JP6521995B2 - 選択的マトリックスメタロプロテイナーゼ阻害剤 - Google Patents
選択的マトリックスメタロプロテイナーゼ阻害剤 Download PDFInfo
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- JP6521995B2 JP6521995B2 JP2016553463A JP2016553463A JP6521995B2 JP 6521995 B2 JP6521995 B2 JP 6521995B2 JP 2016553463 A JP2016553463 A JP 2016553463A JP 2016553463 A JP2016553463 A JP 2016553463A JP 6521995 B2 JP6521995 B2 JP 6521995B2
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- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- SEEPANYCNGTZFQ-UHFFFAOYSA-N sulfadiazine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)NC1=NC=CC=N1 SEEPANYCNGTZFQ-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-L sulfite Chemical class [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- KQKPFRSPSRPDEB-UHFFFAOYSA-N sumatriptan Chemical compound CNS(=O)(=O)CC1=CC=C2NC=C(CCN(C)C)C2=C1 KQKPFRSPSRPDEB-UHFFFAOYSA-N 0.000 description 1
- 229960003708 sumatriptan Drugs 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
- 230000035900 sweating Effects 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 230000001975 sympathomimetic effect Effects 0.000 description 1
- 229940064707 sympathomimetics Drugs 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- YLJREFDVOIBQDA-UHFFFAOYSA-N tacrine Chemical compound C1=CC=C2C(N)=C(CCCC3)C3=NC2=C1 YLJREFDVOIBQDA-UHFFFAOYSA-N 0.000 description 1
- 229960001685 tacrine Drugs 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 229960003080 taurine Drugs 0.000 description 1
- UMOZLQVSOVNSCA-UHFFFAOYSA-N tert-butyl n-(diaminomethylidene)carbamate Chemical compound CC(C)(C)OC(=O)NC(N)=N UMOZLQVSOVNSCA-UHFFFAOYSA-N 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 210000001103 thalamus Anatomy 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- 150000003557 thiazoles Chemical class 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 229960002663 thioctic acid Drugs 0.000 description 1
- 230000035922 thirst Effects 0.000 description 1
- 206010048627 thoracic outlet syndrome Diseases 0.000 description 1
- 208000016686 tic disease Diseases 0.000 description 1
- 230000036964 tight binding Effects 0.000 description 1
- 210000001578 tight junction Anatomy 0.000 description 1
- 229960004605 timolol Drugs 0.000 description 1
- 229960000454 timolol hemihydrate Drugs 0.000 description 1
- 238000003354 tissue distribution assay Methods 0.000 description 1
- 230000008467 tissue growth Effects 0.000 description 1
- 230000017423 tissue regeneration Effects 0.000 description 1
- 230000007838 tissue remodeling Effects 0.000 description 1
- 230000001256 tonic effect Effects 0.000 description 1
- 229940100615 topical ointment Drugs 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
- 230000007704 transition Effects 0.000 description 1
- 208000009174 transverse myelitis Diseases 0.000 description 1
- 230000008736 traumatic injury Effects 0.000 description 1
- PHLBKPHSAVXXEF-UHFFFAOYSA-N trazodone Chemical compound ClC1=CC=CC(N2CCN(CCCN3C(N4C=CC=CC4=N3)=O)CC2)=C1 PHLBKPHSAVXXEF-UHFFFAOYSA-N 0.000 description 1
- 229960003991 trazodone Drugs 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 125000001425 triazolyl group Chemical group 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
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 206010044652 trigeminal neuralgia Diseases 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- YDGHCKHAXOUQOS-BTJKTKAUSA-N trimipramine maleate Chemical compound [O-]C(=O)\C=C/C([O-])=O.C1CC2=CC=CC=C2[NH+](CC(C[NH+](C)C)C)C2=CC=CC=C21 YDGHCKHAXOUQOS-BTJKTKAUSA-N 0.000 description 1
- 229960002835 trimipramine maleate Drugs 0.000 description 1
- 208000006961 tropical spastic paraparesis Diseases 0.000 description 1
- 208000009999 tuberous sclerosis Diseases 0.000 description 1
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- 230000005751 tumor progression Effects 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 229950008081 unoprostone isopropyl Drugs 0.000 description 1
- 210000001364 upper extremity Anatomy 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 230000036325 urinary excretion Effects 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 229960005356 urokinase Drugs 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
- 238000010200 validation analysis Methods 0.000 description 1
- MSRILKIQRXUYCT-UHFFFAOYSA-M valproate semisodium Chemical compound [Na+].CCCC(C(O)=O)CCC.CCCC(C([O-])=O)CCC MSRILKIQRXUYCT-UHFFFAOYSA-M 0.000 description 1
- 229960000604 valproic acid Drugs 0.000 description 1
- 229910052720 vanadium Inorganic materials 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 210000005166 vasculature Anatomy 0.000 description 1
- 230000000304 vasodilatating effect Effects 0.000 description 1
- 229960003726 vasopressin Drugs 0.000 description 1
- 229960003895 verteporfin Drugs 0.000 description 1
- ZQFGRJWRSLZCSQ-ZSFNYQMMSA-N verteporfin Chemical compound C=1C([C@@]2([C@H](C(=O)OC)C(=CC=C22)C(=O)OC)C)=NC2=CC(C(=C2C=C)C)=NC2=CC(C(=C2CCC(O)=O)C)=NC2=CC2=NC=1C(C)=C2CCC(=O)OC ZQFGRJWRSLZCSQ-ZSFNYQMMSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
- 230000009278 visceral effect Effects 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 230000001755 vocal effect Effects 0.000 description 1
- 230000021542 voluntary musculoskeletal movement Effects 0.000 description 1
- 235000012431 wafers Nutrition 0.000 description 1
- 235000020234 walnut Nutrition 0.000 description 1
- 229960005080 warfarin Drugs 0.000 description 1
- PJVWKTKQMONHTI-UHFFFAOYSA-N warfarin Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-UHFFFAOYSA-N 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 208000016261 weight loss Diseases 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- 229940045860 white wax Drugs 0.000 description 1
- 239000009637 wintergreen oil Substances 0.000 description 1
- 208000015897 writing disease Diseases 0.000 description 1
- 229940071104 xylenesulfonate Drugs 0.000 description 1
- 229960000523 zalcitabine Drugs 0.000 description 1
- 229960001360 zolmitriptan Drugs 0.000 description 1
- ULSDMUVEXKOYBU-ZDUSSCGKSA-N zolmitriptan Chemical compound C1=C2C(CCN(C)C)=CNC2=CC=C1C[C@H]1COC(=O)N1 ULSDMUVEXKOYBU-ZDUSSCGKSA-N 0.000 description 1
Classifications
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4245—Oxadiazoles
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- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
したがって本発明は、式I:
[式中、
R1は、−CH2−NHRa(ここでRaは、H又は(C1〜C6)アルカノイルである)、−NH−C(=NH)−NH2又は
であり;
Jは、S又はOであり;
G、T及びQは、それぞれ独立して、H、(C1〜C6)アルキル又は−CNであり;
各R2は、独立して、H、OH、(C1〜C6)アルキル、(C1〜C6)アルコキシ、(C1〜C6)アルカノイル、(C1〜C6)アルカノイルオキシ、アリール、ヘテロアリール、カルボキシ、シアノ、ニトロ、ハロ、トリフルオロメチル、トリフルオロメトキシ、SRz、SO2N(Rz)2、NRzRz又はCOORzであり、ここで各Rzは、独立して、H、(C1〜C6)アルキル、(C1〜C6)アルカノイル、(C6〜C10)アロイル、アリール、アリール(C1〜C6)アルキル、ヘテロアリール、ヘテロアリール(C1〜C6)アルキルであるか又はRzが窒素原子に共有結合している場合、任意選択で窒素保護基であり;各nは、独立して、0、1、2、3又は4である]
の化合物、又はその塩を提供する。
である。
[式中、R1、R2、n及びJは、式Iに定義されたとおりである]
の化合物である。
又はその薬学的に許容される塩である。
又はその薬学的に許容される塩である。
又はその薬学的に許容される塩である。
以下の定義は、本明細書及び特許請求の範囲の明確で一貫した理解を提供するために含まれる。本明細書で使用されるとき、列挙された用語は、以下の意味を有する。本明細書で使用される他の全ての用語及び語句は、当業者が理解するような通常の意味を有する。そのような通常の意味は、Hawley’s Condensed Chemical Dictionary 14th Edition,by R.J.Lewis,John Wiley & Sons,New York,N.Y.,2001などの専門用語辞典を参照して得ることができる。
ここでシクロアルキル基は、任意の水素原子の位置に結合している。
ここで複素環基は、任意の水素原子の位置に結合している。
ここでヘテロアリールは、任意の水素原子の位置に結合している。
(C1〜C6)アルコキシは、メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、イソ−ブトキシ、sec−ブトキシ、ペントキシ、3−ペントキシ又はヘキシルオキシありうる;
(C2〜C6)アルケニルは、ビニル、アリル、1−プロペニル、2−プロペニル、1−ブテニル、2−ブテニル、3−ブテニル、1,−ペンテニル、2−ペンテニル、3−ペンテニル、4−ペンテニル、1−ヘキセニル、2−ヘキセニル、3−ヘキセニル、4−ヘキセニル又は5−ヘキセニルでありうる;
(C2〜C6)アルキニルは、エチニル、1−プロピニル、2−プロピニル、1−ブチニル、2−ブチニル、3−ブチニル、1−ペンチニル、2−ペンチニル、3−ペンチニル、4−ペンチニル、1−ヘキシニル、2−ヘキシニル、3−ヘキシニル、4−ヘキシニル又は5−ヘキシニルでありうる;
(C1〜C6)アルカノイルは、アセチル、プロパノイル又はブタノイルでありうる;
(C2〜C6)アルカノイルオキシは、アセトキシ、プロパノイルオキシ、ブタノイルオキシ、イソブタノイルオキシ、ペンタノイルオキシ又はヘキサノイルオキシでありうる;
(C3〜C8)シクロアルキルは、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル又はシクロオクチルでありうる;
アリールは、フェニル、インデニル、5,6,7,8−テトラヒドロナフチル又はナフチルでありうる;及び
二環式アリールは、インデニル又はナフチルでありうる。
ニューロンへの損傷及びニューロンのアポトーシス死が、急性及び慢性神経障害を含む多くの状態及び障害の病因に役割を果たしているという証拠が、蓄積している。これらの障害は、急性脳卒中、頭部外傷及びてんかんから、ハンチントン病、アルツハイマー病、HIV関連認知症、多発性硬化症及び緑内障などのより慢性な状態までの範囲がある。これらの疾患のうちのいくつかへの寄与因子は、細胞外マトリックスにおけるマトリックスメタロプロテイナーゼ(MMP)の活性化である。
式Iの化合物又はその薬学的に許容される塩若しくは溶媒和物(まとめて、「活性剤」)は、本発明の方法において、MMP阻害剤として又はMMP阻害剤をインビボ若しくはインビトロで提供するために有用である。活性剤は、上記の背景技術のセクションに記載された状態を含む、本明細書に記載されているものなどの様々なMMPの阻害又は調節により媒介される医学的状態(例えば、創傷)、疾患又は障害の治療又は予防に使用されうる。本発明の活性剤は、したがって、鎮痛薬、抗うつ薬、認識賦活薬又は神経保護薬として、また、下記に記載される状態の治療のために使用されうる。
本明細書に記載されている化合物及び組成物を使用して、以下の疾患、障害及び状態の症状を治療又は低減することができる。
選択的マトリックスメタロプロテイナーゼ(MMP)阻害剤は、糖尿病性創傷又は慢性創傷を含む創傷の治癒を推進することが見出されている。多数の選択的阻害剤化合物が、様々な慢性創傷の治癒過程を有意に加速することが発見されている。本明細書に記載されている評価は、これらの化合物が糖尿病の哺乳動物において治癒過程を加速することに実際に効果的であることを実証している。注目すべきは、療法が糖尿病マウスには有効であったが、非糖尿病マウスには有効でなかったことである。MMP阻害剤により治療された非糖尿病マウスは、創傷治癒にいかなる加速効果も示すことができなかった。これらの化合物は、この種類の療法について、最初に発見されたものである。糖尿病患者において創傷治癒過程を加速できる臨床剤は現在存在せず、したがって、本明細書に記載されている化合物、組成物及び方法は、慢性創傷を治療する治療方法を必要とする患者及び医師たちにとって大変重要である。
以下の記載では、構成成分「(b)」は、本明細書に記載されている1つ以上の作用物質(例えば、式Iの化合物)を表すと理解されるべきである。したがって、構成成分(a)及び(b)が同時又は独立して処理される場合、構成成分(b)の各作用物質も、同時又は独立して処理されうる。構成成分(a)及び(b)は、組合せ生成物として単一投与単位に一緒に処方されうる(すなわち、例えば1つのローション剤、クリーム剤、ゲル剤、軟膏剤又は注射用製剤に一緒に組み合わされうる)。構成成分(a)及び(b)が、単一投与単位に一緒に処方されないとき、構成成分(a)は、構成成分(b)と同時に又は任意の順番で投与されうる。例えば構成成分(a)が最初に投与され、続いて構成成分(b)が投与される又は逆の順番で投与されうる。構成成分(b)が1つを超える作用物質、例えば、血栓溶解剤及びNSAIDを含有する場合、これらの作用物質は一緒に又は任意の順番で別々に投与されうる。同時に投与されないとき、構成成分(a)及び(b)の投与は、約1日未満のうちに又は約10時間未満の間隔を置いて又はいくつかの実施形態では約1時間の間隔を置いて実施することができる。
抗緑内障剤、ベータアドレナリン作動遮断剤、炭酸脱水酵素阻害剤、縮瞳剤、交感神経刺激剤、アセチルコリン遮断剤、抗ヒスタミン薬、抗ウイルス剤、キノロン、抗炎症剤、非ステロイド性抗炎症剤、ステロイド性抗炎症剤、抗うつ薬(例えば、セロトニン再取り込み阻害剤、SSRI)、心理療法剤、抗不安剤、鎮痛薬、抗てんかん剤、抗痙攣薬、ガバペンチン(gabapentine)、抗高血圧剤、ベンゾポルフィリン光感作物質(phtosensitiser)、免疫抑制性代謝拮抗薬、バルビツール酸塩、ベンゾジアゼピン、GABA阻害剤、ヒダントイン、抗精神病薬、神経遮断薬(neurolaptic)、抗運動障害薬(antidysknetic)、アドレナリン作動剤、三環系抗うつ薬、抗血糖降下薬、グルコース溶液、ポリペプチド(plypeptide)ホルモン、抗生物質、血栓溶解剤、血液希釈剤、抗不整脈剤、コルチコステロイド、発作性障害剤、抗コリンエステラーゼ、ドーパミン遮断薬、抗パーキンソン病剤、筋弛緩薬、抗不安筋弛緩薬、CNS刺激薬、制吐薬、ベータアドレナリン作動遮断剤、麦角誘導体、イソメテプテン、抗セロトニン剤、鎮痛薬、選択的セロトニン再取り込み阻害剤(SSRI)、モノアミンオキシダーゼ阻害剤、抗感染症剤、ヌクレオシド系逆転写酵素、プロテアーゼ阻害剤又はtPAなどの血栓溶解剤。
ベータアドレナリン作動遮断剤、炭酸脱水酵素阻害剤、コリンエステラーゼ阻害剤、コリン作動薬(縮瞳薬)、ドコサノイド、プロスタグランジン、三環系抗うつ薬、心理療法剤、抗不安剤、鎮痛剤、抗てんかん剤、神経障害性疼痛に鎮痛効果を有する三環系抗うつ薬、リノレン酸、補酵素、ビタミン、免疫抑制性代謝拮抗薬、抗ウイルス薬、コポリマー、バルビツール酸塩、ベンゾジアゼピン、GABA阻害剤、ヒダントイン、精神安定薬、抗精神病薬、ノルエフェドリン、ペプチド、抗菌薬、組織プラスミノーゲン活性化剤(tPA)、血液希釈剤/抗凝固薬、心臓刺激薬(cardiostimulant)、炭酸脱水酵素阻害剤、カルバマゼピンのケト誘導体、アセチルコリンエステラーゼ、抗精神病薬、アルカロイド、GABA−B受容体作動薬、ベンゾジアゼピン、抗パーキンソン病薬、抗うつ薬、CNS刺激薬、受容体拮抗薬、ベータアドレナリン作動遮断剤、麦角誘導体(抗片頭痛薬)、抗痙攣薬、セロトニン(5−HT)受容体作動薬、抗躁薬、SSRI、MAOI、AIDS補助抗感染症剤(aids adjunct anti−infective agent)、抗ウイルス薬又はプロテアーゼ阻害剤。
チモロールマレイン酸塩;チモロール半水和物;ベタキソロールHCl;メチプラノロール;ブリモニジン酒石酸塩;ブリンゾラミド;ドルゾラミド;アセタゾラミド;エコチオパートヨウ化物;ピロカルピンHCl;ウノプロストンイソプロピルエステル;ラタノプロスト;アカンプロセート;アミトリプチリン;ペルフェナジン;クロルジアゼポキシド;トリミプラミンマレイン酸塩;クロルジアゼポキシド(Chlodiazepoxide)HCl;アルプラゾラム;ヒドロキシジン二塩酸塩;メプロバメート;ドキセピン(Doxipin)HCl;ヒドロキシジンパモ酸塩;アスピリン;アセトアミノフェン;イブプロフェン;カルバマゼピン(Carbamazipine);フルピルチン;ラモトリギン;フェニトインナトリウム;ペントキシフィリン(Pentaxifylline);チオクト酸;レボカルニチン;ビオチン;ニコチン酸;タウリン;ベルテポルフィン;アザチオプリン;インターフェロンベータ1;インターフェロンベータ1;シクロホスファミド;メトトレキセート;ネラメキサン(Neurmexane);メホバルビタール(Mephobarbitol);ペントバルビタール(Pentobarbitol);ロラゼパム(Lorazipam);クロナゼパム;クロラゼプテート(Chlorazeptate)二カリウム塩;ホスフェニトインナトリウム;オランザピン;ハロペリドール(Heloperidol);トリフルオペラジン(Trifluoperizine);フルフェナジン;フェニルプロパノールアミン;プソイドエフェドリンHCl;イミプラミン;グルカゴン;グルカゴン関連ペプチド−1;グルカゴン関連ペプチド−2;ペニシリンG、N、O又はV;アンピシリン;クロラムフェニコール;ホルボール;ヘパリン、L−イズロン酸又はD−グルクロン酸を有するD−グルコサミン;ワルファリン;エピネフリン;アミオダロン;リドカイン;ニトログリセリン、二硝酸イソソルビド、アミル、ブチル、イソブチル又は神経保護的であることが示されている様々な他の硝酸塩;アテノロール;デキサメタゾン;プレドニゾロン;アセタゾラミド;フェニトイン;チアガビンHCl;ガバペンチン;オクスカルバゼピン(Oxacarbazepine);タクリン;ドネペジル;リバスチグミン;ハロペリドール(Heloperidol);フェノチアジン;レセルピン;テトラベナジン(Tetrabenazene);ブロモクリプチン(Bromocryptine);チアプリド;バクロフェン;ジアゼパム;トリヘキシフェニジルHCl;アミトリプチリン(Amitrityline);アンフェタミン;メチルフェニデート;アミトリプチリンc(Amitritylinec);クロミプラミン;ドラセトロン;グラニセトロン;フペルジン(Huperzine);メトクロプラミド;プロクロルペラジン;デキサメタゾン;チモロール水素マレイン酸塩;プロプラノロール(Propanolol);イソメテプテン(Isometheptine);アテノロール;メトプロロール;ナドロール;エルゴタミン;ジヒドロエルゴタミン(Dihydroargotamine);ナラトリプタン;スマトリプタン;リザトリプタン;ゾルミトリプタン;イミプラミンHCl;ドーパミン;クロザピン;バルプロ酸;アミトリプチリンc;イミプラミンHCl;イミプラミンパモ酸塩;クロミプラミン;アンフェタミン;メチルフェニデート;フェニトイン;フェノバルビタール;アミトリプチリン(Amitryptyline);イミプラミンパモ酸塩;ノルトリプチリン(Nortrityline);トラゾドン;ネファゾドン;セルトラリン;フルオキセチン;パロキセチン;フェネルジン(Phenalzine);トラニルシプロミン;エリスロポイエチン、糖タンパク質;免疫グロブリン(ガンマグロブリン);テトラヒドロカンナビノール;アリトレチノイン;ラミブジン;スタブジン;ザルシタビン;アバカビル;リトナビル;インジナビル;及びネルフィナビル。これらの化学名は、当該技術において良く知られており、また米国特許出願公開第2009/0209615号(Liption et al.)に記載されており、これは参照により本明細書に組み込まれる。MMP阻害剤は、米国特許第6,703,415号(Mobashery et al.)及び同第7,928,127号(Lee et al.)、国際公開第2011/026107号(Mobashery et al.)及び米国特許出願公開第2013/0064878号(Chang et al.)に記載されている化合物を含む追加のMMP阻害剤と共に投与することができ、これらの特許文書は、参照により本明細書に組み込まれる。上記の化合物のいずれか1つ以上を、その薬学的に許容される塩形態、溶媒和物形態(例えば、一若しくは二水和物)又は任意の組合せで使用することができる。
本発明は、上記に記載されたものなどの、本明細書に記載されている式により表される化合物及び本明細書に例示されている特定の化合物の薬学的に許容される塩及び/又は溶媒和物、並びにそのような塩及び/又は溶媒和物を使用する治療方法も含む。
本明細書に記載されている化合物を使用して、例えば、化合物を薬学的に許容される希釈剤、賦形剤又は担体と組み合わせることによって、治療医薬組成物を調製することができる。化合物を、塩又は溶媒和物の形態で担体に加えることができる。例えば、化合物が、安定で非毒性の酸又は塩基の塩を形成するために十分に塩基性又は酸性である場合、化合物を塩として投与することが適切でありうる。薬学的に許容される塩の例は、生理学に許容可能なアニオンを形成する酸、例えば、トシル酸、メタンスルホン酸、酢酸、クエン酸、マロン酸、酒石酸、コハク酸、安息香酸、アスコルビン酸、α−ケトグルタル酸及びβ−グリセロリン酸と形成される有機酸付加塩である。塩酸塩、ハロゲン化物、硫酸塩、硝酸塩、重炭酸塩及び炭酸塩を含む適切な無機塩も形成されうる。
本発明は、化合物SB−3CT(1)のp−アミノメチルオキサジアゾール(4)、p−アミノメチル(5、ND−336)、p−アセトアミドメチル(6、ND−378)及びp−グアニジノ(7)類似体などの選択的MMP阻害剤、並びにそれらの使用方法を提供する。化合物は、1よりも10〜14,000倍の水溶性があり、MMP−2に対して遅延結合性阻害挙動を保持し、血液脳関門(BBB)を通過することができる。p−アセトアミドメチル類似体(化合物6)は、MMP−2の選択的ナノモル遅延結合性阻害剤であり、密接に関係するMMP−9又はMMP−14を阻害しない。標的MMP−2からの化合物6の解離が遅いため、6の濃度がKi値を下回って下降しても、MMP−2の持続的阻害をもたらす。この阻害剤は、治療介入にとって及び神経疾患におけるMMP−2の役割についての調査にとって有用なツールである。p−アミノメチル誘導体(化合物5)は、MMP−2、MMP−9及びMMP−14の水溶性ナノモル遅延結合性阻害剤であり、MMP−9に結合したメタロプロテイナーゼ1又は2の組織阻害剤(TIMP−1又はTIMP−2)より6〜7倍長い阻害滞留時間を、これらの酵素に対して有する。
a試薬及び条件:(a)臭化アリル、K2CO3、94%;(b)4−フルオロベンゾニトリル、Cs2CO3、DMF、100℃、82%;(c)ヒドロキシルアミン(水中50%)、EtOH、還流;(d)Boc−グリシン、HCTU、DIEA、DMF、100℃、2ステップで78%;(e)m−CPBA、CH2Cl2、0℃から室温(約22℃)、8日間、36〜74%;(f)チオ尿素、MeOH/CH2Cl2、室温、24時間、58〜78%;(g)4N HCl(1,4−ジオキサン中)、EtOAc/CH2Cl2、0℃から室温、24時間、98〜99%;(h)LiAlH4、THF;(i)(Boc)2O、I2、MeOH/CH2Cl2、2ステップで55%:(j)塩化アセチル、TEA、THF、0℃から室温(約22℃)、66%;(k)N,N’−ジ−Boc−1H−ピラゾール−1−カルボキサミジン、DIEA(2.2当量)、THF、室温、24時間、68%;(l)HCl(ガス)、EtOAc/CH2Cl2、0℃、3分間、95%。
化学。全ての反応は、特に示されない限り、窒素雰囲気下で実施した。1H及び13C NMRスペクトルは、Varian INOVA−500(Varian Inc.、Palo Alto、CA、USA)、Varian UnityPlus 300分光計(Varian Inc.、Palo Alto、CA、USA)、Bruker AVANCE III HD 500(Bruker Corporation、Billerica、MA、USA)又はBruker AVANCE III HD 400(Bruker Corporation、Billerica、MA、USA)で記録した。TLCシリカゲル60F254アルミニウムシート(EMD Millipore Corporation、Billerica、MA、USA)を、薄層クロマトグラフィーに使用した。フラッシュクロマトグラフィーを、自動クロマトグラフ装置:Combiflash RF 200i UV/Vis(Teledyne Isco、Lincoln、NE、USA)により実施した。高解像度質量スペクトルは、BrukermicrOTOF/Q2質量分析計(BrukerDaltonik、Bremen、Germany)を使用して、ESIイオン化によって得た。調製された化合物の純度は、UPLCにより確認すると、一般に>95%であった。条件は、UPLCセクションに詳述されている。4−(アリルチオ)フェノール(9)は、以前に記載されたように調製した(Ikejiri et al.,J.Biol.Chem.2005,280,33992−34002;Goux et al.,C.;Tetrahedron 1994,50,10321−10330)。
血漿及び脳における化合物の定量化は、化合物と内部基準とのピーク面積の比及び較正曲線から得た線形回帰パラメーターを使用して得た。決定係数(R2)は、>0.99であり、アッセイは、100μMの濃度まで線形であった。
外傷性脳傷害(TBI)は、持続性の認知欠陥により特徴付けられる慢性疾患過程をもたらしうる一次及び二次障害により引き起こされる、壊滅的な疾患である。この疾患過程は、数か月から数年後に脳細胞損傷及び細胞死をもたらす、生化学的変化から出発する。マトリックスメタロプロテイナーゼ−9(MMP−9)は、二次障害をもたらす事象の生化学的カスケードの上位にある。本発明者らは、MMP−9の選択的阻害が、TBIからもたらされる二次損傷を減弱することを示した。本発明者らは、TBIの治療領域における治療上の必要性に対処するため、水溶性の選択的MMP−9阻害剤を作り出した(表2.1)。化合物のND−336及びND−378は、血液脳関門を通過し、脳に治療濃度を達成する(図5)。
真性糖尿病の発生率は増加している。2010年には、米国の人口の8.3%が糖尿病を有していた(およそ2千5百80万人のアメリカ人)。2年後には、率は9.3%に増加した(2千9百10万人)。糖尿病の合併症は、創傷を治癒する能力が無いことであり、その結果、手足の非外傷性切断の60%超が、糖尿病を有する個人において発生している。下肢切断の数は、2006年には65,700件であり、2010年には73,000件に増加した。
化合物1xの合成。選択的MMP−2阻害剤(化合物1)を、以前に記載された本発明者らの方法(Gooyit et al.,J.Med.Chem.(2013)56,8139−8150)により調製し、DMSO 20%/プロピレングリコール80%に5.0mg/mLの濃度で溶解した。投与溶液及び対応するビヒクル溶液を、アクロディスク(Acrodisc)シリンジフィルター(Pall Life Sciences)に接続した0.2μmで直径が13mmのPTFE膜に通して滅菌した。
以下の製剤は、本明細書に記載されている式の化合物、本明細書に特定的に開示されている化合物又はその薬学的に許容される塩若しくは溶媒和物(以下、「化合物X」と呼ぶ)の治療のための又は予防のための投与に使用することができる代表的な医薬剤形を説明する。
「化合物X」 100.0
ラクトース 77.5
ポビドン 15.0
クロスカルメロースナトリウム 12.0
微晶質セルロース 92.5
ステアリン酸マグネシウム 3.0
300.0
「化合物X」 20.0
微晶質セルロース 410.0
デンプン 50.0
デンプングリコール酸ナトリウム(sodium starch glycolate) 15.0
ステアリン酸マグネシウム 5.0
500.0
「化合物X」 10.0
コロイド状二酸化ケイ素 1.5
ラクトース 465.5
アルファ化デンプン 120.0
ステアリン酸マグネシウム 3.0
600.0
「化合物X」(遊離酸形態) 1.0
第二リン酸ナトリウム(Dibasic sodium phosphate)
12.0
第一リン酸ナトリウム(Monobasic sodium phosphate)
0.7
塩化ナトリウム 4.5
1.0N水酸化ナトリウム溶液 十分量
(pHを7.0〜7.5に調整)
注射剤用水 1.mLにする十分量
「化合物X」(遊離酸形態) 10.0
第一リン酸ナトリウム 0.3
第二リン酸ナトリウム 1.1
ポリエチレングリコール400 200.0
0.1N水酸化ナトリウム溶液 十分量
(pHを7.0〜7.5に調整)
注射剤用水 1mLにする十分量
「化合物X」 20
オレイン酸 10
トリクロロモノフルオロメタン 5,000
ジクロロジフルオロメタン 10,000
ジクロロテトラフルオロエタン 5,000
「化合物X」 5%
カルボマー934 1.25%
トリエタノールアミン 十分量
(pHを5〜7に調整)
メチルパラベン 0.2%
精製水 100gにする十分量
「化合物X」 5%
メチルセルロース 2%
メチルパラベン 0.2%
プロピルパラベン 0.02%
精製水 100gにする十分量
「化合物X」 5%
プロピレングリコール 1%
無水軟膏基剤 40%
ポリソルベート80 2%
メチルパラベン 0.2%
精製水 100gにする十分量
「化合物X」 5%
白ロウ 10%
流動パラフィン 30%
ベンジルアルコール 5%
精製水 100gにする十分量
「化合物X」 5%
ステアリン酸 10%
モノステアリン酸グリセリン 3%
ポリオキシエチレンステアリルエーテル 3%
ソルビトール 5%
パルミチン酸イソプロピル 2%
メチルパラベン 0.2%
精製水 100gにする十分量
本出願は、2014年2月20日出願の米国仮特許出願第61/942.516号及び2014年12月5日出願の同第62/088,380号に基づく優先権を米国特許法119条(e)に基づいて主張し、これらの出願は、参照により組み込まれる。
Claims (25)
- 下式:
[式中、
R1は、−CH2−NHRa(ここでRaは、H又は(C1〜C6)アルカノイルである)、−NH−C(=NH)−NH2又は
であり;
Jは、S又はOであり;
各R2は、独立して、H、OH、(C1〜C6)アルキル、(C1〜C6)アルコキシ、(C1〜C6)アルカノイル、(C1〜C6)アルカノイルオキシ、アリール、ヘテロアリール、カルボキシ、シアノ、ニトロ、ハロ、トリフルオロメチル、トリフルオロメトキシ、SRz、SO2N(Rz)2、NRzRz又はCOORzであり、ここで各Rzは、独立して、H、(C1〜C6)アルキル、(C1〜C6)アルカノイル、(C6〜C10)アロイル、アリール、アリール(C1〜C6)アルキル、ヘテロアリール、ヘテロアリール(C1〜C6)アルキルであるか又はRzが窒素原子に共有結合している場合、任意選択で窒素保護基であり;
各nは、独立して、0、1、2、3又は4である]
の化合物、又はその塩。 - R1が−CH2−NHRaである、請求項1に記載の化合物。
- RaがH又は−C(=O)CH3である、請求項2に記載の化合物。
- R1が−NH−C(=NH)−NH2である、請求項1に記載の化合物。
- R1が、
である、請求項1に記載の化合物。 - R1が、R1が結合しているフェニル基の酸素に対してパラ位に位置する、請求項1〜5のいずれか一項に記載の化合物。
- JがSである、請求項1〜5のいずれか一項に記載の化合物。
-
又はその薬学的に許容される塩である、請求項1に記載の化合物。 - MMP−2、MMP−9、MMP−14又はこれらの組合せの選択的阻害剤である、請求項1又は8に記載の化合物。
- 請求項1〜5又は8のいずれか一項に記載の化合物を、薬学的に許容される希釈剤、賦形剤又は担体と組み合わせて含む組成物。
- 請求項1〜5又は8のいずれか一項に記載の化合物を含む、MMP−2、MMP−9、MMP−14又はこれらの組合せの阻害剤。
- インビトロにおいて使用される、請求項11に記載の阻害剤。
- インビボにおいて使用される、請求項11に記載の阻害剤。
- MMP−8の存在下においてMMP−2に対して選択的である、請求項11に記載の阻害剤。
- MMP−8の存在下においてMMP−9に対して選択的である、請求項11に記載の阻害剤。
- MMP−9及びMMP−14の両方の存在下においてMMP−2に対して選択的である、請求項11に記載の阻害剤。
- 前記化合物が、MMP−2、MMP−9及びMMP−14のナノモルの遅延結合性阻害剤であり、前記化合物が、MMP−8を非競合的に弱く阻害する、請求項11に記載の阻害剤。
- 請求項1〜5のいずれか一項に記載の化合物を含む、神経学的状態を治療するための組成物。
- 前記神経学的状態が、急性脳卒中、虚血性脳卒中又は出血性脳卒中などの脳卒中、動脈瘤、てんかん、筋萎縮性側索硬化症(ALS)、アルツハイマー病、ハンチントン病、パーキンソン病、HIV関連認知症、多発性硬化症、緑内障、周産期低酸素症などの低酸素症、虚血、再灌流傷害、頭部外傷又は脊髄損傷である、請求項18に記載の組成物。
- 請求項1〜5のいずれか一項に記載の化合物又はその薬学的に許容される塩を含む、創傷の治癒過程を加速するための組成物であって、前記化合物は選択的MMP阻害剤である、組成物。
- 前記創傷に隣接する組織の上皮化を向上する、請求項20に記載の組成物。
- 請求項1〜5のいずれか一項に記載の化合物を含む、外傷性脳傷害を治療するための組成物。
-
の化合物又はその薬学的に許容される塩を含む、外傷性脳傷害を治療するための組成物。 -
の化合物又はその薬学的に許容される塩を含む、糖尿病性創傷の治癒を向上させるための組成物。 - 請求項1〜5のいずれか一項に記載の化合物を含む、癌を治療するための組成物。
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US61/942,516 | 2014-02-20 | ||
US201462088380P | 2014-12-05 | 2014-12-05 | |
US62/088,380 | 2014-12-05 | ||
PCT/US2015/016950 WO2015127302A1 (en) | 2014-02-20 | 2015-02-20 | Selective matrix metalloproteinase inhibitors |
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US10357546B2 (en) * | 2014-09-19 | 2019-07-23 | University Of Notre Dame Du Lac | Acceleration of diabetic wound healing |
US11345758B2 (en) | 2017-06-27 | 2022-05-31 | Translational Sciences, Inc. | Inhibition of vascular matrix metalloproteinase-9 to treat ischemic injury |
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