JP5567650B2 - ジペプチジルペプチダーゼ阻害剤の投与 - Google Patents
ジペプチジルペプチダーゼ阻害剤の投与 Download PDFInfo
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- JP5567650B2 JP5567650B2 JP2012276223A JP2012276223A JP5567650B2 JP 5567650 B2 JP5567650 B2 JP 5567650B2 JP 2012276223 A JP2012276223 A JP 2012276223A JP 2012276223 A JP2012276223 A JP 2012276223A JP 5567650 B2 JP5567650 B2 JP 5567650B2
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Classifications
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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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/131—Amines acyclic
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Description
本発明は、ジペプチジルジペプチダーゼIVを阻害するために使用される化合物の投与の方法、およびそのような投与に基づく治療方法に関連する。
ジペプチジルジペプチダーゼIV(IUBMB酵素命名(Enzyme Nomenclature)EC.3.4.14.5)は、広く様々な名前で文献に参照されているII型膜タンパク質であって、DPP4、DP4、DAP−IV、FAPβ、アデノシンデアミナーゼ複合タンパク質2、アデノシンデアミナーゼ結合タンパク質(ADAbp)、ジペプジルアミノペプチダーゼIV、Xaa−Pro−ジペプジル−アミノペプチダーゼ、Gly−Proナフチルアミダーゼ、ポストプロリン ジペプジルアミノペプチダーゼIV、リンパ球抗原CD26、糖
タンパク質GP110、ジペプチジルジペプチダーゼIV、グリシルプロリン アミノペ
プチダーゼ、グリシルプロリン アミノペプチダーゼ、X−プロリルジペプチジル アミノペプチダーゼ、pepX、白血球抗原CD26、グリシルプロリルジペプチジルアミノペプチダーゼ、ジペプチジル−ペプチドヒドラーゼ、グリシルプロリル アミノペプチダー
ゼ、ジペプチジル−アミノペプチダーゼIV、DPP IV/CD26、アミノアシル−
プロリルジペプチジル アミノペプチダーゼ、T細胞トリガー分子(T cell triggering molecule)Tp103、X−PDAPが挙げられる。ジペプチジルジペプチダーゼIVは
、本明細書中「DPP−IV」と呼ぶ。
阻害剤でのイン・ビボ/イン・ビトロの研究に基づいて、DPP−IVは、イン・ビボでのGLP−l(7−36)の初めの分解酵素であることが示された。GLP−l(7−36)は、DPP−IVによってGLP−l(9−36)に効率よく分解され、GLP−l(7−36)への生理学的拮抗薬として作用すると考えられている。イン・ビボでのDPP−IVの阻害は、それ故GLP−l(7−36)の内因性の値を増強し、その拮抗剤であるGLP−l(9−36)の形成を減弱させるのに有用であると信じられている。それ故、DPP−IV阻害剤は、DPP−IVに介在される病態、特に糖尿病、さらに、より具体的には、2型糖尿病、糖尿病性脂質代謝異常、耐糖能異常(IGT)状態、空腹時血糖異常(IFG)状態、代謝性アシドーシス、ケトーシス、食欲調節および肥満の予防、進行の遅延、および/または治療のための有用な薬剤であると信じられている。
患者に5mg/日から250mg/日の間の化合物I、随意に10mgから200mgの化合物I、随意に10mgから150mgの化合物I、さらに随意に10mgから100mgの化合物Iの1日用量を投与することを包含する方法が提供される。一つのバリエーションにおいて、10mg、12.5mg、20mg、25mg、50mg、75mgまたは100mgの化合物Iの1日用量が投与される。
、局所送達経由、皮下、脂肪内、関節内、腹腔内および鞘内から成る群より選ばれる経路を含むが、限定されない広範な経路の投与経路で行われてよい。一つの特有のバリエーションにおいて、投与は経口で行われる。
空腹時血糖異常(IFG)、代謝性アシドーシス、ケトーシス、食欲調節、肥満、糖尿病に関連する合併症(糖尿病性神経障害、糖尿病性網膜症および腎臓疾患が挙げられる)、脂質異常症(高トリグリセリド血症、高コレステロール血症、低HDL症(hypoHDLemia
)および食後の脂質異常症が挙げられる)、動脈硬化症、高血圧、心筋梗塞、狭心症、脳梗塞、脳卒中および代謝症候群のような、DPP−IVに介在される病態を患った患者を治療するために行われる。
スフェラーゼ阻害剤、グルコース−6−ホスファターゼ阻害剤、フルクトース−1,6−ビスホスファターゼ阻害剤、グリコーゲンホスホリラーゼ阻害剤、グルカゴン受容体拮抗薬、ホスホエノールピルビン酸カルボキシキナーゼ阻害剤、ピルビン酸デヒドロゲナーゼキナーゼ阻害剤、アルファ−グルコシダーゼ阻害剤、胃内容排出の阻害剤、グルコキナーゼ活性剤、GLP−1受容体作動薬、GLP−2受容体作動薬、UCPモジュレーター、RXRモジュレーター、GSK−3阻害剤、PPARモジュレーター、メトホルミン、インスリン、及びα2−アドレナリン拮抗薬から成る群より選ばれてもよい。
病性チアゾリジンジオン、非グリタゾン型PPARガンマ作動薬、デュアルPPARガンマ/PPARアルファ作動薬、抗糖尿病性バナジウム含有化合物およびビグアニドから成る群より選ばれてもよい。
5−{[4−(2−(1−インドリル)エトキシ)フェニル]メチル}−チアゾリジン−2,4−ジオン、5−{4−[2−(5−メチル−2−フェニル−4−オキサゾリル(oxazoly))−エトキシ)]ベンジル}−チアゾリジン−2,4−ジオン、5−(2−ナフチ
ルスルホニル)−チアゾリジン−2,4−ジオン、ビス{4−[(2,4−ジオキソ−5−チアゾリジニル)−メチル]フェニル}メタン、5−{4−[2−(5−メチル−2−フェニル−4−オキサゾリル)−2−ヒドロキシエトキシ]−ベンジル}−−チアゾリジン−2,4−ジオン、5−[4−(1−フェニル−1−シクロプロパンカルボニルアミノ)−ベンジル]−チアゾリジン−2,4−ジオン、5−{[4−(2−(2,3−ジヒドロインドール−1−イル)エトキシ)フェニルメチル)−チアゾリジン−2,4−ジオン、5−[3−(4−クロロ−フェニル])−2−−プロピニル]−5−フェニルスルホニル)チアゾリジン−2,4−ジオン、5−[3−(4−クロロフェニル])−−2−プロピニル]−5−(4−フルオロフェニル−スルホニル)チアゾリジン−2,4−ジオン、5−{[4−(2−(メチル−2−ピリジニル−アミノ)−エトキシ)フェニル]メチル}−チアゾリジン−2,4−ジオン、5−{[4−(2−(5−エチル−2−ピリジル)エトキシ)フェニル]−メチル}−チアゾリジン−2,4−ジオン、5−{[4−((3,4−ジヒドロ−6−ヒドロキシ−2,5,7,8−テトラメチル−2H−1−ベンゾピラン−2−イル)メトキシ)−フェニル]−メチル)−チアゾリジン−2,4−ジオン、5−[6−(2−フルオロ−ベンジルオキシ)−ナフタレン−2−イルメチル]−チアゾリジン−2,4−ジオン、5−([2−(2−ナフチル)−ベンゾオキサゾール−5−イル]−メチル}チアゾリジン−2,4−ジオンおよび5−(2,4−ジオキソチアゾリジン−5−イルメチル)−2−メトキシ−N−(4−トリフルオロメチル−ベンジル)ベンズアミドから成る群より選ばれるチアゾリジンジオンであってもよい。
。
るメトホルミンは、一つ以上のその医薬上許容され得る塩を包含する。一つの特有のバリエーションにおいて、この組み合わせにおけるメトホルミンは、メトホルミンHCl塩を包含する。他の特有のバリエーションにおいて、この組み合わせにおけるメトホルミンは、125から2550mgの間の1日用量で投与される。更なる他のバリエーションにおいて、この組み合わせにおけるメトホルミンは、250から2550mgの間の1日用量で投与される。
クトース−1,6−ビスホスファターゼ阻害剤、グリコーゲンホスホリラーゼ阻害剤、グルカゴン受容体拮抗薬、ホスホエノールピルビン酸カルボキシキナーゼ阻害剤、ピルビン酸デヒドロゲナーゼキナーゼ阻害剤、アルファ−グルコシダーゼ阻害剤、胃内容排出の阻害剤、グルコキナーゼ活性剤、GLP−1受容体作動薬、GLP−2受容体作動薬、UCPモジュレーター、RXRモジュレーター、GSK−3阻害剤、PPARモジュレーター、メトホルミン、インスリン、およびα2−アドレナリン拮抗薬から成る群より選ばれてもよい。
ュレーター、抗糖尿病性チアゾリジンジオン、非グリタゾン型PPARガンマ作動薬、デュアルPPARガンマ/PPARアルファ作動薬、抗糖尿病性バナジウム含有化合物およびビグアニドから成る群より選ばれてもよい。
、5−(2−ナフチルスルホニル)−チアゾリジン−2,4−ジオン、ビス{4−[(2,4−ジオキソ−5−チアゾリジニル)−メチル]フェニル}メタン、5−{4−[2−(5−メチル−2−フェニル−4−オキサゾリル)−2−ヒドロキシエトキシ]−ベンジル}−−チアゾリジン−2,4−ジオン、5−[4−(1−フェニル−1−シクロプロパンカルボニルアミノ)−ベンジル]−チアゾリジン−2,4−ジオン、5−{[4−(2−(2,3−ジヒドロインドール−1−イル)エトキシ)フェニルメチル)−チアゾリジン−2,4−ジオン、5−[3−(4−クロロ−フェニル])−2−−プロピニル]−5−フェニルスルホニル)チアゾリジン−2,4−ジオン、5−[3−(4−クロロフェニル])−−2−プロピニル]−5−(4−フルオロフェニル−スルホニル)チアゾリジン−2,4−ジオン、5−{[4−(2−(メチル−2−ピリジニル−アミノ)−エトキシ)フェニル]メチル}−チアゾリジン−2,4−ジオン、5−{[4−(2−(5−エチル−2−ピリジル)エトキシ)フェニル]−メチル}−チアゾリジン−2,4−ジオン、5−{[4−((3,4−ジヒドロ−6−ヒドロキシ−2,5,7,8−テトラメチル−2H−1−ベンゾピラン−2−イル)メトキシ)−フェニル]−メチル)−チアゾリジン−2,4−ジオン、5−[6−(2−フルオロ−ベンジルオキシ)−ナフタレン−2−イルメチル]−チアゾリジン−2,4−ジオン、5−([2−(2−ナフチル)−ベンゾオキサゾール−5−イル]−メチル}チアゾリジン−2,4−ジオンおよび5−(2,4−ジオキソチアゾリジン−5−イルメチル)−2−メトキシ−N−(4−トリフルオロメチル−ベンジル)ベンズアミドから成る群より選ばれるチアゾリジンジオンであってよい。
ド、トラザミド、グリピザイド、カルブタミド、グリクイドン、グリヘキサミド、フェンブタミド、トルシクラミド、グリメピリドおよびグリクラジドから成る群より選ばれる抗糖尿病性化合物が挙げられる。一つのバリエーションにおいて、医薬組成物中に含有される一つ以上の抗糖尿病性化合物としては、グリメピリドが挙げられる。
一つの特有のバリエーションにおいて、この組み合わせにおけるピオグリタゾンは、ピオグリタゾンHCl塩を包含する。他の特有のバリエーションにおいて、この組み合わせにおけるピオグリタゾンは、7.5から60mgの間の1日用量で投与される。更なる他の特有のバリエーションにおいて、この組み合わせにおけるピオグリタゾンは、15から45mgの間の1日用量で投与される。
てもよい。
の投与方法に関する指示から成る群の一つ以上の要素を示すラベルをさらに包含する。
いて、態様は、オープンエンド(open ended)として解釈されるべきである。同様に、特に定めのない限り、医薬組成物、キットおよび製造品としては、他の医薬上の活性物質を含む他の物質をさらに挙げられてよい。
に有効量の化合物の投与も意味し、:
(1)疾患に罹りやすい可能性があるが、疾患の病理又は症候をまだ経験していない又は示していない動物における、疾患の発症の予防
(2)疾患の病理又は症候を経験している又は示している動物における、疾患の阻害(即ち、病理及び/又は症候のさらなる進行の停止)、あるいは
(3)疾患の病理又は症候を経験している又は示している動物における、疾患の改善(すなわち、病理及び/又は症候の反転)
が挙げられる。
ジニトロ安息香酸塩、ドデシル硫酸塩、フマル酸塩、ガラクタル酸(粘液酸由来)、ガラクツロン酸塩、グルコヘプタオエート(glucoheptaoate)、グルコン酸塩、グルタミン酸塩、グリセロリン酸塩、ヘミコハク酸塩、ヘミ硫酸塩、ヘプタン酸塩、ヘキサン酸塩、馬尿酸塩、塩酸塩、臭化水素酸塩、ヨウ化水素酸塩、2−ヒドロキシエタンスルホン酸塩、ヨウ化物塩、イセチオン酸塩、イソ−酪酸塩、乳酸塩、ラクトビオン酸塩、リンゴ酸塩、マロン酸塩、マンデル酸塩、メタリン酸塩、メタンスルホン酸塩、メチル安息香酸塩、リン酸一水素塩、2−ナフタレンスルホン酸塩、ニコチン酸塩、硝酸塩、シュウ酸塩、オレイン酸塩、パモ酸塩、ペクチン酸塩、過硫酸塩、フェニル酢酸塩、3−フェニルプロピオン酸塩、リン酸塩、ホスホン酸塩およびフタル酸塩が挙げられるが、限定されない。
に、血糖値の上昇が食後に起こる前に、化合物Iが体循環にある状態にすることは、有益であり得る。
どのような患者もに投与されてよい。化合物Iの投与が25mg/日、100mg/日および400mg/日の用量水準での14日後の患者の血漿DPPIV活性について有する観測される効果を、図面1は図示し、かつ実施例3は記載する。
患者への化合物Iの投与は、一つ以上の心臓血管測定値(cardiovascular measurement)を改善するであろうと信じられる。改善されてよい心臓測定値(cardiac measurement)
の例としては、平均最高血圧の低下、HDLコレステロールの増加、LDL/HDL比の改善およびトリグリセリドの減少が挙げられるが、限定されない。
調節な肝臓でのグルコースの生産に影響する化合物(グルコース−6−ホスファターゼ(G6Pase)阻害剤、フルクトース−1,6−ビスホスファターゼ(F−1,6−BPase)阻害剤、グリコーゲンホスホリラーゼ(GP)阻害剤、グルカゴン受容体拮抗薬およびホスホエノールピルビン酸カルボキシキナーゼ(PEPCK)阻害剤)、ピルビン酸デヒドロゲナーゼキナーゼ(PDHK)阻害剤、インスリン感受性エンハンサー(インスリン増感剤)、インスリン分泌エンハンサー(インスリン分泌促進剤)、アルファ−グルコシダーゼ阻害剤、胃内容排出の阻害剤、グルコキナーゼ活性剤、GLP−1受容体作動薬、GLP−2受容体作動薬、UCPモジュレーター、RXRモジュレーター、GSK−3阻害剤、PPARモジュレーター、メトホルミン、インスリン、およびα2−アドレナリン拮抗薬が挙げられるが、限定されない。化合物Iは、単回投与で同時に、別々の投与として同時に、あるいは、連続して(即ち、他を投与する前または後に投与する)、そのような少なくとも一つの他の抗糖尿病化合物と共に投与されてよい。
36に記載のものが挙げられるが、限定されない。
CPモジュレーター、抗糖尿病性チアゾリジンジオン(グリタゾン)、非グリタゾン型PPARガンマ作動薬、デュアルPPARガンマ/PPARアルファ作動薬、抗糖尿病性バナジウム含有化合物およびメトホルミンのようなビグアニドが挙げられるが、限定されない。
boratories)ならびに、米国特許番号5,705,515ならびにPCT公開番号WO99/29672、WO98/32753、WO98/20005、WO98/09625、WO97/46556、およびWO97/37646に記載のものが挙げられるが、限定されない。
ン−2,4−ジオン(BM−13.1246)、5−(2−ナフチルスルホニル)−チアゾリジン−2,4−ジオン(AY−31637)、ビス{4−[(2,4−ジオキソ−5−チアゾリジニル)−メチル]フェニル}メタン(YM268)、5−{4−[2−(5−メチル−2−フェニル−4−オキサゾリル)−2−ヒドロキシエトキシ]−ベンジル}−−チアゾリジン−2,4−ジオン(AD−5075)、5−[4−(1−フェニル−1−シクロプロパンカルボニルアミノ)−ベンジル]−チアゾリジン−2,4−ジオン(DN−108) 5−{[4−(2−(2,3−ジヒドロインドール−1−イル)エトキシ)フェニルメチル)−チアゾリジン−2,4−ジオン、5−[3−(4−クロロ−フェニル])−2−−プロピニル]−5−フェニルスルホニル)チアゾリジン−2,4−ジオン、5−[3−(4−クロロフェニル])−−2−プロピニル]−5−(4−フルオロフェニル−スルホニル)チアゾリジン−2,4−ジオン、5−{[4−(2−(メチル−2−ピリジニル−アミノ)−エトキシ)フェニル]メチル}−チアゾリジン−2,4−ジオン(ロシグリタゾン)、5−{[4−(2−(5−エチル−2−ピリジル)エトキシ)フェニル]−メチル}−チアゾリジン−2,4−ジオン(ピオグリタゾン、ACTOSTMの商標で市販)、5−[6−(2−フルオロ−ベンジルオキシ)−ナフタレン−2−イルメチル]−チアゾリジン−2,4−ジオン(MCC555)、5−([2−(2−ナフチル)−ベンゾオキサゾール−5−イル]−メチル}チアゾリジン−2,4−ジオン(T−174)、エダグリタゾン(BM−13−1258)、リボグリタゾン(CS−011)、および5−(2,4−ジオキソチアゾリジン−5−イルメチル)−2−メトキシ−N−(4−トリフルオロメチル−ベンジル)ベンズアミド(KRP297)が挙げられるが、限定されない。
ドは、実験式C184H282N50O60Sおよび4186.6ダルトンの分子量を有する。エクセナチドのアミノ酸配列は、以下の通りである。H−His−Gly−Glu−Gly−Thr−Phe−Thr−Ser−Asp−Leu−Ser−Lys−Gln−Met−Glu−Glu−Glu−Ala−Val−Arg−Leu−Phe−Ile−Glu−Trp−Leu−Lys−Asn−Gly−Gly−Pro−Ser−Ser−Gly−Ala−Pro−Pro−Pro−Ser−NH2
グリタザール、ピオグリタゾン、グリソキセピド、グリブリド、グリベンクラミド、アセトヘキサミド、クロロプロパミド、グリボルヌリド、トルブタミド、トラザミド、グリピザイド、カルブタミド、グリクイドン、グリヘキサミド、フェンブタミド、トルシクラミド、グリメピリドおよびグリクラジドから成る群より選ばれる。
製および製剤の例は、本明細書中に記載の特許、出願および参照文献に開示される。
−メチル−1−イミダゾリル)−5−[3−(2−メチルフェノキシ)プロピル]オキサゾール))、神経再生刺激剤(例、Y−128)、PKC阻害剤(例、ルボキシスタウリン メシレート)、AGE阻害剤(例、ALT946、ピマゲジン、N−フェナシルチア
ゾリウムブロミド(ALT766)、ALT−711、EXO−226、ピリドリンおよびピリドキサミン)、活性酸素スカベンジャー(例、チオクト酸)、脳血管拡張薬(例、チアプリドおよびメキシレチン)、ソマトスタチン受容体作動薬(例、BIM23190)、ならびにアポトーシスシグナル調整キナーゼ−1(ASK−1)阻害剤が挙げられるが、限定されない。抗脂質異常症化合物の例としては、HMG−CoA還元酵素阻害剤(例、プラバスタチン、シンバスタチン、ロバスタチン、アトルバスタチン、フルバスタチン、ロスバスタチンおよびピタバスタチン)、スクアレン合成酵素阻害剤(例、WO97/10224に記載の化合物(例、N−[[(3R,5S)−1−(3−アセトキシ−2,2−ジメチルプロピル)−7−クロロ−5−(2,3−ジメトキシフェノール)−2−オキソ−1,2,3,5−テトラヒドロ−4,1−ベンゾキサゼピン−3−イル]アセチル]-ピペリジン−4−酢酸))、フィブラート化合物(ベザフィブラート、クロフィブ
ラート、シンフィブラートおよびクリノフィブラート)、ACAT阻害剤(例、アバシマイブおよびエフルシマイブ)、陰イオン交換樹脂(例、コレスチラミン)、プロブコール、ニコチン酸剤(例、ニコモールおよびニセリトロール)、イコサペント酸エチル、および植物ステロール(例、ソイステロールおよびg−オリザノール)が挙げられるが、限定
されない。抗肥満化合物の例としては、デクスフェンフルラミン、フェンフルラミン、フェンタミン、シブトラミン、アンフェプラモン、デキサンフェタミン、マジンドール、フェニルプロパノールアミン、クロベンゾレックス、MCH受容体拮抗薬(例、SB−568849およびSNAP−7941)、神経ペプチドY拮抗薬(例、CP−422935)、カンナビノイド受容体拮抗薬(SR−141716およびSR−147778)、グレリン拮抗薬、11b−ヒドロキシステロイド脱水素酵素阻害剤(例、BVT−3498
)、膵リパーゼ阻害剤(例、オーリスタットおよびATL−962)、ベータ−3 AR
作動薬(例、AJ−9677)、ペプチド性食欲抑制剤(例、レプチンおよびCNTF(毛様体神経栄養因子))、コレシストキニン作動薬(例、リンチトリプトおよびFPL−15849)、および摂食抑制物質(例、P−57)が挙げられるが、限定されない。抗高血圧化合物の例としては、アンジオテンシン変換酵素阻害剤(例、カプトプリル、エナラプリルおよびデラプリル)、アンジオテンシンII拮抗薬(例、カンデサルタン シレ
キセチル、ロサルタン、エプロサルタン、バルサルタン、テルミサルタン、イルベサルタン、オルメサルタン メドキソミル、タソサルタンおよび1−[[2’−(2,5−ジヒ
ドロ−5−オキソ−4H−1,2,4−オキサジアゾール−3−イル)ビフェニル−4−イル]メチル]−2−エトキシ−1H−ベンズイミダゾール−7−カルボン酸)、カルシウムチャンネル遮断薬(マニジピン、ニフェジピン、ニカルジピン、アムロジピンおよびエホニジピン)、カリウムチャンネル開口薬(例、レブクロマカリム、L−27152、AL0671およびNIP−121)、およびクロニジンが挙げられる。
。従って、本発明の組成物は、経口投与に適合していてよい。一つのバリエーションにおいて、そのような医薬組成物は、経口投与に適合した固形製剤である。この点において、組成物は、例えば、錠剤またはカプセルの形態でよい。実施例2は、経口投与に適合した化合物Iを含有する固形製剤の例を提供する。他のバリエーションにおいて、そのような医薬組成物は、経口投与に適合した液体製剤である。
節な肝臓でのグルコースの生産に影響する化合物(例、グルコース−6−ホスファターゼ(G6Pase)阻害剤、フルクトース−1,6−ビスホスファターゼ(F−1,6−BPase)阻害剤、グリコーゲンホスホリラーゼ(GP)阻害剤、グルカゴン受容体拮抗薬およびホスホエノールピルビン酸カルボキシキナーゼ(PEPCK)阻害剤)、ピルビン酸デヒドロゲナーゼキナーゼ(PDHK)阻害剤、インスリン感受性エンハンサー(インスリン増感剤)、インスリン分泌エンハンサー(インスリン分泌促進剤)、アルファ−グルコシダーゼ阻害剤、胃内容排出の阻害剤、グルコキナーゼ活性剤、GLP−1受容体作動薬、GLP−2受容体作動薬、UCPモジュレーター、RXRモジュレーター、GSK−3阻害剤、PPARモジュレーター、メトホルミン、インスリン、およびα2−アドレナリン拮抗薬から成る群の一つ以上の要素が挙げられる。化合物Iは、そのような少なくとも一つの他の抗糖尿病化合物と、単一剤として同時に、別々の剤として同時に、あるいは連続して(即ち、他が投与される前または後に投与される)投与されてよい。
(oxazoly))−エトキシ)]ベンジル}−チアゾリジン−2,4−ジオン(BM−13.
1246)、5−(2−ナフチルスルホニル)−チアゾリジン−2,4−ジオン(AY−31637)、ビス{4−[(2,4−ジオキソ−5−チアゾリジニル)−メチル]フェニル}メタン−e(YM268)、5−{4−[2−(5−メチル−2−フェニル−4−オキサゾリル)−2−ヒドロキシエトキシ]−ベンジル}−チアゾリジン−2,4−ジオン(AD−5075)、5−[4−(1−フェニル−1−シクロプロパンカルボニルアミノ)−ベンジル]−チアゾリジン−2,4−ジオン(DN−108) 5−{[4−(2−(2,3−ジヒドロインドール−1−イル)エトキシ)フェニルメチル)−チアゾリジン−2,4−ジオン、5−[3−(4−クロロ−フェニル])−2−−プロピニル]−5−フェニルスルホニル)チアゾリジン−2,4−ジオン、5−[3−(4−クロロフェニル])−2−プロピニル]−5−(4−フルオロフェニル−スルホニル)チアゾリジン−2,4−ジオン、5−{[4−(2−(メチル−2−ピリジニル−アミノ)−エトキシ)フェニル]メチル}−チアゾリジン−2,4−ジオン(ロシグリタゾン)、5−{[4−(2−(5−エチル−2−ピリジル)エトキシ)フェニル]−メチル}−チアゾリジン−2,4−ジオン(ピオグリタゾン)、5−[6−(2−フルオロ−ベンジルオキシ)−ナフタレン−2−イルメチル]−チアゾリジン−2,4−ジオン(MCC555)、5−([2−(2−ナフチル)−ベンゾオキサゾール−5−イル]−メチル}チアゾリジン−2,4−ジオン(T−174)、エダグリタゾン(BM−13−1258)、リボグリタゾン(CS−011)および5−(2,4−ジオキソチアゾリジン−5−イルメチル)−2−メトキシ(met-hoxy)−N−(4−トリフルオロメチル−ベンジル)ベンズアミド(KRP297)が挙げられるが、限定されない。
ド、アセトヘキサミド、クロロプロパミド、グリボルヌリド、トルブタミド、トラザミド、グリピザイド、カルブタミド、グリクイドン、グリヘキサミド、フェンブタミド、トルシクラミド、グリメピリドおよびグリクラジドから成る群より選ばれる。
シレート)、AGE阻害剤(例、ALT946、ピマゲジン、N−フェナシルチアゾリウムブロミド(ALT766)、ALT−711、EXO−226、ピリドリンおよびピリドキサミン)、活性酸素スカベンジャー(例、チオクト酸)、脳血管拡張薬(例、チアプリドおよびメキシレチン)、ソマトスタチン受容体作動薬(例、BIM23190)、ならびにアポトーシスシグナル調整キナーゼ−1(ASK−1)阻害剤が挙げられるが、限定されない。抗脂質異常症化合物の例としては、HMG−CoA還元酵素阻害剤(例、プラバスタチン、シンバスタチン、ロバスタチン、アトルバスタチン、フルバスタチン、ロスバスタチンおよびピタバスタチン)、スクアレン合成酵素阻害剤(例、WO97/10224に記載の化合物(例、N−[[(3R,5S)−1−(3−アセトキシ−2,2−ジメチルプロピル)−7−クロロ−5−(2,3−ジメトキシフェノール)−2−オキソ−1,2,3,5−テトラヒドロ−4,1−ベンゾキサゼピン−3−イル]アセチル]-
ピペリジン−4−酢酸))、フィブラート化合物(例、ベザフィブラート、クロフィブラート、シンフィブラートおよびクリノフィブラート)、ACAT阻害剤(例、アバシマイブおよびエフルシマイブ)、陰イオン交換樹脂(例、コレスチラミン)、プロブコール、
ニコチン酸剤(例、ニコモールおよびニセリトロール)、イコサペント酸エチル、および植物ステロール(例、ソイステロールおよびg−オリザノール)が挙げられるが、限定さ
れない。抗肥満化合物の例としては、デクスフェンフルラミン、フェンフルラミン、フェンタミン、シブトラミン、アンフェプラモン、デキサンフェタミン、マジンドール、フェニルプロパノールアミン、クロベンゾレックス、MCH受容体拮抗薬(例、SB−568849およびSNAP−7941)、神経ペプチドY拮抗薬(例、CP−422935)、カンナビノイド受容体拮抗薬(例、SR−141716およびSR−147778)、グレリン拮抗薬、11b−ヒドロキシステロイド脱水素酵素阻害剤(例、BVT−349
8)、膵リパーゼ阻害剤(例、オーリスタットおよびATL−962)、ベータ−3 A
R作動薬(例、AJ−9677)、ペプチド性食欲抑制剤(例、レプチンおよびCNTF(毛様体神経栄養因子))、コレシストキニン作動薬(例、リンチトリプトおよびFPL−15849)、および摂食抑制物質(例、P−57)が挙げられるが、限定されない。抗高血圧化合物の例としては、アンジオテンシン変換酵素阻害剤(例、カプトプリル、エナラプリルおよびデラプリル)、アンジオテンシンII拮抗薬(例、カンデサルタン シ
レキセチル、ロサルタン、エプロサルタン、バルサルタン、テルミサルタン、イルベサルタン、オルメサルタン メドキソミル、タソサルタンおよび1−[[2’−(2,5−ジ
ヒドロ−5−オキソ−4H−1,2,4−オキサジアゾール−3−イル)ビフェニル−4−イル]メチル]−2−エトキシ−1H−ベンズイミダゾール−7−カルボン酸)、カルシウムチャンネル遮断薬(例、マニジピン、ニフェジピン、ニカルジピン、アムロジピンおよびエホニジピン)、カリウムチャンネル開口薬(例、レブクロマカリム、L−27152、AL0671およびNIP−121)、およびクロニジンが挙げられる。
製造品は、包装材料をさらに含む。一つのバリエーションにおいて、包装材料は、組成物を保管する容器を含む。他のバリエーションにおいて、本発明は、容器が、組成物が投与されるべき病状、保管情報、用量情報および/または組成物の投与方法に関する指示から成る群の一つ以上の要素を指示するラベルを含む、製造品を提供する。
物を含み、そのような医薬組成物は、本明細書に記載の用量域の一つにおける化合物Iを含有する単一剤形である。
容器を形成してよいことを特に言及する。容器は、医薬上許容され得る物質からつくられる、当業界で知られているどのような通常の形または形態、例えば、紙もしくは段ボールの箱、ガラスもしくはプラスチックのボトルもしくは広口瓶(jar)、再閉可能な袋(re-sealable bag)(例えば、異なった容器へ移すために錠剤の「詰め替え」をするため)または治療計画により個々の用量で包装の外に出すためのブリスター包装であり得る。用いられる容器は、関係する的確な投与形態により異なるであろう。一つより多い容器が単一剤形を市販するための個別包装中に一緒に使用されることがふさわしい。例えば、錠剤は、箱の中に順に収納されたボトルの中に収納されてよい。
沈殿物を濾過で集めた。粗生成物を熱いAcOEt−CHCl3中に懸濁し、5分間超音波処理し、0℃で1時間置き、続いて濾過して表題化合物の白色固体(19g)を収率54%で得た。1H-NMR(400 MHz, DMSO): δ 11.82 (s, 1H), 7.87 (d, 1H, J = 7.6 Hz), 7.71 (t, 1H, J = 7.6 Hz), 7.51 (t, 1H, J = 7.6 Hz), 7.37 (d, 1H, J = 8 Hz), 6.06 (s, 1H), 5.31 (s, 2H). MS (ES) [m+H] calc’d for C12H9ClN3O2, 262.0; found 262.0.
ジン−1−イルメチル)−ベンゾニトリル(IV).窒素下でDMF−THF(1:1,300mL)中のベンジル化された6−クロロウラシルIII(10g,38mmol)の冷えた(0℃)溶液に、NaH(60%,1.6g,39.9mmol)を分けて加え、続いてLiBr(2g)を加えた。混合物を室温で20分間攪拌した。ヨードメタン(5.4mL,76mmol)を加えた後、フラスコを塞いで、この温度で10分間、室温で2時間、そして35℃で終夜攪拌し、続いて真空で濃縮した。残渣をCHCl3中に溶解し、水及び食塩水で洗浄し、乾燥し(Na2SO4)、濾過して、真空で濃縮した。粗生成物をTHF−ヘキサンから結晶化して、7.6g(72%)の表題化合物IVを得た。1H NMR (400 MHz, DMSO): δ 7.87 (d, 1H, J = 7.6 Hz), 7.70 (t, 1H, J = 7.6 Hz),
7.51 (t, 1H, J = 7.6 Hz), 7.40 (d, 1H, J = 8 Hz), 6.21 (s, 1H), 5.38 (s, 2H), 3.28 (s, 3H). MS (ES) [m+H] calc’d for C13H11ClN3O2, 276.1; found 276.1.
MS (ES) [m+H] calc’d for C18H22N5O2, 340.2; found, 340.2である。
10:1): δ 7.82 (d, 1H, J = 7.6 Hz), 7.65 (t, 1H, J = 7.6 Hz), 7.46 (t, 1H, J = 7.6 Hz), 7.23 (d, 1H, J = 8.0 Hz), 5.42 (s, 1H), 5.50-5.00 (ABq, 2H, J = 41.6, 15.2 Hz), 3.30 (m, 2H), 3.16 (s, 3H), 2.91 (m, 1H), 2.76 (m, 2H), 1.93 (m, 1H), 1.79 (m, 1H), 1.51 (m, 2H). MS (ES) [m+H] calc’d for C18H22N5O2, 340.2; found,
340.2.
= 7.6 Hz), 7.65 (t, 1H, J = 7.6 Hz), 7.46 (t, 1H, J = 7.6 Hz), 7.23 (d, 1H, J =
8.0 Hz), 5.42 (s, 1H), 5.20, 5.08 (ABq, 2H, J = 41.6, 15.2 Hz), 3.30 (m, 2H), 3.16 (s, 3H), 2.91 (m, 1H), 2.76 (m, 2H), 2.50 (bs, 2 H), 1.93 (m, 1H), 1.79 (m, 1H), 1.51 (m, 2H). MS (ES) [m+H] calc’d for C18H22N5O2, 340.2; found, 340.2.
ジヒドロ−3−メチル−2,4−ジオキソ−1(2H)−ピリミジニル]メチル]−ベンゾニトリルの安息香酸塩(安息香酸塩)(化合物I)を投与するために使用されてよい錠剤製剤を提供する。本明細書中で提供される製剤は、当業界で知られているように変更されてよいことを特に言及する。
錠剤当たり12.5mgの化合物I(遊離の塩基形態の重量)
核錠剤製剤
(1)2−[[6−[(3R)−3−アミノ−1−ピペリジニル]−3,4−ジヒドロ−3−メチル−2,4−ジオキソ−1(2H)−ピリミジニル]メチル]−ベンゾニトリル(安息香酸塩) 17.0mg
(2)乳糖一水和物,NF,Ph,Eur 224.6mg
(FOREMOST 316 FAST FLO)
(3)微結晶性セルロース,NF,Ph,Eur 120.1mg
(AVICEL PH 102)
(4)クロスカルメロース ナトリウム,NF,Ph,Eur 32.0mg
(AC−DI−SOL)
(5)コロイド状二酸化ケイ素,NF,Ph,Eur 3.2mg
(CAB−O−SIL M−5P)
(6)ステアリン酸マグネシウム,NF,Ph,Eur 3.2mg
(MALLINCKRODT,Non−bovine Hyqual)
総量 400.0mg
(錠剤当たり)
(1)Opadry II 85F18422,白-1部(COLORCON)
(2)Opadry II 85F18422,白-2部(COLORCON)
(3)Opadry II 85F18422,白-3部(COLORCON)
核錠剤製剤
(1)2−[[6−[(3R)−3−アミノ−1−ピペリジニル]−3,4−ジヒドロ−3−メチル−2,4−ジオキソ−1(2H)−ピリミジニル]メチル]−ベンゾニトリル(安息香酸塩) 34.0mg
(2)乳糖一水和物,NF,Ph,Eur 207.6mg
(FOREMOST 316 FAST FLO)
(3)微結晶性セルロース,NF,Ph,Eur 120.1mg
(AVICEL PH 102)
(4)クロスカルメロース ナトリウム,NF,Ph,Eur 32.0mg
(AC−DI−SOL)
(5)コロイド状二酸化ケイ素,NF,Ph,Eur 3.2mg
(CAB−O−SIL M−5P)
(6)ステアリン酸マグネシウム,NF,Ph,Eur 3.2mg
(MALLINCKRODT,Non−bovine Hyqual)
総量 400.0mg
(錠剤当たり)
(1)Opadry II 85F18422,白-1部(COLORCON)
(2)Opadry II 85F18422,白-2部(COLORCON)
(3)Opadry II 85F18422,白-3部(COLORCON)
核錠剤製剤
(1)2−[[6−[(3R)−3−アミノ−1−ピペリジニル]−3,4−ジヒドロ−3−メチル−2,4−ジオキソ−1(2H)−ピリミジニル]メチル]−ベンゾニトリル(安息香酸塩) 68.0mg
(2)乳糖一水和物,NF,Ph,Eur 173.6mg
(FOREMOST 316 FAST FLO)
(3)微結晶性セルロース,NF,Ph,Eur 120.1mg
(AVICEL PH 102)
(4)クロスカルメロース ナトリウム,NF,Ph,Eur 32.0mg
(AC−DI−SOL)
(5)コロイド状二酸化ケイ素,NF,Ph,Eur 3.2mg
(CAB−O−SIL M−5P)
(6) ステアリン酸マグネシウム,NF,Ph,Eur 3.2mg
(MALLINCKRODT, Non−bovine Hyqual)
総量 400.0mg
(錠剤当たり)
(1)Opadry II 85F18422,白-1部(COLORCON)
(2)Opadry II 85F18422,白-2部(COLORCON)
(3)Opadry II 85F18422,白-3部(COLORCON)
間の食後グルコース濃度(Cavg)の変化の平均に基づいた。図面1は、朝食後に測定された第一の有効性の評価項目をまとめた表を提供する。14日間の化合物Iでの治療後、すべての化合物Iのグループでの朝食後4時間の食後グルコース濃度(Cavg B)は、プラセボと比較した基準から大きく減少した。化合物Iでの14日間の治療は、25mg、100mg、および400−mgの化合物Iのグループに対して、それぞれ、33mg/dL、37mg/dL、および66mg/dLのCavg Bの基準からの平均減少を実現した。パーセント変化で計算した時、25mg、100mg、および400mgの化合物Iのグループで、それぞれ、15%、17%、および24%の平均減少が観察された。
eprdb/+Leprdb)マウス(6週齢、CLEA Japan(日本、東京))をグループAないしグループDの4つのグループ(それぞれのグループでn=8)に分けた。グループAは、21日間CE−2粉末餌(CLEA Japan)を自由に入手できた。グループBは、21日間0.03%(w/w)の化合物Iの安息香酸塩を含むCE−2粉末餌(CLEA Japan)を自由に入手できた。グループBにおける化合物Iの用量は、76.4±8.0(平均±SD)mg/kg体重/日と計算された。グループCは、21日間0.0075%(w/w)のピオグリタゾン塩酸塩を含むCE−2粉末餌(CLEA Japan)を自由に入手できた。グループCにおけるピオグリタゾンの用量は、15.4±1.5(平均±SD)mg/kg体重/日と計算された。グループDは、21日間0.0075%(w/w)のピオグリタゾン塩酸塩との組み合わせにおける0.03%(w/w)の化合物Iの安息香酸塩を含むCE−2粉末餌(CLEA Japan)を自由に入手できた。グループDにおける化合物Iおよびピオグリタゾンの用量は、そ
れぞれ、56.5±3.1(平均±SD)mg/kg体重/日および14.1±0.8(平均±SD)mg/kg体重/日と計算された。21日のその粉末餌の投与の間、上記の4グループにおいて粉末餌の投与の量での大きな違いはなかった。粉末餌の投与の21日後、血液サンプルを摂食状態下でキャピラリーピペットによりマウスの眼窩静脈から採取し、グリコシル化ヘモグロビン値をGHb Analyzer HLC−723 G7(日本、TOSOH)で自動化されたTOSOHを使用してHPLCに基づく方法で測定した。
グロビン値の低下に優れた効果を示した。
prdb)マウス(6週齢、CLEA Japan(東京、日本))をグループAなしいグループDの4つのグループ(それぞれのグループでn=6)に分けた。グループAは、21日間CE−2粉末餌(CLEA Japan)を自由に入手できた。グループBは、21日間0.03%(w/w)の化合物Iの安息香酸塩を含むCE−2粉末餌(CLEA
Japan)を自由に入手できた。グループBにおける化合物Iの用量は、72.8±1.8(平均±SD)mg/kg体重/日と計算された。グループCは、21日間0.001%(w/w)のボグリボースを含むCE−2粉末餌(CLEA Japan)を自由に入手できた。グループCにおけるボグリボースの用量は、1.8±0.1(平均±SD)mg/kg体重/日と計算された。グループDは、21日間0.001%(w/w)のボグリボースとの組み合わせにおける0.03%(w/w)の化合物Iの安息香酸塩を含むCE−2粉末餌(CLEA Japan)を自由に入手できた。グループDにおける化合物Iおよびボグリボースの用量は、それぞれ、53.8±3.7(平均±SD)mg/kg体重/日および1.8±0.1(平均±SD)mg/kg体重/日と計算された。21日のその粉末餌の投与の間、上記の4グループにおいて粉末餌の投与の量での大きな違いはなかった。粉末餌の投与の21日後、血液サンプルを摂食状態下でキャピラリーピペットによりマウスの眼窩静脈から採取し、血漿グルコース値をAutoanalyzer
7080(日本、日立)を使用して酵素的に測定した。
な改良および変化を化合物、組成物、キット、および本発明の方法になすことができることを明白に理解するであろう。それ故、本発明は、付記した請求項およびそれらの等価体の範囲内にあることを条件に、本発明の修正およびバリエーションにわたることを意図する。
Claims (32)
- 単一剤形に製剤される医薬組成物であって、当該単一剤形が5mgから250mgの間の式:
を有する化合物I(ここで、化合物Iは、医薬上許容され得る塩または遊離の塩基として存在する)およびそのどのような医薬上許容され得る塩も含むメトホルミンを含有する、該医薬組成物。 - 当該単一剤形が10mgから200mgの間の化合物Iを含有する、請求項1に記載の医薬組成物。
- 当該単一剤形が10mgから150mgの間の化合物Iを含有する、請求項1に記載の医薬組成物。
- 当該単一剤形が10mgから100mgの間の化合物Iを含有する、請求項1に記載の医薬組成物。
- 当該単一剤形が10mgの化合物Iを含有する、請求項1に記載の医薬組成物。
- 当該単一剤形が12.5mgの化合物Iを含有する、請求項1に記載の医薬組成物。
- 当該単一剤形が20mgの化合物Iを含有する、請求項1に記載の医薬組成物。
- 当該単一剤形が25mgの化合物Iを含有する、請求項1に記載の医薬組成物。
- 当該単一剤形が50mgの化合物Iを含有する、請求項1に記載の医薬組成物。
- 当該単一剤形が75mgの化合物Iを含有する、請求項1に記載の医薬組成物。
- 当該単一剤形が100mgの化合物Iを含有する、請求項1に記載の医薬組成物。
- 単一剤形に製剤される医薬組成物であって、当該単一剤形が式:
を有する化合物I(ここで、化合物Iは、医薬上許容され得る塩または遊離の塩基として存在する)およびそのどのような医薬上許容され得る塩も含むメトホルミンを包含する、該医薬組成物。 - メトホルミンがメトホルミンHCl塩として存在する、請求項1〜12のいずれか一つに記載の医薬組成物。
- 1日用量が250mgから2550mgの間であるようにメトホルミンを含有する、請求項1〜13のいずれか一つに記載の医薬組成物。
- 当該単一剤形が、経口、非経口、腹腔内、静脈内、動脈内、経皮、舌下、筋肉内、直腸内、口腔内、鼻腔内、リポソーム、吸入経由、膣内、眼内、局所送達経由、皮下、脂肪内、関節内、および鞘内から成る群より選ばれる経路による投与に適合している、請求項1〜14のいずれか一つに記載の医薬組成物。
- 当該単一剤形が経口投与に適合した、請求項1〜14のいずれか一つに記載の医薬組成物。
- 当該単一剤形が経口投与に適合した固形製剤である、請求項1〜14のいずれか一つに記載の医薬組成物。
- 当該単一剤形が経口投与に適合した、錠剤またはカプセルである、請求項1〜14のいずれか一つに記載の医薬組成物。
- 当該単一剤形が経口投与に適合した徐放性製剤を包含する、請求項1〜14のいずれか一つに記載の医薬組成物。
- 化合物Iが医薬組成物中に遊離の塩基として存在する、請求項1〜19のいずれか一つに記載の医薬組成物。
- 化合物Iが医薬上許容され得る塩として医薬組成物中に存在する、請求項1〜19のいずれか一つに記載の医薬組成物。
- 化合物Iが安息香酸塩として医薬組成物中に存在する、請求項1〜19のいずれか一つに記載の医薬組成物。
- 化合物Iがトルエンスルホン酸塩として医薬組成物中に存在する、請求項1〜19のいずれか一つに記載の医薬組成物。
- 化合物Iが塩酸塩として医薬組成物中に存在する、請求項1〜19のいずれか一つに記載の医薬組成物。
- DPP−IVに介在される病態の治療のための医薬品の製造における、請求項1〜24のいずれか一つに記載の医薬組成物の使用。
- I型糖尿病の治療のための医薬品の製造における、請求項1〜24のいずれか1項記載の医薬組成物の使用。
- II型糖尿病の治療のための医薬品の製造における、請求項1〜24のいずれか1項記載の医薬組成物の使用。
- 前糖尿病(prediabetic)の治療のための医薬品の製造における、請求項1〜24のいずれか1項記載の医薬組成物の使用。
- 複数回分の請求項1〜24のいずれか一つに記載の医薬組成物、ならびに医薬組成物が投与されるべき病状の表示、医薬組成物の保管情報、用量情報および医薬組成物の投与方法に関する指示から成る群より選ばれる一つ以上の情報の形態を包含する指示を含む、キット。
- 複数回分の請求項1〜24のいずれか一つに記載の医薬組成物、および包装材料を含む、製造品。
- 包装材料が複数回分の医薬組成物を保管する容器を包含する、請求項30に記載の製造品。
- 容器が、化合物が投与されるべき病状、保管情報、用量情報および/または組成物の投与方法に関する指示から成る群の一つ以上の要素を指示するラベルを含む、請求項31に記載の製造品。
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- 2014-05-19 US US14/280,942 patent/US20140256757A1/en not_active Abandoned
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2017
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2018
- 2018-09-04 NO NO2018029C patent/NO2018029I2/no unknown
- 2018-09-04 NO NO2018028C patent/NO2018028I2/no unknown
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2019
- 2019-02-15 US US16/277,537 patent/US20190314352A1/en not_active Abandoned
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