CN103539709A - N-(-1-hydro-indenyl-1-yl)sulfonamide compound and its preparation method and use - Google Patents
N-(-1-hydro-indenyl-1-yl)sulfonamide compound and its preparation method and use Download PDFInfo
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- CN103539709A CN103539709A CN201310476325.2A CN201310476325A CN103539709A CN 103539709 A CN103539709 A CN 103539709A CN 201310476325 A CN201310476325 A CN 201310476325A CN 103539709 A CN103539709 A CN 103539709A
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- halogen
- branched
- straight
- replaced
- replace
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- -1 sulfonamide compound Chemical class 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title abstract description 34
- 229940124530 sulfonamide Drugs 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 85
- 239000003814 drug Substances 0.000 claims abstract description 24
- 208000007536 Thrombosis Diseases 0.000 claims abstract description 15
- 201000010099 disease Diseases 0.000 claims abstract description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 11
- 206010020772 Hypertension Diseases 0.000 claims abstract description 8
- 102000003938 Thromboxane Receptors Human genes 0.000 claims abstract description 8
- 108090000300 Thromboxane Receptors Proteins 0.000 claims abstract description 8
- 150000003839 salts Chemical class 0.000 claims abstract description 8
- 239000012453 solvate Substances 0.000 claims abstract description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 96
- 150000002367 halogens Chemical class 0.000 claims description 96
- 125000000217 alkyl group Chemical group 0.000 claims description 48
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 40
- 229910052739 hydrogen Inorganic materials 0.000 claims description 34
- 239000001257 hydrogen Substances 0.000 claims description 34
- 125000003545 alkoxy group Chemical group 0.000 claims description 29
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 22
- 150000002431 hydrogen Chemical class 0.000 claims description 20
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 18
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims description 13
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 12
- 239000000126 substance Substances 0.000 claims description 11
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- 125000000623 heterocyclic group Chemical group 0.000 claims description 10
- 125000004432 carbon atom Chemical group C* 0.000 claims description 9
- 238000006482 condensation reaction Methods 0.000 claims description 9
- 229910052760 oxygen Inorganic materials 0.000 claims description 9
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 8
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 8
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- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- 239000000460 chlorine Substances 0.000 claims description 8
- 229910052731 fluorine Inorganic materials 0.000 claims description 8
- 239000011737 fluorine Substances 0.000 claims description 8
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 claims description 7
- 238000009833 condensation Methods 0.000 claims description 7
- 230000005494 condensation Effects 0.000 claims description 7
- 125000006645 (C3-C4) cycloalkyl group Chemical group 0.000 claims description 6
- 230000004048 modification Effects 0.000 claims description 6
- 238000012986 modification Methods 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 6
- 125000005842 heteroatom Chemical group 0.000 claims description 5
- 238000006460 hydrolysis reaction Methods 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
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- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 150000002240 furans Chemical class 0.000 claims description 4
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- 150000003233 pyrroles Chemical class 0.000 claims description 4
- 229930192474 thiophene Natural products 0.000 claims description 4
- 125000004417 unsaturated alkyl group Chemical group 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 3
- 238000006268 reductive amination reaction Methods 0.000 claims description 3
- 238000007363 ring formation reaction Methods 0.000 claims description 3
- KTZQTRPPVKQPFO-UHFFFAOYSA-N 1,2-benzoxazole Chemical compound C1=CC=C2C=NOC2=C1 KTZQTRPPVKQPFO-UHFFFAOYSA-N 0.000 claims description 2
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 claims description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 2
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 2
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 2
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- 150000002460 imidazoles Chemical class 0.000 claims description 2
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- 150000002475 indoles Chemical class 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 239000011630 iodine Substances 0.000 claims description 2
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 claims description 2
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- 229940079593 drug Drugs 0.000 abstract description 3
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- 0 CC(C(C=C1Cl)*(NC2c3cccc(CC(CC(O)=O)=O)c3C=C2)=O)C=C1F Chemical compound CC(C(C=C1Cl)*(NC2c3cccc(CC(CC(O)=O)=O)c3C=C2)=O)C=C1F 0.000 description 27
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 24
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 23
- 239000002904 solvent Substances 0.000 description 20
- XTWYTFMLZFPYCI-KQYNXXCUSA-N 5'-adenylphosphoric acid Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O XTWYTFMLZFPYCI-KQYNXXCUSA-N 0.000 description 17
- XTWYTFMLZFPYCI-UHFFFAOYSA-N Adenosine diphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(O)=O)C(O)C1O XTWYTFMLZFPYCI-UHFFFAOYSA-N 0.000 description 17
- 210000001772 blood platelet Anatomy 0.000 description 17
- 239000003513 alkali Substances 0.000 description 16
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 16
- 239000003146 anticoagulant agent Substances 0.000 description 15
- 238000004440 column chromatography Methods 0.000 description 15
- 238000000746 purification Methods 0.000 description 15
- 239000002253 acid Substances 0.000 description 13
- 230000002785 anti-thrombosis Effects 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 230000000694 effects Effects 0.000 description 12
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- 239000003153 chemical reaction reagent Substances 0.000 description 10
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
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- 208000024172 Cardiovascular disease Diseases 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- 229940114079 arachidonic acid Drugs 0.000 description 8
- 235000021342 arachidonic acid Nutrition 0.000 description 8
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 8
- 238000003810 ethyl acetate extraction Methods 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 8
- VIMMECPCYZXUCI-MIMFYIINSA-N (4s,6r)-6-[(1e)-4,4-bis(4-fluorophenyl)-3-(1-methyltetrazol-5-yl)buta-1,3-dienyl]-4-hydroxyoxan-2-one Chemical compound CN1N=NN=C1C(\C=C\[C@@H]1OC(=O)C[C@@H](O)C1)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 VIMMECPCYZXUCI-MIMFYIINSA-N 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 229940127218 antiplatelet drug Drugs 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- 235000002639 sodium chloride Nutrition 0.000 description 7
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 6
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- HVAUUPRFYPCOCA-AREMUKBSSA-N 2-O-acetyl-1-O-hexadecyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCOC[C@@H](OC(C)=O)COP([O-])(=O)OCC[N+](C)(C)C HVAUUPRFYPCOCA-AREMUKBSSA-N 0.000 description 5
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
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- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 4
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Abstract
The invention provides a compound. The compound is an N-(-1-hydro-indenyl-1-yl)sulfonamide compound shown in the formula I, or its enantiomer, diastereoisomer, raceme, pharmaceutically acceptable salt, crystalline hydrate or solvate. The N-(-1-hydro-indenyl-1-yl)sulfonamide compound can be used for preparation of drugs for treating or preventing thromboxane receptor-related diseases or for treating or preventing thrombosis and/or hypertension.
Description
Technical field
The present invention relates to field of medicaments, concrete, the present invention relates to N-(1-hydrogen-indenes-1-yl) sulfamide compound and its production and use.More specifically, the present invention relates to N-(1-hydrogen-indenes-1-yl) sulfamide compound and the derivative shown in the general formula Ι of a class formation novelty, its preparation method, pharmaceutical composition and the application in preparation treatment disease, the especially medicine of the cardiovascular disorder such as thrombosis, hypertension relevant to thromboxane receptor thereof.
Background technology
Cardiovascular disorder is in the world today, to threaten one of disease that the mankind are the most serious, the whole world approximately to have every year 1700 ten thousand people to die from cardiovascular disorder, and its M & M has surpassed tumor disease and leapt to the first in the world.According to WHO statistics, cardiovascular disorder death toll accounts for 35% of total death toll.At majority state, cardiovascular diseases is 45 years old above male sex's first cause of death, is women's second cause of the death.The ratio that ， China urban population in 2009 is died from cardiovascular disorder is according to statistics 128.19 people/100,000 people.
Sickness rate under being in not has also brought huge market scale.In China's clinical application amount of money, Drugs for Cardiovascular Diseases ranks first three after coming microbiotic and antitumour drug always for many years.Within 2009, the market sales revenue approaches 70,000,000,000 yuan, and annual average rate of increase reaches 17%.Wherein, also there has been growth faster in antithrombotic reagent market.2011, antithrombotic reagent world market scale was expected to over 18,000,000,000 dollars.
At present, for antithrombotic medicine, mainly contain anticoagulant, Thrombolytic Drugs and antiplatelet drug clinically.Wherein, antiplatelet drug is used the widest, is the important means of thrombotic diseases control, accounts for the important means of thrombotic diseases control, accounts for antithrombotic reagent more than 50%.Yet, at the Antiplatelet therapy medicine using at present, still exist different defects, as: the weak inhibition of platelet function, ADP-mediation signal transmission path gets clogged, onset time is long, intravenous integrin alpha IIb β 3 antagonist therapies cannot be converted into oral therapy, and can not reduce thoroughly thrombotic generation etc.Therefore, developing more efficient, safe newtype drug is the study hotspot that each large medicine is looked forward at present.
Two kinds of caused diseases of pathologic process of thrombosis and thromboembolism, are called thrombotic diseases clinically.The thrombotic diseases serious threat mankind's life and health, its sickness rate is in first of various diseases, and also has in recent years cumulative gesture, is one of the emphasis of contemporary medical science research and focus.In recent years, under the cumulative promotion of clinical demand, antithrombotic reagent market had had faster and had increased.2011, antithrombotic reagent world market scale approached 18,000,000,000 dollars.
At present, for antithrombotic medicine, use the widest clinically and be antiplatelet drug, account for antithrombotic reagent more than 50%, so antiplatelet drug have huge market potential.Meanwhile, because the antiplatelet drug having gone on the market at present all exists shortcoming to a certain degree, and good effect, medicine safe and easy administration are considerably less, and therefore successfully exploitation antiplatelet new drug has huge social value and economic benefit.
Summary of the invention
The present invention one of is intended to solve the problems of the technologies described above at least to a certain extent or at least provides a kind of useful business to select.For this reason, one object of the present invention is to propose a kind of compound of preparing medicine that can be used in.
The following discovery of the present invention based on contriver completes:
Due to the central role of thrombocyte in cardiovascular and cerebrovascular thrombosis, Antiplatelet therapy is one of effective method in treatment cardiovascular and cerebrovascular artery disease method.But, at the Antiplatelet therapy medicine using at present, still exist different defects, and curative effect, security is excellent and the medicine of easy administration is considerably less, therefore successfully exploitation antiplatelet new drug has huge social value and economic benefit.
According to the difference of mechanism of action, antiplatelet drug can be divided into TXA
2inhibitor (COX
1inhibitor and TP receptor antagonist), ADP antagonist, GPIIb/IIIa receptor antagonist, PAR1 receptor antagonist, PDE inhibitor, anticoagulant etc.We have selected TP receptor antagonist as research emphasis.Former because:
1.TP receptor antagonist has inhibition TXA
2synthetic effect, therefore just can play positive restraining effect at the thrombosis initial stage;
2.TP receptor antagonist with can suppress TXA equally
2synthetic COX
1inhibitor is compared, and has stronger specific aim, thereby has avoided selection COX
1during for point of application, poor selectivity obtains shortcoming, therefore has better treatment potentiality;
Make a general survey of to go on the market and at the antiplatelet drug grinding, the TP receptor antagonist that success is gone on the market be blank, therefore avoids the competition of Liao Yu world Ge great drugmaker, researches and develops space larger.
In a first aspect of the present invention, the present invention proposes a kind of compound.According to embodiments of the invention, described compound is N-shown in formula I (1-hydrogen-indenes-1-yl) sulfamide compound or its enantiomer, diastereomer, racemic modification, pharmacy acceptable salt, crystalline hydrate or solvate,
Wherein,
X is selected from C, O and N, and preferably X is C or O, and more preferably X is O;
R
1be selected from the alkyl of the C1-C12 straight or branched that does not replace or replaced by 1～3 halogen, the alkoxyl group of the C1-C12 straight or branched that does not replace or replaced by 1～3 halogen or phenyl, the C3-C6 cycloalkyl that does not replace or replaced by 1～3 halogen, the alkyl of the C1-C6 straight or branched being replaced by C1-C6 alkoxyl group, alkyl by the C1-C6 straight or branched of C3-C6 cycloalkyl substituted, hydroxyl, the hydroxyalkyl of C1-C6 straight or branched, replace or unsubstituted phenyl ring, and replacement or the unsubstituted aromatic heterocycle that contains 1～4 heteroatomic C5-C12, wherein, described heteroatoms is independently selected from O, S and N,
R
2be selected from hydrogen or its isotropic substance, the alkyl of the C1-C12 straight or branched that does not replace or replaced by 1～3 halogen, the C3-C6 cycloalkyl that does not replace or replaced by 1～3 halogen, the alkyl of the C1-C6 straight or branched being replaced by C1-C6 alkoxyl group, by the alkyl of the C1-C6 straight or branched of C3-C6 cycloalkyl substituted, the carboxyl of the C1-C6 straight or branched that does not replace or replaced by 1～3 halogen or phenyl, hydroxyl, the hydroxyalkyl of C1-C6 straight or branched, carboxyl, sulfydryl ,-N R
4r
5,-NCO R
4r
5,-SO
2r
4,-SO
2nR
4r
5, and-OCOR
4;
R
3be selected from hydrogen or its isotropic substance, halogen, the alkyl of the C1-C12 straight or branched that does not replace or replaced by 1～3 halogen, the alkoxyl group of the C1-C12 straight or branched that does not replace or replaced by 1～3 halogen or phenyl, the C3-C6 cycloalkyl that does not replace or replaced by 1～3 halogen, the alkyl of the C1-C6 straight or branched being replaced by C1-C6 alkoxyl group, alkyl by the C1-C6 straight or branched of C3-C6 cycloalkyl substituted, hydroxyl, cyano group, nitro, the hydroxyalkyl of C1-C6 straight or branched, carboxyl, sulfydryl ,-NR
4r
5,-NCO R
4r
5,-SO
2r
4,-SO
2n R
4r
5, and-OCOR
4;
R
4and R
5respectively independently selected from hydrogen or its isotropic substance, halogen, the alkyl of the C1-C6 straight or branched that does not replace or replaced by 1～3 halogen, and the C3-C6 cycloalkyl that does not replace or replaced by 1～3 halogen;
Described halogen is fluorine, chlorine, bromine or iodine.
Contriver is surprised to find, and above-claimed cpd can be used for the treatment of or prevent thromboxane receptor relative disease, or is used for the treatment of or prevents thrombosis and/or hypertension.
In one embodiment of the invention, for the phenyl ring of described replacement or the aromatic heterocycle of replacement, on each ring, comprise 1～3 substituting group, described substituting group is independently selected from hydrogen or its isotropic substance, halogen, the alkyl of the C1-C12 straight or branched that does not replace or replaced by 1～3 halogen, the alkoxyl group of the C1-C12 straight or branched that does not replace or replaced by 1～3 halogen and/or phenyl, the unsaturated alkyl of the C2-C12 straight or branched that does not replace or replaced by 1～3 halogen, the C3-C6 cycloalkyl that does not replace or replaced by 1～3 halogen, the alkyl of the C1-C6 straight or branched being replaced by C1-C6 alkoxyl group, alkyl by the C1-C6 straight or branched of C3-C6 cycloalkyl substituted, hydroxyl, cyano group, nitro, the hydroxyalkyl of C1-C6 straight or branched, and sulfydryl,-NR
4r
5,-NCOR
4r
5,-SR
4,-SO
2r
4,-SO
2nR
4r
5,-COR
4,-CONR
4r
5or-OCOR
5.
In one embodiment of the invention, for the phenyl ring of described replacement or the aromatic heterocycle of replacement, the phenyl ring of described replacement or the aromatic heterocycle of replacement are replaced by a plurality of substituting groups, wherein, two carbon atoms that are adjacent in described a plurality of substituting group or heteroatoms form together and contain 1～3 and be selected from N, heteroatomic 5～7 yuan of heterocycles in O and S, described 5～7 yuan of heterocycles are optionally selected from following substituting group and are replaced: hydrogen or its isotropic substance, halogen, the alkyl of the C1-C6 straight or branched that does not replace or replaced by 1～3 halogen, the alkoxyl group of the C1-C6 straight or branched that does not replace or replaced by 1～3 halogen, and hydroxyl.
In one embodiment of the invention, R
1for replacing or being unsubstitutedly selected from following group: phenyl ring, pyrroles, furans, thiophene, pyrazoles, oxazole, isoxazole, thiazole, imidazoles, benzopyrazoles, benzoxazole, benzoisoxazole, indoles, pyridine, pyrimidine, quinoline, isoquinoline 99.9 or purine.
In one embodiment of the invention, R
1being selected from following substituting group replaces: hydrogen, the alkyl of the C1-C6 straight or branched that does not replace or replaced by 1～3 halogen, the alkoxyl group of the C1-C6 straight or branched that does not replace or replaced by 1～3 halogen or phenyl, the unsaturated alkyl of the C2-C6 straight or branched that does not replace or replaced by 1～3 halogen, the C3-C4 cycloalkyl that does not replace or replaced by 1～3 halogen, the alkyl of the C1-C6 straight or branched being replaced by C1-C6 alkoxyl group, alkyl by the C1-C6 straight or branched of C3-C4 cycloalkyl substituted, hydroxyl ,-SO
2r
4,-COR
4,-SO
2nR
4r
5,-OCOR
4,-NR
4r
5and-NCO R
4r
5; Optionally, R
1by a plurality of substituting groups, replaced, the carbon atom that two substituting groups in described a plurality of substituting groups are adjacent forms 5 yuan of heterocycles that contain 2 O atoms together;
R
2the carboxyl of the alkoxyl group of the alkyl of the C1-C6 straight or branched that is selected from hydrogen, carboxyl, does not replace or is replaced by 1～3 halogen, the C1-C6 straight or branched that do not replace or replaced by 1～3 halogen or phenyl, the C1-C6 straight or branched that does not replace or replaced by 1～3 halogen or phenyl;
R
3alkoxyl group, the hydroxyl ,-NR of the alkyl of the C1-C6 straight or branched that is selected from hydrogen, halogen, does not replace or is replaced by 1～3 halogen, the C1-C6 straight or branched that do not replace or replaced by 1～3 halogen or phenyl
4r
5,-NCOR
4r
5,-SO
2r
4,-SO
2nR
4r
5or-OCOR
4;
R
4and R
5be the alkyl of hydrogen, halogen or the C1-C4 straight or branched that do not replace or replaced by 1～3 halogen independently of one another;
Described halogen is fluorine, chlorine or bromine.
In one embodiment of the invention, R
1for replacing or being unsubstitutedly selected from following group: phenyl ring, pyrroles, furans, thiophene and pyridine.
In one embodiment of the invention, R
1being selected from following substituting group replaces: hydrogen, halogen, the alkyl of the C1-C4 straight or branched that does not replace or replaced by 1～3 halogen, the alkoxyl group of the C1-C4 straight or branched that does not replace or replaced by 1～3 halogen or phenyl, by the alkyl of the C1-C4 straight or branched of C3-C4 cycloalkyl substituted, and hydroxyl; Optionally, R
1by a plurality of substituting groups, replaced, the carbon atom that two substituting groups in described a plurality of substituting groups are adjacent is connected to form 5 yuan of heterocycles that contain 2 O atoms together;
R
2for being selected from hydrogen, and the carboxyl of the C1-C6 straight or branched that does not replace or replaced by 1～3 halogen or phenyl;
R
3be selected from hydrogen, halogen, the alkoxyl group of the C1-C4 straight or branched that does not replace or replaced by 1～3 halogen or phenyl, hydroxyl and-OCOR
4;
R
4and R
5be selected from independently of one another hydrogen, halogen, and the alkyl of the C1-C4 straight or branched that does not replace or replaced by 1～3 halogen;
Described halogen is fluorine or chlorine.
In one embodiment of the invention, R
1for replacing or unsubstituted phenyl ring,
Optionally, R
1being selected from following substituting group replaces: hydrogen, halogen and hydroxyl;
Optionally, R
1by a plurality of substituting groups, replaced, the carbon atom that two substituting groups in described a plurality of substituting groups are adjacent forms 5 yuan of heterocycles that contain 2 O atoms together;
R
2for hydrogen;
R
3be selected from hydrogen, halogen, the alkoxyl group of the C1-C4 straight or branched that does not replace or replaced by 1～3 halogen or phenyl, and hydroxyl;
R
4and R
5be hydrogen or methyl independently of one another;
Described halogen is fluorine or chlorine.
In one embodiment of the invention, described compound is to be selected from following a kind of or its enantiomer, diastereomer, racemic modification, pharmacy acceptable salt, crystalline hydrate or solvate.
Thus, preferably, N-of the present invention (1-hydrogen-indenes-1-yl) sulfamide compound is selected from following compounds:
The term that used in the present invention, " pharmacy acceptable salt " is the conventional non-toxic salt of compound of Formula I and mineral acid or organic acid reaction formation.For example, the non-toxic salt of described routine can make by compound of Formula I and mineral acid or organic acid reaction, described mineral acid comprises hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, amidosulfonic acid and phosphoric acid etc., and described organic acid comprises citric acid, tartrate, lactic acid, pyruvic acid, acetic acid, Phenylsulfonic acid, tosic acid, methylsulfonic acid, naphthene sulfonic acid, ethyl sulfonic acid, naphthalene disulfonic acid, toxilic acid, oxysuccinic acid, propanedioic acid, fumaric acid, succsinic acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, flutter acid, hydroxymaleic acid, toluylic acid, phenylformic acid, Whitfield's ointment, L-glutamic acid, xitix, para-anilinesulfonic acid, Aspirin and isethionic acid etc., or compound of Formula I and propionic acid, oxalic acid, propanedioic acid, succsinic acid, fumaric acid, toxilic acid, lactic acid, oxysuccinic acid, tartrate, citric acid, aspartic acid or L-glutamic acid form after ester sodium salt, sylvite, calcium salt, aluminium salt or the ammonium salt forming with mineral alkali again, or methylamine salt, ethylamine salt or ethanolamine salt that compound of Formula I and organic bases form, or compound of Formula I and Methionin, arginine, ornithine form after ester the more corresponding inorganic acid salt forming with hydrochloric acid, Hydrogen bromide, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid or the corresponding organic acid salt forming with formic acid, acetic acid, picric acid, methylsulfonic acid and ethyl sulfonic acid.The term that used in this article " alkyl " can be straight chain or branched-chain alkyl, such as thinking methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, hexyl, heptyl, octyl group, nonyl, decyl, dodecyl, octadecyl etc.; Replace or unsubstituted cycloalkyl, according to embodiments of the invention, cycloalkyl contains 3～10 carbon atoms, can be saturated or undersaturated but does not have aromatic character, according to concrete example of the present invention, cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc.; Replace or unsubstituted Heterocyclylalkyl, according to embodiments of the invention, in Heterocyclylalkyl, can contain the heteroatoms that at least one is selected from O, N and S.
In a second aspect of the present invention, the present invention proposes a kind of method of preparing compound noted earlier, it is characterized in that, comprise the following steps:
Make compound shown in compound shown in formula 1a and formula 2a carry out condensation, so that compound shown in the formula of acquisition 3a;
Make compound generation ring-closure reaction described in described formula 3a, so that compound shown in the formula of acquisition 4a;
Make compound generation reductive amination process shown in compound shown in described formula 4a and formula 5a, so that compound shown in the formula of acquisition 6a;
Make compound shown in described formula 6a and diethyl malonate generation condensation reaction, so that compound shown in the formula of acquisition 7a;
Make the hydrolysis reaction of compound generation shown in described formula 7a, so that compound shown in the formula of acquisition 8a; And
Based on following one of at least, shown in described formula 8a, compound obtains compound shown in described formula I:
Make compound shown in described formula 8a and amino acid ester or propanedioic acid methyl esters monopotassium salt generation condensation reaction, and described condensation reaction products is hydrolyzed under alkaline condition, so that compound shown in the formula of acquisition I
Wherein,
R
1～R
3for as above in defined.
Contriver finds, utilizes the method can effectively prepare foregoing compound, and this preparation method has that reaction conditions gentleness, abundant raw material are easy to get, operation and the advantage such as aftertreatment is simple, corresponding selection is good.
In a third aspect of the present invention, the present invention proposes a kind of pharmaceutical composition.According to embodiments of the invention, this pharmaceutical composition comprises:
Foregoing compound; And
Acceptable vehicle pharmaceutically,
Optionally described pharmaceutical composition is for being used for the treatment of or preventing thromboxane receptor relative disease, or is used for the treatment of or prevents thrombosis and/or hypertension.This medicinal compositions can also further comprise the conventional additives such as odorant agent, flavouring agent.
It is that 1%～99% general formula (I) compound is as active ingredient that pharmaceutical composition provided by the present invention preferably contains weight ratio, preferably, compound of Formula I accounts for 65%～99% of pharmaceutical composition gross weight as activeconstituents, and rest part is pharmaceutically acceptable carrier and/or conventional additives.
Compound provided by the present invention and pharmaceutical composition can be various ways, as tablet, capsule, pulvis, syrup, solution shape, suspension and aerosol etc., and may reside in the carrier of suitable solid or liquid or diluent and the suitable disinfector for injecting or instiling.
The various formulations of pharmaceutical composition of the present invention can be according to conventional preparation method's preparation of pharmaceutical field.General formula (I) compound that comprises 0.05mg～200mg in the unit metering of its pharmaceutical formulation, preferably, general formula (I) compound that comprises 0.1mg～100mg in the metering of the unit of pharmaceutical formulation.
Compound of the present invention and pharmaceutical composition can comprise humans and animals to the clinical use of Mammals, can pass through the administration of mouth, nose, skin, lung or gi tract etc.Most preferred route of administration is oral.Most preferred per daily dose is 0.01mg/kg～200mg/kg body weight, disposable taking, or 0.01mg/kg～100mg/kg body weight, part vic.No matter adopt which kind of instructions of taking, individual's optimal dose should be determined according to concrete treatment plan.Be generally from low dose, increase gradually dosage until find optimal dosage.
In a fourth aspect of the present invention, the present invention proposes the purposes of foregoing compound in preparing medicine, wherein, described medicine is used for the treatment of or prevents thromboxane receptor relative disease, or is used for the treatment of or prevents thrombosis and/or hypertension.
Additional aspect of the present invention and advantage in the following description part provide, and part will become obviously from the following description, or recognize by practice of the present invention.
Embodiment
In following embodiment, will further illustrate the present invention.These embodiment are only for the present invention is described, but do not limit the present invention in any way.All parameters in embodiment and remaining explanation unless otherwise indicated, are all to take quality as explanation foundation.In specification sheets, not writing preparation method's various raw materials exactly all can business buy.
General method
Below the general method of the preparation N-that adopted in an embodiment of the present invention (1-hydrogen-indenes-1-yl) sulfamide compound is described:
Compound to be synthesized is as follows:
The present invention also provides the preparation method of compound of Formula I, and the raw materials used and reagent of the present invention if no special instructions, is business and buys.
Compound A-40 01-A014 presses reaction scheme one preparation:
Reaction scheme one:
The preparation method of reaction scheme one is described in detail as follows:
Route one step a: the preparation of compound 3a: under the effect of catalyzer, compound 1a and compound 2a carry out condensation, obtain compound 3a; Wherein, described catalyzer is palladium catalyst, preferably palladium;
Particularly, the compound 1a of chemical dose and compound 2a are dissolved in appropriate anhydrous solvent, under room temperature, under the condition of appropriate palladium catalyst, phase-transfer catalyst and appropriate salt of wormwood, carry out condensation, product, through column chromatography purification, obtains compound 3a; Described solvent is preferably DMF;
Route one step b: the preparation of compound 4a: under sour effect, ring-closure reaction occurs compound 3a, obtains compound 4a; Wherein, described acid is PPA, the vitriol oil, aluminum chloride etc., wherein, and the preferred PPA of described condensing agent;
Particularly, 3a is dissolved in appropriate PPA, is heated to 90 degrees Celsius, TLC monitoring has been reacted and has been obtained compound 4a.Under ice bath, drip suitable quantity of water, ethyl acetate extraction 3 times, organic phase is extremely neutral with saturated sodium bicarbonate aqueous solution washing, dried over sodium sulfate, evaporate to dryness, product, through column chromatography purification, obtains compound 4a;
Route one step c: the preparation of compound 6a: under the effect of catalyzer and reductive agent, reductive amination process occurs for compound 4a and compound 5a, obtains compound 6a; Wherein, described catalyzer is TiCl
4, AlCl
3deng Lewis acid; Wherein, described reductive agent is sodium borohydride, sodium cyanoborohydride or acetoxyl sodium borohydride.
Particularly, by the compound 4a obtaining, take appropriate methylene dichloride and toluene as solvent, use appropriate Lewis acid catalyst, carry out enamine with 5a and react, obtain imine intermediate.Reaction is at room temperature carried out, and the time is 16 hours～20 hours.Subsequently, in reaction solution, add the acid of equivalent, and in reaction solution, add appropriate reductive agent in every 1 hour～2 hours.After having reacted with alkali lye neutralization reaction liquid, thin up, ethyl acetate extraction, dried over sodium sulfate, solvent evaporated, column chromatography purification.Wherein, described Lewis acid catalyst is TiCl
4, AlCl
3be preferably 0.3:1 with the mol ratio of compound 4a; Use appropriate sodium borohydride, sodium cyanoborohydride or acetoxyl sodium borohydride to reduce, at room temperature, react 7 hours～12 hours, add suitable quantity of water, ethyl acetate extraction, dried over sodium sulfate, is spin-dried for solvent, column chromatography purification;
Route one steps d: the preparation of compound 7a: under the effect of alkali, compound 6a and diethyl malonate generation condensation reaction, obtain compound 7a; Wherein, described alkali is NaH or MeONa;
Particularly, diethyl malonate is dissolved in appropriate solvent, under ice bath, adds alkali, react after 2 hours, drip 6a.Under room temperature, react 6 hours～8 hours.Aftertreatment is adjusted to neutrality, and organic solvent extraction is spin-dried for, and column chromatography purification obtains compound 7a; Described solvent is DMF or THF; Alkali is NaH or MeONa; The equivalence ratio of 6a and diethyl malonate and alkali is 1:3:3.3.
Route one step e: the preparation of compound 8a: under sour effect, hydrolysis reaction occurs compound 7a, obtains compound 8a; Wherein said acid is concentrated hydrochloric acid, the vitriol oil.
Particularly, 7a is dissolved in suitable solvent, adds the acid of 1-3 equivalent, back flow reaction 48 hours.After completion of the reaction, saturated common salt water washing, dry, be spin-dried for, column chromatography purification obtains compound 8a(compound A-40 01-A014).
Compound A-40 15-A028 presses reaction scheme two preparations:
Reaction circuit two:
Compound 11a(A015-A028) preparation, under the effect of alkali, compound 8a and propanedioic acid methyl esters monopotassium salt generation condensation reaction, under alkaline condition, hydrolysis obtains 11a subsequently.
Particularly, 8a is dissolved in suitable solvent, adds alkali activation 2 hours, add again propanedioic acid methyl esters monopotassium salt, react after 10 hours, add the aqueous solution of alkali, room temperature reaction is after 2 hours, reaction solution is adjusted to neutrality, ethyl acetate extraction, saturated common salt water washing, dry, be spin-dried for, column chromatography purification obtains compound 11a(A015-A028).
Compound A-40 29-A076 is prepared by reaction circuit three:
Reaction scheme three:
Preparation method by reaction scheme three is described in detail as follows:.
Route three step a: the preparation of compound 9a: under the effect of alkali and condensation reagent, compound 8a and amino acid ester generation condensation reaction, obtain compound 9a, and wherein condensation reagent is TBTU or DCC, HOBt;
Particularly, the 8a solvent being made by route one, in suitable solvent, adds suitable alkali and condensation reagent, reacts 2 hours～16 hours under room temperature, after completion of the reaction, adds water stopped reaction, dichloromethane extraction, saturated common salt water washing.Dry, be spin-dried for solvent, column chromatography purification obtains compound 9a.
Route three step b: preparation compound 10a(A029-A076), under the effect of alkali, there is hydrolysis reaction in compound 9a, obtains compound 10a; Wherein alkali is NaOH or KOH or LiOH;
Particularly, 9a is dissolved in suitable solvent, adds the aqueous solution of alkali, stirring at normal temperature 1 hour～2 hours.Reaction solution is adjusted to neutrality, extraction, dry, be spin-dried for solvent, column chromatography purification obtains 10a; Described solvent is THF or dioxane.
Embodiment 1:2-(1-(4-fluorobenzene sulfoamido)-1-hydrogen-indenes-4-yl) acetic acid (A001) (pressing reaction scheme one preparation)
The preparation of 1.13-(2-(brooethyl) phenyl) methyl acrylate
2.97g is faced to iodine benzyl bromine, 1.72g methyl acrylate, 225mg palladium, 2.78g tetrabutylammonium chloride, 4.14g salt of wormwood and 50mL dry DMF and join in 250mL reaction flask, nitrogen replacement 3 times, stirred overnight at room temperature.Reaction solution is poured into water, and ethyl acetate extraction 3 times, merges organic phase, 0.1N HCl washing 2 times for organic phase, and saturated common salt water washing 2 times, dry, filter, be spin-dried for solvent, column chromatography purification, obtains the faint yellow oily matter of 2.1g.
1H?NMR(CDCl
3,400MHz):δ8.07(d,J=16.0Hz,1H),7.67-7.56(m,1H),7.42-7.31(m,3H),6.45(d,J=16.0Hz,1H),4.60(s,2H),3.84(s,3H).ESI-MS?m/z:256[M+H]
+.
The preparation of 1.24-brooethyl-1-hydrogen-1-benzofuran
In 100mL reaction flask, add 2.1g3-(2-(brooethyl) phenyl) methyl acrylate and 30mL PPA, be heated to 90 degrees Celsius, reaction is spent the night.Under ice bath, drip 50mL water, ethyl acetate extraction 3 times, organic phase is extremely neutral with saturated sodium bicarbonate aqueous solution washing, dried over sodium sulfate, evaporate to dryness, product, through column chromatography purification, obtains 1.46g white solid.
ESI-MS?m/z:245[M+Na]
+.
The preparation of 1.31-(4-fluorobenzene sulfoamido)-4-brooethyl-1-hydrogen-indenes
In 100mL reaction flask, add 2.23g4-brooethyl-1-hydrogen-1-benzofuran, 1.75g4-fluorobenzene sulphonamide, 190mg TiCl
4and 20mL DCM and 20mL toluene, stirring at room, after 16 hours, is divided and is added 3.78g sodium cyanoborohydride three times, every minor tick 1 hour～2 hours.After adding, continue room temperature reaction 2 hours.After having reacted with alkali lye neutralization reaction liquid, thin up, ethyl acetate extraction, dried over sodium sulfate, solvent evaporated, column chromatography purification.Obtain 2.3g faint yellow solid.
1H?NMR(d
6-DMSO,400MHz):δ7.96-7.87(m,2H),7.42-7.10(m,6H),6.53(d,J=2.4Hz,1H),6.33(d,J=2.4Hz,1H),4.69(s,2H).ESI-MS?m/z:404[M+Na]
+.
The preparation of 1.42-((1-(4-fluorobenzene sulfoamido)-1-hydrogen-indenes-4-yl) methyl) diethyl malonate
2.4g diethyl malonate is dissolved in appropriate anhydrous THF, under ice bath, adds 0.66g NaH (60%), react after 2 hours, drip the THF solution of 1.91g1-(4-fluorobenzene sulfoamido)-4-brooethyl-1-hydrogen-indenes.Under room temperature, react 6 hours～8 hours.Aftertreatment is adjusted to neutrality, and organic solvent extraction is spin-dried for, and obtains crude product, not purified, is directly used in next step.
ESI-MS?m/z:484[M+Na]
+.
The preparation of 1.52-(1-(4-fluorobenzene sulfoamido)-1-hydrogen-indenes-4-yl) acetic acid
The product of previous step is dissolved in THF, adds the concentrated hydrochloric acid of 3 equivalents, back flow reaction 48 hours.After completion of the reaction, saturated common salt water washing, dry, be spin-dried for, column chromatography purification obtains off-white color solid.
1H?NMR(d
6-DMSO,400MHz):δ12.14(br,1H),7.96-7.87(m,2H),7.42-7.10(m,6H),6.53(d,J=2.4Hz,1H),6.33(d,J=2.4Hz,1H),4.69(s,2H),2.85-2.37(m,4H).ESI-MS?m/z:384[M+Na]
+.
Embodiment 2:2-(1-(4-fluorobenzene sulfoamido)-1-hydrogen-indenes-4-yl)-3-oxy butyrate (A015) (pressing reaction scheme two preparations)
3.6g compound A-40 01 is dissolved in THF, add EDCI reaction 2 hours, then add 1.1 equivalent propanedioic acid methyl esters monopotassium salts, react after 10 hours, the aqueous solution that adds the NaOH of 2N, after room temperature reaction 2 hours, reaction solution is adjusted to neutrality, ethyl acetate extraction, saturated common salt water washing, dry, be spin-dried for, column chromatography purification obtains off-white color solid.
1H?NMR(d
6-DMSO,400MHz):δ12.34(br,1H),7.96-7.87(m,2H),7.42-7.10(m,6H),6.53(d,J=2.4Hz,1H),6.33(d,J=2.4Hz,1H),4.69(s,2H),3.45-3.37(m,4H).ESI-MS?m/z:412[M+Na]
+.
Embodiment 3:2-(2-(1-(4-fluorobenzene alkylsulfonyl)-hydrogen-indenes-4-yl) kharophen) acetic acid (A029) (pressing reaction scheme three preparations)
The preparation of 3.12-(2-(1-(4-fluorobenzene alkylsulfonyl)-hydrogen-indenes-4-yl) kharophen) ethyl acetate
3.6g compound A-40 01,1.37g glycine methyl ester hydrochloride, 1.1 equivalent TBTU, 1.1 equivalent triethylamines and 40mL DCM are joined in reaction flask, and room temperature reaction is after 2 hours, and 0.1N HCl washs 3 times, saturated common salt water washing 2 times, dry, filter, be spin-dried for solvent and obtain crude product.Be directly used in next step.
ESI-MS?m/z:455[M+Na]
+.
The preparation of 3.22-(2-(1-(4-fluorobenzene alkylsulfonyl)-hydrogen-indenes-4-yl) kharophen) acetic acid
The product of previous step is dissolved in 40mL THF, adds the NaOH aqueous solution of 40mL2N, vigorous stirring 2 hours.Reaction solution is adjusted to neutrality, extraction, dry, be spin-dried for solvent, column chromatography purification obtains off-white color solid.
1H?NMR(d
6-DMSO,400MHz):δ12.37(br,1H),7.96-7.87(m,2H),7.42-7.10(m,7H),6.53(d,J=2.4Hz,1H),6.33(d,J=2.4Hz,1H),4.69(s,2H),4.4.52-4.37(m,4H),2.85-2.37(m,4H).ESI-MS?m/z:441[M+Na]
+.
Pharmaceutical research
Embodiment 4: the test of rat platelet aggregation
Experimental technique:
By SD rat random packet: blank group 5.0mL/kg, acetylsalicylic acid 25mg/kg, sample sets 25mg/kg dosage group.Each organizes rat oral gavage administration every day 1 time, 11d continuously, and after last administration, water 12h is can't help in fasting, and in morning next day, after 3% vetanarcol anesthesia, abdominal aortic blood, measures platelet aggregation rate.
Liquor sodii citratis (0.109 mol/L) anti-freezing (blood: antithrombotics=9:1), the centrifugal 5min of 800r/min, getting supernatant is partly platelet rich plasma (platelet rich plasma, PRP), the centrifugal 10min of remainder 3000r/min, getting supernatant is partly platelet poor plasma (platelet poor plasma, PPP).In PRP, platelet count is 3.00/mm
3left and right.Platelet rich plasma (PRP) room temperature preservation is used in 4 hours after getting blood.
According to BornShi turbidimetry, the opacity tube that fills 200 μ L PRP and 1 little bar magnet is placed in to platelet aggregation instrument, 37 ℃ of insulation 1min after PPP demarcates, add inductor induction to assemble under stirring state.The final concentration of inductor used is: adenosine diphosphate (ADP) (ADP, adenosine diphosphate) 5.67 μ g/mL, arachidonic acid (AA, arachidonic acid) 78.2 μ g/mL, platelet activation factor (PAF, platelet activating factor) 0.41 μ g/mL.According to MA, analyze the impact of medicine on platelet aggregation.
Data analysis:
Measure thrombocyte MA, and calculate L-Arginine:
Platelet is assembled inhibiting rate=(Normal group platelet aggregation rate-administration group platelet aggregation rate)/Normal group platelet aggregation rate
The reactivity of same medicine various dose is done nonlinear regression analysis with GraphPad Prism software, obtains dose response curve and records IC
50value.Data are explained with mean+SD, are three independent experiment results, and each experiment is three multiple holes.
Acquired results is in Table 4:
Table 4
| Sequence number | Numbering | IC 50（nM） |
| 1 | A001 | 516.4±84.5 |
| 2 | A003 | 91.5±51.1 |
| 3 | A005 | 25.7±10.6 |
| 4 | A007 | 413.3±164.2 |
| 5 | A010 | 600.1±167.2 |
| 6 | A012 | 20.3±16.1 |
| 7 | A016 | 105.0±27.4 |
| 8 | A017 | 268.1±88.1 |
| 9 | A020 | 360.5±115.5 |
| 10 | A023 | 134.1±84.2 |
| 11 | A024 | 110.1±28.5 |
| 12 | A025 | 908.1±123.7 |
| 13 | A026 | 61.1±51.3 |
| 14 | A031 | 261.5±101.6 |
| 15 | A032 | 366.1±101.3 |
| 16 | A035 | 612.6±202.2 |
| 17 | A036 | 1009.9±255.3 |
| 18 | A041 | 81.9±18.2 |
| 19 | A052 | 852.1±119.8 |
| 20 | A063 | 455.0±120.0 |
| 21 | A070 | 1516.1±196.2 |
| 22 | A074 | 122.3±56.1 |
Compound of the present invention is hematoblastic high reactivity antagonist, the wherein IC of 9 compounds
50lower than the level of 200nM, the IC of 5 compounds
50lower than 100nM.In vitro tests finds, compound of the present invention is to by ADP(adenosine diphosphate), PAF(platelet activating factor) and AA(arachidonic acid) rabbit platelet aggregation that excites has obvious restraining effect.
Embodiment 5: the test of rabbit extracorporeal platelet aggregation
Experimental technique:
By white big ear rabbit random packet: blank group 5.0mL/kg, acetylsalicylic acid 25mg/kg, sample sets 25mg/kg dosage group.Administration group is pressed described dosage gastric infusion, control group gavage equal-volume solvent, once a day, and successive administration 7d, 1h after last administration, after 3% vetanarcol anesthesia, puncture ear medium sized artery is got blood, measures platelet aggregation rate.
Liquor sodii citratis (0.109 mol/L) anti-freezing (blood: antithrombotics=9:1), the centrifugal 5min of 800r/min, getting supernatant is partly platelet rich plasma (platelet rich plasma, PRP), the centrifugal 10min of remainder 3000r/min, getting supernatant is partly platelet poor plasma (platelet poor plasma, PPP).In PRP, platelet count is 3.00/mm
3left and right.Platelet rich plasma (PRP) room temperature preservation is used in 4 hours after getting blood.
According to BornShi turbidimetry, the opacity tube that fills 200 μ L PRP and 1 little bar magnet is placed in to platelet aggregation instrument, 37 ℃ of insulation 1min after PPP demarcates, add inductor induction to assemble under stirring state.The final concentration of inductor used is: adenosine diphosphate (ADP) (ADP, adenosine diphosphate) 5.67 μ g/mL, arachidonic acid (AA, arachidonic acid) 78.2 μ g/mL, platelet activation factor (PAF, platelet activating factor) 0.41 μ g/mL.According to MA, analyze the impact of medicine on platelet aggregation.
Data analysis:
Measure thrombocyte MA, and calculate L-Arginine:
Platelet is assembled inhibiting rate=(Normal group platelet aggregation rate-administration group platelet aggregation rate)/Normal group platelet aggregation rate
The reactivity of same medicine various dose is done nonlinear regression analysis with GraphPad Prism software, obtains dose response curve and records IC
50value.Data are explained with mean+SD, are three independent experiment results, and each experiment is three multiple holes.
Acquired results is in Table 5:
Table 5
| Sequence number | Numbering | IC 50（nM） |
| 1 | A001 | 301.0±77.5 |
| 2 | A003 | 141.5±35.6 |
| 3 | A005 | 43.2±18.3 |
| 4 | A007 | 502.3±195.4 |
| 5 | A010 | 552.3±218.5 |
| 6 | A012 | 25.1±11.7 |
| 7 | A016 | 80.3±19.4 |
| 8 | A017 | 531.6±105.3 |
| 9 | A020 | 257.1±95.3 |
| 10 | A023 | 267.7±164.6 |
| 11 | A024 | 83.7±34.8 |
| 12 | A025 | 798.7±196.7 |
| 13 | A026 | 90.1±46.3 |
| 14 | A031 | 306.1±79.1 |
| 15 | A036 | 921.3±181.3 |
| 16 | A041 | 76.6±9.7 |
| 17 | A052 | 1720.1±120.3 |
| 18 | A063 | 160.2±54.6 |
| 19 | A070 | 2017.5±89.1 |
Compound of the present invention is hematoblastic high reactivity antagonist, the wherein IC of 8 compounds
50lower than the level of 200nM, the IC of 6 compounds
50lower than 100nM.External can the inhibition by ADP(adenosine diphosphate), PAF(platelet activating factor) and AA(arachidonic acid) rabbit platelet aggregation that excites, and show obvious dose-dependence.Conclusion: this compounds has obvious antiplatelet aggregative activity.
This compounds has good antithrombotic application prospect, thereby the good commercial value of tool.
Embodiment 6: the test of dog extracorporeal platelet aggregation
Experimental technique:
By the administration of Beagle dog random packet, with vetanarcol (30mg/kg i.v.), anaesthetize laggard row arterial blood extracting, liquor sodii citratis (0.109 mol/L) anti-freezing (blood: antithrombotics=9:1), the centrifugal 5min of 800r/min, getting supernatant is partly platelet rich plasma (platelet rich plasma, PRP), the centrifugal 10min of remainder 3000r/min, getting supernatant is partly platelet poor plasma (platelet poor plasma, PPP).In PRP, platelet count is 3.00/mm
3left and right.Platelet rich plasma (PRP) room temperature preservation is used in 4 hours after getting blood.
According to BornShi turbidimetry, the opacity tube that fills 200 μ L PRP and 1 little bar magnet is placed in to platelet aggregation instrument, 37 ℃ of insulation 1min after PPP demarcates, add inductor induction to assemble under stirring state.The final concentration of inductor used is: adenosine diphosphate (ADP) (ADP, adenosine diphosphate) 5.67 μ g/mL, arachidonic acid (AA, arachidonic acid) 78.2 μ g/mL, platelet activation factor (PAF, platelet activating factor) 0.41 μ g/mL.According to MA, analyze the impact of medicine on platelet aggregation.
Data analysis:
Measure thrombocyte MA, and calculate L-Arginine:
Platelet is assembled inhibiting rate=(Normal group platelet aggregation rate-administration group platelet aggregation rate)/Normal group platelet aggregation rate
The reactivity of same medicine various dose is done nonlinear regression analysis with GraphPad Prism software, obtains dose response curve and records IC
50value.Data are explained with mean+SD, are three independent experiment results.
Acquired results is in Table 8:
Table 8
| Sequence number | Numbering | IC 50（nM） |
| 1 | A005 | 27.6±16.3 |
| 2 | A012 | 12.6±12.2 |
| 3 | A026 | 106.1±19.9 |
| 4 | A041 | 173.1±96.4 |
Result shows compound A-40 05, and the Beagle dog platelet aggregation that A012 causes agonist all has obvious restraining effect.
This compounds has good antithrombotic application prospect, thereby the good commercial value of tool.
From above-mentioned experimental result, can find out, the preparation method of N-of the present invention (1-hydrogen-indenes-1-yl) sulfamide compound and derivative has that reaction conditions gentleness, abundant raw material are easy to get, operation and the advantage such as aftertreatment is simple, corresponding selection is good.
The high reactivity antagonist that N-of the present invention (1-hydrogen-indenes-1-yl) sulfamide compound and derivative are platelet aggregation.
Therefore, N-of the present invention (1-hydrogen-indenes-1-yl) sulfamide compound and derivative can be used for preparation treatment disease, the especially medicine of the cardiovascular disorder such as thrombosis, hypertension relevant to thromboxane receptor.
In the description of this specification sheets, the description of reference term " embodiment ", " some embodiment ", " example ", " concrete example " or " some examples " etc. means to be contained at least one embodiment of the present invention or example in conjunction with specific features, structure, material or the feature of this embodiment or example description.In this manual, the schematic statement of above-mentioned term is not necessarily referred to identical embodiment or example.And the specific features of description, structure, material or feature can be with suitable mode combinations in any one or more embodiment or example.
Although illustrated and described embodiments of the invention above, be understandable that, above-described embodiment is exemplary, can not be interpreted as limitation of the present invention, those of ordinary skill in the art can change above-described embodiment within the scope of the invention in the situation that not departing from principle of the present invention and aim, modification, replacement and modification.
Claims (10)
1. a compound, is characterized in that, described compound is N-shown in formula I (1-hydrogen-indenes-1-yl) sulfamide compound or its enantiomer, diastereomer, racemic modification, pharmacy acceptable salt, crystalline hydrate or solvate,
Wherein,
X is selected from C, O and N, and preferably X is C or O, and more preferably X is O;
R
1be selected from the alkyl of the C1-C12 straight or branched that does not replace or replaced by 1-3 halogen, the alkoxyl group of the C1-C12 straight or branched that does not replace or replaced by 1-3 halogen or phenyl, the C3-C6 cycloalkyl that does not replace or replaced by 1-3 halogen, the alkyl of the C1-C6 straight or branched being replaced by C1-C6 alkoxyl group, alkyl by the C1-C6 straight or branched of C3-C6 cycloalkyl substituted, hydroxyl, the hydroxyalkyl of C1-C6 straight or branched, replace or unsubstituted phenyl ring, and replacement or the unsubstituted aromatic heterocycle that contains 1～4 heteroatomic C5-C12, wherein, described heteroatoms is independently selected from O, S and N,
R
2be selected from hydrogen or its isotropic substance, the alkyl of the C1-C12 straight or branched that does not replace or replaced by 1-3 halogen, do not replace or by the C3-C6 cycloalkyl of 1-3 halogen replacement, the alkyl of the C1-C6 straight or branched being replaced by C1-C6 alkoxyl group, by the alkyl of the C1-C6 straight or branched of C3-C6 cycloalkyl substituted, the carboxyl of the C1-C6 straight or branched that does not replace or replaced by 1-3 halogen or phenyl, hydroxyl, the hydroxyalkyl of C1-C6 straight or branched, carboxyl, sulfydryl ,-N R
4r
5,-NCO R
4r
5,-SO
2r
4,-SO
2nR
4r
5, and-OCOR
4;
R
3be selected from hydrogen or its isotropic substance, halogen, the alkyl of the C1-C12 straight or branched that does not replace or replaced by 1-3 halogen, the alkoxyl group of the C1-C12 straight or branched that does not replace or replaced by 1-3 halogen or phenyl, the C3-C6 cycloalkyl that does not replace or replaced by 1-3 halogen, the alkyl of the C1-C6 straight or branched being replaced by C1-C6 alkoxyl group, alkyl by the C1-C6 straight or branched of C3-C6 cycloalkyl substituted, hydroxyl, cyano group, nitro, the hydroxyalkyl of C1-C6 straight or branched, carboxyl, sulfydryl ,-NR
4r
5,-NCO R
4r
5,-SO
2r
4,-SO
2n R
4r
5, and-OCOR
4;
R
4and R
5respectively independently selected from hydrogen or its isotropic substance, halogen, the alkyl of the C1-C6 straight or branched that does not replace or replaced by 1-3 halogen, and do not replace or by the C3-C6 cycloalkyl of 1-3 halogen replacement;
Described halogen is fluorine, chlorine, bromine or iodine.
2. compound according to claim 1, it is characterized in that, for the phenyl ring of described replacement or the aromatic heterocycle of replacement, on each ring, comprise 1～3 substituting group, described substituting group is independently selected from hydrogen or its isotropic substance, halogen, the alkyl of the C1-C12 straight or branched that does not replace or replaced by 1-3 halogen, the alkoxyl group of the C1-C12 straight or branched that does not replace or replaced by 1-3 halogen and/or phenyl, the unsaturated alkyl of the C2-C12 straight or branched that does not replace or replaced by 1-3 halogen, the C3-C6 cycloalkyl that does not replace or replaced by 1-3 halogen, the alkyl of the C1-C6 straight or branched being replaced by C1-C6 alkoxyl group, alkyl by the C1-C6 straight or branched of C3-C6 cycloalkyl substituted, hydroxyl, cyano group, nitro, the hydroxyalkyl of C1-C6 straight or branched, and sulfydryl,-NR
4r
5,-NCOR
4r
5,-SR
4,-SO
2r
4,-SO
2nR
4r
5,-COR
4,-CONR
4r
5or-OCOR
5.
3. compound according to claim 1, for the phenyl ring of described replacement or the aromatic heterocycle of replacement, the phenyl ring of described replacement or the aromatic heterocycle of replacement are replaced by a plurality of substituting groups, wherein, two carbon atoms that are adjacent in described a plurality of substituting group or heteroatoms form together and contain 1 to 3 and be selected from N, the first heterocycle of heteroatomic 5-7 in O and S, the first heterocycle of described 5-7 is optionally selected from following substituting group and is replaced: hydrogen or its isotropic substance, halogen, the alkyl of the C1-C6 straight or branched that does not replace or replaced by 1-3 halogen, the alkoxyl group of the C1-C6 straight or branched that does not replace or replaced by 1-3 halogen, and hydroxyl.
4. compound according to claim 1, is characterized in that,
R
1for replacing or being unsubstitutedly selected from following group: phenyl ring, pyrroles, furans, thiophene, pyrazoles, oxazole, isoxazole, thiazole, imidazoles, benzopyrazoles, benzoxazole, benzoisoxazole, indoles, pyridine, pyrimidine, quinoline, isoquinoline 99.9 or purine,
Optionally, R
1being selected from following substituting group replaces: hydrogen, the alkyl of the C1-C6 straight or branched that does not replace or replaced by 1-3 halogen, the alkoxyl group of the C1-C6 straight or branched that does not replace or replaced by 1-3 halogen or phenyl, the unsaturated alkyl of the C2-C6 straight or branched that does not replace or replaced by 1-3 halogen, the C3-C4 cycloalkyl that does not replace or replaced by 1-3 halogen, the alkyl of the C1-C6 straight or branched being replaced by C1-C6 alkoxyl group, alkyl by the C1-C6 straight or branched of C3-C4 cycloalkyl substituted, hydroxyl ,-SO
2r
4,-COR
4,-SO
2nR
4r
5,-OCOR
4,-NR
4r
5and-NCO R
4r
5; Optionally, R
1by a plurality of substituting groups, replaced, the carbon atom that two substituting groups in described a plurality of substituting groups are adjacent forms 5 yuan of heterocycles that contain 2 O atoms together;
R
2the alkoxyl group of the alkyl of the C1-C6 straight or branched that is selected from hydrogen, carboxyl, does not replace or is replaced by 1-3 halogen, the C1-C6 straight or branched that do not replace or replaced by 1-3 halogen or phenyl, not replacement or by the carboxyl of the C1-C6 straight or branched of 1-3 halogen or phenyl replacement;
R
3the alkyl of the C1-C6 straight or branched that is selected from hydrogen, halogen, does not replace or is replaced by 1-3 halogen, do not replace or by alkoxyl group, the hydroxyl ,-NR of the C1-C6 straight or branched of 1-3 halogen or phenyl replacement
4r
5,-NCOR
4r
5,-SO
2r
4,-SO
2nR
4r
5or-OCOR
4;
R
4and R
5be hydrogen, halogen independently of one another or do not replace or by the alkyl of the C1-C4 straight or branched of 1-3 halogen replacement;
Described halogen is fluorine, chlorine or bromine.
5. compound according to claim 1, wherein,
R
1for replacing or being unsubstitutedly selected from following group: phenyl ring, pyrroles, furans, thiophene and pyridine;
Optionally, R
1being selected from following substituting group replaces: hydrogen, halogen, the alkyl of the C1-C4 straight or branched that does not replace or replaced by 1-3 halogen, the alkoxyl group of the C1-C4 straight or branched that does not replace or replaced by 1-3 halogen or phenyl, by the alkyl of the C1-C4 straight or branched of C3-C4 cycloalkyl substituted, and hydroxyl; Optionally, R
1by a plurality of substituting groups, replaced, the carbon atom that two substituting groups in described a plurality of substituting groups are adjacent is connected to form 5 yuan of heterocycles that contain 2 O atoms together;
R
2for being selected from hydrogen, and the carboxyl of the C1-C6 straight or branched that does not replace or replaced by 1-3 halogen or phenyl;
R
3be selected from hydrogen, halogen, does not replace or by the alkoxyl group of the C1-C4 straight or branched of 1-3 halogen or phenyl replacement, hydroxyl and-OCOR
4;
R
4and R
5be selected from independently of one another hydrogen, halogen, and the alkyl of the C1-C4 straight or branched that does not replace or replaced by 1-3 halogen;
Described halogen is fluorine or chlorine.
6. compound according to claim 1, is characterized in that,
R
1for replacing or unsubstituted phenyl ring,
Optionally, R
1being selected from following substituting group replaces: hydrogen, halogen and hydroxyl;
Optionally, R
1by a plurality of substituting groups, replaced, the carbon atom that two substituting groups in described a plurality of substituting groups are adjacent forms 5 yuan of heterocycles that contain 2 O atoms together;
R
2for hydrogen;
R
3be selected from hydrogen, halogen, the alkoxyl group of the C1-C4 straight or branched that does not replace or replaced by 1-3 halogen or phenyl, and hydroxyl;
R
4and R
5be hydrogen or methyl independently of one another;
Described halogen is fluorine or chlorine.
7. compound according to claim 1, it is characterized in that, described compound is to be selected from following a kind of or its enantiomer, diastereomer, racemic modification, pharmacy acceptable salt, crystalline hydrate or solvate
8. a method of preparing compound described in claim 1～7 any one, is characterized in that, comprises the following steps:
Make compound shown in compound shown in formula 1a and formula 2a carry out condensation, so that compound shown in the formula of acquisition 3a;
Make compound generation ring-closure reaction described in described formula 3a, so that compound shown in the formula of acquisition 4a;
Make compound generation reductive amination process shown in compound shown in described formula 4a and formula 5a, so that compound shown in the formula of acquisition 6a;
Make compound shown in described formula 6a and diethyl malonate generation condensation reaction, so that compound shown in the formula of acquisition 7a;
Make the hydrolysis reaction of compound generation shown in described formula 7a, so that compound shown in the formula of acquisition 8a; And
Based on following one of at least, shown in described formula 8a, compound obtains compound shown in described formula I:
Make compound shown in described formula 8a and amino acid ester or propanedioic acid methyl esters monopotassium salt generation condensation reaction, and described condensation reaction products is hydrolyzed under alkaline condition, so that compound shown in the formula of acquisition I,
Wherein,
R
1～R
3for as defined in claim 1～7 any one.
9. a pharmaceutical composition, is characterized in that, comprising:
Compound described in claim 1～7 any one; And
Acceptable vehicle pharmaceutically,
Optionally described pharmaceutical composition is for being used for the treatment of or preventing thromboxane receptor relative disease, or is used for the treatment of or prevents thrombosis and/or hypertension.
10. the purposes of the compound described in claim 1～7 any one in preparing medicine, wherein, described medicine is used for the treatment of or prevents thromboxane receptor relative disease, or is used for the treatment of or prevents thrombosis and/or hypertension.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1043703A (en) * | 1988-12-22 | 1990-07-11 | 田边制药株式会社 | The method for preparing indan derivative |
| US5030652A (en) * | 1987-11-18 | 1991-07-09 | Tanabe Seiyaku Co., Ltd. | Indan derivatives and pharmaceutical preparation thereof |
| US5093356A (en) * | 1990-01-16 | 1992-03-03 | Merck Frosst Canada, Inc. | Indenyl hydroxamic acids and hydroxy ureas as inhibitors of 5-lipoxygenase |
| JPH0469335A (en) * | 1990-07-09 | 1992-03-04 | Tanabe Seiyaku Co Ltd | Thromboxan a2 antagonist |
| EP0589037B1 (en) * | 1991-03-01 | 1996-05-29 | Zeria Pharmaceutical Co., Ltd. | Indian derivative and thromboxane antagonist containing the same |
-
2013
- 2013-10-11 CN CN201310476325.2A patent/CN103539709B/en not_active Expired - Fee Related
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5030652A (en) * | 1987-11-18 | 1991-07-09 | Tanabe Seiyaku Co., Ltd. | Indan derivatives and pharmaceutical preparation thereof |
| CN1043703A (en) * | 1988-12-22 | 1990-07-11 | 田边制药株式会社 | The method for preparing indan derivative |
| US5093356A (en) * | 1990-01-16 | 1992-03-03 | Merck Frosst Canada, Inc. | Indenyl hydroxamic acids and hydroxy ureas as inhibitors of 5-lipoxygenase |
| JPH0469335A (en) * | 1990-07-09 | 1992-03-04 | Tanabe Seiyaku Co Ltd | Thromboxan a2 antagonist |
| EP0589037B1 (en) * | 1991-03-01 | 1996-05-29 | Zeria Pharmaceutical Co., Ltd. | Indian derivative and thromboxane antagonist containing the same |
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