EA035349B1 - ЗАМЕЩЕННЫЕ ПИРИМИДИНОВЫЕ ОБРАТНЫЕ ИНГИБИТОРЫ Bmi-1 - Google Patents
ЗАМЕЩЕННЫЕ ПИРИМИДИНОВЫЕ ОБРАТНЫЕ ИНГИБИТОРЫ Bmi-1 Download PDFInfo
- Publication number
- EA035349B1 EA035349B1 EA201890142A EA201890142A EA035349B1 EA 035349 B1 EA035349 B1 EA 035349B1 EA 201890142 A EA201890142 A EA 201890142A EA 201890142 A EA201890142 A EA 201890142A EA 035349 B1 EA035349 B1 EA 035349B1
- Authority
- EA
- Eurasian Patent Office
- Prior art keywords
- fluoro
- diamine
- benzimidazol
- methyl
- pyrimidin
- Prior art date
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- 101100058550 Mus musculus Bmi1 gene Proteins 0.000 title claims abstract description 195
- 239000003112 inhibitor Substances 0.000 title description 20
- 230000002441 reversible effect Effects 0.000 title description 4
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 449
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 181
- 201000011510 cancer Diseases 0.000 claims abstract description 120
- 230000001404 mediated effect Effects 0.000 claims abstract description 46
- -1 1H-benzimidazolyl Chemical group 0.000 claims description 590
- 125000000217 alkyl group Chemical group 0.000 claims description 249
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 53
- 229910052736 halogen Inorganic materials 0.000 claims description 51
- 125000003545 alkoxy group Chemical group 0.000 claims description 49
- 150000002367 halogens Chemical class 0.000 claims description 49
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 43
- 125000001424 substituent group Chemical group 0.000 claims description 42
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 37
- MISVBCMQSJUHMH-UHFFFAOYSA-N pyrimidine-4,6-diamine Chemical compound NC1=CC(N)=NC=N1 MISVBCMQSJUHMH-UHFFFAOYSA-N 0.000 claims description 32
- 238000011282 treatment Methods 0.000 claims description 32
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 28
- 239000008194 pharmaceutical composition Substances 0.000 claims description 26
- 125000004414 alkyl thio group Chemical group 0.000 claims description 22
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 21
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 21
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 20
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 20
- 125000003342 alkenyl group Chemical group 0.000 claims description 18
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 18
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 claims description 17
- 239000002246 antineoplastic agent Substances 0.000 claims description 17
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 17
- 230000002401 inhibitory effect Effects 0.000 claims description 16
- 239000003814 drug Substances 0.000 claims description 15
- 229940127089 cytotoxic agent Drugs 0.000 claims description 14
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 11
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 11
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 10
- SIYIEJHEMHWDMZ-UHFFFAOYSA-N 2-(4-methylphenyl)pyrimidine-4,6-diamine Chemical compound C1=CC(C)=CC=C1C1=NC(N)=CC(N)=N1 SIYIEJHEMHWDMZ-UHFFFAOYSA-N 0.000 claims description 9
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 9
- UQTDYCJEMJXGHA-UHFFFAOYSA-N 2-[4-(trifluoromethyl)phenyl]pyrimidine-4,6-diamine Chemical compound NC1=CC(N)=NC(C=2C=CC(=CC=2)C(F)(F)F)=N1 UQTDYCJEMJXGHA-UHFFFAOYSA-N 0.000 claims description 8
- 150000001204 N-oxides Chemical class 0.000 claims description 8
- KMZNRYRZJJJUKT-UHFFFAOYSA-N 2-(4-methoxyphenyl)pyrimidine-4,6-diamine Chemical compound C1=CC(OC)=CC=C1C1=NC(N)=CC(N)=N1 KMZNRYRZJJJUKT-UHFFFAOYSA-N 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 5
- SRRMBKTXOKLLES-UHFFFAOYSA-N 2-[4-(trifluoromethoxy)phenyl]pyrimidine-4,6-diamine Chemical compound FC(OC1=CC=C(C=C1)C1=NC(=CC(=N1)N)N)(F)F SRRMBKTXOKLLES-UHFFFAOYSA-N 0.000 claims description 4
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Classifications
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- 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
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
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