JP2019531279A - ピペラジンカルバメート、及びその製造と使用の方法 - Google Patents
ピペラジンカルバメート、及びその製造と使用の方法 Download PDFInfo
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- JP2019531279A JP2019531279A JP2019512859A JP2019512859A JP2019531279A JP 2019531279 A JP2019531279 A JP 2019531279A JP 2019512859 A JP2019512859 A JP 2019512859A JP 2019512859 A JP2019512859 A JP 2019512859A JP 2019531279 A JP2019531279 A JP 2019531279A
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- Prior art keywords
- pharmaceutically acceptable
- solvate
- acceptable salt
- compound
- formula
- 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.)
- Granted
Links
- 238000000034 method Methods 0.000 title claims description 118
- CWPIBZMCMRNFHK-UHFFFAOYSA-N piperazin-1-ium;carbamate Chemical compound NC(O)=O.C1CNCCN1 CWPIBZMCMRNFHK-UHFFFAOYSA-N 0.000 title abstract description 4
- 238000004519 manufacturing process Methods 0.000 title description 2
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- 208000002193 Pain Diseases 0.000 claims abstract description 22
- 150000003839 salts Chemical class 0.000 claims description 834
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- -1 —OH Chemical group 0.000 claims description 245
- 125000000217 alkyl group Chemical group 0.000 claims description 228
- 229910052736 halogen Inorganic materials 0.000 claims description 187
- 150000002367 halogens Chemical class 0.000 claims description 187
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 171
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- 229910052757 nitrogen Inorganic materials 0.000 claims description 131
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- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 100
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 87
- 125000001072 heteroaryl group Chemical group 0.000 claims description 82
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 29
- 125000004432 carbon atom Chemical group C* 0.000 description 29
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- 150000001413 amino acids Chemical class 0.000 description 20
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 20
- RFIOZSIHFNEKFF-UHFFFAOYSA-M piperazine-1-carboxylate Chemical compound [O-]C(=O)N1CCNCC1 RFIOZSIHFNEKFF-UHFFFAOYSA-M 0.000 description 20
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- LZZVRRMMBYPJSZ-UHFFFAOYSA-N 1,1,1,3,3,3-hexafluoropropan-2-yl piperazine-1-carboxylate Chemical compound FC(F)(F)C(C(F)(F)F)OC(=O)N1CCNCC1 LZZVRRMMBYPJSZ-UHFFFAOYSA-N 0.000 description 19
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 19
- 238000000746 purification Methods 0.000 description 19
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 18
- 229940124597 therapeutic agent Drugs 0.000 description 18
- 239000002253 acid Substances 0.000 description 17
- 125000003710 aryl alkyl group Chemical group 0.000 description 17
- 239000012043 crude product Substances 0.000 description 17
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 16
- 125000002947 alkylene group Chemical group 0.000 description 16
- 239000003208 petroleum Substances 0.000 description 16
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 16
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 15
- 125000003709 fluoroalkyl group Chemical group 0.000 description 15
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 15
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 15
- 238000002953 preparative HPLC Methods 0.000 description 15
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 14
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- 125000001309 chloro group Chemical group Cl* 0.000 description 13
- 229910000027 potassium carbonate Inorganic materials 0.000 description 13
- 238000002360 preparation method Methods 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 11
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- MWRBWPQBGGARAY-UHFFFAOYSA-M tert-butyl acetate;chlorozinc(1+) Chemical compound [Zn+]Cl.CC(C)(C)OC([CH2-])=O MWRBWPQBGGARAY-UHFFFAOYSA-M 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
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- 238000003354 tissue distribution assay Methods 0.000 description 1
- UPSPUYADGBWSHF-UHFFFAOYSA-N tolmetin Chemical compound C1=CC(C)=CC=C1C(=O)C1=CC=C(CC(O)=O)N1C UPSPUYADGBWSHF-UHFFFAOYSA-N 0.000 description 1
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- TVYLLZQTGLZFBW-GOEBONIOSA-N tramadol Natural products COC1=CC=CC([C@@]2(O)[C@@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-GOEBONIOSA-N 0.000 description 1
- LLPOLZWFYMWNKH-UHFFFAOYSA-N trans-dihydrocodeinone Natural products C1C(N(CCC234)C)C2CCC(=O)C3OC2=C4C1=CC=C2OC LLPOLZWFYMWNKH-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
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- PHYFQTYBJUILEZ-IUPFWZBJSA-N triolein Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CCCCCCCC)COC(=O)CCCCCCC\C=C/CCCCCCCC PHYFQTYBJUILEZ-IUPFWZBJSA-N 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
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- 125000005500 uronium group Chemical group 0.000 description 1
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- 230000002227 vasoactive effect Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 235000019871 vegetable fat Nutrition 0.000 description 1
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- 239000003981 vehicle Substances 0.000 description 1
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- 210000001260 vocal cord Anatomy 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229940093612 zein Drugs 0.000 description 1
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- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P23/00—Anaesthetics
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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 hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
- C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- 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
- C07D211/08—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/26—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
-
- 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
- C07D211/56—Nitrogen atoms
- C07D211/58—Nitrogen atoms attached in position 4
-
- 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
-
- 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
- C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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Abstract
Description
本出願は、2016年9月19日に出願された米国仮特許出願第62/396,561号の利益を主張するものであり、当該文献は参照により全体として本明細書に組み込まれる。
各R1は独立して、ハロゲン、C1−6アルキル、C1−6ハロアルキル、C1−6アルコキシ、C1−6ハロアルコキシ、C3−8シクロアルキル、−OH、又は−CNであり;
nは1又は2であり;及び
pは0、1、2、3、又は4である。
各R1は独立して、ハロゲン、C1−6アルキル、C1−6ハロアルキル、C1−6アルコキシ、C1−6ハロアルコキシ、C3−8シクロアルキル、−OH、又は−CNであり;
R2とR3は、それらが結合する炭素と一体となって、
(i)C2−C7ヘテロシクロアルキル;又は
(ii)C2−C9ヘテロアリールを形成し;
ここで、C2−C7ヘテロシクロアルキル又はC2−C9ヘテロアリールは、1つのR4で置換され、及び、ハロゲン、C1−6アルキル、C1−6ハロアルキル、及びC1−6アルコキシから選択された1又は2つの追加の置換基で随意に置換され;
R4は−CO2H又は−C1−6アルキル−CO2Hであり;及び
pは0、1、2、3、又は4である。
Xは、−N(R2)(R3)、−C1−6アルキル−N(R4)(R5)、又は−C(O)N(R4)(R5)であり;
各R1は独立して、ハロゲン、C1−6アルキル、C1−6ハロアルキル、C1−6アルコキシ、C1−6ハロアルコキシ、C3−8シクロアルキル、−OH、又は−CNであり;
R2とR3は、それらが結合する窒素と一体となって、
(i)C2−C8ヘテロシクロアルキル;又は
(ii)C2−C8ヘテロアリールを形成し;
ここで、C2−C8ヘテロシクロアルキル又はC2−C8ヘテロアリールは、1つのR6で置換され、及び、ハロゲン、C1−6アルキル、C1−6ハロアルキル、及びC1−6アルコキシから選択された1又は2つの追加の置換基で随意に置換され;
R4とR5は、それらが結合する窒素と一体となって、
(i)C2−C8ヘテロシクロアルキル;又は
(ii)C2−C8ヘテロアリールを形成し;
ここで、C2−C8ヘテロシクロアルキル又はC2−C8ヘテロアリールは、1つのR7で置換され、及び、ハロゲン、C1−6アルキル、C1−6ハロアルキル、及びC1−6アルコキシから選択された1又は2つの追加の置換基で随意に置換され;
R6は、−C1−6アルキル−CO2H又は−N(R8)−C1−6アルキル−CO2Hであり;
R7は、−CO2H、−C1−6アルキル−CO2H又は−N(R9)−C1−6アルキル−CO2Hであり;
R8はH又はC1−6アルキルであり;
R9はH又はC1−6アルキルであり;及び
pは0、1、2、3、又は4である。
Yは
各R1は独立して、ハロゲン、C1−6アルキル、C1−6ハロアルキル、C1−6アルコキシ、C1−6ハロアルコキシ、C3−8シクロアルキル、−OH、又は−CNであり;
R2はC1−6アルキルであり;
mは0、1、または2であり;
nは0または1であり;及び
pは0、1、2、3、又は4である。
各R1は独立して、ハロゲン、C1−6アルキル、C1−6ハロアルキル、C1−6アルコキシ、C1−6ハロアルコキシ、C3−8シクロアルキル、−OH、又は−CNであり;
R2は−CO2H又は−CH2CO2Hによって置換されたピロリジン環であり;及び
pは0、1、2、3、又は4である。
明細書と添付の請求項で使用されるように、反対の意味に指定されない限り、次の用語は以下に指定する意味を有する。
ハロ、シアノ、ニトロ、オキソ、チオキソ、イミノ、オキシモ、トリメチルシラニル、−ORa、−SRa、−OC(O)−Rf、−N(Ra)2、−C(O)Ra、−C(O)ORa、−C(O)N(Ra)2、−N(Ra)C(O)ORf、−OC(O)−NRaRf、−N(Ra)C(O)Rf、−N(Ra)S(O)tRf(tは1又は2である)、−S(O)tORa(tは1又は2である)、−S(O)tRf(tは1又は2である)、及び−S(O)tN(Ra)2(tは1又は2である);ここで、各Raは独立して、水素、アルキル、フルオロアルキル、シクロアルキル、アリール、アラルキル、ヘテロシクロアルキル、ヘテロアリール又はヘテロアリールアルキルであり、各Rfは独立して、アルキル、フルオロアルキル、シクロアルキル、アリール、アラルキル、ヘテロシクロアルキル、ヘテロアリール又はヘテロアリールアルキルである。
ここで、各Raは独立して水素、アルキル、フルオロアルキル、シクロアルキル、シクロアルキルアルキル、アリール、アラルキル、ヘテロシクロアルキル、ヘテロアリール、またはヘテロアリールアルキルであり、各Rbは独立して直接結合、或いはは直鎖又は分枝鎖のアルキレン鎖或いはアルケニレン鎖であり、Rcは直鎖又は分枝鎖のアルキレン鎖又はアルケニレン鎖である。
C−ヘテロアリールラジカルは、ヘテロアリールラジカルについて上に記載されるように随意に置換される。
同様に、脂肪族のモノカルボン酸及びジカルボン酸、フェニル置換のアルカン酸、ヒドロキシアルカン酸、アルカン二酸(alkanedioic acids)、芳香族酸、脂肪族酸、及び芳香族スルホン酸などの有機酸により形成される塩も含まれ、例えば、酢酸、トリフルオロ酢酸、プロピオン酸、グリコール酸、ピルビン酸、シュウ酸、マレイン酸、マロン酸、コハク酸、フマル酸、酒石酸、クエン酸、安息香酸、桂皮酸、マンデル酸、メタンスルホン酸、エタンスルホン酸、p−トルエンスルホン酸、サリチル酸などを含む。従って、典型的な塩としては、硫酸塩、ピロ硫酸塩、重硫酸塩、亜硫酸塩、重亜硫酸塩、硝酸塩、リン酸塩、一水素リン酸塩(monohydrogenphosphates)、二水素リン酸塩(dihydrogenphosphates)、メタリン酸塩、ピロリン酸塩、塩化物、臭化物、ヨウ化物、酢酸塩、トリフルオロ酢酸塩、プロピオン酸塩、カプリル酸塩、イソ酪酸塩、シュウ酸塩、マロン酸塩、琥珀酸塩、スベリン酸塩、セバシン酸塩、フマル酸塩、マレイン酸塩、マンデル酸塩、安息香酸塩、クロロ安息香酸塩、メチル安息香酸塩、ジニトロ安息香酸塩(dinitrobenzoates)、フタル酸塩、ベンゼンスルホン酸塩、トルエンスルホン酸塩、フェニル酢酸塩、クエン酸塩、乳酸塩、リンゴ酸塩、酒石酸塩、メタンスルホン酸塩などが挙げられる。同様に、アルギン酸塩、グルコン酸塩、及びガラクトウロン酸塩などのアミノ酸の塩も企図されている(例えば、Berge S.M. et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Science, 66:1−19 (1997)。塩基性化合物の酸付加塩は、塩を生成するために十分な量の所望の酸に遊離塩基を接触させることにより調製される。
本明細書に記載される式(I)、(Ia)、(Ib)、(II)、(III)、(IV)、(IVa)、又は(V)の化合物は、MAGL及び/又はABHD6のモジュレーターである。これらの化合物、及びこれらの化合物を含む組成物は疼痛の処置に役立つ。幾つかの実施形態において、本明細書に記載される式(I)、(Ia)、(Ib)、(II)、(III)、(IV)、(IVa)、又は(V)の化合物は、多発性硬化症、アルツハイマー病、又は炎症性腸疾患の処置に役立つ。
各R1は独立して、ハロゲン、C1−6アルキル、C1−6ハロアルキル、C1−6アルコキシ、C1−6ハロアルコキシ、C3−8シクロアルキル、−OH、又は−CNであり;
nは1又は2であり;及び
pは0、1、2、3、又は4である。
各R1は独立して、ハロゲン、C1−6アルキル、C1−6ハロアルキル、C1−6アルコキシ、−OH、−OCF3、又は−CNであり;及び
pは0、1、2、3、又は4である。
各R1は独立して、ハロゲン、C1−6アルキル、C1−6ハロアルキル、C1−6アルコキシ、−OH、−OCF3、又は−CNであり;及び
pは0、1、2、3、又は4である。
各R1は独立して、ハロゲン、C1−6アルキル、C1−6ハロアルキル、C1−6アルコキシ、C1−6ハロアルコキシ、C3−8シクロアルキル、−OH、又は−CNであり;
R2とR3は、それらが結合する炭素と一体となって、(i)C2−C7ヘテロシクロアルキル;
又は(ii)C2−C9ヘテロアリールを形成し;
ここで、C2−C7ヘテロシクロアルキル又はC2−C9ヘテロアリールは、1つのR4で置換され、及び、ハロゲン、C1−6アルキル、C1−6ハロアルキル、及びC1−6アルコキシから選択された1又は2つの追加の置換基で随意に置換され;
R4は−CO2H又は−C1−6アルキル−CO2Hであり;及び
pは0、1、2、3、又は4である。
Xは、−N(R2)(R3)、−C1−6アルキル−N(R4)(R5)、又は−C(O)N(R4)(R5)であり;
各R1は独立して、ハロゲン、C1−6アルキル、C1−6ハロアルキル、C1−6アルコキシ、C1−6ハロアルコキシ、C3−8シクロアルキル、−OH、又は−CNであり;
R2とR3は、それらが結合する窒素と一体となって、(i)C2−C8ヘテロシクロアルキル;
又は(ii)C2−C8ヘテロアリールを形成し;
ここで、C2−C8ヘテロシクロアルキル又はC2−C8ヘテロアリールは、1つのR6で置換され、及び、ハロゲン、C1−6アルキル、C1−6ハロアルキル、及びC1−6アルコキシから選択された1又は2つの追加の置換基で随意に置換され;
R4とR5は、それらが結合する窒素と一体となって、
(i)C2−C8ヘテロシクロアルキル;又は
(ii)C2−C8ヘテロアリールを形成し;
ここで、C2−C8ヘテロシクロアルキル又はC2−C8ヘテロアリールは、1つのR7で置換され、及び、ハロゲン、C1−6アルキル、C1−6ハロアルキル、及びC1−6アルコキシから選択された1又は2つの追加の置換基で随意に置換され;
R6は、−C1−6アルキル−CO2H又は−N(R8)−C1−6アルキル−CO2Hであり;
R7は、−CO2H、−C1−6アルキル−CO2H又は−N(R9)−C1−6アルキル−CO2Hであり;
R8はH又はC1−6アルキルであり;
R9はH又はC1−6アルキルであり;及び
pは0、1、2、3、又は4である。
Yは
各R1は独立して、ハロゲン、C1−6アルキル、C1−6ハロアルキル、C1−6アルコキシ、C1−6ハロアルコキシ、C3−8シクロアルキル、−OH、又は−CNであり;
R2はC1−6アルキルであり;
mは0、1、又は2であり、
nは0又は1であり、及び
pは0、1、2、3、又は4である。
各R1は独立して、ハロゲン、C1−6アルキル、C1−6ハロアルキル、C1−6アルコキシ、C1−6ハロアルコキシ、C3−8シクロアルキル、−OH、又は−CNであり;
R2はC1−6アルキルであり;
mは0、1、又は2であり;
nは0又は1であり;及び
pは0、1、2、3、又は4である。
各R1は独立して、ハロゲン、C1−6アルキル、C1−6ハロアルキル、C1−6アルコキシ、C1−6ハロアルコキシ、C3−8シクロアルキル、−OH、又は−CNであり;
R2は−CO2H又は−CH2CO2Hによって置換されたピロリジン環であり;及び
pは0、1、2、3、又は4である。
本明細書に記載される反応に使用される化合物は、市販の化学物質から及び/又は化学文献に記載される化合物から開始して、既知の有機合成技術に従って作られる。「市販の化学物質」は、Acros Organics (Geel, Belgium)、Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka)、Apin Chemicals Ltd. (Milton Park, UK)、Ark Pharm, Inc. (Libertyville, IL)、Avocado Research (Lancashire, U.K.)、BDH Inc. (Toronto, Canada)、Bionet (Cornwall, U.K.)、Chemservice Inc. (West Chester, PA)、Combi−blocks (San Diego, CA)、Crescent Chemical Co. (Hauppauge, NY)、eMolecules (San Diego, CA)、Fisher Scientific Co. (Pittsburgh, PA)、Fisons Chemicals (Leicestershire, UK)、Frontier Scientific (Logan, UT)、ICN Biomedicals, Inc. (Costa Mesa, CA)、Key Organics (Cornwall, U.K.)、Lancaster Synthesis (Windham, NH)、Matrix Scientific, (Columbia, SC)、Maybridge Chemical Co. Ltd. (Cornwall, U.K.)、Parish Chemical Co. (Orem, UT)、Pfaltz & Bauer, Inc. (Waterbury, CN)、Polyorganix (Houston, TX)、Pierce Chemical Co. (Rockford, IL)、Riedel de Haen AG (Hanover, Germany)、Ryan Scientific, Inc. (Mount Pleasant, SC)、Spectrum Chemicals (Gardena, CA)、Sundia Meditech, (Shanghai, China)、TCI America (Portland, OR)、Trans World Chemicals, Inc. (Rockville, MD)、及びWuXi (Shanghai, China)を含む、標準の商用供給源から入手される。
異性体
更に、幾つかの実施形態において、本明細書に記載された化合物は幾何異性体として存在する。幾つかの実施形態において、本明細書に記載される化合物は1以上の二重結合を持つ。本明細書に示される化合物は、シス、トランス、シン、アンチ、エントゲーゲン(E)、及びツザメン(Z)の異性体、同様にそれらの対応する混合物を全て含む。幾つかの状況において、化合物は互変異性体として存在する。本明細書に記載される化合物は、本明細書に記載される式内に全ての可能な互変異性体を含む。状況によっては、本明細書に記載された化合物は1つ以上のキラル中心を有し、それぞれの中心はR配置又はS配置で存在する。本明細書に記載される化合物は、ジアステレオマー、エナンチオマー、及びエピマーの形態、同様にそれらの対応する混合物全てを含む。本明細書に提供される化合物及び方法の更なる実施形態において、単一の調製工程、組み合わせ、又は相互変換から結果として得られるエナンチオマー及び/又はジアステレオ異性体の混合物は、本明細書に記載される用途に有用である。幾つかの実施形態において、本明細書に記載される化合物は、化合物のラセミ混合物を光学的に活性な分解剤と反応させて一対のジアステレオ異性体化合物を形成し、ジアステレオマーを分離し、光学的に純粋なエナンチオマーを回収することにより、化合物の個々の立体異性体として調製される。幾つかの実施形態において、解離性錯体が好ましい(例えば、結晶性ジアステレオマー塩)。幾つかの実施形態において、ジアステレオマーは、明白な物理的特性(例えば、融点、沸点、溶解度、反応性など)を備えており、これら相違点を利用することにより分離される。幾つかの実施形態において、ジアステレオマーはキラルクロマトグラフィーによって、又は好ましくは、溶解度の相違に基づく分離/分解技術によって分離される。幾つかの実施形態において、光学的に純粋なエナンチオマーは、その後、ラセミ化を生じない任意の実用的な手段により、分解剤と共に回収される。
幾つかの実施形態において、本明細書に記載される化合物は、同位体で標識された形態で存在する。幾つかの実施形態において、本明細書に開示された方法は、そのような同位体で標識された化合物の投与によって疾患を処置する方法を含んでいる。幾つかの実施形態において、本明細書に開示される方法は、医薬組成物として、そのような同位体的に標識された化合物を投与することによって疾患を処置する方法を含む。故に、幾つかの実施形態において、本明細書で開示される化合物は、1以上の原子が通常自然で見られる原子質量又は質量数とは異なる原子質量又は質量数を備えた原子によって置き換えられるという事実を別にすれば、本明細書で列挙されるものと同一である、同位体で標識された化合物を含む。本発明の化合物に組み込まれる同位体の例は、2H、3H、13C、14C、15N、18O、17O、31P、32P、35S、18F、及び36Clなどの、それぞれ、水素、炭素、窒素、酸素、リン、硫黄、フッ素、及び塩化物の同位体を含む。前述の同位体及び/又は他の原子の他の同位体を含有している、本明細書に記載される化合物、及びその薬学的に許容可能な塩、エステル、溶媒和物、水和物又は誘導体は、本発明の範囲内にある。特定の同位体で標識された化合物、例えば、3Hや14Cなどの放射性同位体が取り込まれる同位体で標識された化合物は、薬物及び/又は基質組織分布アッセイに有用である。トリチウム標識した(即ち、3H)及び炭素−14(即ち、14C)の同位体は、それらの調製及び検出性の容易さのために特に好ましい。更に、ジュウテリウム、即ち、2Hなどの重同位体による置換は、代謝の一層の安定から結果として生じる特定の治療上の利点、例えば、インビボでの半減期の増加又は必要用量の減少をもたらす。幾つかの実施形態において、同位体的に標識された化合物、その薬学的に許容可能な塩、エステル、溶媒和物、水和物又は誘導体は、任意の適切な方法によって調製される。
幾つかの実施形態において、本明細書に記載された化合物はその薬学的に許容可能な塩として存在する。幾つかの実施形態において、本明細書に開示される方法は、そのような薬学的に許容可能な塩を投与することにより疾患を処置する方法を含む。幾つかの実施形態において、本明細書に開示される方法は、医薬組成物として、そのような薬学的に許容可能な塩を投与することにより疾患を処置する方法を含む。
幾つかの実施形態において、本明細書に記載された化合物は溶媒和物として存在する。本発明は、そのような溶媒和物の投与により疾患を処置する方法を提供する。本発明は更に、医薬組成物としてそのような溶媒和物を投与することにより疾患を処置する方法を提供する。
幾つかの実施形態において、本明細書に記載される化合物はプロドラッグ形態で存在する。本発明は、そのようなプロドラッグを投与することによって疾患を処置する方法を提供する。本発明は、そのようなプロドラッグを医薬組成物として投与することによって疾患を処置する方法を提供する。
特定の実施形態において、本明細書に記載されるような式(I)、(Ia)、(Ib)、(II)、(III)、(IV)、(IVa)、又は(V)の化合物は、純粋な化学物質として投与される。幾つかの実施形態において、本明細書に記載される式(I)、(Ia)、(Ib)、(II)、(III)、(IV)、(IVa)、又は(V)の化合物は、投与の選択された経路、及び、例えばRemington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005))に記載されるような標準の薬務に基づいて選択される、薬学的に適切な又は許容可能な担体(本明細書では、薬学的に適切な(又は許容可能な)賦形剤、生理学的に適切な(又は許容可能な)賦形剤、或いは生理学的に適切な(又は許容可能な)担体とも称される)と組み合わされる。
本明細書には、MAGL及び/又はABHD6の活性を調節する方法が開示される。企図されている方法は例えば、本明細書に記載される化合物に前記酵素を晒す工程を含む。幾つかの実施形態では、前述の方法の1つ以上によって利用される化合物は、ジェネリック、サブジェネリック、或いは式(I)、(Ia)、(Ib)、(II)、(III)、(IV)、(IVa)、又は(V)の化合物などの本明細書に記載される特定の化合物のうち1つである。MAGL及び/又はABHD6を調節する又は阻害する、本明細書に記載される化合物の能力は、当該技術分野で既知の又は本明細書に記載される手順によって評価される。本開示の別の態様は、患者におけるMAGL及び/又はABHD6の発現或いは活性に関連する疾患を処置する方法を提供する。他の実施形態において、ABHD6と比較して、開示される化合物はMAGLの阻害においてより選択的である。
上記で使用されるように、及び本発明の記載の全体にわたって、以下の略語は、他に明記されない限り、以下の意味を持つものであると理解される:
ACN又はMeCN アセトニトリル
Bn ベンジル
BOC又はBoc tert−ブチルカルバミン酸塩
t−Bu tert−ブチル
Cy シクロヘキシル
DCE ジクロロエタン(ClCH2CH2Cl)
DCM ジクロロメタン(CH2Cl2)
DIPEA又はDIEA ジイソプロピルエチルアミン
DMAP 4−(N,N−ジメチルアミノ)ピリジン
DMF ジメチルホルムアミド
DMA N,N−ジメチルアセトアミド
DMSO ジメチルスルホキシド
equiv 当量
Et エチル
Et2O ジエチルエーテル
EtOH エタノール
EtOAc 酢酸エチル
HPLC 高速液体クロマトグラフィー
Me メチル
MeOH メタノール
MS 質量分光法
NMR 核磁気共鳴
RP−HPLC 逆相高圧液体クロマトグラフィー
TFA トリフルオロ酢酸
THF テトラヒドロフラン
TLC 薄層クロマトグラフィー
別段の明記のない限り、市販の供給元から入手されるような試薬と溶媒を使用した。無水溶媒及び炉乾燥したガラス製品を、湿気及び/又は酸素に敏感な合成変換に使用した。収率を最適化しなかった。反応時間はおおよそのものであり、最適化されたものではない。他に特に明記のない限り、カラムクロマトグラフイーおよび薄層クロマトグラフィー(TLC)を、シリカゲル上で実行した。スペクトルをppm(δ)で与え、結合定数(J)をHertzで報告する。プロトンスペクトルについては、溶媒ピークを参照ピークとして使用した。
結果としてもたらされる溶液を酢酸エチル(3×50mL)で抽出し、有機質層を組み合わせて、ブライン(2×20mL)で洗浄し、無水硫酸ナトリウム上で乾燥させ、濾過し、減圧下で濃縮した。メタノール/ジクロロメタン(1/5)を用いてシリカゲルカラム上で残留物をクロマトグラフィー分離して、黄色固体として5.00g(73%の収率)のtert−ブチル3−(((トリフルオロメチル)スルホニル)オキシ)−2,5−ジヒドロ−1H−ピロール−1−カルボン酸塩を得た。LCM(ESI、m/z):262[M+H−56]+。
LCM(ESI、m/z):608[M+H]+。
LCM(ESI、m/z):594[M+H]+。
化合物を検査し、以下のインビトロ及びインビボのアッセイを使用してそれらのMAGL及びセリンヒドロラーゼ活性を評価した。
プロテオーム(ヒト前前頭皮質又は細胞膜分画)(50μL、1.0−2.0mg/mLの総タンパク質濃度)を、37℃で様々な濃度の阻害剤により予めインキュベートした。30分後、FPRh又はJW912(1.0μL、DMSO中で50μM)を加え、混合物を室温で更に30分間インキュベートした。反応物をSDSローディングバッファー(15μL−4X)によりクエンチし、SDS−PAGE上で実行した。ゲル画像化の後、セリンヒドロラーゼ活性を、ImageJ 1.49kソフトウェアを使用してMAGL及びABHD6に対応するゲルバンド(gel bands)の蛍光強度を測定することにより判定した。このアッセイからのIC50データを表1に示す。
プロテオーム(マウスの脳膜画分又は細胞溶解物)(50μL、1.0mg/mLの総タンパク質濃度)を、37℃で様々な濃度の阻害剤により予めインキュベートした。30分後、FPRhJW912(1.0μL、DMSO中で50μM)を加え、混合物を37℃で更に30分間インキュベートした。反応物をSDSローディングバッファー(50μL−4X)によりクエンチし、SDS−PAGE上で実行した。ゲル画像化の後、セリンヒドロラーゼ活性を、ImageJ 1.49kソフトウェアを使用してMAGL及びABHD6に対応するゲルバンド(gel bands)の蛍光強度を測定することにより判定した。このアッセイからのデータを表1に示す(1μMでの%阻害)。
ポリエチレングリコールのビヒクル中の経口胃管栄養によって野生型C57Bl/6Jに阻害剤を投与した。投与の4時間後に各動物を屠殺し、脳プロテオームを調製し、以前に確立された方法に従い分析した(Niphakis, M. J., et al. (2011) ACS Chem. Neurosci. and Long, J. Z., et al. Nat. Chem. Biol. 5:37−44を参照)。
Claims (99)
- 式(I)の化合物、或いはその薬学的に許容可能な塩又は溶媒和物であって:
各R1は独立して、ハロゲン、C1−6アルキル、C1−6ハロアルキル、C1−6アルコキシ、C1−6ハロアルコキシ、C3−8シクロアルキル、−OH、又は−CNであり;
nは1又は2であり、及び
pは0、1、2、3、又は4である、
化合物、或いはその薬学的に許容可能な塩又は溶媒和物。 - 各R1は独立してハロゲンである、請求項1に記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物。
- 各R1は−Clである、請求項2に記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物。
- 各R1は独立してC1−6ハロアルキルである、請求項1に記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物。
- 各R1は−CF3である、請求項4に記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物。
- 各R1は独立してC1−6アルキルである、請求項1に記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物。
- 各R1は−CH3である、請求項6に記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物。
- 各R1は独立してC1−6アルコキシである、請求項1に記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物。
- 各R1は−OCH3である、請求項8に記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物。
- 各R1は独立してC1−6ハロアルコキシである、請求項1に記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物。
- 各R1は−OCF3である、請求項10に記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物。
- 各R1は独立してC3−8シクロアルキルである、請求項1に記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物。
- pは0、1、2、又は3である、請求項1乃至12の何れか1つに記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物。
- pは1又は2である、請求項1乃至13の何れか1つに記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物。
- pは1である、請求項1乃至14の何れか1つに記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物。
- pは0である、請求項1に記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物。
- nは1である、請求項1乃至16の何れか1つに記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物。
- nは2である、請求項1乃至16の何れか1つに記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物。
- 式(II)の化合物、或いはその薬学的に許容可能な塩又は溶媒和物であって:
各R1は独立して、ハロゲン、C1−6アルキル、C1−6ハロアルキル、C1−6アルコキシ、C1−6ハロアルコキシ、C3−8シクロアルキル、−OH、又は−CNであり;
R2とR3は、それらが結合する炭素と一体となって、
(i)C2−C7ヘテロシクロアルキル;又は
(ii)C2−C9ヘテロアリールを形成し;
ここで、C2−C7ヘテロシクロアルキル又はC2−C9ヘテロアリールは、1つのR4で置換され、及び、ハロゲン、C1−6アルキル、C1−6ハロアルキル、及びC1−6アルコキシから選択された1又は2つの追加の置換基で随意に置換され;
R4は−CO2H又は−C1−6アルキル−CO2Hであり;及び
pは0、1、2、3、又は4である、
化合物、或いはその薬学的に許容可能な塩又は溶媒和物。 - 各R1は独立してハロゲンである、請求項19に記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物。
- 各R1は−Clである、請求項20に記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物。
- 各R1は独立してC1−6ハロアルキルである、請求項19に記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物。
- 各R1は−CF3である、請求項22に記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物。
- 各R1は独立してC1−6アルキルである、請求項19に記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物。
- 各R1は−CH3である、請求項24に記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物。
- 各R1は独立してC1−6アルコキシである、請求項19に記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物。
- 各R1は−OCH3である、請求項26に記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物。
- 各R1は独立してC1−6ハロアルコキシである、請求項19に記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物。
- 各R1は−OCF3である、請求項28に記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物。
- 各R1は独立してC3−8シクロアルキルである、請求項19に記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物。
- pは0、1、2、又は3である、請求項19乃至30の何れか1つに記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物。
- pは1又は2である、請求項19乃至31の何れか1つに記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物。
- pは1である、請求項19乃至32の何れか1つに記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物。
- pは0である、請求項19に記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物。
- R2とR3は、それらが結合する炭素と一体となって、1つのR4で置換されたC2−C7ヘテロシクロアルキルを形成する、請求項19乃至34の何れか1つに記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物。
- R2とR3は、それらが結合する炭素と一体となって、以下から選択されたC2−C7ヘテロシクロアルキルを形成する、請求項35に記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物:
- R2とR3は、それらが結合する炭素と一体となって、1つのR4で置換されたC2−C9ヘテロアリールを形成する、請求項19乃至34の何れか1つに記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物。
- R2とR3は、それらが結合する炭素と一体となって、以下から選択されたC2−C9ヘテロアリールを形成する、請求項37に記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物:
- R4は−CO2Hである、請求項19乃至38の何れか1つに記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物。
- R4は−C1−6アルキル−CO2Hである、請求項19乃至38の何れか1つに記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物。
- 式(III)の化合物、或いはその薬学的に許容可能な塩又は溶媒和物であって:
Xは、−N(R2)(R3)、−C1−6アルキル−N(R4)(R5)、又は−C(O)N(R4)(R5)であり;
各R1は独立して、ハロゲン、C1−6アルキル、C1−6ハロアルキル、C1−6アルコキシ、C1−6ハロアルコキシ、C3−8シクロアルキル、−OH、又は−CNであり;
R2とR3は、それらが結合する窒素と一体となって、
(i)C2−C8ヘテロシクロアルキル;又は
(ii)C2−C8ヘテロアリールを形成し;
ここで、C2−C8ヘテロシクロアルキル又はC2−C8ヘテロアリールは、1つのR6で置換され、及び、ハロゲン、C1−6アルキル、C1−6ハロアルキル、及びC1−6アルコキシから選択された1又は2つの追加の置換基で随意に置換され;
R4とR5は、それらが結合する窒素と一体となって、
(i)C2−C8ヘテロシクロアルキル;
又は(ii)C2−C8ヘテロアリールを形成し;
ここで、C2−C8ヘテロシクロアルキル又はC2−C8ヘテロアリールは、1つのR7で置換され、及び、ハロゲン、C1−6アルキル、C1−6ハロアルキル、及びC1−6アルコキシから選択された1又は2つの追加の置換基で随意に置換され;
R6は、−C1−6アルキル−CO2H又は−N(R8)−C1−6アルキル−CO2Hであり;
R7は、−CO2H、−C1−6アルキル−CO2H又は−N(R9)−C1−6アルキル−CO2Hであり;
R8はH又はC1−6アルキルであり;
R9はH又はC1−6アルキルであり;及び
pは0、1、2、3、又は4である、
化合物、或いはその薬学的の許容可能な塩又は溶媒和物。 - Xは−N(R2)(R3)である、ことを特徴とする請求項41に記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物。
- R2とR3は、それらが結合する窒素と一体となって、1つのR6で置換されたC2−C8ヘテロシクロアルキルを形成する、請求項41又は42に記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物。
- R2とR3は、それらが結合する窒素と一体となって、以下から選択されたC2−C8ヘテロシクロアルキルを形成する、請求項41乃至43の何れか1つに記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物:
- R6は−C1−6アルキル−CO2Hである、請求項41乃至44の何れか1つに記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物。
- R6は−CH2CO2Hである、請求項41乃至45の何れか1つに記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物。
- Xは−C1−6アルキル−N(R4)(R5)又は−C(O)N(R4)(R5)である、請求項41に記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物。
- Xは−C1−6アルキル−N(R4)(R5)である、請求項47に記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物。
- Xは−CH2N(R4)(R5)である、請求項48に記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物。
- Xは−C(O)N(R4)(R5)である、請求項47に記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物。
- R4とR5は、それらが結合する窒素と一体となって、1つのR7で置換されたC2−C8ヘテロシクロアルキルを形成する、請求項47乃至50の何れか1つに記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物。
- R4とR5は、それらが結合する窒素と一体となって、以下から選択されたC2−C8ヘテロシクロアルキルを形成する、請求項51に記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物:
- R7は−C1−6アルキル−CO2Hである、請求項47乃至52の何れか1つに記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物。
- R7は−CH2CO2Hである、請求項47乃至53の何れか1つに記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物。
- R4とR5は、それらが結合する窒素と一体となって、以下から選択されたC2−C8ヘテロシクロアルキルを形成する、請求項51に記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物:
- R7は−CO2Hである、請求項55に記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物。
- R7は−N(R9)−C1−6アルキル−CO2Hである、ことを特徴とする請求項55に記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物。
- R6は−N(R9)−CH2CO2Hである、ことを特徴とする請求項57に記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物。
- R9はHである、請求項57又は58に記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物。
- 式(IV)の化合物、或いはその薬学的に許容可能な塩又は溶媒和物であって:
Yは
各R1は独立して、ハロゲン、C1−6アルキル、C1−6ハロアルキル、C1−6アルコキシ、C1−6ハロアルコキシ、C3−8シクロアルキル、−OH、又は−CNであり;
R2はC1−6アルキルであり;
mは0、1、又は2であり;
nは0又は1であり及び
pは0、1、2、3、又は4である、
化合物、或いはその薬学的の許容可能な塩又は溶媒和物。 - Yは
- mは1であり、nは0である、請求項61に記載の化合物。
- mは2であり、nは0である、請求項61に記載の化合物。
- mは1であり、nは1である、請求項61に記載の化合物。
- Yは
- Yは
- R2は−CH3である、請求項60乃至66の何れか1つに記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物。
- Yは
- 式(V)の化合物、或いはその薬学的に許容可能な塩又は溶媒和物であって:
各R1は独立して、ハロゲン、C1−6アルキル、C1−6ハロアルキル、C1−6アルコキシ、C1−6ハロアルコキシ、C3−8シクロアルキル、−OH、又は−CNであり;
R2は−CO2H又は−CH2CO2Hによって置換されたピロリジン環であり;及び
pは0、1、2、3、又は4である、
化合物、或いはその薬学的に許容可能な塩又は溶媒和物。 - R2は−CO2Hにより置換されたピロリジン環である、請求項69に記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物。
- R2は−CH2CO2Hにより置換されたピロリジン環である、請求項69に記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物。
- R2は、
- 各R1は独立してハロゲンである、請求項1乃至72の何れか1つに記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物。
- 各R1は−Clである、請求項73に記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物。
- 各R1は独立してC1−6ハロアルキルである、請求項1乃至72の何れか1つに記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物。
- 各R1は−CF3である、請求項75に記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物。
- 各R1は独立してC1−6アルキルである、請求項1乃至72の何れか1つに記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物。
- 各R1は−CH3である、請求項77に記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物。
- 各R1は独立してC1−6アルコキシである、請求項1乃至72の何れか1つに記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物。
- 各R1は−OCH3である、請求項79に記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物。
- 各R1は独立してC1−6ハロアルコキシである、請求項1乃至72の何れか1つに記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物。
- 各R1は−OCF3である、請求項81に記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物。
- 各R1は独立してC3−8シクロアルキルである、請求項1乃至72の何れか1つに記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物。
- pは0、1、2、又は3である、請求項1乃至83の何れか1つに記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物。
- pは1又は2である、請求項1乃至84の何れか1つに記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物。
- pは1である、請求項1乃至85の何れか1つに記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物。
- pは0である、請求項1乃至72の何れか1つに記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物。
- 以下から選択される、化合物、或いはその薬学的に許容可能な塩又は溶媒和物:
- 以下から選択される、化合物、或いはその薬学的に許容可能な塩又は溶媒和物:
- 以下の構造を有する、化合物、或いはその薬学的に許容可能な塩又は溶媒和物:
- 以下から選択される、化合物、或いはその薬学的に許容可能な塩又は溶媒和物:
- 請求項1乃至91の何れか1つに記載の化合物、或いはその薬学的に許容可能な塩又は溶媒和物、及び少なくとも1つの薬学的に許容可能な賦形剤を含む、医薬組成物。
- 患者の疼痛を処置する方法であって、上記疼痛を処置するために、請求項1乃至91の何れか1つに記載の治療上有効な量の化合物を患者に投与する工程を含む、方法。
- 疼痛は神経障害性疼痛である、請求項93に記載の方法。
- 疼痛は炎症性疼痛である、請求項93に記載の方法。
- 患者の疾患又は障害を処置する方法であって、該方法は、請求項1乃至91の何れか1つに記載の治療上有効な量の化合物、或いはその薬学的の許容可能な塩又は溶媒和物を患者に投与する工程を含み、疾患は、多発性硬化症、アルツハイマー病、及び炎症性腸疾患から成る群から選択される、方法。
- 疾患又は障害は多発性硬化症である、請求項96に記載の方法。
- 疾患又は障害はアルツハイマー病である、請求項96記載の方法。
- 疾患又は障害は炎症性腸疾患である、請求項96に記載の方法。
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JP7042547B2 (ja) | 2016-11-16 | 2022-03-28 | ルンドベック ラ ホーヤ リサーチ センター,インク. | Magl阻害剤 |
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WO2018053447A1 (en) | 2018-03-22 |
EP3515897A1 (en) | 2019-07-31 |
ES2892952T3 (es) | 2022-02-07 |
CN109996790B (zh) | 2023-05-16 |
EP3515897B1 (en) | 2021-08-18 |
JP7042804B2 (ja) | 2022-03-28 |
US10899737B2 (en) | 2021-01-26 |
EP3515897A4 (en) | 2020-03-25 |
US20190202801A1 (en) | 2019-07-04 |
CN109996790A (zh) | 2019-07-09 |
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