JP2017538760A - レチノイド関連オーファン受容体ガンマ(RORガンマ(t))のインバースアゴニストとしてのベンゼンスルホンアミド誘導体 - Google Patents
レチノイド関連オーファン受容体ガンマ(RORガンマ(t))のインバースアゴニストとしてのベンゼンスルホンアミド誘導体 Download PDFInfo
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- JP2017538760A JP2017538760A JP2017533268A JP2017533268A JP2017538760A JP 2017538760 A JP2017538760 A JP 2017538760A JP 2017533268 A JP2017533268 A JP 2017533268A JP 2017533268 A JP2017533268 A JP 2017533268A JP 2017538760 A JP2017538760 A JP 2017538760A
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- ethylphenyl
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- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 55
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 37
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- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 16
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- ALSHELPJXZVLFR-UHFFFAOYSA-N n-(4-ethylphenyl)-2-methylpropanamide Chemical compound CCC1=CC=C(NC(=O)C(C)C)C=C1 ALSHELPJXZVLFR-UHFFFAOYSA-N 0.000 description 13
- 239000000843 powder Substances 0.000 description 13
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- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
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- TXQWFIVRZNOPCK-UHFFFAOYSA-N pyridin-4-ylmethanamine Chemical compound NCC1=CC=NC=C1 TXQWFIVRZNOPCK-UHFFFAOYSA-N 0.000 description 1
- AUHXBTKGPUVFCB-UHFFFAOYSA-N pyrimidin-4-ylmethanamine Chemical compound NCC1=CC=NC=N1 AUHXBTKGPUVFCB-UHFFFAOYSA-N 0.000 description 1
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- XWGJFPHUCFXLBL-UHFFFAOYSA-M rongalite Chemical compound [Na+].OCS([O-])=O XWGJFPHUCFXLBL-UHFFFAOYSA-M 0.000 description 1
- 239000002453 shampoo Substances 0.000 description 1
- RMBAVIFYHOYIFM-UHFFFAOYSA-M sodium methanethiolate Chemical compound [Na+].[S-]C RMBAVIFYHOYIFM-UHFFFAOYSA-M 0.000 description 1
- QJDUDPQVDAASMV-UHFFFAOYSA-M sodium;ethanethiolate Chemical compound [Na+].CC[S-] QJDUDPQVDAASMV-UHFFFAOYSA-M 0.000 description 1
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- JZKSWGHTUFOAJF-UHFFFAOYSA-N tert-butyl 4-[4-[(4-ethylphenyl)-(2-methylpropyl)sulfamoyl]-2-(methylsulfonimidoyl)phenoxy]piperidine-1-carboxylate Chemical compound C(C)C1=CC=C(C=C1)N(S(=O)(=O)C1=CC(=C(OC2CCN(CC2)C(=O)OC(C)(C)C)C=C1)S(=O)(=N)C)CC(C)C JZKSWGHTUFOAJF-UHFFFAOYSA-N 0.000 description 1
- QZIJVVAKHQPTQY-UHFFFAOYSA-N tert-butyl 6-[4-[(4-ethylphenyl)-(2-methylpropyl)sulfamoyl]-2-(methylsulfonimidoyl)phenyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate Chemical compound C(C)C1=CC=C(C=C1)N(S(=O)(=O)C1=CC(=C(C=C1)N1CC2(CN(C2)C(=O)OC(C)(C)C)C1)S(=O)(=N)C)CC(C)C QZIJVVAKHQPTQY-UHFFFAOYSA-N 0.000 description 1
- ZBBGKXNNTNBRBH-UHFFFAOYSA-N tert-butyl n-(oxiran-2-ylmethyl)carbamate Chemical compound CC(C)(C)OC(=O)NCC1CO1 ZBBGKXNNTNBRBH-UHFFFAOYSA-N 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
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- 238000002877 time resolved fluorescence resonance energy transfer Methods 0.000 description 1
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- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical class OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- 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
- C07D207/18—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 one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—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 one double bond between ring members or between a ring member and a non-ring member 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
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
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- A61K31/33—Heterocyclic compounds
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/541—Non-condensed thiazines containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/10—Anti-acne agents
-
- C—CHEMISTRY; METALLURGY
- 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
- C07C311/22—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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C381/00—Compounds containing carbon and sulfur and having functional groups not covered by groups C07C301/00 - C07C337/00
- C07C381/10—Compounds containing sulfur atoms doubly-bound to 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
- C07D211/08—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
- C07D211/20—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 singly bound oxygen or sulphur atoms
- C07D211/22—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 singly bound oxygen or sulphur atoms by oxygen 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
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent 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
- C07D211/68—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 one double bond between ring members or between a ring member and a non-ring member
- C07D211/72—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 one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D211/74—Oxygen atoms
- C07D211/76—Oxygen atoms attached in position 2 or 6
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
- C07D211/96—Sulfur atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/30—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
- C07D263/18—Oxygen atoms
- C07D263/20—Oxygen atoms attached in position 2
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
- C07D263/18—Oxygen atoms
- C07D263/20—Oxygen atoms attached in position 2
- C07D263/24—Oxygen atoms attached in position 2 with hydrocarbon radicals, substituted by oxygen atoms, attached to other ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/08—1,2,5-Oxadiazoles; Hydrogenated 1,2,5-oxadiazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
- C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
- C07D279/16—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
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Abstract
Description
・qは、0又は1から3の範囲の自然数を表し、
・Lは、単結合又はメチレン基CH2を表し、
・R1は、直鎖状又は分岐状C3〜C5アルキル基、C3〜C5シクロアルキル基、直鎖状又は分岐状C2〜C5アルケニル基、(C1)アルキル(C3〜C5)シクロアルキル基、C4〜C5ヘテロシクロアルキル基、(C1)アルキル(C4〜C5)ヘテロシクロアルキル基を表し、
・R2は、水素原子又はハロゲン原子、直鎖状又は分岐状C1〜C5アルキル基、直鎖状又は分岐状C2〜C4アルケニル基、C1〜C4アルコキシ基、シアノ基-CNを表し;アルキル、アルケニル及びアルコキシ基は、場合により1個又は複数のハロゲン原子で置換されており、
・R3は、水素原子、C1〜C3アルキル基又はアミノ-NH2基を表し、
・R4は、水素原子又は(CHR5)n-(Z)o-(CHR'5)p-R6基を表し、
・n、o及びpは、同一であっても異なっていてもよく、0又は1から3の範囲の自然数を表し、
・Zは、-CH2-、-NH-及び-O-から選択される二価基を表し、
・R5及びR'5は、同一であっても異なっていてもよく、水素原子、メチル基-CH3、ヒドロキシル基-OH、C1ヒドロキシアルキル基、カルボン酸基-COOHを表し
・R6は:
- 水素原子又はハロゲン原子、
- 任意選択で、1個又は複数のハロゲン原子、1個又は複数の直鎖状又は分岐状C1〜C3アルキル基、1個又は複数の-OH基、1個又は複数のカルボニル官能基=O、1個又は複数の直鎖状又は分岐状C1〜C4ヒドロキシアルキル基、ピロリジン環、1個又は複数のアミノ基、1個又は複数の-C(=O)R7基、1個又は複数のS(=O)2R7基で置換されているヘテロシクロアルキル基であって、R7は、直鎖状若しくは分岐状C1〜C3アルキル基、ヒドロキシル基-OH、直鎖状若しくは分岐状C1〜C4アルコキシ基、又はアミノ基N(R7a)(R7b)を表し;R7a及びR7bは、同一であってもよく異なっていてもよく、水素原子、直鎖状若しくは分岐状C1〜C3アルキル基、又はシクロプロピル基を表す、ヘテロシクロアルキル基
- 任意選択で、1個又は複数の-OH基で置換されているC3〜C6シクロアルキル基、
- 1個若しくは複数のハロゲン原子、任意選択で、1個若しくは複数のハロゲン原子で置換されている1個若しくは複数の直鎖状若しくは分岐状C1〜C3アルキル基、1個若しくは複数のC1〜C3アルコキシ基、1個若しくは複数のアミノ基-NR11R12、1個若しくは複数の-COR11基、カルボニル官能基(=O)、1個若しくは複数の-OR11基、1個若しくは複数のC1〜C4ヒドロキシアルキル基、1個若しくは複数の-COOR11基、1個若しくは複数のアミド基-CONR11R12、1個若しくは複数の-SOR11基、1個若しくは複数の-SO2R11基、1個若しくは複数の-NHCOR11基、1個若しくは複数の-NHCOOR11基、1個若しくは複数の-SO2NR11R12基又は1個若しくは複数の-CN基で任意選択で置換されている芳香族若しくはヘテロ芳香族基であって、R11及びR12は、同一であってもよく異なっていてもよく、水素原子、又は任意選択で、1個若しくは複数のハロゲン原子で置換されている直鎖状若しくは分岐状C1〜C3アルキル基を表す、芳香族若しくはヘテロ芳香族基
を表し;
・A1は、-NRa-、-O-、-S-、-SO-、-SO2-、-SO(=NH)-、-CH2-、-C=C-、-CH(Ra)-から選択される二価基を表し;
・A2は、単結合又は-S-、-SO-、-SO2-、-SO(=N-Rb)-、-CH(OH)-、-C(=O)O-から選択される二価基を表すが;
但し:
- A1が、-NRa-、-O-、-CH2-、-C=C-及び-CH(Ra)から選択される二価基の1つを表す場合:A2は、二価基-CH(OH)-及び-C(=O)O-を表さず、R3は、水素原子、アミノ基-NH2又はC1〜C3アルキル基を表さず、
- A2が単結合を表し、R3が水素原子を表す場合、A1は、-SO-及び-SO(=NH)-から選択される二価基の1つを表し:
・Raは、水素原子、直鎖状若しくは分岐状C1〜C3アルキル基、又はアセチル基-C(=O)CH3を表し、
・Rbは、水素原子、直鎖状若しくは分岐状C1〜C3アルキル基、又はシクロプロピル基を表し、
・Q1、Q2、Q3、Q4及びQ5は、同一であっても異なっていてもよく、窒素原子又は-CR'2基を表し
・A2が、-S-、-SO、-SO2-及び-SO(=N-Rb)-から選択される二価基を表す場合、Ra及びR3は、それらが結合する炭素原子と一緒になって、任意選択で、1個又は複数のカルボニル官能基、1個又は複数のC1〜C3アルキル基で置換されていてよいヘテロシクロアルキル基を形成でき、
・A1が-NRa-を表す場合、Ra及びR4は、それらが結合する窒素原子と一緒になって、任意選択で硫黄原子、窒素原子及び酸素原子から選択される1から3個のヘテロ原子を含むC2〜C10ヘテロシクロアルキル基を形成でき;前記ヘテロシクロアルキル基は、任意選択で、少なくとも1個のR14基で置換されており、
・R14は、直鎖状又は分岐状C1〜C3アルキル基、直鎖状又は分岐状C1〜C3アルコキシ基、ハロゲン原子、ヒドロキシル基-OH、シアノ基-CN、-CONR15R16基、-SO2R15基、-COR15基又はアミノ基-NR15R16であり;R15及びR16は、同一であっても異なっていてもよく、水素原子又は直鎖状若しくは分岐状C1〜C3アルキル基を表す。
- A1が以下の二価基:-NRa-、-O-、-CH2-、-C=C-又は-CH(Ra)の1つを表す場合、A2は、単結合又は二価基:-CH(OH)-又は-C(=O)O-を表さず、
- A2-R3が水素原子を表す場合、A1は、以下の二価基:-SO-及び-SO(=NH)の1つを表す
式中:
- R7は、直鎖状若しくは分岐状C1〜C3アルキル基、ヒドロキシル基-OH、C1〜C3アルコキシ基又はアミノ基N(R7a)(R7b)を表し、
- R7a及びR7bは、同一であっても異なっていてもよく、水素原子、直鎖状若しくは分岐状C1〜C3アルキル基、又はシクロプロピル基を表し
- R8及びR9は、同一であっても異なっていてもよく、水素原子、直鎖状又は分岐状C1〜C3アルキル基、ヒドロキシル基-OH、カルボニル基、(C1)ヒドロキシアルキル基(CH2OH)、アミノ基-NH2を表し、
- R8及びR9は、それらが結合する炭素原子と一緒になって、5-から7-員環の炭素環式環を形成できる。
式中:
- R10は、水素原子若しくはハロゲン原子;任意選択で、1個若しくは複数のハロゲン原子で置換されている直鎖状若しくは分岐状C1〜C3アルキル基;カルボニル官能基C(=O)、OR11基、C1〜C4ヒドロキシアルキル基、アミノ基-NR11R12、-COR11基、-COOR11基、アミド基-CONR11R12、-SOR11基、-SO2R11基、-NHCOR11基、-NHCOOR11基、-SO2NR11R12基又はシアノ基-CNを表し、
- R11及びR12は、同一であっても異なっていてもよく、水素原子、又は任意選択で、1個若しくは複数のハロゲン原子で置換されている直鎖状若しく分岐状C1〜C3アルキル基を表し、
- mは、0又は1から3の範囲の自然数を表す。
- R3は、C1〜C3アルキル基を表し、
- R1、R2、R'2、R3、R4、R5、R'5、R6、R7、R7a、R7b、R8、R9、R10、R11、R12、Ra、Rb、Z、Q1、Q2、Q3、Q4、Q5、A1並びに添字q、m、n、o及びpは、以前に指し示したものと同じ意味を有する。
- R1、R2、R'2、R3、Rb、Q1、Q2、Q3、Q4、Q5、A2及び添字qは、先に記載されている式(I)の意味と同じ意味を有し、
- Ra及びR4は、それらが結合する窒素原子と一緒になって、任意選択で、硫黄原子、窒素原子及び酸素原子から選択される1から3個のヘテロ原子を含むC2〜C10ヘテロシクロアルキル基を形成し;前記ヘテロシクロアルキル基は、任意選択で、少なくとも1個のR14基で置換されており、
- R14は、直鎖状若しくは分岐状C1〜C3アルキル基、直鎖状若しくは分岐状C1〜C3アルコキシ基、ハロゲン原子、ヒドロキシル基-OH、シアノ基-CN、-CONR15R16基、-SO2R15基、-COR15基又はアミノ基-NR15R16を表し;R15及びR16は、同一であっても異なっていてもよく、水素原子又は直鎖状若しくは分岐状C1〜C3アルキル基を表す。
HeLa株である株HG5LNから、RORγトランス活性化モデルが開発されており、これは、酵母のGAL4認識ドメインの五量体及びβ-グロビンプロモーターにより制御されるルシフェラーゼレポーター遺伝子を安定的に発現する。HG5LN株は、RORガンマリガンド結合ドメイン(LBD)に融合させたGAL4のDNA結合ドメイン(DBD)により安定的に遺伝子導入された。RORガンマの構成的活性を阻害する分子は、ルシフェラーゼ発現を減少させ、したがって、発光の減少を引き起こす。
このモデルで、CD4+細胞によるIL-17A分泌に対する阻害剤の効果を測定することが可能となる。細胞は、冷凍CD4+細胞(STEMCELL社、#70026)であり、ヒトの末梢血から単離され、抗CD3及び抗CD28抗体で活性化する。分泌されるIL-17aの量は、TR-FRET(キットHTRF(登録商標)Human Interleukin 17A(Cisbio社、#64H17PEC))技術で測定する。
- R3は、C1〜C3アルキル基を表し、
- R1、R2、R'2、R4、R5、R'5、R6、R7、R7a、R7b、R8、R9、R10、R11、R12、Ra、Rb、Z、Q1、Q2、Q3、Q4、Q5、A1及び添字q、n、m、o及びpは、先に記載されている式(I)の意味と同じ意味を有する。
- Ra及びR4は、それらが結合する窒素原子と一緒になって、任意選択で、硫黄原子、窒素原子及び酸素原子から選択される1から3個のヘテロ原子を含むC2〜C10ヘテロシクロアルキル基を形成し;前記ヘテロシクロアルキル基は、任意選択で、少なくとも1個のR14基で置換されており、
- R14は、直鎖状又は分岐状C1〜C3アルキル基、直鎖状若しくは分岐状C1〜C3アルコキシ基、ハロゲン原子、ヒドロキシル基-OH、シアノ基-CN、-CONR15R16基、-SO2R15基、-COR15基又はアミノ基-NR15R16を表し;R15及びR16は、同一であっても異なっていてもよく、水素原子又は直鎖状若しくは分岐状C1〜C3アルキル基を表し、
- R1、R2、R'2、R3、Rb、Q1、Q2、Q3、Q4、Q5、A2及び添字qは、先に記載されている式(I)の意味と同じ意味を有する。
N-(4-エチルフェニル)-N-イソブチル-3-メタンスルファニル-4-(テトラヒドロピラン-4-イルメトキシ)ベンゼンスルホンアミドの合成
MS:[M+H]=179
2.中間体1.2の合成
MS:[M+H]=426
3.中間体1.3の合成
MS:[M+H]=414
4.中間体1.4の合成
MS:[M+H]=512
本発明による化合物25の合成
N-(4-エチルフェニル)-N-イソブチル-3-メタンスルフィニル-4-(テトラヒドロピラン-4-イルメトキシ)ベンゼンスルホンアミドの合成
[超臨界条件100bar、70℃;Chiralpak IC 250×4.6mm、5μカラム]
N-(4-エチルフェニル)-N-イソブチル-3-メタンスルフィニル-4-(テトラヒドロピラン-4-イルメトキシ)ベンゼンスルホンアミド(化合物19) - 化合物27の鏡像異性体A
N-(4-エチルフェニル)-N-イソブチル-3-メタンスルフィニル-4-(テトラヒドロピラン-4-イルメトキシ)ベンゼンスルホンアミド(化合物20) - 化合物27の鏡像異性体B
N-(4-エチルフェニル)-N-イソブチル-3-メタンスルホキシミノ-4-(テトラヒドロピラン-4-イルメトキシ)ベンゼンスルホンアミドの合成
N-(4-エチルフェニル)-N-イソブチル-3-(メタンスルフィニル)-4-(テトラヒドロピラン-4-イルメトキシ)ベンゼンスルホキシミン(化合物7) - 化合物26の鏡像異性体A
MS:[M+H]=509
N-(4-エチルフェニル)-N-イソブチル-3-(メタンスルフィニル)-4-(テトラヒドロピラン-4-イルメトキシ)ベンゼンスルホキシミン(化合物8) - 化合物26の鏡像異性体B
MS:[M+H]=509
N-(4-エチルフェニル)-N-イソブチル-3-メタンスルフィニル-4-(テトラヒドロピラン-4-イルメトキシ)ベンゼン-N-メチルスルホキシミンの合成
N-(4-エチルフェニル)-N-イソブチル-3-メタンスルホニル-4-(テトラヒドロピラン-4-イルメトキシ)ベンゼンスルホンアミドの合成
エタンスルフィニル-N-(4-エチルフェニル)-N-イソブチル-4-(テトラヒドロピラン-4-イルメトキシ)ベンゼンスルホンアミドの合成
MS:[M+H]=492
2.本発明による化合物22の合成
N-(4-エチルフェニル)-N-イソブチル-3-エタンスルホキシミン-4-(テトラヒドロピラン-4-イルメトキシ)ベンゼンスルホンアミドの合成
N-(4-エチルフェニル)-4-(((4-フルオロテトラヒドロ-2H-ピラン-4-イル)メトキシ)-N-イソブチル-3-(S-メチルスルホンイミドイル)ベンゼンスルホンアミドの合成
MS:[M+H]=444
2.中間体12.2の合成
MS:[M+H]=554
3.中間体12.3の合成
MS:[M+H]=474
4.本発明による化合物30の合成
化合物4-((2,4-ジフルオロベンジル)オキシ)-N-(4-エチルフェニル)-N-イソブチル-3-(S-メチルスルホンイミドイル)ベンゼンスルホンアミドの合成
化合物4-(4-シアノフェノキシ)-N-(4-エチルフェニル)-N-イソブチル-3-(S-メチルスルホンイミドイル)ベンゼンスルホンアミドの合成
N-(4-エチルフェニル)-N-イソブチル-3-(S-メチルスルホンイミドイル)-4-(ピペリジン-4-イルメトキシ)ベンゼンスルホンアミドの合成
配座異性体の混合物:
4-((1-アセチルピペリジン-4-イル)オキシ)-N-(4-エチルフェニル)-N-イソブチル-3-(S-メチルスルホンイミドイル)ベンゼンスルホンアミドの合成
N-(4-エチルフェニル)-N-イソブチル-3-(S-メチルスルホンイミドイル)-4-((1-(メチルスルホニル)ピペリジン-4-イル)オキシ)ベンゼンスルホンアミドの合成
N-(4-エチルフェニル)-N-イソブチル-3-(S-メチルスルホンイミドイル)-4-(ピペリジン-4-イルメトキシ)ベンゼンスルホンアミドの合成
4-((1-アセチルピペリジン-4-イル)メトキシ)-N-(4-エチルフェニル)-N-イソブチル-3-(S-メチルスルホンイミドイル)ベンゼンスルホンアミドの合成
N-(4-エチルフェニル)-N-イソブチル-3-(S-メチルスルホンイミドイル)-4-((1-(メチルスルホニルピペリジン-4-イル)メトキシ)ベンゼンスルホンアミドの合成
N-(4-エチルフェニル)-N-イソブチル-3-(S-メチルスルホンイミドイル)-4-[(テトラヒドロピラン-4-イルメチル)アミノ]ベンゼンスルホンアミドの合成
N-(4-エチルフェニル)-N-イソブチル-3-(S-メチルスルホンイミドイル)-4-((オキセタン-3-イルメチル)アミノベンゼンスルホンアミドの合成
N-(4-エチルフェニル)-4-(((3-ヒドロキシシクロブチル)メチル)アミノ)-N-イソブチル-3-(S-メチルスルホンイミドイル)ベンゼンスルホンアミドの合成
N-(4-エチルフェニル)-N-イソブチル-3-(S-メチルスルホンイミドイル)-4-(2,6-ジアザスピロ[3.3]ヘプタン-2-イル)ベンゼンスルホンアミドの合成
4-(6-アセチル-2,6-ジアザスピロ[3.3]ヘプタン-2-イル)-N-(4-エチルフェニル)-N-イソブチル-3-(S-メチルスルホンイミドイル)ベンゼンスルホンアミドの合成
4-(4-アセチルピペラジン-1-イル)-N-(4-エチルフェニル)-N-イソブチル-3-(S-メチルスルホンイミドイル)ベンゼンスルホンアミドの合成
N-(4-エチルフェニル)-N-イソブチル-3-(S-メチルスルホンイミドイル)-4-((ピリジン-4-イルメチル)アミノ)ベンゼンスルホンアミドの合成
N-(4-エチルフェニル)-N-イソブチル-3-(S-メチルスルホンイミドイル)-4-((ピリミジン-4-イルメチル)アミノ)ベンゼンスルホンアミドの合成
N-(4-エチルフェニル)-N-イソブチル-3-(S-メチルスルホンイミドイル)-4-(1,4-オキサゼパン-4-イル)ベンゼンスルホンアミドの合成
4-ブロモ-N-(4-エチルフェニル)-N-イソブチル-3-(S-メチルスルホンイミドイル)ベンゼンスルホンアミド(50.0mg;0.11mmol)を、ジメチルスルホキシド(2ml)に溶解した1,4-オキサゼパン(16.0mg;0.16mmol)及びN,N-ジイソプロピルエチルアミン(0.11ml;0.63mmol)に添加する。
N-(4-エチルフェニル)-N-イソブチル-3-(S-メチルスルホンイミドイル)-4-(ピペラジン-1-イル)ベンゼンスルホンアミドの合成
N-(4-エチルフェニル)-4-(((3-ヒドロキシシクロブチル)メチル)アミノ)-N-イソブチル-3-(S-メチルスルホンイミドイル)ベンゼンスルホンアミドの合成
N-(4-エチルフェニル)-N-イソブチル-3-(S-メチルスルホンイミドイル)-4-(2-モルホリノエチル)ベンゼンスルホンアミドの合成
MS:[M+H]=422
N-(4-エチルフェニル)-N-イソブチル-3-(S-メチルスルホンイミドイル)-4-ビニルベンゼンスルホンアミド(70.0mg;0.17mmol;1.00当量)及びモルホリン(1.0ml;11.59mmol)の混合物を、室温にて30分間撹拌する。
N-(2,4-ジメチルフェニル)-N-イソブチル-3-(S-メチルスルホンイミドイル)-4-((テトラヒドロ-2H-ピラン-4-イル)メトキシ)ベンゼンスルホンアミドの合成
MS:[M+H]=177
2.中間体113.2の合成
MS:[M+H]=177
3.中間体113.3の合成
4.中間体113.4の合成
MS:[M-H]=441
5.中間体113.5の合成
MS:[M-H]=552
6.中間体113.6の合成
MS:[M+H]=475
7.N-(2,4-ジメチルフェニル)-N-イソブチル-3-(S-メチルスルホンイミドイル)-4-((テトラヒドロ-2H-ピラン-4-イル)メトキシ)ベンゼンスルホンアミドの合成
N-イソプロピル-N-(4-メトキシ-2-メチルフェニル)-3-(S-メチルスルホンイミドイル)-4-((テトラヒドロ-2H-ピラン-4-イル)メトキシ)ベンゼンスルホンアミドの合成
MS:[M+H]=180
2.中間体114.2の合成
MS:[M+H]=444
3.中間体114.3の合成
MS:[M-H]=557
4.中間体114.4の合成
MS:[M+H]=477
60%水素化ナトリウム(12.6mg;0.32mmol)を、0℃にて、N,N-ジメチルホルムアミド(2ml)に溶解した(テトラヒドロピラン-4-イル)メタノール(26.8mg;0.23mmol)にゆっくり添加し、続いて4-ブロモ-N-イソプロピル-N-(4-メトキシ-2-メチルフェニル)-3-(S-メチルスルホンイミドイル)ベンゼンスルホンアミド(100mg;0.21mmol)にゆっくり添加する。反応媒体を室温にて1時間撹拌し、60℃の温度にて90分間撹拌し、次いで加水分解し、酢酸エチルで抽出する。有機相を合わせ、次いで飽和塩化ナトリウム溶液で洗浄し、乾燥させる(Na2SO4)。溶媒を留去する。
N-(4-エチルフェニル)-N-イソブチル-4-(テトラヒドロピラン-4-イルメチルスルファニル)ベンゼンスルホンアミドの合成
MS:[M+H]=336
2.中間体116.2の合成
MS:[M+H]=698
炭酸カリウム(0.41g;2.96mmol)を、N,N-ジメチルホルムアミド(15ml)中のビス[4-[(4-エチルフェニル)イソブチルスルファモイル]チオベンゼン]ジスルフィド(1.03g;1.48mmol)の溶液に添加する。反応媒体を5分間撹拌し、続いて4-(ブロモメチル)テトラヒドロピラン(0.53g;2.96mmol)を、次いでホルムアルデヒドスルホキシル酸ナトリウム(0.60g;4.44mmol)及び水(20μl;1.10mmol)を添加する。反応媒体を室温にて1時間撹拌し、加水分解し、酢酸エチルで抽出する。有機相を合わせ、ブラインで洗浄し、乾燥させ(MgSO4)、濾過し、濃縮する。粗生成物をシリカゲル上で、ヘプタン/酢酸エチル、5から30%の酢酸エチルで溶出するクロマトグラフにかける。N-(4-エチルフェニル)-N-イソブチル-4-(テトラヒドロピラン-4-イルメチルスルファニル)ベンゼンスルホンアミド(1.10g;83%)を、固体の形態で得る。
N-(4-エチルフェニル)-N-イソブチル-4-(テトラヒドロピラン-4-イルメチルスルフィニル)ベンゼンスルホンアミドの合成
[超臨界条件:100bar、70℃;Chiralpak IC 250×4.6mm 5μカラム、溶離液:CO2/エタノール:30gのエタノール]
N-(4-エチルフェニル)-N-イソブチル-4-(テトラヒドロピラン-4-イルメタンスルフィニル)ベンゼンスルホキシミン(化合物13) - 化合物29の鏡像異性体A
白色結晶性固体の形態で(150mg;22%)
N-(4-エチルフェニル)-N-イソブチル-4-(テトラヒドロピラン-4-イルメタンスルフィニル)ベンゼンスルホンアミド(化合物14) - 化合物29の鏡像異性体B
白色固体の形態で(120mg;18%)
N-(4-エチルフェニル)-N-イソブチル-4-(テトラヒドロピラン-4-イルメタンスルホキシミニル)ベンゼンスルホンアミドの合成
メチル5-[(4-エチルフェニル)イソブチルスルファモイル]-2-(テトラヒドロピラン-4-イルメチルスルファニル)ベンゾエートの合成
MS:[M+H]=394
2.中間体121.2の合成
MS:[M+H]=263
3.メチル5-[(4-エチルフェニル)イソブチルスルファモイル]-2-(テトラヒドロピラン-4-イルメチルスルファニル)ベンゾエートの合成
メチル5-[(4-エチルフェニル)イソブチルスルファモイル]-2-(テトラヒドロピラン-4-イルメタンスルフィニル)ベンゾエートの合成
5-[(4-エチルフェニル)イソブチルスルファモイル]-2-(テトラヒドロピラン-4-イルメチルスルファニル)安息香酸の合成
N-(4-エチルフェニル)-3-ヒドロキシメチル-N-イソブチル-4-(テトラヒドロピラン-4-イルメチルスルファニル)ベンゼンスルホンアミドの合成
N-(4-エチルフェニル)-3-ヒドロキシメチル-N-イソブチル-4-(テトラヒドロピラン-4-イルメタンスルフィニル)ベンゼンスルホンアミドの合成
[超臨界条件:100bar、70℃;Chiralpak IC 250×4.6mm 5μカラム、溶離液:CO2/メタノール:45%のメタノール]
N-(4-エチルフェニル)-3-ヒドロキシメチル-N-イソブチル-4-(テトラヒドロピラン-4-イルメタンスルフィニル)ベンゼンスルホンアミド(化合物11) - 化合物15の鏡像異性体A
白色固体の形態で(146mg;39%)
N-(4-エチルフェニル)-3-ヒドロキシメチル-N-イソブチル-4-(テトラヒドロピラン-4-イルメタンスルフィニル)ベンゼンスルホンアミド(化合物12) - 白色固体の形態の、化合物15の鏡像異性体B(134mg;36%)
3-オキソ-3,4-ジヒドロ-2H-ベンゾ[1,4]チアジン-6-スルホン酸(4-エチルフェニル)イソブチルアミドの合成
MS:[M+H]=262
2.本発明による化合物10の合成
3,4-ジヒドロ-2H-ベンゾ[1,4]チアジン-6-スルホン酸(4-エチルフェニル)イソブチルアミドの合成
4-(テトラヒドロピラン-4-イルメチル)-3,4-ジヒドロ-2H-ベンゾ[1,4]チアジン-6-スルホン酸(4-エチルフェニル)イソブチルアミドの合成
1-オキソ-4-(テトラヒドロピラン-4-イルメチル)-1,2,3,4-テトラヒドロ-1λ4-ベンゾ[1,4]チアジン-7-スルホン酸(4-エチルフェニル)イソブチルアミドの合成
1-イミノ-1-オキソ-4-(テトラヒドロピラン-4-イルメチル)-1,2,3,4-テトラヒドロ-1λ6-ベンゾ[1,4]チアジン-6-スルホン酸(4-エチルフェニル)イソブチルアミドの合成
3-オキソ-4-(テトラヒドロピラン-4-イルメチル)-3,4-ジヒドロ-2H-ベンゾ[1,4]チアジン-7-スルホン酸(4-エチルフェニル)イソブチルアミドの合成
1,3-ジオキソ-4-(テトラヒドロピラン-4-イルメチル)-1,2,3,4-テトラヒドロ-1λ4-ベンゾ[1,4]チアジン-6-スルホン酸(4-エチルフェニル)イソブチルアミドの合成
1-オキソ-4-(テトラヒドロピラン-4-イルメチル)-1,2,3,4-テトラヒドロ-1λ4-ベンゾ[1,4]チアジン-7-スルホン酸(4-エチルフェニル)イソブチルアミドの合成
MS:[M+H]=381
2.中間体135.2の合成
MS:[M+H]=481。
3.中間体135.3の合成
MS:[M+H]=405
4.中間体135.4の合成
MS:[M+H]=503
5.中間体135.5の合成
MS:[M+H]=519
6.中間体135.6の合成
MS:[M+H]=489
7.本発明による化合物71の合成
1-イミノ-1-オキソ-4-(テトラヒドロピラン-4-イルメチル)-1,2,3,4-テトラヒドロ-1λ6-ベンゾ[1,4]チアジン-7-スルホン酸(4-エチルフェニル)イソブチルアミドの合成
3-オキソ-4-(テトラヒドロピラン-4-イルメチル)-3,4-ジヒドロ-2H-ベンゾ[1,4]チアジン-7-スルホン酸(4-エチルフェニル)イソブチルアミドの合成
MS:[M+H]=391
2.本発明による化合物72の合成
2,2-ジメチル-3-(テトラヒドロピラン-4-イルメチル)-2,3-ジヒドロベンゾチアゾール-6-スルホン酸(4-エチルフェニル)イソブチルアミドの合成
MS:[M+H]=923
2.本発明による化合物73の合成
2,2-ジメチル-1-オキソ-3-(テトラヒドロピラン-4-イルメチル)-2,3-ジヒドロ-1H-1λ4-ベンゾチアゾール-6-スルホン酸(4-エチルフェニル)イソブチルアミドの合成
化合物1-オキソ-3-(テトラヒドロピラン-4-イルメチル)-2,3-ジヒドロ-1H-1λ4-ベンゾチアゾール-6-スルホン酸(4-エチルフェニル)イソブチルアミドの合成
1-イミノ-1-オキソ-3-(テトラヒドロピラン-4-イルメチル)-2,3-ジヒドロ-1H-1λ6-ベンゾチアゾール-6-スルホン酸(4-エチルフェニル)イソブチルアミドの合成
Claims (15)
- 式(I)の化合物、また医薬として許容できるその付加塩、その水和物及び/又はその溶媒和物:
[式(I)中:
・qは、0又は1から3の範囲の自然数を表し、
・Lは、単結合又はメチレン基CH2を表し、
・R1は、直鎖状又は分岐状C3〜C5アルキル基、C3〜C5シクロアルキル基、直鎖状又は分岐状C2〜C5アルケニル基、(C1)アルキル(C3〜C5)シクロアルキル基、C4〜C5ヘテロシクロアルキル基、(C1)アルキル(C4〜C5)ヘテロシクロアルキル基を表し、
・R2は、水素原子又はハロゲン原子、直鎖状又は分岐状C1〜C5アルキル基、直鎖状又は分岐状C2〜C4アルケニル基、C1〜C4アルコキシ基、シアノ基-CNを表し;アルキル、アルケニル及びアルコキシ基は、場合により1個又は複数のハロゲン原子で置換されており、
・R3は、水素原子、C1〜C3アルキル基又はアミノ-NH2基を表し、
・R4は、水素原子又は(CHR5)n-(Z)o-(CHR'5)p-R6基を表し、
・n、o及びpは、同一であっても異なっていてもよく、0又は1から3の範囲の自然数を表し、
・Zは、-CH2-、-NH-及び-O-から選択される二価基を表し、
・R5及びR'5は、同一であっても異なっていてもよく、水素原子、メチル基-CH3、ヒドロキシル基-OH、C1ヒドロキシアルキル基、カルボン酸基-COOHを表し、
・R6は:
- 水素原子又はハロゲン原子、
- 任意選択で、1個又は複数のハロゲン原子、1個又は複数の直鎖状又は分岐状C1〜C3アルキル基、1個又は複数の-OH基、1個又は複数のカルボニル官能基=O、1個又は複数の直鎖状又は分岐状C1〜C4ヒドロキシアルキル基、ピロリジン環、1個又は複数のアミノ基、1個又は複数の-C(=O)R7基、1個又は複数のS(=O)2R7基で置換されているヘテロシクロアルキル基であって、R7が、直鎖状若しくは分岐状C1〜C3アルキル基、ヒドロキシル基-OH、直鎖状若しくは分岐状C1〜C4アルコキシ基、又はアミノ基N(R7a)(R7b)を表し;R7a及びR7bが、同一であってもよく異なっていてもよく、水素原子、直鎖状若しくは分岐状C1〜C3アルキル基、又はシクロプロピル基を表す、ヘテロシクロアルキル基
- 任意選択で1個又は複数の-OH基で置換されているC3〜C6シクロアルキル基;
- 1個若しくは複数のハロゲン原子、任意選択で、1個若しくは複数のハロゲン原子で置換されている1個若しくは複数の直鎖状若しくは分岐状C1〜C3アルキル基、1個若しくは複数のC1〜C3アルコキシ基、1個若しくは複数のアミノ基-NR11R12、1個若しくは複数の-COR11基、カルボニル官能基(=O)、1個若しくは複数の-OR11基、1個若しくは複数のC1〜C4ヒドロキシアルキル基、1個若しくは複数の-COOR11基、1個若しくは複数のアミド基-CONR11R12、1個若しくは複数の-SOR11基、1個若しくは複数の-SO2R11基、1個若しくは複数の-NHCOR11基、1個若しくは複数の-NHCOOR11基、1個若しくは複数の-SO2NR11R12基又は1個若しくは複数の-CN基で任意選択で置換されている芳香族若しくはヘテロ芳香族基であって、R11及びR12が、同一であってもよく異なっていてもよく、水素原子、又は任意選択で、1個若しくは複数のハロゲン原子で置換されている直鎖状若しくは分岐状C1〜C3アルキル基を表す、芳香族若しくはヘテロ芳香族基
を表し;
・A1は、-NRa-、-O-、-S-、-SO-、-SO2-、-SO(=NH)-、-CH2-、-C=C-、-CH(Ra)-から選択される二価基を表し;
・A2は、単結合又は-S-、-SO-、-SO2-、-SO(=N-Rb)-、-CH(OH)-、-C(=O)O-から選択される二価基を表すが;
但し:
- A1が:-NRa-、-O-、-CH2-、-C=C-及び-CH(Ra)から選択される二価基の1つを表す場合、A2は二価基-CH(OH)-及び-C(=O)O-を表さず、R3は、水素原子、アミノ基-NH2又はC1〜C3アルキル基を表さず、
- A2が、単結合を表し、R3が、水素原子を表す場合、A1は-SO-及び-SO(=NH)-から選択される二価基の1つを表し、
・Raは、水素原子、直鎖状若しくは分岐状C1〜C3アルキル基、又はアセチル基-C(=O)CH3を表し、
・Rbは、水素原子、直鎖状若しくは分岐状C1〜C3アルキル基、又はシクロプロピル基を表し
・Q1、Q2、Q3、Q4及びQ5は、同一であっても異なっていてもよく、窒素原子又は-CR'2基を表し、
・A2が、-S-、-SO、-SO2-及び-SO(=N-Rb)-から選択される二価基を表す場合、Ra及びR3は、それらが結合する炭素原子と一緒になって、任意選択で、1個又は複数のカルボニル官能基、1個又は複数のC1〜C3アルキル基で置換されていてよいヘテロシクロアルキル基を形成でき、
・A1が-NRa-を表す場合、Ra及びR4は、それらが結合する窒素原子と一緒になって、任意選択で、硫黄原子、窒素原子及び酸素原子から選択される1から3個のヘテロ原子を含むC2〜C10ヘテロシクロアルキル基を形成でき;前記ヘテロシクロアルキル基は、任意選択で、少なくとも1個のR14基で置換されており、
・R14は、直鎖状若しくは分岐状C1〜C3アルキル基、直鎖状若しくは分岐状C1〜C3アルコキシ基、ハロゲン原子、ヒドロキシル基-OH、シアノ基-CN、-CONR15R16基、-SO2R15基、-COR15基又はアミノ基-NR15R16を表し;R15及びR16は、同一であっても異なっていてもよく、水素原子又は直鎖状若しくは分岐状C1〜C3アルキル基を表す]。 - Lが、単結合を表すことを特徴とする、請求項1又は2に記載の化合物。
- R6が、
式中:
- R7が、直鎖状若しくは分岐状C1〜C3アルキル基、ヒドロキシル基-OH、C1〜C3アルコキシ基又はアミノ基N(R7a)(R7b)を表し、
- R7a及びR7bが、同一であっても異なっていてもよく、水素原子、直鎖状若しくは分岐状C1〜C3アルキル基、又はシクロプロピル基を表し、
- R8及びR9が、同一であっても異なっていてもよく、水素原子、直鎖状又は分岐状C1〜C3アルキル基、ヒドロキシル基-OH、カルボニル基、(C1)ヒドロキシアルキル基(CH2OH)、アミノ基-NH2を表し、
- R8及びR9が、それらが結合する炭素原子と一緒になって、5-から7-員環の炭素環式環を形成できることを特徴とする、請求項1から3のいずれか一項に記載の式(I)の化合物。 - R6が:
式中:
- R10が、水素原子若しくはハロゲン原子;任意選択で、1個若しくは複数のハロゲン原子で置換されている直鎖状若しくは分岐状C1〜C3アルキル基;カルボニル官能基(=O)、OR11基、C1〜C4ヒドロキシアルキル基、アミノ基-NR11R12、-COR11基、-COOR11基、アミド基-CONR11R12、-SOR11基、-SO2R11基、-NHCOR11基、-NHCOOR11基、-SO2NR11R12基又はシアノ基-CNを表し
- R11及びR12が、同一であっても異なっていてもよく、水素原子、又は任意選択で、1個若しくは複数のハロゲン原子で置換されている直鎖状若しくは分岐状C1〜C3アルキル基を表し、
- mが、請求項1に規定の式(I)で指し示されている意味と同一の意味を有する0又は1から3の範囲の自然数を表すことを特徴とする、請求項1から3のいずれか一項に記載の式(I)の化合物。 - 下の式(III)の化合物の化合物から選択され:
- R1、R2、R'2、R3、Rb、Q1、Q2、Q3、Q4、Q5、A2及び添字qが、請求項1から3のいずれか一項に規定の式(I)における意味と同じ意味を有し、
- Ra及びR4が、それらが結合する窒素原子と一緒になって、任意選択で、硫黄原子、窒素原子及び酸素原子から選択される1から3個のヘテロ原子を含むC2〜C10ヘテロシクロアルキル基を形成し;前記ヘテロシクロアルキル基が、任意選択で、少なくとも1個のR14基で置換されており、
- R14が、直鎖状若しくは分岐状C1〜C3アルキル基、直鎖状若しくは分岐状C1〜C3アルコキシ基、ハロゲン原子、ヒドロキシル基-OH、シアノ基-CN、-CONR15R16基、-SO2R15基、-COR15基又はアミノ基-NR15R16を表し;R15及びR16が、同一であっても異なっていてもよく、水素原子又は直鎖状若しくは分岐状C1〜C3アルキル基を表すことを特徴とする、請求項1から5のいずれか一項に記載の式(I)の化合物。 - 医薬としての、請求項1から9のいずれか一項に記載の化合物。
- RORγt受容体により媒介される炎症性障害及び/又は自己免疫性疾患の処置において使用するための、請求項1から10のいずれか一項に記載の化合物。
- 座瘡の処置におけるその使用のための、請求項10に記載の化合物。
- 乾癬の処置におけるその使用のための、請求項10に記載の化合物。
- 請求項1から10のいずれか一項に記載の1つ又は複数の化合物を含む医薬組成物。
- RORγt受容体により媒介される炎症性障害及び/又は自己免疫性疾患、とりわけ座瘡、アトピー性皮膚炎及び/又は乾癬を処置するために使用することを特徴とする、請求項14に記載の医薬組成物。
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