CA2665818A1

CA2665818A1 - Composes therapeutiques

Composes therapeutiques Download PDF

Info

Publication number: CA2665818A1
Authority: CA; Canada
Prior art keywords: compound; independently; formula; nmr; group
Prior art date: 2006-04-25
Legal status : Abandoned

Application number

CA002665818A

Other languages

English (en)

Inventor

Edmond J. Lavoie

Joseph E. Rice

Leroy F. Liu

Current Assignee

University of Medicine and Dentistry of New Jersey

Rutgers State University of New Jersey

Original Assignee

Individual

Priority date

2006-04-25

Filing date

2007-04-24

Publication date

2007-11-08

2007-04-24 Application filed by Individual filed Critical Individual

2007-11-08 Publication of CA2665818A1 publication Critical patent/CA2665818A1/fr

Status Abandoned legal-status Critical Current

Links

150000001875 compounds Chemical class 0.000 title claims abstract description 165
230000001225 therapeutic effect Effects 0.000 title description 4
150000003839 salts Chemical class 0.000 claims abstract description 28
108091081406 G-quadruplex Proteins 0.000 claims abstract description 12
-1 pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino Chemical group 0.000 claims description 47
238000000034 method Methods 0.000 claims description 24
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 18
IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 18
125000003118 aryl group Chemical group 0.000 claims description 16
125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 14
229910052757 nitrogen Inorganic materials 0.000 claims description 12
206010028980 Neoplasm Diseases 0.000 claims description 11
108091033399 Telomestatin Proteins 0.000 claims description 11
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
YVSQVYZBDXIXCC-INIZCTEOSA-N telomestatin Chemical compound N=1C2=COC=1C(N=1)=COC=1C(N=1)=COC=1C(N=1)=COC=1C(N=1)=COC=1C(=C(O1)C)N=C1C(=C(O1)C)N=C1[C@@]1([H])N=C2SC1 YVSQVYZBDXIXCC-INIZCTEOSA-N 0.000 claims description 11
125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 10
201000011510 cancer Diseases 0.000 claims description 10
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 9
239000003814 drug Substances 0.000 claims description 8
229910052717 sulfur Inorganic materials 0.000 claims description 8
125000005605 benzo group Chemical group 0.000 claims description 6
125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 6
238000002560 therapeutic procedure Methods 0.000 claims description 5
241000124008 Mammalia Species 0.000 claims description 4
125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 4
QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 4
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
238000004519 manufacturing process Methods 0.000 claims description 3
239000008194 pharmaceutical composition Substances 0.000 claims description 3
125000006528 (C2-C6) alkyl group Chemical group 0.000 claims description 2
238000013160 medical therapy Methods 0.000 claims description 2
125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 7
239000003937 drug carrier Substances 0.000 claims 1
230000000694 effects Effects 0.000 abstract description 5
230000001028 anti-proliverative effect Effects 0.000 abstract description 3
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 75
230000015572 biosynthetic process Effects 0.000 description 72
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 69
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238000003786 synthesis reaction Methods 0.000 description 62
CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 59
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 55
GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 51
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238000005481 NMR spectroscopy Methods 0.000 description 43
238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 40
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238000006243 chemical reaction Methods 0.000 description 36
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NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 30
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235000011152 sodium sulphate Nutrition 0.000 description 28
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235000019439 ethyl acetate Nutrition 0.000 description 27
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239000000543 intermediate Substances 0.000 description 24
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 24
239000002904 solvent Substances 0.000 description 24
JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 23
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238000002844 melting Methods 0.000 description 22
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VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 21
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238000005303 weighing Methods 0.000 description 21
125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 20
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235000019198 oils Nutrition 0.000 description 19
125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 18
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239000010409 thin film Substances 0.000 description 17
150000001412 amines Chemical class 0.000 description 16
230000002829 reductive effect Effects 0.000 description 16
FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 16
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 16
OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 15
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
239000007832 Na2SO4 Substances 0.000 description 14
239000002253 acid Substances 0.000 description 14
239000012044 organic layer Substances 0.000 description 13
WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 12
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 12
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
125000000217 alkyl group Chemical group 0.000 description 12
150000001408 amides Chemical class 0.000 description 12
229910052786 argon Inorganic materials 0.000 description 12
IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 description 11
150000002148 esters Chemical class 0.000 description 11
239000007788 liquid Substances 0.000 description 11
NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 11
108020004414 DNA Proteins 0.000 description 10
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150000001299 aldehydes Chemical class 0.000 description 10
239000002585 base Substances 0.000 description 10
XNNQFQFUQLJSQT-UHFFFAOYSA-N bromo(trichloro)methane Chemical compound ClC(Cl)(Cl)Br XNNQFQFUQLJSQT-UHFFFAOYSA-N 0.000 description 10
210000004027 cell Anatomy 0.000 description 10
239000012074 organic phase Substances 0.000 description 10
229910000027 potassium carbonate Inorganic materials 0.000 description 10
238000002360 preparation method Methods 0.000 description 10
SZXBQTSZISFIAO-ZETCQYMHSA-N (2s)-3-methyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]butanoic acid Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)OC(C)(C)C SZXBQTSZISFIAO-ZETCQYMHSA-N 0.000 description 9
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
125000004122 cyclic group Chemical group 0.000 description 9
239000010410 layer Substances 0.000 description 9
238000003756 stirring Methods 0.000 description 9
125000001424 substituent group Chemical group 0.000 description 9
FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 9
229960004295 valine Drugs 0.000 description 9
239000004474 valine Substances 0.000 description 9
KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 8
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150000001732 carboxylic acid derivatives Chemical class 0.000 description 8
239000002552 dosage form Substances 0.000 description 8
239000000284 extract Substances 0.000 description 8
NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 8
230000003287 optical effect Effects 0.000 description 8
239000011541 reaction mixture Substances 0.000 description 8
239000003826 tablet Substances 0.000 description 8
238000006646 Dess-Martin oxidation reaction Methods 0.000 description 7
KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 7
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239000004480 active ingredient Substances 0.000 description 7
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 7
229910052681 coesite Inorganic materials 0.000 description 7
229910052906 cristobalite Inorganic materials 0.000 description 7
HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 7
108020004707 nucleic acids Proteins 0.000 description 7
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238000012360 testing method Methods 0.000 description 7
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238000006619 Stille reaction Methods 0.000 description 6
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
125000003545 alkoxy group Chemical group 0.000 description 6
239000007864 aqueous solution Substances 0.000 description 6
239000002775 capsule Substances 0.000 description 6
238000005859 coupling reaction Methods 0.000 description 6
238000001035 drying Methods 0.000 description 6
CFHGBZLNZZVTAY-UHFFFAOYSA-N lawesson's reagent Chemical compound C1=CC(OC)=CC=C1P1(=S)SP(=S)(C=2C=CC(OC)=CC=2)S1 CFHGBZLNZZVTAY-UHFFFAOYSA-N 0.000 description 6
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239000012071 phase Substances 0.000 description 6
125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 6
229940124597 therapeutic agent Drugs 0.000 description 6
239000011701 zinc Substances 0.000 description 6
125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 5
YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 5
XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 5
OJRUSAPKCPIVBY-KQYNXXCUSA-N C1=NC2=C(N=C(N=C2N1[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(CP(=O)(O)O)O)O)O)I)N Chemical compound C1=NC2=C(N=C(N=C2N1[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(CP(=O)(O)O)O)O)O)I)N OJRUSAPKCPIVBY-KQYNXXCUSA-N 0.000 description 5
101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 5
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238000002835 absorbance Methods 0.000 description 5
239000003795 chemical substances by application Substances 0.000 description 5
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229940125758 compound 15 Drugs 0.000 description 5
230000008878 coupling Effects 0.000 description 5
238000010168 coupling process Methods 0.000 description 5
FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 5
238000007327 hydrogenolysis reaction Methods 0.000 description 5
239000000463 material Substances 0.000 description 5
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108010017842 Telomerase Proteins 0.000 description 4
238000010521 absorption reaction Methods 0.000 description 4
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125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 4
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150000002576 ketones Chemical class 0.000 description 4
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235000019359 magnesium stearate Nutrition 0.000 description 4
231100000252 nontoxic Toxicity 0.000 description 4
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150000002916 oxazoles Chemical class 0.000 description 4
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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 4
WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 4
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MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 3
ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 3
GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 3
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NVGBPTNZLWRQSY-UWVGGRQHSA-N Lys-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@H](C(O)=O)CCCCN NVGBPTNZLWRQSY-UWVGGRQHSA-N 0.000 description 3
231100000002 MTT assay Toxicity 0.000 description 3
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229940024606 amino acid Drugs 0.000 description 3
VOBFHFFOFZOEEZ-UHFFFAOYSA-N benzyl 6-formylpyridine-2-carboxylate Chemical compound O=CC1=CC=CC(C(=O)OCC=2C=CC=CC=2)=N1 VOBFHFFOFZOEEZ-UHFFFAOYSA-N 0.000 description 3
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125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
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239000008101 lactose Substances 0.000 description 3
YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 3
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SGNCOKUHMXLGAH-UHFFFAOYSA-N methyl 6-bromopyridine-2-carboxylate Chemical compound COC(=O)C1=CC=CC(Br)=N1 SGNCOKUHMXLGAH-UHFFFAOYSA-N 0.000 description 3
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