WO1997016068A1

WO1997016068A1 - Triterpene derivatives with immunosuppressant activity

Triterpene derivatives with immunosuppressant activity Download PDF

Info

Publication number: WO1997016068A1
Authority: WO; WIPO (PCT)
Prior art keywords: alkyl; defined above; aryl; heteroaryl; hydroxy
Prior art date: 1995-10-31

Application number

PCT/US1996/017211

Other languages

English (en)

French (fr)

Inventor

Robert K. Baker

Jianming Bao

Frank Kayser

William H. Parsons

Kathleen M. Rupprecht

Original Assignee

Merck & Co., Inc.

Priority date

1995-10-31

Filing date

1996-10-28

Publication date

1997-05-09

1996-02-23 Priority claimed from GBGB9603833.6A external-priority patent/GB9603833D0/en

1996-03-12 Priority claimed from GBGB9605156.0A external-priority patent/GB9605156D0/en

1996-10-28 Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.

1996-10-28 Priority to JP9517439A priority Critical patent/JPH11514648A/ja

1996-10-28 Priority to EP96937010A priority patent/EP0877554A1/en

1996-10-28 Priority to AU74781/96A priority patent/AU712015B2/en

1996-10-28 Priority to CA 2235886 priority patent/CA2235886A1/en

1997-05-09 Publication of WO1997016068A1 publication Critical patent/WO1997016068A1/en

Links

230000001861 immunosuppressant effect Effects 0.000 title description 4
150000003648 triterpenes Chemical class 0.000 title description 3
150000001875 compounds Chemical class 0.000 claims abstract description 120
239000003018 immunosuppressive agent Substances 0.000 claims abstract description 13
229940125721 immunosuppressive agent Drugs 0.000 claims abstract description 8
125000001072 heteroaryl group Chemical group 0.000 claims description 92
125000001424 substituent group Chemical group 0.000 claims description 91
125000003118 aryl group Chemical group 0.000 claims description 90
-1 nitro, hydroxy Chemical group 0.000 claims description 75
125000000217 alkyl group Chemical group 0.000 claims description 65
229910052740 iodine Inorganic materials 0.000 claims description 59
229910052801 chlorine Inorganic materials 0.000 claims description 52
125000004093 cyano group Chemical group *C#N 0.000 claims description 52
229910052731 fluorine Inorganic materials 0.000 claims description 52
125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 52
229910052794 bromium Inorganic materials 0.000 claims description 50
238000000034 method Methods 0.000 claims description 44
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 43
208000006673 asthma Diseases 0.000 claims description 38
201000004624 Dermatitis Diseases 0.000 claims description 37
201000010099 disease Diseases 0.000 claims description 35
229910052757 nitrogen Inorganic materials 0.000 claims description 33
125000003342 alkenyl group Chemical group 0.000 claims description 29
125000004432 carbon atom Chemical group C* 0.000 claims description 29
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 29
229910052739 hydrogen Inorganic materials 0.000 claims description 29
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 28
125000004043 oxo group Chemical group O=* 0.000 claims description 27
238000011282 treatment Methods 0.000 claims description 27
125000004430 oxygen atom Chemical group O* 0.000 claims description 25
125000000304 alkynyl group Chemical group 0.000 claims description 23
239000003814 drug Substances 0.000 claims description 22
210000000056 organ Anatomy 0.000 claims description 22
150000003839 salts Chemical group 0.000 claims description 22
229910052760 oxygen Inorganic materials 0.000 claims description 21
238000002054 transplantation Methods 0.000 claims description 21
230000001684 chronic effect Effects 0.000 claims description 19
229940079593 drug Drugs 0.000 claims description 18
230000000694 effects Effects 0.000 claims description 18
125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 17
229910052717 sulfur Inorganic materials 0.000 claims description 17
206010019663 Hepatic failure Diseases 0.000 claims description 15
208000007903 liver failure Diseases 0.000 claims description 15
231100000835 liver failure Toxicity 0.000 claims description 15
239000013078 crystal Chemical group 0.000 claims description 14
125000005842 heteroatom Chemical group 0.000 claims description 13
125000001624 naphthyl group Chemical group 0.000 claims description 13
125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 13
208000009137 Behcet syndrome Diseases 0.000 claims description 12
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 claims description 12
108010036949 Cyclosporine Proteins 0.000 claims description 12
208000010668 atopic eczema Diseases 0.000 claims description 12
125000001309 chloro group Chemical group Cl* 0.000 claims description 12
206010046851 Uveitis Diseases 0.000 claims description 11
201000000306 sarcoidosis Diseases 0.000 claims description 11
125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 11
208000032467 Aplastic anaemia Diseases 0.000 claims description 10
208000023275 Autoimmune disease Diseases 0.000 claims description 10
229930105110 Cyclosporin A Natural products 0.000 claims description 10
206010011831 Cytomegalovirus infection Diseases 0.000 claims description 10
206010019799 Hepatitis viral Diseases 0.000 claims description 10
NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 claims description 10
206010029240 Neuritis Diseases 0.000 claims description 10
208000007536 Thrombosis Diseases 0.000 claims description 10
229960001265 ciclosporin Drugs 0.000 claims description 10
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
208000023589 ischemic disease Diseases 0.000 claims description 10
206010023332 keratitis Diseases 0.000 claims description 10
210000004185 liver Anatomy 0.000 claims description 10
201000005962 mycosis fungoides Diseases 0.000 claims description 10
210000001519 tissue Anatomy 0.000 claims description 10
229920002554 vinyl polymer Polymers 0.000 claims description 10
201000004384 Alopecia Diseases 0.000 claims description 9
230000005764 inhibitory process Effects 0.000 claims description 9
210000004072 lung Anatomy 0.000 claims description 9
230000001404 mediated effect Effects 0.000 claims description 9
206010018364 Glomerulonephritis Diseases 0.000 claims description 8
241000124008 Mammalia Species 0.000 claims description 8
231100000360 alopecia Toxicity 0.000 claims description 8
208000007788 Acute Liver Failure Diseases 0.000 claims description 7
206010000804 Acute hepatic failure Diseases 0.000 claims description 7
201000004681 Psoriasis Diseases 0.000 claims description 7
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 claims description 7
239000003937 drug carrier Substances 0.000 claims description 7
208000014674 injury Diseases 0.000 claims description 7
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
208000023504 respiratory system disease Diseases 0.000 claims description 7
230000035939 shock Effects 0.000 claims description 7
208000017520 skin disease Diseases 0.000 claims description 7
208000008439 Biliary Liver Cirrhosis Diseases 0.000 claims description 6
206010009900 Colitis ulcerative Diseases 0.000 claims description 6
208000011231 Crohn disease Diseases 0.000 claims description 6
208000022559 Inflammatory bowel disease Diseases 0.000 claims description 6
206010034277 Pemphigoid Diseases 0.000 claims description 6
201000006704 Ulcerative Colitis Diseases 0.000 claims description 6
208000000594 bullous pemphigoid Diseases 0.000 claims description 6
206010012601 diabetes mellitus Diseases 0.000 claims description 6
208000035475 disorder Diseases 0.000 claims description 6
206010021198 ichthyosis Diseases 0.000 claims description 6
230000002757 inflammatory effect Effects 0.000 claims description 6
230000002401 inhibitory effect Effects 0.000 claims description 6
201000006417 multiple sclerosis Diseases 0.000 claims description 6
239000001301 oxygen Substances 0.000 claims description 6
230000036961 partial effect Effects 0.000 claims description 6
239000008194 pharmaceutical composition Substances 0.000 claims description 6
206010039073 rheumatoid arthritis Diseases 0.000 claims description 6
201000000596 systemic lupus erythematosus Diseases 0.000 claims description 6
239000003053 toxin Substances 0.000 claims description 6
231100000765 toxin Toxicity 0.000 claims description 6
208000030507 AIDS Diseases 0.000 claims description 5
208000002874 Acne Vulgaris Diseases 0.000 claims description 5
208000009304 Acute Kidney Injury Diseases 0.000 claims description 5
208000026872 Addison Disease Diseases 0.000 claims description 5
201000010000 Agranulocytosis Diseases 0.000 claims description 5
208000035285 Allergic Seasonal Rhinitis Diseases 0.000 claims description 5
208000024827 Alzheimer disease Diseases 0.000 claims description 5
206010002065 Anaemia megaloblastic Diseases 0.000 claims description 5
208000028185 Angioedema Diseases 0.000 claims description 5
206010002660 Anoxia Diseases 0.000 claims description 5
241000976983 Anoxia Species 0.000 claims description 5
201000001320 Atherosclerosis Diseases 0.000 claims description 5
208000032116 Autoimmune Experimental Encephalomyelitis Diseases 0.000 claims description 5
206010003827 Autoimmune hepatitis Diseases 0.000 claims description 5
208000035143 Bacterial infection Diseases 0.000 claims description 5
208000023328 Basedow disease Diseases 0.000 claims description 5
208000033222 Biliary cirrhosis primary Diseases 0.000 claims description 5
108010006654 Bleomycin Proteins 0.000 claims description 5
201000009030 Carcinoma Diseases 0.000 claims description 5
208000031229 Cardiomyopathies Diseases 0.000 claims description 5
206010008609 Cholangitis sclerosing Diseases 0.000 claims description 5
208000002691 Choroiditis Diseases 0.000 claims description 5
206010009208 Cirrhosis alcoholic Diseases 0.000 claims description 5
206010009657 Clostridium difficile colitis Diseases 0.000 claims description 5
208000015943 Coeliac disease Diseases 0.000 claims description 5
208000035473 Communicable disease Diseases 0.000 claims description 5
206010010744 Conjunctivitis allergic Diseases 0.000 claims description 5
206010012442 Dermatitis contact Diseases 0.000 claims description 5
208000007342 Diabetic Nephropathies Diseases 0.000 claims description 5
206010014561 Emphysema Diseases 0.000 claims description 5
206010014950 Eosinophilia Diseases 0.000 claims description 5
206010015150 Erythema Diseases 0.000 claims description 5
206010015218 Erythema multiforme Diseases 0.000 claims description 5
206010016228 Fasciitis Diseases 0.000 claims description 5
206010016654 Fibrosis Diseases 0.000 claims description 5
208000009329 Graft vs Host Disease Diseases 0.000 claims description 5
206010018691 Granuloma Diseases 0.000 claims description 5
208000035895 Guillain-Barré syndrome Diseases 0.000 claims description 5
208000030836 Hashimoto thyroiditis Diseases 0.000 claims description 5
208000035186 Hemolytic Autoimmune Anemia Diseases 0.000 claims description 5
208000032759 Hemolytic-Uremic Syndrome Diseases 0.000 claims description 5
208000005100 Herpetic Keratitis Diseases 0.000 claims description 5
206010020850 Hyperthyroidism Diseases 0.000 claims description 5
206010021074 Hypoplastic anaemia Diseases 0.000 claims description 5
206010021143 Hypoxia Diseases 0.000 claims description 5
201000003838 Idiopathic interstitial pneumonia Diseases 0.000 claims description 5
206010021245 Idiopathic thrombocytopenic purpura Diseases 0.000 claims description 5
201000002287 Keratoconus Diseases 0.000 claims description 5
206010024380 Leukoderma Diseases 0.000 claims description 5
GWNVDXQDILPJIG-SHSCPDMUSA-N Leukotriene C4 Natural products CCCCCC=C/CC=C/C=C/C=C/C(SCC(NC(=O)CCC(N)C(=O)O)C(=O)NCC(=O)O)C(O)CCCC(=O)O GWNVDXQDILPJIG-SHSCPDMUSA-N 0.000 claims description 5
208000012309 Linear IgA disease Diseases 0.000 claims description 5
206010058467 Lung neoplasm malignant Diseases 0.000 claims description 5
241000701076 Macacine alphaherpesvirus 1 Species 0.000 claims description 5
208000000682 Megaloblastic Anemia Diseases 0.000 claims description 5
208000027530 Meniere disease Diseases 0.000 claims description 5
206010027476 Metastases Diseases 0.000 claims description 5
208000019695 Migraine disease Diseases 0.000 claims description 5
206010049567 Miller Fisher syndrome Diseases 0.000 claims description 5
206010027910 Mononeuritis Diseases 0.000 claims description 5
208000024599 Mooren ulcer Diseases 0.000 claims description 5
206010051606 Necrotising colitis Diseases 0.000 claims description 5
206010028980 Neoplasm Diseases 0.000 claims description 5
208000008589 Obesity Diseases 0.000 claims description 5
206010073938 Ophthalmic herpes simplex Diseases 0.000 claims description 5
208000001132 Osteoporosis Diseases 0.000 claims description 5
206010033645 Pancreatitis Diseases 0.000 claims description 5
241000721454 Pemphigus Species 0.000 claims description 5
208000031845 Pernicious anaemia Diseases 0.000 claims description 5
206010036105 Polyneuropathy Diseases 0.000 claims description 5
208000003971 Posterior uveitis Diseases 0.000 claims description 5
208000012654 Primary biliary cholangitis Diseases 0.000 claims description 5
206010036774 Proctitis Diseases 0.000 claims description 5
208000003100 Pseudomembranous Enterocolitis Diseases 0.000 claims description 5
206010037128 Pseudomembranous colitis Diseases 0.000 claims description 5
208000003670 Pure Red-Cell Aplasia Diseases 0.000 claims description 5
208000006311 Pyoderma Diseases 0.000 claims description 5
206010037779 Radiculopathy Diseases 0.000 claims description 5
208000033626 Renal failure acute Diseases 0.000 claims description 5
206010063837 Reperfusion injury Diseases 0.000 claims description 5
208000002200 Respiratory Hypersensitivity Diseases 0.000 claims description 5
206010038910 Retinitis Diseases 0.000 claims description 5
206010039705 Scleritis Diseases 0.000 claims description 5
206010039710 Scleroderma Diseases 0.000 claims description 5
206010039966 Senile dementia Diseases 0.000 claims description 5
206010040047 Sepsis Diseases 0.000 claims description 5
206010040070 Septic Shock Diseases 0.000 claims description 5
208000021386 Sjogren Syndrome Diseases 0.000 claims description 5
208000007107 Stomach Ulcer Diseases 0.000 claims description 5
208000031673 T-Cell Cutaneous Lymphoma Diseases 0.000 claims description 5
208000001106 Takayasu Arteritis Diseases 0.000 claims description 5
208000031981 Thrombocytopenic Idiopathic Purpura Diseases 0.000 claims description 5
231100000579 Toxinosis Toxicity 0.000 claims description 5
206010067584 Type 1 diabetes mellitus Diseases 0.000 claims description 5
206010064996 Ulcerative keratitis Diseases 0.000 claims description 5
208000024780 Urticaria Diseases 0.000 claims description 5
208000001445 Uveomeningoencephalitic Syndrome Diseases 0.000 claims description 5
206010047112 Vasculitides Diseases 0.000 claims description 5
206010047115 Vasculitis Diseases 0.000 claims description 5
208000034705 Vogt-Koyanagi-Harada syndrome Diseases 0.000 claims description 5
206010000496 acne Diseases 0.000 claims description 5
230000001154 acute effect Effects 0.000 claims description 5
206010064930 age-related macular degeneration Diseases 0.000 claims description 5
230000032683 aging Effects 0.000 claims description 5
230000010085 airway hyperresponsiveness Effects 0.000 claims description 5
208000010002 alcoholic liver cirrhosis Diseases 0.000 claims description 5
239000003513 alkali Substances 0.000 claims description 5
201000009961 allergic asthma Diseases 0.000 claims description 5
208000002205 allergic conjunctivitis Diseases 0.000 claims description 5
208000004631 alopecia areata Diseases 0.000 claims description 5
230000007953 anoxia Effects 0.000 claims description 5
230000003110 anti-inflammatory effect Effects 0.000 claims description 5
201000000448 autoimmune hemolytic anemia Diseases 0.000 claims description 5
201000003710 autoimmune thrombocytopenic purpura Diseases 0.000 claims description 5
208000022362 bacterial infectious disease Diseases 0.000 claims description 5
OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical class 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 claims description 5
210000000988 bone and bone Anatomy 0.000 claims description 5
206010006451 bronchitis Diseases 0.000 claims description 5
201000011510 cancer Diseases 0.000 claims description 5
230000000747 cardiac effect Effects 0.000 claims description 5
239000004568 cement Substances 0.000 claims description 5
208000015114 central nervous system disease Diseases 0.000 claims description 5
230000000973 chemotherapeutic effect Effects 0.000 claims description 5
208000020832 chronic kidney disease Diseases 0.000 claims description 5
208000025302 chronic primary adrenal insufficiency Diseases 0.000 claims description 5
201000010002 cicatricial pemphigoid Diseases 0.000 claims description 5
230000007882 cirrhosis Effects 0.000 claims description 5
208000019425 cirrhosis of liver Diseases 0.000 claims description 5
206010009887 colitis Diseases 0.000 claims description 5
208000010247 contact dermatitis Diseases 0.000 claims description 5
201000007241 cutaneous T cell lymphoma Diseases 0.000 claims description 5
201000001981 dermatomyositis Diseases 0.000 claims description 5
208000033679 diabetic kidney disease Diseases 0.000 claims description 5
239000000428 dust Substances 0.000 claims description 5
238000003912 environmental pollution Methods 0.000 claims description 5
230000002327 eosinophilic effect Effects 0.000 claims description 5
201000001564 eosinophilic gastroenteritis Diseases 0.000 claims description 5
231100000321 erythema Toxicity 0.000 claims description 5
208000024711 extrinsic asthma Diseases 0.000 claims description 5
230000035784 germination Effects 0.000 claims description 5
210000004195 gingiva Anatomy 0.000 claims description 5
208000007565 gingivitis Diseases 0.000 claims description 5
230000003779 hair growth Effects 0.000 claims description 5
206010019692 hepatic necrosis Diseases 0.000 claims description 5
208000006454 hepatitis Diseases 0.000 claims description 5
231100000283 hepatitis Toxicity 0.000 claims description 5
201000010884 herpes simplex virus keratitis Diseases 0.000 claims description 5
229960001340 histamine Drugs 0.000 claims description 5
230000003463 hyperproliferative effect Effects 0.000 claims description 5
201000002597 ichthyosis vulgaris Diseases 0.000 claims description 5
208000030603 inherited susceptibility to asthma Diseases 0.000 claims description 5
201000006334 interstitial nephritis Diseases 0.000 claims description 5
230000003903 intestinal lesions Effects 0.000 claims description 5
201000010659 intrinsic asthma Diseases 0.000 claims description 5
208000012947 ischemia reperfusion injury Diseases 0.000 claims description 5
208000023569 ischemic bowel disease Diseases 0.000 claims description 5
230000000302 ischemic effect Effects 0.000 claims description 5
201000010666 keratoconjunctivitis Diseases 0.000 claims description 5
201000010260 leiomyoma Diseases 0.000 claims description 5
230000003902 lesion Effects 0.000 claims description 5
GWNVDXQDILPJIG-NXOLIXFESA-N leukotriene C4 Chemical compound CCCCC\C=C/C\C=C/C=C/C=C/[C@H]([C@@H](O)CCCC(O)=O)SC[C@@H](C(=O)NCC(O)=O)NC(=O)CC[C@H](N)C(O)=O GWNVDXQDILPJIG-NXOLIXFESA-N 0.000 claims description 5
201000011486 lichen planus Diseases 0.000 claims description 5
231100000149 liver necrosis Toxicity 0.000 claims description 5
201000005202 lung cancer Diseases 0.000 claims description 5
208000020816 lung neoplasm Diseases 0.000 claims description 5
206010025135 lupus erythematosus Diseases 0.000 claims description 5
208000008585 mastocytosis Diseases 0.000 claims description 5
231100001016 megaloblastic anemia Toxicity 0.000 claims description 5
230000009401 metastasis Effects 0.000 claims description 5
244000000010 microbial pathogen Species 0.000 claims description 5
206010027599 migraine Diseases 0.000 claims description 5
208000013734 mononeuritis simplex Diseases 0.000 claims description 5
201000005518 mononeuropathy Diseases 0.000 claims description 5
201000006938 muscular dystrophy Diseases 0.000 claims description 5
206010028417 myasthenia gravis Diseases 0.000 claims description 5
230000017074 necrotic cell death Effects 0.000 claims description 5
208000004995 necrotizing enterocolitis Diseases 0.000 claims description 5
201000006195 perinatal necrotizing enterocolitis Diseases 0.000 claims description 5
201000001245 periodontitis Diseases 0.000 claims description 5
210000004261 periodontium Anatomy 0.000 claims description 5
201000006292 polyarteritis nodosa Diseases 0.000 claims description 5
208000005987 polymyositis Diseases 0.000 claims description 5
208000019629 polyneuritis Diseases 0.000 claims description 5
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 claims description 5
238000004321 preservation Methods 0.000 claims description 5
208000025638 primary cutaneous T-cell non-Hodgkin lymphoma Diseases 0.000 claims description 5
230000001737 promoting effect Effects 0.000 claims description 5
230000005855 radiation Effects 0.000 claims description 5
238000002271 resection Methods 0.000 claims description 5
230000002441 reversible effect Effects 0.000 claims description 5
206010039083 rhinitis Diseases 0.000 claims description 5
230000037390 scarring Effects 0.000 claims description 5
208000010157 sclerosing cholangitis Diseases 0.000 claims description 5
230000035945 sensitivity Effects 0.000 claims description 5
208000004003 siderosis Diseases 0.000 claims description 5
229960001967 tacrolimus Drugs 0.000 claims description 5
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 claims description 5
230000008733 trauma Effects 0.000 claims description 5
230000003966 vascular damage Effects 0.000 claims description 5
201000005539 vernal conjunctivitis Diseases 0.000 claims description 5
201000001862 viral hepatitis Diseases 0.000 claims description 5
206010003210 Arteriosclerosis Diseases 0.000 claims description 4
206010066968 Corneal leukoma Diseases 0.000 claims description 4
206010014989 Epidermolysis bullosa Diseases 0.000 claims description 4
208000024869 Goodpasture syndrome Diseases 0.000 claims description 4
208000011775 arteriosclerosis disease Diseases 0.000 claims description 4
210000000987 immune system Anatomy 0.000 claims description 4
230000000414 obstructive effect Effects 0.000 claims description 4
229960002706 gusperimus Drugs 0.000 claims description 3
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 claims description 3
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 claims description 3
229960002930 sirolimus Drugs 0.000 claims description 3
LMEKQMALGUDUQG-UHFFFAOYSA-N azathioprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC=NC2=C1NC=N2 LMEKQMALGUDUQG-UHFFFAOYSA-N 0.000 claims description 2
PZOHOALJQOFNTB-UHFFFAOYSA-M brequinar sodium Chemical compound [Na+].N1=C2C=CC(F)=CC2=C(C([O-])=O)C(C)=C1C(C=C1)=CC=C1C1=CC=CC=C1F PZOHOALJQOFNTB-UHFFFAOYSA-M 0.000 claims description 2
HPNSFSBZBAHARI-UHFFFAOYSA-N micophenolic acid Natural products OC1=C(CC=C(C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-UHFFFAOYSA-N 0.000 claims description 2
IDINUJSAMVOPCM-INIZCTEOSA-N n-[(1s)-2-[4-(3-aminopropylamino)butylamino]-1-hydroxy-2-oxoethyl]-7-(diaminomethylideneamino)heptanamide Chemical compound NCCCNCCCCNC(=O)[C@H](O)NC(=O)CCCCCCN=C(N)N IDINUJSAMVOPCM-INIZCTEOSA-N 0.000 claims description 2
VNYSSYRCGWBHLG-AMOLWHMGSA-M leukotriene B4(1-) Chemical compound CCCCC\C=C/C[C@@H](O)\C=C\C=C\C=C/[C@@H](O)CCCC([O-])=O VNYSSYRCGWBHLG-AMOLWHMGSA-M 0.000 claims 2
XRMDCWJNPDVAFI-UHFFFAOYSA-N 2,2,6,6-tetramethyl-1-oxopiperidin-1-ium-4-ol Chemical compound CC1(C)CC(O)CC(C)(C)[N+]1=O XRMDCWJNPDVAFI-UHFFFAOYSA-N 0.000 claims 1
208000006069 Corneal Opacity Diseases 0.000 claims 1
241001123008 Leukoma Species 0.000 claims 1
229960002170 azathioprine Drugs 0.000 claims 1
ZPUCINDJVBIVPJ-LJISPDSOSA-N cocaine Chemical compound O([C@H]1C[C@@H]2CC[C@@H](N2C)[C@H]1C(=O)OC)C(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-LJISPDSOSA-N 0.000 claims 1
229930182912 cyclosporin Natural products 0.000 claims 1
229960000951 mycophenolic acid Drugs 0.000 claims 1
208000011580 syndromic disease Diseases 0.000 claims 1
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 72
239000000243 solution Substances 0.000 description 67
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 66
238000006243 chemical reaction Methods 0.000 description 59
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 38
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 33
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 33
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 32
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 31
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 26
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 23
239000000203 mixture Substances 0.000 description 23
239000000741 silica gel Substances 0.000 description 23
229910002027 silica gel Inorganic materials 0.000 description 23
230000002829 reductive effect Effects 0.000 description 20
238000004128 high performance liquid chromatography Methods 0.000 description 18
239000002904 solvent Substances 0.000 description 18
108091006146 Channels Proteins 0.000 description 17
QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 16
210000001744 T-lymphocyte Anatomy 0.000 description 15
OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 15
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 14
MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 14
229920006395 saturated elastomer Polymers 0.000 description 14
239000004480 active ingredient Substances 0.000 description 13
238000001819 mass spectrum Methods 0.000 description 12
QBERHIJABFXGRZ-UHFFFAOYSA-M rhodium;triphenylphosphane;chloride Chemical compound [Cl-].[Rh].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 QBERHIJABFXGRZ-UHFFFAOYSA-M 0.000 description 12
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
150000001336 alkenes Chemical group 0.000 description 11
210000004027 cell Anatomy 0.000 description 11
230000002265 prevention Effects 0.000 description 10
239000011995 wilkinson's catalyst Substances 0.000 description 10
150000002596 lactones Chemical class 0.000 description 9
239000007787 solid Substances 0.000 description 9
KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 8
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
241001639960 Spachea Species 0.000 description 8
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 8
238000010898 silica gel chromatography Methods 0.000 description 8
RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 8
KPGXUAIFQMJJFB-UHFFFAOYSA-H tungsten hexachloride Chemical compound Cl[W](Cl)(Cl)(Cl)(Cl)Cl KPGXUAIFQMJJFB-UHFFFAOYSA-H 0.000 description 8
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
241000949473 Correa Species 0.000 description 7
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 7
150000001412 amines Chemical class 0.000 description 7
JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 7
239000000047 product Substances 0.000 description 7
DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
229910052799 carbon Inorganic materials 0.000 description 6
239000003153 chemical reaction reagent Substances 0.000 description 6
WBKFWQBXFREOFH-UHFFFAOYSA-N dichloromethane;ethyl acetate Chemical compound ClCCl.CCOC(C)=O WBKFWQBXFREOFH-UHFFFAOYSA-N 0.000 description 6
229960003444 immunosuppressant agent Drugs 0.000 description 6
210000003734 kidney Anatomy 0.000 description 6
239000010410 layer Substances 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
ATYBXHSAIOKLMG-UHFFFAOYSA-N oxepin Chemical class O1C=CC=CC=C1 ATYBXHSAIOKLMG-UHFFFAOYSA-N 0.000 description 6
239000000843 powder Substances 0.000 description 6
239000000725 suspension Substances 0.000 description 6
AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 6
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
108010002350 Interleukin-2 Proteins 0.000 description 5
241001465754 Metazoa Species 0.000 description 5
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
239000002775 capsule Substances 0.000 description 5
239000003638 chemical reducing agent Substances 0.000 description 5
239000003795 chemical substances by application Substances 0.000 description 5
239000000287 crude extract Substances 0.000 description 5
150000002170 ethers Chemical class 0.000 description 5
210000001035 gastrointestinal tract Anatomy 0.000 description 5
238000002360 preparation method Methods 0.000 description 5
238000000746 purification Methods 0.000 description 5
238000000926 separation method Methods 0.000 description 5
239000003826 tablet Substances 0.000 description 5
238000012360 testing method Methods 0.000 description 5
OVJBOPBBHWOWJI-FYNXUGHNSA-N (2S)-2-[[(2S)-1-[(2S)-2-[[(aS,1R,3aS,4S,10S,16S,19R,22S,25S,28S,34S,37S,40R,45R,48S,51S,57S,60S,63S,69S,72S,75S,78S,85R,88S,91R,94S)-40-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S,3S)-2-[[(2S,3S)-2-[[(2S,3R)-2-amino-3-hydroxybutanoyl]amino]-3-methylpentanoyl]amino]-3-methylpentanoyl]amino]-4-oxobutanoyl]amino]-3-methylbutanoyl]amino]hexanoyl]amino]-25,48,78,88,94-pentakis(4-aminobutyl)-a-(2-amino-2-oxoethyl)-22,63,72-tris(3-amino-3-oxopropyl)-69-benzyl-37-[(1R)-1-hydroxyethyl]-34,60-bis(hydroxymethyl)-51,57,75-trimethyl-16-(2-methylpropyl)-3a-(2-methylsulfanylethyl)-2a,3,5a,9,15,18,21,24,27,33,36,39,47,50,53,56,59,62,65,68,71,74,77,80,87,90,93,96,99-nonacosaoxo-7a,8a,42,43,82,83-hexathia-1a,2,4a,8,14,17,20,23,26,32,35,38,46,49,52,55,58,61,64,67,70,73,76,79,86,89,92,95,98-nonacosazahexacyclo[43.35.25.419,91.04,8.010,14.028,32]nonahectane-85-carbonyl]amino]-3-(4-hydroxyphenyl)propanoyl]pyrrolidine-2-carbonyl]amino]-3-(1H-imidazol-5-yl)propanoic acid Chemical compound CC[C@H](C)[C@H](NC(=O)[C@@H](N)[C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@H]1CSSC[C@@H]2NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](Cc3ccccc3)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCCN)NC(=O)[C@@H]3CSSC[C@H](NC(=O)[C@H](CCCCN)NC(=O)[C@H](CSSC[C@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H]4CCCN4C(=O)[C@H](CO)NC(=O)[C@@H](NC1=O)[C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N3)NC(=O)[C@H](CCCCN)NC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCSC)NC2=O)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1cnc[nH]1)C(O)=O OVJBOPBBHWOWJI-FYNXUGHNSA-N 0.000 description 4
NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
101000997261 Centruroides margaritatus Potassium channel toxin alpha-KTx 2.2 Proteins 0.000 description 4
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
206010061218 Inflammation Diseases 0.000 description 4
ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 4
TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 4
101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 4
QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 4
239000012298 atmosphere Substances 0.000 description 4
230000001363 autoimmune Effects 0.000 description 4
238000005119 centrifugation Methods 0.000 description 4
238000004587 chromatography analysis Methods 0.000 description 4
229940125904 compound 1 Drugs 0.000 description 4
239000012043 crude product Substances 0.000 description 4
230000006378 damage Effects 0.000 description 4
239000002552 dosage form Substances 0.000 description 4
150000002118 epoxides Chemical class 0.000 description 4
239000000469 ethanolic extract Substances 0.000 description 4
239000000284 extract Substances 0.000 description 4
239000007903 gelatin capsule Substances 0.000 description 4
210000002216 heart Anatomy 0.000 description 4
239000001257 hydrogen Substances 0.000 description 4
230000001506 immunosuppresive effect Effects 0.000 description 4
230000004054 inflammatory process Effects 0.000 description 4
238000002347 injection Methods 0.000 description 4
239000007924 injection Substances 0.000 description 4
150000002576 ketones Chemical class 0.000 description 4
208000017169 kidney disease Diseases 0.000 description 4
208000019423 liver disease Diseases 0.000 description 4
229910052943 magnesium sulfate Inorganic materials 0.000 description 4
VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 4
239000012044 organic layer Substances 0.000 description 4
CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
230000008569 process Effects 0.000 description 4
DAEPDZWVDSPTHF-UHFFFAOYSA-M sodium pyruvate Chemical compound [Na+].CC(=O)C([O-])=O DAEPDZWVDSPTHF-UHFFFAOYSA-M 0.000 description 4
239000000126 substance Substances 0.000 description 4
WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 4
239000003643 water by type Substances 0.000 description 4
IQFYYKKMVGJFEH-OFKYTIFKSA-N 1-[(2r,4s,5r)-4-hydroxy-5-(tritiooxymethyl)oxolan-2-yl]-5-methylpyrimidine-2,4-dione Chemical compound C1[C@H](O)[C@@H](CO[3H])O[C@H]1N1C(=O)NC(=O)C(C)=C1 IQFYYKKMVGJFEH-OFKYTIFKSA-N 0.000 description 3
JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 3
BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 3
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
239000007995 HEPES buffer Substances 0.000 description 3
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 3
BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
206010052779 Transplant rejections Diseases 0.000 description 3
239000000443 aerosol Substances 0.000 description 3
238000003556 assay Methods 0.000 description 3
239000002585 base Substances 0.000 description 3
230000000903 blocking effect Effects 0.000 description 3
239000000872 buffer Substances 0.000 description 3
238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 3
KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
238000004440 column chromatography Methods 0.000 description 3
238000002451 electron ionisation mass spectrometry Methods 0.000 description 3
150000002148 esters Chemical class 0.000 description 3
238000010265 fast atom bombardment Methods 0.000 description 3
238000005194 fractionation Methods 0.000 description 3
ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 3
239000003112 inhibitor Substances 0.000 description 3
239000008101 lactose Substances 0.000 description 3
VNYSSYRCGWBHLG-AMOLWHMGSA-N leukotriene B4 Chemical compound CCCCC\C=C/C[C@@H](O)\C=C\C=C\C=C/[C@@H](O)CCCC(O)=O VNYSSYRCGWBHLG-AMOLWHMGSA-N 0.000 description 3
239000008297 liquid dosage form Substances 0.000 description 3
229910052744 lithium Inorganic materials 0.000 description 3
235000019359 magnesium stearate Nutrition 0.000 description 3
108090000765 processed proteins & peptides Proteins 0.000 description 3
102000004169 proteins and genes Human genes 0.000 description 3
108090000623 proteins and genes Proteins 0.000 description 3
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
239000000523 sample Substances 0.000 description 3
230000028327 secretion Effects 0.000 description 3
210000003491 skin Anatomy 0.000 description 3
239000011780 sodium chloride Substances 0.000 description 3
239000007921 spray Substances 0.000 description 3
238000003756 stirring Methods 0.000 description 3
229940124597 therapeutic agent Drugs 0.000 description 3
238000004809 thin layer chromatography Methods 0.000 description 3
238000005406 washing Methods 0.000 description 3
DAXJNUBSBFUTRP-RTQNCGMRSA-N (8r,9s,10r,13s,14s)-6-(hydroxymethyl)-10,13-dimethyl-7,8,9,11,12,14,15,16-octahydro-6h-cyclopenta[a]phenanthrene-3,17-dione Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC(CO)C2=C1 DAXJNUBSBFUTRP-RTQNCGMRSA-N 0.000 description 2
UZOVYGYOLBIAJR-UHFFFAOYSA-N 4-isocyanato-4'-methyldiphenylmethane Chemical compound C1=CC(C)=CC=C1CC1=CC=C(N=C=O)C=C1 UZOVYGYOLBIAJR-UHFFFAOYSA-N 0.000 description 2
CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
208000020084 Bone disease Diseases 0.000 description 2
108091003079 Bovine Serum Albumin Proteins 0.000 description 2
OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
108010023798 Charybdotoxin Proteins 0.000 description 2
208000027932 Collagen disease Diseases 0.000 description 2
CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 2
QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 2
238000002965 ELISA Methods 0.000 description 2
WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
208000027761 Hepatic autoimmune disease Diseases 0.000 description 2
206010020751 Hypersensitivity Diseases 0.000 description 2
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 2
239000002841 Lewis acid Substances 0.000 description 2
208000019693 Lung disease Diseases 0.000 description 2
HZQDCMWJEBCWBR-UUOKFMHZSA-N Mizoribine Chemical compound OC1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 HZQDCMWJEBCWBR-UUOKFMHZSA-N 0.000 description 2
206010029164 Nephrotic syndrome Diseases 0.000 description 2
102000005348 Neuraminidase Human genes 0.000 description 2
108010006232 Neuraminidase Proteins 0.000 description 2
208000022873 Ocular disease Diseases 0.000 description 2
241001494479 Pecora Species 0.000 description 2
102000003992 Peroxidases Human genes 0.000 description 2
ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
102000004257 Potassium Channel Human genes 0.000 description 2
239000012980 RPMI-1640 medium Substances 0.000 description 2
229920002472 Starch Polymers 0.000 description 2
230000006044 T cell activation Effects 0.000 description 2
206010053615 Thermal burn Diseases 0.000 description 2
IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 2
102000003734 Voltage-Gated Potassium Channels Human genes 0.000 description 2
108090000013 Voltage-Gated Potassium Channels Proteins 0.000 description 2
229910003091 WCl6 Inorganic materials 0.000 description 2
208000027418 Wounds and injury Diseases 0.000 description 2
206010000059 abdominal discomfort Diseases 0.000 description 2
238000002835 absorbance Methods 0.000 description 2
231100000836 acute liver failure Toxicity 0.000 description 2
238000003915 air pollution Methods 0.000 description 2
150000001298 alcohols Chemical class 0.000 description 2
208000026935 allergic disease Diseases 0.000 description 2
230000007815 allergy Effects 0.000 description 2
235000019270 ammonium chloride Nutrition 0.000 description 2
150000003863 ammonium salts Chemical class 0.000 description 2
238000004458 analytical method Methods 0.000 description 2
229940121363 anti-inflammatory agent Drugs 0.000 description 2
239000002260 anti-inflammatory agent Substances 0.000 description 2
239000000010 aprotic solvent Substances 0.000 description 2
239000007900 aqueous suspension Substances 0.000 description 2
230000006472 autoimmune response Effects 0.000 description 2
230000008901 benefit Effects 0.000 description 2
PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 2
210000004204 blood vessel Anatomy 0.000 description 2
239000012267 brine Substances 0.000 description 2
229910052791 calcium Inorganic materials 0.000 description 2
239000011575 calcium Substances 0.000 description 2
150000004657 carbamic acid derivatives Chemical class 0.000 description 2
PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
239000000969 carrier Substances 0.000 description 2
239000006285 cell suspension Substances 0.000 description 2
239000001913 cellulose Substances 0.000 description 2
235000010980 cellulose Nutrition 0.000 description 2
229920002678 cellulose Polymers 0.000 description 2
OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
239000007891 compressed tablet Substances 0.000 description 2
210000004087 cornea Anatomy 0.000 description 2
239000006071 cream Substances 0.000 description 2
CNVQLPPZGABUCM-LIGYZCPXSA-N ctx toxin Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@H]3CSSC[C@@H](C(N[C@@H](CC=4C5=CC=CC=C5NC=4)C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CCCNC(N)=N)NC3=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CO)C(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3NC=NC=3)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N2)C(C)C)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H]([C@@H](C)O)NC1=O)=O)CCSC)C(C)C)[C@@H](C)O)NC(=O)[C@H]1NC(=O)CC1)C1=CC=CC=C1 CNVQLPPZGABUCM-LIGYZCPXSA-N 0.000 description 2
229960004397 cyclophosphamide Drugs 0.000 description 2
229940127089 cytotoxic agent Drugs 0.000 description 2
239000002254 cytotoxic agent Substances 0.000 description 2
231100000599 cytotoxic agent Toxicity 0.000 description 2
230000001419 dependent effect Effects 0.000 description 2
WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 2
125000004852 dihydrofuranyl group Chemical group O1C(CC=C1)* 0.000 description 2
125000005043 dihydropyranyl group Chemical group O1C(CCC=C1)* 0.000 description 2
238000010790 dilution Methods 0.000 description 2
239000012895 dilution Substances 0.000 description 2
125000000532 dioxanyl group Chemical group 0.000 description 2
125000005879 dioxolanyl group Chemical group 0.000 description 2
239000006185 dispersion Substances 0.000 description 2
210000001198 duodenum Anatomy 0.000 description 2
238000010828 elution Methods 0.000 description 2
208000030172 endocrine system disease Diseases 0.000 description 2
210000000918 epididymis Anatomy 0.000 description 2
201000010063 epididymitis Diseases 0.000 description 2
210000003743 erythrocyte Anatomy 0.000 description 2
239000003797 essential amino acid Substances 0.000 description 2
235000020776 essential amino acid Nutrition 0.000 description 2
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
230000001747 exhibiting effect Effects 0.000 description 2
208000030533 eye disease Diseases 0.000 description 2
239000012894 fetal calf serum Substances 0.000 description 2
235000013305 food Nutrition 0.000 description 2
150000002430 hydrocarbons Chemical group 0.000 description 2
238000005984 hydrogenation reaction Methods 0.000 description 2
230000001900 immune effect Effects 0.000 description 2
230000002163 immunogen Effects 0.000 description 2
239000012442 inert solvent Substances 0.000 description 2
208000015181 infectious disease Diseases 0.000 description 2
208000028774 intestinal disease Diseases 0.000 description 2
230000000968 intestinal effect Effects 0.000 description 2
238000002955 isolation Methods 0.000 description 2
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 2
150000007517 lewis acids Chemical class 0.000 description 2
230000000670 limiting effect Effects 0.000 description 2
210000004698 lymphocyte Anatomy 0.000 description 2
230000002934 lysing effect Effects 0.000 description 2
229910001629 magnesium chloride Inorganic materials 0.000 description 2
230000014759 maintenance of location Effects 0.000 description 2
238000005259 measurement Methods 0.000 description 2
229950000844 mizoribine Drugs 0.000 description 2
230000001483 mobilizing effect Effects 0.000 description 2
210000000214 mouth Anatomy 0.000 description 2
210000003205 muscle Anatomy 0.000 description 2
XVDBWWRIXBMVJV-UHFFFAOYSA-N n-[bis(dimethylamino)phosphanyl]-n-methylmethanamine Chemical compound CN(C)P(N(C)C)N(C)C XVDBWWRIXBMVJV-UHFFFAOYSA-N 0.000 description 2
229910000069 nitrogen hydride Inorganic materials 0.000 description 2
239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 2
229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 2
QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
239000003921 oil Substances 0.000 description 2
235000019198 oils Nutrition 0.000 description 2
239000002674 ointment Substances 0.000 description 2
238000006772 olefination reaction Methods 0.000 description 2
239000012074 organic phase Substances 0.000 description 2
LXCFILQKKLGQFO-UHFFFAOYSA-N p-hydroxybenzoic acid methyl ester Natural products COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
210000000496 pancreas Anatomy 0.000 description 2
239000003182 parenteral nutrition solution Substances 0.000 description 2
208000028169 periodontal disease Diseases 0.000 description 2
108040007629 peroxidase activity proteins Proteins 0.000 description 2
239000012071 phase Substances 0.000 description 2
239000008363 phosphate buffer Substances 0.000 description 2
229910052700 potassium Inorganic materials 0.000 description 2
239000011591 potassium Substances 0.000 description 2
108020001213 potassium channel Proteins 0.000 description 2
201000000742 primary sclerosing cholangitis Diseases 0.000 description 2
229940072288 prograf Drugs 0.000 description 2
238000011321 prophylaxis Methods 0.000 description 2
QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
239000003223 protective agent Substances 0.000 description 2
LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 2
230000009467 reduction Effects 0.000 description 2
230000001105 regulatory effect Effects 0.000 description 2
230000004044 response Effects 0.000 description 2
125000006413 ring segment Chemical group 0.000 description 2
239000000377 silicon dioxide Substances 0.000 description 2
LFAGQMCIGQNPJG-UHFFFAOYSA-N silver cyanide Chemical compound [Ag+].N#[C-] LFAGQMCIGQNPJG-UHFFFAOYSA-N 0.000 description 2
NDVLTYZPCACLMA-UHFFFAOYSA-N silver oxide Chemical compound [O-2].[Ag+].[Ag+] NDVLTYZPCACLMA-UHFFFAOYSA-N 0.000 description 2
229910052708 sodium Inorganic materials 0.000 description 2
239000011734 sodium Substances 0.000 description 2
BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 2
JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 2
229940054269 sodium pyruvate Drugs 0.000 description 2
GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
238000001228 spectrum Methods 0.000 description 2
239000003381 stabilizer Substances 0.000 description 2
239000008107 starch Substances 0.000 description 2
235000019698 starch Nutrition 0.000 description 2
235000011149 sulphuric acid Nutrition 0.000 description 2
238000001356 surgical procedure Methods 0.000 description 2
CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 2
230000036575 thermal burns Effects 0.000 description 2
FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
VOITXYVAKOUIBA-UHFFFAOYSA-N triethylaluminium Chemical compound CC[Al](CC)CC VOITXYVAKOUIBA-UHFFFAOYSA-N 0.000 description 2
ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 2
210000003905 vulva Anatomy 0.000 description 2
230000029663 wound healing Effects 0.000 description 2
VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
LPMXVESGRSUGHW-UHFFFAOYSA-N Acolongiflorosid K Natural products OC1C(O)C(O)C(C)OC1OC1CC2(O)CCC3C4(O)CCC(C=5COC(=O)C=5)C4(C)CC(O)C3C2(CO)C(O)C1 LPMXVESGRSUGHW-UHFFFAOYSA-N 0.000 description 1
QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
239000005695 Ammonium acetate Substances 0.000 description 1
DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 description 1
206010004659 Biliary cirrhosis Diseases 0.000 description 1
125000000882 C2-C6 alkenyl group Chemical group 0.000 description 1
101150041968 CDC13 gene Proteins 0.000 description 1
UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
241000283707 Capra Species 0.000 description 1
KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
206010012438 Dermatitis atopic Diseases 0.000 description 1
FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
239000004593 Epoxy Substances 0.000 description 1
VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
108010010803 Gelatin Proteins 0.000 description 1
102000006395 Globulins Human genes 0.000 description 1
108010044091 Globulins Proteins 0.000 description 1
208000003084 Graves Ophthalmopathy Diseases 0.000 description 1
CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
239000007760 Iscove's Modified Dulbecco's Medium Substances 0.000 description 1
239000003810 Jones reagent Substances 0.000 description 1
229930182816 L-glutamine Natural products 0.000 description 1
JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
229920000168 Microcrystalline cellulose Polymers 0.000 description 1
229910002651 NO3 Inorganic materials 0.000 description 1
206010029155 Nephropathy toxic Diseases 0.000 description 1
206010029350 Neurotoxicity Diseases 0.000 description 1
NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
LPMXVESGRSUGHW-GHYGWZAOSA-N Ouabain Natural products O([C@@H]1[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O1)[C@H]1C[C@@H](O)[C@@]2(CO)[C@@](O)(C1)CC[C@H]1[C@]3(O)[C@@](C)([C@H](C4=CC(=O)OC4)CC3)C[C@@H](O)[C@H]21 LPMXVESGRSUGHW-GHYGWZAOSA-N 0.000 description 1
229910019142 PO4 Inorganic materials 0.000 description 1
239000004698 Polyethylene Substances 0.000 description 1
208000001647 Renal Insufficiency Diseases 0.000 description 1
DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
235000021355 Stearic acid Nutrition 0.000 description 1
108010090804 Streptavidin Proteins 0.000 description 1
244000166550 Strophanthus gratus Species 0.000 description 1
QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
230000006052 T cell proliferation Effects 0.000 description 1
206010044221 Toxic encephalopathy Diseases 0.000 description 1
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
JEDZLBFUGJTJGQ-UHFFFAOYSA-N [Na].COCCO[AlH]OCCOC Chemical compound [Na].COCCO[AlH]OCCOC JEDZLBFUGJTJGQ-UHFFFAOYSA-N 0.000 description 1
230000002159 abnormal effect Effects 0.000 description 1
230000005856 abnormality Effects 0.000 description 1
DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
239000002253 acid Substances 0.000 description 1
125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 description 1
230000009471 action Effects 0.000 description 1
230000036982 action potential Effects 0.000 description 1
125000003545 alkoxy group Chemical group 0.000 description 1
125000005910 alkyl carbonate group Chemical group 0.000 description 1
150000001350 alkyl halides Chemical class 0.000 description 1
229910052782 aluminium Inorganic materials 0.000 description 1
XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
150000001413 amino acids Chemical class 0.000 description 1
235000019257 ammonium acetate Nutrition 0.000 description 1
229940043376 ammonium acetate Drugs 0.000 description 1
230000003064 anti-oxidating effect Effects 0.000 description 1
238000009175 antibody therapy Methods 0.000 description 1
239000000427 antigen Substances 0.000 description 1
102000036639 antigens Human genes 0.000 description 1
108091007433 antigens Proteins 0.000 description 1
239000007864 aqueous solution Substances 0.000 description 1
235000010323 ascorbic acid Nutrition 0.000 description 1
239000011668 ascorbic acid Substances 0.000 description 1
229960005070 ascorbic acid Drugs 0.000 description 1
201000008937 atopic dermatitis Diseases 0.000 description 1
229960004360 azathioprine sodium Drugs 0.000 description 1
229960000686 benzalkonium chloride Drugs 0.000 description 1
125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 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
IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 1
230000000975 bioactive effect Effects 0.000 description 1
230000033228 biological regulation Effects 0.000 description 1
230000015572 biosynthetic process Effects 0.000 description 1
AZWXAPCAJCYGIA-UHFFFAOYSA-N bis(2-methylpropyl)alumane Chemical compound CC(C)C[AlH]CC(C)C AZWXAPCAJCYGIA-UHFFFAOYSA-N 0.000 description 1
210000000601 blood cell Anatomy 0.000 description 1
210000001185 bone marrow Anatomy 0.000 description 1
UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 description 1
125000001246 bromo group Chemical group Br* 0.000 description 1
125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
239000001110 calcium chloride Substances 0.000 description 1
229910001628 calcium chloride Inorganic materials 0.000 description 1
235000011148 calcium chloride Nutrition 0.000 description 1
230000004094 calcium homeostasis Effects 0.000 description 1
125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
150000001721 carbon Chemical group 0.000 description 1
239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
239000001768 carboxy methyl cellulose Substances 0.000 description 1
150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
150000001735 carboxylic acids Chemical class 0.000 description 1
150000001768 cations Chemical class 0.000 description 1
210000000170 cell membrane Anatomy 0.000 description 1
238000001516 cell proliferation assay Methods 0.000 description 1
229940107810 cellcept Drugs 0.000 description 1
230000001413 cellular effect Effects 0.000 description 1
238000012512 characterization method Methods 0.000 description 1
150000001793 charged compounds Chemical class 0.000 description 1
210000004978 chinese hamster ovary cell Anatomy 0.000 description 1
150000001805 chlorine compounds Chemical class 0.000 description 1
229960004926 chlorobutanol Drugs 0.000 description 1
KRVSOGSZCMJSLX-UHFFFAOYSA-L chromic acid Substances O[Cr](O)(=O)=O KRVSOGSZCMJSLX-UHFFFAOYSA-L 0.000 description 1
125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
238000000576 coating method Methods 0.000 description 1
229940075614 colloidal silicon dioxide Drugs 0.000 description 1
238000004040 coloring Methods 0.000 description 1
229940000425 combination drug Drugs 0.000 description 1
238000002648 combination therapy Methods 0.000 description 1
239000003246 corticosteroid Substances 0.000 description 1
229960001334 corticosteroids Drugs 0.000 description 1
235000012343 cottonseed oil Nutrition 0.000 description 1
239000002385 cottonseed oil Substances 0.000 description 1
238000002425 crystallisation Methods 0.000 description 1
230000008025 crystallization Effects 0.000 description 1
238000012258 culturing Methods 0.000 description 1
125000004122 cyclic group Chemical group 0.000 description 1
125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
239000008121 dextrose Substances 0.000 description 1
125000003963 dichloro group Chemical group Cl* 0.000 description 1
IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 1
239000003085 diluting agent Substances 0.000 description 1
239000001177 diphosphate Substances 0.000 description 1
XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
235000011180 diphosphates Nutrition 0.000 description 1
238000006073 displacement reaction Methods 0.000 description 1
VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 1
239000008298 dragée Substances 0.000 description 1
239000006196 drop Substances 0.000 description 1
238000000132 electrospray ionisation Methods 0.000 description 1
239000000839 emulsion Substances 0.000 description 1
210000001508 eye Anatomy 0.000 description 1
239000003889 eye drop Substances 0.000 description 1
229940012356 eye drops Drugs 0.000 description 1
238000011049 filling Methods 0.000 description 1
125000001153 fluoro group Chemical group F* 0.000 description 1
238000009472 formulation Methods 0.000 description 1
AWJWCTOOIBYHON-UHFFFAOYSA-N furo[3,4-b]pyrazine-5,7-dione Chemical compound C1=CN=C2C(=O)OC(=O)C2=N1 AWJWCTOOIBYHON-UHFFFAOYSA-N 0.000 description 1
125000002541 furyl group Chemical group 0.000 description 1
239000008273 gelatin Substances 0.000 description 1
229920000159 gelatin Polymers 0.000 description 1
235000019322 gelatine Nutrition 0.000 description 1
235000011852 gelatine desserts Nutrition 0.000 description 1
239000003365 glass fiber Substances 0.000 description 1
239000008103 glucose Substances 0.000 description 1
150000002334 glycols Chemical class 0.000 description 1
239000008187 granular material Substances 0.000 description 1
150000004795 grignard reagents Chemical class 0.000 description 1
239000001963 growth medium Substances 0.000 description 1
IDINUJSAMVOPCM-UHFFFAOYSA-N gusperimus Chemical compound NCCCNCCCCNC(=O)C(O)NC(=O)CCCCCCN=C(N)N IDINUJSAMVOPCM-UHFFFAOYSA-N 0.000 description 1
229910052736 halogen Inorganic materials 0.000 description 1
150000002367 halogens Chemical class 0.000 description 1
230000036541 health Effects 0.000 description 1
238000010438 heat treatment Methods 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
GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
230000003284 homeostatic effect Effects 0.000 description 1
230000009097 homeostatic mechanism Effects 0.000 description 1
150000004677 hydrates Chemical class 0.000 description 1
229930195733 hydrocarbon Natural products 0.000 description 1
238000000338 in vitro Methods 0.000 description 1
238000001727 in vivo Methods 0.000 description 1
125000001041 indolyl group Chemical group 0.000 description 1
210000004969 inflammatory cell Anatomy 0.000 description 1
238000001802 infusion Methods 0.000 description 1
230000004073 interleukin-2 production Effects 0.000 description 1
230000003834 intracellular effect Effects 0.000 description 1
238000007918 intramuscular administration Methods 0.000 description 1
238000007912 intraperitoneal administration Methods 0.000 description 1
238000001990 intravenous administration Methods 0.000 description 1
125000002346 iodo group Chemical group I* 0.000 description 1
230000019948 ion homeostasis Effects 0.000 description 1
PGHMRUGBZOYCAA-ADZNBVRBSA-N ionomycin Chemical compound O1[C@H](C[C@H](O)[C@H](C)[C@H](O)[C@H](C)/C=C/C[C@@H](C)C[C@@H](C)C(/O)=C/C(=O)[C@@H](C)C[C@@H](C)C[C@@H](CCC(O)=O)C)CC[C@@]1(C)[C@@H]1O[C@](C)([C@@H](C)O)CC1 PGHMRUGBZOYCAA-ADZNBVRBSA-N 0.000 description 1
PGHMRUGBZOYCAA-UHFFFAOYSA-N ionomycin Natural products O1C(CC(O)C(C)C(O)C(C)C=CCC(C)CC(C)C(O)=CC(=O)C(C)CC(C)CC(CCC(O)=O)C)CCC1(C)C1OC(C)(C(C)O)CC1 PGHMRUGBZOYCAA-UHFFFAOYSA-N 0.000 description 1
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
201000006370 kidney failure Diseases 0.000 description 1
229960000681 leflunomide Drugs 0.000 description 1
239000007788 liquid Substances 0.000 description 1
238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
238000005567 liquid scintillation counting Methods 0.000 description 1
230000003908 liver function Effects 0.000 description 1
229940049920 malate Drugs 0.000 description 1
VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
239000000463 material Substances 0.000 description 1
239000011159 matrix material Substances 0.000 description 1
239000002609 medium Substances 0.000 description 1
239000012528 membrane Substances 0.000 description 1
230000028161 membrane depolarization Effects 0.000 description 1
GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
229960002216 methylparaben Drugs 0.000 description 1
229940016286 microcrystalline cellulose Drugs 0.000 description 1
235000019813 microcrystalline cellulose Nutrition 0.000 description 1
239000008108 microcrystalline cellulose Substances 0.000 description 1
150000007522 mineralic acids Chemical class 0.000 description 1
230000004118 muscle contraction Effects 0.000 description 1
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 1
229960004866 mycophenolate mofetil Drugs 0.000 description 1
230000003589 nefrotoxic effect Effects 0.000 description 1
229940063121 neoral Drugs 0.000 description 1
231100000381 nephrotoxic Toxicity 0.000 description 1
231100000417 nephrotoxicity Toxicity 0.000 description 1
230000007694 nephrotoxicity Effects 0.000 description 1
230000000955 neuroendocrine Effects 0.000 description 1
210000002569 neuron Anatomy 0.000 description 1
230000007135 neurotoxicity Effects 0.000 description 1
231100000228 neurotoxicity Toxicity 0.000 description 1
125000004433 nitrogen atom Chemical group N* 0.000 description 1
125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 description 1
238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
239000012038 nucleophile Substances 0.000 description 1
OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
239000004006 olive oil Substances 0.000 description 1
235000008390 olive oil Nutrition 0.000 description 1
229940054534 ophthalmic solution Drugs 0.000 description 1
239000002997 ophthalmic solution Substances 0.000 description 1
229940100654 ophthalmic suspension Drugs 0.000 description 1
230000003287 optical effect Effects 0.000 description 1
150000007524 organic acids Chemical class 0.000 description 1
239000012285 osmium tetroxide Substances 0.000 description 1
229910000489 osmium tetroxide Inorganic materials 0.000 description 1
210000002997 osteoclast Anatomy 0.000 description 1
LPMXVESGRSUGHW-HBYQJFLCSA-N ouabain Chemical compound O[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1O[C@@H]1C[C@@]2(O)CC[C@H]3[C@@]4(O)CC[C@H](C=5COC(=O)C=5)[C@@]4(C)C[C@@H](O)[C@@H]3[C@@]2(CO)[C@H](O)C1 LPMXVESGRSUGHW-HBYQJFLCSA-N 0.000 description 1
229960003343 ouabain Drugs 0.000 description 1
239000007800 oxidant agent Substances 0.000 description 1
230000001590 oxidative effect Effects 0.000 description 1
238000007248 oxidative elimination reaction Methods 0.000 description 1
238000006385 ozonation reaction Methods 0.000 description 1
238000005949 ozonolysis reaction Methods 0.000 description 1
235000019629 palatability Nutrition 0.000 description 1
238000007911 parenteral administration Methods 0.000 description 1
230000008506 pathogenesis Effects 0.000 description 1
125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
125000004115 pentoxy group Chemical group [*]OC([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
210000005259 peripheral blood Anatomy 0.000 description 1
239000011886 peripheral blood Substances 0.000 description 1
210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 1
230000000144 pharmacologic effect Effects 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
230000035790 physiological processes and functions Effects 0.000 description 1
229920000573 polyethylene Polymers 0.000 description 1
230000003389 potentiating effect Effects 0.000 description 1
238000011533 pre-incubation Methods 0.000 description 1
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 1
229960005205 prednisolone Drugs 0.000 description 1
238000012746 preparative thin layer chromatography Methods 0.000 description 1
239000003755 preservative agent Substances 0.000 description 1
230000035755 proliferation Effects 0.000 description 1
239000003380 propellant Substances 0.000 description 1
125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
229960003415 propylparaben Drugs 0.000 description 1
125000003373 pyrazinyl group Chemical group 0.000 description 1
125000002098 pyridazinyl group Chemical group 0.000 description 1
125000004076 pyridyl group Chemical group 0.000 description 1
125000000714 pyrimidinyl group Chemical group 0.000 description 1
125000000168 pyrrolyl group Chemical group 0.000 description 1
125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
239000011541 reaction mixture Substances 0.000 description 1
230000009257 reactivity Effects 0.000 description 1
238000011160 research Methods 0.000 description 1
230000036390 resting membrane potential Effects 0.000 description 1
229910052701 rubidium Inorganic materials 0.000 description 1
229910001927 ruthenium tetroxide Inorganic materials 0.000 description 1
YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
229960001860 salicylate Drugs 0.000 description 1
229940063122 sandimmune Drugs 0.000 description 1
238000009738 saturating Methods 0.000 description 1
239000002795 scorpion venom Substances 0.000 description 1
238000012216 screening 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
150000003335 secondary amines Chemical class 0.000 description 1
229940098221 silver cyanide Drugs 0.000 description 1
229910001923 silver oxide Inorganic materials 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
229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
239000012419 sodium bis(2-methoxyethoxy)aluminum hydride Substances 0.000 description 1
235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
235000010265 sodium sulphite Nutrition 0.000 description 1
WISNYKIQFMKSDQ-UHFFFAOYSA-N sodium;6-(3-methyl-5-nitroimidazol-4-yl)sulfanylpurin-9-ide Chemical compound [Na+].CN1C=NC([N+]([O-])=O)=C1SC1=NC=NC2=C1[N-]C=N2 WISNYKIQFMKSDQ-UHFFFAOYSA-N 0.000 description 1
239000007909 solid dosage form Substances 0.000 description 1
239000012453 solvate Substances 0.000 description 1
239000000600 sorbitol Substances 0.000 description 1
239000003549 soybean oil Substances 0.000 description 1
235000012424 soybean oil Nutrition 0.000 description 1
238000010561 standard procedure Methods 0.000 description 1
239000007858 starting material Substances 0.000 description 1
239000008117 stearic acid Substances 0.000 description 1
238000007920 subcutaneous administration Methods 0.000 description 1
239000000758 substrate Substances 0.000 description 1
KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
150000003871 sulfonates Chemical class 0.000 description 1
YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical class ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
239000006228 supernatant Substances 0.000 description 1
239000000829 suppository Substances 0.000 description 1
238000013268 sustained release Methods 0.000 description 1
239000012730 sustained-release form Substances 0.000 description 1
239000006188 syrup Substances 0.000 description 1
235000020357 syrup Nutrition 0.000 description 1
229940095064 tartrate Drugs 0.000 description 1
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 1
125000001544 thienyl group Chemical group 0.000 description 1
229940104230 thymidine Drugs 0.000 description 1
JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
238000011200 topical administration Methods 0.000 description 1
230000000699 topical effect Effects 0.000 description 1
HYWCXWRMUZYRPH-UHFFFAOYSA-N trimethyl(prop-2-enyl)silane Chemical compound C[Si](C)(C)CC=C HYWCXWRMUZYRPH-UHFFFAOYSA-N 0.000 description 1
UYPYRKYUKCHHIB-UHFFFAOYSA-N trimethylamine N-oxide Chemical compound C[N+](C)(C)[O-] UYPYRKYUKCHHIB-UHFFFAOYSA-N 0.000 description 1
125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
WMSKLFZMWPHWJI-UHFFFAOYSA-N tris(phenoxymethyl)phosphanium;iodide Chemical compound [I-].C=1C=CC=CC=1OC[PH+](COC=1C=CC=CC=1)COC1=CC=CC=C1 WMSKLFZMWPHWJI-UHFFFAOYSA-N 0.000 description 1
238000002211 ultraviolet spectrum Methods 0.000 description 1
MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 1
FGQOOHJZONJGDT-UHFFFAOYSA-N vanillin Natural products COC1=CC(O)=CC(C=O)=C1 FGQOOHJZONJGDT-UHFFFAOYSA-N 0.000 description 1
235000012141 vanillin Nutrition 0.000 description 1
239000003981 vehicle Substances 0.000 description 1
239000008215 water for injection Substances 0.000 description 1
238000010626 work up procedure Methods 0.000 description 1