CN103342700B - 11beta-Hydroxysteroid dehydrogenase 1 type inhibitor - Google Patents
11beta-Hydroxysteroid dehydrogenase 1 type inhibitor Download PDFInfo
- Publication number
- CN103342700B CN103342700B CN201210017147.2A CN201210017147A CN103342700B CN 103342700 B CN103342700 B CN 103342700B CN 201210017147 A CN201210017147 A CN 201210017147A CN 103342700 B CN103342700 B CN 103342700B
- Authority
- CN
- China
- Prior art keywords
- alkyl
- group
- cycloalkyl
- base
- halo
- 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.)
- Active
Links
- 0 C**C(CC1(C)OC1)(CCN1[Al](*)**(C)[Cl+2]C)OC1=O Chemical compound C**C(CC1(C)OC1)(CCN1[Al](*)**(C)[Cl+2]C)OC1=O 0.000 description 3
Abstract
The invention belongs to medical art, be specifically related to 11beta-Hydroxysteroid dehydrogenase 1 type that can be used as inhibitor, its pharmacy acceptable salt and the isomer thereof shown in general formula (I), wherein, X
1, X
2, R
1, R
2, R
6a, R
6b, A
1, A
2, Cy
1, Cy
2, Cy
3, m and n as in specification sheets define; The invention still further relates to the preparation method of these compounds, pharmaceutical preparation containing these compounds, pharmaceutical composition containing these compounds, and these compounds are preparing the application treated and/or prevented in the medicine of the disease relevant to diabetes and metabolism syndrome etc.
Description
Technical field
The invention belongs to medical art, be specifically related to 11beta-Hydroxysteroid dehydrogenase 1 type inhibitor, its pharmacy acceptable salt or its isomer, the preparation method of these compounds, pharmaceutical preparation containing these compounds, pharmaceutical composition containing these compounds, and these compounds are preparing the purposes treated and/or prevented in the medicine of the disease relevant to diabetes and metabolism syndrome etc.
Background technology
Glucocorticosteroid, as hydrocortisone (hydrocortisone), for regulating the steroid hormone of metabolism of fat, function and distribution, and works in carbohydrate, protein and metabolism of fat.Glucocorticosteroid picks up hormone antagonist as the important of Regular Insulin, can resist by induced insulin, and insulin resistant is the key link of diabetes B morbidity.Excessive glucocorticosteroid can cause hyperinsulinemia, Anomalous lipid metablism, impaired glucose tolerance, hypertension, abdominal obesity, finally develops into diabetes.
11beta-Hydroxysteroid dehydrogenase (11 β-hydroxysteroiddehydrogenase, 11 β-HSD) be the metabolic enzyme of glucocorticosteroid, redox reaction in human body between the ketone group of its catalysis glucocorticosteroid C11 position and hydroxyl, bioactive hydrocortisone (cortisol, hydrocortisone) is transformed mutually with the cortisone (cortisone) of non-activity.In rodent, the conversion between its catalysis Kendall compound (corticosterone) and dehydrocorticosterone (dehydrocorticosterone).
Not only 11 β-HSD1 enzymes have the dual catalytic effect (existing reductase activity but also have dehydrogenase activity) of oxidation and reduction, it mainly plays the activator effect of cortisone in vivo.It makes the cortisone of non-activity be converted into the activated hydrocortisone of tool, thus regulates the concentration of glucocorticosteroid in circulation and arrive the amount of acceptor.Be single-minded reductase enzyme at liver 11 β-HSD1, it can strengthen the activity of glucocorticosteroid, and glucocorticosteroid has the key enzyme that activates glyconeogenesis in liver cell as the effect of PCK (PEPCK) and G-6-Pase, glyconeogenesis is accelerated; It by lowering the expression of receptor protein,intracellular, can also directly suppress the secreting function of beta Cell of islet, thus causes insulin resistant and infringement islet beta cell function.
11 β-HSD1 are NADPH dependent dehydrogenase/oxydo-reductase of a kind of low-affinity, in endocytoplasmic reticulum, while G-6-P (G6P) is converted into 6-phosphogluconolactone, NADP are converted into NADPH.It is distributed widely in the target organ of the glucocorticosteroids such as liver, kidney, vascular system, testis, ovary, fatty tissue and central nervous system.
11beta-Hydroxysteroid dehydrogenase 1 (11 β-hydroxysteroiddehydrogenasetype1,11 β-HSD1) there is tissue specificity, regulating local glucocorticoid concentration in vivo, is the another kind mechanism regulating glucocorticosteroid except hypothalmus-pituitary-adrenal axis.
Suppress 11 β-HSD1 can reduce the amount of activated glucocorticosteroid, reduce insulin resistant, protection islet cells.11 beta-HSD 1 inhibitors are by the activity of Selective depression 11 β-HSD1, reduce in liver and the hydrocortisone concentration of fatty tissue, reduce hepatic gluconeogenic, improve the susceptibility of tissue to Regular Insulin, for the research of diabetes and metabolism syndrome and treatment provide new target spot.
Boehringer Ingelheim discloses 11 following beta hsd 1 inhibitors in WO2010010150:
In addition, Boehringer Ingelheim discloses 11 following beta hsd 1 inhibitors in WO2010127237:
Summary of the invention
The invention provides the 11beta-Hydroxysteroid dehydrogenase 1 type inhibitor with Selective depression 11 β-HSD1 activity.
Technical scheme of the present invention is as follows:
The solution of the present invention 1 there is provided the compound shown in general formula (I), its pharmacy acceptable salt, and isomer:
Wherein, X
1for C (O), S (O)
wor C (=NR
5), w is 0,1 or 2, R
5for cyano group, hydroxyl, C
1-6alkyl, C
3-8cycloalkyl, C
2-6thiazolinyl, C
5-8cycloalkenyl group, C
2-6alkynyl, C
1-6alkoxyl group or C
3-8cycloalkyloxy, described C
1-6alkyl, C
3-8cycloalkyl, C
2-6thiazolinyl, C
5-8cycloalkenyl group, C
2-6alkynyl, C
1-6alkoxyl group and C
3-8cycloalkyloxy can optionally be replaced independently selected from following substituting group by 1-6: halogen atom, cyano group, hydroxyl, carboxyl and amino;
X
2for O, S, N (R
4a) or C (R
4a) (R
4b), R
4aand R
4bbe separately hydrogen atom, C
1-6alkyl, halo C
1-6alkyl, C
3-8cycloalkyl, C
2-6thiazolinyl, C
5-8cycloalkenyl group or C
2-6alkynyl;
R
1for hydrogen, C
1-6alkyl, C
3-8cycloalkyl, C
2-6thiazolinyl, C
5-8cycloalkenyl group, C
2-6alkynyl, C
1-6alkoxyl group, C
1-6alkyl amine group, two (C
1-6alkyl) amido, C
1-6alkylthio, C
1-6alkyl-carbonyl, C
1-6alkyl amine group formyl radical, two (C
1-6alkyl) amido formacyl, C
1-6alkylamidoalkyl, C
1-6alkyl sulphonyl, C
1-6alkyl amine group alkylsulfonyl, two (C
1-6alkyl) amido alkylsulfonyl, C
1-6alkylsulfonamido, C
1-6carbalkoxy, C
1-6alkyl carbonyl oxy, 6-14 unit aryl, 5-14 unit's heteroaryl or 3-14 unit heterocyclic radical, described C
1-6alkyl, C
3-8cycloalkyl, C
2-6thiazolinyl, C
5-8cycloalkenyl group, C
2-6alkynyl and C
1-6alkoxyl group can optionally be replaced independently selected from following substituting group by 1-6: halogen atom, cyano group, hydroxyl, carboxyl, amino, halo C
1-6alkyl, oxo, R
3-, R
3o-, (R
3)
2n-, R
3o (O) C-, R
3c (O) O-, R
3s (O)
2o-, R
3s (O)
2-, R
3c (O) N (R
3)-, (R
3)
2nC (O)-, (R
3)
2nC (O) O-, (R
3)
2nC (O) N (R
3)-, R
3oC (O) N (R
3)-, (R
3)
2nC (NCN) N (R
3)-, (R
3o)
2p (O) O-, (R
3o)
2p (O) N (R
3)-, R
3oS (O)
2n (R
3)-, (R
3)
2nS (O)
2o-, (R
3)
2nS (O)
2n (R
3)-, R
3s (O)
2n (R
3)-, R
3s (O)
2n (R
3) C (O)-, R
3s (O)
2n (R
3) C (O) O-, R
3s (O)
2n (R
3) C (O) N (R
3)-, R
3oS (O)
2n (R
3) C (O)-, R
3oS (O)
2n (R
3) C (O) O-, R
3oS (O)
2n (R
3) C (O) N (R
3)-, (R
3)
2nS (O)
2n (R
3) C (O)-, (R
3)
2nS (O)
2n (R
3) C (O) O-, (R
3)
2nS (O)
2n (R
3) C (O) N (R
3)-, R
3c (O) N (R
3) S (O)
2-, R
3c (O) N (R
3) S (O)
2o-, R
3c (O) N (R
3) S (O)
2n (R
3)-, R
3oC (O) N (R
3) S (O)
2-, R
3oC (O) N (R
3) S (O)
2o-, R
3oC (O) N (R
3) S (O)
2n (R
3)-, (R
3)
2nC (O) N (R
3) S (O)
2-, (R
3)
2nC (O) N (R
3) S (O)
2o-, (R
3)
2nC (O) N (R
3) S (O)
2n (R
3the first aryl of 6-14)-, 5-14 unit's heteroaryl or 3-14 unit heterocyclic radical;
R
2for not existing, C
1-6alkyl, halo C
1-6alkyl or oxo;
R
3for hydrogen, C
1-6alkyl, amino C
1-6alkyl, halo C
1-6alkyl, hydroxyl C
1-6alkyl, C
3-6cycloalkyl, C
1-6alkoxyl group or C
3-6alkoxy C
1-6alkyl;
A
1for key, C
1-6alkyl, C
1-6alkoxyl group, C
2-6thiazolinyl, C
2-6alkynyl or C
1-6alkyl-carbonyl;
A
2for key, O, S (O)
w, N (R
3), C
1-6alkyl or C
1-6alkoxyl group, w is 0,1 or 2, described C
1-6alkyl and C
1-6alkoxyl group can optionally be replaced independently selected from following substituting group by 1-4: methyl, ethyl, trifluoromethyl or oxo;
Cy
1for 6-14 unit aryl, 5-14 unit heteroaryl, C
3-8cycloalkyl or 3-14 unit heterocyclic radical, described 6-14 unit aryl, 5-14 unit heteroaryl, C
3-8cycloalkyl and 3-14 unit heterocyclic radical can optionally be replaced by the individual substituting group independently selected from R ' of 1-4;
Cy
2for hydrogen, 6-14 unit aryl, 5-14 unit heteroaryl, C
3-8cycloalkyl or 3-14 unit heterocyclic radical, described 6-14 unit aryl, 5-14 unit heteroaryl, C
3-8cycloalkyl and 3-14 unit heterocyclic radical can optionally be replaced by the individual substituting group independently selected from R ' of 1-4;
R ' is halogen atom, cyano group, nitro, hydroxyl, carboxyl, amino, oxo, C
1-6alkyl, hydroxyl C
1-6alkyl, C
3-6cycloalkyl, C
1-6alkoxyl group, hydroxyl C
3-6cycloalkyl, halo C
3-6cycloalkyl, C
4-8cycloalkyl C
1-6alkyl, halo C
4-8cycloalkyl C
1-6alkyl, halo C
1-6alkyl, C
2-6thiazolinyl, halo C
2-6thiazolinyl, hydroxyl C
2-6thiazolinyl, C
5-8cycloalkenyl group, C
2-6alkynyl, C
3-6cycloalkyloxy group C
1-6alkoxyl group, halo C
1-6alkoxyl group, C
1-6alkylthio, C
3-6cycloalkylthio, C
1-6alkyl amine group, two (C
1-6alkyl) amido, C
1-6alkyl-carbonyl, formamyl, amino-sulfonyl, C
1-6alkyl amine group formyl radical, C
1-6alkylamidoalkyl, C
1-6alkyl sulphonyl, C
1-6alkyl amine group alkylsulfonyl, C
1-6alkylsulfonamido, two (C
1-6alkyl) amido formacyl, two (C
1-6alkyl) amido alkylsulfonyl, C
1-6carbalkoxy or C
1-6alkyl carbonyl oxy;
Cy
3for 6-14 unit fractional saturation aryl, C
3-8cycloalkyl, C
5-8cycloalkenyl group, 3-14 unit heterocyclic radical, described 6-14 unit fractional saturation aryl, C
3-8cycloalkyl, C
5-8cycloalkenyl group and 3-14 unit heterocyclic radical can be optionally individual independently selected from R by 1-4
8substituting group replace, R
8for hydrogen, halogen atom, cyano group, nitro, hydroxyl, carboxyl, amino, C
1-6alkyl, hydroxyl C
1-6alkyl, C
3-6cycloalkyl, C
1-6alkoxyl group, hydroxyl C
3-6cycloalkyl, halo C
3-6cycloalkyl, C
4-8cycloalkyl C
1-6alkyl, halo C
4-8cycloalkyl C
1-6alkyl, halo C
1-6alkyl, C
2-6thiazolinyl, halo C
2-6thiazolinyl, hydroxyl C
2-6thiazolinyl, C
5-8cycloalkenyl group, C
2-6alkynyl, C
3-6cycloalkyloxy group C
1-6alkoxyl group, halo C
1-6alkoxyl group, C
1-6alkylthio, C
3-6cycloalkylthio, C
1-6alkyl amine group, two (C
1-6alkyl) amido, C
1-6alkyl-carbonyl, formamyl, amino-sulfonyl, C
1-6alkyl amine group formyl radical, two (C
1-6alkyl) amido formacyl, C
1-6alkylamidoalkyl, C
1-6alkyl sulphonyl, C
1-6alkyl amine group alkylsulfonyl, two (C
1-6alkyl) amido alkylsulfonyl, C
1-6alkylsulfonamido, C
1-6carbalkoxy or C
1-6alkyl carbonyl oxy;
R
6aand R
6brepresent hydrogen atom, halogen atom, hydroxyl, cyano group, carboxyl, C respectively
1-6alkyl, C
3-8cycloalkyl, halo C
1-6alkyl, halo C
1-6alkoxyl group, oxo, 6-14 unit aryl, 5-14 unit heteroaryl, the heterocyclic radical of 3-14 unit, R
7ao-, R
7aoC (O)-, R
7bc (O)-, R
7bc (O) NH-, R
7cs (O)-, R
7cs (O)
2-, R
7cs (O)
2nH-, R
7d(OR
7a) CH-, R
7ds-, (R
7er
7f) N-, (R
7er
7f) NC (O)-, 6-14 unit aryl-O-, 6-14 unit aryl-OCH
2-, 6-14 unit aryl-S (O)
2nH-, 6-14 unit's aryl-S (O)
2-,
Or R
6aand R
6bbe interconnected, the Cy be connected with them
3on atom form 3-14 cyclic group together, this cyclic group and Cy
3with and ring, volution, bridged ring form condense, described 3-14 cyclic group contains 0-4 and is selected from C (O), N, O, S, SO and/or SO
2atom, and can be individual independently selected from R by 1-4 further
9substituting group replace, R
9for hydrogen, halogen atom, cyano group, nitro, hydroxyl, carboxyl, amino, C
1-6alkyl, hydroxyl C
1-6alkyl, C
3-6cycloalkyl, C
1-6alkoxyl group, hydroxyl C
3-6cycloalkyl, halo C
3-6cycloalkyl, C
4-8cycloalkyl C
1-6alkyl, halo C
4-8cycloalkyl C
1-6alkyl, halo C
1-6alkyl, C
2-6thiazolinyl, halo C
2-6thiazolinyl, hydroxyl C
2-6thiazolinyl, C
5-8cycloalkenyl group, C
2-6alkynyl, C
3-6cycloalkyloxy group C
1-6alkoxyl group, halo C
1-6alkoxyl group, C
1-6alkylthio, C
3-6cycloalkylthio, C
1-6alkyl amine group, two (C
1-6alkyl) amido, C
1-6alkyl-carbonyl, formamyl, amino-sulfonyl, C
1-6alkyl amine group formyl radical, two (C
1-6alkyl) amido formacyl, C
1-6alkylamidoalkyl, C
1-6alkyl sulphonyl, C
1-6alkyl amine group alkylsulfonyl, two (C
1-6alkyl) amido alkylsulfonyl, C
1-6alkylsulfonamido, C
1-6carbalkoxy or C
1-6alkyl carbonyl oxy;
R
7a, R
7b, R
7c, R
7d, R
7e, R
7fbe respectively hydrogen atom, C
1-6alkyl, C
3-8cycloalkyl, or R
7eand R
7fformed together with the N that they connect and be selected from C (O), N, O, S, SO and/or SO containing 1-4
23-14 unit heterocyclic radical;
M is 0,1 or 2;
N is 0,1,2,3 or 4.
The preferred version of scheme 1 is:
Wherein, X
1, X
2, R
1, R
2, A
1, A
2, Cy
1, Cy
2, Cy
3, m, n be as described in scheme 1;
R
6aand R
6bbe interconnected, the Cy be connected with them
3on atom form 3-14 cyclic group together, this cyclic group and Cy
3condense with volution form, described 3-14 cyclic group contains 0-4 and is selected from C (O), N, O, S, SO and/or SO
2atom, and can be individual independently selected from R by 1-4 further
9substituting group replace, R
9for hydrogen, halogen atom, cyano group, nitro, hydroxyl, carboxyl, amino, C
1-6alkyl, hydroxyl C
1-6alkyl, C
3-6cycloalkyl, C
1-6alkoxyl group, hydroxyl C
3-6cycloalkyl, halo C
3-6cycloalkyl, C
4-8cycloalkyl C
1-6alkyl, halo C
4-8cycloalkyl C
1-6alkyl, halo C
1-6alkyl, C
2-6thiazolinyl, halo C
2-6thiazolinyl, hydroxyl C
2-6thiazolinyl, C
5-8cycloalkenyl group, C
2-6alkynyl, C
3-6cycloalkyloxy group C
1-6alkoxyl group, halo C
1-6alkoxyl group, C
1-6alkylthio, C
3-6cycloalkylthio, C
1-6alkyl amine group, two (C
1-6alkyl) amido, C
1-6alkyl-carbonyl, formamyl, amino-sulfonyl, C
1-6alkyl amine group formyl radical, two (C
1-6alkyl) amido formacyl, C
1-6alkylamidoalkyl, C
1-6alkyl sulphonyl, C
1-6alkyl amine group alkylsulfonyl, two (C
1-6alkyl) amido alkylsulfonyl, C
1-6alkylsulfonamido, C
1-6carbalkoxy or C
1-6alkyl carbonyl oxy.
The preferred version of scheme 1 is:
Wherein, X
1, X
2, R
1, R
2, A
1, A
2, Cy
1, Cy
2, Cy
3, m, n be as described in scheme 1;
R
6aand R
6bbe interconnected, the Cy be connected with them
3on atom form 3-14 cyclic group together, this cyclic group and Cy
3condense with bridged ring form, described 3-14 cyclic group contains 0-4 and is selected from C (O), N, O, S, SO and/or SO
2atom, and can be individual independently selected from R by 1-4 further
9substituting group replace, R
9for hydrogen, halogen atom, cyano group, nitro, hydroxyl, carboxyl, amino, C
1-6alkyl, hydroxyl C
1-6alkyl, C
3-6cycloalkyl, C
1-6alkoxyl group, hydroxyl C
3-6cycloalkyl, halo C
3-6cycloalkyl, C
4-8cycloalkyl C
1-6alkyl, halo C
4-8cycloalkyl C
1-6alkyl, halo C
1-6alkyl, C
2-6thiazolinyl, halo C
2-6thiazolinyl, hydroxyl C
2-6thiazolinyl, C
5-8cycloalkenyl group, C
2-6alkynyl, C
3-6cycloalkyloxy group C
1-6alkoxyl group, halo C
1-6alkoxyl group, C
1-6alkylthio, C
3-6cycloalkylthio, C
1-6alkyl amine group, two (C
1-6alkyl) amido, C
1-6alkyl-carbonyl, formamyl, amino-sulfonyl, C
1-6alkyl amine group formyl radical, two (C
1-6alkyl) amido formacyl, C
1-6alkylamidoalkyl, C
1-6alkyl sulphonyl, C
1-6alkyl amine group alkylsulfonyl, two (C
1-6alkyl) amido alkylsulfonyl, C
1-6alkylsulfonamido, C
1-6carbalkoxy or C
1-6alkyl carbonyl oxy.
The preferred version of scheme 1 is:
Wherein, X
1, X
2, R
1, R
2, A
1, A
2, Cy
1, Cy
2, Cy
3, m, n be as described in scheme 1;
R
6aand R
6bbe interconnected, the Cy be connected with them
3on atom form 3-14 cyclic group together, this cyclic group and Cy
3with and loop type condense, described 3-14 cyclic group contains 0-4 and is selected from C (O), N, O, S, SO and/or SO
2atom, and can be individual independently selected from R by 1-4 further
9substituting group replace, R
9for hydrogen, halogen atom, cyano group, nitro, hydroxyl, carboxyl, amino, C
1-6alkyl, hydroxyl C
1-6alkyl, C
3-6cycloalkyl, C
1-6alkoxyl group, hydroxyl C
3-6cycloalkyl, halo C
3-6cycloalkyl, C
4-8cycloalkyl C
1-6alkyl, halo C
4-8cycloalkyl C
1-6alkyl, halo C
1-6alkyl, C
2-6thiazolinyl, halo C
2-6thiazolinyl, hydroxyl C
2-6thiazolinyl, C
5-8cycloalkenyl group, C
2-6alkynyl, C
3-6cycloalkyloxy group C
1-6alkoxyl group, halo C
1-6alkoxyl group, C
1-6alkylthio, C
3-6cycloalkylthio, C
1-6alkyl amine group, two (C
1-6alkyl) amido, C
1-6alkyl-carbonyl, formamyl, amino-sulfonyl, C
1-6alkyl amine group formyl radical, two (C
1-6alkyl) amido formacyl, C
1-6alkylamidoalkyl, C
1-6alkyl sulphonyl, C
1-6alkyl amine group alkylsulfonyl, two (C
1-6alkyl) amido alkylsulfonyl, C
1-6alkylsulfonamido, C
1-6carbalkoxy or C
1-6alkyl carbonyl oxy.
The solution of the present invention 2 there is provided the compound shown in general formula (II), its pharmacy acceptable salt, and isomer:
Wherein, X
1, X
2, R
1, R
2, A
1, A
2, Cy
1, Cy
2, Cy
3, R
8, R
9, m, n be as described in scheme 1;
Cy
4represent 6-14 unit aryl, 5-14 unit heteroaryl, C
3-8the heterocyclic radical of cycloalkyl or 3-14 unit, with Cy
3with and loop type condense, R
9for halogen atom, hydroxyl, C
1-6alkyl or C
1-6alkoxyl group;
R is 0,1,2,3 or 4;
Q is 0,1,2,3 or 4.
The solution of the present invention 3 there is provided the compound shown in general formula (III), its pharmacy acceptable salt, and isomer:
Wherein, X
1, X
2, R
1, R
2, Cy
1, Cy
2, R
8, R
9, m, n be as described in scheme 1;
X
3for O, S (O)
w, N (R
4a) or C (R
4a) (R
4b), w is 0,1 or 2, R
4aand R
4bbe separately hydrogen atom, C
1-6alkyl, halo C
1-6alkyl, C
3-8cycloalkyl, C
2-6thiazolinyl, C
5-8cycloalkenyl group or C
2-6alkynyl;
X
4, X
5, X
6, X
7be respectively CH or N;
R is 0,1,2,3 or 4;
P is 0,1 or 2.
Q is 0,1,2 or 3.
The preferred version of scheme 3 is
X
1for C (O), S (O)
wor C (=NR
5), w is 0,1 or 2, R
5for cyano group, hydroxyl, C
1-6alkyl, C
1-6alkoxyl group, described C
1-6alkyl, C
1-6alkoxyl group can optionally be replaced independently selected from following substituting group by 1-4: halogen atom, cyano group, hydroxyl, carboxyl and amino;
X
2for O, S or N (R
4a), R
4afor hydrogen atom, C
1-6alkyl, halo C
1-6alkyl;
X
3for O, S (O)
w, N (R
4a) or C (R
4a) (R
4b), w is 0,1 or 2, R
4aand R
4bbe separately hydrogen atom, C
1-6alkyl, halo C
1-6alkyl;
X
4, X
5, X
6, X
7be respectively CH or N;
R
1for hydrogen, C
1-6alkyl, C
3-8cycloalkyl, C
2-6thiazolinyl, C
5-8cycloalkenyl group, C
2-6alkynyl, C
1-6alkoxyl group, C
1-6carbalkoxy, C
1-6alkyl carbonyl oxy or phenyl;
R
2for not existing, C
1-4alkyl, halo C
1-4alkyl or oxo;
Cy
1for 6-10 unit aryl, the single heterocyclic radical of the first single heteroaryl of 5-8 or 3-8 unit, described 6-10 unit aryl, the single heterocyclic radical of the 5-8 single heteroaryl of unit and 3-8 unit can optionally be replaced by the individual substituting group independently selected from R ' of 1-4;
Cy
2for 6-10 unit aryl, the single heterocyclic radical of the first single heteroaryl of 5-8 or 3-8 unit, described 6-10 unit aryl, the single heterocyclic radical of the 5-8 single heteroaryl of unit and 3-8 unit can optionally be replaced by the individual substituting group independently selected from R ' of 1-4;
R ' is halogen atom, cyano group, nitro, hydroxyl, carboxyl, amino, oxo, C
1-6alkyl, hydroxyl C
1-6alkyl, C
3-6cycloalkyl, C
1-6alkoxyl group, halo C
3-6cycloalkyl, C
4-8cycloalkyl C
1-6alkyl, halo C
4-8cycloalkyl C
1-6alkyl, halo C
1-6alkyl, C
2-6thiazolinyl, C
2-6alkynyl, halo C
1-6alkoxyl group, C
1-6alkyl amine group, two (C
1-6alkyl) amido, C
1-6alkyl-carbonyl, formamyl, amino-sulfonyl, C
1-6alkyl amine group formyl radical, two (C
1-6alkyl) amido formacyl, C
1-6alkylamidoalkyl, C
1-6alkyl sulphonyl, C
1-6alkyl amine group alkylsulfonyl, two (C
1-6alkyl) amido alkylsulfonyl, C
1-6alkylsulfonamido, C
1-6carbalkoxy or C
1-6alkyl carbonyl oxy;
R
8for hydrogen, halogen atom, cyano group, nitro, hydroxyl, carboxyl, amino, C
1-6alkyl, hydroxyl C
1-6alkyl, C
3-6cycloalkyl, C
1-6alkoxyl group, hydroxyl C
3-6cycloalkyl, halo C
1-6alkyl, C
2-6thiazolinyl, C
2-6alkynyl, halo C
1-6alkoxyl group, C
1-6alkyl amine group, two (C
1-6alkyl) amido, C
1-6alkyl-carbonyl, formamyl, amino-sulfonyl, C
1-6alkyl amine group formyl radical, two (C
1-6alkyl) amido formacyl, C
1-6alkylamidoalkyl, C
1-6alkyl sulphonyl, C
1-6alkyl amine group alkylsulfonyl, two (C
1-6alkyl) amido alkylsulfonyl, C
1-6alkylsulfonamido, C
1-6carbalkoxy or C
1-6alkyl carbonyl oxy;
R
9for hydrogen, halogen atom, cyano group, nitro, hydroxyl, carboxyl, amino, C
1-6alkyl, hydroxyl C
1-6alkyl, C
3-6cycloalkyl, C
1-6alkoxyl group, hydroxyl C
3-6cycloalkyl, halo C
1-6alkyl, C
2-6thiazolinyl, C
2-6alkynyl, halo C
1-6alkoxyl group, C
1-6alkyl amine group, two (C
1-6alkyl) amido, C
1-6alkyl-carbonyl, formamyl, amino-sulfonyl, C
1-6alkyl amine group formyl radical, two (C
1-6alkyl) amido formacyl, C
1-6alkylamidoalkyl, C
1-6alkyl sulphonyl, C
1-6alkyl amine group alkylsulfonyl, two (C
1-6alkyl) amido alkylsulfonyl, C
1-6alkylsulfonamido, C
1-6carbalkoxy or C
1-6alkyl carbonyl oxy;
M is 0,1 or 2; N is 0,1,2,3 or 4;
R is 0,1 or 2; P is 0,1,2,3 or 4; Q is 0,1,2 or 3.
The preferred version of scheme 3 is
X
1for C (O), S (O)
wor C (=NR
5), w is 0,1 or 2, R
5for cyano group, hydroxyl, C
1-6alkyl, C
1-6alkoxyl group;
X
2for O, S or N (R
4a), R
4afor hydrogen atom or C
1-6alkyl;
X
3for O, S, N (R
4a) or C (R
4a) (R
4b), R
4aand R
4bbe separately hydrogen atom or C
1-4alkyl;
X
4, X
5, X
6, X
7be respectively CH or N;
R
1for hydrogen or C
1-4alkyl;
R
2for not existing or C
1-4alkyl;
Cy
1for 6-10 unit aryl, described 6-10 unit aryl can optionally be replaced by the individual substituting group independently selected from R ' of 1-4;
Cy
2for the single heterocyclic radical of 3-8 unit, the single heterocyclic radical of described 3-8 unit can optionally be replaced by the individual substituting group independently selected from R ' of 1-4;
R ' is halogen atom, cyano group, nitro, hydroxyl, carboxyl, amino, oxo, C
1-6alkyl, hydroxyl C
1-6alkyl, C
3-6cycloalkyl, C
1-6alkoxyl group, halo C
1-6alkyl, C
2-6thiazolinyl, halo C
1-6alkoxyl group, C
1-6alkyl amine group, two (C
1-6alkyl) amido, C
1-6alkyl-carbonyl, formamyl, amino-sulfonyl, C
1-6alkyl amine group formyl radical, two (C
1-6alkyl) amido formacyl, C
1-6alkylamidoalkyl, C
1-6alkyl sulphonyl, C
1-6alkyl amine group alkylsulfonyl, two (C
1-6alkyl) amido alkylsulfonyl, C
1-6alkylsulfonamido, C
1-6carbalkoxy or C
1-6alkyl carbonyl oxy;
R
8for hydrogen or C
1-4alkyl;
R
9for hydrogen, halogen atom, cyano group, nitro, hydroxyl, carboxyl, amino, C
1-6alkyl, hydroxyl C
1-6alkyl, C
3-6cycloalkyl, C
1-6alkoxyl group, halo C
1-6alkyl, halo C
1-6alkoxyl group, C
1-6alkyl amine group, two (C
1-6alkyl) amido, C
1-6alkyl-carbonyl, formamyl, amino-sulfonyl, C
1-6alkyl amine group formyl radical, two (C
1-6alkyl) amido formacyl, C
1-6alkylamidoalkyl, C
1-6alkyl sulphonyl, C
1-6alkyl amine group alkylsulfonyl, two (C
1-6alkyl) amido alkylsulfonyl, C
1-6alkylsulfonamido, C
1-6carbalkoxy or C
1-6alkyl carbonyl oxy;
M is 0,1 or 2; N is 0,1 or 2;
R is 0,1 or 2; P is 0,1 or 2; Q is 0,1 or 2.
The preferred version of scheme 3 is
X
1for C (O) or S (O)
2;
X
2for O;
X
3for O, S, N (R
4a) or C (R
4a) (R
4b), R
4aand R
4bbe separately hydrogen atom or C
1-4alkyl;
X
4, X
5, X
6, X
7be respectively CH or N;
R
1for hydrogen or C
1-4alkyl;
R
2for not existing;
Cy
1for phenyl, described phenyl can optionally be replaced by the individual substituting group independently selected from R ' of 1-4;
Cy
2for the single heterocyclic radical of 5-7 unit, the single heterocyclic radical of described 5-7 unit can optionally be replaced by the individual substituting group independently selected from R ' of 1-4;
R ' is halogen atom, cyano group, nitro, hydroxyl, carboxyl, amino, oxo, C
1-6alkyl, hydroxyl C
1-6alkyl, C
1-6alkoxyl group, halo C
1-6alkyl, halo C
1-6alkoxyl group, C
1-6alkyl amine group, two (C
1-6alkyl) amido, C
1-6alkyl-carbonyl, formamyl, amino-sulfonyl, C
1-6carbalkoxy or C
1-9alkyl carbonyl oxy;
R
8for hydrogen or C
1-4alkyl;
R
9for hydrogen, halogen atom, cyano group, nitro, hydroxyl, carboxyl, amino, C
1-6alkyl, hydroxyl C
1-6alkyl, C
3-6cycloalkyl, C
1-6alkoxyl group, halo C
1-6alkyl, halo C
1-6alkoxyl group, C
1-6alkyl amine group, two (C
1-6alkyl) amido, C
1-6alkyl-carbonyl, formamyl, amino-sulfonyl, C
1-6carbalkoxy or C
1-6alkyl carbonyl oxy;
N is 0 or 1;
R is 0,1 or 2; P is 0,1 or 2; Q is 0,1 or 2.
The preferred version of scheme 3 is
X
1for C (O);
X
2for O;
X
3for O or CH
2;
X
4, X
5, X
6, X
7for CH;
R
1for C
1-4alkyl;
R
2for not existing;
Cy
1for phenyl, described phenyl can optionally be replaced by 1 or 2 substituting group independently selected from R ';
Cy
2for the single heterocyclic radical of 5-6 unit at least containing an atom N, the described single heterocyclic radical of 5-6 unit at least containing an atom N can optionally be replaced by 1 or 2 substituting group independently selected from R ';
R ' is halogen atom, hydroxyl, amino, oxo, C
1-4alkyl, C
1-4alkoxyl group or halo C
1-4alkyl;
R
8for hydrogen or C
1-4alkyl;
R
9for hydrogen, halogen atom or C
1-6alkyl;
N is 0 or 1;
R is 0,1 or 2; P is 0,1 or 2; Q is 0,1 or 2.
" C of the present invention
1-6alkyl " represent straight or branched containing the alkyl of 1-6 carbon atom, specific examples includes but not limited to methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, 2-methyl-propyl, 1-methyl-propyl, 1, 1-dimethyl ethyl, n-pentyl, 3-methyl butyl, 2-methyl butyl, 1-methyl butyl, 1-ethyl propyl, n-hexyl, 4-methyl amyl, 3-methyl amyl, 2-methyl amyl, 1-methyl amyl, 3, 3-dimethylbutyl, 2, 2-dimethylbutyl, 1, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2, 3-dimethylbutyl, 2-ethyl-butyl, 1, 2-dimethyl propyl etc." C of the present invention
1-4alkyl " refer to the specific examples containing 1-4 carbon atom in above-mentioned example.
" C of the present invention
3-8cycloalkyl " for containing the alkyl of the ring-type of 3-8 carbon atom, specific examples includes but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group etc." C of the present invention
3-6cycloalkyl " refer to the specific examples containing 3-6 carbon atom in above-mentioned example." C of the present invention
4-8cycloalkyl " refer to the specific examples containing 4-8 carbon atom in above-mentioned example.
" C of the present invention
2-6thiazolinyl " for containing the thiazolinyl of the straight or branched of 2-6 carbon atom of double bond; include but not limited to vinyl, 1-propenyl, 2-propenyl, 1-butylene base, crotyl, 1; 3-divinyl, 1-pentenyl, pentenyl, 3-pentenyl, 1; 3-pentadiene, 1; 4-pentadiene, 1-hexenyl, 2-hexenyl, 3-hexenyl, Isosorbide-5-Nitrae-hexadiene etc." C of the present invention
2-4thiazolinyl " refer to the specific examples containing 2-4 carbon atom in above-mentioned example.
" C of the present invention
2-6alkynyl " for containing the alkynyl of the straight or branched of 2-6 carbon atom of three key, include but not limited to ethynyl, proyl, ethyl acetylene base, 2-butyne base, 3-methyl isophthalic acid-butynyl, 1-pentynyl, valerylene base, 3-pentynyl, 3-methyl-1-pentene alkynyl, 4-methyl-1-pentene alkynyl, 4-methyl-valerylene base, 1-hexin base, 2-hexin base, 3-hexin base etc." C of the present invention
2-4alkynyl " refer to the specific examples containing 2-4 carbon atom in above-mentioned example." C of the present invention
3-6alkynyl " refer to the specific examples containing 3-6 carbon atom in above-mentioned example.
" C of the present invention
5-8cycloalkenyl group " for containing 5-8 carbon atom and the interior cyclic group containing one or more double bond of ring, include but not limited to
deng.
" C of the present invention
1-6alkoxyl group " refer to " C
1-6alkyl " be connected formed group with Sauerstoffatom, i.e. C
1-6alkyl-O-, specific examples includes but are not limited to methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, tert.-butoxy, sec-butoxy, pentyloxy, neopentyl oxygen, hexyloxy etc." C of the present invention
1-4alkoxyl group " refer to " C
1-4alkyl-O-" mode connects formed group, " C
1-4alkyl " definition as mentioned before.
" C of the present invention
1-6alkylthio " refer to C
1-6alkyl is connected formed group with sulphur atom, i.e. C
1-6alkyl S-, described " C
1-6alkyl " as mentioned before.
" C of the present invention
1-6alkyl amine group " refer to a C
1-6the group that a hydrogen atom in alkyl-substituted amino is formed, i.e. C
1-6alkyl NH-, described " C
1-6alkyl " as mentioned before.
" two (C of the present invention
1-6alkyl) amido " refer to two identical or different C
1-6the group that two hydrogen atom of alkyl respectively in substituted-amino is formed, i.e. (C
1-6alkyl) 2N-, described " C
1-6alkyl " as mentioned before.
" C of the present invention
1-6alkyl-carbonyl " refer to C
1-6alkyl is connected formed group with carbonyl, i.e. C
1-6alkyl C (O)-, described " C
1-6alkyl " as mentioned before." C of the present invention
1-4alkyl-carbonyl " refer to the specific examples containing 1-4 carbon atom in above-mentioned example.
" C of the present invention
1-6alkyl carbonyl oxy " refer to C
1-6alkyl is connected formed group with carbonyl oxygen base, i.e. C
1-6alkyl-C (O) O-, described " C
1-6alkyl " as mentioned before.
" C of the present invention
1-6carbalkoxy " refer to C
1-6alkoxyl group is connected formed group with carbonyl, i.e. (C
1-6alkyl) OC (O)-, described " C
1-6alkoxyl group " as mentioned before.
" C of the present invention
1-6alkyl amine group formyl radical " refer to C
1-6alkyl is connected formed group with amido formacyl, i.e. C
1-6alkyl-NHC (O)-, described " C
1-6alkyl " as mentioned before.
" two (C of the present invention
1-6alkyl) amido formacyl " refer to two identical or different C
1-6the group formed after two hydrogen atoms of alkyl respectively in substituted-amino formyl radical on amido, i.e. (C
1-6alkyl)
2nC (O)-, described " C
1-6alkyl " as mentioned before.
" C of the present invention
1-6alkylamidoalkyl " refer to C
1-6alkyl is connected formed group with formamido-, i.e. (C
1-6alkyl) C (O) NH-, described " C
1-6alkyl " as mentioned before.
" C of the present invention
1-6alkyl sulphonyl " refer to C
1-6alkyl is connected formed group with alkylsulfonyl, i.e. C
1-6alkyl-S (O)
2-, described " C
1-6alkyl " as mentioned before.
" C of the present invention
1-6alkyl amine group alkylsulfonyl " refer to C
1-6alkyl is connected formed group with amino-sulfonyl, i.e. C
1-6alkyl-NHS (O)
2-, described " C
1-6alkyl " as mentioned before.
" two (C of the present invention
1-6alkyl) amido alkylsulfonyl " refer to two identical or different C
1-6the group formed after two hydrogen atoms of alkyl respectively in substituted-amino alkylsulfonyl on amido, i.e. (C
1-6alkyl)
2nS (O)
2-, described " C
1-6alkyl " as mentioned before.
" C of the present invention
1-6alkylsulfonamido " refer to C
1-6alkyl is connected formed group with sulfoamido, i.e. C
1-6alkyl-S (O)
2nH-, described " C
1-6alkyl " as mentioned before.
" hydroxyl C of the present invention
1-6alkyl " refer to that one or more hydroxyl replaces C
1-6the group that hydrogen atom in alkyl is formed, comprise methyl alcohol, ethanol, ethylene glycol, n-propyl alcohol, Virahol, glycerol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol, 2-methyl isophthalic acid, 2-bis-propyl alcohol, amylalcohol, 1,2-pentanediol, 2-methyl-2-butanols, hexanol etc., described " C
1-6alkyl " as mentioned before.
" hydroxyl C of the present invention
2-6thiazolinyl " refer to that one or more hydroxyl replaces C
2-6the group that hydrogen atom in thiazolinyl is formed, described " C
2-6thiazolinyl " as mentioned before.
" hydroxyl C of the present invention
3-6cycloalkyl " refer to that one or more hydroxyl replaces C
3-6the group that cycloalkyl is formed, described " C
3-6cycloalkyl " as mentioned before.
" C of the present invention
4-8cycloalkyl C
1-6alkyl " refer to C
4-8cycloalkyl substituted C
1-6the group that hydrogen atom in alkyl is formed, described " C
4-8cycloalkyl ", " C
1-6alkyl " as mentioned before.
" C of the present invention
3-6cycloalkyloxy group C
1-6alkoxyl group " refer to " C
3-6cycloalkyl-O-C
1-6alkoxyl group-" form connects the group formed, described " C
3-6cycloalkyl ", " C
1-6alkoxyl group " as mentioned before.
" C of the present invention
3-6cycloalkylthio " refer to C
3-6cycloalkyl is connected formed group with sulphur atom, i.e. C
1-6cycloalkyl S-, described " C
3-6cycloalkyl " as mentioned before.
" halo " of the present invention refers to the group that one or more halogen atom replaces one or more hydrogen atom on some group and formed, and " halogen atom " is selected from fluorine atom, chlorine atom, bromine atoms, atomic iodine." halo C
1-6alkyl ", " halo C
1-6alkoxyl group ", " halo C
3-6cycloalkyl ", " halo C
4-8cycloalkyl C
1-6alkyl ", " halo C
2-6thiazolinyl " refer to that one or more halogen atom replaces previously described C
1-6alkyl, C
1-6alkoxyl group, C
3-6cycloalkyl, C
4-8cycloalkyl C
1-6alkyl, halo C
2-6the base that one or more hydrogen atom in thiazolinyl is formed.
" oxo " of the present invention refers to the group that one or more carbon atom is formed by-C (O)-replacement.
" 6-14 unit aryl " of the present invention refers to that annular atoms is all the cyclic aromatic groups of carbon atom, comprises 6-8 unit's monocyclic aryl and 8-14 unit fused ring aryl.6-8 unit monocyclic aryl refers to whole undersaturated aryl, such as phenyl, cyclooctatetraenyl etc.8-14 unit fused ring aryl refers to that the ring that has at least sharing that two adjacent carbon atoms are formed each other by two or more ring texturees is the condensed ring group of undersaturated aromatic nucleus, comprise the unsaturated fused ring aryl of 8-14 unit, such as naphthalene, phenanthrene etc., also comprise 8-14 unit fractional saturation fused ring aryl, such as benzo C
3-8cycloalkyl, benzo C
4-8cycloalkenyl group, specific examples is as 2,3-dihydro-1H-indenyl, 1H-indenyl, 1,2,3,4-tetralyl, Isosorbide-5-Nitrae-dihydro naphthyl etc." 6-10 unit aryl " refers to that annular atoms is all the 6-10 unit cyclic aromatic groups of carbon atom, and comprise monocyclic aryl, also comprise fused ring aryl, and fused ring aryl can be undersaturated, also can be fractional saturation.
" 5-14 unit heteroaryl " of the present invention, refer to the undersaturated cyclic group with aromaticity containing 5-14 annular atoms (wherein at least containing a heteroatoms), comprise the single heteroaryl of 5-8 unit, the thick heteroaryl of 6-14 unit, described heteroatoms is selected from C (O), N, O, S, SO, SO
2deng.
The single heteroaryl of 5-8 unit refers to the cyclic group containing a heteroatomic 5-8 annular atoms of aromaticity, and specific examples includes but are not limited to furyl, thienyl, pyrryl, thiazolyl, isothiazolyl, thiadiazolyl group, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2,3-triazoles base, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, pyridyl, 2-pyridone, 4-pyridone, pyrimidyl, Isosorbide-5-Nitrae-Dioxin base, 2H-1,2-oxazinyl, 4H-1,2-oxazinyl, 6H-1,2-oxazinyl, 4H-1,3-oxazinyl, 6H-1,3-oxazinyl, 4H-1,4-oxazinyl, pyridazinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazines base, 1,3,4-triazinyl, 1,2,4,5-tetrazine base, oxepin base, thia cycloheptatriene base, nitrogen heterocyclic heptantriene base, 1,3-diazacyclo heptantriene base, azepine cyclooctatetraenyl, Isosorbide-5-Nitrae-dihydro-Isosorbide-5-Nitrae-diazacyclo sarohornene, Isosorbide-5-Nitrae-dioxane sarohornene etc.Be preferably " the single heteroaryl of 5-6 unit ", refer to the cyclic group containing a heteroatomic 5-6 annular atoms of aromaticity.
The thick heteroaryl of 6-14 unit, refer to that sharing two adjacent atoms containing 6-14 annular atoms (wherein at least containing a heteroatoms) each other by two or more ring texturees couples together the undersaturated condensed cyclic structure with aromaticity formed, specific examples includes but not limited to: benzofuryl, benzisoxa furyl, benzothienyl, indyl, isoindole, benzoxazolyl, benzimidazolyl-, indazolyl, benzotriazole base, quinolyl, 2-quinolinone, 4-quinolinone, 1-isoquinolines, isoquinolyl, acridyl, phenanthridinyl, benzo pyridazinyl, phthalazinyl, quinazolyl, quinoxalinyl, phenol piperazine base, pteridine radicals, purine radicals, naphthyridinyl, azophenlyene, thiodiphenylamine, Deng.Be preferably " the thick heteroaryl of 9-10 unit ", refer to the cyclic group containing a heteroatomic 9-10 annular atoms of aromaticity.
" 3-14 unit heterocyclic radical " of the present invention, refers to the cyclic group of saturated, the fractional saturation containing 3-14 annular atoms (wherein at least containing a heteroatoms), comprises the 3-8 single heterocyclic radical of unit and the first fused heterocycle base of 6-14.Described heteroatoms is selected from C (O), N, O, S, SO, SO
2deng.
Described " the single heterocyclic radical of 3-8 unit ", its single heterocycle can be saturated, fractional saturation, its specific examples includes but are not limited to: ethylenimine base, 2H-ethylenimine base, diazacyclo propyl, 3H-diazacyclo propenyl, azetidinyl, 1,2-diazetidine base, azete base, 1,2-dioxetanes alkyl, 1,2-diazetine base, dioxirane base, oxetanyl, oxaza propyl, Isosorbide-5-Nitrae-dioxane base, 1,3-dioxane base, thiirane base, Thietane base, 1,3-dithian base, 1,2-dithia cyclobutene base, 1,3-dioxolane base, 1,3-dithiolane base, Isosorbide-5-Nitrae-Dioxin base, Isosorbide-5-Nitrae-dithiins base, Isosorbide-5-Nitrae-oxathiin base, tetrahydrofuran base, pyrrolin base, pyrrolidyl, imidazolidyl, 4,5-glyoxalidine base, pyrazolidyl, 4,5-pyrazoline base, 2,5-dihydro-thiophene base, tetrahydro-thienyl, 4,5-dihydro-thiazolyl, piperidyl, piperazinyl, morpholinyl base, 4,5-dihydro-oxazole base, 4,5-dihydro-isoxazole base, 2,3-dihydro-isoxazole base, 2H-1,2-oxazinyl, 4H-1,2-oxazinyl, 6H-1,2-oxazinyl, 2H-1,3-oxazinyl, 4H-1,3-oxazinyl, 5,6-dihydro-4H-1,3-oxazinyl, 6H-1,3-oxazinyl, 2H-1,4-oxazinyl, 4H-1,4-oxazinyl, 2H-1,3-thiazinyl, 4H-1,3-thiazinyl, 5,6-dihydro-4H-1,3-thiazinyl, 6H-1,3-thiazinyl, 2H-1,4-thiazinyl, 4H-1,4-thiazinyl, 2H-pyranyl, 2H-pyran-2-one base, 3,4-dihydro-2H-pyranyl, 4H-pyranyl, THP trtrahydropyranyl, 4H-pyrans-4-ketone group etc.Be preferably " the single heterocyclic radical of 5-7 unit ", being more preferably " the single heterocyclic radical of 5-6 unit " its ring can be saturated, fractional saturation.
Described " 6-14 unit fused heterocycle base ", its fused heterocycle can be saturated, fractional saturation, example has imidazolidine also [4, 5-c] pyridyl, 3, 4-dihydroquinazoline base, 1, 2-dihydro-quinoxaline base, benzo [d] [1, 3] dioxa cyclopentenyl, 1, 3-dihydroisobenzofuran base, 2H-chromogen thiazolinyl, 2H-chromogen alkene-2-ketone group, 4H-chromenyl, 4H-chromene-4-ketone group, chromanyl, 4H-1, 3-benzoxazinyl, 4, 6-dihydro-1H-furo [3, 4-d] imidazolyl, 3a, 4, 6, 6a-tetrahydrochysene-1H-furo [3, 4-d] imidazolyl, 4, 6-dihydro-1H-thieno-[3, 4-d] imidazolyl, 4, 6-dihydro-1H-pyrrolo-[3, 4-d] imidazolyl, 4, 5, 6, 7-tetrahydrochysene-1H-benzo [d] imidazolyl etc.Be preferably " 9-10 unit fused heterocycle base ", its ring can be saturated, fractional saturation.
" R of the present invention
6aand R
6bbe interconnected, the Cy be connected with them
3on atom form 3-14 cyclic group together " in 3-14 cyclic group, refer to the monocycle containing 3-12 annular atoms and polycyclic moiety, can further containing one or more be selected from C (O), N, O, S, SO, SO
2heteroatoms.This monocycle and polycyclic moiety can be undersaturated, such as aryl, heteroaryl, also can be fractional saturations, and the aryl of such as fractional saturation, the heterocyclic radical of fractional saturation can also be saturated, such as cycloalkyl, cycloalkenyl group, saturated heterocyclic radical etc.For polycyclic moiety, ring wherein can be with and ring, volution, bridged ring form mutually condense.
Described " and ring " refer to a class by two or more ring texturees share each other two adjacent atoms couple together is formed contain carbon atom and/or heteroatomic condensed cyclic structure, described heteroatoms is selected from C (O), N, O, S, SO, SO
2, be preferably the also cyclic group of 6-10 annular atoms, such as 5, 6-glyoxalidine [1.2-a] pyrazine-7 (8H)-Ji, 5, 6-dihydro-1, 7-naphthyridines-7 (8H)-Ji, 5H-pyrroles [3.4-b] pyridine-6 (7H)-Ji, 7, 8-dihydropyridine [4.3-d] pyrimidine-6 (5H)-Ji, 2, 3, 6, 7-tetrahydrochysene-1H-pyrazoles [4.3-c] pyridine-5 (4H)-Ji, 6, 7-thiazoline [5.4-c] pyridine-5 (4H)-Ji, 3-methyl-6, 7-dihydro-3H-pyrazoles [4.5-c] pyridine-5 (4H)-Ji, 2-methyl six hydrogen cyclopentano [c] pyrroles-5-base etc.
Described " volution " refer to a class have two rings to share at least atom formed containing carbon atom and/or heteroatomic condensed cyclic structure, described heteroatoms is selected from C (O), N, O, S, SO, SO
2be preferably the spiro-cyclic groups of 7-10 annular atoms, such as 6-nitrogen spiral shell [2.5] octane-6-base, 7-nitrogen spiral shell [3.5] nonane-7-base, 8-nitrogen spiral shell [4.5] decane-8-base, 1-methyl isophthalic acid, 7-phenodiazine spiral shell [4.4] nonane-7-base, 2-methyl-2,6-phenodiazine spiral shell [3.4] octane-6-base, 6-nitrogen spiral shell [3.4] octane-6-base, 2-oxa--7-nitrogen spiral shell [4.5] certain herbaceous plants with big flowers alkane-7-base, 2-oxa--8-nitrogen spiral shell [4.5] certain herbaceous plants with big flowers alkane-8-base, 2-methyl-2,7-phenodiazine spiral shell [4.5] decane etc.
Described " bridged ring " refer to that any two rings share that the atom that is neither directly connected formed containing carbon atom and/or heteroatomic condensed cyclic structure, described heteroatoms is selected from C (O), N, O, S, SO, SO
2be preferably the bridged cyclic group of 7-10 annular atoms, such as (1S, 4S)-2-methyl-2-nitrogen dicyclo [2.2.1] hexane, 2-nitrogen dicyclo [2.2.1] heptane, 8-methyl bicycle [3.2.1] octane, 3-oxa--8 nitrogen dicyclo [3.2.1] octane, 2-nitrogen dicyclo [2.2.2] octane, 7-nitrogen dicyclo [2.2.1] heptane, 3-nitrogen dicyclo [3.2.1] octane, 3-nitrogen dicyclo [3.3.2] decane, 7-oxabicyclo [2.2.1] heptane, 8-oxabicyclo [3.2.1] octane etc.
Preferred compound of the present invention:
The above-mentioned arbitrary compound pharmacy acceptable salt of the present invention comprises an alkali metal salt, as sodium salt, sylvite, lithium salts etc.; Alkaline earth salt, as calcium salt, magnesium salts etc.; Other metal-salts, as aluminium salt, molysite, zinc salt, mantoquita, nickel salt, cobalt salt etc.; Inorganic base salts, as ammonium salt; Organic alkali salt, as tertiary octyl group amine salt, dibenzyl amine salt, alkylbenzyldimethylasaltsum saltsum, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-METHYL-ALPHA-L-GLUCOSAMINE salt, guanidinesalt, diethylamine salt, triethylamine salt, dicyclohexyl amine salt, N, N '-dibenzyl ethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzyl-styroyl amine salt, piperazine salt, tetramethyl-amine salt, three (methylol) aminomethane salt; When compound of the present invention is alkalescence, can prepare salt by the pharmaceutically acceptable non-toxic acid comprising mineral acid and organic acid, this type of acid comprises: halogen acid salt, as hydrofluoride, hydrochloride, hydrobromate, hydriodate etc.; Inorganic acid salt, as nitrate, perchlorate, vitriol, phosphoric acid salt etc.; Lower alkyl sulfonate, as mesylate, fluoroform sulphonate, esilate etc.; Arylsulphonate, as benzene sulfonate, P-TOLUENE SULFO ACID 99's salt etc.; Organic acid salt, as acetate, malate, fumarate, succinate, Citrate trianion, tartrate, oxalate, maleate etc.; Amino acid salts, as glycinate, Trimethyl glycine salt, arginic acid salt, ornithine salt, glutaminate, aspartate etc.In order to avoid query, one, two or three salt-forming cations may be had, but this depends on the quantity of carboxyl functional group and described cationic valence mumber.It is evident that for those skilled in the art, the pharmacy acceptable salt of the compounds of this invention in formation such as the free carboxy places of this compound, can be obtained by ordinary method.
The isomer of formula (I) compound, refer to when formula (I) compound exists other unsymmetrical carbons, during carbon-carbon double bond etc., its all enantiomers, diastereomer, racemization isomer, cis-trans-isomer, tautomer, geometrical isomer, epimer and composition thereof of producing, described isomer can obtain abundant purity isomer by standard separation techniques and zinc bromide synthesis.
Present invention also offers the preparation method of above-claimed cpd, but be not limited only to following methods, reaction equation is as follows:
Raw material 1 intermediate 1 intermediate 2
Intermediate 3 intermediate 4
Intermediate 5 formula (III) compound
Reactions steps is as follows:
(1) preparation of intermediate 1
Under low temperature, the THF solution that 1.1 work as content of starting materials 2 is slowly added drop-wise in 1.1 equivalent butyllithiums, after reaction for some time, the THF solution that 1 works as content of starting materials 1 is slowly added drop-wise in system, stirring reaction.Saturated NH is added after reaction terminates
4the cancellation of Cl solution, extraction into ethyl acetate, merges organic phase, washing, and saturated common salt is washed, anhydrous sodium sulfate drying, concentrates to obtain intermediate 1.
(2) preparation of intermediate 2
Under low temperature, by the BH of 2-4 equivalent
3.Me
2s solution is slowly added drop-wise in the THF solution of 1 equivalent intermediate 1, room temperature or back flow reaction a few hours, and cooling, adds methyl alcohol cancellation, extraction into ethyl acetate, merges organic phase, washing, and saturated common salt is washed, anhydrous sodium sulfate drying, concentrates to obtain intermediate 2.
(3) preparation of intermediate 3
Under low temperature, work as the monomer of content of starting materials 3,1.5-4 equivalent of tertiary amine by about 1 as Et
3n joins the CH of 1 equivalent intermediate 2
2cl
2or in toluene solution, then continue reaction, after cooling, add shrend and go out, extraction, merge organic phase, washing, saturated common salt is washed, anhydrous sodium sulfate drying, and concentrated, column chromatography obtains intermediate 3.
(4) preparation of intermediate 4
Under low temperature, 1 equivalent intermediate 3 is dissolved in polar solvent as in DMF, adds 1.5 equivalent mineral alkalis as Cs
2cO
3, K
2cO
3with 1.2 when content of starting materials 4, monitoring reaction is carried out, and pours in frozen water after question response terminates, and separates out solid, filters, dry intermediate 4.
(5) preparation of intermediate 5
At appropriate solvent such as 1; in 4-dioxane or toluene; add 1 equivalent intermediate 4,2 equivalent duplex tetramethyl ethylene ketone boric acid ester, 2 equivalent alkali successively if the palladium catalyst of Potassium ethanoate and catalytic amount is as [1; 1 '-bis-(diphenylphosphine) ferrocene] palladium chloride dichloromethane complex; react heated and stirred a few hours under nitrogen protection; cool to obtain intermediate 5, be not treatedly directly used in next step.
(6) preparation of formula (III) compound
In upper step reaction solution after the cooling period (i.e. intermediate 5), add 1 when content of starting materials 5, the palladium catalyst of catalytic amount and appropriate alkali are as 2N sodium carbonate solution.System is reacting by heating a few hours under nitrogen protection, cool to room temperature, filter, are dissolved in methylene dichloride after organic layer concentrating under reduced pressure, and washing successively, saturated common salt washing, anhydrous sodium sulfate drying, concentrated, silica gel column chromatography, obtains formula III compound.
X in above reaction equation
1, X
2, X
3, X
4, X
5, X
6, X
7, R
1, R
2, Cy
1, Cy
2, R
8, R
9, m, n, p, q and r be as described in the either a program of scheme 3 and preferred version thereof.
Present invention also offers the pharmaceutical preparation that formula (I) compound, its pharmacy acceptable salt or its isomer and one or more pharmaceutical carriers are made, this pharmaceutical preparation can make the conventional formulation used clinically, the mode such as oral or administered parenterally can be applied to the patient needing this treatment.As tablet, particle, capsule, powder, injection, inhalation, sublingual administration preparation, syrup, gel, ointment, suppository, lotion, nasal cavity drop, sprays, preparation capable of permeating skin etc.These preparations can pass through ordinary method, add pharmaceutical carrier such as vehicle, tamanori, moistening agent, disintegrating agent, thickening material etc. and are prepared from.
Present invention also offers formula (I) compound, its pharmacy acceptable salt or its isomer treat and/or prevent diabetes in preparation, fat, glucose intolerance, hyperglycemia, hypertension, hyperlipidemia, cognitive loss, dull-witted, glaucoma, cardiovascular disorder, osteoporosis, atherosclerosis, peripheral vascular disease, hyperlipemia, hyperlipoproteinemia, diabetes hyperlipemia, mixed dyslipidemia, hypercholesteremia, hypertriglyceridemia, insulin resistance, inflammation androgen excess (hirsutism, menoxenia, hyperandrogenism), application in the medicine of polycystic ovary syndrome or metabolism syndrome.
Present invention also offers formula (I) compound, the pharmaceutical composition that its pharmacy acceptable salt or its isomer are made with one or more therapeutic active substance, described therapeutic active substance is selected from Regular Insulin and insulin analog, sulfonylurea, prandial glucose regulator, PPAR gamma agonist, aldose reductase inhibitor, Tyrosine O-phosphate phosphatase inhibitors, glucose 6-phosphatase inhibitors, glucagon receptor picks up anti-agent, glucokinase activators, glycogen phosphorylase inhibitors, fructose 1,6 biphosphonate enzyme inhibitorss, L-glutamic acid: fructose-6-phosphate esteramides transferase inhibitor, HMG-CoA reductase inhibitor, PPAR alfa agonists, bile acid chelating agent, cholesterol absorption inhibitor, ileal bile acid absorption inhibitor, cholestery ester transfer protein inhibitors, nicotinic acid and analogue thereof, beta-blocker, ACE inhibitor, calcium picks up anti-agent, angiotensin receptor picks up anti-agent, α picks up anti-agent, aldosterone receptor picks up anti-agent, diuretic(s), the agent of antithrombotic stroke, fibrinolysis activating dose, anti-platelet agents, zymoplasm picks up anti-agent, Xa factor inhibitor, VIIa factor inhibitors, dispersion stabilizer or antiphlogiston.
External pharmacologically active below by way of part the compounds of this invention sets forth the beneficial effect of the compounds of this invention further, other compound of the present invention has identical beneficial effect with part the compounds of this invention cited in test, but this should be interpreted as the compounds of this invention only has following beneficial effect.
experimental example 1 the compounds of this invention is to the restraining effect of 11 β 3-HSD1 enzymes
Trial-product: the compounds of this invention 1-4, chemical name and structural formula are shown in embodiment;
Experimental technique: CortisolKit
1. prepare the trisassaybuffer solution of 333 μMs of NADPH and 266nMCortisone, every hole adds 6 μ l.
2. prepare certain density compound solution with DMSO, four times of gradient dilutions, 10 gradients, after dilute 20 times with trisassaybuffer one by one, obtain the gradient liquid of ultimate density, in every hole, add 2 μ l.
3. prepare the microsomal enzyme solution of 1mg/ml, in every hole, add 2 μ l.
Hatch 2 hours for 4.37 DEG C.
5. add 5 μ lcortisol-d2 and 5 μ lanti-cortisol-cryptate in every hole.
6. incubated at room 2 hours.
7. microplate reader 665nm/620nm reads plate.
8. adopt GraphPadPrism5 processing data, measure IC
50.
Experimental result and conclusion:
The antibacterial activity in vitro of table 1 the compounds of this invention
From table 1, the compounds of this invention 1-4 has very high inhibit activities for 11 β-HSD1 enzymes.
Embodiment
The embodiment of form by the following examples, is described in further detail foregoing of the present invention.But this should be interpreted as that the scope of the above-mentioned theme of the present invention is only limitted to following examples.
The preparation (compound 1) of embodiment 13 '-(1-(4-(1-methyl-2-oxo-1,2-dihydropyridine-4-base) phenyl) ethyl)-3,4-dihydro-2H-spiral shells [naphthalene-1,6 '-[1,3] oxazines]-2 '-one
(1) preparation of 2-(1-hydroxyl-1,2,3,4-naphthane-1-base) acetonitrile
At-78 DEG C, the 20mLTHF solution of the acetonitrile (5.14g, 125mmol) of drying is slowly added drop-wise to 2.5M butyllithium (50mL, 125mmol) with 30mL tetrahydrofuran (THF), 0.5h is stirred in this temperature, be raised to-20 DEG C and stir 0.5h, be again as cold as-78 DEG C, by 3,4-dihydronaphthalene-1 (2H)-one (14.6g, 30mLTHF solution 100mmol) is slowly added drop-wise in system, occurs muddy, is raised to-20 DEG C and stirs 0.5h after stirring 15min.Add saturated NH
4the cancellation of Cl solution, extraction into ethyl acetate, merges organic phase, washing, and saturated common salt is washed, and anhydrous sodium sulfate drying, silica gel column chromatography obtains yellow solid 11.4g, yield 60.9%.
(2) preparation of 1-(2-amino-ethyl)-1,2,3,4-naphthane-1-alcohol
At 0 DEG C, 2.0MBH3.Me2S (62mL, 124mmol) is slowly added drop-wise to 2-(1-hydroxyl-1,2,3,4-naphthane-1-base) acetonitrile (7.82g, in 30mLTHF solution 41.8mmol), then back flow reaction 4 hours, cooling, add methyl alcohol cancellation, extraction into ethyl acetate, merge organic phase, washing, saturated common salt is washed, and anhydrous sodium sulfate drying, directly casts in single step reaction.
The preparation of (3) 3,4-dihydro-2H-spiral shells [naphthalene-1,6 '-[1,3] oxazines]-2 '-one
At 0 DEG C, by triphosgene (two (trichloromethyl) carbonic ether) (4.124g, 13.9mmol) and Et
3n (11.8mL, 85mmol) joins the 50mLCH of 1-(2-amino-ethyl)-1,2,3, the 4-naphthane-1-alcohol that step obtains
2cl
2in solution, then continue reaction 2 hours, add shrend and go out, CH
2cl
2extraction, merges organic phase, washing, and saturated common salt is washed, anhydrous sodium sulfate drying, and concentrated, column chromatography obtains product 3.2g, two step yields 35.2%.
(4) preparation of the bromo-4-of 1-(1-bromotrifluoromethane) benzene
In dry reaction flask, take 1-(4-bromophenyl) ethanol (16g, 79.6mmol), add anhydrous diethyl ether 30mL, drip the diethyl ether solution of phosphorus tribromide (25.99g, 96mmol), room temperature reaction spends the night, concentrated, frozen water cancellation, extraction into ethyl acetate, concentrated, silica gel column chromatography, obtains yellow oil 10g, yield 47.6%.
The preparation of (5) 3 '-(1-(4-bromophenyl) ethyl)-3,4-dihydro-2H-spiral shells [naphthalene-1,6 '-[1,3] oxazines]-2 '-one
3,4-dihydro-2H-spiral shell [naphthalene-1,6 '-[1,3] oxazines]-2 '-one (2g, 9.2mmol) is dissolved in 40mLDMF, adds Cs
2cO
3(6g, 18.4mmol), the bromo-4-of 1-(1-bromotrifluoromethane) benzene (3g, 11.4mmol), react 48 hours, pour in frozen water, extraction into ethyl acetate, organic phase is through saturated common salt water washing, anhydrous sodium sulfate drying, silica gel column chromatography obtains white solid 1.083g, yield 29.5%.
(6) preparation of 1-methyl-4-(4,4,5,5-tetramethyl--1,3,2-dioxaborolan alkane-2-base) pyridine-2 (1H)-one
In dry reaction flask; 1; 4-dioxane (4mL) adds 4-bromo-1-picoline-2 (1H)-one (226mg successively; 1.20mmol); duplex pinacol boric acid ester (457mg; 1.8mmol); Potassium ethanoate (294mg; 3.0mmol) with [1; 1 '-bis-(diphenylphosphine) ferrocene] palladium chloride dichloromethane complex 16mg; under nitrogen protection, stir at 90 DEG C and spend the night, not treatedly after cooling be directly used in next step.
The preparation of (7) 3 '-(1-(4-(1-methyl-2-oxo-1,2-dihydropyridine-4-base) phenyl) ethyl)-3,4-dihydro-2H-spiral shells [naphthalene-1,6 '-[1,3] oxazines]-2 '-one
In the previous step reaction solution of cooling, add 3 '-(1-(4-bromophenyl) ethyl)-3,4-dihydro-2H-spiral shell [naphthalene-1,6 '-[1,3] oxazines]-2 '-one (320mg, 0.80mmol), four (triphenyl phosphorus) palladium 10mg, 2N aqueous sodium carbonate 1.8mL.System in 90 DEG C of reaction 6h, is cooled to room temperature, filters, be dissolved in methylene dichloride after organic layer concentrating under reduced pressure under nitrogen protection; use water, saturated common salt water washing successively, anhydrous sodium sulfate drying, concentrated; silica gel column chromatography, obtains white solid 302mg, yield 88.1%.
Molecular formula: C
27h
28n
2o
3molecular weight: 428.52 mass spectrums (M+H): 429.2
1H-NMR(CDCl
3，400MHz)：δ7.62-7.57(2H，m)，7.55-7.40(3H，m)，7.36(1H，dd)，7.25-7.17(2H，m)，7.12-7.06(1H，m)，6.82(1H，t)，6.45(1H，dt)，5.99-5.90(1H，m)，3.59(3H，s)，3.40-3.31(1H，m)，2.96-2.70(3H，m)，2.30-1.89(5H，m)，1.85-1.70(1H，m)，1.65(3H，d).
The preparation (compound 2) of embodiment 23 '-(1-(4-(1-methyl-2-oxo-1,2-dihydropyridine-4-base) phenyl) ethyl)-2,3-dihydros [indenes-1,6 '-[1,3] oxazines]-2 '-one
(1) preparation of 2-(1-hydroxyl-2,3-dihydro-1H-indenes-1-base) acetonitrile
At-78 DEG C, in dry there-necked flask, add the THF50mL heavily steamed, N
2protection, add the butyllithium (50mL of 2.5M, 125mmo1), stir 5min, acetonitrile (5.137g is slowly dripped in system, THF solution 125mmol), keep-78 DEG C, reaction 30min, be warming up to-20 DEG C and continue reaction 30min, be cooled to-78 DEG C subsequently, slow dropping 2, 3-dihydro-1H-1-Indanone (13.22g, THF solution 100mmol), keep this thermotonus 15min, continue to stir 30min after slowly rising to room temperature, aqueous ammonium chloride solution cancellation, extraction into ethyl acetate, organic phase is through saturated common salt water washing, anhydrous sodium sulfate drying, silica gel column chromatography obtains yellow solid 12g, yield 69.3%.
(2) preparation of 1-(2-amino-ethyl)-2,3-dihydro-1H-indenes-1-alcohol
Under ice-water bath, in dry reaction flask, take 2-(1-hydroxyl-2,3-dihydro-1H-indenes-1-base) acetonitrile (12g, 69.3mmol), add THF50mL, add the borane dimethylsulf iotade tetrahydrofuran solution 69mL (138mmol) of 2M, room temperature reaction spends the night, methyl alcohol cancellation, concentrated, add salt solution, extraction into ethyl acetate, organic phase is through saturated aqueous common salt water washing, anhydrous sodium sulfate drying, directly casts in single step reaction.
The preparation of (3) 2,3-dihydro spiral shells [indenes-1,6 '-[1,3] oxazines]-2 '-one
Under ice-water bath, in dry reaction flask, add the 1-(2-amino-ethyl)-2 that step obtains, 3-dihydro-1H-indenes-1-alcohol, add 100mL methylene dichloride to dissolve, add triphosgene (20.56g, 69.3mmol), triethylamine (29mL is dripped under equality of temperature, 208mmol), dropwise rear continuation reaction 2h, filter, add water, dichloromethane extraction, organic phase through saturated common salt water washing, anhydrous sodium sulfate drying, silica gel column chromatography obtains white solid 9.3g, two step yields 66.1%.
The preparation of (4) 3 '-(1-(4-bromophenyl) ethyl)-2,3-dihydro spiral shells [indenes-1,6 '-[1,3] oxazines]-2 '-one
In dry reaction flask, take 2, 3-dihydro spiral shell [indenes-1, 6 '-[1, 3] oxazines]-2 '-one (1.3g, 6.4mmol), add DMF30mL, cesium carbonate (6.2g, 19mmol), stirred at ambient temperature 15min, add into the bromo-4-of 1-(1-bromotrifluoromethane) benzene (2.53g, 9.58mmol), react four days, filter, add water, extraction into ethyl acetate, organic phase is through saturated common salt water washing, anhydrous sodium sulfate drying, silica gel column chromatography obtains two diastereomers, the white solid 860mg that polarity is little, the white solid 852mg that polarity is large, the yield 69.2% that two isomer are total.
The preparation of (5) 3 '-(1-(4-(4,4,5,5-tetramethyl--1,3,2-dioxaborolan alkane-2-base) phenyl) ethyl)-2,3-dihydro spiral shells [indenes-1,6 '-[1,3] oxazines]-2 '-one
In dry reaction flask; add 15mL dioxane, 3 '-(1-(4-bromophenyl) ethyl)-2 successively; 3-dihydro spiral shell [indenes-1; 6 '-[1; 3] oxazines] isomer (583mg that-2 '-one polarity is little; 1.51mmol); duplex pinacol boric acid ester (571mg; 2.25mmol), Potassium ethanoate (367mg, 3.74mmol) and [1; 1 '-bis-(diphenylphosphine) ferrocene] palladium chloride dichloromethane complex 20mg; under nitrogen protection, stir at 90 DEG C and spend the night, not treatedly after cooling be directly used in next step.
For the large isomer of 3 '-(1-(4-bromophenyl) ethyl)-2,3-dihydro spiral shells [indenes-1,6 '-[1,3] oxazines]-2 '-one polarity with same working method process.
The preparation of (6) 3 '-(1-(4-(1-methyl-2-oxo-1,2-dihydropyridine-4-base) phenyl) ethyl)-2,3-dihydros [indenes-1,6 '-[1,3] oxazines]-2 '-one
(corresponding to 3 '-(1-(4-bromophenyl) ethyl)-2 in the previous step reaction solution of cooling, 3-dihydro spiral shell [indenes-1,6 '-[1,3] oxazines] isomer that-2 '-one polarity is little), add 4-bromo-1-picoline-2 (1H)-one (423mg, 2.25mmol), tetrakis triphenylphosphine palladium 20mg, 2N aqueous sodium carbonate 3mL.System in 90 DEG C of reaction 6h, is cooled to room temperature, filters, be dissolved in methylene dichloride after organic layer concentrating under reduced pressure under nitrogen protection; use water, saturated common salt water washing successively, anhydrous sodium sulfate drying, concentrated; silica gel column chromatography, obtains white solid 450mg, two-step reaction yield 71.9%.
Molecular formula: C
26h
26n
2o
3molecular weight: 414.50 mass spectrums (M+H): 415.2
The isomer of little polarity
1h-NMR (d
6-DMSO, 400MHz): δ 7.79-7.72 (3H, m), 7.46 (2H, d), 7.40-7.25 (4H, m), 6.69 (1H, d), 6.59 (1H, dd), 5.58 (1H, q), 3.44 (3H, s), 3.03-2.92 (1H, m), 2.92-2.78 (2H, m), 2.35-2.25 (1H, m), 2.15 (2H, t), 2.03-1.93 (2H, m), (1.58 3H, d).
The isomer of large polarity
1h-NMR (d
6-DMSO, 400MHz): δ 7.79-7.72 (3H, m), 7.47 (2H, d), 7.33-7.28 (3H, m), 7.25-7.18 (1H, m), 6.69 (1H, d), 6.59 (1H, dd), 5.57 (1H, q), 3.50-3.40 (1H, m), 3.44 (3H, s), 3.06-2.94 (2H, m), 2.92-2.81 (1H, m), 2.33-2.21 (3H, m), 2.00 (1H, dt), (1.59 3H, d).
The preparation (compound 3) of embodiment 33 '-(1-(4-(1-methyl-2-oxo-1,2-dihydropyridine-4-base) phenyl) ethyl) spiral shell [chroman-4,6 '-[1,3] oxazines]-2 '-one
(1) preparation of 2-(4-hydroxychroman-4-base) acetonitrile
At-78 DEG C, in dry there-necked flask, add the THF20mL heavily steamed, N
2protection, add the butyllithium (19.2mL of 2.5M, 48mmol), stir 5min, slow dropping acetonitrile (1.97g, THF solution 48mmol), keep-78 DEG C, reaction 30min, be warming up to-20 DEG C and continue reaction 30min, be cooled to-78 DEG C subsequently, slow dropping chroman-4-on-(5.92g, THF solution 40mmol), keep this thermotonus 15min, continue to stir 30min after slowly rising to room temperature, aqueous ammonium chloride solution cancellation, extraction into ethyl acetate, organic phase is through saturated common salt water washing, anhydrous sodium sulfate drying, silica gel column chromatography obtains yellow solid 3.4g, yield 45.1%.
(2) preparation of 4-(2-amino-ethyl) chroman-4-alcohol
Under ice-water bath, in dry reaction flask, take 2-(4-hydroxychroman-4-base) acetonitrile (3.4g, 18mmol), add THF20mL, add the borane dimethylsulf iotade tetrahydrofuran solution (27mL of 2M, 54mmol), room temperature reaction spends the night, methyl alcohol cancellation, concentrated, add salt solution, extraction into ethyl acetate, organic phase is through saturated aqueous common salt water washing, anhydrous sodium sulfate drying, directly casts in single step reaction.
(3) preparation of spiral shell [chroman-4,6 '-[1,3] oxazines]-2 '-one
Under ice-water bath, in dry reaction flask, add 4-(2-amino-ethyl) chroman-4-alcohol crude product, add 20mL methylene dichloride to dissolve, add triphosgene (1.78g, 6.0mmol), drip triethylamine (5.0mL, 36mmol) under equality of temperature, dropwise rear continuation reaction 2h, filter, add water, dichloromethane extraction, organic phase is through saturated common salt water washing, anhydrous sodium sulfate drying, silica gel column chromatography obtains white solid 1.6g, two step yields 40.6%.
The preparation of (4) 3 '-(1-(4-bromophenyl) ethyl) spiral shells [chroman-4,6 '-[1,3] oxazines]-2 '-one
In dry reaction flask, take spiral shell [chroman-4, 6 '-[1, 3] oxazines]-2 '-one (1.38g, 6.3mmol), add DMF30mL, cesium carbonate (5.13g, 15.7mmol), stirred at ambient temperature 15min, add the bromo-4-of 1-(1-bromotrifluoromethane) benzene (2.98g, 11.3mmol), reaction 48h, filter, add water, extraction into ethyl acetate, organic phase is through saturated common salt water washing, anhydrous sodium sulfate drying, silica gel column chromatography obtains two chiral isomers, the white solid 800mg that polarity is little, the white solid 880mg that polarity is large, the yield 66.3% that two isomer are total.
The preparation of (5) 3 '-(1-(4-(4,4,5,5-tetramethyl--1,3,2-dioxaborolan alkane-2-base) phenyl) ethyl) spiral shell [chroman-4,6 '-[1,3] oxazines]-2 '-one
In dry reaction flask; add 3 '-(1-(4-bromophenyl) ethyl) spiral shell [chroman-4 successively; 6 '-[1; 3] oxazines] isomer (428mg that-2 '-one polarity is little; 1.06mmol); duplex pinacol boric acid ester (381mg; 1.5mmol); Potassium ethanoate (245mg; 2.5mmol) with [1,1 '-bis-(diphenylphosphine) ferrocene] palladium chloride complex compound 20mg, under nitrogen protection; stir at 90 DEG C and spend the night, not treatedly after cooling be directly used in next step.
For the large isomer of 3 '-(1-(4-bromophenyl) ethyl) spiral shell [chroman-4,6 '-[1,3] oxazines]-2 '-one polarity with same working method process.
The preparation of (6) 3 '-(1-(4-(1-methyl-2-oxo-1,2-dihydropyridine-4-base) phenyl) ethyl) spiral shell [chroman-4,6 '-[1,3] oxazines]-2 '-one
In the previous step reaction solution of cooling, add 4-bromo-1-picoline-2 (1H)-one (470mg, 2.5mmol), four (triphenyl phosphorus) palladium 20mg, 2N aqueous sodium carbonate 3mL.System in 90 DEG C of reaction 6h, is cooled to room temperature, filters, be dissolved in methylene dichloride after organic layer concentrating under reduced pressure under nitrogen protection; use water, saturated common salt water washing successively, anhydrous sodium sulfate drying, concentrated; silica gel column chromatography, obtains white solid 312mg, two-step reaction yield 68.4%.
Molecular formula: C
26h
26n
2o
4molecular weight: 430.50 mass spectrums (M+H): 431.2
The isomer of little polarity
1h-NMR (CDCl
3, 400MHz): δ 7.60 (2H, d), 7.47 (2H, d), 7.39 (1H, dd), 7.36 (1H, d), 7.23 (1H, td), 6.97 (1H, td), 6.84 (1H, dd), 6.81 (1H, d), 6.44 (1H, m), 5.91 (1H, q), 4.38-4.29 (1H, m), 4.23-4.15 (1H, m), 3.60 (3H, s), 3.21 (1H, ddd), 2.92-2.82 (1H, m), 2.47 (1H, ddd), 2.27 (1H, ddd), 2.06-1.91 (2H, m), 1.67 (3H, d).
The isomer of large polarity
1h-NMR (CDCl
3, 400MHz): δ 7.60 (2H, d), 7.51 (2H, d), 7.38-7.34 (2H, m), 7.22 (1H, td), 6.93 (1H, td), 6.85 (1H, dd), 6.82 (1H, d), 6.45 (1H, m), 5.95 (1H, q), 4.42-4.33 (1H, m), 4.29-4.20 (1H, m), 3.60 (3H, s), 3.43-3.34 (1H, m), 3.00 (1H, ddd), 2.44-2.33 (2H, m), 2.15 (1H, ddd), 1.97 (1H, ddd) 1.65 (3H, d).
The preparation (compound 4) of embodiment 42,2-dimethyl-3 '-(1-(4-(1-methyl-2-oxo-1,2-dihydropyridine-4-base) phenyl) ethyl) spiral shell [chroman-4,6 '-[1,3] oxazines]-2 '-one
(1) preparation of 2-(4-hydroxyl-2,2-dimethylchroman-4-base) acetonitrile
At-78 DEG C, in dry there-necked flask, add the THF20mL heavily steamed, N
2protection, add the butyllithium (23mL of 2.5M, 57.5mmol), stir 5min, slow dropping acetonitrile (2.36g, THF solution 57.5mmol), keep-78 DEG C, reaction 30min, be warming up to-20 DEG C and continue reaction 30min, be cooled to-78 DEG C subsequently, slow dropping 2, 2-dimethylchroman-4-ketone (8g, THF solution 45.4mmol), keep this thermotonus 15min, continue to stir 30min after slowly rising to room temperature, aqueous ammonium chloride solution cancellation, extraction into ethyl acetate, organic phase is through saturated common salt water washing, anhydrous sodium sulfate drying, silica gel column chromatography obtains yellow solid 5.86g, yield 59.4%.
(2) preparation of 4-(2-amino-ethyl)-2,2-dimethylchroman-4-alcohol
Under ice-water bath, in dry reaction flask, take 2-(4-hydroxyl-2,2-dimethylchroman-4-base) acetonitrile (5.86g, 27mmol), add THF20mL, add the borane dimethylsulf iotade tetrahydrofuran solution (33mL, 66mmol) of 2M, room temperature reaction spends the night, methyl alcohol cancellation, concentrated, add salt solution, extraction into ethyl acetate, organic phase is through saturated aqueous common salt water washing, and anhydrous sodium sulfate drying, directly casts in single step reaction.
The preparation of (3) 2,2-dimethyl spiral shells [chroman-4,6 '-[1,3] oxazines]-2 '-one
Under ice-water bath, in dry reaction flask, add 4-(2-amino-ethyl)-2,2-dimethylchroman-4-alcohol crude product, adds 20mL methylene dichloride and dissolves, add triphosgene (2.67g, 9.0mmol), triethylamine (11.3mL, 81mmol) is dripped under equality of temperature, dropwise rear continuation reaction 2h, filter, add water, dichloromethane extraction, organic phase through saturated common salt water washing, anhydrous sodium sulfate drying, silica gel column chromatography obtains white solid 4.21g, two step yields 63.0%.
The preparation of (4) 3 '-(1-(4-bromophenyl) ethyl)-2,2-dimethyl spiral shells [chroman-4,6 '-[1,3] oxazines]-2 '-one
In dry reaction flask, take 2,2-dimethyl spiral shell [chroman-4,6 '-[1,3] oxazines]-2 '-one (1.7g, 6.87mmol), add DMF20mL, cesium carbonate (6.72g, 20.65mmol), stirred at ambient temperature 15min, adds the bromo-4-of 1-(1-bromotrifluoromethane) benzene (3.63g, 13.75mmol), reaction 48h, filter, add water, extraction into ethyl acetate, organic phase is through saturated common salt water washing, anhydrous sodium sulfate drying, silica gel column chromatography obtains white solid 1.5g, yield 50.7%.
The preparation of (5) 2,2-dimethyl-3 '-(1-(4-(4,4,5,5-tetramethyl--1,3,2-dioxaborolane-2-base) phenyl) ethyl) spiral shell [chroman-4,6 '-[1,3] oxazines]-2 '-one
In dry reaction flask, 30mL dioxane is solvent, add 3 '-(1-(4-bromophenyl) ethyl)-2 successively, 2-dimethyl spiral shell [chroman-4, 6 '-[1, 3] oxazines]-2 '-one (740mg, 1.72mmol), duplex pinacol boric acid ester (655mg, 2.58mmol), Potassium ethanoate (421mg, 4.29mmol) with [1, 1 '-bis-(diphenylphosphine) ferrocene] palladium chloride dichloromethane complex (20mg, 0.02mmol), under nitrogen protection, stir at 90 DEG C and spend the night, not treatedly after cooling be directly used in next step.
The preparation of (6) 2,2-dimethyl-3 '-(1-(4-(1-methyl-2-oxo-1,2-dihydropyridine-4-base) phenyl) ethyl) spiral shell [chroman-4,6 '-[1,3] oxazines]-2 '-one
In the previous step reaction solution of cooling, add 4-bromo-1-picoline-2 (1H)-one (485mg, 2.58mmol), four (triphenyl phosphorus) palladium (20mg, 0.2mmol), 2N aqueous sodium carbonate 3mL.System in 90 DEG C of reaction 6h, is cooled to room temperature, filters, be dissolved in methylene dichloride after organic layer concentrating under reduced pressure under nitrogen protection; use water, saturated common salt water washing successively, anhydrous sodium sulfate drying, concentrated; silica gel column chromatography, obtains white solid 513mg, two-step reaction yield 61.4.0%.
Molecular formula: C
28h
30n
2o
4molecular weight: 458.55 mass spectrums (M+H): 459.3
1H-NMR(CDCl
3，400MHz)：7.80-7.71(3H，m)，7.56-7.43(3H，m)，7.23(1H，t)，6.98-6.92(1H，m)，6.79(1H，td)，6.69(1H，dd)，6.61-6.56(1H，m)，5.56(1H，q)，3.44(3H，s)，3.28-3.18(1H，m)，2.99，2.79(1H，twom)，2.40(1H，ddd)，2.30，2.13(1H，twod)，2.03-1.80(2H，m)，1.60，1.57(3H，twod)，1.34-1.25(6H，m).
Claims (5)
1. the compound shown in general formula (III), its pharmacy acceptable salt,
X
1for C (O);
X
2for O;
X
3for O or CH
2;
X
4, X
5, X
6, X
7for CH;
R
1for hydrogen, C
1-4alkyl or C
3-6cycloalkyl;
R
2for not existing;
Cy
1for phenyl, described phenyl can optionally be replaced by 1 or 2 substituting group independently selected from R ';
Cy
2for the single heterocyclic radical of 5-6 unit at least containing an atom N, the described single heterocyclic radical of 5-6 unit at least containing an atom N can optionally be replaced by 1 or 2 substituting group independently selected from R ';
R ' is halogen atom, hydroxyl, amino, oxo, C
1-4alkyl, C
1-4alkoxyl group or halo C
1-4alkyl;
R
8for hydrogen or C
1-4alkyl;
R
9for hydrogen, halogen atom or C
1-6alkyl;
N is 0 or 1;
R is 0,1 or 2; P is 0,1 or 2; Q is 0,1 or 2.
2. compound as claimed in claim 1, its pharmacy acceptable salt,
3. the pharmaceutical preparation containing the compound described in any one of claim 1-2, its pharmacy acceptable salt, is characterized in that comprising one or more pharmaceutical carriers.
4. the compound described in any one of claim 1-2, its pharmacy acceptable salt treats and/or prevents diabetes in preparation, fat, glucose intolerance, hyperglycemia, hypertension, hyperlipidemia, cognitive loss, dull-witted, glaucoma, cardiovascular disorder, osteoporosis, atherosclerosis, peripheral vascular disease, hyperlipemia, hyperlipoproteinemia, diabetes hyperlipemia, mixed dyslipidemia, hypercholesteremia, hypertriglyceridemia, insulin resistance, application in the medicine of inflammation androgen excess polycystic ovary syndrome or metabolism syndrome.
5. pharmaceutical composition, is characterized in that comprising the compound described in any one of claim 1-2, its pharmacy acceptable salt and one or more therapeutic active substance, described therapeutic active substance is selected from Regular Insulin, sulfonylurea, prandial glucose regulator, PPAR gamma agonist, aldose reductase inhibitor, Tyrosine O-phosphate phosphatase inhibitors, glucose 6-phosphatase inhibitors, glucagon receptor antagonists, glucokinase activators, glycogen phosphorylase inhibitors, fructose 1,6 biphosphonate enzyme inhibitorss, HMG-CoA reductase inhibitor, PPAR alfa agonists, bile acid chelating agent, cholesterol absorption inhibitor, ileal bile acid absorption inhibitor, cholestery ester transfer protein inhibitors, nicotinic acid, beta-blocker, ACE inhibitor, calcium antagonist, angiotensin receptor antagonist, alpha-2 antagonists, aldosterone receptor antagonist, diuretic(s), the agent of antithrombotic stroke, fibrinolysis activating dose, anti-platelet agents, thrombin antagonist, Xa factor inhibitor, VIIa factor inhibitors, dispersion stabilizer or antiphlogiston.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210017147.2A CN103342700B (en) | 2012-01-19 | 2012-01-19 | 11beta-Hydroxysteroid dehydrogenase 1 type inhibitor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210017147.2A CN103342700B (en) | 2012-01-19 | 2012-01-19 | 11beta-Hydroxysteroid dehydrogenase 1 type inhibitor |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103342700A CN103342700A (en) | 2013-10-09 |
| CN103342700B true CN103342700B (en) | 2016-04-20 |
Family
ID=49277536
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210017147.2A Active CN103342700B (en) | 2012-01-19 | 2012-01-19 | 11beta-Hydroxysteroid dehydrogenase 1 type inhibitor |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103342700B (en) |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001045704A1 (en) * | 1999-12-21 | 2001-06-28 | Merck & Co., Inc. | Inhibitors of prenyl-protein transferase |
| WO2008007210A2 (en) * | 2006-07-11 | 2008-01-17 | Universita' Di Pisa | Nitrogenous n-substituted 4-spiro-heterocyclic 2, 2 -dimethylchromane derivatives |
| WO2009134400A1 (en) * | 2008-05-01 | 2009-11-05 | Vitae Pharmaceuticals, Inc. | Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1 |
| WO2010010157A2 (en) * | 2008-07-25 | 2010-01-28 | Boehringer Ingelheim International Gmbh | INHIBITORS OF 11beta-HYDROXYSTEROID DEHYDROGENASE 1 |
| CN102105454A (en) * | 2008-07-25 | 2011-06-22 | 贝林格尔.英格海姆国际有限公司 | Synthesis of inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 |
| CN102421773A (en) * | 2008-07-25 | 2012-04-18 | 贝林格尔·英格海姆国际有限公司 | Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1 |
-
2012
- 2012-01-19 CN CN201210017147.2A patent/CN103342700B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001045704A1 (en) * | 1999-12-21 | 2001-06-28 | Merck & Co., Inc. | Inhibitors of prenyl-protein transferase |
| WO2008007210A2 (en) * | 2006-07-11 | 2008-01-17 | Universita' Di Pisa | Nitrogenous n-substituted 4-spiro-heterocyclic 2, 2 -dimethylchromane derivatives |
| WO2009134400A1 (en) * | 2008-05-01 | 2009-11-05 | Vitae Pharmaceuticals, Inc. | Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1 |
| WO2010010157A2 (en) * | 2008-07-25 | 2010-01-28 | Boehringer Ingelheim International Gmbh | INHIBITORS OF 11beta-HYDROXYSTEROID DEHYDROGENASE 1 |
| CN102105454A (en) * | 2008-07-25 | 2011-06-22 | 贝林格尔.英格海姆国际有限公司 | Synthesis of inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 |
| CN102421773A (en) * | 2008-07-25 | 2012-04-18 | 贝林格尔·英格海姆国际有限公司 | Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1 |
Non-Patent Citations (2)
| Title |
|---|
| Heterocyclic spirane derivatives. VII. Some aminomethyl derivatives (Mannich bases) of cyclopentane-, indane-2- and fluorene-9-spiro-5"-oxazolidinediones;Gonzalez Trigo, G. 等;《Anales de Quimica》;19781231;第74卷(第2期);第289-293页 * |
| Synthesis and biological evaluation of 5-membered spiro heterocycle-benzopyran derivatives against myocardial ischemia;Rapposelli, Simona 等;《European Journal of Medicinal Chemistry》;20110113;第46卷(第3期);第966-973页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103342700A (en) | 2013-10-09 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| ES2700541T3 (en) | Octahidrociclopentapirroles, its preparation and use | |
| CA2735204C (en) | Aryl- and heteroarylcarbonyl derivatives of substituted nortropanes, medicaments containing such compounds and their use | |
| EP3080085B1 (en) | Fused bicyclic heteroaromatic derivatives as modulators of tnf activity | |
| TWI450720B (en) | Pyrimidyl cyclopentanes as akt protein kinase inhibitors | |
| TWI822713B (en) | Modulators of the beta-3 adrenergic receptor useful for the treatment or prevention of disorders related thereto | |
| CN101484441A (en) | Modulators of metabolism and the treatment of disorders related thereto | |
| CN107613769A (en) | Some chemical entities, composition and method | |
| CN104053442A (en) | Certain chemical entities, compositions, and methods | |
| CN104910137B (en) | CDK kinase inhibitor | |
| CN101516883A (en) | Imidazopyrazines as protein kinase inhibitors | |
| CN104744403A (en) | Iminothiadiazine Dioxide Compounds As Bace Inhibitors, Compositions, And Their Use | |
| CN108707151B (en) | Pyrimido-pyridazinone compounds and uses thereof | |
| KR20140068112A (en) | Substituted annellated pyrimidine and the use thereof | |
| CN102361859A (en) | Heteroaryl compounds useful as Raf kinase inhibitors | |
| AU2012328561A1 (en) | Benzoxazolinone compounds with selective activity in voltage-gated sodium channels | |
| CN104788427A (en) | 3-(2-pyrimidine amino) phenyl acrylic amide compound and application thereof | |
| CN102838600A (en) | Phenylquinazoline PI3Kdelta inhibitors | |
| CN102875503A (en) | C-glucoside derivative | |
| AU2009286528B2 (en) | Saturated bicyclic heterocyclic derivatives as Smo antagonists | |
| CN103596939A (en) | 5-substituted iminothiazines and their mono-and dioxides as BACE inhibitors, compositions, and their use | |
| CN108473476A (en) | Alkynyl heterocycle compound for inhibiting protein kinase activity | |
| CN102643272A (en) | Novel thieno [3, 2-d] pyrimidine compound | |
| Shetty et al. | Synthesis and activity of some 3-aryl-and 3-aralkyl-1, 2, 3, 4-tetrahydro-4-oxo-6-quinazolinesulfonamides | |
| CN103374002B (en) | Phosphodiesterase-5 inhibitor | |
| CN104130265A (en) | Spiral ring or bridged ring containing pyrimidine compound |
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 | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20220530 Address after: Room 301, Building 3, East of Qishanzhuang Village, Zhangjiawan Town, Tongzhou District, Beijing Patentee after: Beijing Aohe Pharmaceutical Research Institute Co.,Ltd. Address before: 134000 room 210, service building 2, Jingkai Ring Road, Tonghua Economic Development Zone, Jilin Province Patentee before: TONGHUA JIDA PHARMACEUTICAL Co.,Ltd. |
|
| TR01 | Transfer of patent right |