JP6161614B2 - N−[5−(アミノスルホニル)−4−メチル−1,3−チアゾール−2−イル]−n−メチル−2−[4−(2−ピリジニル)フェニル]アセトアミドメシレート一水和物 - Google Patents
N−[5−(アミノスルホニル)−4−メチル−1,3−チアゾール−2−イル]−n−メチル−2−[4−(2−ピリジニル)フェニル]アセトアミドメシレート一水和物 Download PDFInfo
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- JP6161614B2 JP6161614B2 JP2014532361A JP2014532361A JP6161614B2 JP 6161614 B2 JP6161614 B2 JP 6161614B2 JP 2014532361 A JP2014532361 A JP 2014532361A JP 2014532361 A JP2014532361 A JP 2014532361A JP 6161614 B2 JP6161614 B2 JP 6161614B2
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- JP
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- Prior art keywords
- methyl
- pyridinyl
- phenyl
- aminosulfonyl
- thiazol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 229940114930 potassium stearate Drugs 0.000 description 1
- ANBFRLKBEIFNQU-UHFFFAOYSA-M potassium;octadecanoate Chemical compound [K+].CCCCCCCCCCCCCCCCCC([O-])=O ANBFRLKBEIFNQU-UHFFFAOYSA-M 0.000 description 1
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- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 239000002884 skin cream Substances 0.000 description 1
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- 238000003860 storage Methods 0.000 description 1
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- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K31/435—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
- A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K31/435—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
- A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
- A61P31/22—Antivirals for DNA viruses for herpes viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/38—Nitrogen atoms
- C07D277/44—Acylated amino or imino radicals
- C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Chemical & Material Sciences (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Thiazole And Isothizaole Compounds (AREA)
Description
[発明の背景]
N−[5−(アミノスルホニル)−4−メチル−1,3−チアゾール−2−イル]−N−メチル−2−[4−(2−ピリジニル)フェニル]アセトアミドの合成は、EP1244641B1の記載から公知であり、微粉化されたN−[5−(アミノスルホニル)−4−メチル−1,3−チアゾール−2−イル]−N−メチル−2−[4−(2−ピリジニル)フェニル]アセトアミドを含む錠剤の製剤のためのメタンスルホン酸を含む酸化合物の使用は、WO2006/103011A1に開示されている。
[発明の説明]
本発明は、N−[5−(アミノスルホニル)−4−メチル−1,3−チアゾール−2−イル]−N−メチル−2−[4−(2−ピリジニル)フェニル]アセトアミドおよびそのメシレート塩の改良された新規な合成に関する。この改良された合成は、最先端の昔からある公知の合成と同じ化合物から出発するが、ボロン酸誘導体試薬またはボロラン試薬の使用によって3つの反応ステップを組み合わせる。この改良は、2つの分離および精製ステップを避けることによってより容易に合成を完結し、収率を増加させることもできる。
ステップA:次の一般式A*
R2は1〜6個の炭素原子を有するアルキル基、または3〜6個の炭素原子を有するシクロアルキル基を表す。)
で表される化合物Aを、R1−OH、またはR1−B(OR)2の脱離下で、および、化合物Aの中間体ボロン酸誘導体の形成において、ボロン酸誘導体試薬、ボロラン試薬、ボリナン試薬、またはジボロン酸試薬と反応させること。
ここで、中間体ボロン酸誘導体を、後に、対応するカルボン酸塩のアルカリ性溶液として(4−ピリジン−2−イルフェニル)酢酸を得るために塩基性条件下で次の一般式B*のピリジン化合物Bと反応させる。
結果として生じる(4−ピリジン−2−イルフェニル)酢酸を、種々のpHで簡単な洗浄、およびクリアろ過(clear filtration)ステップに続く沈殿または結晶化によって精製し、好ましくは適切な量の塩基を用いて、(4−ピリジン−2−イルフェニル)酢酸の水性の酸性溶液のpHを3.5〜5.0、好ましくは3.8〜4.7に適切に調節することによって精製する。簡単な洗浄およびろ過ステップに加えて、例えば再結晶またはクロマトグラフィーによる(4−ピリジン−2−イルフェニル)酢酸または任意の中間体のさらなる精製を必要としない。
次の式
ステップE:アセチルサルチル酸、トリフルリジン、イドクスウリジン、フォスカーネット、シドホビル、ガンシクロビル、アシクロビル、ペンシクロビル、バラシクロビルおよび/またはファムシクロビルを、結晶性N−[5−(アミノスルホニル)−4−メチル−1,3−チアゾール−2−イル]−N−メチル−2−[4−(2−ピリジニル)フェニル]アセトアミドメタンスルホン酸一水和物ならびに少なくとも一つの薬学的に許容できる担体、賦形剤、溶媒および/または希釈剤に添加すること。
・有機溶媒(トルエン、MIBK、EtOAc、MeTHFなど)を用いて水性のアルカリ性および酸性生成物溶液の連続的な洗浄による精製およびPd除去である。
・チャコール/セライト処理によるさらなるPd枯渇(depletion)である。
・結晶化は中和によって(好ましくは50〜70℃で)アルカリ性または酸性水溶液のどちらからでも可能であることである。
さらに、本発明は、抗ウイルス剤と組み合わせた結晶性N−[5−(アミノスルホニル)−4−メチル−1,3−チアゾール−2−イル]−N−メチル−2−[4−(2−ピリジニル)−フェニル]アセトアミドメタンスルホン酸一水和物に関する。さらに抗ウイルス剤は、好ましくは代謝拮抗剤であり、最も好ましくは、核塩基類似体薬、ヌクレオチド類似体薬、またはヌクレオシド類似体薬である。さらなる抗ウイルス剤は、ヘルペスウイルスに対して、および/または一つのヘルペスウイルス、もしくは複数のヘルペスウイルスの伝染にたいして有用であり、限定されないが、トリフルリジン、イドクスウリジン、フォスカーネット、シドホビル、ガンシクロビル、アシクロビルもしくはペンシクロビルもしくはアシクロビルのプロドラッグであるバラシクロビルもしくはペンシクロビルのプロドラッグであるファムシクロビルを含む薬物の群から選択されるか、またはトリフルリジン、イドクスウリジン、フォスカーネット、シドホビル、ガンシクロビル、アシクロビルもしくはペンシクロビルもしくはアシクロビルのプロドラッグであるバラシクロビルもしくはペンシクロビルのプロドラッグであるファムシクロビルからなる群から選択されるとさらに好ましい。最も好ましくは、結晶性N−[5−(アミノスルホニル)−4−メチル−1,3−チアゾール−2−イル]−N−メチル−2−[4−(2−ピリジニル)−フェニル]アセトアミドメタンスルホン酸一水和物、およびアシクロビルまたはペンシクロビルまたはアシクロビルのプロドラッグであるバラシクロビルまたはペンシクロビルのプロドラッグであるファムシクロビルの組み合わせである。
薬学的に許容できる担体、賦形剤、および/または希釈剤として、好ましくはラクトース、デンプン、スクロース、セルロース、ステアリン酸マグネシウム、リン酸ジカルシウム、硫酸カルシウム、タルク、マンニトール、エチルアルコール(液体充填カプセル)のような不活性担体などの担体を使用することができ、適切な結合剤はデンプン、ゼラチン、天然糖、コーン甘味料、例えばアカシアなどの天然および合成ゴム、アルギン酸ナトリウム、カルボキシメチルセルロース、ポリエチレングリコールおよびワックス、例えばスクロースなどのような糖、小麦コーン米およびジャガイモ由来のデンプン、例えばアカシア、ゼラチンとトラガカントなどのような天然ゴム、例えばアルギン酸、アルギン酸ナトリウムおよびアンモニウムカルシウムアルギンネートなどのような海草の誘導体、例えばメチルセルロース、カルボキシメチルセルロースナトリウム、およびヒドロキシプロピルメチルセルロースなどのようなセルロース材、ポリビニルピロリドン、および例えばマグネシウムアルミニウムシリケートなどのような無機化合物;ホウ酸、安息香酸ナトリウム、酢酸ナトリウム、塩化ナトリウム、ステアリン酸マグネシウム、ステアリン酸カルシウムまたはステアリン酸カリウム、ステアリン酸、高融点ワックスなどのような潤滑剤、ならびに例えば塩化ナトリウム、安息香酸ナトリウム、酢酸ナトリウム、オレイン酸ナトリウム、ポリエチレングリコール、およびD,L−ロイシンなどのような他の水溶性潤滑剤;例えば、デンプン、メチルセルロース、グアーゴムなどのような崩壊剤(崩壊剤)、例えば、ナトリウムカルボキシメチルデンプンなどのような修飾デンプン、例えば、イナゴマメ、カラヤ、グアー、トラガカントおよび寒天などのような天然および合成ゴム、例えばメチルセルロースおよびカルボキシメチルセルロースナトリウムなどのようなセルロース誘導体、微結晶セルロース、ならびに例えば、クロスカルメロースナトリウムなどのような架橋微結晶セルロース、例えばアルギン酸およびアルギン酸ナトリウムなどのようなアルギネート、例えばベントナイトなどのような粘土ならびに発泡性混合物;着色剤、甘味料、香料、防腐剤を含み;グリデント(glidents)は、例えば二酸化ケイ素およびタルクであり;適切な吸着剤は、粘土、酸化アルミニウムであり、適切な希釈剤は非経口的注射のための水または水/プロピレングリコール溶液、ジュース、例えばラクトース、スクロース、マンニトールおよびソルビトールなどの糖、小麦、コーンライス、およびジャガイモ由来のデンプン、ならびに、例えば微結晶セルロースなどのようなセルロースである。
定義:本願で使用される用語“1vol.”は、各出発物質の1kgあたり1Lを指す(1vol.=各物質または各出発物質の1kgあたり1L)。
ステップ1(鈴木−宮浦カップリングおよび鹸化)
不活性反応容器に、ビス(トリフェニルホスフィン)パラジウム(II)クロリド(0.010eq)を充填し、再不活性化する。その後、トルエン(1.65vol.)を加える。40℃に加熱後、トリエチルアミン(3.00eq.)を加える。トルエン(0.82vol.)中にエチル−4−ブロモフェニルアセテート(1.00eq.)を有する溶液を加える。結果として生じる懸濁液を90〜95℃に加熱し、ピナコールボラン(1.30eq.)を60〜90分間にわたって投与する。90〜95℃で少なくとも後2時間撹拌を続け、HPLCによって反応の変化を検査する。10℃に冷却後、2−クロロピリジン(1.00eq.)を、反応混合物に充填する。その後、30%NaOH(6.00eq.)を加え、続いて55〜60℃に加熱する。この温度で少なくとも4時間撹拌を続け、HPLCによって反応の変化を検査する。反応の変化が完結したとみなされた時点で、反応混合物を、0.8vol.の蒸留物が集められるまで、約300mbarで濃縮する。反応混合物を水(2.72vol.)で希釈し、20℃に冷却し、層を分離する。有機層を捨て、水層のpHを20℃で33%のHClの付加によってpH1に調整する。MIBK(2.30vol.)およびセライト(165g/kg)を加え、結果として生じる混合物を少なくとも15分間20℃で撹拌し、固体を濾過によって取り除く。反応溶液およびフィルターケーキを連続して水でリンスし、混合した濾液を反応容器に再び移す。層を分離し、水層をMIBKで二回より多く洗浄する。水で希釈後、水性酸性生成物溶液を55℃まで加熱し、底にはセライト、上部には活性化されたチャコールで満たされたプラグに通してろ過する。セライト/チャコールプラグを予熱水(0.5vol.、55℃)でもう一度洗浄し、混合した濾液を反応容器に再び充填した。20℃で、30%NaOHの付加によってpHを〜3.0に調整し、生成溶液を60℃まで加熱した。さらにpHを4.1〜4.3に調整するようにNaOHを投与した。結果として生じる懸濁液を1〜1.5時間60℃で撹拌し、20℃まで冷却した。この温度で少なくとも1時間さらに撹拌した後、生成物をろ過し、水で2回洗浄し、N2の気流で予備乾燥し、50〜65℃で真空で最終的に乾燥させた。標準的収率:38〜42%。
反応溶液をステップ1からの生成物(1.00eq.)、および4−メチル−2−(メチルアミンの)−1,3−チアゾール−5−スルホンアミド(1.02eq.)で充填する。THF(7.08vol.)およびNMP(1.11vol.)を加える。結果として生じる懸濁液を、0℃まで冷却し、1−エチル−3−(ジメチルアミノプロピル)カルボジイミド塩酸塩(1.23eq.)を90分間を超える時間にわたって等量ずつ4回で加える。0℃で少なくともあと2時間後、反応混合物を20℃まで暖める。この温度で、さらに2時間撹拌を続け、HPLCによって反応の変化を検査する。その後、10〜15℃で反応混合物の約2%(0.2vol.)を、少なくとも5分以内に水(12.3vol)に加える。結果として生じる薄い懸濁液を少なくとも1時間10〜15℃で撹拌し、残存する大半の反応混合物を4時間を超える時間にわたって投与する。10〜15℃で少なくとも0.5時間撹拌を続け、溶液をろ過し、水で洗浄し、十分な乾燥と見なされるまでN2の定流でヌッチェ(nutsche)フィルターで乾燥させた(LOD<45%w/w;LOD:乾燥減量)。
反応容器をステップ2からの生成物(1.00eq.)、エタノール(4.96vol.)、および水(4.96vol.)で充填する。結果として生じる懸濁液を50〜55℃に加熱後、メタンスルホン酸(1.15eq.)を<15分以内で加える。出発物質の完全な溶解を、添加の最後に典型的に観察する。次の5分以内に、撹拌速度を最小の許容速度に減らし反応混合物を、前述の実施例で所望の多形形態で調製されるN−[5−(アミノスルホニル)−4−メチル−1,3−チアゾール−2−イル]−N−メチル−2−[4−(2−ピリジニル)−フェニル]アセトアミドメタンスルホン酸一水和物(0.005eq.)と混合する。50〜55℃で緩やかな撹拌を60〜90分間続け2.5時間を超えない時間の間に20〜25℃に冷却する。1時間を超える時間撹拌後、溶液をろ過し、5:2V/V(3.10vol.)のエタノール/水で洗浄し、窒素の気流で予備乾燥させ、20〜60℃で真空で最終的な乾燥のために、コニカルドライヤに移す。標準収率:>95%。
微粉化された活性化合物として本発明に係るN−[5−(アミノスルホニル)−4−メチル−1,3−チアゾール−2−イル]−N−メチル−2−[4−(2−ピリジニル)−フェニル]アセトアミドの60mg(遊離塩基形として算出される)を含む錠剤、
活性化合物約59%の含有量(塗装されていない(nonvarnished)錠剤に基づく):
結晶性N−[5−(アミノスルホニル)−4−メチル−1,3−チアゾール−2−イル]−N−メチル−2−[4−(2−ピリジニル)−フェニル]アセトアミドメタンスルホン酸一水和物 77.0mg
アビセルPH 101 118.0mg
ラクトース、微粉 40.0mg
Ac−Di−Sol 20.0mg
ポリイニルピロリドン(Polyinylpyrrolidone) 25 10.0mg
ステアリン酸マグネシウム 2.0mg
実施例3:
微粉化された活性化合物として本発明に係るN−[5−(アミノスルホニル)−4−メチル−1,3−チアゾール−2−イル]−N−メチル−2−[4−(2−ピリジニル)−フェニル]アセトアミドの30mg(遊離塩基形態として算出される)を含む軟膏
結晶性N−[5−(アミノスルホニル)−4−メチル−1,3−チアゾール−2−イル]−N−メチル−2−[4−(2−ピリジニル)−フェニル]アセトアミドメタンスルホン酸一水和物、微粉化 38.4mg
酸化亜鉛 60.0mg
滑石 60.0mg
グリセロール 120.0mg
プロピレングリコール 40.0mg
滅菌水 80.0mg
実施例4:
微粉化された活性化合物として本発明に係るN−[5−(アミノスルホニル)−4−メチル−1,3−チアゾール−2−イル]−N−メチル−2−[4−(2−ピリジニル)−フェニル]アセトアミドの40mg(遊離塩基形態として算出される)を含むゲル。
結晶性N−[5−(アミノスルホニル)−4−メチル−1,3−チアゾール−2−イル]−N−メチル−2−[4−(2−ピリジニル)−フェニル]アセトアミドメタンスルホン酸一水和物、微粉化 51.2mg
水酸化ナトリウム溶液 30.0mg
1,2−プロパンジオール 80.0mg
グリセロール 20.0mg
ポリアクリル酸 60.0mg
滅菌水 280.0mg
実施例5:
微粉化された活性化合物として本発明に係るN−[5−(アミノスルホニル)−4−メチル−1,3−チアゾール−2−イル]−N−メチル−2−[4−(2−ピリジニル)−フェニル]アセトアミドの40mg(遊離塩基形態として算出される)を含むゲル。
結晶性N−[5−(アミノスルホニル)−4−メチル−1,3−チアゾール−2−イル]−N−メチル−2−[4−(2−ピリジニル)−フェニル]アセトアミドメタンスルホン酸一水和物、微粉化 51.2mg
1,2−プロパンジオール 80.0mg
グリセロール 20.0mg
ポリアクリル酸 60.0mg
滅菌水 280.0mg
実施例6:
微粉化された活性化合物として本発明に係るN−[5−(アミノスルホニル)−4−メチル−1,3−チアゾール−2−イル]−N−メチル−2−[4−(2−ピリジニル)−フェニル]アセトアミドの50mg(遊離塩基形態として算出される)を含む錠剤、
活性化合物約59%の含有量(塗装されていない(nonvarnished)錠剤に基づく):
微粉化された結晶性N−[5−(アミノスルホニル)−4−メチル−1,3−チアゾール−2−イル]−N−メチル−2−[4−(2−ピリジニル)−フェニル]アセトアミドメタンスルホン酸一水和物 64.00mg
ポリイニルピロリドン(Polyinylpyrrolidone) 25 3.50mg
微結晶性セルロース 20.00mg
クロスカメロースナトリウム(Croscamellose sodium) 10.00mg
ステアリン酸マグネシウム 0.85mg
任意にHPMCフィルムコーティング 3.00mg
実施例7:N−[5−(アミノスルホニル)−4−メチル−1,3−チアゾール−2−イル]−N−メチル−2−[4−(2−ピリジニル)−フェニル]アセトアミドメタンスルホン酸一水和物の結晶構造
式C19H24N4O7S3、M=516.62、F(000)=540
無色プレート、サイズ0.02 0.13 0.15mm3、三斜昌系、空間群 P−1、Z=2、a=9.4908(7)Å、b=9.5545(7)Å、c=14.4137(9)Å、α=86.130(3)゜、β=72.104(3)゜、γ=68.253(4)゜、V=1153.68(15)Å3、Dcalc.=1.487Mg m−3。結晶を、λ=0.71073Å、Θmax=30.065゜でグラファイトで単色化されたMoKα−放射線を用いて、293Kでノニウスカッパ(Nonius Kappa)CCD回折計で測定した。最小の/最大の伝達 0.95/0.99、μ=0.370mm−1。コレクト(COLLECT)スィート(suite)を、データ収集、および統合のために使用した。合計43492反射から、6761は、独立であった(マージング(merging)r=0.026)。これらから、4955を、観察されると考え(I>3.0σ(I))、298パラメータを精密化するために使用した。構造を、プログラムSIR92を用いてダイレクト法によって解析した。Fに対する最小二乗法リファインメントを、プログラムCRYSTALSを用いてすべての非水素原子で行った。R=0.0313(観察データ)、wR=0.0432(全データ)、GOF=1.0736。最小の/最大の残差電子密度=−0.28/0.33eÅ−3。チェビシェフ(Chebychev)多項式重みを、リファインメントを完了するために使用した。
遊離塩基N−[5−(アミノスルホニル)−4−メチル−1,3−チアゾール−2−イル]−N−メチル−2−[4−(2−ピリジニル)フェニル]アセトアミド(遊離塩基)で行われる13週反復投与毒性研究において、ラットへのN−[5−(アミノスルホニル)−4−メチル−1,3−チアゾール−2−イル]−N−メチル−2−[4−(2−ピリジニル)フェニル]アセトアミドの曝露を、メシレート一水和物で行われる26週反復投与毒性研究で観察される曝露と比較した。両研究において、試験項目を0.5%(w/v)チロース懸濁液として投与し、濃度を遊離塩基N−[5−(アミノスルホニル)−4−メチル−1,3−チアゾール−2−イル]−N−メチル−2−[4−(2−ピリジニル)フェニル]アセトアミド当量に調整した。
Claims (7)
- 以下に示すステップA及びステップBに従って、N−[5−(アミノスルホニル)−4−メチル−1,3−チアゾール−2−イル]−N−メチル−2−[4−(2−ピリジニル)フェニル]アセトアミドを合成する方法。
ステップA:
次の一般式A*
R2は1〜6個の炭素原子を有するアルキル基、または3〜6個の炭素原子を有するシクロアルキル基を表す。)
で表される化合物Aを、
R1−OH、またはR1−B(OR)2の脱離下で、および、化合物Aの中間体ボロン酸誘導体の形成下で、ボロン酸誘導体試薬、ボロラン試薬、ボリナン試薬、またはジボロン酸試薬と反応させるステップであって、
ここで、前記中間体ボロン酸誘導体は、後に精製される(4−ピリジン−2−イルフェニル)酢酸を直接得るために、塩基性条件下で、次の一般式B*
で表されるピリジン化合物Bと反応させるステップ。
ステップB:
ステップAから得られる(4−ピリジン−2−イルフェニル)酢酸を4−メチル−2−(メチルアミノ)−1,3−チアゾール−5−スルホンアミド
次の式
- ステップC:
N−[5−(アミノスルホニル)−4−メチル−1,3−チアゾール−2−イル]−N−メチル−2−[4−(2−ピリジニル)フェニル]アセトアミドをメタンスルホン酸と共に、有機溶媒および水の混合物中で、次の式
をさらに含む、請求項1に記載の方法。 - R1およびR3は、互いに独立して、−F、−Cl、−Br、−I、−OMs、−OTf、および−OTsから選択される、請求項1に記載の方法。
- 前記ボロン酸誘導体試薬、ボロラン試薬、ボリナン試薬、またはジボロン酸試薬は、
式中、R’、R”、Ra、Rb、Rc、Rd、Re、およびRfは、互いに独立して置換もしくは未置換の1〜10個の炭素原子を有する直鎖アルキル基もしくは分岐アルキル基、または、置換もしくは未置換の3〜10個の炭素原子を有するシクロアルキル基を表す、請求項1に記載の方法。 - 前記中間体ボロン酸誘導体試薬またはボロラン試薬の調製のために、前記試薬酢酸パラジウム、トリエチルアミンおよびトリフェニルホスフィン、またはPdCl2(PPh3)2およびトリエチルアミンを使用する、請求項1に記載の方法。
- 有機溶媒および水中に前記N−[5−(アミノスルホニル)−4−メチル−1,3−チアゾール−2−イル]−N−メチル−2−[4−(2−ピリジニル)フェニル]アセトアミドを有する混合物は、昇温でメタンスルホン酸の付加で過飽和溶液を生じ、それから前記N−[5−(アミノスルホニル)−4−メチル−1,3−チアゾール−2−イル]−N−メチル−2−[4−(2−ピリジニル)フェニル]アセトアミドメタンスルホン酸一水和物は、延長された撹拌、混合、または冷却の後に結晶化する、請求項2に記載の方法。
- ステップD:
少なくとも一つの薬学的に許容できる担体、賦形剤、溶媒および/または希釈剤と共に、結晶性N−[5−(アミノスルホニル)−4−メチル−1,3−チアゾール−2−イル]−N−メチル−2−[4−(2−ピリジニル)フェニル]アセトアミドメタンスルホン酸一水和物の医薬組成物を調製すること、
をさらに含む、請求項1〜請求項6のいずれか一項に記載の方法。
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EP11007823A EP2573086A1 (en) | 2011-09-26 | 2011-09-26 | N-[5-(Aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide mesylate monohydrate |
EP11007823.5 | 2011-09-26 | ||
PCT/EP2012/068938 WO2013045479A1 (en) | 2011-09-26 | 2012-09-26 | N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-n-methyl-2-[4-(2-pyridinyl)phenyl]acetamide mesylate monohydrate |
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JP2016249351A Active JP6353022B2 (ja) | 2011-09-26 | 2016-12-22 | N−[5−(アミノスルホニル)−4−メチル−1,3−チアゾール−2−イル]−n−メチル−2−[4−(2−ピリジニル)フェニル]アセトアミドメシレート一水和物 |
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JP2017114859A (ja) * | 2011-09-26 | 2017-06-29 | アイクリス ゲーエムベーハー ウント コー.カーゲー | N−[5−(アミノスルホニル)−4−メチル−1,3−チアゾール−2−イル]−n−メチル−2−[4−(2−ピリジニル)フェニル]アセトアミドメシレート一水和物 |
Families Citing this family (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2573085A1 (en) * | 2011-09-26 | 2013-03-27 | AiCuris GmbH & Co. KG | N-[5-(aminosulfonyl)-4methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl] acetamide mesylate monohydrate having a specific particle size distribution range and a specific surface area range |
PE20181804A1 (es) * | 2016-04-06 | 2018-11-19 | Innovative Molecules Gmbh | Derivados de aminotiazol utiles como agentes antiviricos |
CN109996798B (zh) * | 2016-11-28 | 2023-05-05 | 艾库里斯有限及两合公司 | N-[5-(氨基磺酰基)-4-甲基-1,3-噻唑-2-基]-n-甲基-2-[4-(2-吡啶基)-苯基]-乙酰胺游离碱半水合物、其制造方法和用途 |
JP7316214B2 (ja) | 2016-11-28 | 2023-07-27 | アイクリス ゲゼルシャフト ミット ベシュレンクテル ハフツング ウント コンパニー コマンディトゲゼルシャフト | N-[5-(アミノスルホニル)-4-メチル-1,3-チアゾール-2-イル]-n-メチル-2-[4-(2-ピリジニル)-フェニル]-アセトアミドの遊離塩基形のマレイン酸塩、医薬製剤、製造方法およびヘルペスウイルスの処置のためのその使用 |
TW201825095A (zh) * | 2016-11-28 | 2018-07-16 | 德商艾庫里斯抗感染治療有限公司 | 包含n-[5-(胺基磺醯基)-4-甲基-1,3-噻唑-2-基]-n-甲基-2-[4-(2-吡啶基)-苯基]-乙醯胺之局部醫藥調配物 |
KR102335327B1 (ko) | 2017-04-28 | 2021-12-03 | 현대자동차 주식회사 | 수냉식 이지알 쿨러 |
US11213516B2 (en) * | 2017-06-28 | 2022-01-04 | Aicuris Gmbh & Co. Kg | Intravaginally applicable devices comprising antiviral compounds |
AR113344A1 (es) | 2017-10-05 | 2020-04-22 | Innovative Molecules Gmbh | Enantiómeros de una serie de compuestos antivirales |
JP7150368B2 (ja) * | 2018-07-06 | 2022-10-11 | フェーノ・セラピューティクス・カンパニー・リミテッド | チアゾール系化合物の結晶形およびその応用 |
CA3113353A1 (en) * | 2018-09-19 | 2020-03-26 | Modernatx, Inc. | High-purity peg lipids and uses thereof |
TW202038947A (zh) | 2018-11-28 | 2020-11-01 | 德商創新分子有限責任公司 | 在與溶瘤病毒之組合療法中治療癌症的解旋酶引子酶抑制劑 |
WO2024047508A1 (en) | 2022-08-29 | 2024-03-07 | Assembly Biosciences, Inc. | Pharmaceutical compositions for herpes virus |
WO2024047506A1 (en) | 2022-08-29 | 2024-03-07 | Assembly Biosciences, Inc. | A novel crystalline form of pritelivir |
WO2024047507A1 (en) | 2022-08-29 | 2024-03-07 | Assembly Biosciences, Inc. | A novel crystalline form of pritelivir |
Family Cites Families (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DOP2000000109A (es) | 1999-12-23 | 2002-08-30 | Gerald Kleymann | Derivados de tiazolilamida |
DE10129717A1 (de) * | 2001-06-22 | 2003-01-02 | Bayer Ag | Kombinationspräparate zur Herpes-Behandlung |
DE10129714A1 (de) * | 2001-06-22 | 2003-01-02 | Bayer Ag | Topische Anwendung von Thiazolylamiden |
DE10129716A1 (de) * | 2001-06-22 | 2003-01-02 | Bayer Ag | Kombinationspräparate zur Herpes-Behandlung |
DE10131128A1 (de) * | 2001-06-28 | 2003-01-16 | Bayer Ag | Sekundäre Sulfonamide |
GB0423653D0 (en) * | 2004-10-25 | 2004-11-24 | Piramed Ltd | Pharmaceutical compounds |
DE102005014248A1 (de) | 2005-03-30 | 2006-10-05 | Aicuris Gmbh & Co. Kg | Pharmazeutische Zubereitung von N-[5-(Aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamid |
JP2007314516A (ja) * | 2006-04-25 | 2007-12-06 | Daiichi Sankyo Co Ltd | 2以上の置換基を有するベンゼン化合物を含有する医薬 |
EA200802417A1 (ru) * | 2006-06-09 | 2009-06-30 | Икос Корпорейшн | Замещенные фенилуксусные кислоты как dp-2-антагонисты |
AR070127A1 (es) * | 2008-01-11 | 2010-03-17 | Novartis Ag | Pirrolo - pirimidinas y pirrolo -piridinas |
UA103918C2 (en) * | 2009-03-02 | 2013-12-10 | Айерем Элелси | N-(hetero)aryl, 2-(hetero)aryl-substituted acetamides for use as wnt signaling modulators |
EP2573086A1 (en) * | 2011-09-26 | 2013-03-27 | AiCuris GmbH & Co. KG | N-[5-(Aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide mesylate monohydrate |
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JP2017114859A (ja) * | 2011-09-26 | 2017-06-29 | アイクリス ゲーエムベーハー ウント コー.カーゲー | N−[5−(アミノスルホニル)−4−メチル−1,3−チアゾール−2−イル]−n−メチル−2−[4−(2−ピリジニル)フェニル]アセトアミドメシレート一水和物 |
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