JP2001515470A - アリールスルホンアミド及びそれらの類似体並びに神経変性疾患の治療におけるそれらの使用 - Google Patents
アリールスルホンアミド及びそれらの類似体並びに神経変性疾患の治療におけるそれらの使用Info
- Publication number
- JP2001515470A JP2001515470A JP53621598A JP53621598A JP2001515470A JP 2001515470 A JP2001515470 A JP 2001515470A JP 53621598 A JP53621598 A JP 53621598A JP 53621598 A JP53621598 A JP 53621598A JP 2001515470 A JP2001515470 A JP 2001515470A
- Authority
- JP
- Japan
- Prior art keywords
- group
- alkyl
- formula
- different
- compound
- 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
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- 208000015122 neurodegenerative disease Diseases 0.000 title claims abstract description 7
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- 238000002360 preparation method Methods 0.000 claims abstract description 122
- 238000000034 method Methods 0.000 claims abstract description 40
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- 150000001875 compounds Chemical class 0.000 claims description 139
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 135
- -1 nitro, amino Chemical group 0.000 claims description 126
- 229910052739 hydrogen Inorganic materials 0.000 claims description 68
- 239000001257 hydrogen Substances 0.000 claims description 62
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 57
- 229910052736 halogen Inorganic materials 0.000 claims description 56
- 150000002367 halogens Chemical class 0.000 claims description 55
- 239000000460 chlorine Substances 0.000 claims description 49
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 48
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 47
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 44
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 41
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 38
- 229910052801 chlorine Inorganic materials 0.000 claims description 35
- 229910052757 nitrogen Inorganic materials 0.000 claims description 32
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 30
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 28
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 26
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 26
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 26
- 125000000217 alkyl group Chemical class 0.000 claims description 24
- 238000006243 chemical reaction Methods 0.000 claims description 23
- 238000006467 substitution reaction Methods 0.000 claims description 23
- 229910052731 fluorine Inorganic materials 0.000 claims description 21
- 230000014509 gene expression Effects 0.000 claims description 21
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 21
- 150000003839 salts Chemical class 0.000 claims description 21
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- 125000001424 substituent group Chemical group 0.000 claims description 19
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- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 18
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- 239000012442 inert solvent Substances 0.000 claims description 18
- 229910052717 sulfur Inorganic materials 0.000 claims description 18
- 125000002252 acyl group Chemical group 0.000 claims description 17
- 125000005842 heteroatom Chemical group 0.000 claims description 17
- 125000001624 naphthyl group Chemical group 0.000 claims description 17
- 229910052760 oxygen Inorganic materials 0.000 claims description 17
- 239000002253 acid Substances 0.000 claims description 16
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 16
- 229920006395 saturated elastomer Polymers 0.000 claims description 16
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 15
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 15
- 239000011737 fluorine Substances 0.000 claims description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 15
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- 125000004076 pyridyl group Chemical group 0.000 claims description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- 150000001412 amines Chemical class 0.000 claims description 12
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 12
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 11
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 11
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 10
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 10
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 9
- 125000004122 cyclic group Chemical group 0.000 claims description 9
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 8
- 241001465754 Metazoa Species 0.000 claims description 8
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 8
- 125000005493 quinolyl group Chemical group 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 6
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 6
- 229920001774 Perfluoroether Polymers 0.000 claims description 6
- 206010008118 cerebral infarction Diseases 0.000 claims description 6
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 6
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 6
- 125000001153 fluoro group Chemical group F* 0.000 claims description 6
- 125000002541 furyl group Chemical group 0.000 claims description 6
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- 201000006474 Brain Ischemia Diseases 0.000 claims description 5
- 206010008120 Cerebral ischaemia Diseases 0.000 claims description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 5
- 230000029936 alkylation Effects 0.000 claims description 5
- 238000005804 alkylation reaction Methods 0.000 claims description 5
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 5
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- 238000007796 conventional method Methods 0.000 claims description 5
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- 239000011593 sulfur Substances 0.000 claims description 5
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 claims description 4
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical group CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 claims description 4
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 4
- 150000001299 aldehydes Chemical class 0.000 claims description 4
- 150000003868 ammonium compounds Chemical class 0.000 claims description 4
- 230000001363 autoimmune Effects 0.000 claims description 4
- 239000003638 chemical reducing agent Substances 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000001288 lysyl group Chemical group 0.000 claims description 4
- 210000000056 organ Anatomy 0.000 claims description 4
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 4
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 claims description 4
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 4
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 3
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- 125000001246 bromo group Chemical group Br* 0.000 claims description 3
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- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 3
- 206010061428 decreased appetite Diseases 0.000 claims description 3
- 125000000623 heterocyclic group Chemical group 0.000 claims description 3
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 3
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- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 3
- 125000001544 thienyl group Chemical group 0.000 claims description 3
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- ZFFBIQMNKOJDJE-UHFFFAOYSA-N 2-bromo-1,2-diphenylethanone Chemical compound C=1C=CC=CC=1C(Br)C(=O)C1=CC=CC=C1 ZFFBIQMNKOJDJE-UHFFFAOYSA-N 0.000 claims description 2
- 208000035143 Bacterial infection Diseases 0.000 claims description 2
- 125000005947 C1-C6 alkylsulfonyloxy group Chemical group 0.000 claims description 2
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- 206010028813 Nausea Diseases 0.000 claims description 2
- QWQONZVLXJGXHV-UHFFFAOYSA-N [chlorosulfonyloxy(dimethyl)silyl]methane Chemical compound C[Si](C)(C)OS(Cl)(=O)=O QWQONZVLXJGXHV-UHFFFAOYSA-N 0.000 claims description 2
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- KWEDUNSJJZVRKR-UHFFFAOYSA-N carbononitridic azide Chemical compound [N-]=[N+]=NC#N KWEDUNSJJZVRKR-UHFFFAOYSA-N 0.000 claims description 2
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- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
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- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 claims description 2
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- YONPGGFAJWQGJC-UHFFFAOYSA-K titanium(iii) chloride Chemical compound Cl[Ti](Cl)Cl YONPGGFAJWQGJC-UHFFFAOYSA-K 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical group OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Classifications
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- C07C317/16—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C317/18—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton with sulfone or sulfoxide groups bound to acyclic carbon atoms of the carbon skeleton
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- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
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- C07C217/80—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings
- C07C217/82—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring
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Abstract
Description
Claims (1)
- 【特許請求の範囲】 1. 一般式(I) R1−A−D−E−G−L−R2 (I) 式中、 R1は(C6−C10)−アリール、キノリル、イソキノリルまたは式 式中、 aは数字1または2を表し、 R3は水素、(C2−C6)−アルケニル、(C1−C6)−アルキル または(C1−C6)−アシルを表す、 の基を表し、 そしてその場合に全ての上記の環系及び基が場合により: ハロゲン、カルボキシル、ヒドロキシル、フェニル、(C1−C6) −アルコキシ、(C1−C6)−アルコキシカルボニル、(C1−C8)−アルキル 、このアルキルがハロゲン、 (C1−C6)−アルキルスルホニルオキシ、アジド、アミノ、モノ(C1−C6) −アルキルアミノ、ジ(C1−C6)−アルキルアミノまたはヒドロキシルで置換 されていてもよい、 式−(CO)b−NR4R5の基、 ここで、 bは数字0または1を表し、 R4及びR5は同一または異なり、そして相互に独立して水素 、フェニル、(C1−C6)−アシル、シクロ(C4−C7)−アシル、ベンゾイル または場合によりアミノ、モノ(C1−C6)−アルキルアミノ、ジ(C1−C6) −アルキルアミノで置換されていてもよい(C1−C6)−アルキルを表すか、 あるいは R4及びR5は窒素原子と一緒になって場合によりS及びOよ りなる群からの1個もしくはそれより多いさらなるヘテロ原子並びに/または1 個もしくはそれより多い式−NR8、 式中、 R8は水素、(C1−C6)−アルキルまたは( C1−C6)−アシルを表す、 の基を含有してもよい5または6員の飽和複 素環を形成する、 並びに 式−NR6−SO2−R7の基、 ここで、 R6は水素、フェニル、(C1−C6)−アルキルまたは(C1 −C6)−アシルを表し、 R7はフェニルまたは(C1−C6)−アルキルを表す、 よりなる群から選択される1個またはそれより多い同一または異なる置換 基で適当な場合にはジェミナルに置換されていてもよく、 A及びEは同一または異なり、そして結合または(C1−C4)−アルキレンを 表し、 Dは酸素原子または式−S(O)c−もしくは−N(R9)−の基を表し、 ここで、 cは数字0、1または2を表し、 R9は水素、(C1−C6)−アルキルまたは(C1−C6)−アシルを表し 、 Gは二様に結合した(C6−C10)−アリールまたはS、N及び/もしくはO よりなる群からの3個までのヘテロ原子を有する二様に結合した5ないし7員の 芳香族複素環を表し、それらの各々が場合により: ヒドロキシル、トリフルオロメチル、カルボキシル、ハロゲン、( C1−C6)−アルキル、ヒドロキシ(C1−C6) −アルキル、(C1−C6)−アルコキシ、(C1−C6)−アルコキシカルボニル 、 並びに式 −CO−O−(CH2)d−NR10R11、−NR12−SO2R13、− (CH2)e−(CO)f−NR14R15及び−OR16の基、 ここで、 dは数字1、2、3または4を表し、 e及びfは同一または異なり、そして数字0または1を表し 、 R10及びR11は上に示したR4及びR5の意味を有し、そして これと同一または異なり、 R12は上に示したR6の意味を有し、そしてこれと同一また は異なり、 R13は上に示したR7の意味を有し、そしてこれと同一また は異なり、 R14及びR15は上に示したR4及びR5の意味を有し、そして これと同一または異なるか、 あるいは相互に独立して式−(CH2)g−NR17R18 、 式中、 gは数字1、2、3または4を表し、 そして R17及びR18は上に示したR4及びR5 の意味を有し、そしてこれと同一または異なる、 の基を表し、 R16は(C6−C10)−アリールを表す、 よりなる群から選択される1個またはそれより多い同一または異なる置換 基で置換されていてもよく、 Lは式 −O−,−NH2−, の基を表し、 その場合にGへのそれらの基の結合は左側の結合で起こり、 そしてここで、R19、R20、R21、R22、R23、R24、R25、R26及びR27 は同一または異なり、そして水素または(C1−C4)−アルキルを表すか、あ るいは R19は式−SO2R2の基を表し、 R2は(C6−C10)−アリールまたはS、N及び/もしくはOよりな る群からの3個までのヘテロ原子を有する5ないし7員の飽和もしくは芳香族複 素環を表し、それらの各々が場合により: ハロゲン、トリフルオロメチル、ニトロ、アミノ及び(C1−C6) −アルキル よりなる群から選択される1個またはそれより多い同一または異なる置換 基で置換されていてもよく、 あるいは 式 の基またはモルホリンを表すか、あるいは C3−C8−シクロアルキルを表すか、あるいは (C1−C12)−アルキル、(C2−C12)−アルケニルまたは(C2−C1 2 )−アルキニルを表し、それらの各々が場合により: ハロゲン、トリフルオロメチル、ヒドロキシル、シアノ、アジド、 (C1−C6)−アルコキシ、(C1−C6)−ペルフルオロアルコキシ、部分的に フッ素化された(C1−C6)−アルコキシ、式 式中、R28及びR29は上に示したR4及びR5の意味 を有し、そしてこれと同一または異なる、 の基、 場合により: ハロゲン、ニトロ、ヒドロキシル、(C1−C6)−アルキル 、(C1−C6)−アルコキシ及び式−NR30R31、 式中、R30及びR31は同一または異なり、そして水素ま たは(C1−C6)−アルキルまたは(C1−C6)−アシルを表す、 の基、 よりなる群から選択される1個またはそれより多い同一または異な る置換基で置換されていてもよいフェニル、 並びに場合により: ハロゲン、ニトロ、ヒドロキシル、(C1−C6)−アルキル 、(C1−C6)−アルコキシ及び式−NR30R31、 式中、R30及びR31は上に定義したとおりである、 の基、 よりなる群から選択される1個またはそれより多い同一または異な る置換基で置換されていてもよい、S、N及び/またはOよりなる群からの3個 までのヘテロ原子を有する5ないし6員の芳香族複素環、 よりなる群から選択される1個またはそれより多い同一または異 なる置換基で置換されていてもよく、 あるいは L及びR2は一緒になって式 の基を表す、 の化合物及びそれらの塩類。 2. R1がフェニル、ナフチル、キノリル、イソキノリルまたは式 式中、 aが数字1または2を表し、 R3が水素、(C2−C4)−アルケニル、(C1−C4)−アルキル または(C1−C4)−アシルを表す、 の基を表し、 そしてその場合に全ての上記の環系及び基が場合により: ハロゲン、カルボキシル、ヒドロキシル、フェニル、(C1−C4) −アルコキシ、(C1−C5)−アルコキシカルボニル、(C1−C6)−アルキル 、このアルキルがハロゲン、(C1−C4)−アルキルスルホニルオキシ、アジド 、アミノ、モノ(C1−C4)−アルキルアミノ、ジ(C1−C4)−アルキルアミ ノまたはヒドロキシルで置換されていてもよい、 式−(CO)b−NR4R5の基、 ここで、 bが数字0または1を表し、 R4及びR5が同一または異なり、そして相互に独立して水素 、フェニル、(C1−C4)−アシル、シクロ(C4−C7)−アシル、ベンゾイル または場合によりアミノ、モノ(C1−C4)−アルキルアミノ、ジ(C1−C4) −アルキルで置換されていてもよい(C1−C4)−アルキルを表すか、 あるいは R4及びR5が窒素原子と一緒になってモルホリン、ピペリジ ンまたはN−メチルピペラジン環を形成する、 並びに 式−NR6−SO2−R7の基、 ここで、 R6が水素、フェニル、(C1−C4)−アルキルまたは(C1−C4)−アシルを 表し、 そして R7がフェニルまたは(C1−C5)−アルキルを表す、 よりなる群から選択される1個またはそれより多い同一または異なる置換 基で適当な場合にはジェミナルに置換されていてもよく、 A及びEが同一または異なり、そして結合または(C1−C4)−アルキレンを 表し、 Dが酸素原子または式−S(O)c−もしくは−NR9−の基を表し、 ここで、 cが数字0、1または2を表し、 R9が水素または(C1−C4)−アルキルまたは(C1−C4)−アシルを 表し、 Gが二様に結合したフェニル、ナフチル、ピリミジル、ピリダジニルまたはピ リジルを表し、それらの各々が場合により: ヒドロキシル、トリフルオロメチル、カルボキシル、ハロゲン、( C1−C4)−アルキル、ヒドロキシ(C1−C4)アルキル、(C1−C4)−アル コキシ、(C1−C4)−アルコキシカルボニル並びに式 −CO−O−(CH2)d−NR10R11、−NR12−SO2R13、− (CH2)e−(CO)f−NR14R15及び−OR16の基、 ここで、 dが数字1、2、3または4を表し、 e及びfが同一または異なり、そして数字0または1を表し 、 R10及びR11が上に示したR4及びR5の意味を有し、そして これと同一または異なり、 R12が上に示したR6の意味を有し、そしてこれと同一また は異なり、 R13が上に示したR7の意味を有し、そしてこれと同一また は異なり、 R14及びR15が上に示したR4及びR5の意味を有し、そして これと同一または異なるか、あるいは相互に独立して式 −(CH2)g−NR17R18、 式中、 gが数字1、2または3を表し、 そして R17及びR18が上に示したR10及びR11の意味 を有し、そしてこれと同一または異なる、 の基を表し、 R16がフェニルまたはナフチルを表す、 よりなる群から選択される1個またはそれより多い同一または異なる置換 基で置換されていてもよく、 Lが式 −O−、−NH−、 の基を表し、 その場合にGへのそれらの基の結合が左側の結合で起こり、 そして ここで、 R19、R20、R21、R22、R23、R24、R25、R26及びR27が同一または 異なり、そして水素または(C1−C3)−アルキルを表すか、 あるいは R19が式−SO2R2の基を表し、 R2がフェニル、ナフチル、ピリジル、フリル、チエニルまたはピリミジルを 表し、それらの各々が場合により: ハロゲン、アミノ、トリフルオロメチル、ニトロ及び(C1−C4) −アルキル、 よりなる群から選択される1個またはそれより多い同一または異なる置換 基で置換されていてもよく、 あるいは 式 の基またはモルホリンを表すか、 あるいは シクロプロピル、シクロヘキシルまたはシクロペンチルを表すか、 あるいは (C1−C10)−アルキル、(C2−C10)−アルケニルまたは(C2−C1 0 )−アルキニルを表し、それらの各々が場合により: ハロゲン、トリフルオロメチル、ヒドロキシル、アジド、(C1− C4)−アルコキシ、(C1−C5)−ペルフルオロアルコキシ、部分的にフッ素 化された(C1−C4)−アルコキシ、式 式中、R28及びR29が上に示したR4及びR5の意味を有し、 そしてこれと同一または異なる、 の基、 場合により: ハロゲン、ニトロ、ヒドロキシル、(C1−C4)−アルキル 、(C1−C4)−アルコキシ及び式−NR30R31 式中、R30及びR31が同一または異なり、そして水素 または(C1−C4)−アルキルまたは(C1−C4)−アシルを表す、 の基、 よりなる群から選択される1個またはそれより多い同一または異な る置換基で置換されていてもよいフェニル、場合により: ハロゲン、ニトロ、ヒドロキシル、(C1−C4)−アルキル 、(C1−C4)−アルコキシ及び式−NR30R31 式中、R30及びR31が上に定義したとおりである、 の基、 よりなる群から選択される1個またはそれより多い同一または異な る置換基で置換されていてもよい、ピリジル及びピリミジル、 よりなる群から選択される1個またはそれより多い同一または異なる置換 基で置換されていてもよく、 あるいは L及びR2が一緒になって式 の基を表す、 請求の範囲1の式(I)の化合物及びそれらの塩類。 3. R1がフェニル、ナフチル、キノリル、イソキノリルまたは式 式中、 aが数字1または2を表し、 R3が水素、(C2−C3)−アルケニル、(C1−C3)−アルキル または(C1−C3)−アシルを表す、 の基を表し、 そしてその場合に全ての上記の環系が場合により: 塩素、フッ素、カルボキシル、ヒドロキシル、フェニル、(C1− C3)−アルコキシ、(C1−C4)−アルコキシカ ルボニル、(C1−C4)−アルキル、このアルキルが塩素またはヒドロキシルで 置換されていてもよい、 式−(CO)b−NR4R5の基、 ここで、 bが数字0または1を表し、 R4及びR5が同一または異なり、そして相互に独立して水素 、(C1−C3)−アシル、シクロ(C4−C6)−アシル、ベンゾイルまたは場合 によりアミノ、モノ(C1−C3)−アルキルアミノ、ジ(C1−C3)−アルキル アミノで置換されていてもよい(C1−C3)−アルキルを表すか、 あるいは R4及びR5が窒素原子と一緒になってモルホリン、ピペリジ ンまたはN−メチルピペラジン環を形成する、 並びに 式−NR6−SO2−R7の基、 ここで、 R6が水素、(C1−C3)−アルキルまたは(C1−C3)− アシルを表し、 そして R7がフェニルまたは(C1−C4)−アルキルを表す、 よりなる群から選択される1個またはそれより多い同一または異なる置換 基で適当な場合にはジェミナルに置換されていてもよく、 A及びEが同一または異なり、そして結合または(C1−C3)−アルキルを表 し、 Dが酸素原子または式−S(O)c−もしくは−NR9−の基を表し、 ここで、 cが数字0、1または2を表し、 R9が水素または(C1−C3)−アルキルまたは(C1−C3)−アシルを 表し、 Gが二様に結合したフェニル、ナフチル、ピリミジル、ピリダジニルまたはピ リジルを表し、それらの各々が場合により: ヒドロキシル、トリフルオロメチル、カルボキシル、フッ素、塩素 、臭素、(C1−C3)−アルキル、ヒドロキシ(C1−C3)アルキル、(C1− C3)−アルコキシ、(C1−C3)−アルコキシカルボニル並びに式 −CO−O−(CH2)d−NR10R11、−NR12-SO2R13、−( CH2)e−(CO)f−NR14R15、−CH2OH及び−OR16の基、 ここで、 dが数字1、2または3を表し、 e及びfが同一または異なり、そして数字0または1を表し 、 R10及びR11が水素またはメチルを表し、 R12が水素を表し、 R13が(C1−C4)−アルキルを表し、 R14及びR15が上に示したR4及びR5の意味を有し、そして これと同一または異なるか、あるいは 式−(CH2)g-NR17R18、 式中、 gが数字1、2または3を表し、 そして R17及びR18が水素またはメチルを表す、 の基を表すか、 あるいは R14及びR15が窒素原子と一緒になって式 の基を形成し、 R16がフェニルまたはナフチルを表す、 よりなる群から選択される1個またはそれより多い同一または異なる置換 基で置換されていてもよく、 Lが式 −O−,−NH−, の基を表し、 その場合にGへのそれらの基の結合が左側の結合で起こり、 そして ここで、 R19、R20、R21、R22、R23、R24、R25、R26及びR27が同一または 異なり、そして水素、メチルまたはエチルを表すか、 あるいは R19が式−SO2R2の基を表し、 R2がフェニル、フリルまたはピリジルを表し、それらの各々が場合により: フッ素、塩素、臭素またはトリフルオロメチル、 よりなる群から選択される1個またはそれより多い同一または異なる置換 基で置換されていてもよく、 あるいは 式 の基またはモルホリンを表すか、 あるいは シクロペンチルまたはシクロヘキシルを表すか、あるいは (C1−C8)−アルキル、(C2−C8)−アルケニルまたは(C2−C8) −アルキニルを表し、それらの各々が場合により: フッ素、塩素、臭素、トリフルオロメチル、ヒドロキシル、アジド 、(C1−C3)−アルコキシ、(C1−C4)−ペルフルオロアルコキシ、トリフ ルオロメチルで置換された(C1−C4)−アルコキシ、式 式中、R28及びR29が水素またはメチルを表す、 の基、 場合により: フッ素、塩素、臭素、ニトロ、ヒドロキシル、(C1−C3) −アルキル、(C1−C3)−アルコキシ及び式−NR30R31、 式中、R30及びR31が同一または異なり、そ して水素、メチルまたはメチルカルボニルを表す、 の基、 よりなる群から選択される1個またはそれより多い同一または異な る置換基で置換されていてもよい、フェニル、ピリジル及びピリミジル、 よりなる群から選択される1個またはそれより多い同一または異なる置換 基で置換されていてもよく、 あるいは L及びR2が一緒になって式 の基を表す、 請求の範囲1または2の式(I)の化合物及びそれらの塩類。 4. R1が(C6−C10)−アリール、キノリルまたは式 式中、 aが数字1または2を表す、 の基を表し、 そしてその場合に全ての上記の環系及び基が場合により: ハロゲン、カルボキシル、ヒドロキシル、(C1−C6)− アルコキシ、(C1−C6)−アルコキシカルボニル、(C1−C8)−アルキル、 このアルキルがハロゲンまたはヒドロキシルで置換されていてもよい、 式−(CO)b−NR4R5の基、 ここで、 bが数字0または1を表し、 R4及びR5が同一または異なり、そして水素、フェニルまた は(C1−C6)−アルキルを表す、 並びに 式−NR6−SO2−R7の基、 ここで、 R6が水素、フェニルまたは(C1−C6)−アルキルを表し 、 R7がフェニルまたは(C1−C6)−アルキルを表す、 よりなる群から選択される1ないし3個の同一または異なる置換基で適当 な場合にはジェミナルに置換されていてもよく、 A及びEが同一または異なり、そして結合または(C1−C4)−アルキレンを 表し、 Dが酸素原子または式−S(O)c−もしくは−NH−の基を表し、 ここで、 cが数字0、1または2を表し、 Gが二様に結合した(C6−C10)−アリールまたはS、N及び/もしくはO よりなる群からの3個までのヘテロ原子を有する二様に 結合した5ないし7員の芳香族複素環を表し、それらの各々が場合により: ヒドロキシル、カルボキシル、ハロゲン、(C1−C6)−アルキル 、ヒドロキシ(C1−C6)アルキル、(C1−C6)−アルコキシ、(C1−C6) −アルコキシカルボニル並びに式 −CO−O−(CH2)d−NR10R11、−NR12−SO2R13及び −CO−NR14R15の基、 ここで、 dが数字1、2、3または4を表し、 R10及びR11が上に示したR4及びR5の意味を有し、そして これと同一または異なり、 R12が上に示したR6の意味を有し、そしてこれと同一また は異なり、 R13が上に示したR7の意味を有し、そしてこれと同一また は異なり、 R14及びR15が上に示したR4及びR5の意味を有し、そして これと同一または異なるか、あるいは窒素原子と一緒になって場合によりS及び Oよりなる群からのさらなるヘテロ原子または式−NH−の基をさらに含有して もよい5ないし6員の飽和複素環を形成する、 よりなる群から選択される3個までの同一または異なる置換基で置換され ていてもよく、 Lが式 の基を表し、 その場合にGへのそれらの基の結合が左側の結合で起こり、 そしてここで、R19、R20、R21、R22、R23及びR24は同一または異な り、そして水素または(C1−C4)−アルキルを表し、 R2が場合によりハロゲン、トリフルオロメチル、ニトロ、アミノまたは(C1 −C6)−アルキルで置換されていてもよいフェニルを表し、 R2が式 の基またはモルホリンを表すか、 あるいは 12個までのフッ素原子を有するペルフルオロアルキルを表すか、 あるいは (C1−C12)−アルキルまたは(C2−C12)−アルキニルを表し、それ らの各々が場合によりハロゲン、トリフルオロメチル、ヒドロキシル、アジドま たは式 式中、R28及びR29が上に示したR4及びR5の意味を有し、そして これと同一または異なる、 の基で置換されていてもよく、 そして/あるいは場合によりフェニルまたはS、N及び/もしくはOより なる群からの3個までのヘテロ原子を有する5ないし6員の芳香族複素環で置換 されていてもよく、これらがハロゲン、ニトロ、ヒドロキシル、(C1−C6)− アルキル、(C1−C6)−アルコキシまたは式−NR30R31 式中、R30及びR31が同一または異なり、そして水素、(C1−C6 )−アルキルまたは(C1−C6)−アシルを表す、 の基で同一にまたは異なって2回まで置換されていてもよく、 L及びR2が一緒になって式 の基を表す、 請求の範囲1の式(I)の化合物及びそれらの塩類。 5. R1がヒドロキシル、(C1−C6)−アシルアミノ、アミノまたは(C1 −C6)−アルコキシで置換された(C1−C6)−アルキルで場合により置換さ れていてもよいナフト−1−イル、ヒドロキシ(C1−C6)−アルキルで置換さ れたインダン−4−イル、 式 式中、 R3が(C1−C6)−アルキルである、 の基を表し、 E及びAが結合を表し、 Dが酸素原子を表し、 Gが1,3−フェニレン、1,4−フェニレンまたは2,5−ピリジレンを表 し、それらの各々が場合によりハロゲンで置換されていてもよく、 Lが式−NH−SO2−または−O−SO2−の基を表し、そして R2が(C1−C6)−アルキルを表し、それが場合により塩素、トリフルオロ メチル、式−O−CH2−CF3の基、または臭素もしくは塩素で置換されていて もよいフェニルもしくはピリジルで置換されていてもよい、 請求の範囲1ないし3のいずれかの式(I)の化合物及びそれらの塩類。 6. 以下の式: の請求の範囲1ないし3のいずれかの化合物。 7. [A] 不活性溶媒中で、必要な場合、塩基の存在下で、 一般式(II) R1−A−D−E−G−M−H (II) 式中、 R1、A、D、E及びGは請求の範囲1に示した意味を有し、そして Mは酸素または−N(R32)−を表し、そして R32は水素または(C1−C4)−アルキルである、 の化合物を一般式(III) R33−Q−R2 (III) 式中、 R2は請求の範囲1に示した意味を有し、 R33はハロゲン、好ましくは塩素またはヨウ素を表し、 Qは式-SO2-、−SO-、−CO−、−P(O)(OR27)−の基または 単結合を表し、 ここで R27は上に示した意味を有する、 の化合物と反応させて一般式(Ia) R1−A−D−E−G−M−Q−R2 (Ia) 式中、 R1、A、D、E、G、M、Q及びR2は上に示した意味を有する、 の化合物を生ぜしめるか あるいは [B] 一般式(II)の化合物をまずクロロスルホン酸トリアルキルシリル、好 ましくはクロロスルホン酸トリメチルシリルと反応させ、酸で処理し、次に塩素 化剤、好ましくは五塩化リンと反応させて、一般式(IV) R1−A−D−E−G−M−SO2−Cl (IV) 式中、 R1、A、D、E、G及びMは上に示した意味を有する、 の化合物を生ぜしめ、次に不活性溶媒中で、必要な場合、Bzl−NEt3 +Cl- 及び塩基の存在下で、 一般式(V) H−T−R2 (V) 式中、 R2は請求の範囲1に示した意味を有し、そして Tは酸素または窒素を表す、 の化合物と反応させて、一般式(Ib) R1−A−D−E−G−M−SO2−T−R2 (Ib) 式中、 R1、A、D、E、G、M、T及びR2は上に示した意味を有する、 の化合物を生ぜしめるか あるいは [C] 一般式(VI) R1−A−D’−H (VI) 式中、 R1及びAは上に示した意味を有し、そして D’は酸素、硫黄または−N(R9)−を表し、そして R9は請求の範囲1に示した意味を有する、 の化合物を一般式(VII) R34−E−G−SO2−NH−R2 (VII) 式中、 E、G及びR2は上に示した意味を有し、そして R34は脱離基、好ましくはハロゲン、特に好ましくはフッ素、塩素または 臭素を表す、 の化合物と反応させて、一般式(Ic) R1−A−D’−E−G−SO2−NH−R2 (Ic) 式中、 R1、A、D’、E、G及びR2は上に示した意味を有する、 の化合物を生ぜしめるか あるいは [D] 一般式(Id) R37−A−D−E−G−L−R2 (Id) 式中、 A、D、E、G、L及びR2は上に示した意味を有し、そして R37は式 式中、 R41は(C1−C6)−アルキルを表す、 の基を表す、 の化合物をクロロギ酸エステル、好ましくはクロロギ酸1−(1−クロロ)エチ ルまたはクロロギ酸メチルと、そして次にアルコール、好ましくはメタノールと 必要な場合、塩基の存在下で反応させて、一般式(Ie) R38−A−D−E−G−L−R2 (Ie) 式中、 A、D、E、G、L及びR2は上に示した意味を有し、そして R38は式 の基を表す、 の化合物を生ぜしめるか、 あるいは [E] 還元剤、好ましくはシアノホウ水素化ナトリウムの存在下で、必要な場 合、酸の存在下で、一般式(Ie)の化合物を(C1−C6)−ケトンまたは(C1 −C6)−アルデヒドと反応させて、一般式(If) R39−A−D−E−G−L−R2 (If) 式中、 A、D、E、G、L及びR2は上に示した意味を有し、そして R39は(C3−C6)−アルケニルまたは(C1−C6)−アルキルを表す、 の化合物を生ぜしめるか、 あるいは [F] 不活性溶媒中で、必要な場合、塩基の存在下で、 一般式(Ie)の化合物を一般式(VIII) R35−R3 (VIII) 式中、 R3は請求の範囲1に記述した意味を有し、 R35は脱離基、好ましくはハロゲンを表す、 の化合物と反応させて、一般式(Ig) R40−A−D−E−G−L−R2 (Ig) 式中、 A、D、E、G、L及びR2は上に示した意味を有し、そして R40は式 式中 R3は上に示した意味を有する、 の基を表す、 の化合物を生ぜしめるか、 あるいは [G] 一般式(Ih) 式中、 A、D、E、G、L及びR2は上に示した意味を有する、 の化合物を不活性溶媒中で、例えばN−ブロモスクシンイミドで、遊離基臭素化 により一般式(Ii) 式中、 A、D、E、G、L及びR2は上に示した意味を有する、 の化合物に転化し、そして次に、不活性溶媒中で、必要な場合、塩基の存在下で 、一般式(IX)または(X) CH2(CO2R42)2 (IX) H2N−R3 (X) 式中、 R42は(C1−C6)−アルキルを表し、そして R3は上に示した意味を有する、 の化合物と反応させて一般式(Ij) R43−A−D−E−G−L−R2 (Ij) 式中、 A、D、E、G、L及びR2は上記の意味を有し、そして R43は を表し、 ここで、 R42及びR3は上記の意味を有する、 の化合物を生ぜしめ、 そして必要な場合、上記の置換基を常法に従って導入及び誘導化し、 そして対応するチオエーテル(D=S)から出発する、D=−SO−または−S O2−の場合、常法に従って酸化を実施し、 そして対応するアミンから出発する、アンモニウム化合物の場合、アルキル化を 実施する、 請求の範囲1ないし6のいずれかの式(I)の化合物の製造方法。 8. 一般式(II) R1−A−D−E−G−M−H (II) 式中、 R1、A、D、E、G及びMは請求の範囲1及び7に示した意味を有する 、 の化合物。 9. R1、A、D、E及びGが請求の範囲5に記述した意味を有し、そして Mが請求の範囲7に示した意味を有する、 請求の範囲8の化合物。 10. 一般式(II) R1−A−D−E−G−M−H (II) 式中、 R1、A、D、E及びGは請求の範囲1に示した意味を有し、そして Mは請求の範囲7に示した意味を有する、 の化合物の製造方法で、 [A] 不活性溶媒中で、必要な場合、塩基の存在下で、 一般式(VI) R1−A−D’−H (VI) 式中、 R1、A及びD’は請求の範囲7に示した意味を有する、 の化合物を一般式(XI) R44−E−G−NO2 (XI) 式中、 E及びGは請求の範囲1に示した意味を有し、そして R44は脱離基、好ましくはハロゲンである、 の化合物と反応させ、そして次に、不活性溶媒中で通例の還元剤、好ましくはH2 /Pd/Cとまたはヒドラジン水和物、Pd/Cと反応させ、必要な場合、( C−C)多重結合を同時に水素化して、一般式(IIa) R1−A−D’−E−G−NH2 (IIa) 式中、 R1、A、D’、E及びGは上に示した意味を有する、 の化合物を生ぜしめるか、 あるいは [B] 一般式(IIb) R1−A−D−E−G−NH2 (IIb) 式中、 R1、A、D、E及びGは請求の範囲1に示した意味を有する、 の化合物をニトロソ化剤、好ましくは硫酸及び亜硝酸ナトリウムの水溶液と反応 させ、続いて好ましくは60ないし100°まで温めて、一般式(IIc) R1−A−D−E−G−OH (IIc) 式中、 R1、A、D、E及びGは上記の意味を有する、 の化合物を生ぜしめるか、 あるいは [C] 不活性溶媒、好ましくはジメチルホルムアミドまたはピリジン中で、必 要な場合、塩基、好ましくは炭酸カリウムの存在下で、そして必要な場合、銅( I/II)塩、好ましくは酸化銅(II)またはヨウ化銅(I)の存在下で、0℃か ら200℃まで、好ましくは80ないし150℃の温度範囲及び標準圧力で、 一般式(XII) R1−R36 (XII) 式中、 R1は上に示した意味を有し、そして R36は脱離基、好ましくはハロゲン、特に好ましくは臭素を表す、 の化合物を一般式(XIII) HO−G−O−R45 (XIII) 式中、 Gは上に示した意味を有し、そして R45は(C1−C6)−アルキル、好ましくはメチルを表す、 の化合物と反応させて、一般式(Ik) R1−O−G−O−R45 (Ik) 式中、 R1、G及びR45は上記の意味を有する、 の化合物を生ぜしめ、そして次に酸、好ましくは臭化水素酸の存在下で反応させ て、一般式(IId) R1−O−G−OH (IId) の化合物を生ぜしめるか、 あるいは [D] 不活性溶媒中で、必要な場合、塩基の存在下で、 一般式(VI) R1−A−D’−H (VI) 式中、 R1、A及びD’は請求の範囲7に示した意味を有する、 の化合物を一般式(XIV) R46−E−G’−R47 (XIV) 式中、 R46はR36に対して示した意味を有し、そしてこれと同一または異なり、 Eは上記の意味を有し、 G’は硫黄、窒素及び/または酸素よりなる群からの3個までのヘテロ原 子を有する二様に結合した5ないし7員の芳香族複素環を表し、それが場合によ り請求の範囲1でGに対して定義したような1個またはそれより多い同一または 異なる置換基で置換されていてもよく、そして R47はハロゲン、好ましくは塩素または臭素を表す、 の化合物と反応させて、一般式(XV) R1−A−D’−E−G’−R47 (XV) 式中、 R1、A、D’、E、G’及びR47は上記の意味を有する、 の化合物を生ぜしめ、そして次に液体アンモニア中でカリウムアミドで一般式( IIe) R1−A−D’−E−G’−NH2 (IIe) 式中、 R1、A、D’、E及びG’は上記の意味を有する、 の対応する遊離アミンに転化する、 方法。 11. 一般式(XV) R48−SO2−(CH2)h−U−(CH2)i−CR49R50−CH2−R51 (XV) 式中、 R48は脱離基であり、 Uは酸素または単結合であり、 R49及びR50は同一または異なり、そしてH、F、ClまたはCF3を表 し、 R51はH、F、ClまたはBrであり、 hは数字1または2であり、そして iは数字0または1である、 の化合物で、 式中、 Uが単結合であり、 R49及びR50が同一であり、HまたはFを表し、そして R51がFを表す 化合物を除き、 そして式中、 Uが酸素であり、 R49またはR50がClを表し、そして iが0を表す 化合物を除く。 12. 一般式(XVI)及び(XVII) R48−SO2−CH2−CH2−CH2−CF3 (XVI) または R48−SO2−CH2−CH2−CH2−CF2−CF3 (XVII) 式中、 R48は脱離基である、 の化合物。 13. R48が塩素である請求の範囲11及び12の化合物。 14. 少なくとも1つの製薬学的に許容しうる本質的に無毒のビヒクルまた は賦形剤と一緒に混合された請求の範囲1ないし6のいずれかの少なくとも1つ の化合物を有効成分として含んでなる製薬学的組成物。 15. ヒト及び動物の治療における薬剤としての使用のための請求の範囲1 ないし6のいずれかの化合物。 16. 神経変性疾患の予防及び/または治療のための薬剤の製造のための請 求の範囲1ないし6のいずれかの化合物の使用。 17. 脳虚血及び頭部外傷の予防及び/または治療のための薬剤の製造のた めの請求の範囲1ないし6のいずれかの化合物の使用。 18. 痛み、嘔吐、悪心、緑内障、喘息、食欲不振、痙攣、リューマチ、沈 静及び移動性疾患の状態の治療のための請求の範囲1ないし6のいずれかの化合 物の使用。 19. ヒト及び動物における細菌またはウイルス感染、自己免疫疾患、関節 、骨及び筋肉器官、内部及び外部器官、中枢神経系、感覚器官 並びに造血系の炎症性または自己免疫学的関連疾患の治療のための請求の範囲1 ないし6のいずれかの化合物の使用。
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JP2005529864A (ja) * | 2002-04-11 | 2005-10-06 | バイエル・ヘルスケア・アクチェンゲゼルシャフト | (2−ヒドロキシメチルインダニル−4−オキシ)フェニル4,4,4−トリフルオロブタン−1−スルホネートの水性製剤 |
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JP2007505086A (ja) * | 2003-09-11 | 2007-03-08 | テイボテク・フアーマシユーチカルズ・リミテツド | Hivウイルス侵入阻害剤 |
JP4823063B2 (ja) * | 2003-09-11 | 2011-11-24 | テイボテク・フアーマシユーチカルズ・リミテツド | Hivウイルス侵入阻害剤 |
WO2006051704A1 (ja) * | 2004-11-15 | 2006-05-18 | Taisho Pharmaceutical Co., Ltd. | イミン化合物 |
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