JP4173909B1 - アミノ酸誘導体 - Google Patents
アミノ酸誘導体 Download PDFInfo
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- JP4173909B1 JP4173909B1 JP2008508341A JP2008508341A JP4173909B1 JP 4173909 B1 JP4173909 B1 JP 4173909B1 JP 2008508341 A JP2008508341 A JP 2008508341A JP 2008508341 A JP2008508341 A JP 2008508341A JP 4173909 B1 JP4173909 B1 JP 4173909B1
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- compound
- pain
- compounds
- acid
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- 239000000080 wetting agent Substances 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
- 150000003751 zinc Chemical class 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
- 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
- 210000002517 zygapophyseal joint Anatomy 0.000 description 1
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Abstract
Description
R1はC1〜C6アルキルであり、前記C1〜C6アルキルは場合により1種以上のハロ、‐R5、‐OR5、または‐SR5基によって置換され;
R2は場合により1種以上のフルオロ基によって置換されたメチルであり、
R3はH、(C1〜C6アルキル)、アリール、インダニルまたは(C1〜C6アルキル)オキシカルボニルオキシ(C1〜C6アルキル)であり;
R4はH、(C1〜C6アルキル)C(O)‐、アリールC(O)‐、またはそのカルボキシル基を介して結合してアミドを形成する天然のα‐アミノ酸残基であり;
R5はC1〜C6アルキル、C1〜C6ハロアルキル、C3〜C8シクロアルキルまたはアリールであり;
アリールはフェニルまたはナフチルであり、それぞれが場合によりハロ、‐NR6R6、C1〜C6アルキル、C3〜C8シクロアルキル、C1〜C6アルコキシおよびシアノから選択される1種以上の置換基によって置換され;そして
R6はH、C1〜C6アルキルまたはC3〜C8シクロアルキルである)
または薬剤的に受容できるその塩もしくは溶媒和物の使用を提供する。
R7は:
(a)4−メチルペント−1−イルおよび1−メチルペント−1−イル以外の、分枝したC6〜C10アルキル;
(b)1−フルオロエト−1−イル、ヘプタフルオロプロピル、2,2−ジトリフルオロメチルエト−1−イル、ペンタフルオロエチル、2−フルオロエト−1−イル、2−フルオロペント−1−イルおよび2−フルオロ−3−メチルブト−1−イル以外の、1種以上のフルオロ基によって置換されたC2〜C6アルキル;
(c)シクロヘキシルメチル以外の1種のC3〜C8シクロアルキル基によって置換された
C1〜C6アルキル;
(d)アリールが(他の置換にかかわらず)フェニルまたは−NH2、ヨードもしくはメトキシ基によって置換されたフェニルである場合以外の、1種のアリール基によって置換されたエチル;
(e)アリールがフェニル、3,4−ジヒドロキシフェニルまたは3,4−ジメトキシフェニルである場合以外の、アリールによって置換されたC3〜C4アルキル;
(f)アリールによって置換されたC5〜C6アルキル;
(g)C5〜C6アルコキシによって置換されたC1〜C2アルキル;
(h)C1〜C6アルコキシによって置換されたC3〜C6アルキル;
(i)C3〜C8シクロアルキルオキシによって置換されたC1〜C6アルキル;
(j)(2−メトキシフェニル)オキシメチル、(4−メトキシフェニル)オキシメチル、(4−クロロフェニル)オキシメチル、(2,6−ジメチルフェニル)オキシメチル、(2−メトキシ−5−クロロフェニル)オキシメチル、(2−メトキシ−5−フルオロフェニル)オキシメチルおよび(2−メトキシ−4−クロロフェニル)オキシメチル以外の、アリールオキシによって置換されたC1〜C6アルキル;
(k)ヘキシルチオによって置換されたメチルまたはC1〜C6アルキルチオによって置換されたC4〜C6アルキル;
(l)シクロヘキシルチオメチル以外の、C3〜C8シクロアルキルチオによって置換されたC1〜C6アルキル;または
(m)フェニルチオメチル、(4−クロロフェニル)チオメチル、(4−フルオロフェニル)チオメチル、2−(フェニルチオ)エチル、(4−クロロフェニル)チオエチル、(4−メトキシフェニル)チオメチルおよび(4−メトキシフェニル)チオエチル以外の、アリールチオによって置換されたC1〜C6アルキルであり;
R8は場合により1種以上のフルオロ基によって置換されたメチルであり、
アリールはフェニルまたはナフチルであり、それぞれ場合によりハロ、‐NR9R9、C1〜C6アルキル、C3〜C8シクロアルキル、C1〜C6アルコキシおよびシアノから選択される1種以上の置換基によって置換され;そして
R9はH、C1〜C6アルキルまたはC3〜C8シクロアルキルである)、
または薬剤的に受容できるその塩もしくは溶媒和物を提供する。
(a)場合により1種以上のハロ、‐R5、‐OR5、または‐SR5基によって置換されるC1〜C2アルキルであり、R5は態様Aにおいて定義したとおりである;または
(b)置換されていないC5〜C7アルキルまたはC3〜C8シクロアルキル、アリールまたはアリールオキシから選択される1種の基によって置換されたC1〜C2アルキルであり、アリールは態様Aにおいて定義したとおりである;
(c)分枝した、置換されていないC5〜C7アルキルまたはC3〜C8シクロアルキル、アリールまたはアリールオキシから選択される1種の基によって置換されたC1〜C2アルキルであり、アリールは態様Aにおいて定義したとおりである;
(d)エチルブチル、ジメチルブチル、エチルペンチル、メチルペンチル、メチルブチル、シクロペンチルメチル、シクロブチルメチル、シクロプロピルエチル、フェニルオキシエチルもしくはクロロフェニルメチルである;または
(e)2−エチル−ブト−1−イル、3,3−ジメチルブト−1−イル、3−エチルペント−1−イル、3−メチルペント−1−イル、2−メチル−ブト−1−イル、3−メチル−ブト−1−イル、4−メチルペント−1−イル、シクロペンチルメチル、シクロブチルメチル、2−シクロプロピルエト−1−イル、2−(フェニルオキシ)エト−1−イルもしくは(3−クロロフェニル)メチルである。
(a)4−メチルペント−1−イルおよび1−メチルペント−1−イル以外の、分枝したC6〜C10アルキル;シクロヘキシルメチル以外の、1種のC3〜C8シクロアルキル基によって置換されたC1〜C2アルキル;(2−メトキシフェニル)オキシメチル、(4−メトキシフェニル)オキシメチル、(4−クロロフェニル)オキシメチル、(2,6−ジメチルフェニル)オキシメチル、(2−メトキシ−5−クロロフェニル)オキシメチル、(2−メトキシ−5−フルオロフェニル)オキシメチルおよび(2−メトキシ−4−クロロフェニル)オキシメチル以外の、アリールオキシによって置換されたC1〜C2アルキル;2−メチルブチル;もしくはクロロフェニルメチル;または
(b)2−エチル−ブト−1−イル、3,3−ジメチルブト−1−イル、3−エチルペント−1−イル、3−メチルペント−1−イル、2−メチルブト−1−イル、4−メチルペント−1−イル、シクロペンチルメチル、シクロブチルメチル、2−シクロプロピルエト−1−イル、2−(フェニルオキシ)エト−1−イルまたは(3−クロロフェニル)メチルである。
本発明における使用のための化合物の付加的な例としては:
3−クロロ−アルファ−メチル−L−フェニルアラニン;
4−フェノキシ−L−イソバリン;
2,5−ジメチル−L−ノルロイシン;および
(2S)−2−アミノ−4−シクロプロピル−2−メチルブタン酸;
ならびに薬剤的に受容できるその塩および溶媒和物が挙げられる。
適切な酸付加塩は非毒性塩を形成する酸から形成される。例としては、酢酸塩、アスパラギン酸塩、安息香酸塩、ベシレート、炭酸水素塩/炭酸塩、硫酸水素塩/硫酸塩、硼酸塩、カンシル酸塩、クエン酸塩、エジシル酸塩、エシレート、蟻酸塩、フマル酸塩、グルセプト酸塩、グルコン酸塩、グルクロン酸塩、ヘキサフルオロリン酸塩、ヒベンズ酸塩、塩酸塩/クロリド、臭化水素酸塩/ブロミド、ヨウ化水素酸塩/ヨージド、イセチオン酸塩、乳酸塩、リンゴ酸塩、マレイン酸塩、マロン酸塩、メシル酸塩、メチル硫酸塩、ナフチレート、2−ナプシレート、ニコチン酸塩、硝酸塩、オロテート、蓚酸塩、パルミチン酸塩、パモ酸塩、リン酸塩/水素、リン酸塩/二水素、リン酸塩、糖酸塩、ステアリン酸塩、コハク酸塩、酒石酸塩、トシル酸塩およびトリフルオロ酢酸塩が挙げられる。
適切な塩に関する総説としては、Stahl and WermuthによるHandbook of Pharmaceutical Salts:Properties,Selection,and Use(Wiley−VCH,Weinheim,Germany,2002)を参照されたい。
(i)式(I)の化合物を所望する酸または塩基と反応させること;
(ii)式(I)の化合物の適切な前駆体から酸‐または塩基‐に不安定な保護基を除去すること、もしくは所望する酸または塩基を使用して、適切な環状前駆体を開環すること;または
(iii)適切な酸または塩基との反応によるか、または適切なイオン交換カラムによって、式(I)の化合物の1種の塩を別のものに変換することの中の1種以上によって製造できる。
式(I)の化合物は非溶媒和および溶媒和型の両方で存在してもよい。‘溶媒和’という用語は、本明細書では式(I)の化合物および化学量論的な量の1種以上の薬剤的に受容できる溶媒分子、たとえばエタノールを含有する分子複合体を説明するために使用される。‘水和物’という用語は上記溶媒が水の場合に使用される。
先に定義したような式(I)の化合物は、1種以上の結晶(多形)または異性体型(光学的、幾何学的および互変異性体を含む)で、同位体で標識された型で、またはプロドラッグとして存在してもよい。そのような結晶/異性体型およびプロドラッグのすべては本発明の範囲内であり、以下により詳細に説明される。式(I)の化合物へのすべての言及はそれに応じて解釈されるべきである。
本発明の範囲内には、式(I)の化合物の代謝産物、すなわち、薬物の投与時にin vivoで形成される化合物も包含される。本発明に従った代謝産物のいくつかの例としては以下のものが挙げられる:
(i)式(I)の化合物がメチル基を含有する場合、そのヒドロキシメチル誘導体(−CH3−>−CH2OH):
(ii)式(I)の化合物がアルコキシ基を含有する場合、そのヒドロキシ誘導体(−OR−>−OH);
(iii)式(I)の化合物が第3級アミノ基を含有する場合、その第2級アミノ誘導体(−NR1R2−>−NHR1または−NHR2);
(iv)式(I)の化合物が第2級アミノ基を含有する場合、その第1級誘導体(−NHR1−>−NH2);
(v)式(I)の化合物がフェニル部分(moieties)を含有する場合、そのフェノール誘導体(−Ph−>−PhOH)。
式(I)の化合物はα‐炭素において定義された立体化学を持つα‐アミノ酸である。個々のエナンチオマーの製造/単離のための慣用の技術には、適切な光学的に純粋な前駆体からのキラル合成または、たとえばキラル高圧液体クロマトグラフィー(HPLC)を用いたラセミ体(または塩もしくは誘導体のラセミ体)の分割が挙げられる。
同位体標識した式(I)の化合物は一般に、当業者に公知の慣用の技術により、または以前に使用された非標識試薬のかわりに適切な同位体標識された試薬を使用して、添付の実施例および製造法に記載の工程に類似した工程により製造することができる。
アルファ‐2‐デルタ受容体リガンドである式(I)の化合物は、広範な障害の治療において潜在的に有用である。疼痛、とりわけ神経障害性疼痛の治療は、好ましい用途である。
他の型の疼痛には以下のものが挙げられる:
・筋痛症、線維筋痛症、脊椎炎、血清反応陰性(非リューマチ様)関節症、非関節性リューマチ、ジストロフィン異常症、グリコーゲン分解、多発性筋炎および仙腸性筋炎を含む、筋骨格系障害から生じる疼痛;
・狭心症、心筋梗塞、僧帽弁狭窄症、心膜炎、レイノー現象、水腫硬化症および骨格筋虚血によって引き起こされる疼痛を含む、心臓および血管性疼痛;
・頭部痛、たとえば偏頭痛(前兆のある偏頭痛および前兆のない偏頭痛を含む)、群発頭痛、緊張型頭痛混合頭痛および血管障害に伴う頭痛;および
・歯痛、耳痛、口腔内灼熱症候群および顎関節筋膜痛を含む、口腔顔面痛。
疼痛の他に、式(I)の化合物は潜在的に、アルファ‐2‐デルタリガンドを使用して治療可能であるいずれかの疾患または状態の治療において有用である。そのような状態には、てんかん、消化器障害、早漏、口腔内灼熱症候群、膀胱障害(たとえば過活動膀胱)失神発作、線維筋痛症、運動低下症、頭蓋障害、ほてり、本態性振戦、薬物依存および嗜癖、依存または嗜癖に伴う禁断症状、嗜癖行動、痙縮、関節炎、炎症性障害(たとえばリューマチ様関節炎、骨関節症、乾癬)、利尿、月経前症候群、月経前不快気分障害、耳鳴り、胃損傷、ダウン症候群、脱随疾患(たとえば、多発性硬化症および筋萎縮性側索硬化症(amylolateral sclerosis))、急性または慢性脳血管損傷(たとえば脳梗塞、くも膜下出血または脳水腫)による脳血管障害、頭部外傷、脊髄外傷および、たとえば脳卒中中に、心臓バイパス手術において、頭蓋内出血の事象において、周産期窒息において、心停止において、およびてんかん重積状態において起こる神経損傷が挙げられる。アルファ‐2‐デルタリガンドはまた、せん妄、痴呆および健忘症、ならびに他の認知または神経変性障害(たとえば、パーキンソン病、ハンチントン病、アルツハイマー病、老年性痴呆、記憶障害、血管性痴呆)の治療において有用であってもよい。それらは、無動症、運動障害、けい性(spasticity)、トゥレット症候群、スコット症候群、不全麻痺、無動‐硬直症候群および錐体外路運動障害のような運動障害の治療に有用であってもよい。それらはまた、睡眠障害、気分障害、鬱病、抑鬱障害、双極性障害、不安障害、パニック、境界人格障害、統合失調症、精神障害、精神遅滞に伴う行動障害、自閉障害および行動障害の治療において有用であってもよい。
第1の工程に従って、R3およびR4がHである式(I)の化合物、(A)は式(III)の化合物:
R2M1(V)
の化合物(式中、R2は先に定義したとおりであり、そしてM1は適切な金属であり、場合により1種以上の付加的なリガンドを持つ)で処理することにより;または式(VI)のイミン:
R1M1(VII)
の化合物(式中、R1およびM1は先に定義したとおりである)で処理することにより製造されてもよい。そのようなイミン付加反応において、式(V)または式(VII)の有機金属試薬は典型的には有機リチウムまたは有機マグネシウム誘導体である。M1がMgXであり、Xがハロゲン化物である有機マグネシウム(Grignard)試薬が好ましい。反応はテトラヒドロフランまたはジエチルエーテルのような適切な不活性溶媒中で、低温、典型的には0〜-78℃の間で行われる。好ましい手順において、テトラヒドロフランのような適切な溶媒中の式(IV)または(VI)の化合物の溶液は、-50℃において、そしてホウ素トリフルオリドエーテラートの存在下、それぞれ適切な式(V)または(VII)のGrignard試薬により処理される。
分割は、キラルクロマトグラフィー、ジアステレオマー誘導体(たとえばエステル、エーテルまたは塩)の形成、または化学的もしくは酵素速度論的分割を含む、当業者に公知の多くの方法により行われてもよい。典型的には、式(Ia)の化合物は、適切な有機溶媒中で、キラル塩基または酸により処理されてジアステレオマー塩を形成し、そして分離は最も溶解度の低いジアステレオマーの結晶化によって成し遂げられる。適切な分割試薬には、酒石酸誘導体、マンデル酸、カンファースルホン酸、スパルテイン、アルファ‐メチルベンジルアミン、プソイドエフェドリンおよびアミノアルコールが挙げられる。また、ジアステレオマー塩分割を使用して、エナンチオマー過剰の式(I)の非ラセミ化合物を増加させてもよい。
水素化分解脱保護条件は工程(A)に関して先に記載のとおりである。
あるいは、式(I)の化合物は式(XXIII)の化合物の分割、続いて水素化分解脱保護によって式(XXIII)の化合物から製造することができる。
条件は工程(A)に関して記載のとおりである。式(XXV)の化合物は市販されている。
式(XXVI)の化合物は、塩基性条件下、式(XXVII)の化合物と式(XXVIII)の求電子試薬:
典型的な条件は、-78℃〜室温の温度において、ジクロロメタン、テトラヒドロフランまたはトルエンのような有機溶媒中、場合により相間移動触媒の存在下で、式(XXIX)の化合物を、適切な求電子試薬(たとえば、ヨウ化メチル、ジメチル硫酸、トリメチルオキソニウムテトラフルオロボレート、またはメチルトリフレート)と炭酸カリウムもしくは水酸化ナトリウムのような無機塩基、またはフォスファゼン塩基のような有機塩基で処理することを含む。
あるいは、式(XXIX)の化合物はTetrahedron,2004,60,5919−5930およびTetrahedron Letters,1998,39,8775−8778に記載のとおりに製造されてもよい。
7番目の工程(G)に従って、式(Ia)のラセミ化合物(式中、R3およびR4は両方Hであり、R1およびR5はハロまたはシアノによって置換されず、そしてR2はメチルである)は、かわりに式(XXXI)の化合物:
縮合は、酢酸アンモニウムもしくは炭酸アンモニウム、またはReNH2(式中、ReはC1〜C6アルキル、ベンジル、または場合によりアミノ、(C1〜C6アルキル)アミノ、ヒドロキシル、C1〜C6アルコキシ、スルホネート、スルホンアミド、スルホニル、CF3、ニトロ、C1〜C6アシルまたはニトリルで置換されたアリールである)のようなアンモニア供与源と、シアニド塩のようなアシルアニオン等価物を使用して行ってもよい。加水分解の典型的な条件は、生じたアミノニトリルまたはヒダントインを水性溶媒系中で、酸または塩基のいずれかで処理することを含む。典型的には、アミノニトリルまたはヒダントインは、室温〜100℃までの温度で、6〜12%の過酸化水素を含む、水性塩酸、臭化水素酸、硫酸もしくはリン酸、または水性水酸化カリウムまたは水酸化ナトリウムで処理される。
あるいは、式(Ia)の化合物は、化合物(XXXIIa):
式(XXXIIa)のラセミ化合物は、先の工程(H)に関して記載の条件を使用するが、エナンチオ選択的触媒またはキラル試薬の非存在下で、式(XXXIII)または(XXXV)の化合物から製造することができる。
代表的な錠剤は、約80%までの式(I)の化合物、約10重量%〜約90重量%までの結合剤、約0重量%〜約85重量%までの希釈剤、約2重量%〜約10重量%までの崩壊剤、および約0.25重量%〜10重量%までの潤滑剤を含有する。
非経口製剤の製造に使用される式(I)の化合物の溶解度は、適切な製剤技術、たとえば溶解度‐促進剤の混合のような、適切な製剤技術の使用により高められてもよい。
カプセル(たとえば、ゼラチンまたはヒドロキシプロピルメチルセルロースから作られたもの)、ブリスターおよび吸入器またはガス注入器における使用のためのカートリッジは、式(I)の化合物の粉末混合物、ラクトースまたはデンプンのような適切な粉末基剤、およびl−ロイシン、マンニトール、またはステアリン酸マグネシウムのような性能改善剤を含有するように製剤されてもよい。ラクトースは無水または一水和物の形態、好ましくは後者であってもよい。他の適切な賦形剤には、デキストラン、グルコース、マルトース、ソルビトール、キシリトール、フルクトース、スクロースおよびトレハロースが挙げられる。
適切な香味剤、たとえばメントールおよびレボメントール、または甘味剤、たとえばサッカリンもしくはサッカリンナトリウムが、吸入/鼻腔内投与を意図した製剤に添加されてもよい。
本発明のアルファ−2−デルタリガンドの生物学的活性は、J.Biol.Chem.,1996,271(10),5768−5776に示された方法に基づいて、[3H]ガバペンチンおよびブタ脳組織に由来するα2δサブユニットを使用した放射リガンド結合アッセイで測定されてもよい。このアッセイは以下において再現される。
[3H]ガバペンチン結合アッセイ
脳膜の調製
すべての溶液は終始4℃に維持した。ブタ脳皮質(50gまで)(新鮮または凍結)は、10倍容量のバッファーA(0.32M スクロース/1mM EDTA/1mM EGTA/10mM Hepes/KOH、pH7.4)の中で、600r.p.mのガラス/テフロンホモゲナイザーの6ストロークによってホモゲナイズした。1000gx10分間で得られたペレットの除去後、上清は4,000gで20分間遠心分離し、生じたペレットは10倍容量のバッファーB(1mM EDTA/1mM EGTA/10mM Hepes/KOH、pH7.4)で再懸濁した。30分間連続してかき混ぜた後、バッファーBによる遠心分離によってさらに2回上記のようにペレット化し、約3倍容量の保存バッファー(1.25mM EDTA/1.25mM EGTA/25% グリセロール/12.5mM Hepes/KOH、pH7.4)に最終的に再懸濁し、1ミリリットルにつき約3ミリグラムの濃度のタンパク質を得た。アリコートは必要になるまで-80℃で保存した。
結合アッセイプロトコル:
ブタ皮質膜への[3H]ガバペンチンの結合は、22℃において、10mM Hepes/KOH、pH7.4中、60分間行われた。非特異的結合(nsb)は10μM プレガバリン存在下で得られた結合として定義した。200μlの膜、25μlの試験化合物/バッファー/nsb、25μl [3H]ガバペンチン(最終アッセイ濃度 約10nM)を含む250μlのアッセイ容量を使用した。非結合放射リガンドの分離は、2x1mの冷やした50mM Tris/HCl,pH7.4を使用して、冷した50mM Tris/HCl、pH7.4に浸したGF/Bユニフィルタープレートを通した、真空下での急速濾過により行った。プレートは乾燥させ、microscint‐40を50μl/ウェル添加し、TopCountシンチレーションカウンターを使用して結合放射能の量を測定した。結果はμMまたはnMに換算してIC50として表してもよい。
・オピオイド鎮痛薬、例えば、モルヒネ、ヘロイン、ヒドロモルホン、オキシモルホン、レボルファノール、レバロルファン、メタドン、メペリジン、フェンタニル、コカイン、コデイン、ジヒドロコデイン、オキシコドン、ヒドロコドン、プロポキシフェン、ナルメフェン、ナロルフィン、ナロキソン、ナルトレキソン、ブプレノルフィン、ブトルファノール、ナルブフィンまたはペタゾシン;
・非ステロイド抗炎症薬(NSAID)、たとえば、アスピリン、ジクロフェナック、ジフルシナル、エトドラク、フェンブフェン、フェノプロフェン、フルフェニサル、フルルビプロフェン、イブプロフェン、インドメタシン、ケトプロフェン、ケトロラク、メクロフェナム酸、メフェナム酸、ナブメトン、ナプロキセン、オキサプロジン、フェニルブタゾン、ピロキシカム、スリンダック、トルメチンまたはゾメピラック;
・バルビツレート鎮静薬、たとえばアモバルビタール、アプロバルビタール、ブタバルビタール、ブタビタール、メフォバルビタール、メタルビタール、メトヘキシタール、ペントバルビタール、フェノバルビタール、セコバルビタール、タルブタール、テアミラールまたはチオペンタール;
・鎮静作用を有するベンゾジアゼピン、たとえばクロロジアゼポキシド、クロラゼパート、ジアゼパム、フルラゼパム、ロラゼパム、オキサゼパム、テマゼパムまたはトリアゾラム;
・鎮静作用を有するH1アンタゴニスト、たとえばジフェンヒドラミン、ピリラミン、プロメタジン、クロルフェニラミンまたはクロルシクリジン;
・鎮静剤、たとえばグルテチミド、メプロバメート、メタカロンまたはジクロルアルフェナゾン;
・骨格筋弛緩薬、たとえばバクロフェン、カリソプロドール、クロルゾキサゾン、シクロベンザプリン、メトカルバモールまたはオルフレナジン;
・NMDA受容体アンタゴニスト、たとえばデキストロメトルファン((+)−3−ヒドロキシ−N−メチルモルフィナン)もしくはその代謝産物デキストロルファン((+)−3−ヒドロキシ−N−メチルモルフィナン、ケタミン、メマンチン、ピロロキノリンキノンまたはcis−4−(ホスホノメチル)−2−ピペリジンカルボン酸;
・アルファ‐アドレナリン作動薬、たとえばドキサゾシン、タムスロシン、クロニジンまたは4−アミノ−6,7−ジメトキシ−2−(5−メタンスルホンアミド−1,2,3,4−テトラヒドロイソキノール−2−イル)−5−(2−ピリジル)キナゾリン;
・三環抗うつ剤、たとえばデシプラミン、イミプラミン、アミトリプチリンまたはノルトリプチリン;
・抗痙攣薬、たとえばカルバマゼピンまたはバルプロアート;
・タキキニン(NK)アンタゴニスト、とりわけNK−3、NK−2もしくはNK−1アンタゴニスト、たとえば(αR,9R)−7−[3,5−ビス(トリフルオロメチル)ベンジル]−8,9,10,11−テトラヒドロ−9−メチル−5−(4−メチルフェニル)−7H−[1,4]ジアゾチノ[2,1−g][1,7]ナフタリジン−6−13−ジオン(TAK−637)、5−[[(2R,3S)−2−[(1R)−1−[3,5−ビス(トリフルオロメチル)フェニル]エトキシ−3−(4−フルオロフェニル)−4−モルホリニル]メチル]−1,2−ジヒドロ−3H−1,2,4−トリアゾール−3−オン(MK−869)、ラネピタント、ダピタントまたは3−[[2−メトキシ−5−(トリフルオロメトキシ)フェニル]メチルアミノ]−2−フェニル−ピペリジン(2S,3S);
・ムスカリンアンタゴニスト、たとえばオキシブチン、トルテロジン、プロピベリン、トロプシウムクロリドまたはダリフェナシン;
・選択的COX‐2阻害剤、たとえばセレコキシブ、ロフェコキシブまたはバルデコキシブ;
・非選択的COX阻害剤(好ましくはGI保護を伴う)、たとえばニトロフルビプロフェン(HCT−1026);
・コールタール鎮痛剤、とりわけパラセタモール;
・抗精神病薬、たとえばドロペリドール;
・バニロイド受容体アゴニスト(たとえば、レシフェラトキシン)またはアンタゴニスト(たとえば、カプサゼピン);
・ベータ‐アドレナリン作動薬、たとえばプロプラノロール;
・局所麻酔薬、たとえばメキシレチン;
・コルチコステロイド、たとえばデキサメタゾン;
・5−HT受容体アゴニストまたはアンタゴニスト、とりわけ5−HT1B/1Dアゴニスト、たとえばエレトリプタン、スマトリプタン、ナラトリプタン、ゾルミトリプタンまたはリザトリプタン;
・コリン作動性(ニコチン性)鎮痛薬;
・トラマドール(商標);
・PDEV阻害剤、たとえばシルデナフィル、バルデナフィル、タラダフィル、5−[2−エトキシ−5−(4−エチルピペラジン−1−イルスルホニル)ピリジン−3−イル]−3−エチル−2−[2−メトキシエチル]−2,6−ジヒドロ−7H−ピラゾロ[4,3−d]ピリミジン−7−オン、5−(5−アセチル−2−ブトキシ−3−ピリジニル)−3−エチル−2−(1−エチル−3−アゼチジニル)−2,6−ジヒドロ−7H−
ピラゾロ[4,3−d]ピリミジン−7−オン、1−{6−エトキシ−5−[3−エチル−6,7−ジヒドロ−2−(2−メトキシエチル)−7−オキソ−2H−ピラゾロ[4,3−d]ピリミジン−5−イル]−3−ピリジルスルホニル}−4−エチルピペラジン、またはN−[1−(2−エトキシエチル)−5−(N−エチル−N−メチルアミノ)−7−(4−メチルピリジン−2−イルアミノ)−1H−ピラゾロ[4,3−d]ピリミジン−3−カルボニル]メタンスルホンアミド;
・カンナビノイド;
・代謝型グルタメートサブタイプ1受容体(mGluR1)アンタゴニスト;
・セロトニン再取込阻害剤、たとえばセルトラリン;
・ノルアドレナリン再取込阻害剤、特に選択的ノルアドレナリン再取込阻害剤、たとえば(S,S)−レボキセチン;
・誘導型一酸化窒素シンターゼ(iNOS)阻害剤、たとえばS−[2−[(1−イミノエチル)アミノ]エチル]−2−メチル−L−システインまたは(2S,5Z)−2−アミノ−2−メチル−7−[(1−イミノエチル)アミノ]−5−ヘプテン酸;
・アセチルコリンエステラーゼ阻害剤、たとえばドネペジル;
・ドーパミン2型(D2)アンタゴニスト、たとえばジプラジドン;
・プロスタグランジンE2サブタイプ4(EP4)アンタゴニスト、たとえばN−[({2−[4−(2−エチル−4,6−ジメチル−1H−イミダゾ[4,5−c]ピリジン−1−イル)フェニル]エチル}アミノ)カルボニル]−4−メチルベンゼンスルホンアミドまたは4−[(1S)−1−({[5−クロロ−2−(3−フルオロフェノキシ)ピリジン−3−イル]カルボニル}アミノ)エチル]安息香酸;ならびに薬剤的に受容できるその塩および溶媒和物。
そのようなキットは、2種以上の別個の医薬組成物を含有し、少なくともその1種はアルファ−2−デルタ受容体アンタゴニスト、とりわけ式(I)の化合物、および上記の組成物を別々に保持するための手段、たとえば容器、分割されたボトル、または分割されたホイルパケット(foil packet)を含有する。そのようなキットの例としては、錠剤、カプセル剤などの包装に使用される、よく知られたブリスターパックが挙げられる。
(i)式(II)の化合物または薬剤的に受容できるその塩もしくは溶媒和物;
(ii)式(I)の化合物または薬剤的に受容できるその塩もしくは溶媒和物の製造のための方法;
(iii)式(I)の化合物または薬剤的に受容できるその塩もしくは溶媒和物を薬剤的に受容できる賦形剤と一緒に含有する医薬組成物;
(iv)医薬品としての使用のための、式(I)の化合物または薬剤的に受容できるその塩、溶媒和物もしくは組成物;
(v)アルファ−2−デルタ受容体リガンドが必要とされる疾患を治療するための医薬品の工業的製造のための、式(I)の化合物の、または薬剤的に受容できるその塩、溶媒和物もしくは組成物の使用;
(vi)疼痛の治療のための医薬品の工業的製造のための、式(I)の化合物の、または薬剤的に受容できるその塩、溶媒和物もしくは組成物の使用;
(vii)有効量の式(I)の化合物で、または薬剤的に受容できるその塩、溶媒和物もしくは組成物で、ヒトを含む哺乳動物を治療することを含む、アルファ−2−デルタ受容体リガンドによる上記哺乳動物の治療の方法;
(viii)有効量の式(I)の化合物で、または薬剤的に受容できるその塩、溶媒和物もしくは組成物で、ヒトを含む哺乳動物を治療することを含む、疼痛を治療するための、上記哺乳動物の治療の方法;
(ix)本明細書に開示されたある種の新規中間体;および
(x)式(I)または(II)の化合物と1種以上の付加的な薬理学的に活性な化合物の組み合わせ。
1H核磁気共鳴(NMR)スペクトルは、すべての事例において提案された構造と一致した。特徴的な化学シフト(d)は、主要ピークの名称の慣用の略語を使用して、テトラメチルシランから下流側にppmで示す:たとえば、s、シングレット;d、ダブレット;t、トリプレット;q、カルテット;m、マルチプレット;br、ブロード。マススペクトル(MS)は、エレクトロスプレイイオン化(ESI)または大気圧化学イオン化(APCI)のいずれかを使用して記録した。以下の略語が一般的な溶媒に使用されている:CDCl3、重水素化クロロホルム;D6−DMSO、重水素化ジメチルスルホキシド;CD3OD、重水素化メタノール;THF、テトラヒドロフラン。‘アンモニア’は0.88の比重を有する濃縮アンモニア水溶液を表す。薄層クロマトグラフィー(TLC)が使用されている場合、それはシリカゲル60 F254プレートを使用するシリカゲルTLCを表す。Rfは、TLCプレート上での溶媒先端の移動距離で割った化合物の移動距離である。マイクロウェーブ放射は2.45GHzにおける15〜300Wの出力範囲の機械を使用して行われ、供給された実際の出力は反応経過中変化して、一定の温度を維持した。LCMSは、液体クロマトグラフィー質量分析法を示す(Rt=保持時間)。
(2S)−2−アミノ−4−エチル−2−メチルヘキサン酸
Pearlman触媒(0.15g)は、エタノール(5ml)および1モル水性塩酸(1ml)中の(3S,5S)−3−(2−エチルブチル)−3−メチル−5−フェニルモルホリン−2−オン(0.15g、0.54mmol、製造法1)の溶液に添加した。反応物は水素ガス(414kPa、60psi)下、室温で24時間攪拌した。反応混合物はアルボセル(arbocel)を通して濾過し、エタノール(20ml)で洗浄した。液(liquor)は減圧下で留去し、残渣はジクロロメタン((50ml)と水(20ml)に分配した。有機層を除去し、水相はそれ以外のジクロロメタン(50ml)で抽出した。水相は減圧下で留去し、黄色固体を得た。材料は、Dowex 50 WX8レジン上、0.88水性アンモニア:水(2:98〜14:86)で溶出するイオン交換クロマトグラフィーで精製し、表題化合物を白色結晶性固体(30mg)として得た。
1HNMR(CD3-OD,400MHz)d:0.83−0.89(m,6H),1.29−1.43(m,8H),1.58−1.62(dd,1H),1.81−1.86(dd,1H)。
LRMS(ESI):m/z 174[M+H+],172[M−H−]。
20wt%水酸化パラジウム‐炭素(1.0g;50wt%水 ウェット)は、プロパン−2−オールおよび水(4:1;200ml)中の4−エチル−2−(2−ヒドロキシ−1−フェニル−エチルアミノ)−2−メチル−ヘキサン酸(製造法10、10.0g;34.0mmol)の懸濁液に添加した。容器は窒素、続いて水素により、3回パージし、懸濁液はその後、水素ガス雰囲気(60psi)下、80℃で4時間攪拌した。得られた溶液は次にアルボセル(Arbocel)(登録商標)を通して濾過し、プロパン−2−オールおよび水(4:1;20ml)で洗浄した。プロパン−2−オールおよび水(4:1;100ml)を添加し、その後減圧下で蒸留して溶媒260mlを集めた。付加的な部分のプロパン−2−オール(100ml)を添加し、付加的な溶媒40mlは減圧下で蒸留により除去した。第3の部分のプロパン−2−オール(100ml)を添加し、付加的な溶媒40mlは減圧下で蒸留により除去した。その後、粘性の白色スラリーが見られ、それを22℃に冷却した。生じた溶液スラリーは22℃で30分間攪拌し、その後固体を濾過により分離した。濾過ケーキはプロパン−2−オール(20ml)で洗浄し、真空下で45℃で一晩乾燥し、表題化合物(3.5g粗重量、98%純度、20.2mmol、60%収率)を得た。;1H−NMR(CD3OD,300MHz),δ:0.86(6H,q),1.28-1.40(5H,m),1.44(3H,s),1.57−1.63(1H,dd),1.80−1.87(1H,dd)。
(2S)−2−アミノ−4−エチル−2−メチルヘキサン酸ベンゼンスルホン酸塩
アセトニトリル(50ml)中のベンゼンスルホン酸塩(9.5g)溶液は、アセトニトリル(175ml)中の(2S)−2−アミノ−4−エチル−2−メチルヘキサン酸(10g、0.057mol、実施例1)の懸濁液に添加し、混合物は溶解するまで加熱した。溶液は熱い間に濾過し、一晩冷却し、表題化合物を白色針状結晶(16.5g、86%)として得た。
1HNMR(CD3OD,400MHz)δ:0.87(m,6H),1.36(m,4H),1.41(m,1H),1.54(m,3H),1.75(m,1H),1.88(m,1H),7.42(m,3H),7.83(m,2H)、交換可能(exchangeable)な4つは現れず.
実施例1.2
(2S)−2−アミノ−4−エチル−2−メチルヘキサン酸p−トルエンスルホン酸塩
アセトニトリル(1ml)中のp−トルエンスルホン酸(54mg、0.28mmol)の溶液は、アセトニトリル(1ml)中の(2S)−2−アミノ−4−エチル−2−メチルヘキサン酸(50mg、0.28mmol、実施例1)に添加し、混合物は溶解するまで加熱した。溶液は熱い間に濾過し、一晩冷却し、表題化合物を白色針状結晶(69mg、70%)として得た。
1HNMR(CD3OD,400MHz)δ:0.88(m,6H),1.36(m,5H),1.54(s,3H),1.75(m,1H),1.90(m,1H),2.36(s,3H),7.22(d,2H),7.70(d,2H),交換可能な4つは現れず.
実施例1.3
(2S)−2−アミノ−4−エチル−2−メチルヘキサン酸塩酸塩
メタノール中のHCl溶液は、メタノール(1ml)にアセチルクロリド(0.04ml)を注意深く添加することにより製造した。冷却した溶液はメタノール(1ml)中の(2S)−2−アミノ−4−エチル−2−メチルヘキサン酸(100mg、0.56mmol、実施例1)の懸濁液に添加し、混合物は溶解するまで温め、その後減圧下で留去した。得られた塩酸塩はメタノール/アセトニトリルから再結晶化し、白色固体(63mg、52%)を得た。
1HNMR(CD3OD,400MHz)δ:0.87(m,6H),1.36(m,4H),1.43(m,1H),1.55(s,3H),1.75(m,1H),1.90(m,1H),交換可能な4つは現れず.
実施例2
2,5,5−トリメチル−L−ノルロイシン
1HNMR(CD3-OD,400MHz)d:0.91(s,9H),1.17−1.25(m,1H),1.28−1.36(m,1H),1.44(s,3H),1.59−1.67(m,1H),1.83−1.91(m,1H).
LRMS(ESI):m/z 174[M+H+],172[M−H−].
実施例3
(2S)−2−アミノ−3−シクロペンチル−2−メチルプロパン酸
1HNMR(CD3-OD,400MHz)d:1.08−1.22(m,2H),1.44(s,3H),1.48−1.68(m,4H),1.74−2.00(m,5H).
LRMS(ESI):m/z 174[M+H+],172[M−H−].
実施例4
(2S)−2−アミノ−5−エチル−2−メチルヘプタン酸
1HNMR(CD3-OD,400MHz)d:0.85−0.92(m,6H),1.16−1.48(m,7H),1.56(s,3H),1.72−1.99(m,2H).
LRMS(ESI):m/z 188[M+H+],186[M−H−].
実施例5
(2S)−2−アミノ−3−シクロブチル−2−メチルプロパン酸
1HNMR(CD3-OD,400MHz)d:1.40(s,3H),1.69−1.84 (m,6H),2.04−2.17(m,2H),2.41−2.54(m,1H).
LRMS(ESI):m/z 158[M+H+],156[M−H−].
実施例6
(2S,5R)−2−アミノ−2,5−ジメチルヘプタン酸
1HNMR(CD3-OD,400MHz)d:0.89(6H,m),1.08−1.24(2H,m),1.26−1.49(6H,m),1.56−1.65(1H,m),1.87−1.96(1H,m).
LRMS(APCI):m/z 174[M+H+].
実施例7
(4S)−2,4−ジメチル−L−ノルロイシン
1HNMR(CD3-OD,400MHz)d:0.90−0.92(m,3H),0.94−0.95(m,3H),1.17−1.40(m,2H),1.45(s,3H),1.50−1.58(bs,1H),1.69−1.81(m,1H),1.70−1.83(m,1H).
LRMS(ESI):m/z 262[M+H+].
以下の製造法は先に記載の実施例の製造において使用される中間体がそれら自体どのように合成され得るかを示す。
(3S,5S)−3−(2−エチルブチル)−3−メチル−5−フェニルモルホリン−2−オン
1HNMR(CDCl3,400MHz)d:0.79(q,6H),1.26−1.35(m,5H),1.41(s,3H),1.63(dd,1H),1.91(dd,1H),4.17−4.26(m,1H),4.28−4.35(m,2H),7.25−7.36(m,5H).
LRMS(ESI):m/z 276[M+H+].
製造法2
(3S,5S)−3−(3,3−ジメチルブチル)−3−メチル−5−フェニルモルホリン−2−オン
1HNMR(CDCl3,400MHz)d:0.91(s,9H),1.13−1.31(m,3H),1.42(s,3H),1.67−1.77(bs,1H),2.02−2.10(m,1H),4.31−4.43(m,3H),7.34−7.46(m,5H).
LRMS(ESI):m/z 276[M+H+].
製造法3
(3S,5S)−3−(シクロペンチルメチル)−3−メチル−5−フェニルモルホリン−2−オン
1HNMR(CDCl3,400MHz)d:1.12−1.22(m,2H),1.43−1.65(m,8H),1.78−1.94(m,4H),2.13−2.18(m,1H),4.23−4.42(m,3H),7.31−7.45(m,5H).
LRMS(ESI):m/z 274[M+H+]
製造法4
(3S,5S)−3−(3−エチルペンチル)−3−メチル−5−フェニルモルホリン−2−オン
1HNMR(CDCl3,400MHz)d:0.91(s,9H),1.13−1.31(m,3H),1.42(s,3H),1.67−1.77(bs,1H),2.02−2.10(m,1H),4.31−4.43(m,3H),7.34−7.46(m,5H).
LRMS(ESI):m/z 276[M+H+].
製造法5
(3S,5S)−3−(シクロブチルメチル)−3−メチル−5−フェニルモルホリン−2−オン
1HNMR(CDCl3,400MHz)d:1.43(s,3H),1.73−1.82(m,2H),1.86−1.92(m,2H),2.02−2.12(m,2H),2.14−2.19(m,1H),2.43−2.52(m,1H),4.22−4.27(m,1H),4.33−4.37(m,2H),7.31−7.43(m,5H).
LRMS(ESI):m/z 260[M+H+].
製造法6
(5R)−5−メチルヘプタン−2−オン
1HNMR(CDCl3-,400MHz)d:0.82−0.88(6H,m),1.07−1.19(1H,m),1.25−1.41(3H,m),1.54−1.64(1H,m),2.12(3H,s),2.34−2.47(2H,m).
製造法7
N−[(1E,4R)−1,4−ジメチルヘキシリデン]−(S)−2−メチルプロパン−2−スルホンアミド
1HNMR(CDCl3-,400MHz)d:0.82−0.91(6H,m),1.10−1.23(10H,m),1.29−1.43(3H,m),1.54−1.65(1H,m),2.15(0.6H,s),2.30(2.4H,s),2.32−2.72(2H,m).
LRMS:m/z ESI 232[M+H+]
製造法8
N−[(1S,4R)−1−シアノ−1,4−ジメチルヘキシル]−2−メチルプロパン−(S)−2−スルフィンアミド
1HNMR(CDCl3-,400MHz)d:0.86−0.93(6H,m),1.13−1.26(10H,m),1.29−1.44(3H,m),1.48−1.57(2H,m),1.64(3H,s),1.81−1.98(2H,m),3.41(1H,s).
LRMS(APCI):m/z 259[M+H+].
製造法9
(3S,5S)−3−メチル−3−[(2S)−2−メチルブチル]−5−フェニルモルホリン−2−オン
1HNMR(CDCl3,400MHz)d:0.85−0.88(m,3H),0.94−0.96(m,3H),1.17−1.40(m,H),1.46(s,3H),1.60(bs,1H),1.73−1.78(m,1H),1.88−1.93(m,1H),4.22−4.42(m,3H),7.28−7.42(m,5H).
LRMS(ESI):m/z [M+H+].
製造法10
4−エチル−2−(2−ヒドロキシ−1−フェニル−エチルアミノ)−2−メチル−ヘキサン酸
Claims (8)
- 化合物:(2S)−2−アミノ−4−エチル−2−メチルヘキサン酸、または薬剤的に受容できるその塩もしくは溶媒和物。
- (2S)−2−アミノ−4−エチル−2−メチルヘキサン酸である、請求項1に記載の化合物。
- (2S)−2−アミノ−4−エチル−2−メチルヘキサン酸ベンゼンスルホン酸塩である、薬剤的に受容できる塩である、請求項1に記載の化合物。
- (2S)−2−アミノ−4−エチル−2−メチルヘキサン酸p−トルエンスルホン酸塩である、薬剤的に受容できる塩である、請求項1に記載の化合物。
- (2S)−2−アミノ−4−エチル−2−メチルヘキサン酸塩酸塩である、薬剤的に受容できる塩である、請求項1に記載の化合物。
- 請求項1〜5のいずれか1項に定義された(2S)−2−アミノ−4−エチル−2−メチルヘキサン酸、または薬剤的に受容できるその塩もしくは溶媒和物、および薬剤的に受容できる賦形剤を含有する、医薬組成物。
- 請求項1〜5のいずれか1項に定義された化合物:(2S)−2−アミノ−4−エチル−2−メチルヘキサン酸、または薬剤的に受容できるその塩もしくは溶媒和物を含有する、疼痛治療用の医薬品。
- 請求項1〜5のいずれか1項に定義された化合物:(2S)−2−アミノ−4−エチル−2−メチルヘキサン酸、または薬剤的に受容できるその塩もしくは溶媒和物、および別の薬理学的に活性な化合物を組み合わせてなる医薬品。
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---|---|---|---|---|
JP2009040767A (ja) * | 2005-04-28 | 2009-02-26 | Pfizer Ltd | アミノ酸誘導体 |
JP2012176902A (ja) * | 2011-02-25 | 2012-09-13 | Tosoh F-Tech Inc | 新規な光学活性含フッ素化合物、その製造方法及びそれを用いた光学活性3,3,3−トリフルオロアラニンの製造方法 |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1094757C (zh) | 1996-07-24 | 2002-11-27 | 沃尼尔·朗伯公司 | 用于治疗疼痛的异丁基γ-氨基丁酸及其衍生物 |
US20090227680A1 (en) * | 2005-11-17 | 2009-09-10 | Pfizer, Inc. | Amino Acid Derivatives |
US8278355B2 (en) | 2006-09-12 | 2012-10-02 | Therexcell Pharma Inc. | Isovaline for treatment of pain |
CN101195583B (zh) * | 2006-12-04 | 2012-07-04 | 四川抗菌素工业研究所有限公司 | 一种光学纯米那普仑及其盐的制备方法 |
BR122021020474B1 (pt) * | 2008-09-09 | 2022-06-07 | F. Hoffmann-La Roche Ag | Polimorfos de acil sulfonamidas, seu uso, seu processo de preparação e composição farmacêutica que os compreende |
AT514349B1 (de) * | 2013-06-12 | 2018-05-15 | Red Bull Gmbh | Alpha-alkylierte Aminosäuren (AAAAs) |
Family Cites Families (60)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB504209A (en) | 1937-12-14 | 1939-04-21 | Pirelli General Cable Works | Improvements in or relating to electric cables |
BR6239521D0 (pt) * | 1961-08-09 | 1973-06-14 | Merck & Co Inc | Processo de preparacao de novos amino acidos |
FR2586562B1 (fr) | 1985-09-02 | 1989-03-10 | Inst Nat Sante Rech Med | Composition pharmaceutique contenant de l'a-methylhistamine |
DE3811256A1 (de) | 1988-04-02 | 1989-10-19 | Hoechst Ag | (alpha)-trifluormethylaminosaeure-derivate, verfahren zur herstellung von (alpha)-trifluormethylaminosaeure-derivaten und ihre verwendung als arzneimittel |
EP0484437A4 (en) | 1989-07-27 | 1994-06-01 | Searle & Co | Renal-selective prodrugs for the treatment of hypertension |
FR2681067B1 (fr) * | 1991-09-10 | 1993-12-17 | Elf Sanofi | Derives heterocycliques n-substitues, leur preparation, les compositions pharmaceutiques en contenant. |
JPH042899A (ja) | 1990-04-16 | 1992-01-07 | Arakawa Chem Ind Co Ltd | 紙用サイズ剤および該サイズ剤を用いる紙サイジング方法 |
FR2661909B1 (fr) | 1990-05-09 | 1997-08-14 | Inst Nat Sante Rech Med | Nouveaux composes agonistes du recepteur h3 de l'histamine a usage therapeutique, compositions pharmaceutiques agissant comme agonistes dudit recepteur et procede de preparation. |
JPH051002A (ja) | 1991-02-15 | 1993-01-08 | Nikko Kyodo Co Ltd | α−アミノ酸の製造方法 |
CA2068038A1 (en) | 1991-05-08 | 1992-11-09 | Christopher Yee | Enzymatic resolution of .alpha.-tertiary carboxylic acid esters |
US5993775A (en) * | 1991-11-27 | 1999-11-30 | Diatide, Inc. | Radioactively labeled peptides comprising a single thiol moiety |
GB9200210D0 (en) | 1992-01-07 | 1992-02-26 | British Bio Technology | Compounds |
EP0667773A4 (en) | 1992-10-14 | 1996-09-25 | Merck & Co Inc | FIBRINOGEN RECEPTOR ANTAGONISTS. |
US5362747A (en) | 1992-11-25 | 1994-11-08 | Abbott Laboratories | 2-nitroaryl and 2-cyanoaryl compounds as regulators of nitric oxide synthase |
GB9325368D0 (en) | 1993-12-10 | 1994-02-16 | Univ Bristol | Organic compounds |
GB9325360D0 (en) | 1993-12-10 | 1994-02-16 | Univ Bristol | Organic compounds |
IS4261A (is) | 1994-02-21 | 1995-08-22 | Astra Aktiebolag | Nýir peptíð-ópíóíðar til meðhöndlunar á verkjum og notkun þeirra |
DE19533617A1 (de) | 1995-09-11 | 1997-03-13 | Degussa | Neues Verfahren zur Herstellung von optisch aktiven alpha-Aminosäuren und alpha-Aminosäure-Derivaten |
PT780386E (pt) | 1995-12-20 | 2003-02-28 | Hoffmann La Roche | Inibidores de metaloprotease de matriz |
WO1998014208A1 (en) | 1996-09-30 | 1998-04-09 | President And Fellows Of Harvard College | Reactive ligands and covalent ligand-protein complexes |
US5962523A (en) | 1996-10-25 | 1999-10-05 | Discovery Laboratories, Inc. | Methods of using butyric acid derivatives to protect against hair loss |
JPH10333511A (ja) | 1997-05-30 | 1998-12-18 | Ricoh Co Ltd | 画像除去促進液、該画像除去促進液を用いた被記録材の再生方法及び再生装置 |
JP4205191B2 (ja) | 1997-12-26 | 2009-01-07 | ダイセル化学工業株式会社 | α−アミノニトリル誘導体及びα−アミノ酸の製造方法 |
DE99907899T1 (de) | 1998-03-11 | 2005-01-13 | Kabushiki Kaisha Soken | Hautnormalisierungsmittel |
BR9910130A (pt) * | 1998-04-17 | 2001-01-09 | Kenneth Curry | Derivados de cubana como antagonistas de receptor de glutamato metabotrópico e processo para a sua preparação |
PL348237A1 (en) | 1998-12-18 | 2002-05-20 | Novo Nordisk As | Fused 1,2,4-thiadiazine derivatives, their preparation and use |
AU1857600A (en) | 1998-12-22 | 2000-07-12 | Neurosearch A/S | Ion channel modulating agents |
FR2788271B1 (fr) | 1999-01-07 | 2001-02-09 | Rhone Poulenc Agrochimie | Nouveau procede de preparation d'aminoacides chiraux |
CA2359076A1 (en) | 1999-01-22 | 2000-07-27 | Adnan M. M. Mjalli | A method for the synthesis of compounds of formula 1 and derivatives thereof |
EP1149843A4 (en) | 1999-01-28 | 2012-06-06 | Chugai Pharmaceutical Co Ltd | SUBSTITUTED PHENETHYLAMINE DERIVATIVES |
FR2791982B1 (fr) | 1999-04-06 | 2002-12-27 | Inst Nat Sante Rech Med | Inhibiteurs de lta4 hydrolase et leurs applications therapeutiques. |
WO2001009117A1 (en) * | 1999-07-29 | 2001-02-08 | Allellix Neuroscience Inc. | Tricyclic compounds as glycine transport inhibitors |
FR2796943A1 (fr) | 1999-07-30 | 2001-02-02 | Aventis Pharma Sa | Derives de benzoxazinnes, leur procede de preparation et leur utilisation en therapeutique |
WO2001017944A1 (fr) | 1999-09-07 | 2001-03-15 | Mitsubishi Rayon Co., Ltd. | Procede relatif a l'elaboration d'aminoalcool optiquement actif |
WO2001017499A1 (fr) | 1999-09-07 | 2001-03-15 | Kabushiki Kaisha Soken | Agents d'entretien de la peau |
JP2001081013A (ja) | 1999-09-10 | 2001-03-27 | Soken Kk | 毛髪健全化剤 |
US7300775B2 (en) | 1999-12-29 | 2007-11-27 | Verenium Corporation | Methods for producing α-substituted carboxylic acids using nitrilases and strecker reagents |
US6656958B2 (en) * | 2000-02-02 | 2003-12-02 | Abbott Laboratories | Substituted pyridine compounds useful for controlling chemical synaptic transmission |
DE10121028A1 (de) | 2000-05-05 | 2002-01-31 | Basf Ag | Verfahren zur Herstellung von Aldehyden |
DE10121026A1 (de) | 2000-05-05 | 2002-02-07 | Basf Ag | Verfahren zur Herstellung von Aldehyden |
EP1300392B1 (en) | 2000-05-18 | 2012-09-05 | Mitsubishi Rayon Co., Ltd. | Process for producing optically active alpha-amino acid and optically active alpha-amino acid amide |
WO2003011799A1 (en) | 2000-07-31 | 2003-02-13 | Brandeis University | Kinetic resolutions of chirat 3- and 3-substituted carboxylic acids |
DE10048715A1 (de) * | 2000-09-30 | 2004-05-19 | Grünenthal GmbH | Verwendung von Aminosäure zur Behandlung von Schmerz |
AUPR406901A0 (en) | 2001-03-29 | 2001-04-26 | La Trobe University | Insecticide and method of controlling insects |
JP4715058B2 (ja) | 2001-08-02 | 2011-07-06 | Jsr株式会社 | 感放射性樹脂組成物 |
JP2003221328A (ja) | 2002-01-29 | 2003-08-05 | Soken Kk | 皮膚健全化剤 |
AU2003247374A1 (en) | 2002-05-15 | 2003-12-02 | Genzyme Corporation | Synthesis of 2-alkylcysteines, 2-(hydroxylated phenyl)-4-alkylthiazoline-4-carboxylic acids and derivatives thereof |
JP2006504664A (ja) | 2002-08-01 | 2006-02-09 | ビーエーエスエフ アクチェンゲゼルシャフト | 農薬フルオロアルケン誘導体 |
US20060025471A1 (en) * | 2002-09-13 | 2006-02-02 | Kenneth Curry | Xanthenyl cubane analogs with activity at the metabotropic glutamate receptors |
US20060172393A1 (en) | 2003-01-10 | 2006-08-03 | Kaneka Corporation | Process for producing optically active alpha -methylcysteine derivative |
JP2005060311A (ja) * | 2003-08-13 | 2005-03-10 | Mochida Pharmaceut Co Ltd | N−(ベンゾイル)アミノ酸誘導体を有効成分とするニューロパシー性疼痛治療剤 |
GB0322140D0 (en) * | 2003-09-22 | 2003-10-22 | Pfizer Ltd | Combinations |
JPWO2005044780A1 (ja) | 2003-11-10 | 2007-05-17 | 杏林製薬株式会社 | アミノカルボン酸誘導体とその付加塩及びs1p受容体調節剤 |
EP1718602A4 (en) * | 2004-01-30 | 2007-12-12 | Peplin Biolipids Pty Ltd | THERAPEUTIC AND CARRIER MOLECULES |
GB0405289D0 (en) | 2004-03-09 | 2004-04-21 | Novartis Ag | Organic compounds |
TW200642687A (en) * | 2005-03-01 | 2006-12-16 | Pfizer Ltd | Combinations comprising α-2-δ ligands |
AU2006219643A1 (en) | 2005-03-01 | 2006-09-08 | Pfizer Limited | Use of PDE7 inhibitors for the treatment of neuropathic pain |
CN101160285A (zh) * | 2005-03-17 | 2008-04-09 | 辉瑞大药厂 | 适用于治疗疼痛的n-(n-磺酰氨基甲基)环丙烷甲酰胺衍生物 |
EA200701852A1 (ru) * | 2005-04-28 | 2008-04-28 | Пфайзер Лимитед | Производные аминокислот |
EP1957467A2 (en) * | 2005-12-02 | 2008-08-20 | Pfizer Limited | Spirocyclic derivatives |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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JP2009040767A (ja) * | 2005-04-28 | 2009-02-26 | Pfizer Ltd | アミノ酸誘導体 |
JP2012176902A (ja) * | 2011-02-25 | 2012-09-13 | Tosoh F-Tech Inc | 新規な光学活性含フッ素化合物、その製造方法及びそれを用いた光学活性3,3,3−トリフルオロアラニンの製造方法 |
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