CN107250116A - 3,5‑二氨基吡唑激酶抑制剂 - Google Patents
3,5‑二氨基吡唑激酶抑制剂 Download PDFInfo
- Publication number
- CN107250116A CN107250116A CN201580076521.8A CN201580076521A CN107250116A CN 107250116 A CN107250116 A CN 107250116A CN 201580076521 A CN201580076521 A CN 201580076521A CN 107250116 A CN107250116 A CN 107250116A
- Authority
- CN
- China
- Prior art keywords
- phenyl
- compound
- amino
- bases
- methyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- KGBBJPZIDRELDP-UHFFFAOYSA-N 1h-pyrazole-3,5-diamine Chemical compound NC=1C=C(N)NN=1 KGBBJPZIDRELDP-UHFFFAOYSA-N 0.000 title abstract description 10
- 229940043355 kinase inhibitor Drugs 0.000 title description 6
- 239000003757 phosphotransferase inhibitor Substances 0.000 title description 6
- -1 formula (I) Chemical class 0.000 claims abstract description 244
- 150000001875 compounds Chemical class 0.000 claims abstract description 222
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 85
- 208000024891 symptom Diseases 0.000 claims abstract description 74
- 108091000080 Phosphotransferase Proteins 0.000 claims abstract description 68
- 102000020233 phosphotransferase Human genes 0.000 claims abstract description 68
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 62
- 201000010099 disease Diseases 0.000 claims abstract description 59
- 238000000034 method Methods 0.000 claims abstract description 53
- 230000000694 effects Effects 0.000 claims abstract description 22
- 230000001404 mediated effect Effects 0.000 claims abstract description 13
- 239000000203 mixture Substances 0.000 claims description 183
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 144
- 125000001424 substituent group Chemical group 0.000 claims description 76
- 125000001072 heteroaryl group Chemical group 0.000 claims description 69
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 68
- 150000003839 salts Chemical class 0.000 claims description 58
- 229940002612 prodrug Drugs 0.000 claims description 56
- 239000000651 prodrug Substances 0.000 claims description 56
- 239000003814 drug Substances 0.000 claims description 49
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 49
- 239000012453 solvate Substances 0.000 claims description 47
- 229910052736 halogen Inorganic materials 0.000 claims description 45
- 150000002367 halogens Chemical class 0.000 claims description 45
- GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 36
- 238000006467 substitution reaction Methods 0.000 claims description 36
- 125000000217 alkyl group Chemical group 0.000 claims description 35
- 125000003118 aryl group Chemical group 0.000 claims description 33
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 32
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 32
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 24
- 239000002552 dosage form Substances 0.000 claims description 23
- 210000004027 cell Anatomy 0.000 claims description 22
- WHKWMTXTYKVFLK-UHFFFAOYSA-N 1-propan-2-ylpiperazine Chemical compound CC(C)N1CCNCC1 WHKWMTXTYKVFLK-UHFFFAOYSA-N 0.000 claims description 21
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 20
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 20
- 239000000460 chlorine Chemical group 0.000 claims description 19
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims description 18
- 208000006673 asthma Diseases 0.000 claims description 18
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 17
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 15
- 239000011737 fluorine Substances 0.000 claims description 15
- 229910052731 fluorine Inorganic materials 0.000 claims description 15
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 14
- 239000002775 capsule Substances 0.000 claims description 14
- 150000003053 piperidines Chemical class 0.000 claims description 14
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 13
- 229910052801 chlorine Inorganic materials 0.000 claims description 13
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 13
- FQXXSQDCDRQNQE-UHFFFAOYSA-N markiertes Thebain Natural products COC1=CC=C2C(N(CC3)C)CC4=CC=C(OC)C5=C4C23C1O5 FQXXSQDCDRQNQE-UHFFFAOYSA-N 0.000 claims description 13
- 229930003945 thebaine Natural products 0.000 claims description 13
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims description 10
- 125000003368 amide group Chemical group 0.000 claims description 10
- 125000002757 morpholinyl group Chemical group 0.000 claims description 10
- 125000004193 piperazinyl group Chemical group 0.000 claims description 10
- 201000010105 allergic rhinitis Diseases 0.000 claims description 9
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 8
- 201000004624 Dermatitis Diseases 0.000 claims description 8
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 8
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 8
- 229940124597 therapeutic agent Drugs 0.000 claims description 8
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 7
- 206010010744 Conjunctivitis allergic Diseases 0.000 claims description 7
- 206010012438 Dermatitis atopic Diseases 0.000 claims description 7
- 206010020751 Hypersensitivity Diseases 0.000 claims description 7
- 208000002205 allergic conjunctivitis Diseases 0.000 claims description 7
- 208000024998 atopic conjunctivitis Diseases 0.000 claims description 7
- 201000008937 atopic dermatitis Diseases 0.000 claims description 7
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 7
- 229910052794 bromium Inorganic materials 0.000 claims description 7
- 125000006517 heterocyclyl carbonyl group Chemical group 0.000 claims description 7
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 7
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 claims description 6
- KCKQIVLNKGDTGJ-UHFFFAOYSA-N 4-(3-chloropyridin-2-yl)morpholine Chemical compound ClC1=CC=CN=C1N1CCOCC1 KCKQIVLNKGDTGJ-UHFFFAOYSA-N 0.000 claims description 6
- KUSLAWUUDVNSNN-UHFFFAOYSA-N 4-(3-methylpyridin-2-yl)morpholine Chemical compound CC1=CC=CN=C1N1CCOCC1 KUSLAWUUDVNSNN-UHFFFAOYSA-N 0.000 claims description 6
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 6
- GMCQMCAZFJZFNR-UHFFFAOYSA-N 4-pyridin-3-ylmorpholine Chemical compound C1COCCN1C1=CC=CN=C1 GMCQMCAZFJZFNR-UHFFFAOYSA-N 0.000 claims description 6
- 206010039085 Rhinitis allergic Diseases 0.000 claims description 6
- 208000026935 allergic disease Diseases 0.000 claims description 6
- 208000010247 contact dermatitis Diseases 0.000 claims description 6
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 6
- 208000027866 inflammatory disease Diseases 0.000 claims description 6
- VSEAAEQOQBMPQF-UHFFFAOYSA-N morpholin-3-one Chemical compound O=C1COCCN1 VSEAAEQOQBMPQF-UHFFFAOYSA-N 0.000 claims description 6
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 5
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 5
- XHPVOSNOIWGRQQ-UHFFFAOYSA-N 4-pyridin-2-ylmorpholine Chemical class C1COCCN1C1=CC=CC=N1 XHPVOSNOIWGRQQ-UHFFFAOYSA-N 0.000 claims description 5
- 208000011231 Crohn disease Diseases 0.000 claims description 5
- 201000004681 Psoriasis Diseases 0.000 claims description 5
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 5
- 208000010668 atopic eczema Diseases 0.000 claims description 5
- 208000037903 inflammatory enteropathy Diseases 0.000 claims description 5
- 201000006417 multiple sclerosis Diseases 0.000 claims description 5
- 208000011580 syndromic disease Diseases 0.000 claims description 5
- 230000009885 systemic effect Effects 0.000 claims description 5
- 208000032671 Allergic granulomatous angiitis Diseases 0.000 claims description 4
- 208000006344 Churg-Strauss Syndrome Diseases 0.000 claims description 4
- 206010009900 Colitis ulcerative Diseases 0.000 claims description 4
- 206010012442 Dermatitis contact Diseases 0.000 claims description 4
- 241000196324 Embryophyta Species 0.000 claims description 4
- 208000018428 Eosinophilic granulomatosis with polyangiitis Diseases 0.000 claims description 4
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 4
- 206010063837 Reperfusion injury Diseases 0.000 claims description 4
- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 4
- 208000024780 Urticaria Diseases 0.000 claims description 4
- 230000007815 allergy Effects 0.000 claims description 4
- 229910021529 ammonia Inorganic materials 0.000 claims description 4
- 206010003246 arthritis Diseases 0.000 claims description 4
- 235000010290 biphenyl Nutrition 0.000 claims description 4
- 235000013305 food Nutrition 0.000 claims description 4
- 238000001990 intravenous administration Methods 0.000 claims description 4
- 208000032839 leukemia Diseases 0.000 claims description 4
- 125000005936 piperidyl group Chemical group 0.000 claims description 4
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 4
- IQXXEPZFOOTTBA-UHFFFAOYSA-N 1-benzylpiperazine Chemical compound C=1C=CC=CC=1CN1CCNCC1 IQXXEPZFOOTTBA-UHFFFAOYSA-N 0.000 claims description 3
- MCGBIXXDQFWVDW-UHFFFAOYSA-N 4,5-dihydro-1h-pyrazole Chemical compound C1CC=NN1 MCGBIXXDQFWVDW-UHFFFAOYSA-N 0.000 claims description 3
- UZOFELREXGAFOI-UHFFFAOYSA-N 4-methylpiperidine Chemical compound CC1CCNCC1 UZOFELREXGAFOI-UHFFFAOYSA-N 0.000 claims description 3
- 208000002874 Acne Vulgaris Diseases 0.000 claims description 3
- 208000035285 Allergic Seasonal Rhinitis Diseases 0.000 claims description 3
- 206010004173 Basophilia Diseases 0.000 claims description 3
- 206010010741 Conjunctivitis Diseases 0.000 claims description 3
- 208000005577 Gastroenteritis Diseases 0.000 claims description 3
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 3
- 201000001263 Psoriatic Arthritis Diseases 0.000 claims description 3
- 208000036284 Rhinitis seasonal Diseases 0.000 claims description 3
- 206010000496 acne Diseases 0.000 claims description 3
- 125000002252 acyl group Chemical group 0.000 claims description 3
- SMWDFEZZVXVKRB-UHFFFAOYSA-N anhydrous quinoline Natural products N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 230000001684 chronic effect Effects 0.000 claims description 3
- JMANVNJQNLATNU-UHFFFAOYSA-N glycolonitrile Natural products N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 claims description 3
- 210000003630 histaminocyte Anatomy 0.000 claims description 3
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 3
- 201000008482 osteoarthritis Diseases 0.000 claims description 3
- 125000002971 oxazolyl group Chemical group 0.000 claims description 3
- 208000017022 seasonal allergic rhinitis Diseases 0.000 claims description 3
- 201000009890 sinusitis Diseases 0.000 claims description 3
- RAHZWNYVWXNFOC-UHFFFAOYSA-N sulfur dioxide Inorganic materials O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims description 3
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 claims description 2
- VCQKNBFFAKKOBB-UHFFFAOYSA-N 2-(4-pyrrolidin-1-ylpiperidin-1-yl)pyridine Chemical compound C1CCCN1C1CCN(C=2N=CC=CC=2)CC1 VCQKNBFFAKKOBB-UHFFFAOYSA-N 0.000 claims description 2
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims description 2
- RWNRPQYVWJSAPE-UHFFFAOYSA-N 3-piperidin-1-ylpyridine Chemical compound C1CCCCN1C1=CC=CN=C1 RWNRPQYVWJSAPE-UHFFFAOYSA-N 0.000 claims description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 2
- 125000004568 thiomorpholinyl group Chemical group 0.000 claims description 2
- 206010020880 Hypertrophy Diseases 0.000 claims 2
- 206010044302 Tracheitis Diseases 0.000 claims 2
- 201000009961 allergic asthma Diseases 0.000 claims 2
- FBOFHVFMPNNIKN-UHFFFAOYSA-N dimethylquinoline Natural products C1=CC=C2N=C(C)C(C)=CC2=C1 FBOFHVFMPNNIKN-UHFFFAOYSA-N 0.000 claims 2
- 125000001153 fluoro group Chemical group F* 0.000 claims 2
- 206010039083 rhinitis Diseases 0.000 claims 2
- PIHAZNXSZMDLGZ-UHFFFAOYSA-N 1-phenyl-2-propan-2-ylpiperidine Chemical class CC(C)C1CCCCN1C1=CC=CC=C1 PIHAZNXSZMDLGZ-UHFFFAOYSA-N 0.000 claims 1
- HNVIQLPOGUDBSU-UHFFFAOYSA-N 2,6-dimethylmorpholine Chemical compound CC1CNCC(C)O1 HNVIQLPOGUDBSU-UHFFFAOYSA-N 0.000 claims 1
- RDRCCJPEJDWSRJ-UHFFFAOYSA-N pyridine;1h-pyrrole Chemical compound C=1C=CNC=1.C1=CC=NC=C1 RDRCCJPEJDWSRJ-UHFFFAOYSA-N 0.000 claims 1
- 230000033228 biological regulation Effects 0.000 abstract description 14
- 239000002585 base Substances 0.000 description 200
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 77
- 239000003795 chemical substances by application Substances 0.000 description 75
- 235000002639 sodium chloride Nutrition 0.000 description 59
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 55
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 53
- 230000000155 isotopic effect Effects 0.000 description 35
- 229940079593 drug Drugs 0.000 description 31
- 238000009472 formulation Methods 0.000 description 29
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- 235000019441 ethanol Nutrition 0.000 description 24
- 239000002253 acid Substances 0.000 description 23
- 239000000725 suspension Substances 0.000 description 22
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
- 229910052799 carbon Inorganic materials 0.000 description 20
- 229920001577 copolymer Polymers 0.000 description 19
- 239000007788 liquid Substances 0.000 description 19
- 239000007787 solid Substances 0.000 description 19
- 239000000243 solution Substances 0.000 description 19
- 239000003826 tablet Substances 0.000 description 19
- 239000002202 Polyethylene glycol Substances 0.000 description 18
- 229920002301 cellulose acetate Polymers 0.000 description 18
- 125000004093 cyano group Chemical group *C#N 0.000 description 18
- 238000002360 preparation method Methods 0.000 description 18
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 17
- 239000000843 powder Substances 0.000 description 17
- 229920001223 polyethylene glycol Polymers 0.000 description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- 230000015572 biosynthetic process Effects 0.000 description 14
- 238000012377 drug delivery Methods 0.000 description 14
- 239000000463 material Substances 0.000 description 14
- 239000011159 matrix material Substances 0.000 description 14
- 229920000642 polymer Polymers 0.000 description 14
- 239000002904 solvent Substances 0.000 description 14
- 239000000047 product Substances 0.000 description 13
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 12
- 150000001721 carbon Chemical group 0.000 description 12
- 239000001768 carboxy methyl cellulose Substances 0.000 description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
- 238000005516 engineering process Methods 0.000 description 12
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 12
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 12
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 12
- 150000002466 imines Chemical class 0.000 description 12
- 239000003112 inhibitor Substances 0.000 description 12
- 239000003755 preservative agent Substances 0.000 description 12
- 230000004044 response Effects 0.000 description 12
- 239000012730 sustained-release form Substances 0.000 description 12
- 229920000742 Cotton Polymers 0.000 description 11
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 11
- 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 11
- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 11
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 11
- 229920002472 Starch Polymers 0.000 description 11
- 229940060037 fluorine Drugs 0.000 description 11
- 239000008101 lactose Substances 0.000 description 11
- 239000012528 membrane Substances 0.000 description 11
- 210000004379 membrane Anatomy 0.000 description 11
- 238000007911 parenteral administration Methods 0.000 description 11
- 230000002335 preservative effect Effects 0.000 description 11
- 229940032147 starch Drugs 0.000 description 11
- 239000008107 starch Substances 0.000 description 11
- 235000019698 starch Nutrition 0.000 description 11
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 10
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 10
- 150000001412 amines Chemical class 0.000 description 10
- 239000000839 emulsion Substances 0.000 description 10
- 239000003292 glue Substances 0.000 description 10
- 125000001183 hydrocarbyl group Chemical group 0.000 description 10
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 10
- 238000013507 mapping Methods 0.000 description 10
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 10
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 10
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 10
- 239000000376 reactant Substances 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 230000005540 biological transmission Effects 0.000 description 9
- 235000010980 cellulose Nutrition 0.000 description 9
- 229920002678 cellulose Polymers 0.000 description 9
- 239000001913 cellulose Substances 0.000 description 9
- 230000008859 change Effects 0.000 description 9
- 150000002148 esters Chemical class 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- 229920000159 gelatin Polymers 0.000 description 9
- 239000008273 gelatin Substances 0.000 description 9
- 235000011187 glycerol Nutrition 0.000 description 9
- 125000000623 heterocyclic group Chemical group 0.000 description 9
- 229910052739 hydrogen Inorganic materials 0.000 description 9
- 239000001257 hydrogen Substances 0.000 description 9
- 230000006872 improvement Effects 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- 238000013268 sustained release Methods 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 239000005977 Ethylene Substances 0.000 description 8
- 108010010803 Gelatin Proteins 0.000 description 8
- 239000004372 Polyvinyl alcohol Substances 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- 239000007891 compressed tablet Substances 0.000 description 8
- 235000009508 confectionery Nutrition 0.000 description 8
- 239000003995 emulsifying agent Substances 0.000 description 8
- 239000000499 gel Substances 0.000 description 8
- 235000019322 gelatine Nutrition 0.000 description 8
- 235000011852 gelatine desserts Nutrition 0.000 description 8
- 239000003921 oil Substances 0.000 description 8
- 239000002245 particle Substances 0.000 description 8
- 229920002451 polyvinyl alcohol Polymers 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 7
- 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 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 7
- 229930006000 Sucrose Natural products 0.000 description 7
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 7
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 7
- 230000004913 activation Effects 0.000 description 7
- 239000000853 adhesive Substances 0.000 description 7
- 230000001070 adhesive effect Effects 0.000 description 7
- 125000003342 alkenyl group Chemical group 0.000 description 7
- 239000003085 diluting agent Substances 0.000 description 7
- 238000011010 flushing procedure Methods 0.000 description 7
- 238000010438 heat treatment Methods 0.000 description 7
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 7
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 7
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 7
- 230000008595 infiltration Effects 0.000 description 7
- 238000001764 infiltration Methods 0.000 description 7
- 239000006072 paste Substances 0.000 description 7
- 230000002265 prevention Effects 0.000 description 7
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 7
- 210000000664 rectum Anatomy 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- 239000005720 sucrose Substances 0.000 description 7
- 239000000375 suspending agent Substances 0.000 description 7
- 210000001215 vagina Anatomy 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 6
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 6
- 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 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 229930195725 Mannitol Natural products 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- DLRVVLDZNNYCBX-UHFFFAOYSA-N Polydextrose Polymers OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(O)O1 DLRVVLDZNNYCBX-UHFFFAOYSA-N 0.000 description 6
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 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
- 229920002125 Sokalan® Polymers 0.000 description 6
- KKEYFWRCBNTPAC-UHFFFAOYSA-N Terephthalic acid Chemical compound OC(=O)C1=CC=C(C(O)=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-N 0.000 description 6
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 description 6
- 235000010443 alginic acid Nutrition 0.000 description 6
- 229920000615 alginic acid Polymers 0.000 description 6
- 150000001413 amino acids Chemical group 0.000 description 6
- 239000003963 antioxidant agent Substances 0.000 description 6
- 235000006708 antioxidants Nutrition 0.000 description 6
- 125000004429 atom Chemical group 0.000 description 6
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 6
- 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 6
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 6
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 6
- 229940105329 carboxymethylcellulose Drugs 0.000 description 6
- 238000005253 cladding Methods 0.000 description 6
- 238000007906 compression Methods 0.000 description 6
- 230000006835 compression Effects 0.000 description 6
- 239000002270 dispersing agent Substances 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 239000000594 mannitol Substances 0.000 description 6
- 235000010355 mannitol Nutrition 0.000 description 6
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 6
- 235000019198 oils Nutrition 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 6
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 6
- 239000007921 spray Substances 0.000 description 6
- 239000000829 suppository Substances 0.000 description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 6
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 5
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 5
- 239000001856 Ethyl cellulose Substances 0.000 description 5
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 5
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 5
- 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 5
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 5
- 239000004698 Polyethylene Substances 0.000 description 5
- 239000008156 Ringer's lactate solution Substances 0.000 description 5
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 5
- 229960001138 acetylsalicylic acid Drugs 0.000 description 5
- 238000013019 agitation Methods 0.000 description 5
- 125000000304 alkynyl group Chemical group 0.000 description 5
- 230000000740 bleeding effect Effects 0.000 description 5
- 229960004588 cilostazol Drugs 0.000 description 5
- RRGUKTPIGVIEKM-UHFFFAOYSA-N cilostazol Chemical compound C=1C=C2NC(=O)CCC2=CC=1OCCCCC1=NN=NN1C1CCCCC1 RRGUKTPIGVIEKM-UHFFFAOYSA-N 0.000 description 5
- 238000007796 conventional method Methods 0.000 description 5
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 239000007884 disintegrant Substances 0.000 description 5
- 235000019325 ethyl cellulose Nutrition 0.000 description 5
- 229920001249 ethyl cellulose Polymers 0.000 description 5
- 239000000945 filler Substances 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 235000003599 food sweetener Nutrition 0.000 description 5
- 229920001477 hydrophilic polymer Polymers 0.000 description 5
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 5
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 5
- 239000002502 liposome Substances 0.000 description 5
- 239000000314 lubricant Substances 0.000 description 5
- 229960002900 methylcellulose Drugs 0.000 description 5
- 239000002674 ointment Substances 0.000 description 5
- 125000004043 oxo group Chemical group O=* 0.000 description 5
- 229910052760 oxygen Inorganic materials 0.000 description 5
- 229920000573 polyethylene Polymers 0.000 description 5
- 229920001451 polypropylene glycol Polymers 0.000 description 5
- 238000001556 precipitation Methods 0.000 description 5
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 5
- 235000018102 proteins Nutrition 0.000 description 5
- 102000004169 proteins and genes Human genes 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 235000015424 sodium Nutrition 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- 239000012279 sodium borohydride Substances 0.000 description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 description 5
- 239000003765 sweetening agent Substances 0.000 description 5
- 239000006188 syrup Substances 0.000 description 5
- 235000020357 syrup Nutrition 0.000 description 5
- 230000008685 targeting Effects 0.000 description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- 239000001993 wax Substances 0.000 description 5
- 239000000080 wetting agent Substances 0.000 description 5
- UBLAMKHIFZBBSS-UHFFFAOYSA-N 3-Methylbutyl pentanoate Chemical compound CCCCC(=O)OCCC(C)C UBLAMKHIFZBBSS-UHFFFAOYSA-N 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- 229920001817 Agar Polymers 0.000 description 4
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 4
- 108010058207 Anistreplase Proteins 0.000 description 4
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- 239000004215 Carbon black (E152) Substances 0.000 description 4
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 4
- 108010024121 Janus Kinases Proteins 0.000 description 4
- 102000015617 Janus Kinases Human genes 0.000 description 4
- MQHWFIOJQSCFNM-UHFFFAOYSA-L Magnesium salicylate Chemical compound [Mg+2].OC1=CC=CC=C1C([O-])=O.OC1=CC=CC=C1C([O-])=O MQHWFIOJQSCFNM-UHFFFAOYSA-L 0.000 description 4
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 4
- 229920000881 Modified starch Polymers 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 4
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 4
- YASAKCUCGLMORW-UHFFFAOYSA-N Rosiglitazone Chemical compound C=1C=CC=NC=1N(C)CCOC(C=C1)=CC=C1CC1SC(=O)NC1=O YASAKCUCGLMORW-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
- 241000689674 Soleirolia Species 0.000 description 4
- 108010023197 Streptokinase Proteins 0.000 description 4
- NINIDFKCEFEMDL-NJFSPNSNSA-N Sulfur-34 Chemical compound [34S] NINIDFKCEFEMDL-NJFSPNSNSA-N 0.000 description 4
- NINIDFKCEFEMDL-RNFDNDRNSA-N Sulfur-36 Chemical compound [36S] NINIDFKCEFEMDL-RNFDNDRNSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 235000010489 acacia gum Nutrition 0.000 description 4
- 239000001785 acacia senegal l. willd gum Substances 0.000 description 4
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 4
- 235000001014 amino acid Nutrition 0.000 description 4
- 239000005557 antagonist Substances 0.000 description 4
- 230000003078 antioxidant effect Effects 0.000 description 4
- 238000013459 approach Methods 0.000 description 4
- 239000008135 aqueous vehicle Substances 0.000 description 4
- 125000002619 bicyclic group Chemical group 0.000 description 4
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 4
- 235000015165 citric acid Nutrition 0.000 description 4
- 235000012343 cottonseed oil Nutrition 0.000 description 4
- 239000002385 cottonseed oil Substances 0.000 description 4
- 238000013461 design Methods 0.000 description 4
- 239000000975 dye Substances 0.000 description 4
- 229940088598 enzyme Drugs 0.000 description 4
- 235000019439 ethyl acetate Nutrition 0.000 description 4
- 125000004494 ethyl ester group Chemical group 0.000 description 4
- 239000000796 flavoring agent Substances 0.000 description 4
- 235000019634 flavors Nutrition 0.000 description 4
- 230000006870 function Effects 0.000 description 4
- 230000014509 gene expression Effects 0.000 description 4
- 239000008103 glucose Substances 0.000 description 4
- 229930195733 hydrocarbon Natural products 0.000 description 4
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 4
- 239000000017 hydrogel Substances 0.000 description 4
- 150000002431 hydrogen Chemical class 0.000 description 4
- 150000002576 ketones Chemical class 0.000 description 4
- 239000008297 liquid dosage form Substances 0.000 description 4
- 229940072082 magnesium salicylate Drugs 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 229920000609 methyl cellulose Polymers 0.000 description 4
- 235000010981 methylcellulose Nutrition 0.000 description 4
- 239000001923 methylcellulose Substances 0.000 description 4
- 229940016286 microcrystalline cellulose Drugs 0.000 description 4
- 239000008108 microcrystalline cellulose Substances 0.000 description 4
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 4
- 239000004005 microsphere Substances 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 description 4
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 4
- 239000002687 nonaqueous vehicle Substances 0.000 description 4
- 150000007524 organic acids Chemical class 0.000 description 4
- 230000026731 phosphorylation Effects 0.000 description 4
- 238000006366 phosphorylation reaction Methods 0.000 description 4
- HYAFETHFCAUJAY-UHFFFAOYSA-N pioglitazone Chemical compound N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 HYAFETHFCAUJAY-UHFFFAOYSA-N 0.000 description 4
- 229920001155 polypropylene Polymers 0.000 description 4
- 229920000915 polyvinyl chloride Polymers 0.000 description 4
- 239000004800 polyvinyl chloride Substances 0.000 description 4
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 4
- 229960003415 propylparaben Drugs 0.000 description 4
- WVYADZUPLLSGPU-UHFFFAOYSA-N salsalate Chemical compound OC(=O)C1=CC=CC=C1OC(=O)C1=CC=CC=C1O WVYADZUPLLSGPU-UHFFFAOYSA-N 0.000 description 4
- CXMXRPHRNRROMY-UHFFFAOYSA-N sebacic acid Chemical compound OC(=O)CCCCCCCCC(O)=O CXMXRPHRNRROMY-UHFFFAOYSA-N 0.000 description 4
- 239000008299 semisolid dosage form Substances 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 239000000377 silicon dioxide Substances 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- LXMSZDCAJNLERA-ZHYRCANASA-N spironolactone Chemical compound C([C@@H]1[C@]2(C)CC[C@@H]3[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)SC(=O)C)C[C@@]21CCC(=O)O1 LXMSZDCAJNLERA-ZHYRCANASA-N 0.000 description 4
- 229960002256 spironolactone Drugs 0.000 description 4
- 229960005202 streptokinase Drugs 0.000 description 4
- 230000035882 stress Effects 0.000 description 4
- 229910052717 sulfur Inorganic materials 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N titanium dioxide Inorganic materials O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 4
- 235000010215 titanium dioxide Nutrition 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
- 210000003708 urethra Anatomy 0.000 description 4
- 235000015112 vegetable and seed oil Nutrition 0.000 description 4
- XMAYWYJOQHXEEK-OZXSUGGESA-N (2R,4S)-ketoconazole Chemical compound C1CN(C(=O)C)CCN1C(C=C1)=CC=C1OC[C@@H]1O[C@@](CN2C=NC=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 XMAYWYJOQHXEEK-OZXSUGGESA-N 0.000 description 3
- BLSQLHNBWJLIBQ-OZXSUGGESA-N (2R,4S)-terconazole Chemical compound C1CN(C(C)C)CCN1C(C=C1)=CC=C1OC[C@@H]1O[C@@](CN2N=CN=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 BLSQLHNBWJLIBQ-OZXSUGGESA-N 0.000 description 3
- MQHLMHIZUIDKOO-OKZBNKHCSA-N (2R,6S)-2,6-dimethyl-4-[(2S)-2-methyl-3-[4-(2-methylbutan-2-yl)phenyl]propyl]morpholine Chemical compound C1=CC(C(C)(C)CC)=CC=C1C[C@H](C)CN1C[C@@H](C)O[C@@H](C)C1 MQHLMHIZUIDKOO-OKZBNKHCSA-N 0.000 description 3
- RDJGLLICXDHJDY-NSHDSACASA-N (2s)-2-(3-phenoxyphenyl)propanoic acid Chemical compound OC(=O)[C@@H](C)C1=CC=CC(OC=2C=CC=CC=2)=C1 RDJGLLICXDHJDY-NSHDSACASA-N 0.000 description 3
- MDKGKXOCJGEUJW-VIFPVBQESA-N (2s)-2-[4-(thiophene-2-carbonyl)phenyl]propanoic acid Chemical compound C1=CC([C@@H](C(O)=O)C)=CC=C1C(=O)C1=CC=CS1 MDKGKXOCJGEUJW-VIFPVBQESA-N 0.000 description 3
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 3
- MPIPASJGOJYODL-SFHVURJKSA-N (R)-isoconazole Chemical compound ClC1=CC(Cl)=CC=C1[C@@H](OCC=1C(=CC=CC=1Cl)Cl)CN1C=NC=C1 MPIPASJGOJYODL-SFHVURJKSA-N 0.000 description 3
- DQXKOHDUMJLXKH-PHEQNACWSA-N (e)-n-[2-[2-[[(e)-oct-2-enoyl]amino]ethyldisulfanyl]ethyl]oct-2-enamide Chemical compound CCCCC\C=C\C(=O)NCCSSCCNC(=O)\C=C\CCCCC DQXKOHDUMJLXKH-PHEQNACWSA-N 0.000 description 3
- AFNXATANNDIXLG-SFHVURJKSA-N 1-[(2r)-2-[(4-chlorophenyl)methylsulfanyl]-2-(2,4-dichlorophenyl)ethyl]imidazole Chemical compound C1=CC(Cl)=CC=C1CS[C@H](C=1C(=CC(Cl)=CC=1)Cl)CN1C=NC=C1 AFNXATANNDIXLG-SFHVURJKSA-N 0.000 description 3
- ZCJYUTQZBAIHBS-UHFFFAOYSA-N 1-[2-(2,4-dichlorophenyl)-2-{[4-(phenylsulfanyl)benzyl]oxy}ethyl]imidazole Chemical compound ClC1=CC(Cl)=CC=C1C(OCC=1C=CC(SC=2C=CC=CC=2)=CC=1)CN1C=NC=C1 ZCJYUTQZBAIHBS-UHFFFAOYSA-N 0.000 description 3
- OCAPBUJLXMYKEJ-UHFFFAOYSA-N 1-[biphenyl-4-yl(phenyl)methyl]imidazole Chemical compound C1=NC=CN1C(C=1C=CC(=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 OCAPBUJLXMYKEJ-UHFFFAOYSA-N 0.000 description 3
- LEZWWPYKPKIXLL-UHFFFAOYSA-N 1-{2-(4-chlorobenzyloxy)-2-(2,4-dichlorophenyl)ethyl}imidazole Chemical compound C1=CC(Cl)=CC=C1COC(C=1C(=CC(Cl)=CC=1)Cl)CN1C=NC=C1 LEZWWPYKPKIXLL-UHFFFAOYSA-N 0.000 description 3
- QXHHHPZILQDDPS-UHFFFAOYSA-N 1-{2-[(2-chloro-3-thienyl)methoxy]-2-(2,4-dichlorophenyl)ethyl}imidazole Chemical compound S1C=CC(COC(CN2C=NC=C2)C=2C(=CC(Cl)=CC=2)Cl)=C1Cl QXHHHPZILQDDPS-UHFFFAOYSA-N 0.000 description 3
- FUFLCEKSBBHCMO-UHFFFAOYSA-N 11-dehydrocorticosterone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 FUFLCEKSBBHCMO-UHFFFAOYSA-N 0.000 description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 3
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 3
- VHVPQPYKVGDNFY-DFMJLFEVSA-N 2-[(2r)-butan-2-yl]-4-[4-[4-[4-[[(2r,4s)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N([C@H](C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-DFMJLFEVSA-N 0.000 description 3
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 3
- UYGBSRJODQHNLQ-UHFFFAOYSA-N 4-hydroxy-3,5-dimethylbenzaldehyde Chemical class CC1=CC(C=O)=CC(C)=C1O UYGBSRJODQHNLQ-UHFFFAOYSA-N 0.000 description 3
- ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical compound OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 description 3
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 3
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 3
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 description 3
- PQSUYGKTWSAVDQ-ZVIOFETBSA-N Aldosterone Chemical compound C([C@@]1([C@@H](C(=O)CO)CC[C@H]1[C@@H]1CC2)C=O)[C@H](O)[C@@H]1[C@]1(C)C2=CC(=O)CC1 PQSUYGKTWSAVDQ-ZVIOFETBSA-N 0.000 description 3
- PQSUYGKTWSAVDQ-UHFFFAOYSA-N Aldosterone Natural products C1CC2C3CCC(C(=O)CO)C3(C=O)CC(O)C2C2(C)C1=CC(=O)CC2 PQSUYGKTWSAVDQ-UHFFFAOYSA-N 0.000 description 3
- APKFDSVGJQXUKY-KKGHZKTASA-N Amphotericin-B Natural products O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1C=CC=CC=CC=CC=CC=CC=C[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-KKGHZKTASA-N 0.000 description 3
- 108010064760 Anidulafungin Proteins 0.000 description 3
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Natural products OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 3
- 239000005528 B01AC05 - Ticlopidine Substances 0.000 description 3
- 239000005711 Benzoic acid Substances 0.000 description 3
- MNIPYSSQXLZQLJ-UHFFFAOYSA-N Biofenac Chemical compound OC(=O)COC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl MNIPYSSQXLZQLJ-UHFFFAOYSA-N 0.000 description 3
- MJBPUQUGJNAPAZ-UHFFFAOYSA-N Butine Natural products O1C2=CC(O)=CC=C2C(=O)CC1C1=CC=C(O)C(O)=C1 MJBPUQUGJNAPAZ-UHFFFAOYSA-N 0.000 description 3
- JZUFKLXOESDKRF-UHFFFAOYSA-N Chlorothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O JZUFKLXOESDKRF-UHFFFAOYSA-N 0.000 description 3
- 102000008186 Collagen Human genes 0.000 description 3
- 108010035532 Collagen Proteins 0.000 description 3
- 206010009944 Colon cancer Diseases 0.000 description 3
- MFYSYFVPBJMHGN-ZPOLXVRWSA-N Cortisone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 MFYSYFVPBJMHGN-ZPOLXVRWSA-N 0.000 description 3
- MFYSYFVPBJMHGN-UHFFFAOYSA-N Cortisone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)(O)C(=O)CO)C4C3CCC2=C1 MFYSYFVPBJMHGN-UHFFFAOYSA-N 0.000 description 3
- VPGRYOFKCNULNK-ACXQXYJUSA-N Deoxycorticosterone acetate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)COC(=O)C)[C@@]1(C)CC2 VPGRYOFKCNULNK-ACXQXYJUSA-N 0.000 description 3
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 3
- 239000004375 Dextrin Substances 0.000 description 3
- 229920001353 Dextrin Polymers 0.000 description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 3
- 229930183931 Filipin Natural products 0.000 description 3
- 229920002907 Guar gum Polymers 0.000 description 3
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 3
- SQUHHTBVTRBESD-UHFFFAOYSA-N Hexa-Ac-myo-Inositol Natural products CC(=O)OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O SQUHHTBVTRBESD-UHFFFAOYSA-N 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- SBDNJUWAMKYJOX-UHFFFAOYSA-N Meclofenamic Acid Chemical compound CC1=CC=C(Cl)C(NC=2C(=CC=CC=2)C(O)=O)=C1Cl SBDNJUWAMKYJOX-UHFFFAOYSA-N 0.000 description 3
- ZRVUJXDFFKFLMG-UHFFFAOYSA-N Meloxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=NC=C(C)S1 ZRVUJXDFFKFLMG-UHFFFAOYSA-N 0.000 description 3
- FQISKWAFAHGMGT-SGJOWKDISA-M Methylprednisolone sodium succinate Chemical compound [Na+].C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)COC(=O)CCC([O-])=O)CC[C@H]21 FQISKWAFAHGMGT-SGJOWKDISA-M 0.000 description 3
- BYBLEWFAAKGYCD-UHFFFAOYSA-N Miconazole Chemical compound ClC1=CC(Cl)=CC=C1COC(C=1C(=CC(Cl)=CC=1)Cl)CN1C=NC=C1 BYBLEWFAAKGYCD-UHFFFAOYSA-N 0.000 description 3
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 description 3
- 102000003729 Neprilysin Human genes 0.000 description 3
- 108090000028 Neprilysin Proteins 0.000 description 3
- 229910004749 OS(O)2 Inorganic materials 0.000 description 3
- 239000005642 Oleic acid Substances 0.000 description 3
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 235000019483 Peanut oil Nutrition 0.000 description 3
- 229920001100 Polydextrose Polymers 0.000 description 3
- 229920001214 Polysorbate 60 Polymers 0.000 description 3
- AWGBZRVEGDNLDZ-UHFFFAOYSA-N Rimocidin Natural products C1C(C(C(O)C2)C(O)=O)OC2(O)CC(O)CCCC(=O)CC(O)C(CC)C(=O)OC(CCC)CC=CC=CC=CC=CC1OC1OC(C)C(O)C(N)C1O AWGBZRVEGDNLDZ-UHFFFAOYSA-N 0.000 description 3
- AWGBZRVEGDNLDZ-JCUCCFEFSA-N Rimocidine Chemical compound O([C@H]1/C=C/C=C/C=C/C=C/C[C@H](OC(=O)[C@@H](CC)[C@H](O)CC(=O)CCC[C@H](O)C[C@@]2(O)O[C@H]([C@@H]([C@@H](O)C2)C(O)=O)C1)CCC)[C@@H]1O[C@H](C)[C@@H](O)[C@H](N)[C@@H]1O AWGBZRVEGDNLDZ-JCUCCFEFSA-N 0.000 description 3
- 235000021355 Stearic acid Nutrition 0.000 description 3
- 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 3
- 108090000373 Tissue Plasminogen Activator Proteins 0.000 description 3
- 102000003978 Tissue Plasminogen Activator Human genes 0.000 description 3
- 206010052779 Transplant rejections Diseases 0.000 description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 108090000435 Urokinase-type plasminogen activator Proteins 0.000 description 3
- 102000003990 Urokinase-type plasminogen activator Human genes 0.000 description 3
- 235000009754 Vitis X bourquina Nutrition 0.000 description 3
- 235000012333 Vitis X labruscana Nutrition 0.000 description 3
- 240000006365 Vitis vinifera Species 0.000 description 3
- 235000014787 Vitis vinifera Nutrition 0.000 description 3
- 229960000446 abciximab Drugs 0.000 description 3
- 230000002159 abnormal effect Effects 0.000 description 3
- 229960004420 aceclofenac Drugs 0.000 description 3
- 229960004892 acemetacin Drugs 0.000 description 3
- FSQKKOOTNAMONP-UHFFFAOYSA-N acemetacin Chemical compound CC1=C(CC(=O)OCC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 FSQKKOOTNAMONP-UHFFFAOYSA-N 0.000 description 3
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 3
- 239000008272 agar Substances 0.000 description 3
- 230000002776 aggregation Effects 0.000 description 3
- 238000004220 aggregation Methods 0.000 description 3
- 229960002478 aldosterone Drugs 0.000 description 3
- 229940072056 alginate Drugs 0.000 description 3
- 239000000783 alginic acid Substances 0.000 description 3
- 229960001126 alginic acid Drugs 0.000 description 3
- 150000004781 alginic acids Chemical class 0.000 description 3
- 125000001931 aliphatic group Chemical group 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 229960003204 amorolfine Drugs 0.000 description 3
- APKFDSVGJQXUKY-INPOYWNPSA-N amphotericin B Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-INPOYWNPSA-N 0.000 description 3
- 229960003942 amphotericin b Drugs 0.000 description 3
- 229960003348 anidulafungin Drugs 0.000 description 3
- JHVAMHSQVVQIOT-MFAJLEFUSA-N anidulafungin Chemical compound C1=CC(OCCCCC)=CC=C1C1=CC=C(C=2C=CC(=CC=2)C(=O)N[C@@H]2C(N[C@H](C(=O)N3C[C@H](O)C[C@H]3C(=O)N[C@H](C(=O)N[C@H](C(=O)N3C[C@H](C)[C@H](O)[C@H]3C(=O)N[C@H](O)[C@H](O)C2)[C@@H](C)O)[C@H](O)[C@@H](O)C=2C=CC(O)=CC=2)[C@@H](C)O)=O)C=C1 JHVAMHSQVVQIOT-MFAJLEFUSA-N 0.000 description 3
- 229960000983 anistreplase Drugs 0.000 description 3
- 239000000420 anogeissus latifolia wall. gum Substances 0.000 description 3
- 230000000845 anti-microbial effect Effects 0.000 description 3
- 239000003429 antifungal agent Substances 0.000 description 3
- KXNPVXPOPUZYGB-XYVMCAHJSA-N argatroban Chemical compound OC(=O)[C@H]1C[C@H](C)CCN1C(=O)[C@H](CCCN=C(N)N)NS(=O)(=O)C1=CC=CC2=C1NC[C@H](C)C2 KXNPVXPOPUZYGB-XYVMCAHJSA-N 0.000 description 3
- 229960003856 argatroban Drugs 0.000 description 3
- 235000010323 ascorbic acid Nutrition 0.000 description 3
- 229960005070 ascorbic acid Drugs 0.000 description 3
- 239000011668 ascorbic acid Substances 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- WOIIIUDZSOLAIW-NSHDSACASA-N azapropazone Chemical compound C1=C(C)C=C2N3C(=O)[C@H](CC=C)C(=O)N3C(N(C)C)=NC2=C1 WOIIIUDZSOLAIW-NSHDSACASA-N 0.000 description 3
- 229960001671 azapropazone Drugs 0.000 description 3
- 150000003851 azoles Chemical class 0.000 description 3
- NBMKJKDGKREAPL-DVTGEIKXSA-N beclomethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O NBMKJKDGKREAPL-DVTGEIKXSA-N 0.000 description 3
- 229960004277 benorilate Drugs 0.000 description 3
- FEJKLNWAOXSSNR-UHFFFAOYSA-N benorilate Chemical compound C1=CC(NC(=O)C)=CC=C1OC(=O)C1=CC=CC=C1OC(C)=O FEJKLNWAOXSSNR-UHFFFAOYSA-N 0.000 description 3
- 235000010233 benzoic acid Nutrition 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 229960002206 bifonazole Drugs 0.000 description 3
- OIRCOABEOLEUMC-GEJPAHFPSA-N bivalirudin Chemical compound C([C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)CNC(=O)CNC(=O)CNC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 OIRCOABEOLEUMC-GEJPAHFPSA-N 0.000 description 3
- 108010055460 bivalirudin Proteins 0.000 description 3
- 229960001500 bivalirudin Drugs 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 229960003655 bromfenac Drugs 0.000 description 3
- ZBPLOVFIXSTCRZ-UHFFFAOYSA-N bromfenac Chemical compound NC1=C(CC(O)=O)C=CC=C1C(=O)C1=CC=C(Br)C=C1 ZBPLOVFIXSTCRZ-UHFFFAOYSA-N 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 229960002962 butenafine Drugs 0.000 description 3
- ABJKWBDEJIDSJZ-UHFFFAOYSA-N butenafine Chemical compound C=1C=CC2=CC=CC=C2C=1CN(C)CC1=CC=C(C(C)(C)C)C=C1 ABJKWBDEJIDSJZ-UHFFFAOYSA-N 0.000 description 3
- 229960005074 butoconazole Drugs 0.000 description 3
- SWLMUYACZKCSHZ-UHFFFAOYSA-N butoconazole Chemical compound C1=CC(Cl)=CC=C1CCC(SC=1C(=CC=CC=1Cl)Cl)CN1C=NC=C1 SWLMUYACZKCSHZ-UHFFFAOYSA-N 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 239000001569 carbon dioxide Substances 0.000 description 3
- 229910002092 carbon dioxide Inorganic materials 0.000 description 3
- 229960003184 carprofen Drugs 0.000 description 3
- PUXBGTOOZJQSKH-UHFFFAOYSA-N carprofen Chemical compound C1=C(Cl)C=C2C3=CC=C(C(C(O)=O)C)C=C3NC2=C1 PUXBGTOOZJQSKH-UHFFFAOYSA-N 0.000 description 3
- 229920006217 cellulose acetate butyrate Polymers 0.000 description 3
- 239000002738 chelating agent Substances 0.000 description 3
- 239000007910 chewable tablet Substances 0.000 description 3
- 229960003749 ciclopirox Drugs 0.000 description 3
- SCKYRAXSEDYPSA-UHFFFAOYSA-N ciclopirox Chemical compound ON1C(=O)C=C(C)C=C1C1CCCCC1 SCKYRAXSEDYPSA-UHFFFAOYSA-N 0.000 description 3
- 229960004022 clotrimazole Drugs 0.000 description 3
- VNFPBHJOKIVQEB-UHFFFAOYSA-N clotrimazole Chemical compound ClC1=CC=CC=C1C(N1C=NC=C1)(C=1C=CC=CC=1)C1=CC=CC=C1 VNFPBHJOKIVQEB-UHFFFAOYSA-N 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 229920001436 collagen Polymers 0.000 description 3
- 238000004040 coloring Methods 0.000 description 3
- 239000008139 complexing agent Substances 0.000 description 3
- 238000013270 controlled release Methods 0.000 description 3
- 238000007334 copolymerization reaction Methods 0.000 description 3
- 235000005687 corn oil Nutrition 0.000 description 3
- 239000002285 corn oil Substances 0.000 description 3
- 229960004544 cortisone Drugs 0.000 description 3
- 239000006071 cream Substances 0.000 description 3
- 238000004132 cross linking Methods 0.000 description 3
- 229960004486 desoxycorticosterone acetate Drugs 0.000 description 3
- 229910052805 deuterium Inorganic materials 0.000 description 3
- 229960003957 dexamethasone Drugs 0.000 description 3
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 3
- 235000019425 dextrin Nutrition 0.000 description 3
- 239000008121 dextrose Substances 0.000 description 3
- 125000004473 dialkylaminocarbonyl group Chemical group 0.000 description 3
- 229960001259 diclofenac Drugs 0.000 description 3
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 3
- 229960000616 diflunisal Drugs 0.000 description 3
- HUPFGZXOMWLGNK-UHFFFAOYSA-N diflunisal Chemical compound C1=C(O)C(C(=O)O)=CC(C=2C(=CC(F)=CC=2)F)=C1 HUPFGZXOMWLGNK-UHFFFAOYSA-N 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 3
- 229960002768 dipyridamole Drugs 0.000 description 3
- IZEKFCXSFNUWAM-UHFFFAOYSA-N dipyridamole Chemical compound C=12N=C(N(CCO)CCO)N=C(N3CCCCC3)C2=NC(N(CCO)CCO)=NC=1N1CCCCC1 IZEKFCXSFNUWAM-UHFFFAOYSA-N 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 229960003913 econazole Drugs 0.000 description 3
- 238000009505 enteric coating Methods 0.000 description 3
- 239000002702 enteric coating Substances 0.000 description 3
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 3
- 229960005293 etodolac Drugs 0.000 description 3
- NNYBQONXHNTVIJ-UHFFFAOYSA-N etodolac Chemical compound C1COC(CC)(CC(O)=O)C2=C1C(C=CC=C1CC)=C1N2 NNYBQONXHNTVIJ-UHFFFAOYSA-N 0.000 description 3
- 229960004945 etoricoxib Drugs 0.000 description 3
- MNJVRJDLRVPLFE-UHFFFAOYSA-N etoricoxib Chemical compound C1=NC(C)=CC=C1C1=NC=C(Cl)C=C1C1=CC=C(S(C)(=O)=O)C=C1 MNJVRJDLRVPLFE-UHFFFAOYSA-N 0.000 description 3
- 239000004744 fabric Substances 0.000 description 3
- 229960001419 fenoprofen Drugs 0.000 description 3
- 229960001274 fenticonazole Drugs 0.000 description 3
- 229950000152 filipin Drugs 0.000 description 3
- IMQSIXYSKPIGPD-NKYUYKLDSA-N filipin Chemical compound CCCCC[C@H](O)[C@@H]1[C@@H](O)C[C@@H](O)C[C@@H](O)C[C@@H](O)C[C@@H](O)C[C@@H](O)C[C@H](O)\C(C)=C\C=C\C=C\C=C\C=C\[C@H](O)[C@@H](C)OC1=O IMQSIXYSKPIGPD-NKYUYKLDSA-N 0.000 description 3
- IMQSIXYSKPIGPD-UHFFFAOYSA-N filipin III Natural products CCCCCC(O)C1C(O)CC(O)CC(O)CC(O)CC(O)CC(O)CC(O)C(C)=CC=CC=CC=CC=CC(O)C(C)OC1=O IMQSIXYSKPIGPD-UHFFFAOYSA-N 0.000 description 3
- 239000007888 film coating Substances 0.000 description 3
- 238000009501 film coating Methods 0.000 description 3
- 229960004884 fluconazole Drugs 0.000 description 3
- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 description 3
- 229960003028 flumethiazide Drugs 0.000 description 3
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 3
- 235000010417 guar gum Nutrition 0.000 description 3
- 239000000665 guar gum Substances 0.000 description 3
- 229960002154 guar gum Drugs 0.000 description 3
- 235000019314 gum ghatti Nutrition 0.000 description 3
- 229960002897 heparin Drugs 0.000 description 3
- 229920000669 heparin Polymers 0.000 description 3
- 125000005842 heteroatom Chemical group 0.000 description 3
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 3
- 238000006197 hydroboration reaction Methods 0.000 description 3
- 150000002430 hydrocarbons Chemical class 0.000 description 3
- 235000011167 hydrochloric acid Nutrition 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 3
- CDAISMWEOUEBRE-GPIVLXJGSA-N inositol Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 description 3
- 229960000367 inositol Drugs 0.000 description 3
- 229960004849 isoconazole Drugs 0.000 description 3
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 3
- 239000007951 isotonicity adjuster Substances 0.000 description 3
- 229960004130 itraconazole Drugs 0.000 description 3
- 229960004125 ketoconazole Drugs 0.000 description 3
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 description 3
- 229960000991 ketoprofen Drugs 0.000 description 3
- OZWKMVRBQXNZKK-UHFFFAOYSA-N ketorolac Chemical compound OC(=O)C1CCN2C1=CC=C2C(=O)C1=CC=CC=C1 OZWKMVRBQXNZKK-UHFFFAOYSA-N 0.000 description 3
- 229960004752 ketorolac Drugs 0.000 description 3
- TYQCGQRIZGCHNB-JLAZNSOCSA-N l-ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(O)=C(O)C1=O TYQCGQRIZGCHNB-JLAZNSOCSA-N 0.000 description 3
- OTQCKZUSUGYWBD-BRHMIFOHSA-N lepirudin Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CS)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O)C(C)C)[C@@H](C)O)[C@@H](C)O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC(C)C)[C@@H](C)O)C1=CC=C(O)C=C1 OTQCKZUSUGYWBD-BRHMIFOHSA-N 0.000 description 3
- 229960004408 lepirudin Drugs 0.000 description 3
- 230000003902 lesion Effects 0.000 description 3
- 239000003589 local anesthetic agent Substances 0.000 description 3
- 229960002202 lornoxicam Drugs 0.000 description 3
- OXROWJKCGCOJDO-JLHYYAGUSA-N lornoxicam Chemical compound O=C1C=2SC(Cl)=CC=2S(=O)(=O)N(C)\C1=C(\O)NC1=CC=CC=N1 OXROWJKCGCOJDO-JLHYYAGUSA-N 0.000 description 3
- 229960002373 loxoprofen Drugs 0.000 description 3
- BAZQYVYVKYOAGO-UHFFFAOYSA-M loxoprofen sodium hydrate Chemical compound O.O.[Na+].C1=CC(C(C([O-])=O)C)=CC=C1CC1C(=O)CCC1 BAZQYVYVKYOAGO-UHFFFAOYSA-M 0.000 description 3
- 210000004072 lung Anatomy 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 229960003803 meclofenamic acid Drugs 0.000 description 3
- 229960001929 meloxicam Drugs 0.000 description 3
- LCGLNKUTAGEVQW-UHFFFAOYSA-N methyl monoether Natural products COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 3
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 3
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 3
- 229960004584 methylprednisolone Drugs 0.000 description 3
- 229960002509 miconazole Drugs 0.000 description 3
- 244000005700 microbiome Species 0.000 description 3
- 125000002950 monocyclic group Chemical group 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 229960004313 naftifine Drugs 0.000 description 3
- OZGNYLLQHRPOBR-DHZHZOJOSA-N naftifine Chemical compound C=1C=CC2=CC=CC=C2C=1CN(C)C\C=C\C1=CC=CC=C1 OZGNYLLQHRPOBR-DHZHZOJOSA-N 0.000 description 3
- 125000001624 naphthyl group Chemical group 0.000 description 3
- 229960002009 naproxen Drugs 0.000 description 3
- CMWTZPSULFXXJA-VIFPVBQESA-M naproxen(1-) Chemical compound C1=C([C@H](C)C([O-])=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-M 0.000 description 3
- 229960003512 nicotinic acid Drugs 0.000 description 3
- 235000001968 nicotinic acid Nutrition 0.000 description 3
- 239000011664 nicotinic acid Substances 0.000 description 3
- HYWYRSMBCFDLJT-UHFFFAOYSA-N nimesulide Chemical compound CS(=O)(=O)NC1=CC=C([N+]([O-])=O)C=C1OC1=CC=CC=C1 HYWYRSMBCFDLJT-UHFFFAOYSA-N 0.000 description 3
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 3
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 3
- 229960001699 ofloxacin Drugs 0.000 description 3
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 3
- 235000021313 oleic acid Nutrition 0.000 description 3
- 239000004006 olive oil Substances 0.000 description 3
- 235000008390 olive oil Nutrition 0.000 description 3
- 229960003483 oxiconazole Drugs 0.000 description 3
- QRJJEGAJXVEBNE-MOHJPFBDSA-N oxiconazole Chemical compound ClC1=CC(Cl)=CC=C1CO\N=C(C=1C(=CC(Cl)=CC=1)Cl)\CN1C=NC=C1 QRJJEGAJXVEBNE-MOHJPFBDSA-N 0.000 description 3
- 230000036542 oxidative stress Effects 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 229960000649 oxyphenbutazone Drugs 0.000 description 3
- CNDQSXOVEQXJOE-UHFFFAOYSA-N oxyphenbutazone hydrate Chemical compound O.O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=C(O)C=C1 CNDQSXOVEQXJOE-UHFFFAOYSA-N 0.000 description 3
- 239000005022 packaging material Substances 0.000 description 3
- 239000012188 paraffin wax Substances 0.000 description 3
- 239000000312 peanut oil Substances 0.000 description 3
- 229960000280 phenindione Drugs 0.000 description 3
- NFBAXHOPROOJAW-UHFFFAOYSA-N phenindione Chemical compound O=C1C2=CC=CC=C2C(=O)C1C1=CC=CC=C1 NFBAXHOPROOJAW-UHFFFAOYSA-N 0.000 description 3
- 239000002953 phosphate buffered saline Substances 0.000 description 3
- 229940023488 pill Drugs 0.000 description 3
- 239000006187 pill Substances 0.000 description 3
- 229960002702 piroxicam Drugs 0.000 description 3
- QYSPLQLAKJAUJT-UHFFFAOYSA-N piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 description 3
- 229960002797 pitavastatin Drugs 0.000 description 3
- 239000004584 polyacrylic acid Substances 0.000 description 3
- 235000013856 polydextrose Nutrition 0.000 description 3
- 239000001259 polydextrose Substances 0.000 description 3
- 229940035035 polydextrose Drugs 0.000 description 3
- 229920001282 polysaccharide Polymers 0.000 description 3
- 239000005017 polysaccharide Substances 0.000 description 3
- 150000004804 polysaccharides Chemical class 0.000 description 3
- 229940075065 polyvinyl acetate Drugs 0.000 description 3
- 229920002689 polyvinyl acetate Polymers 0.000 description 3
- 239000011118 polyvinyl acetate Substances 0.000 description 3
- 229960001589 posaconazole Drugs 0.000 description 3
- RAGOYPUPXAKGKH-XAKZXMRKSA-N posaconazole Chemical compound O=C1N([C@H]([C@H](C)O)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@H]3C[C@@](CN4N=CN=C4)(OC3)C=3C(=CC(F)=CC=3)F)=CC=2)C=C1 RAGOYPUPXAKGKH-XAKZXMRKSA-N 0.000 description 3
- 239000001103 potassium chloride Substances 0.000 description 3
- 235000011164 potassium chloride Nutrition 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 229960005205 prednisolone Drugs 0.000 description 3
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 3
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 3
- 238000012545 processing Methods 0.000 description 3
- 235000021251 pulses Nutrition 0.000 description 3
- 150000003235 pyrrolidines Chemical class 0.000 description 3
- OPAHEYNNJWPQPX-RCDICMHDSA-N ravuconazole Chemical compound C=1SC([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC(F)=CC=2)F)=NC=1C1=CC=C(C#N)C=C1 OPAHEYNNJWPQPX-RCDICMHDSA-N 0.000 description 3
- 229950004154 ravuconazole Drugs 0.000 description 3
- 229960002917 reteplase Drugs 0.000 description 3
- 108010051412 reteplase Proteins 0.000 description 3
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 3
- 239000008159 sesame oil Substances 0.000 description 3
- 235000011803 sesame oil Nutrition 0.000 description 3
- 230000019491 signal transduction Effects 0.000 description 3
- 229920005573 silicon-containing polymer Polymers 0.000 description 3
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 3
- 235000010262 sodium metabisulphite Nutrition 0.000 description 3
- 235000010199 sorbic acid Nutrition 0.000 description 3
- 239000004334 sorbic acid Substances 0.000 description 3
- 229940075582 sorbic acid Drugs 0.000 description 3
- 239000008117 stearic acid Substances 0.000 description 3
- 229960002607 sulconazole Drugs 0.000 description 3
- 229960003329 sulfinpyrazone Drugs 0.000 description 3
- MBGGBVCUIVRRBF-UHFFFAOYSA-N sulfinpyrazone Chemical compound O=C1N(C=2C=CC=CC=2)N(C=2C=CC=CC=2)C(=O)C1CCS(=O)C1=CC=CC=C1 MBGGBVCUIVRRBF-UHFFFAOYSA-N 0.000 description 3
- 229960000894 sulindac Drugs 0.000 description 3
- MLKXDPUZXIRXEP-MFOYZWKCSA-N sulindac Chemical compound CC1=C(CC(O)=O)C2=CC(F)=CC=C2\C1=C/C1=CC=C(S(C)=O)C=C1 MLKXDPUZXIRXEP-MFOYZWKCSA-N 0.000 description 3
- 229960004492 suprofen Drugs 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 235000012222 talc Nutrition 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- WZWYJBNHTWCXIM-UHFFFAOYSA-N tenoxicam Chemical compound O=C1C=2SC=CC=2S(=O)(=O)N(C)C1=C(O)NC1=CC=CC=N1 WZWYJBNHTWCXIM-UHFFFAOYSA-N 0.000 description 3
- 229960002871 tenoxicam Drugs 0.000 description 3
- DOMXUEMWDBAQBQ-WEVVVXLNSA-N terbinafine Chemical compound C1=CC=C2C(CN(C\C=C\C#CC(C)(C)C)C)=CC=CC2=C1 DOMXUEMWDBAQBQ-WEVVVXLNSA-N 0.000 description 3
- 229960002722 terbinafine Drugs 0.000 description 3
- 229960000580 terconazole Drugs 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 229960005001 ticlopidine Drugs 0.000 description 3
- PHWBOXQYWZNQIN-UHFFFAOYSA-N ticlopidine Chemical compound ClC1=CC=CC=C1CN1CC(C=CS2)=C2CC1 PHWBOXQYWZNQIN-UHFFFAOYSA-N 0.000 description 3
- 229960004214 tioconazole Drugs 0.000 description 3
- 229960001017 tolmetin Drugs 0.000 description 3
- UPSPUYADGBWSHF-UHFFFAOYSA-N tolmetin Chemical compound C1=CC(C)=CC=C1C(=O)C1=CC=C(CC(O)=O)N1C UPSPUYADGBWSHF-UHFFFAOYSA-N 0.000 description 3
- ILJSQTXMGCGYMG-UHFFFAOYSA-N triacetic acid Chemical compound CC(=O)CC(=O)CC(O)=O ILJSQTXMGCGYMG-UHFFFAOYSA-N 0.000 description 3
- GFNANZIMVAIWHM-OBYCQNJPSA-N triamcinolone Chemical compound O=C1C=C[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@]([C@H](O)C4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 GFNANZIMVAIWHM-OBYCQNJPSA-N 0.000 description 3
- 229960005356 urokinase Drugs 0.000 description 3
- 229960004740 voriconazole Drugs 0.000 description 3
- BCEHBSKCWLPMDN-MGPLVRAMSA-N voriconazole Chemical compound C1([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC(F)=CC=2)F)=NC=NC=C1F BCEHBSKCWLPMDN-MGPLVRAMSA-N 0.000 description 3
- 229960005080 warfarin Drugs 0.000 description 3
- PJVWKTKQMONHTI-UHFFFAOYSA-N warfarin Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-UHFFFAOYSA-N 0.000 description 3
- 229920001285 xanthan gum Polymers 0.000 description 3
- ZXIBCJHYVWYIKI-PZJWPPBQSA-N ximelagatran Chemical compound C1([C@@H](NCC(=O)OCC)C(=O)N2[C@@H](CC2)C(=O)NCC=2C=CC(=CC=2)C(\N)=N\O)CCCCC1 ZXIBCJHYVWYIKI-PZJWPPBQSA-N 0.000 description 3
- 229960001522 ximelagatran Drugs 0.000 description 3
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-NJFSPNSNSA-N ((18)O)water Chemical compound [18OH2] XLYOFNOQVPJJNP-NJFSPNSNSA-N 0.000 description 2
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- NOOLISFMXDJSKH-KXUCPTDWSA-N (-)-Menthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O NOOLISFMXDJSKH-KXUCPTDWSA-N 0.000 description 2
- CIDUJQMULVCIBT-MQDUPKMGSA-N (2r,3r,4r,5r)-2-[(1s,2s,3r,4s,6r)-4-amino-3-[[(2s,3r)-3-amino-6-(aminomethyl)-3,4-dihydro-2h-pyran-2-yl]oxy]-6-(ethylamino)-2-hydroxycyclohexyl]oxy-5-methyl-4-(methylamino)oxane-3,5-diol Chemical compound O([C@@H]1[C@@H](N)C[C@H]([C@@H]([C@H]1O)O[C@@H]1[C@@H]([C@@H](NC)[C@@](C)(O)CO1)O)NCC)[C@H]1OC(CN)=CC[C@H]1N CIDUJQMULVCIBT-MQDUPKMGSA-N 0.000 description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 2
- FYGDTMLNYKFZSV-URKRLVJHSA-N (2s,3r,4s,5s,6r)-2-[(2r,4r,5r,6s)-4,5-dihydroxy-2-(hydroxymethyl)-6-[(2r,4r,5r,6s)-4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxan-3-yl]oxy-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1[C@@H](CO)O[C@@H](OC2[C@H](O[C@H](O)[C@H](O)[C@H]2O)CO)[C@H](O)[C@H]1O FYGDTMLNYKFZSV-URKRLVJHSA-N 0.000 description 2
- NBXPLBPWMYNZTC-IDYPWDAWSA-N (2s,5r,6r)-6-[[(2r)-2-[(4-ethyl-2,3-dioxopiperazine-1-carbonyl)amino]-2-phenylacetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid;hydrate Chemical compound O.O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC=CC=1)C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 NBXPLBPWMYNZTC-IDYPWDAWSA-N 0.000 description 2
- DEQANNDTNATYII-OULOTJBUSA-N (4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-19-[[(2r)-2-amino-3-phenylpropanoyl]amino]-16-benzyl-n-[(2r,3r)-1,3-dihydroxybutan-2-yl]-7-[(1r)-1-hydroxyethyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxa Chemical compound C([C@@H](N)C(=O)N[C@H]1CSSC[C@H](NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)[C@H](CC=2C=CC=CC=2)NC1=O)C(=O)N[C@H](CO)[C@H](O)C)C1=CC=CC=C1 DEQANNDTNATYII-OULOTJBUSA-N 0.000 description 2
- FZKWRPSUNUOXKJ-CVHRZJFOSA-N (4s,4ar,5s,5ar,6r,12ar)-4-(dimethylamino)-1,5,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide;hydrate Chemical compound O.C1=CC=C2[C@H](C)[C@@H]([C@H](O)[C@@H]3[C@](C(O)=C(C(N)=O)C(=O)[C@H]3N(C)C)(O)C3=O)C3=C(O)C2=C1O FZKWRPSUNUOXKJ-CVHRZJFOSA-N 0.000 description 2
- FFTVPQUHLQBXQZ-KVUCHLLUSA-N (4s,4as,5ar,12ar)-4,7-bis(dimethylamino)-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1C2=C(N(C)C)C=CC(O)=C2C(O)=C2[C@@H]1C[C@H]1[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]1(O)C2=O FFTVPQUHLQBXQZ-KVUCHLLUSA-N 0.000 description 2
- GUXHBMASAHGULD-SEYHBJAFSA-N (4s,4as,5as,6s,12ar)-7-chloro-4-(dimethylamino)-1,6,10,11,12a-pentahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1([C@H]2O)=C(Cl)C=CC(O)=C1C(O)=C1[C@@H]2C[C@H]2[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]2(O)C1=O GUXHBMASAHGULD-SEYHBJAFSA-N 0.000 description 2
- 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 2
- WDLWHQDACQUCJR-ZAMMOSSLSA-N (6r,7r)-7-[[(2r)-2-azaniumyl-2-(4-hydroxyphenyl)acetyl]amino]-8-oxo-3-[(e)-prop-1-enyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)/C=C/C)C(O)=O)=CC=C(O)C=C1 WDLWHQDACQUCJR-ZAMMOSSLSA-N 0.000 description 2
- IPYWNMVPZOAFOQ-NABDTECSSA-N (6r,7r)-7-[[(2z)-2-(2-amino-1,3-thiazol-4-yl)-2-(carboxymethoxyimino)acetyl]amino]-3-ethenyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;trihydrate Chemical compound O.O.O.S1C(N)=NC(C(=N\OCC(O)=O)\C(=O)N[C@@H]2C(N3C(=C(C=C)CS[C@@H]32)C(O)=O)=O)=C1 IPYWNMVPZOAFOQ-NABDTECSSA-N 0.000 description 2
- GPYKKBAAPVOCIW-HSASPSRMSA-N (6r,7s)-7-[[(2r)-2-amino-2-phenylacetyl]amino]-3-chloro-8-oxo-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;hydrate Chemical compound O.C1([C@H](C(=O)N[C@@H]2C(N3C(=C(Cl)CC[C@@H]32)C(O)=O)=O)N)=CC=CC=C1 GPYKKBAAPVOCIW-HSASPSRMSA-N 0.000 description 2
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 2
- MINDHVHHQZYEEK-UHFFFAOYSA-N (E)-(2S,3R,4R,5S)-5-[(2S,3S,4S,5S)-2,3-epoxy-5-hydroxy-4-methylhexyl]tetrahydro-3,4-dihydroxy-(beta)-methyl-2H-pyran-2-crotonic acid ester with 9-hydroxynonanoic acid Natural products CC(O)C(C)C1OC1CC1C(O)C(O)C(CC(C)=CC(=O)OCCCCCCCCC(O)=O)OC1 MINDHVHHQZYEEK-UHFFFAOYSA-N 0.000 description 2
- RXZBMPWDPOLZGW-XMRMVWPWSA-N (E)-roxithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=N/OCOCCOC)/[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 RXZBMPWDPOLZGW-XMRMVWPWSA-N 0.000 description 2
- XUBOMFCQGDBHNK-JTQLQIEISA-N (S)-gatifloxacin Chemical compound FC1=CC(C(C(C(O)=O)=CN2C3CC3)=O)=C2C(OC)=C1N1CCN[C@@H](C)C1 XUBOMFCQGDBHNK-JTQLQIEISA-N 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 2
- ICLYJLBTOGPLMC-KVVVOXFISA-N (z)-octadec-9-enoate;tris(2-hydroxyethyl)azanium Chemical compound OCCN(CCO)CCO.CCCCCCCC\C=C/CCCCCCCC(O)=O ICLYJLBTOGPLMC-KVVVOXFISA-N 0.000 description 2
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- LOZWAPSEEHRYPG-UHFFFAOYSA-N 1,4-dithiane Chemical compound C1CSCCS1 LOZWAPSEEHRYPG-UHFFFAOYSA-N 0.000 description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 description 2
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 2
- 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 2
- QLEIDMAURCRVCX-UHFFFAOYSA-N 1-propylpiperazine Chemical compound CCCN1CCNCC1 QLEIDMAURCRVCX-UHFFFAOYSA-N 0.000 description 2
- JLGKQTAYUIMGRK-UHFFFAOYSA-N 1-{2-[(7-chloro-1-benzothiophen-3-yl)methoxy]-2-(2,4-dichlorophenyl)ethyl}imidazole Chemical compound ClC1=CC(Cl)=CC=C1C(OCC=1C2=CC=CC(Cl)=C2SC=1)CN1C=NC=C1 JLGKQTAYUIMGRK-UHFFFAOYSA-N 0.000 description 2
- PNDPGZBMCMUPRI-HVTJNCQCSA-N 10043-66-0 Chemical compound [131I][131I] PNDPGZBMCMUPRI-HVTJNCQCSA-N 0.000 description 2
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 2
- JYGXADMDTFJGBT-MKIDGPAKSA-N 11alpha-Hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-MKIDGPAKSA-N 0.000 description 2
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 2
- JJPSZKIOGBRMHK-UHFFFAOYSA-N 2,6-dimethylquinoline Chemical compound N1=C(C)C=CC2=CC(C)=CC=C21 JJPSZKIOGBRMHK-UHFFFAOYSA-N 0.000 description 2
- OEPOKWHJYJXUGD-UHFFFAOYSA-N 2-(3-phenylmethoxyphenyl)-1,3-thiazole-4-carbaldehyde Chemical compound O=CC1=CSC(C=2C=C(OCC=3C=CC=CC=3)C=CC=2)=N1 OEPOKWHJYJXUGD-UHFFFAOYSA-N 0.000 description 2
- HVAUUPRFYPCOCA-AREMUKBSSA-N 2-O-acetyl-1-O-hexadecyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCOC[C@@H](OC(C)=O)COP([O-])(=O)OCC[N+](C)(C)C HVAUUPRFYPCOCA-AREMUKBSSA-N 0.000 description 2
- JIVPVXMEBJLZRO-CQSZACIVSA-N 2-chloro-5-[(1r)-1-hydroxy-3-oxo-2h-isoindol-1-yl]benzenesulfonamide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC([C@@]2(O)C3=CC=CC=C3C(=O)N2)=C1 JIVPVXMEBJLZRO-CQSZACIVSA-N 0.000 description 2
- MJKVTPMWOKAVMS-UHFFFAOYSA-N 3-hydroxy-1-benzopyran-2-one Chemical compound C1=CC=C2OC(=O)C(O)=CC2=C1 MJKVTPMWOKAVMS-UHFFFAOYSA-N 0.000 description 2
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 2
- SWLAMJPTOQZTAE-UHFFFAOYSA-N 4-[2-[(5-chloro-2-methoxybenzoyl)amino]ethyl]benzoic acid Chemical compound COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(C(O)=O)C=C1 SWLAMJPTOQZTAE-UHFFFAOYSA-N 0.000 description 2
- VRJHQPZVIGNGMX-UHFFFAOYSA-N 4-piperidinone Chemical compound O=C1CCNCC1 VRJHQPZVIGNGMX-UHFFFAOYSA-N 0.000 description 2
- GSDSWSVVBLHKDQ-UHFFFAOYSA-N 9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid Chemical compound FC1=CC(C(C(C(O)=O)=C2)=O)=C3N2C(C)COC3=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-UHFFFAOYSA-N 0.000 description 2
- 239000005995 Aluminium silicate Substances 0.000 description 2
- QGZKDVFQNNGYKY-OUBTZVSYSA-N Ammonia-15N Chemical compound [15NH3] QGZKDVFQNNGYKY-OUBTZVSYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- 241001550224 Apha Species 0.000 description 2
- 108010011485 Aspartame Proteins 0.000 description 2
- 201000001320 Atherosclerosis Diseases 0.000 description 2
- 206010003645 Atopy Diseases 0.000 description 2
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 description 2
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 description 2
- 108010001478 Bacitracin Proteins 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- 208000023328 Basedow disease Diseases 0.000 description 2
- SPFYMRJSYKOXGV-UHFFFAOYSA-N Baytril Chemical compound C1CN(CC)CCN1C(C(=C1)F)=CC2=C1C(=O)C(C(O)=O)=CN2C1CC1 SPFYMRJSYKOXGV-UHFFFAOYSA-N 0.000 description 2
- 208000027496 Behcet disease Diseases 0.000 description 2
- 208000009137 Behcet syndrome Diseases 0.000 description 2
- 229920002498 Beta-glucan Polymers 0.000 description 2
- 229940123208 Biguanide Drugs 0.000 description 2
- 108010006654 Bleomycin Proteins 0.000 description 2
- 239000004322 Butylated hydroxytoluene Substances 0.000 description 2
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 2
- SOGAXMICEFXMKE-UHFFFAOYSA-N Butylmethacrylate Chemical compound CCCCOC(=O)C(C)=C SOGAXMICEFXMKE-UHFFFAOYSA-N 0.000 description 2
- JGLMVXWAHNTPRF-CMDGGOBGSA-N CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O Chemical compound CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O JGLMVXWAHNTPRF-CMDGGOBGSA-N 0.000 description 2
- OKTJSMMVPCPJKN-IGMARMGPSA-N Carbon-12 Chemical compound [12C] OKTJSMMVPCPJKN-IGMARMGPSA-N 0.000 description 2
- OKTJSMMVPCPJKN-OUBTZVSYSA-N Carbon-13 Chemical compound [13C] OKTJSMMVPCPJKN-OUBTZVSYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-NJFSPNSNSA-N Carbon-14 Chemical compound [14C] OKTJSMMVPCPJKN-NJFSPNSNSA-N 0.000 description 2
- 108010020326 Caspofungin Proteins 0.000 description 2
- GNWUOVJNSFPWDD-XMZRARIVSA-M Cefoxitin sodium Chemical compound [Na+].N([C@]1(OC)C(N2C(=C(COC(N)=O)CS[C@@H]21)C([O-])=O)=O)C(=O)CC1=CC=CS1 GNWUOVJNSFPWDD-XMZRARIVSA-M 0.000 description 2
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 2
- DQEFEBPAPFSJLV-UHFFFAOYSA-N Cellulose propionate Chemical compound CCC(=O)OCC1OC(OC(=O)CC)C(OC(=O)CC)C(OC(=O)CC)C1OC1C(OC(=O)CC)C(OC(=O)CC)C(OC(=O)CC)C(COC(=O)CC)O1 DQEFEBPAPFSJLV-UHFFFAOYSA-N 0.000 description 2
- JWBOIMRXGHLCPP-UHFFFAOYSA-N Chloditan Chemical compound C=1C=CC=C(Cl)C=1C(C(Cl)Cl)C1=CC=C(Cl)C=C1 JWBOIMRXGHLCPP-UHFFFAOYSA-N 0.000 description 2
- 229920001268 Cholestyramine Polymers 0.000 description 2
- 208000035473 Communicable disease Diseases 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- 229920002785 Croscarmellose sodium Polymers 0.000 description 2
- 229920000858 Cyclodextrin Polymers 0.000 description 2
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 2
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 2
- 108010036949 Cyclosporine Proteins 0.000 description 2
- FMTDIUIBLCQGJB-UHFFFAOYSA-N Demethylchlortetracyclin Natural products C1C2C(O)C3=C(Cl)C=CC(O)=C3C(=O)C2=C(O)C2(O)C1C(N(C)C)C(O)=C(C(N)=O)C2=O FMTDIUIBLCQGJB-UHFFFAOYSA-N 0.000 description 2
- 206010012559 Developmental delay Diseases 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 2
- 102100023274 Dual specificity mitogen-activated protein kinase kinase 4 Human genes 0.000 description 2
- 102100023401 Dual specificity mitogen-activated protein kinase kinase 6 Human genes 0.000 description 2
- 102000002045 Endothelin Human genes 0.000 description 2
- 108050009340 Endothelin Proteins 0.000 description 2
- 108010056764 Eptifibatide Proteins 0.000 description 2
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 2
- 108010008165 Etanercept Proteins 0.000 description 2
- IMROMDMJAWUWLK-UHFFFAOYSA-N Ethenol Chemical compound OC=C IMROMDMJAWUWLK-UHFFFAOYSA-N 0.000 description 2
- 229920000896 Ethulose Polymers 0.000 description 2
- 239000001859 Ethyl hydroxyethyl cellulose Substances 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- 108010022535 Farnesyl-Diphosphate Farnesyltransferase Proteins 0.000 description 2
- UIOFUWFRIANQPC-JKIFEVAISA-N Floxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=C(F)C=CC=C1Cl UIOFUWFRIANQPC-JKIFEVAISA-N 0.000 description 2
- 229930091371 Fructose Natural products 0.000 description 2
- 239000005715 Fructose Substances 0.000 description 2
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 2
- 241000233866 Fungi Species 0.000 description 2
- JRZJKWGQFNTSRN-UHFFFAOYSA-N Geldanamycin Natural products C1C(C)CC(OC)C(O)C(C)C=C(C)C(OC(N)=O)C(OC)CCC=C(C)C(=O)NC2=CC(=O)C(OC)=C1C2=O JRZJKWGQFNTSRN-UHFFFAOYSA-N 0.000 description 2
- FAEKWTJYAYMJKF-QHCPKHFHSA-N GlucoNorm Chemical compound C1=C(C(O)=O)C(OCC)=CC(CC(=O)N[C@@H](CC(C)C)C=2C(=CC=CC=2)N2CCCCC2)=C1 FAEKWTJYAYMJKF-QHCPKHFHSA-N 0.000 description 2
- 108010056771 Glucosidases Proteins 0.000 description 2
- 102000004366 Glucosidases Human genes 0.000 description 2
- 208000015023 Graves' disease Diseases 0.000 description 2
- 229920000569 Gum karaya Polymers 0.000 description 2
- 206010019280 Heart failures Diseases 0.000 description 2
- 244000043261 Hevea brasiliensis Species 0.000 description 2
- 108010007267 Hirudins Proteins 0.000 description 2
- 102000007625 Hirudins Human genes 0.000 description 2
- 101001115395 Homo sapiens Dual specificity mitogen-activated protein kinase kinase 4 Proteins 0.000 description 2
- 101000624426 Homo sapiens Dual specificity mitogen-activated protein kinase kinase 6 Proteins 0.000 description 2
- 101000997832 Homo sapiens Tyrosine-protein kinase JAK2 Proteins 0.000 description 2
- 101000934996 Homo sapiens Tyrosine-protein kinase JAK3 Proteins 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- 102000004877 Insulin Human genes 0.000 description 2
- 108090001061 Insulin Proteins 0.000 description 2
- 102000004890 Interleukin-8 Human genes 0.000 description 2
- 108090001007 Interleukin-8 Proteins 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 229920000161 Locust bean gum Polymers 0.000 description 2
- TYMRLRRVMHJFTF-UHFFFAOYSA-N Mafenide Chemical compound NCC1=CC=C(S(N)(=O)=O)C=C1 TYMRLRRVMHJFTF-UHFFFAOYSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 2
- CESYKOGBSMNBPD-UHFFFAOYSA-N Methyclothiazide Chemical compound ClC1=C(S(N)(=O)=O)C=C2S(=O)(=O)N(C)C(CCl)NC2=C1 CESYKOGBSMNBPD-UHFFFAOYSA-N 0.000 description 2
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 2
- 108010021062 Micafungin Proteins 0.000 description 2
- 229930192392 Mitomycin Natural products 0.000 description 2
- PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 description 2
- 101100346764 Mus musculus Mtln gene Proteins 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
- FFDGPVCHZBVARC-UHFFFAOYSA-N N,N-dimethylglycine Chemical compound CN(C)CC(O)=O FFDGPVCHZBVARC-UHFFFAOYSA-N 0.000 description 2
- QIAFMBKCNZACKA-UHFFFAOYSA-N N-benzoylglycine Chemical compound OC(=O)CNC(=O)C1=CC=CC=C1 QIAFMBKCNZACKA-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
- BLXXJMDCKKHMKV-UHFFFAOYSA-N Nabumetone Chemical compound C1=C(CCC(C)=O)C=CC2=CC(OC)=CC=C21 BLXXJMDCKKHMKV-UHFFFAOYSA-N 0.000 description 2
- QJGQUHMNIGDVPM-BJUDXGSMSA-N Nitrogen-13 Chemical compound [13N] QJGQUHMNIGDVPM-BJUDXGSMSA-N 0.000 description 2
- 229920000305 Nylon 6,10 Polymers 0.000 description 2
- 108010016076 Octreotide Proteins 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- ZPHBZEQOLSRPAK-UHFFFAOYSA-N Phosphoramidon Natural products C=1NC2=CC=CC=C2C=1CC(C(O)=O)NC(=O)C(CC(C)C)NP(O)(=O)OC1OC(C)C(O)C(O)C1O ZPHBZEQOLSRPAK-UHFFFAOYSA-N 0.000 description 2
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 2
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 2
- OAICVXFJPJFONN-OUBTZVSYSA-N Phosphorus-32 Chemical compound [32P] OAICVXFJPJFONN-OUBTZVSYSA-N 0.000 description 2
- OAICVXFJPJFONN-NJFSPNSNSA-N Phosphorus-33 Chemical compound [33P] OAICVXFJPJFONN-NJFSPNSNSA-N 0.000 description 2
- 108010003541 Platelet Activating Factor Proteins 0.000 description 2
- 239000005062 Polybutadiene Substances 0.000 description 2
- 229920000148 Polycarbophil calcium Polymers 0.000 description 2
- 239000004695 Polyether sulfone Substances 0.000 description 2
- 229920002367 Polyisobutene Polymers 0.000 description 2
- 239000004743 Polypropylene Substances 0.000 description 2
- 239000004793 Polystyrene Substances 0.000 description 2
- TUZYXOIXSAXUGO-UHFFFAOYSA-N Pravastatin Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(O)C=C21 TUZYXOIXSAXUGO-UHFFFAOYSA-N 0.000 description 2
- HCBIBCJNVBAKAB-UHFFFAOYSA-N Procaine hydrochloride Chemical compound Cl.CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 HCBIBCJNVBAKAB-UHFFFAOYSA-N 0.000 description 2
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 description 2
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 2
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- RYMZZMVNJRMUDD-UHFFFAOYSA-N SJ000286063 Natural products C12C(OC(=O)C(C)(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 RYMZZMVNJRMUDD-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 229940100389 Sulfonylurea Drugs 0.000 description 2
- NINIDFKCEFEMDL-AKLPVKDBSA-N Sulfur-35 Chemical compound [35S] NINIDFKCEFEMDL-AKLPVKDBSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical class OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 2
- UNZIDPIPYUMVPA-UHFFFAOYSA-M Sulpyrine Chemical compound O.[Na+].O=C1C(N(CS([O-])(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 UNZIDPIPYUMVPA-UHFFFAOYSA-M 0.000 description 2
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 description 2
- 229940123237 Taxane Drugs 0.000 description 2
- 108010053950 Teicoplanin Proteins 0.000 description 2
- WKDDRNSBRWANNC-UHFFFAOYSA-N Thienamycin Natural products C1C(SCCN)=C(C(O)=O)N2C(=O)C(C(O)C)C21 WKDDRNSBRWANNC-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 101710183280 Topoisomerase Proteins 0.000 description 2
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 2
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 2
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 2
- 102100033444 Tyrosine-protein kinase JAK2 Human genes 0.000 description 2
- 102100025387 Tyrosine-protein kinase JAK3 Human genes 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- SECKRCOLJRRGGV-UHFFFAOYSA-N Vardenafil Chemical compound CCCC1=NC(C)=C(C(N=2)=O)N1NC=2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(CC)CC1 SECKRCOLJRRGGV-UHFFFAOYSA-N 0.000 description 2
- 229940122803 Vinca alkaloid Drugs 0.000 description 2
- BZHJMEDXRYGGRV-UHFFFAOYSA-N Vinyl chloride Chemical compound ClC=C BZHJMEDXRYGGRV-UHFFFAOYSA-N 0.000 description 2
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 2
- PNDPGZBMCMUPRI-XXSWNUTMSA-N [125I][125I] Chemical compound [125I][125I] PNDPGZBMCMUPRI-XXSWNUTMSA-N 0.000 description 2
- 229960002054 acenocoumarol Drugs 0.000 description 2
- VABCILAOYCMVPS-UHFFFAOYSA-N acenocoumarol Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=C([N+]([O-])=O)C=C1 VABCILAOYCMVPS-UHFFFAOYSA-N 0.000 description 2
- 150000001241 acetals Chemical class 0.000 description 2
- ZUAAPNNKRHMPKG-UHFFFAOYSA-N acetic acid;butanedioic acid;methanol;propane-1,2-diol Chemical compound OC.CC(O)=O.CC(O)CO.OC(=O)CCC(O)=O ZUAAPNNKRHMPKG-UHFFFAOYSA-N 0.000 description 2
- 150000003926 acrylamides Chemical class 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
- 230000009471 action Effects 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 239000011149 active material Substances 0.000 description 2
- 239000001361 adipic acid Substances 0.000 description 2
- 235000011037 adipic acid Nutrition 0.000 description 2
- 229960000250 adipic acid Drugs 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 150000001336 alkenes Chemical class 0.000 description 2
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 235000012211 aluminium silicate Nutrition 0.000 description 2
- 229960004821 amikacin Drugs 0.000 description 2
- LKCWBDHBTVXHDL-RMDFUYIESA-N amikacin Chemical compound O([C@@H]1[C@@H](N)C[C@H]([C@@H]([C@H]1O)O[C@@H]1[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O1)O)NC(=O)[C@@H](O)CCN)[C@H]1O[C@H](CN)[C@@H](O)[C@H](O)[C@H]1O LKCWBDHBTVXHDL-RMDFUYIESA-N 0.000 description 2
- 229960003022 amoxicillin Drugs 0.000 description 2
- LSQZJLSUYDQPKJ-NJBDSQKTSA-N amoxicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=C(O)C=C1 LSQZJLSUYDQPKJ-NJBDSQKTSA-N 0.000 description 2
- 229940045799 anthracyclines and related substance Drugs 0.000 description 2
- 239000002260 anti-inflammatory agent Substances 0.000 description 2
- 230000001741 anti-phlogistic effect Effects 0.000 description 2
- 239000003146 anticoagulant agent Substances 0.000 description 2
- 229940127219 anticoagulant drug Drugs 0.000 description 2
- 229940121375 antifungal agent Drugs 0.000 description 2
- 229940127218 antiplatelet drug Drugs 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- VLAXZGHHBIJLAD-UHFFFAOYSA-N arsphenamine Chemical compound [Cl-].[Cl-].C1=C(O)C([NH3+])=CC([As]=[As]C=2C=C([NH3+])C(O)=CC=2)=C1 VLAXZGHHBIJLAD-UHFFFAOYSA-N 0.000 description 2
- 239000000605 aspartame Substances 0.000 description 2
- 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 2
- 235000010357 aspartame Nutrition 0.000 description 2
- 229960003438 aspartame Drugs 0.000 description 2
- 229960005370 atorvastatin Drugs 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
- LMEKQMALGUDUQG-UHFFFAOYSA-N azathioprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC=NC2=C1NC=N2 LMEKQMALGUDUQG-UHFFFAOYSA-N 0.000 description 2
- 229960004099 azithromycin Drugs 0.000 description 2
- MQTOSJVFKKJCRP-BICOPXKESA-N azithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)N(C)C[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 MQTOSJVFKKJCRP-BICOPXKESA-N 0.000 description 2
- 229960003623 azlocillin Drugs 0.000 description 2
- JTWOMNBEOCYFNV-NFFDBFGFSA-N azlocillin Chemical compound N([C@@H](C(=O)N[C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C=1C=CC=CC=1)C(=O)N1CCNC1=O JTWOMNBEOCYFNV-NFFDBFGFSA-N 0.000 description 2
- 229960003071 bacitracin Drugs 0.000 description 2
- 229930184125 bacitracin Natural products 0.000 description 2
- CLKOFPXJLQSYAH-ABRJDSQDSA-N bacitracin A Chemical compound C1SC([C@@H](N)[C@@H](C)CC)=N[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]1C(=O)N[C@H](CCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2N=CNC=2)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)NCCCC1 CLKOFPXJLQSYAH-ABRJDSQDSA-N 0.000 description 2
- 239000011805 ball Substances 0.000 description 2
- 229940092705 beclomethasone Drugs 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 239000000440 bentonite Substances 0.000 description 2
- 229910000278 bentonite Inorganic materials 0.000 description 2
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 2
- 229960002537 betamethasone Drugs 0.000 description 2
- UREBDLICKHMUKA-DVTGEIKXSA-N betamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-DVTGEIKXSA-N 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
- 230000036760 body temperature Effects 0.000 description 2
- MAEIEVLCKWDQJH-UHFFFAOYSA-N bumetanide Chemical compound CCCCNC1=CC(C(O)=O)=CC(S(N)(=O)=O)=C1OC1=CC=CC=C1 MAEIEVLCKWDQJH-UHFFFAOYSA-N 0.000 description 2
- 229960004064 bumetanide Drugs 0.000 description 2
- 229920005549 butyl rubber Polymers 0.000 description 2
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 2
- 229940095259 butylated hydroxytoluene Drugs 0.000 description 2
- 229960002681 calcium alginate Drugs 0.000 description 2
- 235000010410 calcium alginate Nutrition 0.000 description 2
- 239000000648 calcium alginate Substances 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 235000010216 calcium carbonate Nutrition 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- OKHHGHGGPDJQHR-YMOPUZKJSA-L calcium;(2s,3s,4s,5s,6r)-6-[(2r,3s,4r,5s,6r)-2-carboxy-6-[(2r,3s,4r,5s,6r)-2-carboxylato-4,5,6-trihydroxyoxan-3-yl]oxy-4,5-dihydroxyoxan-3-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylate Chemical compound [Ca+2].O[C@@H]1[C@H](O)[C@H](O)O[C@@H](C([O-])=O)[C@H]1O[C@H]1[C@@H](O)[C@@H](O)[C@H](O[C@H]2[C@H]([C@@H](O)[C@H](O)[C@H](O2)C([O-])=O)O)[C@H](C(O)=O)O1 OKHHGHGGPDJQHR-YMOPUZKJSA-L 0.000 description 2
- BPKIGYQJPYCAOW-FFJTTWKXSA-I calcium;potassium;disodium;(2s)-2-hydroxypropanoate;dichloride;dihydroxide;hydrate Chemical compound O.[OH-].[OH-].[Na+].[Na+].[Cl-].[Cl-].[K+].[Ca+2].C[C@H](O)C([O-])=O BPKIGYQJPYCAOW-FFJTTWKXSA-I 0.000 description 2
- BMLSTPRTEKLIPM-UHFFFAOYSA-I calcium;potassium;disodium;hydrogen carbonate;dichloride;dihydroxide;hydrate Chemical compound O.[OH-].[OH-].[Na+].[Na+].[Cl-].[Cl-].[K+].[Ca+2].OC([O-])=O BMLSTPRTEKLIPM-UHFFFAOYSA-I 0.000 description 2
- 229960001631 carbomer Drugs 0.000 description 2
- OKTJSMMVPCPJKN-BJUDXGSMSA-N carbon-11 Chemical compound [11C] OKTJSMMVPCPJKN-BJUDXGSMSA-N 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 229960004562 carboplatin Drugs 0.000 description 2
- 229920003064 carboxyethyl cellulose Polymers 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- OGHNVEJMJSYVRP-UHFFFAOYSA-N carvedilol Chemical compound COC1=CC=CC=C1OCCNCC(O)COC1=CC=CC2=C1C1=CC=CC=C1N2 OGHNVEJMJSYVRP-UHFFFAOYSA-N 0.000 description 2
- 229960004195 carvedilol Drugs 0.000 description 2
- JYIKNQVWKBUSNH-WVDDFWQHSA-N caspofungin Chemical compound C1([C@H](O)[C@@H](O)[C@H]2C(=O)N[C@H](C(=O)N3CC[C@H](O)[C@H]3C(=O)N[C@H](NCCN)[C@H](O)C[C@@H](C(N[C@H](C(=O)N3C[C@H](O)C[C@H]3C(=O)N2)[C@@H](C)O)=O)NC(=O)CCCCCCCC[C@@H](C)C[C@@H](C)CC)[C@H](O)CCN)=CC=C(O)C=C1 JYIKNQVWKBUSNH-WVDDFWQHSA-N 0.000 description 2
- 229960003034 caspofungin Drugs 0.000 description 2
- QYIYFLOTGYLRGG-GPCCPHFNSA-N cefaclor Chemical compound C1([C@H](C(=O)N[C@@H]2C(N3C(=C(Cl)CS[C@@H]32)C(O)=O)=O)N)=CC=CC=C1 QYIYFLOTGYLRGG-GPCCPHFNSA-N 0.000 description 2
- 229960005361 cefaclor Drugs 0.000 description 2
- 229960003012 cefamandole Drugs 0.000 description 2
- OLVCFLKTBJRLHI-AXAPSJFSSA-N cefamandole Chemical compound CN1N=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)[C@H](O)C=3C=CC=CC=3)[C@H]2SC1 OLVCFLKTBJRLHI-AXAPSJFSSA-N 0.000 description 2
- 229960001139 cefazolin Drugs 0.000 description 2
- MLYYVTUWGNIJIB-BXKDBHETSA-N cefazolin Chemical compound S1C(C)=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CN3N=NN=C3)[C@H]2SC1 MLYYVTUWGNIJIB-BXKDBHETSA-N 0.000 description 2
- 229960003719 cefdinir Drugs 0.000 description 2
- RTXOFQZKPXMALH-GHXIOONMSA-N cefdinir Chemical compound S1C(N)=NC(C(=N\O)\C(=O)N[C@@H]2C(N3C(=C(C=C)CS[C@@H]32)C(O)=O)=O)=C1 RTXOFQZKPXMALH-GHXIOONMSA-N 0.000 description 2
- 229960002129 cefixime Drugs 0.000 description 2
- 229960004682 cefoperazone Drugs 0.000 description 2
- GCFBRXLSHGKWDP-XCGNWRKASA-N cefoperazone Chemical compound O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC(O)=CC=1)C(=O)N[C@@H]1C(=O)N2C(C(O)=O)=C(CSC=3N(N=NN=3)C)CS[C@@H]21 GCFBRXLSHGKWDP-XCGNWRKASA-N 0.000 description 2
- 229960004261 cefotaxime Drugs 0.000 description 2
- AZZMGZXNTDTSME-JUZDKLSSSA-M cefotaxime sodium Chemical compound [Na+].N([C@@H]1C(N2C(=C(COC(C)=O)CS[C@@H]21)C([O-])=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 AZZMGZXNTDTSME-JUZDKLSSSA-M 0.000 description 2
- 229960002682 cefoxitin Drugs 0.000 description 2
- 229960005090 cefpodoxime Drugs 0.000 description 2
- WYUSVOMTXWRGEK-HBWVYFAYSA-N cefpodoxime Chemical compound N([C@H]1[C@@H]2N(C1=O)C(=C(CS2)COC)C(O)=O)C(=O)C(=N/OC)\C1=CSC(N)=N1 WYUSVOMTXWRGEK-HBWVYFAYSA-N 0.000 description 2
- 229960002580 cefprozil Drugs 0.000 description 2
- 229960004086 ceftibuten Drugs 0.000 description 2
- SSWTVBYDDFPFAF-DKOGRLLHSA-N ceftibuten dihydrate Chemical compound O.O.S1C(N)=NC(C(=C\CC(O)=O)\C(=O)N[C@@H]2C(N3C(=CCS[C@@H]32)C(O)=O)=O)=C1 SSWTVBYDDFPFAF-DKOGRLLHSA-N 0.000 description 2
- 229960001991 ceftizoxime Drugs 0.000 description 2
- NNULBSISHYWZJU-LLKWHZGFSA-N ceftizoxime Chemical compound N([C@@H]1C(N2C(=CCS[C@@H]21)C(O)=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 NNULBSISHYWZJU-LLKWHZGFSA-N 0.000 description 2
- 229960004755 ceftriaxone Drugs 0.000 description 2
- VAAUVRVFOQPIGI-SPQHTLEESA-N ceftriaxone Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC1=NC(=O)C(=O)NN1C VAAUVRVFOQPIGI-SPQHTLEESA-N 0.000 description 2
- 229960001668 cefuroxime Drugs 0.000 description 2
- JFPVXVDWJQMJEE-IZRZKJBUSA-N cefuroxime Chemical compound N([C@@H]1C(N2C(=C(COC(N)=O)CS[C@@H]21)C(O)=O)=O)C(=O)\C(=N/OC)C1=CC=CO1 JFPVXVDWJQMJEE-IZRZKJBUSA-N 0.000 description 2
- 229960000590 celecoxib Drugs 0.000 description 2
- 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 2
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 2
- 229920001727 cellulose butyrate Polymers 0.000 description 2
- 229920006218 cellulose propionate Polymers 0.000 description 2
- 229940106164 cephalexin Drugs 0.000 description 2
- AVGYWQBCYZHHPN-CYJZLJNKSA-N cephalexin monohydrate Chemical compound O.C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CC=CC=C1 AVGYWQBCYZHHPN-CYJZLJNKSA-N 0.000 description 2
- 229960000541 cetyl alcohol Drugs 0.000 description 2
- JQXXHWHPUNPDRT-BQVAUQFYSA-N chembl1523493 Chemical compound O([C@](C1=O)(C)O\C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)/C=C\C=C(C)/C(=O)NC=2C(O)=C3C(O)=C4C)C)OC)C4=C1C3=C(O)C=2C=NN1CCN(C)CC1 JQXXHWHPUNPDRT-BQVAUQFYSA-N 0.000 description 2
- DDTDNCYHLGRFBM-YZEKDTGTSA-N chembl2367892 Chemical compound CC(=O)N[C@H]1[C@@H](O)[C@H](O)[C@H](CO)O[C@H]1O[C@@H]([C@H]1C(N[C@@H](C2=CC(O)=CC(O[C@@H]3[C@H]([C@H](O)[C@H](O)[C@@H](CO)O3)O)=C2C=2C(O)=CC=C(C=2)[C@@H](NC(=O)[C@@H]2NC(=O)[C@@H]3C=4C=C(O)C=C(C=4)OC=4C(O)=CC=C(C=4)[C@@H](N)C(=O)N[C@H](CC=4C=C(Cl)C(O5)=CC=4)C(=O)N3)C(=O)N1)C(O)=O)=O)C(C=C1Cl)=CC=C1OC1=C(O[C@H]3[C@H]([C@@H](O)[C@H](O)[C@H](CO)O3)NC(C)=O)C5=CC2=C1 DDTDNCYHLGRFBM-YZEKDTGTSA-N 0.000 description 2
- 229960002155 chlorothiazide Drugs 0.000 description 2
- 229960001523 chlortalidone Drugs 0.000 description 2
- 229960001265 ciclosporin Drugs 0.000 description 2
- DHSUYTOATWAVLW-WFVMDLQDSA-N cilastatin Chemical compound CC1(C)C[C@@H]1C(=O)N\C(=C/CCCCSC[C@H](N)C(O)=O)C(O)=O DHSUYTOATWAVLW-WFVMDLQDSA-N 0.000 description 2
- 229960004912 cilastatin Drugs 0.000 description 2
- 229960003405 ciprofloxacin Drugs 0.000 description 2
- 229960002626 clarithromycin Drugs 0.000 description 2
- AGOYDEPGAOXOCK-KCBOHYOISA-N clarithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@](C)([C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)OC)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 AGOYDEPGAOXOCK-KCBOHYOISA-N 0.000 description 2
- 229960003326 cloxacillin Drugs 0.000 description 2
- LQOLIRLGBULYKD-JKIFEVAISA-N cloxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=CC=CC=C1Cl LQOLIRLGBULYKD-JKIFEVAISA-N 0.000 description 2
- 238000004891 communication Methods 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 239000000599 controlled substance Substances 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 229940099112 cornstarch Drugs 0.000 description 2
- 239000002577 cryoprotective agent Substances 0.000 description 2
- 229930182912 cyclosporin Natural products 0.000 description 2
- 229940127089 cytotoxic agent Drugs 0.000 description 2
- 239000002254 cytotoxic agent Substances 0.000 description 2
- 229960002615 dalfopristin Drugs 0.000 description 2
- SUYRLXYYZQTJHF-VMBLUXKRSA-N dalfopristin Chemical compound O=C([C@@H]1N(C2=O)CC[C@H]1S(=O)(=O)CCN(CC)CC)O[C@H](C(C)C)[C@H](C)\C=C\C(=O)NC\C=C\C(\C)=C\[C@@H](O)CC(=O)CC1=NC2=CO1 SUYRLXYYZQTJHF-VMBLUXKRSA-N 0.000 description 2
- 108700028430 dalfopristin Proteins 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 229960002398 demeclocycline Drugs 0.000 description 2
- 239000008355 dextrose injection Substances 0.000 description 2
- JXTHNDFMNIQAHM-UHFFFAOYSA-N dichloroacetic acid Chemical compound OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 0.000 description 2
- 229960001585 dicloxacillin Drugs 0.000 description 2
- YFAGHNZHGGCZAX-JKIFEVAISA-N dicloxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=C(Cl)C=CC=C1Cl YFAGHNZHGGCZAX-JKIFEVAISA-N 0.000 description 2
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- WLOHNSSYAXHWNR-NXPDYKKBSA-N dirithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H]2O[C@H](COCCOC)N[C@H]([C@@H]2C)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 WLOHNSSYAXHWNR-NXPDYKKBSA-N 0.000 description 2
- 229960004100 dirithromycin Drugs 0.000 description 2
- 229960003668 docetaxel Drugs 0.000 description 2
- 229960003722 doxycycline Drugs 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 238000009510 drug design Methods 0.000 description 2
- 229960001484 edetic acid Drugs 0.000 description 2
- 229920001971 elastomer Polymers 0.000 description 2
- ZUBDGKVDJUIMQQ-UBFCDGJISA-N endothelin-1 Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(O)=O)NC(=O)[C@H]1NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@@H](CC=2C=CC(O)=CC=2)NC(=O)[C@H](C(C)C)NC(=O)[C@H]2CSSC[C@@H](C(N[C@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N2)=O)NC(=O)[C@@H](CO)NC(=O)[C@H](N)CSSC1)C1=CNC=N1 ZUBDGKVDJUIMQQ-UBFCDGJISA-N 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- 229960000740 enrofloxacin Drugs 0.000 description 2
- 229920005558 epichlorohydrin rubber Polymers 0.000 description 2
- 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 2
- 210000002919 epithelial cell Anatomy 0.000 description 2
- JUKPWJGBANNWMW-VWBFHTRKSA-N eplerenone Chemical compound C([C@@H]1[C@]2(C)C[C@H]3O[C@]33[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)C(=O)OC)C[C@@]21CCC(=O)O1 JUKPWJGBANNWMW-VWBFHTRKSA-N 0.000 description 2
- 229960001208 eplerenone Drugs 0.000 description 2
- 229930013356 epothilone Natural products 0.000 description 2
- 229960004468 eptifibatide Drugs 0.000 description 2
- GLGOPUHVAZCPRB-LROMGURASA-N eptifibatide Chemical compound N1C(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CCCCNC(=N)N)NC(=O)CCSSC[C@@H](C(N)=O)NC(=O)[C@@H]2CCCN2C(=O)[C@@H]1CC1=CN=C2[C]1C=CC=C2 GLGOPUHVAZCPRB-LROMGURASA-N 0.000 description 2
- 230000003628 erosive effect Effects 0.000 description 2
- AVOLMBLBETYQHX-UHFFFAOYSA-N etacrynic acid Chemical compound CCC(=C)C(=O)C1=CC=C(OCC(O)=O)C(Cl)=C1Cl AVOLMBLBETYQHX-UHFFFAOYSA-N 0.000 description 2
- 229960003199 etacrynic acid Drugs 0.000 description 2
- 229960000403 etanercept Drugs 0.000 description 2
- AEUTYOVWOVBAKS-UWVGGRQHSA-N ethambutol Chemical compound CC[C@@H](CO)NCCN[C@@H](CC)CO AEUTYOVWOVBAKS-UWVGGRQHSA-N 0.000 description 2
- 235000019326 ethyl hydroxyethyl cellulose Nutrition 0.000 description 2
- MMXKVMNBHPAILY-UHFFFAOYSA-N ethyl laurate Chemical compound CCCCCCCCCCCC(=O)OCC MMXKVMNBHPAILY-UHFFFAOYSA-N 0.000 description 2
- 235000010944 ethyl methyl cellulose Nutrition 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- ZPAKPRAICRBAOD-UHFFFAOYSA-N fenbufen Chemical compound C1=CC(C(=O)CCC(=O)O)=CC=C1C1=CC=CC=C1 ZPAKPRAICRBAOD-UHFFFAOYSA-N 0.000 description 2
- 229960001395 fenbufen Drugs 0.000 description 2
- 239000000835 fiber Substances 0.000 description 2
- 239000003527 fibrinolytic agent Substances 0.000 description 2
- 229960004273 floxacillin Drugs 0.000 description 2
- RGUQWGXAYZNLMI-UHFFFAOYSA-N flumethiazide Chemical compound C1=C(C(F)(F)F)C(S(=O)(=O)N)=CC2=C1NC=NS2(=O)=O RGUQWGXAYZNLMI-UHFFFAOYSA-N 0.000 description 2
- 229960002390 flurbiprofen Drugs 0.000 description 2
- SYTBZMRGLBWNTM-UHFFFAOYSA-N flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 description 2
- 238000005187 foaming Methods 0.000 description 2
- 235000019152 folic acid Nutrition 0.000 description 2
- 239000011724 folic acid Substances 0.000 description 2
- YMDXZJFXQJVXBF-STHAYSLISA-N fosfomycin Chemical compound C[C@@H]1O[C@@H]1P(O)(O)=O YMDXZJFXQJVXBF-STHAYSLISA-N 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 239000001530 fumaric acid Substances 0.000 description 2
- 235000011087 fumaric acid Nutrition 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 229960003923 gatifloxacin Drugs 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- QTQAWLPCGQOSGP-GBTDJJJQSA-N geldanamycin Chemical compound N1C(=O)\C(C)=C/C=C\[C@@H](OC)[C@H](OC(N)=O)\C(C)=C/[C@@H](C)[C@@H](O)[C@H](OC)C[C@@H](C)CC2=C(OC)C(=O)C=C1C2=O QTQAWLPCGQOSGP-GBTDJJJQSA-N 0.000 description 2
- YRSVDSQRGBYVIY-GJZGRUSLSA-N gemopatrilat Chemical compound O=C1N(CC(O)=O)C(C)(C)CCC[C@@H]1NC(=O)[C@@H](S)CC1=CC=CC=C1 YRSVDSQRGBYVIY-GJZGRUSLSA-N 0.000 description 2
- 229950006480 gemopatrilat Drugs 0.000 description 2
- 229960004580 glibenclamide Drugs 0.000 description 2
- WIGIZIANZCJQQY-RUCARUNLSA-N glimepiride Chemical compound O=C1C(CC)=C(C)CN1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)N[C@@H]2CC[C@@H](C)CC2)C=C1 WIGIZIANZCJQQY-RUCARUNLSA-N 0.000 description 2
- 229960004346 glimepiride Drugs 0.000 description 2
- ZJJXGWJIGJFDTL-UHFFFAOYSA-N glipizide Chemical compound C1=NC(C)=CN=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZJJXGWJIGJFDTL-UHFFFAOYSA-N 0.000 description 2
- 229960001381 glipizide Drugs 0.000 description 2
- 239000003862 glucocorticoid Substances 0.000 description 2
- ZNNLBTZKUZBEKO-UHFFFAOYSA-N glyburide Chemical compound COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZNNLBTZKUZBEKO-UHFFFAOYSA-N 0.000 description 2
- 125000005456 glyceride group Chemical group 0.000 description 2
- 235000019580 granularity Nutrition 0.000 description 2
- 239000003979 granulating agent Substances 0.000 description 2
- 238000005469 granulation Methods 0.000 description 2
- 230000003179 granulation Effects 0.000 description 2
- 238000000227 grinding Methods 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- MCAHMSDENAOJFZ-BVXDHVRPSA-N herbimycin Chemical compound N1C(=O)\C(C)=C\C=C/[C@H](OC)[C@@H](OC(N)=O)\C(C)=C\[C@H](C)[C@@H](OC)[C@@H](OC)C[C@H](C)[C@@H](OC)C2=CC(=O)C=C1C2=O MCAHMSDENAOJFZ-BVXDHVRPSA-N 0.000 description 2
- 229930193320 herbimycin Natural products 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 229940006607 hirudin Drugs 0.000 description 2
- WQPDUTSPKFMPDP-OUMQNGNKSA-N hirudin Chemical compound C([C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC(OS(O)(=O)=O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H]1NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H]2CSSC[C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)N[C@H](C(NCC(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N2)=O)CSSC1)C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]1NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=2C=CC(O)=CC=2)NC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)C(C)C)[C@@H](C)O)CSSC1)C(C)C)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 WQPDUTSPKFMPDP-OUMQNGNKSA-N 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 229960000890 hydrocortisone Drugs 0.000 description 2
- DMDGGSIALPNSEE-UHFFFAOYSA-N hydroflumethiazide Chemical compound C1=C(C(F)(F)F)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O DMDGGSIALPNSEE-UHFFFAOYSA-N 0.000 description 2
- 229960003313 hydroflumethiazide Drugs 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 2
- 230000009610 hypersensitivity Effects 0.000 description 2
- 229960001680 ibuprofen Drugs 0.000 description 2
- 229960002182 imipenem Drugs 0.000 description 2
- GSOSVVULSKVSLQ-JJVRHELESA-N imipenem hydrate Chemical compound O.C1C(SCCNC=N)=C(C(O)=O)N2C(=O)[C@H]([C@H](O)C)[C@H]21 GSOSVVULSKVSLQ-JJVRHELESA-N 0.000 description 2
- 238000002513 implantation Methods 0.000 description 2
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 2
- 229960000905 indomethacin Drugs 0.000 description 2
- 239000011261 inert gas Substances 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- XKTZWUACRZHVAN-VADRZIEHSA-N interleukin-8 Chemical compound C([C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@@H](NC(C)=O)CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CCSC)C(=O)N1[C@H](CCC1)C(=O)N1[C@H](CCC1)C(=O)N[C@@H](C)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC=1C=CC(O)=CC=1)C(=O)N[C@H](CO)C(=O)N1[C@H](CCC1)C(N)=O)C1=CC=CC=C1 XKTZWUACRZHVAN-VADRZIEHSA-N 0.000 description 2
- 229940096397 interleukin-8 Drugs 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 229940044173 iodine-125 Drugs 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- 229920000554 ionomer Polymers 0.000 description 2
- IQZZFVDIZRWADY-UHFFFAOYSA-N isocoumarin Chemical compound C1=CC=C2C(=O)OC=CC2=C1 IQZZFVDIZRWADY-UHFFFAOYSA-N 0.000 description 2
- 150000002518 isoindoles Chemical class 0.000 description 2
- 229960003350 isoniazid Drugs 0.000 description 2
- QRXWMOHMRWLFEY-UHFFFAOYSA-N isoniazide Chemical compound NNC(=O)C1=CC=NC=C1 QRXWMOHMRWLFEY-UHFFFAOYSA-N 0.000 description 2
- 125000005956 isoquinolyl group Chemical group 0.000 description 2
- 125000001786 isothiazolyl group Chemical group 0.000 description 2
- 150000002540 isothiocyanates Chemical class 0.000 description 2
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 2
- 235000010494 karaya gum Nutrition 0.000 description 2
- 125000000468 ketone group Chemical group 0.000 description 2
- 235000014655 lactic acid Nutrition 0.000 description 2
- 239000004310 lactic acid Substances 0.000 description 2
- 229960000448 lactic acid Drugs 0.000 description 2
- 235000019388 lanolin Nutrition 0.000 description 2
- 235000010445 lecithin Nutrition 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 229940067606 lecithin Drugs 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- TYZROVQLWOKYKF-ZDUSSCGKSA-N linezolid Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C(C=C1F)=CC=C1N1CCOCC1 TYZROVQLWOKYKF-ZDUSSCGKSA-N 0.000 description 2
- 229960003907 linezolid Drugs 0.000 description 2
- 235000010420 locust bean gum Nutrition 0.000 description 2
- 239000000711 locust bean gum Substances 0.000 description 2
- 229960002422 lomefloxacin Drugs 0.000 description 2
- ZEKZLJVOYLTDKK-UHFFFAOYSA-N lomefloxacin Chemical compound FC1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNC(C)C1 ZEKZLJVOYLTDKK-UHFFFAOYSA-N 0.000 description 2
- 229960001977 loracarbef Drugs 0.000 description 2
- 229960004844 lovastatin Drugs 0.000 description 2
- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 description 2
- QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 description 2
- 229960003511 macrogol Drugs 0.000 description 2
- 229960003640 mafenide Drugs 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 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
- 239000011976 maleic acid Substances 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 208000008585 mastocytosis Diseases 0.000 description 2
- HYYBABOKPJLUIN-UHFFFAOYSA-N mefenamic acid Chemical compound CC1=CC=CC(NC=2C(=CC=CC=2)C(O)=O)=C1C HYYBABOKPJLUIN-UHFFFAOYSA-N 0.000 description 2
- 229960003464 mefenamic acid Drugs 0.000 description 2
- 229950004994 meglitinide Drugs 0.000 description 2
- 229960002260 meropenem Drugs 0.000 description 2
- DMJNNHOOLUXYBV-PQTSNVLCSA-N meropenem Chemical compound C=1([C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)S[C@@H]1CN[C@H](C(=O)N(C)C)C1 DMJNNHOOLUXYBV-PQTSNVLCSA-N 0.000 description 2
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 2
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 2
- 229920003087 methylethyl cellulose Polymers 0.000 description 2
- IUBSYMUCCVWXPE-UHFFFAOYSA-N metoprolol Chemical compound COCCC1=CC=C(OCC(O)CNC(C)C)C=C1 IUBSYMUCCVWXPE-UHFFFAOYSA-N 0.000 description 2
- 229960002237 metoprolol Drugs 0.000 description 2
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical group CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 description 2
- 229960000198 mezlocillin Drugs 0.000 description 2
- YPBATNHYBCGSSN-VWPFQQQWSA-N mezlocillin Chemical compound N([C@@H](C(=O)N[C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C=1C=CC=CC=1)C(=O)N1CCN(S(C)(=O)=O)C1=O YPBATNHYBCGSSN-VWPFQQQWSA-N 0.000 description 2
- 229960002159 micafungin Drugs 0.000 description 2
- PIEUQSKUWLMALL-YABMTYFHSA-N micafungin Chemical compound C1=CC(OCCCCC)=CC=C1C1=CC(C=2C=CC(=CC=2)C(=O)N[C@@H]2C(N[C@H](C(=O)N3C[C@H](O)C[C@H]3C(=O)N[C@H](C(=O)N[C@H](C(=O)N3C[C@H](C)[C@H](O)[C@H]3C(=O)N[C@H](O)[C@H](O)C2)[C@H](O)CC(N)=O)[C@H](O)[C@@H](O)C=2C=C(OS(O)(=O)=O)C(O)=CC=2)[C@@H](C)O)=O)=NO1 PIEUQSKUWLMALL-YABMTYFHSA-N 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
- 235000010446 mineral oil Nutrition 0.000 description 2
- 239000002395 mineralocorticoid Substances 0.000 description 2
- 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 2
- 229960004857 mitomycin Drugs 0.000 description 2
- 229960000350 mitotane Drugs 0.000 description 2
- 150000004682 monohydrates Chemical class 0.000 description 2
- 210000000214 mouth Anatomy 0.000 description 2
- 229960003702 moxifloxacin Drugs 0.000 description 2
- FABPRXSRWADJSP-MEDUHNTESA-N moxifloxacin Chemical compound COC1=C(N2C[C@H]3NCCC[C@H]3C2)C(F)=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 FABPRXSRWADJSP-MEDUHNTESA-N 0.000 description 2
- 229960003128 mupirocin Drugs 0.000 description 2
- 229930187697 mupirocin Natural products 0.000 description 2
- DDHVILIIHBIMQU-YJGQQKNPSA-L mupirocin calcium hydrate Chemical compound O.O.[Ca+2].C[C@H](O)[C@H](C)[C@@H]1O[C@H]1C[C@@H]1[C@@H](O)[C@@H](O)[C@H](C\C(C)=C\C(=O)OCCCCCCCCC([O-])=O)OC1.C[C@H](O)[C@H](C)[C@@H]1O[C@H]1C[C@@H]1[C@@H](O)[C@@H](O)[C@H](C\C(C)=C\C(=O)OCCCCCCCCC([O-])=O)OC1 DDHVILIIHBIMQU-YJGQQKNPSA-L 0.000 description 2
- RLWRMIYXDPXIEX-UHFFFAOYSA-N muzolimine Chemical compound C=1C=C(Cl)C(Cl)=CC=1C(C)N1N=C(N)CC1=O RLWRMIYXDPXIEX-UHFFFAOYSA-N 0.000 description 2
- 229960001788 muzolimine Drugs 0.000 description 2
- RTGDFNSFWBGLEC-SYZQJQIISA-N mycophenolate mofetil Chemical compound COC1=C(C)C=2COC(=O)C=2C(O)=C1C\C=C(/C)CCC(=O)OCCN1CCOCC1 RTGDFNSFWBGLEC-SYZQJQIISA-N 0.000 description 2
- 229960004866 mycophenolate mofetil Drugs 0.000 description 2
- 229960004270 nabumetone Drugs 0.000 description 2
- 229960003255 natamycin Drugs 0.000 description 2
- 235000010298 natamycin Nutrition 0.000 description 2
- 239000004311 natamycin Substances 0.000 description 2
- NCXMLFZGDNKEPB-FFPOYIOWSA-N natamycin Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C[C@@H](C)OC(=O)/C=C/[C@H]2O[C@@H]2C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 NCXMLFZGDNKEPB-FFPOYIOWSA-N 0.000 description 2
- 229920003052 natural elastomer Polymers 0.000 description 2
- 229920001194 natural rubber Polymers 0.000 description 2
- 229960000808 netilmicin Drugs 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- NXFQHRVNIOXGAQ-YCRREMRBSA-N nitrofurantoin Chemical compound O1C([N+](=O)[O-])=CC=C1\C=N\N1C(=O)NC(=O)C1 NXFQHRVNIOXGAQ-YCRREMRBSA-N 0.000 description 2
- 125000006574 non-aromatic ring group Chemical group 0.000 description 2
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 2
- 229960001180 norfloxacin Drugs 0.000 description 2
- OGJPXUAPXNRGGI-UHFFFAOYSA-N norfloxacin Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 OGJPXUAPXNRGGI-UHFFFAOYSA-N 0.000 description 2
- 229920001778 nylon Polymers 0.000 description 2
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 2
- LVRLSYPNFFBYCZ-VGWMRTNUSA-N omapatrilat Chemical compound C([C@H](S)C(=O)N[C@H]1CCS[C@H]2CCC[C@H](N2C1=O)C(=O)O)C1=CC=CC=C1 LVRLSYPNFFBYCZ-VGWMRTNUSA-N 0.000 description 2
- 229950000973 omapatrilat Drugs 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- PXQPEWDEAKTCGB-UHFFFAOYSA-N orotic acid Chemical compound OC(=O)C1=CC(=O)NC(=O)N1 PXQPEWDEAKTCGB-UHFFFAOYSA-N 0.000 description 2
- QVGXLLKOCUKJST-BJUDXGSMSA-N oxygen-15 atom Chemical compound [15O] QVGXLLKOCUKJST-BJUDXGSMSA-N 0.000 description 2
- LSQZJLSUYDQPKJ-UHFFFAOYSA-N p-Hydroxyampicillin Natural products O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)C(N)C1=CC=C(O)C=C1 LSQZJLSUYDQPKJ-UHFFFAOYSA-N 0.000 description 2
- 238000004806 packaging method and process Methods 0.000 description 2
- TZRHLKRLEZJVIJ-UHFFFAOYSA-N parecoxib Chemical compound C1=CC(S(=O)(=O)NC(=O)CC)=CC=C1C1=C(C)ON=C1C1=CC=CC=C1 TZRHLKRLEZJVIJ-UHFFFAOYSA-N 0.000 description 2
- 238000005453 pelletization Methods 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 230000010412 perfusion Effects 0.000 description 2
- ZQBAKBUEJOMQEX-UHFFFAOYSA-N phenyl salicylate Chemical compound OC1=CC=CC=C1C(=O)OC1=CC=CC=C1 ZQBAKBUEJOMQEX-UHFFFAOYSA-N 0.000 description 2
- ZPHBZEQOLSRPAK-XLCYBJAPSA-N phosphoramidon Chemical compound N([C@@H](CC(C)C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(O)=O)P(O)(=O)O[C@@H]1O[C@@H](C)[C@H](O)[C@@H](O)[C@H]1O ZPHBZEQOLSRPAK-XLCYBJAPSA-N 0.000 description 2
- 108010072906 phosphoramidon Proteins 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 229940097886 phosphorus 32 Drugs 0.000 description 2
- 229960005095 pioglitazone Drugs 0.000 description 2
- 229960002292 piperacillin Drugs 0.000 description 2
- VGYFMXBACGZSIL-MCBHFWOFSA-N pitavastatin Chemical compound OC(=O)C[C@H](O)C[C@H](O)\C=C\C1=C(C2CC2)N=C2C=CC=CC2=C1C1=CC=C(F)C=C1 VGYFMXBACGZSIL-MCBHFWOFSA-N 0.000 description 2
- RHGYHLPFVJEAOC-FFNUKLMVSA-L pitavastatin calcium Chemical compound [Ca+2].[O-]C(=O)C[C@H](O)C[C@H](O)\C=C\C1=C(C2CC2)N=C2C=CC=CC2=C1C1=CC=C(F)C=C1.[O-]C(=O)C[C@H](O)C[C@H](O)\C=C\C1=C(C2CC2)N=C2C=CC=CC2=C1C1=CC=C(F)C=C1 RHGYHLPFVJEAOC-FFNUKLMVSA-L 0.000 description 2
- 239000000106 platelet aggregation inhibitor Substances 0.000 description 2
- 229910052697 platinum Inorganic materials 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 229960003171 plicamycin Drugs 0.000 description 2
- 229960000540 polacrilin potassium Drugs 0.000 description 2
- 229920001490 poly(butyl methacrylate) polymer Polymers 0.000 description 2
- 229920003229 poly(methyl methacrylate) Polymers 0.000 description 2
- 229950005134 polycarbophil Drugs 0.000 description 2
- 229920000570 polyether Polymers 0.000 description 2
- 229920006393 polyether sulfone Polymers 0.000 description 2
- 229920002338 polyhydroxyethylmethacrylate Polymers 0.000 description 2
- 229920001195 polyisoprene Polymers 0.000 description 2
- 238000006116 polymerization reaction Methods 0.000 description 2
- 239000004926 polymethyl methacrylate Substances 0.000 description 2
- 229920000098 polyolefin Polymers 0.000 description 2
- 229920002223 polystyrene Polymers 0.000 description 2
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 2
- 239000004810 polytetrafluoroethylene Substances 0.000 description 2
- 229920001290 polyvinyl ester Polymers 0.000 description 2
- 229920001289 polyvinyl ether Polymers 0.000 description 2
- 229920001291 polyvinyl halide Polymers 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- WVWZXTJUCNEUAE-UHFFFAOYSA-M potassium;1,2-bis(ethenyl)benzene;2-methylprop-2-enoate Chemical compound [K+].CC(=C)C([O-])=O.C=CC1=CC=CC=C1C=C WVWZXTJUCNEUAE-UHFFFAOYSA-M 0.000 description 2
- 229960002965 pravastatin Drugs 0.000 description 2
- TUZYXOIXSAXUGO-PZAWKZKUSA-N pravastatin Chemical compound C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 TUZYXOIXSAXUGO-PZAWKZKUSA-N 0.000 description 2
- 229960001309 procaine hydrochloride Drugs 0.000 description 2
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 description 2
- 229960000624 procarbazine Drugs 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- ULWHHBHJGPPBCO-UHFFFAOYSA-N propane-1,1-diol Chemical class CCC(O)O ULWHHBHJGPPBCO-UHFFFAOYSA-N 0.000 description 2
- 239000003380 propellant Substances 0.000 description 2
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 2
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 2
- 230000000541 pulsatile effect Effects 0.000 description 2
- 125000003226 pyrazolyl group Chemical group 0.000 description 2
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 2
- 229940044551 receptor antagonist Drugs 0.000 description 2
- 239000002464 receptor antagonist Substances 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 229960002354 repaglinide Drugs 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 210000002345 respiratory system Anatomy 0.000 description 2
- 229960001225 rifampicin Drugs 0.000 description 2
- 229960000371 rofecoxib Drugs 0.000 description 2
- RZJQGNCSTQAWON-UHFFFAOYSA-N rofecoxib Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=C(C=2C=CC=CC=2)C(=O)OC1 RZJQGNCSTQAWON-UHFFFAOYSA-N 0.000 description 2
- 229960004586 rosiglitazone Drugs 0.000 description 2
- BPRHUIZQVSMCRT-VEUZHWNKSA-N rosuvastatin Chemical compound CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC(O)=O BPRHUIZQVSMCRT-VEUZHWNKSA-N 0.000 description 2
- 229960000672 rosuvastatin Drugs 0.000 description 2
- 229960005224 roxithromycin Drugs 0.000 description 2
- 239000005060 rubber Substances 0.000 description 2
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 2
- 229940081974 saccharin Drugs 0.000 description 2
- 235000019204 saccharin Nutrition 0.000 description 2
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 108010073863 saruplase Proteins 0.000 description 2
- 229960005399 satraplatin Drugs 0.000 description 2
- 190014017285 satraplatin Chemical compound 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 2
- 150000003335 secondary amines Chemical class 0.000 description 2
- 229960005429 sertaconazole Drugs 0.000 description 2
- BNRNXUUZRGQAQC-UHFFFAOYSA-N sildenafil Chemical compound CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 BNRNXUUZRGQAQC-UHFFFAOYSA-N 0.000 description 2
- 229920002379 silicone rubber Polymers 0.000 description 2
- 239000004945 silicone rubber Substances 0.000 description 2
- 229960002855 simvastatin Drugs 0.000 description 2
- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 description 2
- 229960002930 sirolimus Drugs 0.000 description 2
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 2
- 210000003491 skin Anatomy 0.000 description 2
- 208000017520 skin disease Diseases 0.000 description 2
- 229940005550 sodium alginate Drugs 0.000 description 2
- 235000010413 sodium alginate Nutrition 0.000 description 2
- 239000000661 sodium alginate Substances 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 235000011121 sodium hydroxide Nutrition 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 235000012424 soybean oil Nutrition 0.000 description 2
- 239000003549 soybean oil Substances 0.000 description 2
- 229960000268 spectinomycin Drugs 0.000 description 2
- UNFWWIHTNXNPBV-WXKVUWSESA-N spectinomycin Chemical compound O([C@@H]1[C@@H](NC)[C@@H](O)[C@H]([C@@H]([C@H]1O1)O)NC)[C@]2(O)[C@H]1O[C@H](C)CC2=O UNFWWIHTNXNPBV-WXKVUWSESA-N 0.000 description 2
- 239000008174 sterile solution Substances 0.000 description 2
- 150000003431 steroids Chemical class 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 239000001384 succinic acid Substances 0.000 description 2
- 229960002673 sulfacetamide Drugs 0.000 description 2
- NINIDFKCEFEMDL-IGMARMGPSA-N sulfur-32 atom Chemical compound [32S] NINIDFKCEFEMDL-IGMARMGPSA-N 0.000 description 2
- NINIDFKCEFEMDL-OUBTZVSYSA-N sulfur-33 atom Chemical compound [33S] NINIDFKCEFEMDL-OUBTZVSYSA-N 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- WOXKDUGGOYFFRN-IIBYNOLFSA-N tadalafil Chemical compound C1=C2OCOC2=CC([C@@H]2C3=C(C4=CC=CC=C4N3)C[C@H]3N2C(=O)CN(C3=O)C)=C1 WOXKDUGGOYFFRN-IIBYNOLFSA-N 0.000 description 2
- 229960000835 tadalafil Drugs 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- DKPFODGZWDEEBT-QFIAKTPHSA-N taxane Chemical class C([C@]1(C)CCC[C@@H](C)[C@H]1C1)C[C@H]2[C@H](C)CC[C@@H]1C2(C)C DKPFODGZWDEEBT-QFIAKTPHSA-N 0.000 description 2
- 229960001608 teicoplanin Drugs 0.000 description 2
- LJVAJPDWBABPEJ-PNUFFHFMSA-N telithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)[C@@H](C)C(=O)O[C@@H]([C@]2(OC(=O)N(CCCCN3C=C(N=C3)C=3C=NC=CC=3)[C@@H]2[C@@H](C)C(=O)[C@H](C)C[C@@]1(C)OC)C)CC)[C@@H]1O[C@H](C)C[C@H](N(C)C)[C@H]1O LJVAJPDWBABPEJ-PNUFFHFMSA-N 0.000 description 2
- ZUHZGEOKBKGPSW-UHFFFAOYSA-N tetraglyme Chemical compound COCCOCCOCCOCCOC ZUHZGEOKBKGPSW-UHFFFAOYSA-N 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 239000002562 thickening agent Substances 0.000 description 2
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N thiocyanic acid Chemical compound SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 2
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 2
- 229960000103 thrombolytic agent Drugs 0.000 description 2
- RZWIIPASKMUIAC-VQTJNVASSA-N thromboxane Chemical compound CCCCCCCC[C@H]1OCCC[C@@H]1CCCCCCC RZWIIPASKMUIAC-VQTJNVASSA-N 0.000 description 2
- 229960004659 ticarcillin Drugs 0.000 description 2
- OHKOGUYZJXTSFX-KZFFXBSXSA-N ticarcillin Chemical compound C=1([C@@H](C(O)=O)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)C=CSC=1 OHKOGUYZJXTSFX-KZFFXBSXSA-N 0.000 description 2
- AGHANLSBXUWXTB-UHFFFAOYSA-N tienilic acid Chemical compound ClC1=C(Cl)C(OCC(=O)O)=CC=C1C(=O)C1=CC=CS1 AGHANLSBXUWXTB-UHFFFAOYSA-N 0.000 description 2
- 229960000356 tienilic acid Drugs 0.000 description 2
- COKMIXFXJJXBQG-NRFANRHFSA-N tirofiban Chemical compound C1=CC(C[C@H](NS(=O)(=O)CCCC)C(O)=O)=CC=C1OCCCCC1CCNCC1 COKMIXFXJJXBQG-NRFANRHFSA-N 0.000 description 2
- 229960003425 tirofiban Drugs 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 229960000187 tissue plasminogen activator Drugs 0.000 description 2
- 239000004408 titanium dioxide Substances 0.000 description 2
- 229960000707 tobramycin Drugs 0.000 description 2
- NLVFBUXFDBBNBW-PBSUHMDJSA-N tobramycin Chemical compound N[C@@H]1C[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N NLVFBUXFDBBNBW-PBSUHMDJSA-N 0.000 description 2
- PKVRCIRHQMSYJX-AIFWHQITSA-N trabectedin Chemical compound C([C@@]1(C(OC2)=O)NCCC3=C1C=C(C(=C3)O)OC)S[C@@H]1C3=C(OC(C)=O)C(C)=C4OCOC4=C3[C@H]2N2[C@@H](O)[C@H](CC=3C4=C(O)C(OC)=C(C)C=3)N(C)[C@H]4[C@@H]21 PKVRCIRHQMSYJX-AIFWHQITSA-N 0.000 description 2
- 229960000977 trabectedin Drugs 0.000 description 2
- RUVINXPYWBROJD-ONEGZZNKSA-N trans-anethole Chemical compound COC1=CC=C(\C=C\C)C=C1 RUVINXPYWBROJD-ONEGZZNKSA-N 0.000 description 2
- LMJSLTNSBFUCMU-UHFFFAOYSA-N trichlormethiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NC(C(Cl)Cl)NS2(=O)=O LMJSLTNSBFUCMU-UHFFFAOYSA-N 0.000 description 2
- 229960004813 trichlormethiazide Drugs 0.000 description 2
- 229940117013 triethanolamine oleate Drugs 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical class OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- DCXXMTOCNZCJGO-UHFFFAOYSA-N tristearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 description 2
- 229910052722 tritium Inorganic materials 0.000 description 2
- GXPHKUHSUJUWKP-UHFFFAOYSA-N troglitazone Chemical compound C1CC=2C(C)=C(O)C(C)=C(C)C=2OC1(C)COC(C=C1)=CC=C1CC1SC(=O)NC1=O GXPHKUHSUJUWKP-UHFFFAOYSA-N 0.000 description 2
- 229960001641 troglitazone Drugs 0.000 description 2
- GXPHKUHSUJUWKP-NTKDMRAZSA-N troglitazone Natural products C([C@@]1(OC=2C(C)=C(C(=C(C)C=2CC1)O)C)C)OC(C=C1)=CC=C1C[C@H]1SC(=O)NC1=O GXPHKUHSUJUWKP-NTKDMRAZSA-N 0.000 description 2
- 229960005041 troleandomycin Drugs 0.000 description 2
- LQCLVBQBTUVCEQ-QTFUVMRISA-N troleandomycin Chemical compound O1[C@@H](C)[C@H](OC(C)=O)[C@@H](OC)C[C@@H]1O[C@@H]1[C@@H](C)C(=O)O[C@H](C)[C@H](C)[C@H](OC(C)=O)[C@@H](C)C(=O)[C@@]2(OC2)C[C@H](C)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)OC(C)=O)[C@H]1C LQCLVBQBTUVCEQ-QTFUVMRISA-N 0.000 description 2
- WVPSKSLAZQPAKQ-CDMJZVDBSA-N trovafloxacin Chemical compound C([C@H]1[C@@H]([C@H]1C1)N)N1C(C(=CC=1C(=O)C(C(O)=O)=C2)F)=NC=1N2C1=CC=C(F)C=C1F WVPSKSLAZQPAKQ-CDMJZVDBSA-N 0.000 description 2
- 229960000497 trovafloxacin Drugs 0.000 description 2
- 201000008827 tuberculosis Diseases 0.000 description 2
- 210000003932 urinary bladder Anatomy 0.000 description 2
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 2
- 229960002381 vardenafil Drugs 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- 229920002554 vinyl polymer Polymers 0.000 description 2
- XLYOFNOQVPJJNP-OUBTZVSYSA-N water-17o Chemical compound [17OH2] XLYOFNOQVPJJNP-OUBTZVSYSA-N 0.000 description 2
- 238000001238 wet grinding Methods 0.000 description 2
- 239000002023 wood Substances 0.000 description 2
- 239000000811 xylitol Substances 0.000 description 2
- 235000010447 xylitol Nutrition 0.000 description 2
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 2
- 229960002675 xylitol Drugs 0.000 description 2
- FTLYMKDSHNWQKD-UHFFFAOYSA-N (2,4,5-trichlorophenyl)boronic acid Chemical compound OB(O)C1=CC(Cl)=C(Cl)C=C1Cl FTLYMKDSHNWQKD-UHFFFAOYSA-N 0.000 description 1
- XUFXOAAUWZOOIT-SXARVLRPSA-N (2R,3R,4R,5S,6R)-5-[[(2R,3R,4R,5S,6R)-5-[[(2R,3R,4S,5S,6R)-3,4-dihydroxy-6-methyl-5-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)-1-cyclohex-2-enyl]amino]-2-oxanyl]oxy]-3,4-dihydroxy-6-(hydroxymethyl)-2-oxanyl]oxy]-6-(hydroxymethyl)oxane-2,3,4-triol Chemical compound O([C@H]1O[C@H](CO)[C@H]([C@@H]([C@H]1O)O)O[C@H]1O[C@@H]([C@H]([C@H](O)[C@H]1O)N[C@@H]1[C@@H]([C@@H](O)[C@H](O)C(CO)=C1)O)C)[C@@H]1[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]1O XUFXOAAUWZOOIT-SXARVLRPSA-N 0.000 description 1
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- GUHPRPJDBZHYCJ-SECBINFHSA-N (2s)-2-(5-benzoylthiophen-2-yl)propanoic acid Chemical compound S1C([C@H](C(O)=O)C)=CC=C1C(=O)C1=CC=CC=C1 GUHPRPJDBZHYCJ-SECBINFHSA-N 0.000 description 1
- OBSLWIKITOYASJ-YDEIVXIUSA-N (3r,4r,5s,6r)-6-(hydroxymethyl)-3-(methylamino)oxane-2,4,5-triol Chemical class CN[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O OBSLWIKITOYASJ-YDEIVXIUSA-N 0.000 description 1
- 229920002818 (Hydroxyethyl)methacrylate Polymers 0.000 description 1
- WHBMMWSBFZVSSR-GSVOUGTGSA-N (R)-3-hydroxybutyric acid Chemical compound C[C@@H](O)CC(O)=O WHBMMWSBFZVSSR-GSVOUGTGSA-N 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- KTZQTRPPVKQPFO-UHFFFAOYSA-N 1,2-benzoxazole Chemical compound C1=CC=C2C=NOC2=C1 KTZQTRPPVKQPFO-UHFFFAOYSA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- QYMGRIFMUQCAJW-UHFFFAOYSA-N 1,2-dihydropyrazine Chemical compound C1NC=CN=C1 QYMGRIFMUQCAJW-UHFFFAOYSA-N 0.000 description 1
- LORRLQMLLQLPSJ-UHFFFAOYSA-N 1,3,5-trithiane Chemical compound C1SCSCS1 LORRLQMLLQLPSJ-UHFFFAOYSA-N 0.000 description 1
- YJTKZCDBKVTVBY-UHFFFAOYSA-N 1,3-Diphenylbenzene Chemical group C1=CC=CC=C1C1=CC=CC(C=2C=CC=CC=2)=C1 YJTKZCDBKVTVBY-UHFFFAOYSA-N 0.000 description 1
- DMBUODUULYCPAK-UHFFFAOYSA-N 1,3-bis(docosanoyloxy)propan-2-yl docosanoate Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCCCCCC DMBUODUULYCPAK-UHFFFAOYSA-N 0.000 description 1
- 229940058015 1,3-butylene glycol Drugs 0.000 description 1
- LDVVTQMJQSCDMK-UHFFFAOYSA-N 1,3-dihydroxypropan-2-yl formate Chemical compound OCC(CO)OC=O LDVVTQMJQSCDMK-UHFFFAOYSA-N 0.000 description 1
- ZOBPZXTWZATXDG-UHFFFAOYSA-N 1,3-thiazolidine-2,4-dione Chemical compound O=C1CSC(=O)N1 ZOBPZXTWZATXDG-UHFFFAOYSA-N 0.000 description 1
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical compound C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- VMLKTERJLVWEJJ-UHFFFAOYSA-N 1,5-naphthyridine Chemical compound C1=CC=NC2=CC=CN=C21 VMLKTERJLVWEJJ-UHFFFAOYSA-N 0.000 description 1
- SGZIDRGWNJDHRL-UHFFFAOYSA-N 1-(4-propan-2-ylphenyl)piperidine Chemical class C1=CC(C(C)C)=CC=C1N1CCCCC1 SGZIDRGWNJDHRL-UHFFFAOYSA-N 0.000 description 1
- TUSDEZXZIZRFGC-UHFFFAOYSA-N 1-O-galloyl-3,6-(R)-HHDP-beta-D-glucose Natural products OC1C(O2)COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC1C(O)C2OC(=O)C1=CC(O)=C(O)C(O)=C1 TUSDEZXZIZRFGC-UHFFFAOYSA-N 0.000 description 1
- 102100025573 1-alkyl-2-acetylglycerophosphocholine esterase Human genes 0.000 description 1
- NZVZVGPYTICZBZ-UHFFFAOYSA-N 1-benzylpiperidine Chemical compound C=1C=CC=CC=1CN1CCCCC1 NZVZVGPYTICZBZ-UHFFFAOYSA-N 0.000 description 1
- JRHNUZCXXOTJCA-UHFFFAOYSA-N 1-fluoropropane Chemical compound CCCF JRHNUZCXXOTJCA-UHFFFAOYSA-N 0.000 description 1
- SJJCQDRGABAVBB-UHFFFAOYSA-N 1-hydroxy-2-naphthoic acid Chemical class C1=CC=CC2=C(O)C(C(=O)O)=CC=C21 SJJCQDRGABAVBB-UHFFFAOYSA-N 0.000 description 1
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 1
- IBXNCJKFFQIKKY-UHFFFAOYSA-N 1-pentyne Chemical compound CCCC#C IBXNCJKFFQIKKY-UHFFFAOYSA-N 0.000 description 1
- FRPZMMHWLSIFAZ-UHFFFAOYSA-N 10-undecenoic acid Chemical compound OC(=O)CCCCCCCCC=C FRPZMMHWLSIFAZ-UHFFFAOYSA-N 0.000 description 1
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- HIYWOHBEPVGIQN-UHFFFAOYSA-N 1h-benzo[g]indole Chemical compound C1=CC=CC2=C(NC=C3)C3=CC=C21 HIYWOHBEPVGIQN-UHFFFAOYSA-N 0.000 description 1
- ZVXKYWHJBYIYNI-UHFFFAOYSA-N 1h-pyrazole-4-carboxamide Chemical compound NC(=O)C=1C=NNC=1 ZVXKYWHJBYIYNI-UHFFFAOYSA-N 0.000 description 1
- YJUFGFXVASPYFQ-UHFFFAOYSA-N 2,3-dihydro-1-benzothiophene Chemical compound C1=CC=C2SCCC2=C1 YJUFGFXVASPYFQ-UHFFFAOYSA-N 0.000 description 1
- JKTCBAGSMQIFNL-UHFFFAOYSA-N 2,3-dihydrofuran Chemical compound C1CC=CO1 JKTCBAGSMQIFNL-UHFFFAOYSA-N 0.000 description 1
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 1
- WGIMXKDCVCTHGW-UHFFFAOYSA-N 2-(2-hydroxyethoxy)ethyl dodecanoate Chemical compound CCCCCCCCCCCC(=O)OCCOCCO WGIMXKDCVCTHGW-UHFFFAOYSA-N 0.000 description 1
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- JKNCOURZONDCGV-UHFFFAOYSA-N 2-(dimethylamino)ethyl 2-methylprop-2-enoate Chemical compound CN(C)CCOC(=O)C(C)=C JKNCOURZONDCGV-UHFFFAOYSA-N 0.000 description 1
- FKOKUHFZNIUSLW-UHFFFAOYSA-N 2-Hydroxypropyl stearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(C)O FKOKUHFZNIUSLW-UHFFFAOYSA-N 0.000 description 1
- FEBUJFMRSBAMES-UHFFFAOYSA-N 2-[(2-{[3,5-dihydroxy-2-(hydroxymethyl)-6-phosphanyloxan-4-yl]oxy}-3,5-dihydroxy-6-({[3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}methyl)oxan-4-yl)oxy]-3,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl phosphinite Chemical compound OC1C(O)C(O)C(CO)OC1OCC1C(O)C(OC2C(C(OP)C(O)C(CO)O2)O)C(O)C(OC2C(C(CO)OC(P)C2O)O)O1 FEBUJFMRSBAMES-UHFFFAOYSA-N 0.000 description 1
- WZPBZJONDBGPKJ-VEHQQRBSSA-L 2-[(z)-[1-(2-amino-1,3-thiazol-4-yl)-2-[[(2s,3s)-2-methyl-4-oxo-1-sulfonatoazetidin-3-yl]amino]-2-oxoethylidene]amino]oxy-2-methylpropanoate Chemical compound O=C1N(S([O-])(=O)=O)[C@@H](C)[C@@H]1NC(=O)C(=N/OC(C)(C)C([O-])=O)\C1=CSC(N)=N1 WZPBZJONDBGPKJ-VEHQQRBSSA-L 0.000 description 1
- CFWRDBDJAOHXSH-SECBINFHSA-N 2-azaniumylethyl [(2r)-2,3-diacetyloxypropyl] phosphate Chemical compound CC(=O)OC[C@@H](OC(C)=O)COP(O)(=O)OCCN CFWRDBDJAOHXSH-SECBINFHSA-N 0.000 description 1
- JRMAQQQTXDJDNC-UHFFFAOYSA-N 2-ethoxy-2-oxoacetic acid Chemical compound CCOC(=O)C(O)=O JRMAQQQTXDJDNC-UHFFFAOYSA-N 0.000 description 1
- QTWJRLJHJPIABL-UHFFFAOYSA-N 2-methylphenol;3-methylphenol;4-methylphenol Chemical compound CC1=CC=C(O)C=C1.CC1=CC=CC(O)=C1.CC1=CC=CC=C1O QTWJRLJHJPIABL-UHFFFAOYSA-N 0.000 description 1
- SSONCJTVDRSLNK-UHFFFAOYSA-N 2-methylprop-2-enoic acid;hydrochloride Chemical compound Cl.CC(=C)C(O)=O SSONCJTVDRSLNK-UHFFFAOYSA-N 0.000 description 1
- ODJHDETXUHRFSM-UHFFFAOYSA-N 2-n,2-n,4-n,4-n,6-n,6-n-hexamethyl-1,3,5-triazine-2,4,6-triamine Chemical compound CN(C)C1=NC(N(C)C)=NC(N(C)C)=N1.CN(C)C1=NC(N(C)C)=NC(N(C)C)=N1 ODJHDETXUHRFSM-UHFFFAOYSA-N 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- PTJMMKCYKMOEPV-UHFFFAOYSA-N 2-phenylpteridine Chemical compound C1=CC=CC=C1C1=NC=C(N=CC=N2)C2=N1 PTJMMKCYKMOEPV-UHFFFAOYSA-N 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- RSEBUVRVKCANEP-UHFFFAOYSA-N 2-pyrroline Chemical compound C1CC=CN1 RSEBUVRVKCANEP-UHFFFAOYSA-N 0.000 description 1
- UJVBZCCNLAAMOV-UHFFFAOYSA-N 2h-1,2-benzothiazine Chemical compound C1=CC=C2C=CNSC2=C1 UJVBZCCNLAAMOV-UHFFFAOYSA-N 0.000 description 1
- UMZCLZPXPCNKML-UHFFFAOYSA-N 2h-imidazo[4,5-d][1,3]thiazole Chemical compound C1=NC2=NCSC2=N1 UMZCLZPXPCNKML-UHFFFAOYSA-N 0.000 description 1
- ONJRTQUWKRDCTA-UHFFFAOYSA-N 2h-thiochromene Chemical compound C1=CC=C2C=CCSC2=C1 ONJRTQUWKRDCTA-UHFFFAOYSA-N 0.000 description 1
- ODJQKYXPKWQWNK-UHFFFAOYSA-N 3,3'-Thiobispropanoic acid Chemical compound OC(=O)CCSCCC(O)=O ODJQKYXPKWQWNK-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
- UOQHWNPVNXSDDO-UHFFFAOYSA-N 3-bromoimidazo[1,2-a]pyridine-6-carbonitrile Chemical compound C1=CC(C#N)=CN2C(Br)=CN=C21 UOQHWNPVNXSDDO-UHFFFAOYSA-N 0.000 description 1
- 125000006201 3-phenylpropyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 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 1
- NZAQRZWBQUIBSF-UHFFFAOYSA-N 4-(4-sulfobutoxy)butane-1-sulfonic acid Chemical compound OS(=O)(=O)CCCCOCCCCS(O)(=O)=O NZAQRZWBQUIBSF-UHFFFAOYSA-N 0.000 description 1
- ASNHGEVAWNWCRQ-UHFFFAOYSA-N 4-(hydroxymethyl)oxolane-2,3,4-triol Chemical compound OCC1(O)COC(O)C1O ASNHGEVAWNWCRQ-UHFFFAOYSA-N 0.000 description 1
- QCXJEYYXVJIFCE-UHFFFAOYSA-N 4-acetamidobenzoic acid Chemical class CC(=O)NC1=CC=C(C(O)=O)C=C1 QCXJEYYXVJIFCE-UHFFFAOYSA-N 0.000 description 1
- WRFYIYOXJWKONR-UHFFFAOYSA-N 4-bromo-2-methoxyaniline Chemical compound COC1=CC(Br)=CC=C1N WRFYIYOXJWKONR-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 description 1
- GEVILTWPAPSGDK-UHFFFAOYSA-N 4-hydroxy-2,3-dimethylbenzaldehyde Chemical class CC1=C(C)C(C=O)=CC=C1O GEVILTWPAPSGDK-UHFFFAOYSA-N 0.000 description 1
- RGHHSNMVTDWUBI-UHFFFAOYSA-N 4-hydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C=C1 RGHHSNMVTDWUBI-UHFFFAOYSA-N 0.000 description 1
- FHQRDEDZJIFJAL-UHFFFAOYSA-N 4-phenylmorpholine Chemical compound C1COCCN1C1=CC=CC=C1 FHQRDEDZJIFJAL-UHFFFAOYSA-N 0.000 description 1
- STWODXDTKGTVCJ-UHFFFAOYSA-N 4-pyrrolidin-1-ylpiperidine Chemical class C1CCCN1C1CCNCC1 STWODXDTKGTVCJ-UHFFFAOYSA-N 0.000 description 1
- YUCINKYUVOIMER-UHFFFAOYSA-N 5-hydroxy-2-methylpentanoic acid Chemical compound OC(=O)C(C)CCCO YUCINKYUVOIMER-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- GHUXAYLZEGLXDA-UHFFFAOYSA-N 8-azido-5-ethyl-6-phenylphenanthridin-5-ium-3-amine;bromide Chemical compound [Br-].C12=CC(N=[N+]=[N-])=CC=C2C2=CC=C(N)C=C2[N+](CC)=C1C1=CC=CC=C1 GHUXAYLZEGLXDA-UHFFFAOYSA-N 0.000 description 1
- GJCOSYZMQJWQCA-UHFFFAOYSA-N 9H-xanthene Chemical compound C1=CC=C2CC3=CC=CC=C3OC2=C1 GJCOSYZMQJWQCA-UHFFFAOYSA-N 0.000 description 1
- 239000005541 ACE inhibitor Substances 0.000 description 1
- OZAIFHULBGXAKX-VAWYXSNFSA-N AIBN Substances N#CC(C)(C)\N=N\C(C)(C)C#N OZAIFHULBGXAKX-VAWYXSNFSA-N 0.000 description 1
- 102000015936 AP-1 transcription factor Human genes 0.000 description 1
- 108050004195 AP-1 transcription factor Proteins 0.000 description 1
- 240000000073 Achillea millefolium Species 0.000 description 1
- 235000007754 Achillea millefolium Nutrition 0.000 description 1
- 206010058284 Allergy to arthropod sting Diseases 0.000 description 1
- 229920001450 Alpha-Cyclodextrin Polymers 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 229920000856 Amylose Polymers 0.000 description 1
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- 206010002329 Aneurysm Diseases 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- WZPBZJONDBGPKJ-UHFFFAOYSA-N Antibiotic SQ 26917 Natural products O=C1N(S(O)(=O)=O)C(C)C1NC(=O)C(=NOC(C)(C)C(O)=O)C1=CSC(N)=N1 WZPBZJONDBGPKJ-UHFFFAOYSA-N 0.000 description 1
- 108010024976 Asparaginase Proteins 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 239000005552 B01AC04 - Clopidogrel Substances 0.000 description 1
- XNCOSPRUTUOJCJ-UHFFFAOYSA-N Biguanide Chemical compound NC(N)=NC(N)=N XNCOSPRUTUOJCJ-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- BRAIZMGEVOORLF-UHFFFAOYSA-N C1CSCC(N1O)O Chemical compound C1CSCC(N1O)O BRAIZMGEVOORLF-UHFFFAOYSA-N 0.000 description 1
- 125000006519 CCH3 Chemical group 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 239000005632 Capric acid (CAS 334-48-5) Substances 0.000 description 1
- 235000008534 Capsicum annuum var annuum Nutrition 0.000 description 1
- 240000008384 Capsicum annuum var. annuum Species 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 208000017897 Carcinoma of esophagus Diseases 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- 208000031229 Cardiomyopathies Diseases 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 229920001747 Cellulose diacetate Polymers 0.000 description 1
- 229920002284 Cellulose triacetate Polymers 0.000 description 1
- 206010008190 Cerebrovascular accident Diseases 0.000 description 1
- 241001227713 Chiron Species 0.000 description 1
- 229920002101 Chitin Polymers 0.000 description 1
- 239000004709 Chlorinated polyethylene Substances 0.000 description 1
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 1
- UDKCHVLMFQVBAA-UHFFFAOYSA-M Choline salicylate Chemical compound C[N+](C)(C)CCO.OC1=CC=CC=C1C([O-])=O UDKCHVLMFQVBAA-UHFFFAOYSA-M 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 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
- 241000207199 Citrus Species 0.000 description 1
- 108010078777 Colistin Proteins 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- PQMOXTJVIYEOQL-UHFFFAOYSA-N Cumarin Natural products CC(C)=CCC1=C(O)C(C(=O)C(C)CC)=C(O)C2=C1OC(=O)C=C2CCC PQMOXTJVIYEOQL-UHFFFAOYSA-N 0.000 description 1
- 244000050510 Cunninghamia lanceolata Species 0.000 description 1
- 229930105110 Cyclosporin A Natural products 0.000 description 1
- 201000003883 Cystic fibrosis Diseases 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- DSLZVSRJTYRBFB-LLEIAEIESA-N D-glucaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O DSLZVSRJTYRBFB-LLEIAEIESA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical class OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 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 1
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- 108010092160 Dactinomycin Proteins 0.000 description 1
- 206010048768 Dermatosis Diseases 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- ZDQWESQEGGJUCH-UHFFFAOYSA-N Diisopropyl adipate Chemical compound CC(C)OC(=O)CCCCC(=O)OC(C)C ZDQWESQEGGJUCH-UHFFFAOYSA-N 0.000 description 1
- 241000522215 Dipteryx odorata Species 0.000 description 1
- 206010013700 Drug hypersensitivity Diseases 0.000 description 1
- 102100031480 Dual specificity mitogen-activated protein kinase kinase 1 Human genes 0.000 description 1
- 101710146526 Dual specificity mitogen-activated protein kinase kinase 1 Proteins 0.000 description 1
- 206010013980 Dyssomnias Diseases 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 208000005189 Embolism Diseases 0.000 description 1
- 241000792859 Enema Species 0.000 description 1
- 208000004232 Enteritis Diseases 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- 208000010228 Erectile Dysfunction Diseases 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- 240000001624 Espostoa lanata Species 0.000 description 1
- 235000009161 Espostoa lanata Nutrition 0.000 description 1
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 239000001263 FEMA 3042 Substances 0.000 description 1
- 229940082863 Factor VIIa inhibitor Drugs 0.000 description 1
- 229940123583 Factor Xa inhibitor Drugs 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 102000009123 Fibrin Human genes 0.000 description 1
- 108010073385 Fibrin Proteins 0.000 description 1
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 240000006927 Foeniculum vulgare Species 0.000 description 1
- 235000004204 Foeniculum vulgare Nutrition 0.000 description 1
- 108700012941 GNRH1 Proteins 0.000 description 1
- DSLZVSRJTYRBFB-UHFFFAOYSA-N Galactaric acid Natural products OC(=O)C(O)C(O)C(O)C(O)C(O)=O DSLZVSRJTYRBFB-UHFFFAOYSA-N 0.000 description 1
- 208000007882 Gastritis Diseases 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 description 1
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 1
- 229930182566 Gentamicin Natural products 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 239000000579 Gonadotropin-Releasing Hormone Substances 0.000 description 1
- 102000009465 Growth Factor Receptors Human genes 0.000 description 1
- 108010009202 Growth Factor Receptors Proteins 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000950669 Homo sapiens Mitogen-activated protein kinase 9 Proteins 0.000 description 1
- 101001018145 Homo sapiens Mitogen-activated protein kinase kinase kinase 3 Proteins 0.000 description 1
- 101001050288 Homo sapiens Transcription factor Jun Proteins 0.000 description 1
- 101000997835 Homo sapiens Tyrosine-protein kinase JAK1 Proteins 0.000 description 1
- WOBHKFSMXKNTIM-UHFFFAOYSA-N Hydroxyethyl methacrylate Chemical compound CC(=C)C(=O)OCCO WOBHKFSMXKNTIM-UHFFFAOYSA-N 0.000 description 1
- SHBUUTHKGIVMJT-UHFFFAOYSA-N Hydroxystearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OO SHBUUTHKGIVMJT-UHFFFAOYSA-N 0.000 description 1
- VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 description 1
- 206010061216 Infarction Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 102100025306 Integrin alpha-IIb Human genes 0.000 description 1
- 101710149643 Integrin alpha-IIb Proteins 0.000 description 1
- JUZNIMUFDBIJCM-ANEDZVCMSA-N Invanz Chemical compound O=C([C@H]1NC[C@H](C1)SC=1[C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)NC1=CC=CC(C(O)=O)=C1 JUZNIMUFDBIJCM-ANEDZVCMSA-N 0.000 description 1
- 108010055717 JNK Mitogen-Activated Protein Kinases Proteins 0.000 description 1
- 102000019145 JUN kinase activity proteins Human genes 0.000 description 1
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 1
- 150000008537 L-aspartic acids Chemical class 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-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
- 239000004166 Lanolin Substances 0.000 description 1
- 241000218652 Larix Species 0.000 description 1
- 235000005590 Larix decidua Nutrition 0.000 description 1
- GSDSWSVVBLHKDQ-JTQLQIEISA-N Levofloxacin Chemical compound C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-JTQLQIEISA-N 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
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 108090000856 Lyases Proteins 0.000 description 1
- 102000004317 Lyases Human genes 0.000 description 1
- 241000195947 Lycopodium Species 0.000 description 1
- 229940124647 MEK inhibitor Drugs 0.000 description 1
- 239000005913 Maltodextrin Substances 0.000 description 1
- 229920002774 Maltodextrin Polymers 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 240000003183 Manihot esculenta Species 0.000 description 1
- 235000016735 Manihot esculenta subsp esculenta Nutrition 0.000 description 1
- 244000246386 Mentha pulegium Species 0.000 description 1
- 235000016257 Mentha pulegium Nutrition 0.000 description 1
- 235000004357 Mentha x piperita Nutrition 0.000 description 1
- FSOGIJPGPZWNGO-UHFFFAOYSA-N Meomammein Natural products CCC(C)C(=O)C1=C(O)C(CC=C(C)C)=C(O)C2=C1OC(=O)C=C2CCC FSOGIJPGPZWNGO-UHFFFAOYSA-N 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 1
- 229940119336 Microtubule stabilizer Drugs 0.000 description 1
- 102100037809 Mitogen-activated protein kinase 9 Human genes 0.000 description 1
- 102100033059 Mitogen-activated protein kinase kinase kinase 3 Human genes 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- UEEJHVSXFDXPFK-UHFFFAOYSA-N N-dimethylaminoethanol Chemical compound CN(C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical class CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- QRUSQHMPERFEKU-UHFFFAOYSA-N N1C(=CC=C1)C(=N)N.[Cl] Chemical compound N1C(=CC=C1)C(=N)N.[Cl] QRUSQHMPERFEKU-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 229930193140 Neomycin Natural products 0.000 description 1
- 244000061176 Nicotiana tabacum Species 0.000 description 1
- 235000002637 Nicotiana tabacum Nutrition 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 239000000020 Nitrocellulose Substances 0.000 description 1
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 description 1
- 208000011623 Obstructive Lung disease Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 241001416149 Ovis ammon Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 239000002033 PVDF binder Substances 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 206010033645 Pancreatitis Diseases 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- 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 description 1
- LRBQNJMCXXYXIU-PPKXGCFTSA-N Penta-digallate-beta-D-glucose Natural products OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@@H]2[C@H]([C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-PPKXGCFTSA-N 0.000 description 1
- 241000009328 Perro Species 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
- 241000255964 Pieridae Species 0.000 description 1
- 235000008331 Pinus X rigitaeda Nutrition 0.000 description 1
- 235000011613 Pinus brutia Nutrition 0.000 description 1
- 241000018646 Pinus brutia Species 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000004952 Polyamide Substances 0.000 description 1
- 108010093965 Polymyxin B Proteins 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- CYLWJCABXYDINA-UHFFFAOYSA-N Polythiazide Polymers ClC1=C(S(N)(=O)=O)C=C2S(=O)(=O)N(C)C(CSCC(F)(F)F)NC2=C1 CYLWJCABXYDINA-UHFFFAOYSA-N 0.000 description 1
- 229940127315 Potassium Channel Openers Drugs 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical class 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 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 239000004373 Pullulan Substances 0.000 description 1
- 229920001218 Pullulan Polymers 0.000 description 1
- KDCGOANMDULRCW-UHFFFAOYSA-N Purine Natural products N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 108090000783 Renin Proteins 0.000 description 1
- 102100028255 Renin Human genes 0.000 description 1
- 240000000528 Ricinus communis Species 0.000 description 1
- 235000004443 Ricinus communis Nutrition 0.000 description 1
- 235000019485 Safflower oil Nutrition 0.000 description 1
- 229920002305 Schizophyllan Polymers 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 239000004147 Sorbitan trioleate Substances 0.000 description 1
- PRXRUNOAOLTIEF-ADSICKODSA-N Sorbitan trioleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCC\C=C/CCCCCCCC)[C@H]1OC[C@H](O)[C@H]1OC(=O)CCCCCCC\C=C/CCCCCCCC PRXRUNOAOLTIEF-ADSICKODSA-N 0.000 description 1
- PFNFFQXMRSDOHW-UHFFFAOYSA-N Spermine Natural products NCCCNCCCCNCCCN PFNFFQXMRSDOHW-UHFFFAOYSA-N 0.000 description 1
- 241000934878 Sterculia Species 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 235000019486 Sunflower oil Nutrition 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 239000012317 TBTU Substances 0.000 description 1
- 108010039185 Tenecteplase Proteins 0.000 description 1
- 208000024313 Testicular Neoplasms Diseases 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- 229940123464 Thiazolidinedione Drugs 0.000 description 1
- 239000003490 Thiodipropionic acid Substances 0.000 description 1
- 108090000190 Thrombin Proteins 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 102100028509 Transcription factor IIIA Human genes 0.000 description 1
- 102100023132 Transcription factor Jun Human genes 0.000 description 1
- 208000030886 Traumatic Brain injury Diseases 0.000 description 1
- FNYLWPVRPXGIIP-UHFFFAOYSA-N Triamterene Chemical compound NC1=NC2=NC(N)=NC(N)=C2N=C1C1=CC=CC=C1 FNYLWPVRPXGIIP-UHFFFAOYSA-N 0.000 description 1
- 102100040247 Tumor necrosis factor Human genes 0.000 description 1
- 102100033438 Tyrosine-protein kinase JAK1 Human genes 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 206010052568 Urticaria chronic Diseases 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 208000002495 Uterine Neoplasms Diseases 0.000 description 1
- 108010059993 Vancomycin Proteins 0.000 description 1
- 206010047115 Vasculitis Diseases 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- NNLVGZFZQQXQNW-ADJNRHBOSA-N [(2r,3r,4s,5r,6s)-4,5-diacetyloxy-3-[(2s,3r,4s,5r,6r)-3,4,5-triacetyloxy-6-(acetyloxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6s)-4,5,6-triacetyloxy-2-(acetyloxymethyl)oxan-3-yl]oxyoxan-2-yl]methyl acetate Chemical compound O([C@@H]1O[C@@H]([C@H]([C@H](OC(C)=O)[C@H]1OC(C)=O)O[C@H]1[C@@H]([C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](COC(C)=O)O1)OC(C)=O)COC(=O)C)[C@@H]1[C@@H](COC(C)=O)O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O NNLVGZFZQQXQNW-ADJNRHBOSA-N 0.000 description 1
- MIOPJNTWMNEORI-OMNKOJBGSA-N [(4s)-7,7-dimethyl-3-oxo-4-bicyclo[2.2.1]heptanyl]methanesulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-OMNKOJBGSA-N 0.000 description 1
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 1
- KIPLYOUQVMMOHB-MXWBXKMOSA-L [Ca++].CN(C)[C@H]1[C@@H]2[C@@H](O)[C@H]3C(=C([O-])[C@]2(O)C(=O)C(C(N)=O)=C1O)C(=O)c1c(O)cccc1[C@@]3(C)O.CN(C)[C@H]1[C@@H]2[C@@H](O)[C@H]3C(=C([O-])[C@]2(O)C(=O)C(C(N)=O)=C1O)C(=O)c1c(O)cccc1[C@@]3(C)O Chemical compound [Ca++].CN(C)[C@H]1[C@@H]2[C@@H](O)[C@H]3C(=C([O-])[C@]2(O)C(=O)C(C(N)=O)=C1O)C(=O)c1c(O)cccc1[C@@]3(C)O.CN(C)[C@H]1[C@@H]2[C@@H](O)[C@H]3C(=C([O-])[C@]2(O)C(=O)C(C(N)=O)=C1O)C(=O)c1c(O)cccc1[C@@]3(C)O KIPLYOUQVMMOHB-MXWBXKMOSA-L 0.000 description 1
- IGHDQTAJLOFGMR-UHFFFAOYSA-N [S].N1=CC=CC2=CC=CC=C21 Chemical compound [S].N1=CC=CC2=CC=CC=C21 IGHDQTAJLOFGMR-UHFFFAOYSA-N 0.000 description 1
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 1
- 239000003082 abrasive agent Substances 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 229960002632 acarbose Drugs 0.000 description 1
- XUFXOAAUWZOOIT-UHFFFAOYSA-N acarviostatin I01 Natural products OC1C(O)C(NC2C(C(O)C(O)C(CO)=C2)O)C(C)OC1OC(C(C1O)O)C(CO)OC1OC1C(CO)OC(O)C(O)C1O XUFXOAAUWZOOIT-UHFFFAOYSA-N 0.000 description 1
- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 description 1
- LCJHLOJKAAQLQW-UHFFFAOYSA-N acetic acid;ethane Chemical compound CC.CC(O)=O LCJHLOJKAAQLQW-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- ODHCTXKNWHHXJC-UHFFFAOYSA-N acide pyroglutamique Natural products OC(=O)C1CCC(=O)N1 ODHCTXKNWHHXJC-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 description 1
- BAPJBEWLBFYGME-UHFFFAOYSA-N acrylic acid methyl ester Natural products COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 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
- 230000003213 activating effect Effects 0.000 description 1
- 230000013564 activation of immune response Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 210000000593 adipose tissue white Anatomy 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical class O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 description 1
- 125000004450 alkenylene group Chemical group 0.000 description 1
- 125000005257 alkyl acyl group Chemical group 0.000 description 1
- 150000008052 alkyl sulfonates Chemical class 0.000 description 1
- 125000001118 alkylidene group Chemical group 0.000 description 1
- 208000002029 allergic contact dermatitis Diseases 0.000 description 1
- 208000030961 allergic reaction Diseases 0.000 description 1
- HFHDHCJBZVLPGP-RWMJIURBSA-N alpha-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO HFHDHCJBZVLPGP-RWMJIURBSA-N 0.000 description 1
- 229940043377 alpha-cyclodextrin Drugs 0.000 description 1
- OBETXYAYXDNJHR-UHFFFAOYSA-N alpha-ethylcaproic acid Natural products CCCCC(CC)C(O)=O OBETXYAYXDNJHR-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
- 229960003318 alteplase Drugs 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- XSDQTOBWRPYKKA-UHFFFAOYSA-N amiloride Chemical compound NC(=N)NC(=O)C1=NC(Cl)=C(N)N=C1N XSDQTOBWRPYKKA-UHFFFAOYSA-N 0.000 description 1
- 229960002576 amiloride Drugs 0.000 description 1
- ZPBWCRDSRKPIDG-UHFFFAOYSA-N amlodipine benzenesulfonate Chemical compound OS(=O)(=O)C1=CC=CC=C1.CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl ZPBWCRDSRKPIDG-UHFFFAOYSA-N 0.000 description 1
- 229960004005 amlodipine besylate Drugs 0.000 description 1
- 238000004176 ammonification Methods 0.000 description 1
- 239000002280 amphoteric surfactant Substances 0.000 description 1
- 229960000723 ampicillin Drugs 0.000 description 1
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000002052 anaphylactic effect Effects 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 239000003098 androgen Substances 0.000 description 1
- 229940011037 anethole Drugs 0.000 description 1
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 1
- 239000003945 anionic surfactant Substances 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000002280 anti-androgenic effect Effects 0.000 description 1
- 230000000879 anti-atherosclerotic effect Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 229940046836 anti-estrogen Drugs 0.000 description 1
- 230000001833 anti-estrogenic effect Effects 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 239000000051 antiandrogen Substances 0.000 description 1
- 230000010100 anticoagulation Effects 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940045719 antineoplastic alkylating agent nitrosoureas Drugs 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 229940003446 arsphenamine Drugs 0.000 description 1
- 239000008122 artificial sweetener Substances 0.000 description 1
- 239000010425 asbestos Substances 0.000 description 1
- 239000000305 astragalus gummifer gum Substances 0.000 description 1
- 229960002170 azathioprine Drugs 0.000 description 1
- 229960003644 aztreonam Drugs 0.000 description 1
- 125000003828 azulenyl group Chemical group 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 229960004495 beclometasone Drugs 0.000 description 1
- 229960003515 bendroflumethiazide Drugs 0.000 description 1
- HDWIHXWEUNVBIY-UHFFFAOYSA-N bendroflumethiazidum Chemical compound C1=C(C(F)(F)F)C(S(=O)(=O)N)=CC(S(N2)(=O)=O)=C1NC2CC1=CC=CC=C1 HDWIHXWEUNVBIY-UHFFFAOYSA-N 0.000 description 1
- UPABQMWFWCMOFV-UHFFFAOYSA-N benethamine Chemical compound C=1C=CC=CC=1CNCCC1=CC=CC=C1 UPABQMWFWCMOFV-UHFFFAOYSA-N 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
- ZSDJVGXBJDDOCD-UHFFFAOYSA-N benzene dioctyl benzene-1,2-dicarboxylate Chemical group C(C=1C(C(=O)OCCCCCCCC)=CC=CC1)(=O)OCCCCCCCC.C1=CC=CC=C1 ZSDJVGXBJDDOCD-UHFFFAOYSA-N 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 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
- 229960001950 benzethonium chloride Drugs 0.000 description 1
- UREZNYTWGJKWBI-UHFFFAOYSA-M benzethonium chloride Chemical compound [Cl-].C1=CC(C(C)(C)CC(C)(C)C)=CC=C1OCCOCC[N+](C)(C)CC1=CC=CC=C1 UREZNYTWGJKWBI-UHFFFAOYSA-M 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- BNBQRQQYDMDJAH-UHFFFAOYSA-N benzodioxan Chemical compound C1=CC=C2OCCOC2=C1 BNBQRQQYDMDJAH-UHFFFAOYSA-N 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004619 benzopyranyl group Chemical group O1C(C=CC2=C1C=CC=C2)* 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 1
- 125000004622 benzoxazinyl group Chemical group O1NC(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- NDTSRXAMMQDVSW-UHFFFAOYSA-N benzthiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(S(N2)(=O)=O)=C1N=C2CSCC1=CC=CC=C1 NDTSRXAMMQDVSW-UHFFFAOYSA-N 0.000 description 1
- 229960001541 benzthiazide Drugs 0.000 description 1
- 229960002903 benzyl benzoate Drugs 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- 108010051210 beta-Fructofuranosidase Proteins 0.000 description 1
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 1
- ITQTTZVARXURQS-UHFFFAOYSA-N beta-methylpyridine Natural products CC1=CC=CN=C1 ITQTTZVARXURQS-UHFFFAOYSA-N 0.000 description 1
- 150000004283 biguanides Chemical class 0.000 description 1
- 229920000080 bile acid sequestrant Polymers 0.000 description 1
- 229910002056 binary alloy Inorganic materials 0.000 description 1
- 230000035587 bioadhesion Effects 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 201000001531 bladder carcinoma Diseases 0.000 description 1
- 229960001561 bleomycin Drugs 0.000 description 1
- 239000002981 blocking agent Substances 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 229940046011 buccal tablet Drugs 0.000 description 1
- 239000006189 buccal tablet Substances 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 0.000 description 1
- QDHFHIQKOVNCNC-UHFFFAOYSA-N butane-1-sulfonic acid Chemical compound CCCCS(O)(=O)=O QDHFHIQKOVNCNC-UHFFFAOYSA-N 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
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- LSPHULWDVZXLIL-QUBYGPBYSA-N camphoric acid Chemical compound CC1(C)[C@H](C(O)=O)CC[C@]1(C)C(O)=O LSPHULWDVZXLIL-QUBYGPBYSA-N 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 235000013877 carbamide Nutrition 0.000 description 1
- DKVNPHBNOWQYFE-UHFFFAOYSA-N carbamodithioic acid Chemical compound NC(S)=S DKVNPHBNOWQYFE-UHFFFAOYSA-N 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 229960003669 carbenicillin Drugs 0.000 description 1
- FPPNZSSZRUTDAP-UWFZAAFLSA-N carbenicillin Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)C(C(O)=O)C1=CC=CC=C1 FPPNZSSZRUTDAP-UWFZAAFLSA-N 0.000 description 1
- 238000003763 carbonization Methods 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 229940063834 carboxymethylcellulose sodium Drugs 0.000 description 1
- 239000004203 carnauba wax Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003729 cation exchange resin Substances 0.000 description 1
- 239000003093 cationic surfactant Substances 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 229960004841 cefadroxil Drugs 0.000 description 1
- NBFNMSULHIODTC-CYJZLJNKSA-N cefadroxil monohydrate Chemical compound O.C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CC=C(O)C=C1 NBFNMSULHIODTC-CYJZLJNKSA-N 0.000 description 1
- AFZFFLVORLEPPO-UVYJNCLZSA-N cefditoren pivoxil Chemical compound S([C@@H]1[C@@H](C(N1C=1C(=O)OCOC(=O)C(C)(C)C)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1\C=C/C=1SC=NC=1C AFZFFLVORLEPPO-UVYJNCLZSA-N 0.000 description 1
- HVFLCNVBZFFHBT-ZKDACBOMSA-N cefepime Chemical compound S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1C[N+]1(C)CCCC1 HVFLCNVBZFFHBT-ZKDACBOMSA-N 0.000 description 1
- 229960002100 cefepime Drugs 0.000 description 1
- 229960000484 ceftazidime Drugs 0.000 description 1
- NMVPEQXCMGEDNH-TZVUEUGBSA-N ceftazidime pentahydrate Chemical compound O.O.O.O.O.S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OC(C)(C)C(O)=O)C=2N=C(N)SC=2)CC=1C[N+]1=CC=CC=C1 NMVPEQXCMGEDNH-TZVUEUGBSA-N 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000004637 cellular stress Effects 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 210000000038 chest Anatomy 0.000 description 1
- 230000001055 chewing effect Effects 0.000 description 1
- 229940112822 chewing gum Drugs 0.000 description 1
- 235000015218 chewing gum Nutrition 0.000 description 1
- 229960005091 chloramphenicol Drugs 0.000 description 1
- WIIZWVCIJKGZOK-RKDXNWHRSA-N chloramphenicol Chemical compound ClC(Cl)C(=O)N[C@H](CO)[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 WIIZWVCIJKGZOK-RKDXNWHRSA-N 0.000 description 1
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960002688 choline salicylate Drugs 0.000 description 1
- 125000003016 chromanyl group Chemical group O1C(CCC2=CC=CC=C12)* 0.000 description 1
- OTAFHZMPRISVEM-UHFFFAOYSA-N chromone Chemical compound C1=CC=C2C(=O)C=COC2=C1 OTAFHZMPRISVEM-UHFFFAOYSA-N 0.000 description 1
- 208000024376 chronic urticaria Diseases 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 125000000259 cinnolinyl group Chemical class N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 235000020971 citrus fruits Nutrition 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- 239000004927 clay Substances 0.000 description 1
- 229960002227 clindamycin Drugs 0.000 description 1
- KDLRVYVGXIQJDK-AWPVFWJPSA-N clindamycin Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@H](C)Cl)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 KDLRVYVGXIQJDK-AWPVFWJPSA-N 0.000 description 1
- GKTWGGQPFAXNFI-HNNXBMFYSA-N clopidogrel Chemical compound C1([C@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl GKTWGGQPFAXNFI-HNNXBMFYSA-N 0.000 description 1
- 229960003009 clopidogrel Drugs 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 229960003346 colistin Drugs 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 210000000795 conjunctiva Anatomy 0.000 description 1
- 208000018631 connective tissue disease Diseases 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 239000003433 contraceptive agent Substances 0.000 description 1
- 230000002254 contraceptive effect Effects 0.000 description 1
- 210000004087 cornea Anatomy 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- ZYGHJZDHTFUPRJ-UHFFFAOYSA-N coumarin Chemical compound C1=CC=C2OC(=O)C=CC2=C1 ZYGHJZDHTFUPRJ-UHFFFAOYSA-N 0.000 description 1
- 229930003836 cresol Natural products 0.000 description 1
- 150000001896 cresols Chemical class 0.000 description 1
- 229960005168 croscarmellose Drugs 0.000 description 1
- 229960000913 crospovidone Drugs 0.000 description 1
- 229920006037 cross link polymer Polymers 0.000 description 1
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- DGJMPUGMZIKDRO-UHFFFAOYSA-N cyanoacetamide Chemical class NC(=O)CC#N DGJMPUGMZIKDRO-UHFFFAOYSA-N 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000001047 cyclobutenyl group Chemical group C1(=CCC1)* 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000003678 cyclohexadienyl group Chemical group C1(=CC=CCC1)* 0.000 description 1
- VBWIZSYFQSOUFQ-UHFFFAOYSA-N cyclohexanecarbonitrile Chemical compound N#CC1CCCCC1 VBWIZSYFQSOUFQ-UHFFFAOYSA-N 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
- HCAJEUSONLESMK-UHFFFAOYSA-N cyclohexylsulfamic acid Chemical compound OS(=O)(=O)NC1CCCCC1 HCAJEUSONLESMK-UHFFFAOYSA-N 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 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
- 231100000599 cytotoxic agent Toxicity 0.000 description 1
- 229960000640 dactinomycin Drugs 0.000 description 1
- 229960002887 deanol Drugs 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000008356 dextrose and sodium chloride injection Substances 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- TXCDCPKCNAJMEE-UHFFFAOYSA-N dibenzofuran Chemical group C1=CC=C2C3=CC=CC=C3OC2=C1 TXCDCPKCNAJMEE-UHFFFAOYSA-N 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 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
- 208000010643 digestive system disease Diseases 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- 150000004683 dihydrates Chemical class 0.000 description 1
- 125000004611 dihydroisoindolyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 description 1
- 125000005043 dihydropyranyl group Chemical group O1C(CCC=C1)* 0.000 description 1
- 125000005052 dihydropyrazolyl group Chemical group N1(NCC=C1)* 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 229940113088 dimethylacetamide Drugs 0.000 description 1
- 239000012972 dimethylethanolamine Substances 0.000 description 1
- OBISXEJSEGNNKL-UHFFFAOYSA-N dinitrogen-n-sulfide Chemical compound [N-]=[N+]=S OBISXEJSEGNNKL-UHFFFAOYSA-N 0.000 description 1
- 125000005879 dioxolanyl group Chemical group 0.000 description 1
- 238000003618 dip coating Methods 0.000 description 1
- WEHWNAOGRSTTBQ-UHFFFAOYSA-N dipropylamine Chemical compound CCCNCCC WEHWNAOGRSTTBQ-UHFFFAOYSA-N 0.000 description 1
- 229940120889 dipyrone Drugs 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000012990 dithiocarbamate Substances 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- POULHZVOKOAJMA-UHFFFAOYSA-M dodecanoate Chemical compound CCCCCCCCCCCC([O-])=O POULHZVOKOAJMA-UHFFFAOYSA-M 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 201000005311 drug allergy Diseases 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 238000010410 dusting Methods 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 230000005611 electricity Effects 0.000 description 1
- 238000005370 electroosmosis Methods 0.000 description 1
- 238000004520 electroporation Methods 0.000 description 1
- 239000003974 emollient agent Substances 0.000 description 1
- 238000004945 emulsification Methods 0.000 description 1
- 238000003821 enantio-separation Methods 0.000 description 1
- 239000007920 enema Substances 0.000 description 1
- 229940095399 enema Drugs 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 239000002662 enteric coated tablet Substances 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- HESCAJZNRMSMJG-KKQRBIROSA-N epothilone A Chemical class C/C([C@@H]1C[C@@H]2O[C@@H]2CCC[C@@H]([C@@H]([C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1)O)C)=C\C1=CSC(C)=N1 HESCAJZNRMSMJG-KKQRBIROSA-N 0.000 description 1
- 150000003883 epothilone derivatives Chemical class 0.000 description 1
- 229960002770 ertapenem Drugs 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 229960003276 erythromycin Drugs 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- 239000000328 estrogen antagonist Substances 0.000 description 1
- 229960000285 ethambutol Drugs 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
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- CGPRUXZTHGTMKW-UHFFFAOYSA-N ethene;ethyl prop-2-enoate Chemical compound C=C.CCOC(=O)C=C CGPRUXZTHGTMKW-UHFFFAOYSA-N 0.000 description 1
- QHZOMAXECYYXGP-UHFFFAOYSA-N ethene;prop-2-enoic acid Chemical compound C=C.OC(=O)C=C QHZOMAXECYYXGP-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- KWBIXTIBYFUAGV-UHFFFAOYSA-N ethylcarbamic acid Chemical compound CCNC(O)=O KWBIXTIBYFUAGV-UHFFFAOYSA-N 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 208000030533 eye disease Diseases 0.000 description 1
- 125000004030 farnesyl group Chemical group [H]C([*])([H])C([H])=C(C([H])([H])[H])C([H])([H])C([H])([H])C([H])=C(C([H])([H])[H])C([H])([H])C([H])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 229950003499 fibrin Drugs 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 229940063190 flagyl Drugs 0.000 description 1
- AAXVEMMRQDVLJB-BULBTXNYSA-N fludrocortisone Chemical compound O=C1CC[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 AAXVEMMRQDVLJB-BULBTXNYSA-N 0.000 description 1
- 229960002011 fludrocortisone Drugs 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 238000003682 fluorination reaction Methods 0.000 description 1
- 125000001207 fluorophenyl group Chemical group 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 229940014144 folate Drugs 0.000 description 1
- 229960000304 folic acid Drugs 0.000 description 1
- KANJSNBRCNMZMV-ABRZTLGGSA-N fondaparinux Chemical compound O[C@@H]1[C@@H](NS(O)(=O)=O)[C@@H](OC)O[C@H](COS(O)(=O)=O)[C@H]1O[C@H]1[C@H](OS(O)(=O)=O)[C@@H](O)[C@H](O[C@@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O[C@@H]4[C@@H]([C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O4)NS(O)(=O)=O)[C@H](O3)C(O)=O)O)[C@@H](COS(O)(=O)=O)O2)NS(O)(=O)=O)[C@H](C(O)=O)O1 KANJSNBRCNMZMV-ABRZTLGGSA-N 0.000 description 1
- 229960001318 fondaparinux Drugs 0.000 description 1
- 235000011194 food seasoning agent Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 229960000308 fosfomycin Drugs 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 229960001625 furazolidone Drugs 0.000 description 1
- PLHJDBGFXBMTGZ-WEVVVXLNSA-N furazolidone Chemical compound O1C([N+](=O)[O-])=CC=C1\C=N\N1C(=O)OCC1 PLHJDBGFXBMTGZ-WEVVVXLNSA-N 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- 229960003883 furosemide Drugs 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- LQJBNNIYVWPHFW-QXMHVHEDSA-N gadoleic acid Chemical class CCCCCCCCCC\C=C/CCCCCCCC(O)=O LQJBNNIYVWPHFW-QXMHVHEDSA-N 0.000 description 1
- DSLZVSRJTYRBFB-DUHBMQHGSA-N galactaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C(O)=O DSLZVSRJTYRBFB-DUHBMQHGSA-N 0.000 description 1
- LRBQNJMCXXYXIU-QWKBTXIPSA-N gallotannic acid Chemical compound OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@H]2[C@@H]([C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-QWKBTXIPSA-N 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- 208000018685 gastrointestinal system disease Diseases 0.000 description 1
- 239000003349 gelling agent Substances 0.000 description 1
- 210000004392 genitalia Anatomy 0.000 description 1
- 229960002518 gentamicin Drugs 0.000 description 1
- XOXYHGOIRWABTC-UHFFFAOYSA-N gentisin Chemical compound C1=C(O)C=C2C(=O)C3=C(O)C=C(OC)C=C3OC2=C1 XOXYHGOIRWABTC-UHFFFAOYSA-N 0.000 description 1
- 229950006191 gluconic acid Drugs 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 125000005908 glyceryl ester group Chemical group 0.000 description 1
- 150000002344 gold compounds Chemical class 0.000 description 1
- 239000010439 graphite Substances 0.000 description 1
- 229910002804 graphite Inorganic materials 0.000 description 1
- 239000003324 growth hormone secretagogue Substances 0.000 description 1
- 210000004209 hair Anatomy 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 210000003128 head Anatomy 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- ULLYUYLDAISRDE-SSPAHAAFSA-N heptanoic acid (2R,3S,4R,5R)-2,3,4,5,6-pentahydroxyhexanal Chemical compound C(CCCCCC)(=O)O.O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO ULLYUYLDAISRDE-SSPAHAAFSA-N 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
- 239000008241 heterogeneous mixture Substances 0.000 description 1
- 229920001519 homopolymer Polymers 0.000 description 1
- 235000001050 hortel pimenta Nutrition 0.000 description 1
- 235000003642 hunger Nutrition 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
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 229960002003 hydrochlorothiazide Drugs 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 229920001600 hydrophobic polymer Polymers 0.000 description 1
- 125000000687 hydroquinonyl group Chemical class C1(O)=C(C=C(O)C=C1)* 0.000 description 1
- 230000000640 hydroxylating effect Effects 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- 229940072106 hydroxystearate Drugs 0.000 description 1
- 239000007946 hypodermic tablet Substances 0.000 description 1
- BBPRUNPUJIUXSE-DXKRWKNPSA-N ifetroban Chemical compound CCCCCNC(=O)C1=COC([C@H]2[C@H]([C@@H]3CC[C@H]2O3)CC=2C(=CC=CC=2)CCC(O)=O)=N1 BBPRUNPUJIUXSE-DXKRWKNPSA-N 0.000 description 1
- 229950004274 ifetroban Drugs 0.000 description 1
- 208000009326 ileitis Diseases 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 125000001841 imino group Chemical group [H]N=* 0.000 description 1
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 1
- 208000003669 immune deficiency disease Diseases 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 201000001881 impotence Diseases 0.000 description 1
- 229940073062 imuran Drugs 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- HOBCFUWDNJPFHB-UHFFFAOYSA-N indolizine Chemical compound C1=CC=CN2C=CC=C21 HOBCFUWDNJPFHB-UHFFFAOYSA-N 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000007574 infarction Effects 0.000 description 1
- 210000004969 inflammatory cell Anatomy 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 206010022437 insomnia Diseases 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 239000004026 insulin derivative Substances 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000007919 intrasynovial administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 235000011073 invertase Nutrition 0.000 description 1
- 239000001573 invertase Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 238000002665 ion therapy Methods 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 230000002262 irrigation Effects 0.000 description 1
- 238000003973 irrigation Methods 0.000 description 1
- 208000012947 ischemia reperfusion injury Diseases 0.000 description 1
- 125000005990 isobenzothienyl group Chemical group 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 1
- 229940074928 isopropyl myristate Drugs 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 229960000318 kanamycin Drugs 0.000 description 1
- 229930027917 kanamycin Natural products 0.000 description 1
- SBUJHOSQTJFQJX-NOAMYHISSA-N kanamycin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N SBUJHOSQTJFQJX-NOAMYHISSA-N 0.000 description 1
- 229930182823 kanamycin A Natural products 0.000 description 1
- 239000000231 karaya gum Substances 0.000 description 1
- 229940039371 karaya gum Drugs 0.000 description 1
- 229940083668 ketek Drugs 0.000 description 1
- 230000006651 lactation Effects 0.000 description 1
- 229940099563 lactobionic acid Drugs 0.000 description 1
- 229940039717 lanolin Drugs 0.000 description 1
- 229940070765 laurate Drugs 0.000 description 1
- 229960000681 leflunomide Drugs 0.000 description 1
- VHOGYURTWQBHIL-UHFFFAOYSA-N leflunomide Chemical compound O1N=CC(C(=O)NC=2C=CC(=CC=2)C(F)(F)F)=C1C VHOGYURTWQBHIL-UHFFFAOYSA-N 0.000 description 1
- 229960003376 levofloxacin Drugs 0.000 description 1
- 229960004873 levomenthol Drugs 0.000 description 1
- QDLAGTHXVHQKRE-UHFFFAOYSA-N lichenxanthone Natural products COC1=CC(O)=C2C(=O)C3=C(C)C=C(OC)C=C3OC2=C1 QDLAGTHXVHQKRE-UHFFFAOYSA-N 0.000 description 1
- 229960004194 lidocaine Drugs 0.000 description 1
- 229940059904 light mineral oil Drugs 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- INHCSSUBVCNVSK-UHFFFAOYSA-L lithium sulfate Inorganic materials [Li+].[Li+].[O-]S([O-])(=O)=O INHCSSUBVCNVSK-UHFFFAOYSA-L 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- UTEFBSAVJNEPTR-RGEXLXHISA-N loprazolam Chemical compound C1CN(C)CCN1\C=C/1C(=O)N2C3=CC=C([N+]([O-])=O)C=C3C(C=3C(=CC=CC=3)Cl)=NCC2=N\1 UTEFBSAVJNEPTR-RGEXLXHISA-N 0.000 description 1
- 229960003019 loprazolam Drugs 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 208000012866 low blood pressure Diseases 0.000 description 1
- 229960000994 lumiracoxib Drugs 0.000 description 1
- KHPKQFYUPIUARC-UHFFFAOYSA-N lumiracoxib Chemical compound OC(=O)CC1=CC(C)=CC=C1NC1=C(F)C=CC=C1Cl KHPKQFYUPIUARC-UHFFFAOYSA-N 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 230000001592 luteinising effect Effects 0.000 description 1
- 201000007275 lymphatic system cancer Diseases 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 229940091250 magnesium supplement Drugs 0.000 description 1
- 229940098895 maleic acid Drugs 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 229940099690 malic acid Drugs 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- CUONGYYJJVDODC-UHFFFAOYSA-N malononitrile Chemical compound N#CCC#N CUONGYYJJVDODC-UHFFFAOYSA-N 0.000 description 1
- 229940035034 maltodextrin Drugs 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N mandelic acid Chemical class OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000000320 mechanical mixture Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical compound ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 1
- 229940057917 medium chain triglycerides Drugs 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000001525 mentha piperita l. herb oil Substances 0.000 description 1
- 229940041616 menthol Drugs 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- LVWZTYCIRDMTEY-UHFFFAOYSA-N metamizole Chemical compound O=C1C(N(CS(O)(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 LVWZTYCIRDMTEY-UHFFFAOYSA-N 0.000 description 1
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 1
- 229960003105 metformin Drugs 0.000 description 1
- 229940117841 methacrylic acid copolymer Drugs 0.000 description 1
- 229920003145 methacrylic acid copolymer Polymers 0.000 description 1
- FBOZXECLQNJBKD-UHFFFAOYSA-N methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-UHFFFAOYSA-N 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical class COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 229960001047 methyl salicylate Drugs 0.000 description 1
- UFEJKYYYVXYMMS-UHFFFAOYSA-N methylcarbamic acid Chemical compound CNC(O)=O UFEJKYYYVXYMMS-UHFFFAOYSA-N 0.000 description 1
- 229960000282 metronidazole Drugs 0.000 description 1
- 239000004200 microcrystalline wax Substances 0.000 description 1
- 239000012982 microporous membrane Substances 0.000 description 1
- 229960004023 minocycline Drugs 0.000 description 1
- 239000003595 mist Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 235000013379 molasses Nutrition 0.000 description 1
- CQDGTJPVBWZJAZ-UHFFFAOYSA-N monoethyl carbonate Chemical compound CCOC(O)=O CQDGTJPVBWZJAZ-UHFFFAOYSA-N 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 125000001064 morpholinomethyl group Chemical group [H]C([H])(*)N1C([H])([H])C([H])([H])OC([H])([H])C1([H])[H] 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- 229940087004 mustargen Drugs 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 206010028417 myasthenia gravis Diseases 0.000 description 1
- SVBNKTIROPNBQH-UHFFFAOYSA-N n'-benzyl-n,n-dimethyl-n'-pyrimidin-2-ylethane-1,2-diamine Chemical compound N=1C=CC=NC=1N(CCN(C)C)CC1=CC=CC=C1 SVBNKTIROPNBQH-UHFFFAOYSA-N 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- JORAUNFTUVJTNG-BSTBCYLQSA-N n-[(2s)-4-amino-1-[[(2s,3r)-1-[[(2s)-4-amino-1-oxo-1-[[(3s,6s,9s,12s,15r,18s,21s)-6,9,18-tris(2-aminoethyl)-3-[(1r)-1-hydroxyethyl]-12,15-bis(2-methylpropyl)-2,5,8,11,14,17,20-heptaoxo-1,4,7,10,13,16,19-heptazacyclotricos-21-yl]amino]butan-2-yl]amino]-3-h Chemical compound CC(C)CCCCC(=O)N[C@@H](CCN)C(=O)N[C@H]([C@@H](C)O)CN[C@@H](CCN)C(=O)N[C@H]1CCNC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](CCN)NC1=O.CCC(C)CCCCC(=O)N[C@@H](CCN)C(=O)N[C@H]([C@@H](C)O)CN[C@@H](CCN)C(=O)N[C@H]1CCNC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](CCN)NC1=O JORAUNFTUVJTNG-BSTBCYLQSA-N 0.000 description 1
- HSZCJVZRHXPCIA-UHFFFAOYSA-N n-benzyl-n-ethylaniline Chemical compound C=1C=CC=CC=1N(CC)CC1=CC=CC=C1 HSZCJVZRHXPCIA-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229960000515 nafcillin Drugs 0.000 description 1
- GPXLMGHLHQJAGZ-JTDSTZFVSA-N nafcillin Chemical compound C1=CC=CC2=C(C(=O)N[C@@H]3C(N4[C@H](C(C)(C)S[C@@H]43)C(O)=O)=O)C(OCC)=CC=C21 GPXLMGHLHQJAGZ-JTDSTZFVSA-N 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 150000005054 naphthyridines Chemical class 0.000 description 1
- 201000003631 narcolepsy Diseases 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 229960004927 neomycin Drugs 0.000 description 1
- 210000000440 neutrophil Anatomy 0.000 description 1
- 229960000965 nimesulide Drugs 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229920001220 nitrocellulos Polymers 0.000 description 1
- 229960000564 nitrofurantoin Drugs 0.000 description 1
- 102000037979 non-receptor tyrosine kinases Human genes 0.000 description 1
- 108091008046 non-receptor tyrosine kinases Proteins 0.000 description 1
- 231100001223 noncarcinogenic Toxicity 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 239000000346 nonvolatile oil Substances 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 229960000988 nystatin Drugs 0.000 description 1
- VQOXZBDYSJBXMA-NQTDYLQESA-N nystatin A1 Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/CC/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 VQOXZBDYSJBXMA-NQTDYLQESA-N 0.000 description 1
- 239000007764 o/w emulsion Substances 0.000 description 1
- 230000000414 obstructive effect Effects 0.000 description 1
- 229960002700 octreotide Drugs 0.000 description 1
- 229960001494 octreotide acetate Drugs 0.000 description 1
- 229960002969 oleic acid Drugs 0.000 description 1
- 201000005443 oral cavity cancer Diseases 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 229960005010 orotic acid Drugs 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 150000002916 oxazoles Chemical class 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- RUVINXPYWBROJD-UHFFFAOYSA-N para-methoxyphenyl Natural products COC1=CC=C(C=CC)C=C1 RUVINXPYWBROJD-UHFFFAOYSA-N 0.000 description 1
- 230000003071 parasitic effect Effects 0.000 description 1
- 229960004662 parecoxib Drugs 0.000 description 1
- 239000006201 parenteral dosage form Substances 0.000 description 1
- 235000010603 pastilles Nutrition 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 235000019371 penicillin G benzathine Nutrition 0.000 description 1
- 150000004686 pentahydrates Chemical class 0.000 description 1
- 125000005981 pentynyl group Chemical group 0.000 description 1
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 1
- 235000019477 peppermint oil Nutrition 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000012466 permeate Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 125000004934 phenanthridinyl group Chemical group C1(=CC=CC2=NC=C3C=CC=CC3=C12)* 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- 125000001791 phenazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 description 1
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 1
- 125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 description 1
- 229960000969 phenyl salicylate Drugs 0.000 description 1
- 229960002895 phenylbutazone Drugs 0.000 description 1
- VYMDGNCVAMGZFE-UHFFFAOYSA-N phenylbutazonum Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 VYMDGNCVAMGZFE-UHFFFAOYSA-N 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000002570 phosphodiesterase III inhibitor Substances 0.000 description 1
- 239000002590 phosphodiesterase V inhibitor Substances 0.000 description 1
- 125000004437 phosphorous atom Chemical group 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- ZTRPYTHOEREHEN-UHFFFAOYSA-N piperazine pyridine Chemical compound N1CCNCC1.N1=CC=CC=C1.N1=CC=CC=C1 ZTRPYTHOEREHEN-UHFFFAOYSA-N 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 239000010773 plant oil Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920001084 poly(chloroprene) Polymers 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 229920002492 poly(sulfone) Polymers 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- 229920002857 polybutadiene Polymers 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 1
- 229940057838 polyethylene glycol 4000 Drugs 0.000 description 1
- 229920002959 polymer blend Polymers 0.000 description 1
- 229920000024 polymyxin B Polymers 0.000 description 1
- XDJYMJULXQKGMM-UHFFFAOYSA-N polymyxin E1 Natural products CCC(C)CCCCC(=O)NC(CCN)C(=O)NC(C(C)O)C(=O)NC(CCN)C(=O)NC1CCNC(=O)C(C(C)O)NC(=O)C(CCN)NC(=O)C(CCN)NC(=O)C(CC(C)C)NC(=O)C(CC(C)C)NC(=O)C(CCN)NC1=O XDJYMJULXQKGMM-UHFFFAOYSA-N 0.000 description 1
- KNIWPHSUTGNZST-UHFFFAOYSA-N polymyxin E2 Natural products CC(C)CCCCC(=O)NC(CCN)C(=O)NC(C(C)O)C(=O)NC(CCN)C(=O)NC1CCNC(=O)C(C(C)O)NC(=O)C(CCN)NC(=O)C(CCN)NC(=O)C(CC(C)C)NC(=O)C(CC(C)C)NC(=O)C(CCN)NC1=O KNIWPHSUTGNZST-UHFFFAOYSA-N 0.000 description 1
- 229960005266 polymyxin b Drugs 0.000 description 1
- 229920000259 polyoxyethylene lauryl ether Polymers 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229960005483 polythiazide Drugs 0.000 description 1
- 229920000046 polythiazide Polymers 0.000 description 1
- 229920002635 polyurethane Polymers 0.000 description 1
- 239000004814 polyurethane Substances 0.000 description 1
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- OTYBMLCTZGSZBG-UHFFFAOYSA-L potassium sulfate Chemical compound [K+].[K+].[O-]S([O-])(=O)=O OTYBMLCTZGSZBG-UHFFFAOYSA-L 0.000 description 1
- 229910052939 potassium sulfate Inorganic materials 0.000 description 1
- 235000011151 potassium sulphates Nutrition 0.000 description 1
- 229960004197 prasugrel Drugs 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- CDOZDBSBBXSXLB-UHFFFAOYSA-N profenamine Chemical compound C1=CC=C2N(CC(C)N(CC)CC)C3=CC=CC=C3SC2=C1 CDOZDBSBBXSXLB-UHFFFAOYSA-N 0.000 description 1
- 229960002262 profenamine Drugs 0.000 description 1
- 239000000583 progesterone congener Substances 0.000 description 1
- ABBQGOCHXSPKHJ-WUKNDPDISA-N prontosil Chemical compound NC1=CC(N)=CC=C1\N=N\C1=CC=C(S(N)(=O)=O)C=C1 ABBQGOCHXSPKHJ-WUKNDPDISA-N 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 239000000473 propyl gallate Substances 0.000 description 1
- 235000010388 propyl gallate Nutrition 0.000 description 1
- 229940075579 propyl gallate Drugs 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- RUOJZAUFBMNUDX-UHFFFAOYSA-N propylene carbonate Chemical compound CC1COC(=O)O1 RUOJZAUFBMNUDX-UHFFFAOYSA-N 0.000 description 1
- 229940093625 propylene glycol monostearate Drugs 0.000 description 1
- 229940121649 protein inhibitor Drugs 0.000 description 1
- 239000012268 protein inhibitor Substances 0.000 description 1
- 230000001185 psoriatic effect Effects 0.000 description 1
- 235000019423 pullulan Nutrition 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 229960005206 pyrazinamide Drugs 0.000 description 1
- IPEHBUMCGVEMRF-UHFFFAOYSA-N pyrazinecarboxamide Chemical compound NC(=O)C1=CN=CC=N1 IPEHBUMCGVEMRF-UHFFFAOYSA-N 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000001725 pyrenyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 229940073095 questran Drugs 0.000 description 1
- WYROLENTHWJFLR-ACLDMZEESA-N queuine Chemical group C1=2C(=O)NC(N)=NC=2NC=C1CN[C@H]1C=C[C@H](O)[C@@H]1O WYROLENTHWJFLR-ACLDMZEESA-N 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
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- SBYHFKPVCBCYGV-UHFFFAOYSA-N quinuclidine Chemical compound C1CC2CCN1CC2 SBYHFKPVCBCYGV-UHFFFAOYSA-N 0.000 description 1
- WTHRRGMBUAHGNI-LCYNINFDSA-N quinupristin Chemical compound N([C@@H]1C(=O)N[C@@H](C(N2CCC[C@H]2C(=O)N(C)[C@@H](CC=2C=CC(=CC=2)N(C)C)C(=O)N2C[C@@H](CS[C@H]3C4CCN(CC4)C3)C(=O)C[C@H]2C(=O)N[C@H](C(=O)O[C@@H]1C)C=1C=CC=CC=1)=O)CC)C(=O)C1=NC=CC=C1O WTHRRGMBUAHGNI-LCYNINFDSA-N 0.000 description 1
- 238000007347 radical substitution reaction Methods 0.000 description 1
- MUPFEKGTMRGPLJ-ZQSKZDJDSA-N raffinose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO[C@@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O2)O)O1 MUPFEKGTMRGPLJ-ZQSKZDJDSA-N 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000003014 reinforcing effect Effects 0.000 description 1
- 230000008085 renal dysfunction Effects 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 229910052895 riebeckite Inorganic materials 0.000 description 1
- 238000009490 roller compaction Methods 0.000 description 1
- LALFOYNTGMUKGG-BGRFNVSISA-L rosuvastatin calcium Chemical compound [Ca+2].CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O.CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O LALFOYNTGMUKGG-BGRFNVSISA-L 0.000 description 1
- 229910052701 rubidium Inorganic materials 0.000 description 1
- 229940085605 saccharin sodium Drugs 0.000 description 1
- 235000005713 safflower oil Nutrition 0.000 description 1
- 239000003813 safflower oil Substances 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229960000953 salsalate Drugs 0.000 description 1
- 201000000306 sarcoidosis Diseases 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 210000000582 semen Anatomy 0.000 description 1
- 208000013223 septicemia Diseases 0.000 description 1
- 239000011257 shell material Substances 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 229960003310 sildenafil Drugs 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 201000002859 sleep apnea Diseases 0.000 description 1
- 239000000779 smoke Substances 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 239000008354 sodium chloride injection Substances 0.000 description 1
- FDRCDNZGSXJAFP-UHFFFAOYSA-M sodium chloroacetate Chemical compound [Na+].[O-]C(=O)CCl FDRCDNZGSXJAFP-UHFFFAOYSA-M 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 229940080313 sodium starch Drugs 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000002195 soluble material Substances 0.000 description 1
- 235000019337 sorbitan trioleate Nutrition 0.000 description 1
- 229960000391 sorbitan trioleate Drugs 0.000 description 1
- 239000012177 spermaceti Substances 0.000 description 1
- 229940084106 spermaceti Drugs 0.000 description 1
- 229940063675 spermine Drugs 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 239000000021 stimulant Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 239000004575 stone Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- SKIVFJLNDNKQPD-UHFFFAOYSA-N sulfacetamide Chemical compound CC(=O)NS(=O)(=O)C1=CC=C(N)C=C1 SKIVFJLNDNKQPD-UHFFFAOYSA-N 0.000 description 1
- 229960005158 sulfamethizole Drugs 0.000 description 1
- VACCAVUAMIDAGB-UHFFFAOYSA-N sulfamethizole Chemical compound S1C(C)=NN=C1NS(=O)(=O)C1=CC=C(N)C=C1 VACCAVUAMIDAGB-UHFFFAOYSA-N 0.000 description 1
- 229960005404 sulfamethoxazole Drugs 0.000 description 1
- NVBFHJWHLNUMCV-UHFFFAOYSA-N sulfamide Chemical compound NS(N)(=O)=O NVBFHJWHLNUMCV-UHFFFAOYSA-N 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- JLKIGFTWXXRPMT-UHFFFAOYSA-N sulphamethoxazole Chemical compound O1C(C)=CC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1 JLKIGFTWXXRPMT-UHFFFAOYSA-N 0.000 description 1
- 239000002600 sunflower oil Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 229940037128 systemic glucocorticoids Drugs 0.000 description 1
- 229960001967 tacrolimus Drugs 0.000 description 1
- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 description 1
- 229920002258 tannic acid Polymers 0.000 description 1
- 229940033123 tannic acid Drugs 0.000 description 1
- 235000015523 tannic acid Nutrition 0.000 description 1
- 238000003419 tautomerization reaction Methods 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
- 229960003250 telithromycin Drugs 0.000 description 1
- 229960000216 tenecteplase Drugs 0.000 description 1
- 229960003676 tenidap Drugs 0.000 description 1
- LXIKEPCNDFVJKC-QXMHVHEDSA-N tenidap Chemical compound C12=CC(Cl)=CC=C2N(C(=O)N)C(=O)\C1=C(/O)C1=CC=CS1 LXIKEPCNDFVJKC-QXMHVHEDSA-N 0.000 description 1
- KUCOHFSKRZZVRO-UHFFFAOYSA-N terephthalaldehyde Chemical compound O=CC1=CC=C(C=O)C=C1 KUCOHFSKRZZVRO-UHFFFAOYSA-N 0.000 description 1
- 229920001897 terpolymer Polymers 0.000 description 1
- 229940063650 terramycin Drugs 0.000 description 1
- RBTVSNLYYIMMKS-UHFFFAOYSA-N tert-butyl 3-aminoazetidine-1-carboxylate;hydrochloride Chemical compound Cl.CC(C)(C)OC(=O)N1CC(N)C1 RBTVSNLYYIMMKS-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 150000004685 tetrahydrates Chemical class 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- FQXXSQDCDRQNQE-VMDGZTHMSA-N thebaine Chemical compound C([C@@H](N(CC1)C)C2=CC=C3OC)C4=CC=C(OC)C5=C4[C@@]21[C@H]3O5 FQXXSQDCDRQNQE-VMDGZTHMSA-N 0.000 description 1
- 150000004867 thiadiazoles Chemical class 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 150000004897 thiazines Chemical class 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- DBDCNCCRPKTRSD-UHFFFAOYSA-N thieno[3,2-b]pyridine Chemical compound C1=CC=C2SC=CC2=N1 DBDCNCCRPKTRSD-UHFFFAOYSA-N 0.000 description 1
- 229940125670 thienopyridine Drugs 0.000 description 1
- 239000002175 thienopyridine Substances 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 235000019303 thiodipropionic acid Nutrition 0.000 description 1
- 229940015849 thiophene Drugs 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 229960004072 thrombin Drugs 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 229960001312 tiaprofenic acid Drugs 0.000 description 1
- 229940098465 tincture Drugs 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 239000003558 transferase inhibitor Substances 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 description 1
- 230000009529 traumatic brain injury Effects 0.000 description 1
- 229960005294 triamcinolone Drugs 0.000 description 1
- 229960001288 triamterene Drugs 0.000 description 1
- 150000004654 triazenes Chemical class 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- YFNKIDBQEZZDLK-UHFFFAOYSA-N triglyme Chemical compound COCCOCCOCCOC YFNKIDBQEZZDLK-UHFFFAOYSA-N 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
- IEDVJHCEMCRBQM-UHFFFAOYSA-N trimethoprim Chemical compound COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 IEDVJHCEMCRBQM-UHFFFAOYSA-N 0.000 description 1
- 229960001082 trimethoprim Drugs 0.000 description 1
- 125000001701 trimethoxybenzyl group Chemical group 0.000 description 1
- PQDJYEQOELDLCP-UHFFFAOYSA-N trimethylsilane Chemical class C[SiH](C)C PQDJYEQOELDLCP-UHFFFAOYSA-N 0.000 description 1
- FQCQGOZEWWPOKI-UHFFFAOYSA-K trisalicylate-choline Chemical compound [Mg+2].C[N+](C)(C)CCO.OC1=CC=CC=C1C([O-])=O.OC1=CC=CC=C1C([O-])=O.OC1=CC=CC=C1C([O-])=O FQCQGOZEWWPOKI-UHFFFAOYSA-K 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 229940046728 tumor necrosis factor alpha inhibitor Drugs 0.000 description 1
- 239000002452 tumor necrosis factor alpha inhibitor Substances 0.000 description 1
- 208000025301 tympanitis Diseases 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 208000010570 urinary bladder carcinoma Diseases 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
- 229960003165 vancomycin Drugs 0.000 description 1
- 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 description 1
- 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 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 239000007762 w/o emulsion Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 230000010148 water-pollination Effects 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
- UGZADUVQMDAIAO-UHFFFAOYSA-L zinc hydroxide Chemical compound [OH-].[OH-].[Zn+2] UGZADUVQMDAIAO-UHFFFAOYSA-L 0.000 description 1
- 229940007718 zinc hydroxide Drugs 0.000 description 1
- 229910021511 zinc hydroxide Inorganic materials 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
Classifications
-
- 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
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/4155—1,2-Diazoles non condensed and 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/422—Oxazoles not condensed and 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and 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
- A61K31/535—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
- 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
- A61K31/54—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 sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/541—Non-condensed thiazines 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
- A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
- A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
-
- 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
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/02—Nasal agents, e.g. decongestants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/04—Antipruritics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/10—Anti-acne agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/14—Decongestants or antiallergics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/38—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
- C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
-
- 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
- C07D403/12—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
- C07D405/14—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
- 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
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/10—Transferases (2.)
- C12N9/12—Transferases (2.) transferring phosphorus containing groups, e.g. kinases (2.7)
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y207/00—Transferases transferring phosphorus-containing groups (2.7)
- C12Y207/11—Protein-serine/threonine kinases (2.7.11)
- C12Y207/11001—Non-specific serine/threonine protein kinase (2.7.11.1), i.e. casein kinase or checkpoint kinase
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Genetics & Genomics (AREA)
- Zoology (AREA)
- Wood Science & Technology (AREA)
- Immunology (AREA)
- Pulmonology (AREA)
- Biomedical Technology (AREA)
- General Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Dermatology (AREA)
- Biotechnology (AREA)
- Microbiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Ophthalmology & Optometry (AREA)
- Rheumatology (AREA)
- Oncology (AREA)
- Otolaryngology (AREA)
- Physical Education & Sports Medicine (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Pain & Pain Management (AREA)
- Hematology (AREA)
Abstract
本文提供了3,5‑二氨基吡唑,例如式(I)的化合物,其适用于调节COPD内调控激酶的活性,及其药物组合物。本文还提供了其用于治疗、预防或改善RC激酶介导的病症、疾病或病状的一种或多种症状的方法。
Description
技术领域
本文提供了3,5-二氨基吡唑,其适用于调节COPD内调控激酶(RC激酶)的活性,及其药物组合物。本文还提供其用于治疗、预防或改善RC激酶介导的病症、疾病或病状的一种或多种症状的方法。
背景技术
COPD内调控激酶(RC激酶)与分别通过使SEK及MEK1/2活化而直接调控应激活化蛋白激酶(SAPK)及细胞外信号调控蛋白激酶(ERK)的路径的MAPKKK3紧密相关。参见美国专利号7,829,685,其披露内容以全文引用方式并入本文中。RC激酶为MAP激酶信号传导级联中的上游活化剂,能够使诸如MKK4及MKK6的MAP激酶磷酸化。MKK4的活化导致JNK型MAP激酶的磷酸化,导致c-Jun的磷酸化且因此导致AP-1转录因子复合物的活化。因此,白介素-8产生得到增加,导致诸如嗜中性白血球的发炎性细胞的募集。MKK6的活化导致p38型MAP激酶的磷酸化,其在免疫反应的活化中重要且为发炎性细胞因子表达的关键调控因子。出现细胞应激、转录因子的活化及过度产生白介素-8为许多发炎性疾病的特征。因此,调控RC激酶活性可潜在地对患有发炎性疾病的患者有益。
已显示RC激酶在肺及气管中高度表达。人类RC激酶的一些表达序列标签还表达于肺上皮细胞及原始肺囊泡性纤维症上皮细胞中。患有慢性阻塞性肺病(COPD)的患者的微阵列分析显示RC激酶在COPD患者的肺中上调。在细胞水平上,已显示RC激酶的表达响应于高渗或氧化应激而上调。例如,在暴露于氯化钾或过氧化氢中之后,细胞中的RC激酶的表达显著增加。氯化钾使细胞经受高渗应激。过氧化氢使细胞经受氧化应激,其削弱B细胞刺激特异性T细胞的能力。细胞中的RC激酶响应于高渗及氧化应激的此类上调表明RC激酶在COPD患者的肺中的较高表达可能为由烟草烟雾中的刺激物造成的细胞应激或由对那些刺激物的发炎反应造成的应激的结果。
因此,RC激酶抑制剂潜在地适用于治疗发炎性疾病,包括COPD。
杰纳斯激酶(JAK)为经由JAK/STAT信号传导路径转导细胞因子介导的信号的胞内非受体酪胺酸激酶家族。此家族包含JAK1、JAK2、JAK3及TYK2(酪胺酸激酶2),其首先描述于超过20年以前,但其活化、调控及多效性信号传导功能中潜在的复杂性仍在进行探索。参见例如Babon,Biochem J.[生物化学杂志]2014;462(1),1-13。破坏或失调的JAK-STAT功能性可能导致多种病症,包括免疫缺陷症候群及癌症。Aaronson等人,Science 2002,296,1653-1655。使用针对非致癌性适应症的大多数激酶抑制剂方案的主要挑战为跨越限制潜在药物的脱靶激酶诱导副作用特征曲线的激酶组界定所需选择性程度。跨越激酶组设计化合物选择性由于激酶活性位点内高度保守性结构而为困难的。参见例如Rokosz等人,ExpertOpin.Ther.Targets[关于治疗靶点的专家意见]2008,12(7)883-903;Bhattacharya等人,Biochemical and Biophysical Research Communications[生物化学与生物物理学研究通讯]2003,307,267-273。
因为破坏JAK-STAT路径可能导致非所需副作用,所以开发可在最低限度地影响JAK功能的同时抑制RC激酶表达的治疗剂极为重要。
发明内容
本文提供式I的3,5-二氨基吡唑:
或其立体异构体、对映异构体、对映异构体的混合物、非对映异构体的混合物或同位素变体;或其药学上可接受的盐、溶剂合物、水合物或前药;其中:
R1为C6-14芳基、杂芳基或杂环基;
R2及R3各自独立地为C1-6烷基或C3-10环烷基;
其中各烷基、环烷基、芳基、杂芳基或杂环基任选地经一个或多个取代基Q取代,其中各Q独立地选自卤基、C1-6烷基、杂芳基及杂环基,其中的每一个进一步任选地经一个或多个C1-6烷基取代;
其前提为该化合物不为3-((3-氯苯基)氨基)-5-((4-羟基-3,5-二甲基苄基)氨基)-1H-吡唑-4-甲酰胺。
在另一个实施例中,本文提供式I的3,5-二氨基吡唑:
或其立体异构体、对映异构体、对映异构体的混合物、非对映异构体的混合物或同位素变体;或其药学上可接受的盐、溶剂合物、水合物或前药;其中:
R1为C6-14芳基、杂芳基或杂环基;
R2及R3各自独立地为C1-6烷基或C3-10环烷基;
其中各烷基、环烷基、芳基、杂芳基或杂环基任选地经一个或多个取代基Q取代,其中各Q独立地选自卤基、氨基、氨基磺酰基、C1-6烷基、C1-6烷氧基、烷基酰氨基、氰基、芳基、杂芳基及杂环基,其中的每一个进一步任选地经一个或多个C1-6烷基、卤基、氰基、氧代基、芳烷基、二烷基氨基、芳基酰氨基、杂环基、杂环基烷基及杂环基羰基取代;
其前提为该化合物不为3-((3-氯苯基)氨基)-5-((4-羟基-3,5-二甲基苄基)氨基)-1H-吡唑-4-甲酰胺。
本文还提供药物组合物,其包含本文所披露的化合物,例如式I的化合物,包括其立体异构体、对映异构体、对映异构体的混合物、非对映异构体的混合物或同位素变体;或其药学上可接受的盐、溶剂合物、水合物或前药;以及一种或多种药学上可接受的赋形剂。
本文进一步提供一种治疗、预防或改善受试者中RC激酶介导的病症、疾病或病状的一种或多种症状的方法,其包含向该受试者给予治疗有效量的本文所披露的化合物,例如式I的化合物,包括其立体异构体、对映异构体、对映异构体的混合物、非对映异构体的混合物或同位素变体;或其药学上可接受的盐、溶剂合物、水合物或前药。
本文另外提供一种调节RC激酶活性的方法,其包含使RC激酶与治疗有效量的本文所披露的化合物,例如式I的化合物,包括其立体异构体、对映异构体、对映异构体的混合物、非对映异构体的混合物或同位素变体;或其药学上可接受的盐、溶剂合物、水合物或前药接触。
本文还提供一种治疗、预防或改善受试者中RC激酶介导的病症、疾病或病状的一种或多种症状的方法,其包含向该受试者给予治疗有效量的本文所披露的化合物,例如式I的化合物,包括其立体异构体、对映异构体、对映异构体的混合物、非对映异构体的混合物或同位素变体;或其药学上可接受的盐、溶剂合物、水合物或前药,其中该化合物显示增加针对RC激酶的效力和/或增加的RC激酶对JAK2的选择性和/或增加的RC激酶对JAK3的选择性。
具体实施方式
为便于理解本文所阐述的本发明,在下文中定义多个术语。
一般而言,本文所用的命名法及本文所描述的有机化学、医药化学及药理学中的实验室程序为熟知且常用于此项技术中的那些那些命名法及实验室程序。除非另外定义,否则本文所用的所有技术及科学术语一般具有与本发明所属领域的本领域普通技术人员通常所理解相同的含义。
术语“受试者”是指动物,包括但不限于灵长类动物(例如人类)、牛、猪、绵羊、山羊、马、犬、猫、兔、大鼠或小鼠。术语“受试者”及“患者”在本文中可互换使用,其指例如哺乳动物受试者,诸如人类受试者,在一个实施例中,人类。
术语“治疗(treat/treating/treatment)”意谓包括缓解或消除病症、疾病、或病状、或与该病症、疾病或病状相关联的一种或多种症状;或缓解或根除该病症、疾病或病状本身的一个或多个起因。
术语“预防(prevent/preventing/prevention)”意谓包括一种实现以下目的的方法:推迟和/或排除病症、疾病或病状和/或其伴随症状的发作;防止受试者罹患病症、疾病或病状;或降低受试者罹患病症、疾病或病状的风险。
术语“治疗有效量”意谓包括在给予时足以防止所治疗的病症、疾病或病状的一种或多种症状的发展或在一定程度上减轻该一种或多种症状的化合物的量。术语“治疗有效量”还指足以引起研究人员、兽医、医生或临床医师所寻求的生物分子(例如蛋白质、酶、RNA或DNA)、细胞、组织、系统、动物或人类的生物学或医学反应的化合物的量。
术语“IC50”或“EC50”是指在量测此类反应的分析法中实现最大反应的50%抑制所需的化合物的量、浓度或剂量。
术语“CC50”是指引起宿主成活力的50%降低的化合物的量、浓度或剂量。在某些实施例中,化合物的CC50为与未经该化合物处理的细胞相比,使经该化合物处理的细胞的成活力降低50%所需的化合物的量、浓度或剂量。
术语“药学上可接受的载剂”、“药学上可接受的赋形剂”、“生理学上可接受的载剂”或“生理学上可接受的赋形剂”是指药学上可接受的材料、组合物或媒剂,诸如液体或固体填充剂、稀释剂、溶剂或包封材料。在一个实施例中,各组分在以下意义上为“药学上可接受的”:与医药配制品的其他成分兼容且适合用于与人类及动物的组织或器官接触而无过度毒性、刺激、过敏反应、免疫原性或其他问题或并发症,与合理益处/风险比相匹配。参见Remington:The Science and Practice of Pharmacy[药剂学的科学和实践],第21版.;Lippincott Williams&Wilkins:Philadelphia,PA,2005;Handbook of PharmaceuticalExcipients[药用辅料手册],第6版;Rowe等人编;The Pharmaceutical Press and theAmerican Pharmaceutical Association:2009;Handbook of Pharmaceutical Additive[医药出版社和美国医药协会:2009;手册药品添加剂]s,第3版;Ash及Ash编;GowerPublishing Company:2007;Pharmaceutical Preformulation and Formulation[药品预制剂和制剂],第2版;Gibson编;CRC Press LLC:Boca Raton,FL,2009。
术语“约”或“大约”意谓如由本领域普通技术人员所测定的特定值的可接受误差,其部分视如何量测或测定该值而定。在某些实施例中,术语“约”或“大约”意谓在1、2、3或4个标准偏差内。在某些实施例中,术语“约”或“大约”意谓在给定值或范围的50%、20%、15%、10%、9%、8%、7%、6%、5%、4%、3%、2%、1%、0.5%或0.05%内。
术语“活性成分”及“活性物质”是指单独或与一种或多种药学上可接受的赋形剂组合向受试者给予以用于治疗、预防或改善病症、疾病或病状的一种或多种症状的化合物。如本文所用,“活性成分”及“活性物质”可为本文所描述的化合物的光学活性异构体或同位素变体。
术语“药物”、“治疗剂”及“化学治疗剂”是指向受试者给予以用于治疗、预防或改善病症、疾病或病状的一种或多种症状的化合物或其药物组合物。
术语“烷基”是指直链或分支链饱和单价烃基,其中该烷基任选地经一个或多个如本文所描述的取代基Q取代。例如,C1-6烷基是指1至6个碳原子的直链饱和单价烃基或3至6个碳原子的分支链饱和单价烃基。在某些实施例中,烷基为具有1至20个(C1-20)、1至15个(C1-15)、1至10个(C1-10)或1至6个(C1-6)碳原子的直链饱和单价烃基,或3至20个(C3-20)、3至15个(C3-15)、3至10个(C3-10)或3至6个(C3-6)碳原子的分支链饱和单价烃基。如本文所用,直链C1-6及分支链C3-6烷基还称为“低级烷基”。烷基的实例包括但不限于甲基、乙基、丙基(包括所有异构形式)、正丙基、异丙基、丁基(包括所有异构形式)、正丁基、异丁基、仲丁基、叔丁基、戊基(包括所有异构形式)及己基(包括所有异构形式)。
术语“烯基”是指含有一个或多个、在一个实施例中一至五个、在另一个实施例中一个碳-碳双键的直链或分支链单价烃基,其中该烯基任选地经一个或多个如本文所描述的取代基Q取代。如本领域普通技术人员所了解,术语“烯基”涵盖具有“顺式”或“反式”构型或其混合物,或替代性地,“Z”或“E”构型或其混合物的基团。例如,C2-6烯基是指2至6个碳原子的直链不饱和单价烃基或3至6个碳原子的分支链不饱和单价烃基。在某些实施例中,烯基为2至20个(C2-20)、2至15个(C2-15)、2至10个(C2-10)或2至6个(C2-6)碳原子的直链单价烃基,或3至20个(C3-20)、3至15个(C3-15)、3至10个(C3-10)或3至6个(C3-6)碳原子的分支链单价烃基。烯基的实例包括但不限于乙烯基、丙烯-1-基、丙烯-2-基、烯丙基、丁烯基及4-甲基丁烯基。
术语“炔基”是指含有一个或多个、在一个实施例中一至五个、在另一个实施例中一个碳-碳三键的直链或分支链单价烃基,其中该炔基任选地经一个或多个如本文所描述的取代基Q取代。例如,C2-6炔基是指2至6个碳原子的直链不饱和单价烃基或3至6个碳原子的分支链不饱和单价烃基。在某些实施例中,炔基为2至20个(C2-20)、2至15个(C2-15)、2至10个(C2-10)或2至6个(C2-6)碳原子的直链单价烃基,或3至20个(C3-20)、3至15个(C3-15)、3至10个(C3-10)或3至6个(C3-6)碳原子的分支链单价烃基。炔基的实例包括但不限于乙炔基(-C≡CH)、丙炔基(包括所有异构形式,例如1-丙炔基(-C≡CCH3)及炔丙基(-CH2C≡CH))、丁炔基(包括所有异构形式,例如1-丁炔-1-基及2-丁炔-1-基)、戊炔基(包括所有异构形式,例如1-戊炔-1-基及1-甲基-2-丁炔-1-基)及己炔基(包括所有异构形式,例如1-己炔-1-基)。
术语“环烷基”是指环状单价烃基,其中该环烷基任选地经一个或多个如本文所描述的取代基Q取代。在一个实施例中,环烷基可为饱和或不饱和但非芳族的,和/或螺环和/或非螺环的,和/或桥连和/或非桥连的,和/或稠合双环基团。在某些实施例中,环烷基具有3至20个(C3-20)、3至15个(C3-15)、3至10个(C3-10)或3至7个(C3-7)碳原子。环烷基的实例包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚烯基、双环[2.1.1]己基、双环[2.2.1]庚基、十氢萘基及金刚烷基。
术语“芳基”是指含有至少一个芳族碳环的单价单环芳族基和/或单价多环芳族基,其中该芳基任选地经一个或多个如本文所描述的取代基Q取代。在某些实施例中,芳基具有6至20个(C6-20)、6至15个(C6-15)或6至10个(C6-10)环原子。芳基的实例包括但不限于苯基、萘基、芴基、薁基、蒽基、菲基、芘基、联苯及联三苯。芳基还指双环或三环碳环,其中环中的一者为芳族且其他环可为饱和、部分不饱和或芳族,例如二氢萘基、茚基、茚满基(indanyl)或四氢萘基(萘满基)。
术语“芳烷基”或“芳基烷基”是指经一个或多个芳基取代的单价烷基,其中该芳烷基或芳基烷基任选地经一个或多个如本文所描述的取代基Q取代。在某些实施例中,芳烷基具有7至30个(C7-30)、7至20个(C7-20)或7至16个(C7-16)碳原子。芳烷基的实例包括但不限于苯甲基、2-苯基乙基及3-苯基丙基。
术语“杂芳基”是指含有至少一个芳环的单价单环芳族基或单价多环芳族基,其中至少一个芳环在环中含有一个或多个独立地选自O、S、N及P的杂原子。杂芳基经由芳环键结至分子的其余部分。杂芳基的各环可含有一个或两个O原子、一个或两个S原子、一至四个N原子和/或一个或两个P原子,其前提为各环中的杂原子的总数为四个或四个以下且各环含有至少一个碳原子。在某些实施例中,杂芳基具有5至20个、5至15个或5至10个环原子。单环杂芳基的实例包括但不限于呋喃基、咪唑基、异噻唑基、异噁唑基、噁二唑基、噁唑基、吡嗪基、吡唑基、哒嗪基、吡啶基、嘧啶基、吡咯基、噻二唑基、噻唑基、噻吩基、四唑基、三嗪基及三唑基。双环杂芳基的实例包括但不限于苯并呋喃基、苯并咪唑基、苯并异噁唑基、苯并吡喃基、苯并噻二唑基、苯并噻唑基、苯并噻吩基、苯并三唑基、苯并噁唑基、呋喃并吡啶基、咪唑并吡啶基、咪唑并噻唑基、吲嗪基、吲哚基、吲唑基、异苯并呋喃基、异苯并噻吩基、异吲哚基、异喹啉基、异噻唑基、萘啶基、噁唑并吡啶基、酞嗪基、蝶啶基、嘌呤基、吡啶并吡啶基、吡咯并吡啶基、喹啉基、喹喔啉基、喹唑啉基、噻二唑并嘧啶基及噻吩并吡啶基。三环杂芳基的实例包括但不限于吖啶基、苯并吲哚基、咔唑基、二苯并呋喃基、咟啶基、菲咯啉基、菲啶基、吩砒嗪基、吩嗪基、吩噻嗪基、吩噁嗪基及夹氧杂蒽基。在某些实施例中,杂芳基任选地经一个或多个如本文所描述的取代基Q取代。
术语“杂芳烷基”或“杂芳基烷基”是指经一个或多个杂芳基取代的单价烷基,其中该烷基及杂芳基各自如本文所定义。在某些实施例中,杂芳烷基任选地经一个或多个如本文所描述的取代基Q取代。
术语“杂环基”或“杂环”是指含有至少一个非芳族环的单价单环非芳环系统或单价多环环系统,其中非芳族环原子中的一个或多个为独立地选自O、S、N及P的杂原子;且其余环原子为碳原子。在某些实施例中,杂环基(heterocyclyl)或杂环基团(heterocyclicgroup)具有3至20个、3至15个、3至10个、3至8个、4至7个或5至6个环原子。杂环基经由非芳族环键结至分子的其余部分。在某些实施例中,杂环基为单环、双环、三环或四环环系统,其可为螺环、稠合或桥联的,且其中氮或硫原子可任选地氧化,氮原子可任选地季铵化,且一些环可部分或完全饱和的或芳族的。杂环基可在任何引起产生稳定化合物的杂原子或碳原子处连接至主结构。此类杂环基团的实例包括但不限于氮杂卓基、苯并二噁烷基、苯并间二氧杂环戊烯基、苯并呋喃酮基、苯并吡喃酮基、苯并吡喃基、苯并四氢呋喃基、苯并四氢噻吩基、苯并硫吡喃基、苯并噁嗪基、β-咔啉基、色满基、色酮基、噌啉基、香豆素基、十氢异喹啉基、二氢苯并异噻嗪基、二氢苯并异噁嗪基、二氢呋喃基、二氢异吲哚基、二氢吡喃基、二氢吡唑基、二氢吡嗪基、二氢吡啶基、二氢嘧啶基、二氢吡咯基、二氧戊环基、1,4-二噻烷基、呋喃酮基、咪唑烷基、咪唑啉基、二氢吲哚基、异苯并四氢呋喃基、异苯并四氢噻吩基、异色满基、异香豆素基、异二氢吲哚基、异噻唑烷基、异噁唑烷基、吗啉基、八氢吲哚基、八氢异吲哚基、噁唑烷酮基、噁唑烷基、环氧乙烷基、哌嗪基、哌啶基、4-哌啶酮基、吡唑啶基、吡唑啉基、吡咯烷基、吡咯啉基、奎宁环基、四氢呋喃基、四氢异喹啉基、四氢吡喃基、四氢噻吩基、硫吗啉基、噻唑烷基、四氢喹啉基及1,3,5-三噻烷基。在某些实施例中,杂环基任选地经一个或多个如本文所描述的取代基Q取代。
术语“杂环基烷基”是指经一个或多个杂环基取代的单价烷基,其中该烷基及杂环基各自如本文所定义。在某些实施例中,杂环基烷基任选地经一个或多个如本文所描述的取代基Q取代。
术语“烷氧基”是指-O-烷基,其中该烷基为如本文所定义。例如,术语“C1-6烷氧基”是指-O-C1-6烷基。
术语“卤素”、“卤化物”或“卤基”是指氟、氯、溴和/或碘。
术语“任选地经取代”旨在是指,诸如烷基、烯基、炔基、环烷基、芳基、芳烷基、杂芳基或杂环基的基团或取代基可经一个或多个取代基Q取代,其中的每一个独立地选自例如(a)氧代基(=O)、卤基、氰基、(-CN)、硝基(-NO2)及五氟硫烷基(-SF5);(b)C1-6烷基、C2-6烯基、C2-6炔基、C3-10环烷基、C6-14芳基、C7-15芳烷基、杂芳基、杂芳烷基、杂环基及杂环基烷基,其中的每一个进一步任选地经一个或多个、在一个实施例中一、二、三或四个取代基Qa取代;以及(c)-B(Ra)ORd、-B(ORa)ORd、-C(O)Ra、-C(O)ORa、-C(O)NRbRc、-C(NRa)NRbRc、-ORa、-OC(O)Ra、-OC(O)ORa、-OC(O)NRbRc、-OC(=NRa)NRbRc、-OS(O)Ra、-OS(O)2Ra、-OS(O)NRbRc、-OS(O)2NRbRc、-NRbRc、-NRaC(O)Rd、-NRaC(O)ORd、-NRaC(O)NRbRc、-NRaC(=NRd)NRbRc、-NRaS(O)Rd、-NRaS(O)2Rd、-NRaS(O)NRbRc、-NRaS(O)2NRbRc、-P(O)RaRd、-P(O)(ORa)Rd、-P(O)(ORa)(ORd)、-SRa、-S(O)Ra、-S(O)2Ra、-S(O)NRbRc及-S(O)2NRbRc,其中各Ra、Rb、Rc及Rd独立地为(i)氢;(ii)C1-6烷基、C2-6烯基、C2-6炔基、C3-10环烷基、C6-14芳基、C7-15芳烷基、杂芳基、杂芳烷基、杂环基或杂环基烷基,其各自任选地经一个或多个、在一个实施例中一、二、三或四个取代基Qa取代;或(iii)Rb及Rc与其所连接的N原子一起形成杂芳基或杂环基,其任选地经一个或多个、在一个实施例中一、二、三或四个取代基Qa取代。如本文所用,除非另外说明,否则所有可经取代的基团均为“任选地经取代”。
在一个实施例中,各Qa独立地选自下组,该组由以下各项组成:(a)氧代基、氰基、卤基、硝基及五氟硫烷基(-SF5);以及(b)C1-6烷基、C2-6烯基、C2-6炔基、C3-10环烷基、C6-14芳基、C7-15芳烷基、杂芳基、杂芳烷基、杂环基及杂环基烷基;以及(c)-B(Re)ORg、-B(ORe)ORg、-C(O)Re、-C(O)ORe、-C(O)NRfRg、-C(NRe)NRfRg、-ORe、-OC(O)Re、-OC(O)ORe、-OC(O)NRfRg、-OC(=NRe)NRfRg、-OS(O)Re、-OS(O)2Re、-OS(O)NRfRg、-OS(O)2NRfRg、-NRfRg、-NReC(O)Rh、-NReC(O)ORh、-NReC(O)NRfRg、-NReC(=NRh)NRfRg、-NReS(O)Rh、-NReS(O)2Rh、-NReS(O)NRfRg、-NReS(O)2NRfRg、-P(O)ReRh、-P(O)(ORe)Rh、-P(O)(ORe)(ORh)、-SRe、-S(O)Re、-S(O)2Re、-S(O)NRfRg及-S(O)2NRfRg;其中各Re、Rf、Rg及Rh独立地为(i)氢、C1-6烷基、C2-6烯基、C2-6炔基、C3-10环烷基、C6-14芳基、C7-15芳烷基、杂芳基、杂芳烷基、杂环基或杂环基烷基;或(ii)Rf及Rg与其所连接的N原子一起形成杂芳基或杂环基。
术语“光学活性”及“对映异构活性”是指具有不低于约50%、不低于约70%、不低于约80%、不低于约90%、不低于约91%、不低于约92%、不低于约93%、不低于约94%、不低于约95%、不低于约96%、不低于约97%、不低于约98%、不低于约99%、不低于约99.5%或不低于约99.8%的对映异构过量的分子的集合。在某些实施例中,以所述外消旋体的总重量计,化合物包含约95%或95%以上的一种对映异构体及约5%或5%以下的另一种对映异构体。
在描述光学活性化合物时,使用前缀R及S表示分子围绕其手性中心的绝对构型。(+)及(-)用于指示化合物的旋亮度,还即偏光平面通过光学活性化合物旋转的方向。(-)前缀指示化合物为左旋性,还即化合物向左或逆时针旋转偏光平面。(+)前缀指示化合物为右旋性,还即化合物向右或顺时针旋转偏光平面。然而,旋亮度的符号(+)及(-)与分子的绝对构型R及S无关。
术语“同位素变体”是指在构成此类化合物的原子中的一个或多个处含有非天然比例的同位素的化合物。在某些实施例中,化合物的“同位素变体”含有非天然比例的一种或多种同位素,包括但不限于氢(1H)、氘(2H)、氚(3H)、碳-11(11C)、碳-12(12C)、碳-13(13C)、碳-14(14C)、氮-13(13N)、氮-14(14N)、氮-15(15N)、氧-14(14O)、氧-15(15O)、氧-16(16O)、氧-17(17O)、氧-18(18O)、氟-17(17F)、氟-18(18F)、磷-31(31P)、磷-32(32P)、磷-33(33P)、硫-32(32S)、硫-33(33S)、硫-34(34S)、硫-35(35S)、硫-36(36S)、氯-35(35Cl)、氯-36(36Cl)、氯-37(37Cl)、溴-79(79Br)、溴-81(81Br)、碘-123(123I)、碘-125(125I)、碘-127(127I)、碘-129(129I)及碘-131(131I)。在某些实施例中,化合物的“同位素变体”呈稳定形式,还即非放射性。在某些实施例中,化合物的“同位素变体”含有非天然比例的一种或多种同位素,包括但不限于氢(1H)、氘(2H)、碳-12(12C)、碳-13(13C)、氮-14(14N)、氮-15(15N)、氧-16(16O)、氧-17(17O)、氧-18(18O)、氟-17(17F)、磷-31(31P)、硫-32(32S)、硫-33(33S)、硫-34(34S)、硫-36(36S)、氯-35(35Cl)、氯-37(37Cl)、溴-79(79Br)、溴-81(81Br)及碘-127(127I)。在某些实施例中,化合物的“同位素变体”呈不稳定形式,还即放射性。在某些实施例中,化合物的“同位素变体”含有非天然比例的一种或多种同位素,包括但不限于氚(3H)、碳-11(11C)、碳-14(14C)、氮-13(13N)、氧-14(14O)、氧-15(15O)、氟-18(18F)、磷-32(32P)、磷-33(33P)、硫-35(35S)、氯-36(36Cl)、碘-123(123I)、碘-125(125I)、碘-129(129I)及碘-131(131I)。应理解,在根据本领域技术人员的判断可行的情况下,在如本文所提供的化合物中,作为实例,任何氢可为2H;或作为实例,任何碳可为13C;或作为实例,任何氮可为15N;且作为实例,任何氧可为18O。在某些实施例中,化合物的“同位素变体”含有非天然比例的氘。
术语“溶剂合物”是指由溶质(例如本文所提供的化合物)的一个或多个分子及溶剂(其以化学计量或非化学计量的量存在)的一个或多个分子形成的复合物或聚集物。适合的溶剂包括但不限于水、MeOH、乙醇、正丙醇、异丙醇及乙酸。在某些实施例中,溶剂为药学上可接受的。在一个实施例中,复合物或聚集物呈结晶形式。在另一个实施例中,复合物或聚集物呈非结晶形式。在溶剂为水的情况下,溶剂合物为水合物。水合物的实例包括但不限于半水合物、单水合物、二水合物、三水合物、四水合物及五水合物。
术语“天然存在”或“原生”在与生物材料(诸如核酸分子、多肽、宿主细胞及其类似物)结合使用时是指在自然界中发现且不受人类操控的材料。类似地,“非天然存在”或“非原生”是指并非在自然界中发现或已由人在结构上修饰或合成的材料。
术语“RC激酶”是指COPD内调控激酶或其变异体。RC激酶变异体包括与天然RC激酶实质上同源的蛋白质,还即相比于天然RC激酶的氨基酸序列具有一个或多个天然或非天然存在的氨基酸缺失、插入或取代的蛋白质(例如RC激酶衍生物、同系物及片段)。RC激酶变异体的氨基酸序列与天然RC激酶具有至少约80%一致性、至少约90%一致性或至少约95%一致性。RC激酶的一些实例披露于美国专利号7,829,685号中,其披露内容以全文引用的方式并入本文中。
术语“RC激酶介导的病症、疾病或病状”及“由RC激酶介导的病症、疾病或病状”是指以异常或失调(例如小于或大于正常)的RC激酶活性为特征的病症、疾病或病状。异常RC激酶功能活性可由于细胞中的RC激酶过度表达,RC激酶在通常并不表达RC激酶的细胞中的表达或归因于例如由RC激酶中的突变造成的构成性活化的失调而产生。RC激酶介导的病症、疾病或病状可完全或部分地由异常或失调的RC激酶活性介导。特定而言,RC激酶介导的病症、疾病或病状为其中RC激酶活性的调节对潜在病症、疾病或病状产生一些影响,例如RC激酶抑制剂在至少一些所治疗的患者中产生一些改善的病症、疾病或病状。
短语“其立体异构体、对映异构体、对映异构体的混合物、非对映异构体的混合物或同位素变体;或其药学上可接受的盐、溶剂合物、水合物或前药”具有与短语“其中所提及的化合物的立体异构体、对映异构体、对映异构体的混合物、非对映异构体的混合物或同位素变体;其中所提及的化合物的药学上可接受的盐、溶剂合物、水合物或前药;或其中所提及的化合物的立体异构体、对映异构体、对映异构体的混合物、非对映异构体的混合物或同位素变体的药学上可接受的盐、溶剂合物、水合物或前药”相同的含义。
化合物
在一个实施例中,本文提供式I的3,5-二氨基吡唑:
或其立体异构体、对映异构体、对映异构体的混合物、非对映异构体的混合物或同位素变体;或其药学上可接受的盐、溶剂合物、水合物或前药;其中:
R1为C6-14芳基、杂芳基或杂环基;
R2及R3各自独立地为C1-6烷基或C3-10环烷基;
其中各烷基、环烷基、芳基、杂芳基或杂环基任选地经一个或多个取代基Q取代,其中各Q独立地选自卤基、C1-6烷基、杂芳基及杂环基,其中的每一个进一步任选地经一个或多个C1-6烷基取代;
其前提为该化合物不为3-((3-氯苯基)氨基)-5-((4-羟基-3,5-二甲基苄基)氨基)-1H-吡唑-4-甲酰胺。
在另一个实施例中,本文提供式I的3,5-二氨基吡唑:
或其立体异构体、对映异构体、对映异构体的混合物、非对映异构体的混合物或同位素变体;或其药学上可接受的盐、溶剂合物、水合物或前药;其中:
R1为C6-14芳基、杂芳基或杂环基;
R2及R3各自独立地为C1-6烷基或C3-10环烷基;
其中各烷基、环烷基、芳基、杂芳基或杂环基任选地经一个或多个取代基Q取代,其中各Q独立地选自卤基、氨基、氨基磺酰基、C1-6烷基、C1-6烷氧基、烷基酰氨基、氰基、芳基、杂芳基及杂环基,其中的每一个进一步任选地经一个或多个C1-6烷基、卤基、氰基、氧代基、芳烷基、二烷基氨基、芳基酰氨基、杂环基、杂环基烷基或杂环基羰基取代;
其前提为该化合物不为3-((3-氯苯基)氨基)-5-((4-羟基-3,5-二甲基苄基)氨基)-1H-吡唑-4-甲酰胺。
在另一个实施例中,本文提供式I的化合物,或其立体异构体、对映异构体、对映异构体的混合物、非对映异构体的混合物或同位素变体;或其药学上可接受的盐、溶剂合物、水合物或前药;其中:
R1为C6-14芳基、杂芳基或杂环基;其中的每一个任选地经一个或多个取代基Q取代,其中各Q独立地选自卤基、C1-6烷基、杂芳基及杂环基,其中的每一个进一步任选地经一个或多个、在一个实施例中一、二、三、四或五个C1-6烷基取代;以及
R2及R3各自为C1-6烷基;
其前提为该化合物不为3-((3-氯苯基)氨基)-5-((4-羟基-3,5-二甲基苄基)氨基)-1H-吡唑-4-甲酰胺。
在另一个实施例中,本文提供式I的化合物,或其立体异构体、对映异构体、对映异构体的混合物、非对映异构体的混合物或同位素变体;或其药学上可接受的盐、溶剂合物、水合物或前药;其中:
R1为C6-14芳基、杂芳基或杂环基;其中的每一个任选地经一个或多个取代基Q取代,其中各Q独立地选自卤基、C1-6烷基、C1-6烷氧基、烷基酰氨基、氨基、磺酰胺、氰基、芳基、杂芳基及杂环基,其中的每一个进一步任选地经一个或多个、在一个实施例中一、二、三、四或五个选自以下的基团取代:卤基、氰基、氧代基、芳烷基、二烷基氨基、芳基酰氨基、杂环基、杂环基烷基、杂芳基及杂环基羰基;
R2及R3各自为C1-6烷基;
其前提为该化合物不为3-((3-氯苯基)氨基)-5-((4-羟基-3,5-二甲基苄基)氨基)-1H-吡唑-4-甲酰胺。
在另一个实施例中,本文提供式I的化合物,或其立体异构体、对映异构体、对映异构体的混合物、非对映异构体的混合物或同位素变体;或其药学上可接受的盐、溶剂合物、水合物或前药;其中:
R1为苯基或吡啶基;其中的每一个任选地经一个或多个取代基Q取代;
R2及R3各自为C1-6烷基;以及
Q如本文所定义;
其前提为该化合物不为3-((3-氯苯基)氨基)-5-((4-羟基-3,5-二甲基苄基)氨基)-1H-吡唑-4-甲酰胺。
在又另一个实施例中,本文提供式I的化合物,或其立体异构体、对映异构体、对映异构体的混合物、非对映异构体的混合物或同位素变体;或其药学上可接受的盐、溶剂合物、水合物或前药;其中:
R1为C6-14芳基、杂芳基或杂环基;其中的每一个任选地经一个或多个取代基Q取代,其中各Q独立地选自氟、氯、溴、碘、甲基、吗啉基、二甲基吗啉基、吡咯基、异丙基哌嗪基、甲基哌嗪基、吡啶基及苄基哌嗪基;
R2及R3各自为C1-6烷基;
其前提为该化合物不为3-((3-氯苯基)氨基)-5-((4-羟基-3,5-二甲基苄基)氨基)-1H-吡唑-4-甲酰胺。
在又另一个实施例中,本文提供式I的化合物,或其立体异构体、对映异构体、对映异构体的混合物、非对映异构体的混合物或同位素变体;或其药学上可接受的盐、溶剂合物、水合物或前药;其中:
R1为C6-14芳基、杂芳基或杂环基;其中的每一个任选地经一个或多个取代基Q取代,其中各Q独立地选自氟、氯、溴、碘、氰基、氨基、氨基磺酰基、甲基、甲氧基、吗啉基、二甲基吗啉基、吡咯基、异丙基哌嗪基、甲基哌嗪基、吡啶基、苄基哌嗪基、苯基、咪唑基、甲氧基、叔丁基、吲唑基、甲基哌啶基、(吡咯烷羰基)哌嗪基、氟哌啶基、二甲基吡喃基、哌啶基、苯甲基、1,1-二氧化(dioxido)硫代吗啉代、吡咯烷基甲基、吗啉基甲基、二甲基氨基、噁唑基、吡唑基、(哌啶羰基)哌嗪基、乙酰氨基、(嘧啶基)哌嗪基、哌啶基甲基、硫代吗啉基、氟苯基酰氨基、甲氧基苯基酰氨基、异丙基哌啶基、氰基甲基、(三氟甲基)苯基酰氨基及氧代吗啉基;
R2及R3各自为C1-6烷基;
其前提为该化合物不为3-((3-氯苯基)氨基)-5-((4-羟基-3,5-二甲基苄基)氨基)-1H-吡唑-4-甲酰胺。
在再另一个实施例中,本文提供式I的化合物,或其立体异构体、对映异构体、对映异构体的混合物、非对映异构体的混合物或同位素变体;或其药学上可接受的盐、溶剂合物、水合物或前药;其中:
R1为3-甲基-4-吗啉代苯基、3-氯-4-吗啉代苯基、4-吗啉代苯基、4-(2,6-二甲基吗啉代)苯基、2-吗啉代-3-氯吡啶-5-基、4-(1H-吡咯-1-基)苯基、2-吗啉代吡啶-5-基、4-(4-异丙基哌嗪-1-基)苯基、4-(吡啶-2-基)苯基、4-(4-甲基哌嗪-1-基)苯基、5-吗啉代吡啶-2-基、2-吗啉代-3-甲基吡啶-5-基、2-(4-异丙基哌嗪-1-基)-3-甲基吡啶-5-基、2-(4-甲基哌嗪-1-基)-3-甲基吡啶-5-基、3-氯-4-(2,6-二甲基吗啉代)苯基、4-(吡啶-3-基)苯基或3-氯-4-(4-异丙基哌嗪-1-基)苯基;
R2及R3各自为甲基;
其前提为该化合物不为3-((3-氯苯基)氨基)-5-((4-羟基-3,5-二甲基苄基)氨基)-1H-吡唑-4-甲酰胺。
在再另一个实施例中,本文提供式I的化合物,或其立体异构体、对映异构体、对映异构体的混合物、非对映异构体的混合物或同位素变体;或其药学上可接受的盐、溶剂合物、水合物或前药;其中:
R1为3-甲基-4-吗啉代苯基、3-氯-4-吗啉代苯基、4-吗啉代苯基、4-(2,6-二甲基吗啉代)苯基、2-吗啉代-3-氯吡啶-5-基、4-(1H-吡咯-1-基)苯基、2-吗啉代吡啶-5-基、4-(4-异丙基哌嗪-1-基)苯基、4-(吡啶-2-基)苯基、4-(4-甲基哌嗪-1-基)苯基、5-吗啉代吡啶-2-基、2-吗啉代-3-甲基吡啶-5-基、2-(4-异丙基哌嗪-1-基)-3-甲基吡啶-5-基、2-(4-甲基哌嗪-1-基)-3-甲基吡啶-5-基、3-氯-4-(2,6-二甲基吗啉代)苯基、4-(吡啶-3-基)苯基、3-氯-4-(4-异丙基哌嗪-1-基)苯基、1,1'-联苯、4-(1H-咪唑-1-基)苯基、4-甲氧基苯基、4-叔丁基苯基、1H-吲唑-5-基、4-(4-甲基-[1,4’-联哌啶]-1'-基)苯基、4-(4-(吡咯烷-1-羰基)哌嗪-1-基)苯基、4-(4-氟哌啶-1-基)苯基、6-(2,6-二甲基四氢-2H-吡喃-4-基)吡啶-3-基、4-(哌啶-1-基)苯基、3-氯-4-(2,6-二甲基吗啉代)苯基、3-甲基-4-(4-甲基哌嗪-1-基)苯基、3-甲基-4-(哌啶-1-基)苯基、4-(4-苯甲基哌嗪-1-基)-3-甲基苯基、4-(1,1-二氧化硫代吗啉代)苯基、(5-(哌啶-1-基)吡啶-2-基)苯基、4-(4-氯哌啶-1-基)苯基、4-(吡咯烷-1-基甲基)苯基、4-(4-(二甲基氨基)哌啶-1-基)苯基、3-氟-4-吗啉代苯基、4-(噁唑-5-基)苯基、4-(4-(吗啉-4-羰基)哌嗪-1-基)苯基、3-乙酰氨基苯基、3-氯-4-(4-甲基哌嗪-1-基)苯基、4-氟苯基、3-氰基苯基、4-(4-(嘧啶-2-基)哌嗪-1-基)苯基、4-(哌啶-1-基甲基)苯基、4-硫代吗啉代苯基、4-氨基苯基、4-(氨基磺酰基)苯基、2-(4-(吡咯烷-1-基)哌啶-1-基)吡啶-5-基、4-(二甲基氨基)苯基、4-(吗啉代甲基)苯基、2-甲氧基苯基、4-(4-氟苯基酰氨基)苯基、4-(4,5-二氢-1H-吡唑-3-基)苯基、4-(2-甲氧基苯基酰氨基)苯基、4-(3-甲氧基苯基酰氨基)苯基、4-(4-甲氧基苯基酰氨基)苯基、4-(4-异丙基哌啶-1-基)苯基、4-(3-氧代吗啉基)苯基、4-(1H-吡唑-1-基)苯基、4-(2-氰基甲基)苯基、4-((4-三氟甲基)苯基酰氨基)苯基或4-(4-甲基哌啶-1-基)苯基;
R2及R3各自为甲基;
其前提为该化合物不为3-((3-氯苯基)氨基)-5-((4-羟基-3,5-二甲基苄基)氨基)-1H-吡唑-4-甲酰胺。
在另一个实施例中,本文提供式II的3,5-二氨基吡唑:
或其立体异构体、对映异构体、对映异构体的混合物、非对映异构体的混合物或同位素变体;或其药学上可接受的盐、溶剂合物、水合物或前药;其中:
R2及R3各自独立地为C1-6烷基或C3-10环烷基;
其中各烷基或环烷基任选地经一个或多个卤基取代;
各R4独立地选自卤基、C1-6烷基、C7-15芳烷基、杂环基,其中的每一个任选地经一个或多个C1-6烷基取代;
其中X及Y各自独立地为N或CH;以及
n为0、1、2、3、4或5;
其前提为该化合物不为3-((3-氯苯基)氨基)-5-((4-羟基-3,5-二甲基苄基)氨基)-1H-吡唑-4-甲酰胺。
在另一个实施例中,本文提供式II的3,5-二氨基吡唑:
或其立体异构体、对映异构体、对映异构体的混合物、非对映异构体的混合物或同位素变体;或其药学上可接受的盐、溶剂合物、水合物或前药;其中:
R2及R3各自独立地为C1-6烷基或C3-10环烷基;
其中各烷基或环烷基任选地经一个或多个卤基取代;
各R4独立地选自卤基、烷基酰氨基、氰基、C1-6烷基、C1-6烷氧基、芳基、C7-15芳烷基、杂环基及杂芳基,其中的每一个任选地经一个或多个卤基、C1-6烷基、芳基、C7-15芳烷基、杂环基、二烷基氨基或二烷基氨基羰基取代;
其中X及Y各自独立地为N或CH;以及
n为0、1、2、3、4或5;
在另一个实施例中,本文提供式II的3,5-二氨基吡唑:
或其立体异构体、对映异构体、对映异构体的混合物、非对映异构体的混合物或同位素变体;或其药学上可接受的盐、溶剂合物、水合物或前药;其中:
R2及R3各自独立地为C1-6烷基或C3-10环烷基;
其中各烷基或环烷基任选地经一个或多个卤基取代;
各R4独立地选自卤基、氨基、氨基磺酰基、烷基酰氨基、芳基酰氨基、氰基、C1-6烷基、C1-6烷氧基、芳基、C7-15芳烷基、杂环基及杂芳基,其中的每一个任选地经一个或多个卤基、氰基、氧代基、C1-6烷基、芳基、C7-15芳烷基、杂环基、氧代基、二烷基氨基或二烷基氨基羰基取代;
其中X及Y各自独立地为N或CH;以及
n为0、1、2、3、4或5;
在另一个实施例中,本文提供式II-a的3,5-二氨基吡唑:
或其立体异构体、对映异构体、对映异构体的混合物、非对映异构体的混合物或同位素变体;或其药学上可接受的盐、溶剂合物、水合物或前药;其中:
R2及R3各自独立地为C1-6烷基或C3-10环烷基;
其中各烷基或环烷基任选地经一个或多个卤基取代;
各R4独立地选自卤基、C1-6烷基、杂芳基及杂环基,其中的每一个任选地经一个或多个C1-6烷基取代;以及
n为0、1、2、3、4或5;
其前提为该化合物不为3-((3-氯苯基)氨基)-5-((4-羟基-3,5-二甲基苄基)氨基)-1H-吡唑-4-甲酰胺。
在另一个实施例中,本文提供式II-a的3,5-二氨基吡唑:
或其立体异构体、对映异构体、对映异构体的混合物、非对映异构体的混合物或同位素变体;或其药学上可接受的盐、溶剂合物、水合物或前药;其中:
R2及R3各自独立地为C1-6烷基或C3-10环烷基;
其中各烷基或环烷基任选地经一个或多个卤基取代;
各R4独立地选自卤基、烷基酰氨基、芳基酰氨基、氨基、氨基磺酰基、氰基、C1-6烷基、C1-6烷氧基、芳基、C7-15芳烷基、杂环基、杂环基烷基及杂芳基,其中的每一个任选地经一个或多个卤基、氰基、氧代基、C1-6烷基、芳基、C7-15芳烷基、杂环基、二烷基氨基或二烷基氨基羰基取代;以及
n为0、1、2、3、4或5;
其前提为该化合物不为3-((3-氯苯基)氨基)-5-((4-羟基-3,5-二甲基苄基)氨基)-1H-吡唑-4-甲酰胺。
在另一个实施例中,本文提供式II-b的3,5-二氨基吡唑:
或其立体异构体、对映异构体、对映异构体的混合物、非对映异构体的混合物或同位素变体;或其药学上可接受的盐、溶剂合物、水合物或前药;其中:
R2及R3各自独立地为C1-6烷基或C3-10环烷基;
其中各烷基或环烷基任选地经一个或多个卤基取代;
各R4独立地选自卤基、C1-6烷基、杂芳基及杂环基,其中的每一个任选地经一个或多个C1-6烷基取代;以及
n为0、1、2、3或4。
在另一个实施例中,本文提供式II-c的3,5-二氨基吡唑:
或其立体异构体、对映异构体、对映异构体的混合物、非对映异构体的混合物或同位素变体;或其药学上可接受的盐、溶剂合物、水合物或前药;其中:
R2及R3各自独立地为C1-6烷基或C3-10环烷基;
其中各烷基或环烷基任选地经一个或多个卤基取代;
各R4独立地选自卤基、C1-6烷基、杂芳基及杂环基,其中的每一个任选地经一个或多个C1-6烷基取代;以及
n为0、1、2、3或4。
在另一个实施例中,本文提供式II-c的3,5-二氨基吡唑:
或其立体异构体、对映异构体、对映异构体的混合物、非对映异构体的混合物或同位素变体;或其药学上可接受的盐、溶剂合物、水合物或前药;其中:
R2及R3各自独立地为C1-6烷基或C3-10环烷基;
其中各烷基或环烷基任选地经一个或多个卤基取代;
各R4独立地选自卤基、C1-6烷基、杂芳基及杂环基,其中的每一个任选地经一个或多个C1-6烷基或杂环基取代;以及
n为0、1、2、3或4。
在本文所描述的式(包括式I、II、II-a、II-b及II-c)中的基团R1、R2、R3、R4、Q及n在本文中进一步定义。本文为此类基团所提供的实施例的所有组合处于本发明的范围内。
在某些实施例中,R1为任选地经一个或多个取代基Q取代的C6-14芳基。在某些实施例中,R1为任选地经一个或多个取代基Q取代的C6-14芳基,其中各Q独立地选自卤基、C1-6烷基、杂芳基及杂环基,其中该烷基、杂芳基及杂环基各自任选地经一个或多个C1-6烷基取代。在某些实施例中,R1为任选地经一个或多个取代基Q取代的C6-14芳基,其中各取代基Q独立地选自氯、甲基、哌嗪基、吡咯基及吗啉基,其中各自任选地经一个或多个C1-6烷基取代。
在某些实施例中,R1为任选地经一个或多个取代基Q取代的C6-14芳基。在某些实施例中,R1为任选地经一个或多个取代基Q取代的C6-14芳基,其中各Q独立地选自卤基、烷基酰氨基、氰基、C1-6烷基、C1-6烷氧基、杂芳基及杂环基,其中该烷基、烷氧基、杂芳基及杂环基各自任选地经一个或多个卤基、C1-6烷基、芳烷基、二烷基氨基、杂环基、杂环基烷基或杂环基羰基取代。在某些实施例中,R1为任选地经一个或多个取代基Q取代的C6-14芳基,其中各取代基Q独立地选自氯、氟、乙酰氨基、氰基、甲基、甲氧基、叔丁基、咪唑基、吲唑基、哌嗪基、哌啶基、吡啶基、吡咯基、吗啉基、1,1-二氧化硫代吗啉基、吡咯烷基甲基、吗啉代甲基、二甲基氨基、噁唑基、吡唑基、(哌啶羰基)哌嗪基、乙酰氨基、(嘧啶基)哌嗪基、哌啶基甲基、硫代吗啉基、氟苯基酰氨基、甲氧基苯基酰氨基、异丙基哌啶基、氰基甲基、(三氟甲基)苯基酰氨基及氧代吗啉基,其中各取代基Q任选地经一个或多个卤基、C1-6烷基、芳基、氰基、氧代基、二烷基氨基、杂环基及杂环基羰基取代。
在某些实施例中,R1为任选地经一个或多个取代基Q取代的苯基。在某些实施例中,R1为任选地经一、二、三、四或五个取代基Q取代的苯基。在某些实施例中,R1为任选地经一、二、三、四或五个取代基Q取代的苯基,其中各取代基Q独立地选自卤基、C1-6烷基、杂芳基及杂环基,其中该烷基、杂芳基及杂环基各自任选地经一个或多个C1-6烷基取代。在某些实施例中,R1为任选地经一、二、三、四或五个取代基Q取代的苯基,其中各取代基Q独立地选自氯、甲基、哌嗪基、吗啉基,其中各自任选地经一个或多个C1-6烷基取代。在某些实施例中,R1为3-甲基-4-吗啉代苯基、3-氯-4-吗啉代苯基、4-吗啉代苯基、4-(2,6-二甲基吗啉代)苯基、4-(1H-吡咯-1-基)苯基、4-(4-异丙基哌嗪-1-基)苯基、4-(吡啶-2-基)苯基、(4-甲基哌嗪-1-基)苯基、3-氯-4-(2,6-二甲基吗啉代)苯基、4-(吡啶-3-基)苯基或3-氯-4-(4-异丙基哌嗪-1-基)苯基。
在某些实施例中,R1为任选地经一个或多个取代基Q取代的苯基。在某些实施例中,R1为任选地经一、二、三、四或五个取代基Q取代的苯基。在某些实施例中,R1为任选地经一、二、三、四或五个取代基Q取代的苯基,其中各取代基Q独立地选自卤基、C1-6烷基、杂芳基及杂环基、及C1-6烷氧基,其中该烷基、烷氧基、杂芳基及杂环基各自任选地经一个或多个卤基、C1-6烷基、芳烷基、二烷基氨基、杂环基、杂环基烷基或杂环基羰基取代。在某些实施例中,R1为任选地经一、二、三、四或五个取代基Q取代的苯基,其中各取代基Q独立地选自氯、氟、甲基、甲氧基、叔丁基、咪唑基、吲唑基、哌嗪基、哌啶基、吡啶基、吡咯基、吗啉基及1,1-二氧化硫代吗啉基,其中各取代基Q任选地经一个或多个卤基、C1-6烷基、芳烷基、杂芳基烷基、杂环基或杂环基羰基取代。在某些实施例中,R1为3-甲基-4-吗啉代苯基、3-氯-4-吗啉代苯基、4-吗啉代苯基、4-(2,6-二甲基吗啉代)苯基、4-(1H-吡咯-1-基)苯基、4-(4-异丙基哌嗪-1-基)苯基、4-(吡啶-2-基)苯基、4-(4-甲基哌嗪-1-基)苯基、3-氯-4-(2,6-二甲基吗啉代)苯基、4-(吡啶-3-基)苯基、3-氯-4-(4-异丙基哌嗪-1-基)苯基、1,1'-联苯、4-(1H-咪唑-1-基)苯基、4-甲氧基苯基、4-叔丁基苯基、4-(4-甲基-[1,4’-联哌啶]-1'-基)苯基、4-(4-(吗啉-4-羰基)哌嗪-1-基)苯基、4-(4-氟哌啶-1-基)苯基、4-(哌啶-1-基)苯基、3-氯-4-(2,6-二甲基吗啉代)苯基、3-甲基-4-(4-甲基哌嗪-1-基)苯基、3-甲基-4-(哌啶-1-基)苯基、4-(4-苯甲基哌嗪-1-基)-3-甲基苯基、4-(1,1-二氧化硫代吗啉代)苯基、(5-(哌啶-1-基)吡啶-2-基)苯基、4-(4-氯哌啶-1-基)苯基、4-(吡咯烷-1-基甲基)苯基、4-(4-(二甲基氨基)哌啶-1-基)苯基、3-氟-4-吗啉代苯基、4-(噁唑-5-基)苯基、4-(4-(哌啶-1-羰基)哌嗪-1-基)苯基、3-乙酰氨基苯基、3-氯-4-(4-甲基哌嗪-1-基)苯基、4-氟苯基、3-氰基苯基、4-(4-(嘧啶-2-基)哌嗪-1-基)苯基、4-(哌啶-1-基甲基)苯基、4-硫代吗啉代苯基、4-氨基苯基、4-(氨基磺酰基)苯基、4-(二甲基氨基)苯基、4-(吗啉代甲基)苯基、2-甲氧基苯基、4-(4-氟苯基酰氨基)苯基、4-(4,5-二氢-1H-吡唑-3-基)苯基、4-(2-甲氧基苯基酰氨基)苯基、4-(3-甲氧基苯基酰氨基)苯基、4-(4-甲氧基苯基酰氨基)苯基、4-(4-异丙基哌啶-1-基)苯基、4-(3-氧代吗啉基)苯基、4-(2-氰基甲基)苯基、4-((4-三氟甲基)苯基酰氨基)苯基或4-(4-甲基哌啶-1-基)苯基。
在某些实施例中,R1为任选地经一个或多个取代基Q取代的杂芳基。在某些实施例中,R1为任选地经一个或多个取代基Q取代的单环杂芳基。在某些实施例中,R1为任选地经一个或多个取代基Q取代的5元或6元杂芳基。在某些实施例中,R1为任选地经一个或多个取代基Q取代的5元杂芳基。在某些实施例中,R1为任选地经一个或多个取代基Q取代的6元杂芳基。在某些实施例中,R1为任选地经一个或多个取代基Q取代的吡啶基。在某些实施例中,R1为2-吗啉代-3-氯吡啶-5-基、2-吗啉代吡啶-5-基、5-吗啉代吡啶-2-基、2-吗啉代-3-甲基吡啶-5-基、2-(4-异丙基哌嗪-1-基)-3-甲基吡啶-5-基或2-(4-甲基哌嗪-1-基)-3-甲基吡啶-5-基。
在某些实施例中,R1为任选地经一个或多个取代基Q取代的杂芳基。在某些实施例中,R1为任选地经一个或多个取代基Q取代的单环杂芳基。R1为任选地经一个或多个取代基Q取代的双环杂芳基。在某些实施例中,R1为任选地经一个或多个取代基Q取代的5元或6元杂芳基。在某些实施例中,R1为任选地经一个或多个取代基Q取代的5元杂芳基。在某些实施例中,R1为任选地经一个或多个取代基Q取代的6元杂芳基。在某些实施例中,R1为任选地经一个或多个取代基Q取代的吡啶基。在某些实施例中,R1为2-吗啉代-3-氯吡啶-5-基、2-吗啉代吡啶-5-基、5-吗啉代吡啶-2-基、2-吗啉代-3-甲基吡啶-5-基、2-(4-异丙基哌嗪-1-基)-3-甲基吡啶-5-基、2-(4-甲基哌嗪-1-基)-3-甲基吡啶-5-基、1H-吲唑-5-基、6-(2,6-二甲基四氢-2H-吡喃-4-基)吡啶-3-基或2-(4-(吡咯烷-1-基)哌啶-1-基)吡啶-5-基。
在某些实施例中,R2为任选地经一个或多个取代基Q取代的C1-6烷基。在某些实施例中,R2为任选地经一个或多个取代基Q取代的C3-10环烷基。在某些实施例中,R2为甲基。
在某些实施例中,R3为任选地经一个或多个取代基Q取代的C1-6烷基。在某些实施例中,R3为任选地经一个或多个取代基Q取代的C3-10环烷基。在某些实施例中,R3为甲基。
在某些实施例中,R4为卤基。在某些实施例中,R4为氟、氯或溴。在某些实施例中,R4为C1-6烷基。在某些实施例中,R4为任选地经一个或多个C1-6烷基取代的杂芳基。在某些实施例中,R4为任选地经一个或多个C1-6烷基取代的杂环基。
在某些实施例中,R4为卤基。在某些实施例中,R4为氟、氯或溴。在某些实施例中,R4为氰基。在某些实施例中,R4为烷基酰氨基。在某些实施例中,R4为乙酰氨基。在某些实施例中,R4为芳基酰氨基。在某些实施例中,R4为氨基。在某些实施例中,R4为二烷基氨基。在某些实施例中,R4氨基磺酰基。在某些实施例中,R4为C1-6烷基。在某些实施例中,R4为经一个或多个氰基取代的C1-6烷基。在某些实施例中,R4为任选地经一个或多个C1-6烷基取代的杂芳基。在某些实施例中,R4为任选地经一个或多个C1-6烷基取代的杂环基。在某些实施例中,R4为任选地经一个或多个氧代取代的杂环基。
在某些实施例中,n为0。在某些实施例中,n为1。在某些实施例中,n为2。在某些实施例中,n为3。在某些实施例中,n为4。在某些实施例中,n为5。
在一个实施例中,本文所提供的化合物是选自:
及其立体异构体、对映异构体、对映异构体的混合物、非对映异构体的混合物及同位素变体;以及其药学上可接受的盐、溶剂合物、水合物及前药。
在一个实施例中,本文所提供的化合物是选自:
及其立体异构体、对映异构体、对映异构体的混合物、非对映异构体的混合物及同位素变体;以及其药学上可接受的盐、溶剂合物、水合物及前药。
除非指定特定立体化学,否则本文所提供的化合物旨在涵盖所有可能立体异构体。在本文所提供的化合物含有烯基或亚烯基的情况下,化合物可以一种几何顺式/反式(或Z/E)异构体或其混合物的形式存在。在结构异构体可互相转化的情况下,化合物可以单一互变异构体或互变异构体的混合物的形式存在。互变异构在含有例如亚氨基、酮基或肟基的化合物中可呈质子互变异构形式;或在含有芳族部分的化合物中可呈所谓的价互变异构形式。因此,单一化合物可展现一种以上类型的异构现象。
本文所提供的化合物可为对映异构纯,诸如单一对映异构体或单一非对映异构体,或为立体异构混合物,诸如对映异构体的混合物,例如两种对映异构体的外消旋混合物;或两种或两种以上非对映异构体的混合物。因此,本领域技术人员将认识到,对于经历活体内差向异构反应的化合物,化合物以其(R)形式给药与化合物以其(S)形式给药为等效的。用于制备/分离个别对映异构体的常规技术包括由适合的光学纯前驱体合成、由非手性起始材料不对称合成或拆分对映异构混合物,例如手性层析、再结晶、拆分、非对映异构盐形成,或衍生成非对映异构加合物接着分离。
当本文所提供的化合物含有酸性或碱性部分时,其还可以药学上可接受的盐的形式提供。参见Berge等人,J.Pharm.Sci.1977,66,1-19;以及Handbook of PharmaceuticalSalts,Properties,and Use[药物盐、属性和使用手册];Stahl及Wermuth编;Wiley-VCHand VHCA:Zurich,Switzerland,2002。
适用于制备药学上可接受的盐的酸包括但不限于乙酸、2,2-二氯乙酸、酰基化氨基酸、己二酸、海藻酸、抗坏血酸、L-天冬胺酸、苯磺酸、苯甲酸、4-乙酰氨基苯甲酸、硼酸、(+)-樟脑酸、樟脑磺酸、(+)-(1S)-樟脑-10-磺酸、癸酸、己酸、辛酸、肉桂酸、柠檬酸、环己胺磺酸、环己烷氨基磺酸、十二基硫酸、乙烷-1,2-二磺酸、乙烷磺酸、2-羟基-乙烷磺酸、甲酸、反丁烯二酸、半乳糖二酸、龙胆酸、葡糖庚酸、D-葡萄糖酸、D-葡糖醛酸、L-谷氨酸、α-氧代戊二酸、乙醇酸、马尿酸、氢溴酸、盐酸、氢碘酸、(+)-L-乳酸、(±)-DL-乳酸、乳糖酸、月桂酸、顺丁烯二酸、(-)-L-苹果酸、丙二酸、(±)-DL-扁桃酸、甲烷磺酸、萘-2-磺酸、萘-1,5-二磺酸、1-羟基-2-萘甲酸、烟酸、硝酸、油酸、乳清酸、草酸、棕榈酸、双羟萘酸、高氯酸、磷酸、L-焦谷氨酸、葡萄糖二酸、水杨酸、4-氨基-水杨酸、癸二酸、硬脂酸、丁二酸、硫酸、鞣酸、(+)-L-酒石酸、硫氰酸、对甲苯磺酸、十一碳烯酸及戊酸。
适用于制备药学上可接受的盐的碱包括但不限于无机碱,诸如氢氧化镁、氢氧化钙、氢氧化钾、氢氧化锌或氢氧化钠;以及有机碱,诸如伯、仲、叔及季、脂族及芳族胺,包括L-精胺酸、苄苯乙胺(benethamine)、苯乍生(benzathine)、胆碱、二甲基乙醇胺、二乙醇胺、二乙胺、二甲胺、二丙胺、二异丙基胺、2-(二乙氨基)-乙醇、乙醇胺、乙胺、乙二胺、异丙胺、N-甲基-葡糖胺、海卓胺(hydrabamine)、1H-咪唑、L-赖胺酸、吗啉、4-(2-羟乙基)-吗啉、甲胺、哌啶、哌嗪、丙胺、吡咯烷、1-(2-羟乙基)-吡咯烷、吡啶、奎宁环、喹啉、异喹啉、仲胺、三乙醇胺、三甲胺、三乙胺、N-甲基-D-葡糖胺、2-氨基-2-(羟甲基)-1,3-丙二醇及氨丁三醇。
本文所提供的化合物还可以前药形式提供,其为例如式I的化合物的官能性衍生物,且可易于活体内转化成母体化合物。前药通常适用,因为在一些情况下,其可能比母体化合物更容易给予。其可例如通过经口给药而生物利用,而母体化合物不能。前药还可在药物组合物中相较于母体化合物具有增强的溶解度。前药可通过各种机制转化成母药,包括酶促方法及代谢水解。参见Harper,Progress in Drug Research 1962,4,221-294;Morozowich等人在Design of Biopharmaceutical Properties through Prodrugs andAnalogs;Roche编,APHA Acad.Pharm.Sci.:1977中;Gangwar等人,Des.Biopharm.Prop.Prodrugs Analogs,1977,409-421;Bundgaard,Arch.Pharm.Chem.1979,86,1-39;Farquhar等人,J.Pharm.Sci.1983,72,324-325;Wernuth在Drug Design:Fact or Fantasy;Jolles等人编;Academic Press:London,1984;第47-72页中;Design of Prodrugs;Bundgaard等人编;Elsevier:1985;Fleisher等人,MethodsEnzymol.1985,112,360-381;Stella等人,Drugs 1985,29,455-473;BioreversibleCarriers in Drug in Drug Design,Theory and Application;Roche编;APHAAcad.Pharm.Sci.:1987;Bundgaard,Controlled Drug Delivery 1987,17,179-96;Waller等人,Br.J.Clin.Pharmac.1989,28,497-507;Balant等人,Eur.J.DrugMetab.Pharmacokinet.1990,15,143-53;Freeman等人,J.Chem.Soc.,Chem.Commun.1991,875-877;Bundgaard,Adv.Drug Delivery Rev.1992,8,1-38;Nathwani及Wood,Drugs1993,45,866-94;Friis及Bundgaard,Eur.J.Pharm.Sci.1996,4,49-59;Fleisher等人,Adv.Drug Delivery Rev.1996,19,115-130;Sinhababu及Thakker,Adv.Drug DeliveryRev.1996,19,241-273;Taylor,Adv.Drug Delivery Rev.1996,19,131-148;Gaignault等人,Pract.Med.Chem.1996,671-696;Browne,Clin.Neuropharmacol.1997,20,1-12;Valentino及Borchardt,Drug Discovery Today 1997,2,148-155;Pauletti等人,Adv.Drug.Delivery Rev.1997,27,235-256;Mizen等人,Pharm.Biotech.1998,11,345-365;Wiebe及Knaus,Adv.Drug Delivery Rev.1999,39,63-80;Tan等人,Adv.DrugDelivery Rev.1999,39,117-151;Balimane及Sinko,Adv.Drug Delivery Rev.1999,39,183-209;Wang等人,Curr.Pharm.Design 1999,5,265-287;Han等人,AAPS Pharmsci.2000,2,1-11;Asgharnejad在Transport Processes in Pharmaceutical Systems;Amidon等人编;Marcell Dekker:2000;第185-218中页;Sinha等人,Pharm.Res.2001,18,557-564;Anand等人,Expert Opin.Biol.Ther.2002,2,607-620;Rao,Resonace 2003,19-27;Sloan等人,Med.Res.Rev.2003,23,763-793;Patterson等人,Curr.Pharm.Des.2003,9,2131-2154;Hu,IDrugs 2004,7,736-742;Robinson等人,Proc.Natl.Acad.Sci.U.S.A.2004,101,14527-14532;Erion等人,J.Pharmacol.Exp.Ther.2005,312,554-560;Fang等人,Curr.Drug Discov.Technol.2006,3,211-224;Stanczak等人,Pharmacol.Rep.2006,58,599-613;Sloan等人,Pharm.Res.2006,23,2729-2747;Stella等人,Adv.DrugDeliv.Rev.2007,59,677-694;Gomes等人,Molecules 2007,12,2484-2506;Krafz等人,ChemMedChem 2008,3,20-53;Rautio等人,AAPS J.2008,10,92-102;Rautio等人,Nat.Rev.Drug.Discov.2008,7,255-270;Pavan等人,Molecules,2008,13,1035-1065;Sandros等人,Molecules 2008,13,1156-1178;Singh等人,Curr.Med.Chem.2008,15,1802-1826;Onishi等人,Molecules,2008,13,2136-2155;Huttunen等人,Curr.Med.Chem.2008,15,2346-2365;以及Serafin等人,Mini Rev.Med.Chem.2009,9,481-497。
合成方法
本文所提供的化合物可通过本领域技术人员已知的任何方法来制备、分离或获得;且以下实例仅为代表性的且不排除其他相关方法及程序。还参见美国专利申请号13/830,486及13/830,712,其中的每一个的披露内容均以全文引用的方式并入本文中。
在一个实施例中,例如,式I的化合物可如流程I中所示来制备。化合物I-1首先通过与二硫化碳及硫酸二甲酯反应来转化成化合物I-2。化合物I-2随后与诸如R1NH2的胺反应以形成化合物I-3。作为替代方案,化合物I-3可通过使异硫氰酸酯(R1NCS)与化合物I-1及碘甲烷反应来制造。随后,化合物I-3与肼反应以形成化合物I-4,该化合物I-4随后经诸如4-羟基-3,5-二甲基苯甲醛的羰基化合物处理以形成式I的化合物,例如化合物I-5。化合物I-5的亚氨基团可用例如硼氢化钠(NaBH4)或氰基硼氢化钠(NaB(CN)H3)的还原剂还原以形成化合物I-6。
方案I
在另一个实施例中,例如,式I的化合物可如方案II中所示来制备。化合物I-7与诸如R2NH2的胺反应以形成化合物I-8。或者,化合物I-8可通过使异硫氰酸酯(R2NCS)与丙二腈及碘甲烷反应来制造。化合物I-8随后经肼处理以形成化合物I-9。化合物I-9的氰基例如通过与过氧化氢反应而转化成氨基羰基。化合物I-4可随后如本文所描述转化成化合物I-5及I-6。
方案II
药物组合物
本文提供药物组合物,其包含本文所提供的化合物,例如式I的化合物(包括其立体异构体、对映异构体、对映异构体的混合物、非对映异构体的混合物或同位素变体;或其药学上可接受的盐、溶剂合物、水合物或前药)作为活性成分;以及药学上的赋形剂。
适合的赋形剂为本领域技术人员所熟知,且适合的赋形剂的非限制性实例提供于本文中。特定赋形剂是否适合于并入药物组合物或剂型中视此项技术中熟知的多种因素而定,包括但不限于给药方法。例如,诸如片剂的口服剂型可含有不适用于非经肠剂型的赋形剂。特定赋形剂的适合性还可视剂型中的具体活性成分而定。例如,一些活性成分的分解可因某些赋形剂(诸如乳糖)或在暴露于水时而加速。包含伯胺或仲胺的活性成分尤其对此类加速分解敏感。因此,本文提供药物组合物及剂型,其含有极少(若存在)乳糖或其他单醣或二醣。如本文所用,术语“无乳糖”意谓所存在的乳糖(若存在)的量不足以实质上提高活性成分的降解速率。在一个实施例中,无乳糖组合物包含本文所提供的活性成分、粘合剂/填充剂及润滑剂。在另一个实施例中,无乳糖剂型包含活性成分、微晶纤维素、预糊化淀粉及硬脂酸镁。
本文所提供的化合物可单独给予,或与本文所提供的的一种或多种其他化合物组合。包含本文所提供的化合物,例如式I的化合物(包括其立体异构体、对映异构体、对映异构体的混合物、非对映异构体的混合物或同位素变体;或其药学上可接受的盐、溶剂合物、水合物或前药)的药物组合物可配制为用于经口、非经肠及局部给药的各种剂型。药物组合物还可配制为改进释放剂型,包括延迟释放、缓释、延长释放、持续释放、脉冲释放、控制释放、加速释放、快速释放、靶向释放、程控释放,及胃滞留剂型。此等剂型可根据本领域技术人员已知的常规方法及技术来制备(参见Remington:The Science and Practice ofPharmacy,同前文献;Modified-Release Drug Delivery Technology,第2版;Rathbone等人编;Marcel Dekker,Inc.:New York,NY,2008)。
在一个实施例中,以用于经口给药的剂型提供药物组合物,其包含本文所提供的化合物,例如式I的化合物(包括其立体异构体、对映异构体、对映异构体的混合物、非对映异构体的混合物或同位素变体;或其药学上可接受的盐、溶剂合物、水合物或前药);以及一种或多种药学上可接受的赋形剂。
在另一个实施例中,以用于非经肠给药的剂型提供药物组合物,其包含本文所提供的化合物,例如式I的化合物(包括其立体异构体、对映异构体、对映异构体的混合物、非对映异构体的混合物或同位素变体;或其药学上可接受的盐、溶剂合物、水合物或前药);以及一种或多种药学上可接受的赋形剂。
在又另一个实施例中,以用于局部给药的剂型提供药物组合物,其包含本文所提供的化合物,例如式I的化合物(包括其立体异构体、对映异构体、对映异构体的混合物、非对映异构体的混合物或同位素变体;或其药学上可接受的盐、溶剂合物、水合物或前药);以及一种或多种药学上可接受的赋形剂。
本文所提供的药物组合物可以单位剂型或多重剂型提供。如本文所用的单位剂型是指以物理方式分散适合于向人类及动物受试者给予的单元,且如此项技术中已知地个别包装。各单位剂量含有预定量的一种或多种活性成分,其与所需药物载剂或赋形剂结合足以产生所要的治疗效应。单位剂型的实例包括安瓿、注射器及个别包装的片剂及胶囊。例如,100mg单位剂量在包装的片剂或胶囊中含有约100mg活性成分。单位剂型可以其部分或倍数给予。多重剂型为多个包装于单一容器中的待以分离的单位剂型形式给予的相同单位剂型。多重剂型的实例包括小瓶、片剂或胶囊的瓶,或品脱或加仑的瓶。
本文所提供的药物组合物可一次性或以时间间隔多次给予。应理解,精确剂量及治疗持续时间可随所治疗的患者的年龄、体重及病状而变化,且可使用已知测试方案凭经验确定或通过自活体内或活体外测试或诊断数据外推来确定。此外,应理解,对于任何特定个体,应根据受试者需要及给予配制品或监督配制品给药的个人的专业判断随时间推移而调整具体剂量方案。
A.经口给药
本文所提供的用于经口给药的药物组合物可以用于经口给药的固体、半固体或液体剂型提供。如本文所用,经口给药还包括颊内、经舌及舌下给药。适合的口服剂型包括但不限于片剂、速溶剂、咀嚼片、胶囊、丸剂、带状物、糖衣锭、口含片、软锭剂、扁囊剂、丸粒、药用口香糖、块状粉末、发泡或非发泡粉末或颗粒、口服喷雾、溶液、乳液、悬浮液、糯米纸囊剂、撒剂、酏剂及糖浆剂。除活性成分以外,药物组合物可含有一种或多种药学上可接受的载剂或赋形剂,包括但不限于粘合剂、填充剂、稀释剂、崩解剂、润湿剂、润滑剂、助流剂、着色剂、染料迁移抑制剂、甜味剂、调味剂、乳化剂、悬浮剂及分散剂、防腐剂、溶剂、非水性液体、有机酸及二氧化碳来源。
粘合剂或造粒剂赋予片剂内聚性以确保片剂在压缩的后保持完整。适合的粘合剂或造粒剂包括但不限于淀粉,诸如玉米淀粉、马铃薯淀粉及预糊化淀粉(例如STARCH1500);明胶;糖,诸如蔗糖、葡萄糖、右旋糖、糖蜜及乳糖;天然及合成胶,诸如阿拉伯胶、海藻酸、海藻酸盐、角叉菜(Irish moss)的提取物、潘沃胶(panwar gum)、茄替胶(ghattigum)、洋车前子(isabgol)果壳的粘液、羧甲基纤维素、甲基纤维素、聚乙烯吡咯烷酮(PVP)、维格姆(Veegum)、松木多糖(larch arabogalactan)、西黄蓍胶粉及瓜尔豆胶;纤维素,诸如乙基纤维素、乙酸纤维素、羧甲基纤维素钙、羧甲基纤维素钠、甲基纤维素、羟乙基纤维素(HEC)、羟丙基纤维素(HPC)、羟丙基甲基纤维素(HPMC);微晶纤维素,诸如AVICEL-PH-101、AVICEL-PH-103、AVICEL RC-581、AVICEL-PH-105(FMC Corp.,Marcus Hook,PA);以及其混合物。适合的填充剂包括但不限于滑石、碳酸钙、微晶纤维素、粉末状纤维素、葡萄糖结合剂、高岭土、甘露醇、硅酸、山梨醇、淀粉、预糊化淀粉及其混合物。本文所提供的药物组合物中的粘合剂或填充剂的量视配制品类型而变化,且可由本领域普通技术人员容易地辨别。粘合剂或填充剂可以约50至约99重量%存在于本文所提供的药物组合物中。
适合的稀释剂包括但不限于磷酸二钙、硫酸钙、乳糖、山梨醇、蔗糖、肌醇、纤维素、高岭土、甘露醇、氯化钠、无水淀粉及粉末状糖。当以足够量存在时,某些稀释剂,诸如甘露醇、乳糖、山梨醇、蔗糖及肌醇,可赋予一些压缩片剂可通过咀嚼而在口中崩解的特性。此类压缩片剂可用作咀嚼片。本文所提供的药物组合物中的稀释剂的量视配制品类型而变化,且可由本领域普通技术人员容易地辨别。
适合的崩解剂包括但不限于琼脂;膨润土;纤维素,诸如甲基纤维素及羧甲基纤维素;木材产品;天然海绵;阳离子交换树脂;海藻酸;胶,诸如瓜尔豆胶及维格姆HV;柑桔渣;交联纤维素,诸如交联羧甲纤维素;交联聚合物,诸如交联维酮(crospovidone);交联淀粉;碳酸钙;微晶纤维素,诸如羟基乙酸淀粉钠;波拉克林钾(polacrilin potassium);淀粉,诸如玉米淀粉、马铃薯淀粉、木薯淀粉及预糊化淀粉;粘土;对准剂;以及其混合物。本文所提供的药物组合物中的崩解剂的量视配制品类型而变化,且可由本领域普通技术人员容易地辨别。本文所提供的药物组合物可含有约0.5至约15重量%或约1至约5重量%的崩解剂。
适合的润滑剂包括但不限于硬脂酸钙;硬脂酸镁;矿物油;轻质矿物油;甘油;山梨醇;甘露醇;二醇,诸如山嵛酸甘油酯及聚乙二醇(PEG);硬脂酸;月桂基硫酸钠;滑石;氢化植物油,包括花生油、棉籽油、葵花油、芝麻油、橄榄油、玉米油及大豆油;硬脂酸锌;油酸乙酯;月桂酸乙酯;琼脂;淀粉;石松粉;二氧化硅或二氧化硅凝胶,诸如200(W.R.Grace Co.,Baltimore,MD)及(Cabot Co.,Boston,MA);以及其混合物。本文所提供的药物组合物可含有约0.1至约5重量%的润滑剂。
适合的助流剂包括但不限于胶态二氧化硅、(Cabot Co.,Boston,MA),及不含石棉的滑石。适合的着色剂包括但不限于任何经批准、经鉴定、可溶于水的FD&C染料,及悬浮于氧化铝水合物上的不可溶于水的FD&C染料,及其色淀及混合物。色淀为由水可溶染料吸附至重金属的含水氧化物而形成的组合,产生染料的不可溶形式。适合的调味剂包括但不限于自植物(诸如果实)提取的天然调味剂,及产生合意口感的化合物(诸如胡椒薄荷及水杨酸甲酯)的合成掺合物。适合的甜味剂包括但不限于蔗糖、乳糖、甘露醇、糖浆剂、甘油及人工甜味剂,诸如糖精及阿斯巴甜糖(aspartame)。适合的乳化剂包括但不限于明胶、阿拉伯胶、黄蓍胶、膨润土及表面活性剂,诸如聚氧化乙烯脱水山梨糖醇单油酸酯(20)、聚氧化乙烯脱水山梨糖醇单油酸酯80(80)及油酸三乙醇胺。适合的悬浮剂及分散剂包括但不限于羧甲基纤维素钠(sodium carboxymethylcellulose)、果胶、黄蓍、维格姆、阿拉伯胶、羧甲基纤维素钠(sodium carbomethylcellulose)、羟丙基甲基纤维素及聚乙烯吡咯烷酮。适合的防腐剂包括但不限于甘油、对羟基苯甲酸甲酯及对羟基苯甲酸丙酯、苯甲酸、苯甲酸钠及醇。适合的润湿剂包括但不限于、丙二醇单硬脂酸酯、脱水山梨糖醇单油酸酯、二甘醇单月桂酸酯及聚氧化乙烯月桂基醚。适合的溶剂包括但不限于甘油、山梨醇、乙醇及糖浆。乳液中所用的适合的非水性液体包括但不限于矿物油及棉籽油。适合的有机酸包括但不限于柠檬酸及酒石酸。适合的二氧化碳来源包括但不限于碳酸氢钠及碳酸钠。
应理解,即使在相同配制品内,许多载剂及赋形剂可提供多种功能。
本文所提供的用于经口给药的药物组合物可提供为压缩片剂、片剂研磨物、咀嚼口含锭、快速溶解片剂、多重压缩片剂或肠溶衣片剂、糖包衣或膜包衣片剂。肠溶衣包覆片剂为压缩片剂,其包覆有抵抗胃酸作用但在肠中溶解或崩解的物质,由此保护活性成分不受胃的酸性环境影响。肠溶衣包括但不限于脂肪酸、脂肪、水杨酸苯基酯、蜡、虫胶、氨化虫胶及邻苯二甲酸乙酸纤维素。糖包衣包覆片剂为由糖包衣包裹的压缩片剂,其可有利地遮盖令人不快的口味或气味且保护片剂免于氧化。膜包衣包覆片剂为压缩片剂,其由水可溶材料的薄层或薄膜覆盖。膜包衣包括但不限于羟乙基纤维素、羧甲基纤维素钠、聚乙二醇4000及邻苯二甲酸乙酸纤维素。膜包衣提供与糖包衣相同的一般特征。多重压缩片剂为通过一个以上压缩循环制造的压缩片剂,包括分层片剂及压缩包衣包覆或干燥包衣包覆片剂。
片剂剂型可由呈粉末、结晶或颗粒形式的活性成分单独或与本文所描述的一种或多种载剂或赋形剂(包括粘合剂、崩解剂、控制释放聚合物、润滑剂、稀释剂和/或着色剂)组合来制备。调味剂及甜味剂尤其适用于形成咀嚼片及口含锭。
本文所提供的用于经口给药的药物组合物可以软或硬胶囊形式提供,其可由明胶、甲基纤维素、淀粉或海藻酸钙制造。硬明胶胶囊,还称为干式填充胶囊(DFC),由两部分组成,一个部分在另一个部分上滑动,由此完全包裹活性成分。软弹性胶囊(SEC)为软的球状壳,诸如明胶壳,其通过添加甘油、山梨醇或类似多元醇而增塑。软明胶壳可含有防腐剂以防止微生物生长。适合的防腐剂为如本文所描述的那些防腐剂,包括对羟苯甲酸甲酯及对羟苯甲酸丙酯、及山梨酸。本文所提供的液体、半固体及固体剂型可包封在胶囊中。适合的液体及半固体剂型包括碳酸亚丙酯、植物油或三酸甘油酯中的溶液及悬浮液。含有此类溶液的胶囊可如美国专利号4,328,245;4,409,239;以及4,410,545中所描述制备。如本领域技术人员已知,还可涂布胶囊以改进或维持活性成分的溶解。
本文所提供的用于经口给药的药物组合物可以液体及半固体剂型提供,包括乳液、溶液、悬浮液、酏剂及糖浆剂。乳液为两相系统,其中一种液体以小球体形式遍及另一种液体分散,其可为水包油或油包水。乳液可包括药学上可接受的非水性液体或溶剂、乳化剂及防腐剂。悬浮液可包括药学上可接受的悬浮剂及防腐剂。水性醇性溶液可包括药学上可接受的缩醛,诸如低级烷基醛的二(低级烷基)缩醛,例如乙醛二乙醇缩乙醛;以及具有一个或多个羟基的水可混溶性溶剂,诸如丙二醇及乙醇。酏剂为澄清、增甜及水醇性溶液。糖浆剂为糖(例如蔗糖)的浓缩水溶液且还可含有防腐剂。对于液体剂型,例如,聚乙二醇中的溶液可用足量的药学上可接受的液体载剂(例如水)稀释,其量量测为便于给药。
其他适用液体及半固体剂型包括但不限于含有本文所提供的活性成分及以下物质的那些剂型:二烷基化单烷二醇或聚烷二醇,包括1,2-二甲氧基甲烷、二乙二醇二甲醚、三乙二醇二甲醚、四乙二醇二甲醚、聚乙二醇-350-二甲醚、聚乙二醇-550-二甲醚、聚乙二醇-750-二甲醚,其中350、550及750是指聚乙二醇的大致平均分子量。此等配制品可进一步包含一种或多种抗氧化剂,诸如丁羟甲苯(BHT)、丁羟茴香醚(BHA)、没食子酸丙酯、维生素E、对苯二酚、羟基香豆素、乙醇胺、卵磷脂、脑磷脂、抗坏血酸、苹果酸、山梨醇、磷酸、亚硫酸氢盐、焦亚硫酸钠、硫二丙酸及其酯及二硫代氨基甲酸酯。
本文所提供的用于经口给药的药物组合物还可以脂质体、胶束、微球体或纳米系统的形式提供。胶束剂型可如美国专利号6,350,458中所描述制备。
本文所提供的用于经口给药的药物组合物可以待复原成液体剂型的非发泡或发泡、颗粒及粉末形式提供。用于非发泡颗粒或粉末中的药学上可接受的载剂及赋形剂可包括稀释剂、甜味剂及润湿剂。用于发泡颗粒或粉末中的药学上可接受的载剂及赋形剂可包括有机酸及二氧化碳来源。
着色剂及调味剂可用于所有以上剂型中。
本文所提供的用于经口给药的药物组合物可以立即或改进释放剂型配制,包括延迟释放形式、持续释放形式、脉冲释放形式、控制释放形式、靶向释放形式及程控释放形式。
B.非经肠给药
本文所提供的药物组合物可通过注射、灌注或植入而非经肠给予,以用于局部或全身给药。如本文所用,非经肠给药包括静脉内、动脉内、腹膜内、鞘内、心室内、尿道内、胸骨内、颅内、肌内、滑膜内、膀胱内及皮下给药。
本文所提供的用于非经肠给药的药物组合物可以任何适合于非经肠给药的剂型(包括溶液、悬浮液、乳液、胶束、脂质体、微球体、纳米系统)及适合于在注射之前溶解或悬浮于液体中的固体形式配制。此类剂型可根据熟习医药科学技术者已知的常规方法来制备(参见Remington:The Science and Practice of Pharmacy,同前文献)。
欲用于非经肠给药的药物组合物可包括一种或多种药学上可接受的载剂及赋形剂,包括但不限于水性媒剂、水可混溶性媒剂、非水性媒剂、对抗微生物生长的抗微生物剂或防腐剂、稳定剂、溶解度增强剂、等渗剂、缓冲剂、抗氧化剂、局部麻醉剂、悬浮剂及分散剂、润湿剂或乳化剂、络合剂、钳合剂或螯合剂、低温保护剂、冻干保护剂、增稠剂、pH值调节剂及惰性气体。
适合的水性媒剂包括但不限于水、食盐水、生理食盐水或磷酸盐缓冲盐水(PBS)、氯化钠注射液、林格氏注射液(Ringers injection)、等渗右旋糖注射液、无菌水注射液、右旋糖及乳酸林格氏注射液。适合的非水性媒剂包括但不限于植物来源的非挥发性油,蓖麻油、玉米油、棉籽油、橄榄油、花生油、薄荷油、红花油、芝麻油、大豆油、氢化植物油、氢化大豆油及椰子油的中链三酸甘油酯,及棕榈籽油。适合的水可混溶性媒剂包括但不限于乙醇、1,3-丁二醇、液体聚乙二醇(例如聚乙二醇300及聚乙二醇400)、丙二醇、甘油、N-甲基-2-吡咯烷酮、N,N-二甲基乙酰胺及二甲亚砜。
适合的抗微生物剂或防腐剂包括但不限于苯酚、甲酚、汞剂、苯甲醇、氯丁醇、对羟基苯甲酸甲酯及对羟基苯甲酸丙酯(methyl and propyl p-hydroxybenzoates)、硫柳汞、苯扎氯铵(例如苄索氯铵)、对羟基苯甲酸甲酯及对羟基苯甲酸丙酯(methyl-and propyl-parabens)以及山梨酸。适合的等渗剂包括但不限于氯化钠、甘油及右旋糖。适合的缓冲剂包括但不限于磷酸盐及柠檬酸盐。适合的抗氧化剂为如本文所描述的那些抗氧化剂,包括亚硫酸氢盐及焦亚硫酸钠。适合的局部麻醉剂包括但不限于盐酸普鲁卡因(procainehydrochloride)。适合的悬浮剂及分散剂为如本文所描述的那些悬浮剂及分散剂,包括羧甲基纤维素钠、羟丙基甲基纤维素及聚乙烯吡咯烷酮。适合的乳化剂为本文中所描述的那些乳化剂,包括聚氧化乙烯脱水山梨糖醇单月桂酸酯、聚氧化乙烯脱水山梨糖醇单油酸酯80及油酸三乙醇胺。适合的钳合剂或螯合剂包括但不限于EDTA。适合的pH值调节剂包括但不限于氢氧化钠、盐酸、柠檬酸及乳酸。适合的络合剂包括但不限于环糊精,包括α-环糊精、β-环糊精、羟丙基-β-环糊精、磺基丁醚-β-环糊精及磺基丁醚7-β-环糊精(CyDex,Lenexa,KS)。
当本文所提供的药物组合物经配制用于多剂量给药时,这些多剂量非经肠配制品必须含有抑制细菌或抑制真菌浓度的抗菌剂。如此项技术中已知及实践的,所有非经肠配制品必须为无菌的。
在一个实施例中,用于非经肠给药的药物组合物以即用型无菌溶液形式提供。在另一个实施例中,药物组合物以待在使用的前用媒剂复原的无菌干燥可溶产品形式提供,包括冻干粉末及皮下片剂。在又另一个实施例中,药物组合物以即用型无菌悬浮液形式提供。在又另一个实施例中,药物组合物以待在使用的前用媒剂复原的无菌干燥不可溶产品形式提供。在再另一个实施例中,药物组合物以即用型无菌乳液形式提供。
本文所提供的用于非经肠给药的药物组合物可以立即或改进释放剂型配制,包括延迟释放形式、持续释放形式、脉冲释放形式、控制释放形式、靶向释放形式及程控释放形式。
本文所提供的用于非经肠给药的药物组合物可以悬浮液、固体、半固体或触便性液体形式配制,以用于以植入储存物形式给药。在一个实施例中,本文所提供的药物组合物分散于固体内部基质中,该内部基质由在体液中不可溶但允许药物组合物中的活性成分扩散通过的外部聚合膜包裹。
适合的内部基质包括但不限于聚甲基丙烯酸甲酯、聚甲基丙烯酸丁酯、增塑或非增塑聚氯乙烯、增塑尼龙、增塑聚对苯二甲酸伸乙酯、天然橡胶、聚异戊二烯、聚异丁烯、聚丁二烯、聚乙烯、乙烯-乙酸乙烯酯共聚物、聚硅氧橡胶、聚二甲基硅氧烷、聚硅氧碳酸酯共聚物、亲水性聚合物(诸如丙烯酸及甲基丙烯酸的酯的水凝胶)、胶原蛋白、交联聚乙烯醇及交联部分水解聚乙酸乙烯酯。
适合的外部聚合膜包括但不限于聚乙烯、聚丙烯、乙烯/丙烯共聚物、乙烯/丙烯酸乙酯共聚物、乙烯/乙酸乙烯酯共聚物、聚硅氧橡胶、聚二甲基硅氧烷、氯丁橡胶、氯化聚乙烯、聚氯乙烯、氯乙烯与乙酸乙烯酯、偏二氯乙烯、乙烯及丙烯的共聚物、离聚物聚对苯二甲酸伸乙酯、丁基橡胶表氯醇橡胶、乙烯/乙烯醇共聚物、乙烯/乙酸乙烯酯/乙烯醇三元共聚物及乙烯/乙烯氧基乙醇共聚物。
C.局部给药
本文所提供的药物组合物可向皮肤、孔口或粘膜局部给予。如本文所用,局部给药包括经皮(皮内)、经结膜、角膜内、眼内、经眼、经耳、透皮、经鼻、经阴道、经尿道、经呼吸道及经直肠给药。
本文所提供的药物组合物可以适合于局部给药的任何剂型配制以获得局部或全身作用,包括乳液、溶液、悬浮液、乳膏、凝胶、水凝胶、软膏、敷粉、敷料、酏剂、洗剂、悬浮液、酊剂、糊剂、发泡体、膜、气雾剂、冲洗剂、喷雾剂、栓剂、绷带及经皮贴片。本文所提供的药物组合物的局部配制品还可包含脂质体、胶束、微球体、纳米系统及其混合物。
适用于本文所提供的局部配制品中的药学上可接受的载剂及赋形剂包括但不限于水性媒剂、水可混溶性媒剂、非水性媒剂、对抗微生物生长的抗微生物剂或防腐剂、稳定剂、溶解度增强剂、等渗剂、缓冲剂、抗氧化剂、局部麻醉剂、悬浮剂及分散剂、润湿剂或乳化剂、络合剂、钳合剂或螯合剂、渗透增强剂、低温保护剂、冻干保护剂、增稠剂及惰性气体。
药物组合物还可通过电致孔、离子电渗法、超声波药物透入疗法、超声波电渗法或微针或无针注射局部给予,诸如POWDERJECTTM(Chiron Corp.,Emeryville,CA)及BIOJECTTM(Bioject Medical Technologies Inc.,Tualatin,OR)。
本文所提供的药物组合物可以软膏、乳膏及凝胶形式提供。适合的软膏媒剂包括油性或烃媒剂,包括猪油、苯甲酸豚脂、橄榄油、棉籽油及其他油、白石蜡脂;可乳化或吸收媒剂,诸如亲水性石蜡脂、羟基硬脂硫酸酯及无水羊毛脂;水可移除型媒剂,诸如亲水性软膏;水可溶软膏媒剂,包括不同分子量的聚乙二醇;乳液媒剂,油包水(W/O)乳液或水包油(O/W)乳液,包括鲸蜡基醇、单硬脂酸甘油酯、羊毛脂及硬脂酸(参见Remington:TheScience and Practice of Pharmacy,同前文献)。此等媒剂为润肤剂,但通常需要添加抗氧化剂及防腐剂。
适合的乳膏基质可为水包油或油包水。适合的乳膏媒剂可为水可洗的,且含有油相、乳化剂及水相。油相还称为“内部”相,其通常包含石蜡脂及脂肪醇,诸如鲸蜡醇或硬脂醇。水相通常(但未必)在体积上超过油相,且通常含有保湿剂。乳膏配制品中的乳化剂可为非离子、阴离子、阳离子或两性表面活性剂。
凝胶为半固体、悬浮液型系统。单相凝胶含有遍及液体载剂基本上均匀分布的有机大分子。适合的胶凝剂包括但不限于交联丙烯酸聚合物,诸如卡波姆(carbomer)、羧基聚亚烷基及;亲水性聚合物,诸如聚氧化乙烯、聚氧化乙烯-聚氧化丙烯共聚物及聚乙烯醇;纤维素聚合物,诸如羟丙基纤维素、羟乙基纤维素、羟丙基甲基纤维素、邻苯二甲酸羟丙基甲基纤维素及甲基纤维素;胶,诸如黄蓍胶及黄原胶;海藻酸钠;以及明胶。为制备均匀凝胶,可添加诸如醇或甘油的分散剂,或可通过湿磨、机械混合和/或搅拌来使胶凝剂分散。
在此提供的药物组合物可以经直肠、经尿道、经阴道、或经膀胱按以下形式给药:栓剂、阴道栓、探条(bougies)、泥敷剂或泥罨剂、糊剂、粉末、敷料、膏、硬膏剂、避孕剂、软膏、溶液、乳液、悬浮液、棉球、凝胶、泡沫、喷雾剂、或灌肠剂。此等剂型可使用如Remington:The Science and Practice of Pharmacy,同前文献中所描述的常规方法制造。
经直肠、经尿道及经阴道栓剂为用于插入身体孔口的固态物体,其在常温下为固体,但在体温下熔融或软化以在孔口内侧释放活性成分。经直肠及经阴道栓剂中所用的药学上可接受的载剂包括基质或媒剂,诸如硬化剂,其在与本文所提供的药物组合物配制时产生接近体温的熔点;以及如本文所描述的抗氧化剂,包括亚硫酸氢盐及焦亚硫酸钠。适合的媒剂包括但不限于可可豆油(可可油)、甘油-明胶、聚乙二醇(聚氧化乙烯二醇)、鲸蜡、石蜡、白色及黄色蜡,及脂肪酸的单甘油酯、二甘油酯及三甘油酯的适当混合物,及水凝胶,诸如聚乙烯醇、甲基丙烯酸羟基乙酯及聚丙烯酸。还可使用各种媒剂的组合。可通过压缩或模制来制备经直肠及经阴道栓剂。经直肠及经阴道栓剂的典型重量为约2至约3g。
本文所提供的药物组合物可以溶液、悬浮液、软膏、乳液、成胶溶液、用于溶液的粉末、凝胶、眼部插入物及植入剂形式经眼给予。
本文所提供的药物组合物可鼻内给予或通过吸入向呼吸道给予。药物组合物可以气雾剂或溶液形式(单独或与适合的推进剂(诸如1,1,1,2-四氟乙烷或1,1,1,2,3,3,3-七氟丙烷)组合)提供,以用于使用加压容器、泵、喷雾器、雾化器(诸如使用电流体动力学以产生精细薄雾的雾化器)或喷洒器传递。药物组合物还可以用于吹入的干粉(单独或与惰性载剂(诸如乳糖或磷脂)组合);以及经鼻滴剂形式提供。对于鼻内使用,粉末可包含生物粘着剂,包括聚葡萄胺糖或环糊精。
用于加压容器、泵、喷雾器、雾化器或喷洒器中的溶液或悬浮液可经配制以含有乙醇、乙醇水溶液或适用于本文所提供的活性成分的分散、增溶或延长释放的替代性试剂;作为溶剂的推进剂;和/或表面活性剂,诸如脱水山梨糖醇三油酸酯、油酸或寡聚乳酸。
本文所提供的药物组合物可微米尺寸化为适用于通过吸入传递的尺寸,诸如约50微米或50微米以下,或约10微米或10微米以下。此类尺寸的粒子可使用本领域技术人员已知的粉碎方法制备,诸如螺旋喷射研磨、流化床喷射研磨、用于形成纳米粒子的超临界流体加工、高压均质化或喷雾干燥。
用于吸入器或吹入器的胶囊、泡罩及药筒可经配制以含有以下物质的粉末混合物:本文所提供的药物组合物;适合的粉末基质,诸如乳糖或淀粉;以及性能改良剂,诸如l-白胺酸、甘露醇或硬脂酸镁。乳糖可为无水的或呈单水合物形式。其他适合的赋形剂或载剂包括但不限于聚葡萄糖、葡萄糖、麦芽糖、山梨醇、木糖醇、果糖、蔗糖及海藻糖。本文所提供的用于吸入/鼻内给药的药物组合物可进一步包含适合的调味剂,诸如薄荷醇及左薄荷脑;和/或甜味剂,诸如糖精及糖精钠。
本文所提供的用于局部给药的药物组合物可经配制以立即释放或改进释放,包括延迟释放、持续释放、脉冲释放、控制释放、靶向释放及程控释放。
D.改进释放
本文所提供的药物组合物可配制为改进释放剂型。如本文所用,术语「改进释放”是指其中在通过相同途径给予时,活性成分的释放速率或位置与立即释放剂型不同的剂型。改进释放剂型包括但不限于延迟释放、缓释、延长释放、持续释放、脉冲释放、控制释放、加速释放及快速释放、靶向释放、程控释放,及胃滞留剂型。改进释放剂型中的药物组合物可使用本领域技术人员已知的多种改进释放装置及方法制备,包括但不限于基质控制释放装置、渗透控制释放装置、多微粒控制释放装置、离子交换树脂、肠溶衣、多层包衣、微球体、脂质体及其组合。还可通过改变活性成分的粒度及多形现象来改良一种或多种活性成分的释放速率。
改进释放的实例包括但不限于描述于以下中的改进释放:美国专利号3,845,770;3,916,899;3,536,809;3,598,123;4,008,719;5,674,533;5,059,595;5,591,767;5,120,548;5,073,543;5,639,476;5,354,556;5,639,480;5,733,566;5,739,108;5,891,474;5,922,356;5,958,458;5,972,891;5,980,945;5,993,855;6,045,830;6,087,324;6,113,943;6,197,350;6,248,363;6,264,970;6,267,981;6,270,798;6,375,987;6,376,461;6,419,961;6,589,548;6,613,358;6,623,756;6,699,500;6,793,936;6,827,947;6,902,742;6,958,161;7,255,876;7,416,738;7,427,414;7,485,322号;Bussemer等人,Crit.Rev.Ther.Drug Carrier Syst.2001,18,433-458;Modified-Release DrugDelivery Technology,第2版;Rathbone等人编;Marcel Dekker AG:2005;Maroni等人,Expert.Opin.Drug Deliv.2005,2,855-871;Shi等人,Expert Opin.Drug Deliv.2005,2,1039-1058;Polymers in Drug Delivery;Ijeoma等人编;CRC Press LLC:Boca Raton,FL,2006;Badawy等人,J.Pharm.Sci.2007,9,948-959;Modified-Release Drug DeliveryTechnology,同前文献;Conway,Recent Pat.Drug Deliv.Formul.2008,2,1-8;Gazzaniga等人,Eur.J.Pharm.Biopharm.2008,68,11-18;Nagarwal等人,Curr.Drug Deliv.2008,5,282-289;Gallardo等人,Pharm.Dev.Technol.2008,13,413-423;Chrzanowski,AAPSPharmSciTech.2008,9,635-638;Chrzanowski,AAPS PharmSciTech.2008,9,639-645;Kalantzi等人,Recent Pat.Drug Deliv.Formul.2009,3,49-63;Saigal等人,RecentPat.Drug Deliv.Formul.2009,3,64-70;以及Roy等人,J.Control Release 2009,134,74-80。
1.基质控制释放装置
本文所提供的改进释放剂型中的药物组合物可使用本领域技术人员已知的基质控制释放装置来制造。参见Takada等人在Encyclopedia of Controlled Drug Delivery;Mathiowitz编;Wiley:1999;第2卷中。
在某些实施例中,本文所提供的改进释放剂型中的药物组合物使用可侵蚀基质装置来配制,该可侵蚀基质装置为水可膨胀、可侵蚀或可溶聚合物,包括但不限于合成聚合物,及天然存在的聚合物及衍生物,诸如多糖及蛋白质。
适用于形成可侵蚀基质的材料包括但不限于几丁质、聚葡萄胺糖、聚葡萄糖及普鲁兰(pullulan);琼脂胶、阿拉伯胶、卡拉牙树胶(gum karaya)、刺槐豆胶、黄蓍胶、角叉菜胶、茄替胶、瓜尔豆胶、黄原胶及硬葡聚糖;淀粉,诸如糊精及麦芽糊精;亲水性胶体,诸如果胶;磷脂,诸如卵磷脂;海藻酸盐;丙二醇海藻酸酯;明胶;胶原蛋白;纤维素材料,诸如乙基纤维素(EC)、甲基乙基纤维素(MEC)、羧甲基纤维素(CMC)、CMEC、羟乙基纤维素(HEC)、羟丙基纤维素(HPC)、乙酸纤维素(CA)、丙酸纤维素(CP)、丁酸纤维素(CB)、乙酸丁酸纤维素(CAB)、CAP、CAT、羟丙基甲基纤维素(HPMC)、HPMCP、HPMCAS、羟丙基甲基乙酸苯偏三酸纤维素(HPMCAT)及乙基羟乙基纤维素(EHEC);聚乙烯吡咯烷酮;聚乙烯醇;聚乙酸乙烯酯;甘油脂肪酸酯;聚丙烯酰胺;聚丙烯酸;乙基丙烯酸与甲基丙烯酸的共聚物(Rohm America,Inc.,Piscataway,NJ);聚(甲基丙烯酸2-羟基乙酯);聚乳酸交酯;L-谷氨酸与L-谷氨酸乙酯的共聚物;可降解乳酸-乙醇酸共聚物;聚-D-(-)-3-羟基丁酸;以及其他丙烯酸衍生物,诸如甲基丙烯酸丁酯、甲基丙烯酸甲酯、甲基丙烯酸乙酯、丙烯酸乙酯、(2-二甲基氨基乙基)甲基丙烯酸酯及(三甲基氨基乙基)甲基丙烯酸酯氯化物的均聚物及共聚物。
在某些实施例中,用非可侵蚀基质装置来配制本文所提供的药物组合物。活性成分溶解或分散于惰性基质中且在给予后主要通过扩散通过惰性基质来释放。适用作非可侵蚀基质装置的材料包括但不限于不可溶塑料,诸如聚乙烯、聚丙烯、聚异戊二烯、聚异丁烯、聚丁二烯、聚甲基丙烯酸甲酯、聚甲基丙烯酸丁酯、氯化聚乙烯、聚氯乙烯、丙烯酸甲酯-甲基丙烯酸甲酯共聚物、乙烯-乙酸乙烯酯共聚物、乙烯/丙烯共聚物、乙烯/丙烯酸乙酯共聚物、氯乙烯与乙酸乙烯酯、偏二氯乙烯、乙烯及丙烯的共聚物、离聚物聚对苯二甲酸伸乙酯、丁基橡胶、表氯醇橡胶、乙烯/乙烯醇共聚物、乙烯/乙酸乙烯酯/乙烯醇三元共聚物、乙烯/乙烯氧基乙醇共聚物、聚氯乙烯、增塑尼龙、增塑聚对苯二甲酸伸乙酯、天然橡胶、聚硅氧橡胶、聚二甲基硅氧烷及聚硅氧碳酸酯共聚物;亲水性聚合物,诸如乙基纤维素、乙酸纤维素、交联维酮及交联部分水解聚乙酸乙烯酯;以及脂肪化合物,诸如巴西棕榈蜡、微晶蜡及三酸甘油酯。
在基质控制释放系统中,可例如经由所采用的聚合物类型、聚合物粘度、聚合物和/或一种或多种活性成分的粒度、一种或多种活性成分与聚合物的比率及组合物中的其他赋形剂或载剂来控制所要的释放动力学。
本文所提供的改进释放剂型中的药物组合物可通过本领域技术人员已知的方法来制备,包括直接压缩、干式或湿式造粒接着压缩,及熔融造粒接着压缩。
2.渗透控制释放装置
本文所提供的改进释放剂型中的药物组合物可使用渗透控制释放装置来制造,包括但不限于单腔室系统、双腔室系统、不对称膜技术(AMT)及挤出芯系统(ECS)。通常,此类装置具有至少两个部件:(a)含有活性成分的芯;以及(b)具有至少一个传递端口的半渗透膜,其包封芯。半渗透膜控制水自水性使用环境流入芯,以便通过挤压通过传递端口来引起药物释放。
除活性成分以外,渗透装置的芯任选地包括渗透剂,其产生用于使水自使用环境输送至装置芯中的驱动力。一类渗透剂为水可膨胀型亲水性聚合物,其还称为“渗透聚合物”及“水凝胶”。适用作为渗透剂的水可膨胀型亲水性聚合物包括但不限于亲水性乙烯基及丙烯酸聚合物、多糖(诸如海藻酸钙)、聚氧化乙烯(PEO)、聚乙二醇(PEG)、聚丙二醇(PPG)、聚(甲基丙烯酸2-羟基乙酯)、聚(丙烯)酸、聚(甲基丙烯)酸、聚乙烯吡咯烷酮(PVP)、交联PVP、聚乙烯醇(PVA)、PVA/PVP共聚物、PVA/PVP与疏水性单体(诸如甲基丙烯酸甲酯及乙酸乙烯酯)的共聚物、含有大PEO嵌段的亲水性聚氨基甲酸酯、交联羧甲纤维素钠、角叉菜胶、羟乙基纤维素(HEC)、羟丙基纤维素(HPC)、羟丙基甲基纤维素(HPMC)、羧甲基纤维素(CMC)及羧基乙基纤维素(CEC)、海藻酸钠、聚卡波非(polycarbophil)、明胶、黄原胶及羟基乙酸淀粉钠。
另一类渗透剂为渗透原(osmogens),其能够吸取水以影响跨越周围包衣的屏障的渗透压梯度。适合的渗透原包括但不限于无机盐,诸如硫酸镁、氯化镁、氯化钙、氯化钠、氯化锂、硫酸钾、磷酸钾、碳酸钠、亚硫酸钠、硫酸锂、氯化钾及硫酸钠;糖,诸如右旋糖、果糖、葡萄糖、肌醇、乳糖、麦芽糖、甘露醇、棉子糖、山梨醇、蔗糖、海藻糖及木糖醇;有机酸,诸如抗坏血酸、苯甲酸、反丁烯二酸、柠檬酸、顺丁烯二酸、癸二酸、山梨酸、己二酸、依地酸(edetic acid)、谷氨酸、对甲苯磺酸、丁二酸及酒石酸;尿素;以及其混合物。
可使用不同溶解速率的渗透剂以影响活性成分最初自剂型传递的速率。例如,非晶形糖(诸如MANNOGEMTMEZ(SPI Pharma,Lewes,DE))可用于在最初数小时期间提供更快的传递以迅速地产生所要的治疗作用,且逐渐及持续释放剩余量以在延长时间段内维持治疗或预防性作用的所要水平。在此情况下,活性成分以此类速率释放以置换代谢及排泄的活性成分的量。
芯还可包括广泛多种如本文所描述的其他赋形剂及载剂,以增强剂型的性能或促进稳定性或加工。
适用于形成半渗透膜的材料包括各种等级的在生理学上相关pH值下水可渗透且不可溶于水,或对通过化学变化(诸如交联)赋予不可溶于水的性质敏感的丙烯酸聚合物、聚乙烯、醚、聚酰胺、聚酯及纤维素衍生物。适用于形成包衣的适合聚合物的实例包括增塑、非增塑及强化乙酸纤维素(CA)、二乙酸纤维素、三乙酸纤维素、丙酸CA、硝酸纤维素、乙酸丁酸纤维素(CAB)、乙基氨基甲酸CA、CAP、甲基氨基甲酸CA、丁二酸CA、乙酸苯偏三酸纤维素(CAT)、二甲基氨基乙酸CA、乙基碳酸CA、氯乙酸CA、乙基草酸CA、甲基磺酸CA、丁基磺酸CA、对甲苯磺酸CA、乙酸琼脂、三乙酸直链淀粉、乙酸β葡聚糖、三乙酸β葡聚糖、二甲基乙酸乙醛、刺槐豆胶的三乙酸酯、羟基化乙烯-乙酸乙烯酯、EC、PEG、PPG、PEG/PPG共聚物、PVP、HEC、HPC、CMC、CMEC、HPMC、HPMCP、HPMCAS、HPMCAT、聚(丙烯)酸及酯以及聚(甲基丙烯)酸及酯及其共聚物、淀粉、聚葡萄糖、糊精、聚葡萄胺糖、胶原蛋白、明胶、聚烯烃、聚醚、聚砜、聚醚砜、聚苯乙烯、聚乙烯卤化物、聚乙烯酯及醚、天然蜡及合成蜡。
半渗透膜还可为疏水性微孔膜,其中孔实质上填充有气体且不由水性介质湿润但对水蒸气是可透的,如美国专利号5,798,119号中所披露。此类疏水性但水蒸气渗透膜典型地由疏水性聚合物(诸如聚烯烃、聚乙烯、聚丙烯、聚四氟乙烯、聚丙烯酸衍生物、聚醚、聚砜、聚醚砜、聚苯乙烯、聚乙烯卤化物、聚偏二氟乙烯、聚乙烯酯及醚、天然蜡及合成蜡)构成。
半渗透膜上的传递端口可在包覆包衣后通过机械或激光钻孔形成。传递端口还可通过对水可溶材料的栓塞进行冲蚀或通过使芯中凹口上膜的较薄部分破裂来现场形成。另外,传递端口可在包覆包衣过程期间形成,如在美国专利号5,612,059及5,698,220中所披露的类型的不对称膜包衣的情况下。
所释放的活性成分的总量及释放速率可基本上经由半渗透膜的厚度及孔隙度、芯的组成以及传递端口的数目、尺寸及位置来调节。
渗透控制释放剂型中的药物组合物可进一步包含其他如本文所描述的习知赋形剂或载剂以有助于配制品的性能或加工。
渗透控制释放剂型可根据本领域技术人员已知的常规方法及技术来制备。参见Remington:The Science and Practice of Pharmacy,同前文献;Santus及Baker,J.Controlled Release 1995,35,1-21;Verma等人,Drug Development and IndustrialPharmacy 2000,26,695-708;以及Verma等人,J.Controlled Release 2002,79,7-27。
在某些实施例中,本文所提供的药物组合物配制为AMT控制释放剂型,其包含包复芯的不对称渗透膜,该芯包含活性成分及其他药学上可接受的赋形剂或载剂。参见美国专利号5,612,059及国际公开案号WO2002/17918。AMT控制释放剂型可根据本领域技术人员已知的常规方法及技术来制备,包括直接压缩、干式造粒、湿式造粒及浸涂方法。
在某些实施例中,本文所提供的药物组合物配制为ESC控制释放剂型,其包含包复芯的渗透膜,该芯包含活性成分、羟乙基纤维素及其他药学上可接受的赋形剂或载剂。
3.多微粒控制释放装置
本文所提供的改进释放剂型中的药物组合物可以多微粒控制释放装置形式制造,其包含大量直径介于约10μm至约3mm、约50μm至约2.5mm或约100μm至约1mm范围内的粒子、颗粒或丸粒。此类多颗粒物可通过本领域技术人员已知的方法来制造,包括湿式及干式造粒、挤压/滚圆、滚筒压实、熔融凝结及通过喷雾包覆种芯。参见例如MultiparticulateOral Drug Delivery;Ghebre-Sellassie编;Marcel Dekker:1994;以及PharmaceuticalPelletization Technology;Ghebre-Sellassie编;Marcel Dekker:1989。
如本文所描述的其他赋形剂或载剂可与药物组合物掺合以帮助加工及形成多颗粒物。所得粒子本身可构成多微粒装置或可由各种成膜材料(诸如肠溶聚合物、水可膨胀及水可溶聚合物)包覆。多颗粒物可进一步加工成胶囊或片剂。
4.靶向传递
本文所提供的药物组合物还可经配制以靶向所治疗的受试者的身体的特定组织、受体或其他区域,包括基于脂质体、重新包封红血球及抗体的传递系统。实例包括但不限于美国专利号5,709,874;5,759,542;5,840,674;5,900,252;5,972,366;5,985,307;6,004,534;6,039,975;6,048,736;6,060,082;6,071,495;6,120,751;6,131,570;6,139,865;6,253,872;6,271,359;6,274,552;6,316,652;以及号7,169,410中所披露的那些实例。
使用方法
在一个实施例中,本文提供一种治疗、预防或改善受试者中RC激酶介导的病症、疾病或病状的一种或多种症状的方法,其包含向该受试者给予本文所提供的化合物,例如式I的化合物,包括其立体异构体、对映异构体、对映异构体的混合物、非对映异构体的混合物或同位素变体;或其药学上可接受的盐、溶剂合物、水合物或前药。
在另一个实施例中,本文提供一种治疗、预防或改善受试者中响应于RC激酶活性调节的病症、疾病或病状的一种或多种症状的方法,其向该受试者给予本文所提供的化合物,例如式I的化合物,包括其立体异构体、对映异构体、对映异构体的混合物、非对映异构体的混合物或同位素变体;或其药学上可接受的盐、溶剂合物、水合物或前药。
在又另一个实施例中,本文提供一种治疗、预防或改善受试者中响应于RC激酶活性抑制的病症、疾病或病状的一种或多种症状的方法,其向该受试者给予本文所提供的化合物,例如式I的化合物,包括其立体异构体、对映异构体、对映异构体的混合物、非对映异构体的混合物或同位素变体;或其药学上可接受的盐、溶剂合物、水合物或前药。
在又另一个实施例中,本文提供一种用于治疗、预防或改善受试者中嗜酸性细胞相关病症、疾病或病状的一种或多种症状的方法,其包含向该受试者给予本文所提供的化合物,例如式I的化合物,包括其立体异构体、对映异构体、对映异构体的混合物、非对映异构体的混合物或同位素变体;或其药学上可接受的盐、溶剂合物、水合物或前药。
在又另一个实施例中,本文提供一种用于治疗、预防或改善受试者中嗜碱性细胞相关病症、疾病或病状的一种或多种症状的方法,其包含向该受试者给予本文所提供的化合物,例如式I的化合物,包括其立体异构体、对映异构体、对映异构体的混合物、非对映异构体的混合物或同位素变体;或其药学上可接受的盐、溶剂合物、水合物或前药。
在又另一个实施例中,本文提供一种用于治疗、预防或改善受试者中肥大细胞相关病症、疾病或病状的一种或多种症状的方法,其包含向该受试者给予本文所提供的化合物,例如式I的化合物,包括其立体异构体、对映异构体、对映异构体的混合物、非对映异构体的混合物或同位素变体;或其药学上可接受的盐、溶剂合物、水合物或前药。
在再另一个实施例中,本文提供一种用于治疗、预防或改善受试者中发炎性疾病的一种或多种症状的方法,其包含向该受试者给予本文所提供的化合物,例如式I的化合物,包括其立体异构体、对映异构体、对映异构体的混合物、非对映异构体的混合物或同位素变体;或其药学上可接受的盐、溶剂合物、水合物或前药。
在一个实施例中,受试者为哺乳动物。在另一个实施例中,受试者为人类。
可用本文所提供的化合物,例如式I的化合物(包括其立体异构体、对映异构体、对映异构体的混合物、非对映异构体的混合物或同位素变体;或其药学上可接受的盐、溶剂合物、水合物或前药)治疗的病症、疾病或病状包括但不限于,(1)发炎性或过敏性疾病,包括全身性过敏反应及超敏反应病症、异位性皮炎、荨麻疹、药物过敏、昆虫螫过敏、食物过敏(包括乳糜泻及其类似疾病)及肥大细胞增多症;(2)发炎性肠病,包括克罗恩氏病(Crohn'sdisease)、溃疡性结肠炎、回肠炎及肠炎;(3)脉管炎及白塞氏症候群(Behcet'ssyndrome);(4)牛皮癣及发炎性皮肤病,包括皮炎、湿疹、异位性皮炎、过敏性接触性皮炎、荨麻疹、病毒性皮肤病变(包括来源于人类乳突状瘤病毒、HIV或RLV感染的那些病变)、细菌、真菌及其他寄生性皮肤病变、及皮肤红斑狼疮;(5)哮喘及呼吸道过敏性疾病,包括过敏性哮喘、运动诱发的哮喘、过敏性鼻炎、中耳炎、过敏性结膜炎、超敏反应肺病及慢性阻塞性肺病;(6)自身免疫疾病,包括关节炎(包括类风湿性及牛皮癣性)、系统性红斑狼疮、I型糖尿病、重症肌无力、多发性硬化症、格雷夫斯氏病(Graves'disease)及丝球体肾炎;(7)移植物排斥(包括同种异体移植排斥及移植物对抗宿主疾病),例如皮肤移植物排斥、实体器官移植排斥、骨髓移植排斥;(8)发热;(9)心血管病症,包括急性心脏衰竭、低血压、高血压、心绞痛、心肌梗塞、心肌病、充血性心脏衰竭、动脉粥样硬化、冠状动脉疾病、再狭窄及血管狭窄;(10)脑血管病症,包括创伤性脑损伤、中风、局部缺血性再灌注损伤及动脉瘤;(11)乳癌、皮肤癌、前列腺癌、子宫颈癌、子宫癌、卵巢癌、睪丸癌、膀胱癌、肺癌、肝癌、喉癌、口腔癌、结肠癌及胃肠道癌(例如食道癌、胃癌、胰脏癌)、脑癌、甲状腺癌、血癌及淋巴系统癌;(12)纤维化、结缔组织疾病及类肉瘤病,(13)生殖器及生殖病症,包括勃起功能障碍;(14)胃肠病症,包括胃炎、溃疡、恶心、胰脏炎及呕吐;(15)神经病症,包括阿兹海默氏病(Alzheimer's disease);(16)睡眠失调,包括失眠、发作性睡病、睡眠呼吸暂停症候群及匹克威克症候群(Pickwick Syndrome);(17)疼痛;(18)肾功能异常;(19)眼部病症,包括青光眼;以及(20)感染性疾病,包括HIV。
在某些实施例中,病症、疾病或病状是选自下组,该组由以下各项组成:哮喘、过敏性哮喘、运动诱发的哮喘、过敏性鼻炎、常年性过敏性鼻炎、季节性过敏性鼻炎、异位性皮炎、接触性超敏反应、接触性皮炎、结膜炎、过敏性结膜炎、嗜酸性细胞性支气管炎、食物过敏、嗜酸性细胞性胃肠炎、发炎性肠病、溃疡性结肠炎、克罗恩氏病、肥大细胞增多症、高IgE综合症、系统性红斑狼疮、牛皮癣、痤疮、多发性硬化症、同种异体移植排斥、再灌注损伤、慢性阻塞性肺病(COPD)、丘-施二氏综合征(Churg-Strauss syndrome)、窦炎、嗜碱性细胞性白血病、慢性荨麻疹、嗜碱性细胞增多、湿疹、关节炎、类风湿性关节炎、牛皮癣性关节炎及骨关节炎。
在某些实施例中,病症、疾病或病状为哮喘、运动诱发的哮喘、过敏性鼻炎、异位性皮炎、慢性阻塞性肺病或过敏性结膜炎。在某些实施例中,病症、疾病或病状为COPD。
视待治疗的病症、疾病或病状及受试者的条件而定,本文所提供的化合物或药物组合物可通过经口、非经肠(例如肌内、腹膜内、静脉内、ICV、脑池内注射或灌注、皮下注射或植入)、吸入、经鼻、经阴道、经直肠、舌下或局部(topical)(例如透皮或局部(local))给药途径给予,且可单独或以适合的剂量单位与适用于各给药途径的药学上可接受的赋形剂、载剂、辅料及媒剂一起配制。本文还提供本文所提供的化合物或药物组合物于储存配制品中的给药,其中活性成分经预定义时段释放。
在治疗、预防或改善病症、疾病及病状的一种或多种症状中,适当剂量水平一般在每天每kg受试者体重约0.001至100毫克(毫克/公斤每天)、每天每kg约0.01至约75毫克、每天每kg约0.1至约50毫克、每天每kg约0.5至约25毫克或每天每kg约1至约20毫克的范围内,其可以单剂量或多剂量给予。在此范围内,剂量可在每天每kg约0.005至约0.05、约0.05至约0.5、约0.5至约5.0、约1至约15、约1至约20或约1至约50mg的范围内。在某些实施例中,剂量水平在每天每kg约0.001至约100mg范围内。在某些实施例中,剂量水平在每天每kg约0.01至约75mg范围内。在某些实施例中,剂量水平在每天每kg约0.1至约50mg范围内。在某些实施例中,剂量水平在每天每kg约0.5至约25mg范围内。在某些实施例中,剂量水平在每天每kg约1至约20mg范围内。
对于经口给药,本文所提供的药物组合物可以以下片剂形式配制,其含有约1.0至约1,000mg活性成分,在一实施例中,约1、约5、约10、约15、约20、约25、约50、约75、约100、约150、约200、约250、约300、约400、约500、约600、约750、约800、约900及约1,000mg活性成分,剂量应相对于待治疗的患者的症状进行调整。药物组合物可以每天1至4次,包括每天一次、两次、三次及四次的方案给予。
然而,应理解,对于任何特定患者,具体剂量水平及给药频率均可变化,且将视多种因素而定,这些因素包括所采用具体化合物的活性、该化合物的代谢稳定性及作用长度、年龄、体重、一般健康状况、性别、饮食、给药模式及时间、排泄速率、药物组合、特定病状的严重性及进行疗法的宿主。
在一个实施例中,本文提供调节RC激酶活性的方法,其包含使RC激酶与本文所提供的化合物,例如式I的化合物(包括其立体异构体、对映异构体、对映异构体的混合物、非对映异构体的混合物或同位素变体;或其药学上可接受的盐、溶剂合物、水合物或前药)接触。在一个实施例中,RC激酶由细胞表达。
本文所提供的化合物,例如式I的化合物(包括其立体异构体、对映异构体、对映异构体的混合物、非对映异构体的混合物或同位素变体;或其药学上可接受的盐、溶剂合物、水合物或前药)还可与适用于治疗、预防或改善本文所提供的化合物适用的病症、疾病或病状的一种或多种症状的其他药剂组合或组合使用,这些病症、疾病或病状包括但不限于哮喘、COPD、过敏性鼻炎、湿疹、牛皮癣、异位性皮炎、发热、败血症、系统性红斑狼疮、糖尿病、类风湿性关节炎、多发性硬化症、动脉粥样硬化、移植排斥、发炎性肠病、癌症、感染性疾病及本文中所指出的那些病变。
在某些实施例中,本文所提供的化合物可与一种或多种此项技术中已知的类固醇药物组合,这些药物包括但不限于醛固酮(aldosterone)、倍氯米松(beclometasone)、倍他米松(betamethasone)、乙酸脱氧皮质酮(deoxycorticosterone acetate)、氟氢可的松(fludrocortisone)、氢皮质酮(hydrocortisone)(皮质醇(cortisol))、泼尼龙(prednisolone)、泼尼松(prednisone)、甲泼尼龙(methylprednisolone)、地塞米松(dexamethasone)及曲安西龙(triamcinolone)。
在某些实施例中,本文所提供的化合物可与一种或多种此项技术中已知的抗细菌剂组合,这些抗细菌剂包括但不限于阿米卡星(amikacin)、阿莫西林(amoxicillin)、安比西林(ampicillin)、阿斯凡纳明(arsphenamine)、阿奇霉素(azithromycin)、安曲南(aztreonam)、阿洛西林(azlocillin)、杆菌肽(bacitracin)、卡本西林(carbenicillin)、头孢克洛(cefaclor)、头孢羟胺苄(cefadroxil)、头孢孟多(cefamandole)、头孢唑林(cefazolin)、头孢力新(cephalexin)、头孢地尼(cefdinir)、头孢托林(cefditorin)、头孢吡肟(cefepime)、头孢克肟(cefixime)、头孢哌酮(cefoperazone)、头孢噻肟(cefotaxime)、头孢西丁(cefoxitin)、头孢泊肟(cefpodoxime)、头孢罗齐(cefprozil)、头孢他啶(ceftazidime)、头孢布坦(ceftibuten)、头孢唑肟(ceftizoxime)、头孢曲松(ceftriaxone)、头孢呋辛(cefuroxime)、氯霉素、西司他丁(cilastin)、环丙沙星(ciprofloxacin)、克拉霉素(clarithromycin)、克林达霉素(clindamycin)、氯唑西林(cloxacillin)、粘菌素、达福普汀(dalfopristin)、地美环素(demeclocycline)、双氯西林(dicloxacillin)、地红霉素(dirithromycin)、多西环素(doxycycline)、红霉素、恩氟沙星(enrofloxacin)、厄他培南(ertepenem)、乙胺丁醇、氟氯西林(flucloxacillin)、磷霉素(fosfomycin)、呋喃唑酮、加替沙星(gatifloxacin)、格尔德霉素(geldanamycin)、庆大霉素(gentamicin)、除莠霉素(herbimycin)、亚胺培南(imipenem)、异烟肼(isoniazid)、康霉素(kanamycin)、左氧氟沙星(levofloxacin)、利奈唑胺(linezolid)、洛美沙星(lomefloxacin)、氯碳头孢(loracarbef)、磺胺米隆(mafenide)、莫西沙星(moxifloxacin)、美罗培南(meropenem)、甲硝哒唑(metronidazole)、美洛西林(mezlocillin)、二甲胺四环素(minocycline)、莫匹罗星(mupirocin)、萘夫西林(nafcillin)、新霉素、奈替米星(netilmicin)、呋喃妥因(nitrofurantoin)、诺氟沙星(norfloxacin)、氧氟沙星(ofloxacin)、土霉素、青霉素、哌拉西林(piperacillin)、平板霉素、多粘菌素B、百浪多息(prontocil)、吡嗪酰胺、奎纽普汀(quinupristine)、利福平(rifampin)、罗红霉素(roxithromycin)、大观霉素(spectinomycin)、链霉素、磺胺醋酰胺(sulfacetamide)、磺胺甲二唑、磺胺甲基异噁唑、替考拉宁(teicoplanin)、泰利霉素(telithromycin)、四环素、替卡西林(ticarcillin)、托普霉素(tobramycin)、三甲氧苄二胺嘧啶(trimethoprim)、醋竹桃霉素(troleandomycin)、曲伐沙星(trovafloxacin)及万古霉素(vancomycin)。
在某些实施例中,本文所提供的化合物可与一种或多种此项技术中已知的抗真菌剂组合,这些抗真菌剂包括但不限于阿莫罗芬(amorolfine)、两性霉素B(amphotericinB)、阿尼芬净(anidulafungin)、联苯苄唑(bifonazole)、布替萘芬(butenafine)、布康唑(butoconazole)、卡泊芬净(caspofungin)、环吡酮(ciclopirox)、克霉唑(clotrimazole)、益康唑(econazole)、芬替康唑(fenticonazole)、非律平(filipin)、氟康唑(fluconazole)、异康唑(isoconazole)、伊曲康唑(itraconazole)、酮康唑(ketoconazole)、米卡芬净(micafungin)、咪康唑(miconazole)、萘替芬(naftifine)、游霉素(natamycin)、制霉素(nystatin)、奥昔康唑(oxyconazole)、雷夫康唑(ravuconazole)、泊沙康唑(posaconazole)、龟裂杀菌素(rimocidin)、舍他康唑(sertaconazole)、硫康唑(sulconazole)、特比萘芬(terbinafine)、特康唑(terconazole)、噻康唑(tioconazole)及伏立康唑(voriconazole)。
在某些实施例中,本文所提供的化合物可与一种或多种此项技术中已知的抗凝血剂组合,这些抗凝血剂包括但不限于醋硝香豆素(acenocoumarol)、阿加曲班(argatroban)、比伐卢定(bivalirudin)、来匹卢定(lepirudin)、方达珀鲁(fondaparinux)、肝素(heparin)、苯茚二酮(phenindione)、华法林(warfarin)及希美加群(ximelagatran)。
在某些实施例中,本文所提供的化合物可与一种或多种此项技术中已知的溶血栓剂组合,这些溶血栓剂包括但不限于阿尼普酶(anistreplase)、瑞替普酶(reteplase)、t-PA(阿替普酶活化酶)、链激酶(streptokinase)、替奈普酶(tenecteplase)及尿激酶(urokinase)。
在某些实施例中,本文所提供的化合物可与一种或多种此项技术中已知的非类固醇消炎剂组合,这些非类固醇消炎剂包括但不限于醋氯芬酸(aceclofenac)、阿西美辛(acemetacin)、阿莫西匹灵(amoxiprin)、阿司匹灵(aspirin)、阿扎丙宗(azapropazone)、贝诺酯(benorilate)、溴芬酸(bromfenac)、卡洛芬(carprofen)、塞内昔布(celecoxib)、胆碱水杨酸镁(choline magnesium salicylate)、双氯芬酸(diclofenac)、二氟尼柳(diflunisal)、依托度酸(etodolac)、依托昔布(etoricoxib)、菲斯胺(faislamine)、芬布芬(fenbufen)、非诺洛芬(fenoprofen)、氟比洛芬(flurbiprofen)、布洛芬(ibuprofen)、吲哚美辛(indometacin)、酮洛芬(ketoprofen)、酮洛酸(ketorolac)、氯诺昔康(lornoxicam)、洛索洛芬(loxoprofen)、鲁米昔布(lumiracoxib)、甲氯芬那酸(meclofenamic acid)、甲芬那酸(mefenamic acid)、美洛昔康(meloxicam)、安乃近(metamizole)、水杨酸甲酯(methyl salicylate)、水杨酸镁(magnesium salicylate)、萘丁美酮(nabumetone)、萘普生(naproxen)、尼美舒利(nimesulide)、羟布宗(oxyphenbutazone)、帕瑞昔布(parecoxib)、苯基丁氮酮(phenylbutazone)、吡罗昔康(piroxicam)、水杨酸水杨酸酯(salicyl salicylate)、舒林酸(sulindac)、苯磺唑酮(sulfinpyrazone)、舒洛芬(suprofen)、替诺昔康(tenoxicam)、噻洛芬酸(tiaprofenicacid)及托美丁(tolmetin)
在某些实施例中,本文所提供的化合物可与一种或多种此项技术中已知的抗血小板剂组合,这些抗血小板剂包括但不限于阿昔单抗(abciximab)、西洛他唑(cilostazol)、克罗匹多(clopidogrel)、双嘧达莫(dipyridamole)、噻氯匹定(ticlopidine)及替罗非班(tirofibin)。
本文所提供的化合物还可与其他类化合物组合给予,这些化合物包括但不限于:(1)α-肾上腺素激导剂;(2)抗心律不整剂;(3)抗动脉粥样硬化剂,诸如ACAT抑制剂;(4)抗生素,诸如蒽环霉素(anthracyclines)、博来霉素(bleomycins)、丝裂霉素(mitomycin)、放线菌素D(dactinomycin)及普卡霉素(plicamycin);(5)抗癌剂及细胞毒性剂,例如烷基化剂,诸如氮芥、烷基磺酸盐、亚硝基脲、伸乙基亚胺及三氮烯;(6)抗凝血剂,诸如醋硝香豆素、阿加曲班、比伐卢定、来匹卢定、方达珀鲁、肝素、苯茚二酮、华法林及希美加群;(7)抗糖尿病剂,诸如双胍(biguanide)(例如二甲双胍(metformin))、葡糖苷酶(glucosidase)抑制剂(例如醣禄(acarbose))、胰岛素(insulins)、美格列奈(meglitinide)(例如瑞格列奈(repaglinide))、磺酰脲(sulfonylureas)(例如格列美脲(glimepiride)、格列本脲(glyburide)及格列吡嗪(glipizide))、噻唑烷二酮(thiozolidinediones)(例如曲格列酮(troglitazone)、罗格列酮(rosiglitazone)及吡格列酮(pioglitazone))及PPAR-γ促效剂;(8)抗真菌剂,诸如阿莫罗芬、两性霉素B、阿尼芬净、联苯苄唑、布替萘芬、布康唑、卡泊芬净、环吡酮、克霉唑、益康唑、芬替康唑、非律平、氟康唑、异康唑、伊曲康唑、酮康唑、米卡芬净、咪康唑、萘替芬、游霉素、制霉素、奥昔康唑、雷夫康唑、泊沙康唑、龟裂杀菌素、舍他康唑、硫康唑、特比萘芬、特康唑、噻康唑及伏立康唑;(9)消炎药,例如非类固醇消炎剂,诸如醋氯芬酸、阿西美辛、阿莫西匹灵、阿司匹灵、阿扎丙宗、贝诺酯、溴芬酸、卡洛芬、塞内昔布、胆碱水杨酸镁、双氯芬酸、二氟尼柳、依托度酸、依托昔布、菲斯胺、芬布芬、非诺洛芬、氟比洛芬、布洛芬、吲哚美辛、酮洛芬、酮洛酸、氯诺昔康、洛索洛芬、鲁米昔布、甲氯芬那酸、甲芬那酸、美洛昔康、安乃近、水杨酸甲酯、水杨酸镁、萘丁美酮、萘普生、尼美舒利、羟布宗、帕瑞昔布、苯基丁氮酮、吡罗昔康、水杨酸水杨酸酯、舒林酸、苯磺唑酮、舒洛芬、替诺昔康、噻洛芬酸及托美丁;(10)抗代谢物,诸如叶酸(folate)拮抗剂、嘌呤类似物及嘧啶类似物;(11)抗血小板剂,诸如GPIIb/IIIa阻断剂(例如阿昔单抗、埃替菲巴肽(eptifibatide)及替罗非班(tirofiban))、P2Y(AC)拮抗剂(例如克罗匹多、噻氯匹定及CS-747)、西洛他唑、双嘧达莫及阿司匹灵(aspirin);(12)抗增生剂,诸如甲氨喋呤(methotrexate)、FK506(他克莫司(tacrolimus))及霉酚酸吗啉乙酯(mycophenolate mofetil);(13)抗TNF抗体或可溶性TNF受体,诸如依那西普(etanercept)、雷帕霉素(rapamycin)及来氟米特(leflunimide);(14)aP2抑制剂;(15)β-肾上腺素激导剂,诸如卡维地洛(carvedilol)及美托洛尔(metoprolol);(16)胆汁酸螯合剂,诸如降胆敏(questran);(17)钙通道阻断剂,诸如胺氯地平苯磺酸盐(amlodipine besylate);(18)化学治疗剂;(19)环加氧酶(cyclooxygenase)-2(COX-2)抑制剂,诸如塞内昔布(celecoxib)及罗非昔布(rofecoxib);(20)环孢素(cyclosporin);(21)细胞毒性药物,诸如硫唑嘌呤(azathioprine)及环磷酰胺(cyclophosphamide);(22)利尿剂,诸如氯噻嗪(chlorothiazide)、氢氯噻嗪(hydrochlorothiazide)、氟甲噻嗪(flumethiazide)、氢氟噻嗪(hydroflumethiazide)、苄氟甲噻嗪(bendroflumethiazide)、甲基氯噻嗪(methylchlorothiazide)、三氯噻嗪(trichloromethiazide)、多噻嗪(polythiazide)、苯并噻嗪(benzothiazide)、依他尼酸(ethacrynic acid)、替尼酸(ticrynafen)、氯噻酮(chlorthalidone)、呋塞米(furosenide)、莫唑胺(muzolimine)、布美他尼(bumetanide)、胺苯蝶啶(triamterene)、胺氯吡脒(amiloride)及螺内酯(spironolactone);(23)内皮素(endothelin)转化酶(ECE)抑制剂,诸如膦酰二肽(phosphoramidon);(24)酶,诸如L-天冬酰胺酸酶(L-asparaginase);(25)因子VIIa抑制剂及因子Xa抑制剂;(26)法呢基(farnesyl)-蛋白质转移酶抑制剂;(27)纤维酸酯;(28)生长因子抑制剂,诸如PDGF活性调节剂;(29)生长激素促泌素;(30)HMG CoA还原酶抑制剂,诸如普伐他汀(pravastatin)、洛伐他汀(lovastatin)、阿托伐他汀(atorvastatin)、辛伐他汀(simvastatin)、NK-104(还称为伊伐他汀(itavastatin)、尼伐他汀(nisvastatin)或尼斯拔他汀(nisbastatin))及ZD-4522(还称为罗素他汀(rosuvastatin)、阿他伐他汀(atavastatin)或维沙他汀(visastatin));中性肽链内切酶(neutral endopeptidase,NEP)抑制剂;(31)激素剂,诸如糖皮质素(glucocorticoids)(例如皮质酮(cortisone))、雌激素/抗雌激素药、雄激素/抗雄激素药、黄体素(progestin)及促黄体激素释放激素(luteinizing hormone-releasing hormone)拮抗剂及乙酸奥曲肽(octreotide acetate);(32)免疫抑制剂;(33)盐皮质素(mineralocorticoid)受体拮抗剂,诸如螺内酯(spironolactone)及依普利酮(eplerenone);(34)微管破裂剂(microtubule-disruptor agent),诸如海鞘素(ecteinascidin);(35)微管稳定剂,诸如紫杉醇(pacitaxel)、多西他赛(docetaxel)及埃博霉素(epothilone)A-F;(36)MTP抑制剂;(37)烟酸(niacin);(38)磷酸二酯酶(phosphodiesterase)抑制剂,诸如PDE III抑制剂(例如西洛他唑(cilostazol))及PDE V抑制剂(例如西地那非(sildenafil)、他达那非(tadalafil)及伐地那非(vardenafil));(39)植物源性产物,诸如长春花生物碱(vincaalkaloids)、表鬼臼毒素(epipodophyllotoxin)及紫杉烷(taxane);(40)血小板活化因子(PAF)拮抗剂;(41)铂配位络合物,诸如顺铂(cisplatin)、赛特铂(satraplatin)及卡铂(carboplatin);(42)钾通道开放剂;(43)异戊二烯基-蛋白质转移酶抑制剂;(44)蛋白质酪胺酸激酶抑制剂;(45)肾素(renin)抑制剂;(46)角鲨烯合成酶(squalene synthetase)抑制剂;(47)类固醇,诸如醛固酮、倍氯米松、倍他米松、乙酸脱氧皮质酮、氟氢可的松、氢皮质酮(皮质醇)、泼尼龙、泼尼松、甲泼尼龙、地塞米松及曲安西龙;(48)TNF-α抑制剂,诸如替尼达普(tenidap);(49)凝血酶(thrombin)抑制剂,诸如水蛭素(hirudin);(50)溶血栓剂,诸如阿尼普酶、瑞替普酶、替奈普酶、组织血纤维蛋白溶酶原活化剂(tissue plasminogenactivator,tPA)、重组tPA、链激酶、尿激酶、前尿激酶(prourokinase)及茴酰化血纤维蛋白溶酶原链激酶活化剂复合物(APSAC);(51)血栓素(thromboxane)受体拮抗剂,诸如伊非曲班(ifetroban);(52)拓扑异构酶(topoisomerase)抑制剂;(53)血管肽酶(vasopeptidase)抑制剂(双重NEP-ACE抑制剂),诸如奥马曲拉(omapatrilat)及吉莫曲拉(gemopatrilat);以及(54)其他杂项药剂,诸如羟基脲(hydroxyurea)、丙卡巴肼(procarbazine)、米托坦(mitotane)、六甲基三聚氰胺(hexamethylmelamine)及金化合物。
此类其他药剂或药物可通过其对应的常用途径及以其对应的常用量,与本文所提供的化合物,例如式I的化合物(包括其立体异构体、对映异构体、对映异构体的混合物、非对映异构体的混合物或同位素变体;或其药学上可接受的盐、溶剂合物、水合物或前药)同时或依序给予。当同时使用本文所提供的化合物与一种或多种其他药物时,可使用除本文所提供的化合物以外含有此类其他药物的药物组合物,但并非所需的。因此,本文所提供的药物组合物包括除本文所提供的化合物以外,还包含一种或多种其他活性成分或治疗剂的那些药物组合物。
本文所提供的化合物与第二活性成分的重量比可变化,且将视各成分的有效剂量而定。一般而言,将使用各自的有效剂量。因此,例如,当本文所提供的化合物与NSAID组合时,该化合物与该NSAID的重量比可在约1,000:1至约1:1,000或约200:1至约1:200的范围内。本文所提供的化合物与其他活性成分的组合一般还将在前述范围内,但在各种情况下,应使用各活性成分的有效剂量。
本文所提供的化合物还可使用本领域技术人员熟知的包装材料以制品形式提供。参见例如美国专利号5,323,907;5,052,558;以及号5,033,252。医药包装材料的实例包括但不限于泡壳包装、瓶子、管、吸入器、泵、袋、小瓶、容器、注射器、瓶子及适合于所选择的配制品及预定给药及治疗模式的任何包装材料。
本文还提供当由医学从业者使用时可简化向受试者给予适量活性成分的试剂盒。在某些实施例中,本文所提供的试剂盒包括容器及本文所提供的化合物,例如式I的化合物(包括其立体异构体、对映异构体、对映异构体的混合物、非对映异构体的混合物或同位素变体;或其药学上可接受的盐、溶剂合物、水合物或前药)的剂型。
在某些实施例中,试剂盒在包含一种或多种本文所描述的其他治疗剂的容器中包括容器,该容器包含本文所提供的化合物,例如式I的化合物(包括其立体异构体、对映异构体、对映异构体的混合物、非对映异构体的混合物或同位素变体;或其药学上可接受的盐、溶剂合物、水合物或前药)的剂型。
本文所提供的试剂盒可进一步包括用于给予活性成分的装置。此类装置的实例包括但不限于注射器、无针注射器滴液袋、贴片及吸入器。本文所提供的试剂盒还可包括用于给予活性成分的保险套。
试剂盒可进一步包括可用于给予一种或多种活性成分的药学上可接受的媒剂。例如,若活性成分以必须经复原以用于非经肠给药的固体形式提供,则试剂盒可包含适合媒剂的密封容器,其中活性成分可溶解以形成适合于非经肠给药的不含微粒的无菌溶液。药学上可接受的媒剂的实例包括但不限于:水性媒剂,包括但不限于注射用水USP、氯化钠注射液、林格氏注射液、右旋糖注射液、右旋糖及氯化钠注射液及乳酸林格氏注射液;水可混溶性媒剂,包括但不限于乙醇、聚乙二醇及聚丙二醇;以及非水性媒剂,包括但不限于玉米油、棉籽油、花生油、芝麻油、油酸乙酯、肉豆蔻酸异丙酯及苯甲酸苯甲酯。
将由以下非限制性实例进一步理解本发明。
实例
如本文所用,无论是否具体地定义特定缩写,此等方法、方案及实例中所用的符号及惯例均与当代科学文献(例如美国化学会志(Journal of the American ChemicalSociety)或生物化学杂志(Journal of Biological Chemistry))中所用一致。具体言之(但非限制性地),可在实例及整个本说明书中使用以下缩写:g(公克);mg(毫克);mL(毫升);μL(微升);L(升);mM(毫摩尔浓度);μM(微摩尔浓度);Hz(赫兹);MHz(兆赫兹);mmol(毫摩尔);eq.(当量);hr或hrs(小时);min(分钟);MS(质谱);NMR(核磁共振);ESI(电喷雾电离);ACN(乙腈);CDCl3(氘代氯仿);DCM(二氯甲烷);DMF(N,N-二甲基甲酰胺);DMSO(二甲亚砜);DMSO-d6(氘代二甲亚砜);EtOAc(乙酸乙酯);EtOH(乙醇);Et2O(二乙醚);MeOH(甲醇);PE(石油醚);TBDME(叔丁基二甲基醚);THF(四氢呋喃);DIPEA(N,N-二异丙基乙胺);TEA(三乙胺);DBU(1,8-二氮杂双环[5.4.0]十一-7-烯);DMAP(4-二甲基氨基吡啶);AIBN(1,1'-偶氮双(环己甲腈));CDI(羰基二咪唑);EDCI或EDC(N'-乙基-N-(3-二甲基氨基丙基)-碳化二亚胺);TBTU(O-(苯并三唑-1-基)-N,N,N',N'-四甲基脲鎓四氟硼酸盐);Me(甲基);Et(乙基);iPr(异丙基);tBu(叔丁基);Boc(叔丁氧基羰基);Cbz(氨基甲酸苯甲酯);Fmoc(氨基甲酸9-芴基甲酯);Bn(苯甲基);PMB(对甲氧基苄基);Bs(4-溴-苯磺酰基);TMS(三甲基硅烷基);TsOH(对甲基苯磺酸);TsO(甲苯磺酸根);DEAD(偶氮二甲酸二乙酯),DIAD(偶氮二甲酸二异丙酯);AcCl(乙酰氯);TFA(三氟乙酸);TBAF(氟化四正丁基铵);及tBuOK(叔丁醇钾)。
对于所有以下实例,可使用本领域技术人员已知的标准处理及纯化方法。除非另外指示,否则所有温度均以℃(摄氏度)表示。除非另外指出,否则所有反应均在室温下进行。本文中的合成方法旨在经由使用具体实例来例示可适用的化学方法且不指示本发明的范围。相关合成的实例可见于例如美国专利申请号13/830,486及13/830,712中,其中的每一个的披露内容以全文引用的方式并入本文中。
在本文所描述的实例中使用的起始材料为市售可得的或可通过本领域技术人员已知的方法来制备。
实例1
5-((4-羟基-3,5-二甲基苄基)氨基)-3-((4-(4-异丙基哌嗪-1-基)苯基)氨基)-1H-吡唑-4-甲酰胺1
根据方案1制备化合物1。
方案1
制备2-氰基-3,3-双(甲基硫基)丙烯酰胺I-2。将2-氰基乙酰胺(10g,118.9mmol)及氢氧化钾(6.661g,118.9)于ACN(100mL)中的混合物在室温下搅拌1小时,接着在室温下缓慢添加二硫化碳(9.054g,118.9mmol)。在于室温下搅拌溶液3小时之后,添加硫酸二甲酯(19.5g,154.6mmol),且将反应混合物在室温下搅拌隔夜。随后在真空下移除挥发物,且将残余物再溶解于EtOAc中,且依序用水及盐水洗涤,经无水MgSO4干燥,且在真空中浓缩。所得固体用EtOAc/己烷湿磨,过滤,且干燥,得到呈黄色固体状的化合物I-2(9.4g,产率42%,纯度99.0%)。
将2-氰基-3,3-双(甲基硫基)丙烯酰胺I-2(0.500g)溶解于15mL EtOH中,且添加4-(4-(2-丙基)-哌嗪-1-基)苯胺(1.0当量)。在75℃下搅拌反应物,直至通过HPLC确定起始酰胺不存在为止。一旦完成(18小时),使反应物达到室温,且过滤,获得呈紫色粉末状的2-氰基-3-((4-(4-异丙基哌嗪-1-基)苯基)氨基)-3-(甲基硫基)丙烯酰胺A1。使产物在真空下干燥1小时。
2-氰基-3-((4-(4-异丙基哌嗪-1-基)苯基)氨基)-3-(甲基硫基)丙烯酰胺A1
随后将2-氰基-3-((4-(4-异丙基哌嗪-1-基)苯基)氨基)-3-(甲基硫基)丙烯酰胺A1悬浮于10mL EtOH中,且逐滴添加水合肼(1.0当量)。在75℃下加热反应物,直至A1不存在(HPLC)为止。一旦中间物不存在(18小时),使反应物达到室温,且过滤,获得呈紫色粉末状的5-氨基-3-((4-(4-异丙基哌嗪-1-基)苯基)氨基)-1H-吡唑-4-甲酰胺A2。使产物在真空下干燥1小时。
5-氨基-3-((4-(4-异丙基哌嗪-1-基)苯基)氨基)-1H-吡唑-4-甲酰胺A2
将5-氨基-3-((4-(4-异丙基哌嗪-1-基)苯基)氨基)-1H-吡唑-4-甲酰胺(0.200g)A2悬浮于EtOH(4mL)及哌啶(5滴)中。在80℃下在搅拌下加热反应混合物,且添加3,5-二甲基-4-羟基苯甲醛(0.122g)。在18小时之后,使反应混合物冷却至室温。通过抽吸过滤来收集所分离的固体,且用乙醇冲洗,得到粗亚胺产物A3,其不经纯化即使用。
在室温下向A3(246mg)于DMF(2mL)及MeOH(4mL)中的悬浮液中缓慢添加硼氢化钠(39mg)。在于室温下搅拌反应混合物1小时之后,添加水,且通过抽吸过滤来收集所得固体。将所回收的沉淀溶解于DMSO中,经由棉花塞过滤,用EtOH进一步冲洗该棉花塞。合并DMSO及EtOH滤液,且添加水,直至沉淀形成为止。将所得悬浮液在冰箱中冷却3小时。过滤所得沉淀,用水洗涤,且干燥,得到呈粉末状的化合物1(75mg,纯度95.1%)。1H-NMR(500MHz,DMSO):11.36(s,1H),8.22(s,1H),8.13(s,1H),7.12(s,2H),6.91(s,2H),6.79(d,J=8Hz,2H),6.12(s,3H),4.16(d,J=8Hz,2H),2.97(m,4H),2.67(m,1H),2.55(m,4H),2.18(s,6H),1.00(s,6H)。
实例2
合成3-((3-氯-4-吗啉代苯基)氨基)-5-((4-羟基-3,5-二甲基苄基)氨基)-1H-吡唑-4-甲酰胺2
以基本上类似于对实例1的A2所描述的方式制备中间物5-氨基-3-((3-氯-4-吗啉代苯基)氨基)-1H-吡唑-4-甲酰胺。
将5-氨基-3-((3-氯-4-吗啉代苯基)氨基)-1H-吡唑-4-甲酰胺(530mg,1.57mmoL)及3,5-二甲基-4-羟基苯甲醛(0.285g,1.90mmol,1.2当量)悬浮于EtOH(9mL)中,且添加哌啶(5滴)。将反应混合物在80℃下加热18小时,且随后冷却至室温。通过抽吸过滤来收集所分离的沉淀,且用乙醇冲洗,得到呈黄色粉末状的粗亚胺。
在室温下向亚胺(312mg,0.67mmoL)于DMF(15mL)及MeOH(3mL)中的悬浮液中缓慢添加硼氢化钠(51mg,1.34mmol,2.0当量)。在于室温下搅拌反应混合物30分钟之后,添加水(100mL),直至获得透明溶液为止。向所得搅拌溶液中逐滴添加HCl(3.0N),直至沉淀持续出现为止。在冰浴上继续搅拌1小时。过滤所得沉淀,用水洗涤,且干燥,得到呈白色粉末状的化合物2(291mg,产率93%,纯度95.7%)。1H-NMR(500MHz,DMSO):11.47(s,1H),8.54(s,1H),7.51(s,1H),7.04(s,2H),6.92(s,2H),6.68(m,3H),4.17(m,2H),3.71(m,4H),2.86(m,4H),2.14(s,6H)。
实例3
合成5-((4-羟基-3,5-二甲基苄基)氨基)-3-((4-吗啉代苯基)氨基)-1H-吡唑-4-甲酰胺3
以基本上类似于对实例1的A2所描述的方式制备中间物5-氨基-3-((4-吗啉代苯基)氨基)-1H-吡唑-4-甲酰胺。
将5-氨基-3-((4-吗啉代苯基)氨基)-1H-吡唑-4-甲酰胺(1.06g,3.51mmoL)及3,5-二甲基-4-羟基苯甲醛(0.790g,5.26mmol,1.5当量)悬浮于EtOH(25mL)及乙酸(2.5mL)中。将反应混合物在80℃下加热24小时,且随后冷却至室温,且在真空中浓缩至原始体积的大约一半。通过抽吸过滤来收集所分离的沉淀,且用乙醇冲洗,得到呈橙色粉末状的粗亚胺。
在室温下向亚胺(1.36g,3.13mmoL)于DMSO(15mL)及MeOH(3mL)中的溶液中添加缓慢硼氢化钠(180mg,6.26mmol,2.0当量)。在于室温下搅拌反应混合物48小时之后,添加水,且通过抽吸过滤来分离所得沉淀,且用水洗涤。将所回收的沉淀溶解于DMSO(6mL)中,经由棉花塞过滤,用EtOH(3mL)进一步冲洗该棉花塞。合并DMSO及EtOH滤液,且添加水,直至沉淀形成为止。将所得悬浮液在冰箱中冷却3小时。过滤所得沉淀,用水洗涤,且干燥,得到呈白色粉末状的化合物3(1.125g,产率82%,纯度97%)。1H-NMR(500MHz,DMSO):11.37(s,1H),8.26(s,1H),8.13(s,1H),7.14(m,2H),6.92(s,2H),6.81(d,J=8Hz,2H),6.63(s,2H),4.16(d,J=8Hz,2H),3.71(m,4H),2.96(m,4H),2.14(s,6H)。
实例4
合成3-((4-(2,6-二甲基吗啉代)苯基)氨基)-5-((4-羟基-3,5-二甲基苄基)氨基)-1H-吡唑-4-甲酰胺4
以基本上类似于对实例1的A2所描述的方式制备中间物5-氨基-3-((4-(2,6-二甲基吗啉代)苯基)氨基)-1H-吡唑-4-甲酰胺。
将5-氨基-3-((4-(2,6-二甲基吗啉代)苯基)氨基)-1H-吡唑-4-甲酰胺(0.530g)悬浮于EtOH(11mL)及哌啶(5滴)中。在80℃下在搅拌下加热反应混合物,且添加3,5-二甲基-4-羟基苯甲醛(0.330g)。在18小时之后,使反应混合物冷却至室温。通过抽吸过滤来收集所分离的固体,且用乙醇冲洗,得到粗亚胺产物,其不经纯化即使用。
在室温下向亚胺(100mg)于DMF(1mL)及MeOH(2mL)中的悬浮液中缓慢添加硼氢化钠(17mg)。在于室温下搅拌反应混合物1小时之后,添加水,且通过抽吸过滤来收集所得固体。将所回收的沉淀溶解于DMSO中,经由棉花塞过滤,用EtOH进一步冲洗该棉花塞。合并DMSO及EtOH滤液,且添加水,直至沉淀形成为止。将所得悬浮液在冰箱中冷却3小时。过滤所得沉淀,用水洗涤,且干燥,得到呈粉末状的化合物4(60mg,纯度99%)。1H-NMR(500MHz,DMSO):11.37(s,1H),8.26(s,1H),8.12(s,1H),7.14(m,2H),6.92(s,2h),6.81(m,2H),6.62(s,3H),4.16(d,J=8Hz,2H),3.68(m,2H),3.37(d,J=8Hz,2H),2.16(s,6H),1.13(d,J=8Hz,6H)。
实例5
合成3-((5-氯-6-吗啉代吡啶-3-基)氨基)-5-((4-羟基-3,5-二甲基苄基)氨基)-1H-吡唑-4-甲酰胺5
以基本上类似于对实例1的A2所描述的方式制备中间物5-氨基-3-((5-氯-6-吗啉代吡啶-3-基)氨基)-1H-吡唑-4-甲酰胺。
将5-氨基-3-((5-氯-6-吗啉代吡啶-3-基)氨基)-1H-吡唑-4-甲酰胺(0.091g)悬浮于EtOH(10mL)及哌啶(5滴)中。在80℃下在搅拌下加热反应混合物,且添加3,5-二甲基-4-羟基苯甲醛(0.060g)。在18小时之后,使反应混合物冷却至室温。通过抽吸过滤来收集所分离的固体,且用乙醇冲洗,得到粗亚胺产物(122mg),其不经纯化即使用。
在室温下向亚胺(122mg)于DMF(3mL)及MeOH(1mL)中的悬浮液中缓慢添加硼氢化钠(20mg)。在于室温下搅拌反应混合物1小时之后,添加水,且通过抽吸过滤来收集所得固体。将所回收的沉淀溶解于DMSO中,经由棉花塞过滤,用EtOH进一步冲洗该棉花塞。合并DMSO及EtOH滤液,且添加水,直至沉淀形成为止。将所得悬浮液在冰箱中冷却3小时。过滤所得沉淀,用水洗涤,且干燥,得到呈粉末状的化合物5(99mg,纯度96.5%)。1H-NMR(500MHz,DMSO):11.51(s,1H),8.74(s,1H),8.19(s,1H),8.13(s,1H),8.08(s,1H),6.92(s,2H),6.74(m,3H),4.17(d,J=8Hz,2H),3.72(m,4H),3.07(m,4H),2.14(s,6H)。
实例6
合成的3-((4-(1H-吡咯-1-基)苯基)氨基)-5-((4-羟基-3,5-二甲基苄基)氨基)-1H-吡唑-4-甲酰胺6
以基本上类似于对实例1的A2所描述的方式制备中间物3-((4-(1H-吡咯-1-基)苯基)氨基)-5-氨基-1H-吡唑-4-甲酰胺。
将3-((4-(1H-吡咯-1-基)苯基)氨基)-5-氨基-1H-吡唑-4-甲酰胺(0.150g)悬浮于EtOH(10mL)及哌啶(5滴)中。在80℃下在搅拌下加热反应混合物,且添加3,5-二甲基-4-羟基苯甲醛(0.040g)。在18小时之后,使反应混合物冷却至室温。通过抽吸过滤来收集所分离的固体,且用乙醇冲洗,得到粗亚胺产物,其不经纯化即使用。
在室温下向亚胺(275mg)于DMF(2mL)及MeOH(4mL)中的悬浮液中缓慢添加硼氢化钠(50mg)。在于室温下搅拌反应混合物1小时之后,添加水,且通过抽吸过滤来收集所得固体。将所回收的沉淀溶解于DMSO中,经由棉花塞过滤,用EtOH进一步冲洗该棉花塞。合并DMSO及EtOH滤液,且添加水,直至沉淀形成为止。将所得悬浮液在冰箱中冷却3小时。过滤所得沉淀,用水洗涤,且干燥,得到呈粉末状的化合物6(75mg,纯度99%)。1H-NMR(500MHz,DMSO):11.50(s,1H),8.65(s,1H),8.14(s,1H),7.35(m,4H),7.19(s,2H),6.93(s,2H),6.68(s,3H),6.20(s,2H),4.18(d,J=8Hz,2H),2.15(s,6H)。
实例7
合成5-((4-羟基-3,5-二甲基苄基)氨基)-3-((6-吗啉代吡啶-3-基)氨基)-1H-吡唑-4-甲酰胺7
以基本上类似于对实例1的A2所描述的方式制备中间物5-氨基-3-((6-吗啉代吡啶-3-基)氨基)-1H-吡唑-4-甲酰胺。
将5-氨基-3-((6-吗啉代吡啶-3-基)氨基)-1H-吡唑-4-甲酰胺(0.200g)悬浮于EtOH(10mL)及哌啶(5滴)中。在80℃下在搅拌下加热反应混合物,且添加3,5-二甲基-4-羟基苯甲醛(0.050g)。在18小时之后,使反应混合物冷却至室温。通过抽吸过滤来收集所分离的固体,且用乙醇冲洗,得到粗亚胺产物,其不经纯化即使用。
在室温下向亚胺(241mg)于DMF(2mL)及MeOH(4mL)中的悬浮液中缓慢添加硼氢化钠(42mg)。在于室温下搅拌反应混合物1小时之后,添加水,且通过抽吸过滤来收集所得固体。将所回收的沉淀溶解于DMSO中,经由棉花塞过滤,用EtOH进一步冲洗该棉花塞。合并DMSO及EtOH滤液,且添加水,直至沉淀形成为止。将所得悬浮液在冰箱中冷却3小时。过滤所得沉淀,用水洗涤,且干燥,得到呈粉末状的化合物7(75mg,纯度99%)。1H-NMR(500MHz,DMSO):11.36(s,1H),8.27(s,1H),8.18(s,1H),8.13(s,1H),7.63(s,1H),6.91(s,2H),6.74(d,J=8Hz,1H),6.66(s,3H),4.16(d,J=8Hz,2H),3.69(m,4H),3.28(m,4H),2.14(s,6H)。
实例8
合成5-((4-羟基-3,5-二甲基苄基)氨基)-3-((3-甲基-4-吗啉代苯基)氨基)-1H-吡唑-4-甲酰胺8
以基本上类似于对实例1的A2所描述的方式制备中间物5-氨基-3-((3-甲基-4-吗啉代苯基)氨基)-1H-吡唑-4-甲酰胺。
将5-氨基-3-((3-甲基-4-吗啉代苯基)氨基)-1H-吡唑-4-甲酰胺(0.150g)悬浮于EtOH(3mL)及哌啶(5滴)中。在80℃下在搅拌下加热反应混合物,且添加3,5-二甲基-4-羟基苯甲醛(0.100g)。在18小时之后,使反应混合物冷却至室温。通过抽吸过滤来收集所分离的固体,且用乙醇冲洗,得到粗亚胺产物,其不经纯化即使用。
在室温下向亚胺(145mg)于DMF(2mL)及MeOH(4mL)中的悬浮液中缓慢添加硼氢化钠(24mg)。在于室温下搅拌反应混合物1小时之后,添加水,且通过抽吸过滤来收集所得固体。将所回收的沉淀溶解于DMSO中,经由棉花塞过滤,用EtOH进一步冲洗该棉花塞。合并DMSO及EtOH滤液,且添加水,直至沉淀形成为止。将所得悬浮液在冰箱中冷却3小时。过滤所得沉淀,用水洗涤,且干燥,得到呈粉末状的化合物8(100mg,纯度99%)。1H-NMR(500MHz,DMSO):11.43(s,1H),8.34(s,1H),8.13(s,1H),7.07(m,2H),6.91(m,3H),6.64(s,3H),4.16(d,J=8Hz,2H),3.70(m,4H),2.74(m,4H),2.19(s,3H),2.15(s,6H)。
实例9
合成5-((4-羟基-3,5-二甲基苄基)氨基)-3-((4-(吡啶-2-基)苯基)氨基)-1H-吡唑-4-甲酰胺9
以基本上类似于对实例1的A2所描述的方式制备中间物5-氨基-3-((4-(吡啶-2-基)苯基)氨基)-1H-吡唑-4-甲酰胺。
将5-氨基-3-((4-(吡啶-2-基)苯基)氨基)-1H-吡唑-4-甲酰胺(0.200g)悬浮于EtOH(4mL)及哌啶(5滴)中。在80℃下在搅拌下加热反应混合物,且添加3,5-二甲基-4-羟基苯甲醛(0.143g)。在18小时之后,使反应混合物冷却至室温。通过抽吸过滤来收集所分离的固体,且用乙醇冲洗,得到粗亚胺产物,其不经纯化即使用。
在室温下向亚胺(350mg)于DMF(3mL)及MeOH(6mL)中的悬浮液中缓慢添加硼氢化钠(62mg)。在于室温下搅拌反应混合物1小时之后,添加水,且通过抽吸过滤来收集所得固体。将所回收的沉淀溶解于DMSO中,经由棉花塞过滤,用EtOH进一步冲洗该棉花塞。合并DMSO及EtOH滤液,且添加水,直至沉淀形成为止。将所得悬浮液在冰箱中冷却3小时。过滤所得沉淀,用水洗涤,且干燥,得到呈粉末状的化合物9(110mg,纯度97.7%)。1H-NMR(500MHz,DMSO):11.58(s,1H),8.85(s,1H),8.57(m,1H),8.15(s,1H),7.95(d,J=8Hz,2H),7.79(m,4H),7.33(m,2H),7.21,(m,1H),6.94(s,2H),6.70(s,3H),4.19(m,2H),2.15(s,6H)。
实例10
合成5-((4-羟基-3,5-二甲基苄基)氨基)-3-((4-(4-甲基哌嗪-1-基)苯基)氨基)-1H-吡唑-4-甲酰胺10
以基本上类似于对实例1的A2所描述的方式制备中间物5-氨基-3-((4-(4-甲基哌嗪-1-基)苯基)氨基)-1H-吡唑-4-甲酰胺。
将5-氨基-3-((4-(4-甲基哌嗪-1-基)苯基)氨基)-1H-吡唑-4-甲酰胺(0.250g)悬浮于EtOH(5mL)及哌啶(5滴)中。在80℃下在搅拌下加热反应混合物,且添加3,5-二甲基-4-羟基苯甲醛(0.167g)。在18小时之后,使反应混合物冷却至室温。通过抽吸过滤来收集所分离的固体,且用乙醇冲洗,得到粗亚胺产物,其不经纯化即使用。
在室温下向亚胺(250mg)于DMF(2mL)及MeOH(4mL)中的悬浮液中缓慢添加硼氢化钠(42mg)。在于室温下搅拌反应混合物1小时之后,添加水,且通过抽吸过滤来收集所得固体。将所回收的沉淀溶解于DMSO中,经由棉花塞过滤,用EtOH进一步冲洗该棉花塞。合并DMSO及EtOH滤液,且添加水,直至沉淀形成为止。将所得悬浮液在冰箱中冷却3小时。过滤所得沉淀,用水洗涤,且干燥,得到呈粉末状的化合物10(30mg,纯度94%)。1H-NMR(500MHz,DMSO):11.38(s,1H),8.29(s,1H),8.13(s,1H),7.15(m,2H),6.92(s,2H),6.84(m,2H),6.63(s,3H),4.16(s,2H),3.11(s,2H),2.99(s,2H),2.89(s,2H),2.58(s,3H),2.14(s,6H),1.57(m,2H),1.23(s,1H)。
实例11
合成5-((4-羟基-3,5-二甲基苄基)氨基)-3-((5-吗啉代吡啶-2-基)氨基)-1H-吡唑-4-甲酰胺11
以基本上类似于对实例1的A2所描述的方式制备中间物5-氨基-3-((5-吗啉代吡啶-2-基)氨基)-1H-吡唑-4-甲酰胺。
将5-氨基-3-((5-吗啉代吡啶-2-基)氨基)-1H-吡唑-4-甲酰胺(0.153g)悬浮于EtOH(3mL)及乙酸(1mL)中。在80℃下在搅拌下加热反应混合物,且添加3,5-二甲基-4-羟基苯甲醛(0.105g)。在18小时之后,使反应混合物冷却至室温。通过抽吸过滤来收集所分离的固体,且用乙醇冲洗,得到粗亚胺产物,其不经纯化即使用。
在室温下向亚胺(80mg)于DMF(4mL)及MeOH(2mL)中的悬浮液中缓慢添加硼氢化钠(140mg)。在于室温下搅拌反应混合物1小时之后,添加水,且通过抽吸过滤来收集所得固体。将所回收的沉淀溶解于DMSO中,经由棉花塞过滤,用EtOH进一步冲洗该棉花塞。合并DMSO及EtOH滤液,且添加水,直至沉淀形成为止。将所得悬浮液在冰箱中冷却3小时。过滤所得沉淀,用水洗涤,且干燥,得到呈粉末状的化合物11(77mg,纯度98.5%)。1H-NMR(500MHz,DMSO):11.93(s,0.4H),11.43(s,0.6H),9.65(s,0.4H),9.15(s,0.6H),8.13(s,0.6H),8.00(s,0.4H),7.95(s,1H),7.59(d,0.6H),7.42(m,0.4H),7.32(m,0.6H),6.94(m,2.3H),6.77(s,0.8H),6.70(s,1.2H),6.56(m,0.6H),5.70(m,0.4H),4.17(m,2H),3.73(s,4H),3.01(m,4H),2.14(s,6H)。
实例12
合成5-((4-羟基-3,5-二甲基苄基)氨基)-3-((5-甲基-6-吗啉代吡啶-3-基)氨基)-1H-吡唑-4-甲酰胺12
以基本上类似于对实例1的A2所描述的方式制备中间物5-氨基-3-((5-甲基-6-吗啉代吡啶-3-基)氨基)-1H-吡唑-4-甲酰胺。
将5-氨基-3-((5-甲基-6-吗啉代吡啶-3-基)氨基)-1H-吡唑-4-甲酰胺(0.340g)悬浮于EtOH(18mL)及乙酸(1mL)中。在80℃下在搅拌下加热反应混合物,且添加3,5-二甲基-4-羟基苯甲醛(0.240g)。在18小时之后,使反应混合物冷却至室温。通过抽吸过滤来收集所分离的固体,且用乙醇冲洗,得到粗亚胺产物,其不经纯化即使用。
在室温下向亚胺(73mg)于DMF(2mL)及MeOH(1mL)中的悬浮液中缓慢添加硼氢化钠(12mg)。在于室温下搅拌反应混合物1小时之后,添加水,且通过抽吸过滤来收集所得固体。将所回收的沉淀溶解于DMSO中,经由棉花塞过滤,用EtOH进一步冲洗该棉花塞。合并DMSO及EtOH滤液,且添加水,直至沉淀形成为止。将所得悬浮液在冰箱中冷却3小时。过滤所得沉淀,用水洗涤,且干燥,得到呈粉末状的化合物12(60mg,纯度97.6%)。1H-NMR(500MHz,DMSO):11.44(s,1H),8.47(s,1H),8.10(s,2H),7.58(s,1H),6.92(s,2H),6.68(s,3H),4.16(d,J=6Hz,2H),3.71(t,J=5Hz,4H),2.91(t,J=5Hz,4H),2.20(s,3H),2.14(s,6H)。
实例13
合成5-((4-羟基-3,5-二甲基苄基)氨基)-3-((6-(4-异丙基哌嗪-1-基)-5-甲基吡啶-3-基)氨基)-1H-吡唑-4-甲酰胺13
以基本上类似于对实例1的A2所描述的方式制备中间物5-氨基-3-((6-(4-异丙基哌嗪-1-基)-5-甲基吡啶-3-基)氨基)-1H-吡唑-4-甲酰胺。
将5-氨基-3-((6-(4-异丙基哌嗪-1-基)-5-甲基吡啶-3-基)氨基)-1H-吡唑-4-甲酰胺(0.210g)悬浮于EtOH(12mL)及乙酸(0.5mL)中。在80℃下在搅拌下加热反应混合物,且添加3,5-二甲基-4-羟基苯甲醛(0.130g)。在18小时之后,使反应混合物冷却至室温。通过抽吸过滤来收集所分离的固体,且用乙醇冲洗,得到粗亚胺产物,其不经纯化即使用。
在室温下向亚胺(50mg)于DMF(3mL)及MeOH(1.5mL)中的悬浮液中缓慢添加硼氢化钠(10mg)。在于室温下搅拌反应混合物1小时之后,添加水,且通过抽吸过滤来收集所得固体。将所回收的沉淀溶解于DMSO中,经由棉花塞过滤,用EtOH进一步冲洗该棉花塞。合并DMSO及EtOH滤液,且添加水,直至沉淀形成为止。将所得悬浮液在冰箱中冷却3小时。过滤所得沉淀,用水洗涤,且干燥,得到呈粉末状的化合物13(41mg,纯度99.3%)。1H-NMR(500MHz,DMSO):11.43(s,1H),8.43(s,1H),8.14(s,1H),8.07(s,1H),7.55(s,1H),6.92(s,2H),6.68(s,3H),4.16(d,J=6,2H),2.90(m,4H),2.66(m,1H)2.56(m,4H),2.18(s,3H),2.14(s,6H),1.00(d,J=7,6H)。
实例14
合成5-((4-羟基-3,5-二甲基苄基)氨基)-3-((5-甲基-6-(4-甲基哌嗪-1-基)吡啶-3-基)氨基)-1H-吡唑-4-甲酰胺14
以基本上类似于对实例1的A2所描述的方式制备中间物5-氨基-3-((5-甲基-6-(4-甲基哌嗪-1-基)吡啶-3-基)氨基)-1H-吡唑-4-甲酰胺。
将5-氨基-3-((5-甲基-6-(4-甲基哌嗪-1-基)吡啶-3-基)氨基)-1H-吡唑-4-甲酰胺(0.21g)悬浮于EtOH(8mL)及乙酸(1mL)中。在80℃下在搅拌下加热反应混合物,且添加3,5-二甲基-4-羟基苯甲醛(0.136g)。在16小时之后,使反应混合物冷却至室温。通过抽吸过滤来收集所分离的固体,且用乙醇冲洗,得到粗亚胺产物,其不经纯化即使用。
在室温下向亚胺(153mg)于DMF(3mL)及MeOH(1mL)中的悬浮液中缓慢添加硼氢化钠(25mg)。在于室温下搅拌反应混合物1小时之后,添加水,且搅拌所得悬浮液30分钟。通过抽吸过滤来收集固体,用水洗涤,且干燥,得到呈白色粉末状的化合物14(41mg,纯度99.3%)。1H-NMR(500MHz,DMSO):11.43(s,1H),8.51及8.44(s,s,1H),8.12及8.08(s,s,2H),7.59及7.56(s,s,1H),6.92(s,2H),6.69(d,J=5Hz,3H),4.16(d,J=6Hz,2H),3.17(m,1H),3.04(m,1H),2.91(m,4H),2.60(s,1H),2.44(s,2H),2.22(s,2H),2.18(d,J=3Hz,3H),2.14(s,6H)。
实例15
合成3-((3-氯-4-(2,6-二甲基吗啉代)苯基)氨基)-5-((4-羟基-3,5-二甲基苄基)氨基)-1H-吡唑-4-甲酰胺15
以基本上类似于对实例1的A2所描述的方式制备中间物5-氨基-3-((3-氯-4-(2,6-二甲基吗啉代)苯基)氨基)-1H-吡唑-4-甲酰胺。
将5-氨基-3-((3-氯-4-(2,6-二甲基吗啉代)苯基)氨基)-1H-吡唑-4-甲酰胺(0.235g)悬浮于EtOH(4.7mL)及哌啶(5滴)中。在80℃下在搅拌下加热反应混合物,且添加3,5-二甲基-4-羟基苯甲醛(0.145g)。在18小时之后,使反应混合物冷却至室温。通过抽吸过滤来收集所分离的固体,且用乙醇冲洗,得到粗亚胺产物,其不经纯化即使用。
在室温下向亚胺(55mg)于DMF(1mL)及MeOH(1mL)中的悬浮液中缓慢添加硼氢化钠(8mg)。在于室温下搅拌反应混合物1小时之后,添加水,且通过抽吸过滤来收集所得固体。将所回收的沉淀溶解于DMSO中,经由棉花塞过滤,用EtOH进一步冲洗该棉花塞。合并DMSO及EtOH滤液,且添加水,直至沉淀形成为止。将所得悬浮液在冰箱中冷却3小时。过滤所得沉淀,用水洗涤,且干燥,得到呈粉末状的化合物15(55mg,纯度97.5%)。1H-NMR(500MHz,DMSO):11.50(s,1H),8.62(s,1H),8.15(s,1H),7.56(s,1H),7.07(d,1H),7.0(d,1H),6.92(s,2H),6.71(m,1H),6.68(s,2H),4.16(m,2H),3.71(m,2H),3.01(d,2H),2.30(t,2H),2.14(s,6H),1.10(d,6H)。
实例16
合成5-((4-羟基-3,5-二甲基苄基)氨基)-3-((4-(吡啶-3-基)苯基)氨基)-1H-吡唑-4-甲酰胺16
以基本上类似于对实例1的A2所描述的方式制备中间物5-氨基-3-((4-(吡啶-3-基)苯基)氨基)-1H-吡唑-4-甲酰胺。
将5-氨基-3-((4-(吡啶-3-基)苯基)氨基)-1H-吡唑-4-甲酰胺(0.330g)悬浮于EtOH(20mL)及哌啶(5滴)中。在80℃下在搅拌下加热反应混合物,且添加3,5-二甲基-4-羟基苯甲醛(0.250g)。在18小时之后,使反应混合物冷却至室温。通过抽吸过滤来收集所分离的固体,且用乙醇冲洗,得到粗亚胺产物,其不经纯化即使用。
在室温下向亚胺(64mg)于DMF(6mL)及MeOH(3mL)中的悬浮液中缓慢添加硼氢化钠(10mg)。在于室温下搅拌反应混合物1小时之后,添加水,且通过抽吸过滤来收集所得固体。将所回收的沉淀溶解于DMSO中,经由棉花塞过滤,用EtOH进一步冲洗该棉花塞。合并DMSO及EtOH滤液,且添加水,直至沉淀形成为止。将所得悬浮液在冰箱中冷却3小时。过滤所得沉淀,用水洗涤,且干燥,得到呈粉末状的化合物16(57mg,纯度98.4%)。1H-NMR(500MHz,DMSO):11.57(s,1H),8.83(m,1H),8.79(s,1H),8.46(m,1H),8.16(s,1H),7.99(m,1H),7.57(d,J=9Hz,2H),7.41(m,1H),7.35(d,J=9Hz,2H),6.93(2H),6.71(m,3H),4.19(d,J=6Hz,2H),2.15(s,6H)。
实例17
合成3-((3-氯-4-(4-异丙基哌嗪-1-基)苯基)氨基)-5-((4-羟基-3,5-二甲基苄基)氨基)-1H-吡唑-4-甲酰胺17
以基本上类似于对实例1的A2所描述的方式制备中间物5-氨基-3-((3-氯-4-(4-异丙基哌嗪-1-基)苯基)氨基)-1H-吡唑-4-甲酰胺。
将5-氨基-3-((3-氯-4-(4-异丙基哌嗪-1-基)苯基)氨基)-1H-吡唑-4-甲酰胺(0.460g)悬浮于EtOH(8mL)及哌啶(5滴)中。在80℃下在搅拌下加热反应混合物,且添加3,5-二甲基-4-羟基苯甲醛(0.270g)。在18小时之后,使反应混合物冷却至室温。通过抽吸过滤来收集所分离的固体,且用乙醇冲洗,得到粗亚胺产物,其不经纯化即使用。
在室温下向亚胺(80mg)于DMF(2mL)及MeOH(1mL)中的悬浮液中缓慢添加硼氢化钠(12mg)。在于室温下搅拌反应混合物1小时之后,添加水,且通过抽吸过滤来收集所得固体。将所回收的沉淀溶解于DMSO中,经由棉花塞过滤,用EtOH进一步冲洗该棉花塞。合并DMSO及EtOH滤液,且添加水,直至沉淀形成为止。将所得悬浮液在冰箱中冷却3小时。过滤所得沉淀,用水洗涤,且干燥,得到呈粉末状的化合物17(60mg,纯度96.1%)。1H-NMR(500MHz,DMSO):11.95(s,1H),8.57(s,1H),8.14(s,1H),7.54(s,1H),7.01(m,2H),6.92(s,2H),6.67(m,3H),4.16(d,J=6Hz,2H),2.86(s,4H),2.68(m,1H),2.57(s,4H),2.14(s,6H),1.00(d,J=7Hz,6H)。
实例18
合成3-([1,1'-联苯]-4-基氨基)-5-((4-羟基-3,5-二甲基苄基)氨基)-1H-吡唑-4-甲酰胺18
以基本上类似于对实例1的A2所描述的方式制备中间物3-([1,1'-联苯]-4-基氨基)-5-氨基-1H-吡唑-4-甲酰胺。
将3-([1,1'-联苯]-4-基氨基)-5-氨基-1H-吡唑-4-甲酰胺(0.086g)悬浮于EtOH(10mL)及乙酸(0.5mL)中。在80℃下在搅拌下加热反应混合物,且添加3,5-二甲基-4-羟基苯甲醛(0.270g)。在20小时之后,使反应混合物冷却至室温。通过抽吸过滤来收集所分离的固体,且用乙醇冲洗,得到粗亚胺产物,其不经纯化即使用。将粗亚胺与DMF(1mL)及MeOH(1mL)组合,且在室温下用2当量硼氢化钠处理。在5小时之后,添加水,且通过抽吸过滤来收集所分离的沉淀,用水洗涤,且干燥,得到呈粉末状的化合物18(60mg)。1H-NMR(500MHz,DMSO):11.54(s,1H),8.71(s,1H),8.15(s,1H),7.59(d,2H),7.50(s,2H),7.40(t,2H),7.31(d,2H),7.24(t,1H),6.93(s,2H),6.69(s,3H),4.19(d,2H),2.15(s,6H)。
实例19
3-((4-(1H-咪唑-1-基)苯基)氨基)-5-((4-羟基-3,5-二甲基苄基)氨基)-1H-吡唑-4-甲酰胺19
以基本上类似于对实例1的A2所描述的方式制备中间物3-((4-(1H-咪唑-1-基)苯基)氨基)-5-氨基-1H-吡唑-4-甲酰胺。
将3-((4-(1H-咪唑-1-基)苯基)氨基)-5-氨基-1H-吡唑-4-甲酰胺(0.246g)悬浮于EtOH(10mL)及哌啶(5滴)中。在80℃下在搅拌下加热反应混合物,且添加1.4当量的3,5-二甲基-4-羟基苯甲醛。在20小时之后,使反应混合物冷却至室温。通过抽吸过滤来收集所分离的固体,且用乙醇冲洗,得到粗亚胺产物,其不经纯化即使用。将粗亚胺与DMF(1mL)及MeOH(1mL)组合,且在室温下用2当量硼氢化钠处理。在5小时之后,添加水,且通过抽吸过滤来收集所分离的沉淀,用水洗涤,且干燥,得到呈粉末状的化合物19(25mg)。1H-NMR(500MHz,DMSO):2.15(s,6H),4.19(d,2H),6.70(s,3H),6.93(s,2H),7.05(s,1H),7.35(s,2H),7.42(d,2H),7.58(s,1H),8.06(s,1H),8.15(s,1H),8.76(s,1H),11.54(s,1H)
实例20
合成5-((4-羟基-3,5-二甲基苄基)氨基)-3-((4-甲氧基苯基)氨基)-1H-吡唑-4-甲酰胺20
以基本上类似于对实例1的A2所描述的方式制备中间物5-氨基-3-((4-甲氧基苯基)氨基)-1H-吡唑-4-甲酰胺。
将5-氨基-3-((4-甲氧基苯基)氨基)-1H-吡唑-4-甲酰胺(160mg)悬浮于EtOH(10mL)及哌啶(5滴)中。在80℃下在搅拌下加热反应混合物,且添加1.4当量的3,5-二甲基-4-羟基苯甲醛。在24小时之后,使反应混合物冷却至室温。通过抽吸过滤来收集所分离的固体,且用乙醇冲洗,得到粗亚胺产物,其不经纯化即使用。将粗亚胺与DMF(1mL)及MeOH(1mL)组合,且在室温下用2当量硼氢化钠处理。在5小时之后,添加水,且通过抽吸过滤来收集所分离的沉淀,用水洗涤,且干燥,得到呈粉末状的化合物20(20mg)。1H-NMR(500MHz,DMSO):2.17(s,6H),3.68(s,3H),4.16(d,2H),6.64(m,3H),6.77(d,2H),6.92(s,2H),7.18(d,2H),8.14(s,1H),8.31(s,1H),11.38(s,1H)。
实例21
合成3-((4-(叔丁基)苯基)氨基)-5-((4-羟基-3,5-二甲基苄基)氨基)-1H-吡唑-4-甲酰胺21
以基本上类似于对实例1的A2所描述的方式制备中间物5-氨基-3-((4-(叔丁基)苯基)氨基)-1H-吡唑-4-甲酰胺。
将5-氨基-3-((4-(叔丁基)苯基)氨基)-1H-吡唑-4-甲酰胺(98mg)悬浮于EtOH(10mL)及哌啶(5滴)中。在80℃下在搅拌下加热反应混合物,且添加1.5当量的3,5-二甲基-4-羟基苯甲醛。在20小时之后,使反应混合物冷却至室温。通过抽吸过滤来收集所分离的固体,且用乙醇冲洗,得到粗亚胺产物,其不经纯化即使用。将粗亚胺与DMF(1mL)及MeOH(1mL)组合,且在室温下用2当量硼氢化钠处理。在5小时之后,添加水,且通过抽吸过滤来收集所分离的沉淀,用水洗涤,且干燥,得到呈粉末状的化合物21(90mg)。1H-NMR(500MHz,DMSO):1.23(s,9H),2.14(s,6H),4.17(d,2H),6.64(m,3H),6.92(s,2H),7.10(m,2H),7.20(d,2H),8.13(s,1H),8.40(s,1H),11.53(s,1H)。
实例22
合成3-((1H-吲唑-5-基)氨基)-5-((4-羟基-3,5-二甲基苄基)氨基)-1H-吡唑-4-甲酰胺22
以基本上类似于对实例1的A2所描述的方式制备中间物3-((1H-吲唑-5-基)氨基)-5-氨基-1H-吡唑-4-甲酰胺。
将3-((1H-吲唑-5-基)氨基)-5-氨基-1H-吡唑-4-甲酰胺(99mg)悬浮于EtOH(10mL)及哌啶(5滴)中。在80℃下在搅拌下加热反应混合物,且添加1.5当量的3,5-二甲基-4-羟基苯甲醛。在20小时之后,使反应混合物冷却至室温。通过抽吸过滤来收集所分离的固体,且用乙醇冲洗,得到粗亚胺产物,其不经纯化即使用。将粗亚胺与DMF(1mL)及MeOH(1mL)组合,且在室温下用2当量硼氢化钠处理。在5小时之后,添加水,且通过抽吸过滤来收集所分离的沉淀,用水洗涤,且干燥,得到呈粉末状的化合物22(112mg)。1H-NMR(500MHz,DMSO):2.15(s,6H),4.18(d,2H),6.66(m,3H),6.93(s,2H),7.12(d,1H),7.37(d,2H),7.66(m,1H),7.86(s,1H),8.14(m,1h0,8.47(s,1H),11.43(s,1H),12.75(s,1H)。
实例23
5-((4-羟基-3,5-二甲基苄基)氨基)-3-((4-(4-甲基-[1,4’-联哌啶]-1'-基)苯基)氨基)-1H-吡唑-4-甲酰胺23
以基本上类似于对实例1的A2所描述的方式制备中间物5-氨基-3-((4-(4-甲基-[1,4’-联哌啶]-1'-基)苯基)氨基)-1H-吡唑-4-甲酰胺。
将5-氨基-3-((4-(4-甲基-[1,4’-联哌啶]-1'-基)苯基)氨基)-1H-吡唑-4-甲酰胺(99mg)悬浮于EtOH(10mL)及哌啶(5滴)中。在80℃下在搅拌下加热反应混合物,且添加1.5当量的3,5-二甲基-4-羟基苯甲醛。在20小时之后,使反应混合物冷却至室温。通过抽吸过滤来收集所分离的固体,且用乙醇冲洗,得到粗亚胺产物,其不经纯化即使用。将粗亚胺与DMF(1mL)及MeOH(1mL)组合,且在室温下用2当量硼氢化钠处理。在5小时之后,添加水,且通过抽吸过滤来收集所分离的沉淀,用水洗涤,且干燥,得到呈粉末状的化合物23(112mg)。1H-NMR(500MHz,DMSO):2.15(s,6H),4.18(d,2H),6.66(m,3H),6.93(s,2H),7.12(d,1H),7.37(d,2H),7.66(m,1H),7.86(s,1H),8.14(m,1h0,8.47(s,1H),11.43(s,1H),12.75(s,1H)。
实例24
合成5-((4-羟基-3,5-二甲基苄基)氨基)-3-((4-(4-(吡咯烷-1-羰基)哌嗪-1-基)苯基)氨基)-1H-吡唑-4-甲酰胺24
以基本上类似于对实例1的A2所描述的方式制备中间物5-氨基-3-((4-(4-(吡咯烷-1-羰基)哌嗪-1-基)苯基)氨基)-1H-吡唑-4-甲酰胺。
将5-氨基-3-((4-(4-(吡咯烷-1-羰基)哌嗪-1-基)苯基)氨基)-1H-吡唑-4-甲酰胺(60mg)悬浮于EtOH(10mL)及哌啶(5滴)中。在80℃下在搅拌下加热反应混合物,且添加1.5当量的3,5-二甲基-4-羟基苯甲醛。在2天之后,使反应混合物冷却至室温。通过抽吸过滤来收集所分离的固体,且用乙醇冲洗,得到粗亚胺产物,其不经纯化即使用。将粗亚胺与DMF(1mL)及MeOH(2mL)组合,且在室温下用2当量硼氢化钠处理。在6小时之后,添加水,且通过抽吸过滤来收集所分离的沉淀,用水洗涤,且干燥,得到呈粉末状的化合物24(40mg)。1H-NMR(500MHz,DMSO):11.38(s,1H),8.28(s,1H),8.14(s,1H),7.14(d,2H),6.92(s,2H),6.82(d,2H),6.64(s,3H),4.16(d,2H),3.28(m,8H),2.97(m,4H),2.14(s,6H),1.75(m,4H)。
实例25
3-((4-(4-氟哌啶-1-基)苯基)氨基)-5-((4-羟基-3,5-二甲基苄基)氨基)-1H-吡唑-4-甲酰胺25
以基本上类似于对实例1的A2所描述的方式制备中间物5-氨基-3-((4-(4-氟哌啶-1-基)苯基)氨基)-1H-吡唑-4-甲酰胺。
将5-氨基-3-((4-(4-氟哌啶-1-基)苯基)氨基)-1H-吡唑-4-甲酰胺(320mg)悬浮于EtOH(15mL)及乙酸(1mL)中。在80℃下在搅拌下加热反应混合物,且添加1.5当量的3,5-二甲基-4-羟基苯甲醛。在16小时之后,使反应混合物冷却至室温。通过抽吸过滤来收集所分离的固体,且用乙醇冲洗,得到粗亚胺产物,其不经纯化即使用。将粗亚胺与DMF(2mL)及MeOH(0.5mL)组合,且在室温下用2当量硼氢化钠处理。在1小时之后,添加水,且通过抽吸过滤来收集所分离的沉淀,用水洗涤,且干燥,得到呈粉末状的化合物25(92mg)。1H-NMR(500MHz,DMSO):11.37(s,1H),8.27(s,1H),8.14(s,1H),7.13(d,2H),6.92(s,2H),6.83(d,2H),6.63(m,3H),4.793(m,1H),4.16(d,2H),3.17(m,2H),2.94(m,2H),2.14(s,6H),1.95(m,2H),7.80(m,2H)。
实例26
3-((6-((2R,6S)-2,6-二甲基四氢-2H-吡喃-4-基)吡啶-3-基)氨基)-5-((4-羟基-3,5-二甲基苄基)氨基)-1H-吡唑-4-甲酰胺26
以基本上类似于对实例1的A2所描述的方式制备中间物5-氨基-3-((6-((2R,6S)-2,6-二甲基四氢-2H-吡喃-4-基)吡啶-3-基)氨基)-1H-吡唑-4-甲酰胺。
将5-氨基-3-((6-((2R,6S)-2,6-二甲基四氢-2H-吡喃-4-基)吡啶-3-基)氨基)-1H-吡唑-4-甲酰胺(1.020g)悬浮于EtOH(3mL)及乙酸(0.5mL)中。在80℃下在搅拌下加热反应混合物,且添加1.5当量的3,5-二甲基-4-羟基苯甲醛。在12小时之后,使反应混合物冷却至室温。通过抽吸过滤来收集所分离的固体,且用乙醇冲洗,得到粗亚胺产物,其不经纯化即使用(0.955g)。将粗亚胺(0.056g)与DMF(2mL)及MeOH(1mL)组合,且在室温下用2当量硼氢化钠处理。在30分钟之后,添加水,且通过抽吸过滤来收集所分离的沉淀,用水洗涤,且干燥,得到呈粉末状的化合物26(36mg)。1H-NMR(500MHz,DMSO):11.35(s,1H),8.27(s,1H),8.15(d,2H),7.64(d,1H),6.91(s,2H),6.74(d,1H),6.68(m,3H),4.16(d,2H),3.92(d,2H),3.62(m,2H),2.25(t,3H),2.14(s,6H),1.14(d,6H)。
实例27
5-((4-羟基-3,5-二甲基苄基)氨基)-3-((4-(哌啶-1-基)苯基)氨基)-1H-吡唑-4-甲酰胺27
以基本上类似于对实例1的A2所描述的方式制备中间物5-氨基-3-((4-(哌啶-1-基)苯基)氨基)-1H-吡唑-4-甲酰胺。
将5-氨基-3-((4-(哌啶-1-基)苯基)氨基)-1H-吡唑-4-甲酰胺(89mg)悬浮于EtOH(10mL)及哌啶(5滴)中。在80℃下在搅拌下加热反应混合物,且添加1.5当量的3,5-二甲基-4-羟基苯甲醛。在20小时之后,使反应混合物冷却至室温。通过抽吸过滤来收集所分离的固体,且用乙醇冲洗,得到粗亚胺产物,其不经纯化即使用。将粗亚胺与DMF(1mL)及MeOH(1mL)组合,且在室温下用2当量硼氢化钠处理。在5小时之后,添加水,且通过抽吸过滤来收集所分离的沉淀,用水洗涤,且干燥,得到呈粉末状的化合物27(36mg)。1H-NMR(500MHz,DMSO):11.37(s,1H),8.23(s,1H),8.14(s,1H),7.11(d,2H),6.92(s,2H),6.79(d,2H),6.63(s,2H),4.16(d,2H),2.95(,5H),2.14(s,6H),1.60(m,4H),1.48(m,2H)。
实例28
合成3-((3-氯-4-((2S,6R)-2,6-二甲基吗啉代)苯基)氨基)-5-((4-羟基-3,5-二甲基苄基)氨基)-1H-吡唑-4-甲酰胺28
以基本上类似于对实例1的A2所描述的方式制备中间物5-氨基-3-((3-氯-4-((2S,6R)-2,6-二甲基吗啉代)苯基)氨基)-1H-吡唑-4-甲酰胺。
将5-氨基-3-((3-氯-4-((2S,6R)-2,6-二甲基吗啉代)苯基)氨基)-1H-吡唑-4-甲酰胺(235mg)悬浮于EtOH(3mL)及乙酸(0.5mL)中。在80℃下在搅拌下加热反应混合物,且添加1.5当量的3,5-二甲基-4-羟基苯甲醛。在5小时之后,使反应混合物冷却至室温。通过抽吸过滤来收集所分离的固体,且用乙醇冲洗,得到粗亚胺产物,其不经纯化即使用。将粗亚胺(55mg)与DMF(1mL)及MeOH(0.5mL)组合,且在室温下用2当量硼氢化钠处理。在1小时之后,添加水,且通过抽吸过滤来收集所分离的沉淀,用水洗涤,且干燥,得到呈粉末状的化合物28(55mg)。1H-NMR(500MHz,DMSO):11.50(s,1H),8.62(s,1H),8.15(s,1H),7.56(s,1H),7.07(d,1H),7.0(d,1H),6.92(s,2H),6.71(m,1H),6.68(s,2H),4.16(m,2H),3.71(m,2H),3.01(d,2H),2.30(t,2H),2.14(s,6H),1.10(d,6H)。
实例29
合成5-((4-羟基-3,5-二甲基苄基)氨基)-3-((3-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)-1H-吡唑-4-甲酰胺29
以基本上类似于对实例1的A2所描述的方式制备中间物5-氨基-3-((3-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)-1H-吡唑-4-甲酰胺。
将5-氨基-3-((3-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)-1H-吡唑-4-甲酰胺(420mg)悬浮于EtOH(10mL)及乙酸(0.5mL)中。在80℃下在搅拌下加热反应混合物,且添加1.5当量的3,5-二甲基-4-羟基苯甲醛。在16小时之后,使反应混合物冷却至室温。通过抽吸过滤来收集所分离的固体,且用乙醇冲洗,得到粗亚胺产物(0.650g),其不经纯化即使用。将粗亚胺(87mg)与DMF(1mL)及MeOH(0.5mL)组合,且在室温下用2当量硼氢化钠处理。在1小时之后,添加水,且通过抽吸过滤来收集所分离的沉淀,用水洗涤,且干燥,得到呈粉末状的化合物29(87mg)。1H-NMR(500MHz,DMSO):11.42(s,1H),8.33(s,1H),8.14(s,1H),7.03(m,2H),6.92(s,2H),6.88(d,1H),6.64(s,3H),4.16(m,2H),2.88(m,1H),2.74(m,4H),2.44(m,3H),2.19(3H),2.15(m,9H)。
实例30
合成5-((4-羟基-3,5-二甲基苄基)氨基)-3-((3-甲基-4-(哌啶-1-基)苯基)氨基)-1H-吡唑-4-甲酰胺30
以基本上类似于对实例1的A2所描述的方式制备中间物5-氨基-3-((3-甲基-4-(哌啶-1-基)苯基)氨基)-1H-吡唑-4-甲酰胺。
将5-氨基-3-((3-甲基-4-(哌啶-1-基)苯基)氨基)-1H-吡唑-4-甲酰胺(240mg)悬浮于EtOH(10mL)及乙酸(0.5mL)中。在80℃下在搅拌下加热反应混合物,且添加1.5当量的3,5-二甲基-4-羟基苯甲醛。在16小时之后,使反应混合物冷却至室温。通过抽吸过滤来收集所分离的固体,且用乙醇冲洗,得到粗亚胺产物(0.240g),其不经纯化即使用。将粗亚胺(51mg)与DMF(1mL)及MeOH(0.5mL)组合,且在室温下用2当量硼氢化钠处理。在1小时之后,添加水,且通过抽吸过滤来收集所分离的沉淀,用水洗涤,且干燥,得到呈粉末状的化合物30(51mg)。1H-NMR(500MHz,DMSO):11.41(s,1H),8.302(s,1H),8.14(s,1H),7.05(s,1H),6.94(m,1H),6.92(s,2H),6.86(m,1H),6.64(s,3H),4.16(m,2H),2.68(m,4H),2.15(m,9H),1.61(m,4H),1.49(m,2H)。
实例31
合成3-((4-(4-苯甲基哌嗪-1-基)苯基)氨基)-5-((4-羟基-3,5-二甲基苄基)氨基)-1H-吡唑-4-甲酰胺31
以基本上类似于对实例1的A2所描述的方式制备中间物5-氨基-3-((4-(4-苯甲基哌嗪-1-基)苯基)氨基)-1H-吡唑-4-甲酰胺。
将5-氨基-3-((4-(4-苯甲基哌嗪-1-基)苯基)氨基)-1H-吡唑-4-甲酰胺(240mg)悬浮于EtOH(5mL)及乙酸(0.5mL)中。在80℃下在搅拌下加热反应混合物,且添加1.4当量的3,5-二甲基-4-羟基苯甲醛。在5小时之后,使反应混合物冷却至室温。通过抽吸过滤来收集所分离的固体,且用乙醇冲洗,得到粗亚胺产物(0.489g),其不经纯化即使用。将粗亚胺(116mg)与DMF(1mL)及MeOH(1mL)组合,且在室温下用2当量硼氢化钠处理。在30分钟之后,添加水,且通过抽吸过滤来收集所分离的沉淀,用水洗涤,且干燥,得到呈粉末状的化合物31(92mg)。1H-NMR(500MHz,DMSO):11.37(s,1H),8.25(s,1H),8.14(s,1H),7.31(m,4H),7.25(m,1H),7.13(d,2H),6.91(s,2H),6.79(d,2H),6.63(s,3H),4.16(d,2H),3.51(s,2H),2.99(s,4H),2.14(s,6H)。
实例32
合成3-((4-(1,1-二氧化硫代吗啉代)苯基)氨基)-5-((4-羟基-3,5-二甲基苄基)氨基)-1H-吡唑-4-甲酰胺32
以基本上类似于对实例1的A2所描述的方式制备中间物5-氨基-3-((4-(1,1-二氧化硫代吗啉代)苯基)氨基)-1H-吡唑-4-甲酰胺。
将5-氨基-3-((4-(1,1-二氧化硫代吗啉代)苯基)氨基)-1H-吡唑-4-甲酰胺(108mg)悬浮于EtOH(5mL)及乙酸(0.5mL)中。在80℃下在搅拌下加热反应混合物,且添加1.4当量的3,5-二甲基-4-羟基苯甲醛。在5小时之后,使反应混合物冷却至室温。通过抽吸过滤来收集所分离的固体,且用乙醇冲洗,得到粗亚胺产物(0.240g),其不经纯化即使用。将粗亚胺(51mg)与DMF(6mL)及MeOH(3mL)组合,且在室温下用2当量硼氢化钠处理。在30分钟之后,添加水,且通过抽吸过滤来收集所分离的沉淀,用水洗涤,且干燥,得到呈粉末状的化合物32(73mg)。1H-NMR(500MHz,DMSO):11.40(s,1H),8.34(s,1H),8.16(s,1H),7.17(s,1H),6.90(m,4H),6.65(s,2H),4.16(d,2H),3.58(s,4H),3.12(m,4H),2.14(s,6H)。
实例33
合成5-((4-羟基-3,5-二甲基苄基)氨基)-3-((5-(哌啶-1-基)吡啶-2-基)氨基)-1H-吡唑-4-甲酰胺33
以基本上类似于对实例1的A2所描述的方式制备中间物5-氨基-3-((5-(哌啶-1-基)吡啶-2-基)氨基)-1H-吡唑-4-甲酰胺。
将5-氨基-3-((5-(哌啶-1-基)吡啶-2-基)氨基)-1H-吡唑-4-甲酰胺(167mg)悬浮于EtOH(10mL)及乙酸(0.5mL)中。在80℃下在搅拌下加热反应混合物,且添加1.5当量的3,5-二甲基-4-羟基苯甲醛。在16小时之后,使反应混合物冷却至室温。通过抽吸过滤来收集所分离的固体,且用乙醇冲洗,得到粗亚胺产物,其不经纯化即使用。将粗亚胺与DMF(1mL)及MeOH(0.5mL)组合,且在室温下用2当量硼氢化钠处理。在1小时之后,添加水,且通过抽吸过滤来收集所分离的沉淀,用水洗涤,且干燥,得到呈粉末状的化合物33(150mg)。1H-NMR(500MHz,DMSO):11.66(m,1H),9.35(m,1H),8.13(s,1H),7.81(m,1H),7.55(d,1H),7.29(m,1H),6.91(s,2H),6.68(s,2H),6.41(m,1H),4.15(m,2H),2.98(m,4H),2.13(s,6H),1.61(m,4H),1.48(m,2H)。
实例34
合成3-((4-(4-氯哌啶-1-基)苯基)氨基)-5-((4-羟基-3,5-二甲基苄基)氨基)-1H-吡唑-4-甲酰胺34
以基本上类似于对实例1的A2所描述的方式制备中间物5-氨基-3-((4-(4-氯哌啶-1-基)苯基)氨基)-1H-吡唑-4-甲酰胺。
将5-氨基-3-((4-(4-氯哌啶-1-基)苯基)氨基)-1H-吡唑-4-甲酰胺(167mg)悬浮于EtOH(10mL)及哌啶(5滴)中。在80℃下在搅拌下加热反应混合物,且添加1.5当量的3,5-二甲基-4-羟基苯甲醛。在16小时之后,使反应混合物冷却至室温。通过抽吸过滤来收集所分离的固体,且用乙醇冲洗,得到粗亚胺产物(0.320g),其不经纯化即使用。将粗亚胺(52mg)与DMF(0.5mL)及MeOH(2mL)组合,且在室温下用2当量硼氢化钠处理。在1小时之后,添加水,且通过抽吸过滤来收集所分离的沉淀,用水洗涤,且干燥,得到呈粉末状的化合物34(52mg)。1H-NMR(500MHz,DMSO):11.38(s,1H),8.27(s,1H),8.14(s,1H),7.13(d,2H),6.92(s,2H),6.82(d,2H),6.64(m,3H),4.33(m,1H),4.16(d,2H),2.87(m,2H),2.13(m,10H),1.86(m,2H)。
实例35
合成5-((4-羟基-3,5-二甲基苄基)氨基)-3-((4-(吡咯烷-1-基甲基)苯基)氨基)-1H-吡唑-4-甲酰胺35
以基本上类似于对实例1的A2所描述的方式制备中间物5-氨基-3-((4-(吡咯烷-1-基甲基)苯基)氨基)-1H-吡唑-4-甲酰胺。
将5-氨基-3-((4-(吡咯烷-1-基甲基)苯基)氨基)-1H-吡唑-4-甲酰胺(400mg)悬浮于EtOH(5mL)及哌啶(5滴)中。在80℃下在搅拌下加热反应混合物,且添加1.5当量的3,5-二甲基-4-羟基苯甲醛。在16小时之后,使反应混合物冷却至室温。通过抽吸过滤来收集所分离的固体,且用乙醇冲洗,得到粗亚胺产物(0.420g),其不经纯化即使用。将粗亚胺(0.182g)与DMF(6mL)及MeOH(3mL)组合,且在室温下用2当量硼氢化钠处理。在30分钟之后,添加水,且通过抽吸过滤来收集所分离的沉淀,用水洗涤,且干燥,得到呈粉末状的化合物35(123mg)。1H-NMR(500MHz,DMSO):11.48(s,1H),8.50(s,1H),8.14(s,1H),7.10(m,4H),6.92(s,2H),6.65(s,2H),4.17(d,2H),3.43(s,2H),3.38(m,4H),2.15(s,6H),1.66(m,4H)。
实例36
合成3-((4-(4-(二甲基氨基)哌啶-1-基)苯基)氨基)-5-((4-羟基-3,5-二甲基苄基)氨基)-1H-吡唑-4-甲酰胺36
以基本上类似于对实例1的A2所描述的方式制备中间物5-氨基-3-((4-(4-(二甲基氨基)哌啶-1-基)苯基)氨基)-1H-吡唑-4-甲酰胺。
将5-氨基-3-((4-(4-(二甲基氨基)哌啶-1-基)苯基)氨基)-1H-吡唑-4-甲酰胺(300mg)悬浮于EtOH(8mL)及哌啶(5滴)中。在80℃下在搅拌下加热反应混合物,且添加1.5当量的3,5-二甲基-4-羟基苯甲醛。在16小时之后,使反应混合物冷却至室温。通过抽吸过滤来收集所分离的固体,且用乙醇冲洗,得到粗亚胺产物(0.470g),其不经纯化即使用。将粗亚胺(50mg)与DMF(2mL)及MeOH(2mL)组合,且在室温下用2当量硼氢化钠处理。在2小时之后,添加水,且通过抽吸过滤来收集所分离的沉淀,用水洗涤,且干燥,得到呈粉末状的化合物36(150mg)。
实例37
合成3-((3-氟-4-吗啉代苯基)氨基)-5-((4-羟基-3,5-二甲基苄基)氨基)-1H-吡唑-4-甲酰胺37
以基本上类似于对实例1的A2所描述的方式制备中间物3-((3-氟-4-吗啉代苯基)氨基)-5-((4-羟基-3,5-二甲基苄基)氨基)-1H-吡唑-4-甲酰胺。
将3-((3-氟-4-吗啉代苯基)氨基)-5-((4-羟基-3,5-二甲基苄基)氨基)-1H-吡唑-4-甲酰胺(400mg)悬浮于EtOH(5mL)及哌啶(5滴)中。在80℃下在搅拌下加热反应混合物,且添加1.4当量的3,5-二甲基-4-羟基苯甲醛。在20小时之后,使反应混合物冷却至室温。通过抽吸过滤来收集所分离的固体,且用乙醇冲洗,得到粗亚胺产物,其不经纯化即使用。将一些粗亚胺(97mg)与DMF(1mL)及MeOH(4mL)组合,且在室温下用2当量硼氢化钠处理。在15分钟之后,添加水,且通过抽吸过滤来收集所分离的沉淀,用水洗涤,且干燥,得到呈粉末状的化合物37(75mg)。1H-NMR(500MHz,DMSO):2.14(s,6H),2.88(t,4H),3.70(t,4H),4.17(d,2H),6.68(m,3H),6.90(m,4H),7.28(d,1H),8.15(s,1H),8.61(s,1H),11.47(s,1H)。
实例38
合成5-((4-羟基-3,5-二甲基苄基)氨基)-3-((4-(噁唑-5-基)苯基)氨基)-1H-吡唑-4-甲酰胺38
以基本上类似于对实例1的A2所描述的方式制备中间物5-氨基-3-((4-(噁唑-5-基)苯基)氨基)-1H-吡唑-4-甲酰胺。
将5-氨基-3-((4-(噁唑-5-基)苯基)氨基)-1H-吡唑-4-甲酰胺(176mg)悬浮于EtOH(5mL)及哌啶(5滴)中。在80℃下在搅拌下加热反应混合物,且添加1.4当量的3,5-二甲基-4-羟基苯甲醛。在18小时之后,使反应混合物冷却至室温。通过抽吸过滤来收集所分离的固体,且用乙醇冲洗,得到粗亚胺产物,将该粗亚胺产物与DMF(1mL)及MeOH(1mL)组合,且在室温下用2当量硼氢化钠处理。在1小时之后,添加水,且通过抽吸过滤来收集所分离的沉淀,用水洗涤,且干燥,得到呈粉末状的化合物38(33mg)。1H-NMR(500MHz,DMSO):2.15(s,6H),4.18(d,2H),6.70(m,3H),6.93(s,2H),7.33(d,2H),7.43(s,1H),7.54(d,2H),8.15(s,1H),8.31(s,1H),8.88(s,1H),11.57(s,1H)。
实例39
合成5-((4-羟基-3,5-二甲基苄基)氨基)-3-((4-(4-(吗啉-4-羰基)哌嗪-1-基)苯基)氨基)-1H-吡唑-4-甲酰胺39
以基本上类似于对实例1的A2所描述的方式制备中间物5-氨基-3-((4-(4-(吗啉-4-羰基)哌嗪-1-基)苯基)氨基)-1H-吡唑-4-甲酰胺。
将5-氨基-3-((4-(4-(吗啉-4-羰基)哌嗪-1-基)苯基)氨基)-1H-吡唑-4-甲酰胺(210mg)悬浮于EtOH(15mL)及哌啶(5滴)中。在80℃下在搅拌下加热反应混合物,且添加1.4当量的3,5-二甲基-4-羟基苯甲醛。在24小时之后,使反应混合物冷却至室温。通过抽吸过滤来收集所分离的固体,且用乙醇冲洗,得到粗亚胺产物,其不经纯化即使用。将粗亚胺与DMF(1mL)及MeOH(2mL)组合,且在室温下用2当量硼氢化钠处理。在30分钟之后,添加水,且通过抽吸过滤来收集所分离的沉淀,用水洗涤,且干燥,得到呈粉末状的化合物39(41mg)。1H-NMR(500MHz,DMSO):11.38(s,1H),8.28(s,1H),8.14(s,1H),7.14(d,2H),6.92(s,2H),6.82(d,2H),6.63(m,3H),4.16(d,2H),3.57(t,4H),3.28(t,4H),3.16(t,4H),2.89(t,4H),2.14(s,6H)。
实例40
合成3-((3-乙酰氨基苯基)氨基)-5-((4-羟基-3,5-二甲基苄基)氨基)-1H-吡唑-4-甲酰胺40
以基本上类似于对实例1的A2所描述的方式制备中间物3-((3-乙酰氨基苯基)氨基)-5-氨基-1H-吡唑-4-甲酰胺。
将3-((3-乙酰氨基苯基)氨基)-5-氨基-1H-吡唑-4-甲酰胺(100mg)悬浮于EtOH(8mL)及哌啶(5滴)中。在80℃下在搅拌下加热反应混合物,且添加1.5当量的3,5-二甲基-4-羟基苯甲醛。在16小时之后,使反应混合物冷却至室温。通过抽吸过滤来收集所分离的固体,且用乙醇冲洗,得到粗亚胺产物,其不经纯化即使用。将粗亚胺与DMF(1mL)及MeOH(2mL)组合,且在室温下用2当量硼氢化钠处理。在1小时之后,添加水,且用乙酸乙酯萃取混合物,用水及饱和NaCl溶液洗涤,经无水硫酸钠干燥,且蒸发,得到粗物质固体。粗物质固体自丙酮及水再结晶,得到化合物40(68mg)。1H-NMR(500MHz,DMSO):11.53(s,1H),9.75(s,1H),8.46(s,1H),8.15(s,1H),7.33(s,1H),7.06(t,2H),6.92(m,3H),6.65(m,3H),4.18(d,2H),2.15(s,6H),2.00(s,3H)。
实例41
合成3-((3-氯-4-(4-甲基哌嗪-1-基)苯基)氨基)-5-((4-羟基-3,5-二甲基苄基)氨基)-1H-吡唑-4-甲酰胺41
以基本上类似于对实例1的A2所描述的方式制备中间物5-氨基-3-((3-氯-4-(4-甲基哌嗪-1-基)苯基)氨基)-1H-吡唑-4-甲酰胺。
将5-氨基-3-((3-氯-4-(4-甲基哌嗪-1-基)苯基)氨基)-1H-吡唑-4-甲酰胺(370mg)悬浮于EtOH(10mL)及哌啶(3滴)中。在80℃下在搅拌下加热反应混合物,且添加1.4当量的3,5-二甲基-4-羟基苯甲醛。在17小时之后,使反应混合物冷却至室温。通过抽吸过滤来收集所分离的固体,且用乙醇冲洗,得到粗亚胺产物(487mg),其不经纯化即使用。将粗亚胺(82mg)与DMF(2mL)及MeOH(2mL)组合,且在室温下用2当量硼氢化钠处理。在30分钟之后,添加水,且通过抽吸过滤来收集所分离的沉淀,用水洗涤,且干燥,得到呈粉末状的化合物41(65mg)。1H-NMR(500MHz,DMSO):11.50(s,1H),8.59(s,1H),8.15(s,1H),7.55(s,1H),7.02(m,2H),6.92(s,2H),6.69(m,3H),4.16(d,2H),2.86(m,4H),2.45(m,4H),2.21(s,3H),2.14(s,6H)。
实例42
合成3-((4-氟苯基)氨基)-5-((4-羟基-3,5-二甲基苄基)氨基)-1H-吡唑-4-甲酰胺42
以基本上类似于对实例1的A2所描述的方式制备中间物5-氨基-3-((4-氟苯基)氨基)-1H-吡唑-4-甲酰胺。
将5-氨基-3-((4-氟苯基)氨基)-1H-吡唑-4-甲酰胺(225mg)悬浮于EtOH(5mL)及哌啶(5滴)中。在80℃下在搅拌下加热反应混合物,且添加1.4当量的3,5-二甲基-4-羟基苯甲醛。在22小时之后,使反应混合物冷却至室温。通过抽吸过滤来收集所分离的固体,且用乙醇冲洗,得到粗亚胺产物(342mg),其不经纯化即使用。将粗亚胺(70mg)与DMF(1mL)及MeOH(1mL)组合,且在室温下用2当量硼氢化钠处理。在3小时之后,添加水,且通过抽吸过滤来收集所分离的沉淀,用水洗涤,且干燥,得到呈粉末状的化合物42(63mg)。1H-NMR(500MHz,DMSO):11.46(s,1H),8.54(s,1H),8.14(s,1H),7.25(m,2H),7.00(t,2H),6.92(s,2H),6.67(m,3H),4.17(d,2H),2.15(s,6H)。
实例43
合成3-((3-氰基苯基)氨基)-5-((4-羟基-3,5-二甲基苄基)氨基)-1H-吡唑-4-甲酰胺43
以基本上类似于对实例1的A2所描述的方式制备中间物5-氨基-3-((3-氰基苯基)氨基)-1H-吡唑-4-甲酰胺。
将5-氨基-3-((3-氰基苯基)氨基)-1H-吡唑-4-甲酰胺(250mg)悬浮于EtOH(5mL)及哌啶(5滴)中。在80℃下在搅拌下加热反应混合物,且添加1.4当量的3,5-二甲基-4-羟基苯甲醛。在22小时之后,使反应混合物冷却至室温。通过抽吸过滤来收集所分离的固体,且用乙醇冲洗,得到粗亚胺产物(342mg),其不经纯化即使用。将粗亚胺(64mg)与DMF(1mL)及MeOH(1mL)组合,且在室温下用2当量硼氢化钠处理。在3小时之后,添加水,且通过抽吸过滤来收集所分离的沉淀,用水洗涤,且干燥,得到呈粉末状的化合物43(47mg)。1H-NMR(500MHz,DMSO):9.01(s,1H),8.15(s,1H),7.84(s,1H),7.46(d,1H),7.36(t,1H),7.16(d,2H),6.93(s,2H),6.74(m,3H),4.18(d,2H),2.15(s,6H)。
实例44
合成5-((4-羟基-3,5-二甲基苄基)氨基)-3-((4-(4-(嘧啶-2-基)哌嗪-1-基)苯基)氨基)-1H-吡唑-4-甲酰胺44
以基本上类似于对实例1的A2所描述的方式制备中间物5-氨基-3-((4-(4-(嘧啶-2-基)哌嗪-1-基)苯基)氨基)-1H-吡唑-4-甲酰胺。
将5-氨基-3-((4-(4-(嘧啶-2-基)哌嗪-1-基)苯基)氨基)-1H-吡唑-4-甲酰胺(104.4mg)悬浮于EtOH(5mL)及哌啶(5滴)中。在80℃下在搅拌下加热反应混合物,且添加1.5当量的3,5-二甲基-4-羟基苯甲醛。在24小时之后,使反应混合物冷却至室温。通过抽吸过滤来收集所分离的固体,且用乙醇冲洗,得到粗亚胺产物(141mg),其不经纯化即使用。将粗亚胺(109mg)与DMF(1mL)及MeOH(3mL)组合,且在室温下用2当量硼氢化钠处理。在18小时之后,添加水,且通过抽吸过滤来收集所分离的沉淀,用水洗涤,且干燥,得到呈粉末状的化合物44(109mg)。1H-NMR(500MHz,DMSO):11.38(s,1H),8.38(m,2H),8.29(s,1H),8.13(s,1H),7.16(d,2H),6.92(s,2H),6.87(d,2H),6.64(m,4H),4.16(d,2H),3.86(t,4H),3.05(t,4H),2.14(s,6H)。
实例45
合成5-((4-羟基-3,5-二甲基苄基)氨基)-3-((4-(哌啶-1-基甲基)苯基)氨基)-1H-吡唑-4-甲酰胺45
以基本上类似于对实例1的A2所描述的方式制备中间物5-氨基-3-((4-(哌啶-1-基甲基)苯基)氨基)-1H-吡唑-4-甲酰胺。
将5-氨基-3-((4-(哌啶-1-基甲基)苯基)氨基)-1H-吡唑-4-甲酰胺(150mg)悬浮于EtOH(3mL)及哌啶(0.5mL)中。在80℃下在搅拌下加热反应混合物,且添加1.4当量的3,5-二甲基-4-羟基苯甲醛。在18小时之后,使反应混合物冷却至室温。通过抽吸过滤来收集所分离的固体,且用乙醇冲洗,得到粗亚胺产物(145mg),其不经纯化即使用。将粗亚胺(100mg)与DMF(2mL)及MeOH(1mL)组合,且在室温下用2当量硼氢化钠处理。在30分钟之后,添加水,且通过抽吸过滤来收集所分离的沉淀,用水洗涤,且干燥,得到呈粉末状的化合物45(100mg)。1H-NMR(500MHz,DMSO):11.48(s,1H),7.14(s,2H),7.06(d,2H),6.92(s,2H),6.65(s,3H),4.17(s,2H),3.28(s,4H),2.27(s,4H),2.14(s,6H),1.46(m,4H),1.36(m,2H)。
实例46
合成5-((4-羟基-3,5-二甲基苄基)氨基)-3-((4-硫代吗啉代苯基)氨基)-1H-吡唑-4-甲酰胺46
以基本上类似于对实例1的A2所描述的方式制备中间物5-氨基-3-((4-硫代吗啉代苯基)氨基)-1H-吡唑-4-甲酰胺。
将5-氨基-3-((4-硫代吗啉代苯基)氨基)-1H-吡唑-4-甲酰胺(389mg)悬浮于EtOH(10mL)及乙酸(0.5mL)中。在80℃下在搅拌下加热反应混合物,且添加1.5当量的3,5-二甲基-4-羟基苯甲醛。在16小时之后,使反应混合物冷却至室温。通过抽吸过滤来收集所分离的固体,且用乙醇冲洗,得到粗亚胺产物(497mg),其不经纯化即使用。将粗亚胺(135mg)与DMF(6mL)及MeOH(2mL)组合,且在室温下用2当量硼氢化钠处理。在30分钟之后添加水,且在80℃下用EtOH湿磨粗产物1小时。通过抽吸过滤来收集沉淀,用EtOH洗涤,且干燥,得到呈粉末状的化合物46(105mg)。1H-NMR(500MHz,DMSO):11.38(s,1H),8.29(s,1H),8.14 9s,1H),7.14(d,2H),6.92(s,2H),6.81(d,2H),6.63(m,3H),4.16(d,2H),3.28(m,4H),2.68(m,4H),2.14(s,6H)。
实例47
合成3-((4-氨基苯基)氨基)-5-((4-羟基-3,5-二甲基苄基)氨基)-1H-吡唑-4-甲酰胺47
以基本上类似于对实例1的A2所描述的方式制备中间物5-氨基-3-((4-硝基苯基)氨基)-1H-吡唑-4-甲酰胺。
将5-氨基-3-((4-硝基苯基)氨基)-1H-吡唑-4-甲酰胺(1.006g)悬浮于EtOH(3mL)及哌啶(5滴)中。在80℃下在搅拌下加热反应混合物,且添加1.5当量的3,5-二甲基-4-羟基苯甲醛。在24小时之后,使反应混合物冷却至室温。通过抽吸过滤来收集所分离的固体,且用乙醇冲洗,得到粗亚胺产物(1.308g),其不经纯化即使用。将粗亚胺(100mg)与DMF(0.5mL)及MeOH(1mL)组合,且在室温下用2当量硼氢化钠处理。在2小时之后,添加水,且通过抽吸过滤来收集所分离的沉淀,用水洗涤。将此沉淀溶解于MeOH(1mL)及THF(2mL)中,用10%钯/碳(20mg)处理,且在氢气氛围(30psi)下搅拌。通过抽吸来收集悬浮液,且随后自DMSO及水再结晶,得到化合物47(18mg)。1H-NMR(500MHz,DMSO):11.28(s,1H),8.13(s,1H),8.00(s,1H),6.91(s,4H),6.60(s,3H),6.46(d,J=9,2H),4.50(s,2H),4.15(d,J=6,2H),2.14(s,6H)。
实例48
合成5-((4-羟基-3,5-二甲基苄基)氨基)-3-((4-氨磺酰基苯基)氨基)-1H-吡唑-4-甲酰胺48
以基本上类似于对实例1的A2所描述的方式制备中间物5-氨基-3-((4-氨磺酰基苯基)氨基)-1H-吡唑-4-甲酰胺。
将5-氨基-3-((4-氨磺酰基苯基)氨基)-1H-吡唑-4-甲酰胺(230mg)悬浮于EtOH(5mL)及哌啶(5滴)中。在80℃下在搅拌下加热反应混合物,且添加1.5当量的3,5-二甲基-4-羟基苯甲醛。在60小时之后,使反应混合物冷却至室温。通过抽吸过滤来收集所分离的固体,且用乙醇冲洗,得到粗亚胺,将该粗亚胺与DMF(1mL)及MeOH(3mL)组合,且在室温下用2当量硼氢化钠处理。在30分钟之后,添加水,且通过抽吸过滤来收集所分离的沉淀,用水洗涤,且干燥,得到呈粉末状的化合物48(244mg)。1H-NMR(500MHz,DMSO):11.65(s,1H),9.08(s,1H),8.16(s,1H),7.62(d,J=9,2H),7.31(d,J=9,2H),7.05(s,2H),6.93(s,2H),6.73(m,3H),4.18(d,J=6,2H),2.15(s,6H)。
实例49
合成5-((4-羟基-3,5-二甲基苄基)氨基)-3-((6-(4-(吡咯烷-1-基)哌啶-1-基)吡啶-3-基)氨基)-1H-吡唑-4-甲酰胺49
以基本上类似于对实例1的A2所描述的方式制备中间物5-氨基-3-((6-(4-(吡咯烷-1-基)哌啶-1-基)吡啶-3-基)氨基)-1H-吡唑-4-甲酰胺。
将5-氨基-3-((6-(4-(吡咯烷-1-基)哌啶-1-基)吡啶-3-基)氨基)-1H-吡唑-4-甲酰胺(46毫克)悬浮于EtOH(5mL)及哌啶(5滴)中。在80℃下在搅拌下加热反应混合物,且添加1.5当量的3,5-二甲基-4-羟基苯甲醛。在36小时之后,使反应混合物冷却至室温。通过抽吸过滤来收集所分离的固体,且用乙醇冲洗,得到粗亚胺产物,将该粗亚胺产物与DMF(1.5mL)及MeOH(2.5mL)组合,且在室温下用2当量硼氢化钠处理。在48小时之后,添加水,且通过抽吸过滤来收集所分离的沉淀,用水洗涤,且干燥,得到呈粉末状的化合物49(29mg)。1H-NMR(500MHz,DMSO):8.21及8.15(s,s,3H),7.60及7.54(d,s,1H),6.91(s,1H),6.81及6.73(d,J=9Hz,d,J=9Hz,1H),6.69及6.66(s,s,3H),4.16,4.05及3.99(m,m,m,4H),2.74(m,3H),2.14(s,6H),1.87(d,J=10Hz,2H),1.67(s,4H),1.38(m,2H)。
实例50
合成3-((4-(二甲基氨基)苯基)氨基)-5-((4-羟基-3,5-二甲基苄基)氨基)-1H-吡唑-4-甲酰胺50
以基本上类似于对实例1的A2所描述的方式制备中间物5-氨基-3-((4-(二甲基氨基)苯基)氨基)-1H-吡唑-4-甲酰胺。
将5-氨基-3-((4-(二甲基氨基)苯基)氨基)-1H-吡唑-4-甲酰胺(95mg)悬浮于EtOH(5mL)及哌啶(5滴)中。在80℃下在搅拌下加热反应混合物,且添加1.5当量的3,5-二甲基-4-羟基苯甲醛。在22小时之后,使反应混合物冷却至室温。通过抽吸过滤来收集所分离的固体,且用乙醇冲洗,得到粗亚胺产物,将该粗亚胺产物与DMF(0.5mL)及MeOH(2.5mL)组合,且在室温下用2当量硼氢化钠处理。在3小时之后,添加水,且通过抽吸过滤来收集所分离的沉淀,用水洗涤,且干燥,得到呈粉末状的化合物50(93mg)。1H-NMR(500MHz,DMSO):11.33(s,1H),8.15(m,2H),7.13(d,J=7,2H),6.92(s,2H),6.65(m,5H),4.16(d,J=6,2H),2.77(s,6H),2.14(s,6H)。
实例51
合成5-((4-羟基-3,5-二甲基苄基)氨基)-3-((4-(吗啉代甲基)苯基)氨基)-1H-吡唑-4-甲酰胺51
以基本上类似于对实例1的A2所描述的方式制备中间物5-氨基-3-((4-(吗啉代甲基)苯基)氨基)-1H-吡唑-4-甲酰胺。
将5-氨基-3-((4-(吗啉代甲基)苯基)氨基)-1H-吡唑-4-甲酰胺(122mg)悬浮于EtOH(5mL)及哌啶(5滴)中。在80℃下在搅拌下加热反应混合物,且添加1.5当量的3,5-二甲基-4-羟基苯甲醛。在24小时之后,使反应混合物冷却至室温。通过抽吸过滤来收集所分离的固体,且用乙醇冲洗,得到粗亚胺产物,将该粗亚胺产物与DMF(1mL)及MeOH(3mL)组合,且在室温下用2当量硼氢化钠处理。在24小时之后,添加水,且通过抽吸过滤来收集所分离的沉淀,用水洗涤,且干燥,得到呈粉末状的化合物51(110mg)。1H-NMR(500MHz,DMSO):11.48(s,1H)8.54(s,1H),8.15(s,1H),7.16(d,J=8,2H),7.08(d,J=8,2H),6.92(s,2H),6.66(s,3H),4.17(d,J=6,2H),3.55(m,4H),2.31(s,4H),2.14(s,6H)。
实例52
合成5-((4-羟基-3,5-二甲基苄基)氨基)-3-((3-甲氧基苯基)氨基)-1H-吡唑-4-甲酰胺52
以基本上类似于对实例1的A2所描述的方式制备中间物5-氨基-3-((3-甲氧基苯基)氨基)-1H-吡唑-4-甲酰胺。
将5-氨基-3-((3-甲氧基苯基)氨基)-1H-吡唑-4-甲酰胺(122mg)悬浮于EtOH(3mL)及乙酸(5滴)中。在80℃下在搅拌下加热反应混合物,且添加1.5当量的3,5-二甲基-4-羟基苯甲醛。在24小时之后,使反应混合物冷却至室温。通过抽吸过滤来收集所分离的固体,且用乙醇冲洗,得到粗亚胺产物,随后将该粗亚胺产物与DMF(0.5mL)及MeOH(2.5mL)组合,且在室温下用2当量硼氢化钠处理。在4小时之后,添加水,且通过抽吸过滤来收集所分离的沉淀,用水洗涤,且干燥,得到呈粉末状的化合物52(35mg)。1H-NMR(500MHz,DMSO):11.52(s,1H),8.63(s,1H),8.15(s,1H),7.05(t,J=9Hz,1H),6.95(s,1H),6.92(s,2H),6.69(m,4H),6.33(d,J=8Hz,1H),4.17(d,J=6Hz,2H),3.69(s,3H),2.14(s,6H)。
实例53
合成3-((4-(4-氟苯甲酰氨基)苯基)氨基)-5-((4-羟基-3,5-二甲基苄基)氨基)-1H-吡唑-4-甲酰胺53
以基本上类似于对实例1的A2所描述的方式制备中间物5-氨基-3-((4-(4-氟苯甲酰氨基)苯基)氨基)-1H-吡唑-4-甲酰胺。
将5-氨基-3-((4-(4-氟苯甲酰氨基)苯基)氨基)-1H-吡唑-4-甲酰胺(84mg)悬浮于EtOH(5mL)及哌啶(5滴)中。在80℃下在搅拌下加热反应混合物,且添加1.5当量的3,5-二甲基-4-羟基苯甲醛。在18小时之后,使反应混合物冷却至室温。通过抽吸过滤来收集所分离的固体,且用乙醇冲洗,得到粗亚胺产物,随后将该粗亚胺产物与DMF(1mL)及MeOH(2mL)组合,且在室温下用2当量硼氢化钠处理。在15分钟之后,添加水,且通过抽吸过滤来收集所分离的沉淀,用水洗涤,且干燥,得到呈粉末状的化合物53(97mg)。1H-NMR(500MHz,DMSO):11.47(s,1H),10.04(s,1H),8.59(s,1H),8.16(s,1H),8.01(m,2H),7.54(d,J=9,2H),7.34(t,J=18Hz,2H),7.23(d,J=9Hz,2H),6.93(s,2H),6.68(s,3H),8.18(d,J=6Hz,2H),2.15(s,6H)。
实例54
合成3-((4-(1H-吡唑-3-基)苯基)氨基)-5-((4-羟基-3,5-二甲基苄基)氨基)-1H-吡唑-4-甲酰胺54
以基本上类似于对实例1的A2所描述的方式制备中间物3-((4-(1H-吡唑-3-基)苯基)氨基)-5-氨基-1H-吡唑-4-甲酰胺。
将3-((4-(1H-吡唑-3-基)苯基)氨基)-5-氨基-1H-吡唑-4-甲酰胺(515mg)悬浮于EtOH(5mL)及哌啶(5滴)中。在80℃下在搅拌下加热反应混合物,且添加1.5当量的3,5-二甲基-4-羟基苯甲醛。在24小时之后,使反应混合物冷却至室温。通过抽吸过滤来收集所分离的固体,且用乙醇冲洗,得到粗亚胺产物,随后将该粗亚胺产物与DMF(0.5mL)及MeOH(1.5mL)组合,且在室温下用2当量硼氢化钠处理。在24小时之后,添加水,且通过抽吸过滤来收集所分离的沉淀,用水洗涤,且干燥,得到呈粉末状的化合物54(19mg)。1H-NMR(500MHz,DMSO):13.02(宽s,.4H),12.65(宽s,.6H),11.52(s,1H),8,90-8.60(2个宽s,1H),8.16(s,1H),7.80-7.18(m,5H),6.93(s,2H),6.69(s,3H),6.53(m,1H),4.18(d,2H),2.15(s,6H)。
实例55
合成5-((4-羟基-3,5-二甲基苄基)氨基)-3-((4-(2-甲氧基苯甲酰氨基)苯基)氨基)-1H-吡唑-4-甲酰胺55
以基本上类似于对实例1的A2所描述的方式制备5-氨基-3-((4-(2-甲氧基苯甲酰氨基)苯基)氨基)-1H-吡唑-4-甲酰胺。
将5-氨基-3-((4-(2-甲氧基苯甲酰氨基)苯基)氨基)-1H-吡唑-4-甲酰胺(49mg)悬浮于EtOH(5mL)及哌啶(5滴)中。在80℃下在搅拌下加热反应混合物,且添加1.5当量的3,5-二甲基-4-羟基苯甲醛。在22小时之后,使反应混合物冷却至室温。通过抽吸过滤来收集所分离的固体,且用乙醇冲洗,得到粗亚胺产物,随后将该粗亚胺产物与DMF(0.5mL)及MeOH(2.5mL)组合,且在室温下用2当量硼氢化钠处理。在3小时之后,添加水,且通过抽吸过滤来收集所分离的沉淀,用水洗涤,且干燥,得到呈粉末状的化合物54(34mg)。1H-NMR(500MHz,DMSO):11.46(s,1H),9.88(s,1H),8.59(s,1H),8.16(s,1H),7.65(d,J=7Hz,1H),7.54(d,J=9Hz,2H),7.48(t,J=8Hz,1H),7.23(d,J=9Hz,2H),7.16(d,J=8Hz,1H),7.05(t,J=8Hz,1H),6.93(s,2H),6.68(s,3H),4.18(d,J=6Hz,2H),3.90(s,3H),2.15(s,6H)。
实例56
合成5-((4-羟基-3,5-二甲基苄基)氨基)-3-((4-(3-甲氧基苯甲酰氨基)苯基)氨基)-1H-吡唑-4-甲酰胺56
以基本上类似于对实例1的A2所描述的方式制备中间物5-氨基-3-((4-(3-甲氧基苯甲酰氨基)苯基)氨基)-1H-吡唑-4-甲酰胺。
将5-氨基-3-((4-(3-甲氧基苯甲酰氨基)苯基)氨基)-1H-吡唑-4-甲酰胺(85mg)悬浮于EtOH(5mL)及哌啶(5滴)中。在80℃下在搅拌下加热反应混合物,且添加1.5当量的3,5-二甲基-4-羟基苯甲醛。在22小时之后,使反应混合物冷却至室温。通过抽吸过滤来收集所分离的固体,且用乙醇冲洗,得到粗亚胺产物,随后将该粗亚胺产物与DMF(0.5mL)及MeOH(2.5mL)组合,且在室温下用2当量硼氢化钠处理。在6小时之后,添加水,且通过抽吸过滤来收集所分离的沉淀,用水洗涤,且干燥,得到呈粉末状的化合物56(75mg)。1H-NMR(500MHz,DMSO):11.82(s,1H),10.00(s,1H),8.59(s,1H),8.16(s,1H),7.54(m,3H),7.47(m,1H),7.42(t,J=8Hz,1H),7.23(d,J=8Hz,2H),7.13(dd,1H),6.93(s,2H),6.68(s,3H),4.18(d,J=6Hz,2H),3.83(s,3H),2.15(s,6H)。
实例57
合成5-((4-羟基-3,5-二甲基苄基)氨基)-3-((4-(4-甲氧基苯甲酰氨基)苯基)氨基)-1H-吡唑-4-甲酰胺57
以基本上类似于对实例1的A2所描述的方式制备中间物5-氨基-3-((4-(4-甲氧基苯甲酰氨基)苯基)氨基)-1H-吡唑-4-甲酰胺。
将5-氨基-3-((4-(4-甲氧基苯甲酰氨基)苯基)氨基)-1H-吡唑-4-甲酰胺(73mg)悬浮于EtOH(5mL)及哌啶(5滴)中。在80℃下在搅拌下加热反应混合物,且添加1.5当量的3,5-二甲基-4-羟基苯甲醛。在22小时之后,使反应混合物冷却至室温。通过抽吸过滤来收集所分离的固体,且用乙醇冲洗,得到粗亚胺产物,随后将该粗亚胺产物与DMF(0.5mL)及MeOH(2.5mL)组合,且在室温下用2当量硼氢化钠处理。在1小时之后,添加水,且通过抽吸过滤来收集所分离的沉淀,用水洗涤,且干燥,得到呈粉末状的化合物57(69mg)。1H-NMR(500MHz,DMSO):11.80(s,1H),9.87(s,1H),8.56(s,1H),8.16(s,1H),7.94(m,2H),7.54(d,J=9Hz,2H),7.22(d,J=8Hz,2H),7.05(m,2H),6.93(s,2H),6.68(s,3H),4.18(d,J=6Hz,2H),3.84(m,3H),2.15(s,1H)。
实例58
合成5-((4-羟基-3,5-二甲基苄基)氨基)-3-((4-(4-异丙基哌啶-1-基)苯基)氨基)-1H-吡唑-4-甲酰胺58
以基本上类似于对实例1的A2所描述的方式制备中间物5-氨基-3-((4-(4-异丙基哌啶-1-基)苯基)氨基)-1H-吡唑-4-甲酰胺。
将5-氨基-3-((4-(4-异丙基哌啶-1-基)苯基)氨基)-1H-吡唑-4-甲酰胺(151mg)悬浮于EtOH(5mL)及哌啶(5滴)中。在80℃下在搅拌下加热反应混合物,且添加1.5当量的3,5-二甲基-4-羟基苯甲醛。在22小时之后,使反应混合物冷却至室温。通过抽吸过滤来收集所分离的固体,且用乙醇冲洗,得到粗亚胺产物,随后将该粗亚胺产物与DMF(1mL)及MeOH(3mL)组合,且在室温下用2当量硼氢化钠处理。在24小时之后,添加水,且通过抽吸过滤来收集所分离的沉淀,用水洗涤,且干燥,得到呈粉末状的化合物58(142mg)。1H-NMR(500MHz,DMSO):11.36(s,1H),8.22(s,1H),8.13(s,1H),7.12(d,J=9Hz,2H),6.92(s,2H),8.79(d,J=9Hz,2H),6.63(m,3H),4.16(d,J=6Hz,2H),5.50(d,J=12Hz,2H),2.46(m,2H),2.14(s,6H),1.71(d,2H),1.44(m,1H),1.28(m,2H),1.08(m,1H),0.88(d,J=7Hz,6H)。
实例59
合成5-((4-羟基-3,5-二甲基苄基)氨基)-3-((4-(3-氧代吗啉代)苯基)氨基)-1H-吡唑-4-甲酰胺59
以基本上类似于对实例1的A2所描述的方式制备中间物5-氨基-3-((4-(3-氧代吗啉代)苯基)氨基)-1H-吡唑-4-甲酰胺。
将5-氨基-3-((4-(3-氧代吗啉代)苯基)氨基)-1H-吡唑-4-甲酰胺(400mg)悬浮于EtOH(8mL)及哌啶(5滴)中。在80℃下在搅拌下加热反应混合物,且添加1.4当量的3,5-二甲基-4-羟基苯甲醛。在20小时之后,使反应混合物冷却至室温。通过抽吸过滤来收集所分离的固体,且用乙醇冲洗,得到粗亚胺产物。将一些粗亚胺(50mg)与DMF(1mL)及MeOH(1mL)组合,且在室温下用2当量硼氢化钠处理。在18小时之后,添加水,且通过抽吸过滤来收集所分离的沉淀,用水洗涤,且干燥,得到呈粉末状的化合物59(36mg)。1H-NMR(500MHz,DMSO):2.15(s,6H),3.64(t,2H),3.94(t,2H),4.15(s,2H),4.18(d,2H),6.68(m,3H),6.93(s,2H),7.15(t,2H),7.22(d,2H),8.15(s,1H),8.63(s,1H),11.53(s,1H)。
实例61
合成3-((4-(氰基甲基)苯基)氨基)-5-((4-羟基-3,5-二甲基苄基)氨基)-1H-吡唑-4-甲酰胺61
以基本上类似于对实例1的A2所描述的方式制备中间物5-氨基-3-((4-(氰基甲基)苯基)氨基)-1H-吡唑-4-甲酰胺。
将5-氨基-3-((4-(氰基甲基)苯基)氨基)-1H-吡唑-4-甲酰胺(86mg)悬浮于EtOH(5mL)及乙酸(5滴)中。在80℃下在搅拌下加热反应混合物,且添加1.5当量的3,5-二甲基-4-羟基苯甲醛。在24小时之后,使反应混合物冷却至室温。通过抽吸过滤来收集所分离的固体,且用乙醇冲洗,得到粗亚胺产物。随后将粗亚胺产物的一部分与DMF(0.5mL)及MeOH(1.5mL)组合,且在室温下用2当量硼氢化钠处理。在2小时之后,添加水,且通过抽吸过滤来收集所分离的沉淀,用水洗涤,且干燥,得到呈粉末状的化合物61(62mg)。1H-NMR(500MHz,DMSO):11.51(s,1H),8.65(s,1H),8.14(s,1H),7.24(d,J=9Hz,2H),7.14(d,J=9Hz,2H),6.92(s,2H),6.67(m,3H),4.18(d,J=6Hz,2H),3.87(s,2H),2.15(s,6H)。
实例62
合成5-((4-羟基-3,5-二甲基苄基)氨基)-3-((4-(4-(三氟甲基)苯甲酰氨基)苯基)氨基)-1H-吡唑-4-甲酰胺62
以基本上类似于对实例1的A2所描述的方式制备中间物5-氨基-3-((4-(4-(三氟甲基)苯甲酰氨基)苯基)氨基)-1H-吡唑-4-甲酰胺。
将5-氨基-3-((4-(4-(三氟甲基)苯甲酰氨基)苯基)氨基)-1H-吡唑-4-甲酰胺(101mg)悬浮于EtOH(5mL)及乙酸(5滴)中。在80℃下在搅拌下加热反应混合物,且添加1.5当量的3,5-二甲基-4-羟基苯甲醛。在24小时之后,使反应混合物冷却至室温。通过抽吸过滤来收集所分离的固体,且用乙醇冲洗,得到粗亚胺产物,随后将该粗亚胺产物与DMF(1mL)及MeOH(3mL)组合,且在室温下用2当量硼氢化钠处理。在2小时之后,添加水,且通过抽吸过滤来收集所分离的沉淀,用水洗涤,且干燥,得到呈粉末状的化合物62(15mg)。1H-NMR(500MHz,DMSO):11.48(s,1H),10.26(s,1H),8.63(s,1H),8.16(s,1H),8.13(d,J=8Hz,2H),7.90(d,J=9Hz,2H),7.58(d,2H),7.25(d,J=7Hz,2H),6.93(s,2H),6.69(s,3H),4.18(d,J=7Hz,2H),2.15(s,6H)。
实例63
合成5-((4-羟基-3,5-二甲基苄基)氨基)-3-((4-(4-甲基哌啶-1-基)苯基)氨基)-1H-吡唑-4-甲酰胺63
以基本上类似于对实例1的A2所描述的方式制备中间物5-氨基-3-((4-(4-甲基哌啶-1-基)苯基)氨基)-1H-吡唑-4-甲酰胺。
将5-氨基-3-((4-(4-甲基哌啶-1-基)苯基)氨基)-1H-吡唑-4-甲酰胺(114mg)悬浮于EtOH(5mL)及哌啶(5滴)中。在80℃下在搅拌下加热反应混合物,且添加1.5当量的3,5-二甲基-4-羟基苯甲醛。在21小时之后,使反应混合物冷却至室温。通过抽吸过滤来收集所分离的固体,且用乙醇冲洗,得到粗亚胺产物,随后将该粗亚胺产物与DMF(0.5mL)及MeOH(2mL)组合,且在室温下用2当量硼氢化钠处理。在30分钟之后,添加水,且通过抽吸过滤来收集所分离的沉淀,用水洗涤,且干燥,得到呈粉末状的化合物63(30mg)。1H-NMR(500MHz,DMSO):11.36(s,1H),8.21(s,2H),8.12(s,2H),7.10(s,2H),6.92(s,2H),6.79(d,2H),6.62(s,2H),4.16(d,2H),3.43(d,2H),2.54(s,1H),2.14(s,6H),1.67(d,2H),1.43(m,1H),1.26(m,2H),0.93(d,3H)。
实例I
激酶抑制剂的质谱数据
激酶抑制剂的质谱数据概括于下表1中。
表1
实例II
激酶抑制活性的酶促分析
对于大多数分析,在来源于BL21菌株的大肠杆菌(E.coli)宿主中制备激酶标记的T7噬菌体菌株。使大肠杆菌生长至对数期(log-phase),且用T7噬菌体感染,且在32℃下伴随震荡培育,直至裂解为止。对裂解物进行离心,且过滤以移除细胞碎片。在HEK-293细胞中产生其余激酶,且随后用DNA标记以用于定量PCR(qPCR)检测。
在室温下用生物素化小分子配位体处理经抗生蛋白链菌素涂布的磁性珠粒持续30分钟,以生成用于激酶分析的亲和树脂。用过量生物素阻断经配位的珠粒,且用阻断缓冲液(SeaBlock(Pierce),1%BSA、0.05%Tween 20、1mM DTT)洗涤以移除未结合的配位体及减少非特异性结合。结合反应通过在1×结合缓冲液(20%SeaBlock、0.17×PBS、0.05%Tween20、6毫米DTT)中组合激酶、经配位的亲和珠粒及测试化合物来组装。所有反应均在聚苯乙烯96孔板中以0.135mL的最终体积进行。将分析板在室温下伴随震荡培育1小时,且用洗涤缓冲液(1×PBS、0.05%Tween 20)洗涤亲和珠粒。随后将珠粒再悬浮于溶离缓冲液(1×PBS、0.05%吐温20、0.5μM非生物素化亲和配位体)中,且在室温下伴随震荡培育30分钟。溶离液中的激酶浓度通过qPCR来测量。
在100%DMSO中以100×最终测试浓度制备各测试化合物的11点、3倍连续稀释液,且随后在分析中稀释至1×(最终DMSO浓度=1%)。大多数Kd值使用化合物最高浓度=30,000nM来测定。若所测定的初始Kd<0.5nM(所测试的最低浓度),则用以较低最高浓度起始的连续稀释液重复量测。此分析的更具体描述可见于Fabian,M.A.等人Nat.Biotechnol.2005,23,329-336,其全文并入本文中。
RC激酶(RCK)及JAK2及JAK3的激酶结构域蛋白质的抑制的生物学结果概括于表2及3中,其中A表示Kd<50nM;B表示50nM<Kd<100nM;C表示100nM<Kd<1000nM;且D表示Kd>1000nM。
另外,如由比率Kd(JAK2):Kd(RCK)所量测的RCK:JAK2选择性表示如下:A表示Kd(JAK2):Kd(RCK)>100;B表示10<Kd(JAK2):Kd(RCK)<100;C表示1<Kd(JAK2):Kd(RCK)<10;且D表示Kd(JAK2):Kd(RCK)<1。
类似地,如由比率Kd(JAK3):Kd(RCK)所量测的RCK:JAK3选择性表示如下:A表示Kd(JAK3):Kd(RCK)>100;B表示10<Kd(JAK3):Kd(RCK)<100;C表示1<Kd(JAK3):Kd(RCK)<10;且D表示Kd(JAK3):Kd(RCK)<1。
表2
表3
*****
提供上文所阐述的实例以向本领域普通技术人员提供如何制得并使用所保护的实施例的全部披露内容及描述,且不旨在限制本文所披露的范围。本领域技术人员显而易见的修改旨在处于以下申请专利范围的范围内。本说明书中所引用的所有公开物、专利及专利申请均以引用的方式并入本文中,如同各此类公开物、专利或专利申请特定地且个别地指示以引用的方式并入本文中一般。
Claims (59)
1.一种式I的化合物:
或其立体异构体、对映异构体、对映异构体的混合物、非对映异构体的混合物或同位素变体;或其药学上可接受的盐、溶剂合物、水合物或前药;其中:
R1为C6-14芳基、杂芳基或杂环基;
R2及R3各自独立地为C1-6烷基或C3-10环烷基;
其中各烷基、环烷基、芳基、杂芳基或杂环基任选地经一个或多个取代基Q取代,其中各Q独立地选自卤基、C1-6烷基、杂芳基及杂环基,其中的每一个进一步任选地经一个或多个C1-6烷基取代;
其前提为该化合物不为3-((3-氯苯基)氨基)-5-((4-羟基-3,5-二甲基苄基)氨基)-1H-吡唑-4-甲酰胺。
2.如权利要求1所述的化合物,其中R1为C6-14芳基或杂芳基,其中的每一个任选地经一个或多个取代基Q取代。
3.如权利要求1或2所述的化合物,其中R1为任选地经一个或多个取代基Q取代的C6-14芳基。
4.如权利要求1至3中任一项所述的化合物,其中R1为任选地经一个或多个取代基Q取代的苯基。
5.如权利要求4所述的化合物,其中Q独立地选自氟、氯、溴、碘、甲基、吗啉基、二甲基吗啉基、吡咯基、异丙基哌嗪基、甲基哌嗪基、吡啶基及苄基哌嗪基。
6.如权利要求3至5中任一项所述的化合物,其中R1为3-甲基-4-吗啉代苯基、3-氯-4-吗啉代苯基、4-吗啉代苯基、4-(2,6-二甲基吗啉代)苯基、4-(1H-吡咯-1-基)苯基、4-(4-异丙基哌嗪-1-基)苯基、4-(吡啶-2-基)苯基、4-(4-甲基哌嗪-1-基)苯基、3-氯-4-(2,6-二甲基吗啉代)苯基、4-(吡啶-3-基)苯基或3-氯-4-(4-异丙基哌嗪-1-基)苯基。
7.如权利要求1或2所述的化合物,其中R1为任选地经一个或多个取代基Q取代的杂芳基。
8.如权利要求7所述的化合物,其中R1为5元或6元杂芳基,其中的每一个任选地经一个或多个取代基Q取代。
9.如权利要求8所述的化合物,其中R1为任选地经一个或多个取代基Q取代的吡啶基。
10.如权利要求9所述的化合物,其中R1为2-吗啉代-3-氯吡啶-5-基、2-吗啉代吡啶-5-基、5-吗啉代吡啶-2-基、2-吗啉代-3-甲基吡啶-5-基、2-(4-异丙基哌嗪-1-基)-3-甲基吡啶-5-基或2-(4-甲基哌嗪-1-基)-3-甲基吡啶-5-基。
11.如权利要求1至10中任一项所述的化合物,其中R2为C1-6烷基。
12.如权利要求1至11中任一项所述的化合物,其中R2为甲基。
13.如权利要求1至12中任一项所述的化合物,其中R3为C1-6烷基。
14.如权利要求1至13中任一项所述的化合物,其中R3为甲基。
15.如权利要求1的化合物,其选自下组,该组由以下各项组成:
及其立体异构体、对映异构体、对映异构体的混合物、非对映异构体的混合物及同位素变体;以及其药学上可接受的盐、溶剂合物、水合物及前药。
16.一种药物组合物,其包含如权利要求1至15中任一项的化合物以及一种或多种药学上可接受的赋形剂。
17.如权利要求16所述的药物组合物,其中该组合物经配制以用于单剂量给予。
18.如权利要求16所述的药物组合物,其中该组合物配制为口服、非经肠或静脉内剂型。
19.如权利要求18所述的药物组合物,其中该口服剂型为片剂或胶囊。
20.如权利要求16所述的药物组合物,其进一步包含第二治疗剂。
21.一种用于治疗、预防或改善受试者中RC激酶介导的病症、疾病或病状的一种或多种症状的方法,其包含向该受试者给予如权利要求1所述的化合物。
22.一种用于治疗、预防或改善受试者中嗜酸性细胞相关病症、疾病或病状的一种或多种症状的方法,其包含向该受试者给予如权利要求1至15中任一项所述的化合物或如权利要求16所述的组合物。
23.一种用于治疗、预防或改善受试者中嗜碱性细胞相关病症、疾病或病状的一种或多种症状的方法,其包含向该受试者给予如权利要求1至15中任一项所述的化合物或如权利要求16所述的组合物。
24.一种用于治疗、预防或改善受试者中肥大细胞相关病症、疾病或病状的一种或多种症状的方法,其包含向该受试者给予如权利要求1至15中任一项的化合物或如权利要求16所述的组合物。
25.一种用于治疗、预防或改善受试者中发炎性疾病的一种或多种症状的方法,其包含向该受试者给予如权利要求1至15中任一项所述的化合物或如权利要求16所述的组合物。
26.如权利要求25所述的方法,其中该病症、疾病或病状是选自下组,该组由以下各项组成:哮喘、过敏性哮喘、运动诱发的哮喘、过敏性鼻炎、常年性过敏性鼻炎、季节性过敏性鼻炎、异位性皮炎、接触性超敏反应、接触性皮炎、结膜炎、过敏性结膜炎、嗜酸性细胞性支气管炎、食物过敏、嗜酸性细胞性胃肠炎、发炎性肠病、溃疡性结肠炎、克罗恩氏病、肥大细胞增多症、高IgE综合症、系统性红斑狼疮、牛皮癣、痤疮、多发性硬化症、同种异体移植排斥、再灌注损伤、慢性阻塞性肺病、丘-施二氏综合征、窦炎、嗜碱性细胞性白血病、慢性荨麻疹、嗜碱性细胞增多、湿疹、关节炎、类风湿性关节炎、牛皮癣性关节炎、骨关节炎及心血管病症。
27.如权利要求26所述的方法,其中该病症、疾病或病状为哮喘、运动诱发的哮喘、过敏性鼻炎、异位性皮炎、慢性阻塞性肺病或过敏性结膜炎。
28.如权利要求21所述的方法,其中该化合物与第二治疗剂组合给予。
29.一种用于调节RC激酶活性所述的方法,其包含使RC激酶与如权利要求1至15中任一项所述的化合物或如权利要求16所述的组合物接触。
30.一种式I的化合物:
或其立体异构体、对映异构体、对映异构体的混合物、非对映异构体的混合物或同位素变体;或其药学上可接受的盐、溶剂合物、水合物或前药;其中:
R1为C6-14芳基、杂芳基或杂环基;
R2及R3各自独立地为C1-6烷基或C3-10环烷基;
其中各烷基、环烷基、芳基、杂芳基或杂环基任选地经一个或多个取代基Q取代,其中各Q独立地选自卤基、C1-6烷基、C1-6烷氧基、芳基、杂芳基及杂环基,其中的每一个进一步任选地经一个或多个C1-6烷基、卤基、芳烷基、二烷基氨基、杂环基、杂环基烷基及杂环基羰基取代;
其前提为该化合物不为3-((3-氯苯基)氨基)-5-((4-羟基-3,5-二甲基苄基)氨基)-1H-吡唑-4-甲酰胺。
31.如权利要求30所述的化合物,其中R1为C6-14芳基或杂芳基,其中的每一个任选地经一个或多个取代基Q取代。
32.如权利要求30或31所述的化合物,其中R1为任选地经一个或多个取代基Q取代的C6-14芳基。
33.如权利要求30至32中任一项所述的化合物,其中R1为任选地经一个或多个取代基Q取代的苯基。
34.如权利要求33所述的化合物,其中Q独立地选自氟、氯、溴、碘、甲基、吗啉基、二甲基吗啉基、吡咯基、异丙基哌嗪基、甲基哌嗪基、吡啶基、苄基哌嗪基、苯基、咪唑基、甲氧基、叔丁基、吲唑基、甲基哌啶基、(吡咯烷羰基)哌嗪基、氟哌啶基、二甲基吡喃基、哌啶基、苯甲基、1,1-二氧化硫代吗啉代、吡咯烷基甲基、二甲基氨基、噁唑基、(哌啶羰基)哌嗪基、乙酰氨基、(嘧啶基)哌嗪基、哌啶基甲基、硫代吗啉基、氟苯基酰氨基、甲氧基苯基酰氨基、异丙基哌啶基、氰基甲基、(三氟甲基)苯基酰氨基及氧代吗啉基。
35.如权利要求32至34中任一项所述的化合物,其中R1为3-甲基-4-吗啉代苯基、3-氯-4-吗啉代苯基、4-吗啉代苯基、4-(2,6-二甲基吗啉代)苯基、4-(1H-吡咯-1-基)苯基、4-(4-异丙基哌嗪-1-基)苯基、4-(吡啶-2-基)苯基、4-(4-甲基哌嗪-1-基)苯基、3-氯-4-(2,6-二甲基吗啉代)苯基、4-(吡啶-3-基)苯基、3-氯-4-(4-异丙基哌嗪-1-基)苯基、1,1'-联苯、4-(1H-咪唑-1-基)苯基、4-甲氧基苯基、4-叔丁基苯基、4-(4-甲基-[1,4’-联哌啶]-1'-基)苯基、4-(4-(吗啉-4-羰基)哌嗪-1-基)苯基、4-(4-氟哌啶-1-基)苯基、4-(哌啶-1-基)苯基、3-氯-4-(2,6-二甲基吗啉代)苯基、3-甲基-4-(4-甲基哌嗪-1-基)苯基、3-甲基-4-(哌啶-1-基)苯基、4-(4-苯甲基哌嗪-1-基)-3-甲基苯基、4-(1,1-二氧化硫代吗啉代)苯基、(5-(哌啶-1-基)吡啶-2-基)苯基、4-(4-氯哌啶-1-基)苯基、4-(吡咯烷-1-基甲基)苯基、4-(4-(二甲基氨基)哌啶-1-基)苯基、3-氟-4-吗啉代苯基、4-(噁唑-5-基)苯基、4-(4-(哌啶-1-羰基)哌嗪-1-基)苯基、3-乙酰氨基苯基、3-氯-4-(4-甲基哌嗪-1-基)苯基、4-氟苯基、3-氰基苯基、4-(4-(嘧啶-2-基)哌嗪-1-基)苯基、4-(哌啶-1-基甲基)苯基、4-硫代吗啉代苯基、4-氨基苯基、4-(氨基磺酰基)苯基、4-(二甲基氨基)苯基、4-(吗啉代甲基)苯基、2-甲氧基苯基、4-(4-氟苯基酰氨基)苯基、4-(4,5-二氢-1H-吡唑-3-基)苯基、4-(2-甲氧基苯基酰氨基)苯基、4-(3-甲氧基苯基酰氨基)苯基、4-(4-甲氧基苯基酰氨基)苯基、4-(4-异丙基哌啶-1-基)苯基、4-(3-氧代吗啉基)苯基、4-(2-氰基甲基)苯基、4-((4-三氟甲基)苯基酰氨基)苯基或4-(4-甲基哌啶-1-基)苯基。
36.如权利要求30或31所述的化合物,其中R1为任选地经一个或多个取代基Q取代的杂芳基。
37.如权利要求36所述的化合物,其中R1为5元或6元杂芳基,其中的每一个任选地经一个或多个取代基Q取代。
38.如权利要求36所述的化合物,其中R1为任选地经一个或多个取代基Q取代的吲唑基。
39.如权利要求37所述的化合物,其中R1为任选地经一个或多个取代基Q取代的吡啶基。
40.如权利要求39所述的化合物,其中R1为2-吗啉代-3-氯吡啶-5-基、2-吗啉代吡啶-5-基、5-吗啉代吡啶-2-基、2-吗啉代-3-甲基吡啶-5-基、2-(4-异丙基哌嗪-1-基)-3-甲基吡啶-5-基、2-(4-甲基哌嗪-1-基)-3-甲基吡啶-5-基、6-(2,6-二甲基四氢-2H-吡喃-4-基)吡啶-3-基或2-(4-(吡咯烷-1-基)哌啶-1-基)吡啶-5-基。
41.如权利要求30至40中任一项所述的化合物,其中R2为C1-6烷基。
42.如权利要求30至41中任一项所述的化合物,其中R2为甲基。
43.如权利要求30至42中任一项所述的化合物,其中R3为C1-6烷基。
44.如权利要求30至43中任一项所述的化合物,其中R3为甲基。
45.如权利要求30所述的化合物,其选自下组,该组由以下各项组成:
及其立体异构体、对映异构体、对映异构体的混合物、非对映异构体的混合物及同位素变体;以及其药学上可接受的盐、溶剂合物、水合物及前药。
46.一种药物组合物,其包含如权利要求30至45中任一项所述的化合物以及一种或多种药学上可接受的赋形剂。
47.如权利要求46所述的药物组合物,其中该组合物经配制以用于单剂量给予。
48.如权利要求46所述的药物组合物,其中该组合物配制为口服、非经肠或静脉内剂型。
49.如权利要求48所述的药物组合物,其中该口服剂型为片剂或胶囊。
50.如权利要求46所述的药物组合物,其进一步包含第二治疗剂。
51.一种用于治疗、预防或改善受试者中RC激酶介导的病症、疾病或病状的一种或多种症状的方法,其包含向该受试者给予如权利要求30所述的化合物。
52.一种用于治疗、预防或改善受试者中嗜酸性细胞相关病症、疾病或病状的一种或多种症状的方法,其包含向该受试者给予如权利要求30至45中任一项所述的化合物或如权利要求46所述的组合物。
53.一种用于治疗、预防或改善受试者中嗜碱性细胞相关病症、疾病或病状的一种或多种症状的方法,其包含向该受试者给予如权利要求30至45中任一项所述的化合物或如权利要求46所述的组合物。
54.一种用于治疗、预防或改善受试者中肥大细胞相关病症、疾病或病状的一种或多种症状的方法,其包含向该受试者给予如权利要求30至45中任一项所述的化合物或如权利要求46所述的组合物。
55.一种用于治疗、预防或改善受试者中发炎性疾病的一种或多种症状的方法,其包含向该受试者给予如权利要求30至45中任一项所述的化合物或如权利要求46所述的组合物。
56.如权利要求55所述的方法,其中该病症、疾病或病状是选自下组,该组由以下各项组成:哮喘、过敏性哮喘、运动诱发的哮喘、过敏性鼻炎、常年性过敏性鼻炎、季节性过敏性鼻炎、异位性皮炎、接触性超敏反应、接触性皮炎、结膜炎、过敏性结膜炎、嗜酸性细胞性支气管炎、食物过敏、嗜酸性细胞性胃肠炎、发炎性肠病、溃疡性结肠炎、克罗恩氏病、肥大细胞增多症、高IgE综合症、系统性红斑狼疮、牛皮癣、痤疮、多发性硬化症、同种异体移植排斥、再灌注损伤、慢性阻塞性肺病、丘-施二氏综合征、窦炎、嗜碱性细胞性白血病、慢性荨麻疹、嗜碱性细胞增多、湿疹、关节炎、类风湿性关节炎、牛皮癣性关节炎、骨关节炎及心血管病症。
57.如权利要求56所述的方法,其中该病症、疾病或病状为哮喘、运动诱发的哮喘、过敏性鼻炎、异位性皮炎、慢性阻塞性肺病或过敏性结膜炎。
58.如权利要求51所述的方法,其中该化合物与第二治疗剂组合给予。
59.一种用于调节RC激酶活性所述的方法,其包含使RC激酶与如权利要求30至45任一项所述的化合物或如权利要求46所述的组合物接触。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201462096308P | 2014-12-23 | 2014-12-23 | |
US62/096,308 | 2014-12-23 | ||
PCT/US2015/067359 WO2016106309A1 (en) | 2014-12-23 | 2015-12-22 | 3,5-diaminopyrazole kinase inhibitors |
Publications (2)
Publication Number | Publication Date |
---|---|
CN107250116A true CN107250116A (zh) | 2017-10-13 |
CN107250116B CN107250116B (zh) | 2020-10-27 |
Family
ID=55174712
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201580076521.8A Active CN107250116B (zh) | 2014-12-23 | 2015-12-22 | 3,5-二氨基吡唑激酶抑制剂 |
Country Status (20)
Country | Link |
---|---|
US (2) | US9546163B2 (zh) |
EP (1) | EP3237407B1 (zh) |
JP (1) | JP6450010B2 (zh) |
KR (1) | KR102034202B1 (zh) |
CN (1) | CN107250116B (zh) |
AR (1) | AR103264A1 (zh) |
AU (1) | AU2015369690B2 (zh) |
DK (1) | DK3237407T3 (zh) |
EA (1) | EA032473B1 (zh) |
ES (1) | ES2805528T3 (zh) |
HU (1) | HUE049801T2 (zh) |
IL (1) | IL252986B (zh) |
MX (1) | MX2017008526A (zh) |
MY (1) | MY191736A (zh) |
NZ (1) | NZ733950A (zh) |
PH (1) | PH12017501334B1 (zh) |
SG (1) | SG11201705088VA (zh) |
TW (1) | TWI703133B (zh) |
UA (1) | UA118312C2 (zh) |
WO (1) | WO2016106309A1 (zh) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP7087306B2 (ja) | 2017-09-04 | 2022-06-21 | 三菱マテリアル株式会社 | カッター |
WO2019226213A2 (en) | 2018-03-08 | 2019-11-28 | Incyte Corporation | AMINOPYRAZINE DIOL COMPOUNDS AS PI3K-y INHIBITORS |
WO2020010003A1 (en) | 2018-07-02 | 2020-01-09 | Incyte Corporation | AMINOPYRAZINE DERIVATIVES AS PI3K-γ INHIBITORS |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20130303492A1 (en) * | 2012-03-16 | 2013-11-14 | Axikin Pharmaceuticals, Inc. | 3,5-diaminopyrazole kinase inhibitors |
Family Cites Families (192)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3536809A (en) | 1969-02-17 | 1970-10-27 | Alza Corp | Medication method |
US3598123A (en) | 1969-04-01 | 1971-08-10 | Alza Corp | Bandage for administering drugs |
US3845770A (en) | 1972-06-05 | 1974-11-05 | Alza Corp | Osmatic dispensing device for releasing beneficial agent |
US3916899A (en) | 1973-04-25 | 1975-11-04 | Alza Corp | Osmotic dispensing device with maximum and minimum sizes for the passageway |
US4008719A (en) | 1976-02-02 | 1977-02-22 | Alza Corporation | Osmotic system having laminar arrangement for programming delivery of active agent |
US4410545A (en) | 1981-02-13 | 1983-10-18 | Syntex (U.S.A.) Inc. | Carbonate diester solutions of PGE-type compounds |
US4328245A (en) | 1981-02-13 | 1982-05-04 | Syntex (U.S.A.) Inc. | Carbonate diester solutions of PGE-type compounds |
US4409239A (en) | 1982-01-21 | 1983-10-11 | Syntex (U.S.A.) Inc. | Propylene glycol diester solutions of PGE-type compounds |
ES8702440A1 (es) | 1984-10-04 | 1986-12-16 | Monsanto Co | Un procedimiento para la preparacion de una composicion de polipeptido inyectable sustancialmente no acuosa. |
IE58110B1 (en) | 1984-10-30 | 1993-07-14 | Elan Corp Plc | Controlled release powder and process for its preparation |
US5033252A (en) | 1987-12-23 | 1991-07-23 | Entravision, Inc. | Method of packaging and sterilizing a pharmaceutical product |
US5052558A (en) | 1987-12-23 | 1991-10-01 | Entravision, Inc. | Packaged pharmaceutical product |
US5073543A (en) | 1988-07-21 | 1991-12-17 | G. D. Searle & Co. | Controlled release formulations of trophic factors in ganglioside-lipsome vehicle |
US5612059A (en) | 1988-08-30 | 1997-03-18 | Pfizer Inc. | Use of asymmetric membranes in delivery devices |
JPH072743B2 (ja) | 1988-10-21 | 1995-01-18 | 富士写真フイルム株式会社 | 1H−ピラゾロ〔5,1−c〕−1,2,4−トリアゾール類およびピラゾール誘導体の製造方法 |
IT1229203B (it) | 1989-03-22 | 1991-07-25 | Bioresearch Spa | Impiego di acido 5 metiltetraidrofolico, di acido 5 formiltetraidrofolico e dei loro sali farmaceuticamente accettabili per la preparazione di composizioni farmaceutiche in forma a rilascio controllato attive nella terapia dei disturbi mentali organici e composizioni farmaceutiche relative. |
PH30995A (en) | 1989-07-07 | 1997-12-23 | Novartis Inc | Sustained release formulations of water soluble peptides. |
US5120548A (en) | 1989-11-07 | 1992-06-09 | Merck & Co., Inc. | Swelling modulated polymeric drug delivery device |
US5585112A (en) | 1989-12-22 | 1996-12-17 | Imarx Pharmaceutical Corp. | Method of preparing gas and gaseous precursor-filled microspheres |
IT1246382B (it) | 1990-04-17 | 1994-11-18 | Eurand Int | Metodo per la cessione mirata e controllata di farmaci nell'intestino e particolarmente nel colon |
US5733566A (en) | 1990-05-15 | 1998-03-31 | Alkermes Controlled Therapeutics Inc. Ii | Controlled release of antiparasitic agents in animals |
US5543390A (en) | 1990-11-01 | 1996-08-06 | State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education, Acting For And On Behalf Of The Oregon Health Sciences University | Covalent microparticle-drug conjugates for biological targeting |
HU219131B (hu) | 1991-10-18 | 2001-02-28 | Monsanto Co. | Módszer és fungicid készítmény növények torsgombabetegségének gátlására és a hatóanyagok |
US5580578A (en) | 1992-01-27 | 1996-12-03 | Euro-Celtique, S.A. | Controlled release formulations coated with aqueous dispersions of acrylic polymers |
US5294612A (en) | 1992-03-30 | 1994-03-15 | Sterling Winthrop Inc. | 6-heterocyclyl pyrazolo [3,4-d]pyrimidin-4-ones and compositions and method of use thereof |
US5323907A (en) | 1992-06-23 | 1994-06-28 | Multi-Comp, Inc. | Child resistant package assembly for dispensing pharmaceutical medications |
HRP921338B1 (en) | 1992-10-02 | 2002-04-30 | Monsanto Co | Fungicides for the control of take-all disease of plants |
TW333456B (en) | 1992-12-07 | 1998-06-11 | Takeda Pharm Ind Co Ltd | A pharmaceutical composition of sustained-release preparation the invention relates to a pharmaceutical composition of sustained-release preparation which comprises a physiologically active peptide. |
US5591767A (en) | 1993-01-25 | 1997-01-07 | Pharmetrix Corporation | Liquid reservoir transdermal patch for the administration of ketorolac |
US6274552B1 (en) | 1993-03-18 | 2001-08-14 | Cytimmune Sciences, Inc. | Composition and method for delivery of biologically-active factors |
US5523092A (en) | 1993-04-14 | 1996-06-04 | Emory University | Device for local drug delivery and methods for using the same |
US5985307A (en) | 1993-04-14 | 1999-11-16 | Emory University | Device and method for non-occlusive localized drug delivery |
US6087324A (en) | 1993-06-24 | 2000-07-11 | Takeda Chemical Industries, Ltd. | Sustained-release preparation |
US6004534A (en) | 1993-07-23 | 1999-12-21 | Massachusetts Institute Of Technology | Targeted polymerized liposomes for improved drug delivery |
DE4405207A1 (de) | 1994-02-18 | 1995-08-24 | Bayer Ag | N-Pyrazolylaniline und N-Pyrazolylaminopyridine |
US5958458A (en) | 1994-06-15 | 1999-09-28 | Dumex-Alpharma A/S | Pharmaceutical multiple unit particulate formulation in the form of coated cores |
US5922751A (en) | 1994-06-24 | 1999-07-13 | Euro-Celtique, S.A. | Aryl pyrazole compound for inhibiting phosphodiesterase IV and methods of using same |
CA2193725A1 (en) | 1994-06-24 | 1996-01-04 | David Cavalla | Aryl derivative compounds and uses to inhibit phosphodiesterase iv acti vity |
IT1270594B (it) | 1994-07-07 | 1997-05-07 | Recordati Chem Pharm | Composizione farmaceutica a rilascio controllato di moguisteina in sospensione liquida |
US5759542A (en) | 1994-08-05 | 1998-06-02 | New England Deaconess Hospital Corporation | Compositions and methods for the delivery of drugs by platelets for the treatment of cardiovascular and other diseases |
US5597826A (en) | 1994-09-14 | 1997-01-28 | Pfizer Inc. | Compositions containing sertraline and a 5-HT1D receptor agonist or antagonist |
US5660854A (en) | 1994-11-28 | 1997-08-26 | Haynes; Duncan H | Drug releasing surgical implant or dressing material |
US6316652B1 (en) | 1995-06-06 | 2001-11-13 | Kosta Steliou | Drug mitochondrial targeting agents |
US5798119A (en) | 1995-06-13 | 1998-08-25 | S. C. Johnson & Son, Inc. | Osmotic-delivery devices having vapor-permeable coatings |
AU6242096A (en) | 1995-06-27 | 1997-01-30 | Takeda Chemical Industries Ltd. | Method of producing sustained-release preparation |
TW448055B (en) | 1995-09-04 | 2001-08-01 | Takeda Chemical Industries Ltd | Method of production of sustained-release preparation |
JP2909418B2 (ja) | 1995-09-18 | 1999-06-23 | 株式会社資生堂 | 薬物の遅延放出型マイクロスフイア |
US6039975A (en) | 1995-10-17 | 2000-03-21 | Hoffman-La Roche Inc. | Colon targeted delivery system |
US5980945A (en) | 1996-01-16 | 1999-11-09 | Societe De Conseils De Recherches Et D'applications Scientifique S.A. | Sustained release drug formulations |
EP0885890A1 (en) | 1996-02-26 | 1998-12-23 | Sumitomo Pharmaceuticals Company, Limited | Sulfonylureidopyrazole derivatives |
US5959109A (en) | 1996-05-15 | 1999-09-28 | Neurocrine Biosciences, Inc. | Compounds and methods for increasing endogenous levels of corticotropin-releasing factor |
TW345603B (en) | 1996-05-29 | 1998-11-21 | Gmundner Fertigteile Gmbh | A noise control device for tracks |
US6264970B1 (en) | 1996-06-26 | 2001-07-24 | Takeda Chemical Industries, Ltd. | Sustained-release preparation |
US6419961B1 (en) | 1996-08-29 | 2002-07-16 | Takeda Chemical Industries, Ltd. | Sustained release microcapsules of a bioactive substance and a biodegradable polymer |
US6375987B1 (en) | 1996-10-01 | 2002-04-23 | Gattefossé, S.A. | Process for the manufacture of pharmaceutical composition with modified release of active principle comprising the matrix |
CA2266629C (en) | 1996-10-01 | 2002-04-16 | Cima Labs Inc. | Taste-masked microcapsule compositions and methods of manufacture |
CA2217134A1 (en) | 1996-10-09 | 1998-04-09 | Sumitomo Pharmaceuticals Co., Ltd. | Sustained release formulation |
ES2221019T3 (es) | 1996-10-31 | 2004-12-16 | Takeda Chemical Industries, Ltd. | Preparacion de liberacion mantenida. |
US6131570A (en) | 1998-06-30 | 2000-10-17 | Aradigm Corporation | Temperature controlling device for aerosol drug delivery |
DE19648576C2 (de) | 1996-11-23 | 1999-08-12 | Lohmann Therapie Syst Lts | Lutschtablette zur modifizierten Freisetzung von Wirkstoffen im Gastrointestinaltrakt |
US6197350B1 (en) | 1996-12-20 | 2001-03-06 | Takeda Chemical Industries, Ltd. | Method of producing a sustained-release preparation |
US5891474A (en) | 1997-01-29 | 1999-04-06 | Poli Industria Chimica, S.P.A. | Time-specific controlled release dosage formulations and method of preparing same |
US6120751A (en) | 1997-03-21 | 2000-09-19 | Imarx Pharmaceutical Corp. | Charged lipids and uses for the same |
US6060082A (en) | 1997-04-18 | 2000-05-09 | Massachusetts Institute Of Technology | Polymerized liposomes targeted to M cells and useful for oral or mucosal drug delivery |
US6350458B1 (en) | 1998-02-10 | 2002-02-26 | Generex Pharmaceuticals Incorporated | Mixed micellar drug deliver system and method of preparation |
US6613358B2 (en) | 1998-03-18 | 2003-09-02 | Theodore W. Randolph | Sustained-release composition including amorphous polymer |
US6048736A (en) | 1998-04-29 | 2000-04-11 | Kosak; Kenneth M. | Cyclodextrin polymers for carrying and releasing drugs |
KR19990085365A (ko) | 1998-05-16 | 1999-12-06 | 허영섭 | 지속적으로 약물 조절방출이 가능한 생분해성 고분자 미립구 및그 제조방법 |
US7169410B1 (en) | 1998-05-19 | 2007-01-30 | Sdg, Inc. | Targeted liposomal drug delivery system |
CA2348871C (en) | 1998-11-02 | 2009-04-14 | John G. Devane | Multiparticulate modified release composition |
US6248363B1 (en) | 1999-11-23 | 2001-06-19 | Lipocine, Inc. | Solid carriers for improved delivery of active ingredients in pharmaceutical compositions |
US6271359B1 (en) | 1999-04-14 | 2001-08-07 | Musc Foundation For Research Development | Tissue-specific and pathogen-specific toxic agents and ribozymes |
HN2000000051A (es) | 1999-05-19 | 2001-02-02 | Pfizer Prod Inc | Derivados heterociclicos utiles como agentes anticancerosos |
US6472416B1 (en) | 1999-08-27 | 2002-10-29 | Abbott Laboratories | Sulfonylphenylpyrazole compounds useful as COX-2 inhibitors |
WO2001016138A1 (en) | 1999-08-27 | 2001-03-08 | Abbott Laboratories | Sulfonylphenylpyrazole compounds useful as cox-2 inhibitors |
US7393842B2 (en) | 2001-08-31 | 2008-07-01 | University Of Connecticut | Pyrazole analogs acting on cannabinoid receptors |
US7119108B1 (en) | 1999-10-18 | 2006-10-10 | University Of Connecticut | Pyrazole derivatives as cannabinoid receptor antagonists |
EP1224173B1 (en) | 1999-10-18 | 2005-10-12 | The University Of Connecticut | Pyrazole derivatives as cannabinoid receptor antagonists |
US8084467B2 (en) | 1999-10-18 | 2011-12-27 | University Of Connecticut | Pyrazole derivatives as cannabinoid receptor antagonists |
AU3217501A (en) | 2000-03-03 | 2001-09-12 | Pfizer Prod Inc | Pyrazole ether derivatives as anti-inflammatory/analgesic agents |
US6623756B1 (en) | 2000-04-27 | 2003-09-23 | Noveon Ip Holdings Corp. | Directly compressed solid dosage articles |
CA2420535A1 (en) | 2000-08-30 | 2002-03-07 | Mary Tanya Am Ende | Sustained release formulations for growth hormone secretagogues |
US6468338B1 (en) | 2000-10-12 | 2002-10-22 | Eastman Kodak Company | Dye for ink jet ink |
US6464767B1 (en) | 2000-10-12 | 2002-10-15 | Eastman Kodak Company | Ink jet printing method |
US6989385B2 (en) | 2000-12-21 | 2006-01-24 | Vertex Pharmaceuticals Incorporated | Pyrazole compounds useful as protein kinase inhibitors |
WO2002053160A1 (en) | 2000-12-29 | 2002-07-11 | Alteon, Inc. | Method for treating glaucoma ivb |
DE10108480A1 (de) | 2001-02-22 | 2002-09-05 | Bayer Ag | Pyrazolylpyrimidine |
GB0106661D0 (en) | 2001-03-16 | 2001-05-09 | Pfizer Ltd | Pharmaceutically active compounds |
US6770645B2 (en) | 2001-03-16 | 2004-08-03 | Pfizer Inc. | Pharmaceutically active compounds |
US6593349B2 (en) | 2001-03-19 | 2003-07-15 | Icagen, Inc. | Bisarylamines as potassium channel openers |
JP2002309137A (ja) | 2001-04-12 | 2002-10-23 | Fuji Photo Film Co Ltd | インクジェット記録用インク組成物 |
DK1381590T3 (da) | 2001-04-16 | 2007-10-22 | Schering Corp | 3,4-disubstituerede cyclobuten-1,2-dioner som CXC-kemokinreceptorligander |
US20040106794A1 (en) | 2001-04-16 | 2004-06-03 | Schering Corporation | 3,4-Di-substituted cyclobutene-1,2-diones as CXC-chemokine receptor ligands |
US20040097547A1 (en) | 2001-04-16 | 2004-05-20 | Taveras Arthur G. | 3,4-Di-substituted cyclobutene-1,2-diones as CXC-chemokine receptor ligands |
US7132445B2 (en) | 2001-04-16 | 2006-11-07 | Schering Corporation | 3,4-Di-substituted cyclobutene-1,2-diones as CXC-chemokine receptor ligands |
ATE339418T1 (de) | 2001-06-01 | 2006-10-15 | Vertex Pharma | Thiazolverbindungen, die sich als inhibitoren von proteinkinasen eignen |
ATE482692T1 (de) | 2001-07-27 | 2010-10-15 | Astellas Pharma Inc | Zusammensetzung enthaltend feine körner mit verzögerter freisetzung für in der mundhöhle schnell zerfallende tabletten |
AU2002331766A1 (en) | 2001-08-31 | 2003-03-18 | University Of Connecticut | Novel pyrazole analogs acting on cannabinoid receptors |
ES2311073T3 (es) | 2001-09-28 | 2009-02-01 | Mcneil-Ppc, Inc. | Forma de dosificacion que tiene un nucleo interno y un revestimiento externo. |
CA2462862A1 (en) | 2001-10-12 | 2003-04-17 | Schering Corporation | 3,4-di-substituted maleimide compounds as cxc-chemokine receptor antagonists |
CA2465207C (en) | 2001-11-01 | 2011-01-04 | Icagen, Inc. | Pyrazole-amides and -sulfonamides |
WO2003037335A1 (en) | 2001-11-02 | 2003-05-08 | Pfizer Products Inc. | 5-heteroatom-substituted pyrazoles |
WO2003037336A1 (en) | 2001-11-02 | 2003-05-08 | Pfizer Products Inc. | 1-(5-sulfonyl-pyridin-2-yl)-5-(methylidene-cycloalkylmethoxy)-1h-pyrazole-4-carbonitrile derivatives and other compounds as cyclooxygenase inhibitors for the treatment of arthritis, neurodegeneration and colon cancer |
KR20040065989A (ko) | 2001-12-19 | 2004-07-23 | 아스트라제네카 아베 | 신규의 필름 코팅 |
CA2471577C (en) | 2001-12-24 | 2011-08-02 | Astrazeneca Ab | Chemical compounds |
US20050113283A1 (en) | 2002-01-18 | 2005-05-26 | David Solow-Cordero | Methods of treating conditions associated with an EDG-4 receptor |
US20040024085A1 (en) | 2002-01-30 | 2004-02-05 | Takahiro Ishizuka | Ink composition and inkjet recording method |
CA2477795A1 (en) | 2002-02-28 | 2003-09-12 | Kandasamy Sakthivel | Nucleoside 5'-monophosphate mimics and their prodrugs |
US6958161B2 (en) | 2002-04-12 | 2005-10-25 | F H Faulding & Co Limited | Modified release coated drug preparation |
US20030232836A1 (en) | 2002-05-23 | 2003-12-18 | Stewart Andrew O. | Acetamides and benzamides that are useful in treating sexual dysfunction |
WO2003099266A2 (en) | 2002-05-23 | 2003-12-04 | Abbott Laboratories | Acetamides and benzamides that are useful in treating sexual dysfunction |
US20040029887A1 (en) | 2002-05-23 | 2004-02-12 | Bhatia Pramila A. | Acetamides and benzamides that are useful in treating sexual dysfunction |
US20060009461A1 (en) | 2002-05-23 | 2006-01-12 | Bhatia Pramila A | Acetamides and benzamides that are useful in treating sexual dysfunction |
US6989451B2 (en) | 2002-06-04 | 2006-01-24 | Valeant Research & Development | Heterocyclic compounds and uses thereof |
WO2004047776A1 (fr) | 2002-11-20 | 2004-06-10 | L'oreal | Utilisation d’un compose pyrazolcarboxamide pour stimuler la pousse des fibres keratiniques et/ou freiner leur chute |
FR2847160A1 (fr) | 2002-11-20 | 2004-05-21 | Oreal | Composition capillaire contenant un compose pyrasol-carboxamide, son utilisation pour stimuler la pousse des cheveux et/ou freiner leur chute |
US7485322B2 (en) | 2002-12-24 | 2009-02-03 | Lek Pharmaceuticals D.D. | Modified release pharmaceutical composition |
US20060270628A1 (en) | 2003-04-29 | 2006-11-30 | Jagattaran Das | Antiinfective 1,2,3-triazole derivatives, process for their preparation and pharmaceutical compositions containing them |
WO2004101531A1 (en) | 2003-04-29 | 2004-11-25 | Dr. Reddy's Laboratories Ltd. | Antiinfective 1,2,3-triazole derivatives, process for their preparation and pharmaceutical compositions containing them |
KR101205257B1 (ko) | 2003-06-06 | 2012-11-27 | 아렉시스 악티에볼라그 | 피부 상태 또는 암 치료를 위한 scce 저해제로서의 융합된 헤테로사이클 화합물의 용도 |
WO2005000309A2 (en) | 2003-06-27 | 2005-01-06 | Ionix Pharmaceuticals Limited | Chemical compounds |
AU2004251181B2 (en) | 2003-06-27 | 2009-10-01 | Axikin Pharmaceuticals, Inc. | Regulation of kinase, 'regulated in COPD kinase' (RC kinase) |
BRPI0412382A (pt) | 2003-07-08 | 2006-09-19 | Astrazeneca Ab | composto , método para a verificação de novos compostos medicinais que se ligam a e modulam a atividade, por agonismo , agonismo parcial, ou antagonismo, do receptor de acetilcolina nicotìnico alfa7, método de tratamento ou profilaxia de uma doença ou condição humana, método para tratamento de jetlag, induzindo interrupção de fumar, vìcio em nicotina, abstinência, dor, e para colite ulcerativa, composição farmacêutica, e, método de tratamento ou prevenção de uma condição ou distúrbio que surge da disfunção de neurotransmissão do receptor de acetilcolina nicotìnico em um mamìfero, e, uso de um composto |
MY141220A (en) | 2003-11-17 | 2010-03-31 | Astrazeneca Ab | Pyrazole derivatives as inhibitors of receptor tyrosine kinases |
AU2005219517A1 (en) | 2004-02-27 | 2005-09-15 | F.Hoffmann-La Roche Ag | Heteroaryl-fused pyrazolo derivatives |
CA2557575A1 (en) | 2004-02-27 | 2005-09-15 | F. Hoffmann-La Roche Ag | Fused derivatives of pyrazole |
KR20050091462A (ko) | 2004-03-12 | 2005-09-15 | 한국과학기술연구원 | 푸로피리미딘 화합물 및 이를 포함하는 ddr2 티로신키나아제 활성 저해제 |
WO2005092899A1 (en) | 2004-03-26 | 2005-10-06 | Methylgene Inc. | Inhibitors of histone deacetylase |
US7253204B2 (en) | 2004-03-26 | 2007-08-07 | Methylgene Inc. | Inhibitors of histone deacetylase |
CA2562244A1 (en) | 2004-04-07 | 2005-10-27 | Takeda Pharmaceutical Company Limited | Cyclic compounds |
US7033425B2 (en) | 2004-04-15 | 2006-04-25 | Eastman Kodak Company | Ink jet ink set |
US20090227648A1 (en) | 2004-04-21 | 2009-09-10 | Astrazeneca Ab | Pyrazole derivatives useful for the treatment of cancer |
SI1784396T1 (sl) | 2004-08-26 | 2011-03-31 | Pfizer | S pirazolom substituirane aminoheteroarilne spojine kot zaviralci protein-kinaze |
US7399317B2 (en) | 2004-08-26 | 2008-07-15 | The Procter & Gamble Company | Keratin dyeing compounds, keratin dyeing compositions containing them, and use thereof |
US7662482B2 (en) | 2004-09-01 | 2010-02-16 | Dow Global Technologies, Inc. | Adhesion promoter |
US7531560B2 (en) | 2004-11-10 | 2009-05-12 | Boehringer Ingelheim Pharmaceuticals, Inc. | Anti-cytokine heterocyclic compounds |
WO2006055831A2 (en) | 2004-11-17 | 2006-05-26 | Miikana Therapeutics, Inc. | Kinase inhibitors |
CN101155800B (zh) | 2005-02-04 | 2012-05-23 | 阿斯利康(瑞典)有限公司 | 可用作激酶抑制剂的吡唑基氨基吡啶衍生物 |
PL1853588T3 (pl) | 2005-02-16 | 2008-11-28 | Astrazeneca Ab | Związki chemiczne |
DE602006015431D1 (de) | 2005-02-16 | 2010-08-26 | Astrazeneca Ab | Chemische verbindungen |
EP1864822A4 (en) | 2005-03-29 | 2012-10-17 | Mitsubishi Kagaku Media Corp Ltd | Optical recording medium, metal complex compound and organic dye compound |
US20090005396A1 (en) | 2005-04-27 | 2009-01-01 | Astrazeneca Ab | Use of Pyrazolyl-Pyrimidine Derivatives in the Treatment of Pain |
EP1888561A1 (en) | 2005-05-05 | 2008-02-20 | AstraZeneca AB | Pyrazolyl-amino- substituted pyrimidines and their use in the treatment of cancer |
CA2613607A1 (en) | 2005-06-29 | 2007-01-04 | Schering Corporation | Di-substituted oxadiazoles as cxc-chemokine receptor ligands |
WO2007022384A2 (en) | 2005-08-18 | 2007-02-22 | Vertex Pharmaceuticals Incorporated | Pyrazine kinase inhibitors |
WO2007023382A2 (en) | 2005-08-25 | 2007-03-01 | Pfizer Inc. | Pyrimidine amino pyrazole compounds, potent kinase inhibitors |
JP2007056213A (ja) | 2005-08-26 | 2007-03-08 | Fujifilm Corp | 焼結含油軸受油用組成物、並びにそれを用いた軸受け装置及び摺動部材 |
NZ594383A (en) | 2005-11-03 | 2013-05-31 | Vertex Pharma | Aminopyrimidines useful as kinase inhibitors |
AU2006315334B2 (en) | 2005-11-16 | 2011-05-19 | Vertex Pharmaceuticals Incorporated | Aminopyrimidines useful as kinase inhibitors |
AU2006320580B2 (en) | 2005-11-30 | 2011-06-23 | Vertex Pharmaceuticals Incorporated | Inhibitors of c-Met and uses thereof |
WO2007084868A2 (en) | 2006-01-17 | 2007-07-26 | Kalypsys, Inc. | Treatment of disorders by activation of the unfolded protein response |
US7427414B2 (en) | 2006-01-18 | 2008-09-23 | Astron Research Limited | Modified release oral dosage form using co-polymer of polyvinyl acetate |
US7868177B2 (en) | 2006-02-24 | 2011-01-11 | Amgen Inc. | Multi-cyclic compounds and method of use |
GB0605691D0 (en) | 2006-03-21 | 2006-05-03 | Novartis Ag | Organic Compounds |
BRPI0716174A2 (pt) | 2006-09-01 | 2013-09-24 | Cv Therapeutics Inc | mÉtodos e composiÇÕes para aumentar a tolerabilidade de paciente durante mÉtodos de imagem do miocÁrdio. |
US20090081120A1 (en) | 2006-09-01 | 2009-03-26 | Cv Therapeutics, Inc. | Methods and Compositions for Increasing Patient Tolerability During Myocardial Imaging Methods |
WO2008030448A1 (en) | 2006-09-07 | 2008-03-13 | Millennium Pharmaceuticals, Inc. | Phenethylamide derivatives with kinase inhibitory activity |
UY30796A1 (es) | 2006-12-15 | 2008-07-31 | Bayer Schering Pharma Ag | 3-h-pirazolopiridinas y sales de éstas, composiciones farmacéuticas que las comprenden, métodos para prepararlas, y sus usos |
WO2008104077A1 (en) | 2007-02-28 | 2008-09-04 | Methylgene Inc. | Small molecule inhibitors of protein arginine methyltransferases (prmts) |
WO2008118822A1 (en) | 2007-03-23 | 2008-10-02 | Rigel Pharmaceuticals, Inc. | Compositions and methods for inhibition of the jak pathway |
MX2009011208A (es) | 2007-04-19 | 2009-10-30 | Novartis Ag | Derivados de acido nicotinico como moduladores del receptor de glutamato metabotropico-5. |
US20090029992A1 (en) | 2007-06-11 | 2009-01-29 | Agoston Gregory E | Substituted pyrazole compounds |
WO2009032703A1 (en) | 2007-08-28 | 2009-03-12 | Irm Llc | 2- (het) arylamino-6-aminopyridine derivatives and fused forms thereof as anaplastic lymphoma kinase inhibitors |
NZ585236A (en) | 2007-10-09 | 2012-03-30 | Merck Patent Gmbh | Pyridine derivatives useful as glucokinase activators |
EP2195330B1 (en) | 2007-10-12 | 2013-03-13 | Merck Patent GmbH | Method and agent for refolding proteins |
AU2008321099A1 (en) | 2007-11-13 | 2009-05-22 | Icos Corporation | Inhibitors of human phosphatidyl-inositol 3-kinase delta |
US20090143451A1 (en) | 2007-11-14 | 2009-06-04 | Andrews William H | Compounds that increase telomerase reverse transcriptase (tert) expression and methods for using the same |
JP5583592B2 (ja) | 2007-11-30 | 2014-09-03 | ニューリンク ジェネティクス コーポレイション | Ido阻害剤 |
CA2716599A1 (en) | 2008-02-25 | 2009-09-03 | Lars Thore Burgdorf | Glucokinase activators |
JP5117885B2 (ja) | 2008-02-29 | 2013-01-16 | 富士フイルム株式会社 | 色素化合物、着色組成物、感熱転写記録用インクシート、感熱転写記録方法、カラートナー、インクジェット用インクおよびカラーフィルター |
CN101970417A (zh) | 2008-03-14 | 2011-02-09 | 巴斯夫欧洲公司 | 作为杀真菌剂使用的取代的吡嗪基甲基磺酰胺 |
JP2009235122A (ja) | 2008-03-25 | 2009-10-15 | Fujifilm Corp | インク組成物、インクセット、及び画像記録方法 |
EP2276746A1 (en) | 2008-04-10 | 2011-01-26 | Basf Se | Substituted pyridazinylmethyl sulfonamides |
TW201012803A (en) | 2008-06-06 | 2010-04-01 | Organon Nv | Heterocyclic derivatives |
PT3289876T (pt) | 2008-06-16 | 2022-10-28 | Univ Tennessee Res Found | Compostos para o tratamento do câncer |
CA2726508C (en) | 2008-06-17 | 2016-06-07 | Astrazeneca Ab | Pyridine compounds |
LT2318006T (lt) | 2008-08-15 | 2017-01-10 | Nivalis Therapeutics, Inc. | Nauji s-nitrozoglutationo reduktazės pirolo inhibitoriai, kaip terapiniai agentai |
WO2010048207A2 (en) | 2008-10-21 | 2010-04-29 | Metabolex, Inc. | Aryl gpr120 receptor agonists and uses thereof |
WO2010048559A2 (en) | 2008-10-24 | 2010-04-29 | Calcimedica Inc. | Phenylpyrazole inhibitors of store operated calcium release |
EP2379684A2 (de) | 2008-12-22 | 2011-10-26 | Basf Se | Mischungen hydrophober und hydrophiler ionischer flüssigkeiten und ihre verwendung in flüssigkeitsringverdichtern |
WO2010096314A1 (en) | 2009-02-18 | 2010-08-26 | Amgen Inc. | INDOLE/BENZIMIDAZOLE COMPOUNDS AS mTOR KINASE INHIBITORS |
HUE047643T2 (hu) | 2009-03-02 | 2020-05-28 | Stemsynergy Therapeutics Inc | Módszerek és készítmények rák kezelésére és a WNT által közvetített hatások csökkentésére egy sejtben |
FR2943057B1 (fr) | 2009-03-12 | 2011-06-03 | Centre Nat Rech Scient | DERIVES DE 10-AMINO-1,2,3,4-TETRAHYDROPYRIDO°2,1-a!ISOINDOL-6(10bH)- ONES, LEUR PROCEDE DE PREPARATION ET LEURS UTILISATIONS THERAPEUTIQUES |
CA2755253A1 (en) | 2009-03-18 | 2010-09-23 | Schering Corporation | Bicyclic compounds as inhibitors of diacylglycerol acyltransferase |
US20100240720A1 (en) | 2009-03-20 | 2010-09-23 | Burnham Institute For Medical Research | Allosteric jnk inhibitors |
GB0910003D0 (en) | 2009-06-11 | 2009-07-22 | Univ Leuven Kath | Novel compounds for the treatment of neurodegenerative diseases |
WO2011050245A1 (en) | 2009-10-23 | 2011-04-28 | Yangbo Feng | Bicyclic heteroaryls as kinase inhibitors |
US9951008B2 (en) | 2009-11-03 | 2018-04-24 | University Of Notre Dame Du Lac | Ionic liquids comprising heteraromatic anions |
RU2581367C2 (ru) | 2010-03-01 | 2016-04-20 | Джи Ти Икс, ИНК. | Соединения для лечения рака |
GB201010196D0 (en) | 2010-06-17 | 2010-07-21 | Respivert Ltd | Methods |
WO2012154880A1 (en) | 2011-05-09 | 2012-11-15 | Proteostasis Therapeutics, Inc. | Proteostasis regulators for treating cystic fibrosis and other protein misfolding diseases |
NZ631142A (en) | 2013-09-18 | 2016-03-31 | Axikin Pharmaceuticals Inc | Pharmaceutically acceptable salts of 3,5-diaminopyrazole kinase inhibitors |
-
2015
- 2015-12-22 ES ES15825997T patent/ES2805528T3/es active Active
- 2015-12-22 HU HUE15825997A patent/HUE049801T2/hu unknown
- 2015-12-22 CN CN201580076521.8A patent/CN107250116B/zh active Active
- 2015-12-22 MX MX2017008526A patent/MX2017008526A/es active IP Right Grant
- 2015-12-22 AU AU2015369690A patent/AU2015369690B2/en active Active
- 2015-12-22 US US14/979,294 patent/US9546163B2/en active Active
- 2015-12-22 TW TW104143239A patent/TWI703133B/zh active
- 2015-12-22 NZ NZ733950A patent/NZ733950A/en unknown
- 2015-12-22 DK DK15825997.8T patent/DK3237407T3/da active
- 2015-12-22 WO PCT/US2015/067359 patent/WO2016106309A1/en active Application Filing
- 2015-12-22 EP EP15825997.8A patent/EP3237407B1/en active Active
- 2015-12-22 SG SG11201705088VA patent/SG11201705088VA/en unknown
- 2015-12-22 JP JP2017533525A patent/JP6450010B2/ja active Active
- 2015-12-22 AR ARP150104275A patent/AR103264A1/es unknown
- 2015-12-22 UA UAA201707114A patent/UA118312C2/uk unknown
- 2015-12-22 MY MYPI2017000936A patent/MY191736A/en unknown
- 2015-12-22 EA EA201791450A patent/EA032473B1/ru not_active IP Right Cessation
- 2015-12-22 KR KR1020177020665A patent/KR102034202B1/ko active IP Right Grant
-
2016
- 2016-11-29 US US15/364,099 patent/US9730914B2/en active Active
-
2017
- 2017-06-18 IL IL25298617A patent/IL252986B/en active IP Right Grant
- 2017-07-24 PH PH12017501334A patent/PH12017501334B1/en unknown
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20130303492A1 (en) * | 2012-03-16 | 2013-11-14 | Axikin Pharmaceuticals, Inc. | 3,5-diaminopyrazole kinase inhibitors |
Also Published As
Publication number | Publication date |
---|---|
EP3237407A1 (en) | 2017-11-01 |
PH12017501334A1 (en) | 2017-12-18 |
CN107250116B (zh) | 2020-10-27 |
AR103264A1 (es) | 2017-04-26 |
PH12017501334B1 (en) | 2017-12-18 |
IL252986B (en) | 2019-11-28 |
AU2015369690B2 (en) | 2019-01-17 |
EA201791450A1 (ru) | 2017-12-29 |
TW201629019A (zh) | 2016-08-16 |
KR20180004702A (ko) | 2018-01-12 |
JP2018500339A (ja) | 2018-01-11 |
US9546163B2 (en) | 2017-01-17 |
DK3237407T3 (da) | 2020-07-20 |
WO2016106309A1 (en) | 2016-06-30 |
KR102034202B1 (ko) | 2019-10-18 |
TWI703133B (zh) | 2020-09-01 |
NZ733950A (en) | 2018-08-31 |
IL252986A0 (en) | 2017-08-31 |
US20160176857A1 (en) | 2016-06-23 |
SG11201705088VA (en) | 2017-07-28 |
UA118312C2 (uk) | 2018-12-26 |
JP6450010B2 (ja) | 2019-01-09 |
ES2805528T3 (es) | 2021-02-12 |
EA032473B1 (ru) | 2019-05-31 |
MY191736A (en) | 2022-07-13 |
AU2015369690A1 (en) | 2017-08-10 |
US20170087131A1 (en) | 2017-03-30 |
EP3237407B1 (en) | 2020-04-15 |
MX2017008526A (es) | 2017-10-25 |
HUE049801T2 (hu) | 2020-10-28 |
US9730914B2 (en) | 2017-08-15 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN103582636B (zh) | (α‑取代的芳烷基氨基和杂芳基烷基氨基)嘧啶基和1,3,5‑三嗪基苯并咪唑、含有其的药物组合物以及这些化合物在治疗增生性疾病中的用途 | |
CN106536506A (zh) | 苯并咪唑衍生物作为erbb酪氨酸激酶抑制剂用于治疗癌症 | |
CN102448958B (zh) | 嘧啶基和1,3,5-三嗪基苯并咪唑磺酰胺和其在癌症治疗中的用途 | |
JP6120941B2 (ja) | 3,5−ジアミノピラゾールキナーゼ阻害剤 | |
JP2011515462A (ja) | 置換されたピリミジン、及びトリアジン、並びに癌療法におけるこれらの使用 | |
TWI705967B (zh) | 苯并咪唑衍生物及其醫藥組合物及使用方法 | |
US10772881B2 (en) | Quinolines that modulate SERCA and their use for treating disease | |
TWI510469B (zh) | 2,5-雙取代芳基磺醯胺ccr3拮抗劑 | |
CN103298786B (zh) | 芳基磺酰胺盐ccr3拮抗剂 | |
CN102892754A (zh) | 芳基磺酰胺ccr3拮抗剂 | |
CN107250116A (zh) | 3,5‑二氨基吡唑激酶抑制剂 | |
CN104177313A (zh) | 2,5-二取代的芳基磺酰胺ccr3拮抗剂 | |
TWI473793B (zh) | 芳基磺醯胺ccr3拮抗劑 | |
US11827626B2 (en) | Quinolines that modulate SERCA and their use for treating disease | |
WO2006115285A1 (ja) | 医薬組成物 | |
CN104781240A (zh) | 同位素富集的芳基磺酰胺ccr3拮抗剂 | |
CN105722836A (zh) | 3,5-二氨基吡唑激酶抑制剂的药学上可接受的盐 | |
EA040851B1 (ru) | Комбинированная терапия |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
CB02 | Change of applicant information | ||
CB02 | Change of applicant information |
Address after: California, USA Applicant after: Esment medical company Address before: California, USA Applicant before: AXIKIN PHARMACEUTICALS, Inc. |
|
GR01 | Patent grant | ||
GR01 | Patent grant |