# US 11,028,073 B2 · Butylphthalide-telmisartan hybrids, preparation method and application thereof

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- Number: US 11,028,073 B2
- Document ID: US11028073B2
- Status: Granted
- Kind: B2
- Application number: 16/478,400
- Filed: 2018-01-04
- Published: 2019-12-12
- Granted: 2021-06-08
- Earliest claimed: 2017-01-18
- Assignees: Guangdong Longfu Medicine Co., Ltd.
- Applicants: Guangdong Longfu Medicine Co., Ltd.
- Inventors: Zhangjian Huang; Tao Pang; Cunfang Wang; Wenbin Zeng; Jinxiang Deng; Weijie Wu; Tingyu Huang
- Web page: https://patentgrep.com/patent/US11028073B2

## CPC

- C07D 403/04: directly linked by a ring-member-to-ring-member bond
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/16: Anti-Parkinson drugs
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- C07D 235/18: with aryl radicals directly attached in position 2
- C07D 257/04: Five-membered rings
- C07D 403/10: linked by a carbon chain containing aromatic rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The invention discloses a butylphthalide-telmisartan heterocomplex, a preparation method and an application thereof. The invention specifically relates to an optically active ring-opening butylphthalide-telmisartan heterocomplex shown in formula I or a pharmaceutically acceptable salt or ester thereof, a preparation method thereof, a pharmaceutical composition containing the compounds, and a pharmaceutical application thereof, particularly application in prevention and treatment of neuroinflammation-related diseases, including ischemic stroke, Alzheimer's disease, brain trauma, Parkinson's disease, multiple sclerosis, depression and so on.

## Claims

### Claim 1

A compound which is an optically active butylphthalide-telmisartan hybrid as shown in general formula I, or an optical isomer, an enantiomer, a diastereomer, a racemate or a racemic mixture thereof, or a pharmaceutically acceptable salt thereof:
wherein, R represents a hydrogen atom H, linear or branched C1-C10 alkyl, or (linear or branched C1-C10 alkylene)-Q, wherein Q represents hydroxyl or halogen;
n represents 1 to 20;
X represents an oxygen atom, a nitrogen atom or a sulfur atom;
Y represents an oxygen atom, a nitrogen atom or a sulfur atom; and
chiral center * is S or R configurated.

### Claim 2 (depends on 1)

The compound or the optical isomer, the enantiomer, the diastereomer, the racemate or the racemic mixture thereof, or the pharmaceutically acceptable salt thereof according to claim 1, wherein R represents a hydrogen atom H;
X represents an oxygen atom or a nitrogen atom; and
Y represents an oxygen atom or a nitrogen atom.

### Claim 3 (depends on 1)

The compound or the optical isomer, the enantiomer, the diastereomer, the racemate or the racemic mixture thereof, or the pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is selected from the group consisting of:
2-O-{2-[(1-acetoxyl)-n-pentyl]benzoic acid}hexanediol telmisartan ester;
4-O-{2-[(1-acetoxyl)n-pentyl]benzoyl}butanediol telmisartan ester;
8-N-{2-[(1-acetoxyl)n-pentyl]benzoyl}octanediamine telmisartan amide;
5-O-{2-[(1-acetoxyl)n-pentyl]benzoyl}pentanediol telmisartan ester;
6-O-{2-[(1-acetoxyl)n-pentyl]benzoyl}hexanediol telmisartan ester;
8-O-{2-[(1-acetoxyl)n-pentyl]benzoyl}octanediol telmisartan ester;
6-N-{2-[(1-acetoxyl)n-pentyl]benzoyl}hexanediamine telmisartan amide;
4-N-{2-[(1-acetoxyl)n-pentyl]benzoyl}butanediamine telmisartan amide;
8-N-{2-[(1-acetoxyl)n-pentyl]benzoyl}octanediamine telmisartan amide; and
8-N-{2-[(1-acetoxy)n-pentyl]benzoyl}octanediamine telmisartan amide hydrochloride.

### Claim 4

A compound or an optical isomer, an enantiomer, a diastereomer, a racemate or a racemic mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
p-methylbenzoyl octanediamine telmisartan amide;
3,5-dichlorobenzoyl octanediamine telmisartan amide;
4-cyanobenzoyl octanediamine telmisartan amide;
p-nitrobenzoyl octanediamine telmisartan amide;
m-methoxybenzoyl octanediamine telmisartan amide;
o-hydroxybenzoyl octanediamine telmisartan amide;
8-N-{2-[(1-acetoxyl)n-pentyl]benzoyl}octanediamine candesartan amide;
8-N-{2-[(1-acetoxyl)n-pentyl]benzoyl}octanediamine valsartan amide; and
8-N-{2-[(1-acetoxyl)n-pentyl]benzoyl}octanediamine losartan amide.

### Claim 5 (depends on 1)

A preparation method of the compound of general formula I according to claim 1, comprising:
allowing (S)- or (R)-butylphthalide to be saponified and acidified to give a ring-opening lactone compound III, allowing the compound III to be esterified with an acyl chloride compound (RCOCl) to give an ester compound IV, allowing the compound IV to be condensed with a diol or a diamine having a different carbon chain length to give an intermediate V, and allowing the intermediate V to be further condensed with telmisartan to give a target compound I; alternatively, allowing telmisartan to be first condensed with a diol or a diamine having a different carbon chain length to give an intermediate VI, and then allowing the intermediate VI to be condensed with the ester compound IV to give the target compound I; a synthetic route is as follows:

### Claim 6 (depends on 5)

The preparation method of the compound of general formula I according to claim 5, wherein,
the compound IV is prepared from the compound III, by using a solvents selected from one or more of the group consisting of acetonitrile, dichloromethane, chloroform, ethyl acetate, acetone, tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide and dioxane, and a base selected from the group consisting of potassium carbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, pyridine, 4-methylaminopyridine, triethylamine, and N, N-diisopropylmethylamine, at a reaction temperature from −20° C. to reflux temperature; and/or,
the compound V is prepared from the compound IV, by using a solvent selected from one or more of the group consisting of acetonitrile, dichloromethane, chloroform, ethyl acetate, acetone, tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide and dioxane, a condensing agent selected from the group consisting of N, N′-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole, and N-hydroxysuccinimide, and a base selected from the group consisting of pyridine, 4-methylaminopyridine, triethylamine, and N, N-diisopropylmethylamine, at a reaction temperature from −20° C. to reflux temperature; and/or,
the compound I is prepared from the compound V, by using a solvent selected from one or more of the group consisting of acetonitrile, dichloromethane, chloroform, ethyl acetate, acetone, tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide and dioxane, a condensing agent selected from the group consisting of N, N′-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole, and N-hydroxysuccinimide, and a base selected from the group consisting of pyridine, 4-methylaminopyridine, triethylamine, and N, N-diisopropylmethylamine, at a reaction temperature from −20° C. to reflux temperature; and/or,
the compound VI is prepared from telmisartan, by using a solvent selected from one or more of the group consisting of acetonitrile, dichloromethane, chloroform, ethyl acetate, acetone, tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide and dioxane, a condensing agent selected from the group consisting of N, N′-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole, and N-hydroxysuccinimide; and a base selected from the group consisting of pyridine, 4-methylaminopyridine, triethylamine, and N, N-diisopropylmethylamine, at a reaction temperature from −20° C. to reflux temperature; and/or,
the compound I is prepared from the compound IV and the compound VI, by using a solvent selected from one or more of the group consisting of acetonitrile, dichloromethane, chloroform, ethyl acetate, acetone, tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide and dioxane, a condensing agent selected from the group consisting of N, N′-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole, and N-hydroxysuccinimide, and a base selected from the group consisting of pyridine, 4-methylaminopyridine, triethylamine, and N, N-diisopropylmethylamine, at a reaction temperature from −20° C. to reflux temperature.

### Claim 7 (depends on 6)

The preparation method of the compound of general formula I according to claim 6, wherein,
the compound IV is prepared from the compound III, by using dichloromethane as the solvent and triethylamine as the base, at the reaction temperature of −20° C.; and/or,
the compound V is prepared from the compound IV, by using dichloromethane as the solvent, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride as the condensing agent, and 4-methylaminopyridine as the base, at the reaction temperature of room temperature; and/or,
the compound I is prepared from the compound V, by using dichloromethane as the solvent, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride as the condensing agent, and 4-methylaminopyridine as the base, at the reaction temperature of room temperature; and/or,
the compound VI is prepared from telmisartan, by using dichloromethane as the solvent, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride as the condensing agent, and 4-methylaminopyridine as the base, at the reaction temperature of room temperature; and/or,
the compound I is prepared from the compound IV and compound VI, by using dichloromethane as the solvent, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride as the condensing agent, and 4-methylaminopyridine as the base, at the reaction temperature of room temperature.

### Claim 8 (depends on 1)

A pharmaceutical composition comprising a therapeutically effective amount of the compound of general formula I, or the optical isomer, the enantiomer, the diastereomer, the racemate or the racemic mixture thereof, or the pharmaceutically acceptable salt thereof according to claim 1, and a medicinal carrier, adjuvant or vehicle.

### Claim 9 (depends on 1)

A method of treating cerebral ischemic stroke, comprising:
administrating to a mammal a pharmaceutical composition comprising the compound, or the optical isomer, the enantiomer, the diastereomer, the racemate or the racemic mixture thereof, or the pharmaceutically acceptable salt thereof according to claim 1.