ZA200300452B - N-[5-[[[5-alkyl-2-oxazolyl]methyl]thio]-2-thiazolyl] carboxamide inhibitors of cyclin dependent kinases. - Google Patents
N-[5-[[[5-alkyl-2-oxazolyl]methyl]thio]-2-thiazolyl] carboxamide inhibitors of cyclin dependent kinases. Download PDFInfo
- Publication number
- ZA200300452B ZA200300452B ZA200300452A ZA200300452A ZA200300452B ZA 200300452 B ZA200300452 B ZA 200300452B ZA 200300452 A ZA200300452 A ZA 200300452A ZA 200300452 A ZA200300452 A ZA 200300452A ZA 200300452 B ZA200300452 B ZA 200300452B
- Authority
- ZA
- South Africa
- Prior art keywords
- composition
- compound
- hydrochloride
- substance
- trifluoroacetate
- Prior art date
Links
- 125000000446 sulfanediyl group Chemical group *S* 0.000 title claims description 77
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 title claims description 24
- 102000003903 Cyclin-dependent kinases Human genes 0.000 title claims description 10
- 108090000266 Cyclin-dependent kinases Proteins 0.000 title claims description 10
- 108091007914 CDKs Proteins 0.000 title claims description 6
- 239000003112 inhibitor Substances 0.000 title description 6
- 125000003917 carbamoyl group Chemical class [H]N([H])C(*)=O 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 195
- 239000000203 mixture Substances 0.000 claims description 189
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 96
- 238000000034 method Methods 0.000 claims description 88
- 150000003839 salts Chemical class 0.000 claims description 84
- -1 dihydrochloride Chemical compound 0.000 claims description 82
- 239000000126 substance Substances 0.000 claims description 80
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 79
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 76
- 230000002401 inhibitory effect Effects 0.000 claims description 51
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 42
- 125000000217 alkyl group Chemical group 0.000 claims description 42
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 41
- 238000002360 preparation method Methods 0.000 claims description 41
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 40
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 40
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 40
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 39
- SXDBWCPKPHAZSM-UHFFFAOYSA-M bromate Inorganic materials [O-]Br(=O)=O SXDBWCPKPHAZSM-UHFFFAOYSA-M 0.000 claims description 39
- SXDBWCPKPHAZSM-UHFFFAOYSA-N bromic acid Chemical compound OBr(=O)=O SXDBWCPKPHAZSM-UHFFFAOYSA-N 0.000 claims description 39
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 39
- 229940095064 tartrate Drugs 0.000 claims description 39
- ICIWUVCWSCSTAQ-UHFFFAOYSA-N iodic acid Chemical class OI(=O)=O ICIWUVCWSCSTAQ-UHFFFAOYSA-N 0.000 claims description 38
- 241000894007 species Species 0.000 claims description 35
- 229910052739 hydrogen Inorganic materials 0.000 claims description 34
- 239000001257 hydrogen Substances 0.000 claims description 33
- 238000011282 treatment Methods 0.000 claims description 26
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 19
- 239000012453 solvate Substances 0.000 claims description 19
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 18
- 150000002431 hydrogen Chemical class 0.000 claims description 18
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 16
- 201000010099 disease Diseases 0.000 claims description 16
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 14
- 206010028980 Neoplasm Diseases 0.000 claims description 13
- JSPCTNUQYWIIOT-UHFFFAOYSA-N piperidine-1-carboxamide Chemical compound NC(=O)N1CCCCC1 JSPCTNUQYWIIOT-UHFFFAOYSA-N 0.000 claims description 11
- 230000002062 proliferating effect Effects 0.000 claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 10
- 201000011510 cancer Diseases 0.000 claims description 9
- 101100005789 Caenorhabditis elegans cdk-4 gene Proteins 0.000 claims description 8
- 102000001253 Protein Kinase Human genes 0.000 claims description 8
- 230000006907 apoptotic process Effects 0.000 claims description 8
- PNZXMIKHJXIPEK-UHFFFAOYSA-N cyclohexanecarboxamide Chemical compound NC(=O)C1CCCCC1 PNZXMIKHJXIPEK-UHFFFAOYSA-N 0.000 claims description 8
- 108060006633 protein kinase Proteins 0.000 claims description 8
- 101150012716 CDK1 gene Proteins 0.000 claims description 7
- 101100059559 Emericella nidulans (strain FGSC A4 / ATCC 38163 / CBS 112.46 / NRRL 194 / M139) nimX gene Proteins 0.000 claims description 7
- 101100273808 Xenopus laevis cdk1-b gene Proteins 0.000 claims description 7
- 206010003246 arthritis Diseases 0.000 claims description 6
- 101150073031 cdk2 gene Proteins 0.000 claims description 6
- 101150059448 cdk7 gene Proteins 0.000 claims description 6
- 238000002512 chemotherapy Methods 0.000 claims description 6
- 101150090188 Cdk8 gene Proteins 0.000 claims description 5
- 101150112625 SSN3 gene Proteins 0.000 claims description 5
- 101100150415 Schizosaccharomyces pombe (strain 972 / ATCC 24843) srb10 gene Proteins 0.000 claims description 5
- 208000022605 chemotherapy-induced alopecia Diseases 0.000 claims description 5
- 206010061218 Inflammation Diseases 0.000 claims description 4
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 4
- 239000002246 antineoplastic agent Substances 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 230000004054 inflammatory process Effects 0.000 claims description 4
- 101150053721 Cdk5 gene Proteins 0.000 claims description 3
- 102100028701 General vesicular transport factor p115 Human genes 0.000 claims description 3
- 101000767151 Homo sapiens General vesicular transport factor p115 Proteins 0.000 claims description 3
- 201000002364 leukopenia Diseases 0.000 claims description 3
- 231100001022 leukopenia Toxicity 0.000 claims description 3
- 206010043554 thrombocytopenia Diseases 0.000 claims description 3
- 238000002054 transplantation Methods 0.000 claims description 3
- 230000023603 positive regulation of transcription initiation, DNA-dependent Effects 0.000 claims description 2
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 21
- QYRFJLLXPINATB-UHFFFAOYSA-N hydron;2,4,5,6-tetrafluorobenzene-1,3-diamine;dichloride Chemical compound Cl.Cl.NC1=C(F)C(N)=C(F)C(F)=C1F QYRFJLLXPINATB-UHFFFAOYSA-N 0.000 claims 6
- 208000035475 disorder Diseases 0.000 claims 2
- MFPWMKHFMBARRG-HAQNSBGRSA-N chembl49618 Chemical compound O1C(C(C)(C)C)=CN=C1CSC(S1)=CN=C1NC(=O)[C@@H]1CC[C@@H](N)CC1 MFPWMKHFMBARRG-HAQNSBGRSA-N 0.000 claims 1
- JJJVIPYJUNRQTI-UHFFFAOYSA-N n-[5-[(5-tert-butyl-1,3-oxazol-2-yl)methylsulfanyl]-1,3-thiazol-2-yl]-1-propan-2-ylpiperidine-4-carboxamide Chemical compound C1CN(C(C)C)CCC1C(=O)NC(S1)=NC=C1SCC1=NC=C(C(C)(C)C)O1 JJJVIPYJUNRQTI-UHFFFAOYSA-N 0.000 claims 1
- 238000002560 therapeutic procedure Methods 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 99
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 93
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 91
- 239000002904 solvent Substances 0.000 description 52
- 238000006243 chemical reaction Methods 0.000 description 44
- 239000007787 solid Substances 0.000 description 42
- 239000000243 solution Substances 0.000 description 34
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 33
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 31
- 239000003153 chemical reaction reagent Substances 0.000 description 31
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- 239000002253 acid Substances 0.000 description 30
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 28
- 239000011541 reaction mixture Substances 0.000 description 25
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- 150000008282 halocarbons Chemical class 0.000 description 20
- 150000002430 hydrocarbons Chemical class 0.000 description 20
- 229930195733 hydrocarbon Natural products 0.000 description 19
- 150000002170 ethers Chemical class 0.000 description 18
- 238000012544 monitoring process Methods 0.000 description 18
- 239000002244 precipitate Substances 0.000 description 18
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 17
- 235000011007 phosphoric acid Nutrition 0.000 description 17
- 239000011877 solvent mixture Substances 0.000 description 17
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 16
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 16
- 125000003118 aryl group Chemical group 0.000 description 16
- 239000000284 extract Substances 0.000 description 16
- 125000001475 halogen functional group Chemical group 0.000 description 16
- 150000001408 amides Chemical class 0.000 description 15
- 239000002585 base Substances 0.000 description 15
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 14
- VKYKSIONXSXAKP-UHFFFAOYSA-N hexamethylenetetramine Chemical compound C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 description 14
- 238000004128 high performance liquid chromatography Methods 0.000 description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 12
- 150000001298 alcohols Chemical class 0.000 description 11
- 238000004458 analytical method Methods 0.000 description 11
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 11
- 239000000741 silica gel Substances 0.000 description 11
- 229910002027 silica gel Inorganic materials 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 10
- 150000002148 esters Chemical class 0.000 description 10
- 229910052736 halogen Inorganic materials 0.000 description 10
- 150000002367 halogens Chemical class 0.000 description 10
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 10
- 229920006395 saturated elastomer Polymers 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 150000001540 azides Chemical class 0.000 description 9
- 230000008878 coupling Effects 0.000 description 9
- 238000010168 coupling process Methods 0.000 description 9
- 238000005859 coupling reaction Methods 0.000 description 9
- 125000001072 heteroaryl group Chemical group 0.000 description 9
- 150000002576 ketones Chemical class 0.000 description 9
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 8
- 150000001412 amines Chemical group 0.000 description 8
- 150000001718 carbodiimides Chemical class 0.000 description 8
- 229910052751 metal Inorganic materials 0.000 description 8
- 239000002184 metal Substances 0.000 description 8
- 125000006239 protecting group Chemical group 0.000 description 8
- 239000002002 slurry Substances 0.000 description 8
- 229910052717 sulfur Inorganic materials 0.000 description 8
- 239000004312 hexamethylene tetramine Substances 0.000 description 7
- 235000010299 hexamethylene tetramine Nutrition 0.000 description 7
- 230000008569 process Effects 0.000 description 7
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 6
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 6
- 150000007513 acids Chemical class 0.000 description 6
- 230000037396 body weight Effects 0.000 description 6
- YSHOWEKUVWPFNR-UHFFFAOYSA-N burgess reagent Chemical compound CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC YSHOWEKUVWPFNR-UHFFFAOYSA-N 0.000 description 6
- 239000013058 crude material Substances 0.000 description 6
- 125000004122 cyclic group Chemical group 0.000 description 6
- NZNMSOFKMUBTKW-UHFFFAOYSA-N cyclohexanecarboxylic acid Chemical compound OC(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-N 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 238000003818 flash chromatography Methods 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 6
- 239000011593 sulfur Substances 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 6
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 5
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 5
- OUSFTKFNBAZUKL-UHFFFAOYSA-N N-(5-{[(5-tert-butyl-1,3-oxazol-2-yl)methyl]sulfanyl}-1,3-thiazol-2-yl)piperidine-4-carboxamide Chemical compound O1C(C(C)(C)C)=CN=C1CSC(S1)=CN=C1NC(=O)C1CCNCC1 OUSFTKFNBAZUKL-UHFFFAOYSA-N 0.000 description 5
- 125000003545 alkoxy group Chemical group 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 5
- RAIPHJJURHTUIC-UHFFFAOYSA-N 1,3-thiazol-2-amine Chemical class NC1=NC=CS1 RAIPHJJURHTUIC-UHFFFAOYSA-N 0.000 description 4
- DETXZQGDWUJKMO-UHFFFAOYSA-N 2-hydroxymethanesulfonic acid Chemical compound OCS(O)(=O)=O DETXZQGDWUJKMO-UHFFFAOYSA-N 0.000 description 4
- 208000024827 Alzheimer disease Diseases 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 239000005909 Kieselgur Substances 0.000 description 4
- 108091000080 Phosphotransferase Proteins 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 4
- 125000002252 acyl group Chemical class 0.000 description 4
- UMGDCJDMYOKAJW-UHFFFAOYSA-N aminothiocarboxamide Natural products NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 4
- 239000007822 coupling agent Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000001530 fumaric acid Substances 0.000 description 4
- 150000004820 halides Chemical class 0.000 description 4
- 229910052744 lithium Inorganic materials 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 229910052763 palladium Inorganic materials 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- 102000020233 phosphotransferase Human genes 0.000 description 4
- 229910052700 potassium Inorganic materials 0.000 description 4
- 125000001453 quaternary ammonium group Chemical group 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 4
- 125000000335 thiazolyl group Chemical group 0.000 description 4
- 150000003585 thioureas Chemical class 0.000 description 4
- 229910052723 transition metal Inorganic materials 0.000 description 4
- 150000003624 transition metals Chemical class 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
- BPDKBTHOMQPYMF-UHFFFAOYSA-N 1-cyclopropylpiperidin-1-ium-4-carboxylate Chemical compound C1CC(C(=O)O)CCN1C1CC1 BPDKBTHOMQPYMF-UHFFFAOYSA-N 0.000 description 3
- QDOQCOOUTPQMKW-UHFFFAOYSA-N 1-propan-2-ylpiperidine-4-carboxylic acid Chemical compound CC(C)N1CCC(C(O)=O)CC1 QDOQCOOUTPQMKW-UHFFFAOYSA-N 0.000 description 3
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical class [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 3
- 125000004414 alkyl thio group Chemical group 0.000 description 3
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- VZFUCHSFHOYXIS-UHFFFAOYSA-N cycloheptane carboxylic acid Natural products OC(=O)C1CCCCCC1 VZFUCHSFHOYXIS-UHFFFAOYSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- LUVKHTGJKFFLMR-UHFFFAOYSA-N ethyl 1-propan-2-ylpiperidine-4-carboxylate Chemical compound CCOC(=O)C1CCN(C(C)C)CC1 LUVKHTGJKFFLMR-UHFFFAOYSA-N 0.000 description 3
- 239000012458 free base Chemical group 0.000 description 3
- 235000011167 hydrochloric acid Nutrition 0.000 description 3
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 238000002955 isolation Methods 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 229960001592 paclitaxel Drugs 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 239000001384 succinic acid Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- VHKIEYIESYMHPT-UHFFFAOYSA-N triethyl(methoxycarbonylsulfamoyl)azanium;hydroxide Chemical compound [OH-].CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC VHKIEYIESYMHPT-UHFFFAOYSA-N 0.000 description 3
- 241000701447 unidentified baculovirus Species 0.000 description 3
- XJLSEXAGTJCILF-RXMQYKEDSA-N (R)-nipecotic acid zwitterion Chemical compound OC(=O)[C@@H]1CCCNC1 XJLSEXAGTJCILF-RXMQYKEDSA-N 0.000 description 2
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- NXILIHONWRXHFA-UHFFFAOYSA-N 1-[(2-methylpropan-2-yl)oxycarbonyl]piperidine-3-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCCC(C(O)=O)C1 NXILIHONWRXHFA-UHFFFAOYSA-N 0.000 description 2
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 2
- UNUCZJRZFFSFFA-UHFFFAOYSA-N 5-[(5-tert-butyl-1,3-oxazol-2-yl)methylsulfanyl]-1,3-thiazol-2-amine Chemical compound O1C(C(C)(C)C)=CN=C1CSC1=CN=C(N)S1 UNUCZJRZFFSFFA-UHFFFAOYSA-N 0.000 description 2
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- 208000032467 Aplastic anaemia Diseases 0.000 description 2
- 239000004475 Arginine Substances 0.000 description 2
- 201000001320 Atherosclerosis Diseases 0.000 description 2
- 108010006654 Bleomycin Proteins 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- 101100314454 Caenorhabditis elegans tra-1 gene Proteins 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 201000009030 Carcinoma Diseases 0.000 description 2
- 102100025064 Cellular tumor antigen p53 Human genes 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- 108010058546 Cyclin D1 Proteins 0.000 description 2
- MNQZXJOMYWMBOU-VKHMYHEASA-N D-glyceraldehyde Chemical compound OC[C@@H](O)C=O MNQZXJOMYWMBOU-VKHMYHEASA-N 0.000 description 2
- FEWJPZIEWOKRBE-LWMBPPNESA-L D-tartrate(2-) Chemical class [O-]C(=O)[C@@H](O)[C@H](O)C([O-])=O FEWJPZIEWOKRBE-LWMBPPNESA-L 0.000 description 2
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- 102100024165 G1/S-specific cyclin-D1 Human genes 0.000 description 2
- 206010018364 Glomerulonephritis Diseases 0.000 description 2
- 108010033040 Histones Proteins 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N L-(-)-Malic acid Natural products OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 2
- 239000004472 Lysine Substances 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 229930012538 Paclitaxel Natural products 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 201000004681 Psoriasis Diseases 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 2
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 2
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 2
- 150000008065 acid anhydrides Chemical class 0.000 description 2
- 125000004423 acyloxy group Chemical group 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 150000001342 alkaline earth metals Chemical class 0.000 description 2
- 150000004703 alkoxides Chemical class 0.000 description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 2
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 239000001099 ammonium carbonate Substances 0.000 description 2
- 235000012501 ammonium carbonate Nutrition 0.000 description 2
- 239000000908 ammonium hydroxide Substances 0.000 description 2
- 239000000010 aprotic solvent Substances 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 125000003289 ascorbyl group Chemical class [H]O[C@@]([H])(C([H])([H])O*)[C@@]1([H])OC(=O)C(O*)=C1O* 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- ZUDYPQRUOYEARG-UHFFFAOYSA-L barium(2+);dihydroxide;octahydrate Chemical compound O.O.O.O.O.O.O.O.[OH-].[OH-].[Ba+2] ZUDYPQRUOYEARG-UHFFFAOYSA-L 0.000 description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 2
- 229940092714 benzenesulfonic acid Drugs 0.000 description 2
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 2
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical class N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 2
- 150000001642 boronic acid derivatives Chemical class 0.000 description 2
- 210000000481 breast Anatomy 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 229910052792 caesium Inorganic materials 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 239000000824 cytostatic agent Substances 0.000 description 2
- 229940127089 cytotoxic agent Drugs 0.000 description 2
- 239000002254 cytotoxic agent Substances 0.000 description 2
- 231100000599 cytotoxic agent Toxicity 0.000 description 2
- 229960001270 d- tartaric acid Drugs 0.000 description 2
- BEFZAMRWPCMWFJ-UHFFFAOYSA-N desoxyepothilone A Natural products O1C(=O)CC(O)C(C)(C)C(=O)C(C)C(O)C(C)CCCC=CCC1C(C)=CC1=CSC(C)=N1 BEFZAMRWPCMWFJ-UHFFFAOYSA-N 0.000 description 2
- XOZIUKBZLSUILX-UHFFFAOYSA-N desoxyepothilone B Natural products O1C(=O)CC(O)C(C)(C)C(=O)C(C)C(O)C(C)CCCC(C)=CCC1C(C)=CC1=CSC(C)=N1 XOZIUKBZLSUILX-UHFFFAOYSA-N 0.000 description 2
- RAABOESOVLLHRU-UHFFFAOYSA-N diazene Chemical compound N=N RAABOESOVLLHRU-UHFFFAOYSA-N 0.000 description 2
- 229910000071 diazene Inorganic materials 0.000 description 2
- HESCAJZNRMSMJG-HGYUPSKWSA-N epothilone A Natural products O=C1[C@H](C)[C@H](O)[C@H](C)CCC[C@H]2O[C@H]2C[C@@H](/C(=C\c2nc(C)sc2)/C)OC(=O)C[C@H](O)C1(C)C HESCAJZNRMSMJG-HGYUPSKWSA-N 0.000 description 2
- HESCAJZNRMSMJG-KKQRBIROSA-N epothilone A Chemical class C/C([C@@H]1C[C@@H]2O[C@@H]2CCC[C@@H]([C@@H]([C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1)O)C)=C\C1=CSC(C)=N1 HESCAJZNRMSMJG-KKQRBIROSA-N 0.000 description 2
- BEFZAMRWPCMWFJ-QJKGZULSSA-N epothilone C Chemical compound O1C(=O)C[C@H](O)C(C)(C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)CCC\C=C/C[C@H]1C(\C)=C\C1=CSC(C)=N1 BEFZAMRWPCMWFJ-QJKGZULSSA-N 0.000 description 2
- XOZIUKBZLSUILX-GIQCAXHBSA-N epothilone D Chemical compound O1C(=O)C[C@H](O)C(C)(C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)CCC\C(C)=C/C[C@H]1C(\C)=C\C1=CSC(C)=N1 XOZIUKBZLSUILX-GIQCAXHBSA-N 0.000 description 2
- RUJPPJYDHHAEEK-UHFFFAOYSA-N ethyl piperidine-4-carboxylate Chemical compound CCOC(=O)C1CCNCC1 RUJPPJYDHHAEEK-UHFFFAOYSA-N 0.000 description 2
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 201000005787 hematologic cancer Diseases 0.000 description 2
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 description 2
- 238000010348 incorporation Methods 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- FEWJPZIEWOKRBE-LWMBPPNESA-N levotartaric acid Chemical class OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 235000011090 malic acid Nutrition 0.000 description 2
- 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 2
- 229960001924 melphalan Drugs 0.000 description 2
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 2
- 229910000000 metal hydroxide Inorganic materials 0.000 description 2
- 150000004692 metal hydroxides Chemical class 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 208000015122 neurodegenerative disease Diseases 0.000 description 2
- 150000002823 nitrates Chemical class 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 210000001672 ovary Anatomy 0.000 description 2
- 125000002971 oxazolyl group Chemical group 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 235000021317 phosphate Nutrition 0.000 description 2
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 2
- UXCDUFKZSUBXGM-UHFFFAOYSA-N phosphoric tribromide Chemical compound BrP(Br)(Br)=O UXCDUFKZSUBXGM-UHFFFAOYSA-N 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- YJGVMLPVUAXIQN-XVVDYKMHSA-N podophyllotoxin Chemical compound COC1=C(OC)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@H](O)[C@@H]3[C@@H]2C(OC3)=O)=C1 YJGVMLPVUAXIQN-XVVDYKMHSA-N 0.000 description 2
- 229920000137 polyphosphoric acid Polymers 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- JCBJVAJGLKENNC-UHFFFAOYSA-M potassium ethyl xanthate Chemical compound [K+].CCOC([S-])=S JCBJVAJGLKENNC-UHFFFAOYSA-M 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 210000002307 prostate Anatomy 0.000 description 2
- KOUKXHPPRFNWPP-UHFFFAOYSA-N pyrazine-2,5-dicarboxylic acid;hydrate Chemical compound O.OC(=O)C1=CN=C(C(O)=O)C=N1 KOUKXHPPRFNWPP-UHFFFAOYSA-N 0.000 description 2
- 150000003222 pyridines Chemical class 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 150000003873 salicylate salts Chemical class 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 2
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- 150000003573 thiols Chemical class 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 2
- AADVCYNFEREWOS-UHFFFAOYSA-N (+)-DDM Natural products C=CC=CC(C)C(OC(N)=O)C(C)C(O)C(C)CC(C)=CC(C)C(O)C(C)C=CC(O)CC1OC(=O)C(C)C(O)C1C AADVCYNFEREWOS-UHFFFAOYSA-N 0.000 description 1
- BZMMRNKDONDVIB-UHFFFAOYSA-N (1-ethoxycyclopropyl)oxy-trimethylsilane Chemical compound CCOC1(O[Si](C)(C)C)CC1 BZMMRNKDONDVIB-UHFFFAOYSA-N 0.000 description 1
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- MCEHFIXEKNKSRW-LBPRGKRZSA-N (2s)-2-[[3,5-dichloro-4-[(2,4-diaminopteridin-6-yl)methyl-methylamino]benzoyl]amino]pentanedioic acid Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=C(Cl)C=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1Cl MCEHFIXEKNKSRW-LBPRGKRZSA-N 0.000 description 1
- QIVUCLWGARAQIO-OLIXTKCUSA-N (3s)-n-[(3s,5s,6r)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl]-2-oxospiro[1h-pyrrolo[2,3-b]pyridine-3,6'-5,7-dihydrocyclopenta[b]pyridine]-3'-carboxamide Chemical compound C1([C@H]2[C@H](N(C(=O)[C@@H](NC(=O)C=3C=C4C[C@]5(CC4=NC=3)C3=CC=CN=C3NC5=O)C2)CC(F)(F)F)C)=C(F)C=CC(F)=C1F QIVUCLWGARAQIO-OLIXTKCUSA-N 0.000 description 1
- NUSVDASTCPBUIP-UHFFFAOYSA-N (5-bromo-1,3-thiazol-2-yl)azanium;bromide Chemical compound [Br-].BrC1=C[NH2+]C(=N)S1 NUSVDASTCPBUIP-UHFFFAOYSA-N 0.000 description 1
- UCGJDVMPLINVCQ-UHFFFAOYSA-N (5-tert-butyl-1,3-oxazol-2-yl)methyl carbamimidothioate;hydrochloride Chemical compound Cl.CC(C)(C)C1=CN=C(CSC(N)=N)O1 UCGJDVMPLINVCQ-UHFFFAOYSA-N 0.000 description 1
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 1
- LKJPYSCBVHEWIU-KRWDZBQOSA-N (R)-bicalutamide Chemical compound C([C@@](O)(C)C(=O)NC=1C=C(C(C#N)=CC=1)C(F)(F)F)S(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-KRWDZBQOSA-N 0.000 description 1
- 102100025573 1-alkyl-2-acetylglycerophosphocholine esterase Human genes 0.000 description 1
- SXFWKZNLYYRHMK-UHFFFAOYSA-N 1h-indolo[7,6-f]quinoline Chemical class C1=CC=C2C3=C(NC=C4)C4=CC=C3C=CC2=N1 SXFWKZNLYYRHMK-UHFFFAOYSA-N 0.000 description 1
- OBTZDIRUQWFRFZ-UHFFFAOYSA-N 2-(5-methylfuran-2-yl)-n-(4-methylphenyl)quinoline-4-carboxamide Chemical compound O1C(C)=CC=C1C1=CC(C(=O)NC=2C=CC(C)=CC=2)=C(C=CC=C2)C2=N1 OBTZDIRUQWFRFZ-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- SCVJRXQHFJXZFZ-KVQBGUIXSA-N 2-amino-9-[(2r,4s,5r)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-3h-purine-6-thione Chemical compound C1=2NC(N)=NC(=S)C=2N=CN1[C@H]1C[C@H](O)[C@@H](CO)O1 SCVJRXQHFJXZFZ-KVQBGUIXSA-N 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- NDMPLJNOPCLANR-UHFFFAOYSA-N 3,4-dihydroxy-15-(4-hydroxy-18-methoxycarbonyl-5,18-seco-ibogamin-18-yl)-16-methoxy-1-methyl-6,7-didehydro-aspidospermidine-3-carboxylic acid methyl ester Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 NDMPLJNOPCLANR-UHFFFAOYSA-N 0.000 description 1
- TVZGACDUOSZQKY-LBPRGKRZSA-N 4-aminofolic acid Chemical compound C1=NC2=NC(N)=NC(N)=C2N=C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 TVZGACDUOSZQKY-LBPRGKRZSA-N 0.000 description 1
- DRNGLYHKYPNTEA-UHFFFAOYSA-N 4-azaniumylcyclohexane-1-carboxylate Chemical compound NC1CCC(C(O)=O)CC1 DRNGLYHKYPNTEA-UHFFFAOYSA-N 0.000 description 1
- ARHCLXWELPFVFQ-UHFFFAOYSA-N 5-bromo-1,3-thiazol-2-amine Chemical compound NC1=NC=C(Br)S1 ARHCLXWELPFVFQ-UHFFFAOYSA-N 0.000 description 1
- SUBDBMMJDZJVOS-UHFFFAOYSA-N 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-UHFFFAOYSA-N 0.000 description 1
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- 206010065040 AIDS dementia complex Diseases 0.000 description 1
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 1
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 1
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 1
- 208000036762 Acute promyelocytic leukaemia Diseases 0.000 description 1
- 102400000068 Angiostatin Human genes 0.000 description 1
- 108010079709 Angiostatins Proteins 0.000 description 1
- 108010024976 Asparaginase Proteins 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 208000003950 B-cell lymphoma Diseases 0.000 description 1
- 101710121713 B1 kinase Proteins 0.000 description 1
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 1
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 1
- 206010058019 Cancer Pain Diseases 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical group ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 1
- 101150008206 Cilk1 gene Proteins 0.000 description 1
- 102000016736 Cyclin Human genes 0.000 description 1
- 108050006400 Cyclin Proteins 0.000 description 1
- 102000003910 Cyclin D Human genes 0.000 description 1
- 108090000259 Cyclin D Proteins 0.000 description 1
- 102000013701 Cyclin-Dependent Kinase 4 Human genes 0.000 description 1
- 108010025464 Cyclin-Dependent Kinase 4 Proteins 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- 201000003883 Cystic fibrosis Diseases 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- AADVCYNFEREWOS-OBRABYBLSA-N Discodermolide Chemical compound C=C\C=C/[C@H](C)[C@H](OC(N)=O)[C@@H](C)[C@H](O)[C@@H](C)C\C(C)=C/[C@H](C)[C@@H](O)[C@@H](C)\C=C/[C@@H](O)C[C@@H]1OC(=O)[C@H](C)[C@@H](O)[C@H]1C AADVCYNFEREWOS-OBRABYBLSA-N 0.000 description 1
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 1
- 102100031480 Dual specificity mitogen-activated protein kinase kinase 1 Human genes 0.000 description 1
- 101710146526 Dual specificity mitogen-activated protein kinase kinase 1 Proteins 0.000 description 1
- 102000001301 EGF receptor Human genes 0.000 description 1
- 108060006698 EGF receptor Proteins 0.000 description 1
- 102400001047 Endostatin Human genes 0.000 description 1
- 108010079505 Endostatins Proteins 0.000 description 1
- 206010014824 Endotoxic shock Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- QXRSDHAAWVKZLJ-OXZHEXMSSA-N Epothilone B Natural products O=C1[C@H](C)[C@H](O)[C@@H](C)CCC[C@@]2(C)O[C@H]2C[C@@H](/C(=C\c2nc(C)sc2)/C)OC(=O)C[C@H](O)C1(C)C QXRSDHAAWVKZLJ-OXZHEXMSSA-N 0.000 description 1
- BEFZAMRWPCMWFJ-JRBBLYSQSA-N Epothilone C Natural products O=C1[C@H](C)[C@@H](O)[C@@H](C)CCC/C=C\C[C@@H](/C(=C\c2nc(C)sc2)/C)OC(=O)C[C@H](O)C1(C)C BEFZAMRWPCMWFJ-JRBBLYSQSA-N 0.000 description 1
- XOZIUKBZLSUILX-SDMHVBBESA-N Epothilone D Natural products O=C1[C@H](C)[C@@H](O)[C@@H](C)CCC/C(/C)=C/C[C@@H](/C(=C\c2nc(C)sc2)/C)OC(=O)C[C@H](O)C1(C)C XOZIUKBZLSUILX-SDMHVBBESA-N 0.000 description 1
- 201000006107 Familial adenomatous polyposis Diseases 0.000 description 1
- 201000008808 Fibrosarcoma Diseases 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- 206010017533 Fungal infection Diseases 0.000 description 1
- 102400001301 Gasdermin-B, C-terminal Human genes 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- 101000713585 Homo sapiens Tubulin beta-4A chain Proteins 0.000 description 1
- 241000701044 Human gammaherpesvirus 4 Species 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 102000015696 Interleukins Human genes 0.000 description 1
- 108010063738 Interleukins Proteins 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- 108010000817 Leuprolide Proteins 0.000 description 1
- JXLYSJRDGCGARV-PJXZDTQASA-N Leurosidine 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-PJXZDTQASA-N 0.000 description 1
- LPGWZGMPDKDHEP-HLTPFJCJSA-N Leurosine Chemical compound C([C@]1([C@@H]2O1)CC)N(CCC=1C3=CC=CC=C3NC=11)C[C@H]2C[C@]1(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 LPGWZGMPDKDHEP-HLTPFJCJSA-N 0.000 description 1
- LPGWZGMPDKDHEP-GKWAKPNHSA-N Leurosine 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@]6(CC)O[C@@H]6[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C LPGWZGMPDKDHEP-GKWAKPNHSA-N 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 108091054455 MAP kinase family Proteins 0.000 description 1
- 102000043136 MAP kinase family Human genes 0.000 description 1
- 229930192392 Mitomycin Natural products 0.000 description 1
- HRHKSTOGXBBQCB-UHFFFAOYSA-N Mitomycin E Natural products O=C1C(N)=C(C)C(=O)C2=C1C(COC(N)=O)C1(OC)C3N(C)C3CN12 HRHKSTOGXBBQCB-UHFFFAOYSA-N 0.000 description 1
- 101100268648 Mus musculus Abl1 gene Proteins 0.000 description 1
- 208000031888 Mycoses Diseases 0.000 description 1
- 201000003793 Myelodysplastic syndrome Diseases 0.000 description 1
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 1
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 1
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 208000009905 Neurofibromatoses Diseases 0.000 description 1
- 102100026379 Neurofibromin Human genes 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 102000003993 Phosphatidylinositol 3-kinases Human genes 0.000 description 1
- 108090000430 Phosphatidylinositol 3-kinases Proteins 0.000 description 1
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 1
- 102000003923 Protein Kinase C Human genes 0.000 description 1
- 108090000315 Protein Kinase C Proteins 0.000 description 1
- 206010063837 Reperfusion injury Diseases 0.000 description 1
- 208000007014 Retinitis pigmentosa Diseases 0.000 description 1
- 201000000582 Retinoblastoma Diseases 0.000 description 1
- 108050002653 Retinoblastoma protein Proteins 0.000 description 1
- 201000010208 Seminoma Diseases 0.000 description 1
- 206010040070 Septic Shock Diseases 0.000 description 1
- 241000710960 Sindbis virus Species 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 229940123237 Taxane Drugs 0.000 description 1
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 description 1
- 102000004357 Transferases Human genes 0.000 description 1
- 108090000992 Transferases Proteins 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 102100036788 Tubulin beta-4A chain Human genes 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 1
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 1
- 241000863480 Vinca Species 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- JXLYSJRDGCGARV-KSNABSRWSA-N ac1l29ym 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-KSNABSRWSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 125000005189 alkyl hydroxy group Chemical group 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 229960000473 altretamine Drugs 0.000 description 1
- 229940037003 alum Drugs 0.000 description 1
- 229960003896 aminopterin Drugs 0.000 description 1
- 229950003476 aminothiazole Drugs 0.000 description 1
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 239000004037 angiogenesis inhibitor Substances 0.000 description 1
- 238000002399 angioplasty Methods 0.000 description 1
- 229940045799 anthracyclines and related substance Drugs 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000003388 anti-hormonal effect Effects 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 238000011394 anticancer treatment Methods 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 229940045696 antineoplastic drug podophyllotoxin derivative Drugs 0.000 description 1
- 229940045988 antineoplastic drug protein kinase inhibitors Drugs 0.000 description 1
- 230000005775 apoptotic pathway Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 239000003886 aromatase inhibitor Substances 0.000 description 1
- 229940046844 aromatase inhibitors Drugs 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- FZCSTZYAHCUGEM-UHFFFAOYSA-N aspergillomarasmine B Natural products OC(=O)CNC(C(O)=O)CNC(C(O)=O)CC(O)=O FZCSTZYAHCUGEM-UHFFFAOYSA-N 0.000 description 1
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 1
- 229960000997 bicalutamide Drugs 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 229960001561 bleomycin Drugs 0.000 description 1
- 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 1
- 229940127093 camptothecin Drugs 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 150000003857 carboxamides Chemical class 0.000 description 1
- XREUEWVEMYWFFA-CSKJXFQVSA-N carminomycin 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=C(O)C=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XREUEWVEMYWFFA-CSKJXFQVSA-N 0.000 description 1
- 229930188550 carminomycin Natural products 0.000 description 1
- XREUEWVEMYWFFA-UHFFFAOYSA-N carminomycin I Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=C(O)C=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XREUEWVEMYWFFA-UHFFFAOYSA-N 0.000 description 1
- 229950001725 carubicin Drugs 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 208000025434 cerebellar degeneration Diseases 0.000 description 1
- 210000003679 cervix uteri Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004296 chiral HPLC Methods 0.000 description 1
- 238000010568 chiral column chromatography Methods 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- WRJWRGBVPUUDLA-UHFFFAOYSA-N chlorosulfonyl isocyanate Chemical compound ClS(=O)(=O)N=C=O WRJWRGBVPUUDLA-UHFFFAOYSA-N 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 208000029664 classic familial adenomatous polyposis Diseases 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 230000001351 cycling effect Effects 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 229960000684 cytarabine Drugs 0.000 description 1
- 230000001085 cytostatic effect Effects 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 229960003901 dacarbazine Drugs 0.000 description 1
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 1
- 229960000975 daunorubicin Drugs 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- ZFTFAPZRGNKQPU-UHFFFAOYSA-N dicarbonic acid Chemical compound OC(=O)OC(O)=O ZFTFAPZRGNKQPU-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 1
- 239000003534 dna topoisomerase inhibitor Substances 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- YJGVMLPVUAXIQN-UHFFFAOYSA-N epipodophyllotoxin Natural products COC1=C(OC)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YJGVMLPVUAXIQN-UHFFFAOYSA-N 0.000 description 1
- 229930013356 epothilone Natural products 0.000 description 1
- QXRSDHAAWVKZLJ-PVYNADRNSA-N epothilone B Chemical compound C/C([C@@H]1C[C@@H]2O[C@]2(C)CCC[C@@H]([C@@H]([C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1)O)C)=C\C1=CSC(C)=N1 QXRSDHAAWVKZLJ-PVYNADRNSA-N 0.000 description 1
- FRPJXPJMRWBBIH-RBRWEJTLSA-N estramustine Chemical compound ClCCN(CCCl)C(=O)OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 FRPJXPJMRWBBIH-RBRWEJTLSA-N 0.000 description 1
- 229960001842 estramustine Drugs 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229960005420 etoposide Drugs 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
- 229960000752 etoposide phosphate Drugs 0.000 description 1
- LIQODXNTTZAGID-OCBXBXKTSA-N etoposide phosphate Chemical compound COC1=C(OP(O)(O)=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 LIQODXNTTZAGID-OCBXBXKTSA-N 0.000 description 1
- 125000004030 farnesyl group Chemical group [H]C([*])([H])C([H])=C(C([H])([H])[H])C([H])([H])C([H])([H])C([H])=C(C([H])([H])[H])C([H])([H])C([H])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- MKXKFYHWDHIYRV-UHFFFAOYSA-N flutamide Chemical compound CC(C)C(=O)NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 MKXKFYHWDHIYRV-UHFFFAOYSA-N 0.000 description 1
- 229960002074 flutamide Drugs 0.000 description 1
- 201000003444 follicular lymphoma Diseases 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 239000000499 gel Substances 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
- 229960005277 gemcitabine Drugs 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 239000003966 growth inhibitor Substances 0.000 description 1
- 230000003394 haemopoietic effect Effects 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 208000014951 hematologic disease Diseases 0.000 description 1
- LZWPOLSJFGLQCE-UHFFFAOYSA-N heptadecane-5,9-dione Chemical compound CCCCCCCCC(=O)CCCC(=O)CCCC LZWPOLSJFGLQCE-UHFFFAOYSA-N 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 1
- UUVWYPNAQBNQJQ-UHFFFAOYSA-N hexamethylmelamine Chemical compound CN(C)C1=NC(N(C)C)=NC(N(C)C)=N1 UUVWYPNAQBNQJQ-UHFFFAOYSA-N 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 229910000040 hydrogen fluoride Inorganic materials 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000001969 hypertrophic effect Effects 0.000 description 1
- 239000000367 immunologic factor Substances 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 229940047124 interferons Drugs 0.000 description 1
- 229940047122 interleukins Drugs 0.000 description 1
- KLEAIHJJLUAXIQ-JDRGBKBRSA-N irinotecan hydrochloride hydrate Chemical compound O.O.O.Cl.C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 KLEAIHJJLUAXIQ-JDRGBKBRSA-N 0.000 description 1
- 208000037906 ischaemic injury Diseases 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 238000000021 kinase assay Methods 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 229940116298 l- malic acid Drugs 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- GFIJNRVAKGFPGQ-LIJARHBVSA-N leuprolide Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 GFIJNRVAKGFPGQ-LIJARHBVSA-N 0.000 description 1
- 229960004338 leuprorelin Drugs 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 229940099690 malic acid Drugs 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 229960001428 mercaptopurine Drugs 0.000 description 1
- FBOZXECLQNJBKD-UHFFFAOYSA-N methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-UHFFFAOYSA-N 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- CXHHBNMLPJOKQD-UHFFFAOYSA-M methyl carbonate Chemical compound COC([O-])=O CXHHBNMLPJOKQD-UHFFFAOYSA-M 0.000 description 1
- HRHKSTOGXBBQCB-VFWICMBZSA-N methylmitomycin Chemical compound O=C1C(N)=C(C)C(=O)C2=C1[C@@H](COC(N)=O)[C@@]1(OC)[C@H]3N(C)[C@H]3CN12 HRHKSTOGXBBQCB-VFWICMBZSA-N 0.000 description 1
- 229960004857 mitomycin 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
- 239000002808 molecular sieve Substances 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 210000002346 musculoskeletal system Anatomy 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 201000004931 neurofibromatosis Diseases 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 125000003835 nucleoside group Chemical group 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 238000000053 physical method Methods 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229960001237 podophyllotoxin Drugs 0.000 description 1
- YVCVYCSAAZQOJI-UHFFFAOYSA-N podophyllotoxin Natural products COC1=C(O)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YVCVYCSAAZQOJI-UHFFFAOYSA-N 0.000 description 1
- 239000003600 podophyllotoxin derivative Substances 0.000 description 1
- 229950004406 porfiromycin Drugs 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000002953 preparative HPLC Methods 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
- 229960000624 procarbazine Drugs 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 239000003909 protein kinase inhibitor Substances 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- CPNGPNLZQNNVQM-UHFFFAOYSA-N pteridine Chemical compound N1=CN=CC2=NC=CN=C21 CPNGPNLZQNNVQM-UHFFFAOYSA-N 0.000 description 1
- 208000005069 pulmonary fibrosis Diseases 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 208000037803 restenosis Diseases 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 230000036573 scar formation Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 201000009890 sinusitis Diseases 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000007614 solvation Methods 0.000 description 1
- 235000014347 soups Nutrition 0.000 description 1
- 208000002320 spinal muscular atrophy Diseases 0.000 description 1
- 102000009076 src-Family Kinases Human genes 0.000 description 1
- 108010087686 src-Family Kinases Proteins 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 102000013498 tau Proteins Human genes 0.000 description 1
- 108010026424 tau Proteins Proteins 0.000 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- 208000001608 teratocarcinoma Diseases 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- ZXUCBXRTRRIBSO-UHFFFAOYSA-L tetrabutylazanium;sulfate Chemical compound [O-]S([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC.CCCC[N+](CCCC)(CCCC)CCCC ZXUCBXRTRRIBSO-UHFFFAOYSA-L 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 229960001196 thiotepa Drugs 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 1
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 1
- 229960000303 topotecan Drugs 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 108700012359 toxins Proteins 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- NOYPYLRCIDNJJB-UHFFFAOYSA-N trimetrexate Chemical compound COC1=C(OC)C(OC)=CC(NCC=2C(=C3C(N)=NC(N)=NC3=CC=2)C)=C1 NOYPYLRCIDNJJB-UHFFFAOYSA-N 0.000 description 1
- 229960001099 trimetrexate Drugs 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- 238000007631 vascular surgery Methods 0.000 description 1
- 229960003048 vinblastine 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
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
N-[5-[[[5-ALKYL-2-OXAZOLYLIMETHYL|THIO}-2-THIAZOLYL]
CARBOXAMIDE INHIBITORS OF CYCLIN DEPENDENT KINASES
The present invention is directed to compounds of formula I
N R4
AN ° ® ED
R 0 hd (CHa
J rd
X y 98 d) and enantiomers, diastereomers, solvates, and pharmaceutically acceptable salts thereof wherein
Ris alkyl;
R! is hydrogen or alkyl; . XisNR? or CHNR’RY | :
R? and R? are each independently hydrogen, alkyl, substituted alkyl, cycloalkyl or substituted cycloalkyl; and nis0,1,2o0r3.
The compounds of formula I are particularly useful as potent, protein kinase inhibitors and are useful in the treatment of proliferative diseases, for example, cancer, inflammation and arthritis. They may also be useful in the treatment of Alzheimer’s disease, chemotherapy-induced alopecia, and cardiovascular disease.
The present invention provides for compounds of formula I, pharmaceutical compositions employing such compounds, and for methods of using such compounds.
Listed below are definitions of various terms used to describe the compounds of the instant invention. These definitions apply to the terms as they are used throughout the ) specification (unless they are otherwise limited in specific instances) either individually or ’ as part of a larger group.
The term "alkyl" or "alk" refers to a monovalent alkane (hydrocarbon) derived radical containing from 1 to 12, preferably 1 to 6, and more preferably 1 to 4, carbon atoms unless otherwise defined. An alkyl group is an optionally substituted straight, branched or cyclic saturated hydrocarbon group. When substituted, alkyl groups can be substituted with up to four substituent groups, R* as defined, at any available point of attachment. When the alkyl group is said to be substituted with an alkyl group, this is used interchangeably with : “branched alkyl group”. Exemplary unsubstituted such groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4- : 5 dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, and the like.
Exemplary substituents may include, but are not limited to, one or more of the following groups: halo (such as F, Cl, Br or I), haloalkyl (such as CCl; or CF;), alkoxy, alkylthio, hydroxy, carboxy, alkylcarbonyl, alkyloxycarbonyl, alkylcarbonyloxy, amino, carbamoyl, urea, amidinyl, or thiol.
Cycloalkyl is a specie of alkyl containing from 3 to 15 carbon atoms, without alternating or resonating double bonds between carbon atoms. It may contain from 1 to 4 rings. Exemplary unsubstituted such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. Exemplary substituents include one or more of the following groups: halogen, alkyl, alkoxy, alkyl hydroxy, amino, nitro, cyano, thiol and/or alkylthio.
The terms "alkoxy" or "alkylthio", as used herein, denote an alkyl group as described above bonded through an oxygen linkage (-O-) or a sulfur linkage (-S-), respectively.
The term "alkyloxycarbonyl", as used herein, denotes an alkoxy group bonded through a carbonyl group. An alkoxycarbonyl radical is represented by the formula: -C(O)OR?, where the R’ group is a straight or branched C4 alkyl group. B
The term "alkylcarbonyl" refers to an alkyl group bonded through a carbonyl group.
The term "alkylcarbonyloxy", as used herein, denotes an alkylcarbonyl group which is bonded through an oxygen linkage.
As used herein, the phrase "compounds of the invention" means, collectively, compounds falling within formula I and pharmaceutically-acceptable salts, and solvates including hydrates thereof. Methods of salt formation, solvation, and hydrate formation are well known in the art. The invention also encompasses mixtures of stereoisomers of compounds of the invention. Stereoisomers include, but are not limited to, enantiomers, diastereomers, and racemates where the compound has one or more chiral centers. All stereoisomers of the compounds of the instant invention are contemplated, . either in admixture or in pure or substantially pure form. The definition of the compounds e according to the invention embraces all possible stereoisomers and their mixtures. It very ‘ particularly embraces the racemic forms and the isolated optical isomers having the specified activity. The racemic forms can be resolved by physical methods, such as, for example, fractional crystallization, separation or crystallization of diastereomeric : derivatives or separation by chiral column chromatography. The individual optical isomers can be obtained from the racemates by conventional methods, such as, for example, salt formation with an optically active acid followed by crystallization. All configurational i isomers of compounds of the present invention are contemplated, either in admixture or in pure or substantially pure form. The definition of compounds of the present invention very . 5 particularly embraces both cis (Z) and trans (E) alkene isomers, as well as cis and trans 1somers of cycloalkyl or heterocycloalkyl rings.
In addition, salts of compounds of formula I that are pharmaceutically unsuitable but useful in other respects, for example, for the isolation or purification of compounds of formula I, are also encompassed by the invention.
The compounds of the invention are defined herein by their chemical structures and/or chemical names. Where a compound is referred to by both a chemical structure and a chemical name, and the chemical structure and chemical name conflict, the chemical structure is determinative of the compound’s identity.
The phrase “pharmaceutically-acceptable salt(s),” as used herein includes, but is not limited to, salts of acidic or basic groups that may be present in the compounds of the invention. Examples of such pharmaceutically acceptable salts include, but are not limited to, hydrochloride, hydrobromide, dihydrochloride, sulfate, trifluoroacetate, tartrate, fumarate, succinate, maleate, citrate, methanesulfonate, bromate and iodate salts and mixtures thereof. Also included are salts formed with other organic and inorganic acids such as hydroxymethane sulfonic acid, acetic acid, benzenesulfonic acid, toluenesulfonic acid and various others, e.g., nitrates, phosphates, borates, benzoates, ascorbates, salicylates, and the like. In addition, pharmaceutically acceptable salts of compounds of formula I can be formed with alkali metals, such as sodium, potassium and lithium; alkaline earth metals, such as calcium and magnesium; organic bases, such as dicyclohexylamine, tributylamine, and pyridines, and the like; and amino acids, such as arginine, lysine, and the like.
Salts of compounds of the invention encompass solvates, racemates, and all ~~ stereoisomeric forms thereof, including enantiomers and diastereomers (for example, D- tartrate and L-tartrate salts). ___ As used herein, the term “solvate” means a compound of the invention or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of one or more . solvent molecules bound by non-covalent intermolecular forces. Preferred solvents are volatile, non-toxic, and/or acceptable for administration to humans in trace amounts. When . the solvent is water the solvate is termed a “hydrate”.
Compounds of formula I can be prepared by adapting the methods set forth in WO 99/65884 and WO 99/24416, both of which are incorporated herein by reference.
Alternatively, the generic method shown in Scheme A below, that illustrates synthesis of the broad genus of compounds of formula XIV, can be used to synthesize compounds of formula I. The starting compounds are commercially available or may be prepared by : methods known to one of ordinary skill in the art. The following terms apply in Scheme A:
R’, R®, and R' are independently hydrogen or alkyl; : 5 Ris alkyl, aryl, or heteroaryl;
R’ is hydrogen, alkyl, aryl, or heteroaryl;
R' and R"" are independently hydrogen, alkyl, aryl, heteroaryl, halogen, hydroxy, or alkoxy;
R" is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, CONR"”R™, COR", or COOR';
R' RY RY and R' are independently hydrogen, alkyl, or aryl; ris an integer ranging from 0 to 5; s is an integer ranging from 0 to 5;
L is a suitable leaving group, such as halogen or sulfonate (R°SO,0", CF,S0,0, etc., wherein R® is alkyl, cycloalkyl, or aryl);
M is hydrogen, Li, Na, K, Cs, or a quaternary ammonium ion, e.g., RN or quaternary ammonium ions comprising cyclic alkenetetramines, such as hexamethylenetetramine;
Q is hydroxy, halogen or acyloxy (R°COO", R°OCOO, etc.);
Y is O, S, NH, N-alkyl, N-aryl or N-acyl;
Z is hydrogen, alkyl, aryl, O-alkyl, O-aryl, S-alkyl, S-aryl, NH,, N-alkyl, N-aryl or
N-acyl; and ’ oT
P is a nitrogen-protecting group (Boc, Cbz, R;Si, efc.). When a functional group is termed “protected,” this means that the group is in modified form to preclude undesired side reactions at the protected site. Suitable protecting groups for the compounds involved in the present processes will be recognized from the specification taking into account the level of 15 skill in the art, and with reference to standard textbooks such as Greene, T.W., Protective
Groups in Organic Synthesis, 3rd edition (1999), incorporated here by reference.
The processes generally involve reaction of o-halo ketones II (commercially available or readily synthesized by well-known methods) with an azide to give a-azido ketones III. Reduction of TI with a reducing reagent gives a-amino ketones IV.
Alternatively and more advantageously, the a-amino ketones IV are prepared by , reaction of a-halo ketones II with a cyclic alkylenetetramine such as hexamethylenetetramine and the like, followed by hydrolysis of the resulting, new ‘ quaternary ammonium salt III". This reaction provides excellent yields of the desired intermediate compound IV, above 90%.
Thereafter, reacting the a-amino ketones TV with an o-halo acyl halide V in the presence of a base of, alternatively, coupling the a-amino ketones IV with an a-halo acid,
produces the corresponding amides VI. Then, ring closure of VI with a dehydrating reagent affords 2-oxazolylalkyl halides VII. When a conventional dehydrating reagent, such as } trihalophosphorus oxide like POC, is used, product isolation is difficult due to the formation of large amounts of hydrochloric and phosphoric acids. Thus, the process of the . 5 present invention preferably utilizes the Burgess” reagent which produces excellent yields and permits easy, safe product isolation from water.
Subsequent treatment of 2-oxazolylalkyl halides VII with sulfur-containing reagent
VHI or VIIT' affords new key intermediate compounds, 2-oxazolylalkyl sulfides IX.
Coupling of IX with 5-halo-2-aminothiazole X gives 5-(2-oxazolylalkylthio)-2- aminothiazoles XI. Coupling of XI with an azacycloalkanoic acid derivative XII affords thiazolyl amides XIII, which may be deprotected (in the case where P is a protecting group, e.g., Boc) to give 5-(2-oxazolylalkylthio)-2-azacycloalkanoylaminothiazoles XIV.
Scheme A ’
MN 0 Io}
Nj;
Co A . J 0] 9 \J
R 0 7°58
R’ R
L
Oo } N Mi NE > R® 0 N R®
NN 9
I LN od Lo Iv
R L-N_/
RS nr
SM
PY Y
9 Yo z 9 oO uy RR RAN L Vili RN s—
N \ | N\ z
R L [ES ) RS _ o . JR
RR 0 R™ 0 FR or i R R
VI vil My” Sz IX vir o R'
R10 N R10 it
N ps H—NH, 9 JN X s P
Ss R N Ss k X \ s—\ xi
SD — ge NH, -
R= 0 FR
XI
R10 R10
Rr? 74 N rR? 74 N
N + y No sy
T \) 8 so : R! a N { 8 sy y Rr!
RO R gt RW © Rf gn 0 N, o ANI
P R
XI $ XIV s
As set forth in Scheme A, the processes for the preparation of 5-(2- oxazolylalkylthio)-2-azacycloalkanoylaminothiazoles and analogs involve the following . transformations:
Step (a) involves reacting an a-substituted ketone II such as, for example, an a-halo ' 5 ketone, with an azide in a suitable solvent or solvent mixtures to give an a-azido ketone III; or, more desirably, (a') reacting an a-substituted ketone II like the a-halo ketone with a cyclic alkylenetetramine such as, for example, hexamethylenetetramine in a suitable solvent or solvent mixtures to give a new quaternary ammonium salt ITI".
The a-halo ketone includes o-halo aliphatic and a-halo aromatic ketones. The preferred a-halo ketones are a-halo pinacolones with a-bromo pinacolone most preferred. A sulfonate, for example, RSO,0- (where R is alkyl, aryl or heteroaryl), CF,SO,0- and the like, may be substituted for the halogen in the a-position. The azides include both metal azides and quaternary ammonium azides. The metal azides are preferred with sodium azide most preferred. Suitable solvent(s) include solvents such as hydrocarbons, ethers, amides, for example, dimethylformamide, ketones, ezc., or mixtures thereof, with ketones such as acetone preferred for both reactions (a) and (a').
Step (b) comprises reacting the a-azido ketone III obtained in step (a) with a reducing reagent in a suitable solvent or solvent mixtures to give an a-amino ketone IV, or, more desirably, (b') reacting the quaternary ammonium salt III' obtained in step (a') with an acid in a suitable solvent or solvent mixtures to give an a-amino ketone IV.
The reducing reagent in reaction (b) includes hydrogen in the presence of a transition metal catalyst such as palladium, trialkyl or triarylphosphines like triphenylphosphine. Hydrogen in the presence of a transition metal catalyst is preferred with hydrogen and palladium over activated carbon most preferred. Suitable solvent(s) in reaction (b) include solvents such as hydrocarbons, ethers, alcohols and the like, or mixtures thereof, with alcohol such as methanol preferred. Alternatively, the reduction reaction can be carried out in the presence of an acidic medium such as, for example, hydrochloric acid in ethanol to give a-amino ketone acid salt which can be isolated as the acid salt or free amine forms.
The acid in reaction (b') includes, but is not limited to, protic acids such as HC, . HBr, HI, H,S0,, H,PO,, etc., with HCI preferred. Suitable solvent(s) in reaction (b") include solvents such as hydrocarbons, ethers, alcohols and the like, or mixtures thereof, : with alcohol such as ethanol preferred. The a-amino ketone product may be isolated as the salt or free base forms.
Step (c) involves reacting (acylating) the a-amino ketone IV or its acid salt obtained in step (b) or (b") with an a-substituted acyl derivative V such as, for example, an a-halo acyl halide, in the presence of a base and in a suitable solvent or solvent mixtures to give an amide VI. : The a-halo acyl halide V includes a-alkyl or aryl substituted or unsubstituted a-halo acyl halide with the latter preferred. The most preferred a-halo acyl hahde is a-chloroacetyl ' 5 chloride. The base used in the reaction includes, but is not limited to, aromatic and aliphatic organic amines with the latter preferred. The most preferred base is triethylamine. Suitable solvent(s) include aprotic solvents such as hydrocarbons, halogenated hydrocarbons, ethers, esters and the like, or mixtures thereof, with halogenated hydrocarbons such as dichloromethane preferred. Alternatively, the reaction can be carried out using an o- substituted acid instead of the a-substituted acyl derivative and then employing a coupling reagent such as a water-soluble diimide like carbodiimide, haloformate, thionyl halide, efc.
In either reaction, a sulfonate, for example, RSO,0- (where R is an alkyl, aryl or heteroaryl), CF,S0,0- and the like, may be substituted for the halogen in the a-position of the a-halo acyl halide or the a-halo acid reactants which are illustrated.
Step (d) concerns reacting the amide V1 obtained in step (c) with a dehydrating reagent in a suitable solvent or solvent mixtures to give the cyclized 2-oxazolylalkyl derivative VII such as, for example, the 2-oxazolylalkyl halide.
Advantageously, the reaction is carried out using (methoxycarbonylsulfamoyl)- triethylammonium hydroxide (Burgess' reagent) as the dehydrating reagent. Suitable solvent(s) include hydrocarbons, halogenated hydrocarbons, ethers and the like, or mixtures thereof. Most preferred is the use of the Burgess’ reagent in tetrahydrofuran. Suitable dehydrating reagents also include, but are not limited to, other bases, acids, acid anhydrides and the like, such as, e.g., concentrated sulfuric acid, polyphosphoric acid, etc. Although less conveniently, the dehydrating reagent, for instance, can be trihalophosphorus oxide such as tribromophosphorus oxide or trichlorophosphorus oxide, alone or with a solvent like : toluene.
Step (e) is directed to reacting the 2-oxazolylalkyl derivative VII obtained in step (d) with a sulfur-containing reagent VIII or VIIT' in a suitable solvent or solvent mixtures to give 2-oxazolylalkyl sulfide IX, a new key intermediate compound.
The sulfur-containing reagent includes N-substituted or unsubstituted thioureas, thio acids or salts such as thioacetic acid or its salt, xanthic acids or salts such as ethylxanthic acid potassium salt. Unsubstituted thiourea is preferred. Suitable solvent(s) include ‘ hydrocarbons, halogenated hydrocarbons, ethers, esters, amides, alcohols and the like, or mixtures thereof, with alcohol such as methanol or ethanol preferred.
Step (f) concerns reacting the 2-oxazolylalkyl sulfide IX obtained in step (e) with a 5-halo-2-aminothiazole X in the presence of a base and in a suitable solvent or solvent } mixtures to give 5-(2-oxazolylalkylthio)-2-aminothiazole XI.
The 5-halo-2-aminothiazole includes 4-N-substituted or unsubstituted 5-halo-2- ; 5 aminothiazoles with 5-bromo-2-aminolhiazole preferred. A suitable base includes, but is not limited to, metal hydroxide, metal alkoxides, metal carbonates and aqueous amines such as ammonium hydroxide. Sodium hydroxide is preferred. Suitable solvent(s) include solvents such as hydrocarbons, halogenated hydrocarbons, ethers, esters, amides, alcohols and the like, or mixtures thereof, with halogenated hydrocarbons such as dichloromethane preferred.
Step (g) involves reacting the 5-(2-oxazolylalkylthio)-2-aminothiazole XI obtained in step (f) with an azacycloalkanoic acid derivative XII in the presence of a coupling reagent in a suitable solvent or solvent mixtures to give thiazolyl amide XIII.
The azacycloalkanoic acid derivative includes N-protected derivatives, for example,
N-protected isonipecotic acid or N-protected nipecotic acid. The preferred nitrogen- protecting groups are Boc, Cbz, silicon derivatives and the like with Boc being the most preferred. The coupling reagent includes, but is not limited to, water-soluble carbodiimides, haloformates and the like, with carbodiimides such as alkylcarbodiimides being preferred.
Suitable solvent(s) include solvents such as hydrocarbons, halogenated hydrocarbons, ethers, esters, amides, efc., or mixtures thereof, with halogenated hydrocarbons such as dichloromethane preferred.
Step (h) is directed to reacting the thiazolyl amide XIII obtained in step (g) with a deprotecting reagent in a suitable solvent or solvent mixtures to give a desired 5-(2- oxazolylalkylthio)-2-azacycloalkanoylaminothiazole XIV (where R'is hydrogen).
The choice of the deprotecting reagent is based on the nature of the protecting group (P). For the Boc protecting group, the preferred deprotecting reagent is an acid such as hydrochloric acid or trifluoroacetic acid and suitable solvent(s) for such deprotecting reaction include solvents such as hydrocarbons, halogenated hydrocarbons, ethers, esters, amides and the like, or mixtures thereof, with halogenated hydrocarbons such as dichloromethane preferred.
A more detailed synthesis of compounds of formula I is shown in Schemes 1-5 below. The starting compounds are commercially available or may be prepared by methods known to one of ordinary skill in the art. In Schemes 1-5 below, the following terms apply:
L is a suitable leaving group, such as halogen or sulfonate (e.g., Br, CL I, R°S0O,0,
CF,S0,0", wherein R® is alkyl, cycloalkyl, heteroaryl, or aryl);
M is hydrogen, Li, Na, K, Cs, or a quaternary ammonium ion, e. 2, RH N or quaternary ammonium ions comprising cyclic alkenetetramines, such as i hexamethylenetetramine;
Q 1s hydroxy, halogen or acyloxy (R®COO~, R°OCOOQ", ezc.); . 5 Y 1s O, S, NH, N-alkyl, N-aryl or N-acyl; and
Z 1s hydrogen, alkyl, aryl, O-alkyl, O-aryl, S-alkyl, S-aryl, NH,, N-alkyl, N-aryl or
N-acyl. Scheme 1 sets forth a synthesis of compounds of formula 11.
Scheme 1: Synthesis of Compounds of Formula 11 . 0]
MN;
N 0) 1g .
L 5
R — N — Nowy, ——
SER ; o 4
A
R L-N_/ 3
Y“ > z Y 0)
H N L 8 N s—4
N Nr N—s Z
R” © or $ R © A 6 7 my” >z 9 8'
N .
L 10 \ _— I $7 “NH, rR” 0 . 11 : . First, step (a) involves reacting a suitable a-substituted ketone 2, such as an a-halo ketone, with an azide in a suitable solvent or solvent mixtures to give an a-azido ketone 3; or, more desirably, (2') reacting ketone 2 with a cyclic alkylenetetramine, such as hexamethylenetetramine in a suitable solvent or solvent mixtures to give quaternary ammonium salt 3". . Suitable a-halo ketones 2 include a-halo aliphatic and a-halo aromatic ketones. The preferred a-halo ketones are a-halo pinacolones with a-bromo pinacolone most preferred. : 5 A sulfonate, for example, R°SO,0 (where, as defined above, R® is alkyl, cycloalkyl, heteroaryl, or aryl), CF,SO,0™ and the like, can be substituted for the halogen (as group L) in the a-position. The azides include both metal azides and quaternary ammonium azides.
The metal azides are preferred, with sodium azide most preferred. Suitable solvent(s) include hydrocarbons, ethers, amides, such as dimethylformamide, ketones, efc., or mixtures thereof, with ketones such as acetone preferred for both reactions (a) and (a).
Step (b) involves reacting the a-azido ketone 3 obtained in step (a) with a reducing reagent in a suitable solvent or solvent mixtures to give an a-amino ketone 4, or, more desirably, (b') reacting the quaternary ammonium salt 3' obtained in step (2') with an acid in a suitable solvent or solvent mixtures to give an a-amino ketone 4.
The reducing reagent in reaction (b) includes hydrogen in the presence of a transition metal catalyst such as palladium, trialkyl- or triarylphosphines, such as triphenylphosphine. Hydrogen in the presence of a transition-metal catalyst is preferred with hydrogen and palladium over activated carbon most preferred. Suitable solvent(s) in reaction (b) include hydrocarbons, ethers, alcohols and the like, or mixtures thereof, with alcohols, such as methanol preferred. Alternatively, the reduction reaction can be carried out in the presence of an acidic medium such as, hydrochloric acid in ethanol to give an a- amino ketone acid salt which can be isolated as the acid salt or free amine forms. - Suitable acids for use in reaction (b') include, but are not limited to, HCl, HBr, HI,
H,SO,, H,PO,, etc., with HCI preferred. Suitable solvent(s) in reaction (b') include hydrocarbons, ethers, alcohols and the like, or mixtures thereof, with alcohols, such as ethanol preferred. The a-amino ketone product can be isolated as the salt or free-base forms. —— Step (c) comprises reacting (acylating) the o~amino ketone 4 or its acid salt obtained in step (b) or (b') with an a-substituted acyl derivative 5, such as an a-halo acyl halide (i.e.,
Q and L = halo), in the presence of a base and in a suitable solvent or solvent mixtures to give an amide 6.
The a-halo acyl halide 5 includes alkyl or aryl-a-halo acyl halides (substituted or : unsubstituted), with the latter preferred. The most preferred a-halo acyl halide is a- chloroacetyl chloride. The base used in the reaction includes, but is not limited to, aromatic and aliphatic organic amines, with the latter preferred. The most preferred base is triethylamine. Suitable solvent(s) include aprotic solvents such as hydrocarbons,
halogenated hydrocarbons, ethers, esters and the like, or mixtures thereof, with halogenated hydrocarbons such as dichloromethane preferred. Alternatively, the reaction can be carried . out using an a-substituted acid (Q = OH) instead of the a-substituted acyl derivative and then employing a coupling reagent, such as a water-soluble diimide (e.g., carbodiimide), a : 5 haloformate, a thionyl halide, etc. In either reaction, a sulfonate, for example, R°SO,0” (where R® is an alkyl, cycloallkyl, aryl or heteroaryl), CF;SO,0™ can be substituted for the halogen in the a-position (i.e., at group L) of compounds 5.
Step (d) involves reacting the amide 6 obtained in step (c) with a dehydrating reagent in a suitable solvent or solvent mixtures to give the cyclized 2-oxazolylalkyl derivative 7, for example, the 2-oxazolylalkyl halide (i.e., L is halo).
Advantageously, the reaction is carried out using (methoxycarbonylsulfamoyl)- triethylammonium hydroxide (Burgess' reagent) as the dehydrating reagent. Suitable solvent(s) include hydrocarbons, halogenated hydrocarbons, ethers and the like, or mixtures thereof. Most preferred is the use of the Burgess’ reagent in tetrahydrofuran. Suitable dehydrating reagents also include, but are not limited to, other bases, acids, acid anhydrides and the like, such as concentrated sulfuric acid, polyphosphoric acid, etc. Less conveniently, the dehydrating can be a trihalophosphorus oxide, such as tribromophosphorus oxide or trichlorophosphorus oxide, alone or with a solvent like toluene.
Step (€) comprises reacting the 2-oxazolylalkyl derivative 7 obtained in step (d) with a sulfur-containing reagent 8 or 8' in a suitable solvent or solvent mixtures to give 2- oxazolylalkyl sulfide 9.
The sulfur-containing reagent includes N-substituted or unsubstituted thioureas, thio acids or salts such as thioacetic acid or its salt, xanthic acids or salts such as ethylxanthic acid potassium salt. Unsubstituted thiourea is preferred. Suitable solvent(s) include ) hydrocarbons, halogenated hydrocarbons, ethers, esters, amides, alcohols and the like, or mixtures thereof, with alcohols such as methanol or ethanol preferred.
Step (f) illustrates reacting the 2-oxazolylalkyl sulfide 9 obtained in step (e) with a 2-aminothiazole 10 (preferably L is halo) in the presence of a base and in a suitable solvent or solvent mixtures to give 5-(2-oxazolylalkylthio)-2-aminothiazole 11. . The 2-aminothiazole 10 includes 4-N-substituted or unsubstituted 5-halo-2- aminothiazoles with 5-bromo-2-aminothiazole preferred. A suitable base includes, but is : not limited to, metal hydroxides, metal alkoxides, metal carbonates and aqueous amines, such as ammonium hydroxide. Sodium hydroxide is preferred. Suitable solvent(s) include hydrocarbons, halogenated hydrocarbons, ethers, esters, amides, alcohols and the like, or mixtures thereof, with halogenated hydrocarbons such as dichloromethane preferred.
Scheme 2 sets forth a general synthesis of compounds of formula I via reaction of amine 11 with a carboxylic acid of formula 12 in the presence of a coupling agent. Suitable coupling reagents include, but are not limited to, water-soluble carbodiimides, haloformates and the like, with carbodiimides such as alkylcarbodiimides being preferred, for example, . 5 thc combination of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and a base.
Scheme 2
N
| J R' n [ (CH),
N X
11 12 coupling agent
N R' [ WT nN Js oS N | - 0 I hg (CHa,
X
N 0 d)
Scheme 3 below illustrates the synthesis of compounds of formula I, wherein X is
NR? and R?is H. First, an amine of formula 11 is reacted with a N-protected carboxylic acid of formula 13 in the presence of a coupling agent to form an N-protected compound of formula 14. Then compound 14 is deprotected to give compounds of formula I. Suitable coupling reagents include, but are not limited to, water-soluble carbodiimides, haloformates and the like, with carbodiimides such as alkylcarbodiimides being preferred, for example, 1- : (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and a base.
Scheme 3
Wl . _-CO,H : > . pr S NH, - - : @) he + Pi 2)n
Ll y
N
P coupling agent [] R
R 0 AC Hz)n ] \
N Oo = 14
Acid [1 A
R 0 CHa); i
N lo} H
I
In the Scheme above, P is a nitrogen-protecting group (for example, Boc, Cbz, R,Si, ete.). When a functional group is termed “protected,” this means that the group is in modified form to preclude undesired side reactions at the protected site. Suitable protecting groups for the compounds involved in the present processes will be recognized from the specification taking into account the level of skill in the art, and with reference to standard textbooks such as Greene, T.W., Protective Groups in Organic Synthesis, 3rd edition i (1999), incorporated herein by reference. The preferred nitrogen-protecting groups are Boc,
Cbz, silicon derivatives, with Boc being the most preferred. Suitable solvent(s) include hydrocarbons, halogenated hydrocarbons, ethers, esters, amides, etc., or mixtures thereof, with halogenated hydrocarbons such as dichloromethane preferred. The choice of the deprotecting reagent is based on the nature of the protecting group (P). For the Boc protecting group, the preferred deprotecting reagent is an acid such as hydrochloric acid or trifluoroacetic acid and suitable solvent(s) for such deprotecting reaction include solvents such as hydrocarbons, halogenated hydrocarbons, ethers, esters, amides and the like, or . 5 mixtures thereof, with halogenated hydrocarbons such as dichloromethane preferred.
Scheme 4 below illustrates the synthesis of compounds of formula I, wherein X is
NR? and R? is 2,3-dihydroxypropyl, by reacting a compound of formula I wherein X is NR* and R* is hydrogen with glyceraldehyde in the presence of a reducing agent such as sodium triacetoxyborohydride and an alcohol such as methanol. 10
Scheme 4 1 ;
Js soup
R @] _(CHa)y i
N 0 H
HOCH,CH(OH)CHO
NaB(0,CCH,);H
CH;0H [] r
Je sn oy
R O : (CHa) | hg hl Nd
[1] o
CH5CH(OH)CH,0OH
Scheme 5 below illustrates the synthesis of compounds of formula I, wherein X is
NR” and R? is 2-hydroxyethyl, by reacting a compound of formula I wherein X is NR? and
R’ is hydrogen with a 2-(bromoethoxy)trialkylsilane of formula 15 to give intermediate 16, and deprotecting intermediate 16 with an acid such as hydrogen fluoride.
Scheme 5
N R' ; | x
S S N ~~
R 0 (CHa)q ne 18%
N o) H
BrCH,CH,O0Si(alkyl), ] oh py S S s ~
R 0) (CHa)n
RET
N 0
CH,CH,0Si(alkyl)3 16
Acid | N R' ~~ | Js S 4 [~ | \
R @) (CHa), hd hl > [7 0
CH,CH,OH €y)
Preferred compounds of formula I are those wherein:
R is alkyl;
R'is hydrogen; :
X is NR? or CHNR’R?; and
R? and R? are independently hydrogen, alkyl, substituted alkyl or cycloalkyl; and : nis 2.
A first group of more preferred compounds of the present invention are those of formula la:
N EN
FJ s_ _N ) (CHa) Yo hs SR?
N 0 (a) and enantiomers, diastereomers, solvates, and pharmaceutically acceptable salts thereof wherein R? is hydrogen, alkyl, substituted alkyl, or cycloalkyl.
A second group of more preferred compounds of this invention are those of formula
Ib:
R2
N NT
AN N
: S S N (CHaC” No hd
N 5 (Ib) and enantiomers, diastereomers, solvates, and pharmaceutically acceptable salts thereof wherein R? is hydrogen, alkyl, substituted alkyl, or cycloalkyl.
A third group of more preferred compounds of the present invention are those of formula Ic:
NR2R®
N
H
. AA S N (CHC No hd . N 0 (Ic)
and enantiomers, diastereomers, solvates, and pharmaceutically acceptable salts thereof wherein R? and R? are each independently hydrogen, alkyl, substituted alkyl, or cycloalkyl.
In another embodiment, compounds of formula I include, but are not limited, to those listed in Table 1 below and enantiomers, diastereomers, solvates, and : 5 pharmaccutically acceptable salts thereof.
Table 1: Compounds of the Invention | N-[5-[[[5-(1,1-dimethylethyl)-2- . ] (HACC NH oxazolyl]methyl]thio]-2-thiazolyl]-4- ) 0 . H piperidinecarboxamide S N at (£)-N-[5-[[[5-(1,1-dimethylethyl)-2- ] ] (HC) C, oxazolyl]methyl]thio}-2-thiazolyl]}-3- 8 S H
NH piperidinecarboxamide 5 N ~~ (£)-1-(2,3-dihydroxypropyl)-N-[ 5-[[[5-(1,1- dimethylethyl)-2-oxazolylJmethyl]thio]-2- M30 NT on 0 H thiazolyl]-4-piperidinecarboxamide r Ss 5 N OH
V%
A peg
N-[5-[[[5-(1,1-dimethylethyl)-2- I oxazolyllmethyl]thio]-2-thiazolyl}-1-(1- (H3C):C N methylethyl)-4-piperidinecarboxamide Ue s. HB s N
A 7
N ) 1-cyclopropyl-N-[5-[[[5-(1,1-dimethylethyl)- A 2-oxazolylJmethyl]thio]-2-thiazolyl]-4- (H30);C N . ae . 0 H piperidinecarboxamide T S SN ~~
N [e] ; N-[5-{[[5-(1,1-dimethylethyl)-2- HsC)s NY oxazolyljmethyljthio]-2-thiazolyl]-1-(2- Tis S N OH . hydroxyethyl)-4-piperidinecarboxamide NG Xr
N lo}
Table 1: (Cont. (R)-N-[5-[{[5-(1,1-dimethylethyl)-2- . . N (HCC oxazolyljmethyljthiol-2-thiazolyl]-3- J 0 S H
Co x NH piperidinecarboxamide I S Ns . Pp ( ' ) (S)-N-[5-[[[5-(1,1-dimethylethyl)-2- ] ] (H3C)5C oxazolyljmethyl]thio]-2-thiazolyl}-3- Ip s H
NH piperidinecarboxamide S N
P~ nl i cis-4-amino-N-[5-[[[5-(1,1-dimethylethyl)-2- NH» . (H3C)C - oxazolyljmethyljthio}-2- 0 u : ani / S\N thiazolyljcyclohexylcarboxamide PS ~
N \ J trans-4-amino-N-[5-[[[5-(1,1-dimethylethyl)- HOC NH, 2-oxazolylJmethyl]thio}-2- 0s o u i thiazolyl]cyclohexylcarboxamide / PS De
N UJ )
Preferred salts of the above compounds are the hydrochloride, the hydrobromide, the dihydrochloride, the sulfate, the trifluoroacetate, the tartrate, the fumarate, the succinate, the maleate, the citrate, the methanesulfonate, the bromate, and the iodate salts or mixtures thereof.
The present invention also includes methods based upon the pharmacological properties of the compounds of the invention. The compounds according to the invention have pharmacological properties; in particular, the compounds of formula I are inhibitors of protein kinases such as the cyclin dependent kinases (cdks), for example, cdc2 (cdkl), cdk2, cdk3, cdk4, cdk5, cdk6, cdk7 and cdk8. Thus, the invention encompasses the use of : compounds of the invention in the treatment, prevention, and/or management of cancer, inflammation or inflammatory disease, arthritis, Alzheimer’s disease and cardiovascular : disease. The invention also encompasses, in a more specific embodiment, the use of compounds of the invention to treat, prevent, and/or manage proliferative diseases or ‘ symptoms thereof. The invention also encompasses use of compounds of the invention in the treatment or prevention of topical and systemic fungal infections.
More specifically, the compounds of formula I are useful in the treatment of a variety of cancers, including (but not limited to) the following: -carcinoma, including that of the bladder, breast, colon, kidney, liver, lung, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin; -hematopoietic tumors of lymphoid lineage, including acute lymphocytic leukemia, B-cell lymphoma, and Burkett's lymphoma; -hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias and promyelocytic leukemia; -tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; and -other tumors, including melanoma, seminoma, teratocarcinoma, osteosarcoma, neuroblastoma and glioma.
Without being limited by any theory, due to the key role of cdks in the regulation of cellular proliferation in general, inhibitors could act as reversible cytostatic agents which may be useful in the treatment of any disease process which features abnormal cellular proliferation, e.g., neuro-fibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis following angioplasty or vascular surgery, hypertrophic scar formation, inflammatory bowel disease, transplantation rejection, angiogenesis, and endotoxic shock.
The invention also encompasses use of compounds of the invention in the treatment of Alzheimer's disease, as suggested by the recent finding that cdkS5 is involved in the phosphorylation of tau protein (J. Biochem, 117, 741-749 (1995)).
The invention also encompasses use of compounds of the invention as inhibitors of other protein kinases, e.g., protein kinase C, her2, rafl, MEK 1, MAP kinase, EGF receptor,
PDGEF receptor, IGF receptor, PI3 kinase, weel kinase, Src, Abl, VEGF, and Ick, and thus be effective in the treatment of diseases associated with other protein kinases.
The invention also encompasses use of compounds of the invention to induce or inhibit apoptosis, a physiological cell death process critical for normal development and homeostasis. Alterations of apoptotic pathways contribute to the pathogenesis of a variety of human diseases. Compounds of formula I, as modulators of apoptosis, will be useful in the treatment of a variety of human diseases with abberations in apoptosis including cancer (particularly, but not limited to, follicular lymphomas, carcinomas with p53 mutations, hormone dependent tumors of the breast, prostate and ovary, and precancerous lesions such as familial adenomatous polyposis), viral infections (including, but not limited to, herpesvirus, poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus), autoimmune diseases (including, but not limited to, systemic lupus, erythematosus, immune mediated
WO (12/10162 PCT/USO1/15081 glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel diseases, and autoimmune diabetes mellitus), neurodegenerative disorders (including, but not limited : Alzheimer’s disease, AIDS-related dementia, Parkinson’s disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellar degeneration), AIDS, : 5 myelodysplastic syndromes, aplastic anemia, ischemic injury associated myocardial infarctions, stroke and reperfusion injury, arrhythmia, atherosclerosis, toxin-induced or alcohol induced liver diseases, hematological diseases (including, but not limited to, chronic anemia and aplastic anemia), degenerative diseases of the musculoskeletal system (including, but not limited to, osteoporosis and arthritis), aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple sclerosis, kidney diseases, and cancer pain.
In another embodiment, the invention encompasses a method of inhibiting cdk in a cell. In particular, the invention encompasses treatment or prevention of diseases associated with cdk modulation by administering one or more compounds of the invention to a mammal in need thereof.
The invention encompasses treatment of mammals, particularly humans.
In addition, compounds of the invention can be used for treating chemotherapy- induced alopecia, chemotherapy-induced thrombocytopenia, chemotherapy-induced leukopenia or mucocitis. In the treatment of chemotherapy-induced alopecia, the compounds of the invention are preferably topically applied in the form of a medicament such as a gel, solution, dispersion or paste.
The compounds of this invention may be used in combination (before, during, after, including cycling administration) with known anti-cancer treatments such as radiation therapy or with cytostatic and cytotoxic agents including, but not limited to, microtuble- stabilizing agents, microtuble-disruptor agents, alkylating agents, anti-metabolites, epidophyllotoxin, an antineoplastic enzyme, a topoisomerase inhibitor, procarbazine, mitoxantrone, platinum coordination complexes, biological response modifiers, growth inhibitors, hormonal/anti-hormonal therapeutic agents, haematopoietic growth factors, and the like.
Classes of anti-cancer agents which may be used in combination with the formula I compounds of this invention include, but are not limited to, the anthracycline family of : drugs, the vinca drugs, the mitomycins, the bleomycins, the cytotoxic nucleosides, the taxanes, the epothilones, discodermolide, the pteridine family of drugs, diynenes, aromatase inhibitors, and the podophyllotoxins. Particular members of those classes include, for example, paclitaxel, docetaxel, 7-O-methylthiomethylpaclitaxel (disclosed in U.S. 5,646,176), 3'-tert-butyl-3'-N-tert-butyloxycarbonyl-4-deacetyl-3'-dephenyl-3'-N- debenzoyl-4-O-methoxycarbonyl-paclitaxel (disclosed in USSN 60/179,965) filed on
February 3, 2000 which is incorporated herein by reference thereto), C-4 methyl carbonate paclitaxel (disclosed in WO 94/14787), epothilone A, epothilone B, epothilone C, epothilone D, desoxyepothilone A, desoxyepothilone B, [1S- [IR*3R*(E),7R*,10S*,11R* 12R*, 16S*1]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1- : 5 methyl-2-(2-methyi-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione (disclosed in WO 99/02514), [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2- (aminomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl- 4,17-dioxabicyclo]14.1.0}heptadecane-5,9-dione (disclosed in USSN 09/506,481 filed on
February 17, 2000 which is incorporated herein by reference thereto), doxorubicin, carminomycin, daunorubicin, aminopterin, methotrexate, methopterin, dichloro- methotrexate, mitomycin C, porfiromycin, 5-fluorouracil, 6-mercaptopurine, gemcitabine, cytosine arabinoside, podophyllotoxin or podophyllotoxin derivatives such as etoposide, etoposide phosphate or teniposide, melphalan, vinblastine, vincristine, leurosidine, vindesine, leurosine, and the like. Other useful anti-cancer agents which may be used in combination with the compounds of the present invention include, but are not limited to, estramustine, cisplatin, carboplatin, cyclophosphamide, bleomycin, tamoxifen, ifosamide, melphalan, hexamethyl melamine, thiotepa, cytarabin, idatrexate, trimetrexate, dacarbazine,
L-asparaginase, camptothecin, CPT-11, topotecan, ara-C, bicalutamide, flutamide, : leuprolide, pyridobenzoindole derivatives, interferons, interleukins, and the like. In addition, the compounds of this-invention may beused in combination with inhibitors of farnesyl protein transferase such as those described in U.S. 6,011,029; anti-angiogenic agents such as angiostatin and endostatin; kinase inhibitors such as her2 specific antibodies; and modulators of p53 transactivation.
If formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range described below and the other pharmaceutically active agent within its approved dosage range. Compounds of formula I may be used sequentially, in any order, with known anti-cancer or cytotoxic agents when a combination formulation is inappropriate. —-
The present invention also provides pharmaceutical compositions which comprise a compound of this invention and a pharmaceutically acceptable carrier. It should be noted . that, in the context of the pharmaceutical compositions of the present invention, the compounds of the invention, or compounds of formula I, refer to the free base, enantiomers, : diastereomers, solvates, as well as pharmaceutically acceptable salts. Examples of such pharmaceutically acceptable salts include, but are not limited to, hydrochloride, dihydrochloride, sulfate, trifluoroacetate, mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, citrate, methanesulfonate, bromate and iodate salts.
Also included are salts formed with other organic and inorganic acids such as hydroxymethane sulfonic acid, acetic acid, benzenesulfonic acid, toluenesulfonic acid and various others, e.g., nitrates, phosphates, borates, benzoates, ascorbates, salicylates, and the like. These salts include racemic forms as well as enantiomers and diastereomers (such as, . 5 for example, D-tartrate and L-tartrate salts). In addition, pharmaceutically acceptable salts of compounds of formula I may be formed with alkali metals such as sodium, potassium and lithium; alkaline earth metals such as calcium and magnesium; organic bases such as dicyclohexylamine, tributylamine, and pyridines, and the like; and amino acids such as arginine, lysine and the like.
The pharmaceutical compositions of the present invention may further comprise one or more pharmaceutically acceptable additional carriers, excipients, or diluents including, but not limited to, ingredient(s) such as alum, stabilizers, antimicrobial agents, buffers, coloring agents, flavoring agents, and the like. The compounds and compositions of this invention may be administered orally or parenterally including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.
For oral use, the compounds and compositions of this invention may be administered, for example, in the form of tablets or capsules, or as solutions or suspensions.
In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch, and lubricating agents such as magnesium stearate are commonly added. For oral administration in capsule form, useful carriers include lactose and corn starch. When aqueous suspensions are used for oral administration, emulsifying and/or suspending agents are commonly added. In addition, sweetening and/or flavoring agents may be added to the oral compositions. For intramuscular, intraperitoneal, subcutaneous and intravenous use, sterile solutions of the active ingredient(s) are usually employed, and the pH of the solutions should be suitably adjusted and buffered. For intravenous use, the total concentration of the solute(s) should be controlled in order to render the preparation isotonic.
Daily dosages for human administration of the compounds of this invention will normally be determined by the prescribing physician with the dosages generally varying according to the age, weight, route of administration, and response of the individual patient, as well as the severity of the patient’s symptoms. A formula I compound of this invention . is preferably administered to humans in an amount from about 0.001 mg/kg of body weight to about 100 mg/kg of body weight per day, more preferably from about 0.01 mg/kg of . body weight to about 50 mg/kg of body weight per day, and most preferably from about 0.1 mg/kg of body weight to about 20 mg/kg of body weight per day.
cdc2/cyclin Bl Kinase Assay cde2/cycelin B1 kinase activity was determined by monitoring the incorporation of *P into histone HI. The reaction consisted of 50 ng baculovirus expressed GST-cdc2, 75 ng baculovirus expressed GST-cyclin B1, 1 pg histone HI (Boehringer Mannheim), 0.2 pCi of
Py-ATP and 25 pM ATP in kinase buffer (50 mM Tris, pH 8.0, 10 mM MgCl, | mM
EGTA, 0.5 mM DTT). The reaction was incubated at 30 °C for 30 minutes and then stopped by the addition of cold trichloroacetic acid (TCA) to a final concentration of 15 % and incubated on ice for 20 minutes. The reaction was harvested onto GF/C unifilter plates (Packard) using a Packard Filtermate Universal harvester, and the filters were counted on a
Packard TopCount 96-well liquid scintillation counter (Marshak, D.R., Vanderberg, M.T.,
Bae, Y.S., Yu, L1., J. of Cellular Biochemistry, 45, 391-400 (1991), incorporated by reference herein). cdk2/cyclin E Kinase Assay cdk2/cyclin E kinase activity was determined by monitoring the incorporation of **P into the retinoblastoma protein. The reaction consisted of 2.5 ng baculovirus expressed
GST-cdk2/cyclin E, 500 ng bacterially produced GST-retinoblastoma protein (aa 776-928), 0.2 uCi *P y-ATP and 25 uM ATP in kinase buffer (50 mM Hepes, pH 8.0, 10 mM MgCl, 5 mM EGTA, 2 mM DTT). The reaction was incubated at 30 °C for 30 minutes and then “stopped by the addition of cold trichloroacetic acid (TCA) to a final concentration of 15 % and incubated on ice for 20 minutes. The reaction was harvested onto GF/C unifilter plates (Packard) using a Packard Filtermate Universal harvester, and the filters were counted ona
Packard TopCount 96-well liquid scintillation counter. cdk 4/cyelin D1 Kinase Activity cdk4/cyclin D1 kinase activity was determined by monitoring the incorporation of *P in to the retinoblastoma protein. The reaction consisted of 165 ng baculovirus expressed --as-GST-cdk4, 282 ng bacterially expressed as S-tag cyclin D1, 500 ng bacterially produced
GST-retinoblastoma protein (aa 776-928), 0.2 pCi **P y-ATP and 25 uM ATP in kinase buffer (50 mM Hepes, pH 8.0, 10 mM MgCl,, 5 mM EGTA, 2 mM DTT). The reaction . was incubated at 30 °C for 1 hour and then stopped by the addition of cold trichloroacetic acid (TCA) to a final concentration of 15 % and incubated on ice for 20 minutes. The reaction was harvested onto GF/C unifilter plates (Packard) using a Packard Filtermate
Universal harvester, and the filters were counted on a Packard TopCount 96-well liquid : scintillation counter (Coleman, K.G., Wantlet, B.S., Morissey, D, Mulheron, J.G., Sedman,
S., Brinkley, P., Price, S., Webster, K.R. (1997) Identification of CDK4 Sequences involved in cyclin D, and p16 binding. J. Biol. Chem. 272,30:18869-18874, incorporated by reference herein). } In order to facilitate a further understanding of the invention, the following examples are presented primarily for the purpose of illustrating specific compounds of the : 5 invention. The scope of the invention should not be deemed limited by the examples, but encompasses the entire subject matter defined in the claims.
EXAMPLE 1: Preparation of S-[S-(t-Butyl)-2-oxazolylmethylthio]-2- (azacycloalkanoylamino-thiazole hydrochloride
N
N s— 1 0 >— sy 0 H
NH « HCI
A. Preparation of a-Azido-pinacolone oO
SO N3 a-Bromo-pinacolone (199.07 g, 1.1115 mol, 1 eq) was combined in 1.785 L of acetone with sodium azide (93.9 g, 1.4444 mol, 1.3 eq). The reaction was stirred at room temperature for 27.5 hours. The resulting slurry was filtered and washed with acetone (3 x 150 mL). The filtrate was concentrated in vacuo to provide 154.3 g (98.4%) of the title compound. HPLC 83.85% at 2.57 minutes (Phenomenex Inc., Torrance, CA, 5 um C18 column 4.6 x 50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm).
B. Preparation of a-Hexamethylenetetramino-pinacolone Bromide ) N o] i
Nil__-N Br a : a-Bromo-pinacolone (179 g, 1 mol, 1 eq) was combined in 2 L of acetone with hexamethylenetetramine (154.21 g, 1.1 mol, 1.1 eq) and the reaction stirred under N, at room temperature for 26 hours. The resulting slurry was filtered, the filter cake was washed with ether (3 x 50 mL) and dried in vacuo at 50°C overnight to provide 330 g (100%) of the title compound containing 7% hexamethylenetetramine. HPLC R.T.=0.17 min (Phenomenex Inc., 5 pm C18 column 4.6 x 50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). : 5
C. Preparation of ¢-Amino-pinacolone Hydrochloride o} > - HCI a-Azido-pinacolone (128.5 g, 0.911 mol) was combined in 4.2 L of methanol with 77.1 mL of concentrated HCl and 15.42 g of 10% Pd/C. The reaction mixture was stirred under hydrogen for 1.5 hours. The catalyst was removed by filtration. The solvent was distilled to give a wet solid. The residual water was azeotropically removed with 1sopropanol (2 x 500 mL). Tert-butyl methyl ether (300 mL) was added and the resulting slurry was stirred, filtered, washed with t-butyl methyl ether (3 x 100 mL) and dried to give 131.0 g (95.5%) of the title compound.
D. Preparation of a-Amino-pinacolone Hydrochloride 0
Sn © HCl a-Hexamethylenetetramino-pinacolone bromide (400 g, 1.254 mol, 1 eq) was combined in 2 L of ethanol with 12 N aqueous HCl (439 mL, 5.26 mol, 4.2 eq). The reaction was stirred at 75°C for 1 hour and then allowed to cool to room temperature, the resulting slurry filtered, the filtrate concentrated in vacuo and isopropyl alcohol was added.
The solution was filtered again. Addition of 1.2 L of ether caused the desired material to precipitate from solution. The material was filtered, washed with ether (2 x 300 mL), and dried in vacuo at 50°C overnight to provide 184.1 g (97%) of the title compound.
E. Preparation of ¢-N-(2-Chloroacetylamino)-pinacolone 0] . > 3a lo) . 5
The title compound of part D (130.96 g, 0.8637 mol, 1 eq) was dissolved in 3.025 L of CH,Cl, under N, at -5°C. Triethylamine (301 mL, 2.16 miol, 2.5 eq) was added, followed by chloroacety! chloride (75.7 mL, 0.450 mol, 1.1 eq) in 175 mL of CH,Cl,. The resulting slurry was stirred at -5 to -10°C for 2 hours. Water (1.575 L) was added, followed by 175 mL of concentrated HCI. The organic phase was washed a second time with 1.75 L of 10% aqueous HCI, and then with 500 mL of water. The organic phase was dried over
Na,SO, and concentrated in vacuo to provide 155.26 g (93.8%) of the title compound.
HPLC R.T.=2.27 min (Phenomenex Inc., 5 pm C18 column 4.6 x 50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).
F. Preparation of 5-(t-Butyl)-2-Oxazolylmethyl Chloride "\
Ad
The title compound of part E (180.13 g, 0.9398 mol, 1 eq) was combined with phosphorus oxychloride (262 mL, 2.8109 mol, 3 eq) under N,. The reaction was heated at 105°C for 1 hour, the mixture was cooled to room temperature, and quenched with 1.3 kg ofice. The aqueous phase was extracted with ethyl acetate (1 L, then 2 x 500 mL). The organic extracts were washed with saturated aqueous NaHCO, (4 x 1 L) which was back- extracted several times with ethyl acetate. The organic phases were combined, washed with saturated aqueous NaHCO; (500 mL) followed by saturated aqueous NaCl (300 mL), dried over MgSO,, and concentrated in vacuo to give a brown oil. The crude material was distilled under high vacuum at 100°C to provide 155.92 g (96%) of the title compound.
HPLC R.T.=3.62 min (Phenomenex Inc., 5 pm C18 column 4.6 x 50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 . nm).
Alternatively, the title compound of part E (10.0 g, 52.17 mmol, 1 eq.) in 50 mL of tetrahydrofuran (THF) was combined with (methoxycarbonylsulfamyl)-triethylammonium hydroxide (Burgess reagent, 105.70 mmol, 2.03 eq., generated in situ from 9.2 mL of chlorosulfonyl isocyanate, 4.4 mL of methanol and 14.8 mL of triethylamine in 100 mL
THF). The reaction was heated to 45°C for 1.5 hours. After cooling to room temperature, : the reaction was quenched with water (50 mL). The organic layer was separated and washed with saturated NaHCO, (2 x 50 mL) and water (50 mL), dried over MgSO, and passed ‘ 5 through a small silica gel plug. The solvent was removed to give an oil which was taken up in a mixture of 15 mL heptane and 90 mL of t-butyl methyl ether, and then washed with 0.2
N HCI (2 x 25 mL), saturated brine (25 mL) and dried (MgSO,). Filtration and removal of solvent gave 10.9 g of the title compound.
G. Preparation of 5-(t-Butyl)-2-oxazolylmethyl Thiouronium Hydrochloride
NH
Ns «Hal » — le}
The title compound of part F (1.77 g, 10.2 mmol, 1.02 eq) was combined with thiourea (0.76 g, 9.98 mmol, 1 eq) under N, in 10 mL of absolute ethanol. The reaction was heated at reflux for 1.5 hours. The mixture was cooled to room temperature and concentrated in vacuo. Trituration of the resulting crude material with t-butyl methyl ether provided 2.32 g (93%) of the title compound. HPLC R.T.=2.05 min (Phenomenex Inc., 5 pum C18 column 4.6 x 50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm); 'H NMR (d,-DMSO): § 9.48 (s, 3H), 6.85 (s, 1H), 4.73 (s, 2H), 1.24 (s, 9H).
H. Preparation of 5-[5-(t-Butyl)-2-oxazolylmethylthio]-2-aminothiazole oa
SA S$” “NH, : The title compound of part G (1.25 g, 5 mmol, 1 eq) was added to a mixture of
NaOH (3.0 g, 75 mmol, 15 eq), water (10 mL), toluene (10 mL) and tetrabutylammonium sulfate (50 mg, 0.086 mmol, 0.017 eq). 5-Bromo-2-aminothiazole hydrobromide (1.70 g, 5 mmol, 1 eq) was added and the reaction was stirred at room temperature for 14.5 hours. The -28 -
Ck mixture was diluted with water and extracted twice with ethyl acetate, the organic extracts washed with water (4 x 10 mL), dried over MgSO, and concentrated in vacuo to provide 1.1 2 (82%) of the title compound. HPLC 86.3% at 2.75 min (Phenomenex Inc., 5 pm C18 column 4.6 x 50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2% . 5 phosphoric acid, 4 mL/min, monitoring at 220 nm); 'H NMR (CDCL,): § 6.97 (s, 1H), 6.59 (s, 1H), 5.40 (br s, 2H), 3.89 (s, 2H), 1.27 (s, 9H).
LL Preparation of 5-[5-(t-Butyl)-2-oxazolylmethylthio]-2-[(N-t-butoxycarbonyl)- azacycloalkanoyl]aminothiazole
N s—/ Eig 0 ae 0 | H
N._©O
MS
The title compound of part H (9.6 g, 35.6 mmol) was dissolved in N,N- dimethylformamide (36 mL) and CH,Cl, (100 mL), to which was added 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (13.8 g, 72 mmol, 2 eq), N-t- butoxycarbonyl-azacycloalkanoic acid (12.6 g, 55 mmol, 1.5 eq), and 4- (dimethylamino)pyridine (2 g, 16 mmol, 0.45 eq). The clear reaction mixture became cloudy as it was stirred at room temperature for 3.5 hours. Water (300 mL) and ethyl acetate (200 mL) were added and the resulting precipitate was removed by filtration. The filtrate was extracted with ethyl acetate, the organic extracts dried over MgSO, and concentrated in vacuo to provide a yellow solid which was combined with the precipitate obtained by filtration. The solid was boiled in a mixture of ethanol, acetone and water for 20 minutes, filtered, washed with an ethanol/water mixture and dried to give 16.6 g (97%) of the title compound.
WO (02/10162 PCT/USO1/15081
J. Preparation of 5-[5-(t-Butyl}-2-oxazolylmethylthio]-2-(azacycloalkanoylamino- thiazole hydrochloride
N sR . 5 | H— Ss “N 0) H
NH « HCI
The title compound of part I (16.6 g) was dissolved in 150 mL of CH,CL, trifluoroacetic acid (30 mL) was added dropwise, and the mixture was stirred at room temperature for 2 hours. The reaction was concentrated in vacuo, diluted with water (300 mL), cooled in ice, made basic with sodium hydroxide, and the resulting solid filtered and recrystallized from ethanol, water and methanol to provide 11.2 g (83%) of the title compound as a yellow solid. The white solid hydrochloride could be obtained by addition of 18 mL of IN aqueous HCl to 7 g of this material in methanol. MS: 381 [M+H]"; HPLC: 100% at 3.12 min (YMC S5 ODS column 4.6 x 50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).
Example 2: Preparation of (£)-N-[5-[[[S-(1,1-Dimethylethyl)-2-oxazolyl}- methylithio]-2-thiazolyl]-3-piperidinecarboxamide
N
AA S N NH
(CH3),C 0 7
N 5
A. +)-N-z-butoxycarbonyl-nipecotic acid
COzH : BOC
Nipecotic acid (1.3 g, 10 mmol, 1 eq) was combined with 10 mL of dioxane, 2 ml, of acetonitrile, 10 mL of water, and 10 mL of 1N aqueous NaOH (1 eq). Di-#-butyl :
dicarbonate (3.3 g, 15 mmol, 1.5 eq) was added and the reaction mixture was stirred at it overnight. The reaction mixture was concentrated in vacuo to remove organic solvent and % aqueous citric acid was added The mixture was extracted with ethyl acetate (3 x 100 mL). The organic extracts were dried over Na,SO,, filtered through silica gel, and . 5 concentrated in vacio. The crude material was recrystallized from ethyl acetate and hexanes to provide 2.2 g (96 %) of (+)-N-z-butoxycarbonyl-nipecotic acid as a white solid.
B. (£)-N-[5-[[[5-(1.1-Dimethylethyl)-2-oxazolylJmethyl]thio]-2-thiazolyl]-(N-z- butoxycarbonyl)-3-piperidinecarboxamide 10 J y \ [S H
AD A
\ J 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (383 mg, 2 mmol, 2 eq) was added to a mixture of 2-amino-5-[[[5-(1,1-dimethylethyl)-2- oxazolyl]methyl]thio]thiazole (270 mg, 1 mmol, 1 eq), N-z-butoxycarbonyl-nipecotic acid h (344 mg, 1.5 mmol, 1.5 eq), 4-(dimethylamino)pyridine (61 mg, 0.5 mmol, 0.5 eq), -20-N,N-dimethylformamide (1 mL) and CH,CL, (6 mL). The reaction mixture was stirred at rt for 1.3 h. Triethylamine (0.28 mL, 2 mmol, 2 eq) was added, and the reaction mixture was stirred for 1h. Additional N-t-butoxycarbonyl-nipecotic acid (340 mg), triethylamine (0.28 mL) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (380 mg) were added. After 1 h, no further change was observed. Additional 4- (dimethylamino)pyridine, N,N-dimethylformamide, triethylamine and starting acid were added and the reaction was stirred overnight at rt. The resulting black solution was diluted with saturated aqueous NaHCO, and extracted with CH,Cl,. The organic extracts were dried, concentrated iz vacuo, and purified by flash chromatography on silica gel eluting with a gradient of 50-100% ethyl acetate in hexanes to provide 397 mg (83 %) of (£)-N-[5- [[[5-(1,1-dimethylethyl)-2-oxazolylJmethyl]thio]-2-thiazolyl]-(N-z-butoxycarbonyl)-3- . piperidinecarboxamide as a yellow glassy solid.
WO (2/10162 PCT/US01/15081
C. (£)-N-[5-[[[5-(1.1-Dimethylethyl)-2-oxazolyllmethyl]thio]-2-thiazolyl]-3- piperidinecarboxamide
N
. 5
AA ® ° A (CH3)sC 0 7 \ J (®)-N-[5-[[[5-(1,1-Dimethylethyl)-2-oxazolylmethyl]thio]-2-thiazolyl]-(N-z- butoxycarbonyl)-3-piperidinecarboxamide (355 mg, 0.74 mmol, 1 eq) was dissolved in 3 mL of CH,Cl,. Trifluoroacetic acid (3 mL) was added, and the mixture was stirred at t for 20 min. The reaction mixture was concentrated in vacuo and neutralized with saturated aqueous NaHCO,. The resulting mixture was extracted with ethyl acetate. The organic extracts were dried over Na,SO,, concentrated in vacuo, and recrystallized from ethyl acetate to provide 142 mg (50 %) of (+)-N-[5-[[[5-(1,1-dimethylethyl)-2- oxazolyllmethyl]thio]-2-thiazolyl]-3-piperidinecarboxamide as a white solid. MS: 381 [M+H]"; HPLC: 100 % at 3.15 min (YMC S5 ODS column 4.6 x 50 mm, 10-90 % aqueous methanol over 4 minutes containing 0.2 % phosphoric acid, 4 mL/min, monitoring at 220 nm).
Example 3: Preparation of (+)-1-(2,3-Dihydroxypropyl)-N-[5- [[[S-(1,1-dimethylethyl)-2-oxazolylJmethyl]thio]- 2-thiazolyl}-4-piperidinecarboxamide
N YT yo S N OH (CHa):C 0 hh \ /
N-[5-[[[5-(1,1-Dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4- . piperidinecarboxamide (66 mg, 0.17 mmol, 1 eq) was combined with glyceraldehyde (69 mg, 0.77 mmol, 4.5 eq), sodium triacetoxyborohydride (163 mg, 0.77 mmol, 4.5 eq) and . 1,2-dichloroethane (4 mL). The resulting suspension was stirred at rt for 4 h. Methanol (1 mL) was added and the reaction mixture was stirred at rt overnight, concentrated in vacuo and purified by preparative HPLC to provide 69 mg (59 %) of (£)-1-(2,3- dihydroxypropyl)-N-[5-[[[5-(1,1-dimethylethyl)-2-0xazolylJmethyl]thio]-2-thiazolyl]-4-
piperidinecarboxamide as a white solid. MS: 455 [M+H]"; HPLC: 100 % at 3.06 min (YMC
S5 ODS column 4.6 x 50 mm, 10-90 % aqueous methanol over 4 minutes containing 0.2 % } phosphoric acid, 4 mL/min, monitoring at 220 nm).
Example4: Preparation of N-[3-[[[5-(1,1-Dimethylethyl)-2-oxazolyljmethyl|thio]-2- thiazolvl]-1-(1-methvlethyl)-4-piperidinecarboxamide
N BN
AN ° ® ve (CH3)sC 0) hd \
A. Ethyl-1-(1-methylethyl)-4-piperidine carboxylate
CO,Et - : x
Ethyl isonipecotate (3.2 g, 20 mmol, 1 eq) was combined with acetone (5.8 g, 100 mmol, 5 eq), sodium triacetoxyborohydride (10.5 g, 50 mmol, 2.5 eq) and 1,2- dichloroethane (200 mL). The reaction mixture was stirred at rt for 72 h. Saturated aqueous NaHCO, was added, and the mixture was extracted with CH,Cl,. The organic extracts were dried, filtered through a silica gel pad, and concentrated in vacuo to provide 3.72 g (93 %) of ethyl 1-(1-methylethyl)-4-piperidine carboxylate as a colorless liquid.
B. 1-(1-Methylethyl)-4-piperidine carboxvlic acid
COoH
Ethyl 1-(1-methylethyl)-4-piperidine carboxylate (3.6 g, 18 mmol, 1 eq) was combined with barium hydroxide octahydrate (10.4 g, 33 mmol, 1.8 eq) in a mixture of 70 mL of water with 44 mL of ethanol. The mixture was heated at 60°C for 1.3 h. The reaction mixture was concentrated in vacuo and diluted with 70 mL of water. Ammonium carbonate (6.9 g, 87 mmol, 4.8 eq) was added portionwise and the reaction mixture was stirred at rt overnight. The mixture was filtered through diatomaceous earth, concentrated, and lyophilized to provide 3.1 g (100 %) of 1-(1-methylethyl)-4-piperidine carboxylic acid as a white solid.
C. N-[5-[[[5-(1.1-Dimethylethyl)-2-oxazolylJmethyljthio]-2-thiazolyl]-1-(1- methylethyl)-4-piperidinecarboxamide
N A yo S N (CHe)C 0 7
A
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.0 g, 5.2 mmol, 2 eq) was added to a mixture of 2-amino-5-[[[5-(1,1-dimethylethyl)-2- oxazolyl]methyljthio]thiazole (0.7 g, 2.6 mmol, 1 eq), 1-(1-methylethyl)-4-piperidine carboxylic acid (0.78 g, 3.9 mmol, 1.5 eq), 4-(dimethylamino)pyridine (0.16 g, 1.3 mmol, 0.5 eq), N,N-dimethylformamide (2.6 mL) and CH,Cl, (7.8 mL). The reaction mixture was } stirred at rt for 1 h, diluted with 30 mL of water and extracted with ethyl acetate (2 x 70 mL). The organic extracts were dried over Na,SO,, concentrated in vacuo, and purified by flash chromatography on silica gel eluting with a gradient of 5-10 % triethylamine in ethyl acetate. The material was recrystallized from ethanol and water to provide 0.93 g(85
%) of N-[5-[[[5-(1,1-dimethylethyl)-2-0xazolylJmethyl]thio]-2-thiazolyl]-1-(1- methylethyl)-4-piperidinecarboxamide as a yellowish solid. MS: 423 [M+H]"; HPLC: 100 % at 3.15 min (YMC S5 ODS column 4.6 x 50 mm, 10-90 % aqueous methanol over 4 minutes containing 0.2 % phosphoric acid, 4 mL/min, monitoring at 220 nm). . 5
Example 5: Preparation of 1-Cyclopropyl-N-[5-[[[5-(1,1-dimethylethyl)-2- oxazolyllmethyl]thio]-2-thiazolyl]-4-piperidinecarboxamide
N Ng
A pp SON (CH3)}C 0 bd
AO
A. 1-Cyclopropyl-4-piperidine carboxylic acid e
A
Ethyl isonipecotate (1.57 g, 10 mmol, 1 eq) was combined with ((1- ethoxycyclopropyl)oxy)trimethyl silane (8.7 g, 50 mmol, 5 eq) in 100 mL of methanol.
Acetic acid (5.7 mL, 100 mmol, 10 eq) and molecular sieves were added. After 30 min at rt, sodium triacetoxyborohydride (2.5 g, 40 mmol, 4 eq) was added and the reaction mixture was heated at 65°C overnight. The reaction mixture was cooled and Na,CO, (20 g) was added. The mixture was stirred at rt for 2 h and filtered through diatomaceous earth. The diatomaceous earth was washed with methanol. The filtrates were combined, concentrated in vacuo, diluted with water, and extracted with ethyl acetate. The organic extracts were : dried, filtered through a silica gel pad, and concentrated in vacuo to provide 2.4 g of colorless liquid. This material was combined with barium hydroxide octahydrate (5.7 g, 18 mmol, 1.8 eq) in a mixture of 38 mL of water with 24 mL of ethanol. The mixture was heated at 60°C for 1 h. The reaction mixture was concentrated in vacuo and diluted with 38 mL of water. Ammonium carbonate (3.8 g) was added portionwise and the reaction was stirred at rt for 2 h. The mixture was filtered through diatomaceous earth, washing with water. The filtrate was washed with ethyl acetate. Concentration of the aqueous phase provided 1.56 g (92 %) of 1-cyclopropyl-4-piperidine carboxylic acid as a hygroscopic . white solid. : 5 B. 1-CyclopropyI-N-[5-[[[5-(1.1-dimethylethy)-2-oxazolyl]-methyl]thio]-2-thiazolyl]- 4-piperidinecarboxamide
N Ng
Fy ° 71 ) : (CH3)3C 0 | he
N 0 1-(3-Dimethylaminopropy!)-3-ethylcarbodiimide hydrochloride (1.0 g, 5.2 mmol, 2 eq) was added to a mixture of 2-amino-3-[[[5-(1,1-dimethylethyl)-2- oxazolyl]methyl]thio]thiazole (0.7 g, 2.6 mmol, 1 eq), 1-cyclopropyl-4-piperidine carboxylic acid (0.77 g, 3.9 mmol, 1.5 eq), 4-(dimethylamino)pyridine (0.16 g, 1.3 mmol, 0.5 eq), N,N-dimethylformamide (2.6 mL) and CH, Cl, (7.8 mL). The reaction mixture was stirred-atrt-for-1 h, diluted with water (30 mL), and extracted with ethyl acetate (2 x 70 mL). The combined organic extracts were dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by flash chromatography on silica gel eluting with a gradient of 0-10 % triethylamine in ethyl acetate. The material was crystallized from ethyl acetate and hexanes to provide 0.7 g (65 %) of 1-cyclopropyl-N-[5-[[[5-(1,1-dimethylethyl)- 2-oxazolyllmethyl]thio]-2-thiazolyl]-4-piperidinecarboxamide as white crystals. MS: 421 [M+H]"; HPLC: 100 % at 3.13 min (YMC S5 ODS column 4.6 x 50 mm, 10-90 % aqueous methanol over 4 minutes containing 0.2 % phosphoric acid, 4 mL/min, monitoring at 220 nm).
Example 6: Preparation of N-[5-[{[5-(1,1-Dimethylethyl)-2-oxazolyl]methyl]thio]-2- thiazolyl]-1-(2-hydroxvethyl)-4-piperidinecarboxamide
OH
N > (CHa)C o | he
N o) 100 A, N[5-[[[5-(1.1-Dimethylethy])-2-oxazolylJmethyl]thio]-2-thiazolyl]-1-(2-dimethyl-t- butylsilyloxyethyl)-4-piperidinecarboxamide 0
N NTT ON SiCHRCCHa), (CHalC 0 hd
N 0
N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyljmethyl]thio}-2-thiazolyl]-4- piperidinecarboxamide (1.4 g, 3.68 mmol, 1 eq) was dissolved in 30 mL of
N,N-dimethylformamide and 100 mL of tetrahydrofuran. 2-(Bromoethoxy)-z- butyldimethylsilane (0.79 mL, 3.68 mmol, 1 eq), and NaHCO, were added and the reaction mixture was stirred at 50°C for 23 h. Additional 2-(bromoethoxy)-z-butyldimethylsilane "(0.9 mL) was added, and the reaction mixture was stirred at 50°C for 22 h, cooled, concentrated in vacuo and diluted with water (25 mL). The resultant aqueous mixture was extracted with ethyl acetate (50 mL). The organic extract was dried over Na,SO,, concentrated in vacuo, and purified by flash chromatography on silica gel eluting with a gradient of 0-5 % triethylamine in ethyl acetate to provide 1.7g (84 %) of N-[5-[[[5-(1,1- " dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-1-(2-dimethyl-z-butylsilyloxyethyl)-4- -piperidinecarboxamide-as a yellow solid. MS: 539 [M+H]"; HPLC: 98 % at 4.01 min (YMC . 30 g5 ODS column 4.6 x 50 mm, 10-90 % aqueous methanol over 4 minutes containing 0.2 % phosphoric acid, 4 mL/min, monitoring at 220 nm).
B. N-[5-[[[5-(1.1-Dimethylethyl)-2-oxazolyllmethyl]thio]-2-thiazolyl]-1-(2- hydroxyethyl)-4-piperidinecarboxamide
OH
N
Ad ° 1 i : (CH3)3C 0 | hg
N 0
N-[5-[[[5-(1,1-Dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-1-(2-dimethyl-z- butylsilyloxyethyl)-4-piperidinecarboxamide (1.45 g, 2.7 mmol, 1 eq) was dissolved in 100 mL of acetonitrile and combined with aqueous HF (48 % aqueous, 2.5 mL). The reaction mixture was stirred for 4 h at rt. An additional 2.5 mL of aqueous HF was added, and the reaction mixture was stirred overnight. Ethyl acetate (100 mL) and saturated aqueous NaHCO; (50 mL) were added. Additional solid NaHCO, was added to make the mixture basic. The mixture was extracted with ethyl acetate (2 x 50 mL). The organic extracts were dried over Na,SQ,, filtered through a pad of silica gel, and concentrated in vacuo. The resulting white solid was crystallized from ethanol and water to provide 1.6 g (59 %) of N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolylmethyl]thio]-2-thiazolyl]-1-(2- hydroxyethyl)-4-piperidinecarboxamide as a white solid. MS: 425 [M+H]"; HPLC: 100 % at 3.05 min (YMC S5 ODS column 4.6 x 50 mm, 10-90 % aqueous methanol over 4 minutes containing 0.2 % phosphoric acid, 4 mL/min, monitoring at 220 nm).
Example 7: Preparation of (R)-N-{5-[[[5-(1,1-Dimethylethy})-2- oxazolyl]methyl]thio]-2-thiazolyl]-3-piperidine- carboxamide hydrochloride
N - HCI ww NY
N )
A. (R)- and (S)-N-[5-[[[5-(1.1-Dimethylethyl)-2-oxazolylJmethyl]thio]-2-thiazolyl-(N- t-butoxycarbonyl)-3-piperidinecarboxamide
N
A py ® h ) AN " (CHa)sC 0 | he hi BOC
N lo] ®)
N
A Ao ° Y ) NS AN (CHa)sC 0] | hd BOC
N Oo ©) 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.8 g, 20 mmol, 2 eq) was added to a mixture of 2-amino-5-[[[5-(1,1-dimethylethyl)-2- oxazolyllmethyl]thio}thiazole (2.7 g, 10 mmol, 1 eq), N-t-butoxycarbonyl-nipecotic acid (3.4 g, 1.5 mmol, 1.5 eq), N,N-dimethylformamide (10 mL) and CH,Cl, (30 mL). The reaction mixture was stirred at rt for 4 h. The resulting black solution was concentrated in ‘vacuo, diluted with water (90 mL) and extracted with ethyl acetate (100 mL, then 2 x 75 } mL). The organic extracts were dried over Na,CO,, concentrated in vacuo, and purified by flash chromatography on silica gel eluting with a gradient of 50-100 % ethyl acetate in . hexanes to provide 3.8 g (79 %) of a yellow solid. The enantiomers were separated by chiral HPLC (Chiral Pak AD 5 x 50 cm 20 p: eluent 10 % (0.1 % triethylamine in isopropanol) in hexanes; 45 mL/min, detection at 254 nm, loading 300 mg in 5S mL of isopropanol) to give each of the two optically pure isomers: 1.65 g of the R isomer and 1.65 g of the S isomer.
B. (R)-N-[5-[[[5-(1.1-Dimethvlethyl)-2-oxazolyllmethyl]thio]-2-thiazolyl}-3- piperidinecarboxamide hydrochloride / \ + HCI
H
AX S S N aw NH {CH3)sC 0 ’ Co]
N lo}
The (R) isomer of Part A (1.65 g, 3.43 mmol, 1 eq) was dissolved in 10 mL of
CH,CI,. Trifluoroacetic acid (6 mL) was added, and the mixture was stirred at rt for several hours. The reaction mixture was concentrated in vacuo and neutralized with saturated 15 aqueous NaHCO,. The resulting mixture was stirred with ethyl acetate for 1 h. The organic extracts were dried over Na,SO, and concentrated in vacuo to provide a yellowish solid.
The solid was dissolved in methanol and 1 eq of IN aqueous HCI was added. The resulting solution was lyophilized to provide 1 g (77 %) of (R)-N-[5-[[[5-(1,1-dimethylethy])-2- oxazolyl]methyl]thio]-2-thiazolyl]-3-piperidinecarboxamide hydrochloride as a yellow -20 ~solid: MS: 381 [M+HT"; HPLC: "100 % at 3.14 min (YMC S5 ODS column 4.6 x 50 mm, 10-90 % aqueous methanol over 4 minutes containing 0.2 % phosphoric acid, 4 mL/min, monitoring at 220 nm).
Example 8: Preparation of (S)-N-[5-[[[5-(1,1-Dimethylethyl)-2-oxazolyl]- ns methyl]thio]-2-thiazolyl]-3-piperidine carboxamide hydrochloride
N * HCI (CHa)aC 0 | hd 30 N 0
The (S) isomer of Example 7, Part A (1.65 g, 3.43 mmol, 1 eq) was dissolved in mL of CH,Cl,. Trifluoroacetic acid (6 mL) was added, and the mixture was stirred at rt for several hours. The reaction was concentrated in vacuo and neutralized with saturated aqueous NaHCO,. The resulting mixture was stirred with ethyl acetate for 1 h. The organic extracts were dried over Na,SO, and concentrated in vacuo to provide a yellowish solid.
The solid was dissolved in methanol and 1 eq of IN aqueous HC] was added. The resulting solution was lyophilized to provide 0.918 g (70 %) of (S)-N-[5-[[[5-(1,1-dimethylethyl)-2- oxazolyllmethyl]thio]-2-thiazolyl]-3-piperidinecarboxamide hydrochloride as a yellow solid. MS: 381 [M+H]"; HPLC: 100 % at 3.15 min (YMC S5 ODS column 4.6 x 50 mm, : 5 10-90 % aqueous methanol over 4 minutes containing 0.2 % phosphoric acid, 4 mL/min, monitoring at 220 nm).
Example 9: Preparation of cis-4-Amino-N-{5-[[[5-(1,1-dimethylethy])-2-oxazolyl]- methyl]thio]-2-thiazolyl]cyclohexylcarboxamide hydrochloride and trans-4-Amino-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl|methyl]thio]-2- thiazolyl]-cyclohexylearboxamide hydrochloride
N NH, / * HCI
S NH erane—{ Is
Ue
Oo wNH a a. * HCI (CHg3)3C SS a \
N O
A. 4-(z-Butoxycarbonylamino)cyclohexane carboxylic acid
Or NHiBOC
HO,C
To a solution of 2.86 g (20 mmol) of 4-aminocyclohexane carboxylic acid in 40 mL of 0.5M aqueous NaOH solution, 20 mL of dioxane and 4 mL of acetonitrile was added a total of 6.5 g (30 mmol) of /Boc anhydride at room temperature. After 20 h, 100 mL of ethyl acetate and 100 mL of 10 % aqueous citric acid solution were introduced. The aqueous layer which formed was separated and extracted with three-50 mL portions of ethyl acetate. The organic phases were combined, dried (sodium sulfate) and concentrated in vacuo to give 6.0 g (125 %) of crude 4-(¢-butoxycarbonylamino)cyclohexane carboxylic acid as a colorless oil which solidified upon standing.
B. 4-(¢-Butoxycarbonylamino)-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]-methyl]thio]- 2-thiazolyllcyclohexylcarboxamide
NHBOC
: Va
S<_S<_NH (CHy)sC Ae Or
N 0
To a solution of 5 g of crude 4-(z-butoxycarbonylamino)cyclohexane carboxylic acid and 3.50 g (13 mmol) of 2-amino-5-[[[5-(1,1-dimethylethyl)-2- oxazolyljmethyl]thio]thiazole in 13 mL of N,N-dimethylformamide and 36 mL of methylene chloride was added 5.0 g (26 mmol) of 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride at room temperature. The reaction mixture was stirred overmght and diluted with 100 mL of water. The aqueous layer was separated and extracted with two-150 mL portions of ethyl acetate. The combined organic phases were dried (sodium sulfate) then filtered through a pad of silica gel. The filtrate was concentrated in vacuo to afford an orange solid. The crude material was recrystallized (95 % ethanol) to give 4-(t-butoxycarbonylamino)-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolylimethyl]thio]-2- thiazolyljcyclohexylcarboxamide as a yellow solid. The mother liquors were also -concentrated-in vacuo to give additional 4-(z-butoxycarbonylamino)-N-[5-[[[5-(1,1- dimethylethyl)-2-oxazolyljmethyl]thio]-2-thiazolyl]cyclohexylcarboxamide as a brown solid.
C. cis-4- Amino-N-[5-[[[5-(1.1-dimethvlethyl)-2-oxazolyl]methyl]thio]- 2-thiazolyl]eyclohexylcarboxamide hydrochloride and trans-4- . Amino-N-[5-[[[5-(1,1-dimethylethy])-2-oxazolyl|methyl]thio]-2- thiazolyl]-cyclohexvlcarboxamide hydrochloride : 5
N NH, corgeL Is ou JT HCI
A
N 0 7 N NH» cre s Sy w J * HCl
A
N Oo
To a suspension of 4-(z-butoxycarbonylamino)-N-[5-[[[5-(1,1-dimethylethyl)-2- oxazolyllmethyl]thio]-2-thiazolyl]cyclohexylcarboxamide (from Part B mother liquors) suspended in 15 mL of methylene chloride was added 5 mL of trifluoroacetic acid at room temperature. The reaction mixture was stirred for 2 h then concentrated in vacuo to remove 70 volatiles. The residue was diluted with water, basified with aqueous NaOH solution then the resulting aqueous solution was extracted with ethyl acetate. The combined organic extracts were dried (sodium sulfate) to give a crude cis/trans product. The crude material was purified by flash chromatography (Merck silica, 25x3 cm, 1:9 isopropylamine/ethyl acetate then 1:2:7 methanol/isopropylamine/ethyl acetate) to afford 0.74 g of the cis isomer as a yellow solid and 0.50 g of the trans isomer as a brown solid. The cis isomer was dissolved in methanol then 0.34 mL of 5N aqueous HCl was added. The solution was concentrated in vacuo, washed with ether, diluted with water and lyophilized to afford 0.80 g of cis-4-amino-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolylJmethyl]thio]-2~ thiazolyl]cyclohexylcarboxamide hydrochloride as a yellow solid. MS: 395 [M+H];
HPLC-HI 98 % at 3.17 min (YMC S5 ODS column 4.6 x 50 mm, 10-90 % aqueous : methanol over 4 minutes containing 0.2 % phosphoric acid, 4 mL/min, monitoring at 220 nm). The trans isomer was dissolved in methanol then 0.24 mL of SN aqueous HCI was : added. The solution was concentrated in vacuo, washed with ether, diluted with water and lyophilized to afford 0.54 g of trans-4-amino-N-[5-[[[5-(1,1-dimethylethyl)-2- oxazolylmethyl]thio]-2-thiazolyljcyclohexylcarboxamide hydrochloride as an orange solid.
MS: 395 [M+H]"; HPLC-HI 96 % at 3.22 min (YMC S5 ODS column 4.6 x 50 mm, 10-90
% aqueous methanol over 4 minutes containing 0.2 % phosphoric acid, 4 mL/min, monitoring at 220 nm).
Example 10: N-[5-[[[5-(1,1-Dimethylethyl)-2-oxazolyl]methyl]thio}-2-thiazolyl]-4- piperidinecarboxamide, monohvdrochloride
N NH+HCI
AN :
S S N
(CHg)sC 0 hd
N 0]
To a solution of 40 mL of absolute EtOH cooled in an ice-bath was added acetyl chloride (0.28 mL, 3.9 mmol) dropwise. The reaction mixture was allowed to warm to room temperature over 30 min then N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]-thio]- 2-thiazolyl]-4-piperidinecarboxamide (1.50 g, 3.94 mmol, 1 eq) was introduced in one portion with stirring to give a thick slurry. Water (~4 mL) was added until homogeneous then concentrated in vacuo to give a crude pale yellow solid. The crude material was recrystallized (aq EtOH) to afford the title compound (70%) as a white solid, mp 256-258°.
Analysis calc'd for C17H24N402S2+HCI: C, 48.96; H, 6.04; N, 13.43; S, 15.38; Cl, 8.50.
Found: C,48.69; H, 5.99; N, 13.24; S, 15.27; C1, 8.31.
Example 11: N-[5-[{[5-(1,1-Dimethylethyl)-2-oxazolylJmethyl]thio]-2-thiazolyl]-4- piperidinecarboxamide, monohydrobromide
N NH-HBr
ANC :
S S N
(CHz)sC 0 hd \ /
To a solution of IM HBr in EtOH (0.5 mL) was added N-[5-[[[5-(1,1- dimethylethyl)-2-oxazolyllmethyl]thio]-2-thiazolyl]-4-piperidinecarboxamide (190 mg, 0.5 mmol, 1 eq) then cooled to -40°C overnight. The solid precipitate that formed was collected on a Buchner funnel, washed with absolute EtOH then dried under vacuum at 100°C to afford the title compound (72%) as a fine white powder, mp 235-237° C.
Analysis calc'd for C17H24N402S2-HBr: C, 44.24; H, 5.46; N, 12.14; S, 13.89; Br, 17.31.
Found: C, 44.16; H, 5.40; N, 12.12; §, 13.91; Br, 17.70.
Example 12: N-[5-[[[5-(1,1-Dimethylethyl)-2-oxazolylJmethyl]thio]-2-thiazolyl]-4- piperidinecarboxamide, 0.5-L-tartaric acid salt
N NH=0.5 L-Tartrate . 5 AA S H ae hd \ J
To a warm solution of N-[5-[[[5-(1,1-dimethylethyl)-2-0xazolyljmethyl]thio]-2- thiazolyl]-4-piperidinecarboxamide (1.75 g, 4.6 mmol) in absolute EtOH (70 mL) was added a solution of L-tartaric acid (345 mg, 2.3 mmol, 0.5 eq) in absolute EtOH (5 mL). A precipitate started to form after several minutes. The mixture was allowed to stand for 4 hr at room temperature then the solid precipitate was collected on a Buchner funnel, washed with absolute EtOH and dried under vacuum at 85°C for 24 hr to afford the title compound (94%) as pale yellow crystals, mp 234-236°C. Analysis calc'd for C17H24N4028240.5-L-
Tartaric acid: C, 50.09; H, 5.97; N, 12.29; S, 14.07. Found: C, 49.85; H, 5.90; N, 12.12;
S, 13.75.
Example 13: N-[5-[[[5-(1,1-Dimethylethyl)-2-oxazolylJmethyl]thio]-2-thiazolyl]-4- piperidinecarboxamide, 0.5-D-tartaric acid salt
N NH«0.5 D-Tartrate
Fy :
S S N
(CH3);C 0 NXT \ 7]
To a warm solution of N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolylJmethyl]thio]-2- thiazolyl]-4-piperidinecarboxamide (1.00 g, 2.63 mmol) in absolute EtOH (40 mL) was added a solution of D-fartaric acid (198 mg, 1.32 mmol, 0.5 eq) in absolute EtOH (4 mL).
A precipitate started to form after several minutes. The mixture was allowed to stand for 18 hr at room temperature then the solid precipitate was collected on a Buchner funnel, washed with absolute EtOH and dried under vacuum at 65°C for 6 hr to afford the title compound (73%) as a white solid, mp 232-233°C. Analysis calc'd for C17H24N402S2+0.5-D-Tartaric acid: C, 50.09; H, 5.97; N, 12.29; S, 14.07. Found: C, 49.75; H, 5.81; N, 12.04; S, 13.37.
Example 14: N-[5-[[[5-(1,1-Dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4- piperidinecarboxamide, 0.5-fumaric acid salt
N NH+0.5-Fumarate ’ A do ° ° (CH3)sC 0] bd
AO
To a warm solution of N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyljmethyl]thio]-2- thiazolyl]-4-piperidinecarboxamide (1.75 g, 4.6 mmol) in absolute EtOH (100 mL) was added a solution of fumaric acid (276 mg, 2.3 mmol, 0.5 eq) in absolute EtOH (5 mL). A precipitate started to form after 10 minutes. The mixture was allowed to stand for 2 hr at room temperature then at 5°C for 16 hr. The solid precipitate which formed was collected on a Buchner funnel, washed with absolute EtOH and dried under vacuum at 65°C for 24 hr to afford the title compound (84%) as a white solid, mp 206-207° C. Analysis calc'd for
C17H24N40282+0.5-Fumaric acid: C, 52.04; H, 5.98; N, 12.77; §, 14.62. Found: C, 51.74; H, 5.76; N, 12.57; S, 14.19. Recrystallization (95% aq EtOH) afforded the title compound containing 1 mol EtOH (83%) as large colorless crystals, mp 212-214° C.
Analysis calc'd for C17H24N402S2+0.5-Fumaric acid*EtOH: C, 52.05; H, 6.66; N, 11.56; 5.13.23. Found: C, 52.03; H, 6.06; N, 11.50; S, 12.99.
Example 15: N-[5-[[[5-(1,1-Dimethylethyl)-2-oxazolyl] methyl] thio]-2-thiazolyl]-4- piperidinecarboxamide, 0.5-succinic acid salt
N NH+0.5 Succinate
A PGE > N (CHy)sC 0 h 4
N oO
To a warm solution of N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolylJmethyl]thio]-2- thiazolyl]-4-piperidinecarboxamide (50 mg, 0.13 mmol) in absolute EtOH (2 mL) was i added a solution of succinic acid (7.7 mg, 0.065 mmol, 0.5 eq) in absolute EtOH (0.25 mL).
A precipitate started to form after 10 minutes. The mixture was allowed to stand for 1 hr at room temperature then the precipitate was collected on a Buchner funnel, washed with absolute EtOH and dried under vacuum at 100° C for 24 hr to afford the title compound (70%) as a white solid, mp 190-192° C. Analysis calc'd for C17H24N40282+0.5-Succinic acid*0.46H20: C, 50.96; H, 6.28; N, 12.51; S, 14.32. Found: C, 50.96; H, 6.20; N, 12.49;
S, 14.23.
Example 16: N-[5-[[[5-(1,1-Dimethylethyl)-2-oxazolylJmethyl]thio]-2-thiazolyl]-4- ) c piperidinecarboxamide, 0.5-sulfuric acid salt
N NH-0.5 H,S0,
AN
S S N
N 0
To a warm solution of N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyljmethyl]thio]-2- thiazolyl]-4-piperidinecarboxamide (50 mg, 0.13 mmol) in absolute EtOH (2 mL) was added a IM aq solution of sulfuric acid (0.065 mL, 0.065 mmol, 0.5 eq). A precipitate
IS" formed almost immediately. The mixture was cooled to 5° C. for 2 hr then the precipitate was collected on a Buchner funnel, washed with absolute EtOH and dried under vacuum at 100° C for 24 hr to afford the title compound (79%) as a white solid, mp 256-258° C.
Analysis calc'd for C17H24N402S2+0.5H2504+0.68H20: C, 46.22; H, 6.01; N, 12.68; S, 18.14. Found: C, 46.21; H, 5.95; N, 12.71; S, 18.23.
Example 17: N-[5-{[[5-(1,1-Dimethylethyl)-2-oxazolyljmethyl] thio}-2-thiazolyl]-4- piperidinecarboxamide, 0.5-citric acid salt
N NH-0.5 Citrate
H
(CHa)C 0 hd \ /
To a warm solution of N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyljmethyl]thio]-2- . thiazolyl]-4-piperidinecarboxamide (50 mg, 0.13 mmol) in absolute EtOH (2 mL) was added a solution of citric acid (8.3 mg, 0.043 mmol, 0.33 eq ). The solution was cooled to 5° C for 18 hr then the precipitate which formed was collected on a Buchner funnel, washed with absolute EtOH and dried under vacuum at 100° C for 24 hr to afford the title compound (68%) as a white solid, mp 214-216° C. Analysis calc'd for
C17H24N402S82+0.5-Citric acid*0.10H20: C, 50.21; H, 5.94; N, 11.71; S, 13.40. Found:
C, 50.21; H, 6.01; N, 11.83; S, 13.44. ]
Example 18: N-[5-[{[5-(1,1-Dimethylethyl)-2-oxazolyl] methyl]thio]-2-thiazolyl]-4- piperidinecarboxamide, methanesulfonic acid salt
N NH-MeSO,H
AA S N
\ /
To a slurry of N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolylJmethyl]thio]-2-thiazolyl]-4- piperidinecarboxamide (100 mg, 0.26 mmol) in isopropyl alcohol (0.75 mL) was added methanesulfonic acid (0.017 mL, 0.26 mmol, 1 eq ). The slurry was heated to 70° C to give a clear solution then methyl t-butyl ether (1.5 mL) was added. Within 15 minutes a precipitate formed. The resulting mixture was stirred at 55° C for 2 hr then at room temperature for 14 hr. The precipitate which formed was collected by filtration then dried under vacuum at 50° C for 14 hr to afford the title compound (85%) as a colorless powder, mp 105° C. Analysis calc'd for C17H24N402S2-MSA-H20: C, 43.70; H, 6.11; N, 11.32;
S, 19.44. Found: C, 43.53; H, 6.14; N, 11.15; §, 19.15.
Example 19: N-[5-[[[5-(1,1-Dimethylethyl)-2-oxazolylJmethyl]thio}-2-thiazolyl}-4- piperidinecarboxamide, 0.5-D.L-malic acid salt
N NH+0.5 Malic acid
AN N
S S N
(CHz)sC 0” ~ ™ hd \ J ] ]
To a solution of N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolylJmethyl]thio]-2-thiazolyl]- 4-piperidinecarboxamide (100 mg, 0.26 mmol) in isopropyl alcohol (0.80 mL) was added slowly at 70° C a solution of D,L-malic acid (35 mg, 0.13 mmol, 0.5 eq ) in isopropyl alcohol (0.3 mL). A precipitate formed immediately. The resulting mixture was stirred at 55° C for 2 hr then at room temperature for 14 hr. The precipitate was collected by filtration then dried under vacuum at 50° C for 14 hr to afford the title compound (75%) as a colorless powder, mp 216° C. Analysis calc'd for C17H24N40282+0.5-C4H605+H20:
C, 50.98; H, 6.08; N, 12.51; S, 14.32. Found: C, 50.55; H, 6.17; N, 12.29; S, 14.05.
Claims (113)
1. A compound of formula I : 5 N Ri AN os FN R 0) (CHa)y AO N 0 D and enantiomers, diastereomers, solvates, and pharmaceutically acceptable salts thereof, : wherein: Ris alkyl; R'is hydrogen or alkyl; X is NR? or CHNR?R?; R? and R? are each independently hydrogen, alkyl, substituted alkyl, cycloalkyl or substituted cycloalkyl; and nis0,1,2o0r3.
2. The compound according to claim 1 wherein: R is alkyl, R'is hydrogen; Xis NR? or CHNR’R?; R? and R? are each independently hydrogen, alkyl, substituted alkyl or cycloalkyl; and nis 2.
3. The compound according to claim 1 of formula Ia N (CHa) (6) hd SR, : 5 N 0 (Ia) and enantiomers, diastereomers, solvates, and pharmaceutically acceptable salts thereof wherein R? is hydrogen, alkyl, substituted alkyl or cycloalkyl.
4. The compound according to claim 1 of formula Ib N | nN Re / \ y S S N (CHg)s 0 hd \ J (Ib) and enantiomers, diastereomers, solvates, and pharmaceutically acceptable salts thereof wherein R? is hydrogen, alkyl, substituted alkyl or cycloalkyl. :
5. The compound according to claim 1 of formula Ic NR;Rz N (CHs)s 0 hd \ / (© and enantiomers, diasteromers, solvates, and pharmaceutically acceptable salts thereof : wherein R? and R? are each independently hydrogen, alkyl, substituted alkyl or cycloalkyl.
6. The compound according to claim 1 selected from the group consisting of: N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolylJmethyl]thio]-2-thiazolyl]-4- : piperidinecarboxamide; (£)-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl Jmethyl]thio]-2-thiazolyl]-3- piperidinecarboxamide; (£)-1-(2,3-dihydroxypropyl)-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolylJmethy!]thio]- 2-thiazolyl]-4-piperidinecarboxamide; N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-1-(1- methylethyl)-4-piperidinecarboxamide; I-cyclopropyl-N-[5-[[[5-(1,1-dimethylethyl)-2-0xazolyl[methyl]thio]-2-thiazolyl]-4- piperidinecarboxamide; N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolylmethyl]thio]-2-thiazolyl]-1-(2- hydroxyethyl)-4-piperidinecarboxamide; (R)-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolylJmethyl]thio]-2-thiazolyl]-3- piperidinecarboxamide; (S)-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolylJmethyl]thio]-2-thiazolyl]-3- piperidinecarboxamide; cis-4-amino-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolylJmethyl]thio]-2- thiazolyl]cyclohexylcarboxamide; and trans-4-amino-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyljmethyl]thio}-2- thiazolyl]cyclohexylcarboxamide; and enantiomers, diastereomers, solvates, and pharmaceutically acceptable salts thereof.
7. N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolylJmethyl]thio]-2-thiazolyl}-4- piperidinecarboxamide and enantiomers, diastereomers, solvates, and pharmaceutically acceptable salts thereof.
8. (&)-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyljmethyl]thio}-2-thiazolyl}-3- piperidinecarboxamide and enantiomers, diastereomers, solvates, and pharmaceutically acceptable salts thereof.
9. (R)-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyljmethyl]thio]-2-thiazolyl]-3- : piperidinecarboxamide and pharmaceutically acceptable salts thereof.
10. (S)-N-[5-[[[5-(1,1-dimethylethyl)-2-0xazolylJmethyl]thio]-2-thiazolyl]-3- piperidinecarboxamide and pharmaceutically acceptable salts thereof.
® PCT/US01/15081
11. cis-4-amino-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolylJmethyl]thio]-2- thiazolyl]cyclohexylcarboxamide and enantiomers, diastereomers, solvates, and pharmaceutically acceptable salts thereof.
12. trans-4-amino-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2- thiazolyl]cyclohexylcarboxamide and enantiomers, diastereomers, solvates, and pharmaceutically acceptable salts thereof.
13. A pharmaceutical composition comprising a compound of claim 1 and 2 pharmaceutically acceptable carrier.
14. A pharmaceutical composition comprising a compound of claim 1 in combination with a pharmaceutically acceptable carrier and an anti-cancer agent formulated as a fixed dose. : RK
15. A pharmaceutical composition comprising a compound of claim 1 in combination with a pharmaceutically acceptable carrier and a modulator of p53 transactivation formulated as a fixed dose.
16. A method for modulating apoptosis comprising administering to a mammalian specie an effective apoptosis modulating amount of a compound of claim 1.
17. A method for inhibiting protein kinases comprising administering to a mammalian specie an effective protein kinase inhibiting amount of a compound of claim 1.
18. A method for inhibiting cyclin dependent kinases comprising administering to a mammalian specie an effective cyclin dependent kinase inhibiting amount of a compound of claim 1.
19. A method for inhibiting cdc2 (cdkl) comprising administering to a mammalian specie an effective cdc2 inhibiting amount of a compound of claim 1. -52- AMENDED SHEET
[ PCT/US01/15081
20. A method for inhibiting cdk2 comprising administering to a mammalian specie an effective cdk2 inhibiting amount of a compound of claim 1.
21. A method for inhibiting cdk3 comprising administering to a mammalian specie an effective cdk3 inhibiting amount of a compound of claim 1.
22. A method for inhibiting cdk4 comprising administering to a mammalian specie an effective cdk4 inhibiting amount of a compound of claim 1.
23. A method for inhibiting cdk5 comprising administering to a mammalian specie an effective cdkS inhibiting amount of a compound of claim 1.
24. A method for inhibiting cdk6 comprising administering to a mammalian specie an effective cdké6 inhibiting amount of a compound of claim 1.
25. A method for inhibiting cdk7 comprising administering to a mammalian specie an effective cdk7 inhibiting amount of a compound of claim 1.
26. A method for inhibiting cdk8 comprising administering to a mammalian specie an effective cdk8 inhibiting amount of a compound of claim 1.
27. A method for preventing proliferative diseases comprising administering to a mammalian specie an effective amount of a composition of claim 13.
28. Use of a compound of claim 1, in the manufacture of a preparation for treating cancer.
29. Use of a compound of claim 1, in the manufacture of a preparation for treating inflammation, inflammatory bowel disease or transplantation rejection.
30. Use of a compound of claim 1, in the manufacture of a preparation for treating arthritis. -53- AMENDED SHEET
® PCT/US01/15081
31. A method for preventing proliferative diseases comprising administering to a mammalian specie an effective amount of a composition of claim 14.
32. Use of a composition of claim 14, in the manufacture of a preparation for treating cancer.
33. A method for preventing proliferative diseases comprising administering to a mammalian specie an effective amount of a composition of claim 15.
34. Use of a composition of claim 15, in the manufacture of a preparation for treating cancer.
35. Use of at least one compound of claim 1, in the manufacture of a preparation for the treatment of a cyclin dependent kinase-associated disorder.
36. Use of a compound of claim 1, in the manufacture of a preparation for treating chemotherapy-induced alopecia, chemotherapy-induced thrombocytopenia, chemotherapy-induced leukopenia or mucocitis.
37. The compound of claim 1 wherein said pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, dihydrochloride, sulfate, trifluoroacetate, mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, citrate, methanesulfonate, bromate and iodate salts.
38. The compound of claim 2 wherein said pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, dihydrochloride, sulfate, trifluoroacetate, mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, . maleate, citrate, methanesulfonate, bromate and iodate salts.
39. The compound of claim 3 wherein said pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, dihydrochloride, sulfate,
WO (12/10162 PCT/USO1/15081 trifluoroacetate, mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, citrate, methanesulfonate, bromate and iodate salts.
40. The compound of claim 4 wherein said pharmaceutically acceptable salt is , 5 selected from the group consisting of hydrochloride, dihydrochloride, sulfate, trifluoroacetate, mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, citrate, methanesulfonate, bromate and iodate salts.
41. The compound of claim 5 wherein said pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, dihydrochloride, sulfate, trifluoroacetate, mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, citrate, methanesulfonate, bromate and iodate salts.
42. The compound of claim 6 wherein said pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, dihydrochloride, sulfate, trifluoroacetate, mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, citrate, methanesulfonate, bromate and iodate salts.
43. The compound of claim 7 wherein said pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, dihydrochloride, sulfate, trifluoroacetate, mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, citrate, methanesulfonate, bromate and iodate salts.
44. The compound of claim 8 wherein said pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, dihydrochloride, sulfate, trifluoroacetate, mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, citrate, methanesulfonate, bromate and 1odate salts.
45. The compound of claim 9 wherein said pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, dihydrochloride, sulfate, . . trifluoroacetate, mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, citrate, methanesulfonate, bromate and iodate salts.
46. The compound of claim 10 wherein said pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, dihydrochloride, sulfate,
trifluoroacetate, mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, citrate, methanesulfonate, bromate and iodate salts.
47. The compound of claim 11 wherein said pharmaceutically acceptable salt is : 5 selected from the group consisting of hydrochloride, dihydrochloride, sulfate, trifluoroacetate, mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, citrate, methanesulfonate, bromate and iodate salts.
48. The compound of claim 12 wherein said pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, dihydrochloride, sulfate, trifluoroacetate, mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, citrate, methanesulfonate, bromate and iodate salts.
49. The pharmaceutical composition of claim 13 wherein said pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, dihydrochloride, sulfate, trifluoroacetate, mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, citrate, methanesulfonate, bromate and iodate salts.
50. The pharmaceutical composition of claim 14 wherein said pharmaceutically "720 "acceptable salt’is selected from the group consisting of hydrochloride, dihydrochloride, sulfate, trifluoroacetate, mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, citrate, methanesulfonate, bromate and iodate salts.
51. The pharmaceutical composition of claim 15 wherein said pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, dihydrochloride, sulfate, trifluoroacetate, mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, citrate, methanesulfonate, bromate and iodate salts.
52. The method of claim 17 wherein said pharmaceutically acceptable salt of said compound is selected from the group consisting of hydrochloride, dihydrochloride, . sulfate, trifluoroacetate, mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, citrate, methanesulfonate, bromate and iodate salts.
53. The method of claim 18 wherein said pharmaceutically acceptable salt of said compound is selected from the group consisting of hydrochloride, dihydrochloride,
® PCT/US01/15081 sulfate, trifluoroacetate, mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, citrate, methanesulfonate, bromate and iodate salts.
54. The method of claim 20 wherein said pharmaceutically acceptable salt of said compound is selected from the group consisting of hydrochloride, dihydrochloride, sulfate, trifluoracetate, mixture of trifluoracetate and hydrochloride, tartrate, fumarate, succinate, maleate, citrate, methanesulfonate, bromate and iodate salts.
55. The method of claim 27 wherein said pharmaceutically acceptable salt of said compound is selected from the group consisting of hydrochloride, dihydrochloride, sulfate, trifluoroacetate, mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, citrate, methanesulfonate, bromate and iodate salts.
56. Use of claim 28 wherein said pharmaceutically acceptable salt of said compound is selected from the group consisting of hydrochloride, dihydrochloride, sulfate, trifluoroacetate, mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, citrate, methanesulfonate, bromate and iodate salts.
57. The method of claim 31 wherein said pharmaceutically acceptable salt of said compound is selected from the group consisting of hydrochloride, dihydrochloride, sulfate, trifluoroacetate, mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, citrate, methanesulfonate, bromate and iodate salts.
58. Use of claim 32 wherein said pharmaceutically acceptable salt of said compound is selected from the group consisting of hydrochloride, dihydrochloride, sulfate, trifluoroacetate, mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, citrate, methanesulfonate, bromate and iodate salts.
59. Use of claim 36 wherein said pharmaceutically acceptable salt of said compound is selected from the group consisting of hydrochloride, dihydrochloride, sulfate, trifluoroacetate, mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, citrate, methanesulfonate, bromate and iodate salts.
60. Use of a compound of claim 1, in the manufacture of a preparation for modulating apoptosis. -57- AMENDED SHEET
® PCT/US01/15081
61. Use of a compound of claim 1, in the manufacture of a preparation for inhibiting protein kinases.
62. Use of a compound of claim 1, in the manufacture of a preparation for inhibiting cyclin dependent Kinases.
63. Use of a compound of claim 1, in the manufacture of a preparation for inhibiting cdc2 (cdkl).
64. Use of a compound of claim 1, in the manufacture of a preparation for inhibiting cdk2.
65. Use of a compound of claim 1, in the manufacture of a preparation for inhibiting cdk3.
66. Use of a compound of claim 1, in the manufacture of a preparation for inhibiting cdk4.
67. Use of a compound of claim 1, in the manufacture of a preparation for inhibiting cdks5.
68. Use of a compound of claim 1, in the manufacture of a preparation for inhibiting cdk®6.
69. Use of a compound of claim 1, in the manufacture of a preparation for inhibiting cdk7.
70. Use of a compound of claim 1, in the manufacture of a preparation for inhibiting cdks8.
71. Use of a compound of claim 1, in the manufacture of a preparation for treating proliferative diseases.
72. Use of a composition of claim 14, in the manufacture of a preparation for treating proliferative diseases. -58- AMENDED SHEET
PCT/US01/15081
73. Use of a composition of claim 15, in the manufacture of a preparation for treating proliferative diseases.
74. Use of claim 61 wherein said pharmaceutically acceptable salt of said compound is selected from the group consisting of hydrochloride, dihydrochloride, sulfate, trifluoroacetate, mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, citrate, methanesulfonate, bromate and iodate salts.
75. Use of claim 62 wherein said pharmaceutically acceptable salt of said compound is selected from the group consisting of hydrochloride, dihydrochloride, sulfate, trifluoroacetate, mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, citrate, methanesulfonate, bromate and iodate salts.
76. Use of claim 64 wherein said pharmaceutically acceptable salt of said compound is selected from the group consisting of hydrochloride, dihydrochloride, sulfate, trifluoroacetate, mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, citrate, methanesulfonate, bromate and iodate salts.
77. Use of claim 71 wherein said pharmaceutically acceptable salt of said compound is selected from the group consisting of hydrochloride, dihyrochloride, sulfate, trifluoroacetate, mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, citrate, methanesulfonate, bromate and iodate salts.
78. Use of claim 72 wherein said pharmaceutically acceptable salt of said compound is selected from the group consisting of hydrochloride, dihydrochloride, sulfate, trifluoroacetate, mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, citrate, methanesulfonate, bromate and iodate salts.
79. A substance or composition for use in a method for modulating apoptosis, said substance or composition comprising a compound of claim 1, and said method comprising administering an effective apoptosis modulating amount of said substance or composition to a mammalian specie in need thereof.
80. A substance or composition for use in a method for inhibiting protein kinases, said substance or composition comprising a compound of claim 1, and said
-59.- AMENDED SHEET
¢ PCT/US01/15081 method comprising administering an effective protein kinase inhibiting amount of said substance or composition to a mammalian specie in need thereof.
81. A substance or composition for use in a method for inhibiting cyclin dependent kinases, said substance or composition comprising a compound of claim 1, and said method comprising administering an effective cyclin dependent kinase inhibiting amount of said substance or composition to a mammalian specie in need thereof.
82. A substance or composition for use in a method for inhibiting cdc2 (cdkl), said substance or composition comprising a compound of claim 1, and said method comprising administering an effective cdc2 inhibiting amount of said substance or composition to a mammalian specie in need thereof.
83. A substance or composition for use in a method for inhibiting cdk2, said substance or composition comprising a compound of claim 1, and said method comprising administering an effective cdk2 inhibiting amount of said substance or composition to a mammalian specie in need thereof.
84. A substance or composition for use in a method for inhibiting cdk3, said substance or composition comprising a compound of claim 1, and said method comprising administering an effective cdk3 inhibiting amount of said substance or composition to a mammalian specie in need thereof.
85. A substance or composition for use in a method for inhibiting cdk4, said substance or composition comprising a compound of claim 1, and said method comprising administering an effective cdk4 inhibiting amount of said substance or composition to a mammalian specie in need thereof.
86. A substance or composition for use in a method for inhibiting cdkS5, said substance or composition comprising a compound of claim 1, and said method comprising administering an effective cdk5 inhibiting amount of said substance or composition to a mammalian specie in need thereof.
87. A substance or composition for use in a method for inhibiting cdk6, said -60- AMENDED SHEET
® PCT/US01/15081 substance or composition comprising a compound of claim 1, and said method comprising administering an effective cdk6 inhibiting amount of said substance or composition to a mammalian specie in need thereof.
88. A substance or composition for use in a method for inhibiting cdk7, said substance or composition comprising a compound of claim 1, and said method comprising administering an effective cdk7 inhibiting amount of said substance or composition to a mammalian specie in need thereof.
89. A substance or composition for use in a method for inhibiting cdk8, said substance or composition comprising a compound of claim 1, and said method comprising administering an effective cdk8 inhibiting amount of said substance or composition to a mammalian specie in need thereof.
90. A substance or composition for use in a method for treating proliferative diseases, said substance or composition comprising a compound of claim 1, and said method comprising administering a therapeutically effective amount of said substance or composition to a mammalian specie in need thereof.
91. A substance or composition for use in a method for treating cancer, said substance or composition comprising a compound of claim 1, and said method comprising administering a therapeutically effective amount of said substance or composition to a mammalian specie in need thereof.
92. A substance or composition for use in a method for treating inflammation, inflammatory bowel disease or transplantation rejection, said substance or composition comprising a compound of claim 1, and said method comprising administering a therapeutically effective amount of said substance or composition to a mammalian specie in need thereof.
93. A substance or composition for use in a method for treating arthritis, said substance or composition comprising a compound of claim 1, and said method comprising administering a therapeutically effective amount of said substance or composition to a mammalian specie in need thereof. -61- AMENDED SHEET
® PCT/US01/15081
94. A substance or composition for use in a method for treating proliferative diseases, said substance or composition comprising a composition of claim 14, and said method comprising administering a therapeutically effective amount of said substance or composition to a mammalian specie in need thereof.
95. A substance or composition for use in a method for treating cancer, said substance or composition comprising a composition of claim 14, and said method comprising administering a therapeutically effective amount of said substance or composition to a mammalian specie in need thereof.
96. A substance or composition for use in a method for treating proliferative diseases, said substance or composition comprising a composition of claim 15, and said method comprising administering a therapeutically effective amount of said substance or composition to a mammalian specie in need thereof.
97. A substance or composition for use in a method for treating cancer, said substance or composition comprising a composition of claim 15, and said method comprising administering a therapeutically effective amount of said substance or composition to a mammalian specie in need thereof.
08. A substance or composition for use in a method for the treatment of a cyclin dependent kinase-associated disorder, said substance or composition comprising at least one compound of claim 1, and said method comprising administering an effective amount of said substance or composition to a subject in need thereof.
99. A substance or composition for use in a method for treating chemotherapy-induced alopecia, chemotherapy-induced thrombocytopenia, chemotherapy-induced leukopenia or mucocitis, said substance or composition comprising a compound of claim 1, and said method comprising administering a therapeutically effective amount of said substance or composition to a mammalian specie in need thereof.
100. A substance or composition for use in a method of treatment of claim 80 wherein said pharmaceutically acceptable salt of said compound is selected from the group consisting of hydrochloride, dihydrochloride, sulfate, trifluoroacetate, mixture of -62- AMENDED SHEET
® PCT/US01/15081 trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, citrate, methanesulfonate, bromate and iodate salts.
101. A substance or composition for use in a method of treatment of claim 81 wherein said pharmaceutically acceptable salt of said compound is selected from the group consisting of hydrochloride, dihydrochloride, sulfate, trifluoroacetate, mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, citrate, methanesulfonate, bromate and iodate salts.
102. A substance or composition for use in a method of treatment of claim 83 wherein said pharmaceutically acceptable salt of said compound is selected from the group consisting of hydrochloride, dihydrochloride, sulfate, trifluoroacetate, mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, citrate, methanesulfonate, bromate and iodate salts.
103. A substance or composition for use in a method of treatment of claim 90 wherein said pharmaceutically acceptable salt of said compound is selected from the group consisting of hydrochloride, dihyrochloride, sulfate, trifluoroacetate, mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, citrate, methanesulfonate, bromate and iodate salts.
104. A substance or composition for use in a method of treatment of claim 91 wherein said pharmaceutically acceptable salt of said compound is selected from the group consisting of hydrochloride, dihyrochloride, sulfate, trifluoroacetate, mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, citrate, methanesulfonate, bromate and iodate salts.
105. A substance or composition for use in a method of treatment of claim 94 wherein said pharmaceutically acceptable salt of said compound is selected from the group consisting of hydrochloride, dihyrochloride, sulfate, trifluoroacetate, mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, citrate, methanesulfonate, bromate and iodate salts.
106. A substance or composition for use in a method of treatment of claim 95 wherein said pharmaceutically acceptable salt of said compound is selected from the -63- AMENDED SHEET
$ PCT/US01/15081 group consisting of hydrochloride, dihyrochloride, sulfate, trifluoroacetate, mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, citrate, methanesulfonate, bromate and iodate salts.
107. A substance or composition for use in a method of treatment of claim 99 wherein said pharmaceutically acceptable salt of said compound is selected from the group consisting of hydrochloride, dihyrochloride, sulfate, trifluoroacetate, mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, citrate, methanesulfonate, bromate and iodate salts. :
108. A compound according to claim 1, or any one of claims 7 to 12, substantially as herein described and illustrated.
109. A composition according to claim 13, or claim 14, or claim 15, substantially as herein described and illustrated.
110. A method according to any of claims 16 to 27, or 31, or 33, substantially as herein described and illustrated.
111. Use according to any of claims 28 to 30, or 32, or 34 to 36, or 60 to 73, substantially as herein described and illustrated.
112. A substance or composition for use in a method of treatment according to any of claims 79 to 99, substantially as herein described and illustrated.
113. A new compound; a new composition; a new non-therapeutic method of treatment; a new use of a compound of claim 1; a new use of a composition of claim 14; a new use of a composition of claim 15; or a substance or composition for a new use in a method of treatment, substantially as herein described. -64- AMENDED SHEET
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US61662700A | 2000-07-26 | 2000-07-26 |
Publications (1)
Publication Number | Publication Date |
---|---|
ZA200300452B true ZA200300452B (en) | 2004-06-22 |
Family
ID=34079666
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
ZA200300452A ZA200300452B (en) | 2000-07-26 | 2003-01-16 | N-[5-[[[5-alkyl-2-oxazolyl]methyl]thio]-2-thiazolyl] carboxamide inhibitors of cyclin dependent kinases. |
Country Status (2)
Country | Link |
---|---|
CN (1) | CN100379739C (en) |
ZA (1) | ZA200300452B (en) |
-
2001
- 2001-05-02 CN CNB2005101041461A patent/CN100379739C/en not_active Expired - Fee Related
-
2003
- 2003-01-16 ZA ZA200300452A patent/ZA200300452B/en unknown
Also Published As
Publication number | Publication date |
---|---|
CN1743331A (en) | 2006-03-08 |
CN100379739C (en) | 2008-04-09 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US6515004B1 (en) | N-[5-[[[5-alkyl-2-oxazolyl]methyl]thio]-2-thiazolyl]-carboxamide inhibitors of cyclin dependent kinases | |
ZA200204349B (en) | N-[5-[[[5-alkyl-2-oxazolyl]methyl]thio]-2-thiazolyl] carboxamide inhibitors of cyclin dependent kinases. | |
AU2001259704A1 (en) | N-(5-(((5-alkyl-2-oxazolyl)methyl)thio)-2-thiazolyl) carboxamide inhibitors of cyclin dependent kinases | |
EP1240165B1 (en) | N-[5-[[[5-alkyl-2-oxazolyl]methyl]thio]-2-thiazolyl]-carboxamide inhibitors of cyclin dependent kinases | |
EP1240166B1 (en) | N-[5-[[[5-alkyl-2-oxazolyl]methyl]thio]-2-thiazolyl carboxamide inhibitors of cyclin dependent kinases | |
WO2001081348A1 (en) | USE OF 5-THIO-, SULFINYL- AND SULFONYLPYRAZOLO[3,4-b]-PYRIDINES AS CYCLIN DEPENDENT KINASE INHIBITORS | |
LT5106B (en) | Nuo ciklinu priklausomu kinaziu n-[5-[[[5-alkil-2-oxazolil]metil]tio]-2-tiazolil]karboksamido inhibitoriai | |
ZA200300452B (en) | N-[5-[[[5-alkyl-2-oxazolyl]methyl]thio]-2-thiazolyl] carboxamide inhibitors of cyclin dependent kinases. |