CN102757370B - Derivatives of p-aminobenzoic acid and applications thereof - Google Patents

Derivatives of p-aminobenzoic acid and applications thereof Download PDF

Info

Publication number
CN102757370B
CN102757370B CN2011101040500A CN201110104050A CN102757370B CN 102757370 B CN102757370 B CN 102757370B CN 2011101040500 A CN2011101040500 A CN 2011101040500A CN 201110104050 A CN201110104050 A CN 201110104050A CN 102757370 B CN102757370 B CN 102757370B
Authority
CN
China
Prior art keywords
nmr
dmso
alkyl
etoac
300mhz
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
CN2011101040500A
Other languages
Chinese (zh)
Other versions
CN102757370A (en
Inventor
杨大成
晏菊芳
唐雪梅
陈欣
范莉
张燕
汪航
唐光霞
唐敏辉
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Southwest University
Original Assignee
Southwest University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Southwest University filed Critical Southwest University
Priority to CN2011101040500A priority Critical patent/CN102757370B/en
Publication of CN102757370A publication Critical patent/CN102757370A/en
Application granted granted Critical
Publication of CN102757370B publication Critical patent/CN102757370B/en
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Landscapes

  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses p-aminobenzoic acid derivatives with a general structure shown below. R<1> is C1-C8 alkyl or aryl; n is 0 or 1; either R<2a> or R<2b> is selected; either R<3a> or R<3b> is selected; R<2a> and R<3a> are each independently hydrogen, unsubstituted or substituted C1-C5 alkyl or aryl; R<2b> or R<3b> and adjacent nitrogen atom and carbon atom connected therewith form a nitrogen-containing heterocyclic group; R<4> is-OR<5> or -NR<6>R<7>, or a structure represented below. R<5> is hydrogen, C1-C5 alkyl or C1-C5 haloalkyl; R6 and R7 are each independently hydrogen, hydroxy, C1-C5 alkyl, C1-C5 haloalkyl or C1-C5 hydroxyalkyl; X is O, S, NH, or CH2; p is 0,1 or 2; q is 1, 2, or 3; and the sum of p and q is 2 or 3. The p-aminobenzoic acid derivatives described above have PPAR agonistic activity, and has potential application prospect to be developed into PPAR agonist.

Description

Para-amino benzoic acid derivative and application thereof
Technical field
The invention belongs to chemical field, relate to the para-amino benzoic acid derivative, and the application aspect pharmacy.
Background technology
Diabetes are a kind of whole body chronic metabolic disease that determined by gene, due to the relative of Regular Insulin in body or the definitely not enough disorder that causes sugar, fat and protein metabolism.Diabetes can be divided into insulin-dependent (1 type) and non-insulin-depending type (2 type), and wherein 2 type patients account for more than 90% of diabetes cases.At present, the type 1 diabetes curative is mainly Regular Insulin and analogue thereof; The diabetes B curative mainly contains 5 classes: sulfonylurea, D-phenylalanine class Drugs Promoting Insulin Secretion, biguanides, a-glucosidase inhibitor, euglycemic agent.
Peroxisome proliferation-activated receptors (Peroxisome Proliferator-Activated Receptor, PPAR) is a kind of nuclear receptor and transcription factor relevant with the several genes adjusting that activated by part.Its part comprises endogenous lipid acid and the multiple compounds such as meta-bolites, technical chemistry preparation and synthetic medicine thereof.After by part, being activated, thereby PPAR can be with the PPAR response element (PPRE) of target gene upstream in conjunction with the transcriptional expression of regulating target gene, the regulate several biological processes such as wide participation steatogenesis, metabolism of fat, insulin sensitivity, glucose metabolism, inflammatory reaction, blood pressure regulation, Growth of Cells and differentiation.Previously research shows, the PPAR agonist can reach by the insulin sensitivity enhancing mechanism of number of ways and fall hypoglycemic purpose, no matter is in experimentation on animals or in clinical trial, and the curative effect of PPAR agonist class antidiabetic medicine is all well confirmed.Therefore, the hot fields of PPAR current antidiabetic medicine research as the euglycemic agent of target spot becomes is take in exploitation.
Amino acid is the important signaling molecule of a class, very important effect is arranged affecting aspect insulinoma cell proliferation and insulin secretion.Yoshiko equals nineteen eighty-two and just points out first that some amino acid derivative may become that a class is novel, the antidiabetic medicine of low toxicity.The novel non-sulfonylurea Drugs Promoting Insulin Secretion nateglinide (Nateglinide) that 1990s occurs namely belongs to phenylalanine derivative, and repaglinide (Repaglinide) belongs to the benzoic acids amino acid derivative.In addition, the research discovery, some TYR derivative has very strong PPAR γ in conjunction with activity, and the TYR excitomotor has been considered to PPAR γ, be combined at present a best compounds.International Patent Application WO 0121602 has also been reported the amino acid derivative of a class as PPAR α/γ economic benefits and social benefits agonist, and this analog derivative may become potential antidiabetic medicine.Therefore, the synthetic and anti-diabetic activity research of amino acid derivative becomes the focus that the investigator pays close attention to.
Para-amino benzoic acid (PABA) is important Chemicals and medicine intermediate (synthetic narcotic, folic acid etc.), also can be used as polyurethane adhesive and fodder additives etc.The discovery of Shaman Pharm company, the Compound SP-1 (structural formula is as follows) that contains the PABA structure has anti-diabetic activity preferably, has entered at present clinical study.Chinese patent application 200710157940.1 reports, the 2H-1-chromen-2-one compounds that contains the PABA structure has good alpha-glucosidase and suppresses active.The contriver also finds in early-stage Study, the Beta-aminoketones compound that separately amino in PABA is carried out structural modification and simultaneously the amino in PABA and carboxyl carried out to the structural modification gained all has alpha-glucosidase preferably and suppresses active and PPAR agonist activity (Chinese patent application 200810237001.2), but (structural formula is as follows to adopt chiral amino acid separately the carboxyl in PABA to be carried out to the compd A of structural modification gained, be para-amino benzoic acid chiral amino acid ester derivant) but demonstrate weak PPAR agonist activity (Chinese patent application 200810237245.0), the PPAR agonist activity that wants to improve compd A is described, must carry out further structural modification or transformation to compd A.
Figure BDA0000057306170000021
Summary of the invention
In view of this, the object of the invention is to compd A is carried out to further structural modification or transformation, with searching, have the molecule of better PPAR agonist activity.
For achieving the above object, the invention provides following technical scheme:
Figure BDA0000057306170000022
In formula, R 1For C 1-C 8Alkyl or aryl;
N is 0 or 1;
R 2aWith R 2bOptional one: R 2aFor hydrogen, C 1-C 5Alkyl or aryl, wherein C 1-C 5Alkyl can be by hydroxyl, the C that replaces of replacement or aryl or heterocyclic radical not 1-C 5Alkoxyl group, the C that replaces of replacement or aryl or heterocyclic radical not 1-C 5Alkylthio replaces; R 2bTogether with its adjacent nitrogen atom connected and carbon atom, form nitrogen heterocycle;
R 3aWith R 3bOptional one: R 3aFor hydrogen, C 1-C 5Alkyl or aryl, wherein C 1-C 5Alkyl can be by hydroxyl, the C that replaces of replacement or aryl or heterocyclic radical not 1-C 5Alkoxyl group, the C that replaces of replacement or aryl or heterocyclic radical not 1-C 5Alkylthio replaces; R 3bTogether with its adjacent nitrogen atom connected and carbon atom, form nitrogen heterocycle;
R 4For-OR 5,-NR 6R 7Or
Figure BDA0000057306170000023
R 5For hydrogen, C 1-C 5Alkyl or C 1-C 5Haloalkyl; R 6And R 7Be hydrogen, hydroxyl, C independently of one another 1-C 5Alkyl, C 1-C 5Haloalkyl or C 1-C 5Hydroxyalkyl; X is O, S, NH or CH 2, p be 0,1 or 2, q be 1,2 or 3, p and q sum be 2 or 3.
Further, R 1For C 1-C 8Alkyl or phenyl, wherein phenyl can be selected from arbitrarily following substituting group by 1 to 3 and replace: halogen atom, hydroxyl, nitro, amino, cyano group, carboxyl, ester group, amide group, amine formyl, C 1-C 5Alkyl, C 1-C 5Alkoxyl group and C 1-C 5Alkylthio.
Further, R 2aFor hydrogen, C 1-C 5Alkyl or phenyl, wherein C 1-C 5Alkyl can be by hydroxyl, do not replace or methylthio group, phenyl or 2-indyl that the 5-uracil base replaces replace, and phenyl can be selected from arbitrarily following substituting group by 1 to 3 and replace: halogen atom, hydroxyl, nitro, cyano group, C 1-C 5Alkyl, C 1-C 5Alkoxyl group and C 1-C 5Alkylthio.Further, R 2bThe nitrogen heterocycle formed together with its adjacent nitrogen atom connected and carbon atom is
Figure BDA0000057306170000031
Further, R 3aFor hydrogen, C 1-C 5Alkyl or phenyl, wherein C 1-C 5Alkyl can be by hydroxyl, do not replace or methylthio group, phenyl or 2-indyl that the 5-uracil base replaces replace, and phenyl can be selected from arbitrarily following substituting group by 1 to 3 and replace: halogen atom, hydroxyl, nitro, cyano group, C 1-C 5Alkyl, C 1-C 5Alkoxyl group and C 1-C 5Alkylthio.
Further, R 3bThe nitrogen heterocycle formed together with its adjacent nitrogen atom connected and carbon atom is
Figure BDA0000057306170000033
Further, R 4For-OR 5Or-NR 6R 7R 5For hydrogen, C 1-C 5Alkyl or C 1-C 5Haloalkyl; R 6And R 7Be hydrogen, hydroxyl, C independently of one another 1-C 5Alkyl, C 1-C 5Haloalkyl or C 1-C 5Hydroxyalkyl.
Further, R 1For methyl or phenyl, wherein phenyl can be selected from arbitrarily following substituting group by 1 to 3 and replace: fluorine atom, chlorine atom, bromine atoms, nitro, methyl and methoxyl group; R 2aFor hydrogen, do not replace or the C of phenyl substituted 1-C 4Alkyl; R 2bThe nitrogen heterocycle formed together with its adjacent nitrogen atom connected and carbon atom is
Figure BDA0000057306170000034
R 3aFor hydrogen, C 1-C 4Alkyl or phenyl, wherein C 1-C 4Alkyl can be by hydroxyl, do not replace or methylthio group, phenyl or 2-indyl that the 5-uracil base replaces replace, and phenyl can be replaced by 1 hydroxyl or nitro; R 3bThe nitrogen heterocycle formed together with its adjacent nitrogen atom connected and carbon atom is
Figure BDA0000057306170000035
R 4For-OR 5Or-NR 6R 7R 5For hydrogen, C 1-C 5Alkyl or C 1-C 5Fluoro-alkyl; R 6And R 7Be hydrogen, hydroxyl, C independently of one another 1-C 2Alkyl or C 1-C 2Hydroxyalkyl.
Further, described para-amino benzoic acid derivative be in following compound any (test-results shows, following Compound Phase for the positive with reference to the exciting rate of PPAR of medicine pioglitazone all higher than 40%):
Figure BDA0000057306170000036
Figure BDA0000057306170000041
On the technique scheme basis, in view of above-mentioned para-amino benzoic acid derivative all has certain PPAR agonist activity, the present invention further provides the application of these para-amino benzoic acid derivatives in preparation PPAR agonist.
Beneficial effect of the present invention is: the invention provides the novel para-amino benzoic acid derivative of a class, these derivatives all have certain PPAR agonist activity, wherein the relative agonist activity of the PPAR of compound 1b is up to 87.16%, have and develop the potential application foreground that becomes the PPAR agonist, help the research of Novel diabetes medicine.
Embodiment
In order to make the purpose, technical solutions and advantages of the present invention clearer, below will be described in detail the preferred embodiments of the present invention.
Key instrument used in preferred embodiment: the accurate micro melting point apparatus (Beijing Fu Kai Instrument Ltd.) of X-6 type, WZZ-2S type digital automatic polarimeter (Shanghai Precision Scientific Apparatus Co., Ltd), Spectrum GX type Fourier transformation infrared spectrometer (U.S. PerkinElmer company), AV-300 type NMR spectrometer with superconducting magnet (Switzerland Bruker company), Agilent1946B ESI-MS type mass spectrograph (U.S. Agilent company), Varian 7.0T FTICR-MS type high-resolution mass spectrometer (U.S. Varian company).Main agents: amino acid (Chengdu triumphant safe new technology limited liability company, analytical pure); P-methyl benzene sulfonic chloride, to anisole SULPHURYL CHLORIDE, 4-Nitrobenzenesulfonyl chloride, m-nitrobenzene sulfonyl chloride, Methanesulfonyl chloride (the special Chengdu of Ace medicine technology company limited, analytical pure); Parachloroben-zenesulfonyl chloride, p-bromobenzenesulfonyl chloride (Shanghai reach auspicious fine chemicals company limited); Para-amino benzoic acid (Long Huagongshijichang of Chengdu section, analytical pure); N, N '-DIC (DIC), N, N '-dicyclohexylcarbodiimide (DCC) (Shandong Zibo is industry and trade company limited smoothly, analytical pure); Other conventional reagent and solvent are commercially available analytical pure.
Embodiment 1, compound 1 and 2 synthetic
Figure BDA0000057306170000051
1, intermediate 1-m's is synthetic: add 41.14g para-amino benzoic acid and a certain amount of salt of wormwood in the 1000mL round-bottomed flask, add the water stirring and dissolving, after ice bath is cooling, drip the acetone soln of 74.34g TsCl, finish the stirring at room reaction, thin-layer chromatography (TLC) monitoring reaction process.After having reacted, regulate pH to 6～8 with 2mol/L HCl, vacuum rotary steam is removed acetone, then with 2mol/L HCl, regulates pH to 2～3 under ice bath stirs, separate out solid, standing, filtering and washing, obtain faint yellow solid, vacuum-drying, TLC tests pure, the 87.39g that weighs, yield 96.9%.
2, compound 1 is synthetic: in flask I, add amino acid methyl ester hydrochloride 11mmol, anhydrous tetrahydro furan (THF) 30mL, after stirring 10min, splash into the N of equivalent, N '-diisopropylethylamine (DIPEA).In flask II, add intermediate 1-m10mmol and I-hydroxybenzotriazole (HOBt) 12mmol, add anhydrous THF 30mL, after stirring and dissolving, add DIC or DCC 12mmol, after stir-activating 15min, add liquid in flask I (shifting with a small amount of THF washing), 25 ℃ of lucifuge stirring reactions, TLC monitoring reaction process.After having reacted, filter insolubles, filtrate decompression is revolved to boil off and is desolventized, then adds ethyl acetate (EtOAc) 250mL, and stirring and dissolving, use 0.5mol/L NaHCO successively 3The aqueous solution (3 * 100mL) and the saturated NaCl aqueous solution (2 * 150mL) washing, water layer with EtOAc (2 * 100mL) extraction; Merge the EtOAc layer, anhydrous Na 2SO 4Drying, suction filtration, filtrate is revolved to steam and is removed EtOAc and obtain crude product, then obtains sterling 1 through column chromatography [elutriant is sherwood oil (PE) and the mixed solution of ethyl acetate (EA)].Test-results is in Table 1.
Synthesizing of table 1 compound 1
Figure BDA0000057306170000052
Figure BDA0000057306170000061
Figure BDA0000057306170000071
1a: 1H NMR (DMSO-d 6, 300MHz) δ: 2.33 (s, 3H, CH 3), 3.63 (s, 3H, COOCH 3), 3.96 (d, 2H, J=5.4Hz, NH CH 2 ), 7.17 (d, 2H, J=8.37Hz, Ar-H), 7.36 (d, 2H, J=7.98Hz, Ar-H), 7.74-7.68 (m, 4H, Ar-H), 8.81 (t, 1H, J=5.31Hz, NHCH 2), 10.64 (s, 1H, SO 2NH) .HR MS:C 17H 18N 2O 5S[M+Na] +Calculated value 385.0829, measured value 385.0833.
1b: 1H NMR (DMSO-d 6, 300MHz) δ: 1.36 (d, 3H, J=7.23Hz, CH CH 3 ), 2.33 (s, 3H, CH 3), 3.61 (s, 3H, COOCH 3), 4.39-4.44 (m, 1H, CH), 7.16 (d, 2H, J=8.16Hz, Ar-H), (7.35 d, 2H, J=7.92Hz, Ar-H), 7.70 (d, 2H, J=8.04Hz, Ar-H), (7.74 d, 2H, J=8.22Hz, Ar-H), 8.65 (d, 1H, J=6.72Hz NHCH), 10.63 (s, 1H, SO 2NH). 13C NMR (DMSO-d 6, 75MHz) δ: 173.2,165.6,143.6,140.8,136.3,129.8,128.8,126.8,118.2,51.9,48.2,30.7,20.9,16.7.HR MS:C 18H 20N 2O 5S[M+Na] +Calculated value 399.0985, measured value 399.0991.
Figure BDA0000057306170000072
(c 2mg/mL, EtOAc).
1c: 1H NMR (CDCl 3, 300MHz) δ: 0.96 (s, 6H, 2CH 3), 1.63-1.76 (m, 3H, CH 2CH), 2.36 (s, 3H, Ar-CH 3), 3.75 (s, 3H, COOCH 3), 4.79-4.85 (m, 1H, C HN), 6.58 (d, 1H, J=8.10Hz, NHCH), 7.14 (d, 2H, J=8.40Hz, Ar-H), 7.21 (d, 2H, J=7.80Hz, Ar-H), 7.64 (d, 2H, J=8.40Hz, Ar-H), 7.69 (d, 2H, J=8.10Hz, Ar-H), 8.08 (s, 1H, SO 2NH). 13C NMR (CDCl 3, 300MHz) δ: 174.04,166.66,144.03,144.00,140.52,135.97,135.87,129.69,129.29,129.22,128.41,128.36,127.14,119.38,52.44,51.20,30.95,23.37,22.81,21.87,21.49.HR MS:C 21H 26N 2O 5S[M-H] calculated value 417.1490, measured value 417.1487.
Figure BDA0000057306170000073
(c 2mg/mL, EtOAc).
1d: 1H NMR (CDCl 3, 300MHz) δ: 0.91-0.95 (t, 3H, J=6.84Hz, CH 2 CH 3 ), 1.14 (d, 3H, J=6.42Hz, CH CH 3 ), 1.23-1.52 (m, 2H, CH 2 CH 3), 1.96-1.98 (m, 1H, CH), 2.36 (s, 3H, Ar-CH 3), 3.79 (s, 3H, COOCH 3), 4.74-4.79 (m, 1H, CHN), 6.59 (d, 1H, J=8.37Hz, NHCH), 7.16 (d, 2H, J=8.40Hz, Ar-H), 7.22 (d, 2H, J=8.04Hz, Ar-H), 7.65 (d, 2H, J=8.40Hz, Ar-H), 7.69 (d, 2H, J=8.10Hz, Ar-H), 7.78 (s, 1H, SO 2NH). 13C NMR (CDCl 3, 300MHz) δ: 172.83,166.65,144.00,140.62,135.97,129.70,129.41,128.38,12815,119.41,56.88,52.26,42.18,23.37,21.49,15.47,11.53.HR MS:C 21H 26N 2O 5S[M-H] -Calculated value 417.1490, measured value 417.1487.
Figure BDA0000057306170000081
(c 2mg/mL, EtOAc).
1e: 1H NMR (CDCl 3, 300MHz) δ: 1.00 (d, 6H, J=6.00Hz, CH (CH 3 ) 2 ), 2.20-2.33 (m, 1H, CH), 2.39 (s, 3H, Ar-CH 3), 3.78 (s, 3H, COOCH 3), 4.73-4.78 (m, 1H, CHN), 6.60 (d, 1H, J=8.10Hz, CH NH), 7.19 (d, 2H, J=8.40Hz, Ar-H), 7.24 (d, 2H, J=8.10Hz, Ar-H), 7.69 (d, 2H, J=8.39Hz, Ar-H), 7.72 (d, 2H, J=8.12Hz, Ar-H), 8.00 (bs, 1H, SO 2NH). 13C NMR (CDCl 3, 300MHz) δ: 172.81,166.71,144.067,140.52,135.96,129.73,129.65,128.29,127.18,119.49,57.50,52.31,30.94,23.39,18.98,17.99.HR MS:C 20H 24N 2O 5S[M-H] -Calculated value 403.1333, measured value 403.1327.
Figure BDA0000057306170000082
Figure BDA0000057306170000083
(c 2mg/mL, EtOAc).
1f: 1H NMR (CDCl 3, 300MHz) δ: 2.37 (s, 3H, Ar-CH 3), 3.18-3.25 (m, 2H, CH 2), 3.76 (s, 3H, COOCH 3), 5.02-5.06 (m, 1H, CHN), 6.50 (d, 1H, J=7.45Hz, CH NH), 7.11 (d, 4H, J=8.03Hz, Ar-H), 7.21-7.29 (m, 5H, Ar-H), 7.43 (s, 1H, NH), 7.57 (d, 2H, J=8.38Hz, Ar-H), 7.69 (d, 2H, J=8.08Hz, Ar-H). 13C NMR (CDCl 3, 75MHz) δ: 172.21,166.11,144.27,140.14,135.77,135.71,129.81,129.68,129.24,128.65,128.40,127.22,127.19,119.55,53.51,52.50,37.81,21.54.HR MS:C 24H 24N 2O 5S[M-H] -Calculated value 451.1333, measured value 451.1330.
Figure BDA0000057306170000084
(c 2mg/mL, EtOAc).
1g: 1H NMR (CDCl 3, 300MHz) δ: 2.38 (s, 3H, Ar-CH 3), 3.29-345 (m, 2H, CH CH 2 ), 3.78 (s, 3H, COOCH 3), 5.08-5.11 (m, 1H, CHN), 6.65 (d, 1H, J=7.20Hz, CH NH), 7.13 (d, 2H, J=8.40Hz, Ar-H), (7.24 d, 2H, J=8.10Hz, Ar-H), (7.30 d, 2H, J=8.40Hz, Ar-H), (7.60 d, 2H, J=8.40Hz, Ar-H), (7.71 d, 2H, J=8.40Hz, Ar-H), (8.13 d, 2H, J=8.70Hz, Ar-H) .HR MS:C 24H 23N 3O 7S[M-H] -Calculated value 496.1184, measured value 496.1176. (c 2mg/mL, EtOAc).
1h: 1H NMR (DMSO-d 6, 300MHz) δ: 2.33 (s, 3H, Ar-CH 3), 2.87-3.02 (m, 2H, CH 2), 3.59 (s, 3H, COOCH 3), 4.48-4.50 (m, 1H, CHN), 6.63 (d, 2H, J=8.10Hz, Ar-H), 7.05 (d, 2H, J=8.10Hz, Ar-H), 7.15 (d, 2H, J=8.40Hz, Ar-H), 7.35 (d, 2H, J=7.80Hz, Ar-H), 7.65-7.70 (m, 4H, Ar-H), 8.64 (d, 1H, J=7.50Hz NHCH), 9.21 (s, 1H, SO 2NH), 10.62 (s, 1H, OH). 13C NMR (DMSO-d 6, 75MHz) δ: 172.79,166.22,156.32,143.99,141.25,136.79,130.38,130.22,129.12,129.10,128.05,127.17,118.61,115.46,55.11,52.26,23.72,21.38.HR MS:C 24H 24N 2O 6S[M-H] -Calculated value 467.1282, measured value 467.1280.
Figure BDA0000057306170000086
(c 2mg/mL, EtOAc).
1i: 1H NMR (DMSO-d 6, 300MHz) δ: 2.32 (s, 3H, CH 3), 3.65 (s, 3H, COOCH 3), 4.08-4.13 (m, 1H, C H), 7.17 (d, 2H, J=8.40Hz, Ar-H), 7.35 (d, 2H, J=8.10Hz, Ar-H), 7.68 (t, 3H, J=7.50Hz Ar-H), 7.76 (d, 2H, J=8.70Hz, Ar-H), (7.93 d, 1H, J=7.80Hz, Ar-H), 8.21 (d, 1H, J=8.10Hz, Ar-H), 8.36 (s, 1H, Ar-H), 9.26 (d, 1H, J=7.20Hz, CON H), 10.66 (s, 1H, SO 2NH). 13C NMR (DMSO-d 6, 75MHz) δ: 170.76,166.14,148.15,144.00,141.55,139.22,136.79,135.66,130.40,130.22,129.41,128.58,127.19,123.48,123.43,118.60,56.26,53.02,21.38.HR MS:C 23H 21N 3O 7S[M-H] -Calculated value 482.1027, measured value 482.1024.
Figure BDA0000057306170000091
(c 2mg/mL, EtOAc).
1j： 1H NMR(CDCl 3，300MHz)δ：2.39(s，3H，CH 3)，3.16-3.26(m，2H，CH CH 2 )，3.59-3.71(m，3H，COOCH 3)，4.50-4.73(m，2H，N CH 2 )，5.16-5.44(m，1H，N CH)，6.92(m，1H，SO 2 NH)，7.17-7.24(m，8H，Ar-H)，7.39-7.41(m，2H，Ar-H)，7.71(d，2H，J＝8.10Hz，Ar-H).
Figure BDA0000057306170000092
(c 2mg/mL，EtOAc).
1k: 1H NMR (DMSO-d 6, 300MHz) δ: 2.32 (s, 3H, CH 3), 3.16-3.27 (m, 2H, CH CH 2 ), 3.60 (s, 3H, COOCH 3), 4.58-4.65 (m, 1H, NHC H), 6.97 (t, 1H, J=7.50Hz, Ar-H), 7.06 (t, 1H, J=7.20Hz, Ar-H), 7.13 (d, 2H, J=8.70Hz, Ar-H), 7.18 (s, 1H, indoles-C H), 7.31-7.36 (m, 3H, Ar-H), 7.53 (d, 1H, J=7.80Hz, Ar-H), 7.68 (d, 4H, J=8.10Hz, Ar-H), 8.66 (d, 1H, J=7.20Hz, CON H), 10.61 (s, 1H, SO 2NH), 10.83 (s, 1H, indoles-N H). 13C NMR (DMSO-d 6, 75MHz) δ: 173.00,166.19,144.00,141.22,136.78,136.52,130.22,129.16,129.11,127.44,127.18,124.09,121.41,118.84,118.61,118.41,111.91,110.36,54.22,52.31,27.06,21.38.HR MS:C 26H 25N 3O 5S[M-H] -Calculated value 490.1442, measured value 490.1447.
Figure BDA0000057306170000093
(c 2mg/mL, EtOAc).
1l: 1H NMR (CDCl 3, 300MHz) δ: 1.85-2.05 (m, 4H, 1 CH 2 2 CH 2 ), 2.36 (s, 3H, CH 3), 3.51-3.64 (m, 2H, 3 CH 2 ), 3.75 (s, 3H, COOCH 3), 4.64 (m, 1H, C H), 7.10 (d, 2H, J=8.10Hz, Ar-H), 7.22 (d, 2H, J=8.10Ar-H), 7.45 (d, 2H, J=8.40Hz, Ar-H), 7.68 (d, 3H, J=7.50Hz, Ar-H and SO 2NH). 13C NMR (CDCl 3, 75MHz) δ: 172.83,169.12,143.83,139.29,136.18,131.41,129.62,128.73,127.15,119.49,59.37,52.32,50.05,29.26,25.41,21.43.HR MS:C 20H 22N 2O 5S[M-H] -Calculated value 401.1177, measured value 401.1172.
Figure BDA0000057306170000094
(c 2mg/mL, EtOAc).
1m: 1H NMR (DMSO-d 6, 300MHz) δ: 2.33 (s, 3H, ArCH 3), 3.62 (s, 3H, COOCH 3), 4.08-4.13 (m, 2H, CH CH 2 ), 4.99-5.03 (m, 1H, CHCH 2), 5.03 (t, 1H, J=6.03Hz, CH 2 OH), 7.16 (d, 2H, J=8.43Hz, Ar 1-H), 7.35 (d, 2H, J=7.80Hz, Ar 1-H), 7.69 (d, 2H, J=8.13Hz, Ar 2-H), 7.74 (d, 2H, J=8.43Hz, Ar 2-H), 8.42 (d, 1H, J=6.93Hz, NHCH), 10.61 (s, 1H, SO 2NH). 13C NMR (DMSO-d 6, 75MHz) δ: 171.47,166.22,143.92,141.41,136.91,130.17,129.14,129.08,127.16,118.73,55.99,52.24,23.71,21.36.HR MS:C 18H 20N 2O 6S[M-H] -Calculated value 391.0969, measured value 391.0966.
Figure BDA0000057306170000095
(c2mg/mL, EtOAc).
1n: 1H NMR (CDCl 3, 300MHz) δ: 2.11 (s, 3H, SCH 3), 2.24-2.28 (m, 2H, CH CH 2 ), 2.38 (s, 3H, ArCH 3), 2.57 (t, 2H, J=6.93Hz, CH 2 SCH 3), 3.79 (s, 3H, COOCH 3), 4.86-4.93 (m, 1H, CHCH 2), 6.92 (d, 1H, J=7.20Hz, NHCH), 7.14 (d, 2H, J=8.73Hz, Ar 1-H), 7.24 (t, 2H, J=6.60Hz, Ar 1-H), 7.36 (s, 1H, SO 2NH), 7.67-7.71 (m, 4H, Ar 2-H). 13C NMR (CDCl 3, 75MHz) δ: 172.74,166.37,144.26,140.24,135.76,129.81,129.45,128.49,127.19,119.55,52.71,52.13,31.31,30.10,21.54,15.50.HR MS:C 20H 24N 2O 5S 2[M-H] -Calculated value 435.1054, measured value 435.1050.
Figure BDA0000057306170000096
(c 2mg/mL, EtOAc).
1o: 1H NMR (DMSO-d 6, 300MHz) δ: 2.32 (s, 3H, ArCH 3), 2.73-2.97 (m, 2H, CH CH 2 ), 3.16 (d, 2H, J=5.10Hz, SCH 2), 3.63 (s, 3H, COOCH 3), 4.54-4.62 (m, 1H, CHCH 2), 7.17 (d, 2H, J=8.13Hz, Ar 1-H), 7.35 (d, 2H, J=8.12Hz, Ar 1-H), 7.41 (d, 1H, J=8.43Hz, uridylic-6-H), 7.70 (m, 4H, Ar-H), 8.72 (d, 1H, J=7.53Hz, NHCH), 10.63 (s, 1H, SO 2NH) .10.84 (d, 1H, J=7.23Hz, uridylic-1-N H), 11.16 (s, 1H, uridylic-3-N H). 13C NMR (DMSO-d 6, 75MHz) δ: 171.76,166.19,164.13,151.66,144.02,141.31,139.80,136.74,130.22,129.17,128.96,127.18,118.66,109.44,53.00,52.52,32.33,27.45,21.38.HR MS:C 23H 24N 4O 7S 2[M-H] -Calculated value 531.1014, measured value 531.1013.
Figure BDA0000057306170000101
(c 2mg/mL, EtOAc).
3, compound 2 is synthetic: compound 1 is dissolved in appropriate THF, adds the 1mol/L LiOH aqueous solution, ice bath stirring reaction, TLC monitoring reaction process under ice bath stirs.After having reacted, with 2mol/L HCl, regulate pH to weakly alkaline under ice bath stirs, vacuum rotary steam is removed THF, then regulates pH to 3～4, with the EtOAc extraction, merges organic phase, with saturated NaCl solution washing 2 times, and anhydrous Na 2SO 4Drying, suction filtration, filtrate is revolved and is steamed to the dry sterling 2 that obtains.Test-results is in Table 2.
Synthesizing of table 2 compound 2
Figure BDA0000057306170000102
2a： 1H NMR(DMSO-d 6，300MHz)δ：2.32(s，3H，ArCH 3)，3.86(d，2H，J＝5.70Hz，NH CH 2 )，7.16(d，2H，J＝8.49Hz，Ar 2-H)，7.35(d，2H，J＝8.10Hz，Ar 1-H)，7.69(d，2H，J＝8.40Hz，Ar 1-H)，7.74(d，2H，J＝8.73Hz，Ar 2-H)，8.70(t，1H，J＝5.40Hz， NHCH 2)，10.62(s，1H，SO 2NH)，12.53(s，1H，COOH). 13C NMR(DMSO-d 6，75MHz)δ：171.75，166.23，143.99，141.15，136.83，130.22，129.35，128.92，127.15，118.76，41.58，21.38.
2b： 1H NMR(DMSO-d 6，300MHz)δ：1.00(d，3H，J＝6.60Hz，CH CH 3 )，2.32(s，3H，ArCH 3)，4.30-4.00(m，1H， CHCH 3)，7.16(d，2H，J＝8.73Hz，Ar 2-H)，7.35(d，2H，J＝7.8Hz，Ar 1-H)，7.69(d，2H，J＝8.13Hz，Ar 1-H)，7.74(d，2H，J＝8.43Hz，Ar 2-H)，8.50(d，1H，J＝7.23Hz， NHCH)，10.61(s，1H，SO 2NH)，12.40(s，1H，COOH). 13C NMR(DMSO-d 6，75MHz)δ：174.74，165.83，143.98，141.07，136.76，130.21，129.43，129.10，127.18，48.59，21.37，17.35.
Figure BDA0000057306170000111
(c 2mg/mL，EtOAc).
2c： 1H NMR(DMSO-d 6，300MHz)δ：0.84(d，3H，J＝6.00Hz，CH CH 3 )，0.89(d，3H，J＝6.00Hz，CH CH 3 )，1.50-1.57(m，1H， CHCH 3)，1.61-1.77(m，2H， CH 2 CH)，2.32(s，3H，ArCH 3)，4.33-4.41(m，1H， CHCH 2)，7.15(d，2H，J＝8.49Hz，Ar 2-H)，7.35(d，2H，J＝8.10Hz，Ar 1-H)，7.69(d，2H，J＝8.43Hz，Ar 1-H)，7.73(d，2H，J＝8.73Hz，Ar 2-H)，8.43(d，1H，J＝7.83Hz， NHCH)，10.60(s，1H，SO 2NH)，12.44(s，1H，COOH). 13C NMR(DMSO-d 6，75MHz)δ：174.69，166.19，143.99，141.08，136.83，130.21，129.49，129.13，127.17，118.69，51.22，23.72，23.39，21.54，21.52，21.38. (c2mg/mL，EtOAc).
2d： 1H NMR(DMSO-d 6，300MHz)δ：0.84(t，3H，J＝7.30Hz，CH 2 CH 3 )，0.89(d，3H，J＝6.60Hz，CH CH 3 )，1.15-1.28(m，1H， CH 2 CH 3)，1.43-1.51(m，1H， CH 2 CH 3)，1.88-1.90(m，1H， CHCH 2)，2.33(s，3H，ArCH 3)，4.23-4.28(m，1H，NH CH)，7.15(d，2H，J＝8.49Hz，Ar 2-H)，7.35(d，2H，J＝7.80Hz，Ar 1-H)，7.69(d，2H，J＝8.13Hz，Ar 1-H)，7.74(d，2H，J＝8.73Hz，Ar 2-H)，8.27(d，1H，J＝7.83Hz， NHCH)，10.60(s，1H，SO 2NH)，12.52(s，1H，COOH). 13C NMR(DMSO-d 6，75MHz)δ：173.65，166.48，143.98，141.06，136.81，130.22，129.54，129.31，127.18，118.59，57.59，25.52，23.72，21.38，16.06，11.44.
Figure BDA0000057306170000113
(c 2mg/mL，EtOAc).
2e： 1H NMR(DMSO-d 6，300MHz)δ：0.91-0.95(m，6H，CH CH 3 )，2.09-2.20(m，1H， CHCH 3)，2.33(s，3H，ArCH 3)，4.19-4.24(m，1H，NH CH)，7.16(d，2H，J＝8.70Hz，Ar 2-H)，7.36(d，2H，J＝8.10Hz，Ar 1-H)，7.69(d，2H，J＝8.13Hz，Ar 1-H)，7.75(d，2H，J＝8.49Hz，Ar 2-H)，8.26(d，1H，J＝8.13Hz， NHCH)，10.60(s，1H，SO 2NH)，12.57(s，1H，COOH). 13C NMR(DMSO-d 6，75MHz)δ：173.61，166.61，143.98，141.07，136.82，130.21，129.56，129.33，127.18，58.71，23.72，21.37，19.72，19.20.
Figure BDA0000057306170000114
(c 2mg/mL，EtOAc).
2f： 1H NMR(DMSO-d 6，300MHz)δ：2.32(s，3H，Ar-CH 3)，3.01-3.18(m，2H，CH CH 2 )，4.50-4.56(m，1H， CHN)，7.13(d，2H，J＝8.40Hz，Ar-H)，7.22-7.29(m，4H，Ar-H)，7.35(d，2H，J＝8.10Hz，Ar-H)，7.63-7.69(m，5H，Ar-H)，8.56(d，1H，J＝8.10Hz， NHCH)，10.59(s，1H，SO 2NH)，12.70(s，1H，COOH). 13C NMR(DMSO-d 6，75MHz)δ：173.65，166.14，144.01，141.13，138.58，136.78，130.23，129.43，129.33，129.05，128.60，127.16，126.77，118.62，60.20，54.62，21.39.
Figure BDA0000057306170000121
(c 2mg/mL，EtOAc).
2g： 1H NMR(DMSO-d 6，300MHz)δ：2.32(s，3H，ArCH 3)，3.12-3.29(m，2H，CH CH 2 )，4.60-4.68(m，1H， CHCH 2)，7.13(d，2H，J＝8.43Hz，Ar 1-H)，7.35(d，2H，J＝8.13Hz，Ar 3-H)，7.57(d，2H，J＝8.49Hz，Ar 2-H)，7.64(d，2H，J＝8.73Hz，Ar 2-H)，7.68(d，2H，J＝7.89Hz，Ar 3-H)，8.13(d，2H，J＝8.19Hz，Ar 1-H)，8.65(d，1H，J＝8.13Hz， NHCH)，10.61(s，1H，SO 2NH)，12.81(s，1H，COOH). 13C NMR(DMSO-d 6，75MHz)δ：173.16，166.19，146.96，146.67，143.98，141.20，136.83，130.82，130.20，129.20，129.03，127.15，123.68，118.66，53.92，23.72，21.36.
Figure BDA0000057306170000122
(c 2mg/mL，EtOAc).
2h： 1H NMR(DMSO-d 6，300MHz)δ：2.32(s，3H，Ar-CH 3)，2.84-2.92，2.99-3.05(m，2H，CH CH 2 )，4.41-4.48(m，1H， CHN)，6.63(d，2H，J＝8.10Hz，Ar-H)，7.06(d，2H，J＝8.40Hz，Ar-H)，7.13(d，2H，J＝8.40Hz，Ar-H)，7.34(d，2H，J＝7.50Hz，Ar-H)，7.64-7.69(m，4H，Ar-H)，8.47(d，1H，J＝7.80Hz， NHCH)，9.18(s，1H，SO 2NH)，10.59(s，1H，OH)，12.63(s，1H，COOH). 13C NMR(DMSO-d 6，75MHz)δ：173.80，166.13，156.22，144.01，141.09，136.77，130.23，129.43，129.05，128.57，127.16，118.65，115.40，60.20，55.02，21.39.
Figure BDA0000057306170000123
(c 2mg/mL，EtOAc).
2i： 1H NMR(DMSO-d 6，300MHz)δ：2.32(s，3H，CH 3)，5.79(d，1H，J＝7.50Hz，NHC H)，7.18(d，2H，J＝8.40Hz，Ar-H)，7.35(d，2H，J＝8.10Hz，Ar-H)，7.65-7.68(m，3H，Ar-H)，7.79(d，2H，J＝8.40Hz，Ar-H)，7.94(d，1H，J＝7.80Hz，Ar-H)，8.19(d，1H，J＝7.80Hz，Ar-H)，8.38(s，1H，Ar-H)，9.14(d，1H，J＝7.50Hz，CON H)，10.64(s，1H，SO 2NH)，13.19(s，1H，COOH).
Figure BDA0000057306170000124
(c 2mg/mL，EtOAc).
2k: 1H NMR (DMSO-d 6, 300MHz) δ: 2.32 (s, 3H, CH 3), 3.11-3.29 (m, 2H, CH CH 2 ), 4.55-4.62 (m, 1H, NHC H), 6.96 (t, 1H, J=7.50Hz, Ar-H), 7.05 (t, 1H, J=7.80Hz, Ar-H), 7.11-7.16 (m, 3H, Ar-H and indoles-C H), 7.29-7.35 (m, 3H, Ar-H), 7.56 (d, 1H, J=7.80Hz, Ar-H), 7.67 (d, 4H, J=7.20Hz, Ar-H), 8.48 (d, 1H, J=7.80Hz, NHCH), 10.58 (s, 1H, indoles-N H), 10.79 (s, 1H, SO 2NH), 12.60 (s, 1H, COOH). 13C NMR (DMSO-d 6, 75MHz) δ: 174.04,166.07,144.00,141.08,136.50,130.22,129.39,129.06,127.52,127.16,123.96,121.35,118.64,111.84,110.84,60.24,54.07,21.39.
Figure BDA0000057306170000125
Figure BDA0000057306170000126
(c 2mg/mL, EtOAc).
2l： 1H NMR(DMSO-d 6，300MHz)δ：1.80-1.84(m，2H，NCH 2 CH 2 )，1.86-1.91(m，1H， CH 2 CH)，2.16-2.26(m，1H， CH 2 CH)，2.33(s，3H，ArCH 3)，4.31-4.35(m，2H，N CH 2 )，7.14(d，2H，J＝8.10Hz，Ar 2-H)，7.36(d，2H，J＝7.80Hz，Ar 1-H)，7.42(d，2H，J＝8.40Hz，Ar 1-H)，7.68(d，2H，J＝8.10Hz，Ar 2-H)，10.55(s，1H，SO 2NH)，12.47-12.49(m，1H，COOH). 13C NMR(DMSO-d 6，75MHz)δ：173.74，167.85，143.96，139.98，136.89，131.54，130.21，129.07，127.13，118.85，59.51，49.95，29.31，25.48，21.39.
Figure BDA0000057306170000131
(c 2mg/mL，EtOAc).
2m： 1H NMR(DMSO-d 6，300MHz)δ：2.32(s，3H，ArCH 3)，3.75(d，2H，J＝4.80Hz，CH CH 2 )，4.36-4.41(m，1H， CHCH 2)，7.16(d，2H，J＝8.73Hz，Ar-H)，7.35(d，2H，J＝8.1Hz，Ar-H)，7.68(d，2H，J＝8.13Hz，Ar-H)，7.79(d，2H，J＝8.43Hz，Ar-H)，8.36(d，1H，J＝7.23Hz， NHCH 2)，10.64(s，1H，SO 2NH). 13C NMR(DMSO-d 6，75MHz)δ：172.33，166.05，143.98，141.16，136.77，130.21，129.32，129.17，127.18，118.71，61.48，56.24，21.39.
Figure BDA0000057306170000132
(c 2mg/mL，EtOAc).
2n： 1H NMR(DMSO-d 6，300MHz)δ：1.99-2.04(m，2H，CH CH 2 )，2.03(s，3H，SCH 3)，2.33(s，3H，ArCH 3)，2.54-2.59(m，2H， CH 2 SCH 3)，4.42-4.49(m，1H， CHCH 2)，7.16(d，2H，J＝8.40Hz，Ar-H)，7.35(d，2H，J＝8.10Hz，Ar-H)，7.69(d，2H，J＝7.80Hz，Ar-H)，7.73(d，2H，J＝8.40Hz，Ar-H)，8.48(d，1H，J＝7.80Hz， NHCH 2)，10.60(s，1H，SO 2NH)，12.59(m，1H，COOH). 13C NMR(DMSO-d 6，75MHz)δ：173.94，166.38，144.01，141.12，136.75，130.22，129.39，129.17，127.17，118.66，51.97，30.49，21.39，14.96.
Figure BDA0000057306170000133
(c 2mg/mL，EtOAc).
Synthesizing of embodiment 2, compound 3
Figure BDA0000057306170000134
1, intermediate 3-m's is synthetic: in round-bottomed flask, add para-amino benzoic acid and a certain amount of salt of wormwood (using sodium carbonate while preparing intermediate 3-m-g), add the water stirring and dissolving, after ice bath is cooling, drip RSO 2The acetone soln of Cl, finish the stirring at room reaction, TLC monitoring reaction process.After having reacted, regulate pH to 6～8 with 2mol/L HCl, vacuum rotary steam is removed acetone, then with 2mol/L HCl, regulates pH to 2～3 under ice bath stirs, and separates out solid, and standing, filtering and washing, obtain faint yellow solid, vacuum-drying, and TLC tests pure, weighs.Test-results is in Table 3.
Table 3 intermediate 3-m's is synthetic
Compound R PABA/g RSO 2Cl/g PABA/RSO 2Cl Yield/% Fusing point/℃
3-m-a p-BrC 6H 4- 4.122 10.655 1.0∶1.3 64.7 259.8-263.1
3-m-b p-ClC 6H 4- 4.111 8.258 1.0∶1.3 88.9 210.3-212.1
3-m-c o-NO 2C 6H 4- 6.860 17.006 1.0∶1.5 53.4 199.8-201-1
3-m-d m-NO 2C 6H 4- 6.864 14.415 1.0∶1.3 51.3 255.3-258.1
3-m-e p-NO 2C 6H 4- 2.763 5.386 1.0∶1.2 50.3 273.7～275.4
3-m-f p-CH 3OC 6H 4- 6.867 13.434 1.0∶1.3 89.3 218.4～220.7
3-m-g CH 3- 6.926 7.458 1.0∶1.5 27.1 230.4-232.2
3-m-h p-FC 6H 4- 6.373 12.656 1.0∶1.3 85.4 231.1-233.0
3-m-i 2，4，6-triCH 3C 6H 2- 6.874 14.237 1.0∶1.3 74.3 204.1-206.3
2, compound 3 is synthetic: in flask I, add alanine methyl ester hydrochloride 10.5mmol, anhydrous THF 30mL, after stirring 10min, splash into the DIPEA of equivalent.In flask II, add intermediate 3-m 10mmol and HOBt 12mmol, add anhydrous THF 40mL, after stirring and dissolving, add DCC 12mmol, after stir-activating 15min, add liquid in flask I (shifting with a small amount of THF washing), room temperature lucifuge stirring reaction, TLC monitoring reaction process.After having reacted, filter insolubles, filtrate decompression is revolved to boil off and is desolventized, then adds EtOAc 205mL, and stirring and dissolving, use 0.5mol/L NaHCO successively 3The aqueous solution (3 * 155mL) and the saturated NaCl aqueous solution (2 * 145mL) washing, water layer with EtOAc (2 * 110mL) extraction; Merge the EtOAc layer, anhydrous Na 2SO 4Drying, suction filtration, filtrate decompression is revolved to steam and is removed EtOAc and obtain crude product, then obtains sterling 3 through column chromatography (PE/EA).Test-results is in Table 4.
Synthesizing of table 4 compound 3
Figure BDA0000057306170000141
Figure BDA0000057306170000151
3a: 1H NMR (DMSO-d 6, 300MHz) δ: 1.36 (d, 3H, J=7.20Hz, CH CH 3 ), 3.62 (s, 3H, COOCH 3), 4.37-4.44 (m, 1H, CHCH 3), 7.17 (d, 2H, J=8.43Hz, Ar-H), 7.77-7.81 (m, 6H, Ar-H), 8.67 (d, 1H, J=6.60Hz, NHCH), 10.76 (s, 1H, SO 2NH). 13C NMR (DMSO-d 6, 75MHz) δ: 173.59,165.95,140.74,138.92,132.92,129.59,129.25,129.12,127.51,119.16,52.27,48.66,17.14.HR MS:C 17H 17BrN 2O 5S[M-H] -Calculated value 438.9969, measured value 438.9967.
Figure BDA0000057306170000152
(c 2mg/mL, EtOAc).
3b: 1H NMR (CDCl 3, 300MHz) δ: 1.51 (d, 3H, J=6.90Hz, CH CH 3 ), 3.79 (s, 3H, COOCH 3), 4.79-4.81 (m, 1H, CH), 6.73 (d, 1H, J=7.20Hz, NHCH), 7.19 (d, 2H, J=8.73Hz, Ar 1-H), 7.40 (d, 2H, J=8.46Hz, Ar 2-H), 7.68 (d, 2H, J=8.73Hz, Ar 1-H), 7.75 (d, 2H, J=8.43Hz, Ar 2-H), 8.50 (s, 1H, SO 2NH). 13C NMR (CDCl 3, 75MHz) δ: 173.79,166.13,140.13,139.62,137.55,129.81,129.38,128.58,128.45,119.89,52.66,49.29,18.47.HR MS:C 17H 17ClN 2O 5S[M-H] -Calculated value 395.0474, measured value 395.0476.
Figure BDA0000057306170000153
(c 2mg/mL, EtOAc).
3c： 1H NMR(DMSO-d 6，300MHz)δ：1.36(d，3H，J＝7.50Hz，CH CH 3 )，3.62(s，3H，COOCH 3)，4.40-4.45(m，1H， CHCH 3)，7.20(d，2H，J＝8.10Hz，Ar-H)，7.79(d，2H，J＝8.40Hz，Ar-H)，7.83(d，2H，J＝6.60Hz，Ar-H)，7.99-8.04(m，2H，Ar-H)，8.69(d，1H，J＝6.90Hz， NHCH)，11.12(s，1H，SO 2NH).
3d: 1H NMR (DMSO-d 6, 300MHz) δ: 1.36 (d, 3H, J=7.50Hz, CH CH 3 ), 3.61 (s, 3H, COOCH 3), 4.39-4.44 (m, 1H, CHCH 3), 7.21 (d, 2H, J=8.43Hz, Ar 1-H), 7.78 (d, 2H, J=8.7Hz, Ar 1-H), 7.85-7.90 (m, 1H, Ar 2-H), 8.19 (d, 1H, J=7.83Hz, Ar 2-H), 8.46 (d, 1H, J=8.10Hz, Ar 2-H), 8.55 (s, 1H, Ar 2-H), 8.69 (d, 1H, J=6.90Hz, NHCH), 10.97 (s, 1H, SO 2NH). 13C NMR (DMSO-d 6, 75MHz) δ: 173.56,165.86,148.37,141.13,140.25,133.03,131.93,129.96,129.34,128.25,121.87,119.57,52.27,48.64,17.12.HR MS:C 17H 17N 3O 7S[M-H] -Calculated value 406.0714, measured value 406.0711.
Figure BDA0000057306170000154
Figure BDA0000057306170000155
(c 2mg/mL, EtOAc).
3e: 1H NMR (DMSO-d 6, 300MHz) δ: 1.36 (d, 3H, J=7.20Hz, CH CH 3 ), 3.62 (s, 3H, COOCH 3), 4.39-4.44 (m, 1H, CHCH 3), 7.20 (d, 2H, J=8.43Hz, Ar 1-H), 7.78 (d, 2H, J=8.40Hz, Ar 1-H), 8.05 (d, 2H, J=8.40Hz, Ar 2-H), 8.39 (d, 2H, J=8.70Hz, Ar 2-H), 8.69 (d, 1H, J=6.90Hz, NHCH), 11.00 (s, 1H, SO 2NH). 13C NMR (DMSO-d 6, 75MHz) δ: 173.57,165.86,150.39,144.96,140.29,129.89,129.33,128.75,125.18,119.45,52.28,48.65,17.12.HR MS:C 17H 17N 3O 7S[M-H] -Calculated value 406.0714, measured value 406.0708.
Figure BDA0000057306170000156
(c 2mg/mL, EtOAc).
3f: 1H NMR (DMSO-d 6, 300MHz) δ: 1.36 (d, 3H, J=7.20Hz, CH CH 3 ), 3.62 (s, 3H, COOCH 3), 3.79 (s, 3H, Ar-OCH 3), 4.39-4.44 (m, 1H, CHCH 3), 7.07 (d, 2H, J=8.73Hz, Ar-H), 7.16 (d, 2H, J=8.10Hz, Ar-H), 7.73-7,76 (m, 4H, Ar-H), 8.64 (d, 1H, J=6.90Hz, NHCH), 10.55 (s, 1H, SO 2NH). 13C NMR (DMSO-d 6, 75MHz) δ: 173.61,166.01,163.02,141.33,131.22,129.38,129.14,129.07,129.02,118.61,114.89,56.05,52.26,48.64,17.14.HR MS:C 18H 20N 2O 6S[M-H] -Calculated value 391.0969, measured value 391.0964.
Figure BDA0000057306170000161
(c 2mg/mL, EtOAc).
3g: 1H NMR (DMSO-d 6, 300MHz) δ: 1.39 (d, 3H, J=7.20Hz, CH CH 3 ), 3.07 (s, 3H, SO 2CH 3), 3.64 (s, 3H, COOCH 3), 4.44-4.48 (m, 1H, CHCH 3), 7.25 (d, 2H, J=8.43Hz, Ar-H), 7.86 (d, 2H, J=8.40Hz, Ar-H), 8.70 (d, 1H, J=8.70Hz, NHCH), 10.15 (s, 1H, SO 2NH). 13C NMR (DMSO-d 6, 75MHz) δ: 173.67,166.02,141.83,129.31,128.77,118.27,52.97,48.67,31.12,17.19.HR MS:C 12H 16N 2O 5S[M-H] -Calculated value 299.0707, measured value 299.0706.
Figure BDA0000057306170000162
(c 2mg/mL, EtOAc).
3h： 1H NMR(DMSO-d 6，300MHz)δ：1.36(d，3H，J＝7.20Hz，CH CH 3 )，3.62(s，3H，COOCH 3)，4.39-4.44(m，1H， CHCH 3)，7.18(d，2H，J＝8.40Hz，Ar-H)，7.40(d，2H，J＝7.80Hz，Ar-H)，7.76(d，2H，J＝8.40Hz，Ar-H)，7.85-7.89(m，2H，Ar-H)，8.66(d，1H，J＝6.9Hz， NHCH)，10.71(s，1H，SO 2NH). 13C NMR(DMSO-d 6，75MHz)δ：173.59，166.52，140.87，136.00，130.29，130.16，129.46，129.23，119.05，117.18，52.27，48.65，17.13.
3i： 1H NMR(DMSO-d 6，300MHz)δ：1.34(d，3H，J＝7.20Hz，CH CH 3 )，2.21(s，3H，Ar-CH 3)，2.58(s，6H，Ar-CH 3)，3.60(s，3H，COOCH 3)，4.37-4.41(m，1H， CHCH 3)，7.02(s，4H，Ar-H)，7.71(d，2H，J＝7.20Hz，Ar-H)，8.58(d，1H，J＝6.00Hz， NHCH)，10.63(s，1H，SO 2NH). 13C NMR(DMSO-d 6，75MHz)δ：173.61，166.01，142.82，141.14，139.14，133.84，132.30，129.16，128.54，117.53，52.26，48.63，22.81，20.79，17.12.
Synthesizing of embodiment 3, compound 4
1, compound 4a～4e's is synthetic: in the 500mL round-bottomed flask, add ROH 50mL, cryosel is bathed the cooling lower SOCl that is equivalent to 3 times of molar weights of compound 2b that slowly splashes into 2, finish and stir 0.5h, then add compound 2b 10mmol in batches, finish the stirring at room reaction, TLC monitoring reaction process.After reacting completely, remove excessive SOCl in reaction system at first as far as possible 2And by product HCl, then take different treatment processs according to different reaction solvents, final curing, obtain product 4a～4e.Test-results is in Table 5.
2, compound 4f～4j's is synthetic: add NHR in flask I 1R 211mmol, anhydrous THF 35mL, after stirring 10min, splash into the DIPEA of equivalent.In flask II, take compound 2b 10mmol and HOBt 12mmol, add anhydrous THF 30mL, after stirring and dissolving, add DIC or DCC 12mmol, after stir-activating 15min, add liquid in flask I (shifting with a small amount of THF washing), room temperature lucifuge stirring reaction, TLC monitoring reaction process.After having reacted, filter insolubles, filtrate decompression is concentrated adds 200mL EtOAc except desolventizing, and stirring and dissolving, use 0.5mol/L NaHCO successively 3The aqueous solution (3 * 145mL) and the saturated NaCl aqueous solution (2 * 135mL) washing, water layer with EtOAc (2 * 100mL) extraction; Merge the EtOAc layer, anhydrous Na 2SO 4Drying, suction filtration, filtrate decompression is revolved to steam and is removed EtOAc and obtain crude product, then through column chromatography (PE/EA or CHCl 3/ CH 3OH) obtain sterling 4f～4j.Test-results is in Table 5.
Synthesizing of table 5 compound 4
Figure BDA0000057306170000171
Figure BDA0000057306170000181
4a: 1H NMR (DMSO-d 6, 300MHz) δ: 1.08-1.16 (m, 3H, CH 2 CH 3 ), 1.35 (d, 3H, J=7.20Hz, CH CH 3 ), 2.32 (s, 3H, ArCH 3), 3.71-3.78 (m, 2H, CH 2 CH 3), 4.32-4.57 (m, 1H, CHCH 3), 7.16 (d, 2H, J=8.43Hz, Ar 2-H), 7.35 (d, 2H, J=7.82Hz, Ar 1-H), 7.68 (d, 2H, J=8.13Hz, Ar 1-H), 7.74 (d, 2H, J=8.43Hz, Ar 2-H), 8.53 (d, 1H, J=6.93Hz, NHCH), 10.65 (s, 1H, SO 2NH). 13C NMR (DMSO-d 6, 75MHz) δ: 174.64,165.90,143.97,141.13,136.75,130.19,129.30,129.13,129.09,127.19,118.72,118.68,61.81,48.54,21.38,17.27,15.53.HR MS:C 19H 22N 2O 5S[M-H] -Calculated value 389.1177, measured value 389.1174. (c 2mg/mL, EtOAc).
4b: 1H NMR (DMSO-d 6, 300MHz) δ: 0.85 (t, 3H, J=7.50Hz, CH 2 CH 3 ), 1.35 (d, 3H, J=7.20Hz, CH CH 3 ), 1.52-1.59 (m, 2H, CH 2 CH 3), 2.32 (s, 3H, ArCH 3), 3.96-4.02 (m, 2H, OCH 2), 4.36-4.40 (m, 1H, CHCH 3), 7.15 (d, 2H, J=8.43Hz, Ar 2-H), 7.35 (d, 2H, J=7.82Hz, Ar 1-H), 7.68 (d, 2H, J=8.13Hz, Ar 1-H), 7.74 (d, 2H, J=8.43Hz, Ar 2-H), 8.62 (d, 1H, J=6.93Hz, NHCH), 10.61 (s, 1H, SO 2NH). 13C NMR (DMSO-d 6, 75MHz) δ: 173.17,166.07,143.98,141.17,136.82,130.19,129.24,129.12,127.17,118.68,66.20,48.80,21.96,21.37,17.14,10.58.HR MS:C 20H 24N 2O 5S[M-H] -Calculated value 403.1333, measured value 403.1338.
Figure BDA0000057306170000183
(c 2mg/mL, EtOAc).
4c: 1H NMR (DMSO-d 6, 300MHz) δ: 0.80-0.87 (m, 3H, CH 2 CH 3 ), 1.24-1.30 (m, 2H, CH 2 CH 3), 1.33-1.37 (m, 3H, CH CH 3 ), 1.46-1.54 (m, 2H, OCH 2 CH 2 ), 2.32 (s, 3H, ArCH 3), 3.99-4.06 (m, 2H, OCH 2), 4.34-4.40 (m, 1H, CHCH 3), 7.13-7.16 (m, 2H, Ar 2-H), 7.33-7.36 (m, 2H, Ar 1-H), 7.67 (m, 2H, Ar 1-H), 7.71 (d, 2H, J=8.43Hz, Ar 2-H), 8.59-8.61 (m, 1H, NHCH), 10.61 (s, 1H, SO 2NH). 13C NMR (DMSO-d 6, 75MHz) δ: 173.14,166.07,143.97,141.17,136.81,130.19,129.24,129.11,127.17,118.68,64.44,48.81,30.57,21.37,18.93,17.11,13.91.HR MS:C 21H 26N 2O 5S[M-H] -Calculated value 417.1490, measured value 417.1488.
Figure BDA0000057306170000184
(c 2mg/mL, EtOAc).
4d: 1H NMR (DMSO-d 6, 300MHz) δ: 0.79 (t, 3H, J=6.48Hz, CH 2 CH 3 ), 1.23-1.35 (m, 4H, CH 2 CH 2 CH 3), 1.35 (d, 3H, J=7.20Hz, CH CH 3 ), 1.51-1.55 (m, 2H, OCH 2 CH 2 ), 2.32 (s, 3H, ArCH 3), 3.97-4.06 (m, 2H, OCH 2), 4.35-4.40 (m, 1H, CHCH 3), 7.16 (d, 2H, J=8.43Hz, Ar 2-H), 7.35 (d, 2H, J=8.10Hz, Ar 1-H), 7.69 (d, 2H, J=8.13Hz, Ar 1-H), 7.73 (d, 2H, J=8.73Hz, Ar 2-H), 8.62 (d, 1H, J=6.63Hz, NHCH), 10.61 (s, 1H, SO 2NH). 13C NMR (DMSO-d 6, 75MHz) δ: 173.12,166.06,143.96,141.17,136.82,130.18,129.24,129.11,127.17,118.67,64.71,48.82,28.19,27.89,22.12,21.36,17.10,14.20.HR MS:C 22H 28N 2O 5S[M-H] -Calculated value 431.1646, measured value 431.1650.
Figure BDA0000057306170000191
Figure BDA0000057306170000192
(c 2mg/mL, EtOAc).
4e： 1H NMR(DMSO-d 6，300MHz)δ：1.40(d，3H，J＝7.23Hz，CH CH 3 )，2.33(s，3H，ArCH 3)，4.45-4.50(m，1H， CHCH 3)，4.70-4.85(m，2H， CH 2 CF 3)，7.17(d，2H，J＝8.73Hz，Ar-H)，7.35(d，2H，J＝8.19Hz，Ar-H)，7.70(d，2H，J＝8.42Hz，Ar-H)，7.73(d，2H，J＝8.74Hz，Ar-H)，8.76(d，1H，J＝6.39Hz， NHCH)，10.63(s，1H，SO 2NH). 13C NMR(DMSO-d 6，75MHz)δ：171.93，166.29，144.00，141.31，136.80，130.19，129.17，128.92，127.18，118.65，60.63，48.66，21.35，16.75. (c2mg/mL，EtOAc).
4f： 1H NMR(DMSO-d 6，300MHz)δ：1.27(d，3H，J＝7.20Hz，CH CH 3 )，2.33(s，3H，ArCH 3)，2.56(d，3H，J＝4.50Hz，NH CH 3 )，4.34-4.38(m，1H， CHCH 3)，7.14(d，2H，J＝8.40Hz，Ar-H)，7.35(d，2H，J＝8.10Hz，Ar-H)，7.69(d，2H，J＝8.10Hz，Ar-H)，7.76(d，2H，J＝840Hz，Ar-H)，7.95(s，1H， NH)，8.33(d，1H，J＝7.50Hz， NHCH)，10.58(s，1H，SO 2NH). 13C NMR(DMSO-d 6，75MHz)δ：173.10，165.73，143.96，140.99，136.81，130.19，129.59，129.23，127.18，118.59，49.29，26.04，21.37，18.38. (c 2mg/mL，EtOAc).
4g： 1H NMR(DMSO-d 6，300MHz)δ：0.99(t，3H，J＝7.20Hz，CH 2 CH 3 )，1.26(d，3H，J＝7.20Hz，CH CH 3 )，2.32(s，3H，ArCH 3)，3.01-3.07(m，2H， CH 2 CH 3)，4.33-4.38(m，1H， CHCH 3)，7.14(d，2H，J＝8.40Hz，Ar-H)，7.35(d，2H，J＝8.10Hz，Ar-H)，7.68(d，2H，J＝7.80Hz，Ar-H)，7.75(d，2H，J＝8.70Hz，Ar-H)，7.86(s，1H， NH)，8.28(d，1H，J＝7.50Hz， NHCH)，10.57(s，1H，SO 2NH). 13CNMR(DMSO-d 6，75MHz)δ：172.37，165.68，143.94，140.99，136.18，130.18，129.65，129.18，127.17，118.66，49.28，33.85，21.36，18.50，15.12.
Figure BDA0000057306170000195
(c 2mg/mL，EtOAc).
4h： 1H NMR(DMSO-d 6，300MHz)δ：1.28(d，3H，J＝7.20Hz，CH CH 3 )，2.32(s，3H，ArCH 3)，4.24-4.37(m，1H， CHCH 3)，7.14(d，2H，J＝8.49Hz，Ar-H)，7.35(d，2H，J＝8.13Hz，Ar-H)，7.68(d，2H，J＝8.13Hz，Ar-H)，7.74(d，2H，J＝8.73Hz，Ar-H)，8.25(d，1H，J＝7.50Hz， NHCH)，10.57(s，1H，SO 2NH). 13C NMR(DMSO-d 6，75MHz)δ：174.86，165.68，143.97，140.96，136.80，130.19，129.67，129.15，127.17，118.64，49.11，21.37，18.42.
Figure BDA0000057306170000196
(c 2mg/mL，EtOAc).
4i： 1H NMR(DMSO-d 6，300MHz)δ：1.23-1.32(m，3H，CH CH 3 )，2.08(s，3H，NCH 3)，2.32(s，3H，ArCH 3)，3.44-3.49(m，2H，NCH 2)，3.58-3.60(m，2H， CH 2 OH)，4.81-4.93(m，1H， CHCH 3)，7.14(d，2H，J＝7.53Hz，Ar-H)，7.35(d，2H，J＝8.19Hz，Ar-H)，7.69(d，2H，J＝8.12Hz，Ar-H)，7.74(d，2H，J＝8.44Hz，Ar-H)，8.37-8.42(m，1H， NHCH)，10.58(s，1H，SO 2NH). 13C NMR(DMSO-d 6，75MHz)δ：172.81，165.43，143.97，141.07，136.79，130.20，129.16，129.12，127.16，118.64，59.18，50.57，45.73，21.38，18.09，17.50. (c 2mg/mL，EtOAc).
4j： 1H NMR(DMSO-d 6，300MHz)δ：1.28(d，3H，J＝7.20Hz，CH CH 3 )，2.32(s，3H，ArCH 3)，4.31-4.35(m，1H， CHCH 3)，6.93(bs，1H，N OH)，7.14(d，2H，J＝8.40Hz，Ar-H)，7.35(d，2H，J＝8.10Hz，Ar-H)，7.68(d，2H，J＝8.10Hz，Ar-H)，7.74(d，2H，J＝8.70Hz，Ar-H)，8.33(d，1H，J＝7.50Hz， NHCH)，8.79(bs，1H， NHOH)，10.62(s，1H，SO 2NH). 13C NMR(DMSO-d 6，75MHz)δ：169.70，165.73，154.86，143.91，141.12，136.88，130.17，129.44，129.20，127.17，118.59，47.29，21.37，18.51.
Figure BDA0000057306170000201
(c 2mg/mL，EtOAc).
Synthesizing of embodiment 4, compound 5
Figure BDA0000057306170000202
1, intermediate 5-m1's is synthetic: add amino acid (1) and a certain amount of K in round-bottomed flask 2CO 3, stirring and dissolving under ice bath, the acetone soln of dropping TsCl (2), finish the stirring at room reaction, TLC monitoring reaction process.After having reacted, vacuum rotary steam is removed acetone, and ice bath stirs the lower 2mol/L of using HCl and regulates pH to 3～4, separates out solid, and standing, filtering and washing, obtain white solid, vacuum-drying, and it is pure that TLC tests, and weighs.Test-results is in Table 6.
Table 6 intermediate 5-m1's is synthetic
Figure BDA0000057306170000203
2, intermediate 5-m2's is synthetic: in round-bottomed flask, add intermediate 5-m1 and appropriate methylene dichloride (DCM), stirring and dissolving, splash into the SOCl with respect to intermediate 5-m12 times molar weight 2, stirring at room 2h, reheat back flow reaction, TLC monitoring reaction process.After having reacted, vacuum rotary steam is removed excessive SOCl 2And by product HCl, the transparent oily matter of gained (containing synthetic acyl chlorides) is directly used in next step reaction.In reaction flask, add PABA and a certain amount of DCM, stir and make abundant dissolving, then add the dry K that is equivalent to 5～6 times of weight of PABA 2CO 3Powder, stir the lower DCM solution that drips acyl chlorides (being aforementioned transparent oily matter), the reaction of room temperature vigorous stirring, TLC monitoring reaction process.After having reacted, suction filtration, the DCM washing leaching cake, collect filter cake, is dissolved in water, and regulates pH to acid with 2mol/L HCl, separates out solid, suction filtration, drying, obtain product.Test-results is in Table 7.
Table 7 intermediate 5-m2's is synthetic
3, compound 5 is synthetic: in flask I, add amino acid methyl ester hydrochloride 11mmol, anhydrous THF 40mL, after stirring 10min, splash into the DIPEA of equivalent.In flask II, add intermediate 5-m2 10mmol and HOBt 12mmol, add anhydrous THF 45mL, after stirring and dissolving, add DIC or DCC 12mmol, after stir-activating 15min, add liquid in flask I (shifting with a small amount of THF washing), room temperature lucifuge stirring reaction, TLC monitoring reaction process.After having reacted, filter insolubles, filtrate decompression is revolved to boil off and is desolventized, and adds 220mL EtOAc, and stirring and dissolving is used 0.5mol/L NaHCO successively 3The aqueous solution (3 * 145mL) and the saturated NaCl aqueous solution (2 * 150mL) washing, water layer with EtOAc (2 * 120mL) extraction; Merge the EtOAc layer, anhydrous Na 2SO 4Drying, suction filtration, filtrate is revolved to steam and is removed EtOAc and obtain crude product, then obtains sterling 5 through column chromatography (PE/EA).Test-results is in Table 8.
Synthesizing of table 8 compound 5
Figure BDA0000057306170000212
Figure BDA0000057306170000221
Figure BDA0000057306170000231
5a: 1H NMR (DMSO-d 6, 300MHz) δ: 1.39 (d, 3H, J=7.50Hz, CH CH 3 ), 2.34 (s, 3H, ArCH 3), 3.64 (s, 3H, COOCH 3), 3.67 (d, 2H, J=5.40Hz, NH CH 2 ), 4.43-4.45 (m, 1H, CHCH 3), 7.36 (d, 2H, J=7.89Hz, Ar-H), (7.58 d, 2H, J=8.43Hz, Ar-H), (7.71 d, 2H, J=8.19Hz, Ar-H), (7.83 d, 2H, J=8.43Hz, Ar-H), (8.04 d, 1H, J=4.80Hz, CONH), 8.68 (d, 1H, J=6.60Hz NHCH), 10.57 (m, 1H, SO 2NH). 13C NMR (DMSO-d 6, 75MHz) δ: 173.69,167.18,166.07,143.13,141.87,137.91,129.93,128.73,128.66,127.07,118.70,52.28,48.66,46.42,21.37,17.20.HR MS:C 20H 23N 3O 6S[M-H] -Calculated value 432.1235, measured value 432.1231.
Figure BDA0000057306170000232
(c 2mg/mL, EtOAc).
5b: 1H NMR (DMSO-d 6, 300MHz) δ: 1.18 (d, 3H, J=6.60Hz, SO 2NHCH CH 3 ), 1.40 (d, 3H, J=7.20Hz, CONHCH CH 3 ), 2.26 (s, 3H, ArCH 3), 3.64 (s, 3H, COOCH 3), 3.94-3.98 (m, 1H, SO 2NH CH), 4.44-4.48 (m, 1H, CONH CH), 7.27 (d, 2H, J=7.85Hz, Ar-H), (7.51 d, 2H, J=8.43Hz, Ar-H), (7.67 d, 2H, J=8.19Hz, Ar-H), (7.82 d, 2H, J=8.43Hz, Ar-H), (8.17 d, 1H, J=8.10Hz, ArNH), 8.68 (d, 1H, J=6.60Hz NHCH), 10.22 (s, 1H, SO 2NH). 13C NMR (DMSO-d 6, 75MHz) δ: 173.72,170.84,166.04,142.95,141.91,138.38,129.74,128.53,127.00,118.80,53.56,52.28,48.67,21.29,19.39,17.20.HR MS:C 21H 25N 3O 6S[M-H] -Calculated value 446.1391, measured value 446.1387.
Figure BDA0000057306170000233
(c2mg/mL, EtOAc).
5c: 1H NMR (DMSO-d 6, 300MHz) δ: 0.82-0.87 (m, 6H, 2CH 3), 1.39 (d, 3H, J=7.20Hz, CH 3), 2.16 (s, 3H, Ar-CH 3), 3.58-3.61 (m, 1H, CH), 3.62 (s, 3H, COOCH 3), 4.43-4.48 (m, 1H, CH), 7.17 (d, 2H, J=7.50Hz, Ar-H), (7.41 d, 2H, J=8.70Hz, Ar-H), 7.64 (d, 2H, J=7.80Hz, Ar-H), (7.80 d, 2H, J=8.10Hz, Ar-H), 8.02 (d, 1H, J=9.30Hz, Ar NH), 8.66 (d, 1H, J=6.90Hz, CH NH), 10.15 (s, 1H, SO 2NH). 13C NMR (DMSO-d 6, 75MHz) δ: 173.70,169.79,166.06,142.76,141.63,138.41,129.51,128.62,128.48,127.04,118.86,63.26,52.27,48.66,31.20,21.23,19.39,18.96,17.21.HR MS:C 23H 29N 3O 6S[M-H] -Calculated value 474.1704, measured value 474.1699.
Figure BDA0000057306170000241
(c 2mg/mL, EtOAc).
5d： 1H NMR(DMSO-d 6，300MHz)δ：0.78-0.82(m，6H，CH CH 3 and CH 2 CH 3 )，1.09-1.19(m，1H， CHCH 3)，1.40(d，3H，J＝7.20Hz，CH CH 3 )，1.52-1.58，1.66-1.68(m，2H， CH 2 CH 3)，2.15(s，3H，ArCH 3)，3.64-3.67(m，1H， CHNH)，3.68(s，3H，COOCH 3)，4.44-4.49(m，1H， CHNH)，7.17(d，2H，J＝8.10Hz，Ar-H)，7.49(d，2H，J＝8.40Hz，Ar-H)，7.63(d，2H，J＝7.80Hz，Ar-H)，7.80(d，2H，J＝8.40Hz，Ar-H)，7.99(d，1H，J＝9.30Hz， NHAr)，8.64(d，1H，J＝6.90Hz， NHCH)，10.04(s，1H，SO 2NH). 13C NMR(DMSO-d 6，75MHz)δ：173.70，169.82，166.03，142.75，141.52，138.41，129.48，128.66，128.49，127.01，118.87，61.58，52.28，48.65，37.01，24.72，21.22，17.21，15.44，10.69.
Figure BDA0000057306170000242
(c2mg/mL，EtOAc).
5e： 1H NMR(DMSO-d 6，300MHz)δ：0.76(d，3H，J＝6.30Hz，CHCH 3)，0.84(d，3H，J＝6.60Hz，CHCH 3)，1.24-1.35(m，1H， CH 2 CH)，1.40(d，3H，J＝7.50Hz，CHCH 3)，1.44-1.49(m，1H， CH 2 CH)，1.58-1.60(m，1H， CHCH 3)，2.21(s，3H，ArCH 3)，3.64(s，3H，COOCH 3)，3.88-3.90(m，1H， CHNH)，4.44-4.49(m，1H， CHNH)，7.22(d，2H，J＝8.10Hz，Ar-H)，7.44(d，2H，J＝8.70Hz，Ar-H)，7.65(d，2H，J＝8.10Hz，Ar-H)，7.80(d，2H，J＝8.40Hz，Ar-H)，8.03(d，1H，J＝9.30Hz，Ar NH)，8.65(d，1H，J＝6.90Hz，CH NH)，10.10(s，1H，SO 2NH). 13C NMR(DMSO-d 6，75MHz)δ：173.71，170.58，166.34，142.85，141.74，138.43，129.58，128.54，127.01，118.93，111.44，55.84，52.38，48.66，24.90，24.36，23.21，21.74，21.38，17.21.
Figure BDA0000057306170000243
(c 2mg/mL，EtOAc).
5f: 1H NMR (DMSO-d 6, 300MHz) δ: 1.40 (d, 3H, J=7.20Hz, CH CH 3 ), 2.51 (s, 3H, ArCH 3), 2.75-2.82 (m, 1H, CH CH 2 ), 2.92-2.98 (m, 1H, CH CH 2 ), 3.64 (s, 3H, COOCH 3), 4.09-4.14 (m, 1H, CH 2 CH), 4.44-4.48 (m, 1H, CHCH 3), 7.10 (d, 2H, J=6.90Hz, Ar-H), 7.21 (s, 5H, Ar-H), (7.46-7.48 m, 4H, Ar-H), 7.80 (d, 2H, J=8.70Hz, Ar-H), (8.32-8.35 m, 1H, ArNH), 8.68 (d, 1H, J=6.60Hz, CH NH), 10.39-10.44 (m, 1H, SO 2NH). 13C NMR (DMSO-d 6, 75MHz) δ: 173.74,169.91,166.09,142.63,141.83,138.25,137.37,129.77,129.49,128.52,128.44,126.80,118.84,59.35,52.29,48.68,21.25,17.20.HR MS:C 27H 29N 3O 6S[M-H] -Calculated value 522.1704, measured value 522.1701.
5g: 1H NMR (CDCl 3, 300MHz) δ: 1.07-1.16,1.28-1.37 (m, 2H, NCH 2 CH 2 ), 1.53 (d, 3H, J=7.20Hz, CH CH 3 ), 1.67-1.71 (m, 2H, CH CH 2 ), 1.90-1.94 (m, 2H, NCH 2), 2.47 (s, 3H, ArCH 3), 3.80 (s, 3H, COOCH 3), 4.17-4.20 (m, 1H, CHCH 2), 4.78-4.83 (m, 1H, CHCH 3), 6.73 (d, 1H, J=6.90Hz, NHCH), 7.39 (d, 2H, J=7.80Hz, Ar-H), 7.69 (d, 2H, J=8.10Hz, Ar-H), 7.76-7.83 (m, 4H, Ar-H), 9.00 (s, 1H, ArNH). 13C NMR (CDCl 3, 75MHz) δ: 173.73,169.36,166.13,144.78,140.58,132.36,130.12,129.47,128.11,127.87,119.33,62.95,52.54,50.12,48.97,48.47,33.89,29.53,25.59,24.92,24.47,21.59,18.51.HR MS:C 23H 27N 3O 6S[M-H] -Calculated value 472.1548, measured value 472.1541. (c 2mg/mL, EtOAc).
5h： 1H NMR(DMSO-d 6，300MHz)δ：0.83(d，3H，J＝6.48Hz，CHC H 3 )，0.87(d，3H，J＝6.51Hz，CHC H 3 )，1.86～1.91(m，1H，CH)，2.17(s，3H，Ar-CH 3)，3.58-3.61(m，1H，CH)，3.65(s，3H，OCH 3)，3.99(d，2H，J＝4.80Hz，NH CH 2 )，7.19(d，2H，J＝7.56Hz，Ar-H)，7.40(d，2H，J＝7.95Hz，Ar-H)，7.63(d，2H，J＝7.50Hz，Ar-H)，7.78(d，2H，J＝7.92Hz，Ar-H)，7.99(d，1H，J＝9.30Hz，ArNH)，8.84(s，1H，CH NH)，10.06(s，1H，SO 2NH). 13C NMR(DMSO-d 6，75MHz)δ：170.55，169.36，166.03，142.41，141.19，138.03，129.14，127.97，126.64，118.58，62.62，51.77，30.81，20.85，18.97，18.54.
Figure BDA0000057306170000251
(c 2mg/mL，EtOAc).
5i： 1H NMR(DMSO-d 6，300MHz)δ：0.83(d，3H，J＝6.90Hz，CHC H 3 )，0.86(d，3H，J＝6.60Hz，CHC H 3 )，0.93(d，3H，J＝6.60Hz，CHC H 3 )，0.97(d，3H，J＝6.60Hz，CHC H 3 )，1.84～1.89(m，1H， CHCH 3)，2.09-2.16(m，1H， CHCH 3)，2.18(s，3H，ArCH 3)，3.59-3.62(m，1H，NH CH)，3.65(s，3H，COOCH 3)，4.25-4.30(m，1H，NH CH)，7.19(d，2H，J＝8.10Hz，Ar-H)，7.41(d，2H，J＝8.40Hz，Ar-H)，7.64(d，2H，J＝8.10Hz，Ar-H)，7.81(d，2H，J＝8.40Hz，Ar-H)，7.98(d，1H，J＝9.30Hz，ArNH)，8.43(d，1H，J＝7.80Hz，CH NH)，10.05(s，1H，SO 2NH). 13C NMR(DMSO-d 6，75MHz)δ：172.77，169.75，166.68，142.78，141.53，138.48，129.53，128.85，128.73，127.01，118.82，63.02，59.01，52.04，31.23，29.96，21.23，19.59，19.52，19.37，18.91.
Figure BDA0000057306170000252
(c 2mg/mL，EtOAc).
5j： 1H NMR(DMSO-d 6，300MHz)δ：0.82-0.90(m，12H，CH CH 3 ，CH 2 CH 3 )，1.23-1.28(m，1H， CHCH 3)，1.50-1.53(m，1H， CH 2 CH 3)，1.84-1.89(m，1H， CHCH 2)，1.91-1.98(m，1H， CH 2 CH 3)，2.18(s，3H，ArCH 3)，3.59-3.61(m，1H，SO 2NH CH)，3.65(s，3H，COOCH 3)，4.31-4.36(m，1H，CONH CH)，7.19(d，2H，J＝8.10Hz，Ar-H)，7.41(d，2H，J＝8.40Hz，Ar-H)，7.64(d，2H，J＝8.10Hz，Ar-H)，7.81(d，2H，J＝8.70Hz，Ar-H)，7.99(d，1H，J＝9.30Hz，ArNH)，8.45(d，1H，J＝7.50Hz，CH NH)，10.05(s，1H，SO 2NH). 13C NMR(DMSO-d 6，75MHz)δ：173.65，169.75，166.34，142.77，141.56，138.47，129.52，128.74，128.57，127.01，118.86，63.02，52.27，51.30，31.22，24.89，23.72，23.27，21.60，21.22，19.37，18.91.
Figure BDA0000057306170000253
(c 2mg/mL，EtOAc).
5k： 1H NMR(DMSO-d 6，300MHz)δ：0.82-0.88(m，9H，CH CH 3 )，0.91-1.02(m，3H，CH CH 3 )，1.57-1.70(m，2H， CH 2 CH 3)，1.74-1.78(m，1H， CHCH 2)，1.82-1.89(m，1H， CHCH 3)，2.18(s，3H，ArCH 3)，3.59-3.60(m，1H，NH CH)，3.64(s，3H，COOCH 3)，4.49(s，1H，CONH CH)，7.19(d，2H，J＝7.80Hz，Ar-H)，7.41(d，2H，J＝7.80Hz，Ar-H)，7.64(d，2H，J＝7.50Hz，Ar-H)，7.81(d，2H，J＝7.80Hz，Ar-H)，7.98(d，1H，J＝9.30Hz，ArNH)，8.57(d，1H，J＝7.50Hz，CH NH)，10.05(s，1H，SO 2NH). 13C NMR(DMSO-d 6，75MHz)δ：172.82，169.75，166.59，142.77，141.53，138.48，129.52，128.81，128.72，127.01，118.81，63.01，57.70，51.99，31.23，25.67，21.22，19.37，18.91，15.94，11.27.
Figure BDA0000057306170000254
Figure BDA0000057306170000255
(c 2mg/mL，EtOAc).
5l： 1H NMR(DMSO-d 6，300MHz)δ：0.83(d，3H，J＝6.60Hz，CHC H 3 )，0.87(d，3H，J＝6.30Hz，CHC H 3 )，1.88～1.93(m，1H， CHCH 3)，2.13(s，3H，ArCH 3)，3.11-3.18(m，2H，Ar CH 2 )，3.59-3.61(m，1H，SO 2NH CH)，3.64(s，3H，COOCH 3)，4.60-4.68(m，1H，CONH CH)，7.16(d，2H，J＝7.80Hz，Ar-H)，7.24(m，5H，Ar-H)，7.42(d，2H，J＝8.40Hz，Ar-H)，7.64(d，2H，J＝8.10Hz，Ar-H)，7.72(d，2H，J＝8.40Hz，Ar-H)，8.08(s，1H，ArNH)，8.74(d，1H，J＝7.80Hz，CH NH)，10.24-10.25(m，1H，SO 2NH). 13C NMR(DMSO-d 6，75MHz)δ：172.71，169.85，166.19，142.67，141.74，138.21，129.50，129.46，128.63，128.45，128.36，127.03，126.86，118.82，63.55，54.71，52.35，31.18，21.21，19.42，19.04.
Figure BDA0000057306170000261
(c 2mg/mL，EtOAc).
5m： 1H NMR(DMSO-d 6，300MHz)δ：0.83(d，3H，J＝6.90Hz，CHC H 3 )，0.86(d，3H，J＝6.90Hz，CHC H 3 )，1.86-1.89(m，1H， CHCH 3)，2.17(s，3H，ArCH 3)，3.59-3.64(m，1H，SO 2NH CH)，3.69(s，3H，COOCH 3)，5.94(d，1H，J＝7.20Hz，Ar CH)，7.19(d，2H，J＝7.80Hz，Ar-H)，7.43(d，2H，J＝8.40Hz，Ar-H)，7.64(d，2H，J＝8.10Hz，Ar-H)，7.68-7.74(m，1H，Ar-H)，7.84(d，2H，J＝8.70Hz，Ar-H)，7.97(d，1H，J＝6.30Hz，Ar-H)，8.00(s，1H，ArNH)，8.23(d，1H，J＝7.80Hz，Ar-H)，8.40(s，1H，Ar-H)，9.28(d，1H，J＝7.50Hz，CH NH)，10.08(m，1H，SO 2NH). 13C NMR(DMSO-d 6，75MHz)δ：170.79，169.80，166.18，148.23，142.79，141.83，139.38，138.49，135.67，135.64，130.42，129.52，128.78，128.30，127.01，123.47，123.36，118.93，63.03，56.29，53.03，31.22，21.22，19.36，18.89.
Figure BDA0000057306170000262
(c 2mg/mL，EtOAc).
5n： 1H NMR(DMSO-d 6，300MHz)δ：0.82(d，3H，J＝6.60Hz，CHC H 3 )，0.86(d，3H，J＝6.60Hz，CHC H 3 )，1.86-1.89(m，1H， CHCH 3)，2.14(s，3H，ArCH 3)，3.23-3.28(m，2H，CH CH 2 )，3.58-3.60(m，1H，SO 2NH CH)，3.63(s，3H，COOCH 3)，4.66-4.68(m，1H，CH 2 CH)，6.99-7.09(m，2H，Ar-H)，7.16(s，1H，Ar-H)，7.19(d，2H，J＝8.10Hz，Ar-H)，7.33(d，1H，J＝7.80Hz，Ar-H)，7.39(d，2H，J＝8.70Hz，Ar-H)，7.56(d，1H，J＝7.50Hz，Ar-H)，7.63(d，2H，J＝7.10Hz，Ar-H)，7.74(d，2H，J＝8.70Hz，Ar-H)，8.01(d，1H，J＝9.30Hz，ArNH)，8.65(d，1H，J＝7.50Hz，CH NH)，10.08(m，1H，SO 2NH)，10.87(s，1H，CNH). 13C NMR(DMSO-d 6，75MHz)δ：173.05，169.81，166.22，142.72，141.66，138.47，136.55，129.48，128.63，128.42，127.50，127.02，124.10，121.37，118.83，118.41，111.90，110.39，63.39，54.26，52.29，25.78，21.21，19.41，18.99.
Figure BDA0000057306170000263
(c 2mg/mL，EtOAc).
5o： 1H NMR(DMSO-d 6，300MHz)δ：0.83(d，3H，J＝6.90Hz，CHC H 3 )，0.86(d，3H，J＝6.90Hz，CHC H 3 )，1.88-1.93(m，1H， CHCH 3)，2.138(s，3H，ArCH 3)，3.59-3.61(m，1H，SO 2NH CH)，3.64(s，3H，COOCH 3)，3.77-3.81(m，2H， CH 2 OH)，4.51-4.54(m，1H，CH 2 CH)，5.04-5.08(t，1H，J＝6.00Hz，CH 2 OH)7.20(d，2H，J＝8.40Hz，Ar-H)，7.42(d，2H，J＝8.40Hz，Ar-H)，7.64(d，2H，J＝7.80Hz，Ar-H)，7.82(d，2H，J＝8.40Hz，Ar-H)，7.98(d，1H，J＝9.30Hz，ArNH)，8.42(d，1H，J＝7.50Hz，CH NH)，10.06(m，1H，SO 2NH). 13C NMR(DMSO-d 6，75MHz)δ：171.58，169.77，166.29，142.80，141.59，138.45，129.52，128.72，128.55，127.02，118.90，63.02，61.51，56.03，52.29，31.22，21.25，19.37，18.91.
Figure BDA0000057306170000264
(c 2mg/mL，EtOAc).
5p： 1H NMR(DMSO-d 6，300MHz)δ：0.83(d，3H，J＝6.60Hz，CHC H 3 )，0.87(d，3H，J＝6.60Hz，CHC H 3 )，1.84-1.88(m，1H， CHCH 3)，2.15(s，3H，ArCH 3)，2.97-3.02(m，2H，Ar CH 2 )，3.58(m，1H，SO 2NH CH)，3.62(s，3H，COOCH 3)，4.54(d，1H，J＝5.70Hz，CH 2 CH)，6.64(d，2H，J＝8.10Hz，Ar-H)，7.07(d，2H，J＝7.80Hz，Ar-H)，7.18(d，2H，J＝8.10Hz，Ar-H)，7.38(d，2H，J＝8.40Hz，Ar-H)，7.63(d，2H，J＝7.80Hz，Ar-H)，7.73(d，2H，J＝8.40Hz，Ar-H)，7.97(d，1H，J＝9.60Hz，ArNH)，8.62(d，1H，J＝7.50Hz，CH NH)，10.03(s，1H，SO 2NH)，9.21(s，1H，ArOH). 13C NMR(DMSO-d 6，75MHz)δ：172.86，169.73，166.16，142.80，141.53，138.42，130.41，129.52，128.68，128.47，128.11，128.02，118.86，115.44，63.02，55.08，52.28，31.22，24.89，21.23，19.37，18.93.
Figure BDA0000057306170000271
(c 2mg/mL，EtOAc).
The PPAR agonist activity of embodiment 5, part of compounds 1-5 detects
The HepG2 cell is inoculated in to 96 orifice plates, overnight incubation, with reference to the transfection reagent specification sheets, carry out plasmid transfection, the plasmid of transfection comprises the plasmid pPPRE-Luc with PPRE gene and Photinus pyralis LUC (Luc) reporter gene, and the phRL-TK of the plasmid with the renilla luciferase reporter gene that is used as the transfection internal reference, the low sugar DMEM substratum that contains 10.00 μ g/mL samples is used in transfection instead after 24 hours, blank (the HepG2 cell of untransfected) is set simultaneously, negative control (the HepG2 cell of the transfection substratum that does not contain sample) and positive control (the HepG2 cell of the transfection substratum that contains 0.78 μ g/mL pioglitazone), continue to cultivate after 24 hours and detect uciferase activity (being chemiluminescence intensity L value) by luciferase reporter gene detection kit (Promega company), according to chemiluminescence intensity L value, calculate exciting rate: exciting rate (%)=[(L1 sample-L1 blank)/(L1 negative-L1 blank)]/[(L2 sample-L2 blank)/(L2 negative-L2 blank)] * 100, wherein L1 is the chemiluminescence intensity of Photinus pyralis LUC, L2 is the chemiluminescence intensity of internal reference renilla luciferase.Relatively exciting rate (%) is the exciting rate of sample with respect to positive control.Test-results is in Table 9.
The PPAR agonist activity detected result of table 9 part of compounds 1-5
Compound Relatively exciting rate (%) Compound Relatively exciting rate (%) Compound Relatively exciting rate (%)
1-m 46.54 2g 29.51 5a 14.97
1a 29.81 2h 14.12 5b 20.69
1b 87.16 2i 22.68 5c 11.86
1c 49.26 2j 12.52 5d -25.08
1d 47.90 2k 19.06 5e -20.47
1e 63.34 2l 32.85 5f -2.11
1f 44.08 2m 19.78 5g 31.66
1g 15.43 2n 31.25 5h 24.07
1h 5.26 3a 39.81 5-m1-a 9.61
1i 19.78 3b 69.12 5-m1-b 8.26
1j 18.33 3d 30.51 5-m1-c 25.84
1k 28.49 3e 27.64 5-m1-d 15.92
1l 3.81 3f 25.19 5-m1-e -5.88
1m 0.91 3g 14.57 5-m1-f 11.29
1n 28.49 4a 21.51 5-m2-a -20.18
1o 10.79 4b 68.52 5-m2-b -11.60
2a -15.06 4c 42.07 5-m2-c 16.43
2b 25.14 4d 24.94 5-m2-d 10.48
2c 11.07 4f 16.20 5-m2-e -2.61
2d 63.02 4g 36.64 5-m2-f -2.61
2e 48.82 4h 8.71 Pioglitazone 100.00
2f 36.21 4i 6.45
The alpha-glucosidase of embodiment 6, part of compounds 1-2 suppresses active and detects
In rat intestinal, extract alpha-glucosidase, the maltose of take detects the activity of alpha-glucosidase as substrate.In 100 μ L reaction systems, contain appropriate alpha-glucosidase, 67nM sodium phosphate buffer (pH6.8) and 10.00 μ g/mL samples, blank (not containing enzyme and sample), negative control (not containing sample) and positive control (containing 1.00 μ g/mL vogliboses) are set simultaneously, 37 ℃ of reaction 10min, add 0.1M maltose, room temperature reaction 10min, add again glucose detection reagent (company is built up in Nanjing) 200 μ L, after mixing, measure OD value, the inhibiting rate of calculation sample to enzymic activity: inhibiting rate=[1-(OD in wavelength 490nm place Sample Product-OD Blank)/(OD Negative-OD Blank)] * 100%.Test-results is in Table 10.
The alpha-glucosidase of table 10 part of compounds 1-2 suppresses active detected result
Compound Inhibiting rate (%) Compound Inhibiting rate (%) Compound Inhibiting rate (%)
1-m -14.58 1i -10.01 2d -7.74
1a -9.63 1j -1.24 2e -0.31
1b -4.46 1k -2.16 2g -8.08
1c -4.20 1l -1.25 2j -5.61
1d -1.30 1m -7.64 2l 3.26
1e -0.42 1n -9.31 2m -11.18
1f -3.70 2a -10.73 Voglibose 92.38
1g -4.98 2b -6.98
1h -3.97 2c -9.84
The dipeptidyl peptidase-IV of embodiment 7, part of compounds 1-5 (DPP-IV) suppresses active and detects
With dipeptidyl peptidase enzyme substrates GLY-PRO-GLY-GLY, detect the activity of DPP-IV (Sigma).In 200 μ L reaction systems, contain appropriate DPP-IV, 25mM HEPES damping fluid (contains 140mM NaCl, 80mM MgCl 2With mass volume ratio be 1% bovine serum albumin) and 10.00 μ g/mL samples, blank (not containing enzyme and sample), negative control (not containing sample) and positive control (containing 0.30 μ g/mL KR-62436) are set simultaneously, room temperature reaction 10min, add GLY-PRO-GLY-GLY, room temperature reaction 25-40min, measure fluorescence intensity F (excitation wavelength 355nm, emission wavelength 460nm), the inhibiting rate of calculation sample to enzymic activity: inhibiting rate=[1-(F Sample-F Blank)/(F Negative-F Blank)] * 100%.Test-results is in Table 11.
The DPP-IV of table 11 part of compounds 1-5 suppresses active detected result
Compound Inhibiting rate (%) Compound Inhibiting rate (%) Compound Inhibiting rate (%)
1a 0.01 3g 5.06 5g 3.51
1b 9.75 4a 1.9 5h -14.65
1c -2.05 4b 8.31 5-m1-a -5.26
1d -17.47 4c 6.86 5-m1-b -1.17
1o 3.87 4d 7.11 5-m1-c 2.35
2f 3.37 4f -5.25 5-m1-d -1.6
2h 11.66 4g -3.22 5-m1-e 6.37
2i 13.05 4h 1.54 5-m1-f -2.94
2k 20.64 4i 6.17 5-m2-a -12.27
2n 12.63 5a -5.02 5-m2-b -7.42
3a 0 5b -3.66 5-m2-c 8.91
3b -3.85 5c -11.51 5-m2-d -13
3d -3.26 5d 10.82 5-m2-e -5.12
3e 8.33 5e -4.57 5-m2-f -14.51
3f -2.71 5f -9.11 KR-62436 73.11
Finally explanation is, above embodiment is only unrestricted in order to technical scheme of the present invention to be described, although by invention has been described with reference to the preferred embodiments of the present invention, but those of ordinary skill in the art is to be understood that, can to it, make various changes in the form and details, and not depart from the spirit and scope of the present invention that appended claims limits.

Claims (3)

1. para-amino benzoic acid derivative is characterized in that: have following general structure:
In formula, n is 0 or 1;
R 1For methyl or substituted-phenyl, described substituted-phenyl is that phenyl is selected from arbitrarily following substituting group by 1 to 3 and replaces: fluorine atom, chlorine atom, bromine atoms, nitro, methyl and methoxyl group;
R 2aWith R 2bOptional one: R 2aFor hydrogen, do not replace or the C of phenyl substituted 1-C 4Alkyl; R 2bTogether with its adjacent nitrogen atom connected and carbon atom, form
Figure FDA0000383223240000012
R 3aWith R 3bOptional one: R 3aFor hydrogen, C 1-C 4The C of alkyl, replacement 1-C 4Alkyl, phenyl or substituted-phenyl, the C of described replacement 1-C 4Alkyl is C 1-C 4Alkyl is replaced by methylthio group, phenyl or the 2-indyl that hydroxyl, methylthio group, 5-uracil base replace, and described substituted-phenyl is that phenyl is replaced by 1 hydroxyl or nitro; R 3bTogether with its adjacent nitrogen atom connected and carbon atom, form Or
Figure FDA0000383223240000014
R 4For-OR 5Or-NR 6R 7R 5For hydrogen, C 1-C 5Alkyl or C 1-C 5Fluoro-alkyl; R 6And R 7Be hydrogen, hydroxyl, C independently of one another 1-C 2Alkyl or C 1-C 2Hydroxyalkyl.
2. para-amino benzoic acid derivative according to claim 1 is characterized in that: be any in following compound:
Figure FDA0000383223240000015
Figure FDA0000383223240000021
3. the application of para-amino benzoic acid derivative claimed in claim 1 in preparation PPAR agonist.
CN2011101040500A 2011-04-25 2011-04-25 Derivatives of p-aminobenzoic acid and applications thereof Expired - Fee Related CN102757370B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN2011101040500A CN102757370B (en) 2011-04-25 2011-04-25 Derivatives of p-aminobenzoic acid and applications thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN2011101040500A CN102757370B (en) 2011-04-25 2011-04-25 Derivatives of p-aminobenzoic acid and applications thereof

Publications (2)

Publication Number Publication Date
CN102757370A CN102757370A (en) 2012-10-31
CN102757370B true CN102757370B (en) 2013-11-27

Family

ID=47052054

Family Applications (1)

Application Number Title Priority Date Filing Date
CN2011101040500A Expired - Fee Related CN102757370B (en) 2011-04-25 2011-04-25 Derivatives of p-aminobenzoic acid and applications thereof

Country Status (1)

Country Link
CN (1) CN102757370B (en)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015016293A1 (en) * 2013-08-02 2015-02-05 国立大学法人 富山大学 (benzenesulfonylamino)benzamide derivative, and ship2 inhibitor containing same as active ingredient
WO2016172325A1 (en) 2015-04-22 2016-10-27 University Of Pittsburgh - Of The Commonwealth System Of Higher Education Novel small molecule fiel1 inhibitor in inflammatory and fibrotic lung injury

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5958457A (en) * 1993-04-22 1999-09-28 Emisphere Technologies, Inc. Compositions for the delivery of antigens

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5958457A (en) * 1993-04-22 1999-09-28 Emisphere Technologies, Inc. Compositions for the delivery of antigens

Also Published As

Publication number Publication date
CN102757370A (en) 2012-10-31

Similar Documents

Publication Publication Date Title
EP3207043B1 (en) Dihydropyrrolopyridine inhibitors of ror-gamma
EP3497086B1 (en) Amino pyrimidine ssao inhibitors
AU2015266481B2 (en) Dihydropyrimido fused ring derivative as HBV inhibitor
EP3590928B1 (en) Pyrimidine derivatives for the treatment of viral infections
TW200938192A (en) Hepatitis C virus inhibitors
UA124270C2 (en) 7-substituted sulfonimidoylpurinone compounds for the treatment and prophylaxis of virus infection
BRPI0806592A2 (en) TIAZOLIDINE DERIVATIVES AND METHODS FOR PREPARATION.
IL213277A (en) Inhibitors of hcv ns5a
CN104220429A (en) Non-systemic tgr5 agonists
TW200938191A (en) Hepatitis C virus inhibitors
CN102711473A (en) Bruton&#39;s tyrosine kinase inhibitors
EP4089102A1 (en) Modulators of sortilin activity
CN103097367A (en) Phenylpropionic acid compound, preparation method therefor and medicinal use thereof
WO2018037120A1 (en) Prodrugs activated by reactive oxygen species for use in the treatment of inflammatory diseases and cancer
JP2024517678A (en) Modulators of sortilin activity
CN102757370B (en) Derivatives of p-aminobenzoic acid and applications thereof
TW201927368A (en) Creatine prodrugs, compositions and methods of use thereof
ES2564366T3 (en) Encephalin analogues
CN106905193A (en) Aroyl guanidine radicals Oseltamivir carboxylic acid derivates and its preparation method and application
CN101735286B (en) Amino acid modified glucosamine as well as preparation method and application thereof
US20230147756A1 (en) Crystalline forms of a farnesoid x receptor agonist
CN116806150A (en) Novel autotaxin inhibitors
KR102025415B1 (en) Compounds for inhibiting hepatitis c virus, pharmaceutical compositions and uses thereof
CN104001150A (en) Optically pure dipeptide derivative, preparation method and medical application thereof
CA3174790A1 (en) Bi- and monocyclic nucleoside analogs for treatment of hepatitis e

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20131127

Termination date: 20160425