UA71538C2

UA71538C2 - Piperazine or piperidine derivatives, a method for the preparation thereof (variants), a pharmaceutical composition and a method for treatment of diseases (variants)

Piperazine or piperidine derivatives, a method for the preparation thereof (variants), a pharmaceutical composition and a method for treatment of diseases (variants) Download PDF

Info

Publication number: UA71538C2
Authority: UA; Ukraine
Prior art keywords: сно; compound; piperazinyl; benzyl; allyl
Prior art date: 1995-12-22

Application number

UA98074034A

Other languages

English (en)

Ukrainian (uk)

Original Assignee

Astra Pharma Inc

Priority date

1995-12-22

Filing date

1996-11-12

Publication date

2004-12-15

1996-11-12 Application filed by Astra Pharma Inc filed Critical Astra Pharma Inc

2004-12-15 Publication of UA71538C2 publication Critical patent/UA71538C2/uk

Links

239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 7
238000002360 preparation method Methods 0.000 title claims description 94
238000000034 method Methods 0.000 title claims description 80
GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 title claims description 39
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims description 4
150000003053 piperidines Chemical class 0.000 title claims description 3
201000010099 disease Diseases 0.000 title description 2
150000001875 compounds Chemical class 0.000 claims abstract description 162
150000003839 salts Chemical class 0.000 claims abstract description 27
208000002193 Pain Diseases 0.000 claims abstract description 6
230000036407 pain Effects 0.000 claims abstract description 6
RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims description 42
-1 copyrryl Chemical group 0.000 claims description 42
229910052739 hydrogen Inorganic materials 0.000 claims description 28
239000001257 hydrogen Substances 0.000 claims description 28
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 26
125000000217 alkyl group Chemical group 0.000 claims description 23
UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims description 21
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 19
150000002431 hydrogen Chemical class 0.000 claims description 18
125000001424 substituent group Chemical group 0.000 claims description 17
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
229910052736 halogen Inorganic materials 0.000 claims description 14
150000002367 halogens Chemical class 0.000 claims description 13
KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 12
125000000753 cycloalkyl group Chemical group 0.000 claims description 12
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
229910052757 nitrogen Inorganic materials 0.000 claims description 10
NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 9
125000003118 aryl group Chemical group 0.000 claims description 9
125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 9
125000001624 naphthyl group Chemical group 0.000 claims description 9
229910052717 sulfur Inorganic materials 0.000 claims description 9
239000011593 sulfur Substances 0.000 claims description 9
SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 8
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
125000004433 nitrogen atom Chemical group N* 0.000 claims description 8
229910052799 carbon Inorganic materials 0.000 claims description 7
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
239000003795 chemical substances by application Substances 0.000 claims description 6
125000001072 heteroaryl group Chemical group 0.000 claims description 6
YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 claims description 5
239000002253 acid Substances 0.000 claims description 5
125000004429 atom Chemical group 0.000 claims description 5
WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 5
125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 5
125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 claims description 5
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 5
125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 claims description 5
125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 5
125000000723 dihydrobenzofuranyl group Chemical group O1C(CC2=C1C=CC=C2)* 0.000 claims description 5
125000002541 furyl group Chemical group 0.000 claims description 5
125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 claims description 5
125000001041 indolyl group Chemical group 0.000 claims description 5
125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 5
125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 5
125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 5
125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 claims description 5
125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 claims description 5
238000002560 therapeutic procedure Methods 0.000 claims description 5
125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 4
125000005119 alkyl cycloalkyl group Chemical group 0.000 claims description 4
150000001413 amino acids Chemical class 0.000 claims description 4
230000000202 analgesic effect Effects 0.000 claims description 4
150000003857 carboxamides Chemical group 0.000 claims description 4
150000004820 halides Chemical class 0.000 claims description 4
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims description 4
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
208000018522 Gastrointestinal disease Diseases 0.000 claims description 3
108010029485 Protein Isoforms Proteins 0.000 claims description 3
102000001708 Protein Isoforms Human genes 0.000 claims description 3
150000002576 ketones Chemical class 0.000 claims description 3
239000012038 nucleophile Substances 0.000 claims description 3
JTHRRMFZHSDGNJ-UHFFFAOYSA-N piperazine-2,3-dione Chemical compound O=C1NCCNC1=O JTHRRMFZHSDGNJ-UHFFFAOYSA-N 0.000 claims description 3
150000004885 piperazines Chemical class 0.000 claims description 3
229940002612 prodrug Drugs 0.000 claims description 3
239000000651 prodrug Substances 0.000 claims description 3
125000000719 pyrrolidinyl group Chemical group 0.000 claims description 3
125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 2
WVYILDQAQCPQGY-UHFFFAOYSA-N 4-[(1-piperazin-1-ylcyclohexa-2,4-dien-1-yl)methyl]benzonitrile;dihydrochloride Chemical compound Cl.Cl.C1=CC(C#N)=CC=C1CC1(N2CCNCC2)C=CC=CC1 WVYILDQAQCPQGY-UHFFFAOYSA-N 0.000 claims description 2
SRBFZHDQGSBBOR-IOVATXLUSA-N D-xylopyranose Chemical group O[C@@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-IOVATXLUSA-N 0.000 claims description 2
239000007818 Grignard reagent Substances 0.000 claims description 2
239000004480 active ingredient Substances 0.000 claims description 2
125000003342 alkenyl group Chemical group 0.000 claims description 2
210000005056 cell body Anatomy 0.000 claims description 2
239000003153 chemical reaction reagent Substances 0.000 claims description 2
208000035475 disorder Diseases 0.000 claims description 2
239000003937 drug carrier Substances 0.000 claims description 2
150000004795 grignard reagents Chemical class 0.000 claims description 2
150000004677 hydrates Chemical class 0.000 claims description 2
HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 claims description 2
125000001979 organolithium group Chemical group 0.000 claims description 2
125000001725 pyrenyl group Chemical group 0.000 claims description 2
238000006467 substitution reaction Methods 0.000 claims description 2
BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims description 2
210000002820 sympathetic nervous system Anatomy 0.000 claims description 2
KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 claims 2
PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims 2
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 2
QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims 1
239000005711 Benzoic acid Substances 0.000 claims 1
230000010933 acylation Effects 0.000 claims 1
238000005917 acylation reaction Methods 0.000 claims 1
230000029936 alkylation Effects 0.000 claims 1
238000005804 alkylation reaction Methods 0.000 claims 1
235000010233 benzoic acid Nutrition 0.000 claims 1
125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 1
239000012634 fragment Substances 0.000 claims 1
230000003993 interaction Effects 0.000 claims 1
WEABSCRJVJGCCN-UHFFFAOYSA-N methyl 4-[phenyl(piperazin-1-yl)methyl]benzoate;dihydrochloride Chemical compound Cl.Cl.C1=CC(C(=O)OC)=CC=C1C(C=1C=CC=CC=1)N1CCNCC1 WEABSCRJVJGCCN-UHFFFAOYSA-N 0.000 claims 1
125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims 1
GWJZGGXZBCMQHF-UHFFFAOYSA-N tert-butyl 4-[(4-methoxycarbonylphenyl)-phenylmethyl]piperazine-1-carboxylate Chemical compound C1=CC(C(=O)OC)=CC=C1C(C=1C=CC=CC=1)N1CCN(C(=O)OC(C)(C)C)CC1 GWJZGGXZBCMQHF-UHFFFAOYSA-N 0.000 claims 1
238000012876 topography Methods 0.000 claims 1
150000001412 amines Chemical class 0.000 description 40
230000015572 biosynthetic process Effects 0.000 description 40
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 39
238000003786 synthesis reaction Methods 0.000 description 39
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239000002904 solvent Substances 0.000 description 33
238000005481 NMR spectroscopy Methods 0.000 description 32
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
239000000243 solution Substances 0.000 description 30
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 29
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WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 20
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229940126214 compound 3 Drugs 0.000 description 14
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
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YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 14
238000004587 chromatography analysis Methods 0.000 description 13
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ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
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238000006243 chemical reaction Methods 0.000 description 11
229940125904 compound 1 Drugs 0.000 description 11
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YUGLCLJRAKICTC-UHFFFAOYSA-N 4-[[4-[(2-methylpropan-2-yl)oxycarbonyl]piperazin-1-yl]-phenylmethyl]benzoic acid Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1C(C=1C=CC(=CC=1)C(O)=O)C1=CC=CC=C1 YUGLCLJRAKICTC-UHFFFAOYSA-N 0.000 description 7
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
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239000002287 radioligand Substances 0.000 description 7
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IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
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BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 6
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KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 5
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KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 5
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