CN101386617B - Substituted tetrahydroisoquinoline derivatives, preparation method thereof and pharmaceutical compositions containing same - Google Patents

Abstract

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

Substituted tetrahydroisoquinoline derivatives, their preparation methods and pharmaceutical compositions containing them

technical field

The present invention relates to tetrahydroisoquinoline derivatives substituted by sulfonamides, their synthesis methods and pharmaceutical compositions containing them.

Background technique

Diabetes, especially type 2 diabetes, is the third chronic non-communicable disease that seriously threatens human health after tumors and cardiovascular diseases. Currently, there are about 200 million diabetics in the world, which is expected to increase to 300 million by 2025. In 2007, China had 40 million diabetic patients, second only to India with 40.9 million diabetic patients, ranking second in the world. It is estimated that by 2025, the number of diabetic patients in my country will exceed 60 million, of which type 2 diabetes accounts for about the total number of diabetic patients More than 90% of.

Diabetes mellitus is an absolute or relative lack of insulin, which causes glucose metabolism disorder, secondary fat, protein, water, salt and other metabolic disorders, and a variety of acute and chronic complications. The etiology of diabetes is very complex, often accompanied by increased platelet aggregation, arterial dyslipidemia, myocardial infarction, cerebrovascular disorders and other vascular complications. Diabetes is the direct cause of death in only 1-4% of patients, and most of them die from chronic complications. Drugs for diabetes treatment have made great progress in recent years, such as highly effective sulfonylurea hypoglycemic drugs, peroxisome proliferator-activated receptor agonists, insulin secretion promoters and other new drugs have been launched one after another, making the treatment of diabetes more effective. many choices. Although the existing hypoglycemic drugs can promote insulin secretion and lower blood sugar, most of them have disadvantages such as hypoglycemic side effects, weak insulin sensitization, and poor therapeutic effect on cardiovascular complications. medicine is of great importance.

Contents of the invention

The object of the present invention is to provide a novel hypoglycemic drug.

The object of the present invention is also to provide a preparation method for synthesizing the hypoglycemic drug.

Another object of the present invention is to provide a pharmaceutical preparation containing this type of hypoglycemic drug.

Detailed invention content is as follows:

The present invention has synthesized a series of compounds of general formula (I):

Wherein the SO ₂ NHR ₁ position is the 5th, 6th, 7th, and 8th positions on the mother ring of tetrahydroisoquinoline;

Wherein _R represents: alkyl, substituted alkyl, aryl, aralkyl, substituted aryl, substituted aralkyl, heterocycle, substituted heterocycle;

Preferred compounds are:

(s)-3-{1-[(s)-2-cyanopyrrolidinyl]carbonyl}-7-[N-(4-fluorophenyl)sulfamoyl]-1,2,3,4- Tetrahydroisoquinoline (I ₁ );

(s)-3-{1-[(s)-2-cyanopyrrolidinyl]carbonyl}-7-[N-(2,6-xylyl)aminosulfonyl]-1,2,3, 4-Tetrahydroisoquinoline (I ₂ );

(s)-3-{1-[(s)-2-cyanopyrrolidinyl]carbonyl}-7-{N-[4-(1,1-dimethylethyl)phenyl]aminosulfonyl }-1,2,3,4-tetrahydroisoquinoline (I ₃ );

(s)-3-{1-[(s)-2-cyanopyrrolidinyl]carbonyl}-7-(N-benzylsulfamoyl)-1,2,3,4-tetrahydroisoquinoline (I ₄ );

(s)-3-{1-[(s)-2-cyanopyrrolidinyl]carbonyl}-7-[N-(2-phenylethyl)sulfamoyl]-1,2,3,4 - Tetrahydroisoquinoline (I ₅ );

(s)-3-{1-[(s)-2-cyanopyrrolidinyl]carbonyl}-7-(N-n-butylaminosulfonyl)-1,2,3,4-tetrahydroisoquinol morphine (I ₆ );

(s)-3-{1-[(s)-2-cyanopyrrolidinyl]carbonyl}-7-[N-(1-methylethyl)sulfamoyl]-1,2,3,4 - Tetrahydroisoquinoline (I ₇ );

(s)-3-{1-[(s)-2-cyanopyrrolidinyl]carbonyl}-7-(N-methylsulfamoyl)-1,2,3,4-tetrahydroisoquinoline (I ₈ );

(s)-3-{1-[(s)-2-cyanopyrrolidinyl]carbonyl}-7-[N-(2-methoxyethyl)sulfamoyl]-1,2,3, 4-Tetrahydroisoquinoline (I ₉ );

(s)-3-{1-[(s)-2-cyanopyrrolidinyl]carbonyl}-7-[N-(2-hydroxyethyl)sulfamoyl]-1,2,3,4- Tetrahydroisoquinoline (I ₁₀ ).

Its corresponding structural formula:

I ₆ CH ₃ CH ₂ CH ₂ CH ₂

I ₇ (CH ₃ ) ₂ CH

I ₈ CH ₃ -

I ₉ CH ₃ OCH ₂ CH ₂

I ₁₀ HOCH ₂ CH ₂

According to the present invention, pharmaceutically acceptable salts include addition salts formed with the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, citric acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, trifluoroacetic acid, maleic acid, Benzenesulfonic acid.

The preparation method of the compound of general formula I _1-10 is as follows: react with 3-(s)-carboxy-1,2,3,4-tetrahydroisoquinoline and chloroacetyl chloride to generate intermediate (IX), and then react with methyl ester to obtain intermediate (VIII), then react with chlorosulfonic acid to obtain (VII), then react with corresponding amine to obtain intermediate (VI), and then hydrolyze in aqueous sodium hydroxide solution to obtain intermediate (V), Then react with tert-butoxyanhydride to obtain (IV), then condense with 2-(s)-formamido-2,3,4,5-tetrahydropyrrole to obtain intermediate (III), and then react with trifluoroacetic acid Anhydride reaction to obtain intermediate (II), and finally react with trifluoroacetic acid to generate target compound (I _1-10 ). The route is as follows:

The following are the pharmacological test data of some compounds of the present invention:

(1) In vivo hypoglycemic activity test of compounds

Take 10-week-old Kunming mice, weighing 18-22 g, half male and half male, and randomly divide them into three groups according to body weight: blank control group, positive control group and test drug group, with 10 mice in each group. Normal drinking water, fasting overnight. Dock the tail to take blood, and measure the blood sugar level (recorded as -0.5h). Then three groups of mice were given 0.5% CMC-Na (10 μmol/Kg), Saxagliptin (10 μmol/Kg) and test compound (10 μmol/Kg) by intragastric administration respectively, and the glucose solution of 18 mmol/Kg was injected intraperitoneally after 30 minutes, and at 0 , 0.25, 0.5, 1, 2h Measure the blood sugar value with a blood glucose meter.

As shown in Table 1, I ₁ , I ₅ , I ₆ , I ₇ , I ₈ and I ₁₀ all have different degrees of hypoglycemic activity, and the hypoglycemic activity of I ₇ and I ₁₀ is better than that of the positive control drug Saxagliptin.

Table 1. Test results of hypoglycemic activity in normal mice (n=10, mean±SEM)

*P<0.05，**P<0.01，***P<0.001 vs saline

(2) Multiple hypoglycemic activity tests of active compounds in vivo

Take 10-week-old Kunming mice, weighing 18-22 g, half male and half male, and randomly divide them into three groups according to body weight: blank control group, positive control group and test drug group, with 10 mice in each group. Normal drinking water, fasting overnight. 0.5% CMC-Na (20 μmol/Kg), Saxagliptin (20 μmol/Kg) and the test compound (20 μmol/Kg) were administered by intragastric administration respectively, and 18 mmol/Kg of glucose solution was injected intraperitoneally after 30 minutes, and at 0, 0.25, 0.5, 1, 2h tail docking blood, blood glucose monitoring with blood glucose meter. After measuring blood glucose in each group at 4 hours, 18 mmol/Kg glucose solution was injected intraperitoneally immediately, and blood glucose was monitored at 0, 0.25, 0.5, 1, and 2 hours thereafter.

In this experiment, the hypoglycemic effect of the six compounds with hypoglycemic activity in the test (1) was observed in mice through multiple high-glucose stimulations for 6 hours. As shown in Table 2, the six compounds have different degrees of The hypoglycemic effect, the results are shown in Table 2.

Table 2. Results of multiple hypoglycemic activity tests in normal mice. (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 2 hours 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 6 hours 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 includes pharmaceutical preparations comprising a compound of general formula (I) as an active agent and a pharmaceutically acceptable carrier. A pharmaceutically acceptable carrier refers to one or several inert, non-toxic solid or liquid fillers, diluents, auxiliary agents, etc., which do not reversely interact with active compounds or patients.

The dosage forms of the composition of the present invention can be commonly used pharmaceutical dosage forms such as tablets, capsules, pills, suppositories, soft capsules, oral liquids, suspensions, and injections.

Tablets and capsules for oral administration contain conventional excipients such as fillers, diluents, lubricants, dispersing agents and binders, and may be prepared by methods well known in the art.

Dosages of the above active agents will vary from formulation to formulation.

In general, amounts of the compound of formula (I) administered in a total amount of about 0.01-100 mg per kilogram of body weight per 24 hours have proven advantageous to achieve the desired result, preferably in a total amount of about 0.1-50 mg/kg. Administer in several single doses, if necessary. However, it is also possible, if necessary, to deviate from the above-mentioned dosages, i.e. it depends on the type and body weight of the subject to be treated, the individual's behavior towards the drug, the nature and severity of the disease, the type of formulation and administration, and the time of administration. or interval.

The present invention will be further described below by way of examples.

Detailed ways

Example 1

Preparation of (s)-2-acetyl-3-carboxy-1,2,3,4-tetrahydroisoquinoline (IX):

(s)-3-carboxy-1,2,3,4-tetrahydroisoquinoline 10g (0.047mol) mixed with 100ml acetone, 40ml sodium hydroxide aqueous solution (2mol/L), at room temperature, drop 8.01ml at the same time Acetyl chloride (0.094mol) and 2mol/L sodium hydroxide aqueous solution, after dropwise addition, keep the pH value of the reaction solution greater than 9, and continue to stir for 2 hours. Evaporate most of the solvent, acidify the remaining liquid with 3mol/L dilute hydrochloric acid, cool, and precipitate a white solid, filter, wash with water, and dry. .

Example 2

Preparation of (s)-2-acetyl-3-formyl-1,2,3,4-tetrahydroisoquinoline (VIII):

At 0° C., 4.05 ml (0.057 mol) of thionyl chloride was added dropwise to 30 ml of anhydrous methanol. After the dropwise addition was completed, the mixture was stirred at room temperature for 2 hours. Add 5.0 g (0.023 mol) of (s)-2-acetyl-3-carboxy-1,2,3,4-tetrahydroisoquinoline to the above reaction solution, heat to reflux for 3 hours, and evaporate the solvent. Add ethyl acetate to dissolve, wash with saturated sodium bicarbonate and saturated brine respectively until neutral, dry over anhydrous sodium sulfate, evaporate the solvent, and dry to obtain a light yellow solid with a crude product weight of 5.04 g (94.1%).

Example 3

Preparation of (s)-2-acetyl-3-carboxymethyl-7-chlorosulfonyl-1,2,3,4-tetrahydroisoquinoline (VII):

At -5°C, add 5.0 g (0.021 mol) of (s)-2-acetyl-3-methylcarboxylate-1,2,3,4-tetrahydroisoquinoline to 15 ml of chlorosulfonic acid in batches After the addition was complete, stir overnight at room temperature. The reaction solution was poured into a large amount of crushed ice, stirred, and filtered to obtain 12 g (wet weight) of a white solid, which was directly used in the next reaction.

Example 4

(s)-2-Acetyl-3-methylcarboxylate-7-[N-(4-fluorophenyl)aminosulfonyl]-1,2,3,4-tetrahydroisoquinoline (VI ₁ ) Preparation of:

Dissolve 12 g wet weight of (s)-2-acetyl-3-carboxymethyl-7-chlorosulfonyl-1,2,3,4-tetrahydroisoquinoline in 50 ml acetone and 30 ml saturated sodium bicarbonate , add 3.98ml (0.042mol) of p-fluoroaniline, stir overnight at room temperature, evaporate the solvent, after cooling, dissolve with 2mol/L sodium hydroxide aqueous solution, extract twice with ethyl acetate, acidify the obtained aqueous layer with concentrated hydrochloric acid, filter, After drying, 2.32 g (27.2%) of a crude beige solid was obtained.

(s)-2-Acetyl-3-methylcarboxylate-7-[N-(2,6-xylyl)aminosulfonyl]-1,2,3,4-tetrahydroisoquinoline (VI ₂ ) Preparation:

Dissolve 12 g wet weight of (s)-2-acetyl-3-carboxymethyl-7-chlorosulfonyl-1,2,3,4-tetrahydroisoquinoline in 50 ml acetone and 30 ml saturated sodium bicarbonate , 5.18ml (0.042mol) of 2,6-dimethylaniline was added, and according to the preparation method of VI ₁ , 2.75g (31.5%) of a beige solid crude product was obtained.

(s)-2-Acetyl-3-methylcarboxylate-7-{N-[4-(1,1-dimethylethyl)phenyl]aminosulfonyl}-1,2,3,4 - Preparation of tetrahydroisoquinoline (VI ₃ ):

Dissolve 12 g wet weight of (s)-2-acetyl-3-carboxymethyl-7-chlorosulfonyl-1,2,3,4-tetrahydroisoquinoline in 50 ml acetone and 30 ml saturated sodium bicarbonate , 6.68ml (0.042mol) of 4-(1,1-dimethylethyl)aniline was added, and according to the preparation method of VI ₁ , 2.02g (21.7%) of a crude beige solid was obtained.

Preparation of (s)-2-acetyl-3-methylcarboxylate-7-(N-benzylaminosulfonyl)-1,2,3,4-tetrahydroisoquinoline (VI ₄ ):

Dissolve 12 g wet weight of (s)-2-acetyl-3-carboxymethyl-7-chlorosulfonyl-1,2,3,4-tetrahydroisoquinoline in 50 ml acetone and 30 ml saturated sodium bicarbonate , 4.57ml (0.042mol) of benzylamine was added, and according to the preparation method of VI ₁ , 2.70g (32.0%) of a beige solid crude product was obtained.

(s)-2-Acetyl-3-methylcarboxylate-7-[N-(2-phenylethyl)aminosulfonyl]-1,2,3,4-tetrahydroisoquinoline (VI ₅ ) preparation:

Dissolve 12 g wet weight of (s)-2-acetyl-3-carboxymethyl-7-chlorosulfonyl-1,2,3,4-tetrahydroisoquinoline in 50 ml acetone and 30 ml saturated sodium bicarbonate , 5.27ml (0.042mol) of phenethylamine was added, and according to the preparation method of VI ₁ , 2.69g (30.8%) of a beige solid crude product was obtained. Preparation of (s)-2-acetyl-3-methylcarboxylate-7-(N-n-butylaminosulfonyl)-1,2,3,4-tetrahydroisoquinoline (VI ₆ ):

Dissolve 12 g wet weight of (s)-2-acetyl-3-carboxymethyl-7-chlorosulfonyl-1,2,3,4-tetrahydroisoquinoline in 50 ml acetone and 30 ml saturated sodium bicarbonate , 4.18ml (0.042mol) of n-butylamine was added, and according to the preparation method of VI ₁ , 1.72g (22.2%) of a beige solid crude product was obtained.

(s)-2-Acetyl-3-methylcarboxylate-7-[N-(1-methylethyl)aminosulfonyl]-1,2,3,4-tetrahydroisoquinoline (VI ₇ ) preparation:

Dissolve 12 g wet weight of (s)-2-acetyl-3-carboxymethyl-7-chlorosulfonyl-1,2,3,4-tetrahydroisoquinoline in 50 ml acetone and 30 ml saturated sodium bicarbonate , 3.60ml (0.042mol) of 2-methylethylamine was added, and according to the preparation method of VI ₁ , 1.90g (25.6%) of a crude beige solid was obtained.

Preparation of (s)-2-acetyl-3-methylcarboxylate-7-(N-methylaminosulfonyl)-1,2,3,4-tetrahydroisoquinoline (VI ₈ ):

Dissolve 12 g wet weight of (s)-2-acetyl-3-carboxymethyl-7-chlorosulfonyl-1,2,3,4-tetrahydroisoquinoline in 50 ml acetone and 30 ml saturated sodium bicarbonate , 5.40ml (0.063mol) of 40% methylamine aqueous solution was added, and according to the preparation method of VI ₁ , 0.92g (13.4%) of the crude beige solid was obtained.

(s)-2-Acetyl-3-methylcarboxylate-7-[N-(2-methoxyethyl)aminosulfonyl]-1,2,3,4-tetrahydroisoquinoline (VI ₉ ) Preparation:

Dissolve 12 g wet weight of (s)-2-acetyl-3-carboxymethyl-7-chlorosulfonyl-1,2,3,4-tetrahydroisoquinoline in 50 ml acetone and 30 ml saturated sodium bicarbonate , 5.40ml (0.042mol) of 2-methoxyethylamine was added, and according to the preparation method of VI ₁ , 0.92g (13.4%) of a beige solid crude product was obtained.

(s)-2-Acetyl-3-methylcarboxylate-7-[N-(2-hydroxyethyl)aminosulfonyl]-1,2,3,4-tetrahydroisoquinoline (VI ₁₀ ) Preparation of:

Dissolve 12 g wet weight of (s)-2-acetyl-3-carboxymethyl-7-chlorosulfonyl-1,2,3,4-tetrahydroisoquinoline in 50 ml acetone and 30 ml saturated sodium bicarbonate , 5.40ml (0.042mol) of 2-hydroxyethylamine was added, and according to the preparation method of VI ₁ , 0.92g (13.4%) of a beige solid crude product was obtained.

Example 5

Preparation of (s)-3-carboxy-7-[N-(4-fluorophenyl)aminosulfonyl]-1,2,3,4-tetrahydroisoquinoline hydrochloride (V ₁ ):

(s)-2-Acetyl-3-methylcarboxylate-7-[N-(4-fluorophenyl)aminosulfonyl]-1,2,3,4-tetrahydroisoquinoline (VI ₁ ) 1.2 g (0.003 mol) was mixed with 10 ml of 6 mol/L concentrated hydrochloric acid, heated to reflux overnight, and evaporated to dryness to obtain 0.98 g (93.3%) of solid. used directly in the next reaction.

Preparation of (s)-3-carboxy-7-[N-(2,6-xylyl)aminosulfonyl]-1,2,3,4-tetrahydroisoquinoline hydrochloride (V ₂ ):

(s)-2-Acetyl-3-methylcarboxylate-7-[N-(2,6-xylyl)aminosulfonyl]-1,2,3,4-tetrahydroisoquinoline (VI ₂ ) 1.25g (0.003mol), mixed with 10ml of 6mol/L concentrated hydrochloric acid, according to the preparation method of _V1 , to obtain 0.97g (89.8%) of solid. used directly in the next reaction.

(s)-3-Carboxy-7-{N-[4-(1,1-dimethylethyl)phenyl]aminosulfonyl}-1,2,3,4-tetrahydroisoquinoline hydrochloride Preparation of salt (V ₃ ):

(s)-2-Acetyl-3-methylcarboxylate-7-{N-[4-(1,1-dimethylethyl)phenyl]aminosulfonyl}-1,2,3,4 - 1.33 g (0.003 mol) of tetrahydroisoquinoline (VI ₃ ), mixed with 10 ml of 6 mol/L concentrated hydrochloric acid, and followed the preparation method of V ₁ to obtain 1.13 g (97.1%) of solid. used directly in the next reaction.

Preparation of (s)-3-carboxy-7-(N-benzylaminosulfonyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (V ₄ ):

(s)-2-Acetyl-3-methylcarboxylate-7-(N-benzylsulfamoyl)-1,2,3,4-tetrahydroisoquinoline (VI ₄ ) 1.20g (0.003mol ), mixed with 10ml of concentrated hydrochloric acid of 6mol/L, according to the preparation method of _V1 , 0..97g (93.4%) of solid was obtained. used directly in the next reaction.

Preparation of (s)-3-carboxy-7-[N-(2-phenylethyl)sulfamoyl]-1,2,3,4-tetrahydroisoquinoline hydrochloride (V ₅ ):

(s)-2-Acetyl-3-methylcarboxylate-7-[N-(2-phenylethyl)aminosulfonyl]-1,2,3,4-tetrahydroisoquinoline (VI ₅ ) 1.25g (0.003mol), mixed with 10ml of concentrated hydrochloric acid of 6mol/L, and according to the preparation method of _V1 , 1.02g (97.1%) of solid was obtained. used directly in the next reaction.

Preparation of (s)-3-carboxy-7-(N-n-butylaminosulfonyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (V ₆ ):

(s)-2-Acetyl-3-methylcarboxylate-7-(N-n-butylaminosulfonyl)-1,2,3,4-tetrahydroisoquinoline (VI ₆ ) 1.11g (0.003 mol), mixed with 10ml of concentrated hydrochloric acid of 6mol/L, according to the preparation method of _V1 , 0.91g (96.6%) of solid was obtained. used directly in the next reaction.

Preparation of (s)-3-carboxy-7-[N-(1-methylethyl)sulfamoyl]-1,2,3,4-tetrahydroisoquinoline hydrochloride (V ₇ ):

(s)-2-Acetyl-3-methylcarboxylate-7-[N-(2-methylethyl)aminosulfonyl]-1,2,3,4-tetrahydroisoquinoline (VI ₇ ) 1.06g (0.003mol), mixed with 10ml of concentrated hydrochloric acid of 6mol/L, and according to the preparation method of _V1 , 0.85g (95.2%) of solid was obtained. used directly in the next reaction.

Preparation of (s)-3-carboxy-7-(N-methylaminosulfonyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (V ₈ ):

(s)-2-acetyl-3-methylcarboxylate-7-(N-methylaminosulfonyl)-1,2,3,4-tetrahydroisoquinoline (VI ₈ ) 0.98g (0.003mol ), mixed with 10ml of concentrated hydrochloric acid of 6mol/L, according to the preparation method of _V1 , 0.79g (96.8%) of solid was obtained. used directly in the next reaction.

Preparation of (s)-3-carboxy-7-[N-(2-methoxyethyl)aminosulfonyl]-1,2,3,4-tetrahydroisoquinoline hydrochloride (V ₉ ):

(s)-2-Acetyl-3-methylcarboxylate-7-[N-(2-methoxyethyl)aminosulfonyl]-1,2,3,4-tetrahydroisoquinoline (VI ₉ ) 1.11g (0.003mol), mixed with 10ml of 6mol/L concentrated hydrochloric acid, according to the preparation method of _V1 , to obtain 0.93g (97.9%) of solid. used directly in the next reaction.

Preparation of (s)-3-carboxy-7-[N-(2-hydroxyethyl)sulfamoyl]-1,2,3,4-tetrahydroisoquinoline hydrochloride (V ₁₀ ):

(s)-2-Acetyl-3-methylcarboxylate-7-[N-(2-hydroxyethyl)aminosulfonyl]-1,2,3,4-tetrahydroisoquinoline (VI ₁₀ ) 1.07g (0.003mol), mixed with 10ml of 6mol/L concentrated hydrochloric acid, according to the preparation method of _V1 , to obtain 0.87g (95.8%) of solid. used directly in the next reaction.

Example 6

(s)-2-(tert-butoxycarbonyl)-3-carboxy-7-[N-(4-fluorophenyl)aminosulfonyl]-1,2,3,4-tetrahydroisoquinoline (IV ₁ ) preparation:

(s)-3-Carboxy-7-[N-(4-fluorophenyl)aminosulfonyl]-1,2,3,4-tetrahydroisoquinoline (V ₁ ) 1.05g (0.003mol), room temperature Dissolve it in 5ml of 10% sodium hydroxide aqueous solution, add 0.91g (0.0042mol) of di-tert-butyl dicarbonate, stir overnight at room temperature, extract twice with ethyl acetate, and acidify the aqueous layer with 1mol/L dilute hydrochloric acid , filtered, and dried to obtain 1.17 g (86.5%) of a khaki solid.

(s)-2-(tert-butoxycarbonyl)-3-carboxy-7-[N-(2,6-xylyl)aminosulfonyl]-1,2,3,4-tetrahydroisoquinoline ( IV ₂ ) Preparation:

(s)-3-Carboxy-7-[N-(2,6-xylyl)aminosulfonyl]-1,2,3,4-tetrahydroisoquinoline (V ₂ ) 1.08g (0.003mol) and 0.91 g (0.0042 mol) of di-tert-butyl dicarbonate, according to the preparation method of IV ₁ , 1.16 g (83.9%) of khaki solid was obtained.

(s)-2-(tert-butoxycarbonyl)-3-carboxy-7-{N-[4-(1,1-dimethylethyl)phenyl]aminosulfonyl}-1,2,3, Preparation of 4-tetrahydroisoquinoline (IV ₃ ):

(s)-3-carboxy-7-{N-[4-(1,1-dimethylethyl)phenyl]aminosulfonyl}-1,2,3,4-tetrahydroisoquinoline (V ₃ ) 1.16g (0.003mol) and 0.91g (0.0042mol) of di-tert-butyl dicarbonate were prepared according to the preparation method of IV ₁ to obtain 1.18g (80.3%) of a khaki solid.

Preparation of (s)-2-(tert-butoxycarbonyl)-3-carboxy-7-(N-benzylaminosulfonyl)-1,2,3,4-tetrahydroisoquinoline (IV ₄ ):

(s)-3-carboxy-7-(N-benzylaminosulfonyl)-1,2,3,4-tetrahydroisoquinoline (V ₄ ) 1.04g (0.003mol) and di-tert-butyl dicarbonate 0.91g (0.0042mol), according to the preparation method of IV ₁ , 1.07g (79.8%) of khaki solid was obtained.

(s)-2-(tert-butoxycarbonyl)-3-carboxy-7-[N-(2-phenylethyl)aminosulfonyl]-1,2,3,4-tetrahydroisoquinoline (IV ₅ ) Preparation:

(s)-3-carboxy-7-[N-(2-phenylethyl)aminosulfonyl]-1,2,3,4-tetrahydroisoquinoline (V ₅ ) 1.08g (0.003mol) and Di-tert-butyl dicarbonate 0.91g (0.0042mol), according to IV ₁ . According to the preparation method, 1.17 g (84.5%) of khaki solid was obtained.

Preparation of (s)-2-(tert-butoxycarbonyl)-3-carboxy-7-(N-n-butylaminosulfonyl)-1,2,3,4-tetrahydroisoquinoline (IV ₆ ):

(s)-3-carboxy-7-(N-n-butylaminosulfonyl)-1,2,3,4-tetrahydroisoquinoline (V ₆ ) 0.94g (0.003mol) and di-tert-butyl dicarbonate 0.91 g (0.0042 mol) of ester, according to the preparation method of IV ₁ , 0.97 g (78.3%) of khaki solid was obtained.

(s)-2-(tert-butoxycarbonyl)-3-carboxy-7-[N-(1-methylethyl)sulfamoyl]-1,2,3,4-tetrahydroisoquinoline (IV ₇ ) Preparation:

(s)-3-carboxy-7-[N-(2-methylethyl)aminosulfonyl]-1,2,3,4-tetrahydroisoquinoline (V ₇ ) 0.90g (0.003mol) and 0.91 g (0.0042 mol) of di-tert-butyl dicarbonate was prepared according to the preparation method of IV ₁ to obtain 0.90 g (75.3%) of a khaki solid.

Preparation of (s)-2-(tert-butoxycarbonyl)-3-carboxy-7-(N-methylaminosulfonyl)-1,2,3,4-tetrahydroisoquinoline (IV ₈ ):

(s)-3-carboxy-7-(N-methylaminosulfonyl)-1,2,3,4-tetrahydroisoquinoline (V ₈ ) 0.81g (0.003mol) and di-tert-butyl dicarbonate 0.91g (0.0042mol), according to the preparation method of IV ₁ , 0.82g (73.8%) of khaki solid was obtained.

(s)-2-(tert-butoxycarbonyl)-3-carboxy-7-[N-(2-methoxyethyl)aminosulfonyl]-1,2,3,4-tetrahydroisoquinoline ( IV ₉ ) Preparation:

(s)-3-Carboxy-7-[N-(2-methoxyethyl)aminosulfonyl]-1,2,3,4-tetrahydroisoquinoline (V ₉ ) 0.95g (0.003mol) and 0.91 g (0.0042 mol) of di-tert-butyl dicarbonate, according to the preparation method of IV ₁ , 0.98 g (78.8%) of khaki solid was obtained.

(s)-2-(tert-butoxycarbonyl)-3-carboxy-7-[N-(2-hydroxyethyl)aminosulfonyl]-1,2,3,4-tetrahydroisoquinoline (IV ₁₀ ) preparation:

(s)-3-carboxy-7-[N-(2-hydroxyethyl)aminosulfonyl]-1,2,3,4-tetrahydroisoquinoline (V ₁₀ ) 0.90g (0.003mol) and di 0.91 g (0.0042 mol) of di-tert-butyl carbonate was prepared according to the preparation method of IV ₁ to obtain 0.87 g (72.6%) of a khaki solid.

Example 7

(s)-2-(tert-butoxycarbonyl)-3-{1-[(s)-2-formamidopyrrolidinyl]carbonyl}-7-[N-(4-fluorophenyl)aminosulfonyl ]-1,2,3,4-tetrahydroisoquinoline (III ₁ ):

(s)-2-(tert-butoxycarbonyl)-3-carboxy-7-[N-(4-fluorophenyl)aminosulfonyl]-1,2,3,4-tetrahydroisoquinoline (IV ₁ ) 0.9g (0.002mol), mixed with 15ml of dry dichloromethane, under ice-bath condition, add 2-[1-(1H)-benzotriazolyl]-1,1,3,3-tetrazole Methylurea hexafluorophosphate (HBTU) 0.76g (0.002mol), (s)-2-formamidopyrrolidine 0.28g (0.0025mol) and diisopropylethylamine 0.99ml (0.006mol), react After 2 hours, the reaction solution was washed with saturated sodium bicarbonate, saturated brine, 1mol/L dilute hydrochloric acid and saturated brine, dried, and evaporated to dryness to obtain a light yellow solid, which was separated by column chromatography (chloroform:methanol= 20:1), 1.02 g (93.0%) of white solid was obtained.

(s)-2-(tert-butoxycarbonyl)-3-{1-[(s)-2-formamidopyrrolidinyl]carbonyl}-7-[N-(2,6-xylyl)amino Preparation of sulfonyl]-1,2,3,4-tetrahydroisoquinoline (III ₂ ):

(s)-2-(tert-butoxycarbonyl)-3-carboxy-7-[N-(2,6-xylyl)aminosulfonyl]-1,2,3,4-tetrahydroisoquinoline ( IV ₂ ) 0.92 (0.002mol), according to the preparation method of III ₁ , 1.0 g (90.3%) of white solid was obtained.

(s)-2-(tert-butoxycarbonyl)-3-{1-[(s)-2-formamidopyrrolidinyl]carbonyl}-7-{N-[4-(1,1-dimethyl Preparation of (ethyl ethyl) phenyl] aminosulfonyl}-1,2,3,4-tetrahydroisoquinoline (III ₃ ):

(s)-2-(tert-butoxycarbonyl)-3-carboxy-7-{N-[4-(1,1-dimethylethyl)phenyl]aminosulfonyl}-1,2,3, 4-Tetrahydroisoquinoline (IV ₃ ) 0.98 (0.002 mol), according to the preparation method of III ₁ , a white solid 1.04 g (89.3%) was obtained.

(s)-2-(tert-butoxycarbonyl)-3-{1-[(s)-2-formamidopyrrolidinyl]carbonyl}-7-(N-benzylaminosulfonyl)-1,2 , Preparation of 3,4-tetrahydroisoquinoline (III ₄ ):

(s)-2-(tert-butoxycarbonyl)-3-carboxy-7-(N-benzylaminosulfonyl)-1,2,3,4-tetrahydroisoquinoline (IV ₄ ) 0.89 (0.002mol ), according to the preparation method of III ₁ , 0.97g (89.7%) of white solid was obtained.

(s)-2-(tert-butoxycarbonyl)-3-{1-[(s)-2-formamidopyrrolidinyl]carbonyl}-7-[N-(2-phenylethyl)sulfamate Preparation of acyl]-1,2,3,4-tetrahydroisoquinoline (III ₅ ):

(s)-2-(tert-butoxycarbonyl)-3-carboxy-7-[N-(2-phenylethyl)aminosulfonyl]-1,2,3,4-tetrahydroisoquinoline (IV ₅ ) 0.92 (0.002mol), according to the preparation method of III ₁ , a white solid 1.03g (92.2%) was obtained.

(s)-2-(tert-butoxycarbonyl)-3-{1-[(s)-2-formamidopyrrolidinyl]carbonyl}-7-(N-n-butylaminosulfonyl)-1, Preparation of 2,3,4-tetrahydroisoquinoline (III ₆ ):

(s)-2-(tert-butoxycarbonyl)-3-carboxy-7-(N-n-butylaminosulfonyl)-1,2,3,4-tetrahydroisoquinoline (IV ₆ ) 0.83(0.002 mol), according to the preparation method of III ₁ , 0.90 g (88.7%) of white solid was obtained.

(s)-2-(tert-butoxycarbonyl)-3-{1-[(s)-2-formamidopyrrolidinyl]carbonyl}-7-[N-(1-methylethyl)sulfamate Preparation of acyl]-1,2,3,4-tetrahydroisoquinoline (III ₇ ):

(s)-2-(tert-butoxycarbonyl)-3-carboxy-7-[N-(2-methylethyl)sulfamoyl]-1,2,3,4-tetrahydroisoquinoline (IV ₇ ) 0.80 (0.002mol), according to the preparation method of III ₁ , a white solid 0.90g (90.6%) was obtained.

(s)-2-(tert-butoxycarbonyl)-3-{1-[(s)-2-formamidopyrrolidinyl]carbonyl}-7-(N-methylaminosulfonyl)-1,2 , Preparation of 3,4-tetrahydroisoquinoline (III ₈ ):

(s)-2-(tert-butoxycarbonyl)-3-carboxy-7-(N-methylaminosulfonyl)-1,2,3,4-tetrahydroisoquinoline (IV ₈ ) 0.74 (0.002mol ), according to the preparation method of III ₁ , a white solid 0.81g (86.8%) was obtained.

(s)-2-(tert-butoxycarbonyl)-3-{1-[(s)-2-formamidopyrrolidinyl]carbonyl}-7-[N-(2-methoxyethyl)amino Preparation of sulfonyl]-1,2,3,4-tetrahydroisoquinoline (III ₉ ):

(s)-2-(tert-butoxycarbonyl)-3-carboxy-7-[N-(2-methoxyethyl)aminosulfonyl]-1,2,3,4-tetrahydroisoquinoline ( IV ₉ ) 0.83 (0.002mol), according to the preparation method of III ₁ , a white solid 0.92g (89.6%) was obtained.

(s)-2-(tert-butoxycarbonyl)-3-{1-[(s)-2-formamidopyrrolidinyl]carbonyl}-7-[N-(2-hydroxyethyl)sulfamoyl ]-1,2,3,4-tetrahydroisoquinoline (III ₁₀ ):

(s)-2-(tert-butoxycarbonyl)-3-carboxy-7-[N-(2-hydroxyethyl)aminosulfonyl]-1,2,3,4-tetrahydroisoquinoline (IV ₁₀ ) 0.80 (0.002mol), according to the preparation method of III ₁ , 0.85g (85.4%) of white solid was obtained.

Example 8

(s)-2-(tert-butoxycarbonyl)-3-{1-[(s)-2-cyanopyrrolidinyl]carbonyl}-7-[N-(4-fluorophenyl)aminosulfonyl] - Preparation of 1,2,3,4-tetrahydroisoquinoline (II ₁ ):

(s)-2-(tert-butoxycarbonyl)-3-{1-[(s)-2-formamidopyrrolidinyl]carbonyl}-7-[N-(4-fluorophenyl)aminosulfonyl ]-1,2,3,4-Tetrahydroisoquinoline (III ₁ ) 1.10g (0.002mol) was dissolved in 10ml of dry tetrahydrofuran, added 0.56ml (0.004mol) of trifluoroacetic anhydride, stirred at room temperature for 2 hours , evaporate the solvent to dryness, add 20ml of dichloromethane, wash with saturated sodium bicarbonate and saturated brine respectively, dry, and evaporate the solvent to obtain a beige solid, which is separated by column chromatography (chloroform:methanol=30:1) to obtain a white Solid 0.98g (93.0%). MS (ESI, m/z): 529 (M+1, base peak)

(s)-2-(tert-butoxycarbonyl)-3-{1-[(s)-2-cyanopyrrolidinyl]carbonyl}-7-[N-(2,6-xylyl)sulfamate Preparation of acyl]-1,2,3,4-tetrahydroisoquinoline (II ₂ ):

(s)-2-(tert-butoxycarbonyl)-3-{1-[(s)-2-formamidopyrrolidinyl]carbonyl}-7-[N-(2,6-xylyl)amino Sulfonyl]-1,2,3,4-tetrahydroisoquinoline (III ₂ ) 1.11 g (0.002 mol), followed the preparation method of II ₁ to obtain 1.00 g (92.8%) of a white solid. MS (ESI, m/z): 539 (M+1, base peak)

(s)-2-(tert-butoxycarbonyl)-3-{1-[(s)-2-cyanopyrrolidinyl]carbonyl}-7-{N-[4-(1,1-dimethyl Preparation of ethyl)phenyl]aminosulfonyl}-1,2,3,4-tetrahydroisoquinoline (II ₃ ):

(s)-2-(tert-butoxycarbonyl)-3-{1-[(s)-2-formamidopyrrolidinyl]carbonyl}-7-{N-[4-(1,1-dimethyl ethyl) phenyl] aminosulfonyl}-1,2,3,4-tetrahydroisoquinoline (III ₃ ) 1.12g (0.002mol), according to the preparation method of II ₁ , a white solid 1.02g (90.3 %). MS (ESI, m/z): 567 (M+1, base peak)

(s)-2-(tert-butoxycarbonyl)-3-{1-[(s)-2-cyanopyrrolidinyl]carbonyl}-7-(N-benzylaminosulfonyl)-1,2, Preparation of 3,4-tetrahydroisoquinoline (II ₄ ):

(s)-2-(tert-butoxycarbonyl)-3-{1-[(s)-2-formamidopyrrolidinyl]carbonyl}-7-(N-benzylaminosulfonyl)-1,2 , 1.10 g (0.002 mol) of 3,4-tetrahydroisoquinoline (III ₄ ), according to the preparation method of II ₁ , 1.00 g (94.5%) of a white solid was obtained. MS (ESI, m/z): 525 (M+1, base peak)

(s)-2-(tert-butoxycarbonyl)-3-{1-[(s)-2-cyanopyrrolidinyl]carbonyl}-7-[N-(2-phenylethyl)sulfamoyl ]-1,2,3,4-tetrahydroisoquinoline (II ₅ ):

(s)-2-(tert-butoxycarbonyl)-3-{1-[(s)-2-formamidopyrrolidinyl]carbonyl}-7-[N-(2-phenylethyl)sulfamate Acyl]-1,2,3,4-tetrahydroisoquinoline (III ₅ ) 1.11g (0.002mol), according to the preparation method of II ₁ , a white solid 0.96g (89.1%) was obtained. MS (ESI, m/z): 539 (M+1, base peak)

(s)-2-(tert-butoxycarbonyl)-3-{1-[(s)-2-cyanopyrrolidinyl]carbonyl}-7-(N-n-butylaminosulfonyl)-1,2 , Preparation of 3,4-tetrahydroisoquinoline (II ₆ ):

(s)-2-(tert-butoxycarbonyl)-3-{1-[(s)-2-formamidopyrrolidinyl]carbonyl}-7-(N-n-butylaminosulfonyl)-1, 1.02 g (0.002 mol) of 2,3,4-tetrahydroisoquinoline (III ₆ ), followed the preparation method of II ₁ to obtain 0.91 g (92.3%) of a white solid. MS (ESI, m/z): 491 (M+1, base peak)

(s)-2-(tert-butoxycarbonyl)-3-{1-[(s)-2-cyanopyrrolidinyl]carbonyl}-7-[N-(1-methylethyl)sulfamoyl ]-1,2,3,4-tetrahydroisoquinoline (II ₇ ):

(s)-2-(tert-butoxycarbonyl)-3-{1-[(s)-2-formamidopyrrolidinyl]carbonyl}-7-[N-(2-methylethyl)sulfamate Acyl]-1,2,3,4-tetrahydroisoquinoline (III ₇ ) 0.99g (0.002mol), according to the preparation method of II ₁ , a white solid 0.86g (90.1%) was obtained. MS (ESI, m/z): 477 (M+1, base peak)

(s)-2-(tert-butoxycarbonyl)-3-{1-[(s)-2-cyanopyrrolidinyl]carbonyl}-7-(N-methylaminosulfonyl)-1,2, Preparation of 3,4-tetrahydroisoquinoline (II ₈ ):

(s)-2-(tert-butoxycarbonyl)-3-{1-[(s)-2-formamidopyrrolidinyl]carbonyl}-7-(N-methylaminosulfonyl)-1,2 , 0.93 g (0.002 mol) of 3,4-tetrahydroisoquinoline (III ₈ ), according to the preparation method of II ₁ , 0.85 g (94.5%) of a white solid was obtained. MS (ESI, m/z): 449 (M+1, base peak)

(s)-2-(tert-butoxycarbonyl)-3-{1-[(s)-2-cyanopyrrolidinyl]carbonyl}-7-[N-(2-methoxyethyl)sulfamate Preparation of acyl]-1,2,3,4-tetrahydroisoquinoline (II ₉ ):

(s)-2-(tert-butoxycarbonyl)-3-{1-[(s)-2-formamidopyrrolidinyl]carbonyl}-7-[N-(2-methoxyethyl)amino Sulfonyl]-1,2,3,4-tetrahydroisoquinoline (III ₉ ) 1.02g (0.002mol), according to the preparation method of II ₁ , a white solid 0.87g (88.3%) was obtained. MS (ESI, m/z): 493 (M+1, base peak)

(s)-2-(tert-butoxycarbonyl)-3-{1-[(s)-2-cyanopyrrolidinyl]carbonyl}-7-[N-(2-hydroxyethyl)sulfamoyl] - Preparation of 1,2,3,4-tetrahydroisoquinoline (II ₁₀ ):

(s)-2-(tert-butoxycarbonyl)-3-{1-[(s)-2-formamidopyrrolidinyl]carbonyl}-7-[N-(2-hydroxyethyl)sulfamoyl ]-1,2,3,4-tetrahydroisoquinoline (III ₁₀ ) 1.00 g (0.002 mol), according to the preparation method of II ₁ , a white solid 0.89 g (92.7%) was obtained. MS (ESI, m/z): 479 (M+1, base peak)

Example 9

(s)-3-{1-[(s)-2-cyanopyrrolidinyl]carbonyl}-7-[N-(4-fluorophenyl)sulfamoyl]-1,2,3,4- Preparation of Tetrahydroisoquinoline (I ₁ ):

(s)-2-(tert-butoxycarbonyl)-3-{1-[(s)-2-cyanopyrrolidinyl]carbonyl}-7-[N-(4-fluorophenyl)aminosulfonyl] -1,2,3,4-Tetrahydroisoquinoline (II ₁ ) 1.05g (0.002mol) was dissolved in 5ml of dichloromethane, added 5ml of trifluoroacetic acid, stirred at room temperature for 1 hour, evaporated to dryness, added 5ml of ethyl acetate The ester was cooled and filtered to obtain 0.82 g (95.6%) of a white solid, mp 202-204.5°C.

IR (cm ^-1 , KBr): 3333, 2162, 1625, 1344, 1312, 1160, 1091

¹ HNMR (DMSO-d ₆ ): 1.95-2.35 (m, 4H, CH ₂ CH 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 peak)

Example 10

(s)-3-{1-[(s)-2-cyanopyrrolidinyl]carbonyl}-7-[N-(2,6-xylyl)aminosulfonyl]-1,2,3, Preparation of 4-tetrahydroisoquinoline (I ₂ ):

(s)-2-(tert-butoxycarbonyl)-3-{1-[(s)-2-cyanopyrrolidinyl]carbonyl}-7-[N-(2,6-xylyl)sulfamate Acyl]-1,2,3,4-tetrahydroisoquinoline (II ₂ ) 1.08g (0.002mol), according to the preparation method of I ₁ , a white solid 0.82g (93.5%) was obtained, mp215.6～218.0℃ .

IR (cm ^-1 , KBr): 3342, 2170, 1615, 1311, 1290, 1156, 1087

¹ HNMR (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 peak)

Example 11

(s)-3-{1-[(s)-2-cyanopyrrolidinyl]carbonyl}-7-{N-[4-(1,1-dimethylethyl)phenyl]aminosulfonyl Preparation of }-1,2,3,4-tetrahydroisoquinoline (I ₃ ):

(s)-2-(tert-butoxycarbonyl)-3-{1-[(s)-2-cyanopyrrolidinyl]carbonyl}-7-{N-[4-(1,1-dimethyl Ethyl)phenyl]aminosulfonyl}-1,2,3,4-tetrahydroisoquinoline (II ₃ ) 1.13g (0.002mol), according to the preparation method of I ₁ , a white solid 0.86g (92.1% ), mp 185.4-187.3°C.

IR (cm ^-1 , KBr): 3338, 2158, 1646, 1358, 1326, 1168, 1104

¹ HNMR (DMSO-d ₆ ): 1.35 (s, 9H, C(CH ₃ ) ₃ ), 1.90-2.35 (m, 4H, CH ₂ CH ₂ ), 2.75-3.35 (m, 2H, CH ₂ ), 3.60 -3.65(m, 2H, _CH2 ), 4.38(s, 2H, _CH2 ), 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 peak)

Example 12

(s)-3-{1-[(s)-2-cyanopyrrolidinyl]carbonyl}-7-(N-benzylsulfamoyl)-1,2,3,4-tetrahydroisoquinoline Preparation of (I ₄ ):

(s)-2-(tert-butoxycarbonyl)-3-{1-[(s)-2-cyanopyrrolidinyl]carbonyl}-7-(N-benzylaminosulfonyl)-1,2, 1.05 g (0.002 mol) of 3,4-tetrahydroisoquinoline (II ₄ ), according to the preparation method of I ₁ , gave 0.77 g (90.3%) of a white solid, mp 226.3-229.1°C.

IR (cm ^-1 , KBr): 3327, 2180, 1634, 1363, 1325, 1147, 1064

¹ HNMR (DMSO-d ₆ ): 1.95-2.35 (m, 4H, CH ₂ CH 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, aromatic H)

MS (ESI, m/z): 425 (M+1, base peak)

Example 13

(s)-3-{1-[(s)-2-cyanopyrrolidinyl]carbonyl}-7-[N-(2-phenylethyl)sulfamoyl]-1,2,3,4 - Preparation of tetrahydroisoquinoline (I ₅ ):

(s)-2-(tert-butoxycarbonyl)-3-{1-[(s)-2-cyanopyrrolidinyl]carbonyl}-7-[N-(2-phenylethyl)sulfamoyl ]-1,2,3,4-tetrahydroisoquinoline (II ₅ ) 1.10 g (0.002 mol), according to the preparation method of I ₁ , a white solid 0.83 g (94.8%) was obtained, mp 232.0-234.0 °C.

IR (cm ^-1 , KBr): 3330, 2155, 1645, 1358, 1324, 1174, 1116

¹ HNMR (DMSO-d ₆ ): 1.90-2.35 (m, 4H, CH ₂ CH ₂ ), 2.76-3.33 (m, 6H, CH ₂ , CH ₂ CH ₂ ), 3.60-3.65 (m, 2H, CH ₂ ), 4.30(s, 2H, _CH2 ), 4.55(m, 1H, CH), 4.65(s, 2H, _CH2 ), 4.85(m, 1H, CH), 6.95-7.50(m, 8H, aromaticH)

MS (ESI, m/z): 439 (M+1, base peak)

Example 14

(s)-3-{1-[(s)-2-cyanopyrrolidinyl]carbonyl}-7-(N-n-butylaminosulfonyl)-1,2,3,4-tetrahydroisoquinol Preparation of morphine (I ₆ ):

(s)-2-(tert-butoxycarbonyl)-3-{1-[(s)-2-cyanopyrrolidinyl]carbonyl}-7-(N-n-butylaminosulfonyl)-1,2 , 3,4-tetrahydroisoquinoline (II ₆ ) 0.98g (0.002mol), according to the preparation method of I ₁ , a white solid 0.74g (94.3%) was obtained, mp 164.5～166.2℃.

IR (cm ^-1 , KBr): 3354, 2146, 1643, 1336, 1295, 1184, 1105

¹ HNMR (DMSO-d ₆ ): 1.05-1.50 (m, 7H, CH ₃ CH ₂ CH ₂ ), 1.90-2.35 (m, 4H, CH ₂ CH 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, aromatic H)

MS (ESI, m/z): 391 (M+1, base peak)

Example 15

(s)-3-{1-[(s)-2-cyanopyrrolidinyl]carbonyl}-7-[N-(1-methylethyl)sulfamoyl]-1,2,3,4 - Preparation of tetrahydroisoquinoline (I ₇ ):

(s)-2-(tert-butoxycarbonyl)-3-{1-[(s)-2-cyanopyrrolidinyl]carbonyl}-7-[N-(1-methylethyl)sulfamoyl ]-1,2,3,4-Tetrahydroisoquinoline (II ₇ ) 0.95g (0.002mol), according to the preparation method of I ₁ , a white solid 0.68g (90.6%) was obtained, mp 158.2～160.0℃.

IR (cm ^-1 , KBr): 3317, 2146, 1674, 1316, 1287, 1146, 1086

¹ HNMR (DMSO-d ₆ ): 1.05-1.10 (m, 6H, (CH ₃ ) ₂ ), 1.90-2.35 (m, 4H, CH ₂ CH 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, aromatic H)

MS (ESI, m/z): 377 (M+1, base peak)

Example 16

(s)-3-{1-[(s)-2-cyanopyrrolidinyl]carbonyl}-7-(N-methylsulfamoyl)-1,2,3,4-tetrahydroisoquinoline Preparation of (I ₈ ):

(s)-2-(tert-butoxycarbonyl)-3-{1-[(s)-2-cyanopyrrolidinyl]carbonyl}-7-(N-methylaminosulfonyl)-1,2, 0.90 g (0.002 mol) of 3,4-tetrahydroisoquinoline (II ₈ ) was prepared according to the preparation method of I ₁ to obtain 0.64 g (92.5%) of a white solid, mp 176.5-178.6°C.

IR (cm ^-1 , KBr): 3356, 2162, 1646, 1355, 1332, 1148, 1054

¹ HNMR (DMSO-d ₆ ): 1.95-2.35 (m, 4H, CH ₂ CH 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 peak)

Example 17

(s)-3-{1-[(s)-2-cyanopyrrolidinyl]carbonyl}-7-[N-(2-methoxyethyl)sulfamoyl]-1,2,3, Preparation of 4-tetrahydroisoquinoline (I ₉ ):

(s)-2-(tert-butoxycarbonyl)-3-{1-[(s)-2-cyanopyrrolidinyl]carbonyl}-7-[N-(2-methoxyethyl)sulfamate Acyl]-1,2,3,4-tetrahydroisoquinoline (II ₉ ) 0.99g (0.002mol), according to the preparation method of I ₁ , a white solid 0.70g (89.6%) was obtained, mp196.0～197.8℃ .

IR (cm ^-1 , KBr): 3387, 3325, 2096, 1648, 1354, 1308, 1186, 1112

¹ HNMR (DMSO-d ₆ ): 1.95-2.35 (m, 4H, CH ₂ CH ₂ ), 2.80-3.30 (m, 2H, CH ₂ ), 3.47 (s, 3H, CH ₃ ), 3.60-3.90 (m , 6H, CH ₂ , CH ₂ CH 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 peak)

Example 18

(s)-3-{1-[(s)-2-cyanopyrrolidinyl]carbonyl}-7-[N-(2-hydroxyethyl)sulfamoyl]-1,2,3,4- Preparation of Tetrahydroisoquinoline (I ₁₀ ):

(s)-2-(tert-butoxycarbonyl)-3-{1-[(s)-2-cyanopyrrolidinyl]carbonyl}-7-[N-(2-hydroxyethyl)sulfamoyl] -1,2,3,4-tetrahydroisoquinoline (II ₁₀ ) 0.96g (0.002mol), according to the preparation method of I ₁ , a white solid 0.71g (93.2%) was obtained, mp 214.0～216.2℃.

IR (cm ^-1 , KBr): 3378, 3330, 2156, 1630, 1355, 1318, 1176, 1124

¹ HNMR (DMSO-d ₆ ): 1.95-2.35 (m, 4H, CH ₂ CH ₂ ), 2.80-3.30 (m, 2H, CH ₂ ), 3.60-3.90 (m, 6H, CH ₂ , CH ₂ CH 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 peak)

Example 19

Tablets containing active agent I ₅ :

Contains per tablet (mg)

I ₅ 50mg

Lactose 100mg

cornstarch 40mg

Magnesium stearate 1.5mg

Alcohol Appropriate amount

The raw and auxiliary materials are mixed, granulated, dried and pressed into tablets according to conventional methods.

Claims (3)

1. the compound and the pharmacologically acceptable salt thereof of general formula (I):

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.

2. the preparation method of the compound of the described general formula of claim 1 (I):

Substituent R wherein ₁Like the definition in the claim 1.

3. a pharmaceutical composition wherein contains general formula according to claim 1 (I) compound or pharmaceutically acceptable salt thereof and the pharmaceutically acceptable carrier of treating significant quantity.