CN101386617A - Substituted tetrahydroisoquinoline derivatives, their preparation methods and pharmaceutical compositions containing them - Google Patents
Substituted tetrahydroisoquinoline derivatives, their preparation methods and pharmaceutical compositions containing them Download PDFInfo
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- CN101386617A CN101386617A CNA2008101550766A CN200810155076A CN101386617A CN 101386617 A CN101386617 A CN 101386617A CN A2008101550766 A CNA2008101550766 A CN A2008101550766A CN 200810155076 A CN200810155076 A CN 200810155076A CN 101386617 A CN101386617 A CN 101386617A
- Authority
- CN
- China
- Prior art keywords
- tetrahydroisoquinoline
- sulfonyl
- amino
- preparation
- carbonyl
- 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.)
- Granted
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 124
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 5
- 125000003039 tetrahydroisoquinolinyl group Chemical class C1(NCCC2=CC=CC=C12)* 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 16
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 76
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 70
- BQMPGKPTOHKYHS-UHFFFAOYSA-N pyrrole-2-carbonitrile Natural products N#CC1=CC=CN1 BQMPGKPTOHKYHS-UHFFFAOYSA-N 0.000 claims description 30
- -1 6-xylyl Chemical group 0.000 claims description 19
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 claims description 6
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 6
- 125000000623 heterocyclic group Chemical group 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 238000000034 method Methods 0.000 claims description 3
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 3
- 125000003107 substituted aryl group Chemical group 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 3
- 230000003178 anti-diabetic effect Effects 0.000 abstract 1
- 230000000144 pharmacologic effect Effects 0.000 abstract 1
- 239000007787 solid Substances 0.000 description 66
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 33
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 27
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 239000000243 solution Substances 0.000 description 14
- 239000000203 mixture Substances 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 239000008280 blood Substances 0.000 description 12
- 210000004369 blood Anatomy 0.000 description 12
- 239000012043 crude product Substances 0.000 description 12
- 206010012601 diabetes mellitus Diseases 0.000 description 12
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 11
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- 239000001257 hydrogen Substances 0.000 description 10
- 229910052739 hydrogen Inorganic materials 0.000 description 10
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 10
- IYRMNDOLPONSCJ-UHFFFAOYSA-N isoquinolin-2-ium;chloride Chemical compound Cl.C1=NC=CC2=CC=CC=C21 IYRMNDOLPONSCJ-UHFFFAOYSA-N 0.000 description 10
- MFPWEWYKQYMWRO-UHFFFAOYSA-N tert-butyl carboxy carbonate Chemical compound CC(C)(C)OC(=O)OC(O)=O MFPWEWYKQYMWRO-UHFFFAOYSA-N 0.000 description 10
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
- 239000008103 glucose Substances 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 239000003472 antidiabetic agent Substances 0.000 description 6
- 230000037396 body weight Effects 0.000 description 6
- 230000002218 hypoglycaemic effect Effects 0.000 description 6
- 235000002639 sodium chloride Nutrition 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
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- 239000007924 injection Substances 0.000 description 4
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 230000001684 chronic effect Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
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- QGJUIPDUBHWZPV-SGTAVMJGSA-N saxagliptin Chemical compound C1C(C2)CC(C3)CC2(O)CC13[C@H](N)C(=O)N1[C@H](C#N)C[C@@H]2C[C@@H]21 QGJUIPDUBHWZPV-SGTAVMJGSA-N 0.000 description 3
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- KUZFXJLUTSELPP-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CC2=CC(=CC=C2CC1C(=O)O)S(=O)(=O)NCCCC Chemical compound C(C)(C)(C)OC(=O)N1CC2=CC(=CC=C2CC1C(=O)O)S(=O)(=O)NCCCC KUZFXJLUTSELPP-UHFFFAOYSA-N 0.000 description 2
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- URWXRTMWAMVVRD-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CC2=CC(=CC=C2CC1C(=O)O)S(=O)(=O)NCCOC Chemical compound C(C)(C)(C)OC(=O)N1CC2=CC(=CC=C2CC1C(=O)O)S(=O)(=O)NCCOC URWXRTMWAMVVRD-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 238000012449 Kunming mouse Methods 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 206010068676 Pneumoretroperitoneum Diseases 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- 208000005727 Retropneumoperitoneum Diseases 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 229940127003 anti-diabetic drug Drugs 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
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- 239000003651 drinking water Substances 0.000 description 2
- 235000020188 drinking water Nutrition 0.000 description 2
- 238000003810 ethyl acetate extraction Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 230000003914 insulin secretion Effects 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000463 material Substances 0.000 description 2
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- 239000011734 sodium Substances 0.000 description 2
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- XTHPWXDJESJLNJ-UHFFFAOYSA-N sulfurochloridic acid Chemical compound OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 150000003526 tetrahydroisoquinolines Chemical class 0.000 description 2
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 2
- BWKMGYQJPOAASG-VIFPVBQESA-N (3s)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid Chemical compound C1=CC=C2CN[C@H](C(=O)O)CC2=C1 BWKMGYQJPOAASG-VIFPVBQESA-N 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
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- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
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- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及医药领域，公开了一组通式为(I)的新的磺酰胺取代的四氢异喹啉衍生物，并公开了其制备方法、含有它们的药物组合物。药理学试验显示，通式(I)化合物具有优良的抗糖尿病作用。
The invention relates to the field of medicine, and discloses a group of novel sulfonamide-substituted tetrahydroisoquinoline derivatives with the general formula (I), a preparation method thereof and a pharmaceutical composition containing them. Pharmacological tests show that the compound of general formula (I) has excellent antidiabetic effect.
Description
Technical field
The present invention relates to the tetrahydro isoquinoline derivative of sulfonamide substitutions, their synthetic method contains their pharmaceutical composition.
Background technology
Diabetes especially diabetes B are the Chronic Non-Communicable Diseasess of the third-largest serious threat human health after tumour, cardiovascular disorder.At present, the whole world has 200,000,000 diabetic subjects approximately, expects 2025 and will increase to 300,000,000.2007, in state-owned 4,000 ten thousand diabetic subjects, be only second to the India that 4,090 ten thousand diabeticss are arranged and occupy second in the whole world, expect 2025, China diabetic subject number will break through 6,000 ten thousand, and wherein diabetes B accounts for more than 90% of diabetic subject's total number of persons.
Diabetes are that Regular Insulin is absolute or lack, and cause a kind of common metabolic disease of metabolism obstacle such as carbohydrate metabolism disturbance, secondary fat, protein, water, salt and multiple acute and chronic complication relatively.The diabetes cause of disease is very complicated, often with vascular complications such as platelet aggregation increase, artery hyperlipemia, myocardial infarction, cerebrovascular disorders.Diabetes only have 1-4% as direct cause of death in the patient, the overwhelming majority dies from chronic complicating diseases.Remedies for diabetes has been obtained bigger development in recent years, goes on the market in succession as new drugs such as sulfonylurea hypoglycemic agent, peroxidase vegetation activated receptor agonist, insulin secretion stimulators efficiently, makes the diabetes treatment of diseases that more selection be arranged.Though existing antidiabetic drug can promote insulin secretion, lowering blood glucose, but mostly exist cause the hypoglycemia side effect, strong to insulin-sensitizing effect, to shortcomings such as the cardiovascular complication therapeutic action are relatively poor, it is significant therefore to develop efficient ideal antidiabetic drug.
Summary of the invention
The object of the present invention is to provide the novel hypoglycemic drug of a class.
The present invention also aims to provide a kind of preparation method of synthetic such hypoglycemic drug.
Another object of the present invention is to provide a kind of pharmaceutical preparation that contains the type hypoglycemic drug.
Summary of the invention is as follows in detail:
The present invention has synthesized a series of general formulas (I) compound:
SO wherein
2NHR
1The position is 5 on the female ring of tetrahydroisoquinoline, 6, and 7,8;
R wherein
1Representative: alkyl, substituted alkyl, aryl, aralkyl, substituted aryl, substituted aralkyl, heterocycle, substituted heterocycle;
Preferred compound is:
(s)-3-{1-[(s)-and 2-cyanopyrrole alkyl] carbonyl }-7-[N-(4-fluorophenyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (I
1);
(s)-3-{1-[(s)-and 2-cyanopyrrole alkyl] carbonyl }-7-[N-(2, the 6-xylyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (I
2);
(s)-3-{1-[(s)-and 2-cyanopyrrole alkyl] carbonyl }-7-{N-[4-(1, the 1-dimethyl ethyl) phenyl] amino-sulfonyl }-1,2,3,4-tetrahydroisoquinoline (I
3);
(s)-3-{1-[(s)-and 2-cyanopyrrole alkyl] carbonyl }-7-(N-benzylamino alkylsulfonyl)-1,2,3,4-tetrahydroisoquinoline (I
4);
(s)-3-{1-[(s)-and 2-cyanopyrrole alkyl] carbonyl }-7-[N-(2-phenylethyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (I
5);
(s)-3-{1-[(s)-and 2-cyanopyrrole alkyl] carbonyl }-7-(N-normal-butyl amino-sulfonyl)-1,2,3,4-tetrahydroisoquinoline (I
6);
(s)-3-{1-[(s)-and 2-cyanopyrrole alkyl] carbonyl }-7-[N-(1-methylethyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (I
7);
(s)-3-{1-[(s)-and 2-cyanopyrrole alkyl] carbonyl }-7-(N-methylamino alkylsulfonyl)-1,2,3,4-tetrahydroisoquinoline (I
8);
(s)-3-{1-[(s)-and 2-cyanopyrrole alkyl] carbonyl }-7-[N-(2-methoxy ethyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (I
9);
(s)-3-{1-[(s)-and 2-cyanopyrrole alkyl] carbonyl }-7-[N-(2-hydroxyethyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (I
10).
The structural formula that it is corresponding:
R
1
I
1 
I
2 
I
3 
I
4 
I
5
I
6 CH
3CH
2CH
2CH
2
I
7 (CH
3)
2CH
I
8 CH
3-
I
9 CH
3OCH
2CH
2
I
10 HOCH
2CH
2
According to the present invention, pharmacy acceptable salt comprises the additive salt that forms with following acid: hydrochloric acid, Hydrogen bromide, sulfuric acid, citric acid, tartrate, phosphoric acid, lactic acid, pyruvic acid, acetate, trifluoroacetic acid, toxilic acid, Phenylsulfonic acid.
General formula I
1-10Compounds process for production thereof is as follows: with 3-(s)-carboxyl-1,2, and 3,4-tetrahydroisoquinoline and chloroacetyl chloride reaction generate intermediate (IX), again with methanol esterification, obtain intermediate (VIII), obtain (VII) with the chlorsulfonic acid reaction again, with corresponding amine reaction, obtain intermediate (VI) then, hydrolysis in aqueous sodium hydroxide solution again, obtain intermediate (V), with uncle's fourth oxygen anhydride reaction, obtain (IV) again, then with 2-(s)-formamido--2,3,4, the condensation of 5-Pyrrolidine, obtain intermediate (III), with the trifluoroacetic anhydride (TFAA) reaction, obtain intermediate (II) again, last and trifluoracetic acid reaction generates purpose compound (I
1-10).Route is as follows:
Below be the pharmacology test data of part of compounds of the present invention:
(1) hypoglycemic activity test in the chemical combination object
Get 10 age in week kunming mice, body weight 18 ~ 22g, male and female half and half are divided into three groups at random by body weight: blank group, positive controls and be subjected to reagent thing group, 10 every group.Drinking-water is normal, overnight fasting.Blood is got in docking, the mensuration blood glucose value (be designated as-0.5h).Three groups of mouse are irritated stomach respectively and give 0.5%CMC-Na (10 μ mol/Kg), Saxagliptin (10 μ mol/Kg) and test-compound (10 μ mol/Kg) then, the glucose solution of 30min pneumoretroperitoneum injection 18mmol/Kg, and in 0,0.25,0.5,1,2h measures blood glucose value with blood glucose meter.
As shown in table 1, I
1, I
5, I
6, I
7, I
8And I
10Hypoglycemic activity is in various degree all arranged, wherein I
7And I
10Hypoglycemic activity be better than positive control drug Saxagliptin.
Hypoglycemic activity test-results in the table 1. normal mouse body (n=10, mean ± SEM)
*P<0.05，**P<0.01，***P<0.001 vs saline
(2) the intravital repeatedly hypoglycemic activity test of active compound
Get 10 age in week kunming mice, body weight 18 ~ 22g, male and female half and half are divided into three groups at random by body weight: blank group, positive controls and be subjected to reagent thing group, 10 every group.Drinking-water is normal, overnight fasting.Irritate stomach respectively and give 0.5%CMC-Na (20 μ mol/Kg), Saxagliptin (20 μ mol/Kg) and test-compound (20 μ mol/Kg), the glucose solution of 30min pneumoretroperitoneum injection 18mmol/Kg, and in 0,0.25,0.5,1, blood is got in the 2h docking, monitors blood sugar with blood glucose meter.In 4h measured respectively organize blood sugar after, the glucose solution of abdominal injection 18mmol/Kg immediately, and in after this 0,0.25,0.5,1,2h monitors blood sugar.
This test is by repeatedly high sugar stimulation, and having observed has the blood sugar reducing function of six compounds of hypoglycemic activity at mouse internal metabolism 6h in the test (), as shown in table 2, and interior six compounds of 6h all have blood sugar reducing function in various degree, the results are shown in Table 2.
Table 2. normal mouse is the hypoglycemic activity test-results repeatedly.(n＝10，mean±SEM)
| Time | control | Saxa | I 1 | I 5 | I 6 | I 7 | I 8 | I 10 |
| 0h | 7.50± 0.50 | 7.38± 0.78 | 7.05± 0.59 | 7.85± 0.52 | 7.22± 1.14 | 6.83± 0.86 | 6.77± 0.90 | 7.18± 0.85 |
| 0.25h | 23.27± 0.83 | 22.72± 1.16 | 21.03± 2.66 | 22.35± 1.19 | 21.65± 1.82 | 23.37± 1.96 | 21.43± 2.15 | 23.05± 2.85 |
| 0.5h | 18.73± | 14.23± | 13.92± | 12.80± | 13.47± | 14.23± | 13.92± | 13.47± |
| 0.62 | 2.39** | 2.52** | 2.35*** | 2.10*** | 2.21*** | 2.64** | 1.45*** | |
| 1h | 10.75± 2.44 | 8.48± 0.84 | 8.30± 0.49* | 7.82± 1.02* | 7.62± 0.60* | 8.37± 1.47 | 9.02± 1.11 | 8.43± 1.92 |
| 2h | 7.68± 1.00 | 7.20± 0.69 | 6.80± 0.87 | 6.60± 0.64* | 6.42± 0.48* | 6.23± 1.00* | 6.63± 1.22 | 7.03± 1.14 |
| 4h | 6.30± 0.69 | 6.78± 0.71 | 5.90± 0.70 | 5.75± 0.80 | 5.83± 0.37 | 5.27± 0.85* | 5.92± 1.09 | 6.17± 1.28 |
| 4.25h | 26.6± 2.12 | 25.82± 2.56 | 23.87± 2.50 | 26.55± 1.26 | 23.97± 2.15 | 26.03± 1.44 | 22.77± 2.16* | 21.85± 2.97** |
| 4.5 | 19.27± 1.36 | 15.42± 2.36** | 14.82± 2.64** | 13.88± 2.06*** | 14.80± 2.13** | 14.43± 2.36** | 15.78± 2.38* | 17.25± 2.01 |
| 5h | 9.35± 0.59 | 8.55± 0.88 | 8.13± 1.04* | 8.17± 0.76* | 7.80± 1.02** | 7.95± 1.55 | 7.70± 1.83 | 8.18± 1.89 |
| 6h | 7.63± 0.94 | 7.12± 0.89 | 6.42± 1.06 | 6.60± 0.92 | 6.73± 0.61 | 6.10± 0.94* | 6.60± 1.10 | 6.78± 1.33 |
*P<0.05，**P<0.01，***P<0.001 vs sal ine
The present invention also comprises pharmaceutical preparation, and said preparation comprises general formula (I) compound and the pharmaceutically acceptable carrier as promoting agent.Pharmaceutically acceptable carrier is meant one or more inert, atoxic solid or liquid filler material, thinner, auxiliary agent etc., and they are not reverse to have an effect with active compound or patient.
The formulation of the present composition can be a formulation commonly used on the pharmaceuticies such as tablet, capsule, pill, suppository, soft capsule, oral liquid, suspensoid, injection liquid.
Tablet for oral use and capsule contain traditional vehicle such as weighting material, thinner, lubricant, dispersion agent and tackiness agent, can be prepared according to the method for knowing in this area.
The dosage of above promoting agent will be different because of prescription.
Usually, proved favourable amount, for reaching required result, the total amount of formula (I) compound of every kg body weight administration in per 24 hours is about 0.01-100mg, the preferred about 0.1-50mg/kg of total amount.If necessary, with the form administration of single dose several times.Yet, if necessary, also can depart from above-mentioned consumption, promptly this depends on experimenter's to be treated type and body weight, individual behavior to medicine, the character of disease and type and the administration time or the interval of seriousness, preparation and administration.
By the following examples the present invention is further described.
Embodiment
Embodiment 1
(s)-and 2-ethanoyl-3-carboxyl-1,2,3, the preparation of 4-tetrahydroisoquinoline (IX):
(s)-3-carboxyl-1,2,3,4-tetrahydroisoquinoline 10g (0.047mol) mixes with 100ml acetone, 40ml aqueous sodium hydroxide solution (2mol/L), under the room temperature, drip the aqueous sodium hydroxide solution of 8.01ml Acetyl Chloride 98Min. (0.094mol) and 2mol/L simultaneously, after dropwising, the pH value that keeps reaction solution continues to stir 2 hours greater than 9.Boil off most of solvent, with the dilute hydrochloric acid acidifying residual solution of 3mol/L, white solid is separated out in cooling, filters washing, drying, the heavy 9.1g (88.4%) of crude product, fusing point 170-171 ℃ (document 171-173 ℃).
Embodiment 2
(s)-and 2-ethanoyl-3-methyl-formiate base-1,2,3, the preparation of 4-tetrahydroisoquinoline (VIII):
Under 0 ℃, sulfur oxychloride 4.05ml (0.057mol) is dropped in the 30ml anhydrous methanol, after dropwising, stirring at room 2 hours.With (s)-2-ethanoyl-3-carboxyl-1,2,3; 4-tetrahydroisoquinoline 5.0g (0.023mol) adds in the above-mentioned reaction solution; heating reflux reaction 3 hours boils off solvent, adds acetic acid ethyl dissolution; be washed to neutrality with saturated sodium bicarbonate, saturated common salt respectively; anhydrous sodium sulfate drying boils off solvent, drying; get light yellow solid, the heavy 5.04g (94.1%) of crude product.
Embodiment 3
(s)-and 2-ethanoyl-3-methyl-formiate base-7-chlorosulfonyl-1,2,3, the preparation of 4-tetrahydroisoquinoline (VII):
Under-5 ℃, with (s)-2-ethanoyl-3-methyl-formiate base-1,2,3,4-tetrahydroisoquinoline 5.0g (0.021mol) adds in the 15ml chlorsulfonic acid in batches, behind reinforced the finishing, and stirred overnight at room temperature.In a large amount of trash ices of reaction solution impouring, stir, filter, get white solid 12g (weight in wet base), be directly used in the next step.
Embodiment 4
(s)-and 2-ethanoyl-3-methyl-formiate base-7-[N-(4-fluorophenyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (VI
1) preparation:
With 12g weight in wet base (s)-2-ethanoyl-3-methyl-formiate base-7-chlorosulfonyl-1,2,3; the 4-tetrahydroisoquinoline is dissolved in 50ml acetone and the 30ml saturated sodium bicarbonate, adds para-fluoroaniline 3.98ml (0.042mol), stirred overnight at room temperature; boil off solvent; after the cooling, with the dissolving of 2mol/L aqueous sodium hydroxide solution, ethyl acetate extraction 2 times; the gained water layer is with the concentrated hydrochloric acid acidifying; filter, drying gets beige solid crude product 2.32g (27.2%).
(s)-and 2-ethanoyl-3-methyl-formiate base-7-[N-(2, the 6-xylyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (VI
2) preparation:
With 12g weight in wet base (s)-2-ethanoyl-3-methyl-formiate base-7-chlorosulfonyl-1,2,3, the 4-tetrahydroisoquinoline is dissolved in 50ml acetone and the 30ml saturated sodium bicarbonate, adds 2, and 6-xylidine 5.18ml (0.042mol) presses VI
1The preparation method, beige solid crude product 2.75g (31.5%).
(s)-and 2-ethanoyl-3-methyl-formiate base-7-{N-[4-(1, the 1-dimethyl ethyl) phenyl] amino-sulfonyl }-1,2,3,4-tetrahydroisoquinoline (VI
3) preparation:
With 12g weight in wet base (s)-2-ethanoyl-3-methyl-formiate base-7-chlorosulfonyl-1,2,3, the 4-tetrahydroisoquinoline is dissolved in 50ml acetone and the 30ml saturated sodium bicarbonate, adds 4-(1, the 1-dimethyl ethyl) aniline 6.68ml (0.042mol), presses VI
1The preparation method, beige solid crude product 2.02g (21.7%).
(s)-and 2-ethanoyl-3-methyl-formiate base-7-(N-benzylamino alkylsulfonyl)-1,2,3,4-tetrahydroisoquinoline (VI
4) preparation:
With 12g weight in wet base (s)-2-ethanoyl-3-methyl-formiate base-7-chlorosulfonyl-1,2,3, the 4-tetrahydroisoquinoline is dissolved in 50ml acetone and the 30ml saturated sodium bicarbonate, adds benzylamine 4.57ml (0.042mol), presses VI
1The preparation method, beige solid crude product 2.70g (32.0%).
(s)-and 2-ethanoyl-3-methyl-formiate base-7-[N-(2-phenylethyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (VI
5) preparation:
With 12g weight in wet base (s)-2-ethanoyl-3-methyl-formiate base-7-chlorosulfonyl-1,2,3, the 4-tetrahydroisoquinoline is dissolved in 50ml acetone and the 30ml saturated sodium bicarbonate, adds phenylethylamine 5.27ml (0.042mol), presses VI
1The preparation method, beige solid crude product 2.69g (30.8%).
(s)-and 2-ethanoyl-3-methyl-formiate base-7-(N-normal-butyl amino-sulfonyl)-1,2,3,4-tetrahydroisoquinoline (VI
6) preparation:
With 12g weight in wet base (s)-2-ethanoyl-3-methyl-formiate base-7-chlorosulfonyl-1,2,3, the 4-tetrahydroisoquinoline is dissolved in 50ml acetone and the 30ml saturated sodium bicarbonate, adds n-Butyl Amine 99 4.18ml (0.042mol), presses VI
1The preparation method, beige solid crude product 1.72g (22.2%).
(s)-and 2-ethanoyl-3-methyl-formiate base-7-[N-(1-methylethyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (VI
7) preparation:
With 12g weight in wet base (s)-2-ethanoyl-3-methyl-formiate base-7-chlorosulfonyl-1,2,3, the 4-tetrahydroisoquinoline is dissolved in 50ml acetone and the 30ml saturated sodium bicarbonate, adds 2-methyl ethyl-amine 3.60ml (0.042mol), presses VI
1The preparation method, beige solid crude product 1.90g (25.6%).
(s)-and 2-ethanoyl-3-methyl-formiate base-7-(N-methylamino alkylsulfonyl)-1,2,3,4-tetrahydroisoquinoline (VI
8) preparation:
With 12g weight in wet base (s)-2-ethanoyl-3-methyl-formiate base-7-chlorosulfonyl-1,2,3, the 4-tetrahydroisoquinoline is dissolved in 50ml acetone and the 30ml saturated sodium bicarbonate, adds 40% aqueous methylamine solution 5.40ml (0.063mol), presses VI
1The preparation method, beige solid crude product 0.92g (13.4%).
(s)-and 2-ethanoyl-3-methyl-formiate base-7-[N-(2-methoxy ethyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (VI
9) preparation:
With 12g weight in wet base (s)-2-ethanoyl-3-methyl-formiate base-7-chlorosulfonyl-1,2,3, the 4-tetrahydroisoquinoline is dissolved in 50ml acetone and the 30ml saturated sodium bicarbonate, adds 2-methoxyethyl amine 5.40ml (0.042mol), presses VI
1The preparation method, beige solid crude product 0.92g (13.4%).
(s)-and 2-ethanoyl-3-methyl-formiate base-7-[N-(2-hydroxyethyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (VI
10) preparation:
With 12g weight in wet base (s)-2-ethanoyl-3-methyl-formiate base-7-chlorosulfonyl-1,2,3, the 4-tetrahydroisoquinoline is dissolved in 50ml acetone and the 30ml saturated sodium bicarbonate, adds 2 hydroxy ethylamine 5.40ml (0.042mol), presses VI
1The preparation method, beige solid crude product 0.92g (13.4%).
Embodiment 5
(s)-and 3-carboxyl-7-[N-(4-fluorophenyl) amino-sulfonyl]-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt (V
1) preparation:
(s)-and 2-ethanoyl-3-methyl-formiate base-7-[N-(4-fluorophenyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (VI
1) 1.2g (0.003mol), to mix with the concentrated hydrochloric acid 10ml of 6mol/L, reflux is spent the night, and evaporate to dryness gets solid 0.98g (93.3%).Be directly used in the next step.
(s)-and 3-carboxyl-7-[N-(2, the 6-xylyl) amino-sulfonyl]-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt (V
2) preparation:
(s)-and 2-ethanoyl-3-methyl-formiate base-7-[N-(2, the 6-xylyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (VI
2) 1.25g (0.003mol), mix with the concentrated hydrochloric acid 10ml of 6mol/L, press V
1The preparation method, solid 0.97g (89.8%).Be directly used in the next step.
(s)-and 3-carboxyl-7-{N-[4-(1, the 1-dimethyl ethyl) phenyl] amino-sulfonyl }-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt (V
3) preparation:
(s)-and 2-ethanoyl-3-methyl-formiate base-7-{N-[4-(1, the 1-dimethyl ethyl) phenyl] amino-sulfonyl }-1,2,3,4-tetrahydroisoquinoline (VI
3) 1.33g (0.003mol), mix with the concentrated hydrochloric acid 10ml of 6mol/L, press V
1The preparation method, solid 1.13g (97.1%).Be directly used in the next step.
(s)-and 3-carboxyl-7-(N-benzylamino alkylsulfonyl)-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt (V
4) preparation:
(s)-and 2-ethanoyl-3-methyl-formiate base-7-(N-benzylamino alkylsulfonyl)-1,2,3,4-tetrahydroisoquinoline (VI
4) 1.20g (0.003mol), mix with the concentrated hydrochloric acid 10ml of 6mol/L, press V
1The preparation method, solid 0..97g (93.4%).Be directly used in the next step.
(s)-and 3-carboxyl-7-[N-(2-phenylethyl) amino-sulfonyl]-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt (V
5) preparation:
(s)-and 2-ethanoyl-3-methyl-formiate base-7-[N-(2-phenylethyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (VI
5) 1.25g (0.003mol), mix with the concentrated hydrochloric acid 10ml of 6mol/L, press V
1The preparation method, solid 1.02g (97.1%).Be directly used in the next step.
(s)-and 3-carboxyl-7-(N-normal-butyl amino-sulfonyl)-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt (V
6) preparation:
(s)-and 2-ethanoyl-3-methyl-formiate base-7-(N-normal-butyl amino-sulfonyl)-1,2,3,4-tetrahydroisoquinoline (VI
6) 1.11g (0.003mol), mix with the concentrated hydrochloric acid 10ml of 6mol/L, press V
1The preparation method, solid 0.91g (96.6%).Be directly used in the next step.
(s)-and 3-carboxyl-7-[N-(1-methylethyl) amino-sulfonyl]-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt (V
7) preparation:
(s)-and 2-ethanoyl-3-methyl-formiate base-7-[N-(2-methylethyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (VI
7) 1.06g (0.003mol), mix with the concentrated hydrochloric acid 10ml of 6mol/L, press V
1The preparation method, solid 0.85g (95.2%).Be directly used in the next step.
(s)-and 3-carboxyl-7-(N-methylamino alkylsulfonyl)-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt (V
8) preparation:
(s)-and 2-ethanoyl-3-methyl-formiate base-7-(N-methylamino alkylsulfonyl)-1,2,3,4-tetrahydroisoquinoline (VI
8) 0.98g (0.003mol), mix with the concentrated hydrochloric acid 10ml of 6mol/L, press V
1The preparation method, solid 0.79g (96.8%).Be directly used in the next step.
(s)-and 3-carboxyl-7-[N-(2-methoxy ethyl) amino-sulfonyl]-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt (V
9) preparation:
(s)-and 2-ethanoyl-3-methyl-formiate base-7-[N-(2-methoxy ethyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (VI
9) 1.11g (0.003mol), mix with the concentrated hydrochloric acid 10ml of 6mol/L, press V
1The preparation method, solid 0.93g (97.9%).Be directly used in the next step.
(s)-and 3-carboxyl-7-[N-(2-hydroxyethyl) amino-sulfonyl]-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt (V
10) preparation:
(s)-and 2-ethanoyl-3-methyl-formiate base-7-[N-(2-hydroxyethyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (VI
10) 1.07g (0.003mol), mix with the concentrated hydrochloric acid 10ml of 6mol/L, press V
1The preparation method, solid 0.87g (95.8%).Be directly used in the next step.
Embodiment 6
(s)-and 2-(tertbutyloxycarbonyl)-3-carboxyl-7-[N-(4-fluorophenyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (IV
1) preparation:
(s)-and 3-carboxyl-7-[N-(4-fluorophenyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (V
1) 1.05g (0.003mol), be dissolved in 5ml concentration under the room temperature and be 10% aqueous sodium hydroxide solution, add tert-Butyl dicarbonate 0.91g (0.0042mol), stirred overnight at room temperature, with ethyl acetate extraction 2 times, water layer filters with the dilute hydrochloric acid acidifying of 1mol/L, drying gets khaki color solid 1.17g (86.5%).
(s)-and 2-(tertbutyloxycarbonyl)-3-carboxyl-7-[N-(2, the 6-xylyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (IV
2) preparation:
(s)-and 3-carboxyl-7-[N-(2, the 6-xylyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (V
2) 1.08g (0.003mol) and tert-Butyl dicarbonate 0.91g (0.0042mol), press IV
1The preparation method, khaki color solid 1.16g (83.9%).
(s)-and 2-(tertbutyloxycarbonyl)-3-carboxyl-7-{N-[4-(1, the 1-dimethyl ethyl) phenyl] amino-sulfonyl }-1,2,3,4-tetrahydroisoquinoline (IV
3) preparation:
(s)-and 3-carboxyl-7-{N-[4-(1, the 1-dimethyl ethyl) phenyl] amino-sulfonyl }-1,2,3,4-tetrahydroisoquinoline (V
3) 1.16g (0.003mol) and tert-Butyl dicarbonate 0.91g (0.0042mol), press IV
1The preparation method, khaki color solid 1.18g (80.3%).
(s)-and 2-(tertbutyloxycarbonyl)-3-carboxyl-7-(N-benzylamino alkylsulfonyl)-1,2,3,4-tetrahydroisoquinoline (IV
4) preparation:
(s)-and 3-carboxyl-7-(N-benzylamino alkylsulfonyl)-1,2,3,4-tetrahydroisoquinoline (V
4) 1.04g (0.003mol) and tert-Butyl dicarbonate 0.91g (0.0042mol), press IV
1The preparation method, khaki color solid 1.07g (79.8%).
(s)-and 2-(tertbutyloxycarbonyl)-3-carboxyl-7-[N-(2-phenylethyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (IV
5) preparation:
(s)-and 3-carboxyl-7-[N-(2-phenylethyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (V
5) 1.08g (0.003mol) and tert-Butyl dicarbonate 0.91g (0.0042mol), press IV
1The preparation method, khaki color solid 1.17g (84.5%).
(s)-and 2-(tertbutyloxycarbonyl)-3-carboxyl-7-(N-normal-butyl amino-sulfonyl)-1,2,3,4-tetrahydroisoquinoline (IV
6) preparation:
(s)-and 3-carboxyl-7-(N-normal-butyl amino-sulfonyl)-1,2,3,4-tetrahydroisoquinoline (V
6) 0.94g (0.003mol) and tert-Butyl dicarbonate 0.91g (0.0042mol), press IV
1The preparation method, khaki color solid 0.97g (78.3%).
(s)-and 2-(tertbutyloxycarbonyl)-3-carboxyl-7-[N-(1-methylethyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (IV
7) preparation:
(s)-and 3-carboxyl-7-[N-(2-methylethyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (V
7) 0.90g (0.003mol) and tert-Butyl dicarbonate 0.91g (0.0042mol), press IV
1The preparation method, khaki color solid 0.90g (75.3%).
(s)-and 2-(tertbutyloxycarbonyl)-3-carboxyl-7-(N-methylamino alkylsulfonyl)-1,2,3,4-tetrahydroisoquinoline (IV
8) preparation:
(s)-and 3-carboxyl-7-(N-methylamino alkylsulfonyl)-1,2,3,4-tetrahydroisoquinoline (V
8) 0.81g (0.003mol) and tert-Butyl dicarbonate 0.91g (0.0042mol), press IV
1The preparation method, khaki color solid 0.82g (73.8%).
(s)-and 2-(tertbutyloxycarbonyl)-3-carboxyl-7-[N-(2-methoxy ethyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (IV
9) preparation:
(s)-and 3-carboxyl-7-[N-(2-methoxy ethyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (V
9) 0.95g (0.003mol) and tert-Butyl dicarbonate 0.91g (0.0042mol), press IV
1The preparation method, khaki color solid 0.98g (78.8%).
(s)-and 2-(tertbutyloxycarbonyl)-3-carboxyl-7-[N-(2-hydroxyethyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (IV
10) preparation:
(s)-and 3-carboxyl-7-[N-(2-hydroxyethyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (V
10) 0.90g (0.003mol) and tert-Butyl dicarbonate 0.91g (0.0042mol), press IV
1The preparation method, khaki color solid 0.87g (72.6%).
Embodiment 7
(s)-and 2-(tertbutyloxycarbonyl)-3-{1-[(s)-2-formamido group pyrrolidyl] carbonyl }-7-[N-(4-fluorophenyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (III
1) preparation:
(s)-and 2-(tertbutyloxycarbonyl)-3-carboxyl-7-[N-(4-fluorophenyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (IV
1) 0.9g (0.002mol), mix with 15ml exsiccant methylene dichloride, under condition of ice bath, add 2-[1-(1H)-benzotriazole base successively]-1,1,3,3-tetramethyl-urea hexafluorophosphate (HBTU) 0.76g (0.002mol), (s)-2-formamido group tetramethyleneimine 0.28g (0.0025mol) and diisopropyl ethyl amine 0.99ml (0.006mol), react after 2 hours, with reaction solution respectively with saturated sodium bicarbonate, saturated aqueous common salt, the dilute hydrochloric acid of 1mol/L and saturated common salt water washing, drying, solvent evaporated, get light yellow solid, column chromatography for separation (chloroform: methyl alcohol=20:1), get white solid 1.02g (93.0%).
(s)-and 2-(tertbutyloxycarbonyl)-3-{1-[(s)-2-formamido group pyrrolidyl] carbonyl }-7-[N-(2, the 6-xylyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (III
2) preparation:
(s)-and 2-(tertbutyloxycarbonyl)-3-carboxyl-7-[N-(2, the 6-xylyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (IV
2) 0.92 (0.002mol), press III
1The preparation method, white solid 1.0g (90.3%).
(s)-and 2-(tertbutyloxycarbonyl)-3-{1-[(s)-2-formamido group pyrrolidyl] carbonyl }-7-{N-[4-(1, the 1-dimethyl ethyl) phenyl] amino-sulfonyl }-1,2,3,4-tetrahydroisoquinoline (III
3) preparation:
(s)-and 2-(tertbutyloxycarbonyl)-3-carboxyl-7-{N-[4-(1, the 1-dimethyl ethyl) phenyl] amino-sulfonyl }-1,2,3,4-tetrahydroisoquinoline (IV
3) 0.98 (0.002mol), press III
1The preparation method, white solid 1.04g (89.3%).
(s)-and 2-(tertbutyloxycarbonyl)-3-{1-[(s)-2-formamido group pyrrolidyl] carbonyl }-7-(N-benzylamino alkylsulfonyl)-1,2,3,4-tetrahydroisoquinoline (III
4) preparation:
(s)-and 2-(tertbutyloxycarbonyl)-3-carboxyl-7-(N-benzylamino alkylsulfonyl)-1,2,3,4-tetrahydroisoquinoline (IV
4) 0.89 (0.002mol), press III
1The preparation method, white solid 0.97g (89.7%).
(s)-and 2-(tertbutyloxycarbonyl)-3-{1-[(s)-2-formamido group pyrrolidyl] carbonyl }-7-[N-(2-phenylethyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (III
5) preparation:
(s)-and 2-(tertbutyloxycarbonyl)-3-carboxyl-7-[N-(2-phenylethyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (IV
5) 0.92 (0.002mol), press III
1The preparation method, white solid 1.03g (92.2%).
(s)-and 2-(tertbutyloxycarbonyl)-3-{1-[(s)-2-formamido group pyrrolidyl] carbonyl }-7-(N-normal-butyl amino-sulfonyl)-1,2,3,4-tetrahydroisoquinoline (III
6) preparation:
(s)-and 2-(tertbutyloxycarbonyl)-3-carboxyl-7-(N-normal-butyl amino-sulfonyl)-1,2,3,4-tetrahydroisoquinoline (IV
6) 0.83 (0.002mol), press III
1The preparation method, white solid 0.90g (88.7%).
(s)-and 2-(tertbutyloxycarbonyl)-3-{1-[(s)-2-formamido group pyrrolidyl] carbonyl }-7-[N-(1-methylethyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (III
7) preparation:
(s)-and 2-(tertbutyloxycarbonyl)-3-carboxyl-7-[N-(2-methylethyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (IV
7) 0.80 (0.002mol), press III
1The preparation method, white solid 0.90g (90.6%).
(s)-and 2-(tertbutyloxycarbonyl)-3-{1-[(s)-2-formamido group pyrrolidyl] carbonyl }-7-(N-methylamino alkylsulfonyl)-1,2,3,4-tetrahydroisoquinoline (III
8) preparation:
(s)-and 2-(tertbutyloxycarbonyl)-3-carboxyl-7-(N-methylamino alkylsulfonyl)-1,2,3,4-tetrahydroisoquinoline (IV
8) 0.74 (0.002mol), press III
1The preparation method, white solid 0.81g (86.8%).
(s)-and 2-(tertbutyloxycarbonyl)-3-{1-[(s)-2-formamido group pyrrolidyl] carbonyl }-7-[N-(2-methoxy ethyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (III
9) preparation:
(s)-and 2-(tertbutyloxycarbonyl)-3-carboxyl-7-[N-(2-methoxy ethyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (IV
9) 0.83 (0.002mol), press III
1The preparation method, white solid 0.92g (89.6%).
(s)-and 2-(tertbutyloxycarbonyl)-3-{1-[(s)-2-formamido group pyrrolidyl] carbonyl }-7-[N-(2-hydroxyethyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (III
10) preparation:
(s)-and 2-(tertbutyloxycarbonyl)-3-carboxyl-7-[N-(2-hydroxyethyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (IV
10) 0.80 (0.002mol), press III
1The preparation method, white solid 0.85g (85.4%).
Embodiment 8
(s)-and 2-(tertbutyloxycarbonyl)-3-{1-[(s)-2-cyanopyrrole alkyl] carbonyl }-7-[N-(4-fluorophenyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (II
1) preparation:
(s)-and 2-(tertbutyloxycarbonyl)-3-{1-[(s)-2-formamido group pyrrolidyl] carbonyl }-7-[N-(4-fluorophenyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (III
1) 1.10g (0.002mol) is dissolved in the 10ml exsiccant tetrahydrofuran (THF), add trifluoroacetic anhydride (TFAA) 0.56ml (0.004mol), stirred 2 hours under the room temperature, solvent evaporated adds the 20ml methylene dichloride, respectively with saturated sodium bicarbonate and saturated common salt water washing, drying, solvent evaporated gets the beige solid, column chromatography for separation (chloroform: methyl alcohol=30:1), get white solid 0.98g (93.0%).MS (ESI, m/z): 529 (M+1, base peaks)
(s)-and 2-(tertbutyloxycarbonyl)-3-{1-[(s)-2-cyanopyrrole alkyl] carbonyl }-7-[N-(2, the 6-xylyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (II
2) preparation:
(s)-and 2-(tertbutyloxycarbonyl)-3-{1-[(s)-2-formamido group pyrrolidyl] carbonyl }-7-[N-(2, the 6-xylyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (III
2) 1.11g (0.002mol), press II
1The preparation method, white solid 1.00g (92.8%).MS (ESI, m/z): 539 (M+1, base peaks)
(s)-and 2-(tertbutyloxycarbonyl)-3-{1-[(s)-2-cyanopyrrole alkyl] carbonyl }-7-{N-[4-(1, the 1-dimethyl ethyl) phenyl] amino-sulfonyl }-1,2,3,4-tetrahydroisoquinoline (II
3) preparation:
(s)-and 2-(tertbutyloxycarbonyl)-3-{1-[(s)-2-formamido group pyrrolidyl] carbonyl }-7-{N-[4-(1, the 1-dimethyl ethyl) phenyl] amino-sulfonyl }-1,2,3,4-tetrahydroisoquinoline (III
3) 1.12g (0.002mol), press II
1The preparation method, white solid 1.02g (90.3%).MS (ESI, m/z): 567 (M+1, base peaks)
(s)-and 2-(tertbutyloxycarbonyl)-3-{1-[(s)-2-cyanopyrrole alkyl] carbonyl }-7-(N-benzylamino alkylsulfonyl)-1,2,3,4-tetrahydroisoquinoline (II
4) preparation:
(s)-and 2-(tertbutyloxycarbonyl)-3-{1-[(s)-2-formamido group pyrrolidyl] carbonyl }-7-(N-benzylamino alkylsulfonyl)-1,2,3,4-tetrahydroisoquinoline (III
4) 1.10g (0.002mol), press II
1The preparation method, white solid 1.00g (94.5%).MS (ESI, m/z): 525 (M+1, base peaks)
(s)-and 2-(tertbutyloxycarbonyl)-3-{1-[(s)-2-cyanopyrrole alkyl] carbonyl }-7-[N-(2-phenylethyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (II
5) preparation:
(s)-and 2-(tertbutyloxycarbonyl)-3-{1-[(s)-2-formamido group pyrrolidyl] carbonyl }-7-[N-(2-phenylethyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (III
5) 1.11g (0.002mol), press II
1The preparation method, white solid 0.96g (89.1%).MS (ESI, m/z): 539 (M+1, base peaks)
(s)-and 2-(tertbutyloxycarbonyl)-3-{1-[(s)-2-cyanopyrrole alkyl] carbonyl }-7-(N-normal-butyl amino-sulfonyl)-1,2,3,4-tetrahydroisoquinoline (II
6) preparation:
(s)-and 2-(tertbutyloxycarbonyl)-3-{1-[(s)-2-formamido group pyrrolidyl] carbonyl }-7-(N-normal-butyl amino-sulfonyl)-1,2,3,4-tetrahydroisoquinoline (III
6) 1.02g (0.002mol), press II
1The preparation method, white solid 0.91g (92.3%).MS (ESI, m/z): 491 (M+1, base peaks)
(s)-and 2-(tertbutyloxycarbonyl)-3-{1-[(s)-2-cyanopyrrole alkyl] carbonyl }-7-[N-(1-methylethyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (II
7) preparation:
(s)-and 2-(tertbutyloxycarbonyl)-3-{1-[(s)-2-formamido group pyrrolidyl] carbonyl }-7-[N-(2-methylethyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (III
7) 0.99g (0.002mol), press II
1The preparation method, white solid 0.86g (90.1%).MS (ESI, m/z): 477 (M+1, base peaks)
(s)-and 2-(tertbutyloxycarbonyl)-3-{1-[(s)-2-cyanopyrrole alkyl] carbonyl }-7-(N-methylamino alkylsulfonyl)-1,2,3,4-tetrahydroisoquinoline (II
8) preparation:
(s)-and 2-(tertbutyloxycarbonyl)-3-{1-[(s)-2-formamido group pyrrolidyl] carbonyl }-7-(N-methylamino alkylsulfonyl)-1,2,3,4-tetrahydroisoquinoline (III
8) 0.93g (0.002mol), press II
1The preparation method, white solid 0.85g (94.5%).MS (ESI, m/z): 449 (M+1, base peaks)
(s)-and 2-(tertbutyloxycarbonyl)-3-{1-[(s)-2-cyanopyrrole alkyl] carbonyl }-7-[N-(2-methoxy ethyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (II
9) preparation:
(s)-and 2-(tertbutyloxycarbonyl)-3-{1-[(s)-2-formamido group pyrrolidyl] carbonyl }-7-[N-(2-methoxy ethyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (III
9) 1.02g (0.002mol), press II
1The preparation method, white solid 0.87g (88.3%).MS (ESI, m/z): 493 (M+1, base peaks)
(s)-and 2-(tertbutyloxycarbonyl)-3-{1-[(s)-2-cyanopyrrole alkyl] carbonyl }-7-[N-(2-hydroxyethyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (II
10) preparation:
(s)-and 2-(tertbutyloxycarbonyl)-3-{1-[(s)-2-formamido group pyrrolidyl] carbonyl }-7-[N-(2-hydroxyethyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (III
10) 1.00g (0.002mol), press II
1The preparation method, white solid 0.89g (92.7%).MS (ESI, m/z): 479 (M+1, base peaks)
Embodiment 9
(s)-3-{1-[(s)-and 2-cyanopyrrole alkyl] carbonyl }-7-[N-(4-fluorophenyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (I
1) preparation:
(s)-and 2-(tertbutyloxycarbonyl)-3-{1-[(s)-2-cyanopyrrole alkyl] carbonyl }-7-[N-(4-fluorophenyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (II
1) 1.05g (0.002mol) is dissolved in the 5ml methylene dichloride, adds the 5ml trifluoracetic acid, stirring at room 1 hour, solvent evaporated adds the 5ml ethyl acetate, cooling is filtered, white solid 0.82g (95.6%), mp202～204.5 ℃.
IR(cm
-1，KBr)：3333，2162，1625，1344，1312，1160，1091
1HNMR(DMSO-d
6)：1.95-2.35(m，4H，CH
2CH
2)，2.80-3.30(m，2H，CH
2)，3.65-3.60(m，2H，CH
2)，4.3(s，2H，CH
2)，4.55(m，1H，CH)，4.85(m，1H，CH)，6.95-7.50(m，7H，aromaticH)
MS (ESI, m/z): 429 (M+1, base peaks)
Embodiment 10
(s)-3-{1-[(s)-and 2-cyanopyrrole alkyl] carbonyl }-7-[N-(2, the 6-xylyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (I
2) preparation:
(s)-and 2-(tertbutyloxycarbonyl)-3-{1-[(s)-2-cyanopyrrole alkyl] carbonyl }-7-[N-(2, the 6-xylyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (II
2) 1.08g (0.002mol), press I
1The preparation method, white solid 0.82g (93.5%), mp215.6～218.0 ℃.
IR(cm
-1，KBr)：3342，2170，1615，1311，1290，1156，1087
1HNMR(DMSO-d
6)：1.90-2.00(m，2H，CH
2)，2.12(s，6H，2CH
3)，2.25-2.45(m，2H，CH
2)，2.80-3.30(m，2H，CH
2)，3.65-3.60(m，2H，CH
2)，4.33(s，2H，CH
2)，4.55(m，1H，CH)，4.85(m，1H，CH)，6.90-7.65(m，6H，aromaticH)
MS (ESI, m/z): 439 (M+1, base peaks)
Embodiment 11
(s)-3-{1-[(s)-and 2-cyanopyrrole alkyl] carbonyl }-7-{N-[4-(1, the 1-dimethyl ethyl) phenyl] amino-sulfonyl }-1,2,3,4-tetrahydroisoquinoline (I
3) preparation:
(s)-and 2-(tertbutyloxycarbonyl)-3-{1-[(s)-2-cyanopyrrole alkyl] carbonyl }-7-{N-[4-(1, the 1-dimethyl ethyl) phenyl] amino-sulfonyl }-1,2,3,4-tetrahydroisoquinoline (II
3) 1.13g (0.002mol), press I
1The preparation method, white solid 0.86g (92.1%), mp185.4～187.3 ℃.
IR(cm
-1，KBr)：3338，2158，1646，1358，1326，1168，1104
1HNMR(DMSO-d
6)：1.35(s，9H，C(CH
3)
3)，1.90-2.35(m，4H，CH
2CH
2)，2.75-3.35(m，2H，CH
2)，3.60-3.65(m，2H，CH
2)，4.38(s，2H，CH
2)，4.60(m，1H，CH)，4.85(m，1H，CH)，7.10-7.75(m，7H，aromaticH)
MS (ESI, m/z): 467 (M+1, base peaks)
Embodiment 12
(s)-3-{1-[(s)-and 2-cyanopyrrole alkyl] carbonyl }-7-(N-benzylamino alkylsulfonyl)-1,2,3,4-tetrahydroisoquinoline (I
4) preparation:
(s)-and 2-(tertbutyloxycarbonyl)-3-{1-[(s)-2-cyanopyrrole alkyl] carbonyl }-7-(N-benzylamino alkylsulfonyl)-1,2,3,4-tetrahydroisoquinoline (II
4) 1.05g (0.002mol), press I
1The preparation method, white solid 0.77g (90.3%), mp226.3～229.1 ℃.
IR(cm
-1，KBr)：3327，2180，1634，1363，1325，1147，1064
1HNMR(DMSO-d
6)：1.95-2.35(m，4H，CH
2CH
2)，2.80-3.30(m，2H，CH
2)，3.65-3.60(m，2H，CH
2)，4.3(s，2H，CH
2)，4.55(m，1H，CH)，4.65(s，2H，CH
2)，4.85(m，1H，CH)，6.95-7.50(m，8H，aromaticH)
MS (ESI, m/z): 425 (M+1, base peaks)
Embodiment 13
(s)-3-{1-[(s)-and 2-cyanopyrrole alkyl] carbonyl }-7-[N-(2-phenylethyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (I
5) preparation:
(s)-and 2-(tertbutyloxycarbonyl)-3-{1-[(s)-2-cyanopyrrole alkyl] carbonyl }-7-[N-(2-phenylethyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (II
5) 1.10g (0.002mol), press I
1The preparation method, white solid 0.83g (94.8%), mp232.0～234.0 ℃.
IR(cm
-1，KBr)：3330，2155，1645，1358，1324，1174，1116
1HNMR(DMSO-d
6)：1.90-2.35(m，4H，CH
2CH
2)，2.76-3.33(m，6H，CH
2，CH
2CH
2)，3.60-3.65(m，2H，CH
2)，4.30(s，2H，CH
2)，4.55(m，1H，CH)，4.65(s，2H，CH
2)，4.85(m，1H，CH)，6.95-7.50(m，8H，aromaticH)
MS (ESI, m/z): 439 (M+1, base peaks)
Embodiment 14
(s)-3-{1-[(s)-and 2-cyanopyrrole alkyl] carbonyl }-7-(N-normal-butyl amino-sulfonyl)-1,2,3,4-tetrahydroisoquinoline (I
6) preparation:
(s)-and 2-(tertbutyloxycarbonyl)-3-{1-[(s)-2-cyanopyrrole alkyl] carbonyl }-7-(N-normal-butyl amino-sulfonyl)-1,2,3,4-tetrahydroisoquinoline (II
6) 0.98g (0.002mol), press I
1The preparation method, white solid 0.74g (94.3%), mp164.5～166.2 ℃.
IR(cm
-1，KBr)：3354，2146，1643，1336，1295，1184，1105
1HNMR(DMSO-d
6)：1.05-1.50(m，7H，CH
3CH
2CH
2)，1.90-2.35(m，4H，CH
2CH
2)，2.75-3.35(m，4H，CH
2，CH
2)，3.60-3.65(m，2H，CH
2)，4.38(s，2H，CH
2)，4.60(m，1H，CH)，4.85(m，1H，CH)，7.10-7.30(m，3H，aromaticH)
MS (ESI, m/z): 391 (M+1, base peaks)
Embodiment 15
(s)-3-{1-[(s)-and 2-cyanopyrrole alkyl] carbonyl }-7-[N-(1-methylethyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (I
7) preparation:
(s)-and 2-(tertbutyloxycarbonyl)-3-{1-[(s)-2-cyanopyrrole alkyl] carbonyl }-7-[N-(1-methylethyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (II
7) 0.95g (0.002mol), press I
1The preparation method, white solid 0.68g (90.6%), mp158.2～160.0 ℃.
IR(cm
-1，KBr)：3317，2146，1674，1316，1287，1146，1086
1HNMR(DMSO-d
6)：1.05-1.10(m，6H，(CH
3)
2)，1.90-2.35(m，4H，CH
2CH
2)，2.75-3.35(m，3H，CH
2，CH)，3.60-3.65(m，2H，CH
2)，4.38(s，2H，CH
2)，4.60(m，1H，CH)，4.85(m，1H，CH)，7.10-7.30(m，3H，aromaticH)
MS (ESI, m/z): 377 (M+1, base peaks)
Embodiment 16
(s)-3-{1-[(s)-and 2-cyanopyrrole alkyl] carbonyl }-7-(N-methylamino alkylsulfonyl)-1,2,3,4-tetrahydroisoquinoline (I
8) preparation:
(s)-and 2-(tertbutyloxycarbonyl)-3-{1-[(s)-2-cyanopyrrole alkyl] carbonyl }-7-(N-methylamino alkylsulfonyl)-1,2,3,4-tetrahydroisoquinoline (II
8) 0.90g (0.002mol), press I
1The preparation method, white solid 0.64g (92.5%), mp176.5～178.6 ℃.
IR(cm
-1，KBr)：3356，2162，1646，1355，1332，1148，1054
1HNMR(DMSO-d
6)：1.95-2.35(m，4H，CH
2CH
2)，2.50(s，3H，CH
3)，2.80-3.30(m，2H，CH
2)，3.60-3.65(m，2H，CH
2)，4.3(s，2H，CH
2)，4.55(m，1H，CH)，4.65(s，2H，CH
2)，4.85(m，1H，CH)，6.95-7.30(m，3H，aromaticH)
MS (ESI, m/z): 349 (M+1, base peaks)
Embodiment 17
(s)-3-{1-[(s)-and 2-cyanopyrrole alkyl] carbonyl }-7-[N-(2-methoxy ethyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (I
9) preparation:
(s)-and 2-(tertbutyloxycarbonyl)-3-{1-[(s)-2-cyanopyrrole alkyl] carbonyl }-7-[N-(2-methoxy ethyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (II
9) 0.99g (0.002mol), press I
1The preparation method, white solid 0.70g (89.6%), mp196.0～197.8 ℃.
IR(cm
-1，KBr)：3387，3325，2096，1648，1354，1308，1186，1112
1HNMR(DMSO-d
6)：1.95-2.35(m，4H，CH
2CH
2)，2.80-3.30(m，2H，CH
2)，3.47(s，3H，CH
3)，3.60-3.90(m，6H，CH
2，CH
2CH
2)，4.33(s，2H，CH
2)，4.60(m，1H，CH)，4.85(m，1H，CH)，7.10-7.30(m，3H，aromaticH)
MS (ESI, m/z): 393 (M+1, base peaks)
Embodiment 18
(s)-3-{1-[(s)-and 2-cyanopyrrole alkyl] carbonyl }-7-[N-(2-hydroxyethyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (I
10) preparation:
(s)-and 2-(tertbutyloxycarbonyl)-3-{1-[(s)-2-cyanopyrrole alkyl] carbonyl }-7-[N-(2-hydroxyethyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (II
10) 0.96g (0.002mol), press I
1The preparation method, white solid 0.71g (93.2%), mp214.0～216.2 ℃.
IR(cm
-1，KBr)：3378，3330，2156，1630，1355，1318，1176，1124
1HNMR(DMSO-d
6)：1.95-2.35(m，4H，CH
2CH
2)，2.80-3.30(m，2H，CH
2)，3.60-3.90(m，6H，CH
2，CH
2CH
2)，4.33(s，2H，CH
2)，4.60(m，1H，CH)，4.85(m，1H，CH)，7.10-7.30(m，3H，aromaticH)
MS (ESI, m/z): 379 (M+1, base peaks)
Embodiment 19
Contain promoting agent I
5Tablet:
Every contains (mg)
I
5 50mg
Lactose 100mg
W-Gum 40mg
Magnesium Stearate 1.5mg
Ethanol is an amount of
According to a conventional method supplementary material is mixed, granulate drying, compressing tablet.
Claims (4)
1, the compound and the pharmacologically acceptable salt thereof of general formula (I):
SO wherein
2NHR
1The position is 5 on the female ring of tetrahydroisoquinoline, 6, and 7,8;
R wherein
1Representative: alkyl, substituted alkyl, aryl, aralkyl, substituted aryl, substituted aralkyl, heterocycle, substituted heterocycle;
2, the compound of claim 1, wherein SO
2NHR
1The position is 7 on the female ring of tetrahydroisoquinoline, wherein R
1Be alkyl, substituted alkyl, aryl, aralkyl, substituted aryl, substituted aralkyl, heterocycle, substituted heterocycle; Preferably, can be following arbitrary compound and pharmacologically acceptable salt thereof:
(s)-3-{1-[(s)-and 2-cyanopyrrole alkyl] carbonyl }-7-[N-(4-fluorophenyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (I
1);
(s)-3-{1-[(s)-and 2-cyanopyrrole alkyl] carbonyl }-7-[N-(2, the 6-xylyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (I
2);
(s)-3-{1-[(s)-and 2-cyanopyrrole alkyl] carbonyl }-7-{N-[4-(1, the 1-dimethyl ethyl) phenyl] amino-sulfonyl }-1,2,3,4-tetrahydroisoquinoline (I
3);
(s)-3-{1-[(s)-and 2-cyanopyrrole alkyl] carbonyl }-7-(N-benzylamino alkylsulfonyl)-1,2,3,4-tetrahydroisoquinoline (I
4);
(s)-3-{1-[(s)-and 2-cyanopyrrole alkyl] carbonyl }-7-[N-(2-phenylethyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (I
5);
(s)-3-{1-[(s)-and 2-cyanopyrrole alkyl] carbonyl }-7-(N-normal-butyl amino-sulfonyl)-1,2,3,4-tetrahydroisoquinoline (I
6);
(s)-3-{1-[(s)-and 2-cyanopyrrole alkyl] carbonyl }-7-[N-(1-methylethyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (I
7);
(s)-3-{1-[(s)-and 2-cyanopyrrole alkyl] carbonyl }-7-(N-methylamino alkylsulfonyl)-1,2,3,4-tetrahydroisoquinoline (I
8);
(s)-3-{1-[(s)-and 2-cyanopyrrole alkyl] carbonyl }-7-[N-(2-methoxy ethyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (I
9);
(s)-3-{1-[(s)-and 2-cyanopyrrole alkyl] carbonyl }-7-[N-(2-hydroxyethyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (I
10);
3, the preparation method of the compound of claim 2 is prepared by following method:
Substituent R wherein
1As the definition in the claim 1.
4, a kind of pharmaceutical composition wherein contains (I) compound or pharmaceutically acceptable salt thereof of the general formula according to claim 1 or the pharmaceutically acceptable carrier for the treatment of significant quantity.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101791312A (en) * | 2010-03-31 | 2010-08-04 | 中国药科大学 | Use of tetrahydroisoquinoline derivatives |
| CN102260253A (en) * | 2011-06-09 | 2011-11-30 | 中国药科大学 | Benzo[5,6]cycloheptyl[1,2-b]pyridine derivatives and preparation method thereof, and pharmaceutical composition and application thereof in anaphylactic disease resistance |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ATE247090T1 (en) * | 1996-02-02 | 2003-08-15 | Hidaka Hiroyoshi Dr | ISOQUINOLINE DERIVATIVES AND MEDICINAL PRODUCTS |
| WO2000005214A2 (en) * | 1998-07-24 | 2000-02-03 | Pfizer Inc. | Isoquinolines as urokinase inhibitors |
| CN1187332C (en) * | 2002-04-26 | 2005-02-02 | 中国科学院上海有机化学研究所 | Tetrahydroisoquinoline hydroximic acid sulfamide compound, its synthesis method and its application |
-
2008
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101791312A (en) * | 2010-03-31 | 2010-08-04 | 中国药科大学 | Use of tetrahydroisoquinoline derivatives |
| CN102260253A (en) * | 2011-06-09 | 2011-11-30 | 中国药科大学 | Benzo[5,6]cycloheptyl[1,2-b]pyridine derivatives and preparation method thereof, and pharmaceutical composition and application thereof in anaphylactic disease resistance |
| CN102260253B (en) * | 2011-06-09 | 2015-02-18 | 中国药科大学 | Benzo[5,6]cycloheptyl[1,2-b]pyridine derivatives and preparation method thereof, and pharmaceutical composition and application thereof in anaphylactic disease resistance |
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