JP6337135B2 - フマル酸エステルのスルホンアミドプロドラッグ及びスルフィンアミドプロドラッグ並びに種々の疾患の治療におけるその使用 - Google Patents
フマル酸エステルのスルホンアミドプロドラッグ及びスルフィンアミドプロドラッグ並びに種々の疾患の治療におけるその使用 Download PDFInfo
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- JP6337135B2 JP6337135B2 JP2016553405A JP2016553405A JP6337135B2 JP 6337135 B2 JP6337135 B2 JP 6337135B2 JP 2016553405 A JP2016553405 A JP 2016553405A JP 2016553405 A JP2016553405 A JP 2016553405A JP 6337135 B2 JP6337135 B2 JP 6337135B2
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- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 1
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- LDHQCZJRKDOVOX-UHFFFAOYSA-N trans-crotonic acid Natural products CC=CC(O)=O LDHQCZJRKDOVOX-UHFFFAOYSA-N 0.000 description 1
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- 208000009174 transverse myelitis Diseases 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
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- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
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- ODHXBMXNKOYIBV-UHFFFAOYSA-N triphenylamine Chemical compound C1=CC=CC=C1N(C=1C=CC=CC=1)C1=CC=CC=C1 ODHXBMXNKOYIBV-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
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- C—CHEMISTRY; METALLURGY
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- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
- C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C311/03—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C311/06—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms to acyclic carbon atoms of hydrocarbon radicals substituted by carboxyl groups
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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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
- C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C311/03—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C311/04—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms to acyclic carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
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- C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
- C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C311/09—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton the carbon skeleton being further substituted by at least two halogen atoms
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
- C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
- C07C311/17—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
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- C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
- C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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- C07C311/48—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups having nitrogen atoms of sulfonamide groups further bound to another hetero atom
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Description
この出願は、2014年2月24日に出願された米国仮特許出願第61/943,699号の利益を主張する。前記出願の全教示は参照により本明細書に援用される。
本明細書では、フマル酸モノメチルの種々のプロドラッグが提供される。特に、本明細書では、フマル酸モノメチルのスルホンアミド誘導体及びスルフィンアミド誘導体が提供される。発明はまた、種々の疾患の治療方法に関する。
本明細書に記載される方法及び組成物は、フマル酸モノメチル(MMF)の一以上のプロドラッグ(例えばスルホンアミド含有プロドラッグ又はスルフィンアミド含有プロドラッグ)を含む。発明化合物は、経口投与の際にインビボでフマル酸モノメチルに変換され得る。変換の際に、活性部分(即ちフマル酸モノメチル)は、神経学的疾患に苦しむ被験体の治療に効果的である。
R1はC1-C6アルキルであり;
Laは、C1-C6アルキル、C3-C10炭素環、C6-C10アリール、1若しくは2個の5-若しくは6-員環とN、O及びSから選択される1〜4個のヘテロ原子とを含む複素環、又は1若しくは2個の5-若しくは6-員環とN、O及びSから選択される1〜4個のヘテロ原子とを含むヘテロアリールであり、ここで、アルキル基、炭素環基、アリール基、複素環基又はヘテロアリール基は、任意に独立して、ハロゲンで1回以上置換される;
R2は、C1-C10アルキル、C2-C6アルケニル、C2-C6アルキニル、OH、C6-C10アリール、C3-C10炭素環、1若しくは2個の5-若しくは6-員環とN、O及びSから選択される1〜4個のヘテロ原子とを含む複素環、又は1若しくは2個の5-若しくは6-員環とN、O及びSから選択される1〜4個のヘテロ原子とを含むヘテロアリールであり、ここで、アルキル基、アルケニル基、アルキニル基、アリール基、炭素環基、複素環基又はヘテロアリール基は、任意に独立して、C1-C6アルキル、OH、O(C1-C6アルキル)、オキソ、ハロゲン、NH2、N(H)(C1-C6アルキル)、N(C1-C6アルキル)2、SO2H、SO2(C1-C6アルキル)、CHO、CO2H、CO2(C1-C6アルキル)又はCNで1回以上置換される;
R3は、H、C1-C10アルキル、C2-C6アルケニル、C2-C6アルキニル、SO2R4又はS(O)R4であり、ここで、アルキル基、アルケニル基又はアルキニル基は、任意に独立して、C1-C6アルキル、OH、O(C1-C6アルキル)、オキソ、ハロゲン、NH2、N(H)(C1-C6アルキル)、N(C1-C6アルキル)2、SO2H、SO2(C1-C6アルキル)、CHO、CO2H、CO2(C1-C6アルキル)又はCNで1回以上置換される;
R4は、C1-C10アルキル、C2-C6アルケニル、C2-C6アルキニル、OH、C6-C10アリール、C3-C10炭素環、1若しくは2個の5-若しくは6-員環とN、O及びSから選択される1〜4個のヘテロ原子とを含む複素環、又は1若しくは2個の5-若しくは6-員環とN、O及びSから選択される1〜4個のヘテロ原子とを含むヘテロアリールであり、ここで、アルキル基、アルケニル基、アルキニル基、アリール基、炭素環基、複素環基又はヘテロアリール基は、任意に独立して、C1-C6アルキル、OH、O(C1-C6アルキル)、オキソ、ハロゲン、NH2、N(H)(C1-C6アルキル)、N(C1-C6アルキル)2、SO2H、SO2(C1-C6アルキル)、CHO、CO2H、CO2(C1-C6アルキル)又はCNで1回以上置換される;
あるいは、R2及びR3は、それらが結合する原子と一緒になって、1又は2個の5-又は6-員環を含む環状部分を形成し、該環状部分はさらにN、O及びSから選択される1〜5個のさらなるヘテロ原子を任意に含み、ここで、該環はオキソで任意に置換され得る;並びに
nは1又は2である)
の化合物又はその薬学的に許容され得る塩を提供する。
本明細書では、式(I)の化合物を投与することによる神経学的疾患の治療の化合物及び方法、式(I)の化合物を製造するための合成方法、並びに式(I)の化合物を含む医薬組成物が提供される。
R1はC1-C6アルキルであり;
Laは、C1-C6アルキル、C3-C10炭素環、C6-C10アリール、1若しくは2個の5-若しくは6-員環とN、O及びSから選択される1〜4個のヘテロ原子とを含む複素環、又は1若しくは2個の5-若しくは6-員環とN、O及びSから選択される1〜4個のヘテロ原子とを含むヘテロアリールであり、ここで、アルキル基、炭素環基、アリール基、複素環基又はヘテロアリール基は、任意に独立して、ハロゲンで1回以上置換される;
R2は、C1-C10アルキル、C2-C6アルケニル、C2-C6アルキニル、OH、C6-C10アリール、C3-C10炭素環、1若しくは2個の5-若しくは6-員環とN、O及びSから選択される1〜4個のヘテロ原子とを含む複素環、又は1若しくは2個の5-若しくは6-員環とN、O及びSから選択される1〜4個のヘテロ原子とを含むヘテロアリールであり、ここで、アルキル基、アルケニル基、アルキニル基、アリール基、炭素環基、複素環基又はヘテロアリール基は、任意に独立して、C1-C6アルキル、OH、O(C1-C6アルキル)、オキソ、ハロゲン、NH2、N(H)(C1-C6アルキル)、N(C1-C6アルキル)2、SO2H、SO2(C1-C6アルキル)、CHO、CO2H、CO2(C1-C6アルキル)又はCNで1回以上置換される;
R3は、H、C1-C10アルキル、C2-C6アルケニル、C2-C6アルキニル、SO2R4又はS(O)R4であり、ここで、アルキル基、アルケニル基又はアルキニル基は、任意に独立して、C1-C6アルキル、OH、O(C1-C6アルキル)、オキソ、ハロゲン、NH2、N(H)(C1-C6アルキル)、N(C1-C6アルキル)2、SO2H、SO2(C1-C6アルキル)、CHO、CO2H、CO2(C1-C6アルキル)又はCNで1回以上置換される;
R4は、C1-C10アルキル、C2-C6アルケニル、C2-C6アルキニル、OH、C6-C10アリール、C3-C10炭素環、1若しくは2個の5-若しくは6-員環とN、O及びSから選択される1〜4個のヘテロ原子とを含む複素環、又は1若しくは2個の5-若しくは6-員環とN、O及びSから選択される1〜4個のヘテロ原子とを含むヘテロアリールであり、ここで、アルキル基、アルケニル基、アルキニル基、アリール基、炭素環基、複素環基又はヘテロアリール基は、任意に独立して、C1-C6アルキル、OH、O(C1-C6アルキル)、オキソ、ハロゲン、NH2、N(H)(C1-C6アルキル)、N(C1-C6アルキル)2、SO2H、SO2(C1-C6アルキル)、CHO、CO2H、CO2(C1-C6アルキル)又はCNで1回以上置換される;
あるいは、R2及びR3は、それらが結合する原子と一緒になって、1又は2個の5-又は6-員環を含む環状部分を形成し、該環状部分はさらにN、O及びSから選択される1〜5個のさらなるヘテロ原子を任意に含み、ここで、該環はオキソで任意に置換され得る;並びにnは1又は2である)
を有する。
R1はC1-C6アルキルであり;
Laは、C1-C6アルキル、C3-C10炭素環、C6-C10アリール、1若しくは2個の5-若しくは6-員環とN、O及びSから選択される1〜4個のヘテロ原子とを含む複素環、又は1若しくは2個の5-若しくは6-員環とN、O及びSから選択される1〜4個のヘテロ原子とを含むヘテロアリールであり;
R2は、C1-C10アルキル、C2-C6アルケニル、C2-C6アルキニル、OH、C6-C10アリール、C3-C10炭素環、1若しくは2個の5-若しくは6-員環とN、O及びSから選択される1〜4個のヘテロ原子とを含む複素環、又は1若しくは2個の5-若しくは6-員環とN、O及びSから選択される1〜4個のヘテロ原子とを含むヘテロアリールであり、ここで、アルキル基、アルケニル基、アルキニル基、アリール基、炭素環基、複素環基又はヘテロアリール基は、任意に独立して、C1-C6アルキル、OH、O(C1-C6アルキル)、オキソ、ハロゲン、NH2、N(H)(C1-C6アルキル)、N(C1-C6アルキル)2、SO2H、SO2(C1-C6アルキル)、CHO、CO2H、CO2(C1-C6アルキル)又はCNで1回以上置換される;
R3は、H、C1-C10アルキル、C2-C6アルケニル、C2-C6アルキニル、SO2R4又はS(O)R4であり;
R4は、C1-C10アルキル、C2-C6アルケニル、C2-C6アルキニル、OH、C6-C10アリール、C3-C10炭素環、1若しくは2個の5-若しくは6-員環とN、O及びSから選択される1〜4個のヘテロ原子とを含む複素環、又は1若しくは2個の5-若しくは6-員環とN、O及びSから選択される1〜4個のヘテロ原子とを含むヘテロアリールであり、ここで、アルキル基、アルケニル基、アルキニル基、アリール基、炭素環基、複素環基又はヘテロアリール基は、任意に独立して、C1-C6アルキル、OH、O(C1-C6アルキル)、オキソ、ハロゲン、NH2、N(H)(C1-C6アルキル)、N(C1-C6アルキル)2、SO2H、SO2(C1-C6アルキル)、CHO、CO2H、CO2(C1-C6アルキル)又はCNで1回以上置換される;
あるいは、R2及びR3は、それらが結合する原子と一緒になって、1又は2個の5-又は6-員環を含む環状部分を形成し、該環状部分はさらにN、O及びSから選択される1〜5個のさらなるヘテロ原子を任意に含み、ここで、該環はオキソで任意に置換され得る;並びにnは1又は2である。
R1はC1-C6アルキルであり;
Laは、C1-C6アルキル、C3-C10炭素環、C6-C10アリール、1若しくは2個の5-若しくは6-員環とN、O及びSから選択される1〜4個のヘテロ原子とを含む複素環、又は1若しくは2個の5-若しくは6-員環とN、O及びSから選択される1〜4個のヘテロ原子とを含むヘテロアリールであり、ここで、アルキル基、炭素環基、アリール基、複素環基又はヘテロアリール基は、任意に独立して、C1-C6アルキル又はハロゲンで1回以上置換される;
R2は、C1-C10アルキル、C2-C6アルケニル、C2-C6アルキニル、OH、C6-C10アリール、C3-C10炭素環、1若しくは2個の5-若しくは6-員環とN、O及びSから選択される1〜4個のヘテロ原子とを含む複素環、又は1若しくは2個の5-若しくは6-員環とN、O及びSから選択される1〜4個のヘテロ原子とを含むヘテロアリールであり、ここで、アルキル基、アルケニル基、アルキニル基、アリール基、炭素環基、複素環基又はヘテロアリール基は、任意に独立して、C1-C6アルキル、OH、O(C1-C6アルキル)、オキソ、ハロゲン、NH2、N(H)(C1-C6アルキル)、N(C1-C6アルキル)2、SO2H、SO2(C1-C6アルキル)、CHO、CO2H、CO2(C1-C6アルキル)又はCNで1回以上置換される;
R3は、H、C1-C10アルキル、C2-C6アルケニル、C2-C6アルキニル、SO2R4又はS(O)R4であり、ここで、アルキル基、アルケニル基又はアルキニル基は、任意に独立して、C1-C6アルキル、OH、O(C1-C6アルキル)、オキソ、ハロゲン、NH2、N(H)(C1-C6アルキル)、N(C1-C6アルキル)2、SO2H、SO2(C1-C6アルキル)、CHO、CO2H、CO2(C1-C6アルキル)又はCNで1回以上置換される;
R4は、C1-C10アルキル、C2-C6アルケニル、C2-C6アルキニル、OH、C6-C10アリール、C3-C10炭素環、1若しくは2個の5-若しくは6-員環とN、O及びSから選択される1〜4個のヘテロ原子とを含む複素環、又は1若しくは2個の5-若しくは6-員環とN、O及びSから選択される1〜4個のヘテロ原子とを含むヘテロアリールであり、ここで、アルキル基、アルケニル基、アルキニル基、アリール基、炭素環基、複素環基又はヘテロアリール基は、任意に独立して、C1-C6アルキル、OH、O(C1-C6アルキル)、オキソ、ハロゲン、NH2、N(H)(C1-C6アルキル)、N(C1-C6アルキル)2、SO2H、SO2(C1-C6アルキル)、CHO、CO2H、CO2(C1-C6アルキル)又はCNで1回以上置換される;
あるいは、R2及びR3は、それらが結合する原子と一緒になって、1又は2個の5-又は6-員環を含む環状部分を形成し、該環状部分はさらにN、O及びSから選択される1〜5個のさらなるヘテロ原子を任意に含み、ここで、該環はオキソで任意に置換され得る;並びに
nは1又は2である)
を有する。
例えば、神経学的疾患は多発性硬化症である。
例えば、神経学的疾患は再発−寛解型多発性硬化症(RRMS)である。
例えば、神経学的疾患は続発性進行性多発性硬化症である。
例えば、神経学的疾患は原発性進行性多発性硬化症である。
例えば、神経学的疾患は進行性再発型多発性硬化症である。
例えば、式(I)の化合物は本明細書の表1に列挙された化合物である。
例えば、式(I)の化合物において、R1はメチルである。
例えば、式(I)の化合物において、R1はエチルである。
例えば、式(I)の化合物において、LaはC1-C6アルキルリンカーである。
例えば、式(I)の化合物において、LaはC1-C3アルキルリンカーである。
例えば、式(I)の化合物において、LaはC2アルキルリンカーである。
例えば、式(I)の化合物において、Laは非置換のC2アルキルリンカーである。
例えば、式(I)の化合物において、Laはメチルで置換されたC2アルキルリンカーである。
例えば、式(I)の化合物において、Laはジ−メチルで置換されたC2アルキルリンカーである。
例えば、式(I)の化合物において、Laはメチル又はジ−メチルで置換されたC2アルキルリンカーである。
例えば、式(I)の化合物において、R2はC1-C10アルキルである。
例えば、式(I)の化合物において、R2はC1-C6アルキルである。
例えば、式(I)の化合物において、R2は非置換のC1-C6アルキルである。
例えば、式(I)の化合物において、R2はC1-C3アルキルである。
例えば、式(I)の化合物において、R2は非置換のC1-C3アルキルである。
例えば、式(I)の化合物において、R2はC1-C2アルキルである。
例えば、式(I)の化合物において、R2は非置換のC1-C2アルキルである。
例えば、式(I)の化合物において、R3はHである。
例えば、式(I)の化合物において、R3はC1-C6アルキルである。
例えば、式(I)の化合物において、R3は非置換のC1-C6アルキルである。
例えば、式(I)の化合物において、R2はC6-C10アリールである。
例えば、式(I)の化合物において、R2は非置換のC6-C10アリールである。
例えば、式(I)の化合物において、R2はフェニルである。
例えば、式(I)の化合物において、R2は非置換のフェニルである。
例えば、式(I)の化合物において、R2はベンジルである。
例えば、式(I)の化合物において、R2は非置換のベンジルである。
一般手順1
ジメチルホルムアミド(MMF 1g当たり25ml)中フマル酸モノメチル(MMF)(1.0当量)およびHBTU(1.5当量)の混合物にHuenigs塩基(2.0当量)を添加した。暗褐色溶液を10分間撹拌して、茶色の懸濁液に変わった後、アルコール(1.0〜1.5当量)を添加した。反応を室温で18時間撹拌した。水を添加して生成物を3回、酢酸エチルに抽出した。合わせた有機層を水で3回洗浄し、硫酸マグネシウムで乾燥させ、ろ過して真空下、45℃で濃縮し、粗生成物を得た。粗生成物を、シリカクロマトグラフィーで精製し、いくつかの場合は、ジエチルエーテルを用いた粉砕によりさらに精製し、所望のきれいなエステル生成物を得た。全てのアルコールは市販品であったかまたは公知の文献の手法に従って作製した。
フマル酸モノメチル(MMF)(1.3当量)、アルキルメシレート(1当量)および炭酸カリウム(1.5当量)のアセトニトリル(MMF 1g当たり50ml)中の混合物を還流で一晩加熱した。混合物を酢酸エチルと炭酸水素ナトリウム飽和水溶液の間で分離して、有機相を乾燥させた(MgSO4)。濾過および減圧下での溶媒の除去により粗生成物を得て、これをそれぞれの場合にシリカクロマトグラフィーで精製した。
明細書に記載されるNMRスペクトルは、当該技術分野に公知の標準的な技術を使用して、Varian 400MHz NMR分光器により得た。
化合物1:メチル(2-(N-メチルメチルスルホンアミド)エチル)フマレート
MMFプロドラッグの化学的安定性
アセトニトリルまたはアセトニトリル/MeOH中の化合物のストック溶液を0.05Mで調製した。0.010mLアリコートのストックを、1mLの50mMリン酸バッファpH8にスパイクし、37℃でインキュベートした。典型的に、異なる時点でアリコート(0.010mL)をサンプリングし、すぐにUV検出(211nm)を伴うHPLCに注入した。化合物に対応するピーク面積を時間に対してプロットし、一次単一指数関数(mono-exponential)的減衰にデータを適合させ、傾斜から速度定数および半減期を決定した(表2)。
I. 化合物1についての単結晶X線データ(図1):
0.44x0.20x0.12mmの大きさの無色の針状結晶を、極少量のパラトンオイル(paratone oil)を用いてナイロンループ上に設置した。
実験式:C9 H15 N O6 S
式重量:265.28
温度:173(2)K
波長:1.54178Å
空間群:P-1
単位セル寸法:a=5.41860(10)Å α=103.3520(10)°。
:b=7.49550(10)Å β=90.2790(10)°。
:c=15.4618(3)Å γ=100.1950(10)°。
容積:600.674(18)Å3
Z:2
密度(計算):1.467mg/m3
吸収係数:2.592mm-1
F(000):280
結晶サイズ:0.44x0.20x0.12mm3
集められた反射(Reflections collected):9112
独立反射(Independent reflections):2283[R(int)=0.0214]
精密化方法(Refinement method):F2に対する完全マトリクス最小二乗法(Full-matrix least-squares on F2)
F2に対する適合度:1.077
最終R指数[I>2シグマ(I)]R1=0.0306、wR2=0.0808
R指数(全データ):R1=0.0312、wR2=0.0812
0.51x0.17x0.06mmの大きさの無色の板状結晶を、極少量のパラトンオイルを用いてナイロンループ上に設置した。
実験式:C8 H12 N O6 S
式重量:250.25
温度:173(2)K
波長:0.71073Å
空間群:P 21/c
単位セル寸法:a =11.9021(16)Å α=90°。
b=5.4515(7)Å β=95.554(2)°。
c=17.404(2)Å γ=90°。
容積:1123.9(3)Å3
Z:4
密度(計算):1.479mg/m3
吸収係数:0.301mm-1
F(000):524
結晶サイズ:0.51x0.17x0.06mm3
集められた反射:8775
独立反射:2063[R(int)=0.0368]
精密化方法:F2に対する完全マトリクス最小二乗法
F2に対する適合度:1.053
最終R指数[I>2シグマ(I)]R1=0.0356、wR2=0.0959
R指数(全データ):R1=0.0419、wR2=0.1015
0.29x0.18x0.08mmの大きさの無色の板状結晶を、極少量のパラトンオイルを用いてナイロンループ上に設置した。
実験式:C10 H15 N O6 S
式重量:277.29
温度:173(2)K
波長:0.71073Å
空間群:P-1
単位セル寸法:a=6.0125(10)Å α=102.435(2)°。
b=9.1418(15)Å β=99.174(2)°。
c=12.006(2)Å γ=105.445(2)°。
容積:604.45(17)Å3
Z:2
密度(計算):1.524mg/m3
吸収係数:0.288mm-1
F(000):292
結晶サイズ:0.29x0.19x0.08mm3
集められた反射:9989
独立反射:2216[R(int)=0.0389]
精密化方法:F2に対する完全マトリクス最小二乗法
F2に対する適合度:1.087
最終R指数[I>2シグマ(I)]R1=0.0379、wR2=0.0983
R指数(全データ)R1=0.0485、wR2=0.1062
プロドラッグの経口投与時のラットにおけるMMFの送達
ラットを購入し、頸静脈内に前もってカニューレ挿入した。実験の時点で動物は意識があった。全ての動物を一晩絶食させ、4時間後に開示のプロドラッグを投与した。
結晶形態の本プロドラッグ及びDMFの物理的安定性
熱重量分析(TGA)により、本発明の化合物及びフマル酸ジメチル(DMF)の物理的安定性を測定した。図4は、化合物1(10.53 mg)について変化なし、及びDMF(4.97 mg)について2時間未満で約100%の重量消失の、55℃での重量消失対時間のプロットを示す。図5は、化合物2(9.20 mg)について変化なし、及びDMF(4.97mg)について2時間未満で約100%の重量消失の、55℃での重量消失対時間のプロットを示す。これらのデータは、化合物1及び2が同様の条件下で物理的に安定であるのに対して、DMFは昇華することを示す。
Claims (16)
- 式(I):
(式中、
R1はメチルであり;
Laは、C1-C6アルキル、C3-C10炭素環、C6-C10アリール、1若しくは2個の5-若しくは6-員環並びにN、O及びSから選択される1〜4個のヘテロ原子を含む複素環、又は1若しくは2個の5-若しくは6-員環並びにN、O及びSから選択される1〜4個のヘテロ原子を含むヘテロアリールであり、ここで、アルキル基、炭素環基、アリール基、複素環基又はヘテロアリール基は、独立して、ハロゲンで1回以上任意に置換され;
R2は、C1-C10アルキル、C2-C6アルケニル、C2-C6アルキニル、OH、C6-C10アリール、C3-C10炭素環、1若しくは2個の5-若しくは6-員環並びにN、O及びSから選択される1〜4個のヘテロ原子を含む複素環、又は1若しくは2個の5-若しくは6-員環並びにN、O及びSから選択される1〜4個のヘテロ原子を含むヘテロアリールであり、ここで、アルキル基、アルケニル基、アルキニル基、アリール基、炭素環基、複素環基又はヘテロアリール基は、独立して、C1-C6アルキル、OH、O(C1-C6アルキル)、オキソ、NH2、N(H)(C1-C6アルキル)、N(C1-C6アルキル)2、SO2H、SO2(C1-C6アルキル)、CHO、CO2H、CO2(C1-C6アルキル)又はCNで1回以上任意に置換され;
R3は、H、C1-C10アルキル、C2-C6アルケニル、C2-C6アルキニル、SO2R4又はS(O)R4であり、ここで、アルキル基、アルケニル基又はアルキニル基は、独立して、C1-C6アルキル、OH、O(C1-C6アルキル)、オキソ、ハロゲン、NH2、N(H)(C1-C6アルキル)、N(C1-C6アルキル)2、SO2H、SO2(C1-C6アルキル)、CHO、CO2H、CO2(C1-C6アルキル)又はCNで1回以上任意に置換され;
R4は、C1-C10アルキル、C2-C6アルケニル、C2-C6アルキニル、OH、C6-C10アリール、C3-C10炭素環、1若しくは2個の5-若しくは6-員環並びにN、O及びSから選択される1〜4個のヘテロ原子を含む複素環、又は1若しくは2個の5-若しくは6-員環並びにN、O及びSから選択される1〜4個のヘテロ原子を含むヘテロアリールであり、ここで、アルキル基、アルケニル基、アルキニル基、アリール基、炭素環基、複素環基又はヘテロアリール基は、独立して、C1-C6アルキル、OH、O(C1-C6アルキル)、オキソ、ハロゲン、NH2、N(H)(C1-C6アルキル)、N(C1-C6アルキル)2、SO2H、SO2(C1-C6アルキル)、CHO、CO2H、CO2(C1-C6アルキル)又はCNで1回以上任意に置換され;
或いは、R2及びR3は、それらが結合する原子と一緒になって、1又は2個の5-又は6-員環を含む環状部分を形成し、該環状部分はさらにN、O及びSから選択される1〜5個のさらなるヘテロ原子を任意に含み、ここで、該環はオキソで任意に置換され得;
nは1又は2である)
の化合物、又はその薬学的に許容され得る塩。 - R2が、C1-C10アルキル、又はC1-C6アルキル、OH若しくはO(C1-C6アルキル)で1回以上任意に置換されるフェニルである、請求項1に記載の化合物。
- R3がH又はC1-C10アルキルである、請求項1又は2に記載の化合物。
- R2及びR3が、それらが結合する原子と一緒になって、1又は2個の5-又は6-員環を含む環状部分を形成し、該環状部分がさらにN、O及びSから選択される1〜5個のさらなるヘテロ原子を任意に含み、ここで、該環がオキソで任意に置換され得る、請求項1に記載の化合物。
- R4が、ハロゲンで任意に置換されるC1-C10アルキル又はC1-C10アルキルで任意に置換されるC6-C10アリールである、請求項1、2又は3に記載の化合物。
- LaがC1-C6アルキルである、請求項1〜5のいずれかに記載の化合物。
- L aがC1-C6アルキルであり;
R2が、C 1-C10アルキル、又はC1-C10アルキルで任意に置換されるC6-C10アリールであり;
R3が、H、C1-C10アルキル、SO2R4又はS(O)R4であり;
R4が、ハロゲンで任意に置換されるC1-C10アルキル又はC1-C10アルキルで任意に置換されるC6-C10アリールであり;
或いは、R2及びR3は、それらが結合する原子と一緒になって、1又は2個の5-又は6-員環を含む環状部分を形成し、該環状部分はさらにN、O及びSから選択される1〜5個のさらなるヘテロ原子を任意に含み、ここで、該環はオキソで任意に置換され得;
nが1又は2である、請求項1に記載の化合物。 - R 2 が、C 1 -C 10 アルキルであり、R 3 が、H又はC 1 -C 10 アルキルである、請求項7に記載の化合物。
- (i)式(I):
(式中、
R1はメチルであり;
Laは、C1-C6アルキル、C3-C10炭素環、C6-C10アリール、1若しくは2個の5-若しくは6-員環並びにN、O及びSから選択される1〜4個のヘテロ原子を含む複素環、又は1若しくは2個の5-若しくは6-員環並びにN、O及びSから選択される1〜4個のヘテロ原子を含むヘテロアリールであり、ここで、アルキル基、炭素環基、アリール基、複素環基又はヘテロアリール基は、独立して、ハロゲンで1回以上任意に置換され;
R2は、C1-C10アルキル、C2-C6アルケニル、C2-C6アルキニル、OH、C6-C10アリール、C3-C10炭素環、1若しくは2個の5-若しくは6-員環並びにN、O及びSから選択される1〜4個のヘテロ原子を含む複素環、又は1若しくは2個の5-若しくは6-員環並びにN、O及びSから選択される1〜4個のヘテロ原子を含むヘテロアリールであり、ここで、アルキル基、アルケニル基、アルキニル基、アリール基、炭素環基、複素環基又はヘテロアリール基は、独立して、C1-C6アルキル、OH、O(C1-C6アルキル)、オキソ、NH2、N(H)(C1-C6アルキル)、N(C1-C6アルキル)2、SO2H、SO2(C1-C6アルキル)、CHO、CO2H、CO2(C1-C6アルキル)又はCNで1回以上任意に置換され;
R3は、H、C1-C10アルキル、C2-C6アルケニル、C2-C6アルキニル、SO2R4又はS(O)R4であり、ここで、アルキル基、アルケニル基又はアルキニル基は、独立して、C1-C6アルキル、OH、O(C1-C6アルキル)、オキソ、ハロゲン、NH2、N(H)(C1-C6アルキル)、N(C1-C6アルキル)2、SO2H、SO2(C1-C6アルキル)、CHO、CO2H、CO2(C1-C6アルキル)又はCNで1回以上任意に置換され;
R4は、C1-C10アルキル、C2-C6アルケニル、C2-C6アルキニル、OH、C6-C10アリール、C3-C10炭素環、1若しくは2個の5-若しくは6-員環並びにN、O及びSから選択される1〜4個のヘテロ原子を含む複素環、又は1若しくは2個の5-若しくは6-員環並びにN、O及びSから選択される1〜4個のヘテロ原子を含むヘテロアリールであり、ここで、アルキル基、アルケニル基、アルキニル基、アリール基、炭素環基、複素環基又はヘテロアリール基は、独立して、C1-C6アルキル、OH、O(C1-C6アルキル)、オキソ、ハロゲン、NH2、N(H)(C1-C6アルキル)、N(C1-C6アルキル)2、SO2H、SO2(C1-C6アルキル)、CHO、CO2H、CO2(C1-C6アルキル)又はCNで1回以上任意に置換され;
或いは、R2及びR3は、それらが結合する原子と一緒になって、1又は2個の5-又は6-員環を含む環状部分を形成し、該環状部分はさらにN、O及びSから選択される1〜5個のさらなるヘテロ原子を任意に含み、ここで、該環はオキソで任意に置換され得;
nは1又は2である)
の化合物又はその薬学的に許容され得る塩;及び
(ii)薬学的に許容され得る担体又は賦形剤
を含む医薬組成物。 - 神経学的疾患の治療における使用のための、請求項13に記載の医薬組成物。
- 神経学的疾患が多発性硬化症である、請求項14に記載の医薬組成物。
- 神経学的疾患が、再発−寛解型多発性硬化症、続発性進行性多発性硬化症、原発性進行性多発性硬化症、又は進行性再発型多発性硬化症から選択される、請求項14に記載の医薬組成物。
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