CN102477061A - Pyridine androstane derivative and application thereof to preparing medicine for preventing and/or treating prostatic cancer - Google Patents

Pyridine androstane derivative and application thereof to preparing medicine for preventing and/or treating prostatic cancer Download PDF

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Publication number
CN102477061A
CN102477061A CN2010105545730A CN201010554573A CN102477061A CN 102477061 A CN102477061 A CN 102477061A CN 2010105545730 A CN2010105545730 A CN 2010105545730A CN 201010554573 A CN201010554573 A CN 201010554573A CN 102477061 A CN102477061 A CN 102477061A
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formula
coc
ococ
nhc
compound
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殷建明
朱惠霖
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SUZHOU BORUI PARMACEUTICALS Inc
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SUZHOU BORUI PARMACEUTICALS Inc
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Abstract

The invention relates to a novel pyridine androstane derivative and application thereof to preparing a medicine for preventing and/or treating prostatic cancer. The pyridine androstane derivative disclosed by the invention is an ideal selective cytochrome oxidase CYP450c17 inhibitor and can be used for treating or preventing various indications relative to male hormonal functions, in particular prostatic cancer. The pyridine androstane derivative has lower oxidative metabolism and higher effective bioavailability, therefore having the advantages of less application dosage, better tolerance and little side effect.

Description

Pyridine androstane verivate and prevent and/or treat the purposes in the prostate cancer medicine in preparation
Technical field
The present invention relates to pyridine androstane verivate and prevent and/or treat the purposes in the prostate cancer medicine in preparation.
Background technology
Important in the male hormone have testosterone, androsterone, androstanedione and a dehydroisoandrosterone.Testosterone is a most important male hormone in the body by the mesenchymal cell secretion of testis.Androsterone, androstanedione and dehydroisoandrosterone are the meta-bolitess (testosterone → androsterone → androstanedione → dehydroisoandrosterone) of testosterone.Adrenal cortex also can be secreted a kind of male hormone, i.e. adrenosterone.These hormones can stimulate the prostate cancer growth.So the first-selection of treatment prostate cancer is to suppress the male hormone generation of testis through medicine or operation.But these methods can not be blocked other positions of health and produce male sex hormone.
Steroid hormone is synthetic all to originate in SUV, through the common pathway of Vitarrine, progesterone, and synthetic at last different hormone.In this process, Cytochrome P450 (CYP450) plays keying action.The synthetic series reaction that relates to Cytochrome P450 and the participation of sterol desaturase of steroid hormone in the organism.CYP450c17 is a kind of microsomal enzyme, and it can two kinds of independent regulation steroid17s of catalysis and C17, and the enzymic activity of 20-lyase is synthesized thereby regulate in the body of sex steroid precursor at testis and other positions of health.
Summary of the invention
Technical problem to be solved by this invention provides a kind of pyridine androstane compound, and the key enzyme CYP450c17 during it synthesizes through male sex hormone reduces the male sex hormone level, and it also has restraining effect to the male sex hormone at testis and other positions of health.
For solving above technical problem, the present invention takes following technical scheme:
Compound and pharmacologically acceptable salt thereof with logical formula I:
Figure BSA00000355548400011
In the said formula I:
R 01, R 02, R 03, R 04, R 05, R 06, R 07, R 08, R 09, R 10, R 11, R 12, R 13, R 14, R 15, R 16Be hydrogen or deuterium independently;
R XFor being selected from a kind of in the following groups:
COC nH 2n+1；
COC nH 2nNH 2；
COC nH 2nNHC nH 2n+1；
COC nH 2nN(C nH 2n+1)C mH 2m+1；
COC nH 2nN(COC nH 2n+1)C mH 2m+1；
CON(C nH 2n+1)C nH 2nCOOH；
CH 2OCOC nH 2nNH 2；
CH 2OCOC nH 2nNHC nH 2n+1；
CH 2OCOC nH 2nN(C nH 2n+1)C mH 2m+1；
CH 2OCOC nH 2nN(COC nH 2n+1)C mH 2m+1；
CH(CH 3)OCOC nH 2nNH 2；
CH(CH 3)OCOC nH 2nNHC nH 2n+1；
CH(CH 3)OCOC nH 2nNHCOC nH 2n+1；
CH 2OP(OH) 3；
CH(CH 3)OP(OH) 3；
CONC nH 2n+1CH(R AA)COOH；
CH 2OCOCH(R AA)NHC nH 2n+1；
CH 2OCOCH(R AA)NHCOC nH 2n+1；
CH(CH 3)OCOCH(R AA)NHC nH 2n+1；
COCH(R AA)NHC nH 2n+1；
COCH(R AA)NHCOC nH 2n+1；
COCH(R AA)N(C nH 2n+1)C mH 2m+1；
COCH(R AA)N(COC nH 2n+1)C mH 2m+1；
Figure BSA00000355548400021
In the above-mentioned chemical formula, R AAThe amino acid side chain of expression dietary protein origin and/or non-dietary protein origin;
R MExpression OH, OC nH 2n+1, OCOC nH 2n+1, NH 2, NH (C nH 2n+1), N (C nH 2n+1) 2, SH, SC nH 2n+1, SCOC nH 2n+1, CN, F, Cl, Br or I;
N, m are the integer between 1～6 independently;
R YFor
Figure BSA00000355548400031
Perhaps
Figure BSA00000355548400032
According to the present invention, n is preferably 2 or 3.
According to the present invention, representational compound has the compound of formula II, formula III, formula IV, formula (V), formula VI, formula (VII) and formula (VIII) expression.
Figure BSA00000355548400033
Figure BSA00000355548400041
According to the present invention, described pharmacologically acceptable salt includes but not limited to hydrochloride, phosphoric acid salt, vitriol, acetate, PHENRAMINE MALEATE, benzene sulfonate, toluenesulfonate, fumarate, tartrate etc.
The compounds of this invention pyridine androstane verivate is a Terminal oxidase P450c17 suppressor factor; Through suppressing the key enzyme-CYP450c17 of male sex hormone in synthetic; It can reduce the male sex hormone level, and it all has restraining effect to the male sex hormone at testis and other positions of health simultaneously.Therefore The compounds of this invention can be used for preparing treatment or prevents particularly prostate cancer of the various indications relevant with the male hormone function.
Above-mentioned R AAThe amino acid side chain of expression dietary protein origin and/or non-dietary protein origin, for example L-L-Ala side chain.
Because the enforcement of above technical scheme, the present invention compared with prior art has following advantage:
Compound first pass effect of the present invention reduces; Effectively bioavailability is high; It is as selecting cell chromo-oxidase P450c17 suppressor factor; Can be used for treating or prevent the various indications relevant with the male hormone function, it is few to have using dosage when particularly it is used to treat prostate cancer, the advantage that spinoff is little.
Embodiment
Below in conjunction with specific embodiment the present invention is done further detailed explanation, but the present invention is not limited to following examples
Embodiment 1
The compound that present embodiment provides a kind of formula II to represent:
Figure BSA00000355548400051
Embodiment 2
The compound that present embodiment provides a kind of formula III to represent:
Figure BSA00000355548400052
Embodiment 3
The compound that present embodiment provides a kind of formula IV to represent:
Figure BSA00000355548400053
Embodiment 4
Present embodiment provides the compound of a kind of formula (V) expression:
Figure BSA00000355548400061
Embodiment 5
The compound that present embodiment provides a kind of formula VI to represent:
Figure BSA00000355548400062
Embodiment 6
Present embodiment provides the compound of a kind of formula (VII) expression:
Figure BSA00000355548400063
Embodiment 7
Present embodiment provides the compound of a kind of formula (VIII) expression:
Figure BSA00000355548400071
Embodiment 8～11
Have following general formula according to embodiment 8～11, the substituting group that each embodiment is corresponding is seen table 1.
Table 1
Embodiment 8 Embodiment 9 Embodiment 10 Embodiment 11
R 01～R 06 H D H H
R 07～R 09 H H D H
R 10～R 13 H H H H
R 14～R 16 H H H D
Rx COC 2H 5 COC 2H 5 CH 2OCOC 2H 4NH 2 CH 2OP(OH) 3
The foregoing description only is explanation technical conceive of the present invention and characteristics, and its purpose is to let the personage who is familiar with this technology can understand content of the present invention and enforcement according to this, can not limit protection scope of the present invention with this.All equivalences of doing based on spirit of the present invention change or modify, and all should be encompassed within protection scope of the present invention.

Claims (6)

1. the compound and the pharmacologically acceptable salt thereof that have logical formula I:
Figure FSA00000355548300011
It is characterized in that: in the said formula I:
R 01, R 02, R 03, R 04, R 05, R 06, R 07, R 08, R 09, R 10, R 11, R 12, R 13, R 14, R 15, R 16Be hydrogen or deuterium independently;
R XFor being selected from a kind of in the following groups:
COC nH 2n+1；
COC nH 2nNH 2；
COC nH 2nNHC nH 2n+1；
COC nH 2nN(C nH 2n+1)C mH 2m+1；
COC nH 2nN(COC nH 2n+1)C mH 2m+1；
CON(C nH 2n+1)C nH 2nCOOH；
CH 2OCOC nH 2nNH 2；
CH 2OCOC nH 2nNHC nH 2n+1；
CH 2OCOC nH 2nN(C nH 2n+1)C mH 2m+1；
CH 2OCOC nH 2nN(COC nH 2n+1)C mH 2m+1；
CH(CH 3)OCOC nH 2nNH 2；
CH(CH 3)OCOC nH 2nNHC nH 2n+1；
CH(CH 3)OCOC nH 2nNHCOC nH 2n+1；
CH 2OP(OH) 3；
CH(CH 3)OP(OH) 3；
CONC nH 2n+1CH(R AA)COOH；
CH 2OCOCH(R AA)NHC nH 2n+1；
CH 2OCOCH(R AA)NHCOC nH 2n+1；
CH(CH 3)OCOCH(R AA)NHC nH 2n+1；
COCH(R AA)NHC nH 2n+1；
COCH(R AA)NHCOC nH 2n+1；
COCH(R AA)N(C nH 2n+1)C mH 2m+1；
COCH(R AA)N(COC nH 2n+1)C mH 2m+1；
Figure FSA00000355548300021
In the above-mentioned chemical formula, R AAThe amino acid side chain of expression dietary protein origin and/or non-dietary protein origin;
R MExpression OH, OC nH 2n+1, OCOC nH 2n+1, NH 2, NH (C nH 2n+1), N (C nH 2n+1) 2, SH, SC nH 2n+1, SCOC nH 2n+1, CN, F, Cl, Br or I;
N, m are the integer between 1～6 independently;
R YFor
Figure FSA00000355548300022
Perhaps
Figure FSA00000355548300023
2. compound according to claim 1 and pharmacologically acceptable salt thereof is characterized in that: said n is 2 or 3.
3. compound according to claim 1 and pharmacologically acceptable salt thereof is characterized in that: said compound is a kind of in the compound of formula II, formula III, formula IV, formula (V), formula VI, formula (VII) and formula (VIII) expression.
Figure FSA00000355548300031
4. described compound of each claim and pharmacologically acceptable salt thereof the purposes in the preparation indication medicine relevant in the claim 1 to 3 with the male hormone function.
5. purposes according to claim 4 is characterized in that: the said indication relevant with the male hormone function is prostate cancer.
6. described compound of each claim and pharmacologically acceptable salt thereof are being regulated the purposes of selecting cell chromo-oxidase CYP450c17 aspect active in the claim 1 to 3.
CN2010105545730A 2010-11-23 2010-11-23 Pyridine androstane derivative and application thereof to preparing medicine for preventing and/or treating prostatic cancer Pending CN102477061A (en)

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Cited By (7)

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WO2014111815A3 (en) * 2013-01-18 2014-11-06 Cortendo Ab (Publ) Abiraterone and analogs thereof for the treatment of diseases associated with cortisol overproduction
WO2016082792A1 (en) * 2014-11-28 2016-06-02 四川海思科制药有限公司 Abiraterone derivative, and preparation method therefor and medical applications thereof
CN107188922A (en) * 2016-03-14 2017-09-22 四川海思科制药有限公司 A kind of salt of abiraterone derivative and preparation method thereof and medical usage
CN107188921A (en) * 2016-03-15 2017-09-22 四川海思科制药有限公司 The preparation method of abiraterone derivative and its new solid-state form and purposes
CN107365343A (en) * 2016-05-12 2017-11-21 四川海思科制药有限公司 A kind of benzimidazole androstane derivative and preparation method thereof and medical usage
WO2021100019A1 (en) 2019-11-22 2021-05-27 Suven Life Sciences Limited Prodrugs of abiraterone
WO2022199408A1 (en) * 2021-03-25 2022-09-29 中国医学科学院生物医学工程研究所 Preparation method for and application of novel injection abiraterone derivative

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014111815A3 (en) * 2013-01-18 2014-11-06 Cortendo Ab (Publ) Abiraterone and analogs thereof for the treatment of diseases associated with cortisol overproduction
TWI641616B (en) * 2014-11-28 2018-11-21 四川海思科製藥有限公司 Abiraterone derivative, preparation method and medical use thereof
WO2016082792A1 (en) * 2014-11-28 2016-06-02 四川海思科制药有限公司 Abiraterone derivative, and preparation method therefor and medical applications thereof
CN105646637A (en) * 2014-11-28 2016-06-08 四川海思科制药有限公司 Abiraterone derivative, preparation method and medical applications thereof
CN106061990A (en) * 2014-11-28 2016-10-26 四川海思科制药有限公司 Abiraterone derivative, and preparation method therefor and medical applications thereof
CN106061990B (en) * 2014-11-28 2019-09-10 四川海思科制药有限公司 A kind of abiraterone derivative and preparation method thereof and medical usage
CN107188922B (en) * 2016-03-14 2019-12-20 四川海思科制药有限公司 Salt of abiraterone derivative and preparation method and medical application thereof
CN107188922A (en) * 2016-03-14 2017-09-22 四川海思科制药有限公司 A kind of salt of abiraterone derivative and preparation method thereof and medical usage
CN107188921A (en) * 2016-03-15 2017-09-22 四川海思科制药有限公司 The preparation method of abiraterone derivative and its new solid-state form and purposes
CN107365343A (en) * 2016-05-12 2017-11-21 四川海思科制药有限公司 A kind of benzimidazole androstane derivative and preparation method thereof and medical usage
WO2021100019A1 (en) 2019-11-22 2021-05-27 Suven Life Sciences Limited Prodrugs of abiraterone
WO2022199408A1 (en) * 2021-03-25 2022-09-29 中国医学科学院生物医学工程研究所 Preparation method for and application of novel injection abiraterone derivative
AU2022244858B2 (en) * 2021-03-25 2023-10-05 Tianjin Hairunjiahe Innovative Pharmaceutical Research Limited Liability Company Preparation method for and application of novel injection abiraterone derivative
US11944685B2 (en) 2021-03-25 2024-04-02 Tianjin Hairunjahe Innovative Pharmaceutical Research Limited Liability Company Preparation method and application of novel injection abiraterone derivative

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