CN106279343A - A kind of compound as CYP11B, CYP17, CYP21 inhibitor - Google Patents
A kind of compound as CYP11B, CYP17, CYP21 inhibitor Download PDFInfo
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- CN106279343A CN106279343A CN201510356953.6A CN201510356953A CN106279343A CN 106279343 A CN106279343 A CN 106279343A CN 201510356953 A CN201510356953 A CN 201510356953A CN 106279343 A CN106279343 A CN 106279343A
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Abstract
There is provided herein formula A CYP11B, CYP17 and or CYP21 inhibitor, for treating Androgen-dependent type disease, disease and the purposes of condition of illness.
Description
Technical field
The invention provides a kind of compound as CYP11B, CYP17, CYP21 inhibitor, oral administration or drug administration by injection approach, as treating Androgen-dependent type disease, disease and the purposes of condition of illness.There is also described herein the synthetic method of this compound.
Technical background
Carcinoma of prostate is the distinctive diseases of the mankind, is one of modal malignant tumor of male America and Europe, accounts for the 1st at U.S.'s prostate-cancer incidence, and mortality rate is only second to pulmonary carcinoma.Asian countries's prostate-cancer incidence such as China, Japan, India are far below America and Europe, but have growth trend.
In China, carcinoma of prostate increases to 7.9/10 ten thousand male from 1.71/10 ten thousand male demographic of 1993, and with the speed increase of annual 10%.Being on the rise along with Chinese society ageing phenomenon, the morbidity of following China carcinoma of prostate is possibly into peak period.
It has been proved that androgen carcinoma of prostate development, grow and be in progress in play an important role.Two kinds of important androgens are testis sterone and dihydro-testosterone sterone.The testis sterone of testis synthesis about 90%, remaining 10% is synthesized by adrenal gland.Testis sterone is further converted to more effective androgen DHT by concentrating on prostatic enzyme sterin.
Because carcinoma of prostate is usually Androgen-dependent type, therefore surgical operation or pharmacology castrate the primary treatment scheme reducing androgen generation as this indication.Androgen-deprivation has been used for the therapy of advanced prostate cancer and metastatic prostate cancer.But the androgen that orchiectomy reduces testis produces, but have no effect on androgenic generation in adrenal gland.CYP17 relates to the biosynthetic key intermediate of androgen, thus its pharmacology suppression become promising therapeutic scheme, wherein testis, adrenal gland and peripheral androgen biosynthesis all will minimizings, therefore CYP17 suppresses to be important carcinoma of prostate research direction.
Apply CPY17 inhibitor medicaments, as Abiraterone acetate is in Nikkei U.S. FDA approval listing April 28 in 2011, with prednisone combination treatment castration carcinoma of prostate.Abiraterone targeted inhibition regulation androgen generates the activity of enzyme CYP17, reduces androgenic generation, thus alleviates the growth of tumor.The patent of abiraterone is: [US8822438] [US5604213].
And issue on " naturally " (Nature) magazine on June 1st, 2015, research worker from clinic, Cleveland (Cleveland Clinic) finds for the first time, the metabolite (D4A) of abiraterone (abiraterone, Abi) has the anticancer property of more strength than its precursor.
CYP21 and CYP11B1 is that hydrocortisone synthesizes vital two kinds of enzymes, and the excessive generation of hydrocortisone, has involved storehouse Xing Shi disease group.Storehouse Xing Shi disease group refers to be exposed to for a long time the form of expression of excessive glucocorticoid cortin induction, and it can be caused by a variety of causes.Spontaneous storehouse Xing Shi disease group can be caused by each reason, and all reasons have in common that adrenal gland's long-term excessive secretion hydrocortisone.
The short-term of hypercortisolism and long-term treatment consequence require the necessary normalization of Determination of cortisol, and surgery removes pituitary adenoma and still represents first-line treatment, in the case of surgery failure, and then radiotherapy.And still lacking the safely and effectively medicine that cortisol blocker excess produces, Drug therapy is not main therapeutic scheme.
On Drug therapy direction, it is rational treatment strategies to block CYP21 and CYP11B1.Having had some medicines for storehouse Xing Shi disease group, this medicine includes that first is than ketone, ketoconazole, methylbenzyl rice ester and mitotane.Although these medicines have significant curative effect clinically, but effect for want of blocks CYP11B1 activity usefulness and restricted.
The D4A prodrug that the present invention provides, D4A can be metabolized in vivo, there is ratio abiraterone (abiraterone, Abi) higher anticancer property, can effectively suppress CYP11B, CYP17, CYP21, as for treating Androgen-dependent type disease, disease and the purposes of condition of illness, include but not limited to carcinoma of prostate, storehouse Xing Shi disease group, there is higher clinical value.
Summary of the invention
Attempting herein providing abiraterone metabolite D4A prodrug, rapid metabolization becomes D4A in vivo.Prodrug, as treating Androgen-dependent type disease, disease and the purposes of condition of illness, includes but not limited to carcinoma of prostate, storehouse Xing Shi disease group, to obtaining higher clinical value.
The present invention provides compound or its pharmaceutically acceptable salt shown in a kind of chemical structural formula A:
R1Alkyl, aromatic radical, such as: methyl, ethyl, isopropyl, the tert-butyl group, benzyl, phenyl, cyclohexyl, propyl group, butyl, amyl group, hexyl, heptyl, octyl group.
The present invention provides compound or its pharmaceutically acceptable salt shown in a kind of chemical structural formula B:
R2For alkyl, aromatic radical, such as: methyl, ethyl, isopropyl, the tert-butyl group, benzyl, phenyl, cyclohexyl, propyl group, butyl, amyl group, hexyl, heptyl, octyl group.
The present invention provides compound or its pharmaceutically acceptable salt shown in a kind of chemical structural formula C:
R3For methyl, ethyl, isopropyl, the tert-butyl group, phenyl, cyclohexyl, propyl group, butyl, amyl group, hexyl, heptyl, octyl group, methoxyl group, ethyoxyl, benzyloxy, isopropoxy, tert-butoxy, cyclohexyloxy.
Compound or its pharmaceutically acceptable salt shown in described chemical formula A, it is characterised in that acceptable salt includes phosphate, sulfate, borate, carbonate, bicarbonate, formates, acetate, propionate, benzoate, pyridine carboxylic acid salt, fumarate, malate, maleate, Fructus Lycii hydrochlorate, succinate, mesylate, toluene fulfonate, fluoroform sulphonate, tetrafluoroborate, hexafluoro borate, chloride, bromide or iodide.
Gained compound of the present invention is utilized to be administered orally administration in people.Solid dosage forms for oral administration includes capsule, tablet, pill, powder and granule.In these solid dosage formss, the compounds of this invention mixes with at least one conventional inert adjuvant, such as starch, microcrystalline Cellulose, or following compositions mixing: (a) filler, such as lactose, starch, microcrystalline Cellulose, dextrin, calcium hydrogen phosphate, mannitol；B () binding agent, such as starch slurry, cellulose derivative, polyvinyl pyrrolidone；C () disintegrating agent, such as cross-linked carboxymethyl cellulose sodium, CCMS-Na, dried starch；D () lubricant, such as Pulvis Talci, Polyethylene Glycol, dodecyl sodium sulfate, magnesium stearate.
Liquid formulation for oral administration includes pharmaceutically acceptable emulsion, suspension, solution, syrup.In addition to the compounds of this invention, liquid dosage form can comprise the conventional inert diluent used in this area, such as water and other solvents, solubilizing agent and emulsifying agent.
The compounds of this invention injectable administering mode is in people.In addition to the compounds of this invention, injection type comprises the inert diluent that this area routine uses, such as water and other solvents, solubilizing agent.
Detailed description of the invention
Illustrating the present invention below with reference to embodiment, embodiments of the invention are merely to illustrate technical scheme, and the essence of the non-limiting present invention.
Example one: by 3.62g SM in ether, adds triethylamine 2.2g, 1.2g (ethoxymethyl) acyl chlorides, room temperature reaction 2h.Adding 50ml EA, add 10ml water and wash twice, anhydrous sodium sulfate is dried organic facies, and decompression boils off organic solvent, the about 3.5g product of dichloromethane crystallization.
Example two: by 3.62g SM in oxolane, adds 5.0g iron powder, drips 0.95g chloroacetic chloride, room temperature reaction 5h.Adding 50ml EA, add 10ml water and wash twice, anhydrous sodium sulfate is dried organic facies, and decompression boils off organic solvent, the about 2.7g product of dichloromethane crystallization.
Example three: by 3.62g SM in ether, adds 0.95g chloroacetic chloride, room temperature reaction 2h, filters.Adding 50ml EA in mother solution, add 10ml water and wash twice, anhydrous sodium sulfate is dried organic facies, and decompression boils off organic solvent, the about 2.7g product of dichloromethane crystallization.
Claims (16)
1. the compound of formula A
R1Alkyl, aromatic radical.
2. formula A as claimed in claim 1, R1For methyl, ethyl, isopropyl, the tert-butyl group, benzyl, phenyl, cyclohexyl, propyl group, butyl, amyl group, hexyl, heptyl, octyl group.
3. a formula B compound:
R2For alkyl, aromatic radical.
4. formula B as claimed in claim 3, R2For methyl, ethyl, isopropyl, the tert-butyl group, phenyl, cyclohexyl, propyl group, butyl, amyl group, hexyl, heptyl, octyl group.
5. compound described in formula C:
R3For alkyl, aromatic radical, alkoxyl.
Wherein R3For methyl, ethyl, isopropyl, the tert-butyl group, phenyl, cyclohexyl, propyl group, butyl, amyl group, hexyl, heptyl, octyl group, methoxyl group, ethyoxyl, benzyloxy, isopropoxy, tert-butoxy, cyclohexyloxy.
7. compound shown in the chemical formula as described in claim 1-6 or its pharmaceutically acceptable salt, it is characterised in that acceptable salt includes phosphate, sulfate, borate, carbonate, bicarbonate, formates, acetate, propionate, benzoate, pyridine carboxylic acid salt, fumarate, malate, maleate, Fructus Lycii hydrochlorate, succinate, mesylate, toluene fulfonate, fluoroform sulphonate, tetrafluoroborate, hexafluoro borate, chloride, bromide or iodide.
8. a pharmaceutical composition, it is characterised in that comprise compound described in claim 1-7 or its pharmaceutically acceptable salt and more than one pharmaceutically acceptable filler, binding agent, disintegrating agent, lubricants；Or with one or more this areas the conventional inert diluent used, such as water and other solvents, solubilizing agent and emulsifying agent.
9. pharmaceutical composition as claimed in claim 8, it is characterised in that described compositions can be the liquid forms such as tablet, capsule, granule, oral liquid or suspension.
10. compound described in claim 1-7 or its pharmaceutically acceptable salt, it is characterised in that institute and one or more pharmaceutically acceptable solvents.
11. pharmaceutical compositions as claimed in claim 10, it is characterised in that injection type.
12. 1 kinds suppress CYP11B, CYP17 and or the method for CYP21 enzyme, it include the compound described in claim 1-9 or the arbitrary compound of pharmaceutical composition or pharmaceutically acceptable salt or pharmaceutical composition and CYP11B, CYP17 and or CYP21 enzyme contact.
13. compounds as described in claim 1-7 or 8-10 pharmaceutical composition are in the application for the treatment of Androgen-dependent type disease, such as carcinoma of prostate, benign prostatauxe, prostatic intraepithelial neoplasm sample pathological changes, hirsutism, acne, androgenetic alopecia, polycystic ovary disease.
14. such as claim 13, wherein this Androgen-dependent type disease is carcinoma of prostate.
15. compounds as described in claim 1-7 or 8-10 pharmaceutical composition are in the method treating the relevant disease of high cortisol symptom.
16. such as claim 15, wherein disease is storehouse Xing Shi disease group.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201510356953.6A CN106279343A (en) | 2015-06-12 | 2015-06-12 | A kind of compound as CYP11B, CYP17, CYP21 inhibitor |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106928299A (en) * | 2015-12-31 | 2017-07-07 | 中国医学科学院药物研究所 | One class derives from the compound of the root bark of Chinese wolf-berry, its preparation method and the application in terms of hypoglycemic |
| CN114106077A (en) * | 2021-08-18 | 2022-03-01 | 广东中科药物研究有限公司 | Abiraterone derivative and preparation and application thereof |
-
2015
- 2015-06-12 CN CN201510356953.6A patent/CN106279343A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106928299A (en) * | 2015-12-31 | 2017-07-07 | 中国医学科学院药物研究所 | One class derives from the compound of the root bark of Chinese wolf-berry, its preparation method and the application in terms of hypoglycemic |
| CN106928299B (en) * | 2015-12-31 | 2021-04-13 | 中国医学科学院药物研究所 | Compound from cortex lycii radicis, preparation method and application thereof in aspect of reducing blood sugar |
| CN114106077A (en) * | 2021-08-18 | 2022-03-01 | 广东中科药物研究有限公司 | Abiraterone derivative and preparation and application thereof |
| CN114106077B (en) * | 2021-08-18 | 2023-01-24 | 广东中科药物研究有限公司 | Abiraterone derivative and preparation and application thereof |
| WO2023020135A1 (en) * | 2021-08-18 | 2023-02-23 | 广东中科药物研究有限公司 | Abiraterone derivative and preparation and application thereof |
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