CN107417666A - 溴代苄醚衍生物、及其制法和药物组合物与用途 - Google Patents
溴代苄醚衍生物、及其制法和药物组合物与用途 Download PDFInfo
- Publication number
- CN107417666A CN107417666A CN201710365696.1A CN201710365696A CN107417666A CN 107417666 A CN107417666 A CN 107417666A CN 201710365696 A CN201710365696 A CN 201710365696A CN 107417666 A CN107417666 A CN 107417666A
- Authority
- CN
- China
- Prior art keywords
- bromo
- chlorine
- bromine
- fluorine
- base
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- OCOMTTHSJBIAMZ-UHFFFAOYSA-N benzyl hypobromite Chemical class BrOCC1=CC=CC=C1 OCOMTTHSJBIAMZ-UHFFFAOYSA-N 0.000 title claims abstract description 43
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 15
- 238000002360 preparation method Methods 0.000 title abstract description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 83
- 150000003839 salts Chemical class 0.000 claims abstract description 53
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 44
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 14
- 208000023275 Autoimmune disease Diseases 0.000 claims abstract description 11
- 208000035473 Communicable disease Diseases 0.000 claims abstract description 6
- 208000035475 disorder Diseases 0.000 claims abstract description 4
- 102000008096 B7-H1 Antigen Human genes 0.000 claims abstract 3
- 108010074708 B7-H1 Antigen Proteins 0.000 claims abstract 3
- -1 acetylamino, carbamyl Chemical group 0.000 claims description 126
- 239000002585 base Substances 0.000 claims description 116
- 238000006467 substitution reaction Methods 0.000 claims description 97
- 239000000460 chlorine Substances 0.000 claims description 72
- 229910052801 chlorine Inorganic materials 0.000 claims description 72
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 66
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 66
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 66
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 66
- 229910052794 bromium Inorganic materials 0.000 claims description 66
- 239000011737 fluorine Substances 0.000 claims description 66
- 229910052731 fluorine Inorganic materials 0.000 claims description 66
- 125000001424 substituent group Chemical group 0.000 claims description 56
- 239000001257 hydrogen Substances 0.000 claims description 51
- 229910052739 hydrogen Inorganic materials 0.000 claims description 51
- FFNVQNRYTPFDDP-UHFFFAOYSA-N 2-cyanopyridine Chemical compound N#CC1=CC=CC=N1 FFNVQNRYTPFDDP-UHFFFAOYSA-N 0.000 claims description 49
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims description 48
- 125000003282 alkyl amino group Chemical group 0.000 claims description 48
- ZRALSGWEFCBTJO-UHFFFAOYSA-N anhydrous guanidine Natural products NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 48
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims description 48
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 48
- 125000003545 alkoxy group Chemical group 0.000 claims description 40
- 125000000217 alkyl group Chemical group 0.000 claims description 40
- GZPHSAQLYPIAIN-UHFFFAOYSA-N 3-pyridinecarbonitrile Chemical compound N#CC1=CC=CN=C1 GZPHSAQLYPIAIN-UHFFFAOYSA-N 0.000 claims description 31
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 28
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 26
- JMANVNJQNLATNU-UHFFFAOYSA-N oxalonitrile Chemical compound N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 claims description 26
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 26
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 26
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 26
- 229920002554 vinyl polymer Polymers 0.000 claims description 26
- 150000002431 hydrogen Chemical group 0.000 claims description 25
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 24
- 125000002971 oxazolyl group Chemical group 0.000 claims description 24
- 125000001439 semicarbazido group Chemical group [H]N([H])C(=O)N([H])N([H])* 0.000 claims description 24
- 150000003536 tetrazoles Chemical class 0.000 claims description 24
- 125000000335 thiazolyl group Chemical group 0.000 claims description 24
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea group Chemical group NC(=O)N XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 24
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 claims description 19
- 235000004400 serine Nutrition 0.000 claims description 19
- 150000003053 piperidines Chemical class 0.000 claims description 18
- ROSDSFDQCJNGOL-UHFFFAOYSA-N protonated dimethyl amine Natural products CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 18
- 239000003814 drug Substances 0.000 claims description 16
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 16
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 16
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 15
- 239000002253 acid Substances 0.000 claims description 14
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims description 13
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 13
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 12
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 claims description 10
- 239000004473 Threonine Substances 0.000 claims description 10
- 201000011510 cancer Diseases 0.000 claims description 10
- 201000010099 disease Diseases 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 8
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 8
- 229910052717 sulfur Inorganic materials 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 239000002994 raw material Substances 0.000 claims description 7
- CDUUKBXTEOFITR-BYPYZUCNSA-N 2-methyl-L-serine Chemical class OC[C@@]([NH3+])(C)C([O-])=O CDUUKBXTEOFITR-BYPYZUCNSA-N 0.000 claims description 6
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 6
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 6
- 201000005202 lung cancer Diseases 0.000 claims description 6
- 208000020816 lung neoplasm Diseases 0.000 claims description 6
- 239000004480 active ingredient Substances 0.000 claims description 5
- 150000007522 mineralic acids Chemical class 0.000 claims description 5
- 150000007530 organic bases Chemical class 0.000 claims description 5
- 206010006187 Breast cancer Diseases 0.000 claims description 4
- 208000026310 Breast neoplasm Diseases 0.000 claims description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
- 235000004279 alanine Nutrition 0.000 claims description 4
- 229910001420 alkaline earth metal ion Inorganic materials 0.000 claims description 4
- 235000015165 citric acid Nutrition 0.000 claims description 4
- 235000019253 formic acid Nutrition 0.000 claims description 4
- 210000000056 organ Anatomy 0.000 claims description 4
- 150000007524 organic acids Chemical class 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 4
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 3
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims description 3
- 235000015459 Lycium barbarum Nutrition 0.000 claims description 3
- 244000241838 Lycium barbarum Species 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 3
- 150000003863 ammonium salts Chemical class 0.000 claims description 3
- 150000001768 cations Chemical class 0.000 claims description 3
- 229940125782 compound 2 Drugs 0.000 claims description 3
- 239000004310 lactic acid Substances 0.000 claims description 3
- 235000014655 lactic acid Nutrition 0.000 claims description 3
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 230000009885 systemic effect Effects 0.000 claims description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 3
- HXRVTZVVSGPFEC-BTJKTKAUSA-N (z)-but-2-enedioic acid;2,3-dihydroxybutanedioic acid Chemical compound OC(=O)\C=C/C(O)=O.OC(=O)C(O)C(O)C(O)=O HXRVTZVVSGPFEC-BTJKTKAUSA-N 0.000 claims description 2
- 208000004300 Atrophic Gastritis Diseases 0.000 claims description 2
- 241000894006 Bacteria Species 0.000 claims description 2
- 208000019838 Blood disease Diseases 0.000 claims description 2
- 208000003174 Brain Neoplasms Diseases 0.000 claims description 2
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 claims description 2
- 201000009030 Carcinoma Diseases 0.000 claims description 2
- 206010009900 Colitis ulcerative Diseases 0.000 claims description 2
- 208000002699 Digestive System Neoplasms Diseases 0.000 claims description 2
- 208000036495 Gastritis atrophic Diseases 0.000 claims description 2
- 208000032612 Glial tumor Diseases 0.000 claims description 2
- 206010018338 Glioma Diseases 0.000 claims description 2
- 208000024869 Goodpasture syndrome Diseases 0.000 claims description 2
- 208000001204 Hashimoto Disease Diseases 0.000 claims description 2
- 208000030836 Hashimoto thyroiditis Diseases 0.000 claims description 2
- 206010020850 Hyperthyroidism Diseases 0.000 claims description 2
- HBBGRARXTFLTSG-UHFFFAOYSA-N Lithium ion Chemical compound [Li+] HBBGRARXTFLTSG-UHFFFAOYSA-N 0.000 claims description 2
- JLVVSXFLKOJNIY-UHFFFAOYSA-N Magnesium ion Chemical compound [Mg+2] JLVVSXFLKOJNIY-UHFFFAOYSA-N 0.000 claims description 2
- 208000003250 Mixed connective tissue disease Diseases 0.000 claims description 2
- 206010029240 Neuritis Diseases 0.000 claims description 2
- 241000721454 Pemphigus Species 0.000 claims description 2
- 208000031845 Pernicious anaemia Diseases 0.000 claims description 2
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 claims description 2
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims description 2
- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 2
- 208000006593 Urologic Neoplasms Diseases 0.000 claims description 2
- 230000001154 acute effect Effects 0.000 claims description 2
- 229910001413 alkali metal ion Inorganic materials 0.000 claims description 2
- 239000010953 base metal Substances 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 229910001424 calcium ion Inorganic materials 0.000 claims description 2
- 208000016644 chronic atrophic gastritis Diseases 0.000 claims description 2
- 238000009833 condensation Methods 0.000 claims description 2
- 201000001981 dermatomyositis Diseases 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 239000001530 fumaric acid Substances 0.000 claims description 2
- 235000011087 fumaric acid Nutrition 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 2
- 208000014951 hematologic disease Diseases 0.000 claims description 2
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001841 imino group Chemical group [H]N=* 0.000 claims description 2
- 208000015181 infectious disease Diseases 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 229910001416 lithium ion Inorganic materials 0.000 claims description 2
- 229910001425 magnesium ion Inorganic materials 0.000 claims description 2
- 229910021645 metal ion Inorganic materials 0.000 claims description 2
- 201000006417 multiple sclerosis Diseases 0.000 claims description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 230000001613 neoplastic effect Effects 0.000 claims description 2
- 201000011682 nervous system cancer Diseases 0.000 claims description 2
- 206010061311 nervous system neoplasm Diseases 0.000 claims description 2
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 229910001414 potassium ion Inorganic materials 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 230000009467 reduction Effects 0.000 claims description 2
- 210000004994 reproductive system Anatomy 0.000 claims description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 2
- 208000035408 type 1 diabetes mellitus 1 Diseases 0.000 claims description 2
- 230000009385 viral infection Effects 0.000 claims description 2
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims 12
- 125000002252 acyl group Chemical group 0.000 claims 12
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims 2
- 208000035186 Hemolytic Autoimmune Anemia Diseases 0.000 claims 1
- 208000035868 Vascular inflammations Diseases 0.000 claims 1
- 201000000448 autoimmune hemolytic anemia Diseases 0.000 claims 1
- 230000005784 autoimmunity Effects 0.000 claims 1
- 230000003694 hair properties Effects 0.000 claims 1
- 208000026037 malignant tumor of neck Diseases 0.000 claims 1
- 206010028417 myasthenia gravis Diseases 0.000 claims 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims 1
- 102100040678 Programmed cell death protein 1 Human genes 0.000 abstract description 26
- 101710089372 Programmed cell death protein 1 Proteins 0.000 abstract description 25
- 239000000203 mixture Substances 0.000 abstract description 7
- 235000002639 sodium chloride Nutrition 0.000 description 34
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 19
- 239000007787 solid Substances 0.000 description 19
- 241000699666 Mus <mouse, genus> Species 0.000 description 16
- 210000004027 cell Anatomy 0.000 description 16
- 230000008859 change Effects 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 13
- 239000003795 chemical substances by application Substances 0.000 description 13
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 12
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 12
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- 230000003993 interaction Effects 0.000 description 10
- 239000003826 tablet Substances 0.000 description 10
- 238000011282 treatment Methods 0.000 description 10
- 210000001744 T-lymphocyte Anatomy 0.000 description 8
- 210000004369 blood Anatomy 0.000 description 8
- 239000008280 blood Substances 0.000 description 8
- 210000004881 tumor cell Anatomy 0.000 description 8
- 0 Bc1c(COc2cc(O*)c(C*)cc2)cccc1I Chemical compound Bc1c(COc2cc(O*)c(C*)cc2)cccc1I 0.000 description 7
- 241001465754 Metazoa Species 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 230000002401 inhibitory effect Effects 0.000 description 7
- 239000007924 injection Substances 0.000 description 7
- 238000002347 injection Methods 0.000 description 7
- 229960002621 pembrolizumab Drugs 0.000 description 7
- 238000007920 subcutaneous administration Methods 0.000 description 7
- VYUNGCYZRCTLKE-UHFFFAOYSA-N 6-(2-methylphenyl)-2,3-dihydro-1,4-benzodioxine Chemical compound CC1=CC=CC=C1C1=CC=C(OCCO2)C2=C1 VYUNGCYZRCTLKE-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical group [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 229910021529 ammonia Inorganic materials 0.000 description 6
- 235000015177 dried meat Nutrition 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 201000001441 melanoma Diseases 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 230000002829 reductive effect Effects 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 210000001519 tissue Anatomy 0.000 description 6
- 238000002054 transplantation Methods 0.000 description 6
- DWNBOPVKNPVNQG-LURJTMIESA-N (2s)-4-hydroxy-2-(propylamino)butanoic acid Chemical compound CCCN[C@H](C(O)=O)CCO DWNBOPVKNPVNQG-LURJTMIESA-N 0.000 description 5
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 230000000259 anti-tumor effect Effects 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 238000009169 immunotherapy Methods 0.000 description 5
- 210000004698 lymphocyte Anatomy 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 210000000952 spleen Anatomy 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 238000012546 transfer Methods 0.000 description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- 238000007792 addition Methods 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 description 4
- 230000034994 death Effects 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 239000007884 disintegrant Substances 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000008103 glucose Substances 0.000 description 4
- 238000011081 inoculation Methods 0.000 description 4
- 210000004072 lung Anatomy 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- RTFPTPXBTIUISM-UHFFFAOYSA-N 1-(bromomethyl)-3-phenylbenzene Chemical class BrCC1=CC=CC(C=2C=CC=CC=2)=C1 RTFPTPXBTIUISM-UHFFFAOYSA-N 0.000 description 3
- QQLVDPWCGDJXFC-UHFFFAOYSA-N BrC1C(C(=O)O)=CC=CC1(C(=O)O)C Chemical class BrC1C(C(=O)O)=CC=CC1(C(=O)O)C QQLVDPWCGDJXFC-UHFFFAOYSA-N 0.000 description 3
- 238000011740 C57BL/6 mouse Methods 0.000 description 3
- DHVADSUVDTWNJX-JEDNCBNOSA-N C=C1[C@H](N(CC1)Br)C(=O)O.C(#N)C=1C=CC=NC1 Chemical group C=C1[C@H](N(CC1)Br)C(=O)O.C(#N)C=1C=CC=NC1 DHVADSUVDTWNJX-JEDNCBNOSA-N 0.000 description 3
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 206010048612 Hydrothorax Diseases 0.000 description 3
- 229930195725 Mannitol Natural products 0.000 description 3
- 206010027458 Metastases to lung Diseases 0.000 description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 3
- 239000004305 biphenyl Substances 0.000 description 3
- 235000010290 biphenyl Nutrition 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 238000002512 chemotherapy Methods 0.000 description 3
- 238000004140 cleaning Methods 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 239000007887 hard shell capsule Substances 0.000 description 3
- 230000001900 immune effect Effects 0.000 description 3
- 210000000987 immune system Anatomy 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- 239000000594 mannitol Substances 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 3
- 239000008108 microcrystalline cellulose Substances 0.000 description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 description 3
- 229960003301 nivolumab Drugs 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 3
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 3
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 3
- 239000002504 physiological saline solution Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 235000018102 proteins Nutrition 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 239000007901 soft capsule Substances 0.000 description 3
- 238000002198 surface plasmon resonance spectroscopy Methods 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- 239000000080 wetting agent Substances 0.000 description 3
- BACZSVQZBSCWIG-UHFFFAOYSA-N 1-(bromomethyl)-3-iodobenzene Chemical class BrCC1=CC=CC(I)=C1 BACZSVQZBSCWIG-UHFFFAOYSA-N 0.000 description 2
- CDUUKBXTEOFITR-UHFFFAOYSA-N 2-methylserine zwitterion Chemical compound OCC([NH3+])(C)C([O-])=O CDUUKBXTEOFITR-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- 239000004342 Benzoyl peroxide Substances 0.000 description 2
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 2
- HOOXYRJKUBBARK-UHFFFAOYSA-N BrBrCC1=CC(C2=CC=CC=C2)=CC=C1 Chemical class BrBrCC1=CC(C2=CC=CC=C2)=CC=C1 HOOXYRJKUBBARK-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 229920001353 Dextrin Polymers 0.000 description 2
- 239000004375 Dextrin Substances 0.000 description 2
- 241000790917 Dioxys <bee> Species 0.000 description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 2
- 208000017604 Hodgkin disease Diseases 0.000 description 2
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 2
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 2
- 241000521257 Hydrops Species 0.000 description 2
- 206010027336 Menstruation delayed Diseases 0.000 description 2
- 206010030113 Oedema Diseases 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 206010035603 Pleural mesothelioma Diseases 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 235000019400 benzoyl peroxide Nutrition 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- GCUVBACNBHGZRS-UHFFFAOYSA-N cyclopenta-1,3-diene cyclopenta-2,4-dien-1-yl(diphenyl)phosphane iron(2+) Chemical compound [Fe++].c1cc[cH-]c1.c1cc[c-](c1)P(c1ccccc1)c1ccccc1 GCUVBACNBHGZRS-UHFFFAOYSA-N 0.000 description 2
- 239000003405 delayed action preparation Substances 0.000 description 2
- 235000019425 dextrin Nutrition 0.000 description 2
- MCWXGJITAZMZEV-UHFFFAOYSA-N dimethoate Chemical compound CNC(=O)CSP(=S)(OC)OC MCWXGJITAZMZEV-UHFFFAOYSA-N 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 210000003743 erythrocyte Anatomy 0.000 description 2
- 239000002024 ethyl acetate extract Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 210000001508 eye Anatomy 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 235000001727 glucose Nutrition 0.000 description 2
- 238000002868 homogeneous time resolved fluorescence Methods 0.000 description 2
- 229960002591 hydroxyproline Drugs 0.000 description 2
- 230000036039 immunity Effects 0.000 description 2
- 230000002147 killing effect Effects 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 239000008297 liquid dosage form Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 210000002751 lymph Anatomy 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000010534 mechanism of action Effects 0.000 description 2
- 230000001394 metastastic effect Effects 0.000 description 2
- 206010061289 metastatic neoplasm Diseases 0.000 description 2
- 210000004279 orbit Anatomy 0.000 description 2
- 230000003204 osmotic effect Effects 0.000 description 2
- 238000010979 pH adjustment Methods 0.000 description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 2
- UQPUONNXJVWHRM-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 UQPUONNXJVWHRM-UHFFFAOYSA-N 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 239000008299 semisolid dosage form Substances 0.000 description 2
- 125000003607 serino group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C(O[H])([H])[H] 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 239000007909 solid dosage form Substances 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 125000000341 threoninyl group Chemical group [H]OC([H])(C([H])([H])[H])C([H])(N([H])[H])C(*)=O 0.000 description 2
- DCXXMTOCNZCJGO-UHFFFAOYSA-N tristearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 1
- PJXZIEDLTHQYBC-UHFFFAOYSA-N 2-bromo-1-(bromomethyl)-3-phenylbenzene Chemical compound BrCC1=CC=CC(C=2C=CC=CC=2)=C1Br PJXZIEDLTHQYBC-UHFFFAOYSA-N 0.000 description 1
- KZMAWJRXKGLWGS-UHFFFAOYSA-N 2-chloro-n-[4-(4-methoxyphenyl)-1,3-thiazol-2-yl]-n-(3-methoxypropyl)acetamide Chemical compound S1C(N(C(=O)CCl)CCCOC)=NC(C=2C=CC(OC)=CC=2)=C1 KZMAWJRXKGLWGS-UHFFFAOYSA-N 0.000 description 1
- PMMYEEVYMWASQN-BKLSDQPFSA-N 4-hydroxy-L-proline Chemical group OC1C[NH2+][C@H](C([O-])=O)C1 PMMYEEVYMWASQN-BKLSDQPFSA-N 0.000 description 1
- IPOSHVWRFQTHGK-UHFFFAOYSA-N 5-chloro-2,4-dihydroxybenzaldehyde Chemical class OC1=CC(O)=C(C=O)C=C1Cl IPOSHVWRFQTHGK-UHFFFAOYSA-N 0.000 description 1
- PVFOHMXILQEIHX-UHFFFAOYSA-N 8-[(6-bromo-1,3-benzodioxol-5-yl)sulfanyl]-9-[2-(2-bromophenyl)ethyl]purin-6-amine Chemical compound C=1C=2OCOC=2C=C(Br)C=1SC1=NC=2C(N)=NC=NC=2N1CCC1=CC=CC=C1Br PVFOHMXILQEIHX-UHFFFAOYSA-N 0.000 description 1
- 239000004925 Acrylic resin Substances 0.000 description 1
- 229920000178 Acrylic resin Polymers 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- HTHAVHNSWGSDML-LJAQVGFWSA-N C=[Br]c1c(CCc(cc(c(CN[C@@H](CO)C(O)=O)c2)OCc3cncc(C#N)c3)c2Cl)cccc1-c1ccccc1 Chemical compound C=[Br]c1c(CCc(cc(c(CN[C@@H](CO)C(O)=O)c2)OCc3cncc(C#N)c3)c2Cl)cccc1-c1ccccc1 HTHAVHNSWGSDML-LJAQVGFWSA-N 0.000 description 1
- QFMGTBNUXRTHHW-UHFFFAOYSA-N CC(C(C(O)=O)NCc(c(OCc1ccnc(C#N)c1)c1)cc(Cl)c1OCc(cccc1-c2ccccc2)c1[Br]=C)O Chemical compound CC(C(C(O)=O)NCc(c(OCc1ccnc(C#N)c1)c1)cc(Cl)c1OCc(cccc1-c2ccccc2)c1[Br]=C)O QFMGTBNUXRTHHW-UHFFFAOYSA-N 0.000 description 1
- SYFVRKHJSMUCTF-UHFFFAOYSA-N CC(C(C(O)=O)NCc(c(OCc1cncc(C#N)c1)c1)cc(Cl)c1OCc(cccc1-c2ccccc2)c1[Br]=C)O Chemical compound CC(C(C(O)=O)NCc(c(OCc1cncc(C#N)c1)c1)cc(Cl)c1OCc(cccc1-c2ccccc2)c1[Br]=C)O SYFVRKHJSMUCTF-UHFFFAOYSA-N 0.000 description 1
- MEJOKQPUQUXVDY-UHFFFAOYSA-N CC(CO)(C(O)=O)NCc(c(OCc1cncc(C#N)c1)c1)cc(Cl)c1OCc1cccc(-c2ccccc2)c1Br Chemical compound CC(CO)(C(O)=O)NCc(c(OCc1cncc(C#N)c1)c1)cc(Cl)c1OCc1cccc(-c2ccccc2)c1Br MEJOKQPUQUXVDY-UHFFFAOYSA-N 0.000 description 1
- IBKZORCVTJQMQE-UHFFFAOYSA-N CC(O1)=C(COC=O)OC1=O Chemical compound CC(O1)=C(COC=O)OC1=O IBKZORCVTJQMQE-UHFFFAOYSA-N 0.000 description 1
- 210000001266 CD8-positive T-lymphocyte Anatomy 0.000 description 1
- FEENHSAXHDXIBU-IBGZPJMESA-N C[C@@H](C(O)=O)NCc(cc(c(OCc(cccc1-c2ccccc2)c1Br)c1)Cl)c1OCc1cncc(C#N)c1 Chemical compound C[C@@H](C(O)=O)NCc(cc(c(OCc(cccc1-c2ccccc2)c1Br)c1)Cl)c1OCc1cncc(C#N)c1 FEENHSAXHDXIBU-IBGZPJMESA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- 241001269238 Data Species 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 1
- 206010018498 Goitre Diseases 0.000 description 1
- 101001117317 Homo sapiens Programmed cell death 1 ligand 1 Proteins 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 101100519207 Mus musculus Pdcd1 gene Proteins 0.000 description 1
- 101100407308 Mus musculus Pdcd1lg2 gene Proteins 0.000 description 1
- DGSBHTCCTCQKCX-SANMLTNESA-N N#Cc1cc(COc(c(CN[C@@H](CO)C(O)=O)c2)cc(OCc(cccc3-c(cc4)cc5c4OCCO5)c3Br)c2Cl)cnc1 Chemical compound N#Cc1cc(COc(c(CN[C@@H](CO)C(O)=O)c2)cc(OCc(cccc3-c(cc4)cc5c4OCCO5)c3Br)c2Cl)cnc1 DGSBHTCCTCQKCX-SANMLTNESA-N 0.000 description 1
- UBNHUNIPYUNFCW-SANMLTNESA-N N#Cc1cc(COc(cc2OCc(cccc3-c4ccc5OCCOc5c4)c3Br)c(CN[C@@H](CO)C(O)=O)cc2Cl)ccn1 Chemical compound N#Cc1cc(COc(cc2OCc(cccc3-c4ccc5OCCOc5c4)c3Br)c(CN[C@@H](CO)C(O)=O)cc2Cl)ccn1 UBNHUNIPYUNFCW-SANMLTNESA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 239000012270 PD-1 inhibitor Substances 0.000 description 1
- 239000012668 PD-1-inhibitor Substances 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 1
- 206010036105 Polyneuropathy Diseases 0.000 description 1
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 1
- 108700030875 Programmed Cell Death 1 Ligand 2 Proteins 0.000 description 1
- 102100024216 Programmed cell death 1 ligand 1 Human genes 0.000 description 1
- 102100024213 Programmed cell death 1 ligand 2 Human genes 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 208000004732 Systemic Vasculitis Diseases 0.000 description 1
- 208000003721 Triple Negative Breast Neoplasms Diseases 0.000 description 1
- 206010047115 Vasculitis Diseases 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- 238000005299 abrasion Methods 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000001785 acacia senegal l. willd gum Substances 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 125000003295 alanine group Chemical group N[C@@H](C)C(=O)* 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 239000012491 analyte Substances 0.000 description 1
- 238000011224 anti-cancer immunotherapy Methods 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 201000003433 benign pleural mesothelioma Diseases 0.000 description 1
- 150000001555 benzenes Chemical class 0.000 description 1
- 201000001531 bladder carcinoma Diseases 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- 229940095672 calcium sulfate Drugs 0.000 description 1
- 235000011132 calcium sulphate Nutrition 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000007910 chewable tablet Substances 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 230000037029 cross reaction Effects 0.000 description 1
- 238000004163 cytometry Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
- 239000007919 dispersible tablet Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 239000007938 effervescent tablet Substances 0.000 description 1
- 235000013601 eggs Nutrition 0.000 description 1
- 239000002662 enteric coated tablet Substances 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 230000005496 eutectics Effects 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 239000010408 film Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
- 201000005787 hematologic cancer Diseases 0.000 description 1
- 208000007475 hemolytic anemia Diseases 0.000 description 1
- 235000012907 honey Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 230000003832 immune regulation Effects 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 238000002649 immunization Methods 0.000 description 1
- 230000003053 immunization Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 230000016507 interphase Effects 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 238000011898 label-free detection Methods 0.000 description 1
- 208000001921 latent autoimmune diabetes in adults Diseases 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 229940040145 liniment Drugs 0.000 description 1
- 239000000865 liniment Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 208000037841 lung tumor Diseases 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 210000005075 mammary gland Anatomy 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 229940102396 methyl bromide Drugs 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000003595 mist Substances 0.000 description 1
- JKQOBWVOAYFWKG-UHFFFAOYSA-N molybdenum trioxide Chemical compound O=[Mo](=O)=O JKQOBWVOAYFWKG-UHFFFAOYSA-N 0.000 description 1
- 210000002200 mouth mucosa Anatomy 0.000 description 1
- 210000003928 nasal cavity Anatomy 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 229940121655 pd-1 inhibitor Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- RPGWZZNNEUHDAQ-UHFFFAOYSA-N phenylphosphine Chemical compound PC1=CC=CC=C1 RPGWZZNNEUHDAQ-UHFFFAOYSA-N 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 210000004910 pleural fluid Anatomy 0.000 description 1
- 229960000502 poloxamer Drugs 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 208000019629 polyneuritis Diseases 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- ULWHHBHJGPPBCO-UHFFFAOYSA-N propane-1,1-diol Chemical class CCC(O)O ULWHHBHJGPPBCO-UHFFFAOYSA-N 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 238000011897 real-time detection Methods 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 238000009288 screen filtration Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 description 1
- 229910001948 sodium oxide Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000008279 sol Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 235000013599 spices Nutrition 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 210000000115 thoracic cavity Anatomy 0.000 description 1
- 230000002992 thymic effect Effects 0.000 description 1
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 description 1
- 208000022679 triple-negative breast carcinoma Diseases 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 230000005760 tumorsuppression Effects 0.000 description 1
- 208000010570 urinary bladder carcinoma Diseases 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000003809 water extraction Methods 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
Classifications
-
- 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
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
-
- 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/401—Proline; Derivatives thereof, e.g. captopril
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/443—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
- C07C17/10—Preparation of halogenated hydrocarbons by replacement by halogens of hydrogen atoms
- C07C17/14—Preparation of halogenated hydrocarbons by replacement by halogens of hydrogen atoms in the side-chain of aromatic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/26—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton
- C07C17/263—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton by condensation reactions
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
- C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
- C07C211/29—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/12—Formation of amino and carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/16—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions not involving the amino or carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/22—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated the carbon skeleton being further substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
- C07C229/36—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/34—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
- C07C233/35—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/36—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C235/18—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the singly-bound oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. phenoxyacetamides
- C07C235/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the singly-bound oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. phenoxyacetamides having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
- C07C235/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C239/00—Compounds containing nitrogen-to-halogen bonds; Hydroxylamino compounds or ethers or esters thereof
- C07C239/08—Hydroxylamino compounds or their ethers or esters
- C07C239/18—Hydroxylamino compounds or their ethers or esters having nitrogen atoms of hydroxylamino groups further bound to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C255/54—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and etherified hydroxy groups bound to the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
- C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
- C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/02—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from isocyanates with formation of carbamate groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/62—Compounds containing any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylcarbamates
- C07C271/64—Y being a hydrogen or a carbon atom, e.g. benzoylcarbamates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C273/00—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/04—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms
- C07C275/06—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an acyclic and saturated carbon skeleton
- C07C275/16—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an acyclic and saturated carbon skeleton being further substituted by carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
- C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C311/03—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C311/05—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms to acyclic carbon atoms of hydrocarbon radicals substituted by nitrogen atoms, not being part of nitro or nitroso groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/16—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C317/22—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/57—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
- C07C323/58—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
- C07C45/70—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form
- C07C45/71—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form being hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/30—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/84—Nitriles
- C07D213/85—Nitriles in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D295/182—Radicals derived from carboxylic acids
- C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
- C07D295/205—Radicals derived from carbonic acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/14—Nitrogen atoms not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
- C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
- C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
- C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
- C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D319/18—Ethylenedioxybenzenes, not substituted on the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D405/02—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 two hetero rings
- C07D405/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
-
- 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
- A61K31/275—Nitriles; Isonitriles
- A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
- A61K31/36—Compounds containing methylenedioxyphenyl groups, e.g. sesamin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Oncology (AREA)
- Immunology (AREA)
- Communicable Diseases (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Virology (AREA)
- Emergency Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyridine Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Pyrrole Compounds (AREA)
- Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
Abstract
本发明公开了一类溴代苄醚衍生物、及其制法和药物组合物与用途。具体而言,涉及通式I所示的溴代苄醚衍生物,其可药用盐,其立体异构体及其制备方法,含有一个或多个这化合物的组合物,和该类化合物在治疗与PD‑1/PD‑L1信号通路有关的疾病如癌症、感染性疾病、自身免疫性疾病方面的用途。
Description
发明领域
本发明公开了一类溴代苄醚衍生物、及其制法和药物组合物与用途。具体而言,涉及通式I所示的溴代苄醚类衍生物,其可药用盐,其立体异构体及其制备方法,含有一个或多个这化合物的组合物,和该类化合物在治疗与PD-1/PD-L1信号通路有关的疾病如癌症、感染性疾病、自身免疫性疾病方面的用途。
发明背景
随着对肿瘤免疫研究的深入,人们发现肿瘤微环境可以保护肿瘤细胞不被机体免疫系统识别和杀伤,肿瘤细胞的免疫逃逸在肿瘤发生、发展中扮演了非常重要的角色。2013年Science杂志将肿瘤免疫治疗列为十大突破之首,再次让免疫治疗成为肿瘤治疗领域的“焦点”。机体免疫细胞的激活或抑制是通过正性信号和负性信号来调节,其中程序性死亡分子1(programmed death 1,PD-1)/PD-1配体(PD-1 ligand,PD-L1)便是负性免疫调节信号,抑制了肿瘤特异性CD8+ T细胞的免疫活性,介导了免疫逃逸。
肿瘤细胞所具有的逃避免疫系统的能力,是通过在其表面产生的程序性死亡配体(PD-L1)结合到T细胞的PD-1蛋白上实现的。机体内的肿瘤微环境会诱导浸润的T细胞高表达PD-1分子,肿瘤细胞会高表达PD-1的配体PD-L1和PD-L2,导致肿瘤微环境中PD-1通路持续激活,T细胞功能被抑制而不能发现肿瘤以至于不能向免疫系统发出需要攻击肿瘤和杀伤肿瘤细胞的治疗。PD-1抗体是针对PD-1或者PD-L1的一种抗体蛋白,使得前两种蛋白不能发生结合,阻断这一通路,部分恢复T细胞的功能,使这些细胞能够继续杀伤肿瘤细胞。
基于PD1/PDL1的免疫疗法是当前备受瞩目的新一代免疫疗法,旨在利用人体自身的免疫系统抵御肿瘤,通过阻断PD-1/PD-L1信号通路诱导凋亡,具有治疗多种类型肿瘤潜力。最近,一系列令人惊喜的研究结果证实PDl/PD-Ll抑制性抗体对多种肿瘤具有强大的抗瘤活性,格外引人注目。2014年9月4日美国默克的(pembrolizumab)成为FDA批准的首例PD-1单抗用于治疗对其它药物治疗无效的晚期或无法切除的黑色素瘤患者。目前,默沙东正在30多种不同类型的癌症中调查Keytruda的潜力,包括各类血液癌症、肺癌、乳腺癌、膀胱癌、胃癌、头颈部癌症。2014年12月22日,制药巨头百时美施贵宝公司不负重望,率先发力,获得美国食品药品监督管理局(FDA)加速批准,其研发的抗癌免疫疗法药物nivolumab以Opdivo的商品名上市,用于治疗对其它药物没有应答的不可切除的或转移性黑色素瘤患者,是继默沙东Keytruda之后第二个在美国上市的PD-1抑制剂。FDA于2015年3月4日批准了nivolumab用于治疗在经铂为基础化疗期间或化疗后发生疾病进展的转移性鳞性非小细胞肺癌。根据默沙东公布的Keytruda(pembrolizumab)治疗实体瘤的一项Ib期KEYNOTE-028研究数据,Keytruda治疗在25例胸膜间皮瘤(pleuralmesothelioma,PM)患者中取得了28%的总缓解率(ORR),并有48%的患者病情稳定,疾病控制率达到了76%。对当前任何已获批药物均无治疗反应的晚期霍奇金淋巴瘤(HL)患者,接受默沙东Keytruda和百时美Opdvio治疗后,能够达到完全缓解。在2015AACR年会上,约翰霍普金斯基梅尔癌症中心(Kimmel Cancer Center)的肿瘤内科学副教授Leisha A.Emens,MD,PhD做出的报道指出,罗氏的MPDL3280A这一具有抗PD-L1作用的单克隆抗体,在晚期三阴性乳腺癌中表现出了持久的疗效。
虽然肿瘤免疫治疗被认为是靶向治疗后癌症治疗的革命。但是,单抗治疗药物有其本身的缺陷:易被蛋白酶分解,因而在体内不稳定,不能口服;易产生免疫交叉反应;产品质量不易控制,制作技术要求高;大量制备和纯化比较困难,生产成本高;使用不方便,只能注射或点滴。所以,PDl/PD-Ll相互作用小分子抑制剂是肿瘤免疫治疗的更佳选择。
发明内容
本发明解决的技术问题是提供一种具有抑制PDl/PD-Ll相互作用的结构通式I的溴代苄醚衍生物,以及其立体异构体及其可药用盐,其制备方法、药物组合物和其在制备预防或治疗与PDl/PD-Ll信号通路有关疾病药物中的用途。
为解决本发明的技术问题,本发明提供如下技术方案:
本发明技术方案的第一方面是提供一类如通式I所示的溴代苄醚衍生物及其立体异构体以及其可药用盐,
式中
R1选自:
Y选自:取代吡啶亚甲基,取代基选自氰基、甲磺酰基、乙酰氨基、氨甲酰基、二甲胺甲酰基、氟、氯、溴、碘、三氟甲基、C1-5烷基、C1-5烷氧基;
R3选自:取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基,取代基选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基、
所述的取代基包括单取代、双取代、三取代、四取代;
X选自:氢、氟、氯、溴、碘、C1-4烷基、乙烯基、三氟甲基、甲氧基。
优选的溴代苄醚衍生物及其立体异构体以及其可药用盐,其特征在于,所述的化合物如式(IA)所示:
式中
R1选自:
Y选自:取代吡啶亚甲基,取代基选自氰基、甲磺酰基、乙酰氨基、氨甲酰基、二甲胺甲酰基、氟、氯、溴、碘、三氟甲基、C1-5烷基、C1-5烷氧基;
R3选自:取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基,取代基选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基、
所述的取代基包括单取代、双取代、三取代、四取代;
X选自:氢、氟、氯、溴、碘、C1-4烷基、乙烯基、三氟甲基、甲氧基。
优选的溴代苄醚衍生物及其立体异构体以及其可药用盐,其特征在于,所述的化合物如式(IA1)所示:
式中
Y选自:取代吡啶亚甲基,取代基选自氰基、甲磺酰基、乙酰氨基、氨甲酰基、二甲胺甲酰基、氟、氯、溴、碘、三氟甲基、C1-5烷基、C1-5烷氧基;
R3选自:取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基,取代基选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基、
所述的取代基包括单取代、双取代、三取代、四取代;
X选自:氢、氟、氯、溴、碘、C1-4烷基、乙烯基、三氟甲基、甲氧基。
优选的溴代苄醚衍生物及其立体异构体以及其可药用盐,其特征在于,所述的化合物如式(IA1-1)所示:
式中
R2选自:氰基、甲磺酰基、乙酰氨基、氨甲酰基、二甲胺甲酰基、氟、氯、溴、碘、三氟甲基、C1-5烷基、C1-5烷氧基;
R3选自:取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基,取代基选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基、
所述的取代基包括单取代、双取代、三取代、四取代;
X选自:氢、氟、氯、溴、碘、C1-4烷基、乙烯基、三氟甲基、甲氧基。
优选的溴代苄醚衍生物及其立体异构体以及其可药用盐,其特征在于,所述的化合物如式(IA1-1a)所示:
式中
R3选自:取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基,取代基选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基、
所述的取代基包括单取代、双取代、三取代、四取代;
X选自:氢、氟、氯、溴、碘、C1-4烷基、乙烯基、三氟甲基、甲氧基。
优选的溴代苄醚衍生物及其立体异构体以及其可药用盐,其特征在于,所述的化合物如式(IA1-2)所示:
R2选自:氰基、甲磺酰基、乙酰氨基、氨甲酰基、二甲胺甲酰基、氟、氯、溴、碘、三氟甲基、C1-5烷基、C1-5烷氧基;
R3选自:取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基,取代基选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基、
所述的取代基包括单取代、双取代、三取代、四取代;
X选自:氢、氟、氯、溴、碘、C1-4烷基、乙烯基、三氟甲基、甲氧基。
优选的溴代苄醚衍生物及其立体异构体以及其可药用盐,其特征在于,所述的化合物如式(IA1-2a)所示:
式中
R3选自:取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基,取代基选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基、
所述的取代基包括单取代、双取代、三取代、四取代;
X选自:氢、氟、氯、溴、碘、C1-4烷基、乙烯基、三氟甲基、甲氧基。
优选的溴代苄醚衍生物及其立体异构体以及其可药用盐,其特征在于,所述的化合物如式(IA2)所示:
Y选自:取代吡啶亚甲基,取代基选自氰基、甲磺酰基、乙酰氨基、氨甲酰基、二甲胺甲酰基、氟、氯、溴、碘、三氟甲基、C1-5烷基、C1-5烷氧基;
R3选自:取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基,取代基选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基、
所述的取代基包括单取代、双取代、三取代、四取代;
X选自:氢、氟、氯、溴、碘、C1-4烷基、乙烯基、三氟甲基、甲氧基。
优选的溴代苄醚衍生物及其立体异构体以及其可药用盐,其特征在于,所述的化合物如式(IA2-1)所示:
R2选自:氰基、甲磺酰基、乙酰氨基、氨甲酰基、二甲胺甲酰基、氟、氯、溴、碘、三氟甲基、C1-5烷基、C1-5烷氧基;
R3选自:取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基,取代基选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基、
所述的取代基包括单取代、双取代、三取代、四取代;
X选自:氢、氟、氯、溴、碘、C1-4烷基、乙烯基、三氟甲基、甲氧基。
优选的溴代苄醚衍生物及其立体异构体以及其可药用盐,其特征在于,所述的化合物如式(IA2-1a)所示:
R3选自:取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基,取代基选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基、
所述的取代基包括单取代、双取代、三取代、四取代;
X选自:氢、氟、氯、溴、碘、C1-4烷基、乙烯基、三氟甲基、甲氧基。
优选的溴代苄醚衍生物及其立体异构体以及其可药用盐,其特征在于,所述的化合物如式(IA2-2)所示:
R2选自:氰基、甲磺酰基、乙酰氨基、氨甲酰基、二甲胺甲酰基、氟、氯、溴、碘、三氟甲基、C1-5烷基、C1-5烷氧基;
R3选自:取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基,取代基选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基、
所述的取代基包括单取代、双取代、三取代、四取代;
X选自:氢、氟、氯、溴、碘、C1-4烷基、乙烯基、三氟甲基、甲氧基。
优选的溴代苄醚衍生物及其立体异构体以及其可药用盐,其特征在于,所述的化合物如式(IA2-2a)所示:
R3选自:取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基,取代基选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基、
所述的取代基包括单取代、双取代、三取代、四取代;
X选自:氢、氟、氯、溴、碘、C1-4烷基、乙烯基、三氟甲基、甲氧基。
以上通式中,优选的溴代苄醚衍生物及其立体异构体以及其可药用盐,其特征在于,所述R3选自
R=甲基、乙基、丙基、异丙基、丁基、戊基、己基、庚基、辛基;
X选自:氢、氟、氯、溴、甲基、乙烯基、三氟甲基。
最优选的溴代苄醚衍生物及其立体异构体以及其可药用盐,所述的化合物选自:
(S)-N-[2-(2-氰基吡啶-4-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]脯氨酸
N-[2-(2-氰基吡啶-4-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]环丙亚胺-2-羧酸
(S,S)-N-[2-(2-氰基吡啶-4-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]-4-羟基脯氨酸
(S)-N-[2-(2-氰基吡啶-4-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]哌啶-2-羧酸
(S)-N-[2-(2-氰基吡啶-4-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]丝氨酸
N-[2-(2-氰基吡啶-4-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]2-甲基丝氨酸
N-[2-(2-氰基吡啶-4-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]苏氨酸
(S)-N-[2-(5-氰基吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]哌啶-2-羧酸
N-[2-(5-氰基吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]2-甲基丝氨酸
(S)-N-[2-(5-氰基吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]丝氨酸
(S)-N-[2-(5-氰基吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]脯氨酸
N-[2-(5-氰基吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]苏氨酸
(S)-N-[2-(5-氰基吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]丙氨酸
(S)-N-[2-(2-氰基吡啶-4-亚甲氧基)-4-(2-溴-3-(3,4-乙二氧苯基)苄氧基)-5-氯苄基]丝氨酸
(S)-N-[2-(2-氰基吡啶-4-亚甲氧基)-4-(2-溴-3-(3,4-乙二氧苯基)苄氧基)-5-氯苄基]哌啶-2-甲酸
(S)-N-[2-(5-氰基吡啶-3-亚甲氧基)-4-(2-溴-3-(3,4-乙二氧苯基)苄氧基)-5-氯苄基]丝氨酸
以上所述的溴代苄醚衍生物及其立体异构体以及其可药用盐,其特征在于,所述的药用盐包括与无机酸、有机酸、碱金属离子、碱土金属离子或能提供生理上可接受的阳离子的有机碱结合形成的盐以及铵盐。
进一步所述的无机酸选自盐酸、氢溴酸、磷酸或硫酸;所述的有机酸选自甲磺酸、对甲苯磺酸、三氟乙酸、枸杞酸、马来酸酒石酸、富马酸、柠檬酸或乳酸;所述的碱金属离子选自锂离子,钠离子,钾离子;所述的碱土金属离子选自钙离子,镁离子;所述的能提供生理上可接受的阳离子的有机碱选自甲胺、二甲胺、三甲胺、哌啶、吗啉或三(2-羟乙基)胺。
本发明技术方案的第二方面是提供了第一方面所述化合物的制备方法:
为了制备本发明通式I所述的化合物,依据通式I的结构,本发明制备通式I化合物将分为以下几步。
(a)以2-溴-3-碘甲苯1和苯或取代苯的硼酸或硼酸酯为基本原料,通过suzuki偶联反应得到中间体化合物2;
(b)以中间体2为原料,通过溴代试剂使甲基溴化得到溴代物中间体3;
(c)以中间体3为原料,在碱性条件下与2,4-二羟基-X取代苯甲醛反应,得到苄芳醚中间体4;
(d)以中间体4为原料,在碱性条件下与取代的吡啶亚甲基卤反应,得到中间体化合物5;
(e)以含醛基的中间体化合物5为原料,与含氨基或亚氨基的HR3缩合及还原得到目标化合物I;
所述的R1、R3、Y、X的定义同第一方面所述相同。
另外,上述反应中的起始原料及中间体容易得到,各步反应可依据已报道的文献或对本领域熟练技术人员来说可以用有机合成中的常规方法很容易合成。通式I所述化合物可以溶剂化物或非溶剂化物的形式存在,利用不同的溶剂进行结晶可能得到不同的溶剂化物。通式I所述药学上可接受的盐包括不同酸加成盐,如下列无机酸或有机酸的酸加成盐:盐酸,氢溴酸,磷酸,硫酸,甲磺酸,对甲苯磺酸,三氟乙酸,枸杞酸,马来酸,酒石酸,富马酸,柠檬酸,乳酸。通式I所述药学上可接受的盐还包括不同碱金属盐(锂,钠,钾盐),碱土金属盐(钙,镁盐)及铵盐,和能提供生理上可接受的阳离子的有机碱的盐,如甲胺,二甲胺,三甲胺,哌啶,吗啉及三(2-羟乙基)胺的盐。在本发明范围内的所有这些盐都可采用常规方法制备。在所述的通式I化合物及其溶剂化物和其盐的制备过程中,不同结晶条件可能出现多晶或共晶。
本发明技术方案的第三方面是提供了一种药物组合物,所述的药物组合物包含作为有效成分的本发明第一方面所述的溴代苄醚衍生物及其立体异构体以及其可药用盐和药学上可接受的载体或赋形剂。
本发明还涉及以本发明化合物作为活性成份的药物组合物。该药物组合物可根据本领域公知的方法制备。可通过将本发明化合物与一种或多种药学上可接受的固体或液体赋形剂和/或辅剂结合,制成适于人或动物使用的任何剂型。本发明化合物在其药物组合物中的含量通常为0.1-95重量%。
本发明化合物或含有它的药物组合物可以单位剂量形式给药,给药途径可为肠道或非肠道,如口服、静脉注射、肌肉注射、皮下注射、鼻腔、口腔粘膜、眼、肺和呼吸道、皮肤、阴道、直肠等。
给药剂型可以是液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂(包括真溶液和胶体溶液)、乳剂(包括o/w型、w/o型和复乳)、混悬剂、注射剂(包括水针剂、粉针剂和输液)、滴眼剂、滴鼻剂、洗剂和搽剂等;固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气(粉)雾剂、喷雾剂等;半固体剂型可以是软膏剂、凝胶剂、糊剂等。
本发明化合物可以制成普通制剂、也制成是缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
为了将本发明化合物制成片剂,可以广泛使用本领域公知的各种赋形剂,包括稀释剂、黏合剂、润湿剂、崩解剂、润滑剂、助流剂。稀释剂可以是淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露醇、山梨醇、木糖醇、微晶纤维素、硫酸钙、磷酸氢钙、碳酸钙等;湿润剂可以是水、乙醇、异丙醇等;粘合剂可以是淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、微晶纤维素、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、乙基纤维素、丙烯酸树脂、卡波姆、聚乙烯吡咯烷酮、聚乙二醇等;崩解剂可以是干淀粉、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、碳酸氢钠与枸橼酸、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠等;润滑剂和助流剂可以是滑石粉、二氧化硅、硬脂酸盐、酒石酸、液体石蜡、聚乙二醇等。
还可以将片剂进一步制成包衣片,例如糖包衣片、薄膜包衣片、肠溶包衣片,或双层片和多层片。
为了将给药单元制成胶囊剂,可以将有效成分本发明化合物与稀释剂、助流剂混合,将混合物直接置于硬胶囊或软胶囊中。也可将有效成分本发明化合物先与稀释剂、黏合剂、崩解剂制成颗粒或微丸,再置于硬胶囊或软胶囊中。用于制备本发明化合物片剂的各稀释剂、黏合剂、润湿剂、崩解剂、助流剂品种也可用于制备本发明化合物的胶囊剂。
为将本发明化合物制成注射剂,可以用水、乙醇、异丙醇、丙二醇或它们的混合物作溶剂并加入适量本领域常用的增溶剂、助溶剂、pH调剂剂、渗透压调节剂。增溶剂或助溶剂可以是泊洛沙姆、卵磷脂、羟丙基-β-环糊精等;pH调剂剂可以是磷酸盐、醋酸盐、盐酸、氢氧化钠等;渗透压调节剂可以是氯化钠、甘露醇、葡萄糖、磷酸盐、醋酸盐等。如制备冻干粉针剂,还可加入甘露醇、葡萄糖等作为支撑剂。
此外,如需要,也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂或其它添加剂。
为达到用药目的,增强治疗效果,本发明的药物或药物组合物可用任何公知的给药方法给药。
本发明化合物药物组合物的给药剂量依照所要预防或治疗疾病的性质和严重程度,患者或动物的个体情况,给药途径和剂型等可以有大范围的变化。一般来讲,本发明化合物的每天的合适剂量范围为0.001-150mg/Kg体重,优选为0.01-100mg/Kg体重。上述剂量可以一个剂量单位或分成几个剂量单位给药,这取决于医生的临床经验以及包括运用其它治疗手段的给药方案。
本发明的化合物或组合物可单独服用,或与其他治疗药物或对症药物合并使用。当本发明的化合物与其它治疗药物存在协同作用时,应根据实际情况调整它的剂量。
本发明技术方案的第四方面是提供了溴代苄醚衍生物及其立体异构体以及其可药用盐在制备预防和/或治疗与PD-1/PD-L1信号通路有关疾病的药物中的应用。所述的与PD-1/PD-L1信号通路有关的疾病选自癌症、感染性疾病、自身免疫性疾病。所述的癌症选自皮肤癌、肺癌、泌尿系肿瘤、血液肿瘤、乳腺癌、胶质瘤、消化系统肿瘤、生殖系统肿瘤、淋巴瘤、神经系统肿瘤、脑瘤、头颈癌。所述的感染性疾病选自细菌感染、病毒感染。所述的自身免疫性疾病选自器官特异性自身免疫病、系统性自身免疫病,其中,所述的器官特异性自身免疫病包括慢性淋巴细胞性甲状腺炎、甲状腺功能亢进、胰岛素依赖型糖尿病、重症肌无力、溃疡性结肠炎、恶性贫血伴慢性萎缩性胃炎、肺出血肾炎综合征、原发性胆汁性肝硬化、多发性脑脊髓硬化症、急性特发性多神经炎,所述的系统性自身免疫病包括类风湿关节炎、系统性红斑狼疮、系统性血管炎、硬皮病、天疱疮、皮肌炎、混合性结缔组织病、自身免疫性溶血性贫血。
血。
有益技术效果:
本发明化合物对PD-1/PD-L1相互作用具有很高的抑制活性,远高于已报道的化合物;与PD-L1蛋白具有很强的结合能力,甚至强于PD-L1的抗体;并具有解除PD-L1抑制IFNγ的能力,体内药效研究表明,本发明化合物无论从肿瘤体积还是重量上,都可显著的抑制皮下肿瘤的生长,并可明显增加小鼠血液中、脾脏中各淋巴细胞数量。
具体实施方式
以下将结合实施例对发明作进一步说明,但并不限制本发明的范围。
测定仪器:核磁共振光谱用Vaariaan Mercury 300型核磁共振仪。质谱用ZAD-2F和VG300质谱仪。
实施例1:(S)-N-[2-(2-氰基吡啶-4-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]脯氨酸
2-溴-3-苯基甲苯:
置2-溴-3-碘甲苯(700mg)于100ml单口瓶中,加入二氧六环/水(体积比5/1)搅拌,鼓吹氩气10min排除溶液中溶解的氧气,然后依次加入苯硼酸(350mg)、碳酸铯(1800mg)、三苯基膦合钯(80mg)。氩气保护,80-100℃下搅拌12h。停止反应,降至室温,用硅藻土过滤。滤液减压浓缩后,加入水和乙酸乙酯萃取3次。合并有机相,有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压蒸干,得到2-溴-3-苯基甲苯无色油状物480mg。1H NMR(400MHz,DMSO-d6),δ7.49–7.29(m,7H,Ar-H),7.14(d,1H,Ar-H),2.42(s,3H,Ar-CH3)。MS(FAB):248(M+1)。
2-溴-3-苯基苄溴;
称取原料2-溴-3-苯基甲苯(450mg)于100ml单口瓶中,加入40ml CCl4,使之溶解完全,搅拌下加入NBS(360mg),升温至80℃,回流,然后加入过氧化苯甲酰(8mg),2h后再次加入过氧化苯甲酰(8mg),继续反应2h,停止反应,冷至室温,加水淬灭反应,然后加入二氯甲烷和水进行萃取,有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压蒸干,得到2-溴-3-苯基苄溴黄色油状物380mg。直接用于下一步的反应。
2-羟基-4-(2-溴-3-苯基苄氧基)-5-氯苯甲醛:
称取2,4-二羟基-5-氯苯甲醛(160mg)置于50ml单口瓶中,以12ml无水乙腈溶解,然后加入碳酸氢钠(200mg)。室温搅拌40min后,将2-溴-3-苯基苄溴(380mg)溶于16ml DMF中,用恒压滴液漏斗缓慢加入至反应体系,加热回流至反应完全。降至室温,加入水和乙酸乙酯进行萃取。有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压蒸干,通过硅胶柱层析得到2-羟基-4-(2-溴-3-苯基苄氧基)-5-氯苯甲醛白色固体300mg。1H NMR(400MHz,DMSO-d6)δ10.99(s,1H,-OH),10.03(s,1H,-CHO),7.64(d,1H,Ar-H),7.57(d,1H,Ar-H),7.45(m,4H,Ar-H),7.37(d,2H,Ar-H),6.67(d,1H,Ar-H),6.59(s,1H,Ar-H),5.25(s,2H,-CH2-)。MS(FAB):418(M+1)。
2-(2-氰基吡啶-4-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苯甲醛:
将2-羟基-4-(2-溴-3-苯基苄氧基)-5-氯苯甲醛(100mg)置于50ml单口瓶中,用6mlDMF溶解。加入碳酸铯(127.53mg),室温搅拌15min后,滴加2-氰基吡啶-4-亚甲基溴(76.65mg)的DMF(4ml)溶液。在80℃下搅拌2h后停止反应。降至室温,加入水和乙酸乙酯萃取分离,有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压蒸干,通过硅胶柱层析得到2-(2-氰基吡啶-4-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苯甲醛白色固体65mg。1H NMR(400MHz,DMSO-d6)δ10.32(s,1H,-CHO),8.78(d,J=5.2Hz,1H,ArH),8.22(s,1H,ArH),7.88(dd,J1=1.2Hz,J2=4.8Hz,1H,ArH),7.77(s,1H,ArH),7.66(dd,J1=1.6Hz,J2=7.6Hz,1H,ArH),7.56-7.36(m,7H,ArH),7.17(s,1H,ArH),5.54(s,2H,-CH2-),5.43(s,2H,-CH2-)。MS(FAB):535(M+1)
(S)-N-[2-(2-氰基吡啶-4-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]脯氨酸:
将2-(2-氰基吡啶-4-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苯甲醛(80mg)溶于5ml DMF中,加入脯氨酸(59mg),冰醋酸(57mg)至反应体系中。室温搅拌20min后,加入氰基硼氢化钠(25mg),25℃下搅拌14h。停止反应,加入水和乙酸乙酯萃取分离。有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压蒸干,再加乙醇回流至反应完全,蒸干,通过硅胶柱层析得到(S)-N-[2-(2-氰基吡啶-4-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]脯氨酸类白色固体。1H NMR(400MHz,DMSO-d6)δ7.51(s,1H,ArH),7.05(s,1H,ArH),6.83(s,1H,ArH),6.67-6.31(m,9H,ArH),6.12(s,1H,ArH),4.92-4.77(m,2H,-CH2-),4.72(s,2H,-CH2-),3.75(dd,J1=10.4Hz,J2=42.0Hz,2H,-CH2-),3.28(s,1H,-CH-),3.07(s,1H,-CH2-),2.70(s,1H,-CH2-),2.20(s,1H,-CH2-),2.10-1.74(m,3H,-CH2-).MS(FAB):633(M).
实施例2:N-[2-(2-氰基吡啶-4-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]环丙亚胺-2-羧酸
用环丙亚胺-2-羧酸代替脯氨酸,操作同实施例1,得到N-[2-(2-氰基吡啶-4-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]环丙亚胺-2-羧酸白色固体。1H NMR(400MHz,DMSO-d6)δ8.76(d,J=5.2Hz,1H,ArH),8.20(s,1H,ArH),7.91(dd,J1=1.2Hz,J2=5.2Hz,1H,ArH),7.63(dd,J1=1.6Hz,J2=7.6Hz,1H,ArH),7.53-7.34(m,8H,ArH),7.01(s,1H,ArH),5.46-5.32(dd,J1=14.8Hz,J2=20.0Hz,2H,-CH2-),5.28(s,2H,-CH2-),4.04(d,J=13.2Hz,1H,-CH2-),3.97(t,J=8.8Hz,1H,-CH-),3.82(d,J=13.2Hz,1H,-CH2-),3.39(m,1H,-CH2-),3.27(q,J=8.8Hz,1H,-CH2-),2.33-2.22(m,1H,-CH2-),2.17(d,J=8.8Hz,1H,-CH2-).MS(FAB):620(M+1)。
实施例3:(S,S)-N-[2-(2-氰基吡啶-4-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]-4-羟基脯氨酸
用4-羟基脯氨酸代替脯氨酸,操作同实施例1,得到(S,S)-N-[2-(2-氰基吡啶-4-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]-4-羟基脯氨酸白色固体。1H NMR(400MHz,DMSO-d6)δ8.75(d,J=4.8Hz,1H,ArH),8.16(s,1H,ArH),7.85(d,J=5.2Hz,1H,ArH),7.63(dd,J1=1.2Hz,J2=7.6Hz,1H,ArH),7.54-7.34(m,8H,ArH),7.00(s,1H,ArH),5.38(q,J=14.4Hz,2H,-CH2-),5.27(s,2H,-CH2-),5.07(s,1H,-OH),4.28-4.20(m,1H,-CH-),3.98(dd,J1=13.6Hz,J2=58.4Hz,2H,-CH2-),3.56(t,J=8.0Hz,1H,-CH2-),3.25(q,J=5.2Hz,1H,-CH2-),2.54(dd,J1=4.0Hz,J2=10.4Hz,1H,-CH2-),2.00(m,2H,-CH2-).MS(FAB):650(M+1)。
实施例4:(S)-N-[2-(2-氰基吡啶-4-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]哌啶-2-羧酸
用哌啶-2-羧酸代替脯氨酸,操作同实施例1,得到(S)-N-[2-(2-氰基吡啶-4-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]哌啶-2-羧酸白色固体。1H NMR(400MHz,DMSO-d6)δ8.76(d,J=5.2Hz,1H,ArH),8.12(s,1H,ArH),7.82(d,J=4.8Hz,1H,ArH),7.62(d,J=7.2Hz,1H,ArH),7.55-7.33(m,8H,ArH),6.99(s,1H,ArH),5.37(s,2H,-CH2-),5.27(s,2H,-CH2-),3.75(dd,J1=13.6Hz,J2=61.2Hz,2H,-CH2-),3.25-3.12(m,1H,-CH-),3.01-2.85(m,1H,-CH2-),2.32(m,1H,-CH2-),1.87-1.68(m,2H,-CH2-),1.50(br s,3H,-CH2-),1.39(br s,1H,-CH2-).MS(FAB):648(M+1)。
实施例5:(S)-N-[2-(2-氰基吡啶-4-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]丝氨酸
用丝氨酸代替脯氨酸,操作同实施例1,得到(S)-N-[2-(2-氰基吡啶-4-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]丝氨酸白色固体。1H NMR(400MHz,DMSO-d6)δ8.75(d,J=4.8Hz,1H,ArH),8.17(s,1H,ArH),7.90(d,J=4.4Hz,1H,ArH),7.62(d,J=7.6Hz,1H,ArH),7.57(s,1H,ArH),7.53-7.34(m,7H,ArH),7.02(s,1H,ArH),5.40(s,2H,-CH2-),5.29(s,2H,-CH2-),4.06(s,2H,-CH2-),3.80-3.69(m,1H,-CH-),3.69-3.60(m,1H,-CH2-),3.21(m,1H,-CH2-).MS(FAB):624(M+1)。
实施例6:N-[2-(2-氰基吡啶-4-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]2-甲基丝氨酸
用2-甲基丝氨酸代替脯氨酸,操作同实施例1,得到N-[2-(2-氰基吡啶-4-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]2-甲基丝氨酸白色固体。MS(FAB):638(M+1)。
实施例7:N-[2-(2-氰基吡啶-4-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]苏氨酸
用苏氨酸代替脯氨酸,操作同实施例1,得到N-[2-(2-氰基吡啶-4-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]苏氨酸白色固体。MS(FAB):638(M+1)。
实施例8:(S)-N-[2-(5-氰基吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]哌啶-2-羧酸
用5-氰基吡啶-3-亚甲基溴代替2-氰基吡啶-4-亚甲基溴,用哌啶-2-羧酸代替脯氨酸,操作同实施例1,得到(S)-N-[2-(5-氰基吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]哌啶-2-羧酸白色固体。MS(FAB):648(M+1)。
实施例9:N-[2-(5-氰基吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]2-甲基丝氨酸
用5-氰基吡啶-3-亚甲基溴代替2-氰基吡啶-4-亚甲基溴,用2-甲基丝氨酸代替脯氨酸,操作同实施例1,得到N-[2-(5-氰基吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]2-甲基丝氨酸白色固体。MS(FAB):638(M+1)。
实施例10:(S)-N-[2-(5-氰基吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]丝氨酸
用5-氰基吡啶-3-亚甲基溴代替2-氰基吡啶-4-亚甲基溴,用丝氨酸代替脯氨酸,操作同实施例1,得到(S)-N-[2-(5-氰基吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]丝氨酸白色固体。MS(FAB):624(M+1)。
实施例11:(S)-N-[2-(5-氰基吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]脯氨酸
用5-氰基吡啶-3-亚甲基溴代替2-氰基吡啶-4-亚甲基溴,操作同实施例1,得到(S)-N-[2-(5-氰基吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]脯氨酸白色固体。MS(FAB):634(M+1)。
实施例12:N-[2-(5-氰基吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]苏氨酸
用5-氰基吡啶-3-亚甲基溴代替2-氰基吡啶-4-亚甲基溴,用苏氨酸代替脯氨酸,操作同实施例1,得到N-[2-(5-氰基吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]苏氨酸白色固体。MS(FAB):638(M+1)。
实施例13:(S)-N-[2-(5-氰基吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]丙氨酸
用5-氰基吡啶-3-亚甲基溴代替2-氰基吡啶-4-亚甲基溴,用丙氨酸代替脯氨酸,操作同实施例1,得到(S)-N-[2-(5-氰基吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]丙氨酸白色固体。MS(FAB):638(M+1)。
实施例14:(S)-N-[2-(2-氰基吡啶-4-亚甲氧基)-4-(2-溴-3-(3,4-乙二氧苯基)苄氧基)-5-氯苄基]丝氨酸
(1)2-溴-3-(3,4-乙二氧基苯基)甲苯
用2-(3,4-乙二氧苯基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷代替苯硼酸,用[1,1'-双(二苯基膦基)二茂铁]二氯化钯代替三苯基膦钯,碳酸钾代替碳酸铯,操作同实施例1,得到化合物2-溴-3-(3,4-乙二氧基苯基)甲苯,淡黄色油状物。1H NMR(400MHz,Chloroform-d)δ7.21(d,2H,-ArH),7.11(m,1H,-ArH),6.90(d,2H,-ArH),6.86(d,1H,-ArH),4.30(m,4H,-OCH2CH2O-),2.48(s,3H,-CH3).
(2)(S)-N-[2-(2-氰基吡啶-4-亚甲氧基)-4-(2-溴-3-(3,4-乙二氧苯基)苄氧基)-5-氯苄基]丝氨酸
用2-溴-3-(3,4-乙二氧基苯基)甲苯代替2-溴-3-甲基-1,1'-联苯,操作同实施例1。得到产物(S)-N-[2-(2-氰基吡啶-4-亚甲氧基)-4-(2-溴-3-(3,4-乙二氧苯基)苄氧基)-5-氯苄基]丝氨酸白色固体粉末。MS(FAB):682(M+1)。
实施例15:(S)-N-[2-(2-氰基吡啶-4-亚甲氧基)-4-(2-溴-3-(3,4-乙二氧苯基)苄氧基)-5-氯苄基]哌啶-2-甲酸
用2-溴-3-(3,4-乙二氧基苯基)甲苯代替2-溴-3-甲基-1,1'-联苯,用哌啶-2-甲酸代替丝氨酸,操作同实施例1。得到产物(S)-N-[2-(2-氰基吡啶-4-亚甲氧基)-4-(2-溴-3-(3,4-乙二氧苯基)苄氧基)-5-氯苄基]哌啶-2-甲酸白色固体粉末。MS(FAB):706(M+1)。
实施例16:(S)-N-[2-(5-氰基吡啶-3-亚甲氧基)-4-(2-溴-3-(3,4-乙二氧苯基)苄氧基)-5-氯苄基]丝氨酸
(1)2-溴-3-(3,4-乙二氧基苯基)甲苯
用2-(3,4-乙二氧苯基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷代替苯硼酸,用[1,1'-双(二苯基膦基)二茂铁]二氯化钯代替三苯基膦钯,碳酸钾代替碳酸铯,操作同实施例1,得到化合物2-溴-3-(3,4-乙二氧基苯基)甲苯,淡黄色油状物。1H NMR(400MHz,Chloroform-d)δ7.21(d,2H,-ArH),7.11(m,1H,-ArH),6.90(d,2H,-ArH),6.86(d,1H,-ArH),4.30(m,4H,-OCH2CH2O-),2.48(s,3H,-CH3).
(2)(S)-N-[2-(5-氰基吡啶-3-亚甲氧基)-4-(2-溴-3-(3,4-乙二氧苯基)苄氧基)-5-氯苄基]丝氨酸
用2-溴-3-(3,4-乙二氧基苯基)甲苯代替2-溴-3-甲基-1,1'-联苯,用5-氰基吡啶-3-亚甲基溴代替2-氰基吡啶-4-亚甲基溴,操作同实施例1,得到(S)-N-[2-(5-氰基吡啶-3-亚甲氧基)-4-(2-溴-3-(3,4-乙二氧苯基)苄氧基)-5-氯苄基]丝氨酸白色固体。MS(FAB):682(M+1)。
药理活性
1、体外活性评价:体外酶学水平的检测方法采用Cisbio公司PD-1/PD-L1 bindingassay kit检测试剂盒。
PD-1/PD-L1小分子抑制剂的筛选原理和方法
1)原理:PD-1蛋白带HIS标签,PD-1的配体PD-L1带hFc标签,分别用Eu标记的anti-hFc抗体和XL665标记的anti-HIS抗体与两个标签蛋白结合,激光激发后,能量能够从供体Eu上转移到受体XL665,使得XL665发光,而加入抑制剂(化合物或抗体)后,阻断PD-1与PD-L1的结合,使得Eu和XL665距离较远,能量不能转移,XL665不会发光。
2)实验方法:具体方法可参考Cisbio公司的PD-1/PD-L1试剂盒(货号64CUS000C-2)。简单叙述如下,384孔白色酶标板,每孔加入2μl稀释液或者用稀释液稀释的目标化合物,然后每孔再加入4μl PD-1蛋白和4μl PD-L1蛋白,常温孵育15min,再每孔加入10μlanti-Tag1-Eu3+和anti-Tag2-XL665的混合液,室温孵育1h-4h后用Envison仪器检测665nm和620nm处的荧光信号。HTRF率=(665nm/620nm)*104。每个化合物检测8-10个浓度,采用Graphpad软件计算IC50。
3)筛选结果见表1:
表1.实施例化合物在分子水平对PD-1与PD-L1相互作用的抑制活性评价
实施例 | IC50(M) | 实施例 | IC50(M) |
1 | 4.10×10--11 | 8 | 10-10~10-11 |
2 | 6.43×10--11 | 9 | 10-10~10-11 |
3 | 3.14×10--11 | 10 | 10-10~10-11 |
4 | 8.0×10--14 | 11 | 10-9~10-10 |
5 | 4.5×10-13 | 12 | 10-9~10-10 |
6 | 10-11~10-12 | 13 | 10-9~10-10 |
10-11~10-12 | 14 | 10-11~10-12 | |
15 | 10-11~10-12 | 16 | 10-9~10-10 |
Cisbio HTRF检测结果表明,实施例化合物在分子水平可显著抑制PD-1与PD-L1的相互作用,个别化合物IC50<10-13mol/L。
2、实施例化合物解除配体PD-L1抑制IFNγ的能力
IFNγ的表达水平能够反映T淋巴细胞的增殖活性。利用提取的人PBMC(人单个核细胞),在anti-CD3/anti-CD28抗体激活T淋巴细胞的基础上,加入配体PD-L1抑制T淋巴细胞,考察待测化合物解除配体抑制作用的能力。
具体操作如下,采用达科为公司的人淋巴细胞分离液(货号DKW-KLSH-0100)提取人全血中的PBMC,将PBMC接种到96孔板中,每孔接种数为3×105个。分别加入人的PD-L1蛋白(终浓度5μg/ml),anti-CD3/anti-CD28抗体(终浓度1μg/ml)和等比例稀释的实施例化合物。72h后采用Cisbio公司的IFNγ检测试剂盒检测上清中IFNγ的表达量。实验结果显示,实施例化合物在10nM时就能部分解除PD-L1对IFNγ的抑制作用。
3、实施例化合物体内药效
药效学研究方法如下:
皮下移植瘤方法如下:将培养的特定肿瘤细胞消化后离心收集细胞,用无菌生理盐水清洗两遍后计数,用生理盐水调整细胞浓度为5×106/ml,将0.2ml细胞混悬液接种到C57BL/6或Bablc小鼠右侧腋下。接种后次日动物随机分组,每组6-7只,称重后给药,待测化合物每天给药1次,监测小鼠肿瘤体积大小,待肿瘤体积达到一定大小后,称量小鼠体重,眼眶取血后脱颈处死小鼠,剥取肿瘤组织、胸腺组织和脾组织并分别称重。最后计算肿瘤抑制率,以肿瘤抑制率评价抗肿瘤作用强度。
B16F10肺转移模型方法如下:将培养的B16F10肿瘤细胞消化离心,用无菌生理盐水清洗两遍后计数,用生理盐水调整细胞浓度为2.5×106/ml,将0.2ml细胞通过尾静脉注射入到C57BL/6小鼠体内,肿瘤细胞将在小鼠肺部聚集。接种后次日动物随机分组,每组6-7只,称重后给药,待测化合物每天给药1次,3周后称量小鼠体重,处死动物,剥取小鼠肺组织并称重,包式液固定后计数肺部肿瘤数目。最后计算化合物对肿瘤的抑制率,以肿瘤抑制率评价抗肿瘤作用强度。
Lewis肺癌胸水模型方法如下:将小鼠皮下Lewis移植瘤肿匀浆后,用无菌生理盐水清洗两遍后计数,用生理盐水调整细胞浓度为2.5×105/ml,将0.2ml细胞注射入到C57BL/6小鼠胸腔内。接种后次日动物随机分组,每组6-7只,称重后给药,待测化合物每天给药1次,待对照组小鼠体重突然下降时处死动物,用注射器抽取胸腔内的积液,记录积液体积。
在以上各模型作用机制研究中,各类型T细胞占总细胞比例的试验方法采用流式细胞术方法,具体步骤如下:先处理样品,对于血液组织,在处理小鼠时,取小鼠的眼眶血,先用红细胞裂解液去除红细胞后,然后用PBS溶液进行漂洗后收集细胞;对于小鼠的肿瘤和脾脏器官,先用匀浆器研磨组织,再加入PBS缓冲液稀释,然后用300目的筛网过滤。计数各样本的细胞数后,取1×106的细胞加入EP管中后进行流式抗体的染色,在冰上孵育1h后,用PBS溶液漂洗2遍。用BD公司的VERSE流式仪器进行细胞群的分析。其中,肿瘤组织总上样细胞数为1×105个,血液和脾脏组织总上样细胞数为1×104个。在流式仪器上圈门后分析各类型T细胞占总进样细胞数的比例。
(1)黑色素瘤高转移株B16F10皮下移植瘤模型
对于黑色素瘤高转移株B16F10,实施例化合物无论从肿瘤体积还是重量上,都可显著的抑制皮下肿瘤的生长。
从其作用机制分析,实施例化合物可增加肿瘤浸润的各淋巴细胞比例,实施例化合物可增加脾中各淋巴细胞比例。
(2)黑色素瘤高转移株B16F10肺转移模型
对于黑色素瘤高转移株B16F10肺转移模型,实施例化合物能显著抑制肺部转移灶数量。
从其作用机制分析,实施例化合物可增加小鼠血液中各淋巴细胞数量。
(3)小鼠乳腺癌EMT6皮下移植瘤模型
对于小鼠乳腺癌EMT6皮下移植瘤模型,实施例化合物具有一定的抗肿瘤作用。另外联合环磷酰胺给药后,实施例化合物能使环磷酰胺的抑瘤率提高。
(4)小鼠Lewis肺癌胸水模型
对于小鼠Lewis肺癌胸水模型,实施例化合物具有一定的抗肿瘤作用。实施例化合物能降低胸水发生率。
(5)小鼠结肠癌MC38皮下移植瘤模型
对于小鼠结肠癌MC38皮下移植瘤模型,实施例化合物具有显著的抗肿瘤作用。联合环磷酰胺CTX给药后,具有良好的协同作用。
4、利用Biacore设备测试实施例化合物以及PD-L1抗体与PD-L1蛋白的相互作用
(1)实验原理
表面等离子体是一种金属表面的电磁波,由自由振动的光子和电子相互作用产生。表面等离子体共振(surface-plasmon resonance,SPR)是一种发生在两种介质表面的光学现象,这种现象可以由光子或电子诱导。光从光密介质射入光疏介质发生全反射现象,会形成消逝波进入光疏介质。当全反射的消逝波与金属表面的等离子波相遇时,可能会发生共振,反射光能量下降,在反射光能量谱上出现共振峰,这种共振称为表面等离子体共振,引起表面等离子体共振的入射角称为SPR角。SPR生物传感器提供了一个灵敏的、实时监测分子将相互作用的非标记检测技术。该传感器检测的是SPR角的变化,SPR又与金属表面的折射率相关。当有分析物结合到芯片表面后,导致了芯片表面折射率的改变,从而引起SPR角度变化,这就是SPR生物传感器实时检测分子间相互作用的基本原理。在相互作用分析时,SPR角度的改变被实时记录在传感图上。
(2)实验方法:
采用捕获法将PD-L1蛋白捕获于NTA芯片Fc4通道上;结合缓冲液体系为PBS-P+,pH7.4,0.01%DMSO。将配制好的一系列浓度的化合物及PD-L1抗体流经芯片表面,进行相互作用测定。
(3)实验结果:
初步确定实施例化合物的结合蛋白为PD-L1,进一步采用Biacore实验证实,实施例化合物与PD-L1具有很强的结合能力。
Claims (21)
1.如通式I所示的溴代苄醚衍生物及其立体异构体以及其可药用盐,
式中
R1选自:
Y选自:取代吡啶亚甲基,取代基选自氰基、甲磺酰基、乙酰氨基、氨甲酰基、二甲胺甲酰基、氟、氯、溴、碘、三氟甲基、C1-5烷基、C1-5烷氧基;
R3选自:取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基,取代基选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基、
所述的取代基包括单取代、双取代、三取代、四取代;
X选自:氢、氟、氯、溴、碘、C1-4烷基、乙烯基、三氟甲基、甲氧基。
2.根据权利要求1的溴代苄醚衍生物及其立体异构体以及其可药用盐,其特征在于,所述的化合物如式(IA)所示:
式中
R1选自:
Y选自:取代吡啶亚甲基,取代基选自氰基、甲磺酰基、乙酰氨基、氨甲酰基、二甲胺甲酰基、氟、氯、溴、碘、三氟甲基、C1-5烷基、C1-5烷氧基;
R3选自:取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基,取代基选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基、
所述的取代基包括单取代、双取代、三取代、四取代;
X选自:氢、氟、氯、溴、碘、C1-4烷基、乙烯基、三氟甲基、甲氧基。
3.根据权利要求2的溴代苄醚衍生物及其立体异构体以及其可药用盐,其特征在于,所述的化合物如式(IA1)所示:
式中
Y选自:取代吡啶亚甲基,取代基选自氰基、甲磺酰基、乙酰氨基、氨甲酰基、二甲胺甲酰基、氟、氯、溴、碘、三氟甲基、C1-5烷基、C1-5烷氧基;
R3选自:取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基,取代基选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基、
所述的取代基包括单取代、双取代、三取代、四取代;
X选自:氢、氟、氯、溴、碘、C1-4烷基、乙烯基、三氟甲基、甲氧基。
4.根据权利要求3的溴代苄醚衍生物及其立体异构体以及其可药用盐,其特征在于,所述的化合物如式(IA1-1)所示:
式中
R2选自:氰基、甲磺酰基、乙酰氨基、氨甲酰基、二甲胺甲酰基、氟、氯、溴、碘、三氟甲基、C1-5烷基、C1-5烷氧基;
R3选自:取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基,取代基选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基、
所述的取代基包括单取代、双取代、三取代、四取代;
X选自:氢、氟、氯、溴、碘、C1-4烷基、乙烯基、三氟甲基、甲氧基。
5.根据权利要求4的溴代苄醚衍生物及其立体异构体以及其可药用盐,其特征在于,所述的化合物如式(IA1-1a)所示:
式中
R3选自:取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基,取代基选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基、
所述的取代基包括单取代、双取代、三取代、四取代;
X选自:氢、氟、氯、溴、碘、C1-4烷基、乙烯基、三氟甲基、甲氧基。
6.根据权利要求3的溴代苄醚衍生物及其立体异构体以及其可药用盐,其特征在于,所述的化合物如式(IA1-2)所示:
R2选自:氰基、甲磺酰基、乙酰氨基、氨甲酰基、二甲胺甲酰基、氟、氯、溴、碘、三氟甲基、C1-5烷基、C1-5烷氧基;
R3选自:取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基,取代基选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基、
所述的取代基包括单取代、双取代、三取代、四取代;
X选自:氢、氟、氯、溴、碘、C1-4烷基、乙烯基、三氟甲基、甲氧基。
7.根据权利要求6的溴代苄醚衍生物及其立体异构体以及其可药用盐,其特征在于,所述的化合物如式(IA1-2a)所示:
式中
R3选自:取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基,取代基选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基、
所述的取代基包括单取代、双取代、三取代、四取代;
X选自:氢、氟、氯、溴、碘、C1-4烷基、乙烯基、三氟甲基、甲氧基。
8.根据权利要求2的溴代苄醚衍生物及其立体异构体以及其可药用盐,其特征在于,所述的化合物如式(IA2)所示:
Y选自:取代吡啶亚甲基,取代基选自氰基、甲磺酰基、乙酰氨基、氨甲酰基、二甲胺甲酰基、氟、氯、溴、碘、三氟甲基、C1-5烷基、C1-5烷氧基;
R3选自:取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基,取代基选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基、
所述的取代基包括单取代、双取代、三取代、四取代;
X选自:氢、氟、氯、溴、碘、C1-4烷基、乙烯基、三氟甲基、甲氧基。
9.根据权利要求8的溴代苄醚衍生物及其立体异构体以及其可药用盐,其特征在于,所述的化合物如式(IA2-1)所示:
R2选自:氰基、甲磺酰基、乙酰氨基、氨甲酰基、二甲胺甲酰基、氟、氯、溴、碘、三氟甲基、C1-5烷基、C1-5烷氧基;
R3选自:取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基,取代基选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基、
所述的取代基包括单取代、双取代、三取代、四取代;
X选自:氢、氟、氯、溴、碘、C1-4烷基、乙烯基、三氟甲基、甲氧基。
10.根据权利要求9的溴代苄醚衍生物及其立体异构体以及其可药用盐,其特征在于,所述的化合物如式(IA2-1a)所示:
R3选自:取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基,取代基选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基、
所述的取代基包括单取代、双取代、三取代、四取代;
X选自:氢、氟、氯、溴、碘、C1-4烷基、乙烯基、三氟甲基、甲氧基。
11.根据权利要求8的溴代苄醚衍生物及其立体异构体以及其可药用盐,其特征在于,所述的化合物如式(IA2-2)所示:
R2选自:氰基、甲磺酰基、乙酰氨基、氨甲酰基、二甲胺甲酰基、氟、氯、溴、碘、三氟甲基、C1-5烷基、C1-5烷氧基;
R3选自:取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基,取代基选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基、
所述的取代基包括单取代、双取代、三取代、四取代;
X选自:氢、氟、氯、溴、碘、C1-4烷基、乙烯基、三氟甲基、甲氧基。
12.根据权利要求11的溴代苄醚衍生物及其立体异构体以及其可药用盐,其特征在于,所述的化合物如式(IA2-2a)所示:
R3选自:取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基,取代基选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基、
所述的取代基包括单取代、双取代、三取代、四取代;
X选自:氢、氟、氯、溴、碘、C1-4烷基、乙烯基、三氟甲基、甲氧基。
13.根据权利要求1-12任一项的溴代苄醚衍生物及其立体异构体以及其可药用盐,其特征在于,所述R3选自
R=甲基、乙基、丙基、异丙基、丁基、戊基、己基、庚基、辛基;
X选自:氢、氟、氯、溴、甲基、乙烯基、三氟甲基。
14.根据权利要求1的溴代苄醚衍生物及其立体异构体以及其可药用盐,所述的化合物选自:
(S)-N-[2-(2-氰基吡啶-4-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]脯氨酸
N-[2-(2-氰基吡啶-4-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]环丙亚胺-2-羧酸
(S,S)-N-[2-(2-氰基吡啶-4-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]-4-羟基脯氨酸
(S)-N-[2-(2-氰基吡啶-4-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]哌啶-2-羧酸
(S)-N-[2-(2-氰基吡啶-4-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]丝氨酸
N-[2-(2-氰基吡啶-4-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]2-甲基丝氨酸
N-[2-(2-氰基吡啶-4-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]苏氨酸
(S)-N-[2-(5-氰基吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]哌啶-2-羧酸
N-[2-(5-氰基吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]2-甲基丝氨酸
(S)-N-[2-(5-氰基吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]丝氨酸
(S)-N-[2-(5-氰基吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]脯氨酸
N-[2-(5-氰基吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]苏氨酸
(S)-N-[2-(5-氰基吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]丙氨酸
(S)-N-[2-(2-氰基吡啶-4-亚甲氧基)-4-(2-溴-3-(3,4-乙二氧苯基)苄氧基)-5-氯苄基]丝氨酸
(S)-N-[2-(2-氰基吡啶-4-亚甲氧基)-4-(2-溴-3-(3,4-乙二氧苯基)苄氧基)-5-氯苄基]哌啶-2-甲酸
(S)-N-[2-(5-氰基吡啶-3-亚甲氧基)-4-(2-溴-3-(3,4-乙二氧苯基)苄氧基)-5-氯苄基]丝氨酸
15.根据权利要求1的溴代苄醚衍生物及其立体异构体以及其可药用盐,其特征在于,所述的药用盐包括与无机酸、有机酸、碱金属离子、碱土金属离子或能提供生理上可接受的阳离子的有机碱结合形成的盐以及铵盐。
16.根据权利要求15的溴代苄醚衍生物及其立体异构体以及其可药用盐,其特征在于,所述的无机酸选自盐酸、氢溴酸、磷酸或硫酸;所述的有机酸选自甲磺酸、对甲苯磺酸、三氟乙酸、枸杞酸、马来酸酒石酸、富马酸、柠檬酸或乳酸;所述的碱金属离子选自锂离子,钠离子,钾离子;所述的碱土金属离子选自钙离子,镁离子;所述的能提供生理上可接受的阳离子的有机碱选自甲胺、二甲胺、三甲胺、哌啶、吗啉或三(2-羟乙基)胺。
17.制备权利要求1-16任一项所述的溴代苄醚类衍生物及其立体异构体以及其可药用盐的方法:
为了制备本发明通式I所述的化合物,依据通式I的结构,本发明制备通式I化合物分为两步:
(a)以2-羟基-4-(2-溴-3-R1苄氧基)-X取代的苯甲醛1为原料,在碱性条件下与取代的吡啶亚甲基卤反应得到含醛基的中间体化合物2;
(b)以含醛基的中间体化合物2为原料,与含氨基或亚氨基的HR3缩合及还原得到目标化合物I;
所述的R1、R3、Y、X的定义同权利要求1-16任一项所述。
18.一种药物组合物,其特征在于,所述的药物组合物包含作为有效成分的权利要求1-16任一项所述的溴代苄醚类衍生物及其立体异构体以及其可药用盐和药学上可接受的载体或赋形剂。
19.权利要求1-16任一项所述的溴代苄醚类衍生物及其立体异构体以及其可药用盐在制备预防和/或治疗与PD-1/PD-L1信号通路有关疾病的药物中的应用。
20.根据权利要求19的应用,其特征在于,所述的与PD-1/PD-L1信号通路有关的疾病选自癌症、感染性疾病、自身免疫性疾病。
21.根据权利要求20的应用,其特征在于,所述的癌症选自皮肤癌、肺癌、泌尿系肿瘤、血液肿瘤、乳腺癌、胶质瘤、消化系统肿瘤、生殖系统肿瘤、淋巴瘤、神经系统肿瘤、脑瘤、头颈癌;所述的感染性疾病选自细菌感染、病毒感染;所述的自身免疫性疾病选自器官特异性自身免疫病、系统性自身免疫病,其中,所述的器官特异性自身免疫病包括慢性淋巴细胞性甲状腺炎、甲状腺功能亢进、胰岛素依赖型糖尿病、重症肌无力、溃疡性结肠炎、恶性贫血伴慢性萎缩性胃炎、肺出血肾炎综合征、原发性胆汁性肝硬化、多发性脑脊髓硬化症、急性特发性多神经炎,所述的系统性自身免疫病包括类风湿关节炎、系统性红斑狼疮、系统性血管炎、硬皮病、天疱疮、皮肌炎、混合性结缔组织病、自身免疫性溶血性贫血。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2016103439607 | 2016-05-23 | ||
CN201610343960 | 2016-05-23 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN107417666A true CN107417666A (zh) | 2017-12-01 |
Family
ID=60411053
Family Applications (10)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201780031899.5A Active CN109311792B (zh) | 2016-05-23 | 2017-05-23 | 苯醚类衍生物、及其制法和药物组合物与用途 |
CN201780031943.2A Active CN109195960B (zh) | 2016-05-23 | 2017-05-23 | 溴代苄醚衍生物、及其制法和药物组合物与用途 |
CN201710365696.1A Pending CN107417666A (zh) | 2016-05-23 | 2017-05-23 | 溴代苄醚衍生物、及其制法和药物组合物与用途 |
CN201780031954.0A Active CN109153670B (zh) | 2016-05-23 | 2017-05-23 | 烟醇醚类衍生物、及其制法和药物组合物与用途 |
CN202210287082.7A Pending CN114853634A (zh) | 2016-05-23 | 2017-05-23 | 烟醇醚类衍生物、及其制法和药物组合物与用途 |
CN201710363523.6A Pending CN107417506A (zh) | 2016-05-23 | 2017-05-23 | 2‑羟基‑4‑(2,3‑双取代苄氧基)‑5‑取代苯甲醛衍生物的制备方法 |
CN201710359979.5A Pending CN107417564A (zh) | 2016-05-23 | 2017-05-23 | 苯醚类衍生物、及其制法和药物组合物与用途 |
CN201780031942.8A Active CN109153626B (zh) | 2016-05-23 | 2017-05-23 | 2-羟基-4-(2,3-双取代苄氧基)-5-取代苯甲醛衍生物的制备方法 |
CN201710365671.1A Pending CN107417572A (zh) | 2016-05-23 | 2017-05-23 | 苄苯醚类衍生物、及其制法和药物组合物与用途 |
CN201780031898.0A Active CN109219592B (zh) | 2016-05-23 | 2017-05-23 | 苄苯醚类衍生物、及其制法和药物组合物与用途 |
Family Applications Before (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201780031899.5A Active CN109311792B (zh) | 2016-05-23 | 2017-05-23 | 苯醚类衍生物、及其制法和药物组合物与用途 |
CN201780031943.2A Active CN109195960B (zh) | 2016-05-23 | 2017-05-23 | 溴代苄醚衍生物、及其制法和药物组合物与用途 |
Family Applications After (7)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201780031954.0A Active CN109153670B (zh) | 2016-05-23 | 2017-05-23 | 烟醇醚类衍生物、及其制法和药物组合物与用途 |
CN202210287082.7A Pending CN114853634A (zh) | 2016-05-23 | 2017-05-23 | 烟醇醚类衍生物、及其制法和药物组合物与用途 |
CN201710363523.6A Pending CN107417506A (zh) | 2016-05-23 | 2017-05-23 | 2‑羟基‑4‑(2,3‑双取代苄氧基)‑5‑取代苯甲醛衍生物的制备方法 |
CN201710359979.5A Pending CN107417564A (zh) | 2016-05-23 | 2017-05-23 | 苯醚类衍生物、及其制法和药物组合物与用途 |
CN201780031942.8A Active CN109153626B (zh) | 2016-05-23 | 2017-05-23 | 2-羟基-4-(2,3-双取代苄氧基)-5-取代苯甲醛衍生物的制备方法 |
CN201710365671.1A Pending CN107417572A (zh) | 2016-05-23 | 2017-05-23 | 苄苯醚类衍生物、及其制法和药物组合物与用途 |
CN201780031898.0A Active CN109219592B (zh) | 2016-05-23 | 2017-05-23 | 苄苯醚类衍生物、及其制法和药物组合物与用途 |
Country Status (7)
Country | Link |
---|---|
US (4) | US10975049B2 (zh) |
EP (4) | EP3466944B1 (zh) |
JP (3) | JP6980767B2 (zh) |
KR (3) | KR102456572B1 (zh) |
CN (10) | CN109311792B (zh) |
RU (3) | RU2735541C2 (zh) |
WO (5) | WO2017202277A1 (zh) |
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109305934A (zh) * | 2018-08-07 | 2019-02-05 | 成都海博锐药业有限公司 | 苯醚类衍生物及可药用盐、医药上的用途 |
CN111662270A (zh) * | 2019-03-05 | 2020-09-15 | 中国医学科学院药物研究所 | 碘同位素标记苄苯醚衍生物、及其制法和药物组合物与用途 |
CN111943876A (zh) * | 2020-09-08 | 2020-11-17 | 江苏省原子医学研究所 | 一种n2s2类溴代苄醚衍生物、制备方法及应用 |
CN111978287A (zh) * | 2019-05-23 | 2020-11-24 | 中国科学院上海有机化学研究所 | 一类免疫检查点小分子抑制剂及其制备方法和用途 |
CN113444075A (zh) * | 2020-03-27 | 2021-09-28 | 中国医学科学院药物研究所 | 二氢吲哚衍生物、及其制法和药物组合物与用途 |
CN114956977A (zh) * | 2022-06-09 | 2022-08-30 | 朗捷睿(苏州)生物科技有限公司 | 一种联苯类化合物、药物组合物及其制备方法和应用 |
WO2023050104A1 (zh) * | 2021-09-28 | 2023-04-06 | 中国医学科学院药物研究所 | 二氢吲哚衍生物、及其制法和药物组合物与用途 |
CN116589395A (zh) * | 2023-05-17 | 2023-08-15 | 浙江工业大学 | 咔唑甲基苯基醚类衍生物、其制备方法和应用 |
WO2024183756A1 (zh) * | 2023-03-07 | 2024-09-12 | 上海再极医药科技有限公司 | 一种含苯环类化合物及其制备方法和应用 |
Families Citing this family (45)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2017202277A1 (zh) | 2016-05-23 | 2017-11-30 | 中国医学科学院药物研究所 | 2-羟基-4-(2,3-双取代苄氧基)-5-取代苯甲醛衍生物的制备方法 |
AU2017289038B2 (en) | 2016-06-27 | 2021-07-22 | Chemocentryx, Inc. | Immunomodulator compounds |
WO2018121560A1 (zh) * | 2016-12-29 | 2018-07-05 | 深圳微芯生物科技有限责任公司 | 脲类化合物、其制备方法及其应用 |
JOP20180040A1 (ar) | 2017-04-20 | 2019-01-30 | Gilead Sciences Inc | مثبطات pd-1/pd-l1 |
CN111225896B (zh) | 2017-07-28 | 2024-03-26 | 凯莫森特里克斯股份有限公司 | 免疫调节剂化合物 |
WO2019032547A1 (en) | 2017-08-08 | 2019-02-14 | Chemocentryx, Inc. | MACROCYCLIC IMMUNOMODULATORS |
IL300572A (en) | 2018-02-13 | 2023-04-01 | Gilead Sciences Inc | PD–1/PD–L1 inhibitors |
JP7387616B2 (ja) | 2018-02-22 | 2023-11-28 | ケモセントリックス,インコーポレイティド | Pd-l1アンタゴニストとしてのインダン-アミン |
WO2019191624A1 (en) * | 2018-03-29 | 2019-10-03 | Arbutus Biopharma, Inc. | Substituted 1,1'-biphenyl compounds, analogues thereof, and methods using same |
EP3781556A1 (en) | 2018-04-19 | 2021-02-24 | Gilead Sciences, Inc. | Pd-1/pd-l1 inhibitors |
EP3810109B1 (en) | 2018-05-31 | 2024-08-07 | Peloton Therapeutics, Inc. | Compounds and compositions for inhibiting cd73 |
JP7388635B2 (ja) | 2018-05-31 | 2023-11-29 | 小野薬品工業株式会社 | 免疫チェックポイント阻害薬の有効性判定バイオマーカー |
KR20230159715A (ko) | 2018-07-13 | 2023-11-21 | 길리애드 사이언시즈, 인코포레이티드 | Pd-1/pd-l1 억제제 |
CN110872275A (zh) * | 2018-08-31 | 2020-03-10 | 深圳微芯生物科技股份有限公司 | 作为免疫调节剂的联苯化合物及其用途 |
CA3115749A1 (en) | 2018-10-11 | 2020-04-16 | Ono Pharmaceutical Co., Ltd. | Sting agonistic compound |
US11236085B2 (en) | 2018-10-24 | 2022-02-01 | Gilead Sciences, Inc. | PD-1/PD-L1 inhibitors |
CN112876411A (zh) * | 2019-02-21 | 2021-06-01 | 杭州阿诺生物医药科技有限公司 | 化合物及其在合成pdl1拮抗剂类药物分子中的应用 |
CN109761952A (zh) * | 2019-02-25 | 2019-05-17 | 南方医科大学 | 一种含取代联苯的间苯二酚甲醚衍生物及其用途 |
US20220168268A1 (en) | 2019-03-22 | 2022-06-02 | Guangzhou Maxinovel Pharmaceuticals Co., Ltd. | Small-molecule inhibitor of pd-1/pd-l1, pharmaceutical composition thereof with pd-l1 antibody, and application of same |
KR20220009420A (ko) | 2019-05-15 | 2022-01-24 | 케모센트릭스, 인크. | Pd-l1 질환의 치료를 위한 트리아릴 화합물 |
CN112028870B (zh) * | 2019-06-04 | 2021-11-05 | 中国科学院上海药物研究所 | 一种具有苄氧基芳环结构的化合物,其制备方法和用途 |
US11485708B2 (en) | 2019-06-20 | 2022-11-01 | Chemocentryx, Inc. | Compounds for treatment of PD-L1 diseases |
KR20220034829A (ko) | 2019-07-10 | 2022-03-18 | 케모센트릭스, 인크. | Pd-l1 억제제로서의 인단 |
WO2021011891A1 (en) | 2019-07-18 | 2021-01-21 | Gilead Sciences, Inc. | Long-acting formulations of tenofovir alafenamide |
AU2020327251A1 (en) | 2019-08-05 | 2022-03-03 | National Cancer Center Japan | Biomarker for accessing efficacy of immune checkpoint inhibitor |
CN110256290A (zh) * | 2019-08-06 | 2019-09-20 | 宜春学院 | 一种4-氰基苄氧基-4′-氰基苯基醚的制备方法 |
JP2022547208A (ja) * | 2019-09-09 | 2022-11-10 | 中国医学科学院薬物研究所 | ニコチニルアルコールエーテル誘導体のマレイン酸塩、その結晶形、及びその使用 |
WO2021076691A1 (en) | 2019-10-16 | 2021-04-22 | Chemocentryx, Inc. | Heteroaryl-biphenyl amides for the treatment of pd-l1 diseases |
CR20220216A (es) | 2019-10-16 | 2023-01-09 | Chemocentryx Inc | Aminas de heteroaril-bifenilo para el tratamiento de enfermedades pd-l1 |
CN111187172B (zh) * | 2020-01-20 | 2021-10-29 | 中国药科大学 | 硝基苯醚类化合物、其制备方法和药物组合物与用途 |
JP2023518433A (ja) | 2020-03-20 | 2023-05-01 | ギリアード サイエンシーズ, インコーポレイテッド | 4’-c-置換-2-ハロ-2’-デオキシアデノシンヌクレオシドのプロドラッグ並びにその製造法及び使用法 |
WO2021206158A1 (ja) | 2020-04-10 | 2021-10-14 | 小野薬品工業株式会社 | がん治療方法 |
EP4134134A4 (en) | 2020-04-10 | 2023-12-27 | ONO Pharmaceutical Co., Ltd. | STING AGONIST COMPOUND |
CN111333629B (zh) * | 2020-04-10 | 2021-03-05 | 颜建发 | 苯基-1h-吡唑类衍生物及其在抗肿瘤药物中的应用 |
CN113563260A (zh) * | 2020-04-28 | 2021-10-29 | 药康众拓(江苏)医药科技有限公司 | 苯甲酰胺类化合物、制备方法及用途 |
BR112022022335A2 (pt) | 2020-05-05 | 2023-01-10 | Teon Therapeutics Inc | Moduladores de receptor canabinoide tipo 2 (cb2) e usos dos mesmos |
CN114075123B (zh) * | 2020-08-11 | 2023-06-06 | 中国人民解放军军事科学院军事医学研究院 | 苄胺类衍生物及其制备方法与用途 |
CN113135895A (zh) * | 2021-04-30 | 2021-07-20 | 中国药科大学 | 一种新型联苯类衍生物及其制备方法与医药用途 |
WO2023034530A1 (en) | 2021-09-02 | 2023-03-09 | Teon Therapeutics, Inc. | Methods of improving growth and function of immune cells |
WO2023081730A1 (en) | 2021-11-03 | 2023-05-11 | Teon Therapeutics, Inc. | 4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide derivatives as cannabinoid cb2 receptor modulators for the treatment of cancer |
WO2023097211A1 (en) | 2021-11-24 | 2023-06-01 | The University Of Southern California | Methods for enhancing immune checkpoint inhibitor therapy |
WO2023104744A1 (en) | 2021-12-06 | 2023-06-15 | Helmholtz-Zentrum Dresden-Rossendorf E.V. | 3-((3-([1,1'-biphenyl]-3-ylmethoxy)phenoxy)methyl)benzonitrile derivatives and the use thereof |
CN114181144B (zh) * | 2021-12-06 | 2023-04-04 | 浙江工业大学 | 一种氟代联苯甲基间苯二酚醚类衍生物、其制备方法和应用 |
WO2024015372A1 (en) | 2022-07-14 | 2024-01-18 | Teon Therapeutics, Inc. | Adenosine receptor antagonists and uses thereof |
CN115417870B (zh) * | 2022-09-20 | 2024-02-27 | 中国药科大学 | Pd-l1&nampt双靶点抑制剂和用途 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103787902A (zh) * | 2014-02-17 | 2014-05-14 | 华东理工大学 | 苄基取代的苯胺类化合物及其应用 |
WO2015034820A1 (en) * | 2013-09-04 | 2015-03-12 | Bristol-Myers Squibb Company | Compounds useful as immunomodulators |
WO2015160641A2 (en) * | 2014-04-14 | 2015-10-22 | Bristol-Myers Squibb Company | Compounds useful as immunomodulators |
CN109195960B (zh) * | 2016-05-23 | 2021-05-04 | 中国医学科学院药物研究所 | 溴代苄醚衍生物、及其制法和药物组合物与用途 |
Family Cites Families (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4329518A (en) | 1979-09-18 | 1982-05-11 | Fmc Corporation | Insecticidal [1,1'-biphenyl]-3-ylmethyl esters |
ZA816442B (en) * | 1980-10-02 | 1982-12-29 | Fmc Corp | Insecticidal(1,1'-biphenyl)-3-ylmethyl esters |
DE69505490T2 (de) | 1994-08-04 | 1999-06-24 | Sumitomo Chemical Co., Ltd., Osaka | Dihalopropenverbindungen, sie enthaltende insektizide/akarizide mittel, und zwischenprodukte |
US6291465B1 (en) | 1999-03-09 | 2001-09-18 | Hoffmann-La Roche Inc. | Biphenyl derivatives |
JP4594611B2 (ja) * | 2002-11-08 | 2010-12-08 | 武田薬品工業株式会社 | 受容体機能調節剤 |
CN1735408A (zh) | 2002-11-08 | 2006-02-15 | 武田药品工业株式会社 | 受体机能调节剂 |
JP2007114968A (ja) * | 2005-10-19 | 2007-05-10 | Junji Mizuma | バッテリの充電システムおよび充電方法 |
CA2646430A1 (en) * | 2006-03-14 | 2007-09-20 | Amgen Inc. | Bicyclic carboxylic acid derivatives useful for treating metabolic disorders |
KR101589332B1 (ko) * | 2008-12-05 | 2016-01-27 | 아스텔라스세이야쿠 가부시키가이샤 | 2h-크로멘 화합물 및 그의 유도체 |
CN101735408B (zh) * | 2010-01-18 | 2011-12-21 | 中国海洋石油总公司 | 一种高装饰性醇酸-有机硅丙烯酸复合水性树脂 |
CA2865247A1 (en) * | 2012-02-21 | 2013-08-29 | Allergan, Inc. | Phenoxy derivatives as sphingosine 1-phosphate (s1p) receptor modulators |
MX2016000675A (es) * | 2013-07-18 | 2016-05-10 | Novartis Ag | Derivados de amino-metil-biarilo como inhibidores del factor de complemento d y usos de los mismos. |
-
2017
- 2017-05-23 WO PCT/CN2017/085421 patent/WO2017202277A1/zh unknown
- 2017-05-23 US US16/303,649 patent/US10975049B2/en active Active
- 2017-05-23 EP EP17802120.0A patent/EP3466944B1/en active Active
- 2017-05-23 JP JP2019514167A patent/JP6980767B2/ja active Active
- 2017-05-23 CN CN201780031899.5A patent/CN109311792B/zh active Active
- 2017-05-23 WO PCT/CN2017/085418 patent/WO2017202274A1/zh unknown
- 2017-05-23 CN CN201780031943.2A patent/CN109195960B/zh active Active
- 2017-05-23 WO PCT/CN2017/085420 patent/WO2017202276A1/zh unknown
- 2017-05-23 RU RU2018145296A patent/RU2735541C2/ru active
- 2017-05-23 RU RU2018145009A patent/RU2743165C2/ru active
- 2017-05-23 US US16/303,641 patent/US10882833B2/en active Active
- 2017-05-23 CN CN201710365696.1A patent/CN107417666A/zh active Pending
- 2017-05-23 KR KR1020187037129A patent/KR102456572B1/ko active IP Right Grant
- 2017-05-23 WO PCT/CN2017/085419 patent/WO2017202275A1/zh active Application Filing
- 2017-05-23 RU RU2018145534A patent/RU2744975C2/ru active
- 2017-05-23 EP EP17802123.4A patent/EP3459925B1/en active Active
- 2017-05-23 CN CN201780031954.0A patent/CN109153670B/zh active Active
- 2017-05-23 CN CN202210287082.7A patent/CN114853634A/zh active Pending
- 2017-05-23 KR KR1020187037375A patent/KR102400592B1/ko active IP Right Grant
- 2017-05-23 CN CN201710363523.6A patent/CN107417506A/zh active Pending
- 2017-05-23 US US16/303,650 patent/US10815208B2/en active Active
- 2017-05-23 CN CN201710359979.5A patent/CN107417564A/zh active Pending
- 2017-05-23 KR KR1020187037378A patent/KR102364344B1/ko active IP Right Grant
- 2017-05-23 JP JP2019514168A patent/JP7075928B2/ja active Active
- 2017-05-23 EP EP17802119.2A patent/EP3450423B1/en active Active
- 2017-05-23 EP EP17802122.6A patent/EP3459926B1/en active Active
- 2017-05-23 CN CN201780031942.8A patent/CN109153626B/zh active Active
- 2017-05-23 WO PCT/CN2017/085417 patent/WO2017202273A1/zh unknown
- 2017-05-23 CN CN201710365671.1A patent/CN107417572A/zh active Pending
- 2017-05-23 CN CN201780031898.0A patent/CN109219592B/zh active Active
- 2017-05-23 JP JP2019514166A patent/JP6905053B2/ja active Active
- 2017-05-23 US US16/303,646 patent/US10941129B2/en active Active
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2015034820A1 (en) * | 2013-09-04 | 2015-03-12 | Bristol-Myers Squibb Company | Compounds useful as immunomodulators |
CN103787902A (zh) * | 2014-02-17 | 2014-05-14 | 华东理工大学 | 苄基取代的苯胺类化合物及其应用 |
WO2015160641A2 (en) * | 2014-04-14 | 2015-10-22 | Bristol-Myers Squibb Company | Compounds useful as immunomodulators |
CN109195960B (zh) * | 2016-05-23 | 2021-05-04 | 中国医学科学院药物研究所 | 溴代苄醚衍生物、及其制法和药物组合物与用途 |
Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109305934A (zh) * | 2018-08-07 | 2019-02-05 | 成都海博锐药业有限公司 | 苯醚类衍生物及可药用盐、医药上的用途 |
CN111662270A (zh) * | 2019-03-05 | 2020-09-15 | 中国医学科学院药物研究所 | 碘同位素标记苄苯醚衍生物、及其制法和药物组合物与用途 |
CN111978287A (zh) * | 2019-05-23 | 2020-11-24 | 中国科学院上海有机化学研究所 | 一类免疫检查点小分子抑制剂及其制备方法和用途 |
CN113444075A (zh) * | 2020-03-27 | 2021-09-28 | 中国医学科学院药物研究所 | 二氢吲哚衍生物、及其制法和药物组合物与用途 |
CN111943876A (zh) * | 2020-09-08 | 2020-11-17 | 江苏省原子医学研究所 | 一种n2s2类溴代苄醚衍生物、制备方法及应用 |
CN111943876B (zh) * | 2020-09-08 | 2022-04-19 | 江苏省原子医学研究所 | 一种n2s2类溴代苄醚衍生物、制备方法及应用 |
WO2023050104A1 (zh) * | 2021-09-28 | 2023-04-06 | 中国医学科学院药物研究所 | 二氢吲哚衍生物、及其制法和药物组合物与用途 |
CN114956977A (zh) * | 2022-06-09 | 2022-08-30 | 朗捷睿(苏州)生物科技有限公司 | 一种联苯类化合物、药物组合物及其制备方法和应用 |
CN114956977B (zh) * | 2022-06-09 | 2024-03-26 | 朗捷睿(苏州)生物科技有限公司 | 一种联苯类化合物、药物组合物及其制备方法和应用 |
WO2024183756A1 (zh) * | 2023-03-07 | 2024-09-12 | 上海再极医药科技有限公司 | 一种含苯环类化合物及其制备方法和应用 |
CN116589395A (zh) * | 2023-05-17 | 2023-08-15 | 浙江工业大学 | 咔唑甲基苯基醚类衍生物、其制备方法和应用 |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN107417666A (zh) | 溴代苄醚衍生物、及其制法和药物组合物与用途 | |
CN103917536A (zh) | 1-吡唑基-3-(4-((2-(苯氨基嘧啶-4-基)氧基)萘-1-基)用作p38 MAP激酶抑制剂 | |
AU2008229483A1 (en) | Kinase protein binding inhibitors | |
CN113444075B (zh) | 二氢吲哚衍生物、及其制法和药物组合物与用途 | |
CN109824693B (zh) | Brd4抑制剂及其在肿瘤治疗药物中的应用 | |
US20180200233A1 (en) | Compositions for preventing cancers associated with human papilloma viruses | |
WO2023050104A1 (zh) | 二氢吲哚衍生物、及其制法和药物组合物与用途 | |
JP2022542723A (ja) | がん治療用組成物及びその応用、並びに医薬品 | |
CN115504973B (zh) | 苯并异噁唑类化合物、及其制法和药物组合物与用途 | |
CN107501219A (zh) | 不对称姜黄色素类化合物及其在制备抗胃癌药物中的应用 | |
CN107434789A (zh) | 苯并三氮唑类衍生物、及其制法和药物组合物与用途 | |
CN108771670A (zh) | 一种药物组合物及其在制备抗前列腺癌药物中的应用 | |
CN107011337A (zh) | N‑[5‑(1,2,4‑三唑‑1‑基)噻唑‑2‑基]哌啶基酰胺及其医药用途 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20171201 |
|
WD01 | Invention patent application deemed withdrawn after publication |