TW201920123A - 作為腺苷受體拮抗劑之喹㗁啉衍生物 - Google Patents
作為腺苷受體拮抗劑之喹㗁啉衍生物 Download PDFInfo
- Publication number
- TW201920123A TW201920123A TW107128914A TW107128914A TW201920123A TW 201920123 A TW201920123 A TW 201920123A TW 107128914 A TW107128914 A TW 107128914A TW 107128914 A TW107128914 A TW 107128914A TW 201920123 A TW201920123 A TW 201920123A
- Authority
- TW
- Taiwan
- Prior art keywords
- compound
- group
- formula
- atoms
- cancer
- Prior art date
Links
- 125000001567 quinoxalinyl group Chemical class N1=C(C=NC2=CC=CC=C12)* 0.000 title abstract description 3
- 239000000296 purinergic P1 receptor antagonist Substances 0.000 title description 5
- 229940121359 adenosine receptor antagonist Drugs 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 300
- 238000011282 treatment Methods 0.000 claims abstract description 46
- 208000035473 Communicable disease Diseases 0.000 claims abstract description 27
- 230000002265 prevention Effects 0.000 claims abstract description 26
- 230000003463 hyperproliferative effect Effects 0.000 claims abstract description 23
- 208000015181 infectious disease Diseases 0.000 claims abstract description 16
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 10
- -1 SO Inorganic materials 0.000 claims description 118
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 claims description 101
- 239000000203 mixture Substances 0.000 claims description 85
- 238000000034 method Methods 0.000 claims description 79
- 150000003839 salts Chemical class 0.000 claims description 70
- 239000002126 C01EB10 - Adenosine Substances 0.000 claims description 50
- 229960005305 adenosine Drugs 0.000 claims description 50
- 125000004432 carbon atom Chemical group C* 0.000 claims description 49
- 206010028980 Neoplasm Diseases 0.000 claims description 43
- 239000003814 drug Substances 0.000 claims description 39
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 37
- 239000012453 solvate Substances 0.000 claims description 37
- 238000006243 chemical reaction Methods 0.000 claims description 35
- 239000002253 acid Substances 0.000 claims description 34
- 229940002612 prodrug Drugs 0.000 claims description 32
- 239000000651 prodrug Substances 0.000 claims description 32
- 239000007787 solid Substances 0.000 claims description 31
- 229910052760 oxygen Inorganic materials 0.000 claims description 28
- 201000010099 disease Diseases 0.000 claims description 26
- 201000011510 cancer Diseases 0.000 claims description 23
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 23
- 229910052717 sulfur Inorganic materials 0.000 claims description 23
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 21
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 19
- 238000002360 preparation method Methods 0.000 claims description 19
- 125000000217 alkyl group Chemical group 0.000 claims description 18
- 239000002671 adjuvant Substances 0.000 claims description 17
- 239000003795 chemical substances by application Substances 0.000 claims description 17
- 125000003118 aryl group Chemical group 0.000 claims description 16
- 125000000623 heterocyclic group Chemical group 0.000 claims description 15
- 230000002829 reductive effect Effects 0.000 claims description 15
- 238000006467 substitution reaction Methods 0.000 claims description 14
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 12
- 208000035475 disorder Diseases 0.000 claims description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 11
- 150000002367 halogens Chemical class 0.000 claims description 11
- 230000001991 pathophysiological effect Effects 0.000 claims description 11
- 230000009467 reduction Effects 0.000 claims description 11
- 210000001519 tissue Anatomy 0.000 claims description 11
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 10
- 150000001412 amines Chemical class 0.000 claims description 10
- 229910052731 fluorine Inorganic materials 0.000 claims description 10
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 10
- 230000015572 biosynthetic process Effects 0.000 claims description 9
- 125000002950 monocyclic group Chemical group 0.000 claims description 9
- 241001430294 unidentified retrovirus Species 0.000 claims description 8
- 125000005842 heteroatom Chemical group 0.000 claims description 7
- 239000007788 liquid Substances 0.000 claims description 7
- 238000005576 amination reaction Methods 0.000 claims description 6
- 239000004202 carbamide Substances 0.000 claims description 6
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 6
- 125000004367 cycloalkylaryl group Chemical group 0.000 claims description 6
- 230000003211 malignant effect Effects 0.000 claims description 6
- 201000001441 melanoma Diseases 0.000 claims description 6
- 206010006187 Breast cancer Diseases 0.000 claims description 5
- 208000026310 Breast neoplasm Diseases 0.000 claims description 5
- 102000004190 Enzymes Human genes 0.000 claims description 5
- 108090000790 Enzymes Proteins 0.000 claims description 5
- 206010021143 Hypoxia Diseases 0.000 claims description 5
- 125000004429 atom Chemical group 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 claims description 5
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 claims description 4
- 241000894006 Bacteria Species 0.000 claims description 4
- 208000003174 Brain Neoplasms Diseases 0.000 claims description 4
- 241000192125 Firmicutes Species 0.000 claims description 4
- 241000710781 Flaviviridae Species 0.000 claims description 4
- 241000713666 Lentivirus Species 0.000 claims description 4
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 claims description 4
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 claims description 4
- 229930182555 Penicillin Natural products 0.000 claims description 4
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 claims description 4
- 241000191967 Staphylococcus aureus Species 0.000 claims description 4
- 208000024770 Thyroid neoplasm Diseases 0.000 claims description 4
- 108010059993 Vancomycin Proteins 0.000 claims description 4
- 230000009435 amidation Effects 0.000 claims description 4
- 238000007112 amidation reaction Methods 0.000 claims description 4
- 208000022362 bacterial infectious disease Diseases 0.000 claims description 4
- 208000037976 chronic inflammation Diseases 0.000 claims description 4
- 230000006020 chronic inflammation Effects 0.000 claims description 4
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 claims description 4
- 230000007954 hypoxia Effects 0.000 claims description 4
- 230000003834 intracellular effect Effects 0.000 claims description 4
- 229960003085 meticillin Drugs 0.000 claims description 4
- 231100000590 oncogenic Toxicity 0.000 claims description 4
- 230000002246 oncogenic effect Effects 0.000 claims description 4
- 229940049954 penicillin Drugs 0.000 claims description 4
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 4
- 201000002510 thyroid cancer Diseases 0.000 claims description 4
- 241001529453 unidentified herpesvirus Species 0.000 claims description 4
- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 claims description 4
- 229960003165 vancomycin Drugs 0.000 claims description 4
- 206010005003 Bladder cancer Diseases 0.000 claims description 3
- 206010009944 Colon cancer Diseases 0.000 claims description 3
- 241000588748 Klebsiella Species 0.000 claims description 3
- 241000588621 Moraxella Species 0.000 claims description 3
- 241000588768 Providencia Species 0.000 claims description 3
- 206010039491 Sarcoma Diseases 0.000 claims description 3
- 241000191940 Staphylococcus Species 0.000 claims description 3
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 3
- 241000194017 Streptococcus Species 0.000 claims description 3
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 3
- 208000008383 Wilms tumor Diseases 0.000 claims description 3
- 239000002552 dosage form Substances 0.000 claims description 3
- 206010017758 gastric cancer Diseases 0.000 claims description 3
- 206010020718 hyperplasia Diseases 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- 208000032839 leukemia Diseases 0.000 claims description 3
- 210000000056 organ Anatomy 0.000 claims description 3
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 3
- 201000011549 stomach cancer Diseases 0.000 claims description 3
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 3
- DQJCDTNMLBYVAY-ZXXIYAEKSA-N (2S,5R,10R,13R)-16-{[(2R,3S,4R,5R)-3-{[(2S,3R,4R,5S,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}-5-(ethylamino)-6-hydroxy-2-(hydroxymethyl)oxan-4-yl]oxy}-5-(4-aminobutyl)-10-carbamoyl-2,13-dimethyl-4,7,12,15-tetraoxo-3,6,11,14-tetraazaheptadecan-1-oic acid Chemical compound NCCCC[C@H](C(=O)N[C@@H](C)C(O)=O)NC(=O)CC[C@H](C(N)=O)NC(=O)[C@@H](C)NC(=O)C(C)O[C@@H]1[C@@H](NCC)C(O)O[C@H](CO)[C@H]1O[C@H]1[C@H](NC(C)=O)[C@@H](O)[C@H](O)[C@@H](CO)O1 DQJCDTNMLBYVAY-ZXXIYAEKSA-N 0.000 claims description 2
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 claims description 2
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 claims description 2
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 2
- 208000006468 Adrenal Cortex Neoplasms Diseases 0.000 claims description 2
- 241000224482 Apicomplexa Species 0.000 claims description 2
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 claims description 2
- 241000223836 Babesia Species 0.000 claims description 2
- 241001446316 Bohle iridovirus Species 0.000 claims description 2
- 241000714266 Bovine leukemia virus Species 0.000 claims description 2
- 241000713756 Caprine arthritis encephalitis virus Species 0.000 claims description 2
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 2
- 241000606161 Chlamydia Species 0.000 claims description 2
- 241001647372 Chlamydia pneumoniae Species 0.000 claims description 2
- 208000006332 Choriocarcinoma Diseases 0.000 claims description 2
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 claims description 2
- 241000588923 Citrobacter Species 0.000 claims description 2
- 241000193163 Clostridioides difficile Species 0.000 claims description 2
- 241000224483 Coccidia Species 0.000 claims description 2
- 208000011231 Crohn disease Diseases 0.000 claims description 2
- 206010012689 Diabetic retinopathy Diseases 0.000 claims description 2
- 206010014733 Endometrial cancer Diseases 0.000 claims description 2
- 206010014759 Endometrial neoplasm Diseases 0.000 claims description 2
- 241000588914 Enterobacter Species 0.000 claims description 2
- 241000194032 Enterococcus faecalis Species 0.000 claims description 2
- 241000194031 Enterococcus faecium Species 0.000 claims description 2
- 241000713730 Equine infectious anemia virus Species 0.000 claims description 2
- 241000588722 Escherichia Species 0.000 claims description 2
- 241000588724 Escherichia coli Species 0.000 claims description 2
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 2
- 208000032027 Essential Thrombocythemia Diseases 0.000 claims description 2
- 241000713800 Feline immunodeficiency virus Species 0.000 claims description 2
- 206010016654 Fibrosis Diseases 0.000 claims description 2
- 208000032612 Glial tumor Diseases 0.000 claims description 2
- 206010018338 Glioma Diseases 0.000 claims description 2
- 108010015899 Glycopeptides Proteins 0.000 claims description 2
- 102000002068 Glycopeptides Human genes 0.000 claims description 2
- 241000700735 Ground squirrel hepatitis virus Species 0.000 claims description 2
- 208000031886 HIV Infections Diseases 0.000 claims description 2
- 241000606790 Haemophilus Species 0.000 claims description 2
- 208000017604 Hodgkin disease Diseases 0.000 claims description 2
- 208000010747 Hodgkins lymphoma Diseases 0.000 claims description 2
- 206010020460 Human T-cell lymphotropic virus type I infection Diseases 0.000 claims description 2
- 241000714260 Human T-lymphotropic virus 1 Species 0.000 claims description 2
- 241000714259 Human T-lymphotropic virus 2 Species 0.000 claims description 2
- 241000701024 Human betaherpesvirus 5 Species 0.000 claims description 2
- 241000713772 Human immunodeficiency virus 1 Species 0.000 claims description 2
- 241000713340 Human immunodeficiency virus 2 Species 0.000 claims description 2
- 208000037147 Hypercalcaemia Diseases 0.000 claims description 2
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 2
- 208000007766 Kaposi sarcoma Diseases 0.000 claims description 2
- 241000222722 Leishmania <genus> Species 0.000 claims description 2
- 241000186779 Listeria monocytogenes Species 0.000 claims description 2
- 208000028018 Lymphocytic leukaemia Diseases 0.000 claims description 2
- 206010025323 Lymphomas Diseases 0.000 claims description 2
- 241000588655 Moraxella catarrhalis Species 0.000 claims description 2
- 208000034578 Multiple myelomas Diseases 0.000 claims description 2
- 241000187479 Mycobacterium tuberculosis Species 0.000 claims description 2
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 claims description 2
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims description 2
- 241000588653 Neisseria Species 0.000 claims description 2
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 claims description 2
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims description 2
- 206010033128 Ovarian cancer Diseases 0.000 claims description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 2
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 2
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 claims description 2
- 208000002158 Proliferative Vitreoretinopathy Diseases 0.000 claims description 2
- 206010060862 Prostate cancer Diseases 0.000 claims description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 2
- 241000588769 Proteus <enterobacteria> Species 0.000 claims description 2
- 241000589516 Pseudomonas Species 0.000 claims description 2
- 201000004681 Psoriasis Diseases 0.000 claims description 2
- 208000006265 Renal cell carcinoma Diseases 0.000 claims description 2
- 206010038933 Retinopathy of prematurity Diseases 0.000 claims description 2
- 206010038934 Retinopathy proliferative Diseases 0.000 claims description 2
- 241000607142 Salmonella Species 0.000 claims description 2
- 241000607720 Serratia Species 0.000 claims description 2
- 241000607768 Shigella Species 0.000 claims description 2
- 241000580858 Simian-Human immunodeficiency virus Species 0.000 claims description 2
- 208000000453 Skin Neoplasms Diseases 0.000 claims description 2
- 206010041067 Small cell lung cancer Diseases 0.000 claims description 2
- 208000021712 Soft tissue sarcoma Diseases 0.000 claims description 2
- 241000295644 Staphylococcaceae Species 0.000 claims description 2
- 241000191984 Staphylococcus haemolyticus Species 0.000 claims description 2
- 241000192087 Staphylococcus hominis Species 0.000 claims description 2
- 241001147691 Staphylococcus saprophyticus Species 0.000 claims description 2
- 241000193985 Streptococcus agalactiae Species 0.000 claims description 2
- 241000194049 Streptococcus equinus Species 0.000 claims description 2
- 235000014897 Streptococcus lactis Nutrition 0.000 claims description 2
- 241000193998 Streptococcus pneumoniae Species 0.000 claims description 2
- 241000193996 Streptococcus pyogenes Species 0.000 claims description 2
- 241000194023 Streptococcus sanguinis Species 0.000 claims description 2
- 241000194005 Streptococcus sp. 'group G' Species 0.000 claims description 2
- 241001312524 Streptococcus viridans Species 0.000 claims description 2
- 208000024313 Testicular Neoplasms Diseases 0.000 claims description 2
- 206010057644 Testis cancer Diseases 0.000 claims description 2
- 241000223777 Theileria Species 0.000 claims description 2
- 241000223104 Trypanosoma Species 0.000 claims description 2
- 208000008385 Urogenital Neoplasms Diseases 0.000 claims description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 2
- 206010047115 Vasculitis Diseases 0.000 claims description 2
- 241000700605 Viruses Species 0.000 claims description 2
- 208000033559 Waldenström macroglobulinemia Diseases 0.000 claims description 2
- 201000006449 West Nile encephalitis Diseases 0.000 claims description 2
- 206010057293 West Nile viral infection Diseases 0.000 claims description 2
- 208000003152 Yellow Fever Diseases 0.000 claims description 2
- 208000017733 acquired polycythemia vera Diseases 0.000 claims description 2
- 230000001154 acute effect Effects 0.000 claims description 2
- 206010064930 age-related macular degeneration Diseases 0.000 claims description 2
- 201000008680 babesiosis Diseases 0.000 claims description 2
- 208000002458 carcinoid tumor Diseases 0.000 claims description 2
- 201000010881 cervical cancer Diseases 0.000 claims description 2
- 230000007882 cirrhosis Effects 0.000 claims description 2
- 208000019425 cirrhosis of liver Diseases 0.000 claims description 2
- 208000029742 colonic neoplasm Diseases 0.000 claims description 2
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 claims description 2
- 229940032049 enterococcus faecalis Drugs 0.000 claims description 2
- 201000004101 esophageal cancer Diseases 0.000 claims description 2
- 208000005017 glioblastoma Diseases 0.000 claims description 2
- 210000002768 hair cell Anatomy 0.000 claims description 2
- 201000010536 head and neck cancer Diseases 0.000 claims description 2
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 2
- 230000000148 hypercalcaemia Effects 0.000 claims description 2
- 208000030915 hypercalcemia disease Diseases 0.000 claims description 2
- 208000025095 immunoproliferative disease Diseases 0.000 claims description 2
- 230000006698 induction Effects 0.000 claims description 2
- 208000003747 lymphoid leukemia Diseases 0.000 claims description 2
- 201000000564 macroglobulinemia Diseases 0.000 claims description 2
- 208000002780 macular degeneration Diseases 0.000 claims description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 2
- 201000005962 mycosis fungoides Diseases 0.000 claims description 2
- 208000025113 myeloid leukemia Diseases 0.000 claims description 2
- 208000021971 neovascular inflammatory vitreoretinopathy Diseases 0.000 claims description 2
- 238000006396 nitration reaction Methods 0.000 claims description 2
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 2
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims description 2
- 201000002528 pancreatic cancer Diseases 0.000 claims description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 2
- 208000021255 pancreatic insulinoma Diseases 0.000 claims description 2
- 244000045947 parasite Species 0.000 claims description 2
- 230000004963 pathophysiological condition Effects 0.000 claims description 2
- 230000004962 physiological condition Effects 0.000 claims description 2
- 208000037244 polycythemia vera Diseases 0.000 claims description 2
- 201000007914 proliferative diabetic retinopathy Diseases 0.000 claims description 2
- 230000006785 proliferative vitreoretinopathy Effects 0.000 claims description 2
- 230000002207 retinal effect Effects 0.000 claims description 2
- 201000000849 skin cancer Diseases 0.000 claims description 2
- 208000000587 small cell lung carcinoma Diseases 0.000 claims description 2
- 206010041823 squamous cell carcinoma Diseases 0.000 claims description 2
- 229940037649 staphylococcus haemolyticus Drugs 0.000 claims description 2
- 229940031000 streptococcus pneumoniae Drugs 0.000 claims description 2
- 238000006277 sulfonation reaction Methods 0.000 claims description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 2
- 201000003120 testicular cancer Diseases 0.000 claims description 2
- 238000002054 transplantation Methods 0.000 claims description 2
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 2
- 241000701161 unidentified adenovirus Species 0.000 claims description 2
- 208000037964 urogenital cancer Diseases 0.000 claims description 2
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims 3
- 230000035479 physiological effects, processes and functions Effects 0.000 claims 3
- FCSKOFQQCWLGMV-UHFFFAOYSA-N 5-{5-[2-chloro-4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]pentyl}-3-methylisoxazole Chemical compound O1N=C(C)C=C1CCCCCOC1=CC=C(C=2OCCN=2)C=C1Cl FCSKOFQQCWLGMV-UHFFFAOYSA-N 0.000 claims 1
- 241000186216 Corynebacterium Species 0.000 claims 1
- 241000194035 Lactococcus lactis Species 0.000 claims 1
- 206010029260 Neuroblastoma Diseases 0.000 claims 1
- 210000003679 cervix uteri Anatomy 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 claims 1
- 206010022498 insulinoma Diseases 0.000 claims 1
- 201000008968 osteosarcoma Diseases 0.000 claims 1
- 210000000496 pancreas Anatomy 0.000 claims 1
- 108091006082 receptor inhibitors Proteins 0.000 claims 1
- 208000017572 squamous cell neoplasm Diseases 0.000 claims 1
- 210000003699 striated muscle Anatomy 0.000 claims 1
- 230000002792 vascular Effects 0.000 claims 1
- 241000124008 Mammalia Species 0.000 abstract description 6
- 102000005962 receptors Human genes 0.000 description 77
- 108020003175 receptors Proteins 0.000 description 77
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 55
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 37
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 37
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 37
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
- 239000000243 solution Substances 0.000 description 34
- 102000009346 Adenosine receptors Human genes 0.000 description 32
- 108050000203 Adenosine receptors Proteins 0.000 description 32
- 210000001744 T-lymphocyte Anatomy 0.000 description 29
- 210000004027 cell Anatomy 0.000 description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 28
- 230000000694 effects Effects 0.000 description 26
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 24
- 241000282414 Homo sapiens Species 0.000 description 23
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 22
- 239000003112 inhibitor Substances 0.000 description 22
- 239000000556 agonist Substances 0.000 description 21
- 239000005557 antagonist Substances 0.000 description 21
- 239000002585 base Substances 0.000 description 21
- 235000019439 ethyl acetate Nutrition 0.000 description 19
- 230000005764 inhibitory process Effects 0.000 description 19
- 241000699670 Mus sp. Species 0.000 description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 17
- 238000004128 high performance liquid chromatography Methods 0.000 description 16
- 230000028993 immune response Effects 0.000 description 16
- IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 description 15
- 239000000460 chlorine Substances 0.000 description 15
- 230000006378 damage Effects 0.000 description 14
- 239000002904 solvent Substances 0.000 description 14
- 238000009472 formulation Methods 0.000 description 13
- 239000012071 phase Substances 0.000 description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-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
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- 241000700159 Rattus Species 0.000 description 12
- 238000003818 flash chromatography Methods 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 11
- 230000001506 immunosuppresive effect Effects 0.000 description 11
- 239000007858 starting material Substances 0.000 description 11
- 238000005481 NMR spectroscopy Methods 0.000 description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- 238000002560 therapeutic procedure Methods 0.000 description 10
- PAOANWZGLPPROA-RQXXJAGISA-N CGS-21680 Chemical compound O[C@@H]1[C@H](O)[C@@H](C(=O)NCC)O[C@H]1N1C2=NC(NCCC=3C=CC(CCC(O)=O)=CC=3)=NC(N)=C2N=C1 PAOANWZGLPPROA-RQXXJAGISA-N 0.000 description 9
- 102000004127 Cytokines Human genes 0.000 description 9
- 108090000695 Cytokines Proteins 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 206010062016 Immunosuppression Diseases 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 150000001413 amino acids Chemical class 0.000 description 9
- 230000000259 anti-tumor effect Effects 0.000 description 9
- 230000009977 dual effect Effects 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- 238000001727 in vivo Methods 0.000 description 9
- 230000001965 increasing effect Effects 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- 241000699666 Mus <mouse, genus> Species 0.000 description 8
- 208000018737 Parkinson disease Diseases 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 8
- 108060000200 adenylate cyclase Proteins 0.000 description 8
- 102000030621 adenylate cyclase Human genes 0.000 description 8
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 8
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 8
- 125000001072 heteroaryl group Chemical group 0.000 description 8
- 230000002401 inhibitory effect Effects 0.000 description 8
- 229940090044 injection Drugs 0.000 description 8
- 238000002347 injection Methods 0.000 description 8
- 239000007924 injection Substances 0.000 description 8
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 8
- 230000001404 mediated effect Effects 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 8
- 108091006027 G proteins Proteins 0.000 description 7
- 102000030782 GTP binding Human genes 0.000 description 7
- 108091000058 GTP-Binding Proteins 0.000 description 7
- JADDQZYHOWSFJD-FLNNQWSLSA-N N-ethyl-5'-carboxamidoadenosine Chemical compound O[C@@H]1[C@H](O)[C@@H](C(=O)NCC)O[C@H]1N1C2=NC=NC(N)=C2N=C1 JADDQZYHOWSFJD-FLNNQWSLSA-N 0.000 description 7
- 239000002467 adenosine A2a receptor antagonist Substances 0.000 description 7
- 238000001816 cooling Methods 0.000 description 7
- 239000012442 inert solvent Substances 0.000 description 7
- 238000001990 intravenous administration Methods 0.000 description 7
- 239000003208 petroleum Substances 0.000 description 7
- 230000003389 potentiating effect Effects 0.000 description 7
- 230000028327 secretion Effects 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- 230000004614 tumor growth Effects 0.000 description 7
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 230000002159 abnormal effect Effects 0.000 description 6
- 150000007513 acids Chemical class 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- 238000010171 animal model Methods 0.000 description 6
- 239000000427 antigen Substances 0.000 description 6
- 108091007433 antigens Proteins 0.000 description 6
- 102000036639 antigens Human genes 0.000 description 6
- 239000002246 antineoplastic agent Substances 0.000 description 6
- 239000012298 atmosphere Substances 0.000 description 6
- 230000008901 benefit Effects 0.000 description 6
- 230000000903 blocking effect Effects 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 230000002708 enhancing effect Effects 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 6
- 230000001976 improved effect Effects 0.000 description 6
- 239000003446 ligand Substances 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 230000004783 oxidative metabolism Effects 0.000 description 6
- 239000001301 oxygen Substances 0.000 description 6
- 238000007911 parenteral administration Methods 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 230000011664 signaling Effects 0.000 description 6
- 241000894007 species Species 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- 241000282472 Canis lupus familiaris Species 0.000 description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 5
- 241000282412 Homo Species 0.000 description 5
- 206010029113 Neovascularisation Diseases 0.000 description 5
- 102000057297 Pepsin A Human genes 0.000 description 5
- 108090000284 Pepsin A Proteins 0.000 description 5
- 102000004357 Transferases Human genes 0.000 description 5
- 108090000992 Transferases Proteins 0.000 description 5
- 230000004913 activation Effects 0.000 description 5
- 229910052783 alkali metal Inorganic materials 0.000 description 5
- 238000003556 assay Methods 0.000 description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 5
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical class C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 5
- 229910052801 chlorine Inorganic materials 0.000 description 5
- 210000002865 immune cell Anatomy 0.000 description 5
- 238000000338 in vitro Methods 0.000 description 5
- 238000011534 incubation Methods 0.000 description 5
- 230000007774 longterm Effects 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 229940111202 pepsin Drugs 0.000 description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 230000004044 response Effects 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- 210000004881 tumor cell Anatomy 0.000 description 5
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 4
- HUJXGQILHAUCCV-MOROJQBDSA-N 3-iodobenzyl-5'-N-methylcarboxamidoadenosine Chemical compound O[C@@H]1[C@H](O)[C@@H](C(=O)NC)O[C@H]1N1C2=NC=NC(NCC=3C=C(I)C=CC=3)=C2N=C1 HUJXGQILHAUCCV-MOROJQBDSA-N 0.000 description 4
- 102100022464 5'-nucleotidase Human genes 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 4
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 4
- 101000678236 Homo sapiens 5'-nucleotidase Proteins 0.000 description 4
- 206010061218 Inflammation Diseases 0.000 description 4
- 102100037850 Interferon gamma Human genes 0.000 description 4
- 108010074328 Interferon-gamma Proteins 0.000 description 4
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic acid anhydride Natural products CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 4
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 4
- 125000003277 amino group Chemical group 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 210000004556 brain Anatomy 0.000 description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 229960001948 caffeine Drugs 0.000 description 4
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 4
- 210000003169 central nervous system Anatomy 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 229910052805 deuterium Inorganic materials 0.000 description 4
- 238000009826 distribution Methods 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 229940088598 enzyme Drugs 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
- 239000011737 fluorine Substances 0.000 description 4
- 230000006870 function Effects 0.000 description 4
- 230000004054 inflammatory process Effects 0.000 description 4
- 150000007530 organic bases Chemical class 0.000 description 4
- 239000011591 potassium Substances 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 239000003379 purinergic P1 receptor agonist Substances 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 229940044551 receptor antagonist Drugs 0.000 description 4
- 239000002464 receptor antagonist Substances 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- RIRGCFBBHQEQQH-SSFGXONLSA-N (-)-n6-(2-phenylisopropyl)adenosine Chemical compound C([C@@H](C)NC=1C=2N=CN(C=2N=CN=1)[C@H]1[C@@H]([C@H](O)[C@@H](CO)O1)O)C1=CC=CC=C1 RIRGCFBBHQEQQH-SSFGXONLSA-N 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- QNSBVYWSABGVGX-UHFFFAOYSA-N 3-methoxy-6-pyridin-4-ylbenzene-1,2-diamine Chemical compound COC1=C(C(=C(C=C1)C1=CC=NC=C1)N)N QNSBVYWSABGVGX-UHFFFAOYSA-N 0.000 description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 3
- XSYWMHGRYQVGBC-UHFFFAOYSA-N 5-methoxy-8-phenyl-4H-pyrido[3,4-b]pyrazin-3-one Chemical compound COC1=NC=C(C=2C1=NC(=CN=2)O)C1=CC=CC=C1 XSYWMHGRYQVGBC-UHFFFAOYSA-N 0.000 description 3
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 3
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical class O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 description 3
- ZKHQWZAMYRWXGA-KQYNXXCUSA-J ATP(4-) Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-J 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 229940122614 Adenosine receptor agonist Drugs 0.000 description 3
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
- 108090000312 Calcium Channels Proteins 0.000 description 3
- 102000003922 Calcium Channels Human genes 0.000 description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 3
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 3
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 3
- 101000914514 Homo sapiens T-cell-specific surface glycoprotein CD28 Proteins 0.000 description 3
- 208000023105 Huntington disease Diseases 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 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 description 3
- 108010002350 Interleukin-2 Proteins 0.000 description 3
- 102000000588 Interleukin-2 Human genes 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 206010027476 Metastases Diseases 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 3
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 102100027213 T-cell-specific surface glycoprotein CD28 Human genes 0.000 description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 3
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 3
- 125000006242 amine protecting group Chemical group 0.000 description 3
- 150000003863 ammonium salts Chemical class 0.000 description 3
- 239000003708 ampul Substances 0.000 description 3
- 230000000692 anti-sense effect Effects 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 125000002619 bicyclic group Chemical group 0.000 description 3
- 229920002988 biodegradable polymer Polymers 0.000 description 3
- 239000004621 biodegradable polymer Substances 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052791 calcium Inorganic materials 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 230000004663 cell proliferation Effects 0.000 description 3
- 238000002512 chemotherapy Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000006071 cream Substances 0.000 description 3
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 3
- AFABGHUZZDYHJO-UHFFFAOYSA-N dimethyl butane Natural products CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 239000012153 distilled water Substances 0.000 description 3
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 3
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 3
- IIEWJVIFRVWJOD-UHFFFAOYSA-N ethyl cyclohexane Natural products CCC1CCCCC1 IIEWJVIFRVWJOD-UHFFFAOYSA-N 0.000 description 3
- 230000002349 favourable effect Effects 0.000 description 3
- 239000000796 flavoring agent Substances 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 3
- 238000002868 homogeneous time resolved fluorescence Methods 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 208000028867 ischemia Diseases 0.000 description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
- 239000002502 liposome Substances 0.000 description 3
- 239000007937 lozenge Substances 0.000 description 3
- 210000004072 lung Anatomy 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000002503 metabolic effect Effects 0.000 description 3
- 239000002207 metabolite Substances 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 3
- 210000001577 neostriatum Anatomy 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- 239000002674 ointment Substances 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 230000003204 osmotic effect Effects 0.000 description 3
- 230000036470 plasma concentration Effects 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- DTYWJKSSUANMHD-UHFFFAOYSA-N preladenant Chemical compound C1=CC(OCCOC)=CC=C1N1CCN(CCN2C3=C(C4=NC(=NN4C(N)=N3)C=3OC=CC=3)C=N2)CC1 DTYWJKSSUANMHD-UHFFFAOYSA-N 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- 150000003252 quinoxalines Chemical class 0.000 description 3
- 210000003289 regulatory T cell Anatomy 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 230000004936 stimulating effect Effects 0.000 description 3
- 235000000346 sugar Nutrition 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- 210000001179 synovial fluid Anatomy 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 229960001278 teniposide Drugs 0.000 description 3
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 3
- 230000000699 topical effect Effects 0.000 description 3
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 3
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 3
- 229960005486 vaccine Drugs 0.000 description 3
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 3
- LDDMACCNBZAMSG-BDVNFPICSA-N (2r,3r,4s,5r)-3,4,5,6-tetrahydroxy-2-(methylamino)hexanal Chemical compound CN[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO LDDMACCNBZAMSG-BDVNFPICSA-N 0.000 description 2
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 2
- LOZWAPSEEHRYPG-UHFFFAOYSA-N 1,4-dithiane Chemical compound C1CSCCS1 LOZWAPSEEHRYPG-UHFFFAOYSA-N 0.000 description 2
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 2
- XFWBPNPOHJWYAY-UHFFFAOYSA-N 1-bromo-4-methoxy-2,3-dinitrobenzene Chemical compound COC1=CC=C(Br)C([N+]([O-])=O)=C1[N+]([O-])=O XFWBPNPOHJWYAY-UHFFFAOYSA-N 0.000 description 2
- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 description 2
- XALCNCGDFQAKMX-UHFFFAOYSA-N 2-methoxy-3-nitro-5-phenylpyridin-4-amine Chemical compound COC1=NC=C(C(=C1[N+](=O)[O-])N)C1=CC=CC=C1 XALCNCGDFQAKMX-UHFFFAOYSA-N 0.000 description 2
- ALDZAORRWWNDAG-UHFFFAOYSA-N 2-methoxy-5-phenylpyridine-3,4-diamine Chemical compound COC1=NC=C(C(=C1N)N)C1=CC=CC=C1 ALDZAORRWWNDAG-UHFFFAOYSA-N 0.000 description 2
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 2
- TYEYBOSBBBHJIV-UHFFFAOYSA-M 2-oxobutanoate Chemical compound CCC(=O)C([O-])=O TYEYBOSBBBHJIV-UHFFFAOYSA-M 0.000 description 2
- HQSBCDPYXDGTCL-UHFFFAOYSA-N 3-[(4-amino-3-methylphenyl)methyl]-7-(furan-2-yl)triazolo[4,5-d]pyrimidin-5-amine Chemical compound C1=C(N)C(C)=CC(CN2C3=NC(N)=NC(=C3N=N2)C=2OC=CC=2)=C1 HQSBCDPYXDGTCL-UHFFFAOYSA-N 0.000 description 2
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 description 2
- GMWINOBJANURAX-UHFFFAOYSA-N 4-(4-methoxy-2,3-dinitrophenyl)pyridine Chemical compound COC1=C(C(=C(C=C1)C1=CC=NC=C1)[N+](=O)[O-])[N+](=O)[O-] GMWINOBJANURAX-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- MUDMILZFFXFMHF-UHFFFAOYSA-N 4-hydroxy-N-(5-methoxy-8-phenylpyrido[3,4-b]pyrazin-3-yl)-4-methylpiperidine-1-carboxamide Chemical compound OC1(CCN(CC1)C(=O)NC1=CN=C2C(=N1)C(=NC=C2C1=CC=CC=C1)OC)C MUDMILZFFXFMHF-UHFFFAOYSA-N 0.000 description 2
- CXBLQEIODBBSQD-UHFFFAOYSA-N 4-methylpiperidin-4-ol Chemical compound CC1(O)CCNCC1 CXBLQEIODBBSQD-UHFFFAOYSA-N 0.000 description 2
- XTWYTFMLZFPYCI-KQYNXXCUSA-N 5'-adenylphosphoric acid Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O XTWYTFMLZFPYCI-KQYNXXCUSA-N 0.000 description 2
- RDLRPVPZIHNWKC-UHFFFAOYSA-N 5-methoxy-8-phenylpyrido[3,4-b]pyrazin-3-amine Chemical compound COC1=NC=C(C=2C1=NC(=CN=2)N)C1=CC=CC=C1 RDLRPVPZIHNWKC-UHFFFAOYSA-N 0.000 description 2
- KURQKNMKCGYWRJ-HNNXBMFYSA-N 7-(5-methylfuran-2-yl)-3-[[6-[[(3s)-oxolan-3-yl]oxymethyl]pyridin-2-yl]methyl]triazolo[4,5-d]pyrimidin-5-amine Chemical compound O1C(C)=CC=C1C1=NC(N)=NC2=C1N=NN2CC1=CC=CC(CO[C@@H]2COCC2)=N1 KURQKNMKCGYWRJ-HNNXBMFYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- XTWYTFMLZFPYCI-UHFFFAOYSA-N Adenosine diphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(O)=O)C(O)C1O XTWYTFMLZFPYCI-UHFFFAOYSA-N 0.000 description 2
- ZKHQWZAMYRWXGA-UHFFFAOYSA-N Adenosine triphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O ZKHQWZAMYRWXGA-UHFFFAOYSA-N 0.000 description 2
- 208000024827 Alzheimer disease Diseases 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- BFYIZQONLCFLEV-DAELLWKTSA-N Aromasine Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC(=C)C2=C1 BFYIZQONLCFLEV-DAELLWKTSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 description 2
- 108010006654 Bleomycin Proteins 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 2
- 229940045513 CTLA4 antagonist Drugs 0.000 description 2
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 2
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 description 2
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 2
- OHCQJHSOBUTRHG-KGGHGJDLSA-N FORSKOLIN Chemical compound O=C([C@@]12O)C[C@](C)(C=C)O[C@]1(C)[C@@H](OC(=O)C)[C@@H](O)[C@@H]1[C@]2(C)[C@@H](O)CCC1(C)C OHCQJHSOBUTRHG-KGGHGJDLSA-N 0.000 description 2
- 241000282326 Felis catus Species 0.000 description 2
- 108010029961 Filgrastim Proteins 0.000 description 2
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- VWUXBMIQPBEWFH-WCCTWKNTSA-N Fulvestrant Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3[C@H](CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F)CC2=C1 VWUXBMIQPBEWFH-WCCTWKNTSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 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 2
- 102100039619 Granulocyte colony-stimulating factor Human genes 0.000 description 2
- 101001059454 Homo sapiens Serine/threonine-protein kinase MARK2 Proteins 0.000 description 2
- 108091008036 Immune checkpoint proteins Proteins 0.000 description 2
- 102000037982 Immune checkpoint proteins Human genes 0.000 description 2
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 2
- 239000004472 Lysine Substances 0.000 description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 2
- 108010038807 Oligopeptides Proteins 0.000 description 2
- 102000015636 Oligopeptides Human genes 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- 102000016979 Other receptors Human genes 0.000 description 2
- 208000002193 Pain Diseases 0.000 description 2
- 102000004257 Potassium Channel Human genes 0.000 description 2
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 241000700157 Rattus norvegicus Species 0.000 description 2
- 102100028904 Serine/threonine-protein kinase MARK2 Human genes 0.000 description 2
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 2
- 102000014384 Type C Phospholipases Human genes 0.000 description 2
- 108010079194 Type C Phospholipases Proteins 0.000 description 2
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 2
- 235000011054 acetic acid Nutrition 0.000 description 2
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 150000003838 adenosines Chemical class 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 238000004220 aggregation Methods 0.000 description 2
- 238000007605 air drying Methods 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 2
- 150000001342 alkaline earth metals Chemical class 0.000 description 2
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 229960002932 anastrozole Drugs 0.000 description 2
- YBBLVLTVTVSKRW-UHFFFAOYSA-N anastrozole Chemical compound N#CC(C)(C)C1=CC(C(C)(C#N)C)=CC(CN2N=CN=C2)=C1 YBBLVLTVTVSKRW-UHFFFAOYSA-N 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 238000009175 antibody therapy Methods 0.000 description 2
- 230000007503 antigenic stimulation Effects 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 206010003246 arthritis Diseases 0.000 description 2
- 125000005098 aryl alkoxy carbonyl group Chemical group 0.000 description 2
- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- 208000006673 asthma Diseases 0.000 description 2
- 208000015802 attention deficit-hyperactivity disease Diseases 0.000 description 2
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 2
- 239000011324 bead Substances 0.000 description 2
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 2
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 229960000397 bevacizumab Drugs 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 235000010290 biphenyl Nutrition 0.000 description 2
- 229960001561 bleomycin Drugs 0.000 description 2
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 238000010504 bond cleavage reaction Methods 0.000 description 2
- 230000005587 bubbling Effects 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 2
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 2
- 159000000007 calcium salts Chemical class 0.000 description 2
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 2
- 229940127093 camptothecin Drugs 0.000 description 2
- FAKRSMQSSFJEIM-RQJHMYQMSA-N captopril Chemical compound SC[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O FAKRSMQSSFJEIM-RQJHMYQMSA-N 0.000 description 2
- 229960000830 captopril Drugs 0.000 description 2
- FFGPTBGBLSHEPO-UHFFFAOYSA-N carbamazepine Chemical compound C1=CC2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 FFGPTBGBLSHEPO-UHFFFAOYSA-N 0.000 description 2
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
- 229960004562 carboplatin Drugs 0.000 description 2
- 210000000845 cartilage Anatomy 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 125000003636 chemical group Chemical group 0.000 description 2
- 229960004630 chlorambucil Drugs 0.000 description 2
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 2
- VDANGULDQQJODZ-UHFFFAOYSA-N chloroprocaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1Cl VDANGULDQQJODZ-UHFFFAOYSA-N 0.000 description 2
- 229960002023 chloroprocaine Drugs 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 2
- 229960001231 choline Drugs 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 229960004316 cisplatin Drugs 0.000 description 2
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 2
- 230000000295 complement effect Effects 0.000 description 2
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 2
- 239000013058 crude material Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- SNRCKKQHDUIRIY-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloromethane;dichloropalladium;iron(2+) Chemical compound [Fe+2].ClCCl.Cl[Pd]Cl.C1=C[CH-]C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.C1=C[CH-]C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 SNRCKKQHDUIRIY-UHFFFAOYSA-L 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 125000004431 deuterium atom Chemical group 0.000 description 2
- 150000004683 dihydrates Chemical class 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 230000006806 disease prevention Effects 0.000 description 2
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 229960004679 doxorubicin Drugs 0.000 description 2
- SIQPXVQCUCHWDI-UHFFFAOYSA-N enprofylline Chemical compound O=C1NC(=O)N(CCC)C2=C1NC=N2 SIQPXVQCUCHWDI-UHFFFAOYSA-N 0.000 description 2
- 229960001904 epirubicin Drugs 0.000 description 2
- 229960001433 erlotinib Drugs 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 230000029142 excretion Effects 0.000 description 2
- 229960000255 exemestane Drugs 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000010265 fast atom bombardment Methods 0.000 description 2
- 229960004177 filgrastim Drugs 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 235000019634 flavors Nutrition 0.000 description 2
- 229960000961 floxuridine Drugs 0.000 description 2
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 description 2
- 229960000390 fludarabine Drugs 0.000 description 2
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 2
- 229960002949 fluorouracil Drugs 0.000 description 2
- 229960002258 fulvestrant Drugs 0.000 description 2
- 230000005714 functional activity Effects 0.000 description 2
- 229960002584 gefitinib Drugs 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 2
- 229960005277 gemcitabine Drugs 0.000 description 2
- 238000010914 gene-directed enzyme pro-drug therapy Methods 0.000 description 2
- 229960002442 glucosamine Drugs 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- KWIUHFFTVRNATP-UHFFFAOYSA-N glycine betaine Chemical compound C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 description 2
- 230000005283 ground state Effects 0.000 description 2
- 239000003102 growth factor Substances 0.000 description 2
- 229940093915 gynecological organic acid Drugs 0.000 description 2
- 210000002216 heart Anatomy 0.000 description 2
- 229940022353 herceptin Drugs 0.000 description 2
- 210000003630 histaminocyte Anatomy 0.000 description 2
- 150000002430 hydrocarbons Chemical group 0.000 description 2
- 238000007327 hydrogenolysis reaction Methods 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 230000003832 immune regulation Effects 0.000 description 2
- 230000036039 immunity Effects 0.000 description 2
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Chemical compound OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 description 2
- 230000005445 isotope effect Effects 0.000 description 2
- 125000000842 isoxazolyl group Chemical group 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 229940043355 kinase inhibitor Drugs 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 210000004698 lymphocyte Anatomy 0.000 description 2
- 159000000003 magnesium salts Chemical class 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000002826 magnetic-activated cell sorting Methods 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- PSGAAPLEWMOORI-PEINSRQWSA-N medroxyprogesterone acetate Chemical compound C([C@@]12C)CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@](OC(C)=O)(C(C)=O)CC[C@H]21 PSGAAPLEWMOORI-PEINSRQWSA-N 0.000 description 2
- 229960002985 medroxyprogesterone acetate Drugs 0.000 description 2
- 210000003071 memory t lymphocyte Anatomy 0.000 description 2
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 2
- 229910052753 mercury Inorganic materials 0.000 description 2
- 150000002739 metals Chemical class 0.000 description 2
- 230000009401 metastasis Effects 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 150000004682 monohydrates Chemical class 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 210000000653 nervous system Anatomy 0.000 description 2
- 208000015122 neurodegenerative disease Diseases 0.000 description 2
- 229910017604 nitric acid Inorganic materials 0.000 description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 125000002971 oxazolyl group Chemical group 0.000 description 2
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- HCIILQFSFXNRJQ-UHFFFAOYSA-N phenyl N-(5-methoxy-8-phenylpyrido[3,4-b]pyrazin-3-yl)carbamate Chemical compound COC1=NC=C(C=2C1=NC(=CN=2)NC(OC1=CC=CC=C1)=O)C1=CC=CC=C1 HCIILQFSFXNRJQ-UHFFFAOYSA-N 0.000 description 2
- 235000011007 phosphoric acid Nutrition 0.000 description 2
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 2
- 230000035790 physiological processes and functions Effects 0.000 description 2
- 239000011505 plaster Substances 0.000 description 2
- 229920000768 polyamine Polymers 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 108020001213 potassium channel Proteins 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 2
- 229960004919 procaine Drugs 0.000 description 2
- 230000002062 proliferating effect Effects 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 2
- 238000011002 quantification Methods 0.000 description 2
- 125000004260 quinazolin-2-yl group Chemical group [H]C1=NC(*)=NC2=C1C([H])=C([H])C([H])=C2[H] 0.000 description 2
- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 229940044601 receptor agonist Drugs 0.000 description 2
- 239000000018 receptor agonist Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 210000000952 spleen Anatomy 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 239000011550 stock solution Substances 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 125000003107 substituted aryl group Chemical group 0.000 description 2
- 150000003460 sulfonic acids Chemical class 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 239000013589 supplement Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 230000000451 tissue damage Effects 0.000 description 2
- 231100000827 tissue damage Toxicity 0.000 description 2
- 239000003053 toxin Substances 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 239000002691 unilamellar liposome Substances 0.000 description 2
- 229960003048 vinblastine Drugs 0.000 description 2
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- BMKDZUISNHGIBY-ZETCQYMHSA-N (+)-dexrazoxane Chemical compound C([C@H](C)N1CC(=O)NC(=O)C1)N1CC(=O)NC(=O)C1 BMKDZUISNHGIBY-ZETCQYMHSA-N 0.000 description 1
- NWXMGUDVXFXRIG-WESIUVDSSA-N (4s,4as,5as,6s,12ar)-4-(dimethylamino)-1,6,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4,4a,5,5a-tetrahydrotetracene-2-carboxamide Chemical compound C1=CC=C2[C@](O)(C)[C@H]3C[C@H]4[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]4(O)C(=O)C3=C(O)C2=C1O NWXMGUDVXFXRIG-WESIUVDSSA-N 0.000 description 1
- JHMCFFPNEXMGEL-UHFFFAOYSA-N (5-methoxy-8-phenylpyrido[3,4-b]pyrazin-3-yl) 4-methylbenzenesulfonate Chemical compound CC1=CC=C(C=C1)S(=O)(=O)OC1=CN=C2C(=N1)C(=NC=C2C1=CC=CC=C1)OC JHMCFFPNEXMGEL-UHFFFAOYSA-N 0.000 description 1
- YJGVMLPVUAXIQN-LGWHJFRWSA-N (5s,5ar,8ar,9r)-5-hydroxy-9-(3,4,5-trimethoxyphenyl)-5a,6,8a,9-tetrahydro-5h-[2]benzofuro[5,6-f][1,3]benzodioxol-8-one Chemical compound COC1=C(OC)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O)[C@@H]3[C@@H]2C(OC3)=O)=C1 YJGVMLPVUAXIQN-LGWHJFRWSA-N 0.000 description 1
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 1
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 1
- LKJPYSCBVHEWIU-KRWDZBQOSA-N (R)-bicalutamide Chemical compound C([C@@](O)(C)C(=O)NC=1C=C(C(C#N)=CC=1)C(F)(F)F)S(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-KRWDZBQOSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 1
- 125000005919 1,2,2-trimethylpropyl group Chemical group 0.000 description 1
- SPZCXVPOFSVCFS-UHFFFAOYSA-N 1,2-dichloroethane;tetrachloromethane Chemical compound ClCCCl.ClC(Cl)(Cl)Cl SPZCXVPOFSVCFS-UHFFFAOYSA-N 0.000 description 1
- GEYOCULIXLDCMW-UHFFFAOYSA-N 1,2-phenylenediamine Chemical compound NC1=CC=CC=C1N GEYOCULIXLDCMW-UHFFFAOYSA-N 0.000 description 1
- VDFVNEFVBPFDSB-UHFFFAOYSA-N 1,3-dioxane Chemical compound C1COCOC1 VDFVNEFVBPFDSB-UHFFFAOYSA-N 0.000 description 1
- HPARLNRMYDSBNO-UHFFFAOYSA-N 1,4-benzodioxine Chemical compound C1=CC=C2OC=COC2=C1 HPARLNRMYDSBNO-UHFFFAOYSA-N 0.000 description 1
- HJTAZXHBEBIQQX-UHFFFAOYSA-N 1,5-bis(chloromethyl)naphthalene Chemical compound C1=CC=C2C(CCl)=CC=CC2=C1CCl HJTAZXHBEBIQQX-UHFFFAOYSA-N 0.000 description 1
- PAJRLOFUBZXVOC-UHFFFAOYSA-N 1-(1,5-dipropylcyclohexa-2,4-dien-1-yl)-2,6-dioxo-3,7-dihydropurine-8-sulfonic acid Chemical compound C1C(CCC)=CC=CC1(CCC)N1C(=O)C(NC(=N2)S(O)(=O)=O)=C2NC1=O PAJRLOFUBZXVOC-UHFFFAOYSA-N 0.000 description 1
- BMUGOSJLZCHJKW-UHFFFAOYSA-N 1-(2-methoxyethyl)pyrazole-4-carboxylic acid Chemical compound COCCN1C=C(C(O)=O)C=N1 BMUGOSJLZCHJKW-UHFFFAOYSA-N 0.000 description 1
- KCOBIBRGPCFIGF-UHFFFAOYSA-N 1-bromo-4-methoxy-2-nitrobenzene Chemical compound COC1=CC=C(Br)C([N+]([O-])=O)=C1 KCOBIBRGPCFIGF-UHFFFAOYSA-N 0.000 description 1
- 125000006218 1-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- DFPYXQYWILNVAU-UHFFFAOYSA-N 1-hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1.C1=CC=C2N(O)N=NC2=C1 DFPYXQYWILNVAU-UHFFFAOYSA-N 0.000 description 1
- PJUPKRYGDFTMTM-UHFFFAOYSA-N 1-hydroxybenzotriazole;hydrate Chemical compound O.C1=CC=C2N(O)N=NC2=C1 PJUPKRYGDFTMTM-UHFFFAOYSA-N 0.000 description 1
- OIGDISKECPMPBN-UHFFFAOYSA-N 1-methoxy-2,3-dinitrobenzene Chemical compound COC1=CC=CC([N+]([O-])=O)=C1[N+]([O-])=O OIGDISKECPMPBN-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
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001462 1-pyrrolyl group Chemical class [*]N1C([H])=C([H])C([H])=C1[H] 0.000 description 1
- ABEXEQSGABRUHS-UHFFFAOYSA-N 16-methylheptadecyl 16-methylheptadecanoate Chemical compound CC(C)CCCCCCCCCCCCCCCOC(=O)CCCCCCCCCCCCCCC(C)C ABEXEQSGABRUHS-UHFFFAOYSA-N 0.000 description 1
- NHBKXEKEPDILRR-UHFFFAOYSA-N 2,3-bis(butanoylsulfanyl)propyl butanoate Chemical compound CCCC(=O)OCC(SC(=O)CCC)CSC(=O)CCC NHBKXEKEPDILRR-UHFFFAOYSA-N 0.000 description 1
- JKTCBAGSMQIFNL-UHFFFAOYSA-N 2,3-dihydrofuran Chemical compound C1CC=CO1 JKTCBAGSMQIFNL-UHFFFAOYSA-N 0.000 description 1
- VEPOHXYIFQMVHW-XOZOLZJESA-N 2,3-dihydroxybutanedioic acid (2S,3S)-3,4-dimethyl-2-phenylmorpholine Chemical compound OC(C(O)C(O)=O)C(O)=O.C[C@H]1[C@@H](OCCN1C)c1ccccc1 VEPOHXYIFQMVHW-XOZOLZJESA-N 0.000 description 1
- 125000001917 2,4-dinitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C(=C1*)[N+]([O-])=O)[N+]([O-])=O 0.000 description 1
- TXQPXJKRNHJWAX-UHFFFAOYSA-N 2-(3-aminopropylamino)ethylsulfanylphosphonic acid;trihydrate Chemical compound O.O.O.NCCCNCCSP(O)(O)=O TXQPXJKRNHJWAX-UHFFFAOYSA-N 0.000 description 1
- OXQGTIUCKGYOAA-UHFFFAOYSA-N 2-Ethylbutanoic acid Chemical compound CCC(CC)C(O)=O OXQGTIUCKGYOAA-UHFFFAOYSA-N 0.000 description 1
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
- CDAWCLOXVUBKRW-UHFFFAOYSA-N 2-aminophenol Chemical compound NC1=CC=CC=C1O CDAWCLOXVUBKRW-UHFFFAOYSA-N 0.000 description 1
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical compound CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 description 1
- 229940013085 2-diethylaminoethanol Drugs 0.000 description 1
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
- WAVYAFBQOXCGSZ-UHFFFAOYSA-N 2-fluoropyrimidine Chemical compound FC1=NC=CC=N1 WAVYAFBQOXCGSZ-UHFFFAOYSA-N 0.000 description 1
- 125000002941 2-furyl group Chemical class O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- GUPGZURVZDIQPM-UHFFFAOYSA-N 2-oxoethyl acetate Chemical compound CC(=O)OCC=O GUPGZURVZDIQPM-UHFFFAOYSA-N 0.000 description 1
- KSXDGNGBGPLXEI-UHFFFAOYSA-N 2-phenylpyridine-3,4-diamine Chemical compound NC1=CC=NC(C=2C=CC=CC=2)=C1N KSXDGNGBGPLXEI-UHFFFAOYSA-N 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000004485 2-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])C1([H])* 0.000 description 1
- RSEBUVRVKCANEP-UHFFFAOYSA-N 2-pyrroline Chemical compound C1CC=CN1 RSEBUVRVKCANEP-UHFFFAOYSA-N 0.000 description 1
- 125000000389 2-pyrrolyl group Chemical class [H]N1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000175 2-thienyl group Chemical class S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- ZSLUVFAKFWKJRC-IGMARMGPSA-N 232Th Chemical compound [232Th] ZSLUVFAKFWKJRC-IGMARMGPSA-N 0.000 description 1
- PFEOZHBOMNWTJB-UHFFFAOYSA-N 3 MP Natural products CCC(C)CC PFEOZHBOMNWTJB-UHFFFAOYSA-N 0.000 description 1
- NDMPLJNOPCLANR-UHFFFAOYSA-N 3,4-dihydroxy-15-(4-hydroxy-18-methoxycarbonyl-5,18-seco-ibogamin-18-yl)-16-methoxy-1-methyl-6,7-didehydro-aspidospermidine-3-carboxylic acid methyl ester Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 NDMPLJNOPCLANR-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 125000003682 3-furyl group Chemical class O1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 125000006482 3-iodobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(I)=C1[H])C([H])([H])* 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001397 3-pyrrolyl group Chemical class [H]N1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 125000001541 3-thienyl group Chemical class S1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- IWALGNIFYOBRKC-UHFFFAOYSA-N 4-(2,6-dioxo-1,3-dipropyl-7h-purin-8-yl)benzenesulfonic acid Chemical compound N1C=2C(=O)N(CCC)C(=O)N(CCC)C=2N=C1C1=CC=C(S(O)(=O)=O)C=C1 IWALGNIFYOBRKC-UHFFFAOYSA-N 0.000 description 1
- NLTIETZTDSJANS-UHFFFAOYSA-N 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC=NC=C1 NLTIETZTDSJANS-UHFFFAOYSA-N 0.000 description 1
- AKJHMTWEGVYYSE-AIRMAKDCSA-N 4-HPR Chemical compound C=1C=C(O)C=CC=1NC(=O)/C=C(\C)/C=C/C=C(C)C=CC1=C(C)CCCC1(C)C AKJHMTWEGVYYSE-AIRMAKDCSA-N 0.000 description 1
- PWTBZOIUWZOPFT-UHFFFAOYSA-N 4-[2-[[7-amino-2-(2-furanyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-yl]amino]ethyl]phenol Chemical compound N=1C2=NC(C=3OC=CC=3)=NN2C(N)=NC=1NCCC1=CC=C(O)C=C1 PWTBZOIUWZOPFT-UHFFFAOYSA-N 0.000 description 1
- PLXYHOBIHWLDSZ-UHFFFAOYSA-N 4-[6-amino-9-methyl-8-(triazol-2-yl)purin-2-yl]butan-2-one Chemical compound CN1C2=NC(CCC(=O)C)=NC(N)=C2N=C1N1N=CC=N1 PLXYHOBIHWLDSZ-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- HVCNXQOWACZAFN-UHFFFAOYSA-N 4-ethylmorpholine Chemical compound CCN1CCOCC1 HVCNXQOWACZAFN-UHFFFAOYSA-N 0.000 description 1
- SGOOQMRIPALTEL-UHFFFAOYSA-N 4-hydroxy-N,1-dimethyl-2-oxo-N-phenyl-3-quinolinecarboxamide Chemical compound OC=1C2=CC=CC=C2N(C)C(=O)C=1C(=O)N(C)C1=CC=CC=C1 SGOOQMRIPALTEL-UHFFFAOYSA-N 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- KDDQRKBRJSGMQE-UHFFFAOYSA-N 4-thiazolyl Chemical compound [C]1=CSC=N1 KDDQRKBRJSGMQE-UHFFFAOYSA-N 0.000 description 1
- 125000004539 5-benzimidazolyl group Chemical group N1=CNC2=C1C=CC(=C2)* 0.000 description 1
- ZHUHTAKLCNHPCS-UHFFFAOYSA-N 5-bromo-2-methoxy-3-nitropyridin-4-amine Chemical compound COC1=NC=C(Br)C(N)=C1[N+]([O-])=O ZHUHTAKLCNHPCS-UHFFFAOYSA-N 0.000 description 1
- IMLRJDYBLVFLRP-UHFFFAOYSA-N 5-bromo-2-methoxypyridin-4-amine Chemical compound COC1=CC(N)=C(Br)C=N1 IMLRJDYBLVFLRP-UHFFFAOYSA-N 0.000 description 1
- CWDWFSXUQODZGW-UHFFFAOYSA-N 5-thiazolyl Chemical group [C]1=CN=CS1 CWDWFSXUQODZGW-UHFFFAOYSA-N 0.000 description 1
- QGXBDMJGAMFCBF-HLUDHZFRSA-N 5α-Androsterone Chemical compound C1[C@H](O)CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC[C@H]21 QGXBDMJGAMFCBF-HLUDHZFRSA-N 0.000 description 1
- NCWQLHHDGDXIJN-UHFFFAOYSA-N 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine Chemical compound ClC1=NC(C)=CC(C=2C(=NC(N)=NN=2)C=2C=CC(F)=CC=2)=C1 NCWQLHHDGDXIJN-UHFFFAOYSA-N 0.000 description 1
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 1
- PFWLFWPASULGAN-UHFFFAOYSA-N 7-methylxanthine Chemical compound N1C(=O)NC(=O)C2=C1N=CN2C PFWLFWPASULGAN-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- MHUQGIMGNNMPLF-UHFFFAOYSA-N 8-(1,5-diethylcyclohexa-2,4-dien-1-yl)-3,7-dihydropurine-2,6-dione Chemical compound C(C)C1(CC(=CC=C1)CC)C1=NC=2NC(NC(C=2N1)=O)=O MHUQGIMGNNMPLF-UHFFFAOYSA-N 0.000 description 1
- MSJODEOZODDVGW-UHFFFAOYSA-N 9-chloro-2-(2-furanyl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine Chemical compound N=1N2C(N)=NC3=CC=C(Cl)C=C3C2=NC=1C1=CC=CO1 MSJODEOZODDVGW-UHFFFAOYSA-N 0.000 description 1
- SHGAZHPCJJPHSC-ZVCIMWCZSA-N 9-cis-retinoic acid Chemical compound OC(=O)/C=C(\C)/C=C/C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-ZVCIMWCZSA-N 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 1
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 1
- 229930195573 Amycin Natural products 0.000 description 1
- 102000012936 Angiostatins Human genes 0.000 description 1
- 108010079709 Angiostatins Proteins 0.000 description 1
- 108020000948 Antisense Oligonucleotides Proteins 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 108091023037 Aptamer Proteins 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 102000015790 Asparaginase Human genes 0.000 description 1
- 108010024976 Asparaginase Proteins 0.000 description 1
- 108010011485 Aspartame Proteins 0.000 description 1
- 206010003658 Atrial Fibrillation Diseases 0.000 description 1
- 102000036365 BRCA1 Human genes 0.000 description 1
- 108700020463 BRCA1 Proteins 0.000 description 1
- 101150072950 BRCA1 gene Proteins 0.000 description 1
- 102000052609 BRCA2 Human genes 0.000 description 1
- 108700020462 BRCA2 Proteins 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 108700031361 Brachyury Proteins 0.000 description 1
- 101150008921 Brca2 gene Proteins 0.000 description 1
- 102100025399 Breast cancer type 2 susceptibility protein Human genes 0.000 description 1
- 108010037003 Buserelin Proteins 0.000 description 1
- CRLLPIHNGPMVEI-UHFFFAOYSA-N C(=CC)NC=1C=C2C(=NC=NC2=CC1OCCCN1CCOCC1)NC1=CC(=C(C=C1)F)Cl Chemical compound C(=CC)NC=1C=C2C(=NC=NC2=CC1OCCCN1CCOCC1)NC1=CC(=C(C=C1)F)Cl CRLLPIHNGPMVEI-UHFFFAOYSA-N 0.000 description 1
- NYHLRBMDXQBOIB-UHFFFAOYSA-N CC(C)OC(=O)C1=C(C)NC2=NC3=CC=CC=C3N2C1C1=CC=CO1 Chemical compound CC(C)OC(=O)C1=C(C)NC2=NC3=CC=CC=C3N2C1C1=CC=CO1 NYHLRBMDXQBOIB-UHFFFAOYSA-N 0.000 description 1
- 241000282465 Canis Species 0.000 description 1
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 description 1
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-NJFSPNSNSA-N Carbon-14 Chemical compound [14C] OKTJSMMVPCPJKN-NJFSPNSNSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 1
- 206010007710 Cartilage injury Diseases 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- 102000000844 Cell Surface Receptors Human genes 0.000 description 1
- 108010001857 Cell Surface Receptors Proteins 0.000 description 1
- 229920001661 Chitosan Polymers 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- PTOAARAWEBMLNO-KVQBGUIXSA-N Cladribine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 PTOAARAWEBMLNO-KVQBGUIXSA-N 0.000 description 1
- RGJOEKWQDUBAIZ-IBOSZNHHSA-N CoASH Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCS)O[C@H]1N1C2=NC=NC(N)=C2N=C1 RGJOEKWQDUBAIZ-IBOSZNHHSA-N 0.000 description 1
- 108010065152 Coagulase Proteins 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 241001517041 Corynebacterium jeikeium Species 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- 102000002004 Cytochrome P-450 Enzyme System Human genes 0.000 description 1
- 108010015742 Cytochrome P-450 Enzyme System Proteins 0.000 description 1
- 102000000311 Cytosine Deaminase Human genes 0.000 description 1
- 108010080611 Cytosine Deaminase Proteins 0.000 description 1
- IGXWBGJHJZYPQS-SSDOTTSWSA-N D-Luciferin Chemical compound OC(=O)[C@H]1CSC(C=2SC3=CC=C(O)C=C3N=2)=N1 IGXWBGJHJZYPQS-SSDOTTSWSA-N 0.000 description 1
- 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 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- 239000003155 DNA primer Substances 0.000 description 1
- FFBDFADSZUINTG-UHFFFAOYSA-N DPCPX Chemical compound N1C=2C(=O)N(CCC)C(=O)N(CCC)C=2N=C1C1CCCC1 FFBDFADSZUINTG-UHFFFAOYSA-N 0.000 description 1
- 108010092160 Dactinomycin Proteins 0.000 description 1
- CYCGRDQQIOGCKX-UHFFFAOYSA-N Dehydro-luciferin Natural products OC(=O)C1=CSC(C=2SC3=CC(O)=CC=C3N=2)=N1 CYCGRDQQIOGCKX-UHFFFAOYSA-N 0.000 description 1
- SUZLHDUTVMZSEV-UHFFFAOYSA-N Deoxycoleonol Natural products C12C(=O)CC(C)(C=C)OC2(C)C(OC(=O)C)C(O)C2C1(C)C(O)CCC2(C)C SUZLHDUTVMZSEV-UHFFFAOYSA-N 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- ZQZFYGIXNQKOAV-OCEACIFDSA-N Droloxifene Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=C(O)C=CC=1)\C1=CC=C(OCCN(C)C)C=C1 ZQZFYGIXNQKOAV-OCEACIFDSA-N 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 102400001047 Endostatin Human genes 0.000 description 1
- 108010079505 Endostatins Proteins 0.000 description 1
- 241000194033 Enterococcus Species 0.000 description 1
- 241001468179 Enterococcus avium Species 0.000 description 1
- 102400001368 Epidermal growth factor Human genes 0.000 description 1
- 101800003838 Epidermal growth factor Proteins 0.000 description 1
- QGXBDMJGAMFCBF-UHFFFAOYSA-N Etiocholanolone Natural products C1C(O)CCC2(C)C3CCC(C)(C(CC4)=O)C4C3CCC21 QGXBDMJGAMFCBF-UHFFFAOYSA-N 0.000 description 1
- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical compound [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 description 1
- VTLYFUHAOXGGBS-UHFFFAOYSA-N Fe3+ Chemical class [Fe+3] VTLYFUHAOXGGBS-UHFFFAOYSA-N 0.000 description 1
- BJGNCJDXODQBOB-UHFFFAOYSA-N Fivefly Luciferin Natural products OC(=O)C1CSC(C=2SC3=CC(O)=CC=C3N=2)=N1 BJGNCJDXODQBOB-UHFFFAOYSA-N 0.000 description 1
- 208000022072 Gallbladder Neoplasms Diseases 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 102000034354 Gi proteins Human genes 0.000 description 1
- 108091006101 Gi proteins Proteins 0.000 description 1
- 239000004366 Glucose oxidase Substances 0.000 description 1
- 108010015776 Glucose oxidase Proteins 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 108010069236 Goserelin Proteins 0.000 description 1
- BLCLNMBMMGCOAS-URPVMXJPSA-N Goserelin Chemical compound C([C@@H](C(=O)N[C@H](COC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(=O)NNC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 BLCLNMBMMGCOAS-URPVMXJPSA-N 0.000 description 1
- 102000009465 Growth Factor Receptors Human genes 0.000 description 1
- 108010009202 Growth Factor Receptors Proteins 0.000 description 1
- 108090000100 Hepatocyte Growth Factor Proteins 0.000 description 1
- 102100021866 Hepatocyte growth factor Human genes 0.000 description 1
- 241001272567 Hominoidea Species 0.000 description 1
- 101000582950 Homo sapiens Platelet factor 4 Proteins 0.000 description 1
- 101000904173 Homo sapiens Progonadoliberin-1 Proteins 0.000 description 1
- 101001117317 Homo sapiens Programmed cell death 1 ligand 1 Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 description 1
- 208000004454 Hyperalgesia Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 1
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 description 1
- WRYCSMQKUKOKBP-UHFFFAOYSA-N Imidazolidine Chemical compound C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 description 1
- 102000013462 Interleukin-12 Human genes 0.000 description 1
- 108010065805 Interleukin-12 Proteins 0.000 description 1
- 102000004388 Interleukin-4 Human genes 0.000 description 1
- 108090000978 Interleukin-4 Proteins 0.000 description 1
- 241000764238 Isis Species 0.000 description 1
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 1
- SHGAZHPCJJPHSC-NUEINMDLSA-N Isotretinoin Chemical compound OC(=O)C=C(C)/C=C/C=C(C)C=CC1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-NUEINMDLSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 1
- UTLPKQYUXOEJIL-UHFFFAOYSA-N LSM-3822 Chemical compound N1=CC=2C3=NC(C=4OC=CC=4)=NN3C(N)=NC=2N1CCC1=CC=CC=C1 UTLPKQYUXOEJIL-UHFFFAOYSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 239000004166 Lanolin Substances 0.000 description 1
- 229930192956 Lavendustin Natural products 0.000 description 1
- 108010000817 Leuprolide Proteins 0.000 description 1
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 1
- DDWFXDSYGUXRAY-UHFFFAOYSA-N Luciferin Natural products CCc1c(C)c(CC2NC(=O)C(=C2C=C)C)[nH]c1Cc3[nH]c4C(=C5/NC(CC(=O)O)C(C)C5CC(=O)O)CC(=O)c4c3C DDWFXDSYGUXRAY-UHFFFAOYSA-N 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 229940124041 Luteinizing hormone releasing hormone (LHRH) antagonist Drugs 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- WAEMQWOKJMHJLA-UHFFFAOYSA-N Manganese(2+) Chemical class [Mn+2] WAEMQWOKJMHJLA-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229920003091 Methocel™ Polymers 0.000 description 1
- ONXPDKGXOOORHB-BYPYZUCNSA-N N(5)-methyl-L-glutamine Chemical compound CNC(=O)CC[C@H](N)C(O)=O ONXPDKGXOOORHB-BYPYZUCNSA-N 0.000 description 1
- AJBBEYXFRYFVNM-UHFFFAOYSA-N N-(4-cyanophenyl)-2-[4-(2,6-dioxo-1,3-dipropyl-7H-purin-8-yl)phenoxy]acetamide Chemical compound N1C=2C(=O)N(CCC)C(=O)N(CCC)C=2N=C1C(C=C1)=CC=C1OCC(=O)NC1=CC=C(C#N)C=C1 AJBBEYXFRYFVNM-UHFFFAOYSA-N 0.000 description 1
- UEEJHVSXFDXPFK-UHFFFAOYSA-N N-dimethylaminoethanol Chemical compound CN(C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-N 0.000 description 1
- HTLZVHNRZJPSMI-UHFFFAOYSA-N N-ethylpiperidine Chemical compound CCN1CCCCC1 HTLZVHNRZJPSMI-UHFFFAOYSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- FIWILGQIZHDAQG-UHFFFAOYSA-N NC1=C(C(=O)NCC2=CC=C(C=C2)OCC(F)(F)F)C=C(C(=N1)N)N1N=C(N=C1)C1(CC1)C(F)(F)F Chemical compound NC1=C(C(=O)NCC2=CC=C(C=C2)OCC(F)(F)F)C=C(C(=N1)N)N1N=C(N=C1)C1(CC1)C(F)(F)F FIWILGQIZHDAQG-UHFFFAOYSA-N 0.000 description 1
- 238000012565 NMR experiment Methods 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- 102000004459 Nitroreductase Human genes 0.000 description 1
- MSHZHSPISPJWHW-UHFFFAOYSA-N O-(chloroacetylcarbamoyl)fumagillol Chemical compound O1C(CC=C(C)C)C1(C)C1C(OC)C(OC(=O)NC(=O)CCl)CCC21CO2 MSHZHSPISPJWHW-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- OZSRBVWTNPCLNR-UHFFFAOYSA-N OOB(OO)C1=CC=CC=C1 Chemical compound OOB(OO)C1=CC=CC=C1 OZSRBVWTNPCLNR-UHFFFAOYSA-N 0.000 description 1
- REYJJPSVUYRZGE-UHFFFAOYSA-N Octadecylamine Chemical compound CCCCCCCCCCCCCCCCCCN REYJJPSVUYRZGE-UHFFFAOYSA-N 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 108090000854 Oxidoreductases Proteins 0.000 description 1
- 102000004316 Oxidoreductases Human genes 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 239000004264 Petrolatum Substances 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 108010038512 Platelet-Derived Growth Factor Proteins 0.000 description 1
- 102000010780 Platelet-Derived Growth Factor Human genes 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229920000604 Polyethylene Glycol 200 Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920001710 Polyorthoester Polymers 0.000 description 1
- 229920000388 Polyphosphate Polymers 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 102100024028 Progonadoliberin-1 Human genes 0.000 description 1
- 102100024216 Programmed cell death 1 ligand 1 Human genes 0.000 description 1
- 208000001431 Psychomotor Agitation Diseases 0.000 description 1
- 239000012979 RPMI medium Substances 0.000 description 1
- 206010038743 Restlessness Diseases 0.000 description 1
- XZQYTGKSBZGQMO-UHFFFAOYSA-I Rhenium(V) chloride Inorganic materials Cl[Re](Cl)(Cl)(Cl)Cl XZQYTGKSBZGQMO-UHFFFAOYSA-I 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 206010039897 Sedation Diseases 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 108020004459 Small interfering RNA Proteins 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 241000191963 Staphylococcus epidermidis Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 244000057717 Streptococcus lactis Species 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 235000019486 Sunflower oil Nutrition 0.000 description 1
- 101000996723 Sus scrofa Gonadotropin-releasing hormone receptor Proteins 0.000 description 1
- 238000006069 Suzuki reaction reaction Methods 0.000 description 1
- 230000006044 T cell activation Effects 0.000 description 1
- 230000005867 T cell response Effects 0.000 description 1
- NAVMQTYZDKMPEU-UHFFFAOYSA-N Targretin Chemical compound CC1=CC(C(CCC2(C)C)(C)C)=C2C=C1C(=C)C1=CC=C(C(O)=O)C=C1 NAVMQTYZDKMPEU-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 229940123237 Taxane Drugs 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- 229910052776 Thorium Inorganic materials 0.000 description 1
- 102000002938 Thrombospondin Human genes 0.000 description 1
- 108060008245 Thrombospondin Proteins 0.000 description 1
- IVTVGDXNLFLDRM-HNNXBMFYSA-N Tomudex Chemical compound C=1C=C2NC(C)=NC(=O)C2=CC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)S1 IVTVGDXNLFLDRM-HNNXBMFYSA-N 0.000 description 1
- 101710120037 Toxin CcdB Proteins 0.000 description 1
- XNBRWUQWSKXMPW-UHFFFAOYSA-N Tozadenant Chemical compound C1=2SC(NC(=O)N3CCC(C)(O)CC3)=NC=2C(OC)=CC=C1N1CCOCC1 XNBRWUQWSKXMPW-UHFFFAOYSA-N 0.000 description 1
- 206010052779 Transplant rejections Diseases 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical group ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- 108010042352 Urokinase Plasminogen Activator Receptors Proteins 0.000 description 1
- 102000004504 Urokinase Plasminogen Activator Receptors Human genes 0.000 description 1
- 229940122803 Vinca alkaloid Drugs 0.000 description 1
- MMWCIQZXVOZEGG-HOZKJCLWSA-N [(1S,2R,3S,4S,5R,6S)-2,3,5-trihydroxy-4,6-diphosphonooxycyclohexyl] dihydrogen phosphate Chemical compound O[C@H]1[C@@H](O)[C@H](OP(O)(O)=O)[C@@H](OP(O)(O)=O)[C@H](O)[C@H]1OP(O)(O)=O MMWCIQZXVOZEGG-HOZKJCLWSA-N 0.000 description 1
- WFIHKLWVLPBMIQ-UHFFFAOYSA-N [1,3]thiazolo[5,4-b]pyridine Chemical compound C1=CN=C2SC=NC2=C1 WFIHKLWVLPBMIQ-UHFFFAOYSA-N 0.000 description 1
- GHVZOJONCUEWAV-UHFFFAOYSA-N [K].CCO Chemical compound [K].CCO GHVZOJONCUEWAV-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 229940022663 acetate Drugs 0.000 description 1
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000002730 additional effect Effects 0.000 description 1
- UDMBCSSLTHHNCD-KQYNXXCUSA-N adenosine 5'-monophosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H]1O UDMBCSSLTHHNCD-KQYNXXCUSA-N 0.000 description 1
- 229940009456 adriamycin Drugs 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 108700025316 aldesleukin Proteins 0.000 description 1
- 229960005310 aldesleukin Drugs 0.000 description 1
- 229960000548 alemtuzumab Drugs 0.000 description 1
- 229960001445 alitretinoin Drugs 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 206010053552 allodynia Diseases 0.000 description 1
- 229960003459 allopurinol Drugs 0.000 description 1
- OFCNXPDARWKPPY-UHFFFAOYSA-N allopurinol Chemical compound OC1=NC=NC2=C1C=NN2 OFCNXPDARWKPPY-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229960000473 altretamine Drugs 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001409 amidines Chemical class 0.000 description 1
- 229960001097 amifostine Drugs 0.000 description 1
- 150000005010 aminoquinolines Chemical class 0.000 description 1
- XCPGHVQEEXUHNC-UHFFFAOYSA-N amsacrine Chemical compound COC1=CC(NS(C)(=O)=O)=CC=C1NC1=C(C=CC=C2)C2=NC2=CC=CC=C12 XCPGHVQEEXUHNC-UHFFFAOYSA-N 0.000 description 1
- 229960001220 amsacrine Drugs 0.000 description 1
- 229940061641 androsterone Drugs 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 229940045799 anthracyclines and related substance Drugs 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000002280 anti-androgenic effect Effects 0.000 description 1
- 230000001772 anti-angiogenic effect Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 230000003172 anti-dna Effects 0.000 description 1
- 229940046836 anti-estrogen Drugs 0.000 description 1
- 230000001833 anti-estrogenic effect Effects 0.000 description 1
- 230000003432 anti-folate effect Effects 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 230000005809 anti-tumor immunity Effects 0.000 description 1
- 239000000051 antiandrogen Substances 0.000 description 1
- 229940030495 antiandrogen sex hormone and modulator of the genital system Drugs 0.000 description 1
- 229940127074 antifolate Drugs 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 239000000074 antisense oligonucleotide Substances 0.000 description 1
- 238000012230 antisense oligonucleotides Methods 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000013011 aqueous formulation Substances 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- OIRDTQYFTABQOQ-UHFFFAOYSA-N ara-adenosine Natural products Nc1ncnc2n(cnc12)C1OC(CO)C(O)C1O OIRDTQYFTABQOQ-UHFFFAOYSA-N 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 229960003121 arginine Drugs 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 239000003886 aromatase inhibitor Substances 0.000 description 1
- 229940046844 aromatase inhibitors Drugs 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- GOLCXWYRSKYTSP-UHFFFAOYSA-N arsenic trioxide Inorganic materials O1[As]2O[As]1O2 GOLCXWYRSKYTSP-UHFFFAOYSA-N 0.000 description 1
- 229960002594 arsenic trioxide Drugs 0.000 description 1
- 210000001188 articular cartilage Anatomy 0.000 description 1
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 229960003272 asparaginase Drugs 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-M asparaginate Chemical compound [O-]C(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-M 0.000 description 1
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- 229960003438 aspartame Drugs 0.000 description 1
- FZCSTZYAHCUGEM-UHFFFAOYSA-N aspergillomarasmine B Natural products OC(=O)CNC(C(O)=O)CNC(C(O)=O)CC(O)=O FZCSTZYAHCUGEM-UHFFFAOYSA-N 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 230000005784 autoimmunity Effects 0.000 description 1
- DCBDOYDVQJVXOH-UHFFFAOYSA-N azane;1h-indole Chemical compound N.C1=CC=C2NC=CC2=C1 DCBDOYDVQJVXOH-UHFFFAOYSA-N 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- LFYJSSARVMHQJB-QIXNEVBVSA-N bakuchiol Chemical compound CC(C)=CCC[C@@](C)(C=C)\C=C\C1=CC=C(O)C=C1 LFYJSSARVMHQJB-QIXNEVBVSA-N 0.000 description 1
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 1
- 229910001863 barium hydroxide Inorganic materials 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- XFILPEOLDIKJHX-QYZOEREBSA-N batimastat Chemical compound C([C@@H](C(=O)NC)NC(=O)[C@H](CC(C)C)[C@H](CSC=1SC=CC=1)C(=O)NO)C1=CC=CC=C1 XFILPEOLDIKJHX-QYZOEREBSA-N 0.000 description 1
- 229950001858 batimastat Drugs 0.000 description 1
- OZKIMYLEHNQVTI-UHFFFAOYSA-N benzene;carbonochloridic acid Chemical compound OC(Cl)=O.C1=CC=CC=C1 OZKIMYLEHNQVTI-UHFFFAOYSA-N 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000005874 benzothiadiazolyl group Chemical group 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 102000005936 beta-Galactosidase Human genes 0.000 description 1
- 108010005774 beta-Galactosidase Proteins 0.000 description 1
- 229960003237 betaine Drugs 0.000 description 1
- 229960002938 bexarotene Drugs 0.000 description 1
- 229960000997 bicalutamide Drugs 0.000 description 1
- 238000011325 biochemical measurement Methods 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 150000004074 biphenyls Chemical class 0.000 description 1
- 229920001400 block copolymer Polymers 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- LHHCSNFAOIFYRV-DOVBMPENSA-N boceprevir Chemical compound O=C([C@@H]1[C@@H]2[C@@H](C2(C)C)CN1C(=O)[C@@H](NC(=O)NC(C)(C)C)C(C)(C)C)NC(C(=O)C(N)=O)CC1CCC1 LHHCSNFAOIFYRV-DOVBMPENSA-N 0.000 description 1
- 238000006664 bond formation reaction Methods 0.000 description 1
- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 description 1
- 229960001467 bortezomib Drugs 0.000 description 1
- 230000006931 brain damage Effects 0.000 description 1
- 231100000874 brain damage Toxicity 0.000 description 1
- 208000029028 brain injury Diseases 0.000 description 1
- CUWODFFVMXJOKD-UVLQAERKSA-N buserelin Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](COC(C)(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 CUWODFFVMXJOKD-UVLQAERKSA-N 0.000 description 1
- 229960002719 buserelin Drugs 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 230000001593 cAMP accumulation Effects 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 229950009823 calusterone Drugs 0.000 description 1
- IVFYLRMMHVYGJH-PVPPCFLZSA-N calusterone Chemical compound C1C[C@]2(C)[C@](O)(C)CC[C@H]2[C@@H]2[C@@H](C)CC3=CC(=O)CC[C@]3(C)[C@H]21 IVFYLRMMHVYGJH-PVPPCFLZSA-N 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 230000009400 cancer invasion Effects 0.000 description 1
- OMZCMEYTWSXEPZ-UHFFFAOYSA-N canertinib Chemical compound C1=C(Cl)C(F)=CC=C1NC1=NC=NC2=CC(OCCCN3CCOCC3)=C(NC(=O)C=C)C=C12 OMZCMEYTWSXEPZ-UHFFFAOYSA-N 0.000 description 1
- 229950002826 canertinib Drugs 0.000 description 1
- 229960004117 capecitabine Drugs 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 229940045200 cardioprotective agent Drugs 0.000 description 1
- 239000012659 cardioprotective agent Substances 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 229960005243 carmustine Drugs 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 229960000590 celecoxib Drugs 0.000 description 1
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 229960005395 cetuximab Drugs 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- OGEBRHQLRGFBNV-RZDIXWSQSA-N chembl2036808 Chemical class C12=NC(NCCCC)=NC=C2C(C=2C=CC(F)=CC=2)=NN1C[C@H]1CC[C@H](N)CC1 OGEBRHQLRGFBNV-RZDIXWSQSA-N 0.000 description 1
- 210000000038 chest Anatomy 0.000 description 1
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 1
- USJRLGNYCQWLPF-UHFFFAOYSA-N chlorophosphane Chemical compound ClP USJRLGNYCQWLPF-UHFFFAOYSA-N 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- VDHAWDNDOKGFTD-MRXNPFEDSA-N cinacalcet Chemical compound N([C@H](C)C=1C2=CC=CC=C2C=CC=1)CCCC1=CC=CC(C(F)(F)F)=C1 VDHAWDNDOKGFTD-MRXNPFEDSA-N 0.000 description 1
- 229960003315 cinacalcet Drugs 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 229960002436 cladribine Drugs 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- 235000012716 cod liver oil Nutrition 0.000 description 1
- 239000003026 cod liver oil Substances 0.000 description 1
- RGJOEKWQDUBAIZ-UHFFFAOYSA-N coenzime A Natural products OC1C(OP(O)(O)=O)C(COP(O)(=O)OP(O)(=O)OCC(C)(C)C(O)C(=O)NCCC(=O)NCCS)OC1N1C2=NC=NC(N)=C2N=C1 RGJOEKWQDUBAIZ-UHFFFAOYSA-N 0.000 description 1
- 239000005515 coenzyme Substances 0.000 description 1
- 239000005516 coenzyme A Substances 0.000 description 1
- 229940093530 coenzyme a Drugs 0.000 description 1
- 230000001149 cognitive effect Effects 0.000 description 1
- OHCQJHSOBUTRHG-UHFFFAOYSA-N colforsin Natural products OC12C(=O)CC(C)(C=C)OC1(C)C(OC(=O)C)C(O)C1C2(C)C(O)CCC1(C)C OHCQJHSOBUTRHG-UHFFFAOYSA-N 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 150000001879 copper Chemical class 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 229960000684 cytarabine Drugs 0.000 description 1
- 230000016396 cytokine production Effects 0.000 description 1
- 239000000430 cytokine receptor antagonist Substances 0.000 description 1
- 239000000824 cytostatic agent Substances 0.000 description 1
- 230000001085 cytostatic effect Effects 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 229960003901 dacarbazine Drugs 0.000 description 1
- 229960000640 dactinomycin Drugs 0.000 description 1
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 1
- 229960000975 daunorubicin Drugs 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 210000004443 dendritic cell Anatomy 0.000 description 1
- 229960002923 denileukin diftitox Drugs 0.000 description 1
- 108010017271 denileukin diftitox Proteins 0.000 description 1
- CFCUWKMKBJTWLW-UHFFFAOYSA-N deoliosyl-3C-alpha-L-digitoxosyl-MTM Natural products CC=1C(O)=C2C(O)=C3C(=O)C(OC4OC(C)C(O)C(OC5OC(C)C(O)C(OC6OC(C)C(O)C(C)(O)C6)C5)C4)C(C(OC)C(=O)C(O)C(C)O)CC3=CC2=CC=1OC(OC(C)C1O)CC1OC1CC(O)C(O)C(C)O1 CFCUWKMKBJTWLW-UHFFFAOYSA-N 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- KDTSHFARGAKYJN-UHFFFAOYSA-N dephosphocoenzyme A Natural products OC1C(O)C(COP(O)(=O)OP(O)(=O)OCC(C)(C)C(O)C(=O)NCCC(=O)NCCS)OC1N1C2=NC=NC(N)=C2N=C1 KDTSHFARGAKYJN-UHFFFAOYSA-N 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 229960000605 dexrazoxane Drugs 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 229940039227 diagnostic agent Drugs 0.000 description 1
- 239000000032 diagnostic agent Substances 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 229940043237 diethanolamine Drugs 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- 125000000723 dihydrobenzofuranyl group Chemical group O1C(CC2=C1C=CC=C2)* 0.000 description 1
- 125000004582 dihydrobenzothienyl group Chemical group S1C(CC2=C1C=CC=C2)* 0.000 description 1
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 1
- HBNBMOGARBJBHS-UHFFFAOYSA-N dimethylarsane Chemical compound C[AsH]C HBNBMOGARBJBHS-UHFFFAOYSA-N 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 208000002173 dizziness Diseases 0.000 description 1
- 239000003534 dna topoisomerase inhibitor Substances 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 230000002222 downregulating effect Effects 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 229950004203 droloxifene Drugs 0.000 description 1
- 229940017825 dromostanolone Drugs 0.000 description 1
- NOTIQUSPUUHHEH-UXOVVSIBSA-N dromostanolone propionate Chemical compound C([C@@H]1CC2)C(=O)[C@H](C)C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](OC(=O)CC)[C@@]2(C)CC1 NOTIQUSPUUHHEH-UXOVVSIBSA-N 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 230000036267 drug metabolism Effects 0.000 description 1
- 238000002036 drum drying Methods 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 229950000579 enprofylline Drugs 0.000 description 1
- 238000001952 enzyme assay Methods 0.000 description 1
- 229940116977 epidermal growth factor Drugs 0.000 description 1
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 1
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 230000001037 epileptic effect Effects 0.000 description 1
- YJGVMLPVUAXIQN-UHFFFAOYSA-N epipodophyllotoxin Natural products COC1=C(OC)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YJGVMLPVUAXIQN-UHFFFAOYSA-N 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 229940082789 erbitux Drugs 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 229960001842 estramustine Drugs 0.000 description 1
- FRPJXPJMRWBBIH-RBRWEJTLSA-N estramustine Chemical compound ClCCN(CCCl)C(=O)OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 FRPJXPJMRWBBIH-RBRWEJTLSA-N 0.000 description 1
- 239000000328 estrogen antagonist Substances 0.000 description 1
- 239000002834 estrogen receptor modulator Substances 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 239000000469 ethanolic extract Substances 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 229940012017 ethylenediamine Drugs 0.000 description 1
- 125000006125 ethylsulfonyl group Chemical group 0.000 description 1
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 229960005420 etoposide Drugs 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000002550 fecal effect Effects 0.000 description 1
- 210000003608 fece Anatomy 0.000 description 1
- 229950003662 fenretinide Drugs 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- DBEPLOCGEIEOCV-WSBQPABSSA-N finasteride Chemical compound N([C@@H]1CC2)C(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)NC(C)(C)C)[C@@]2(C)CC1 DBEPLOCGEIEOCV-WSBQPABSSA-N 0.000 description 1
- 229960004039 finasteride Drugs 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- RMBPEFMHABBEKP-UHFFFAOYSA-N fluorene Chemical compound C1=CC=C2C3=C[CH]C=CC3=CC2=C1 RMBPEFMHABBEKP-UHFFFAOYSA-N 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- MKXKFYHWDHIYRV-UHFFFAOYSA-N flutamide Chemical compound CC(C)C(=O)NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 MKXKFYHWDHIYRV-UHFFFAOYSA-N 0.000 description 1
- 229960002074 flutamide Drugs 0.000 description 1
- 230000004907 flux Effects 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 239000004052 folic acid antagonist Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Substances O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 125000003838 furazanyl group Chemical group 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 108020001507 fusion proteins Proteins 0.000 description 1
- 102000037865 fusion proteins Human genes 0.000 description 1
- 201000010175 gallbladder cancer Diseases 0.000 description 1
- 229940083124 ganglion-blocking antiadrenergic secondary and tertiary amines Drugs 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 238000001415 gene therapy Methods 0.000 description 1
- 229940045109 genistein Drugs 0.000 description 1
- TZBJGXHYKVUXJN-UHFFFAOYSA-N genistein Natural products C1=CC(O)=CC=C1C1=COC2=CC(O)=CC(O)=C2C1=O TZBJGXHYKVUXJN-UHFFFAOYSA-N 0.000 description 1
- 235000006539 genistein Nutrition 0.000 description 1
- ZCOLJUOHXJRHDI-CMWLGVBASA-N genistein 7-O-beta-D-glucoside Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=C2C(=O)C(C=3C=CC(O)=CC=3)=COC2=C1 ZCOLJUOHXJRHDI-CMWLGVBASA-N 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 229940116332 glucose oxidase Drugs 0.000 description 1
- 235000019420 glucose oxidase Nutrition 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- XLXSAKCOAKORKW-UHFFFAOYSA-N gonadorelin Chemical compound C1CCC(C(=O)NCC(N)=O)N1C(=O)C(CCCN=C(N)N)NC(=O)C(CC(C)C)NC(=O)CNC(=O)C(NC(=O)C(CO)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C(CC=1NC=NC=1)NC(=O)C1NC(=O)CC1)CC1=CC=C(O)C=C1 XLXSAKCOAKORKW-UHFFFAOYSA-N 0.000 description 1
- 229960002913 goserelin Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 210000003714 granulocyte Anatomy 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 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 description 1
- 125000004366 heterocycloalkenyl group Chemical group 0.000 description 1
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 1
- UUVWYPNAQBNQJQ-UHFFFAOYSA-N hexamethylmelamine Chemical compound CN(C)C1=NC(N(C)C)=NC(N(C)C)=N1 UUVWYPNAQBNQJQ-UHFFFAOYSA-N 0.000 description 1
- 229960001915 hexamidine Drugs 0.000 description 1
- OQLKNTOKMBVBKV-UHFFFAOYSA-N hexamidine Chemical compound C1=CC(C(=N)N)=CC=C1OCCCCCCOC1=CC=C(C(N)=N)C=C1 OQLKNTOKMBVBKV-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 210000001320 hippocampus Anatomy 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 229960002885 histidine Drugs 0.000 description 1
- 102000052196 human PF4 Human genes 0.000 description 1
- XGIHQYAWBCFNPY-AZOCGYLKSA-N hydrabamine Chemical compound C([C@@H]12)CC3=CC(C(C)C)=CC=C3[C@@]2(C)CCC[C@@]1(C)CNCCNC[C@@]1(C)[C@@H]2CCC3=CC(C(C)C)=CC=C3[C@@]2(C)CCC1 XGIHQYAWBCFNPY-AZOCGYLKSA-N 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000008309 hydrophilic cream Substances 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 229960001330 hydroxycarbamide Drugs 0.000 description 1
- 230000036543 hypotension Effects 0.000 description 1
- 210000003016 hypothalamus Anatomy 0.000 description 1
- 229960000908 idarubicin Drugs 0.000 description 1
- 238000005417 image-selected in vivo spectroscopy Methods 0.000 description 1
- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical compound C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000000415 inactivating effect Effects 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 239000003978 infusion fluid Substances 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 238000012739 integrated shape imaging system Methods 0.000 description 1
- 229940125798 integrin inhibitor Drugs 0.000 description 1
- 229940117681 interleukin-12 Drugs 0.000 description 1
- 229940028885 interleukin-4 Drugs 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 230000037041 intracellular level Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 1
- 229960004768 irinotecan Drugs 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 229960002725 isoflurane Drugs 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 229960005280 isotretinoin Drugs 0.000 description 1
- IQVRBWUUXZMOPW-PKNBQFBNSA-N istradefylline Chemical compound CN1C=2C(=O)N(CC)C(=O)N(CC)C=2N=C1\C=C\C1=CC=C(OC)C(OC)=C1 IQVRBWUUXZMOPW-PKNBQFBNSA-N 0.000 description 1
- 229950009028 istradefylline Drugs 0.000 description 1
- 238000011813 knockout mouse model Methods 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- 235000019388 lanolin Nutrition 0.000 description 1
- 229940039717 lanolin Drugs 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
- 229960003881 letrozole Drugs 0.000 description 1
- HPJKCIUCZWXJDR-UHFFFAOYSA-N letrozole Chemical compound C1=CC(C#N)=CC=C1C(N1N=CN=C1)C1=CC=C(C#N)C=C1 HPJKCIUCZWXJDR-UHFFFAOYSA-N 0.000 description 1
- GFIJNRVAKGFPGQ-LIJARHBVSA-N leuprolide Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 GFIJNRVAKGFPGQ-LIJARHBVSA-N 0.000 description 1
- 229960004338 leuprorelin Drugs 0.000 description 1
- 229960004194 lidocaine Drugs 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 230000004130 lipolysis Effects 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- HWYHZTIRURJOHG-UHFFFAOYSA-N luminol Chemical compound O=C1NNC(=O)C2=C1C(N)=CC=C2 HWYHZTIRURJOHG-UHFFFAOYSA-N 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 229960003646 lysine Drugs 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229940057948 magnesium stearate Drugs 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- MMIPFLVOWGHZQD-UHFFFAOYSA-N manganese(3+) Chemical class [Mn+3] MMIPFLVOWGHZQD-UHFFFAOYSA-N 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- OCSMOTCMPXTDND-OUAUKWLOSA-N marimastat Chemical compound CNC(=O)[C@H](C(C)(C)C)NC(=O)[C@H](CC(C)C)[C@H](O)C(=O)NO OCSMOTCMPXTDND-OUAUKWLOSA-N 0.000 description 1
- 229950008959 marimastat Drugs 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229960004961 mechlorethamine Drugs 0.000 description 1
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical class ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 1
- 229960001924 melphalan Drugs 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 230000007074 memory dysfunction Effects 0.000 description 1
- 150000002734 metacrylic acid derivatives Chemical class 0.000 description 1
- 239000003475 metalloproteinase inhibitor Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 229960004452 methionine Drugs 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 230000003228 microsomal effect Effects 0.000 description 1
- CFCUWKMKBJTWLW-BKHRDMLASA-N mithramycin Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@H](O)[C@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@@H](O)[C@H](O)[C@@H](C)O1 CFCUWKMKBJTWLW-BKHRDMLASA-N 0.000 description 1
- 230000002438 mitochondrial effect Effects 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- DNIAPMSPPWPWGF-UHFFFAOYSA-N monopropylene glycol Natural products CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 1
- 125000004312 morpholin-2-yl group Chemical group [H]N1C([H])([H])C([H])([H])OC([H])(*)C1([H])[H] 0.000 description 1
- 125000004572 morpholin-3-yl group Chemical group N1C(COCC1)* 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 230000007659 motor function Effects 0.000 description 1
- 210000002200 mouth mucosa Anatomy 0.000 description 1
- 238000002552 multiple reaction monitoring Methods 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- ZKUCFFYOQOJLGT-UHFFFAOYSA-N n-(4-acetylphenyl)-2-[4-(2,6-dioxo-1,3-dipropyl-7h-purin-8-yl)phenoxy]acetamide Chemical compound N1C=2C(=O)N(CCC)C(=O)N(CCC)C=2N=C1C(C=C1)=CC=C1OCC(=O)NC1=CC=C(C(C)=O)C=C1 ZKUCFFYOQOJLGT-UHFFFAOYSA-N 0.000 description 1
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 210000003757 neuroblast Anatomy 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- XWXYUMMDTVBTOU-UHFFFAOYSA-N nilutamide Chemical compound O=C1C(C)(C)NC(=O)N1C1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 XWXYUMMDTVBTOU-UHFFFAOYSA-N 0.000 description 1
- 229960002653 nilutamide Drugs 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 150000002828 nitro derivatives Chemical class 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 108020001162 nitroreductase Proteins 0.000 description 1
- OSTGTTZJOCZWJG-UHFFFAOYSA-N nitrosourea Chemical compound NC(=O)N=NO OSTGTTZJOCZWJG-UHFFFAOYSA-N 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 210000001009 nucleus accumben Anatomy 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- NIHNNTQXNPWCJQ-UHFFFAOYSA-N o-biphenylenemethane Natural products C1=CC=C2CC3=CC=CC=C3C2=C1 NIHNNTQXNPWCJQ-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 239000003921 oil Substances 0.000 description 1
- 229940046166 oligodeoxynucleotide Drugs 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 230000001582 osteoblastic effect Effects 0.000 description 1
- 229960003552 other antineoplastic agent in atc Drugs 0.000 description 1
- 238000000643 oven drying Methods 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- AZHVQJLDOFKHPZ-UHFFFAOYSA-N oxathiazine Chemical compound O1SN=CC=C1 AZHVQJLDOFKHPZ-UHFFFAOYSA-N 0.000 description 1
- 125000005968 oxazolinyl group Chemical group 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000007310 pathophysiology Effects 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 229940066842 petrolatum Drugs 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000004634 pharmacological analysis method Methods 0.000 description 1
- 238000009521 phase II clinical trial Methods 0.000 description 1
- 238000009522 phase III clinical trial Methods 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 150000003906 phosphoinositides Chemical class 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229940075930 picrate Drugs 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 description 1
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 229960003171 plicamycin Drugs 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 description 1
- 229920001610 polycaprolactone Polymers 0.000 description 1
- 229920002721 polycyanoacrylate Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 238000003752 polymerase chain reaction Methods 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000001205 polyphosphate Substances 0.000 description 1
- 235000011176 polyphosphates Nutrition 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 229920002223 polystyrene 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
- 238000010837 poor prognosis Methods 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 230000018656 positive regulation of gluconeogenesis Effects 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- CJOWSBOERSTJAR-UHFFFAOYSA-M potassium;4-(2,6-dioxo-1-propyl-3,7-dihydropurin-8-yl)benzenesulfonate Chemical compound [K+].N1C=2C(=O)N(CCC)C(=O)NC=2N=C1C1=CC=C(S([O-])(=O)=O)C=C1 CJOWSBOERSTJAR-UHFFFAOYSA-M 0.000 description 1
- 229950008939 preladenant Drugs 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 238000009516 primary packaging Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 229960003387 progesterone Drugs 0.000 description 1
- 239000000186 progesterone Substances 0.000 description 1
- 239000000583 progesterone congener Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 239000003528 protein farnesyltransferase inhibitor Substances 0.000 description 1
- 230000000722 protumoral effect Effects 0.000 description 1
- 229940001470 psychoactive drug Drugs 0.000 description 1
- 239000004089 psychotropic agent Substances 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- XFTQRUTUGRCSGO-UHFFFAOYSA-N pyrazin-2-amine Chemical compound NC1=CN=CC=N1 XFTQRUTUGRCSGO-UHFFFAOYSA-N 0.000 description 1
- 125000004944 pyrazin-3-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 1
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 description 1
- 125000004943 pyrimidin-6-yl group Chemical group N1=CN=CC=C1* 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- ZVJHJDDKYZXRJI-UHFFFAOYSA-N pyrroline Natural products C1CC=NC1 ZVJHJDDKYZXRJI-UHFFFAOYSA-N 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 229960004622 raloxifene Drugs 0.000 description 1
- GZUITABIAKMVPG-UHFFFAOYSA-N raloxifene Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 GZUITABIAKMVPG-UHFFFAOYSA-N 0.000 description 1
- 229960004432 raltitrexed Drugs 0.000 description 1
- 238000009790 rate-determining step (RDS) Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 229930002330 retinoic acid Natural products 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229960004641 rituximab Drugs 0.000 description 1
- 229960003522 roquinimex Drugs 0.000 description 1
- 108091008601 sVEGFR Proteins 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 208000019116 sleep disease Diseases 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- RCOSUMRTSQULBK-UHFFFAOYSA-N sodium;propan-1-olate Chemical compound [Na+].CCC[O-] RCOSUMRTSQULBK-UHFFFAOYSA-N 0.000 description 1
- 238000003797 solvolysis reaction Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 210000004988 splenocyte Anatomy 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 238000003153 stable transfection Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-N sulfamic acid Chemical compound NS(O)(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-N 0.000 description 1
- HHVIBTZHLRERCL-UHFFFAOYSA-N sulfonyldimethane Chemical group CS(C)(=O)=O HHVIBTZHLRERCL-UHFFFAOYSA-N 0.000 description 1
- 239000002600 sunflower oil Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 229940065721 systemic for obstructive airway disease xanthines Drugs 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229940033134 talc Drugs 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- ATFXVNUWQOXRRU-UHFFFAOYSA-N taminadenant Chemical compound BrC=1C(N)=NC(N2N=CC=C2)=NC=1N1C=CC=N1 ATFXVNUWQOXRRU-UHFFFAOYSA-N 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 238000004885 tandem mass spectrometry Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 229940063683 taxotere Drugs 0.000 description 1
- 229960001674 tegafur Drugs 0.000 description 1
- WFWLQNSHRPWKFK-ZCFIWIBFSA-N tegafur Chemical compound O=C1NC(=O)C(F)=CN1[C@@H]1OCCC1 WFWLQNSHRPWKFK-ZCFIWIBFSA-N 0.000 description 1
- DKACXUFSLUYRFU-UHFFFAOYSA-N tert-butyl n-aminocarbamate Chemical compound CC(C)(C)OC(=O)NN DKACXUFSLUYRFU-UHFFFAOYSA-N 0.000 description 1
- UXMRNSHDSCDMLG-UHFFFAOYSA-J tetrachlororhenium Chemical compound Cl[Re](Cl)(Cl)Cl UXMRNSHDSCDMLG-UHFFFAOYSA-J 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 238000010257 thawing Methods 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 1
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 1
- 229960000303 topotecan Drugs 0.000 description 1
- XFCLJVABOIYOMF-QPLCGJKRSA-N toremifene Chemical compound C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 XFCLJVABOIYOMF-QPLCGJKRSA-N 0.000 description 1
- 229960005026 toremifene Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 229950000564 tozadenant Drugs 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 229960000575 trastuzumab Drugs 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 230000000472 traumatic effect Effects 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- UBOXGVDOUJQMTN-UHFFFAOYSA-N trichloroethylene Natural products ClCC(Cl)Cl UBOXGVDOUJQMTN-UHFFFAOYSA-N 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 1
- 238000004724 ultra fast liquid chromatography Methods 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 1
- 239000004066 vascular targeting agent Substances 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- HHJUWIANJFBDHT-KOTLKJBCSA-N vindesine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(N)=O)N4C)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 HHJUWIANJFBDHT-KOTLKJBCSA-N 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- 229950003008 vipadenant Drugs 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
- 229940075420 xanthine Drugs 0.000 description 1
- UGOMMVLRQDMAQQ-UHFFFAOYSA-N xphos Chemical compound CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 UGOMMVLRQDMAQQ-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
- PAPBSGBWRJIAAV-UHFFFAOYSA-N ε-Caprolactone Chemical compound O=C1CCCCCO1 PAPBSGBWRJIAAV-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
- C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
- C07D241/40—Benzopyrazines
- C07D241/44—Benzopyrazines 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 carbon atoms of the hetero ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
-
- 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
- A61P35/00—Antineoplastic agents
-
- 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
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing 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
- C07D405/04—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 directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/10—Spiro-condensed systems
Abstract
Description
本發明係關於通式I之喹㗁啉衍生物,
及本發明化合物用於治療及/或預防哺乳動物(尤其人類)之過度增生性或傳染性疾病及病症之用途,及含有此等化合物之醫藥組合物。
及本發明化合物用於治療及/或預防哺乳動物(尤其人類)之過度增生性或傳染性疾病及病症之用途,及含有此等化合物之醫藥組合物。
腺苷為眾多生理活動(特定言之心血管、神經及免疫系統內之生理活動)之無處不在的調節劑。腺苷與生物活性核苷酸三磷酸腺苷(ATP)、二磷酸腺苷(ADP)、單磷酸腺苷(AMP)及環狀單磷酸腺苷(cAMP),與生物化學甲基化劑S-腺苷基-L-甲硫胺酸(SAM)結構上及代謝上均相關且與輔酶NAD、FAD及輔酶A及與RNA結構上相關。
經由細胞表面受體,腺苷調節多種生理功能,包括誘導鎮靜、血管舒張、抑制心率及收縮率、抑制血小板聚集性、刺激糖質新生及抑制脂解。研究顯示腺苷能激活腺苷酸環化酶、打開鉀通道、減少通過鈣通道的通量及經由受體介導機制抑制或刺激磷酸肌醇轉換(Muller C. E.及Stein B.,Current Pharmaceutical Design, 2: 501, 1996;Muller C. E., Exp. Opin. Ther. Patents, 7(5): 419, 1997)。
腺苷受體屬於G蛋白偶合受體(GPCR)之超家族。腺苷受體之四個主要亞型已經在藥理上、結構上及功能上表徵(Fredholm等人,Pharm. Rev., 46: 143-156, 1994)且稱作A1
、A2A
、A2B
及A3
。雖然相同腺苷受體可與不同G蛋白偶合,但是腺苷A1
及A3
受體通常與稱作Gi
及G0
之抑制G蛋白偶合,該等抑制G蛋白抑制腺苷酸環化酶且下調細胞cAMP水平。相反,腺苷A2A
及A2B
受體與稱作GS
之刺激G蛋白偶合,該等刺激G蛋白激活腺苷酸環化酶且增加cAMP之細胞內水平(Linden J., Annu. Rev. Pharmacol. Toxicol., 41: 775-87 2001)。
根據本發明,「腺苷受體選擇性配位體」為選擇性結合至腺苷受體之一或多個亞型,因此模擬腺苷之作用(腺苷促效劑)或阻斷其作用(腺苷拮抗劑)之物質。根據其受體選擇性,可將腺苷受體選擇性配位體分成不同類別,例如,選擇性結合至A1
或A2
受體之配位體及亦於後者之情況下,例如,選擇性結合至A2A
或A2B
受體之彼等。亦可為選擇性結合至複數個腺苷受體亞型之腺苷受體配位體,例如,選擇性結合至A1
及A2
,但是不結合至A3
受體之配位體。上述受體選擇性可藉由物質對利用對應cDNA穩定轉染後表現討論中之受體亞型之細胞株的作用確定(Olah, M. E.等人,J. Biol. Chem., 267: 10764-10770, 1992)。物質對此等細胞株之作用可藉由細胞內信使cAMP之生物化學量測來監測(Klotz, K. N.等人,Naunyn Schmiedebergs Arch. Pharmacol. 357: 1-9, 1998)。
已知A1
受體系統包括磷脂酶C之激活及鉀及鈣離子通道二者之調節。A3
亞型(除了其與腺苷酸環化酶相關外)亦刺激磷脂酶C且亦激活鈣離子通道。
A1
受體(326至328個胺基酸)係自具有哺乳動物物種中之90至95%序列同一性之各種物種(犬、人類、大鼠、狗、雞、牛、幾內亞豬)選殖。A2A
受體(409至412個胺基酸)係自犬、大鼠、人類、幾內亞豬及小鼠選殖。A2B
受體(332個胺基酸)係自人類及小鼠選殖,其中人類A2B
與人類A1
及A2A
受體具有45%同源性。A3
受體(317至320個胺基酸)係自人類、大鼠、狗、兔及綿羊選殖。
提議A1
及A2A
受體亞型於能量供給之腺苷調節中起著互補作用。腺苷(其為ATP之代謝產物)自細胞擴散且局部作用激活腺苷受體以減少氧需求(A1
及A3
)或增加氧供給(A2A
)及因此使組織內之能量供給/需求之平衡恢復。兩種亞型之作用為增加組織可得氧之量及保護細胞免受由氧之短期不平衡造成之損傷。內源性腺苷之重要功能中之一者為防止創傷(諸如缺氧、缺血、低血壓及癲癇活動)期間之損傷。此外,已知腺苷受體促效劑與表現大鼠A3
受體之肥大細胞之結合導致增加之三磷酸肌醇及細胞內鈣濃度,其增強抗原誘導之發炎性介體之分泌。因此,A3
受體於介導哮喘發作及其他過敏反應中起作用。
此等腺苷受體藉由不同基因編碼且根據其對腺苷類似物及甲基黃嘌呤拮抗劑之親和力分類(Klinger等人,Cell Signal., 14 (2): 99-108, 2002)。
關於腺苷對神經系統之作用,對最廣泛使用之所有精神活性藥物(為咖啡因)之作用作出第一次觀察。實際上,咖啡因為熟知腺苷受體拮抗劑,其能增強哺乳動物之意識及學習能力。腺苷A2A
受體路徑為此等作用負責(Fredholm等人,Pharmacol. Rev., 51 (1): 83-133, 1999;Huang等人,Nat Neurosci., 8 (7): 858-9, 2005),及咖啡因對腺苷A2A
受體信號傳導路徑之作用鼓勵高度特異性及強效腺苷A2A
拮抗劑之研究。
於哺乳動物中,腺苷A2A
受體於腦中具有有限分佈且發現於紋狀體、嗅結節及伏核中(Dixon等人,Br. J. Pharmacol., 118 (6): 1461-8, 1996)。高及中間水平之表現可於免疫細胞、心臟、肺及血管中觀察到。於外周系統中,G3
似乎為與腺苷A2A
受體相關之主要G蛋白,但是於紋狀體中,顯示紋狀體腺苷A2A
受體通過激活稱作Go
if之G蛋白介導其作用(Kull等人,Mol. Pharmacol., 58 (4): 772-7, 2000),該G蛋白類似於G3
且亦與腺苷酸環化酶偶合。
迄今為止,對基因改造小鼠之研究及藥理學分析表明A2A
受體為用於治療以下疾病之有前景的治療靶:中樞神經系統(CNS)病症及疾病,諸如帕金森氏病(Parkinson's disease)、亨廷頓氏病(Huntington's disease)、注意力缺陷多動症(ADHD)、中風(缺血性腦損傷)及阿兹海默氏病(Alzheimer's disease) (Fredholm等人,Annu. Rev. Pharmacol. Toxicol., 45: 385-412, 2005;Higgins等人,Behav. Brain Res. 185: 32-42, 2007;Dall' Igna等人,Exp. Neurol., 203 (1): 241-5, 2007;Arendash等人,Neuroscience, 142 (4): 941-52, 2006;Trends in Neurosci., 29 (11), 647-654, 2006;Expert Opinion Ther. Patents, 17, 979-991, 2007;Exp. Neurol., 184 (1), 285-284, 2003;Prog. Brain Res, 183, 183-208, 2010;J. Alzheimer Dis., 增刊1, 1 17-126, 2010;J. Neurosci., 29 (47), 14741-14751, 2009;Neuroscience, 166 (2), 590-603, 2010;J. Pharmacol. Exp. Ther., 330 (1), 294-303, 2009;Frontiers Biosci., 13, 2614-2632, 2008)而且還用於治療有機體來源之各種精神病(Weiss等人,Neurology, 61 (11 增刊6): 88-93, 2003)。
使用腺苷A2A
受體基因敲除小鼠已顯示,腺苷A2A
受體失活保護免於藉由缺血(Chen等人,J. Neurosci., 19 (21): 9192-200, 1999及Monopoli等人,Neuroreport, 9 (17): 3955-9, 1998)及線粒體毒素3-NP (Blum等人,J. Neurosci., 23 (12): 5361-9, 2003)誘導之神經元細胞死亡。彼等結果提供利用腺苷A2A
拮抗劑治療缺血及亨廷頓氏病之基礎。腺苷A2A
受體之阻斷亦具有抗抑鬱作用(El Yacoubi等人,Neuropharmacology, 40 (3): 424-32, 2001)。最後,此阻斷防止記憶功能障礙(Cunha等人,Exp. Neurol., 210 (2): 776-81, 2008;Takahashi等人,Front. Biosci., 13: 2614-32, 2008)及此可為用於治療及/或預防阿兹海默氏病之有前景的治療途徑。
關於A2A
腺苷受體之評論參見(例如) Moreau等人(Brain Res. Reviews 31: 65-82, 1999)及Svenningsson等人(Progress in Neurobiology 59: 355-396, 1999)。
迄今為止,若干腺苷A2A
受體拮抗劑已顯示用於治療帕金森氏病之有前景的潛力。作為實例,在美國完成III期臨床試驗之KW-6002 (伊曲茶鹼(Istradefylline))於研究後證實其減輕該疾病症狀之功效(Bara-Himenez等人,Neurology, 61 (3): 293-6, 2003及Hauser等人,Neurology, 61 (3): 297-303, 2003)。SCH420814 (瑞德南特(Preladenant)),其現在在美國正在進行II期臨床試驗及於帕金森氏病之動物模型中(Neustadt等人,Bioorg. Med. Chem. Lett., 17 (5): 1376-80, 2001)且亦於人類患者中(Hunter J. C, poster Boston 2006 - http://www.a2apd.org/Speaker abstracts/Hunter.pdf)產生運動功能之改善。
除了A2A
受體拮抗劑治療神經退行性疾病之受歡迎效用外,已認為彼等化合物用於互補症狀適應症。此等係基於以下證據:A2A
受體激活可有助於一系列神經精神病症及功能障礙(諸如抑鬱、白天睡眠過多、多動腿症候群、注意力缺陷多動症及認知疲勞)之病理生理學(Neurology, 61 (增刊6), 82-87, 2003;Behav. Pharmacol., 20 (2), 134-145, 2009;CNS Drug Discov., 2 (1), 1-21, 2007)。
一些作者建議應用A2A
拮抗劑來治療糖尿病(WO1999035147、WO2001002400)。其他研究表明A2A
腺苷受體涉及傷口癒合或心房顫動(Am. J. Path., 6, 1774- 1778, 2007;Arthritis & Rheumatism, 54 (8), 2632-2642, 2006)。
過去由醫藥公司發現之一些強效腺苷A2A
拮抗劑已推進入臨床試驗,其顯示積極結果且證實此化合物類別用於治療神經退行性病症(如帕金森氏病、亨廷頓氏病或阿兹海默氏病)而且於其他CNS相關疾病(如抑鬱、躁動症候群、睡眠障礙及焦慮症)中之潛力(Clin. Neuropharmacol., 33, 55-60, 2010;J. Neurosci., 30 (48), 2010), 16284-16292;Parkinson Relat. Disord., 16 (6), 423-426, 2010;Expert Opinion Ther. Patents, 20(8), 987-1005, 2010;Current Opinion in Drug Discovery & Development, 13 (4), 466-480, 2010及其中的參考文獻;Mov. Disorders, 25 (2), S305, 2010)。
已知A2A
抑制劑為伊曲茶鹼(KW-6002)、瑞德南特(SCH420814)、SCH58261、CGS15943、托紮南特(Tozadenant)、維帕南特(Vipadenant) (V-2006)、V-81444 (CPI-444)、HTL-1071、PBF-509、Medi-9447、PNQ-370、ZM-241385、ASO-5854、ST-1535、ST-4206、DT1133及DT-0926,於大多數情況下其經開發用於帕金森氏病。
採用標準聚合酶鏈式反應技術利用經設計以識別大多數G蛋白偶合受體之保守區之簡併寡核苷酸引物,將腺苷A2B
受體自大鼠下丘腦(Rivkees及Repper,1992)、人類海馬體(Pierce等人,1992)及小鼠肥大細胞(Marquardt等人,1994)選殖。人類A2B
受體與大鼠及小鼠A2B
受體共用86至87%胺基酸序列同源性(Rivkees及Reppert,1992;Pierce等人,1992;Marquardt等人,1994)及與人類A1
及A2A
受體共用45%胺基酸序列同源性。如對於密切相關物種所預期,大鼠及小鼠A2B
受體共用96%胺基酸序列同源性。相比之下,來自各種物種之A1
受體之間之總胺基酸同一性為87% (Palmer及Stiles,1995)。A2A
受體在物種之間共用90%之同源性(Ongini及Fredholm,1996),其中大多數差異發生在第二胞外環及長C-端域中(Palmer及Stiles,1995)。針對A3
受體序列觀察到最低(72%)程度之同一性(Palmer及Stiles,1995)。
腺苷類似物NECA仍為最強效A2B
促效劑(Bruns,1981;Feoktistov及Biaggioni,1993, 1997;Brackett及Daly,1994),其中產生用於刺激腺苷酸環化酶之半最大效應之濃度(EC50
)為約2 µM。然而,其係非選擇性且以甚至更高親和力激活其他腺苷受體,其中EC50
在低奈莫耳(A1
及A2A
)或高奈莫耳(A3
)範圍內。因此,A2B
受體之表徵經常依靠於化合物之有效性之缺乏,該等化合物為其他受體類型之強效且選擇性促效劑。A2B
受體藉由排除方法(即,藉由特異性針對其他受體之促效劑之功效的缺乏)表徵。A2A
選擇性促效劑CGS-21680 (Webb等人,1992) (例如)可用於A2A
與A2B
腺苷受體之間之區分(Hide等人,1992;Chern等人,1993;Feoktistov及Biaggioni,1995;van der Ploeg等人,1996)。兩種受體與腺苷酸環化酶積極偶合且藉由非選擇性促效劑NECA激活。CGS-21680對A2B
受體實際上無效但是於激活A2A
受體方面與NECA一樣強效,其中針對兩種促效劑之EC50
在低莫耳範圍內(Jarvis等人,1989;Nakane及Chiba,1990;Webb等人,1992;Hide等人,1992;Feoktistov及Biaggioni,1993;Alexander等人,1996)。A2B
受體亦對A1
選擇性促效劑R-PIA (Feoktistov及Biaggioni,1993;Brackett及Daly,1994)以及對A3
選擇性促效劑N6
-(3-碘苄基)-N-甲基-5′-胺甲醯基腺苷(IB-MECA) (Feoktistov及Biaggioni,1997)具有非常低親和力。於A2B
介導之cAMP累積之人類紅血球性白血病(HEL)細胞中測定促效劑特性NECA > R-PIA = IB-MECA > CGS-21680。NECA與其餘促效劑之EC50
之間之差異為約兩個數量級。因此,藉由以低微莫耳範圍(1至10 μM)內之濃度下之NECA,但是非藉由R-PIA、IB-MECA或CGS-21680引起之反應為A2B
受體之特徵。
雖然A2B
受體相較於其他受體亞型具有(一般而言)對促效劑之更低親和力,但是此對於拮抗劑係不真的。雖然腺苷拮抗劑對A2B
受體之結構活性關係未經完全表徵,但是至少一些黃嘌呤為較其他亞型與A2B
受體亞型之拮抗劑一樣強效或更強效。特定言之,DPSPX (1,3-二丙基-8-磺苯基黃嘌呤)、DPCPX (1,3-二丙基-8c-基環戊基黃嘌呤)、DPX (1,3-二乙基苯基黃嘌呤)、平喘劑藥恩丙茶鹼(enprofylline) (3-正丙基黃嘌呤)及非黃嘌呤化合物2,4-二側氧基苯并喋啶(咯肼)具有中至高nM範圍內之親和力。
其他已知A2B
抑制劑為ATL801、PSB-605、PSB-1115、ISAM-140、GS6201、MRS1706及MRS1754。
本文中揭示腺苷受體藉由充當生理「停止」(終止機制)於活體內發炎之下調中起著非多餘作用,該「停止」可限制免疫反應及從而保護正常組織在不同疾病之發病期間免受過度免疫損傷。
A2A
受體拮抗劑藉由降低T細胞介導之抗原刺激耐受性、增強記憶T細胞之誘導及增強用於治療癌症及傳染性疾病之被動抗體投與之功效來提供免疫反應之長期增強,而A2A
受體促效劑藉由增強T細胞介導之抗原刺激耐受性來提供免疫反應之長期減少,特定言之以減少免疫抑制劑於某些病狀中之使用。
免疫調節為治療許多疾病及病症之關鍵態樣。T細胞(特定言之)於抗感染中起著至關重要作用且具有識別及破壞癌細胞之能力。增強T細胞介導之反應為增強對治療劑之反應的關鍵組成部分。然而,於免疫調節中關鍵的是免疫反應之任何增強與防止自身免疫以及慢性發炎之需要平衡。慢性發炎及T細胞之自身識別為全身性病症(諸如類風濕性關節炎、多發性硬化及全身性紅斑狼瘡)發病之主要原因。此外,於防止移植器官或移植物排斥中需要長期免疫抑制。
腫瘤誘導之免疫抑制為目前癌症療法之功效之主要障礙。因為其抗更寬範圍之癌症之顯著臨床功效,利用免疫檢查點阻斷抑制劑(諸如抗CTLA-4及抗PD-1/PDL1)之最近成功正在改革癌症治療。腺苷為於臨床前研究中顯示的新的有前景之免疫抑制靶中之一者。此代謝產物藉由在宿主抑制子細胞及腫瘤細胞上表現之胞外酶-CD73產生。CD73之增加之表現與患有許多癌症之患者之差的預後相關,該等癌症包括結腸直腸癌(Liu等人,J. Surgical Oncol, 2012)、胃癌(Lu等人,World J. Gastroenterol., 2013)、膽囊癌(Xiong等人,Cell and Tissue Res., 2014)。臨床前研究證實可藉由腺苷介導之免疫抑制(至少部分)驅動CD73之促腫瘤效應。如上所揭示,腺苷結合至四種已知受體A1
、A2A
、A2B
及A3
,其中已知A2A
及A2B
受體之激活抑制許多免疫細胞之效應子功能(即,A2A
及A2B
受體誘導cAMP之腺苷酸環化酶依賴性累積,從而導致免疫抑制)。因為拮抗A1
及A3
將抵消所需效應且A1
及A3
促效劑充當潛在心臟保護劑,所以需達成對A1
及A3
之選擇性(Antonioli等人,Nat. rev. Cancer, 2013,Thiel等人,Microbes and Infection, 2003)。於腫瘤微環境中,已證實A2A
及A2B
受體二者激活抑制抗腫瘤免疫且增加CD73腫瘤之擴散。此外,利用小分子拮抗劑之A2A
或A2B
阻斷可減少腫瘤轉移。已發現A2A
受體之阻斷可克服包括失能及由腫瘤細胞造成之調節性T細胞誘導二者之腫瘤逃逸機制且造成對治療之長期腫瘤易感性。Ohta等人證實相較於正常小鼠中無排斥,於A2A
受體缺失小鼠中之建立之CL8-1黑色素瘤之約60%的排斥(Ohta等人;PNAS 103 (35): 13132-7, 2006)。一致同意,研究者亦顯示於利用A2A
受體拮抗劑治療後,藉由抗腫瘤T細胞之改善之腫瘤生長之抑制、轉移酶之破壞及新生血管形成之預防。
腫瘤已顯示藉由阻礙通過B7-CD28及TNF家族中之共刺激因子之抑制之T細胞激活以及藉由吸引抑制抗腫瘤T細胞反應之調節性T細胞來逃避免疫破壞(Wang, Cancer. Semin. Cancer. Biol. 16: 73-79, 2006;Greenwald等人,Ann. Rev. Immunol. 23: 515-48, 2005;Watts, Ann. Rev. Immunol. 23: 23-68, 2005;Sadum等人,Clin. Cane. Res. 13 (13): 4016-4025, 2007)。因為於激活後A2A
受體表現於淋巴細胞中增加,釋放淋巴細胞效應子反應之療法(諸如抗CTLA-4及抗PD-1)亦可增加A2A
介導之免疫抑制之效應。免疫檢查點阻斷與A2A
或雙重A2A/2B
拮抗劑組合增加對腫瘤及轉移之免疫反應之量級。因此,A2A
抑制與抗PD-1療法組合增強由與MC38腫瘤細胞共培養之T細胞之IFN-γ產生,提高4T1乳腺瘤模型中之小鼠生存及減少AT-3ovadim
CD73+
腫瘤中之腫瘤生長(Beavis等人,Cancer Immunol. Res., 2015;Mittal等人,Cancer Res., 2014)。
此外,臨床前研究證實,A2B
抑制導致路易士肺癌、MB49膀胱癌、原發性4T1乳腺癌模型中之小鼠之減少之腫瘤生長及延長之生存期(Ryzhov等人,2009,Cekic等人,2012)及A2B
抑制與抗PD-1療法之組合減少B16-F10黑色素瘤之肺轉移且提高4T1乳腺瘤模型中之小鼠生存。
WO 03/050241描述藉由投與抑制細胞外腺苷或抑制腺苷受體之藥劑增加對抗原之免疫反應、增加疫苗功效或增加對腫瘤抗原或免疫細胞介導之腫瘤破壞之免疫反應之方法。
WO 2004/089942、WO 2005/000842及WO 2006/008041揭示苯并噻唑衍生物,包括作為A2A
抑制劑用於治療帕金森氏病之托紮南特。WO 2004/092171及WO 2005/028484揭示亦作為A2A
抑制劑用於治療帕金森氏病之相似噻唑并吡啶及吡唑并嘧啶衍生物。然而,此等化合物於大鼠(帕金森氏病動物模型)中但是非於小鼠(癌症動物模型)中不顯示顯著A2B
抑制活性且僅顯示良好藥物動力學性質。此外,該等化合物不顯示,其能防止免疫抑制及因此能支持抗腫瘤T細胞誘導之腫瘤生長之抑制,轉移酶之減少或破壞及新生血管形成之預防。
因此,仍需要提供對特定抗原之免疫反應之長期增強,特定言之用於治療及預防過度增生性及傳染性疾病及病症之療法及因此本發明之目標為提供治療方法,該等治療方法允許簡化治療方案及增強對某些抗原之免疫反應。本發明之特定目標為提供預防或治療宿主之過度增生性及傳染性疾病及病症之改善的方法,尤其提供用於治療及預防此等疾病之有效A2A
或雙重A2A/2B
拮抗劑。
出人意料地,已發現根據本發明之喹㗁啉衍生物為A2A
腺苷受體或A2A
及A2B
腺苷受體二者之高效抑制劑且同時具有超過A1
及A3
腺苷受體之高選擇性,及因此本發明化合物可用於治療過度增生性疾病及病症(諸如癌症)及傳染性疾病及病症。
特定言之,與已知腺苷A2A
受體拮抗劑托紮南特及相似苯并噻唑衍生物相比,本發明化合物出人意料地顯示A2A
/A2B
雙重活性,其對於治療及/或預防如上所揭示之過度增生性及傳染性疾病及病症而言較佳或本發明化合物顯示至少高A2A
抑制活性連同本文中所揭示之其他出人意料的優點,其導致治療及/或預防過度增生性及傳染性疾病及病症之高功效性。
此外,與已知腺苷A2A
受體拮抗劑托紮南特及相似苯并噻唑衍生物相比,本發明化合物出人意料地顯示於作為癌症相關之動物模型之小鼠中之更佳藥物動力學性質,其對於治療及/或預防如上所揭示之過度增生性及傳染性疾病及病症而言較佳。
此外,如上所討論,腫瘤微環境中之腺苷可藉由通過A2A
受體之信號傳導抑制T細胞活性且藉由T細胞抑制細胞激素分泌。A2A
特異性促效劑(如CGS-21680)類似於腺苷抑制活體外及活體內之T細胞細胞激素分泌。相反,潛在A2A
拮抗劑或A2A
/A2B
雙重拮抗劑可營救T細胞免於此抑制。與已知腺苷A2A
受體拮抗劑托紮南特相比,本發明化合物顯示其能營救T細胞免於抑制且能防止如藉由腺苷或A2A
特異性促效劑(如CGS-2168)誘導之細胞激素分泌之抑制,其對於治療及/或預防如上所揭示之過度增生性及傳染性疾病及病症而言較佳。因此,出人意料地,本發明化合物能防止免疫抑制及因此能支持抗腫瘤T細胞誘導之腫瘤生長之抑制,轉移酶之減少或破壞及新生血管形成之預防。
本發明係關於通式I之喹㗁啉衍生物,
其中
Q、Y彼此獨立地為CH或N,
R1 為鹵素或含有1至10個C原子之直鏈或分支鏈烷基(其未經取代或經R4 單取代、二取代或三取代且其中1至4個C原子可彼此獨立地經O、S、SO、SO2 、NH、NCH3 、–OCO–、–NHCONH–、–NHCO–、–NR5 SO2 R6 –、–COO–、–CONH–、–NCH3 CO–、–CONCH3 –、–C≡C–基團及/或–CH=CH–基團置換,及/或此外,1至10個H原子可經F及/或Cl置換),或含有3至7個C原子之單環或雙環環烷基(其未經取代或經R4 單取代、二取代或三取代且其中1至4個C原子可彼此獨立地經O、S、SO、SO2 、NH、NCH3 、–OCO–、–NHCONH–、–NHCO–、–NR5 SO2 R6 –、–COO–、–CONH–、–NCH3 CO–、–CONCH3 –、–C≡C–基團及/或經–CH=CH–基團置換及/或此外,1至10個H原子可經F及/或Cl置換),或含有3至14個碳原子及獨立地選自N、O及S之0至4個雜原子之單環或雙環雜芳基、雜環基、芳基或環烷基芳基(其未經取代或經R4 單取代、二取代或三取代),
R2 為含有1至10個C原子之直鏈或分支鏈烷基(其未經取代或經R4 單取代、二取代或三取代且其中1至4個C原子可彼此獨立地經O、S、SO、SO2 、NH、NCH3 、–OCO–、–NHCONH–、–NHCO–、–NR5 SO2 R6 –、–COO–、–CONH–、–NCH3 CO–、–CONCH3 –、–C≡C-基團及/或–CH=CH–基團置換,及/或此外,1至10個H原子可經F及/或Cl置換),或含有3至7個C原子之環烷基(其未經取代或經R4 單取代、二取代或三取代且其中1至4個C原子可彼此獨立地經O、S、SO、SO2 、NH、NCH3 、–OCO–、–NHCONH–、–NHCO–、–NR5 SO2 R6 –、–COO–、–CONH–、–NCH3 CO–、–CONCH3 –、–C≡C–基團及/或經–CH=CH–基團置換及/或此外,1至11個H原子可經F及/或Cl置換),或含有3至14個碳原子及獨立地選自N、O及S之0至4個雜原子之單環或雙環雜芳基、雜環基、芳基或環烷基芳基(其未經取代或經R4 單取代、二取代或三取代),
R3 為含有1至6個C原子之直鏈或分支鏈烷基或O-烷基或含有3至6個C原子之環烷基,其未經取代或經H、=S、=NH、=O、OH、含有3至6個C原子之環烷基、COOH、鹵素、NH2 、SO2 CH3 、SO2 NH2 、CN、CONH2 、NHCOCH3 、NHCONH2 或NO2 單取代、二取代或三取代,
R4 為H、R5 、=S、=NR5 、=O、OH、COOH、鹵素、NH2 、SO2 CH3 、SO2 NH2 、CN、CONH2 、NHCOCH3 、NHCONH2 、NO2 或含有1至10個C原子之直鏈或分支鏈烷基(其未經取代或經R5 單取代、二取代或三取代且其中1至4個C原子可彼此獨立地經O、S、SO、SO2 、NH、NCH3 、–OCO–、–NHCONH–、–NHCO–、–NR5 SO2 R6 –、–COO–、–CONH–、–NCH3 CO–、–CONCH3 –、–C≡C–基團及/或–CH=CH–基團置換,及/或此外,1至10個H原子可經F及/或Cl置換),或含有3至7個C原子之單環或雙環環烷基(其未經取代或經R5 單取代、二取代或三取代且其中1至4個C原子可彼此獨立地經O、S、SO、SO2 、NH、NCH3 、–OCO–、–NHCONH–、–NHCO–、–NRSO2 R4 –、–COO–、–CONH–、–NCH3 CO–、–CONCH3 –、–C≡C–基團及/或經–CH=CH–基團置換及/或此外,1至10個H原子可經F及/或Cl置換),或含有3至14個碳原子及獨立地選自N、O及S之0至4個雜原子之單環或雙環雜芳基、雜環基、芳基或環烷基芳基(其未經取代或經R5 單取代、二取代或三取代),
R5 、R6 彼此獨立地選自由以下組成之群:H、=S、=NH、=O、OH、COOH、鹵素、NH2 、SO2 CH3 、SO2 NH2 、CN、CONH2 、NHCOCH3 、NHCONH2 、NO2 及含有1至10個C原子之直鏈或分支鏈烷基(其中1至4個C原子可彼此獨立地經O、S、SO、SO2 、NH、NCH3 、–OCO–、–NHCONH–、–NHCO–、–COO–、–CONH–、–NCH3 CO–、–CONCH3 –、–C≡C–基團及/或–CH=CH–基團置換,及/或此外,1至10個H原子可經F及/或Cl置換),
鹵素為F、C、Br或I,
及其生理學上可接受之鹽、衍生物、溶劑化物、前藥及立體異構體,包括其等依所有比率之混合物。
其中
Q、Y彼此獨立地為CH或N,
R1 為鹵素或含有1至10個C原子之直鏈或分支鏈烷基(其未經取代或經R4 單取代、二取代或三取代且其中1至4個C原子可彼此獨立地經O、S、SO、SO2 、NH、NCH3 、–OCO–、–NHCONH–、–NHCO–、–NR5 SO2 R6 –、–COO–、–CONH–、–NCH3 CO–、–CONCH3 –、–C≡C–基團及/或–CH=CH–基團置換,及/或此外,1至10個H原子可經F及/或Cl置換),或含有3至7個C原子之單環或雙環環烷基(其未經取代或經R4 單取代、二取代或三取代且其中1至4個C原子可彼此獨立地經O、S、SO、SO2 、NH、NCH3 、–OCO–、–NHCONH–、–NHCO–、–NR5 SO2 R6 –、–COO–、–CONH–、–NCH3 CO–、–CONCH3 –、–C≡C–基團及/或經–CH=CH–基團置換及/或此外,1至10個H原子可經F及/或Cl置換),或含有3至14個碳原子及獨立地選自N、O及S之0至4個雜原子之單環或雙環雜芳基、雜環基、芳基或環烷基芳基(其未經取代或經R4 單取代、二取代或三取代),
R2 為含有1至10個C原子之直鏈或分支鏈烷基(其未經取代或經R4 單取代、二取代或三取代且其中1至4個C原子可彼此獨立地經O、S、SO、SO2 、NH、NCH3 、–OCO–、–NHCONH–、–NHCO–、–NR5 SO2 R6 –、–COO–、–CONH–、–NCH3 CO–、–CONCH3 –、–C≡C-基團及/或–CH=CH–基團置換,及/或此外,1至10個H原子可經F及/或Cl置換),或含有3至7個C原子之環烷基(其未經取代或經R4 單取代、二取代或三取代且其中1至4個C原子可彼此獨立地經O、S、SO、SO2 、NH、NCH3 、–OCO–、–NHCONH–、–NHCO–、–NR5 SO2 R6 –、–COO–、–CONH–、–NCH3 CO–、–CONCH3 –、–C≡C–基團及/或經–CH=CH–基團置換及/或此外,1至11個H原子可經F及/或Cl置換),或含有3至14個碳原子及獨立地選自N、O及S之0至4個雜原子之單環或雙環雜芳基、雜環基、芳基或環烷基芳基(其未經取代或經R4 單取代、二取代或三取代),
R3 為含有1至6個C原子之直鏈或分支鏈烷基或O-烷基或含有3至6個C原子之環烷基,其未經取代或經H、=S、=NH、=O、OH、含有3至6個C原子之環烷基、COOH、鹵素、NH2 、SO2 CH3 、SO2 NH2 、CN、CONH2 、NHCOCH3 、NHCONH2 或NO2 單取代、二取代或三取代,
R4 為H、R5 、=S、=NR5 、=O、OH、COOH、鹵素、NH2 、SO2 CH3 、SO2 NH2 、CN、CONH2 、NHCOCH3 、NHCONH2 、NO2 或含有1至10個C原子之直鏈或分支鏈烷基(其未經取代或經R5 單取代、二取代或三取代且其中1至4個C原子可彼此獨立地經O、S、SO、SO2 、NH、NCH3 、–OCO–、–NHCONH–、–NHCO–、–NR5 SO2 R6 –、–COO–、–CONH–、–NCH3 CO–、–CONCH3 –、–C≡C–基團及/或–CH=CH–基團置換,及/或此外,1至10個H原子可經F及/或Cl置換),或含有3至7個C原子之單環或雙環環烷基(其未經取代或經R5 單取代、二取代或三取代且其中1至4個C原子可彼此獨立地經O、S、SO、SO2 、NH、NCH3 、–OCO–、–NHCONH–、–NHCO–、–NRSO2 R4 –、–COO–、–CONH–、–NCH3 CO–、–CONCH3 –、–C≡C–基團及/或經–CH=CH–基團置換及/或此外,1至10個H原子可經F及/或Cl置換),或含有3至14個碳原子及獨立地選自N、O及S之0至4個雜原子之單環或雙環雜芳基、雜環基、芳基或環烷基芳基(其未經取代或經R5 單取代、二取代或三取代),
R5 、R6 彼此獨立地選自由以下組成之群:H、=S、=NH、=O、OH、COOH、鹵素、NH2 、SO2 CH3 、SO2 NH2 、CN、CONH2 、NHCOCH3 、NHCONH2 、NO2 及含有1至10個C原子之直鏈或分支鏈烷基(其中1至4個C原子可彼此獨立地經O、S、SO、SO2 、NH、NCH3 、–OCO–、–NHCONH–、–NHCO–、–COO–、–CONH–、–NCH3 CO–、–CONCH3 –、–C≡C–基團及/或–CH=CH–基團置換,及/或此外,1至10個H原子可經F及/或Cl置換),
鹵素為F、C、Br或I,
及其生理學上可接受之鹽、衍生物、溶劑化物、前藥及立體異構體,包括其等依所有比率之混合物。
較佳地,本發明係關於式I化合物,其中R1
為鹵素或含有1至10個C原子之直鏈或分支鏈烷基(其未經取代或經R4
單取代、二取代或三取代且其中1至4個C原子可彼此獨立地經O、S、SO、SO2
、NH、NCH3
、–OCO–、–NHCONH–、–NHCO–、–NR5
SO2
R6
–、–COO–、–CONH–、–NCH3
CO–、–CONCH3
–、–C≡C–基團及/或–CH=CH–基團置換,及/或此外,1至10個H原子可經F及/或Cl置換),或下列結構中之一者:
其未經取代或經R4 單取代、二取代或三取代
且其中Q、Y、R2 、R3 、R4 、R5 及R6 具有以上所揭示之含義。
其未經取代或經R4 單取代、二取代或三取代
且其中Q、Y、R2 、R3 、R4 、R5 及R6 具有以上所揭示之含義。
較佳地,本發明係關於式I化合物,其中
Q為CH或N
Y為CH
且其中R1 、R2 、R3 、R4 、R5 及R6 具有如技術方案1中所揭示之含義,及其生理學上可接受之鹽、衍生物、溶劑化物、前藥及立體異構體,包括其等依所有比率之混合物。
Q為CH或N
Y為CH
且其中R1 、R2 、R3 、R4 、R5 及R6 具有如技術方案1中所揭示之含義,及其生理學上可接受之鹽、衍生物、溶劑化物、前藥及立體異構體,包括其等依所有比率之混合物。
特別佳地,本發明係關於式I化合物,其中R2
為下列結構中之一者:
其未經取代或經R5 單取代、二取代或三取代
且其中Q、Y、R1 、R3 、R4 、R5 及R6 具有以上所揭示之含義。
其未經取代或經R5 單取代、二取代或三取代
且其中Q、Y、R1 、R3 、R4 、R5 及R6 具有以上所揭示之含義。
較佳地,本發明係關於式I化合物,其中
R3 為下列結構中之一者:且Q、Y、R1 、R2 、R4 、R5 及R6 具有以上所揭示之含義。
R3 為下列結構中之一者:且Q、Y、R1 、R2 、R4 、R5 及R6 具有以上所揭示之含義。
較佳地,本發明係關於式I化合物,其中
R3 為含有1至6個C原子之O-烷基,其未經取代或經F單取代、二取代或三取代
且Q、Y、R1 、R2 、R4 、R5 及R6 具有以上所揭示之含義。
R3 為含有1至6個C原子之O-烷基,其未經取代或經F單取代、二取代或三取代
且Q、Y、R1 、R2 、R4 、R5 及R6 具有以上所揭示之含義。
較佳地,本發明係關於式I化合物,其中
R3 為OMe
且Q、Y、R1 、R2 、R4 、R5 及R6 具有以上所揭示之含義。
R3 為OMe
且Q、Y、R1 、R2 、R4 、R5 及R6 具有以上所揭示之含義。
特別佳地,本發明係關於一種化合物,其選自由以下組成之群:
及其生理學上可接受之鹽、衍生物、溶劑化物、前藥及立體異構體,包括其等依所有比率之混合物。
式I化合物之以上自由基之所有上述較佳、特別佳及極佳含義應以如下方式理解,使得此等較佳、特別佳及極佳含義或實施例可以任何可能組合彼此組合以得到式I化合物及此類型之較佳、特別佳及極佳式I化合物同樣明確揭示於本文中。
鹵素表示氟、氯、溴及碘,特定言之氟、溴或氯。
−(C=O)−或=O表示羰基氧且代表或藉助雙鍵鍵結至碳原子之氧原子。
烷基為飽和未分支(直鏈)或分支烴鏈且含有1、2、3、4、5、6、7、8、9或10個C原子。烷基較佳地表示烯基甲基,此外乙基、丙基、異丙基、丁基、異丁基、第二丁基或第三丁基,此外亦戊基、1-、2-或3-甲基丁基、1,1-、1,2-或2,2-二甲基丙基、1-乙基丙基、己基、1-、2-、3-或4-甲基戊基、1,1-、1,2-、1,3-、2,2-、2,3-或3,3-二甲基丁基、1-或2-乙基丁基、1-乙基-1-甲基丙基、1-乙基-2-甲基丙基、1,1,2-或1,2,2-三甲基丙基、直鏈或分支鏈庚基、辛基、壬基或癸基,另外較佳地,例如,三氟甲基。
環狀烷基或環烷基為飽和環烴鏈且含有3至10個、較佳地3至7個C原子且較佳地表示環丙基、環丁基、環戊基、環己基或環庚基。環烷基亦表示部分不飽和環狀烷基,諸如例如,環己烯基或環己炔基。
烯基表示不飽和未分支(直鏈)或分支烴鏈且含有1、2、3、4、5、6、7、8、9或10個C原子。
O-烷基或OA表示含有1至6個C原子之直鏈或分支鏈烷氧基,且較佳地為甲氧基,此外亦(例如)乙氧基、正丙氧基、異丙氧基、正丁氧基、異丁氧基、第二丁氧基或第三丁氧基。
烷氧羰基係指本發明之羧酸衍生物之直鏈或分支鏈酯,即,甲氧羰基(MeOCO-)、乙氧羰基或丁氧羰基。
烷基羰基係指直鏈或分支鏈烷基及羧酸基團。
芳基、Ar或芳族環表示單環或多環芳族或完全不飽和環烴鏈,例如,未經取代之苯基、萘基或聯苯基,此外較佳地苯基、萘基或聯苯基,其各者(例如)經以下單取代、二取代或三取代:A、氟、氯、溴、碘、羥基、甲氧基、乙氧基、丙氧基、丁氧基、戊氧基、己氧基、硝基、氰基、甲醯基、乙醯基、丙醯基、三氟甲基、胺基、甲胺基、乙胺基、二甲胺基、二乙胺基、苄氧基、磺胺基、甲基磺胺基、乙基磺胺基、丙基磺胺基、丁基磺胺基、二甲基磺胺基、苯基磺胺基、羧基、甲氧羰基、乙氧羰基、胺基羰基。
雜環及雜環基係指含有選自O、S及N (其另外包含S之氧化形式,即,SO及SO2
)之至少一個雜原子之飽和或不飽和非芳族環或環系。雜環之實例包括四氫呋喃(THF)、二氫呋喃、1,4-二㗁烷、嗎啉、1,4-二噻烷、哌嗪、哌啶、1,3-二㗁茂烷、咪唑啶、咪唑啉、吡咯啉、吡咯啶、四氫哌喃、二氫哌喃、㗁噻茂烷、二噻茂烷、1,3-二㗁烷、1,3-二噻烷、㗁噻烷、硫嗎啉及類似者。
雜芳基意指含有選自O、S及N之至少一個環雜原子之芳族或部分芳族雜環。因此雜芳基包括稠合至其他種類之環(諸如芳基、環烷基及非芳族雜環)之雜芳基。雜芳基之實例包括:吡咯基、異㗁唑基、異噻唑基、吡唑基、吡啶基、㗁唑基、㗁二唑基、噻二唑基、噻唑基、咪唑基、***基、四唑基、呋喃基、三嗪基、噻吩基、嘧啶基、苯并異㗁唑基、苯并㗁唑基、苯并噻唑基、苯并噻二唑基、二氫苯并呋喃基、吲唑啉基、嗒嗪基、吲唑基、異㗁唑基、異吲哚基、二氫苯并噻吩基、吲嗪基、噌啉基、酞嗪基、喹唑啉基、萘啶基、哢唑基、苯并二㗁英、苯并二茂、喹㗁啉基、嘌呤基、呋咱基、苯硫基、異苄基呋喃基、苯并咪唑基、苯并呋喃基、苯并噻吩基、喹啉基、吲唑基、異喹啉基、二苯并呋喃基及類似者。針對形成1至3個環之雜環基及雜芳基,包括含有3至15個原子之環及環系。
單環或雙環飽和、不飽和或芳族雜環較佳地表示未經取代或經單取代、二取代或三取代之2-或3-呋喃基、2-或3-噻吩基、1-、2-或3-吡咯基、1-、2-、4-或5-咪唑基、1-、3-、4-或5-吡唑基、2-、4-或5-㗁唑基、3-、4-或5-異㗁唑基、2-、4-或5-噻唑基、3-、4-或5-異噻唑基、2-、3-或4-吡啶基、2-、4-、5-或6-嘧啶基,此外較佳地1,2,3-***-1-、-4-或-5-基、1,2,4-***-1-、-3-或5-基、1-或5-四唑基、1,2,3-㗁二唑-4-或-5-基、1,2,4-㗁二唑-3-或-5-基、1,3,4-噻二唑-2-或-5-基、1,2,4-噻二唑-3-或-5-基、1,2,3-噻二唑-4-或-5-基、3-或4-嗒嗪基、吡嗪基、1-、2-、3-、4-、5-、6-或7-吲哚基、4-或5-異吲哚基、1-、2-、4-或5-苯并咪唑基、1-、3-、4-、5-、6-或7-苯并吡唑基、2-、4-、5-、6-或7-苯并㗁唑基、3-、4-、5-、6-或7-苯并異㗁唑基、2-、4-、5-、6-或7-苯并噻唑基、2-、4-、5-、6-或7-苯并異噻唑基、4-、5-、6-或7-苯并-2,1,3-㗁二唑基、2-、3-、4-、5-、6-、7-或8-喹啉基、1-、3-、4-、5-、6-、7-或8-異喹啉基、3-、4-、5-、6-、7-或8-噌啉基、2-、4-、5-、6-、7-或8-喹唑啉基、5-或6-喹㗁啉基、2-、3-、5-、6-、7-或8-2H-苯并-1,4-㗁嗪基,另外較佳地1,3-苯并二茂-5-基、1,4-苯并二㗁烷-6-基、2,1,3-苯并噻二唑-4-或-5-基或2,1,3-苯并㗁二唑-5-基。
雜環自由基亦可經部分或完全氫化且亦表示(例如) 2,3-二氫-2-、-3-、-4-或-5-呋喃基、2,5-二氫-2-、-3-、-4-或5-呋喃基、四氫-2-或-3-呋喃基、1,3-二㗁茂烷-4-基、四氫-2-或-3-噻吩基、2,3-二氫-1-、-2-、-3-、-4-或-5-吡咯基、2,5-二氫-1-、-2-、-3-、-4-或-5-吡咯基、1-、2-或3-吡咯啶基、四氫-1-、-2-或-4-咪唑基、2,3-二氫-1-、-2-、-3-、-4-或-5-吡唑基、四氫-1-、-3-或-4-吡唑基、1,4-二氫-1-、-2-、-3-或-4-吡啶基、1,2,3,4-四氫-1-、-2-、-3-、-4-、-5-或-6-吡啶基、1-、2-、3-或4-哌啶基、2-、3-或4-嗎啉基、四氫-2-、-3-或-4-哌喃基、1,4-二㗁烷基、1,3-二㗁烷-2-、-4-或-5-基、六氫-1-、-3-或-4-嗒嗪基、六氫-1-、-2-、-4-或-5-嘧啶基、1-、2-或3-哌嗪基、1,2,3,4-四氫-1-、-2-、-3-、-4-、-5-、-6-、-7-或-8-喹啉基、1,2,3,4-四氫-1-、-2-、-3-、-4-、-5-、-6-、-7-或-8-異喹啉基、2-、3-、5-、6-、7-或8-3,4-二氫-2H-苯并-1,4-㗁嗪基,另外較佳地2,3-亞甲基二氧基苯基、3,4-亞甲基二氧基苯基、2,3-伸乙基二氧基苯基、3,4-伸乙基二氧基苯基、3,4-(二氟亞甲基二氧基)苯基、2,3-二氫苯并呋喃-5-或6-基、2,3-(2-側氧基亞甲基二氧基)苯基或亦3,4-二氫-2H-1,5-苯并二㗁呯-6-或-7-基,此外較佳地2,3-二氫苯并呋喃基或2,3-二氫-2-側氧基呋喃基。
此外雜環表示(例如) 2-側氧基哌啶-1-基、2-側氧基吡咯啶-1-基、2-側氧基-1H
-吡啶-1-基、3-側氧基嗎啉-4-基、4-側氧基-1H
-吡啶-1-基、2,6-二側氧基哌啶-1-基、2-側氧基哌嗪-1-基、2,6-二側氧基哌嗪-1-基、2,5-二側氧基吡咯啶-1-基、2-側氧基-1,3-㗁唑啶-3-基、3-側氧基-2H
-嗒嗪-2-基、2-己內醯胺-1-基(= 2-側氧基氮雜環庚烷-1-基)、2-羥基-6-側氧基哌嗪-1-基、2-甲氧基-6-側氧基哌嗪-1-基或2-氮雜二環[2.2.2]辛-3-酮-2-基。
本文中雜環烷基表示完全氫化或飽和雜環,雜環烯基(一或多個雙鍵)或雜環炔基(一或多個三鍵)表示部分或不完全氫化或不飽和雜環,雜芳基表示芳族或完全不飽和雜環。
與本發明有關之環烷基芳基意指一或兩個芳族環Ar縮合至未經取代或經單取代或二取代之環烷基中,其中一或兩個CH2
基團及/或此外,1至11個H原子可經置換,(諸如例如)於下述自由基中:
。
。
此外,以下縮略語具有下列含義:
Boc 第三丁氧羰基
CBZ 苄氧羰基
DNP 2,4-二硝基苯基
FMOC 9-茀基甲氧羰基
imi-DNP 於咪唑環中之1位置中之2,4-二硝基苯基
OMe 甲酯
POA 苯氧乙醯基
DCCI 二環己基碳二亞胺
HOBt 1-羥基苯并***
Boc 第三丁氧羰基
CBZ 苄氧羰基
DNP 2,4-二硝基苯基
FMOC 9-茀基甲氧羰基
imi-DNP 於咪唑環中之1位置中之2,4-二硝基苯基
OMe 甲酯
POA 苯氧乙醯基
DCCI 二環己基碳二亞胺
HOBt 1-羥基苯并***
因此本發明係關於一種醫藥製劑,其包含根據本發明化合物及/或其生理學上可接受之鹽、衍生物、溶劑化物、前藥及立體異構體中之一者(包括其等依所有比率之混合物)。
本發明亦關於此類型之根據本發明之醫藥製劑,其另外包含賦形劑及/或佐劑。
此外,本發明係關於以上根據本發明之醫藥製劑,其包含至少一種其他藥物活性化合物。
醫藥上或生理學上可接受之衍生物意指(例如)本發明化合物之鹽及亦所謂之前藥化合物。前藥化合物意指已藉助(例如)烷基或醯基(亦參見以下胺基保護基及羥基保護基)、糖或寡肽修飾且於生物體中快速裂解或釋放以形成有效分子之本發明化合物的衍生物。此等亦包括本發明化合物之可生物降解聚合物衍生物,如(例如)於Int. J. Pharm. 115 (1995), 61-67中所述。
本發明化合物可呈其最終非鹽形式使用。另一方面,本發明亦涵蓋使用呈其醫藥上可接受之鹽形式之胃蛋白酶抑制素(pepstatin),該等鹽可藉由此項技術中已知程序,自各種有機鹼及無機鹼衍生。胃蛋白酶抑制素之醫藥上可接受之鹽形式大部分藉由習知方法製備。若本發明化合物含有羧基,則其一種適宜鹽可藉由本發明化合物與適宜鹼反應形成,得到對應鹼加成鹽。此等鹼為(例如)鹼金屬氫氧化物,包括氫氧化鉀、氫氧化鈉及氫氧化鋰;鹼土金屬氫氧化物,諸如氫氧化鋇及氫氧化鈣;鹼金屬烷醇鹽,例如,乙醇鉀及丙醇鈉;及各種有機鹼,諸如哌啶、二乙醇胺及N-甲基-麩胺醯胺。同樣包括胃蛋白酶抑制素之鋁鹽。
此外,本發明化合物之鹼式鹽包括鋁鹽、銨鹽、鈣鹽、銅鹽、鐵(III)鹽、亞鐵(II)鹽、鋰鹽、鎂鹽、錳(III)鹽、亞錳(II)鹽、鉀鹽、鈉鹽及鋅鹽,但是無意代表限制。
上述鹽中,較佳為銨鹽、鹼金屬鈉及鉀鹽及鹼土金屬鈣及鎂鹽。衍生自醫藥上可接受之有機無毒鹼之本發明化合物之鹽包括以下之鹽:一級、二級及三級胺、經取代之胺,亦包括自然產生之經取代之胺、環胺及鹼性離子交換劑樹脂,例如,精胺酸、甜菜鹼、咖啡因、氯普魯卡因(chloroprocaine)、膽鹼、N,N'-二苄基乙二胺(苄星)、二環己基胺、二乙醇胺、二乙胺、2-二乙胺基乙醇、2-二甲胺基乙醇、乙醇胺、乙二胺、N-乙基嗎啉、N-乙基哌啶、葡糖胺、胺基葡萄糖、組胺酸、海巴明(hydrabamine)、異丙胺、利多卡因(lidocaine)、離胺酸、甲葡胺、N-甲基-D-葡糖胺、嗎啉、哌嗪、哌啶、聚胺樹脂、普魯卡因(procaine)、嘌呤、可哥鹼、三乙醇胺、三乙胺、三甲胺、三丙胺及三(羥甲基)甲胺(胺丁三醇),但是此不旨在表示限制。
如所提及,利用金屬或胺(諸如鹼金屬及鹼土金屬或有機胺)形成胃蛋白酶抑制素之醫藥上可接受之鹼加成鹽。較佳金屬為鈉、鉀、鎂及鈣。較佳有機胺為N,N’-二苄基乙二胺、氯普魯卡因、膽鹼、二乙醇胺、乙二胺、N-甲基-D-葡糖胺及普魯卡因。
藉由使游離酸形式與足夠量之所需鹼接觸,以習知方式造成鹽之形成來製備本發明化合物之鹼加成鹽。游離酸可藉由使鹽形式與酸接觸且以習知方式單離該游離酸再生。關於某些物理性質(諸如於極性溶劑中之溶解度),游離酸形式於某方面不同於其對應鹽形式;然而,出於本發明之目的,鹽原本對應於其各自游離酸形式。
鑑於上述情況,可看出於本聯繫中術語「醫藥上可接受之鹽」意指活性化合物,其包括呈其鹽中之一者之形式之本發明化合物,特定言之若與活性化合物之游離形式或更早使用之活性化合物之任何其他鹽形式相比,此鹽形式賦予活性化合物之改善之藥物動力學性質。活性化合物之醫藥上可接受之鹽形式亦可第一次提供具有所需藥物動力學性質之此活性化合物,該活性化合物早期不具有該性質且甚至可關於其於體內之療效對此活性化合物之藥物動力學產生積極影響。
本發明化合物之溶劑化物意指惰性溶劑分子胃蛋白酶抑制素之加合物,該等加合物由於其相互吸引力而形成。溶劑化物為(例如)水合物(諸如一水合物或二水合物)或醇化物(即,與醇(諸如例如,與甲醇或乙醇)之加成化合物)。
此等化合物之所有生理學上可接受之鹽、衍生物、溶劑化物及立體異構體(包括其等依所有比率之混合物)亦與本發明一致。
通式I之化合物可含有一或多個對掌性中心,使得本發明亦主張通式I化合物之所有立體異構體、對映異構體、非對映異構體等。
本發明亦關於此等化合物之光學活性形式(立體異構體)、對映異構體、外消旋體、非對映異構體及水合物及溶劑化物。
由於其分子結構,根據本發明之式I化合物可係對掌性及因此可呈各種對映異構形式出現。因此其可呈外消旋或光學活性形式。因為根據本發明化合物之外消旋體或立體異構體之醫藥功效可不同,所以可期望使用對映異構體。於此等情況下,可藉由為熟習此項技術者已知或已於合成中如此採用之化學或物理措施將不僅最終產物而且甚至中間體分離成對映異構化合物。
醫藥上或生理上可接受之衍生物意指(例如)根據本發明化合物之鹽及亦所謂之前藥化合物。前藥化合物意指已利用(例如)烷基或醯基(亦參見以下胺基保護基及羥基保護基)、糖或寡肽修飾且於生物體中快速裂解或釋放以形成根據本發明之有效化合物之式I化合物。此等亦包括根據本發明化合物之可生物降解聚合物衍生物,如(例如)於Int. J. Pharm. 115 (1995), 61-67中所述。
適宜酸加成鹽為所有生理學上或醫藥上可接受之酸之無機或有機鹽,例如,鹵化物(特定言之鹽酸鹽或氫溴酸鹽)、乳酸鹽、硫酸鹽、檸檬酸鹽、酒石酸鹽、馬來酸鹽、富馬酸鹽、草酸鹽、乙酸鹽、磷酸鹽、甲基磺酸鹽或對甲苯磺酸鹽。
極佳為根據本發明之化合物之鹽酸鹽、三氟乙酸鹽或雙三氟乙酸鹽。
式I化合物之溶劑化物意指式I化合物上之惰性溶劑分子之加合物,該加合物由於其相互吸引力形成。溶劑化物為(例如)水合物(諸如一水合物或二水合物)或醇化物(即,與醇(諸如例如,與甲醇或乙醇)之加成化合物)。
此外,期望式I化合物包括其同位素標記形式。式I化合物之同位素標記形式與此化合物相同,不同在於以下事實:化合物之一或多個原子已經具有不同於通常自然出現之原子之原子質量或質量數之原子質量或質量數之原子置換。容易市面上購得且可藉由熟知方法併入式I化合物中之同位素之實例包括氫、碳、氮、氧、磷、氟及氯之同位素,例如,各自為2
H、3
H、13
C、14
C、15
N、18
O、17
O、31
P、32
P、35
S、18
F及36
Cl。含有上述同位素中之一或多者及/或其他原子之其他同位素之式I化合物、其前藥或醫藥上可接受之鹽意在為本發明之部分。可以許多有益方式使用同位素標記之式I化合物。例如,已併入(例如)放射性同位素(諸如3
H或14
C)之式I之同位素標記化合物適用於藥劑及/或受質組織分佈檢定。此等放射性同位素,即,氚(3
H)及碳-14 (14
C)係特別佳的,由於其簡單製備及優異可探測性。較重同位素(例如,氘(2
H))併入式I化合物具有治療性優點,由於此同位素標記化合物之更高代謝穩定性。更高代謝穩定性直接轉化成增加之活體內半衰期或更低劑量,其在大多數情況下將代表本發明之較佳實施例。同位素標記之式I化合物通常可藉由進行於合成反應圖及相關描述中、於本文之實例部分及製備部分中所揭示之程序,利用容易購得之同位素標記之反應物替換非同位素標記之反應物製備。
為藉由主要動力學同位素效應操縱化合物之氧化代謝,亦可將氘(2
H)併入式I化合物中。主要動力學同位素效應為由同位素核之交換引起之化學反應速率的變化,其繼而由用於此同位素交換後之共價鍵形成必需之基態能量的變化造成。較重同位素之交換通常導致化學鍵之基態能量之降低及因此造成速率限制鍵斷裂中之速率降低。若鍵斷裂發生於沿著多產物反應之坐標之鞍點區域或於其附近,則可大體上更改產物分佈比率。關於解釋:若於非可交換位置將氘鍵結至碳原子,則kM
/kD
= 2-7之速率差異係典型。若將此速率差異成功地應用至易氧化之式I化合物,則活體內此化合物之特性從而可大幅修改且導致改善之藥物動力學性質。
當發現及開發治療劑時,熟習此項技術者試圖最佳化藥物動力學參數,同時保留所需活體外性質。合理假定具有差的藥物動力學特性之許多化合物易於氧化代謝。現有活體外肝微粒體檢定在此類型之氧化代謝過程中提供有價值資訊,其繼而允許通過對此氧化代謝之抗性合理設計具有提高穩定性之氘化式I化合物。從而獲得式I化合物之藥物動力學特性之顯著改善且可根據活體內半衰期(T/2)之增加、最大療效下之濃度(Cmax
)、劑量反應曲線下面積(AUC)及F;及根據降低之清除率、劑量及材料成本定量表示。
下列意欲說明上述:將具有多個氧化代謝之潛在攻擊位點(例如,苄氫原子及鍵結至氮原子之氫原子)之式I化合物製備為一系列類似物,其中各種組合之氫原子經氘原子置換,使得此等氫原子中之大多數或所有經氘原子置換。半衰期測定使能有利且精確測定對氧化代謝之抗性之改善改善之程度。以此方式,確定母體化合物之半衰期可由於此類型之氘-氫交換而延長多達100%。
亦可使用於式I化合物中氘置換氫以達成起始化合物之代謝光譜之有利修改以減少或消除非所需毒性代謝產物。例如,若毒性代謝產物通過氧化碳-氫(C-H)鍵斷裂產生,則可合理假定氘化類似物將極大減少或消除非所需代謝產物之產生,即使特定氧化為非速率決定步驟。例如,於Hanzlik等人,J. Org. Chem. 55, 3992-3997, 1990;Reider等人,J. Org. Chem. 52, 3326-3334, 1987;Foster, Adv. Drug Res. 14, 1-40, 1985;Gillette等人,Biochemistry 33(10), 2927-2937, 1994及Jarman等人,Carcinogenesis 16(4), 683-688, 1993中提供關於氘-氫交換之申請專利當時之技術水平之其他資訊。
本發明亦關於根據本發明之式I化合物之混合物,例如,兩種非對映異構體例如以1:1、1:2、1:3、1:4、1:5、1:10、1:100或1:1000之比率之混合物。此等為兩種立體異構化合物之特別佳混合物。然而,亦較佳為兩種或更多種式I化合物之混合物。
此外,本發明係關於一種製備式I化合物之方法,其特徵在於:
a)使式II化合物經歷硝化反應,接著還原以得到式IV化合物,將式IV化合物環化以得到式V化合物,將式V化合物氯化,接著銅催化胺化反應以得到化合物VII,採用觸酶及鹼使式VII化合物於鈴木型反應中反應成為式VIII化合物,藉由標準醯胺化或脲形成條件將式VIII化合物轉化成式I化合物,其中Q、Y、R1 、R2 及R3 具有如上所揭示之含義,
b)在鈴木型反應條件下,使式III化合物與二羥基硼酸酯或酸反應以得到式IX化合物或在提高溫度下於親核取代反應中與胺反應以形成式IX化合物,將式IX化合物還原為式X化合物並環化為式XI化合物,將式XI化合物氯化,接著銅催化胺化以得到化合物VIII及最終在標準醯胺化或脲形成條件下使化合物VIII反應成為式I化合物且其中Q、Y、R1 、R2 及R3 具有如上所揭示之含義,
c)在鈴木型反應條件下,使式XIII化合物與二羥基硼酸酯或酸反應以得到式XIV化合物,將式XIV化合物還原為式X化合物並環化為式XI化合物,將式XI化合物甲苯磺酸酯化,接著金屬催化胺化以得到化合物VIII及最終在標準醯胺化或脲形成條件下使化合物VIII反應成為式I化合物且其中Q、Y、R1 、R2 及R3 具有如上所揭示之含義,
d)藉由用酸處理將式I化合物之鹼轉化成其鹽中之一者,或
e)藉由用鹼處理將式I化合物之酸轉化成其鹽中之一者。
a)使式II化合物經歷硝化反應,接著還原以得到式IV化合物,將式IV化合物環化以得到式V化合物,將式V化合物氯化,接著銅催化胺化反應以得到化合物VII,採用觸酶及鹼使式VII化合物於鈴木型反應中反應成為式VIII化合物,藉由標準醯胺化或脲形成條件將式VIII化合物轉化成式I化合物,其中Q、Y、R1 、R2 及R3 具有如上所揭示之含義,
b)在鈴木型反應條件下,使式III化合物與二羥基硼酸酯或酸反應以得到式IX化合物或在提高溫度下於親核取代反應中與胺反應以形成式IX化合物,將式IX化合物還原為式X化合物並環化為式XI化合物,將式XI化合物氯化,接著銅催化胺化以得到化合物VIII及最終在標準醯胺化或脲形成條件下使化合物VIII反應成為式I化合物且其中Q、Y、R1 、R2 及R3 具有如上所揭示之含義,
c)在鈴木型反應條件下,使式XIII化合物與二羥基硼酸酯或酸反應以得到式XIV化合物,將式XIV化合物還原為式X化合物並環化為式XI化合物,將式XI化合物甲苯磺酸酯化,接著金屬催化胺化以得到化合物VIII及最終在標準醯胺化或脲形成條件下使化合物VIII反應成為式I化合物且其中Q、Y、R1 、R2 及R3 具有如上所揭示之含義,
d)藉由用酸處理將式I化合物之鹼轉化成其鹽中之一者,或
e)藉由用鹼處理將式I化合物之酸轉化成其鹽中之一者。
亦可於各種情況下進行逐步反應及適應保護基觀念以修改構建塊之聯接反應之順序。
起始物質或起始化合物一般係已知。若其係新穎的,則其可藉由本身已知方法製備。
若所需,則起始物質亦可藉由不將其自反應混合物單離,但是代之以立即將其進一步轉化成式I化合物而原位形成。
較佳地,式I化合物藉由溶解分解,特定言之藉由水解或藉由氫解將其自其含官能基之衍生物釋放獲得。用於溶劑分解或氫解之較佳起始物質為含有代替一或多個游離胺基、羧基及/或羥基之對應保護胺基、羧基及/或羥基之彼等,較佳地攜帶代替與N原子連接之H原子之胺基保護基之彼等。此外較佳為攜帶代替羥基之H原子之羥基保護基之起始物質。亦較佳為攜帶代替游離羧基之經保護羧基之起始物質。複數個相同或不同經保護胺基、羧基及/或羥基亦可存在於起始物質之分子中。若存在之保護基彼此不同,則可將其於許多情況下選擇性地裂解除去。
術語「胺基保護基」一般係已知及關於適用於保護(阻止)胺基避免化學反應但是可於分子中其他地方進行所需化學反應後容易移除之基團。此等基團之典型為(特定言之)未經取代或經取代之醯基,此外未經取代或經取代之芳基(例如,2,4-二硝基苯基)或芳烷基(例如,苄基、4-硝基苄基、三苯基甲基)。因為胺基保護基於所需反應或反應順序後移除,所以此外其類型及大小係不關鍵,但是較佳為含有1至20個,特定言之1至8個C原子之彼等。應以與本方法有關之最廣泛意義上理解術語「醯基」。其涵蓋衍生自脂族、芳脂族(araliphatic)、芳族或雜環羧酸或磺酸之醯基,及特定言之,烷氧羰基、芳氧羰基及尤其芳烷氧羰基。此等醯基之實例為烷醯基(諸如乙醯基、丙醯基、丁醯基)、芳烷醯基(諸如苯乙醯基)、芳醯基(諸如苯甲醯基或甲苯甲醯基)、芳氧基烷醯基(諸如,苯氧基乙醯基)、烷氧羰基(諸如甲氧羰基、乙氧羰基、2,2,2-三氯乙氧羰基、BOC、2-碘乙氧羰基)、芳烷氧基羰基(諸如CBZ、4-甲氧基苄氧羰基或FMOC)。較佳醯基為CBZ、FMOC、苄基及乙醯基。
術語「酸保護基」或「羧基保護基」同樣一般係已知及關於適用於保護-COOH基團避免化學反應但是可於分子中其他地方進行所需化學反應後容易移除之基團。使用酯代替游離酸,例如,使用經取代及未經取代之烷基酯(諸如甲基、乙基、第三丁基及其經取代之衍生物),使用經取代及未經取代之苄基酯或甲矽烷基酯係典型。酸保護基之類型及大小係不關鍵,但是較佳為含有1至20個,特定言之1至10個C原子之彼等。
術語「羥基保護基」同樣一般係已知及關於適用於保護羥基避免化學反應但是可於分子中其他地方進行所需化學反應後容易移除之基團。此等基團之典型為上述未經取代或經取代之芳基、芳烷基或醯基,此外亦烷基。羥基保護基之其類型及大小係不關鍵,但是較佳為含有1至20個,特定言之1至10個C原子之彼等。羥基保護基之實例為(尤其)苄基、對硝基苯甲醯基、對甲苯磺醯基及乙醯基,其中苄基及乙醯基係較佳。
胺基保護基、酸保護基及羥基保護基之其他典型實例見於(例如)「Greene’s Protective Groups in Organic Synthesis」,第四版,Wiley-Interscience,2007。
可藉由如(例如)於該等標準著作及專利申請案中所述之胺基酸及肽合成之已知方法製備待用作起始物質之式I化合物之含官能基衍生物。
取決於使用之保護基,例如,藉助強酸,不僅有利地使用三氟乙酸或高氯酸,而且使用其他強無機酸(諸如鹽酸或硫酸)、強有機酸(諸如三氟乙酸或磺酸(諸如苯甲醯基磺酸或對甲苯磺酸)),將式I化合物自其含官能基衍生物釋放。額外惰性溶劑及/或觸媒之存在係可能,但是不總是必要。
取決於各自合成途徑,起始物質可視情況在惰性溶劑之存在下反應。
適宜惰性溶劑為(例如)庚烷、己烷、石油醚、DMSO、苯、甲苯、二甲苯、三氯乙烯、1,2-二氯乙烷-四氯化碳、氯仿或二氯甲烷;醇,諸如甲醇、乙醇、異丙醇、正丙醇、正丁醇或第三丁醇;醚,諸如***、二異丙醚(較佳地在吲哚氮上之取代)、四氫呋喃(THF)或二㗁烷;二醇醚,諸如乙二醇單甲醚或單***、乙二醇二甲基-l醚(二甘醇二甲醚);酮,諸如丙酮或丁酮;醯胺,諸如乙醯胺、二甲基乙醯胺、N-甲基吡咯啶酮(NMP)或二甲基甲醯胺(DMF);腈,諸如乙腈;酯,諸如乙酸乙酯;羧酸或酸酐,諸如,例如,諸如乙酸或乙酸酐;硝基化合物,諸如硝基甲烷或硝基苯,視情況亦該等溶劑彼此之混合物或與水之混合物。
溶劑之量係不關鍵;較佳地每克待反應之式I化合物可添加10 g至500 g溶劑。
可有利地添加酸結合劑,例如,鹼金屬或鹼土金屬氫氧化物、碳酸鹽或重碳酸鹽或弱酸之其他鹼金屬鹽或鹼土金屬鹽,較佳地鉀鹽、鈉鹽或鈣鹽,或添加有機鹼,諸如例如,三乙胺、二甲胺、吡啶或喹啉,或過量胺組分。
所得根據本發明之化合物可自對應溶液分離,其中其可製備(例如,藉由離心及洗滌)且可於分離後儲存於另一組合物中,或其可直接保留於製備溶液中。所得根據本發明之化合物亦可溶於期望溶劑中用於特定用途。
反應持續時間取決於所選之反應條件。一般而言,反應持續時間為0.5小時至10天,較佳地1至24小時。使用微波時,反應時間可減少至1至60分鐘之值。
此外,藉由如文獻(例如,標準著作,諸如Houben-Weyl, Methoden der organischen Chemie [有機化學方法], Georg-Thieme-Verlag, Stuttgart)中所述之已知方法,(例如)在已知且適用於該等反應之反應條件下製備式I化合物及亦用於其製備之起始物質。本文中亦可使用本身已知之變型,本文中未更詳細描述該等變型。
習知處理步驟,諸如例如,添加水至反應混合物中及萃取使於移除溶劑後能獲得化合物。對於產物之進一步純化,隨後利用蒸餾或結晶或進行層析法純化可係有利的。
使用鹼,例如,藉由等量酸及鹼於惰性溶劑(諸如乙醇)中之反應及包括蒸發將式I之酸轉化成相關加成鹽。用於此反應之適宜鹼為(特定言之)提供生理學上可接受之鹽之彼等。因此,可使用鹼(例如,氫氧化鈉、氫氧化鉀、碳酸鈉或碳酸鉀)將式I之酸轉化成對應金屬鹽(特定言之鹼金屬鹽或鹼土金屬鹽)或對應銨鹽。提供生理學上可接受之鹽之有機鹼(諸如,例如,乙醇胺)亦適用於此反應。
另一方面,可使用酸,例如,藉由等量鹼及酸於惰性溶劑(諸如乙醇)中之反應,隨後蒸發將式I之鹼轉化成相關酸加成鹽。用於此反應之適宜酸為(特定言之)提供生理學上可接受之鹽之彼等。因此,可使用無機酸,例如,硫酸、硝酸、氫鹵酸(諸如鹽酸或氫溴酸)、磷酸(諸如正磷酸)、胺基磺酸,此外有機酸,特定言之脂族、脂環族、芳脂族、芳族或雜環單羧酸或多元羧酸、磺酸或硫酸,例如,甲酸、乙酸、丙酸、新戊酸、二乙基乙酸、丙二酸、琥珀酸、庚二酸、富馬酸、馬來酸、乳酸、酒石酸、蘋果酸、檸檬酸、葡糖酸、抗壞血酸、菸酸、異菸酸、甲磺酸或乙磺酸、乙烷二磺酸、2-羥基磺酸、苯磺酸、對甲苯磺酸、萘單磺酸及二磺酸或月桂基硫酸。可使用含有生理學上不可接受之酸之鹽(例如,苦味酸鹽)用於式I化合物之單離及/或純化。
已發現式I化合物係良好耐受且具有有價值之藥理性質。
因為顯示腺苷受體(諸如A2A
及A2B
)下調發炎期間之免疫反應及保護組織免受免疫損傷,所以可使用通過腺苷受體之信號傳導之抑制以增強且延長免疫反應。
本文中提供增加免疫反應之方法。於一實例中,該方法增加所需及靶向組織損傷,諸如腫瘤(例如,癌症)損傷。本文中揭示抑制有助於細胞外腺苷之產生及腺苷觸發之通過腺苷受體之信號傳導之一或多個過程的方法。例如,藉由以下實現免疫反應、局部組織發炎及靶向組織破壞之增強:抑制或減少腺苷產生之局部組織缺氧;降解(或使失活)累積之細胞外腺苷;防止或減少免疫細胞上之腺苷受體之表現;及/或抑制/拮抗藉由腺苷配位體通過腺苷受體之信號傳導。本文中揭示之結果證實,藉由對患有各種疾病(例如,癌症及敗血症)之個體活體內投與擾亂「缺氧->腺苷累積->免疫抑制腺苷受體向免疫細胞之信號傳導」路徑之藥劑可導致腫瘤之活體內治療或提高之免疫。
於一實例中,該方法包括投與細胞外腺苷之一或多種抑制劑及/或腺苷受體抑制劑(諸如腺苷受體拮抗劑)。為增加疫苗之功效,可聯合疫苗投與一或多種腺苷受體抑制劑及/或細胞外腺苷之抑制劑。於一實例中,投與一或多種腺苷受體抑制劑或細胞外腺苷之抑制劑以增加免疫反應/發炎。於另一實例中,提供一種方法以達成靶向組織損傷,諸如用於腫瘤破壞。
因此,本發明此外係關於根據本發明化合物用於製備用於治療及/或預防由腺苷或其他A2A
及/或A2B
受體促效劑引起、促進及/或傳播之疾病之藥劑的用途。
因此本發明亦關於(特定言之)一種藥劑,其包含至少一種根據本發明之化合物及/或其生理學上可接受之鹽、衍生物、溶劑化物、前藥及立體異構體中之一者(包括其等依所有比率之混合物),其用於治療及/或預防生理學及/或病理生理學狀態。
特別佳為(特定言之)與腺苷A2A
及/或A2B
受體相關之生理學及/或病理生理學狀態。
生理學及/或病理生理學狀態意指醫學相關之生理學及/或病理生理學狀態,諸如例如,疾病或病及醫學病症、疾患、症狀或併發症及類似者,特定言之疾病。
此外本發明係關於一種藥劑,其包含至少一種根據本發明之化合物及/或其生理學上可接受之鹽、衍生物、溶劑化物、前藥及立體異構體中之一者(包括其等依所有比率之混合物),其用於治療及/或預防選自由過度增生性及傳染性疾病及病症組成之群之生理學及/或病理生理學狀態。
本發明另外關於一種藥劑,其包含至少一種根據本發明之化合物及/或其生理學上可接受之鹽、衍生物、溶劑化物、前藥及立體異構體中之一者(包括其等依所有比率之混合物),其用於治療及/或預防選自由過度增生性及傳染性疾病及病症組成之群之生理學及/或病理生理學狀態,其中該過度增生性疾病或病症為癌症。
因此本發明特別佳地關於一種藥劑,其包含至少一種根據本發明之化合物及/或其生理學上可接受之鹽、衍生物、溶劑化物、前藥及立體異構體中之一者(包括其等依所有比率之混合物),其中該癌症係選自由以下組成之群:急性及慢性淋巴細胞性白血病、急性粒細胞性白血病、腎上腺皮質癌、膀胱癌、腦癌、乳癌、子宮頸癌、子宮頸增生、絨膜癌、慢性粒細胞性白血病、慢性淋巴細胞性白血病、結腸癌、子宮內膜癌、食道癌、原發性血小板增多症、泌尿生殖道癌、神經膠質瘤、神經膠質母細胞瘤、毛細胞白血病、頭頸癌、霍奇金氏病(Hodgkin's disease)、卡波西氏肉瘤(Kaposi's sarcoma)、肺癌、淋巴瘤、惡性類癌、惡性高鈣血症、惡性黑色素瘤、惡性胰臟胰島素瘤、骨髓性甲狀腺癌、黑色素瘤、多發性骨髓瘤、蕈樣肉芽腫、骨髓性及淋巴細胞性白血病、神經母細胞瘤、非霍奇金氏淋巴瘤、非小細胞肺癌、骨原性肉瘤、卵巢癌、胰癌、真性紅血球增多症、原發性腦癌、原發性巨球蛋白血症、***癌、腎細胞癌、橫紋肌肉瘤、皮膚癌、小細胞肺癌、軟組織肉瘤、鱗狀細胞癌、胃癌、睾丸癌、甲狀腺癌及威爾姆氏瘤(Wilms' tumor)。
本發明另外較佳地關於一種藥劑,其包含至少一種根據本發明之化合物及/或其生理學上可接受之鹽、衍生物、溶劑化物、前藥及立體異構體中之一者(包括其等依所有比率之混合物),其用於治療及/或預防選自由過度增生性及傳染性疾病及病症組成之群之生理學及/或病理生理學狀態,其中該過度增生性疾病或病症係選自由以下組成之群:年齡相關之黃斑部變性、克羅恩氏病(Crohn's disease)、肝硬化、慢性發炎相關病症、增生性糖尿病視網膜病變、增生性玻璃體視網膜病變、早產兒視網膜病變、肉芽腫病、與器官或組織移植相關之免疫過度增生及選自由發炎性腸病、牛皮癬、類風濕性關節炎、全身性紅斑狼瘡(SLE)、繼發於視網膜缺氧及血管炎之血管過度增生組成之群之免疫增生性疾病或病症。
本發明另外較佳地關於一種藥劑,其包含至少一種根據本發明之化合物及/或其生理學上可接受之鹽、衍生物、溶劑化物、前藥及立體異構體中之一者(包括其等依所有比率之混合物),其用於治療及/或預防選自由過度增生性及傳染性疾病及病症組成之群之生理學及/或病理生理學狀態,其中該傳染性疾病或病症係選自由以下組成之群:
a)由逆轉錄病毒、嗜肝DNA病毒、皰疹病毒、黃病毒科及/或腺病毒引起之病毒誘導之傳染性疾病,其中該逆轉錄病毒係選自慢病毒或致癌逆轉錄病毒,其中該慢病毒係選自由HIV-1、HIV-2、FIV、BIV、SIV、SHIV、CAEV、VMV及EIAV組成之群及該致癌逆轉錄病毒係選自由HTLV-I、HTLV-II及BLV組成之群,該嗜肝DNA病毒係選自由HBV、GSHV及WHV組成之群,該皰疹病毒係選自由HSV I、HSV II、EBV、VZV、HCMV或HHV 8組成之群及該黃病毒科係選自由HCV、西尼羅河(West nile)熱及黃熱病(Yellow Fever)組成之群,
b)由革蘭氏陽性細菌引起之細菌傳染性疾病,其中該革蘭氏陽性細菌係選自由以下組成之群:甲氧西林(methicillin)易感及甲氧西林抗藥性葡萄球菌(staphylococci) (包括金黃色葡萄球菌(Staphylococcus aureus)、表皮葡萄球菌(Staphylococcus epidermidis)、溶血性葡萄球菌(Staphylococcus haemolyticus)、人葡萄球菌(Staphylococcus hominis)、腐生性葡萄球菌(Staphylococcus saprophyticus)及凝固酶陰性葡萄球菌)、糖肽中間體易感性金黃色葡萄球菌(GISA)、盤尼西林(penicillin)易感及盤尼西林抗藥性鏈球菌(streptococci) (包括肺炎鏈球菌(Streptococcus pneumoniae)、化膿性鏈球菌(Streptococcus pyogenes)、無乳鏈球菌(Streptococcus agalactiae)、鳥鏈球菌(Streptococcus avium)、牛鏈球菌(Streptococcus bovis)、乳鏈球菌(Streptococcus lactis)、血鏈球菌(Streptococcus sanguis)及鏈球菌C組(GCS)、鏈球菌G組(GGS)及草綠色鏈球菌(viridans streptococci))、腸球菌(enterococci) (包括萬古黴素(vancomycin)易感及萬古黴素抗藥性株(諸如糞腸球菌(Enterococcus faecalis)及屎腸球菌(Enterococcus faecium))、艱難梭菌(Clostridium difficile)、單核細胞增生性李斯特氏菌(listeria monocytogenes)、傑氏棒狀桿菌(Corynebacterium jeikeium)、衣原體屬(Chlamydia spp) (包括肺炎衣原體(C. pneumoniae))及結核分枝桿菌(Mycobacterium tuberculosis),
c)由革蘭氏陰性細菌引起之細菌傳染性疾病,其中該革蘭氏陰性細菌係選自由腸桿菌屬(Genus Enterobacteriacae)組成之群,該腸桿菌屬包括埃希氏菌屬(Escherichia spp.) (包括大腸桿菌(Escherichia coli))、克雷伯氏菌屬(Klebsiella spp.)、腸桿菌屬(Enterobacter spp.)、檸檬酸桿菌屬(Citrobacter spp.)、沙雷氏菌屬(Serratia spp.)、變形桿菌屬(Proteus spp.)、普羅威登斯菌屬(Providencia spp.)、沙門氏菌屬(Salmonella spp.)、志賀氏菌屬(Shigella spp.)、假單胞菌屬(genus Pseudomonas) (包括綠膿桿菌(P. aeruginosa))、莫拉氏菌屬(Moraxella spp.) (包括卡他莫拉菌(M. catarrhalis))、嗜血桿菌屬(Haemophilus spp.)及奈瑟氏菌屬(Neisseria spp.),
d)由選自由以下組成之群之細胞內活性寄生蟲誘導之傳染性疾病:頂複門(Apicomplexa)或肉足鞭毛門(Sarcomastigophora) (包括錐蟲屬(Trypanosoma)、瘧原蟲屬(Plasmodia)、利什曼原蟲屬(Leishmania)、巴貝蟲屬(Babesia)或泰勒原蟲屬(Theileria))、隱孢子蟲屬(Cryptosporidia)、肉孢子蟲科(Sacrocystida)、變形蟲屬(Amoebia)、球蟲屬(Coccidia)及毛滴蟲屬(Trichomonadia)。
a)由逆轉錄病毒、嗜肝DNA病毒、皰疹病毒、黃病毒科及/或腺病毒引起之病毒誘導之傳染性疾病,其中該逆轉錄病毒係選自慢病毒或致癌逆轉錄病毒,其中該慢病毒係選自由HIV-1、HIV-2、FIV、BIV、SIV、SHIV、CAEV、VMV及EIAV組成之群及該致癌逆轉錄病毒係選自由HTLV-I、HTLV-II及BLV組成之群,該嗜肝DNA病毒係選自由HBV、GSHV及WHV組成之群,該皰疹病毒係選自由HSV I、HSV II、EBV、VZV、HCMV或HHV 8組成之群及該黃病毒科係選自由HCV、西尼羅河(West nile)熱及黃熱病(Yellow Fever)組成之群,
b)由革蘭氏陽性細菌引起之細菌傳染性疾病,其中該革蘭氏陽性細菌係選自由以下組成之群:甲氧西林(methicillin)易感及甲氧西林抗藥性葡萄球菌(staphylococci) (包括金黃色葡萄球菌(Staphylococcus aureus)、表皮葡萄球菌(Staphylococcus epidermidis)、溶血性葡萄球菌(Staphylococcus haemolyticus)、人葡萄球菌(Staphylococcus hominis)、腐生性葡萄球菌(Staphylococcus saprophyticus)及凝固酶陰性葡萄球菌)、糖肽中間體易感性金黃色葡萄球菌(GISA)、盤尼西林(penicillin)易感及盤尼西林抗藥性鏈球菌(streptococci) (包括肺炎鏈球菌(Streptococcus pneumoniae)、化膿性鏈球菌(Streptococcus pyogenes)、無乳鏈球菌(Streptococcus agalactiae)、鳥鏈球菌(Streptococcus avium)、牛鏈球菌(Streptococcus bovis)、乳鏈球菌(Streptococcus lactis)、血鏈球菌(Streptococcus sanguis)及鏈球菌C組(GCS)、鏈球菌G組(GGS)及草綠色鏈球菌(viridans streptococci))、腸球菌(enterococci) (包括萬古黴素(vancomycin)易感及萬古黴素抗藥性株(諸如糞腸球菌(Enterococcus faecalis)及屎腸球菌(Enterococcus faecium))、艱難梭菌(Clostridium difficile)、單核細胞增生性李斯特氏菌(listeria monocytogenes)、傑氏棒狀桿菌(Corynebacterium jeikeium)、衣原體屬(Chlamydia spp) (包括肺炎衣原體(C. pneumoniae))及結核分枝桿菌(Mycobacterium tuberculosis),
c)由革蘭氏陰性細菌引起之細菌傳染性疾病,其中該革蘭氏陰性細菌係選自由腸桿菌屬(Genus Enterobacteriacae)組成之群,該腸桿菌屬包括埃希氏菌屬(Escherichia spp.) (包括大腸桿菌(Escherichia coli))、克雷伯氏菌屬(Klebsiella spp.)、腸桿菌屬(Enterobacter spp.)、檸檬酸桿菌屬(Citrobacter spp.)、沙雷氏菌屬(Serratia spp.)、變形桿菌屬(Proteus spp.)、普羅威登斯菌屬(Providencia spp.)、沙門氏菌屬(Salmonella spp.)、志賀氏菌屬(Shigella spp.)、假單胞菌屬(genus Pseudomonas) (包括綠膿桿菌(P. aeruginosa))、莫拉氏菌屬(Moraxella spp.) (包括卡他莫拉菌(M. catarrhalis))、嗜血桿菌屬(Haemophilus spp.)及奈瑟氏菌屬(Neisseria spp.),
d)由選自由以下組成之群之細胞內活性寄生蟲誘導之傳染性疾病:頂複門(Apicomplexa)或肉足鞭毛門(Sarcomastigophora) (包括錐蟲屬(Trypanosoma)、瘧原蟲屬(Plasmodia)、利什曼原蟲屬(Leishmania)、巴貝蟲屬(Babesia)或泰勒原蟲屬(Theileria))、隱孢子蟲屬(Cryptosporidia)、肉孢子蟲科(Sacrocystida)、變形蟲屬(Amoebia)、球蟲屬(Coccidia)及毛滴蟲屬(Trichomonadia)。
預期以上所揭示之藥劑包括根據本發明化合物用於製備用於治療及/或預防以上生理學及/或病理生理學狀態之藥劑的對應用途。
此外預期以上所揭示之藥劑包括用於治療及/或預防以上生理學及/或病理生理學狀態之對應方法,其中對有需要此治療之患者投與至少一種根據本發明之化合物。
根據本發明化合物較佳地展示有利生物活性,其於如實例中所述之酵素檢定及動物實驗中可容易地證實。於此等基於酵素之檢定中,根據本發明化合物較佳地展示且引起抑制作用,該抑制作用通常藉由適宜範圍(較佳地微莫耳範圍及更佳地奈莫耳範圍)之IC50
值記錄在案。
根據本發明化合物可對人類或動物(特定言之哺乳動物,諸如猿、狗、貓、大鼠或小鼠)投與且可用於人類或動物體之治療性治療且用於防治上述疾病。此外其可用作診斷劑或用作試劑。
此外,根據本發明化合物可用於單離及研究腺苷A2A
及/或A2B
受體之活性或表現。此外,其特定言之適用於與擾亂之腺苷A2A
及/或A2B
受體活性相關之疾病之診斷方法中。因此,此外本發明關於根據本發明化合物用於單離及研究腺苷A2A
及/或A2B
受體之活性或表現或作為腺苷A2A
及/或A2B
受體之結合劑及抑制劑的用途。
出於診斷目的,根據本發明化合物(例如)可經放射性標記。放射性標記之實例為3
H、14
C、231
I及125
I。較佳標記方法為碘原法(Fraker等人,1978)。此外,根據本發明化合物可藉由酵素、螢光團及化學團標記。酵素之實例為鹼性磷酸酶、β-半乳糖苷酶及葡萄糖氧化酶,螢光團之實例為螢光素,化學團之實例為魯米諾(luminol)及(例如)於US 4,125,828及US 4,207,554中描述(例如)用於螢光染色之自動檢測系統。
本發明另外關於含有本發明化合物之醫藥組合物及其用於治療及/或預防疾病及病症之用途,其中腺苷A2A
及/或A2B
受體之部分或完全失活可係有益的。
式I化合物可用於製備醫藥製劑,特定言之藉由非化學方法製備。於此情況下,將其與至少一種固體、液體及/或半液體賦形劑或佐劑及視情況與一或多種其他活性化合物組合一起進入適宜劑型中。
因此,本發明另外關於醫藥製劑,其包含至少一種式I化合物及/或其生理學上可接受之鹽、衍生物、溶劑化物及立體異構體,包括其等依所有比率之混合物。特定言之,本發明亦關於另外包含賦形劑及/或佐劑之醫藥製劑,及亦關於包含至少一種其他藥物活性化合物之醫藥製劑。
特定言之,本發明亦關於一種製備醫藥製劑之方法,其特徵在於將式I化合物及/或其生理學上可接受之鹽、衍生物、溶劑化物及立體異構體中之一者(包括其等依所有比率之混合物)與固體、液體或半液體賦形劑或佐劑一起及視情況與其他藥物活性化合物一起進入適宜劑型中。
根據本發明之醫藥製劑可用作人類或獸醫醫學中之藥劑。患者或宿主可屬於任何哺乳動物物種,例如,靈長類動物,特定言之人類;齧齒動物,包括小鼠、大鼠及倉鼠;兔子;馬;牛;狗;貓等。動物模型係受關注用於實驗研究,其中其提供用於治療人類疾病之模型。
適宜載劑物質為適用於經腸(例如,口服)、非經腸或局部投與且不與新穎化合物反應之有機或無機物質,例如,水、植物油(諸如向日葵油或魚肝油)、苄醇、聚乙二醇、明膠、碳水化合物(諸如乳糖或澱粉)、硬脂酸鎂、滑石、羊毛脂或凡士林。由於其專門知識,熟習此項技術者熟悉哪些佐劑適用於所需藥劑調配物。除了溶劑(例如,水、生理鹽水溶液或醇(諸如例如,乙醇、丙醇或甘油)、糖溶液(諸如葡萄糖或甘露醇溶液)或該等溶劑之混合物)、凝膠形成物、錠劑助劑及其他活性成分載劑外,亦可使用(例如)潤滑劑、穩定劑及/或潤濕劑、乳化劑、影響滲透壓之鹽、抗氧化劑、分散劑、消泡劑、緩衝物質、調味劑及/或香味或風味矯味劑、防腐劑、增溶劑或染料。若所需,則根據本發明之製劑或藥劑可包含一或多種其他活性化合物,例如,一或多種維生素。
若所需,則根據本發明之製劑或藥劑可包含一或多種其他活性化合物及/或一或多種作用增強劑(佐劑)。
出於本發明之目的,術語「醫藥調配物」及「醫藥製劑」作為同義詞使用。
如本文中所用,「醫藥上耐受的」係指促進對哺乳動物投與由此獲得之醫藥製劑而無非所需生理副作用(諸如例如,惡心、頭暈、消化問題或類似者)之藥劑、沈澱劑、賦形劑、佐劑、穩定劑、溶劑及其他藥劑。
於用於非經腸投與之醫藥製劑中,要求調配物之等滲性、水合正常及耐受性及安全性(低毒性)、採用之佐劑之安全性及初級包裝之安全性。出入意料地,根據本發明化合物較佳地具有可直接使用之優點及因此在醫藥調配物中使用根據本發明化合物之前用於移除毒理學上不可接受之物劑(諸如例如,高濃度有機溶劑)或其他毒理學上不可接受之佐劑之進一步純化步驟係不必要。
特別佳地,本發明亦關於醫藥製劑,其包含呈沈澱非晶型、沈澱晶型或呈溶解或懸浮形式之至少一種根據本發明之化合物及視情況賦形劑及/或佐劑及/或其他醫藥活性化合物。
較佳地根據本發明化合物使能製備高濃度調配物而無根據本發明化合物之不利、非所需聚集發生。因此,可藉助根據本發明化合物與水性溶劑或於水性介質中製備具有高活性成分含量之即用型溶液。
亦可將化合物及/或其生理學上可接受之鹽及溶劑化物凍乾及所得凍乾物用於(例如)製備注射製劑。
可藉由將根據本發明化合物溶解或懸浮於水溶液中及視情況添加佐劑製備水性製劑。為此,將包含限定濃度之該等其他佐劑之限定體積之儲備溶液有利地添加至含有限定濃度之根據本發明化合物之溶液或懸浮液中,及視情況將該混合物用水稀釋至預先計算之濃度。或者,可呈固體形式添加佐劑。隨後可將於各者情況下必要之儲備溶液及/或水之量添加至獲得之水溶液或懸浮液中。亦可有利地將根據本發明化合物直接溶解或懸浮於包含所有其他佐劑之溶液中。
可有利地製備包含根據本發明化合物且具有4至10之pH,較佳地具有5至9之pH,及250至350 mOsmol/kg之滲透壓之溶液或懸浮液。因此可將醫藥製劑經靜脈內、經動脈內、經關節內、經皮下或經皮實質上無痛直接投與。此外,亦可將製劑添加至輸注溶液(諸如例如,葡萄糖溶液、等滲鹽水溶液或林格氏溶液(Ringer‘s solution))中,該等輸注溶液亦可含有其他活性化合物,因此亦使能投與相對較大量之活性化合物。
根據本發明之醫藥製劑亦可包含複數種根據本發明化合物之混合物。
根據本發明之製劑係生理學上良好耐受,易於製備,可精確分配且較佳地關於在儲存及運輸期間及在多個冷凍及解凍製程期間之檢定、分解產物及聚集係穩定。較佳地在冰箱溫度(2至8℃)及在室溫(23至27℃)及60%相對大氣濕度(R.H.)下將其以適宜方式儲存至少三個月至兩年之時間。
例如,可藉由乾燥將根據本發明化合物以適宜方式儲存且必要時,藉由溶解或懸浮將其轉化成即用型醫藥製劑。可能乾燥方法為(例如) (不限於此等實例)氮氣乾燥、真空烘箱乾燥、冷凍乾燥、用有機溶劑洗滌及隨後空氣乾燥、液態床乾燥、流化床乾燥、噴霧乾燥、滾筒乾燥、分層乾燥、在室溫下空氣乾燥及其他方法。
術語「有效量」表示於組織、系統、動物或人類中引起(例如)藉由研究者或醫師尋求或期望之生物或醫學反應之藥劑或醫藥活性化合物的量。
此外,術語「治療上有效量」表示相較於尚未接受此量之對應個體具有下列結果之量:改善之疾病、症候群、疾病狀態、疾患、病症之治療、治癒、預防或消除或副作用之預防或亦疾病、疾患或病症之進展之減少。術語「治療上有效量」亦涵蓋有效增加正常生理功能之量。
使用根據本發明之製劑或藥劑時,一般類似於已知、可市面上購得之製劑或藥劑使用根據本發明化合物及/或其生理學上可接受之鹽及溶劑化物,較佳地以每使用單位0.1與500 mg之間,特定言之5與300 mg之間之劑量。較佳地每日劑量係在0.001與250 mg/kg體重之間,特定言之0.01與100 mg/kg體重之間。可每天一或多次(例如,每天兩次、三次或四次)投與製劑。然而,患者之個別劑量取決於許多個別因素,諸如例如,取決於所使用之特定化合物之功效,取決於年齡、體重、一般健康狀態、性別、營養,取決於投與時間及方法,取決於排洩率,取決於與其他藥劑之組合及取決於特定疾病之嚴重度及持續時間。
藥劑活性化合物於生物體中之攝入之量度為其生物可利用率。若以注射溶液之形式將藥劑活性化合物經靜脈內遞送至生物體,則其絕對生物可利用率(即,以不變形式到達全身血液(即,主要循環)之醫藥比例)為100%。於治療活性化合物之口服投與之情況下,活性化合物於調配物中一般呈固體形式且因此必須首先溶解以便其能克服進入障壁(例如,胃腸道、口腔黏膜、鼻膜或皮膚,特定言之角質層)或可藉由身體吸收。可類似於J. Shaffer等人,J. Pharm. Sciences,88 (1999),313-318之方法獲得關於藥物動力學(即,關於生物可利用率)之資料。
此外,可藉助一般於醫藥技術中已知之方法中之一者製備此類型之藥劑。
藥劑可適於經由任何所需適宜途徑,例如,藉由經口(包括頰或舌下)、直腸、肺、鼻、局部(包括頰、舌下或經皮)、***或非經腸(包括皮下、肌肉內、靜脈內、皮內及特定言之關節內)途徑之投與。可藉助醫藥技術中已知之所有方法藉由(例如)活性化合物與賦形劑或佐劑組合製備此類型之藥劑。
較佳地非經腸投與適用於根據本發明之藥劑之投與。於非經腸投與之情況下,關節內投與係特別佳的。
因此,較佳地,本發明亦關於用於關節內投與之根據本發明之醫藥製劑於治療及/或預防選自由骨關節炎、創傷性軟骨損傷、關節炎、疼痛、異常性疼痛或痛覺過敏組成之群之生理學及/或病理生理學狀態中的用途。
關節內投與具有以下優點:根據本發明化合物可直接投至關節軟骨附近之滑液中且亦可自滑液處擴散至軟骨組織。因此,根據本發明之醫藥製劑亦可直接注射入關節間隙中且因此直接在所期望作用位點上發展其作用。根據本發明化合物亦適用於製備具有活性化合物之緩慢、持續及/或可控釋放之待非經腸投與之藥劑。因此,其亦適用於製備延遲釋放調配物,該等調配物對患者有利,因為僅在相對較大的時間間隔必要投與。
適於非經腸投與之藥劑包括包含抗氧化劑、緩衝劑、抗菌劑及溶質之水性及非水性無菌注射溶液,藉助該等物劑使調配物與所治療之接受者之血液或滑液等滲;以及水性及非水性無菌懸浮液,其可包含懸浮介質及增稠劑。調配物可於單一劑量或多劑量容器(例如,密封安瓿及小瓶)中遞送且以凍乾(冷凍乾燥)狀態儲存,使得在使用之前出於注射目的僅立即添加無菌載液(例如,水)係必要的。可自無菌粉末、顆粒及錠劑製備按照調配物製備之注射溶液及懸浮液。
根據本發明化合物亦可呈脂質體遞送系統(諸如,例如,小單層囊泡、大單層囊泡及多層囊泡)之形式投與。脂質體可自各種磷脂(諸如,例如,膽固醇、硬脂醯胺或卵磷脂)形成。
根據本發明化合物亦可與作為靶向藥劑賦形劑之可溶性聚合物偶合。此等聚合物可涵蓋聚乙烯吡咯啶酮、哌喃共聚物、聚羥丙基異丁烯醯胺基苯酚、聚羥乙基天門冬醯胺基苯酚或經棕櫚醯基自由基取代之聚環氧乙烷聚離胺酸。此外根據本發明化合物可與以下適用於達成藥劑之緩慢釋放之一類可生物降解聚合物偶合:例如,聚乳酸、聚-ε-己內酯、聚羥基丁酸、聚原酸酯、聚乙縮醛、聚二氫基哌喃、聚氰基丙烯酸酯、聚乳酸共乙醇酸、諸如在右旋糖苷與甲基丙烯酸酯之間共軛物之聚合物、聚磷酸酯、各種多醣及聚胺及聚-e-己內酯、白蛋白、殼聚糖、膠原蛋白或改質明膠及水凝膠之交聯或兩性嵌段共聚物。
適用於經腸投與(口或直腸)為(特定言之)錠劑、糖衣丸、膠囊、糖漿、果汁、滴劑或栓劑,及適用於局部用途為軟膏、乳霜、膏劑、洗液、凝膠、噴霧、泡沫、氣溶膠、溶液(例如,醇溶液(諸如乙醇或異丙醇)、乙腈、DMF、二甲基乙醯胺、1,2-丙二醇或其彼此及/或與水之混合物)或粉末。特定言之亦適用於局部使用為脂質體製劑。
於調配物為軟膏之情況下,可用石蠟或水可混溶乳霜基採用活性化合物。或者,可將活性化合物用水包油乳霜基或油包水基調配成乳霜。
適於經皮投與之藥劑可作為與接受者之表皮廣泛密切接觸之獨立膏藥遞送。因此,例如,活性化合物可藉助如於Pharmaceutical Research, 3 (6), 318 (1986)中概括所述之離子電滲療法自膏藥供給。
毋庸贅言,除了以上特別提及之成分外,根據本發明之藥劑亦可包含通常於關於醫藥調配物之特定類型之技術中之其他物劑。
本發明亦關於一種套組,其由以下分開包裝組成:
a)有效量之式I化合物及/或其生理學上可接受之鹽、衍生物、溶劑化物、前藥及立體異構體(包括其等依所有比率之混合物),及
b)有效量之其他藥物活性化合物。
a)有效量之式I化合物及/或其生理學上可接受之鹽、衍生物、溶劑化物、前藥及立體異構體(包括其等依所有比率之混合物),及
b)有效量之其他藥物活性化合物。
套組包含適宜容器,諸如盒或硬紙盒、個別瓶、包或安瓿。套組可(例如)包含分開安瓿,該等安瓿各者含有有效量之式I化合物及/或其醫藥上可接受之鹽、衍生物、溶劑化物、前藥及立體異構體(包括其等依所有比率之混合物),及有效量之呈溶解或凍乾形式之其他藥物活性化合物。
此外,可使用根據本發明之藥劑以於某些已知療法中提供附加或協同效應及/或可使用根據本發明之藥劑以恢復某些現有療法之功效。
除了根據本發明化合物外,根據本發明之醫藥製劑亦可包含(例如)用於治療癌症之其他藥物活性化合物(其他抗腫瘤藥劑)。用於治療提及之其他疾病,除了根據本發明化合物外,根據本發明之醫藥製劑亦可包含為熟習其治療技術者已知之其他藥物活性化合物。
於一主要實施例中,提供增強有需要之宿主之免疫反應的方法。免疫反應可藉由降低T細胞耐受(包括藉由增加IFN-γ釋放、藉由減少調節性T細胞產生或激活或藉由增加宿主中之抗原特異性記憶T細胞產生)增強。於一實施例中,該方法包括與抗體組合或交替對宿主投與本發明化合物。於特定實施例中,該抗體為治療性抗體。於一特定實施例中,提供一種增強被動抗體療法之功效之方法,其包括與一或多種被動抗體組合或交替投與本發明化合物。該方法可增強用於治療異常細胞增生性病症(諸如癌症)之抗體療法之功效或可增強治療或預防傳染性疾病之療法之功效。可與抗體(諸如例如,利妥昔單抗(rituximab)、赫賽汀(herceptin)或愛必妥(erbitux))組合或交替投與本發明化合物。
於另一主要實施例中,提供一種治療或預防異常細胞增生之方法,其包括在另一抗癌劑實質上不存在下,對有需要之宿主投與本發明化合物。
於另一主要實施例中,提供一種治療或預防有需要之宿主之異常細胞增生之方法,其包括首先對該宿主投與本發明化合物實質上與第一抗癌劑組合及隨後投與第二A2A
及/或A2B
受體拮抗劑。於一子實施例中,在另一抗癌劑不存在下投與該第二拮抗劑。於另一主要實施例中,提供一種治療或預防有需要之宿主之異常細胞增生之方法,其包括對該宿主實質上與第一抗癌劑組合投與本發明化合物及隨後在拮抗劑不存在下投與第二抗癌劑。
因此,可作為利用本發明化合物之療法或與手術、照射或化療組合進行本文中所揭示之癌症治療。此類型之化療可包括使用下列類別之抗腫瘤活性化合物中之一或多種活性化合物:
(i)如腫瘤內科中所用之抗增生性/抗腫瘤性/DNA損傷活性化合物及其組合,諸如烷基化活性化合物(例如,順鉑(cis-platin)、卡鉑(carboplatin)、環磷醯胺、氮芥、美法侖(melphalan)、苯丁酸氮芥(chlorambucil)、白消安(busulphan)及亞硝基脲)、抗代謝物(例如抗葉酸劑,諸如氟嘧啶,諸如5-氟尿嘧啶及替加氟(tegafur)、雷替曲塞(raltitrexed)、甲胺喋呤(methotrexate)、阿糖胞苷(cytosine arabinoside)、羥基脲及吉西他濱(gemcitabine))、抗腫瘤抗生素(例如,蒽環類,諸如阿黴素(adriamycin)、博來黴素(bleomycin)、多柔比星(doxorubicin)、道諾黴素(daunomycin)、表柔比星(epirubicin)、伊達比星(idarubicin)、絲裂黴素(mitomycin)-C、更生黴素(dactinomycin)及光神黴素(mithramycin))、抗有絲***活性化合物(例如,長春花生物鹼(諸如長春新鹼(vincristine)、長春鹼(vinblastine)、長春地辛(vindesine)及長春瑞濱(vinorelbine))及紫杉烷(taxoid) (諸如紫杉酚(taxol)及紫杉特爾(taxotere)))、拓撲異構酶抑制劑(例如,表鬼臼毒素(epipodophyllotoxin),諸如依託泊苷(etoposide)及替尼泊苷(teniposide)、安吖啶(amsacrine)、托泊替康(topotecan)、伊立替康(irinotecan)及喜樹鹼(camptothecin))及細胞分化活性化合物(例如,全反式視黃酸、13-順式視黃酸及芬維A胺(fenretinide));
(ii)細胞生長抑制活性化合物,諸如抗***(例如,他莫西芬(tamoxifen)、托瑞米芬(toremifene)、雷洛昔芬(raloxifene)、屈洛昔芬(droloxifene)及iodoxyfene)、***受體調節素(例如,氟維司群(fulvestrant))、抗雄激素(例如,比卡魯胺(bicalutamide)、氟他胺(flutamide)、尼魯米特(nilutamide)及乙酸環丙孕酮)、LHRH拮抗劑或LHRH促效劑(例如,戈舍瑞林(goserelin)、亮丙瑞林(leuprorelin)及布舍瑞林(buserelin))、孕激素(例如,乙酸甲地孕酮)、芳香酶抑制劑(例如,阿那曲唑(anastrozole)、來曲唑(letrozole)、伏氯唑(vorazole)及依西美坦(exemestane))及5a還原酶抑制劑(諸如非那司提(finasteride));
(iii)抑制癌症入侵之活性化合物,包括(例如)金屬蛋白酶抑制劑(如馬立馬司他(marimastat))及尿激酶纖溶酶原激活劑受體功能抑制劑;
(iv)生長因子功能抑制劑(例如,生長因子抗體、生長因子受體抗體,例如,抗erbb2抗體曲妥珠單抗(trastuzumab) [HerceptinTM ]及抗erbbl抗體西妥昔單抗(cetuximab) [C225])、法尼基(farnesyl)轉移酶抑制劑、酪胺酸激酶抑制劑及絲胺酸/蘇胺酸激酶抑制劑(例如,表皮生長因子家族抑制劑(例如,EGFR家族酪胺酸激酶抑制劑,諸如N-(3-氯-4-氟苯基)-7-甲氧基-6-(3-嗎啉基丙氧基)喹唑啉-4-胺(吉非替尼(gefitinib),AZD1839)、N-(3-乙炔基苯基)-6,7-雙(2-甲氧乙氧基)喹唑啉-4-胺(埃羅替尼(erlotinib),OSI-774)及6-丙烯醯胺基-N-(3-氯-4-氟苯基)-7-(3-嗎啉基丙氧基)喹唑啉-4-胺(CI 1033)),例如,血小板源性生長因子家族抑制劑及例如,肝細胞生長因子家族抑制劑);
(v)抗血管生成活性化合物,諸如貝伐單抗(bevacizumab)、血管抑素(angiostatin)、內皮他丁(endostatin)、利諾胺(linomide)、巴馬司他(batimastat)、卡托普利(captopril)、軟骨源性抑制劑、染料木黃酮(genistein)、介白素12、熏草菌素(lavendustin)、乙酸甲羥孕酮、重組人類血小板因子4、特科加蘭(tecogalan)、凝血栓蛋白(thrombospondin)、TNP-470、抗VEGF單株抗體、可溶性VEGF受體嵌合蛋白、抗VEGF受體抗體、抗PDGF受體、整聯蛋白抑制劑、酪胺酸激酶抑制劑、絲胺酸/蘇胺酸激酶抑制劑、反義寡核苷酸、反義寡脫氧核苷酸、siRNA、抗VEGF適體、色素上皮細胞衍生因子及已於國際專利申請案WO 97/22596、WO 97/30035、WO 97/32856及WO 98/13354中公開之化合物;
(vi)血管破壞劑,諸如考布他汀(combretastatin) A4及已於國際專利申請案WO 99/02166、WO 00/40529、WO 00/41669、WO 01/92224、WO 02/04434及WO 02/08213中公開之化合物;
(vii)反義療法,例如,彼等針對上述標靶者,諸如ISIS 2503(抗Ras反義);
(viii)基因治療方法,包括(例如)替換異常改造基因(諸如異常p53或異常BRCA1或BRCA2)之方法、GDEPT方法(基因導向酵素前藥療法) (諸如彼等使用胞嘧啶脫胺酶、胸苷激酶或細菌硝基還原酶酵素者)及提高患者對化療或放射療法之耐受性之方法(諸如多重藥物性療法);及
(ix)免疫治療方法,包括(例如)增加患者之腫瘤細胞之免疫原性的離體及活體內方法(諸如利用細胞激素(諸如介白素2、介白素4或粒細胞巨噬細胞群落刺激因子)轉染)、減少T細胞失能之方法、使用經轉染免疫細胞(諸如經細胞激素轉染之樹突狀細胞)之方法、使用經細胞激素轉染之腫瘤細胞之方法及使用抗獨特型抗體之方法;
(x)化療劑,包括(例如)阿巴瑞克(abarelix)、阿地白介素(aldesleukin)、阿侖單抗(alemtuzumab)、阿利維A酸(alitretinoin)、別嘌呤醇(allopurinol)、六甲蜜胺(altretamine)、阿米福汀(amifostine)、阿那曲唑、三氧化二砷、天冬醯胺酶、注射用卡介苗(BCG live)、貝伐單抗、貝沙羅汀(bexarotene)、博來黴素、硼替佐米(bortezomib)、白消安、卡魯睪酮(calusterone)、喜樹鹼、卡培他濱(capecitabine)、卡鉑、卡莫司汀(carmustine)、塞來考昔(celecoxib)、西妥昔單抗、苯丁酸氮芥、西那卡塞(cinacalcet)、順鉑、克拉屈濱(cladribine)、環磷醯胺、阿糖胞苷(cytarabine)、達卡巴嗪(dacarbazine)、更生黴素、達依泊汀(darbepoetin) α、道諾黴素、地尼白介素毒素連接物(denileukin diftitox)、右雷佐生(dexrazoxane)、多西他奇(docetaxel)、多柔比星、屈他雄酮(dromostanolone)、表柔比星、阿法依泊汀(epoetin alfa)、雌莫司汀(estramustine)、依託泊苷、依西美坦、非格司亭(filgrastim)、氟尿苷(floxuridine)、氟達拉濱(fludarabine)、氟尿嘧啶(fluorouracil)、氟維司群及吉西他濱。
(i)如腫瘤內科中所用之抗增生性/抗腫瘤性/DNA損傷活性化合物及其組合,諸如烷基化活性化合物(例如,順鉑(cis-platin)、卡鉑(carboplatin)、環磷醯胺、氮芥、美法侖(melphalan)、苯丁酸氮芥(chlorambucil)、白消安(busulphan)及亞硝基脲)、抗代謝物(例如抗葉酸劑,諸如氟嘧啶,諸如5-氟尿嘧啶及替加氟(tegafur)、雷替曲塞(raltitrexed)、甲胺喋呤(methotrexate)、阿糖胞苷(cytosine arabinoside)、羥基脲及吉西他濱(gemcitabine))、抗腫瘤抗生素(例如,蒽環類,諸如阿黴素(adriamycin)、博來黴素(bleomycin)、多柔比星(doxorubicin)、道諾黴素(daunomycin)、表柔比星(epirubicin)、伊達比星(idarubicin)、絲裂黴素(mitomycin)-C、更生黴素(dactinomycin)及光神黴素(mithramycin))、抗有絲***活性化合物(例如,長春花生物鹼(諸如長春新鹼(vincristine)、長春鹼(vinblastine)、長春地辛(vindesine)及長春瑞濱(vinorelbine))及紫杉烷(taxoid) (諸如紫杉酚(taxol)及紫杉特爾(taxotere)))、拓撲異構酶抑制劑(例如,表鬼臼毒素(epipodophyllotoxin),諸如依託泊苷(etoposide)及替尼泊苷(teniposide)、安吖啶(amsacrine)、托泊替康(topotecan)、伊立替康(irinotecan)及喜樹鹼(camptothecin))及細胞分化活性化合物(例如,全反式視黃酸、13-順式視黃酸及芬維A胺(fenretinide));
(ii)細胞生長抑制活性化合物,諸如抗***(例如,他莫西芬(tamoxifen)、托瑞米芬(toremifene)、雷洛昔芬(raloxifene)、屈洛昔芬(droloxifene)及iodoxyfene)、***受體調節素(例如,氟維司群(fulvestrant))、抗雄激素(例如,比卡魯胺(bicalutamide)、氟他胺(flutamide)、尼魯米特(nilutamide)及乙酸環丙孕酮)、LHRH拮抗劑或LHRH促效劑(例如,戈舍瑞林(goserelin)、亮丙瑞林(leuprorelin)及布舍瑞林(buserelin))、孕激素(例如,乙酸甲地孕酮)、芳香酶抑制劑(例如,阿那曲唑(anastrozole)、來曲唑(letrozole)、伏氯唑(vorazole)及依西美坦(exemestane))及5a還原酶抑制劑(諸如非那司提(finasteride));
(iii)抑制癌症入侵之活性化合物,包括(例如)金屬蛋白酶抑制劑(如馬立馬司他(marimastat))及尿激酶纖溶酶原激活劑受體功能抑制劑;
(iv)生長因子功能抑制劑(例如,生長因子抗體、生長因子受體抗體,例如,抗erbb2抗體曲妥珠單抗(trastuzumab) [HerceptinTM ]及抗erbbl抗體西妥昔單抗(cetuximab) [C225])、法尼基(farnesyl)轉移酶抑制劑、酪胺酸激酶抑制劑及絲胺酸/蘇胺酸激酶抑制劑(例如,表皮生長因子家族抑制劑(例如,EGFR家族酪胺酸激酶抑制劑,諸如N-(3-氯-4-氟苯基)-7-甲氧基-6-(3-嗎啉基丙氧基)喹唑啉-4-胺(吉非替尼(gefitinib),AZD1839)、N-(3-乙炔基苯基)-6,7-雙(2-甲氧乙氧基)喹唑啉-4-胺(埃羅替尼(erlotinib),OSI-774)及6-丙烯醯胺基-N-(3-氯-4-氟苯基)-7-(3-嗎啉基丙氧基)喹唑啉-4-胺(CI 1033)),例如,血小板源性生長因子家族抑制劑及例如,肝細胞生長因子家族抑制劑);
(v)抗血管生成活性化合物,諸如貝伐單抗(bevacizumab)、血管抑素(angiostatin)、內皮他丁(endostatin)、利諾胺(linomide)、巴馬司他(batimastat)、卡托普利(captopril)、軟骨源性抑制劑、染料木黃酮(genistein)、介白素12、熏草菌素(lavendustin)、乙酸甲羥孕酮、重組人類血小板因子4、特科加蘭(tecogalan)、凝血栓蛋白(thrombospondin)、TNP-470、抗VEGF單株抗體、可溶性VEGF受體嵌合蛋白、抗VEGF受體抗體、抗PDGF受體、整聯蛋白抑制劑、酪胺酸激酶抑制劑、絲胺酸/蘇胺酸激酶抑制劑、反義寡核苷酸、反義寡脫氧核苷酸、siRNA、抗VEGF適體、色素上皮細胞衍生因子及已於國際專利申請案WO 97/22596、WO 97/30035、WO 97/32856及WO 98/13354中公開之化合物;
(vi)血管破壞劑,諸如考布他汀(combretastatin) A4及已於國際專利申請案WO 99/02166、WO 00/40529、WO 00/41669、WO 01/92224、WO 02/04434及WO 02/08213中公開之化合物;
(vii)反義療法,例如,彼等針對上述標靶者,諸如ISIS 2503(抗Ras反義);
(viii)基因治療方法,包括(例如)替換異常改造基因(諸如異常p53或異常BRCA1或BRCA2)之方法、GDEPT方法(基因導向酵素前藥療法) (諸如彼等使用胞嘧啶脫胺酶、胸苷激酶或細菌硝基還原酶酵素者)及提高患者對化療或放射療法之耐受性之方法(諸如多重藥物性療法);及
(ix)免疫治療方法,包括(例如)增加患者之腫瘤細胞之免疫原性的離體及活體內方法(諸如利用細胞激素(諸如介白素2、介白素4或粒細胞巨噬細胞群落刺激因子)轉染)、減少T細胞失能之方法、使用經轉染免疫細胞(諸如經細胞激素轉染之樹突狀細胞)之方法、使用經細胞激素轉染之腫瘤細胞之方法及使用抗獨特型抗體之方法;
(x)化療劑,包括(例如)阿巴瑞克(abarelix)、阿地白介素(aldesleukin)、阿侖單抗(alemtuzumab)、阿利維A酸(alitretinoin)、別嘌呤醇(allopurinol)、六甲蜜胺(altretamine)、阿米福汀(amifostine)、阿那曲唑、三氧化二砷、天冬醯胺酶、注射用卡介苗(BCG live)、貝伐單抗、貝沙羅汀(bexarotene)、博來黴素、硼替佐米(bortezomib)、白消安、卡魯睪酮(calusterone)、喜樹鹼、卡培他濱(capecitabine)、卡鉑、卡莫司汀(carmustine)、塞來考昔(celecoxib)、西妥昔單抗、苯丁酸氮芥、西那卡塞(cinacalcet)、順鉑、克拉屈濱(cladribine)、環磷醯胺、阿糖胞苷(cytarabine)、達卡巴嗪(dacarbazine)、更生黴素、達依泊汀(darbepoetin) α、道諾黴素、地尼白介素毒素連接物(denileukin diftitox)、右雷佐生(dexrazoxane)、多西他奇(docetaxel)、多柔比星、屈他雄酮(dromostanolone)、表柔比星、阿法依泊汀(epoetin alfa)、雌莫司汀(estramustine)、依託泊苷、依西美坦、非格司亭(filgrastim)、氟尿苷(floxuridine)、氟達拉濱(fludarabine)、氟尿嘧啶(fluorouracil)、氟維司群及吉西他濱。
來自表1之藥劑可較佳地(但非排他地)與式I化合物組合。
即使無其他實施例,仍假定熟習此項技術者將能以最寬範圍使用以上描述。因此應僅將較佳實施例認作描述性揭示內容,其絕對不以任何方式限制。
因此下列實例意欲解釋本發明而非限制其。除非另有指明,否則數據%表示重量%。以攝氏度指示所有溫度。「習知處理」:若需要,則添加水,若需要,則將pH調整至2與10之間之值(取決於最終產物之構成),將混合物用乙酸乙酯或二氯甲烷萃取,分離相,將有機相經硫酸鈉乾燥,過濾及蒸發,及將產物藉由層析法在矽膠上純化及/或藉由結晶純化。
矽膠上之Rf值;質譜法:EI (電子碰撞電離):M+
,FAB (快原子轟擊):(M+H)+
,THF (四氫呋喃),NMP (N-甲基吡咯啶酮),DMSO (二甲亞碸),EA (乙酸乙酯),MeOH (甲醇),TLC (薄層層析法)。
縮略語列表
AUC 血漿藥物濃度-時間曲線下面積
Cmax 最大血漿濃度
CL 清除率
CV 變異係數
CYP 細胞色素P450
DMSO 二甲亞碸
F 生物可利用率
fa 吸收分率
iv 靜脈內
LC-MS/MS 液相層析法串聯質譜法
LLOQ 定量下限
NC 尚未計算
ND 尚未測定
PEG 聚二乙醇
Pgp 滲透性醣蛋白
PK 藥物動力學
po 經口(口服)
t1/2 半衰期
tmax 達到藥物之最大血漿濃度之時間
UPLC 超高效液相層析法
Vss 分佈體積(在穩態下)
v/v 體積對體積
AUC 血漿藥物濃度-時間曲線下面積
Cmax 最大血漿濃度
CL 清除率
CV 變異係數
CYP 細胞色素P450
DMSO 二甲亞碸
F 生物可利用率
fa 吸收分率
iv 靜脈內
LC-MS/MS 液相層析法串聯質譜法
LLOQ 定量下限
NC 尚未計算
ND 尚未測定
PEG 聚二乙醇
Pgp 滲透性醣蛋白
PK 藥物動力學
po 經口(口服)
t1/2 半衰期
tmax 達到藥物之最大血漿濃度之時間
UPLC 超高效液相層析法
Vss 分佈體積(在穩態下)
v/v 體積對體積
實例 1 :本發明化合物之實例
本發明尤其關於表2之化合物及其生理學上可接受之鹽、衍生物、溶劑化物、前藥及立體異構體,包括其等依所有比率之混合物。
本發明尤其關於表2之化合物及其生理學上可接受之鹽、衍生物、溶劑化物、前藥及立體異構體,包括其等依所有比率之混合物。
表
2-
本發明化合物之實例
表 3- 本發明化合物之 NMR 特性
本文中引用之編號對應於表2中所揭示之化合物之編號。
本文中引用之編號對應於表2中所揭示之化合物之編號。
實例 2 :本發明化合物之製法及分析方法
使用之所有溶劑係可市面上購得且使用無需進一步純化。通常在氮氣之惰性氛圍下使用無水溶劑運行反應。一般使用矽膠60 (0.035至0.070 mm粒度)進行急驟管柱層析法。
使用之所有溶劑係可市面上購得且使用無需進一步純化。通常在氮氣之惰性氛圍下使用無水溶劑運行反應。一般使用矽膠60 (0.035至0.070 mm粒度)進行急驟管柱層析法。
針對質子NMR,在配備有Bruker 400 BBFO探針的Bruker Mercury Plus 400 NMR光譜儀上在400 MHz下或針對質子NMR,在配備有Bruker 300 BBFO探針的Bruker Mercury Plus 300 NMR光譜儀上在300 MHz下記錄所有NMR實驗。所有氘化溶劑通常含有0.03%至0.05% v/v四甲基矽烷,將其用作參考信號(針對1H與13C二者設置在ppm =0.00)。
在由UFLC 20-AD系統及LCMS 2020 MS檢測器或Agilent Technologies 1200系列組成之SHIMADZU LC-MS機器上進行LC-MS分析。於不同HPLC方法中描述使用之管柱及條件。管柱溫度係在40℃,其中指定流量。二極體陣列檢測器自200至400 nm掃描。將質譜儀配備以正模式或負模式操作之電噴霧離子源(ES)。將質譜儀在m/z 90與900之間掃描,其中掃描時間為0.6 s。
1. N-[8-甲氧基-5-(㗁烷-4-基)喹㗁啉-2-基]-1-(2-甲氧基乙基)-1H-吡唑-4-甲醯胺
a. 1-溴-4-甲氧基-2,3-二硝基-苯
向250 mL三頸圓底燒瓶中放置含1-溴-4-甲氧基-2-硝基苯(50.0 g,205 mmol)之硫酸(100 ml)。在0℃下,在攪拌下逐滴添加硝酸(24 mL,530 mmol)。將溶液在室溫下攪拌1小時及用1000 ml冰水中止。將溶液用1000 ml乙酸乙酯萃取兩次,將合併之有機層經無水硫酸鈉乾燥及濃縮至乾。將粗物質自乙酸乙酯/己烷(2:3)再結晶以得到20.0 g (32%)呈黃色固體之1-溴-4-甲氧基-2,3-二硝基苯。熔點:150至153℃。1 H NMR (400 MHz, DMSO-d6) ppm = 8.19 (d, J = 9.3 Hz, 1H), 7.70 (d, J = 9.3 Hz, 1H), 4.02 (s, 3H)。HPLC/MS (純度) 91%。Rt 1.73分鐘(方法A)。[M+H]+ 276.8,278.9。
a. 1-溴-4-甲氧基-2,3-二硝基-苯
向250 mL三頸圓底燒瓶中放置含1-溴-4-甲氧基-2-硝基苯(50.0 g,205 mmol)之硫酸(100 ml)。在0℃下,在攪拌下逐滴添加硝酸(24 mL,530 mmol)。將溶液在室溫下攪拌1小時及用1000 ml冰水中止。將溶液用1000 ml乙酸乙酯萃取兩次,將合併之有機層經無水硫酸鈉乾燥及濃縮至乾。將粗物質自乙酸乙酯/己烷(2:3)再結晶以得到20.0 g (32%)呈黃色固體之1-溴-4-甲氧基-2,3-二硝基苯。熔點:150至153℃。1 H NMR (400 MHz, DMSO-d6) ppm = 8.19 (d, J = 9.3 Hz, 1H), 7.70 (d, J = 9.3 Hz, 1H), 4.02 (s, 3H)。HPLC/MS (純度) 91%。Rt 1.73分鐘(方法A)。[M+H]+ 276.8,278.9。
鈴木反應之一般程序:
b. 4-(4-甲氧基-2,3-二硝基-苯基)-3,6-二氫-2H-哌喃
向用氬氣之惰性氛圍淨化及維持之350-ml壓力罐式反應器中放置1-溴-4-甲氧基-2,3-二硝基苯,91% (15.7 g,51.4 mmol)、2-(3,6-二氫-2H-哌喃-4-基)-4,4,5,5-四甲基-1,3,2-二氧雜硼㖦,95% (13.7 g,61.7 mmol)、Pd(dppf)Cl2 二氯甲烷複合物,95% (4.42 g,5.14 mmol)、碳酸鉀(8.53 g,61.7 mmol,溶解於水(12 ml))中)、乙醇(31.6 ml)及甲苯(316 ml)。將混合物在100℃下攪拌1小時,冷卻至室溫及在真空下濃縮至乾。將殘餘物藉由管柱層析法(乙酸乙酯/石油醚:1/1)純化以得到13.0 g (86%)呈橙色固體之4-(4-甲氧基-2,3-二硝基苯基)-3,6-二氫-2H-哌喃。HPLC/MS (純度) 95%。Rt 1.17分鐘(方法B)。[M+H]+ 281.2。
b. 4-(4-甲氧基-2,3-二硝基-苯基)-3,6-二氫-2H-哌喃
向用氬氣之惰性氛圍淨化及維持之350-ml壓力罐式反應器中放置1-溴-4-甲氧基-2,3-二硝基苯,91% (15.7 g,51.4 mmol)、2-(3,6-二氫-2H-哌喃-4-基)-4,4,5,5-四甲基-1,3,2-二氧雜硼㖦,95% (13.7 g,61.7 mmol)、Pd(dppf)Cl2 二氯甲烷複合物,95% (4.42 g,5.14 mmol)、碳酸鉀(8.53 g,61.7 mmol,溶解於水(12 ml))中)、乙醇(31.6 ml)及甲苯(316 ml)。將混合物在100℃下攪拌1小時,冷卻至室溫及在真空下濃縮至乾。將殘餘物藉由管柱層析法(乙酸乙酯/石油醚:1/1)純化以得到13.0 g (86%)呈橙色固體之4-(4-甲氧基-2,3-二硝基苯基)-3,6-二氫-2H-哌喃。HPLC/MS (純度) 95%。Rt 1.17分鐘(方法B)。[M+H]+ 281.2。
c. 3-甲氧基-6-(四氫-哌喃-4-基)-苯-1,2-二胺
向250-ml圓底燒瓶中放置碳載鈀,10% (4.00 g,3.76 mmol)、甲醇(100 ml)及4-(4-甲氧基-2,3-二硝基苯基)-3,6-二氫-2H-哌喃,95% (10.5 g,33.9 mmol)。在氫氣氛圍下,在35℃下,將混合物攪拌15小時。將固體過濾掉並丟棄。將濾液蒸發至乾及將殘餘物藉由管柱層析法(乙酸乙酯/己烷,70/30)純化以得到4.51 g (58%)呈黃色固體之3-甲氧基-6-(㗁烷-4-基)-苯-1,2-二胺。熔點:116至117℃。1 H NMR (400 MHz,氯仿-d) 6.67 (d, J = 8.5 Hz, 1H), 6.45 (d, J = 8.5 Hz, 1H), 4.18 -4.09 (m, 2H), 3.86 (s, 3H), 3.65 -3.53 (m, 2H), 3.46(s, 4H), 2.82 -2.64 (m, 1H), 1.93 -1.73 (m, 4H)。HPLC/MS (純度) 97%。Rt 1.01分鐘(方法C)。[M+H]+ 223.1。
向250-ml圓底燒瓶中放置碳載鈀,10% (4.00 g,3.76 mmol)、甲醇(100 ml)及4-(4-甲氧基-2,3-二硝基苯基)-3,6-二氫-2H-哌喃,95% (10.5 g,33.9 mmol)。在氫氣氛圍下,在35℃下,將混合物攪拌15小時。將固體過濾掉並丟棄。將濾液蒸發至乾及將殘餘物藉由管柱層析法(乙酸乙酯/己烷,70/30)純化以得到4.51 g (58%)呈黃色固體之3-甲氧基-6-(㗁烷-4-基)-苯-1,2-二胺。熔點:116至117℃。1 H NMR (400 MHz,氯仿-d) 6.67 (d, J = 8.5 Hz, 1H), 6.45 (d, J = 8.5 Hz, 1H), 4.18 -4.09 (m, 2H), 3.86 (s, 3H), 3.65 -3.53 (m, 2H), 3.46(s, 4H), 2.82 -2.64 (m, 1H), 1.93 -1.73 (m, 4H)。HPLC/MS (純度) 97%。Rt 1.01分鐘(方法C)。[M+H]+ 223.1。
環化為喹㗁啉環之一般程序
d. 8-甲氧基-5-(四氫-哌喃-4-基)-1H-喹㗁啉-2-酮
將3-甲氧基-6-(四氫-哌喃-4-基)-苯-1,2-二胺,97% (3.41 g,15.8 mmol)溶解於甲醇(80 ml)中,添加50%乙醛酸乙酯之甲苯溶液(9.64 ml,94.7 mmol)及將混合物在80℃下攪拌2小時。將反應混合物蒸發至乾及將粗物質用乙酸乙酯研磨。將形成之固體過濾掉及藉由急驟層析法(乙酸乙酯/環己烷,梯度)純化以得到1.62 g (31%)無色固體。HPLC/MS (純度) 80%。Rt 1.79分鐘(方法D)。[M+H]+ 261.1。
d. 8-甲氧基-5-(四氫-哌喃-4-基)-1H-喹㗁啉-2-酮
將3-甲氧基-6-(四氫-哌喃-4-基)-苯-1,2-二胺,97% (3.41 g,15.8 mmol)溶解於甲醇(80 ml)中,添加50%乙醛酸乙酯之甲苯溶液(9.64 ml,94.7 mmol)及將混合物在80℃下攪拌2小時。將反應混合物蒸發至乾及將粗物質用乙酸乙酯研磨。將形成之固體過濾掉及藉由急驟層析法(乙酸乙酯/環己烷,梯度)純化以得到1.62 g (31%)無色固體。HPLC/MS (純度) 80%。Rt 1.79分鐘(方法D)。[M+H]+ 261.1。
引入氯之一般程序
e. 2-氯-8-甲氧基-5-(四氫-哌喃-4-基)-喹㗁啉
在室溫下,將8-甲氧基-5-(四氫-哌喃-4-基)-1H-喹㗁啉-2-酮,80% (1.62 g, 4.98 mmol)溶解於磷醯氯(27.1 g,177 mmol)中及將混合物在105℃下攪拌3小時。於冷卻至室溫後,將混合物分配在飽和NaHCO3 水溶液與二氯甲烷之間及在室溫下再攪拌1小時。分離有機層及將水相用二氯甲烷萃取三次。將合併之有機層經硫酸鈉乾燥,過濾及將濾液蒸發至乾,以得到1.74 g (100%)呈黃色固體之標題化合物。HPLC/MS (純度) 80%。Rt 2.36分鐘(方法D)。[M+H]+ 279.1。
e. 2-氯-8-甲氧基-5-(四氫-哌喃-4-基)-喹㗁啉
在室溫下,將8-甲氧基-5-(四氫-哌喃-4-基)-1H-喹㗁啉-2-酮,80% (1.62 g, 4.98 mmol)溶解於磷醯氯(27.1 g,177 mmol)中及將混合物在105℃下攪拌3小時。於冷卻至室溫後,將混合物分配在飽和NaHCO3 水溶液與二氯甲烷之間及在室溫下再攪拌1小時。分離有機層及將水相用二氯甲烷萃取三次。將合併之有機層經硫酸鈉乾燥,過濾及將濾液蒸發至乾,以得到1.74 g (100%)呈黃色固體之標題化合物。HPLC/MS (純度) 80%。Rt 2.36分鐘(方法D)。[M+H]+ 279.1。
合成胺基喹㗁啉之一般程序
f. 8-甲氧基-5-(四氫-哌喃-4-基)-喹㗁啉-2-基胺
於高壓管中,將2-氯-8-甲氧基-5-(四氫-哌喃-4-基)-喹㗁啉,80% (1.74 g,4.98 mmol)溶解於THF (20 ml)中。向此混合物中添加氨水溶液,32% (60 ml)及碘化銅(I) (500 mg,2.62 mmol),將容器密封及將混合物在140℃下攪拌4小時(最大21巴壓力)。於冷卻至室溫後,將混合物蒸發至乾及藉由急驟層析法(乙酸乙酯/環己烷,梯度)純化以得到1.00 g (60%)無色固體。HPLC/MS (純度) 79%。Rt 1.71分鐘(方法D)。[M+H]+ 260.1。
f. 8-甲氧基-5-(四氫-哌喃-4-基)-喹㗁啉-2-基胺
於高壓管中,將2-氯-8-甲氧基-5-(四氫-哌喃-4-基)-喹㗁啉,80% (1.74 g,4.98 mmol)溶解於THF (20 ml)中。向此混合物中添加氨水溶液,32% (60 ml)及碘化銅(I) (500 mg,2.62 mmol),將容器密封及將混合物在140℃下攪拌4小時(最大21巴壓力)。於冷卻至室溫後,將混合物蒸發至乾及藉由急驟層析法(乙酸乙酯/環己烷,梯度)純化以得到1.00 g (60%)無色固體。HPLC/MS (純度) 79%。Rt 1.71分鐘(方法D)。[M+H]+ 260.1。
醯胺形成之一般程序
g. N-[8-甲氧基-5-(㗁烷-4-基)喹㗁啉-2-基]-1-(2-甲氧基乙基)-1H-吡唑-4-甲醯胺
將8-甲氧基-5-(四氫-哌喃-4-基)-喹㗁啉-2-基胺,79% (100 mg, 0.305 mmol)、1-(2-甲氧基乙基)-1H-吡唑-4-甲酸(67.4 mg,0.396 mmol)、N-(3-二甲基胺丙基)-N'-乙基碳二亞胺鹽酸鹽(75.9 mg,0.396 mmol)、1-羥基苯并***水合物(53.5 mg,0.396 mmol)溶解於N,N-二甲基甲醯胺(5.00 ml)中。在室溫下,添加N-乙基二異丙胺(0.13 ml,0.762 mmol)及將混合物在室溫下攪拌3天。將反應混合物蒸發至乾及藉由急驟層析法用乙腈/水純化及將預純化溶離份用二氯甲烷/水再純化,以得到6.00 mg (5%)呈淺米色固體之標題化合物。1 H NMR (500 MHz, DMSO-d6) ppm = 11.20 (s, 1H), 9.65 (s, 1H), 8.58 - 8.57 (m, 1H), 8.24 - 8.23 (m, 1H), 7.51 (d, J = 8.2 Hz, 1H), 7.24 (d, J = 8.2 Hz, 1H), 4.33 (t, J = 5.2 Hz, 2H), 4.02 - 3.97 (m, 2H), 3.96 (s, 3H), 3.96 - 3.90 (m, 1H), 3.72 (t, J = 5.2 Hz, 2H), 3.56 (td, J = 11.5, 2.5 Hz, 2H), 3.26 (s, 3H), 1.87 - 1.73 (m, 4H)。HPLC/MS (純度) 100%。Rt 2.26分鐘(方法D)。[M+H]+ 272.1
g. N-[8-甲氧基-5-(㗁烷-4-基)喹㗁啉-2-基]-1-(2-甲氧基乙基)-1H-吡唑-4-甲醯胺
將8-甲氧基-5-(四氫-哌喃-4-基)-喹㗁啉-2-基胺,79% (100 mg, 0.305 mmol)、1-(2-甲氧基乙基)-1H-吡唑-4-甲酸(67.4 mg,0.396 mmol)、N-(3-二甲基胺丙基)-N'-乙基碳二亞胺鹽酸鹽(75.9 mg,0.396 mmol)、1-羥基苯并***水合物(53.5 mg,0.396 mmol)溶解於N,N-二甲基甲醯胺(5.00 ml)中。在室溫下,添加N-乙基二異丙胺(0.13 ml,0.762 mmol)及將混合物在室溫下攪拌3天。將反應混合物蒸發至乾及藉由急驟層析法用乙腈/水純化及將預純化溶離份用二氯甲烷/水再純化,以得到6.00 mg (5%)呈淺米色固體之標題化合物。1 H NMR (500 MHz, DMSO-d6) ppm = 11.20 (s, 1H), 9.65 (s, 1H), 8.58 - 8.57 (m, 1H), 8.24 - 8.23 (m, 1H), 7.51 (d, J = 8.2 Hz, 1H), 7.24 (d, J = 8.2 Hz, 1H), 4.33 (t, J = 5.2 Hz, 2H), 4.02 - 3.97 (m, 2H), 3.96 (s, 3H), 3.96 - 3.90 (m, 1H), 3.72 (t, J = 5.2 Hz, 2H), 3.56 (td, J = 11.5, 2.5 Hz, 2H), 3.26 (s, 3H), 1.87 - 1.73 (m, 4H)。HPLC/MS (純度) 100%。Rt 2.26分鐘(方法D)。[M+H]+ 272.1
2. 4-羥基-N-[8-甲氧基-5-(吡啶-4-基)喹㗁啉-2-基]-4-甲基哌啶-1-甲醯胺
h. 4-(4-甲氧基-2,3-二硝基-苯基)吡啶
向用氬氣之惰性氛圍淨化及維持之350-ml壓力罐式反應器中放置1-溴-4-甲氧基-2,3-二硝基苯,95% (5.00 g,17.2 mmol)、4-(四甲基 -1,3,2-二氧雜硼㖦-2-基)吡啶,95% (4.44 g,20.6 mmol)、Pd(dppf)Cl2二氯甲烷複合物,90% (1.56 g,1.72 mmol)、碳酸鉀(2.99 g,20.6 mmol,溶解於水(2 ml)中)、乙醇(10 ml)及甲苯(100 ml)。將混合物在100℃下攪拌15小時及於冷卻後蒸發至乾。將殘餘物藉由管柱層析法(乙酸乙酯/己烷,80/20)純化以得到4.01 g (81%)呈黃色固體之4-(4-甲氧基-2,3-二硝基苯基)吡啶。HPLC/MS (純度) 95%。Rt 0.90分鐘(方法E)。[M+H]+ 276.1。
h. 4-(4-甲氧基-2,3-二硝基-苯基)吡啶
向用氬氣之惰性氛圍淨化及維持之350-ml壓力罐式反應器中放置1-溴-4-甲氧基-2,3-二硝基苯,95% (5.00 g,17.2 mmol)、4-(四甲基 -1,3,2-二氧雜硼㖦-2-基)吡啶,95% (4.44 g,20.6 mmol)、Pd(dppf)Cl2二氯甲烷複合物,90% (1.56 g,1.72 mmol)、碳酸鉀(2.99 g,20.6 mmol,溶解於水(2 ml)中)、乙醇(10 ml)及甲苯(100 ml)。將混合物在100℃下攪拌15小時及於冷卻後蒸發至乾。將殘餘物藉由管柱層析法(乙酸乙酯/己烷,80/20)純化以得到4.01 g (81%)呈黃色固體之4-(4-甲氧基-2,3-二硝基苯基)吡啶。HPLC/MS (純度) 95%。Rt 0.90分鐘(方法E)。[M+H]+ 276.1。
硝基還原之一般程序
i. 3-甲氧基-6-吡啶-4-基-苯-1,2-二胺
向250-ml圓底燒瓶中放置碳載鈀,10% (2.13 g,19.9 mmol)、甲醇(60 ml)及4-(4-甲氧基-2,3-二硝基苯基)吡啶,95% (4.00 g,13.8 mmol)。在室溫下,在氫氣氛圍下,將混合物攪拌15小時。將固體過濾掉並丟棄。將濾液蒸發至乾及將殘餘物藉由管柱層析法(乙酸乙酯/MeOH,95/5)純化以得到2.0 g (52%)呈黃色固體之3-甲氧基-6-(吡啶-4-基)苯-1,2-二胺。1 H NMR (400 MHz, DMSO-d6) 8.57 (d, J = 1.7 Hz, 2H), 7.42 (d, J = 1.7 Hz, 2H), 6.46 (d, J = 8.4 Hz, 2H), 4.33 (s, 4H), 3.78 (s, 3H)。熔點:165至166℃。HPLC/MS (純度) 91%。Rt 0.64分鐘(方法A)。[M+H]+ 216.0。
i. 3-甲氧基-6-吡啶-4-基-苯-1,2-二胺
向250-ml圓底燒瓶中放置碳載鈀,10% (2.13 g,19.9 mmol)、甲醇(60 ml)及4-(4-甲氧基-2,3-二硝基苯基)吡啶,95% (4.00 g,13.8 mmol)。在室溫下,在氫氣氛圍下,將混合物攪拌15小時。將固體過濾掉並丟棄。將濾液蒸發至乾及將殘餘物藉由管柱層析法(乙酸乙酯/MeOH,95/5)純化以得到2.0 g (52%)呈黃色固體之3-甲氧基-6-(吡啶-4-基)苯-1,2-二胺。1 H NMR (400 MHz, DMSO-d6) 8.57 (d, J = 1.7 Hz, 2H), 7.42 (d, J = 1.7 Hz, 2H), 6.46 (d, J = 8.4 Hz, 2H), 4.33 (s, 4H), 3.78 (s, 3H)。熔點:165至166℃。HPLC/MS (純度) 91%。Rt 0.64分鐘(方法A)。[M+H]+ 216.0。
j. 8-甲氧基-5-吡啶-4-基-1H-喹㗁啉-2-酮
將3-甲氧基-6-吡啶-4-基-苯-1,2-二胺,91% (1.77 g,7.48 mmol)及3-甲氧基-6-吡啶-4-基-苯-1,2-二胺,93% (2.00 g,8.64 mmol)溶解於甲醇(80 ml)中,然後在室溫下添加50%乙醛酸乙酯之甲苯溶液(9.85 mL,96.7 mmol)及將反應混合物在80℃下攪拌3小時。將混合物蒸發至乾及將殘餘物用乙酸乙酯研磨以得到沈澱,於過濾後,將該沈澱進一步藉由急驟層析法(二氯甲烷/乙醇,梯度)純化以得到1.80 g (44%)呈無色固體之標題化合物。HPLC/MS (純度) 100%。Rt 1.43分鐘(方法D)。[M+H]+ 254.1。
將3-甲氧基-6-吡啶-4-基-苯-1,2-二胺,91% (1.77 g,7.48 mmol)及3-甲氧基-6-吡啶-4-基-苯-1,2-二胺,93% (2.00 g,8.64 mmol)溶解於甲醇(80 ml)中,然後在室溫下添加50%乙醛酸乙酯之甲苯溶液(9.85 mL,96.7 mmol)及將反應混合物在80℃下攪拌3小時。將混合物蒸發至乾及將殘餘物用乙酸乙酯研磨以得到沈澱,於過濾後,將該沈澱進一步藉由急驟層析法(二氯甲烷/乙醇,梯度)純化以得到1.80 g (44%)呈無色固體之標題化合物。HPLC/MS (純度) 100%。Rt 1.43分鐘(方法D)。[M+H]+ 254.1。
k. 2-氯-8-甲氧基-5-吡啶-4-基-喹㗁啉
在室溫下,將8-甲氧基-5-吡啶-4-基-1H-喹㗁啉-2-酮(1.800 g,7.107 mmol)溶解於磷醯氯(32.7 g,213 mmol)中及將混合物在105℃下攪拌3小時。於冷卻至室溫後,將混合物分配在飽和NaHCO3 水溶液與二氯甲烷之間及在室溫下再攪拌1小時。將沈澱過濾掉以得到870 mg (34%)呈黃色固體之標題化合物。HPLC/MS (純度) 75%。Rt 1.89分鐘(方法D)。[M+H]+ 254.1。
在室溫下,將8-甲氧基-5-吡啶-4-基-1H-喹㗁啉-2-酮(1.800 g,7.107 mmol)溶解於磷醯氯(32.7 g,213 mmol)中及將混合物在105℃下攪拌3小時。於冷卻至室溫後,將混合物分配在飽和NaHCO3 水溶液與二氯甲烷之間及在室溫下再攪拌1小時。將沈澱過濾掉以得到870 mg (34%)呈黃色固體之標題化合物。HPLC/MS (純度) 75%。Rt 1.89分鐘(方法D)。[M+H]+ 254.1。
l. 8-甲氧基-5-吡啶-4-基-喹㗁啉-2-基胺
於高壓管中,將2-氯-8-甲氧基-5-吡啶-4-基-喹㗁啉,75% (870 mg,2.40 mmol)溶解於THF (20 ml)中。向此混合物中添加32%氨水溶液(50 ml)及碘化銅(I) (229 mg,1.20 mmol),將容器密封及將混合物在140℃下攪拌5小時(最大21巴壓力)。於冷卻至室溫後,將混合物蒸發至乾及藉由急驟層析法(乙酸乙酯/環己烷,梯度)純化,以得到140 mg (23%)無色固體。HPLC/MS (純度) 100%。Rt 1.33分鐘(方法D)。[M+H]+ 253.1。
於高壓管中,將2-氯-8-甲氧基-5-吡啶-4-基-喹㗁啉,75% (870 mg,2.40 mmol)溶解於THF (20 ml)中。向此混合物中添加32%氨水溶液(50 ml)及碘化銅(I) (229 mg,1.20 mmol),將容器密封及將混合物在140℃下攪拌5小時(最大21巴壓力)。於冷卻至室溫後,將混合物蒸發至乾及藉由急驟層析法(乙酸乙酯/環己烷,梯度)純化,以得到140 mg (23%)無色固體。HPLC/MS (純度) 100%。Rt 1.33分鐘(方法D)。[M+H]+ 253.1。
脲形成之一般程序
m. 4-羥基-N-[8-甲氧基-5-(吡啶-4-基)喹㗁啉-2-基]-4-甲基哌啶-1-甲醯胺
將8-甲氧基-5-吡啶-4-基-喹㗁啉-2-基胺(140 mg,0.555 mmol)及1,1'-羰二咪唑(117 mg,0.721 mmol)懸浮於二氯甲烷(4 ml)中及在70℃下攪拌20小時。然後在70℃下添加4-甲基哌啶-4-醇(83.1 mg,0.721 mmol)及將混合物在70℃下再攪拌3小時。將反應混合物蒸發至乾及藉由急驟層析法(水/乙腈,梯度)直接純化。將幾滴1N HCl溶液添加至含產物之孔中以於蒸發至乾後得到21.0 mg (9%)呈黃色固體之標題化合物之鹽酸鹽。1 H NMR (500 MHz, DMSO-d6) ppm = 10.14 (s, 1H), 9.30 (s, 1H), 8.97 - 8.94 (m, 2H), 8.42 - 8.39 (m, 2H), 7.97 (d, J = 8.3 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 4.06 (s, 3H), 3.82 (dt, J = 13.4, 4.3 Hz, 2H), 3.34 - 3.26 (m, 2H), 1.54 - 1.44 (m, 4H), 1.16 (s, 3H)。HPLC/MS (純度) 100%。Rt 1.76分鐘(方法D)。[M+H]+ 394.2。
m. 4-羥基-N-[8-甲氧基-5-(吡啶-4-基)喹㗁啉-2-基]-4-甲基哌啶-1-甲醯胺
將8-甲氧基-5-吡啶-4-基-喹㗁啉-2-基胺(140 mg,0.555 mmol)及1,1'-羰二咪唑(117 mg,0.721 mmol)懸浮於二氯甲烷(4 ml)中及在70℃下攪拌20小時。然後在70℃下添加4-甲基哌啶-4-醇(83.1 mg,0.721 mmol)及將混合物在70℃下再攪拌3小時。將反應混合物蒸發至乾及藉由急驟層析法(水/乙腈,梯度)直接純化。將幾滴1N HCl溶液添加至含產物之孔中以於蒸發至乾後得到21.0 mg (9%)呈黃色固體之標題化合物之鹽酸鹽。1 H NMR (500 MHz, DMSO-d6) ppm = 10.14 (s, 1H), 9.30 (s, 1H), 8.97 - 8.94 (m, 2H), 8.42 - 8.39 (m, 2H), 7.97 (d, J = 8.3 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 4.06 (s, 3H), 3.82 (dt, J = 13.4, 4.3 Hz, 2H), 3.34 - 3.26 (m, 2H), 1.54 - 1.44 (m, 4H), 1.16 (s, 3H)。HPLC/MS (純度) 100%。Rt 1.76分鐘(方法D)。[M+H]+ 394.2。
3. 4-羥基-N-[5-甲氧基-8-苯基吡啶并[3,4-b]吡嗪-3-基]-4-甲基哌啶-1-甲醯胺
n. 5-溴-2-甲氧基-3-硝基吡啶-4-胺
在0℃下,在攪拌下將發煙硝酸(109 ml)及濃硫酸(160 mL)之混合物逐滴添加至含5-溴-2-甲氧基吡啶-4-胺(36.00 g,177 mmol)之圓底燒瓶中。將混合物在室溫下攪拌12小時及用冰水(400 ml)中止。將混合物用DCM (4次,每次500 ml)萃取。合併有機相,用鹽水洗滌,經無水Na2 SO4 乾燥及過濾。將濾液在減壓下濃縮及將殘餘物藉由急驟層析法(EtOAc/石油醚,梯度)純化以得到呈黃色固體之5-溴-2-甲氧基-3-硝基吡啶-4-胺(5.54 g,13%)。MS:m/z = 249.8 [M+H]+ 。1 H NMR (300 MHz, DMSO-d6) δ 8.11 (s, 1 H), 7.14 (s, 1 H), 3.88 (s, 3 H)。
n. 5-溴-2-甲氧基-3-硝基吡啶-4-胺
在0℃下,在攪拌下將發煙硝酸(109 ml)及濃硫酸(160 mL)之混合物逐滴添加至含5-溴-2-甲氧基吡啶-4-胺(36.00 g,177 mmol)之圓底燒瓶中。將混合物在室溫下攪拌12小時及用冰水(400 ml)中止。將混合物用DCM (4次,每次500 ml)萃取。合併有機相,用鹽水洗滌,經無水Na2 SO4 乾燥及過濾。將濾液在減壓下濃縮及將殘餘物藉由急驟層析法(EtOAc/石油醚,梯度)純化以得到呈黃色固體之5-溴-2-甲氧基-3-硝基吡啶-4-胺(5.54 g,13%)。MS:m/z = 249.8 [M+H]+ 。1 H NMR (300 MHz, DMSO-d6) δ 8.11 (s, 1 H), 7.14 (s, 1 H), 3.88 (s, 3 H)。
o. 2-甲氧基-3-硝基-5-苯基吡啶-4-胺
在室溫下,向含於二㗁烷(174 ml)中之5-溴-2-甲氧基-3-硝基吡啶-4-胺(4.95 g,20.0 mmol)之溶液中添加苯基二羥基硼酸(2.48 g,20.4 mmol)、Pd(dppf)Cl2 CH2 Cl2 (652 mg,0.80 mmol)、碳酸鉀(5.92g,42.9 mmol)及水(37 ml)。於向混合物中氮氣鼓泡5分鐘後,將混合物在80℃下攪拌16小時。將固體過濾掉。將濾液在減壓下濃縮及將殘餘物藉由急驟層析法(EtOAc/石油醚,梯度)純化以得到呈黃色固體之2-甲氧基-3-硝基-5-苯基吡啶-4-胺(3.96 g,81%)。MS:m/z = 246.3 [M+H]+ 。
在室溫下,向含於二㗁烷(174 ml)中之5-溴-2-甲氧基-3-硝基吡啶-4-胺(4.95 g,20.0 mmol)之溶液中添加苯基二羥基硼酸(2.48 g,20.4 mmol)、Pd(dppf)Cl2 CH2 Cl2 (652 mg,0.80 mmol)、碳酸鉀(5.92g,42.9 mmol)及水(37 ml)。於向混合物中氮氣鼓泡5分鐘後,將混合物在80℃下攪拌16小時。將固體過濾掉。將濾液在減壓下濃縮及將殘餘物藉由急驟層析法(EtOAc/石油醚,梯度)純化以得到呈黃色固體之2-甲氧基-3-硝基-5-苯基吡啶-4-胺(3.96 g,81%)。MS:m/z = 246.3 [M+H]+ 。
p. 2-甲氧基-5-苯基吡啶-3,4-二胺
向含於MeOH (138 ml)中之2-甲氧基-3-硝基-5-苯基吡啶-4-胺(3.96 g,16.2 mmol)之溶液中放置碳載鈀,10% (515 mg,4.84 mmol)。在H2 氛圍下,在室溫下,將混合物攪拌16小時。當反應完成時,將固體過濾掉。將濾液在真空下濃縮以得到呈黃色固體之2-甲氧基-5-苯基吡啶-3,4-二胺(3.37 g,97%)。MS:m/z = 216.3 [M+H]+ 。
向含於MeOH (138 ml)中之2-甲氧基-3-硝基-5-苯基吡啶-4-胺(3.96 g,16.2 mmol)之溶液中放置碳載鈀,10% (515 mg,4.84 mmol)。在H2 氛圍下,在室溫下,將混合物攪拌16小時。當反應完成時,將固體過濾掉。將濾液在真空下濃縮以得到呈黃色固體之2-甲氧基-5-苯基吡啶-3,4-二胺(3.37 g,97%)。MS:m/z = 216.3 [M+H]+ 。
q. 5-甲氧基-8-苯基吡啶并[3,4-b]吡嗪-3-醇
在室溫下,向含於甲醇(181 ml)中之2-甲氧基-5-苯基吡啶-3,4-二胺(3.37 g,15.6 mmol)之溶液中添加2-側氧基乙酸乙酯(10.86 g,106 mmol)。將混合物在80℃下攪拌3小時。於冷卻至室溫後,將其在減壓下濃縮及將殘餘物藉由急驟層析法(EtOAc/石油醚,梯度)純化。收集兩種區域異構體及將第一溶離份確定為呈黃色固體之5-甲氧基-8-苯基吡啶并[3,4-b]吡嗪-3-醇(750 mg,19%)。MS:m/z = 254.0 [M+H]+ 。
在室溫下,向含於甲醇(181 ml)中之2-甲氧基-5-苯基吡啶-3,4-二胺(3.37 g,15.6 mmol)之溶液中添加2-側氧基乙酸乙酯(10.86 g,106 mmol)。將混合物在80℃下攪拌3小時。於冷卻至室溫後,將其在減壓下濃縮及將殘餘物藉由急驟層析法(EtOAc/石油醚,梯度)純化。收集兩種區域異構體及將第一溶離份確定為呈黃色固體之5-甲氧基-8-苯基吡啶并[3,4-b]吡嗪-3-醇(750 mg,19%)。MS:m/z = 254.0 [M+H]+ 。
r. 4-甲基苯-1-磺酸5-甲氧基-8-苯基吡啶并[3,4-b]吡嗪-3-基酯
在室溫下,向含於二氯甲烷(24 ml)中之5-甲氧基-8-苯基吡啶并[3,4-b]吡嗪-3-醇(750 mg,2.97 mmol)之溶液中添加4-甲基苯-1-磺醯氯 (616 mg,3.25 mmol)、4-二甲胺基吡啶(39 mg,0.28 mmol)及三乙胺(414 mg,4.14 mmol)。將溶液在室溫下攪拌2小時及然後用水(50 ml)中止。將混合物用二氯甲烷(150 ml,3次)萃取及合併有機相,用鹽水洗滌及經無水Na2 SO4 乾燥。在減壓下移除溶劑及將殘餘物藉由急驟層析法(EtOAc/石油醚,梯度)純化以得到呈綠色固體之4-甲基苯-1-磺酸5-甲氧基-8-苯基吡啶并[3,4-b]吡嗪-3-基酯(806 mg,67%)。MS:m/z = 408.2 [M+H]+ 。
在室溫下,向含於二氯甲烷(24 ml)中之5-甲氧基-8-苯基吡啶并[3,4-b]吡嗪-3-醇(750 mg,2.97 mmol)之溶液中添加4-甲基苯-1-磺醯氯 (616 mg,3.25 mmol)、4-二甲胺基吡啶(39 mg,0.28 mmol)及三乙胺(414 mg,4.14 mmol)。將溶液在室溫下攪拌2小時及然後用水(50 ml)中止。將混合物用二氯甲烷(150 ml,3次)萃取及合併有機相,用鹽水洗滌及經無水Na2 SO4 乾燥。在減壓下移除溶劑及將殘餘物藉由急驟層析法(EtOAc/石油醚,梯度)純化以得到呈綠色固體之4-甲基苯-1-磺酸5-甲氧基-8-苯基吡啶并[3,4-b]吡嗪-3-基酯(806 mg,67%)。MS:m/z = 408.2 [M+H]+ 。
s. 5-甲氧基-8-苯基吡啶并[3,4-b]吡嗪-3-胺
向含於二㗁烷(85 ml)中之4-甲基苯-1-磺酸5-甲氧基-8-苯基吡啶并[3,4-b]吡嗪-3-基酯(806 mg,1.97 mmol)之溶液中添加胺基甲酸第三丁酯(463 mg,3.94 mmol)、Pd(OAc)2 (47 mg,0.2 mmol)、XPhos (198 mg,0.39 mmol)及Cs2 CO3 (966 mg,2.97 mmol)。於向混合物中氮氣鼓泡5分鐘後,將混合物在100℃下攪拌16小時。當反應完成時,將固體過濾掉。將濾液在減壓下濃縮及將殘餘物藉由急驟層析法(EtOAc/石油醚,梯度)純化以得到呈黑色固體之5-甲氧基-8-苯基吡啶并[3,4-b]吡嗪-3-胺(185 mg,37%)。MS:m/z = 253.3 [M+H]+ 。
向含於二㗁烷(85 ml)中之4-甲基苯-1-磺酸5-甲氧基-8-苯基吡啶并[3,4-b]吡嗪-3-基酯(806 mg,1.97 mmol)之溶液中添加胺基甲酸第三丁酯(463 mg,3.94 mmol)、Pd(OAc)2 (47 mg,0.2 mmol)、XPhos (198 mg,0.39 mmol)及Cs2 CO3 (966 mg,2.97 mmol)。於向混合物中氮氣鼓泡5分鐘後,將混合物在100℃下攪拌16小時。當反應完成時,將固體過濾掉。將濾液在減壓下濃縮及將殘餘物藉由急驟層析法(EtOAc/石油醚,梯度)純化以得到呈黑色固體之5-甲氧基-8-苯基吡啶并[3,4-b]吡嗪-3-胺(185 mg,37%)。MS:m/z = 253.3 [M+H]+ 。
t. N-[5-甲氧基-8-苯基吡啶并[3,4-b]吡嗪-3-基]胺基甲酸苯酯
在室溫下,向含於THF (50 ml)中之5-甲氧基-8-苯基吡啶并[3,4-b]吡嗪-3-胺(120 mg,0.48 mmol)之溶液中添加碳酸鈉(252 mg,2.38 mmol)、氯甲酸苯酯(744 mg,4.76 mmol)及吡啶(188 mg,2.38 mmol)。 將混合物在50℃下攪拌6小時。當反應完成時,將固體過濾掉。將濾液在減壓下濃縮以得到呈白色固體之N-[5-甲氧基-8-苯基吡啶并[3,4-b]吡嗪-3-基]胺基甲酸苯酯(300 mg,粗製物)。MS:m/z = 373.2 [M+H]+ 。
在室溫下,向含於THF (50 ml)中之5-甲氧基-8-苯基吡啶并[3,4-b]吡嗪-3-胺(120 mg,0.48 mmol)之溶液中添加碳酸鈉(252 mg,2.38 mmol)、氯甲酸苯酯(744 mg,4.76 mmol)及吡啶(188 mg,2.38 mmol)。 將混合物在50℃下攪拌6小時。當反應完成時,將固體過濾掉。將濾液在減壓下濃縮以得到呈白色固體之N-[5-甲氧基-8-苯基吡啶并[3,4-b]吡嗪-3-基]胺基甲酸苯酯(300 mg,粗製物)。MS:m/z = 373.2 [M+H]+ 。
u. 4-羥基-N-[5-甲氧基-8-苯基吡啶并[3,4-b]吡嗪-3-基]-4-甲基哌啶-1-甲醯胺
在室溫下,向含於THF (10 ml)中之N-[5-甲氧基-8-苯基吡啶并[3,4-b]吡嗪-3-基]胺基甲酸苯酯(100 mg,粗製物)之溶液中添加4-甲基哌啶-4-醇(31 mg,0.27 mmol)及二異丙基乙胺(34.0 mg,0.27 mmol)。將溶液在60℃下攪拌12小時。於冷卻至室溫後,將反應藉由添加水(20 ml)中止。將混合物用DCM (50 ml,3次)萃取。合併有機相,用鹽水洗滌,經無水Na2 SO4 乾燥及過濾。將濾液在減壓下濃縮及將殘餘物藉由在下列條件下之製備型HPLC純化:管柱,XBridge Prep C18 OBD管柱,19 x 150 mm 5 um;MeCN/水(含有10 mmol/l NH4 HCO3 +0.1%NH3 .H2 O),於8分鐘中30%至50%梯度;檢測器,UV 254/220 nm,以得到呈黃色固體之4-羥基-N-[5-甲氧基-8-苯基吡啶并[3,4-b]吡嗪-3-基]-4-甲基哌啶-1-甲醯胺(30.0 mg,針對2個步驟為47%)。HPLC:99.3%純度,室溫= 4.14分鐘。MS:m/z = 394.3 [M+H]+ 。1 H NMR (400 MHz, DMSO-d6) δ 10.22 (s, 1 H), 9.38 (s, 1 H), 8.19 (s, 1 H), 7.68-7.60 (m, 2 H), 7.54-7.38 (m, 3 H), 4.37 (s, 1 H), 4.10 (s, 3 H), 3.87-3.76 (m, 2 H), 3.34-3.24 (m, 2 H), 1.56-1.42 (m, 4 H), 1.16 (s, 3 H)。
在室溫下,向含於THF (10 ml)中之N-[5-甲氧基-8-苯基吡啶并[3,4-b]吡嗪-3-基]胺基甲酸苯酯(100 mg,粗製物)之溶液中添加4-甲基哌啶-4-醇(31 mg,0.27 mmol)及二異丙基乙胺(34.0 mg,0.27 mmol)。將溶液在60℃下攪拌12小時。於冷卻至室溫後,將反應藉由添加水(20 ml)中止。將混合物用DCM (50 ml,3次)萃取。合併有機相,用鹽水洗滌,經無水Na2 SO4 乾燥及過濾。將濾液在減壓下濃縮及將殘餘物藉由在下列條件下之製備型HPLC純化:管柱,XBridge Prep C18 OBD管柱,19 x 150 mm 5 um;MeCN/水(含有10 mmol/l NH4 HCO3 +0.1%NH3 .H2 O),於8分鐘中30%至50%梯度;檢測器,UV 254/220 nm,以得到呈黃色固體之4-羥基-N-[5-甲氧基-8-苯基吡啶并[3,4-b]吡嗪-3-基]-4-甲基哌啶-1-甲醯胺(30.0 mg,針對2個步驟為47%)。HPLC:99.3%純度,室溫= 4.14分鐘。MS:m/z = 394.3 [M+H]+ 。1 H NMR (400 MHz, DMSO-d6) δ 10.22 (s, 1 H), 9.38 (s, 1 H), 8.19 (s, 1 H), 7.68-7.60 (m, 2 H), 7.54-7.38 (m, 3 H), 4.37 (s, 1 H), 4.10 (s, 3 H), 3.87-3.76 (m, 2 H), 3.34-3.24 (m, 2 H), 1.56-1.42 (m, 4 H), 1.16 (s, 3 H)。
HPLC方法:
方法A:
Shimadzu LCMS-2020;管柱:Poroshell HPH-C18,3.0 x 50 mm,2.7 µm;流動相A:水/5 mM NH4 HCO3 ,流動相B:乙腈;流量:1.0 mL/min;梯度:於2.2分鐘中10% B至95% B,保持1.0分鐘;波長:254 nm
方法B:
Shimadzu LCMS-2020;管柱:Poroshell HPH-C18,3.0 x 50 mm,2.7 µm;流動相A:水/5 mM NH4 HCO3 ,流動相B:乙腈;流量:1.3 mL/min;梯度:於2.1分鐘中10% B至95% B,保持0.6分鐘;波長:254 nm
方法C:
Shimadzu LCMS-2020;管柱:Shim-pack XR-ODS,3.0 x 50 mm,2.2 µm;流動相A:水/0.05% TFA,流動相B:乙腈/0.05% TFA;流量:1.2 mL/min;梯度:於2.2分鐘中5% B至100% B,保持1.0分鐘;波長:254 nm
方法D:
Agilent Technologies 1200系列;管柱:Chromolith Performance RP18e;100 x 3 mm;流動相A:水/0.1% TFA,流動相B:乙腈/0.1% TFA;梯度:1% B持續0.2分鐘,於3.8分鐘中1% B至100% B,保持0.4分鐘;流量:2 mL/min,波長:220 nm
方法E:
Shimadzu LCMS-2020;管柱:Shim-pack XR-ODS,3.0 x 50 mm,2.2 µm;流動相A:水/0.05% TFA,流動相B:乙腈/0.05% TFA;流量:1.2 mL/min;梯度:於2.0分鐘中5% B至100% B,保持0.5分鐘;波長254 nm。
方法A:
Shimadzu LCMS-2020;管柱:Poroshell HPH-C18,3.0 x 50 mm,2.7 µm;流動相A:水/5 mM NH4 HCO3 ,流動相B:乙腈;流量:1.0 mL/min;梯度:於2.2分鐘中10% B至95% B,保持1.0分鐘;波長:254 nm
方法B:
Shimadzu LCMS-2020;管柱:Poroshell HPH-C18,3.0 x 50 mm,2.7 µm;流動相A:水/5 mM NH4 HCO3 ,流動相B:乙腈;流量:1.3 mL/min;梯度:於2.1分鐘中10% B至95% B,保持0.6分鐘;波長:254 nm
方法C:
Shimadzu LCMS-2020;管柱:Shim-pack XR-ODS,3.0 x 50 mm,2.2 µm;流動相A:水/0.05% TFA,流動相B:乙腈/0.05% TFA;流量:1.2 mL/min;梯度:於2.2分鐘中5% B至100% B,保持1.0分鐘;波長:254 nm
方法D:
Agilent Technologies 1200系列;管柱:Chromolith Performance RP18e;100 x 3 mm;流動相A:水/0.1% TFA,流動相B:乙腈/0.1% TFA;梯度:1% B持續0.2分鐘,於3.8分鐘中1% B至100% B,保持0.4分鐘;流量:2 mL/min,波長:220 nm
方法E:
Shimadzu LCMS-2020;管柱:Shim-pack XR-ODS,3.0 x 50 mm,2.2 µm;流動相A:水/0.05% TFA,流動相B:乙腈/0.05% TFA;流量:1.2 mL/min;梯度:於2.0分鐘中5% B至100% B,保持0.5分鐘;波長254 nm。
實例 3 :測試本發明化合物對重組細胞中之人類腺苷受體之抑制活性
藉由cAMP (為腺苷受體之第二信使)之定量測定人類A2A 、A2B 、A1 及A3 受體之功能活性。出於此目的,表現人類A2A 或A2B 受體(均為Gs偶合)之重組HEK293細胞接種至394-孔微量滴定盤中,添加測試化合物及促效劑(NECA)。於15分鐘培育後,添加HTRF試劑(cAMP動態2,Cis Bio)及使用ENVISION (Perkin Elmer)板讀取器測定細胞cAMP水平。
藉由cAMP (為腺苷受體之第二信使)之定量測定人類A2A 、A2B 、A1 及A3 受體之功能活性。出於此目的,表現人類A2A 或A2B 受體(均為Gs偶合)之重組HEK293細胞接種至394-孔微量滴定盤中,添加測試化合物及促效劑(NECA)。於15分鐘培育後,添加HTRF試劑(cAMP動態2,Cis Bio)及使用ENVISION (Perkin Elmer)板讀取器測定細胞cAMP水平。
針對人類A1
及A3
受體,使用表現A1
或A3
受體之重組CHO細胞。因為受體均與Gi蛋白質偶合,所以適於以下檢定方案:
將細胞接種至384-孔板中,添加毛喉素(forskolin)、測試化合物及促效劑(針對A1 受體為CPA及針對A3 受體為IB-MECA)。於30分鐘培育後,添加HTRF試劑(cAMP動態2,Cis Bio)及使用ENVISION (Perkin Elmer)板讀取器測定細胞cAMP水平。
將細胞接種至384-孔板中,添加毛喉素(forskolin)、測試化合物及促效劑(針對A1 受體為CPA及針對A3 受體為IB-MECA)。於30分鐘培育後,添加HTRF試劑(cAMP動態2,Cis Bio)及使用ENVISION (Perkin Elmer)板讀取器測定細胞cAMP水平。
將獲得之原始數據對抑制劑對照及中性對照(DMSO)歸一化及使用GeneData軟體將經歸一化之數據擬合。
本發明化合物顯示高的對腺苷A2A
及A2B
受體超過腺苷A1
及A3
受體之選擇性(參見例如,表4中本發明化合物之一些實例的資料)。
特定言之,與已知腺苷A2A
受體拮抗劑托紮南特及相似苯并噻唑衍生物相比,本發明化合物出人意料地顯示A2A
/A2B
雙重活性(參見表4),該雙重活性對於治療及/或預防如上所揭示之過度增生性及傳染性疾病及病症而言較佳或本發明化合物至少顯示高A2A
抑制活性連同本文中所揭示之其他驚人優點,該等優點導致高效治療及/或預防過度增生性及傳染性疾病及病症。
表 4
A意指IC50
值係< 10 nM,B意指IC50
值係< 100 nM,C意指IC50
值係< 1 µM,D意指IC50
值係> 1 µM。
表 4
實例 4 :測試本發明化合物對內源性人類 A2A 受體之效應
於T細胞中量測Gs偶合之人類A2A 受體之內源性功能活性,T細胞中此受體高度表現。藉由cAMP之定量完成受體活性之測定,該cAMP為腺苷受體之第二信使。
於T細胞中量測Gs偶合之人類A2A 受體之內源性功能活性,T細胞中此受體高度表現。藉由cAMP之定量完成受體活性之測定,該cAMP為腺苷受體之第二信使。
簡言之,人類泛T細胞係自衍生自新鮮全血之人類PBMC單離(MACS泛T細胞單離套組,Miltenyi Biotec)。將該等T細胞接種於384-孔微量滴定盤中及用測試化合物處理。於室溫下培育10分鐘後,添加A2A
腺苷受體促效劑CGS-21680,及將該等板再培育45分鐘。最後,將HTRF試劑(cAMP Femto套組,CisBio)添加至孔中,及於1小時後,使用ENVISION (Perkin Elmer)板讀取器測定細胞cAMP水平。
將獲得之原始數據對抑制劑對照及中性對照(DMSO)歸一化及使用Genedata Screener軟體將歸一化之數據擬合。
本發明化合物顯示,其能抑制於利用A2A
腺苷受體促效劑CGS-21680培育之人類T細胞中表現之A2A
受體(如藉由cAMP之定量所量測),其對於治療及/或預防如上所揭示之過度增生性及傳染性疾病及病症而言較佳。因此,出人意料地,本發明化合物能預防免疫抑制及因此能支持抗腫瘤T細胞誘導之腫瘤生長之抑制,轉移酶之減少或破壞及新生血管形成之預防。
實例 5 :測試本發明化合物於大鼠及小鼠中之藥物動力學性質
研究之目標為獲得關於本發明化合物於單一靜脈內及口服投與後於雌性Wistar大鼠/小鼠中之藥物動力學性質的資訊。
研究之目標為獲得關於本發明化合物於單一靜脈內及口服投與後於雌性Wistar大鼠/小鼠中之藥物動力學性質的資訊。
材料及方法: 動物實驗(一生中階段) 雌性Wistar大鼠/小鼠(n=6)接受測試化合物之單一靜脈內(團式)注射或口服投與(藉由強飼法)。分別經靜脈內及經口提供0.2及10 mg/kg (每種化合物)之劑量,針對靜脈內投與呈含於DMSO (0.2%)/PEG 200 (40%)/水中之溶液及針對口服給藥呈含於甲基纖維素(Methocel) (0.5%)/Tween 20 (0.25%)/水中之懸浮液。於0.1 (僅靜脈內)、0.25 (僅經口)、0.5、1、2、4、6及24小時後在異氟醚吸入下自3隻動物/投與途徑舌下採集連續血液樣品及進一步處理以獲得血漿。同樣,在0至24小時之時間間隔內收集3隻大鼠/投與途徑之尿及糞便樣品並匯總用於分析。
生物分析:
使用UPLC方法利用「藥物代謝及藥物動力學研究所(Institute of Drug Metabolism and Pharmacokinetics)」先前開發之串聯質譜法檢測(LC-MS/MS)定量血漿、糞便中之化合物之濃度。LC-MS/MS系統由耦合至AB Sciex質譜儀API 5500 Q-阱之Waters Acquity UPLC組成。在逆向管柱(HSS T3,1.8 µM,2.1 ´ 50 mm)上使用流動相梯度利用0.1%甲酸及乙腈作為溶離劑進行UPLC分離。使用以正電離模式之多反應監測進行化合物之檢測。將內部標準(20 µl)加料血漿樣品及使用第三丁基甲基醚(tBME)自基質提取分析物。在氮氣流下,將有機相蒸發至乾。將殘餘物溶解於乙腈/0.1%甲酸中用於LC-MS/MS分析。將糞便樣品用4倍於其體積之乙醇/水混合物(4:1,v/v)均質化。將內部標準加料水性乙醇性提取物之等分試樣,用乙腈/水(1:1,v/v)稀釋及直接注射入LC-MS/MS系統。
使用UPLC方法利用「藥物代謝及藥物動力學研究所(Institute of Drug Metabolism and Pharmacokinetics)」先前開發之串聯質譜法檢測(LC-MS/MS)定量血漿、糞便中之化合物之濃度。LC-MS/MS系統由耦合至AB Sciex質譜儀API 5500 Q-阱之Waters Acquity UPLC組成。在逆向管柱(HSS T3,1.8 µM,2.1 ´ 50 mm)上使用流動相梯度利用0.1%甲酸及乙腈作為溶離劑進行UPLC分離。使用以正電離模式之多反應監測進行化合物之檢測。將內部標準(20 µl)加料血漿樣品及使用第三丁基甲基醚(tBME)自基質提取分析物。在氮氣流下,將有機相蒸發至乾。將殘餘物溶解於乙腈/0.1%甲酸中用於LC-MS/MS分析。將糞便樣品用4倍於其體積之乙醇/水混合物(4:1,v/v)均質化。將內部標準加料水性乙醇性提取物之等分試樣,用乙腈/水(1:1,v/v)稀釋及直接注射入LC-MS/MS系統。
藥物動力學評價:
自觀察到之資料取得藥物動力學參數Cmax 及tmax 。使用定製軟體「DDS-TOX」計算曲線下面積(AUC)、清除率(CL)、體積(V)、半衰期(t1/2 )、F及所有劑量歸一化之值。針對若干化合物評價「DDS-TOX」值及顯示與藉由驗證軟體WinNonLin給定之值可相比。藉由非隔室分析使用線性上/對數下(linear up/log down)方法計算AUC值。將平均血漿濃度及衍生之藥物動力學參數之數據四捨五入至3個有效數字用於提交。使用2個有效數字顯示表示為劑量之%之口服生物可利用率及***數據。
自觀察到之資料取得藥物動力學參數Cmax 及tmax 。使用定製軟體「DDS-TOX」計算曲線下面積(AUC)、清除率(CL)、體積(V)、半衰期(t1/2 )、F及所有劑量歸一化之值。針對若干化合物評價「DDS-TOX」值及顯示與藉由驗證軟體WinNonLin給定之值可相比。藉由非隔室分析使用線性上/對數下(linear up/log down)方法計算AUC值。將平均血漿濃度及衍生之藥物動力學參數之數據四捨五入至3個有效數字用於提交。使用2個有效數字顯示表示為劑量之%之口服生物可利用率及***數據。
與已知腺苷A2A
受體拮抗劑托紮南特及相似苯并噻唑衍生物相比,本發明化合物於作為癌症相關之動物模型之小鼠中出人意料地顯示更佳藥物動力學性質(參見表6),其對於治療及/或預防如上所揭示之過度增生性及傳染性疾病及病症而言較佳。
表 6- 小鼠中之 PK 資料
表 6- 小鼠中之 PK 資料
實例 6 : 測試本發明化合物對小鼠 T 細胞之效應
背景:
腫瘤微環境中之腺苷(Ado)可抑制藉由通過A2A 受體信號傳導之T細胞活性及抑制藉由T細胞之細胞激素分泌。A2A 特異性促效劑(如CGS-21680)類似抑制活體外及活體內T細胞細胞激素分泌。潛在A2A 拮抗劑或A2A /A2B 雙重拮抗劑可自此抑制營救T細胞。本文中,吾人描述吾人使用來自小鼠脾臟之泛T細胞建立之活體外系統以針對其活性篩選潛在A2A 拮抗劑或A2A /A2B 雙重拮抗劑。描述之方法涉及使用CD3/CD28預塗覆珠粒以刺激自小鼠脾細胞純化之泛T細胞,與添加A2A 促效劑連同潛在A2A 或A2A /A2B 雙重拮抗劑組合以評價T細胞細胞激素產生之增強。
背景:
腫瘤微環境中之腺苷(Ado)可抑制藉由通過A2A 受體信號傳導之T細胞活性及抑制藉由T細胞之細胞激素分泌。A2A 特異性促效劑(如CGS-21680)類似抑制活體外及活體內T細胞細胞激素分泌。潛在A2A 拮抗劑或A2A /A2B 雙重拮抗劑可自此抑制營救T細胞。本文中,吾人描述吾人使用來自小鼠脾臟之泛T細胞建立之活體外系統以針對其活性篩選潛在A2A 拮抗劑或A2A /A2B 雙重拮抗劑。描述之方法涉及使用CD3/CD28預塗覆珠粒以刺激自小鼠脾細胞純化之泛T細胞,與添加A2A 促效劑連同潛在A2A 或A2A /A2B 雙重拮抗劑組合以評價T細胞細胞激素產生之增強。
檢定描述:
簡言之,根據製造商之協定,使用泛T細胞單離套組小鼠II (MACS Miltenyi biotech目錄號訂單號130-095-130)將小鼠泛T細胞自BALB/c小鼠之脾臟純化。將經純化之T細胞接種於Nunc™ 96-孔聚苯乙烯圓底微孔板中之含有10%熱滅活胎牛血清之RPMI培養基。使細胞在37℃下靜置1小時,然後用CD3/CD28預塗覆之珠粒(Dynabeads™小鼠T-激活劑CD3/CD28;目錄號11456D)激活。於30分鐘後,將細胞用變化劑量之測試拮抗劑處理。將細胞在37℃下再培育30分鐘,然後用A2A 促效劑CGS-21680 (1 µM)或中性對照(DMSO)處理。根據製造商之協定,藉由ELISA量測於24小時培育後上清液中之IL-2水平及於48小時培育後上清液中之IFN-γ水平(R&D Systems目錄號DY402 (IL-2);DY485 (IFN-γ))。一旦計算出濃度,就計算DMSO對照及促效劑單獨對照之細胞激素濃度之差異(稱作Δ)及使用Microsoft Excel計算藉由各濃度之拮抗劑營救之百分比。將細胞激素營救以拮抗劑之劑量依賴性方式之此等百分比於GraphPad Prism軟體中作圖並計算IC50 。
簡言之,根據製造商之協定,使用泛T細胞單離套組小鼠II (MACS Miltenyi biotech目錄號訂單號130-095-130)將小鼠泛T細胞自BALB/c小鼠之脾臟純化。將經純化之T細胞接種於Nunc™ 96-孔聚苯乙烯圓底微孔板中之含有10%熱滅活胎牛血清之RPMI培養基。使細胞在37℃下靜置1小時,然後用CD3/CD28預塗覆之珠粒(Dynabeads™小鼠T-激活劑CD3/CD28;目錄號11456D)激活。於30分鐘後,將細胞用變化劑量之測試拮抗劑處理。將細胞在37℃下再培育30分鐘,然後用A2A 促效劑CGS-21680 (1 µM)或中性對照(DMSO)處理。根據製造商之協定,藉由ELISA量測於24小時培育後上清液中之IL-2水平及於48小時培育後上清液中之IFN-γ水平(R&D Systems目錄號DY402 (IL-2);DY485 (IFN-γ))。一旦計算出濃度,就計算DMSO對照及促效劑單獨對照之細胞激素濃度之差異(稱作Δ)及使用Microsoft Excel計算藉由各濃度之拮抗劑營救之百分比。將細胞激素營救以拮抗劑之劑量依賴性方式之此等百分比於GraphPad Prism軟體中作圖並計算IC50 。
與已知腺苷A2A
受體拮抗劑托紮南特相比,本發明化合物顯示其能營救T細胞免於抑制且能預防如由腺苷或A2A
特異性促效劑(如CGS-2168)所誘導之細胞活性分泌之抑制(參見表7),其對於治療及/或預防如上所揭示之過度增生性及傳染性疾病及病症而言較佳。因此,出人意料地,本發明化合物能預防免疫抑制及因此能支持抗腫瘤T細胞誘導之腫瘤生長之抑制,轉移酶之減少或破壞及新生血管形成之預防。
表 7
表 7
實例 7 : 注射小瓶
使用2N鹽酸將含於3 l再蒸餾水中之100 g本發明化合物及5 g磷酸氫二鈉之溶液調整至pH 6.5,在無菌條件下過濾,轉移至注射小瓶中,在無菌條件下凍乾及在無菌條件下密封。各注射小瓶含有5 mg本發明化合物。
使用2N鹽酸將含於3 l再蒸餾水中之100 g本發明化合物及5 g磷酸氫二鈉之溶液調整至pH 6.5,在無菌條件下過濾,轉移至注射小瓶中,在無菌條件下凍乾及在無菌條件下密封。各注射小瓶含有5 mg本發明化合物。
實例 8 :溶液
自1 g本發明化合物、9.38 g NaH2 PO4 2H2 O、28.48 g Na2 HPO4 ·12H2 O及0.1 g苯紮氯銨(benzalkonium chloride)於940 ml再蒸餾水中製備溶液。將pH調整至6.8,及使溶液補足至1 l及藉由照射滅菌。
自1 g本發明化合物、9.38 g NaH2 PO4 2H2 O、28.48 g Na2 HPO4 ·12H2 O及0.1 g苯紮氯銨(benzalkonium chloride)於940 ml再蒸餾水中製備溶液。將pH調整至6.8,及使溶液補足至1 l及藉由照射滅菌。
實例 9 :安瓿
將含於60 l再蒸餾水中之1 kg本發明化合物之溶液在無菌條件下過濾,轉移至安瓿,在無菌條件下凍乾及在無菌條件下密封。各安瓿含有10 mg本發明化合物。
將含於60 l再蒸餾水中之1 kg本發明化合物之溶液在無菌條件下過濾,轉移至安瓿,在無菌條件下凍乾及在無菌條件下密封。各安瓿含有10 mg本發明化合物。
Claims (20)
- 一種式I化合物, 其中 Q、Y彼此獨立地為CH或N, R1 為鹵素或含有1至10個C原子之直鏈或分支鏈烷基(其未經取代或經R4 單取代、二取代或三取代且其中1至4個C原子可彼此獨立地經O、S、SO、SO2 、NH、NCH3 、–OCO–、–NHCONH–、–NHCO–、–NR5 SO2 R6 –、–COO–、–CONH–、–NCH3 CO–、–CONCH3 –、–C≡C–基團及/或–CH=CH–基團置換,及/或此外,1至10個H原子可經F及/或Cl置換),或含有3至7個C原子之單環或雙環環烷基(其未經取代或經R4 單取代、二取代或三取代且其中1至4個C原子可彼此獨立地經O、S、SO、SO2 、NH、NCH3 、–OCO–、–NHCONH–、–NHCO–、–NR5 SO2 R6 –、–COO–、–CONH–、–NCH3 CO–、–CONCH3 –、–C≡C–基團及/或經–CH=CH–基團置換及/或此外,1至10個H原子可經F及/或Cl置換),或含有3至14個碳原子及獨立地選自N、O及S之0至4個雜原子之單環或雙環雜芳基、雜環基、芳基或環烷基芳基(其未經取代或經R4 單取代、二取代或三取代), R2 為含有1至10個C原子之直鏈或分支鏈烷基(其未經取代或經R4 單取代、二取代或三取代且其中1至4個C原子可彼此獨立地經O、S、SO、SO2 、NH、NCH3 、–OCO–、–NHCONH–、–NHCO–、–NR5 SO2 R6 –、–COO–、–CONH–、–NCH3 CO–、–CONCH3 –、–C≡C–基團及/或–CH=CH–基團置換,及/或此外,1至10個H原子可經F及/或Cl置換),或含有3至7個C原子之環烷基(其未經取代或經R4 單取代、二取代或三取代且其中1至4個C原子可彼此獨立地經O、S、SO、SO2 、NH、NCH3 、–OCO–、–NHCONH–、–NHCO–、–NR5 SO2 R6 –、–COO–、–CONH–、–NCH3 CO–、–CONCH3 –、–C≡C–基團及/或經–CH=CH–基團置換,及/或此外,1至11個H原子可經F及/或Cl置換),或含有3至14個碳原子及獨立地選自N、O及S之0至4個雜原子之單環或雙環雜芳基、雜環基、芳基或環烷基芳基(其未經取代或經R4 單取代、二取代或三取代), R3 為含有1至6個C原子之直鏈或分支鏈烷基或O-烷基或含有3至6個C原子之環烷基,其未經取代或經H、=S、=NH、=O、OH、含有3至6個C原子之環烷基、COOH、鹵素、NH2 、SO2 CH3 、SO2 NH2 、CN、CONH2 、NHCOCH3 、NHCONH2 或NO2 單取代、二取代或三取代, R4 為H、R5 、=S、=NR5 、=O、OH、COOH、鹵素、NH2 、SO2 CH3 、SO2 NH2 、CN、CONH2 、NHCOCH3 、NHCONH2 、NO2 或含有1至10個C原子之直鏈或分支鏈烷基(其未經取代或經R5 單取代、二取代或三取代且其中1至4個C原子可彼此獨立地經O、S、SO、SO2 、NH、NCH3 、–OCO–、–NHCONH–、–NHCO–、–NR5 SO2 R6 –、–COO–、–CONH–、–NCH3 CO–、–CONCH3 –、–C≡C–基團及/或–CH=CH–基團置換,及/或此外,1至10個H原子可經F及/或Cl置換),或含有3至7個C原子之單環或雙環環烷基(其未經取代或經R5 單取代、二取代或三取代且其中1至4個C原子可彼此獨立地經O、S、SO、SO2 、NH、NCH3 、–OCO–、–NHCONH–、–NHCO–、–NRSO2 R4 –、–COO–、–CONH–、–NCH3 CO–、–CONCH3 –、–C≡C–基團及/或經–CH=CH–基團置換及/或此外,1至10個H原子可經F及/或Cl置換),或含有3至14個碳原子及獨立地選自N、O及S之0至4個雜原子之單環或雙環雜芳基、雜環基、芳基或環烷基芳基(其未經取代或經R5 單取代、二取代或三取代), R5 、R6 彼此獨立地選自由以下組成之群:H、=S、=NH、=O、OH、COOH、鹵素、NH2 、SO2 CH3 、SO2 NH2 、CN、CONH2 、NHCOCH3 、NHCONH2 、NO2 及含有1至10個C原子之直鏈或分支鏈烷基(其中1至4個C原子可彼此獨立地經O、S、SO、SO2 、NH、NCH3 、–OCO–、–NHCONH–、–NHCO–、–COO–、–CONH–、–NCH3 CO–、–CONCH3 –、–C≡C–基團及/或–CH=CH–基團置換,及/或此外,1至10個H原子可經F及/或Cl置換), 鹵素為F、C、Br或I, 及其生理學上可接受之鹽、衍生物、溶劑化物、前藥及立體異構體,包括其等依所有比率之混合物。
- 如請求項1之化合物,其中 R1 為含有1至10個C原子之直鏈或分支鏈烷基(其未經取代或經R4 單取代、二取代或三取代且其中1至4個C原子可彼此獨立地經O、S、SO、SO2 、NH、NCH3 、–OCO–、–NHCONH–、–NHCO–、–NR5 SO2 R6 –、–COO–、–CONH–、–NCH3 CO–、–CONCH3 –、–C≡C–基團及/或–CH=CH–基團置換,及/或此外,1至10個H原子可經F及/或Cl置換),或下列結構中之一者: 其未經取代或經R4 單取代、二取代或三取代 且其中Q、Y、R2 、R3 、R4 、R5 及R6 具有如請求項1中所揭示之含義,及其生理學上可接受之鹽、衍生物、溶劑化物、前藥及立體異構體,包括其等依所有比率之混合物。
- 如請求項1或2之化合物,其中 Q為CH或N Y為CH 且其中R1 、R2 、R3 、R4 、R5 及R6 具有如請求項1中所揭示之含義,及其生理學上可接受之鹽、衍生物、溶劑化物、前藥及立體異構體,包括其等依所有比率之混合物。
- 如請求項1至3中任一項之化合物,其中R2 為下列結構中之一者: 其未經取代或經R5 單取代、二取代或三取代 且其中Q、Y、R1 、R3 、R4 、R5 及R6 具有如請求項1中所揭示之含義,及其生理學上可接受之鹽、衍生物、溶劑化物、前藥及立體異構體,包括其等依所有比率之混合物。
- 如請求項1至4中任一項之化合物,其中 R3 為下列結構中之一者 且Q、Y、R1 、R2 、R4 、R5 及R6 具有如請求項1中所揭示之含義,及其生理學上可接受之鹽、衍生物、溶劑化物、前藥及立體異構體,包括其等依所有比率之混合物。
- 如請求項1至5中任一項之化合物,其中 R3 為OMe 且Q、Y、R1 、R2 、R4 、R5 及R6 具有如請求項1中所揭示之含義,及其生理學上可接受之鹽、衍生物、溶劑化物、前藥及立體異構體,包括其等依所有比率之混合物。
- 一種化合物,其選自由以下組成之群:
- 一種製備式I化合物之方法,其特徵在於 a)使式II化合物經歷硝化反應,接著還原以得到式IV化合物,將式IV化合物環化以得到式V化合物,將式V化合物氯化,接著銅催化胺化反應以得到化合物VII,採用觸酶及鹼使式VII化合物於鈴木型反應中反應成為式VIII化合物,藉由標準醯胺化或脲形成條件將式VIII化合物轉化成式I化合物,其中Q、Y、R1 、R2 及R3 具有如上所揭示之含義, b)在鈴木型反應條件下,使式III化合物與二羥基硼酸酯或酸反應以得到式IX化合物,或在提高溫度下於親核取代反應中與胺反應以形成式IX化合物,將式IX化合物還原為式X化合物並環化為式XI化合物,將式XI化合物氯化,接著銅催化胺化以得到化合物VIII,及最終在標準醯胺化或脲形成條件下使化合物VIII反應成為式I化合物且其中Q、Y、R1 、R2 及R3 具有如上所揭示之含義, c)在鈴木型反應條件下,使式XIII化合物與二羥基硼酸酯或酸反應以得到式XIV化合物,將式XIV化合物還原為式X化合物並環化為式XI化合物,將式XI化合物甲苯磺酸化,接著金屬催化胺化以得到化合物VIII及最終在標準醯胺化或脲形成條件下使化合物VIII反應成為式I化合物且其中Q、Y、R1 、R2 及R3 具有如上所揭示之含義, d)藉由用酸處理將式I化合物之鹼轉化成其鹽中之一者,或 e)藉由用鹼處理將式I化合物之酸轉化成其鹽中之一者。
- 如請求項1至7中任一項之化合物及其生理學上可接受之鹽、衍生物、溶劑化物、前藥及立體異構體,包括其等依所有比率之混合物,其作為腺苷A2A 及/或A2B 受體抑制劑。
- 一種醫藥製劑,其包含至少一種如請求項1至7中任一項之化合物及/或其生理學上可接受之鹽、衍生物、溶劑化物、前藥及立體異構體,包括其等依所有比率之混合物。
- 如請求項10之醫藥製劑,其另外包含賦形劑及/或佐劑。
- 一種醫藥製劑,其包含至少一種如請求項1至7中任一項之化合物及/或其生理學上可接受之鹽、衍生物、溶劑化物、前藥及立體異構體(包括其等依所有比率之混合物)及至少一種其他藥物活性化合物。
- 一種製備醫藥製劑之方法,其特徵在於將如請求項1至7中任一項之化合物及/或其生理學上可接受之鹽、衍生物、溶劑化物、前藥及立體異構體(包括其等依所有比率之混合物)中之一者與固體、液體或半液體賦形劑或佐劑一起形成適宜劑型。
- 一種藥劑,其包含至少一種如請求項1至7中任一項之化合物及/或其生理學上可接受之鹽、衍生物、溶劑化物、前藥及立體異構體(包括其等依所有比率之混合物)中之一者,其用於治療及/或預防生理及/或病理生理狀態。
- 一種藥劑,其包含至少一種如請求項1至7中任一項之化合物及/或其生理學上可接受之鹽、衍生物、溶劑化物、前藥及立體異構體(包括其等依所有比率之混合物)中之一者,其用於治療及/或預防選自由過度增生性及傳染性疾病及病症組成之群之生理及/或病理生理狀態。
- 如請求項15之藥劑,其中該過度增生性疾病或病症為癌症。
- 如請求項16之藥劑,其中該癌症係選自由以下組成之群:急性及慢性淋巴細胞性白血病、急性粒細胞性白血病、腎上腺皮質癌、膀胱癌、腦癌、乳癌、子宮頸癌、子宮頸增生、絨膜癌、慢性粒細胞性白血病、慢性淋巴細胞性白血病、結腸癌、子宮內膜癌、食道癌、原發性血小板增多症、泌尿生殖道癌、神經膠質瘤、神經膠質母細胞瘤、毛細胞白血病、頭頸癌、霍奇金氏病(Hodgkin's disease)、卡波西氏肉瘤(Kaposi's sarcoma)、肺癌、淋巴瘤、惡性類癌、惡性高鈣血症、惡性黑色素瘤、惡性胰臟胰島素瘤、骨髓性甲狀腺癌、黑色素瘤、多發性骨髓瘤、蕈樣肉芽腫、骨髓性及淋巴細胞性白血病、神經母細胞瘤、非霍奇金氏淋巴瘤、非小細胞肺癌、骨原性肉瘤、卵巢癌、胰癌、真性紅血球增多症、原發性腦癌、原發性巨球蛋白血症、***癌、腎細胞癌、橫紋肌肉瘤、皮膚癌、小細胞肺癌、軟組織肉瘤、鱗狀細胞癌、胃癌、睾丸癌、甲狀腺癌及威爾姆氏瘤(Wilms' tumor)。
- 如請求項15之藥劑,其中該過度增生性疾病或病症係選自由以下組成之群:年齡相關之黃斑部變性、克羅恩氏病(Crohn's disease)、肝硬化、慢性發炎相關病症、增生性糖尿病視網膜病變、增生性玻璃體視網膜病變、早產兒視網膜病變、肉芽腫病、與器官或組織移植相關之免疫過度增生及選自由發炎性腸病、牛皮癬、類風濕性關節炎、全身性紅斑狼瘡(SLE)、繼發於視網膜缺氧及血管炎之血管過度增生所組成之群之免疫增生性疾病或病症。
- 如請求項15之藥劑,其中該傳染性疾病或病症係選自由以下組成之群: a)由逆轉錄病毒、嗜肝DNA病毒、皰疹病毒、黃病毒科及/或腺病毒引起之病毒誘導之傳染性疾病,其中該逆轉錄病毒係選自慢病毒或致癌逆轉錄病毒,其中該慢病毒係選自由HIV-1、HIV-2、FIV、BIV、SIV、SHIV、CAEV、VMV及EIAV組成之群及該致癌逆轉錄病毒係選自由HTLV-I、HTLV-II及BLV組成之群,該嗜肝DNA病毒係選自由HBV、GSHV及WHV組成之群,該皰疹病毒係選自由HSV I、HSV II、EBV、VZV、HCMV或HHV 8組成之群及該黃病毒科係選自由HCV、西尼羅河(West nile)熱及黃熱病(Yellow Fever)組成之群, b)由革蘭氏陽性細菌引起之細菌傳染性疾病,其中該革蘭氏陽性細菌係選自由以下組成之群:甲氧西林(methicillin)易感性及甲氧西林抗藥性葡萄球菌(staphylococci) (包括黃色葡萄球菌(Staphylococcus aureus)、表皮葡萄球菌(Staphylococcus epidermidis)、溶血性葡萄球菌(Staphylococcus haemolyticus)、人葡萄球菌(Staphylococcus hominis)、腐生性葡萄球菌(Staphylococcus saprophyticus)及凝固酶陰性葡萄球菌)、糖肽中間體易感性金黃色葡萄球菌(GISA)、盤尼西林(penicillin)易感性及盤尼西林抗藥性鏈球菌(streptococci) (包括肺炎鏈球菌(Streptococcus pneumoniae)、化膿性鏈球菌(Streptococcus pyogenes)、無乳鏈球菌(Streptococcus agalactiae)、鳥鏈球菌(Streptococcus avium)、牛鏈球菌(Streptococcus bovis)、乳鏈球菌(Streptococcus lactis)、血鏈球菌(Streptococcus sanguis)及鏈球菌C組(GCS)、鏈球菌G組(GGS)及草綠色鏈球菌(viridans streptococci))、腸球菌(enterococci) (包括萬古黴素(vancomycin)易感性及萬古黴素抗藥性株(諸如糞腸球菌(Enterococcus faecalis)及屎腸球菌(Enterococcus faecium))、艱難梭菌(Clostridium difficile)、單核細胞增生性李斯特氏菌(listeria monocytogenes)、傑氏棒狀桿菌(Corynebacterium jeikeium)、衣原體屬(Chlamydia spp) (包括肺炎衣原體(C. pneumoniae ))及結核分枝桿菌(Mycobacterium tuberculosis), c)由革蘭氏陰性細菌引起之細菌傳染性疾病,其中該革蘭氏陰性細菌係選自由以下組成之群:腸桿菌屬(Genus Enterobacteriacae),該腸桿菌屬包括埃希氏菌屬(Escherichia spp.) (包括大腸桿菌(Escherichia coli))、克雷伯氏菌屬(Klebsiella spp.)、腸桿菌屬(Enterobacter spp.)、檸檬酸桿菌屬(Citrobacter spp.)、沙雷氏菌屬(Serratia spp.)、變形桿菌屬(Proteus spp.)、普羅威登斯菌屬(Providencia spp.)、沙門氏菌屬(Salmonella spp.)、志賀氏菌屬(Shigella spp.)、假單胞菌屬(genus Pseudomonas) (包括綠膿桿菌(P. aeruginosa))、莫拉氏菌屬(Moraxella spp.) (包括卡他莫拉菌(M. catarrhalis))、嗜血桿菌屬(Haemophilus spp.)及奈瑟氏菌屬(Neisseria spp.), d)由選自由以下組成之群之細胞內活性寄生蟲誘導之傳染性疾病: 頂複門(Apicomplexa)或肉足鞭毛門(Sarcomastigophora) (包括錐蟲屬(Trypanosoma)、瘧原蟲屬(Plasmodia)、利什曼原蟲屬(Leishmania)、巴貝蟲屬(Babesia)或泰勒原蟲屬(Theileria))、隱孢子蟲屬(Cryptosporidia)、肉孢子蟲科(Sacrocystida)、變形蟲屬(Amoebia)、球蟲屬(Coccidia)及毛滴蟲屬(Trichomonadia)。
- 一種套組(set/kit),其由以下之分開包裝組成: a)有效量之如請求項1至7中任一項之化合物及/或其生理學上可接受之鹽、衍生物、溶劑化物、前藥及立體異構體,包括其等依所有比率之混合物,及 b)有效量之其他藥物活性化合物。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP17187100 | 2017-08-21 | ||
??17187100.7 | 2017-08-21 |
Publications (1)
Publication Number | Publication Date |
---|---|
TW201920123A true TW201920123A (zh) | 2019-06-01 |
Family
ID=59677147
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW107128914A TW201920123A (zh) | 2017-08-21 | 2018-08-20 | 作為腺苷受體拮抗劑之喹㗁啉衍生物 |
Country Status (14)
Country | Link |
---|---|
US (1) | US11192899B2 (zh) |
EP (1) | EP3672951B1 (zh) |
JP (1) | JP7287951B2 (zh) |
KR (1) | KR20200043434A (zh) |
CN (1) | CN110944994B (zh) |
AU (1) | AU2018320672B2 (zh) |
BR (1) | BR112020003283A2 (zh) |
CA (1) | CA3073343A1 (zh) |
DK (1) | DK3672951T3 (zh) |
ES (1) | ES2964026T3 (zh) |
IL (1) | IL272638B1 (zh) |
SG (1) | SG11202001340VA (zh) |
TW (1) | TW201920123A (zh) |
WO (1) | WO2019038214A1 (zh) |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2020182929A1 (en) | 2019-03-13 | 2020-09-17 | Bayer Aktiengesellschaft | Substituted ureas and derivatives as new antifungal agents |
WO2020192762A1 (zh) * | 2019-03-28 | 2020-10-01 | 基石药业(苏州)有限公司 | 一种a2a受体拮抗剂的盐型、晶型及其制备方法 |
CA3186758A1 (en) * | 2020-07-23 | 2022-01-27 | Haiping Wu | Compound having kinase inhibitory activity |
WO2022058327A1 (en) | 2020-09-15 | 2022-03-24 | Bayer Aktiengesellschaft | Substituted ureas and derivatives as new antifungal agents |
US20220127231A1 (en) * | 2020-10-27 | 2022-04-28 | Shilpa Medicare Ltd | Process for the prepartion of amifampridine phosphate |
EP4059498A1 (en) * | 2021-03-16 | 2022-09-21 | Centre Hospitalier Universitaire Vaudois (CHUV) | Methods and compositions for treating conditions associated with hypermineralization |
WO2022258622A1 (en) | 2021-06-07 | 2022-12-15 | Ares Trading S.A. | Combination treatment of cancer |
CN116514803A (zh) * | 2022-01-21 | 2023-08-01 | 上海赛岚生物科技有限公司 | 一种激酶抑制剂的盐晶型和自由碱晶型 |
Family Cites Families (23)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4207554A (en) | 1972-08-04 | 1980-06-10 | Med-El Inc. | Method and apparatus for automated classification and analysis of cells |
US4125828A (en) | 1972-08-04 | 1978-11-14 | Med-El Inc. | Method and apparatus for automated classification and analysis of cells |
GB9624482D0 (en) | 1995-12-18 | 1997-01-15 | Zeneca Phaema S A | Chemical compounds |
US6184225B1 (en) | 1996-02-13 | 2001-02-06 | Zeneca Limited | Quinazoline derivatives as VEGF inhibitors |
DE69709319T2 (de) | 1996-03-05 | 2002-08-14 | Astrazeneca Ab | 4-anilinochinazolin derivate |
GB9718972D0 (en) | 1996-09-25 | 1997-11-12 | Zeneca Ltd | Chemical compounds |
GB9714249D0 (en) | 1997-07-08 | 1997-09-10 | Angiogene Pharm Ltd | Vascular damaging agents |
AU1688599A (en) | 1998-01-05 | 1999-07-26 | Eisai Co. Ltd. | Purine derivatives and adenosine a2 receptor antagonists serving as preventives/remedies for diabetes |
GB9900334D0 (en) | 1999-01-07 | 1999-02-24 | Angiogene Pharm Ltd | Tricylic vascular damaging agents |
GB9900752D0 (en) | 1999-01-15 | 1999-03-03 | Angiogene Pharm Ltd | Benzimidazole vascular damaging agents |
EP1221444B1 (en) | 1999-07-02 | 2005-08-31 | Eisai Co., Ltd. | Fused imidazole compounds and remedies for diabetes mellitus |
JP2003535078A (ja) | 2000-05-31 | 2003-11-25 | アストラゼネカ アクチボラグ | 血管損傷活性のあるインドール誘導体 |
BR0112224A (pt) | 2000-07-07 | 2003-06-10 | Angiogene Pharm Ltd | Composto, composição farmacêutica, uso de um composto ou de um sal, solvato ou pró-droga farmaceuticamente aceitável do mesmo, e, processo para preparar um composto |
EP1301498A1 (en) | 2000-07-07 | 2003-04-16 | Angiogene Pharmaceuticals Limited | Colchinol derivatives as angiogenesis inhibitors |
WO2004089942A2 (en) | 2001-10-02 | 2004-10-21 | Acadia Pharmaceuticals Inc. | Benzimidazolidinone derivatives as muscarinic agents |
AU2002356962C1 (en) | 2001-12-12 | 2008-05-01 | The Government Of The United States Of America As Represented By The Secretary, Department Of Health And Human Services | Methods for using extracellular adenosine inhibitors and adenosine receptor inhibitors to enhance immune response and inflammation |
EP1618108A2 (en) | 2003-04-09 | 2006-01-25 | Biogen Idec MA Inc. | Triazolo[1,5-a]pyrimidines and pyrazolo[1,5-a]pyrimidines useful as a2a adenosine receptor antagonists |
RU2351597C2 (ru) * | 2003-05-19 | 2009-04-10 | Ф.Хоффманн-Ля Рош Аг | Производные бензотиазола в качестве лигандов аденозиновых рецепторов |
AU2004274154A1 (en) | 2003-09-19 | 2005-03-31 | F. Hoffmann-La Roche Ag | Thiazolopyridine derivatives as adenosine receptor ligands |
JP2005154434A (ja) * | 2003-11-05 | 2005-06-16 | Kyowa Hakko Kogyo Co Ltd | 2−アミノキナゾリン誘導体 |
EA011279B1 (ru) | 2004-05-24 | 2009-02-27 | Ф. Хоффманн-Ля Рош Аг | (4-метокси-7-морфолин-4-илбензотиазол-2-ил)-амид 4-гидрокси-4-метилпиперидин-1-карбоновой кислоты |
RU2382782C2 (ru) | 2004-07-22 | 2010-02-27 | Ф. Хоффманн-Ля Рош Аг | Производные бензотиазола |
EP2282999B1 (en) | 2008-03-04 | 2014-05-21 | Merck Sharp & Dohme Corp. | Amino-quinoxaline and amino-quinoline compounds for use as adenosine a2a receptor antagonists |
-
2018
- 2018-08-20 TW TW107128914A patent/TW201920123A/zh unknown
- 2018-08-20 WO PCT/EP2018/072397 patent/WO2019038214A1/en unknown
- 2018-08-20 BR BR112020003283-2A patent/BR112020003283A2/pt unknown
- 2018-08-20 KR KR1020207008007A patent/KR20200043434A/ko active IP Right Grant
- 2018-08-20 EP EP18753208.0A patent/EP3672951B1/en active Active
- 2018-08-20 ES ES18753208T patent/ES2964026T3/es active Active
- 2018-08-20 AU AU2018320672A patent/AU2018320672B2/en active Active
- 2018-08-20 CN CN201880054521.1A patent/CN110944994B/zh active Active
- 2018-08-20 CA CA3073343A patent/CA3073343A1/en active Pending
- 2018-08-20 US US16/640,526 patent/US11192899B2/en active Active
- 2018-08-20 SG SG11202001340VA patent/SG11202001340VA/en unknown
- 2018-08-20 DK DK18753208.0T patent/DK3672951T3/da active
- 2018-08-20 IL IL272638A patent/IL272638B1/en unknown
- 2018-08-20 JP JP2020511322A patent/JP7287951B2/ja active Active
Also Published As
Publication number | Publication date |
---|---|
EP3672951B1 (en) | 2023-08-30 |
BR112020003283A2 (pt) | 2020-08-25 |
US11192899B2 (en) | 2021-12-07 |
CA3073343A1 (en) | 2019-02-28 |
DK3672951T3 (da) | 2023-11-20 |
ES2964026T3 (es) | 2024-04-03 |
WO2019038214A1 (en) | 2019-02-28 |
US20200354375A1 (en) | 2020-11-12 |
AU2018320672A1 (en) | 2020-04-02 |
AU2018320672B2 (en) | 2023-09-07 |
EP3672951A1 (en) | 2020-07-01 |
IL272638B1 (en) | 2024-01-01 |
JP7287951B2 (ja) | 2023-06-06 |
CN110944994A (zh) | 2020-03-31 |
SG11202001340VA (en) | 2020-03-30 |
KR20200043434A (ko) | 2020-04-27 |
JP2020531526A (ja) | 2020-11-05 |
CN110944994B (zh) | 2023-06-09 |
IL272638A (en) | 2020-03-31 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
TW201920123A (zh) | 作為腺苷受體拮抗劑之喹㗁啉衍生物 | |
US9102631B2 (en) | 1-(arylmethyl)-5,6,7,8-tetrahydroquinazoline-2,4-diones and analogs and the use thereof | |
KR20210098960A (ko) | Helios의 소분자 분해제 및 사용 방법 | |
ES2701903T3 (es) | Inhibidores de cinasa a base de quinolina | |
JP7336434B2 (ja) | アデノシン受容体アンタゴニストとしてのチアゾロピリジン誘導体 | |
AU2014249003A1 (en) | Novel compounds and compositions for inhibition of FASN | |
AU2015320142B2 (en) | Novel imidazopyridazine compounds and their use | |
WO2013013614A1 (zh) | 4-(3-杂芳基芳基氨基)喹唑啉和1-(3-杂芳基芳基氨基)异喹啉作为Hedgehog通路抑制剂及其应用 | |
CN110997657A (zh) | 咪唑烷化合物 | |
TWI791593B (zh) | 做為腺苷受體拮抗劑之苯并咪唑衍生物 | |
KR20210116572A (ko) | 아데노신 수용체 길항제로서의 티아졸로피리딘 유도체 | |
JP6885962B2 (ja) | 1,4−ジカルボニル−ピペリジル誘導体 | |
KR20210083293A (ko) | 아데노신 수용체 안타고니스트로서의 5-아자인다졸 유도체 | |
RU2791168C1 (ru) | Хиноксалиновые производные в качестве антагонистов аденозиновых рецепторов | |
US20230056497A1 (en) | CD206 Modulators Their Use and Methods for Preparation | |
RU2781429C2 (ru) | Бензимидазольные производные в качестве антагонистов аденозиновых рецепторов | |
RU2790011C2 (ru) | Тиазолопиридиновые производные в качестве антагонистов аденозиновых рецепторов | |
RU2810114C2 (ru) | Тиазолопиридиновые производные в качестве антагонистов аденозиновых рецепторов | |
EP3484875A1 (en) | Pyrazolylaminobenzimidazole derivatives as jak inhibitors | |
JP2023542548A (ja) | 新規アミノピリジン及びその癌治療への使用 | |
JP2023512205A (ja) | トール様受容体7(TLR7)アゴニストとしての1H-ピラゾロ[4,3-d]ピリミジン化合物 | |
ES2371928T3 (es) | Nuevos aza-heterociclos que actúan como inhibidores de la quinasa. |