JP2007505097A - アルファ−2−デルタリガンドとセロトニン/ノルアドレナリン再取込み阻害薬を含む組合せ - Google Patents
アルファ−2−デルタリガンドとセロトニン/ノルアドレナリン再取込み阻害薬を含む組合せ Download PDFInfo
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- JP2007505097A JP2007505097A JP2006525924A JP2006525924A JP2007505097A JP 2007505097 A JP2007505097 A JP 2007505097A JP 2006525924 A JP2006525924 A JP 2006525924A JP 2006525924 A JP2006525924 A JP 2006525924A JP 2007505097 A JP2007505097 A JP 2007505097A
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- pain
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
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Abstract
Description
本発明は、疼痛治療のための、アルファ−2−デルタリガンドとデュアルセロトニン−ノルアドレナリン再取込み阻害薬(DSNRI)か又は選択的セロトニン再取込み阻害薬(SSRI)及び選択的ノルアドレナリン再取込み阻害薬(SNRI)の片方又は両方との相乗的組合せに関する。本発明はまた、有効量のアルファ−2−デルタリガンドとDSNRIか又はSSRI及びSNRIの片方又は両方との相乗的組合せの使用による疼痛の治療法にも関する。
アルファ−2−デルタ受容体リガンドは、ヒトカルシウムチャンネルのいずれかのサブタイプのアルファ−2−デルタサブユニットに結合する任意の分子である。カルシウムチャンネルのアルファ−2−デルタサブユニットはいくつかの受容体サブタイプを含む。これらについては文献に記載されている。例えば、N.S.Gee,J.P.Brown,V.U.Dissanayake,J.Offord,R.Thurlow,及びG.N.Woodruff,J−Biol−Chem 271(10):5768−76,1996(タイプ1);Gong,J.Hang,W.Kohler,Z.Li,及びT−Z.Su,J.Membr.Biol.184(1):35−43,2001,(タイプ2及び3);E.Marais,N.Klugbauer,及びF.Hofmann,Mol.Pharmacol.59(5):1243−1248,2001.(タイプ2及び3);並びにN.Qin,S.Yagel,M.L.Momplaisir,E.E.Codd,及びM.R.D’Andrea.Mol.Pharmacol.62(3):485−496,2002,(タイプ4)などの文献である。それらはGABA類似体としても知られている。
R2は、水素又は所望により1〜5個のフッ素原子で置換されていてもよい(C1−C6)アルキルであるか;又は
R1及びR2は、それらが結合している炭素と一緒になって、3〜6員のシクロアルキル環を形成し;
R3は、(C1−C6)アルキル、(C3−C6)シクロアルキル、(C3−C6)シクロアルキル−(C1−C3)アルキル、フェニル、フェニル−(C1−C3)アルキル、ピリジル、ピリジル−(C1−C3)アルキル、フェニル−N(H)−、又はピリジル−N(H)−であり、前記アルキル部分のそれぞれは、所望により1〜5個のフッ素原子、好ましくは0〜3個のフッ素原子で置換されていてもよく、前記フェニル及び前記ピリジル及び前記フェニル−(C1−C3)アルキル及び前記ピリジル−(C1−C3)アルキルのそれぞれフェニル及びピリジル部分は、所望により、クロロ、フルオロ、アミノ、ニトロ、シアノ、(C1−C3)アルキルアミノ、所望により1〜3個のフッ素原子で置換されていてもよい(C1−C3)アルキル及び所望により1〜3個のフッ素原子で置換されていてもよい(C1−C3)アルコキシから独立して選ばれる1〜3個の置換基、好ましくは0〜2個の置換基で置換されていてもよく;
R4は、水素又は所望により1〜5個のフッ素原子で置換されていてもよい(C1−C6)アルキルであり;
R5は、水素又は所望により1〜5個のフッ素原子で置換されていてもよい(C1−C6)アルキルであり;そして
R6は、水素又は(C1−C6)アルキルである}の化合物、又はその製薬学的に許容しうる塩が記載されている。
発明の要旨
今般、アルファ−2−デルタリガンドと、デュアルセロトニン−ノルアドレナリン再取込み阻害薬(DSNRI)か又は選択的セロトニン再取込み阻害薬(SSRI)及び選択的ノルアドレナリン再取込み阻害薬(SNRI)の片方又は両方のいずれかとの併用療法が疼痛の治療に改善をもたらすことを見出した。さらに、同時、順次又は別個に投与すると、アルファ−2−デルタリガンドとDSNRIか又はSSRI及びSNRIの片方又は両方のいずれかとは、相乗的に相互作用して疼痛をコントロールすることができる。この相乗作用のために各化合物の所要量の削減が可能となり、副作用の軽減と該化合物の臨床的有用性の向上がもたらされる。
nは、0、1又は2であり;そして
R1、R1a、R2、R2a、R3、R3a、R4及びR4aは、H及びC1−C6アルキルから独立して選ばれるか、又はR1とR2又はR2とR3は、一緒になってC3−C7シクロアルキル環を形成し、それは所望によりC1−C6アルキルから選ばれる1又は2個の置換基で置換されていてもよい)、又はその製薬学的に許容しうる塩によって示される。
nは、0又は1であり、R1は水素又は(C1−C6)アルキルであり;R2は水素又は(C1−C6)アルキルであり;R3は水素又は(C1−C6)アルキルであり;R4は水素又は(C1−C6)アルキルであり;R5は水素又は(C1−C6)アルキルであり、そしてR2は水素又は(C1−C6)アルキルである}、又はその製薬学的に許容しうる塩で示される。
n及びn1は、独立して1、2又は3であり;
基R及びR1のそれぞれは、同じでも異なっていてもよいが、水素;ハロゲン;ハロ−C1−C6アルキル;ヒドロキシ;C1−C6アルコキシ;所望により置換されていてもよいC1−C6アルキル;所望により置換されていてもよいアリール−C1−C6アルキル;所望により置換されていてもよいアリール−C1−C6アルコキシ;−NO2;
R2は、水素;所望により置換されていてもよいC1−C12アルキル、又はアリール−C1−C6アルキルであり;
基R3及びR4のそれぞれは、同一でも異なっていてもよいが、水素、所望により置換されていてもよいC1−C6アルキル、C2−C4アルケニル、C2−C4アルキニル、所望により置換されていてもよいアリール−C2−C4アルキル、所望により置換されていてもよいC3−C7シクロアルキル、又はR3及びR4はそれらが結合している窒素原子と共に5原子又は6原子の飽和又は不飽和の、所望により置換されていてもよいヘテロ単環式ラジカル(所望により、O、S及びNのクラスに属する他のヘテロ原子を含有していてもよい)を形成し;又はR2及びR4は、一緒になって、−CH2−CH2−ラジカルを形成する。式(IV)の好適な化合物はレボキセチンによって表される。
n及びmは、独立して、1、2及び3から選ばれ;
R1及びR2は、独立して、水素、(C1−C4)アルキル、(C2−C4)アルケニル、及び(C2−C4)アルキニルから選ばれるか、又はR1とR2は、それらが結合している窒素と一緒になって、R1とR2が結合している窒素を含めて1又は2個のヘテロ原子を含有する4〜8員の飽和環を形成し、第二のヘテロ原子が存在する場合、それは、酸素、窒素及び硫黄から選ばれるが、ただし、前記環は2個の隣接する酸素原子又は2個の隣接する硫黄原子を含有できず、また、前記環は、所望により、利用可能な結合部位で、ヒドロキシ及び(C1−C6)アルキルから独立して選ばれる1〜3個の置換基で置換されていてもよく;
R3及びR4は、独立して、水素及び所望により1〜3個のフッ素原子で置換されていてもよい(C1−C4)アルキルから選ばれるか、又はR3とR4はそれらが結合している炭素と一緒になって4〜8員の飽和炭素環を形成し、前記環は、所望により、利用可能な結合部位で、ヒドロキシ及び(C1−C6)アルキルから独立して選ばれる1〜3個の置換基で置換されていてもよく;
又はR2とR3は、R2が結合している窒素及びR3が結合している炭素と一緒になって、R2が結合している窒素を含めて1又は2個のヘテロ原子を含有する4〜8員の飽和環を形成し、第二のヘテロ原子が存在する場合、それは、酸素、窒素及び硫黄から選ばれるが、ただし、前記環は2個の隣接する酸素原子又は2個の隣接する硫黄原子を含有できず、また、前記環は、所望により、利用可能な結合部位で、ヒドロキシ及び(C1−C6)アルキルから独立して選ばれる1〜3個の置換基で置換されていてもよく;
各Xは、独立して、水素、ハロ(すなわち、クロロ、フルオロ、ブロモ又はヨード)、所望により1〜3個のフッ素原子で置換されていてもよい(C1−C4)アルキル、所望により1〜3個のフッ素原子で置換されていてもよい(C1−C4)アルコキシ、シアノ、ニトロ、アミノ、(C1−C4)アルキルアミノ、ジ−[(C1−C4)アルキル]アミノ、NR5(C=O)(C1−C4)アルキル、SO2NR5R6及びSOp(C1−C6)アルキル{式中、R5及びR6は、独立して、水素及び(C1−C6)アルキルから選ばれ、pは0、1又は2である}から選ばれ;そして
各Yは、独立して、水素、(C1−C6)アルキル及びハロから選ばれ;
ただし、(a)NR1R2、CR3R4及びR2NCR3の一つしか(no more than one)環を形成できず;そして(b)(i)R3及びR4がどちらも水素の場合、(ii)R1及びR2が、独立して、水素及び(C1−C4)アルキルから選ばれる場合、及び(iii)環Bが、1又は2個のハロ基でそれぞれ置換されているモノ又はジ置換の場合、少なくとも1個のXは水素以外でなくてはならない]の化合物、及びその製薬学的に許容しうる塩によって表すことができる。式(V)による化合物はWO00/50380に記載されている。
ガバペンチンとセルトラリン;
ガバペンチンとミルナシプラン;
ガバペンチンとデュロキセチン;
ガバペンチンとベンラファキシン;
ガバペンチンとマプロチリン;
ガバペンチンとデシプラミン;
ガバペンチンとブプロプリオン;
ガバペンチンとレボキセチン;
ガバペンチンとS,S−レボキセチン;
プレガバリンとセルトラリン;
プレガバリンとミルナシプラン;
プレガバリンとデュロキセチン;
プレガバリンとベンラファキシン;
プレガバリンとマプロチリン;
プレガバリンとデシプラミン;
プレガバリンとブプロプリオン;
プレガバリンとレボキセチン;
プレガバリンとS,S−レボキセチン;
[(1R,5R,6S)−6−(アミノメチル)ビシクロ[3.2.0]ヘプタ−6−イル]酢酸とセルトラリン;
[(1R,5R,6S)−6−(アミノメチル)ビシクロ[3.2.0]ヘプタ−6−イル]酢酸とミルナシプラン;
[(1R,5R,6S)−6−(アミノメチル)ビシクロ[3.2.0]ヘプタ−6−イル]酢酸とデュロキセチン;
[(1R,5R,6S)−6−(アミノメチル)ビシクロ[3.2.0]ヘプタ−6−イル]酢酸とベンラファキシン;
[(1R,5R,6S)−6−(アミノメチル)ビシクロ[3.2.0]ヘプタ−6−イル]酢酸とマプロチリン;
[(1R,5R,6S)−6−(アミノメチル)ビシクロ[3.2.0]ヘプタ−6−イル]酢酸とデシプラミン;
[(1R,5R,6S)−6−(アミノメチル)ビシクロ[3.2.0]ヘプタ−6−イル]酢酸とブプロプリオン;
[(1R,5R,6S)−6−(アミノメチル)ビシクロ[3.2.0]ヘプタ−6−イル]酢酸とレボキセチン;
[(1R,5R,6S)−6−(アミノメチル)ビシクロ[3.2.0]ヘプタ−6−イル]酢酸とS,S−レボキセチン;
(1α,3α,5α)(3−アミノ−メチル−ビシクロ[3.2.0]ヘプタ−3−イル)−酢酸とセルトラリン;
(1α,3α,5α)(3−アミノ−メチル−ビシクロ[3.2.0]ヘプタ−3−イル)−酢酸とミルナシプラン;
(1α,3α,5α)(3−アミノ−メチル−ビシクロ[3.2.0]ヘプタ−3−イル)−酢酸とデュロキセチン;
(1α,3α,5α)(3−アミノ−メチル−ビシクロ[3.2.0]ヘプタ−3−イル)−酢酸とベンラファキシン;
(1α,3α,5α)(3−アミノ−メチル−ビシクロ[3.2.0]ヘプタ−3−イル)−酢酸とマプロチリン;
(1α,3α,5α)(3−アミノ−メチル−ビシクロ[3.2.0]ヘプタ−3−イル)−酢酸とデシプラミン;
(1α,3α,5α)(3−アミノ−メチル−ビシクロ[3.2.0]ヘプタ−3−イル)−酢酸とブプロプリオン;
(1α,3α,5α)(3−アミノ−メチル−ビシクロ[3.2.0]ヘプタ−3−イル)−酢酸とレボキセチン;
(1α,3α,5α)(3−アミノ−メチル−ビシクロ[3.2.0]ヘプタ−3−イル)−酢酸とS,S−レボキセチン;
(3S,4S)−(1−アミノメチル−3,4−ジメチル−シクロペンチル)−酢酸とセルトラリン;
(3S,4S)−(1−アミノメチル−3,4−ジメチル−シクロペンチル)−酢酸とミルナシプラン;
(3S,4S)−(1−アミノメチル−3,4−ジメチル−シクロペンチル)−酢酸とデュロキセチン;
(3S,4S)−(1−アミノメチル−3,4−ジメチル−シクロペンチル)−酢酸とベンラファキシン;
(3S,4S)−(1−アミノメチル−3,4−ジメチル−シクロペンチル)−酢酸とマプロチリン;
(3S,4S)−(1−アミノメチル−3,4−ジメチル−シクロペンチル)−酢酸とデシプラミン;
(3S,4S)−(1−アミノメチル−3,4−ジメチル−シクロペンチル)−酢酸とブプロプリオン;
(3S,4S)−(1−アミノメチル−3,4−ジメチル−シクロペンチル)−酢酸とレボキセチン;及び
(3S,4S)−(1−アミノメチル−3,4−ジメチル−シクロペンチル)−酢酸とS,S−レボキセチン;
又はそれらの製薬学的に許容しうる塩から選ばれる。
そこで、本発明の更なる側面として、アルファ−2−デルタリガンドとDSNRIか又はSSRI及びSNRIの片方又は両方を含む、ヒトへの投与用の相乗的組合せを提供する。この場合、各成分の血漿中濃度範囲は、最初に相乗的相互作用を確認するのに使用されたヒト以外の動物モデル、好ましくはラットモデルで観察された絶対的範囲に対応する。適切には、ヒトにおける血漿中濃度範囲は、アルファ−2−デルタリガンドの場合、ラットモデルにおける0.05μg/ml〜10.5μg/mlの範囲に対応する。
本発明の化合物は、当業者に周知の方法によって製造される。具体的には、本明細書の上文に記載した特許、特許出願及び公開(これらはいずれも引用によって本明細書に援用する)に、本発明による組合せ、医薬組成物、方法及びキットに使用できる化合物が例示され、それらの化合物の製造法が言及されている。
本発明の化合物の範囲内にはその多形も含まれる。
(1)例えばエステラーゼ又はリパーゼによって切断されうるエステル又はアミド誘導体。エステル誘導体の場合、エステルは薬物分子のカルボン酸部分から公知手段によって誘導される。アミド誘導体の場合、アミドは薬物分子のカルボン酸部分又はアミン部分から公知手段によって誘導されうる。
(2)特異的又は非特異的プロテイナーゼによって認識されうるペプチド。ペプチドは、薬物分子に、公知手段によって薬物分子のアミン又はカルボン酸部分とアミド結合を形成することによって結合できる。
(3)プロドラッグ形又は修飾プロドラッグ形の膜選別を通じて作用部位に蓄積する誘導体。
(4)1〜3の任意の組合せ。
でありうる。
−筋骨格障害、例えば、筋痛、線維筋痛、脊椎炎、血清陰性(非リウマチ様)関節症、関節外リウマチ、ジストロフィン異常症、グリコーゲン分解、多発性筋炎、化膿性筋炎などであるが、これらに限定されない。
−内臓痛、及び胃腸障害。内臓は腹腔内の臓器を包含する。これらの臓器には、性器、脾臓及び消化器系の一部が含まれる。内臓に伴う痛みは消化器系の内臓痛と非消化器系の内臓痛に分けられる。一般にみられる消化管(GI)障害は、機能性腸疾患(FBD)と炎症性腸疾患(IBD)を含む。これらのGI障害は、現在は中等度にしかコントロールされていない広範な疾患状態を含む。例えば、FBDについては、胃食道逆流、消化不良、過敏性腸症候群(IBS)及び機能性腹痛症候群(FAPS)、IBDについては、クローン病、回腸炎、及び潰瘍性大腸炎などであるが、いずれも恒常的に内臓痛を生ずる。その他の内臓痛としては、月経困難、骨盤痛、膀胱炎及び膵臓炎に伴う痛みなどである。
−口腔顔面痛、例えば、歯痛、顎関節性筋筋膜疼痛などであるが、これらに限定されない。
更なる側面として、アルファ−2−デルタリガンドとDSNRIか又はSSRI及びSNRIの片方又は両方を、疼痛、特に神経因性疼痛の治癒的、予防的又は対症的治療用医薬品の製造に使用することを提供する。ただし、WO02/85839の化合物(i)〜(xxv)とセロトニン再取込み阻害薬、特にフルオキセチン、パロキセチン、シタロプラム及びセルトラリン、混合セロトニン−ノルアドレナリン再取込み阻害薬、特にミルナシプラン、ベンラファキシン及びデュロキセチン、及びノルアドレナリン再取込み阻害薬、特にレボキセチンとの組合せは除外する。
本発明の化合物がデュアルセロトニン−ノルアドレナリン又は選択的ノルアドレナリン再取込み阻害薬として働く能力は、確立された方法に従って、特に上記文献の方法に従って測定できる。
(i)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、フェンタニール、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、ナルブフィン及びペンタゾシン;
(ii)非ステロイド系抗炎症薬(NSAID)、例えば、アスピリン、ジクロフェナク、ジフルシナール(diflusinal)、エトドラク、フェンブフェン、フェノプロフェン、フルフェニサール、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、ケトロラック、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、スリンダク、トルメチン、ゾメピラック、及びそれらの製薬学的に許容しうる塩;
(iii)バルビツレート鎮静薬、例えば、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(butabital)、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(theamylal)、チオペンタール及びそれらの製薬学的に許容しうる塩;
(iv)鎮静作用を有するベンゾジアゼピン類、例えば、クロルジアゼポキシド、クロラゼペート、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、トリアゾラム、及びそれらの製薬学的に許容しうる塩;
(v)鎮静作用を有するH1アンタゴニスト、例えば、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、クロルシクリジン、及びそれらの製薬学的に許容しうる塩;
(vi)その他の鎮静薬、例えば、グルテチミド、メプロバメート、メタカロン、ジクロラールフェナゾン、及びそれらの製薬学的に許容しうる塩;
(vii)骨格筋弛緩薬、例えば、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、オルフレナジン(orphrenadine)、及びそれらの製薬学的に許容しうる塩;
(viii)NMDA受容体アンタゴニスト、例えば、デキストロメトルファン((+)−3−ヒドロキシ−N−メチルモルヒナン)及びその代謝産物のデキストロルファン((+)−3−ヒドロキシ−N−メチルモルヒナン)、ケタミン、メマンチン、ピロロキノリンキノン及びシス−4−(ホスホノメチル)−2−ピペリジンカルボン酸、及びそれらの製薬学的に許容しうる塩;
(ix)アルファ−アドレナリン作動性化合物、例えば、ドキサゾシン、タムスロシン、クロニジン、及び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;
(x)三環系抗うつ薬、例えば、デシプラミン、イミプラミン、アミトリプチリン、及びノルトリプチリン;
(xi)抗痙攣薬、例えば、カルバマゼピン及びバルプロエート;
(xii)タキキニン(NK)アンタゴニスト、特に、NK−3、NK−2及びNK−1アンタゴニスト、例えば、(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]−ジアゾシノ[2,1−g][1,7]ナフチリジン−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(lanepitant)、ダピタント(dapitant)、及び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);
(xiii)ムスカリン様アンタゴニスト、例えば、オキシブチン(oxybutin)、トルテロジン、プロピベリン、塩化トロプシウム(tropsium chloride)、及びダリフェナシン;
(xiv)COX−2阻害薬、例えば、セレコキシブ、ロフェコキシブ及びバルデコキシブ;
(xv)非選択的COX阻害薬(好ましくはGI保護を有する)、例えば、ニトロフルルビプロフェン(nitroflurbiprofen)(HCT−1026);
(xvi)コールタール鎮痛薬、特に、パラセタモール;
(xvii)神経弛緩薬、例えばドロペリドール;
(xviii)バニロイド受容体アゴニスト、例えばレシンフェラトキシン(resinferatoxin);
(xix)ベータ−アドレナリン作動性化合物、例えばプロプラノロール;
(xx)局所麻酔薬、例えばメキシレチン;
(xxi)コルチコステロイド、例えばデキサメタゾン;
(xxii)セロトニン受容体アゴニスト及びアンタゴニスト;
(xxiii)コリン作動性(ニコチン性)鎮痛薬;
(xxiv)その他の薬剤、例えばTramadol(登録商標);
(xxv)PDEV阻害薬、例えば、シルデナフィル、バルデナフィル又はタラダフィル(taladafil)
などである。
医薬製剤のエレメントは好ましくは単位剤形に配合される。そのような形態の場合、製剤は、適量の活性成分を含有する単位用量に小分割される。単位剤形は、パックされた錠剤、カプセル、及びバイアル又はアンプル入り散剤のような包装製剤になっており、各包装に個別量の製剤が含まれている。単位剤形は、カプセル、錠剤、カシェ剤、又はロゼンジそのものであってもよく、又はこれらのいずれかが適当な数で包装された形態であってもよい。単位用量製剤中の活性成分の量は、特定の用途及び活性成分の効力に応じて0.1mg〜1gの範囲で変動又は調整できる。医学的使用の場合、薬物は1日3回、例えば100又は300mgのカプセルとして投与されうる。治療的使用の場合、本発明の医薬学的方法で利用される化合物は、初期用量として1日約0.01mg〜約100mg/kg投与される。1日の用量範囲としては約0.01mg〜約100mg/kgが好適である。しかしながら、用量は、患者の要件、治療される状態の重症度、及び使用する化合物によって変動しうる。特定の状況についての適正な用量の決定は専門家の範囲内である。一般的に、治療は、化合物の最適用量より少ない用量で開始する。その後、その状況下で最適な効果に達するまで用量を少量ずつ増やす。便宜上、所望であれば、総日用量を分割し、その日の間に何回かに分けて投与してもよい。
生物学的実施例
方法
動物
Charles River(英国ケント州マーゲート)から入手した雄のSprague Dawleyラット(200〜250g)を6匹の群にしてケージに収容した。全動物は12時間の明/暗サイクル(07時00分に点灯)下に維持し、餌と水は自由に与えた。全実験とも薬物処置について知らされていない観察者によって行われた。
動物をイソフルランで麻酔した。以前Bennett及びXieによって1988年に報告された通りに坐骨神経を結紮した。処置中、動物は保温毛布上に置いた。手術の準備後、総坐骨神経を大腿中央部で大腿2頭筋の鈍的切開によって露出した。坐骨神経3分岐の近位で約7mmの神経を付着組織から遊離し、その周囲を約1mmの間隔で4回緩く結紮(4−0絹糸)した。切開部を層ごとに閉じ、傷口を局所抗生物質で処置した。
最初に、ガバペンチン、DSNRI、SSRI及びSNRIに対する用量反応試験を単独でCCIモデルで実施した。組合せは策定した固定比に従って調べた。固定された用量比の各組合せに対する用量反応試験を実施した。試験日ごとに薬物処置前に、von Frey毛に対するベースラインの足底逃避閾値(PWT)及び綿棒刺激に対する足底逃避までの潜伏時間(PWL)を測定した。
静的異痛は、Semmes−Weinstein von Frey毛(米国イリノイ州Stoelting)を用いて測定した。動物を金網底のケージに入れ、動物の足底面から接近できるようにした。動物をこの環境に慣れさせてから実験を開始した。静的異痛は、動物の右後肢の足底面をvon Frey毛で最大6秒間、昇順の力(0.7、1.2、1.5、2、3.6、5.5、8.5、11.8、15.1及び29g)で触れることにより試験した。逃避反応が確立されたら、その下の力のvon Frey毛から降順に反応が見られなくなるまで再試験した。最大の29gの力で足を持ち上げ、反応が引き出されたので、これを終止点とした。反応を引き出すのに要した最低量の力をPWTとしてグラムで記録した。
用量反応試験はまず、アルファ−2−デルタリガンド(p.o.)とDSNRI又はSSRI及び/又はSNRI(s.c.又はp.o.)の両方に対して単独で実施する。次にいくつかの固定用量比の組合せについて試験できる。各固定用量比に対する用量反応試験は、各個別比率の抗異痛作用の持続時間によって決定された各実験の時間経過について実施した。重量による様々な固定用量比の組合せが試験できる。
本発明の適切なアルファ−2−デルタリガンド化合物は、本明細書の以下に記載のように、又は前述の参照特許文献に記載のようにして製造できる。これを以下の非制限的実施例及び中間体によって説明する。
化学的実施例
実施例1.(3S,5R)−3−アミノ−5−メチル−オクタン酸ヒドロクロリド
(R)−2,6−ジメチル−ノナ−2−エン。 THF(800mL)中の(S)−シトロネリルブロミド(50g、0.228mol)に0℃でLiCl(4.3g)、次いでCuCl2(6.8g)を加えた。30分後、塩化メチルマグネシウム(THF中3M溶液152mL、Aldrich)を加え、該溶液を室温に温めた。10時間後、該溶液を0℃に冷却し、飽和塩化アンモニウム水溶液を注意深く加えた。得られた2層を分離し、水性相をエーテルで抽出した。合わせた有機相を乾燥させ(MgSO4)、濃縮して(R)−2,6−ジメチル−ノナ−2−エンを得た。32.6g;93%。それ以上精製せずに使用した。
メタンスルホン酸(S)−3,7−ジメチル−オクタ−6−エニル−エステル。 CH2Cl2(800mL)中のS−(−)−シトロネロール(42.8g、0.274mol)及びトリエチルアミン(91mL、0.657mol)に、0℃でCH2Cl2(200mL)中のメタンスルホニルクロリド(26mL、0.329mol)を加えた。0℃で2時間置いた後、該溶液を1NのHCl、次いで食塩水で洗浄した。有機相を乾燥させ(MgSO4)、濃縮して標記化合物を油として得た(60.5g、94%)。これをそれ以上精製せずに使用した。MS,m/z(相対強度):139[100%],143[100%]。
(R)−4−メチル−オクタン酸。 塩化リチウム(0.39g、9.12mmol)と塩化銅(I)(0.61g、4.56mmol)を周囲温度で45mlのTHF中で合わせ、15分間撹拌して0℃に冷却し、その時点で臭化エチルマグネシウム(THF中1M溶液、45mL、45mmol)を加えた。(S)−シトロネリルブロミド(5.0g、22.8mmol)を滴下添加し、該溶液を一晩撹拌しながら周囲温度にゆっくり温まらせた。反応を飽和NH4Cl(水溶液)を注意深く添加してクエンチングし、Et2O及び飽和NH4Cl(水溶液)と共に30分間撹拌した。相分離したので、有機相を乾燥(MgSO4)及び濃縮した。粗(R)−2,6−ジメチル−デカ−2−エンを精製せずに使用した。(R)−2,6−ジメチル−デカ−2−エン(3.8g、22.8mmol)の50mLアセトン中溶液に0℃でJones試薬(H2SO4(水溶液)中2.7M、40mL、108mmol)を加え、該溶液を一晩撹拌しながら周囲温度にゆっくり温まらせた。混合物をEt2OとH2Oの間で分配させて相分離させ、有機相を食塩水で洗浄し、乾燥(MgSO4)及び濃縮した。残渣をフラッシュクロマトグラフィー(8:1のヘキサン:EtOAc)で精製して2.14g(59%)の標記化合物を無色油として得た。LRMS:m/z 156.9(M+)。Jones試薬は、26.7gのCrO3、23mLのH2SO4を合わせ、H2Oで希釈して100mLにすることによって2.7M溶液として調製した。
以下の実施例において、‘活性化合物’又は‘活性成分’という用語は、本発明に従ってアルファ−2−デルタリガンドとDSNRI又はSSRI及びSNRIの片方又は両方及び/又は製薬学的に許容しうる塩の適切な組合せ又は個々のエレメントのことを言う。
(i)錠剤組成物
以下の組成物A及びBは、成分(a)〜(c)及び(a)〜(d)とポビドン溶液との湿式造粒、次いでステアリン酸マグネシウムの添加、そして圧縮によって製造できる。
組成物G(腸溶錠)
組成物Cの腸溶錠は、錠剤を25mg/錠の腸溶ポリマー、例えば、セルロースアセテートフタレート、ポリビニルアセテートフタレート、ヒドロキシプロピルメチル−セルロースフタレート、又はメタクリル酸とメタクリル酸メチルエステルのアニオンポリマー(Eudragit L)などでコーティングすることによって製造できる。Eudragit Lを除き、これらのポリマーには10%(使用したポリマーの量の重量%)の可塑剤を加えてコーティング時又は貯蔵時の膜のひび割れを防止しなければならない。適切な可塑剤は、ジエチルフタレート、クエン酸トリブチル及びトリアセチンなどである。
組成物H(腸溶性の制御放出錠)
組成物Fの腸溶錠は、錠剤を50mg/錠の腸溶ポリマー、例えば、セルロースアセテートフタレート、ポリビニルアセテートフタレート、ヒドロキシプロピルメチル−セルロースフタレート、又はメタクリル酸とメタクリル酸メチルエステルのアニオンポリマー(Eudragit L)などでコーティングすることによって製造できる。Eudragit Lを除き、これらのポリマーには10%(使用したポリマーの量の重量%)の可塑剤を加えてコーティング時又は貯蔵時の膜のひび割れを防止しなければならない。適切な可塑剤は、ジエチルフタレート、クエン酸トリブチル及びトリアセチンなどである。
(ii)カプセル組成物
組成物A
カプセルは上記組成物Dの成分を混合し、得られた混合物を2部式の硬質ゼラチンカプセルに詰めることによって製造できる。組成物B(下記)も同様にして製造できる。
組成物G(腸溶性の制御放出カプセル)
組成物Eの腸溶カプセルは、制御放出ペレットを50mg/カプセルの腸溶ポリマー、例えば、セルロースアセテートフタレート、ポリビニルアセテートフタレート、ヒドロキシプロピルメチルセルロースフタレート、又はメタクリル酸とメタクリル酸メチルエステルのアニオンポリマー(Eudragit L)などでコーティングすることによって製造できる。Eudragit Lを除き、これらのポリマーには10%(使用したポリマーの量の重量%)の可塑剤を加えてコーティング時又は貯蔵時の膜のひび割れを防止すべきである。適切な可塑剤は、ジエチルフタレート、クエン酸トリブチル及びトリアセチンなどである。
(iii)静脈内注射用組成物
(iv)筋肉内注射用組成物
(v)シロップ組成物
(vi)坐剤組成物
(vii)ペッサリー組成物
(viii)経皮組成物
Claims (19)
- 相乗効果量のアルファ−2−デルタリガンドとデュアルセロトニン−ノルアドレナリン再取込み阻害薬(DSNRI)か又は選択的セロトニン再取込み阻害薬(SSRI)及び選択的ノルアドレナリン再取込み阻害薬(SNRI)の片方又は両方、又はそれらの製薬学的に許容しうる塩を含む疼痛治療のための組合せ。
- アルファ−2−デルタリガンドが、ガバペンチン、プレガバリン、[(1R,5R,6S)−6−(アミノメチル)ビシクロ[3.2.0]ヘプタ−6−イル]酢酸、3−(1−アミノメチル−シクロヘキシルメチル)−4H−[1,2,4]オキサジアゾール−5−オン、C−[1−(1H−テトラゾール−5−イルメチル)−シクロヘプチル]−メチルアミン、(3S,4S)−(1−アミノメチル−3,4−ジメチル−シクロペンチル)−酢酸、(1α,3α,5α)(3−アミノ−メチル−ビシクロ[3.2.0]ヘプタ−3−イル)−酢酸、(3S,5R)−3−アミノメチル−5−メチル−オクタン酸、(3S,5R)−3−アミノ−5−メチル−ヘプタン酸、(3S,5R)−3−アミノ−5−メチル−ノナン酸及び(3S,5R)−3−アミノ−5−メチル−オクタン酸、又はそれらの製薬学的に許容しうる塩から選ばれる、請求項1又は2に記載の組合せ。
- アルファ−2−デルタリガンドがガバペンチンである、請求項1又は2に記載の組合せ。
- アルファ−2−デルタリガンドがプレガバリンである、請求項1又は2に記載の組合せ。
- アルファ−2−デルタリガンドがSSRI、又はその製薬学的に許容しうる塩と組み合わされている、請求項1〜4のいずれか1項に記載の組合せ。
- SSRIが、セルトラリン、フルオキセチン、フルボキサミン、パロキセチン、シタロプラム、d,l−フェンフルラミン、フェモキセチン、トラゾドン、セリクラミン、イフォキセチン、シアノドチエピン及びリトキセチン、又はそれらの製薬学的に許容しうる塩から選ばれる、請求項1〜5のいずれか1項に記載の組合せ。
- SSRIがセルトラリンである、請求項1〜6のいずれか1項に記載の組合せ。
- アルファ−2−デルタリガンドがSNRI、又はその製薬学的に許容しうる塩と組み合わされている、請求項1〜4のいずれか1項に記載の組合せ。
- SNRIが、レボキセチン、S,S−レボキセチン、デシプラミン、マプロチリン、ロフェプラミン、ミアンセリン、ミルタゼピン、オキサプロチリン、フェゾラミン、トモキセチン及びブプロプリオン、又はそれらの製薬学的に許容しうる塩から選ばれる、請求項1〜4及び8のいずれか1項に記載の組合せ。
- SNRIが、マプロチリン、デシプラミン、ブプロプリオン、レボキセチン及びS,S−レボキセチン、又はそれらの製薬学的に許容しうる塩から選ばれる、請求項1〜4及び8〜9のいずれか1項に記載の組合せ。
- SNRIが、S,S−レボキセチン、又はその製薬学的に許容しうる塩である、請求項1〜4及び8〜10のいずれか1項に記載の組合せ。
- アルファ−2−デルタリガンドがDSNRI、又はその製薬学的に許容しうる塩と組み合わされている、請求項1〜4のいずれか1項に記載の組合せ。
- DSNRIが、ベンラファキシン、ベンラファキシンの代謝産物O−デスメチルベンラファキシン、クロミプラミン、クロミプラミンの代謝産物デスメチルクロミプラミン、デュロキセチン、ミルナシプラン、及びイミプラミン、又はそれらの製薬学的に許容しうる塩から選ばれる、請求項1〜4及び12のいずれか1項に記載の組合せ。
- DSNRIが、ミルナシプラン、デュロキセチン及びベンラファキシン、又はそれらの製薬学的に許容しうる塩から選ばれる、請求項1〜4及び12〜13のいずれか1項に記載の組合せ。
- 治療上有効量の請求項1〜14のいずれか1項に記載の組合せ、又はそれらの製薬学的に許容しうる塩及び適切な担体又は賦形剤を含む、疼痛の治癒的、予防的又は対症的治療のための医薬組成物。
- 疼痛の治癒的、予防的又は対症的治療のための医薬製造における、相乗効果量のアルファ−2−デルタリガンドとDSNRIか又はSSRI及びSNRIの片方又は両方、又はそれらの製薬学的に許容しうる塩の使用。
- 疼痛が神経因性疼痛である、請求項16に記載の使用。
- 疼痛、特に神経因性疼痛の治癒的、予防的又は対症的治療法であって、治療上相乗効果量のアルファ−2−デルタリガンドとDSNRIか又はSSRI及びSNRIの片方又は両方、又はそれらの製薬学的に許容しうる塩を、前記治療を必要とする哺乳動物に同時、順次又は別個に投与することを含む方法。
- 疼痛が神経因性疼痛である、請求項18に記載の方法。
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- 2004-09-06 RU RU2006107552/15A patent/RU2320369C2/ru not_active IP Right Cessation
- 2004-09-06 JP JP2006525924A patent/JP2007505097A/ja not_active Withdrawn
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JP2012533552A (ja) * | 2009-07-15 | 2012-12-27 | ポートラ ファーマシューティカルズ, インコーポレイテッド | 第Xa因子インヒビターの解毒剤の単位用量処方物およびその使用方法 |
US10765726B2 (en) | 2009-07-15 | 2020-09-08 | Portola Pharmaceuticals, Inc. | Unit dose formulation of antidotes for factor Xa inhibitors and methods of using the same |
WO2014112152A1 (ja) * | 2013-01-18 | 2014-07-24 | 有限会社ケムフィズ | 神経因性疾病の治療のための医薬 |
JP5926406B2 (ja) * | 2013-01-18 | 2016-05-25 | 有限会社ケムフィズ | 神経因性疾病の治療のための医薬 |
US10004710B2 (en) | 2013-01-18 | 2018-06-26 | Kemphys Ltd. | Medicament for therapeutic treatment of neuropathic disease |
US10485776B2 (en) | 2013-01-18 | 2019-11-26 | Kemphys Ltd. | Medicament for therapeutic treatment of neuropathic disease |
Also Published As
Publication number | Publication date |
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ATE449633T1 (de) | 2009-12-15 |
EP1663398B1 (en) | 2009-11-25 |
TW200526249A (en) | 2005-08-16 |
ZA200602077B (en) | 2007-06-27 |
ES2334673T3 (es) | 2010-03-15 |
CA2537402C (en) | 2009-05-05 |
RU2006107552A (ru) | 2007-09-20 |
AU2004271800A1 (en) | 2005-03-24 |
KR20060082861A (ko) | 2006-07-19 |
BRPI0414343A (pt) | 2006-11-07 |
EP1663398A1 (en) | 2006-06-07 |
CN1849153A (zh) | 2006-10-18 |
WO2005025675A1 (en) | 2005-03-24 |
IL173904A0 (en) | 2006-07-05 |
EP2156863A2 (en) | 2010-02-24 |
EP2156863A3 (en) | 2011-01-12 |
US20140206670A1 (en) | 2014-07-24 |
AR045634A1 (es) | 2005-11-02 |
US20050059715A1 (en) | 2005-03-17 |
US20120329781A1 (en) | 2012-12-27 |
CA2537402A1 (en) | 2005-03-24 |
NZ545494A (en) | 2009-10-30 |
DE602004024317D1 (de) | 2010-01-07 |
RU2320369C2 (ru) | 2008-03-27 |
KR100828218B1 (ko) | 2008-05-07 |
US20100081718A1 (en) | 2010-04-01 |
JP2012144545A (ja) | 2012-08-02 |
NO20061083L (no) | 2006-06-06 |
MXPA06002789A (es) | 2006-06-14 |
CO5660280A2 (es) | 2006-07-31 |
AU2011200717A1 (en) | 2011-03-10 |
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