NZ711794B2 - Dipeptide and tripeptide epoxy ketone protease inhibitors - Google Patents
Dipeptide and tripeptide epoxy ketone protease inhibitors Download PDFInfo
- Publication number
- NZ711794B2 NZ711794B2 NZ711794A NZ71179414A NZ711794B2 NZ 711794 B2 NZ711794 B2 NZ 711794B2 NZ 711794 A NZ711794 A NZ 711794A NZ 71179414 A NZ71179414 A NZ 71179414A NZ 711794 B2 NZ711794 B2 NZ 711794B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- compound
- mmol
- disease
- amino
- oxopropanyl
- Prior art date
Links
- CURLTUGMZLYLDI-UHFFFAOYSA-N epoxyketone group Chemical group O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 title abstract description 7
- 108010016626 Dipeptides Proteins 0.000 title abstract description 4
- 229940042399 direct acting antivirals Protease inhibitors Drugs 0.000 title abstract description 4
- 239000000137 peptide hydrolase inhibitor Substances 0.000 title abstract description 4
- 239000000203 mixture Substances 0.000 claims abstract description 214
- 150000001875 compounds Chemical class 0.000 claims abstract description 165
- 201000010099 disease Diseases 0.000 claims abstract description 53
- 239000011780 sodium chloride Substances 0.000 claims abstract description 40
- 150000003839 salts Chemical class 0.000 claims abstract description 39
- 201000011510 cancer Diseases 0.000 claims abstract description 23
- 206010003816 Autoimmune disease Diseases 0.000 claims abstract description 10
- -1 C1-6aralkyl Chemical group 0.000 claims description 183
- 210000004027 cells Anatomy 0.000 claims description 71
- 230000002401 inhibitory effect Effects 0.000 claims description 51
- 229910052739 hydrogen Inorganic materials 0.000 claims description 47
- 239000001257 hydrogen Substances 0.000 claims description 44
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 41
- 125000003118 aryl group Chemical group 0.000 claims description 35
- 125000001072 heteroaryl group Chemical group 0.000 claims description 32
- 150000002431 hydrogen Chemical group 0.000 claims description 21
- 125000001424 substituent group Chemical group 0.000 claims description 20
- 125000000623 heterocyclic group Chemical group 0.000 claims description 19
- 229910052760 oxygen Inorganic materials 0.000 claims description 19
- 125000000217 alkyl group Chemical group 0.000 claims description 16
- 239000003814 drug Substances 0.000 claims description 15
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 14
- 210000000056 organs Anatomy 0.000 claims description 12
- 230000001404 mediated Effects 0.000 claims description 11
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 230000001684 chronic Effects 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 7
- 229910052717 sulfur Inorganic materials 0.000 claims description 7
- 206010061218 Inflammation Diseases 0.000 claims description 6
- 206010022114 Injury Diseases 0.000 claims description 6
- 229940035295 Ting Drugs 0.000 claims description 6
- 125000003342 alkenyl group Chemical group 0.000 claims description 6
- 125000004452 carbocyclyl group Chemical group 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- 230000004054 inflammatory process Effects 0.000 claims description 6
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 6
- 210000003169 Central Nervous System Anatomy 0.000 claims description 5
- 201000009596 autoimmune hypersensitivity disease Diseases 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 150000003951 lactams Chemical class 0.000 claims description 5
- 201000010874 syndrome Diseases 0.000 claims description 5
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 claims description 4
- 108010047814 Antigen-Antibody Complex Proteins 0.000 claims description 4
- 208000006673 Asthma Diseases 0.000 claims description 4
- 206010012601 Diabetes mellitus Diseases 0.000 claims description 4
- 206010021972 Inflammatory bowel disease Diseases 0.000 claims description 4
- 208000002098 Purpura, Thrombocytopenic, Idiopathic Diseases 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-K [O-]P([O-])([O-])=O Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 4
- 125000003368 amide group Chemical group 0.000 claims description 4
- 201000008937 atopic dermatitis Diseases 0.000 claims description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 4
- 201000004624 dermatitis Diseases 0.000 claims description 4
- 150000002596 lactones Chemical class 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 201000006417 multiple sclerosis Diseases 0.000 claims description 4
- 239000010452 phosphate Substances 0.000 claims description 4
- 201000004681 psoriasis Diseases 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 4
- 206010009900 Colitis ulcerative Diseases 0.000 claims description 3
- 206010011401 Crohn's disease Diseases 0.000 claims description 3
- 210000000265 Leukocytes Anatomy 0.000 claims description 3
- 206010060862 Prostate cancer Diseases 0.000 claims description 3
- LSNNMFCWUKXFEE-UHFFFAOYSA-L Sulphite Chemical compound [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 claims description 3
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims description 3
- 125000000304 alkynyl group Chemical group 0.000 claims description 3
- 230000000172 allergic Effects 0.000 claims description 3
- 150000001409 amidines Chemical class 0.000 claims description 3
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 3
- 125000005418 aryl aryl group Chemical group 0.000 claims description 3
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 125000004475 heteroaralkyl group Chemical group 0.000 claims description 3
- 150000002466 imines Chemical class 0.000 claims description 3
- 125000002757 morpholinyl group Chemical group 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- LFGREXWGYUGZLY-UHFFFAOYSA-N oxophosphanyl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 claims description 3
- ACVYVLVWPXVTIT-UHFFFAOYSA-M phosphinate Chemical compound [O-][PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-M 0.000 claims description 3
- 125000004193 piperazinyl group Chemical group 0.000 claims description 3
- 125000003386 piperidinyl group Chemical group 0.000 claims description 3
- 201000000306 sarcoidosis Diseases 0.000 claims description 3
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 claims description 3
- 201000009594 systemic scleroderma Diseases 0.000 claims description 3
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 claims description 3
- 201000008827 tuberculosis Diseases 0.000 claims description 3
- 201000006704 ulcerative colitis Diseases 0.000 claims description 3
- 201000004304 Addison's disease Diseases 0.000 claims description 2
- 208000007502 Anemia Diseases 0.000 claims description 2
- 208000003343 Antiphospholipid Syndrome Diseases 0.000 claims description 2
- 206010003210 Arteriosclerosis Diseases 0.000 claims description 2
- 208000005783 Autoimmune Thyroiditis Diseases 0.000 claims description 2
- 206010050245 Autoimmune thrombocytopenia Diseases 0.000 claims description 2
- 206010004161 Basedow's disease Diseases 0.000 claims description 2
- 208000000594 Bullous Pemphigoid Diseases 0.000 claims description 2
- 206010009887 Colitis Diseases 0.000 claims description 2
- 206010051392 Diapedesis Diseases 0.000 claims description 2
- 208000005679 Eczema Diseases 0.000 claims description 2
- 206010014599 Encephalitis Diseases 0.000 claims description 2
- 208000007465 Giant Cell Arteritis Diseases 0.000 claims description 2
- 206010018364 Glomerulonephritis Diseases 0.000 claims description 2
- 208000003807 Graves Disease Diseases 0.000 claims description 2
- 201000004779 Graves' disease Diseases 0.000 claims description 2
- 208000007475 Hemolytic Anemia Diseases 0.000 claims description 2
- 208000010159 IGA Glomerulonephritis Diseases 0.000 claims description 2
- 206010021263 IgA nephropathy Diseases 0.000 claims description 2
- 206010025135 Lupus erythematosus Diseases 0.000 claims description 2
- 206010028417 Myasthenia gravis Diseases 0.000 claims description 2
- 206010029240 Neuritis Diseases 0.000 claims description 2
- 206010034277 Pemphigoid Diseases 0.000 claims description 2
- 241000721454 Pemphigus Species 0.000 claims description 2
- 208000005987 Polymyositis Diseases 0.000 claims description 2
- 208000004358 Polyneuropathy Diseases 0.000 claims description 2
- 208000002574 Reactive Arthritis Diseases 0.000 claims description 2
- 206010038294 Reiter's syndrome Diseases 0.000 claims description 2
- 206010072148 Stiff person syndrome Diseases 0.000 claims description 2
- 206010043207 Temporal arteritis Diseases 0.000 claims description 2
- 206010046851 Uveitis Diseases 0.000 claims description 2
- 206010047115 Vasculitis Diseases 0.000 claims description 2
- 125000004414 alkyl thio group Chemical group 0.000 claims description 2
- 201000001320 atherosclerosis Diseases 0.000 claims description 2
- 231100000406 dermatitis Toxicity 0.000 claims description 2
- 231100001003 eczema Toxicity 0.000 claims description 2
- 230000000366 juvenile Effects 0.000 claims description 2
- 201000001779 leukocyte adhesion deficiency Diseases 0.000 claims description 2
- 201000009906 meningitis Diseases 0.000 claims description 2
- 201000008383 nephritis Diseases 0.000 claims description 2
- NJRWNWYFPOFDFN-UHFFFAOYSA-L phosphonate(2-) Chemical compound [O-][P]([O-])=O NJRWNWYFPOFDFN-UHFFFAOYSA-L 0.000 claims description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 2
- 206010039073 Rheumatoid arthritis Diseases 0.000 claims 3
- 206010028424 Myasthenic syndrome Diseases 0.000 claims 1
- 201000002491 encephalomyelitis Diseases 0.000 claims 1
- 200000000018 inflammatory disease Diseases 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 28
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 22
- 230000002062 proliferating Effects 0.000 abstract description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 154
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 87
- 238000005160 1H NMR spectroscopy Methods 0.000 description 85
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 83
- 239000000243 solution Substances 0.000 description 83
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N DMSO-d6 Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 72
- 235000019439 ethyl acetate Nutrition 0.000 description 70
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 65
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 57
- JNWBBCNCSMBKNE-UHFFFAOYSA-N HATU Chemical compound F[P-](F)(F)(F)(F)F.C1=CN=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 JNWBBCNCSMBKNE-UHFFFAOYSA-N 0.000 description 54
- 239000011541 reaction mixture Substances 0.000 description 51
- 102000004245 Proteasome Endopeptidase Complex Human genes 0.000 description 50
- 108090000708 Proteasome Endopeptidase Complex Proteins 0.000 description 50
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 49
- 229910001868 water Inorganic materials 0.000 description 49
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 48
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 47
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 46
- 239000000741 silica gel Substances 0.000 description 44
- 229910002027 silica gel Inorganic materials 0.000 description 44
- 238000003818 flash chromatography Methods 0.000 description 42
- 239000002253 acid Substances 0.000 description 39
- 239000012267 brine Substances 0.000 description 37
- 229910052938 sodium sulfate Inorganic materials 0.000 description 37
- 235000011152 sodium sulphate Nutrition 0.000 description 37
- 239000007787 solid Substances 0.000 description 36
- 235000002639 sodium chloride Nutrition 0.000 description 33
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 32
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 31
- WMFOQBRAJBCJND-UHFFFAOYSA-M lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 29
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 28
- 238000000746 purification Methods 0.000 description 28
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 26
- 235000018102 proteins Nutrition 0.000 description 24
- 102000004169 proteins and genes Human genes 0.000 description 24
- 108090000623 proteins and genes Proteins 0.000 description 24
- 239000003795 chemical substances by application Substances 0.000 description 23
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 23
- 238000007792 addition Methods 0.000 description 22
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 22
- 239000003921 oil Substances 0.000 description 22
- 239000012074 organic phase Substances 0.000 description 22
- UIIMBOGNXHQVGW-UHFFFAOYSA-M buffer Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 21
- 235000019198 oils Nutrition 0.000 description 21
- 239000003112 inhibitor Substances 0.000 description 20
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 19
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 19
- 239000000725 suspension Substances 0.000 description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
- 230000000694 effects Effects 0.000 description 17
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 17
- 230000002797 proteolythic Effects 0.000 description 17
- 238000003756 stirring Methods 0.000 description 17
- 101700067048 CDC13 Proteins 0.000 description 16
- 102000004190 Enzymes Human genes 0.000 description 16
- 108090000790 Enzymes Proteins 0.000 description 16
- 239000000706 filtrate Substances 0.000 description 16
- 239000008079 hexane Substances 0.000 description 16
- 239000006166 lysate Substances 0.000 description 16
- 230000015556 catabolic process Effects 0.000 description 15
- 230000004059 degradation Effects 0.000 description 15
- 238000006731 degradation reaction Methods 0.000 description 15
- 239000000543 intermediate Substances 0.000 description 15
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 14
- 239000007832 Na2SO4 Substances 0.000 description 14
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 14
- KXDHJXZQYSOELW-UHFFFAOYSA-M carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 14
- 239000002904 solvent Substances 0.000 description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 14
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 13
- 239000003208 petroleum Substances 0.000 description 13
- 206010028980 Neoplasm Diseases 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- 239000008346 aqueous phase Substances 0.000 description 12
- 125000004122 cyclic group Chemical group 0.000 description 12
- 239000000463 material Substances 0.000 description 12
- SJRJJKPEHAURKC-UHFFFAOYSA-N n-methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 12
- 239000000126 substance Substances 0.000 description 12
- 239000000969 carrier Substances 0.000 description 11
- 230000000875 corresponding Effects 0.000 description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 11
- 239000000284 extract Substances 0.000 description 11
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 11
- 238000000034 method Methods 0.000 description 11
- 229910052757 nitrogen Inorganic materials 0.000 description 11
- 239000000843 powder Substances 0.000 description 11
- 210000001519 tissues Anatomy 0.000 description 11
- 210000000988 Bone and Bones Anatomy 0.000 description 10
- 108050006400 Cyclins Proteins 0.000 description 10
- 102000016736 Cyclins Human genes 0.000 description 10
- 239000004480 active ingredient Substances 0.000 description 10
- 125000004429 atoms Chemical group 0.000 description 10
- 125000000753 cycloalkyl group Chemical group 0.000 description 10
- 230000014509 gene expression Effects 0.000 description 10
- 239000007788 liquid Substances 0.000 description 10
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium;hydroxide;hydrate Chemical compound [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 10
- 239000012044 organic layer Substances 0.000 description 10
- VZCGEDTVPJTYHY-UHFFFAOYSA-N propanamide Chemical compound CCC(N)=O.CCC(N)=O VZCGEDTVPJTYHY-UHFFFAOYSA-N 0.000 description 10
- 239000003207 proteasome inhibitor Substances 0.000 description 10
- RMAQACBXLXPBSY-UHFFFAOYSA-N Silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 9
- 102100019730 TP53 Human genes 0.000 description 9
- 101710026335 TP53 Proteins 0.000 description 9
- 235000001014 amino acid Nutrition 0.000 description 9
- 229910052799 carbon Inorganic materials 0.000 description 9
- 125000000392 cycloalkenyl group Chemical group 0.000 description 9
- 201000009910 diseases by infectious agent Diseases 0.000 description 9
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 description 9
- 229920001223 polyethylene glycol Polymers 0.000 description 9
- XBDQKXXYIPTUBI-UHFFFAOYSA-M propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 9
- 230000017854 proteolysis Effects 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 9
- 230000004913 activation Effects 0.000 description 8
- 150000001413 amino acids Chemical class 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 8
- 239000010410 layer Substances 0.000 description 8
- 238000004949 mass spectrometry Methods 0.000 description 8
- 239000012071 phase Substances 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- 239000011734 sodium Substances 0.000 description 8
- 235000017557 sodium bicarbonate Nutrition 0.000 description 8
- 239000003826 tablet Substances 0.000 description 8
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 8
- 241000282414 Homo sapiens Species 0.000 description 7
- 206010035226 Plasma cell myeloma Diseases 0.000 description 7
- 229940083542 Sodium Drugs 0.000 description 7
- 230000027455 binding Effects 0.000 description 7
- 239000002775 capsule Substances 0.000 description 7
- 125000004432 carbon atoms Chemical group C* 0.000 description 7
- 235000019441 ethanol Nutrition 0.000 description 7
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 7
- 230000028993 immune response Effects 0.000 description 7
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 7
- 201000003793 myelodysplastic syndrome Diseases 0.000 description 7
- 239000001301 oxygen Substances 0.000 description 7
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical group O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 7
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 7
- 229910052708 sodium Inorganic materials 0.000 description 7
- 239000000758 substrate Substances 0.000 description 7
- 239000000829 suppository Substances 0.000 description 7
- 230000001225 therapeutic Effects 0.000 description 7
- 230000003612 virological Effects 0.000 description 7
- 210000004369 Blood Anatomy 0.000 description 6
- 108010010803 Gelatin Proteins 0.000 description 6
- 210000002216 Heart Anatomy 0.000 description 6
- 229940088597 Hormone Drugs 0.000 description 6
- 241000725303 Human immunodeficiency virus Species 0.000 description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N MeOtBu Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 6
- CHKVPAROMQMJNQ-UHFFFAOYSA-M Potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 6
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 6
- 239000012298 atmosphere Substances 0.000 description 6
- 239000008280 blood Substances 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- 239000012230 colorless oil Substances 0.000 description 6
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 239000002552 dosage form Substances 0.000 description 6
- 229940079593 drugs Drugs 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 239000008273 gelatin Substances 0.000 description 6
- 229920000159 gelatin Polymers 0.000 description 6
- 235000019322 gelatine Nutrition 0.000 description 6
- 235000011852 gelatine desserts Nutrition 0.000 description 6
- 125000005842 heteroatoms Chemical group 0.000 description 6
- 239000005556 hormone Substances 0.000 description 6
- 238000000338 in vitro Methods 0.000 description 6
- 201000009251 multiple myeloma Diseases 0.000 description 6
- 201000007224 myeloproliferative neoplasm Diseases 0.000 description 6
- 239000002674 ointment Substances 0.000 description 6
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 6
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 6
- 230000002265 prevention Effects 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 230000001105 regulatory Effects 0.000 description 6
- 239000007921 spray Substances 0.000 description 6
- 235000000346 sugar Nutrition 0.000 description 6
- 230000020382 suppression by virus of host antigen processing and presentation of peptide antigen via MHC class I Effects 0.000 description 6
- 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 6
- BMTZEAOGFDXDAD-UHFFFAOYSA-M 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium;chloride Chemical compound [Cl-].COC1=NC(OC)=NC([N+]2(C)CCOCC2)=N1 BMTZEAOGFDXDAD-UHFFFAOYSA-M 0.000 description 5
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 description 5
- CZMRCDWAGMRECN-UGDNZRGBSA-N D-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 5
- 241000206602 Eukaryota Species 0.000 description 5
- 206010016654 Fibrosis Diseases 0.000 description 5
- 101700006721 LMP2 Proteins 0.000 description 5
- 102100018286 PSMB8 Human genes 0.000 description 5
- 101710033537 PSMB8 Proteins 0.000 description 5
- 102100018285 PSMB9 Human genes 0.000 description 5
- 101710033536 PSMB9 Proteins 0.000 description 5
- 239000002202 Polyethylene glycol Substances 0.000 description 5
- 210000003491 Skin Anatomy 0.000 description 5
- CZMRCDWAGMRECN-GDQSFJPYSA-N Sucrose Natural products O([C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1)[C@@]1(CO)[C@H](O)[C@@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-GDQSFJPYSA-N 0.000 description 5
- 238000010521 absorption reaction Methods 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-M acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 5
- 239000000443 aerosol Substances 0.000 description 5
- 230000000111 anti-oxidant Effects 0.000 description 5
- 230000030741 antigen processing and presentation Effects 0.000 description 5
- 239000003963 antioxidant agent Substances 0.000 description 5
- 235000006708 antioxidants Nutrition 0.000 description 5
- 239000011230 binding agent Substances 0.000 description 5
- 238000004166 bioassay Methods 0.000 description 5
- 230000001413 cellular Effects 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 5
- 230000001419 dependent Effects 0.000 description 5
- 239000003995 emulsifying agent Substances 0.000 description 5
- 239000002158 endotoxin Substances 0.000 description 5
- 230000004761 fibrosis Effects 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 229910052731 fluorine Inorganic materials 0.000 description 5
- 239000011737 fluorine Substances 0.000 description 5
- YCKRFDGAMUMZLT-UHFFFAOYSA-N fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 5
- 238000005755 formation reaction Methods 0.000 description 5
- 239000000499 gel Substances 0.000 description 5
- 235000011187 glycerol Nutrition 0.000 description 5
- 239000004615 ingredient Substances 0.000 description 5
- 230000003834 intracellular Effects 0.000 description 5
- 150000002500 ions Chemical class 0.000 description 5
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 5
- 244000045947 parasites Species 0.000 description 5
- 239000002245 particle Substances 0.000 description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
- 235000019260 propionic acid Nutrition 0.000 description 5
- XBDQKXXYIPTUBI-UHFFFAOYSA-N propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- 230000002829 reduced Effects 0.000 description 5
- 239000005720 sucrose Substances 0.000 description 5
- 150000008163 sugars Chemical class 0.000 description 5
- XJKJWTWGDGIQRH-BFIDDRIFSA-N Alginic acid Chemical compound O1[C@@H](C(O)=O)[C@@H](OC)[C@H](O)[C@H](O)[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](C)[C@@H](O)[C@H]1O XJKJWTWGDGIQRH-BFIDDRIFSA-N 0.000 description 4
- 206010059512 Apoptosis Diseases 0.000 description 4
- 241000416162 Astragalus gummifer Species 0.000 description 4
- SESFRYSPDFLNCH-UHFFFAOYSA-N Benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 4
- 210000001185 Bone Marrow Anatomy 0.000 description 4
- 102000007350 Bone Morphogenetic Proteins Human genes 0.000 description 4
- 108010007726 Bone Morphogenetic Proteins Proteins 0.000 description 4
- 229940112869 Bone morphogenetic proteins Drugs 0.000 description 4
- 206010012289 Dementia Diseases 0.000 description 4
- RAXXELZNTBOGNW-UHFFFAOYSA-N Imidazole Chemical compound C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 4
- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 description 4
- 206010024324 Leukaemias Diseases 0.000 description 4
- 206010061232 Lymphoproliferative disease Diseases 0.000 description 4
- 208000008585 Mastocytosis Diseases 0.000 description 4
- 210000003205 Muscles Anatomy 0.000 description 4
- 206010028576 Myeloproliferative disease Diseases 0.000 description 4
- 208000006551 Parasitic Disease Diseases 0.000 description 4
- 240000004713 Pisum sativum Species 0.000 description 4
- 235000010582 Pisum sativum Nutrition 0.000 description 4
- 102000001253 Protein Kinases Human genes 0.000 description 4
- JNYAEWCLZODPBN-CTQIIAAMSA-N Sorbitan Chemical compound OCC(O)C1OCC(O)[C@@H]1O JNYAEWCLZODPBN-CTQIIAAMSA-N 0.000 description 4
- 210000001744 T-Lymphocytes Anatomy 0.000 description 4
- 206010042971 T-cell lymphoma Diseases 0.000 description 4
- 229920001615 Tragacanth Polymers 0.000 description 4
- 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 4
- UQYZFNUUOSSNKT-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium;hexafluorophosphate Chemical compound F[P-](F)(F)(F)(F)F.C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 UQYZFNUUOSSNKT-UHFFFAOYSA-N 0.000 description 4
- 230000001154 acute Effects 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 239000000427 antigen Substances 0.000 description 4
- 108091007172 antigens Proteins 0.000 description 4
- 102000038129 antigens Human genes 0.000 description 4
- 230000006907 apoptotic process Effects 0.000 description 4
- 210000002449 bone cell Anatomy 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 230000003197 catalytic Effects 0.000 description 4
- 230000024881 catalytic activity Effects 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 230000001808 coupling Effects 0.000 description 4
- 238000010168 coupling process Methods 0.000 description 4
- 238000005859 coupling reaction Methods 0.000 description 4
- 239000006071 cream Substances 0.000 description 4
- 239000006185 dispersion Substances 0.000 description 4
- 238000003379 elimination reaction Methods 0.000 description 4
- KVXNKFYSHAUJIA-UHFFFAOYSA-M ethoxyethane;acetate Chemical compound CC([O-])=O.CCOCC KVXNKFYSHAUJIA-UHFFFAOYSA-M 0.000 description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- 150000002430 hydrocarbons Chemical class 0.000 description 4
- 239000003701 inert diluent Substances 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- GUBGYTABKSRVRQ-XLOQQCSPSA-N 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
- 239000008101 lactose Substances 0.000 description 4
- 239000002502 liposome Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 230000000269 nucleophilic Effects 0.000 description 4
- 125000004043 oxo group Chemical group O=* 0.000 description 4
- 238000007911 parenteral administration Methods 0.000 description 4
- 230000037361 pathway Effects 0.000 description 4
- 239000006187 pill Substances 0.000 description 4
- 229920000120 polyethyl acrylate Polymers 0.000 description 4
- 239000003755 preservative agent Substances 0.000 description 4
- 102000004196 processed proteins & peptides Human genes 0.000 description 4
- 108090000765 processed proteins & peptides Proteins 0.000 description 4
- 230000002035 prolonged Effects 0.000 description 4
- 201000003176 severe acute respiratory syndrome Diseases 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- 238000006467 substitution reaction Methods 0.000 description 4
- 201000008736 systemic mastocytosis Diseases 0.000 description 4
- 239000000454 talc Substances 0.000 description 4
- 229910052623 talc Inorganic materials 0.000 description 4
- 235000012222 talc Nutrition 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- 239000001993 wax Substances 0.000 description 4
- 239000011701 zinc Substances 0.000 description 4
- ZJTDCIZEZMJDEN-UHFFFAOYSA-N (4-methoxyphenyl) propanoate Chemical compound CCC(=O)OC1=CC=C(OC)C=C1 ZJTDCIZEZMJDEN-UHFFFAOYSA-N 0.000 description 3
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 description 3
- 125000006718 (C3-C7) heterocycloalkenyl group Chemical group 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 description 3
- DYCLHZPOADTVKK-UHFFFAOYSA-N 2-(2-azaniumyl-1,3-thiazol-4-yl)acetate Chemical compound NC1=NC(CC(O)=O)=CS1 DYCLHZPOADTVKK-UHFFFAOYSA-N 0.000 description 3
- JCLFHZLOKITRCE-UHFFFAOYSA-N 4-pentoxyphenol Chemical compound CCCCCOC1=CC=C(O)C=C1 JCLFHZLOKITRCE-UHFFFAOYSA-N 0.000 description 3
- 108010022579 ATP dependent 26S protease Proteins 0.000 description 3
- 229920001817 Agar Polymers 0.000 description 3
- 208000003950 B-Cell Lymphoma Diseases 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 3
- 230000037010 Beta Effects 0.000 description 3
- 102000004127 Cytokines Human genes 0.000 description 3
- 108090000695 Cytokines Proteins 0.000 description 3
- FBPFZTCFMRRESA-KAZBKCHUSA-N D-Mannitol Natural products OC[C@@H](O)[C@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KAZBKCHUSA-N 0.000 description 3
- 210000003238 Esophagus Anatomy 0.000 description 3
- 208000006800 Gastro-enteropancreatic neuroendocrine tumor Diseases 0.000 description 3
- 241000700721 Hepatitis B virus Species 0.000 description 3
- 210000000987 Immune System Anatomy 0.000 description 3
- 102000000588 Interleukin-2 Human genes 0.000 description 3
- 108010002350 Interleukin-2 Proteins 0.000 description 3
- 108090001005 Interleukin-6 Proteins 0.000 description 3
- 241000229754 Iva xanthiifolia Species 0.000 description 3
- 229940067606 Lecithin Drugs 0.000 description 3
- 208000000429 Leukemia, Lymphocytic, Chronic, B-Cell Diseases 0.000 description 3
- 210000004185 Liver Anatomy 0.000 description 3
- 210000004698 Lymphocytes Anatomy 0.000 description 3
- 206010025323 Lymphomas Diseases 0.000 description 3
- 206010024579 Lysosomal storage disease Diseases 0.000 description 3
- FBPFZTCFMRRESA-KVTDHHQDSA-N Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 3
- FEWJPZIEWOKRBE-XIXRPRMCSA-N Mesotartaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-XIXRPRMCSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 241000711466 Murine hepatitis virus Species 0.000 description 3
- 206010028289 Muscle atrophy Diseases 0.000 description 3
- 206010053643 Neurodegenerative disease Diseases 0.000 description 3
- 206010025310 Other lymphomas Diseases 0.000 description 3
- 108010035766 P-Selectin Proteins 0.000 description 3
- 229920000954 Polyglycolide Polymers 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
- 108060006633 Protein Kinases Proteins 0.000 description 3
- 102100003519 SELP Human genes 0.000 description 3
- 206010040070 Septic shock Diseases 0.000 description 3
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 229940116362 Tragacanth Drugs 0.000 description 3
- 108090000848 Ubiquitin Proteins 0.000 description 3
- 102400000757 Ubiquitin Human genes 0.000 description 3
- 206010047461 Viral infection Diseases 0.000 description 3
- 208000001756 Virus Disease Diseases 0.000 description 3
- 241000209149 Zea Species 0.000 description 3
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 3
- 238000009825 accumulation Methods 0.000 description 3
- 239000002671 adjuvant Substances 0.000 description 3
- 230000000240 adjuvant Effects 0.000 description 3
- 235000010419 agar Nutrition 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 230000000259 anti-tumor Effects 0.000 description 3
- 229960000070 antineoplastic Monoclonal antibodies Drugs 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 235000012216 bentonite Nutrition 0.000 description 3
- MJSHDCCLFGOEIK-UHFFFAOYSA-N benzyl (2,5-dioxopyrrolidin-1-yl) carbonate Chemical compound O=C1CCC(=O)N1OC(=O)OCC1=CC=CC=C1 MJSHDCCLFGOEIK-UHFFFAOYSA-N 0.000 description 3
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 3
- 230000033228 biological regulation Effects 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 239000001768 carboxy methyl cellulose Substances 0.000 description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N cdcl3 Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 3
- 230000021164 cell adhesion Effects 0.000 description 3
- 230000022131 cell cycle Effects 0.000 description 3
- 230000000973 chemotherapeutic Effects 0.000 description 3
- 238000004296 chiral HPLC 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
- 101700016683 cnn Proteins 0.000 description 3
- 239000003086 colorant Substances 0.000 description 3
- 235000005822 corn Nutrition 0.000 description 3
- 235000005824 corn Nutrition 0.000 description 3
- 230000026374 cyclin catabolic process Effects 0.000 description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 239000003623 enhancer Substances 0.000 description 3
- 230000002708 enhancing Effects 0.000 description 3
- FFLYUXVZEPLMCL-UHFFFAOYSA-N ethylchloranuidyl formate Chemical compound CC[Cl-]OC=O FFLYUXVZEPLMCL-UHFFFAOYSA-N 0.000 description 3
- 239000000796 flavoring agent Substances 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 230000012010 growth Effects 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 3
- 230000003463 hyperproliferative Effects 0.000 description 3
- 230000028709 inflammatory response Effects 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 239000000787 lecithin Substances 0.000 description 3
- 235000010445 lecithin Nutrition 0.000 description 3
- 239000006210 lotion Substances 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 230000003211 malignant Effects 0.000 description 3
- 239000000594 mannitol Substances 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- 150000004702 methyl esters Chemical class 0.000 description 3
- 108010045030 monoclonal antibodies Proteins 0.000 description 3
- 229960000060 monoclonal antibodies Drugs 0.000 description 3
- 102000005614 monoclonal antibodies Human genes 0.000 description 3
- 201000000585 muscular atrophy Diseases 0.000 description 3
- 230000003000 nontoxic Effects 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 239000004006 olive oil Substances 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 230000011164 ossification Effects 0.000 description 3
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 3
- 239000006072 paste Substances 0.000 description 3
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 230000002335 preservative Effects 0.000 description 3
- 230000035755 proliferation Effects 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 230000036303 septic shock Effects 0.000 description 3
- 235000012239 silicon dioxide Nutrition 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 230000002194 synthesizing Effects 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- 230000000699 topical Effects 0.000 description 3
- 235000010487 tragacanth Nutrition 0.000 description 3
- 239000000196 tragacanth Substances 0.000 description 3
- 230000001131 transforming Effects 0.000 description 3
- 230000001810 trypsinlike Effects 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- 230000017613 viral reproduction Effects 0.000 description 3
- SHLYZEAOVWVTSW-SCSAIBSYSA-N (2R)-1-methyl-5-oxopyrrolidine-2-carboxylic acid Chemical compound CN1[C@@H](C(O)=O)CCC1=O SHLYZEAOVWVTSW-SCSAIBSYSA-N 0.000 description 2
- QVHJQCGUWFKTSE-YFKPBYRVSA-N (2S)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound OC(=O)[C@H](C)NC(=O)OC(C)(C)C QVHJQCGUWFKTSE-YFKPBYRVSA-N 0.000 description 2
- CFCUWKMKBJTWLW-BGLFSJPPSA-N (2S,3S)-2-[(2S,4R,5R,6R)-4-[(2S,4R,5R,6R)-4-[(2S,4S,5R,6R)-4,5-dihydroxy-4,6-dimethyloxan-2-yl]oxy-5-hydroxy-6-methyloxan-2-yl]oxy-5-hydroxy-6-methyloxan-2-yl]oxy-3-[(1S,3S,4R)-3,4-dihydroxy-1-methoxy-2-oxopentyl]-6-[(2S,4R,5S,6R)-4-[(2S,4R,5S,6R)-4,5-dih 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-BGLFSJPPSA-N 0.000 description 2
- GWQBXRYSVSZLSL-NJXYFUOMSA-N (7aR)-3-(trichloromethyl)-5,6,7,7a-tetrahydro-3H-pyrrolo[1,2-c][1,3]oxazol-1-one Chemical compound C1CCN2C(C(Cl)(Cl)Cl)OC(=O)[C@H]21 GWQBXRYSVSZLSL-NJXYFUOMSA-N 0.000 description 2
- CQNBNGSUEQTECE-NQPNHJOESA-N (7aR)-7a-methyl-3-(trichloromethyl)-3,5,6,7-tetrahydropyrrolo[1,2-c][1,3]oxazol-1-one Chemical compound C1CCN2C(C(Cl)(Cl)Cl)OC(=O)[C@]21C CQNBNGSUEQTECE-NQPNHJOESA-N 0.000 description 2
- HPXNTHKXCYMIJL-UHFFFAOYSA-N 1,1'-bis(diphenylphosphanyl)ferrocene Chemical compound C12C3C4C5[Fe]4322346(C7(C2C6C4C37)P(C=2C=CC=CC=2)C=2C=CC=CC=2)C15P(C=1C=CC=CC=1)C1=CC=CC=C1 HPXNTHKXCYMIJL-UHFFFAOYSA-N 0.000 description 2
- PIICEJLVQHRZGT-UHFFFAOYSA-N 1,2-ethanediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 2
- 102000010400 1-phosphatidylinositol-3-kinase activity proteins Human genes 0.000 description 2
- 108040005185 1-phosphatidylinositol-3-kinase activity proteins Proteins 0.000 description 2
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-Lutidine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 2
- LMKPHJYTFHAGHK-UHFFFAOYSA-N 2-(diethylamino)ethyl 2-(1-hydroxycyclopentyl)-2-phenylacetate Chemical compound C1CCCC1(O)C(C(=O)OCCN(CC)CC)C1=CC=CC=C1 LMKPHJYTFHAGHK-UHFFFAOYSA-N 0.000 description 2
- NSKBUHCUWDXWDI-UHFFFAOYSA-N 2-(hydroxymethyl)butanamide Chemical compound CCC(CO)C(N)=O NSKBUHCUWDXWDI-UHFFFAOYSA-N 0.000 description 2
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical class CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 2
- PIMQWRZWLQKKBJ-SFHVURJKSA-N 2-[(2S)-1-[3-ethyl-7-[(1-oxidopyridin-1-ium-3-yl)methylamino]pyrazolo[1,5-a]pyrimidin-5-yl]piperidin-2-yl]ethanol Chemical compound C=1C(N2[C@@H](CCCC2)CCO)=NC2=C(CC)C=NN2C=1NCC1=CC=C[N+]([O-])=C1 PIMQWRZWLQKKBJ-SFHVURJKSA-N 0.000 description 2
- VUKAUDKDFVSVFT-UHFFFAOYSA-N 2-[6-[4,5-bis(2-hydroxypropoxy)-2-(2-hydroxypropoxymethyl)-6-methoxyoxan-3-yl]oxy-4,5-dimethoxy-2-(methoxymethyl)oxan-3-yl]oxy-6-(hydroxymethyl)-5-methoxyoxane-3,4-diol Chemical compound COC1C(OC)C(OC2C(C(O)C(OC)C(CO)O2)O)C(COC)OC1OC1C(COCC(C)O)OC(OC)C(OCC(C)O)C1OCC(C)O VUKAUDKDFVSVFT-UHFFFAOYSA-N 0.000 description 2
- YQEMORVAKMFKLG-UHFFFAOYSA-N 2-stearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 2
- ODHCTXKNWHHXJC-GSVOUGTGSA-N 5-oxo-D-proline Chemical compound OC(=O)[C@H]1CCC(=O)N1 ODHCTXKNWHHXJC-GSVOUGTGSA-N 0.000 description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N Acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 2
- 208000010444 Acidosis Diseases 0.000 description 2
- WNROFYMDJYEPJX-UHFFFAOYSA-K Aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 2
- 206010001897 Alzheimer's disease Diseases 0.000 description 2
- 206010001935 American trypanosomiasis Diseases 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 102000014303 Amyloid beta-Protein Precursor Human genes 0.000 description 2
- 108010079054 Amyloid beta-Protein Precursor Proteins 0.000 description 2
- 206010003594 Ataxia telangiectasia Diseases 0.000 description 2
- 208000000659 Autoimmune Lymphoproliferative Syndrome Diseases 0.000 description 2
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 description 2
- 102100005377 BMP2 Human genes 0.000 description 2
- 101700000123 BMP2 Proteins 0.000 description 2
- 206010004146 Basal cell carcinoma Diseases 0.000 description 2
- 210000000601 Blood Cells Anatomy 0.000 description 2
- 206010065687 Bone loss Diseases 0.000 description 2
- 210000004556 Brain Anatomy 0.000 description 2
- 208000009899 Burkitt Lymphoma Diseases 0.000 description 2
- 229940095259 Butylated Hydroxytoluene Drugs 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
- IGDWARGPVYWWPS-SECBINFHSA-N COC(=O)[C@H]1CCCN1CC(=O)OC(C)(C)C Chemical compound COC(=O)[C@H]1CCCN1CC(=O)OC(C)(C)C IGDWARGPVYWWPS-SECBINFHSA-N 0.000 description 2
- 102100008563 CTRL Human genes 0.000 description 2
- 101700024612 CTRL Proteins 0.000 description 2
- MIOPJNTWMNEORI-UHFFFAOYSA-N Camphorsulfonic acid Chemical class C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 2
- VSJKWCGYPAHWDS-FQEVSTJZSA-N Camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate dianion Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- HAWPXGHAZFHHAD-UHFFFAOYSA-N Chlormethine Chemical compound ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 2
- 206010008958 Chronic lymphocytic leukaemia Diseases 0.000 description 2
- BGTOWKSIORTVQH-UHFFFAOYSA-N Cyclopentanone Chemical compound O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 0.000 description 2
- 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 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N D-Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- 101700061444 DDX25 Proteins 0.000 description 2
- 210000004443 Dendritic Cells Anatomy 0.000 description 2
- 208000008334 Dermatofibrosarcoma Diseases 0.000 description 2
- 206010057070 Dermatofibrosarcoma protuberans Diseases 0.000 description 2
- NKLCNNUWBJBICK-UHFFFAOYSA-N Dess–Martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 2
- 206010058314 Dysplasia Diseases 0.000 description 2
- 102000033147 ERVK-25 Human genes 0.000 description 2
- 210000003743 Erythrocytes Anatomy 0.000 description 2
- LVGKNOAMLMIIKO-QXMHVHEDSA-N Ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 2
- 210000001508 Eye Anatomy 0.000 description 2
- 102100008255 GAA Human genes 0.000 description 2
- 101710010383 GAA Proteins 0.000 description 2
- 241000206672 Gelidium Species 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- 206010053185 Glycogen storage disease type II Diseases 0.000 description 2
- 102000004269 Granulocyte Colony-Stimulating Factor Human genes 0.000 description 2
- 108010017080 Granulocyte Colony-Stimulating Factor Proteins 0.000 description 2
- 210000003780 Hair Follicle Anatomy 0.000 description 2
- 210000003958 Hematopoietic Stem Cells Anatomy 0.000 description 2
- 208000005252 Hepatitis A Diseases 0.000 description 2
- 208000002672 Hepatitis B Diseases 0.000 description 2
- 208000005176 Hepatitis C Diseases 0.000 description 2
- 208000005331 Hepatitis D Diseases 0.000 description 2
- 108090000353 Histone deacetylases Proteins 0.000 description 2
- 102000003964 Histone deacetylases Human genes 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 229960003445 Idelalisib Drugs 0.000 description 2
- 206010027665 Immune disorder Diseases 0.000 description 2
- 206010021425 Immune system disease Diseases 0.000 description 2
- 206010061598 Immunodeficiency Diseases 0.000 description 2
- 206010021449 Immunodeficiency common variable Diseases 0.000 description 2
- 102000013463 Immunoglobulin Light Chains Human genes 0.000 description 2
- 108010065825 Immunoglobulin Light Chains Proteins 0.000 description 2
- 206010062016 Immunosuppression Diseases 0.000 description 2
- 102000010789 Interleukin-2 Receptors Human genes 0.000 description 2
- 108010038453 Interleukin-2 Receptors Proteins 0.000 description 2
- 210000000936 Intestines Anatomy 0.000 description 2
- 210000003734 Kidney Anatomy 0.000 description 2
- 210000000822 Killer Cells, Natural Anatomy 0.000 description 2
- 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 2
- 239000005511 L01XE05 - Sorafenib Substances 0.000 description 2
- GOTYRUGSSMKFNF-UHFFFAOYSA-N Lenalidomide Chemical compound C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O GOTYRUGSSMKFNF-UHFFFAOYSA-N 0.000 description 2
- 240000007472 Leucaena leucocephala Species 0.000 description 2
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 2
- 208000008456 Leukemia, Myelogenous, Chronic, BCR-ABL Positive Diseases 0.000 description 2
- 210000004072 Lung Anatomy 0.000 description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 2
- 101700084861 MTA2 Proteins 0.000 description 2
- 208000002780 Macular Degeneration Diseases 0.000 description 2
- 208000000516 Mast-Cell Leukemia Diseases 0.000 description 2
- 229960004961 Mechlorethamine Drugs 0.000 description 2
- 210000004379 Membranes Anatomy 0.000 description 2
- NPPQSCRMBWNHMW-UHFFFAOYSA-N Meprobamate Chemical compound NC(=O)OCC(C)(CCC)COC(N)=O NPPQSCRMBWNHMW-UHFFFAOYSA-N 0.000 description 2
- 230000036740 Metabolism Effects 0.000 description 2
- OSWPMRLSEDHDFF-UHFFFAOYSA-N Methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- 206010028095 Mucopolysaccharidosis IV Diseases 0.000 description 2
- 102000008934 Muscle Proteins Human genes 0.000 description 2
- 108010074084 Muscle Proteins Proteins 0.000 description 2
- 208000009525 Myocarditis Diseases 0.000 description 2
- 108010020856 N-terminal nucleophile hydrolase Proteins 0.000 description 2
- 108010057466 NF-kappa B Proteins 0.000 description 2
- 102000003945 NF-kappa B Human genes 0.000 description 2
- 210000004693 NK cell Anatomy 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 208000004485 Nijmegen Breakage Syndrome Diseases 0.000 description 2
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Nitrumon Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 2
- 208000002154 Non-Small-Cell Lung Carcinoma Diseases 0.000 description 2
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N Oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N Oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- AHHWIHXENZJRFG-UHFFFAOYSA-N Oxetane Chemical compound C1COC1 AHHWIHXENZJRFG-UHFFFAOYSA-N 0.000 description 2
- 101700073430 PID Proteins 0.000 description 2
- 210000000496 Pancreas Anatomy 0.000 description 2
- 108091005771 Peptidases Proteins 0.000 description 2
- 241000224016 Plasmodium Species 0.000 description 2
- 229960003171 Plicamycin Drugs 0.000 description 2
- 229920002732 Polyanhydride Polymers 0.000 description 2
- 229920001710 Polyorthoester Polymers 0.000 description 2
- ZNNZYHKDIALBAK-UHFFFAOYSA-M Potassium thiocyanate Chemical compound [K+].[S-]C#N ZNNZYHKDIALBAK-UHFFFAOYSA-M 0.000 description 2
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 2
- 239000004365 Protease Substances 0.000 description 2
- 210000003324 RBC Anatomy 0.000 description 2
- 210000000664 Rectum Anatomy 0.000 description 2
- 208000009527 Refractory Anemia Diseases 0.000 description 2
- 206010072684 Refractory cytopenia with unilineage dysplasia Diseases 0.000 description 2
- 102000003800 Selectins Human genes 0.000 description 2
- 108090000184 Selectins Proteins 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L Sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N Thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- 206010052779 Transplant rejections Diseases 0.000 description 2
- 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 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N Trimethylsilyl chloride Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- HWKQNAWCHQMZHK-UHFFFAOYSA-N Trolnitrate Chemical compound [O-][N+](=O)OCCN(CCO[N+]([O-])=O)CCO[N+]([O-])=O HWKQNAWCHQMZHK-UHFFFAOYSA-N 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- 206010047505 Visceral leishmaniasis Diseases 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Vitamin C Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 208000006110 Wiskott-Aldrich Syndrome Diseases 0.000 description 2
- 102000001392 Wiskott-Aldrich Syndrome Protein Human genes 0.000 description 2
- 108010093528 Wiskott-Aldrich Syndrome Protein Proteins 0.000 description 2
- 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 2
- 239000012346 acetyl chloride Substances 0.000 description 2
- 230000002378 acidificating Effects 0.000 description 2
- 201000005510 acute lymphocytic leukemia Diseases 0.000 description 2
- 201000000028 adult respiratory distress syndrome Diseases 0.000 description 2
- 201000008217 aggressive systemic mastocytosis Diseases 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 239000000783 alginic acid Substances 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 229960001126 alginic acid Drugs 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminum Chemical class [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 239000003098 androgen Substances 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 230000000844 anti-bacterial Effects 0.000 description 2
- 230000002927 anti-mitotic Effects 0.000 description 2
- 230000001028 anti-proliferant Effects 0.000 description 2
- 108090001123 antibodies Proteins 0.000 description 2
- 102000004965 antibodies Human genes 0.000 description 2
- 230000000890 antigenic Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 229960005070 ascorbic acid Drugs 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- 201000003710 autoimmune thrombocytopenic purpura Diseases 0.000 description 2
- TVXXEYSOBIMTAB-UHFFFAOYSA-N azetidine-1-carbothioamide Chemical compound NC(=S)N1CCC1 TVXXEYSOBIMTAB-UHFFFAOYSA-N 0.000 description 2
- 230000001580 bacterial Effects 0.000 description 2
- 239000000440 bentonite Substances 0.000 description 2
- 229910000278 bentonite Inorganic materials 0.000 description 2
- RLMHWGDKMJIEHH-DDWIOCJRSA-N benzyl (2R)-2-aminopropanoate;hydrochloride Chemical compound Cl.C[C@@H](N)C(=O)OCC1=CC=CC=C1 RLMHWGDKMJIEHH-DDWIOCJRSA-N 0.000 description 2
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 2
- 229920002988 biodegradable polymer Polymers 0.000 description 2
- 239000004621 biodegradable polymer Substances 0.000 description 2
- 238000006065 biodegradation reaction Methods 0.000 description 2
- 239000007844 bleaching agent Substances 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 125000002837 carbocyclic group Chemical group 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 230000002490 cerebral Effects 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- 201000006934 chronic myeloid leukemia Diseases 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 229940110456 cocoa butter Drugs 0.000 description 2
- 235000019868 cocoa butter Nutrition 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 201000003874 common variable immunodeficiency Diseases 0.000 description 2
- 235000012343 cottonseed oil Nutrition 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- HAAOHBCJARVREN-UHFFFAOYSA-N cyclopenten-1-yl trifluoromethanesulfonate Chemical compound FC(F)(F)S(=O)(=O)OC1=CCCC1 HAAOHBCJARVREN-UHFFFAOYSA-N 0.000 description 2
- 230000003247 decreasing Effects 0.000 description 2
- 230000003111 delayed Effects 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 239000002270 dispersing agent Substances 0.000 description 2
- 239000002612 dispersion media Substances 0.000 description 2
- 239000008298 dragée Substances 0.000 description 2
- 239000006196 drop Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 229940093471 ethyl oleate Drugs 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 210000002950 fibroblast Anatomy 0.000 description 2
- 201000008808 fibrosarcoma Diseases 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 230000004907 flux Effects 0.000 description 2
- 238000010575 fractional recrystallization Methods 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 201000004502 glycogen storage disease II Diseases 0.000 description 2
- 230000003394 haemopoietic Effects 0.000 description 2
- 201000010284 hepatitis E Diseases 0.000 description 2
- 201000011075 histiocytic and dendritic cell cancer Diseases 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine hydrate Chemical compound O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- USZLCYNVCCDPLQ-UHFFFAOYSA-N hydron;N-methoxymethanamine;chloride Chemical compound Cl.CNOC USZLCYNVCCDPLQ-UHFFFAOYSA-N 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- IFSDAJWBUCMOAH-HNNXBMFYSA-N idelalisib Chemical compound C1([C@@H](NC=2C=3N=CNC=3N=CN=2)CC)=NC2=CC=CC(F)=C2C(=O)N1C1=CC=CC=C1 IFSDAJWBUCMOAH-HNNXBMFYSA-N 0.000 description 2
- 230000001506 immunosuppresive Effects 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 201000009004 indolent systemic mastocytosis Diseases 0.000 description 2
- 125000001041 indolyl group Chemical group 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 230000002757 inflammatory Effects 0.000 description 2
- 238000001802 infusion Methods 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
- 238000001990 intravenous administration Methods 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 239000007951 isotonicity adjuster Substances 0.000 description 2
- 230000002147 killing Effects 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 2
- 229960004942 lenalidomide Drugs 0.000 description 2
- 239000008297 liquid dosage form Substances 0.000 description 2
- 201000005244 lung non-small cell carcinoma Diseases 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 201000008749 mast-cell sarcoma Diseases 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 230000035800 maturation Effects 0.000 description 2
- 239000002609 media Substances 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 230000035786 metabolism Effects 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 229960000485 methotrexate Drugs 0.000 description 2
- 239000004530 micro-emulsion Substances 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 230000011278 mitosis Effects 0.000 description 2
- 230000000394 mitotic Effects 0.000 description 2
- QDHHCQZDFGDHMP-UHFFFAOYSA-N monochloramine Chemical compound ClN QDHHCQZDFGDHMP-UHFFFAOYSA-N 0.000 description 2
- 238000000465 moulding Methods 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N n-butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N n-heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- 239000002105 nanoparticle Substances 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 239000012038 nucleophile Substances 0.000 description 2
- OIPZNTLJVJGRCI-UHFFFAOYSA-M octadecanoyloxyaluminum;dihydrate Chemical compound O.O.CCCCCCCCCCCCCCCCCC(=O)O[Al] OIPZNTLJVJGRCI-UHFFFAOYSA-M 0.000 description 2
- 235000008390 olive oil Nutrition 0.000 description 2
- 231100000590 oncogenic Toxicity 0.000 description 2
- 230000002246 oncogenic Effects 0.000 description 2
- 150000002894 organic compounds Chemical class 0.000 description 2
- 125000003566 oxetanyl group Chemical group 0.000 description 2
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 2
- 230000003071 parasitic Effects 0.000 description 2
- 239000002304 perfume Substances 0.000 description 2
- 230000002093 peripheral Effects 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 229920001983 poloxamer Polymers 0.000 description 2
- 125000003367 polycyclic group Polymers 0.000 description 2
- 239000008389 polyethoxylated castor oil Substances 0.000 description 2
- 229920005862 polyol Polymers 0.000 description 2
- 150000003077 polyols Chemical class 0.000 description 2
- 229920000136 polysorbate Polymers 0.000 description 2
- 229960005205 prednisolone Drugs 0.000 description 2
- 239000003380 propellant Substances 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 230000002633 protecting Effects 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 2
- 200000000008 restenosis Diseases 0.000 description 2
- 210000001995 reticulocyte Anatomy 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 239000008159 sesame oil Substances 0.000 description 2
- 235000011803 sesame oil Nutrition 0.000 description 2
- 230000019491 signal transduction Effects 0.000 description 2
- 235000017550 sodium carbonate Nutrition 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
- XYGBKMMCQDZQOZ-UHFFFAOYSA-M sodium;4-hydroxybutanoate Chemical compound [Na+].OCCCC([O-])=O XYGBKMMCQDZQOZ-UHFFFAOYSA-M 0.000 description 2
- 239000007909 solid dosage form Substances 0.000 description 2
- 239000008247 solid mixture Substances 0.000 description 2
- 229960003787 sorafenib Drugs 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 230000003393 splenic Effects 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000008223 sterile water Substances 0.000 description 2
- 150000003431 steroids Chemical class 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N t-BuOH Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 229960001367 tartaric acid Drugs 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000004496 thiazol-5-yl group Chemical group S1C=NC=C1* 0.000 description 2
- 150000007970 thio esters Chemical class 0.000 description 2
- 150000003568 thioethers Chemical class 0.000 description 2
- 125000000341 threoninyl group Chemical group [H]OC([H])(C([H])([H])[H])C([H])(N([H])[H])C(*)=O 0.000 description 2
- WYWHKKSPHMUBEB-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 2
- 230000035897 transcription Effects 0.000 description 2
- 108090000464 transcription factors Proteins 0.000 description 2
- 102000003995 transcription factors Human genes 0.000 description 2
- 229960005294 triamcinolone Drugs 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- JNAHVYVRKWKWKQ-CYBMUJFWSA-N veliparib Chemical compound N=1C2=CC=CC(C(N)=O)=C2NC=1[C@@]1(C)CCCN1 JNAHVYVRKWKWKQ-CYBMUJFWSA-N 0.000 description 2
- 229960002066 vinorelbine Drugs 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- XLOMVQKBTHCTTD-UHFFFAOYSA-N zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N β-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- FMCGSUUBYTWNDP-MWLCHTKSSA-N (1S,2R)-2-(dimethylamino)-1-phenylpropan-1-ol Chemical compound CN(C)[C@H](C)[C@@H](O)C1=CC=CC=C1 FMCGSUUBYTWNDP-MWLCHTKSSA-N 0.000 description 1
- SSJXIUAHEKJCMH-WDSKDSINSA-N (1S,2S)-cyclohexane-1,2-diamine Chemical compound N[C@H]1CCCC[C@@H]1N SSJXIUAHEKJCMH-WDSKDSINSA-N 0.000 description 1
- YONLFQNRGZXBBF-ZIAGYGMSSA-N (2R,3R)-2,3-dibenzoyloxybutanedioic acid Chemical compound O([C@@H](C(=O)O)[C@@H](OC(=O)C=1C=CC=CC=1)C(O)=O)C(=O)C1=CC=CC=C1 YONLFQNRGZXBBF-ZIAGYGMSSA-N 0.000 description 1
- SHLYZEAOVWVTSW-BYPYZUCNSA-N (2S)-1-methyl-5-oxopyrrolidine-2-carboxylic acid Chemical compound CN1[C@H](C(O)=O)CCC1=O SHLYZEAOVWVTSW-BYPYZUCNSA-N 0.000 description 1
- IJXJGQCXFSSHNL-MRVPVSSYSA-N (2S)-2-amino-2-phenylethanol Chemical compound OC[C@@H](N)C1=CC=CC=C1 IJXJGQCXFSSHNL-MRVPVSSYSA-N 0.000 description 1
- WQAVPPWWLLVGFK-VTNASVEKSA-N (2S)-3-(4-methoxyphenyl)-N-[(2S)-1-[(2R)-2-methyloxiran-2-yl]-1-oxo-3-phenylpropan-2-yl]-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1=CC(OC)=CC=C1C[C@@H](C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)[C@]1(C)OC1)NC(=O)[C@H](C)NC(=O)CN1CCOCC1 WQAVPPWWLLVGFK-VTNASVEKSA-N 0.000 description 1
- RNAICSBVACLLGM-GNAZCLTHSA-N (3S,4R)-3-ethyl-4-[(3-methyl-1H-imidazol-3-ium-4-yl)methyl]oxolan-2-one;chloride Chemical compound Cl.C1OC(=O)[C@@H](CC)[C@H]1CC1=CN=CN1C RNAICSBVACLLGM-GNAZCLTHSA-N 0.000 description 1
- PMATZTZNYRCHOR-CGLBZJNRSA-N (3S,6S,9S,12R,15S,18S,21S,24S,30S,33S)-30-ethyl-33-[(E,1R,2R)-1-hydroxy-2-methylhex-4-enyl]-1,4,7,10,12,15,19,25,28-nonamethyl-6,9,18,24-tetrakis(2-methylpropyl)-3,21-di(propan-2-yl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotritriacontane-2,5,8,11,14,17 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 1
- OMJKFYKNWZZKTK-UXBLZVDNSA-N (5E)-5-(dimethylaminohydrazinylidene)imidazole-4-carboxamide Chemical compound CN(C)N\N=C1\N=CN=C1C(N)=O OMJKFYKNWZZKTK-UXBLZVDNSA-N 0.000 description 1
- NRUKOCRGYNPUPR-QBPJDGROSA-N (5S,5aR,8aR,9R)-5-[[(2R,4aR,6R,7R,8R,8aS)-7,8-dihydroxy-2-thiophen-2-yl-4,4a,6,7,8,8a-hexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy]-9-(4-hydroxy-3,5-dimethoxyphenyl)-5a,6,8a,9-tetrahydro-5H-[2]benzofuro[6,5-f][1,3]benzodioxol-8-one Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
- OGPWIDANBSLJPC-RFPWEZLHSA-N (6S,8S,9R,10S,11S,13S,14S,16R,17S)-6,9-difluoro-11-hydroxy-17-(2-hydroxyacetyl)-10,13,16-trimethyl-7,8,11,12,14,15,16,17-octahydro-6H-cyclopenta[a]phenanthren-3-one Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@H](C(=O)CO)[C@@]2(C)C[C@@H]1O OGPWIDANBSLJPC-RFPWEZLHSA-N 0.000 description 1
- SLVCCRYLKTYUQP-DVTGEIKXSA-N (8S,9R,10S,11S,13S,14S,17R)-9-fluoro-11,17-dihydroxy-17-[(2S)-2-hydroxypropanoyl]-10,13-dimethyl-6,7,8,11,12,14,15,16-octahydrocyclopenta[a]phenanthren-3-one Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1CC[C@@](C(=O)[C@@H](O)C)(O)[C@@]1(C)C[C@@H]2O SLVCCRYLKTYUQP-DVTGEIKXSA-N 0.000 description 1
- CZBOZZDZNVIXFC-VRRJBYJJSA-N (8S,9S,10R,11S,13S,14S,17R)-11,17-dihydroxy-10,13-dimethyl-17-[2-(4-methylpiperazin-1-yl)acetyl]-7,8,9,11,12,14,15,16-octahydro-6H-cyclopenta[a]phenanthren-3-one Chemical compound C1CN(C)CCN1CC(=O)[C@]1(O)[C@@]2(C)C[C@H](O)[C@@H]3[C@@]4(C)C=CC(=O)C=C4CC[C@H]3[C@@H]2CC1 CZBOZZDZNVIXFC-VRRJBYJJSA-N 0.000 description 1
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 1
- ASZLNPRMVCGYCI-UHFFFAOYSA-N 1$l^{2}-azolidine Chemical group C1CC[N]C1 ASZLNPRMVCGYCI-UHFFFAOYSA-N 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N 1,4-Butanediol, dimethanesulfonate Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- CNDHHGUSRIZDSL-UHFFFAOYSA-N 1-chlorooctane Chemical compound CCCCCCCCCl CNDHHGUSRIZDSL-UHFFFAOYSA-N 0.000 description 1
- HEWZVZIVELJPQZ-UHFFFAOYSA-N 2,2-Dimethoxypropane Chemical compound COC(C)(C)OC HEWZVZIVELJPQZ-UHFFFAOYSA-N 0.000 description 1
- 125000004778 2,2-difluoroethyl group Chemical group [H]C([H])(*)C([H])(F)F 0.000 description 1
- SPSOPRDXHBKLRQ-UHFFFAOYSA-N 2-(2-amino-1,3-oxazol-4-yl)acetic acid Chemical compound NC1=NC(CC(O)=O)=CO1 SPSOPRDXHBKLRQ-UHFFFAOYSA-N 0.000 description 1
- APIMXAGCLCGUGB-UHFFFAOYSA-N 2-(2-azaniumyl-1,3-thiazol-5-yl)acetate Chemical compound NC1=NC=C(CC(O)=O)S1 APIMXAGCLCGUGB-UHFFFAOYSA-N 0.000 description 1
- UZYQSNQJLWTICD-UHFFFAOYSA-N 2-(N-benzoylanilino)-2,2-dinitroacetic acid Chemical compound C=1C=CC=CC=1N(C(C(=O)O)([N+]([O-])=O)[N+]([O-])=O)C(=O)C1=CC=CC=C1 UZYQSNQJLWTICD-UHFFFAOYSA-N 0.000 description 1
- WVCHIGAIXREVNS-UHFFFAOYSA-N 2-HYDROXY-1,4-NAPHTHOQUINONE Chemical compound C1=CC=C2C(O)=CC(=O)C(=O)C2=C1 WVCHIGAIXREVNS-UHFFFAOYSA-N 0.000 description 1
- CTRPRMNBTVRDFH-UHFFFAOYSA-N 2-N-methyl-1,3,5-triazine-2,4,6-triamine Chemical class CNC1=NC(N)=NC(N)=N1 CTRPRMNBTVRDFH-UHFFFAOYSA-N 0.000 description 1
- PUYVJBBSBPUKBT-AWEZNQCLSA-N 2-[(1S)-1-[(2-amino-7H-purin-6-yl)amino]ethyl]-5-methyl-3-(2-methylphenyl)quinazolin-4-one Chemical compound C1([C@@H](NC=2C=3NC=NC=3N=C(N)N=2)C)=NC2=CC=CC(C)=C2C(=O)N1C1=CC=CC=C1C PUYVJBBSBPUKBT-AWEZNQCLSA-N 0.000 description 1
- GLSBCLIRXWIXQC-UHFFFAOYSA-N 2-[2-(dimethylamino)-1,3-thiazol-4-yl]acetic acid Chemical compound CN(C)C1=NC(CC(O)=O)=CS1 GLSBCLIRXWIXQC-UHFFFAOYSA-N 0.000 description 1
- RTQWWZBSTRGEAV-PKHIMPSTSA-N 2-[[(2S)-2-[bis(carboxymethyl)amino]-3-[4-(methylcarbamoylamino)phenyl]propyl]-[2-[bis(carboxymethyl)amino]propyl]amino]acetic acid Chemical compound CNC(=O)NC1=CC=C(C[C@@H](CN(CC(C)N(CC(O)=O)CC(O)=O)CC(O)=O)N(CC(O)=O)CC(O)=O)C=C1 RTQWWZBSTRGEAV-PKHIMPSTSA-N 0.000 description 1
- BAMUAAIPBLVVHU-UHFFFAOYSA-N 2-acetyl-2-acetyloxy-3-hydroxybutanedioic acid Chemical compound CC(=O)OC(C(O)=O)(C(C)=O)C(O)C(O)=O BAMUAAIPBLVVHU-UHFFFAOYSA-N 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- HUSXNIFVQFHSEA-UHFFFAOYSA-N 2-hydroxypropanoic acid;hydrochloride Chemical compound Cl.CC(O)C(O)=O HUSXNIFVQFHSEA-UHFFFAOYSA-N 0.000 description 1
- JNODDICFTDYODH-UHFFFAOYSA-N 2-hydroxytetrahydrofuran Chemical compound OC1CCCO1 JNODDICFTDYODH-UHFFFAOYSA-N 0.000 description 1
- PJYFXNZOOMGPIL-UHFFFAOYSA-N 2-methylmorpholin-4-ium;chloride Chemical compound Cl.CC1CNCCO1 PJYFXNZOOMGPIL-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N 289-95-2 Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K 2qpq Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N 3-Methylbutanoic acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- LWXNHFZBFJMHGU-UHFFFAOYSA-M 4,5,6,7-tetrahydro-1H-indazole-3-carboxylate Chemical compound C1CCCC2=C1NN=C2C(=O)[O-] LWXNHFZBFJMHGU-UHFFFAOYSA-M 0.000 description 1
- YTXSYWAKVMZICI-PVCZSOGJSA-N 4-(carboxymethyl)-2-[(1R)-1-[[2-[(2,5-dichlorobenzoyl)amino]acetyl]amino]-3-methylbutyl]-6-oxo-1,3,2-dioxaborinane-4-carboxylic acid Chemical compound N([C@@H](CC(C)C)B1OC(CC(O)=O)(CC(=O)O1)C(O)=O)C(=O)CNC(=O)C1=CC(Cl)=CC=C1Cl YTXSYWAKVMZICI-PVCZSOGJSA-N 0.000 description 1
- PAOFPNGYBWGKCO-UHFFFAOYSA-N 4-[(2,6-dichlorobenzoyl)amino]-N-piperidin-4-yl-1H-pyrazole-5-carboxamide;hydrochloride Chemical compound Cl.ClC1=CC=CC(Cl)=C1C(=O)NC1=CNN=C1C(=O)NC1CCNCC1 PAOFPNGYBWGKCO-UHFFFAOYSA-N 0.000 description 1
- BHQCQFFYRZLCQQ-UMZBRFQRSA-N 4-[(3R,5S,7R,12S)-3,7,12-trihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoic acid Chemical class C([C@H]1C[C@H]2O)[C@H](O)CCC1(C)C1C2C2CCC(C(CCC(O)=O)C)C2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-UMZBRFQRSA-N 0.000 description 1
- YJISHJVIRFPGGN-UHFFFAOYSA-N 5-[5-[3,4-dihydroxy-6-(hydroxymethyl)-5-methoxyoxan-2-yl]oxy-6-[[3,4-dihydroxy-6-(hydroxymethyl)-5-methoxyoxan-2-yl]oxymethyl]-3,4-dihydroxyoxan-2-yl]oxy-6-(hydroxymethyl)-2-methyloxane-3,4-diol Chemical compound O1C(CO)C(OC)C(O)C(O)C1OCC1C(OC2C(C(O)C(OC)C(CO)O2)O)C(O)C(O)C(OC2C(OC(C)C(O)C2O)CO)O1 YJISHJVIRFPGGN-UHFFFAOYSA-N 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N 5-flurouricil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- ILYBMUDLGFMEMU-UHFFFAOYSA-N 7-$l^{1}-oxidanyl-2,3,4,5,6,7-hexaoxoheptan-1-olate Chemical compound [O]C(=O)C(=O)C(=O)C(=O)C(=O)C(=O)C[O-] ILYBMUDLGFMEMU-UHFFFAOYSA-N 0.000 description 1
- 101710004747 ACSBG1 Proteins 0.000 description 1
- 102100002719 ACSBG1 Human genes 0.000 description 1
- AOJJSUZBOXZQNB-TZSSRYMLSA-N ADRIAMYCIN Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 1
- 102100020405 AGA Human genes 0.000 description 1
- 108060005293 AGA Proteins 0.000 description 1
- 206010065040 AIDS dementia complex Diseases 0.000 description 1
- 102100001249 ALB Human genes 0.000 description 1
- 229940100198 ALKYLATING AGENTS Drugs 0.000 description 1
- 229940100197 ANTIMETABOLITES Drugs 0.000 description 1
- 101700007241 APOC4 Proteins 0.000 description 1
- 102100004323 ASPG Human genes 0.000 description 1
- 206010000565 Acquired immunodeficiency syndrome Diseases 0.000 description 1
- 208000004476 Acute Coronary Syndrome Diseases 0.000 description 1
- 206010000880 Acute myeloid leukaemia Diseases 0.000 description 1
- 208000009956 Adenocarcinoma Diseases 0.000 description 1
- 206010052747 Adenocarcinoma pancreas Diseases 0.000 description 1
- 208000000230 African Trypanosomiasis Diseases 0.000 description 1
- FJXOGVLKCZQRDN-PHCHRAKRSA-N Alclometasone Chemical compound C([C@H]1Cl)C2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O FJXOGVLKCZQRDN-PHCHRAKRSA-N 0.000 description 1
- 108010090838 Alemtuzumab Proteins 0.000 description 1
- 229940045714 Alkyl sulfonate alkylating agents Drugs 0.000 description 1
- 206010027654 Allergic conditions Diseases 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- PZZYQPZGQPZBDN-UHFFFAOYSA-N Aluminium silicate Chemical compound O=[Al]O[Si](=O)O[Al]=O PZZYQPZGQPZBDN-UHFFFAOYSA-N 0.000 description 1
- 229960003099 Amcinonide Drugs 0.000 description 1
- ILKJAFIWWBXGDU-MOGDOJJUSA-N Amcinonide Chemical compound O([C@@]1([C@H](O2)C[C@@H]3[C@@]1(C[C@H](O)[C@]1(F)[C@@]4(C)C=CC(=O)C=C4CC[C@H]13)C)C(=O)COC(=O)C)C12CCCC1 ILKJAFIWWBXGDU-MOGDOJJUSA-N 0.000 description 1
- ROBVIMPUHSLWNV-UHFFFAOYSA-N Aminoglutethimide Chemical compound C=1C=C(N)C=CC=1C1(CC)CCC(=O)NC1=O ROBVIMPUHSLWNV-UHFFFAOYSA-N 0.000 description 1
- 229960003437 Aminoglutethimide Drugs 0.000 description 1
- 210000001691 Amnion Anatomy 0.000 description 1
- 206010073478 Anaplastic large-cell lymphoma Diseases 0.000 description 1
- YBBLVLTVTVSKRW-UHFFFAOYSA-N Anastrozole Chemical compound N#CC(C)(C)C1=CC(C(C)(C#N)C)=CC(CN2N=CN=C2)=C1 YBBLVLTVTVSKRW-UHFFFAOYSA-N 0.000 description 1
- 206010002449 Angioimmunoblastic T-cell lymphoma Diseases 0.000 description 1
- 229940064005 Antibiotic throat preparations Drugs 0.000 description 1
- 229940083879 Antibiotics FOR TREATMENT OF HEMORRHOIDS AND ANAL FISSURES FOR TOPICAL USE Drugs 0.000 description 1
- 229940042052 Antibiotics for systemic use Drugs 0.000 description 1
- 229940042786 Antitubercular Antibiotics Drugs 0.000 description 1
- 235000003276 Apios tuberosa Nutrition 0.000 description 1
- 240000005781 Arachis hypogaea Species 0.000 description 1
- 235000010777 Arachis hypogaea Nutrition 0.000 description 1
- 235000010744 Arachis villosulicarpa Nutrition 0.000 description 1
- 241000203069 Archaea Species 0.000 description 1
- BFYIZQONLCFLEV-DAELLWKTSA-N Aromasine Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC(=C)C2=C1 BFYIZQONLCFLEV-DAELLWKTSA-N 0.000 description 1
- 229940046844 Aromatase inhibitors Drugs 0.000 description 1
- 206010062599 Arterial occlusive disease Diseases 0.000 description 1
- 206010003211 Arteriosclerosis coronary artery Diseases 0.000 description 1
- 206010003246 Arthritis Diseases 0.000 description 1
- 229960001230 Asparagine Drugs 0.000 description 1
- 108010023546 Aspartylglucosylaminase Proteins 0.000 description 1
- 206010003571 Astrocytoma Diseases 0.000 description 1
- 206010003694 Atrophy Diseases 0.000 description 1
- 206010003882 Axonal neuropathy Diseases 0.000 description 1
- 210000003719 B-Lymphocytes Anatomy 0.000 description 1
- 206010073480 B-cell prolymphocytic leukaemia Diseases 0.000 description 1
- 108060000885 BCL2 Proteins 0.000 description 1
- 102100013894 BCL2 Human genes 0.000 description 1
- 210000002469 Basement Membrane Anatomy 0.000 description 1
- 229940092705 Beclomethasone Drugs 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N Benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 108010005144 Bevacizumab Proteins 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 210000000013 Bile Ducts Anatomy 0.000 description 1
- 229940093761 Bile Salts Drugs 0.000 description 1
- 230000036912 Bioavailability Effects 0.000 description 1
- CGVWPQOFHSAKRR-NDEPHWFRSA-N Biricodar Chemical compound COC1=C(OC)C(OC)=CC(C(=O)C(=O)N2[C@@H](CCCC2)C(=O)OC(CCCC=2C=NC=CC=2)CCCC=2C=NC=CC=2)=C1 CGVWPQOFHSAKRR-NDEPHWFRSA-N 0.000 description 1
- 229950005124 Biricodar Drugs 0.000 description 1
- 210000001772 Blood Platelets Anatomy 0.000 description 1
- 210000004204 Blood Vessels Anatomy 0.000 description 1
- 208000003432 Bone Disease Diseases 0.000 description 1
- 206010073106 Bone giant cell tumour malignant Diseases 0.000 description 1
- GXJABQQUPOEUTA-RDJZCZTQSA-N Bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 208000001183 Brain Injury Diseases 0.000 description 1
- 210000000481 Breast Anatomy 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 206010006451 Bronchitis Diseases 0.000 description 1
- CQFNOACVVKSEOJ-VBQPQCOESA-N Bronilide Chemical compound O.C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O CQFNOACVVKSEOJ-VBQPQCOESA-N 0.000 description 1
- 229960004436 Budesonide Drugs 0.000 description 1
- VOVIALXJUBGFJZ-VXKMTNQYSA-N Budesonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3O[C@@H](CCC)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O VOVIALXJUBGFJZ-VXKMTNQYSA-N 0.000 description 1
- 206010067184 Burkitt's leukaemia Diseases 0.000 description 1
- 208000006448 Buruli Ulcer Diseases 0.000 description 1
- CZBZUDVBLSSABA-UHFFFAOYSA-N Butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 description 1
- LQZKWFMKXKOCGL-QGZVFWFLSA-N C(C)[Si](OC1(CC1)[C@@H](CO)NC(OCC1=CC=CC=C1)=O)(CC)CC Chemical compound C(C)[Si](OC1(CC1)[C@@H](CO)NC(OCC1=CC=CC=C1)=O)(CC)CC LQZKWFMKXKOCGL-QGZVFWFLSA-N 0.000 description 1
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 1
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 1
- RYDHJQDUUJKFNB-UHFFFAOYSA-N CC1(NOC=C1)C(=O)O Chemical compound CC1(NOC=C1)C(=O)O RYDHJQDUUJKFNB-UHFFFAOYSA-N 0.000 description 1
- HCZIQIOQWQJKPC-MRXNPFEDSA-N CC[Si](CC)(CC)OC1(CC1)[C@H](NC(=O)OCc1ccccc1)C(O)=O Chemical compound CC[Si](CC)(CC)OC1(CC1)[C@H](NC(=O)OCc1ccccc1)C(O)=O HCZIQIOQWQJKPC-MRXNPFEDSA-N 0.000 description 1
- 102100003729 CD40LG Human genes 0.000 description 1
- 101710003804 CD40LG Proteins 0.000 description 1
- OXGWJFOKRZQBLD-BBTUJRGHSA-N COc1ccc(C[C@H](N)C(=O)N[C@@H](CC2=CCCC2)C(=O)[C@@]2(C)CO2)cc1 Chemical compound COc1ccc(C[C@H](N)C(=O)N[C@@H](CC2=CCCC2)C(=O)[C@@]2(C)CO2)cc1 OXGWJFOKRZQBLD-BBTUJRGHSA-N 0.000 description 1
- 101700057734 CRTC1 Proteins 0.000 description 1
- 102100006400 CSF2 Human genes 0.000 description 1
- 101710024147 CYP716A53v2 Proteins 0.000 description 1
- ZVHNDZWQTBEVRY-UHFFFAOYSA-N CYT387 Chemical compound C1=CC(C(NCC#N)=O)=CC=C1C1=CC=NC(NC=2C=CC(=CC=2)N2CCOCC2)=N1 ZVHNDZWQTBEVRY-UHFFFAOYSA-N 0.000 description 1
- 206010006895 Cachexia Diseases 0.000 description 1
- 229960005069 Calcium Drugs 0.000 description 1
- 229960003563 Calcium Carbonate Drugs 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
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- OLESAACUTLOWQZ-UHFFFAOYSA-L Carboplatin Chemical compound O=C1O[Pt]([N]([H])([H])[H])([N]([H])([H])[H])OC(=O)C11CCC1 OLESAACUTLOWQZ-UHFFFAOYSA-L 0.000 description 1
- 229960004562 Carboplatin Drugs 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 208000002458 Carcinoid Tumor Diseases 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- 206010007572 Cardiac hypertrophy Diseases 0.000 description 1
- 229920002301 Cellulose acetate Polymers 0.000 description 1
- 210000003679 Cervix Uteri Anatomy 0.000 description 1
- 108010022830 Cetuximab Proteins 0.000 description 1
- 201000003884 Chagas disease Diseases 0.000 description 1
- 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 1
- 229960002327 Chloral Hydrate Drugs 0.000 description 1
- RNFNDJAIBTYOQL-UHFFFAOYSA-N Chloral hydrate Chemical compound OC(O)C(Cl)(Cl)Cl RNFNDJAIBTYOQL-UHFFFAOYSA-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
- 229960004926 Chlorobutanol Drugs 0.000 description 1
- NPSLCOWKFFNQKK-ZPSUVKRCSA-N Chloroprednisone 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]3C[C@H](Cl)C2=C1 NPSLCOWKFFNQKK-ZPSUVKRCSA-N 0.000 description 1
- 208000006990 Cholangiocarcinoma Diseases 0.000 description 1
- 208000005243 Chondrosarcoma Diseases 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- DQRYQEXVRPRHTD-WCCKRBBISA-N Cl.N[C@@](C(=O)OC)(C)O Chemical compound Cl.N[C@@](C(=O)OC)(C)O DQRYQEXVRPRHTD-WCCKRBBISA-N 0.000 description 1
- PTOAARAWEBMLNO-KVQBGUIXSA-N Cladribine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 PTOAARAWEBMLNO-KVQBGUIXSA-N 0.000 description 1
- YTJIBEDMAQUYSZ-FDNPDPBUSA-N Cloprednol 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]3C=C(Cl)C2=C1 YTJIBEDMAQUYSZ-FDNPDPBUSA-N 0.000 description 1
- 206010009905 Collagen-vascular disease Diseases 0.000 description 1
- 210000001072 Colon Anatomy 0.000 description 1
- 102000007644 Colony-Stimulating Factors Human genes 0.000 description 1
- 108010071942 Colony-Stimulating Factors Proteins 0.000 description 1
- 206010052360 Colorectal adenocarcinoma Diseases 0.000 description 1
- 206010010099 Combined immunodeficiency Diseases 0.000 description 1
- 206010010144 Completed suicide Diseases 0.000 description 1
- 206010056370 Congestive cardiomyopathy Diseases 0.000 description 1
- 241000711573 Coronaviridae Species 0.000 description 1
- OMFXVFTZEKFJBZ-HJTSIMOOSA-N Corticosterone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@H](CC4)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OMFXVFTZEKFJBZ-HJTSIMOOSA-N 0.000 description 1
- JYGXADMDTFJGBT-VWUMJDOOSA-N Cortisol 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 1
- 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 1
- RKHQGWMMUURILY-UHRZLXHJSA-N Cortivazol Chemical compound C([C@H]1[C@@H]2C[C@H]([C@]([C@@]2(C)C[C@H](O)[C@@H]1[C@@]1(C)C2)(O)C(=O)COC(C)=O)C)=C(C)C1=CC1=C2C=NN1C1=CC=CC=C1 RKHQGWMMUURILY-UHRZLXHJSA-N 0.000 description 1
- 241000223935 Cryptosporidium Species 0.000 description 1
- 208000006343 Cutaneous Mastocytosis Diseases 0.000 description 1
- 108010068150 Cyclin B Proteins 0.000 description 1
- 102000002427 Cyclin B Human genes 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 229940097362 Cyclodextrins Drugs 0.000 description 1
- 229960004397 Cyclophosphamide Drugs 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- 229940119017 Cyclosporine Drugs 0.000 description 1
- 108010036949 Cyclosporine Proteins 0.000 description 1
- 229960001305 Cysteine Hydrochloride Drugs 0.000 description 1
- 229960000684 Cytarabine Drugs 0.000 description 1
- 206010067477 Cytogenetic abnormality Diseases 0.000 description 1
- 210000000805 Cytoplasm Anatomy 0.000 description 1
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytosar Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 1
- 210000000172 Cytosol Anatomy 0.000 description 1
- ONIBWKKTOPOVIA-SCSAIBSYSA-N D-proline Chemical compound OC(=O)[C@H]1CCCN1 ONIBWKKTOPOVIA-SCSAIBSYSA-N 0.000 description 1
- MTCFGRXMJLQNBG-UWTATZPHSA-N D-serine Chemical compound OC[C@@H](N)C(O)=O MTCFGRXMJLQNBG-UWTATZPHSA-N 0.000 description 1
- STQGQHZAVUOBTE-VGBVRHCVSA-N DAUNOMYCIN Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 1
- YVGGHNCTFXOJCH-UHFFFAOYSA-N DDT Chemical compound C1=CC(Cl)=CC=C1C(C(Cl)(Cl)Cl)C1=CC=C(Cl)C=C1 YVGGHNCTFXOJCH-UHFFFAOYSA-N 0.000 description 1
- 101700079085 DLD Proteins 0.000 description 1
- 230000004568 DNA-binding Effects 0.000 description 1
- 229960000640 Dactinomycin Drugs 0.000 description 1
- 108010092160 Dactinomycin Proteins 0.000 description 1
- 229960000975 Daunorubicin Drugs 0.000 description 1
- BUROJSBIWGDYCN-GAUTUEMISA-N Deforolimus Chemical compound C1C[C@@H](OP(C)(C)=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 BUROJSBIWGDYCN-GAUTUEMISA-N 0.000 description 1
- 208000006313 Delayed Hypersensitivity Diseases 0.000 description 1
- 206010067647 Delivery Diseases 0.000 description 1
- 206010061811 Demyelinating polyneuropathy Diseases 0.000 description 1
- 206010012438 Dermatitis atopic Diseases 0.000 description 1
- WBGKWQHBNHJJPZ-LECWWXJVSA-N Desonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O WBGKWQHBNHJJPZ-LECWWXJVSA-N 0.000 description 1
- 229960002593 Desoximetasone Drugs 0.000 description 1
- 229960003957 Dexamethasone Drugs 0.000 description 1
- 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 1
- 208000007342 Diabetic Nephropathy Diseases 0.000 description 1
- 208000001636 Diabetic Neuropathy Diseases 0.000 description 1
- 206010061835 Diabetic nephropathy Diseases 0.000 description 1
- 206010012680 Diabetic neuropathy Diseases 0.000 description 1
- 206010012689 Diabetic retinopathy Diseases 0.000 description 1
- 206010012713 Diaphragmatic hernia Diseases 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
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N Diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N Diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 206010012818 Diffuse large B-cell lymphoma Diseases 0.000 description 1
- 229950009859 Dinaciclib Drugs 0.000 description 1
- 229960004679 Doxorubicin Drugs 0.000 description 1
- 235000004418 Durio kutejensis Nutrition 0.000 description 1
- 108010024212 E-Selectin Proteins 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 241000244170 Echinococcus granulosus Species 0.000 description 1
- 241000223924 Eimeria Species 0.000 description 1
- 229960004137 Elotuzumab Drugs 0.000 description 1
- 206010014561 Emphysema Diseases 0.000 description 1
- 208000000999 Encephalomyelitis, Autoimmune, Experimental Diseases 0.000 description 1
- 210000001163 Endosomes Anatomy 0.000 description 1
- 241000792859 Enema Species 0.000 description 1
- 229940079360 Enema for Constipation Drugs 0.000 description 1
- 241000224431 Entamoeba Species 0.000 description 1
- 241000224432 Entamoeba histolytica Species 0.000 description 1
- 229940007078 Entamoeba histolytica Drugs 0.000 description 1
- 241001464851 Entamoeba invadens Species 0.000 description 1
- AXRCEOKUDYDWLF-UHFFFAOYSA-N Enzastaurin Chemical compound C12=CC=CC=C2N(C)C=C1C(C(NC1=O)=O)=C1C(C1=CC=CC=C11)=CN1C(CC1)CCN1CC1=CC=CC=N1 AXRCEOKUDYDWLF-UHFFFAOYSA-N 0.000 description 1
- 229950002189 Enzastaurin Drugs 0.000 description 1
- 206010048653 Enzyme inhibition Diseases 0.000 description 1
- DOGIDQKFVLKMLQ-JTHVHQAWSA-N Epoxomicin Chemical compound CC[C@H](C)[C@H](N(C)C(C)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)[C@@]1(C)CO1 DOGIDQKFVLKMLQ-JTHVHQAWSA-N 0.000 description 1
- 229950009760 Epratuzumab Drugs 0.000 description 1
- 229960001433 Erlotinib Drugs 0.000 description 1
- AAKJLRGGTJKAMG-UHFFFAOYSA-N Erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 1
- 229940109526 Ery Drugs 0.000 description 1
- 208000002047 Essential Thrombocythemia Diseases 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- VJJPUSNTGOMMGY-MRVIYFEKSA-N Etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 229960005420 Etoposide Drugs 0.000 description 1
- HKVAMNSJSFKALM-GKUWKFKPSA-N Everolimus Chemical compound C1C[C@@H](OCCO)[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 HKVAMNSJSFKALM-GKUWKFKPSA-N 0.000 description 1
- 208000006168 Ewing Sarcoma Diseases 0.000 description 1
- 210000002744 Extracellular Matrix Anatomy 0.000 description 1
- 206010061850 Extranodal marginal zone B-cell lymphoma (MALT type) Diseases 0.000 description 1
- 206010015848 Extraskeletal osteosarcomas Diseases 0.000 description 1
- 229940012356 Eye Drops Drugs 0.000 description 1
- 101710038729 F2R Proteins 0.000 description 1
- BYZCJOHDXLROEC-RBWIMXSLSA-N FLUAZACORT Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)=N[C@@]3(C(=O)COC(=O)C)[C@@]1(C)C[C@@H]2O BYZCJOHDXLROEC-RBWIMXSLSA-N 0.000 description 1
- 102100002070 FOS Human genes 0.000 description 1
- 108060001038 FOS Proteins 0.000 description 1
- 201000005603 Fabry disease Diseases 0.000 description 1
- 208000001948 Farber Lipogranulomatosis Diseases 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N Floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 description 1
- 229960000961 Floxuridine Drugs 0.000 description 1
- NJNWEGFJCGYWQT-VSXGLTOVSA-N Fluclorolone acetonide Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(Cl)[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1Cl NJNWEGFJCGYWQT-VSXGLTOVSA-N 0.000 description 1
- 229960003721 Fluclorolone acetonide Drugs 0.000 description 1
- POPFMWWJOGLOIF-XWCQMRHXSA-N Fludroxycortide Chemical compound C1([C@@H](F)C2)=CC(=O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O POPFMWWJOGLOIF-XWCQMRHXSA-N 0.000 description 1
- 229940013399 Flumethasone Drugs 0.000 description 1
- 229960001347 Fluocinolone Acetonide Drugs 0.000 description 1
- FEBLZLNTKCEFIT-VSXGLTOVSA-N Fluocinolone acetonide Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O FEBLZLNTKCEFIT-VSXGLTOVSA-N 0.000 description 1
- 229960003973 Fluocortolone Drugs 0.000 description 1
- GAKMQHDJQHZUTJ-ULHLPKEOSA-N Fluocortolone Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@@H](C)[C@H](C(=O)CO)[C@@]2(C)C[C@@H]1O GAKMQHDJQHZUTJ-ULHLPKEOSA-N 0.000 description 1
- 229960002949 Fluorouracil Drugs 0.000 description 1
- 229960000618 Fluprednisolone Drugs 0.000 description 1
- MYYIMZRZXIQBGI-HVIRSNARSA-N Fluprednisolone 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]3C[C@H](F)C2=C1 MYYIMZRZXIQBGI-HVIRSNARSA-N 0.000 description 1
- 229940013644 Flurandrenolide Drugs 0.000 description 1
- WMWTYOKRWGGJOA-CENSZEJFSA-N Fluticasone propionate Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)SCF)(OC(=O)CC)[C@@]2(C)C[C@@H]1O WMWTYOKRWGGJOA-CENSZEJFSA-N 0.000 description 1
- 208000004057 Focal Nodular Hyperplasia Diseases 0.000 description 1
- 208000009553 Follicular Dendritic Cell Sarcoma Diseases 0.000 description 1
- QNXUUBBKHBYRFW-QWAPGEGQSA-N Formocortal Chemical compound C1C(C=O)=C2C=C(OCCCl)CC[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)COC(=O)C)[C@@]1(C)C[C@@H]2O QNXUUBBKHBYRFW-QWAPGEGQSA-N 0.000 description 1
- 210000001652 Frontal Lobe Anatomy 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- IECPWNUMDGFDKC-MZJAQBGESA-N Fusidic acid Chemical class O[C@@H]([C@@H]12)C[C@H]3\C(=C(/CCC=C(C)C)C(O)=O)[C@@H](OC(C)=O)C[C@]3(C)[C@@]2(C)CC[C@@H]2[C@]1(C)CC[C@@H](O)[C@H]2C IECPWNUMDGFDKC-MZJAQBGESA-N 0.000 description 1
- 101700030975 GALC Proteins 0.000 description 1
- 102100017667 GALC Human genes 0.000 description 1
- 102100000899 GNRH1 Human genes 0.000 description 1
- 208000009796 Gangliosidosis Diseases 0.000 description 1
- 210000001035 Gastrointestinal Tract Anatomy 0.000 description 1
- SDUQYLNIPVEERB-QPPQHZFASA-N Gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 1
- 229960003297 Gemtuzumab ozogamicin Drugs 0.000 description 1
- 208000000527 Germinoma Diseases 0.000 description 1
- 208000003884 Gestational Trophoblastic Disease Diseases 0.000 description 1
- 241000224467 Giardia intestinalis Species 0.000 description 1
- 229940085435 Giardia lamblia Drugs 0.000 description 1
- 208000010055 Globoid Cell Leukodystrophy Diseases 0.000 description 1
- 206010061989 Glomerulosclerosis Diseases 0.000 description 1
- 229940096919 Glycogen Drugs 0.000 description 1
- BYSGBSNPRWKUQH-UJDJLXLFSA-N Glycogen Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)[C@H](O)[C@@H](O)[C@@H](O[C@@H]2[C@H](O[C@H](O)[C@H](O)[C@H]2O)CO)O1 BYSGBSNPRWKUQH-UJDJLXLFSA-N 0.000 description 1
- 229920002527 Glycogen Polymers 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 229920002683 Glycosaminoglycan Polymers 0.000 description 1
- 108010084340 Gonadotropin-Releasing Hormone Proteins 0.000 description 1
- BLCLNMBMMGCOAS-URPVMXJPSA-N Goserelin Chemical compound C([C@@H](C(=O)N[C@H](COC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(=O)NNC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 BLCLNMBMMGCOAS-URPVMXJPSA-N 0.000 description 1
- 229960002913 Goserelin Drugs 0.000 description 1
- 108010069236 Goserelin Proteins 0.000 description 1
- 206010018651 Graft versus host disease Diseases 0.000 description 1
- 208000009329 Graft vs Host Disease Diseases 0.000 description 1
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 1
- 210000003714 Granulocytes Anatomy 0.000 description 1
- 102000034429 Gs proteins Human genes 0.000 description 1
- 108091006049 Gs proteins Proteins 0.000 description 1
- 229960000789 Guanidine Hydrochloride Drugs 0.000 description 1
- PJJJBBJSCAKJQF-UHFFFAOYSA-N Guanidinium chloride Chemical compound [Cl-].NC(N)=[NH2+] PJJJBBJSCAKJQF-UHFFFAOYSA-N 0.000 description 1
- 208000002183 Guillain-Barre Syndrome Diseases 0.000 description 1
- 229940093922 Gynecological Antibiotics Drugs 0.000 description 1
- 101700075495 HEXA Proteins 0.000 description 1
- 102100012716 HEXA Human genes 0.000 description 1
- 208000005721 HIV Infections Diseases 0.000 description 1
- MUQNGPZZQDCDFT-JNQJZLCISA-N Halcinonide Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CCl)[C@@]1(C)C[C@@H]2O MUQNGPZZQDCDFT-JNQJZLCISA-N 0.000 description 1
- 230000036499 Half live Effects 0.000 description 1
- GGXMRPUKBWXVHE-MIHLVHIWSA-N Halometasone Chemical compound C1([C@@H](F)C2)=CC(=O)C(Cl)=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]2(C)C[C@@H]1O GGXMRPUKBWXVHE-MIHLVHIWSA-N 0.000 description 1
- 208000002927 Hamartoma Diseases 0.000 description 1
- 210000003128 Head Anatomy 0.000 description 1
- 208000001258 Hemangiosarcoma Diseases 0.000 description 1
- 208000002250 Hematologic Neoplasms Diseases 0.000 description 1
- 241000700739 Hepadnaviridae Species 0.000 description 1
- 206010019629 Hepatic adenoma Diseases 0.000 description 1
- 206010019663 Hepatic failure Diseases 0.000 description 1
- 208000006454 Hepatitis Diseases 0.000 description 1
- 208000006359 Hepatoblastoma Diseases 0.000 description 1
- 206010073071 Hepatocellular carcinoma Diseases 0.000 description 1
- 208000009889 Herpes Simplex Diseases 0.000 description 1
- LJQLCJWAZJINEB-UHFFFAOYSA-N Hexafluorophosphate Chemical compound F[P-](F)(F)(F)(F)F LJQLCJWAZJINEB-UHFFFAOYSA-N 0.000 description 1
- 239000004705 High-molecular-weight polyethylene Substances 0.000 description 1
- 208000002291 Histiocytic Sarcoma Diseases 0.000 description 1
- 108010027412 Histocompatibility Antigens Class II Proteins 0.000 description 1
- 102000018713 Histocompatibility Antigens Class II Human genes 0.000 description 1
- 206010020243 Hodgkin's disease Diseases 0.000 description 1
- 206010020244 Hodgkin's disease nodular sclerosis Diseases 0.000 description 1
- 201000006743 Hodgkin's lymphoma Diseases 0.000 description 1
- 102000032167 Host cell factor Human genes 0.000 description 1
- 108091009189 Host cell factor Proteins 0.000 description 1
- 201000001971 Huntington's disease Diseases 0.000 description 1
- 102000004157 Hydrolases Human genes 0.000 description 1
- 108090000604 Hydrolases Proteins 0.000 description 1
- 241000257303 Hymenoptera Species 0.000 description 1
- 206010066130 Hyper IgM syndrome Diseases 0.000 description 1
- 208000003352 Hyper-IgM Immunodeficiency Syndrome Diseases 0.000 description 1
- 208000003532 Hypothyroidism Diseases 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- 239000003458 I kappa b kinase inhibitor Substances 0.000 description 1
- 229960000908 Idarubicin Drugs 0.000 description 1
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin hydrochloride Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 1
- 229960001101 Ifosfamide Drugs 0.000 description 1
- HOMGKSMUEGBAAB-UHFFFAOYSA-N Ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 1
- 102000018358 Immunoglobulins Human genes 0.000 description 1
- 108060003951 Immunoglobulins Proteins 0.000 description 1
- 206010061216 Infarction Diseases 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N Intaxel 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
- 208000005045 Interdigitating Dendritic Cell Sarcoma Diseases 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 102000004889 Interleukin-6 Human genes 0.000 description 1
- 108010063738 Interleukins Proteins 0.000 description 1
- 102000015696 Interleukins Human genes 0.000 description 1
- 229940047122 Interleukins Drugs 0.000 description 1
- 208000006897 Interstitial Lung Disease Diseases 0.000 description 1
- 241000726306 Irus Species 0.000 description 1
- 206010061255 Ischaemia Diseases 0.000 description 1
- 210000004153 Islets of Langerhans Anatomy 0.000 description 1
- WFKAJVHLWXSISD-UHFFFAOYSA-N Isobutyramide Chemical compound CC(C)C(N)=O WFKAJVHLWXSISD-UHFFFAOYSA-N 0.000 description 1
- 229960003648 Ixazomib Drugs 0.000 description 1
- 101700034277 JAK1 Proteins 0.000 description 1
- 102100019517 JAK1 Human genes 0.000 description 1
- 102100012486 JUN Human genes 0.000 description 1
- 108060001040 JUN Proteins 0.000 description 1
- 241000347881 Kadua laxiflora Species 0.000 description 1
- 208000007766 Kaposi Sarcoma Diseases 0.000 description 1
- 208000001083 Kidney Disease Diseases 0.000 description 1
- 201000011451 Krabbe disease Diseases 0.000 description 1
- DCXYFEDJOCDNAF-UWTATZPHSA-N L-Asparagine Natural products OC(=O)[C@H](N)CC(N)=O DCXYFEDJOCDNAF-UWTATZPHSA-N 0.000 description 1
- DLNKOYKMWOXYQA-APPZFPTMSA-N L-Norpseudoephedrine Chemical compound C[C@@H](N)[C@H](O)C1=CC=CC=C1 DLNKOYKMWOXYQA-APPZFPTMSA-N 0.000 description 1
- QAQJMLQRFWZOBN-LAUBAEHRSA-N L-ascorbyl-6-palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](O)[C@H]1OC(=O)C(O)=C1O QAQJMLQRFWZOBN-LAUBAEHRSA-N 0.000 description 1
- 239000011786 L-ascorbyl-6-palmitate Substances 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
- XUJNEKJLAYXESH-REOHCLBHSA-N L-cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 1
- 229960000448 Lactic acid Drugs 0.000 description 1
- 201000007687 Langerhans cell sarcoma Diseases 0.000 description 1
- 201000005099 Langerhans-cell histiocytosis Diseases 0.000 description 1
- TULGGJGJQXESOO-UHFFFAOYSA-N Laniquidar Chemical compound C12=CC=CC=C2CCN2C(C(=O)OC)=CN=C2C1=C1CCN(CCC=2C=CC(OCC=3N=C4C=CC=CC4=CC=3)=CC=2)CC1 TULGGJGJQXESOO-UHFFFAOYSA-N 0.000 description 1
- 229950010652 Laniquidar Drugs 0.000 description 1
- 206010023791 Large granular lymphocytosis Diseases 0.000 description 1
- 241001523179 Lasia <small-headed fly> Species 0.000 description 1
- 206010024190 Leiomyosarcomas Diseases 0.000 description 1
- 241000222722 Leishmania <genus> Species 0.000 description 1
- 241000222727 Leishmania donovani Species 0.000 description 1
- 241000222697 Leishmania infantum Species 0.000 description 1
- 206010024229 Leprosy Diseases 0.000 description 1
- HPJKCIUCZWXJDR-UHFFFAOYSA-N Letrozole Chemical compound C1=CC(C#N)=CC=C1C(N1N=CN=C1)C1=CC=C(C#N)C=C1 HPJKCIUCZWXJDR-UHFFFAOYSA-N 0.000 description 1
- 208000003697 Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative Diseases 0.000 description 1
- 208000002490 Leukemia, Myelomonocytic, Juvenile Diseases 0.000 description 1
- 208000000015 Leukemia, Neutrophilic, Chronic Diseases 0.000 description 1
- 208000001152 Leukemia, Prolymphocytic, B-Cell Diseases 0.000 description 1
- 208000000748 Leukemia, Prolymphocytic, T-Cell Diseases 0.000 description 1
- 229940008250 Leuprolide Drugs 0.000 description 1
- 108010000817 Leuprolide Proteins 0.000 description 1
- 229960004338 Leuprorelin Drugs 0.000 description 1
- 208000009829 Lewy Body Disease Diseases 0.000 description 1
- 201000002832 Lewy body dementia Diseases 0.000 description 1
- 102000003960 Ligases Human genes 0.000 description 1
- 108090000364 Ligases Proteins 0.000 description 1
- 206010024627 Liposarcoma Diseases 0.000 description 1
- 208000007903 Liver Failure Diseases 0.000 description 1
- 208000009856 Lung Disease Diseases 0.000 description 1
- 108009000252 Lung fibrosis Proteins 0.000 description 1
- 210000001165 Lymph Nodes Anatomy 0.000 description 1
- 210000003563 Lymphoid Tissue Anatomy 0.000 description 1
- 208000006557 Lymphoma, B-Cell, Marginal Zone Diseases 0.000 description 1
- 208000008968 Lymphoma, Large-Cell, Anaplastic Diseases 0.000 description 1
- 208000007282 Lymphomatoid Papulosis Diseases 0.000 description 1
- 210000003712 Lysosomes Anatomy 0.000 description 1
- 201000003791 MALT lymphoma Diseases 0.000 description 1
- 101710029807 MAPK14 Proteins 0.000 description 1
- 102100000918 MAPK14 Human genes 0.000 description 1
- 229950002736 MARIZOMIB Drugs 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L Magnesium hydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 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
- 208000006178 Malignant Mesothelioma Diseases 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N Mandelic acid Chemical compound OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 206010026798 Mantle cell lymphomas Diseases 0.000 description 1
- 210000000138 Mast Cells Anatomy 0.000 description 1
- 229950002555 Mazipredone Drugs 0.000 description 1
- GZENKSODFLBBHQ-ILSZZQPISA-N Medrysone Chemical compound 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@@H](C(C)=O)CC[C@H]21 GZENKSODFLBBHQ-ILSZZQPISA-N 0.000 description 1
- 208000000172 Medulloblastoma Diseases 0.000 description 1
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N Melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 1
- 206010027260 Meningitis viral Diseases 0.000 description 1
- 240000006217 Mentha pulegium Species 0.000 description 1
- 235000016257 Mentha pulegium Nutrition 0.000 description 1
- PIDANAQULIKBQS-RNUIGHNZSA-N Meprednisone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)CC2=O PIDANAQULIKBQS-RNUIGHNZSA-N 0.000 description 1
- 208000002030 Merkel Cell Carcinoma Diseases 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N Methyl iodide Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- STZCRXQWRGQSJD-GEEYTBSJSA-M Methyl orange Chemical compound [Na+].C1=CC(N(C)C)=CC=C1\N=N\C1=CC=C(S([O-])(=O)=O)C=C1 STZCRXQWRGQSJD-GEEYTBSJSA-M 0.000 description 1
- 229940012189 Methyl orange Drugs 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N Methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- VHRSUDSXCMQTMA-PJHHCJLFSA-N Methylprednisolone Chemical compound 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)CO)CC[C@H]21 VHRSUDSXCMQTMA-PJHHCJLFSA-N 0.000 description 1
- 210000004080 Milk Anatomy 0.000 description 1
- 206010049567 Miller Fisher syndrome Diseases 0.000 description 1
- 229960004857 Mitomycin Drugs 0.000 description 1
- 229960000350 Mitotane Drugs 0.000 description 1
- KKZJGLLVHKMTCM-UHFFFAOYSA-N Mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 1
- 229960001156 Mitoxantrone Drugs 0.000 description 1
- 241000840267 Moma Species 0.000 description 1
- 229960001664 Mometasone Drugs 0.000 description 1
- 210000001616 Monocytes Anatomy 0.000 description 1
- 210000000214 Mouth Anatomy 0.000 description 1
- 208000008955 Mucolipidosis Diseases 0.000 description 1
- 206010072927 Mucolipidosis type I Diseases 0.000 description 1
- 206010056893 Mucopolysaccharidosis VII Diseases 0.000 description 1
- 210000004400 Mucous Membrane Anatomy 0.000 description 1
- 208000005314 Multi-Infarct Dementia Diseases 0.000 description 1
- 206010066289 Mycobacterium ulcerans infection Diseases 0.000 description 1
- 210000000066 Myeloid Cells Anatomy 0.000 description 1
- 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 1
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 description 1
- XLXSAKCOAKORKW-KPKRHBJMSA-N N-[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[2-[[(2S)-1-[[(2S)-1-[(2S)-2-[(2-amino-2-oxoethyl)carbamoyl]pyrrolidin-1-yl]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-2-oxoethyl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl] Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)C1NC(=O)CC1)C1=CC=C(O)C=C1 XLXSAKCOAKORKW-KPKRHBJMSA-N 0.000 description 1
- LGGHDPFKSSRQNS-UHFFFAOYSA-N N-[2-[[4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)ethyl]phenyl]carbamoyl]-4,5-dimethoxyphenyl]quinoline-3-carboxamide Chemical compound C1=CC=CC2=CC(C(=O)NC3=CC(OC)=C(OC)C=C3C(=O)NC3=CC=C(C=C3)CCN3CCC=4C=C(C(=CC=4C3)OC)OC)=CN=C21 LGGHDPFKSSRQNS-UHFFFAOYSA-N 0.000 description 1
- RIWRFSMVIUAEBX-UHFFFAOYSA-N N-methyl-1-phenylmethanamine Chemical compound CNCC1=CC=CC=C1 RIWRFSMVIUAEBX-UHFFFAOYSA-N 0.000 description 1
- HWYHDWGGACRVEH-UHFFFAOYSA-N N-methyl-N-(4-pyrrolidin-1-ylbut-2-ynyl)acetamide Chemical compound CC(=O)N(C)CC#CCN1CCCC1 HWYHDWGGACRVEH-UHFFFAOYSA-N 0.000 description 1
- 229940073569 N-methylephedrine Drugs 0.000 description 1
- 125000000729 N-terminal amino-acid group Chemical group 0.000 description 1
- 229910017852 NH2NH2 Inorganic materials 0.000 description 1
- 229910020936 NaC Inorganic materials 0.000 description 1
- 229940086322 Navelbine Drugs 0.000 description 1
- 210000003739 Neck Anatomy 0.000 description 1
- 208000001628 Nerve Sheath Neoplasms Diseases 0.000 description 1
- 206010052639 Nerve injury Diseases 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 206010029266 Neuroendocrine carcinoma of the skin Diseases 0.000 description 1
- 206010052399 Neuroendocrine tumour Diseases 0.000 description 1
- 206010029273 Neurofibrosarcomas Diseases 0.000 description 1
- 206010029331 Neuropathy peripheral Diseases 0.000 description 1
- 241000221961 Neurospora crassa Species 0.000 description 1
- 208000006660 Niemann-Pick Disease Diseases 0.000 description 1
- 206010029461 Nodal marginal zone B-cell lymphomas Diseases 0.000 description 1
- 210000004940 Nucleus Anatomy 0.000 description 1
- SVHYGBLKBNPNGQ-LJYZBVLISA-N OC(CC(=O)N[C@@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)[C@@H]1OC1)CC1=CC=C(C=C1)C)CC1=CC=C(C=C1)OC)C)(C)C Chemical compound OC(CC(=O)N[C@@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)[C@@H]1OC1)CC1=CC=C(C=C1)C)CC1=CC=C(C=C1)OC)C)(C)C SVHYGBLKBNPNGQ-LJYZBVLISA-N 0.000 description 1
- FAQDUNYVKQKNLD-UHFFFAOYSA-N Olaparib Chemical compound FC1=CC=C(CC2=C3[CH]C=CC=C3C(=O)N=N2)C=C1C(=O)N(CC1)CCN1C(=O)C1CC1 FAQDUNYVKQKNLD-UHFFFAOYSA-N 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- 206010073131 Oligoastrocytoma Diseases 0.000 description 1
- 101710027499 Os03g0268000 Proteins 0.000 description 1
- 108009000065 Osteoblast differentiation Proteins 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 210000001672 Ovary Anatomy 0.000 description 1
- 210000003101 Oviducts Anatomy 0.000 description 1
- 101700036247 PARP1 Proteins 0.000 description 1
- 102100014579 PARP1 Human genes 0.000 description 1
- 101700053624 PARP2 Proteins 0.000 description 1
- 101800000628 PDH precursor-related peptide Proteins 0.000 description 1
- 108010079844 PR-957 Proteins 0.000 description 1
- 101700027237 PROA Proteins 0.000 description 1
- 229960001592 Paclitaxel Drugs 0.000 description 1
- 235000003177 Panax trifolius Nutrition 0.000 description 1
- 206010033645 Pancreatitis Diseases 0.000 description 1
- FWZRWHZDXBDTFK-ZHACJKMWSA-N Panobinostat Chemical compound CC1=NC2=CC=C[CH]C2=C1CCNCC1=CC=C(\C=C\C(=O)NO)C=C1 FWZRWHZDXBDTFK-ZHACJKMWSA-N 0.000 description 1
- 229960002858 Paramethasone Drugs 0.000 description 1
- MKPDWECBUAZOHP-AFYJWTTESA-N Paramethasone Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]2(C)C[C@@H]1O MKPDWECBUAZOHP-AFYJWTTESA-N 0.000 description 1
- 206010061536 Parkinson's disease Diseases 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 229960002340 Pentostatin Drugs 0.000 description 1
- FPVKHBSQESCIEP-JQCXWYLXSA-N Pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 description 1
- 229950010632 Perifosine Drugs 0.000 description 1
- SZFPYBIJACMNJV-UHFFFAOYSA-N Perifosine Chemical compound CCCCCCCCCCCCCCCCCCOP([O-])(=O)OC1CC[N+](C)(C)CC1 SZFPYBIJACMNJV-UHFFFAOYSA-N 0.000 description 1
- 210000000578 Peripheral Nerves Anatomy 0.000 description 1
- 206010034636 Peripheral vascular disease Diseases 0.000 description 1
- 206010034695 Pernicious anaemia Diseases 0.000 description 1
- 210000003800 Pharynx Anatomy 0.000 description 1
- YNPNZTXNASCQKK-UHFFFAOYSA-N Phenanthrene Chemical compound C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 description 1
- 229960000395 Phenylpropanolamine Drugs 0.000 description 1
- PQGCEDQWHSBAJP-TXICZTDVSA-N Phosphoribosyl pyrophosphate Chemical compound O[C@H]1[C@@H](O)[C@@H](O[P@](O)(=O)OP(O)(O)=O)O[C@@H]1COP(O)(O)=O PQGCEDQWHSBAJP-TXICZTDVSA-N 0.000 description 1
- 108091000081 Phosphotransferases Proteins 0.000 description 1
- 240000009188 Phyllostachys vivax Species 0.000 description 1
- 208000007452 Plasmacytoma Diseases 0.000 description 1
- 241000223960 Plasmodium falciparum Species 0.000 description 1
- 241000223821 Plasmodium malariae Species 0.000 description 1
- 206010035501 Plasmodium malariae infection Diseases 0.000 description 1
- 241001505293 Plasmodium ovale Species 0.000 description 1
- 206010035502 Plasmodium ovale infection Diseases 0.000 description 1
- 206010035503 Plasmodium vivax infection Diseases 0.000 description 1
- 206010035603 Pleural mesothelioma Diseases 0.000 description 1
- 241000233872 Pneumocystis carinii Species 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229920000776 Poly(Adenosine diphosphate-ribose) polymerase Polymers 0.000 description 1
- 239000004952 Polyamide Substances 0.000 description 1
- 208000008696 Polycythemia Vera Diseases 0.000 description 1
- 229940068965 Polysorbates Drugs 0.000 description 1
- UVSMNLNDYGZFPF-UHFFFAOYSA-N Pomalidomide Chemical compound O=C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O UVSMNLNDYGZFPF-UHFFFAOYSA-N 0.000 description 1
- FNPXMHRZILFCKX-KAJVQRHHSA-N Prednicarbate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)CC)(OC(=O)OCC)[C@@]1(C)C[C@@H]2O FNPXMHRZILFCKX-KAJVQRHHSA-N 0.000 description 1
- 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 1
- 229960001917 Prednylidene Drugs 0.000 description 1
- WSVOMANDJDYYEY-CWNVBEKCSA-N Prednylidene Chemical group O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](C(=C)C4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 WSVOMANDJDYYEY-CWNVBEKCSA-N 0.000 description 1
- 208000000814 Primary Cutaneous Anaplastic Large Cell Lymphoma Diseases 0.000 description 1
- 206010036700 Primary immunodeficiency syndrome Diseases 0.000 description 1
- CPTBDICYNRMXFX-UHFFFAOYSA-N Procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 description 1
- 229960002429 Proline Drugs 0.000 description 1
- 229940075579 Propyl Gallate Drugs 0.000 description 1
- 210000002307 Prostate Anatomy 0.000 description 1
- 108009000611 Proteasome Degradation Proteins 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- 102000000850 Proto-Oncogene Proteins c-rel Human genes 0.000 description 1
- 108010001859 Proto-Oncogene Proteins c-rel Proteins 0.000 description 1
- 208000005069 Pulmonary Fibrosis Diseases 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N Pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N Pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 1
- 101700007902 RELB Proteins 0.000 description 1
- 229960001487 RIMEXOLONE Drugs 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 206010038272 Refractory anaemia with ringed sideroblasts Diseases 0.000 description 1
- 206010038435 Renal failure Diseases 0.000 description 1
- 206010063837 Reperfusion injury Diseases 0.000 description 1
- 229940120975 Revlimid Drugs 0.000 description 1
- QTTRZHGPGKRAFB-OOKHYKNYSA-N Rimexolone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CC)(C)[C@@]1(C)C[C@@H]2O QTTRZHGPGKRAFB-OOKHYKNYSA-N 0.000 description 1
- 108010001645 Rituximab Proteins 0.000 description 1
- 102100003520 SELE Human genes 0.000 description 1
- 102100001435 SH2D1A Human genes 0.000 description 1
- 101710013575 SH2D1A Proteins 0.000 description 1
- 229940100996 SODIUM BISULFATE Drugs 0.000 description 1
- 102100014920 SREBF1 Human genes 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 235000019485 Safflower oil Nutrition 0.000 description 1
- NGWSFRIPKNWYAO-SHTIJGAHSA-N Salinosporamide A Chemical compound C([C@@H]1[C@H](O)[C@]23C(=O)O[C@]2([C@H](C(=O)N3)CCCl)C)CCC=C1 NGWSFRIPKNWYAO-SHTIJGAHSA-N 0.000 description 1
- 201000008894 Sandhoff disease Diseases 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 206010039580 Scar Diseases 0.000 description 1
- BTIHMVBBUGXLCJ-OAHLLOKOSA-N Seliciclib Chemical compound C=12N=CN(C(C)C)C2=NC(N[C@@H](CO)CC)=NC=1NCC1=CC=CC=C1 BTIHMVBBUGXLCJ-OAHLLOKOSA-N 0.000 description 1
- 229950000055 Seliciclib Drugs 0.000 description 1
- 229920002684 Sepharose Polymers 0.000 description 1
- 210000002966 Serum Anatomy 0.000 description 1
- 108010071390 Serum Albumin Proteins 0.000 description 1
- 241000700584 Simplexvirus Species 0.000 description 1
- 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 1
- 208000006641 Skin Disease Diseases 0.000 description 1
- 102000007374 Smad Proteins Human genes 0.000 description 1
- 108010007945 Smad Proteins Proteins 0.000 description 1
- 208000000587 Small Cell Lung Carcinoma Diseases 0.000 description 1
- 208000004346 Smoldering Multiple Myeloma Diseases 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M Sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- MFBOGIVSZKQAPD-UHFFFAOYSA-M Sodium butyrate Chemical compound [Na+].CCCC([O-])=O MFBOGIVSZKQAPD-UHFFFAOYSA-M 0.000 description 1
- UKLNMMHNWFDKNT-UHFFFAOYSA-M Sodium chlorite Chemical compound [Na+].[O-]Cl=O UKLNMMHNWFDKNT-UHFFFAOYSA-M 0.000 description 1
- JQWHASGSAFIOCM-UHFFFAOYSA-M Sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 1
- 229940091252 Sodium supplements Drugs 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L Sodium thiosulphate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 240000001016 Solanum tuberosum Species 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- 229940075582 Sorbic Acid Drugs 0.000 description 1
- 208000008513 Spinal Cord Injury Diseases 0.000 description 1
- 210000000952 Spleen Anatomy 0.000 description 1
- 229940032147 Starch Drugs 0.000 description 1
- 108010074436 Sterol Regulatory Element Binding Protein 1 Proteins 0.000 description 1
- 210000002784 Stomach Anatomy 0.000 description 1
- 108010090804 Streptavidin Proteins 0.000 description 1
- 229960001052 Streptozocin Drugs 0.000 description 1
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N Streptozotocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 1
- 206010042863 Synovial sarcoma Diseases 0.000 description 1
- 208000006379 Syphilis Diseases 0.000 description 1
- 206010042953 Systemic sclerosis Diseases 0.000 description 1
- 206010042985 T-cell prolymphocytic leukaemia Diseases 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N TFA trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 108060008443 TPPP Proteins 0.000 description 1
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 1
- 229960001603 Tamoxifen Drugs 0.000 description 1
- AYUNIORJHRXIBJ-TXHRRWQRSA-N Tanespimycin 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(NCC=C)C(=O)C=C1C2=O AYUNIORJHRXIBJ-TXHRRWQRSA-N 0.000 description 1
- 229950005890 Tariquidar Drugs 0.000 description 1
- 201000008902 Tay-Sachs disease Diseases 0.000 description 1
- 102000004591 Telomerase Human genes 0.000 description 1
- 108010017842 Telomerase Proteins 0.000 description 1
- CBPNZQVSJQDFBE-FUXHJELOSA-N Temsirolimus Chemical compound C1C[C@@H](OC(=O)C(C)(CO)CO)[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 CBPNZQVSJQDFBE-FUXHJELOSA-N 0.000 description 1
- 229960001278 Teniposide Drugs 0.000 description 1
- 206010043276 Teratoma Diseases 0.000 description 1
- 210000001550 Testis Anatomy 0.000 description 1
- FPGGTKZVZWFYPV-UHFFFAOYSA-M Tetra-n-butylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 1
- 229960003433 Thalidomide Drugs 0.000 description 1
- UEJJHQNACJXSKW-UHFFFAOYSA-N Thalidomide Chemical compound O=C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O UEJJHQNACJXSKW-UHFFFAOYSA-N 0.000 description 1
- 229940033663 Thimerosal Drugs 0.000 description 1
- FOCVUCIESVLUNU-UHFFFAOYSA-N ThioTEPA Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 description 1
- 229960005454 Thioguanine Drugs 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L Thiomersal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229960001196 Thiotepa Drugs 0.000 description 1
- 210000001685 Thyroid Gland Anatomy 0.000 description 1
- VXUYXOFXAQZZMF-UHFFFAOYSA-N Titanium isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 1
- AOBORMOPSGHCAX-DGHZZKTQSA-N Tocofersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2O[C@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-DGHZZKTQSA-N 0.000 description 1
- 229940024982 Topical Antifungal Antibiotics Drugs 0.000 description 1
- 229940118701 Toxoplasma gondii Drugs 0.000 description 1
- 241000223997 Toxoplasma gondii Species 0.000 description 1
- 102000006289 Transcription Factor TFIIA Human genes 0.000 description 1
- 108010083262 Transcription Factor TFIIA Proteins 0.000 description 1
- 108010010691 Trastuzumab Proteins 0.000 description 1
- 229960002117 Triamcinolone Acetonide Drugs 0.000 description 1
- YNDXUCZADRHECN-JNQJZLCISA-N Triamcinolone acetonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O YNDXUCZADRHECN-JNQJZLCISA-N 0.000 description 1
- TZIZWYVVGLXXFV-FLRHRWPCSA-N Triamcinolone hexacetonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)COC(=O)CC(C)(C)C)[C@@]1(C)C[C@@H]2O TZIZWYVVGLXXFV-FLRHRWPCSA-N 0.000 description 1
- RTKIYFITIVXBLE-QEQCGCAPSA-N Trichostatin A Chemical compound ONC(=O)/C=C/C(/C)=C/[C@@H](C)C(=O)C1=CC=C(N(C)C)C=C1 RTKIYFITIVXBLE-QEQCGCAPSA-N 0.000 description 1
- WVLBCYQITXONBZ-UHFFFAOYSA-N Trimethyl phosphate Chemical compound COP(=O)(OC)OC WVLBCYQITXONBZ-UHFFFAOYSA-N 0.000 description 1
- 229960004824 Triptorelin Drugs 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Tris Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 239000007984 Tris EDTA buffer Substances 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K Trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- 241000223104 Trypanosoma Species 0.000 description 1
- 241000223105 Trypanosoma brucei Species 0.000 description 1
- 241000223109 Trypanosoma cruzi Species 0.000 description 1
- 102000006275 Ubiquitin-Protein Ligases Human genes 0.000 description 1
- 108010083111 Ubiquitin-Protein Ligases Proteins 0.000 description 1
- 108010005705 Ubiquitinated Proteins Proteins 0.000 description 1
- 210000003932 Urinary Bladder Anatomy 0.000 description 1
- 210000004291 Uterus Anatomy 0.000 description 1
- 206010053648 Vascular occlusion Diseases 0.000 description 1
- 229950011257 Veliparib Drugs 0.000 description 1
- SGTNSNPWRIOYBX-UHFFFAOYSA-N Verapamil Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-UHFFFAOYSA-N 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 229960003048 Vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 1
- 241000863480 Vinca Species 0.000 description 1
- 229960000237 Vorinostat Drugs 0.000 description 1
- WAEXFXRVDQXREF-UHFFFAOYSA-N Vorinostat Chemical compound ONC(=O)CCCCCCC(=O)NC1=CC=CC=C1 WAEXFXRVDQXREF-UHFFFAOYSA-N 0.000 description 1
- 206010047802 Waldenstrom's macroglobulinaemias Diseases 0.000 description 1
- VPAHZSUNBOYNQY-DLVGLDQCSA-N Zalypsis Chemical compound C([C@H]1C2=C3OCOC3=C(C)C(OC(C)=O)=C2C[C@@H]2N1[C@@H](O)[C@@H]1CC3=CC(C)=C(C(=C3[C@H]2N1C)O)OC)NC(=O)\C=C\C1=CC=CC(C(F)(F)F)=C1 VPAHZSUNBOYNQY-DLVGLDQCSA-N 0.000 description 1
- QIJRTFXNRTXDIP-JIZZDEOASA-N [(1R)-1-carboxy-2-sulfanylethyl]azanium;chloride;hydrate Chemical compound O.Cl.SC[C@H](N)C(O)=O QIJRTFXNRTXDIP-JIZZDEOASA-N 0.000 description 1
- BDSYKGHYMJNPAB-LICBFIPMSA-N [(6S,8S,9R,10S,11S,13S,14S,16S,17R)-17-(2-chloroacetyl)-6,9-difluoro-11-hydroxy-10,13,16-trimethyl-3-oxo-6,7,8,11,12,14,15,16-octahydrocyclopenta[a]phenanthren-17-yl] propanoate Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@H](C)[C@@](C(=O)CCl)(OC(=O)CC)[C@@]2(C)C[C@@H]1O BDSYKGHYMJNPAB-LICBFIPMSA-N 0.000 description 1
- BOFKYYWJAOZDPB-FZNHGJLXSA-N [(8S,9S,10R,11S,13S,14S,17R)-11-hydroxy-17-(2-hydroxyacetyl)-10,13-dimethyl-3-oxo-7,8,9,11,12,14,15,16-octahydro-6H-cyclopenta[a]phenanthren-17-yl] pentanoate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)CO)(OC(=O)CCCC)[C@@]1(C)C[C@@H]2O BOFKYYWJAOZDPB-FZNHGJLXSA-N 0.000 description 1
- DEFOZIFYUBUHHU-IYQKUMFPSA-N [2-[(8S,9R,10S,11S,13S,14S,17R)-9-fluoro-11,17-dihydroxy-10,13-dimethyl-16-methylidene-3-oxo-7,8,11,12,14,15-hexahydro-6H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl] acetate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1CC(=C)[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)C[C@@H]2O DEFOZIFYUBUHHU-IYQKUMFPSA-N 0.000 description 1
- HHNLJRLNDSEYOX-UHFFFAOYSA-M [Br-].CC=C[Mg+] Chemical compound [Br-].CC=C[Mg+] HHNLJRLNDSEYOX-UHFFFAOYSA-M 0.000 description 1
- ANMNOXJEJSOYSF-UHFFFAOYSA-N [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylidene]-dimethylazanium;N-ethyl-N-propan-2-ylpropan-2-amine;hexafluorophosphate Chemical compound F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C1=CN=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 ANMNOXJEJSOYSF-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 239000003655 absorption accelerator Substances 0.000 description 1
- 239000003070 absorption delaying agent Substances 0.000 description 1
- 150000007513 acids Chemical class 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
- 230000010398 acute inflammatory response Effects 0.000 description 1
- 125000002015 acyclic group Chemical group 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive Effects 0.000 description 1
- 230000001058 adult Effects 0.000 description 1
- 201000006966 adult T-cell leukemia Diseases 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 229960000552 alclometasone Drugs 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229960000548 alemtuzumab Drugs 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229930013930 alkaloids Natural products 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 150000008052 alkyl sulfonates Chemical class 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940087168 alpha Tocopherol Drugs 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N alpha-Tocopherol Natural products OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229960002932 anastrozole Drugs 0.000 description 1
- 230000019552 anatomical structure morphogenesis Effects 0.000 description 1
- 201000003076 angiosarcoma Diseases 0.000 description 1
- 150000003931 anilides Chemical class 0.000 description 1
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 1
- 230000003042 antagnostic Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000003110 anti-inflammatory Effects 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940045719 antineoplastic alkylating agents Nitrosoureas Drugs 0.000 description 1
- 229940027983 antiseptics and disinfectants Quaternary ammonium compounds Drugs 0.000 description 1
- 201000007201 aphasia Diseases 0.000 description 1
- 239000003886 aromatase inhibitor Substances 0.000 description 1
- 101700004528 arp Proteins 0.000 description 1
- 235000010385 ascorbyl palmitate Nutrition 0.000 description 1
- 239000012131 assay buffer Substances 0.000 description 1
- 201000004892 atypical chronic myeloid leukemia Diseases 0.000 description 1
- 239000003719 aurora kinase inhibitor Substances 0.000 description 1
- HGQULGDOROIPJN-UHFFFAOYSA-N azetidin-1-ium;chloride Chemical compound Cl.C1CNC1 HGQULGDOROIPJN-UHFFFAOYSA-N 0.000 description 1
- NOWKCMXCCJGMRR-UHFFFAOYSA-N aziridine Chemical class C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 1
- 230000003385 bacteriostatic Effects 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 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 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-M benzoate Chemical compound [O-]C(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-M 0.000 description 1
- 229960002903 benzyl benzoate Drugs 0.000 description 1
- 229960002537 betamethasone Drugs 0.000 description 1
- 229960000397 bevacizumab Drugs 0.000 description 1
- 239000003833 bile salt Substances 0.000 description 1
- 230000035514 bioavailability Effects 0.000 description 1
- 230000003115 biocidal Effects 0.000 description 1
- 239000000560 biocompatible material Substances 0.000 description 1
- 229920000249 biocompatible polymer Polymers 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- 229960001467 bortezomib Drugs 0.000 description 1
- 231100000874 brain damage Toxicity 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 229960002092 busulfan Drugs 0.000 description 1
- IJDNQMDRQITEOD-UHFFFAOYSA-N butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 description 1
- 239000001273 butane Substances 0.000 description 1
- XWTIDFOGTCVGQB-FHIVUSPVSA-N butyl 2-[(6S,8S,9S,10R,11S,13S,14S,16R,17S)-6-fluoro-11-hydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthren-17-yl]-2-oxoacetate Chemical group C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@@H](C)[C@H](C(=O)C(=O)OCCCC)[C@@]2(C)C[C@@H]1O XWTIDFOGTCVGQB-FHIVUSPVSA-N 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
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 235000012241 calcium silicate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- AOGYCOYQMAVAFD-UHFFFAOYSA-M carbonochloridate Chemical compound [O-]C(Cl)=O AOGYCOYQMAVAFD-UHFFFAOYSA-M 0.000 description 1
- 150000003857 carboxamides Chemical class 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 201000009030 carcinoma Diseases 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 229960005243 carmustine Drugs 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000033077 cellular process Effects 0.000 description 1
- 229960005395 cetuximab Drugs 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 210000000038 chest Anatomy 0.000 description 1
- 229950006229 chloroprednisone Drugs 0.000 description 1
- 230000012085 chronic inflammatory response Effects 0.000 description 1
- 201000010903 chronic neutrophilic leukemia Diseases 0.000 description 1
- 230000037012 chymotrypsin-like activity Effects 0.000 description 1
- 229960001265 ciclosporin Drugs 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 239000004927 clay Substances 0.000 description 1
- 229910052570 clay Inorganic materials 0.000 description 1
- 229960002842 clobetasol Drugs 0.000 description 1
- FCSHDIVRCWTZOX-DVTGEIKXSA-N clobetasol 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)CCl)(O)[C@@]1(C)C[C@@H]2O FCSHDIVRCWTZOX-DVTGEIKXSA-N 0.000 description 1
- 229960004299 clocortolone Drugs 0.000 description 1
- YMTMADLUXIRMGX-RFPWEZLHSA-N clocortolone Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(Cl)[C@@H]2[C@@H]2C[C@@H](C)[C@H](C(=O)CO)[C@@]2(C)C[C@@H]1O YMTMADLUXIRMGX-RFPWEZLHSA-N 0.000 description 1
- 229960002219 cloprednol Drugs 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 201000011231 colorectal cancer Diseases 0.000 description 1
- 201000010989 colorectal carcinoma Diseases 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000002860 competitive Effects 0.000 description 1
- 239000007891 compressed tablet Substances 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 201000005890 congenital diaphragmatic hernia Diseases 0.000 description 1
- 201000006233 congestive heart failure Diseases 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 201000008739 coronary artery disease Diseases 0.000 description 1
- 230000002596 correlated Effects 0.000 description 1
- 230000001054 cortical Effects 0.000 description 1
- 229960004544 cortisone Drugs 0.000 description 1
- 229960003840 cortivazol Drugs 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 239000002385 cottonseed oil Substances 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
- SNRCKKQHDUIRIY-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloromethane;dichloropalladium;iron(2+) Chemical compound [Fe+2].ClCCl.Cl[Pd]Cl.C1=C[CH-]C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.C1=C[CH-]C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 SNRCKKQHDUIRIY-UHFFFAOYSA-L 0.000 description 1
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 1
- IKPDAPSSTDFYQJ-UHFFFAOYSA-N cyclopenten-1-yl propanoate Chemical compound CCC(=O)OC1=CCCC1 IKPDAPSSTDFYQJ-UHFFFAOYSA-N 0.000 description 1
- 201000003808 cystic echinococcosis Diseases 0.000 description 1
- 201000003883 cystic fibrosis Diseases 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 230000002354 daily Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 230000002638 denervation Effects 0.000 description 1
- 230000000779 depleting Effects 0.000 description 1
- 229960003662 desonide Drugs 0.000 description 1
- VWVSBHGCDBMOOT-IIEHVVJPSA-N desoximetasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@H](C(=O)CO)[C@@]1(C)C[C@@H]2O VWVSBHGCDBMOOT-IIEHVVJPSA-N 0.000 description 1
- 230000001809 detectable Effects 0.000 description 1
- 239000003599 detergent Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229960004154 diflorasone Drugs 0.000 description 1
- WXURHACBFYSXBI-XHIJKXOTSA-N diflorasone Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@H](C)[C@@](C(=O)CO)(O)[C@@]2(C)C[C@@H]1O WXURHACBFYSXBI-XHIJKXOTSA-N 0.000 description 1
- 229960004091 diflucortolone Drugs 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- 201000010046 dilated cardiomyopathy Diseases 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 201000008325 diseases of cellular proliferation Diseases 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 229950008597 drug INN Drugs 0.000 description 1
- 108010061937 elotuzumab Proteins 0.000 description 1
- 239000012156 elution solvent Substances 0.000 description 1
- 201000011523 endocrine gland cancer Diseases 0.000 description 1
- 230000002357 endometrial Effects 0.000 description 1
- 239000007920 enema Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 230000002327 eosinophilic Effects 0.000 description 1
- 108010007604 epratuzumab Proteins 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N ethanolamine Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 description 1
- HESKTUHERVMQMI-UHFFFAOYSA-N ethyl 4,5,6,7-tetrahydro-1H-indazole-3-carboxylate Chemical compound C1CCCC2=C1NN=C2C(=O)OCC HESKTUHERVMQMI-UHFFFAOYSA-N 0.000 description 1
- ZXYAWONOWHSQRU-UHFFFAOYSA-N ethyl 4-oxocyclohexane-1-carboxylate Chemical compound CCOC(=O)C1CCC(=O)CC1 ZXYAWONOWHSQRU-UHFFFAOYSA-N 0.000 description 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-N ethyl amine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 1
- CQDGTJPVBWZJAZ-UHFFFAOYSA-M ethyl carbonate Chemical compound CCOC([O-])=O CQDGTJPVBWZJAZ-UHFFFAOYSA-M 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- MMXKVMNBHPAILY-UHFFFAOYSA-N ethyl laurate Chemical compound CCCCCCCCCCCC(=O)OCC MMXKVMNBHPAILY-UHFFFAOYSA-N 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- KCWYOFZQRFCIIE-UHFFFAOYSA-N ethylsilane Chemical compound CC[SiH3] KCWYOFZQRFCIIE-UHFFFAOYSA-N 0.000 description 1
- 210000003527 eukaryotic cell Anatomy 0.000 description 1
- 229960005167 everolimus Drugs 0.000 description 1
- 229960000255 exemestane Drugs 0.000 description 1
- 201000008915 extracutaneous mastocytoma Diseases 0.000 description 1
- 201000008815 extraosseous osteosarcoma Diseases 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 239000003885 eye ointment Substances 0.000 description 1
- 235000020828 fasting Nutrition 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229950002335 fluazacort Drugs 0.000 description 1
- 229940094766 flucloronide Drugs 0.000 description 1
- 229960004511 fludroxycortide Drugs 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 229960003469 flumetasone Drugs 0.000 description 1
- WXURHACBFYSXBI-GQKYHHCASA-N flumethasone Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]2(C)C[C@@H]1O WXURHACBFYSXBI-GQKYHHCASA-N 0.000 description 1
- 229960000676 flunisolide Drugs 0.000 description 1
- 229950008509 fluocortin butyl Drugs 0.000 description 1
- 229960003590 fluperolone Drugs 0.000 description 1
- 229960002650 fluprednidene acetate Drugs 0.000 description 1
- 229960000289 fluticasone propionate Drugs 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical class 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 1
- 201000003444 follicular lymphoma Diseases 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 229960000671 formocortal Drugs 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N furane Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 201000006440 gangliosidosis Diseases 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229960005277 gemcitabine Drugs 0.000 description 1
- 102000034448 gene-regulatory proteins Human genes 0.000 description 1
- 108091006088 gene-regulatory proteins Proteins 0.000 description 1
- 201000003115 germ cell cancer Diseases 0.000 description 1
- 201000010915 glioblastoma multiforme Diseases 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 201000008977 glycoproteinosis Diseases 0.000 description 1
- 150000002339 glycosphingolipids Chemical class 0.000 description 1
- 200000000028 growth disorder Diseases 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 230000003779 hair growth Effects 0.000 description 1
- 201000009277 hairy cell leukemia Diseases 0.000 description 1
- 229960002383 halcinonide Drugs 0.000 description 1
- 229940048498 halobetasol propionate Drugs 0.000 description 1
- 229960002475 halometasone Drugs 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 239000003481 heat shock protein 90 inhibitor Substances 0.000 description 1
- 201000011066 hemangioma Diseases 0.000 description 1
- 230000002489 hematologic Effects 0.000 description 1
- 230000011132 hemopoiesis Effects 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 125000004366 heterocycloalkenyl group Chemical group 0.000 description 1
- 239000000833 heterodimer Substances 0.000 description 1
- 235000001050 hortel pimenta Nutrition 0.000 description 1
- 201000001820 human immunodeficiency virus infectious disease Diseases 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 230000003301 hydrolyzing Effects 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 229960001330 hydroxycarbamide Drugs 0.000 description 1
- VSNHCAURESNICA-UHFFFAOYSA-N hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 description 1
- 229940027318 hydroxyurea Drugs 0.000 description 1
- 230000002989 hypothyroidism Effects 0.000 description 1
- 230000001146 hypoxic Effects 0.000 description 1
- 230000000642 iatrogenic Effects 0.000 description 1
- 229960001001 ibritumomab tiuxetan Drugs 0.000 description 1
- 108010061572 ibritumomab tiuxetan Proteins 0.000 description 1
- 201000009794 idiopathic pulmonary fibrosis Diseases 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 150000003949 imides Chemical class 0.000 description 1
- 230000002519 immonomodulatory Effects 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 239000003547 immunosorbent Substances 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 201000009298 indolent myeloma Diseases 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910003480 inorganic solid Inorganic materials 0.000 description 1
- 230000035992 intercellular communication Effects 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 229940079866 intestinal antibiotics Drugs 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 230000004068 intracellular signaling Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 description 1
- 238000000752 ionisation method Methods 0.000 description 1
- 230000002427 irreversible Effects 0.000 description 1
- 230000000302 ischemic Effects 0.000 description 1
- 239000000644 isotonic solution Substances 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 201000005992 juvenile myelomonocytic leukemia Diseases 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 150000002605 large molecules Chemical class 0.000 description 1
- POULHZVOKOAJMA-UHFFFAOYSA-M laurate Chemical compound CCCCCCCCCCCC([O-])=O POULHZVOKOAJMA-UHFFFAOYSA-M 0.000 description 1
- 229940070765 laurate Drugs 0.000 description 1
- 229960003881 letrozole Drugs 0.000 description 1
- GFIJNRVAKGFPGQ-LIJARHBVSA-N leuprolide Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 GFIJNRVAKGFPGQ-LIJARHBVSA-N 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 230000000670 limiting Effects 0.000 description 1
- 108010053632 lipopolysaccharide-binding protein Proteins 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 201000004044 liver cirrhosis Diseases 0.000 description 1
- 231100000835 liver failure Toxicity 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 238000011068 load Methods 0.000 description 1
- 229960003744 loteprednol etabonate Drugs 0.000 description 1
- DMKSVUSAATWOCU-HROMYWEYSA-N loteprednol etabonate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)OCCl)(OC(=O)OCC)[C@@]1(C)C[C@@H]2O DMKSVUSAATWOCU-HROMYWEYSA-N 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 201000005296 lung carcinoma Diseases 0.000 description 1
- 201000009546 lung large cell carcinoma Diseases 0.000 description 1
- 201000007919 lymphoplasmacytic lymphoma Diseases 0.000 description 1
- 230000002934 lysing Effects 0.000 description 1
- 230000001868 lysosomic Effects 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- RMGJCSHZTFKPNO-UHFFFAOYSA-M magnesium;ethene;bromide Chemical compound [Mg+2].[Br-].[CH-]=C RMGJCSHZTFKPNO-UHFFFAOYSA-M 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 201000004792 malaria Diseases 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-L maleate(2-) Chemical compound [O-]C(=O)\C=C/C([O-])=O VZCYOOQTPOCHFL-UPHRSURJSA-L 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229940099690 malic acid Drugs 0.000 description 1
- 201000004593 malignant giant cell tumor Diseases 0.000 description 1
- 239000003628 mammalian target of rapamycin inhibitor Substances 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 210000003826 marginal zone B cell Anatomy 0.000 description 1
- 201000000638 mature B-cell neoplasm Diseases 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229960001011 medrysone Drugs 0.000 description 1
- 229960001924 melphalan Drugs 0.000 description 1
- 108020004084 membrane receptors Proteins 0.000 description 1
- 102000006240 membrane receptors Human genes 0.000 description 1
- 229960001810 meprednisone Drugs 0.000 description 1
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 1
- 229960001428 mercaptopurine Drugs 0.000 description 1
- 230000002503 metabolic Effects 0.000 description 1
- 201000011442 metachromatic leukodystrophy Diseases 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- AWIJRPNMLHPLNC-UHFFFAOYSA-M methanethioate Chemical compound [O-]C=S AWIJRPNMLHPLNC-UHFFFAOYSA-M 0.000 description 1
- RBCBNPWEIZVSFB-MRVPVSSYSA-N methyl (2R)-1-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]-5-oxopyrrolidine-2-carboxylate Chemical compound COC(=O)[C@H]1CCC(=O)N1CC(=O)OC(C)(C)C RBCBNPWEIZVSFB-MRVPVSSYSA-N 0.000 description 1
- ABAOXDQXQHQRFA-YFKPBYRVSA-N methyl (2S)-1-methyl-5-oxopyrrolidine-2-carboxylate Chemical compound COC(=O)[C@@H]1CCC(=O)N1C ABAOXDQXQHQRFA-YFKPBYRVSA-N 0.000 description 1
- WPUFSWHRJVPGBU-NSHDSACASA-N methyl (2S)-3-(cyclopenten-1-yl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate Chemical compound CC(C)(C)OC(=O)N[C@H](C(=O)OC)CC1=CCCC1 WPUFSWHRJVPGBU-NSHDSACASA-N 0.000 description 1
- SANNKFASHWONFD-LURJTMIESA-N methyl (2S)-3-hydroxy-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate Chemical compound COC(=O)[C@H](CO)NC(=O)OC(C)(C)C SANNKFASHWONFD-LURJTMIESA-N 0.000 description 1
- 229960001047 methyl salicylate Drugs 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 229960004584 methylprednisolone Drugs 0.000 description 1
- 238000002493 microarray Methods 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 201000004058 mixed glioma Diseases 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000006011 modification reaction Methods 0.000 description 1
- 230000000051 modifying Effects 0.000 description 1
- 239000007932 molded tablet Substances 0.000 description 1
- QLIIKPVHVRXHRI-CXSFZGCWSA-N mometasone 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)CCl)(O)[C@@]1(C)C[C@@H]2O QLIIKPVHVRXHRI-CXSFZGCWSA-N 0.000 description 1
- YNAVUWVOSKDBBP-UHFFFAOYSA-N morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 1
- 229940113083 morpholine Drugs 0.000 description 1
- 230000004660 morphological change Effects 0.000 description 1
- 239000002324 mouth wash Substances 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 201000005962 mycosis fungoide Diseases 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- 239000007908 nanoemulsion Substances 0.000 description 1
- 125000005487 naphthalate group Chemical group 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 239000006218 nasal suppository Substances 0.000 description 1
- 239000005445 natural product Substances 0.000 description 1
- 229930014626 natural products Natural products 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 230000001537 neural Effects 0.000 description 1
- 230000000626 neurodegenerative Effects 0.000 description 1
- 201000011519 neuroendocrine tumor Diseases 0.000 description 1
- 230000002887 neurotoxic Effects 0.000 description 1
- 231100000189 neurotoxic Toxicity 0.000 description 1
- 230000001264 neutralization Effects 0.000 description 1
- 230000003472 neutralizing Effects 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 150000002829 nitrogen Chemical group 0.000 description 1
- 125000004433 nitrogen atoms Chemical group N* 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- 230000036963 noncompetitive Effects 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 229960000572 olaparib Drugs 0.000 description 1
- 201000010133 oligodendroglioma Diseases 0.000 description 1
- 102000025475 oncoproteins Human genes 0.000 description 1
- 108091008124 oncoproteins Proteins 0.000 description 1
- 229940005935 ophthalmologic Antibiotics Drugs 0.000 description 1
- 210000004789 organ systems Anatomy 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 150000002895 organic esters Chemical class 0.000 description 1
- 230000004072 osteoblast differentiation Effects 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M palmitate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- 201000002094 pancreatic adenocarcinoma Diseases 0.000 description 1
- 229960005184 panobinostat Drugs 0.000 description 1
- 239000003182 parenteral nutrition solution Substances 0.000 description 1
- 230000036961 partial Effects 0.000 description 1
- 235000010603 pastilles Nutrition 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 235000006678 peppermint Nutrition 0.000 description 1
- 235000015132 peppermint Nutrition 0.000 description 1
- 235000007735 peppermint Nutrition 0.000 description 1
- 201000004266 pericardial mesothelioma Diseases 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 201000005528 peripheral nervous system neoplasm Diseases 0.000 description 1
- 229940021222 peritoneal dialysis Isotonic solutions Drugs 0.000 description 1
- 201000002513 peritoneal mesothelioma Diseases 0.000 description 1
- 230000002085 persistent Effects 0.000 description 1
- 230000036377 pgph activity Effects 0.000 description 1
- 210000001539 phagocyte Anatomy 0.000 description 1
- 230000000090 phagocyte Effects 0.000 description 1
- 230000000275 pharmacokinetic Effects 0.000 description 1
- 230000036231 pharmacokinetics Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229960003742 phenol Drugs 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 230000000865 phosphorylative Effects 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- IBBMAWULFFBRKK-UHFFFAOYSA-N picolinamide Chemical compound NC(=O)C1=CC=CC=N1 IBBMAWULFFBRKK-UHFFFAOYSA-N 0.000 description 1
- 201000007286 pilocytic astrocytoma Diseases 0.000 description 1
- NQRYJNQNLNOLGT-UHFFFAOYSA-N piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 1
- 239000000106 platelet aggregation inhibitor Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920000747 poly(lactic acid) polymer Polymers 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- 239000011528 polyamide (building material) Substances 0.000 description 1
- 239000004633 polyglycolic acid Substances 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 229960000688 pomalidomide Drugs 0.000 description 1
- 230000001323 posttranslational Effects 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229940116357 potassium thiocyanate Drugs 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- OZAIFHULBGXAKX-UHFFFAOYSA-N precursor Substances N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 1
- 229960002794 prednicarbate Drugs 0.000 description 1
- 229960002943 prednisolone sodium phosphate Drugs 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- 229950000696 prednival Drugs 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 230000000770 pro-inflamatory Effects 0.000 description 1
- 229960000624 procarbazine Drugs 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 201000002212 progressive supranuclear palsy Diseases 0.000 description 1
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 235000010409 propane-1,2-diol alginate Nutrition 0.000 description 1
- ZTHYODDOHIVTJV-UHFFFAOYSA-N propyl 3,4,5-trihydroxybenzoate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 description 1
- 239000000473 propyl gallate Substances 0.000 description 1
- 235000010388 propyl gallate Nutrition 0.000 description 1
- 239000003197 protein kinase b inhibitor Substances 0.000 description 1
- 230000004844 protein turnover Effects 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000002685 pulmonary Effects 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 230000001698 pyrogenic Effects 0.000 description 1
- KAESVJOAVNADME-UHFFFAOYSA-N pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- 230000001172 regenerating Effects 0.000 description 1
- 230000022983 regulation of cell cycle Effects 0.000 description 1
- 239000003488 releasing hormone Substances 0.000 description 1
- 230000000268 renotropic Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
- 239000003340 retarding agent Substances 0.000 description 1
- 201000000582 retinoblastoma Diseases 0.000 description 1
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 1
- 229960001302 ridaforolimus Drugs 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229960004641 rituximab Drugs 0.000 description 1
- 229960003452 romidepsin Drugs 0.000 description 1
- OHRURASPPZQGQM-GCCNXGTGSA-N romidepsin Chemical compound O1C(=O)[C@H](C(C)C)NC(=O)C(=C/C)/NC(=O)[C@H]2CSSCC\C=C\[C@@H]1CC(=O)N[C@H](C(C)C)C(=O)N2 OHRURASPPZQGQM-GCCNXGTGSA-N 0.000 description 1
- 108010091666 romidepsin Proteins 0.000 description 1
- 235000005713 safflower oil Nutrition 0.000 description 1
- 239000003813 safflower oil Substances 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
- 231100000241 scar Toxicity 0.000 description 1
- 230000037390 scarring Effects 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 231100000486 side effect Toxicity 0.000 description 1
- 108091006008 signal transducing proteins Proteins 0.000 description 1
- 102000034377 signal transducing proteins Human genes 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 201000008123 signet ring cell adenocarcinoma Diseases 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- 229960002930 sirolimus Drugs 0.000 description 1
- 201000002612 sleeping sickness Diseases 0.000 description 1
- 230000001340 slower Effects 0.000 description 1
- 201000009295 smoldering myeloma Diseases 0.000 description 1
- 150000003385 sodium Chemical class 0.000 description 1
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 1
- 239000001187 sodium carbonate Substances 0.000 description 1
- 229960002218 sodium chlorite Drugs 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- BBMHARZCALWXSL-UHFFFAOYSA-M sodium;dihydrogen phosphate;hydrate Chemical compound O.[Na+].OP(O)([O-])=O BBMHARZCALWXSL-UHFFFAOYSA-M 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- WSWCOQWTEOXDQX-UHFFFAOYSA-N sorbic acid Chemical compound CC=CC=CC(O)=O WSWCOQWTEOXDQX-UHFFFAOYSA-N 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 235000013599 spices Nutrition 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-M stearate Chemical compound CCCCCCCCCCCCCCCCCC([O-])=O QIQXTHQIDYTFRH-UHFFFAOYSA-M 0.000 description 1
- 239000008227 sterile water for injection Substances 0.000 description 1
- 230000001954 sterilising Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000000021 stimulant Substances 0.000 description 1
- 230000004936 stimulating Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 230000002739 subcortical Effects 0.000 description 1
- 230000002142 suicide Effects 0.000 description 1
- 125000001273 sulfonato group Chemical class [O-]S(*)(=O)=O 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 229930003347 taxol Natural products 0.000 description 1
- 229960000235 temsirolimus Drugs 0.000 description 1
- 125000006633 tert-butoxycarbonylamino group Chemical group 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- DUYAAUVXQSMXQP-UHFFFAOYSA-M thioacetate Chemical compound CC([S-])=O DUYAAUVXQSMXQP-UHFFFAOYSA-M 0.000 description 1
- 125000000101 thioether group Chemical group 0.000 description 1
- YTPLMLYBLZKORZ-UHFFFAOYSA-N thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 1
- 230000002992 thymic Effects 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 201000005161 thyroid carcinoma Diseases 0.000 description 1
- 229910052718 tin Inorganic materials 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N tin hydride Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- 229960004631 tixocortol Drugs 0.000 description 1
- BISFDZNIUZIKJD-XDANTLIUSA-N tixocortol pivalate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)CSC(=O)C(C)(C)C)(O)[C@@]1(C)C[C@@H]2O BISFDZNIUZIKJD-XDANTLIUSA-N 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- 229960005267 tositumomab Drugs 0.000 description 1
- 230000002588 toxic Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 108060008606 traP Proteins 0.000 description 1
- 108091006090 transcriptional activators Proteins 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- LXZZYRPGZAFOLE-UHFFFAOYSA-L transplatin Chemical compound [H][N]([H])([H])[Pt](Cl)(Cl)[N]([H])([H])[H] LXZZYRPGZAFOLE-UHFFFAOYSA-L 0.000 description 1
- 229960000575 trastuzumab Drugs 0.000 description 1
- 230000000472 traumatic Effects 0.000 description 1
- 229960004221 triamcinolone hexacetonide Drugs 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- STMPXDBGVJZCEX-UHFFFAOYSA-N triethylsilyl trifluoromethanesulfonate Chemical compound CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F STMPXDBGVJZCEX-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 125000002827 triflate group Chemical group FC(S(=O)(=O)O*)(F)F 0.000 description 1
- 125000000725 trifluoropropyl group Chemical group [H]C([H])(*)C([H])([H])C(F)(F)F 0.000 description 1
- VXKHXGOKWPXYNA-PGBVPBMZSA-N triptorelin Chemical compound C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 VXKHXGOKWPXYNA-PGBVPBMZSA-N 0.000 description 1
- 239000011778 trisodium citrate Substances 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 238000004450 types of analysis Methods 0.000 description 1
- 238000010798 ubiquitination Methods 0.000 description 1
- 229950008396 ulobetasol propionate Drugs 0.000 description 1
- 230000036967 uncompetitive Effects 0.000 description 1
- 230000004906 unfolded protein response Effects 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-M valerate Chemical compound CCCCC([O-])=O NQPDZGIKBAWPEJ-UHFFFAOYSA-M 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 201000004810 vascular dementia Diseases 0.000 description 1
- 235000019871 vegetable fat Nutrition 0.000 description 1
- 229960001722 verapamil Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- GBABOYUKABKIAF-IELIFDKJSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-IELIFDKJSA-N 0.000 description 1
- CILBMBUYJCWATM-IJDPFCGHSA-N vinorelbine L-tartrate Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.OC(=O)[C@H](O)[C@@H](O)C(O)=O.C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC CILBMBUYJCWATM-IJDPFCGHSA-N 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 201000010044 viral meningitis Diseases 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
- 235000014692 zinc oxide Nutrition 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
- VEZXCJBBBCKRPI-UHFFFAOYSA-N β-Propiolactone Chemical compound O=C1CCO1 VEZXCJBBBCKRPI-UHFFFAOYSA-N 0.000 description 1
- WHGYBXFWUBPSRW-FOUAGVGXSA-N β-cyclodextrin Chemical class 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
- YEJRWHAVMIAJKC-UHFFFAOYSA-N γ-lactone 4-hydroxy-butyric acid Chemical compound O=C1CCCO1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/06—Tripeptides
-
- 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
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- 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
- A61P17/04—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
- A61P17/08—Antiseborrheics
-
- 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
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
-
- 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
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- 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
- 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
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
- A61P31/06—Antibacterial agents for tuberculosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
- A61P5/00—Drugs for disorders of the endocrine system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/06—Antianaemics
-
- 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
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
- C07D303/32—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by aldehydo- or ketonic radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/0202—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/0205—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)3-C(=0)-, e.g. statine or derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/0606—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing heteroatoms not provided for by C07K5/06086 - C07K5/06139, e.g. Ser, Met, Cys, Thr
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/0606—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing heteroatoms not provided for by C07K5/06086 - C07K5/06139, e.g. Ser, Met, Cys, Thr
- C07K5/06069—Ser-amino acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06104—Dipeptides with the first amino acid being acidic
- C07K5/06113—Asp- or Asn-amino acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06104—Dipeptides with the first amino acid being acidic
- C07K5/06113—Asp- or Asn-amino acid
- C07K5/06121—Asp- or Asn-amino acid the second amino acid being aromatic or cycloaliphatic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
- C07K5/06147—Dipeptides with the first amino acid being heterocyclic and His-amino acid; Derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
- C07K5/06173—Dipeptides with the first amino acid being heterocyclic and Glp-amino acid; Derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
- C07K5/0806—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0821—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp
Abstract
Provided herein are dipeptide and tripeptide epoxy ketone protease inhibitors, methods of their preparation, related pharmaceutical compositions, and methods of using the same. For example, provided herein are compounds of Formula (II): and pharmaceutically acceptable salts and compositions including the same. The compounds and compositions provided herein may be used, for example, in the treatment of proliferative diseases including cancer and autoimmune diseases. g the same. The compounds and compositions provided herein may be used, for example, in the treatment of proliferative diseases including cancer and autoimmune diseases.
Description
Dipeptide and Tripeptide Epoxy Ketone Protease Inhibitors
CROSS-REFERENCE TO D APPLICATIONS
This application claims the benefit of US. Provisional Application Nos. 61/941,798
(filed February 19, 2014), 61/883,798 (filed on September 27, 2013), 61/856,847 (filed on
July 22, 2013), ,780 (filed on July 18, 2013), 61/786,086 (filed on March 14,2013),
61/883,843 (filed on September 27, 2013), and 61/785,608 (filed on March 14, 2013), each of
which is orated herein by reference in its entirety.
BACKGROUND OF THE INVENTION
Field of the Invention
This disclosure relates to dipeptide and tripeptide epoxy ketone protease inhibitors
including methods of making and using the same.
Description of Related Technology
In eukaryotes, protein degradation is predominately mediated h the tin
pathway in which proteins targeted for destruction are d to the 76 amino acid
ptide ubiquitin. Once targeted, ubiquitinated proteins then serve as substrates for the
26S proteasome, a multicatalytic protease, which s proteins into short es through
the action of its three major proteolytic activities. While having a general function in
intracellular protein turnover, proteasome-mediated degradation also plays a key role in many
processes such as major histocompatibility complex (MHC) class I antigen presentation,
sis, cell growth regulation, NF-KB activation, antigen processing, and transduction of
pro-inflammatory signals.
The 20S proteasome is a 700 kDa cylindrical-shaped multicatalytic protease
complex comprised of 28 subunits organized into four rings. In yeast and other eukaryotes, 7
different or subunits form the outer rings and 7 different B subunits comprise the inner rings.
The 0L subunits serve as binding sites for the 19S (PA700) and 11S (PA28) regulatory
complexes, as well as a physical barrier for the inner proteolytic chamber formed by the two
[3 subunit rings. Thus, in vivo, the proteasome is believed to exist as a 26S particle (“the 26S
proteasome”). In vivo experiments have shown that tion of the 20S form of the
some can be readily correlated to inhibition of 26S proteasome. Cleavage of amino-
terminal prosequences of [3 subunits during particle formation expose amino-terminal
threonine residues, which serve as the catalytic nucleophiles. The subunits responsible for
catalytic activity in somes thus possess an amino terminal nucleophilic residue, and these
subunits belong to the family of inal nucleophile (Ntn) hydrolases (where the nucleophilic
N-terminal residue is, for example, Cys, Ser, Thr, and other nucleophilic moieties). This family
includes, for example, llin G acylase (PGA), llin V acylase (PVA), glutamine PRPP
amidotransferase (GAT), and bacterial glycosylasparaginase. In addition to the ubiquitously
sed ts, higher vertebrates also possess three interferon--inducible subunits (LMP7,
LMP2 and MECLl), which replace their normal counterparts, 5, 1 and 7 respectively, thus altering
the catalytic activities of the proteasome. Through the use of different peptide substrates, three major
proteolytic activities have been defined for the eukaryote 20S proteasome: chymotrypsin-like ty
(CT-L), which cleaves after large hobic residues; trypsin-like activity (T-L), which cleaves
after basic residues; and peptidylglutamyl peptide hydrolyzing ty , which cleaves after
acidic residues. Two additional less characterized ties have also been ascribed to the proteasome:
BrAAP activity, which cleaves after ed-chain amino acids; and SNAAP activity, which cleaves
after small neutral amino acids. The major proteasome proteolytic activities appear to be contributed
by different catalytic sites, since inhibitors, point mutations in subunits and the exchange of
interferon-inducing subunits alter these activities to various degrees.
New compositions and methods for preparing and formulating proteasome inhibitor(s) would
be useful.
SUMMARY OF THE INVENTION
Provided herein is a compound having a structure of Formula (X) or a pharmaceutically
acceptable salt thereof,
with substituents defined as discussed in detail below.
Also provided herein is a pharmaceutical composition comprising a pharmaceutically
acceptable carrier or diluent and a compound provided herein, or a pharmaceutically able salt
thereof.
[0007a]In another aspect, the present invention provides a compound having a structure selected from
the group consisting of:
, ,
, ,
, ,
, and ,
or a pharmaceutically acceptable salt thereof.
[0007b]In yet r aspect, the present invention provides a compound of Formula (II) or a
pharmaceutically acceptable salt thereof,
(II)
wherein: X is selected from O, S, NH, and N-C1-6alkyl; R2 and R3 are each independently selected from
aryl, C1-6aralkyl, heteroaryl, and C1-6heteroaralkyl; R5 is selected from hydrogen, OH, C1-6aralkyl, and C1-
6 is heteroaryl, piperidinyl, piperazinyl, morpholinyl, a lactone, a lactam, or
6alkyl; R ; and R8 is
selected from en, C1-6alkyl, and C1-6aralkyl,
wherein a kyl, aryl, alkyl, heteroaryl, and C1-6heteroaralkyl can optionally be substituted with a
substituent selected from the group consisting of alkyl, alkenyl, alkynyl, a
halogen, a hydroxyl, a yl, a thiocarbonyl, an alkoxyl, a phosphoryl, a phosphate, a onate,
a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an
hio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a carbocyclyl, a heterocyclyl,
an aralkyl, a heteroaralkyl, an aryl or heteroaryl.
[0007c] In yet another aspect, the present invention provides a compound having a structure selected
from the group consisting of:
, ,
, ,
, , and
or a pharmaceutically acceptable salt thereof.
The compounds and compositions provided herein are useful in ting LMP2.
2b followed by page 3
The compounds and compositions provided herein also are useful in the treatment of diseases
or disorders, such as an immune-related disease, cancer, inflammation, infection, proliferative
disease, and neurodegenerative disease. Accordingly, provided herein is a method of treating
a disease or disorder in a patient, the method comprising administering a therapeutically
effective amount of a compound or ition as provided herein.
Unless otherwise defined, all technical and scientific terms used herein have the
same meaning as commonly understood by one of ordinary skill in the art to which this
disclosure belongs. Methods and materials are described herein for use in the present
disclosure; other, suitable methods and materials known in the art can also be used. The
materials, methods, and examples are illustrative only and not intended to be limiting. All
ations, patent applications, patents, sequences, database entries, and other references
mentioned herein are incorporated by reference in their entirety. In case of conflict, the
present specification, including definitions, will l.
Other es and ages of the disclosure will be nt from the following
detailed description and figures, and from the claims.
DETAILED DESCRIPTION
Definitions
For the terms “for example” and “such as” and grammatical equivalences thereof,
the phrase “and without tion” is understood to follow unless explicitly stated ise.
As used herein, the term “about” is meant to account for variations due to experimental error.
All measurements reported herein are tood to be modified by the term ,”
whether or not the term is explicitly used, unless explicitly stated otherwise. As used herein,
the singular forms “ 3, (C
a an,” and “the” include plural referents unless the context clearly
dictates otherwise.
As used herein, chemical structures which contain one or more stereocenters
ed with dashed and bold bonds (i.e., ------ and -— ) are meant to indicate te
stereochemistry of the stereocenter(s) present in the chemical structure. As used herein,
bonds symbolized by a simple line do not indicate a -preference. Unless ise
indicated to the contrary, chemical structures that include one or more stereocenters which
are illustrated herein without indicating absolute or relative stereochemistry encompass all
possible stereoisomeric forms of the compound (e. g., diastereomers, enantiomers) and
mixtures thereof Structures with a single bold or dashed line, and at least one additional
2014/026980
simple line, encompass a single enantiomeric series of all possible diastereomers.
Resolution of racemic mixtures of nds can be carried out by any of
numerous methods known in the art. An exemplary method includes fractional
recrystallization using a chiral resolving acid which is an optically active, salt-forming
organic acid. Suitable resolving agents for fractional recrystallization methods are, for
example, optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric
acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, or the various optically
active camphorsulfonic acids such as camphorsulfonic acid. Other resolving agents suitable
for fractional crystallization methods include stereoisomerically pure forms of
methylbenzylamine (e. g., S and R forms, or diastereomerically pure forms), 2-phenylglycinol,
norephedrine, ine, N—methylephedrine, exylethylamine, 1,2-
diaminocyclohexane, and the like.
tion of racemic mixtures can also be carried out by n on a column
packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Suitable
elution solvent compositions can be determined by one skilled in the art.
Compounds provided herein can also include all es of atoms occurring in the
intermediates or final compounds. Isotopes include those atoms having the same atomic
number but different mass numbers. For example, isotopes of hydrogen include hydrogen,
tritium, and ium.
The term, “compound,” as used herein is meant to include all stereoisomers,
geometric isomers, ers, and isotopes of the ures depicted. Compounds herein
identified by name or structure as one particular tautomeric form are intended to include other
tautomeric forms unless ise specified.
All compounds, and pharmaceutically able salts thereof, can be found
together with other substances such as water and solvents (e.g., hydrates and solvates).
The term “Cx_yalkyl” refers to substituted or unsubstituted saturated hydrocarbon
, including straight-chain alkyl and branched-chain alkyl groups that contain from x to
y carbons in the chain. For example, C1_7alkyl refers to an alkyl groups having a number of
carbon atoms encompassing the entire range (i.e., l to 7 carbon atoms), as well as all
subgroups (e.g., 1-6, 2-7, 1-5, 3-6, 1,2, 3, 4, 5, 6, and 7 carbon atoms). The terms
“C2_yalkenyl” and “C2_yalkynyl” refer to substituted or unsubstituted unsaturated aliphatic
groups analogous in length and possible substitution to the alkyls described above, but that
WO 52127
contain at least one double or triple bond, respectively.
The term “alkoxy” refers to an alkyl group having an oxygen attached thereto.
Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy and the like. An
“ether” is two hydrocarbons covalently linked by an oxygen. Accordingly, the substituent of
an alkyl that renders that alkyl an ether is or les an alkoxy.
The term, “Cx_yalkoxyalkyl” refers to a Cx_yalkyl group, as previously ,
substituted with an alkoxy group. For example, the term lkoxyalkyl” refers to a C1-
6alkyl group substituted with an alkoxy group, thereby forming an ether.
The term, “Cx_yaralkyl” refers to a Cx_yalkyl group, as previously defined,
substituted with an aryl group. For e, the term “C1_6aralkyl”, as used herein, refers to
a C1_6alkyl group substituted with an aryl group.
The terms “amine” and “amino” are art-recognized and refer to both tituted
and substituted amines and salts thereof, e.g., a moiety that can be represented by the general
8 3+
_N —[}]—R
formulae: R or R where each R group independently represents a hydrogen, an
alkyl, an alkenyl, —(CH2)b—T, or two of the R groups taken together with the N atom to
which they are attached te a heterocycle having from 4 to 8 atoms in the ring
structure; T represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocyclyl or a polycyclyl;
and b is zero or an integer from 1 to 8. In certain embodiments, an amino group is basic,
meaning its protonated form has a pKa above 7.00. In some embodiments, the terms “amine”
and “amino” refer to a moiety that is covalently bonded to a unsubstituted or substituted
nitrogen atom.
The terms “amide” and “amido” are art-recognized as an amino-substituted
carbonyl and include a moiety that can be represented by the general formula: w'w
. In
some embodiments, the amide will not include imides, which may be unstable.
The term “aryl” as used herein includes 5-, 6-, and 7-membered substituted or
unsubstituted single-ring ic groups in which each atom of the ring is carbon. The term
“aryl” also includes polycyclic ring systems having two or more cyclic rings in which two or
more carbons are common to two adjoining rings wherein at least one of the rings is
ic, e. g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls,
heteroaryls, and/or heterocyclyls. Aryl groups include benzene, naphthalene, phenanthrene,
phenol, aniline, and the like. In some embodiments, an aryl ring can be substituted with a
n, such as fluorine.
The terms “carbocycle” and “carbocyclyl”, as used herein, refer to a 3- to 7-
membered non-aromatic substituted or unsubstituted ring in which each atom of the ring is
carbon. The ring may be completely saturated or may have one or more rated bonds
such that the ring remains non-aromatic. The terms “carbocycle” and “carbocyclyl” also
include polycyclic ring systems haVing two or more cyclic rings in which one or more
s are common to two adjoining rings n at least one of the rings is carbocyclic,
e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls,
heteroaryls, and/or heterocyclyls. Carbocyclyls include cyclopropyl, cyclopentyl,
cyclopentenyl, cyclohexyl, exylmethyl, and ylcyclohexyl. Examples of
polycyclic carbocyclyls include bicyclo[2.2.l]heptanyl, spiro[2.4]heptanyl, yl, and
adamantyl.
The term “cycloalkyl” as used herein refers to a 3- to 7-membered ted
substituted or tituted ring in which each atom of the ring is carbon. The term
“cycloalkyl” also includes polycyclic ring systems haVing two or more cyclic rings in which
one or more carbon atoms are common to two adjoining rings n at least one of the
rings is a cycloalkyl.
The term “cycloalkenyl” as used herein refers to a 3- to 7-membered substituted or
unsubstituted ring in which each atom of the ring is carbon. The ring has one or more
unsaturated bonds such that the ring remains non-aromatic. The term “cycloalkenyl” also
includes polycyclic ring systems haVing two or more cyclic rings in which one or more
carbon atoms are common to two adjoining rings wherein at least one of the rings is a
cycloalkenyl.
The term “carbonyl” is art-recognized and includes moieties containing a C=O
)Lx’R
group, such as, for example, those represented by the general formulae: 01'
X R' wherein X is a bond or represents an oxygen or a sulfur, and R represents a
hydrogen, an alkyl, an alkenyl, —(CH2)b—T or a pharmaceutically acceptable salt, R’
represents a hydrogen, an alkyl, an alkenyl or —(CH2)b—T, where m and T are as defined
above. Where X is an oxygen and R or R’ is not hydrogen, the formula represents an “ester”.
Where X is an oxygen and R is a hydrogen, the formula represents a “carboxylic acid”.
The term, “Cx_yheteroaralkyl” refers to a Cx_yalkyl group, as previously defined,
substituted with a heteroaryl group. For example, the term eteroaralkyl”, as used
herein, refers to a C1_6alkyl group substituted with a heteroaryl group.
The term “heteroaryl” includes substituted or unsubstituted aromatic 5- to 7-
ed ring structures, for example, 5- to 6-membered rings, whose ring structures
include one to four heteroatoms. The term “heteroaryl” also includes polycyclic ring systems
having two or more cyclic rings in which two or more carbons are common to two adjoining
rings n at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be
cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole,
thiazole, triazole, pyrazole, pyridine, ne, pyridazine, and pyrimidine, and the like. In
some embodiments, a heteroaryl ring can be substituted with a halogen, such as fluorine.
The term “heteroatom” as used herein means an atom of any element other than
carbon or hydrogen. For example, heteroatoms include nitrogen, oxygen, phosphorus, and
sulfur.
The term “heterocyclyl” or “heterocyclic group” refers to substituted or
unsubstituted non-aromatic 3- to 10-membered ring structures, for example, 3- to 7-
membered rings, whose ring structures include one to four heteroatoms. The ring may be
completely saturated (e.g., cycloalkyl) or may have one or more unsaturated bonds
such that the ring remains non-aromatic (e.g., heterocycloalkenyl). The term “heterocyclyl”
or “heterocyclic group” also es polycyclic ring s having one or more cyclic rings
in which two or more s are common to two adjoining rings n at least one of the
rings is heterocyclic, e. g., the other cyclic rings can be cycloalkyls, cycloalkenyls,
cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Heterocyclyl groups include, for
example, piperidine, piperazine, idine, morpholine, lactones, lactams, and the like.
The term, “Cx_yhydroxyalkyl” refers to a Cx_yalkyl group, as usly defined,
substituted with a hydroxy group. For example, the term “C1_6hydroxyalkyl” refers to a C1_
6alkyl group substituted with a hydroxy group.
The term “thioether” refers to an alkyl group, as defined above, having a sulfur
moiety attached thereto. In some embodiments, the “thioether” is represented by —S—
alkyl. Representative thioether groups include methylthio, ethylthio, and the like.
The term “substituted,” refers to moieties having substituents replacing a hydrogen
on one or more drogen atoms of the molecule. It will be understood that
“substitution” or “substituted with” includes the implicit proviso that such substitution is in
accordance with permitted valence of the substituted atom and the tuent, and that the
substitution results in a stable compound, e.g., which does not spontaneously undergo
transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the
term “substituted” is contemplated to include all permissible substituents of organic
nds. In a broad aspect, the permissible substituents include acyclic and cyclic,
branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic
substituents of organic compounds. The sible substituents can be one or more and the
same or ent for appropriate organic compounds. For purposes of this disclosure, the
heteroatoms such as nitrogen may have hydrogen tuents and/or any permissible
substituents of organic nds described herein which satisfy the valences of the
heteroatoms. Substituents can include, for example, an alkyl, alkenyl, alkynyl, a halogen, a
hydroxyl, a carbonyl (such as a carboxyl, an ester, a thioester, an alkoxycarbonyl, a formyl,
or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a
phosphoryl, a ate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an
imine, a cyano, a nitro, an azido, a dryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl,
a sulfonamido, a sulfonyl, a carbocyclyl (e. g., cycloalkyl, cycloalkenyl), a cyclyl (e. g.,
heterocycloalkyl), an aralkyl, a heteroaralkyl, or an ic (i.e., aryl) or heteroaromatic
(i.e., heteroaryl) moiety. It will be understood by those skilled in the art that the moieties
substituted on the hydrocarbon chain can themselves be substituted, if appropriate. In some
embodiments, the substituent is a halogen, such as fluorine. When a chemical fianctional
group includes more than one substituent, the substituents can be bound to the same carbon
atom or to two or more different carbon atoms. A tuted chemical functional group can
itself include one or more substituents.
In some embodiments, the compounds provided herein, or salts f, are
substantially isolated or purified. By “substantially isolated” is meant that the compound is at
least partially or substantially separated from the environment in which it was formed or
detected. Partial separation can e, for example, a composition ed in the
compounds provided herein. ntial separation can include compositions containing at
least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about
90%, at least about 95%, at least about 97%, or at least about 99% by weight of the
nds, or salt thereof. Methods for isolating compounds and their salts are routine in
the art.
The term “prophylactic or therapeutic” treatment is cognized and includes
stration to the host of one or more of the subject compositions. If the subject
composition is administered prior to clinical manifestation of the unwanted ion (e.g.,
disease or other unwanted state of the host animal) then the treatment is prophylactic, (i.e., it
protects the host against developing the unwanted condition), whereas if the subject
composition is administered after manifestation of the unwanted condition, the treatment is
therapeutic, (i.e., it is intended to diminish, rate, or stabilize the existing unwanted
condition or side effects thereof).
The term “proteasome” as used herein is meant to include immuno- and constitutive
proteasomes. In some embodiments, a nd of the disclosure preferentially inhibits the
immunoproteasome.
The term “i208” as used herein refers to the 208 immunoproteasome.
The term “c208” as used herein refers to the constitutive ZOS proteasome.
As used herein, the term “inhibitor” is meant to describe a compound that blocks or
reduces an activity of an enzyme or system of enzymes, receptors, or other pharmacological
target (for example, inhibition of proteolytic cleavage of standard fluorogenic e
substrates such as succinyl-Leu-Leu-Val-Tyr-AMC, Boc-Leu-Leu-Arg-AMC and Z-Leu-
Leu-Glu-AMC, inhibition of various tic activities of the ZOS proteasome). An tor
can act with competitive, uncompetitive, or noncompetitive inhibition. An inhibitor can bind
reversibly or irreversibly, and therefore, the term includes compounds that are suicide
ates of an enzyme. An tor can modify one or more sites on or near the active site
of the enzyme, or it can cause a conformational change elsewhere on the enzyme. The term
inhibitor is used more broadly herein than scientific literature so as to also encompass other
classes of pharmacologically or therapeutically useful agents, such as agonists, nists,
stimulants, co-factors, and the like.
A “therapeutically effective ” of a compound with t to the subject
method of treatment, refers to an amount of the compound(s) in a preparation which, when
administered as part of a desired dosage regimen (to a patient, e. g., a human) alleviates a
symptom, ameliorates a condition, or slows the onset of disease conditions according to
clinically acceptable standards for the disorder or condition to be treated or the cosmetic
purpose, e.g., at a reasonable benefit/risk ratio able to any medical treatment.
As used herein, the term “treating” or “treatment” includes reversing, reducing, or
ing the symptoms, clinical signs, and underlying pathology of a condition in manner to
improve or stabilize a patient's condition.
Comp_ounds
In one aspect, the disclosure provides a compound having a structure of Formula
(X), or a pharmaceutical salt thereof:
O R2 O
H H
N N R4
JW H (X)
o R 1 0 O
R3 )q
wherein:
p is 0 or 1;
q is 0, l, or 2;
J is selected from the group consisting of C1_6alkyleneR5, C2_6alkenyleneR5,
OC1_6alkyleneR5, CF3, C0_6alkyleneN(R6)2, aryl, heteroaryl, polyetherCH3, and
C3_6cycloalkenyl, wherein J is ally tuted with one or more
substituents selected from the group ting of C1_6alkyl, halo, CF3, 0R6,
SR6, N(R6)2, and 3-7 membered heterocycloalkyl;
R1 is selected from the group consisting of H, C1_2alkyleneR7, C3_6cycloalkyl, and 3-6
membered heterocycloalkyl, n R1 is optionally substituted with one or
more substituents selected from the group consisting of halo, 0R6, SR6, and
N(R6)2;
R2 is C1_2alkylene—G; wherein G is selected from the group consisting of
cloalkenyl, aryl, and heteroaryl, with the proviso that when R2 is
nyl, the phenyl is substituted with one or more tuents selected
from the group consisting of 0R6, halo, C1_3alkyl, and SOZR6;
R3 is selected from the group consisting of C3_7cycloalkyl, C3_7cycloalkenyl, a 3-7
membered heterocycloalkyl, a 3-7 membered heterocycloalkenyl and aryl,
wherein R3 is ally substituted with one or more substituents selected
from the group consisting OR6 and C1_6alkyl;
R4 is H or C1_3alkyl;
R5 is selected from the group consisting of H, CF3, 0R6, C1_6alkoxyl, and aryl;
each R6 is independently H or C1_6alkyl; and,
R7 is selected from the group consisting of H, 0R6, COOR6, CN, and 3-6 membered
heterocycloalkyl.
In some embodiments, p is 0. In other embodiments, p is l.
In some embodiments q is 0. In other embodiments, q is 1. In various
embodiments, q is 2.
In some embodiments, J is C1_6alkyleneR5, C2_6alkenyleneR5, OC1_6alkyleneR5,
polyetherCH3, CF3 or N(R6)2. In exemplary embodiments, J is selected from the group
ting of methyl, ethyl, propyl, isopropyl, butyl, difluoromethyl, 2,2-difluoroethyl,
hydroxymethyl, methoxy, ethoxy, propoxy, butoxy, trifluoromethyl, hydroxyethyl,
MeOCHzOCHzCH2-, MeOCHzCHgOCH2-, yethyl, ethoxymethyl, 2-hydroxy
methylpropyl, 2-hydroxypropyl, 2-hydroxymethylbutyl, oxymethyl
trifluoropropyl, l-trifluoromethylhydroxyethyl, NH2, NH(CH3), NH(CH2CH3), N(CH3)2,
and C(CH3)2NH2.
In other embodiments, J is aryl, such as phenyl or l. In some of these
embodiments, the aryl is tuted with one or more substituent selected from the group
consisting of , ethyl, propyl, isopropyl, hydroxy, fluoro, chloro, methoxy, ethoxy,
trifluromethyl, and amino. For example, I can include CW; 0‘; or
, ,
In some embodiments, J is heteroaryl. For example, I can include oxazolyl,
isoxazolyl, thiazolyl, benimidazolyl, pyridyl, imidazolyl, lyl, tetrahydroindazolyl,
yl, or pyrazinyl. Optionally, the heteroaryl can be substituted With one or more
substituents selected from the group consisting of methyl, ethyl, amino, dimethylamino,
inyl, and pyrolidinyl. In some ary embodiments, J is selected from the group
consisting of
MemeHG‘CfiUEW‘0
In s embodiments, J is cloalkenyl, such as cyclohexenyl or
cyclopentenyl.
In some ments, R1 is methyl. In other embodiments, R1 is ymethyl.
In still other embodiments, R1 is CH2C02R6. In various embodiments, R1 is H,
CH2morpholinyl, oxetanyl, or l-hydroxyl-cyclopropyl. In various embodiments, the carbon
to which R1 is attached is in the (S) ration.
In some embodiments, R2 is CHz-G. In other embodiments, R2 is CH2CH2-G. In
various embodiments, G is aryl. In other embodiments, G is cloalkenyl. In yet other
embodiments, G is a heteroaryl. In embodiments, G is selected from the group consisting of
4-methoxyphenyl, 3-hydroxymethoxyphentyl, indolyl, and 4-methylsulfonylphenyl. In
some ary embodiments, G comprises 4-methoxyphenyl. In other exemplary
embodiments, G is 3-hydroxymethoxyphenyl. In still other exemplary embodiments, G is
indolyl. In embodiments, G can include 4-methylsulfonylphenyl.
In some embodiments, R3 is C3_7cycloalkyl. In other embodiments, R3 is C3_
7cycloalkenyl. In still other embodiments, R3 is a 3-7 membered heterocycloalkyl. In various
embodiments, R3 is a 3-7 membered heterocycloalkenyl. In embodiments, R3 is aryl. In
some exemplary embodiments, R3 is selected from the group consisting of phenyl,
cyclopentyl, 4-methylphenyl, and cyclopentenyl.
In embodiments, q is l and R3 is C3_7cycloalkyl. In other embodiments, q is l and
R3 is C3_7cycloalkenyl. In various embodiments, q is l and R3 is a 3-7 membered
heterocycloalkyl. In yet other ments, q is l and R3 is a 3-7 membered
heterocycloalkenyl. In some embodiments, q is l and R3 is aryl. In some exemplary
embodiments, q is l and R3 is selected from the group ting of phenyl, cyclopentyl, 4-
methylphenyl, and cyclopentenyl.
In some embodiments, R4 is C1_3alkyl, such as methyl or ethyl. In various
embodiments, R4 is H. In some cases, R4 is methyl.
In some embodiments, q is l; R1 is H, methyl or hydroxymethyl; R2 is ed
from the group consisting of CH2-(4-methoxyphenyl), CH2- indolyl, CH2-(4-
methylsulfonylphenyl), and CH2-(3-hydroxymethoxyphenyl); R3 is selected from the
group consisting of , cyclopentyl, 4-methylphenyl, and cyclopentenyl; and R4 is
methyl.
Specifically contemplated is a compound of Formula X including J, as described in
paragraphs [0047]-[0050], R1 as described in paragraph [0051], R2 as described in paragraph
, R3 as described in paragraph [0053], and R4 as described in paragraph .
In some embodiments, a compound of Formula (X) is selected from:
O \NH
O O
)LJfifN0 o o ‘ ijLNH H
H N
GAO H H H
o o O
o o
, 9
O O F F O O
O/ O/
9 9
O O O O O O
)L H Hod H
H H
O O O O
o/ 0/
2014/026980
0:227 ZI O O O o
FYLMF H
F o o
0/ o/
O 0 J1 H ijJ\H/N O
\vo N
HO H
2014/026980
O O O
H H
; 4:I2 ZI I
O 0 O
9 9
\ o O N\ o O
0/ 0/
9 9
o O o
O O O
H OJLNifN N
N#N N
N H H
v o o
H H O/\
N o o
o o o o o o
N N
a N N N
O H H
o o dimH H
o o
0/ 0/
o o 0
0 0 0 ZI
Z ZI
/ I20:? I2
I202% I2 0
z; 0
'fiWREL fififih
OHONJWVN\6E>\:O fij/OO’PILO
O \NH
)1?” o o
O O u ZI
0o N N kaNH
H O\fiE—I>\O0/,N o o 0
\\S/
O NO 0 HO HO
O o o 0 Ho 0
O O
H H
OH 0 o o
WO 52127
IO O :7 0
TI ZI
TI I2
O O
IO; 4:I2
O 0
:=O O
IZ 0:27 AZ I
:=o 0:2; O
,2\ IZ I
o O
O H
H H CNflfls
H N
\ s N N N
/‘<}\1IoN 3Wka N 0 o o
o o
CNNs
H H HzN“<\ I N
I N N 0 0 0
N o o o
O O o O O o
NH H
N N
H H )LN/YNH H
o o o o
O/ O/
9 9
F F
o o o o
O/ O/
9 9
\M N N
M H2N N N
H H
o o o o
o/ o/
O O o O o
H H
\N N
H PM2 u H H
o o o o
o/ o/
O O o
\/O\)J\ JWVNH O O o
O O H H
O O
O/ and 0/
, ,
or a pharmaceutically acceptable salt thereof.
In some exemplary embodiments, a compound of Formula (X) is ed from the
group consisting of:
C-2003,0/
WO 52127
O E O O
\O "1,,
HN/\n/N\:)LN : H
O O
: : \O/
C-2018,
O O O
\O H¢LN ,, \/O\)J\N N\-)J\N ”U,
H : H H E H
O O O O
00/ : : \O/
, C-2020,
g1 0 O O O
\/O - U1
myN ”"1 \MNJWW/N 'u,
; H H - H
O :
00/ N’O O O
C-2021, C-2022,
O E Hi 0 O E O O
M H
- I
H/\[O]/ N O
\ N\)J\
N N ,, ”’1,
N’0 : H N’ I N/\fl/H H
O \ 2
O O
C-2024,
WO 52127
WO 52127
WO 52127
PCT/USZOl4/026980
O o
H H
HOwNfiN
NQI’“
0 o o
C-2060,
O E O
N H\)OLN ”"1
</ fix”?N . N
H
H U0/
C-2062,
O E m H\)OL O
N/\n/ N "I,
. N /
N\ | H a H
0 00
C-2064,
0 o
H H
N H
o 5 o o
C-2066,
0 o
N¢HNH H
N o 5 H
o NQLKE o
C-2068,
WO 52127
ijfl l,
H 5 «:fl ¥L gig
C-2069, C-2070,
VOQLMJWO‘VNngO O O
H O O
"1,, kHangL”
O _
C-2079, and C-2080,
or a pharmaceutically acceptable salt thereof.
In another aspect, provided herein is a compound having a structure of Formula (I)
or a pharmaceutically acceptable salt thereof,
1 R7
R O R3
RHW/ #N|'1] X
0 R2 R8 0
wherein:
B is absent or is N(R9)R10;
L is absent or is selected from C=O, C=S, and 802;
Q is absent or is selected from O, NH, and N—C1_6alkyl;
X is selected from O, S, NH, and N—C1_6alkyl;
M is absent or C1_12alkyl;
each of R1, R2, and R3 are independently selected from en, -C1_6alkyl-B, C2_6alkenyl,
C2_6alkynyl, C1_6hydroxyalkyl, koxyalkyl, yclyl, carbocyclylM-, heterocyclyl,
heterocyclylM-, aryl, C1_6aralkyl, heteroaryl, and teroaralkyl;
R4 is N(R5)L-Q-R6;
R5 is selected from hydrogen, OH, C1_6aralkyl, and C1_6alkyl;
R6 is selected from hydrogen, and C1_6alkyl;
R7 and R8 are independently selected from hydrogen, C1_6alkyl, and C1_6aralkyl;
R9 is selected from hydrogen, OH, and C1_6alkyl; and
R10 is an N—terminal protecting group; and
R15 is selected from hydrogen, C1_6alkyl, C1_6hydroxyalkyl, C1_6alkoxy, -C(O)OC1_6alkyl, -
C(O)NHC1_6alkyl, and C 1-6aralkyl.
In some ments, R7 and R8 are independently selected from hydrogen and C1-
6alkyl. For example, R7 and R8 can both be hydrogen.
In some embodiments, R15 is ed from hydrogen, C1_6alkyl and C1_
6hydroxyalkyl. For example, R15 can be selected from hydrogen, methyl, ethyl,
hydroxymethyl, and 2-hydroxyethyl.
In some embodiments, R5 is hydrogen.
In some embodiments, R2 is selected from C1_6aralkyl and C1_6heteroaralkyl. For
example, R2 can be selected from C1_6alkyl-phenyl, C1_6alkyl-indolyl, C1_6alkyl-thienyl, C1_
6alkyl-thiazolyl, and C1_6alkyl-isothiazolyl. In some embodiments, R2 is selected from
D D D D
‘/\ N/‘X
| '/,§J/\),§|N~x ~/:N s/é/‘D
| Dis
/)f JI\/),
\ D
”‘L..\ S‘/\ ._K3 N\R
D {if}
. and p’iflLN/ .
9 9
n D is selected from hydrogen, methoxy, t-butoxy, hydroxy, halogen, cyano,
romethyl, and C1_4alkyl; and
R is hydrogen or a suitable protecting group.
In some ments, R3 is selected from yclylM-, C1_6aralkyl and C1_
6heteroaralkyl. For example, R3 can be selected from C1_6alkyl-cyclopentyl, C1_6alkyl-
entenyl, C1_6alkyl-phenyl and C1_6alkyl-indolyl. In some embodiments, R3 is selected
do\/D “*1
from r: / R
and D wherein D is selected from hydrogen, methoxy, t-
butoxy, hydroxy, halogen, cyano, trifluoromethyl, and C1_4alkyl; and R is hydrogen or a
suitable protecting group.
In some embodiments, R6 is C1_6alkyl. In some embodiments, R1 is substituted with
one or more ns, such as fluorine.
In some embodiments, R1 is selected from en, -C1_6alkyl-B, C1-
6hydroxyalkyl, C1_6alkoxyalkyl, aryl, and C1_6aralkyl. For example, R1 can be selected from -
C1_6alkle and C1_6aralkyl. Non-limiting examples of R1 include methyl, ethyl, isopropyl,
carboxymethyl, and benzyl. In some embodiments, R1 is substituted with one or more
halogens, such as fluorine.
WO 52127
In some embodiments, L is C=O, Q is absent, and R6 is -C1_6alkyl. In some
embodiments, R6 is substituted with one or more ns, such as e. In other
embodiments, L is C=O, Q is absent, and R6 is hydrogen.
Also provided herein is a compound of Formula (II) or a pharmaceutically
acceptable salt thereof,
O R
R2 R8 o
(11)
L is absent or is ed from C=O, C=S, and 802;
M is absent or is C1_12alkyl;
Q is absent or is selected from O, NH, and N-C1_6alkyl;
X is selected from O, S, NH, and N-C1_6alkyl;
each Z is independently selected from O, S, NH, and N-C1_6alkyl; or
Z is optionally a covalent bond when adjacent to an ence of A;
R2 and R3 are each independently selected from aryl, C1_6aralkyl, heteroaryl, and C1_
6heteroaralkyl;
R4 is N(R5)L-Q-R6;
R5 is selected from hydrogen, OH, C1_6aralkyl, and kyl;
R6 is selected from C1_6alkyl, heterocyclyl, heteroaryl, C1_6heteroaralkyl, heterocyclylM-,
carbocyclylM; and
R8 is selected from hydrogen, C1_6alkyl, and C1_6aralkyl.
In some embodiments, R8 is selected from hydrogen and C1_6alkyl. For example,
R8 can be hydrogen.
In some embodiments, R5 is hydrogen.
In some embodiments, R2 is selected from alkyl and C1_6heteroaralkyl. For
example, R2 can be selected from C1_6alkyl-phenyl, C1_6alkyl-indolyl, C1_6alkyl-thienyl, C1-
6alkyl-thiazolyl, and C1_6alkyl-isothiazolyl. In some embodiments, R2 is selected from
D D D D
\/\ NAA
| |N~z ~/:N 3/640
| DES
: /,:'/,;X),s /,5W,;'/,
\ D
”La \ S‘/\ I
N\ D—
D 512%?
_ and Eli/L“ -
9 9
wherein D is ed from hydrogen, methoxy, t-butoxy, hydroxy, n, cyano,
trifluoromethyl, and C1_4alkyl; and
R is hydrogen or a suitable protecting group.
In some embodiments, R3 is selected from C1_6aralkyl and C1_6heteroaralkyl. For
example, R3 can be selected from C1_6alkyl-phenyl and C1_6alkyl-indolyl. In some
JO\/D “
embodiments, R3 is selected from *‘é / and D R.
Wherein D is selected from en, methoxy, t-butoxy, hydroxy, cyano, trifluoromethyl,
and C1_4alkyl; and
R is hydrogen or a suitable protecting group.
In some embodiments, R6 is ed from heterocyclyl, heteroaryl, and
heterocyclylM-.
In some embodiments, L is C=O, Q is , and R6 is heterocyclyl. In other
embodiments, L is C=O, Q is absent, and R6 is heteroaryl. In certain embodiments, L is
C=O, Q is absent, and R6 is heterocyclylM-.
Non-limiting examples of a compound of Formula (II) include:
N N 0
W/ o o 0 W000 o
HN HN
N N
H H
\o \o
9 9
WO 52127
HN o o o
o o o
,N\N N HO HN
NI N
\él H H
o o
0/ \o
, ,
H N2
o o o
O HO O o
N N
H F H
F o o
\O O/
’ ’
o o
NH NH
/ o o o o o o
o o
HN HN
N N
H H
\O \O
9 9
HN o o o o o o
o o
HN HN
N N
H H
\o \O
, ,
o o
/ O O O
OfiHN N
WO 52127
WO 52127
022;?
H CODEX
N N
NH2 O O
HOW“
o O O
OH O/ 0/
HOWN N
o o
O/ WE;
o Moi
WO 52127
O O O O
O O
IOi? 32I
2 IQ;I2
I2 I2
/ /
OQ; O
O O 9IO O
O O
I$32 OH HN
I2 IZ
/ /CQ;
(03O O O 5)O O O
2 2
I2 IZ
/ /
OQ; OQ;
O 0
Iif I zIXJ
C O O 0
O 0
”Q; z
u u
9IO O
O 0
2 / ZI
I2 O / I2
\ Z O
/ \
OQ; 0
W000 0 0/}bNMMiMoF o o
g” H
\O ,and 0/
or a pharmaceutically acceptable salt form thereof.
For example, a compound of a (II) can be selected from the group consisting
2014/026980
HO O
FflNQLc H $6510
F _
' 3:;onV:Omfi)
F o
I 0%?C-3008,
O O 0 I z o Oo O
I Z L4 8:C-3010,\ )‘VIZ\—/
Q... C; E)
C-3009,
I Z 0 O O O
IIIII O f0 k
I Z \.—4/
z HNE?
Q. Q:II 015% E)
C-3011, C-3012,
z \\I
_\\ O E—él :O $510
Q Q:z \ \o’:éoigm};0
C-3013, C-3014,
\ O 0 :O
EIII-g: \—4/
I2 \
: OO
/ 3:2
C-3015, C-3016
WO 52127
WO 52127
WO 52127
WO 52127
[NEW/o 0 ongo
O 0\\\“‘ko
. O
HO ‘ j
IO I$2:
_ o 07ka
WO 52127
ZI ZI
3i—\O O O\—4( 0 5
IO \ IZ OHI I2"mg:
Illn< I2
0 0 0 O O O
0 O
9 E Hz Olm-I I Z \—4{
IZ x‘
Inn I2 IIII-
/ 3 /
O OQ
C-3062,
iI—\O O O I2Q3?
\—4{
H IZ
C-3063, C-3064,
o0Y0
o o
\o 0g
C-3065,
Qua/0 o o ' o
O 0 O
_\\ 0
C-3069, C-3070,
doHN
Ci9??
\O : @ar‘
, C-3072
N N
WOO!“| ojwko o F
HN GMHQL_
\o/©/ o
, and C-3074,
or a pharmaceutically acceptable salt form thereof.
The compounds provided herein can be synthesized using conventional techniques
using readily available starting materials. In general, the compounds provided herein are
iently obtained via standard organic chemistry synthesis methods. For example, the
nds provided herein may be prepared using the methods bed herein or using the
synthetic methods described in US. Patent Nos. 7,232,818; 7,417,042; 7,687,456; 7,691,852;
and 8,088,741, each of Which is incorporated by reference in its entirety.
Methods ofUse
The compounds disclosed herein can be used to inhibit the immunoproteasome (iP).
In some cases, the compounds disclosed herein inhibit LMP2 of the iP. LMP2 has been
implicated in regulating cell growth of various tumors, and may be implicated in prostate
cancer. See Wehenkel et al., Brit. J. Cancer, 107:53-62 (2012) and Ho et al., Chem. & Biol,
-430 (2007).
The biological consequences of proteasome inhibition are numerous. Proteasome
inhibition has been suggested as a prevention and/or treatment of a multitude of diseases
including, but not limited to, proliferative diseases, neurotoxic/degenerative diseases,
Alzheimer's, ic conditions, ation, auto-immune diseases, HIV, cancers, organ
graft rejection, septic shock, inhibition of antigen tation, decreasing viral gene
expression, parasitic infections, conditions associated with acidosis, macular degeneration,
pulmonary conditions, muscle wasting diseases, f1brotic diseases, and bone and hair growth
diseases. Therefore, pharmaceutical ations for proteasome-specific compounds, such
as the epoxy ketone class of molecules, provide a means of administering a drug to a patient
and treating these conditions.
At the cellular level, the accumulation of polyubiquitinated proteins, cell
morphological changes, and apoptosis have been reported upon treatment of cells with
s some inhibitors. Proteasome inhibition has also been suggested as a possible
antitumor therapeutic strategy. The fact that epoxomicin was initially identified in a screen
for antitumor compounds validates the proteasome as an antitumor chemotherapeutic .
Accordingly, these compositions are useful for ng cancer.
Both in vitro and in vivo models have shown that ant cells, in general, are
susceptible to proteasome inhibition. In fact, proteasome inhibition has already been
validated as a eutic strategy for the treatment of multiple myeloma. This could be due,
in part, to the highly proliferative ant cell's dependency on the proteasome system to
rapidly remove proteins (Rolfe et al., J. M01. Med. (1997) 75:5-17; Adams, Nature (2004) 4:
0). Therefore, provided herein is a method of treating a cancer sing
administering to a patient in need of such treatment a therapeutically effective amount of a
compound or composition as provided herein.
As used , the term “cancer” includes, but is not limited to, blood born and
solid tumors. Cancer refers to e of blood, bone, organs, skin tissue, and the vascular
system, including, but not limited to, cancers of the bladder, blood, bone, brain, breast,
cervix, chest, colon, trium, esophagus, eye, head, kidney, liver, lung, lymph nodes,
mouth, neck, ovaries, pancreas, prostate, rectum, renal, skin, stomach, testis, throat, and
uterus. Specific cancers include, but are not limited to, leukemia (acute lymphocytic
leukemia (ALL), acute lyelogenous leukemia (AML), chronic lymphocytic leukemia (CLL),
chronic myelogenous leukemia (CML), hairy cell leukemia), mature B cell neoplasms (small
lymphocytic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma
(such as Waldenstrom's macroglobulinemia), splenic al zone lymphoma, plasma cell
myeloma, plasmacytoma, monoclonal immunoglobulin deposition diseases, heavy chain
es, extranodal marginal zone B cell ma (MALT lymphoma), nodal marginal
zone B cell lymphoma (NMZL), follicular lymphoma, mantle cell lymphoma, diffilse B cell
lymphoma, diffilse large B cell lymphoma (DLBCL), mediastinal (thymic) large B cell
lymphoma, intravascular large B cell lymphoma, primary effiasion lymphoma and Burkitt
lymphoma/leukemia), mature T cell and natural killer (NK) cell neoplasms (T cell
prolymphocytic leukemia, T cell large granular lymphocytic leukemia, aggressive NK cell
ia, adult T cell leukemia/lymphoma, extranodal NK/T cell lymphoma, enteropathy-
type T cell lymphoma, splenic T cell lymphoma, blastic NK cell lymphoma, mycosis
fungoides y syndrome), primary cutaneous anaplastic large cell lymphoma,
lymphomatoid papulosis, angioimmunoblastic T cell lymphoma, unspecified eral T cell
lymphoma and anaplastic large cell lymphoma), Hodgkin lymphoma (nodular sclerosis,
mixed celluarity, lymphocyte-rich, lymphocyte depleted or not ed, nodular lymphocyte-
predominant), myeloma (multiple myeloma, indolent myeloma, smoldering myeloma),
chronic myeloproliferative disease, myelodysplastic/myeloproliferative disease,
myelodysplastic syndromes, immunodeficiency-associated lymphoproliferative disorders,
histiocytic and dendritic cell neoplasms, mastocytosis, chondrosarcoma, Ewing sarcoma,
fibrosarcoma, malignant giant cell tumor, a bone disease, osteosarcoma, breast cancer
(hormone dependent, hormone independent), gynecological cancers cal, endometrial,
fallopian tube, gestational trophoblastic disease, ovarian, neal, uterine, l and
vulvar), basal cell carcinoma (BCC), us cell carcinoma (SCC), malignant ma,
dermatofibrosarcoma protuberans, Merkel cell carcinoma, Kaposi's sarcoma, astrocytoma,
pilocytic astrocytoma, dysembryoplastic pithelial tumor, oligodendrogliomas,
moma, glioblastoma multiforme, mixed gliomas, oligoastrocytomas,
medulloblastoma, retinoblastoma, neuroblastoma, germinoma, teratoma, malignant
mesothelioma (peritoneal mesothelioma, pericardial mesothelioma, pleural mesothelioma),
gastro-entero-pancreatic or gastroenteropancreatic neuroendocrine tumor (GEP-NET),
carcinoid, pancreatic endocrine tumor (PET), pancreatic adenocarcinoma, colorectal
adenocarcinoma, colorectal carcinoma, aggressive neuroendocrine tumor,
osarcomamucinous arcinoma, Signet Ring cell adenocarcinoma, hepatocellular
carcinoma, cholangiocarcinoma, hepatoblastoma, hemangioma, hepatic adenoma, focal
nodular hyperplasia (nodular regenerative lasia, hamartoma), non-small cell lung
carcinoma (NSCLC) (squamous cell lung carcinoma, adenocarcinoma, large cell lung
carcinoma), small cell lung carcinoma, lung cancer, thyroid carcinoma, prostate cancer
(hormone refractory, androgen independent, androgen dependent, hormone-insensitive), and
soft tissue as (fibrosarcoma, malignant fibrous cytoma, dermatofibrosarcoma,
liposarcoma, rhabdomyosarcoma leiomyosarcoma, hemangiosarcoma, synovial sarcoma,
ant peripheral nerve sheath tumor/neurofibrosarcoma, extraskeletal osteosarcoma).
In some embodiments, a compound ed herein, or a pharmaceutical
ition comprising the same, can be administered to treat multiple myeloma in a patient.
For example, multiple myeloma can include relapsed and/or refractory multiple myeloma.
Many tumors of the hematopoietic and lymphoid tissues are characterized by an
increase in cell proliferation, or a particular type of cell. The chronic myeloproliferative
diseases (CMPDs) are clonal hematopoietic stem cell disorders characterized by proliferation
in the bone marrow of one or more of the myeloid lineages, resulting in increased numbers of
granulocytes, red blood cells and/or platelets in the peripheral blood. As such, use of a
compound provided herein for the treatment of such diseases is attractive and being examined
(Cilloni et al., ologica (2007) 92: 229). CMPD can include chronic
enous leukemia, chronic neutrophilic leukemia, chronic eosinophilic ia,
polycythaemia vera, chronic idiopathic myelof1brosis, essential thrombocythaemia and
unclassifiable chronic myeloproliferative disease. Provided herein is a method of treating
CMPD comprising administering to a patient in need of such ent a therapeutically
effective amount of a compound provided herein.
Myelodisplastic/myeloproliferative diseases, such as c onocytic
leukemia, atypical chronic myeloid leukemia, juvenile myelomonocytic leukemia and
unclassifiable myelodysplastic/myeloproliferative disease, are characterized by
hypercellularity of the bone marrow due to proliferation in one or more of the myeloid
lineages. Inhibiting the proteasome with a composition described herein, can serve to treat
these myelodisplatic/myeloproliferative diseases by providing a patient in need of such
ent a therapeutically effective amount of the composition.
Myelodysplastic syndromes (MDS) refer to a group of hematopoietic stem cell
disorders characterized by dysplasia and ineffective hematopoiesis in one or more of the
major myeloid cell lines. Targeting NF-kB with a proteasome inhibitor in these hematologic
malignancies induces apoptosis, thereby killing the malignant cell (Braun et al. Cell Death
and Dyferentiation (2006) 13 :748-75 8). r provided herein is a method to treat MDS
comprising stering to a patient in need of such treatment a therapeutically effective
amount of a compound provided herein. MDS includes refractory anemia, refractory anemia
with ringed sideroblasts, refractory nia with multilineage dysplasia, refractory anemia
with excess , unclassif1able myelodysplastic syndrome and myelodysplastic syndrome
associated with isolated del (Sq) chromosome abnormality.
ytosis is a proliferation of mast cells and their subsequent accumulation in
one or more organ systems. Mastocytosis includes, but is not limited to, cutaneous
mastocytosis, indolent systemic mastocytosis (ISM), systemic ytosis with associated
clonal hematological non-mast-cell-lineage disease (SM-AHNMD), aggressive systemic
mastocytosis (ASM), mast cell leukemia (MCL), mast cell sarcoma (MCS) and
extracutaneous mastocytoma. Further provided herein is a method to treat mastocytosis
comprising administering an effect amount of the compound sed herein to a patient
diagnosed with mastocytosis.
The some regulates NF-KB, which in turn regulates genes involved in the
immune and inflammatory response. For example, NF-KB is required for the expression of
the immunoglobulin light chain K gene, the IL-2 receptor (x-chain gene, the class I major
histocompatibility complex gene, and a number of ne genes encoding, for example, IL-
2, IL-6, granulocyte colony-stimulating factor, and IFN—B (Palombella et al., Cell (1994)
78:773-785). Thus, provided herein are methods of affecting the level of expression of IL-2,
MHC-I, IL-6, TNFu, IFN-B or any of the other previously-mentioned proteins, each method
comprising administering to a patient a therapeutically ive amount of a compound or
composition disclosed .
Also ed herein is a method of treating an autoimmune disease in a patient
comprising administering a therapeutically effective amount of the compound described
herein. An “autoimmune disease” as used herein is a disease or disorder arising from and
directed against an dual’s own tissues. Examples of autoimmune diseases include, but
are not limited to, inflammatory responses such as atory skin diseases including
psoriasis and itis (e.g., atopic dermatitis); systemic scleroderma and sclerosis;
responses associated with inflammatory bowel disease (such as s disease and
ulcerative colitis); respiratory distress syndrome (including adult respiratory distress
syndrome(ARDS)); dermatitis; meningitis; alitis; uveitis; colitis; glomerulonephritis;
allergic conditions such as eczema and asthma and other conditions involving infiltration ofT
cells and chronic inflammatory responses; sclerosis; leukocyte adhesion deficiency;
toid arthritis; systemic lupus erythematosus (SLE); es mellitus (e.g., Type I
diabetes us or insulin dependent diabetes mellitus); multiple sclerosis; Reynaud’s
me; autoimmune thyroiditis; allergic encephalomyelitis; Sjorgen’s syndrome; juvenile
onset diabetes; and immune responses associated with acute and delayed hypersensitivity
mediated by cytokines and T-lymphocytes typically found in tuberculosis, sarcoidosis,
2014/026980
polymyositis, granulomatosis and vasculitis; pernicious anemia (Addison’s disease); diseases
involving leukocyte diapedesis; central nervous system (CNS) inflammatory er;
multiple organ injury syndrome; hemolytic anemia (including, but not limited to
cryoglobinemia or Coombs positive anemia); myasthenia gravis; antigen-antibody complex
mediated diseases; lomerular basement membrane disease; antiphospholipid syndrome;
allergic neuritis; Graves’ disease; Lambert-Eaton enic syndrome; pemphigoid bullous;
pemphigus; mune polyendocrinopathies; Reiter’s disease; stiff-man syndrome; Beheet
disease; giant cell arteritis; immune complex nephritis; IgA nephropathy; IgM
polyneuropathies; immune thrombocytopenic purpura (ITP) or autoimmune
thrombocytopenia.
The immune system s for autologous cells that are y infected, have
undergone oncogenic transformation or present unfamiliar peptides on their surface.
Intracellular proteolysis generate small peptides for presentation to hocytes to induce
MHC class I-mediated immune responses. Thus, provided herein is a method of using a
compound or composition provided herein as an immunomodulatory agent for inhibiting or
altering antigen presentation in a cell, comprising exposing the cell (or administering to a
patient) to the compound described herein. ic embodiments include a method of
treating graft or transplant-related diseases, such as graft-versus-host disease or host versusgraft
disease in a patient, comprising administering a therapeutically effective amount of the
compound bed herein. The term “graft” as used herein refers to biological material
derived from a donor for transplantation into a recipient. Grafts include such diverse material
as, for example, isolated cells such as islet cells; tissue such as the amniotic membrane of a
newborn; bone ; hematopoietic precursor cells; ocular tissue, such as corneal tissue;
and organs such as skin, heart, liver, spleen, pancreas, thyroid lobe, lung, , and tubular
organs (e.g., intestine, blood vessels, or esophagus). The tubular organs can be used to
replace damaged portions of esophagus, blood s, or bile duct. The skin grafts can be
used not only for burns, but also as a dressing to damaged intestine or to close certain defects
such as diaphragmatic hernia. The graft is derived from any mammalian source, including
human, r from cadavers or living . In some cases, the donor and recipient is the
same patient. In some embodiments, the graft is bone marrow or an organ such as heart and
the donor of the graft and the host are matched for HLA class II antigens.
Histiocytic and tic cell neoplasms are derived from phagocytes and accessory
cells, which have major roles in the processing and presentation of antigens to lymphocytes.
Depleting the some t in dendritic cells has been shown to alter their antigen-
induced responses (Chapatte et al. Cancer Res. (2006) 66:5461-5468). In some
embodiments, a composition provided herein can be administered to a patient with histiocytic
or dendritic cell neoplasm. Histiocytic and dendritic cell neoplasms include histiocytic
sarcoma, Langerhans cell histiocytosis, Langerhans cell sarcoma, interdigitating dendritic cell
sarcoma/tumor, follicular dendritic cell sarcoma/tumor, and non-specified tic cell
sarcoma.
Inhibition of the proteasome has been shown to be beneficial to treat diseases
whereby a cell type is proliferating and immune disorders; thus, in some embodiments, the
treatment of lymphoproliferative diseases (LPD) associated with primary immune ers
(PID) is provided comprising administering a therapeutically effective amount of the
disclosed compound to a patient in need thereof The most common clinical settings of
immunodeficiency ated with an increased incidence of lymphoproliferative disorders,
including B-cell and T-cell neoplasms and mas, are primary immunodeficiency
syndromes and other primary immune disorders, infection with the human immunodeficiency
virus (HIV), iatrogenic immunosuppression in patients who have received solid organ or bone
marrow allografts, and iatrogenis immunosuppression associated with methotrexate
treatment. Other PIDs commonly associated with LPDs, but not limited to, are ataxia
telangiectasia (AT), Wiskott-Aldrich syndrome (WAS), common variable immunodeficiency
(CVID), severe combined immunodeficiency (SCID), X-linked proliferative er
(XLP), Nijmegen breakage syndrome (NBS), hyper-IgM syndrome, and autoimmune
lymphoproliferative syndrome (ALPS).
Proteasome inhibition has also been ated with inhibition ofNF-KB activation
and stabilization of p53 levels. Thus, compositions provided herein may also be used to
inhibit NF-KB activation, and stabilize p53 levels in cell culture. Since NF-KB is a key
tor of inflammation, it is an attractive target for anti-inflammatory eutic
intervention. Thus, compositions provided herein may be useful for the treatment of
conditions associated with inflammation, including, but not limited to COPD, psoriasis,
asthma, bronchitis, emphysema, and cystic fibrosis.
The sed compositions can be used to treat conditions mediated directly by the
proteolytic fianction of the proteasome such as muscle wasting, or ed indirectly via
proteins which are processed by the proteasome such as NF-KB. The proteasome participates
in the rapid elimination and post-translational sing of ns (e.g., enzymes) involved
2014/026980
in cellular regulation (6.g. cell cycle, gene ription, and metabolic ys),
intercellular communication, and the immune response (e.g., antigen presentation). c
examples discussed below include B-amyloid protein and regulatory ns such as cyclins
and transcription factor NF-KB.
In some embodiments, a composition provided herein is useful for the treatment of
neurodegenerative es and conditions, including, but not limited to, , ischemic
damage to the nervous , neural trauma (e.g, percussive brain damage, spinal cord
injury, and traumatic damage to the nervous system), multiple sclerosis, and other immune-
mediated neuropathies (e.g. Guillain-Barre syndrome and its variants, acute motor axonal
neuropathy, acute inflammatory demyelinating polyneuropathy, and Fisher Syndrome),
HIV/AIDS dementia complex, axonomy, diabetic neuropathy, Parkinson’s disease,
Huntington’s disease, bacterial, parasitic, fiangal, and viral meningitis, encephalitis, vascular
dementia, multi-infarct dementia, Lewy body dementia, frontal lobe dementia such as Pick’s
e, subcortical dementias (such as Huntington or progressive supranuclear palsy), focal
cortical atrophy syndromes (such as primary aphasia), metabolic-toxic dementias (such as
chronic hypothyroidism or B12 deficiency), and dementias caused by infections (such as
syphilis or chronic itis).
Alzheimer’s e is characterized by extracellular deposits of B-amyloid protein
(B-AP) in senile plaques and cerebral vessels. B-AP is a peptide fragment of 39 to 42 amino
acids derived from an amyloid protein precursor (APP). At least three ms ofAPP are
known (695, 75 l and 770 amino acids). Alternative splicing ofmRNA generates the
isoforms; normal processing affects a portion of the B-AP sequence, thereby preventing the
generation of B-AP. It is believed that abnormal protein sing by the proteasome
contributes to the abundance of B-AP in the Alzheimer brain. The APP-processing enzyme in
rats contains about ten different ts (22 kDa-32 kDa). The 25 kDa subunit has an N-
terminal sequence of X-Gln-Asn-Pro-Met-X-Thr-Gly-Thr—Ser, which is identical to the [3-
subunit of human macropain (Kojima, S. et al., Fed. Eur. Biochem. Soc., (1992) 304:57-60).
The APP-processing enzyme cleaves at the Gln15--Lysl6 bond; in the ce of calcium
ion, the enzyme also cleaves at the Met-l--Aspl bond, and the Aspl--Ala2 bonds to release
the extracellular domain of B-AP.
One embodiment, therefore, is a method of treating Alzheimer’s disease, including
administering to a patient a therapeutically effective amount of a composition provided
herein. Such treatment includes reducing the rate of B-AP processing, reducing the rate of B-
AP plaque formation, reducing the rate of B-AP generation, and reducing the clinical signs of
Alzheimer’s disease.
Also provided herein are methods of treating cachexia and muscle-wasting
diseases. The proteasome degrades many proteins in maturing reticulocytes and growing
fibroblasts. In cells deprived of insulin or serum, the rate of proteolysis nearly s.
Inhibiting the proteasome reduces proteolysis, thereby reducing both muscle protein loss and
the nitrogenous load on kidneys or liver. Peptide proteasome inhibitors (e.g., a nd or
ition provided herein) are useful for treating conditions such as cancer, chronic
infectious diseases, fever, muscle disuse hy) and denervation, nerve injury, fasting,
renal failure associated with acidosis, kidney disease, and hepatic failure. See, e.g., Goldberg,
US. Pat. No. 5,340,736. Methods of treatment include: reducing the rate of muscle n
degradation in a cell; reducing the rate of intracellular protein degradation; reducing the rate
of degradation of p53 protein in a cell; and ting the growth of p53-related cancers.
Each of these methods includes contacting a cell (in vivo or in vitro, e.g., a muscle in a
patient) with an ive amount of a pharmaceutical ition disclosed herein to reduce
the rate of muscle protein degradation in the cell; reduce the rate of intracellular protein
degradation in the cell; and/or reduce the rate of degradation of p53 protein in the cell. In
some embodiments, the methods include administering to a patient a therapeutically effective
amount of a pharmaceutical composition disclosed herein.
Fibrosis is the excessive and persistent formation of scar tissue resulting from the
hyperproliferative grth of fibroblasts and is associated with activation of the TGF-B
signaling pathway. Fibrosis es extensive deposition of extracellular matrix and can
occur within virtually any tissue or across several ent tissues. Normally, the level of
intracellular signaling protein (Smad) that activates transcription of target genes upon TGF-B
stimulation is ted by proteasome ty. However, accelerated degradation of the
TGF-B signaling components has been observed in s and other hyperproliferative
conditions. Thus, in certain embodiments, a method for treating hyperproliferative conditions
such as diabetic retinopathy, macular degeneration, diabetic nephropathy, glomerulosclerosis,
IgA pathy, cirrhosis, y atresia, congestive heart failure, derma, radiation-
induced fibrosis, and lung fibrosis (idiopathic pulmonary fibrosis, collagen vascular disease,
sarcoidosis, interstitial lung diseases, and extrinsic lung disorders) is provided. The treatment
of burn victims is often hampered by fibrosis, thus, in some ments a compound
provided herein may be administered by topical or ic administration to treat burns.
Wound closure following y is often associated with disfiguring scars, which may be
prevented by inhibition of fibrosis. Thus, in certain embodiments, a method for the
prevention or reduction of scarring is provided herein.
Another protein processed by the proteasome is NF-KB, a member of the Rel
n family. The Rel family of transcriptional activator proteins can be divided into two
groups. The first group requires proteolytic processing, and includes p50 (NF-KBl, 105 kDa)
and p52 (NF-K2, 100 kDa). The second group does not e proteolytic processing, and
includes p65 (RelA, Rel (c-Rel), and RelB). Both homo- and heterodimers can be formed by
Rel family members; NF-KB, for example, is a p5 0-p65 heterodimer. After orylation
and ubiquitination of IKB and p105, the two proteins are degraded and sed,
respectively, to produce active NF-KB which translocates from the cytoplasm to the nucleus.
Ubiquitinated p105 is also processed by purified proteasomes (Palombella et al., Cell (1994)
78:773-785). Active NF-KB forms a specific enhancer complex with other
transcriptional activators and, e.g, HMG I(Y), inducing selective expression of a particular
gene.
] NF-KB regulates genes involved in the immune and inflammatory response, and
mitotic events. For example, NF-KB is required for the expression of the immunoglobulin
light chain K gene, the IL-2 receptor (x-chain gene, the class I major ompatibility
complex gene, and a number of cytokine genes encoding, for example, IL-2, IL-6,
granulocyte colony-stimulating factor, and IFN-B (Palombella et al., Cell (1994) 78:773-785).
Some embodiments include methods of affecting the level of expression of IL-2, MHC-I, IL-
6, TNFOL, IFN—B, or any of the other usly-mentioned proteins, each method including
administering to a patient a therapeutically effective amount of a composition disclosed
herein. Complexes including p50 are rapid mediators of acute inflammatory and immune
responses s, D. and Maniatis, T., Cell (1995) 80:529-532).
NF-KB also ipates in the expression of the cell on genes that encode E-
selectin, P-selectin, ICAM, and VCAM-l (Collins, T., Lab. Invest. (1993) 68:499-508). In
some embodiments, a method for inhibiting cell adhesion (e.g, cell adhesion mediated by E-
selectin, P-selectin, ICAM, or VCAM-l) is ed, including contacting a cell with an
effective amount of a pharmaceutical composition disclosed herein. In some embodiments, a
method for inhibiting cell on (e.g. cell adhesion mediated by E-selectin, P-selectin,
ICAM, or VCAM-l) is provided, including administering to a patient a eutically
effective amount of a pharmaceutical composition disclosed herein.
WO 52127
Ischemia and reperfilsion injury results in hypoxia, a condition in which there is a
deficiency of oxygen reaching the tissues of the body. This condition causes increased
degradation of IK-Bu, thereby resulting in the activation ofNF-KB. It has been demonstrated
that the severity of injury resulting in a can be d with the administration of a
proteasome inhibitor. Thus, provided herein is a method of treating an ic condition or
reperfusion injury comprising administering to a t in need of such treatment a
therapeutically effective amount of a compound provided herein. Examples of such
conditions or injuries include, but are not limited to, acute coronary syndrome (vulnerable
plaques), arterial occlusive disease (cardiac, cerebral, peripheral arterial, and vascular
occlusions), atherosclerosis (coronary sclerosis, coronary artery disease), infarctions, heart
e, pancreatitis, myocardial hypertrophy, is, and restenosis.
NF-KB also binds specifically to the HIV-enhancer/promoter. When compared to
the Nef of , the HIV regulatory protein Nef of pbj l4 s by two amino acids in the
region which controls protein kinase binding. It is believed that the protein kinase signals the
phosphorylation of IKB, triggering IKB degradation through the tin-proteasome
pathway. After degradation, NF-KB is released into the s, thus enhancing the
transcription of HIV (Cohen, J., Science, (1995) 267:960). Provided herein is a method for
inhibiting or ng HIV infection in a patient, and a method for decreasing the level of
viral gene expression, each method including administering to the patient a therapeutically
effective amount of a composition disclosed herein.
Viral infections contribute to the pathology ofmany diseases. Heart conditions
such as ongoing myocarditis and dilated cardiomyopathy have been linked to the
kievirus B3. In a comparative genome microarray analyses of infected mouse
hearts, specific some subunits were uniformly up-regulated in hearts of mice which
developed chronic myocarditis (Szalay et al, Am JPathol 42-52, 2006). Some s
utilize the ubiquitin-proteasome system in the viral entry step where the Virus is released from
the endosome into the cytosol. The mouse hepatitis virus (MHV) belongs to the
Coronaviridae family, which also includes the severe acute respiratory syndrome (SARS)
irus. Yu and Lai (J Viral 79:644-648, 2005) demonstrated that treatment of cells
infected with MHV with a proteasome inhibitor resulted in a decrease in viral replication,
correlating with reduced viral titer as compared to that of untreated cells. The human
hepatitis B virus (HBV), a member of the Hepadnaviridae virus family, likewise requires
virally encoded envelop proteins to propagate. Inhibiting the proteasome degradation
WO 52127
pathway causes a significant reduction in the amount of secreted pe ns (Simsek
et al, J Viral 79:12914-12920, 2005). In addition to HBV, other hepatitis viruses (A, C, D and
E) may also utilize the ubiquitin-proteasome degradation pathway for secretion,
morphogenesis and pathogenesis. Accordingly, in certain embodiments, a method for ng
viral infection, such as SARS or hepatitis A, B, C, D and E, is ed comprising
contacting a cell with an effective amount of the compound disclosed herein. In some
embodiments, a method for treating viral infection, such as SARS or hepatitis A, B, C, D and
E, is provided comprising administering to a t a therapeutically effective amount of the
compound disclosed .
Overproduction of lipopolysaccharide (LPS)—induced cytokines such as TNFOL is
considered to be central to the processes associated with septic shock. Furthermore, it is
generally accepted that the first step in the activation of cells by LPS is the binding of LPS to
specific membrane receptors. The 0L- and B-subunits of the 208 proteasome complex have
been identified as LPS-binding proteins, suggesting that the LPS-induced signal transduction
may be an ant therapeutic target in the treatment or prevention of sepsis (Qureshi, N. et
al., J. Immun. (2003) 171: 1515-1525). Therefore, in certain embodiments, compositions as
provided herein may be used for the inhibition of TNFOL to prevent and/or treat septic shock.
Intracellular proteolysis generates small peptides for presentation to T-
lymphocytes to induce MHC class I-mediated immune responses. The immune system
screens for autologous cells that are y infected or have undergone oncogenic
transformation. One embodiment is a method for inhibiting antigen presentation in a cell,
including exposing the cell to a composition bed herein. In some embodiments, the cell
is contacted with an effective amount of a compound or composition provided herein to
inhibit antigen tation in the cell. A filrther ment is a method for suppressing the
immune system of a patient (6.g.
, inhibiting transplant rejection, y, asthma), including
administering to the patient a therapeutically effective amount of a composition described
. Compositions provided herein can also be used to treat autoimmune diseases such as
lupus, rheumatoid tis, multiple sclerosis, and inflammatory bowel diseases such as
ulcerative colitis and Crohn’s disease.
Another embodiment is a method for altering the repertoire of antigenic peptides
produced by the proteasome or other Ntn with multicatalytic activity. For example, if the
PGPH activity of ZOS proteasome is selectively inhibited, a different set of antigenic es
will be produced by the proteasome and presented in MHC molecules on the surfaces of cells
than would be produced and presented either without any enzyme inhibition, or with, for
e, selective inhibition of chymotrypsin-like activity of the proteasome.
Certain some tors block both degradation and processing of
ubiquitinated NF-KB in vitro and in vivo. Proteasome inhibitors also block IKB-(x degradation
and NF-KB activation (Palombella, et al. Cell (1994) 78:773-785; and Traenckner, et al.,
EMBO J. (1994) 13:5433-5441). In some embodiments, a method for inhibiting IKB-(x
degradation is provided, including contacting a cell with a composition described herein. In
some embodiments, a cell is contacted with an effective amount of the composition to inhibit
IKB-(x degradation. A further embodiment is a method for reducing the ar content of
NF-KB in a cell, muscle, organ, or t, including contacting the cell, , organ, or
patient with a composition described herein. In some embodiments, a cell is contacted with
an effective amount of the composition to reduce the cellular content ofNF-KB in a cell.
Other eukaryotic transcription factors that require proteolytic processing include
the general ription factor TFIIA, herpes simplex virus VPl6 accessory protein (host cell
factor), virus-inducible IFN regulatory factor 2 protein, and the membrane-bound sterol
regulatory element-binding protein 1.
Further provided herein are methods for affecting cyclin-dependent eukaryotic cell
cycles, including exposing a cell (in vitro or in vivo) to a composition disclosed herein.
Cyclins are proteins involved in cell cycle control. The proteasome participates in the
degradation of cyclins. Examples of cyclins include mitotic s, Gl cyclins, and cyclin
B. Degradation of cyclins enables a cell to exit one cell cycle stage (e.g., mitosis) and enter
another (e.g., division). It is believed all cyclins are ated with p34cdc2 protein kinase
or related kinases. The proteolysis targeting signal is localized to amino acids 42-
ISEN—SO (destruction box). There is evidence that cyclin is converted to a form
vulnerable to a ubiquitin ligase or that a cyclin-specific ligase is activated during mitosis
(Ciechanover, A., Cell, (1994) 79:13-21). tion of the proteasome inhibits cyclin
degradation, and therefore inhibits cell eration, for example, in cyclin-related cancers
(Kumatori et al., Proc. Natl. Acad. Sci. USA (1990) 87:7071-7075). ed herein is a
method for treating a erative disease in a patient (e.g., cancer, psoriasis, or restenosis),
including administering to the patient a therapeutically effective amount of a composition
disclosed . Also provided herein is a method for treating cyclin-related inflammation in
a patient, including administering to a patient a therapeutically ive amount of a
composition described herein.
WO 52127
onal embodiments include methods for affecting the proteasome-dependent
regulation of oncoproteins and methods of treating or inhibiting cancer growth, each method
including exposing a cell (in viva, e.g., in a patient, or in vitro) to a composition disclosed
. HPV—l6 and HPV—l 8-derived E6 proteins stimulate ATP- and ubiquitin-dependent
conjugation and degradation of p53 in crude reticulocyte lysates. The recessive oncogene
p53 has been shown to accumulate at the nonpermissive temperature in a cell line with a
d thermolabile El. Elevated levels of p53 may lead to apoptosis. Examples of proto-
oteins degraded by the ubiquitin system include c-Mos, c-Fos, and c-Jun. One
embodiment is a method for treating p53-related apoptosis, including administering to a
patient a therapeutically effective amount of a composition disclosed herein.
In another embodiment, the sed compositions are useful for the ent of
a parasitic infection, such as infections caused by protozoan parasites. The some of
these parasites is considered to be involved primarily in cell differentiation and replication
activities (Paugam et al., Trends Parasitol. 2003, 19(2): 55-59). Furthermore, entamoeba
species have been shown to lose encystation capacity when exposed to proteasome inhibitors
(Gonzales, et al., Arch. Med. Res. 1997, 28, Spec No: 139-140). In certain such
embodiments, the disclosed compositions are useful for the treatment of parasitic infections
in humans caused by a protozoan parasite selected from Plasmodium sps. (including P.
falciparum, P. vivax, P. malariae, and P. ovale, which cause malaria), Trypanosoma sps.
(including T. cruzi, which causes Chagas’ disease, and T. brucei which causes n
sleeping sickness), Leishmania sps. (including L. amazonesis, L. donovani, L. infantum, L.
na, etc.), Pneumocystis carinii (a protozoan known to cause pneumonia in AIDS and
other immunosuppressed patients), Toxoplasma gondii, Entamoeba histolytica, Entamoeba
invadens, and Giardia lamblia. In certain embodiments, the disclosed compositions are
useful for the treatment of tic infections in animals and livestock caused by a protozoan
parasite selected from Plasmodium hermani, Cryptosporidium sps., Echinococcus granulosus,
Eimeria a, ystis a, and Neurospora crassa. Other compounds useful as
proteasome inhibitors in the treatment of parasitic diseases are described in W0 98/10779,
which is incorporated herein in its ty.
] In certain embodiments, the disclosed compositions inhibit proteasome activity
irreversibly in a parasite. Such irreversible tion has been shown to induce shutdown in
enzyme activity without recovery in red blood cells and white blood cells. In certain such
embodiments, the long ife of blood cells may provide prolonged protection with regard
to therapy against recurring exposures to tes. In certain embodiments, the long half-life
of blood cells may provide prolonged protection with regard to chemoprophylaxis against
future infection.
Prokaryotes have what is equivalent to the eukaryote ZOS proteasome particle.
Albeit, the subunit composition of the prokaryote ZOS le is simpler than that of
eukaryotes, it has the ability to hydrolyze peptide bonds in a similar manner. For example,
the nucleophilic attack on the peptide bond occurs h the threonine residue on the N-
terminus of the B-subunits. In some ments, a method of ng prokaryotic
ions is provided, comprising administering to a patient a therapeutically effective
amount of a compound or composition provided herein. Prokaryotic infections may include
diseases caused by either cteria (such as tuberculosis, leprosy or Buruli Ulcer) or
archaebacteria.
It has also been demonstrated that inhibitors that bind to the ZOS proteasome
stimulate bone formation in bone organ cultures. Furthermore, when such inhibitors have
been administered systemically to mice, certain some inhibitors sed bone volume
and bone formation rates over 70% (Garrett, I. R. et al., J. Clin. Invest. (2003) 111: 1771-
1782), therefore suggesting that the ubiquitin-proteasome ery regulates osteoblast
differentiation and bone formation. Therefore, the disclosed compositions may be useful in
the treatment and/or prevention of diseases associated with bone loss, such as osteoporosis.
Provided herein is a method for treating a e or condition selected from
cancer, autoimmune disease, graft or transplant-related condition, neurodegenerative disease,
f1brotic-associated condition, ic-related ions, infection (viral, parasitic or
prokaryotic), and es associated with bone loss, comprising administering a compound
as ed herein.
Bone tissue is an excellent source for factors which have the capacity for
stimulating bone cells. Thus, extracts of bovine bone tissue contain not only structural
proteins which are responsible for maintaining the structural integrity of bone, but also
biologically active bone grth factors which can stimulate bone cells to proliferate. Among
these latter factors are a recently described family of proteins called bone morphogenetic
proteins (BMPs). All of these growth factors have effects on other types of cells, as well as
on bone cells, including Hardy, M. H., et al., Trans Genet (1992) 8:55-61 describes evidence
that bone morphogenetic proteins (BMPs), are differentially expressed in hair follicles during
development. Harris, S. E., et al., JBone Miner Res (1994) 863 describes the effects of
TGF-B on expression of BMP-2 and other substances in bone cells. BMP-2 expression in
mature follicles also occurs during maturation and after the period of cell proliferation
(Hardy, et al. (1992, supra). Thus, compounds provided herein may also be useful for hair
follicle growth stimulation.
Also provided herein is a method for treating a lysosomal storage disorder.
Lysosomal storage disorders are a group of es resulting from the al metabolism
of various substrates, including glycosphingolipids, glycogen, mucopolysaccharides, and
glycoproteins. The lism of exo- and endogenous high molecular weight compounds
normally occurs in the lysosomes, and the process is normally regulated in a stepwise process
by ation enzymes. Therefore, a deficient activity in one enzyme may impair the
process, resulting in an accumulation of particular substrates. It has been shown that
inhibition of the proteasome can improve the fianction of certain substrates in patients
suffering from a lysosomal storage disorder (Y. Shimada et al. Biochem. Biophys. Res.
. (2011) 415(2):274-8). Most of these diseases can be clinically classified into
subtypes: i) infantile-onset; ii) juvenile-onset; or iii) late-onset. The ile-onset forms are
often the most severe usually with no residual enzyme activity. The later-onset forms are
often milder with low, but often detectable residual enzyme activity. The severity of the
juvenile-onset forms are in n the infantile-onset and late-onset forms. Non-limiting
examples of such disorders include: Pompe disease, r disease, Fabry disease, GMl-
gangliosidosis, Tay-Sachs disease, Sandhoff disease, Niemann-Pick disease, Krabbe disease,
Farber disease, Metachromatic leukodystrophy, Hurler-Scheie disease, Hunter disease,
Sanfilippo disease A, Sanfilippo disease B, Sanfilippo disease C, Sanfilippo disease D,
Morquio disease A, Morquio disease B, Maroteaux-Lamy disease, Sly disease, 0L-
idosis, B-mannosidosis, dosis, sialidosis, and Schindler-Kanzaki disease. One
embodiment, therefore, is a method of treating Pompe disease, including administering to a
patient a therapeutically effective amount of a composition provided herein.
] The disclosed itions are also useful as stic agents (e.g., in stic
kits or for use in clinical laboratories) for screening for proteins (e.g., enzymes, transcription
factors) sed by Ntn hydrolases, including the proteasome. The disclosed itions
are also useful as research reagents for specif1cally binding the X/MBl subunit or (x-chain
and inhibiting the proteolytic activities associated with it. For example, the activity of (and
specific inhibitors of) other subunits of the proteasome can be determined.
Most cellular proteins are subject to proteolytic processing during maturation or
activation. Enzyme tors disclosed herein can be used to determine whether a cellular,
developmental, or physiological process or output is regulated by the proteolytic activity of a
particular Ntn hydrolase. One such method es obtaining an organism, an intact cell
preparation, or a cell extract; exposing the organism, cell preparation, or cell t to a
ition disclosed herein; exposing the compound-exposed organism, cell preparation, or
cell extract to a signal; and monitoring the process or output. The high selectivity of the
compounds disclosed herein permits rapid and accurate elimination or implication of the Ntn
(for example, the ZOS proteasome) in a given ar, developmental, or physiological
pI'OCGSS.
Pharmaceutical Compositions and Administration
The methods provided herein include the cture and use of pharmaceutical
compositions, which include one or more of the compounds provided herein. Also ed
are the pharmaceutical compositions themselves.
In some embodiments, the compounds provided herein can be formulated as
described in US. Patent No. 7,737,112 and US. Application Serial No. 13/614,829, each of
which is incorporated herein by reference in its entirety. Pharmaceutical compositions
typically include a pharmaceutically able carrier.
The phrase “pharmaceutically acceptable” is employed herein to refer to those
s, materials, compositions, and/or dosage forms which are, within the scope of sound
medical judgment, suitable for use in contact with the tissues of human beings and animals
without excessive toxicity, irritation, allergic response, or other problem or complication,
commensurate with a reasonable /risk ratio.
The phrase “pharmaceutically acceptable carrier” as used herein means a
pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler,
diluent, excipient, solvent or ulating material. As used herein the language
“pharmaceutically acceptable carrier” includes buffer, sterile water for ion, solvents,
dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption
delaying agents, and the like, compatible with pharmaceutical stration. Each carrier
must be “acceptable” in the sense of being compatible with the other ingredients of the
formulation and not ous to the patient. Some examples of materials which can serve as
pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and
sucrose; (2) starches, such as corn , potato starch, and substituted or unsubstituted B-
cyclodextrin; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl
cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8)
excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil,
cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols,
such as propylene glycol; (l l) polyols, such as glycerin, ol, mannitol, and polyethylene
glycol; (12) , such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents,
such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free
water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer
solutions; and (21) other non-toxic compatible substances employed in pharmaceutical
formulations. In certain embodiments, pharmaceutical compositions provided herein are non-
pyrogenic, i.e., do not induce significant temperature elevations when administered to a
patient.
The term “pharmaceutically able salt” refers to the relatively xic,
inorganic and organic acid addition salts of a compound ed herein. These salts can be
ed in situ during the final isolation and purification of a compound provided herein, or
by separately reacting the compound in its free base form with a suitable organic or inorganic
acid, and isolating the salt thus formed. Representative salts include the hydrobromide,
hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, , palmitate,
stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, filmarate, ate,
tartrate, naphthylate, mesylate, glucoheptonate, ionate, sulphonate salts, and
amino acid salts, and the like. (See, for example, Berge et al. (1977) “Pharmaceutical Salts”,
J. Pharm. Sci. 66: 1-19.)
In some embodiments, a compound ed herein may n one or more
acidic functional groups and, thus, is capable of forming pharmaceutically acceptable salts
with pharmaceutically acceptable bases. The term “pharmaceutically acceptable salts” in
these instances refers to the relatively non-toxic inorganic and organic base addition salts of a
compound provided herein. These salts can likewise be prepared in situ during the final
isolation and ation of the compound, or by separately reacting the purified compound
in its free acid form with a suitable base, such as the ide, carbonate, or bicarbonate of a
ceutically acceptable metal cation, with ammonia, or with a pharmaceutically
acceptable organic primary, secondary, or tertiary amine. entative alkali or alkaline
earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts,
2014/026980
and the like. Representative organic amines useful for the formation of base addition salts
include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine,
piperazine, and the like (see, for example, Berge et al., supra).
Wetting , emulsifiers, and lubricants, such as sodium lauryl sulfate and
magnesium stearate, as well as coloring agents, release agents, g agents, sweetening,
flavoring, and perfuming agents, preservatives and antioxidants can also be present in the
compositions.
Examples of pharmaceutically acceptable antioxidants include: (1) water soluble
antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium
metabisulf1te, sodium sulfite, and the like; (2) oil-soluble antioxidants, such as ascorbyl
palmitate, butylated yanisole (BHA), butylated hydroxytoluene (BHT), lecithin,
propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric
acid, ethylenediamine cetic acid (EDTA), ol, tartaric acid, phosphoric acid, and
the like.
A pharmaceutical composition may also contain adjuvants such as preservatives,
wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of
microorganisms may be ensured by the inclusion of various antibacterial and antifiangal
agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be
desirable to include tonicity-adjusting agents, such as sugars and the like into the
compositions. In addition, prolonged tion of the inj ectable pharmaceutical form may
be brought about by the inclusion of agents which delay absorption such as aluminum
monostearate and gelatin.
In some cases, in order to prolong the effect of one or more compounds ed
herein, it is desirable to slow the tion of the compound from aneous or
intramuscular injection. For example, delayed absorption of a parenterally administered
nd can be accomplished by dissolving or suspending the nd in an oil vehicle.
Compositions prepared as described herein can be administered in various forms,
depending on the er to be treated and the age, condition, and body weight of the
t, as is well known in the art. For example, where the compositions are to be
administered orally, they may be formulated as tablets, es, granules, powders, or
syrups; or for parenteral administration, they may be formulated as injections (intravenous,
intramuscular, or subcutaneous), drop on preparations, or suppositories. For application
by the ophthalmic mucous membrane route, they may be ated as eye drops or eye
ointments. These formulations can be prepared by conventional means in conjunction with
the methods described herein, and, if desired, the active ingredient may be mixed with any
conventional additive or ent, such as a binder, a egrating agent, a ant, a
corrigent, a solubilizing agent, a suspension aid, an emulsifying agent, or a coating agent.
Formulations suitable for oral administration may be in the form of capsules (e.g.,
gelatin capsules), cachets, pills, tablets, es (using a flavored basis, usually sucrose and
acacia or tragacanth), powders, troches, granules, or as a solution or a suspension in an
aqueous or non-aqueous liquid, or as an oil-in-water or in-oil liquid emulsion, or as an
elixir or syrup, or as pastilles (using an inert matrix, such as gelatin and glycerin, or sucrose
and ) and/or as mouthwashes, and the like, each containing a predetermined amount of
a compound ed herein as an active ingredient. A composition may also be
administered as a bolus, electuary, or paste. Oral compositions generally include an inert
diluent or an edible carrier.
Pharmaceutically compatible binding agents, and/or adjuvant materials can be
included as part of an oral composition. In solid dosage forms for oral administration
(capsules, tablets, pills, dragees, powders, es, and the like), the active ingredient can be
mixed with one or more ceutically able carriers, such as sodium citrate or
dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches,
cyclodextrins, lactose, sucrose, rin, glucose, mannitol, and/or silicic acid; (2) binders,
such as, for example, carboxymethylcellulose, microcrystalline cellulose, gum tragacanth,
tes, gelatin, polyvinyl idone, sucrose, and/or acacia; (3) humectants, such as
glycerol; (4) disintegrating agents, such as agar-agar, m carbonate, potato, corn, or
tapioca starch, alginic acid, Primogel, certain silicates, and sodium carbonate; (5) solution
retarding agents, such as paraffln; (6) absorption accelerators, such as quaternary ammonium
compounds; (7) wetting agents, such as, for example, acetyl alcohol and glycerol
monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc,
calcium stearate, magnesium stearate, Sterotes, solid polyethylene glycols, sodium lauryl
sulfate, and mixtures thereof; (10) a glidant, such as colloidal silicon dioxide; (ll) coloring
agents; and (12) a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
In the case of capsules, tablets, and pills, the pharmaceutical compositions may also comprise
ing agents. Solid compositions of a similar type may also be employed as flllers in soft
and hard-filled gelatin capsules using such ents as lactose or milk sugars, as well as
2014/026980
high molecular weight polyethylene glycols, and the like.
A tablet may be made by compression or molding, optionally with one or more
accessory ingredients. Compressed tablets may be prepared using binder (for example,
gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant
(for example, sodium starch glycolate or linked sodium carboxymethyl cellulose),
e-active or dispersing agent. Molded tablets may be made by molding in a suitable
machine a mixture of a powdered compound moistened with an inert liquid t.
Tablets, and other solid dosage forms, such as dragees, capsules, pills, and
granules, may optionally be scored or prepared with gs and shells, such as enteric
coatings and other coatings well known in the ceutical-formulating art. They may
also be formulated so as to provide slow or controlled release of the active ingredient therein
using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the
desired release profile, other polymer matrices, liposomes, microspheres, and/or
nanoparticles. They may be sterilized by, for example, filtration h a bacteria-retaining
filter, or by incorporating izing agents in the form of sterile solid compositions which
can be dissolved in sterile water, or some other sterile inj ectable medium immediately before
use. These compositions may also ally contain opacifying agents and may be of a
composition that they release the active ingredient(s) only, or entially, in a certain
portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding
compositions which can be used include ric substances and waxes. The active
ingredient can also be in micro-encapsulated form, if riate, with one or more of the
above-described excipients.
] Liquid dosage forms for oral administration include pharmaceutically acceptable
emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the
active ingredient, the liquid dosage forms may contain inert diluents ly used in the
art, such as, for example, water or other solvents, solubilizing agents, and emulsifiers such as
ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl l, benzyl
benzoate, propylene glycol, l,3-butylene glycol, oils (in particular, cottonseed, groundnut,
corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene
glycols, and fatty acid esters of sorbitan, and mixtures thereof.
Besides inert diluents, the oral compositions can also include adjuvants such as
g agents, emulsifying and suspending agents, sweetening, flavoring, coloring,
perfuming, and preservative agents.
Suspensions, in addition to the active compound(s) may contain suspending agents
as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters,
microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and anth,
and mixtures thereof.
Pharmaceutical itions suitable for parenteral administration can include
one or more compounds provided herein in combination with one or more pharmaceutically
acceptable sterile aqueous or nonaqueous ons, dispersions, suspensions or emulsions, or
sterile powders which may be reconstituted into sterile inj e solutions or dispersions just
prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the
formulation isotonic with the blood of the intended recipient or ding or thickening
agents.
Examples of suitable aqueous and nonaqueous rs which may be employed in
the pharmaceutical compositions provided herein include water for injection (e.g., sterile
water for injection), bacteriostatic water, ethanol, polyols (such as glycerol, propylene glycol,
polyethylene glycol such as liquid polyethylene glycol, and the like), sterile buffer (such as
citrate buffer), and suitable mixtures thereof, ble oils, such as olive oil, inj ectable
organic esters, such as ethyl oleate, and Cremophor ELTM (BASF, pany, NJ). In all
cases, the composition must be sterile and should be fluid to the extent that easy syringability
exists. Proper fluidity can be maintained, for example, by the use of g materials, such
as lecithin, by the maintenance of the required particle size in the case of dispersions, and by
the use of surfactants.
The composition should be stable under the conditions of manufacture and storage
and must be preserved against the inating action of microorganisms such as bacteria
and fungi. Prevention of the action of rganisms can be achieved by various
antibacterial and antifilngal , for example, parabens, butanol, phenol, ascorbic
acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents,
for e, sugars, polyalcohols such as mannitol, sorbitol, and sodium chloride in the
composition. Prolonged absorption of the inj ectable compositions can be brought about by
including in the composition an agent that delays absorption, for example, aluminum
monostearate and gelatin.
Sterile injectable ons can be prepared by incorporating the active compound
in the ed amount in an appropriate solvent with one or a combination of ingredients
enumerated above, as required, followed by filtered sterilization. Generally, dispersions are
prepared by incorporating the active compound into a sterile vehicle, which contains a basic
dispersion medium and the ed other ingredients from those enumerated above. In the
case of e powders for the preparation of sterile inj ectable solutions, the preferred
methods of preparation is freeze-drying (lyophilization), which yields a powder of the active
ingredient plus any additional desired ingredient from a previously sterile-filtered solution
thereof.
] Injectable depot forms can be made by forming microencapsule or capsule
matrices of a compound provided herein in biodegradable polymers such as polylactide-
polyglycolide. Depending on the ratio of drug to polymer, and the nature of the ular
r employed, the rate of drug release can be lled. Examples of other
biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot inj e
formulations are also prepared by entrapping the drug in liposomes,microemulsions or
nanoemulsions, which are compatible with body tissue.
For administration by inhalation, the compounds can be delivered in the form of
an aerosol spray from a pressured container or dispenser that contains a suitable propellant,
e. g., a gas such as carbon dioxide, or a nebulizer. Such methods include those described in
US. Patent No. 6,468,798, which is incorporated herein by reference in its entirety.
Additionally, intranasal delivery can be accomplished, as described in, inter alia, Hamajima
et al., Clin. Immunol. Immunopathol., 88(2), 205-10 (1998). Liposomes (e.g., as described in
US. Patent No. 6,472,375, which is incorporated herein by reference in its entirety),
microencapsulation and nanoencapsulation can also be used. radable targetable
microparticle delivery systems or biodegradable targetable nanoparticle delivery systems can
also be used (e.g., as described in US. Patent No. 6,471,996, which is incorporated herein by
reference in its entirety).
Systemic administration of a therapeutic compound as described herein can also
be by transmucosal or transdermal means. Dosage forms for the topical or transdermal
administration of a compound provided herein include powders, sprays, ointments, pastes,
creams, lotions, gels, solutions, patches, and inhalants. The active component may be mixed
under sterile conditions with a ceutically acceptable carrier, and with any
vatives, s, or lants which may be required. For transmucosal or
transdermal administration, ants appropriate to the barrier to be permeated are used in
the formulation. Such penetrants are generally known in the art, and include, for example,
for transmucosal administration, detergents, bile salts, and fusidic acid derivatives.
Transmucosal stration can be accomplished through the use of nasal sprays or
suppositories. For ermal administration, the active compounds are ated into
ointments, salves, gels, or creams as generally known in the art.
The ointments, pastes, creams, and gels may contain, in addition to one or more
compounds provided herein, excipients, such as animal and vegetable fats, oils, waxes,
paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites,
silicic acid, talc, and zinc oxide, or mixtures thereof.
Powders and sprays can contain, in addition to a compound provided ,
excipients such as lactose, talc, silicic acid, um ide, calcium silicates, and
polyamide powder, or mixtures of these substances. Sprays can additionally contain
customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted
hydrocarbons, such as butane and propane.
A compound provided herein can be administered by aerosol. This is
accomplished by preparing an aqueous aerosol, liposomal preparation, or solid particles
containing a compound or ition provided herein. A nonaqueous (e.g., arbon
lant) sion could be used. In some embodiments, sonic nebulizers are preferred
because they minimize exposing the agent to shear, which can result in degradation of the
compound.
Ordinarily, an aqueous aerosol can be made by formulating an aqueous solution or
sion of the agent together with conventional pharmaceutically acceptable carriers and
izers. The rs and stabilizers vary with the requirements of the particular
composition, but lly include nonionic surfactants (TWEEN® (polysorbates),
PLURONIC® (poloxamers), sorbitan esters, lecithin, CREMOPHOR® (polyethoxylates)),
pharmaceutically acceptable co-solvents such as polyethylene glycol, innocuous proteins like
serum albumin, sorbitan esters, oleic acid, in, amino acids such as glycine, buffers, salts,
sugars, or sugar alcohols. Aerosols generally are ed from isotonic solutions.
Transdermal patches have the added advantage of providing controlled delivery of
a compound provided herein to the body. Such dosage forms can be made by dissolving or
dispersing the agent in the proper medium. Absorption enhancers can also be used to
increase the flux of the nd across the skin. The rate of such flux can be controlled by
2014/026980
either providing a rate controlling membrane or dispersing the compound in a polymer matrix
or gel.
The ceutical compositions can also be prepared in the form of
suppositories or retention enemas for rectal and/or vaginal delivery. Formulations presented
as a suppository can be prepared by mixing one or more compounds provided herein with one
or more suitable nonirritating excipients or carriers comprising, for e, cocoa butter,
glycerides, polyethylene glycol, a suppository wax or a salicylate, which is solid at room
temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal
caVity and release the active agent. Formulations which are suitable for vaginal
administration also include pessaries, tampons, creams, gels, pastes, foams, or spray
formulations containing such carriers as are known in the art to be riate.
In one embodiment, the therapeutic compounds are prepared with carriers that will
protect the therapeutic compounds against rapid elimination from the body, such as a
controlled release formulation, including implants and microencapsulated delivery systems.
Biodegradable, biocompatible polymers can be used, such as ethylene Vinyl e,
polyanhydrides, polyglycolic acid, en, polyorthoesters, and polylactic acid. Such
formulations can be prepared using standard techniques, or obtained commercially, e.g., from
Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including
liposomes targeted to selected cells with monoclonal antibodies to cellular antigens) can also
be used as pharmaceutically able carriers. These can be prepared ing to methods
known to those d in the art, for example, as bed in US. Patent No. 4,522,811.
As described above, the preparations of one or more compounds provided herein
may be given orally, parenterally, topically, or rectally. They are, of course, given by forms
suitable for each administration route. For example, they are administered in tablets or
capsule form, by injection, inhalation, eye lotion, nt, suppository, infusion; topically
by lotion or ointment; and rectally by suppositories. In some embodiments, administration is
oral.
The phrases “parenteral administration” and “administered parenterally” as used
herein means modes of administration other than enteral and topical stration, usually
by injection, and includes, without limitation, intravenous, uscular, intraarterial,
hecal, intracapsular, intraorbital, ardiac, intradermal, eritoneal, transtracheal,
subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and
2014/026980
intrastemal injection, and infusion.
The phrases “systemic administration33 ECadministered systemically3) (C
, , peripheral
administration”, and istered peripherally” as used herein mean the administration of a
ligand, drug, or other material via route other than ly into the central nervous system,
such that it enters the patient’s system and thus, is t to metabolism and other like
processes, for example, subcutaneous administration.
A compound provided herein may be administered to humans and other animals
for therapy by any suitable route of administration, including , nasally, as by, for
example, a spray, rectally, intravaginally, parenterally, intracistemally, and topically, as by
powders, ointments or drops, including buccally and sublingually. Regardless of the route of
administration selected, a compound provided herein, which may be used in a suitable
hydrated form, and/or the pharmaceutical compositions provided herein, is formulated into a
pharmaceutically acceptable dosage form by tional methods known to those of skill in
the art. In another embodiment, the pharmaceutical composition is an oral on or a
parenteral solution. Another embodiment is a freeze-dried ation that can be
reconstituted prior to administration. As a solid, this formulation may also include tablets,
capsules or powders.
Actual dosage levels of the active ients in the pharmaceutical compositions
provided herein may be varied so as to obtain an amount of the active ingredient which is
effective to achieve the desired therapeutic response for a particular patient, composition, and
mode of administration, without being toxic to the patient.
The concentration of a compound provided herein in a ceutically
acceptable mixture will vary depending on l factors, including the dosage of the
compound to be administered, the pharmacokinetic characteristics of the compound(s)
employed, and the route of administration. In some embodiments, the compositions provided
herein can be provided in an aqueous solution containing about 01-10% w/v of a compound
disclosed herein, among other substances, for parenteral administration. Typical dose ranges
can include from about 0.01 to about 50 mg/kg of body weight per day, given in 1-4 d
doses. Each divided dose may contain the same or different nds. The dosage will be
a therapeutically effective amount ing on several factors including the overall health
of a patient, and the formulation and route of administration of the selected compound(s).
Dosage forms or compositions containing a compound as described herein in the
range of 0.005% to 100% with the e made up from non-toxic carrier may be prepared.
Methods for ation of these compositions are known to those skilled in the art. The
contemplated compositions may contain 0.001%-100% active ient, in one embodiment
01-95%, in r embodiment 75-85%. Although the dosage will vary depending on the
symptoms, age and body weight of the patient, the nature and severity of the er to be
d or prevented, the route of administration and the form of the drug, in general, a daily
dosage of from 0.01 to 2000 mg of the compound is recommended for an adult human
patient, and this may be administered in a single dose or in divided doses. The amount of
active ingredient which can be combined with a carrier material to produce a single dosage
form will generally be that amount of the nd which produces a eutic effect.
The pharmaceutical composition may be administered at once, or may be divided
into a number of smaller doses to be administered at intervals of time. It is understood that
the e dosage and duration of treatment is a function of the disease being treated and
may be determined empirically using known testing ols or by extrapolation from in
vivo or in vitro test data. It is to be noted that concentrations and dosage values may also
vary with the severity of the condition to be alleviated. It is to be fiarther understood that for
any particular patient, specific dosage regimens should be ed over time according to the
individual need and the professional judgment of the person administering or supervising the
administration of the compositions, and that the concentration ranges set forth herein are
exemplary only and are not intended to limit the scope or practice of the claimed
compositions.
The precise time of administration and/or amount of the composition that will
yield the most effective results in terms of efficacy of treatment in a given patient will depend
upon the activity, pharmacokinetics, and bioavailability of a particular nd,
physiological condition of the patient (including age, sex, e type and stage, general
physical condition, responsiveness to a given dosage, and type of medication), route of
administration, etc. However, the above guidelines can be used as the basis for fine-tuning
the treatment, e.g., determining the optimum time and/or amount of administration, which
will require no more than routine experimentation consisting of monitoring the patient and
adjusting the dosage and/or timing.
The pharmaceutical compositions can be included in a container, pack, or
ser together with instructions for administration.
Also ed herein is a conjoint therapy wherein one or more other therapeutic
agents are administered with a compound or a pharmaceutical composition comprising a
compound provided herein. Such conjoint treatment may be achieved by way of the
simultaneous, sequential, or separate dosing of the individual components of the ent.
Non-limiting examples of conjoint therapies include those provided in .
In certain ments, a composition provided herein is conjointly stered
with one or more other proteasome inhibitor(s) (see, e.g., US. Patent Nos. 7,232,818 and
8,088,741, each of which is incorporated herein by reference in its entirety). Additional
examples of proteasome inhibitors e bortezomib, MLN9708, marizomib, zomib
(see, e. g., US. Patent No. 7,417,042, which is orated herein by reference in its
entirety), and those compounds disclosed in US. Patent No. 7,687,456 and US. Patent No.
7,691,852, each of which is incorporated herein by reference in its entirety.
In certain ments, a composition provided herein is conjointly administered
with a chemotherapeutic. Suitable chemotherapeutics may include, natural products such as
vinca alkaloids (e.g., vinblastine, stine, and vinorelbine), paclitaxel,
epidipodophyllotoxins (e.g., etoposide and teniposide), antibiotics (e.g., dactinomycin
omycin D), daunorubicin, doxorubicin, and idarubicin), cyclines, mitoxantrone,
cins, plicamycin (mithramycin), mitomycin, enzymes (e.g., L-asparaginase which
systemically metabolizes L-asparagine and deprives cells which do not have the capacity to
synthesize their own gine), antiplatelet agents, antiproliferative/antimitotic alkylating
agents such as nitrogen mustards (e.g., mechlorethamine, cyclophosphamide and analogs,
melphalan, and mbucil), ethylenimines and methylmelamines (e.g.,
hexaamethylmelaamine and thiotepa), CDK inhibitors (e.g., seliciclib, UCN—Ol, Pl446A-05,
PD-033299 l, dinaciclib, P27-00,AT—7519, RGB28663 8, and SCH727965), alkyl sulfonates
(e.g., busulfan), nitrosoureas (e.g., carmustine (BCNU) and analogs, and streptozocin),
trazenes-dacarbazinine (DTIC), antiproliferative/antimitotic antimetabolites such as folic acid
analogs (e.g., methotrexate), pyrimidine analogs (e.g., fluorouracil, floxuridine, and
cytarabine), purine analogs and related inhibitors (e.g., mercaptopurine, thioguanine,
pentostatin and 2-chlorodeoxyadenosine), aromatase inhibitors (e.g., anastrozole,
exemestane, and letrozole), and platinum coordination complexes (e.g., cisplatin and
carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide, histone deacetylase
(HDAC) inhibitors (e.g., trichostatin, sodium butyrate, an, suberoyl anilide hydroamic
acid, vorinostat, LBH 589, romidepsin, ACY—lZlS, and nostat), mTor inhibitors (e.g.,
temsirolimus, everolimus, ridaforolimus, and sirolimus), KSP(Eg5) inhibitors (e.g., Array
520), DNA binding agents (e.g., Zalypsis), PI3K delta inhibitor (e.g., GS-1101 and TGR-
1202), PI3K delta and gamma inhibitor (e.g., CAL-130), multi-kinase inhibitor (e.g., TG02
and sorafenib), hormones (e.g., estrogen) and hormone agonists such as izing hormone
releasing hormone (LHRH) ts (e.g., goserelin, leuprolide and triptorelin), BAFF-
neutralizing dy (e.g., LY2127399), IKK inhibitors, p38MAPK inhibitors, anti-IL-6
(e.g., CNTO328), telomerase tors (e.g., GRN 163L), aurora kinase inhibitors (e.g,
7), cell surface monoclonal antibodies (e.g, anti-CD38 (HUMAX-CD3 8), anti-CSl
(e.g., elotuzumab), HSP90 inhibitors (e.g., 17 AAG and KOS 953), P13K / Akt inhibitors
(e.g., perifosine), Akt tor (e.g., GSK-2141795), PKC inhibitors (e.g., enzastaurin), FTIs
(e.g., ZamestraTM), anti-CD138 (e.g., BT062), Torc1/2 specific kinase inhibitor (e.g.,
), kinase inhibitor (e.g., GS-1101), ER/UPR targeting agent (e.g., MKC-3946), cFMS
inhibitor (6.g. ARRY—3 82), JAK1/2 inhibitor (6.g. CYT387), PARP inhibitor (6.g.
, , , olaparib
and veliparib (ABT—888)), BCL-2 antagonist. Other chemotherapeutic agents may include
mechlorethamine, camptothecin, ifosfamide, tamoxifen, fene, gemcitabine, navelbine,
sorafenib, or any analog or tive variant of the foregoing.
In certain embodiments, a pharmaceutical composition as provided herein is
conjointly administered with a cytokine. Cytokines include, but are not limited to, Interferon-
y, -(X, and -B, Interleukins 1-8, 10 and 12, ocyte Monocyte Colony-Stimulating factor
(GM-CSF), TNF-(x and -B, and TGF-B.
In certain embodiments, a pharmaceutical composition provided herein is
ntly administered with a steroid. le steroids may include, but are not limited to,
21-acetoxypregnenolone, alclometasone, one, amcinonide, beclomethasone,
betamethasone, budesonide, chloroprednisone, clobetasol, clocortolone, cloprednol,
corticosterone, cortisone, cortivazol, cort, desonide, desoximetasone, dexamethasone,
diflorasone, diflucortolone, difiJprednate, one, fluazacort, flucloronide, flumethasone,
flunisolide, fluocinolone acetonide, onide, fluocortin butyl, fluocortolone,
etholone, fluperolone acetate, fluprednidene acetate, fluprednisolone, flurandrenolide,
fluticasone propionate, formocortal, halcinonide, halobetasol propionate, halometasone,
hydrocortisone, loteprednol etabonate, mazipredone, medrysone, meprednisone,
methylprednisolone, mometasone filroate, paramethasone, prednicarbate, prednisolone,
prednisolone 25-diethylaminoacetate, prednisolone sodium phosphate, prednisone, prednival,
prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide, triamcinolone
WO 52127
benetonide, triamcinolone hexacetonide, and salts and/or derivatives thereof.
In some embodiments, a ceutical composition provided herein is conjointly
administered with an therapeutic agent. Suitable therapeutic agents may
include, but are not limited to, MDR modulators (e.g., verapamil, valspordar, biricodar,
tariquidar, laniquidar), cyclosporine, thalidomide, lenalidomide (REVLIMID®),
pomalidomide, and monoclonal antibodies. The monoclonal dies can be either naked
or conjugated such as rituximab, tositumomab, alemtuzumab, epratuzumab, ibritumomab
tiuxetan, gemtuzumab ozogamicin, bevacizumab, cetuximab, erlotinib, and trastuzumab.
EXAMPLES
General Experimental Methods
Nuclear Magnetic Resonance (NMR) spectra were recorded at 400 MHz for 1H.
Chemical shifts (5) are given in ppm ld from ethylsilane, an internal standard,
and coupling constants ues) are in hertz (Hz). Mass spectrometry (MS) was used to
confirm the mass of the compounds by ionizing the nds to generate charged
molecules or molecule fragments and measuring their o-charge ratios (m/z). As the
ionization method, EI (electron impact) ionization was used.
Synthetic Procedures—Dipeptide and Tripeptide Epoxy Ketone Compounds
Exam le 1 T e A
Preparation of (R)—N—((S)(4-methoxyphenyl)- l -(((S)- l -((R)methyloxiran
yl)-l -oxo-3 -phenylpropanyl)amino)-l -oxopropanyl)methyloxopyrrolidine
carboxamide (C-3010):
(R)---2methyl---5
1. Boc-LMeO-Phe oxopyrrolidine---2
DMTMM carboxylic acid
2. TFA H N DMTMM
2 \iN N
H2N o MHEfiN
TFA 0 :\©\0/ 00/
Preparation of300-(S)amin0(4-meth0xyphenyU-N- ((S)-I-((R)methy10xiran-
2-yl)-I-0x0phenylpropanyl)pr0panamide using 4-(4, 6-Dimeth0xy-I, 3, 5-triazinyl)
methylmorpholinium chloride )
DMTMM (8.65 g, 31.3mmol) and N—methylmorpholine (4.0 mg, 39 mmol) were
added to a solution of Boc-LMeO-phenylalanine (4.6 g, 15.7 mmol) and (S)amino-l-
((R)methyloxiranyl)phenylpropan-l-one (trifluoroacetic acid (TFA) salt, 5.0 g, 15.7
mmol) in methylene chloride (100 mL) and dimethylformamide (DMF, 10 mL) at 0 °C with
stirring. The suspension was stirred for 1 h at room ature. The mixture was
trated and the residue was purified by flash column chromatography on silica gel
(methylene chloride/methanol = 20: 1) to afford Boc-(S)amino(4-methoxyphenyl)-N-
((S)—1-((R)methyloxiranyl)oxophenylpropanyl)propanamide (6.9 g, 91%
yield).
Preparation of300-(S)amin0(4-meth0xyphenyU-N- ((S)-I-((R)methyloxiran-
2-yl)-I-0x0phenylpropany0pr0panamide using s(dimethylamin0)methylene]-1H-
I,2,3-trz'a2010[4,5-bjpyrl'dl'm'um 3-0xz'd hexafluorophosphate (HATU)
To a flask charged with Boc-LMeO-phenylalanine (3.1 g, 10.3 mmol), (S)
amino((R)methyloxiranyl)-3 lpropanone (TFA salt, 3.0 g, 9.4mmol) and
HATU (3.2 g, 10.3 mmol) was added dichloromethane (DCM, 20 mL). The e was
cooled to 0°C and basifled with N,N—Diisopropylethylamine (DIPEA) to pH=8. The reaction
mixture was stirred at room temperature for 30 min and then quenched with water (30 mL).
The resulting mixture was extracted with methyl tertiary butyl ether (MTBE; 30 mL><3). The
cs were combined, dried over anhydrous sodium sulfate and concentrated. The e
was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate =
:1 to 4: 1) to afford Boc-(S)amino(4-methoxyphenyl)-N-((S)—1-((R)methyloxiran
yl)oxophenylpropanyl)propanamide as a white solid (4.5 g, 88% yield).
TFA (2 mL) was added to a solution of Boc-(S)amino(4-methoxyphenyl)-N-
((S)—1-((R)methyloxiranyl)oxophenylpropanyl)propanamide (800 mg, 1 .66
mmol) in CH2C12 (5 mL) at 0°C with stirring. The reaction mixture was stirred for 1 h and
then concentrated to dryness. The residue was azeotroped three times with EtOAc (5 mL><3)
to remove residual TFA to afford (S)—2-amino(4-methoxyphenyl)-N-((S)((R)
methyloxiranyl)oxophenylpropanyl)propanamide (1.66 mmol) as its TFA salt,
which was used in the next step without further purification. DMTMM (916 mg, 3.3 mmol)
and ylmorpholine (500 mg, 5 mmol) were added to a solution of (S)amino(4-
methoxyphenyl)-N-((S)— 1 -((R)methyloxiranyl)oxophenylpropan
yl)propanamide (1.66 mmol) and (R)—2-methyloxopyrrolidinecarboxylic (500 mg, 4
mmol) in CH2C12 (20 mL) and DMF (5 mL) at 0°C with stirring. The suspension was stirred
for 1 h at room temperature and EtOAc (100 mL) and water (100 mL) were added. The
resulting two phases were separated and the aqueous phase was extracted with EtOAc (50
mL><3). The combined organic phases were washed with brine (50 mL><3), dried over NaZSO4
and concentrated. The residue was purified by flash column chromatography on silica gel
(CHzClz/MeOH = 20: 1) to afford (R)-N-((S)-3 -(4-methoxyphenyl)(((S)((R)
methyloxiranyl)-1 -oxophenylpropanyl)amino)oxopropanyl)methyl-5 -
oxopyrrolidinecarboxamide (150 mg, 17% yield) as a yellow solid.
1H NMR (300 MHz,CDC13): 8 7.20~7.30 (m, 4H), 7.15 (d, J: 8.7 Hz, 2H),
6.95~7.10 (m, 3H), 6.85 (d, J: 8.7 Hz, 2H), 6.65 (m, 1H), 6.25 (m, 1H), 4.75 (m, 1H), 4.45
(m, 1H), 3.80 (s, 3H), 3.25 (d, J: 4.8 Hz, 1H), 3.10 (m, 1H), .99 (m, 3H), 2.70 (m,
1H), 2.10~2.35 (m, 3H), 1.95 (m, 1H), 1.49 (s, 3H), 1.40 (s, 3H). MS (EI) for C28H33N306,
found 506.1 [M-H]-.
The following compounds were sized in a similar :
[00 1 77] (S)-N-((S)(4-methoxyphenyl)(((S)((R)methyloxiranyl)oxo-3 -
phenylpropanyl)amino)oxopropanyl)methyloxopyrrolidinecarboxamide (C-
3011): 1H NMR (300 MHz, : 5 7.20~7.30 (m, 4H), 7.10~7.20 (m, 5H), 6.85 (d, J =
8.7 Hz, 2H), 6.80 (m, 1H), 6.50 (m, 1H), 4.75 (m, 1H), 4.56 (m, 1H), 3.80 (s, 3H), 3.28 (d, J
= 4.8 Hz, 1H), 3.10 (m, 1H), 2.80~2.99 (m, 3H), 2.70 (m, 1H), 2.00~2.30 (m, 3H), 1.90 (m,
1H), 1.47 (s, 3H), 1.41 (s, 3H). MS (EI) for C28H33N306, found 508.1 [M+H]+.
[00 1 78] ((S)(4-methoxyphenyl)(((S)((R)methyloxiranyl)oxo-3 -
phenylpropanyl)amino)oxopropanyl)oxoazetidinecarboxamide (C-3002): 1H
NMR (400 MHz, CDClg): 5 7.26-7.21 (m, 2H), 7.10 (d, J = 8.8 Hz, 2H), 7.03-7.01 (m, 2H),
6.83-6.78 (m, 3H), .18 (m, 2H), 4.73-4.70 (m, 1H), 4.56 (q, J = 8.0 Hz, 1H), 3.99-3.97
(m, 1H), 3.78 (s, 3H), 3.27-3.21 (m, 2H), 3.12-3.08 (m, 1H), 2.94-2.92 (m, 3H), 2.71-2.61
(M, 2H), 1.50 (s, 3H). MS (EI) for C26H29N306, found 480.2 [M+H]+.
[00 1 79] (R)-N-((S)(4-methoxyphenyl)(((S)((R)methyloxiranyl)oxo-3 -
phenylpropanyl)amino)oxopropanyl)oxoazetidinecarboxamide (C-3003) : 1H
NMR (400 MHz, CDClg): 5 7.26-7.20 (m, 3H), 7.09 (d, J = 6.8 Hz, 2H), 7.02-7.01 (m, 2H),
6.93 (d, J = 7.6 Hz, 1H), 6.81 (d, J = 8.8 Hz, 2H), 6.38 (s, 1H), 6.33 (d, J = 6.8, 1H), 4.71-
4.69 (m, 1H), 4.55 (q, J = 7.6 Hz, 1H), 3.98 (q, J = 2.8 Hz, 1H), 3.78 (s, 3H), 3.26-3.20 (m,
2H), 3.08 (dd, J = 12.0, 4.8 Hz, 1H), 2.95-2.91 (m, 3H), 2.81-2.77 (m, 1H), 2.62 (dd, J =
13.8, 8.6 Hz, 1H), 1.72 (s, 1H), 1.48 (s, 3H). MS (EI) for C26H29N306, found 480.2 [M+H]+
[00 1 80] Methyl ((S)(((S)(4-methoxyphenyl)(((S)((R)methyloxiranyl)
oxophenylpropanyl)amino)oxopropanyl)amino)oxopropanyl)carbamate (C-
2009): 1H NMR (400 MHz,CDC13): 5 8.41 (d, J = 7.2 Hz, 1H), 7.75 (d, J = 8.0, 1H), 7.31—
7.19 (m, 6H), .55 (m, 1H), 4.45—4.35 (m, 1H), 3.97-3.86 (m, 1H0, 3.70 (s, 3H), 3.50 (s,
3H), 3.20-3.14(rn, 1H), 2.98—2.80 (m, 3H), 275-26 (m, 2H), 1.35 (s, 3H), 1.14 (d, J = 8.4
Hz, 1H0, 1.08-1.05 (m, 3H). LC-MS for C27H33N307, found 512.38 [M+H]+.
[00 1 8 1] Methyl ((R)(((S)-3 -(4-rneth0xyphenyl)(((S)((R)rnethyloxiranyl)
0X0phenylpr0panyl)amin0)—1-oxopropanyl)amino)ox0propanyl)carbarnate (C-
2010): 1H NMR (400 MHz, DMSO-dg): 5 8.42 (d, J = 7.2 Hz, 1H), 7.95 (d, J = 8.8 Hz, 1H),
7.31-7.21 (m, 5H), 7.07 (d, J = 8.4 Hz, 2H), 6.767 (d, J = 8.8 Hz, 2H), 4.60-4.44 (m, 2H),
3.98-3.94 (m, 1H), 3.69 (s, 3H), 3.50 (s, 3H), 3.22 (d, J = 5.6 Hz, 1H), 3.00-2.89 (m, 3H),
2.76-2.70 (m, 1H), 2.61-2.55 (1H), 1.35 (s, 3H), 0.93 (s, 3H). MS (EI) for C27H33N307, found
5123 [M+H]+.
[00 1 82] (S)-3 -(4-Meth0xyphenyl)—N—((S)—1-((R)rnethyloxiranyl)0X0-3 -
phenylpropany1)—2-((S)(2,2,2-trifluor0acetarnido)propanamido)propanamide (C-20 1 1):
1H NMR (400 MHz, DMSO-dg): 8 9.43 (d, J = 7.6 Hz, 1H), 8.45 (d, J = 7.2 Hz, 1H), 8.06 (d,
J = 8.4 Hz, 1H), 7.34-7.15 (m, 5H), 7.08 (d, J = 8.4 Hz, 2H), 6.76 (d, J = 8.4 Hz, 2H), 4.70-
4.50 (m, 1H), 4.48-4.40 (m, 1H), 4.36-4.31 (m, 1H), 3.70 (s, 3H), 3.18-3.16 (m, 1H), 2.99-
2.85 (m, 3H0, 2.73-2.68 (m, 2H), 1.35 (s, 3H0, 1.23-1.05 (m, 3H). MS (EI) for C26H29N505,
found 492.48 .
(S)(2-(1H-1,2,3-Triazolyl)acetamido)(4-meth0xypheny1)-N—((S)—1-((R)-
2-methyloxiranyl)0X0phenylpropany1)propanarnide (C-3004): 1H NMR (400
MHz, DMSO-dg): 8 8.61(d, J = 7.2 Hz, 1H), 8.42 (d, J = 8.0 Hz, 1H), 8.36 (s, 1H), 7.91 (s,
1H), 7.34-7.22 (m, 5H), 7.09 (d, J = 8.4 Hz, 2H), 6.80 (d, J = 8.4 Hz), .78 (m, 2H), 3.72
(s, 3H), 3.20-3.19 (m, 1H), .87 (m, 3H), 2.72-2.62 (m, 3H), 1.36 (s, 3H). MS (EI) for
C27H30F3N306, found 55051 [M+H]+.
[00 1 84] 2-Amin0-N—((S)—3-(4-rneth0xyphenyl)(((S)((R)—2-rnethyloxiranyl)0X0-
3-phenylpropany1)arnin0)ox0pr0pany1)rnethylpr0panarnide (C-3006): 1H NMR
(400 MHz,CDC13): 5 7.97 (d, J: 8.1 Hz, 1H), 7.26 — 7.19 (m, 3H), 7.13 (d, J: 8.7 Hz, 2H),
6.98 (dd, J: 7.5, 1.8 Hz, 2H), 6.85 — 6.79 (m, 2H), 6.36 (d, J: 7.2 Hz, 1H), 4.74 (td, J: 7.6,
.1 Hz, 1H), 4.50 — 4.39 (m, 1H), 3.78 (s, 3H), 3.27 (d, J: 4.9 Hz, 1H), 3.05 (dd, J: 14.0,
.0 Hz, 1H), 2.97 (dd, J: 6.9, 2.0 Hz, 2H), 2.90 (d, J: 4.9 Hz, 1H), 2.71 (dd, J: 14.0, 7.8
Hz, 1H), 1.22 (d, J: 13.6 Hz, 6H). MS (EI) for C26H33N305, found 468.3 [M+H]+.
(R)-3 ,3 ,3-Triflu0r0hydroxy-N—((S)(4-rneth0xyphenyl)—1-(((S)((R)
methyloxiranyl)-1 -phenylpropanyl)arnino)-1 -0X0pr0panyl)
methylpropanamide 7): 1H NMR (400 MHz, CDC13) 5 7.23 (dd, J: 5.1, 2.0 Hz, 3H),
7.15 (d, J: 8.6 Hz, 2H), 6.94 (dd, J: 7.1, 2.3 Hz, 2H), 6.84 (d, J: 8.6 Hz, 2H), 5.80 (d, J:
7.0 Hz, 1H), 4.72 — 4.62 (m, 1H), 4.55 — 4.46 (m, 1H), 4.11 (s, 1H), 3.80 (s, 3H), 3.24 (d, J:
4.9 Hz, 1H), 3.06 (td, J: 14.4, 5.3 Hz, 2H), 2.96 (s, 2H), 2.95 — 2.81 (m, 2H), 2.60 (dd, J:
13.9, 8.2 Hz, 1H), 1.51 (s, 3H), 1.47 (s, 3H). MS (EI) for C26H29F3N206, found 523.0
[M+H]+.
N—((S)-3 -(4-Methoxypheny1)(((S)((R)methyloxirany1)oxo
phenylpropany1)an1ino)— 1 -oxopropany1)oxo- 1 ,6-dihydropyridinecarboxamide (C-
3008): 1H NMR (400 MHz, DMSO-dg): 5 11.13 (s, 0H), 8.76 (s, 1H), 8.17 (s, 1H), 7.74 (s,
1H), 7.44 (s, 1H), 7.33 — 7.11 (m, 7H), 7.02 (s, 2H), 6.84 — 6.72 (m, 4H), 4.72 (s, 1H), 4.62
(ddd, J: 9.3, 7.6, 4.4 Hz, 1H), 3.68 (s, 3H), 3.17 (d, J: 5.0 Hz, 2H), 3.06 — 2.91 (m, 4H),
2.86 — 2.76 (m, 2H), 2.75-2.65 (m, 7H), 1.38 (s, 3H). MS (EI) for C28H29N306, found 504.0
[M+H]+.
((S)(4-Methoxypheny1)(((S)((R)methyloxirany1)oxo
phenylpropany1)an1ino)—1-oxopropany1)oxopiperidinecarboxamide (C-3009): 1H
NMR (400 MHz, CDC13) 5 7.26 — 7.20 (m, 3H), 7.15 — 7.11 (m, 2H), 6.99 (dd, J: 7.6, 1.8
Hz, 2H), 6.89 — 6.80 (m, 2H), 6.55 (d, J: 7.6 Hz, 1H), 6.08 — 5.97 (m, 2H), 4.74 — 4.65 (m,
1H), 4.49 (q, .1: 7.4 Hz, 1H), 3.89 (td, J: 7.2, 6.1, 2.4 Hz, 1H), 3.80 (s, 3H), 3.24 (d, J: 4.9
Hz, 1H), 3.08 (dd, J: 14.0, 4.8 Hz, 1H), 3.02 — 2.86 (m, 3H), 2.62 (dd, J: 14.0, 8.3 Hz, 1H),
2.33 (td, J: 6.4, 2.1 Hz, 2H), 1.99 — 1.90 (m, 1H), 1.79 — 1.64 (m, 3H), 1.59 (s, 3H), 1.50 (s,
3H). MS (EI) for C28H33N306, found 508.0 [M+H]+.
[00 1 88] (R)-tert-Buty1 3 -(((benzyloxy)carbony1)amino)—4-(((S)(4-methoxypheny1)— 1 -
(((S)((R)methyloxirany1)oxopheny1propany1)an1ino)—1-oxopropan
y1)an1ino)—4-oxobutanoate (C-2016): 1H NMR (400 MHz, Chloroform-d) 8 7.44 — 7.32 (m,
5H), 7.23 — 7.10 (m, 4H), 7.09 — 6.96 (m, 6H), 6.78 — 6.68 (m, 4H), 6.38 (d, J = 7.3 Hz, 1H),
3.09 — 2.92 (m, 4H), 2.89 (d, J = 5.0 Hz, 1H), 2.84 (dd, J = 14.0, 6.6 Hz, 1H), 2.65 (dd, J =
13.8, 8.9 Hz, 1H), 2.55 (dd, J = 17.3, 5.7 Hz, 1H), 1.62 (s, 2H), 1.45 (s, 3H), 1.42 (s, 8H).
MS (EI) for C38H45N309, found 688.0 .
N—((S)(((S)Cyclopenty1—1-((R)methyloxirany1)oxopropan
y1)an1ino)-3 -(4-methoxypheny1)oxopropany1)—6-oxo- 1 ,6-dihydropyridine
carboxamide (C-3014): 1H NMR (400 MHz, CDC13) 5 7.61 (d, J: 6.6 Hz, 1H), 7.50 (dd, J:
9.0, 6.9 Hz, 1H), 7.18 (d, J: 8.7 Hz, 2H), 6.87 — 6.79 (m, 5H), 6.75 (d, J: 9.1 Hz, 1H), 6.21
— 6.09 (m, 1H), 4.77 (q, .1: 7.0, 6.5 Hz, 1H), 4.51 — 4.43 (m, 1H), 3.78 (s, 3H), 3.22 (d, .1:
4.7 Hz, 1H), 3.15 (dd, .1: 13.9, 6.1 Hz, 1H), 3.03 (dd, .1: 13.9, 7.5 Hz, 1H), 2.90 (d, .1: 5.0
Hz, 1H), 1.78 — 1.30 (m, 12H), 1.19 — 0.89 (m, 2H). LC-MS for C27H33N306, found 496.0
[M+H]+.
N—((S)(((S)(Cyc10penteny1)—1-((R)rnethy10xirany1)0X0pr0pan-
2-y1)arnin0)—3-(4-rneth0xypheny1)0X0propany1)0X0-1 ,6-dihydr0pyridine
amide (C-3015): 1H NMR (400 MHz, CDC13): 8 7.50 (dd, J = 9.2, 6.8 Hz, 1H), 7.23
(d, J = 8.4 Hz, 2H), 6.87-6.76 (m, 4H), 5.85 (d, J = 6.4 Hz, 1H), 5.25 (app 5, 1H), 4.72-4.69
(m, 1H), 4.52-4.48 (m, 1H), 3.79 (s 3H), 3.26 (d, J = 4.8 Hz, 1H), 3.15 (dd, J = 13.6, 5.2 Hz,
1H), 2.99 (dd, J = 13.6, 8.4 Hz, 1H), 2.91 (d, J = 5.2 Hz, 1H), 2.55-2.45 (m, 1H), 2.19-2.11
(m, 6H), 1.82-1.76 (m, 4H), 1.52 (s, 3H), 1.49-1.42 (m ,1H). MS (EI) for C27H33N306, found
494.2 [M+H]+.
N—((S)(((S)((R)—2-Methy10xirany1)—1-0X0pheny1propany1)arnino)—1-
oxopropany1)oxo-1,6-dihydropyridinecarboxamide (C-3016): 1H NMR (400 MHz,
DMSO-dg): 8 11.19 (br s, 1H), 8.62 (br s, 1H), 8.32 (br s, 1H), 7.75 (br s, 1H), 7.29-7.17 (m,
8H), 6.78 (br s, 1H), 4.58-4.74 (m, 2H), 3.22 (d, J = 5.2 Hz, 1H), 3.03 (d, J = 5.2 Hz, 1H),
2.96 (dd, J = 14.4, 4.0 Hz, 1H), 2.69-2.63 (m, 1H), 1.38 (s, 3H), 1.26 (d, 6.8 Hz, 3H). MS
(EI) for C21H23N305, found 398.0 [M+H]+.
[00 1 92] N—((S)-3 xy(((S)((R)rnethy10xirany1)0X0pheny1propan
y1)arnin0)ox0pr0pany1)0X0-1,6-dihydropyridinecarboxarnide (C-3017): 1H NMR
(400 MHz, DMSO-dg): 8 11.23 (s, 1H), 8.58-8.56 (m, 1H), 8.31-8.29 (m, 1H), 7.79 (br s,
1H), 7.50 (br s, 1H), 7.27-7.16 (m, 5H), 6.84 (br s, 1H), 5.10-4.90 (m, 1H), 4.65-4.60 (m,
1H), 4.53-4.48 (m, 1H), .61 (m, 2H), 3.20 (d, J = 5.2 Hz, 1H), 3.00 (d, J = 5.2 Hz, 1H),
2.93 (dd, J = 14.0, 4.8 Hz, 1H), 2.70 (dd, J = 14.0, 9.6 Hz, 1H), 1.36 (s, 3H). MS (EI) for
C21H23N306, found 414.0 [M+H]+.
N—((S)-1 -(((S)Cyc10penty1—1-((R)rnethy10xirany1)—1-0X0pr0pan
y1)arnin0)ox0pr0pany1)0X0-1,6-dihydropyridinecarboxarnide (C-3018): 1H NMR
(400 MHz, DMSO-dg): 8 11.19 (s, 1H), 8.51-8.20 (m, 2H), 7.80-7.25 (m, 2H), 6.83 (br s,
1H), 4.60-4.55 (m, 1H), 4.34-4.28 (m, 1H), 3.18 (d, J = 5.2 Hz, 1H), 3.02 (d, J = 5.2 Hz, 1H),
1.82-1.41 (m, 12H), 1.29 (d, J = 7.2 Hz, 3H), 1.39-1.10 (m, 2H). MS (EI) for N305,
found 390.0 [M+H]+.
[00 1 94] N—((S)(((S)Cyc10penty1—1-((R)rnethy10xirany1)—1-0X0propan
yl)an1ino)hydroxyoxopropanyl)oxo-1,6-dihydropyridinecarboxaniide (C-
3019): 1H NMR (400 MHz, DMSO-dg): 5 11.25 (s, 1H), 8.45-8.25 (m, 2H), 8.80 (br s, 1H),
8.50 (br s, 1H), 7.80 (br s, 1H), .97 (m, 1H), 4.58-4.53 (m, 1H), 4.38-4.35 (n1, 1H),
3.66-6.63 (m, 2H), 3.18 (d, J = 4.8 Hz, 1H), 3.01 (d, J = 4.8 Hz, 1H), 1.90-1.40 (n1, 11H),
1.15-1.05 (n1, 4H). MS (EI) for C20H27N306, found 406.0 [M+H]+.
[00 1 95] (R)(((Benzyloxy)carbonyl)an1ino)(((S)(4-n1ethoxyphenyl)—1-(((S)((R)-
hyloxiranyl)oxo-3 -phenylpropanyl)an1ino)oxopropanyl)an1ino)
oxobutanoic acid (C-2017): 1H NMR (400 MHz, DMSO-d6) 8 8.54 (d, J = 7.1 Hz, 1H), 8.47
(d, J: 7.6 Hz, 1H), 7.44 — 7.09 (m, 15H), 7.04 (d, J: 8.6 Hz, 2H), 6.71 (d, J: 8.5 Hz, 2H),
.01 (s, 2H), 4.54 (ddd, J: 8.9, 7.1, 4.9 Hz, 1H), 4.38 (td, J: 9.2, 4.0 Hz, 1H), 4.13 (q, .1:
6.4 Hz, 1H), 3.67 (s, 3H), 3.44 — 3.19 (m, 3H), 2.87 (ddt, J: 33.0, 22.8, 7.1 Hz, 6H), 2.61
(dd, J: 13.8, 9.5 Hz, 1H), 2.25 (dd, J: 16.0, 5.6 Hz, 1H), 2.14 (dd, J: 16.0, 6.5 Hz, 1H),
1.34 (s, 3H). MS (EI) for C34H37N309, found 630.2 [M-H]-.
Benzyl ((S)—1-(1-hydroxycyclopropyl)(((S)(4-n1ethoxyphenyl)(((S)
((R)n1ethyloxiranyl)oxo-3 -phenylpropanyl)an1ino)oxopropanyl)an1ino)
oxoethyl)carban1ate 6): 1H NMR (300 MHz, DMSO-d6): 5 8.45 (d, J = 6.9 Hz, 1H),
7.75 (d, J: 8.4 Hz, 1H), 7.20~7.60 (m, 9H), 7.00~7.15 (m, 3H), 6.75 (d, J: 8.4 Hz, 2H),
.48 (s, 1H), 5.03 (s, 2H), 4.65 (m, 1H), 4.55 (m, 1H), 3.95 (d, J: 9.0 Hz, 1H), 3.70 (s, 3H),
3.18 (m, 1H), 2.85~3.00 (m, 3H), 2.65~2.80 (m, 1H), 1.34 (s, 3H), 0.50~0.80 (m, 4H). LC-
MS for C35H39N308, found 630.3 .
[00 1 97] (S)—2-(((benzyloxy)carbonyl)an1ino)(1 -((triethylsilyl)oxy)cyclopropyl)acetic
acid was used in the final coupling followed by standard TBAF deprotection. 1H NMR (300
MHz, DMSO-d6): 5 8.45 (d, J: 6.9 Hz, 1H), 7.75 (d, J: 8.4 Hz, 1H), 7.20~7.60 (m, 9H),
7.00~7.15 (m, 3H), 6.75 (d, J: 8.4 Hz, 2H), 5.48 (s, 1H), 5.03 (s, 2H), 4.65 (n1, 1H), 4.55 (n1,
1H), 3.95 (d, J: 9.0 Hz, 1H), 3.70 (s, 3H), 3.18 (m, 1H), 2.85~3.00 (m, 3H), 2.65~2.80 (m,
1H), 1.34 (s, 3H), 0.50~0.80 (m, 4H). LC-MS for C35H39N308, found 630.3 [M+H]+.
Exam le 2 T e A2
Preparation of benzyl ((S)—2-(((S)(4-n1ethoxyphenyl)(((S)((R)
oxiranyl)-1 -oxophenylpropanyl)an1ino)oxopropanyl)an1ino)— 1 -(oxetan-
2-oxoethyl)carbamate (C-2035)
1. LiOH
2. Coupling with O
H—Phe(4—OMe)-0Me
Oxetanone O
o 1. H2, Pd/C O 3. Separation by
COO'V'e
DBU Chiral HPLC N
Jx ,9 2. Cbz OSu.
' —’CszN $0Me
CszN P | :
, ‘OMe O
MeO CszN COOMe CszN COOMe
1.LiOH
2. HAN/$2 0
H2N H O
TFA o —>CszNifNEJkH
Methyl 2-(benzyloxycarbonylamin0)(0xetanylz'dene)acetate
1,8-Diazabicycloundecene (DBU; 16.25 g, 95 mmol) was added dropwise to a
solution ofN—benzyloxy carbonyl-(phosphono glycine trimethylester) (23.0 g, 70 mmol) and
one (5.0 g, 70 mmol) in ene chloride (200 mL) at room temperature under
N2. The on mixture was stirred for 48 h at room temperature. The solvent was removed
and the residue was dissolved in EtOAc (500 mL). The resulting on was washed with
% aqueous KHSO4 (300 mL><2), saturated aqueous NaHC03 (300 mL><3) and brine (200
mL><1), respectively. The organic phase was dried over anhydrous sodium sulfate and
trated. The residue was purified by flash column chromatography on silica gel
(Hexane/EtOAc = 5:1) to afford methyl zyloxycarbonylamino)(oxetan
ylidene)acetate (13.5 g, 69% yield).
Methyl 2-(benzyloxycarbonylamin0)(0xetany0acetate
Pd/C (10%, 5.0 g) was added to a solution of compound methyl 2-
(benzyloxycarbonylamino)(oxetanylidene)acetate (10.0 g, 36 mmol) in MeOH (100
mL). The suspension was stirred under hydrogen atmosphere at room temperature for 12 h.
The catalyst was filtered off and washed with MeOH (100 mL). The filtrate and washings
were combined followed by addition of Cbz-OSu (10.0 g, 40 mmol) and triethylamine (15.2
mL, 108 mmol). The reaction mixture was stirred for 12 h at room temperature and then
concentrated. The residue was purified by flash column chromatography on silica gel
(Hexane/EtOAc = 5:1) to afford methyl zyloxycarbonylamino)(oxetanyl)acetate
(4.3 g, 41% yield) as a yellow solid.
(S)-Methyl 2-((S)(benzyloxycarbonylamin0)(0xetany0acetaml'd0)(4-
methoxyphenyl)pr0pan0ate
A solution of LiOH (650 mg, 27 mmol) in water (10 mL) was added to a solution
of methyl 2-(benzyloxycarbonylamino)(oxetanyl)acetate (2.5 g, 9.0 mmol) in THF (50
mL) at 0°C with stirring. The reaction mixture was stirred for 12 h and then acidified with 2
N aqueous HCl to pH=3. Most of the solvent was removed and the remaining mixture was
extracted with EtOAc (50 mL><3). The combined organic phases were washed with brine (50
mL>< 1), dried over anhydrous sodium sulfate and concentrated to afford the corresponding
acid (2.0 g), which was used directly without further purification.
DMTMM (4.4 g, 16 mmol) and N—methylmorpholine (3.2 g, 32 mmol) were added
to a solution of the acid (2.0 g, 8.0 mmol) and Lmethoxylphenylalanine methyl ester
hydrochloride (2.0 g, 8.2 mmol) in methylene chloride (100 mL) at 0°C with stirring. The
suspension was stirred for l h at room temperature and then washed with 5% aqueous
KHSO4 (100 mL><2), saturated s NaHC03 (100 mL><3) and brine (50 mL>< 1),
respectively. The c phase was dried over anhydrous sodium sulfate and concentrated.
The residue was purified by flash column chromatography on silica gel (Hexane/EtOAc =
3: l) to afford a mixture of two diastereomers (2.5 g), which was fiarther separated by chiral
prep-HPLC to give (S)—Methyl 2-((S)(benzyloxycarbonylamino)(oxetan
tamido)(4- methoxyphenyl)propanoate (l .l g, 26% yield) as a white solid.
Benzyl - (((S)(4-meth0xyphenyU-I-(((S)-I-((R)methyloxiranyl)-I-0x0
phenylpropanyl)amin0)-I—0x0pr0panyl)amin0)-I-(0xetanyl)0xoethyl)carbamate.
A solution of LiOH (70 mg, 2.8 mmol) in water (10 mL) was added to a solution
of (S)-Methyl 2-((S)(benzyloxycarbonylamino)(oxetanyl)acetamido)(4-
methoxyphenyl)propanoate (0.50 g, 0.94 mmol) in tetrahydrofuran (THF; 50 mL) at 0°C with
stirring. The reaction mixture was stirred for 3 h and then acidified with 2 N aqueous HCl to
pH=3. Most of the solvent was d and the remaining mixture was extracted with
EtOAc (50 mL><3). The combined organic phases were washed with brine (50 mL>< 1), dried
over ous sodium sulfate and trated to afford the corresponding acid (0.50 g),
which was used directly t fiarther purification. HATU (380 mg, 1.0 mmol) and DIPEA
(0.62 mL, 3.6 mmol) were added to a solution of the acid (0.5 g, 0.9 mmol) and amino-
—2-methyloxiranyl)-3 -phenylpropan-l-one (TFA salt, 290 mg, 0.9 mmol) in DMF
(20 mL) at 0°C with stirring. The suspension was stirred for l h at room temperature and then
diluted with EtOAc (100 mL). The resulting mixture was washed with 5% aqueous KHSO4
(50 mL><3), saturated aqueous NaHC03 (50 mL><3) and brine (50 mL>< 1), respectively. The
organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was
purified by flash column chromatography on silica gel (Hexane/EtOAc = 3: l) to afford
Benzyl ((S)—2-(((S)(4-methoxyphenyl)- l -(((S)- l -((R)methyloxiranyl)-l -oxo-3 -
propanyl)amino)- l -oxopropanyl)amino)- l -(oxetan-3 -yl)oxoethyl)carbamate
(200 mg, 35% yield) as a white solid.
1H NMR (300 MHz, CDClg): 8 7.30~7.50 (m, 5H), .30 (m, 2H), 7.08 (d, .1
= 8.4 Hz, 2H), 6.95~7.05 (m, 2H), 6.80 (d, .1: 8.4 Hz, 2H), 6.70 (m, 1H), 6.15 (m, 1H), 5.40
(m, 1H), 5.15 (2d, 2H), 4.60~4.80 (m, 3H), 4.30~4.50 (m, 4H), 3.78 (s, 3H), 3.28 (m, 2H),
3.10 (m, 1H), 2.90~3.00 (m, 2 H), 2.70 (m, 1H), 1.60~1.70 (m, 4H), 1.51 (s, 3H). LC-MS for
C35H39N308, found 630.4 [M+H]+.
Exam le 3 T e A3
(R)-N—((S)—3-(4-methoxyphenyl)- l -(((S)— l -((R)methyloxiranyl)-l -oxo-3 -
phenylpropanyl)amino)- l -oxopropanyl)oxopyrrolidinecarboxamide
1. H2, Pd/C
O o 2. HBTU,
H2N\)J\oan D-Pyroglutamic acid H O
0A? HBTU,D|PEA 'I'll/N\-)J\OB“ iii I) O
: 0
E —> H “J
_ —> N "III . N
U O U
H :
o — H
OMe O 00/O
nzyl 3-(4-meth0xyphenyl)((R)0x0pyrr0lidinecarb0xami610) propanoate
To a solution of (S)-benzyl 2-amino(4-methoxyphenyl)propanoate (1.0 g, 2.26
mmol) in DMF (10 mL) at 0°C were added HBTU (1.02 g, 2.7 mmol) and HOBt (457 mg,
3.39 mmol). The mixture was stirred for 5 min and D-pyroglutamic acid (321 mg, 2.5 mmol)
and DIPEA (1.58 mL, 9.04 mmol) were added. The reaction mixture was stirred at room
temperature for 30 min and saturated sodium onate (50 mL) was added. The resulting
mixture was extracted with ethyl e (50 mL><2) and the combined extracts were washed
with brine (50 mL), dried over anhydrous NaZSO4 and concentrated. The residue was purified
by flash column chromatography on silica gel (Heptane to Heptane/EtOAc = 2:3) to afford
nzyl 3-(4-methoxyphenyl)((R)oxopyrrolidinecarboxamido) propanoate (800
mg, 89% yield) as a white solid.
(R)-N- ((S)(4-meth0xyphenyl)-I-(((S)-I-((R)methy10xiranyl)-I-0x0
phenylpropanyl)amin0)-I-0x0pr0panyl)0x0pyrr0lidinecarb0xamide
To a solution of (S)-benzyl 3-(4-methoxyphenyl)((R)oxopyrrolidine
carboxamido) propanoate (800 mg, 2.02 mmol) in THF (10 mL) was added Pd/C (10%, 500
mg). The suspension was stirred under hydrogen here at room temperature for 4 h.
The catalyst was filtered off and washed with MeOH (5 mL). The filtrate and washings were
combined and concentrated to dryness to afford the ponding acid (700 mg,
quantitative), which was used directly without fidrther purification.
To a solution of the acid (700 mg, 2.29 mmol) in DMF (7 mL) at 0°C was added
HBTU (1.3 g, 3.44 mmol). The mixture was d for 5 min and compound amino
((R)methyloxiranyl)phenylpropanone (469 mg, 2.29 mmol) and DIPEA (1.59 mL,
9.16 mmol) were added. The reaction mixture was stirred at room temperature for 30 min and
saturated sodium bicarbonate (50 mL) was added. The resulting mixture was extracted with
ethyl acetate (50 mL><2) and the combined extracts were washed with brine (50 mL), dried
over anhydrous Na2SO4 and concentrated. The residue was purified by flash column
tography on silica gel (DCM/MeOH = 50:1 to 10: 1) to afford (R)-N—((S)(4-
methoxyphenyl)(((S)((R)methyloxiranyl)-1 -oxophenylpropanyl)amino)-1 -
oxopropanyl)oxopyrrolidinecarboxamide (220 mg, 22% yield over two steps) as a
white solid.
1H NMR (300 MHz, CDClg): 5 7.28~7.23 (m, 5H), 7.19-7.08 (m, 5H), 7.05 (q, .1:
3.7 Hz, 2H), 7.00 (dd, .1: 7.4, 2.0 Hz, 2H), 6.81 (d, .1: 8.4 Hz, 1H), 6.70 (br s, 1H), 6.55 (d,
J: 7.2 Hz, 1H), 4.74 (m, 1H), 4.65~4.62 (m, 1H), 4.03 (m, 1H), 3.79 (s, 3H), 3.27 (d, .1: 4.8
Hz, 1H), 3.11 (d, .1: 4.5 Hz, 1H), 3.07 (d, .1: 4.8 Hz, 1H), 2.98 (m, 2H), 2.68 (dd, .1: 13.8,
8.1 Hz, 1H), 2.30 (m, 1H), 2.22 (m, 2H), 2.20 (m, 3H), 1.48 (s, 3H). MS (EI) for
C27H31N306, found 494.2 [M+H]+.
] The following compounds were synthesized in a r manner:
[0021 1] (S)-N-((S)(4-methoxyphenyl)(((S)((R)methyloxiranyl)oxo
phenylpropanyl)amino)oxopropanyl)oxopyrrolidinecarboxamide (C-3013): 1H
NMR (300 MHz, CDClg): 5 7.28~7.23 (m, 5H), 7.19-7.08 (m, 5H), 7.07 (m, 2H), 7.00 (dd, J
= 7.4, 2.0 Hz, 2H), 6.82 (d, J = 8.4 Hz, 1H), 6.70 (br s, 1H), 6.55 (d, J = 7.2 Hz, 1H), 4.74 (m,
1H), 4.65~4.62 (m, 1H), 4.03 (m, 1H), 3.79 (s, 3H), 3.27 (d, J = 4.8 Hz, 1H), 3.11 (d, J = 4.5
Hz, 1H), 3.07 (d, J = 4.8 Hz, 1H), 2.98 (m, 2H), 2.68 (dd, J = 13.8, 8.1 Hz, 1H), 2.30 (m, 1H),
2.22 (m, 2H), 2.20 (m, 3H), 1.48 (s, 3H). MS (EI) for C27H31N306, found 494.1 [M+H]+.
Exam le 4 T e D
Preparation of (S)((S)(2-(2-aminothiazolyl)acetamido)propanamido)-N-
((S)—3 -(cyclopentenyl)((R)methyloxiranyl)oxopropanyl)-3 -(4-
methoxyphenyl)propanamide (C-2066)
WO 52127
8 COOH
H2N_<\ f
o N
HzNJY :9” o o
H 0 H
HATU DIPEA 0
N 1 H N4M2 N
S N . N
HATU (635 mg, 1.68 mmol) and DIPEA (0.78 mL, 4.48 mmol) were added to a
solution of ((S)aminopropanamido)-N-((S)(cyclopentenyl)((R)
methyloxiranyl)oxopropanyl)(4-methoxyphenyl)propanamide (TFA salt, 600 mg,
1.11 mmol) and 2-(2-aminothiazolyl)acetic acid (175 mg, 1.11 mmol) in DMF (10 mL) at
0°C. The reaction mixture was d to warm to room temperature and stirred for 1 h. The
e was concentrated and the residue was purified by flash column chromatography on
silica gel (CH2Cl2/MeOH = 50: 1) to afford the title compound (150 mg, 23% yield) as a
white solid.
1H NMR (300 MHz, DMSO-d6): 5 8.31 (d, J = 7.2 Hz, 1H), 8.11 (d, J = 7.5 Hz,
1H), 7.93 (d, J = 8.1 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 6.79-6.64 (m, 5H), 5.39 (br s, 2H),
4.49 (m, 2H), 4.42 (m, 1H), 3.70 (s, 3H), 3.42 (m, 2H), 3.17 (d, J = 4.8 Hz, 1H), 2.98 (d, J =
4.8 Hz, 1H), 2.86 (m, 1H), 2.66 (m, 1H), 2.41 (m, 1H), 2.23 (m, 5H), 1.81 (m, 2H), 1.37 (s,
3H), 1.11 (d, J = 4.8 Hz, 3H). LC-MS for C29H37N506S, found 584.91 [M+H]+.
The following compounds were synthesized in a similar manner:
(S)-N—((S)(cyclopentenyl)((R)—2-methyloxiranyl)oxopropan
yl)((S)(2-(2-(dimethylamino)thiazolyl)acetamido)propanamido)-3 -(4-
methoxyphenyl)propanamide (C-2067): 1H NMR (300 MHZ, DMSO-d6): 5 8.23 (d, J = 7.2
Hz, 1H), 8.18 (d, J: 6.9 Hz, 1H), 7.93 (d, J: 7.8 Hz, 1H), 7.08 (d, J: 8.4 Hz, 2H), 6.85 (s,
1H), 6.78 (d, J: 8.4 Hz, 2H), 5.38 (s, 1H), 4.40~4.60 (m, 2H), 4.20 (m, 1H), 3.69 (s, 3H),
3.48 (m, 2H), 3.18 (m, 1H), 2.80~3.10 (m, 8H), 2.65 (m, 1H), 2.40 (m, 1H), 2.10~2.30 (m,
5H), 1.70~1.90 (m, 2H), 1.37 (s, 3H), 1.12 (d, J: 6.9 Hz, 3H). LC-MS for C31H41N506S,
found 610.33 [M-H]'.
(S)((S)(2-(2-(azetidinyl)thiazolyl)acetamido)propanamido)-N-((S)—3-
(cyclopenten-1 -yl)((R)methyloxiranyl)oxopropanyl)—3 -(4-
yphenyl)propanamide (C-2068): 1H NMR (300 MHZ, DMSO-d6): 5 8.25 (d, J = 6.6
Hz, 1H), 8.18 (d, J: 6.9 Hz, 1H), 7.93 (d, J: 7.5 Hz, 1H), 7.08 (d, J: 8.4 Hz, 2H), 6.84 (s,
1H), 6.78 (d, J: 8.4 Hz, 2H), 5.38 (m, 1H), 4.40~4.60 (m, 2H), 4.20 (m, 1H), 3.95 (m, 4H),
WO 52127
3.69 (s, 3H), 3.48 (m, 2H), 3.18 (m, 1H), 3.00 (m, 1H), 2.90 (m, 1H), 2.50~2.80 (m, 2H),
2.30~2.50 (m, 4H), 2.10~2.30 (m, 5H), 1.70~1.90 (m, 2H), 1.37 (s, 3H), 1.12 (d, .1: 6.9 Hz,
3H). LC-MS for C32H41N506S, found 623.72 .
(S)-N—((S)(cyclopcntcnyl)((R)—2-nicthyloxiranyl)oxopropan
y1)-3 -(4-mcthoxyphcny1)((S)(2-(2-(pyrrolidiny1)thiazol-5 -
yl)acctan1ido)propanamido)propanan1idc (C-2069): 1H NMR (300 MHZ, DMSO-d6): 5 8.25
(d, J: 6.9 Hz, 1H), 8.15 (d, J: 7.2 Hz, 1H), 7.93 (d, J: 7.2 Hz, 1H), 7.08 (d, J: 8.4 Hz,
2H), 6.84 (s, 1H), 6.78 (d, J: 8.4 Hz, 2H), 5.38 (s, 1H), 4.40~4.60 (m, 2H), 4.20 (m, 1H),
3.69 (s, 3H), 3.50 (m, 2H), 3.30 (m, 4H), 3.18 (m, 1H), 3.00 (m, 1H), 2.90 (m, 1H), 2.65 (m,
1H), 2.40 (m, 1H), 2.10~2.30 (m, 5H), 1.90~2.00 (m, 4H), 1.85 (m, 2H), 1.37 (s, 3H), 1.12
(d, J: 6.9 Hz, 3H). LC-MS for C33H43N506S, found 638.64 [M+H]+.
] (S)((S)(2-(2-an1inooxazoly1)acctamido)propanan1ido)—N—((S)—3-
(cyclopcntcn-1 -y1)-1 -((R)nicthyloxirany1)-1 -oxopropanyl)—3 -(4-
methoxyphcnyl)propanan1idc (C-2070): 1H NMR (300 MHz, DMSO-d6): 5 8.29 (d, J = 7.2
Hz, 1H), 8.11 (d, J: 7.5 Hz, 1H), 7.98 (d, J: 8.4 Hz, 1H), 7.11 (d, J: 8.4 Hz, 2H), 6.79 (d,
J: 8.4 Hz, 2H), 6.38 (m, 3H), 5.39 (br s, 1H), 4.49 (m, 2H), 4.42 (m, 1H), 3.70 (s, 3H), 3.17
(d, J: 7.6 Hz, 1H), 2.98 (d, J: 5.1 Hz, 1H), 2.86 (m, 1H), 2.66 (m, 1H), 2.37 (m, 1H), 2.21
(m, 5H), 1.81 (m, 2H), 1.37 (s, 3H), 1.11 (d, J: 4.8 Hz, 3H). LC-MS for C29H37N507, found
568.76 [M+H]+.
(S)acctan1idohydroxy-N—((S)(4-nicthoxyphcnyl)(((S)((R)
methyloxiran-Z-yl)-1 -oxophcnylpropany1)an1ino)oxopropany1)propanan1idc
utilizing (S)an1inohydroxy-N—((S)—3 -(4-nicthoxyphcnyl)(((S)((R)nicthyloxiran-
2-y1)-1 -oxo-3 -phcnylpropany1)an1ino)oxopropany1)propanan1idc and corresponding
activated acid (C-2007): 1H
NMR (400 MHz, CDC13)2 8 7.43 (d, J: 8.2 Hz, 1H), 7.14 (d, J:
8.4 Hz, 1H), 7.07 (d, J: 8.7 Hz, 2H), 6.86 (d, J: 8.6 Hz, 2H), 6.78 (d, J: 8.7 Hz, 2H), 6.70
(d, J: 8.6 Hz, 2H), 6.57 (d, J: 7.7 Hz, 1H), 6.22 (d, J: 7.6 Hz, 1H), 6.11 (s, 1H), 4.69 (td, J
= 8.1, 4.7 Hz, 1H), 4.48 (q, .1: 7.2 Hz, 1H), 4.38 (p, .1: 6.9 Hz, 1H), 3.77 (s, 3H), 3.73-3.65
(m, 5H), 3.22 (d, J: 4.9 Hz, 1H), 3.09 — 2.79 (m, 8H), 2.58 (dd, J: 14.1, 8.3 Hz, 1H), 2.53 —
2.39 (m, 4H), 1.63 (s, 3H), 1.51 (s, 3H), 1.30 (s, 3H). MS (EI) for C27H33N307, found 512.3
[M+H]+.
[0022 1] (S)((S)(3 -hydroxypropanamido)propanan1ido)—3-(4-mcthoxyphcnyl)—N—((S)—
1 2-nicthyloxirany1)-1 -oxo-3 1propany1)propanan1idc utilizing (S)—2-((S)—2-
aminopropananiido)-3 -(4-n1ethoxyphenyl)—N—((S)— 1 2-n1ethyloxiranyl)— 1 -oxo-3 -
phenylpropanyl)propanan1ide and corresponding activated acid (C-2012): 1H NMR (400
MHz, DMSO-dg): 5 8.34 (d, J = 7.2 Hz, 1H), 7.96 (d, J = 7.2 Hz, 1H), 7.78 (d, J = 8.4 Hz,
1H), 7.31-7.22 (m, 5H), 7.06 (d, J = 8.4 Hz, 1H), 6.77 (d, J = 8.4 Hz, 1H), 4.64-4.57 (n1, 2H),
4.39-4.38 (m, 1H), .19 (m, 1H), 3.70 (s, 3H), 3.58-3.56 (m, 2H), 3.17 (d, J = 4.8 Hz,
1H), 2.98-2.91 (n1, 3H), 2.74-2.64 (n1, 2H), 2.25-2.22 (m, 2H), 1.34 (s, 3H), 1.07 (d, J = 7.2
Hz, 3H). MS (EI) for C28H35N307, found 526.3 [M+H]+.
(S)((S)(3-(n1ethoxymethoxy)propanamido)propanan1ido)—3-(4-
methoxyphenyl)-N—((S)— 1 -((R)n1ethyloxiranyl)— 1 -oxophenylpropan
yl)propanan1ide utilizing (S)((S)an1inopropanan1ido)(4-n1ethoxyphenyl)-N—((S)
((R)n1ethyloxiranyl)oxophenylpropanyl)propanan1ide and corresponding
activated acid (C-2013): 1H NMR (400 MHz, DMSO-dg): 5 8.38 (d, J = 7.2 Hz, 1H), 7.98 (d,
J = 7.2 Hz, 1H), 7.78 (d, 8.0 Hz, 1H), 7.31-7.20 (m, 5H), 7.06 (d, J = 8.4 Hz, 2H), 6.77 (d, J =
8.4 Hz, 2H), 4.58-4.57 (n1, 1H), 4.48 (s, 2H), 4.41-4.40 (n1, 2H), 4.23-4.19 (n1, 1H), 3.70 (s,
3H), 3.63-3.58 (m, 2H), 3.19-3.16 (m, 4H), 2.98-2.86 (m, 3H), 2.74-2.65 (m, 2H), 2.37-2.30
(n1, 2H), 1.45 (s, 3H), 1.07 (d, J = 6.8 Hz, 3H). MS (EI) for C30H39N308, found 570.57
[M+H]+.
N—((S)(((S)(4-n1ethoxyphenyl)—1-(((S)((R)n1ethyloxiranyl)—1-oxo
phenylpropanyl)an1ino)oxopropanyl)an1ino)oxopropanyl)n1ethyl-1H-
indenecarboxan1ide utilizing (S)—2-((S)an1inopropanan1ido)—3-(4-n1ethoxyphenyl)-N—
((S)—1-((R)n1ethyloxiranyl)—1-oxophenylpropanyl)propanan1ide and
corresponding ted acid (C-2049): 1H NMR (400 MHz, CDgOD) 5 7.49 (t, J = 5.7, 5.7
Hz, 2H), 7.44—7.28 (m, 2H), 7.28—7.09 (m, 5H), 7.03 (d, J: 8.6 Hz, 2H), 6.65 (d, J: 8.6 Hz,
2H), 4.75 (dd, J: 9.1, 4.6 Hz, 1H), 4.54 (d, J: 14.0 Hz, 1H), 4.48 (d, J: 24.2 Hz, 1H),
3.66—3.47 (m, 5H), 3.21 (d, J: 5.0 Hz, 1H), 3.06 (d, J: 14.0 Hz, 1H), 2.98 (dd, J: 13.9, 5.8
Hz, 1H), 2.91 (d, J: 5.0 Hz, 1H), 2.81 (dd, J: 13.9, 8.2 Hz, 1H), 2.72 (dd, J: 13.8, 9.2 Hz,
1H), 2.43 (t, J: 2.2, 2.2 Hz, 3H), 1.41 (s, 3H), 1.33 (d, J: 7.1 Hz, 3H). LC-MS for
C32H39N506, found 610.0 [M+H]+.
3 -hydroxy-N—((R)—1-(((S)—3 -(4-n1ethoxyphenyl)—1-(((S)((R)n1ethyloxiran
yl)— 1 -oxo-3 lpropanyl)an1ino)-1 -oxopropanyl)an1ino)oxopropanyl)-3 -
methylbutananiide utilizing ((R)an1inopropanan1ido)(4-n1ethoxyphenyl)-N-((S)
((R)n1ethyloxiranyl)oxophenylpropanyl)propanan1ide and ponding
activated acid 6): 1H NMR (400 MHz, DMSO-d6) 5 8.41 (d, J: 7.3 Hz, 1H), 8.07 (d,
.1: 8.7 Hz, 1H), 7.95 (d, .1: 7.4 Hz, 1H), 7.34 — 7.17 (rn, 5H), 7.09 (d, .1: 8.7 Hz, 2H), 6.78
(d, .1: 8.8 Hz, 2H), 4.76 (s, 1H), 4.58 (ddd, J: 9.2, 7.6, 4.6 Hz, 1H), 4.50 — 4.40 (rn, 1H),
4.22 (p, .1: 7.4 Hz, 1H), 3.69 (s, 3H), 3.67 — 3.57 (m, 1H), 3.22 (d, .1: 5.1 Hz, 1H), 3.18 —
3.10 (m, 1H), 3.01 — 2.89 (rn, 3H), 2.79 — 2.67 (rn, 1H),2.61— 2.53 (rn, 1H), 2.19 (s, 1H),
2.07 (s, 1H), 1.34 (s, 3H), 1.28 — 1.19 (m, 6H), 1.11 (d, .1: 4.7 Hz, 5H), 0.94 (d, .1: 7.0 Hz,
3H). LC-MS for C30H39N307, found 554.2 [M+H]+
N—((R)—1-(((S)(4-rnethoxypheny1)(((S)((R)—2-rnethyloxirany1)oxo
pheny1propany1)arnino)—1-oxopropany1)arnino)oxopropany1)-1H-indene
carboxarnide ing (S)((R)arninopropanarnido)(4-rnethoxypheny1)-N—((S)—1-((R)-
2-rnethyloxirany1)oxopheny1propany1)propanarnide and ponding activated
acid (C-2057): 1H NMR (400 MHz, DMSO-d6) 5 8.44 (d, J: 7.3 Hz, 1H), 8.15 (d, J: 7.2
Hz, 1H), 8.03 (d, J: 8.7 Hz, 1H), 7.95 (s, 1H), 7.63 (s, 0H), 7.57 — 7.49 (rn, 1H), 7.37 — 7.25
(rn, 6H), 7.24 — 7.16 (rn, 1H), 7.07 (d, J: 8.7 Hz, 2H), 6.72 (d, J: 8.7 Hz, 2H), 4.65 — 4.52
(m, 1H), 4.51 — 4.41 (m, 1H), 4.40 — 4.30 (m, 1H), 3.63 (s, 3H), 3.22 (d, J: 5.3 Hz, 1H), 3.00
— 2.90 (rn, 3H), 2.89 (s, 2H), 2.78 (dd, J: 13.9, 9.3 Hz, 1H), 2.73 (s, 1H), 2.61 (dd, J: 13.8,
.1 Hz, 1H), 1.34 (s, 3H), 1.09 (d, J: 7.2 Hz, 3H). LC-MS for C30H39N307, found 594.2
[M-HT
N—((R)—1-(((S)(4-rnethoxypheny1)(((S)((R)—2-rnethyloxirany1)oxo
pheny1propany1)arnino)— 1 -oxopropany1)an1ino)-1 -oxopropany1)cyclopent
enecarboxarnide utilizing (S)—2-((R)an1inopropanarnido)(4-rnethoxypheny1)-N—((S)-1 -
((R)rnethyloxirany1)oxopheny1propany1)propanarnide and corresponding
activated acid (C-2058): 1H NMR (400 MHz, ) 5 8.40 (d, J: 7.3 Hz, 1H), 8.28 — 8.03 (rn,
2H), 7.99 (d, J: 8.7 Hz, 1H), 7.95 (s, 1H), 7.71 (d, J: 7.2 Hz, 1H), 7.33 — 1, 3H),
7.24 — 7.17 (rn, 1H), 7.07 (d, J: 8.7 Hz, 2H), 6.76 (d, J: 8.7 Hz, 2H), 6.53 (t, J: 1.9 Hz,
1H), 4.58 (ddd, J: 9.2, 7.3, 4.6 Hz, 2H), 4.42 (td, J: 10.1, 4.0 Hz, 1H), 4.24 (t, J: 7.2 Hz,
1H), 3.69 (s, 3H), 3.62 (pd, J: 6.6, 4.0 Hz, 3H), 3.22 (d, J: 5.4 Hz, 1H), 3.14 (qd, J: 7.4,
4.3 Hz, 4H), 3.02 — 2.90(n1, 3H),2.89(s, 3H),2.73 (s, 3H), 2.69 (s, 4H), 2.58 (dd, J: 13.7,
.2 Hz, 1H), 2.47 — 2.37 (m, 4H), 1.85 (p, J: 7.7 Hz, 2H), 1.35 (s, 3H), 1.31 — 1.19 (rn,
31H), 1.02 (d, J: 7.1 Hz, 3H). LC-MS for C32H39N506, found 548.0 [M+H]+.
Exam le5 T eE
WO 52127
1.H2,Pd/C
2. HATU, NMM
RCOOH
O QCOOMB HM _ “\iOMe
E HATU,D|PEA NH2
2“;OB“ —. OBn ”/7; ;
HN N
Ho W
1. LiOH
2. HATU, NMM, o
H/\H/ H2,Pd/C N
i H <— H/\fl/ a]:_
O '
\QOMeO
O mom}O
OH OBn
Preparation of N—((R)(((S)—1-(((S)-3 -cyclopentyl((R)methyloxiranyl)oxopropanyl)amino)-3 droxymethoxyphenyl)oxopropanyl)amino)
oxopropanyl)hydroxy-3 -methylbutanamide (C-2059)
nzyl 2-(3-hydr0xymethyl!)utanamid0)pr0pan0ate
DIPEA (8.9 mL, 77 mmol) was added to a mixture of oxy
methylbutanoic acid (2.2 g, 18.6 mmol), (R)—benzyl 2-aminopropanoate hydrochloride (3.7 g,
17.1 mmol) and HATU (7.2 g, 18.9 mmol) in dichloromethane (50 mL) at 0°C. The reaction
mixture was stirred for 1 h at room temperature. Water (100 mL) was added and the two
layers were separated. The aqueous layer was extracted with dichloromethane (100 mL><3).
The organic phases were combined, dried over anhydrous sodium sulfate and concentrated.
The residue was purified by flash column tography on silica gel (petroleum
ether/ethyl acetate = 10:1 to 3:1) to give (R)-benzyl 2-(3-hydroxy
methylbutanamido)propanoate (4.7 g, 98% yield).
(S)-Methyl 3-(3-(benzyloxy)meth0xyphenyl)((R)(3-hydr0xymethyl
butanamid0)pr0panamid0)pr0pan0ate
] (R)-Benzyl 2-(3-hydroxymethylbutanamido)propanoate (4.7 g, 16.8 mmol) was
hydrogenated in the presence of Pd/C (0.5 g) in methanol (20 mL) for 1 h at room
temperature. Pd/C was filtered off and the filtrate was concentrated to give the corresponding
acid (3.0 g) as an off-white solid.
The acid (1.5 g, 7.9 mmol) was dissolved in dichloromethane (30 mL) and (S)-
methyl o(3-(benzyloxy)methoxyphenyl)propanoate (TFA salt, 3.4 g, 7.9 mmol)
and HATU (3.3 g, 8.7 mmol) were added. Then ylmorpholine (2.4 g, 23.7 mmol) was
added to the resulting solution at 0°C. The on mixture was stirred for 1 h at room
temperature and water (100 mL) was added. The two layers were separated and the aqueous
layer was extracted with dichloromethane (100 mL><3). The c phases were combined,
dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash
column chromatography on silica gel (dichloromethane/methanol = 200:1 to 100: 1) to give
(S)-methyl 3 -(3 -(benzyloxy)methoxyphenyl)((R)(3-hydroxy-3 l
butanamido)propanamido)propanoate (1.5 g, 39% yield).
N-((R)-I -((S) (3- (Benzyloxy)meth0xyphenyl)-I-((S)cyclopentyl—I-((R)
methyloxirany0-I—0x0pr0panylamin0)-I—0x0pr0panylamin0)-I—0x0pr0panyU
hydroxymethylbutanamide
(S)-Methyl benzyloxy)methoxyphenyl)((R)(3-hydroxymethyl
butanamido)propanamido)propanoate (1.5 g, 3.1 mmol) was treated with a solution of lithium
hydroxide-H2O (0.26 g, 6.2 mmol) in water/THF (10 mL/4 mL) for 30 min. THF was
removed and the aqueous phase was acidified to pH=3-4 with 10% aqueous KHSO4. The
resulting mixture was extracted with ethyl acetate (50 mL><3). The organic extracts were
combined, dried over anhydrous sodium sulfate and concentrated to give the corresponding
acid (1.2 g) as a yellow solid. The acid (0.63 g, 1.3 mmol) was dissolved in dichloromethane
(30 mL) and (S)aminocyclopentyl((R)methyloxiranyl)propanone (TFA salt,
0.4 g, 1.3 mmol) and HATU (0.56 g, 1.4 mmol) were added. N—Methylmorpholine (0.33 g,
3.2 mmol) was added to the resulting solution at 0°C. The reaction mixture was stirred for 1 h
at room temperature and water (100 mL) was added. The two layers were separated and the
aqueous layer was extracted with dichloromethane (100 . The organic phases were
combined, dried over anhydrous sodium e and concentrated. The residue was purified
by flash column chromatography on silica gel (dichloromethane/methanol = 200:1 to 100: 1)
to give —1-((S)-3 -(3 -(benzyloxy)methoxyphenyl)((S)-3 -cyclopentyl((R)
methyloxiranyl)-1 -oxopropanylamino)oxopropanylamino)oxopropanyl)-3 -
hydroxymethylbutanamide (0.3 g, 35% yield).
N-((R)-I -(((S)-I-(((S)cyclopentyl—I -((R)methyloxiranyl)-I-0x0pr0pan
yUamino)(3-hydr0xymethoxyphenyl)-I-0x0pr0panyl)amin0)-I-0x0pr0panyl)
hydroxymethylbutanamide
N—((R)—1-((S)-3 -(3 -(Benzyloxy)methoxyphenyl)((S)cyclopentyl((R)
methyloxiranyl)-1 -oxopropanylamino)oxopropanylamino)oxopropanyl)-3 -
hydroxymethylbutanamide (0.3 g, 0.46 mmol) was hydrogenated in the presence of Pd/C
(0.1 g) in methanol (20 mL) for 2 h at 0°C. Pd/C was filtered off and the filtrate was
concentrated. The residue was purified by flash column chromatography on silica gel
(dichloromethane/methanol = 100:1 to 50: 1) to afford N-((R)-I—(((S)-I—(((S)cyclopentyl—I—
((R)methyloxiranyl)-I-0x0pr0panyl)amin0) r0xymethoxyphenyb-I-
0x0pr0panyl)amin0)-I-0x0pr0panyl)hydr0xymethylbutanamz'de (162 mg, 62%
yield) as a white solid.
1H NMR (300 MHz, DMSO-d6): 5 8.70 (s, 1H), 8.21 (d, J = 7.2 Hz, 1H), 8.11 (d,
J = 8.7 Hz, 1H), 7.99 (d, J = 7.2 Hz, 1H), 6.76 (d, J = 8.4 Hz, 1H), 6.65 (d, J =18 Hz, 1H),
6.59 (dd, J = 1.8, 8.4 Hz, 1H), 4.77 (s, 1H), 4.31 (m, 1H), 4.26 (m, 2H), 3.72 (s, 3H), 3.23 (d,
J = 5.4 Hz, 1H), 3.01 (d, J = 5.4 Hz, 1H), 2.86 (m, 1H), 2.50 (m, 1H), 2.20 (s, 2H), 1.41—1.93
(m, 11H), 1.41 (s, 3H), 1.12 (s, 6H), 0.98 (d, J = 6.9 Hz, 3H). LC-MS for C29H43N308, found
5623 [M+H]+.
The following compounds were synthesized in a similar :
N—((R)—1-(((S)—1-(((S)-3 -cyclopentyl((R)-oxiranyl)oxopropan
yl)amino)(4-(methylsulfonyl)phenyl)oxopropanyl)amino)oxopropanyl)-3 -
hydroxymethylbutanamide 5): 1H NMR (300 MHZ, 6): 5 8.39 (d, J = 6.9
Hz, 1H), 8.34 (d, J: 8.7 Hz, 1H), 8.03 (d, J: 6.6 Hz, 1H), 7.84 (d, J: 8.1 Hz, 2H), 7.50 (d,
J: 8.1 Hz, 2H), 4.65 (m, 1H), 4.30 (m, 1H), 4.25 (m, 1H), 3.70 (s, 1H), 3.20 (m, 1H), 3.17
(s, 3H), 3.05 (m, 1H), 2.80~2.90 (m, 2H), 2.20 (s, 2H), .90 (m, 10H), 1.00~1.30 (m,
8H), 0.94 (d, J: 7.2 Hz, 3H). LC-MS for C28H41N308S, found 580.3 [M+H]+.
N—((R)—1-(((S)—1-(((S)-3 -cyclopentyl((R)methyloxiranyl)oxopropan
yl)amino)(4-(methylsulfonyl)phenyl)oxopropanyl)amino)oxopropanyl)-3 -
hydroxymethylbutanamide (C-2050): 1H NMR (300 MHZ, 6): 5 8.32 (d, J = 7.2
Hz, 1H), 8.22 (d, J: 9.0 Hz, 1H), 8.00 (d, J: 6.9 Hz, 1H), 7.81 (d, J: 8.4 Hz, 2H), 7.47 (d,
J: 8.4 Hz, 2H), 4.65 (m, 1H), 4.30 (m, 1H), 4.25 (m, 1H), 3.20 (m, 2H), 3.17 (s, 3H), 3.10
(m, 1H), 3.00 (m, 1H), 2.80 (m, 1H), 1.40~1.90 (m, 13H), 1.40 (s, 3H), 1.00~1.30 (m, 9H),
0.94 (d, J: 6.9 Hz, 3H). LC-MS for C29H43N308S, found 594.3 [M+H]+
N—((R)—1-(((S)—1-(((S)-3 -(cyclopentenyl)((R)methyloxiranyl)
oxopropanyl)amino)-3 -(3-hydroxymethoxyphenyl)oxopropanyl)amino)
oxopropanyl)hydroxy-3 -methylbutanamide with order final coupling and deprotection
of the benzyl acid switched (C-2060): 1H NMR (300 MHz, DMSO-d6): 8 8.71 (s, 1H), 8.25
(d, J: 7.5 Hz, 1H), 8.09 (d, J: 8.4 Hz, 1H), 7.97 (d, J: 6.6 Hz, 1H), 6.75 (d, J: 8.1 Hz,
1H), 6.66 (m, 1H), 6.58 (d, J: 7.8 Hz, 1H), 5.41 (s, 1H), 4.78 (s, 1H), 4.51 (m, 2H), 4.27 (m,
1H), 3.71 (s, 3H), 3.23 (d, J: 4.2 Hz, 1H), 2.99 (d, J: 4.8 Hz, 1H), 2.84 (m, 1H), 2.40 (m,
1H), 2.24 (m, 6H), 1.81 (m, 2H), 1.38 (s, 3H), 1.12 (s, 6H), 0.90 (d, J: 6.9 Hz, 3H). LC-MS
for C29H41N308, found 582.4 [M+Na]+.
Exam le 6 T e F
Preparation of N—((R)(((S)—1-(((S)-3 -cyclopentyl((R)methyloxiranyl)-
1-oxopropanyl)amino)(4-methoxyphenyl)oxopropanyl)amino)oxopropan
4,4-trifluoro-3 -hydroxy-3 -methylbutanamide (C-2054)
E “WO : HO : HATU,NMM ;
cooH +
F30 OB” F30 ”/1;OBn
1.H2,Pd/C
2. LMeOPhe-OBn
HATU,NMM
1.H2,Pd/C 1*“ Ho><j>L 0
uWVkOBn: H
”Ox/OM NJ ZHATU'NMM'H”TFA
\QO F30
F30 N O
HW a u 1““
o ' o (1
nOMe
enzyl 2- (4,4, 4-trzfluorohydr0xymethyl!)utanamid0)pr0pan0ate
N—Methylmorpholine (1.17 g, 11.6 mmol) was added to a mixture of 4,4,4-
trifluorohydroxymethylbutanoic acid (1.0 g, 5.8 mmol), (R)-benzyl 2-aminopropanoate
hydrochloride (1.25 g, 5.8 mmol) and HATU (2.42 g, 6.4 mmol) in dichloromethane (50 mL)
at 0°C. The reaction mixture was stirred for 1 h at room temperature and water (50 mL) was
added. The resulting mixture was ted with dichloromethane (50 mL>< 3). The c
extracts were combined, dried over anhydrous Na2SO4 and concentrated. The residue was
purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate = 10:1
to 5:1) to give (2R)-benzyl 2-(4,4,4-trifluorohydroxymethylbutanamido)propanoate (1.4
g, 72% yield).
(2S)-Benzyl 3-(4-meth0xyphenyU ((2R) (4, 4, 4-trzflu0r0hydr0xymethyl
butanamid0)pr0panamid0)pr0pan0ate
] (2R)-Benzyl 2-(4,4,4-trifluorohydroxymethylbutanamido)propanoate (0.63
g, 1.8 mmol) was hydrogenated in the presence of Pd/C (0.1 g) in methanol (20 mL) for 1 h at
room temperature. The catalyst was filtered off and the filtrate was concentrated. The residue
was dissolved in romethane (30 mL) ed by addition of LMeOPhe-OBn (HCl
salt, 0.67 g, 2.0 mmol) and HATU (0.79 g, 2.0 mmol). N—Methylmorpholine (1.1 g, 10.8
mmol) was added to the solution at 0°C. The reaction mixture was stirred for 1 h at room
temperature and water (30 mL) was added. The ing mixture was extracted with
dichloromethane (30 mL><3). The organic extracts were ed, dried over anhydrous
Na2SO4 and concentrated. The residue was purified by flash column chromatography on
silica gel (petroleum ether/ethyl acetate = 10:1 to 1:1) to give compound (2S)-Benzyl 3-(4-
methoxyphenyl)((2R)(4,4,4-trifiuorohydroxy-3 -methyl
mido)propanamido)propanoate (0.7 g, 76% yield).
[0024 1] N—((R)—1-(((S)—1-(((S)-3 -cyclopentyl((R)—2-methyloxiranyl)oxopropan
yl)amino)(4-methoxyphenyl)oxopropanyl)amino)oxopropanyl)-4,4,4-trifluoro-
3-hydroxymethylbutanamide
(2S)-Benzyl 3-(4-methoxyphenyl)((2R)(4,4,4-trifluorohydroxymethyl
mido)propanamido)propanoate (0.7 g, 1.3 mmol) was hydrogenated in the ce of
Pd/C (0.1 g) in methanol (20 mL) for 1 h at room temperature. The catalyst was filtered off
and the filtrate was concentrated. The residue was dissolved in dichloromethane (30 mL)
followed by addition of (S)—2-aminocyclopentyl((R)methyloxiranyl)propanone
(0.44 g, 1.3 mmol) and HATU (0.53 g, 1.3 mmol). N—Methylmorpholine (0.8 g, 7.9 mmol)
was added to the solution at 0°C. The reaction mixture was stirred for 1 h at room
temperature followed by addition of water (30 mL). The resulting mixture was extracted with
dichloromethane (30 mL><3). The organic extracts were combined, dried over anhydrous
Na2SO4 and concentrated. The residue was purified by flash column chromatography on
silica gel (petroleum ethyl acetate = 10:1 to 1:1) to afford a mixture of N—((R)(((S)—1-
(((S)-3 pentyl((R)methyloxiranyl)-1 -oxopropanyl)amino)-3 -(4-
methoxyphenyl)oxopropanyl)amino)oxopropanyl)-4,4,4-trifluorohydroxy-3 -
methylbutanamide isomers (140 mg, 18% yield).
] 1H NMR (300 MHz, DMSO-d6): 5 8.27 (m, 1H), 8.17 (m, 2H), 7.13 (d, J = 7.8
Hz, 2H), 6.80 (d, J = 8.4 Hz, 2H), 6.27 (m, 1H), 4.51 (m, 1H), 4.29 (m, 2H), 3.71 (s, 3H),
3.22 (d, J = 4.5 Hz, 1H), 3.02 (d, J = 5.1 Hz, 1H), 2.95 (m, 1H), 2.21-2.65 (m, 3H), 1.42 (s,
3H), 1.28 (m, 3H), 1.07—1.93 (m, 11H), 0.96 (d, J = 6.6 Hz, 3H). LC-MS for C30H45N307,
found 600.2 [M+H]+
] The ing compounds were synthesized in a similar manner, with the
exception that ection of benzyl esters was performed with 1.2 eq of LiOH in 2:1
mixture of MeOH:H20 followed by acidification to pH 3 and filtration:
N—(2-(((S)(((S)cyclopentyl((R)methyloxiranyl)oxopropan
yl)amino)-3 thoxyphenyl)oxopropanyl)amino)oxoethyl)methyl-1H-indene-
2-carboxamide (C-2039): 1H NMR (300 MHz, DMSO-d6): 8 7.49 (m, 2H), 7.39 (m, 2H),
7.11 (d, J: 8.7 Hz, 2H), 6.80 (m, 1H), 6.72 (d, J: 8.7 Hz, 2H), 6.70 (m, 1H), 6.52 (m, 1H),
6.49 (m, 3H), 4.66 (m, 1H), 4.52 (m, 1H), 4.05 (d, J: 5.7 Hz, 1H), 3.62 (s, 3H), 3.59 (m,
2H), 3.27 (d, J: 5.1 Hz, 1H), 3.10 (m, 1H), 3.06 (m, 1H), 2.88 (d, J: 4.8 Hz, 1H), 2.53 (s,
3H), 2.06-1.83 (m, 2H), 1.71-1.70 (m, 3H), 1.68 (m, 3H), 1.48 (s, 3H), 1.28 (m, 1H), 1.11 (m,
1H), 1.06 (m, 1H), 0.90 (m, 1H). LC-MS for C34H41N306, found 588.8 [M+H]+.
N—((R)—1-(((S)—1-(((S)-3 -cyclopentyl((R)methyloxiranyl)oxopropan
yl)amino)(1H-indol-3 -yl)-1 -oxopropanyl)amino)oxopropanyl)methyl-1H-
indenecarboxamide (C-2047): 1H NMR (300 MHZ, DMSO-d6): 5 10.81 (br s, 1H), 8.25
(d, J: 6.9 Hz, 1H), 8.11 (d, J: 8.4 Hz, 1H), 7.76 (d, J: 6.9 Hz, 1H), 7.58 (d, J: 8.1 Hz,
1H), 7.47 (m, 2H), 7.29 (m, 3H),7.11-6.94 (m, 3H), 4.39 (m, 1H), 4.37 (m, 2H), 3.65 (m,
2H), 3.15 (m, 3H), 3.01 (m, 2H), 2.96 (m, 2H), 2.51 (s, 3H), 1.98 (m, 1H), 1.70 (m, 5H), 1.42
(s, 3H), 1.40 (m, 6H), 1.24 (d, J: 6.9 Hz, 3H), 0.80 (m, 2H). LC-MS for C36H42N405, found
611.3 [M+H]+
N—((R)(((S)—3-(4-methoxyphenyl)(((S)—1-((R)—2-methyloxiranyl)-1 -oxo
phenylpropanyl)amino)oxopropanyl)amino)oxopropanyl)methyl-1H-
indenecarboxamide (C-2048): 1H NMR (300 MHZ, DMSO-d6): 5 8.44 (d, J = 8.4 Hz,
1H), 8.04 (d, J: 8.7 Hz, 1H), 7.74 (d, J: 6.9 Hz, 1H), 7.50 (d, J: 6.9 Hz, 2H), 7.36-7.23
(m, 7H), 7.10 (d, J: 8.1 Hz, 2H), 6.72 (d, J: 8.4 Hz, 2H), 4.61 (m, 1H), 4.50 (m, 1H), 4.37
(m, 1H), 3.71 (m, 2H), 3.61 (s, 3H), 3.23 (m, 1H), 3.01 (m, 2H), 2.80~2.52 (m, 4H), 2.40 (s,
3H), 1.42 (s, 3H), 1.10 (d, J: 6.9 Hz, 3H). LC-MS for N306, found 610.3 [M+H]+
Exam le 7 T e H
ation of (R)-N-((R)—1-(((S)(((S)—3-cyclopentyl((R)methyloxiran
yl)— 1 -oxopropanyl)amino)(4-methoxyphenyl)oxopropanyl)amino)oxopropan-
2-yl)-4,5 ,6,7-tetrahydro-1H-indazolecarboxamide (C-2064) and (S)-N-((R)(((S)— 1 -
(((S)-3 -cyclopentyl((R)—2-methyloxiranyl)oxopropanyl)amino)-3 -(4-
methoxyphenyl)oxopropanyl)amino)oxopropanyl)-4,5 ,6,7-tetrahydro-1H-
indazole-S-carboxamide (C-2065)
o 1. A O 1. LiOH O
2. NH2NH2 2. SOCI2, MeOH
EtO —>EC \ —>MGO
| ,N | \,N
N N
0 H H
tion by 1
MeO \ chiral HPLC
I N
: O 1.TFA O ll 0
BocHNWNgkOBn: H : HA).
- 2. 1 2 RAH/Yb]- 3. ngPd/C
O ' O
lDIPEA,H2N NOHATU, [:0
’6‘"
\ O - O
| ,N )L i O
H HQL R H/\“/N . N
F10?” a H
o o
N o/
Ethyl 4,5, 6, 7-tetrahydr0-IH-indazolecarb0xylate
A solution of ethyl 4-oxocyclohexanecarboxylate (50 g, 0.29 mol) in DMF-DMA
(275 mL) was heated at 110°C for 12 h. The mixture was concentrated to afford the desired
intermediate, which was used directly without further purification.
A mixture of the intermediate (66.1 g, 0.29 mol) and hydrazine hydrate (73.5 g,
1.47 mol) in ethanol (1000 mL) was heated under reflex overnight. Most of l was
removed and the remaining mixture was treated with water (400 mL). The resulting mixture
was extracted with EtOAc (400 ml><2). The combined organic layers were washed with brine
(400 mL) and trated. The residue was purified by flash column chromatography on
silica gel (DCM/MeOH = 30: 1) to afford crude ethyl 7-tetrahydro-1H-indazole
carboxylate (18 g) as a white solid.
Methyl 4,5, 6, 7-tetrahydr0-IH-indazolecarb0xylate
To a solution of ethyl 4,5,6,7-tetrahydro-1H-indazolecarboxylate (3.0 g, 15.5
mmol) in ol (10 mL) were added water (10 mL) and lithium hydroxide hydrate (780
mg, 5.9 mmol). The reaction mixture was stirred at room temperature overnight and then
concentrated to remove most of methanol. The ing mixture was acidified with d
aqueous HCl to pH=4 and then concentrated. The residue was dried under vacuum to afford
the corresponding acid (1.7 g, 66% yield) as a white solid, which was used directly without
further purification. A mixture of the acid (1.7 g, 10 mmol) and SOC12 (2.5 g, 21 mmol) in
methanol (20 mL) was heated under reflux for 2 h. The mixture was cooled to room
temperature and then concentrated. The residue was purified by flash column
chromatography on silica gel (DCM/MeOH = 30: 1) to afford compound 10 (1.0 g, 55%
yield) as a light yellow solid, which was further separated by preparative chiral-HPLC to
afford (S)— and thyl 4,5,6,7-tetrahydro-1H-indazolecarboxylate (0.2 g), (0.2g),
respectively.
(S)-4, 5, 6, ahydro-IH-indazolecarb0xylic acid
To a solution of (S)—methyl 4,5,6,7-tetrahydro-1H-indazolecarboxylate (500
mg, 2.8 mmol) in methanol (20 mL) were added water (10 mL) and lithium hydroxide
hydrate (234 mg, 5.57 mmol) at 0°C. The reaction mixture was stirred at room temperature
for 2 h and then concentrated to remove most of methanol. The remaining mixture was
ed with diluted aqueous HCl to pH=4 and then trated. The residue was dried
under vacuum to afford 5,6,7-tetrahydro-1H-indazolecarboxylic acid (380 mg, 81%
yield) as a white solid, which was used directly without further purification.
(R)-4, 5, 6, ahydro-IH-indazolecarb0xylic acid
Prepared from (R)-methyl 4,5,6,7-tetrahydro-1H-indazolecarboxylate following
the same procedure for (S)-4,5,6,7-Tetrahydro-1H-indazolecarboxylic acid.
(S)(4-Meth0xyphenyU ((R) ((S)-4, 5, 6, 7-tetrahydr0-IH-indazole
carboxamid0)pr0panamid0)pr0pan0ic acid
To a solution of (S)—benzyl 2-((R)((tert-butoxycarbonyl)amino)propanamido)-
3-(4-methoxyphenyl)propanoate (1.0 g, 2.2 mmol) in DCM (6 mL) was added TFA (6 mL).
The reaction mixture was stirred for 15 min at room temperature and then concentrated to
dryness to afford (S)-benzyl 2-((R)aminopropanamido)(4-methoxyphenyl)propanoate
as its TFA salt.
To a solution of (S)—4,5,6,7-tetrahydro-1H-indazolecarboxylic acid (300 mg,
1.81 mmol) in DMF (20 mL) at 0°C was added HATU (826 mg, 2.17 mmol). The mixture
was d for 5 min followed by on of (S)-benzyl 2-((R)aminopropanamido)(4-
methoxyphenyl)propanoate (TFA salt, 819 mg, 1.81 mmol) and DIPEA (1.26 mL, 7.24
mmol). The reaction mixture was d to warm to room temperature and stirred for 30
min. Saturated aqueous sodium bicarbonate (50 mL) was added and the resulting mixture
was extracted with ethyl acetate (50 . The combined extracts were dried over
anhydrous sodium sulfate and concentrated to afford (S)—benzyl 3-(4-methoxyphenyl)((R)-
2-((R)—4,5,6,7-tetrahydro-1H-indazole-S-carboxamido)propanamido)propanoate (970 mg,
94% yield) as a white solid. To a on of (S)-benzyl 3-(4-methoxyphenyl)((R)((R)-
4,5,6,7-tetrahydro-1H-indazole-S-carboxamido)propanamido)propanoate (300 mg, 0.6 mol)
in methanol (10 mL) was added Pd/C (100 mg, 10%). The mixture was stirred under
hydrogen atmosphere (1 atm) at room temperature ght and then filtered through a pad
of celite. The filtrate was concentrated to dryness to (S)—3-(4-methoxyphenyl)((R)(2-
((R)-4,5,6,7-tetrahydro-1H-indazol-S-yl)acetamido)propanamido)propanoic acid (250 mg,
quantitative) as a white solid.
(S)-N- ((S)cyclopentyl—I-((R)methy10xiranyl)-I-0x0pr0panyl) (4-
methoxyphenyZ)((R)(2- ((R)-4, 5, 6, 7—tetrahydr0-IH-z'ndazol—5-
y!)acetamid0)pr0panamid0)pr0panamide
A mixture of (S)aminocyclopentyl((R)methyloxiranyl)propanone
(TFA salt, 180 mg, 0.61 mmol), (S)(4-methoxyphenyl)((R)—2-(2-((R)-4,5,6,7-
tetrahydro-1H-indazol-S-yl)acetamido)propanamido)propanoic acid (250 mg, 0.61 mmol)
and HATU (278 mg, 0.73 mmol) in DMF (10 mL) was cooled to 0°C and DIPEA (0.43 mL,
2.44 mmol) was added. The reaction mixture was allowed to warm to room temperature and
stirred for 15 min. Saturated aqueous sodium bicarbonate (50 mL) was added and the
resulting mixture was ted with ethyl acetate (50 mL><2). The combined extracts were
dried over anhydrous sodium e and trated. The residue was purified by flash
column chromatography on silica gel (DCM/MeOH = 50: 1 to 20: 1) to afford (S)—N—((S)—3-
cyclopentyl((R)methyloxiranyl)-1 -oxopropanyl)-3 -(4-methoxyphenyl)((R)
(2-((R)-4,5,6,7-tetrahydro-1H-indazol-S-yl)acetamido)propanamido)propanamide (103 mg,
28% yield) as a white solid.
1H NMR (300 MHz, DMSO-d6): 5 12.27 (br s, 1 H), 8.25 (d, J = 6.0 Hz, 1H), 8.05
(d, J = 8.1 Hz, 1H), 8.00 (d, J = 6.6 Hz, 1H), 7.11 (d, J = 8.1 Hz, 2H), 6.80 (d, J = 7.8 Hz,
2H), 4.45 (m, 1H), 4.23 (m, 2H), 3.69 (s, 3H), 3.22 (m, 2H), 3.01 (m, 2H), 2.77 (m, 2H), 2.09
(m, 2H), 1.90 (m, 3H), 1.69-1.67 (m, 6H), 1.50 (s, 3H), 1.28 (m, 1H), 1.04 (d, J = 6.3 Hz,
3H), 0.96 (d, J = 7.2 Hz, 3H). LC-MS for C32H43N506, found 594.31 [M+H]+.
(S)-N—((R)— l -(((S)-l -(((S)-3 -cyclopentyl- l -((R)methyloxiranyl)— l -
oxopropanyl)amino)-3 -(4-methoxyphenyl)- l -oxopropanyl)amino)- l -oxopropanyl)-
4,5 ,6,7-tetrahydro- l H-indazolecarboxamide
(S)-N—((R)— l -(((S)-l -(((S)-3 -cyclopentyl- l -((R)methyloxiranyl)— l -
panyl)amino)-3 -(4-methoxyphenyl)- l -oxopropanyl)amino)- l -oxopropanyl)-
4,5 ,6,7-tetrahydro- l H-indazolecarboxamide was prepared from 5 ,6,7-tetrahydro- l H-
indazolecarboxylic acid following the same procedure for (S)—N—((S)—3-cyclopentyl- l -
((R)methyloxiranyl)- l -oxopropanyl)-3 -(4-methoxyphenyl)((R)—2-(2-((R)—4,5 ,6,7-
tetrahydro- l zol-5 -yl)acetamido)propanamido)propanamide.
1H NMR (300 MHz, DMSO-d6): 5 12.28 (br s, 1 H), 8.26 (d, J = 7.2 Hz, 1H), 8.08
(d, J = 7.5 Hz, 1H), 8.05 (d, J = 6.6 Hz, 1H), 7.12 (d, J = 8.7 Hz, 2H), 6.80 (d, J = 8.1 Hz,
2H), 4.45 (m, 1H), 4.23 (m, 2H), 3.70 (s, 3H), 3.22 (m, 1H), 3.01 (m, 2H), 2.65 (m, 2H), 2.09
(m, 2H), 1.90 (m, 3H), 1.69-1.67(n1, 6H), 1.50 (s, 3H), 1.28 (m, 1H), 1.04 (d, J = 6.3 Hz,
3H), 0.97 (d, J = 7.2 Hz, 3H). LC-MS for C32H43N506, found 594.31 .
The following compounds were sized in a r manner:
3-hydroxy-N—((R)— l -(((S)—3-(4-methoxyphenyl)— l -(((S)-l -((R)-oxiranyl)- l -
oxo(p-tolyl)propanyl)amino)- l -oxopropanyl)amino)— l -oxopropanyl)-3 -
methylbutanamide (C-2053): 1H NMR (300 MHZ, DMSO-d6): 5 8.46 (d, J = 6.3 Hz, 1H),
8.20 (d, J: 8.7 Hz, 1H), 8.00 (d, J: 7.2 Hz, 1H), 7.lO~7.30 (m, 6H), 6.80 (d, J: 8.4 Hz,
2H), 4.78 (s, 1H), 4.40~4.60 (m, 2H), 4.25 (m, 1H), 3.75 (s, 3H), 3.70 (m, 1H), 3.45 (m, 1H),
2.70~3.lO (m, 5H), 2.60 (m, 1H), 2.25 (s, 3H), 2.18 (m, 2H), 1.10 (s, 6H), 0.98 (d, J: 6.9 Hz,
3H). LC-MS for C30H39N307, found 552.2 [M-H]'
Exam le 8 T e H2
Preparation of (S)-N-((R)- l -(((S)— l -(((S)-3 -cyclopentyl- l -((R)methyloxiran
yl)—l opanyl)amino)(4-methoxyphenyl)- l -oxopropanyl)amino)— l opan-
2-yl)hydroxymethylpentanamide (C-205 1)
2014/026980
1.TFA
2. HATU, DIPEA,
OHOS
: O HO O : O
BocHN /\[01/ . N NH/jl/ . N
a H a H
O O
o/ 0/
] TFA (4 mL) was added to a solution of 0.1 M tert-butyl ((R)—1-(((S)(((S)
cyclopentyl((R)methyloxiranyl)-1 -oxopropanyl)amino)-3 thoxyphenyl)
oxopropanyl)amino)oxopropanyl)carbamate in CH2Cl2 at 0°C with stirring. The
reaction mixture was stirred for 1 h and then concentrated to dryness. The residue was
azeotroped three times with EtOAc (5 mL for each portion) to remove residual TFA. The
crude product and (S)—3-hydroxymethylpentanoic acid (1.3 eq) was dissolved in DMF to
0.05 M in starting material and HATU (1.8 eq) and DIPEA were added at 0°C with stirring.
The resulting suspension was stirred for 1 h at room ature. EtOAc (100 mL) and water
(100 mL) were added. The two layers were ted and the aqueous phase was extracted
with EtOAc (50 mL><3). The combined c phases were washed with brine (50 mL><3),
dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column
chromatography on silica gel to afford ((R)—1-(((S)(((S)cyclopentyl((R)
methyloxiranyl)-1 -oxopropanyl)amino)(4-methoxyphenyl)oxopropan
yl)amino)oxopropanyl)hydroxymethylpentanamide. 1H NMR (300 MHz, DMSO-
d6): 5 8.25 (d, J = 7.5 Hz, 1H), 8.11 (d, J = 8.7 Hz, 1H), 8.02 (d, J = 7.2 Hz, 2H), 7.12 (d, J =
8.4 Hz, 2H), 6.79 (d, J = 8.4 Hz, 2H), 4.67 (s ,1H), 4.60 (m, 1H), 4.20~4.40 (m, 2H), 3.71 (s,
3H), 3.22 (d, J = 5.4 Hz, 1H), 2.90~3.10 (m, 2H), 2.65 (m, 1H), 2.15 (s, 2H), 1.50~2.00 (m,
8H), 1.42 (s, 3H), 1.10~1.30 (m, 4H), 1.10 (s, 3H), 0.96 (d, J = 6.6 Hz, 3H), 0.80 (t, J = 7.5
Hz, 3H). LC-MS for C30H45N307, found 558.4 [M-H]'
The following compounds were synthesized in a similar manner:
(R)-N-((R)(((S)(((S)—3-cyclopentyl((R)methyloxiranyl)-1 -
oxopropanyl)amino)-3 -(4-methoxyphenyl)oxopropanyl)amino)oxopropanyl)-
3-hydroxymethylpentanamide (C-2052): 1H NMR (300 MHZ, DMSO-d6): 5 8.24 (d, J =
7.2 Hz, 1H), 8.11 (d, J: 8.1 Hz, 1H), 8.00 (d, J: 7.2 Hz, 2H), 7.12 (d, J: 8.4 Hz, 2H), 6.79
(d, J: 8.4 Hz, 2H), 4.67 (s ,1H), 4.50 (m, 1H), 4.20~4.40 (m, 2H), 3.71 (s, 3H), 3.22 (d, J:
.4 Hz, 1H), 2.90~3.10 (m, 2H), 2.65 (m, 1H), 2.15 (2d, 2H), 1.90 (m, 1H), 1.50~1.85 (m,
8H), 1.45 (s, 3H), 1.10~1.40 (m, 3H), 1.10 (s, 3H), 0.96 (d, .1: 6.6 HZ, 3H), 0.80 (t, .1: 7.5
HZ, 3H). LC-MS fOI' C30H45N307, found 558.2 [M-H]
N—((R)—1-(((S)—1-(((S)-3 -cyc10penty1— 1 -((R)methy10xirany1)-1 -oxopropan
1no)(4-methoxypheny1)oxopropany1)an11no)oxopropany1)—1H-indaZ016-5 -
carboxamide (C-2061): 1H NMR (300 MHZ, DMSO-d6): 5 13.29 (s, 1H), 8.48 (d, J: 6.6 HZ,
1H), 8.38 (s, 1H), 8.27 (d, J: 6.9 HZ, 1H), 8.21 (s, 1H), 8.09 (d, J: 8.4 HZ, 1H), 7.87 (d, J:
8.7 HZ, 1H), 7.56 (d, J: 8.7 HZ, 1H), 7.10 (d, J: 8.4 HZ, 2H), 6.70 (d, J: 8.4 HZ, 2H),
4.40~4.60 (m, 2H), 4.30 (m, 1H), 3.64 (s, 3H), 3.22 (m, 1H), .10 (m, 2H), 2.70 (m,
1H), 1.95 (m, 1H), 1.40~1.80 (m, 6H), 1.41 (s, 3H), 1.16 (d, J: 6.9 HZ, 3H). LC-MS for
C32H39N506, found 59024 .
N—((R)—1-(((S)—1-(((S)-3 -cyc10penty1— 1 -((R)methy10xirany1)-1 -oxopropan
y1)an11no)(4-methoxypheny1)oxopropany1)an11no)oxopropany1)—1H-
benzo[d]in11daZ016carboxan11de (C-2062): 1H NMR (300 MHZ, DMSO-d6): 5 12.53 (br s,
1H), 8.30~8.40 (m, 3H), 8.10 (m, 1H), 7.94 (d, J = 6.6 HZ, 1H), 7.60~7.90 (m, 3H), 7.06 (d, J
= 8.4 HZ, 2H), 6.68 (d, J = 8.4 HZ, 2H), 4.30~4.60 (m, 3H), 3.64 (s, 3H), 3.22 (m, 1H),
2.90~3.10 (m, 2H), 2.75 (m, 1H), 1.95 (m, 1H), 1.40~1.80 (m, 6H), 1.41 (s, 3H), 1.16 (d, J =
6.9 HZ, 3H). LC-MS for C32H39N506, found 590.18 [M+H]+.
N—((R)—1-(((S)—1-(((S)-3 -cyc10penty1— 1 -((R)methy10xirany1)-1 -oxopropan
y1)an11no)(4-methoxypheny1)oxopropany1)an11no)oxopropany1)—1H-indazole
carboxamide (C-2063): 1H NMR (300 MHZ, DMSO-d6): 5 13.39 (s, 1H), 8.61 (d, J: 7.2 HZ,
1H), 8.27 (d, J: 6.9 HZ, 1H), 8.10~8.20 (m, 3H), 7.82 (d, J: 7.2 HZ, 1H), 7.62 (d, J: 8.4
HZ, 1H), 7.10 (d, J: 8.4 HZ, 2H), 6.70 (d, J: 8.4 HZ, 2H), 4.40~4.60 (m, 2H), 4.30 (m, 1H),
3.64 (s, 3H), 3.22 (m, 1H), 2.90~3.10 (m, 2H), 2.70 (m, 1H), 1.95 (m, 1H), 1.40~1.80 (m,
6H), 1.41 (s, 3H), 1.16 (d, J: 6.9 HZ, 3H). LC-MS for N506, found 590.24 [M+H]+.
N—((R)—1-(((S)—1-(((S)-3 -cyc10penty1— 1 -((R)methy10xirany1)-1 -oxopropan
y1)an11no)(4-methoxypheny1)oxopropany1)an11no)oxopropany1)—2-
methylthiazolecarboxan11de 6): 1H NMR (300 MHZ, g): 5 8.64 (d, J = 7.2
HZ, 1H), 8.28 (s, 1H), 8.26 (d, J = 6.6 HZ, 1H), 8.18 (d, J = 9.0 HZ, 1H), 7.12 (d, J = 8.7 HZ,
2H), 6.75 (d, J = 8.9 HZ, 2H), 4.60 (m, 1H), 4.25~4.50 (m, 2H), 3.69 (s, 3H), 3.50 (s, 3H),
3.22 (d, J = 5.4 HZ, 1H), 3.02 (d, J = 5.4 HZ, 1H), 2.70 (s, 3H), 2.65 (m, 1H), 1.95 (m, 1H),
1.50~1.85 (m, 7H), 1.40 (s, 3H), 1.00~1.20 (m, 2H), 1.26 (d, J = 6.6 HZ, 3H). MS (EI) for
C29H38N4O6S, found 571.7 [M+H]+.
N—((R)—1-(((S)—1-(((S)-3 -cyclopenty1—1-((R)methyloxirany1)oxopropan
ino)-3 -(4-methoxypheny1)oxopropany1)an1ino)hydroxyoxopropany1)-3 -
methylisoxazole-S-carboxan1ide (C-2030): 1H NMR (300 MHZ, : 5 7.63 (d, J = 7.2
HZ, 1H), 7.06 (d, J = 8.7 HZ, 2H), 6.99 (d, J = 7.8 HZ, 1H), 6.81 (s, 1H), 6.73 (d, J = 8.7 HZ,
2H), 6.54 (d, J = 7.8 HZ, 1H), 4.66 (m, 3H), 4.12 (m, 1H), 3.76 (s, 3H), 3.75 (m, 1H), 3.26 (d,
J = 4.8 HZ, 1H), 3.08 (m, 1H), 3.00 (m, 1H), 2.90 (d, J = 4.8 HZ, 1H), 2.47 (s, 3H), 1.50 (s,
3H), 1.27-1.71 (m, 11H). LC-MS for C29H38N4Og, found 571.4 [M+H]+.
N—((S)(((S)(((S)—3-cyclopenty1—1-((R)methyloxirany1)oxopropan
y1)an1ino)-3 -(4-methoxypheny1)oxopropany1)an1ino)n10rpholinooxopropany1)—
3-methylisoxazolecarboxan1ide (C-2044): 1H NMR (300 MHZ, DMSO-d6): 5 8.75 (d, J =
8.4 HZ, 1H), 8.52 (d, J: 8.4 HZ, 1H), 8.35 (d, J: 6.9 HZ, 1H), 7.10 (d, J: 8.4 HZ, 2H), 6.99
(s, 1H), 6.77 (d, J: 8.4 HZ, 2H), 4.57 (m, 2H), 4.33 (m, 1H), 3.70 (s, 3H), 3.44 (m 4H), 3.20
(d, J: 4.8 HZ, 1H), 3.03 (d, J: 5.4 HZ, 1H), 2.94 (m, 1H), 2.67 (m, 1H), 2.30-2.45 (m, 5H),
2.31 (m, 4H), 1.42 (s, 3H), 1.03-1.93 (m, 11H). LC-MS for C33H45N508, found 639.9
[M+H]+.
N—((R)—1-(((S)—1-(((S)-3 -cyclopenty1—1-((R)methyloxirany1)oxopropan
y1)an1ino)-3 -(4-methoxypheny1)oxopropany1)an1ino)n10rpholinooxopropany1)—
3-methylisoxazolecarboxan1ide (C-2045): 1H NMR (300 MHZ, DMSO-d6): 5 8.73 (d, J =
8.1 HZ, 1H), 8.39 (d, J: 8.1 HZ, 1H), 8.33 (d, J: 7.5 HZ, 1H), 7.08 (d, J: 8.7 HZ, 2H), 6.98
(s, 1H), 6.75 (d, J: 8.7 HZ, 2H), 4.56 (m, 2H), 4.35 (m, 1H), 3.68 (s, 3H), 3.43 (m 4H), 3.16
(d, J: 5.7 HZ, 1H), 3.02 (d, J: 5.1 HZ, 1H), 2.91 (m, 1H), 2.68 (m, 1H), 2.36 (m, 4H), 2.31
(s, 3H), 1.42 (s, 3H), 1.07-1.93 (m, 11H). LC-MS for N508, found 640.7 [M+H]+.
Exam le 9 T e H3
Preparation of N—((S)(((S)(((S)—3 -cyclopenty1— 1 2-methyloxirany1)-
1-oxopropany1)an1ino)(4-methoxypheny1)oxopropany1)an1ino)—1-oxopropan
y1)-3 -methy1isoxazolecarboxan1ide (C-2022)
1.TFA
o o 2. R-COOH o o
H H
H N2 \i)J\OBn Boc—L-AIa-OH N N
PEA BocHN/‘fif kaBn 3_E/3LU'NMM RA \JLOH
—> 2 —>
TFA HzN
0 O
—>\<§,}LNHATU,D|PEA NHi ”’1
(S)-Benzyl 2-((R)((tert-butoxycarbonyl)amin0)pr0panamid0)(4-
methoxyphenyl)pr0pan0ate
HATU (19.3 g, 51mmol) and DIPEA (29.6 mL, 170 mmol) were added to a
solution of Boc-L-alanine (7.7 g, 40.7 mmol) and LMeO-phenylalanine benzyl ester p-
toluenesulfonate salt (15.0 g, 34 mmol) in DMF (200 mL) at 0°C with stirring. The reaction
mixture was allowed to warm to room temperature and stirred for 12 h. The mixture was
concentrated and the residue was purified by flash column chromatography on silica gel
(Hexane/EtOAc = 3:1) to afford (S)-benzyl 2-((R)((tert-
butoxycarbonyl)amino)propanamido)-3 -(4-methoxyphenyl)propanoate (13.7 g, 88% yield).
(4-Meth0xyphenyU((S)(3-methylz'soxazolecarb0xamid0)
propanamid0)pr0pan0ic acid
TFA (10 mL) was added to a solution of (S)-benzyl 2-((R)((tert-
butoxycarbonyl)amino)propanamido)-3 -(4-methoxyphenyl)propanoate (1.02 g, 2.2 mmol) in
CH2Cl2 (20 mL) at 0°C with stirring. The on mixture was stirred for 1 h and then
concentrated to dryness. The e was azeotroped three times with EtOAc (5 mL for each
portion) to remove residual TFA. The crude product and 3-methylisoxazolecarboxylic
acid (280 mg, 2.2 mmol) were dissolved in DMF (10 mL) and the on was cooled to
0°C. HATU (1.25 g, 3.3 mmol) and NMM (0.72 mL, 6.0 mmol) were added. The reaction
mixture was stirred for 12 h at room temperature. The mixture was concentrated and the
residue was purified by flash column chromatography on silica gel (Hexane/EtOAc = 2: 1) to
afford benzyl ester of 3a (0.81 g, 78% yield over two steps). The benzyl ester (650 mg, 1.4
mmol) was ved in MeOH (20 mL) and a solution of LiOH (400 mg, 9.6 mmol) in water
(10 mL) was added at 0°C with stirring. The reaction mixture was stirred for 3 h and then
acidified with 2 N aqueous HCl to pH=3. Removal of the volatiles gave compound 3a (0.61
g, quantitative), which was used in the next step without filrther purification.
N-((S)-I-(((S)-I-(((S)cyclopentyl—I-((R)methyloxiranyl)-I-0x0pr0pan
yl)amin0)(4-meth0xyphenyl)-I—0x0pr0panyl)amin0)-I—0x0pr0panyU
z'soxazolecarb0xamide
HATU (604 mg, 1.6 mmol) and DIPEA (0.89 mL, 6.0 mmol) were added to a
solution of compound (S)—3-(4-Methoxyphenyl)((S)(3-methylisoxazolecarboxamido)
propanamido)propanoic acid (375 mg, 1.1 mmol) and aminocyclopentyl((R)
methyloxiranyl)propanone (TFA salt, 314 mg, 1.1 mmol) in DMF (30 mL) at 0°C. The
reaction mixture was stirred for 1 h at room temperature. The mixture was concentrated and
the residue was purified by flash column chromatography on silica gel
/CH2Cl2/MeOH = 120.01) to afford N—((S)—1-(((S)(((S)cyclopentyl((R)
methyloxiranyl)-1 -oxopropanyl)amino)(4-methoxyphenyl)oxopropan
yl)amino)oxopropanyl)methylisoxazolecarboxamide (150 mg, 25% yield).
1H NMR (300 MHz, DMSO-d6): 5 8.85 (d, J = 7.5 Hz, 1H), 8.22 (d, J = 7.2 Hz,
1H), 7.97 (d, J = 8.7 Hz, 1H), 7.10 (d, J = 8.7 Hz, 2H), 6.98 (s, 1H), 6.75 (d, J = 8.1 Hz, 2H),
4.30~4.60 (m, 3H), 3.68 (s, 3H), 3.17 (d, J = 5.4 Hz, 1H), 3.02 (d, J = 5.4 Hz, 1H), 2.96 (m,
1H), 2.70 (m, 1H), 2.30 (s, 3H), 1.90 (m, 1H), 1.50~1.85 (m, 7H), 1.40 (s, 3H), .20 (m,
2H), 1.26 (d, J = 6.6 Hz, 3H). MS (EI) for N4O7, found 555.2 [M+H]+.
The following compounds were synthesized in a similar manner:
N—((R)—1-(((S)—1-(((S)-3 -cyclopentyl((R)—2-methyloxiranyl)oxopropan
yl)amino)-3 thoxyphenyl)oxopropanyl)amino)oxopropanyl)picolinamide
(C-2031): 1H NMR (300 MHz, DMSO-d6): 5 8.60~8.70 (m, 1H), 8.30~8.40 (m, 2H),
7.95~8.10 (m, 2H), 7.65 (m, 1H), 7.13 (d, J = 8.4 Hz, 2H), 6.77 (d, J = 8.4 Hz, 2H),
.60 (m, 2H), 4.30 (m, 1H), 3.69 (s, 3H), 3.20 (d, J = 5.1 Hz, 1H), 2.95~3.05 (m, 2H),
2.65 (m, 1H), 1.95 (m, 1H), 1.50~1.85 (m, 7H), 1.40 (s, 3H), 1.26 (d, J = 6.6 Hz, 3H). LC-
MS for C30H38N4O6, found 551.4 [M+H]+.
N—((R)—1-(((S)—1-(((S)-3 -cyclopentyl((R)—2-methyloxiranyl)oxopropan
yl)amino)-3 -(4-methoxyphenyl)oxopropanyl)amino)oxopropanyl)nicotinamide
(C-2032): 1H NMR (300 MHz, DMSO-d6): 5 9.02 (s, 1H), 8.70~8.80 (m, 2H), 8.10~8.30
(m, 3H), 7.53 (m, 1H), 7.13 (d, J = 8.4 Hz, 2H), 6.77 (d, J = 8.4 Hz, 2H), 4.30~4.60 (m, 2H),
4.30 (m, 1H), 3.69 (s, 3H), 3.20 (d, J = 5.1 Hz, 1H), 2.95~3.05 (m, 2H), 2.65 (m, 1H), 1.95
(m, 1H), 1.50~1.85 (n1, 7H), 1.40 (s, 3H), 1.26 (d, J = 6.6 Hz, 3H). LC-MS for C30H38N4O6,
found 551.7 [M+H]+.
(S)-N-((S)cyclopenty1((R)methyloxiranyl)oxopropanyl)-3 -(4-
yphenyl)((R)(3-methoxypropanamido)propanan1ido)propanamide (C-2018): 1H
NMR (300 MHz, CDClg): 5 7.12 (d, J = 8.4 Hz, 2H), 6.83 (d, J = 8.7 Hz, 2H), 6.72 (n1, 2H),
6.55 (d, J = 8.1 Hz, 1H), 4.60 (m, 1H), 4.53 (m, 1H), 4.37 (m, 1H), 3.79 (s, 3H), 3.65 (m,
2H), 3.38 (s, 3H), 3.30 (d, J = 4.8 Hz, 1H), 3.03 (m, 2H), 2.89 (d, J = 4.8 Hz, 1H), 2.49 (t, J =
.7 Hz, 2H), 1.50 (s, 3H), 1.31 (d, J = 6.9 Hz, 3H), 0.85-1.83 (n1, 11H). MS (EI) for
C28H41N307, found 532.9 [M+H]+.
(S)-N-((S)cyclopenty1((R)methyloxiranyl)oxopropany1)((S)-
2-(2-ethoxyacetamido)propanan1ido)—3-(4-methoxyphenyl)propanan1ide (C-2020): 1H NMR
(CDCI3, 300 MHz): 7.12 (d, J = 8.4 Hz, 2H), 6.83 (d, J = 7.2 Hz, 1H), 6.78 (d, J = 8.4 Hz,
2H), 6.77 (d, J = 7.2 Hz, 1H), 6.36 (d, J = 7.2 Hz, 1H), 4.47~4.61 (m, 3H), 3.92 (d, J = 15.3
Hz, 1H), 3.80 (d, J =15.3 Hz, 1H), 3.79 (s, 3H), 3.56 (q, J = 6.9 Hz, 2H), 3.27 (d, J = 4.8 Hz,
1H), 2.99~3.04 (m, 2H), 2.90 (d, J = 4.8 Hz, 1H), 1.53~1.90 (m, 9H), 1.52 (s, 3H), 1.39 (d, J
= 7.2 Hz, 3H), 1.26 (t, J = 6.9 Hz, 3H), 1.10~1.20 (m, 2H). LC-MS for C28H41N307, found
532.1 [M+H]+.
((S)cyclopenty1((R)methyloxiranyl)oxopropanyl)((R)-
2-(2-ethoxyacetamido)propanan1ido)—3-(4-methoxyphenyl)propanan1ide (C-2021): 1H NMR
(300 MHz, : 5 7.13 (d, J = 8.4 Hz, 2H), 7.04 (d, J = 7.2 Hz, 1H), 6.82 (d, J = 8.7 Hz,
2H), 6.68 (d, J = 8.1 Hz, 1H), 6.47 (d, J = 8.1Hz, 1H), 4.62 (n1, 1H), 4.50 (n1, 1H), 4.39 (n1,
1H), 3.94 (s, 2H), 3.79 (s, 3H), 3.57 (m, 2H), 3.29 (d, J = 5.1 Hz, 1H), 3.03 (m, 2H), 2.89 (d,
J = 4.8 Hz, 1H), 2.83 (s, 3 H), 2.49 (t, J = 5.7 Hz, 2H), 1.51 (s, 3H), 1.34 (d, J = 6.9 Hz, 3H),
1.27 (t, J = 3.5 Hz, 3H), 0.95-1.78 (m, 6H). MS (EI) for C28H41N307, found 532.2 [M+H]+.
(S)-N-((S)cyclopenty1((R)methyloxiranyl)oxopropanyl)-3 -(4-
methoxyphenyl)((R)(2-(3-methylisoxazoly1)acetamido)propanan1ido)propanamide
(C-2015): 1H NMR (300 MHz, DMSO-d6): 5 8.35 (d, J = 7.5 Hz, 1H), 8.28 (d, J = 6.9 Hz,
1H), 8.18 (d, J = 9.0 Hz, 1H), 7.12 (d, J = 8.7 Hz, 2H), 6.75 (d, J = 8.7 Hz, 2H), 4.55 (n1, 1H),
4.25~4.40 (m, 2H), 3.70 (s, 3H), 3.65 (s, 2H), 3.22 (d, J = 5.4 Hz, 1H), 3.02 (d, J = 5.4 Hz,
1H), 2.70 (n1, 1H), 2.15 (s, 3H), 1.95 (m, 1H), 1.50~1.85 (m, 7H), 1.40 (s, 3H), 1.00~1.20 (m,
2H), 1.26 (d, J = 6.6 Hz, 3H). MS (EI) for C30H40N4O7, found 569.7 .
N—((S)(((S)(((S)—3-cyclopentyl((R)methyloxirany1)oxopropan
y1)an1ino)(4-methoxypheny1)oxopropany1)an1ino)oxopropany1)—2-
methylthiazole-S-carboxan1ide (C-2025): 1H NMR (300 MHz, DMSO-dg): 5 8.65 (d, J = 7.8
Hz, 1H), 8.29 (s, 1H), 8.20 (d, J = 7.5 Hz, 1H), 7.90 (d, J = 8.1 Hz, 1H), 7.12 (d, J = 8.7 Hz,
2H), 6.75 (d, J = 8.4 Hz, 2H), 4.25~4.50 (m, 3H), 3.69 (s, 3H), 3.50 (s, 3H), 3.22 (d, J = 5.4
Hz, 1H), 3.02 (d, J = 5.4 Hz, 1H), 2.70 (s, 3H), 2.65 (m, 1H), 1.95 (m, 1H), 1.50~1.85 (m,
7H), 1.40 (s, 3H), 1.00~1.20 (m, 2H), 1.26 (d, J = 6.6 Hz, 3H). MS (EI) for C29H38N4O6S,
found 571.2 [M+H]+.
N—((R)—1-(((S)—1-(((S)-3 -cyclopenty1—1-((R)methyloxirany1)oxopropan
y1)an1ino)(4-methoxypheny1)oxopropany1)an1ino)oxopropany1)—3 -
methylisoxazole-S-carboxan1ide (C-2023): 1H NMR (300 MHz, DMSO-dg): 5 8.82 (d, J =
7.5 Hz, 1H), 8.32 (d, J = 7.2 Hz, 1H), 8.16 (d, J = 8.7 Hz, 1H), 7.10 (d, J = 8.7 Hz, 2H), 6.96
(s, 1H), 6.75 (d, J = 8.1 Hz, 2H), 4.30~4.60 (m, 3H), 3.69 (s, 3H), 3.22 (d, J = 5.4 Hz, 1H),
3.02 (d, J = 5.4 Hz, 1H), 2.96 (m, 1H), 2.70 (m, 1H), 2.30 (s, 3H), 1.90 (m, 1H), 1.50~1.85
(n1, 7H), 1.40 (s, 3H), 1.00~1.20 (m, 2H), 1.26 (d, J = 6.6 Hz, 3H). MS (EI) for C29H38N4O7,
found 555.2 [M+H]+.
] N—((S)(((S)(((S)—3-cyclopenty1—1-((R)methyloxirany1)oxopropan
y1)an1ino)(4-methoxypheny1)oxopropany1)an1ino)oxopropany1)—3-hydroxy-3 -
methylbutanamide (C-2027): 1H NMR (CDC13, 300 MHz): 7.10 (d, J = 8.4 Hz, 2H),
6.91~7.00 (m, 1H), 6.81 (d, J = 8.4 Hz, 2H), 6.38~6.52 (m, 2H), 4.60~4.67 (n1, 1H),
4.47~4.53 (m, 3H), 3.79 (s, 3H), 3.21 (d, J = 4.8 Hz, 1H), 2.92~3.01 (m, 2H), 2.90 (d, J = 4.8
Hz, 1H), 2.36 (d, J = 5.4 Hz, 2H), 1.53~1.90 (m, 9H), 1.52 (s, 3H), 1.39 (d, J = 7.5 Hz, 3H),
1.30 (s, 6H), 1.03~1.16 (m, 2H). LC-MS for C29H43N307, found 546.4 [M+H]+.
N—((R)—1-(((S)—1-(((S)-3 -cyclopenty1—1-((R)methyloxirany1)oxopropan
y1)an1ino)(4-methoxypheny1)oxopropany1)an1ino)oxopropany1)—3-hydroxy-3 -
methylbutanamide (C-2028): 1H NMR (300 MHz, : 5 7.11 (d, J = 8.7 Hz, 2H), 6.88
(d, J = 7.8 Hz, 1H), 6.83 (d, J = 8.7 Hz, 2H), 6.69 (d, J = 7.5 Hz, 1H), 6.48 (d, J = 8.1Hz,
1H), 4.62 (n1, 1H), 4.47 (n1, 2H), 3.79 (s, 3H), 3.25 (d, J = 4.8 Hz, 1H), 3.01 (m, 2H), 2.89 (d,
J = 4.8 Hz, 1H), 2.37 (n1, 2H), 1.55 (s, 3H), .78 (m, 20H). LC-MS for N307,
found 546.4 [M+H]+.
[0029 1] N—((R)—1-(((S)—1-(((S)-3 -cyclopenty1—1-((R)methyloxirany1)oxopropan
y1)an1ino)(4-methoxypheny1)oxopropany1)an1ino)oxopropany1)—1H-
d]imidazolecarboxan1ide (02029): 1H NMR (300 MHz, CDC13): 5 8 .27 (br s, 1H),
2014/026980
8.15 (br s, 1H), 7.67 (br s, 2H), 7.36~7.40 (n1, 2H), 7.12 (d, J = 8.4 Hz, 2H), 6.78 (br s, 1H),
6.70 (d, J = 8.4 Hz, 2H), 5.12~5.22 (n1, 1H), .88 (n1, 1H), 4.48~4.56 (n1, 1H), 3.56 (s,
3H), 3.18 (d, J = 5.1 Hz, 1H), 3.07 (d, J = 6.9 Hz, 1H), 2.82 (d, J = 5.1 Hz, 1H), 1.54~1.67
(m, 4H), 1.54 (s, 3H), 1.51 (d, J = 6.3 Hz, 3H), 1.26~1.51 (n1, 4H), .06 (n1, 3H). LC-
MS for C32H39N506, found 590.5 [M+H]+.
(S)-N—((S)cyclopenty1((R)methyloxirany1)oxopropany1)-3 -(4-
ypheny1)((S)(3-methoxypropanamido)propanamido)propanan1ide (C-2019): 1H
NMR (300 MHz, DMSO-d6): 5 8.17 (d, J = 7.2 Hz, 1H), 8.03 (d, J = 7.2 Hz, 1H), 7.78 (d, J =
8.1 Hz, 1H), 7.11 (d, J = 8.4 Hz, 2H), 6.80 (d, J = 8.4 Hz, 2H), 4.55 (n1, 1H), 4.30 (n1, 1H),
4.20 (m, 1H), 3.72 (s, 3H), 3.50 (m, 2H), 3.15~3.30 (m, 4H), 3.05 (m, 1H), 2.95 (n1, 1H),
2.70 (m, 1H), 2.30 (m, 2H), 1.50~1.95 (m, 8H), 1.40 (s, 3H), 1.00~1.20 (n1, 2H), 1.14 (d, J =
6.6 Hz, 3H). LC-MS for C28H41N307, found 532.5 [M+H]+.
N—((R)—1-(((S)—1-(((S)-3 -cyclopenty1—1-((R)—2-methyloxirany1)oxopropan
y1)an1ino)(4-methoxypheny1)oxopropany1)an1ino)oxopropany1)—3-methy1-1H-
indenecarboxan1ide 0): 1H NMR (300 MHZ, CDC13): 5 7.50 (m, 2H), 7.48 (m, 2H),
7.39 (m, 2H), 7.15 (m, 2H), 6.80 (d, J = 8.4 Hz, 1H), 4.58 (m, 3H), 3.74 (s, 3H), 3.62 (m,
2H), 3.26 (d, J: 4.8 Hz, 1H), 3.04 (m, 2H), 2.87 (d, J: 5.1 Hz, 1H), 2.54 (s, 3H), 1.73-1.64
(n1, 10H), 1.42 (d, J: 6.9 Hz, 3H), 1.41-0.91 (m, 3H). LC-MS for C35H43N306, found 602.5
[M+H]+.
(S)-N—((S)cyclopenty1((R)methyloxirany1)oxopropany1)-3 -(4-
methoxypheny1)((S)(2-(3 -methy1isoxazoly1)acetamido)propanamido)propanan1ide
(C-2014): 1H NMR (400 MHz, CDC13) 5 7.11 (d, J: 8.6 Hz, 2H), 6.81 (d, J: 8.6 Hz, 2H),
6.53 (d, J: 7.8 Hz, 1H), 6.32 (d, J: 7.1 Hz, 1H), 6.19 (d, J: 7.9 Hz, 1H), 6.07 (s, 1H), 4.63
— 4.36 (m, 5H), 3.78 (s, 4H), 3.65 (s, 3H), 3.22 (d, J: 5.0 Hz, 1H), 2.98 (qd, J: 14.1, 6.9 Hz,
3H), 2.89 (d, J: 5.0 Hz, 1H), 2.80 (s, 1H), 2.29 (s, 4H), 1.81 — 1.42 (n1, 10H), 1.33 (d, J:
7.0 Hz, 4H), 1.22 — 0.94 (n1, 1H). MS (EI) for C30H40N4O7, found 569.0 [M+H]+.
N—((R)—1-(((S)—1-(((S)-3 -cyclopenty1—1-((R)—2-methyloxirany1)oxopropan
y1)an1ino)-3 -(4-methoxypheny1)oxopropany1)an1ino)oxopropany1)isonicotinan1ide
(C-2033): 1H NMR (300 MHz, CDC13): 5 7.28~7.23 (m, 5H), 7.19-7.08 (m, 5H), 7.05 (q, J
= 3.7 Hz, 2H), 7.00 (dd, J = 7.4, 2.0 Hz, 2H), 6.81 (d, J = 8.4 Hz, 1H), 6.70 (br s, 1H), 6.55
(d, J = 7.2 Hz, 1H), 4.74 (n1, 1H), 4.65~4.62 (m, 1H), 4.03 (m, 1H), 3.79 (s, 3H), 3.27 (d, J =
4.8 Hz, 1H), 3.11 (d, J = 4.5 Hz, 1H), 3.07 (d, J = 4.8 Hz, 1H), 2.98 (m, 2H), 2.68 (dd, J =
13.8, 8.1 Hz, 1H), 2.30 (m, 1H), 2.22 (m, 2H), 2.20 (m, 3H), 1.48 (s, 3H). LC-MS for
C30H38N406, found 551.6 [M+H]+.
—1-(((S)—1-(((S)-3 -cyclopenty1—1-((R)methyloxirany1)oxopropan
1no)(4-methoxypheny1)oxopropany1)an11no)oxopropany1)—1H-in11dazole-
2-carboxan11de 4): 1H NMR (300 MHz, CDC13): 5 8.00~8.28 (br s, 2H), 7.20 (s, 2H),
7.11 (d, J = 8.4 Hz, 2H), 6.73 (d, J = 8.4 Hz, 2H), 4.90~5.00 (m, 1H), 4.75~4.83 (m, 1H),
4.45~4.52 (m, 1H), 3.75 (s, 3H), 3.20 (d, J = 5.1 Hz, 1H), 3.10 (d, J = 6.3 Hz, 1H), 2.88 (d, J
= 5.1 Hz, 1H), 1.58~1.69 (m, 4H), 1.51 (s, 3H), 1.41 (d, J = 6.6 Hz, 3H), 1.26~1.51 (m, 5H),
0.95~1.06 (m, 2H). LC-MS for C28H37N506, found 540.6 [M+H]+.
—1-(((S)—1-(((S)-3 -cyclopenty1—1-((R)methyloxirany1)oxopropan
y1)an11no)(4-methoxypheny1)oxopropany1)an11no)oxopropany1)—1H-indene
carboxamide (C-2036): 1H NMR (300 MHz, DMSO-d6): 8 8.30 (d, J = 6.9 Hz, 1H), 8.20 (d,
J = 6.9 Hz, 1H), 8.10 (d, J = 6.9 Hz, 1H), 7.64 (s, 1H), 7.55 (d, J = 4.8 Hz, 2H), 7.33 (d, J =
4.8 Hz, 2H), 7.12 (m, 2H), 6.75 (m, 2H), 4.38 (m, 1H), 4.32 (m, 2H), 3.66 (s, 3H), 3.23 (m,
1H), 3.03 (m, 2H), 2.72 (m, 1H),1.90 (m, 1H), 1.72 (m, 2H), 1.54 (m, 6H), 1.26 (s, 3H), 1.24
(m, 1H), 1.13 (d, J = 6.9 Hz, 3H). LC-MS for N306, found 588.8 [M+H]+.
N—((R)—1-(((S)—1-(((S)-3 -cyclopenty1—1-((R)methyloxirany1)oxopropan
y1)an11no)-3 -(4-nlethoxypheny1)oxopropany1)an11no)oxopropany1)cyclopent
enecarboxamide (C-2037): 1H NMR (300 MHz, CDC13): 8 7.12 (d, J = 8.7 Hz, 2H), 6.83 (d,
J = 8.4 Hz, 3H), 6.76 (d, J = 8.4 Hz, 2H), 6.57 (m, 1H), 4.62 (m, 1H), 4.27 (m, 2H), 3.79 (s,
3H), 3.30 (m, 2H), 2.87 (m, 1H), 2.54 (m, 4H), 2.06 (m, 2H), 1.61 (m, 4H), 1.54 (m, 3H),
1.51 (m, 6H), 1.37 (d, J = 6.9 Hz, 3H), 1.32 (m, 2H), 1.28 (m, 1H). LC-MS for C30H41N306,
found 540.4 [M+H]+.
N—((R)—1-(((S)—1-(((S)-3 -cyclopenty1—1-((R)methyloxirany1)oxopropan
y1)an11no)(4-methoxypheny1)oxopropany1)an11no)oxopropany1)—4-
methylisoxazole-S-carboxan11de (C-2024): 1H NMR (300 MHZ, DMSO-d6): 5 9.02 (s, 1H),
8.65~8.80 (m, 2H), 8.10~8.30 (m, 3H), 7.55 (m, 1H), 7.12 (d, J: 8.4 Hz, 2H), 6.75 (d, J:
8.4 Hz, 2H), .60 (m, 3H), 3.69 (s, 3H), 3.23 (d, J: 5.1 Hz, 1H), 2.95~3.05 (m, 2H),
2.65 (m, 1H), 1.95 (m, 1H), 1.50~1.85 (m, 10H), 1.40 (s, 3H), 1.00~1.20 (m, 2H), 1.26 (d, J
= 6.6 Hz, 3H). LC-MS for C29H38N4O7, found 555.4 [M+H]+.
N—((R)—1-(((S)—1-(((S)-3 -cyclopenty1—1-((R)methyloxirany1)oxopropan
y1)an11no)(4-methoxypheny1)oxopropany1)an11no)oxopropany1)—1-methy1-1H-
benZO[d]imidaZ016carboxan1ide (C-2038): 1H NMR (300 MHZ, CDC13): 5 8.12 (d, J = 6.6
HZ, 1H), 7.80 (d, J: 6.9 HZ, 2H), .47 (m, 3H), 7.11 (d, J: 8.7 HZ, 2H), 6.70 (d, J:
8.7 HZ, 2H), 6.68 (d, J: 6.6 HZ, 1H), 6.44 (d, J: 6.6 HZ, 1H), 4.50~4.70 (m, 3H), 4.20 (s,
3H), 3.66 (s, 3H), 3.27 (d, J: 5.1 HZ, 1H), .15 (m, 2H), 2.88 (d, J: 5.1 HZ, 1H),
1.50~2.00 (m, 8H), 1.51 (d, J: 7.2 HZ, 3H), 1.49 (s, 3H), .16 (m, 3H). LC-MS for
C33H41N506, found 604.5 [M+H]+.
] N—((R)—1-(((S)—1-(((S)-3 -cyc10penty1— 1 -((R)methy10xirany1)-1 -ox0pr0pan
y1)an1in0)(4-methoxypheny1)ox0pr0pany1)an1ino)oxopr0pany1)is0va016-5 -
carboxamide (C-2041): 1H NMR (300 MHZ, DMSO-d6): 5 8.90 (d, J: 7.5 HZ, 1H), 8.75 (s,
1H), 8.30 (d, J: 6.9 HZ, 1H), 8.19 (d, J: 8.4 HZ, 1H), 7.13 (s, 1H), 7.12 (d, J: 8.7 HZ, 2H),
6.75 (d, J: 8.7 HZ, 2H), 4.50 (m, 1H), 4.40 (m, 1H), 4.30 (m, 1H), 3.69 (s, 3H), 3.23 (d, J:
.4 HZ, 1H), 3.02 (d, J: 5.4 HZ, 1H), 2.95 (m, 1H), 2.65 (m, 1H), 1.95 (m, 1H), 1.50~ 1.85
(m, 7H), 1.40 (s, 3H), 1.00~1.20 (m, 2H), 1.26 (d, J: 6.6 HZ, 3H). LC-MS for C28H36N4O7,
found 541.4 [M+H]+.
(R)-N—((R)(((S)(((S)—3-cyclopenty1((R)methy10xirany1)
oxopropany1)an1ino)-3 -(4-methoxypheny1)oxopr0pany1)an1ino)0X0propany1)-
3-hydr0xybutanan1ide (C-2042): 1H_NMR (300 MHZ, DMSO-d6): 5 8.26 (d, J = 6.3 HZ, 1H),
8.06 (d, J: 8.4 HZ, 1H), 7.97 (d, J: 6.6 HZ, 1H), 7.12 (d, J: 8.4 HZ, 2H), 6.80 (d, J: 8.1
HZ, 2H), 4.66 (d, J: 4.8 HZ, 1H), 4.30 (m, 1H), 4.21 (m, 1H), 4.08 (m, 1H), 3.96 (m, 1H),
3.71 (s, 3H), 3.22 (d, J: 5.1 HZ, 1H), 3.02 (d, J: 5.1 HZ, 1H), 2.94 (m, 2H), 2.52 (m, 1H),
2.18- 2.12 (m, 2H), 1.83 (m, 2H), 1.59-1.42 (m, 6H), 1.42 (s, 3H), 1.18 (m, 2H), 1.04 (d, J:
6.0 HZ, 3H), 0.96 (d, J: 7.2 HZ, 3H). LC-MS for C28H41N307, found 532.4 .
(S)-N—((R)—1-(((S)(((S)cyc10penty1—1-((R)methy10xirany1)—1-
oxopropany1)an1ino)-3 -(4-methoxypheny1)oxopr0pany1)an1ino)0X0propany1)-
3-hydr0xybutanan1ide (C-2043): 1H NMR (300 MHZ, DMSO-d6): 5 8.23 (d, J = 6.9 HZ, 1H),
8.05 (d, J: 8.1 HZ, 1H), 7.95 (d, J: 7.8 HZ, 1H), 7.11 (d, J: 8.4 HZ, 2H), 6.80 (d, J: 8.7
HZ, 2H), 4.61 (d, J: 4.8 HZ, 1H), 4.30 (m, 1H), 4.20 (m, 1H), 4.08 (m, 1H), 3.96 (m, 1H),
3.71 (s, 3H), 3.23 (d, J: 5.1 HZ, 1H), 3.00 (m, 2H), 2.52 (m, 1H), 2.18-2.12 (m, 2H), 1.83
(m, 2H), 1.59-1.42 (m, 6H), 1.39 (s, 3H), 1.18 (m, 2H), 1.04 (d, J: 6.3 HZ, 3H), 0.96 (d, J:
7.2 HZ, 3H). LC-MS for C28H41N307, found 532.6 [M+H]+.
Synthesis of Select Intermediates
Example 10
Preparation of (R)—2-methyloxopyrrolidinecarboxylic acid (Building block
for C-3010):
CI3CCHO (R) 1. SOCIZ, MeOH
O O
{‘R) Mgso4 N LDA, Mel N (R) 2. BoczO, Et3N W
N ’CO2H —’ o —’ o —’ N COOMe
H CI 3) CI 3)
CI CI CI CI
1. TFA
NaIO4, RuCI3 fl 2. LiOH A
N (R) COOMe —> O N (R) COOH
Boc H
(7aR) (Trichloromethyl)tetrahydropyrr010[I,2-c]oxazol-I (3H)-0ne
ous MgSO4 (105 g, 0.88 mol) was added to a solution of D-proline (50 g,
0.43 mol) and chloral hydrate (108 g, 0.66 mol) in chloroform (800 mL). The suspension was
heated under reflux for 6 h and then cooled to room temperature. The mixture was washed
with water (300 mL><3) and the aqueous phase was extracted with chloroform (200 mL><3).
The combined organic phases were washed with brine (500 mL><1), dried over Na2SO4 and
concentrated. The residue was tallized from EtOH to afford compound (7aR)
(trichloromethyl)tetrahydropyrrolo[1,2-c]oxazol-1(3H)-one (42 g, 40% yield) as an off-white
solid.
(7aR)- 7a-Methyl—3-(trichloromethyl)tetrahydropyrr010[I, 2-c]0xazol—I (3H)-0ne
LDA (2M, 68 mL, 0.136 mol) was added dropwise to a solution of nd
(7aR)(trichloromethyl)tetrahydropyrrolo[1,2-c]oxazol-1(3H)-one (22.2 g, 91 mmol) in
THF (150 mL) at -78°C with stirring. The mixture was d for 1 h and iodomethane (38.7
g, 0.272mol) was added dropwise at -78°C. The reaction mixture was stirred for 0.5 h at -
78°C and then d to warm to room temperature and stirred overnight. The reaction was
quenched with water (200 mL) and the resulting mixture was extracted with CH2C12 (200
. The combined c phases were washed with brine (500 mL><1), dried over
Na2SO4 and concentrated. The residue was purified by flash column chromatography on
silica gel (Hexane/EtOAc =4: 1) to afford compound (7aR)-7a-methyl
(trichloromethyl)tetrahydropyrrolo[1,2-c]oxazol-1(3H)-one (17.8 g, 75% yield).
(R)-N—Bocmethylpr0[ine methyl ester
SOC12 (10 mL, 138 mmol) was added dropwise to a solution of nd (7aR)-
7a-methyl(trichloromethyl)tetrahydropyrrolo[1,2-c]oxazol-1(3H)-one (17.8 g, 69 mmol) in
MeOH (200 mL) at 0°C with stirring. The reaction mixture was stirred for 1 h and then
allowed to warm to room temperature and stirred for 0.5 h. The mixture was further heated
under reflux for 5 h. After the mixture was cooled to room temperature, it was concentrated
to s. The residue was dissolved in CH2C12 (200 mL) and BoczO (18.1 g, 83 mmol) and
ylamine (48 mL, 345 mmol) were added. The reaction mixture was stirred for 5 h at
room temperature and then washed with 5% aqueous KHSO4 (100 mL><3), saturated aqueous
NaHC03 (100 mL><3) and brine (100 mL>< 1), respectively. The organic phase was dried over
Na2SO4 and concentrated. The e was purified by flash column chromatography on
silica gel (Hexane/EtOAc=4: 1) to afford compound (R)-N-Bocmethylproline methyl ester
(12.1 g, 72% .
(R)-N-Bocmethylpyroglatamic acid methyl ester
] A solution ofNaIO4 (8.2 g, 38 mmol) in water (40 mL) and RuC13 (20 mg) were
added to a solution of compound (R)-N—Bocmethylproline methyl ester (2.3 g, 9.6 mmol)
in EtOH (40 mL). The reaction e was stirred overnight at room temperature. The two
layers were separated and the aqueous phase was extracted with EtOAc (50 mL><3). The
combined organic phases were washed with brine (50 mL><3), dried over Na2SO4 and
concentrated. The residue was ed by flash column chromatography on silica gel
(Hexane/EtOAc =4: 1) to afford compound (R)-N-Bocmethylpyroglutamic acid methyl
ester (1.5 g, 61% yield) as a pale yellow solid.
(R)Methylpyr0glatamic acid
TFA (10 mL) was added to a solution of compound Boc
methylpyroglutamic acid methyl ester (2.0 g, 7.8 mmol) in CH2C12 (20 mL) at 0°C with
stirring. The mixture was stirred for further 1 h and concentrated to dryness. And the residue
was azeotroped three times with EtOAc (5 mL><3) to remove residual TFA. The crude was
dissolved in MeOH (20 mL) and a solution of LiOH (1.3 g, 31 mmol) in water (10 mL) was
added at 0°C with ng. After the reaction mixture was stirred for 3 h, it was acidified with
2 N aqueous HCl to pH=3. The resulting mixture was concentrated to afford crude (R)
methylpyroglutamic acid (~100% yield), which was used in the next step without fiarther
purification.
(S)Methylpyr0glatamic acid
(S)Methylpyroglutamic acid was prepared from L-proline in seven steps
following the same procedures for (R)methylpyroglutamic acid.
Example 11
Preparation of (S)(((benzyloxy)carbonyl)amino)(l-
thylsilyl)oxy)cyclopropyl)acetic acid (Building block for C-2046)
1. AcCI 2,2'-dimethoxypropane
OH OH
g/ 2. U :/ BF3-Elzo X
/\ /\ CbZN\‘/O
H2N COOH CszN COOMe 5
MeOOC
EtMSBF X 1. TESOTf
r)4 0sz PPTS 0“
o 2. AcOH/THF/HZO OTES
—> ] / —> —>
DR 0H OH
CszN CszN
1. DMP OSiEt3
2. NaC|02
—> 0H
CszN
(R)-Methyl 2-(benzyloxycarbonylamino)hydr0xypr0pan0ate (4)
Acetyl chloride (40 mL, 0.57 mol) was added to a suspension of D-serine (50.0 g,
0.47 mol) in MeOH (300 mL) at 0°C with stirring. The reaction mixture was stirred for 12 h
and then concentrated to dryness. The residue was dissolved in MeOH (200 mL) followed by
addition of triethylamine (50 mL). Cbz-OSu (93.0 g, 0.4 mol) was added at 0°C and the
reaction mixture was stirred for 12 h. The mixture was concentrated to dryness and the
residue was dissolved in methylene chloride (500 mL). The resulting solution was washed
with brine (200 mL><2), dried over ous sodium sulfate and concentrated to give crude
nd (R)-methyl 2-(benzyloxycarbonylamino)hydroxypropanoate (68.0 g, 57%
yield) as an oil, which was used directly without further purification.
(R)Benzyl 4-methyl 2,2-dimethyloxazoll'dine-3,4-dz'carb0xylate
A mixture of compound (R)-methyl 2-(benzyloxycarbonylamino)
hydroxypropanoate (43.0 g, 0.17 mol), 2,2-dimethoxypropane (200 mL, 1.7 mol) and boron
ride diethyl etherate (5 mL) was stirred for 2 h at room temperature and then heated
under reflux for 4 h. The mixture was cooled to room temperature and then trated. The
residue was poured into a mixture of water (200 mL) and EtOAc (200 mL). The two phases
were separated and the aqueous phase was extracted EtOAc (200 mL><2). The combined
organic phases were washed with saturated aqueous NaHC03 (500 mL><3) and brine (200
mL>< 1), dried over anhydrous sodium sulfate and trated. The residue was purified by
flash column chromatography on silica gel e/EtOAc = 3:1) to afford compound (R)
benzyl 4-methyl 2,2-dimethyloxazolidine-3,4-dicarboxylate (38.2 g, 77% yield).
nzyl 4-(1-hydr0xycyclopr0pyl)-2,2-dz'methyloxazolidinecarb0xylate
Titanium(IV) isopropoxide (1.45 g, 5.1 mmol) was added to a solution of
compound (R)-3 -benzyl 4-methyl 2,2-dimethyloxazolidine-3,4-dicarboxylate (5.0 g, 17.1
mmol) in THF (100 mL ) at 0°C and then EtMgBr (42.7 mmol, a solution in Eth) was added
dropwise over 30 min. The deep dark solution was stirred at room temperature for 18 h. The
reaction was quenched by slow addition of water (20 mL) and the ing mixture was
ted with EtOAc (100 mL><3). The combined organic phases were washed with saturated
aqueous NaHC03 (100 mL><3) and brine (100 mL><1), dried over anhydrous sodium sulfate
and concentrated. The residue was purified by flash column chromatography on silica gel
(Hexane/EtOAc = 2: 1) to afford compound (R)-benzyl 4-(1-hydroxycyclopropyl)-2,2-
dimethyloxazolidinecarboxylate (2.8 g, 56% yield).
(R)-Benzyl 0xy-I-(I-hydr0xycyclopr0pyl)ethylcarbamate
nium p-toluenesulfonate (10.0 g, 40 mmol) was added to a solution of
compound (R)-benzyl 4-(1-hydroxycyclopropyl)-2,2-dimethyloxazolidinecarboxylate (9.0
g, 3.1 mmol) in MeOH (100 mL ) at 0°C. The mixture was stirred at room ature for 18
h and then concentrated. The residue was dissolved in water (200 mL) and the resulting
solution was extracted with EtOAc (100 mL><3). The combined organic phases were washed
with saturated aqueous NaHC03 (100 mL><3) and brine (100 mL><1), dried over anhydrous
sodium sulfate and concentrated. The residue was purified by flash column chromatography
on silica gel e/EtOAc = 1:1) to afford compound (R)-benzyl 2-hydroxy(1-
hydroxycyclopropyl)ethylcarbamate (3.8 g, 48% yield).
(R)-Benzyl I-(I-(triethylsilyloxy)cyclopropyl)hydr0xyethylcarbamate
Triethylsilyl triflate (3.2 mL, 12 mmol) was added to a solution of compound (R)-
benzyl 2-hydroxy(1-hydroxycyclopropyl)ethylcarbamate (1.2 g, 4.8 mmol) in
dichloromethane (10 mL) containing TEA (10 mL) at -78°C with stirring. The reaction
e was allowed to warm to room temperature and d for 12 h. The reaction was
quenched with ted aqueous NaHC03 (50 mL) and the resulting mixture was extracted
with EtOAc (50 mL><3). The combined organic phases were washed with saturated aqueous
NaHC03 (50 mL><3) and brine (30 mL><1), dried over anhydrous sodium sulfate and
concentrated to dryness. The residue was purified by flash column chromatography on silica
gel (Hexane/EtOAc = 10: 1) to afford compound di-TES protected (R)-benzyl (2-hydroxy
1 09
(1-hydroxycyclopropyl)ethyl)carbamate (780 mg). Di-TES protected (R)-benzyl (2-
hydroxy(1-hydroxycyclopropyl)ethyl)carbamate (5.0 g, 10.4 mmol) was added to a
mixture /THF/HZO (26 mL, 4:8: 1) at 0°C. The reaction mixture was stirred for 2 h
and then NaHC03 was added. The mixture was extracted with EtOAc (50 mL><3). The
combined organic phases were washed with saturated aqueous NaHC03 (50 mL><3) and brine
(30 mL><1), dried over anhydrous sodium sulfate and concentrated to afford compound (R)-
benzyl 1-(1-(triethylsilyloxy)cyclopropyl)hydroxyethylcarbamate (4.8 g, 43% yield),
which was used ly without fiarther purification.
(S) (Benzyloxycarbonylamin0)(I—(triethylsilyloxy)cyclopropybacetic acid
Dess-Martin periodinane (3.2 g, 7.5 mmol) was added to a solution of nd
(R)-benzyl 1-(1-(triethylsilyloxy)cyclopropyl)hydroxyethylcarbamate (2.1 g, 5.8 mmol) in
dichloromethane (30 mL). The reaction mixture was stirred at room temperature for 12 h and
then washed with s sodium hydroxide (1N, 50 mL><3), aqueous sodium thiosulfate
(1N, 50 mL><3), saturated aqueous NaHC03 (50 mL><3) and brine (30 mL><1), respectively.
The organic phase was dried over anhydrous sodium sulfate and trated to give the
corresponding aldehyde.
The crude aldehyde was ved in tert-butyl alcohol (20 mL) and THF (20 mL)
and a solution of sodium chlorite (80%, 2.5 g, 22 mmol) and sodium dihydrogenphosphate
monohydrate (7.9 g, 66 mmol) in water (20 mL) was added dropwise over 1 h at room
temperature. The reaction mixture was stirred for 3 h and then diluted with hydrochloric acid
(0.1N, 100 mL). The resulting mixture was extracted with EtOAc (50 mL><1). The ed
organic layers were washed with 5% aqueous KHSO4 (100 mL><3) and brine (100 mL><1),
dried over anhydrous sodium sulfate and concentrated to dryness. The residue was purified
by flash column chromatography on silica gel (Hexane/EtOAc = 2: 1) to afford compound
(S)(benzyloxycarbonylamino)(1-(triethylsilyloxy)cyclopropyl)acetic acid (1.3 g, 59%
yield).
Example 12
Preparation of utyl ((S)cyclopentyl((R)-oxiranyl)oxopropan
bamate d 1; Intermediate for C-2053 and C-2055)
2014/026980
O O BoczO,NEt3, o
AcCI,MeOH DCM
HO OH —’ Ho OMe —» HO OMe
NH2 NHZHCI NHBOC
|2,PPh3, O
—>I OMe
NHBoc
szo,
Na2C03, | OMe
0:0 DCM NHBoc
—> OTf —, OMe
Zn,TMS-CI
NHBoc
Pd(dppf)CI2, DMF
ethyl
LiOH H20 H2, Pd/C’ O chloroformate,
M—>eOH meOH NMM, THF/DCM;
OH —> OH —>
MeONHMe HCI,
NHBOC NHBOC
DCM,TEA
/MgBr
BOCHN THF BocHN
Methanol (450 mL) in a round-bottom flask was cooled to 0 oC and acetyl
chloride (55 mL, 0.77 mol) was added dropwise. After completion of the addition, the
mixture was stirred at ambient ature for 10 min and OH (30 g, 0.29 mol) was
added in three portions. The reaction mixture was heated at 80 CC for 2 h and then
concentrated. The residue was dried under vacuum to afford (S)-methyl 2-amino
hydroxypropanoate hydrochloride (quantitative) as a colorless solid, which was used in the
next step without further purification.
The crude (S)-methyl 2-aminohydroxypropanoate hydrochloride (0.29 mol)
was suspended in DCM (200 mL) and to this mixture was added triethylamine (79 mL, 0.57
mol) and BoczO (68 g, 0.31 mol) at 0 oC. The cooling bath was removed and the reaction
e was stirred at ambient temperature ght and then diluted with MTBE (300 mL).
The e was filtered and the filtrate was concentrated under reduced pressure. The
residue was purified by flash column chromatography on silica gel to afford (S)-methyl 2-
((tert-butoxycarbonyl)amino)—3-hydroxypropanoate (60 g, 94% yield) as a colorless oil.
A mixture of triphenylphosphine (131 g, 0.500 mol) and imidazole (34 g, 0.50
mol) in DCM (600 mL) was cooled to 0 oC and iodide (127 g, 0.50 mol) was added in small
portions over 0.5 h. The cooling bath was removed and the mixture was stirred for 0.5 h.
After the mixture was re-cooled to 0 CC, a solution of (S)-methyl 2-((tert-
butoxycarbonyl)amino)hydroxypropanoate (73 g, 0.33 mol) in DCM (300 mL) was added
dropwise. After the addition, the cooling bath was removed and the mixture was allowed to
warm to ambient temperature and stirred for 1.5 h. The mixture was filtered and the e
was concentrated to remove most of the solvent. MTBE (400 mL) was added to the e
and the mixture was filtered to remove nylphosphine oxide. The filtrate was
concentrated and the residue was purified by flash column chromatography on silica gel to
afford (R)-methyl 2-((tert-butoxycarbonyl)amino)iodopropanoate (74.0 g, 68% yield) as a
colorless solid.
To a solution of cyclopentanone (55 g, 0.66 mol) in DCM (1.3 L) was added
Na2C03 (104 g, 0.98 mol) and the mixture was cooled to -20 OC. Trifluoromethanesulfonic
ide (121 mL, 0.72 mol) was added dropwise. After the addition, the cooling bath was
removed and the reaction mixture was d at ambient temperature overnight. GC-MS
analysis showed the reaction was not te and more trifluoromethanesulfonic anhydride
(33 mL, 0.20 mol) was added. The reaction mixture was stirred for r 4 h and then
quenched with water (800 mL). The resulting two phases were separated and the aqueous
phase was ted with DCM (300 mL). The organic layers were combined, washed with
brine, and concentrated to afford cyclopent-l-en-l-yl trifiuoromethanesulfonate as s oil
(104 g, 73% yield), which was used in the next step without r purification.
To a suspension of zinc (123 g, 1.90 mol) in DMF (500 mL) was added TMSCl
(46 mL) dropwise. The mixture was stirred at ambient temperature for 45 min. The upper
clear liquid was drained out and the residue was washed with DMF (2><200 mL). The
resulting solid was re-suspended in DMF (200 mL) and the mixture was cooled to 0 0C. A
solution of (R)-methyl 2-((tert—butoxycarbonyl)amino)iodopropanoate (104 g, 0.32 mol) in
DMF (300 mL) was added. The e was stirred at 0 CC under nitrogen for 20 min. The
upper clear liquid was drained out and added dropwise to a solution of cyclopentenyl
trifluoromethanesulfonate (90 g, 0.37 mol) and Pd(dppf)C12 (3.9 g, 4.7 mmol) in DMF (500
mL). After addition, the reaction mixture was stirred at 50 CC under nitrogen overnight then
cooled to ambient temperature. Brine (500 mL) was added and the resulting e was
extracted with MTBE (3 X300 mL). The organic layers were combined, washed with brine,
and concentrated. The e was d by flash column chromatography on silica gel
(petroleum ether/EtOAc = 100:1 to 40: 1) to afford (S)-methyl 2-((tert—
butoxycarbonyl)amino)(cyclopent-l-en-l-yl)propanoate as a viscous oil (62 g, 72% yield).
To a solution of (S)-methyl rt—butoxycarbonyl)amino)(cyclopent-l -en-l-
yl)propanoate (62 g, 0.23 mol) in water/methanol (900 mL, 2: 1) was added lithium hydroxide
hydrate (19.3 g, 0.46 mol). The reaction mixture was stirred at ambient temperature ght
and then concentrated to remove most of the methanol. The residue was washed with DCM
(400 mL) and the aqueous phase was acidified with dilute HCl to pH=3 -4. The resulting
mixture was extracted with DCM (3 X300 mL). The organic layers were ed and
trated to afford ((tert—butoxycarbonyl)amino)(cyclopentenyl)propanoic
acid (56 g, 95% yield) as viscous oil, which was used in the next step without fiarther
purification.
To a solution of (S)((tert—butoxycarbonyl)amino)(cyclopenten-1 -
yl)propanoic acid (56 g, 0.22 mol) in methanol (500 mL) was added Pd/C (23 g, 0.022 mol,
%). The mixture was stirred under a hydrogen atmosphere (1 atm) at ambient temperature
overnight and then filtered h a pad of celite. The filtrate was concentrated under
reduced pressure to afford (S)((tert—butoxycarbonyl)amino)cyclopentylpropanoic acid
(55 g, 97% yield) as viscous oil, which was used in the next step without further purification.
To a flask charged with compound (S)((tert-butoxycarbonyl)amino)
cyclopentylpropanoic acid (55 g, 214 mmol) was added THF/DCM (800 mL, 1:1). The
solution was cooled to 0 oC and ethyl chloroformate (24.5 mL, 257 mmol) and NMM (28.4
mL, 257 mmol) was added dropwise sequentially. After addition, the mixture was stirred at 0
CC under en for 1 h. To the other flask charged with N,O-dimethylhydroxylamine HCl
(25 g, 257 mmol) was added DCM (400 mL). The mixture was cooled to 0 oC and TEA (38.7
mL, 278 mmol) was added. The resulting mixture was transferred into the former reaction
flask. The reaction mixture was allowed to warm to ambient temperature and stirred
overnight. The reaction was then quenched with water (500 mL) and the two phases were
ted. The organic phase was washed with water (500 mL), dried over anhydrous sodium
e, and concentrated to afford (S)-tert—butyl (3 -cyclopentyl(methoxy(methyl)amino)-
1-oxopropanyl)carbamate as colorless oil (60 g, 93% yield), which was used in the next
step without further purification.
To a solution of (S) -tert-butyl (3-cyclopentyl-l-(methoxy(methyl)amino)
WO 52127
oxopropanyl)carbamate (2.5 g, 8.3 mmol) in THF (35 mL) was added Vinylmagnesium
bromide (16.7 mL, 33.3 mol) at 0 oC dropwise. After completion of the addition, the reaction
mixture was d at 0 CC for 2 h and then quenched with saturated aqueous ammonium
chloride (30 mL). The resulting mixture was extracted with EtOAc (2X40 mL). The organic
layers were combined, dried over ous sodium e, and concentrated. The residue
was purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 100: 1)
to afford (S)-tert—butyl (1 -cyclopentyloxopentenyl)carbamate as a yellow oil (854
mg, 38% yield).
A solution of (S)-tert-butyl (1-cyclopentyl-3 -oxopentenyl)carbamate (854
mg, 3.2 mmol) in DMF (70 mL) was cooled to -20 OC and a bleach solution (9.5 mL, 12.8
mmol, 10% active spice) was added dropwise under nitrogen. The reaction mixture was
warmed to 0 oC and d for 1.5 h. Water (70 mL) was added and the mixture was
extracted with EtOAc (2X50 mL). The organic phases were combined, washed with brine
(2X50 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified
by flash column chromatography on silica gel (petroleum EtOAc = 80: 1) to afford tert-
butyl ((S)cyclopentyl((R)-oxiranyl)oxopropanyl)carbamate as a Viscous oil
(390 mg, contaminated with some impurities, 43% yield) as a yellow oil.
e 13
Preparation of tert-butyl ((S)-3 -(cyclopentenyl)((R)methyloxiranyl)-
1-oxopropanyl)carbamate (Intermediate for: C-3001, C-2060, C-2066, C-2067, C-2068,
C-2069, and C-2070)
I/YKOMe
NHBoc
Zn TMS-CI
Tf O, Na CO ’ O
0:0 #, on Pd(dppf)Cl2
DCM DMF NHBo?Vle
MeONHMe HCI,
O O
ethylchloroformate,
LIOH_ A
OH T/O\ MgBr
—> O
NHBoc BocHN
To a solution of cyclopentanone (55 g, 0.66 mol) in DCM (1.3 L) was added
Na2CO3 (104 g, 0.980 mol) and the mixture was cooled to -20 OC. Trifluoromethanesulfonic
anhydride (121 mL, 0.720 mol) was added dropwise. After the on, the cooling bath was
removed and the reaction mixture was stirred at ambient temperature overnight. GC-MS
analysis showed the reaction was not complete and additional trifluoromethane sulfonic
anhydride (33 mL, 0.20 mol) was added. The on mixture was stirred for another 4 h
then quenched with water (800 mL). The aqueous phase was extracted with DCM (300 mL).
The organics were ed, washed with brine, and concentrated to afford
cyclopentenyltrifluoromethanesulfonate as viscous oil (104 g, 73% yield), which was used in
the next step without fiarther purification.
To a sion of zinc (123 g, 1.90 mol) in DMF (500 mL) was added TMSCl
(46 mL) dropwise. The mixture was d at ambient temperature for 45 min. The upper
clear liquid was removed and the residue was washed with DMF (200 mL><2). The resulting
solid was re-suspended in DMF (200 mL) and the mixture was cooled to 0 0C. A on of
(R)-methyl 2-((tert-butoxycarbonyl)amino)iodopropanoate (104 g, 0.320 mol) in DMF
(300 mL) was added. The mixture was stirred at 0 0C under nitrogen for 20 min. The upper
clear liquid was removed and added to a solution of ent-l -enyl
trifluoromethanesulfonate (90 g, 0.37 mol) and Pd(dppf)Cl2 (3.9 g, 4.7 mmol) in DMF (500
l 15
mL) dropwise. After addition, the reaction mixture was stirred at 50 CC under nitrogen
overnight then cooled to ambient temperature. Brine (500 mL) was added and the resulting
mixture was ted with MTBE (300 mL><3). The cs were combined, washed with
brine, and concentrated. The residue was purified by flash column chromatography on silica
gel (petroleum ether/EtOAc = 100:1 to 40: 1) to afford (S)-Methyl 2-(tert-
butoxycarbonylamino)-3 -cyclopentenylpropanoate as s oil (62 g, 72% yield). 1H NMR
(300 MHz, CDClg): 5 5.48 (br s, 1H), 4.97 (d, J = 6.6 Hz, 1H), 4.40-4.43 (m, 1H), 3.74 (s,
3H), 2.46-2.63 (m, 2H), 2.23-2.34 (m, 4H), 1.82-1.93 (m, 2H), 1.45 (s, 9H).
To a solution of (S)—Methyl 2-(tert-butoxycarbonylamino)
cyclopentenylpropanoate (62 g, 0.23 mol) in methanol (900 mL, 2:1) was added
lithium hydroxide hydrate (19.3 g, 0.460 mol). The reaction mixture was stirred at ambient
temperature overnight and then trated to remove the majority of methanol. The e
was washed with DCM (400 mL) and the aqueous phase was acidified with diluted HCl to
pH=3-4. The resulting mixture was ted with DCM (300 mL ><3). The organic layers
were combined and concentrated to afford (S)(tert-Butoxycarbonylamino)
cyclopentenylpropanoic acid (56 g, 95% yield) as viscous oil, which was used in the next step
without further purification. 1H NMR (300 MHZ, CDClg): 5 10.47 (br. s, 1H), 5.52 (br. s,
1H), 4.98 (d, J = 8.1 Hz, 1H), 4.40-4.44 (m, 1H), 2.50-2.70 (m, 2H), 2.25-2.34 (m, 4H), 1.79-
1.93 (m, 2H), 1.45 (s, 9H).
To a flask charged with (S)—2-(tert-Butoxycarbonylamino)
cyclopentenylpropanoic acid (55.0 g, 214 mmol) was added THF/DCM (800 mL, 1:1). The
solution was cooled to 0 oC and ethyl chloroformate (24.5 mL, 257 mmol) and NMM (28.4
mL, 257 mmol) were added dropwise sequentially. After addition, the mixture was stirred at
0 °C under nitrogen for 1 h. To the other flask charged with N,O-dimethylhydroxylamine
HCl (25 g, 257 mmol) was added DCM (400 mL). The mixture was cooled to 0 oC and TEA
(38.7 mL, 278 mmol) was added. The resulting mixture was transferred into the former
reaction flask. The reaction mixture was d to warm to ambient temperature and stirred
overnight. The mixture was quenched with water (500 mL) and the organic phase was
washed with water (500 mL), dried over anhydrous sodium sulfate, and concentrated to
afford (S)—tert-butyl (3 -(cyclopentenyl)-1 -(methoxy(methyl)amino)oxopropan
bamate as colorless oil (60 g, 93% , which was used in the next step without
further purification.
To a solution of (S)—tert-butyl (3-(cyclopentenyl)
1 16
(methoxy(methyl)amino)oxopropanyl)carbamate (81 g, 0.27 mol) in THF (600 mL)
was added freshly prepared prop-l-enylmagnesium bromide (96.0 mL, 1.08 mol) at 0 oC
dropwise. After completion of the addition, the reaction mixture was stirred at 0 CC for 2 h
then quenched with saturated s ammonium chloride (500 mL). The resulting mixture
was ted with EtOAc (400 mL><2). The organic phases were combined, dried over
anhydrous sodium sulfate, and concentrated. The residue was d by flash column
chromatography on silica gel (petroleum ether/EtOAc = 100: 1) to afford (S)-tert-butyl (1-
(cyclopent-l-en-l-yl)methyloxopentenyl)carbamate as colorless oil (39.3 g, 52%
yield).
A solution of (S)—tert-butyl (l-(cyclopent-l-en-l-yl)methyloxopenten
yl)carbamate (10.0 g, 35.6 mmol) in DMF (180 mL) was cooled to -20 oC and bleach (54.0
mL, 71.2 mmol, 10%) was added dropwise under nitrogen. The reaction mixture was warmed
to 0 °C and stirred for 1.5 h. Water (200 mL) was added and the mixture was ted with
EtOAc (200 mL><2). The organic phases were combined, washed with brine (200 mL><2),
dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash
column chromatography on silica gel to afford tert-butyl ((S)(cyclopentenyl)((R)-
2-methyloxiranyl)oxopropanyl)carbamate as s oil (5.6 g, 53% yield). 1H
NMR (300 MHz, CDCl3): 5 4.62 (s, l H), 4.91 (d, J = 7.5 Hz, 1 H), 4.44-4.37 (m, 1H), 3.29
(d, J = 4.8 Hz, 1H), 2.89 (d, J = 4.8 Hz, 1H), .52 (m, 1H), 2.29-2.26 (m, 5H), 1.92-1.82
(m, 2H), 1.51 (s, 3H), 1.41 (s, 9H) .
Example 14
Preparation of tert-butyl ((S)cyclopentyl((R)methyloxiranyl)
oxopropanyl)carbamate (Method 2) (Intermediate for: C-3014, C-3018, , C-2014,
C-2015, C-2018, C-2019, C-2020, C-2021, C-2022, C-2023, C-2025, C-2026, C-2027, C-
2028, C-2029, C-2030, C-2031, C-2032, C-2033, C-2034, C-2036, C-2037, C-2038, C-
2039, C-2040, C-2041, , C-2043, C-2044, C-2045, C-2047, C-2050, C-2051, C-
2052, C-2054, C-2059, C-2061, , C-2063, , and C-2065)
WOH o
H2 Pd/C WOH e O
N’ \
NHBoc NHBoc |
)‘MgBr
WNaOCI —>
NHBoc BocHN
To a solution of (S)—2-(tert-Butoxycarbonylamino)cyclopentenylpropanoic acid
(56 g, 0.22 mol) in methanol (500 mL) was added Pd/C (23 g, 0.022 mol, 10%). The mixture
was stirred under a hydrogen atmosphere (1 atm) at t temperature overnight and then
filtered through a pad of . The filtrate was concentrated under reduced pressure to afford
(S)—2-(tert-Butoxycarbonylamino)cyclopentylpropanoic acid (55 g, 97% yield) as Viscous
oil, which was used in the next step without r purification.
The remainder of the synthesis of tert-butyl ((S)—3 -cyclopentyl((R)
methyloxiranyl)oxopropanyl)carbamate was carried out in a r manner to the
synthesis of tert-butyl ((S)—3 -(cyclopent-1 -enyl)((R)methyloxiranyl)
oxopropanyl)carbamate. 1H NMR (300 MHz, CDCl3): 5 4.90 (m, 1H), 4.30 (m, 1H), 3.30
(d, J = 5.0 Hz, 1H), 2.90 (d, J = 5.0 Hz, 1H), 1.57 (s, 3H), 1.51 (s, 9H), 1.95-1.20 (m, 11H).
Example 15
Preparation of 2-(2-Aminothiazolyl)acetic acid (Intermediate toward C-2066)
1. NaOH (00002 0 O
o \I:C> A,2.3 B OBn &
HO OBn i
H H
o W08“
0 Br 0
H2N NH2
cyc/ization S COOBn LiOH 8 COOH
H2N—<\ | —> H2N—<\ |
o N N
HJWOBn
Br 0
Benzyl 4-hydr0xybutan0ate
To a solution of dihydrofuran-2(3H)-one (20.0 g, 23.3 mmol) in ethanol (200 mL)
were added water (100 ml) and sodium hydroxide (9.3 g, 233 mmol). The reaction mixture
was heated under reflux overnight. The mixture was concentrated and the residue was washed
with THF/EtOH (1 :1, 100 mL) to afford sodium 4-hydroxy butanoate (26.1 g, 89% yield) as a
white solid.
A mixture of sodium 4-hydroxybutanoate (26.1 g, 20.7 mmol) and benzyl bromide
(42.5 g, 24.9 mmol) in DMF (500 ml) was stirred at room temperature for 1.5 h. Water (300
mL) was added and the resulting mixture was ted with EtOAc (300 . The
combine organic layers were washed with water (300 mL) and brine (300 mL), dried over
ous Na2SO4 and concentrated. The residue was d by flash column
chromatography on silica gel (petroleum ether/EtOAc = 5:1 to 2: 1) to afford nd
benzyl oxybutanoate (8.0 g, 19% yield) as an oil.
Benzyl 4-0x0butan0ate
A flame-dried flask was charged with DCM (26 mL) and then cooled to -78°C
with dry etone bath. Oxalyl chloride (2.62 g, 20.6 mmol) was added ed by
DMSO (2.41 g, 30.9 mmol). The mixture was kept at -78°C for 15 min and a solution of
compound 16 (2.0 g, 10.3 mmol) in DCM (10 mL) was added. The reaction mixture was
stirred at -78°C for 1 h and triethylamine (7 mL, 51 mmol) was added. The mixture was
allowed to warm to room temperature over 30 min and then poured into ice-cold 1N aqueous
HCl (100 mL). The resulting mixture was extracted with ethyl acetate (100 mL><2). The
combined organic layers were washed with water (100 mL) and brine (100 mL), dried over
anhydrous Na2SO4 and concentrated. The residue was purified by flash column
chromatography on silica gel (petroleum ether/EtOAc = 5: 1) to afford compound benzyl 4-
oxobutanoate (1.78 g, 89% yield) as a yellow oil.
Benzyl 3-br0m00x0butan0ate
Bromine (1.46 g, 9.13 mmol) was added dropwise to a solution of compound 17
(1.75 g, 9.13 mmol) in diethyl ether (8 mL) and dioxane (0.1 mL). The on mixture was
stirred for 1 h at room temperature and then poured into dichloromethane (10 mL). Calcium
carbonate (2.28 g, 22.8 mmol) and sodium bicarbonate (0.76 g, 10 mmol) were added and the
mixture was stirred for 12 h at room temperature. The inorganic solids were removed by
filtration and the filtrate was concentrated under reduced pressure to afford compound benzyl
3-bromooxobutanoate (2.44 g, ning 30% of 17 by proton NMR analysis) as a red oil,
which was used directly in the next step without further purification.
Benzyl 2-(2-amz'n0thiazol—5-y0acetate
A suspension of nd 18 (crude, 2.4 g, 8.86 mmol) and thiourea (0.64 g,
8.42 mmol) in methanol (10 mL) was heated under reflux for 4 h. The solvent was ated
and the residue was diluted with ethyl acetate (30 mL). The solid was collected by filtration
and treated with 10% aqueous NaHCO3 (30 mL). The ing mixture was extracted with
ethyl acetate (50 ml><2). The combined organic layers were washed with water (50 mL) and
brine (50 mL), dried over anhydrous Na2SO4 and concentrated. The residue was suspended
in petroleum ether/EtOAc (2: l 30 mL) and the yellow solid was collected by ion to
afford compound benzyl minothiazolyl)acetate (0.93 g, 42% yield).
2-(2-Aminothiazol—5-yl)acetic acid
To a mixture of compound 19 (930 mg, 3.75 mmol) in methanol (12 mL) were
added water (6 mL) and lithium hydroxide (236 mg, 5.6 mmol). The reaction mixture was
stirred at room temperature for 0.5 h and then diluted with water (50 mL). The resulting
mixture was washed with ethyl acetate (25 mL). The aqueous phase was adjusted to pH=4
with 2N aqueous HCl (20 mL) and the itate was ted by filtration and dried to
afford compound 2-(2-aminothiazolyl)acetic acid (330 mg, 55% yield) as a yellow solid.
2-(2-aminooxazolyl)acetic acid was synthesized in similar fashion utilizing
urea instead of thiourea.
Example 16
] Preparation of (S)((S)aminopropanamido)-N-((S)(cyclopent- l -en-l -yl)- l -
((R)methyloxiranyl)- l -oxopropanyl)-3 -(4-methoxyphenyl)propanamide
(intermediate for: C-2066, C-2067, C-2068, C-2069, and C-2070)
BOCHNQJxOH TFA
+ o 1. HATU DIEA DMF
i :2N\:)LN :0
H N2
U 2. TFA DCM
OMe \©\0MeU:
BocHN%(OH
1. HATU, DIEA, DMF “\A o
H2N ;
2. TFA, DCM : M
o o
To (S)((tert-butoxycarbonyl)amino)(4-methoxyphenyl)propanoic acid (2.00
g, 6.78 mmol) and (S)amino(cyclopent-l-en-l-yl)- l -((R)methyloxiranyl)propan-
l-one (1.98 g, 6.78 mmol) in DMF (10 mL) at 0 0C was added HATU (3.00 g, 8.36 mmol)
followed by DIEA (5.90 mL, 33.9 mmol) and the mixture was stirred for 15 min then
quenched with NaHCO3 (sat., aq.), extracted with EtOAc (2><), washed with brine, dried with
sodium sulfate, d, and concentrated. Purification by column chromatography (1 :l
hexanes/EtOAc) provided tert-butyl ((S)(((S)—3 -(cyclopentenyl)-1 -((R)
methyloxiranyl)-l -oxopropanyl)amino)(4-methoxyphenyl)- l -oxopropan
yl)carbamate (2.62 g, 82%) as a colorless oil. MS(EI) for C26H36N206, found 473.3 (MH)+.
To utyl ((S)- l -(((S)-3 -(cyclopentenyl)- l -((R)methyloxiranyl)- l -
oxopropanyl)amino)-3 -(4-methoxyphenyl)- l -oxopropanyl)carbamate (0.99 g, 2.1
mmol) was added DCM (5 mL) and TFA (5 mL). The mixture was allowed to stand at
ambient temperature for 30 min then it was trated to e crude (S)—2-amino-N—
((S)—3 -(cyclopentenyl)-l -((R)methyloxiranyl)- l -oxopropanyl)-3 -(4-
methoxyphenyl)propanamide (quant.) and carried forward without filrther purification.
MS(EI) for N204, found 373.2 (MH)+.
To (S)amino-N-((S)(cyclopent-l-en-l-yl)-l-((R)methyloxiranyl)-l-
oxopropanyl)(4-methoxyphenyl)propanamide (TFA salt, 2.00 g, 4.26 mmol) and (S)—2-
((tert-butoxycarbonyl)amino)propanoic acid (805 mg, 4.26 mmol) in DMF (10 mL) at 0 0C
was added HATU (l .94 g, 5. ll mmol) followed by DIEA (4.37 mL, 256 mmol) and the
mixture was stirred for 15 min then ed with NaHCO3 (sat., aq.), extracted with EtOAc
(2 ><), washed with brine, dried with sodium e, filtered, and concentrated. Purification by
column chromatography (1 : 1 hexanes/EtOAc) provided tert-butyl ((S)—1-(((S)—1-(((S)
(cyclopenten-1 -yl)((R)methyloxiranyl)oxopropanyl)amino)—3 -(4-
methoxyphenyl)oxopropanyl)amino)oxopropanyl)carbamate (1.94 g, 84%) as a
colorless oil. MS(EI) for C29H41N307, found 544.3 (MH)+.
To tert-butyl ((S)(((S)(((S)—3 -(cyclopentenyl)((R)methyloxiran-
2-yl)oxopropanyl)amino)(4-methoxyphenyl)— 1 -oxopropanyl)amino)— 1 -
oxopropanyl)carbamate (1 .94 g, 2.18 mmol) was added DCM (10 mL) and TFA (10 mL).
The mixture was allowed to stand at ambient ature for 30 min then it was concentrated
to provide (S)—2-((S)—2-aminopropanamido)-N-((S)(cyclopentenyl)—1-((R)
oxiranyl)oxopropanyl)(4-methoxyphenyl)propanamide (quant.) which was
carried forward without further purification. MS(EI) for C24H33N305, found 444.2 (MH)+.
(S)aminohydroxy-N-((S)-3 -(4-methoxyphenyl)—1-(((S)((R)
methyloxiranyl)-1 -phenylpropanyl)amino)oxopropanyl)propanamide
(intermediate for C-2007), (S)((S)aminopropanamido)(4-methoxyphenyl)-N—((S)— 1 -
((R)methyloxiranyl)oxophenylpropanyl)propanamide (intermediate for C-
2012, C-2013 , C-2049) and (S)—2-((R)aminopropanamido)(4-methoxyphenyl)-N-((S)-
1-((R)—2-methyloxiranyl)oxophenylpropanyl)propanamide were synthesized in a
similar manner.
Example 17
Preparation of 2-(2-(azetidinyl)thiazolyl)acetic acid (intermediate for C-
2068)
o ggfipd/c o
CIMOE’E —,- 2 OEt
0 Br 0
1.Heat
<:N%\]/\8 2. LiOH COOH
KSCN S
cm —» CH
Ethyl 00x0butan0ate
Pd/C (10%, 4 g) was added to a solution of omethoxypropionyl chloride
(18.0 g, 0.11 mol) and 2,6-dimethylpyridine (12.5 g, 0.11 mol) in THF (250 ml). The
suspension was stirred under hydrogen atmosphere at room temperature for 10 h. Pd/C was
filtered off and washed with THF (50 mL). The filtrate and washings were combined and
trated to dryness. The residue was dissolved in Et20 (200 mL) and the resulting
solution was washed with aqueous HCl (IN, 100 mL><3), saturated aqueous NaHCO3 (100
mL><3) and brine (100 mL><1), respectively. The organic solution was dried over anhydrous
Na2SO4 and concentrated to dryness.
The e was dissolved in Et20 (50 mL) and 1,4-dioxane (50 ml) and bromine
(l 8.0 g, 0. 11 mmol) was added over 0.5 h. After the addition was complete, the reaction
mixture was stirred for l h at room temperature. The mixture was diluted with CH2Cl2 (150
ml) and sodium hydrogen carbonate (20.0 g, 0.24 mol) was added. The resulting mixture was
stirred overnight. The solids were filtered off and the filtrate was trated to afford crude
compound ethyl 3-bromooxobutanoate (23 g, ~100% yield).
Azetidine-I—carbothioamide
A solution of HCl in dioxane (4N, 5.3 ml, 21 mmol) was added to a solution of
azetidine hydrochloride (1.9 g, 21 mmol) in THF (10 mL) followed by addition of potassium
thiocyanate (2.0 g, 21 mmol). The reaction e was heated under reflux for 4 h and then
cooled to room temperature. The mixture was d and the filtrate was concentrated to
dryness to afford crude azetidine-l-carbothioamide (2.0 g, ~100% , which was used
directly without further purification.
Azetz'dz'n-I—yl)thiazol—5-yl)acetic acid
A solution of compounds 5 (2.0 g, crude) and 6 (2.0 g, crude) in EtOH (20 mL)
was heated under reflux for 4 h and then cooled to room temperature. The solvent was
d and the residue was dissolved in EtOAc (100 mL) followed by addition of aqueous
ammonia (10%, 100 mL). The organic phase was separated, washed with brine (50 mL>< 1),
dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column
chromatography on silica gel (hexane/EtOAc = 5:1) to afford 2-(2-(azetidin-l-yl)thiazol
tic acid-ethyl ester (300 mg, ~6% yield).
Compound 2-(2-(azetidin-l-yl)thiazolyl)acetic acid -ethyl ester (300 mg, 1.2
mmol) was treated with a on of lithium hydroxide-H2O (360 mg, 8.6 mmol) in
water/THF (10 mL/4 mL) for 1 h. THF was removed and the aqueous phase was acidified to
pH=3-4 with 1N HCl. The mixture was concentrated to dryness to afford crude 2-(2-
(azetidin-l-yl)thiazol-5 etic acid (~100% yield), which was used directly without fithher
2014/026980
purification.
2-(2-(pyrrolidin-l-yl)thiazolyl)acetic acid (intermediate for C-2069), and 2-(2-
(dimethylamino)thiazolyl)acetic acid (intermediate for C-2067) were synthesized in
similar fashion.
Example 18
Preparation of tert-butyl ((R)— l -(((S)-l -(((S)cyclopentyl- l -((R)
methyloxiranyl)-l -oxopropanyl)amino)(4-methoxyphenyl)- l -oxopropan
no)-l-oxopropanyl)carbamate (intermediate for: C-2051, C-2052, C-2061, C-2062,
C-2063, C-2026, C-2030, C-2044, and C-2045)
O O
\n’N\E)J\OBn§ H i H
H2, Pd/C BocHN/\n’N\E)J\OH
' —>
o o '
\©\0/ 00/ 5 Hi!“ 0
TFA H2N
(S)((R)(tert—Butoxycarbonylamin0)pr0panamid0)(4-
methoxyphenyl)pr0pan0ic acid
Pd/C (10%, 10 g) was added to a solution of (S)—benzyl ((tert-
butoxycarbonyl)amino)propanamido)-3 -(4-methoxyphenyl)propanoate (4.6 g, 10 mmol) in
MeOH (200 mL). The suspension was stirred under hydrogen atmosphere at room
temperature for 12 h. Pd/C was filtered off and washed with MeOH (50 mL). The filtrate and
washings were combined and concentrated to dryness to afford (S)((R)(tert-
Butoxycarbonylamino)propanamido)(4-methoxyphenyl)propanoic acid (4.1 g, ~100%
yield) as a white solid.
tert—Butyl ((R)-I-(((S)-I -(((S)cyclopentyl—I-((R)methyloxiranyl)-I -
0x0pr0panyl)amin0)(4-meth0xyphenyl)-I-0x0pr0panyl)amin0)-I—0x0pr0pan
yUcarbamate
HATU (3.0 g, 8 mmol) and DIPEA (4.45 mL, 30 mmol) were added to a solution
of ((R)—2-(tert-Butoxycarbonylamino)propanamido)(4-methoxyphenyl)propanoic
acid (2.1 g, 5.5 mmol) and crude aminocyclopentyl-l-((R)methyloxiran
yl)propan-l-one (TFA salt, 15 g, 5.5 mmol) in DMF (50 mL) at 0°C. The reaction mixture
was allowed to warm to room temperature and stirred for 1 h. The mixture was concentrated
and the e was purified by flash column chromatography on silica gel (EtOAc/hexane =
1 :5) to afford compound tert-Butyl ((R)(((S)-1 cyclopentyl((R)—2-methyloxiran-
2-yl)oxopropanyl)amino)(4-methoxyphenyl)— 1 -oxopropanyl)amino)
oxopropanyl)carbamate (2.3 g, 88% yield).
1H NMR (300 MHz, DMSO-d6): 5 8.20 (m, 1H), 7.93 (m, 1H), 7.09 (m, 2H), 6.80
(m, 2H), 4.49 (m, 1H), 4.33 (m, 1H), 3.90 (m, 1H), 3.71 (s, 3H), 3.20 (m, 1H), 2.90~3.10 (m,
2H), 1.70 (m, 1H), 1.50~2.00 (m, 8H), 1.40 (s, 3H), 1.00~1.20 (m, 4H), 0.95 (d, J = 6.6 Hz,
3H). LC-MS for C29H43N307, found 54424 [M-H]-.
Assays
Example 19 —Proteasome Subunit Assays
An ELISA-based que, the proteasome constitutive/immunoproteasome
subunit enzyme-linked immunosorbent (ProCISE) assay, was utilized for quantitative
assessment of subunit-specific activity as previously described in Parlati, et al. Blood (2009)
114:3439-3447. This assay was used to assess the inhibitory activity against each of LMP2,
LMP7, MECLl, [31, [32, and [35. Briefly, test compounds were ly diluted in DMSO at
100K concentration, then diluted to 10X in s hypotonic lysis . Lysate from the
human acute lymphoblastic leukemia cell line, MOLT-4, was treated for 1 hour at 25°C with
compound at a final 1X concentration. Treated cell lysate was then incubated with a
biotinylated proteasome -site binding probe for 2 hours at 25°C. Following this, lysate
was denatured in guanidine hydrochloride, and ts bound to probe were isolated with
streptavidin-conjugated sepharose beads. Individual subunits were probed with subunit-
specific primary antibodies, followed by HRP-conjugated secondary antibodies. A
chemiluminescent substrate was used to generate signal associated with HRP binding, which
was detected on a plate reader. Luminescent signal was normalized to protein t, then,
percent ty calculated relative to DMSO-treated controls to generate 1C50 curves.
_0mp0und MECLl I31 I35
1316 4293 435
0VOL
hr“Midi)”
UGMe
(ONX-0914)
109 5155 >250K 99,212 >250K 20,582
OangLNH/ O
I H o
= H
o o
Results for select compounds provided herein are shown in the following table:
Cmpd ProCISE betas ProCISE LMPZ ProCISE LMP7 Solubility
MOLT4 lysate Hu 1h MOLT4 lysate Hu 1h MOLT4 lysate Hu 1h pH 7
CONT: IC50(nM) CONT: IC50 (nM) CONT: 1C50 (nM) ( _/mL)
C-2003——— 0.7
——— 1.9
C-2005——— 735.3
C2006 17984 3443 NT
C2007 47798 21144 728.5
C-2008— \T 2331.1
C-2009— \T NT 162.8
C-2010 \T NT 300.5
C-2011 3415 \T 97.08 NT
C-2012 \T NT 3828.4
C-2013 358.72 \T 66.67 725.2
C-2014 372.34 \T 56.39 NT
02015 3035492 \T 3063.63 169.2
C-2016 279.16 \T 69.72 NT
C-2017 129.43 \T 3717 NT
02018 3492921 \T 1181.56 1293
CNN \T NT 3156
CNN \T NT 59.1
C-2021 37 \T 1891.13 102.8
C-2022 429.15 \T 194.61 84.7
C-2023 2690.25 \T 318.19 100.5
C-2024 \T NT 44.1
C-2025 \T NT 1442
C-2026 345313 \T 169.63 126.1
C-2027 3601.4 \T 617.59 753.1
02028 1163.98 \T 75.69 7757
C-2029 \T NT 1 7
C-2030 2127.26 \T 31474 2864
C-2031 26730.69 \T 1448.56 41.7
C-2032 4045.94 \T 451.59 172.1
C-2033 >250000 \T 46736.39 164.8
C-2034 >250000 471.02 04 55.5
C-2035 21.06 \T 1321 3.1
C-2036 4863.52 \T 130.28 2.1
C-2037 9632.93 \T 465.76 3.6
C-2038 2698.61 \T 286.46 1.8
Cmpd PI'OCISE betas ProCISE LMPZ ProCISE LMP7 Solubility
MOLT4 lysate Hu 1h MOLT4 lysate Hu 1h MOLT4 lysate Hu 1h pH 7
CONT: IC50 (nM) CONT: IC50 (nM) CONT: IC50 (nM) ( _/mL)
/////////////////// aaaaaaaaaaaaaaaaaaaaaaaaa 1.7
74.96 0.3
NT 65.9
620.95 1834.5
593.46 2382.9
NT 130.5
219.79 159.9
NT 10.7
68.74 0.3
48.64 1.4
45.78 0.8
67.05 6157.8
54.28 240.7
38.5 160.2
1.82 1259.3
74.98 122.1
17.61 1972.5
52.24 3725.8
57.36 0.8
539.02 45.4
70.97 2447.5
60.43 3014.8
NT 26.3
NT 56
NT 21.4
1245.72 138.68 143.9
910.47 156.83 120.9
/////S1’/////aaaaauaaaaa O\ NT 43.6
NT 61.6
NT 54.6
NT 26.6
NT 1019.1
£11 4766.89 NT
934.35 1463.1
512.78 1200
NT 995.7
NT 1915
NT 384.7
273.74 3456.3 86.7
109.3 5154.72 NT
517.46 4573.92 NT
NT 1164.51 1381.1
NT NT 1228.9
NT 2745.4 4408.6
NT 3478.43 1908.6
34.85 NT 69.4
ProCISE betas ProCISE LMPZ ProCISE LMP7 Solubility
MOLT4 lysate Hu 1h MOLT4 lysate Hu 1h MOLT4 lysate Hu 1h
CONT. IC50 (nM) CONT. IC50 (nM) CONT. IC50 (nM) (_/mL)(pH 7
_————
C—3016————
66393
03018
03019
NT = not tested
e 20 — 20S Proteasome Assays
Proteasome chymotrypsin-like, e-like, and trypsin-like activities for various
compounds provided herein were determined using succinyl-Leu-Leu-Val-Tyr-AMC (10
Amol/L), Z-Leu-Leu-Glu-AMC (10 Amol/L), and Boc-Leu-Arg-Arg-AMC (50 Amol/L),
respectively, with d human 2OS proteasome (2, 4, and 8.0 nmol/L, respectively) or HT-
29 cell lysate (0.125, 0.25, and 0.25 Ag protein/mL, respectively). Assay buffer consisted of
TE buffer [20 mmol/L Tris (pH 8.0), 0.5 mmol/L EDTA] with (208) or without (cell lysate)
0.03% SDS. Reactions were initiated by enzyme or lysate addition and monitored for AMC
product formation at 27jC with a plate-based spectofluorometer (Tecan). IC50 values were
determined based on the reaction ty measured between 60 and 75 min. See also Demo,
S. D. et al., Cancer Res. 2007, 67, 6383—6391.
Results for select compounds provided herein are shown in the ing
table:
LLVY i208 Hu 1h CONT: IC50 LLVY 0208 Hu 1h CONT: IC50
Structure
(nM) (nM)
WO 52127
LLVY i208 Hu 1h CONT: IC50 LLVY c208 Hu 1h CONT: IC50
Structure
(nM) (“ND
02034 19500 64400
C-2036 1380 5140
02037 6080
02024 2270 6030
02038 3550
02039 2520 3950
02040 4610
02041 1400 9800
02042 9450
02044 1604
02043 15100
02045 1290
02050
02051
02052
02054
02059
02060
02035
02046
02007
02008 1590
02010 1051
02079 0.235 0.0301
02080 00314
02006
02011
02012
02013
02056
03009 9890 87800
03010 1605 4080
03011 4550 3320
03012 4790 14500
03013 4050 15900
02018 12800
02020
02021 1220 99000
02027 2130
02028
02019
02042 9450
02043 15100
02050
02051
WO 52127
LLVY i208 Hu 1h CONT: IC50 LLVY c208 Hu 1h CONT: IC50
Structure
(nM) (“ND
02052
02054
02059
OTHER EMBODIMENTS
It is to be understood that while the disclosure is read in conjunction with the
ed description thereof, the foregoing description is intended to illustrate and not limit
the scope of the disclosure, which is defined by the scope of the appended claims. Other
aspects, advantages, and modifications are within the scope of the following claims.
Claims (28)
1. A nd having a structure selected from the group consisting of: , , O O NH NH O O O O O O O O HN HN N N H H O , O , O O H H H H O N N O N N N N H H O O O O O O , , , and , or a pharmaceutically acceptable salt f.
2. A ceutical composition comprising the compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
3. Use of the compound of claim 1 or the ition of claim 2 for the manufacture of a medicament for inhibiting immunoproteasome of a cell in a subject.
4. The use of claim 3, wherein the subject s from an autoimmune disease.
5. The use of claim 4, wherein the autoimmune disease is psoriasis, dermatitis, systemic scleroderma, sclerosis, Crohn’s disease, ulcerative colitis; respiratory distress syndrome, meningitis; encephalitis; uveitis; colitis; glomerulonephritis; eczema, asthma, chronic inflammation; atherosclerosis; leukocyte adhesion deficiency; rheumatoid arthritis; systemic lupus erythematosus (SLE); diabetes mellitus (e.g., Type I diabetes mellitus or insulin dependent diabetes mellitus); multiple sis; Reynaud’s syndrome; autoimmune thyroiditis; ic encephalomyelitis; Sjorgen’s syndrome; juvenile onset diabetes; tuberculosis, sarcoidosis, polymyositis, granulomatosis and vasculitis; ious anemia (Addison’s disease); diseases involving leukocyte diapedesis; central nervous system (CNS) inflammatory disorder; multiple organ injury syndrome; hemolytic anemia; myasthenia gravis; antigen-antibody complex mediated diseases; anti-glomerular basement ne disease; antiphospholipid syndrome; allergic neuritis; Graves’ disease; t-Eaton myasthenic syndrome; pemphigoid bullous; pemphigus; mune polyendocrinopathies; Reiter’s disease; stiff-man syndrome; Behçet disease; giant cell arteritis; immune complex nephritis; IgA nephropathy; IgM polyneuropathies; or autoimmune thrombocytopenia (ITP).
6. Use of the compound of claim 1 or the ition of claim 2 for the cture of a ment for the treatment of an immune-related disease.
7. The use of claim 6, wherein the -related disease is rheumatoid arthritis, lupus, inflammatory bowel disease, multiple sis, or Crohn’s disease.
8. Use of the compound of claim 1 or the composition of claim 2 for the manufacture of a medicament for the treatment of cancer.
9. The use of claim 8, wherein the cancer is prostate cancer.
10. Use of the compound of claim 1 or the composition of claim 2 for the cture of a medicament for the treatment of inflammation.
11. The compound of claim 1 having a structure selected from the group consisting of C-3004, C-3007, C-3014, C-3015, C-3016, C-3017, C-3018, and , or a ceutically acceptable salt thereof.
12. A compound of Formula (II) or a pharmaceutically acceptable salt thereof, (II) wherein: X is ed from O, S, NH, and N-C1-6alkyl; R2 and R3 are each independently selected from aryl, C1-6aralkyl, heteroaryl, and C1-6heteroaralkyl; R5 is selected from hydrogen, OH, C1-6aralkyl, and C1-6alkyl; R6 is heteroaryl, piperidinyl, piperazinyl, morpholinyl, a lactone, a lactam, or ; R8 is selected from hydrogen, C1-6alkyl, and C1-6aralkyl, wherein a C1-6alkyl, aryl, C1-6aralkyl, heteroaryl, and C1-6heteroaralkyl can optionally be substituted with a substituent selected from the group consisting of alkyl, alkenyl, alkynyl, a halogen, a hydroxyl, a carbonyl, a thiocarbonyl, an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a yl, a carbocyclyl, a heterocyclyl, an l, a heteroaralkyl, an aryl or heteroaryl.
13. The compound of claim 12, wherein R5 and R8 are each hydrogen.
14. The compound of claim 12 or claim 13, wherein X is O.
15. The compound of any one of claims 12 to 14, wherein R2 is selected from C1-6aralkyl and C1-6heteroaralkyl.
16. The nd of claim 15, wherein R2 is C1-6aralkyl.
17. The compound of any one of claims 12 to 16, wherein R3 is ed from C1-6aralkyl and C1-6heteroaralkyl.
18. The nd of claim 17, wherein R3 is C1-6aralkyl.
19. A compound having a structure selected from the group consisting of: , , , , , , and or a pharmaceutically acceptable salt thereof.
20. The compound of claim 19 having a structure selected from the group ting of C-3001, C-3002, C-3003, C-3005, C-3008, C-3009, , , C-3012, and C-3013, or a pharmaceutically acceptable salt thereof.
21. The compound of any one of claims 12 to 18, wherein R6 is heteroaryl.
22. The compound of any one of claims 12 to 18, wherein R6 is piperidinyl, piperazinyl, morpholinyl, a lactone, or a lactam.
23. The compound of any one of claims 12 to 18, n R6 is a lactam.
24. The compound of any one of claims 12 to 18, wherein R6 is .
25. Use of the compound of any one of claims 12 to 24 for the manufacture of a medicament for the treatment of a disease selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus (SLE), inflammatory bowel disease, multiple sclerosis, and s disease.
26. The compound of any one of claims 1, 11, 12 or 19 substantially as herein described with reference to any one or more of the es.
27. The composition of claim 2, substantially as herein described with reference to any one or more of the examples.
28. The use of any one of claims 3, 6, 8, 10, or 25, substantially as herein described with reference to any one or more of the examples.
Applications Claiming Priority (15)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201361786086P | 2013-03-14 | 2013-03-14 | |
US201361785608P | 2013-03-14 | 2013-03-14 | |
US61/786,086 | 2013-03-14 | ||
US61/785,608 | 2013-03-14 | ||
US201361847780P | 2013-07-18 | 2013-07-18 | |
US61/847,780 | 2013-07-18 | ||
US201361856847P | 2013-07-22 | 2013-07-22 | |
US61/856,847 | 2013-07-22 | ||
US201361883798P | 2013-09-27 | 2013-09-27 | |
US201361883843P | 2013-09-27 | 2013-09-27 | |
US61/883,843 | 2013-09-27 | ||
US61/883,798 | 2013-09-27 | ||
US201461941798P | 2014-02-19 | 2014-02-19 | |
US61/941,798 | 2014-02-19 | ||
PCT/US2014/026980 WO2014152127A1 (en) | 2013-03-14 | 2014-03-14 | Dipeptide and tripeptide epoxy ketone protease inhibitors |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ711794A NZ711794A (en) | 2020-12-18 |
NZ711794B2 true NZ711794B2 (en) | 2021-03-19 |
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU2019203282B2 (en) | Dipeptide and tripeptide epoxy ketone protease inhibitors | |
US11078233B2 (en) | Tripeptide epoxy ketone protease inhibitors | |
AU2007261345B2 (en) | Peptide epoxyketones for proteasome inhibition | |
IL238247A (en) | Crystalline salt and method for preparing crystalline citrate salt of n-{(2s)-2-[(morpholin-4-yl-acetyl)amino]-4-phenylbutanoyl}-l-leucyl-n-{(2s)-4-methyl-1-[(2r)-2-methyloxiran-2-yl]-1-oxopentan-2-yl}-l-phenylalaninamide | |
US8697646B2 (en) | Crystalline peptide epoxyketone immunoproteasome inhibitor | |
KR20110114566A (en) | New 4-amino-4-oxobutanoyl peptides as inhibitors of viral replication | |
US8609610B2 (en) | Inhibitors of the trypsin-like site of the proteasome and methods of use thereof | |
NZ711794B2 (en) | Dipeptide and tripeptide epoxy ketone protease inhibitors | |
NZ711715B2 (en) | Tripeptide epoxy ketone protease inhibitors |