CN103601674A - Compounds for inhibiting dipeptide kininase, preparation method and applications thereof - Google Patents
Compounds for inhibiting dipeptide kininase, preparation method and applications thereof Download PDFInfo
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Abstract
The invention provides compounds for inhibiting dipeptide kininase and pharmaceutically acceptable salts thereof. The compounds and salts thereof are obtained through Vilsmerier reactions, Willamson reactions, and reductive amination reactions. The primary pharmacological experiments have proved that the compounds have a strong inhibiting effect on DPP-IV, have a prominent hypoglycemic effect on a normal rat, have no liver toxicity, and can be applied to preparation of drugs for treating II type diabetes. The preparation method has the advantages of reasonable design, short synthesis route, cheap and available raw materials, and practicability. The structure formula is represented in the description.
Description
Technical field
This case is dividing an application of application number 201210008855.X.The invention belongs to medical technical field, relate to compound and the pharmacy acceptable salt thereof of a kind of inhibition 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, be due to Regular Insulin definitely or the relative deficiency organism metabolic disorder that causes blood sugar increasing to 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 the more than 90% of diabetic.The complication of diabetes comprises hyperlipidemia, hypertension, retinal diseases and renal insufficiency.Mostly the at present research of 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); Regular Insulin succagoga, comprises sulfonylurea (as than lattice row piperazine); And alpha-glucosidase inhibitor (as acarbose) etc.Yet these medicines are all with as side effects 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 reduces glucose level, so this may be just the novel targets for the treatment of diabetes.DPP-IV is a kind of glycoprotein being distributed widely in body, and its function class is similar to serine protease, by the shearing of polypeptide is made to its inactivation, thereby reaches the effect of regulation of physiological functions.GLP-1 plays an important role in carbohydrate metabolism, for example, and the secretion of (1) GLP-1 strengthening Regular Insulin; (2), expression of insulin is secreted necessary gene; (3) stimulate the differentiation of induction pancreaticβ-cell; (4) secretion of glucagon suppression; (5) suppress Alimentary secretion and wriggling; (6) depress appetite.Therefore, GLP-1 has restricted the absorption of food, has postponed digestion and the absorption process of food, has improved blood sugar utilization.Therefore, the treatment plan based on GLP-1 can be controlled blood sugar effectively, but GLP-1 as the substrate of DPP-IV, the transformation period is very short, after secretion, just by DPP-IV, is cut off rapidly inactivation in 1-2min.Therefore, use DPP-IV inhibitor can maintain by the inactivation mechanism of blocking-up GLP-1 the activity of GLP-1, thereby can treat and prevent the various diseases relevant with carbohydrate metabolism, non insulin dependent diabetes (type ii diabetes) (E. Matteucci particularly, O. Giampietro, Curr. Med. Chem., 2009,16,2943).
The DPP-IV inhibitor of the treatment type ii diabetes of listing comprises Sitagliptin, Saxagliptin, Linagliptin, Alogliptin, Vildagliptin at present.These compounds have good security and tolerance, also find that at present the patient who uses has body weight to increase or potential losing weight and the symptom (G. R. Lankas, et al., Diabetes, 2005,54,2988) such as oedema.Yet although highly active DPP-IV inhibitor is a lot, the problems such as the selectivity of DPP-IV, specificity are still difficult to solve.Therefore the DPP-IV of, being badly in need of the how better renewal of exploitation suppresses the needs (S. H. Havale, M. Pal, Bioorg. Med. Chem., 2009,17,1783) that medicine meets clinical application.
Summary of the invention
First object of the present invention provides a kind of compound and pharmacy acceptable salt thereof that suppresses 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 or unsubstituted phenyl ring or fragrant heterocycle by 1-4 R;
R represents hydrogen atom, halogen atom, and carboxyl, amino, cyano group, is replaced or unsubstituted low alkyl group or lower alkoxy by one or more halogen atoms, containing straight or branched alkyl or the alkoxyl group of 1 to 3 carbon atom;
R
1represent without replacement, monosubstituted, two replacement or trisubstituted aromatic rings, the substituting group on ring can be hydrogen atom, halogen atom, amino, contains alkyl or the alkoxyl group of the straight or branched of 1 to 3 carbon atom;
R
2represent the condensed ring of naphthenic hydrocarbon, aromatic ring, fragrant heterocycle or 4-10 the carbon of 4 to 7 carbon, wherein aromatic ring, fragrant heterocycle, condensed ring can be without replacement, monosubstituted, dibasic aromatic ring, fragrant heterocycle, and the substituting group on ring can be hydrogen atom, halogen atom, hydroxyl, carboxyl, amino, contains alkyl or the alkoxyl group of the straight or branched of 1 to 3 carbon atom.
Another object of the present invention is to provide a kind of preparation method who suppresses compound and the pharmacy acceptable salt thereof of dipeptides kininase, by following concrete steps, realizes:
(1) compound of the compou nd synthesis formula III of the compound of formula I and formula II;
Formula I compound can carry out Williamson with formula II compound and react to obtain formula III compound under alkaline condition, reactions steps is generally carried out in as dimethyl formamide (DMF), N,N-DIMETHYLACETAMIDE (DMA), dimethyl sulfoxide (DMSO) at polar solvent, 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 ℃, and the product obtaining can column chromatography purification.
(2) compound of the compounds accepted way of doing sth V of the compound of formula III and formula IV;
formula III compound can carry out reductive amination process with formula IV compound and obtain formula V compound under neutrality or alkaline condition, reactions steps is generally carried out in as methyl alcohol, ethanol, methyl alcohol~water, ethanol~water at protic solvent, reduction reagent used comprises various boron hydrogen sodium salts, sodium borohydride for example, sodium cyanoborohydride etc., temperature of reaction is room temperature, and the product obtaining 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.
A wherein, X, R, R
1, R
2definition with front identical; 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.) by Vilsmeier, react and obtain or buy commercial compound, formula II and formula IV are commercial compound.
A further 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 inhibition dipeptides kininase.Pharmacological evaluation is found: described compound and pharmacy acceptable salt thereof have good restraining effect, IC to DPP-IV
50value, between 0.014~10.019 μ M, and has obvious blood sugar reducing function to diabetes model rat.This compounds of these data declarations has the value of better research and development.
Feature of the present invention: the activated DPP-IV inhibitor of the tool of usining, as research object, utilizes various medicinal designs and synthetic method, obtains the DPP-IV that has that a class formation is brand-new and suppresses active compound, and synthetic route is brief, and raw material is cheap and easy to get, is suitable for practicality.Preliminary pharmacological activity screening experiment shows that these compounds all have stronger DPP-IV and suppress active, and normal rat is had to obvious blood sugar reducing function, has good DEVELOPMENT PROSPECT.
Embodiment
The present invention is further described in conjunction with the embodiments, rather than limits the present invention by any way.
The chloro-3-formaldehyde of the bromo-2-of embodiment 1,5-pyridine 2a
The chloro-3-pyridine carboxylic acid of the bromo-2-of the 5-of take is raw material (32.9g, 0.151mol) be dissolved in 167ml phosphorus trichloride, the DMF that adds 10.5ml, reflux 4h, reaction finishes, be cooled to room temperature, the thionyl chloride that reclaim under reduced pressure is unnecessary, drips the sodium cyanoborohydride aqueous solution (31.42g under ice-water bath, 0.5mol), stirred overnight at room temperature, after reaction finishes, is extracted with ethyl acetate, saturated sodium-chloride washing, anhydrous sodium sulfate drying, decompression and solvent recovery, the intermediate obtaining does not carry out purifying and continues to drop into next step reaction.Resulting intermediate 1a(2.01g, 9.02mmol) be dissolved in 20ml anhydrous methylene chloride, add PCC(2.35g, 10.8mmol), stirring at room 24h, reaction finishes decompression and solvent recovery, washing, ethyl acetate extraction, saturated sodium-chloride washing, the anhydrous sodium sulfate drying, (sherwood oil: methylene dichloride=20:1) carry out column chromatography of eluent for decompression and solvent recovery, obtain white solid 2a 1.65 g, yield: 83%; Fusing point: 112-113 ℃
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, the chloro-3-formaldehyde of 5-methyl-2-pyridine 4a
Benzylamine is that raw material (5g, 46mmol) adds in the flask of 50ml, slowly drips propionic aldehyde (2.71g, 46mmol) at 0 ℃, 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 ℃, stirred overnight at room temperature, obtains intermediate 3a, productive rate 88%.At 0 ℃ by DMF(13.5g, 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 ℃ of reaction 4h, after reaction finishes, mixture is poured in frozen water into dichloromethane extraction, saturated sodium-chloride washing, anhydrous sodium sulfate drying, (the sherwood oil: methylene dichloride=20:1) carry out column chromatography, obtain white solid 4a, yield: 64% of eluent for decompression and solvent recovery; Fusing point: 42-45 ℃.
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)。
The chloro-6-methyl-3-quinolin of embodiment 3,2-formaldehyde 5a
At 0-5 ℃, drip phosphorus trichloride (13ml, 98.28mmol) 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 ℃ and stir 8h, after reaction finishes, 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 ℃.
Embodiment 4,3-chloro-quinoxaline-2-formaldehyde 6a
Operating process, with example 1, is just used 3-chloro-quinoxaline-2-formic acid is replaced to the chloro-3-pyridine carboxylic acid of the bromo-2-of 5-, obtains faint yellow solid compound 6a, yield: 38%; Fusing point: 63-65 ℃.
Embodiment 5,2-are chloro-1,8-naphthyridine-3-formaldehyde 7a
Operating process is with example 1, and just chloro-1 with 2-, 8-naphthyridine-3-carboxylic acid replaces the chloro-3-pyridine carboxylic acid of the bromo-2-of 5-, obtains faint yellow solid compound 7a, yield: 24%; Fusing point: 143-144 ℃.
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 ℃.
Embodiment 7,2-are chloro-6,7-dimethoxy-quinoline-3-formaldehyde 9a
Operating process is with example 1, and just chloro-6 with 2-, 7-dimethoxy-quinoline-3-carboxylic acid replaces the chloro-3-pyridine carboxylic acid of the bromo-2-of 5-, obtains faint yellow solid compound 9a, yield: 76%; Fusing point: 175-176 ℃.
Embodiment 8,6-chlorothiophene be [2,3-b] pyridine-5-formaldehyde 10a also
Operating process, with example 1, is just used the also chloro-3-pyridine carboxylic acid of [2,3-b] pyridine-5-carboxylic acid replacement bromo-2-of 5-of 6-chlorothiophene, obtains faint yellow solid compound 10a, yield: 77%; Fusing point: 157-158 ℃.
The chloro-6-methylpyrazine-2-of embodiment 9,3-formaldehyde 11a
Operating process, with example 1, just replaces the chloro-3-pyridine carboxylic acid of the bromo-2-of 5-with the chloro-6-methylpyrazine-2-carboxylic acid of 3-, obtains faint yellow solid compound 11a, yield: 45%; Fusing point: 123-124 ℃.
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 ℃.
Embodiment 11,2-(4-chlorophenoxy) pyridine-3-aldehyde 1b
Chloro-3 pyridylaldehydes (141mg, 1mmol) of compound 2-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 finishes, washing, is extracted with ethyl acetate, saturated sodium-chloride washing, anhydrous sodium sulfate drying, decompression and solvent recovery, obtains yellow crude product 1b, yield: 84%; Fusing point: 93-94 ℃.
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 ℃.
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 ℃.
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 ℃.
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 ℃.
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, with 4-methoxyphenol, replaces para-chlorophenol, obtains yellow solid compound 6b, yield: 67%; Fusing point: 123-124 ℃.
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 ℃.
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 ℃.
Embodiment 19,2-(4-chloro-phenyl-is amino) 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 ℃.
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, with 3,4-DCA, replaces para-chlorophenol, obtains yellow solid compound 10b, yield: 33%; Fusing point: 171-172 ℃.
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 ℃.
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, with 4-methoxyphenol, replaces para-chlorophenol, obtains yellow solid compound 12b, yield: 43%; Fusing point: 123-124 ℃.
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, with 4-methylphenol, replaces para-chlorophenol, obtains yellow solid compound 13b, yield: 36%; Fusing point: 144-145 ℃.
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, with 3,4-xylenol, replaces para-chlorophenol, obtains yellow solid compound 14b, yield: 77%; Fusing point: 146-147 ℃.
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, with 3,4-DCA, replaces para-chlorophenol, obtains yellow solid compound 15b, yield: 41%; Fusing point: 165-166 ℃.
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), stir 2h at 70 ℃, be cooled to room temperature, add sodium borohydride (15mg, 0.4mmol), under room temperature, stir 2h, after reaction finishes, decompression and solvent recovery, washing, ethyl acetate extraction, saturated sodium-chloride washing, anhydrous sodium sulfate drying, decompression and solvent recovery, with eluent (sherwood oil: ethyl acetate: triethylamine=5:1:0.1) carry out column chromatography, 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-yl)-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-fluorobenzene methyl) 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-yl)-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-hydroxybenzene methylamino) 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 benzene methyl)-1-(2-(4-methoxyphenoxy) pyridin-3-yl) methylamine 7c
Operating process, with example 26, just replaces 1b with compound 5b, with 3,4-dimethyl benzylamine, replaces 3-aminomethyl-pyridine, obtains colourless transparent liquid 7c, yield: 74%.
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-yl) 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-yl)-N-(4-methylbenzene methyl) 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-methylbenzene methylamino) 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-fluorobenzene methylamino) 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-yl)-N-(4-methylbenzene methyl) 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-fluorobenzene methyl)-1-(3-(4-methoxyphenoxy)-7-(trifluoromethyl) quinoxaline-2-yl) methylamine 14c
Operating process, with example 26, just replaces 1b with compound 12b, with 4-flunamine, replaces 3-aminomethyl-pyridine, obtains colourless transparent liquid 14c, yield: 42%.
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-yl) methyl) cyclopentamine 15c
Operating process, with example 26, just replaces 1b with compound 13b, by cyclopentamine, replaces 3-aminomethyl-pyridine, obtains colourless transparent liquid 15c, yield: 55%.
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-yl) methyl) cyclopentamine 16c
Operating process, with example 26, just replaces 1b with compound 15b, by cyclopentamine, replaces 3-aminomethyl-pyridine, obtains colourless transparent liquid 16c, yield: 76%.
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-yl)-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-methylbenzene methyl)-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, with 4-methylbenzylamine, replaces 3-aminomethyl-pyridine, obtains colourless transparent liquid 18c, yield: 51%.
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, under ice-water bath, drip dilute hydrochloric acid 25ml, stir 30min, decompression is spin-dried for solvent, obtains white solid 1d, yield 78%; Fusing point: >200 ℃.
Embodiment 45, N-((2-(4-chlorophenoxy) pyridin-3-yl) methyl) cyclopentamine hydrochloride 2d
Operating process, with example 44, just replaces 1c by compound 2c, obtains white solid 2d, yield 89%; Fusing point: >200 ℃.
Embodiment 46,1-(benzo [d] [1,3] bis-oxazole-5-yl)-N-((2-(4-chlorophenoxy) pyridin-3-yl) methyl) methylamine vitriol 3d
Operating process, with example 44, just replaces 1c by compound 3c, substitutes dilute hydrochloric acid obtain white solid 3d, yield 77% with dilute sulphuric acid; Fusing point: >200 ℃.
Embodiment 47,1-(2-(2,4 dichloro benzene oxygen base) pyridin-3-yl)-N-(4-fluorobenzene methyl) methylamine hydrochloride 4d
Operating process, with example 44, just replaces 1c by compound 4c, obtains white solid 4d, yield 87%; Fusing point: >200 ℃.
Embodiment 48,1-(furans-2-yl)-N-((2-(p-tolyloxy) pyridin-3-yl) methyl) methylamine hydrochloride 5d
Operating process, with example 44, just replaces 1c by compound 5c, obtains white solid 5d, yield 89%; Fusing point: >200 ℃.
Embodiment 49,2-(3-((4-hydroxybenzene methylamino) methyl) pyridine-2-oxygen base) cyanobenzene hydrochloride 6d
Operating process, with example 44, just replaces 1c by compound 6c, obtains white solid 6d, yield 72%; Fusing point: >200 ℃.
Embodiment 50, N-(3,4-dimethyl benzene methyl)-1-(2-(4-methoxyphenoxy) pyridin-3-yl) acephatemet hydrochlorate 7d
Operating process, with example 44, just replaces 1c by compound 7c, with phosphoric acid, replaces dilute hydrochloric acid to obtain white solid 7d, yield 88%; Fusing point: >200 ℃.
Embodiment 51,4-(((the bromo-2-of 5-(4-methoxyphenoxy) pyridin-3-yl) methylamino) methyl) benzoate hydrochlorate 8d
Operating process, with example 44, just replaces 1c by compound 8c, obtains white solid 8d, yield 75%; Fusing point: >200 ℃.
Embodiment 52,4-(((2-(4-chlorophenoxy)-5-picoline-3-yl) methylamino) methyl) anilinechloride 9d
Operating process, with example 44, just replaces 1c by compound 9c, obtains white solid 9d, yield 86%; Fusing point: >200 ℃.
Embodiment 53,1-(3-(4-chlorophenoxy)-6-methylpyrazine-2-yl)-N-(4-methylbenzene methyl) methylamine hydrochloride 10d
Operating process, with example 44, just replaces 1c by compound 10c, obtains white solid 10d, yield 70%; Fusing point: >200 ℃.
Embodiment 54, N-(4-chloro-phenyl-)-3-((4-methylbenzene methylamino) methyl) pyridine-2-amine hydrochlorate 11d
Operating process, with example 44, just replaces 1c by compound 11c, obtains white solid 11d, yield 78%; Fusing point: >200 ℃.
Embodiment 55, N-(3,4-dichlorophenyl)-3-((4-fluorobenzene methylamino) methyl) pyrazine-2-amine hydrochlorate 12d
Operating process, with example 44, just replaces 1c by compound 12c, obtains white solid 12d, yield 69%; Fusing point: >200 ℃.
Embodiment 56,1-(2-(4-chlorophenoxy) quinoline-3-yl)-N-(4-methylbenzene methyl) methylamine hydrochloride 13d
Operating process, with example 44, just replaces 1c by compound 13c, obtains white solid 13d, yield 86%; Fusing point: >200 ℃.
Embodiment 57, N-(4-fluorobenzene methyl)-1-(3-(4-methoxyphenoxy)-7-(trifluoromethyl) quinoxaline-2-yl) methylamine hydrochloride 14d
Operating process, with example 44, just replaces 1c by compound 14c, obtains white solid 14d, yield 75%; Fusing point: >200 ℃.
Embodiment 58, N-((2-(p-tolyloxy)-1,8-naphthyridine-3-yl) methyl) cyclopentamine hydrochloride 15d
Operating process, with example 44, just replaces 1c by compound 15c, obtains white solid 15d, yield 67%; Fusing point: >200 ℃.
Embodiment 59, N-((6-(3,4-dichlorophenoxy) thieno-[2,3-b] pyridine-5-yl) methyl) cyclopentamine hydrochloride 16d
Operating process, with example 44, just replaces 1c by compound 16c, obtains white solid 16d, yield 88%; Fusing point: >200 ℃.
Embodiment 60,1-(2-(3,4-dimethyl phenoxy)-6,7-dimethoxy-quinoline-3-yl)-N-(pyridin-3-yl methyl) methylamine hydrochloride 17d
Operating process, with example 44, just replaces 1c by compound 17c, obtains white solid 17d, yield 90%; Fusing point: >200 ℃.
Embodiment 61, N-(4-methylbenzene methyl)-1-(2-(pyridine-4-oxygen base) pyridin-3-yl) methylamine hydrochloride 18d
Operating process, with example 44, just replaces 1c by compound 18c, obtains white solid 18d, yield 74%; Fusing point: >200 ℃.
Embodiment 62, DPP-IV suppress determination of activity:
Compound provided by the invention can be used 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.The Laemmli buffer system Laemmli that this system contains the amino luciferin of DPP-IV substrate Gly-Pro-and luciferase activity detection, DPP-IV-Glo
tMafter being cut by DPP-IV, can activate luciferase and react, 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 damping fluid separately, and concentration is 100 μ mol/L, every hole 25 μ mol; Enzyme gradient dilution, initial concentration is DPP-IV:0.01mU/ μ l, by 5 times of dilutions, every hole 25 μ l, mix; 37 ℃, 360/460nm measures the dynamic change of fluorescent value, measures 30 minutes; With absorbancy, linearly rise, the enzyme concn of S/N >=5 is working concentration.
Inhibitor activity is measured: all enzymes, inhibitor, all with analysis buffer preparation, arrange without compound contrast, without enzyme liquid, contrast.Press 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, mix; Add the GP-AMC solution 50 μ l that diluted, mix; 37 ℃ are reacted 20 minutes, and 360/460nM measures fluorescent value.The IC of the inhibiting rate of the vitro inhibition DPP-IV activity of compound and compound pharmacy acceptable salt vitro inhibition DPP-IV activity
50(μ M) value is in Table 1.
As can be seen from the above table, 1) 18 all compounds all have certain inhibition active to DPP-IV.2) parent nucleus is that the DPP-IV of the compound of the pyridine of 5 replacements or the quinoline of 6 replacements suppresses active, than parent nucleus, be high without the activity of the compound of the pyridine of replacement.3) DPP-IV of the compound of clogP value between 4-5 suppresses the chemical combination object height that specific activity clogP value is greater than 5, for example compound 11d and compound 12d, the wherein IC of compound 11d
50value reaches 0.014 μ M.
Example 63, the impact test of part of compounds on diabetes rat oral glucose tolerance
Adopt intact animal, impaired glucose tolerance or diabetes model animal, give test-compound, with the negative contrast of solvent, the positive contrast of Xi Gelieting, carries out oral glucose tolerance test, and under glucose tolerance curve, area calculates by trapezoidal method.
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 the 12c of corresponding dosage, after 0.5h, gavage gives glucose 1g/kg, with rapid blood sugar instrument, measure before administration, after administration and to the blood glucose value of 20,40,60,120 each time points of min after glucose, calculate area AUC under 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 and Xi Gelieting comparison unknown significance difference (
p>0.05).Each administration group and normal rat control group comparison 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.
tcheck, with the comparison of rat model control group, *
p<0.05, * *
p<0.01, * * *
p<0.001.
To sum up, from above biologically active data, can find out, this compounds has good hypoglycemic application prospect, thereby the good commercial value of tool.
Claims (8)
1. the compound and the pharmacy acceptable salt thereof that suppress dipeptides kininase, its general structure is as follows:
Wherein:
X represents carbon or nitrogen-atoms; Y represents oxygen or nitrogen-atoms;
R represents hydrogen atom or 1-4 replacement that is selected from following group: halogen atom, and carboxyl, amino, cyano group, is replaced or unsubstituted low alkyl group or lower alkoxy by one or more halogen atoms, containing straight or branched alkyl or the alkoxyl group of 1 to 3 carbon atom;
R
1represent without replacement, monosubstituted, two replacement or trisubstituted aromatic rings, the substituting group on ring can be hydrogen atom, halogen atom, amino, contains alkyl or the alkoxyl group of the straight or branched of 1 to 3 carbon atom;
R
2represent the condensed ring of naphthenic hydrocarbon, aromatic ring, fragrant heterocycle or 4-10 the carbon of 4 to 7 carbon, wherein aromatic ring, fragrant heterocycle, condensed ring can be without replacement, monosubstituted, dibasic aromatic ring, fragrant heterocycle, and the substituting group on ring can be hydrogen atom, halogen atom, hydroxyl, carboxyl, amino, contains alkyl or the alkoxyl group of the straight or branched of 1 to 3 carbon atom.
2. a preparation method who suppresses compound and the pharmacy acceptable salt thereof of dipeptides kininase, is characterized in that, by following concrete steps, realizes:
(1) formula I compound carries out Williamson with formula II compound and reacts to obtain formula III compound under alkaline condition, and reaction is carried out in polar solvent, temperature of reaction 80-120 ℃, and the product obtaining is with column chromatography purification;
(2) formula III compound carries out reductive amination process with formula IV compound and obtains formula V compound under neutrality or alkaline condition, and reaction is carried out in protic solvent, and temperature of reaction is room temperature, and the product obtaining 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 formula V compound;
A wherein, X, R, R
1, R
2definition identical with claim 1; Hal is selected from chlorine or bromine;
Reaction formula is:
。
3. a kind of preparation method who suppresses compound and the pharmacy acceptable salt thereof of dipeptides kininase according to claim 2, is characterized in that, step (1) Semi-polarity solvent is selected dimethyl formamide, N,N-DIMETHYLACETAMIDE or dimethyl sulfoxide (DMSO).
4. a kind of preparation method who suppresses compound and the pharmacy acceptable salt thereof of dipeptides kininase according to claim 2, is characterized in that, step (1) neutral and alkali material is selected salt of wormwood, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride KH; Catalyzer is selected cuprous iodide, cuprous bromide or cuprous chloride.
5. a kind of preparation method who suppresses compound and the pharmacy acceptable salt thereof of dipeptides kininase according to claim 2, is characterized in that, in step (2), protic solvent is selected methyl alcohol, ethanol, methyl alcohol~water, ethanol~water.
6. a kind of preparation method who suppresses compound and the pharmacy acceptable salt thereof of dipeptides kininase according to claim 2, is characterized in that, the original reagent of going back used in step (2) is selected boron hydrogen sodium salt.
7. a kind of preparation method who suppresses compound and the pharmacy acceptable salt thereof of dipeptides kininase according to claim 2, is characterized in that, in step (3), hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid or oxalic acid are selected in acid.
8. a kind of compound and the application of pharmacy acceptable salt in preparation treatment type ii diabetes medicine thereof that suppresses dipeptides kininase according to claim 2.
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