JP6391071B2 - シスタチオニン−γ−リアーゼ(CSE)阻害剤 - Google Patents
シスタチオニン−γ−リアーゼ(CSE)阻害剤 Download PDFInfo
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- JP6391071B2 JP6391071B2 JP2015524402A JP2015524402A JP6391071B2 JP 6391071 B2 JP6391071 B2 JP 6391071B2 JP 2015524402 A JP2015524402 A JP 2015524402A JP 2015524402 A JP2015524402 A JP 2015524402A JP 6391071 B2 JP6391071 B2 JP 6391071B2
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- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 235000011008 sodium phosphates Nutrition 0.000 description 1
- ODFAPIRLUPAQCQ-UHFFFAOYSA-M sodium stearoyl lactylate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC(=O)OC(C)C(=O)OC(C)C([O-])=O ODFAPIRLUPAQCQ-UHFFFAOYSA-M 0.000 description 1
- 229940080352 sodium stearoyl lactylate Drugs 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- JAJWGJBVLPIOOH-IZYKLYLVSA-M sodium taurocholate Chemical compound [Na+].C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCS([O-])(=O)=O)C)[C@@]2(C)[C@@H](O)C1 JAJWGJBVLPIOOH-IZYKLYLVSA-M 0.000 description 1
- 235000010339 sodium tetraborate Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000007886 soft shell capsule Substances 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 239000007962 solid dispersion Substances 0.000 description 1
- 239000012439 solid excipient Substances 0.000 description 1
- 239000008137 solubility enhancer Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000008347 soybean phospholipid Substances 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 235000019408 sucralose Nutrition 0.000 description 1
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 description 1
- 238000009495 sugar coating Methods 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- WBWWGRHZICKQGZ-GIHLXUJPSA-N taurocholic acid Chemical compound C([C@@H]1C[C@H]2O)[C@@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@@H]([C@@H](CCC(=O)NCCS(O)(=O)=O)C)[C@@]2(C)[C@H](O)C1 WBWWGRHZICKQGZ-GIHLXUJPSA-N 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- 229940090016 tegretol Drugs 0.000 description 1
- 201000004415 tendinitis Diseases 0.000 description 1
- INXJVKHQEHIAAA-UHFFFAOYSA-N tert-butyl n-[ethyl(2h-tetrazol-5-ylcarbamoyl)amino]carbamate Chemical compound CC(C)(C)OC(=O)NN(CC)C(=O)NC=1N=NNN=1 INXJVKHQEHIAAA-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- BSYVTEYKTMYBMK-UHFFFAOYSA-N tetrahydrofurfuryl alcohol Chemical compound OCC1CCCO1 BSYVTEYKTMYBMK-UHFFFAOYSA-N 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 239000000892 thaumatin Substances 0.000 description 1
- 235000010436 thaumatin Nutrition 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000005308 thiazepinyl group Chemical group S1N=C(C=CC=C1)* 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000001583 thiepanyl group Chemical group 0.000 description 1
- 125000002053 thietanyl group Chemical group 0.000 description 1
- 125000000858 thiocyanato group Chemical group *SC#N 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 206010043554 thrombocytopenia Diseases 0.000 description 1
- 210000001541 thymus gland Anatomy 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 206010043778 thyroiditis Diseases 0.000 description 1
- 230000009092 tissue dysfunction Effects 0.000 description 1
- 208000037816 tissue injury Diseases 0.000 description 1
- 235000010384 tocopherol Nutrition 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- 229960001295 tocopherol Drugs 0.000 description 1
- 239000012443 tonicity enhancing agent Substances 0.000 description 1
- 206010044008 tonsillitis Diseases 0.000 description 1
- 239000003860 topical agent Substances 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- 229960004380 tramadol Drugs 0.000 description 1
- TVYLLZQTGLZFBW-GOEBONIOSA-N tramadol Natural products COC1=CC=CC([C@@]2(O)[C@@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-GOEBONIOSA-N 0.000 description 1
- 239000006211 transdermal dosage form Substances 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 208000009174 transverse myelitis Diseases 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 150000003852 triazoles Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 229940078499 tricalcium phosphate Drugs 0.000 description 1
- 235000019731 tricalcium phosphate Nutrition 0.000 description 1
- 229910000391 tricalcium phosphate Inorganic materials 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 229940061414 trileptal Drugs 0.000 description 1
- XFXIRAGUWFFKDE-UHFFFAOYSA-N trimethylsilyl thiocyanate Chemical compound C[Si](C)(C)SC#N XFXIRAGUWFFKDE-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-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
- MDYZKJNTKZIUSK-UHFFFAOYSA-N tyloxapol Chemical compound O=C.C1CO1.CC(C)(C)CC(C)(C)C1=CC=C(O)C=C1 MDYZKJNTKZIUSK-UHFFFAOYSA-N 0.000 description 1
- 229920001664 tyloxapol Polymers 0.000 description 1
- 229960004224 tyloxapol Drugs 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 125000004417 unsaturated alkyl group Chemical group 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 230000006442 vascular tone Effects 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 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
- 230000003442 weekly effect Effects 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 229940100445 wheat starch Drugs 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
- 229910052984 zinc sulfide Inorganic materials 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
- DRDVZXDWVBGGMH-UHFFFAOYSA-N zinc;sulfide Chemical compound [S-2].[Zn+2] DRDVZXDWVBGGMH-UHFFFAOYSA-N 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
- C07D257/06—Five-membered rings with nitrogen atoms directly attached to the ring carbon atom
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
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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
- C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
- C07D271/07—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
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- A61K31/433—Thidiazoles
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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
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- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
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- 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
- C07C311/19—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 carboxyl groups
-
- 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
- C07C311/50—Compounds containing any of the groups, X being a hetero atom, Y being any atom
- C07C311/52—Y being a hetero atom
- C07C311/54—Y being a hetero atom either X or Y, but not both, being nitrogen atoms, e.g. N-sulfonylurea
- C07C311/57—Y being a hetero atom either X or Y, but not both, being nitrogen atoms, e.g. N-sulfonylurea having sulfur atoms of the sulfonylurea groups bound to carbon atoms of six-membered aromatic rings
- C07C311/61—Y being a hetero atom either X or Y, but not both, being nitrogen atoms, e.g. N-sulfonylurea having sulfur atoms of the sulfonylurea groups bound to carbon atoms of six-membered aromatic rings having nitrogen atoms of the sulfonylurea groups further bound to another hetero atom
-
- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles 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
- C07D249/14—Nitrogen atoms
-
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- C07D255/00—Heterocyclic compounds containing rings having three nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D249/00 - C07D253/00
- C07D255/02—Heterocyclic compounds containing rings having three nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D249/00 - C07D253/00 not condensed with other rings
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pulmonology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Immunology (AREA)
- Neurology (AREA)
- Physical Education & Sports Medicine (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Dermatology (AREA)
- Urology & Nephrology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Aはカルボン酸同配体であり;
R1は、置換又は非置換のC3−C6アルキル、置換又は非置換のヘテロアルキル、置換又は非置換のヘテロシクロアルキル、置換又は非置換のアリール、或いは置換又は非置換のヘテロアリールである。
R1は、H、置換又は非置換のアルキル、置換又は非置換のヘテロアルキル、置換又は非置換のヘテロシクロアルキル、置換又は非置換のアリール、或いは置換又は非置換のヘテロアリールであり;
Aは、
R1は、H、置換又は非置換のアルキル、置換又は非置換のヘテロアルキル、置換又は非置換のヘテロシクロアルキル、置換又は非置換のアリール、或いは置換又は非置換のヘテロアリールであり;
Aは、−SO3H、−SO2NHR4、−P(O)(OR4)2、−P(O)(R4)(OR4)、−CON(R4)2、−CONHNHSO2R4、−CONHSO2R4、−C(R4)2B(OR5)2、及び−CON(R4)C(R4)2B(OR5)2から選択されるカルボン酸同配体であり;ここで、各R4は独立して、H、OH、置換又は非置換のアルキル、或いは置換又は非置換のアリールであり;及びR5はH又はC1−C6アルキルである。
Aは、
R1は、置換又は非置換のC2−C6アルキル、置換又は非置換のヘテロアルキル、置換又は非置換のヘテロシクロアルキル、置換又は非置換のアリール、或いは置換又は非置換のヘテロアリールである。
Aは、
R1は、H、置換又は非置換のC3−C6アルキル、置換又は非置換のヘテロアルキル、置換又は非置換のヘテロシクロアルキル、置換又は非置換のアリール、或いは置換又は非置換のヘテロアリールでる。
(E)−4−((2−(1H−テトラゾール−5−イル)ヒドラゾノ)メチル)−N,N−ジエチルアニリン、(E)−1−((2−(1H−テトラゾール−5−イル)ヒドラゾノ)メチル)ナフタレン−2−ol、(E)−5−(2−(ベンゾ[d][1,3]ジオキソール−5−イルメチレン)ヒドラジニル)−1H−テトラゾール、(E)−4−((2−(1H−テトラゾール−5−イル)ヒドラゾノ)メチル)フェノール、(E)−5−(2−(4−ニトロベンジリデン)ヒドラジニル)−1H−テトラゾール、(E)−5−(2−(フラン−2−イルメチレン)ヒドラジニル)−1H−テトラゾール、5−ヒドラジニル−1H−テトラゾール、5−(1−メチルヒドラジニル)−1H−テトラゾール、5−(1−メチルヒドラジニル)−1H−1,2,4−トリアゾール−3(2H)−オン、5−(1−エチルヒドラジニル)−1H−1,2,4−トリアゾール−3(2H)−オン、又は5−(ヒドラジニルメチル)−1H−テトラゾールの投与を含む。
本明細書には、特定の実施形態において、必要とする個体における神経障害性疼痛を処置する方法が開示される。神経障害性疼痛は、活性な組織傷害プロセスが付随する、又は付随しない場合がある、複雑な、慢性の、病的な疼痛状態である。神経障害性疼痛により、神経繊維自体は、ダメージを受ける、機能障害性である、又は損傷を受け得る。これらのダメージを受けた神経繊維は、他の疼痛中心へ不正確な信号を送り、中枢神経系のレベルでの機能の変更を潜在的にもたらす。神経繊維損傷の影響力は、損傷の部位及び損傷の周囲の領域の両方での、神経機能の変化を含む。
本明細書には、特定の実施形態において、必要とする個体における疾患又は疾病に関連する疼痛を処置する方法が開示される。幾つかの実施形態において、疾患又は疾病は自己免疫疾患である。幾つかの例において、自己免疫疾患は関節リウマチである。幾つかの実施形態において、自己免疫疾患は狼瘡である。幾つかの実施形態において、自己免疫疾患は、全身性エリトマトーデスである。幾つかの実施形態において、疾患又は疾病は炎症性疾患である。幾つかの例において、炎症性疾患は膵臓炎、急性膵炎、又は慢性膵炎である。幾つかの実施形態において、炎症性疾患は喘息である。幾つかの例において、炎症性疾患は関節炎である。幾つかの例において、炎症性疾患は骨関節炎である。幾つかの例において、炎症性疾患は痛風である。幾つかの例において、炎症性疾患は関節リウマチである。幾つかの例において、炎症性疾患は強直性脊椎炎である。幾つかの例において、炎症性疾患は、炎症性腸疾患又は過敏性腸症候群である。幾つかの実施形態において、疾患又は疾病は癌である。幾つかの実施形態では、癌は、癌腫、肉腫、メラノーマ、リンパ腫、又は白血病である。幾つかの実施形態において、癌は、膵癌、肺癌、前立腺癌、脳腫瘍、腸癌、咽喉癌、結腸癌、及び乳癌である。幾つかの例において、疾患又は疾病は肺疾患である。幾つかの例において、肺疾患は慢性閉塞性肺疾患である。幾つかの例において、肺疾患は慢性気管支炎である。幾つかの実施形態において、肺疾患は肺気腫である。幾つかの実施形態において、前記方法はCSE阻害剤を投与する工程を含む。幾つかの実施形態において、前記方法は、第2処置レジメンと組み合わせて、CSE阻害剤を投与する工程を含む。幾つかの実施形態において、前記方法は、第2処置レジメンの前、同時、又はその後に、CSE阻害剤を投与する工程を含む。
本明細書には、特定の実施形態において、必要とする個体における急性術後疼痛を処置、予防、又は減少する方法が開示される。術後痛(外科手術の結果として)は通常、標準であると考えられる。しかし、制御が不十分な場合、疼痛は、心拍数及び呼吸数の増加、不安、悪心嘔吐、尿閉、並びに、アドレナリン及びコルチゾールのレベルの上昇、又は、免疫応答の減少及び感染の危険の増加を引き起こす。
本明細書には、特定の実施形態において、必要とする個体における、毒剤(例えば、シスプラチン、アミノグリコシド、及び放射線の造影剤)に付随して起こる急性腎臓損傷(AKI)の発生を予防又は減少させる方法が、開示される。幾つかの実施形態において、前記方法はCSE阻害剤を投与する工程を含む。幾つかの実施形態において、前記方法は、第2処置レジメンと組み合わせて、CSE阻害剤を投与する工程を含む。幾つかの実施形態において、前記方法は、第2処置レジメンの前、同時、又はその後に、CSE阻害剤を投与する工程を含む。
本明細書には、特定の実施形態において、必要とする個体における自己免疫疾患を処置する方法が開示される。自己免疫疾患は大抵、身体に通常存在する物質及び組織に対する、身体の不適当な免疫応答から生じる。要するに、免疫系は、病原体として身体の幾つかの部分を間違えて、それ自身の細胞を攻撃する。これは、(例えば、自己免疫性甲状腺炎における)特定の臓器に制限され得、又は、異なる場所における特定の組織に関係し得る(例えば、肺と腎臓の両方における基底膜に影響し得るグッドパスチャー病)。自己免疫疾患の処置は典型的に、免疫抑制(免疫応答を減少させる薬物投与)によるものである。
本明細書には、特定の実施形態において、必要とする個体における炎症性疾患を処置する方法が開示される。炎症は、病原微生物、損傷を受けた細胞、又は刺激物などの、有害な刺激に対する維管束組織の複雑な生体応答の一部である。炎症は、有害な刺激を取り除き且つ治癒プロセスを開始するための、生物体による保護的な試みである。炎症は、炎症が感染によって引き起こされる場合でさえ、感染について同意語ではない。感染は微生物によって引き起こされるが、炎症は病原体に対する生物体の反応の1つである。しかし、炎症は常同的な反応であり、それ故、それは、適応免疫と比較して、各病原体に特異的である先天性免疫の機構と見なされる。
本明細書には、特定の実施形態において、必要とする個体における頭痛を処置する方法が開示される。本明細書には、特定の実施形態において、必要とする個体における片頭痛を処置する方法が開示される。本明細書には、特定の実施形態において、必要とする個体における単純性片頭痛(simple migraine headache)を処置する方法が開示される。本明細書には、特定の実施形態において、必要とする個体における複雑型片頭痛を処置する方法が開示される。本明細書には、特定の実施形態において、必要とする個体における緊張性頭痛を処置する方法が開示される。本明細書には、特定の実施形態において、必要とする個体における群発性頭痛を処置する方法が開示される。幾つかの実施形態において、前記方法はCSE阻害剤を投与する工程を含む。幾つかの実施形態において、前記方法は、第2処置レジメンと組み合わせて、CSE阻害剤を投与する工程を含む。幾つかの実施形態において、前記方法は、第2処置レジメンの前、同時、又はその後に、CSE阻害剤を投与する工程を含む。
脳卒中は、脳への血液供給における妨害による、脳機能の急速な損失である。虚血性脳血管障害において、脳の一部への血液供給が減少し、その領域において脳組織の機能不全に通じる。現在の証拠は、H2Sが大脳のニューロンに対する直接的な退行性効果によって虚血性障害を促進するが、脳血流に対する効果は除外されない場合がある、ことを示唆する。
用語「処置する(treat)」、「処置している(treating)」、及び「処置(treatment)」は、本明細書で使用されるように、疾患又は疾病の少なくとも1つの症状を軽減、減少、又は改善すること、更なる症状を予防すること、疾病の進行を予防すること、疾患又は疾病を阻害すること(例えば、疾患又は疾病の進行を阻止すること)、疾患又は疾病を緩和すること、疾患又は疾病を退行させること、疾患又は疾病により生じる状態を緩和すること、或いは疾患又は疾病の症状を止めることを含む。1つの実施形態において、処置は予防的処置である。別の実施形態において、処置は治療上の処置を指す。
単環式ヘテロアリール基の例は、以下のものを含むがこれらに限定されない:
本明細書に記載される方法で使用するのに適切なCSE阻害化合物の以下の記載において、標準の化学用語に言及する定義は、(本明細書において定義されなければ)「Carey and Sundberg “Advanced Organic Chemistry 4th Ed.” Vols. A (2000) and B (2001), Plenum Press, New York」を含む参考資料において見出され得る。特に指示がない限り、当業者の考え得る範囲内で、質量分析、NMR、HPCL、タンパク質化学、生化学、組換えDNA技術、及び薬理学の従来の方法が、使用される。特定の定義が与えられなければ、本明細書に記載される分析化学、有機合成化学、医薬、及び薬化学と組み合わせて利用した命名法、及び、それらの検査法並びに技術は、当業者に既知のものである。標準的な技術は、化学合成、化学分析、薬学的調製、製剤、送達、及び患者の処置に、使用される。
Aはカルボン酸同配体であり;
R1は、置換又は非置換のC3−C6アルキル、置換又は非置換のヘテロアルキル、置換又は非置換のヘテロシクロアルキル、置換又は非置換のアリール、或いは置換又は非置換のヘテロアリールである。
R1は、H、置換又は非置換のアルキル、置換又は非置換のヘテロアルキル、置換又は非置換のヘテロシクロアルキル、置換又は非置換のアリール、或いは置換又は非置換のヘテロアリールであり;
Aは、
R1は、H、置換又は非置換のアルキル、置換又は非置換のヘテロアルキル、置換又は非置換のヘテロシクロアルキル、置換又は非置換のアリール、或いは置換又は非置換のヘテロアリールであり;
Aは、−SO3H、−SO2NHR4、−P(O)(OR4)2、−P(O)(R4)(OR4)、−CON(R4)2、−CONHNHSO2R4、−CONHSO2R4、−C(R4)2B(OR5)2、及び−CON(R4)C(R4)2B(OR5)2から選択されるカルボン酸同配体であり;ここで、各R4は独立して、H、OH、置換又は非置換のアルキル、或いは置換又は非置換のアリールであり;及びR5はH又はC1−C6アルキルである。
Aは、
R1は、置換又は非置換のC2−C6アルキル、置換又は非置換のヘテロアルキル、置換又は非置換のヘテロシクロアルキル、置換又は非置換のアリール、或いは置換又は非置換のヘテロアリールである。
Aは、
R1は、H、置換又は非置換のC3−C6アルキル、置換又は非置換のヘテロアルキル、置換又は非置換のヘテロシクロアルキル、置換又は非置換のアリール、或いは置換又は非置換のヘテロアリールである。
Aはカルボン酸同配体であり;
R1は、H、置換又は非置換のアルキル、置換又は非置換のヘテロアルキル、置換又は非置換のヘテロシクロアルキル、置換又は非置換のアリール、或いは置換又は非置換のヘテロアリールであり;
R2は、置換又は非置換のアルキル、置換又は非置換のヘテロアルキル、置換又は非置換のヘテロシクロアルキル、置換又は非置換のアリール、置換又は非置換のヘテロアリール、又は−CH2C(O)(置換又は非置換のアリール)であり;
R3は、H、或いは置換又は非置換のアルキルであり;又は
R2とR3は、それらが付けられる炭素原子と共に、シクロアルキル又はヘテロシクロアルキルの環を形成する。
適切な投与経路は、経口投与、静脈内投与、直腸投与、エアロゾル投与、非経口投与、経眼投与、経肺投与、経粘膜投与、経皮投与、経鼻投与、及び局所投与を含むが、これらに限定されない。更に、ほんの一例ではあるが、非経口送達は、筋肉内、皮下、静脈内、髄内の注入に加え、同様に、くも膜下腔内、直接脳室内、腹腔内、リンパ内、及び/又は鼻腔内の注入も含む。
幾つかの実施形態において、本明細書に記載の化合物は、医薬組成物へと処方される。医薬組成物は、活性化合物の、薬学的に使用され得る製剤への処理を促進する、1以上の生理学的に許容可能な不活性成分を使用する従来の方法で、処方される。適切な製剤は、選択される投与経路に依存する。本明細書に記載される医薬組成物の概要は、例えば、Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980;及び、Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins1999)において見出され得、それらは開示のために、引用により本明細書に組み込まれる。
幾つかの実施形態において、式(I)、(II)、(III)、(IV)、(V)、又は(VI)の化合物は、経皮剤形として調製される。1つの実施形態において、本明細書に記載される経皮製剤は、少なくとも3つの構成成分:(1)式(I)、(II)、(III)、(IV)、(V)、又は(VI)の化合物の製剤:(2)浸透促進剤;及び(3)任意の水性アジュバントを含む。幾つかの実施形態において、経皮製剤は、限定されないがゲル化剤、クリーム剤、及び軟膏基剤などの追加の構成成分を含む。幾つかの実施形態において、経皮製剤は、パッチ又は創傷包帯として提供される。幾つかの実施形態において、経皮製剤は更に、吸収を促進し、且つ皮膚から経皮製剤の除去を防ぐために、織布又は不織布のバッキング材を含む。他の実施形態において、本明細書に記載される経皮製剤は、皮膚への拡散を促進するために、飽和又は過飽和の状態を維持することができる。
1つの態様において、式(I)、(II)、(III)、(IV)、(V)、又は(VI)の化合物は、創傷包帯の一部として提供される。包帯は、治癒を促進し及び/又は更なる傷害を防ぐために、創傷への適用のために使用されるアジュバントである。包帯は、創傷と直接接触するように設計される。幾つかの実施形態において、本明細書に記載されるCSE阻害剤を含む創傷包帯が、CSE阻害剤の制御放出を提供する。他の実施形態において、本明細書に記載されるCSE阻害剤を含む創傷包帯が、CSE阻害剤の持続放出を提供する。他の実施形態において、本明細書に記載されるCSE阻害剤を含む創傷包帯が、CSE阻害剤の中間放出を提供する。更なる実施形態において、本明細書に記載されるCSE阻害剤を含む創傷包帯が、CSE阻害剤の中間放出を提供する。他の実施形態において、本明細書に記載されるCSE阻害剤を含む創傷包帯が、CSE阻害剤の持続放出、中間放出、又は即時放出の組み合わせを提供する。
1つの態様において、式(I)、(II)、(III)、(IV)、(V)、又は(VI)の化合物は、筋肉内、皮下、又は静脈内の注入に適切な医薬組成物へと処方される。1つの態様において、筋肉内、皮下、腫瘍周囲、又は静脈内の注入に適切な製剤は、生理学的に許容可能な無菌の水性又は非水性の溶液、分散液、懸濁液又は乳剤、及び無菌の注入可能な溶液又は分散液への再構成のための無菌の粉末剤を含む。適切な水性及び非水性の担体、希釈剤、溶媒、又はビヒクルの例は、水、エタノール、ポリオール(プロピレングリコール、ポリエチレングリコール、グリセロール、cremophorなど)、それらの適切な混合物、植物油(オリーブ油など)、及びオレイン酸エチルなどの有機エステルを含む。適切な流動性は、例えば、レシチンなどのコーティングの使用、分散の場合に必要とされた粒径の維持、及び界面活性剤の使用によって、維持され得る。幾つかの実施形態において、皮下注入に適した製剤は、保存料、湿潤剤、乳化剤、及び分配剤(dispensing agent)などの添加剤も含む。微生物の増殖の予防は、パラベン、クロロブタノール、フェノール、ソルビン酸などの様々な抗菌性及び抗真菌性の薬剤によって確認され得る。幾つかの場合において、糖、塩化ナトリウムなどの等張性の薬剤を含むことが望ましい。モノステアリン酸アルミニウム及びゼラチンなどの、吸収を遅らせる薬剤の使用によって、注射可能な医薬形態の持続的吸収が引き起こされ得る。
幾つかの実施形態において、医薬剤形は、式(I)、(II)、(III)、(IV)、(V)、又は(VI)の化合物の制御放出を提供するように処方される。制御放出は、長期間にわたり所望の特性に従って組み込まれる剤形からの、化合物の放出を指す。制御放出特性は、例えば、持続放出、長期放出、パルス放出、及び遅延放出の特性を含む。即時放出組成物とは対照的に、制御放出組成物は、予め定義した特性に従って、長期間にわたる被験体への薬剤の送達を可能にする。そのような放出速度は、長期間、治療上効果的なレベルの薬剤を提供し、その結果として、より長期間の薬理反応を提供し、一方で、従来の急速放出剤形と比較して、副作用を最小限にする。そのような長期間の反応は、対応する短い作用の、即時放出調製により達成されない多くの固有の利益を提供する。
前記処置を必要とする被験体における本明細書に記載される疾患又は疾病の何れかを処置する方法は、治療上効果的な量で、少なくとも1つの式(I)、(II)、(III)、(IV)、(V)、又は(VI)の化合物、又はその薬学的に許容可能な塩、薬学的に許容可能なプロドラッグ、又は薬学的に許容可能な溶媒和物を含む医薬組成物の、前記被験体への投与を含む。別の実施形態において、式(I)、(II)、(III)、(IV)、(V)、又は(VI)の化合物は、毒剤(例えばシスプラチン、アミノグリコシド、及び放射線の造影剤)に付随して起こる急性腎臓損傷(AKI)、侵害受容性疼痛、急性の術後痛、神経障害性疼痛(例えば三叉神経痛、糖尿病性末梢性ニューロパチー、及び疱疹性神経痛)、炎症性疼痛、神経障害性疼痛と炎症性疼痛が合わさった状態、関節リウマチ、炎症性腸疾患、過敏性腸症候群、変形性関節症、急性膵炎、慢性膵炎、急性膵炎に関連した疼痛、慢性膵炎に関連した疼痛、片頭痛、痛風、強直性脊椎炎、全身性エリトマトーデス(SLE)、システム炎症反応症候群(SIRS)、多臓器機能不全症候群(MODS)、喘息、慢性閉塞性肺疾患(COPD)、敏感肌(例えば、ざ瘡、酒さ、燃焼、刺痛、及び接触皮膚炎)、又は癌(例えば膵癌、肺癌、前立腺癌、及び乳癌)に関連した疼痛、或いは本明細書に記載される疾病の処置のための薬の調製に使用される。
1つの実施形態において、式(I)、(II)、(III)、(IV)、(V)、又は(VI)のCSE阻害剤は、抗炎症剤と組み合わせて、必要とする個体に投与される。そのような抗炎症剤の例は、限定されないが、鎮痛剤、非ステロイド系抗炎症薬(NSAID)、COX−2阻害剤などを含む。
また、本明細書には、本明細書に記載される治療のためのキットが提供される。幾つかの実施形態において、キットは、CSE阻害剤及び第2処置レジメンを含む。このようなキットは、本明細書に開示されるような1以上の活性薬剤、及びキットを使用するための指示書を含む。
幾つかの実施形態において、CSE阻害剤は、インビトロ(in vitro)のアッセイの使用により識別される。一例として、CSE酵素活性のためのインビトロのアッセイは、Zhong et al. Chinese Medical Journal, 2009, 122, 326−330に記載される。幾つかの実施形態において、インビトロの酵素アッセイは、任意の適切な方法を使用する、ハイスループットスクリーニング(HTS)に適している。
(a)試験化合物を投与した試験動物から臓器又は組織のホモジネートを調製する工程;及び
(b)吸収に基づいてH2S濃度を計算する工程、を含み;
ここで、H2S濃度の減少は、試験化合物がCSE阻害剤であることを示す。前述のアッセイの幾つかの実施形態において、試験動物は、ノルモキシア、急性低酸素状態、慢性の断続的な低酸素症、高炭酸ガス血症、又はそれらの組み合わせにさらされる。任意の中間の工程は:
L−システインに対する酵素反応を達成する工程;
酢酸亜鉛とトリクロロ酢酸との酵素反応をクエンチする工程;
硫化亜鉛を、酸性のN,N−ジメチル−p−フェニルエンジアミンスルファート及び塩化第二鉄と反応させる工程;及び
マイクロプレートリーダーによりアッセイ混合物の吸収を測定する工程を含む。
(a)試験化合物を投与した試験動物から臓器又は組織を分離する工程;
(b)酸素及び/又は二酸化炭素の変動するレベルで記録チャンバを潅流することにより、記録チャンバにおいて臓器又は組織を負荷する工程;及び
(c)作用電位を記録する工程、を含み;
ここで、作用電位の減少は、試験化合物がCSE阻害剤であることを示す。前述のアッセイの幾つかの実施形態において、試験動物は、ノルモキシア、急性低酸素状態、慢性の断続的な低酸素症、高炭酸ガス血症、又はそれらの組み合わせにさらされる。任意の中間の工程は:
暖かい生理的食塩水で灌流した記録チャンバに、臓器又は組織を入れる工程を含む。
2−プロパノール(5mL)中の5−ブロモ−1−(4−メトキシベンジル)−1H−テトラゾール(1)(500mg、1.85mmol)と(3−ヒドラジノプロピル)ジメチルアミン(436mg、3.72mmol)の混合物を18時間、80℃で撹拌した。反応混合物を蒸発させ、残基を、ジクロロメタン(20mL)とブライン(10mL)の混合物中に溶解した。層を分離し、水層をジクロロメタン(20mL)で抽出した。組み合わせた有機質層を、水(10ml)で洗浄し、硫酸ナトリウムで乾燥し、濾過し、蒸発させた。未精製の生成物を、ジクロロメタン:メタノール:トリエチルアミン(100:5:0.5)で溶出するカラムクロマトグラフィにより精製し、オレンジ色油として3−(1−(1−(4−メトキシベンジル)−1H−テトラゾール−5−イル)ヒドラジニル)−N,N−ジメチルプロパン−1−アミン(2)(320mg、1.05mmol、57%)を得た。ESMS m/z 306(M+H)+。
(3−{N−[1−(4−メトキシベンジル)−1H−テトラゾール−5−イル]ヒドラジノ}プロピル)ジメチルアミン(120mg、0.39mmol)と6M塩酸(1.2mL)の混合物を1.5時間、120℃で、マイクロ波照射下で加熱した。反応混合物を蒸発させ、未精製の生成物をジクロロメタン:メタノール:アンモニア(4:1:0.2→1:1:0.5)で溶出するカラムクロマトグラフィにより精製した。生成物をメタノールで粉末化し、白色結晶固形物として3−(1−(1H−テトラゾール−5−イル)ヒドラジニル)−N,N−ジメチルプロパン−1−アミン(3)(10mg、0.05mmol、13%)を得た。ESMS m/z 186(M+H)+;1H NMR(400MHz, D2O)δ 3.55(t,J=6.5Hz, 2H), 3.16−3.27(m, 2H), 2.90(s, 6H), 2.03−2.13(m, 2H)。
ジクロロメタン(16.5mL)中の臭化シアノジェン(0.37g、3.49mmol)の溶液に、0℃で、水(10mL)中のprop−2−イニルヒドラジン二塩化水素化物(5)(0.50g、3.49mmol)及び炭酸カリウム(0.97g、6.99mmol)の混合物を加えた。反応混合物を1時間、0℃で撹拌した。層を分離し、水層をジクロロメタン(2×30mL)で抽出した。組み合わせた有機質層を硫酸マグネシウムで乾燥し、濾過し、蒸発させた。残基を、ジクロロメタン:メタノール(100:1)で溶出するカラムクロマトグラフィにより精製し、浅黄色油として1−(prop−2−イニル)ヒドラジンカルボニトリル(6)(120mg、1.26mmol、36%)を得た。ESMS m/z 96(M+H)+;1H NMR(500MHz, CDCl3) δ 4.25(br. s, 2H), 3.97(d, J=2.4Hz, 2H), 2.53(t, J=2.4Hz, 1H)。
N,N−ジメチルホルムアミド(2mL)中の1−(prop−2−イニル)ヒドラジンカルボニトリル(6)(145mg、1.52mmol)、ナトリウムアジド(119mg、1.83mmol)、及び塩化アンモニウム(98mg、1.83mmol)の混合物を1時間、90℃で撹拌した。結果として生じる混合物を濾過し、蒸発させた。残基を、ジクロロメタン:メタノール:アンモニウムヒドロキシド(4:1:0.2)により溶出するカラムクロマトグラフィにより精製し、浅黄色ガムとして表題化合物(120mg、0.87mmol、57%)を得た。ESMS m/z 139(M+H)+;1H NMR(500MHz, DMSO−d6, 塩) δ 4.13(d, J=2.0Hz, 2H), 3.05(br. s, 1H)。
以下の化合物を、工程1の適切に官能化したヒドラジンを使用して、実施例3の方法により調製した。
無水クロロホルム(30mL)中の塩化チオニル(8.68g、1.32mmol)の溶液に、3−アミノプロパン−1−ol(4.49g、59.19mmol)を滴下で加え、その間、温度を0−10℃で維持した。混合物を室温にまで温め、その後3時間、還流で加熱した。混合物を室温にまで冷却し、沈殿物を集め、緑色固形物として3−クロロプロピルアミン塩酸塩(8)(7.07g、55.15mmol、93%)を得た。ESMS m/z 94(M+H)+。
ジクロロメタン中の3−クロロプロピルアミン塩酸塩(8)(5.00g、38.46mmol)及びトリエチルアミン(4.11g、40.58mmol)の混合物を30分間、室温で撹拌した。混合物を0℃に冷却し、ジクロロメタン(30mL)中のジ−tert−ブチル重炭酸塩(8.86g、40.58mmol)の溶液を加えた。混合物を2時間、暗所の中、室温で撹拌した。反応混合物を、10%の水性の硫酸水素カリウム(40mL)及び水(40mL)で洗浄した。有機質層を硫酸ナトリウムで乾燥し、濾過し、蒸発させ、淡褐色油としてtert−ブチル3−クロロプロピルカルバマート(9)(7.89g、40.77mmol、定量)を得た。未精製の材料を、更に精製することなく次の工程で使用した。ESMS m/z 138(M+H−t−Bu)+。
エタノール(14.5mL)中のヒドラジン水和物(6.40g、128.00mmol)の還流溶液に、エタノール(14.5mL)中のtert−ブチル3−クロロプロピルカルバマート(9)(3.80g、19.62mmol)の溶液を、80分にわたり滴下で加えた。混合物を1時間、還流で撹拌した。その後、反応混合物を蒸発させ、残基をジエチルエーテル(60mL)で希釈した。2つの層を分離した。有機質層を、飽和炭酸ナトリウム溶液(17mL)で洗浄し、蒸発させ、黄色油としてtert−ブチル3−ヒドラジニルプロピルカルバマート(10)(1.60g、8.45mmol、43%)を得た。未精製の材料を、更に精製することなく次の工程で使用した。ESMS m/z 190(M+H)+。
ジクロロメタン(50mL)中の臭化シアノジェン(1.68g、15.8mmol)の溶液を、0℃で、水(16mL)中のtert−ブチル3−ヒドラジニルプロピルカルバマート(10)(3.00g、15.85mmol)と水(16mL)中の炭酸ナトリウム(837mg、7.90mmol)の溶液との混合物と同時に加えた。反応混合物を1時間、0℃で撹拌した。その後、2つの層を分離した。有機質層を硫酸ナトリウムで乾燥し、濾過し、蒸発させ、その間温度を10℃未満に維持して、黄色油としてtert−ブチル3−(1−シアノヒドラジニル)プロピルカルバマート(11)(2.12g、9.89mmol、63%)を得た。ESMS m/z 159(M+H−t−Bu)+。
無水N,N−ジメチルホルムアミド(20mL)中のtert−ブチル3−(1−シアノヒドラジニル)プロピルカルバマート(11)(2.12g、9.89mmol)、ナトリウムアジド(780mg、12.00mmol)、及び塩化アンモニウム(642mg、12.00mmol)の混合物を18時間、40℃で撹拌した。反応混合物を濾過し、蒸発させた。残基を、クロロホルム:メタノール(95:5)で溶出するカラムクロマトグラフィにより精製し、黄色油としてtert−3−(1−(1H−テトラゾール−5−イル)ヒドラジニル)プロピルカルバマート(12)(1.08、4.20mmol、42%)を得た。ESMS m/z 258(M+H)+。
tert−ブチル3−(1−(1H−テトラゾール−5−イル)ヒドラジニル)プロピルカルバマート(12)(134mg、0.52mmol)に、メタノール(1.5mL)中の塩化水素の4.0M溶液を加え、混合物を2時間、室温で撹拌した。沈殿物を集め、メタノール(2×0.5mL)で洗浄し、白色固形物として3−(1−(1H−テトラゾール−5−イル)ヒドラジニル)プロパノ−1−アミン二塩化水素化物(13)(59mg、0.26mmol、51%)を得た。ESMS m/z 158(M+H)+;1H NMR(500MHz, D2O) δ 3.73(t, J=5.0Hz, 2H), 3.13(m, 2H), 2.14(m, 2H)。
以下の化合物を、工程1の適切に官能化したアミンを使用して、実施例12の方法により調製した。
2−プロパノール(25mL)中の5−ブロモ−1−(4−メトキシベンジル)−1H−テトラゾール(1)(3.10g、11.43mmol)とヒドラジン水和物(2.21mL、45.67mmol)の混合物を16時間、60℃で撹拌した。2−プロパノールを蒸発させ、残基を水(20mL)で粉末化し、オフホワイト結晶固形物として5−ヒドラジニル−1−(4−メトキシベンジル)−1H−テトラゾール(15)(2.04g、9.17mmol、80%)を得た。ESMS m/z 221(M+H)+。
ジエチルエーテル中の[1−(4−メトキシベンジル)−1H−テトラゾール−5−イル]ヒドラジン(15)(1.80g、8.17mmol)、アセトン(18mL)、及び3滴の4M塩酸の混合物を16時間、室温で撹拌した。沈殿物を集め、オフホワイト結晶固形物として1−(4−メトキシベンジル)−5−(2−(プロパノ−2−イリデン)ヒドラジニル)−1H−テトラゾール(16)(1.91g、7.33mmol、90%)を得た。ESMS m/z 261(M+H)+。
1−(4−メトキシベンジル)−5−(2−(プロパノ−2−イリデン)ヒドラジニル)−1H−テトラゾール(16)(0.50g、1.92mmol)、水素化ナトリウム(0.12g、3.00mmol、60%分散)、及び無水テトラヒドロフラン(5mL)の混合物を0.5時間、0℃で撹拌した。4−ブロモブチロニトリル(285μL、2.87mmol)を0℃で、撹拌した混合物に加え、反応混合物を室温に暖め、18時間撹拌した。水素化ナトリウム(76mg、1.90mmol、60%)及び4−ブロモブチロニトリル(190μL、1.90mmol)の追加部分を室温で加え、反応混合物を24時間撹拌し、蒸発させた。残基を水(15mL)中で溶解し、ジクロロメタン(3×15mL)で抽出した。組み合わせた有機質層を硫酸ナトリウムで乾燥し、濾過し、蒸発させた。未精製の生成物を、n−ヘキサン:酢酸エチル(2:3v/v)で溶出するカラムクロマトグラフィにより精製し、黄色油として4−(1−(1−(4−メトキシベンジル)−1H−テトラゾール−5−イル)−2−(プロパノ−2−イリデン)ヒドラジニル)ブタンニトリル(17)(492mg、1.50mmol、78%)を得た。ESMS m/z 328(M+H)+。
無水N,N−ジメチルホルムアミド(10mL)中の4−(1−(1−(4−メトキシベンジル)−1H−テトラゾール−5−イル)−2−(プロパノ−2−イリデン)ヒドラジニル)ブタンニトリル(17)(490mg、1.50mmol)、ナトリウムアジド(117mg、1.80mmol)、及び塩化アンモニウム(96mg、1.80mmol)の混合物を18時間、90℃で撹拌した。更にナトリウムアジド(78mg、1.20mmol)及び塩化アンモニウム(64mg、1.20mmol)を混合物に加え、撹拌を更に18時間、90℃で続けた。ナトリウムアジド(2×78mg、1.20mmol)及び塩化アンモニウム(2×64mg、1.20mmol)の追加部分を、24時間の間隔で混合物に加え、反応物を90℃で撹拌した。合計3日後に、混合物を蒸発させ、残基を2−プロパノール(20mL)中で懸濁し、濾過した。濾液を蒸発させ、黄色油として5−(1−(3−(1H−テトラゾール−5−イル)プロピル)ヒドラジニル)−1−(4−メトキシベンジル)−1H−テトラゾール(18)(320mg、0.97mmol、65%)を得た。(M+H)+331。未精製の生成物を、精製することなく次の工程で使用した。
水中の5−(1−(3−(1H−テトラゾール−5−イル)プロピル)ヒドラジニル)−1−(4−メトキシベンジル)−1H−テトラゾール(18)(320mg、0.97mmol)と6M塩酸の混合物を、マイクロ波加熱下で3時間、100℃で撹拌した。混合物を蒸発させ、ジクロロメタン:メタノール:アンモニア(4:1:0.2→3:2:0.5)で溶出するカラムクロマトグラフィにより精製した。生成物をエタノールから再結晶化し、オフホワイト結晶固形物として5−(3−(1−(1H−テトラゾール−5−イル)ヒドラジニル)プロピル)−1H−テトラゾール(19)(15mg、0.07mmol、7%)を得た。ESMS m/z 211(M+H)+;1H NMR(400MHz, MeOH−d4) δ 3.66(t, J=6.9Hz, 2H), 3.03(t, J=7.4Hz, 2H), 2.23(quint, J=7.2Hz, 2H)。
以下の化合物を、適切に機能化したアルデヒド又はケトンを使用して、実施例17の方法により調製した。
無水テトラヒドロフラン(10mL)中の4−ジメチルアミノアセトフェノン(1.00g、6.13mmol)及びギ酸エチル(580μL、7.16mmol)の混合物に、メタノール(1.70mL、7.18mmol)中の25%ナトリウムメトキシドを、0−5℃で加えた。反応混合物をこの温度で1時間撹拌し、その後室温で18時間撹拌した。沈殿物を集め、ジエチルエーテル(10mL)で洗浄し、浅黄色結晶固形物として3−(4−(ジメチルアミノ)フェニル)−3−オキソプロパナール(22)(0.53g、2.48mmol、40%)を得た。ESMS m/z 192(M+H)+。
3−(4−(ジメチルアミノ)フェニル)−3−オキソプロパナール(22)(50mg、0.23mmol)及びエタノール(3mL)の混合物に、0℃で(1H−テトラゾール−5−イル)ヒドラジン塩酸塩(37mg、0.27mmol)を加えた。反応混合物を10分間、この温度で撹拌した。沈殿物を集め、エタノール(1ml)で洗浄し、浅黄色結晶固形物として(E)−3−(2−(1H−テトラゾール−5−イル)ヒドラゾノ)−1−(4−(ジメチルアミノ)フェニル)プロパノ−1−オン(23)(31mg、0.11mmol、48%、4:1 E:Z)を得た。ESMS m/z 274(M+H)+;1H NMR(500MHz, DMSO−d6) δ 11.41(s, 0.8H), 10.93(s, 0.2H), 7.80−7.89(m, 2H), 7.56(t, J=5.6Hz, 0.8H), 7.09(t, J=5.1Hz, 0.2H), 6.71−6.78(m, 2H), 4.10(d, J=5.4Hz, 0.4H), 3.93(d, J=5.9Hz, 1.6H), 3.04(s, 1.2H), 3.03(s, 4.8H)。
2−プロパノール(5.3mL)中の5−ブロモ−1−(4−メトキシベンジル)−1H−テトラゾール(1)(600mg、2.23mmol)とメチルヒドラジン(235μL、4.46mmol)の混合物を20時間、60℃で撹拌した。反応混合物を蒸発させ、残基を2−プロパノールから再結晶化し、オフホワイト結晶固形物として1−(4−メトキシベンジル)−5−(1−メチルヒドラジニル)−1H−テトラゾール(24)(54mg、0.23mmol、10%)を得た。ESMS m/z 235(M+H)+。
メタノール(4mL)中の1−(4−メトキシベンジル)−5−(1−メチルヒドラジニル)−1H−テトラゾール(24)(391mg、1.67mmol)と10%パラジウム/炭素(195mg)の混合物を20時間、水素雰囲気下で撹拌した。反応混合物をセライトに通して濾過し、濾液を蒸発させた。未精製の生成物を2−プロパノール(3mL)から再結晶化し、オフホワイト結晶固形物として5−(1−メチルヒドラジニル)−1H−テトラゾール(25)(72mg、0.63mmol、38%)を得た。ESMS m/z 114(M+H)+;1H NMR(500MHz, DMSO−d6) δ 14.57(br. s, 1H), 4.94(br. s, 2H), 3.14(s, 3H)。
1,4−ジオキサン中の5−(1−メチルヒドラジニル)−1H−テトラゾール(25)(20mg、0.18mmol)、4−ジメチルアミノベンズアルデヒド(26mg、0.17mmol)、及び少量の3.8M塩化水素溶液の混合物を18時間、室温で1,4−ジオキサン(400μL)中で撹拌した。沈殿物を集め、白色結晶固形物として(E)−N,N−ジメチル−4−((2−メチル−2−(1H−テトラゾール−5−イル)ヒドラゾノ)メチル)アニリン(26)(17mg、0.07mmol、37%)を得た。ESMS m/z 246(M+H)+;1H NMR(500MHz, DMSO−d6) δ 7.84(s, 1H), 7.78(d, J=8.8Hz, 2H), 6.92(br. s, 2H), 3.54(s, 3H), 3.00(s, 6H)。
トルエン(15mL)中のtert−ブチルヒドラジンカルボキシラート30(2.0g、12.6mmol)の撹拌溶液に、アセトアルデヒド(0.7ml、13.9mmol)を加えた。溶液を1時間、50℃に加熱し、その後24時間、室温で撹拌した。混合物を濃縮し、無色の油として(E)−tert−ブチル2−エチリデンヒドラジンカルボキシラート(31)を得た(97.5%)。ESMS:159(M++1)。
−78℃のTHF(50mL)中の(E)−tert−ブチル2−エチリデンヒドラジンカルボキシラート(31)(6.6g、37.0mmol)の撹拌溶液に、トルエン中の1.5M溶液としてDIBAL(31ml、92.6mmol)を加えた。反応物を2時間、−78℃で維持し、その後2時間、−40℃で維持した。その後、ロシェル塩(水性の酒石酸ナトリウムカリウム)溶液を加え、及び反応混合物を室温で一晩撹拌する前に、混合物を室温にまで暖めた。有機質相を分離し、水相をEt2O(2×75mL)で抽出した。混合した有機抽出物をブラインで洗浄し、乾燥し(Na2SO4)、濾過し、真空下で濃縮した。シリカゲル上のフラッシュクロマトグラフィによる精製により、無色の油としてtert−ブチル2−エチルヒドラジンカルボキシラート(32)を得た(3.0g、49%)。ESMS:183(M++23)。
酢酸エチル(30mL)中のtert−ブチル2−エチルヒドラジンカルボキシラート(32)(5.8g、36.6mmol)の撹拌溶液にTMSSCN(4.8g、36.6mmol)を加え、反応混合物を5時間、還流で加熱した。反応の完了後、溶媒を減圧下で蒸発させ、48%の収率でtert−ブチル−2−カルバモチオイル−2−エチルヒドラジンカルボキシラート(33)を得た。1H NMR(400MHz, CD3OD) δ 1.2(t, 3H), 1.5(s, 9H), 4.1(br s, 2H), 6.2(br s, 2H), 6.4(br s, 1H)。
アセトニトリル(30mL)中のtert−ブチル2−カルバモチオイル−2−エチルヒドラジンカルボキシラート(33)(3g、13.2mmol)の撹拌溶液に、ヨウ化メチル(9.38g、66mmol)を加え、反応混合物を1時間、60℃で加熱した。反応の完了後、溶媒を減圧下で蒸発させ、未精製の残基をジエチルエーテルで洗浄し、乾燥して、94%の収率でtert−ブチル2−エチル−2−(イミノ(メチルチオ)メチル)ヒドラジンカルボキシラート(34)を得た。ESMS:234.1(M++1)。
ジメチルホルムアミド(10ml)中のtert−ブチル2−エチル−2−(イミノ(メチルチオ)メチル)ヒドラジンカルボキシラート(34)(500mg、2.14mmol)とホルミルヒドラジド(35)(155mg、2.57mmol)の撹拌溶液に、ジイソプロピルエチルアミン(830mg、6.43mmol)を加え、反応混合物を15時間、還流に加熱した。反応の完了後、水を反応混合物に加え、酢酸エチル(2×50ml)で抽出した。有機質層を分離し、硫酸ナトリウムで乾燥し、濾過し、減圧下で濃縮して、未精製の生成物を得た。未精製の生成物をシリカゲルカラムクロマトグラフィによって精製し、12%の収率でtert−ブチル2−エチル−2−(1H−1,2,4−トリアゾール−5−イル)ヒドラジンカルボキシラート(36)を得た。1H NMR(400MHz, CD3OD) δ 1.2(t, 3H), 1.5(s, 9H), 3.6(br s, 2H), 7.7(br s, 1H)。
MeOH・HCl(5ml)の撹拌溶液に、tert−ブチル2−エチル−2−(1H−1,2,4−トリアゾール−5−イル)ヒドラジンカルボキシラート(36)(40mg、0.17mmol)を加え、結果として生じる混合物を12時間、室温で撹拌した。反応の完了後、溶媒を減圧下で除去し、エーテルで2回洗浄し、減圧下で乾燥して、75%の収率で5−(1−エチルヒドラジニル)−1H−1,2,4−トリアゾール塩酸塩(37)を得た。1H NMR(400MHz, CD3OD) δ 1.2(t, 3H), 3.6(q, 2H), 8.5(s, 1H), 10.2−10.4(brs, 2H)。HPLC純度:90.89%;ESMS:127.85(M+)。
MeOH(200mL)及びAcOH(200mL)中のベンゾフェノン(18g、100mmol)の溶液に、メチルヒドラジン(12mL、100mmol)を20℃で加えた。3時間70℃での撹拌後、混合物を濃縮し、酢酸エチル(10mL)及び水(15mL)で希釈した。有機質層を分離した。水層を、酢酸エチル(10ml×2)で洗浄した。組み合わせた有機質層をブラインで洗浄し、Na2SO4で乾燥し、濾過し、減圧下で濃縮し、白色油(10.5g)として38を得た。LCMS(ESI):m/z 211.1(M+1)+。
DMF(100mL)中の38(10.5g、50mmol)及びBrCN(5.3g、50mmol)の混合物を50℃に加熱し、その後、K2CO3を加え、50℃で一晩撹拌した。EtOAc(250mL)を加え、溶液をブライン(250mL×3)で洗浄し、Na2SO4で乾燥し、濾過し、減圧下で濃縮し、フラッシュカラムクロマトグラフィ(PE/酢酸エチル=20:1)によって精製される残基を得て、白色固形物として39(5g)を得た。1H NMR(CDCl3):δ3.39(s, 3 H), 7.35−7.40(m, 4H), 7.45−7.49(m, 1H), 7.52−7.55(m, 5H)。LCMS (ESI):m/z 236(M+1)+。
EtOH(80mL)中の39(5.5g、20mmol)、ヒドロキシルアミン塩酸塩(2.2g、30mmol)、及びAcONa(3.2g、40mmol)の混合物を、25℃で一晩撹拌した。溶媒を減圧下で除去し、EtOAc(100mL)を加え、水及びブライン(100mL)で洗浄し、Na2SO4で乾燥し、減圧下で濃縮して、黄色固形物として40(5.5g)を得た。LCMS(ESI):m/z 269.1(M+1)+。
THF(60mL)中の40(5.5g、20mmol)及びCDI(5g、30mmol)の混合物を5時間、還流で撹拌した。混合物を冷却し、減圧下で濃縮し、フラッシュカラムクロマトグラフィ(PE/酢酸エチル=3:1)で精製して、黄色固形物として41(4g)を得た。LCMS (ESI):m/z 295.1 (M+1)+。
酢酸エチル(10mL)中の41(0.9g、9mmol)の溶液に、酢酸エチル(15mL)中の4M HClを加え、混合物を室温で一晩撹拌した。その後、混合物を濾過し、固形物を酢酸エチルとMeOHで洗浄し、白色固形物として3−(1−メチルヒドラジニル)−1,2,4−オキサジアゾール−5(4H)−オンHCl塩(42)(0.25g、1.5mmol)を得た。1H NMR(400 MHz, DMSO−d6):δ3.07(s,3H)。LCMS (ESI):m/z 131.1(M+1)+。
EtOH(10mL)中の43(500mg、3.5mmol)の溶液に、KOH(591mg、0.1M)を加えた。混合物を室温で3分間撹拌し、濾過した。固形物を冷たいEtOHで洗浄し、その後真空下で乾燥し、白色固形物として44(500mg)を得た。化合物を、更に精製することなく次の工程で使用した。
ジクロロメタン(20mL)中の44(500mg、3.3mmol)及びtert−ブチル2−エチルヒドラジンカルボキシラート(631mg、3.9mmol)の混合物に、HOBT(533mg、3.9mmol)及びEDCI(863mg、4.9mmol)を加えた。混合物を14時間、室温で撹拌し、水で洗浄し、その後、有機質層を濃縮した。残基をHPLCによって精製し、油として45(220mg)を得た。1H NMR(CDCl3):δ 1.32(t, J=7.2Hz, 3H), 1.42(s, 9H), 3.84(q, J=7.2Hz, 2H), 7.56(br.s, 1H)。
4M HCl/酢酸エチル(15mL)中の45(220mg)の混合物を0.5時間、室温で撹拌した。溶液を濃縮し、固形物を酢酸エチルで洗浄し、濾過し、白色固形物としてN−エチル−1H−テトラゾール−5−カルボヒドラジド(46)(150mg)を得た。1H NMR(400MHz, DMSO−d6):δ 1.15−1.33(m, 3H), 3.63(m, 1H), 4.04(br. s., 1H)。LCMS(ESI):m/z 157.1[M+1]+。
THF(20mL)中の2H−テトラゾール−5−アミン(100mg、1.18mmol)及び4−ニトロフェニルカルボノクロリデート(carbonochloridate)(718.6mg、3.54mmol)の混合物を、還流に加熱し、3時間撹拌した。溶媒を蒸発させ、残基をシリカゲルカラム(酢酸エチル/PE=1:10)上で精製し、白色固形物として47(330mg)を得た。
トルエン(20mL)中の47(310mg、1.24mmol)及びtert−ブチル2−エチルヒドラジンカルボキシラート(294.1mg、1.86mmol)の混合物を加熱し、3時間還流した。反応溶液を室温に冷却し、水で洗浄し、濃縮した。残基を分取HPLCによって精製し、油として48(193mg)を得た。
4M HCl−酢酸エチル(15mL)中の48(193mg)を30分間、室温で撹拌した。溶媒を除去した。残基を酢酸エチルで洗浄し、濾過して、白色固形物として化合物1−エチル−N−(1H−テトラゾール−5−イル)ヒドラジンカルボキサミド(49)(100mg)を得た。1H NMR(400MHz, D2O):δ 1.07(t, J=7.2Hz, 3H), 3.47(q, J=7.2Hz, 2H)。LCMS(ESI):m/z 172.1[M+1]+。
30mLのCHCl3中のベンジルヒドラジンカルボキシラート(5g、30.08mmol)、MgSO4(5g)の混合物を、0℃で無水CH3CHO(2g、45.13mmol)に加えた。混合物を2時間、室温で撹拌し、その後濾過し、濃縮して、黄色固形物として50(5.9g)を得て、それを更に精製することなく次の工程に使用した。
30mLのTHF中のLiAlH4(1.37g、36mmol)の混合物を、窒素雰囲気下で、0℃で40mLのTHF中の50(5.9g、前の工程からの未精製の生成物)に加え、0℃で1時間撹拌し、その後、室温で1時間撹拌した。その後、水(1.37mL)を滴下で加え、その後10%水性NaOH(1.37mL)を加えた。混合物を濾過し、濃縮し、(酢酸エチル中の5%−50%のPEで溶出する)シリカゲル上のフラッシュクロマトグラフィによって精製し、白色固形物として51(3.5g)を得た。1H NMR(CDCl3):δ 1.08(t, J=7.2Hz, 3H), 2.84−2.98(m, 2H), 3.63(s, 1H), 5.15(s, 2H), 6.60(br. s, 1H), 7.30−7.44(m, 5H)。
51(1.0g、6.36mmol)、50mLのアセトン中のK2CO3(2.2g、15.92mmol)、及び5mLのアセトン中のエチルクロロホルメート(4.04g、37.2mmol)の混合物を1時間、還流で撹拌した。溶媒を蒸発させ、残基を水中で溶解し、濃縮したHCl(pH=1)で酸性化し、酢酸エチルで2回抽出した。組み合わせた有機質層を水で2回洗浄し、濃縮し、無色の油として52(1.1g)を得た。1H NMR(CDCl3):δ 1.23(t, J=7.2Hz, 3H), 4.13−4.20(m, 2H), 7.56−7.62(m, 2H), 7.64−7.71(m, 1H), 7.86(s, 1H), 8.06−8.09(m, 2H)。
20mLのトルエン中の52(704mg、3.07mmol)及び51(1.2g、6.14mmol)の混合物を、還流で一晩撹拌した。混合物を冷却し、濃縮し、(酢酸エチル中の5%−20%のPEで溶出する)フラッシュカラムクロマトグラフィによって精製し、白色固形物として53(569mg)を得た。1H NMR(CDCl3):δ 1.07(t, J=7.2Hz, 3H), 3.60(br. s, 2H), 5.18(s, 2H), 6.92(s, 1H), 7.28−7.48(m, 5H), 7.49−7.53(m, 2H), 7.61−7.65(m, 1H), 8.04(d, J=7.6Hz, 2H), 8.64(br.s, 1H)。
40mLのMeOH中の53(400mg、1.06mmol)及びPd/C(0.2g)の混合物を、水素雰囲気下で(バルーン)、2時間、室温で撹拌した。混合物を濾過し、濃縮し、固形物を酢酸エチル/PE(1:1)で洗浄し、白色固形物として1−エチル−N−(フェニルスルホニル)ヒドラジンカルボキサミド(54)(100mg)を得た。1H NMR(400MHz, DMSO−d6):δ 0.99(t, J=7.2Hz, 3H), 3.25−3.35(m, 3H), 6.70(br.s, 2H), 7.53−7.70(m, 3H), 7.90−7.95(d, J=7.2Hz, 2H)。LCMS(ESI):m/z 244.0[M+1]+。
H2Sレベルの測定。肝臓のH2Sレベルを以下のようにアッセイした。簡潔に、肝臓組織ホモジネートを、100mMリン酸カリウムバッファー、pH7.4+0.5% Triron−X100の中で調製した。酵素反応を、TFE/Silicone MicroMat密封カバー(Sun−SRI Cat. #400 026)を備えた700μlのガラスインサート(Waters Corporation Cat. #186000349)を伴う、96ウェルの深型正方形ウェルプレート中で実行した。200μlの全容積の外部のウェルにおいて、アッセイ混合物は、(終末濃度で):Lシステイン(5mM);ピリドキサール’5−リン酸塩(50μM);リン酸カリウムバッファー、pH7.4(100mM);及び組織ホモジネート(500μgのタンパク質)を含んだ。ガラスインサートは、生成されたH2Sを捕捉するために100μlのアルカリ亜鉛酢酸塩溶液(0.1N NaOH中で1%)を含んだ。反応混合物を3時間、37℃でインキュベートし、反応の終わりに、100μlのN,N−ジメチル−p−パラフェニレンジアミン硫酸塩(7N HCl中で20μM)及び100μlの塩化第二鉄(1.2N HCl中で30μM)を、ガラスインサートに加えた。マイクロプレートリーダーを使用し、671nmで吸収を測定した。Na2Sの濃度と吸収を関連づける標準曲線を使用し、H2S濃度を計算して、ナノモルのH2Sがタンパク質1ミリグラムにつき1時間ごとに形成されることを表わした。
(DMSO保存溶液からの)試験化合物を、全容積が190μlの96ウェルプレートにおいて、アッセイバッファー(100mMのリン酸カリウム、pH7.6)中の50μMのPLPを加えた(終末濃度の)20μg/mlの酵素溶液(ヒト、マウス、又はラットの組み換え型CSE)に加えた。10μlの200mM(アッセイバッファーにおいて20X最終)DL−ホモシステイン基質を各ウェルに加える前に、プレートを30分間、室温でインキュベートした。プレートを3時間、37℃でインキュベートした。7.2N HCl中の50μlの20mM DMPDAを各ウェルに加え、その後、1.2N HCl中の50μlの30mM FeCl3を加えた。室温で振り混ぜることでプレートを10分間インキュベートし、その後、Promega GloMaxマイクロプレートリーダーにおいて671nmでの吸収を読み取った。
術後痛を持つラットの抗痛覚過敏活性を検知する方法は、Brennan et al (Pain, 64, 493−501, 1996)に記載されるものに従う。
熱刺激のために、装置(Ugo Basile, Reference: 7371)を、高いガラス床に置かれた個々のアクリル酸プラスチック箱(18×11.5×14cm)で構成した。ラットを箱に入れ、10分間、慣らすために自由にした。携帯式の赤外線放射ソース(96±10mW/cm2)を、切開していない後足に、その後切開した後足に集中させ、足の離脱(paw−withdrawal)の潜在期を自動的に記録した。組織損傷を予防するために、45秒後に熱源を自動的に切った。
デバイスは、修正済の電子動力計に接続された2つの歪みゲージを備えた、1対の大きな鈍い鉗子(large blunt forcep)(長さ15cm;水平な接触域:平滑縁7mm×1.5mm)から成る。鉗子の先端を、試験動物の後足周辺に置き、加えられる力は、足離脱反応まで手によって増加される。傷害のある足に加えられる最大の力を、動力計によって自動的に記録し、表示した。組織損傷を予防するために、加えられた力を最大1kgに制限した。この手順を3回行い、足ごとの平均の力を計算した。
神経障害性疼痛を持つラットの抗痛覚過敏活性を検知する方法は、Bennett and Xie (Pain, 33, 87−107, 1988)に記載されるものに従う。
触覚刺激のために、動物を、グリッド床上の逆アクリル酸プラスチック箱(inverted acrylic plastic box)(18×11.5×14cm)の下に置いた。その後、電子的なフォンフレイプローブの先端を、傷害のある足(予備試験のための2つの後足)への力を増加させることにより加え、足の離脱を誘発するのに必要な力を自動的に記録した。この手順を3回行い、足ごとの平均の力を計算した(図1)。
熱刺激のために、装置は、高いガラス床に置かれた個々のアクリル酸プラスチック箱(18×11.5×14cm)から成る。ラットを箱に入れ、10分間、慣らすために自由にした。その後、携帯型の赤外線放射ソースを、傷害のある後足に集中させ、足の離脱の潜在期を自動的に記録した。組織損傷を予防するために、45秒後に熱源を自動的に切った(図2)。
デバイスは、修正済の電子動力計に接続された2つの歪みゲージを備えた、1対の大きな鈍い鉗子(長さ15cm;水平な接触域:平滑縁7mm×1.5mm)から成る。鉗子の先端を、試験動物の後足周辺に置き、加えられる力は、足離脱反応まで手によって増加される。傷害のある足に加えられる最大の力を、動力計によって自動的に記録し、表示した。組織損傷を予防するために、加えられた力を最大1kgに制限した。この手順を3回行い、足ごとの平均の力を計算した(図3)。
神経障害性疼痛を持つラットの抗痛覚過敏活性を検知する方法は、Bennett and Xie (Pain, 33, 87−107, 1988)に記載されるものに従う。
触覚刺激のために、動物を、グリッド床上の逆アクリル酸プラスチック箱(18×11.5×14cm)の下に置いた。その後、電子的なフォンフレイプローブの先端を、傷害のある足への力を増加させることにより加え、足の離脱を誘発するのに必要な力を自動的に記録した。この手順を5回行い、足ごとの平均の力を計算した(図6)。
急性炎性に苦しむラットの鎮痛性/抗炎症性活性を検知する方法は、Butler et al (Pain, 48, 73−81, 1992)に記載されるものに従う。
触覚刺激のために、動物を、グリッド床上の逆アクリル酸プラスチック箱(18×11.5×14cm)の下に置いた。その後、電子的なフォンフレイプローブの先端を、傷害のある足(予備試験のための2つの後足)への力を増加させることにより加え、足の離脱を誘発するのに必要な力を自動的に記録した。この手順を3回行い、足ごとの平均の力を計算した(図4)。
熱刺激のために、装置は、高いガラス床に置かれた個々のアクリル酸プラスチック箱(18×11.5×14cm)から成る。ラットを箱に入れ、10分間、慣らすために自由にした。その後、携帯型の赤外線放射ソースを、最初に炎症のない後足に、次に炎症のある後足に集中させ、足の離脱の潜在期を自動的に記録した。組織損傷を予防するために、45秒後に熱源を自動的に切った(図5)。
急性炎性に苦しむラットの鎮痛性/抗炎症性活性を検知する方法は、Butler et al (Pain, 48, 73−81, 1992)に記載されるものに従う。
触覚刺激のために、動物を、グリッド床上の逆アクリル酸プラスチック箱(18×11.5×14cm)の下に置いた。その後、電子的なフォンフレイプローブの先端を、傷害のある足(予備試験のための2つの後足)への力を増加させることにより加え、足の離脱を誘発するのに必要な力を自動的に記録した。この手順を3回行い、足ごとの平均の力を計算した(図7)。
骨関節炎の誘発後のラットの鎮痛性/抗炎症性活性を検知する方法は、Guingamp et al (Arthritis & Rheumatism, 40(9):1670−9, 1997)に記載されるものに従う。
触覚刺激のために、動物を、グリッド床上の逆アクリル酸プラスチック箱(18×11.5×14cm)の下に置いた。その後、電子的なフォンフレイプローブの先端を、傷害のない足及び傷害のある足への力を増加させることにより加え、足の離脱を誘発するのに必要な力を自動的に記録した。この手順を各足に3回行い、離脱を誘発する力の平均の差を計算した(図8)。
<標的結合(Target Engagement)>
インビボのCSE阻害を評価するために、オスのスピローグドーリーラット(およそ300グラム)に、0.1、0.3、1、3mg/kgの化合物A(化合物Aは5−(1−エチルヒドラジニル)−1H−テトラゾールである)又はビヒクル(水中で20% HPβCD)を経口投与した。投与の2時間後、動物にイソフルランで麻酔をかけ、およそ1グラムの肝臓組織を取り除き、素早く氷冷の生理食塩水ですすぎ、BioSpec Products Tissue−Tearorを使用して、0.5%のTriton X−100を加えた氷冷のアッセイバッファー(100mMのリン酸カリウム、pH7.6)の中で均質化した。サンプルを30分間、20,000XGで、4℃で遠心分離し、上清を集めた。標準としてBSAを使用する、Pierce BCAアッセイにより、タンパク質を決定した。
CSE阻害の効果のインビボの持続時間を評価するために、オスのスピローグドーリーラット(およそ300グラム)に、0.1、0.3、3mg/kgの化合物A(化合物Aは5−(1−エチルヒドラジニル)−1H−テトラゾールである)又はビヒクル(水中で20% HPβCD)を経口投与した。投与の2、24、48、72、又は96時間後、動物にイソフルランで麻酔をかけ、およそ1グラムの肝臓組織を取り除き、素早く氷冷の生理食塩水ですすぎ、BioSpec Products Tissue−Tearorを使用して、0.5%のTriton X−100を加えた氷冷のアッセイバッファー(100mMのリン酸カリウム、pH7.6)の中で均質化した。サンプルを30分間、20,000XGで、4℃で遠心分離し、上清を集めた。標準としてBSAを使用する、Pierce BCAアッセイにより、タンパク質を決定した。
この研究の目的は、帯状疱疹後神経痛及び外傷後の神経痛と診断された患者において、中度から重度の神経障害性疼痛の処置におけるCSE阻害剤の安全性及び効果を評価することである。
目的:糖尿病性神経障害性疼痛を持つ被験体における、プラセボと比較した、式(I)、(II)、(III)、(IV)、(V)、又は(VI)の化合物の効果及び安全性を評価すること。糖尿病を持つ人々は、手、腕、足、及び脚部における疼痛、刺痛、又はしびれ感(感覚の損失)などの症状を持つ身体の全体にわたって、神経損傷を経時的に進行し得る。
Claims (8)
- 以下の構造を有する式(IV)の化合物、その薬学的に許容可能な塩、又は溶媒和物であって:
式中、
Aは
であり;
R1は、置換又は非置換のC2−C6アルキルである、
化合物。 - R1は−CH2CH3である、ことを特徴とする請求項1に記載の化合物。
- 以下の構造を有する式(V)の化合物、その薬学的に許容可能な塩、又は溶媒和物であって:
式中、
Aは、
であり;
R1は、置換又は非置換のC3−C6アルキルである、
化合物。 - 医薬組成物であって、該医薬組成物は、薬学的に許容可能な賦形剤、請求項1乃至3の何れかに記載の化合物、その薬学的に許容可能な塩、又は薬学的に許容可能な溶媒和物を含む、医薬組成物。
- シスプラチン、アミノグリコシド、及び放射線学の造影剤を含む毒剤に付随して起こる急性腎臓損傷(AKI)、侵害受容性疼痛、急性の術後痛、神経障害性疼痛、三叉神経痛、糖尿病性末梢性ニューロパチー、疱疹性神経痛、帯状疱疹後神経痛、炎症性疼痛、混合神経障害性疼痛及び炎症性疼痛状態、関節リウマチ、炎症性大腸疾患、過敏性大腸症候群、変形性関節症、急性膵炎、慢性膵炎、急性膵炎に関連する疼痛、慢性膵炎に関連する疼痛、片頭痛、痛風、強直性脊椎炎、全身性エリトマトーデス(SLE)、システム炎症反応症候群(SIRS)、多臓器機能不全症候群(MODS)、喘息、慢性閉塞性肺疾患(COPD)、敏感肌、ざ瘡、酒さ、接触皮膚炎、或いは癌に関連する疼痛の発生を処置、予防、又は減少するための薬の製造における、請求項1乃至3の何れか1つに記載の化合物、薬学的に許容可能な塩、又は薬学的に許容可能な溶媒和物、もしくは請求項4に記載の医薬組成物の使用。
- 急性の術後痛、神経障害性疼痛、三叉神経痛、糖尿病性末梢性ニューロパチー、疱疹性神経痛、帯状疱疹後神経痛、炎症性疼痛、関節リウマチ、変形性関節症、又は片頭痛の発生を処置、予防、又は減少させるための、薬の製造における、請求項1乃至3の何れか1つに記載の化合物、薬学的に許容可能な塩、又は薬学的に許容可能な溶媒和物、もしくは請求項4に記載の医薬組成物の使用。
- 炭酸脱水酵素阻害剤、コリンエステラーゼ阻害剤、アデノシン阻害剤、プロゲステロン製剤、オピオイドアンタゴニスト、中枢神経興奮薬、選択的セロトニン再吸収阻害剤(SSRI)、二重5−HT−NE再摂取阻害剤(SNRI’s)、抗うつ薬、抗高血圧剤、カルシウムチャンネルアンタゴニスト、ACE阻害剤、呼吸興奮薬、アルファ−2アドレナリンアンタゴニスト、γ−アミノ酪酸アゴニスト、抗てんかん薬、NSAID、ステロイド、及びグルタミン酸アンタゴニストから選択される第2薬剤をさらに含む、請求項5または6に記載の医薬製剤の製造における請求項1乃至3に記載の化合物、薬学的に許容可能な塩、又は薬学的に許容可能な溶媒和物、もしくは請求項4に記載の医薬組成物の使用。
- アセタゾラミド、テオフィリン、プロゲステロン、ドネペジル、ナロキソン、ニコチン、パロキセチン、プロトリプチリン、メトプロロール、シラザプリル、プロプラノロール、アテノロール、ヒドロクロロチアジド、イスラジピン、スピラプリル、ドキサプラム、クロニジン、バクロフェン、サベルゾール、ガバペンチン、プレガバリン、及びデュロキセチンから選択された第2薬剤をさらに含む、請求項5または6に記載の医薬製剤の製造における請求項1乃至3に記載の化合物、薬学的に許容可能な塩、又は薬学的に許容可能な溶媒和物、もしくは請求項4に記載の医薬組成物の使用。
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RU2661879C2 (ru) | 2018-07-20 |
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CN104662007B (zh) | 2018-03-16 |
CA2879879A1 (en) | 2014-01-30 |
AR091857A1 (es) | 2015-03-04 |
TW201406711A (zh) | 2014-02-16 |
WO2014018570A1 (en) | 2014-01-30 |
US20170327478A1 (en) | 2017-11-16 |
HK1210614A1 (en) | 2016-04-29 |
EP2877457A4 (en) | 2016-04-20 |
TWI684583B (zh) | 2020-02-11 |
CA2879879C (en) | 2020-09-08 |
AU2018200632B2 (en) | 2019-10-24 |
JP2015524807A (ja) | 2015-08-27 |
EP2877457B1 (en) | 2020-09-23 |
AU2013293090A1 (en) | 2015-02-19 |
IN2015DN01161A (ja) | 2015-06-26 |
KR20150041635A (ko) | 2015-04-16 |
CN104662007A (zh) | 2015-05-27 |
AU2018200632A1 (en) | 2018-02-15 |
US20150266837A1 (en) | 2015-09-24 |
EP2877457A1 (en) | 2015-06-03 |
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