AU2015233642B2 - 2,7-diazaspiro[3.5]nonane compounds - Google Patents
2,7-diazaspiro[3.5]nonane compounds Download PDFInfo
- Publication number
- AU2015233642B2 AU2015233642B2 AU2015233642A AU2015233642A AU2015233642B2 AU 2015233642 B2 AU2015233642 B2 AU 2015233642B2 AU 2015233642 A AU2015233642 A AU 2015233642A AU 2015233642 A AU2015233642 A AU 2015233642A AU 2015233642 B2 AU2015233642 B2 AU 2015233642B2
- Authority
- AU
- Australia
- Prior art keywords
- 6alkyl
- diazaspiro
- alkyl
- group
- i2aryl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
Links
- DROZYMFJWSYDRY-UHFFFAOYSA-N 2,7-diazaspiro[3.5]nonane Chemical class C1NCC11CCNCC1 DROZYMFJWSYDRY-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 386
- -1 -NR20R21 Chemical group 0.000 claims description 830
- 125000000623 heterocyclic group Chemical group 0.000 claims description 418
- 125000001072 heteroaryl group Chemical group 0.000 claims description 398
- 229910052739 hydrogen Inorganic materials 0.000 claims description 376
- 239000001257 hydrogen Substances 0.000 claims description 363
- 229910052799 carbon Inorganic materials 0.000 claims description 238
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 238
- 125000005843 halogen group Chemical group 0.000 claims description 195
- 229910052717 sulfur Inorganic materials 0.000 claims description 164
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 142
- 125000005842 heteroatom Chemical group 0.000 claims description 134
- 238000000034 method Methods 0.000 claims description 133
- 229910052757 nitrogen Inorganic materials 0.000 claims description 92
- 150000003839 salts Chemical class 0.000 claims description 88
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 74
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 72
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 54
- 229920006395 saturated elastomer Polymers 0.000 claims description 54
- 239000012453 solvate Substances 0.000 claims description 50
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 48
- 125000004432 carbon atom Chemical group C* 0.000 claims description 40
- 239000008194 pharmaceutical composition Substances 0.000 claims description 40
- 238000011282 treatment Methods 0.000 claims description 39
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 38
- 125000004429 atom Chemical group 0.000 claims description 33
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 33
- 239000003814 drug Substances 0.000 claims description 32
- GVNJESYLNCMALL-UHFFFAOYSA-N n-(3-cyanophenyl)-7-methylsulfonyl-2,7-diazaspiro[3.5]nonane-2-carboxamide Chemical compound C1CN(S(=O)(=O)C)CCC11CN(C(=O)NC=2C=C(C=CC=2)C#N)C1 GVNJESYLNCMALL-UHFFFAOYSA-N 0.000 claims description 31
- BCYYATIMCMWEAV-UHFFFAOYSA-N n-(4-methoxyphenyl)-7-methylsulfonyl-2,7-diazaspiro[3.5]nonane-2-carboxamide Chemical compound C1=CC(OC)=CC=C1NC(=O)N1CC2(CCN(CC2)S(C)(=O)=O)C1 BCYYATIMCMWEAV-UHFFFAOYSA-N 0.000 claims description 30
- LVWKQKBWFTVHLB-UHFFFAOYSA-N 7-(benzenesulfonyl)-n-(3-fluorophenyl)-2,7-diazaspiro[3.5]nonane-2-carboxamide Chemical compound FC1=CC=CC(NC(=O)N2CC3(C2)CCN(CC3)S(=O)(=O)C=2C=CC=CC=2)=C1 LVWKQKBWFTVHLB-UHFFFAOYSA-N 0.000 claims description 29
- SGODQWIOWBOYKT-UHFFFAOYSA-N 7-(benzenesulfonyl)-n-phenyl-2,7-diazaspiro[3.5]nonane-2-carboxamide Chemical compound C1C2(CCN(CC2)S(=O)(=O)C=2C=CC=CC=2)CN1C(=O)NC1=CC=CC=C1 SGODQWIOWBOYKT-UHFFFAOYSA-N 0.000 claims description 29
- MIPCJURDXWBZGS-UHFFFAOYSA-N 7-methylsulfonyl-n-phenyl-2,7-diazaspiro[3.5]nonane-2-carboxamide Chemical compound C1CN(S(=O)(=O)C)CCC11CN(C(=O)NC=2C=CC=CC=2)C1 MIPCJURDXWBZGS-UHFFFAOYSA-N 0.000 claims description 29
- VIFSDEIEVJLEFA-UHFFFAOYSA-N 7-(benzenesulfonyl)-n-(4-methoxyphenyl)-2,7-diazaspiro[3.5]nonane-2-carboxamide Chemical compound C1=CC(OC)=CC=C1NC(=O)N1CC2(CCN(CC2)S(=O)(=O)C=2C=CC=CC=2)C1 VIFSDEIEVJLEFA-UHFFFAOYSA-N 0.000 claims description 28
- IJMSCUUGZYBRML-UHFFFAOYSA-N 2h-benzotriazol-5-yl-[7-[2-(3-chlorophenyl)ethylsulfonyl]-2,7-diazaspiro[3.5]nonan-2-yl]methanone Chemical compound ClC1=CC=CC(CCS(=O)(=O)N2CCC3(CN(C3)C(=O)C3=CC4=NNN=C4C=C3)CC2)=C1 IJMSCUUGZYBRML-UHFFFAOYSA-N 0.000 claims description 27
- 230000002265 prevention Effects 0.000 claims description 27
- BLOKECMLIIWMCH-UHFFFAOYSA-N 7-(benzenesulfonyl)-n-propan-2-yl-2,7-diazaspiro[3.5]nonane-2-carboxamide Chemical compound C1N(C(=O)NC(C)C)CC21CCN(S(=O)(=O)C=1C=CC=CC=1)CC2 BLOKECMLIIWMCH-UHFFFAOYSA-N 0.000 claims description 26
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 26
- RPFCWYZXPVGZMD-UHFFFAOYSA-N n-(3-fluorophenyl)-7-methylsulfonyl-2,7-diazaspiro[3.5]nonane-2-carboxamide Chemical compound C1CN(S(=O)(=O)C)CCC11CN(C(=O)NC=2C=C(F)C=CC=2)C1 RPFCWYZXPVGZMD-UHFFFAOYSA-N 0.000 claims description 26
- 208000018737 Parkinson disease Diseases 0.000 claims description 24
- 125000002393 azetidinyl group Chemical group 0.000 claims description 24
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 23
- 208000024827 Alzheimer disease Diseases 0.000 claims description 22
- 206010012601 diabetes mellitus Diseases 0.000 claims description 21
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 19
- 208000000501 Lipidoses Diseases 0.000 claims description 15
- 206010024585 Lipidosis Diseases 0.000 claims description 15
- 208000001089 Multiple system atrophy Diseases 0.000 claims description 14
- 125000005549 heteroarylene group Chemical group 0.000 claims description 14
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 14
- 239000000651 prodrug Substances 0.000 claims description 13
- 229940002612 prodrug Drugs 0.000 claims description 13
- 201000001421 hyperglycemia Diseases 0.000 claims description 12
- 230000004770 neurodegeneration Effects 0.000 claims description 12
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 12
- 208000007153 proteostasis deficiencies Diseases 0.000 claims description 12
- 206010067889 Dementia with Lewy bodies Diseases 0.000 claims description 11
- 201000010374 Down Syndrome Diseases 0.000 claims description 11
- 208000032928 Dyslipidaemia Diseases 0.000 claims description 11
- 208000004930 Fatty Liver Diseases 0.000 claims description 11
- 208000002705 Glucose Intolerance Diseases 0.000 claims description 11
- 206010019708 Hepatic steatosis Diseases 0.000 claims description 11
- 208000031773 Insulin resistance syndrome Diseases 0.000 claims description 11
- 208000009829 Lewy Body Disease Diseases 0.000 claims description 11
- 208000017170 Lipid metabolism disease Diseases 0.000 claims description 11
- 208000001145 Metabolic Syndrome Diseases 0.000 claims description 11
- 208000008589 Obesity Diseases 0.000 claims description 11
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 claims description 11
- 208000010706 fatty liver disease Diseases 0.000 claims description 11
- 235000020824 obesity Nutrition 0.000 claims description 11
- 201000009104 prediabetes syndrome Diseases 0.000 claims description 11
- 231100000240 steatosis hepatitis Toxicity 0.000 claims description 11
- 208000030159 metabolic disease Diseases 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 125000006591 (C2-C6) alkynylene group Chemical group 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 8
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 7
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- BKIMMITUMNQMOS-UHFFFAOYSA-N nonane Chemical compound CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 claims 11
- OQHQOOLVQDEIGL-UHFFFAOYSA-N 2-methyl-2,7-diazaspiro[4.4]nonane Chemical compound C1N(C)CCC11CNCC1 OQHQOOLVQDEIGL-UHFFFAOYSA-N 0.000 claims 3
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims 2
- KCVKVMKMXZXHEN-UHFFFAOYSA-N 2-methylnonanamide Chemical compound CCCCCCCC(C)C(N)=O KCVKVMKMXZXHEN-UHFFFAOYSA-N 0.000 claims 1
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims 1
- 229920006358 Fluon Polymers 0.000 claims 1
- 244000131360 Morinda citrifolia Species 0.000 claims 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims 1
- CKJNUZNMWOVDFN-UHFFFAOYSA-N methanone Chemical compound O=[CH-] CKJNUZNMWOVDFN-UHFFFAOYSA-N 0.000 claims 1
- APVPOHHVBBYQAV-UHFFFAOYSA-N n-(4-aminophenyl)sulfonyloctadecanamide Chemical compound CCCCCCCCCCCCCCCCCC(=O)NS(=O)(=O)C1=CC=C(N)C=C1 APVPOHHVBBYQAV-UHFFFAOYSA-N 0.000 claims 1
- 235000017524 noni Nutrition 0.000 claims 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims 1
- KRCQSTCYZUOBHN-UHFFFAOYSA-N rabeprazole sodium Chemical compound [Na+].COCCCOC1=CC=NC(CS(=O)C=2[N-]C3=CC=CC=C3N=2)=C1C KRCQSTCYZUOBHN-UHFFFAOYSA-N 0.000 claims 1
- 125000003003 spiro group Chemical group 0.000 claims 1
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims 1
- KUAZQDVKQLNFPE-UHFFFAOYSA-N thiram Chemical group CN(C)C(=S)SSC(=S)N(C)C KUAZQDVKQLNFPE-UHFFFAOYSA-N 0.000 claims 1
- 150000001721 carbon Chemical group 0.000 description 222
- 239000000543 intermediate Substances 0.000 description 123
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 120
- 125000000217 alkyl group Chemical group 0.000 description 113
- 150000002431 hydrogen Chemical class 0.000 description 110
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 88
- 150000003573 thiols Chemical class 0.000 description 50
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 41
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 38
- 239000000203 mixture Substances 0.000 description 35
- 239000011541 reaction mixture Substances 0.000 description 32
- 210000004027 cell Anatomy 0.000 description 28
- 239000000243 solution Substances 0.000 description 26
- 125000005553 heteroaryloxy group Chemical group 0.000 description 25
- 125000005844 heterocyclyloxy group Chemical group 0.000 description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 25
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 22
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 20
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 19
- 125000003118 aryl group Chemical group 0.000 description 19
- 235000019439 ethyl acetate Nutrition 0.000 description 18
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 17
- 125000004414 alkyl thio group Chemical group 0.000 description 17
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 16
- 125000005368 heteroarylthio group Chemical group 0.000 description 16
- 125000004468 heterocyclylthio group Chemical group 0.000 description 16
- 239000013058 crude material Substances 0.000 description 15
- 125000001424 substituent group Chemical group 0.000 description 15
- 125000006555 (C3-C5) cycloalkyl group Chemical group 0.000 description 14
- 125000003320 C2-C6 alkenyloxy group Chemical group 0.000 description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 14
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- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 12
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- 150000004677 hydrates Chemical class 0.000 description 12
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 12
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- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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Landscapes
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Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
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| EP14160344 | 2014-03-17 | ||
| EP14160344.9 | 2014-03-17 | ||
| PCT/EP2015/055494 WO2015140132A1 (en) | 2014-03-17 | 2015-03-17 | 2,7-diazaspiro[3.5]nonane compounds |
Publications (2)
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| AU2015233642A1 AU2015233642A1 (en) | 2016-09-08 |
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| GB201416352D0 (en) * | 2014-09-16 | 2014-10-29 | Shire Internat Gmbh | Spirocyclic derivatives |
| GB201416351D0 (en) | 2014-09-16 | 2014-10-29 | Shire Internat Gmbh | Heterocyclic derivatives |
| CA3079188A1 (en) | 2017-10-17 | 2019-04-25 | Vanderbilt University | Antagonists of the muscarinic acetylcholine receptor m4 |
| WO2019126559A1 (en) | 2017-12-20 | 2019-06-27 | Vanderbilt University | Antagonists of the muscarinic acetylcholine receptor m4 |
| JP7714665B2 (ja) * | 2021-01-29 | 2025-07-29 | コリア リサーチ インスティチュート オブ ケミカル テクノロジー | ベンゾチアゾール及びベンズイミダゾール誘導体、薬学的に許容可能な塩、その製造方法及びそれを有効成分として含む医薬組成物 |
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| US20080247964A1 (en) * | 2006-05-08 | 2008-10-09 | Yuelian Xu | Substituted azaspiro derivatives |
| PH12012501800A1 (en) | 2010-03-19 | 2012-12-10 | Pfizer | 2,3 dihydro- 1h - inden- 1 - yl -2,7 -diazaspirol [ 3.5 ] nonane derivatives and their use as antagonists or inverse agonists of the ghrelin receptor |
| CN104379563B (zh) * | 2012-04-10 | 2018-12-21 | 加利福尼亚大学董事会 | 用于治疗癌症的组合物和方法 |
| TWI633087B (zh) | 2012-06-13 | 2018-08-21 | 赫孚孟拉羅股份公司 | 新穎二氮雜螺環烷及氮雜螺環烷 |
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| US20170157137A1 (en) | 2017-06-08 |
| US9750745B2 (en) | 2017-09-05 |
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| CN106103439A (zh) | 2016-11-09 |
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| US20170015665A1 (en) | 2017-01-19 |
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| CN106103439B (zh) | 2019-03-08 |
| WO2015140132A1 (en) | 2015-09-24 |
| NO3119782T3 (forum.php) | 2018-06-30 |
| DK3119782T3 (en) | 2018-03-12 |
| PT3119782T (pt) | 2018-04-17 |
| RS57129B1 (sr) | 2018-07-31 |
| EA032470B1 (ru) | 2019-05-31 |
| CA2941196A1 (en) | 2015-09-24 |
| CA2941196C (en) | 2019-09-03 |
| EP3119782A1 (en) | 2017-01-25 |
| HRP20180585T1 (hr) | 2018-07-13 |
| ES2666173T3 (es) | 2018-05-03 |
| EP3119782B1 (en) | 2018-01-31 |
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