methyl alcohol ~ water, ethanol ~ water.
5. according to claim 1ly a kind ofly suppress the compound of dipeptides kininase and the preparation method of pharmacy acceptable salt thereof, it is characterized in that, original reagent of going back used in step (2) selects boron hydrogen sodium salt.
6. according to claim 1ly a kind ofly suppress the compound of dipeptides kininase and the preparation method of pharmacy acceptable salt thereof, it is characterized in that, in step (3), hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid or oxalic acid are selected in acid.
CN201310301406.9A 2012-01-12 2012-01-12 A kind of suppress dipeptides kininase compound and preparation method and purposes Expired - Fee Related CN103601674B (en)

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