CN103857667A - Synthesis of a group of hydantoin derivatives and use thereof - Google Patents
Synthesis of a group of hydantoin derivatives and use thereof Download PDFInfo
- Publication number
- CN103857667A CN103857667A CN201280048526.6A CN201280048526A CN103857667A CN 103857667 A CN103857667 A CN 103857667A CN 201280048526 A CN201280048526 A CN 201280048526A CN 103857667 A CN103857667 A CN 103857667A
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- CN
- China
- Prior art keywords
- bases
- cyano group
- dimethyl
- oxos
- thio
- Prior art date
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- 150000001469 hydantoins Chemical class 0.000 title claims description 29
- 230000015572 biosynthetic process Effects 0.000 title abstract description 4
- 238000003786 synthesis reaction Methods 0.000 title abstract description 4
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- 208000000236 Prostatic Neoplasms Diseases 0.000 claims abstract description 35
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 15
- 230000000694 effects Effects 0.000 claims abstract description 15
- 201000010099 disease Diseases 0.000 claims abstract description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 3
- 125000003003 spiro group Chemical group 0.000 claims description 51
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 49
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 49
- 238000002560 therapeutic procedure Methods 0.000 claims description 47
- 230000002280 anti-androgenic effect Effects 0.000 claims description 46
- 239000003814 drug Substances 0.000 claims description 33
- ATRQECRSCHYSNP-UHFFFAOYSA-N 2-(trifluoromethyl)pyridine Chemical compound FC(F)(F)C1=CC=CC=N1 ATRQECRSCHYSNP-UHFFFAOYSA-N 0.000 claims description 31
- -1 nitro, carboxyl Chemical group 0.000 claims description 29
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 20
- 125000001424 substituent group Chemical group 0.000 claims description 16
- 239000000126 substance Substances 0.000 claims description 14
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
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- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
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- SCVJRXQHFJXZFZ-KVQBGUIXSA-N 2-amino-9-[(2r,4s,5r)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-3h-purine-6-thione Chemical compound C1=2NC(N)=NC(=S)C=2N=CN1[C@H]1C[C@H](O)[C@@H](CO)O1 SCVJRXQHFJXZFZ-KVQBGUIXSA-N 0.000 claims description 2
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- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- VUHJZBBCZGVNDZ-TTYLFXKOSA-N chlormadinone Chemical compound C1=C(Cl)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)C)(O)[C@@]1(C)CC2 VUHJZBBCZGVNDZ-TTYLFXKOSA-N 0.000 description 1
- 229960003996 chlormadinone Drugs 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 150000003948 formamides Chemical class 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- JMANVNJQNLATNU-UHFFFAOYSA-N glycolonitrile Natural products N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 description 1
- 210000002149 gonad Anatomy 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 150000002461 imidazolidines Chemical class 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 208000024714 major depressive disease Diseases 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 201000003995 melancholia Diseases 0.000 description 1
- 229960002653 nilutamide Drugs 0.000 description 1
- XWXYUMMDTVBTOU-UHFFFAOYSA-N nilutamide Chemical compound O=C1C(C)(C)NC(=O)N1C1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 XWXYUMMDTVBTOU-UHFFFAOYSA-N 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000002271 resection Methods 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 125000004417 unsaturated alkyl group Chemical group 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
- A61P13/08—Drugs for disorders of the urinary system of the prostate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/14—Drugs for genital or sexual disorders; Contraceptives for lactation disorders, e.g. galactorrhoea
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/26—Androgens
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- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Endocrinology (AREA)
- Diabetes (AREA)
- Gynecology & Obstetrics (AREA)
- Pregnancy & Childbirth (AREA)
- Reproductive Health (AREA)
- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Provided in the present invention are the pharmaceutical composition, synthesis procedure and medicinal use of a group of HYDANTOIN derivatives. Since these compounds have an inhibiting effect on an androgen receptor, the compounds can be used to treat prostate cancer and other diseases and physiological disorders related to androgen receptor activity.
Description
A kind of synthesis of hydantoin derivatives and its applied technical field
The invention belongs to drug field, more specifically, the present invention relates to the composition of hydantoin derivatives and its medical application.Background technology
Prostate cancer is the common disease of more than 50 years old male.In recent years, the incidence of disease of prostate cancer shows the trend increased rapidly.In western countries, its incidence of disease has been occupied first of male malignancy, and the death rate also occupies second.In China, 1991 by 2001 during the decade, the prostate-cancer incidence in Shanghai City increases to 12.7/10 ten thousand by 2.7/100,000；The same period, Changchun sick incidence of disease also increases 4.7 times；Changchun generaI investigation finds that the prostate-cancer incidence of more than 50 years old male is 1.28%.Obviously, prostate cancer has constituted the major disease of harm modern's health.
For the prostate cancer in situ of a small number of early detections, after surgery excision and radiotherapy, nearly 70% patient can be effected a radical cure, but still the patient for having 30 more than % the transfer of prostate gland cancer cell can occur in the postoperative recurrence of tumor resection.The patients with prostate cancer of usual clinical definite reaches middle and advanced stage, and now cancer cell has breached the barrier of capsula prostatica, there occurs the diffusion of adjacent tissue and/or the transfer of distal organs.Because the growth of prostate gland cancer cell depends on the androgen receptor of androgen activation, therefore clinical treatment late cancer mainly uses anti androgenic therapy at present.Anti androgenic therapy has two kinds：One is by using gonadotropin releasing hormone analogues（GnRH- α, such as Goserelin, goserelin), or row orchiectomy, to reduce the androgen-level in patient's body；Two be to use androgen receptor antagonist medicine, the activity of Reverse transcriptase androgen receptor, to control the development of cancer.Clinically it is used for the androgen antagonist medicine for treating anti androgenic therapy sensitive prostate carcinoma (Hormone sensitive) at present, conventional has Bicalutamide（Bicalutamide；), Flutamide (Flutamide), cyproterone acetate (Cyproterone Acetate, abbreviation CPA), Ni Lute meter (nilutamide), and Chlormadinone.Bicalutamide and Flutamide have similar drug effect in this kind of medicine, and side effect is several smaller than other, so they occupy the absolute market advantage.However, the term of validity of anti androgenic therapy is very short, patient is average no longer sensitive nearly all to the therapy in 1-2, produces tolerance, ultimately results in death.Due to disclosing the molecule mechanism of anti androgenic therapy tolerance (Hormone refractory) generation and finding the basis that its drug target is design active drug, the research of anti androgenic therapy tolerance mechanism is always one of topmost problem of prostate cancer research field.
Pass through the research and a large amount of cells and zoopery of genetic chip, we have found the reason for overexpression of androgen receptor (Androgen receptor) is anti androgenic therapy tolerance recently, this important discovery has the high androgen receptor expressed to match with the phenomenon anti androgenic therapy tolerance prostate cancer that clinic is frequently observed, and demonstrate the drug target that androgen receptor is still anti androgenic therapy tolerance prostate cancer, and explain another reason for anti androgenic therapy fails, the bioactivity of androgen receptor i.e. expressed by anti androgenic therapy tolerance prostate cancer has occurred that the change of matter.When using gonadotropin releasing hormone analogues（GnRH- α, such as Goserelin, goserelin) or row orchiectomy reduction patient's body in androgen-level after, its androgen receptor still can by low concentration androgen activate；And the androgen receptor antagonist medicine of Clinical practice does not have inhibitory action not only to the androgen receptor expressed by anti androgenic therapy tolerance prostate cancer at present, and androgen receptor is activated on the contrary in high concentration.Therefore, if confrontation can be found
Androgen receptor expressed by androgenotherapy tolerance prostate cancer has strong inhibitory action, and the androgen antagonist medicine of new generation of the androgen receptor expressed by anti androgenic therapy tolerance prostate cancer will not be activated in high concentration, the prostate cancer of anti androgenic therapy tolerance will can be just treated, chance for survival and the time of patient is improved.
The prostate cancer of anti androgenic therapy tolerance is still the evil disease pasted medical help at present, although some clinical tests report some chemotherapeutics as mitoxantrone (Mitoxantrone), Docetaxel (Docetaxel) and metacortandracin (pr edni sone) have the pain for reducing these patients, the effect improved the quality of living, but targeted drug in the world still without the advanced prostate cancer for treating anti androgenic therapy tolerance at present.Although there is the drug research and development project for androgen receptor in many biotech companies and big pharmaceutical factory in the world, but due to causing the mechanism of anti androgenic therapy tolerance prostate cancer until recently by it was found that so the drug development research of the prostate cancer of anti androgenic therapy tolerance can not just be carried out exactly.Only according to our new discovery, i.e. androgen receptor is still the drug target of anti androgenic therapy tolerance prostate cancer, the characteristics of change of matter being had occurred that with the bioactivity of the androgen receptor of anti androgenic therapy tolerance prostate cancer, effective screening technique can be just designed, the medicine of new generation of anti androgenic therapy tolerance prostate cancer can be treated by screening.The content of the invention
The invention provides the composition of the medicine available for treatment prostate cancer and other diseases relevant with estrogen receptor activity and physiologic derangement, building-up process and their application, these compounds are hydantoins HYDANTOIN derivatives, it is characterised in that the derivative has following chemical structure of general formula I：
I
Wherein：
R1 is cyano group or nitro；
R2 is halogen, trifluoromethyl or other halogen substituents；
A, B and C can be carbon or nitrogen respectively, but they at least one be nitrogen；
R3 and R4 are respectively the C3-C6 cyclic hydrocarbon radicals that methyl or connection are circularized；
R5, R6, R7 and R8 can be respectively hydrogen, halogen or halogen substituents；
R9 is alkyl or its substituent; substituent can be element, plain substituent, cyano group, amide groups, acid amides substituent, amino, nitro, carboxyl, carbonyl, hydroxyl, oxyalkyl, oxygen alkyl carbonyl, aminoalkyl, sulfydryl, sulfonyl, sulfone or sulfoxide, sulfanyl, sulfanilamide (SN), carbamyl, mephenesin Carbamate, urea base, oxyammonia or hydroxy amide, and an alkyl can have one or more substituents simultaneously.
Term " halogen or halogen substituents " refers to fluorine, chlorine, bromine and iodine, and their substituent.Halogen substituents
Can be substituent, the substituent containing multiple halogens, trifluoromethyl or trichloromethyl containing single halogen.
Term " cyclic hydrocarbon radical " refers to containing the cyclic alkyl, alkenyl or alkynyl being linked to be from 3 to 6 carbon.Wherein alkyl is the carbochain of saturation, alkenyl is the unsaturated carbon chains containing one or more double bonds and alkynyl is the unsaturated carbon chains containing one or more three keys, the carbochain that a cyclic hydrocarbon radical simultaneously can be containing zero, one or more double or triple bonds.
Term " alkyl " refers to alkyl, the alkenyl or alkynyl of the straight or branched containing zero carbon or from 1 to 8 carbon.Wherein alkyl is the carbochain of saturation, alkenyl is the unsaturated carbon chains containing one or more double bonds and alkynyl is the unsaturated carbon chains containing one or more three keys, the carbochain that an alkyl simultaneously can be containing zero, one or more double or triple bonds.
Term " acid amides substituent " refers to that the hydrogen atom on amidoamino can be replaced by one or two methyl.
Term " oxyalkyl ", " aminoalkyl ", " sulfanyl " refer respectively to be inserted with one or more oxygen, nitrogen or sulphur atom in the carbochain of a saturation or unsaturated alkyl and its substituent.
Term " oxygen alkyl carbonyl " refers to an oxyalkyl connected by carbonyl or its substituent.
The selection of substituent mentioned above or the position of substitution should meet chemical requirements and form stable compound, simultaneously, will all be supplemented either with or without any position for meeting valence by hydrogen atom to meet its valence, and, if substituent can be connected by multiple atoms and other parts, so, substituent is connected by any one atom and other parts and belongs to the scope of the invention.Present inventors have surprisingly found that, when described R9 is：
When, the more other groups of effect that Formulas I compound suppresses androgen receptor are significantly more excellent.
The hydantoin derivatives of estrogen receptor activity are adjusted, following particular compound is included：
4- [3- (6- cyano group -5- trifluoromethyl pyridine -3- bases) -5,5- dimethyl -4- oxo -2- thiocarbamoyl imidazole alkane -1- bases]-fenbutyramidum；
4- [3- (6- cyano group -5- Fluoromethylpyridin -3- bases) -5,5- dimethyl -4- oxo -2- thiocarbamoyl imidazole alkane -1- bases]-N- methyl-fenbutyramidum；
4- [3- (6- cyano group -5- Fluoromethylpyridin -3- bases) -5,5- dimethyl -4- oxo -2- thiocarbamoyl imidazole alkane -1- bases]-Ν, Ν-dimethyl-fenbutyramidum；
4- [3- (6- cyano group -5- Fluoromethylpyridin -3- bases；) -5,5- dimethyl -4- oxo -2- thiocarbamoyl imidazole alkane -1- bases]-benzene fourth
The base of picoline -3) thio -5,7- diaza spiros [3.4] the octyl- 5- yls of -8- oxos -6-)-fenbutyramidum；
4- (7- (6- cyano group-- thio -5,7- diaza spiros [3.4] the octyl- 5- yls of (base of trifluoromethyl pyridine -3) -8- oxos -6-)-Ν-methyl-fenbutyramidum；
4- (7- (6- cyano group -5- (the bases of trifluoromethyl pyridine -3）Thio -5,7- diaza spiros [3.4] the octyl- 5- yls of -8- oxos -6-) -Ν,Ν- dimethyl-fenbutyramidum；
4- (7- (thio -5,7- diaza spiros [3.4] the octyl- 5- yls of 6- cyano group -5- (base of trifluoromethyl pyridine -3) -8- oxos -6-)-benzene butyl cyanides；
3- (thio-l- of 4- oxos -2- (4- butyramides benzene) -1,3- diaza spiros [4.4] nonyl- 3- yls) -5- trifluoromethyl -6- Cyano-pyridins；
3- (thio -1- of 4- oxos -2- (4- Ν-methyl-butyramide benzene) -1,3- diaza spiros [4.4] nonyl- 3- yls) -5- trifluoromethyl -6- Cyano-pyridins；
3-(thio-1- of 4- oxos-2- (4- Ν, Ν-dimethyl-butyramide benzene)-1,3- diaza spiros [4.4] nonyl- 3- yls)-5- trifluoromethyl-6- Cyano-pyridins；
3- (thio -1- of 4- oxos -2- (4- butyl benzonitrile) -1,3- diaza spiros [4.4] nonyl- 3- yls) -5- trifluoromethyl -6- Cyano-pyridins；
4- [3- (6- cyano group -5- trifluoromethyl pyridine -3- bases) -5,5- dimethyl -4- oxo -2- thiocarbamoyl imidazole alkane -1- bases] -2- fluoro- Ν, Ν-dimethyl-stupid formamide；
4- [7- (6- cyano group -5- trifluoromethyl pyridine -3- bases;) thio -5,7- diaza spiros [3.4] the octyl- 5- yls of -8- oxos -6-] -2- fluoro- Ν, Ν-dimethyl-stupid formamide；
4- [3- (6- cyano group -5- trifluoromethyl pyridine -3- bases) -5,5- dimethyl -4- oxo -2- thiocarbamoyl imidazole alkane -1- bases] fluoro- fenbutyramidums of -2-；
4- [3- (6- cyano group -5- trifluoromethyl pyridine -3- bases) -5,5- dimethyl -4- oxo -2- thiocarbamoyl imidazole alkane -1- bases] -2- methyl fluorides-fenbutyramidum；
4- [3- (6- cyano group -5- trifluoromethyl pyridine -3- bases) -5,5- dimethyl -4- oxo -2- thiocarbamoyl imidazole alkane -1- bases] fluoro- Ν of -2-, Ν-dimethyl-fenbutyramidum；
4- (7- (thio -5,7- diaza spiros [3.4] the octyl- 5- yls of 6- cyano group -5- (base of trifluoromethyl pyridine -3) -8- oxos -6-) fluoro- fenbutyramidums of -2-；
4- (7- (thio -5,7- diaza spiros [3.4] the octyl- 5- yls of 6- cyano group -5- (base of trifluoromethyl pyridine -3) -8- oxos -6-) -2- methyl fluorides-fenbutyramidum；Or
4- (7- (thio -5,7- diaza spiros [3.4] the octyl- 5- yls of 6- cyano group -5- (base of trifluoromethyl pyridine -3) -8- oxos -6-) fluoro- Ν of -2-, Ν-dimethyl-fenbutyramidum.
The present invention also includes contained hydantoin derivatives or the precursor of particular compound in chemical structure of general formula I." contained hydantoin derivatives or the precursor of particular compound in chemical structure of general formula I " refers to that the precursor is metabolized or chemically reacted in vivo and is transformed into chemical structure of general formula I contained hydantoin derivatives or the salt of particular compound in contained hydantoin derivatives or particular compound or chemical structure of general formula I after medicine enters in vivo.
The invention also includes the solid or optical isomeric compound of contained hydantoin derivatives or particular compound in chemical structure of general formula I, also including chemically or pharmaceutically contained hydantoin derivatives or the trim of particular compound in obvious chemical structure of general formula I.
Example cited in the invention is enumerated to more easily illustrate, does not represent the invention and is only limited to these examples.The invention provides the medicine or medicine composition for treating human and animal's disease or physiologic derangement, these medicines or medicine composition contain the salt that contained hydantoin derivatives or particular compound are constituted in hydantoin derivatives or particular compound, or the pharmaceutically acceptable I containing chemical structure of general formula suitably contained by chemical structure of general formula I.These diseases
Include prostate cancer (including to the sensitive prostate cancer of anti androgenic therapy and prostate cancer to anti androgenic therapy tolerance) and other diseases related to androgen receptor and malaise symptoms to physiologic derangement, breast cancer, hyperplasia of prostate, hirsutism, powder is perverse, bald head, muscle depletion, gonad function is weak, osteoporosis, cholesterol is too high, male sterility, male's sexual is bad, anaemia, it is fat, the disease relevant with central nervous system and malaise symptoms, sexual desire is hoped low, melancholia and other obstacles at heart.These medicines or medicine composition can be also used for the growth and maintenance of male contraception, the auxiliary treatment of kidney failure, regulation skeleton and muscle.
Medicine or the medicine composition of the invention can comprise only contained hydantoin derivatives or the medicine composition of particular compound in chemical structure of general formula I, or the medicine composition for not being included in contained hydantoin derivatives or the other drugs of particular compound in chemical structure of general formula I is added containing contained hydantoin derivatives or particular compound in chemical structure of general formula I.Medicine or the medicine composition of the invention can be added on preparation according to known pharmaceutical formulation method, can be solid or liquid, can contain carrier or pharmacy additive.
These hydantoin derivatives can efficiently suppress to the sensitive prostate cancer of anti androgenic therapy and the activity to the androgen receptor in the prostate gland cancer cell of anti androgenic therapy tolerance, and the inhibition than the northern card Shandong amine of clinical conventional medicine at present is good.
These hydantoin derivatives can efficiently suppress the growth of the prostate gland cancer cell to the sensitive prostate cancer of anti androgenic therapy and to anti androgenic therapy tolerance.Brief description of the drawings
Fig. 1, hydantoin derivatives are to the sensitive prostate gland cancer cell LNCaP (Figure 1A) of anti androgenic therapy and the prostate gland cancer cell VCaP (Figure 1B) of anti androgenic therapy tolerance relative suppression growth ability.LNCaP cells are incubated in the Iscove's culture mediums containing 10% hyclone (Charcoal-stripped FBS) for falling androgen through wood charcoal adsorption and cultivated, after three days, androgen R1881 is added in nutrient solution and has the test compound of finite concentration tonsure, its ultimate density is set to reach 200 pmols of R1881 and 1,2.5, with the compound of 5 micro-molar concentration tonsures, after cultivating five to six days, the TCS of growth is calculated.When the TCS grown when subtracting using 200 pmols of the R1881 cell growth sums induced and be not added with R1881 being shown in figure as 100% growth ability, the sensitive prostate gland cancer cell LNCaP (Figure 1A) of anti androgenic therapy and the prostate gland cancer cell VCaP (Figure 1B) of anti androgenic therapy tolerance relative growth ability in the presence of various concentrations compound.The hydantoin derivatives that the present invention is synthesized can effectively suppress the growth of LNCaP and VCaP cells, illustrate that they can suppress sensitive and to anti androgenic therapy tolerance prostate cancer the growth of anti androgenic therapy, the inhibition than the northern card Shandong amine of clinical conventional medicine at present is good.Embodiment
Compound CD1
4-[3-(6- cyano group-5- trifluoromethyl pyridine-3- base）
It is dissolved in 18 milliliters of THF 5- amino -2- cyano group -3- (trifluoromethyl) pyridine（10 grams) it is slowly added in the aqueous solution containing 5 milliliters of thiophosgenes (120 milliliters), it is stirred at room temperature after 50 minutes, (100 milliliters three times) is extracted with dichloromethane, organic phase is washed through salt, crosses anhydrous Na2S04Dry, be concentrated under reduced pressure, silicagel column is crossed, through PE-EA (20:1) compound as white solid 1A (5- isothiocyanic acid -2- cyano group -3- (trifluoromethyl) pyridine, 10 grams are eluted to obtain；).(2 grams of p-aminophenyl butyric acid）, acetone cyanohydrin (16 milliliters) and MgS04(6 g) is heated to 80 °C, stirs 24 hours, and 50 milliliters of ethyl acetate and water extracting are added after room temperature, and organic phase crosses MgS04, it is concentrated under reduced pressure, is dried in vacuo to obtain (2.5 grams of 1B）.The 1A (2 grams) for being dissolved in 5 milliliters of DMF and (2 grams) mixing of 1B for being dissolved in 5 milliliters of DMF, stirring adds 40 ml methanols and 20 milliliters of 2N HC1 after 24 hours, temperature rising reflux 3 hours, drop to after room temperature, in the frozen water for mixture being poured into 100 milliliters, (3x30 milliliters are then extracted with ethyl acetate；), organic phase crosses silicagel column and obtains compound lC (4- [3- (6- cyano group -5- trifluoromethyl pyridine -3- bases) -5,5- dimethyl -4- oxo -2- thiocarbamoyl imidazole alkane -1- bases]-benzenebutanoic acid methyl esters, 1.3 grams）.It is dissolved in (1 gram of the compound 1C of 20 ml methanols;) and sodium hydroxide (20 milliliters, 2M) 4 hours are stirred at room temperature.After methanol evaporation, reactant mixture is adjusted to pH=5 with 2M HC1, is then extracted with ethyl acetate.Organic layer in vacuo obtains compound lD (4- [3- (6- cyano group -5- trifluoromethyl pyridine -3- bases) -5,5- dimethyl -4- oxo -2- thiocarbamoyl imidazole alkane -1- bases]-benzenebutanoic acids, 0.9 gram after drying）.20 milliliters of THF compound 1D (0.2 gram) and thionyl chloride (40 microlitres) are dissolved in after -5 °C are stirred 1 hour, it is slowly added into excess of ammonia gas, reactant mixture is after -80 °C are flowed back 1 hour, evaporate excess of ammonia, cross post it is dry compound CDl (4- [3- (6- cyano group -5- trifluoromethyl pyridine -3- bases) -5,5- dimethyl -4- oxo -2- thiocarbamoyl imidazole alkane -1- bases]-fenbutyramidum, 190 milligrams；).Compound CD2
4- [3- (6- cyano group -5- trifluoromethyl pyridine -3- bases) -5,5- dimethyl -4- oxo -2- thiocarbamoyl imidazole alkane -1- bases]-N- methyl-fenbutyramidum
10 milliliters of THF compound 1D (0.1 gram) and thionyl chloride (20 microlitres) are dissolved in after -5 °C are stirred 1 hour, it is slowly added into excessive methylamine, reactant mixture is after -80 °C are flowed back 1 hour, evaporate excessive methylamine, cross post it is dry compound CD2 (4- [3- (6- cyano group -5- trifluoromethyl pyridine -3- bases) -5,5- dimethyl -4- oxo -2- thiocarbamoyl imidazole alkane -1- bases] methyl-fenbutyramidum, 91 milligrams；).Compound CD3
4- [3- (6- cyano group -5- trifluoromethyl pyridine -3- bases) -5,5- dimethyl -4- oxo -2- thiocarbamoyl imidazole alkane -1- bases]-Ν, Ν-dimethyl-benzene fourth
10 milliliters of THF compound 1D (0.1 gram) and thionyl chloride (20 microlitres) are dissolved in after -5 °C are stirred 1 hour, it is slowly added into excessive dimethylamine, reactant mixture is after -80 °C are flowed back 1 hour, cross post it is dry compound CD3 (4- [3- (6- cyano group -5- trifluoromethyl pyridine -3- bases) -5,5- dimethyl -4- oxo -2- thiocarbamoyl imidazole alkane -1- bases]-Ν, Ν-dimethyl-fenbutyramidum, 97 milligrams).Compound CD4
4- [3- base -4- oxo -2- thiocarbamoyl imidazole alkane -1- bases]-benzene butyl cyanide
30 microlitres of DMSO for being dissolved in 3 milliliters of dichloromethane are added into and are cooled to -80 °C and are dissolved in 30 microlitres of ethanedioly chlorides of 6 milliliters of dichloromethane, the 0.1 g of compound CDl (4- [3- (6- cyano group -5- trifluoromethyl pyridine -3- bases) -5 for being dissolved in dichloromethane are added after well mixed, 5- dimethyl -4- oxo -2- thiocarbamoyl imidazole alkane -1- bases]-fenbutyramidum, stirring adds 0.1 milliliter of triethylamine after 0.5 hour, continue after -80 °C are reacted 0.5 hour, add NH4C1 and dichloromethane extracting, organic phase cross post it is dry compound CD4 (4- [3- (6- cyano group -5- trifluoromethyl pyridine -3- bases) -5,5- dimethyl -4- oxo -2- thiocarbamoyl imidazole alkane -1- bases]-benzene butyl cyanides, 85 milligrams；).Compound CD5
Azaspiro [3.4] octyl- 5- yls)-benzene butyryl
(2 grams of trimethylsilyl cyanide;) dropwise it is added to (2 grams of p-aminophenyl butyric acid for being dissolved in 40 milliliters of 1,4- dioxane；), cyclobutanone（1.5 gram;) and (4 grams of sodium sulphate；) in solution, mixture is stirred at room temperature 24 hours, and concentrated post obtains (2.3 grams of 2A）.The 1A (2 grams) for being dissolved in 5 milliliters of DMF and (2 grams) mixing of 2A for being dissolved in 5 milliliters of DMF, it is stirred at room temperature after 24 hours and adds 40 ml methanols and 20 milliliters of 2N HC1, temperature rising reflux 3 hours, drop to after room temperature, in the frozen water for mixture being poured into 100 milliliters, (3x30 milliliters are then extracted with ethyl acetate；), organic phase crosses silicagel column and obtains compound 2B (4- (7- (6- cyano group -5- (base of trifluoromethyl pyridine -3) -8- oxos -6- thio -5,7- diaza spiros [3.4] octyl- 5- yls)-benzenebutanoic acid methyl esters, 1.5 grams）.It is dissolved in (1 gram of the compound 2B of 20 ml methanols;) and sodium hydroxide (20 milliliters, 2M) 4 hours are stirred at room temperature.After methanol evaporation, reactant mixture is adjusted to pH=5 with 2M HC1, is then extracted with ethyl acetate.Organic layer in vacuo obtains compound 2C (4- (7- (thio -5,7- diaza spiros [3.4] the octyl- 5- bases of 6- cyano group -5- (base of trifluoromethyl pyridine -3) -8- oxos -6- after drying;)-benzenebutanoic acid, 0.85 gram；).20 milliliters of THF compound 2C (0.2 gram) and thionyl chloride (40 microlitres) are dissolved in after -5 °C are stirred 1 hour, it is slowly added into excess of ammonia gas, reactant mixture is after -80 °C are flowed back 1 hour, evaporate excess of ammonia, cross post it is dry compound CD5 (4- (7- (6- cyano group -5- (base of trifluoromethyl pyridine -3) -8- oxos -6- thio -5,7- diaza spiros [3.4] octyl- 5- yls)-fenbutyramidum, 180 milligrams).Compound CD6
4- (7- (thio -5,7- diaza spiros [3.4] the octyl- 5- yls of 6- cyano group -5- (base of trifluoromethyl pyridine -3) -8- oxos -6-)-N- methyl
- benzene butyryl
10 milliliters of THF compound 2C (0.1 gram) and thionyl chloride (20 microlitres) are dissolved in after -5 °C are stirred 1 hour, it is slowly added into excessive methylamine, reactant mixture is after -80 °C are flowed back 1 hour, evaporate excessive methylamine, cross post it is dry compound CD6 (4- (7- (6- cyano group -5- (base of trifluoromethyl pyridine -3) -8- oxos -6- thio -5,7- diaza spiros [3.4] octyl- 5- yls) methyl-fenbutyramidum, 89 milligrams).
Compound CD7
4- (7- (thio -5,7- diaza spiros [3.4] the octyl- 5- yls of 6- cyano group -5- (base of trifluoromethyl pyridine -3) -8- oxos -6-)-Ν, Ν-dimethyl-benzene
10 milliliters of THF compound 2C (0.1 gram) and thionyl chloride (20 microlitres) are dissolved in after -5 °C are stirred 1 hour, it is slowly added into excessive dimethylamine, reactant mixture is after -80 °C are flowed back 1 hour, cross post it is dry compound CD7 (4- (7- (6- cyano group -5- (base of trifluoromethyl pyridine -3) -8- oxos -6- thio -5,7- diaza spiros [3.4] octyl- 5- yls)-Ν, Ν-dimethyl-fenbutyramidum, 93 milligrams).Compound CD8
4- (7- (thio -5,7- diaza spiros [3.4] the octyl- 5- yls of 6- cyano group -5- (base of trifluoromethyl pyridine -3) -8- oxos -6-)-benzene butyl
30 microlitres of DMSO for being dissolved in 3 milliliters of dichloromethane are added into and are cooled to -80 °C and are dissolved in 30 microlitres of ethanedioly chlorides of 6 milliliters of dichloromethane, 0.1 g of compound CD5 (4- (7- (6- cyano group -5- (base of trifluoromethyl pyridine-the 3) -8- oxos -6- thio -5 for being dissolved in dichloromethane are added after well mixed, 7- diaza spiros [3.4] octyl- 5- yls)-fenbutyramidum, stirring adds 0.1 milliliter of triethylamine after 0.5 hour, continue after -80 °C are reacted 0.5 hour, add NH4C1 and dichloromethane extracting, organic phase cross post it is dry compound CD8 (4- (7- (6- cyano group -5- (base of trifluoromethyl pyridine -3) -8- oxos -6- thio -5,7- diaza spiros [3.4] octyl- 5- yls)-benzene butyl cyanide, 81 milligrams).Compound CD9
3- (the miscellaneous spiral shells of 4- [4.4] nonyl- 3- yls) -5- trifluoromethyl -6- Cyano-pyridins
(2 grams of trimethylsilyl cyanide；) little by little it is added to (2 grams of p-aminophenyl butyric acid;) and (1.5 grams of cyclopentanone；), mixture is stirred at room temperature 16 hours, crosses post and obtains (2.1 grams of 3A）.The 1A (2 grams) for being dissolved in 5 milliliters of DMF and (2 grams) mixing of 3A for being dissolved in 5 milliliters of DMF, it is stirred at room temperature after 24 hours and adds 40 ml methanols and 20 milliliters of 2N HC1, temperature rising reflux 3 hours, drops to after room temperature and mixture is poured into
In 100 milliliters of frozen water, (3x30 milliliters are then extracted with ethyl acetate；), organic phase crosses silicagel column and obtains compound 3B (3- (thio -1- of 4- oxos -2- (4 butyric acid methyl esters benzene) -1,3- diaza spiros [4.4] nonyl- 3- yls) -5- trifluoromethyl -6- Cyano-pyridins, 1.2 grams）.It is dissolved in (1 gram of the compound 3B of 20 ml methanols;) and sodium hydroxide (20 milliliters, 2M) 4 hours are stirred at room temperature.After methanol evaporation, reactant mixture is adjusted to pH=5 with 2M HC1, is then extracted with ethyl acetate.Organic layer in vacuo obtains compound 3C (3- (thio -1- of 4- oxos -2- (4 butyric acid benzene) -1,3- diaza spiros [4.4] nonyl- 3- yls) -5- trifluoromethyl -6- Cyano-pyridins, 0.8 gram after drying）.20 milliliters of THF compound 3C (0.2 gram) and thionyl chloride (40 microlitres) are dissolved in after -5 °C are stirred 1 hour, it is slowly added into excess of ammonia gas, reactant mixture is after -80 °C are flowed back 1 hour, evaporate excess of ammonia, cross post it is dry the compound CD9 (3- (thio -1- of 4- oxos -2- (4- butyramides benzene) -1,3- diaza spiros [4.4] nonyl- 3- yls) -5- trifluoromethyl -6- Cyano-pyridins, 170 milligrams）.Compound CD 10
- (thio -1- of 4- oxos -2- (4- Ν-methyl-butyramide benzene) -1,3- diaza spiros [4.4] nonyl- 3- yls) -5- trifluoromethyl -6- cyanogen
10 milliliters of THF compound 3C (0.1 gram) and thionyl chloride (20 microlitres) are dissolved in after -5 °C are stirred 1 hour, it is slowly added into excessive methylamine, reactant mixture is after -80 °C are flowed back 1 hour, evaporate excessive methylamine, cross post it is dry the compound CD10 (3- (thio -1- of 4- oxos -2- (4- Ν-methyl-butyramide benzene) -1,3- diaza spiros [4.4] nonyl- 3- yls) -5- trifluoromethyl -6- Cyano-pyridins, 85 milligrams）.Compound CD 11
3- (thio -1- of 4- oxos -2- (4- Ν, Ν-dimethyl-butyramide benzene) -1,3- diaza spiros [4.4] nonyl- 3- yls) -5- trifluoromethyls
- 6- cyano group-
10 milliliters of THF compound 3C (0.1 gram) and thionyl chloride (20 microlitres) are dissolved in after -5 °C are stirred 1 hour, it is slowly added into excessive dimethylamine, reactant mixture is after -80 °C are flowed back 1 hour, cross post it is dry the compound CDl l (3- (thio -1- of 4- oxos -2- (4- Ν, Ν-dimethyl-butyramide benzene) -1,3- diaza spiros [4.4] nonyl- 3- yls) -5- fluoroforms
Base -6- Cyano-pyridins, 89 milligrams）.Compound CD12
3- (4- spiral shells [4.4] nonyl- 3- yls) -5- trifluoromethyl -6- Cyano-pyridins
30 microlitres of DMSO for being dissolved in 3 milliliters of dichloromethane are added into and are cooled to -80 °C and are dissolved in 30 microlitres of ethanedioly chlorides of 6 milliliters of dichloromethane, the 0.1 g of compound CD9 (3- (thio -1- of 4- oxos -2- (4- butyramides benzene) -1 for being dissolved in dichloromethane are added after well mixed, 3- diaza spiros [4.4] nonyl- 3- yls) -5- trifluoromethyl -6- Cyano-pyridins, stirring adds 0.1 milliliter of triethylamine after 0.5 hour, continue after -80 °C are reacted 0.5 hour, add NH4C1 and dichloromethane extracting, organic phase cross post it is dry the compound CD12 (3- (thio-1- of 4- oxos-2- (4- butyl benzonitrile)-1,3- diaza spiros [4.4] nonyl-3-yl)-5-trifluoromethyl-6-cyano group-batch pyridine, 70 milligrams）.Compound CD 13
4- [3- (6- cyano group -5- trifluoromethyl pyridine -3- bases) -5,5- dimethyl -4- oxo -2- thiocarbamoyl imidazole alkane -1- bases] -2- fluoro- Ν, Ν-dimethyl-stupid formamide
C2 grams of thionyl chloride) be added into be dissolved in 20 milliliters DMFC-5 °C) the fluoro- 4- nitrobenzoic acids of 2- (；2 grams), stirring is slowly added into excessive dimethylamine after 2 hours, continue to be concentrated under reduced pressure after stirring 2 hours, then extracted with ethyl acetate and water, organic layer obtains 13A (2- fluoro- Ν, Ν-stupid formamide of dimethyl -4- nitros, 2 grams) after filtration drying.13 Α (2 grams), iron powder (8 grams) and ammonium chloride (8 grams) for being dissolved in 100 ml methanols are heated to reflux 3 hours, reduce and filtered after room temperature, it is concentrated under reduced pressure, then extracted with ethyl acetate and water, organic layer is through filtering and concentrating, cross and 13 Β (2- fluoro- Ν, Ν-stupid formamides of dimethyl -4- amino, 1.3 grams is obtained after silicagel column；).(0.5 gram of 13 Β）, acetone cyanohydrin (4 milliliters) and magnesium sulfate（1.5g) mixture is heated to 80 °C, stirs 24 hours, is down to after room temperature and is diluted with water, and is washed after sediment filtering with ethyl acetate and ether, dry (0.25 gram of 13C）.It is dissolved in 1AC0.2 grams of 2 milliliters of DMF) and 13CC0.2 grams) stirred 24 hours at 120 °C, it is down to after room temperature and uses methanol dilution, and adds 3 milliliters of 2 N HC1 ,-a backflow 3 hours, drop to after room temperature, reactant mixture quilt
In the cold water of 20 milliliters of injection, cross and (4- [the 3- (6- cyano group-5- trifluoromethyl pyridine-3- bases)-5 of compound CD 13 are obtained after silicagel column, -1-yl of 5- dimethyl-4- oxo-2- thiocarbamoyl imidazole alkane] the fluoro- Ν of-2-, Ν-dimethyl-stupid formamide, 52 milligrams).Compound CD 14
4- [7- (6- cyano group -5- trifluoromethyl pyridine -3- bases;) thio -5,7- diaza spiros [3.4] the octyl- 5- yls of -8- oxos -6-] -2- fluoro- Ν, Ν
(0.5 gram of 13 Β）, cyclobutanone (4 grams) and TMSCN (5 grams) heated overnight at reflux together is concentrated under reduced pressure, after post (0.2 gram of 14A；).1 A (0.2 gram) and 14A (0.2 gram) for being dissolved in 2 milliliters of DMF are heated to reflux 4 hours, it is down to after room temperature and uses methanol dilution, and add 3 milliliters of 2 N HC1,-play backflow 3 hours, drop to after room temperature, reactant mixture is injected into 20 milliliters of cold water, cross and (4- [7- (6- cyano group -5- trifluoromethyl pyridine -3- the bases) -8- oxos -6- thio -5 of compound CD 14 are obtained after silicagel column, 7- diaza spiros [3.4] octyl- 5- yls] the fluoro- Ν of -2-, Ν-dimethyl-stupid formamide, 45 milligrams；).Compound CD 15
4- [- 1-yl of 3- (6- cyano group-5- trifluoromethyl pyridine-3- bases)-5,5- dimethyl-4- oxo-2- thiocarbamoyl imidazole alkane] fluoro- fenbutyramidums of-2-
By compound 4- (4- amino -2- fluorobenzene;) butyric acid formicester (5 g, 24 mmol), 2- hydroxy-iso-butyronitriles (20ml) and magnesium sulfate
The mixture of (10g) is stirred overnight under 80 °C.Reacting liquid filtering is concentrated, and residue crosses post (ethyl acetate：N-hexane=1：15) colorless oil compound 15A (5 g are obtained;85% yield）.
iHNMR (400MHz, CDC13) δ:7.061-7.019 (1 Η, the Hz of J=8.4, t), 6.616-6.582 (2H, m), 3.723 (1H, s), 3.666 (3H, s), 2.618-2.580 (2H, the Hz of J=7.6, t), (Hz of 2H, J=7.6 of 2.355-2.3 18, t), (2H, m) is by compound 15A (5 g, 18.0 mmol) and the A of compound 1 (5- isothiocyanic acid-2- cyano group-3- (trifluoromethyl) pyridines (8 g by 1.948- 1.873:34.9 mmol) DMF (5ml) solution be stirred at room temperature overnight.Then methanol is added（10ml) and hydrochloric acid（1N, 10ml) mixture is heated to reflux 1 hour, is cooled to room temperature and diluted with ethyl acetate.Solution is washed with saturated nacl aqueous solution, is had
Machine is mutually dried and post (ethyl acetate is crossed after concentration：N-hexane=1：3) compound as white solid 15B (4.0 g are obtained;44% yield).In compound 15B (4.0 g, 7.9 mmol) tetrahydrofuran (40ml) and water（15ml) solution adds lithium hydroxide（1.0 g: 25 mmol)0Reaction solution is stirred 4 hours, then adjusts pH 6, and rear ethyl acetate extraction is diluted with water, is washed with saturated sodium-chloride.Organic phase, which is dried, crosses post (ethyl acetate after concentration：N-hexane=1：3) white solid 15C (3.5 g are obtained;90% yield).Thionyl chloride (5ml) stirring reaction 2 hours at room temperature are added in compound 15C (2 g, 4.0 mmol) dichloromethane (20ml) solution.Tetrahydrofuran (30ml) is dissolved in after reaction solution concentration.Then pass to ammonia (gas) stirring reaction 10 minutes.Reaction solution is washed after being diluted with ethyl acetate with saturated nacl aqueous solution, and organic phase prepares (1.2 g of compound as white solid 15 after drying concentration;60% yield；).Compound CD 16
4- [3- (6- cyano group -5- trifluoromethyl pyridine -3- bases) -5,5- dimethyl -4- oxo -2- thiocarbamoyl imidazole alkane -1- bases] fluoro- N- methyl of -2-
Thionyl chloride (5ml) stirring reaction 2 hours at room temperature are added in compound 15C (2 g, 4.0 mmol) dichloromethane (20ml) solution.Tetrahydrofuran (30ml) is dissolved in after reaction solution concentration.Then pass to methylamine (gas) stirring reaction 10 minutes.Reaction solution is washed after being diluted with ethyl acetate with saturated nacl aqueous solution, and organic phase, which is dried, crosses post (ethyl acetate after concentration：Petroleum ether=1：1) (1.3 g of compound as white solid 16 are obtained;63% yield；).
iHNMR (400MHz, CD30D) δ:9.183-9.179 (Hz of 1 Η, J=2.4, d), 8.696-8.691 (Hz of 1H, J=2.0, d), 7.490-7.449 (1H, the Hz of J=8.0, t), 7.203-7.176 (2H, m), 2.791-2.753 (2H, J=7.6 Hz t), 2.735 (3H, s), 2.302-2.264 (Hz of 2H, J=7.6, t), 2.031-1.966 (2H, m), 1.603 (6H, s) compounds CD 17
4- [3- (6- cyano group -5- trifluoromethyl pyridine -3- bases) -5,5- dimethyl -4- oxo -2- thiocarbamoyl imidazole alkane -1- bases] fluoro- N of -2-, N- diformazans
Thionyl chloride (5ml) stirring reaction 2 hours at room temperature are added in compound 15C (2 g, 4.0 mmol) dichloromethane (20ml) solution.Tetrahydrofuran (30ml) is dissolved in after reaction solution concentration, dimethylamine hydrochloride (4.0 g, 49.1 mmol) and triethylamine (10ml) stirring reaction 2 hours is then added.Reaction solution is washed after being diluted with ethyl acetate with saturated nacl aqueous solution, and organic phase obtains (1 g of compound as white solid 17 after drying concentration by preparing chromatogram;50% yield).Compound CD 18
Azaspiro [3.4] octyl- 5- yls) -2- is fluoro-
Compound 4-C4- amino -2- fluorobenzene;) butyric acid formicester (10 g, 47 mmol) TMSCN and cyclobutanone pOml) solution heated overnight at reflux, then the concentrated post of reaction solution is purified（Ethyl acetate：N-hexane=1：15) colorless oil compound 18A (12 g are obtained;87% yield）.
iHNMR (400MHz, CDC13) δ:7.042 (1 Η, the Hz of J=8.4, t), 6.392-6.330 (2H, m), 4.102 (1H, s), 3.884 (3H, s), 2.830-2.586 (6H, m), 2.407-2.318 (4H, m), 2.002-1.901 (2H, m) is by compound 18A (10 g, 34.5 mmol) and compound 1A (5- isothiocyanic acid -2- cyano group -3- (trifluoromethyl) pyridine (15 g, 65.5 mmol) is dissolved in DMF (30ml) and is stirred at room temperature overnight.Then methanol is added（10ml) and hydrochloric acid（1N, 10ml) mixture is heated to reflux 1 hour, and reaction solution is cooled to after room temperature to be diluted with ethyl acetate, and solution is washed with saturated nacl aqueous solution, and organic phase, which is dried, crosses post (ethyl acetate after concentration：N-hexane=1：3) compound as white solid 18B (8.2 g are obtained;46% yield）.
iHNMR (400MHz, CDC13) δ:9.031-9.026 (Hz of 1 Η, J=2.0, d), 8.294-8.288 (Hz of 1H, J=2.4, d), 7.384-7.344 (Hz of 1H, J=8.0, t), 7.002-6.943 (2H, m), 3.633 (3H, s), 2.739-1.946 (12H, m) tetrahydrofurans of the in compound 18B (8.2 g, 15.8 mmol)（120 ml) and water (45 ml) solution in lithium hydroxide (2g,
50mmol) o reaction solutions reacted after 4 hours at room temperature, were neutralized to pH 6.Reaction solution is extracted with ethyl acetate after being diluted with water.Organic phase is washed with saturated nacl aqueous solution, dries and post (ethyl acetate is crossed after concentration：N-hexane=1:5) compound as white solid 18CC6.5 g are obtained;81% yield；).
1Beautiful MR (400MHz, DMS0-d6) δ:9.285-9.281 (1 Η, the Hz of J=1.6, d), 8.832-8.829 (1H, the Hz of J=1.2, d), the 7.633-7.591 (Hz of 1H, J=8.4, t), 7.315-7.291 (2H, m), 2.806-2.340 (8H, m), 2.052-1.886 (4H, m) thionyl chloride (5ml) is added in compound 18C (2 g, 4.0 mmol) dichloromethane (20ml) solution and is stirred at room temperature
Mix reaction 2 hours.Tetrahydrofuran (30ml) is dissolved in after reaction solution concentration.Then pass to ammonia (gas) stirring reaction 10 minutes.Reaction solution is washed after being diluted with ethyl acetate with saturated nacl aqueous solution, and organic phase prepares (1.3 g of compound as white solid 18 after drying concentration;63% yield；).
iHNMR (400MHz, CD30D) δ:9.166-9.163 (Hz of 1 Η, J=1.2, d), 8.650-8.647 (Hz of 1H, J=1.2, d), 7.547-7.506 (1H, the Hz of J=8.4, t), 7.228-7.202 (2H, m), 2.837-2.799 (2H, J=7.6 Hz t), 2.722-2.675 (2H, m), 2.636-2.556 (2H, m), 2.353-2.316 (2H, the Hz of J=7.6, t), 2.157-2.13 1 (1H, m), 2.050-1.993 (2H, m), 1.669-1.643 (1H, m) compounds CD 19
4- (7- (thio -5,7- diaza spiros [3.4] the octyl- 5- yls of 6- cyano group -5- (base of trifluoromethyl pyridine -3) -8- oxos -6-) -2- fluorine
Thionyl chloride (5ml) stirring reaction 2 hours at room temperature are added in compound 18C (2 g, 4.0 mmol) dichloromethane (20ml) solution.Tetrahydrofuran (30ml) is dissolved in after reaction solution concentration, methylamine (gas) stirring reaction is then passed to 10 minutes.Reaction solution is washed after being diluted with ethyl acetate with saturated nacl aqueous solution, and organic phase, which is dried, crosses post (ethyl acetate after concentration：Petroleum ether=1：1) (1.3 g of compound as white solid 19 are obtained;63% yield；).
iHNMR (400MHz, CD30D) δ:9.168-9.164 (1 Η, the Hz of J=1.6, d), 8.652-8.647 (1H, the Hz of J=2.0, d), 7.538-7.496 (1H, the Hz of J=8.4, t), 7.226-7.199 (2H, m), 2.815-2.776 (2H, Hz t of J=8.0), 2.740 (3H, s), 2.714-2.666 (2H, m), 2.635-2.579 (2H, m), 2.319-2.282 (2H, the Hz of J=7.6, t), 2.160-2.132 (1H, m), 2.031- 1.988 (2H, m), 1.667-1.641 (1H, m) compounds CD20
4- (7- (thio -5,7- diaza spiros [3.4] the octyl- 5- yls of 6- cyano group -5- (base of trifluoromethyl pyridine -3) -8- oxos -6-) fluoro- Ν of -2-, Ν-dimethyl-fenbutyramidum
Thionyl chloride (5ml) stirring reaction 2 hours at room temperature are added in compound 18C (2 g, 4.0 mmol) dichloromethane (20ml) solution.Tetrahydrofuran (30ml) is dissolved in after reaction solution concentration, dimethylamine hydrochloride (4.0 g, 49.1 mmol) and triethylamine (10ml) stirring reaction 2 hours is then added.Reaction solution is washed after being diluted with ethyl acetate with saturated nacl aqueous solution, and organic phase obtains (1.1 g of compound as white solid 20 after drying concentration by preparing chromatogram;52% yield).
iHNMR (400MHz, CD30D) δ: 9.161 (1Η, s), 8.648 (1H, s), 7.550-7.508 (1H, J = 8.4
Hz, t), 7.226-7.200 (2H, m), 3.058 (3H, s), 2.957 (3H, s), 2.852-2.814 (2H, J = 7.6 Hz, t):2.721-2.674 (2H, m), 2.634-2.554 (2H, m), 2.511-2.474 (2H, the Hz of J=7.6, t), 2.177-2.105 (1H m), 2.053-1.966 (2H, m), 1.673-1.628 (1H, m) compounds suppression androgen receptor abilities
Influence of the hydantoin derivatives to androgen receptor bioactivity is examined with prostate gland cancer cell, cell is LNCaP and VCaP.LNCaP is a kind of sensitive prostate gland cancer cell model of conventional anti androgenic therapy, and VCaP is a kind of prostate gland cancer cell model of anti androgenic therapy tolerance.We measure the influence of the concentration for the prostate specific antigen (Prostate-Specific Antigen, PSA) that these compounds are secreted to it.
Prostate specific antigen is an important indicator of prostate cancer, and its expression is regulated and controled by androgen receptor, therefore, and the expression of prostate specific antigen reflects the physiologically active of androgen receptor.In order to examine compound to the rejection ability of androgen receptor body function, the androgen R1881 that we manually synthesize effectively induces the expression of prostate specific antigen, then measures the rejection ability that the prostate specific antigen that compound induce R1881 is expressed.With the Iscove's medium culture prostate gland cancer cells containing 10% hyclone, before testing drug suppresses androgen receptor ability of immigrants, this cell culture is cultivated in the culture medium for fall through wood charcoal adsorption the Iscove's of hyclone (Charcoal-stripped FBS) of androgen containing 10%, after three days, artificial synthesized androgen R1881 is added in nutrient solution and has the test compound of finite concentration tonsure, their ultimate density is set to reach 200 pmols of R1881 and 60, 125, the test compound of 250 and 500 nanomole (nM) concentration tonsures, after culture four days, the concentration of the prostate specific antigen of nutrient solution is secreted into integrated enzyme reaction reagent measuring, then the rejection ability of percentage 50 (IC50) that test compound suppresses prostate specific antigen is calculated.Table 1 is shown, the hydantoin derivatives that the present invention is illustrated can effectively suppress the expression of LNCaP and VCaP cell prostate specific antigens, illustrate that they can suppress the activity of the androgen receptor of sensitive and to anti androgenic therapy tolerance the prostate gland cancer cell of anti androgenic therapy, the inhibition than the northern card Shandong amine of clinical conventional medicine at present is good.Table 1, the sensitive model of human prostate carcinoma cell LNCaP of Compounds Against androgenotherapy and the prostate gland cancer cell VCaP to anti androgenic therapy tolerance suppress the inhibition concentration of percentage 50 (IC50) of prostate specific antigen expression.
Imidazolidine -1- bases]-N, N- dimethyl-stupid butyramide
[3- (6- cyano group -5- trifluoromethyl pyridine -3- bases) -5,5- dimethyl -4- oxos -2- is thio by 4-
CD4 imidazolidine -1- bases]-stupid butyl cyanide 123 189
4- (7- (thio -5,7- the diazas of 6- cyano group -5- (base of trifluoromethyl pyridine -3) -8- oxos -6-
CD5 spiral shells [3.4] octyl- 5- yls)-stupid butyramide 109 164
4- (7- (thio -5,7- the diazas of 6- cyano group -5- (base of trifluoromethyl pyridine -3) -8- oxos -6-
CD6 spiral shells [3.4] octyl- 5- yls)-N- methyl-stupid butyramide 102 136
4- (7- (thio -5,7- the diazas of 6- cyano group -5- (base of trifluoromethyl pyridine -3) -8- oxos -6-
CD7 spiral shells [3.4] octyl- 5- yls)-Ν, Ν-dimethyl-stupid butyramide 91 128
4- (7- (thio -5,7- the diazas of 6- cyano group -5- (base of trifluoromethyl pyridine -3) -8- oxos -6-
CD8 spiral shells [3.4] octyl- 5- yls)-stupid butyl cyanide 139 177
3- (thio -1- of 4- oxos -2- (4- butyramides are stupid) -1,3- diaza spiros [4.4] nonyl- 3- yls) -5-
CD9 trifluoromethyl -6- Cyano-pyridins 163 239
3- (thio-the 1- of 4- oxos -2- (4- Ν-methyl-butyramide is stupid) -1,3- diaza spiros [4.4] nonyls
CD10-3-yl)-5-trifluoromethyl-6-Cyano-pyridin 148 219
3- (4- oxos-2- thio-1-(4- Ν, Ν-dimethyl-butyramide are stupid;) -1,3- diaza spiros
CD11 [4.4] nonyl- 3- yls) -5- trifluoromethyl -6- Cyano-pyridins 126 211
3- (thio -1- of 4- oxos -2- (4- butyl cyanides are stupid) -1,3- diaza spiros [4.4] nonyl- 3- yls) -5-
CD12 trifluoromethyl -6- Cyano-pyridins 198 293
[3- (6- cyano group -5- trifluoromethyl pyridine -3- bases) -5,5- dimethyl -4- oxos -2- is thio by 4-
CD13 imidazolidine -1- bases] -2- fluoro- Ν, Ν-dimethyl-stupid formamide 128 192
4- [7- (6- cyano group -5- trifluoromethyl pyridine -3- bases) thio -5,7- diazas of -8- oxos -6-
CD14 spiral shells [3.4] octyl- 5- yls] -2- fluoro- Ν, Ν-dimethyl-stupid formamide 120 204
[3- (6- cyano group -5- trifluoromethyl pyridine -3- bases) -5,5- dimethyl -4- oxos -2- is thio by 4-
CD15 imidazolidine -1- bases] the fluoro- fenbutyramidums 109 157 of -2-
[3- (6- cyano group -5- trifluoromethyl pyridine -3- bases) -5,5- dimethyl -4- oxos -2- is thio by 4-
- 1-yl of CD16 imidazolidines] the fluoro- Ν-methyl-fenbutyramidums 105 152 of-2-
[3- (6- cyano group -5- trifluoromethyl pyridine -3- bases) -5,5- dimethyl -4- oxos -2- is thio by 4-
CD17 imidazolidine -1- bases] the fluoro- Ν of -2-, Ν-dimethyl-fenbutyramidum 101 132
4- (7- (thio -5,7- the diazas of 6- cyano group -5- (base of trifluoromethyl pyridine -3) -8- oxos -6-
CD18 spiral shells [3.4] octyl- 5- yls) the fluoro- fenbutyramidums 111 171 of -2-
4- (7- (thio -5,7- the diazas of 6- cyano group -5- (base of trifluoromethyl pyridine -3) -8- oxos -6-
CD19 spiral shells [3.4] octyl- 5- yls) the fluoro- Ν-methyl-fenbutyramidums 99 148 of -2-
4- (7- (thio -5,7- the diazas of 6- cyano group -5- (base of trifluoromethyl pyridine -3) -8- oxos -6-
CD20 spiral shells [3.4] octyl- 5- yls) the fluoro- Ν of -2-, Ν-dimethyl-fenbutyramidum 98 135
Compound suppresses the ability of prostate carcinoma cell growth
We also examine the model of human prostate carcinoma cell for the anti androgenic therapy sensitivity that some compounds are induced androgen
LNCaP and the prostate cancer VCaP cells of anti androgenic therapy tolerance growth inhibition effect.It is similar with above method, LNCaP and VCaP cells are placed on after being cultivated three days in the Iscove's culture mediums containing 10% hyclone for falling androgen through wood charcoal adsorption, the test compound of androgen and finite concentration tonsure is added in nutrient solution, its ultimate density is set to reach the compound of 200 pmols of the micro-molar concentration tonsure of R1881 and 1,2.5 and 5, after culture five to six days, the TCS of growth is calculated.When the TCS grown when being subtracted using the cell growth sum of 200 pmols of R1881 inductions and be not added with R1881 is shown as 100% growth ability in Fig. 1, the sensitive prostate gland cancer cell LNCaP (Figure 1A) of anti androgenic therapy and the prostate gland cancer cell VCaP (Figure 1B) of anti androgenic therapy tolerance relative growth ability in the presence of the compound of various concentrations.The hydantoin derivatives that the present invention is synthesized can effectively suppress the growth of LNCaP cells, illustrate that they can effectively suppress the growth of the sensitive prostate gland cancer cell of anti androgenic therapy, and the inhibition than the northern card Shandong amine of clinical conventional medicine at present is good.The hydantoin derivatives that the present invention is synthesized also can effectively suppress the growth of VCaP cells, illustrate that they can suppress the growth of the prostate gland cancer cell of anti androgenic therapy tolerance, and northern card Shandong amine is without inhibition.
Claims (7)
1. adjust the hydantoin derivatives of estrogen receptor activity, it is characterised in that the derivative has following chemical structure of general formula I：
I
Wherein：
R1 is cyano group or nitro；
R2 is halogen, trifluoromethyl or other halogen substituents；
A, B and C are independently selected from carbon or nitrogen, but they at least one be nitrogen；
The C3-C6 cyclic hydrocarbon radicals that R3 and R4 is circularized independently selected from methyl or connection；
R5, R6, R7 and R8 are independently selected from hydrogen, halogen or halogen substituents；
R9 is alkyl or its substituent; substituent is selected from element, plain substituent, cyano group, amide groups, acid amides substituent, amino, nitro, carboxyl, carbonyl, hydroxyl, oxyalkyl, oxygen alkyl carbonyl, aminoalkyl, sulfydryl, sulfonyl, sulfone or sulfoxide, sulfanyl, sulfanilamide (SN), carbamyl, mephenesin Carbamate, urea base, oxyammonia or hydroxy amide, and an alkyl can have one or more substituents simultaneously.
2. hydantoin derivatives as claimed in claim 1, it is characterised in that described R9 is:
0 0
^Ri° or/；
Wherein, R10 is selected from the amino of amino, list or dimethyl substitution.
3. hydantoin derivatives as claimed in claim 1, it is characterised in that R5, R6, R7 and R8 are independently selected from hydrogen or fluorine.4. the hydantoin derivatives stated such as claim 1-3 offices, it is characterised in that the derivative is：
4- [3- (6- cyano group -5-：Fluoromethylpyridin -3- bases；) -5,5- dimethyl -4- oxo -2- thiocarbamoyl imidazole alkane -1- bases]-fenbutyramidum；
4- [3- (6- cyano group -5-：Fluoromethylpyridin -3- bases) -5,5- dimethyl -4- oxo -2- thiocarbamoyl imidazole alkane -1- bases]-N- methyl-fenbutyramidum；
4- [3- (6- cyano group -5-：Fluoromethylpyridin -3- bases) -5,5- dimethyl -4- oxo -2- thiocarbamoyl imidazole alkane -1- bases]-Ν, Ν -
Dimethyl-fenbutyramidum；
4- [3- (6- cyano group -5- trifluoromethyl pyridine -3- bases) -5,5- dimethyl -4- oxo -2- thiocarbamoyl imidazole alkane -1- bases]-benzene butyl cyanide；
4- (7- (thio -5,7- diaza spiros [3.4] the octyl- 5- yls of 6- cyano group -5- (base of trifluoromethyl pyridine -3) -8- oxos -6-)-fenbutyramidums；
4- (7- (thio -5,7- diaza spiros [3.4] the octyl- 5- yls of 6- cyano group -5- (base of trifluoromethyl pyridine -3) -8- oxos -6-)-N- methyl-fenbutyramidum；
4- (7- (6- cyano group -5- (the bases of trifluoromethyl pyridine -3）Thio -5,7- diaza spiros [3.4] the octyl- 5- yls of -8- oxos -6-) -N,N- dimethyl-fenbutyramidum；
4- (7- (thio -5,7- diaza spiros [3.4] the octyl- 5- yls of 6- cyano group -5- (base of trifluoromethyl pyridine -3) -8- oxos -6-)-benzene butyl cyanides；
3- (thio -1- of 4- oxos -2- (4- butyramides benzene) -1,3- diaza spiros [4.4] nonyl- 3- yls) -5- trifluoromethyl -6- Cyano-pyridins；
3- (thio -1- of 4- oxos -2- (4- Ν-methyl-butyramide benzene) -1,3- diaza spiros [4.4] nonyl- 3- yls) -5- trifluoromethyl -6- Cyano-pyridins；
3- (thio -1- of 4- oxos -2- (4- Ν, Ν-dimethyl-butyramide benzene) -1,3- diaza spiros [4.4] nonyl- 3- yls) -5- trifluoromethyl -6- Cyano-pyridins；
3- (thio -1- of 4- oxos -2- (4- butyl benzonitrile) -1,3- diaza spiros [4.4] nonyl- 3- yls) -5- trifluoromethyl -6- Cyano-pyridins；
4- [3- (6- cyano group -5- trifluoromethyl pyridine -3- bases) -5,5- dimethyl -4- oxo -2- thiocarbamoyl imidazole alkane -1- bases] -2- fluorine
- Ν, Ν-dimethyl-stupid formamide；
4- [7- (6- cyano group -5- trifluoromethyl pyridine -3- bases;) thio -5,7- diaza spiros [3.4] the octyl- 5- yls of -8- oxos -6-] -2- fluoro- Ν, Ν-dimethyl-stupid formamide；
4- [3- (6- cyano group -5- trifluoromethyl pyridine -3- bases) -5,5- dimethyl -4- oxo -2- thiocarbamoyl imidazole alkane -1- bases] fluoro- fenbutyramidums of -2-；
4- [3- (6- cyano group -5- trifluoromethyl pyridine -3- bases) -5,5- dimethyl -4- oxo -2- thiocarbamoyl imidazole alkane -1- bases] -2- methyl fluorides-fenbutyramidum；
4- [3- (6- cyano group -5- trifluoromethyl pyridine -3- bases) -5,5- dimethyl -4- oxo -2- thiocarbamoyl imidazole alkane -1- bases] fluoro- Ν of -2-, Ν-dimethyl-fenbutyramidum；
4- (7- (thio -5,7- diaza spiros [3.4] the octyl- 5- yls of 6- cyano group -5- (base of trifluoromethyl pyridine -3) -8- oxos -6-) -2- fluorine
- fenbutyramidum；
4- (7- (thio -5,7- diaza spiros [3.4] the octyl- 5- yls of 6- cyano group -5- (base of trifluoromethyl pyridine -3) -8- oxos -6-) -2- methyl fluorides-fenbutyramidum；Or
4- (7- (thio -5,7- diaza spiros [3.4] the octyl- 5- yls of 6- cyano group -5- (base of trifluoromethyl pyridine -3) -8- oxos -6-) fluoro- Ν of -2-, Ν-dimethyl-fenbutyramidum.
5. the hydantoin derivatives as described in claim 1-3 is any are preparing treatment and the application in estrogen receptor activity relevant disease medicine.
6. the application as described in claim 5, it is characterised in that described estrogen receptor activity relevant disease medicine is：Suppress the medicine of estrogen receptor activity.
7. the application as described in claim 5, it is characterised in that wherein described estrogen receptor activity relevant disease is that prostate cancer (including to the sensitive prostate cancer of anti androgenic therapy and prostate cancer to anti androgenic therapy tolerance), hyperplasia of prostate, hirsutism, perverse, bareheaded powder, breast cancer, sexual desire are excited.
8.-kind of pharmaceutical composition, it is characterised in that including：Any described hydantoin derivatives of claim 1-3, with
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| CN201280048526.6A CN103857667A (en) | 2011-10-22 | 2012-05-08 | Synthesis of a group of hydantoin derivatives and use thereof |
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