NO312957B1

NO312957B1 - Benzyl(iden)-laktamderivater, anvendelse derav og farmasöytisk sammensetning

Benzyl(iden)-laktamderivater, anvendelse derav og farmasöytisk sammensetning Download PDF

Info

Publication number: NO312957B1
Authority: NO; Norway
Prior art keywords: methylpiperazin; benzylidene; disorder; pyrrolidin; formula
Prior art date: 1996-03-29

Application number

NO19984513A

Other languages

English (en)

Norwegian (no)

Other versions

NO984513L (no

NO984513D0 (no

Inventor

Harry R Howard

Original Assignee

Pfizer

Priority date

1996-03-29

Filing date

1998-09-28

Publication date

2002-07-22

1998-09-28 Application filed by Pfizer filed Critical Pfizer

1998-09-28 Publication of NO984513L publication Critical patent/NO984513L/no

1998-09-28 Publication of NO984513D0 publication Critical patent/NO984513D0/no

2002-07-22 Publication of NO312957B1 publication Critical patent/NO312957B1/no

Links

239000008194 pharmaceutical composition Substances 0.000 title claims description 15
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 title description 5
150000001875 compounds Chemical class 0.000 claims description 159
QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 claims description 68
150000003839 salts Chemical class 0.000 claims description 45
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 27
208000035475 disorder Diseases 0.000 claims description 27
-1 1-(3,4-dichlorophenyl)-3-[2-(4-methylpiperazin-1-yl)-benzylidene]-1,3-dihydro-indol-2-one Chemical compound 0.000 claims description 25
229910052739 hydrogen Inorganic materials 0.000 claims description 20
239000000126 substance Substances 0.000 claims description 20
239000001257 hydrogen Substances 0.000 claims description 19
239000003112 inhibitor Substances 0.000 claims description 18
VGKDLMBJGBXTGI-SJCJKPOMSA-N sertraline Chemical compound C1([C@@H]2CC[C@@H](C3=CC=CC=C32)NC)=CC=C(Cl)C(Cl)=C1 VGKDLMBJGBXTGI-SJCJKPOMSA-N 0.000 claims description 18
229960002073 sertraline Drugs 0.000 claims description 17
208000018737 Parkinson disease Diseases 0.000 claims description 14
239000000460 chlorine Substances 0.000 claims description 14
241000124008 Mammalia Species 0.000 claims description 13
208000019695 Migraine disease Diseases 0.000 claims description 13
206010027599 migraine Diseases 0.000 claims description 13
239000003937 drug carrier Substances 0.000 claims description 12
208000021384 Obsessive-Compulsive disease Diseases 0.000 claims description 11
208000019906 panic disease Diseases 0.000 claims description 11
206010012335 Dependence Diseases 0.000 claims description 10
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
150000002431 hydrogen Chemical group 0.000 claims description 10
208000024827 Alzheimer disease Diseases 0.000 claims description 9
WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 9
206010008025 Cerebellar ataxia Diseases 0.000 claims description 9
ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 9
206010020772 Hypertension Diseases 0.000 claims description 9
208000026139 Memory disease Diseases 0.000 claims description 9
208000002193 Pain Diseases 0.000 claims description 9
206010047163 Vasospasm Diseases 0.000 claims description 9
208000022804 avoidant personality disease Diseases 0.000 claims description 9
GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 9
229910052794 bromium Inorganic materials 0.000 claims description 9
229910052801 chlorine Inorganic materials 0.000 claims description 9
210000001035 gastrointestinal tract Anatomy 0.000 claims description 9
230000004899 motility Effects 0.000 claims description 9
208000022821 personality disease Diseases 0.000 claims description 9
208000019899 phobic disease Diseases 0.000 claims description 9
208000028173 post-traumatic stress disease Diseases 0.000 claims description 9
230000028327 secretion Effects 0.000 claims description 9
125000001424 substituent group Chemical group 0.000 claims description 9
206010009094 Chronic paroxysmal hemicrania Diseases 0.000 claims description 8
208000006561 Cluster Headache Diseases 0.000 claims description 8
208000030814 Eating disease Diseases 0.000 claims description 8
208000017701 Endocrine disease Diseases 0.000 claims description 8
208000019454 Feeding and Eating disease Diseases 0.000 claims description 8
PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 8
206010019233 Headaches Diseases 0.000 claims description 8
208000008589 Obesity Diseases 0.000 claims description 8
208000018912 cluster headache syndrome Diseases 0.000 claims description 8
235000014632 disordered eating Nutrition 0.000 claims description 8
239000011737 fluorine Substances 0.000 claims description 8
229910052731 fluorine Inorganic materials 0.000 claims description 8
231100000869 headache Toxicity 0.000 claims description 8
235000020824 obesity Nutrition 0.000 claims description 8
208000007777 paroxysmal Hemicrania Diseases 0.000 claims description 8
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
230000002265 prevention Effects 0.000 claims description 8
230000000862 serotonergic effect Effects 0.000 claims description 8
230000005062 synaptic transmission Effects 0.000 claims description 8
108091032151 5-hydroxytryptamine receptor family Proteins 0.000 claims description 7
102000040125 5-hydroxytryptamine receptor family Human genes 0.000 claims description 7
208000011688 Generalised anxiety disease Diseases 0.000 claims description 7
230000002708 enhancing effect Effects 0.000 claims description 7
208000029364 generalized anxiety disease Diseases 0.000 claims description 7
206010036596 premature ejaculation Diseases 0.000 claims description 7
208000019553 vascular disease Diseases 0.000 claims description 7
125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 5
ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 5
201000001880 Sexual dysfunction Diseases 0.000 claims description 5
229910052740 iodine Inorganic materials 0.000 claims description 5
239000011630 iodine Chemical group 0.000 claims description 5
231100000872 sexual dysfunction Toxicity 0.000 claims description 5
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
230000003042 antagnostic effect Effects 0.000 claims description 4
239000002464 receptor antagonist Substances 0.000 claims description 4
229940044551 receptor antagonist Drugs 0.000 claims description 4
QUBOFKHGVPGAKC-UHFFFAOYSA-N 1-(3,4-dichlorophenyl)-3-[[5-fluoro-2-(4-methylpiperazin-1-yl)phenyl]methylidene]piperidin-2-one Chemical compound C1CN(C)CCN1C1=CC=C(F)C=C1C=C1C(=O)N(C=2C=C(Cl)C(Cl)=CC=2)CCC1 QUBOFKHGVPGAKC-UHFFFAOYSA-N 0.000 claims description 3
SVUVRUJADOUWEN-UHFFFAOYSA-N 1-(3,4-difluorophenyl)-3-[[2-(4-methylpiperazin-1-yl)phenyl]methylidene]pyrrolidin-2-one Chemical compound C1CN(C)CCN1C1=CC=CC=C1C=C1C(=O)N(C=2C=C(F)C(F)=CC=2)CC1 SVUVRUJADOUWEN-UHFFFAOYSA-N 0.000 claims description 3
TWFJKRVEOJPLHP-UHFFFAOYSA-N 3-[[2-(4-methylpiperazin-1-yl)phenyl]methyl]-1-phenylpyrrolidin-2-one Chemical compound C1CN(C)CCN1C1=CC=CC=C1CC1C(=O)N(C=2C=CC=CC=2)CC1 TWFJKRVEOJPLHP-UHFFFAOYSA-N 0.000 claims description 3
OTIKXZGZQMSIQE-UHFFFAOYSA-N 3-[[2-(4-methylpiperazin-1-yl)phenyl]methylidene]-1-phenylpyrrolidin-2-one Chemical compound C1CN(C)CCN1C1=CC=CC=C1C=C1C(=O)N(C=2C=CC=CC=2)CC1 OTIKXZGZQMSIQE-UHFFFAOYSA-N 0.000 claims description 3
125000000649 benzylidene group Chemical group [H]C(=[*])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
KQCKXYYIIYEARL-UHFFFAOYSA-N 1-(3,4-dichlorophenyl)-3-[[2-(4-methylpiperazin-1-yl)phenyl]methyl]piperidin-2-one Chemical compound C1CN(C)CCN1C1=CC=CC=C1CC1C(=O)N(C=2C=C(Cl)C(Cl)=CC=2)CCC1 KQCKXYYIIYEARL-UHFFFAOYSA-N 0.000 claims description 2
OEFLQFJSZMVNQS-UHFFFAOYSA-N 1-(3,4-dichlorophenyl)-3-[[2-(4-methylpiperazin-1-yl)phenyl]methylidene]pyrrolidin-2-one Chemical compound C1CN(C)CCN1C1=CC=CC=C1C=C1C(=O)N(C=2C=C(Cl)C(Cl)=CC=2)CC1 OEFLQFJSZMVNQS-UHFFFAOYSA-N 0.000 claims description 2
DHEGHIMXBFHOJK-UHFFFAOYSA-N 1-(3,4-dichlorophenyl)-3-[[2-[2-(dimethylamino)ethoxy]phenyl]methylidene]pyrrolidin-2-one Chemical compound CN(C)CCOC1=CC=CC=C1C=C1C(=O)N(C=2C=C(Cl)C(Cl)=CC=2)CC1 DHEGHIMXBFHOJK-UHFFFAOYSA-N 0.000 claims description 2
BTYTYIJITBBUAC-UHFFFAOYSA-N 1-(3,4-dichlorophenyl)-3-[[5-fluoro-2-(4-methylpiperazin-1-yl)phenyl]methylidene]pyrrolidin-2-one Chemical compound C1CN(C)CCN1C1=CC=C(F)C=C1C=C1C(=O)N(C=2C=C(Cl)C(Cl)=CC=2)CC1 BTYTYIJITBBUAC-UHFFFAOYSA-N 0.000 claims description 2
LWCHTDNWGXRROT-UHFFFAOYSA-N 1-(3,4-difluorophenyl)-3-[[2-(4-methylpiperazin-1-yl)phenyl]methyl]pyrrolidin-2-one Chemical compound C1CN(C)CCN1C1=CC=CC=C1CC1C(=O)N(C=2C=C(F)C(F)=CC=2)CC1 LWCHTDNWGXRROT-UHFFFAOYSA-N 0.000 claims description 2
NBRKHSQLNPOVMR-UHFFFAOYSA-N 1-(4-chlorophenyl)-3-[[5-fluoro-2-(4-methylpiperazin-1-yl)phenyl]methylidene]piperidin-2-one Chemical compound C1CN(C)CCN1C1=CC=C(F)C=C1C=C1C(=O)N(C=2C=CC(Cl)=CC=2)CCC1 NBRKHSQLNPOVMR-UHFFFAOYSA-N 0.000 claims description 2
WFZDDRBHAPGODK-UHFFFAOYSA-N 1-(4-methoxyphenyl)-3-[[2-(4-methylpiperazin-1-yl)phenyl]methylidene]-4h-quinolin-2-one Chemical compound C1=CC(OC)=CC=C1N(C1=O)C2=CC=CC=C2CC1=CC1=CC=CC=C1N1CCN(C)CC1 WFZDDRBHAPGODK-UHFFFAOYSA-N 0.000 claims description 2
YMYPGNNKKHIXNU-UHFFFAOYSA-N 1-(4-methylphenyl)-3-[[2-(4-methylpiperazin-1-yl)phenyl]methylidene]pyrrolidin-2-one Chemical compound C1CN(C)CCN1C1=CC=CC=C1C=C1C(=O)N(C=2C=CC(C)=CC=2)CC1 YMYPGNNKKHIXNU-UHFFFAOYSA-N 0.000 claims description 2
OTSMEBWZAZWKHO-UHFFFAOYSA-N 1-[(2,4-dichlorophenyl)methyl]-3-[[2-(4-methylpiperazin-1-yl)phenyl]methylidene]pyrrolidin-2-one Chemical compound C1CN(C)CCN1C1=CC=CC=C1C=C1C(=O)N(CC=2C(=CC(Cl)=CC=2)Cl)CC1 OTSMEBWZAZWKHO-UHFFFAOYSA-N 0.000 claims description 2
FLKALFUHLVCIIN-UHFFFAOYSA-N 1-[(3,4-dichlorophenyl)methyl]-3-[[2-(4-methylpiperazin-1-yl)phenyl]methylidene]piperidin-2-one Chemical compound C1CN(C)CCN1C1=CC=CC=C1C=C1C(=O)N(CC=2C=C(Cl)C(Cl)=CC=2)CCC1 FLKALFUHLVCIIN-UHFFFAOYSA-N 0.000 claims description 2
OQYDLIREXXETDC-UHFFFAOYSA-N 1-[(4-chlorophenyl)methyl]-3-[[2-(4-methylpiperazin-1-yl)phenyl]methylidene]piperidin-2-one Chemical compound C1CN(C)CCN1C1=CC=CC=C1C=C1C(=O)N(CC=2C=CC(Cl)=CC=2)CCC1 OQYDLIREXXETDC-UHFFFAOYSA-N 0.000 claims description 2
MWBXFRXUKYXCRG-UHFFFAOYSA-N 1-[(4-chlorophenyl)methyl]-3-[[2-(4-methylpiperazin-1-yl)phenyl]methylidene]pyrrolidin-2-one Chemical compound C1CN(C)CCN1C1=CC=CC=C1C=C1C(=O)N(CC=2C=CC(Cl)=CC=2)CC1 MWBXFRXUKYXCRG-UHFFFAOYSA-N 0.000 claims description 2
CYYVAMWJVZZZAQ-UHFFFAOYSA-N 1-[(4-chlorophenyl)methyl]-3-[[5-fluoro-2-(4-methylpiperazin-1-yl)phenyl]methylidene]pyrrolidin-2-one Chemical compound C1CN(C)CCN1C1=CC=C(F)C=C1C=C1C(=O)N(CC=2C=CC(Cl)=CC=2)CC1 CYYVAMWJVZZZAQ-UHFFFAOYSA-N 0.000 claims description 2
CVYOLTKZNMYOND-UHFFFAOYSA-N 1-methyl-3-[[2-(4-methylpiperazin-1-yl)phenyl]methylidene]indol-2-one Chemical compound C12=CC=CC=C2N(C)C(=O)C1=CC1=CC=CC=C1N1CCN(C)CC1 CVYOLTKZNMYOND-UHFFFAOYSA-N 0.000 claims description 2
FJPZQQXEVVFGPJ-UHFFFAOYSA-N 3-[[2-(4-methylpiperazin-1-yl)phenyl]methylidene]-1-phenylindol-2-one Chemical compound C1CN(C)CCN1C1=CC=CC=C1C=C1C2=CC=CC=C2N(C=2C=CC=CC=2)C1=O FJPZQQXEVVFGPJ-UHFFFAOYSA-N 0.000 claims description 2
GVZDDZHOCZYDBT-UHFFFAOYSA-N 3-[[2-(4-methylpiperazin-1-yl)phenyl]methylidene]-1h-indol-2-one Chemical compound C1CN(C)CCN1C1=CC=CC=C1C=C1C2=CC=CC=C2NC1=O GVZDDZHOCZYDBT-UHFFFAOYSA-N 0.000 claims description 2
HXFUANDJXSGPMX-UHFFFAOYSA-N 3-[[2-(4-methylpiperazin-1-yl)phenyl]methylidene]piperidin-2-one Chemical compound C1CN(C)CCN1C1=CC=CC=C1C=C1C(=O)NCCC1 HXFUANDJXSGPMX-UHFFFAOYSA-N 0.000 claims description 2
QDUYHSWCSDUISH-UHFFFAOYSA-N 3-[[2-(4-methylpiperazin-1-yl)phenyl]methylidene]pyrrolidin-2-one Chemical compound C1CN(C)CCN1C1=CC=CC=C1C=C1C(=O)NCC1 QDUYHSWCSDUISH-UHFFFAOYSA-N 0.000 claims description 2
GJKSPFSIHQBAAA-UHFFFAOYSA-N 3-[[4-fluoro-2-(4-methylpiperazin-1-yl)phenyl]methylidene]-1-phenylpyrrolidin-2-one Chemical compound C1CN(C)CCN1C1=CC(F)=CC=C1C=C1C(=O)N(C=2C=CC=CC=2)CC1 GJKSPFSIHQBAAA-UHFFFAOYSA-N 0.000 claims description 2
WXUKTUAHUGLOSG-UHFFFAOYSA-N 3-[[5-fluoro-2-(4-methylpiperazin-1-yl)phenyl]methylidene]pyrrolidin-2-one Chemical compound C1CN(C)CCN1C1=CC=C(F)C=C1C=C1C(=O)NCC1 WXUKTUAHUGLOSG-UHFFFAOYSA-N 0.000 claims description 2
FHFDVGZHHVTHEK-UHFFFAOYSA-N 5-chloro-3-[[2-(4-methylpiperazin-1-yl)phenyl]methylidene]-1h-indol-2-one Chemical compound C1CN(C)CCN1C1=CC=CC=C1C=C1C2=CC(Cl)=CC=C2NC1=O FHFDVGZHHVTHEK-UHFFFAOYSA-N 0.000 claims description 2
OPSDVIJHGJHJNS-UHFFFAOYSA-N 6-chloro-3-[[2-(4-methylpiperazin-1-yl)phenyl]methylidene]-1h-indol-2-one Chemical compound C1CN(C)CCN1C1=CC=CC=C1C=C1C2=CC=C(Cl)C=C2NC1=O OPSDVIJHGJHJNS-UHFFFAOYSA-N 0.000 claims description 2
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
238000004519 manufacturing process Methods 0.000 claims description 2
239000000825 pharmaceutical preparation Substances 0.000 claims description 2
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HRIJMEXHEDAGJI-UHFFFAOYSA-N 3-[[2-(4-methylpiperazin-1-yl)phenyl]methyl]-1-[4-(trifluoromethyl)phenyl]pyrrolidin-2-one Chemical compound C1CN(C)CCN1C1=CC=CC=C1CC1C(=O)N(C=2C=CC(=CC=2)C(F)(F)F)CC1 HRIJMEXHEDAGJI-UHFFFAOYSA-N 0.000 claims 1
VILVQZDPIFCZSB-UHFFFAOYSA-N 3-[[2-(4-methylpiperazin-1-yl)phenyl]methylidene]-1-[4-(trifluoromethyl)phenyl]pyrrolidin-2-one Chemical compound C1CN(C)CCN1C1=CC=CC=C1C=C1C(=O)N(C=2C=CC(=CC=2)C(F)(F)F)CC1 VILVQZDPIFCZSB-UHFFFAOYSA-N 0.000 claims 1
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 51
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WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 40
238000000034 method Methods 0.000 description 39
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 28
239000002585 base Substances 0.000 description 26
238000006243 chemical reaction Methods 0.000 description 25
239000002253 acid Substances 0.000 description 21
239000000243 solution Substances 0.000 description 21
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238000000921 elemental analysis Methods 0.000 description 20
239000000203 mixture Substances 0.000 description 20
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 20
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