NZ581817A - Benzamide mglur5 positive allosteric modulators and methods of making and using same - Google Patents
Benzamide mglur5 positive allosteric modulators and methods of making and using sameInfo
- Publication number
- NZ581817A NZ581817A NZ581817A NZ58181708A NZ581817A NZ 581817 A NZ581817 A NZ 581817A NZ 581817 A NZ581817 A NZ 581817A NZ 58181708 A NZ58181708 A NZ 58181708A NZ 581817 A NZ581817 A NZ 581817A
- Authority
- NZ
- New Zealand
- Prior art keywords
- optionally substituted
- compound
- phenyl
- phenylethynyl
- methanone
- Prior art date
Links
- 238000000034 method Methods 0.000 title description 100
- 230000003281 allosteric effect Effects 0.000 title description 33
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 title description 14
- 150000001875 compounds Chemical class 0.000 claims abstract description 393
- 150000003839 salts Chemical class 0.000 claims abstract description 65
- 150000001204 N-oxides Chemical class 0.000 claims abstract description 39
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 31
- 201000000980 schizophrenia Diseases 0.000 claims abstract description 21
- 208000035475 disorder Diseases 0.000 claims abstract description 15
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- 208000019901 Anxiety disease Diseases 0.000 claims abstract description 3
- 208000002193 Pain Diseases 0.000 claims abstract description 3
- 230000007000 age related cognitive decline Effects 0.000 claims abstract description 3
- 230000036506 anxiety Effects 0.000 claims abstract description 3
- 208000024714 major depressive disease Diseases 0.000 claims abstract 4
- 208000017194 Affective disease Diseases 0.000 claims abstract 2
- 208000020925 Bipolar disease Diseases 0.000 claims abstract 2
- 206010048962 Brain oedema Diseases 0.000 claims abstract 2
- 208000021465 Brief psychotic disease Diseases 0.000 claims abstract 2
- 206010008748 Chorea Diseases 0.000 claims abstract 2
- 206010012218 Delirium Diseases 0.000 claims abstract 2
- 208000024254 Delusional disease Diseases 0.000 claims abstract 2
- 206010012289 Dementia Diseases 0.000 claims abstract 2
- 208000020401 Depressive disease Diseases 0.000 claims abstract 2
- 208000014094 Dystonic disease Diseases 0.000 claims abstract 2
- 208000030814 Eating disease Diseases 0.000 claims abstract 2
- 208000019454 Feeding and Eating disease Diseases 0.000 claims abstract 2
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- 208000019022 Mood disease Diseases 0.000 claims abstract 2
- 208000016285 Movement disease Diseases 0.000 claims abstract 2
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- 208000020186 Schizophreniform disease Diseases 0.000 claims abstract 2
- 208000006752 brain edema Diseases 0.000 claims abstract 2
- 208000012601 choreatic disease Diseases 0.000 claims abstract 2
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- 235000014632 disordered eating Nutrition 0.000 claims abstract 2
- 208000010118 dystonia Diseases 0.000 claims abstract 2
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- -1 2,6-dimethylmorpholino Chemical group 0.000 claims description 350
- 229910052739 hydrogen Inorganic materials 0.000 claims description 228
- 239000001257 hydrogen Substances 0.000 claims description 228
- 125000004432 carbon atom Chemical group C* 0.000 claims description 191
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 145
- 125000001072 heteroaryl group Chemical group 0.000 claims description 142
- 229910052736 halogen Inorganic materials 0.000 claims description 141
- 150000002367 halogens Chemical class 0.000 claims description 141
- 125000004366 heterocycloalkenyl group Chemical group 0.000 claims description 126
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 126
- 125000003107 substituted aryl group Chemical group 0.000 claims description 123
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 114
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 105
- 125000001424 substituent group Chemical group 0.000 claims description 104
- 150000003573 thiols Chemical class 0.000 claims description 98
- 229930195712 glutamate Natural products 0.000 claims description 96
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 96
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 94
- 102000012777 Metabotropic Glutamate 5 Receptor Human genes 0.000 claims description 93
- 108010065028 Metabotropic Glutamate 5 Receptor Proteins 0.000 claims description 92
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 91
- 230000004044 response Effects 0.000 claims description 82
- 125000000304 alkynyl group Chemical group 0.000 claims description 73
- 125000003342 alkenyl group Chemical group 0.000 claims description 72
- 125000000217 alkyl group Chemical group 0.000 claims description 68
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 67
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 61
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 42
- 229910052799 carbon Inorganic materials 0.000 claims description 34
- 239000008194 pharmaceutical composition Substances 0.000 claims description 34
- 125000000623 heterocyclic group Chemical group 0.000 claims description 32
- 238000011282 treatment Methods 0.000 claims description 32
- 101001032838 Rattus norvegicus Metabotropic glutamate receptor 5 Proteins 0.000 claims description 26
- 241000124008 Mammalia Species 0.000 claims description 25
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 24
- 239000003937 drug carrier Substances 0.000 claims description 24
- 210000003292 kidney cell Anatomy 0.000 claims description 24
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- 125000004122 cyclic group Chemical group 0.000 claims description 8
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 229910052727 yttrium Inorganic materials 0.000 claims description 4
- STNLQJRBZHAGSO-UHFFFAOYSA-N 1-piperidin-4-ylethanone Chemical compound CC(=O)C1CCNCC1 STNLQJRBZHAGSO-UHFFFAOYSA-N 0.000 claims description 3
- FRICBZWJFIRJOB-UHFFFAOYSA-N 2-piperazin-1-ylbenzonitrile Chemical compound N#CC1=CC=CC=C1N1CCNCC1 FRICBZWJFIRJOB-UHFFFAOYSA-N 0.000 claims description 3
- BYNBAMHAURJNTR-UHFFFAOYSA-N 3-piperidin-4-yl-1h-benzimidazol-2-one Chemical compound O=C1NC2=CC=CC=C2N1C1CCNCC1 BYNBAMHAURJNTR-UHFFFAOYSA-N 0.000 claims description 3
- FJCHFVDZYLYFBX-UHFFFAOYSA-N 5-chloro-3-piperidin-4-yl-1h-benzimidazol-2-one Chemical compound C12=CC(Cl)=CC=C2NC(=O)N1C1CCNCC1 FJCHFVDZYLYFBX-UHFFFAOYSA-N 0.000 claims description 3
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims 6
- 208000031091 Amnestic disease Diseases 0.000 claims 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 1
- FRVAFFCBUNGKIU-UHFFFAOYSA-N n-(4-fluorophenyl)-4-(2-methylpiperidine-1-carbonyl)benzamide Chemical compound CC1CCCCN1C(=O)C1=CC=C(C(=O)NC=2C=CC(F)=CC=2)C=C1 FRVAFFCBUNGKIU-UHFFFAOYSA-N 0.000 abstract description 5
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 183
- 150000003254 radicals Chemical class 0.000 description 161
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 122
- 229940049906 glutamate Drugs 0.000 description 86
- 125000005415 substituted alkoxy group Chemical group 0.000 description 69
- 125000004644 alkyl sulfinyl group Chemical group 0.000 description 67
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 67
- WSFSSNUMVMOOMR-BJUDXGSMSA-N methanone Chemical compound O=[11CH2] WSFSSNUMVMOOMR-BJUDXGSMSA-N 0.000 description 67
- 125000004001 thioalkyl group Chemical group 0.000 description 67
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 66
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 66
- 150000003857 carboxamides Chemical class 0.000 description 66
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 58
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 54
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 53
- 125000006716 (C1-C6) heteroalkyl group Chemical group 0.000 description 52
- 229910052757 nitrogen Inorganic materials 0.000 description 52
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 49
- 239000000203 mixture Substances 0.000 description 49
- 125000000753 cycloalkyl group Chemical group 0.000 description 45
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 41
- 239000000556 agonist Substances 0.000 description 39
- 230000000694 effects Effects 0.000 description 39
- 102000016193 Metabotropic glutamate receptors Human genes 0.000 description 38
- 108010010914 Metabotropic glutamate receptors Proteins 0.000 description 38
- 125000003118 aryl group Chemical group 0.000 description 37
- 238000006243 chemical reaction Methods 0.000 description 35
- 238000005859 coupling reaction Methods 0.000 description 35
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 34
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 33
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 32
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 30
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 29
- 230000008878 coupling Effects 0.000 description 29
- 238000010168 coupling process Methods 0.000 description 29
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- 125000003545 alkoxy group Chemical group 0.000 description 24
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 23
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- 239000000164 antipsychotic agent Substances 0.000 description 22
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- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 17
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 17
- IEFPMGGLOAFVMU-UHFFFAOYSA-N 2-(2-phenylethynyl)benzamide Chemical compound NC(=O)C1=CC=CC=C1C#CC1=CC=CC=C1 IEFPMGGLOAFVMU-UHFFFAOYSA-N 0.000 description 16
- 201000010099 disease Diseases 0.000 description 16
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- NTICECSDNWSORF-UHFFFAOYSA-N [4-(hydroxymethyl)piperidin-1-yl]-[4-(2-phenylethynyl)phenyl]methanone Chemical compound C1CC(CO)CCN1C(=O)C1=CC=C(C#CC=2C=CC=CC=2)C=C1 NTICECSDNWSORF-UHFFFAOYSA-N 0.000 description 13
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- LCEDQNDDFOCWGG-UHFFFAOYSA-N morpholine-4-carbaldehyde Chemical compound O=CN1CCOCC1 LCEDQNDDFOCWGG-UHFFFAOYSA-N 0.000 description 11
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- 208000024891 symptom Diseases 0.000 description 11
- FPDBSDNGFNDSSK-UHFFFAOYSA-N (4-hydroxypiperidin-1-yl)-[4-(2-phenylethynyl)phenyl]methanone Chemical compound C1CC(O)CCN1C(=O)C1=CC=C(C#CC=2C=CC=CC=2)C=C1 FPDBSDNGFNDSSK-UHFFFAOYSA-N 0.000 description 10
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 description 10
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- XTENNUBLYMOFRL-UHFFFAOYSA-N 4-(2-pyridin-2-ylethynyl)benzamide Chemical class C1=CC(C(=O)N)=CC=C1C#CC1=CC=CC=N1 XTENNUBLYMOFRL-UHFFFAOYSA-N 0.000 description 8
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- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 7
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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JP2010513283A (ja) | 2006-12-15 | 2010-04-30 | アボット・ラボラトリーズ | 新規なオキサジアゾール化合物 |
US8853392B2 (en) | 2007-06-03 | 2014-10-07 | Vanderbilt University | Benzamide mGluR5 positive allosteric modulators and methods of making and using same |
US8034806B2 (en) | 2007-11-02 | 2011-10-11 | Vanderbilt University | Bicyclic mGluR5 positive allosteric modulators and methods of making and using same |
GB0811643D0 (en) | 2008-06-25 | 2008-07-30 | Cancer Rec Tech Ltd | New therapeutic agents |
TW201028421A (en) * | 2009-01-15 | 2010-08-01 | Abbott Lab | Novel benzenesulfonamides as calcium channel blockers |
US8389536B2 (en) | 2009-10-27 | 2013-03-05 | Hoffmann-La Roche Inc. | Positive allosteric modulators (PAM) |
US8586581B2 (en) | 2009-12-17 | 2013-11-19 | Hoffmann-La Roche Inc | Ethynyl compounds useful for treatment of CNS disorders |
NZ600605A (en) | 2009-12-18 | 2013-08-30 | Janssen Pharmaceutica Nv | Bicyclic thiazoles as allosteric modulators of mglur5 receptors |
CA2784830C (en) | 2009-12-18 | 2018-03-27 | Sunovion Pharmaceuticals Inc. | Compounds for treating disorders mediated by metabotropic glutamate receptor 5, and methods of use thereof |
US9174953B2 (en) | 2009-12-18 | 2015-11-03 | Janssen Pharmaceutica Nv | Bicyclic thiazoles as allosteric modulators of mGluR5 receptors |
EA021568B1 (ru) | 2009-12-23 | 2015-07-30 | Такеда Фармасьютикал Компани Лимитед | Конденсированные гетероароматические пирролидиноны как ингибиторы syk |
US8420661B2 (en) * | 2010-04-13 | 2013-04-16 | Hoffmann-La Roche Inc. | Arylethynyl derivatives |
CN103037693A (zh) * | 2010-05-24 | 2013-04-10 | 范德比尔特大学 | 作为mglur5正向变构调节剂的取代的6-甲基烟酰胺 |
WO2012088266A2 (en) | 2010-12-22 | 2012-06-28 | Incyte Corporation | Substituted imidazopyridazines and benzimidazoles as inhibitors of fgfr3 |
US8772300B2 (en) | 2011-04-19 | 2014-07-08 | Hoffmann-La Roche Inc. | Phenyl or pyridinyl-ethynyl derivatives |
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- 2008-06-03 KR KR1020097027281A patent/KR20100033981A/ko not_active Withdrawn
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IL202508A0 (en) | 2010-06-30 |
CN101795689B (zh) | 2014-11-19 |
SG185285A1 (en) | 2012-11-29 |
CN101795689A (zh) | 2010-08-04 |
KR20100033981A (ko) | 2010-03-31 |
EP2162136A1 (en) | 2010-03-17 |
BRPI0812363A2 (pt) | 2015-02-03 |
JP5622568B2 (ja) | 2014-11-12 |
CA2689282A1 (en) | 2008-12-11 |
AU2008259776A1 (en) | 2008-12-11 |
WO2008151184A1 (en) | 2008-12-11 |
MX2009013169A (es) | 2010-04-30 |
AU2008259776A2 (en) | 2010-01-28 |
EA200971143A1 (ru) | 2010-06-30 |
JP2010529135A (ja) | 2010-08-26 |
HK1147068A1 (en) | 2011-07-29 |
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