JPWO2020185368A5 - - Google Patents

Description

の化合物またはその塩もしくはＮ－オキシドであり、式中、Ａｒ６およびＡｒ７は、互いに独立して同じまたは異なり、それぞれ置換されていてもよい５員ヘテロアリール基であり、Ａｌｋは、アルキル基であり、Ｒ３６およびＲ３７は、それらが結合している原子と一緒になって、置換されていてもよい５員複素環を形成し、Ｒ３８は、Ｈ、置換もしくは非置換アルキル、置換もしくは非置換シクロアルキルアルキル、置換もしくは非置換ヘテロシクロアルキルアルキル、置換もしくは非置換アリール、置換もしくは非置換アリールアミドアルキル、置換もしくは非置換ヘテロアリールアミドアルキル、置換もしくは非置換アリールアルキル、置換もしくは非置換アリールアルコキシ、置換もしくは非置換ヘテロアリール、置換もしくは非置換ヘテロアリールアルキル、またはハロアルキルである。
いくつかの変形例では、式Ｉの化合物は、Ｒ３６およびＲ３７によって形成された５員複素環がヒダントインまたは置換もしくは非置換環状尿素、またはその塩もしくはＮ－オキシドである化合物である。
いくつかの変形例では、当該製剤に使用される苦味マスク剤化合物は、式ＩＩ：

の化合物またはその塩もしくはＮ－オキシドであり、式中、Ａｒ６およびＡｒ７は、互いに独立して同じまたは異なり、それぞれ置換されていてもよい５員ヘテロアリール基であり、Ａｌｋは、アルキル基であり、Ｒ３８は、Ｈ、置換もしくは非置換アルキル、置換もしくは非置換シクロアルキルアルキル、置換もしくは非置換ヘテロシクロアルキルアルキル、置換もしくは非置換アリール、置換もしくは非置換アリールアミドアルキル、置換もしくは非置換ヘテロアリールアミドアルキル、置換もしくは非置換アリールアルキル、置換もしくは非置換アリールアルコキシ、置換もしくは非置換ヘテロアリール、置換もしくは非置換ヘテロアリールアルキル、またはハロアルキルであり、Ｒ３９およびＲ４０は、互いに独立して同じまたは異なり、Ｈ、置換もしくは非置換アルキル、置換もしくは非置換シクロアルキルアルキル、置換もしくは非置換ヘテロシクロアルキルアルキル、置換もしくは非置換アリール、置換もしくは非置換アリールアミドアルキル、置換もしくは非置換アリールアルキルアミドアルキル、置換もしくは非置換ヘテロアリールアミドアルキル、置換もしくは非置換ヘテロアリールアルキルアミドアルキル、置換もしくは非置換アリールアルキル、置換もしくは非置換アリールアルコキシ、置換もしくは非置換ヘテロアリール、置換もしくは非置換ヘテロアリールアルキル、ハロアルキルであるか、またはＲ３９およびＲ４０は、それらが結合している炭素原子と一緒になって、Ｃ＝Ｏ基または置換もしくは非置換アルケニル基を形成する。
いくつかの変形例では、式ＩＩの苦味マスク剤化合物は、Ｒ３６およびＲ３７によって形成される５員複素環がウラゾールまたはその塩もしくはＮ－オキシドである化合物である。
いくつかの変形例では、当該製剤に使用される苦味マスク剤化合物は、式ＩＩＩ：

の化合物またはその塩もしくはＮ－オキシドであり、式中、Ａｒ６およびＡｒ７は、互いに独立して同じまたは異なり、それぞれ置換されていてもよい５員ヘテロアリール基であり、Ａｌｋはアルキル基であり、Ｒ３８は、Ｈ、置換もしくは非置換アルキル、置換もしくは非置換シクロアルキルアルキル、置換もしくは非置換ヘテロシクロアルキルアルキル、置換もしくは非置換アリール、置換もしくは非置換アリールアミドアルキル、置換もしくは非置換ヘテロアリールアミドアルキル、置換もしくは非置換アリールアルキル、置換もしくは非置換アリールアルコキシ、置換もしくは非置換ヘテロアリール、置換もしくは非置換ヘテロアリールアルキル、またはハロアルキルであり、Ｒ４１は、Ｈ、置換もしくは非置換アルキル、置換もしくは非置換シクロアルキルアルキル、置換もしくは非置換ヘテロシクロアルキルアルキル、置換もしくは非置換アリール、置換もしくは非置換アリールアミドアルキル、置換もしくは非置換アリールアルキルアミドアルキル、置換もしくは非置換ヘテロアリールアミドアルキル、置換もしくは非置換ヘテロアリールアルキルアミドアルキル、置換もしくは非置換アリールアルキル、置換もしくは非置換アリールアルコキシ、置換もしくは非置換ヘテロアリール、置換もしくは非置換ヘテロアリールアルキル、またはハロアルキルである。
いくつかの変形例では、当該製剤に使用される苦味マスク剤化合物は、式ＩＶ：

の化合物またはその塩もしくはＮ－オキシドであり、式中、Ａｌｋはアルキル基であり、Ｍ１は、ＮまたはＣＲ４９であり、式中、Ｒ４９は、Ｈまたは置換もしくは非置換アルキルであり、Ｍ２は、ＮまたはＣＲ５０であり、式中、Ｒ５０は、Ｈまたは置換もしくは非置換アルキルであり、Ｒ３６およびＲ３７は、それらが結合している原子と一緒になって、置換されていてもよい５員複素環を形成し、Ｒ３８は、Ｈ、置換もしくは非置換アルキル、置換もしくは非置換シクロアルキルアルキル、置換もしくは非置換ヘテロシクロアルキルアルキル、置換もしくは非置換アリール、置換もしくは非置換アリールアミドアルキル、置換もしくは非置換ヘテロアリールアミドアルキル、置換もしくは非置換アリールアルキル、置換もしくは非置換アリールアルコキシ、置換もしくは非置換ヘテロアリール、置換もしくは非置換ヘテロアリールアルキル、またはハロアルキルであり、Ｒ４７は、Ｈ、置換もしくは非置換アルキル、置換もしくは非置換アルコキシ、置換もしくは非置換アリール、置換もしくは非置換アリールアルキル、またはハロであり、Ｒ４８は、Ｈ、置換もしくは非置換アルキル、置換もしくは非置換アルコキシ、置換もしくは非置換アリール、置換もしくは非置換アリールアルキル、またはハロである。
いくつかの変形例では、当該製剤に使用される苦味マスク剤化合物は、式Ｖ：

の化合物またはその塩もしくはＮ－オキシドであり、式中、Ａｌｋは、アルキル基であり、Ｇは、Ｃ＝Ｏであり、Ｑは、ＣＲ５１Ｒ５２またはＮＲ５１であり、式中、Ｒ５１およびＲ５２は、互いに独立して同じまたは異なり、Ｈ、置換もしくは非置換アルキル、置換もしくは非置換シクロアルキルアルキル、置換もしくは非置換ヘテロシクロアルキルアルキル、置換もしくは非置換アリール、置換もしくは非置換アリールアミドアルキル、置換もしくは非置換アリールアルキルアミドアルキル、置換もしくは非置換ヘテロアリールアミドアルキル、置換もしくは非置換ヘテロアリールアルキルアミドアルキル、置換もしくは非置換アリールアルキル、置換もしくは非置換アリールアルコキシ、置換もしくは非置換ヘテロアリール、置換もしくは非置換ヘテロアリールアルキル、ハロアルキルであるか、またはＲ５１およびＲ５２は、それらが結合している炭素原子と一緒になって、Ｃ＝Ｏ基または置換もしくは非置換アルケニル基を形成し、Ｍ１は、ＮまたはＣＲ４９であり、式中、Ｒ４９は、Ｈまたは置換もしくは非置換アルキルであり、Ｍ２は、ＮまたはＣＲ５０であり、式中、Ｒ５０は、Ｈまたは置換もしくは非置換アルキルであり、Ｒ３８は、Ｈ、置換もしくは非置換アルキル、置換もしくは非置換シクロアルキルアルキル、置換もしくは非置換ヘテロシクロアルキルアルキル、置換もしくは非置換アリール、置換もしくは非置換アリールアミドアルキル、置換もしくは非置換ヘテロアリールアミドアルキル、置換もしくは非置換アリールアルキル、置換もしくは非置換アリールアルコキシ、置換もしくは非置換ヘテロアリール、置換もしくは非置換ヘテロアリールアルキル、またはハロアルキルであり、Ｒ４７は、Ｈ、置換もしくは非置換アルキル、置換もしくは非置換アルコキシ、置換もしくは非置換アリール、置換もしくは非置換アリールアルキル、またはハロであり、Ｒ４８は、Ｈ、置換もしくは非置換アルキル、置換もしくは非置換アルコキシ、置換もしくは非置換アリール、置換もしくは非置換アリールアルキル、またはハロである。
当該製剤で使用するのに特に好ましい苦味マスク剤は、３－（１－（（３，５－ジメチルイソオキサゾール－４－イル）メチル）－１Ｈ－ピラゾール－４－イル－１－（３－ヒドロキシベンジル）イミダゾリジン－２，４－ジオンとして知られている化合物であり、式ＶＩ：

の化合物またはその塩もしくはＮ－オキシドである。
当該製剤で使用される苦味マスク剤に関して、および上記の式Ｉ～ＶＩのうちの１つ以上の範囲内の化合物のさらなる説明において、以下の２３段落は、言及される様々なグループ分けを詳述する。
上記文献で使用される場合、「アルキル」ならびに接頭辞「ａｌｋ」を有する他の基、例えばアルコキシ、アルカノイル、アルケニル、アルキニルなどは、直鎖もしくは分岐鎖またはそれらの組み合わせであり得る炭素鎖を意味する。アルキル基の例としては、メチル、エチル、プロピル、イソプロピル、ブチル、ｓｅｃ－およびｔｅｒｔ－ブチル、ペンチル、ヘキシル、ヘプチルなどが挙げられる。好ましいアルキル基は１～４つの炭素を有する。「アルケニル」および他の同様の用語は、少なくとも１つの不飽和炭素－炭素結合を含む炭素鎖を含む。「アルキニル」および他の同様の用語は、少なくとも１つの炭素－炭素三重結合を含む炭素鎖を含む。
「シクロアルキル」という用語は、ヘテロ原子を含まない炭素環を意味し、単環式、二環式および三環式飽和炭素環、ならびに縮合環系を含む。シクロアルキルの例としては、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、デカヒドロナフタレン、アダマンタン、インダニル、インデニル、フルオレニル、１，２，３，４－テトラヒドロナフタレンなどが挙げられる。
「アリール」という用語は、単環または縮合した多環である芳香族置換基を意味する。例示的なアリール基としては、限定されないが、フェニル、ナフチル、アントラセニル、ピリジニル、ピラジニル、ピリミジニル、トリアジニル、チオフェニル、フラニル、ピロリル、オキサゾリル、イミダゾリル、トリアジオリル、およびテトラゾリル基が挙げられる。１つ以上のヘテロ原子を含むアリール基（例えば、ピリジニル）は、しばしば「ヘテロアリール基」と呼ばれる。多環で形成される場合、構成する環の少なくとも１つは芳香族である。いくつかの実施形態では、多環の少なくとも１つはヘテロ原子を含み、それによりヘテロ原子含有アリール基を形成する。ヘテロ原子含有アリール基としては、限定されないが、ベンゾオキサゾリル、ベンゾイミダゾリル、キノキサリニル、ベンゾフラニルおよび１Ｈ－ベンゾ［ｄ］［１，２，３］トリアゾリル基が挙げられる。ヘテロ原子含有アリール基としては、限定されないが、２，３－ジヒドロベンゾ［ｂ］［１，４］ジオキシニルおよびベンゾ［ｄ］［１，３］ジオキソリル基も挙げられる。ヘテロ原子含有アリール基としては、少なくとも１つのヘテロ原子および少なくとも１つのカルボニル基を含む複素環に縮合した芳香環も挙げられる。そのような基としては、限定されないが、ジオキソテトラヒドロキノキサリニルおよびジオキソテトラヒドロキナゾリニル基が挙げられる。
「アリールアルコキシ」という用語はアルコキシ基に結合したアリール基を意味する。
「アリールアミドアルキル」という用語は、アリール－Ｃ（Ｏ）ＮＲ－アルキルまたはアリール－ＮＲＣ（Ｏ）－アルキルを意味する。
「アリールアルキルアミドアルキル」という用語は、アリール－アルキル－Ｃ（Ｏ）ＮＲ－アルキルまたはアリール－アルキル－ＮＲＣ（Ｏ）－アルキルを意味し、式中、Ｒは以下に列挙される任意の適切な基である。
「アリールアルキル」という用語は、アルキル基に結合したアリール基を指す。
「ハロゲン」または「ハロ」という用語は、塩素、臭素、フッ素またはヨウ素を指す。
「ハロアルキル」という用語は、１つ以上のハロゲン原子を有するアルキル基（例えば、ＣＦ _３ ）を意味する。
「ヘテロアルキル」という用語は、Ｎ、Ｏ、Ｐ、Ｂ、ＳまたはＳｉなどのヘテロ原子を含むアルキル部分を指す。ヘテロ原子は、飽和または不飽和結合によってヘテロアルキル部分の残りの部分に結合していてもよい。したがって、ヘテロシクロアルキル、置換ヘテロシクロアルキル、ヘテロアリール、置換ヘテロアリール、アルコキシ、アリールオキシ、ボリル、ホスフィノ、アミノ、シリル、チオまたはセレノなどの基で置換されたアルキルは、ヘテロアルキルという用語の範囲内である。ヘテロアルキルの例としては、限定されないが、シアノ、ベンゾイル、２－ピリジルおよび２－フリルが挙げられる。
「ヘテロアリールアルキル」という用語は、アルキル基が結合しているヘテロアリール基を意味する。
「複素環」という用語は、１つまたは２つの多重結合を有していてもよい炭素原子および水素原子を含む単環式または多環式環を意味し、環原子は、窒素、酸素および硫黄から独立して選択される少なくとも１つのヘテロ原子、具体的には１～４つのヘテロ原子を含む。複素環構造としては、限定されないが、単環式、二環式および三環式化合物が挙げられる。特定の複素環は、単環式または二環式である。代表的な複素環としては、環状尿素、モルホリニル、ピロリジノニル、ピロリジニル、ピペリジニル、ピペラジニル、ヒダントイニル、バレロラクタミル、オキシラニル、オキセタニル、テトラヒドロフラニル、テトラヒドロピラニル、テトラヒドロピリジニル、テトラヒドロプリミジニル、テトラヒドロチオフェニル、テトラヒドロチオピラニル、テトラゾリルおよびウラゾリルが挙げられる。複素環は、非置換であっても置換されていてもよい。好ましい複素環は、５員および６員の複素環、特にヒダントイニルおよびウラゾリルである。
「ヘテロシクロアルキル」という用語は、環内の炭素原子の少なくとも１つがヘテロ原子（例えば、Ｏ、ＳまたはＮ）で置き換えられているシクロアルキル基を指す。
「ヘテロシクロアルキルアルキル」という用語は、アルキル基が結合しているヘテロシクロアルキル基を意味する。
「置換された」という用語は、当技術分野で一般的な１つ以上の置換を特に想定し、可能にする。しかしながら、置換基は、化合物の有用な特徴に悪影響を及ぼさないように、またはその機能を妨げないように選択されるべきであることが当業者には一般に理解される。適切な置換基としては、例えば、ハロ基、ペルフルオロアルキル基、ペルフルオロアルコキシ基、アルキル基、アルケニル基、アルキニル基、ヒドロキシ基、オキソ基、メルカプト基、アルキルチオ基、アルコキシ基、アリール基またはヘテロアリール基、アリールオキシ基またはヘテロアリールオキシ基、アラルキル基またはヘテロアラルキル基、アラルコキシ基またはヘテロアラルコキシ基、アミノ基、アルキルおよびジアルキルアミノ基、カルバモイル基、アルキルカルボニル基、カルボキシル基、アルコキシカルボニル基、アルキルアミノカルボニル基、ジアルキルアミノカルボニル基、アリールカルボニル基、アリールオキシカルボニル基、アルキルスルホニル基、アリールスルホニル基、シクロアルキル基、シアノ基、Ｃ１～Ｃ６アルキルチオ基、アリールチオ基、ニトロ基、ケト基、アシル基、ボロナート基またはボロニル基、ホスファート基またはホスホニル基、スルファミル基、スルホニル基、スルフィニル基、およびそれらの組み合わせが挙げられる。「置換アリールアルキル」などの置換された組み合わせの場合、アリール基もしくはアルキル基のいずれかが置換されていてもよく、またはアリール基およびアルキル基の両方が１つ以上の置換基で置換されていてもよい。さらに、いくつかの場合には、適切な置換基が組み合わさって、当業者に公知の１つ以上の環を形成してもよい。
上記文献に記載の化合物は、１つ以上の二重結合を含み、したがって、シス／トランス異性体、あるいは他の配座異性体を生じ得る。上記文献の発明は、すべてのそのような可能な異性体、あるいはそのような異性体の混合物を含む。
上記文献に記載の化合物、特に上記の置換基は、１つ以上の不斉中心を含み得、したがってジアステレオマーおよび光学異性体を生じ得る。上記文献の発明は、すべてのそのような可能なジアステレオマーあるいはそれらのラセミ混合物、それらの実質的に純粋な分解エナンチオマー、すべての可能な幾何異性体、およびそれらの許容され得る塩を含む。さらに、立体異性体の混合物あるいは単離された特定の立体異性体も含まれる。そのような化合物を調製するために使用される合成手順の過程において、または当業者に公知のラセミ化もしくはエピマー化手順を使用する際に、そのような手順の生成物は、立体異性体の混合物であり得る。
上記文献で使用される場合、「塩」および「薬学的に許容され得る塩」という用語は、親化合物がその酸性塩または塩基性塩を作製することによって修飾されている、開示される化合物の誘導体を指す。薬学的に許容され得る塩の例としては、限定されないが、アミンなどの塩基性基の鉱酸塩または有機酸塩、およびカルボン酸などの酸性基のアルカリ塩または有機塩が挙げられる。薬学的に許容され得る塩としては、例えば、非毒性の無機酸または有機酸から形成される親化合物の従来の非毒性塩または第四級アンモニウム塩が挙げられる。例えば、そのような従来の非毒性塩としては、塩酸、臭化水素酸、硫酸、スルファミン酸、リン酸および硝酸などの無機酸から得られるもの、ならびに酢酸、プロピオン酸、コハク酸、グリコール酸、ステアリン酸、乳酸、リンゴ酸、酒石酸、クエン酸、アスコルビン酸、パモ酸、マレイン酸、ヒドロキシマレイン酸、フェニル酢酸、グルタミン酸、安息香酸、サリチル酸、スルファニル酸、２－アセトキシ安息香酸、フマル酸、トルエンスルホン酸、メタンスルホン酸、エタンジスルホン酸、シュウ酸およびイセチオン酸などの有機酸から調製された塩が挙げられる。
上記文献の発明の薬学的に許容され得る塩は、従来の化学的方法によって、塩基性部分または酸性部分を含む親化合物から合成することができる。一般に、このような塩は、これらの化合物の遊離酸または遊離塩基形態を、化学量論量の適切な塩基または酸と、水もしくは有機溶媒中、または２つの混合物中で反応させることによって調製することができ、一般に、エーテル、酢酸エチル、エタノール、イソプロパノールまたはアセトニトリルなどの非水性媒体が好ましい。適切な塩のリストは、Ｒｅｍｉｎｇｔｏｎ’ｓ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｓｃｉｅｎｃｅｓ，１７ｔｈ ｅｄ．，Ｍａｃｋ Ｐｕｂｌｉｓｈｉｎｇ Ｃｏｍｐａｎｙ，Ｅａｓｔｏｎ，Ｐａ．，１９８５，ｐ．１４１８を参照されたい。
「溶媒和物」という用語は、非共有結合分子間力によって結合された化学量論量または非化学量論量の溶媒をさらに含む化合物またはその塩を意味する。溶媒が水である場合、溶媒和物は水和物である。
「プロドラッグ」という用語は、生物学的条件下（インビトロまたはインビボ）で加水分解、酸化、またはそうでなければ反応して活性化合物、特に上記文献の発明の化合物を提供することができる化合物の誘導体を意味する。プロドラッグの例としては、限定されないが、生物加水分解性アミド、生物加水分解性エステル、生物加水分解性カルバマート、生物加水分解性カルボナート、生物加水分解性ウレイド、および生物加水分解性ホスファート類似体などの生物加水分解性部分を含む上記文献の発明の化合物の誘導体および代謝物が挙げられる。カルボキシル官能基を有する化合物の特定のプロドラッグは、カルボン酸の低級アルキルエステルである。カルボン酸エステルは、分子上に存在するカルボン酸部分のいずれかをエステル化することによって好都合に形成される。プロドラッグは、典型的には、Ｂｕｒｇｅｒ’ｓ Ｍｅｄｉｃｉｎａｌ Ｃｈｅｍｉｓｔｒｙ ａｎｄ Ｄｒｕｇ Ｄｉｓｃｏｖｅｒｙ ６ｔｈ ｅｄ．（Ｄｏｎａｌｄ Ｊ．Ａｂｒａｈａｍ ｅｄ．，２００１，Ｗｉｌｅｙ）、およびＤｅｓｉｇｎ ａｎｄ Ａｐｐｌｉｃａｔｉｏｎ ｏｆ Ｐｒｏｄｒｕｇｓ（Ｈ．Ｂｕｎｄｇａａｒｄ ｅｄ．，１９８５，Ｈａｒｗｏｏｄ Ａｃａｄｅｍｉｃ Ｐｕｂｌｉｓｈｅｒｓ Ｇｍｆｈ）に記載の方法などの周知の方法を使用して調製することができる。
上記文献で使用される場合、特に明記しない限り、「生物加水分解性アミド」、「生物加水分解性エステル」、「生物加水分解性カルバマート」、「生物加水分解性カルボナート」、「生物加水分解性ウレイド」、「生物加水分解性ホスファート」という用語は、１）化合物の生物学的活性を妨げないが、その化合物にインビボで有利な特性、例えば取り込み、作用持続時間、または作用の開始を付与することができるか、または２）生物学的に不活性であるが、インビボで生物学的に活性な化合物に変換されるかのいずれかの化合物のアミド、エステル、カルバマート、カルボナート、ウレイド、またはホスファートをそれぞれ意味する。生物加水分解性エステルの例としては、限定されないが、低級アルキルエステル、アルコキシアシルオキシエステル、アルキルアシルアミノアルキルエステルおよびコリンエステルが挙げられる。生物加水分解性アミドの例としては、限定されないが、低級アルキルアミド、α－アミノ酸アミド、アルコキシアシルアミドおよびアルキルアミノアルキルカルボニルアミドが挙げられる。生物加水分解性カルバマートの例としては、限定されないが、低級アルキルアミン、置換エチレンジアミン、アミノ酸、ヒドロキシアルキルアミン、複素環式および複素芳香族アミン、ならびにポリエーテルアミンが挙げられる。
上記文献で使用される場合、上記文献に開示される化合物の文脈における「その類似体」という用語は、化合物のジアステレオマー、水和物、溶媒和物、塩、プロドラッグ、およびＮ－オキシドを含む。 Taste masking of foul-tasting oral substances is traditionally practiced, particularly in medical practice, particularly with oral administration of foul-tasting drugs and botanical extracts. The basic method has been to add a palatable, non-toxic substance to help overcome an unpalatable drug compound or extract. Sweeteners (sugar or honey) were usually simply added to the formulation. Unfortunately, this method has been only marginally effective in a limited number of situations. Another method was the addition of natural (and now synthetic) fragrances, also. Again, this method has been effective only in a limited few situations as well.
The specification of US Pat. No. 7,939,671, which constitutes the background art of the present application, describes the following matters.
Bitterness masking compounds for use in such formulations have formula I:

or a salt or N-oxide thereof, wherein Ar6 and Ar7 are independently the same or different and each is an optionally substituted 5-membered heteroaryl group, and Alk is an alkyl group , R36 and R37 together with the atoms to which they are attached form an optionally substituted 5-membered heterocyclic ring, and R38 is H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl alkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylamidoalkyl, substituted or unsubstituted heteroarylamidoalkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted arylalkoxy, substituted or unsubstituted unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, or haloalkyl.
In some variations, compounds of Formula I are those in which the five-membered heterocycle formed by R36 and R37 is a hydantoin or a substituted or unsubstituted cyclic urea, or a salt or N-oxide thereof.
In some variations, the bitterness masking compound used in the formulation has Formula II:

or a salt or N-oxide thereof, wherein Ar6 and Ar7 are independently the same or different and each is an optionally substituted 5-membered heteroaryl group, and Alk is an alkyl group , R38 is H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylamidoalkyl, substituted or unsubstituted heteroarylamide alkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted arylalkoxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, or haloalkyl; R39 and R40 are independently the same or different; , substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylamidoalkyl, substituted or unsubstituted arylalkylamidoalkyl, substituted or unsubstituted is substituted or unsubstituted heteroarylamidoalkyl, substituted or unsubstituted heteroarylalkylamidoalkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted arylalkoxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, haloalkyl; Or R39 and R40 together with the carbon atom to which they are attached form a C=O group or a substituted or unsubstituted alkenyl group.
In some variations, the bitter masker compound of Formula II is a compound wherein the 5-membered heterocycle formed by R36 and R37 is urazole or a salt or N-oxide thereof.
In some variations, the bitterness masking compound used in the formulation has formula III:

or a salt or N-oxide thereof, wherein Ar6 and Ar7 are independently the same or different and each is an optionally substituted 5-membered heteroaryl group, Alk is an alkyl group, R38 is H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylamidoalkyl, substituted or unsubstituted heteroarylamidoalkyl , substituted or unsubstituted arylalkyl, substituted or unsubstituted arylalkoxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, or haloalkyl, and R41 is H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylamidoalkyl, substituted or unsubstituted arylalkylamidoalkyl, substituted or unsubstituted heteroarylamidoalkyl, substituted or unsubstituted hetero arylalkylamidoalkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted arylalkoxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, or haloalkyl.
In some variations, the bitterness masking compound used in the formulation has formula IV:

or a salt or N-oxide thereof, wherein Alk is an alkyl group, M1 is N or CR49, wherein R49 is H or substituted or unsubstituted alkyl, M2 is N or CR50, wherein R50 is H or substituted or unsubstituted alkyl, and R36 and R37, together with the atom to which they are attached, are an optionally substituted 5-membered heterocyclic ring and R38 is H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylamidoalkyl, substituted or unsubstituted heteroarylamidoalkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted arylalkoxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, or haloalkyl, wherein R47 is H, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, or halo, and R48 is H, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted substituted arylalkyl, or halo.
In some variations, the bitterness masking compound used in the formulation has Formula V:

or a salt or N-oxide thereof, wherein Alk is an alkyl group, G is C=O, Q is CR51R52 or NR51, wherein R51 and R52 are independently the same or different, H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylamidoalkyl, substituted or unsubstituted arylalkylamidoalkyl, substituted or unsubstituted heteroarylamidoalkyl, substituted or unsubstituted heteroarylalkylamidoalkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted arylalkoxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted hetero arylalkyl, haloalkyl, or R51 and R52 together with the carbon atom to which they are attached form a C═O group or a substituted or unsubstituted alkenyl group, and M1 is N or CR49 wherein R49 is H or substituted or unsubstituted alkyl, M2 is N or CR50, wherein R50 is H or substituted or unsubstituted alkyl, and R38 is H, substituted or unsubstituted unsubstituted alkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylamidoalkyl, substituted or unsubstituted heteroarylamidoalkyl, substituted or unsubstituted arylalkyl , substituted or unsubstituted arylalkoxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, or haloalkyl, and R47 is H, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl , substituted or unsubstituted arylalkyl, or halo, and R48 is H, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, or halo.
A particularly preferred bitter masking agent for use in such formulations is 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl-1-(3-hydroxy benzyl)imidazolidine-2,4-dione, and has formula VI:

or a salt or N-oxide thereof.
Regarding the bitterness masking agents used in such formulations, and in further description of compounds within one or more of Formulas I-VI above, the following 23 paragraphs detail the various groupings referred to. do.
As used in the above references, "alkyl" as well as other groups having the prefix "alk", such as alkoxy, alkanoyl, alkenyl, alkynyl, etc., refer to carbon chains which may be linear or branched or combinations thereof. do. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl and the like. Preferred alkyl groups have 1 to 4 carbons. "Alkenyl" and other similar terms include carbon chains containing at least one unsaturated carbon-carbon bond. "Alkynyl" and other similar terms include carbon chains containing at least one carbon-carbon triple bond.
The term "cycloalkyl" means carbocycles containing no heteroatoms, and includes mono-, bi- and tricyclic saturated carbocycles, as well as fused ring systems. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decahydronaphthalene, adamantane, indanyl, indenyl, fluorenyl, 1,2,3,4-tetrahydronaphthalene, and the like.
The term "aryl" means an aromatic substituent that is a single ring or multiple condensed rings. Exemplary aryl groups include, without limitation, phenyl, naphthyl, anthracenyl, pyridinyl, pyrazinyl, pyrimidinyl, triazinyl, thiophenyl, furanyl, pyrrolyl, oxazolyl, imidazolyl, triaziolyl, and tetrazolyl groups. An aryl group that contains one or more heteroatoms (eg, pyridinyl) is often referred to as a "heteroaryl group." When formed in multiple rings, at least one of the constituent rings is aromatic. In some embodiments, at least one of the polycycles contains a heteroatom, thereby forming a heteroatom-containing aryl group. Heteroatom-containing aryl groups include, but are not limited to, benzoxazolyl, benzimidazolyl, quinoxalinyl, benzofuranyl and 1H-benzo[d][1,2,3]triazolyl groups. Heteroatom-containing aryl groups also include, but are not limited to, 2,3-dihydrobenzo[b][1,4]dioxinyl and benzo[d][1,3]dioxolyl groups. A heteroatom-containing aryl group also includes an aromatic ring fused to a heterocycle that contains at least one heteroatom and at least one carbonyl group. Such groups include, but are not limited to, dioxotetrahydroquinoxalinyl and dioxotetrahydroquinazolinyl groups.
The term "arylalkoxy" means an aryl group attached to an alkoxy group.
The term "arylamidoalkyl" means aryl-C(O)NR-alkyl or aryl-NRC(O)-alkyl.
The term "arylalkylamidoalkyl" means aryl-alkyl-C(O)NR-alkyl or aryl-alkyl-NRC(O)-alkyl, wherein R is any suitable is the base.
The term "arylalkyl" refers to an aryl group attached to an alkyl group.
The term "halogen" or "halo" refers to chlorine, bromine, fluorine or iodine.
The term "haloalkyl" means an alkyl group (eg, CF3) _having one or more halogen atoms.
The term "heteroalkyl" refers to alkyl moieties containing heteroatoms such as N, O, P, B, S or Si. A heteroatom may be attached to the remainder of the heteroalkyl moiety through a saturated or unsaturated bond. Thus, alkyl substituted with groups such as heterocycloalkyl, substituted heterocycloalkyl, heteroaryl, substituted heteroaryl, alkoxy, aryloxy, boryl, phosphino, amino, silyl, thio or seleno are within the scope of the term heteroalkyl. is within. Examples of heteroalkyl include, but are not limited to, cyano, benzoyl, 2-pyridyl and 2-furyl.
The term "heteroarylalkyl" means a heteroaryl group attached to an alkyl group.
The term "heterocycle" means a monocyclic or polycyclic ring containing carbon and hydrogen atoms which may have one or two multiple bonds, the ring atoms being nitrogen, oxygen and sulfur. at least one heteroatom, specifically from 1 to 4 heteroatoms independently selected from Heterocyclic structures include, but are not limited to, monocyclic, bicyclic and tricyclic compounds. Certain heterocycles are monocyclic or bicyclic. Representative heterocycles include cyclic urea, morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydroprimidinyl, tetrahydrothio Phenyl, tetrahydrothiopyranyl, tetrazolyl and urazolyl. A heterocycle may be unsubstituted or substituted. Preferred heterocycles are 5- and 6-membered heterocycles, especially hydantoinyl and urazolyl.
The term "heterocycloalkyl" refers to a cycloalkyl group in which at least one carbon atom in the ring has been replaced with a heteroatom (eg, O, S or N).
The term "heterocycloalkylalkyl" means a heterocycloalkyl group attached to an alkyl group.
The term "substituted" specifically envisages and allows for one or more substitutions common in the art. However, it is generally understood by those skilled in the art that substituents should be chosen so as not to adversely affect useful characteristics of the compound or interfere with its function. Suitable substituents include, for example, halo, perfluoroalkyl, perfluoroalkoxy, alkyl, alkenyl, alkynyl, hydroxy, oxo, mercapto, alkylthio, alkoxy, aryl or heteroaryl groups. , aryloxy or heteroaryloxy, aralkyl or heteroaralkyl, aralkoxy or heteroaralkoxy, amino, alkyl and dialkylamino, carbamoyl, alkylcarbonyl, carboxyl, alkoxycarbonyl, alkyl aminocarbonyl group, dialkylaminocarbonyl group, arylcarbonyl group, aryloxycarbonyl group, alkylsulfonyl group, arylsulfonyl group, cycloalkyl group, cyano group, C1-C6 alkylthio group, arylthio group, nitro group, keto group, acyl group , boronate or boronyl groups, phosphate or phosphonyl groups, sulfamyl groups, sulfonyl groups, sulfinyl groups, and combinations thereof. For substituted combinations such as "substituted arylalkyl", either the aryl group or the alkyl group may be substituted, or both the aryl group and the alkyl group may be substituted with one or more substituents. good too. Additionally, in some cases, suitable substituents may combine to form one or more rings known to those of skill in the art.
The compounds described in the above references contain one or more double bonds and may therefore give rise to cis/trans isomers or other conformational isomers. The invention of the above document includes all such possible isomers or mixtures of such isomers.
The compounds described in the above references, especially the substituents mentioned above, may contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers. The invention of the above references includes all such possible diastereomers or racemic mixtures thereof, substantially pure resolved enantiomers thereof, all possible geometric isomers and acceptable salts thereof. Also included are mixtures of stereoisomers or isolated specific stereoisomers. During the course of synthetic procedures used to prepare such compounds, or when using racemization or epimerization procedures known to those skilled in the art, the products of such procedures are mixtures of stereoisomers. can be
As used in the above references, the terms "salt" and "pharmaceutically acceptable salt" refer to compounds of the disclosure wherein the parent compound is modified by making acid or base salts thereof. Refers to derivatives. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic groups such as amines, and alkali or organic salts of acidic groups such as carboxylic acids. Pharmaceutically acceptable salts include, for example, conventional non-toxic or quaternary ammonium salts of the parent compounds formed from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids, as well as acetic, propionic, succinic, glycolic, Stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfone Acids include salts prepared from organic acids such as methanesulfonic acid, ethanedisulfonic acid, oxalic acid and isethionic acid.
Pharmaceutically acceptable salts of the above documented invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or free base form of these compounds with stoichiometric amounts of the appropriate base or acid in water or an organic solvent, or in a mixture of the two. can be used, and generally non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th ed. , Mack Publishing Company, Easton, Pa.; , 1985, p. See 1418.
The term "solvate" means a compound or salt thereof that further comprises stoichiometric or non-stoichiometric amounts of solvent bound by non-covalent intermolecular forces. When the solvent is water the solvate is a hydrate.
The term "prodrug" refers to a compound that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide an active compound, particularly the compounds of the above documented invention. Derivative means. Examples of prodrugs include, but are not limited to, biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogs. derivatives and metabolites of the compounds of the above document invention containing the biohydrolyzable portion of Particular prodrugs of compounds with a carboxyl functional group are the lower alkyl esters of carboxylic acids. Carboxylic acid esters are conveniently formed by esterifying any of the carboxylic acid moieties present on the molecule. Prodrugs are typically reviewed in Burger's Medicinal Chemistry and Drug Discovery 6th ed. (Donald J. Abraham ed., 2001, Wiley), and Design and Application of Prodrugs (H. Bundgaard ed., 1985, Harwood Academic Publishers Gmfh). can.
As used in the above references, unless otherwise specified, "biohydrolyzable amide", "biohydrolysable ester", "biohydrolysable carbamate", "biohydrolyzable carbonate", "biohydrolyzable The terms ureido, "biohydrolyzable phosphate" are used to 1) not interfere with the biological activity of the compound, but impart advantageous properties to the compound in vivo, such as uptake, duration of action, or onset of action. or 2) amides, esters, carbamates, carbonates, ureides, or phosphates of compounds that are either biologically inert but are converted in vivo to biologically active compounds. respectively. Examples of biohydrolyzable esters include, but are not limited to, lower alkyl esters, alkoxyacyloxy esters, alkylacylaminoalkyl esters and choline esters. Examples of biohydrolyzable amides include, but are not limited to, lower alkylamides, α-amino acid amides, alkoxyacylamides and alkylaminoalkylcarbonylamides. Examples of biohydrolyzable carbamates include, but are not limited to, lower alkylamines, substituted ethylenediamines, amino acids, hydroxyalkylamines, heterocyclic and heteroaromatic amines, and polyetheramines.
As used in the above documents, the term "analogs thereof" in the context of the compounds disclosed in the above documents includes diastereomers, hydrates, solvates, salts, prodrugs and N-oxides of the compounds. including.

Whenever the term "comprising" is mentioned, the terms "consisting essentially of" and "consisting of" are intended to be disclosed as well . Any use of the term "about" shall be interpreted to mean that the last digit of the number immediately following defines the number as in the non-limiting examples below. (a) "about 0.54" is considered to encompass the range of at least 0.535 to <0.545; (b) "about 24" is taken to mean a range of at least 23.5 to <24.5; All numbers preceded by "about " are considered to disclose their absolute value, similarly in "about 0.54" a specific number of "0.54" and ranges in the preamble are considered to be disclosed. shall be deemed

The off-tasting ketone body substance is (a) an alkali metal salt of the ketone body, which may independently be the lithium, sodium or potassium salt of the ketone body or mixtures thereof; (b) the ketone body and other ketone bodies; such as, but not limited to, 3-(3-hydroxybutyroyl)-O-butyric acid, 3-(acetoacetyl)-O-butyric acid, or mixtures thereof, (c) ketone bodies and ketone bodies esters with precursors such as, but not limited to, 3-butyryl-O-butyric acid, or mixtures thereof; (d) esters of ketone bodies with glycerol, such as US Pat. No. 7,807,718; (incorporated by reference in its entirety), particularly glyceryl-tris(3-hydroxybutyrate) ester (hereinafter "GTβHB"), or (e) ketone bodies with physiologically acceptable amines. amides such as, but not limited to, tris(hydroxymethyl)aminomethane (TRIS); Preferably, the ketone body material is 3-hydroxybutyl-3-hydroxybutyrate, 1,3-butanediol-3-hydroxybutyrate monoester, and US Pat. incorporated herein), most preferably glyceryl-tris(3-hydroxybutyrate) (hereinafter "GTβHB"). The remainder of this disclosure relates to G T βHB, but should be understood to be equally applicable to the other ketone body substances listed above (unless the context clearly indicates otherwise). is.

The ethanol is preferably 95% ethanol, but may be of lower concentration, such as 70% ethanol or 50% ethanol (with the balance being water), in which case the excess water provided over 95% Subtract from the amount of water component below. When 95% ethanol is used, it is used in an amount of about 0.278 pbw to about 0.415 pbw, preferably about 0.309 pbw to about 0.378 pbw, more preferably about 0.343 pbw, but generally , about 0.278 pbw, about 0.280 pbw, about 0.290 pbw, about 0.300 pbw, about 0.309 pbw, about 0.310 pbw, about 0.320 pbw, about 0.330 pbw, about 0.40 pbw, about 0.341 pbw , about 0.342 pbw, about 0.343 pbw, about 0.35 pbw, about 0.36 pbw, about 0.37 pbw, about 0.378 pbw, about 0.380 pbw, about 0.39 pbw, about 0.40 pbw, about 0.41 pbw and It may be selected from any range comprised by two amounts selected from about 0.415 pbw, and may be specifically selected from any of the specified values above. Without limitation, if a lower concentration of ethanol is used, such as 70% ethanol, 70% ethanol provides the same amount of pure ethanol content as 95% ethanol provides above. used. In addition to the water provided by 95% ethanol, the extra water provided by the use of lower % ethanol is another water component found below when analyzing for total water content of a particular formulation. must be subtracted from the amount of water added as Since the above amounts of ethanol, and the separately added water below, are parts by weight, the water provided by the ethanol is subtracted from the weight of the ethanol, so that a fair comparison can be made for determining infringement, At the same time it must be added to the weight of water.

The separately added water component is present in an amount of about 0.381 pbw to about 0.569 pbw, preferably about 0.424 pbw to about 0.518 pbw, more preferably 0.471 pbw, but generally about 0.381 pbw, about 0.39 pbw, about 0.40 pbw, about 0.41 pbw, about 0.42 pbw, about 0.424 pbw, about 0.43 pbw, about 0.44 pbw, about 0.45 pbw, about 0.46 pbw , about 0.47 pbw, about 0.471 pbw, about 0.48 pbw, about 0.49 pbw, about 0.50 pbw, about 0.51 pbw, about 0.518 pbw, about 0.52 pbw, about 0.53 pbw, about 0.54 pbw , about 0.55 pbw, about 0.56 pbw and about 0.569 pbw, and may be specifically selected from any of the above specified values. good. The separately added amount of water above does not include the water introduced via the 95% ethanol used in the previous paragraph, and for comparison to possible infringement issues, the total amount of water content is It is assumed that the water provided from 95% ethanol is added to these separately added water amounts. If an ethanol concentration lower than 95% is used for the ethanol component, the water provided by the ethanol, in addition to the water that would be provided by the 95% ethanol, must be subtracted from the separately added amount of water above. (to provide the same amount of pure ethanol that is in 95% ethanol).

Propylene glycol, which is added separately as a primary solvent, is in an amount ranging from about 8.3 pbw to about 10.925 pbw, preferably from about 8.625 pbw to about 10.550 pbw, more preferably about 9.588 pbw, based on the final formulation. but more commonly about 8.3 pbw, about 8.320 pbw, about 8.322 pbw, about 8.4 pbw, about 8.5 pbw, about 8.6 pbw, about 8.625 pbw, about 8.629 pbw , about 8.630 pbw, about 8.7 pbw, about 8.8 pbw, about 8.9 pbw, about 8.93 pbw, about 8.935 pbw, about 8.936 pbw, about 8.94 pbw, about 8.95 pbw, about 8.975 pbw , about 9.00 pbw, about 9.10 pbw, about 9.20 pbw, about 9.1 pbw, about 9.2 pbw, about 9.24 pbw, about 9.246 pbw, about 9.250 pbw, about 9.3 pbw, about 9.4 pbw, about 9.5 pbw about 9.55 pbw, about 9.575 pbw, about 9.585 pbw about 9.588 pbw, about 9.6 pbw, about 9.7 pbw, about 9.8 pbw, about 9.9 pbw, about 9.91 pbw, about 9 .92 pbw, about 9.929 pbw, about 9.93 pbw, about 9.939 pbw, about 9.95 pbw, about 10.00 pbw, about 10.1 pbw, about 10.15 pbw, about 10.16 pbw, about 10.17 pbw, about About can be selected from any range constituted by two amounts selected from 10.9 pbw, about 10.918 pbw, about 10.92 pbw and about 10.922 pbw, and specifically selected from any of the above specified values may be The total amount of propylene glycol in the formulation is the sum of the propylene glycol incorporated into the preblend and the propylene glycol added as the main solvent.

The high intensity sweetener can be any high intensity sweetener, but sucralose is preferred. The high intensity sweetener ranges from about 1.609 pbw to about 2.404 pbw, preferably from 1.788 pbhw to about 2.185 pbw, more preferably from about 1.788 pbw to about 2.185 pbw, still more, in the final formulation. Preferably present in an amount of 1.986 pbw, but generally about 1.609 pbw, about 1.65 pbw, about 1.70 pbw, about 1.75 pbw, about 1.78 pbw, about 1.788 pbw, about 1.78 pbw 1.89 pbw, about 1.85 pbw, about 1.90 pbw, about 1.95 pbw, about 1.96 pbw, about 1.967 pbw, about 1.970 pbw, about 1.980 pbw, about 1.986 pbw, about 1.98 pbw 99 pbw, about 2 . 00 pbw; .25 pbw, about 2.30 pbw, about 2.35 pbw, about 2.40 pbw and about 2.404 pbw, and can be selected from any of the above specified values. It may be specifically selected.

を有する、３－（１－（（３，５－ジメチルイソオキサゾール－４－イル）メチル）－１Ｈ－ピラゾール－４－イル－１－（３－ヒドロキシベンジル）イミダゾリジン－２，４－ジオンとしても知られ、さらにＳｅｎｏｍｙｘ ＢＢ６８およびＳｅｎｏｍｙｘ Ｓ６８２１としても知られている、同特許の請求項２７の化合物である。苦味マスキング剤は、０．０３９ｐｂｗ～約０．０５８ｐｂｗ、好ましくは約０．０４２ｐｂｗ～約０．０５３ｐｂｗの範囲、より好ましくは約０．０４８ｐｂｗの量で存在するが、一般的には、約０．０３９ｐｂｗ、約０．０４０ｐｂｗ、約０．０４１ｐｂｗ、約０．０４２ｐｂｗ、約０．０４３ｐｂｗ、約０．０４４ｐｂｗ、約０．０４５ｐｂｗ、約０．０４６ｐｂｗ、約０．０４７ｐｂｗ、約０．０４８ｐｂｗ、約０．０４９ｐｂｗ、約０．０５０ｐｂｗ、約０．０５１ｐｂｗ、約０．０５２ｐｂｗ、約０．０５３ｐｂｗ、約０．０５４ｐｂｗ、約０．０５５ｐｂｗ、約０．００５６ｐｂｗ、約０．０５７ｐｂｗおよび約０．０５８ｐｂｗから選択される２つの量によって構成される任意の範囲から選択でき、また上記の特定の値のいずれかから具体的に選択されてもよい。 Bitter taste masking agents are selected from compounds within the scope of U.S. Pat. No. 7,939,671, which is incorporated herein by reference, preferably having the following structure:

as 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl-1-(3-hydroxybenzyl)imidazolidine-2,4-dione having is the compound of claim 27 of the same patent, also known as Senomyx BB68 and Senomyx S6821, The bitterness masking agent comprises from 0.039 pbw to about 0.058 pbw, preferably from about 0.042 pbw to about present in an amount in the range of 0.053 pbw, more preferably about 0.048 pbw, but generally about 0.039 pbw, about 0.040 pbw, about 0.041 pbw, about 0.042 pbw, about 0.043 pbw; about 0.044 pbw, about 0.045 pbw, about 0.046 pbw, about 0.047 pbw, about 0.048 pbw, about 0.049 pbw, about 0.050 pbw, about 0.051 pbw, about 0.052 pbw, about 0.053 pbw, can be selected from any range constituted by two amounts selected from about 0.054 pbw, about 0.055 pbw, about 0.0056 pbw, about 0.057 pbw and about 0.058 pbw, and any of the above specific values; may be specifically selected from.

The ketone compound is present in an amount ranging from about 85 pbw to about 89 pbw, preferably about 87 pbw, but generally about 85 pbw, 85.25 pbw, about 85.5 pbw, about 85.6 pbw, about 85.7 pbw. , about 85.8 pbw, about 85.9 pbw, about 86 pbw, about 86.1 pbw, about 86.2 pbw, about 86.3 pbw, about 86.4 pbw, about 86.5 pbw, about 86.6 pbw, about 86.7 pbw, about 86 .8 pbw, about 86.9 pbw, about 87.0 pbw , about 87.1 pbw, about 87.2 pbw, about 87.3 pbw, about 87.4 pbw, about 87.5 pbw, about 87.6 pbw, about 87.7 pbw, can be selected from any range constituted by two amounts selected from about 87.8 pbw, about 87.9 pbw, about 88.0 pbw, about 88.1 pbw, about 88.2 pbw and about 88.3 pbw; may be specifically selected from any of the values of

が、単一のグリセロール分子において、１つ、２つまたは３つすべてのヒドロキシ基をエステル化するものであり得る。３－ヒドロキシブチロイル基によってエステル化されるグリセロールヒドロキシ基が３つ未満である場合、残りのグリセロールヒドロキシ基は、エステル化されないままである、またはω－３脂肪酸、ω－６脂肪酸、ω－３，６－脂肪酸、中鎖脂肪酸もしくはこれらの混合物によってエステル化されることができる。（中鎖脂肪酸とは、通常８つ、１０つまたは１２つの炭素の炭素鎖を有する脂肪酸であり、例えば精製されたこのような中鎖脂肪酸がカプリル酸であるが、これに限定されない。）各分子中の各３－ヒドロキシブチロイル基は、独立してＤ体またはＬ体のいずれかであり、投与されるバルク化合物は、いずれかの混合またはすべて同一であることができる（すなわち、（ａ）すべての３－ヒドロキシブチロイル基がＤ体である、（ｂ）すべての３－ヒドロキシブチロイル基がＬ体である、（ｃ）一部の３－ヒドロキシブチロイル基がＤ体であり、残りがＬ体である、ならびに（ｄ）（１）ａおよびｂ、（２）ａおよびｃ、ならびに（３）ａ、ｂおよびｃから選択される化合物の混合物、を有する化合物の混合）。３－ヒドロキシブチロイル基のＤ体およびＬ体は、どちらも活性であるが、Ｌ体は活用されるのがより遅く、したがって３－ヒドロキシブチロイル基は、実質的にすべて、または実質的にすべてＤ体であるのが好ましい。特に好ましい実施形態では、３－ヒドロキシブチロイル基の約９０％～９８％、より好ましくは約９６％はＤ体である。それでもなお、Ｄ体対Ｌ体のその他の量を使用することは本発明の範囲内であり、１００％Ｄ体から１００％Ｌ体まで、任意の比率でのＤ体およびＬ体の任意の混合物を選択できる。さらに、１つ、２つまたは３つの（３－ヒドロキシブチリル）基を有するエステルと、（ａ）その他にエステル化していない、または（ｂ）オメガ脂肪酸（３－ω、６－ωもしくは３，６－ωもしくはこれらの混合物）とのさらなるエステル化、または（ｃ）中鎖脂肪酸もしくは異なる中鎖脂肪酸の混合物とのさらなるエステル化、または（ｄ）ω脂肪酸および中鎖脂肪酸の両方とのさらなるエステル化、との混合物もまた、本発明に使用する化合物の範囲内であると検討される。非常に好ましい実施形態では、本発明に利用される化合物がグリセリルトリス（３－ヒドロキシブチラート）であり、さらに極めて好ましい化合物はグリセリルトリス（ＤＬ ３－ヒドロキシブチラート）であるが、ＤＬはバルク化合物に関するものであり、必ずしも特定の分子中の混合物についてではない。これらの化合物およびそれらの製造の方法は、米国特許第７，８０７，７１８号明細書により詳細に記載され、同明細書は、上記化合物およびそれらの製造の説明に関して本明細書に組み込まれる。 Glyceryl esters of ketone bodies have a 3-hydroxybutyroyl group:

can esterify one, two or all three hydroxy groups in a single glycerol molecule. When less than 3 glycerol hydroxy groups are esterified by a 3-hydroxybutyroyl group, the remaining glycerol hydroxy groups remain unesterified or ω-3 fatty acids, ω-6 fatty acids, ω-3 ,6-fatty acids, medium chain fatty acids or mixtures thereof. (Medium chain fatty acids are usually fatty acids having carbon chains of 8, 10 or 12 carbons; for example, but not limited to, such purified medium chain fatty acids are caprylic acid.) Each Each 3-hydroxybutyroyl group in the molecule is independently in either the D- or L-configuration, and the bulk compound administered can be any mixture or all the same (i.e., (a (b) all 3-hydroxybutyroyl groups are in the L configuration; (c) some 3-hydroxybutyroyl groups are in the D configuration; (d) a mixture of compounds selected from (1) a and b, (2) a and c, and (3) a, b and c). Both the D- and L-forms of the 3-hydroxybutyroyl group are active, but the L-form is slower to be utilized, and thus the 3-hydroxybutyroyl group is substantially all or substantially All are preferably D-form. In particularly preferred embodiments, about 90% to 98%, more preferably about 96%, of the 3-hydroxybutyroyl groups are in the D configuration. Nevertheless, it is within the scope of the invention to use other amounts of D to L, from 100% D to 100% L, and any mixture of D and L in any ratio. can be selected. Additionally, esters having one, two or three (3-hydroxybutyryl) groups and (a) otherwise non-esterified or (b) omega fatty acids (3-ω, 6-ω or 3, 6-ω or mixtures thereof), or (c) further esterification with medium chain fatty acids or mixtures of different medium chain fatty acids, or (d) further esterification with both ω and medium chain fatty acids. are also contemplated within the scope of compounds for use in the present invention. In a highly preferred embodiment, the compound utilized in the present invention is glyceryl tris(3-hydroxybutyrate), and a further highly preferred compound is glyceryl tris(DL 3-hydroxybutyrate), where DL is the bulk compound. and not necessarily mixtures in a particular molecule. These compounds and methods for their preparation are described in more detail in US Pat. No. 7,807,718, which is incorporated herein for a description of said compounds and their preparation.

本発明で使用されるエステルが経口的に摂取されると、エステルは主に腸管内で膵リパーゼによって加水分解され、体に吸収される３－ヒドロキシブチラート部分を放出する。体は３－ヒドロキシブチラートをアセトアセタートに変換することによって利用し、今度はアセトアセタートが細胞によって実際に使用される。）当該技術分野における当業者は、上記の１回の投与量が正しい範囲内の血中濃度にならないような、非典型的な生体内分布および／または代謝を示す対象において、これらの投与量を調整する方法を理解しているだろう。（このような修正した投与量は、本明細書の他の部分に記載される、投与される「サービングサイズ」範囲または化合物バルクのｇの範囲外であるにも関わらず、３－ヒドロキシブチラートおよびアセトアセタートの組合せの血中濃度を、２ｍＭ～１０ｍＭの範囲に上昇させる場合、本発明の範囲内と考えられる。）エステルが、以下により詳細に議論されるその他のエステルである場合、最終的にグリセリルトリス（３－ヒドロキシブチラート）によって送達される、３－ヒドロキシブチロイル部分およびアセトアセタート部分の組合せに相当する量を送達するように、１回の投与量は計算される。 When the ester is glyceryl tris(3-hydroxybutyrate), usually orally/enterally, usually in an amount ranging from 0.5 g/kg to 2.0 g/kg of body weight per day (more specifically 0.5 g/kg, 0.55 g/kg, 0.6 g/kg, 0.65 g/kg, 0.7 g/kg, 0.75 g/kg, 0.8 g/kg, 0.8 g/kg, 85 g/kg, 0.9 g/kg, 0.95 g/kg, 1 g/kg, 1.1 g/kg, 1.2 g/kg, 1.3 g/kg, 1.4 g/kg, 1.5 g/kg, 1.6 g/kg, 1.7 g/kg, 1.8 g/kg, 1.9 g/kg or 2 g/kg, and amounts intermediate to any of these specifically recited amounts) from 2 to It is administered in 3 divided single doses. For a 60 kg woman, about 10-40 g/serving (more specifically 10 g/serving, 12.5 g/serving, 15 g/serving, 17.5 g/serving, 20 g/serving, 22.5 g/serving, 25 g/serving). serving, 30 g/serving, 35 g/serving, 40 g/serving and amounts in between any of these specifically recited amounts) three times a day (about every 8 hours) to about 15-60 g/ Servings (more specifically 15g/serving, 17.5g/serving, 20g/serving, 22.5g/serving, 25g/serving, 27.5g/serving, 30g/serving, 35g/serving, 40g/serving, 45g /serving, 50 g/serving, 55 g/serving or 60 g/serving and amounts in between any of these specifically recited amounts) twice daily (about every 12 hours) plus a 70 kg male about 12 to 47 g/serving (more specifically 12 g/serving, 15 g/serving, 17.5 g/serving, 20 g/serving, 22.5 g/serving, 25 g/serving, 30 g/serving, 35 g/serving, 40 g/serving, 45 g/serving, 47 g/serving and amounts in between any of these specifically recited amounts) three times a day (about every 8 hours) to about 17.5 to 70 g/ Servings (more specifically 17.5g/serving, 20g/serving, 22.5g/serving, 25g/serving, 27.5g/serving, 30g/serving, 35g/serving, 40g/serving, 45g/serving, 50g /serving, 55 g/serving, 60 g/serving, 65 g/serving, 70 g/serving and amounts in between any of these specifically recited amounts) twice daily (about every 12 hours). is. These single doses and serving sizes are such that in the average typical subject to whom these compounds are administered, total ketone body (3-hydroxybutyrate and acetoacetate combined) concentrations in the blood are 2-10 mM (more specifically 2 mM, 2.25 mM, 2.5 mM, 2.75 mM, 3 mM, 3.25 mM, 3.5 mM, 4 mM, 4.25 mM, 4.5 mM, 4.6 mM, 4.7 mM , 4.8 mM, 4.9 mM, 5.0 mM, 5.1 mM, 5.2 mM, 5.3 mM, 5.4 mM, 5.5 mM, 5.6 mM, 5.7 mM, 5.8 mM, 5.9 mM, 6 .0mM, 6.1mM, 6.2mM, 6.3mM, 6.4mM, 6.5mM, 6.6mM, 6.7mM, 6.8mM, 6.9mM, 7.0mM, 7.1mM, 7.2mM , 7.3 mM, 7.4 mM, 7.5 mM 7.6 mM, 7.7 mM, 7.8 mM, 7.9 mM, 8.0 mM, 8.25 mM, 8.5 mM, 8.75 mM, 9.0 mM, 9.25 mM , 9.5 mM, 9.75 mM and 10 mM and concentrations intermediate any of these specifically recited concentrations, provided that the upper end of the range is greater than the lower end of the range. , which may be the lower end of the range or the upper end of the range). (Acetoacetate is the oxidized form of 3-hydroxybutyrate in which the 3-hydroxy group is replaced by a 3-oxo group.

When the esters used in the present invention are orally ingested, they are hydrolyzed primarily by pancreatic lipase in the intestinal tract, releasing the 3-hydroxybutyrate moiety that is absorbed by the body. The body utilizes 3-hydroxybutyrate by converting it to acetoacetate, which in turn is actually used by the cells. ) Those skilled in the art should consider these doses in subjects exhibiting atypical biodistribution and/or metabolism such that the above single doses do not result in blood concentrations within the correct range. You will understand how to adjust. (Such modified dosage amounts are outside the administered "serving size" range or g of compound bulk, as described elsewhere herein, 3-hydroxybutyrate and acetoacetate to raise the blood concentration of the combination to the range of 2 mM to 10 mM is considered within the scope of the invention.) Finally, if the ester is other esters discussed in more detail below, A single dose is calculated to deliver an amount equivalent to the combined 3-hydroxybutyroyl and acetoacetate moieties delivered by glyceryl tris(3-hydroxybutyrate).

（アセトアセタート基とともに）の血中濃度によって特徴づけられる、治療的な高ケトン血症を誘導することである。当該技術分野の当業者は、本主題のその他の変更を理解するであろう。 The ester compound for use in the present invention is 0.5 g/kg to 2.0 g/kg body weight of glycerol tris(3-hydroxybutyrate) in an amount equivalent to orally administered It is administered in amounts that deliver the 3-hydroxybutyroyl and/or acetoacetate moieties. Again, the focus is on the appropriate ketone body concentration (3-hydroxybutyroyl concentration and acetoacetate concentration) in the blood, 2 mM to 10 mM, preferably 4.5 mM to 7 mM, more preferably 5 mM to 7 mM, most preferably The goal is to achieve 5.5 mM to 7.5 mM. If the actual volume or weight of this amount is unwieldy or undesirable for a single dose, the single dose may be divided into multiple portions of desired size and provided multiple times per day, or multiple dose units may be used. It can be provided in a single dose (ie, multiple dose units within seconds as desired). It is preferred to divide the single dose into 2-3 divided doses approximately equally spaced over a 24 hour period, so that twice daily dosing is about every 12 hours and 3 times daily. Dosing results in dosing approximately every 8 hours. As an example, if a 50g dose is desired, it can be made as a single dose of 50g in a single formulation or apportioned in food or drink, or half the 50g dose twice daily. Two doses that can be administered or are provided within seconds of each other (preferably within seconds of each other if substantially a single dose is desired) of a formulation containing one-half of a single dose Can be administered in units. If multiple doses per day are desired, or single doses in multiple dosage units per day are desired, other divided doses and multiple dosage units will be understood by those of skill in the art and 3 times, 1/3 of the above amount, or 3 dosage units administered at about the same time, 4 times a day, 1/4 of the above amount, or 4 dosage units at about the same time Examples include, but are not limited to, administering at the same time or two dosage units twice daily. The intention and purpose of the present invention is comparable to the blood concentration achieved by ketone or fasting, 2 mm to 10 mm (for example, 4.5 mm, 5.0 mm, 5.5 mm, 6.0mm, 6.5 mm, 6.5 mm, 6.5 mm, 6.5 mm. 3-hydroxybutyroyl group at 0 mM or 7.5 mM and all mM concentrations between any of these specifically recited amounts are expressly disclosed as well)

(together with the acetoacetate group) to induce therapeutic hyperketonemia, characterized by blood levels. Those skilled in the art will appreciate other variations of the present subject matter.

A preferred formulation of GTβHB is prepared as described in Table I below.

Perfume Ingredients Premix Perfume Oil 0.439% (95% orange oil, 5% other natural flavors)
Propylene glycol 0.125%
95% ethanol 0.343%
Water 0.471%
Subtotal 1.378%

Combine propylene glycol, water and ethanol and set aside.

Second Premix Propylene Glycol 9.588%
Sucralose 1.986%
Senomyx BB68 0.048%
Subtotal 11.622%

Warm the propylene glycol to 50° C., add the sucralose and dissolve. Then add the Senomyx BB68 and mix until dissolved. Allow the solution to cool to 25°C. The perfume premix is then added to the second premix to obtain a mixture that constitutes 13% of the final formulation. This mixture is then combined with glyceryl tris(3-hydroxybutyrate) in an amount of 87% of the final formulation to obtain a final formulation of 100%.
Aspects or embodiments that can be included in the present invention are summarized as follows.
[1].
An orally administrable formulation of an off-tasting ketogenic substance comprising:
(a) ketone body alkali metal salts, ketone body esters of ketone bodies with additional ketone bodies, ketone body esters of ketone bodies with ketone body precursors, ketone body esters with glycerol, and physiologically with ketone bodies a ketone body material selected from amides with acceptable amines;
(b) propylene glycol,
(c) ethanol,
(d) water;
(e) natural or synthetic flavors selected from bitter orange, grape and mixtures thereof;
(f) high-intensity sweeteners, and
(g) a bitterness masking agent;
A formulation containing
[2].
2. The formulation according to item 1 above, wherein the ketone body substance is an ester of a ketone body and glycerin.
[3].
3. The formulation of item 2 above, wherein the ketone body substance is glyceryl (3-hydroxybutyrate).
[4].
The glyceryl (3-hydroxybutyrate) is glyceryl tris(3-hydroxybutyrate), glyceryl bis(3-hydroxybutyrate), glyceryl mono(3-hydroxybutyrate), glyceryl bis(3-hydroxybutyrate) -mono (3-ω fatty acyl ester), glyceryl bis (3-hydroxybutyrate)-mono (6-ω fatty acyl ester), glyceryl mono (3-hydroxybutyrate)-di (6-ω fatty acyl ester) , glyceryl mono(3-hydroxybutyrate)-mono(3-ω fatty acyl ester)-mono(6-ω fatty acyl ester), glyceryl bis(3-hydroxybutyrate)-mono(3,6-ω fatty acyl ester) ester), glyceryl mono(3-hydroxybutyrate)-di(3-ω fatty acyl ester), glyceryl mono(3-hydroxybutyrate)-di(3,6-ω fatty acyl ester), glyceryl mono(3- hydroxybutyrate)-mono(3-ω fatty acyl ester)-mono(3,6-ω fatty acyl ester), glyceryl mono(3-hydroxybutyrate)-mono(6-ω fatty acyl ester)-mono(3 1 Multiple ω fatty acyl groups in a molecule may be the same or different, multiple medium chain fatty acyl groups in one molecule may be the same or different, and each 3-hydroxybutyrate group is independently D 3. A formulation according to item 3 above, which is selected from the L-form and the L-form.
[5].
4 above, wherein said glyceryl (3-hydroxybutyrate) is glyceryl tris(3-hydroxybutyrate), and each 3-hydroxybutyrate group is independently D or L and mixtures thereof Formulation as described.
[6].
6. The formulation of item 5 above, wherein the glyceryl tris(3-hydroxybutyrate) is glyceryl tris(DL-3-hydroxybutyrate).
[7].
The formulation is
(a) ketone body alkali metal salts, ketone body esters of ketone bodies with additional ketone bodies, ketone body esters of ketone bodies with ketone body precursors, ketone body esters with glycerol, and physiologically with ketone bodies 85.7 pbw to 88.3 pbw of a ketone body material selected from amides with acceptable amines;
(b) 8.9 pbw to 10.3 pbw propylene glycol;
(c) 0.027 pbw to 0.42 pbw of 95% ethanol;
(d) 0.38 pbw to 0.57 pbw water (excluding water provided by said ethanol);
(e) 0.35 pbw to 0.54 pbw of natural or synthetic fragrances;
(f) 12.6 pbw to 2.41 pbw high intensity sweetener, and
(g) 0.39 pbw to 0.06 pbw of a bitter masking agent;
The formulation according to item 1 above.
[8].
9. The formulation of item 8 above, wherein the ketone body substance is glyceryl tris(3-hydroxybutyrate).
[9].
The bitterness-masking agent is the compound 3-(1-((3,5-dimethylisookisazol-4-yaru)methyl)-1H-pyrazol-4-yl-1-(3-hydroxybenzyl)imidazolidine -2,4-dione, the formulation according to item 1 above.
[10].
the bitterness masking agent is the compound 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl-1-(3-hydroxybenzyl)imidazolidine-2, The formulation according to item 7 above, which is a 4-dione.
[11].
The formulation is
(a) ketone body alkali metal salts, ketone body esters of ketone bodies with additional ketone bodies, ketone body esters of ketone bodies with ketone body precursors, ketone body esters with glycerol, and physiologically with ketone bodies about 87 pbw of a ketone body material selected from amides with acceptable amines;
(b) about 9.613 pbw propylene glycol;
(c) about 0.343 pbw of 95% ethanol;
(d) about 0.471 pbw of additional water;
(e) about 0.439 pbw of natural or synthetic fragrance;
(f) about 1.986 sucralose, and
(g) about 0.048 pbw of said compound, 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl-1-(3-hydroxybenzyl)imidazo; a bitter masking agent which is lysine-2,4-dione;
The formulation according to item 1 above, comprising
[12].
The formulation is
(a) ketone body alkali metal salts, ketone body esters of ketone bodies with additional ketone bodies, ketone body esters of ketone bodies with ketone body precursors, ketone body esters with glycerol, and physiologically with ketone bodies about 87 pbw of a ketone body material selected from amides with acceptable amines;
(b) about 9.613 pbw propylene glycol;
(c) about 0.343 pbw of 95% ethanol;
(d) about 0.471 pbw of additional water;
(e) about 0.439 pbw of natural or synthetic fragrance;
(f) about 1.986 sucralose, and
(g) about 0.048 pbw of said compound, 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl-1-(3-hydroxybenzyl)imidazo; a bitter masking agent which is lysine-2,4-dione;
12. The formulation according to item 11 above, which consists of:
[13].
The formulation is
(a) ketone body alkali metal salts, ketone body esters of ketone bodies with additional ketone bodies, ketone body esters of ketone bodies with ketone body precursors, ketone body esters with glycerol, and physiologically with ketone bodies 87 pbw of a ketone body selected from amides with acceptable amines;
(b) about 9.613 pbw propylene glycol;
(c) about 0.343 pbw of 95% ethanol;
(d) about 0.471 pbw of additional water;
(e) about 0.439 pbw of natural or synthetic fragrance;
(f) about 1.986 sucralose, and
(g) about 0.048 pbw of said compound, 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl-1-(3-hydroxybenzyl)imidazo; a bitter masking agent which is lysine-2,4-dione;
12. The formulation according to item 11 above, which consists of:
[14].
14. The formulation of item 13, wherein said natural or synthetic flavor is a natural flavor, at least 90% of which is orange or grape natural flavor.

Claims (16)

An oral dosage form of at least one bad-tasting ketogenic substance,
(a) said at least one bad-tasting ketogenic substance;
(b) propylene glycol;
(c) aqueous ethanol;
(d) water in addition to the water contributed by said aqueous ethanol, hereinafter "additional water" ;
(e) a natural or synthetic flavor comprising at least one flavor oil, wherein at least 90% of said at least one flavor oil is orange flavor oil, grape flavor oil, or mixtures thereof;
(f) a high intensity sweetener, and
(g) a bitterness masking agent ;
wherein said at least one off-tasting ketone body substance comprises at least one of the group consisting of one or more alkali metal salts of one or more first ketone body compounds, one or more ketone body esters, and ketone body amides; selected from substances,
the one or more first ketone body compounds are independently selected from the group consisting of 3-hydroxybutyric acid and acetoacetic acid;
wherein the one or more ketone body esters are (i) an ester between a hydroxyl group of a first 3-hydroxybutyric acid and an acid group of a second ketone body compound, wherein the second ketone body compound is (ii) an ester between said first ketone body compound and a precursor of said second ketone body compound; (iii) said first independently selected from the group consisting of an ester between a ketone compound and glycerin, and (iv) mixtures thereof;
said one or more ketone body amides is selected from the group consisting of amides formed between said first ketone body compound and a physiologically acceptable amine;
The bitterness masking agent has formula I:

or salts or N-oxides thereof, wherein Ar6 and Ar7 are independently the same or different and each is an optionally substituted 5-membered heteroaryl group, and Alk is an alkyl R36 and R37 together with the atoms to which they are attached form an optionally substituted 5-membered heterocyclic ring, and R38 is H, substituted or unsubstituted alkyl, substituted or unsubstituted substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylamidoalkyl, substituted or unsubstituted heteroarylamidoalkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted arylalkoxy , substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, or haloalkyl,
Oral formulation. 2. The formulation of claim 1, wherein said at least one off-tasting ketone body substance is selected from said esters between said first ketone body compound and glycerin . 3. The formulation of claim 2, wherein said at least one bad-tasting ketone body substance is glyceryl (3-hydroxybutyrate). The glyceryl (3-hydroxybutyrate) is glyceryl tris(3-hydroxybutyrate), glyceryl bis(3-hydroxybutyrate), glyceryl mono(3-hydroxybutyrate), glyceryl bis(3-hydroxybutyrate) - mono (3- omega fatty acid ester), glyceryl bis (3-hydroxybutyrate)-mono (6- omega fatty acid ester), glyceryl mono (3-hydroxybutyrate)-di (6- omega fatty acid ester), glyceryl mono (3-hydroxybutyrate)-mono (3- omega fatty acid ester)-mono (6- omega fatty acid ester), glyceryl bis(3-hydroxybutyrate)-mono (3,6- omega fatty acid ester), glyceryl mono ( 3-hydroxybutyrate)-di(3- omega fatty acid ester), glyceryl mono(3-hydroxybutyrate)-di(3,6- omega fatty acid ester), glyceryl mono(3-hydroxybutyrate)-mono(3 -omega fatty acid ester)-mono (3,6- omega fatty acid ester), glyceryl mono (3-hydroxybutyrate)-mono (6- omega fatty acid ester)-mono (3,6- omega fatty acid ester), and these mixtures, any of the above wherein one or more omega fatty acids or non-esterified hydroxyl groups are replaced by medium chain fatty acid ester groups, and wherein multiple omega fatty acid groups in a single molecule are the same Or different, wherein the multiple medium chain fatty acid groups in a single molecule are the same or different and each 3-hydroxybutyrate group is independently selected from its D and L forms. pharmaceutical formulation. The glyceryl (3-hydroxybutyrate) is glyceryl tris (3-hydroxybutyrate), each 3-hydroxybutyrate group is independently D or L, glyceryl tris (D-3-hydroxy butyrate), glyceryl tris(L-3-hydroxybutyrate), glyceryl bis(D-3-hydroxybutyrate)-mono(L-3-hydroxybutyrate), and glyceryl bis(L-3-hydroxybutyrate) )-mono(D-3-hydroxybutyrate) . 6. The formulation of claim 5, wherein said glyceryl tris(3-hydroxybutyrate) is glyceryl tris(DL-3-hydroxybutyrate). The formulation is
(a ) 85.7 pbw to 88.3 pbw of said at least one off-taste ketogenic substance;
(b) 8.9 pbw to 10.3 pbw of said propylene glycol;
(c) an amount of said aqueous ethanol equivalent to 0.278 pbw to 0.415 pbw of 95% ethanol based on its ethanol content ;
(d) 0.38 pbw to 0.57 pbw of said additional water ;
(e) 0.35 pbw to 0.54 pbw of said natural or synthetic fragrance;
(f) 1.609 pbw to 2.404 pbw of said high intensity sweetener, and
(g) 0.039 pbw to 0.058 pbw of said bitter masking agent. 8. The oral dosage form of claim 7 , wherein said at least one bad-tasting ketone body substance is glycerol tris(3-hydroxybutyrate). The bitterness-masking agent is the compound 3- (1-((3,5-dimethylisoxazol-4- yl )methyl)-1H-pyrazol-4-yl-1-(3-hydroxybenzyl)imidazolidine- 2. The oral formulation of claim 1, which is a 2,4-dione or its salt or N-oxide . (a ) about 87 pbw of said at least one off-taste ketogenic substance;
(b) about 9.613 pbw of said propylene glycol;
(c) about 0.343 pbw of said aqueous ethanol , which is 95% ethanol ;
(d) about 0.471 pbw of said additional water;
(e) about 0.439 pbw of said natural or synthetic fragrance;
(f) about 1.986 pbw of said high intensity sweetener ; and
(g) about 0.048 pbw of said compound 3- (1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl-1-(3-hydroxybenzyl)imidazo 2. The oral dosage form of claim 1, comprising said bitter masking agent that is lysine-2,4-dione. (a ) about 87 pbw of said at least one off-taste ketogenic substance;
(b) about 9.613 pbw of said propylene glycol;
(c) about 0.343 pbw of said aqueous ethanol , which is 95% ethanol ;
(d) about 0.471 pbw of said additional water;
(e) about 0.439 pbw of said natural or synthetic fragrance;
(f) about 1.986 pbw of said high intensity sweetener which is sucralose ; and
(g) about 0.048 pbw of said compound 3- (1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl-1-(3-hydroxybenzyl)imidazo 2. An oral dosage form according to claim 1 , comprising said bitter masking agent which is lysine-2,4-dione. 2. An oral dosage form according to claim 1 , wherein said natural or synthetic flavor is a natural flavor composition and comprises at least 90 % orange natural flavor or grape natural flavor. The bitterness masking agent has the formula:

or a salt or N-oxide thereof, wherein Ar6 and Ar7 are independently the same or different and each is an optionally substituted 5-membered heteroaryl group, and Alk is an alkyl group , R38 is H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylamidoalkyl, substituted or unsubstituted heteroarylamide alkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted arylalkoxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, or haloalkyl; R39 and R40 are independently the same or different; , substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylamidoalkyl, substituted or unsubstituted arylalkylamidoalkyl, substituted or unsubstituted is substituted or unsubstituted heteroarylamidoalkyl, substituted or unsubstituted heteroarylalkylamidoalkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted arylalkoxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, haloalkyl; or R39 and R40 together with the carbon atom to which they are attached form a C═O group or a substituted or unsubstituted alkenyl group. The bitterness masking agent has the formula:

or a salt or N-oxide thereof, wherein Ar6 and Ar7 are independently the same or different and each is an optionally substituted 5-membered heteroaryl group, Alk is an alkyl group, R38 is H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylamidoalkyl, substituted or unsubstituted heteroarylamidoalkyl , substituted or unsubstituted arylalkyl, substituted or unsubstituted arylalkoxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, or haloalkyl, and R41 is H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylamidoalkyl, substituted or unsubstituted arylalkylamidoalkyl, substituted or unsubstituted heteroarylamidoalkyl, substituted or unsubstituted hetero 2. The oral dosage form of claim 1, which is arylalkylamidoalkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted arylalkoxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, or haloalkyl. The bitterness masking agent has the formula:

or a salt or N-oxide thereof, wherein Alk is an alkyl group, M1 is N or CR49, wherein R49 is H or substituted or unsubstituted alkyl, M2 is N or CR50, wherein R50 is H or substituted or unsubstituted alkyl, and R36 and R37, together with the atom to which they are attached, are an optionally substituted 5-membered heterocyclic ring and R38 is H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylamidoalkyl, substituted or unsubstituted heteroarylamidoalkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted arylalkoxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, or haloalkyl, wherein R47 is H, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, or halo, and R48 is H, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted 2. The oral dosage form of claim 1, which is substituted arylalkyl, or halo. The bitterness masking agent has the formula:

or a salt or N-oxide thereof, wherein Alk is an alkyl group, G is C=O, Q is CR51R52 or NR51, wherein R51 and R52 are independently the same or different, H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylamidoalkyl, substituted or unsubstituted arylalkylamidoalkyl, substituted or unsubstituted heteroarylamidoalkyl, substituted or unsubstituted heteroarylalkylamidoalkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted arylalkoxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted hetero arylalkyl, haloalkyl, or R51 and R52 together with the carbon atom to which they are attached form a C═O group or a substituted or unsubstituted alkenyl group, and M1 is N or CR49 wherein R49 is H or substituted or unsubstituted alkyl, M2 is N or CR50, wherein R50 is H or substituted or unsubstituted alkyl, and R38 is H, substituted or unsubstituted unsubstituted alkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylamidoalkyl, substituted or unsubstituted heteroarylamidoalkyl, substituted or unsubstituted arylalkyl , substituted or unsubstituted arylalkoxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, or haloalkyl, and R47 is H, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl , substituted or unsubstituted arylalkyl, or halo, and R48 is H, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, or halo 1. Oral formulation according to 1.