Carboxyl group-containing benzothiadiazide derivatives, as well as preparation method and application thereof

Abstract

The invention discloses carboxyl group-containing benzothiadiazide derivatives, a preparation method thereof, a medicine composition containing the compound and an application thereof in treatment or prevention for complications of vascular hypertension and serum hyperuricemia and / or hypercholesteremia. The benzothiadiazide derivative compounds meet a general formula (I) specified in the description. The carboxyl group-containing benzothiadiazide derivatives are synthesised by a one-step method, as well as are simple in synthesis process, simple in separation and purification methods, high in yield, good in repeatability, free of strong acid-resistant special equipment, and suitable for large-batch production.

Description

technical field

[0001] The invention relates to a carboxyl-bearing benzothiadiazine derivative, a preparation method thereof, a pharmaceutical composition containing the compound and its application in treating hypertension. Background technique

[0002] Compounds with benzothiadiazine as the skeleton are an important class of skeleton compounds, which can be used to treat endocrine system diseases, diabetes, schizophrenia, hypertension, complications of serum hyperuricemia and / or hypercholesterolemia, and the like.

[0003] For example, CN122910A discloses a 1,2,4-benzothiadiazine derivative, its pharmaceutical composition and its preparation method, the composition is used to treat central nervous system, cardiovascular system, pulmonary system, gastrointestinal system and endocrine system diseases; CN1402717A discloses a benzothiadiazine derivative, its preparation method and a pharmaceutical composition containing them, which can be used for the treatment of schizophreni...

Examples

preparation example Construction

[0030] In the preparation method of any of the above-mentioned compounds, the synthetic route is as follows:

[0031]

[0032] The synthesis steps include: using compound (II) and compound (III) as raw materials, in the presence of acetic acid and concentrated hydrochloric acid, heating and reacting to obtain compound (I).

[0033] Wherein, the molar ratio of the compound (II) to the compound (III) is 1:(1-2), for example 1:1.5; the mass ratio of the acetic acid to concentrated hydrochloric acid is (5-15):1, more preferably (8-12):1, such as 10:1; the reaction temperature of the above heating reaction is 80-120° C., and the reaction time is at least 2 hours.

Embodiment 1

[0036] This embodiment provides a carboxyl-containing benzothiadiazine derivative compound (1):

[0037]

[0038] The synthetic route of this compound (1) is as follows:

[0039]

[0040] Synthetic steps include:

[0041] Dissolve sulfanilamide (20g, 0.19mol) and ethyl cyanoformate (26.3g, 0.29mol) in 100ml of acetic acid, gradually add 10ml of concentrated hydrochloric acid at room temperature, stir evenly, and heat to a temperature of 100°C. The reaction was carried out at this temperature for 5 hours. Take a small amount, add water and ethyl acetate, monitor the reaction result with TLC, the raw material aminobenzenesulfonamide has reacted completely. The reaction was stopped, most of the acetic acid was distilled off under reduced pressure, the remaining reaction liquid was cooled to room temperature, and water was added. Solids were precipitated, stirred evenly, filtered, and washed with water for 3 times. Vacuum drying gave a white solid product (19.1 g, yield:...

Embodiment 2

[0047] This embodiment provides a carboxyl-containing benzothiadiazine derivative compound (2):

[0048]

[0049] The synthetic route of this compound (2) is as follows:

[0050]

[0051] Synthetic steps include:

[0052] Dissolve sulfanilamide (20g, 0.19mol) and methyl cyanoformate (32.3g, 0.38mol) in 100ml of acetic acid, gradually add 10ml of concentrated hydrochloric acid at room temperature, stir evenly, and heat to a temperature of 100°C. The reaction was carried out at this temperature for 5 hours. Take a small amount, add water and ethyl acetate, monitor the reaction result with TLC, the raw material aminobenzenesulfonamide has reacted completely. The reaction was stopped, most of the acetic acid was distilled off under reduced pressure, the remaining reaction liquid was cooled to room temperature, and water was added. Solids were precipitated, stirred evenly, filtered, and washed with water for 3 times. Vacuum drying gave a white solid product (18.5 g, yield...

technical field

[0001] The invention relates to a carboxyl-bearing benzothiadiazine derivative, a preparation method thereof, a pharmaceutical composition containing the compound and its application in treating hypertension. Background technique

[0002] Compounds with benzothiadiazine as the skeleton are an important class of skeleton compounds, which can be used to treat endocrine system diseases, diabetes, schizophrenia, hypertension, complications of serum hyperuricemia and / or hypercholesterolemia, and the like.

[0003] For example, CN122910A discloses a 1,2,4-benzothiadiazine derivative, its pharmaceutical composition and its preparation method, the composition is used to treat central nervous system, cardiovascular system, pulmonary system, gastrointestinal system and endocrine system diseases; CN1402717A discloses a benzothiadiazine derivative, its preparation method and a pharmaceutical composition containing them, which can be used for the treatment of schizophreni...

Examples

preparation example Construction

[0030] In the preparation method of any of the above-mentioned compounds, the synthetic route is as follows:

[0031]

[0032] The synthesis steps include: using compound (II) and compound (III) as raw materials, in the presence of acetic acid and concentrated hydrochloric acid, heating and reacting to obtain compound (I).

[0033] Wherein, the molar ratio of the compound (II) to the compound (III) is 1:(1-2), for example 1:1.5; the mass ratio of the acetic acid to concentrated hydrochloric acid is (5-15):1, more preferably (8-12):1, such as 10:1; the reaction temperature of the above heating reaction is 80-120° C., and the reaction time is at least 2 hours.

Embodiment 1

[0036] This embodiment provides a carboxyl-containing benzothiadiazine derivative compound (1):

[0037]

[0038] The synthetic route of this compound (1) is as follows:

[0039]

[0040] Synthetic steps include:

[0041] Dissolve sulfanilamide (20g, 0.19mol) and ethyl cyanoformate (26.3g, 0.29mol) in 100ml of acetic acid, gradually add 10ml of concentrated hydrochloric acid at room temperature, stir evenly, and heat to a temperature of 100°C. The reaction was carried out at this temperature for 5 hours. Take a small amount, add water and ethyl acetate, monitor the reaction result with TLC, the raw material aminobenzenesulfonamide has reacted completely. The reaction was stopped, most of the acetic acid was distilled off under reduced pressure, the remaining reaction liquid was cooled to room temperature, and water was added. Solids were precipitated, stirred evenly, filtered, and washed with water for 3 times. Vacuum drying gave a white solid product (19.1 g, yield:...

Embodiment 2

[0047] This embodiment provides a carboxyl-containing benzothiadiazine derivative compound (2):

[0048]

[0049] The synthetic route of this compound (2) is as follows:

[0050]

[0051] Synthetic steps include:

[0052] Dissolve sulfanilamide (20g, 0.19mol) and methyl cyanoformate (32.3g, 0.38mol) in 100ml of acetic acid, gradually add 10ml of concentrated hydrochloric acid at room temperature, stir evenly, and heat to a temperature of 100°C. The reaction was carried out at this temperature for 5 hours. Take a small amount, add water and ethyl acetate, monitor the reaction result with TLC, the raw material aminobenzenesulfonamide has reacted completely. The reaction was stopped, most of the acetic acid was distilled off under reduced pressure, the remaining reaction liquid was cooled to room temperature, and water was added. Solids were precipitated, stirred evenly, filtered, and washed with water for 3 times. Vacuum drying gave a white solid product (18.5 g, yield...

Images