CN112174863A - Aromatic derivative, pharmaceutical composition containing same and application - Google Patents

Aromatic derivative, pharmaceutical composition containing same and application Download PDF

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CN112174863A
CN112174863A CN201910598718.8A CN201910598718A CN112174863A CN 112174863 A CN112174863 A CN 112174863A CN 201910598718 A CN201910598718 A CN 201910598718A CN 112174863 A CN112174863 A CN 112174863A
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substituted
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aromatic derivative
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殷建明
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Jinfu Pharmaceutical Suzhou Co ltd
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Abstract

The invention relates to a novel aromatic derivative, application thereof in preparing a medicament for preventing and/or treating indications related to PPAR functions and a pharmaceutical composition containing the same. The structural general formula of the aromatic derivative is shown as the formula (I) and the formula (II). The aromatic derivatives of the present invention are ideal potent PPAR agonists and are useful for the treatment or prevention of diseases associated with cerebral blood vessels and inflammation, as well as diseases associated with neurodegeneration, lipid or glucose metabolism disorders, cell proliferation and differentiation, aging of the skin or central nervous system, and the like.

Description

Aromatic derivative, pharmaceutical composition containing same and application
Technical Field
The invention relates to an aromatic derivative, and application and a pharmaceutical composition thereof.
Background
Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear receptors activated by ligands, including PPARalpha, PPARbeta and PPARgamma. PPAR is distributed in various organs, PPAR α is highly expressed in liver, skeletal muscle, kidney, heart and blood vessel wall, PPAR β/is relatively highly expressed in brain, stomach and colon, and PPAR γ is expressed in adipose tissue, vascular smooth muscle tissue and cardiac muscle tissue.
PPARs play an important role in regulating cell differentiation, development, metabolism and tumorigenesis. For example, activation of PPAR α lowers triglyceride levels and is involved in the regulation of energy homeostasis, activation of PPAR β/causes insulin sensitization and enhances glucose metabolism, and activation of PPAR γ enhances fatty acid metabolism.
Disclosure of Invention
The technical problem to be solved by the present invention is to provide a novel aromatic derivative, which is an ideal PPAR agonist, and which is useful for effectively preventing or treating diseases associated with cerebrovascular and inflammatory diseases, and diseases associated with neurodegeneration, lipid or glucose metabolism disorder, cell proliferation and differentiation, and skin or central nervous system aging.
In order to solve the technical problems, the invention adopts the following technical scheme:
an aromatic derivative, a pharmaceutically acceptable salt, a hydrate thereof, or a metabolite thereof formed by metabolism in any form, wherein the aromatic derivative has a structural general formula shown in formula (I) or (II):
Figure BDA0002118540160000011
wherein:
R1、R2、R3independently selected from hydrogen, halogen, C1-6Haloalkyl, cyano, -OR8、-SR8Wherein R is8Selected from hydrogen, substituted/unsubstituted alkyl;
R4、R5independently selected from hydrogen, substituted/unsubstituted alkyl;
R6is-OR9、-SR9Wherein R is9Selected from hydrogen, unsubstituted or substituted by radicals selected from-COOR10、-CONR11R12、-SOR10、-SO2R11Substituted C1-6Alkyl radical, wherein R10、R11、R12Selected from hydrogen, C1-6An alkyl group;
R7selected from hydrogen, substituted/unsubstituted alkyl;
w is CR13R14Or C ═ O, where R13、R14Independently selected from hydrogen, substituted/unsubstituted alkyl;
x is N or CR15，R15Selected from hydrogen, substituted/unsubstituted alkyl;
y is N or CR16，R16Selected from hydrogen, substituted/unsubstituted alkyl;
said substituted alkyl is selected from C1-6Alkoxy radical, C1-6Alkylcarbonyl, halogen, cyano, C1-6An alkyl group substituted with one or two or more substituent groups among the haloalkyl groups;
the halogen comprises fluorine, chlorine, bromine;
the aromatic derivatives, pharmaceutically acceptable salts, hydrates, or metabolites formed by metabolism in any form, have non-exchangeable hydrogens that are unsubstituted or partially or fully substituted with deuterium.
Preferably, the substituted/unsubstituted alkyl group is a substituted/unsubstituted straight, branched or cyclic C1-8An alkyl group.
In some embodiments according to the invention, the substituted/unsubstituted alkyl is substituted/unsubstituted methyl, ethyl, propyl, butyl, isopropyl, fluoro, chloro, cyano, methoxy, ethoxy, hydroxy, cyclopropyl, cyclobutyl or cyclopentyl.
Preferably, R1、R2、R3The three are not hydrogen at the same time.
Preferably, R1、R2、R3At least one, preferably two, of them are selected from halogen, C1-6Haloalkyl, cyano, -OR8、-SR8. Further preferably, R1、R2、R3At least one, preferably two, selected from fluorine, chlorine, trifluoromethyl, -SH, -OH and-SCH3、-SCH2CH3Methoxy, ethoxy, methylcarbonyloxy, ethylcarbonyloxy.
Preferably, R4、R5、R6At most two of the three are hydrogen.
Preferably, R4Is hydrogen.
Preferably, R5Is C1-6Alkyl, fluoro, chloro.
Preferably, R6is-OR9、-SR9Wherein R is9Selected from-COOH, -COOCH3、-COOCH2CH3、-COOCH(CH3)2、-CONH2、-CONHCH3、-CONHCH2CH3、-CON(CH3)2、-SOCH3、-SOCH2CH3、-SOCH(CH3)2、-SO2CH3、-SO2CH2CH3、-SO2CH(CH3)2Substituted C1-6An alkyl group. Wherein C is1-6The alkyl group is more preferably ethyl or isoPropyl, and the like.
In some embodiments according to the invention, R9Is unsubstituted or substituted isopropyl. Further preferably, R9Is selected from-COOH, -COOCH3、-COOCH2CH3、-COOCH(CH3)2、-CONH2、-CONHCH3、-CONHCH2CH3、-CON(CH3)2、-SOCH3、-SOCH2CH3、-SOCH(CH3)2、-SO2CH3、-SO2CH2CH3、-SO2CH(CH3)2A substituted isopropyl group.
Further, X is preferably N, CH or C-OH.
Further, Y is preferably N, CH, C-OH or C-CH3。
Further, W is preferably CH2Or C ═ O.
Further, in the aromatic derivative, the pharmaceutically acceptable salt, the hydrate thereof, or the metabolite formed by metabolism in any form, the non-exchangeable hydrogen is unsubstituted, or partially or fully substituted by deuterium. In some embodiments, one, two, three, four, five, six, and more hydrogens of the non-exchangeable hydrogens are replaced with deuterium.
Typical aromatic derivatives of the present invention are, for example, the compounds shown below.
Figure BDA0002118540160000031
Figure BDA0002118540160000041
The present invention also provides a pharmaceutical composition for preventing and/or treating an indication related to PPAR function, comprising the aromatic derivative, the pharmaceutically acceptable salt, the hydrate thereof, or the metabolite formed by metabolism in any form, as described above.
Further, the indications related to PPAR function include diseases related to cerebral blood vessels and inflammation, and diseases related to neurodegeneration, lipid or glucose metabolism disorder, cell proliferation and differentiation, skin or central nervous system aging, and the like.
The pharmaceutical composition according to the invention, wherein the compound according to the invention is preferably present in a therapeutically effective amount.
The pharmaceutical composition also comprises pharmaceutically acceptable carriers, such as pharmaceutically acceptable diluent, excipient, filler, binder, disintegrant, absorption enhancer, surfactant, lubricant, flavoring agent, sweetener, etc.
The medicine prepared by taking the compound of the invention as an active ingredient can be various forms such as tablets, powder, capsules, granules, oral liquid, injection preparations and the like.
The medicaments in various dosage forms can be prepared by the conventional method in the pharmaceutical field.
According to the invention, the compound not only comprises a single compound form, but also comprises a plurality of compound mixtures with the structure meeting the requirements of the general formula (I), and different isomer forms of the same compound, such as raceme, enantiomer, diastereoisomer and the like. The pharmaceutically acceptable salts include, but are not limited to, hydrochloride, phosphate, sulfate, acetate, maleate, benzenesulfonate, benzoate, methylbenzenesulfonate, succinate, fumarate, tartrate, gallate, citrate, and the like. The "prodrug of the compound having the general formula (I)" refers to a substance which, when administered by an appropriate method, undergoes a metabolic or chemical reaction in a subject to be converted into at least one compound of the structural formula (I) or a salt thereof.
The compounds of the invention may be prepared by synthetic routes analogous to those well known in the chemical arts, particularly by synthesizing the compounds of the invention according to the description contained herein. Reagents are generally obtained from commercial sources or readily prepared using methods well known to those skilled in the art.
Due to the implementation of the technical scheme, compared with the prior art, the invention has the following advantages:
the compounds provided by the present invention are novel aromatic derivatives that are ideal, highly potent PPAR agonists. The compounds of the present invention are therefore useful in the preparation of a medicament for the treatment or prevention of a variety of indications related to PPAR function, including but not limited to diseases associated with cerebral blood vessels and inflammation, as well as diseases associated with neurodegeneration, lipid or glucose metabolism disorders, cell proliferation differentiation, skin or central nervous system aging, and the like.
Detailed Description
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 "salt" refers to a pharmaceutically acceptable salt of a compound of the invention with an acid, which may be an organic or inorganic acid, and is specifically selected from: phosphoric acid, sulfuric acid, hydrochloric acid, hydrobromic acid, citric acid, maleic acid, malonic acid, mandelic acid, succinic acid, fumaric acid, acetic acid, lactic acid, nitric acid, sulfonic acid, p-toluenesulfonic acid, malic acid, methanesulfonic acid, or the like.
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 "hydrocarbyl" refers to a straight, branched, or cyclic, saturated or unsaturated substituent consisting essentially of carbon and hydrogen. Preferably 1 to 20 carbon atoms, more preferably 1 to 12 carbon atoms. The term "alkyl" refers to a straight, branched, or cyclic saturated hydrocarbon group. Alkyl includes in particular methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, cyclobutyl, n-pentyl, isopentyl, neopentyl, cyclohexyl, n-hexyl, isohexyl, 2, -methylbutyl and 2, 3-dimethylbutyl, 16-alkyl, 18-alkyl. The term "C1-6 alkyl" refers to a straight, branched, or cyclic saturated hydrocarbon group containing 1 to 6 carbon atoms. Alkyl radicals including substitutedAnd unsubstituted alkyl. When the alkyl group is substituted, the substituent may be substituted at any available point of attachment, and the substituent may be mono-or poly-substituted. The substituents are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, deuterium, halogen, thiol, hydroxy, nitro, carboxy, ester, cyano, cycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, oxo, the substituents usually being placed before the alkyl group when named, e.g. C1-3Alkoxy substituted C1-3An alkyl group.
The term "cycloalkyl" refers to a saturated and/or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group. A single ring may comprise 3-10 carbon atoms. Non-limiting examples of monocyclocycloalkane groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl and the like. Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups. Cycloalkyl includes unsubstituted and substituted. The substituent is selected from one or more substituent groups, including but not limited to the following groups, independently selected from alkyl, cycloalkyl, alkoxy, halogen, carboxyl, ester group, amino, amido, hydroxyl, cyano, nitro, aryl, heteroaryl.
The term "halogen" means fluorine, chlorine, bromine, iodine, preferably fluorine, chlorine, bromine. The term "haloalkyl" refers to an alkyl group substituted with at least one halogen atom.
The term "deuterium" is an isotope of hydrogen with an atomic mass 2 times that of the latter and is more strongly bound to carbon. Deuterated "and" deuterium "indicate that hydrogen is replaced with deuterium at the indicated position. One "deuterated substituent" is a substituent wherein at least one hydrogen is replaced with deuterium enriched in the specified percentage.
The present invention will be described in further detail with reference to specific examples, but the present invention is not limited to the following examples.
Example 1
This example provides a compound represented by the formula (I-1):
Figure BDA0002118540160000061
example 2
This example provides a compound represented by the formula (I-2):
Figure BDA0002118540160000062
example 3 this example provides a compound represented by the formula (I-4):
Figure BDA0002118540160000071
example 4 this example provides a compound represented by the formula (I-6):
Figure BDA0002118540160000072
example 5 this example provides a compound represented by the formula (I-7):
Figure BDA0002118540160000073
example 6 this example provides a compound represented by the formula (I-13):
Figure BDA0002118540160000074
example 7 this example provides a compound represented by the formula (I-14):
Figure BDA0002118540160000075
example 8 this example provides a compound represented by formula (II-1):
Figure BDA0002118540160000081
example 9 this example provides a compound represented by formula (II-3):
Figure BDA0002118540160000082
example 10 this example provides a compound represented by formula (II-7):
Figure BDA0002118540160000083
example 11 this example provides a compound represented by formula (II-10):
Figure BDA0002118540160000084
example 12
This example provides a compound represented by the formula (II-15):
Figure BDA0002118540160000091
the above embodiments are merely illustrative of the technical ideas and features of the present invention, and the purpose thereof is to enable those skilled in the art to understand the contents of the present invention and implement the present invention, and not to limit the protection scope of the present invention. All equivalent changes and modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.

Claims (10)

1. An aromatic derivative, a pharmaceutically acceptable salt, hydrate, or metabolite formed metabolically in any form, characterized by: the structural general formula of the aromatic derivative is shown as the formula (I) or (II):
Figure FDA0002118540150000011
wherein:
R1、R2、R3independently selected from hydrogen, halogen, C1-6Haloalkyl, cyano, -OR8、-SR8Wherein R is8Selected from hydrogen, substituted/unsubstituted alkyl;
R4、R5independently selected from hydrogen, substituted/unsubstituted alkyl;
R6is-OR9、-SR9Wherein R is9Selected from hydrogen, unsubstituted or substituted by radicals selected from-COOR10、-CONR11R12、-SOR10、-SO2R11Substituted C1-6Alkyl radical, wherein R10、R11、R12Selected from hydrogen, C1-6An alkyl group;
R7selected from hydrogen, substituted/unsubstituted alkyl;
w is CR13R14Or C ═ O, where R13、R14Independently selected from hydrogen, substituted/unsubstituted alkyl;
x is N or CR15，R15Selected from hydrogen, substituted/unsubstituted alkyl;
y is N or CR16，R16Selected from hydrogen, substituted/unsubstituted alkyl;
said substituted alkyl is selected from C1-6Alkoxy radical, C1-6Alkylcarbonyl, halogen, cyano, C1-6An alkyl group substituted with one or two or more substituent groups among the haloalkyl groups;
the halogen comprises fluorine, chlorine, bromine;
the aromatic derivatives, pharmaceutically acceptable salts, hydrates, or metabolites formed by metabolism in any form, have non-exchangeable hydrogens that are unsubstituted or partially or fully substituted with deuterium.
2. The aromatic derivative according to claim 1, which is a pharmaceutically acceptable salt, hydrate, or metabolite formed metabolically in any form, characterized in that: the takingSubstituted/unsubstituted alkyl is substituted/unsubstituted straight, branched or cyclic C1-8An alkyl group.
3. The aromatic derivative according to claim 1, which is a pharmaceutically acceptable salt, hydrate, or metabolite formed metabolically in any form, characterized in that: the substituted/unsubstituted alkyl group is a substituted/unsubstituted methyl, ethyl, propyl, butyl, isopropyl, fluoro, chloro, cyano, methoxy, ethoxy, hydroxy, cyclopropyl, cyclobutyl, or cyclopentyl group.
4. The aromatic derivative according to claim 1, which is a pharmaceutically acceptable salt, hydrate, or metabolite formed metabolically in any form, characterized in that: r1、R2、R3The three are not hydrogen at the same time; preferably, R1、R2、R3At least one, preferably two, of them are selected from halogen, C1-6Haloalkyl, cyano, -OR8、-SR8(ii) a Further preferably, R1、R2、R3At least one, preferably two, selected from fluorine, chlorine, trifluoromethyl, -SH, -OH and-SCH3、-SCH2CH3Methoxy, ethoxy, methylcarbonyloxy, ethylcarbonyloxy.
5. The aromatic derivative according to claim 1, which is a pharmaceutically acceptable salt, hydrate, or metabolite formed metabolically in any form, characterized in that: r4、R5、R6At most two of the three being hydrogen, preferably, R4Is hydrogen; preferably, R5Is C1-6Alkyl, fluoro, chloro.
6. The aromatic derivative according to claim 1, which is a pharmaceutically acceptable salt, hydrate, or metabolite formed metabolically in any form, characterized in that: r6is-OR9、-SR9Wherein R is9Selected from-COOH, -COOCH3、-COOCH2CH3、-COOCH(CH3)2、-CONH2、-CONHCH3、-CONHCH2CH3、-CON(CH3)2、-SOCH3、-SOCH2CH3、-SOCH(CH3)2、-SO2CH3、-SO2CH2CH3、-SO2CH(CH3)2Substituted C1-6An alkyl group.
7. The aromatic derivative according to claim 1 or 6, which is a pharmaceutically acceptable salt, hydrate, or metabolite formed metabolically in any form, characterized in that: r9Is unsubstituted or substituted isopropyl.
8. The aromatic derivative according to claim 1, which is a pharmaceutically acceptable salt, hydrate, or metabolite formed metabolically in any form, characterized in that: x is N, CH, C-OH; and/or Y is N, CH, C-OH, C-CH3(ii) a And/or W is CH2Or C ═ O.
9. The aromatic derivative according to claim 1, which is a pharmaceutically acceptable salt, hydrate, or metabolite formed metabolically in any form, characterized in that: the aromatic derivative is one or a mixture of compounds represented by the following structural formula:
Figure FDA0002118540150000021
Figure FDA0002118540150000031
Figure FDA0002118540150000041
10. a pharmaceutical composition for the prevention and/or treatment of indications related to PPAR function, characterized in that: comprising the aromatic derivative, the pharmaceutically acceptable salt, the hydrate thereof, or the metabolite thereof formed metabolically in any form, according to any one of claims 1 to 9, for indications relating to PPAR function including, but not limited to, diseases associated with cerebral blood vessels and inflammation, and diseases associated with neurodegeneration, disorders of lipid or glucose metabolism, cell proliferation and differentiation, skin or central nervous system aging, and the like.
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