WO2014154026A1 - PI3K和/或mTOR抑制剂的前药 - Google Patents
PI3K和/或mTOR抑制剂的前药 Download PDFInfo
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- WO2014154026A1 WO2014154026A1 PCT/CN2014/000343 CN2014000343W WO2014154026A1 WO 2014154026 A1 WO2014154026 A1 WO 2014154026A1 CN 2014000343 W CN2014000343 W CN 2014000343W WO 2014154026 A1 WO2014154026 A1 WO 2014154026A1
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- alkyl
- trifluoromethyl
- hydroxyl
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- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
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- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
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- 238000007918 intramuscular administration Methods 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
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- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- VDBNYAPERZTOOF-UHFFFAOYSA-N isoquinolin-1(2H)-one Chemical compound C1=CC=C2C(=O)NC=CC2=C1 VDBNYAPERZTOOF-UHFFFAOYSA-N 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
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- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000000394 mitotic effect Effects 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
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- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 125000004365 octenyl group Chemical group C(=CCCCCCC)* 0.000 description 1
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- QYZLKGVUSQXAMU-UHFFFAOYSA-N penta-1,4-diene Chemical compound C=CCC=C QYZLKGVUSQXAMU-UHFFFAOYSA-N 0.000 description 1
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- 229950000688 phenothiazine Drugs 0.000 description 1
- 150000003905 phosphatidylinositols Chemical class 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- PMJHHCWVYXUKFD-UHFFFAOYSA-N piperylene Natural products CC=CC=C PMJHHCWVYXUKFD-UHFFFAOYSA-N 0.000 description 1
- 238000007747 plating Methods 0.000 description 1
- 150000003057 platinum Chemical class 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- KCXFHTAICRTXLI-UHFFFAOYSA-N propane-1-sulfonic acid Chemical compound CCCS(O)(=O)=O KCXFHTAICRTXLI-UHFFFAOYSA-N 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
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- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
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- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
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- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
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- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 210000003802 sputum Anatomy 0.000 description 1
- 208000024794 sputum Diseases 0.000 description 1
- 239000008227 sterile water for injection Substances 0.000 description 1
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- 229960001603 tamoxifen Drugs 0.000 description 1
- 229940127072 targeted antineoplastic agent Drugs 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000003507 tetrahydrothiofenyl group Chemical group 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000002053 thietanyl group Chemical group 0.000 description 1
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- 239000001226 triphosphate Substances 0.000 description 1
- 235000011178 triphosphate Nutrition 0.000 description 1
- UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical compound OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 0.000 description 1
- 238000002525 ultrasonication Methods 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
Definitions
- the present invention relates to prodrugs of PI3K and/or mTOR inhibitors, pharmaceutically acceptable salts thereof and stereoisomers thereof, and pharmaceutical compositions comprising these compounds.
- the present invention also relates to a process for the preparation of the above-mentioned prodrug compound and its use in the preparation of a medicament for the treatment and/or prevention of a proliferative disease. Background technique
- a tumor is a new organism formed by the body under the action of various tumorigenic factors, causing changes in cellular genetic material, resulting in abnormal gene expression and abnormal cell proliferation.
- Tumor cells lose normal growth regulation and have the ability to grow autonomously or relatively independently. When the tumorigenic factors stop, they can continue to grow and consume a lot of nutrients. If found and treated in time, cancer cells can also be transferred to all parts of the body to grow and reproduce, and release a variety of toxins, leading to body weight loss, anemia, impaired organ function and even death.
- PI3K phosphatidylinositol 3-kinase pathway
- mTOR mammalian target of rapamycin
- PI3K a member of the lipid kinase family, regulates cellular metabolism and growth by producing phosphoryl phosphatidylinositol triphosphate (PIP3) via phosphorylation of the phosphatidyl alcohol.
- PIP3 phosphoryl phosphatidylinositol triphosphate
- mTOR is a silk/threonine protein kinase present in the cytoplasm and belongs to the phosphoinositide 3 kinase-associated protein kinase family. It exists in the form of two complexes in vivo, namely mTORCl (the action of rapamycin). Target) and mTORC2 (not inhibited by rapamycin).
- mTOR is a cell signal transduction protein that regulates the response of tumor cells to nutrients and growth factors and controls the blood supply to the tumor by acting on vascular endothelial growth factor. mTOR inhibitors can starve cancer cells and shrink tumor size by inhibiting the action of mTOR.
- PI3K and/or mTOR inhibiting compounds are disclosed in International Application No. PCT/CN2013/001061, filed on Sep. 12, 2013, which is incorporated herein by reference.
- the compound is prepared as a prodrug, the prodrug compound has the physical and chemical properties of the original drug, improves the selectivity of the drug to the target site, and improves the pharmacokinetic process of absorption, distribution, transport and metabolism of the drug in the body.
- the development of crystal forms is of great significance.
- the invention relates to:
- a and B are each independently CR 6 , and R 6 is hydrogen, a halogen atom, a cyano group, a hydroxyl group, a carboxyl group, -(CH 2 ) n NR 8a R 8b , -(CH 2 ) n C(0)R 9 , (CH 2 ) n C(0)NR 8a R 8b , -(CH 2 ) n OC(0)R 9 , -(CH 2 ) n C(0)(CH 2 ) n OR 9 , -(CH 2 ) n N(R 8a )C(0)R 9 , or optionally 1-3 C 1-6 alkyl, alkoxy substituted with a halogen atom, a hydroxyl group, a carboxyl group;
- R 1 is hydrogen, or C 1-6 alkyl, C 2-8 alkenyl, C 2-8 block, C 3-8 cycloalkyl, 6-14, optionally substituted by 1-5 R 7a
- R 2 is hydrogen, or C 1-6 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 6-14, optionally substituted by 1 to 5 R 7b
- R 3 is hydrogen, or optionally 1-3 alkyl groups selected from a halogen atom, a hydroxyl group, a carboxyl group;
- R 4 and R 5 are each independently hydrogen, or optionally 1-3 are selected from a halogen atom, a hydroxyl group or a carboxyl group substituted d. 6 alkyl group;
- n 1 ⁇ 3;
- E is hydrogen, or a cation of an inorganic or organic base capable of forming a salt with phosphoric acid
- R 7a and R 7b are each independently
- R 8a and R 8b are each independently hydrogen, or optionally 1 to 3 hydroxyl groups, a halogen atom, a cyano group, a carboxyl group, (this group is defined by R 8a , R 8b , R 8a , R 8b ) ⁇ sulfonyl group , carbamoyl, sulfonylamino substituted alkyl,. . 38 cycloalkyl, 6-14 membered aryl, 5-14 membered heteroaryl, 3-14 membered heterocyclyl;
- R 9 is hydrogen, or optionally 1-3 C 1-6 alkyl group selected from a halogen atom, a cyano group, a hydroxyl group, a carboxyl group, -(CH 2 ) n NR 8a R 8b , a sulfonyl group, a decanoyl group , C 1-6 alkoxy; n is 0 to 4.
- a and B are each independently CR 6 , R 6 is hydrogen, or optionally 1-3 d. 6 alkyl groups selected from a halogen atom, a hydroxyl group, a carboxyl group;
- R 1 is a 6-10 membered aryl group optionally substituted by 1 to 3 R 7a , a 5-6 membered monoheteroaryl group, a 9-10 membered heteroaryl group, a 5-6 membered monoheterocyclic group, 9- 10-membered fused heterocyclic group;
- R 2 is a 6-10 membered aryl group optionally substituted by 1 to 3 R 7b , a 5-6 membered monoheteroaryl group, a 9-10 membered heteroaryl group, a 5-6 membered monoheterocyclic group, 9- 10-membered fused heterocyclic group;
- R 3 is hydrogen
- R 4 and R 5 are each independently hydrogen or d. 6 alkyl
- E is hydrogen, or a metal cation of an inorganic or organic base capable of forming a salt with phosphoric acid
- R 7a and R 7b are each independently
- R 8a and R 8b are each independently hydrogen or d_6 alkyl
- R 9 is hydrogen or an alkyl group
- n 0 ⁇ 2.
- a and B are each independently CR 6 and R 6 is hydrogen or an alkyl group
- R 4 and R 5 are each independently hydrogen
- n 1;
- E is hydrogen or sodium ion.
- R 1 is phenyl optionally substituted by 1-3 R 7a , 5-6 membered monoheteroaryl;
- R 2 is phenyl optionally substituted by 1 to 3 R 7b , 5-6 membered monoheteroaryl, 9-10 membered fused heteroaryl;
- a halogen atom a cyano group, a hydroxyl group, a trifluoromethyl group, -NR 8a R 8b , -C(0)R 9 , -C(0)NR 8a R 8b , -OC(0)R 9 , -N (R 8a )C(0)R 9 ,
- R 8a and R 8b are each independently hydrogen or d_6 alkyl
- R 9 is hydrogen or an alkyl group.
- R 1 is phenyl, pyridinium 5 ⁇ , pyrimidine 1 ⁇ optionally substituted by 3 1 7 <
- R 2 is optionally substituted with 1-3
- R 7b is phenyl, pyridyl, pyrimidinyl, thienyl, pyrazolyl, indazolyl 11 sit yl, indazol noise, pyrazolyl, pyrrolyl and 17 set, and each of the pyrazole-pyrazol P ⁇ J ⁇ , pyridinopyridin>3 ⁇ 4 ⁇ , phenyl group;
- halogen atom a hydroxyl group, a trifluoromethyl group, -NH 2 , -C(0)R 9 , -SR 9 , -S(0) 2 R 9 , -NHC(0)R 9 ,
- pyrrolyl optionally pyrrolyl, pyrazolyl, imidazole selected from 1 to 3 halogen atoms, hydroxy, cyano, trifluoromethyl, C- 4 alkyl, Ci- 4 alkoxy, -NH 2 Base, piperidinyl, piperazinyl, morpholinyl;
- R 9 is hydrogen or d. 4 alkyl.
- R 1 is phenyl, pyridyl 1 ⁇ optionally substituted by 1-3 1 73 ;
- R 2 is phenyl, pyridyl, pyrimidinyl, thienyl, pyrazolyl, oxazolyl, anthranyl, pyridopyrrolyl, pyrrolopyridyl "pyridyl", optionally substituted by 1-3 1 715 Zizolopyryl 3 ⁇ 4 ⁇ , quinolinyl;
- a halogen atom a cyano group, a hydroxyl group, a trifluoromethyl group, -NH 2 , (2) optionally consisting of 1-2 methyl, ethyl, isopropyl groups selected from hydroxy, cyano, trifluoromethyl,
- halogen atom a cyano group, a hydroxyl group, a trifluoromethyl group, -NH 2 , -SR 9 , -S(0) 2 R 9 , -NHC(0)R 9 ,
- R 9 is hydrogen, decyl or ethyl.
- halogen atom as used in the present invention includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
- d- 6 alkyl group as used in the present invention means a straight or branched alkyl group having 1 to 6 carbon atoms, and specific examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, and Butyl, 2-methylpropyl, 1-methylpropyl, 1 ,1-didecylethyl, n-pentyl, 3-methylbutyl, 2-methylbutyl, 1-methylbutyl Base, 1-ethylpropyl, n-hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl,
- C 3-8 cycloalkyl group as used in the present invention means a cyclic alkyl group having 3 to 8 carbon atoms, and specific examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Cycloheptyl, cyclooctyl and the like.
- the "C 2-8 alkenyl group” may be straight-chain or branched, and includes, for example, “C 2 - 6 alkenyl", “C 2 - 4 alkenyl”, “C 2 - 3 alkenyl", “C” 3 _6 cycloalkenyl” and the like, specific examples include, but are not limited to: vinyl, 1-propanyl, 2-propenyl, 1-butenyl, 2-butenyl, 1,3-butadiene, 1 -pentenyl,
- the "C 2-8 alkynyl group” may be linear or branched, and includes, for example, “Cw alkynyl group”, “C 2-4 alkynyl group”, “C 2-3 alkynyl group”, C 3-8 block "", specific examples include but are not limited to: ethynyl, propynyl, 2-butynyl, 2-pentynyl, 3-pentynyl, 4-methyl-2-pentyne , 2-hexynyl, 3-hexynyl, 5-methyl-2-hexynyl, 2-heptynyl, 5-methyl-2-heptynyl, 2-octynyl, 3- Octyl group and the like.
- CM alkoxy group as used in the present invention means "CW alkyl group - 0-", wherein "Cw alkyl group” is as defined above.
- the "6-14 membered aryl group" of the present invention includes a 6 to 8 membered monocyclic aryl group and a 8 to 14 membered fused ring aryl group.
- the 6 to 8 membered monocyclic aryl group includes, for example, a phenyl group, a cyclooctadecenyl group, and the like.
- the 8 ⁇ 14 membered fused ring aryl group includes naphthalene, phenanthrene, 2,3-dihydroindenyl, fluorenyl, 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl, etc. (recommendation: Aryl groups already have a well-known meaning, and it is recommended that such groups be no longer customized to reduce errors and save space and thus reduce costs).
- the "5-14 membered heteroaryl group" of the present invention includes a 5-8 membered monoheteroaryl group, a 6-14 membered fused heteroaryl group, and the hetero atom has nitrogen, oxygen, sulfur, etc., and includes a carbon atom. The case where the nitrogen atom and the sulfur atom are replaced by oxo.
- 5-8 membered monoheteroaryl group include, but are not limited to, a furyl group, a thiop group, a pyrrolyl group, a thiazolyl group, an isothiazolyl group, a thiadiazolyl group, a thiol group, an isoxazolyl group, and an oxox group.
- the "6-14 membered heteroaryl group” include, but are not limited to, benzofuranyl, benzisofuranyl, benzothienyl, fluorenyl, isoindole, benzoxazolyl, benzo Imidazolyl, carbazolyl, benzotriazolyl, quinolinyl, 2-quinolinone, 4-quinolinone, isoquinolinone, isoquinolyl, acridinyl, phenanthryl, benzopyrene Azinyl, pyridazinyl, quinazolinyl, quinoxalinyl, phenolzinyl, acridinyl, fluorenyl, naphthyridinyl, phenazine, phenothiazine, etc., preferably "9-10 yuan thick heteroaryl" base".
- the "5-10 membered heteroaryl group" of the present invention includes a monocyclic heteroaryl group and a fused ring heteroaryl group, and the hetero atom includes nitrogen, oxygen, sulfur, etc., and includes a carbon atom, a nitrogen atom and a sulfur atom. The case of being replaced by oxygen.
- the "3-14 membered heterocyclic group" described in the present invention includes a 3-8 membered monoheterocyclic group and a 6-14 membered fused heterocyclic group.
- the hetero atom includes nitrogen, oxygen, sulfur, and the like, and includes a case where a carbon atom, a nitrogen atom, and a sulfur atom are substituted by oxo.
- 3-8 membered monoheterocyclic group examples include, but are not limited to: aziridine group, 2/7-azetidinyl group, diaziryl group, 3-diazepine Heterocyclic propenyl, azetidinyl, 1,2-diazetanyl, azetidinyl, 1,2-dioxetane,
- the "6-14 membered fused heterocyclic group" of the present invention include, but are not limited to, tetrahydroimidazo[4,5-c]pyridinyl, 3,4-dihydroquinazolinyl, 1, 2-dihydroquinoxalinyl, benzo[[1,3]dioxolyl, 1, 3-dihydroisobenzofuranyl, 2-chromogenyl, 2//-chromogen Alk-2-one, 4-alkenyl, 4//-chromen-4-one, chromanyl, 4 -1 ,3-benzoxazinyl, 4,6-dihydrofuran 3,4- ⁇ ]Imidazolyl, 3 ⁇ ,4,6,6-tetrahydrofuro[3,4-imidazolyl, 4,6-dihydrothieno[3,4-t]imidazolyl, 4,6-di Hydropyrrolo[3,4-imidazolyl, 4,5,6,7-
- the "5-10 membered heterocyclic group" as used in the present invention includes a monoheterocyclic group and a fused heterocyclic group, and the hetero atom includes nitrogen, oxygen, sulfur, and the like, and includes a carbon atom, a nitrogen atom, and a sulfur atom by oxygen. Generation.
- the "7-12-membered bridged ring group" as used in the present invention means a structure in which any two rings share two non-adjacent atoms and contains 7 to 12 carbon atoms or/and hetero atoms, and the hetero atom has Nitrogen, oxygen and sulfur, etc., include, for example, “7-10 yuan bridge ring", “7-9 yuan bridge ring”, “7-8 yuan bridge ring”, “7-8 yuan bridge ring” and the like. Examples thereof include, but are not limited to, for example:
- 7-12 membered spirocyclyl as used in the present invention means a structure having at least two rings sharing one atom and having 7 to 12 carbon atoms or/and hetero atoms, said hetero atom having nitrogen, oxygen and Sulfur, etc., include, for example, “7-10 yuan spiro ring", “7-9 yuan spiro ring”, “7-8 element spiro ring”, “7-8 element spiro ring", and the like. Examples include, but are not limited to, for example:
- the compounds of the present invention can be synthesized by the methods described in the following schemes and/or other techniques known to those of ordinary skill in the art, but are not limited to the following methods.
- the intermediate 2 is dissolved in a suitable solvent (e.g., methanol, ethanol or tetrahydrofuran) which is miscible with water, and an aqueous solution of three equivalents of lithium hydroxide is added dropwise. After the dropwise addition was completed, the reaction was carried out at room temperature for 4 hours. After completion of the reaction, the solvent is removed by rotary evaporation, an appropriate amount of water is added, and the pH is adjusted with hydrochloric acid until the product is completely precipitated, and the intermediate 3 is obtained by suction filtration or recrystallization or column chromatography.
- a suitable solvent e.g., methanol, ethanol or tetrahydrofuran
- the intermediate 3 was suspended in an appropriate amount of thionyl chloride for several hours, and concentrated to remove volatile substances. It is then dispersed in an appropriate amount of tetrahydrofuran to control the temperature at 0. Under C, a mixture of an appropriate amount of triethylamine and a protecting agent-containing amine shield (PG-NH 2 ) was added dropwise. The reaction solution was stirred at room temperature until the reaction was completed by TLC, solvent was evaporated, and Intermediate 4 was obtained by recrystallization or column chromatography.
- PG-NH 2 protecting agent-containing amine shield
- the intermediate 4 was dispersed in an appropriate amount of ethyl chloroformate, and stirred under reflux until the completion of the reaction was confirmed by TLC, and the volatile matter was removed by rotary evaporation, and the intermediate 5 was obtained by recrystallization or column chromatography.
- the raw material 2 and an appropriate amount of an organic or inorganic base, and a palladium reagent and/or a corresponding phosphine ligand are placed in an organic solvent (such as toluene, dioxane, dimethylformamide, ethylene glycol dimethyl ether, etc.) and In a mixed solvent of water, under a nitrogen atmosphere, the reaction was heated to TLC to monitor the consumption of the starting material, and the compound of the formula ( ⁇ ) was isolated by column chromatography.
- an organic solvent such as toluene, dioxane, dimethylformamide, ethylene glycol dimethyl ether, etc.
- the intermediate 8 was dissolved in methanol, and a base was added thereto, and the mixture was stirred for 10 minutes, and the solvent was evaporated to dryness and dried to give the compound of the formula (I).
- RR 2 , R 3 , R 4 , R 5 , A, B, E and m are as defined above, and Hal represents a halogen selected from a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, preferably a chlorine atom.
- the "pharmaceutically acceptable salt" of the compound of the formula (I) of the present invention means an acidic functional group (for example, -COOH, -OH, S0 3 H, etc.) present in the compound of the formula (I) with an appropriate inorganic base or organic A salt formed by a cation of a base, such as an alkali metal salt; and a salt formed by a basic functional group (for example, -NH 2 or the like) present in the compound of the formula (I) with an appropriate inorganic acid or organic acid anion.
- E has been defined above as a cation, not a salt).
- the compound of the formula (I), a pharmaceutically acceptable salt thereof and stereoisomers thereof of the present invention can be administered orally, parenterally (intravenously, intramuscularly, subcutaneously or rectally, etc.), pulmonaryly, locally, etc.
- the method is administered to a mammal, such as a human.
- the daily dose of the compound of the present invention may be from about 5 mg to 500 mg, preferably from 50 to 300 mg.
- the compound of the formula (I), a pharmaceutically acceptable salt thereof and stereoisomers thereof of the present invention may be formulated into a pharmaceutical composition with one or more pharmaceutically acceptable carriers, and may be formulated into any pharmaceutically acceptable dosage form. It is administered orally, parenterally, or the like to a patient in need of such treatment.
- the compound of the formula (I) of the present invention for oral administration, the compound of the formula (I) of the present invention, a pharmaceutically acceptable salt thereof and stereoisomers thereof, and conventional fillers, binders, disintegrators, lubricants and/or Or a diluent or the like to prepare a conventional solid preparation, such as a tablet, a capsule, a pill, a granule, etc.; or an oral liquid preparation, such as a solution of a mouth I, a suspension of a sputum, a syrup, etc. ;
- parenteral administration it can be formulated into injections, including injections, sterile powders for injection and concentrated solutions for injection.
- the compounds of the formula (I), pharmaceutically acceptable salts thereof and stereoisomers thereof of the present invention can be used for the treatment and/or prevention of proliferative diseases, and can be combined with one or more other therapies
- the agent is especially a combination of an antitumor agent and an immunosuppressive agent.
- the anti-tumor agent and immunosuppressive agent are selected from the group consisting of antimetabolites, including but not limited to capecitabine, gemcitabine, pemetrexed disodium; growth factor inhibitors, including but not limited to pazopanib, imatin Nie, erlotinib, lapatinib, gefitinib, vandetanib; antibodies, including but not limited to Herceptin, bevacizumab; mitotic inhibitors, including but not limited to paclitaxel, vinorelbine , docetaxel, doxorubicin; anti-tumor hormones, including but not limited to letrozole, tamoxifen, fulvestrant, flutamide, triptorelin; alkylating agents, including but Not limited to cyclophosphamide, nitrogen mustard, melphalan, cyclamate, carmustine; metal platinum, including but not limited to carboplatin, cisplatin, oxaliplatin; topoisome
- the invention further relates to the use of a compound of formula U), a pharmaceutically acceptable salt thereof, and a stereoisomer thereof, for the manufacture of a medicament for the treatment and/or prevention of a proliferative disease, such as a tumor.
- the proliferative diseases include cancer and non-cancerous proliferative diseases selected from the group consisting of brain tumors, lung cancer, squamous cells, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer.
- cervical cancer endometrial cancer
- rectal cancer liver cancer, kidney cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, solid tumor, prostate cancer, thyroid cancer, carcinoma in situ, lymphoma, neurofibromatosis, bone Cancer, skin cancer, colon cancer, testicular cancer, gastrointestinal stromal tumor, mast cell tumor, multiple myeloma, melanoma, glioma or sarcoma; the non-cancerous proliferative disease is selected from, for example, skin or Benign hyperplasia of the prostate.
- the compounds of the present invention are PI3K and/or mTOR inhibitors, have a good therapeutic effect on proliferative diseases such as (malignant tumors) caused by abnormal expression of PDKa and/or mTOR signaling pathway; and the compounds of the present invention have good solubility,
- the physicochemical properties are stable, which is beneficial to the development of injectable preparations.
- the in vivo pharmacokinetic experiments of injection administration prove that the compound has good pharmacokinetic properties, fast onset, and can be administered by injection, which can effectively solve the problem that critically ill patients cannot be taken orally.
- the problem of drug administration is to expand the clinical application.
- HEPES hydroxyethylpiperazine ethyl sulphate
- EGTA ethylene glycol diethyl ether diamine tetraacetic acid
- PIP2 4,5-diphosphophosphatidylinositol
- ATP adenosine triphosphate
- DMSO dimethyl sulfoxide
- Tween-20 Tween 20.
- Experimental Example 1 In vitro enzymatic inhibitory activity of compounds A and B
- Test compound Compounds A, B prepared from Examples 1 and 3;
- 1.1 1X kinase buffer 50 mM HEPES, pH 7.5, 10 mM MgCl 2 , 1 mM EGTA, 3 mM MnCl 2 , 0.01% Tween-20, 2 mM DTT;
- test solution 100 times of DMSO solution was prepared in 100% DMSO, diluted 25 times with 1 ⁇ kinase buffer to obtain 4 times different concentrations of test substance solution;
- test solution Prepare a test solution containing 2 times the final concentration of EDTA and 4EBP1 phosphorylated antibody.
- the final concentration of EDTA is 8 mM
- the final concentration of 4EBP phosphorylated antibody is 2 nM.
- Inhibition rate % (sample value - minimum value) / (maximum value - minimum value) ⁇ 100
- the “maximum value” is the DMSO control well reading and the “minimum” is the control well reading without the kinase.
- 1.1 1X kinase buffer 50 mM HEPES, pH 7.5, 3 mM MgCl 2 , 1 mM EGTA, 100 mM NaCl, 0.03 % CHAPS, 2 mM DTT;
- test solution 100 times of DMSO solution was prepared in 100% DMSO, diluted 25 times with 1 ⁇ kinase buffer to obtain 4 times different concentrations of test substance solution;
- the “maximum” is the control well reading without kinase, and the “minimum” is the DMSO control well reading.
- Test compound Compound A prepared by the preparation of Example 1;
- A549 human lung cancer packet
- U87MG human brain astrocyte cell line
- PC-3 human prostate cancer cell line
- SKOV-3 human ovarian cancer cell line
- XTT test working solution Weigh 100 mg of methyltetrazolium salt (XTT) powder, dissolve it in 300 mL of phenol red-free serum-free RPMI1640 medium heated to 50 °C, filter, and dispense. Use immediately or within a week, all processes need to be protected from light.
- XTT methyltetrazolium salt
- test compound stock solution Dissolve the compound powder in DMSO at a concentration of 10 mM.
- the cell cryotube was taken out from the liquid nitrogen and placed in a 37 ° C ⁇ 39 ° C water bath for rapid melting. Transfer the cryopreservation solution to a 15 mL sterile centrifuge tube, add 10 times the volume of the cryopreservation solution, and centrifuge at 1000 rpm for 5 min at 4 °C. Discard the medium in the centrifuge tube, force the medium containing 10% FBS, resuspend the cells, transfer to the flask, and change the solution the next day.
- Logarithmic growth phase cells were digested with digestive juice containing 0.25% trypsin and 0.02% EDTA to prepare a cell suspension, which was centrifuged at 1000 rpm for 5 min at 4 °C. The culture solution was discarded, and a cryopreservation solution containing 10% DMSO and 90% FBS was added, and the cells were resuspended, and 2 ⁇ 10 6 cells per tube were dispensed into a cryotube. The cryotubes were placed in a programmed cooling box and placed at -80 °C for 24 h, then transferred to liquid nitrogen for cryopreservation.
- Drug treatment Add the diluted test compound to the cell culture plate for a total of three replicates, 100 final volume per well, 200 initial concentration of 10 ⁇ , 4 fold dilution, a total of 10 concentration gradients; put into C0 2 cells Incubate in an incubator for 72 hours;
- XTT assay for cell viability remove the medium, add XTT assay solution, 150 per well, place in a 37 ° C, 5 % C0 2 cell incubator for 2 hours, and place in the microplate reader to read 450 nm absorbance. ;
- Inhibition rate % (solvent control well reading - test substance well reading) / (solvent control well reading White control well reading) ⁇ 100%;
- Test animals Male SD rats, 3 / route of administration / compound, weighing 230-250 g. testing sample
- the compound of the present invention prepared by the preparation of Example 2, was dissolved in 30% DMF + 70% sterile water for injection.
- the compound 1 of the present invention is converted into the active compound A by a catalytic or non-enzymatic action of an enzyme in a rat to exert a pharmacological action, and the active compound A is referred to as a original drug of the compound of the present invention, so LC-MS/MS monitors and analyzes The blood concentration of Compound A.
- Compound A prepared as in Example 1, was prepared using 30% DMF + 50 °/. PEG400+2 0% (0.9% sodium chloride injection) (with hydrochloric acid water.
- test sample is administered by intravenous bolus injection (iv) at a dose of 2 mg/kg, a concentration of 1 mg/kg, and a dose of 2 mL/kg; the test article is administered by gavage (po), The dose was 4 mg/kg, the concentration was 1 mg/kg, and the dose was 4 mL/kg.
- the sample was subjected to protein precipitation: 20 plasma was added, 200 ⁇ m internal standard (BEZ-235 methanol solution 50 ng/mL) was added, vortexed at 1500 rpm for 3 min, and then centrifuged at 12,000 rpm. Centrifuge for 5 min, take supernatant 50 and add 150 water, vortex and mix.
- 20 ⁇ m internal standard BEZ-235 methanol solution 50 ng/mL
- the blood concentration of the prodrug compound 1 and its prodrug compound A was simultaneously measured by LC-MS/MS.
- the prodrug compound 1 IV was administered at 2 mg/kg for 5 min.
- the average plasma concentration of the prodrug compound 1 of the three animals was about 700 ng/mL, and the average blood concentration of 15 mm was about 50 ng/mL, 30 min and later.
- the blood concentration was not detected at the time point, indicating that the prodrug compound 1 was converted into the original drug compound A within 30 min;
- AUCi as t represents the area under the curve of medicine 0 ⁇ t
- V ss represents the steady-state apparent volume of distribution
- T 1/2 represents half life
- T max represents the peak time of blood medicine
- c max represents peak plasma concentration
- the prodrug compound 1 was administered to rats IV and PO, and all of them were rapidly converted into the original drug compound A in rats. As seen from Tables 3 and 4 above, both Compound 1 and Compound A of the present invention have good pharmacokinetic properties. After administration of Compound 1 in rats, the pharmacokinetic profile of Compound A was monitored similar to the pharmacokinetic characteristics of Compound A monomer administration, such as clearance, AUC, and bioavailability, indicating that Compound 1 is transformed in rats.
- the original drug compound A which exerts pharmacological activity by the compound A, and the compound A is prepared as the prodrug compound 1, does not affect the pharmacological activity of the compound itself, and indicates that the compound of the present invention is caused by abnormal expression of the PDKct and mTOR signaling pathways. For example, tumors have significant Inhibition.
- Example 4 Comparison of dissolution properties of Compound 1 and Compound A of the present invention
- Test article The drug compound A of the compound 1 of the present invention was obtained by the preparation of Example 1.
- Compound 1 of the present invention is prepared by the preparation of Example 2;
- Buffer 0.02 mol/L ammonium dihydrogen phosphate (add 0.2% triethylamine and adjust the pH to 6.0 with phosphoric acid)
- Test compound of the present invention 1 solution is:
- test sample 2 mg put it into a suitable container, add 0.5 mL of pH 6.0 buffer, sonicate for 5 min, filter, and take the filtrate as the test solution.
- test sample 2 mg two parts, put in a suitable container, add the appropriate amount of pH 7.0, pH 9.0 buffer solution, record the volume of each added solvent, shake until completely dissolved, as the test solution.
- test sample 2 mg three parts, add 2 mL of pH 5.0, pH 7.0, pH 9.0 buffer, ultrasonic for 5 min, filter, and take the filtrate as the test solution.
- each reference (C) is plotted on the abscissa and the peak area (Y) is plotted on the ordinate.
- Linear regression is performed to obtain a linear equation.
- the peak area of each test solution was substituted into a linear equation to obtain the solution concentration of the test solution.
- Test product The original drug compound B of the compound 14 of the present invention was obtained by the preparation of Example 3.
- the compound of the present invention 14 was prepared by the preparation of Example 4; the crude drug compound C of the compound 31 of the present invention was obtained by the preparation of Example 5.
- the compound 31 of the present invention is prepared by the method of Example 6; Experimental method: 2 mg of each of the compound 14, the compound B, the compound 31, and the compound C are separately added, and ultrapure water is successively added, each ultrasonication for 5 minutes, until the sample is completely dissolved.
- Compound C has a solubility in water of less than 0.1 mg/mL.
- the solubility of compound 31 in water is > 5 mg/mL;
- the prodrug compound of the present invention has better physicochemical properties, facilitates the preparation of a pharmaceutically acceptable dosage form, and in particular can be formulated as an injection, and can effectively expand the development of clinical dosage forms.
- PE petroleum ether
- HATU 2-(7-azobenzotriazole)- ⁇ , ⁇ , ⁇ ', ⁇ '-tetramethyluron hexafluorotate
- DCM dichloromethane
- Ethyl 4,6-dichloro-1,5-naphthyridine-3-carboxylate (5.4 g, 20 mmol) (for the preparation method, see WO2013/2071698, page 38), m-trifluoromethylaniline (4.5 g, 28 mmol) and potassium carbonate (5.5 g, 40 mmol) were added to 150 mL of tert-butanol and heated to 90 ° C for 18 hours. The reaction solution was cooled to room temperature and then dried. EtOAc (3 mL, EtOAc) Ethyl fluoromethyl)phenyl)amino)-1,5-naphthyridine-3-carboxylate as a yellow solid (6.0 g).
- Ethyl 6-chloro-4-((3-(trifluoromethyl)phenyl)amino)-1,5-naphthyridine-3-carboxylate (3.95 g, 10 mmol) was dissolved in 50 mL methanol and 50 mL A solution of lithium hydroxide (1.26 g, 30 mmol) in water (50 mL) was added dropwise in tetrahydrofuran. After the completion of the dropwise addition, the reaction was carried out at room temperature for 4 hours. The reaction mixture was concentrated, water (200 mL) was added, and the mixture was adjusted to pH 3 with hydrochloric acid, and the obtained solid was filtered, and then evaporated to dryness to give a white solid (3.6 g:).
- 6-Chloro-4-((3-(trifluoromethyl)phenyl)amino)-1,5-naphthyridin-3-carboxylic acid (3.6 g, 9.8 mmol) was suspended in 50 mL of thionyl chloride Stir and heat to 75 ° (maintaining the reaction for 4 hours. Cool to room temperature and concentrate to give a yellow solid. Dissolve in 100 mL of tetrahydrofuran, and add triethylamine (3.03 g, 30 mmol) at 0 °C and A mixture of p-methoxybenzylamine (1.6 g, 13 mmol). The reaction mixture was stirred at room temperature for 4 hr, then evaporated and evaporated.
- Ethyl 6-chloro-4-((4-(2-cyanopropan-2-yl)phenyl)amino)-1,5-naphthyridin-3-carboxylate (6.9 g, 17.5 mmol)
- 50 mL of an aqueous solution of lithium hydroxide (2.2 g, 52.4 mmol) was added dropwise at room temperature. After the dropwise addition was completed, the reaction was carried out for 4 hours at room temperature.
- the reaction solution was concentrated, water (200 mL) was added, and the mixture was adjusted to pH 2-3 with hydrochloric acid.
- Ethyl chloroantimonate (1.36 g, 12.5 mmol) was slowly added dropwise to the reaction solution under a water bath, and after the completion of the dropwise addition, the mixture was heated to 60 ° C for 16 hours. After cooling to room temperature, the mixture was poured into EtOAc EtOAc (EtOAc). 0 ⁇ 1/5), gave a pale yellow solid (1.2 g).
Abstract
提供一种通式(I)所示的化合物、其药学上可接受的盐和立体异构体,以及含有通式(I)化合物的药物组合物。还提供这些化合物、其药学上可接受的盐和立体异构体在制备治疗和/或预防增殖性疾病的药物中的用途。
Description
PI3K和 /或 mTOR抑制剂的前药 技术领域
本发明涉及 PI3K和 /或 mTOR抑制剂的前药、 其药学上可接受的盐 和它们的立体异构体、 以及包含这些化合物的药物组合物。 本发明还 涉及上述前药化合物的制备方法及其在制备治疗和 /或预防增殖性疾病的 药物中的应用。 背景技术
肿瘤是机体在各种致瘤因子作用下, 引起细胞遗传物质改变, 导 致基因表达失常, 细胞异常增殖而形成的新生物。 肿瘤细胞失去正常 生长调节功能, 具有自主或相对自主生长能力, 当致瘤因子停止后仍 能继续生长, 大量消耗人体的营养物质。 如果发现和治疗不及时, 癌 细胞还可转移到全身各处生长繁殖, 并释放出多种毒素, 导致人体消 瘦、 贫血、 脏器功能受损乃至死亡。
***的方法主要包含三个方面: 药物治疗、 手术治疗和放射 治疗。 由于手术治疗、 放射治疗难以彻底才艮除肿瘤, 而且对中晚期肿 瘤病人作用不明显, 因此药物治疗在肿瘤治疗中的地位越来越明显。 传统抗肿瘤药物无法区分肿瘤细胞和正常组织细胞, 常导致严重的副 作用, 靶向药物以癌细胞作为特异性靶点, 能准确的作用于肿瘤, 极 大的提高了治疗水平, 并降低了不良反应率, 例如使晚期大肠癌的中 位生存时间增加 66.7%, 晚期乳腺癌的治疗有效率提高 71.3%。
由于各制药公司对靶向类抗肿瘤药的研制加速, 再加上市场对这 一类别的抗肿瘤药需求强劲, 分子靶向药物已经成为了全球抗肿瘤药 物市场中增长最快的单元。 磷脂酰肌醇 3激酶(PI3K )通路是人体癌细 胞中最常发生变异的地方, 可导致细胞增殖, 活化, 放大信号。 PI3K 和哺乳动物雷帕霉素靶蛋白 (mTOR )是 PI3K信号通路的重要激酶。
PI3K是脂激酶家族成员, 可通过磷脂酰醇的 3位磷酸化产生磷脂酰 肌醇三磷酸脂(PIP3 )来调节细胞代谢和生长。 该脂类的第二信使 PIP3 可以使 P13K与下游的效应物(特别是 Akt) 己对结合, 从而导致膜募集和 磷酸化, 细胞增殖, 活化。 因此抑制 PI3K激酶, 可以影响 PI3K通路, 从而抑制癌细胞增殖, 活化。
mTOR是存在于胞浆中的一种丝 /苏氨酸蛋白激酶,属于磷酸肌醇 3激酶相关蛋白激酶家族, 在生物体内以两种复合物的形式存在, 即 mTORCl (雷帕霉素的作用靶点) 和 mTORC2 (不被雷帕霉素抑制)。 mTOR是一种细胞信号转导蛋白,它调节肿瘤细胞对养分和生长因子的 反应, 并通过对血管内皮生长因子的作用控制肿瘤的血液供给。 mTOR 抑制剂会使癌细胞饥饿, 并且通过抑制 mTOR的作用使肿瘤体积缩小。
诺华公司的专利申请 WO2006122806和辉瑞公司的专利申请 WO201003816中, 报道了对 PI3K和 mTOR均有抑制作用的系列化合物, 这些化合物具有良好的肿瘤治疗活性。 Jo urnal of Medicinal Chemistry (2011), 54(5), 1473-1480 , "Discovery of 9-(6-Aminopyridin- 3-yl)-l -(3-(trifluoromethyl)phenyl)benzo[h][l ,6]naphthyridin-2(l H)-one (Torin2) as a potent, selective, and orally available mammalian target of rapamycin (mTOR) inhibitor for treatment of cancer. 公开了名为 Torin2 的化合物, 并报道了对其体内药代动力学的研究结果。
但是此类化合物大都存在水溶性差的缺点, 导致向患者输送药物 困难。 因为化合物的低水溶性, 不利于制剂的形成, 必须配置助溶剂 如表面活性剂等。 再者, 较差的水溶性会使这些化合物在制剂存储和 / 或运输过程可能从溶剂中结晶析出, 从而导致药物临床应用的安全性 存在隐患。
综上所述, 寻找对于 PI3K和 /或 mTOR具有抑制作用, 且活性好、 选择性高并且能解决此类化合物的溶解性低的问题, 有效克服制成口 服、 静脉注射、 肌肉注射等各种制剂的困难, 并扩大临床应用的化合 物, 已成为当前抗肿瘤药物研究的热点。 发明内容
申请日为 2013年 9月 12 日的国际申请 PCT/CN2013/001061 中公 开了 PI3K和 /或 mTOR抑制化合物, 该类化合物活性好、 选择性高, 本发明将 PCT/CN2013/001061 中记载的式(I )化合物制备成前药, 该 前药化合物具有改善原药的物理化学性质, 提高药物对靶部位作用的 选择性, 改善药物在体内的吸收、 分布、 转运与代谢等药代动力学过 程, 对于制剂的开发, 晶型的开发具有重要意义。
因此, 本发明的目的是提供一类 PI3K和 /或 mTOR抑制剂的前药,
具体地, 本发明涉及:
( 1 )通式 (I ) 所示的化合物、 及其药学上可接受的盐以及它们 的立体异构体:
A和 B分别独立地为 CR6, R6为氢、 卤素原子、 氰基、 羟基、 羧基、 -(CH2)nNR8aR8b、 -(CH2)nC(0)R9、 -(CH2)nC(0)NR8aR8b、 -(CH2)nOC(0)R9、 -(CH2)nC(0)(CH2)nOR9、 -(CH2)nN(R8a)C(0)R9,或任选被 1-3个选自卤素原 子、 羟基、 羧基取代的 C1-6烷基、 烷氧基;
R1为氢, 或任选被 1-5个 R7a取代的 C1-6烷基、 C2-8烯基、 C2-8块基、 C3-8环烷基、 6-14元芳基、 5-14元杂芳基、 3-14元杂环基、 7-12元螺环基、 7-12元桥环基;
R2为氢, 或任选被 1-5个 R7b取代的 C1-6烷基、 C2-8烯基、 C2-8炔基、 C3-8环烷基、 6-14元芳基、 5-14元杂芳基、 3-14元杂环基、 7-12元螺环基、 7-12元桥环基;
R3为氢,或任选被 1-3个选自卤素原子、羟基、羧基取代的 烷基; R4、 R5分别独立地为氢, 或任选被 1-3个选自卤素原子、 羟基、 羧基 取代的 d.6烷基;
m为 1~3;
E为氢, 或为能与磷酸形成盐的无机碱或有机碱的阳离子;
R7a、 R7b分别独立地为
( 1 )卤素原子、氰基、羟基、三氟甲基、 -(CH2)nNR8aR8b、-(CH2)nC(0)R9、 -(C¾)nSR9、 -(CH2)nS(0)2R9、 -(CH2)nS(0)眞 8aR8b、 -(CH2)nN(R8a)S(0)2R9、 -(CH2)nC(0)NR8aR8b 、 -(CH2)nOC(0)R9 、 -(CH2)nC(0)(CH2)nOR9 、 -(CH2)nN(R8a)C(0)R9,
( 2 )任选被 1-3个选自卤素原子、 羟基、 氰基、 三氟曱基取代的 d_6 烷基、 C2-8烯基、 C2-8炔基、 烷氧基;
( 3 )任选被 1-3个选自卤素原子、 羟基、 、 三氟甲基、 C 烷基、 C2-8烯基、 C2-8炔基、 d-6烷氧基、 -(CH2)nNR8aR8b、 -(CH2)nC(0)R9、
-(CH2)nSR9、 -(CH2)nS(0)2Ry、 -(CH2)nS(0)2NR8aR8b, -(CH2)nN(R8a)S(0)2Rv, -(CH2)nC(0)N 8aR8b 、 -(CH2)nOC(0)R9 、 -(CH2)nC(0)(CH2)nOR9 、 -(CH2)nN(R8a)C(0)R9取代的 C3-8环烷基、 6-14元芳基、 5-14元杂芳基、 3-14 元杂环基;
R8a、 R8b分别独立地为氢, 或任选被 1-3个羟基、 卤素原子、 氰基、 羧基、 (此基团是用 R8a、 R8b定义 R8a、 R8b ) ^磺酰基、 氨基甲酰基、 磺酰胺基取代的 烷基、。3.8环烷基、 6-14元芳基、 5-14元杂芳基、 3-14 元杂环基;
R9为氢, 或任选被 1-3 个选自卤素原子、 氰基、 羟基、 羧基、 -(CH2)nNR8aR8b、 磺酰基、 ^曱酰基取代的 C1-6烷基、 C1-6烷氧基; n为 0~4。
( 2 ) 上述(1 ) 所述的通式(I ) 所示的化合物、 及其药学上可 接受的盐以及它们的立体异构体, 其中:
A和 B分别独立地为 CR6, R6为氢, 或任选被 1-3个选自卤素原子、 羟基、 羧基取代的 d.6烷基;
R1为任选被 1-3个 R7a取代的 6-10元芳基、 5-6元单杂芳基、 9-10元 稠杂芳基、 5-6元单杂环基、 9-10元稠杂环基;
R2为任选被 1-3个 R7b取代的 6-10元芳基、 5-6元单杂芳基、 9-10元 稠杂芳基、 5-6元单杂环基、 9-10元稠杂环基;
R3为氢;
R4、 R5分别独立地为氢或 d.6烷基;
m为 〜 3;
E为氢, 或为能与磷酸形成盐的无机碱或有机碱的金属阳离子;
R7a、 R7b分别独立地为
( 1 ^素原子、氰基、羟基、三氟曱基、 -(CH2)nNR8aR8b、-(CH2)nC(0)R9、 -(CH2)nSR9、 -(CH2)nS(0)2R9、 -(CH2)nS(0)2NR8aR8b、 -(CH2)nN(R8a)S(0)2R9、 -(CH2)nC(0)NR8aR8b 、 -(CH2)nOC(0)R9 、 -(CH2)nC(0)(CH2)nOR9 、 -(CH2)nN(R8a)C(0)R9,
( 2 )任选被 1-3个选自卤素原子、 羟基、 氰基、 三氟甲基取代的 C1-6 烷基、 烷氧基;
( 3 )任选被 1-3个选自卤素原子、 羟基、氰基、 三氟甲基、 烷基、 烷氧基、 -(CH2)nNR8aR8\ -(CH2)nC(0)R9、 -(CH2)nSR9、 -(CH2)nS(0)2R9、
-(CH2)nS(0)2NR8aR8b 、 -(CH2)nN(R8a)S(0)2Ry 、 -(CH2)nC(0)NR8aR8b 、 -(CH2)nOC(0)R9、 -(CH2)nC(0)(CH2)nOR9、 -(CH2)nN(R8a)C(0)R9取代的 C3.8 环烷基、 5-10元杂芳基、 5-10元杂环基;
R8a、 R8b分别独立地为氢或 d_6烷基;
R9为氢或 烷基;
n为 0~2。
(3)上述(2)所述的通式(I) 所示的化合物、 及其药学上可接 受的盐以及它们的立体异构体, 其中:
A和 B分别独立地为 CR6, R6为氢或 烷基;
R4、 R5分别独立地为氢;
m为 1;
E为氢或钠离子。
(4)上述(3) 所述的通式(I) 所示的化合物、 及其药学上可接 受的盐以及它们的立体异构体, 其中:
R1为任选被 1-3个 R7a取代的苯基、 5-6元单杂芳基;
R2为任选被 1-3个 R7b取代的苯基、 5-6元单杂芳基、 9-10元稠杂芳 基;
( 1 ) 卤素原子、 氰基、 羟基、 三氟甲基、 -NR8aR8b、 -C(0)R9、 -C(0)NR8aR8b、 -OC(0)R9、 -N(R8a)C(0)R9,
(2)任选被 1-3个选自卤素原子、 羟基、 氰基、 三氟曱基取代的 C1-6 烷基、 C1-6烷氧基,
(3)任选被 1-3个选自卤素原子、 羟基、氰基、三氟甲基、 烷基、 C_6烷氧基、 -NR8aR8b、 -C(0)R9、 -C(0)NR8aR8b、 -OC(0)R9、 -N(R8a)C(0)R9 取代的 5-6元单杂环基;
(1) 鹵素原子、 氰基、 羟基、 三氟甲基、 -NR8aR8b、 -C(0)R9、 -SR9、 -S(0)2R9、 -C(0)NR8aR8b、 -OC(0)R9、 -N(R8a)C(0)R9,
(2)任选被 1-3个选自卤素原子、 羟基、 氰基、 三氟甲基取代的(^6 烷基、 C 烷氧基;
(3)任选被 1-3个选自卤素原子、 羟基、 、 三氟曱基、 烷基、 C 烷氧基、 -NR8aR8b、 -C(0)R9、 -C(0)N 8aR8b、 -OC(0)R9、 -N(R8a)C(0)R9
取代的 5-6元单杂芳基、 5-6元单杂环基;
R8a、 R8b分别独立地为氢或 d_6烷基;
R9为氢或 烷基。
(5)上述(4) 中所述的通式(I) 所示的化合物、 及其药学上可 接受的盐以及它们的立体异构体, 其中:
R1为任选被 3个 17&取代的苯基、 吡5^、 嘧1^;
R2为任选被 1-3个 R7b取代的苯基、 吡啶基、 嘧啶基、 噻吩基、 吡唑 基、 吲11坐基、 吲噪基、 吡17定并吡咯基、 吡各并吡 P^J^、 吡唾并吡 >¾ ~、 啉基;
R7a为
( 1 ) 卤素原子、 氰基、 羟基、 三氟曱基、 -NH2,
(2)任选被 1-3个选自卤素原子、 羟基、 氰基、 三氟甲基取代的 CM 烷基,
(3)任选被 1-3个选自卤素原子、 羟基、氰基、 三氟甲基、 C1-4烷基、 C 4烷氧基取代的哌啶基、 哌嗪基;
R7b为
( 1 )卤素原子、 、羟基、三氟甲基、 -NH2、 -C(0)R9、 -SR9、 -S(0)2R9、 -NHC(0)R9,
(2)任选被 1-3个选自卤素原子、 羟基、 氰基、 三氟甲基取代的 CM 坑^^、 C>4坑 ί^ί^;
(3)任选被 1-3个选自卤素原子、 羟基、氰基、 三氟甲基、 C-4烷基、 Ci_4烷氧基、 -NH2取代的吡咯基、 吡唑基、 咪唑基、 哌啶基、 哌嗪基、 吗 啉基;
R9为氢或 d.4烷基。
(6)上述(5) 所述的通式(I) 所示的化合物、 及其药学上可接 受的盐以及它们的立体异构体, 其中:
R1为任选被 1-3个 173取代的苯基、 吡1^;
R2为任选被 1-3个 1715取代的苯基、 吡啶基、 嘧啶基、 噻吩基、 吡唑 基、 吲唑基、 吲味基、 吡 并吡咯基、 吡咯并吡"定基、 吡唑并吡¾^、 喹 啉基;
( 1 ) 卤素原子、 氰基、 羟基、 三氟曱基、 -NH2,
(2)任选被 1-2个选自羟基、 氰基、 三氟甲基取代的甲基、 乙基、 异丙基,
(3)任选被 1-2个选自羟基、 氰基、 三氟曱基、 甲基、 曱氧基取代 的哌啶基、 哌。秦基;
R7b为
( 1) 鹵素原子、 氰基、 羟基、 三氟甲基、 -NH2、 -SR9、 -S(0)2R9、 -NHC(0)R9,
(2)任选被 1-2个选自羟基、 氰基、 三氟甲基取代的曱基、 乙基、 正丙基、 异丙基、 甲氧基、 乙氧基;
(3)任选被 1-2个选自羟基、 氰基、 三氟甲基、 甲基、 乙基、 甲氧 乙氧基、 _NH2取代的吡咯基、 吡唑基、 哌嗪基、 吗啉基;
R9为氢、 曱基或乙基。
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本发明所述的 "卤素原子"包括氟原子、 氯原子、 溴原子和碘原子。
本发明所述的 "d_6烷基"指含有 1-6个碳原子的直链或支链烷基, 具 体实例包括但不限于: 甲基、 乙基、 正丙基、 异丙基、 正丁基、 2-甲基丙 基、 1-甲基丙基、 1 ,1-二曱基乙基、 正戊基、 3-甲基丁基、 2-甲基丁基、 1- 甲基丁基、 1-乙基丙基、 正己基、 4-甲基戊基、 3-甲基戊基、 2-甲基戊基、
1-曱基戊基、 3,3-二甲基丁基、 2,2-二曱基丁基、 1,1-二甲基丁基、 1,2-二甲 基丁基、 1,3-二甲基丁基、 2,3-二甲基丁基、 2-乙基丁基、 1,2-二甲基丙基等。
本发明所述的 "C3-8环烷基"指含有 3-8个碳原子的环状烷基, 具体实 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。
本发明所述的 "C2-8烯基"可以为直链或支链, 包括例如" C2_6烯基"、 "C2_4烯基"、 "C2-3烯基"、 "C3_6环烯基"等, 具体实例包括但不限于: 乙烯 基、 1-丙婦基、 2-丙烯基、 1-丁烯基、 2-丁烯基、 1,3-丁二烯、 1-戊烯基、
2-戊烯基、 3-戊烯基、 1 ,3-戊二烯、 1,4-戊二烯、 1-己烯基、 2-己烯基、 3- 己烯基、 1,4-己二烯、 环戊烯基、 1 ,3-环戊二烯基、 环己烯基、 1 ,4-环己二 烯基、 环庚烯基、 1 ,4-环庚二烯基、 环辛烯基、 1,5-环辛二烯基等。 (似乎 应该是双键两边的基团为顺式和反式, 这种说明似乎优点多余)
本发明所述的 "C2-8炔基" 可以为直链或支链状, 其中包括例如 "Cw 炔基"、 "C2-4炔基"、 "C2-3炔基"、 "C3-8块基"等, 具体实例包括但不限于: 乙炔基、 丙炔基、 2-丁炔基、 2-戊炔基、 3-戊炔基、 4-甲基 -2-戊炔基、 2- 己炔基、 3-己炔基、 5-甲基 -2-己炔基、 2-庚炔基、 5-甲基 -2-庚炔基、 2-辛 炔基、 3-辛炔基等。
本发明所述的 "CM烷氧基 "是指 "CW烷基 -0-", 其中 "Cw烷基"的定义 如前文所述。
本发明所述的 "6-14元芳基 "包括 6 ~ 8元单环芳基和 8 ~ 14元稠环 芳基。 6 ~ 8 元单环芳基包括例如苯基、 环辛四烯基等。 8 ~ 14 元稠环 芳基包括萘、 菲、 2,3-二氢 茚基、 茚基、 1 ,2,3,4-四氢萘基、 1 ,4- 二氢萘基等 (建议: 芳基已经具有公知的含义, 对于这样的基团建议尽 量不要再自定义, 以减少出错并节约篇幅从而降低成本)。
本发明所述的 "5-14元杂芳基"包括 5-8元单杂芳基、 6-14元稠杂芳基, 所述的杂原子有氮、 氧和硫等, 同时包括碳原子、 氮原子和硫原子被氧代 的情况。
"5-8元单杂芳基" 的具体实例包括但不仅限于呋喃基、 噻 p分基、 吡 咯基、 噻唑基、 异噻唑基、 噻二唑基、 噁峻基、 异噁唑基、 噁二唑基、 咪
唑基、 吡唑基、 1 ,2,3-***基、 1,2,4-***基、 1,2,3-噁二峻基、 1,2,4-噁二 唑基、 1 ,2,5-噁二唑基、 1,3,4-噁二唑基、 吡啶基、 2-吡啶酮、 4-吡啶酮、 嘧1^、 1,4-二氧杂环己二烯基、 2 -1,2-噁嗪基、 4/ -1 ,2-噁 基、 6/ - 1 ,2- 噁嗪基、 4/ -1,3-噁嗪基、 6/ -1,3-噁嗪基、 4 /-1,4-噁嗪基、 哒嗪基、 吡嗪 基、 1,2,3-三嗪基、 1,2,4-三嗪基、 1,3,5-三嗪基、 1,3,4-三嗪基、 1,2,4,5-四 嗪基、 氧杂环庚三烯基、 疏杂环庚三浠基、 氮杂环庚三烯基、 1,3-二氮杂 环庚三烯基、 氮杂环辛四烯基、 1 ,4-二氢 -1 ,4-二氮杂环辛三烯、 1,4-二氧杂 环辛三烯等, 优选为 "5-6元单杂芳基"。
"6-14元稠杂芳基" 的具体实例包括但不限于: 苯并呋喃基、 苯并异 呋喃基、 苯并噻吩基、 吲哚基、 异吲哚、 苯并噁唑基、 苯并咪唑基、 吲唑 基、 苯并***基、 喹啉基、 2-喹啉酮、 4-喹啉酮、 异喹啉酮、 异喹啉基、 吖啶基、 菲啶基、 苯并哒嗪基、 酞嗪基、 喹唑啉基、 喹喔啉基、 酚嗪基、 喋啶基、 嘌呤基、 萘啶基、 吩嗪、 吩噻嗪等, 优选为 "9-10元稠杂芳基"。
本发明所述的 "5-10元杂芳基"包括单环杂芳基和稠环杂芳基,所述的 杂原子有氮、氧和硫等, 同时包括碳原子、氮原子和硫原子被氧代的情况。
本发明所述的 "3-14元杂环基"包括 3-8元单杂环基, 6-14元稠杂环 基。 所述的杂原子有氮、 氧和硫等, 同时包括碳原子、 氮原子和硫原子被 氧代的情况。
本发明所述的 "3-8 元单杂环基"的具体实例包括但不仅限于: 氮杂环 丙烷基、 2/7-氮杂环丙烷基、 二氮杂环丙烷基、 3 -二氮杂环丙烯基、 氮杂 环丁烷基、 1,2-二氮杂环丁烷基、 氮杂环丁二烯基、 1,2-二氧杂环丁坑基、
1.2-二氮杂环丁烯基、 二氧杂环丙烷基、 氧杂环丁烷基、 氧氮杂环丙烷基、 1,4-二氧杂环己烷基、 1,3-二氧杂环己烷基、硫杂环丙烷基、硫杂环丁烷基、
1.3-二硫杂环己烷基、 1,2-二硫杂环丁烯基、 1,3-二氧杂环戊烷基、 1,3-二硫 杂环戊烷基、 1,4-二氧杂环己二烯基、 1,4-二硫杂环己二烯基、 1,4-氧硫杂 环己二烯基、 四氢呋喃基、 二氢吡咯基、 p比咯烷基、 咪唑烷基、 4,5-二氢 咪唑基、 吡唑烷基、 4,5-二氢吡唑基、 2,5-二氢 吩基、 四氢噻吩基、 4,5- 二氢噻唑基、 哌啶基、 哌嗪基、 吗啉基基、 4,5-二氢噁唑基、 4,5-二氢异噁 唑基、 2,3-二氢异噁唑基、 2 -1,2-噁嗪基、 4/ -1,2-噁嗪基、 6/ -1,2-噁嗪基、 2 -1,3-噁嗪基、 4 -1,3-噁嗪基、 5,6-二氢 -4/7-1,3-噁嗪基、 6 -1,3-噁嗪基、 2 /-1,4-噁嗪基、 4 -1 ,4-噁嗪基、 2//-1,3-噻嗪基、 4/ -1,3-噻嗪基、 5,6-二氢 -4/ -1,3-噻嗪基、 6 -1,3-噻嗪基、 2 -1,4-噻嗪基、 4 -1,4-噻嗪基、 2 /-吡喃
基、 2 -吡喃 -2-酮基、 3,4-二氢 -2 -吡喃基、 4 /-吡喃基、 四氢吡喃基、 H- 吡喃 -4-酮基等, 优选为 "5-6元单杂环基"。
本发明所述的 "6-14元稠杂环基"的具体实例包括但不仅限于:四氢咪 唑并 [4,5-c]吡啶基、 3,4-二氢喹唑啉基、 1,2-二氢喹喔啉基、 苯并 [ [1,3] 二氧杂环戊烯基、 1 ,3-二氢异苯并呋喃基、 2 -色原烯基、 2//-色原烯 -2- 酮基、 4 -色烯基、 4//-色烯 -4-酮基、 色满基、 4 -1 ,3-苯并噁嗪基、 4,6- 二氢 呋喃并 [3,4-ί ]咪唑基、 3α,4,6,6 -四氢 呋喃并 [3,4- 咪唑基、 4,6-二氢 噻吩并 [3,4-t ]咪唑基、 4,6-二氢 吡咯并 [3,4- 咪唑基、 4,5,6,7-四氢 苯并 [i/j咪唑基等, 优选为 "9-10元稠杂环基"。
本发明所述的 "5-10元杂环基"包括单杂环基和稠杂环基,所述的杂原 子有氮、 氧和硫等, 同时包括碳原子、 氮原子和硫原子被氧代的情况。
本发明所述的 "7-12 元桥环基"是指任意两个环共用两不相邻的原子 形成的含有 7-12个碳原子或 /和杂原子的结构, 所述的杂原子有氮、 氧和 硫等, 包括例如" 7-10元桥环"、 "7-9元桥环"、 "7-8元桥环"、 "7-8元桥环" 等。 其实例包括但不限于例如:
Φ、 Θ、 、 、 ¾ gr、 、 、
本发明的术语 "7-12 元螺环基"是指至少有两个环共享一个原子形成 的含有 7-12个碳原子或 /和杂原子的结构,所述的杂原子有氮、氧和硫等, 包括例如" 7-10元螺环"、 "7-9元螺环"、 "7-8元螺环"、 "7-8元螺环 "等。 其实例包括但不仅限于例如:
本发明的化合物可以釆用下述流程中描述的方法和 /或本领域普通 技术人员已知的其它技术来合成, 但不仅限于以下方法。
反应步骤:
(1) 中间体 2的制备
将中间体 1 (其制备方法参见 WO2013/2071698说明书第 38页)、 1.5 倍当量的 R1 - NH2和适量的碳酸钾溶于叔丁醇中, 加热反应。 用 TLC监 测确定反应完毕后, 自然冷却, 旋蒸除去溶剂, 通过硅胶柱层析分离或重 结晶得中间体 2。
(2) 中间体 3的制备
将中间体 2溶于能与水互溶的适当溶剂 (例如甲醇、 乙醇或四氢呋喃) 中, 滴加 3倍当量的氢氧化锂的水溶液。 滴加完毕后, 在室温下反应 4小 时。 反应结束后, 旋蒸除去溶剂, 加适量水, 用盐酸调节 pH值至产品完 全析出 , 通过抽滤或重结晶或柱层析纯化得中间体 3。
(3) 中间体 4的制备
将中间体 3 悬浮于适量氯化亚砜中反应数小时, 浓缩除去挥发性物 质。 然后将其分散于适量四氢呋喃中, 控制温度在 0 。C下, 滴加适量的三 乙胺和连有保护基的胺类物盾 (PG-NH2)的混合物。将反应液在室温下搅拌 至通过 TLC监测反应完毕, 旋蒸除去溶剂, 通过重结晶或柱层析获得中 间体 4。
(4) 中间体 5的制备
将中间体 4分散于适量氯甲酸乙酯中, 搅拌回流, 至通过 TLC监测 确定反应完毕, 旋蒸除去挥发性物质, 通过重结晶或柱层析得中间体 5。
(5) 中间体 6的制备根据保护基 PG的不同,选择相应的反应条件脱 去氨基保护基, 得中间体 6。
(6) 式(Γ )化合物的制备
将原料 2和适量的有机或无机碱, 及钯试剂和 /或相应膦配体置于有 机溶剂(如曱苯, 二氧六环, 二甲基曱酰胺, 乙二醇二甲醚等)和水的混合 溶剂中, 在氮气保护下, 加热反应至 TLC监测原料消耗完毕, 通过柱层 析分离得式(Γ )化合物。
(7) 中间体 7的制备
将式(Γ )化合物 和 1.5当量的原料 3溶于二曱亚砜中, 依次加入碳 酸钾和碘化钠, 搅拌并加热至约 50°C反应 16小时后, 冷却至室温, 然后 将反应液倾入水中, 过滤, 干燥得中间体 7。
(8) 中间体 8的制备
将中间体 7溶于二氯甲烷中, 加入三氟乙酸, 室温搅拌反应 3小时,
浓缩, 分离干燥得中间体 8。
(9) 式 (I )化合物的制备
将中间体 8溶于甲醇中, 加入碱, 搅拌反应 10分钟, 旋蒸除去溶剂 并干燥得式(I )化合物。
反应方程式中, R R2、 R3、 R4、 R5、 A、 B、 E和 m如前文所定义, Hal代表鹵素, 选自氟原子、 氯原子、 溴原子、 碘原子, 优选氯原子。
本发明式(I )化合物的"药学上可接受的盐", 是指式(I )化合物 中存在的酸性官能团 (例如, -COOH, -OH, S03H等) 与适当的无机 碱或者有机碱的阳离子形成的盐, 例如碱金属盐; 以及式 (I )化合物 中存在的碱性官能团 (例如, -NH2等) 与适当的无机酸或者有机酸阴 离子形成的盐。 (前文中已有定义 E为阳离子, 而不是盐)。
本发明式(I )化合物的"立体异构体", 是指当式(I )化合物存在 不对称碳原子、 碳碳双键等时, 所产生的所有立体异构体, 包括对映 异构体、 非对映异构体、 消旋异构体、 顺反异构体、 互变异构体、 几 何异构体、 差向异构体及其混合物, 均包括在本发明范围中。
本发明通式 (I )化合物、 其药学上可接受的盐以及它们的立体异 构体, 可以经口服、 肠胃外(静脉内、 肌肉内、 皮下或直肠等)、 经肺、 局部等给药方式施用于哺乳动物, 例如人。 本发明化合物的日剂量可 以为大约 5mg〜500mg, 优选 50~300mg。
本发明式 (I )化合物、 其药学上可接受的盐以及它们的立体异构 体, 可以与一种或多种药用载体制成药物组合物, 可以制成药学上可 接受的任一剂型, 以口服、 肠胃外给药等方式施用于需要这种治疗的 患者。
用于口服给药时, 可将本发明式 (I )化合物、 其药学上可接受的 盐以及它们的立体异构体, 与常规的填充剂、 粘合剂、 崩解剂、 润滑 剂和 /或稀释剂等混合制成常规的固体制剂, 如片剂、 胶嚢剂、 丸剂、 颗粒剂等; 也可制成口服液体制剂, 如口 I 溶液剂、 口 Λ良混悬剂、 糖 浆剂等;
用于肠胃外给药时, 可配制成注射剂, 包括注射液、 注射用无菌 粉末与注射用浓溶液。
本发明式 (I )化合物、 其药学上可接受的盐以及它们的立体异构 体能够用于治疗和 /或预防增殖性疾病, 并可以与一种或多种其他治疗
剂特别是抗肿瘤剂和免疫抑制剂联合用药。 所述抗肿瘤剂和免疫抑制 剂选自抗代谢物, 包括但不仅限于卡培他滨、 吉西他滨、 培美曲塞二 钠; 生长因子抑制剂, 包括但不仅限于帕唑帕尼、 伊马替尼、 埃罗替 尼、 拉帕替尼、 吉非替尼、 凡德他尼; 抗体, 包括但不仅限于赫赛汀、 贝伐单抗; 有丝***抑制剂, 包括但不仅限于紫杉醇、 长春瑞滨、 多 西他赛、 多柔比星; 抗肿瘤激素类, 包括但不仅限于来曲唑、 他莫西 芬、 氟维司群、 氟他胺、 曲普瑞林; 烷化剂类, 包括但不仅限于环磷 酰胺、 氮芥、 马法兰、 瘤可宁、 卡莫司汀; 金属铂类, 包括但不仅限 于卡铂、 顺铂、 奥沙利铂; 拓朴异构酶抑制剂, 包括但不仅限于拓朴 特肯、 喜树碱、 拓朴替康、 依立替康; 免疫抑制类, 包括但不仅限于 依维莫司、 西罗莫司、 特癌适; 嘌呤类似物, 包括但不仅限于 6-巯基 嘌呤、 6-硫鸟嘌呤、 石充唑嘌呤; 抗生素类, 包括但不仅限于菌素 D、 柔 红霉素、 阿霉素、 米托蒽醌、 争光霉素、 普卡霉素; 铂配合物, 包括 但不仅限于顺铂、 卡波铂; 腎上腺皮质抑制剂类, 包括但不仅限于氨 鲁米特等。 联合用药时各药物可同时给药或依次顺序地分开用药, 以 同一制剂形式或以分开的不同制剂的形式给药。
本发明还涉及式 U )化合物、 其药学上可接受的盐以及它们的立 体异构体在制备治疗和 /或预防增殖性疾病例如肿瘤的药物中的用途。
所述的增殖性疾病包括癌症和非癌性增殖性疾病, 所述癌症选自 脑瘤、 肺癌、 鳞状上皮细胞、 膀胱癌、 胃癌、 卵巢癌、 腹膜癌、 胰腺 癌、 乳腺癌、 头颈癌、 子***、 子宫内膜癌、 直肠癌、 肝癌、 肾癌、 食管腺癌、 食管鳞状细胞癌、 实体瘤、 ***癌、 甲状腺癌、 原位癌、 淋巴瘤、 神经纤维瘤病、 骨癌、 皮肤癌、 结肠癌、 睾丸癌、 胃肠道间 质瘤、 肥大细胞肿瘤、 多发性骨髓瘤、 黑色素瘤、 胶质瘤或肉瘤等; 所述非癌性增殖性疾病选自例如皮肤或***的良性增生等。
实验证明,本发明化合物是 PI3K和 /或 mTOR抑制剂,对由 PDKa 和 /或 mTOR信号通路表达异常引起的增殖性疾病例如(恶性肿瘤 )具 有良好的治疗效果; 并且本发明化合物溶解性好, 理化性质稳定, 利 于注射制剂的开发, 注射给药的体内药代动力学实验证明, 该化合物 且具有良好的药代动力学特性, 起效快, 可以注射给药, 可有效解决 危重患者无法口服给药的难题, 扩大临床应用。
以下进一步阐述本发明化合物的有益效果,本发明其它化合物与试验
中所列举的部分本发明化合物具有相同的有益效果,但不应将此理解为本 发明化合物仅具有下列有益效果。
下述实验中缩写所代表的含义如下:
HEPES: 羟乙基哌嗪乙硫横酸;
EGTA: 乙二醇二***二胺四乙酸;
CHAPS: 3-[3- (胆酰胺丙基)二曱氨基]丙磺酸内盐
DTT: 二^ L苏糖醇;
PIP2: 4,5-二磷酸磷脂酰肌醇;
ATP: 三磷酸腺苷;
DMSO: 二甲基亚砜;
Tween-20: 吐温 20。 实验例 1 化合物 A、 B的体外酶学抑制活性
测试物 化合物 A、 B , 由实施例 1、 3制备所得;
mTOR酶学实验方法
1. 试剂配制
1.1 1倍激酶緩冲液: 50 mM HEPES , pH 7.5 , 10 mM MgCl2, 1 mM EGTA, 3 mM MnCl2, 0.01 % Tween-20 , 2 mM DTT;
1.2 4倍激酶溶液: 1 倍激酶緩冲液中加入 mTOR激酶, 配制 4 倍激酶溶液, 终浓度为 2.5 nM;
1.3 2倍底物和 ATP溶液: 1倍激酶緩沖液中加入底物 4EBP1和 ATP, 配制 2倍底物溶液, 4EBP1终浓度为 50 nM, ATP终浓度为 10.8 μΜ;
1.4 4倍测试物溶液: 采用 100 % DMSO配制 100倍不同浓度梯 度的测试物溶液, 用 1倍激酶緩冲液稀释 25倍, 得到 4倍不同浓度梯 度的测试物溶液;
1.5 检测液的配制: 配制含 2倍终浓度 EDTA和 4EBP1磷酸化抗 体的检测液, EDTA终浓度为 8 mM, 4EBP磷酸化抗体终浓度为 2 nM。
2. 实^^步骤
2.1 往 384孔板中每孔加入 2.5 系列稀释的 4倍测试物溶液, 复孔;
2.2 每孔加入 2.5 4倍激酶溶液, 震动混匀;
2.3 每孔加入 5 2倍底物和 ATP溶液, 室温孵育 1小时;
2.4 最后加入 10 检测液终止反应, 60分钟后, Envision 读取 数据 Lance signal ( 665 nM )。
3. 数据处理
抑制率%= (样本值 -最小值 )/(最大值 -最小值 )χ 100
其中"最大值 "为 DMSO对照孔读数, "最小值"为不加激酶的对照 孔读数。
输入 GraphPad Prism 5,0 作图, 得到曲线及 IC50。
ΡΙ3Κα酶学实验方法
1. 试剂配制
1.1 1倍激酶緩冲液: 50 mM HEPES , pH 7.5, 3 mM MgCl2, 1 mM EGTA, 100 mM NaCl , 0.03 % CHAPS , 2 mM DTT;
1.2 4倍激酶溶液: 1倍激酶緩冲液中加入 ΡΙ3Κα激酶, 配制 4 倍激酶溶液, 终浓度为 1.65 nM;
1.3 2倍底物和 ATP溶液: 1 倍激酶緩冲液中加入底物 PIP2和 ATP ,配制 2倍底物溶液, PIP2终浓度为 50 μΜ, ATP终浓度为 25 μΜ;
1.4 4倍测试物溶液: 采用 100 % DMSO配制 100倍不同浓度梯 度的测试物溶液, 用 1倍激酶緩冲液稀释 25倍, 得到 4倍不同浓度梯 度的测试物溶液;
1.5 K ina s e- G l o reagent试剂, 将其放至升温到室温, 用来终止 反应并产生检测信号。
2. 实验步骤
2.1 往 384孔板中每孔加入 2.5 系列稀释的 4倍测试物溶液;
2.2 每孔加入 2.5 4倍激酶溶液, 震动混匀;
2.3 每孔加入 5 L 2倍底物和 ATP溶液, 室温孵育 1小时;
2.4 最后加入 10 μL检测溶液终止反应, 緩慢震摇 15分钟后, Flexstation 读取数据 RLU。
3. 数据处理
抑制率。/。= 100 - (样本值 -最小值 )/(最大值 -最小值)χ 100
其中"最大值"为不加激酶的对照孔读数, "最小值"为 DMSO对照 孔读数。
输入 GraphPad Prism5.0 作图, 得到曲线及 IC50。
实验结果
化合物 A、 B的体外酶学活性 (IC50)
测试物 ΡΒΚα (η M) mTOR (ηΜ)
化合物 A 7.8 2.5
化合物 B 15.2 2.66
实验结论
由表 1可以看出, 化合物 Α、 Β体外对 ΡΙ3Κα和 mTOR酶均具有 很好的抑制活性, 说明化合物 A、 B对由 ΡΙ3Κα和 mTOR信号通路表 达异常引起的疾病有抑制作用。 实验例 2 化合物 A的体外细胞学抑制活性
测试物 化合物 A, 由实施例 1制备所得;
下述实验中所用细胞株代表的含义如下:
A549: 人肺癌细包株;
U87MG: 人脑星形胶质母细胞瘤细胞株;
PC-3: 人***癌细胞林;
SKOV-3: 人卵巢癌细胞株;
实验方法
1. 试剂和化合物配制
1.1 酉己置石粦酸緩冲液(PBS ): 分别称取 8 g NaCl , 0.2 g KCl , 1.44 g Na2HP04和 0.24 g KH2P04, 加入 800 mL 超纯水, 调至 pH=7.4 , 加 入超纯水, 定容至 1 L, 高压灭菌 20 min。
1.2 配置 XTT检测工作液: 称取 lOO mg 甲基四氮盐 (XTT )粉 末, 避光溶解于 300 mL 加热至 50 °C的不含酚红的无血清 RPMI1640 培养液中, 过滤, 分装, 立即或一周内使用, 所有过程需避光。
1.3 配置测试化合物
配置测试化合物储液: 将化合物粉末溶解于 DMSO中, 浓度为 10 mM。
配置测试化合物梯度稀释溶液: 取 10 mM 的测试化合物储液用
DMS0 4倍连续梯度稀释,共 10个浓度。然后分别取 2 的 DMSO 稀 释的化合物加到 998 μ 含 10% 胎牛血清( FBS )的培养液中, 测试物 最高浓度为 20 μΜ, DMSO 浓度为 0.2 %, 共 10个浓度梯度。
2. 细胞培养
2.1 细胞复苏
从液氮中取出细胞冻存管, 置于 37°C ~ 39 °C水浴中, 快速融化。 将冻存液转移至 15 mL 无菌离心管中, 加入 10倍于冻存液体积 的培养液, 于 1000 rpm, 4°C离心 5 min。 弃除离心管中培养液, 力口入 含 10% FBS的培养液, 重悬细胞, 转移到培养瓶中, 第二天换液。
2.2 细胞传代
取对数生长期细胞, 弃除培养液, 加入适量体积 PBS洗一次, 再 加入适量体积的含 0.25 %胰酶和 0.02 % EDTA 的消化液。37°C放置 2 ~ 5 min, 弃去消化液, PBS洗一次。 加入适量体积含 10 % FBS 的培养 液终止消化, 移液管轻轻吹打, 将细胞消化后制成细胞悬液供传代和 实验。
2.3 细胞冻存
取对数生长期细胞, 用含 0.25 %胰酶和 0.02 % EDTA 的消化液消 化细胞, 制成细胞悬液, 于 1000 rpm、 4 °C离心 5 min。 弃去培养液, 加入含 10 % DMSO和 90 % FBS 的冻存液, 重悬细胞, 每管 2 χ 106 个细胞分装于冻存管中。 将冻存管置于程序降温盒中, 在 - 80 °C放置 24 h后, 转移到液氮中冻存。
3. 细胞铺板
3.1 制备细胞悬液: 去除培养瓶中的培养基; 用 PBS 润洗细胞两 遍; 加胰酶消化离心收集; 用含 10 % FBS胎牛血清的培养基重悬, 计 数并调整到合适浓度(细胞活力必须大于 90%);细胞浓度为 5 X 104/mL;
3.2 将细胞悬液加入 96孔板每孔 100 μί, 置于 37 °C, 5 % C02 细胞培养箱中培养过夜;
4. 药物处理: 向细胞培养板中加入稀释好的测试化合物, 共三个 重复, 每孔 100 终体积 200 起始浓度为 10 μΜ, 4 倍稀释, 共 10个浓度梯度; 放入 C02细胞培养箱中培养 72小时;
5. XTT 法检测细胞活力:去除培养基,加入 XTT检测工作液, 150 每孔, 在 37 °C、 5 % C02细胞培养箱中放置 2小时, 放入酶标仪中 读取 450 nm吸光;
6. 数据处理
1 ) 抑制率%= (溶剂对照孔读数-测试物孔读数) /(溶剂对照孔读数
白对照孔读数 )χ 100%;
2) 输入 GraphPad Prism 5.0作图, 得到曲线及 IC
实验结果
化合物 A体外细胞学活性 (IC50)
测试物 U87MG (nM) A549(nM) PC-3(nM) SKOV-3(nM) 化合物 A 29.48 63.16 33.73 51.17
实验结论
ΡΙ3Κα和 mTOR信号通路表达异常会导致 U87MG、 A549细胞的 增值, 由表 2可以看出, 化合物 A可以有效地抑制 U87MG、 A549、 PC-3、 SKOV-3细胞的增殖, 说明化合物 A对由 ΡΙ3Κα和 mTOR信号 通路表达异常引起的疾病有抑制作用。 实验例 3 本发明化合物 1的大鼠体内药代动力学实验
受试动物 雄性 SD大鼠, 3只 /给药途径 /化合物,体重 230-250 g。 供试品
本发明化合物 1, 由实施例 2制备所得, 用 30 %DMF+70 %灭菌注射 用水溶解。 本发明化合物 1在大鼠体内经过酶的催化或非酶作用, 转化为 活性化合物 A从而发挥药理作用, 该活性化合物 A称为本发明化合物的 原药, 故 LC-MS/MS监测分析的是化合物 A的血药浓度。
化合物 A,由实施例 1制备所得,釆用 30%DMF+5 0°/。 PEG400+2 0%( 0. 9% 氯化钠注射液) (用盐酸水 。
化合物 A
内标物
实验方法
给药 供试品静脉推注给药(iv), 给药剂量为 2mg/kg, 给药浓度 1 mg/kg,给药体积 2 mL/kg;供试品灌胃给药( po ),给药剂量为 4 mg/kg, 给药浓度 1 mg/kg , 给药体积 4 mL/kg。
采血 IV给药后 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 24 h, 进行 尾静脉釆血, PO给药后 0.167, 0.5, 1, 2, 4, 6, 8, 24 h, 进行尾静 脉采血,每个时间点采取 100 μL·左右全血置于肝素钠抗凝管中,在 8000 转 /分的高速低温离心机中离心 6 min分离血浆, 血浆于 -80 °C¾箱冻 存。
血浆样品分析
供试品采用蛋白沉淀法:取 20 血浆,加入 200 μ 内标( BEZ-235 的甲醇溶液 50 ng/mL),, 1500转 /分钟涡旋 3 min, 然后在 12000转 /分 钟的高速离心机中离心 5 min, 取上清液 50 加入 150 水, 涡旋混 匀。
样品追踪
LC-MS/MS同时检测前药化合物 1及其原药化合物 A的血药浓度。 前药化合物 1 IV给药 2 mg/kg, 5 min三只动物的前药化合物 1的 平均血药浓度约为 700 ng/mL, 15mm平均血药浓度约为 50 ng/mL, 30 min及以后的时间点基本未检测到血药浓度, 说明前药化合物 1 在 30 min以内转化成原药化合物 A;
前药化合物 1 PO给药 4 mg/kg, 所有采血时间点基本未检测到前 药化合物 1血药浓度, 说明前药化合物 1在大鼠体内较快速度 (5 min 以内) 转化成原药化合物 A。
本发明化合物的大鼠 PK评价结果 (iv )
AUClast CI Vss 供试品
(测定由化合物 1转化 8687 0.23 0.85 成的化合物 A的数据)
化合物 A 9130 0.21 1.26 表 4 本发明化合物的大鼠 PK评价结果(po )
T AUClast C max Tmax
供试品 F%
(h) (h*ng/mL) (ng/mL) (h)
化合物 1
(测定由化合物 1转化 9.04 1695 143.3 4.00 12.2 成的化合物 A的数据)
化合物 A 5.77 2549 205 6.00 14.0
AUCiast代表药时曲线下面积 0→t
CL代表清除率
Vss代表稳态表观分布容积
T1/2代表半衰期
Tmax代表血药达峰时间
cmax代表血药峰浓度
F%代表绝对生物利用度 实验结论
前药化合物 1进行大鼠 IV和 PO给药, 均会快速的在大鼠体内全 部转化成原药化合物 A。 由上表 3和 4可见, 本发明化合物 1和化合 物 A均具有良好的药代动力学特性。 化合物 1 大鼠给药后, 监测化合 物 A的药代动力学特征与化合物 A单体给药的药代动力学特征例如清 除率、 AUC以及生物利用度类似, 说明化合物 1在大鼠体内会转化成 其原药化合物 A, 由化合物 A发挥药理活性, 将化合物 A制备成其前 药化合物 1, 不影响化合物本身的药理活性, 说明本发明化合物 1对于 由 PDKct和 mTOR信号通路表达异常引起的疾病例如肿瘤具有显著的
抑制作用。 实施例 4 本发明化合物 1和化合物 A的溶解性能比较
供试品: 本发明化合物 1的原药化合物 A, 由实施例 1制备所得。
本发明化合物 1, 由实施例 2制备所得;
本发明化合物 1的色谱条件
仪器: 高效液相色谱议( Agilent 1200 series )
色谱柱: Agilent Eclipse XDB-Cis (填料为 5 μηι的十八烷基硅烷键合 石圭胶, 内径 4.6 mm, 柱长 150 mm )
柱温: 30 °C; 流速: 1.0 mL/min; 检测波长: 214 nm; 进样量: 10 L; 流动相:
緩冲液: 0.02 mol/L磷酸二氢铵(加入 0.2%三乙胺, 并用磷酸调节 pH值至 6.0 )
流动相 A: 缓冲液 -乙腈(90: 10 ) 流动相 B: 緩冲液 -乙腈(20:80 ) 梯度洗脱条件:
时间 (分钟) 流动相 A ( % ) 流动相 B ( % )
0 80 20
5 50 50
10 20 80
12 0 100
18 0 100
20 80 20
22 80 20 化合物 A的色 i普条件
仪器: 高效液相色谱议( Agilent 1200 series )
色谱柱: YMC-Pack-Pro C18(填料为 5 μπι的十八烷基硅烷键合硅胶, 内径 4.6 mm, 柱长 150 mm )
柱温: 30 °C ;流速: 1.0 mL/min;检测波长: 214 nm;进样量: 10 μΐ^ 流动相:
緩冲液: 0.02 mol/L磷酸二氢铵(加入 0.2%三乙胺, 并用磷酸调节 pH值至 6.0 )
流动相 A: 緩冲液 -乙腈(90: 10 ) 流动相 B: 緩冲液 -乙腈(20:80 ) 流动相 A: 流动相 B=65:35
供试品的溶液配制:
本发明化合物 1的溶液配制:
供试品本发明化合物 1溶液:
精密称取供试品 2 mg两份, 置合适容器中, 分别加入 pH4.0、 pH5.0 緩冲液 0.5 mL, 超声 5 min, 再置于 25 °C水浴中 2小时, 过滤, 取滤液作 为供试品溶液。
精密称取供试品 2 mg, 置合适容器中, 加入 pH6.0緩冲液 0.5 mL, 超声 5 min, 过滤, 取滤液作为供试品溶液。
精密称取供试品 2 mg 两份, 置合适容器中, 分别加入 pH7.0、 pH9.0 緩冲溶液适量, 记录每次加入的溶剂体积, 振摇直至完全溶解, 作为供试 品溶液。
对照品本发明化合物 1溶液:
精密称取对照品 4.7 mg, 置 10 mL量瓶中, 加入 DMSO lmL使其溶 解, 再用甲醇定容至刻度制成每 1 mL中含 0.47 mg的溶液, 做为母液入。 用曱醇将母液 A分别逐步稀释制成每 1 mL中含 0.047 mg、 0.0094 mg的 对照品 B和对照品(。
化合物 A溶液配制:
供.试品化合物 A溶液:
精密称取供试品 2 mg三份, 分别加入 pH5.0、 pH7.0、 pH9.0緩冲液 2 mL, 超声 5 min, 过滤, 取滤液作为供试品溶液。
对照品化合物 A溶液:
精密称取对照品 12.47 mg,加 DMSO 50 mL制成每 1 mL中含 0.2494 mg的溶液, 摇勾, 作为对照品母液。 再用 DMSO将母液 A分别逐步稀释 制成每 1 mL中含 0.04988 mg、 0.02494 mg、 0.009976 mg、 0.004988 mg、 0.002494 mg的溶液, 作为各对照品溶液。
试验结果:
以各对照品浓度 ( C )为横坐标, 峰面积(Y ) 为纵坐标, 进行线性 回归, 得到线性方程。 将各供试品溶液峰面积代入线性方程得出供试品溶 液浓度。
本发明化合物 1对照品线性方程为: Y=18821C,相关系数尸 0.9999。
化合物 A对照品线性方程为: Y=29144C, 相关系数 r=1.0000。
测定结果如下:
表 5 化合物 A在不同 pH緩冲液下的溶解度 理论浓度 (mg/mL) 緩冲液 pH值 实测浓度 (mg/mL)
5 1.89x 1ο-5
9 0 表 6 本发明化合物 1在不同 pH緩冲液下的溶解度
理论浓度 (mg/mL) 緩冲液 pH值 实测浓度 (mg/mL)
4 0.189
4 5 0.556
6 3.20
1 7 ≥5且< 7
1 9 ≥15且< 20 实验结论
由表 5和表 6可知, 緩冲液 pH值为 5、 7、 9时, 化合物 A的溶解实 测浓度分别低于相同緩冲液 pH值本发明化合物 1的实测浓度, 说明本发 明化合物 1 的溶解性比化合物 A的溶解性更好, 有显著区别; 且本发明 化合物的溶解性随緩冲液 pH值的增大而增大, 理化性质更好, 利于制成 药学上可接受的任一剂型, 尤其是可以制成注射剂。 实施例 5 本发明化合物在水中的溶解度比较
供试品: 本发明化合物 14的原药化合物 B, 由实施例 3制备所得。
本发明化合物 14, 由实施例 4制备所得; 本发明化合物 31的原药化合物 C, 由实施例 5制备所得。 本发明化合物 31 , 由实施例 6制备所得; 实验方法: 分别取化合物 14、 化合物 B、 化合物 31、 化合物 C样品 各 2 mg, 逐次加入超纯水, 每次超声 5 min, 直到样品完全溶解。
实验结果: 化合物 B在水中的溶解度< 0.1 mg/mL。
化合物 14在水中的溶解度 > 5 mg/mL;
化合物 C在水中的溶解度小于 0.1 mg/mL。
化合物 31在水中的溶解度 > 5 mg/mL;
实验结论:
由上面结果可以看出, 化合物 14在水中的溶解度是其原药化合物 B 在水中的溶解度的 50倍, 化合物 31 在水中的溶解度是其原药化合物 C 在水中的溶解度的 50倍, 由此可以得出结论, 本发明的前药化合物理化 性质更好, 利于制成药学上可接受的剂型, 尤其是可以制成注射剂, 可有 效扩大临床用药剂型的开发。 具体实施方式
以下通过实施例形式的具体实施方式,对本发明的上述内容作进一步 的详细说明。 但不应将此理解为本发明上述主题的范围仅限于以下实施 例。
EtOAc: 乙酸乙酯;
EA: 乙酸乙酯;
PE: 石油醚;
HATU: 2-(7-偶氮苯并三氮唑) -Ν,Ν,Ν',Ν'-四甲基脲六氟磚酸酯; DCM: 二氯甲烷;
DMF: 二甲基甲酰胺。
5-(4,4,5,5-四甲基 -1 ,3,2-二氧杂环戊硼烷 -2-基)吡啶 -2-胺, 自制, 制备 方法如下:
将 2-氨基 -5溴吡啶 ( 5.1 g, 30 mmol )、 联硼酸频那醇酯 ( 10.7 g, 45 mmol )、 碳酸钾( 8.3 g, 60 mmol )、 四(三苯基膦 巴 ( 693 mg, 0.6 mmol ) 加入到 150 mL二氧六环和 2 mL水中, 在氮气保护下回流反应 4小时。 冷却到室温, 过滤, 浓缩, 粗品溶于 300 mL二氯甲烷, 用水洗涤, 用无 水硫酸钠干燥,浓缩至剩余少量溶剂时,向其中加入石油醚析出黄色固体, 过滤, 得到产物 (1.8 g )。 实施例 1 9-(6-氨基吡啶 -3-基) -1-(3- (三氟甲基)苯基)嘧啶并
[5,4-c】【l,5】萘啶 -2,4(1 3 -二酮 (化合物 A ) 的制备
将 4,6-二氯 -1,5-萘啶 -3-羧酸乙酯 (5.4 g, 20 mmol) (其制备方法参见 WO2013/2071698说明书第 38页)、间三氟甲基苯胺 (4.5 g, 28 mmol) 和碳 酸钾 (5.5 g, 40 mmol)加入到 150 mL叔丁醇中,加热至 90 °C反应 18小时。 将反应液冷却至室温后旋干, 加入 300 mL水, 将所得固体过滤, 用乙酸 乙酯和石油醚 (1/20, 50 mL)洗涤, 得到 6-氯 -4-((3- (三氟甲基)苯基)氨 基) -1,5-萘啶 -3-甲酸乙酯, 为黄色固体 (6.0 g)。
2 ) 6-氯
将 6-氯 -4-((3- (三氟甲基)苯基)氨基) -1,5-萘啶 -3-甲酸乙酯 (3.95 g, 10 mmol)溶于 50 mL甲醇和 50 mL四氢呋喃中, 滴加氢氧化锂 (1.26 g, 30 mmol)的水 (50 mL)溶液。 滴加完毕后, 在室温下反应 4小时。 将反应液浓 缩, 加入 200 mL水, 用盐酸调节 pH值至 3, 所得固体过滤, 真空千燥得 到黄色固体 (3.6 g:)。
3 ) Λ 4-甲氧苄基) -6-氯 -4-((3- (三氟甲基)苯基)氨基) -1,5-萘啶 -3-曱酰 胺
将 6-氯 -4-((3- (三氟甲基)苯基)氨基) -1,5-萘啶 -3-羧酸 (3.6 g, 9.8 mmol) 悬浮于 50 mL氯化亚砜中, 搅拌加热至 75 °(保持反应 4小时。 自然冷却 至室温, 浓缩, 得到黄色固体。 将其分散于 100 mL四氢呋喃中, 在 0 °C 下滴入三乙胺 (3.03 g, 30 mmol)和对甲氧基苄胺 (1.6 g, 13 mmol)的混合物。 反应液在室温下搅拌 4小时, 旋蒸除去溶剂, 向残余物加入 300 mL水,
抽滤, 滤饼用乙酸乙酯和石油醚洗涤 (体积比 1/10, 100 mL)洗涤, 干燥, 得到 Λ 4-曱氧苄基 )-6-氯 -4-((3- (三氟甲基)苯基)氨基) -1,5-萘啶 -3-甲酰胺, 为淡黄色固体 (4.5 g)。
4 ) 9-氯 -3-(4-甲氧基苄基) - 1 -(3- (三氟甲基)苯基)嘧啶并 [5,4-c] [ 1 ,5]萘啶 -2,4(1 /,3 )-二酮的制备
将 曱氧苄基 )-6-氯 -4-((3- (三氟甲基)苯基)氨基) -1,5-萘啶 -3-甲酰 胺 (4.5 g, 9.2 mmol)悬浮于氯甲酸乙酯 (50 mL)中,加热至 90 V ,搅拌 120 小时。 旋蒸除去挥发性物质, 硅胶柱层析 (EtOAc/PE=0〜l/4)分离得到 9- 氯 _3-(4-曱氧基苄基)-1 -(3-(三氟甲基)苯基)嘧啶并 [5,4-c][l,5]萘啶 -2,4(1/ ,3 /)-二酮, 为黄色油状物 (700 mg)。
5 ) 9-氯小 (3- (三氟甲基)苯基)嘧啶并 [5,4-C][l,5]萘啶 -2,4(1/ ,3 /)-二酮 的制备
将 9-氯 -3-(4-甲氧基苄基) -1-(3- (三氟甲基)苯基)嘧啶并 [5,4-c][l,5]萘啶 -2,4(1 ,3 )-二酮 (700 mg, 1.36 mmol)溶于乙腈 (40 mL)和水(10 mL)中, 在 室温下分批加入硝酸铈铵 (2.9 g, 5.65 mmol)。 反应液在室温下搅拌 18小时 后旋蒸除去溶剂, 粗品硅胶柱层析 (EtOAc/PE=0〜l/4)分离得到黄色固体 (400 mg)。
将 9-氯- 1 -(3- (三氟甲基)苯基)嘧啶并 [5,4-c] [ 1 ,5]萘啶 -2,4( 1 ,3/ )-二酮 (400 mg, 1 mmol)、 5-(4,4,5,5-四曱基 -1,3,2-二氧杂环戊硼烷 -2-基)吡啶 -2- 胺 (440 mg, 2.0 mmol)、碳酸钾 (414 mg, 3.0 0111101)和四(三苯基膦)钯(58 mg, 0.05 mmol)加入到 40 mL二氧六环和 2 mL水中,在氮气保护下回流反应 18 h, 冷却到室温, 硅藻土过滤, 浓缩, 硅胶柱层析 (EtOAc/PE=0~10/l) 分离得到粗品, 用曱醇洗涤,得 9-(6-氨基吡啶 -3-基) -1-(3- (三氟曱基)苯基) 嘧啶并 [5,4-c][l,5]萘啶 -2,4(1 ,3 /)-二酮, 为黄色固体 (56 mg)。
分子式: C22H13F3N602 LC-MS(m/e): 451.1(M+H)
^-NMR (400 MHz, DMSO-^6) δ: 12.28 (br. s., IH), 9.26 (s, IH), 8.33 (m, IH), 8.21 - 8.26 (m, IH), 8.16 (m, IH), 7.93 (s, 1H), 7.81 (br. s., 1H), 7.70 (m, 2H), 6.76 (m, 1H), 6.46 (s, 2H), 6.24 (m, IH). 实施例 2 (9-(6-氨基吡啶 -3-基) -2,4-二氧代 -l-(3- (三氟甲基)苯 基) -1,2-二氢嘧啶并 [5,4-c】[l,5〗萘啶 -3(4 -基)甲基磷酸酯二钠 (化合物 1)的 制备
1 ) (9-(6-氨基吡啶 -3 -基) -2,4-二氧代- 1 -(3- (三氟曱基)苯基) - 1,2-二氢嘧 啶并 [5,4-c|[l,5]萘啶 -3(4/ )-基)甲基二叔丁基磷酸酯的制备(比较后觉得萘 啶更好一些, 也有利于后期中译英, 所以将二氮杂萘统一改为萘啶)
将 9-(6-氨基吡啶 -3-基 )小(3- (三氟甲基)苯基)嘧啶并 [5,4-c][l,5]萘啶 -2,4(1 ,3 / 二酮 (900mg, 2mmol) (化合物 A ) 和二叔丁基氯甲基磷酸酯 (购于南京精瑞久安生物技术有限公司) (673 mg, 2.6 mmol) 溶于 15 mL DMSO中, 依次加入 K2C03 (673 mg, 2.6 mmol)和 Nal (30 mg, 0.2 mmol), 搅拌并加热至 50°C保持 16小时后,冷却至室温,然后将反应液倾入水中, 抽滤, 滤饼干燥, 得标题化合物粗品 1.5 g。
2) (9-(6-氨基吡啶 -3-基) -2,4-二氧代小(3- (三氟甲基)苯基) -1,2-二氢嘧 -c][l,5]萘啶 -3(4 )-基)甲基二氢磷酸酯的制备
将 (9-(6-氨基吡啶 -3-基) -2,4-二氧代 - 1 -(3- (三氟甲基)苯基) - 1,2-二氢嘧 啶并 [5,4-c][l,5]萘啶 -3(4//)-基)甲基二叔丁基磷酸酯 (1,5 g粗品) 置于 10 mL二氯甲烷中, 加入三氟乙酸(10 mL), 室温搅拌 3小时, 真空浓缩, C-18 ODS 色谱柱(甲醇 /水, 0~60%)分离得到淡黄色固体, 用少量甲醇洗 涤, 干燥得标题化合物 (150 mg)。
3) (9-(6-氨基吡啶 -3-基) -2,4-二氧代- 3- (三氟甲基)苯基) - 1 ,2-二氢嘧 啶 [5,4-c][l,5]萘啶 -3(4//)-基)甲基磷酸酯二钠盐的制备
将 (9-(6-氨基吡啶 -3-基) -2,4-二氧代小 (3- (三氟甲基)苯基) -1,2-二氢嘧 啶并 [5,4-c][l,5]萘啶 -3(4 )-基)曱基二氢磷酸酯 (150 mg, 0.27 mmol) 置于
10 mL 曱醇中, 搅拌下加入曱醇钠 (29 mg, 0.54 mmol ), 搅拌 10分钟, 旋蒸除去溶剂并干燥得固体标题化合物 (163 mg)。
分子式: C23H14F3N6Na206P 分子量: 604.34 LC-MS(m/e): 560.7 (M+H)
1H-NMR(400MHz, CDC13) δ: 9.28(s, IH), 8.13~8.30(m, 3H), 7.92(s, IH) 7.81(m, IH), 7.70(m, 2H), 6.76(m, IH), 6.48(s, 2H), 6.24(m, IH), 5.59(m, 2H). 实施例 3 9-(2-氨基嘧啶 -5-基) -l-(3- (三氟甲基)苯基)嘧啶并 【5,4-c l,5】萘啶 -2,4(li,3 -二酮 (化合物 B ) 的制备
将 9-氯 -1-(3- (三氟曱基)苯基)嘧啶 [5,4-c][l ,5]萘啶 -2,4(1 ,3/ )-二酮 (300 mg, 0.77 mmol)、 5-(4,4,5,5-四甲基 -1,3,2-二氧杂环戊硼烷 -2-基)嘧 啶 -2-胺(170 mg, 0.77 mmol), 碳酸钾 (317 mg, 2.3 mmol)和四(三苯基膦) 钯 (45 mg, 0.04 mmol) 加入到 40 mL二氧六环和 2 mL水中, 在氮气保 护下回流反应 18 h, 冷却到室温, 浓缩, 加入 400mL水, 过滤得到粗 品。 将粗品溶于 20mL 6M浓盐酸中, 用二氯曱烷洗涤( 4 x 50mL ), 将 水相滴加到碳酸钠水溶液中, 过滤, 水洗, 粗品用甲醇洗涤, 得 9-(2- 氨基嘧啶 -5-基) -1-(3- (三氟曱基)苯基)嘧啶 [5,4-c][l,5]萘啶 -2,4(1 ,3/ )- 二酮(160 mg)。
分子式: C2iH12F3N702 LC-MS(m/e): 452.1 (M+H)
^-NMR (400 MHz, DMSO-d6) δ: 12.25 (br. s., IH), 9.29(s, IH), 8.38 (d, IH), 8.24 (d, J = 9.2, IH), 8.00 (s, 2H), 7.70-7.84 (m, 4H), 7.14 (s, 2H). 实施例 4 (9-ί2-氨基嘧啶 -5-基) -2,4-二氧代 -W3- (三氟甲基)苯 基) -1,2-二氢嘧啶并『5,4-cl『l,51萘啶 -3(4 -基)甲基磷酸酯二钠 (化合物 14) 的制备
1) (9-(2-氨基嘧啶 -5-基) -2,4-二氧代小 (3- (三氟甲基)苯基) -1,2-二氢嘧啶 并 [5,4-c][l,5]萘啶 -3(4 /)-基)甲基二叔丁基磷酸酯的制备
将 9-(2-氨基嘧啶 -5-基) -1-(3- (三氟曱基)苯基)嘧啶并 [5,4-c][l,5]萘啶
-2,4(1 ,3 /)-二酮 (400 mg, 0.89 mmol)和碳酸钾 (491 mg, 3.56 mmol)溶于 30 mL DMSO中, 加热至 60°C , 滴加入二叔丁基氯甲基磷酸酯 (298 mg, 1.15 mmol), 60°C反应 30分钟, 冷却至室温, 倒入水中, 析出固体过滤, 真空干燥得到黄色固体状标题化合物 (450 mg粗品),不经纯化直接用于下 步反应。
2) (9-(2-氨基嘧啶 -5-基) -2,4-二氧代 - 1 -(3- (三氟甲基)苯基)- 1 ,2-二氢嘧 啶 [5,4-c|[l,5]萘啶 -3(4 )-基)甲基二氢璘酸酯的制备
将 (9-(2-氨基嘧啶 -5-基) -2,4-二氧代 -1-(3- (三氟曱基)苯基) -1,2-二氢嘧 啶并 [5,4-c][l,5]萘啶 -3(4 /)-基)甲基二叔丁基磷酸酯 (450 mg粗品)悬浮于 二氯甲烷 (10 mL)中, 加入三氟乙酸 (10 mL), 室温搅拌 3小时, 真空浓缩, 所得粗品反相柱层析(乙腈:水 =0~40%)得到淡黄色油状物,加入少量甲醇, 所得固体过滤, 甲醇洗涤,真空干燥得到淡黄色固体状标题化合物 (10 mg, 两步产率: 2%)。
3) (9-(2-氨基嘧啶 -5-基) -2,4-二氧代小(3- (三氟甲基)苯基) -1,2-二氢嘧
啶并 5,4-c][l,5]萘啶 -3(4 )-基)甲基磷酸酯二钠的制备
将 (9-(2-氨基嘧啶 -5-基) -2,4-二氧代 -1-(3- (三氟甲基)苯基) -1,2-二氢嘧 啶并 [5,4-c][l,5]萘啶 -3(4 )-基)甲基二氢磷酸酯(10 mg, 0.018 mmol) 分散 于甲醇(10 mL)中, 加入曱醇钠的甲醇溶液(质量分数 2%, 96 mg, 0.036 mmol ), 搅拌 10分钟, 所得溶液真空浓缩, 得到淡黄色固体状标题化合 物(12 mg)。
分子式: C22H13F3N7Na206P 分子量: 605.3 LC-MS(M/e): 562.1
Ή-ΝΜΚ(400 MHz, MeOD-^) δ 9.48(s, 1H), 8.55(s, 1H), 8.39(d,
J=8.8 Hz, 1H), 8.15(d, J=9.2Hz, 1H), 8.07(s, 2H), 7.80-7.82(m, 1H), 7.72-7.77(m, 3H), 5.93(d, J=8.8 Hz, 2H). 实施例 5 2-(4-(9- (氨基吡啶 -3-基) -2,4-二氧代 -3,4-二氢嘧啶 【5,4-c】[l,5]萘啶 -1(2 )-基)苯基) -2-甲基丙腈 (化合物 C)的制备
将 2-(4-硝基苯基)乙腈 (4.86 g, 30 mmol)溶于 50mL二氯甲烷中, 向 其中滴加3011^氢氧化钠(3.6 g, 90 mmol)的水溶液, 然后向其中滴加碘 甲烷(10.65 g, 75 mmol)。 滴加完毕后, 在室温下避光反应 16小时。 加入 50 mL水和 l OO mL 二氯甲烷, 分液, 水相用 100 mL二氯曱烷萃取, 合 并有机相, 用无水^ L酸钠干燥, 浓缩, 粗品通过硅胶柱层析 (EtOAc/PE=0~l/20)得到淡黄色固体 2-甲基 -2-(4-硝基苯基)丙腈 (4.5 g)
将 2-甲基 -2-(4-硝基苯基)丙腈 (4.5 g, 23.6 mmol)加到反应瓶中, 依 次加入 Pd/C (450 mg) 和 50 mL乙酸乙酯, 体系抽真空, 通入氢气, 在 室温下反应 15小时, 所得反应液通过硅藻土过滤, 用乙酸乙酯洗涤, 所得滤液浓缩得到无色油状物 2-(4-氨基苯基) -2-甲基丙腈 (3.5 g)。
3) 6-氯 -4-((4-(2-氰基丙 -2-基)苯基)氨基) -1,5- 啶 -3-羧酸乙酯
将 4,6-二氯 -1 ,5-萘啶 -3-羧酸乙酯 (5.9 g, 21.9 mmol)和 2-(4-氨基苯 基) -2-甲基丙腈 (3.5 g, 21.9 mmol) 溶于 lOOmL叔丁醇中, 加入碳酸钾 (6.0 g, 43.8 mmol), 加热至回流反应 15小时。 反应液冷却至室温后减压 浓缩,残余物加入 100 mL水和 100 mL DCM,分液,水相用 lOO mL DCM 萃取, 合并有机相, 用无水硫酸钠干燥, 浓缩, 粗品通过硅胶柱层析 (EtOAc/PE=0〜l/2)得到淡黄色固体 6-氯 -4-((4-(2-氰基丙 -2-基)苯基)氨 基) -1,5-萘啶 -3-羧酸乙酯 (6.9 g)。
4) 6-氯 -4-((4-(2-氰基丙 -2-基)苯基)氨基) - (4-甲氧苄基) -1,5-萘啶 -3-
将 6-氯 -4-((4-(2-氰基丙 -2-基)苯基)氨基) - 1 ,5-萘啶 -3-羧酸乙酯 (6.9 g, 17.5 mmol)溶于 50mL曱醇和 50mL四氢呋喃中,室温下滴加 50mL氢氧化 锂 (2.2 g, 52.4 mmol)的水溶液。 滴加完毕后, 在室温下反应 4小时。 将 反应液浓缩, 加入 200mL水, 用盐酸调节 pH值至 2 ~ 3 , 将所得固体过 滤, 真空干燥得到黄色固体。 然后将其分散于 l OOmL二氯曱烷中, 加入
0.05mL DMF。 在冰浴下, 向其中滴加草酰氯 (4.2 g, 33.3 mmol), 滴加 完毕后升至室温反应 4小时, 减压蒸除溶剂并用 lOOmL二氯曱烷溶解, 水浴下滴入三乙胺 (5.0 g, 49.8 mmol) 和对甲氧基苄胺 (2.7 g, 19.9 mmol) 的混合物。 滴加完毕后, 反应液在室温下反应 15小时, 加入 50 mL水和 lOO mL DCM, 分液, 水相用 100 mL DCM萃取, 合并有机相, 用无水 硫酸钠干燥, 浓缩, 粗品硅胶柱层析 (EtOAc/PE=l/10~3/2)得到淡黄色 固体 (4.0 g)。
5) 2-(4-(9-氯 -3-(4-甲氧苄基) -2,4-二氧代 -3,4-二氢嘧啶 [5,4-c][l,5] 萘 - 1 (2 /)-基)苯基) -2-曱基丙腈
将氢化钠(1.0 g, 25 mmol)悬浮于 25 mL DMF中,室温下往其中慢慢 滴入 6-氯 -4-((4-(2-氰基丙 -2-基)苯基)氨基) -ΛΚ4-曱氧苄基) - 1 ,5-萘啶 -3- 甲酰胺 (2.43 g, 5 mmol)的 DMF溶液 (25 mL),滴加完毕后升温至 60 °C反 应 1小时。 水浴下将氯曱酸乙酯(1.36 g, 12.5 mmol)緩慢滴加至反应液 中, 滴加完毕后升温至 60°C反应 16小时。 冷却至室温后緩慢倒入水中, 用乙酸乙酯萃取 (3 < 150mL), 合并有机相, 用饱和食盐水洗涤, 用无水 硫酸钠干燥, 浓缩, 粗品通过硅胶柱层析 (EtOAc/PE=0 ~ 1/5), 得到淡 黄色固体 (1.2 g)。
6) 2-(4-(9-氯 -2,4-二氧代 -3,4-二氢嘧啶 [5,4-c][l,5]萘啶 -1(2 /)-基)苯 基) -2-
将 2-(4-(9-氯 -3-(4-曱氧苄基) -2,4-二氧代 -3,4-二氢嘧啶 [5,4-c][l,5] 萘啶 -1(2/ )-基)苯基) -2-曱基丙腈(1.2 g, 2.3 mmol) 溶于乙腈 (80 mL)和 水 (20mL)中, 在室温下分批加入硝酸铈铵 (5.1 g, 9.4 mmol)。 反应液在
室温下反应 16小时后浓缩, 加入 100 mL水, 过滤, 固体用 EA和 PE(1:1) 洗涤, 真空干燥, 得到黄色固体 (600 mg:)。
7) 2-(4-(9-(6-氨基吡啶 -3-基) -2,4-二氧代 -3,4-二氢嘧啶 [5,4-c][l,5] 萘啶- 1 2 /)-基)苯基) -2-甲基丙腈
将 2-(4-(9-氯 -2,4-二氧代 -3,4-二氢嘧啶 [5,4-c][l,5]萘啶 -1(2 基)苯 基) -2-甲基丙腈 (392 mg, 1.0 mmol), 5-(4,4,5,5-四甲基 -1,3,2-二氧杂环戊 硼烷 -2-基)吡啶 -2-胺 (440 mg, 1.0 mmol, 含量 50%)和四(三苯基膦)钯 (46 mg, 0.04 mmol) 溶于 40 mL二氧六环中,往其中加入碳酸钾 (276 mg, 2 mmol)的 1 mL水溶液。 在氮气保护下于 100°C反应 15 ~ 18小时, 然后 冷却到室温, 浓缩, 过滤, 水洗, 粗品依次用乙酸乙酯、 甲醇洗涤, 得到淡黄色固体 2-(4-(9-(6-氨基吡啶 -3-基) -2,4-二氧代 -3,4-二氢嘧啶 [5,4-c][l,5]萘啶 -1(2 )-基)苯基) -2-甲基丙腈 (150 mg)。
分子式: C25H19N702 ' LC-MS(m/e): 450.1(M+H) iH-NMR OOMz, DMSO-ί ί) δ: 12.19(br. s, 1H), 9.24(s, 1H), 8.30(d, J = 8.8, 1H), 8.17(d, J = 8.8, 1H), 7.97(m, 1H), 7.59(m, 2H), 7.42(m, 2H), 7.20(m, 1H), 6.32~6.40(m, 3H), 1.73(s, 6H). 实施例 6 (9-(6-氨基吡啶 -3-基) -l-(4-(2-氰基丙烷 -2-基)苯基) -2,4- 二氧代 -1,2-二氢嘧啶并 [5,4-c】[l,5】萘啶 -3(4H)-基)甲基磷酸酯二钠 (化 合物 31) 的制备
1) (9-(6-氨基吡啶 -3-基) -1-(4-(2-氰基丙烷 -2-基)苯基) -2,4-二氧代 -12-二氢嘧啶并 [5,4-c][l,5]萘啶 -3(4 /)-基)甲基二叔丁基磷酸酯的制备
将 2-(4-(9-(6-氨基吡啶 -3-基) -2,4-二氧代 -3,4-二氢嘧啶并 [5,4-c][l ,5] 萘啶 -1(2 )-基)苯基) -2-甲基丙腈 (60 mg, 0.134 mmol)和碳酸钾(37 mg, 0.268 mmol)加入到 6mL二甲亚砜中, 加热至 50。C。 待溶液完全澄清时, 将二叔丁基氯甲基磷酸酯 (62 mg, 0.24 mmol)滴加至溶液中, 继续反应 lh, LC-MS检测反应完成。 将反应液倒入 10mL水中, 过滤, 得到的固体干 燥, 称重得粗品 50mg, 产率: 55.6%。
2) (9-(6-氨基吡啶 -3-基) -1-(4-(2-氰基丙烷 -2-基)苯基) -2,4-二氧代 -1,2-二氢嘧啶并 [5,4-c][l,5]萘啶 -3(4 /)-基)甲基二氢磷酸酯的制备
将 (9-(6-氨基吡啶 -3-基) - (4-(2-氰基丙烷 -2-基)苯基) -2,4-二氧代 -1,2-二氢嘧啶并 [5,4-c][l,5]萘啶 -3(4//)-基)甲基二叔丁基磷酸酯 (50 mg, 0.075 mmol)溶解在 5mL三氟乙酸和二氯甲烷的混合溶液中 (体积比 1 : 1), 室温下搅拌 lh。 LC-MS检测反应完成, 将溶剂旋干, 剩余物经反相制备 色谱分离, 得到产物 3mg, 产率 7.1%。
3) (9-(6-氨基吡啶 -3-基) -1 -(4-(2-氰基丙烷 -2-基)苯基) -2,4-二氧代 - -c][l,5]萘啶 -3(4 )-基)曱基磷酸酯二钠的制备
将 (9-(6-氨基吡啶 -3-基) -1-(4-(2-氰基丙烷 -2-基)苯基) -2,4-二氧代 -1,2-二氢嘧啶并 [5,4-c][l,5]萘啶 -3(4 )-基)甲基二氢磷酸酯 (3 mg, 0.0054 mmol)溶解在 5mL曱醇钠 (0.6 mg, 0.011 mmol)的曱醇溶液中, 搅拌 0.5h, 过滤, 溶液旋干, 得到 2 mg产物, 产率: 61.5%。
分子式: C26H20N7Na2O6P 分子量: 603.43 LC-MS(M/e): 560.2(M+H+)
!H-NMR (400 MHz, MeOD) δ: 9.45 (s,lH), 8.31 (d, 1H, J = 8.8Hz),
.12 (d, 2H, J= 9.2Hz), 7.63 (d, 2H, J = 8.4Hz), 7.48 (d, 2U, J = 8.8Hz),.36-7.38 (m, IH), 6,53 (d, IH, J= 8.8Hz), 5.90 (d, 2H, J=9.6Hz), 2.66 (s,H), 1.71 (s, 6H).
Claims
1、 通式( I ) 所示的化合物、 或其药学上可接受的盐或立体异构
A和 B分别独立地为 CR6, R6为氢、 卤素原子、 氰基、 羟基、 羧基、 -(C¾)nNR8aR8b、 -(CH2)nC(0)R9、 -(CH2)nC(0)NR8aR8b、 -(CH2)nOC(0)R9、 -(CH2)nC(0)(CH2)nOR9、 -(CH2)nN(R8a)C(0)R9,或任选被 1-3个选自卤素原 子、 羟基、 羧基取代的 烷基、 d_6烷氧基;
R1为氢, 或任选被 1-5个 R7a取代的 烷基、 C2-8烯基、 C2-8炔基、 C3-8环烷基、 6-14元芳基、 5-14元杂芳基、 3-14元杂环基、 7-12元螺环基、 7-12元桥环基;
R2为氢, 或任选被 1-5个 R7b取代的 C1-6烷基、 C2.8烯基、 C2-8炔基、 C3-8环烷基、 6-14元芳基、 5-14元杂芳基、 3-14元杂环基、 7-12元螺环基、 7-12元桥环基;
R3为氢,或任选被 1-3个选自卤素原子、羟基、羧基取代的 d.6烷基; R4、 R5分别独立地为氢, 或任选被 1-3个选自卤素原子、 羟基、 羧基 取代的 d.6烷基;
m为 1~3;
E为氢, 或为能与磷酸形成盐的无机碱或有机碱的阳离子;
R7a、 R7b分别独立地为
( 1 )卤素原子、氰基、羟基、三氟曱基、 -(C¾)nNR8aR8b、 -(CH2)nC(0)R9、 -(CH2)nSR9、 -(CH2)nS(0)2R9、 -(CH2)nS(0)2NR8aR8b、 -(CH2)nN(R8a)S(0)2R9、 -(CH2)nC(0)NR8aR8b 、 -(CH2)nOC(0)R9 、 -(CH2)nC(0)(CH2)nOR9 、 -(CH2)nN(R8a)C(0)R9,
( 2 )任选被 1-3个选自鹵素原子、 羟基、 氰基、 三氟甲基取代的 C1-6 烷基、 C2.8烯基、 C2-8炔基、 C1-6烷氧基;
( 3 )任选被 1-3个选自卤素原子、羟基、氰基、 三氟甲基、 C1-6烷基、
C2-8烯基、 C2-8炔基、 d.6烷氧基、 -(CH2)nNR8aR8b、 -(CH2)nC(0)R9、 -(CH2)nSR9、 -(CH2)nS(0)2R9 -(CH2)nS(0)2NR8aR8b、 -(CH2)nN(R8a)S(0)2R9、 -(CH2)nC(0)N 8aR8b 、 -(CH2)nOC(0)R9 、 -(CH2)nC(0)(CH2)nOR9 、 -(CH2)nN(R8a)C(0)R9取代的 C3.8环烷基、 6-14元芳基、 5-14元杂芳基、 3-14 元杂环基;
R8a、 R8b分别独立地为氢, 或任选被 1-3个羟基、 卤素原子、 氰基、 羧基、 -(CH2)nNR8aR8\ 氨基磺酰基、 氨基曱酰基、 磺酰胺基取代的 烷基、 C3.8环烷基、 6-14元芳基、 5-14元杂芳基、 3-14元杂环基;
R9为氢, 或任选被 1-3 个选自卤素原子、 氰基、 羟基、 羧基、 ' -(CH2)nNR8aRsb、 磺酰基、 氨基甲酰基取代的 d-6烷基、 C1-6烷氧基; n为 0~4。
2、如权利要求 1所述的化合物、或其药学上可接受的盐或立体异构 体:
A和 B分别独立地为 CR6, R6为氢, 或任选被 1-3个选自卤素原子、 羟基、 羧基取代的 烷基;
R1为任选被 1-3个 R7a取代的 6-10元芳基、 5-6元单杂芳基、 9-10元 稠杂芳基、 5-6元单杂环基、 9-10元稠杂环基;
R2为任选被 3个 R7b取代的 6-10元芳基、 5-6元单杂芳基、 9-10元 稠杂芳基、 5-6元单杂环基、 9-10元稠杂环基;
R3为氢;
R4、 R5分别独立地为氢, 或 C1-6烷基;
m为 1-3;
E为氢, 或为能与磷酸形成盐的无机碱或有机碱的金属阳离子;
R7a、 R7b分别独立地为
( 1 )卤素原子、氰基、羟基、三氟甲基、 -(CH2)nN 8aR8b、-(CH2)nC(0)R9、 -(CH2)nSR9、 -(CH2)nS(0)2R9、 -(CH2)nS(0)2NR8aR8b、 -(CH2)nN(R8a)S(0)2R9、 -(CH2)nC(0)NR8aR8b 、 -(CH2)nOC(0)R9 、 -(CH2)nC(0)(CH2)nOR9 、 -(CH2)nN(R8a)C(0)R9,
( 2 )任选被 1-3个选自卤素原子、 羟基、 氰基、 三氟甲基取代的 烷基、 烷氧基;
( 3 )任选被 1-3个选自卤素原子、羟基、氰基、 三氟甲基、 烷基、 烷氧基、 -(CH2)nNR8aR8b、 -(CH2)nC(0)R9、 -(CH2)nSR9、 -(CH2)nS(0)2R9、
-(CH2)nS(0)2NR8aR8b 、 -(CH2)nN(R8a)S(0)2R9 、 -(CH2)nC(0)NR8aR8b 、 -(CH2)nOC(0)R9、 -(CH2)nC(0)(CH2)nOR9、 -(CH2)nN(R8a)C(0)R9取代的 C3.8 环烷基、 5-10元杂芳基、 5-10元杂环基;
R8a、 R8b分别独立地为氢, 或(^6烷基;
R9为氢, 或 C1-6烷基; ,
n为 0~2。
3、 如权利要求 2所述的化合物、 或其药学上可接受的盐或立体异构 体:
A和 B分别独立地为 CR6, R6为氢, 或 烷基;
R R5分别独立地为氢;
m为 1 ;
E为氢, 或钠离子。
4、 如权利要求 3所述的化合物、 或其药学上可接受的盐或立体异构 体:
R1为任选被 1-3个 R7a取代的苯基、 5-6元单杂芳基;
R2为任选被 1-3个 R7b取代的苯基、 5-6元单杂芳基、 9-10元稠杂芳 基;
( 1 ) 卤素原子、 氰基、 羟基、 三氟甲基、 -NR8aR8b、 -C(0)R9、 -C(0)NR8aR8b、 -OC(0)R9、 -N(R8a)C(0)R9,
( 2 )任选被 1-3个选自卤素原子、 羟基、 氰基、 三氟甲基取代的 烷基、 烷氧基,
( 3 )任选被 1-3个选自鹵素原子、羟基、氰基、 三氟曱基、 d-6烷基、 烷氧基、 -N 8aR8b、 -C(0)R9、 -C(0)NR8aR8b、 -OC(0)R9、 -N(R8a)C(0)R9 取代的 5-6元单杂环基;
R7b为
( 1 ) 卤素原子、 、 羟基、 三氟甲基、 -NR8aR8b、 -C(0)R9、 -SR9、 -S(0)2R9、 -C(0)NR8aR8b、 -OC(0) R9、 -N(R8a)C(0)R9 ,
( 2 )任选被 1 -3个选自卤素原子、 羟基、 氰基、 三氟曱基取代的 烷基、 C1-6烷氧基;
( 3 )任选被 1-3个选自卤素原子、羟基、氰基、 三氟甲基、 C1-6烷基、 烷氧基、 -NR8aR8b、 -C(0)R9、 -C(0)N 8aR8b、 -OC(0)R9、 -N(R8a)C(0)R9
取代的 5-6元单杂芳基、 5-6元单杂环基;
R8a、 R8b分别独立地为氢, 或 C^6烷基;
R9为氢, 或 C1-6烷基。
5、如权利要求 4所述的化合物、或其药学上可接受的盐或立体异构 体:
R1为任选被 1-3个 R7a取代的苯基、 吡啶基、 嘧啶基;
R2为任选被 1-3个 1 715取代的苯基、 吡啶基、 嘧啶基、 噻吩基、 吡唑 基、 吲唑基、 吲味基、 吡啶并吡咯基、 吡咯并吡1 ¾^、 (权 6中有此基团, 此处漏掉)、 吡唑并吡啶基、 会啉基;
( 1 ) 卤素原子、 氰基、 羟基、 三氟甲基、 -NH2,
( 2 )任选被 1-3个选自卤素原子、 羟基、 氰基、 三氟曱基取代的 C1-4 烷基,
( 3 )任选被 1-3个选自卤素原子、羟基、 、 三氟曱基、 烷基、 d.4烷氧基取代的哌啶基、 哌嗪基;
( 1 )卤素原子、 羟基、三氟甲基、 -NH2、 -C(0)R9、 -SR9、 -S(0)2R9 -NHC(0)R9,
( 2 )任选被 1-3个选自鹵素原子、 羟基、 氰基、 三氟曱基取代的<^_4 烷基、 C 烷氧基;
( 3 )任选被 1-3个选自卤素原子、羟基、 、 三氟甲基、 C"烷基、 d.4烷氧基、 -NH2取代的吡咯基、 吡唑基、 咪唑基、 哌啶基、 哌嗪基、 吗 啉基;
R9为氢, 或 烷基。
6、如权利要求 5所述的化合物、或其药学上可接受的盐或立体异构 体:
R1为任选被 1-3个 1 73取代的苯基、 吡啶基;
R2为任选被 1-3个 R7b取代的苯基、 吡啶基、 嘧啶基、 噻吩基、 吡唑 基、 吲唑基、 吲味基、 吡57定并吡洛基、 吡各并吡 p定基、 吡唑并吡1 ^J^、 全 啉基;
R7a为
( 1 ) 卤素原子、 氰基、 羟基、 三氟甲基、 -NH2,
(2)任选被 1-2个选自羟基、 氰基、 三氟甲基取代的曱基、 乙基、 异丙基,
(3)任选被 1-2个选自羟基、 氰基、 三氟甲基、 甲基、 甲氧基取代 的哌啶基、 哌嗪基;
R7b为
( 1) 卤素原子、 氰基、 羟基、 三氟甲基、 -NH2、 -SR9、 -S(0)2R9、 -NHC(0)R9,
(2)任选被 1-2个选自羟基、 氰基、 三氟甲基取代的甲基、 乙基、 正丙基、 异丙基、 甲氧基、 乙氧基;
(3)任选被 1-2个选自羟基、 氰基、 三氟甲基、 甲基、 乙基、 曱氧 基、 乙氧基、 - NH2取代的吡咯基、 吡唑基、 哌嗪基、 吗啉基;
R9为氢, 甲基, 或乙基。
7、如权利要求 1所述的化合物、或其药学上可接受的盐或立体异构
£f£000/M0ZN3/X3d
05
£5
9、 如权利要求 8所述的药物組合物, 其中还包含一种或多种抗肿 瘤剂和 /或免疫抑制剂, 所述的抗肿瘤剂和免疫抑制剂为抗代谢物, 选 自卡培他滨、 吉西他滨、 培美曲塞二钠; 为生长因子抑制剂, 选自帕 唑帕尼、 伊马替尼、 埃罗替尼、 拉帕替尼、 吉非替尼、 凡德他尼; 为 抗体, 选自赫赛汀、 贝伐单抗; 为有丝***抑制剂, 选自紫杉醇、 长 春瑞滨、 多西他赛、 多柔比星; 为抗肿瘤激素类, 选自来曲唑、 他莫 西芬、 氟维司群、 氟他胺、 曲普瑞林; 为烷化剂类, 选自环磷酰胺、 氮芥、 马法兰、 瘤可宁、 卡莫司汀; 为金属铂类, 选自卡铂、 顺铂、
奥沙利铂; 为拓朴异构酶抑制剂, 选自拓朴特肯喜树碱、 拓朴替康、 依立替康; 为免疫抑制类, 选自依维莫司、 西罗莫司、 特癌适; 为嘌 呤类似物, 选自 6-巯基嘌呤、 6-硫鸟嘌呤、 硫唑嘌呤; 为抗生素类, 选自菌素 D、 柔红霉素、 阿霉素、 米托蒽醌、 争光霉素、 普卡霉素; 为肾上腺皮质抑制剂类, 选自氨鲁米特。
10、 权利要求 1所述的化合物、 或其药学上可接受的盐或立体异构 体在制备治疗和 /或预防增殖性疾病的药物中的用途, 所述增殖性疾病为 癌症或非癌性增殖性疾病, 所述癌症选自脑瘤、 肺癌、 鳞状上皮细胞、 膀胱癌、 胃癌、 卵巢癌、 腹膜癌、 胰腺癌、 乳腺癌、 头颈癌、 子宫颈 癌、 子宫内膜癌、 直肠癌、 肝癌、 肾癌、 食管腺癌、 食管鳞状细胞癌、 实体瘤、 ***癌、 曱状腺癌、 雌性生殖道癌、 原位癌、 淋巴瘤、 神 经纤维瘤病、 骨癌、 皮肤癌、 结肠癌、 睾丸癌、 胃肠道间质瘤、 肥大 细胞肿瘤、 多发性骨髓瘤、 黑色素瘤、 胶质瘤或肉瘤; 所述非癌性增 殖性疾病选自皮肤或***的良性增生。
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TW201113286A (en) * | 2009-09-03 | 2011-04-16 | Array Biopharma Inc | Substituted pyrazolo[1,5-a]pyrimidine compounds as mTOR inhibitors |
CN102256966A (zh) * | 2008-10-17 | 2011-11-23 | 白头生物医学研究所 | 可溶性mTOR复合物和其调节剂 |
CN102399218A (zh) * | 2010-09-16 | 2012-04-04 | 和记黄埔医药(上海)有限公司 | 一类并合三杂环及其作为pi3k抑制剂的用途 |
CN102399220A (zh) * | 2010-09-15 | 2012-04-04 | 黄振华 | 三并环类PI3K和mTOR双重抑制剂 |
CN102625803A (zh) * | 2009-09-11 | 2012-08-01 | 赛林药物股份有限公司 | 药学上有用的杂环-取代的内酰胺 |
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CN102256966A (zh) * | 2008-10-17 | 2011-11-23 | 白头生物医学研究所 | 可溶性mTOR复合物和其调节剂 |
TW201113286A (en) * | 2009-09-03 | 2011-04-16 | Array Biopharma Inc | Substituted pyrazolo[1,5-a]pyrimidine compounds as mTOR inhibitors |
CN102625803A (zh) * | 2009-09-11 | 2012-08-01 | 赛林药物股份有限公司 | 药学上有用的杂环-取代的内酰胺 |
CN102399220A (zh) * | 2010-09-15 | 2012-04-04 | 黄振华 | 三并环类PI3K和mTOR双重抑制剂 |
CN102399218A (zh) * | 2010-09-16 | 2012-04-04 | 和记黄埔医药(上海)有限公司 | 一类并合三杂环及其作为pi3k抑制剂的用途 |
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