WO2011124087A1 - 噁二唑基哌嗪衍生物及其用途 - Google Patents
噁二唑基哌嗪衍生物及其用途 Download PDFInfo
- Publication number
- WO2011124087A1 WO2011124087A1 PCT/CN2011/000489 CN2011000489W WO2011124087A1 WO 2011124087 A1 WO2011124087 A1 WO 2011124087A1 CN 2011000489 W CN2011000489 W CN 2011000489W WO 2011124087 A1 WO2011124087 A1 WO 2011124087A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- methyl
- hydroxy
- phenyl
- oxadiazol
- allyl
- Prior art date
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- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 title abstract description 3
- 150000004885 piperazines Chemical class 0.000 title 1
- 229940066771 systemic antihistamines piperazine derivative Drugs 0.000 title 1
- OFLXLNCGODUUOT-UHFFFAOYSA-N acetohydrazide Chemical class C\C(O)=N\N OFLXLNCGODUUOT-UHFFFAOYSA-N 0.000 claims abstract description 94
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims abstract description 37
- 150000001875 compounds Chemical class 0.000 claims abstract description 37
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 179
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 61
- -1 trifluoromethoxy, amino Chemical group 0.000 claims description 54
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 52
- 125000000623 heterocyclic group Chemical group 0.000 claims description 51
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 46
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 36
- 125000003118 aryl group Chemical group 0.000 claims description 33
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- 125000001072 heteroaryl group Chemical group 0.000 claims description 28
- 229910052739 hydrogen Inorganic materials 0.000 claims description 28
- 239000001257 hydrogen Substances 0.000 claims description 28
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 28
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 28
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 26
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 25
- 125000000217 alkyl group Chemical group 0.000 claims description 25
- 125000003342 alkenyl group Chemical group 0.000 claims description 24
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- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 21
- 125000006612 decyloxy group Chemical group 0.000 claims description 18
- 125000000304 alkynyl group Chemical group 0.000 claims description 17
- 125000004495 thiazol-4-yl group Chemical group S1C=NC(=C1)* 0.000 claims description 17
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- 229910052757 nitrogen Inorganic materials 0.000 claims description 14
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- 201000004101 esophageal cancer Diseases 0.000 description 1
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- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 229960005420 etoposide Drugs 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 125000005567 fluorenylene group Chemical group 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Substances O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 1
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- 125000002541 furyl group Chemical group 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 1
- 229960005277 gemcitabine Drugs 0.000 description 1
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- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- VKYKSIONXSXAKP-UHFFFAOYSA-N hexamethylenetetramine Chemical compound C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 201000005249 lung adenocarcinoma Diseases 0.000 description 1
- 210000002751 lymph Anatomy 0.000 description 1
- 229940050906 magnesium chloride hexahydrate Drugs 0.000 description 1
- DHRRIBDTHFBPNG-UHFFFAOYSA-L magnesium dichloride hexahydrate Chemical compound O.O.O.O.O.O.[Mg+2].[Cl-].[Cl-] DHRRIBDTHFBPNG-UHFFFAOYSA-L 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
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- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
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- 125000002757 morpholinyl group Chemical group 0.000 description 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 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
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- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
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- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
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- 230000008569 process Effects 0.000 description 1
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- 230000005522 programmed cell death Effects 0.000 description 1
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- QZWHWHNCPFEXLL-UHFFFAOYSA-N propan-2-yl n-[2-(1,3-thiazol-4-yl)-3h-benzimidazol-5-yl]carbamate Chemical compound N1C2=CC(NC(=O)OC(C)C)=CC=C2N=C1C1=CSC=N1 QZWHWHNCPFEXLL-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound 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
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- SMQUZDBALVYZAC-UHFFFAOYSA-N salicylaldehyde Chemical compound OC1=CC=CC=C1C=O SMQUZDBALVYZAC-UHFFFAOYSA-N 0.000 description 1
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- 238000012216 screening Methods 0.000 description 1
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- 239000003381 stabilizer Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical compound [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
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- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
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- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
-
- 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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- C07D417/12—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 linked by a chain containing hetero atoms as chain links
-
- 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
- C07D417/14—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 three or more hetero rings
Definitions
- the invention belongs to the technical field of medicine, and relates to an oxadiazolyl piperazine derivative and a use thereof, in particular to an oxadiazolyl piperazine derivative, a pharmaceutical composition thereof, and a preparation thereof for preparing a cell proliferation inhibitor for treatment and/or Or use in drugs that prevent various cancers.
- Tumor is a disease that seriously threatens human health. In recent years, the incidence and mortality of tumors have been increasing year by year. Cytotoxic drugs can kill tumor cells, but they are not selective for cancer cells and normal cells, so they have strong toxic side effects.
- Apoptosis also known as programmed cell death, plays an important role in the development and progression of tumors. In recent years, an important class of protein caspase has been discovered in cells.
- procaspase-3 can be activated into caspase-3 in vivo, which induces apoptosis.
- the process by which procaspase-3 forms caspase-3 is destroyed, thus causing tumor tissue growth.
- the technical problem solved by the present invention is to synthesize a series of compounds containing oxadiazolyl piperazine and to screen for antitumor activity in vitro, and the results show that the antitumor activity is good.
- the present invention relates to an oxadiazole-containing piperazine acetohydrazide derivative of the formula I, and geometric isomers thereof or a pharmaceutically acceptable hydrate or solvate thereof,
- Ar 1 is an aryl group, an aryl group (-C 4 ) fluorenyl group, and Ar 1 is optionally substituted with 1-3 R 2 groups;
- R 2 is hydrogen, halogen, trifluoromethyl, trifluoromethoxy, amino, nitro, (-C decyl, (dC 4 )alkenyl, (-C4)alkynyl, (d-C4)oxyl Base, (dC alkylthio, allyl, (2-methyl)allyl, (3-methyl)allyl, (dC 4 )nonyloxymethyl, (dC 3 )indenylene Oxylate
- R 1 is aryl, naphthyl, 5-10 membered heteroaryl, 5-10 membered heteroaryl(dC 4 )alkyl, 5-10 membered saturated or partially saturated heterocyclic group, 5-10 member saturated or Partially saturated heterocyclic (d-)indenyl, said heteroaryl and heterocyclyl containing 1-3 heteroatoms selected from 0, N and S, and R 1 optionally 1-3 R 3 substituted ;
- R 3 is hydrogen, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, amino, nitro, fluorenyl, (dC 4 ) fluorenyl, (C!-C alkenyl, (C r C 4 ) alkynyl , (dC 4 ) alkoxy, (dC 4 )alkylthio, hydroxy(-)indenyl, allyl, (2-methyl)allyl, (dC 4 )nonyloxymethyl, (- C3) fluorenyldioxy, aryl(-C 4 )fluorenyl, aryl(d-)decyloxy, 5-10 membered heteroaryl (C G -C4) fluorenyl, 5-10 membered Aryl (C Q -C 4 ) decyloxy, 5-10 membered saturated or partially saturated heterocyclic (C Q -C 4 ) fluorenyl, 5-10 membered saturated or partially saturated heterocyclic group (
- R 4 is hydrogen, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, amino, nitro, fluorenyl, fluorenyl, (-C4)alkenyl, (C CA)alkynyl, (CrC 4 )alkoxy Base, (C r C 4 ) sulfonyl, hydroxy (dC 4 ) alkyl, allyl, (2-methyl)allyl, (dC 4 )nonyloxymethyl, (CC 3 ) alum Di-dioxy, aryl (C r C 4 ) fluorenyl, aryl (d-Ca) decyloxy, 5-10 membered heteroaryl (C 4 ) alkyl, 5-10 membered heteroaryl (CC 4 ) a decyloxy group, a 5-10 membered saturated or partially saturated heterocyclic group C r C 4 alkyl group, a 5-10 membered saturated or partially saturated heterocyclic group dC 4
- the present invention preferably relates to derivatives of the formula I, and geometric isomers thereof, or pharmaceutically acceptable salts, hydrates or solvates thereof,
- Ar 1 is phenyl, phenyl dC 4 fluorenyl, and Ar 1 is optionally substituted with 1-3 R 2 ;
- R 2 is hydrogen, halogen, trifluoromethyl, trifluoromethoxy, amino, nitro, (-C4)decyl, (dC 4 )alkenyl, (-C alkynyl, (dC 4 )decyloxy, (-C4)alkylthio, allyl, (2-methyl)allyl, (3-methyl)allyl, (-C4) a decyloxymethyl group, (dC 3 ) adenylene dioxy group;
- R 1 is an aryl group, a naphthyl group, a 5-10 membered heteroaryl group, a 5-10 membered saturated or partially saturated heterocyclic group, and the heteroaryl group and the heterocyclic group have 1 to 3 selected from 0, N and a hetero atom of S, and R 1 is optionally substituted with 1-3 R 3 ;
- R 3 is hydrogen, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, amino, nitro, fluorenyl, (dC 4 )alkyl, (dC 4 )alkenyl, (dC 4 )alkynyl, (dC 4 ) alkoxy, (dC 4 )alkylthio, hydroxy (dC 4 )indolyl, allyl, (2-methyl)allyl, (dC 4 )nonyloxymethyl, (dC 3 ) N-decyldioxy, aryl(-C 2 )indenyl, arylmethoxy, 5-10 membered heteroaryl(Co-C 2 )alkyl, 5-10 membered heteroarylmethoxy, a 5-10 membered saturated or partially saturated heterocyclic group (C G -C 2 )indenyl, a 5-10 membered saturated or partially saturated heterocyclic methoxy group, said heteroaryl group and heterocyclic
- R 4 is hydrogen, hydroxy, trifluoromethyl, trifluoromethoxy, amino, nitro, fluorenyl, (dC 4 ) fluorenyl, (-C4)alkenyl, (dC 4 )alkynyl, (dC 4 ) decyloxy, (dC 4 ) thiol, hydroxy (-C4) fluorenyl, allyl, (2-methyl)allyl, (dC 4 ) decyloxymethyl, (dC 3 ) N-decyldioxy, aryl (CC 2 ) fluorenyl, 5-10 membered heteroaryl (-C2) fluorenyl, 5-10 membered saturated or partially saturated heterocyclic (d-) fluorenyl group,
- the heteroaryl and heterocyclic groups contain from 1 to 3 heteroatoms selected from the group consisting of 0, N and S.
- the present invention also preferably relates to a derivative of the formula I, and a geometric isomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof,
- Ar 1 is phenyl, benzyl, and Ar 1 is optionally substituted with 1-3 R 2 ;
- R 2 is hydrogen, halogen, trifluoromethyl, trifluoromethoxy, amino, nitro, (-C4)decyl, alkenyl, alkynyl, (-C decyloxy, (dC 4 ) thiol , allyl, (2-methyl)allyl, (3-methyl)allyl, (dC 4 ) alkoxymethyl, (C!-)-indenyldioxy;
- R 1 is phenyl, naphthyl, 5-10 membered heteroaryl, 5-10 membered saturated or partially saturated heterocyclic group, and said heteroaryl and heterocyclic group contain 1-3 selected from 0, N and a hetero atom of S, and R 1 is optionally substituted with 1-3 R 3 ;
- R 3 is hydrogen, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, amino, nitro, fluorenyl, (-C4)indenyl, (Cr)alkenyl, (dC 4 )decyloxy, (dC 4 ) sulfhydryl, hydroxy (dC 4 ) fluorenyl, allyl, (2-methyl)allyl, (C r C 4 ) alkoxymethyl, (dC 3 ) fluorenyldioxy , aryl (dC 2 ) alkyl, aryl methoxy, 5-10 membered heteroaryl (C Q -C 2 ) fluorenyl, 5-10 membered heteroarylmethoxy, 5-10 member saturated or a partially saturated heterocyclic group (C G -C 2 ) alkyl group, a 5-10 membered saturated or partially saturated heterocyclic methoxy group, said heteroaryl group and heterocyclic group having 1-3 selected from 0, a hetero
- the present invention particularly preferably defines a compound of formula I, and geometric isomers thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof,
- Ar 1 is phenyl, benzyl, and Ar 1 is optionally substituted with 1-3 R 2 ;
- R 2 is hydrogen, halogen, trifluoromethyl, allyl, (2-methyl)allyl;
- R 1 is phenyl, naphthyl, 5-10 membered heteroaryl, 5-10 membered saturated or partially saturated heterocyclic group, and said heteroaryl and heterocyclic group contain 1-3 selected from 0, N and a hetero atom of S, and R 1 is optionally substituted with 1-3 R 3 ;
- R 3 is hydrogen, halogen, hydroxy, fluorenyl, (C r C 4 )alkenyl, allyl, (2-methyl)allyl, (3-methyl)allyl, (-C 3 ) N-decyldioxy, arylmethoxy, 5-10 membered heteroaryl(Co-C 2 )indenyl, 5-10 membered heteroarylmethoxy, said heteroaryl containing 1-3 a hetero atom selected from 0, N and S, and the aryl and heteroaryl are optionally substituted with from 1 to 3 R 4 ;
- R 4 is hydrogen, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, (dC alkyl, (dC 4 ) alkenyl, (dC 4 ) alkynyl, (Ci-C 4 ) decyloxy, ene Propyl, (2-methyl)allyl, (dC 3 ) fluorenylenedioxy, benzyl, 3,4-dioxymethylenebenzyl.
- Ar 1 is a phenyl group, and Ar 1 is optionally substituted with 1-3 R 2 ;
- R 2 is halogen, trifluoromethyl
- R 1 is phenyl, naphthyl, ⁇ ⁇ , and R 1 is optionally substituted with 1-3 R 3 ;
- R 3 is hydrogen, halogen, hydroxy, (CC 4 )alkyl, (dC 4 )alkenyl, allyl, (2-methyl)allyl, (3-methyl)allyl, phenyl Oxyl, 4-thiazolyl, 4-thiazolylmethoxy, and the phenyl and thiazolyl are optionally substituted with from 1 to 3 R 4 ;
- R 4 is hydrogen, halogen, hydroxy, trifluoromethyl, (-C4) fluorenyl, (C!-Cs) fluorenylenedioxy, benzyl, 3,4-dioxymethylenebenzyl .
- the compounds of the formula I according to the invention, and their geometric isomers or pharmaceutically acceptable salts, hydrates or solvates thereof, are preferably the following compounds, but these compounds are not meant to limit the invention in any way:
- the derivatives of the above formula I in the present invention may form a pharmaceutically acceptable salt with an acid according to some usual methods in the art to which the present invention pertains.
- Pharmaceutically acceptable addition salts include inorganic acids and organic acid addition salts, added to the following acids Salts are particularly preferred: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalene disulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, horse Acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid, etc.
- the invention also includes prodrugs of the derivatives of the invention.
- Prodrugs of the derivatives of the invention are derivatives of formula I which may themselves have weak or even no activity, but after administration, under physiological conditions (for example by metabolism, solvolysis or otherwise) Converted to the corresponding biologically active form.
- halogen means fluorine, chlorine, bromine or iodo
- mercapto means a straight or branched fluorenyl group
- alkylene means a straight or branched fluorenylene group
- Aryl means a phenyl group having no substituent or a substituent
- heteroaryl means a monocyclic or polycyclic ring system containing one or more hetero atoms selected from N, 0, S, ring The system is aromatic, such as thiazolyl, imidazolyl, pyridyl, pyrazolyl, (1,2,3)- and (1,2,4)-triazolyl, furyl, thienyl, pyrrolyl , benzothiazolyl, oxazolyl, isoxazolyl, naphthyl, quinolyl, isoquinolyl, benzimidazolyl, benzoxazolyl, etc.; "saturated or partially saturated heterocyclic
- the present invention may contain a derivative of the above formula I, and a pharmaceutically acceptable salt, hydrate or solvate thereof as an active ingredient, mixed with a pharmaceutically acceptable carrier or excipient to prepare a composition, and prepared into a clinical preparation.
- a pharmaceutically acceptable carrier or excipient means any diluent, adjuvant and/or carrier which can be used in the pharmaceutical field.
- the derivatives of the present invention can be used in combination with other active ingredients as long as they do not cause other adverse effects such as allergic reactions.
- compositions of the present invention can be formulated in a number of dosage forms containing some of the commonly used excipients in the pharmaceutical arts.
- a plurality of dosage forms as described above may be administered as a medicament such as an injection, a tablet, a capsule, an aerosol, a suppository, a film, a pill, a tanning agent, an ointment or the like.
- Carriers for use in the pharmaceutical compositions of the present invention are common types available in the pharmaceutical arts, including: binders, lubricants, disintegrants, solubilizers, diluents, stabilizers, suspending agents, non-pigmenting, flavoring agents , preservatives, solubilizers and matrices.
- the pharmaceutical preparations can be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or locally), and if certain drugs are unstable under gastric conditions, they can be formulated into enteric coated tablets.
- the in vitro antitumor activity test indicates that the derivative of the formula I of the present invention has antitumor activity, and thus the compound of the present invention can be used for the preparation of a medicament for treating and/or preventing various cancers such as breast, lung, liver, kidney, colon , rectum, stomach, prostate, bladder, uterus, pancreas, bone marrow, testis, ovary, lymph, soft tissue, head and neck, thyroid, esophageal cancer and leukemia, neuroblastoma, etc. Especially for the preparation of treatment and / or prevention of white blood Diseased drugs.
- various cancers such as breast, lung, liver, kidney, colon , rectum, stomach, prostate, bladder, uterus, pancreas, bone marrow, testis, ovary, lymph, soft tissue, head and neck, thyroid, esophageal cancer and leukemia, neuroblastoma, etc.
- white blood Diseased drugs Especially for the preparation of treatment and / or prevention of white blood Disease
- the active compound of the present invention or a pharmaceutically acceptable salt thereof and a solvate thereof can be used alone as the sole antitumor drug, or can be combined with an antitumor drug which has been marketed (for example, the platinum drug cisplatin, the camptothecin drug irinotene). Kang, vinca alkaloids noviben, deoxycytidine drugs gemcitabine, etoposide, paclitaxel, etc.). Combination therapy is achieved by administering the individual therapeutic components simultaneously, sequentially or separately.
- the invention synthesizes a series of compounds containing oxadiazolyl piperazine for the first time.
- the preparation method is simple and reproducible, and the prepared compound has high purity, high yield and good antitumor activity.
- the nuclear magnetic resonance spectrum of the derivative was determined by Bruker ARX-600, qualitatively pure or chemically pure.
- Example 1 > ⁇ -(2-hydroxy-4-((2-((benzo[[1,3]dioxolan-5-yl)methyl)thiazol-4-yl)methoxy)) Phenylmethylene)-2-(4-((3-(4-((2-(trifluoromethyl))phenoxy)methyl)phenyl)-1,2,4-oxadiazole- 5-yl)methyl)piperazin-1-yl) acetohydrazide hydrochloride
- Step D 1-((3-(4-((2-(Trifluoromethyl))phenoxy)methyl)phenyl)-5-(chloromethyl)-1,2,4-oxadiazole- 5-yl)methyl)piperazine
- Step E 2-(4-((3-(4-((2-(trifluoromethyl))phenoxy)methyl)phenyl)-5-(chloromethyl)-1,2,4- Ethyl-5-yl)methyl)piperazin-1-yl)ethyl acetate
- Step F 2-(4-((3-(4-((2-(trifluoromethyl))phenoxy)methyl)phenyl)-5-(chloromethyl)-1,2,4- Diazol-5-yl)methyl)piperazine small acetyl hydrazide
- Step G 4-((2-Benzo[ ⁇ ]] 1,3]dioxolan-5-yl)methyl)thiazol-4-yl)methoxy)-2-hydroxybenzaldehyde
- the compound BI is reacted with sodium hydrosulfide to obtain the intermediate B-II, which is then cyclized with 1,3-dichloroacetone to obtain the intermediate ⁇ - ⁇ , and finally reacted with 2,4-dihydroxybenzaldehyde to obtain 4 -((2-((Benzyl[[1,3]dioxolan-5-yl)methyl)thiazol-4-yl)methoxy)-2-hydroxybenzaldehyde, as shown in Scheme 2 .
- the specific preparation method is as follows:
- Step G-2 2- (Preparation of (benzo[rf][l,3]dioxolan-5-yl)methyl)-4-(chloromethyl)thiazole
- Step H > ⁇ -( 4 -((2-((Benzyl)[rf][l,3]dioxolan-5-yl)methyl)thiazol-4-yl)methoxy)-2-hydroxyl Benzamethylene)-2-(4-((3-(4-((2-(trifluoromethyl))phenoxy)methyl)phenyl)-1,2,4-oxadiazole-5 Of -methyl)methyl)piperazin-1-yl)acetohydrazide hydrochloride
- Example 1 According to the method of Example 1, starting with 4-chloromethylbenzonitrile and a suitable substituted phenol as starting materials
- the oxadiazolyl piperazine acetohydrazide derivative A-VII is obtained by a six-step reaction; and then the compound of Examples 2 and 3 is obtained by reacting with a suitable aldehyde prepared according to the method of Step G.
- Example 2 Hydroxy-4-((2-((benzo[Z,3]dioxolan-5-yl)methyl)thiazol-4-yl)methoxy)phenylmethylene) -2-(4-((3-(4-(4-chlorophenoxy)methyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)piperazine-1 -yl)acetyl sulfonium salt '(He 's)£l'l7 '(HI ' ⁇ ' ⁇ '(HZ: 'P)80 XUZ 's)l3'g '(HZ: 'ui)gg-9 '(HZ: ' ⁇ ) ⁇ '(HZ.
- 3 ⁇ 4 « (3 ⁇ 4- ⁇ - )3 ⁇ 4(3 ⁇ 4 ⁇ (3 ⁇ 4-5-3 ⁇ 4) ⁇ [ ⁇ - ⁇ -(3 ⁇ 4 *(3 ⁇ 4 ⁇ ( ⁇ )) inch) - ⁇ ) -(3 ⁇ 4 ⁇ 3 ⁇ 4* (Love 3 ⁇ 4 ⁇ ⁇ ⁇ - ⁇ m ⁇ .
- 3 ⁇ 4 ⁇ 3 ⁇ 4 « (3 ⁇ 4- ⁇ -# ⁇ 3 ⁇ 4 ⁇ (3 ⁇ 4 ⁇ (»- ⁇ -3 ⁇ 4 ⁇ 3 ⁇ 4
- Example 22 ⁇ -(2-Hydroxy-3-(2-methylallyl)phenylmethylene)-2-(4-((3-(4-)(4-fluorophenoxy)) methyl) phenyl) -I, 2, 4 - oxadiazol-5-yl) methyl) piperazin-1-yl) acetohydrazide hydrochloride
- Example 24 ⁇ -(2-Hydroxy-3-(5-(2-benzylthiazol-4-yl)phenylmethylene)-2-(4-((3-(4-((3, 4-Difluorophenoxy)methyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)piperazin-1-yl)acetohydrazide hydrochloride
- Step K-1 Preparation of 2-phenylthioacetamide
- 3 ⁇ 4 ⁇ 3 ⁇ 4 depicting 3 ⁇ 4@7(3 ⁇ 4 ⁇ (3 ⁇ 4 ⁇ ( - 2
- Example 27 was obtained according to the method of Example 1.
- Example 28 ⁇ -( (4-methyl-7-hydroxy-2-oxo-2H-chromen-6-yl)methylene)-2-(4-((3-(4-((3,4-difluorobenzene)) Oxy)methyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)piperazin-1-yl)acetohydrazide hydrochloride
- Example 28 The compound of Example 28 was prepared in the same manner as in Example 1. MS [MH + ] (m/z): 645.
- the compound of the above formula I according to the present invention is inhibited in vitro by human leukemia cell line HL-60, human prostate cancer cell line DU145, human lung adenocarcinoma cell line A549, human colon cancer cell line Colon 205, human lung cancer cell line NCI-H226, human liver cancer Cell Hep3B, human gastric cancer cell HGC-27, human hepatoma cell HepG2, human breast cancer cell MCF-7, human glioma cell line U87 activity screening, control substance ⁇ -((2-hydroxy-3-allyl)benzene
- PAC-1 benzylidene-2-(4-benzylpiperazin-1-yl)acetohydrazide
- test sample (2) Dissolve the test sample with 50 dimethyl sulfoxide, then add the appropriate amount of the culture solution to dissolve the sample into 2 mg/mL solution, and then dilute the sample to 20, 4, 0.8, 0.16 in a 24-well plate. , 0.032 g/mL. Each concentration was added to 3 wells, and the growth of the surrounding two rows and two columns was greatly affected by the environment and was only used as a blank cell well.
- the 96-well plate was placed in an incubator for 72 h.
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Description
噁二唑基哌嗪衍生物及其用途 m
本发明属于医药技术领域, 涉及噁二唑基哌嗪衍生物及其用途, 具体涉及噁二唑 基哌嗪衍生物、其药物组合物, 及其在制备细胞增殖抑制剂, 用于治疗和 /或预防各种 癌症的药物中的用途。
背景技术
肿瘤是一种严重威胁人类生命健康的疾病, 近年来, 肿瘤的发生率和死亡率呈逐 年上升的趋势。细胞毒性药物能够杀死肿瘤细胞,但对癌细胞与正常细胞缺乏选择性, 因此具有较强的毒副作用。
寻找能够选择性地杀死癌细胞, 对正常增殖细胞无影响的靶向性抗肿瘤药物已成 为新型抗肿瘤药物研发的重要方向。 细胞凋亡又称细胞程序性死亡, 在肿瘤的发生和 发展过程中起着重要作用。 近年来人们在细胞内发现了一类重要的蛋白质半胱天冬酶
-3酶原蛋白(procaspase-3 ), procaspase-3在体内可被活化为半胱天冬酶 -3 (caspase-3 ), 进而诱导细胞的凋亡。 但在癌变细胞中, procaspase-3形成 caspase-3的过程被破坏, 因此造成肿瘤组织的生长。
2006年, Alan G Porter在 Nature Chemical Biology上公开了一个能够选择性激活 procaspase-3的化合物 PAC-1 (其结构式如下) , 并且进一步阐明了 caspase-3在诱导 细胞凋亡过程中的作用机理, 研究表明, 能够活化 procaspase-3的化合物可以作为靶 向分子从而诱导癌细胞的凋亡。 由于 procaspase-3在正常细胞中含量较低, 因此健康 细胞对 PAC-1 并不敏感, 通过对同一个肿瘤患者的正常细胞与肿瘤细胞进行化验表 明, 癌变细胞对 PAC-1的敏
PAC-1结构式
发明内容
本发明所解决的技术问题是合成一系列含有噁二唑基哌嗪的化合物, 并进行了体 外抗肿瘤活性筛选, 结果表明具有较好的抗肿瘤活性。
其中,
Ar1为芳基, 芳基 ( -C4)垸基, 且 Ar1任选 1-3个 R2取代;
R2为氢, 卤素, 三氟甲基, 三氟甲氧基, 氨基, 硝基, ( -C 垸基, (d-C4)烯基, ( -C4)炔基, (d-C4)垸氧基, (d-C 烷硫基, 烯丙基, (2-甲基)烯丙基, (3-甲基)烯丙 基, (d-C4)垸氧基甲基, (d-C3)亚垸基二氧基;
R1为芳基, 萘基, 5-10元杂芳基, 5-10元杂芳基 (d-C4)烷基, 5-10元饱和或部分 饱和的杂环基, 5-10元饱和或部分饱和的杂环基 (d- )垸基, 所述杂芳基和杂环基含 有 1-3个选自 0、 N和 S的杂原子, 且 R1任选 1-3个 R3取代;
R3为氢, 卤素, 羟基, 三氟甲基, 三氟甲氧基, 氨基, 硝基, 巯基, (d-C4)垸基, (C!-C烯基, (CrC4)炔基, (d-C4)烷氧基, (d-C4)烷硫基, 羟基 ( - )垸基, 烯丙基, (2-甲基)烯丙基, (d-C4)垸氧基甲基, ( -C3)亚垸基二氧基, 芳基 ( -C4)垸基, 芳基 (d- )垸氧基, 5-10元杂芳基 (CG-C4)垸基, 5-10元杂芳基 (CQ-C4)垸氧基, 5-10元饱和 或部分饱和的杂环基 (CQ-C4)垸基, 5-10元饱和或部分饱和的杂环基 (CQ-C4)烷氧基, 所 述杂芳基和杂环基含有 1-3个选自 0、 N和 S的杂原子, 且所述芳基、 杂芳基和杂环 基任选 1-3个 R4取代;
R4为氢, 卤素, 羟基, 三氟甲基, 三氟甲氧基, 氨基, 硝基, 巯基, 垸基, ( -C4)烯基, (C CA)炔基, (CrC4)烷氧基, (CrC4)垸硫基, 羟基 (d-C4)烷基, 烯丙基, (2-甲基)烯丙基, (d-C4)垸氧基甲基, (C C3)亚垸基二氧基, 芳基 (CrC4)垸基, 芳基 (d-Ca)垸氧基, 5-10元杂芳基 (C C4)烷基, 5-10元杂芳基 (C C4)垸氧基, 5-10元饱和 或部分饱和的杂环基 CrC4烷基, 5-10元饱和或部分饱和的杂环基 d-C4垸氧基, 所 述杂芳基和杂环基含有 1-3个选自 0、 N和 S的杂原子。
本发明优选涉及定义如下的通式 I衍生物, 及其几何异构体或其药学上可接受的 盐、 水合物或溶剂化物,
其中,
Ar1为苯基, 苯基 d-C4垸基, 且 Ar1任选 1-3个 R2取代;
R2为氢, 卤素, 三氟甲基, 三氟甲氧基, 氨基, 硝基, ( -C4)垸基, (d-C4)烯基,
( -C 炔基, (d-C4)垸氧基, ( -C4)烷硫基, 烯丙基, (2-甲基)烯丙基, (3-甲基)烯丙 基, ( -C4)垸氧基甲基, (d-C3)亚垸基二氧基;
R1为芳基, 萘基, 5-10元杂芳基, 5-10元饱和或部分饱和的杂环基, 所述杂芳基 和杂环基含有 1-3个选自 0、 N和 S的杂原子, 且 R1任选 1-3个 R3取代;
R3为氢, 卤素, 羟基, 三氟甲基, 三氟甲氧基, 氨基, 硝基, 巯基, (d-C4)烷基, (d-C4)烯基, (d-C4)炔基, (d-C4)烷氧基, (d-C4)烷硫基, 羟基 (d-C4)垸基, 烯丙基, (2-甲基)烯丙基, (d-C4)垸氧基甲基, (d-C3)亚垸基二氧基, 芳基 ( -C2)垸基, 芳基 甲氧基, 5-10元杂芳基 (Co-C2)烷基, 5-10元杂芳基甲氧基, 5-10元饱和或部分饱和的 杂环基 (CG-C2)垸基, 5-10元饱和或部分饱和的杂环基甲氧基, 所述杂芳基和杂环基含 有 1-3个选自 0、 N和 S的杂原子,且所述芳基、杂芳基和杂环基任选 1-3个 R4取代;
R4为氢, 素, 羟基, 三氟甲基, 三氟甲氧基, 氨基, 硝基, 巯基, (d-C4)垸基, ( -C4)烯基, (d-C4)炔基, (d-C4)垸氧基, (d-C4)垸硫基, 羟基 ( -C4)垸基, 烯丙基, (2-甲基)烯丙基, (d-C4)垸氧基甲基, (d-C3)亚垸基二氧基, 芳基 (C C2)垸基, 5-10 元杂芳基 ( -C2)垸基, 5-10元饱和或部分饱和的杂环基 (d- )垸基, 所述杂芳基和杂 环基含有 1-3个选自 0、 N和 S的杂原子。
本发明还优选涉及定义如下的通式 I衍生物, 及其几何异构体或其药学上可接受 的盐、 水合物或溶剂化物,
其中,
Ar1为苯基, 苯甲基, 且 Ar1任选 1-3个 R2取代;
R2为氢, 卤素, 三氟甲基, 三氟甲氧基, 氨基, 硝基, ( -C4)垸基, 烯基, 炔基, ( -C 垸氧基, (d-C4)垸硫基, 烯丙基, (2-甲基)烯丙基, (3-甲基)烯丙 基, (d-C4)烷氧基甲基, (C!- )亚垸基二氧基;
R1为苯基, 萘基, 5-10元杂芳基, 5-10元饱和或部分饱和的杂环基, 所述杂芳基 和杂环基含有 1-3个选自 0、 N和 S的杂原子, 且 R1任选 1-3个 R3取代;
R3为氢, 卤素, 羟基, 三氟甲基, 三氟甲氧基, 氨基, 硝基, 巯基, ( -C4)垸基, (Cr )烯基, (d-C4)垸氧基, (d-C4)垸硫基, 羟基 (d-C4)垸基, 烯丙基, (2-甲基)烯 丙基, (CrC4)烷氧基甲基,(d-C3)亚垸基二氧基, 芳基 (d-C2)烷基, 芳基甲氧基, 5-10 元杂芳基 (CQ-C2)垸基, 5-10元杂芳基甲氧基, 5-10元饱和或部分饱和的杂环基 (CG-C2) 烷基, 5-10元饱和或部分饱和的杂环基甲氧基, 所述杂芳基和杂环基含有 1-3个选自 0、 N和 S的杂原子, 且所述芳基、 杂芳基和杂环基任选 1-3个 R4取代;
R4为氢, 卤素, 羟基, 三氟甲基, 三氟甲氧基, 氨基, 硝基, 巯基, (d-C4)烷基, (CrCt)烯基, ( -C4)块基, ( -C4)垸氧基, (CrCt)垸硫基, 羟基 (d-C4)垸基, 烯丙基, (2-甲基)烯丙基, ( -C4)烷氧基甲基, (d-C3)亚垸基二氧基, 苯甲基, 3,4-二氧亚甲基 苯甲基。
本发明特别优选定义如下的通式 I化合物, 及其几何异构体或其药学上可接受的 盐、 水合物或溶剂化物,
其中,
Ar1为苯基, 苯甲基, 且 Ar1任选 1-3个 R2取代;
R2为氢, 卤素, 三氟甲基, 烯丙基, (2-甲基)烯丙基;
R1为苯基, 萘基, 5-10元杂芳基, 5-10元饱和或部分饱和的杂环基, 所述杂芳基 和杂环基含有 1-3个选自 0、 N和 S的杂原子, 且 R1任选 1-3个 R3取代;
R3为氢, 卤素, 羟基, 垸基, (CrC4)烯基, 烯丙基, (2-甲基)烯丙基, (3- 甲基)烯丙基, ( -C3)亚垸基二氧基, 芳基甲氧基, 5-10 元杂芳基 (Co-C2)垸基, 5-10 元杂芳基甲氧基, 所述杂芳基含有 1-3个选自 0、 N和 S的杂原子, 且所述芳基和杂 芳基任选 1-3个 R4取代;
R4为氢, 卤素, 羟基, 三氟甲基, 三氟甲氧基, (d-C 烷基, (d-C4)烯基,(d-C4) 炔基, (Ci-C4)垸氧基, 烯丙基, (2-甲基)烯丙基, (d-C3)亚垸基二氧基, 苯甲基, 3,4- 二氧亚甲基苯甲基。
本发明还特别优选定义如下的通式 I化合物, 及其几何异构体或其药学上可接受 的盐、 水合物或溶剂化物,
其中,
Ar1为苯基, 且 Ar1任选 1-3个 R2取代;
R2为卤素, 三氟甲基;
R1为苯基, 萘基, ~^ ^, 且 R1任选 1-3个 R3取代;
R3为氢, 卤素, 羟基, (C C4)烷基, (d-C4)烯基, 烯丙基, (2-甲基)烯丙基, (3- 甲基)烯丙基, 苯基甲氧基, 4-噻唑基, 4-噻唑基甲氧基, 且所述苯基和噻唑基任选 1-3 个 R4取代;
R4为氢, 卤素, 羟基, 三氟甲基, ( -C4)垸基, (C!-Cs)亚垸基二氧基, 苯甲基, 3,4-二氧亚甲基苯甲基。
本发明通式 I化合物, 及其几何异构体或其药学上可接受的盐、 水合物或溶剂化 物优选以下化合物, 但这些化合物并不意味着对本发明的任何限制:
>^-(2-羟基 -4-((2- ((苯并 [ [1,3]二氧戊环 -5-基)甲基)噻唑 -4-基)甲氧基)苯基亚甲 基) -2-((4-((3-(4-((2-三氟甲基)苯氧基)甲基)苯基) -1,2,4-噁二唑 -5-基)甲基)哌嗪 -1-基)乙 酰肼;
^-(2-羟基 -4-苄氧基苯基亚甲基) -2-((4-((3-(4-(4-氯苯氧基)甲基)苯基) -1,2,4-噁二 唑 -5-基)甲基)哌嗪小基)乙酰肼;
N -(2-羟基 -4-(2,4-二氯苄氧基)苯基亚甲基 )-2-((4-((3-(4-(4-氟苯氧基)甲基)苯 基) -1 ,2,4-噁二唑 -5-基)甲基)哌嗪 -1 -基)乙酰肼;
^-(2-羟基 -4-(3-三氟甲基苄氧基)苯基亚甲基) -2-((4-((3-(4-(4-氟苯氧基)甲基)苯 基) -1,2,4-噁二唑 -5-基)甲基)哌嗪 -1-基)乙酰肼;
N7-(2-羟基 -4-(4-叔丁基苄氧基)苯基亚甲基 )-2-((4-((3-(4-(4-氯苯氧基)甲基)苯 基) - 1 ,2,4-噁二唑 -5-基)甲基)哌嗪小基)乙酰肼;
N;-(2-羟基 -4-(2,4-二氯苄氧基)苯基亚甲基 )-2-((4-((3-(4-(4-氯苯氧基)甲基)苯 基) -1,2,4-噁二唑 -5-基)甲基)哌嗪小基)乙酰肼;
^-(2-羟基 -3-烯丙基苯基亚甲基) -2-((4-((3-(4-(4-氯苯氧基)甲基)苯基) -1,2,4-噁二 唑 -5-基)甲基)哌嗪小基)乙酰肼;
N (2-羟基 -4-((2- ((苯并 [ [1,3]二氧戊环 -5-基)甲基)噻唑 -4-基)甲氧基)苯基亚甲 基) -2-((4-((3-(4-(4-氯苯氧基)甲基)苯基) -1,2,4-噁二唑 -5-基)甲基)哌嗪 -1-基)乙酰肼; N -(2-羟基 -4-(4-叔丁基苄氧基)苯基亚甲基 )-2-((4-((3-(4-(4-氟苯氧基)甲基)苯 基) - 1 ,2,4-噁二唑 -5-基)甲基)哌嗪 - 1 -基)乙酰肼;
羟基 -4-((2- ((苯并 [ [1,3]二氧戊环 -5-基)甲基)噻唑 -4-基)甲氧基)苯基亚甲 基) -2-((4-((3-(4-(4-氟苯氧基)甲基)苯基) -1,2,4-噁二唑 -5-基)甲基)哌嗪 -1-基)乙酰肼; 羟基 -3-烯丙基苯基亚甲基) -2-((4-((3-(4-(4-氟苯氧基)甲基)苯基) -1,2,4-噁二 唑 -5-基)甲基)哌嗪 -1-基)乙酰肼; .
^-(2-羟基 -4-苄氧基苯基亚甲基) -2-((4-((3-(4-(3,4-二氟苯氧基)甲基)苯基) -1,2,4-噁 二唑 -5-基)甲基)哌嗪 - 1 -基)乙酰肼;
N -(2-羟基 -4-(4-氯苄氧基)苯基亚甲基 )-2-((4-((3-(4-(3,4-二氟苯氧基)甲基)苯 基) -1,2,4-噁二唑 -5-基)甲基)哌嗪 -1-基)乙酰肼;
^-(2-羟基 -4-(2,4-二氯苄氧基)苯基亚甲基) -2-((4-((3-(4-(3,4-二氟苯氧基)甲基)苯
基) - 1 ,2,4-噁二唑 -5-基)甲基)哌嗪小基)乙酰肼;
^-(2-羟基 -3-烯丙基苯基亚甲基) -2-((4-((3-(4-(3-氯苯氧基)甲基)苯基) -1,2,4-噁二 唑 -5-基)甲基)哌嗪小基)乙酰肼;
Ν -(2-羟基 -3-(2-甲基烯丙基)苯基亚甲基 )-2-((4-((3-(4-(4-氟苯氧基)甲基)苯 基) -1,2,4-噁二唑 -5-基)甲基)哌嗪 -1-基)乙酰肼;
^-(2-羟基 -3-(2-甲基烯丙基)苯基亚甲基) -2-((4-((3-(4-(3,4-二氟苯氧基)甲基)苯 基) -1,2,4-噁二唑 -5-基)甲基)哌嗪 -1-基)乙酰肼;
N _(2-羟基 -4-(4-叔丁基苄氧基)苯基亚甲基) -2-((4-((3-(4-(2-三氟甲基苯氧基)甲基) 苯基) -1,2,4-噁二唑 -5-基)甲基)哌嗪 -1-基)乙酰肼;
羟基 -3-烯丙基苯亚甲基) -2-((4-((3-(4-(2-三氟甲基苯氧基)甲基)苯基) -1,2,4- 噁二唑 -5-基)甲基)哌嗪 - 1 -基)乙酰肼;
甲基 -2-羟基 -6-异丙基苯基亚甲基) -2-((4-((3-(4-(3,4-二氟苯氧基)甲基)苯 基)- 1 ,2,4-噁二唑 -5-基)甲基)哌嗪- 1 -基)乙酰肼;
羟基 -4-(3-氟苄氧基)苯基亚甲基) -2-((4-((3-(4-(2-三氟甲基苯氧基)甲基)苯 基) -1,2,4-噁二唑 -5-基)甲基)哌嗪小基)乙酰肼;
^-(2-羟基 -5-(3-氯苄氧基)苯基亚甲基) -2-((4-((3-(4-(4-氯苯氧基)甲基)苯基) -1,2,4- 噁二唑 -5-基)甲基)哌嗪 -1-基)乙酰肼;
^-(2-羟基 -5-苄氧基苯基亚甲基) -2-((4-((3-(4-(3,4-二氟苯氧基)甲基)苯基) - 1,2,4-噁 二唑 -5-基)甲基)哌嗪 -1 -基)乙酰肼;
^-(2-羟基 -5-(4-氯苄氧基)苯基亚甲基) -2-((4-((3-(4-(4-氯苯氧基)甲基)苯基) -1,2,4- 噁二唑 -5-基)甲基)哌嗪 -1-基)乙酰肼;
^-(2-羟基 -5-(2-苄基噻唑 -4-基)苯基亚甲基) -2-((4-((3-(4-(4-氯苯氧基)甲基)苯 基) - 1 ,2,4-噁二唑 -5-基)甲基)哌嗪- 1 -基)乙酰肼;
N (2-羟基 -5-(2-苄基噻唑 -4-基)苯基亚甲基) -2-((4-((3-(4-(3,4-二氟苯氧基)甲基)苯 基) - 1 ,2,4-噁二唑 -5-基)甲基)哌嗪 - 1 -基)乙酰肼;
本发明特别优选以下化合物:
^-(2-羟基 -3-烯丙基苯基亚甲基) -2-((4-((3-(4-(4-氯苯氧基)甲基)苯基) -1,2,4-噁二 唑 -5-基)甲基)哌嗪 - 1 -基)乙酰肼;
N (2-羟基 -4-((2- ((苯并 [ [1,3]二氧戊环 -5-基)甲基)噻唑 -4-基)甲氧基)苯基亚甲 基) -2-((4-((3-(4-(4-氯苯氧基)甲基)苯基) -1,2,4-噁二唑 -5-基)甲基)哌嗪 -1-基)乙酰肼;
>^-(2-羟基 -3-烯丙基苯基亚甲基) -2-((4-((3-(4-(4-氟苯氧基)甲基)苯基) -1,2,4-噁二 唑 -5-基)甲基)哌嗪 -1-基)乙酰肼;
^-(2-羟基 -4-((2- ((苯并 [ [1,3]二氧戊环 -5-基)甲基)噻唑 -4-基)甲氧基)苯基亚甲 基) -2-((4-((3-(4-(4-氟苯氧基)甲基)苯基) -1,2,4-噁二唑 -5-基)甲基)哌嗪小基)乙酰肼; 羟基 -4-苄氧基苯基亚甲基) -2-((4-((3-(4-(3,4-二氟苯氧基)甲基)苯基) -1,2,4-噁 二唑 -5-基)甲基)哌嗪 -1-基)乙酰肼;
N7-(2-羟基 -4-(4-氯苄氧基)苯基亚甲基 )-2-((4-((3-(4-(3,4-二氟苯氧基)甲基)苯 基) -1,2,4-噁二唑 -5-基)甲基)哌嗪 -1-基)乙酰肼;
羟基 -3-烯丙基苯基亚甲基) -2-((4-((3-(4-(3-氯苯氧基)甲基)苯基) -1,2,4-噁二 唑 -5-基)甲基)哌嗪 -1-基)乙酰肼;
^-(2-羟基 -3-(2-甲基烯丙基)苯基亚甲基) -2-((4-((3-(4-(3,4-二氟苯氧基)甲基)苯 基) - 1 ,2,4-噁二唑 -5-基)甲基)哌嗪小基)乙酰肼;
N -(2-羟基 -3-(2-甲基烯丙基)苯基亚甲基 )-2-((4-((3-(4-(4-氟苯氧基)甲基)苯 基) -1,2,4-噁二唑 -5-基)甲基)哌嗪 -1-基)乙酰肼;
羟基 -4-(4-叔丁基苄氧基)苯基亚甲基) -2-((4-((3-(4-(2-三氟甲基苯氧基)甲基) 苯基) -1,2,4-噁二唑 -5-基)甲基)哌嗪 -1-基)乙酰肼;
N/_(2—羟基 _3_烯丙基苯亚甲基) _2_((4-((3-(4-(2-三氟甲基苯氧基)甲基)苯基) -1,2,4- 噁二唑 -5-基)甲基)哌嗪小基)乙酰肼;
^-(3-甲基 -2-羟基 -6-异丙基苯基亚甲基) -2-((4-((3-(4-(3,4-二氟苯氧基)甲基)苯 基) - 1,2,4-噁二唑 -5-基)甲基)哌嗪- 1 -基)乙酰肼;
羟基 -5-苄氧基苯基亚甲基) -2-((4-((3-(4-(3,4-二氟苯氧基)甲基)苯基) -1,2,4-噁 二唑 -5-基)甲基)哌嗪 -1-基)乙酰肼;
^-(2-羟基 -5-(4-氯苄氧基)苯基亚甲基) -2-((4-((3-(4-(4-氯苯氧基)甲基)苯基) -1,2,4- 噁二唑 -5-基)甲基)哌嗪 -1-基)乙酰肼;
>^-(2-羟基 -5-(2-苄基噻唑 -4-基)苯基亚甲基) -2-((4-((3-(4-(4-氯苯氧基)甲基)苯 基) -1,2,4-噁二唑 -5-基)甲基)哌嗪 -1-基)乙酰肼;
^-(2-羟基 -5-(2-苄基噻唑 -4-基)苯基亚甲基) -2-((4-((3-(4-(3,4-二氟苯氧基)甲基)苯 基) -1,2,4-噁二唑 -5-基)甲基)哌嗪 -1-基)乙酰肼;
而且, 按照本发明所属领域的一些通常方法, 本发明中上式 I的衍生物可以与酸 生成药学上可接受的盐。 可药用加成盐包括无机酸和有机酸加成盐, 与下列酸加成的
盐是特别优选的: 盐酸、 氢溴酸、 硫酸、 磷酸、 甲磺酸、 乙磺酸、 对甲苯磺酸、 苯磺 酸、 萘二磺酸、 乙酸、 丙酸、 乳酸、 三氟乙酸、 马来酸、 柠檬酸、 富马酸、 草酸、 酒 石酸、 苯甲酸等。
此外, 本发明还包括本发明衍生物的前药。 本发明衍生物的前药是通式 I的衍生 物, 它们自身可能具有较弱的活性甚至没有活性, 但是在给药后, 在生理条件下 (例 如通过代谢、 溶剂分解或另外的方式) 被转化成相应的生物活性形式。
本发明中"卤素"是指氟、氯、溴或碘代; "垸基 "是指直链或支链的垸基; "亚烷基" 是指直链或支链的亚垸基; "芳基 "是指无取代基或连有取代基的苯基; "杂芳基"是指 含有一个或多个选自 N、 0、 S 杂原子的单环或多环的环状体系, 环状体系是芳香性 的, 如噻唑基, 咪唑基、 吡啶基、 吡唑基、 (1,2,3)-和 (1,2,4)-三唑基、 呋喃基、 噻吩基、 吡咯基, 苯并噻唑基, 噁唑基, 异噁唑基, 萘基, 喹啉基, 异喹啉基, 苯并咪唑基, 苯并噁唑基等; "饱和或部分饱和的杂环基 "是指含有一个或多个选自 N、 0、 S的杂原 子的单环或多环的环状体系, 如 2H-1-苯并吡喃 -2-酮基、 吡咯烷基、 吗啉基、 哌嗪基、 哌啶基、 吡唑烷基、 咪唑垸基和噻唑啉基等。
本发明可以含有上式 I的衍生物, 及其药学上可接受的盐、 水合物或溶剂化物作 为活性成份, 与药学上可接受的载体或赋型剂混合制备成组合物, 并制备成临床上可 接受的剂型, 上述药学上可接受的赋型剂是指任何可用于药学领域的稀释剂、 辅助剂 和 /或载体。本发明的衍生物可以与其他活性成份组合使用, 只要它们不产生其他不利 的作用, 例如过敏反应。
本发明的药用组合物可配制成若干种剂型, 其中含有药物领域中一些常用的赋形 剂。 如上所述的若干种剂型可以采用注射剂、 片剂、 胶囊剂、 气雾剂、 栓剂、 膜剂、 滴丸剂、 外用搽剂、 软膏剂等剂型药物。
用于本发明药物组合物的载体是药物领域中可得到的常见类型, 包括: 粘合剂、 润滑剂、 崩解剂、 助溶剂、 稀释剂、 稳定剂、 悬浮剂、 无色素、 矫味剂、 防腐剂、 加 溶剂和基质等。 药物制剂可以经口服或胃肠外方式 (例如静脉内、 皮下、 腹膜内或局 部) 给药, 如果某些药物在胃部条件下不稳定的, 可将其配制成肠衣片剂。
体外抗肿瘤活性试验表明, 本发明的通式 I的衍生物具有抗肿瘤活性, 因此本发 明化合物可以用于制备治疗和 /或预防各种癌症的药物, 如乳腺、 肺、 肝脏、 肾脏、 结 肠、 直肠、 胃、 前列腺、 膀胱、 子宫、 胰腺、 骨髓、 睾丸、 卵巢、 淋巴、 软组织、 头 颈、 甲状腺、 食道的癌和白血病、 成神经细胞瘤等。 特别用于制备治疗和 /或预防白血
病的药物。
本发明的活性化合物或其可药用盐及其溶剂化物可作为唯一的抗肿瘤药物单独 使用, 或者可以与现已上市的抗肿瘤药物(如铂类药物顺铂、喜树碱类药物伊立替康、 长春花碱类药物诺维本、脱氧胞昔类药物吉西他滨、足叶乙甙、紫杉醇等)联合使用。 联合治疗通过将各个治疗组分同时、 顺序或隔开给药来实现。
下文中提供的实施例和制备例进一步阐明和举例说明本发明化合物及其制备方 法。 应当理解, 下述实例和制备例的范围并不以任何方式限制本发明的范围。
下面的合成路线 1描述了本发明的式 I衍生物的制备, 所有的原料都是通过这些 示意图中描述的方式、 通过有机化学领域普通技术人员熟知的方法制备的或者可商 购。 本发明的全部最终衍生物都是通过这些示意图中描述的方法或通过与其类似的方 法制备的, 这些方法是有机化学领域普通技术人员熟知的。 这些示意图中应用的全部 可变
合成路线 按照本发明的式 I衍生物, 可按照路线 1的方法, 以 4-氯甲基苯腈为起始原料,
首先与化合物 A-I进行取代反应得中间体 A-II, 与盐酸羟胺加成得中间体 Α-ΠΙ, 之后 与氯乙酰氯环合得含 1,2,4-噁二唑结构的中间体 A-IV, 再与哌嗪发生取代反应后与氯 乙酸乙酯反应得中间体 A-VI, 之后与水合肼反应得中间体 A-VII, 最后与相应的醛经 缩合, 制得式 I化合物。 其中相应的醛可以通过有机化学领域普通技术人员熟知的方 法制备或者可商购。
本发明首次合成了一系列含有噁二唑基哌嗪的化合物, 其制备方法简单, 重现性 好, 制备的化合物纯度高, 收率高, 且具有较好的抗肿瘤活性。
具体实施方式:
实施例 1 : >^-(2-羟基 -4-((2- ((苯并 [ [1,3]二氧戊环 -5-基)甲基)噻唑 -4-基)甲氧基)苯基亚 甲基) -2-(4-((3-(4-((2- (三氟甲基)苯氧基)甲基)苯基) -1,2,4-噁二唑 -5-基)甲基)哌嗪 -1-基) 乙酰肼盐酸盐
步骤 A 4-((2- (三氟甲基)苯氧基)甲基)苯腈的制备
将 10g(0.066mol) 4-氯甲基苯腈, 9.7g(0.060mol) 2- (三氟甲基)苯酚与 12g(0.087mol) 碳酸钾溶于 50mL的 DMF中, 60°C反应 2h, 向反应溶液中加入 250mL水, 搅拌, 静 置, 抽滤, 水洗滤饼至中性, 干燥, 得白色固体 17g, 收率 93%, MS [MH+] (m/z): 277。
步骤 B 4-((2- (三氟甲基)苯氧基)甲基) 羟基苯甲脒的制备
将 86g(0.31mol) 4-((2- (三氟甲基)苯氧基)甲基)苯腈, 24g(0.34mol) 盐酸羟胺,
15g(0.375mol) 氢氧化钠于 200mL乙醇中回流 4h, 减压蒸干溶剂, 残余物加水, 析出 固体, 抽滤, 干燥, 得白色固.体 79g, 收率 82%, MS [MH+] (m/z): 311。
步骤 C 3-(4-((2- (三氟甲基)苯氧基)甲基)苯基) -5- (氯甲基) -1,2,4-噁二唑的制备
将 8.5g (0.027mol) 4-((2- (三氟甲基)苯氧基)甲基) 羟基苯甲脒溶于 lOOmL甲苯 中, 室温滴加 1.5g(0.014mol)氯乙酰氯的甲苯溶液 25mL, 滴毕, 再加入 30mL甲苯, 回流 2h, 反应毕, 将反应液冷却, 析出固体, 抽滤, 弃去滤饼。 将滤液蒸干, 得白色 固体, 收率 56%, MS [MH+] (m/z): 369。
步骤 D 1-((3-(4-((2- (三氟甲基)苯氧基)甲基)苯基) -5- (氯甲基) -1,2,4-噁二唑 -5-基)甲基) 哌嗪
将 9.5g(0.0258mol) 3-(4-((2- (三氟甲基)苯氧基)甲基)苯基) -5- (氯甲基) -1,2,4-噁二唑 与 40g(0.206mol)哌嗪溶于 150ml乙醇中, 室温反应 4h, 反应毕, 将溶剂蒸干, 氯仿
溶解, 水洗, 有机层干燥, 减压浓缩, 得白色固体 8g, 收率 62%, MS [MH+] (m/z): 418。
步骤 E 2-(4-((3-(4-((2- (三氟甲基)苯氧基)甲基)苯基) -5- (氯甲基) -1,2,4-噁二唑 -5-基)甲 基)哌嗪 -1-基)乙酸乙酯
将 8g(0.02mol) 1 -((3 -(4-((2- (三氟甲基)苯氧基)甲基)苯基) -5- (氯甲基) - 1 ,2,4-噁二唑 -5-基)甲基)哌嗪, 2.6g(0.021mol) 氯乙酸乙酯与 2.4g(0.028mol) 碳酸氢钠溶于 60ml乙 醇, 60°C反应 6h, 反应毕, 减压浓缩, 残余物倒入水中, 析出固体, 抽滤, 干燥, 得 白色固体 5.4g, 收率 56%, MS [MH+] (m/z): 505。
步骤 F 2-(4-((3-(4-((2- (三氟甲基)苯氧基)甲基)苯基) -5- (氯甲基) -1,2,4-噁二唑 -5-基)甲 基)哌嗪小基)乙酰肼
将 2g(0.004mol) 2-(4-((3-(4-((2- (三氟甲基)苯氧基)甲基)苯基) -5- (氯甲基) - 1,2,4-噁 二唑 -5-基)甲基)哌嗪 -1-基)乙酸乙酯与 2g(0.04mol) 水合肼在乙醇中回流 5h, 反应毕, 自然冷却, 有固体析出, 抽滤, 干燥, 得白色固体 1.5g, 收率 77%, MS [MH+] (m/z): 490。
步骤 G 4-((2- ((苯并【< ]〖1,3】二氧戊环 -5-基)甲基)噻唑 -4-基)甲氧基 )-2-羟基苯甲醛的制 备
首先用化合物 B-I与硫氢化钠反应, 得到中间体 B-II, 再与 1,3-二氯丙酮环合得 到中间体 Β-ΠΙ, 最后与 2,4-二羟基苯甲醛反应, 制得 4-((2- ((苯并 [ [1,3]二氧戊环 -5- 基)甲基)噻唑 -4-基)甲氧基 )-2-羟基苯甲醛, 如合成路线 2所示。
0
具体制备方法如下:
步骤 G-1 2- (苯并 [rf][l,31二氧戊环 -5-基)硫代乙酰胺的制备
将 14g(0.25mol)硫氢化钠、 25.4g(0.125mol) MgCl2'6H20、 16.1g(0.1mol) 2- (苯并 [ί ][1,3]二氧戊环 -5-基)乙腈依次加入 DMF和水的混合溶剂中,室温反应 15h,反应毕,
将反应液倒入冰水中, 用盐酸调 PH值 4〜5, 有大量乳白色的固体析出, 抽滤, 干燥, 得白色固体 10.3g, 收率 53%, MS [MH+] (m/z): 195。
步骤 G-2 2- ((苯并 [rf][l,3】二氧戊环 -5-基)甲基) -4- (氯甲基)噻唑的制备
将 10.3g(0.05mol) 2- (苯并 [ [1,3]二氧戊环 -5-基)硫代乙酰胺与 7g(0.05mol) 1,3-二 氯丙酮溶于乙腈, 50Ό反应 4h, 反应毕, 析出固体, 抽滤, 水洗滤饼, 得浅黄色固体 8.7g, 收率 61%, MS [MH+] (m/z): 268。
步骤 G-3 4-((2- ((苯并^^, 二氧戊环 -5-基)甲基)噻唑 -4-基)甲氧基 )-2-羟基苯甲醛的 制备
将 8.7g(0.03mol) 2- ((苯并 [ [1,3]二氧戊环 -5-基)甲基) -4- (氯甲基)噻唑, 4.5g(0.03mol) 2,4-二羟基苯甲醛, 3.2g(0.035mol) 碳酸氢钠与 lg碘化钾加入乙腈中, 80°C反应 2h, 反应毕, 减压浓缩, 残余物加入甲醇加热溶解, 活性碳脱色, 抽滤, 滤 液自然冷却,有棕黄色固体析出,抽滤,干燥,得固体 7.6g,收率 64%, MS [MH+] (m/z): 369。
步骤 H >^-(4-((2- ((苯并 [rf][l,3】二氧戊环 -5-基)甲基)噻唑 -4-基)甲氧基 )-2-羟基苯亚甲 基) -2-(4-((3-(4-((2- (三氟甲基)苯氧基)甲基)苯基) -1,2,4-噁二唑 -5-基)甲基)哌嗪 -1-基)乙 酰肼盐酸盐的制备
将 2g(0.004mol) 2-(4-((3-(4-((2- (三氟甲基)苯氧基)甲基)苯基) -5- (氯甲基) -1,2,4-噁 二唑 -5-基)甲基)哌嗪 -1-基)乙酰肼与 1.5g(0.004mol) 4-((2- ((苯并 [ [1,3]二氧戊环 -5-基) 甲基)噻唑 -4-基)甲氧基 )-2-羟基苯甲醛在乙醇中回流 10h, 反应毕,有固体析出,抽滤, 干燥。 将所得固体溶于氯仿, 滴加饱和盐酸乙醇溶液, 析出白色固体, 抽滤, 干燥, 得白色固体 1.7g, 收率 48%。
MS [MH+] (m/z): 842; 1H NMR (DMSO-i^): S 8.42(s, 1H), 8.26(d, 2H), 7.6 l(m, 6H), 7.3 l(d, 1H), 7.09(t, 1H), 6.86(m, 3H), 6.56(m, 2H), 5.96(s, 2H), 5.51(br, 1H), 5.35(s, 2H), 5.06(d, 2H), 4.52(s, 1H), 4.21(s, 5H), 3.55~2.91(m, 8H). 按照实施例 1的方法, 首先以 4-氯甲基苯腈和适合的取代苯酚为起始原料, 经六 步反应, 制备得到噁二唑基哌嗪乙酰肼类衍生物 A-VII; 之后再与按照步骤 G的方法 制备得到的适合的醛反应, 制备得到实施例 2和 3的化合物。
实施例 2: 羟基 -4-((2- ((苯并 |[l,3]二氧戊环 -5-基)甲基)噻唑 -4-基)甲氧基)苯基亚 甲基) -2-(4-((3-(4-((4-氯苯氧基)甲基)苯基) -1,2,4-噁二唑 -5-基)甲基)哌嗪 -1-基)乙酰肼盐
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步反应, 制备得到噁二唑基哌嗪乙酰肼类衍生物 A-VII; 之后再与按照步骤 I的方法 制备得到的适合的醛反应, 制备得到实施例 5~17的化合物。
实施例 5: 羟基 -4-(2,4-二氯苄氧基) -苯基亚甲基 )-2-(4-((3-(4-((4-氟苯氧基)甲基) 苯基) -1,2,4-噁二唑 -5-基)甲基)哌嗪 -1-基)乙酰肼盐酸盐
MS [MH+] (m/z): 720; 1H NMR (DMSO-a6): δ 8.29(s, IH), 8.04(d, 2H), 7.59(m, 5H),
7.47(t, IH), 7.11(t, 2H), 7.02(m, 2H), 6.55(m, 2H), 5.18(m, 4H), 4.54(s, IH), 4.19(s, 3H), 3.56(m, 2H), 3.3 l(m, 2H), 3.12(m, 2H), 2.88(m, 2H).
实施例 6: >^-(2-羟基 -4-(3-三氟甲基苄氧基)苯基亚甲基) -2-(4-((3-(4-((4-氟苯氧基)甲基) 苯基) -1,2,4-噁二唑 -5-基)甲基)哌嗪 -1-基)乙酰肼盐酸盐
MS [Mt^] (m/z): 718; Ή NMR (DMSO- ): δ 8.29(s, IH), 8.04(d, 2H), 7.80(m, 2H),
7.63(m, 5H), 7.13(t, 2H), 7.06(m, 2H), 6.60(m, 2H), 5.19(s, 4H), 4.54(s, IH), 4.20(s, 3H), 3.56(m, 2H), 3.3 l(m, 2H), 3.13(m, 2H), 2.89(m, 2H).
实施例 Ί: ^-(2-羟基 -4-(4-叔丁基苄氧基)苯基亚甲基) -2-(4-((3-(4-((4-氯苯氧基)甲基) 苯基) -1,2,4-噁二唑 -5-基)甲基)哌嗪 -1-基)乙酰肼盐酸盐
MS [MH+] (m/z): 723; Ή NMR (DMSO- tf): δ 8.27(s, 1H), 8.04(d, 2H), 7.63(d, 2H),
7.34(m, 6H), 7.04(d, 2H), 6.56(m, 2H), 5.21(s, 2H), 5.04(d, 2H), 4.52(s, IH), 4.13(s, 3H), 3.53(m, 2H), 3.34(m, 2H), 3.06(m, 2H), 2.80(m, 2H), 1.28(s, 9H).
实施例 8: (2-羟基 -4-(2,4-二氯苄氧基)苯基亚甲基) -2-(4-((3-(4-((4-氯苯氧基)甲基)苯 基) -1,2,4-噁二唑 -5-基)甲基)哌嗪 -1-基)乙酰肼盐酸盐
MS [MH+] (m/z): 736.
实施例 9: 羟基 -4-(4-叔丁基苄氧基)苯基亚甲基) -2-(4-((3-(4-((4-氟苯氧基)甲基) 苯基) -1,2,4-噁二唑 -5-基)甲基)哌嗪 -1-基)乙酰肼盐酸盐
MS [MH+] (m/z): 706.
实施例 10 : 羟基 -4-苄氧基苯基亚甲基) -2-(4-((3-(4-((3,4-二氟苯氧基)甲基)苯 基) -1,2,4-噁二唑 -5-基)甲基)哌嗪 -1-基)乙酰肼盐酸盐
MS [MH+] (m/z): 669; Ή NMR (DMSO-c¾: S 8.41(s, IH), 8.03(d, 2H), 7.62(d, 2H), 7.33(m, 7H), 7.15(m, IH), 6.85(d, IH), 6.50(m, 2H), 5.20(s, 2H), 5.11(s, 2H), 3.99(s, 2H), 3.3 l(s, IH), 3.09(s, IH), 2.62(m, 8H).
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苯基) -1,2,4-噁二唑 -5-基)甲基)哌嗪 -1-基)乙酰肼盐酸盐
MS [MH+] (m/z): 635; 1H NMR (DMSO- 6): δ 8.48(s, 1H), 8.04(d, 2H), 7.60(m, 5H), 7.3 l(m, IH), 7.17(m, IH), 7.08(m, IH), 6.85(m, IH), 5.88(m, 1H), 5.36(s, 2H), 5.00(m, 2H), 4.60(s, IH), 4.16(d, 3H), 3.54-2.91(m, 10H).
实施例 22: ^-(2-羟基 -3-(2-甲基烯丙基)苯基亚甲基) -2-(4-((3-(4-((4-氟苯氧基)甲基)苯 基) -I,2,4-噁二唑 -5-基)甲基)哌嗪 -1-基)乙酰肼盐酸盐
MS [MH+] (m/z): 599; 1H NMR (DMSO- ): δ 8.50(s, IH), 8.04(d, 2H), 7.63(d, 2H), 7.16-7.02(m, 6H), 6.90(m, IH), 5.19(s, 2H), 4.75(m, IH), 4.56(m, 2H), 4.17(d, 3H), 3.54-2.88(m, 10H), 1.67(s, 3H).
实施例 23 : N (2-羟基 -3-(2-甲基烯丙基)苯基亚甲基) -2-(4-((3-(4-((3,4-二氟苯氧基)甲 基)苯基) -1,2,4-噁二唑 -5-基)甲基)哌嗪 -1-基)乙酰肼盐酸盐
MS [MH+] (m/z): 617; Ή NMR (DMSO- ): δ 8.52(s, 1Η), 8.04(d, 2Η), 7.63(d, 2H), 7.32(m, 2H), 7.15(m, 2H), 6.86(m, 2H), 5.64(br, IH), 5.20(s, 2H), 4.75(m, IH), 4.55(d, 2H): 4.18(d, 3H), 3.57-3.03(m, 10H), 1.678(s, 3H).
实施例 24: ^-(2-羟基 -3-(5-(2-苄基噻唑 -4-基)苯基亚甲基) -2-(4-((3-(4-((3,4-二氟苯氧 基)甲基)苯基) -1,2,4-噁二唑 -5-基)甲基)哌嗪 -1-基)乙酰肼盐酸盐
步
合成路线 5
首先将苯乙腈与硫氢化钠反应, 得到中间体 K-A; 再将邻羟基苯甲醛与氯乙酰氯 反应, 得到中间体 K-B; 最后将 K-A与 K-B反应, 得到 2-羟基 -5-(2-苄基 -噻唑 -4-基) 苯甲醛, 如合成路线 5所示, 具体制备方法如下:
步骤 K-1: 2-苯基硫代乙酰胺的制备
将 6g(0.1070mol)硫氢化钠, 溶于水中, 加入 100ml的 DMF和 10.8g(0.0530mol) 六水氯化镁,室温搅拌 10分钟,加入 10g(0.085mol)苯乙腈, 室温反应 0.5h。反应液倒入 冰水中,析出黄色固体,抽滤,盐酸水溶液和水分别洗滤饼,干燥,得淡黄色固体 8.2g,
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681^000/1 T0iN3/X3d Z,80 i/ll0l OAV
稀盐酸调 pH至 2~3, 乙醚萃取, 无水硫酸钠干燥, 减压蒸干, 得白色固体 1.3g, 收 率 58%, MS [MH+] (m/z): 175。
再按照实施例 1的方法制备得到实施例 27化合物。
MS [MH+] (m/z): 619; 1H NMR (DMSO-i/6): δ 8.95(s, 1H), 8.05(d, 2H), 7.64(d, 2H), 7.33(m, 1H), 7.17(m, 2H), 6.87(m, 1H), 6.76(m, 1H), 5.2 l(s, 2H), 4.60(s, 1H), 4.16(m, 3H), 3.55(m, 2H), 3.32(m, 2H), 3.19(m, 1H), 3.11(m, 2H), 2.85(m, 2H), 2.12(d, 3H), 1.19(t, 6H). 实施例 28 : ^-((4-甲基 -7-羟基 -2-氧代 -2H-色烯 -6-基)亚甲基 )-2-(4-((3-(4-((3,4-二氟苯 氧基)甲基)苯基) -1,2,4-噁二唑 -5-基)甲基)哌嗪 -1-基)乙酰肼盐酸盐
步骤 M: 4-甲基 -7-羟基 -2-氧代 -2H-色稀 -6-甲醛的制备
将 17.6g(0.1mol)4-甲基 -7-羟基 -2H-色烯 -2-酮、 42g(0.3mol)乌洛托品依次加入 10ml 三氟乙酸中, 100°C反应 3h, 反应毕, 冷却后将反应液倒入水中, 乙醚萃取。 有机层 用氯化钠饱和溶液洗 2-3次, 无水硫酸镁干燥, 减压浓缩。 残余物溶物 50%甲醇, 之 后加入 13.8g(0.1mol)碳酸钾, 室温继续反应 lh, 用稀盐酸调 pH2-3, 乙酸乙酯萃取, 有机层用氯化钠饱和溶液洗 2-3次, 无水硫酸镁干燥, 减压浓缩, 得白色固体 9.8g, 收率 48%, MS [MH+] (m/z): 204。
再按照实施例 1的方法制备得到实施例 28化合物。 MS [MH+] (m/z): 645.
本发明产物的药理研究
对按照本发明的上式 I的化合物进行了体外抑制人白血病细胞株 HL-60, 人前列 腺癌细胞 DU145,人肺腺癌细胞 A549,人结肠癌细胞 Colon205,人肺癌细胞 NCI-H226, 人肝癌细胞 Hep3B,人胃癌细胞 HGC-27,人肝癌细胞 HepG2,人乳腺癌细胞 MCF-7, 人脑胶质瘤细胞 U87活性筛选,对照品 ^-((2-羟基 -3-烯丙基)苯基亚甲基) -2-(4-苄基哌 嗪 -1-基)乙酰肼 (PAC-1 ) 按照专利 WO2006128173所述方法制备得到。
( 1 ) 细胞复苏并传代 2-3次稳定后, 用胰蛋白酶溶液 (0.25%) 使其从培养瓶底 部消化下来。 将细胞消化液倒入离心管中后, 之后加入培养液以终止消化。 将离心管 在 800r/min下离心 lOmin,弃去上清液后加入 5 mL培养液,吹打混匀细胞,吸取 10 μL 细胞混悬液加入细胞计数板中计数, 调整细胞浓度为 104个 /孔。 96孔板中除 A1孔为 空白孔不加细胞外, 其余皆加入 100 细胞混悬液。将 96孔板放入培养箱中培养 24 h。
(2 )用 50 二甲基亚砜溶解受试样品, 然后加入适量培养液, 使样品溶解成 2 mg/mL药液, 然后在 24孔板中将样品稀释为 20, 4, 0.8, 0.16, 0.032 g/mL。
每个浓度加入 3孔, 其中周围两行两列细胞长势受环境影响较大, 只作为空白细 胞孔使用。 将 96孔板放入培养箱中培养 72 h。
(3 ) 将 96孔板中带药培养液弃去, 用磷酸缓冲溶液 (PBS) 将细胞冲洗两遍, 在每孔中加入 MTT (四氮唑) (0.5 mg/mL) 100 放入培养箱中 4 h后, 弃去 MTT 溶液,加入二甲基亚砜 100 。在磁力振荡器上振荡使存活细胞与 ΜΤΤ反应产物甲臜 充分溶解, 放入酶标仪中测定结果。 通过 Bliss法可求出药物 IC5o值。
化合物的抑制多种肿瘤细胞株活性结果见表 2。
表 2 实施例化合物体外抗肿瘤活性
IC50 ( g/mL)
实施例 NCI-H HGC-2
HL-60 DU 145 A549 Colon205 Hep3B HepG2 MCF-7 U87
226 7
1 1.08
2 0.43 0.08 0.42 1.99 1.86 1.10 0.44 0.67 1.31 1.66
3 0.07 0.08 1.78 1.10 2.58 0,86 0.99 0.22 2.80 1.05
4 1.26
5 1.02
6 0.98 1.02 19.4 26.77 8.36 2.02 9.30 .78 5.41 13.26
7 0.67
8 1.07
9 1.70
10 0.34
11 0.30
12 0.71
13 0.40
14 1.93
15 >20
16 0.02 1 1.9 50.72 38.34 42.59 5.95 20.31 53.09 6.55 12.86
17 0.03
18 0.25
19 0.39
20 0.30 1.04 40.42 10.39 11.04 1.84 2.64 10.10 12.09 8.29
21 0.35
22 0.15
23 0.45
24 0.30
25 0.06 13.77 7.78 1.09 6.51 10.05 2.20 2.55
26 1.35
27 0.45
28 10.73
PAC-1 2.1 10.20 9.99 4.49 11.27 9.99 5.17 6.41 4.96 3.46 从上述试验结果可以清楚地看出, 本发明所要保护的通式 I的化合物, 具有良好 的体外抗肿瘤活性, 因此本发明的化合物具有很好的工业应用前景。
Claims
1、 通式 I的化合物, 及其几何异构体或其药学上可接受的盐、 水合物或溶剂化物,
I H
其中,
Ar1为芳基, 芳基 (d-C垸基, 且 Ar1任选 1-3个 R2取代;
R2为氢, 卤素, 三氟甲基, 三氟甲氧基, 氨基, 硝基, (d-C4)垸基, (d-C4)烯基, ( -C4)炔基, (d-C4)垸氧基, (d-C4)烷硫基, 烯丙基, (2-甲基)烯丙基, (3-甲基)烯丙 基, (Ci-C 垸氧基甲基, (C!- )亚烷基二氧基;
R1为芳基, 萘基, 5-10元杂芳基, 5-10元杂芳基 (d-C4)垸基, 5-10元饱和或部分 饱和的杂环基, 5-10元饱和或部分饱和的杂环基 (d-C4)烷基, 所述杂芳基和杂环基含 有 1-3个选自 0、 N和 S的杂原子, 且 R1任选 1-3个 R3取代;
R3为氢, 素, 羟基, 三氟甲基, 三氟甲氧基, 氨基, 硝基, 巯基, (d- )垸基, (C!- )烯基, (d-C4)炔基, (d-C^垸氧基, (d- )垸硫基, 羟基 (CrC4)垸基, 烯丙基, (2-甲基)烯丙基, (d-C4)垸氧基甲基, (d-C3)亚垸基二氧基, 芳基 (d-C4)垸基, 芳基 (d- )垸氧基, 5-10元杂芳基 (CQ-C4)烷基, 5-10元杂芳基 (CG-C4)垸氧基, 5-10元饱和 或部分饱和的杂环基 (C。-C4)烷基, 5-10元饱和或部分饱和的杂环基 (CQ-C4)烷氧基, 所 述杂芳基和杂环基含有 1-3个选自 0、 N和 S的杂原子, 且所述芳基、 杂芳基和杂环 基任选 1-3个 R4取代;
R4为氢, 卤素, 羟基, 三氟甲基, 三氟甲氧基, 氨基, 硝基, 巯基, (d-C4)垸基, 烯基, (d-C4)炔基, (C!-C 垸氧基, (d-C4)垸硫基, 羟基 (CrC4)烷基, 烯丙基, (2-甲基)烯丙基, (d-C4)垸氧基甲基, ( - )亚垸基二氧基, 芳基 ( -C4)垸基, 芳基 (d-C4)烷氧基, 5-10元杂芳基 (d-C4)垸基, 5-10元杂芳基 (C C4)垸氧基, 5-10元饱和 或部分饱和的杂环基 d-C4垸基, 5-10元饱和或部分饱和的杂环基 d-C4烷氧基, 所 述杂芳基和杂环基含有 1-3个选自 0、 N和 S的杂原子。
2、 权利要求 1 的通式 I化合物, 及其几何异构体或其药学上可接受的盐、 水合物或 溶剂化物,
其中, Ar'为苯基, 苯基 d-C4垸基, 且 Ar1任选 1-3个 R2取代;
R2为氢, 卤素, 三氟甲基, 三氟甲氧基, 氨基, 硝基, (d-C4)垸基, ( -C4)烯基, (C C4)炔基, (d-C4)垸氧基, (d-C4)烷硫基, 烯丙基, (2-甲基)烯丙基, (3-甲基)烯丙 基, (Ci- )垸氧基甲基, (d- )亚烷基二氧基;
R1为芳基, 萘基, 5-10元杂芳基, 5-10元饱和或部分饱和的杂环基, 所述杂芳基 和杂环基含有 1-3个选自 0、 N和 S的杂原子, 且 R1任选 1-3个 R3取代;
R3为氢, 卤素, 羟基, 三氟甲基, 三氟甲氧基, 氨基, 硝基, 巯基, (d-C4)垸基, (d-C4)烯基, (d-C4)炔基, (d-C烷氧基, ( -C4)烷硫基, 羟基 (CrC4)垸基, 烯丙基, (2-甲基)烯丙基, (d-C4)垸氧基甲基, ( -C3)亚垸基二氧基, 芳基 (d-C2)烷基, 芳基 甲氧基, 5-10元杂芳基 (Co-C2)垸基, 5-10元杂芳基甲氧基, 5-10元饱和或部分饱和的 杂环基 (Cc-C2)垸基, 5-10元饱和或部分饱和的杂环基甲氧基, 所述杂芳基和杂环基含 有 1-3个选自 0、 N和 S的杂原子,且所述芳基、杂芳基和杂环基任选 1-3个 R4取代;
R4为氢, 卤素, 羟基, 三氟甲基, 三氟甲氧基, 氨基, 硝基, 巯基, (d-C4)垸基, (d- )烯基, (d-C4)炔基, (Cr )垸氧基, (d-C4)垸硫基, 羟基 (C C^烷基, 烯丙基, (2-甲基)烯丙基, (d-C4)垸氧基甲基, (d-C3)亚烷基二氧基, 芳基 (C C2)烷基, 5-10 元杂芳基 垸基, 5-10元饱和或部分饱和的杂环基 (d- )垸基, 所述杂芳基和杂 环基含有 1-3个选自 0、 N和 S的杂原子。
3、 权利要求 2 的通式 I化合物, 及其几何异构体或其药学上可接受的盐、 水合物或 溶剂化物,
其中,
Ar1为苯基, 苯甲基, 且 Ar1任选 1-3个 R2取代;
R2为氢, 卤素, 三氟甲基, 三氟甲氧基, 氨基, 硝基, ( -C4)烷基, (d-C4)烯基, (Ci-C 炔基, (d-C4)垸氧基, (CrC4)垸硫基, 烯丙基, (2-甲基)烯丙基, (3-甲基)烯丙 基, (d-C4)垸氧基甲基, ( -C3)亚垸基二氧基;
R1为苯基, 萘基, 5-10元杂芳基, 5-10元饱和或部分饱和的杂环基, 所述杂芳基 和杂环基含有 1-3个选自 0、 N和 S的杂原子, 且 R1任选 1-3个 R3取代;
R3为氢, 卤素, 羟基, 三氟甲基, 三氟甲氧基, 氨基, 硝基, 巯基, 烷基, (C!-C )烯基, (d-C4)垸氧基, (d-C4)垸硫基, 羟基 (d-C4)烷基, 烯丙基, (2-甲基)烯 丙基,(d-Ca)垸氧基甲基, ( -C 亚垸基二氧基, 芳基 ( -C2)垸基, 芳基甲氧基, 5-10 元杂芳基 (CQ-C2)垸基, 5-10元杂芳基甲氧基, 5-10元饱和或部分饱和的杂环基 (CQ-C2) 烷基, 5-10元饱和或部分饱和的杂环基甲氧基, 所述杂芳基和杂环基含有 1-3个选自 0、 N和 S的杂原子, 且所述芳基、 杂芳基和杂环基任选 1-3个 R4取代;
R4为氢, 卤素, 羟基, 三氟甲基, 三氟甲氧基, 氨基, 硝基, 巯基, ( -C4)烷基, (d-C4)烯基, (d-C4)炔基, (d-C4)垸氧基, (CrC4)烷硫基, 羟基 (d-C4)烷基, 烯丙基, (2-甲基)烯丙基, (d-C4)垸氧基甲基, (d-C3)亚垸基二氧基, 苯甲基, 3,4-二氧亚甲基 苯甲基。
4、 权利要求 3 的通式 I化合物, 及其几何异构体或其药学上可接 的盐、 水合物或 溶剂化物,
其中,
Ar1为苯基, 苯甲基, 且 Ar1任选 1-3个 R2取代;
R2为氢, 素, 三氟甲基, 烯丙基, (2-甲基)烯丙基;
R1为苯基, 萘基, 5-10元杂芳基, 5-10元饱和或部分饱和的杂环基, 所述杂芳基 和杂环基含有 1-3个选自 0、 Ν和 S的杂原子, 且 R1任选 1-3个 R3取代;
R3为氢, 卤素, 羟基, (CrC4)垸基, (C!-C4)烯基, 烯丙基, (2-甲基)烯丙基, (3- 甲基)烯丙基, (Cr )亚垸基二氧基, 芳基甲氧基, 5-10 元杂芳基 (Co-C2)烷基, 5-10 元杂芳基甲氧基, 所述杂芳基含有 1-3个选自 0、 N和 S的杂原子, 且所述芳基和杂 芳基任选 1-3个 R4取代;
R4为氢, 卤素,羟基, 三氟甲基, 三氟甲氧基,(CrC4)烷基,(C!- )烯基, (C,-C4) 炔基, 垸氧基, 烯丙基, (2-甲基)烯丙基, (d-C3)亚垸基二氧基, 苯甲基, 3,4- 二氧亚甲基苯甲基。
5、 权利要求 4 的通式 I化合物, 及其几何异构体或其药学上可接受的盐、 水合物或 溶剂化物,
其中,
Ar1为苯基, 且 Ar1任选 1-3个 R2取代;
R2为卤素, 三氟甲
R3为氢, 卤素, 羟基, (CrC4)垸基, ( -C4)烯基, 烯丙基, (2-甲基)烯丙基, (3- 甲基)烯丙基, 苯基甲氧基, 4-噻唑基, 4-噻唑基甲氧基, 且所述苯基和噻唑基任选 1-3 个 R4取代; R4为氢, 卤素, 羟基, 三氟甲基, ( -C4)垸基, (d-C3)亚垸基二氧基, 苯甲基, 3,4-二氧亚甲基苯甲基。
6、 权利要求 1 的通式 I的衍生物, 及其几何异构体或其药学上可接受的盐、 水合物 或溶剂化物, 优选:
(2-羟基 -4-((2- ((苯并 [ [1,3]二氧戊环 -5-基)甲基)噻唑 -4-基)甲氧基)苯基亚甲 基) -2-((4-((3-(4-((2-三氟甲基)苯氧基)甲基)苯基) -1,2,4-噁二唑 -5-基)甲基)哌嗪 -1-基)乙 酰肼;
^-(2-羟基 -4-苄氧基苯基亚甲基) -2-((4-((3-(4-(4-氯苯氧基)甲基)苯基) -1,2,4-噁二唑 -5- 基)甲基)哌嗪 -1-基)乙酰肼;
(2-羟基 -4-(2,4-二氯苄氧基)苯基亚甲基) -2-((4-((3-(4-(4-氟苯氧基)甲基)苯基) -1,2,4- 噁二唑 -5-基)甲基)哌嗪小基)乙酰肼;
N7-(2-羟基 -4-(3-三氟甲基苄氧基)苯基亚甲基 )-2-((4-((3-(4-(4-氟苯氧基)甲基)苯 基) -1,2,4-噁二唑 -5-基)甲基)哌嗪 -1-基)乙酰肼;
羟基 -4-(4-叔丁基苄氧基)苯基亚甲基) -2-((4-((3-(4-(4-氯苯氧基)甲基)苯基) -1,2,4- 噁二唑 -5-基)甲基)哌嗪 - 1 -基)乙酰肼;
N/_(2—羟基 _4-(2,4-二氯苄氧基)苯基亚甲基) -2-((4-((3-(4-(4-氯苯氧基)甲基)苯基) -1,2,4- 噁二唑 -5-基)甲基)呢嘆 -1-基)乙酰肼;
N (2-羟基 -3-烯丙基苯基亚甲基) -2-((4-((3-(4-(4-氯苯氧基)甲基)苯基) -1,2,4-噁二唑 -5- 基)甲基)哌嗪 -1-基)乙酰肼;
^-(2-羟基 -4-((2- ((苯并 [ [1,3]二氧戊环 -5-基)甲基)噻唑 -4-基)甲氧基)苯基亚甲 基) -2-((4-((3-(4-(4-氯苯氧基)甲基)苯基) -1,2,4-噁二唑 -5-基)甲基)哌嗪 -1-基)乙酰肼; 羟基 -4-(4-叔丁基苄氧基)苯基亚甲基) -2-((4-((3-(4-(4-氟苯氧基)甲基)苯基) -1,2,4- 噁二唑 -5-基)甲基)哌嗪 -1-基)乙酰肼;
1^-(2-羟基 -4-((2- ((苯并 [ [1,3]二氧戊环 -5-基)甲基)噻唑 -4-基)甲氧基)苯基亚甲 基) -2-((4-((3-(4-(4-氟苯氧基)甲基)苯基) -1,2,4-噁二唑 -5-基)甲基)哌嗪 -1-基)乙酰肼;
^-(2-羟基 -3-烯丙基苯基亚甲基) -2-((4-((3-(4-(4-氟苯氧基)甲基)苯基 )-1,2,4-噁二唑 -5- 基)甲基)呢嗪 -1-基)乙酰肼;
羟基 -4-苄氧基苯基亚甲基) -2-((4-((3-(4-(3,4-二氟苯氧基)甲基)苯基) -1,2,4-噁二唑
-5-基)甲基)哌嗉小基)乙酰肼;
-(2-羟基 -4-(4-氯苄氧基)苯基亚甲基) -2-((4-((3-(4-(3,4-二氟苯氧基)甲基)苯基) -1,2,4- 噁二唑 -5-基)甲基)哌嗪 - 1 -基)乙酰肼;
N7-(2-羟基 -4-(2,4-二氯苄氧基)苯基亚甲基 )-2-((4-((3-(4-(3,4-二氟苯氧基)甲基)苯 基) -1,2,4-噁二唑 -5-基)甲基)哌嗪 -1-基)乙酰肼;
^-(2-羟基 -3-烯丙基苯基亚甲基) -2-((4-((3-(4-(3-氯苯氧基)甲基)苯基) -1,2,4-噁二唑 -5- 基)甲基)哌嗪 -1-基)乙酰肼;
羟基 -3-(2-甲基烯丙基)苯基亚甲基) -2-((4-((3-(4-(4-氟苯氧基)甲基)苯基) -1 ,2,4-噁 二唑 -5-基)甲基)哌嗪 -1-基)乙酰肼;
N -(2-羟基 -3-(2-甲基烯丙基)苯基亚甲基 )-2-((4-((3-(4-(3,4-二氟苯氧基)甲基)苯 基) -1,2,4-噁二唑 -5-基)甲基)哌嗪 -1-基)乙酰肼;
NZ-(2-羟基 -4-(4-叔丁基苄氧基)苯基亚甲基) -2-((4-((3-(4-(2-三氟甲基苯氧基)甲基)苯 基) -1,2,4-噁二唑 -5-基)甲基)哌嗪 -1-基)乙酰肼;
羟基 -3-烯丙基苯亚甲基) -2-((4-((3-(4-(2-三氟甲基苯氧基)甲基)苯基) -1,2,4-噁二 唑 -5-基)甲基)哌嗪 - 1 -基)乙酰肼;
^-(3-甲基 -2-羟基 -6-异丙基苯基亚甲基 )-2-((4-((3-(4-(3,4-二氟苯氧基)甲基)苯 基) -1,2,4-噁二唑 -5-基)甲基)哌嗪小基)乙酰肼;
N;-(2-羟基 -4-(3-氟苄氧基)苯基亚甲基 )-2-((4-((3-(4-(2-三氟甲基苯氧基)甲基)苯 基) -1,2,4-噁二唑 -5-基)甲基)哌嗪 -1-基)乙酰肼;
^-(2-羟基 -5-(3-氯苄氧基)苯基亚甲基) -2-((4-((3-(4-(4-氯苯氧基)甲基)苯基) -1,2,4-噁二 -5- )甲基)哌嗪 - 1 -基)乙酰肼;
^-(2-羟基 -5-苄氧基苯基亚甲基) -2-((4-((3-(4-(3,4-二氟苯氧基)甲基)苯基) -1,2,4-噁二唑 -5-基)甲基)哌嗪 -1-基)乙酰肼;
^-(2-羟基 -5-(4-氯苄氧基)苯基亚甲基) -2-((4-((3-(4-(4-氯苯氧基)甲基)苯基) -1,2,4-噁二 唑 -5-基)甲基)哌嚷 -1-基)乙酰肼;
N (2-羟基 -5-(2-苄基噻唑 -4-基)苯基亚甲基) -2-((4-((3-(4-(4-氯苯氧基)甲基)苯基) -1,2,4- 噁二唑 -5-基)甲基)哌嗪 -1-基)乙酰肼;
N -(2-羟基 -5-(2-苄基噻唑 -4-基)苯基亚甲基 )-2-((4-((3-(4-(3,4-二氟苯氧基)甲基)苯 基) -1,2,4-噁二唑 -5-基)甲基)哌嗪 -1-基)乙酰肼;
7、 权利要求 1 的通式 I的衍生物, 及其几何异构体或其药学上可接受的盐、 水合物 或溶剂化物, 特别优选- 羟基 -3-烯丙基苯基亚甲基) -2-((4-((3-(4-(4-氯苯氧基)甲基)苯基) -1,2,4-噁二唑 -5- 基)甲基)哌嗪 -1-基)乙酰肼;
^-(2-羟基 -4-((2- ((苯并 [ [1,3]二氧戊环 -5-基)甲基)噻唑 -4-基)甲氧基)苯基亚甲 基) -2-((4-((3-(4-(4-氯苯氧基)甲基)苯基) -1,2,4-噁二唑 -5-基)甲基)哌嗪 -1-基)乙酰肼; ^-(2-羟基 -3-烯丙基苯基亚甲基) -2-((4-((3-(4-(4-氟苯氧基)甲基)苯基) -1,2,4-噁二唑 -5- 基)甲基)哌嗪 -1-基)乙酰肼;
^-(2-羟基 -4-((2- ((苯并 [ [1,3]二氧戊环 -5-基)甲基)噻唑 -4-基)甲氧基)苯基亚甲 基) -2-((4-((3-(4-(4-氟苯氧基)甲基)苯基) -1,2,4-噁二唑 -5-基)甲基)哌嗪小基)乙酰肼; ^-(2-羟基 -4-苄氧基苯基亚甲基) -2-((4-((3-(4-(3,4-二氟苯氧基)甲基)苯基) -1,2,4-噁二唑 -5-基)甲基)哌嗪小基)乙酰肼;
^-(2-羟基 -4-(4-氯苄氧基)苯基亚甲基) -2-((4-((3-(4-(3,4-二氟苯氧基)甲基)苯基) -1,2,4- 噁二唑 -5-基)甲基)哌嗪 -1-基)乙酰肼;
^-(2-羟基 -3-烯丙基苯基亚甲基) -2-((4-((3-(4-(3-氯苯氧基)甲基)苯基) -1,2,4-噁二唑 -5- 基)甲基)呢嗪 -1-基)乙酰肼;
N7-(2-羟基 -3-(2-甲基烯丙基)苯基亚甲基 )-2-((4-((3-(4-(3,4-二氟苯氧基)甲基)苯 基) - 1 ,2,4-噁二唑 -5-基)甲基)哌嗪- 1 -基)乙酰肼;
W-P-羟基 -3-(2-甲基烯丙基)苯基亚甲基) -2-((4-((3-(4-(4-氟苯氧基)甲基)苯基) -1,2,4-噁 二唑 -5-基)甲基)哌嗪 -1-基)乙酰肼;
^-(2-羟基 -4-(4-叔丁基苄氧基)苯基亚甲基) -2-((4-((3-(4-(2-三氟甲基苯氧基)甲基)苯 基) -1,2,4-噁二唑 -5-基)甲基)哌嗪 -1-基)乙酰肼;
-(2-羟基 -3-烯丙基苯亚甲基) -2-((4-((3-(4-(2-三氟甲基苯氧基)甲基)苯基) -1,2,4-噁二 唑 -5-基)甲基)哌嗪 - 1 -基)乙酰肼;
N;-(3-甲基 -2-羟基 -6-异丙基苯基亚甲基 )-2-((4-((3-(4-(3,4-二氟苯氧基)甲基)苯 基)- 1 ,2,4-噁二唑 -5-基)甲基)哌嗪 - 1 -基)乙酰肼;
W-p-羟基 -5-苄氧基苯基亚甲基) -2-((4-((3-(4-(3,4-二氟苯氧基)甲基)苯基) -1,2,4-噁二唑 -5-基)甲基)哌嗪 - 1 -基)乙酰肼;
羟基 -5-(4-氯苄氧基)苯基亚甲基) -2-((4-((3-(4-(4-氯苯氧基)甲基)苯基) -1,2,4-噁二 唑 -5-基)甲基)哌嗪 - 1 -基)乙酰肼;
^-(2-羟基 -5-(2-苄基噻唑 -4-基)苯基亚甲基) -2-((4-((3-(4-(4-氯苯氧基)甲基)苯基) -1,2,4- 噁二唑 -5-基)甲基)哌嗪 - 1 -基)乙酰肼;
羟基 -5-(2-苄基噻唑 -4-基)苯基亚甲基) -2-((4-((3-(4-(3,4-二氟苯氧基)甲基)苯 基) -1,2,4-噁二唑 -5-基)甲基)哌嗪小基)乙酰肼;
8、 一种药用组合物, 包含权利要求 1-7中任何一项的化合物, 及其几何异构体或其药 学上可接受的盐、 水合物或溶剂化物作为活性成分以及药学上可接受的赋型剂。
9、 权利要求 1-7中任何一项的化合物, 及其几何异构体或其药学上可接受的盐、水合 物或溶剂化物在制备治疗和 /或预防各种癌症疾病的药物中的应用。
10、 权利要求 9所述的应用, 其特征在于: 所述的癌症包括白血病、 肺癌、 肝癌、 前 列腺癌、 结肠癌、 胃癌、 乳腺癌、 脑胶质瘤。
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CN102643252B (zh) * | 2012-04-17 | 2014-06-25 | 沈阳药科大学 | 含哌嗪乙酰肼的双芳基脲类衍生物及其应用 |
CN103864797A (zh) * | 2012-12-10 | 2014-06-18 | 韩冰 | 一类具有神经保护作用的化合物及其用途 |
CN103622965B (zh) * | 2013-12-10 | 2016-03-16 | 沈阳药科大学 | 噁二唑基哌嗪化合物在制备抗血管新生药物中的用途 |
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WO2008134474A2 (en) * | 2007-04-27 | 2008-11-06 | The Board Of Trustees Of The University Of Illinois | Compositions and methods including cell death inducers and procaspase activation |
WO2008141731A2 (en) * | 2007-05-18 | 2008-11-27 | Bayer Healthcare Ag | Inhibitors of hypoxia inducible factor (hif) useful for treating hyper-proliferative disorders and diseases associated with angiogenesis |
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