JP4630669B2 - 頭蓋内圧亢進、二次性虚血、および細胞傷害性反応性酸素種のレベルの増加と関連する障害の治療に関するプテリジン誘導体の使用 - Google Patents
頭蓋内圧亢進、二次性虚血、および細胞傷害性反応性酸素種のレベルの増加と関連する障害の治療に関するプテリジン誘導体の使用 Download PDFInfo
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- JP4630669B2 JP4630669B2 JP2004569858A JP2004569858A JP4630669B2 JP 4630669 B2 JP4630669 B2 JP 4630669B2 JP 2004569858 A JP2004569858 A JP 2004569858A JP 2004569858 A JP2004569858 A JP 2004569858A JP 4630669 B2 JP4630669 B2 JP 4630669B2
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- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
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- 239000003925 fat Substances 0.000 description 1
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- 235000012208 gluconic acid Nutrition 0.000 description 1
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- 125000000350 glycoloyl group Chemical group O=C([*])C([H])([H])O[H] 0.000 description 1
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- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
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- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 1
- LKPFBGKZCCBZDK-UHFFFAOYSA-N n-hydroxypiperidine Chemical compound ON1CCCCC1 LKPFBGKZCCBZDK-UHFFFAOYSA-N 0.000 description 1
- YZMHQCWXYHARLS-UHFFFAOYSA-N naphthalene-1,2-disulfonic acid Chemical compound C1=CC=CC2=C(S(O)(=O)=O)C(S(=O)(=O)O)=CC=C21 YZMHQCWXYHARLS-UHFFFAOYSA-N 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- 208000015122 neurodegenerative disease Diseases 0.000 description 1
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- 238000012148 non-surgical treatment Methods 0.000 description 1
- 125000001400 nonyl 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])[H] 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 125000002347 octyl 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])[H] 0.000 description 1
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- 239000002674 ointment Substances 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
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- 150000002923 oximes Chemical class 0.000 description 1
- 125000004043 oxo group Chemical group O=* 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
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- 125000006678 phenoxycarbonyl group Chemical group 0.000 description 1
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
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- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
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- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
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- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
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- 239000011734 sodium Substances 0.000 description 1
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- 239000012453 solvate Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
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- 239000003381 stabilizer Substances 0.000 description 1
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- 239000007858 starting material Substances 0.000 description 1
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- 238000007460 surgical drainage Methods 0.000 description 1
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- 239000000725 suspension Substances 0.000 description 1
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- 230000008961 swelling Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
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- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- NYERMPLPURRVGM-UHFFFAOYSA-N thiazepine Chemical group S1C=CC=CC=N1 NYERMPLPURRVGM-UHFFFAOYSA-N 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- IBBLKSWSCDAPIF-UHFFFAOYSA-N thiopyran Chemical compound S1C=CC=C=C1 IBBLKSWSCDAPIF-UHFFFAOYSA-N 0.000 description 1
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- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- FIQMHBFVRAXMOP-UHFFFAOYSA-N triphenylphosphane oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
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- 230000025033 vasoconstriction Effects 0.000 description 1
- 230000003639 vasoconstrictive effect Effects 0.000 description 1
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- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D475/00—Heterocyclic compounds containing pteridine ring systems
- C07D475/06—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4
- C07D475/08—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4 with a nitrogen atom directly attached in position 2
-
- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/06—Free radical scavengers or antioxidants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
Description
R1は、水素、(C1〜C20)−アルキル、(C1〜C20)−アルケニル、(C1〜C20)アルキニル、好ましくは(C1〜C10)−アルキル、シクロアルキル、シクロアルケニル、好ましくは(C3〜C8)−シクロアルキル、シクロアルキルアルキル、アリール、アルキルアリール、好ましくは(C1〜C3)−アルキルアリールまたはアリールアルキルであって、ここで、有機基、好ましくはアルキル基が、1つ以上の置換基、好ましくは置換基R6によって置換されていてもよく、
R2は、R1と独立して、水素、(C1〜C20)−アルキル、(C1〜C20)−アルケニル、(C1〜C20)−アルキニル、好ましくは(C1〜C10)−アルキル、シクロアルキル、シクロアルケニル、好ましくは(C3〜C8)−シクロアルキル、シクロアルキルアルキル、アリール、アルキルアリール、好ましくは(C1〜C3)−アルキルアリール、またはアリールアルキルであって、ここで、有機基、好ましくはアルキル基が、1つ以上の置換基、好ましくは置換基R6によって置換されていてもよく、
R1およびR2は、それらを有する窒素原子と一緒に、3から8員環を形成し、前記環は、系列N、O、Sからの0、1、または2個のさらなるヘテロ原子を場合により含んでいてもよく、前記環は1つ以上の基、好ましくはR6基によって場合により含んでいてもよく、
R3は、水素、−CO−アルキル、好ましくは、−CO−(C1〜C7)−アルキル、−CO−アルキルアリール、好ましくは−CO−(C1〜C3)−アルキルアリールまたは−CO−アリールであり、
R4は、アルキル、アルケニル、アルキニル、好ましくは、(C1〜C10)−アルキル、シクロアルキル、シクロアルケニル、好ましくは(C3〜C8)−シクロアルキル、シクロアルキルアルキル、アリール、またはアルキルアリール、好ましくは(C1〜C3)−アルキルアリール、アリールアルキル、−CO−O−アルキル、好ましくは−CO−O−(C1〜C5)−アルキル、−CO−O−アリール、−CO−アルキル、好ましくは−CO−(C1〜C5)−アルキルまたは−CO−アリールであって、ここで、有機基、好ましくはアルキル基が、1つ以上の置換基、特に置換基R7によって置換されていてもよく、
R5は、R3とは独立して、水素、−CO−アルキル、好ましくは、−CO−(C1〜C7)−アルキル、−CO−アルキルアリール、好ましくは−CO−(C1〜C3)−アルキルアリールまたは−CO−アリールであり、
R6は、−F、−OH、−O−(C1〜C10)−アルキル、−O−フェニル、−O−CO−(C1〜C10)−アルキル、−O−CO−アリール、−NR8R9、オキソ、フェニル、−CO−(C1〜C5)−アルキル、−CF3、−CN、−CONR8R9、−COOH、−CO−O−(C1〜C5)−アルキル、−CO−O−アリール、−S(O)n−(C1〜C5)アルキル、−SO2−NR8R9であり、
R7は、R6と独立して、R6の意味の1つを有し、
R8は、水素または(C1〜C20)−アルキル、好ましくは(C1〜C5)−アルキルであり、
R9は、水素または(C1〜C20)−アルキル、好ましくは(C1〜C5)−アルキルまたはアリール、好ましくはフェニルであり、
R10は、水素または(C1〜C20)−アルキル、好ましくは(C1〜C5)−アルキル、アルコキシ、またはアリールであり、
アリールは、好ましくは、フェニル、ナフチル、またはヘテロアリールであり、これらの各々は非置換であるかまたは置換されていてもよく、例えば、以下の系列:ハロゲン、(C1〜C20)−アルキル、好ましくは(C1〜C5)−アルキルまたはフェニル、−OH、−O−(C1〜C20)−アルキル、好ましくは−O−(C1〜C5)−アルキル、(C1〜C20)−アルキレンジオキシ、好ましくは(C1〜C2)−アルキレンジオキシ、−N8R9、−NO2、−CO−(C1〜C5)−アルキル、−CF3、−CN、−CONR8R9、−COOH、−CO−O−(C1〜C5)−アルキル、−S(O)n−(C1〜C5)−アルキル、−SO2−NR8R9からの1つ以上の同一のまたは異なる置換基によって置換されていてもよく、
ヘテロアリールは、系列O、N、Sからの1つ以上のヘテロ原子を含む、5から7員の不飽和ヘテロ環であり、
nは0、1、または2であり、
すべてのこれらの立体異性体および互変異性体、ならびにすべての比率のこれらの混合物、ならびにこれらの生理学的に許容される塩、水和物、およびエステルである。式(Ic)の化合物は、WO01/21619またはWO00/39129において記載されるように合成され得る。式(Ic)の2,4−ジアミノプテリン誘導体はまた、例えば、出発物質として、WO97/21711の式(II)に従うそれぞれのオキシム誘導体と反応される2,4,5,6−テトラアミノピリミジン−ジヒドロクロライドを使用して、WO97/21711において記載されたプロセスによって入手され得る。
R1は、好ましくは、水素、1つ以上の置換基R6によって置換されていてもよい(C2〜C4)−アルキル、または(C1〜C2)−アルキルアリールであって、R1は特に好ましくは、アリールメチルであり、
R2は、好ましくは、1つ以上の置換基R6によって置換されていてもよい(C2〜C40)−アルキル、または(C1〜C2)−アルキルアリールであり、およびR2は、特に好ましくは、アリールメチルである。
XはOまたはNHであり;
R1は、水素、メチル、(C1〜C5)−アルカノイル、ニコチノイル、または(1−メチル−3−ピリジニオ)カルボニルであり;
R2は、水素またはメチルであり;
R3は、水素、メチル、エチル、ベンジル、(C1〜C5)アルカノイル、非置換ベンゾイル、置換ベンゾイル、ピリドイル、チエニルカルボニル、基
R4は、水素、(C2〜C5)−アルキル、非置換フェニル、置換フェニル、または基R4a−CH2−であり;
R4aは、水素、(C1〜C4)−アルキルメルカプト、基−S(O)mR10、ここでmは数字1もしくは2、基−NR11R12または基−OR13であり、あるいは
R3およびR4aは一緒に、基−CO−O−であり、そのカルボニル炭素原子がプテリジン分子の5位に結合され;
R5は水素またはフェニルであり;
R6は水素であり;
R7は水素またはメチルであり;
R8は(C1〜C10)−アルキルまたはベンジルであり;
R9は水素、(C1〜C6)−アルキル、シクロヘキシル、フェニル、またはベンゾイルであり;
R9aは水素、メチル、またはエチルであり;
R10はメチルであり;
R11およびR12は互いに独立して、水素またはメチルであり;
R13は水素、(C1〜C10)−アルキル、2−メトキシエチル、フェニル、3−フェニルプロピル、3−シクロヘキシルプロピル、(C1〜C5)−アルカノイル、ヒドロキシアセチル、2−アミノ−(C2〜C6)−アルカノイル、これは、非置換であるかまたはフェニル基もしくは((C1〜C2)−アルコキシ)カルボニルによってアルキル部分において置換され;
Aは薬理学的に許容されるアニオンであり;ならびにこれらの互変異性体およびこれらの薬理学的に許容される塩である。
XはO、NHまたはN−(C1〜C5)−アルカノイルであり;
Rは水素であり、かつ
R1は、水素、もしくは(C1〜C5)−アルカノイルであるか、または、RおよびR1はこれらが結合する窒素原子と一緒にジメチルアミノメチレンアミノ基を形成し;
R2は、水素、メチル、フェニル、ヒドロキシル、メトキシ、またはアミノであり;
R3は、基−OR4、−NR5R6、または−S(O)mR7であり、ここでmは数字0、1、または2を表し;
R4は、水素、(C1−C10)−アルキル、シクロヘキシル、ベンジル、フェニル、これは非置換であるかまたは塩素もしくは基−COR8によって置換され、アミノカルボニルメチル、これは、非置換であるか、または1つもしくは2つの同一のもしくは異なる(C1−C4)−アルキル基によって窒素上で置換され、2−メトキシエチル、(2,2−ジメチル−1,3−ジオキソラン−4−イル)メチル基または基−COR9であり;
R5は、水素、メチル、エチル、2−ヒドロキシエチル、2−クロロエチル、ベンジル、ピリジルメチル、フェニルエチル、ピリジルエチル、またはアセチルであり;
R6は、R5の意味と独立して、R5について示される意味を有し、またはR5が水素もしくはメチルである場合、R6はまた、シクロヘキシル、3−(2−エトキシエトキシ)−プロピル、フェニル環上に1つもしくは2つの塩素原子または基−COR10を有するベンジル、(C1−C5)−アルカノイル、基−COR10、または基−(CH2)4−COR10であり;
R7は(C1−C4)−アルキル、ベンジル、非置換であるかまたは塩素、基−COR8、もしくは基−CO−O−CO−(C1−C4)−アルキルで置換されたフェニル、あるいはナフチルであり;
R8は水素、メトキシ、アミノ、またはR10であり;
R9は(C1−C4)−アルキル、ヒドロキシメチル、トリフルオロメチル、(C1−C2)−アルコキシまたはR11であり;
R10は基
R12はヒドロキシまたは(C1−C2)−アルコキシであり;
R13は(C1−C4)−アルキルまたはベンジルであり;
R14は水素またはベンジルオキシカルボニルであり;ならびにこれらの互変異性体およびこれらの薬理学的に許容される塩である。
2,4−ジアミノ−5,6,7,8−テトラヒドロ−6−(L−エリスロ−1,2−ジヒドロキシプロピル)−プテリジンを以下のように合成した。
生理学的に関連する種々のレセプターへのH4−アミノビオプテリンの結合の挙動を、放射活性標識したリガンドを使用する競合結合アッセイにおいて決定した。NO−シンターゼについてのIC50値の決定を、POLLOCK,J.S.,FORSTERMANN,U.,MITCHELL,J.A.,WARNER,T.D.,SCHMIDT,H.H.H.,NAKANE,M.およびMURAD,F.(1991)Proc.Natl.Acad.Sci.USA,88 10480−10484(Cerep,Paris,France,2002版のカタログの試験参照番号766−cもまた参照のこと)において公開されたプロトコールに従って実行した。
H4−アミノビオプテリンのNOシンターゼに対する生理学的効果を、Cerep,Paris,France,2002版のカタログ(表2を参照のこと)において記載されるプロトコールの使用によって、関連するレセプターを発現する細胞を用いる細胞培養試験において試験した。H4−アミノビオプテリンの結合特異性を決定するために選択された他のレセプターの各々についてのIC50値の決定もまた、再度、Cerep,Paris,France,2002版のカタログに記載されるように実行した。さらに、β−アドレナリンレセプター−Gタンパク質カップリングに対するH4−アミノビオプテリンの調節効果(表3)を、Cerepカタログの2002版の参照番号758−2a(134頁)および758−2b(134頁)において記載されるアッセイによって研究した。
単離されたラット脳底動脈(BA)および中大脳動脈(MCA)における2,4−ジアミノ−5,6,7,8−テトラヒドロ−6−(L−エリスロ−1,2−ジヒドロキシプロピル)−プテリジンの収縮効果を、Schillingら、Peptides 21(2000)91−99によって記載されているように試験した。
Claims (22)
- 式(Ia)におけるR1およびR4が水素であり、R2がメチルであり、かつR3がヒドロキシルである、請求項1に記載の使用。
- 化合物が、2,4−ジアミノ−5,6,7,8−テトラヒドロ−6−(L−エリスロ−1,2−ジヒドロキシプロピル)−プテリジンである、請求項2に記載の使用。
- 頭蓋内圧亢進が閉鎖頭蓋脳外傷または非外傷性脳損傷によって引き起こされる、請求項1〜3のいずれか一項に記載の使用。
- 哺乳動物の治療のための、請求項1〜4のいずれか一項に記載の使用。
- 前記哺乳動物がヒトである、請求項5に記載の使用。
- R5がメチルであり、R3が水素であり、R2およびR4が両方とも水素であり、かつR1が水素またはヒドロキシルのいずれかである、請求項7に記載の使用。
- 頭蓋内圧亢進が閉鎖頭蓋脳外傷または非外傷性脳損傷によって引き起こされる、請求項7または8に記載の使用。
- 哺乳動物の治療のための、請求項7〜9のいずれか一項に記載の使用。
- 前記哺乳動物がヒトである、請求項10に記載の使用。
- 式(Ia)のR1およびR4が水素であり、R2がメチル、およびR3がヒドロキシルである、請求項12に記載の使用。
- 化合物が、2,4−ジアミノ−5,6,7,8−テトラヒドロ−6−(L−エリスロ−1,2−ジヒドロキシプロピル)−プテリジンである、請求項13に記載の使用。
- 炎症性プロセスが閉鎖頭蓋脳外傷または非外傷性脳損傷によって引き起こされる、請求項12〜14のいずれか一項に記載の使用。
- 哺乳動物の治療のための、請求項12〜15のいずれか一項に記載の使用。
- 前記哺乳動物がヒトである、請求項16に記載の使用。
- R5がメチルであり、R3が水素であり、R2およびR4が両方とも水素であり、かつR1が水素またはヒドロキシルのいずれかである、請求項18に記載の使用。
- 炎症性プロセスが閉鎖頭蓋脳外傷または非外傷性脳損傷によって引き起こされる、請求項18または19に記載の使用。
- 哺乳動物の治療のための、請求項18〜20のいずれか一項に記載の使用。
- 前記哺乳動物がヒトである、請求項21に記載の使用。
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BRPI0821970A2 (pt) * | 2008-01-03 | 2015-06-23 | Biomarin Pharm Inc | Análogos de pterina para tratamento de condição responsiva a bh4 |
PT2926805T (pt) | 2014-03-31 | 2016-07-15 | Vasopharm Gmbh | Composições farmacêuticas sólidas que contêm derivados de biopterina e utilizações dessas composições |
CA3235704A1 (en) | 2021-12-03 | 2023-06-08 | Verinos Operations Gmbh | Methods of treating patients suffering from brain injury and methods of increasing the value of the extended glasgow outcome scale of patients suffering from brain injury |
TW202406555A (zh) | 2022-05-06 | 2024-02-16 | 德商veriNOS運營有限公司 | 治療患有與增加的麩胺酸水平相關的疾病狀況或病症的患者的方法 |
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CA2519919C (en) | 2009-09-08 |
CA2519919A1 (en) | 2004-10-07 |
KR101103888B1 (ko) | 2012-01-12 |
US8222238B2 (en) | 2012-07-17 |
DE60307327D1 (de) | 2006-09-14 |
PL213123B1 (pl) | 2013-01-31 |
WO2004084906A1 (en) | 2004-10-07 |
AU2003293607B2 (en) | 2009-12-03 |
EP1605947A1 (en) | 2005-12-21 |
US20130184281A1 (en) | 2013-07-18 |
MXPA05009491A (es) | 2006-02-22 |
DE60307327T2 (de) | 2007-10-25 |
PL378633A1 (pl) | 2006-05-15 |
ATE334681T1 (de) | 2006-08-15 |
WO2005037286A1 (en) | 2005-04-28 |
ES2270151T3 (es) | 2007-04-01 |
US9382252B2 (en) | 2016-07-05 |
EP1605947B1 (en) | 2006-08-02 |
CN1758913A (zh) | 2006-04-12 |
AU2003293607A1 (en) | 2004-10-18 |
CN1758913B (zh) | 2010-04-28 |
KR20060002861A (ko) | 2006-01-09 |
JP2006514965A (ja) | 2006-05-18 |
RU2005128956A (ru) | 2006-04-27 |
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US20130131071A1 (en) | 2013-05-23 |
US9422289B2 (en) | 2016-08-23 |
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