AU724216B2

AU724216B2 - A method of treating cancer

A method of treating cancer Download PDF

Info

Publication number: AU724216B2
Authority: AU; Australia
Prior art keywords: alkyl; aryl; substituted; unsubstituted; cycloalkyl
Prior art date: 1997-04-07
Legal status : Ceased

Application number

AU69532/98A

Other languages

English (en)

Other versions

AU6953298A (en

Inventor

Mark E. Duggan

George D. Hartman

David C. Heimbrook

Allen I. Oliff

Current Assignee

Merck and Co Inc

Original Assignee

Merck and Co Inc

Priority date

1997-04-07

Filing date

1998-04-06

Publication date

2000-09-14

1998-01-16 Priority claimed from GBGB9800976.4A external-priority patent/GB9800976D0/en

1998-04-06 Application filed by Merck and Co Inc filed Critical Merck and Co Inc

1998-10-30 Publication of AU6953298A publication Critical patent/AU6953298A/en

2000-09-14 Application granted granted Critical

2000-09-14 Publication of AU724216B2 publication Critical patent/AU724216B2/en

2018-04-06 Anticipated expiration legal-status Critical

Status Ceased legal-status Critical Current

Links

238000000034 method Methods 0.000 title claims description 89
206010028980 Neoplasm Diseases 0.000 title claims description 27
201000011510 cancer Diseases 0.000 title claims description 15
125000000217 alkyl group Chemical group 0.000 claims description 644
125000003118 aryl group Chemical group 0.000 claims description 433
150000001875 compounds Chemical class 0.000 claims description 178
-1 3) OR 6 4) 6 Chemical group 0.000 claims description 166
229910052739 hydrogen Inorganic materials 0.000 claims description 150
239000001257 hydrogen Substances 0.000 claims description 148
125000000623 heterocyclic group Chemical group 0.000 claims description 128
RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 128
150000002431 hydrogen Chemical class 0.000 claims description 110
GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 108
125000003545 alkoxy group Chemical group 0.000 claims description 99
125000000753 cycloalkyl group Chemical group 0.000 claims description 80
125000001424 substituent group Chemical group 0.000 claims description 71
XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 65
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 64
125000005842 heteroatom Chemical group 0.000 claims description 57
125000004432 carbon atom Chemical group C* 0.000 claims description 55
125000003107 substituted aryl group Chemical group 0.000 claims description 55
125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 51
229910052799 carbon Inorganic materials 0.000 claims description 49
125000003282 alkyl amino group Chemical group 0.000 claims description 48
229910052736 halogen Inorganic materials 0.000 claims description 48
150000002367 halogens Chemical class 0.000 claims description 48
229910052757 nitrogen Inorganic materials 0.000 claims description 48
125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 46
125000005010 perfluoroalkyl group Chemical group 0.000 claims description 45
125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 44
229910052731 fluorine Inorganic materials 0.000 claims description 44
102000006495 integrins Human genes 0.000 claims description 42
108010044426 integrins Proteins 0.000 claims description 42
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 41
125000003342 alkenyl group Chemical group 0.000 claims description 39
125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 39
239000003528 protein farnesyltransferase inhibitor Substances 0.000 claims description 39
239000002253 acid Substances 0.000 claims description 38
125000004448 alkyl carbonyl group Chemical group 0.000 claims description 38
125000002947 alkylene group Chemical group 0.000 claims description 38
125000001072 heteroaryl group Chemical group 0.000 claims description 38
229940123038 Integrin antagonist Drugs 0.000 claims description 37
125000004949 alkyl amino carbonyl amino group Chemical group 0.000 claims description 37
UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 36
125000004466 alkoxycarbonylamino group Chemical group 0.000 claims description 36
125000003806 alkyl carbonyl amino group Chemical group 0.000 claims description 36
229910052794 bromium Inorganic materials 0.000 claims description 36
229910052801 chlorine Inorganic materials 0.000 claims description 36
235000001014 amino acid Nutrition 0.000 claims description 35
125000004663 dialkyl amino group Chemical group 0.000 claims description 35
ORTFAQDWJHRMNX-UHFFFAOYSA-N hydroxidooxidocarbon(.) Chemical group O[C]=O ORTFAQDWJHRMNX-UHFFFAOYSA-N 0.000 claims description 35
150000003839 salts Chemical class 0.000 claims description 35
229910052717 sulfur Inorganic materials 0.000 claims description 35
125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 34
125000000304 alkynyl group Chemical group 0.000 claims description 33
125000004122 cyclic group Chemical group 0.000 claims description 33
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 32
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 32
230000001225 therapeutic effect Effects 0.000 claims description 32
150000001413 amino acids Chemical class 0.000 claims description 31
239000003814 drug Substances 0.000 claims description 31
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 30
125000004656 alkyl sulfonylamino group Chemical group 0.000 claims description 30
150000001721 carbon Chemical group 0.000 claims description 30
125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 29
125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 29
229910052760 oxygen Inorganic materials 0.000 claims description 28
125000004433 nitrogen atom Chemical group N* 0.000 claims description 27
125000002950 monocyclic group Chemical group 0.000 claims description 26
125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 25
125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 25
125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 25
125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 24
239000005557 antagonist Substances 0.000 claims description 24
125000005195 alkyl amino carbonyloxy group Chemical group 0.000 claims description 23
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 23
150000002460 imidazoles Chemical class 0.000 claims description 23
229940124597 therapeutic agent Drugs 0.000 claims description 23
108090000623 proteins and genes Proteins 0.000 claims description 22
239000003112 inhibitor Substances 0.000 claims description 20
102000004169 proteins and genes Human genes 0.000 claims description 19
235000004279 alanine Nutrition 0.000 claims description 18
125000004391 aryl sulfonyl group Chemical group 0.000 claims description 18
125000002883 imidazolyl group Chemical group 0.000 claims description 18
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 18
235000018102 proteins Nutrition 0.000 claims description 18
125000002877 alkyl aryl group Chemical group 0.000 claims description 17
125000003710 aryl alkyl group Chemical group 0.000 claims description 17
125000004442 acylamino group Chemical group 0.000 claims description 16
JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Substances N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 16
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 16
230000000694 effects Effects 0.000 claims description 16
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 16
238000011282 treatment Methods 0.000 claims description 16
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 15
125000006574 non-aromatic ring group Chemical group 0.000 claims description 15
239000008194 pharmaceutical composition Substances 0.000 claims description 15
241000124008 Mammalia Species 0.000 claims description 14
125000004043 oxo group Chemical group O=* 0.000 claims description 14
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 13
125000005100 aryl amino carbonyl group Chemical group 0.000 claims description 13
150000001732 carboxylic acid derivatives Chemical group 0.000 claims description 13
125000003367 polycyclic group Chemical group 0.000 claims description 13
101001043818 Mus musculus Interleukin-31 receptor subunit alpha Proteins 0.000 claims description 12
RUZLIIJDZBWWSA-INIZCTEOSA-N methyl 2-[[(1s)-1-(7-methyl-2-morpholin-4-yl-4-oxopyrido[1,2-a]pyrimidin-9-yl)ethyl]amino]benzoate Chemical group COC(=O)C1=CC=CC=C1N[C@@H](C)C1=CC(C)=CN2C(=O)C=C(N3CCOCC3)N=C12 RUZLIIJDZBWWSA-INIZCTEOSA-N 0.000 claims description 12
125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 11
PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 11
DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 11
239000011737 fluorine Substances 0.000 claims description 11
229920006395 saturated elastomer Chemical group 0.000 claims description 11
239000003558 transferase inhibitor Substances 0.000 claims description 11
229910052720 vanadium Inorganic materials 0.000 claims description 11
QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims description 10
150000001408 amides Chemical class 0.000 claims description 10
125000005143 heteroarylsulfonyl group Chemical group 0.000 claims description 10
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 10
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 10
125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 9
229940123468 Transferase inhibitor Drugs 0.000 claims description 9
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 9
PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 claims description 9
125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 8
125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 8
150000008574 D-amino acids Chemical class 0.000 claims description 8
125000001931 aliphatic group Chemical group 0.000 claims description 8
229910052786 argon Inorganic materials 0.000 claims description 8
125000003435 aroyl group Chemical group 0.000 claims description 8
125000004093 cyano group Chemical group *C#N 0.000 claims description 8
125000004475 heteroaralkyl group Chemical group 0.000 claims description 8
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
230000005764 inhibitory process Effects 0.000 claims description 8
125000004076 pyridyl group Chemical group 0.000 claims description 8
125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 7
UKAUYVFTDYCKQA-UHFFFAOYSA-N -2-Amino-4-hydroxybutanoic acid Natural products OC(=O)C(N)CCO UKAUYVFTDYCKQA-UHFFFAOYSA-N 0.000 claims description 7
125000000033 alkoxyamino group Chemical group 0.000 claims description 7
125000001769 aryl amino group Chemical group 0.000 claims description 7
229930195733 hydrocarbon Natural products 0.000 claims description 7
XLSZMDLNRCVEIJ-UHFFFAOYSA-N methylimidazole Natural products CC1=CNC=N1 XLSZMDLNRCVEIJ-UHFFFAOYSA-N 0.000 claims description 7
125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 6
LXBGSDVWAMZHDD-UHFFFAOYSA-N 2-methyl-1h-imidazole Chemical compound CC1=NC=CN1 LXBGSDVWAMZHDD-UHFFFAOYSA-N 0.000 claims description 6
125000001963 4 membered heterocyclic group Chemical group 0.000 claims description 6
125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 6
125000004008 6 membered carbocyclic group Chemical group 0.000 claims description 6
125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 6
125000001960 7 membered carbocyclic group Chemical group 0.000 claims description 6
125000003341 7 membered heterocyclic group Chemical group 0.000 claims description 6
YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 6
125000002252 acyl group Chemical group 0.000 claims description 6
125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 6
150000002148 esters Chemical class 0.000 claims description 6
IWELDVXSEVIIGI-UHFFFAOYSA-N piperazin-2-one Chemical compound O=C1CNCCN1 IWELDVXSEVIIGI-UHFFFAOYSA-N 0.000 claims description 6
125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 6
125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 claims description 6
125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 5
125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 5
125000001054 5 membered carbocyclic group Chemical group 0.000 claims description 5
BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 claims description 5
QJPWUUJVYOJNMH-VKHMYHEASA-N L-homoserine lactone Chemical compound N[C@H]1CCOC1=O QJPWUUJVYOJNMH-VKHMYHEASA-N 0.000 claims description 5
125000003277 amino group Chemical group 0.000 claims description 5
125000005129 aryl carbonyl group Chemical group 0.000 claims description 5
150000002430 hydrocarbons Chemical class 0.000 claims description 5
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
230000003287 optical effect Effects 0.000 claims description 5
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
239000000758 substrate Substances 0.000 claims description 5
125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 5
230000004614 tumor growth Effects 0.000 claims description 5
FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 claims description 4
125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 claims description 4
SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 4
QEFRNWWLZKMPFJ-ZXPFJRLXSA-N L-methionine (R)-S-oxide Chemical compound C[S@@](=O)CC[C@H]([NH3+])C([O-])=O QEFRNWWLZKMPFJ-ZXPFJRLXSA-N 0.000 claims description 4
QEFRNWWLZKMPFJ-UHFFFAOYSA-N L-methionine sulphoxide Natural products CS(=O)CCC(N)C(O)=O QEFRNWWLZKMPFJ-UHFFFAOYSA-N 0.000 claims description 4
HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 4
125000005199 aryl carbonyloxy group Chemical group 0.000 claims description 4
125000005002 aryl methyl group Chemical group 0.000 claims description 4
IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 claims description 4
125000004802 cyanophenyl group Chemical group 0.000 claims description 4
125000004473 dialkylaminocarbonyl group Chemical group 0.000 claims description 4
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 3
UCUNFLYVYCGDHP-BYPYZUCNSA-N L-methionine sulfone Chemical compound CS(=O)(=O)CC[C@H](N)C(O)=O UCUNFLYVYCGDHP-BYPYZUCNSA-N 0.000 claims description 3
125000006598 aminocarbonylamino group Chemical group 0.000 claims description 3
125000004658 aryl carbonyl amino group Chemical group 0.000 claims description 3
125000005162 aryl oxy carbonyl amino group Chemical group 0.000 claims description 3
125000004657 aryl sulfonyl amino group Chemical group 0.000 claims description 3
125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 3
238000004519 manufacturing process Methods 0.000 claims description 3
125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 3
229930192474 thiophene Natural products 0.000 claims description 3
BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 claims description 2
HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims description 2
WEQPBCSPRXFQQS-UHFFFAOYSA-N 4,5-dihydro-1,2-oxazole Chemical compound C1CC=NO1 WEQPBCSPRXFQQS-UHFFFAOYSA-N 0.000 claims description 2
UDFSQTKNKSQMRH-UHFFFAOYSA-N 4-[[5-(4-phenylphenoxy)imidazol-1-yl]methyl]benzonitrile Chemical compound C1=CC(C#N)=CC=C1CN1C(OC=2C=CC(=CC=2)C=2C=CC=CC=2)=CN=C1 UDFSQTKNKSQMRH-UHFFFAOYSA-N 0.000 claims description 2
OITGWZQOTKBNHC-MHAHJAEUSA-N [(3s)-4-[(2r)-2-amino-3-hydroxyheptadecyl]-3-butylpiperazin-1-yl]-naphthalen-1-ylmethanone Chemical compound C1[C@H](CCCC)N(C[C@@H](N)C(O)CCCCCCCCCCCCCC)CCN1C(=O)C1=CC=CC2=CC=CC=C12 OITGWZQOTKBNHC-MHAHJAEUSA-N 0.000 claims description 2
125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 2
125000005140 aralkylsulfonyl group Chemical group 0.000 claims description 2
125000005161 aryl oxy carbonyl group Chemical group 0.000 claims description 2
125000004104 aryloxy group Chemical group 0.000 claims description 2
RFRXIWQYSOIBDI-UHFFFAOYSA-N benzarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 RFRXIWQYSOIBDI-UHFFFAOYSA-N 0.000 claims description 2
102220389089 c.33G>T Human genes 0.000 claims description 2
230000002860 competitive effect Effects 0.000 claims description 2
229940125782 compound 2 Drugs 0.000 claims description 2
MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical compound C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 claims description 2
PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 2
RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 2
CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 claims description 2
102200160920 rs35304565 Human genes 0.000 claims description 2
150000003457 sulfones Chemical class 0.000 claims description 2
125000004494 ethyl ester group Chemical group 0.000 claims 9
UKAUYVFTDYCKQA-VKHMYHEASA-N L-homoserine Chemical compound OC(=O)[C@@H](N)CCO UKAUYVFTDYCKQA-VKHMYHEASA-N 0.000 claims 4
150000002596 lactones Chemical class 0.000 claims 4
SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims 4
150000004702 methyl esters Chemical class 0.000 claims 3
125000004471 alkyl aminosulfonyl group Chemical group 0.000 claims 2
125000004691 alkyl thio carbonyl group Chemical group 0.000 claims 2
ROBXZHNBBCHEIQ-BYPYZUCNSA-N ethyl (2s)-2-aminopropanoate Chemical compound CCOC(=O)[C@H](C)N ROBXZHNBBCHEIQ-BYPYZUCNSA-N 0.000 claims 2
NLZOACWOGZPESV-UHFFFAOYSA-N 4-[[2-[1-[4-(3-chlorophenyl)-3-oxopiperazin-1-yl]ethyl]-1h-imidazol-5-yl]methyl]benzonitrile Chemical compound N=1C=C(CC=2C=CC(=CC=2)C#N)NC=1C(C)N(CC1=O)CCN1C1=CC=CC(Cl)=C1 NLZOACWOGZPESV-UHFFFAOYSA-N 0.000 claims 1
101150004219 MCR1 gene Proteins 0.000 claims 1
101100521345 Mus musculus Prop1 gene Proteins 0.000 claims 1
108091008648 NR7C Proteins 0.000 claims 1
108700017836 Prophet of Pit-1 Proteins 0.000 claims 1
XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims 1
XSAJRSTXUWYGPC-KGLYDCNGSA-N [(3s)-4-butan-2-yl-3-[(2r)-3-hydroxy-2-[(4-nitrophenyl)methylamino]propyl]piperazin-1-yl]-naphthalen-1-ylmethanone Chemical compound N([C@@H](CO)C[C@H]1CN(CCN1C(C)CC)C(=O)C=1C2=CC=CC=C2C=CC=1)CC1=CC=C([N+]([O-])=O)C=C1 XSAJRSTXUWYGPC-KGLYDCNGSA-N 0.000 claims 1
125000005078 alkoxycarbonylalkyl group Chemical group 0.000 claims 1
125000004689 alkyl amino carbonyl alkyl group Chemical group 0.000 claims 1
125000002768 hydroxyalkyl group Chemical group 0.000 claims 1
229910052740 iodine Inorganic materials 0.000 claims 1
VTASBSNTCSICES-UHFFFAOYSA-N n-[2-[3-[(4-cyanophenyl)methyl]imidazol-4-yl]ethyl]-4-phenylbenzamide Chemical compound C=1C=C(C=2C=CC=CC=2)C=CC=1C(=O)NCCC1=CN=CN1CC1=CC=C(C#N)C=C1 VTASBSNTCSICES-UHFFFAOYSA-N 0.000 claims 1
STTPMEVACJNPEF-YADHBBJMSA-N n-[[(2r)-2-amino-3-[(2s)-2-butyl-4-(naphthalene-1-carbonyl)piperazin-1-yl]propyl]sulfanylmethyl]acetamide Chemical compound C1CN(C[C@@H](N)CSCNC(C)=O)[C@@H](CCCC)CN1C(=O)C1=CC=CC2=CC=CC=C12 STTPMEVACJNPEF-YADHBBJMSA-N 0.000 claims 1
102200029256 rs121964925 Human genes 0.000 claims 1
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 162
238000006243 chemical reaction Methods 0.000 description 113
239000000543 intermediate Substances 0.000 description 102
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 69
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 67
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 63
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 55
238000010992 reflux Methods 0.000 description 48
101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 44
238000003786 synthesis reaction Methods 0.000 description 38
229960005141 piperazine Drugs 0.000 description 37
150000001299 aldehydes Chemical class 0.000 description 36
230000015572 biosynthetic process Effects 0.000 description 36
238000005804 alkylation reaction Methods 0.000 description 34
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 33
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 33
239000000047 product Substances 0.000 description 33
239000000460 chlorine Substances 0.000 description 31
235000019439 ethyl acetate Nutrition 0.000 description 31
229940024606 amino acid Drugs 0.000 description 28
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 27
102000004357 Transferases Human genes 0.000 description 25
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