CN101875617B - Carbamyl aromatic acid compound with alkoxy replacing aromatic ring, preparation method and application thereof - Google Patents

Carbamyl aromatic acid compound with alkoxy replacing aromatic ring, preparation method and application thereof Download PDF

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CN101875617B
CN101875617B CN201010139761.7A CN201010139761A CN101875617B CN 101875617 B CN101875617 B CN 101875617B CN 201010139761 A CN201010139761 A CN 201010139761A CN 101875617 B CN101875617 B CN 101875617B
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oxygen base
compound
base
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unsubstituted
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CN101875617A (en
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吴松
叶菲
郝玲花
童元峰
陈锋
张裴
田金英
陶荣亚
贺伊博
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Connaught Technology (Beijing) Co., Ltd.
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Institute of Materia Medica of CAMS
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Abstract

The invention relates to a carbamyl aromatic acid compound with alkoxy replacing aromatic ring, physiologically-accepted salt, solvent compounds, and stereoisomer thereof, monocrystalline type or polycrystal type thereof, a preparation method thereof; medicine combination containing the compound; and application in regulating bioactivity of protein-tyrosinase-1B (PTP1B), preventing or treating diseases related to protein-tyrosine-phosphatase-1B, or application of protein-tyrosine-phosphatase-1B inhibitors in medicine.

Description

Alkoxyl group replaces the carboxamide base class aromatic acid compound of aromatic ring and method for making thereof and purposes
Technical field
The present invention relates to the carboxamide base class aromatic acid compound of aromatic ring that a kind of new alkoxyl group replaces, its preparation method and for preventing or treat the disease relevant with Protein tyrosine phosphatase-1B or as the application of Protein tyrosine phosphatase 1B inhibitor in medicine.
Background technology
Diabetes are a kind of common metabolic disturbance diseases, its number of patients is just along with the raising of living standards of the people, the aging of population, living-pattern preservation and increasing sharply, after cardiovascular disorder, tumour, become the Chronic Non-Communicable Diseases that third place in the world is serious, be the worldwide problem of serious threat human health.
Diabetes generally can be divided into insulin-dependent diabetes mellitus (I type) and non insulin dependent diabetes (II type), and wherein II type patient accounts for diabetic subject's more than 80%.At present for the treatment of type i diabetes, research direction is the effective insulin preparation of exploitation convenient drug administration; And for the treatment of type ii diabetes, medicine is in the market many, mainly contain following a few class: (1) insulin secretion stimulators, as sulfonylureas tolbutamide, Glyburide, Glipizide etc. and Postprandial glucose control agent medicine repaglinide, nateglinide etc.; (2) euglycemic agent, as biguanides N1,N1-Dimethylbiguanide and Thiazolidinediones rosiglitazone, pioglitazone etc.; (3) alpha-glucosidase inhibitor, as medicine acarbose, voglibose, miglitol etc.; (4) inhibitors of dipeptidyl IV, as medicine sitagliptin, vildagliptin; (5) Regular Insulin of various preparation type; (6) treatment by Chinese herbs etc.
In recent years, the Study on Molecular Mechanism that development occurs due to diabetes makes great progress, and the research of new drug turns to the more specific drug research of searching because new action target spot finds.The pathogeneticing characteristic of type ii diabetes is that periphery produces resistant function to Regular Insulin, molecular level show as Regular Insulin to be combined with insulin receptor after signal transduction lack.The phosphorylation level of protein-tyrosine is the important regulate factors that Intracellular signals forwards to, it is by protein tyrosine kinase (PTK) and Protein-tyrosine-phosphatase (PTP) regulation and control (Curr Med Chem jointly, 2003,10 (5): 1407-1421).Recent research finds, PTP 1B (PTP1B) can dephosphorylation protein-tyrosine, important negative regulation effect (J Int Med, 2002,251 (6): 467-475) is played in Insulin signaling pathway.Knock out PTP1B gene (Science, 1999,283 (5407:1544-1548; MolCell Biol, 2000,20 (15): 5479-5489), or use antisense nucleotide (ASO) to suppress expression (the Proc Nat Acad Sci of PTP1B albumen and mRNA in body, 2002,99 (17): 11357-11362), not only can significantly improve the susceptibility of test mice to Regular Insulin, and obviously can reduce the ill probability of obesity.These researchs show, PTP1B likely becomes the novel targets for the treatment of type ii diabetes.Therefore, one of focus of euglycemic agent in recent years has been become to the research of small molecules PTP1B inhibitor.
At present, the PTP1B inhibitor studied mainly comprises two large classes: a class is macromole inhibitor, antisense oligonu-cleotides Compound I SIS-113715 as ISIS Pharmaceuticals Inc.'s exploitation has now entered clinical II phase conceptual phase (Curt Opin MolTher, 2004,6 (3): 33); Another kind of is micromolecular inhibitor: as difluoro methylene phosphate compound, intend peptides, 2-carboxymethoxyl benzoic acid derivative, (the NatRev Drug Discov such as N-oxamyl benzoic acid derivative and cumarone sulfamide compound, 2002,1 (9): 696-709).Above-mentioned found have in the compound of PTP1B activity, existing multiple compound is in clinical trial.Wherein, great majority are efficient, the micromolecular inhibitor of highly selective, because the easy ionization of compound itself, cell permeability and bioavailability are not very desirable, are thus difficult to become the medicine having therapeutic value.Seeking validity, balance between specificity and pharmaceutical properties, is the huge challenge that research and development small molecules PTP1B inhibitor faces as oral diabetes drug.
In the existing constitutional features of each type small molecular inhibitor of analysis and the basis of biological activity mutual relationship, use SARS drug design method, rational design of the present invention has also synthesized the compound that a class has the suppression PTP1B activity of novel texture, and shows inhibit activities to a certain degree.
Summary of the invention
The object of the invention is the carboxamide base class aromatic acid compound being the aromatic ring providing a kind of alkoxyl group to replace, and physiologically acceptable salt, solvated compounds and steric isomer, its monocrystalline type or polymorphic.
Another object of the present invention is the preparation method that there are provided the compounds of this invention.
Another object of the present invention is to provide a kind of pharmaceutical composition containing one or more the compounds of this invention.
Another object of the present invention is to provide a kind of the compounds of this invention in treatment diabetes, and the purposes in the medicine of the disease relevant to PTP1B.
In order to complete the object of the present invention, adopt following technical scheme:
The carboxamide base class aromatic acid compound of the aromatic ring that alkoxyl group of the present invention replaces, and physiologically acceptable salt, represented by general formula (I):
Wherein:
X and Y is selected from C or atom N, and X is 2 to 6 replacements of A ring, and Y is 2, B ring or 5 replacements;
R 1o is the optional C of ortho position, a position or contraposition 8-24straight or branched alkoxyl group;
R 2for one or more substituting group, be selected from H, halogen, nitro, C 1-6alkoxyl group, the C that fluorine replaces 1-4alkoxyl group, cyano group, trifluoromethyl, the amide group of replacement, C 1-6straight or branched fatty group, C 1-6alkoxy carbonyl, carboxyl, piperidyl, morpholinyl; The amide group wherein replaced comprises the amide group of alkyl, cycloalkyl, aryl or heteroaryl;
R 3be selected from H, the mono-substituted or polysubstituted halogen of ortho position, a position or contraposition, nitro, C 1-6alkoxyl group, the C that fluorine replaces 1-4alkoxyl group, cyano group, trifluoromethyl, the amide group of replacement, the amide group wherein replaced comprises the amide group of alkyl, cycloalkyl, aryl or heteroaryl.
The C that preferred fluorine replaces 1-4alkoxyl group is selected from 1-fluothane methoxyl group, two fluothane methoxyl groups, 1-fluothane oxyethyl group, 1,1-bis-fluothane oxyethyl group, 1,2-bis-fluothane oxyethyl group, 1-fluothane propoxy-, 1,2,3-tri-fluothane propoxy-, 3-fluothane propoxy-, 4-fluothane butoxy;
Preferred alkyl is selected from C 1-10alkyl, preferred alkyl is selected from C 1-6alkyl, most preferred alkyl is selected from methyl, ethyl, propyl group, normal-butyl, n-pentyl, n-hexyl, sec.-propyl, 2-methyl-propyl, 1-methyl-propyl, 1-methyl butyl, 2-methyl butyl, 3-methyl butyl, 1,1-dimethylbutyl, 1,2-methyl butyl etc.;
Preferred cycloalkyl is selected from C 3-10alkyl, preferred alkyl is selected from C 3-8alkyl, most preferred cycloalkyl be selected from cyclopropane, tetramethylene, hexanaphthene, 1,1-dimethylcyclopropane, 1,2-dimethylcyclopropane, methylcyclohexane, 1,4-dimethyl cyclohexane, 1,3-dimethyl cyclohexane etc.;
Preferred aryl and heteroaryl are selected from phenyl, phenylol, naphthyl, furyl, imidazolyl, pyridyl, thiazolyl, pyrryl, thienyl, pyranyl etc.
According to the present invention, the compound shown in preferred general formula (I) comprises, but is not limited to the compound shown in general formula (IA), and physiologically acceptable salt:
Wherein, R 1o is the optional C of ortho position, a position or contraposition 8-24straight or branched alkoxyl group;
R 2for one or more substituting group, be selected from H, halogen, nitro, C 1-6alkoxyl group, C 1-6straight or branched fatty group, C 1-6alkoxy carbonyl, carboxyl, piperidyl, morpholinyl;
R 3be selected from H, the mono-substituted or polysubstituted halogen of ortho position, a position or contraposition or nitro.
According to the present invention, the compound shown in preferred general formula (IA) comprises, but is not limited to the compound shown in general formula (IAa), and physiologically acceptable salt:
Wherein, R 1o is the optional C of ortho position, a position or contraposition 10-24straight or branched alkoxyl group;
R 2for one or more substituting group, be selected from H, halogen, nitro or C 1-6alkoxyl group, C 1-6straight or branched fatty group, C 1-6alkoxy carbonyl, carboxyl, piperidyl, morpholinyl.
According to the present invention, the compound shown in preferred general formula (IAa) comprises, but is not limited to the compound shown in general formula (IAa1), and physiologically acceptable salt:
Wherein, R 1for decane base, n-undecane base, dodecyl, n-tridecane base, n-tetradecane base, Pentadecane base, n-hexadecyl, n-heptadecane base, Octadecane base, NSC 77136 base, NSC 62789 base, heneicosane base or n-docosane base that ortho position, a position or contraposition are optional; Preferred decane base, n-undecane base, dodecyl, n-tetradecane base, n-hexadecyl, Octadecane base or n-docosane base.
According to the present invention, the compound shown in preferred general formula (IAa) comprises, but is not limited to the compound shown in general formula (IAa2), its physiologically acceptable salt:
Wherein, R 1for decane base, n-undecane base, dodecyl, n-tridecane base, n-tetradecane base, Pentadecane base, n-hexadecyl, n-heptadecane base, Octadecane base, NSC 77136 base, NSC 62789 base, heneicosane base or n-docosane base that ortho position, a position or contraposition are optional; Preferred decane base, n-undecane base, dodecyl, n-tetradecane base, n-hexadecyl, Octadecane base or n-docosane base;
R 2be selected from F, Cl, Br or I.
According to the present invention, the compound shown in preferred general formula (IAa) comprises, but is not limited to the compound shown in general formula (IAa3), and physiologically acceptable salt:
Wherein, R 1for decane base, n-undecane base, dodecyl, n-tridecane base, n-tetradecane base, Pentadecane base, n-hexadecyl, n-heptadecane base, Octadecane base, NSC 77136 base, NSC 62789 base, heneicosane base or n-docosane base that ortho position, a position or contraposition are optional; Preferred decane base, n-undecane base, dodecyl, n-tetradecane base, n-hexadecyl, Octadecane base or n-docosane base;
R 2be selected from methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy or pentyloxy.
According to the present invention, the compound shown in preferred general formula (IAa) comprises, but is not limited to the compound shown in general formula (IAa4), and physiologically acceptable salt:
Wherein, R 1for decane base, n-undecane base, dodecyl, n-tridecane base, n-tetradecane base, Pentadecane base, n-hexadecyl, n-heptadecane base, Octadecane base, NSC 77136 base, NSC 62789 base, heneicosane base or n-docosane base that ortho position, a position or contraposition are optional; Preferred decane base, n-undecane base, dodecyl, n-tetradecane base, n-hexadecyl, Octadecane base or n-docosane base.
According to the present invention, the compound shown in preferred general formula (IA) comprises, but is not limited to the compound shown in general formula (IAb), and physiologically acceptable salt:
Wherein, R 1for the C that ortho position, a position or contraposition are optional 8-24straight or branched fatty group; Preferred decane base, n-undecane base, dodecyl, n-tridecane base, n-tetradecane base, Pentadecane base, n-hexadecyl, n-heptadecane base, Octadecane base, NSC 77136 base, NSC 62789 base, heneicosane base or n-docosane base; Most preferably decane base, n-undecane base, dodecyl, n-tetradecane base, n-hexadecyl, Octadecane base or n-docosane base.
According to the present invention, the compound shown in preferred general formula (IA) comprises, but is not limited to the compound shown in general formula (IAc), and physiologically acceptable salt:
Wherein, R 1for the C that ortho position, a position or contraposition are optional 8-24straight or branched fatty group; Preferred decane base, n-undecane base, dodecyl, n-tridecane base, n-tetradecane base, Pentadecane base, n-hexadecyl, n-heptadecane base, Octadecane base, NSC 77136 base, NSC 62789 base, heneicosane base or n-docosane base; Most preferably decane base, n-undecane base, dodecyl, n-tetradecane base, n-hexadecyl, Octadecane base or n-docosane base;
R 3be selected from F, Cl, Br or I.
According to the present invention, the compound shown in preferred general formula (I) comprises, but is not limited to the compound shown in general formula (IB), and physiologically acceptable salt:
Wherein, R 1for the C that ortho position, a position or contraposition are optional 8-24straight or branched fatty group; Preferred C 10-22straight or branched fatty group; More preferably decane base, n-undecane base, dodecyl, n-tridecane base, n-tetradecane base, Pentadecane base, n-hexadecyl, n-heptadecane base, Octadecane base, NSC 77136 base, NSC 62789 base, heneicosane base or n-docosane base; Most preferably decane base, n-undecane base, dodecyl, n-tetradecane base, n-hexadecyl, Octadecane base or n-docosane base;
R 2for one or more substituting group, be selected from H, halogen, nitro, C 1-6alkoxyl group, C 1-6straight or branched fatty group, C 1-6alkoxy carbonyl, carboxyl, piperidyl, morpholinyl;
R 3be selected from H, the mono-substituted or polysubstituted halogen of ortho position, a position or contraposition or nitro.
According to the present invention, the compound shown in preferred general formula (I) comprises, but is not limited to the compound shown in general formula (IC), and physiologically acceptable salt:
Wherein, R 1o is the optional C of ortho position, a position or contraposition 8-24straight or branched alkoxyl group; Preferred C 10-22straight or branched fatty group; More preferably decane base, n-undecane base, dodecyl, n-tridecane base, n-tetradecane base, Pentadecane base, n-hexadecyl, n-heptadecane base, Octadecane base, NSC 77136 base, NSC 62789 base, heneicosane base or n-docosane base; Most preferably decane base, n-undecane base, dodecyl, n-tetradecane base, n-hexadecyl, Octadecane base or n-docosane base;
R 2for one or more substituting group, be selected from H, halogen, nitro, C 1-6alkoxyl group, C 1-6straight or branched fatty group, C 1-6alkoxy carbonyl, carboxyl, piperidyl, morpholinyl;
R 3be selected from H, ortho position, the mono-substituted or polysubstituted halogen of a position or contraposition or nitro.
According to the present invention, the compound shown in preferred general formula (I) comprises, but is not limited to the compound shown in general formula (ID), and physiologically acceptable salt:
Wherein, R 1o is the optional C of ortho position, a position or contraposition 8-24straight or branched alkoxyl group; Preferred C 10-22straight or branched fatty group; More preferably decane base, n-undecane base, dodecyl, n-tridecane base, n-tetradecane base, Pentadecane base, n-hexadecyl, n-heptadecane base, Octadecane base, NSC 77136 base, NSC 62789 base, heneicosane base or n-docosane base; Most preferably decane base, n-undecane base, dodecyl, n-tetradecane base, n-hexadecyl, Octadecane base or n-docosane base;
R 2for one or more substituting group, be selected from H, halogen, nitro, C 1-6alkoxyl group, C 1-6straight or branched fatty group, C 1-6alkoxy carbonyl, carboxyl, piperidyl, morpholinyl;
R 3be selected from H, ortho position, the mono-substituted or polysubstituted halogen of a position or contraposition or nitro.
Wherein, C 8-24straight or branched fatty group can also be selected from: octyl group, positive nine alkyl, 2-Methyl Octyl, 3-ethyloctanyl, 2,3-dimethyl octyl group, 2-methyl nine alkyl, 3-ethyl nine alkyl, 2,3-dimethyl nine alkyl etc.;
Halogen is selected from fluorine, chlorine, bromine, iodine;
C 1-6alkoxyl group is selected from methoxyl group, oxyethyl group, propoxy-, butoxy, pentyloxy, oneself supports base, isopropoxy, 1-methyl propoxy-, 2-methyl propoxy-, 1, 1-dimethyl propoxy-, 2, 2-dimethyl propoxy-, 1, 2-dimethyl propoxy-, 1-methylbutoxy group, 2-methylbutoxy group, 3-methyl butyl, 1, 1-dimethyl butoxy, 2, 2-dimethyl butoxy, 1, 2-dimethyl butoxy, 3, 3-dimethyl butoxy, 1, 2--dimethyl butoxy, 1, 3--dimethyl butoxy, 2, 3--dimethyl butoxy, 1-ethyl-butoxy, 2-ethyl-butoxy etc.
For completing object of the present invention, preferred compound including but not limited to:
Present invention also offers the preparation method of the compounds of this invention.
Compound of the present invention can be prepared from following reaction path:
(1) substituted or unsubstituted nitrophenols, substituted or unsubstituted hydroxyl nitropyridine and halohydrocarbon generation substitution reaction, generate substituted or unsubstituted alkoxyl nitrobenzene, substituted or unsubstituted alkoxynitro pyridine, obtain alkoxyl aniline, substituted or unsubstituted alkoxy pyridines amine through reduction reaction:
(2) substituted or unsubstituted alkoxyl aniline obtained for step (1), substituted or unsubstituted alkoxy pyridines amine and substituted or unsubstituted Tetra hydro Phthalic anhydride, dinicotinic acid anhydride reactant are obtained the compound shown in general formula (I):
Or react to obtain the compound shown in general formula (I) with substituted or unsubstituted alkoxyl aniline, substituted or unsubstituted alkoxy pyridines amine and substituted or unsubstituted adjacent benzoyl chloride, substituted or unsubstituted adjacent benzene active ester, substituted or unsubstituted acyl chlorides pyridine, substituted or unsubstituted active methylester pyridine:
Wherein R is halogen atom or active ester, R 4it is easy leavings group.Described easy leavings group comprises methoxyl group, oxyethyl group, tert.-butoxy, benzyloxy.
Wherein, in step (1):
Be starting raw material according to substituted or unsubstituted amino-phenol, then directly and halohydrocarbon generation substitution reaction:
The reaction conditions of step (1) is:
When substituted or unsubstituted nitrophenols, replacement or non-substituted-amino phenol and halohydrocarbon generation substitution reaction: the preferred Tetrabutyl amonium bromide of catalyzer; The preferred acetone of reaction solvent, the hydrogen halide that preferred Anhydrous potassium carbonate absorption reaction produces; Reaction times is 15 ~ 24 hours, preferably 18 ~ 20 hours, most preferably 18 hours; Temperature of reaction is preferably reflux temperature.
When substituted or unsubstituted hydroxyl nitropyridine and halohydrocarbon generation substitution reaction: by substituted or unsubstituted hydroxyl nitropyridine and aqueous sodium hydroxide solution, silver nitrate aqueous solution room temperature reaction 0.5 ~ 2 hour, preferably 2 hours, after reaction, drying obtains the silver salt of substituted or unsubstituted hydroxyl nitropyridine.Again the silver salt of substituted or unsubstituted hydroxyl nitropyridine is reacted with haloalkane in organic solvent, obtain substituted or unsubstituted alkoxynitro pyridine, wherein: the mixture of the preferred DMF of organic solvent and acetonitrile, temperature of reaction preferably 70 ~ 90 DEG C, more preferably 75 ~ 85 DEG C, most preferably 80 DEG C; Preferably 18 ~ 24 hours reaction times, more preferably 20 ~ 22 hours, most preferably 20 hours; Reaction terminates rear filtration, through concentrating under reduced pressure removing organic solvent, then obtains substituted or unsubstituted alkoxynitro pyridine through reduced pressure chromatography.
The preferred palladium-carbon catalyst of reduction anticatalyzer of substituted or unsubstituted nitrophenols, substituted or unsubstituted alkoxynitro pyridine, the preferred dehydrated alcohol of solvent, preferably 6 ~ 10 hours reaction times, more preferably 7 ~ 9 hours, most preferably 8 hours.
The reaction conditions of step (2) is: the preferred acetone of reaction solvent; Reaction times is 1 ~ 5 hour, preferably 1 ~ 3 hour, most preferably 2 hours; Temperature of reaction is 15 ~ 25 DEG C; Reaction process is monitored with TLC; After completion of the reaction through concentrating under reduced pressure, silica gel column chromatography (methylene chloride/methanol is 20 ~ 10: 1), obtains formula (I) compound with sherwood oil/acetone (ratio is 30 ~ 10) recrystallization.
The preparation method of the compound shown in formula of of the present invention (IA) is:
(1) by substituted or unsubstituted amino-phenol and halohydrocarbon generation substitution reaction, substituted or unsubstituted alkoxyl aniline is generated; Or by substituted or unsubstituted nitrophenols and halohydrocarbon generation substitution reaction, generate substituted or unsubstituted alkoxyl nitrobenzene, obtain substituted or unsubstituted alkoxyl aniline through reduction reaction.
(2) substituted or unsubstituted alkoxyl aniline and substituted or unsubstituted phthalic anhydride are obtained the compound shown in general formula (IA) by obtained for step (1):
Or react to obtain the compound shown in general formula (IA) by substituted or unsubstituted alkoxyl aniline and substituted or unsubstituted adjacent benzoyl chloride, substituted or unsubstituted adjacent benzene active ester:
Wherein R is halogen atom or active ester, R 4it is easy leavings group.
The preparation method of the compound shown in formula of of the present invention (IB) is:
(1) by substituted or unsubstituted amino-phenol and halohydrocarbon generation substitution reaction, substituted or unsubstituted alkoxyl aniline is generated; Or by substituted or unsubstituted nitrophenols and halohydrocarbons reaction, generate substituted or unsubstituted alkoxyl nitrobenzene, obtain substituted or unsubstituted alkoxyl aniline through reduction reaction.
(2) substituted or unsubstituted alkoxyl aniline obtained for step (1) and substituted or unsubstituted 2,3-dinicotinic acid anhydride reactants are obtained the compound shown in general formula (IB):
Or react to obtain the compound shown in general formula (IB) by substituted or unsubstituted alkoxyl aniline and substituted or unsubstituted pyridine acyl chlorides, pyridine active ester:
Wherein R is halogen atom or active ester, R 4it is easy leavings group.
The preparation method of the compound shown in formula of of the present invention (IC) is:
(1) by substituted or unsubstituted hydroxyl nitropyridine and halohydrocarbon generation substitution reaction, generate substituted or unsubstituted alkoxynitro pyridine, then obtain substituted or unsubstituted alkoxy pyridines amine through reduction reaction;
(2) by obtained for step (1) substituted or unsubstituted alkoxy pyridines amine and replacement or do not replace phthalic anhydride and obtain the compound shown in general formula (IC),
Or react to obtain the compound shown in general formula (IC) by substituted or unsubstituted alkoxy pyridines amine and substituted or unsubstituted adjacent benzoyl chloride, substituted or unsubstituted adjacent benzene active ester:
Wherein R is halogen atom or active ester, R 4it is easy leavings group.
The preparation method of the compound shown in formula of of the present invention (ID) is:
(1) by substituted or unsubstituted hydroxyl nitropyridine and halohydrocarbon generation substitution reaction, generate substituted or unsubstituted alkoxynitro pyridine, then obtain substituted or unsubstituted alkoxy pyridines amine through reduction reaction;
(2) substituted or non-substituted alkoxy pyridines amine obtained for step (1) and substituted or unsubstituted 2,3-dinicotinic acid anhydride reactants are obtained the compound shown in general formula (ID):
Or react to obtain the compound shown in general formula (ID) with substituted or unsubstituted alkoxy pyridines amine and substituted or unsubstituted pyridine acyl chlorides, the active methyl esters of substituted or unsubstituted pyridine:
Wherein R is halogen atom or active ester, R 4it is easy leavings group.
The invention still further relates to a kind of pharmaceutical composition containing arbitrary compound of the present invention and pharmaceutically acceptable carrier containing effective dose.
In addition, the starting raw material in above-mentioned reaction and intermediate are easy to obtain, or can be easy to synthesis to those skilled in the art by the ordinary method in organic synthesis.
According to embodiment of the present invention, described the compounds of this invention also comprises corresponding pharmacy acceptable salt class, solvated compounds and steric isomer.
The compounds of this invention pharmaceutically acceptable salt comprises different acid salt, as following mineral acid or organic acid acid salt: hydrochloric acid, sulfuric acid, phosphoric acid, Hydrogen bromide, oxalic acid, methylsulfonic acid, tosic acid, Phenylsulfonic acid, Citric Acid, toxilic acid, fumaric acid, lactic acid, tartrate etc.The compounds of this invention pharmaceutically acceptable salt also comprises: an alkali metal salt (lithium, sodium, sylvite), alkaline earth salt (calcium, magnesium, strontium salt) and ammonium salt, with the salt that can provide physiologically acceptable cationic organic bases, as methylamine, dimethylamine, the salt of piperidines, morpholine, Trometamol.Ordinary method all can be adopted to prepare at all these salt of the scope of the invention.In the preparation process of the compounds of this invention and solvate and its salt, may there is monocrystalline type or polymorphic or eutectic in different crystallization condition.
The invention still further relates to a kind of containing the compound of the present invention of medicine effective dose and the pharmaceutical composition of pharmaceutically acceptable carrier.Usual pharmaceutical composition of the present invention contains the compounds of this invention of 0.1 ~ 95% (weight percent).In unit dosage form, the general content of the compounds of this invention is 0.1 ~ 100mg, and preferred unit dosage form contains 5 ~ 50mg.
The pharmaceutical composition of the compounds of this invention according to method well known in the art, can make the suitable type of service or dosage form that can be used as people's drug use.The compounds of this invention or the pharmaceutical composition containing it can with oral method or parenteral route medications.Oral medication can be tablet, granule, capsule, soft capsule, oral liquid etc.; Parenteral route drug formulation has injection (comprising intravenous injection, subcutaneous injection, intramuscular injection, local target injection etc.), lyophilized injectable powder and the embedding preparation of local target, suppository etc.; Also can be delay, controlled release preparation, targeting preparation, Percutaneously administrable preparation and various particulate delivery systems etc.These preparations prepare according to the method known by those skilled in the art.For the auxiliary material manufacturing tablet, granule, capsule, soft capsule used is conventional auxiliary agent, such as starch, lactose, gelatin, syrup, glycerine, beeswax, gum arabic, micropowder silica gel, talcum powder, polyoxyethylene glycol etc.Liquid dosage form solvent used such as has water, ethanol, propylene glycol, and plant oil is Semen Maydis oil, peanut oil, olive wet goods such as.Other auxiliary agents can also be had, such as tensio-active agent, lubricant, antioxidant, disintegrating agent, sanitas, correctives, pigment etc. containing in the preparation of the compounds of this invention.
In tablet, granule, capsule, soft capsule, injection and suppository containing the dosage of compound of Formula I of the present invention be with unit dosage form in the compound gauge that exists calculate.In unit dosage form, general formula I of the present invention and the general content of Compounds of formula II are 0.1 ~ 100mg, and preferred unit dosage form contains 5 ~ 50mg.
Such as, in order to the compounds of this invention is made capsule, the compounds of this invention of effective dose can be mixed with above-mentioned various carrier, and the mixture obtained thus is placed in Capsules.
And for example, in order to compound of the present invention is made injection, by soluble in water for the compounds of this invention of effective dose, and by appropriate acid or alkali adjust ph, osmotic pressure can be regulated with appropriate sodium-chlor or glucose, makes the formulation of applicable drug administration by injection.
In addition, as needs, also tinting material, sanitas, spices, correctives or other pharmaceutical excipient can be added in pharmaceutical preparation.
Pharmaceutical research shows, it is active that the compounds of this invention has certain suppression PTP1B.The invention still further relates to compound of the present invention for preventing or treat the disease relevant with Protein tyrosine phosphatase-1B or the application of Protein tyrosine phosphatase 1B inhibitor in medicine; Wherein, described medicine is this kind of disease for the treatment of, includes but not limited to the diseases such as type ii diabetes, hypertension, obesity, hyperlipidemia.For reaching medication object, strengthen result for the treatment of, the compounds of this invention and pharmaceutical composition thereof can with any known medication administrations.
The dosage of the compounds of this invention and pharmaceutical composition thereof depends on many factors, the character of the disease such as will prevented or treat and severity, age of patient, body weight, physical appearance and individual reaction, route of administration, administration number of times etc., therefore therapeutic dose of the present invention can have change in a big way.In general, can by the known method of those skilled in the art, according to the optimal balance point of curative effect and side effect as the foundation determining dosage.The compounds of this invention and pharmaceutical composition thereof can be used alone, or merge with other medicine and use.
Figure of description:
Fig. 1 is the impact of compound 11 on glucose level after IR mouse glucose load.(n＝9.##，###，p＜0.01，0.001 vs Con；*，**，***，p＜0.05，0.01，0.001 vs IR.)
Fig. 2 is the impact of compound 11 on area under blood sugar-time curve after IR mouse glucose load.(n＝9.###，p＜0.001 vsCon；**，***，p＜0.01，0.001 vs IR.)
Fig. 3 is the effect diagram of glucose level after compound 11 pairs of IR mouse islets element loads.(n＝9.###，p＜0.001 vs Con；*，**，***，p＜0.05，0.01，0.001 vs IR.)
Fig. 4 is the effect diagram of area under blood sugar-time curve after compound 11 pairs of IR mouse islets element loads.
(n＝9.###，p＜0.001vs Con；*，***，p＜0.05，0.001 vs IR.)
Embodiment
The following examples are used for further illustrating the present invention, but this and do not mean that any limitation of the invention.
The structure of compound is determined by nucleus magnetic resonance (NMR) or mass spectrum (MS).M.p. be with DEG C fusing point provided, the non-correction up of temperature.Column chromatography silica gel generally uses silica gel H, 100-200 order silica gel or 200-300 order silica gel.It is CDCl that NMR measures solvent 3, d 6-DMSO, is inside designated as TMS, and chemical shift provides using ppm as unit.Mensuration AutoSpec Ultima-TOF mass spectrograph or Q-Trap LC/MS/MS System, the Turbo ionspray source mass spectrograph of MS.
Abbreviation:
D 6-DMSO: deuterated dimethyl sulfoxide
CDCl 3: deuterochloroform
Mmol: mmole
The preparation of embodiment 1:N-(2-oxygen in last of the ten Heavenly stems base phenyl) adjacent carbamyl phenylformic acid (compound 1)
A) synthesis of 2-oxygen in last of the ten Heavenly stems base aniline:
O-NP (0.5g, 3.6mmol) is added successively, acetone 25ml in reaction flask, 1-bromine n-decane (0.75ml, 3.6mmol), Anhydrous potassium carbonate (1g, 7.2mmol) with appropriate Tetrabutyl amonium bromide, stirring and refluxing reaction 18h.Filter, filtrate reduced in volume recycling design obtains yellow oil, not purified direct input next step.
Dehydrated alcohol 20ml is added, the Pd/C palladium-carbon catalyst of 0.2g 10%, normal pressure hydrogenation reaction 8h in above-mentioned residue.Filter, remove catalyzer, through column chromatography after filtrate is concentrated, obtain colorless oil 0.76g, yield 85%.
1H-NMR(CDCl 3)：δ6.798-6.689(m，4H)，3.986(t，2H)，3.623(s，NH 2)，1.812(m，2H)，1.473-1.281(m，14H)，0.890(t，3H)。
B) N-(2-oxygen in last of the ten Heavenly stems base phenyl) the benzoic synthesis of adjacent carbamyl:
Add 2-oxygen in last of the ten Heavenly stems base aniline (0.64g, 2.6mmol) successively in reaction flask, acetone (40ml), Tetra hydro Phthalic anhydride (0.38g, 2.6mmol), reacts 2h under room temperature.TLC monitoring reaction is complete.Concentrating under reduced pressure recycling design obtains crude product, obtains target compound, white solid 0.75g, yield 73% after silica gel column chromatography with sherwood oil/acetone recrystallization.
1H-NMR(d 6-DMSO)：δ13.016(s，1H)，9.150(s，NH)，6.908-7.909(m，8H)，3.981(t，2H)，1.701(m，2H)，1.207-1.381(m，14H)，0.839(t，3H)。
ESI-MS(m/z)：398，420。mp：72.9-73.8℃。
The preparation of embodiment 2:N-(2-undecane oxygen base phenyl)-adjacent carbamyl phenylformic acid (compound 2)
A) synthesis of 2-undecane oxygen base aniline:
O-NP (0.5g, 3.6mmol) is added successively, acetone 25ml in reaction flask, 1-bromine n-undecane (0.8ml, 3.6mmol), Anhydrous potassium carbonate (1g, 7.2mmol) with appropriate Tetrabutyl amonium bromide, stirring and refluxing reaction 18h.Filter, filtrate reduced in volume recycling design obtains yellow oil, not purified direct input next step.
Dehydrated alcohol 20ml is added, 0.2g 10%Pd/C palladium-carbon catalyst, normal pressure hydrogenation reaction 8h in above-mentioned residue.Filter, remove Pd/C, through column chromatography after filtrate is concentrated, obtain colorless oil 0.83g, yield 87%.
1H-NMR(CDCl 3)：δ6.813-6.683(m，4H)，3.987(t，2H)，3.628(s，NH 2)，1.812(m，2H)，1.473-1.278(m，16H)，0.890(t，3H)。
B) N-(2-undecane oxygen base phenyl) the benzoic synthesis of adjacent carbamyl:
Add 2-undecane oxygen base aniline (0.67g, 2.6mmol) successively in reaction flask, acetone (40ml), Tetra hydro Phthalic anhydride (0.38g, 2.6mmol), reacts 2h under room temperature.TLC monitoring reaction is complete.Concentrating under reduced pressure recycling design obtains crude product, obtains target compound, white solid 0.79g, yield 75% after silica gel column chromatography with sherwood oil/acetone recrystallization.
1H-NMR(d 6-DMSO)：δ13.014(s，1H)，9.154(s，NH)，6.930-7.907(m，8H)，3.981(t，2H)，1.699(m，2H)，1.208-1.382(m，16H)，0.841(t，3H)。
ESI-MS(m/z)：412，434。mp：77.9-79.5℃。
The preparation of embodiment 3:N-(2-dodecyloxy phenyl) adjacent carbamyl phenylformic acid (compound 3)
A) synthesis of 2-dodecyloxy aniline:
O-NP (3.0g, 21.5mmol) is added successively, acetone 50ml in reaction flask, 1-bromine n-dodecane (5.2ml, 21.5mmol), Anhydrous potassium carbonate (6g, 43.0mmol) with appropriate Tetrabutyl amonium bromide, stirring and refluxing reaction 18h.Filter, filtrate reduced in volume recycling design obtains yellow oil, not purified direct input next step.
Dehydrated alcohol 50ml is added, 0.8g 10%Pd/C palladium-carbon catalyst, normal pressure hydrogenation reaction 8h in above-mentioned residue.Filter, remove Pd/C, through column chromatography after filtrate is concentrated, obtain colorless oil 4.8g, yield 81%.
1H-NMR(CDCl 3)：δ6.799-6.685(m，4H)，3.987(t，2H)，3.651(s，NH 2)，1.813(m，2H)，1.474-1.276(m，18H)，0.892(t，3H)。
B) N-(2-dodecyloxy phenyl) the benzoic synthesis of adjacent carbamyl:
Add 2-dodecyloxy aniline (0.92g, 3.3mmol) successively in reaction flask, acetone (40ml), Tetra hydro Phthalic anhydride (0.49g, 3.3mmol), reacts 2h under room temperature.TLC monitoring reaction is complete.Concentrating under reduced pressure recycling design obtains crude product, obtains target compound, white solid 1.1g, yield 78% after silica gel column chromatography with sherwood oil/acetone recrystallization.
1H-NMR(d 6-DMSO)：δ13.019(s，1H)，9.188(s，NH)，6.930-7.910(m，8H)，3.980(t，2H)，1.699(m，2H)，1.210-1.381(m，18H)，0.842(t，3H)。
ESI-MS(m/z)：426，448。mp：77.4-79.3℃。
The preparation of embodiment 4:N-(2-tetradecyloxyaniline phenyl) adjacent carbamyl phenylformic acid (compound 4)
A) synthesis of 2-tetradecyloxyaniline aniline:
O-NP (5.0g, 36.0mmol) is added successively, acetone 100ml in reaction flask, 1-bromine n-tetradecane (10.7ml, 36.0mmol), Anhydrous potassium carbonate (10g, 72mmol) with appropriate Tetrabutyl amonium bromide, stirring and refluxing reaction 18h.Filter, filtrate reduced in volume recycling design obtains yellow oil, not purified direct input next step.
Dehydrated alcohol 50ml is added, 1.0g 10%Pd/C palladium-carbon catalyst, normal pressure hydrogenation reaction 8h in above-mentioned residue.Filter, remove Pd/C, through column chromatography after filtrate is concentrated, obtain colorless oil 9.1g, yield 83%.
1H-NMR(DMSO)：δ6.743-6.472(m，4H)，4.579(s，NH 2)，3.885(t，2H)，1.699(m，2H)，1.407-1.231(m，22H)，0.842(t，3H)。
B) N-(2-tetradecyloxyaniline phenyl) the benzoic synthesis of adjacent carbamyl:
Add 2-tetradecyloxyaniline aniline (0.6g, 1.9mmol) successively in reaction flask, acetone (40ml), Tetra hydro Phthalic anhydride (0.29g, 1.9mmol), reacts 2h under room temperature.TLC monitoring reaction is complete.Concentrating under reduced pressure recycling design obtains crude product, obtains target compound, white solid 0.68g, yield 77% after silica gel column chromatography with sherwood oil/acetone recrystallization.
1H-NMR(d 6-DMSO)：δ13.011(s，1H)，9.149(s，NH)，6.932-7.908(m，8H)，3.980(t，2H)，1.700(m，2H)，1.216-1.380(m，22H)，0.841(t，3H)。
ESI-MS(m/z)：454，476。mp：83.0-83.7℃。
The preparation of embodiment 5:N-(3-oxygen in last of the ten Heavenly stems base phenyl) adjacent carbamyl phenylformic acid (compound 5)
A) synthesis of 3-oxygen in last of the ten Heavenly stems base aniline:
Metha Amino Phenon (3.5g, 32.0mmol) is added successively, acetone 50ml in reaction flask, 1-bromine n-decane (10.7ml, 36.0mmol), Anhydrous potassium carbonate (9g, 64mmol) with appropriate Tetrabutyl amonium bromide, stirring and refluxing reaction 18h.Filter, filtrate reduced in volume recycling design obtains white solid 5.3g, yield 66%.
1H-NMR(CDCl 3)：δ7.074-6.256(m，4H)，3.907(t，2H)，3.668(s，NH 2)，1.753(m，2H)，1.434-1.273(m，14H)，0.884(t，3H)。
B) N-(3-oxygen in last of the ten Heavenly stems base phenyl) the benzoic synthesis of adjacent carbamyl:
Add 3-oxygen in last of the ten Heavenly stems base aniline (0.65g, 2.6mmol) successively in reaction flask, acetone (40ml), Tetra hydro Phthalic anhydride (0.38g, 2.6mmol), reacts 2h under room temperature.TLC monitoring reaction is complete.Concentrating under reduced pressure recycling design obtains crude product, obtains target compound, white solid 0.72g, yield 70% after silica gel column chromatography with sherwood oil/acetone recrystallization.
1H-NMR(d 6-DMSO)：δ13.012(s，1H)，10.275(s，NH)，6.629-7.873(m，8H)，3.911(t，2H)，1.697(m，2H)，1.244-1.392(m，14H)，0.822(t，3H)。
ESI-MS(m/z)：398，420。mp：134.4-135.1℃。
The preparation of embodiment 6:N-(3-undecane oxygen base phenyl) adjacent carbamyl phenylformic acid (compound 6)
A) synthesis of 3-undecane oxygen base aniline:
Metha Amino Phenon (3.5g, 32.0mmol) is added successively, acetone 50ml in reaction flask, 1-bromine n-undecane (7.2ml, 32.0mmol), Anhydrous potassium carbonate (9g, 64mmol) with appropriate Tetrabutyl amonium bromide, stirring and refluxing reaction 18h.Filter, filtrate reduced in volume recycling design obtains white solid 5.6g, yield 66%.
1H-NMR(CDCl 3)：δ7.075-6.262(m，4H)，3.905(t，2H)，1.751(m，2H)，1.432-1.264(m，16H)，0.881(t，3H)。
B) N-(3-undecane oxygen base phenyl) the benzoic synthesis of adjacent carbamyl:
Add 3-undecane oxygen base aniline (0.53g, 2.0mmol) successively in reaction flask, acetone (40ml), Tetra hydro Phthalic anhydride (0.30g, 2.0mmol), reacts 2h under room temperature.TLC monitoring reaction is complete.Concentrating under reduced pressure recycling design obtains crude product, obtains target compound, white solid 0.56g, yield 68% after silica gel column chromatography with sherwood oil/acetone recrystallization.
1H-NMR(d 6-DMSO)：δ13.009(s，1H)，10.264(s，NH)，6.628-7.875(m，8H)，3.910(t，2H)，1.696(m，2H)，1.235-1.393(m，16H)，0.819(t，3H)。
ESI-MS(m/z)：412，434。mp：132.7-133.7℃。
The preparation of embodiment 7:N-(3-dodecyloxy phenyl) adjacent carbamyl phenylformic acid (compound 7)
A) synthesis of 3-dodecyloxy aniline:
Metha Amino Phenon (3.0g, 27.5mmol) is added successively, acetone 50ml in reaction flask, 1-bromine n-dodecane (7.2ml, 32.0mmol), Anhydrous potassium carbonate (9g, 64mmol) with appropriate Tetrabutyl amonium bromide, stirring and refluxing reaction 18h.Filter, filtrate reduced in volume recycling design obtains white solid 4.6g, yield 60%.
1H-NMR(CDCl 3)：δ7.100-6.333(m，4H)，3.910(t，2H)，1.753(m，2H)，1.433-1.268(m，18H)，0.882(t，3H)。
B) N-(3-dodecyloxy phenyl) the benzoic synthesis of adjacent carbamyl:
Add 3-dodecyloxy aniline (1.31g, 4.7mmol) successively in reaction flask, acetone (40ml), Tetra hydro Phthalic anhydride (0.70g, 4.7mmol), reacts 2h under room temperature.TLC monitoring reaction is complete.Concentrating under reduced pressure recycling design obtains crude product, obtains target compound, white solid 1.61g, yield 80% after silica gel column chromatography with sherwood oil/acetone recrystallization.
1H-NMR(d 6-DMSO)：δ13.010(s，1H)，10.263(s，NH)，6.628-7.876(m，8H)，3.910(t，2H)，1.695(m，2H)，1.235-1.391(m，18H)，0.818(t，3H)。
ESI-MS(m/z)：426，448。mp：132.3-133.2℃。
The preparation of embodiment 8:N-(4-oxygen in last of the ten Heavenly stems base phenyl) adjacent carbamyl phenylformic acid (compound 8)
A) synthesis of 4-oxygen in last of the ten Heavenly stems base aniline:
4-nitrophenols (4.0g, 28.8mmol) is added successively, acetone 50ml in reaction flask, 1-bromine n-decane (6.0ml, 28.8mmol), Anhydrous potassium carbonate (8g, 57.6mmol) with appropriate Tetrabutyl amonium bromide, stirring and refluxing reaction 18h.Filter, filtrate reduced in volume recycling design obtains yellow oil, not purified direct input next step.
Dehydrated alcohol 50ml is added, 0.8g 10%Pd/C palladium-carbon catalyst, normal pressure hydrogenation reaction 8h in above-mentioned residue.Filter, remove Pd/C, through column chromatography after filtrate is concentrated, obtain colorless oil 5.0g, yield 70%.
1H-NMR(CDCl 3)：δ6.758-6.628(m，4H)，3.875(t，2H)，1.737(m，2H)，1.430-1.270(m，14H)，0.883(t，3H)。
B) N-(4-oxygen in last of the ten Heavenly stems base phenyl) the benzoic synthesis of adjacent carbamyl:
Add 4-oxygen in last of the ten Heavenly stems base aniline (0.37g, 1.5mmol) successively in reaction flask, acetone (40ml), Tetra hydro Phthalic anhydride (0.22g, 1.5mmol), reacts 2h under room temperature.TLC monitoring reaction is complete.Concentrating under reduced pressure recycling design obtains crude product, obtains target compound, white solid 0.45g, yield 76% after silica gel column chromatography with sherwood oil/acetone recrystallization.
1H-NMR(d 6-DMSO)：δ12.960(s，1H)，10.145(s，NH)，6.857-7.855(m，8H)，3.913(t，2H)，1.681(m，2H)，1.248-1.387(m，14H)，0.850(t，3H)。
ESI-MS(m/z)：398，420。mp：136.2-137.4℃。
The preparation of embodiment 9:N-(4-undecane oxygen base phenyl) adjacent carbamyl phenylformic acid (compound 9)
A) synthesis of 4-undecane oxygen base aniline:
4-nitrophenols (4.0g, 28.8mmol) is added successively, acetone 50ml in reaction flask, 1-bromine n-undecane (6.2ml, 28.8mmol), Anhydrous potassium carbonate (8g, 57.6mmol) with appropriate Tetrabutyl amonium bromide, stirring and refluxing reaction 18h.Filter, filtrate reduced in volume recycling design obtains yellow oil, not purified direct input next step.
Dehydrated alcohol 50ml is added, 0.8g 10%Pd/C, normal pressure hydrogenation reaction 8h in above-mentioned residue.Filter, remove Pd/C, through column chromatography after filtrate is concentrated, obtain colorless oil 4.8g, yield 63%.
1H-NMR(CDCl 3)：δ6.757-6.632(m，4H)，3.873(t，2H)，1.734(m，2H)，1.427-1.263(m，16H)，0.879(t，3H)。
B) N-(4-undecane oxygen base phenyl) the benzoic synthesis of adjacent carbamyl:
Add 4-undecane oxygen base aniline (0.40g, 1.5mmol) successively in reaction flask, acetone (40ml), Tetra hydro Phthalic anhydride (0.22g, 1.5mmol), reacts 2h under room temperature.TLC monitoring reaction is complete.Concentrating under reduced pressure recycling design obtains crude product, obtains target compound, white solid 0.46g, yield 75% after silica gel column chromatography with sherwood oil/acetone recrystallization.
1H-NMR(d 6-DMSO)：δ12.967(s，1H)，10.145(s，NH)，6.856-7.856(m，8H)，3.912(t，2H)，1.682(m，2H)，1.243-1.385(m，16H)，0.848(t，3H)。
ESI-MS(m/z)：412，434。mp：134.4-135.2℃。
The preparation of embodiment 10:N-(4-dodecyloxy phenyl) adjacent carbamyl phenylformic acid (compound 10)
A) synthesis of 4-dodecyloxy aniline:
4-nitrophenols (3.0g, 21.6mmol) is added successively, acetone 50ml in reaction flask, 1-bromine n-dodecane (5.5ml, 21.6mmol), Anhydrous potassium carbonate (6g, 43.2mmol) with appropriate Tetrabutyl amonium bromide, stirring and refluxing reaction 24h.Filter, filtrate reduced in volume recycling design obtains yellow oil, not purified direct input next step.
Dehydrated alcohol 50ml is added, 0.8g 10%Pd/C palladium-carbon catalyst, normal pressure hydrogenation reaction 8h in above-mentioned residue.Filter, remove Pd/C, through column chromatography after filtrate is concentrated, obtain colorless oil 3.9g, yield 65%.
1H-NMR(CDCl 3)：δ6.759-6.636(m，4H)，3.873(t，2H)，1.734(m，2H)，1.427-1.261(m，18H)，0.880(t，3H)。
B) N-(4-dodecyloxy phenyl) the benzoic synthesis of adjacent carbamyl:
Add 4-dodecyloxy aniline (0.69g, 2.5mmol) successively in reaction flask, acetone (40ml), Tetra hydro Phthalic anhydride (0.37g, 2.5mmol), reacts 2h under room temperature.TLC monitoring reaction is complete.Concentrating under reduced pressure recycling design obtains crude product, obtains target compound, white solid 0.86g, yield 81% after silica gel column chromatography with sherwood oil/acetone recrystallization.
1H-NMR(d 6-DMSO)：δ12.960(s，1H)，10.137(s，NH)，6.859-7.850(m，8H)，3.912(t，2H)，1.680(m，2H)，1.240-1.405(m，18H)，0.846(t，3H)。
ESI-MS(m/z)：426，448。mp：135.5-135.8℃。
The preparation of embodiment 11:N-(2-tetradecyloxyaniline phenyl)-3-nitro-adjacent carbamyl phenylformic acid (compound 11)
A) synthesis of 2-tetradecyloxyaniline aniline:
O-NP (5.0g, 36.0mmol) is added successively, acetone 100ml in reaction flask, 1-bromine n-tetradecane (10.7ml, 36.0mmol), Anhydrous potassium carbonate (10g, 72mmol) with appropriate Tetrabutyl amonium bromide, stirring and refluxing reaction 18h.Filter, filtrate reduced in volume recycling design obtains yellow oil, not purified direct input next step.
Dehydrated alcohol 50ml is added, 1.0g 10%Pd/C palladium-carbon catalyst, normal pressure hydrogenation reaction 8h in above-mentioned residue.Filter, remove Pd/C, through column chromatography after filtrate is concentrated, obtain colorless oil 9.1g, yield 83%.
1H-NMR(DMSO)：δ6.743-6.472(m，4H)，4.579(s，NH 2)，3.885(t，2H)，1.699(m，2H)，1.407-1.231(m，22H)，0.842(t，3H)。
B) the benzoic synthesis of the adjacent carbamyl of N-(2-tetradecyloxyaniline phenyl)-3-nitro:
Add 2-tetradecyloxyaniline aniline (0.54g, 1.8mmol) successively in reaction flask, acetone (40ml), 3-nitrophthalic acid acid anhydride (0.34g, 1.8mmol), reacts 2h under room temperature.TLC monitoring reaction is complete.Concentrating under reduced pressure recycling design obtains crude product, obtains target compound, white solid 0.38g, yield 43% after silica gel column chromatography with sherwood oil/acetone recrystallization.
1H-NMR(d 6-DMSO)：δ13.525(s，1H)，9.729(s，NH)，6.908-8.299(m，7H)，3.951(t，2H)，1.676(m，2H)，1.221-1.357(m，22H)，0.844(t，3H)。
ESI-MS(m/z)：499，521。mp：114.0-115.4℃。
The preparation of embodiment 12:N-(3-dodecyloxy phenyl)-6-nitro-adjacent carbamyl phenylformic acid (compound 12)
A) synthesis of 3-dodecyloxy aniline:
Metha Amino Phenon (3.0g, 27.5mmol) is added successively, acetone 50ml in reaction flask, 1-bromine n-dodecane (7.2ml, 32.0mmol), Anhydrous potassium carbonate (9g, 64mmol) with appropriate Tetrabutyl amonium bromide, stirring and refluxing reaction 18h.Filter, filtrate reduced in volume recycling design obtains white solid 4.6g, yield 60%.
1H-NMR(CDCl 3)：δ7.100-6.333(m，4H)，3.910(t，2H)，1.753(m，2H)，1.433-1.268(m，18H)，0.882(t，3H)。
B) the benzoic synthesis of the adjacent carbamyl of N-(3-dodecyloxy phenyl)-6-nitro:
Add 3-dodecyloxy aniline (0.31g, 1.1mmol) successively in reaction flask, acetone (40ml), 3-nitrophthalic acid acid anhydride (0.22g, 1.1mmol), reacts 2h under room temperature.TLC monitoring reaction is complete.Concentrating under reduced pressure recycling design obtains crude product, obtains target compound, white solid 0.1g, yield 19% after silica gel column chromatography with sherwood oil/acetone recrystallization.
1H-NMR(d 6-DMSO)：δ13.811(s，1H)，10.625(s，NH)，6.667-8.189(m，7H)，3.922(t，2H)，1.699(m，2H)，1.233-1.397(m，18H)，0.840(t，3H)。
ESI-MS(m/z)：471，493。mp：131.5-132.1℃。
The preparation of embodiment 13:N-(4-oxygen in last of the ten Heavenly stems base phenyl)-3-nitro-adjacent carbamyl phenylformic acid (compound 13)
A) synthesis of 4-oxygen in last of the ten Heavenly stems base aniline:
4-nitrophenols (4.0g, 28.8mmol) is added successively, acetone 50ml in reaction flask, 1-bromine n-decane (6.0ml, 28.8mmol), Anhydrous potassium carbonate (8g, 57.6mmol) with appropriate Tetrabutyl amonium bromide, stirring and refluxing reaction 18h.Filter, filtrate reduced in volume recycling design obtains yellow oil, not purified direct input next step.
Dehydrated alcohol 50ml is added, 0.8g 10%Pd/C, normal pressure hydrogenation reaction 8h in above-mentioned residue.Filter, remove Pd/C, through column chromatography after filtrate is concentrated, obtain colorless oil 5.0g, yield 70%.
1H-NMR(CDCl 3)：δ6.758-6.628(m，4H)，3.875(t，2H)，1.737(m，2H)，1.430-1.270(m，14H)，0.883(t，3H)。
B) synthesis of N-(4-oxygen in last of the ten Heavenly stems base phenyl)-3-nitro phthalamic acid:
Add 4-oxygen in last of the ten Heavenly stems base aniline (0.60g, 2.4mmol) successively in reaction flask, acetone (40ml), 3-nitrophthalic acid acid anhydride (0.46g, 2.4mmol), reacts 2h under room temperature.TLC monitoring reaction is complete.Concentrating under reduced pressure recycling design obtains crude product, obtains target compound, white solid 0.36g, yield 34% after silica gel column chromatography with sherwood oil/acetone recrystallization.
1H-NMR(d 6-DMSO)：δ13.783(s，1H)，10.397(s，NH)，6.855-8.276(m，7H)，3.918(t，2H)，1.686(m，2H)，1.245-1.396(m，14H)，0.848(t，3H)。
ESI-MS(m/z)：443。mp：160.0-161.7℃。
The preparation of embodiment 14:N-(2-octadecyloxyphenyl group)-adjacent carbamyl phenylformic acid (compound 14)
A) synthesis of 2-octadecane oxygen base aniline:
O-NP (0.3g, 2.2mmol) is added successively, acetone 20ml in reaction flask, 1-bromine Octadecane (0.72g, 2.2mmol), Anhydrous potassium carbonate (0.6g, 4.3mmol) with appropriate Tetrabutyl amonium bromide, stirring and refluxing reaction 18h.Filter, filtrate reduced in volume recycling design obtains yellow oil, not purified direct input next step.
Dehydrated alcohol 20ml is added, 0.1g 10%Pd/C palladium-carbon catalyst, normal pressure hydrogenation reaction 8h in above-mentioned residue.Filter, remove Pd/C, through column chromatography after filtrate is concentrated, obtain colorless oil 0.61g, yield 79%.
1H-NMR(DMSO)：δ6.742-6.470(m，4H)，4.578(s，NH 2)，3.885(t，2H)，1.696(m，2H)，1.405-1.223(m，30H)，0.840(t，3H)。
B) N-(2-tetradecyloxyaniline phenyl) the benzoic synthesis of adjacent carbamyl:
Add 2-octadecane oxygen base aniline (0.56g, 1.6mmol) successively in reaction flask, acetone (40ml), Tetra hydro Phthalic anhydride (0.23g, 1.6mmol), reacts 2h under room temperature.TLC monitoring reaction is complete.Concentrating under reduced pressure recycling design obtains crude product, obtains target compound, white solid 0.59g, yield 75% after silica gel column chromatography with sherwood oil/acetone recrystallization.
1H-NMR(d 6-DMSO)：δ13.010(s，1H)，9.147(s，NH)，6.930-8.099(m，8H)，3.981(t，2H)，1.700(m，2H)，1.222-1.378(m，30H)，0.840(t，3H)。
ESI-MS(m/z)：510，532。mp：87.4-89.2℃。
The preparation of the chloro-N-of embodiment 15:3,4,5,6-tetra-(3-undecane oxygen base phenyl) adjacent carbamyl phenylformic acid (compound 15)
A) synthesis of 3-undecane oxygen base aniline is with embodiment 6;
B) 3,4,5,6-tetra-chloro-N-(3-undecane oxygen base phenyl) the benzoic synthesis of adjacent carbamyl:
Add 3-undecane oxygen base aniline (0.53g, 2.0mmol) successively in reaction flask, acetone (40ml), 3,4,5,6-tetrachlorophthalic tetrachlorophthalic anhydrid (0.57g, 2.0mmol), reacts 2h under room temperature.TLC monitoring reaction is complete.Concentrating under reduced pressure recycling design obtains crude product, obtains target compound, white solid 0.66g, yield 60% after silica gel column chromatography with sherwood oil/ethyl alcohol recrystallization.
1H-NMR(d 6-DMSO)：δ14.431(s，1H)，10.715(s，NH)，6.685-7.276(m，4H)，3.918(t，2H)，1.693(m，2H)，1.232-1.392(m，16H)，0.839(t，3H)。
mp：104.8-106.9℃。
The preparation of the chloro-N-of embodiment 16:3,4,5,6-tetra-(2-tetradecyloxyaniline phenyl) adjacent carbamyl phenylformic acid (compound 16)
A) synthesis of 2-tetradecyloxyaniline aniline: with embodiment 4;
B) 3,4,5,6-tetra-chloro-N-(2-tetradecyloxyaniline phenyl) the benzoic synthesis of adjacent carbamyl:
Add 2-tetradecyloxyaniline aniline (0.75g, 2.5mmol) successively in reaction flask, acetone (40ml), 3,4,5,6-tetrachlorophthalic tetrachlorophthalic anhydrid (0.71g, 2.5mmol), reacts 2h under room temperature.TLC monitoring reaction is complete.Concentrating under reduced pressure recycling design obtains crude product, obtains target compound, white solid 0.89g, yield 61% after silica gel column chromatography with sherwood oil/ethyl alcohol recrystallization.
1H-NMR(d 6-DMSO)：δ14.354(s，1H)，9.870(s，NH)，6.905-7.852(m，4H)，3.978(t，2H)，1.697(m，2H)，1.217-1.396(m，18H)，0.839(t，3H)。
ESI-MS(m/z)：592，614。mp：129.5-130.2℃。
The preparation of embodiment 17:N-(3-chloro-4-tetradecyloxyaniline phenyl) adjacent carbamyl phenylformic acid (compound 17)
A) synthesis of 3-chloro-4-tetradecyloxyaniline aniline:
The chloro-PAP (0.5g, 3.6mmol) of 2-is added successively, acetone 20ml in reaction flask, 1-bromine n-tetradecane (1.1ml, 3.6mmol), Anhydrous potassium carbonate (1.0g, 7.0mmol) with appropriate Tetrabutyl amonium bromide, stirring and refluxing reaction 18h.Filter, filtrate reduced in volume recycling design, through column chromatography, obtains white solid 0.83g, yield 69%.
1H-NMR(DMSO)：δ6.823-6.425(m，3H)，4.868(s，NH 2)，3.834(t，2H)，1.633(m，2H)，1.384-1.227(m，22H)，0.841(t，3H)。
B) N-(3-chloro-4-tetradecyloxyaniline phenyl) the benzoic synthesis of adjacent carbamyl:
Add 3-chloro-4-tetradecyloxyaniline aniline (0.49g, 1.4mmol) successively in reaction flask, acetone (40ml), Tetra hydro Phthalic anhydride (0.21g, 1.4mmol), reacts 2h under room temperature.TLC monitoring reaction is complete.Concentrating under reduced pressure recycling design obtains crude product, obtains target compound, white solid 0.49g, yield 70% after silica gel column chromatography with sherwood oil/acetone recrystallization.
1H-NMR(d 6-DMSO)：δ13.024(s，1H)，10.296(s，NH)，7.092-7.875(m，7H)，4.004(t，2H)，1.710(m，2H)，1.233-1.417(m，22H)，0.843(t，3H)。
ESI-MS(m/z)：488，505。mp：138.2-139.1℃。
The preparation of embodiment 18:N-(3-tetradecyloxyaniline-4-p-methoxy-phenyl) adjacent carbamyl phenylformic acid (compound 18)
A) synthesis of 3-tetradecyloxyaniline-4-anisidine:
2-methoxyl group-5-amino-phenol (0.5g, 3.5mmol) is added successively, acetone 20ml in reaction flask, 1-bromine n-tetradecane (1.0ml, 3.5mmol), Anhydrous potassium carbonate (1.0g, 7.0mmol) with appropriate Tetrabutyl amonium bromide, stirring and refluxing reaction 18h.Filter, filtrate reduced in volume recycling design, through column chromatography, obtains white solid 0.83g, yield 70%.
1H-NMR(DMSO)：δ6.626-6.014(m，3H)，4.607(s，NH 2)，3.812(t，2H)，3.586(s，3H)1.637(m，2H)，1.365-1.230(m，22H)，0.842(t，3H)。
B) N-(2-tetradecyloxyaniline phenyl) the benzoic synthesis of adjacent carbamyl:
Add 3-tetradecyloxyaniline-4-anisidine (0.46g, 1.4mmol) successively in reaction flask, acetone (40ml), Tetra hydro Phthalic anhydride (0.21g, 1.4mmol), reacts 2h under room temperature.TLC monitoring reaction is complete.Concentrating under reduced pressure recycling design obtains crude product, obtains target compound, white solid 0.44g, yield 66% after silica gel column chromatography with sherwood oil/acetone recrystallization.
1H-NMR(d 6-DMSO)：δ12.961(s，1H)，10.117(s，NH)，6.871-7.851(m，7H)，3.879(t，2H)，3.715(s，3H)，1.704(m，2H)，1.226-1.397(m，22H)，0.839(t，3H)。
ESI-MS(m/z)：484，506。mp：142.7-144.2℃。
The preparation of embodiment 19:2-(2-tetradecyloxyaniline phenylcarbamoyl) nicotinic acid (compound 19)
A) synthesis of 2-tetradecyloxyaniline aniline: with embodiment 11;
B) synthesis of 2-(2-tetradecyloxyaniline phenylcarbamoyl) nicotinic acid:
Add 2-tetradecyloxyaniline aniline (0.45g, 1.5mmol) successively in reaction flask, acetone (40ml), 2,3-dinicotinic acid acid anhydride (0.22g, 1.5mmol), reacts 2h under room temperature.TLC monitoring reaction is complete.Concentrating under reduced pressure recycling design obtains crude product, obtains target compound, white solid 0.57g, yield 86% after silica gel column chromatography with sherwood oil/ethyl alcohol recrystallization.
1H-NMR(d 6-DMSO)：δ13.295(s，1H)，10.363(s，NH)，6.975-8.711(m，7H)，4.112(t，2H)，1.792(m，2H)，1.520(m，2H)，1.188-1.353(m，20H)，0.834(t，3H)。
ESI-MS(m/z)：455，477。mp：86.0-86.7℃。
The preparation of embodiment 20:2-(3-dodecyloxy phenylcarbamoyl) nicotinic acid (compound 20)
A) synthesis of 3-dodecyloxy aniline: with embodiment 12;
B) synthesis of 2-(3-dodecyloxy phenylcarbamoyl) nicotinic acid:
Add 3-dodecyloxy aniline (0.34g, 1.2mmol) successively in reaction flask, acetone (40ml), 2,3-dinicotinic acid acid anhydride (0.19g, 1.2mmol), reacts 2h under room temperature.TLC monitoring reaction is complete.Concentrating under reduced pressure recycling design obtains crude product, obtains target compound, white solid 0.45g, yield 85% after silica gel column chromatography with sherwood oil/ethyl alcohol recrystallization.
1H-NMR(d 6-DMSO)：δ13.360(s，1H)，10.494(s，NH)，6.649-8.766(m，7H)，3.928(t，2H)，1.704(m，2H)，1.241-1.402(m，18H)，0.843(t，3H)。
ESI-MS(m/z)：427。mp：87.0-87.9℃。
The preparation of embodiment 21:2-(4-dodecyloxy phenylcarbamoyl) nicotinic acid (compound 21)
A) synthesis of 4-dodecyloxy aniline: with embodiment 10;
B) synthesis of 2-(4-dodecyloxy phenylcarbamoyl) nicotinic acid:
Add 4-dodecyloxy aniline (0.38g, 1.4mmol) successively in reaction flask, acetone (40ml), 2,3-dinicotinic acid acid anhydride (0.20g, 1.4mmol), reacts 2h under room temperature.TLC monitoring reaction is complete.Concentrating under reduced pressure recycling design obtains crude product, obtains target compound, white solid 0.51g, yield 88% after silica gel column chromatography with sherwood oil/ethyl alcohol recrystallization.
1H-NMR(d 6-DMSO)：δ13.312(s，1H)，10.406(s，NH)，6.879-8.756(m，7H)，3.922(t，2H)，1.685(m，2H)，1.238-1.394(m，18H)，0.844(t，3H)。
ESI-MS(m/z)：427，449。mp：100.2-101.2℃。
The preparation of embodiment 22:2-(4-dodecyloxy-pyridyl-3-carbamyl) nicotinic acid (compound 22)
A) synthesis of 3-amino-4-dodecyloxy pyridine:
500ml distilled water is added successively, 3-nitro-4-pyridone (2.5g, 17.8mmol) in reaction flask, sodium hydroxide (0.71g, 17.8mmol), stirred at ambient temperature 0.5h.Add silver nitrate aqueous solution (3g, 17.8mmol dissolve in 50ml distilled water), stirring at room temperature 1h.Decompression filters, and obtains yellow solid, washing.Vacuum-drying obtains silver salt 4.4g.
In reaction flask, add DMF (30ml), acetonitrile (100ml), silver salt (4.4g, 17.8mmol), 1-bromine n-dodecane (4.3ml, 17.8mmol), reacts 20h at 80 DEG C in oil bath, filtering insolubles, after filtrate reduced in volume, reduced pressure chromatography obtains yellow solid 3.5g, yield 64%.
1H-NMR(DMSO)：8.960-6.485(m，3H)，3.992(t，2H)，1.733(m，2H)，1.284-1.222(m，18H)，0.840(t，3H)。
Dehydrated alcohol 70ml is added, 0.7g 10%Pd/C palladium-carbon catalyst, normal pressure hydrogenation reaction 3h in above-mentioned residue.Filter, remove Pd/C, through column chromatography after filtrate is concentrated, obtain colorless oil 2.68g, yield 85%.
1H-NMR(CDCl 3)：δ7.111-6.293(m，3H)，3.723(t，2H)，1.748(m，2H)，1.244(m，18H)，0.869(t，3H)。
B) synthesis of 2-(4-dodecyloxy-pyridyl-3-carbamyl) nicotinic acid:
Add 4-dodecyloxy-3-aminopyridine (0.68g, 2.5mmol) successively in reaction flask, acetone (40ml), 2,3-dinicotinic acid acid anhydride (0.37g, 2.46mmol), reacts 2h under room temperature.TLC monitoring reaction is complete.Concentrating under reduced pressure recycling design obtains crude product, obtains target compound, white solid 0.64g, yield 71% after silica gel column chromatography with sherwood oil/ethyl alcohol recrystallization.
1H-NMR(d 6-DMSO)：δ13.220(s，1H)，10.494(s，NH)，6.290-8.842(m，6H)，3.987(t，2H)，1.706(m，2H)，1.206-1.240(m，18H)，0.823(t，3H)。
ESI-MS(m/z)：428，450。mp：139.7-141.8℃。
The preparation of embodiment 23:2-(4-dodecyloxy-pyridyl-3-carbamyl) nicotinic acid (compound 23)
A) synthesis of 3-amino-4-dodecyloxy pyridine:
500ml distilled water is added successively, 3-nitro-4-pyridone (2.5g, 17.8mmol) in reaction flask, sodium hydroxide (0.71g, 17.8mmol), stirred at ambient temperature 0.5h.Add silver nitrate aqueous solution (3g, 17.8mmol dissolve in 50ml distilled water), stirring at room temperature 1h.Decompression filters, and obtains yellow solid, washing.Vacuum-drying obtains silver salt 4.4g.
In reaction flask, add DMF (30ml), acetonitrile (100ml), silver salt (4.4g, 17.8mmol), 1-bromine n-dodecane (4.3ml, 17.8mmol), reacts 20h at 80 DEG C in oil bath, filtering insolubles, after filtrate reduced in volume, reduced pressure chromatography obtains yellow solid 3.7g, yield 67%.
1H-NMR(DMSO)：δ8.382-6.394(m，3H)，3.989(t，2H)，1.639(m，2H)，1.248-1.223(m，18H)，0.840(t，3H)。
Dehydrated alcohol 70ml is added, 0.8g 10%Pd/C, normal pressure hydrogenation reaction 3h in above-mentioned residue.Filter, remove Pd/C, through column chromatography after filtrate is concentrated, obtain colorless oil 2.75g, yield 87%.
1H-NMR(CDCl 3)：δ6.710-6.022(m，3H)，3.931(t，2H)，1.742(m，2H)，1.306-1.245(m，18H)，0.875(t，3H)。
B) synthesis of 2-(4-dodecyloxy-pyridyl-3-carbamyl) nicotinic acid:
Add 4-dodecyloxy-3-aminopyridine (0.60g, 2.2mmol) successively in reaction flask, acetone (40ml), 2,3-dinicotinic acid acid anhydride (0.32g, 2.2mmol), reacts 2h under room temperature.TLC monitoring reaction is complete.Concentrating under reduced pressure recycling design obtains crude product, obtains target compound, white solid 0.47g, yield 51% after silica gel column chromatography with sherwood oil/ethyl alcohol recrystallization.
1H-NMR(d 6-DMSO)：δ13.327(s，1H)，10.537(s，NH)，6.341-8.777(m，6H)，3.966(t，2H)，1.656(m，2H)，1.209-1.247(m，18H)，0.823(t，3H)。
ESI-MS(m/z)：428，450。mp：144.0-145.2℃。
The preparation of embodiment 24:2-(2-octadecyloxyphenyl group carbamyl) nicotinic acid (compound 24)
A) synthesis of 2-octadecane oxygen base aniline: with embodiment 14;
B) synthesis of 2-(2-octadecyloxyphenyl group carbamyl) nicotinic acid:
Add 2-octadecane oxygen base aniline (0.61g, 1.7mmol) successively in reaction flask, acetone (20ml), 2,3-dinicotinic acid acid anhydride (0.25g, 1.7mmol), reacts 2h under room temperature.TLC monitoring reaction is complete.Concentrating under reduced pressure recycling design obtains crude product, obtains target compound, white solid 0.58g, yield 67% after silica gel column chromatography with sherwood oil/ethyl alcohol recrystallization.
1H-NMR(d 6-DMSO)：δ13.276(s，1H)，10.366(s，NH)，6.969-8.740(m，7H)，4.103(t，2H)，1.780(m，2H)，1.516(m，2H)，1.201-1.344(m，28H)，0.829(t，3H)。
ESI-MS(m/z)：511，533。mp：91.4-92.9℃。
The preparation of embodiment 25:2-(2-docosane oxygen base phenylcarbamoyl) nicotinic acid (compound 25)
A) preparation of 2-docosane oxygen base aniline:
O-NP (0.3g, 2.2mmol) is added successively, acetone 20ml in reaction flask, 1-bromine n-docosane (0.84g, 2.2mmol), Anhydrous potassium carbonate (0.6g, 4.3mmol) with appropriate Tetrabutyl amonium bromide, stirring and refluxing reaction 18h.Filter, filtrate reduced in volume recycling design obtains yellow oil, not purified direct input next step.
Dehydrated alcohol 20ml is added, 0.1g 10%Pd/C palladium-carbon catalyst, normal pressure hydrogenation reaction 8h in above-mentioned residue.Filter, remove Pd/C, through column chromatography after filtrate is concentrated, obtain colorless oil 0.72g, yield 80%.
1H-NMR(CDCl 3)：δ6.794-6.722(m，4H)，3.981(t，2H)，1.806(m，2H)，1.463-1.255(m，38H)，0.879(t，3H)。
B) synthesis of 2-(2-docosane oxygen base phenylcarbamoyl) nicotinic acid
Add 2-docosane oxygen base aniline (0.85g, 2.04mmol) successively in reaction flask, acetone (20ml), 2,3-dinicotinic acid acid anhydride (0.30g, 2.04mmol), reacts 2h under room temperature.TLC monitoring reaction is complete.Concentrating under reduced pressure recycling design obtains crude product, obtains target compound, white solid 0.74g, yield 64% after silica gel column chromatography with sherwood oil/ethyl alcohol recrystallization.
1H-NMR(d 6-DMSO)：δ13.281(s，1H)，10.372(s，NH)，6.966-8.696(m，7H)，4.095(t，2H)，1.777(m，2H)，1.511(m，2H)，1.195-1.339(m，36H)，0.822(t，3H)。
ESI-MS(m/z)：567。mp：96.5-97.9℃。
The preparation of embodiment 26:2-(2-n-Hexadecane oxygen base phenylcarbamoyl) nicotinic acid (compound 26)
A) synthesis of 2-n-Hexadecane oxygen base aniline:
O-NP (0.3g, 2.2mmol) is added successively, acetone 20ml in reaction flask, 1-bromine n-hexadecane (0.6ml, 2.2mmol), Anhydrous potassium carbonate (0.6g, 4.3mmol) with appropriate Tetrabutyl amonium bromide, stirring and refluxing reaction 18h.Filter, filtrate reduced in volume recycling design obtains yellow oil, not purified direct input next step.
Dehydrated alcohol 20ml is added, 0.1g 10%Pd/C, normal pressure hydrogenation reaction 8h in above-mentioned residue.Filter, remove Pd/C, through column chromatography after filtrate is concentrated, obtain colorless oil 0.61g, yield 85%.
1H-NMR(CDCl 3)：δ6.742-6.453(m，4H)，4.578(s，NH 2)，3.884(t，2H)，1.697(m，2H)，1.406-1.227(m，26H)，0.841(t，3H)。
B) synthesis of 2-(2-n-Hexadecane oxygen base phenylcarbamoyl) nicotinic acid:
Add 2-n-Hexadecane oxygen base aniline (0.8g, 2.4mmol) successively in reaction flask, acetone (20ml), 2,3-dinicotinic acid acid anhydride (0.36g, 2.4mmol), reacts 2h under room temperature.TLC monitoring reaction is complete.Concentrating under reduced pressure recycling design obtains crude product, obtains target compound, white solid 0.73g, yield 63% after silica gel column chromatography with sherwood oil/ethyl alcohol recrystallization.
1H-NMR(d 6-DMSO)：δ13.291(s，1H)，10.362(s，NH)，6.972-8.710(m，7H)，4.110(t，2H)，1.788(m，2H)，1.518(m，2H)，1.204-1.346(m，24H)，0.834(t，3H)。
ESI-MS(m/z)：483，505。mp：86.9-88.6℃。
The preparation of the chloro-N-of embodiment 27:3,4,5,6-tetra-(2-dodecyloxy pyridyl-3-base) adjacent carbamyl phenylformic acid (compound 27)
A) synthesis of 2-dodecyloxy-3-aminopyridine:
500ml water is added, 3-nitro-2 hydroxy pyrimidine (2.5g, 17.8mmol) in reaction flask, sodium hydroxide (0.71g, 17.8mmol), stirred at ambient temperature 0.5h, add silver nitrate aqueous solution 50ml (3g, 17.8mmol) again, stirring at room temperature 1h.Filter, obtain yellow solid, washing is dry afterwards obtains silver salt 4.4g.
In reaction flask, add silver salt (4.4g, 17.8mmol) successively, DMF30ml, acetonitrile 100ml, 1-bromine n-dodecane (4.3ml, 17.8mmol), at 80 DEG C, react 20h.Filter, through silica gel column chromatography (using petrol ether/ethyl acetate gradient elution) after filtrate reduced in volume, obtain yellow solid 3.5g, yield 64%.
1H-NMR(d 6-DMSO)：δ8.960-6.485(m，3H)，3.992(t，2H)，1.733(m，2H)，1.284-1.222(m，18H)，0.840(t，3H)。
3-nitro-2-dodecyloxy pyridine (3.5g, 11.4mmol) is added, dehydrated alcohol 70ml, 0.7g 10%Pd/C palladium-carbon catalyst, normal pressure hydrogenation reaction 3h in reaction flask.Filter, with sherwood oil/acetone recrystallization after filtrate reduced in volume, obtain faint yellow solid 2.68g, yield 85%.
1H-NMR(CDCl 3)：δ7.111-6.293(m，3H)，3.723(t，2H)，1.748(m，2H)，1.244(m，18H)，0.869(t，3H)。
B) 3,4,5,6-tetra-chloro-N-(2-dodecyloxy pyridyl-3-base) the benzoic synthesis of adjacent carbamyl:
Add 2-dodecyloxy-3-aminopyridine (0.37g, 1.3mmol) successively in reaction flask, acetone (40ml), 3,4,5,6-tetrachlorophthalic tetrachlorophthalic anhydrid (0.38g, 1.3mmol), reacts 2h under room temperature.TLC monitoring reaction is complete.Concentrating under reduced pressure recycling design obtains crude product, obtains target compound, white solid 0.41g, yield 55% after silica gel column chromatography with sherwood oil/ethyl alcohol recrystallization.
1H-NMR(d 6-DMSO)：δ14.280(s，1H)，10.204(s，NH)，6.261-8.286(m，4H)，3.918(t，2H)，1.632(m，2H)，1.217-1.365(m，18H)，0.837(t，3H)。
ESI-MS(m/z)：563，565。mp：109.0-109.8℃。
The preparation of embodiment 28:N-(2-dodecyloxy-4-nitrophenyl) adjacent carbamyl phenylformic acid (compound 28)
A) synthesis of 2-dodecyloxy-4-N-methyl-p-nitroaniline:
Acetone (50ml) is added, 2-Amino-5-nitrophenol (5.0g, 32.4mmol) in 100ml there-necked flask, 1-bromine n-dodecane (7.8ml, 32.4mmol), Anhydrous potassium carbonate (9g, 64mmol), and Tetrabutyl amonium bromide (0.5g).Back flow reaction 15h.Insoluble solids is removed in decompression, and after filtrate reduced in volume, reduced pressure chromatography (petrol ether/ethyl acetate, gradient), obtains white solid 9.9g, yield 95%.
1H-NMR(CDCl 3)：δ7.819-6.634(m，3H)，4.073(t，2H)，1.845(m，2H)，1.476-1.269(m，18H)，0.881(t，3H)。
B) N-(2-dodecyloxy-4-nitrophenyl) the benzoic synthesis of adjacent carbamyl:
Add 2-dodecyloxy-4-N-methyl-p-nitroaniline (0.80g, 2.5mmol) successively in reaction flask, acetone (20ml), Tetra hydro Phthalic anhydride (0.37g, 2.5mmol), reacts 2h under room temperature.TLC monitoring reaction is complete.Concentrating under reduced pressure recycling design obtains crude product, obtains target compound, obtains white solid 0.19g, yield 16% after silica gel column chromatography with sherwood oil/acetone recrystallization.
1H-NMR(d 6-DMSO)：δ13.112(s，1H)，9.722(s，NH)，7.521-8.343(m，7H)，4.137(t，2H)，1.741(m，2H)，1.212-1.380(m，18H)，0.840(t，3H)。
ESI-MS(m/z)：471，493。mp：104.2-105.4℃。
The preparation of embodiment 29:N-(4-dodecyloxy-3-pyridyl) adjacent carbamyl phenylformic acid (compound 29)
A) synthesis of 3-nitro-4-dodecyloxy pyridine:
500ml water is added, 3-nitro-4-pyridone (2.5g, 17.8mmol) in reaction flask, sodium hydroxide (0.71g, 17.8mmol), stirred at ambient temperature 0.5h, add silver nitrate aqueous solution 50ml (3g, 17.8mmol) again, stirring at room temperature 1h.Filter, obtain yellow solid, washing is dry afterwards obtains silver salt 4.4g.
In reaction flask, add silver salt (4.4g, 17.8mmol) successively, DMF30ml, acetonitrile 100ml, 1-bromine n-dodecane (4.3ml, 17.8mmol), at 80 DEG C, react 20h.Filter, through silica gel column chromatography (using petrol ether/ethyl acetate gradient elution) after filtrate reduced in volume, obtain yellow solid 3.5g, yield 64%.
1H-NMR(d 6-DMSO)：δ8.960-6.485(m，3H)，3.992(t，2H)，1.733(m，2H)，1.284-1.222(m，18H)，0.840(t，3H)。
B) synthesis of 3-amino-4-dodecyloxy pyridine:
3-nitro-4-dodecyloxy pyridine (3.5g, 11.4mmol) is added, dehydrated alcohol 70ml, 0.7g 10%Pd/C palladium-carbon catalyst, normal pressure hydrogenation reaction 3h in reaction flask.Filter, with sherwood oil/acetone recrystallization after filtrate reduced in volume, obtain faint yellow solid 2.68g, yield 85%.
1H-NMR(CDCl 3)：δ7.111-6.293(m，3H)，3.723(t，2H)，1.748(m，2H)，1.244(m，18H)，0.869(t，3H)。
C) N-(4-dodecyloxy-3-pyridyl) adjacent carbamyl phenylformic acid:
Add 4-dodecyloxy-3-aminopyridine (0.80g, 2.8mmol) successively in reaction flask, acetone (40ml), Tetra hydro Phthalic anhydride (0.42g, 2.8mmol), reacts 2h under room temperature.TLC monitoring reaction is complete.Concentrating under reduced pressure recycling design obtains crude product, obtains white solid 1.11g, yield 91% after silica gel column chromatography with sherwood oil/ethyl alcohol recrystallization.
1H-NMR(d 6-DMSO)：δ13.151(s，1H)，8.928(s，NH)，6.245-8.765(m，7H)，3.973(t，2H)，1.705(m，2H)，1.227(m，18H)，0.836(t，3H)。
ESI-MS(m/z)：427。mp：131.9-132.7℃。
The preparation of embodiment 30:N-(2-dodecyloxy-3-pyridyl)-adjacent carbamyl phenylformic acid (compound 30)
A) synthesis of 2-dodecyloxy-3-aminopyridine: with embodiment 27;
B) N-(2-dodecyloxy-3-the pyridyl)-benzoic synthesis of adjacent carbamyl:
Add 2-dodecyloxy-3-aminopyridine (0.18g, 0.65mmol) successively in reaction flask, acetone (40ml), Tetra hydro Phthalic anhydride (0.10g, 0.65mmol), reacts 2h under room temperature.TLC monitoring reaction is complete.Concentrating under reduced pressure recycling design obtains crude product, obtains white solid 0.24g, yield 87% after silica gel column chromatography with sherwood oil/ethyl alcohol recrystallization.
1H-NMR(d 6-DMSO)：δ13.049(s，1H)，9.096(s，NH)，6.286-8.261(m，7H)，3.926(t，2H)，1.636(m，2H)，1.221(m，18H)，0.836(t，3H)。
ESI-MS(m/z)：427，449。mp：124.1-124.9℃。
The preparation of embodiment 31:N-(2-tetradecyloxyaniline phenyl)-2-carbamyl-6-fluorobenzoic acid (compound 31)
Add 2-tetradecyloxyaniline aniline (0.61g, 2.0mmol) successively in reaction flask, acetone (40ml), 3-difluorophthalic anhydride (0.33g, 2.0mmol), reacts 2h under room temperature.TLC monitoring reaction is complete.Concentrating under reduced pressure recycling design obtains crude product, obtains target compound, white solid 0.79g, yield 84% after silica gel column chromatography with sherwood oil/acetone recrystallization.
1H-NMR(d 6-DMSO)：δ13.267(s，1H)，9.450(s，NH)，7.953-7.979(d，1H)，7.741-7.764(d，1H)，7.464-7.601(m，2H)，7.003-7.111(m，2H)，6.905-6.955(t，2H)，3.945(t，2H)，1.701(m，2H)，1.207-1.381(m，22H)，0.745(t，3H)。
ESI-MS(m/z)：472，494。
The preparation of embodiment 32:N-(2-tetradecyloxyaniline-5-tert-butyl-phenyl)-2-carbamyl phenylformic acid (compound 32)
Add 2-tetradecyloxyaniline-5-tertiary butyl aniline (0.72g, 2.0mmol) successively in reaction flask, acetone (40ml), Tetra hydro Phthalic anhydride (0.3g, 2.0mmol), reacts 2h under room temperature.TLC monitoring reaction is complete.Concentrating under reduced pressure recycling design obtains crude product, after silica gel column chromatography, obtain target compound with sherwood oil/acetone recrystallization, off-white color solid 0.8g, yield 78%.
1H-NMR(d 6-DMSO)：7.979(s，1H)，7.805-7.830(d，1H)，7.527-7.616(m，3H)，7.087-7.117(d，1H)，6.927-6.955(d，1H)，3.949(t，2H)，1.673(m，2H)，1.210-1.361(m，31H)，0.834(t，3H)。
ESI-MS(m/z)：510，532。
The preparation of embodiment 33:N-(2-tetradecyloxyaniline-5-isopropyl phenyl)-2-carbamyl-6-fluorobenzoic acid (compound 33)
Add 2-tetradecyloxyaniline-5-isopropyl aniline (0.64g, 2.0mmol) successively in reaction flask, acetone (40ml), 3-difluorophthalic anhydride (0.33g, 2.0mmol), reacts 2h under room temperature.TLC monitoring reaction is complete.Concentrating under reduced pressure recycling design obtains crude product, obtains target compound, light yellow solid 0.79g, yield 77% after silica gel column chromatography with sherwood oil/acetone recrystallization.
1H-NMR(d 6-DMSO)：7.861(s，1H)，7.735-7.759(d，1H)，7.475-7.606(m，2H)，6.913-6.979(m，2H)，3.929(t，2H)，2.817(m，1H)，1.658(m，2H)，1.210-1.361(m，28H)，0.834(t，3H)。ESI-MS(m/z)：514，536。
The preparation of embodiment 34:N-(2-tetradecyloxyaniline-3,4-3,5-dimethylphenyl)-2-carbamyl-6-fluorobenzoic acid (compound 34)
Add 2-tetradecyloxyaniline-3,4-xylidine (0.67g, 2.0mmol) successively in reaction flask, acetone (40ml), 3-difluorophthalic anhydride (0.33g, 2.0mmol), reacts 2h under room temperature.TLC monitoring reaction is complete.Concentrating under reduced pressure recycling design obtains crude product, after silica gel column chromatography, obtain target compound with sherwood oil/acetone recrystallization, off-white color solid 0.61g, yield 61%.
1H-NMR(d 6-DMSO)：7.745-7.770(d，1H)，7.510-7.636(m，3H)，6.897-6.925(d，1H)，3.723(t，2H)，2.194(s，3H)，2.118(s，3H)，1.666(m，2H)，1.207-1.381(m，22H)，0.837(t，3H)。
ESI-MS(m/z)：500，522。
The preparation of embodiment 35:N-(2-tetradecyloxyaniline-3,5-di-tert-butyl-phenyl)-2-carbamyl-6-fluorobenzoic acid (compound 35)
Add 2-tetradecyloxyaniline-3,4-di-tert-butyl aniline (0.83g, 2.0mmol) successively in reaction flask, acetone (40ml), 3-difluorophthalic anhydride (0.33g, 2.0mmol), reacts 2h under room temperature.TLC monitoring reaction is complete.Concentrating under reduced pressure recycling design obtains crude product, obtains target compound, light yellow solid 0.68g, yield 58% after silica gel column chromatography with sherwood oil/acetone recrystallization.
1H-NMR(d 6-DMSO)：7.733-7.784(m，2H)，7.470-7.565(m，2H)，7.113(s，1H)，3.888(t，2H)1.703(m，2H)，1.207-1.381(m，22H)，0.835(t，3H)。
ESI-MS(m/z)：584，606。
The preparation of embodiment 36:N-(2-tetradecyloxyaniline-3,5-3,5-dimethylphenyl)-2-carbamyl phenylformic acid (compound 36)
Add 2-tetradecyloxyaniline-3,5-xylidine (0.67g, 2.0mmol) successively in reaction flask, acetone (40ml), Tetra hydro Phthalic anhydride (0.3g, 2.0mmol), reacts 2h under room temperature.TLC monitoring reaction is complete.Concentrating under reduced pressure recycling design obtains crude product, obtains target compound, white solid 0.79g, yield 82% after silica gel column chromatography with sherwood oil/acetone recrystallization.
1H-NMR(d 6-DMSO)：9.227(s，NH)，7.824-7.848(d，1H)，7.501-7.619(m，4H)，6.805(s，1H)，3.747(t，2H)，2.260(s，3H)，2.179(s，3H)，1.637(m，2H)，1.180-1.372(m，22H)，0.843(t，3H)。
ESI-MS(m/z)：482，504。
The preparation of embodiment 37:N-(2-tetradecyloxyaniline-4,5-3,5-dimethylphenyl)-2-carbamyl phenylformic acid (compound 37)
Add 2-tetradecyloxyaniline-4,5-xylidine (0.67g, 2.0mmol) successively in reaction flask, acetone (40ml), Tetra hydro Phthalic anhydride (0.3g, 2.0mmol), reacts 2h under room temperature.TLC monitoring reaction is complete.Concentrating under reduced pressure recycling design obtains crude product, obtains target compound, white solid 0.69g, yield 72% after silica gel column chromatography with sherwood oil/acetone recrystallization.
1H-NMR(d 6-DMSO)：9.044(s，NH)，7.794-7.819(d，1H)，7.494-7.601(m，4H)，6.652(s，1H)，3.903(t，2H)，2.182(s，3H)，2.144(s，3H)，1.669(m，2H)，1.180-1.372(m，22H)，0.836(t，3H)。
ESI-MS(m/z)：482，504。
The preparation of embodiment 38:N-(2-tetradecyloxyaniline-3,6-3,5-dimethylphenyl)-2-carbamyl phenylformic acid (compound 38)
Add 2-tetradecyloxyaniline-3,6-xylidine (0.67g, 2.0mmol) successively in reaction flask, acetone (40ml), Tetra hydro Phthalic anhydride (0.3g, 2.0mmol), reacts 2h under room temperature.TLC monitoring reaction is complete.Concentrating under reduced pressure recycling design obtains crude product, obtains target compound, white solid 0.78g, yield 81% after silica gel column chromatography with sherwood oil/acetone recrystallization.
1H-NMR(d 6-DMSO)：7.814-7.839(d，1H)，7.515-7.538(d，1H)，7.278-7.324(m，2H)，6.959-6.984(d，1H)，6.846-6.871(d，1H)，3.705(t，2H)，2.169(s，3H)，2.105(s，3H)，1.551(m，2H)，1.101-1.381(m，22H)，0.840(t，3H)。
ESI-MS(m/z)：482，504。
The preparation of embodiment 39:N-(2-tetradecyloxyaniline-3,4-3,5-dimethylphenyl)-2-carbamyl phenylformic acid (compound 39)
Add 2-tetradecyloxyaniline-3,4-xylidine (0.67g, 2.0mmol) successively in reaction flask, acetone (40ml), Tetra hydro Phthalic anhydride (0.3g, 2.0mmol), reacts 2h under room temperature.TLC monitoring reaction is complete.Concentrating under reduced pressure recycling design obtains crude product, obtains target compound, white solid 0.71g, yield 74% after silica gel column chromatography with sherwood oil/acetone recrystallization.
1H-NMR(d 6-DMSO)：7.820-7.844(d，1H)，7.510-7.668(m，4H)，6.900-6.926(d，1H)，3.736(t，2H)，2.194(s，3H)，2.121(s，3H)，1.655(m，2H)，1.179-1.344(m，22H)，0.838(t，3H)。
ESI-MS(m/z)：482，504。
The preparation of embodiment 40:N-(2-tetradecyloxyaniline-4-aminomethyl phenyl)-2-carbamyl phenylformic acid (compound 40)
Add 2-tetradecyloxyaniline-4-monomethylaniline (0.64g, 2.0mmol) successively in reaction flask, acetone (40ml), Tetra hydro Phthalic anhydride (0.3g, 2.0mmol), reacts 2h under room temperature.TLC monitoring reaction is complete.Concentrating under reduced pressure recycling design obtains crude product, obtains target compound, white solid 0.76g, yield 80% after silica gel column chromatography with sherwood oil/acetone recrystallization.
1H-NMR(d 6-DMSO)：δ12.975(s，1H)，9.041(s，NH)，7.508-7.7.796(m，5H)，6.830(s，1H)，6.693-6.723(d，1H)，3.928(t，2H)，2.268(s，3H)，1.683(m，2H)，1.206-1.381(m，22H)，0.839(t，3H)。
ESI-MS(m/z)：468，490。
The preparation of embodiment 41:N-(2-tetradecyloxyaniline-4-methoxycarbonyl-phenyl)-2-carbamyl phenylformic acid (compound 41)
Add 2-tetradecyloxyaniline-4-methoxycarbonyl aniline (0.73g, 2.0mmol) successively in reaction flask, acetone (40ml), Tetra hydro Phthalic anhydride (0.3g, 2.0mmol), reacts 2h under room temperature.TLC monitoring reaction is complete.Concentrating under reduced pressure recycling design obtains crude product, obtains target compound, white solid 0.65g, yield 64% after silica gel column chromatography with sherwood oil/acetone recrystallization.
1H-NMR(d 6-DMSO)：δ13.082(s，1H)，9.428(s，NH)，8.179-8.205(d，1H)，7.848-7.870(d，1H)，7.521-7.654(m，5H)，4.054(t，2H)，3.837(s，3H)，1.723(m，2H)，1.207-1.381(m，22H)，0.839(t，3H)。
ESI-MS(m/z)：512，534。
The preparation of embodiment 42:N-(2-tetradecyloxyaniline-5-methoxycarbonyl-phenyl)-2-carbamyl phenylformic acid (compound 42)
Add 2-tetradecyloxyaniline-5-methoxycarbonyl aniline (0.73g, 2.0mmol) successively in reaction flask, acetone (40ml), Tetra hydro Phthalic anhydride (0.3g, 2.0mmol), reacts 2h under room temperature.TLC monitoring reaction is complete.Concentrating under reduced pressure recycling design obtains crude product, obtains target compound, white solid 0.51g, yield 50% after silica gel column chromatography with sherwood oil/acetone recrystallization.
1H-NMR(d 6-DMSO)：9.139(s，NH)，7.814-7.834(d，2H)，7.514-7.616(m，3H)，6.987(s，2H)，3.966(t，2H)，3.604(s，3H)，1.688(m，2H)，1.207-1.371(m，22H)，0.840(t，3H)。
ESI-MS(m/z)：512，534。
The preparation of embodiment 43:N-(2-tetradecyloxyaniline-4-morpholino phenyl)-2-carbamyl phenylformic acid (compound 43)
Add 2-tetradecyloxyaniline-4-morpholinyl phenylamine (0.78g, 2.0mmol) successively in reaction flask, acetone (40ml), Tetra hydro Phthalic anhydride (0.3g, 2.0mmol), reacts 2h under room temperature.TLC monitoring reaction is complete.Concentrating under reduced pressure recycling design obtains crude product, obtains target compound, yellow solid 0.63g, yield 58% after silica gel column chromatography with sherwood oil/acetone recrystallization.
1H-NMR(d 6-DMSO)：6.513-7.862(m，7H)，3.980(t，2H)，3.769(s，4H)，3.110(s，4H)，1.718(m，2H)，1.207-1.381(m，22H)，0.886(t，3H)。
ESI-MS(m/z)：539，561。
Embodiment 44:
The prescription of the tablet of the 50mg/ sheet of compound 19:2-(2-tetradecyloxyaniline phenylcarbamoyl) nicotinic acid prepared by embodiment 19 and technique (by 1000 calculating):
Compound 19 50g
Sodium starch glycolate 10g
Microcrystalline Cellulose 20g
Lactose 165g
Polyvinylpyrrolidone: appropriate
Magnesium Stearate: 0.5%
Preparation technology: compound 19 and auxiliary material are pulverized, compound 19 is crossed 120 mesh sieves, and it is for subsequent use that 100 mesh sieves crossed by auxiliary material.
By recipe quantity Weigh Compound 19, sodium starch glycolate 10g, Microcrystalline Cellulose, lactose, by equivalent progressively increase principle mixing, crossing 60 mesh sieves makes it more even, with the aqueous solution softwood of 10% polyvinylpyrrolidone, crosses 20 mesh sieve wet granulars, 60 DEG C of oven dry of ventilating, dry particle crosses the whole grain of 20 mesh sieve, adds Magnesium Stearate, mixes.
Measure content, calculate sheet weight, with diameter 8.5mm drift compressing tablet, inspection, packing, to obtain final product.
Pharmacological evaluation
Experimental example 1: the compounds of this invention is to the inhibit activities of PTP1B
1. method
Utilize BL21E.Coli intestinal bacteria to prepare the people PTP1B engineering bacteria of gene recombination, and apply GST affinitive layer purification albumen, obtain PTP1B albumen.With nitro phosphoric acid salt for substrate, carry out the zymetology reaction of PTP1B, observation in vitro medicine is on the impact of PTP1B protein-active.
2. result
Determine above-mentioned part of compounds as shown in table 1 to the inhibiting rate of the people PTP1B of gene recombination when final concentration is 10 μMs:
Table 1 compound is to the restraining effect of PTP1B
Numbering Inhibiting rate (%) Numbering Inhibiting rate (%) Numbering Inhibiting rate (%)
Compound 1 26.9 Compound 13 80.8 Compound 34 101.1
Compound 2 88.3 Compound 19 98.5 Compound 35 104.3
Compound 4 98.9 Compound 20 76.0 Compound 36 100.9
Compound 5 61.5 Compound 21 98.5 Compound 37 101.9
Compound 6 98.4 Compound 22 61.7 Compound 38 100.6
Compound 7 99.8 Compound 28 97.5 Compound 39 100.4
Compound 8 54.8 Compound 30 73.1 Compound 40 100.6
Compound 9 97.1 Compound 31 99.7 Compound 41 99.3
Compound 10 99.9 Compound 32 102.0 Compound 42 99.3
Compound 11 97.8 Compound 33 101.1 Compound 43 34.5
Compound 12 98.6
Measure and calculate the IC of several the compounds of this invention 50, result is as shown in table 2.
The inhibiting IC of PTP1B of table 2 part of compounds of the present invention 50(μM).
Numbering IC 50 Numbering IC 50 Numbering IC 50
Compound 2 0.59 Compound 32 0.34 Compound 38 0.75
Compound 4 0.59 Compound 33 0.18 Compound 39 0.25
Compound 11 0.44 Compound 34 0.41 Compound 40 0.32
Compound 19 0.39 Compound 35 0.39 Compound 41 0.20
Compound 28 0.85 Compound 36 0.09 Compound 42 0.43
Compound 31 0.11 Compound 37 0.63
The above results illustrates that the compounds of this invention has certain restraining effect to PTP1B (one of euglycemic agent target spot).
Experimental example 2. compound 11 improves the effect of insulin resistant (IR) Mouse oral glucose tolerance
1. method:
With high-sugar-fat-diet, feed C57BL mouse and form insulin resistant mice model (IR).Meanwhile, feed as Normal group (Con) using normal diet with batch C57BL mouse.
(1) laboratory animal grouping:
Laboratory animal is divided into Normal group (Con) and insulin resistant model group (IR): wherein select C57BL mouse (n=9) to feed with normal diet for Normal group (Con); Insulin resistant model group (IR) selects C57BL mouse (n=27) high-sugar-fat-diet to feed, and insulin resistant model group (IR) is divided into 3 groups at random, is respectively:
Animal pattern control group (IR): oral water;
Rosiglitazone group: oral positive control drug rosiglitazone (15mg/kg);
Compound group: oral administration of compound 11 (100mg/kg).
(2) experimentation:
Successive administration 14 days, to animal oral glucose 2g/kg, the change of blood sugar after observation animal glucose load, and area (AUC) under calculating blood sugar-time curve, i.e. oral glucose tolerance test (OGTT).
2. result:
Result shows, and compare with Con, each time point glucose level of IR treated animal all obviously raises, and demonstrates obvious glucose tolerance phenomenon.Compare with IR treated animal, after compound group and rosiglitazone group glucose load, each time point blood sugar all obviously reduces, and glycemic peaks obviously reduces, as shown in Figure 1;
And area AUC obviously reduces under blood sugar-time curve, as shown in Figure 2, the effect of the oral glucose tolerance obviously improving animal is demonstrated; Illustrate that the insulin resistant mice tool of compound 11 pairs of diet induced has some improvement the effect of glucose tolerance of body, the effect of this effect and euglycemic agent rosiglitazone is similar.
Experimental example 3. compound 11 improves the effect of IR mouse islets element tolerance
1. experimental technique:
With high-sugar-fat-diet, feed C57BL mouse and form insulin resistant mice model (IR).Meanwhile, feed as Normal group (Con) using normal diet with batch C57BL mouse.
(1) laboratory animal grouping:
Laboratory animal is divided into Normal group (Con) and insulin resistant model group (IR): wherein select C57BL mouse (n=9) to feed with normal diet for Normal group (Con); Insulin resistant model group (IR) selects C57BL mouse (n=27) high-sugar-fat-diet to feed, and insulin resistant model group (IR) is divided into 3 groups at random, is respectively:
Animal pattern control group (IR) (n=9): oral water;
Rosiglitazone group (n=9): oral positive control drug rosiglitazone (15mg/kg);
Compound group (n=9): oral administration of compound 11 (100mg/kg).
(2) experimentation: successive administration 10 days, to animal skin hemostasis 0.4U/kg Regular Insulin, the change of blood sugar after observation Regular Insulin load, and area (AUC) under calculating blood sugar-time curve, i.e. insulin tolerance tests (ITT).
2. result:
Result shows, and after Regular Insulin load, each time point glucose level of IR treated animal is all apparently higher than normal control Con group, demonstrates obvious Insulin resistance.Compare with IR animal pattern, after rosiglitazone group Regular Insulin load, each time point blood sugar fall all obviously increases, and illustrates that the susceptibility of animal to Regular Insulin obviously raises; After compound 11 treated animal Regular Insulin load, each time point blood sugar all decreases (as shown in Figure 3), and under blood sugar-time curve, area (AUC) obviously reduces (as shown in Figure 4).The effect of this effect and euglycemic agent rosiglitazone is similar, illustrates that the insulin resistant IR mouse of compound 11 pairs of diet induced has the effect of certain increase insulin sensitivity.
Conclusion: compound 11, when dosage is 100mg/kg, obviously can improves insulin tolerance and the oral glucose tolerance of the insulin resistant IR mouse of diet induced, illustrate to have certain insulin-sensitizing effect.

Claims (17)

1. a carboxamide base class aromatic acid compound for the aromatic ring that the alkoxyl group represented by following general formula (IAa) replaces, and physiologically acceptable salt:
Wherein, R 1o is the optional C of ortho position, a position or contraposition 10-24straight or branched alkoxyl group;
R 2for one or more substituting group, be selected from H, halogen, nitro or C 1-6alkoxyl group, C 1-6straight or branched fatty group, C 1-6alkoxy carbonyl, carboxyl.
2. compound according to claim 1, is characterized in that, described compound is the compound shown in general formula (IAa1), and physiologically acceptable salt:
Wherein, R 1o is optional decane oxygen base, n-undecane oxygen base, n-dodecane oxygen base, n-tridecane oxygen base, n-tetradecane oxygen base, Pentadecane oxygen base, n-hexadecane oxygen base, n-heptadecane oxygen base, Octadecane oxygen base, NSC 77136 oxygen base, NSC 62789 oxygen base, heneicosane oxygen base or the n-docosane oxygen base of ortho position, a position or contraposition.
3. compound according to claim 1, is characterized in that, described compound is the compound shown in general formula (IAa2), and physiologically acceptable salt:
Wherein, R 1o is optional decane oxygen base, n-undecane oxygen base, n-dodecane oxygen base, n-tridecane oxygen base, n-tetradecane oxygen base, Pentadecane oxygen base, n-hexadecane oxygen base, n-heptadecane oxygen base, Octadecane oxygen base, NSC 77136 oxygen base, NSC 62789 oxygen base, heneicosane oxygen base or the n-docosane oxygen base of ortho position, a position or contraposition;
R 2be selected from F, Cl, Br or I.
4. compound according to claim 1, is characterized in that, described compound is the compound shown in general formula (IAa3), and physiologically acceptable salt:
Wherein, R 1o is optional decane oxygen base, n-undecane oxygen base, n-dodecane oxygen base, n-tridecane oxygen base, n-tetradecane oxygen base, Pentadecane oxygen base, n-hexadecane oxygen base, n-heptadecane oxygen base, Octadecane oxygen base, NSC 77136 oxygen base, NSC 62789 oxygen base, heneicosane oxygen base or the n-docosane oxygen base of ortho position, a position or contraposition;
R 2be selected from methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy or pentyloxy.
5. compound according to claim 1, is characterized in that, described compound is the compound shown in general formula (IAa4), and physiologically acceptable salt:
Wherein, R 1o is optional decane oxygen base, n-undecane oxygen base, n-dodecane oxygen base, n-tridecane oxygen base, n-tetradecane oxygen base, Pentadecane oxygen base, n-hexadecane oxygen base, n-heptadecane oxygen base, Octadecane oxygen base, NSC 77136 oxygen base, NSC 62789 oxygen base, heneicosane oxygen base or the n-docosane oxygen base of ortho position, a position or contraposition.
6. a carboxamide base class aromatic acid compound for the aromatic ring that the alkoxyl group represented by following general formula (IAb) replaces, and physiologically acceptable salt:
Wherein, R 1o is optional decane oxygen base, n-undecane oxygen base, n-dodecane oxygen base, n-tridecane oxygen base, n-tetradecane oxygen base, Pentadecane oxygen base, n-hexadecane oxygen base, n-heptadecane oxygen base, Octadecane oxygen base, NSC 77136 oxygen base, NSC 62789 oxygen base, heneicosane oxygen base or the n-docosane oxygen base of ortho position, a position or contraposition.
7. a carboxamide base class aromatic acid compound for the aromatic ring that the alkoxyl group represented by following general formula (IAc) replaces, and physiologically acceptable salt:
Wherein, R 1o is optional decane oxygen base, n-undecane oxygen base, n-dodecane oxygen base, n-tridecane oxygen base, n-tetradecane oxygen base, Pentadecane oxygen base, n-hexadecane oxygen base, n-heptadecane oxygen base, Octadecane oxygen base, NSC 77136 oxygen base, NSC 62789 oxygen base, heneicosane oxygen base or the n-docosane oxygen base of ortho position, a position or contraposition;
R 3be selected from F, Cl, Br or I.
8. a carboxamide base class aromatic acid compound for the aromatic ring that the alkoxyl group represented by following general formula (IB) replaces, and physiologically acceptable salt:
Wherein, R 1o is the optional C of ortho position, a position or contraposition 10-22straight or branched alkoxyl group;
R 2for one or more substituting group, be selected from H, halogen, nitro, C 1-6alkoxyl group, C 1-6straight or branched fatty group, C 1-6alkoxy carbonyl, carboxyl;
R 3be selected from H, the mono-substituted or polysubstituted halogen of ortho position, a position or contraposition or nitro.
9. the carboxamide base class aromatic acid compound of the aromatic ring of a class alkoxyl group replacement, and physiologically acceptable salt:, it is characterized in that, described compound is selected from:
10. the preparation method of the compound described in any one of claim 1 ~ 9, is characterized in that, comprises the steps:
Substituted or unsubstituted alkoxyl aniline and substituted or unsubstituted Tetra hydro Phthalic anhydride, dinicotinic acid anhydride reactant are obtained the compound shown in general formula (I):
Or obtain the compound shown in general formula (I) with substituted or unsubstituted alkoxyl aniline and substituted or unsubstituted adjacent benzoyl chloride, substituted or unsubstituted pyridine acyl chloride reaction:
Wherein, R is chlorine
, R 4for methoxyl group, oxyethyl group, tert.-butoxy or benzyloxy;
X is C atom, Y is selected from C or atom N,
R 1, R 2and R 3definition and claim 1-9 any one of identical.
11. preparation methods according to claim 10, it is characterized in that: by substituted or unsubstituted nitrophenols and halohydrocarbon generation substitution reaction, generate substituted or unsubstituted alkoxyl nitrobenzene, obtain substituted or unsubstituted alkoxyl aniline through reduction reaction:
X is C atom, R 1and R 2definition and claim 1-9 any one of identical.
12. preparation methods according to claim 10, is characterized in that: described substituted or unsubstituted alkoxyl aniline is by by substituted or unsubstituted amino-phenol and halohydrocarbon generation substitution reaction, generates substituted or unsubstituted alkoxyl aniline:
R 1and R 2definition and claim 1-9 any one of identical.
13. 1 kinds of pharmaceutical compositions, is characterized in that, the compound as described in any one of claim 1 ~ 9 containing effective dose and pharmaceutically acceptable carrier.
14. pharmaceutical compositions according to claim 13, is characterized in that described pharmaceutical composition is selected from tablet, capsule, pill, injection, sustained release preparation, controlled release preparation or particulate delivery system.
The application of compound described in 15. any one of claim 1 ~ 9 in the medicine for the preparation of prevention or the treatment disease relevant with Protein tyrosine phosphatase-1B.
16. application according to claim 15, is characterized in that, described disease is selected from type II diabetes, hypertension, obesity, hyperlipidaemic conditions.
Compound described in 17. any one of claim 1 ~ 9 is preparing the application in Protein tyrosine phosphatase 1B inhibitor.
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