CN101429191B - Uses of substituted tetrahydrochysene isoquinoline derivant - Google Patents
Uses of substituted tetrahydrochysene isoquinoline derivant Download PDFInfo
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- CN101429191B CN101429191B CN2008101550770A CN200810155077A CN101429191B CN 101429191 B CN101429191 B CN 101429191B CN 2008101550770 A CN2008101550770 A CN 2008101550770A CN 200810155077 A CN200810155077 A CN 200810155077A CN 101429191 B CN101429191 B CN 101429191B
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- tetrahydroisoquinoline
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- amino
- tertbutyloxycarbonyl
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Abstract
The invention relates to a general formula (I) compound and application of salt thereof to preparation of drugs, in particular to application of the salt thereof to preparation of antidiabetic drugs. Pharmacological experiments show that the compound has good antidiabetic effect.
Description
Technical field
The present invention relates to the tetrahydro isoquinoline derivative of sulfonamide substitutions, it is used to prepare the purposes of medicine, specifically prepares the purposes of antidiabetic medicine.
Background technology
Mellitus 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.
Mellitus 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 mellitus cause of disease is very complicated, often with vascular complications such as the increase of platelet aggregation property, artery hyperlipemia, myocardial infarction, cerebrovascular disorders.Mellitus 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 like new drugs such as sulfonylurea hypoglycemic agent, peroxidase vegetation activated receptor agonist, insulin secretion stimulators efficiently, makes the mellitus treatment of diseases that more selection arranged.Though existing antidiabetic drug can promote insulin secretion; Lowering blood glucose; But mostly exist cause the hypoglycemia spinoff, 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 purposes of the tetrahydro isoquinoline derivative of one type of new sulfonamide substitutions, specifically antidiabetic purposes.
Summary of the invention is following in detail:
The present invention has synthesized a series of general formulas (I) compound and pharmacy acceptable salt thereof:
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:
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, Hydrocerol A, tartrate, phosphoric acid, lactic acid, pyruvic acid, acetate, trifluoroacetic acid, toxilic acid, Phenylsulfonic acid.
General formula I
1-10Compounds process for production thereof is following: with 3-(s)-carboxyl-1,2,3,4-tetrahydroisoquinoline and chloroacetyl chloride reaction generate midbody (IX); With methanol esterification, obtain midbody (VIII) again, obtain (VII) with the chlorsulfonic acid reaction again, with corresponding amine reaction, obtain midbody (VI) then; Hydrolysis in aqueous sodium hydroxide solution again obtains midbody (V), with uncle's fourth oxygen anhydride reaction, obtains (IV) again; Then with 2-(s)-formamido--2,3,4, the condensation of 5-Pyrrolidine; Obtain midbody (III), with the trifluoroacetic anhydride (TFAA) reaction, obtain midbody (II) again, last and trifluoracetic acid reaction generates purpose compound (I
1-10).Route is following:
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 tried drug 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 tried drug 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 through 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 six compounds all have blood sugar reducing function in various degree in the 6h, and the result sees 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?saline
The present invention also comprises pharmaceutical prepn, 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 prepare 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.
Below through embodiment 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)-and 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 Hydrogen chloride acidifying residual solution of 3mol/L, white solid is separated out in cooling, filters washing, drying, the heavy 9.1g (88.4%) of bullion, 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 till neutrality with saturated sodium bicarbonate, saturated aqueous common salt respectively, anhydrous sodium sulfate drying boils off solvent; Drying gets light yellow solid, the heavy 5.04g (94.1%) of bullion.
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), directly be used for step reaction down.
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; Add para-fluoroaniline 3.98ml (0.042mol), stirred overnight at room temperature boils 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%).Directly be used for step reaction down.
(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%).Directly be used for step reaction down.
(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%).Directly be used for step reaction down.
(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%).Directly be used for step reaction down.
(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%).Directly be used for step reaction down.
(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%).Directly be used for step reaction down.
(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%).Directly be used for step reaction down.
(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%).Directly be used for step reaction down.
(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%).Directly be used for step reaction down.
(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%).Directly be used for step reaction down.
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 Hydrogen chloride 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)-2-(tertbutyloxycarbonyl)-3-{1-[(s)-and 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]-1,1,3 successively; 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) reacted after 2 hours, with reaction solution respectively with Hydrogen chloride and the saturated common salt water washing of saturated sodium bicarbonate, saturated aqueous common salt, 1mol/L; Drying, solvent evaporated gets light yellow solid; Column chromatography for separation (chloroform: methyl alcohol=20:1), get white solid 1.02g (93.0%).
(s)-2-(tertbutyloxycarbonyl)-3-{1-[(s)-and 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)-2-(tertbutyloxycarbonyl)-3-{1-[(s)-and 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)-2-(tertbutyloxycarbonyl)-3-{1-[(s)-and 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)-2-(tertbutyloxycarbonyl)-3-{1-[(s)-and 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)-2-(tertbutyloxycarbonyl)-3-{1-[(s)-and 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)-2-(tertbutyloxycarbonyl)-3-{1-[(s)-and 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)-2-(tertbutyloxycarbonyl)-3-{1-[(s)-and 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)-2-(tertbutyloxycarbonyl)-3-{1-[(s)-and 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)-2-(tertbutyloxycarbonyl)-3-{1-[(s)-and 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)-2-(tertbutyloxycarbonyl)-3-{1-[(s)-and 2-cyanopyrrole alkyl] carbonyl }-7-[N-(4-fluorophenyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (II
1) preparation:
(s)-2-(tertbutyloxycarbonyl)-3-{1-[(s)-and 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 THF, adds 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)-2-(tertbutyloxycarbonyl)-3-{1-[(s)-and 2-cyanopyrrole alkyl] carbonyl }-7-[N-(2, the 6-xylyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (II
2) preparation:
(s)-2-(tertbutyloxycarbonyl)-3-{1-[(s)-and 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)-2-(tertbutyloxycarbonyl)-3-{1-[(s)-and 2-cyanopyrrole alkyl] carbonyl }-7-{N-[4-(1, the 1-dimethyl ethyl) phenyl] amino-sulfonyl }-1,2,3,4-tetrahydroisoquinoline (II
3) preparation:
(s)-2-(tertbutyloxycarbonyl)-3-{1-[(s)-and 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)-2-(tertbutyloxycarbonyl)-3-{1-[(s)-and 2-cyanopyrrole alkyl] carbonyl }-7-(N-benzylamino alkylsulfonyl)-1,2,3,4-tetrahydroisoquinoline (II
4) preparation:
(s)-2-(tertbutyloxycarbonyl)-3-{1-[(s)-and 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)-2-(tertbutyloxycarbonyl)-3-{1-[(s)-and 2-cyanopyrrole alkyl] carbonyl }-7-[N-(2-phenylethyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (II
5) preparation:
(s)-2-(tertbutyloxycarbonyl)-3-{1-[(s)-and 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)-2-(tertbutyloxycarbonyl)-3-{1-[(s)-and 2-cyanopyrrole alkyl] carbonyl }-7-(N-normal-butyl amino-sulfonyl)-1,2,3,4-tetrahydroisoquinoline (II
6) preparation:
(s)-2-(tertbutyloxycarbonyl)-3-{1-[(s)-and 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)-2-(tertbutyloxycarbonyl)-3-{1-[(s)-and 2-cyanopyrrole alkyl] carbonyl }-7-[N-(1-methylethyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (II
7) preparation:
(s)-2-(tertbutyloxycarbonyl)-3-{1-[(s)-and 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)-2-(tertbutyloxycarbonyl)-3-{1-[(s)-and 2-cyanopyrrole alkyl] carbonyl }-7-(N-methylamino alkylsulfonyl)-1,2,3,4-tetrahydroisoquinoline (II
8) preparation:
(s)-2-(tertbutyloxycarbonyl)-3-{1-[(s)-and 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)-2-(tertbutyloxycarbonyl)-3-{1-[(s)-and 2-cyanopyrrole alkyl] carbonyl }-7-[N-(2-methoxy ethyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (II
9) preparation:
(s)-2-(tertbutyloxycarbonyl)-3-{1-[(s)-and 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)-2-(tertbutyloxycarbonyl)-3-{1-[(s)-and 2-cyanopyrrole alkyl] carbonyl }-7-[N-(2-hydroxyethyl) amino-sulfonyl]-1,2,3,4-tetrahydroisoquinoline (II
10) preparation:
(s)-2-(tertbutyloxycarbonyl)-3-{1-[(s)-and 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)-2-(tertbutyloxycarbonyl)-3-{1-[(s)-and 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 5ml ETHYLE 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)-2-(tertbutyloxycarbonyl)-3-{1-[(s)-and 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)-2-(tertbutyloxycarbonyl)-3-{1-[(s)-and 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)-2-(tertbutyloxycarbonyl)-3-{1-[(s)-and 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)-2-(tertbutyloxycarbonyl)-3-{1-[(s)-and 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)-2-(tertbutyloxycarbonyl)-3-{1-[(s)-and 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)-2-(tertbutyloxycarbonyl)-3-{1-[(s)-and 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)-2-(tertbutyloxycarbonyl)-3-{1-[(s)-and 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)-2-(tertbutyloxycarbonyl)-3-{1-[(s)-and 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)-2-(tertbutyloxycarbonyl)-3-{1-[(s)-and 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
By ordinary method supplementary material is mixed, granulate drying, compressing tablet.
Claims (1)
1. the compound of general formula (I) and pharmacologically acceptable salt thereof the purposes in preparation anti-diabetic medicine:
SO wherein
2NHR
1The position is 7 on the female ring of tetrahydroisoquinoline;
R wherein
1Representative: 4-fluorophenyl, 2,6-xylyl, 4-(1, the 1-dimethyl ethyl) phenyl, benzyl, 2-phenylethyl, normal-butyl, 1-methylethyl, methyl, 2-methoxy ethyl, 2-hydroxyethyl.
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|---|---|---|---|
| CN2008101550770A CN101429191B (en) | 2008-11-03 | 2008-11-03 | Uses of substituted tetrahydrochysene isoquinoline derivant |
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| CN101429191B true CN101429191B (en) | 2012-05-23 |
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Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101791312B (en) * | 2010-03-31 | 2012-01-04 | 中国药科大学 | Use of tetrahydroisoquinoline derivatives |
| 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 |
| MA41140A (en) | 2014-12-12 | 2017-10-17 | Cancer Research Tech Ltd | 2,4-DIOXO-QUINAZOLINE-6-SULFONAMIDE DERIVATIVES AS PARG INHIBITORS |
| MA41179A (en) | 2014-12-19 | 2017-10-24 | Cancer Research Tech Ltd | PARG INHIBITOR COMPOUNDS |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997028130A1 (en) * | 1996-02-02 | 1997-08-07 | Nippon Shinyaku Co., Ltd. | Isoquinoline derivatives and drugs |
| US6093731A (en) * | 1998-07-24 | 2000-07-25 | Pfizer | Isoquinolines |
| CN1380288A (en) * | 2002-04-26 | 2002-11-20 | 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
- 2008-11-03 CN CN2008101550770A patent/CN101429191B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997028130A1 (en) * | 1996-02-02 | 1997-08-07 | Nippon Shinyaku Co., Ltd. | Isoquinoline derivatives and drugs |
| US6093731A (en) * | 1998-07-24 | 2000-07-25 | Pfizer | Isoquinolines |
| CN1380288A (en) * | 2002-04-26 | 2002-11-20 | 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 |
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| CN101429191A (en) | 2009-05-13 |
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