CN116606340A - Steroid compound, preparation method, application and pharmaceutical composition thereof - Google Patents
Steroid compound, preparation method, application and pharmaceutical composition thereof Download PDFInfo
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- CN116606340A CN116606340A CN202211257431.7A CN202211257431A CN116606340A CN 116606340 A CN116606340 A CN 116606340A CN 202211257431 A CN202211257431 A CN 202211257431A CN 116606340 A CN116606340 A CN 116606340A
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- -1 Steroid compound Chemical class 0.000 title claims abstract description 28
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 10
- 150000003431 steroids Chemical class 0.000 claims abstract description 11
- 150000001875 compounds Chemical class 0.000 claims description 84
- 238000006243 chemical reaction Methods 0.000 claims description 36
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- 125000000217 alkyl group Chemical group 0.000 claims description 22
- 230000009471 action Effects 0.000 claims description 20
- 239000003153 chemical reaction reagent Substances 0.000 claims description 20
- 239000002904 solvent Substances 0.000 claims description 16
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 15
- 239000003513 alkali Substances 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 12
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 12
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 claims description 10
- 239000002585 base Substances 0.000 claims description 8
- 230000008569 process Effects 0.000 claims description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 7
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- 230000002140 halogenating effect Effects 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- MENYRYNFSIBDQN-UHFFFAOYSA-N 5,5-dibromoimidazolidine-2,4-dione Chemical compound BrC1(Br)NC(=O)NC1=O MENYRYNFSIBDQN-UHFFFAOYSA-N 0.000 claims description 4
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 4
- 150000001408 amides Chemical class 0.000 claims description 4
- 238000005893 bromination reaction Methods 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
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- 125000003118 aryl group Chemical group 0.000 description 4
- 238000007664 blowing Methods 0.000 description 4
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 4
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- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 3
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- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 3
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- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical group [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 3
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- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 3
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 2
- NVKAWKQGWWIWPM-ABEVXSGRSA-N 17-β-hydroxy-5-α-Androstan-3-one Chemical compound C1C(=O)CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@H]21 NVKAWKQGWWIWPM-ABEVXSGRSA-N 0.000 description 2
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- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
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- 229910000020 calcium bicarbonate Inorganic materials 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
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- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
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- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
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- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
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- 239000011630 iodine Substances 0.000 description 1
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- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 1
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- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
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- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
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- 150000007524 organic acids Chemical class 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
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- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
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- 239000011734 sodium Substances 0.000 description 1
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- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
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- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000004289 sodium hydrogen sulphite Substances 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
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- 208000024891 symptom Diseases 0.000 description 1
- ISXSCDLOGDJUNJ-UHFFFAOYSA-N tert-butyl prop-2-enoate Chemical compound CC(C)(C)OC(=O)C=C ISXSCDLOGDJUNJ-UHFFFAOYSA-N 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
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- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
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- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J3/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by one carbon atom
- C07J3/005—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by one carbon atom the carbon atom being part of a carboxylic function
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Urology & Nephrology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Steroid Compounds (AREA)
Abstract
The application relates to a steroid compound, a preparation method, application and a pharmaceutical composition thereof. The C-10 methyl of the steroid derivative is in a reversed alpha configuration, shows good pharmaceutical activity for treating benign prostatic hyperplasia, and has obviously improved dissolution under acidic condition, is favorable for gastrointestinal tract absorption and has higher bioavailability.
Description
Technical Field
The application relates to the technical field of medicines, in particular to a steroid compound, a preparation method, application and a pharmaceutical composition thereof.
Background
Eplerenone, also known as irinotecan, has the chemical name 17β (N-tert-butyl-amino-formyl) androstane-3, 5-diene-3-carboxylic acid, and has the structural formula shown below, and is a novel 5α reductase inhibitor, which inhibits the conversion of testosterone into dihydrotestosterone by forming a ternary complex with steroid 5α reductase and nicotinamide adenine dinucleotide phosphate, thereby reducing the content of dihydrotestosterone in the prostate and causing hyperplastic prostate atrophy. Clinical application shows that eplerenone has better curative effects in improving urination symptoms, increasing urine flow rate, reducing residual urine volume, reducing prostate volume and the like, has low adverse reaction incidence rate, and is an ideal benign prostatic hyperplasia treatment drug.
However, eplerenone is a strongly hydrophobic substance, insoluble in water, low in dissolution and low in bioavailability.
Disclosure of Invention
The present application provides a steroid compound having the structure of formula I or a pharmaceutically acceptable salt thereof:
wherein R is selected from C 1~5 An alkyl group;
represents a single bond or a double bond;
when a certain isIn the case of double bonds, adjacent thereto +.>Is a single bond.
In some embodiments of the application, the R is selected from isopropyl, isobutyl, or tert-butyl.
In some embodiments of the application, the steroid is selected from the following structural formulas:
in some embodiments of the application, the steroid is selected from the following structural formulas:
the application provides a preparation method of a steroid compound, which comprises the following steps:
s1: carrying out haloform reaction on the compound of the formula A under the action of a halogenating reagent and alkali to generate a compound of the formula B,
s2: the compound of the formula B is reacted with R-NH under the action of thionyl chloride and alkali 2 Performing an amide reaction to produce a compound of formula C,
s3: carrying out bromination reaction on the compound of the formula C under the action of a brominating reagent to generate a compound of the formula D,
s4: subjecting a compound of formula D to a cyanation reaction under the action of a cyanating reagent to produce a compound of formula E,
and
s5: the compound of formula E is subjected to a hydrolysis reaction under the action of a base to produce the compound of formula I.
In some embodiments of the application, the compound of formula A has the structure of formula A1,
in some embodiments of the application, the compound of formula B has the structure of formula B1,
in some embodiments of the application, the compound of formula C has the structure of formula C1,
in some embodiments of the application, the compound of formula D has the structure of formula D1,
in some embodiments of the application, the compound of formula E has the structure of formula E1,
in some embodiments of the application, the compound of formula C has the structure of formula C2,
in some embodiments of the application, the compound of formula D has the structure of formula D2,
in some embodiments of the application, the compound of formula E has the structure of formula E2,
in some embodiments of the application, in step S1,
the halogenating agent is selected from bromine, dibromohydantoin, dichlorohydantoin, N-bromosuccinimide (NBS) or N-chlorosuccinimide (NCS);
the alkali is selected from sodium hydroxide or potassium hydroxide; and/or
The step S1 is carried out in the presence of a solvent selected from 1, 4-dioxane; and/or
The reaction temperature of the step S1 is 0 to 20 ℃.
In some embodiments of the application, in step S2,
the base is selected from triethylamine, pyridine or N, N-dimethylformamide; and/or
The step S2 is carried out in the presence of a solvent selected from dichloromethane, chloroform or tetrahydrofuran; and/or
The reaction temperature of the step S2 is 0 to 20 ℃.
In some embodiments of the application, in step S3,
the brominating reagent is selected from phosphorus tribromide or boron tribromide; and/or
The step S3 is performed in the presence of a solvent selected from formic acid or acetic acid; and/or
The reaction temperature of the step S3 is 20 to 40 ℃.
In some embodiments of the application, in step S4,
the cyanating reagent is selected from cuprous cyanide; and/or
The step S4 is performed in the presence of a solvent selected from the group consisting of N, N-dimethylformamide; and/or
The reaction temperature of the step S4 is 160 to 200 ℃.
In some embodiments of the present application, in step S5,
the alkali is selected from sodium hydroxide or potassium hydroxide; and/or
The step S5 is performed in the presence of a solvent selected from ethanol or methanol; and/or
The reaction temperature of step S5 is 60 to 80 ℃.
The application provides application of the steroid compound in preparing medicines for treating prostatic diseases.
In some embodiments of the application, the prostate disease includes decreased urine flow rate, increased residual urine volume, increased prostate volume, and/or benign prostatic hyperplasia.
The application provides a pharmaceutical composition, which comprises the steroid compound and pharmaceutically acceptable auxiliary materials.
In contrast to the prior art, the present application unexpectedly achieves at least the following beneficial technical effects, for example:
the C-10 methyl of the compound is alpha configuration, and the drug activity for treating benign prostatic hyperplasia is equivalent to or even higher than that of eplerenone;
unexpectedly, compared with eplerenone, the compound has obviously improved dissolution under acidic condition, is favorable for gastrointestinal tract absorption and has higher bioavailability.
In addition, the synthetic route of the steroid compound has the advantages of easily obtained raw materials, simple process, relatively mild reaction conditions and high total yield, and has good application and industrialization prospects.
Detailed Description
The present application will be described in further detail below in order to make the objects, technical solutions and advantages of the present application more apparent. It is to be understood that the description is only intended to illustrate the application and is not intended to limit the scope of the application.
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 application belongs, and the terms used herein in this description of the application are for the purpose of describing particular embodiments only and are not intended to be limiting of the application. Reagents and instruments used herein are commercially available, and reference to characterization means is made to the relevant description of the prior art and will not be repeated herein.
Definition of the definition
In the present application, the term "alkyl" refers to a straight or branched chain saturated aliphatic hydrocarbon group. In some embodiments, the alkyl groups have 1-8 carbon atoms (denoted as C1-8 alkyl). In some embodiments, the alkyl groups have 1-6 carbon atoms (C1-6 alkyl). In some embodiments, the alkyl groups have 1-3 carbon atoms (C1-3 alkyl groups). Non-limiting examples of C1-6 alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, and various branched isomers thereof, and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, carbocyclyl, alkoxy, halogen, hydroxy, oxo, amino, acyl, acyloxy, or ester groups.
The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond. In some embodiments, alkenyl is C2-8 alkenyl. In some embodiments, alkenyl is C2-6 alkenyl. In some embodiments, alkenyl is C2-4 alkenyl. The carbon-carbon double bond may be internal (e.g., in 2-butenyl) or terminal (e.g., in 1-butenyl). Non-limiting examples of C2-6 alkenyl groups include vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, and the like. Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, alkoxy, halogen, hydroxy, oxo, amino, acyl, acyloxy, or ester groups.
The term "alkynyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond. In some embodiments, alkynyl is C2-8 alkynyl. In some embodiments, alkynyl is C2-6 alkynyl. In some embodiments, alkynyl is C2-4 alkynyl. Non-limiting examples include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, and the like. Alkynyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, alkoxy, halogen, hydroxy, oxo, amino, acyl, acyloxy or ester groups.
"alkoxy" refers to-O- (alkyl) and-O- (cycloalkyl), wherein alkyl and carbocyclyl are as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopentyloxy, cyclohexyloxy, and the like.
"ester" refers to the group-COORc, wherein Rc is alkyl, alkenyl, alkynyl, carbocyclyl, or aryl as defined herein.
"haloalkyl" refers to an alkyl group substituted with one or more halogens, where alkyl is as defined above.
"halogen" means fluorine, chlorine, bromine or iodine.
When numerical ranges are recited, each numerical value and subrange within the stated range is intended to be included. For example, "C1-6 alkyl" includes C1, C2, C3, C4, C5, C6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl.
"plurality" means two or more, for example, 2-5, 2-3, 2, 3, 4, or 5, etc.
The different expressions of "X is selected from A, B or C", "X is selected from A, B and C", "X is A, B or C", "X is A, B and C", etc. all express the same meaning, that is, X can be any one or several of A, B, C.
"optional" or "optionally," "optionally," or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "aryl optionally substituted with alkyl" means that alkyl groups may be, but need not be, present, and the description includes both cases where aryl is substituted with alkyl and cases where aryl is not substituted with alkyl.
"substituted" means that one or more hydrogen atoms in the group are replaced by a corresponding number of substituents independently of each other. It goes without saying that substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort.
By "pharmaceutically acceptable salt" is meant a salt of a compound of the application which is pharmaceutically acceptable and which has the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic and may be organic or inorganic acid addition salts and base addition salts.
Steroid compounds of the application
For ease of understanding herein, the carbon atom labels of the steroid compounds of the application are shown below, e.g., carbon atom number 10 may be noted as the C-10 position. The four rings are each numbered A, B, C, D from left to right, and the carbon numbers (1-17) on each ring are as follows.
The compounds described herein may exist in a variety of isomeric forms, such as enantiomers and/or diastereomers. For example, the compounds described herein may be individual enantiomers, diastereomers, or geometric isomers, or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers may be separated from the mixtures by methods known to those skilled in the art, including chiral High Pressure Liquid Chromatography (HPLC) and formation and crystallization of chiral salts; alternatively, the preferred isomer may be prepared by asymmetric synthesis. The application additionally includes compounds described herein as individual isomers substantially free of other isomers, or as mixtures of isomers.
The steroid compound provided by the application has a structure shown in the following formula I or pharmaceutically acceptable salt thereof:
in some embodiments of the application, the steroid is selected from the following structural formulas:
in some embodiments of the application, the steroid is selected from the following structural formulas:
use of the steroid compounds of the application
The application provides application of a steroid compound in preparing a medicament for treating prostate diseases.
In the compound of the application, the C-10 methyl is alpha configuration, and compared with the compound eplerenone with the C-10 methyl beta configuration, the drug activity for treating benign prostatic hyperplasia is equivalent to or even higher than that of eplerenone.
However, unexpectedly, although the configuration of the specific group at the specific position is only transformed, namely, the configuration of the C-10 methyl of the epristeride is only adjusted to the alpha configuration from the beta configuration, compared with the epristeride, the compound with the C-10 methyl of the application in the alpha configuration has obviously improved dissolution under the acidic condition, is beneficial to gastrointestinal tract absorption and has higher bioavailability.
Preparation of steroid compounds of the application
The application provides a preparation method of a steroid compound, which comprises the following steps:
s1: carrying out haloform reaction on the compound of the formula A under the action of a halogenating reagent and alkali to generate a compound of the formula B,
s2: the compound of the formula B is reacted with R-NH under the action of thionyl chloride and alkali 2 Performing an amide reaction to produce a compound of formula C,
s3: carrying out bromination reaction on the compound of the formula C under the action of a brominating reagent to generate a compound of the formula D,
s4: subjecting a compound of formula D to a cyanation reaction under the action of a cyanating reagent to produce a compound of formula E,
and
s5: the compound of formula E is subjected to a hydrolysis reaction under the action of a base to produce the compound of formula I.
Specifically, in one embodiment of the present application, the compounds of the present application are synthesized by the following process route.
Specifically, the process route comprises the following steps:
s1: compound 1 (i.e., compound A2) (a known compound, which can be synthesized by the method reported in CN 101360832B) undergoes haloform reaction under the action of a halogenating reagent and a base to produce compound 2 (i.e., compound B2); the halogenating reagent can be bromine, dibromohydantoin, dichloro hydantoin, N-bromosuccinimide (NBS) and N-chlorosuccinimide (NCS), the alkali can be sodium hydroxide or potassium hydroxide, the solvent can be 1, 4-dioxane, and the reaction temperature is 0-20 ℃;
s2: compound 2 (i.e., compound B2) undergoes an amide reaction with tert-butylamine under the action of thionyl chloride and a base to form compound 3 (i.e., compound C2); the alkali can be triethylamine, pyridine, N-Dimethylformamide (DMF), the solvent can be dichloromethane, chloroform and tetrahydrofuran, and the reaction temperature is 0-20 ℃;
s3: compound 3 (i.e., compound C2) undergoes a bromination reaction under the action of a brominating reagent to produce compound 4 (i.e., compound D2); the catalyst can be phosphorus tribromide or boron tribromide, the solvent can be formic acid or acetic acid, and the reaction temperature is 20-40 ℃;
s4: compound 4 (i.e., compound D2) undergoes a cyanation reaction under the action of a cyanating reagent to produce compound 5 (i.e., compound E2); the cyanidation reagent can be cuprous cyanide, the solvent can be N, N-Dimethylformamide (DMF), and the reaction temperature is 160-200 ℃;
s5: the compound 5 (i.e., the compound E2) undergoes a hydrolysis reaction under the action of a base to produce the compound 6 (i.e., the compound I-2); the alkali can be sodium hydroxide and potassium hydroxide, the solvent can be ethanol or methanol, and the reaction temperature is 60-80 ℃.
Specifically, the process route comprises the following steps:
s1: dissolving the compound 1 in 1, 4-dioxane, adding a proper amount of aqueous solution of alkali, slowly adding a halogenated reagent in batches, maintaining a certain reaction temperature, adding an aqueous solution of sodium bisulphate into the reaction solution after the reaction is finished, quenching the reaction, adjusting the pH value to be acidic by hydrochloric acid, distilling at normal pressure to recover the dioxane, filtering, and air-drying to obtain the compound 2;
s2: dissolving the compound 2 and alkali in a solvent, dropwise adding thionyl chloride, reacting for a period of time at a certain temperature, dropwise adding tert-butylamine, maintaining a certain reaction temperature, adding sodium hydroxide aqueous solution after the reaction is finished to quench the reaction, separating liquid, adding a proper amount of water into an organic phase, then decompressing and distilling, cooling and crystallizing, filtering, and drying by blowing to obtain a compound 3;
s3: dissolving the compound 3 in a solvent, slowly dropwise adding a brominating reagent, separating out a large amount of solids after the reaction is finished, cooling for crystallization, filtering, eluting with a small amount of solvent, and drying by blowing to obtain a compound 4;
s4: dissolving the compound 4 in DMF, adding a cyanating reagent, maintaining a certain reaction temperature, filtering to remove insoluble substances after the reaction is finished, filtering, recrystallizing with acetone-water, and drying by air blast to obtain a compound 5;
s5: dissolving the compound 5 and a solvent, adding an aqueous solution of alkali, maintaining a certain reaction temperature, removing the solvent by reduced pressure distillation after the reaction is finished, adjusting the pH by dilute hydrochloric acid, filtering, and drying by blowing to obtain the compound 6.
The synthetic route of the steroid compound has the advantages of easily obtained raw materials, simple process, relatively mild reaction conditions and high total yield, and has good application and industrialization prospects.
Pharmaceutical compositions of the application
The application provides a pharmaceutical composition, which comprises the steroid compound and pharmaceutically acceptable auxiliary materials.
The dosage form of the pharmaceutical composition of the present application comprises: tablets, capsules, granules, powders, suspensions, solutions, emulsions, injections and the like. They are administered by oral, sublingual, injection, etc. routes according to the characteristics of the respective dosage forms.
In some embodiments of the application, the pharmaceutical compositions provided herein are oral solid formulations, preferably tablets. The oral solid preparation contains pharmaceutical excipients besides active ingredients. The pharmaceutical excipients are all pharmaceutical excipients which are conventional in the art and comprise a filling agent (also known as a diluent), a disintegrating agent, an adhesive or wetting agent, a lubricant (comprising a glidant) and the like. The dosage of the pharmaceutical excipients can be conventional dosage.
The fillers generally include lactose, microcrystalline cellulose, mannitol, pregelatinized starch, sucrose, dextrin, sorbitol, calcium carbonate, calcium bicarbonate, hydroxypropyl methylcellulose, ethylcellulose, and the like. They may be used alone or in combination.
The disintegrating agent generally comprises starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose and the like. They may be used alone or in combination.
The binder or wetting agent generally comprises povidone (polyvinylpyrrolidone), hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethylcellulose, polyethylene glycol, starch slurry, water, ethanol solutions of various concentrations, and the like. They may be used alone or in combination.
The lubricant generally comprises zinc stearate, magnesium stearate, calcium stearate, sodium stearyl fumarate, talcum powder, sucrose fatty acid ester, micro silica gel, stearic acid, solid polyethylene glycol and the like. They may be used alone or in combination.
Other adjuvants such as sweetener (such as aspartame, steviosin, etc.), colorant (such as yellow ferric oxide, red ferric oxide, etc.), stabilizer (such as citric acid, lactic acid, malic acid, etc.), and pH regulator (such as sodium bicarbonate, fumaric acid, citric acid, etc.) can be added into the above composition if necessary.
Other suitable active ingredients may also be included in the above compositions, if desired.
The preparation of the above-mentioned oral solid preparation may be carried out according to a conventional method for preparing oral solid preparations in the art, such as: the tablet can be prepared by adopting wet granulation tabletting, dry granulation tabletting, fluid bed granulation tabletting, powder mixing direct tabletting and the like. When the oral solid preparation is a tablet, the tablet can be further coated according to the need to prepare a film coated tablet and a sugar coated tablet. Wherein the coating material comprises celluloses, acrylics and saccharides such as hydroxypropyl methylcellulose and sucrose, and plasticizer, anti-adhesion agent and opacifier can be added.
The present application will be described in further detail with reference to examples.
Example 1
40g of compound 1 is dissolved in 450ml of 1, 4-dioxane, 180ml of 40% sodium hydroxide aqueous solution is added, 80g of dibromohydantoin is slowly added three times, after stirring for 2 hours at room temperature, 40ml of 15% sodium bisulphite is added for quenching reaction, concentrated hydrochloric acid is used for adjusting pH to be=2, 1, 4-dioxane is recovered by normal pressure distillation, 800ml of water is added, stirring and filtering are carried out, a filter cake is leached to be neutral by water, and the compound 2 is obtained by forced air drying at 50 ℃ with the yield of 98.8%.
Dissolving 35g of compound 2 in 400ml of chloroform, cooling to 0 ℃, dropwise adding 30g of thionyl chloride at a temperature of 0-10 ℃, keeping the temperature of 0-10 ℃ for 2 hours after dropwise adding, dropwise adding 70g of tert-butylamine at a temperature of 0-10 ℃ after finishing adding, keeping the temperature of 0-10 ℃ for 2 hours after adding, adding 400ml of water for quenching reaction after finishing the reaction, separating liquid, adding 400ml of water into an organic phase, distilling under reduced pressure until dichloromethane is removed, cooling, filtering, washing a filter cake with water to neutrality, and carrying out forced air drying at 50 ℃ to obtain the compound 3 with the yield of 98.4%.
35g of Compound 3 was dissolved in 200ml of glacial acetic acid and 17ml of phosphorus tribromide were slowly added dropwise at room temperature; the reaction is carried out for 1 hour at the temperature of 20 to 30 ℃, after the reaction is finished, the filtration is carried out, a filter cake is leached by a little glacial acetic acid, and the vacuum drying is carried out at the temperature of 50 ℃ to obtain the compound 4, and the yield is 93.9 percent.
30g of compound 4 was dissolved in 200ml of DMF, 15g of cuprous cyanide was added, after stirring for 12 hours at 180℃and cooling to room temperature, insoluble material was removed by filtration, and the mixture was also slowly added dropwise to 1000ml of ice water, filtered, the filter cake was rinsed with water, recrystallised from acetone-water and air-dried at 50℃to give compound 5 in 85.3% yield.
Dissolving 20g of compound 5 in 300ml of ethanol, adding 40ml of 20% sodium hydroxide aqueous solution, heating to reflux for 4 hours, distilling off ethanol under reduced pressure after the reaction is finished, adjusting pH to be 2 with 1mol/L dilute hydrochloric acid, stirring for 1 hour, filtering, leaching a filter cake to be neutral with water, and drying by blowing at 50 ℃ to obtain the compound 6, wherein the yield is 92.2%.
Compound 6 was detected: 1 H-NMR(500MHz,DMSO)δ(ppm):0.59(s,3H),0.76(s,3H),1.01~1.08(m,3H),1.27~1.52(m,5H),1.43(s,9H),1.83~2.19(m,6H),2.33~2.45(m,1H),2.83~2.87(m,1H),5.47~5.53(m,1H),5.62(s,1H),5.92(d,1H),6.87(d,1H),6.93(s,1H),12.15(s,1H)。
MS-EI m/z:398[M-H] -
the dissolution rate was measured by the following method.
Dissolution rate measurement: 6 samples were taken, and 2ml of the dissolution medium was 800ml of hydrochloric acid (9.fwdarw.1000) at 75rpm in the second method of the general rule 0931 of ChP2020, and 2ml of the dissolution medium was sampled and 2ml of the dissolution medium was supplemented at 10, 20 and 30 minutes, respectively, under investigation of dissolution conditions at 37 ℃. Compound 6 or eplerenone 10mg is weighed, ethanol is diluted to 100mL, 2mL is measured, and the dissolution medium is diluted to 50mL. The dissolution was calculated by measuring absorbance at 266nm wavelength by ultraviolet-visible spectrophotometry.
Example 2
Prescription: 6.10 g of compound, 100g of lactose, 90g of starch, 6g of povidone and 0.2g of magnesium stearate.
Adding lactose, starch and crushed compound 6 into a fluidized bed, when the temperature of the material is raised to more than 50 ℃, starting spraying povidone aqueous solution, granulating, drying, finishing (the aperture of a screen is 2.0 mm), adding magnesium stearate, mixing, and tabletting. The dissolution rate measurement results are shown in table 1 below:
dissolution of Compound 6 of Table 1
Time/min | 10 | 20 | 30 |
Cumulative dissolution% | 47.5 | 70.6 | 85.3 |
Comparative example 1
Prescription: 10g of eplerenone, 100g of lactose, 90g of starch, 6g of povidone and 0.2g of magnesium stearate.
Adding lactose, starch and crushed eplerite into a fluidized bed, when the temperature of the materials is raised to more than 50 ℃, starting spraying povidone aqueous solution, granulating, drying, finishing (the aperture of a screen is 2.0 mm), adding magnesium stearate, mixing, and tabletting. The dissolution rate measurement results are shown in table 2 below:
TABLE 2 dissolution of eplerenone
Time/minute | 10 | 20 | 30 |
Cumulative dissolution% | 34.4 | 58.7 | 73.1 |
As can be seen from the measurement results in tables 1 and 2, the compound of the present application, namely, compound 6, showed higher dissolution rate at 37 ℃ at three times of 10, 20 and 30 minutes, further indicating that the compound 6 of the present application was higher than the intended bioavailability of eplerenone.
The foregoing is illustrative of the present application and is not to be construed as limiting thereof, but rather as various modifications, equivalent arrangements, or improvements within the spirit and principles of the present application are intended to be included within the scope of the present application.
Claims (10)
1. A steroid compound characterized by having the structure of formula I:
wherein R is selected from C 1~5 An alkyl group;
represents a single bond or a double bond;
when a certain isIn the case of double bonds, adjacent thereto +.>Is a single bond.
2. A steroid as in claim 1, characterized in that R is selected from isopropyl, isobutyl or tert-butyl.
3. A steroid according to any one of claims 1 to 2, characterized in that it is selected from the following structural formulae:
4. a steroid according to any one of claims 1 to 2, characterized in that it is selected from the following structural formulae:
5. a process for the preparation of a steroid according to any one of claims 1 to 4, characterized in that it comprises the following steps:
s1: carrying out haloform reaction on the compound of the formula A under the action of a halogenating reagent and alkali to generate a compound of the formula B,
s2: the compound of the formula B is reacted with R-NH under the action of thionyl chloride and alkali 2 Performing an amide reaction to produce a compound of formula C,
s3: carrying out bromination reaction on the compound of the formula C under the action of a brominating reagent to generate a compound of the formula D,
s4: subjecting a compound of formula D to a cyanation reaction under the action of a cyanating reagent to produce a compound of formula E,
and
s5: the compound of formula E is subjected to a hydrolysis reaction under the action of a base to produce the compound of formula I.
6. The process according to claim 5, wherein the compound of formula A has the structure of formula A1,
the compound of formula B has the structure of formula B1,
the compound of formula C has the structure of formula C1,
the compound of formula D has the structure of formula D1,
the compound of formula E has the structure of formula E1,
the compound of the formula I has the structure shown in the following formula I-1,
7. the process according to claim 6, wherein the compound of formula C has the structure of formula C2,
the compound of formula D has the structure of formula D2,
the compound of formula E has the structure of formula E2,
the compound of the formula I has the structure of the following formula I-2,
8. the preparation method according to claim 5 to 7, wherein in step S1,
the halogenating agent is selected from bromine, dibromohydantoin, dichloro hydantoin, N-bromosuccinimide or N-chlorosuccinimide; and/or
The alkali is selected from sodium hydroxide or potassium hydroxide; and/or
The step S1 is carried out in the presence of a solvent selected from 1, 4-dioxane; and/or
The reaction temperature of the step S1 is 0 to 20 ℃.
9. Use of a steroid according to any one of claims 1 to 4 for the preparation of a medicament for the treatment of a prostate disease.
10. A pharmaceutical composition, characterized in that it comprises a steroid according to any one of claims 1 to 4 and a pharmaceutically acceptable adjuvant.
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