CN113443993A - Novel prostaglandin derivative, pharmaceutical composition and use - Google Patents

Novel prostaglandin derivative, pharmaceutical composition and use Download PDF

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CN113443993A
CN113443993A CN202010228516.7A CN202010228516A CN113443993A CN 113443993 A CN113443993 A CN 113443993A CN 202010228516 A CN202010228516 A CN 202010228516A CN 113443993 A CN113443993 A CN 113443993A
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prostaglandin derivative
pharmaceutically acceptable
solvate
hydrogen
crystal
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冯子侠
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C203/00—Esters of nitric or nitrous acid
    • C07C203/02—Esters of nitric acid
    • C07C203/04—Esters of nitric acid having nitrate groups bound to acyclic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D317/18—Radicals substituted by singly bound oxygen or sulfur atoms
    • C07D317/22—Radicals substituted by singly bound oxygen or sulfur atoms etherified
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated

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Abstract

The invention discloses a novel prostaglandin derivative, a pharmaceutical composition and application thereof in preparing medicaments for treating and/or preventing glaucoma or ocular hypertension, wherein the prostaglandin derivative has a structure shown as the following formula (I):

Description

Novel prostaglandin derivative, pharmaceutical composition and use
Technical Field
The invention belongs to the field of medicinal chemistry, and particularly relates to a novel prostaglandin derivative for treating glaucoma, a pharmaceutical composition and application thereof.
Background
At present, glaucoma is the second leading cause of blindness diseases worldwide, is the second largest vision killer second to cataract, and seriously threatens the life quality of people. The main recognized risk factors are pathological intraocular pressure rise, which causes that nutrient substances can not be normally transported, causes ischemia and anoxia of local tissues and retina, edema and degeneration of various organelles, leads to progressive atrophy of optic nerve under various adverse factors, and gradually lacks visual field and even blindness.
Ocular hypertension is now a well-defined risk factor leading to the progressive development of glaucoma, and it has subsequently been found that apoptosis and axonal degeneration of the optic ganglion cells are also involved in the progression of the disease. Therefore, the main purposes of stably and durably reducing intraocular pressure, protecting and repairing damaged optic nerve cells as much as possible, improving the life quality of patients and avoiding blindness are to treat glaucoma. The current clinical medication mainly reduces intraocular pressure and avoids further damage to optic nerve cells, and the main medicines are as follows:
(1) prostaglandin derivatives: the medicine mainly reduces intraocular pressure by accelerating the outflow rate of aqueous humor from a uveoscleral way, can be used for primary open-angle glaucoma, ocular hypertension, neovascular glaucoma and the like, is recommended by Europe and America as a first-line medicine for treating glaucoma, has large blood pressure reduction amplitude and lasting medicine effect, can be used by dripping once a day, has few local side effects and good patient compliance, but has higher price and is the defect of limiting the application.
(2) Alpha adrenergic receptor agonists: the alpha adrenergic receptors that are currently more commonly used include apraclonidine, brimonidine, and the like. The medicine can reduce the generation of aqueous humor by ciliary muscle epithelium, and can increase the outflow of aqueous humor in uveoscleral route.
(3) Parasympathomimetic agents: the medicine is a traditional eye-pressure-reducing medicine applied to clinic, pilocarpine is commonly used, the main mechanism is that closed angle glaucoma opens the angle of the atrium by contracting the sphincter pupillae, and open angle glaucoma can increase the outflow of aqueous humor through trabecular meshwork and restore the normal circulation of aqueous humor. Is a short-term pressure reduction means before operation, in emergency treatment and the like, is not used as a long-term medicament independently, and is often used together with other medicaments.
(4) Beta adrenoceptor blockers: it is divided into selective blockers (betaxolol, etc.) and non-selective blockers (timolol, carteolol, etc.), which reduce intraocular pressure mainly by inhibiting aqueous humor formation.
(5) Carbonic anhydrase inhibitors: mainly comprises acetazolamide, methazolamide, brinzolamide and the like, can inhibit the activity of carbonic anhydrase in ciliary epithelial cells to reduce the secretion of aqueous humor so as to reduce intraocular pressure, and has oral administration and local eye drops as administration modes.
Among the above drugs, prostaglandin derivatives account for the largest share in the international market at present. International ophthalmologists believe that prostaglandins are most effective in open angle glaucoma and have minimal side effects. However, the price of imported drugs is much higher than that of other anti-glaucoma drugs, and the imported eye drops cannot be reimbursed, so that the glaucoma patients in China currently use domestic beta-blocker glaucoma eye drops, and the most common variety is 'timolol maleate' eye drops. Since prolonged use of timolol (i.e., timolol) causes symptoms such as heart rate changes, bronchospasm, etc., such ophthalmic drugs are rarely used in developed countries. Since timolol has side effects and the imported prostanoid is expensive, development of the prostanoid to replace the imported product is expected to have a wide market space. However, at present, China has no independently innovative anti-glaucoma drug.
Disclosure of Invention
The technical problem to be solved by the present invention is to provide a novel prostaglandin derivative having a desirable intraocular pressure lowering effect.
The present invention also provides a pharmaceutical composition comprising the above novel prostaglandin derivative, a stereoisomer, a pharmaceutically acceptable salt, a solvate or a crystal thereof, which can be used for the prevention and/or treatment of glaucoma or ocular hypertension.
The invention also provides application of the novel prostaglandin derivative in preparation of drugs for preventing and/or treating glaucoma.
In order to solve the technical problems, the invention adopts the following technical scheme:
a prostaglandin derivative having the formula (I) or an isomer, a pharmaceutically acceptable salt, a solvate or a crystal thereof (sometimes collectively referred to herein as "the present compound"):
Figure BDA0002428546720000021
wherein:
x is O, S or NH;
y is-CnH2n-, and n is 1, 2, 3, 4, 5, 6, 7 or 8;
R1、R2independently selected from hydroxy, mercapto, carbonyl, C1-6Alkoxy, carboxyl, halogen and hydrogen, and R1、R2Not halogen or hydrogen at the same time;
R3、R4one of them is hydrogen and the other is selected from hydroxyl, mercapto, halogen, C1-6Alkoxy, carboxyl and hydrogen, or; r3、R4Together form-OCpH2pO-or carbonyl, wherein p is 2, 3 or 4; or, R3、R4Are all halogen;
R5selected from hydrogen, C1-6Alkyl radical, C1-6Alkoxy, halogen, C1-6A haloalkyl group;
m is 1, 2, 3, 4 or 5, and when m is greater than 1, a plurality of R5The same or different.
In the present invention, halogen may be fluorine, chlorine, bromine or iodine, and preferably fluorine, chlorine or bromine.
According to some preferred and specific aspects of the invention, Y is-CH2-、-CH2CH2-、-CH2CH2CH2-、-CH2CH2CH2CH2-or-CH2CH2CH2CH2CH2CH2-。
According to some preferred and specific aspects of the invention, R1、R2Independently selected from hydroxy, mercapto, carbonyl, C1-6An alkoxy group. In some embodiments of the invention, C1-6The alkoxy group may be methoxy, ethoxy, propoxy, butoxy, isopropoxy, and the like.
According to some preferred and specific aspects of the invention, R1、R2Are all hydroxyl; or, R1、R2One of which is a hydroxyl group and the other is a carbonyl group.
According to some preferred and specific aspects of the present invention, the prostaglandin derivative has a structure represented by the following formula (I-a):
Figure BDA0002428546720000031
wherein each group is as defined above.
According to some preferred and specific aspects of the invention, R3、R4One of which is hydrogen and the other is selected from hydroxy, mercapto, methoxy, fluoro, chloro.
According to further aspects of the invention, R3、R4And is also fluorine.
According to some specific aspects of the invention, R5Selected from hydrogen, methyl, ethyl, isopropyl, methoxy, fluoro, chloro, bromo, fluoromethyl, chloromethyl, bromomethyl.
According to some preferred aspects of the present invention, the prostaglandin derivative has a structure represented by the following formula (I-b):
Figure BDA0002428546720000041
wherein each group is as defined in the preceding claims.
According to some preferred and specific aspects of the invention, in formula (I-b), n is 3 or 4 or 5, R4Is hydroxy, mercapto or fluoro; r5Is hydrogen, trifluoromethyl, methyl, methoxy, fluorine, chlorine or bromine.
According to some preferred and specific aspects of the present invention, the prostaglandin derivative is selected from the following compounds:
Figure BDA0002428546720000042
the invention provides another technical scheme that: a pharmaceutical composition for preventing and/or treating glaucoma or ocular hypertension, comprising one or more prostaglandin derivatives selected from the group consisting of the above-mentioned stereoisomers, pharmaceutically acceptable salts, solvates or crystals thereof.
One skilled in the art will readily recognize that for administration or manufacture of a medicament, the disclosed compounds may be combined with pharmaceutically acceptable adjuvants, which are well known per se in the art, to form a pharmaceutical composition. Especially for topical administration to the eye, in the form of eye drops; preferably aqueous solution eye drops, oily solution eye drops, suspension eye drops, emulsion eye drops, ophthalmic ointment or the like; the pharmaceutical compositions optionally include pharmaceutically acceptable adjuvants in the carrier, such as water, saline, aqueous dextrose, glycerol, ethanol, and the like, to form solutions or suspensions. If desired, the pharmaceutical compositions to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like. Specific methods of preparing these dosage forms are known or will be apparent to those skilled in the art.
The pharmaceutical composition according to the invention, wherein the compound of the invention is preferably present in a therapeutically effective amount.
The invention also provides the application of the prostaglandin derivative or the isomer, the pharmaceutically acceptable salt, the hydrate, the solvate, the crystal or the pharmaceutical composition of the prostaglandin derivative in treating and/or preventing glaucoma or ocular hypertension.
The present invention also relates to a method of treating a patient suffering from glaucoma or ocular hypertension, comprising administering to the patient suffering from glaucoma or ocular hypertension the above-described pharmaceutical composition of the present invention.
Due to the implementation of the technical scheme, compared with the prior art, the invention has the following advantages:
the present invention provides a novel prostaglandin derivative which can lower intraocular pressure more significantly than existing prostaglandin derivatives.
Detailed Description
Definition of terms
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
The term "isomer" refers to isomers resulting from the difference in the arrangement of atoms in a molecule in space. Including cis-trans isomers, enantiomers, and conformers. All stereoisomers are within the scope of the present invention. The compounds of the invention may be individual stereoisomers or mixtures of other isomers, such as racemates, or mixtures of all other stereoisomers.
The term "salt" refers to a pharmaceutically acceptable salt of a compound of the present invention with an acid or base.
The term "solvate" refers to a form of a compound of the present invention that forms a solid or liquid complex by coordination with a solvent molecule. Hydrates are a special form of solvates in which coordination occurs with water. Within the scope of the present invention, the solvate is preferably a hydrate.
The term "crystalline" refers to the various solid forms formed by the compounds of the present invention, including crystalline forms, amorphous forms.
The term "hydrogen", when not otherwise specified, comprises all isotopes of hydrogen, specifically protium (H), deuterium (D) or tritium (T), preferably the hydrogens at different positions are independently selected from protium or deuterium. Wherein the "hydrogen" at the active hydrogen position is protium. The term "deuterium" is an isotope of protium with an atomic mass 2 times greater than the latter, and is more strongly bonded to carbon. Deuterated and deuterium means protium is replaced with deuterium at the indicated position.
The following examples are presented to enable one of ordinary skill in the art to more fully understand the present invention and are not intended to limit the invention in any way. All compounds have the structure1H NMR，13C NMR and MS.
Example 1
This example provides a prostaglandin derivative having the following structure:
Figure BDA0002428546720000061
example 2
This example provides a prostaglandin derivative having the following structure:
Figure BDA0002428546720000062
example 3
This example provides a prostaglandin derivative having the following structure:
Figure BDA0002428546720000063
example 4
This example provides a prostaglandin derivative having the following structure:
Figure BDA0002428546720000071
the above description of the embodiments is only intended to facilitate the understanding of the method of the invention and its core idea. It should be noted that, for those skilled in the art, it is possible to make various improvements and modifications to the present invention without departing from the principle of the present invention, and those improvements and modifications also fall within the scope of the claims of the present invention.

Claims (10)

1. A prostaglandin derivative represented by the general formula (I), a stereoisomer, a pharmaceutically acceptable salt, a solvate or a crystal thereof,
Figure FDA0002428546710000011
wherein:
x is O, S or NH;
y is-CnH2n-, and n is 1, 2, 3, 4, 5, 6, 7 or 8;
R1、R2independently selected from hydroxy, mercapto, carbonyl, C1-6Alkoxy, carboxyl, halogen and hydrogen, and R1、R2Not halogen or hydrogen at the same time;
R3、R4one of them is hydrogen and the other is selected from hydroxyl, mercapto, halogen, C1-6Alkoxy, carboxyl and hydrogen, or; r3、R4Together form-OCpH2pO-or carbonyl, wherein p is 2, 3 or 4; or, R3、R4Are all halogen;
R5selected from hydrogen, C1-6Alkyl radical, C1-6Alkoxy, halogen, C1-6A haloalkyl group;
m is 1, 2, 3, 4 or 5, and when m is greater than 1, a plurality of R5The same or different.
2. The prostaglandin derivative according to claim 1, a stereoisomer, a pharmaceutically acceptable salt, a solvate, or a crystal thereof, wherein: y is-CH2-、-CH2CH2-、-CH2CH2CH2-、-CH2CH2CH2CH2-or-CH2CH2CH2CH2CH2CH2-。
3. The prostaglandin derivative according to claim 1, a stereoisomer, a pharmaceutically acceptable salt, a solvate, or a crystal thereof, wherein: r1、R2Independently selected from hydroxy, mercapto, carbonyl, C1-6An alkoxy group.
4. The prostaglandin derivative according to claim 1, a stereoisomer, a pharmaceutically acceptable salt, a solvate, or a crystal thereof, wherein: r1、R2Are all hydroxyl; or, R1、R2One of which is a hydroxyl group and the other is a carbonyl group.
5. The prostaglandin derivative according to claim 1, a stereoisomer, a pharmaceutically acceptable salt, a solvate, or a crystal thereof, wherein: the prostaglandin derivative has a structure shown as the following formula (I-a):
Figure FDA0002428546710000021
wherein each group is as defined in the preceding claims.
6. The prostaglandin derivative according to claim 1, a stereoisomer, a pharmaceutically acceptable salt, a solvate, or a crystal thereof, wherein: r3、R4One of which is hydrogen and the other is selected from hydroxy, mercapto, methoxy, fluoro, chloro, or R3、R4And at the same time is fluorine; and/or, R5Selected from hydrogen, methyl, ethyl, isopropyl, methoxy, fluoro, chloro, bromo, fluoromethyl, chloromethyl, bromomethyl.
7. The prostaglandin derivative, a stereoisomer, a pharmaceutically acceptable salt, a solvate, or a crystal thereof according to any one of claims 1 to 6, characterized in that: the prostaglandin derivative has a structure shown as the following formula (I-b):
Figure FDA0002428546710000022
wherein each group is as defined in the preceding claims.
8. The prostaglandin derivative according to claim 7, a stereoisomer, a pharmaceutically acceptable salt, a solvate, or a crystal thereof, wherein: in the formula (I-b), n is 3 or 4 or 5, R4Is hydroxy, mercapto or fluoro; r5Is hydrogen, trifluoromethyl, methyl, methoxy, fluorine, chlorine or bromine.
9. The prostaglandin derivative according to claim 1, a stereoisomer, a pharmaceutically acceptable salt, a solvate, or a crystal thereof, wherein: the prostaglandin derivative is selected from the following compounds:
Figure FDA0002428546710000031
10. a pharmaceutical composition for preventing and/or treating glaucoma or ocular hypertension, characterized in that: comprising one or more prostaglandin derivatives, stereoisomers, pharmaceutically acceptable salts, solvates or crystals thereof, selected from the group as claimed in any of claims 1 to 9.
CN202010228516.7A 2020-03-27 2020-03-27 Novel prostaglandin derivative, pharmaceutical composition and use Pending CN113443993A (en)

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