WO2015018356A1 - 二芳基乙内酰脲衍生物、其制备方法、药物组合物和应用 - Google Patents
二芳基乙内酰脲衍生物、其制备方法、药物组合物和应用 Download PDFInfo
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- WO2015018356A1 WO2015018356A1 PCT/CN2014/083935 CN2014083935W WO2015018356A1 WO 2015018356 A1 WO2015018356 A1 WO 2015018356A1 CN 2014083935 W CN2014083935 W CN 2014083935W WO 2015018356 A1 WO2015018356 A1 WO 2015018356A1
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- WIPO (PCT)
- Prior art keywords
- group
- diarylhydantoin
- formula
- pharmaceutically acceptable
- tautomers
- Prior art date
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- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- ZZVKMAYHGHXRGV-UHFFFAOYSA-N n-iodoformamide Chemical compound INC=O ZZVKMAYHGHXRGV-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- YZMHQCWXYHARLS-UHFFFAOYSA-N naphthalene-1,2-disulfonic acid Chemical compound C1=CC=CC2=C(S(O)(=O)=O)C(S(=O)(=O)O)=CC=C21 YZMHQCWXYHARLS-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YCWSUKQGVSGXJO-NTUHNPAUSA-N nifuroxazide Chemical group C1=CC(O)=CC=C1C(=O)N\N=C\C1=CC=C([N+]([O-])=O)O1 YCWSUKQGVSGXJO-NTUHNPAUSA-N 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 210000004940 nucleus Anatomy 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 238000011474 orchiectomy Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000003544 oxime group Chemical group 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000006201 parenteral dosage form Substances 0.000 description 1
- 229960003893 phenacetin Drugs 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- KPBSJEBFALFJTO-UHFFFAOYSA-N propane-1-sulfonyl chloride Chemical compound CCCS(Cl)(=O)=O KPBSJEBFALFJTO-UHFFFAOYSA-N 0.000 description 1
- 210000005267 prostate cell Anatomy 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 229940043131 pyroglutamate Drugs 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical class O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 229960001404 quinidine Drugs 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000033764 rhythmic process Effects 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 229940116351 sebacate Drugs 0.000 description 1
- CXMXRPHRNRROMY-UHFFFAOYSA-L sebacate(2-) Chemical compound [O-]C(=O)CCCCCCCCC([O-])=O CXMXRPHRNRROMY-UHFFFAOYSA-L 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000037351 starvation Effects 0.000 description 1
- 229940114926 stearate Drugs 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 125000005017 substituted alkenyl group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical compound [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 1
- QWCJHSGMANYXCW-UHFFFAOYSA-N sulfaphenazole Chemical compound C1=CC(N)=CC=C1S(=O)(=O)NC1=CC=NN1C1=CC=CC=C1 QWCJHSGMANYXCW-UHFFFAOYSA-N 0.000 description 1
- 229960004818 sulfaphenazole Drugs 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- HONNWTDYWUAZJF-UHFFFAOYSA-N tert-butyl 4-[2-[4-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxyindol-1-yl]acetyl]piperazine-1-carboxylate Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC1=C2C=CN(C2=CC=C1)CC(=O)N1CCN(CC1)C(=O)OC(C)(C)C HONNWTDYWUAZJF-UHFFFAOYSA-N 0.000 description 1
- IRACFEVNFLMIIO-UHFFFAOYSA-N tert-butyl 5-bromo-3-cyanoindole-1-carboxylate Chemical compound BrC1=CC=C2N(C(=O)OC(C)(C)C)C=C(C#N)C2=C1 IRACFEVNFLMIIO-UHFFFAOYSA-N 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M trans-cinnamate Chemical compound [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- 238000007832 transition metal-catalyzed coupling reaction Methods 0.000 description 1
- 229960003741 tranylcypromine Drugs 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000002889 tridecyl 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])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229960001124 trientine Drugs 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 229940075466 undecylenate Drugs 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Classifications
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- 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
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- 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
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
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- 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
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/10—Anti-acne agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/14—Drugs for dermatological disorders for baldness or alopecia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/06—Antianaemics
-
- 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
-
- 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
- C07D401/14—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 three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Definitions
- This invention relates to the field of medicinal chemistry, and more particularly to diarylhydantoin derivatives, methods for their preparation, pharmaceutical compositions and uses. Background technique
- the androgen receptor (AR) is a 110,000 Dalton (llOKDa) protein that is a member of the steroid receptor. Similar to other steroid receptors, AR contains three domains: an N-terminal domain, a central DNA binding site and a domain containing a nuclear transfer signal, and a C-terminal domain containing a ligand binding site.
- the N-terminal domain contains a transcriptional functional site called activation function 1 that does not require additional structural regions, which itself activates transcription of the target gene.
- the C-terminus contains a transcriptional site called activation function 2, which activates the transcription of its target gene upon activation of its ligand.
- the ligand-free AR is mainly distributed in the cytoplasm and forms a complex with heat shock proteins.
- AR When combined with androgens (such as testosterone and dihydrotestosterone), AR is released from the complex formed by heat shock proteins, undergoes phosphorylation, forms dimers, and transfers to the nucleus, binding to it. Related to the DNA fragment, thereby stimulating the transcription of its target gene.
- the transcriptional activity of the ligand-activated androgen receptor is thought to be coordinated by a group of proteins called coactivators such as SRC-1, TIF-2 and AIB-1.
- coactivators modify the nuclear chromatin structure and help attract and stabilize transcripts to the target gene for transcription.
- corepressors such as NCoR or SMRT are attracted, resulting in inhibition of transcription.
- the main role of selective AR antagonists is to directly prevent testosterone or dihydrotestosterone from binding to the androgen receptor, blocking the action of androgens on the cells, causing the cells to "starvation” and ultimately promoting apoptosis. It can be used to: 1) prevent, prevent or eliminate PC (Prostate Cancer), breast cancer, ovarian cancer, cervical cancer, bladder 2) Treatment includes benign prostatic enlargement, acne, baldness and hair hyperplasia; 3) male contraception; 4) treatment of a series of male hormone-related disorders such as excessive sexual desire and libido; 5) prevention Symptoms associated with reduced androgen, such as fever after castration; 6) specifically for preventing or inhibiting muscle growth in women during transfusion therapy.
- PC Prostate Cancer
- Treatment includes benign prostatic enlargement, acne, baldness and hair hyperplasia
- male contraception Treatment of a series of male hormone-related disorders such as excessive sexual desire and libido
- prevention Symptoms associated with reduced androgen such as fever
- PC has the highest prevalence rate and the second highest mortality rate among male malignant tumors.
- 2008 alone there were 186,320 new PC cases in the United States, and another 26,660 patients died.
- the incidence rate in China is lower than that in the West, with the continuous improvement of life rhythm, living standard and diagnostic level, PC is on the rise.
- This cancer is a malignant tumor that has progressed rapidly. It cannot be diagnosed early. From the time of symptom discovery, the average survival time is only 3-5 years. Early PC can be effectively controlled by surgery or chemotherapy.
- the general treatment strategy is based on antiandrogen therapy with androgen and its receptor (AR), namely surgical castration (such as bilateral orchiectomy) and antiandrogen therapy.
- AR androgen and its receptor
- CPO Castration-Resistant Prostate Cancer
- Drugs no longer have an inhibitory effect on CRPC, but some drugs such as flutamide and bicalutamide have an agonistic effect on CRPC, and 80% of patients eventually die from CRPC.
- MDV3100 is used to treat CRPC.
- 1199 CRPCs who received a docetaxel-based chemotherapy regimen were randomized into a MDV3100 treatment group and a placebo group.
- the results showed that the median overall survival was significantly increased in the MDV3100-treated group compared with the placebo group (18.4 vs 13.6 months, P ⁇ 0.0001), and the risk of death was 37% lower than in the placebo group.
- ARN-509 is also used to treat CRPC, Now in stage I/II clinical. Advances in MDV3100 and ARN-509 indicate that diaryl hydantoin AR antagonists have very good development prospects. Summary of the invention
- the technical problem to be solved by the present invention is to provide a diarylhydantoin derivative, a preparation method, a pharmaceutical composition and an application which are completely different from the prior art.
- the diarylhydantoin derivative of the present invention has high AR antagonistic activity and can be used for the preparation of a medicament for treating androgen receptor-related diseases, particularly prostate cancer.
- the present invention provides a diarylhydantoin derivative of the formula I, a pharmaceutically acceptable salt thereof, a solvate, a metabolite, a body,
- the anthracene ring is a 6 to 10 membered aryl group or a 6 to 10 membered heteroaryl group;
- the B ring is a 7- to 12-membered fused heteroaryl or an oxo 7- to 12-membered fused heteroaryl group, and at least one of the heteroatoms in the 7- to 12-membered fused heteroaryl group is a nitrogen atom, R 3 and a nitrogen atom in the 7- to 12-membered fused heteroaryl;
- n is the number of substituents Ra on the A ring, and m Ra is each independently a cyano group, a nitro group, a fluorenyl group, a halogen (such as fluorine, chlorine, bromine or iodine) substituted d ⁇ C 4 fluorenyl or halogen (such as fluorine, chlorine, bromine or iodine), m is 2, 3 or 4, and m Ra are not identical to each other;
- n is the number of substituents Rb on the B ring, and n Rb are each independently hydrogen, halogen (such as fluorine, chlorine, bromine or Iodine) or d ⁇ C 4 fluorenyl, n is 0, 1, 2 or 3;
- R 1 and R 2 are each independently Wherein R 4 is hydrogen, hydroxy, halogen (such as fluorine, chlorine, bromine or iodine), carboxyl or d ⁇ C 4 decyloxy; or, I 1 , R 2 and carbon labeled 8 are linked to form 3 to 6 a fluorenyl group or a 4-6 membered heterocyclic fluorenyl group;
- R 3 is hydrogen, halogen (such as fluorine, chlorine, bromine or iodine), nitro, cyano, amino, carboxyl, d ⁇ C 4 fluorenyl, d ⁇ C 4 ,
- R 5 and R 6 are each independently CH 4 fluorenyl, d-C 4 alkenyl, d-C 4 alkynyl, C 3 -C 6 cyclodecyl, 3-6-membered heterocyclic fluorenyl, 6-10.
- Aryl or 6-10 membered heteroaryl, W is halogen (such as fluorine, chlorine, or iodine), nitro, cyano, hydroxy
- Base amino, carboxyl, C-C 4 methoxy, S, , R, C 3 ⁇ C 6 cyclodecyl, 3-6-membered heterocyclic fluorenyl, 6-10 aryl or 6-10 a heteroaryl group, p is 1, 2, 3 or 4, and R 7 and R 8 are each independently a d-C 4 group;
- D is oxygen or sulfur.
- the 6-10 membered aryl group in the ring A is preferably a phenyl group; and the 6-10 membered heteroaryl group in the ring A is preferably a hetero atom of 1 A 6- to 10-membered heteroaryl group of a nitrogen atom is more preferably a pyridyl group.
- the heteroatoms in the 7- to 12-membered fused heteroaryl group in the B ring are preferably nitrogen, and the number of heteroatoms is preferably from 1 to 3;
- the 7- to 12-membered fused heteroaryl group described in the ring is more preferably an oxazolyl group, an isoquinolyl group, a quinolinyl group, a quinazolinyl group or an azacarbazolyl group;
- the oxo 7- to 12-membered fused heteroaryl group is more preferably an isoquinolinone group or a quinazolinone group;
- the oxazolyl group is preferably a 1H-carbazolyl group or a 2H-carbazolyl group.
- the nitrogen The oxazolyl group is preferably a 7-azacarbazolyl group.
- the 2H-carbazolyl group is preferably
- the m Ra groups are preferably each independently a cyano group, a nitro group, a halogen or a d-C 4 halogenated fluorenyl group, and m is 2 or 3; more preferably, m Ra groups are each independently cyanide.
- Base, halogen or trifluoromethyl, m is 2 or 3.
- the m Ra is preferably at least 2 Ra adjacently substituted on the A ring, and one of the Ra and the diaryl hydantoin derivative as shown in Formula I is labeled 10
- the nitrogen of the position forms a para-substitution.
- the Ra is preferably a cyano group or a chlorine.
- n Rbs are preferably each independently fluorine, chlorine, bromine or d ⁇ C 4 fluorenyl, n is 0, 1 or 2; more preferably n Rb are each independently fluorine or A Base, n is 0 or 1.
- the nitrogen labeled as the 7-position in the diarylhydantoin derivative of the formula I is preferably bonded to the aromatic ring containing no hetero atom or the ring containing the least hetero atom in the B ring.
- the linkage (for example, the compound VII described below in the present invention, the nitrogen at the 7-position is linked to the benzene ring in the isoquinolinone group; or the compound VI described below, the nitrogen at the 7-position is bonded to the pyridine ring).
- the R 4 is preferably hydrogen, hydroxy or decyloxy, more preferably hydrogen.
- the oxime group in R 4 is preferably a methoxy group or an ethoxy group.
- the 3-6-membered ring fluorenyl group is preferably a cyclopropyl group.
- the cyclobutyl or cyclopentyl group is further preferably a cyclopropyl group or a cyclobutyl group, more preferably a cyclobutyl group; and the 4- to 6-membered heterocyclic fluorenyl group is preferably an oxetanyl group or an azetidinyl group.
- tetrahydrofuranyl group, pyrrolidinyl group, dioxolyl group, piperidinyl group or fluorenyl-methylpiperidinyl group is more preferably an oxetanyl group or an azetidinyl group, and more preferably an oxetanyl group.
- R 3 is preferably hydrogen, halogen, cyano, CH 4 fluorenyl, CH 4 alkenyl, $,
- R 5 and R 6 are preferably each independently a d fluorenyl group or a d alkenyl group.
- the W is preferably halogen (e.g., fluorine, chlorine, bromine or iodine), cyano group, hydroxyl group, oxime
- RCC 6 cyclodecyl, 3-6-membered heterocyclic fluorenyl, 6-10 aryl or 6-10 heteroaryl.
- the 6 to 10 membered aryl group in R 3 R 5 R 6 or W is preferably a phenyl group; the 6 to 10 membered heteroaryl group in the R 3 R 5 R 6 or W is preferably a hetero atom. It is a 6-10 membered heteroaryl group having 1 nitrogen atom, more preferably a pyridyl group.
- the D ⁇ C 4 fluorenyl group in the R 3 R 5 or R 6 is preferably a methyl group, an ethyl group, a propyl group or a t-butyl group; and the olefin in the R 3 R 5 or R 6
- the group is a vinyl group, a propenyl group or an allyl group; and the d ⁇ C 4 alkynyl group in said R 3 R 5 or R 6 is preferably an ethynyl group or a propynyl group; said R 3 R 5
- the C 3 -C 6 cyclodecyl group in R 6 or W is preferably a cyclopropenyl group, a cyclobutenyl group, a cyclopentyl group or a cyclohexyl group; the R 3 R 5 or R 6 is 3 to 6 Heterocyclic fluorenyl is preferably azetidinyl, pyrrole
- the W in the 3 ⁇ 6 Said W is the W in the 3 ⁇ 6 Said W
- embankment group is preferably a methoxy group; said w is preferably in ⁇
- the D is preferably sulfur.
- the diarylhydantoin derivative of the formula I described in the present invention is preferably a compound of the formula II III IV-i IV-ii V VI VII VIII IX X or XI: L
- the diarylhydantoin derivative represented by Formula I described in the present invention is further preferably of the formula xn-i, xn-ii,
- Rb, R ⁇ R 2 and R 3 are as defined above, and R 1Q is halogen or trifluoromethyl.
- diarylhydantoin derivative of the formula I described in the present invention is further preferably a compound as described below:
- the present invention also provides a process for the preparation of the above described diarylhydantoin derivative of the formula I, which employs any of the following methods:
- Method 1 The compound P and the compound Q are subjected to a ring-forming reaction to obtain a compound I;
- Method 2 reacting compound S with compound T to obtain compound I;
- LG group (Leaving Group, leaving group) in the compound oxime is halogen, sulfonate group, alcohol
- the compound ⁇ is an acylating agent (such as an acid chloride, an acid anhydride, a carboxylic acid ester or a mixed acid anhydride, etc.) or a sulfonylating agent (such as a sulfonyl chloride or a sulfonic acid anhydride); As mentioned above.
- an acylating agent such as an acid chloride, an acid anhydride, a carboxylic acid ester or a mixed acid anhydride, etc.
- a sulfonylating agent such as a sulfonyl chloride or a sulfonic acid anhydride
- both the first method and the second method are conventional methods for such a reaction in the art, and the following reaction conditions are particularly preferred in the present invention:
- the compound P and the compound Q are added to the first polar solvent, and the mixture is heated (the heating method may be heated by microwave or oil bath, the temperature is 30 to 150 ° C) until the reaction is completed, and the reaction mixture is added to the reaction mixture.
- An aqueous solution of a mineral acid and a second polar solvent (which is the same as or different from the first solvent) are added, and the mixture is heated under reflux until the reaction is completed, and the target compound I is isolated and purified.
- the first polar solvent is selected from one or more of DMF, DMA, DMSO and MP, preferably DMF;
- the second polar solvent is selected from the group consisting of methanol, ethanol, isopropanol, n-propanol, n-butanol and DMF One or more of them, preferably methanol;
- the inorganic acid is selected from one or more of hydrochloric acid, sulfuric acid and phosphoric acid, preferably hydrochloric acid and/or sulfuric acid.
- the compound S and the compound T may be in an alkaline condition (such as an organic base such as triethylamine, potassium carbonate, sodium carbonate or sodium hydride or
- an organic base such as triethylamine, potassium carbonate, sodium carbonate or sodium hydride or
- the target compound I can be obtained;
- the LG group in the compound T is an alcoholic hydroxyl group, the compound S and the compound T can be mixed in an organic solvent (such as tetrahydrofuran or dichloromethane).
- an organic solvent such as tetrahydrofuran or dichloromethane
- the compound T when the compound T is an acylating agent (such as an acid chloride, an acid anhydride, a carboxylic acid ester or a mixed acid anhydride, etc.) or a sulfonylating agent (such as a sulfonyl chloride, a sulfonic acid anhydride, etc.), the compound S and the compound T may be in an organic solvent (The acylation reaction is carried out under conditions such as dichloromethane or DMF and basic conditions (such as triethylamine or sodium hydrogencarbonate) to obtain the objective product I.
- an acylating agent such as an acid chloride, an acid anhydride, a carboxylic acid ester or a mixed acid anhydride, etc.
- a sulfonylating agent such as a sulfonyl chloride, a sulfonic acid anhydride, etc.
- the compound Q can be obtained by reacting the intermediate E with the starting material F, or by reacting the intermediate E, the starting material G with the metal cyanide (NaCN, KCN, etc.) or tridecyl cyanoprene.
- the reaction conditions and procedures can be as disclosed in the international patent application WO2006/124118 and the journal J. Med. Chem. 2010, 53, 2779-2796.
- the present invention also provides the diarylhydantoin derivative of the formula I, a pharmaceutically acceptable salt, solvate, metabolite, stereoisomer, tautomer thereof, and more Use of a crystalline form or a prodrug thereof for the preparation of a medicament for treating an androgen receptor-associated disease.
- the androgen receptor-related diseases are preferably prostate cancer, breast cancer, benign prostatic hyperplasia, hirsutism, whitefly, baldness, muscle failure, gonadal dysfunction, osteoporosis, cholesterol One or more of over-high, male infertility, male sexual dysfunction, anemia, obesity, low sexual desire and depression.
- the androgen receptor-associated disease is preferably castration-tolerant prostate cancer.
- the present invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising a diarylhydantoin derivative of the formula I, a pharmaceutically acceptable salt thereof, a solvate, a metabolite, a stereoisomer, an interconversion An isomer, a polymorph or a prodrug thereof, and one or more pharmaceutically acceptable excipients.
- the diarylhydantoin derivative of the formula I, the pharmaceutically acceptable salt, solvate, metabolite, stereoisomer, tautomer thereof The content of the body, the polymorph or the prodrug thereof is a therapeutically effective amount, preferably a mass percentage of 1% to 99% ; and the mass percentage is a diaryl B group as shown in Formula I
- the ureide derivative, a pharmaceutically acceptable salt, solvate, metabolite, stereoisomer, tautomer, polymorph or prodrug thereof as a percentage of the total mass of the pharmaceutical composition.
- the sum of the mass fractions of the components of the pharmaceutical composition described in the present invention is 100%; the sum of the mass percentages of the components in the pharmaceutical composition is 100%.
- the pharmaceutical composition includes an oral dosage form, a parenteral administration form, an external dosage form, and a rectal administration dosage form.
- the oral dosage form of the pharmaceutical composition includes tablets, capsules, pills, powders, controlled release preparations, solutions and suspensions, and the like, and parenteral dosage forms include sterile solutions, suspensions or emulsions.
- the external dosage form includes an ointment, an oil, an emulsion, a gel, a suspension, a solution, a lotion or a cream, and the rectal administration form includes a suppository and a drop.
- the choice of pharmaceutical excipients varies depending on the route of administration and the characteristics of the action, and can generally be a filler, a diluent, a binder, a wetting agent, a disintegrant, a lubricant, an emulsifier or a suspending agent.
- the pharmaceutical composition further comprises at least one additional therapeutic agent.
- the pharmaceutical composition provided by the present invention is an oral dosage form.
- the present invention also provides a pharmaceutical composition for the preparation of a medicament for treating androgen receptor-related diseases. use.
- the androgen receptor-related diseases may be diseases caused by changes in androgen receptors conventional in the art, preferably prostate cancer, breast cancer, benign prostatic hyperplasia, hirsutism, whiteflies, baldness, muscles One or more of failure, gonadal dysfunction, osteoporosis, hypercholesterolemia, male infertility, male sexual dysfunction, anemia, obesity, low sexual desire, and depression.
- the androgen receptor-associated disease is more preferably castration-tolerant prostate cancer.
- Halogen means fluorine, chlorine, bromine or iodine.
- Carboxyl means -COOH.
- DMA refers to hydrazine, hydrazine-dimethylacetamide.
- ⁇ refers to ⁇ -methylpyrrolidone
- d ⁇ C 4 means that the number of carbon atoms in the group (e.g., fluorenyl, decyloxy, cyclodecyl, etc.) defined therein is 1, 2, 3 or 4. From this, the meaning of other terms described in a similar manner, such as “CHV”, “C 3 ⁇ C 6 ", etc., can be inferred.
- 6 ⁇ 10 yuan means a closed ring system group (such as an aryl group, a heteroaryl group, a fused heteroaryl group, a cyclodecyl group, a heterocyclic fluorenyl group, etc.) defined therein, which is surrounded by the closed ring skeleton itself.
- the number of atoms is 6, 7, 8, 9, or 10, and may be different depending on the number of rings of the closed ring group, the degree of saturation, and the nature of the atoms constituting the ring, etc., and the atoms surrounding the closed ring skeleton itself It can be either a carbon atom or a hetero atom. From this, the meaning of other terms described in a similar manner, such as “3 ⁇ 6 yuan", “4 ⁇ 6 yuan”, etc., can be inferred.
- Mercapto refers to a straight or branched hydrocarbon chain group consisting only of carbon atoms and hydrogen atoms, free of unsaturated bonds, having, for example, 1 to 12 carbon atoms, and attached to the remainder of the molecule through a single bond.
- examples of thiol include Not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethyl Propyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, decyl and decyl.
- Cyclononyl means a stable, non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, and may include fused ring systems, bridged ring systems or spiro ring systems, usually having from 3 to 15 carbons atom. It can be attached to the remainder of the molecule via a single bond via any suitable carbon atom on the ring.
- examples of cyclodecyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
- Alkoxy means a group formed by linking a fluorenyl group to an oxygen atom.
- examples of the decyloxy group include, but are not limited to, a methoxy group (-OCH 3 ), an ethoxy group (-OCH 2 CH 3 ), and the like. .
- Alkenyl means a straight-chain, branched or cyclic non-aromatic hydrocarbon radical containing the specified number of carbon atoms and at least one carbon-carbon double bond. Preferably there is one carbon-carbon double bond and up to four non-aromatic carbon-carbon double bonds may be present.
- d ⁇ C 4 alkenyl refers to an alkenyl group having from 1 to 4 carbon atoms, including but not limited to ethenyl, propenyl, allyl, butenyl, 2-methylbutenyl, and Cyclohexenyl and the like.
- the linear, branched or cyclic moiety of the alkenyl group may contain a double bond and, if indicated to be a substituted alkenyl group, may be substituted.
- Alkynyl means a straight-chain, branched or cyclic hydrocarbon radical containing the specified number of carbon atoms and at least one carbon-carbon triple bond. There may be up to three carbon-carbon triple bonds.
- C ⁇ alkynyl means an alkynyl group having from 1 to 4 carbon atoms, including but not limited to ethynyl, propynyl, butynyl and 3-methylbutynyl, and the like.
- heterocyclic fluorenyl group which is not limited means that the carbon atom and one to four hetero atoms selected from nitrogen, oxygen and sulfur are common.
- a stable non-aromatic cyclic group consisting of a ring system of monocyclic, bicyclic, tricyclic or more rings, and may also include a fused ring system, a bridged ring system or a spiro ring system. It can be attached to the remainder of the molecule via a single bond via any suitable carbon or heteroatom on the ring.
- heterocyclic fluorenyl examples include, but are not limited to, azacyclopropyl, azetidinyl, oxetanyl, pyrrolidinyl, imidazolinyl, pyrazolyl, imidazolyl, thiazolyl , isothiazolyl, isoxazolyl, tetrahydrofuranyl, dioxolanyl, morpholinyl, piperazinyl, N-substituted piperazinyl, homopiperazinyl, N-substituted homopiperazinyl, piperazine Pyridyl, N-substituted piperidinyl, dioxolyl, indanyl, tetrahydroisoquinolinyl, decahydroisoquinolyl and the like
- the "aryl group” which is not limited means a conjugated aromatic hydrocarbon ring system group composed of carbon atoms, and may be a monocyclic, bicyclic, tricyclic or more ring system. . It can be attached to the remainder of the molecule via a single bond via an atom on the aromatic ring.
- examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthryl, anthryl and the like.
- the undefined "heteroaryl group” means a combination of a carbon atom and 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur.
- the conjugated aromatic ring system may be a monocyclic, bicyclic, tricyclic or more ring system which may be attached to the remainder of the molecule via a single bond via an atom on the aromatic ring.
- the carbon atom on the aromatic ring may optionally be substituted with oxo.
- heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, triazolyl, tetra Azazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, fluorenyl, isodecyl, oxazolyl, azacarbazolyl, benzimidazolyl, benzotriazolyl, quin A phenyl group, an isoquinolyl group, a benzothiazolyl group, a benzoxazinyl group, a quinazolinyl group, a quinoxalinyl group or the like.
- the "fused heteroaryl group” which is not defined means a carbon atom and 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur.
- a conjugated aromatic ring system having a bicyclic ring or more, wherein the carbon atom of the aromatic ring in the fused heteroaryl group may be optionally oxo, for example, an isoquinolinone quinazoxazole in the embodiment of the present invention A ketone ketone group or the like.
- R is optionally substituted at the position of the benzene ring of the quinoline.
- “Pharmaceutically acceptable salt” means a salt formed with an inorganic or organic acid capable of retaining the bioavailability of the free base without other side effects.
- Inorganic acid salts include, but are not limited to, hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, and the like; organic acid salts include, but are not limited to, formate, acetate, 2,2-dichloroacetate , trifluoroacetate, propionic acid Salt, caproate, caprylate, decanoate, undecylenate, glycolate, gluconate, lactate, sebacate, adipate, glutarate, c Diacid salt, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate, cinnamate, laurate, Malate, glutamate, pyroglutamate, aspartate, benzoate, methanesulfonate
- “Pharmaceutically acceptable base addition salt” means a salt formed with an inorganic base or an organic base capable of maintaining the bioavailability of the free acid without other side effects.
- Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, and the like.
- Preferred inorganic salts are ammonium salts, sodium salts, potassium salts, calcium salts and magnesium salts.
- Salts derived from organic bases include, but are not limited to, the following salts: primary amines, secondary amines and tertiary amines, substituted amines, including naturally substituted amines, cyclic amines, and basic ion exchange resins.
- primary amines secondary amines and tertiary amines
- substituted amines including naturally substituted amines, cyclic amines, and basic ion exchange resins.
- ammonia isopropylamine, trimethylamine, diethylamine, ethylenediamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylamino Ethanol, dicyclohexylamine, lysine, arginine, histidine, glucosamine, and the like.
- These salts can be prepared by methods known in the art.
- Solvate means an aggregate formed by the association of one or more solvent molecules during the crystallization of certain compound molecules of the present invention.
- the solvent molecule can be water or other organic solvent (such as methanol, ethanol, acetone, etc.).
- Prodrug means a pharmaceutically acceptable metabolic precursor of certain compounds of the invention which are generally inactive but which can be converted to a biologically active parent compound of the invention under physiological conditions in vivo.
- the properties of the parent compound in terms of solubility, histocompatibility or pharmacokinetics are generally improved.
- Stepoisomer means a compound composed of the same atom, bonded by the same bond, but having a different three-dimensional structure.
- the compounds of formula I according to the invention encompass various possible optical isomers, cis and trans isomers and mixtures thereof.
- Tautomer refers to an isomer formed by the transfer of a proton from one atom of a molecule to another atom of the same molecule.
- the compounds of formula I described herein encompass a wide variety of possible tautomers and mixtures thereof.
- Polymorph refers to a different solid crystalline phase of certain compounds of the invention resulting from the presence of two or more different molecular arrangements in a solid state.
- the compounds of formula I described herein encompass a wide variety of possible crystalline forms and mixtures thereof.
- metabolic means that some of the compounds of the present invention are absorbed by the body and passed through the body under the action of the enzyme.
- a compound produced by biotransformation such as a group reaction (I phase biotransformation reaction, including oxidation, reduction, hydrolysis, etc.) and a binding reaction (II phase biotransformation reaction).
- “Pharmaceutical composition” refers to a pharmaceutical formulation consisting of a compound of the invention and optionally a medium generally accepted in the art for delivery of a biologically active compound to a mammal, such as a human.
- the medium includes a pharmaceutically acceptable carrier.
- the purpose of the pharmaceutical composition is to promote the administration of the organism, thereby facilitating the absorption of the active ingredient and thereby exerting biological activity.
- pharmaceutically acceptable carrier includes, but is not limited to, any adjuvant, carrier, which is approved by the relevant government authorities for use by humans or domestic animals, is relatively non-toxic and does not cause adverse physiological reactions to humans or livestock.
- Excipients glidants, sweeteners, diluents, preservatives, dyes/colorants, flavoring agents, surfactants, wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvents Or emulsifier, etc.
- the reagents and starting materials used in the present invention are commercially available.
- the positive progressive effects of the present invention reside in that:
- the present invention provides a diarylhydantoin derivative, a process for its preparation, a pharmaceutical composition and use which are completely different from the prior art.
- the diarylhydantoin derivative of the present invention has a good effect for treating androgen receptor-related diseases, particularly castration-tolerant prostate cancer. detailed description
- Second step 4-[4,4-Dimethyl-3-(1-methyl-1H-indazol-5-yl)-5-oxo-2-thio-imidazolin-1-yl] Preparation of -2-trifluoromethyl-benzonitrile
- Second step Preparation of methyl 2-(2-dimethylamino-vinyl)-5-nitro-benzoate
- the starting material 2-methyl-5-nitro-benzoic acid methyl ester (1.0 g, 5. lmmol) was mixed with tert-butoxy bis(dimethylamino)formamidine (6 mL), placed in a sealed tube, heated At 115oC, the reaction was carried out for 3.5 hours. The reaction was cooled to room temperature overnight, diluted with a solution of petroleum ether and ethyl acetate (6:1), and allowed to stand at room temperature overnight, filtered, and the obtained solid was directly used for the next reaction.
- the third step preparation of 2-methyl-7-nitro-2H-isoindole-1-one
- Step 6 4-[4,4-Dimethyl-3-(2-methyl-1-oxo-1,2-dihydro-isoquinolin-7-yl)-5-oxo-2 -Preparation of thio-imidazoline small group]-2-trifluoromethyl-benzonitrile
- Step 2 4-(5-(1-Methyl-IH-carbazolyl-5-yl)-8-oxo-6-thio-5,7-diazaspiro[3,4]octyl Preparation of -2-trifluoromethyl-cyanobenzene
- Step 2 4-( 1,3-Dimethyl-IH-carbazolyl-5-yl)-8-oxo-6-thio-5,7-diazaspiro[3,4 Preparation of octyl)-2-trifluoromethyl-cyanobenzene
- Step 2 4-(2-(2-methyl-1-oxo-1,2-dihydroquinolin-7-yl)-8-oxo-6-thio-5,7-diazaspiro Preparation of [3,4]octyl)-2-trifluoromethyl-cyanobenzene
- Example 20 Compound 1-20 (2.5 g, 4 mmol) of Example 20 was dissolved in dichloromethane (15 mL), and 4N hydrogen chloride in dioxane (5 mL) was added dropwise under ice-cooling. The solid was collected by filtration, and the solid was washed with diethyl ether diethyl ether and dried to give 4-[3-(1 ⁇ -oxazol-5-yl) -4,4-dimethyl-5-oxo-2-thio-imidazoline 1-yl]-2-trifluoromethyl-benzonitrile (1.5 g, white solid).
- Example 21 Compound 1-21 (100 mg, 0.23 mmol) of Example 21 was dissolved in anhydrous DMF (10 mL), and then, with stirring, potassium carbonate powder (320 mg, 2.3 mmol) and cyclopropylmethyl bromide (94 mg, 0.70 mmol). ), stir at room temperature overnight. The reaction mixture was diluted with methylene chloride and EtOAc (EtOAc)EtOAc.
- Example 21 Compound 1-21 (100 mg, 0.23 mmol) of Example 21 was dissolved in anhydrous DMF (10 mL), and then, with stirring, potassium carbonate powder (320 mg, 2.3 mmol) and cyclopropylmethyl bromide (94 mg, 0.70 mmol). ), stir at room temperature overnight. The reaction mixture was diluted with methylene chloride and EtOAc (EtOAc)EtOAc.
- Example 21 Using compound 1-21 of Example 21 as a starting material, replacing cyclopropylmethyl bromide with a different halogenated product, the compound I-26 compound 1-41 was prepared by the same synthesis method as in Examples 24 and 25, and the specific chemical structure was identified. The data is shown in Table 4.
- Compound 1-44 compound 1-45 was synthesized in the same manner as in Example 7 using 4-amino-2-fluoro-benzonitrile and 4-amino-2,3-difluoro-benzonitrile as starting materials, respectively.
- the specific chemical structure identification data is shown in Table 5.
- the starting material is 3-methyl-1,1-dioxo-1,2-dihydro-1 ⁇ 6 -benzo[1,2,4]thiadiazine-fluorene-based ammonia (300.0 mg, 1.42 mmol) and acetone (2 ml) were added to 90% glacial acetic acid (17 ml), stirred and dissolved, and NaCN (7 g, 142 mmol) was added, and the reaction was stirred at room temperature for 96.0 hours. The mixture was diluted with EtOAc (EtOAc) (EtOAc) The residue was flash chromatographed (5% MeOH /EtOAc)
- the third step 5-[(2-cyanopropion-2-yl;)amino-1-tert-butoxycarbonyl-3-cyanoindole
- the third step 5-[(2-cyanopropion-2-yl)amino-1-methyl-3-cyanoguanidine
- Example 7 Using the 4-amino-2-chloro-benzonitrile as a starting material and replacing the methylamine of Example 7 with cyclopropylmethylamine, the compound 1-50 was obtained by the same synthetic procedure as in Example 7.
- Example 46 The amino acid of Example 46 was replaced with morpholinoethylamine using 4-amino-2-chloro-benzonitrile as the starting material, and the compound I-51 was obtained by the same procedure as in Example 46.
- the compound 1-52 was prepared by the same synthetic method as in Example 46, using 4-amino-2-trifluoromethyl-benzonitrile as the starting material, and the aqueous ammonia of Example 46 was replaced with methoxyethylamine.
- Example 46 The amino acid of Example 46 was replaced with cyclopropylmethylamine using 4-amino-2-trifluoromethyl-benzonitrile as the starting material, and Compound 1-53 was obtained by the same synthetic procedure as in Example 46.
- Example 54 Example 54
- Example 7 Using 4-amino-2-trifluoromethyl-benzonitrile as a starting material, replacing the methylamine in Example 7 with morpholinylethylamine, The same synthetic procedure as in Example 7 was carried out to give the compound 1-54.
- the compound I-55 was prepared by the same synthesis method as in Example 7 using 4-amino-2-trifluoromethyl-benzonitrile as the starting material, and the methylamine in Example 7 was replaced with benzylamine.
- the compound 1-56 was prepared by the same synthesis method as in Example 7 using 4-amino-2-chloro-benzonitrile as a starting material and replacing the methylamine in Example 7 with methoxyethylamine.
- Example 58 Using the 4-amino-2-trifluoromethyl-benzonitrile as a starting material and replacing the methylamine of Example 7 with ethylamine, the compound 1-57 was obtained by the same procedure as in Example 7.
- Example 58 Example 58
- the third step 2-[(l-(methylammonium))isoquinoline-7-yl;)amino]-2-methylpropionitrile
- the fourth step 4-[3-(l-(methylamino)isoquinolin-7-yl)-4,4-dimethyl-2-thio-5-oxoimidazolium-1-yl] 2-(trifluoromethyl)benzonitrile
- Example 61 Using the 4-amino-2-trifluoromethyl-benzonitrile as a starting material and replacing the methylamine of Example 7 with methoxyethylamine, the compound 1-60 was obtained by the same synthetic procedure as in Example 7.
- Example 61 Example
- Example 61 was prepared by the same synthesis method as in Example 7 except that 4-amino-2-chloro-benzonitrile was used as the starting material and the methylamine in Example 7 was replaced with ethylamine.
- Effect embodiment (1) Biological activity test: Inhibitory effect of test compound on DHT-induced PSA protein secretion in prostate cancer LNCaP cells
- the PSA (Totai;) EIA test kit produced by ALPCO was used to detect the PSA of the cell supernatant: 1. Normally culture LNCaP cells (RPMI1640 medium containing 10% FBS), and replace the culture solution with the digested solution. 10% CS-FBS (carbon adsorption treatment serum) of RPMI1640 medium, seed plate in 96-well plate, cell density of 2 X 104 / ml, about 2000 / hole; 2, after 3 days of seed plate, update with InM DHT RPMI 1640 medium containing 10% CS-FBS (carbon adsorption treated serum).
- CS-FBS carbon adsorption treatment serum
- Dosing set 1 well as negative control well (add InMDHT, no compound), positive compound MDV3100 and the initial concentration of the compound of the example are ⁇ , which are diluted 5 times to 2000, 400, 80, 16, 3.2, 0.64, 0.128 nM. 3. After the compound was treated for 3 days, the supernatant was taken 50 ⁇ l and the PSA (Total) ⁇ detection kit manufactured by ALPCO was used to detect the content of PSA in the supernatant of the cells. FlexStation 3 measures Optical Density (OD) at a wavelength of 450 nm.
- Metabolic stability test Metabolic stability incubation with 150 ⁇ of liver microsomes (final concentration 0.5 mg/ml) containing NADPH (final concentration 1 mM) and ⁇ compound, positive control or negative control, respectively The reaction was stopped with tid-containing acetonitrile at 0 min, 5 min, lOmin and 30 min, vortexed for 10 min, centrifuged at 15000 rmp for 10 min, and 50 ⁇ M supernatant was applied to the 96-well plate for injection. The metabolic stability of the compound was calculated by measuring the relative reduction in the original drug.
- Direct inhibition test Directly inhibit the incubation of human liver microsomes (final concentration 0.2 mg/ml) with system ⁇ , containing NADPH (final concentration lmM), ⁇ compound, positive inhibitor cocktail
- the drug concentration in plasma at different times after intragastric administration and intravenous administration of the compound of the present invention was determined by LC/MS/MS method, and the pharmacokinetic behavior of the compound of the present invention in rats or mice was studied. , to evaluate its pharmacokinetic characteristics.
- test animals were healthy adult male SD rats or BALB/c mice, provided by Shanghai Xipuerkekai Experimental Animal Co., Ltd.; administration mode and sample collection: respectively given to SD rats or BALB/c mice Quiet Pulse injection (3 mg/kg, 1 mg/mL suspension of test compound) and intragastric administration (10 mg/kg, 1 mg/mL suspension of test compound), before administration and Blood samples were taken from rat or mouse fundus venous plexus at 2, 5, 15, 30, 60, 90, 120, 240, 360, 480, and 1440 min after administration; 50 ⁇ of plasma samples were taken and 200 ⁇ were added respectively.
- the protein was precipitated in an acetonitrile solution containing internal standard, vortexed for 10 min, 6000 rpm/separation for 10 min; 200 ⁇ supernatant was centrifuged at 6000 rpm for another 10 min; then 75 supernatant was added, and the gradient initial mobile phase was diluted. 6000 rpm/separation of the heart for 10 min; finally take the supernatant 70 ⁇ into the 96-well plate for injection, the injection volume is 5 ⁇ , and perform LC-MS-MS analysis.
- SCID nude mice male, 6-7 weeks old were surgically removed from the testis under sterile conditions, and one week later, human prostate cancer cells (such as LNCAP, LNCAP-AR, etc.) were subcutaneously inoculated, and the tumor was grown to 100-150 mm 3 .
- Animals were randomly divided into groups (D0), 8-10 per group, divided into drug-administered group and control group.
- the test compound or vehicle control (1% CMC/0.1% Tween-80/5% DMSO) was administered orally once a day at a dose of 10 mg/kg to 100 mg/kg for 21 28 days.
- the tumor volume was measured 2-3 times a week, the rats were weighed, and the data were recorded.
- T/CC%) CT-T0)/(;C-C0)/100, where T and C are the tumor volumes at the end of the experiment; ⁇ 0, CO is the tumor volume at the start of the experiment.
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Abstract
本发明公开了二芳基乙内酰脲衍生物、其制备方法、药物组合物和应用。本发明提供了一种如式I所示的二芳基乙内酰脲衍生物、其药学上可接受的盐、溶剂化物、代谢产物、立体异构体、互变异构体、多晶型物或其药物前体,本发明的二芳基乙内酰脲衍生物对于治疗雄激素受体相关疾病,特别是去势耐受型前列腺癌有着良好的效果。
Description
二芳基乙内酰脲衍生物、 其制备方法、 药物组合物和应用 本申请要求申请日为 2013年 8月 8日的中国专利申请 CN201310345394.X的优先权。 本申请引用上述中国专利申请的全文。 技术领域
本发明涉及医药化学领域, 尤其涉及二芳基乙内酰脲衍生物、 其制备方法、 药物组 合物和应用。 背景技术
雄激素受体(AR)是一种 11万道尔顿(llOKDa)的蛋白质, 是类固醇受体(steroid receptor) 的一个成员。 和其它类固醇受体相似, AR含有三个结构域: N-端结构域, 位 于中央的 DNA结合位点和包含核转移信号的结构域, 以及含有配体结合位点的 C-端结 构域。 N-端结构域含一个被称为激活活性 1 (activation function 1 ) 的转录功能位点, 不 需要其它结构区, 这一转录位点本身就能激活目标基因的转录。 C-端含有被称为激活活 性 2 (activation function 2) 的转录位点, 在其配体的激活下能激活其目标基因的转录。 无配体结合的 AR主要分布于细胞质中, 和热休克蛋白形成复合物。 当与雄激素 (如睾 酮和二氢睾酮等)结合后, AR从热休克蛋白形成的复合体中被释放出来, 进行磷酸化反 应, 形成二聚体, 并转移到细胞核内, 结合到与它相关的 DNA片段上, 从而剌激其目标 基因的转录。 配体结合所激活的雄激素受体的转录活性被认为是由一群被称为共活化子 (coactivators)如 SRC-1、 TIF-2和 AIB-1的蛋白质协调而完成。 共活化子能修饰核染色 体结构, 有助于吸引和稳定转录子到目标基因上进行转录。 而当与抑制剂结合时, 共抑 制子 (corepressors) 如 NCoR或 SMRT会被吸引来, 导致转录受到抑制。
具有选择性的 AR拮抗剂的主要作用是直接阻止睾酮或二氢睾酮与雄激素受体结合, 阻断雄激素对细胞的作用, 使得细胞产生 "饥饿"现象, 最终促使细胞凋亡。 其可用于: 1 ) 预防、 阻止或消除 PC (Prostate Cancer, 前列腺癌)、 乳腺癌、 卵巢癌、 宫颈癌、 膀
胱癌等; 2) 治疗包括良性前列腺肿大、 青春痘、 秃顶和毛发增生等疾病; 3 ) 男性避孕; 4) 治疗一系列与男性荷尔蒙相关的失调如性欲过强和性欲失调; 5 ) 防止与雄激素减少 相关的症状如去势后的发热;6)专门用于预防或抑制妇女在转性治疗过程中的肌肉增长。
治疗 PC是 AR拮抗剂在临床上的一个最重要的应用。 PC在男性恶性肿瘤中高居发 病率第一、死亡率第二, 仅 2008年美国就有 186320个 PC新增病例, 另有 26660病人死 亡。 中国的发病率虽低于西方, 但随着生活节奏、 生活水平和诊断水平的不断提高, PC 正呈不断上升的趋势。 此癌是一种进展比较迅速的恶性肿瘤, 得不到早期诊治, 从发现 症状开始, 平均存活期只有 3-5年。 早期 PC能通过手术或化疗得到有效的控制。 但对于 晚期 PC, 其一般治疗策略是基于雄激素及其受体 (AR) 的抗雄激素疗法, 即手术去势 治疗(如双侧睾丸切除术等)和抗雄激素药物治疗。但绝大多数患者经此治疗后,在 18-24 周会出现病情恶化, 即出现去势耐受型前列腺癌 (Castration-Resistant Prostate Cancer, CRPOo 此时, 现有临床上所使用的抗雄激素药物不再对 CRPC具有抑制作用, 反而有 些药物如氟他胺和比卡鲁胺对 CRPC具有激动作用,有 80%的患者最终因 CRPC而死亡。 进一步的研究表明, 雄激素和它的结合的配体对 CRPC的生长是必需的, 表明雄激素受 体仍是此疾病的重要靶点。 但由于 AR表达增加及 AR突变等原因, 导致现有的抗前列 腺癌药物仅有弱的拮抗活性。因此,需要发展具有更高拮抗活性 AR拮抗剂来治疗 CRPC。
近几年来,对二芳基乙内酰脲类 AR拮抗剂的研究取得了里程碑式进展,如 MDV3100 ( 。
MDV3100 ARN-509
其中, MDV3100用于治疗 CRPC。 在一项随机、 双盲、 安慰剂对照研究将 1199名 曾接受以多西紫杉醇为主的化学治疗方案的 CRPC随机分为 MDV3100治疗组和安慰剂 组。 结果显示: 与安慰剂组相比, MDV3100治疗组患者总生存期中位数显著增加 (18.4 vs 13.6个月, P<0.0001 ),死亡风险则较安慰剂组降低 37%。 ARN-509也用于治疗 CRPC,
现处于 I/II期临床。 MDV3100和 ARN-509的研究进展表明二芳基乙内酰脲类 AR拮抗剂 具有非常良好的发展前景。 发明内容
本发明所要解决的技术问题是提供了一种与现有技术完全不同的二芳基乙内酰脲衍 生物、 其制备方法、 药物组合物和应用。本发明的二芳基乙内酰脲衍生物具有较高的 AR 拮抗活性, 可以用于制备治疗雄激素受体相关疾病、 特别是前列腺癌的药物。
本发明研究人员经过不懈努力, 发现了一类新型结构的二芳基取代乙内酰脲类化合 物, 比 MDV3100具有更高的 AR拮抗活性, 并且具有良好的成药性, 是一类非常有开发 前景的 AR拮抗剂。
本发明提供了一种如式 I所示的二芳基乙内酰脲衍生物、 其药学上可接受的盐、 溶 剂化物、 代谢产物、 体,
B环为 7~12元稠合杂芳基或氧代的 7~12元稠合杂芳基,该 7~12元稠合杂芳基中的 杂原子至少有一个为氮原子, R3与该 7~12元稠合杂芳基中的氮原子连接;
m为 A环上取代基 Ra的个数, 且 m个 Ra各自独立地为氰基、 硝基、 垸基、 卤素 (如氟、 氯、 溴或碘) 取代的 d~C4垸基或卤素 (如氟、 氯、 溴或碘), m为 2、 3 或 4, 且 m个 Ra彼此之间不完全相同;
n为 B环上取代基 Rb的个数, 且 n个 Rb各自独立地为氢、 卤素 (如氟、 氯、 溴或
碘) 或 d~C4垸基, n为 0、 1、 2或 3 ;
R1和 R2各自独立地为
, 其中 R4为氢、 羟基、 卤素 (如氟、 氯、 溴或 碘)、 羧基或 d~C4垸氧基; 或者, I 1、 R2和标记为 8位的碳相连组成 3~6元环垸基或 4-6元杂环垸基;
R3为氢、 卤素 (如氟、 氯、 溴或碘)、 硝基、 氰基、 氨基、 羧基、 d~C4垸基、 d~C4 、
R5和 R6各自独立地为 CH 4垸基、 d~C4烯基、 d~C4炔基、 C3~C6环垸基、 3~6元杂环 垸基、 6~10元芳基或 6~10元杂芳基, W为卤素 (如氟、 氯、 或碘)、 硝基、 氰基、 羟
-¾-NH—— R口 7 -I-N
基、 氨基、 羧基、 C广 C4垸氧基、 S 、 , 、R°、 C3~C6环垸基、 3~6元 杂环垸基、 6~10元芳基或 6~10元杂芳基, p为 1、 2、 3或 4, R7和 R8各自独立地为 d~C4 基;
D为氧或硫。
本发明中, 所述的 A环中所述的 6~10元芳基较佳地为苯基; 所述的 A环中所述的 6-10元杂芳基较佳地为杂原子为 1个氮原子的 6~10元杂芳基, 更佳地为吡啶基。
本发明中,所述的 B环中所述的 7~12元稠合杂芳基中杂原子较佳地为氮,且杂原子 的个数较佳地为 1~3个;所述的 B环中所述的 7~12元稠合杂芳基更佳地为吲唑基、异喹 啉基、 喹啉基、 喹唑啉基或氮杂吲唑基; 所述的 B环中所述的氧代的 7~12元稠合杂芳基 更佳地为异喹啉酮基或喹唑啉酮基; 所述的吲唑基较佳地为 1H-吲唑基或 2H-吲唑基, 所
所述的氮
杂吲唑基较佳 7-氮杂吲唑基。
本发明中, 所述的 m个 Ra较佳地各自独立地为氰基、 硝基、 卤素或 d~C4卤代垸 基, m为 2或 3 ; 更优选 m个 Ra各自独立地为氰基、 卤素或三氟甲基, m为 2或 3。
本发明中, 所述的 m个 Ra较佳地为至少 2个 Ra在 A环上相邻取代, 且其中一个 Ra与如式 I所示的二芳基乙内酰脲衍生物中标记为 10位的氮形成对位取代。当其中一个 Ra与如式 I所示的二芳基乙内酰脲衍生物中标记为 10位的氮形成对位取代时, 该 Ra较 佳地为氰基或氯。
本发明中, 所述的 n个 Rb较佳地各自独立地为氟、 氯、 溴或 d~C4垸基, n为 0、 1 或 2; 更优选 n个 Rb各自独立地为氟或甲基, n为 0或 1。 本发明中,如式 I所示的二芳基乙内酰脲衍生物中标记为 7位的氮较佳地与所述的 B 环中不含杂原子的芳香环或者含最少杂原子的环连接 (例如本发明下述的化合物 VII, 7 位氮与异喹啉酮基中的苯环连接; 或者下述的化合物 VI, 7位氮与吡啶环连接)。 本发明中, 当 R1和 R2各自独立地为 2 时, 所述的 R4较佳地为氢、 羟 基或 垸氧基, 更佳地为氢。 所述的 R4中 垸氧基较佳地为甲氧基或乙氧基。
本发明中,当 R2和标记为 8位的碳相连组成 3~6元环垸基或 4~6元杂环垸基时, 所述的 3~6元环垸基优选为环丙基、 环丁基或环戊基, 进一步优选为环丙基或环丁基, 更优选为环丁基; 所述的 4~6元杂环垸基优选为氧杂环丁基、 氮杂环丁基、 四氢呋喃基、 吡咯垸基、 二氧六环基、 哌啶基或 Ν-甲基哌啶基, 进一步优选为氧杂环丁基或氮杂环丁 基, 更优选为氧杂环丁基。
本发明中, 所述的 W较佳地为卤素 (如氟、 氯、 溴或碘)、 氰基、 羟基、 垸氧
-ζ-ΝΗ— R 冬 N
\ 8
R C C6环垸基、 3~6元杂环垸基、 6~10元芳基或 6~10 元杂芳基。
所述的 R3 R5 R6或 W中 6~10元芳基较佳地为苯基; 所述的 R3 R5 R6或 W中 6-10元杂芳基较佳地为杂原子为 1个氮原子的 6~10元杂芳基, 更佳地为吡啶基。 本发明中, 所述的 R3 R5或 R6中 d~C4垸基较佳地为甲基、 乙基、 丙基或叔丁基; 所述的 R3 R5或 R6中 烯基较佳地为乙烯基、 丙烯基或烯丙基; 所述的 R3 R5或 R6中 d~C4炔基较佳地为乙炔基或丙炔基; 所述的 R3 R5 R6或 W中 C3~C6环垸基较 佳地为环丙垸基、 环丁垸基、 环戊垸基或环己垸基; 所述的 R3 R5或 R6中 3~6元杂环 垸基较佳地为氮杂环丁基、 吡咯
-|-NH— R7
中 垸氧基较佳地为甲氧基; 所述的 w 中 ζ 较佳地为
.CH3 '
- -NH
本发明中所述的如式 I所示的二芳基乙内酰脲衍生物优选如式 II III IV-i IV-ii V VI VII VIII IX X或 XI所示的化合物:
L
SC6C80/M0ZN3/X3d 9SC8T0/S10Z OAV
(Ra)
XI
其中, 各取代基的定义均同上所述。
本发明中所述的如式 I所示的二芳基乙内酰脲衍生物进一步优选如式 xn-i、 xn-ii、
XII-iii、 XII-iiii、 XII-iiiii、 XII-iiiiii、 XII-iiiiiii、 ΧΠ-iiiiiiii或 ΧΠ-iiiiiiiii所示的化合物:
Xll-i
XII-ii
XII-iiiiiiiii
其中, 取代基 Rb、 R\ R2和 R3的定义均同上所述, R1Q为卤素或三氟甲基。
本发明中所述的如式 I所示的二芳基乙内酰脲衍生物进一步再优选如下所述的任- 化合物:
SI
-ι ετ-ι
π-ι π-ι
SC6C80/M0ZN3/X3d 9SC8T0/S10Z OAV
1-62 , 1-63 。
本发明还提供了所述的如式 I所示的二芳基乙内酰脲衍生物的制备方法, 其采用下 述方法中的任一种:
方法一: 将化合物 P和化合物 Q进行成环反应, 即可得到化合物 I;
方法二: 将化合物 S与化合物 T进行反应, 即可制得化合物 I;
S Τ 其中, 化合物 Τ中的 LG基团 (Leaving Group, 离去基团) 为卤素、 磺酸酯基、 醇
制备化合物 I 的方法中, 方法一与方法二均为本领域中此类反应的常规方法, 本发 明中特别优选下述反应条件:
方法一中, 将化合物 P和化合物 Q加入到第一极性溶剂中, 加热该混合物 (加热方 式可采用微波或油浴加热, 温度 30~150°C ) 至反应完全后, 向反应混合液中加入无机酸 的水溶液和第二极性溶剂(其与第一种溶剂相同或不同), 加热回流直至反应完全, 从中 分离纯化得到目标化合物 I。 其中, 第一极性溶剂选自 DMF、 DMA, DMSO和 MP中 的一种或多种, 优选 DMF; 第二极性溶剂选自甲醇、 乙醇、 异丙醇、 正丙醇、 正丁醇和 DMF中的一种或多种, 优选甲醇; 无机酸选自盐酸、 硫酸和磷酸中的一种或多种, 优选 盐酸和 /或硫酸。
方法二中, 当化合物 T中的 LG基团为卤素和磺酸酯基时, 可以将化合物 S和化合 物 T在碱性条件 (如三乙胺、 碳酸钾、 碳酸钠或氢化钠等有机碱或无机碱) 下进行亲核 取代反应, 即可获得目标化合物 I; 当化合物 T中的 LG基团为醇羟基时, 可以将化合物 S和化合物 T混合在有机溶剂(如四氢呋喃或二氯甲垸) 中, 发生 Mitsunobu反应, 即可
获得目标化合物 I; 当化合物 Τ中的 LG
时, 可以将化合物 S和化 合物 Τ混合在有机溶剂 (如 DMF、 乙腈、 二氧六环、 乙醇、 水和甲苯中的一种或多种) 中, 发生过渡金属催化的偶联反应获得目标产物 I; 当化合物 T为酰化试剂(如酰氯, 酸 酐, 羧酸酯或者混合酸酐等) 或者磺酰化试剂 (如磺酰氯, 磺酸酐等) 时, 可以将化合 物 S和化合物 T在有机溶剂 (如二氯甲垸或 DMF等) 和碱性条件 (如三乙胺或碳酸氢 钠) 下进行酰化反应获得目标产物 I。
其中, 化合物 Q可由中间体 E和原料 F反应制得, 或者由中间体 E、 原料 G和金属 氰化物 (NaCN, KCN等) 或三垸基氰硅垸反应制得。 反应条件和操作步骤可按照国际 专利申请 WO2006/124118和期刊文献 J. Med. Chem. 2010, 53, 2779-2796中所公开的内容
根据本发明的一个实施方式, 所述雄激素受体相关疾病较佳地为前列腺癌、 乳腺癌、 前列腺增生、 多毛症、 粉剌、 秃头、 肌肉衰竭、 性腺功能衰弱、 骨质疏松症、 胆固醇过 高、 男性不育、 男性性功能不良、 贫血肥胖、 性欲望低下和忧郁症中的一种或多种。 根 据本发明一个优选的实施方式, 所述的雄激素受体相关疾病较佳地为去势耐受型前列腺 癌。
本发明还提供了一种药物组合物, 其含有如式 I所示的二芳基乙内酰脲衍生物、 其 药学上可接受的盐、 溶剂化物、 代谢产物、 立体异构体、 互变异构体、 多晶型物或其药 物前体, 以及药学上可接受的一种或多种药用辅料。
本发明中, 所述的药物组合物中如式 I所示的二芳基乙内酰脲衍生物、 其药学上可 接受的盐、 溶剂化物、 代谢产物、 立体异构体、 互变异构体、 多晶型物或其药物前体, 的含量为治疗有效量, 优选质量百分含量为 1%〜99%; 所述的质量百分含量为如式 I所 示的二芳基乙内酰脲衍生物、 其药学上可接受的盐、 溶剂化物、 代谢产物、 立体异构体、 互变异构体、 多晶型物或其药物前体, 占药物组合物总质量的百分比。 本发明中所述的 药物组合物各组分的质量分数的总和为 100%;所述的药物组合物中各组份的质量百分含 量之和为 100%。
本发明中, 所述药物组合物包括口服剂型、 胃肠外给药剂型、 外用剂型和直肠给药 剂型。 在一些实施方式中, 所述药物组合物的口服剂型包括片剂、 胶囊、 丸剂、 粉剂、 缓控释制剂、 溶液和悬浮液等, 胃肠外给药剂型包括无菌溶液、 悬浮液或乳液, 外用剂 型包括软膏、 油剂、 乳液、 凝胶、 悬浮液、 溶液、 洗剂或乳膏, 直肠给药剂型包括栓剂、 滴剂。 药用辅料的选择因施用途径和作用特点而异, 通常可为填充剂、 稀释剂、 粘合剂、 润湿剂、 崩解剂、 润滑剂、 乳化剂或助悬剂等。 在其它实施方式中, 所述药物组合物还 包含至少一种其他治疗剂。 较佳地, 本发明提供的药物组合物为口服剂型。
本发明还提供了所述的药物组合物在制备治疗雄激素受体相关疾病的药物中的应
用。
其中, 所述雄激素受体相关疾病可为本领域中常规的由雄激素受体的变化所引起的 疾病, 较佳地为前列腺癌、 乳腺癌、 前列腺增生、 多毛症、 粉剌、 秃头、 肌肉衰竭、 性 腺功能衰弱、 骨质疏松症、 胆固醇过高、 男性不育、 男性性功能不良、 贫血肥胖、 性欲 望低下和忧郁症中的一种或多种。 所述的雄激素受体相关疾病更佳地为去势耐受型前列 腺癌。
某些化学或药学术语除非另外特别指明, 本申请的权利要求书和说明书中的化学术 语和药学术语具有如下所述的含义。
"卤素"是指氟、 氯、 溴或碘。
"氰基"是指 -CN。
"异氰基"是指 -N=C=0。
"异硫氰基"是指 -N=C=S。
"羟基"是指 -OH。
"羧基"是指 -COOH。
"苄氧基"是指 -OCH2C6H5。
缩写 "DMA"是指 Ν,Ν-二甲基乙酰胺。
缩写 "ΝΜΡ"是指 Ν-甲基吡咯垸酮。
"d~C4"是指其所定义的基团 (如垸基、 垸氧基、 环垸基等) 中碳原子数目为 1、 2、 3或 4。 由此可推知其他以类似方式描述的术语的含义, 如 "CHV'、 "C3~C6"等。
"6~10元"是指其所定义的闭合环系基团(如芳基、 杂芳基、 稠合杂芳基、 环垸基、 杂环垸基等) 中围成该闭合环骨架本身的原子数目为 6、 7、 8、 9或 10, 可根据闭合环系 基团的环数、 饱和度以及构成该环的原子性质等而取不同的数目, 其中围成闭合环骨架 本身的原子既可以是碳原子, 也可以是杂原子。 由此可推知其他以类似方式描述的术语 的含义, 如 "3~6元"、 "4~6元"等。
"垸基"是指仅由碳原子和氢原子组成、 不含不饱和键、 具有例如 1至 12个碳原子 且通过单键与分子的其余部分连接的直链或支链的烃链基团。 通常, 垸基的实例包括但
不限于甲基、 乙基、 正丙基、 异丙基、 正丁基、 异丁基、 仲丁基、 叔丁基、 正戊基、 2- 甲基丁基、 2,2-二甲基丙基、 正己基、 庚基、 2-甲基己基、 3-甲基己基、 辛基、 壬基和癸 基等。
"环垸基"是指仅由碳原子和氢原子组成的稳定的非芳香族单环或多环烃基, 可包 括稠合环体系、 桥环体系或螺环体系, 通常具有 3至 15个碳原子。 其可经由环上任何适 宜的碳原子通过单键与分子的其余部分连接。通常, 环垸基的实例包括但不限于环丙基、 环丁基、 环戊基、 环己基、 环庚基、 环辛基等。
"垸氧基"是指垸基与氧原子连结后的生成基团, 通常, 垸氧基的实例包括但不限 于甲氧基 (-OCH3)、 乙氧基 (-OCH2CH3) 等。
"烯基"是指含有指定数目碳原子和至少一个碳碳双键的直链、 支链或者环状非芳 香烃基。优选存在一个碳碳双键, 并且可以存在高达四个非芳香碳碳双键。 由此, "d~C4 烯基"是指具有 1~4个碳原子的烯基, 包括但不限于乙烯基、 丙烯基、 烯丙基、 丁烯基、 2-甲基丁烯基和环己烯基等。 烯基的直链、 支链或者环部分可以含有双键, 并且如果表 明为取代烯基, 那么可以被取代。
"炔基"是指含有指定数目碳原子和至少一个碳碳三键的直链、 支链或者环状烃基。 其中可以存在高达三个碳碳三键。 由此, "C^ 炔基"是指具有 1~4个碳原子的炔基, 包括但不限于乙炔基、 丙炔基、 丁炔基和 3-甲基丁炔基等等。
本发明中除限定了碳原子数、 杂原子种类或杂原子数外, 未进行限定的 "杂环垸基" 是指由碳原子以及 1至 4个选自氮、 氧和硫的杂原子共同组成的稳定的非芳香族环状基 团, 其可以为单环、 双环、 三环或更多环的环体系, 也可包括稠合环体系、 桥环体系或 螺环体系。其可经由环上任意适宜的碳原子或者杂原子通过单键与分子的其余部分连接。 其中的氮原子可任选被其他基团进一步取代以形成叔胺或季铵结构。 通常, 杂环垸基的 实例包括但不限于氮杂环丙基、 氮杂环丁基、 氧杂环丁基、 吡咯垸基、 咪唑啉基、 吡唑 垸基、 咪唑垸基、 噻唑垸基、 异噻唑垸基、 异噁唑垸基、 四氢呋喃基、 二氧戊环基、 吗 啉基、 哌嗪基、 N-取代哌嗪基、 高哌嗪基、 N-取代高哌嗪基、 哌啶基、 N-取代哌啶基、 二氧六环基、 二氢吲哚基、 四氢异喹啉基、 十氢异喹啉基等。
本发明中除限定了碳原子数外, 未进行限定的 "芳基"是指由碳原子构成的共轭芳 香性烃环体系基团, 可以为单环、 双环、 三环或更多环体系。 其可经由芳香环上的原子 通过单键与分子的其余部分连接。 通常, 芳基的实例包括但不限于苯基、 萘基、 蒽基、 菲基、 芴基等。
本发明中除限定了碳原子数、 杂原子种类或杂原子数外, 未进行限定的 "杂芳基" 是指由碳原子和 1至 4个选自氮、 氧和硫的杂原子共同组成的共轭芳香性环系基团, 可 以为单环、 双环、 三环或更多环体系, 其可经由芳香环上的原子通过单键与分子的其余 部分连接。 芳香环上的碳原子可任选被氧代。 通常, 杂芳基的实例包括但不限于吡咯基、 呋喃基、 噻吩基、 咪唑基、 吡唑基、 噻唑基、 噁唑基、 噁二唑基、 异噁唑基、 三氮唑基、 四氮唑基、 吡啶基、 嘧啶基、 吡嗪基、 哒嗪基、 吲哚基、 异吲哚基、 吲唑基、 氮杂吲唑 基、 苯并咪唑基、 苯并三氮唑基、 喹啉基、 异喹啉基、 苯并噻唑基、 苯并哒嗪基、 喹唑 啉基、 喹喔啉基等。
本发明中除限定了碳原子数、 杂原子种类或杂原子数外, 未进行限定的 "稠合杂芳 基"是指由碳原子和 1至 4个选自氮、 氧和硫的杂原子共同组成的双环以上的共轭芳香 性环系基团, 其中该稠合杂芳基中芳香环上的碳原子可任选被氧代, 例如本发明实施例 中的异喹啉酮基 喹唑啉酮基等。
本发明中 R在喹啉的苯环上任意可以取代的位置进行
"药学上可接受的盐"是指能够保留游离碱的生物有效性而无其它副作用的, 与无 机酸或有机酸所形成的盐。 无机酸盐包括但不限于盐酸盐、 氢溴酸盐、 硫酸盐、 硝酸盐、 磷酸盐等; 有机酸盐包括但不限于甲酸盐、 乙酸盐、 2,2-二氯乙酸盐、 三氟乙酸盐、 丙酸
盐、 己酸盐、 辛酸盐、 癸酸盐、 十一碳烯酸盐、 乙醇酸盐、 葡糖酸盐、 乳酸盐、 癸二酸 盐、 己二酸盐、 戊二酸盐、 丙二酸盐、 草酸盐、 马来酸盐、 琥珀酸盐、 富马酸盐、 酒石 酸盐、 柠檬酸盐、 棕榈酸盐、 硬脂酸盐、 油酸盐、 肉桂酸盐、 月桂酸盐、 苹果酸盐、 谷 氨酸盐、 焦谷氨酸盐、 天冬氨酸盐、 苯甲酸盐、 甲磺酸盐、 苯磺酸盐、 对甲苯磺酸盐、 海藻酸盐、 抗坏血酸盐、 水杨酸盐、 4-氨基水杨酸盐、 萘二磺酸盐等。 "药学上可接受的 碱加成盐"是指能够保持游离酸的生物有效性而无其它副作用的、与无机碱或有机碱所形 成的盐。 衍生自无机碱的盐包括但不限于钠盐、 钾盐、 锂盐、 铵盐、 钙盐、 镁盐、 铁盐、 锌盐、 铜盐、 锰盐、 铝盐等。 优选的无机盐为铵盐、 钠盐、 钾盐、 钙盐及镁盐。 衍生自 有机碱的盐包括但不限于以下的盐: 伯胺类、 仲胺类及叔胺类, 被取代的胺类, 包括天 然的被取代胺类、 环状胺类及碱性离子交换树脂, 例如氨、 异丙胺、 三甲胺、 二乙胺、 乙二胺、 三乙胺、 三丙胺、 乙醇胺、 二乙醇胺、 三乙醇胺、 二甲基乙醇胺、 2-二甲氨基 乙醇、 2-二乙氨基乙醇、 二环己胺、 赖氨酸、 精氨酸、 组氨酸、 葡萄糖胺等。 这些盐可 通过本专业已知的方法制备。
"溶剂化物"是指本发明的某些化合物分子在结晶过程中, 与一个或多个溶剂分子 缔合而形成的聚集体。 溶剂分子可以为水或其他有机溶剂 (如甲醇、 乙醇、 丙酮等)。
"前体药物"是指本发明的某些化合物在药学上可接受的代谢前体, 其通常不具有 活性, 但可在体内生理条件下转化成具有生物活性的本发明的母体化合物。 通常可改善 母体化合物在溶解度、 组织相容性或药物代谢动力学等方面的性质。
"立体异构体"是指由相同原子组成, 通过相同的键键合, 但具有不同三维结构的 化合物。 本发明所述的式 I化合物涵盖各种可能的旋光异构体、 顺反异构体及其混合物。
"互变异构体"是指质子从分子的一个原子转移至相同分子的另一个原子而形成的 异构体。 本发明所述的式 I化合物涵盖各种可能的互变异构体及其混合物。
"多晶型物"是指本发明的某些化合物在固体状态下由于存在两种或两种以上不同 分子排列而产生的不同固体结晶相。 本发明所述的式 I化合物涵盖各种可能的晶型及其 混合物。
"代谢产物"是指本发明的某些化合物被机体吸收后, 在酶的作用下经过体内的官
能团化反应 (I相生物转化反应, 包括氧化、 还原、 水解等)和结合反应 (II相生物转化 反应) 等生物转化而产生的化合物。
"药物组合物"是指由本发明的化合物与任选的本领域通常接受的用于将生物活性 化合物输送至哺乳动物 (例如人) 的介质所构成的药物制剂。 该介质包括药学上可接受 的载体。 药物组合物的目的是促进生物体的给药, 利于活性成分的吸收进而发挥生物活 性。 其中, "药学上可接受的载体"包括但不限于任何被相关的政府管理部门许可为可供 人类或家畜使用的、 相对无毒且对人类或家畜不造成不良生理反应的佐剂、 载体、 赋形 剂、 助流剂、 增甜剂、 稀释剂、 防腐剂、 染料 /着色剂、 矫味剂、 表面活性剂、 润湿剂、 分散剂、 助悬剂、 稳定剂、 等渗剂、 溶剂或乳化剂等。
在不违背本领域常识的基础上, 上述各优选条件, 可任意组合, 即得本发明各较佳 实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于: 本发明提供了一种与现有技术完全不同的二芳基乙内 酰脲衍生物、 其制备方法、 药物组合物和应用。 本发明的二芳基乙内酰脲衍生物对于治 疗雄激素受体相关疾病, 特别是去势耐受型前列腺癌有着良好的效果。 具体实施方式
下面通过实施例的方式进一步说明本发明, 但并不因此将本发明限制在所述的实施 例范围之中。 下列实施例中未注明具体条件的实验方法, 按照常规方法和条件, 或按照 商品说明书选择。
下述制备实施例中, 1H-NMR用 Varian Mercury AMX300 型仪测定。 MS 用 VG ZAB-HS或 VG-7070型以及 Esquire 3000 plus-01005测定。
实施例 1
4-[4,4-二甲基 -3-(1-甲基 -1H-吲唑 -5-基) -5-氧代 -2-硫代-咪唑啉 -1-基] -2-三氟甲基 -苯甲 腈 (化合物 1-1 ) 的制备
将 5-胺基 -1甲基吲唑(280mg, 1.9mmol)用丙酮 (10mL)溶解,加入三甲基硅氰(725uL, 5.7mmol ) 和数滴醋酸, 置于封管中, 加热到 90oC并恒温持续搅拌过夜。 反应液冷却到 室温, 减压浓缩后加水稀释,乙酸乙酯 (50mLX 3 ) 萃取,乙酸乙酯层依次用水、 饱和食盐 水洗涤, 无水硫酸钠干燥,过滤, 浓缩得到粗品, 快速柱层析分离(石油醚: 乙酸乙酯 =1 : 1 ) 得到 2-甲基 -2-(1-甲基 -1H-吲唑 -5-基氨基)-丙腈。 MS m/z (ESI): 215.1[M+H]。
第二步: 4-[4,4-二甲基 -3-(1-甲基 -1H-吲唑 -5-基) -5-氧代 -2-硫代-咪唑啉 -1-基] -2-三氟 甲基-苯甲腈的制备
将中间体 2-甲基 -2-(1-甲基 -1H-吲唑 -5-基氨基)丙腈(300mg,1.4mmol)和 4-异硫氰酸 酯 -2-三氟甲基-苯甲腈 (300mg,1.3mmol)溶解于无水 DMF中,置于封管中, 加热到 80°C, 搅拌过夜。 反应液冷却到室温,所得粗品加入甲醇 (10mL)中, 随后加入 2N 的盐酸溶液 (3mL),室温搅拌过夜。浓缩蒸去甲醇,乙酸乙酯萃取,有机层用无水硫酸钠干燥,过滤,浓缩, 所得油状物制备薄层层析 (石油醚:乙酸乙酯 =1 : 1)得到目标化合物 (56mg, 灰色固体)。 1H NMR (400 MHz, DMS0-d6): δ 8.41(d, 1H, J=8.4Hz), 8.32(s, 1H), 8.18(s, 1H), 8.11(d, 1H, J=8.0Hz), 7.82(s,lH), 7.80(s,lH), 7.37(dd, 1H, J=0.8, 8.8 Hz), 4.11(s, 3H), 1.55(s, 6H)。 MS m/z (ESI):444.1[M+H]。
实施例 2~实施例 5
按照实施例 1的相同方法, 制备实施例 2~实施例 5的化合物, 具体化学结构鉴定数
据见表 1。
表 1 化合物 1-2〜化合物 1-5的化学结构鉴定数据表
实施例 6
4-[3-(l-乙基 -IH-吲唑 -5-基) -4,4-二甲基 -5-氧代 -2-硫代-咪唑啉 -1-基] -2-三氟甲基 -苯甲 腈 (化合物 1-6) 的制备
1-6
第一步: 1-乙基 -1H-吲唑 -5-基胺的制备
将 1-乙基 -5-硝基 -1H-吲唑 (5g,26.2mmol ) 用乙醇 (50mL)溶解,加入水 (50mL), 加热 到 90 °C后,一次性加入固体氯化铵 C6g, 112mmol)以及还原铁粉 C6g,107mmoi;), 所得溶液继 续搅拌 1小时。 趁热过滤, 滤液浓缩后快速柱层析 (石油醚: 乙酸乙酯 =3 : 1)得到 1-乙基 -1H-吲唑 -5-基胺(3g,粉红色固体)。 1H MR (400 MHz, CDC13): 57.80(s, IH), 7.27(m, IH), 6.96(s, IH), 6.90(m, IH), 4.39(q, 2H,J=7.2Hz), 1.51(t, 3H, J=7.2Hz) 。 MS m/z(ESI):162.1[M+H
第二步: 2-(l-乙基 -IH-吲唑 -5-基氨基 )-2-甲基 -丙腈的制备
将 5-胺基 -1-乙基吲唑 (1.5g, 9.3mmol ) 用丙酮(15mL)溶解, 加入三甲基硅氰 (2mL,15.7mmol)和数滴醋酸, 置于封管中, 加热到 90 °C并恒温持续搅拌过夜。 反应液 冷却到室温,减压浓缩后加水稀释,乙酸乙酯 (50mL X 3 ) 萃取,有机相分别用水,饱和食盐 水洗涤, 无水硫酸钠干燥, 过滤并浓缩得到粗品。 粗品经快速柱层析分离 (石油醚: 乙 酸乙酯 =1 : 1 ) 纯化得到 2-(1-乙基 -1H-吲唑 -5-基氨基 )-2-甲基 -丙腈 (1.6g,白色固体)。 1H MR(400 MHz,CDCl3): 57.93(s, IH), 7.40- 7.34(m, 2H), 7.12-7.09(m, IH), 4.42(q, 2H,J=7.2Hz), 1.69(s, 6H), 1.53(t, 3H, J=7.2Hz)。 MS m/z(ESI):229.1[M+H
第三步: 4-[3-(l-乙基 -IH-吲唑 -5-基) -4,4-二甲基 -5-氧代 -2-硫代-咪唑啉 -1-基] -2-三氟 甲基-苯甲腈的制备
将中间体 2-甲基 -2-(1-乙基 -1H-吲唑 -5-基氨基)丙腈 (160mg, 0.7mmol) 和 4-异硫氰
酸酯基 -2- (三氟甲基)苯甲腈 (160mg, 0.7mmol)溶解于无水 DMF(5mL), 置于封管中, 加 热到 80°C, 搅拌过夜。 反应液冷却到室温, 所得粗品倒入甲醇 (10mL) 中, 随后加入 2N 的盐酸溶液 (3mL), 室温搅拌过夜, 浓缩蒸去甲醇, 乙酸乙酯萃取。 有机层用无水硫 酸钠干燥, 过滤, 浓缩所得油状物经硅胶柱层析分离纯化 (石油醚:乙酸乙酯 =3 : 1)得到目 标化合物(145mg, 白色固体)。 1H MR(400 MHz,CDCl3): δ 8.11(s, 1H), 8.02-8.00(m,2H), 7.90-7.88(m, 1H), 7.70(s, 1H), 7.59(d, 1H, J=8.4Hz), 7.32(m,lH), 4.50(q, 2H), 1.65(s, 6H), 1.59(t, 2H)。 MS m/z(ESI): 458.1[M+H]。
实施例 7
4-[4,4-二甲基 -3-(2-甲基 -1-氧代 -1,2-二氢-异喹啉 -7-基) -5-氧代 -2-硫代-咪唑啉 -1- 基] -2-三氟甲基-苯甲腈 (化合物 1-7) 的制备
1-7 第一步: 2-甲基 -5-硝基 -苯甲酸甲酯的制备
将原料 2-甲基 -5-硝基-苯甲酸 (1.0g, 5.5mmol)用无水甲醇 (lOOmL)溶解, 室温条件下 滴加氯化亚砜 (10mL), 所得黄色溶液继续室温搅拌过夜, 薄层层析显示反应完成, 浓缩 至干, 所得粗品用乙酸乙酯和水稀释, 分出有机层, 有机相用无水硫酸钠干燥, 过滤,
浓缩得到 2-甲基 -5-硝基 -苯甲酸甲酯(l.Og,黄色固体)。1H NMR(400 MHz,CDCl3): δ 8.77(s, IH), 8.23(d, IH, J=8.0Hz), 7.44(d, IH, J=8.4Hz), 3.96(s, 3H), 2.72(s, 3H)。
第二步: 2-(2-二甲基氨基-乙烯基 )-5-硝基 -苯甲酸甲酯的制备
将原料 2-甲基 -5-硝基-苯甲酸甲酯 (1.0g, 5. lmmol)与叔丁氧基双 (二甲胺基)甲垸 (6mL) 混合, 置于封管中, 加热到 115oC, 反应 3.5小时。 反应夜冷却至室温, 用石油醚和乙酸 乙酯 (6: 1)的溶液稀释, 室温放置过夜, 过滤, 所得固体直接用于下一步反应。
第三步: 2-甲基 -7-硝基 -2H-异吲哚 -1-酮的制备
将上步所得固体(l.Og)用无水乙醇( 1 OmL)溶解, 加入甲胺的乙醇溶液(1 OmL, 20mmol), 所得黄色溶液于 90oC搅拌过夜。 反应结束后将反应混合物浓缩至干, 所得粗 品快速柱层析分离 (石油醚:乙酸乙酯 =1 : 1)得到 2-甲基 -7-硝基 -2H-异吲哚 -1-酮 (800mg, 黄 色固体)。 1H雇 R(400 MHz, CDC13): δ 8.92(d, IH, J=2.4Hz), 8.43 (dd, IH, J=2.4, 8.8Hz), 7.90(d, IH, J=8.8Hz), 7.76(d, IH, J=7.2Hz), 6.79(d, IH, J=7.2Hz), 3.56(s, 3H)。 MS m/z(ESI): 205.1[M+H] o
第四步: 7-氨基 -2-甲基 -2H-异喹啉 -1-酮的制备
以 2-甲基 -7-硝基 -2H-异吲哚 -1-酮为原料, 采用实施例 6第一步相同的方法合成得到 7-氨基 -2-甲基 -2H-异喹啉 -1-酉同 (600mg, 灰色固体)。 1H MR(400 MHz, DMSO-d6): δ 7.34(s, IH), 7.32(s, IH), 7.08(d, IH, J=7.2Hz), 6.97(dd, IH, J=2.4,7.2Hz), 6.40(d, IH, J=3.2Hz), 5.53(s, 2H), 3.45(s, 3H)。 MS m/z(ESI): 175.1[M+H]。
第五步: 2-甲基 -2-(2-甲基 -1-氧代 -1,2-二氢-异喹啉 -7-基氨基) -丙腈的制备
以 7-氨基 -2-甲基 -2H-异喹啉 -1-酮为原料, 采用实施例 1第一步相同的方法合成得到 2-甲基 -2-(2-甲基 -1-氧代 -1,2-二氢-异喹啉 -7-基氨基) -丙腈 (300mg, 淡黄色固体)。 1H MR(400 MHz, DMSO-d6):5 7.64(s, IH), 7.50(d, IH, J=8.4Hz), 7.24-2 l(m, 2H), 6.51-6.48(m: 2H), 3.48(s, 3H), 1.69(s, 6H)。 MS m/z(ESI): 242.1[M+H]。
第六步:4-[4,4-二甲基 -3-(2-甲基 -1-氧代 -1,2-二氢-异喹啉 -7-基) -5-氧代 -2-硫代-咪唑啉 小基] -2-三氟甲基-苯甲腈的制备
以 2-甲基 -2-(2-甲基 -1-氧代 -1,2-二氢-异喹啉 -7-基氨基;)-丙腈为原料, 采用实施例 1
第二步相同的方法合成得到 4-[4,4-二甲基 -3-(2-甲基 -1-氧代 -1,2-二氢-异喹啉 -7-基) -5-氧 代 -2-硫代-咪唑啉 -1-基] -2-三氟甲基-苯甲腈 (84mg, 黄色固体)。 1H MR(400 MHz, DMSO-d6):5 8.41(d, IH, J=2.4Hz), 8.33(d, IH, J=1.2Hz), 8.22(d, IH, J=1.6Hz), 8.11(dd, IH, J=1.6, 8.0Hz), 7.86(d, IH, J=8.4Hz), 7.68(dd, IH, J=2.0, 8.4Hz), 7.60(d, IH, J=7.2Hz), 6.72(d, lH, 7.2Hz), 3.54(s, 3H), 1.56(s, 6H)。 MS m/z(ESI):470.9[M+H]。
实施例 8~实施例 9
按照实施例 7的相同方法, 制备实施例 8~实施例 9的化合物, 具体化学结构鉴定数 据见表 2。
表 2 化合物 1-8〜化合物 1-9的化学结构鉴定数据表
实施例 10
1-10 第一步: 1-((1-甲基 -IH-吲唑 -5-基;)氨基)环丁垸
将 i -甲基 -1H-吲唑 -5-胺 (0.5g, 3.5mmol) 和环丁酮 (0.5g, 7mmol) 及三甲基硅垸 腈(0.9g, 7mmol)混合置于 50mL反应瓶中, 加热至 90°C, 反应 12h。 反应液冷却, 搅 拌下加入到水 (10mL) 中, 乙酸乙酯 (200mLx3) 萃取, 合并乙酸乙酯相, 分别用水, 饱和食盐水洗涤, 无水硫酸钠干燥, 浓缩后用硅胶柱柱层析纯化得到 1-((1-甲基 -1H-吲唑 -5-基)氨基)环丁垸(类白色固体, 0.66g) 1H MR(400MHz, CDC13): δ 7.87(d, J=0.8Hz, 1H), 7.3 l(d, J=8.8Hz, 1H), 6.90-6.86 (m, 2H), 4.06(s, 3H), 2.89-2.82(m, 2H), 2.48-2.41(m, 2H), 2.33-2.19(m, 2H)。 MS m/z(ESI): 227.1[M+H]。
第二步: 4- (5- (1-甲基 -IH-吲唑基 -5-基) -8-氧 -6-硫基 -5,7-二氮杂螺 [3,4]辛基) -2- 三氟甲基 -氰苯的制备
以 1-((1-甲基 -1H-吲唑 -5-基)氨基)环丁垸为原料, 采用实施例 1第二步相同的方法合 成得到 4-(5-(1-甲基 -1H-吲唑基 -5-基) -8-氧 -6-硫基 -5,7-二氮杂螺 [3,4]辛基) -2-三氟甲基-氰 苯(白色固体, 48 mg)。
400MHz): δ 8.12(d, J=0.4Hz, IH), 8.03-8.00(m, 2H), 7.91-7.89(dd, J=1.6, 2.0Hz, IH), 7.74(d, J =1.6Hz, IH), 7.62(d, J=8.8Hz, IH), 7.32(d, J=8.0Hz, IH), 4.12(s, 3H), 2.33-2.19(m, 2H), 2.76-2.59(m, 4H), 2.29-2.22(m, IH), 1.69-1.62(m, 1H)。 MS m/z(ESI):456.1[M+H]。
实施例 11
1-11 第一步: 1-((1,3-二甲基 -1H-B引唑 -5-基)氨基)环丁垸的制备
将 1,3-二甲基 -1H-吲唑 -5-胺 (0.32g, 1.8mmol)和环丁酮 (0.28g, 3.6mmol)及三甲 基硅腈(0.39g, 3.6mmol)混合置于 50mL反应瓶中, 加热至 90°C, 反应 12h, 反应液冷 却, 搅拌下加入水和乙酸乙酯稀释。 分出乙酸乙酯相, 分别用水, 饱和食盐水洗涤, 干 燥, 过滤, 浓缩后柱层析纯化得 1-((1,3-二甲基 -1H-吲唑 -5-基)氨基)环丁垸(类白色固体, 0.22g) o 1H- MR(CDCl3, 400MHz): 57.24(d, J=8.8Hz, IH), 6.86(d, J=1.6Hz, IH), 6.80(s, IH), 3.98(s, 3H), 2.89-2.82(m, 2H), 2.54(s, 3H), 2.49-2.41(m, 2H), 2.32-2.19(m, 2H)。MS m/z(ESI): 241.1[M+H] o
第二步: 4- ( 5- ( 1,3-二甲基 -IH-吲唑基 -5-基) -8-氧 -6-硫基 -5,7-二氮杂螺 [3,4]辛基) -2-三氟甲基 -氰苯的制备
以 1-((1,3-二甲基 -1H-吲唑 -5-基)氨基)环丁垸为原料, 采用实施例 1第一步相同的方 法合成得到 4- ( 5- ( 1,3-二甲基 -1H-吲唑基 -5-基) -8-氧 -6-硫基 -5,7-二氮杂螺 [3,4]辛基) -2- 三氟甲基 -氰苯 (白色固体, 21mg) o 1H- MR(CDC13, 400 MHz): δ 8.39(d, J=8.0Hz, IH), 8.27(d, J=2.0Hz, IH), 8.08(d,J=1.6Hz, IH), 7.78-7.75(m, 2H), 7.36(dd, J=1.6, 2.0Hz, IH), 4.04(s, 3H), 2.68-2.61(m, 2H), 2.53(s, 3H), 2.50-2.49(m, 2H), 2.04-1.93(m, IH), 1.54-1.45(m, 1H)。 MS m/z(ESI): 470.1 [M+H]。
实施例 12~实施例 17
按照实施例 11的相同方法,制备实施例 12~实施例 17的化合物,具体化学结构鉴定 数据见表 3。
实施例 18
4-[5-(2-甲基 -1-氧代 -1,2-二氢-异喹啉 -7-基) -8-氧代 -6-硫代 -5,7-二氮杂-螺 [3.4]辛 -7- 基] -2-三氟甲基-苯甲腈 (化合物 1-18) 的制备
1-18 第一步: 1-((2-甲基 -1-氧 -1,2-二氢喹啉 -7-基)氨基)环丁垸的制备
以 7-氨基 -2-甲基 -2H-异喹啉 -1-酮为原料, 采用与实施例 10第一步相同的方法合成 得到 1-((2-甲基小氧 -1,2-二氢喹啉 -7-基)氨基)环丁垸(白色固体, 0.22 g)。 1H- MR(CDC13, 400MHz): δ 7.65(d, J=2.4Hz, 1H), 7.44 (d, J=8.4Hz, 1H), 7.02(d, J =2.4Hz, 1H), 6.93(d, J=7.2Hz, 1H), 6.44(d, J=7.2Hz, 1H), 3.61(s, 3H), 2.94-2.88(m, 2H), 2.50-2.43(m, 2H), 2.27-2.18 (m, 2H)。 MS m/z(ESI): 254.1[M+H]。
第二步: 4- ( 5- (2-甲基 -1-氧 -1,2-二氢喹啉 -7-基) -8-氧 -6-硫基 -5,7-二氮杂螺 [3,4]辛 基) -2-三氟甲基 -氰苯的制备
以 1-((2-甲基 -1-氧 -1,2-二氢喹啉 -7-基;)氨基)环丁垸为原料,采用与实施例 1第二步相 同的方法合成得到 4- ( 5- (2-甲基 -1-氧 -1,2-二氢喹啉 -7-基) -8-氧 -6-硫基 -5,7-二氮杂螺 [3,4] 辛基) -2-三氟甲基 -氰苯(淡黄色固体,38mg)。1H-NMR(CDCl3, 400 MHz): 58.39(d, J=8.4Hz: 1H), 8.23-8.27(m, 2H), 8.08(d, J=1.6Hz, 1H), 7.89(d, J=8.4Hz, 1H), 7.72(d, J=2.4Hz, 1H), 7.62(d, J=7.2Hz,lH),6.74(d,J=7.6Hz,lH), 3.56(s, 3H), 2.70-2.64(m, 2H), 2.47-2.39(m, 2H), 2.02-1.93(m, 1H), 1.55-1.48(m, 1H)。 MS m/z(ESI):483.1[M+H]。
实施例 19
2—氯 -4-[5-(2-甲基 -1-氧代 -1,2-二氢-异喹啉 -7-基) -8-氧代 -6-硫代 -5,7-二氮杂-螺 [3.4]辛 -7-基]-苯甲腈 (化合物 1-19)
1-19
采用实施例 18 相同的方法合成得到目标化合物 1-19 (淡黄色固体, 20mg )。 1H- MR(CDC13, 400 MHz): δ 8.25(d, J=2.0Hz, IH), 8.18(d, J=8.4Hz, IH), 8.00(d, J=2.0Hz, IH), 7.89(d, J=8.4Hz, IH), 7.75-7.70(m, 2H), 7.62(d, J=7.6Hz, IH), 6.74(d, J=7.2Hz, IH), 3.55(s, 3H), 2.67-2.63(m, 2H), 2.46-2.38(m, 2H), 2.02-1.92(m, IH), 1.55-1.48(m, 1H)。 MS m/z(ESI): 449.1 [M+H]。
实施例 20
5-[3-(4-氰基 -3-三氟甲基-苯基) -5,5-二甲基 -4-氧代 -2-硫代-咪唑啉 -1-基] -吲唑 -1-甲酸 叔丁酯 (化合物 1-20) 的制备
将原料 5-硝基 -1H-吲唑 (8.22 g, 50.4mmol) 用四氢呋喃 (300 mL) 溶解, 加入 4,4-二 甲基氨基吡啶 DMAP(922mg)和三乙胺 (10g), 室温条件下加入 Boc酸酐 (13g). 室温搅拌 过夜, 反应液蒸干后用二氯甲垸溶解, 1N稀盐酸洗涤 (300mLx3), 水洗继而饱和食盐水洗 漆, 二氯甲垸层用无水硫酸钠干燥,过滤并浓缩至干得 5-硝基 -B引唑 -1-甲酸叔丁酯 (llg, 黄色固体)。 1H-NMR(DMSO-d6, 400 MHz): δ 8.89(d, 1H, J=2.0Hz), 8.65(s, 1H), 8.43(dd, 1H, J=2.0, 9.2Hz), 8.26(d,lH, J=9.2Hz), 1.67(s, 9H).
第二步: 5-氨基 -B引唑 -1-甲酸叔丁酯的制备
将 5-硝基 -1H-吲唑 -1-碳酸叔丁基酯 (llg) 用 300mL乙醇和水 (1 : 1体积比)溶解, 加 入氯化铵 (lg)固体, 加热到 90°C, 分批加入还原铁粉 (llg)。 继续加热搅拌 1小时后, 反 应液过滤, 滤饼用 200mL热的甲醇洗涤, 合并滤液, 浓缩至干得到白色固体, 快速柱层 析分离(石油醚: 乙酸乙酯 =3 : 1 )得到 5-氨基 -吲唑 -1-甲酸叔丁酯 (6g;)。 1H-雇 R(CD30D, 400 MHz): 58.06(d, 1H, J=0.8Hz), 7.88(d, 1H, J=8.8Hz), 7.08-7.03(m, 1H), 1.71(s, 9H). MS m/z(ESI):234.1 [M+H]。
第三步: 5- [(氰基-二甲基-甲基)-氨基] -B引唑 -1-甲酸叔丁酯的制备
以 5-氨基 -吲唑 -1-甲酸叔丁酯为原料, 采用实施例 1 第一步相同的方法合成得到 5- [(氰基 -二甲基-甲基)-氨基] -吲唑 -1-甲酸叔丁酉旨。 1H-NMR(DMSO-d6, 400 MHz): δ 8.30(s, 1H), 7.90(d, 1H, J=8.8Hz), 7.20(d, 1H, J=2.0Hz), 7.16(dd, 1H, J=2.0, 9.2Hz), 6.22(s,lH), 1.67(s, 6H), 1.64(s, 9H).
第四步: 5-[3-(4-氰基 -3-三氟甲基-苯基) -5,5-二甲基 -4-氧代 -2-硫代-咪唑啉 -1-基] -吲唑 -1-甲酸叔丁酯的制备
以 5- [(氰基-二甲基-甲基) -氨基] -B引唑 -1-甲酸叔丁酯为原料, 采用实施例 1第二步相 同的方法合成得到目标化合物(白色固体, 2.5g)。 1H- MR(DMSO-d6, 400 MHz): 58.55(s, 1H), 8.41(d, 1H, J=8.0Hz), 8.33(s, 1H), 8.24(d, 1H, J=8.8Hz), 8.12(d, 1H, J= 8.0 Hz), 7.95(s, 1H), 7.61(d,lH, J=8.8Hz), 1.71(s, 9H), 1.56(s, 6H). MS m/z(ESI):530.7[M+H]。
实施例 21 : 4-[3-(1Η-吲唑 -5-基) -4,4-二甲基 -5-氧代 -2-硫代-咪唑啉 -1-基] -2-三氟甲基-
-21 ) 的制备
将实施例 20的化合物 1-20 (2.5g, 4mmol) 溶解在二氯甲垸 (15mL) 中, 冰浴冷却 下滴加 4N的氯化氢的二氧六环溶液 (5mL), 室温搅拌过夜。 过滤收集固体, 固体用少量 无水乙醚洗涤, 干燥得 4-[3-(1Η-吲唑 -5-基) -4,4-二甲基 -5-氧代 -2-硫代-咪唑啉 -1-基] -2-三 氟甲基-苯甲腈 (1.5g, 白色固体)。 1H- MR(DMSO-d6, 400 MHz): 513.34(s, 1H), 8.40(d, 1H, J=8.4Hz), 8.32(s, 1H), 8.21(s, 1H), 8.11(dd, 1H, J=1.6, 8.4Hz), 7.80(d, 1H, J= 1.6Hz), 7.70(d, 1H, J=8.8Hz), 7.32(dd,lH, J=2.0, 8.8Hz), 1.55(s, 6H). MS m/z(ESI):530.5[M+H]。
实施例 22
4-[3-(l-乙酰基 -1H-吲唑 -5-基) -4,4-二甲基 -5-氧代 -2-硫代-咪唑垸 -1-基] -2-三氟甲基-苯 甲腈 (化合物 1-22) 的制备
1-22
将实施例 21的化合物 1-21 ( lOOmg, 0.23mmol )和无水碳酸钾粉末(320mg, 2.3mmol) 悬浮在无水 N, N-二甲基甲酰胺 (10mL) 中。 冰浴冷却下, 向其中滴加乙酰氯 (73mg, 0.93mmol ) o滴加完毕, 反应液在室温搅拌过夜。反应结束,混合物用二氯甲垸和水稀释, 分出有机相, 依次用饱和碳酸氢钠溶液, 水和饱和食盐水洗涤, 无水硫酸钠干燥, 过滤, 减压浓缩。 剩余物用硅胶柱层析分离纯化得到 4-{4,4-二甲基 -5-氧代 -3-[1- (丙垸 -1-磺酰 基) -1H-吲唑 -5-基] -2-硫代-咪唑垸 -1-基}-2-三氟甲基-苯甲腈 (淡黄色粉末, 12mg )。
1H- MR(CDC13, 400MHz): δ 8.65(d, J=9.2 Hz, IH), 8.24(s, IH), 7.96-8.01(m, 2H), 7.88(d, J=8.0 Hz, IH), 7.73(s, IH), 7.50(d, J=8.0 Hz, IH), 2.85(s, 3H), 1.65(s, 6H)。 MS m/z(ESI):471.4[M+H]。
实施例 23
4-{4,4-二甲基 -5-氧代 -3-[l- (丙垸 -1-磺酰基) -IH-吲唑 -5-基] -2-硫代-咪唑垸 -1-基}-2-三 氟甲基-苯甲腈 (化合物 1-23 ) 的制备
1-23 将实施例 21的化合物 1-21 ( lOOmg, 0.23mmol )和无水碳酸钾粉末(320mg, 2.3mmol ) 悬浮在无水 N, N-二甲基甲酰胺( 10mL)中。冰浴冷却下,向其中滴加丙基磺酰氯( 130mg, 0.93mmol)o滴加完毕, 反应液在室温搅拌过夜。反应结束,混合物用二氯甲垸和水稀释, 分出有机相, 依次用饱和碳酸氢钠溶液, 水和饱和食盐水洗涤, 无水硫酸钠干燥, 过滤, 减压浓缩。 剩余物用硅胶柱层析分离纯化得到 4-{4,4-二甲基 -5-氧代 -3-[1- (丙垸 -1-磺酰 基) -1H-吲唑 -5-基] -2-硫代-咪唑垸 -1-基}-2-三氟甲基-苯甲腈 (淡黄色粉末, 21mg )。 1H- MR(CDC13, 400ΜΗζ): δ 8.35(s, IH), 8.28(d, J=9.2 Hz, IH), 8.03-8.01(m, 2H), 7.88(d, 7=8.4 Hz, IH), 7.76(s, IH), 7.49(d, J=9.2 Hz, IH), 3.53(t, J=7.6 Hz, 2H), 1.83-1.89(m, 2H), 1.66(s, 6H), 1.07(t, J=7.6 Hz, 3H)。 MS m/z(ESI):535.6[M+H]。
实施例 24
1-24
将实施例 21的化合物 1-21 ( lOOmg, 0.23mmol) 溶于无水 DMF ( 10 mL) 中, 搅拌 下依次加入碳酸钾粉末(320mg,2.3mmol)和环丙甲基溴(94mg,0.70mmol), 室温搅拌过 夜。 反应液用二氯甲垸和水稀释, 分出有机相, 有机相用水和饱和食盐水洗涤, 无水硫 酸钠干燥, 过滤, 减压浓缩。 剩余物用硅胶柱层析分离纯化依次得到黄色固体, 34mg。 1H- MR(CDC13, 400 MHz) δ 8.11(s, 1Η), 8.00-8.07(m, 2H), 7.89(d, /=8.4 Hz, 1H), 7.71(s, 1H), 7.61(d, /=8.8 Hz, 1H), 7.29(s, 1H), 4.32(d, /=6.8 Hz, 2H), 1.65(s, 6H), 0.90(t, J=5.6 Hz, 2H), 0.66(d, J=6.8 Hz, 2H), 0.49(d, J=4.8 Hz, 1H)。 MS m/z(ESI):483.5 [M+H]。
实施例 25
4-[3-(2-环丙甲基 -2H-吲唑 -5-基) -4,4-二甲基 -5-氧代 -2-硫代-咪唑垸 -1-基] -2-三氟甲基- 苯甲腈 (化合物 1-25 ) 的制
1-25
将实施例 21的化合物 1-21 ( lOOmg, 0.23mmol) 溶于无水 DMF ( 10 mL) 中, 搅拌 下依次加入碳酸钾粉末(320mg,2.3mmol)和环丙甲基溴(94mg,0.70mmol), 室温搅拌过 夜。 反应液用二氯甲垸和水稀释, 分出有机相, 有机相用水和饱和食盐水洗涤, 无水硫 酸钠干燥, 过滤, 减压浓缩。 剩余物用硅胶柱层析分离纯化依次得到黄色固体, 26mg。 1H- MR(CDC13, 400 MHz) δ 8.18(s, lH),7.99-8.02(m, 2H), 7.87-7.96(m, 2H), 7.66(s, 1H), 7.15(dd, J=8.8, 1.2Hz, 1H), 4.35(d, J=7.6 Hz, 2H), 1.65(s, 6H), 0.90(t, J=6.80 Hz, 2H), 0.77(d,
J=7.6 Hz, 2H), 0.52(d, J=4.8 Hz, 1H)。 MS m/z(ESI):483.5 [M+H]。
实施例 26~实施例 41
以实施例 21的化合物 1-21为原料, 用不同的卤代物替换环丙甲基溴,采用与实施例 24和 25相同的合成方法制备得到化合物 I-26 化合物 1-41, 具体化学结构鉴定数据见表 4。
表 4 化合物 1-26〜化合物 1-41的化学结构鉴定数据表
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4-[4,4-二甲基 -3-(l-甲基 -1H-吡唑 [3,4-b]吡啶 -5-基) -5-氧代 -2-硫代-咪唑垸 -1-基] -2-三 氟甲基-苯甲腈 (化合物 1-4
以 1-甲基 -1H-吡唑 [3,4-b]吡啶 -5-基胺为原料, 采用与实施例 1相同的方法合成得到 化合物 1-42。 1H MR(CDC13, 400 MHz): δ 1.66(s, 6 H), 4.24(s, 3 H), 7.89(dd, 1H), 8.01-8.04(m, 3H), 8.13(s, 1H), 8.48(d, 1H)。 MS m/z(ESI): 445.4[M+H]。
实施例 43
2-氯 -4-[4,4-二甲基 -3-(l-甲基 -1H-吡唑 [3,4-b]吡啶 -5-基) -5-氧代 -2-硫代-咪唑垸 -1-基 苯甲腈 (化合物 1-43 ) 的制备
以 1-甲基 -1H-吡唑 [3,4-b]吡啶 -5-基胺为原料, 采用与实施例 1相同的方法合成得到 化合物 1-43。 1H雇 R(CDC13, 400 MHz): δ 1.64(s, 6H), 4.24(s, 3H), 7.56(d, 1H), 7.73(s,lH), 7.85(d,lH), 8.03(d, 1H), 8.13(s, 1H), 8.47(d, 1H)。 MS m/z(ESI): 411.4[M+H]。
实施例 44~实施例 45
分别以 4-氨基 -2-氟-苯甲腈和 4-氨基 -2,3-二氟-苯甲腈为原料, 采用与实施例 7相同 的方法合成得到化合物 I-44 化合物 1-45, 具体化学结构鉴定数据见表 5。
表 5 化合物 1-44〜化合物 1-45的实验数据表
实施例 结构式 核磁与 MS数据 实施例 CDC13, δ 8.09(s, 1H), 8.02-7.99(m, 2H),
44 (化合 7.90-7.88 (m, 2H), 7.65(d, J=1.6 Hz, 1H), 物 1-44) 。 7.16(dd, Jl=2.0, 9.2Hz, 1H), 6.17 -6.12(m, 1H), 5.43-5.38(m, 2H), 5.11(d, J=6.0 Hz, 2H), 1.65(s,
1-44
6H)。 MS m/z(ESI): 469.5 [M+H]。
实施例 V 丄 CDC13, δ 8.10 (s, 1H), 8.01-7.98 (m, 2H), 7.99 45 (化合 (d, J=8.0 Hz, 1H), 7.69 (s, 1H), 7.64-7.59 (m, 物 1-45 ) 。 1H), 7.30 (s, 1H), 4.55(t, J=6.4 Hz, 2H ), 3.39-3.35(m, 5H), 2.24(t, J=6.4 Hz, 2H), 1.65 (s,
1-45
6H)。 MS m/z(ESI): 501.5 [M+H]。
实施例 46
1-46
以 6-氨基 -3H-喹啉啉 -4-酮(参照文献方法合成 Tetrahedron Letters, 2012 , vol. 53, 44, p. 5923 - 5925 )和 4-氨基 -2-三氟甲基-苯甲腈为原料, 采用实施例 1的合成方法, 合成得 到化合物 1-46。 1H NMR(CDC13, 400 MHz): δ 8.27(s,lH), 8.17(s,lH), 8.01-8.04(m,2H), 7.89-8.00(m,2H), 7.81(d, J=5.2Hz, lH), 1.68(s,6H)。 MS m/z(ESI): 458.5 [M+H]。
实施例 47
1-47
将原料 3-甲基 -1,1-二氧代 -1,2-二氢 -1 λ 6-苯并 [1,2,4]噻二嗪 -Ί-基氨
(300.0mg,1.42mmol ) 和丙酮 (2ml ) 加入到 90%冰醋酸 ( 17ml ) 中, 搅拌溶解, 投入 NaCN (7g,142mmol), 室温搅拌反应 96.0小时。 加水稀释, 经硫酸亚铁水溶液处理后用 乙酸乙酯 (20.0ml X 3 ) 萃取, 合并有机相, 分别用饱和碳酸氢钠, 氯化钠洗涤, 无水硫 酸镁干燥, 过滤, 浓缩。 残留物快速柱层析分离 (5%MeOH/DCM), 得到 150.0mg中间 体, 直接用于下步反应。
将上述中间体 (62.0 mg, 0.223mmol) 禾 P 2-三氟甲基 -4-异硫氰基苯甲腈 (127.0 mg, 0.557 mmoL) 加入到无水 DMF (2.0 mL) 中, 于微波 50°C反应 6小时。 加入到 2N HC1
(4.0 mL) 和甲醇 (4.0 mL) 中, 加热回流 1小时。 冷却, 减压蒸去溶剂。 残留物加入 乙酸乙酯和水稀释, 用饱和碳酸氢钠将 pH值调至中性, EA萃取, 合并有机相, 浓缩, 残留物制备薄层层析分离 (MeOH:DCM=l :30), 得目标化合物 (浅黄色固体, 50.0mg), 1H MR (300 MHz,d6-DMSO) δ 12.32(brs, N-H, 1H),8.38-8.40 (m, 1H), 8.26(d, , 1H), 8.04-8.06 (dd, , 1H), 7.84 (dd,lH), 7.63 (dd, 1H), 7.46-7.49(dd, 1H), 2.32 (s, 3H),1.51 (s, 6H)。 MS-EI 507.0[M]+
实施例 48
将原料 5-溴 -3-氰基吲哚 (200.0mg, 0.9 mmoL)、 (Boc)20 (296.2mg, 1.36mmol)禾 P DMAP (22.1mg, 0.18 mmol) 加入到无水 THF (2.0 mL)中, 室温反应 6.0 小时。 浓缩, 残留物 快速柱层析分离(30% EA/PE), 得到中间体 1-叔丁氧羰基 -5-溴 -3-氰基吲哚 273.0mg, 直 接用于下一步。 1H MR (400 MHz, CDC13) δ 8.09 (s, 1H), 8.06 (d, J= 9.0 Hz, 1H), 7.87 (d, J = 1.9 Hz, 1H), 7.54 (dd, J= 8.9, 1.9 Hz, 1H), 1.68 (s, 9H)。
第二步: 1-叔丁氧羰基 -5-氨基 -3-氰基吲哚
将中间体 1-叔丁氧羰基 -5-溴 -3-氰基吲哚 (150.0mg, 0.47 mmoL)和铜粉 (3.0mg, 0.047 mmol) 加入到氨水 (3.6mL)中, 封管 130°C反应 5小时。 过滤, EA洗涤, 浓缩, 残留物 制备薄层层析分离(PE:EA = 2: 1 ),得到中间体 1-叔丁氧羰基 -5-氨基 -3-氰基吲哚 98.5mg, 直接用于下一步。
第三步: 5-[(2-氰基丙垸 -2-基;)氨基 -1-叔丁氧羰基 -3-氰基吲哚
将中间体 1-叔丁氧羰基 -5-氨基 -3-氰基吲哚 (98.54mg, 0.38 mmoL)加入到丙酮 (2.0 mL)中, 接着加入三甲基氰硅垸 (380.0mg, 3.83mmol), 100°C加热反应 4.0h。 将反应液 倒入水中, 加入 DCM萃取三次, 合并有机相, 无水硫酸镁干燥, 过滤, 浓缩。 残留物 快速柱层析分离 (3% EA/PE), 得到中间体 5-[(2-氰基丙垸 -2-基)氨基 -1-叔丁氧羰基 -3-氰 基吲哚 63.4mg, 直接用于下一步。
第四步: 5-{3-[4-氰基 -3- (三氟甲基)苯基] -5,5-二甲基 -4-氧代 -2-硫代咪唑垸 -1-基}-3- 氰基吲哚
将中间体 5-[(2-氰基丙垸 -2-基)氨基 -1-叔丁氧羰基 -3-氰基吲哚 (63.4 mg, 0.20mmoL) 和中间体 4-异硫氰酸酯基 -2-三氟甲基-苯甲腈 (133.8 mg, 0.59 mmoL) 加入到无水 DMF ( 1 mL) 中, 于微波 50°C反应 6小时。 加入到 2N HC1 (2.0 mL) 和甲醇 (2.0 mL) 中, 加热回流 1小时。 冷却, 减压蒸去溶剂。 残留物加入乙酸乙酯和水稀释, 用饱和碳 酸氢钠将 pH值调至中性, EA萃取,合并有机相,浓缩,残留物制备薄层层析分离(PE:EA = 1 : 1 ),得目标化合物 5-{3-[4-氰基 -3- (三氟甲基)苯基] -5,5-二甲基 -4-氧代 -2-硫代咪唑垸 -1- 基}-3-氰基吲哚(白色固体, 36.1mg) o 1H NMR (400 MHz, CDC13) δ 9.38 (s, 1Η), 8.00 (d, J = 8.3 Hz, 2H), 7.88 (dd, J= 8.2, 1.7 Hz, 1H), 7.75 (d, J= 2.9 Hz, 1H), 7.67 (d, J= 1.4 Hz, 1H), 7.52 (d, J= 8.6 Hz, 1H), 7.21 (dd, J= 8.6, 1.9 Hz, 1H), 1.62 (d, J= 9.2 Hz, 6H)。 MS-EI 453.09 [M]+
实施例 49
1-49
第一步: N-甲基 -5-溴 -3-氰基吲哚
将 3-氰基 -5-溴吲哚 (200.0 mg, 0.9 mmoL)和碳酸铯(294.8 mg, 0.9 mmol)加入到无水 DMF (1.5 mL)中, 加入碘甲垸(642.2mg, 4.52mmol)室温搅拌反应 4.0 小时。加水稀释, EA萃取三次, 合并有机相, 饱和氯化钠洗涤, 无水硫酸镁干燥, 过滤, 浓缩, 抽干, 得 到中间体 N-甲基 -5-溴 -3-氰基吲哚 206.0mgo 1H NMR (400 MHz, CDC13) δ 7.88 (d, J= 1.8 Hz, 1H), 7.54 (s, 1H), 7.43 (dd, J= 8.8, 1.8 Hz, 1H), 7.24 (s, 1H), 3.83 (s, 3H)。
第二步: N-甲基 -5-氨基 -3-氰基吲哚
将 N-甲基 -5-溴 -3-氰基吲哚 (lOO.Omg, 0.43 mmoL)和铜粉 (2.7mg, 0.043 mmol) 加入 到氨水 (2.4mL)中, 封管 130°C反应 5小时。 过滤, EA洗涤, 浓缩, 残留物制备薄层层析 分离 (PE:EA = 2: 1 ), 得到中间体 N-甲基 -5-氨基 -3-氰基吲哚 58.3mg, 直接用于下一步。
第三步: 5-[(2-氰基丙垸 -2-基)氨基 -1-甲基 -3-氰基吲哚
将中间体 N-甲基 -5-氨基 -3-氰基吲哚 (58.3mg, 0.34 mmoL)加入到丙酮 (2.0 mL)中,接 着加入三甲基氰硅垸 (337.8mg, 3.41mmol), 100°C加热反应 4.0h。 将反应液倒入水中, 加入 DCM萃取三次, 合并有机相, 无水硫酸镁干燥, 过滤, 浓缩。 残留物快速柱层析 分离, 洗脱剂 (3% EA/PE), 得到中间体 5-[(2-氰基丙垸 -2-基;)氨基 -1-甲基 -3-氰基吲哚 60.8mg, 直接用于下一步。
第四步: 5-{3-[4-氰基 -3- (三氟甲基)苯基] -5,5-二甲基 -4-氧代 -2-硫代咪唑垸 -1-基 }-1- 甲基 -3-氰基吲哚
将中间体 5-[(2-氰基丙垸 -2-基)氨基 -1-甲基 -3-氰基吲哚 (60.86 mg, 0.26mmoL) 和中
间体 4-异硫氰酸酯基 -2-三氟甲基-苯甲腈( 174.8 mg, 0.77 mmoL)加入到无水 DMF( 1 mL) 中, 于微波 50°C反应 6小时。 加入到 2N HC1 (2.0 mL) 和甲醇 (2.0 mL) 中, 加热回 流 1小时。 冷却, 减压蒸去溶剂。 残留物加入乙酸乙酯和水稀释, 用饱和碳酸氢钠将 pH 值调至中性, EA萃取, 合并有机相, 浓缩, 残留物制备薄层层析分离 (PE:EA = 1 :1 ), 得目标化合物(黄色固体, 88.0mg) o 1H MR (300 MHz, CDC13) δ 8.03 - 7.96 (m, 2H), 7.87 (d, J= 8.5 Hz, 1H), 7.70 (s, 2H), 7.57 (d, J= 8.7 Hz, 1H), 7.29 (d, J= 1.8 Hz, 1H), 3.92 (s, 3H) 1.63 (s, 6H)。 MS-EI 467.10 [M]+。
1-50
以 4-氨基 -2-氯-苯甲腈为原料, 用环丙基甲基胺替换实施例 7中的甲胺, 采用实施 例 7 相同的合成方法制备得到化合物 1-50。 1H MR(CDC13, 400 MHz): δ 8.19-8.22 ( m,2H ) ,8.06(s,lH), 7.85(d,J=8.4Hz, 1H), 7.76(d,J=8.4Hz, 1H), 7.64-7.69(m,2H), 6.74(d,J=7.2Hz, 1H), 3.86(d, J=6.8Hz, 2H), 1.55(s,6H), 1.24-1.30(m,lH), 0.50(m, 2H), 0.43(m,2H)。 MS m/z(ESI): 477.2[M+H]。
1-51
以 4-氨基 -2-氯-苯甲腈为原料, 用吗啉基乙胺替换实施例 46中的氨水, 采用实施例 46相同的合成方法制备得到化合物 I-51。1H MR(CDC13, 400 MHz): δ 8.37(s, 1H), 8.01(m: 2H), 7.88(m, 1H), 7.70(d, j= 8.4Hz, 1H), 7.58(d, j= 7.2Hz, 1H), 7.24(d, j= 7.2Hz, 1H), 6.58(d, j= 6.8Hz, 1H), 4.17-4.13(m, 2H), 3.73(s, 4H), 2.78-2.75(m, 2H), 2.57(s, 4H), 1.66(s, 6H)。 MS
m/z(ESI): 537.1 [M+H]。
实施例 52
以 4-氨基 -2-三氟甲基-苯甲腈为原料, 用甲氧基乙胺替换实施例 46中的氨水, 采用 实施例 46相同的合成方法制备得到化合物 1-52。 IH MR(CDC13, 400 MHz): δ 8.27(s, IH), 8.19(s, IH), 8.01(d, J= 8.8Hz, 2H), 7.89(dd, Jl= 8.4Hz, J2= 7.6Hz, 2H), 7.69(d, J= 8.8Hz, IH), 4.23(dd, Jl= 44Hz, J2= 4.4Hz, 2H), 3.71(dd, Jl= 4.4Hz, J2= 4.4Hz, 2H), 3.40(s, 3H), 1.66(s, 6H)。 MS m/z(ESI): 516.5 [M+H]。
实施例 53
以 4-氨基 -2-三氟甲基-苯甲腈为原料, 用环丙甲基胺替换实施例 46中的氨水, 采用 实施例 46相同的合成方法制备得到化合物 1-53。 IH MR(CDC13, 400 MHz): δ 8.29(s, IH), 8.21(s, IH), 8.02(m, 2H), 7.70(m, 2H), 7.69(m, IH), 3.92(d, J= 7.2Hz, 2H), 1.67(s, 6H), 0.93(s: IH), 0.73-0.67(m, 2H), 0.50-0.46(m, 2H)。 MS m/z(ESI): 512.1 [M+H]。 实施例 54
1-54
以 4-氨基 -2-三氟甲基-苯甲腈为原料, 用吗啉基乙胺替换实施例 7中的甲胺, 采用
实施例 7相同的合成方法制备得到化合物 1-54。 1H MR(CDC13, 400 MHz): δ 8.37(s, IH), 8.01(d, J= 6.8Hz, 2H), 7.88(d, J= 7.6Hz, lH),7.70(d, J= 8.4Hz, IH), 7.58(d, J= 7.2Hz, IH), 7.24(d, J= 7.2Hz, IH), 6.58(d, J= 6.8Hz, IH), 4.17-4.13(m, 2H), 3.73(s, 4H), 2.78-2.75(m, 2H): 2.57(s, 4H), 1.66(s, 6H)。 MS m/z(ESI): 570.2 [M+H]。 实施例 55
1-55
以 4-氨基 -2-三氟甲基-苯甲腈为原料, 用苄胺替换实施例 7中的甲胺, 采用实施例 7 相同的合成方法制备得到化合物 I-55。1H MR(CDC13, 400 MHz): δ 8.41(s, IH), 8.01(d, J= 7.6Hz, 2H), 7.88(d, J= 8.0Hz, IH), 7.69(d, J= 8.4Hz, IH), 7.58(d, J= 8.4Hz, IH), 7.38-7.36(m, 5H), 7.23(d, J= 7.6Hz, IH), 6.58(d, J= 7.2Hz, IH), 5.26(s, 2H), 1.66(s, 6H)。 MS m/z(ESI): 547.1 [M+H]。 实施例 56
1-56
以 4-氨基 -2-氯-苯甲腈为原料, 用甲氧基乙胺替换实施例 7中的甲胺, 采用实施例 7 相同的合成方法制备得到化合物 1-56。 IH NMR(CDC13, 400 MHz): δ 8.21-8.19(m, 2H), 8.06(d, J= 1.6Hz, IH), 7.84(d, J= 8.4Hz, IH), 7.76(dd, Jl= 2.0Hz, J2= 1.6Hz, IH), 7.68(dd, Jl= 2.0Hz, J2= 2.0Hz, IH), 7.53(d, J= 7.2Hz, IH), 6.71(d, J= 7.6Hz, IH), 4.17(dd, Jl= 5.2Hz, J2= 5.2Hz, 2H), 3.65(dd, Jl= 5.6Hz, J2= 5.2Hz, 2H), 3.26(s, 3H), 1.55(s, 6H)。 MS m/z(ESI): 481.1 [M+H]。
1-57
以 4-氨基 -2-三氟甲基-苯甲腈为原料, 用乙胺替换实施例 7中的甲胺, 采用实施例 7 相同的合成方法制备得到化合物 1-57。 1H MR(CDC13, 400 MHz): δ 8.39(s, 1H), 8.03(m, 2H), 7.90(d, J= 6.0Hz, 1H), 7.70(d, J=7.6Hz, 1H), 7.56(d, J= 7.2Hz, 1H), 7.22(d, J= 6.0Hz, 1H), 6.61(d, J= 6.4Hz, 1H), 4.14-4.07(m, 2H), 1.66(s, 6H), 1.44-1.41(m, 3H)。 MS m/z(ESI): 485.5 [M+H]。 实施例 58
1-58
第一步: N-甲基 -7-硝基 -1-氨基异喹啉
将原料 1-氯 -7-硝基-异喹啉 ( 150.0mg,0.72mmol ) 和 27%甲胺乙醇溶液 (413.6mg,3.6mmol) 加入到异丙醇 (2.0ml) 中, 室温反应 24h。 浓缩旋干, 残留物制备 薄层层析分离(PE:EA = 2: 1 ),得中间体 N-甲基 -7-硝基 -1-氨基异喹啉 150.0mg , 1H MR (400 MHz, CDC13) δ 8.79 (d, J = 1.7 Hz, 1H), 8.33 (dd, J = 9.0, 2.2 Hz, 1H), 8.18 (d, J = 5.8 Hz, 1H), 7.75 (d, J = 9.0 Hz, 1H), 6.96 (d, J = 5.8 Hz, 1H), 5.76 (s, 1H), 3.20 (d, J = 4.8 Hz, 3H) o
第二步: N-甲基 -7-氨基 -1-氨基异喹啉
将中间体 N-甲基 -7-硝基 -1-氨基异喹啉 ( 180.0mg,0.89mmol ) 禾 P 10%钯碳
(70.0mg,0.07mmol ) 加入到甲醇 (5.0ml) 中, 置换氢气, 室温反应 2h。 过滤, 滤液浓 缩旋干, 残留物制备薄层层析分离 (DCM:MeOH = 10: l ), 得中间体 N-甲基 -7-氨基 -1-氨 基异喹啉 138. Omg 。 1H雇 R (300 MHz, CD3OD) δ 7.49 - 7.38 (m, 1H), 7.32 (dd, J = 6.4, 1.3 Hz, 1H), 7.15 (m, 2H), 6.79 (m, 1H), 3.10 - 3.00 (m, 3H)。
第三步: 2-[(l- (甲基氨;)异喹啉 -7-基;)氨基] -2-甲基丙腈
将中 间体 N-甲基 -Ί-氨基 -1-氨基异喹啉 ( 83.0mg,0.48mmol ) 和丙酮 ( 111.3mg,1.92mmol ) 加入到 90%HAc ( 1.0ml ) 中, 搅拌溶解, 投入 NaCN (47.0mg,0.96mmol), 室温反应 12.0h。 加水稀释, 用乙酸乙酯 (20.0ml X 3 )萃取, 合并 有机相, 分别用饱和碳酸氢钠, 氯化钠洗涤, 无水硫酸镁干燥, 过滤, 浓缩。 残留物制 备薄层层析分离 (DCM:MeOH = 10: 1 ), 得中间体 2-[(1- (甲基氨)异喹啉 -7-基)氨基] -2-甲 基丙腈 50.0mg。 1H MR (400 MHz, DMSO) δ 7.73 (d, J= 8.8 Hz, 1H), 7.46 (dd, J= 8.8, 2.3 Hz, 1H), 7.42 - 7.35 (m, 2H), 7.10 (d, J= 6.9 Hz, 1H), 3.22 (s, 3H), 1.80 (s, 6H)。
第四步: 4-[3-(l- (甲基氨)异喹啉 -7-基) -4,4-二甲基 -2-硫代 -5-氧代咪唑垸 -1基] -2- (三氟 甲基)苯甲腈
将中间体 2-[(1- (甲基氨)异喹啉 -7-基)氨基] -2-甲基丙腈(20.0 mg, 0.08mmoL)和中间 体 4-异硫氰酸酯基 -2-三氟甲基-苯甲腈 (57.0 mg, 0.25 mmoL) 加入到无水 DMF ( l mL) 中, 于微波 50°C反应 6小时。 加入到 2N HC1 (2.0 mL) 和甲醇 (2.0 mL) 中, 加热回流 1小时。 冷却, 减压蒸去溶剂。 残留物加入乙酸乙酯和水稀释, 用饱和碳酸氢钠将 pH值 调至中性, EA萃取,合并有机相,浓缩,残留物制备薄层层析分离(DCM:MeOH = 10: l ), 得 4-[3-(1- (甲基氨)异喹啉 -7-基 )-4,4-二甲基 -2-硫代 -5-氧代咪唑垸 -1基] -2- (三氟甲基)苯甲 腈(黄色固体, 2.0mg) o 1H雇 R (400 MHz, CDC13) δ 8.10 (d, J= 5.9 Hz, 1H), 7.99 (dd, J = 6.8, 5.4 Hz, 2H), 7.85 (dd, J = 8.4, 2.1 Hz, 2H), 7.79 (s, 1H), 7.49 (dd, J = 8.6, 1.9 Hz, 1H), 7.00 (d, J= 5.9 Hz, 1H), 3.18 (s, 3H), 1.65 (s, 6H)。 MS-EI 469.12 [M]+
实施例 59
1-59
得化合物 1-46(15.0 mg, 0.033 mmoL), 碳酸钾 (18.0 mg, 0.132 mmoL)和碘甲垸 (4.0
μΐ^, 0.066 mmoL)加入到无水 DMF 中。 加料完毕, 在室温下搅拌 6小时, TLC检测反应 完全。 加入乙酸乙酯和水, 分液。 有机相减压蒸去溶剂, 残留物用制备板分离 (展开剂 为二氯甲垸:丙酮 =20: 1 ) , 得目标化合物(白色固体, 12.0 mg)。 1H MR (CDCl3) (5 (ppm) 8.25 (s, IH), 8.14 (s, IH), 8.00-7.98 (m, 2H), 7.89-7.84 (m, 2H), 7.67 (d, J=8.4Hz, IH), 3.63 (s: 3H), 1.63 (s, 6H)。 MS-ESI 472.0 [M+H]+
实施例 60
1-60
以 4-氨基 -2-三氟甲基-苯甲腈为原料, 用甲氧基乙胺替换实施例 7中的甲胺, 采用实 施例 7相同的合成方法制备得到化合物 1-60。 IH MR(CDC13, 400 MHz): δ 8.41(d, J= 8.0Hz, IH), 8.34(s, IH), 8.23(s, IH), 8.11(d, j= 8.0Hz, IH), 7.85(d, j= 8.8Hz, IH), 7.68(d, j= 8.0Hz, IH), 7.53(d, j= 7.2Hz, IH), 6.71(d, j= 7.2Hz, IH), 4.17-4.14(m, 2H), 3.65-3.64(m, 2H), 3.27(s, 3H), 1.56(s, 6H)。 MS m/z(ESI): 515.3[M+H]。 实施例 61
1-61
以 4-氨基 -2-氯-苯甲腈为原料, 用乙胺替换实施例 7中的甲胺, 采用实施例 7相同的 合成方法制备得到实施例 61。 1H MR(CDC13, 400 MHz): δ 8.20(d, J= 8.4Hz, 2H), 8.06(s, IH), 7.84(d, J= 8.4Hz, IH), 7.76(d, J= 8.0Hz, IH), 7.67(d, J= 8.4Hz, IH), 7.62(d, J= 8.0Hz, IH), 6.74(d, J= 7.2Hz, IH), 4.05-4.00(m, 2H), 1.54(s, 6H), 1.34-1.30(m, 3H)。 MS m/z(ESI): 451.1[M+H]。
买施例 62
1-62
将 TMS-CN ( 180 mmol)加到 1-乙基 -IH-吲唑 -5-胺 (100 mg)和环丁酮 (2 ml)的溶液中, 将反应液加热到 85°C过夜, 反应液冷却, 用水 (50 ml) /乙酸乙酯 (100 ml ) 萃取, 乙 酸乙酯用无水硫酸镁干燥, 有机相浓缩至析出固体, 放置, 过滤、 干燥得 160 mg白色粉 末。 将上述白色粉末中间体(60 mg)和 5- (异硫氰酸酯) -3- (三氟甲基)氰基吡啶(100 mg, 2 eq) 加到无水 DMF ( 1 ml) 中, 85°C过夜。 反应结束后, 往上述反应液中加入甲 醇 (3 ml)和 2N HC1 (2ml)溶液, 室温搅拌过夜, 固体析出, 将固体过滤干燥, 得目标 化合物 (白色粉末, 43mg)。 H MR(CDC13, 400 Ηζ), δ :9.15(s, IH), 8.42(s, IH), 8.14 (s, IH), 7.74-7.3 l(d, /=8.8Hz, IH), 7.66-7.64(d, /=8.8Hz, IH), 7.31-7.30(d, /=0.8Hz, IH), 4.56-4.50(m, 2H), 2.78-2.62(m, 4H), 2.33-2.21(m, IH), 1.73-1.66(m, IH), 1.63-1.60(m, 3H)。
实施例 63
1-63
将 1-甲基 -IH-吡唑 [3,4-b]吡啶 -5-基胺替换 1-乙基 -1H-吲唑 -5-胺,采用实施例 62相同 的合成方法, 得到目标化合物 1-63 (白色固体, 50mg )。 IH MR(CDC13, 400 Hz), δ :9.16-9.15(d,
IH), 8.17(s, IH), 8.07-8.06(d, /=2.4Hz, IH), 4.23(s, 3H), 2.83-2.77(m, 2H), 2.63-2.55(m, 2H), 2.38-2.23(m, IH), 1.76-1.67(m, 1H)。
效果实施例
(一 )生物活性测试: 测试化合物对 DHT诱导前列腺癌 LNCaP细胞 PSA蛋白分泌 的抑制作用
方法: 使用 ALPCO公司生产的 PSA (Totai;) EIA检测试剂盒,检测细胞上清 PSA的 步骤: 1、 正常培养 LNCaP细胞 (含 10% FBS的 RPMI1640培养基), 消化后将培 养液换成含 10%CS-FBS (炭吸附处理血清) 的 RPMI1640培养液, 种板于 96孔板, 细 胞密度为 2 X 104/ml,约 2000个 /孔; 2、 种板 3天后, 更新含 InM DHT的含 10%CS-FBS (炭吸附处理血清)的 RPMI1640培养液。加药:设置 1孔为阴性对照孔(加入 InMDHT, 不加化合物) , 阳性化合物 MDV3100和实施例化合物起始浓度为 ΙΟΟΟΟηΜ,依次 5倍稀 释为 2000、 400、 80、 16、 3.2、 0.64、 0.128nM。 3、 化合物处理 3d后, 取上清 50μ1使用 ALPCO公司生产的 PSA ( Total ) ΕΙΑ检测试剂盒,检测细胞上清 PSA的含量。 FlexStation 3在波长 450nm处测定光密度值 (Optical Density, OD)。
数据处理和结果: 1、 实验结束时间点, 显微镜下观察, 化合物对细胞生长无明显的 抑制作用, 初步肯定各化合物的细胞生长抑制率低于 30%, 排除细胞毒作用。 2、 PSA蛋 白分泌的抑制率计算: 抑制率 (%) =[1- (药物受试孔-阴性对照孔) /阴性对照孔] χ ΐοο。 3、 根据各浓度的抑制率, 用 GraphPad Prism计算 IC50 (单位: nM), 结果如下表所示:
45.5 11.9 44.6-16) 1-17) 1-18) (化合物 20 (化合物 21 (化合物
19.4 91 52-19) 1-20) 1-21) (化合物 24 (化合物 25 (化合物
56.1 38.3 90.3-22) 1-24) 1-25) (化合物 27 (化合物 28 (化合物
25.8 35.4 53.8-26) 1-27) 1-28) (化合物 30 (化合物 31 (化合物
48.5 40.9 69.5-29) 1-30) 1-31) (化合物 33 (化合物 34 (化合物
124.4 62.8 509.3-32) 1-33) 1-34) (化合物 36 (化合物 37 (化合物
239.3 41.6 59.0-35) 1-36) 1-37) (化合物 39 (化合物 40 (化合物
16.1 170.2 67.9-38) 1-39) 1-40) (化合物 42 (化合物 43 (化合物
152.4 9.6 5.0-41) 1-42) 1-43) (化合物 45 (化合物 46 (化合物
86.5 170.6 5.6-44) 1-45) 1-46) (化合物 48 (化合物 49 (化合物
350.1 5.6 5.3-47) 1-48) 1-49) (化合物 51 (化合物 52 (化合物
14.7 95.7 89.7-50) 1-51) 1-52) (化合物 63.1 54 (化合物 117.9 55 (化合物 46.5
1-53 ) 1-54) 1-55 )
56 (化合物 57 (化合物 58 (化合物
52.2 30.7 52.1 1-56) 1-57) 1-58)
59 (化合物 60 (化合物 61 (化合物
46.8 45.8 12.7 1-59) 1-60) 1-61 )
62 (化合物 63 (化合物
21.7 17.5 MDV3100 37.3 1-62) 1-63 )
(二) 体内外药代动力学性质测试: 本发明化合物的药代动力学测试: 包括体外肝微粒体和代谢酶测试以及大鼠或小鼠 为受试动物的体内代谢动力学测试。
体外肝微粒体实验
代谢稳定性试验: 用体系为 150 μ ΐ 的肝微粒体 (终浓度 0.5mg/ml) 进行代谢稳定性 温孵,体系含 NADPH (终浓度 ImM)和 ΙμΜ化合物、阳性对照或阴性对照,分别在 0min、 5min、 lOmin和 30min 用含 tid 的乙腈终止反应, 涡旋 10min, 15000rmp 离心 10min, 取 50 μ ΐ 上清于 96孔板中进样。 通过测定原药的相对减少量计算化合物代谢稳定性。
直接抑制试验(DI试验): 用体系为 ΙΟΟμΙ 的人肝微粒体(终浓度 0.2mg/ml)进行直 接抑制温孵, 体系含 NADPH (终浓度 lmM)、 ΙΟμΜ化合物、 阳性抑制剂 cocktail
(Ketoconazole 10μΜ, Quinidine 10μΜ, Sulfaphenazole 100μΜ, Naphthoflavone 10μΜ, Tranylcypromine 1000μΜ)、 阴性对照 10(iM DMSO 和混合探针底物 (Midazolam 10 μΜ、 Testosterone 100μΜ、 Dextromethophan 10μΜ、 Diclofenac 20μΜ、 Phenacetin ΙΟΟμΜ, Mephenytoin ΙΟΟμΜ), 温孵 20min 后终止反应。 通过测定代谢物的相对生成量计算酶相 对活性。
应用 LC/MS/MS法测定了大鼠或小鼠分别灌胃和静注给予实施例化合物后不同时刻 血浆中的药物浓度, 研究本发明化合物在大鼠或小鼠体内的药代动力学行为, 评价其药 动学特征。实验方案: 试验动物为健康成年雄性 SD大鼠或 BALB/c小鼠, 由上海西普尔 必凯实验动物有限公司提供; 给药方式及样品采集: 分别给于 SD大鼠或 BALB/c小鼠静
脉注射 (3 mg/kg, 1 mg/mL受试化合物的混悬液) 和灌胃给药 (10 mg/kg, 1 mg/mL受 试化合物的混悬液), 分别于给药前和给药后 2、 5、 15、 30、 60、 90、 120、 240、 360、 480、 1440 min 于大鼠或小鼠眼底静脉丛取血 0.4 mL; 取血浆样品 50 μί, 分别加入 200 μΐ^含内标的乙腈溶液沉淀蛋白, 涡旋 10 min, 6000 转 /分离心 10 min; 取 200 μΐ^上清 6000转 /分再次离心 10 min; 再取 75 上清液, 加梯度初始流动相稀释, 6000转 /分离 心 10 min; 最终取上清液 70 μΐ^于 96 孔板中进样,进样量 5 μί,进行 LC-MS-MS分析。
实验结果显示, 经过研究人员不懈努力, 本发明中实施例化合物 1-5, 1-6, 1-42等的 体内外代谢性质均有明显改善。 对于人、 大鼠等肝微粒体稳定性较好 ( Clint<100(ul/min/mg protein) ), 并且对于各代谢酶亚型均无明显直接抑制作用。
实施例化合物在大鼠体内药代动力学参数
(三) 裸小鼠体内抑瘤实验
将 SCID裸小鼠 (雄性, 6-7周龄)在无菌条件下手术摘除睾丸, 一周后皮下接种人前 列腺癌细胞 (如 LNCAP, LNCAP-AR等), 待肿瘤生长至 100-150mm3后, 将动物随机分 组 (D0),每组 8-10只,分设给药组和对照组。每天一次灌胃给药受试化合物或溶媒对照( 1% CMC/ 0.1% Tween-80/ 5%DMSO), 剂量从 10mg/kg~100mg/kg, 连续给药 21 28天。 每周 测 2— 3次瘤体积, 称鼠重, 记录数据。 肿瘤体积 (V) 计算公式为: V= l/2xaxb2其中 a、 b分别表示长、 宽。 T/CC%)=CT-T0)/(;C-C0)/100, 其中 T、 C为实验结束时的肿瘤体积; Τ0、 CO为实验开始时的肿瘤体积。
结果显示, 部分实施例化合物如实施例 5, 6, 42等, 在本测试条件下, 具有明显的
对前列腺细胞接种肿瘤的生长抑制作用 (T/C小于 50%), 并且呈现剂量相关性; 在本测 试条件下, 受试动物未出现明显的毒副作用。 虽然以上描述了本发明的具体实施方式, 但是本领域的技术人员应当理解, 这些仅 是举例说明, 在不背离本发明的原理和实质的前提下, 可以对这些实施方式做出多种变 更或修改。 因此, 本发明的保护范围由所附权利要求书限定。
Claims
1、 一种如式 I所示的二芳基乙内酰脲衍生物、 其药学上可接受的盐、 溶剂化物、 代 谢产物、 立体异构体、 互变异构体、 多晶型物或其药物前体,
(Ra
其中, A环为 6~10元芳基或 6~10元杂芳基;
B环为 7~12元稠合杂芳基或氧代的 7~12元稠合杂芳基,该 7~12元稠合杂芳基中的 杂原子至少有一个为氮原子, R3与该 7~12元稠合杂芳基中的氮原子连接;
m为 A环上取代基 Ra的个数, 且 m个 Ra各自独立地为氰基、 硝基、 垸基、 卤素取代的 d~C4垸基或卤素, m为 2、 3或 4, 且 m个 Ra彼此之间不完全相同;
n为 B环上取代基 Rb的个数, 且 n个 Rb各自独立地为氢、 卤素或 垸基, n 为 0、 1、 2
R3为氢、 卤素、 硝基、 氰基、 氨基、 羧基、 d 垸基、 d 烯基、 d 炔基、 一 一 一 -
C3~C6环垸基、 3~6元杂环垸基、 6~10元芳基或 6~10元杂芳基, p为 1、 2、 3或 4, R7 和 R8各自独立地为 垸基;
D为氧或硫。
2、如权利要求 1所述的如式 I所示的二芳基乙内酰脲衍生物、其药学上可接受的盐、 溶剂化物、 代谢产物、 立体异构体、 互变异构体、 多晶型物或其药物前体, 其特征在于, 所述的 A环中所述的 6~10元芳基为苯基;所述的 A环中所述的 6~10元杂芳基为杂原子 为 1个氮原子的 6~10元杂芳基。
3、如权利要求 2所述的如式 I所示的二芳基乙内酰脲衍生物、其药学上可接受的盐、 溶剂化物、 代谢产物、 立体异构体、 互变异构体、 多晶型物或其药物前体, 其特征在于, 所述的 A环中所述的 6~10元杂芳基为吡啶基。
4、如权利要求 1所述的如式 I所示的二芳基乙内酰脲衍生物、其药学上可接受的盐、 溶剂化物、 代谢产物、 立体异构体、 互变异构体、 多晶型物或其药物前体, 其特征在于, 所述的 B环中所述的 7~12元稠合杂芳基中杂原子为氮, 且杂原子的个数为 1~3个。
5、如权利要求 4所述的如式 I所示的二芳基乙内酰脲衍生物、其药学上可接受的盐、 溶剂化物、 代谢产物、 立体异构体、 互变异构体、 多晶型物或其药物前体, 其特征在于, 所述的 B环中所述的 7~12元稠合杂芳基为吲唑基、 异喹啉基、 喹啉基、 喹唑啉基或氮杂 吲唑基; 所述的 B环中所述的氧代的 7~12元稠合杂芳基为异喹啉酮基或喹唑啉酮基。
6、如权利要求 5所述的如式 I所示的二芳基乙内酰脲衍生物、其药学上可接受的盐、 溶剂化物、 代谢产物、 立体异构体、 互变异构体、 多晶型物或其药物前体, 其特征在于, 所述的 B环为吲唑基、 异喹啉基、 喹啉基、 异喹啉酮基、 喹唑啉酮基、 喹唑啉基或氮杂 吲唑基。
'、如权利要求 6所述的如式 I所示的二芳基乙内酰脲衍生物、其药学上可接受的盐、 溶剂化物、 代谢产物、 立体异构体、 互变异构体、 多晶型物或其药物前体, 其特征在于,
9、如权利要求 1所述的如式 I所示的二芳基乙内酰脲衍生物、其药学上可接受的盐、 溶剂化物、 代谢产物、 立体异构体、 互变异构体、 多晶型物或其药物前体, 其特征在于, 所述的卤素取代的 垸基为三氟甲基。
10、 如权利要求 1所述的如式 I所示的二芳基乙内酰脲衍生物、 其药学上可接受的 盐、 溶剂化物、 代谢产物、 立体异构体、 互变异构体、 多晶型物或其药物前体, 其特征 在于, 所述的 m个 Ra为至少 2个 Ra在 A环上相邻取代, 且其中一个 Ra与如式 I所示 的二芳基乙内酰脲衍生物中标记为 10位的氮形成对位取代。
11、 如权利要求 10所述的如式 I所示的二芳基乙内酰脲衍生物、 其药学上可接受的 盐、 溶剂化物、 代谢产物、 立体异构体、 互变异构体、 多晶型物或其药物前体, 其特征 在于, 当其中一个 Ra与如式 I所示的二芳基乙内酰脲衍生物中标记为 10位的氮形成对 位取代时, 该 Ra为氰基或氯。
12、 如权利要求 1所述的如式 I所示的二芳基乙内酰脲衍生物、 其药学上可接受的 盐、 溶剂化物、 代谢产物、 立体异构体、 互变异构体、 多晶型物或其药物前体, 其特征 在于, 所述的 n个 Rb各自独立地为氟、 氯、 溴或 垸基, n为 0、 1或 2。
13、 如权利要求 12所述的如式 I所示的二芳基乙内酰脲衍生物、 其药学上可接受的 盐、 溶剂化物、 代谢产物、 立体异构体、 互变异构体、 多晶型物或其药物前体, 其特征 在于, Rb中所述的 d~C4垸基为甲基。
14、 如权利要求 1所述的如式 I所示的二芳基乙内酰脲衍生物、 其药学上可接受的 盐、 溶剂化物、 代谢产物、 立体异构体、 互变异构体、 多晶型物或其药物前体, 其特征 在于, 如式 I所示的二芳基乙内酰脲衍生物中标记为 7位的氮与所述的 B环中不含杂原 子的芳香环或者含最少杂原子的环连接。
15、 如权利要求 1所述的如式 I所示的二芳基乙内酰脲衍生物、 其药学上可接受的 盐、 溶剂化物、 代谢产物、 立体异构体、 互变异构体、 多晶型物或其药物前体, 其特征 在于, 所述的 R4中所述的 d~C4垸氧基为甲氧基或乙氧基。
16、 如权利要求 1所述的如式 I所示的二芳基乙内酰脲衍生物、 其药学上可接受的 盐、 溶剂化物、 代谢产物、 立体异构体、 互变异构体、 多晶型物或其药物前体, 其特征 在于, 当 R2和标记为 8位的碳相连组成 3~6元环垸基或 4~6元杂环垸基时, 所述的 3-6元环垸基为环丙基、 环丁基或环戊基, 所述的 4~6元杂环垸基为氧杂环丁基、 氮杂 环丁基、 四氢呋喃基、 吡咯垸基、 二氧六环基、 哌啶基或 Ν-甲基哌啶基。
17、 如权利要求 1所述的如式 I所示的二芳基乙内酰脲衍生物、 其药学上可接受的 盐、 溶剂化物、 代谢产物、 立体异构体、 互变异构体、 多晶型物或其药物前体, 其特征 在于, 所述的 R3、 R5、 R6或 W中所述的 6~10元芳基为苯基; 所述的 R3、 R5、 R6或 W 中所述的 6~10元杂芳基为杂原子为 1个氮原子的 6~10元杂芳基。
18、 如权利要求 17所述的如式 I所示的二芳基乙内酰脲衍生物、 其药学上可接受的 盐、 溶剂化物、 代谢产物、 立体异构体、 互变异构体、 多晶型物或其药物前体, 其特征 在于, 所述的 R3、 R5、 R6或 W中所述的 6~10元杂芳基为吡啶基。
19、 如权利要求 1所述的如式 I所示的二芳基乙内酰脲衍生物、 其药学上可接受的 盐、 溶剂化物、 代谢产物、 立体异构体、 互变异构体、 多晶型物或其药物前体, 其特征 在于, 所述的 R3、 R5或 R6中所述的 d~C4垸基为甲基、 乙基、 丙基或叔丁基。
20、 如权利要求 1所述的如式 I所示的二芳基乙内酰脲衍生物、 其药学上可接受的
盐、 溶剂化物、 代谢产物、 立体异构体、 互变异构体、 多晶型物或其药物前体, 其特征 在于, 所述的 R3、 R5或 R6中所述的 烯基为乙烯基、 丙烯基或烯丙基。
21、 如权利要求 1所述的如式 I所示的二芳基乙内酰脲衍生物、 其药学上可接受的 盐、 溶剂化物、 代谢产物、 立体异构体、 互变异构体、 多晶型物或其药物前体, 其特征 在于, 所述的 R3、 R5或 R6中所述的 C^ 炔基为乙炔基或丙炔基; 所述的 R3、 R5、 R6 或 W中所述的 C3~C6环垸基为环丙垸基、 环丁垸基、 环戊垸基或环己垸基; 所述的 R3、 R5或 R6中所述 3~6元杂环垸基为氮杂环丁基、 吡咯垸基、 哌啶基、 哌嗪基或吗啉基; 所述的 W中 3~6
所述的 W中 垸氧基为甲氧
22、 如权利要求 1所述的如式 I所示的二芳基乙内酰脲衍生物、 其药学上可接受的 盐、 溶剂化物、 代谢产物、 立体异构体、 互变异构体、 多晶型物或其药物前体, 其特征 在于, 所述的如式 I所示的二芳基乙内酰脲衍生物为如式 II、 III、 IV-i、 IV-ii、 V、 VI、 VII、 VIII、 IX、 X或
II
OL
SC6C80/M0ZN3/X3d 9SC8T0/S10Z OAV
/3/: O £ε6ε80Η1£ 9soiAV
SC6C80/M0ZN3/X3d 9SC8T0/S10Z OAV
23、 如权利要求 1所述的如式 I所示的二芳基乙内酰脲衍生物、 其药学上可接受的 盐、 溶剂化物、 代谢产物、 立体异构体、 互变异构体、 多晶型物或其药物前体, 其特征 在于, 所述的如式 I所示的二芳基乙内酰脲衍生物为如式 XII-i、 XII-ii、 ΧΠ-iii, ΧΙΙ-iiii,
XII-iiiii、 XII-iiiiii、 XII-iiiiiii、 XII-iiiiiiii或 XII-iiiiiiiii所示的化合物:
75
ΧΙΙ-iiiiiiiii
其中, 取代基 Rb、 R1, R2和 R3的定义均同权利要求 1~21 中任一项所述, R1Q为卤 素或三氟甲基。
24、 如权利要求 1所述的如式 I所示的二芳基乙内酰脲衍生物、 其药学上可接受的 盐、 溶剂化物、 代谢产物、 立体异构体、 互变异构体、 多晶型物或其药物前体, 其特征 在于, 所述的如式 I所示的二芳基乙内酰脲衍生物为如下所述的任一化合物:
3
SC6C80/M0ZN3/X3d 9SC8T0/S10Z OAV
1-62 1-63
25、 如权利要求 1~24中任一项所述的如式 I所示的二芳基乙内酰脲衍生物的制备方 其特征在于, 其采用下述方法中的任一种:
一: 将化合物 P和化合物 Q进行成环反应, 即可得到化合物 I;
方法二: 将化合物 S与化合物 T进行反应, 即可制得化合物 I;
26、 如权利要求 1~24中任一项所述的如式 I所示的二芳基乙内酰脲衍生物、 其药学 上可接受的盐、 溶剂化物、 代谢产物、 立体异构体、 互变异构体、 多晶型物或其药物前 体在制备治疗雄激素受体相关疾病的药物中的应用。
27、 如权利要求 26所述的应用, 其特征在于, 所述的雄激素受体相关疾病为前列腺 癌、 乳腺癌、 前列腺增生、 多毛症、 粉剌、 秃头、 肌肉衰竭、 性腺功能衰弱、 骨质疏松 症、 胆固醇过高、 男性不育、 男性性功能不良、 贫血肥胖、 性欲望低下和忧郁症中的一 种或多种。
28、 如权利要求 27所述的应用, 其特征在于, 所述的前列腺癌为去势耐受型前列腺 癌。
29、 一种药物组合物, 其特征在于含有治疗有效量的如权利要求 1~24中任一项所述 的如式 I所示的二芳基乙内酰脲衍生物、 其药学上可接受的盐、 溶剂化物、 代谢产物、 立体异构体、 互变异构体、 多晶型物或其药物前体, 以及药学上可接受的一种或多种药 用辅料。
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