JP2006516268A - ジペプチジルペプチダーゼ−iv阻害剤の燐酸塩 - Google Patents
ジペプチジルペプチダーゼ−iv阻害剤の燐酸塩 Download PDFInfo
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- JP2006516268A JP2006516268A JP2005518292A JP2005518292A JP2006516268A JP 2006516268 A JP2006516268 A JP 2006516268A JP 2005518292 A JP2005518292 A JP 2005518292A JP 2005518292 A JP2005518292 A JP 2005518292A JP 2006516268 A JP2006516268 A JP 2006516268A
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- Prior art keywords
- monohydrate
- salt
- crystalline
- dihydrogen phosphate
- weight
- Prior art date
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- 229910019142 PO4 Inorganic materials 0.000 title claims abstract description 4
- 239000010452 phosphate Substances 0.000 title claims abstract description 4
- 229940124213 Dipeptidyl peptidase 4 (DPP IV) inhibitor Drugs 0.000 title description 4
- 239000003603 dipeptidyl peptidase IV inhibitor Substances 0.000 title description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 title 1
- 150000004682 monohydrates Chemical class 0.000 claims abstract description 68
- 238000000034 method Methods 0.000 claims abstract description 21
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims abstract description 19
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 12
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 8
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- 239000007787 solid Substances 0.000 claims description 38
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- 239000000203 mixture Substances 0.000 claims description 36
- 150000003839 salts Chemical class 0.000 claims description 24
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 23
- 239000002904 solvent Substances 0.000 claims description 15
- 239000004480 active ingredient Substances 0.000 claims description 10
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- OKTJSMMVPCPJKN-OUBTZVSYSA-N Carbon-13 Chemical compound [13C] OKTJSMMVPCPJKN-OUBTZVSYSA-N 0.000 claims description 7
- -1 (2,4,5-trifluorophenyl) butan-2-amine cation Chemical class 0.000 claims description 5
- 238000005384 cross polarization magic-angle spinning Methods 0.000 claims description 5
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- 238000004519 manufacturing process Methods 0.000 claims description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 3
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
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- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 abstract description 22
- 101000930822 Giardia intestinalis Dipeptidyl-peptidase 4 Proteins 0.000 abstract description 15
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- AQCSCRYRCRORET-UHFFFAOYSA-N 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine;hydrochloride Chemical compound Cl.C1NCCN2C(C(F)(F)F)=NN=C21 AQCSCRYRCRORET-UHFFFAOYSA-N 0.000 description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
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- GCIJQCYVJVFFFS-UHFFFAOYSA-N 1-(2,4,5-trifluorophenyl)but-2-en-2-amine Chemical compound CC=C(N)CC1=C(F)C=C(F)C(F)=C1 GCIJQCYVJVFFFS-UHFFFAOYSA-N 0.000 description 5
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 5
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 5
- 239000001506 calcium phosphate Substances 0.000 description 5
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 5
- 229940038472 dicalcium phosphate Drugs 0.000 description 5
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- PAJKMFZVBIVFHI-UHFFFAOYSA-N 1-(2,4,5-trifluorophenyl)butan-2-one Chemical compound CCC(=O)CC1=CC(F)=C(F)C=C1F PAJKMFZVBIVFHI-UHFFFAOYSA-N 0.000 description 4
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Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Abstract
Description
本発明は、下記構造式I:
(a)25℃、エタノール/水系中:
(1)水分濃度が31重量%より高いようなエタノールおよび水における化合物Iの混合物から結晶化、
(2)得られた固相の回収、および
(3)そこからの溶媒の除去。
(1)水分濃度が2.9重量%より高いようなIAAおよび水における化合物Iの混合物からの結晶化、
(2)得られた固相の回収、および
(3)そこからの溶媒の除去。
(1)水分濃度が3.6重量%より高いようなIAAおよび水における化合物Iの混合物からの結晶化、
(2)得られた固相の回収、および
(3)そこからの溶媒の除去。
(1)水分濃度が4.5重量%より高いようなIAAおよび水における化合物Iの混合物からの結晶化、
(2)得られた固相の回収、および
(3)そこからの溶媒の除去。
(1)水分濃度が7.0重量%より高いようなIPAおよび水における化合物Iの混合物からの結晶化、
(2)得られた固相の回収、および
(3)そこからの溶媒の除去。
(1)水分濃度が8.1重量%より高いようなIPAおよび水における化合物Iの混合物からの結晶化、
(2)得られた固相の回収、および
(3)そこからの溶媒の除去。
(1)水分濃度が20重量%より高いようなIPAおよび水における化合物Iの混合物からの結晶化、
(2)得られた固相の回収、および
(3)そこからの溶媒の除去。
3−(トリフルオロメチル)−5,6,7,8−テトラヒドロ[1,2,4]トリアゾロ[4,3−a]ピラジン塩酸塩(1−4)の調製
ヒドラジン(20.1g、水中35重量%、0.22mol)を310mLのアセトニトリルと混合した。31.5gのトリフルオロ酢酸エチル(0.22mol)を60分かけて添加した。その内部温度を14℃から25℃に上昇させた。得られた溶液を22から25℃で60分間、時間を経過させた。その溶液を7℃に冷却した。16℃未満の温度で130分かけて17.9gの50重量%NaOH水溶液(0.22mol)および25.3gの塩化クロロアセチル(0.22mol)を同時に添加した。反応が完了したら、27から30℃、Hgで26〜27の真空下でその混合物を真空蒸留して、水およびエタノールを除去した。その蒸留中、720mLのアセトニトリルをゆっくりと添加して、一定量(約500mL)を維持した。そのスラリーを濾過して、塩化ナトリウムを除去した。そのケークを約100mLのアセトニトリルですすいだ。溶媒を除去することによって、ビス−ヒドラジド1−1(43.2g、収率96.5%、HPLCアッセイによる純度94.4面積%)を生じた。
ACN(82mL)中の段階Aからのビスヒドラジド1−1(43.2g、0.21mol)を5℃に冷却した。温度を10℃未満で維持しながらオキシ塩化燐(32.2g、0.21mol)を添加した。その混合物を80℃に加熱し、HPLCが2面積%未満の1−1を示すまで24時間この温度で時間を経過させた。別の容器で、260mLのIPAcおよび250mLの水を混合し、0℃に冷却した。内部温度を10℃未満に保ちながら、その反応スラリーを前記冷却物に添加した。添加後、その混合物を30分間、激しく攪拌し、その温度を室温まで上昇させて、水性層をカットした。その後、有機層を215mLの水、215mLの5重量%重炭酸ナトリウム水溶液、および最後に215mLの20重量%ブライン水溶液で洗浄した。処理後のHPLCアッセイ収率は、86から92%であった。75から80mmHg、55℃での蒸留によって揮発成分を除去して油を生じた。それは更なる精製をせずに段階Cで直接用いることができた。そうでなければ、その生成物を蒸留によって精製して、収率70から80%で1−2を生じることができる。
−20℃に冷却したメタノール(150mL)中のエチレンジアミン(33.1g、0.55mol)の溶液に、内部温度を−20℃に保ちながら、段階Bからの蒸留オキサジアゾール1−2(29.8g、0.16mol)を添加した。添加が完了した後、得られたスラリーを−20℃で1時間、時間を経過させた。その後、エタノール(225mL)を添加し、そのスラリーをゆっくり−5℃に温めた。−5℃で60分後、スラリーを濾過し、−5℃のエタノール(60mL)で洗浄した。アミジン1−3を白色の固体として収率72%で得た(24.4g、HPLCによる純度99.5面積重量%)。
110mLのメタノール中のアミジン1−3(27.3g、0.13mol)の懸濁液を55℃に温めた。37%塩酸(11.2mL、0.14mol)をこの温度で15分かけて添加した。その添加中、すべての固体が溶解し、結果的に透明な溶液を生じた。反応を30分間、時間を経過させた。その溶液を20℃に冷却し、結晶種層が形成されるまで(10分から1時間)この温度で時間を経過させた。300mLのMTBEを20℃で1時間かけて添加した。得られたスラリーを2℃に冷却し、30分間おいて、濾過した。固体を50mLのエタノール:MTBE(1:3)で洗浄し、真空下、45℃で乾燥させた。トリアゾール1−4の収量は、26.7g(HPLCによる純度99.5面積重量%)であった。
2,4,5−トリフルオロフェニル酢酸(2−1)(150g、0.789mol)、メルドラム酸(125g、0.868mol)、および4−(ジメチルアミノ)ピリジン(DMAP)(7.7g、0063mol)を5Lの3つ口フラスコに入れた。N,N−ジメチルアセトアミド(DMAc)(525mL)を室温で一度に添加して、固体を溶解した。温度を40℃未満で維持しながら、N,N−ジイソプロピルエチルアミン(282mL、1.62mol)を室温で一度に添加した。温度を0℃と5℃の間で維持しながら、塩化ピバロイル(107mL、0.868mol)を1から2時間かけて一滴ずつ添加した。その反応混合物を5℃で1時間おいた。塩酸トリアゾール1−4(180g、0.789mol)を40から50℃で一度に添加した。その反応溶液を70℃で数時間おいた。その後、5%炭酸水素ナトリウム水溶液(625mL)を20から45℃で一滴ずつ添加した。そのバッチに結晶種を入れ、20から30℃で1から2時間おいた。その後、追加の525mLの5%炭酸水素ナトリウム水溶液を2から3時間かけて一滴ずつ添加した。数時間、室温においた後、そのスラリーを0から5℃に冷却し、1時間おいた後、固体を濾過した。その湿潤ケークを、20%DMAc水溶液(300mL)、続いて追加の2バッチの20%DMAc水溶液(400mL)、および最後に水(400mL)で置換洗浄した。そのケークを室温で吸引乾燥させた。最終生成物2−3の単離された収率は、89%であった。
5L丸底フラスコにメタノール(100mL)、ケトアミド2−3(200g)および酢酸アンモニウム(110.4g)を入れた。その後、メタノール(180mL)および28%水酸化アンモニウム水溶液(58.6mL)を添加し、その添加中、温度は30℃未満に保った。追加のメタノール(100mL)をその反応混合物に添加した。その混合物を還流温度で加熱し、2時間おいた。反応を室温に冷却し、その後、氷浴で約5℃に冷却した。30分後、固体を濾過し、乾燥させて、2−4を固体として生じた(180g);融点271.2℃。
500mLフラスコに、窒素雰囲気下で、クロロ(1,5−シクロオクタジエン)ロジウム(I)ダイマー{[Rh(cod)Cl]2}(292mg、1.18mmol)および(R,S)t−ブチルJosiphos(708mg、1.3mmol)を入れた。その後、脱気MeOHを添加し(200mL)、その混合物を室温で1時間攪拌した。4L水素化装置に、エナミンアミド2−4(118g、0.29mol)をMeOH(1L)とともに入れた。そのスラリーを脱気した。その後、前記触媒溶液を窒素下でその水素化装置に移した。3回脱気した後、そのエナミンアミドを200psiの水素ガスのもと、50℃で13時間水素化した。HPLCにより、アッセイ収率は93%であり、光学純度は94%eeであると判定された。
(a)水素化段階が完了したら、その反応混合物に25重量%のエコソルブ(Ecosorb)C−941を添加する。その混合物を窒素下で1時間攪拌し、その後、濾過する。そのケークを2L/kgのメタノールで洗浄する。遊離塩基の回収は、約95%であり、光学純度は、約95%eeである。
溶離剤: 溶媒A: 0.1容量%HClO4/H2O
溶媒B: アセトニトリル
傾斜: 0分 75% A: 25% B
10分 25% A: 75% B
12.5分 25% A: 75% B
15分 75% A: 25% B
流量: 1mL/分
注入量: 10μL
UV検出: 210nm
カラム温度: 40℃
保持時間: 化合物2−4: 9.1分
化合物2−5: 5.4分
t−ブチルJosiphos: 8.7分
次の高速液体クロマトグラフィー(HPLC)条件を用いて、光学純度を決定した:
カラム: キラパック(Chirapak)、AD−H、250mm x 4.6mm
溶離剤: 溶媒A: ヘプタン中の0.2容量%ジエチルアミン
溶媒B: エタノール中の0.1容量%ジエチルアミン
イソクラティック(Isochratic)実行時間: 18分
流速: 0.7mL/分
注入量: 7μL
UV検出: 268nm
カラム温度: 35℃
保持時間: (R)−アミン2−5: 13.8分
(S)−アミン2−5: 11.2分
(2R)−4−オキソ−4−[3−(トリフルオロメチル)−5,6−ジヒドロ[1,2,4]トリアゾロ[4,3−a]ピラジン−7(8H)−イル]−1−(2,4,5−トリフルオロフェニル)ブタン−2−アミン燐酸二水素塩一水和物
オーバーヘッドスターラー、加熱マントルおよび熱電対を装備した250mL丸底フラスコに、31.5mLのイソプロパノール(IPA)、13.5mLの水、15.0g(36.9mmol)の(2R)−4−オキソ−4−[3−(トリフルオロメチル)−5,6−ジヒドロ[1,2,4]トリアゾロ[4,3−a]ピラジン−7(8H)−イル]−1−(2,4,5−トリフルオロフェニル)ブタン−2−アミン遊離塩基および4.25g(36.9mmol)の85%燐酸水溶液を入れた。その混合物を75℃に加熱した。濃厚な白色沈殿が低温で生成したが、75℃に達すると溶解した。その溶液を68℃に冷却し、その後、その温度で2時間保持した。この経過時間中に、固体のスラリー層が形成した[その溶液に、0.5から5重量%の小粒径(アルピーネミルド(alpine milled))一水和物の、結晶種を入れることができる]。その後、そのスラリーを4℃/時の速度で21℃に冷却して、一晩保持した。その後、105mLのIPAをそのスラリーに添加した。1時間後、スラリーを濾過し、45mLのIPAで洗浄した(固体を水/IPA溶液で洗浄して、他の結晶形への転換を回避することもできる)。固体を外気に触れさせながら、フリットで乾燥させた。18.6gの固体を回収した。それらの固体は、HPLC面積百分率(HPLC条件は、上で与えたものと同じであった)により純度99.8%以上であることが判明した。単離した固体の粒径分布分析は、平均PDSが80マイクロメートルであり、95%が180マイクロメートル未満であることを示した。それらの固体の結晶形は、X線粉末回折および熱重量分析により、一水和物であることが証明された。
1)直接圧縮法:
本燐酸二水素塩一水和物は、直接圧縮法によって錠剤に調合することができる。100mg力価の錠剤を、128.4mgの本活性成分、127.8mgの微結晶性セルロース、127.8mgのマンニトール(または127.8mgの燐酸二カルシウム)、8mgのクロスカルメロースナトリウム、8mgのステアリン酸マグネシウムおよび16mgのオパドライ・ホワイト(Opadry white:ペンシルバニア州ウエストポイントのカラーコン(Colorcon)製の有標コーチング材料)から構成した。本活性成分、微結晶性セルロース、マンニトール(または燐酸二カルシウム)およびクロスカルメロースを先ずブレンドし、次に、その混合物をステアリン酸マグネシウムで潤滑させて、錠剤にプレスした。その後、それらの錠剤をオパドライ・ホワイトでフィルムコーチングした。
本燐酸二水素塩一水和物は、ローラー圧縮法によって錠剤に調合することができる。100mg力価の錠剤を、128.4mgの本活性成分、45mgの微結晶性セルロース、111.6mgの燐酸二カルシウム、6mgのクロスカルメロースナトリウム、9mgのステアリン酸マグネシウムおよび12mgのオパドライ・ホワイト(ペンシルバニア州ウエストポイントのカラーコン製の有標コーチング材料)から構成した。本活性成分、微結晶性セルロース、燐酸二カルシウムおよびクロスカルメロースを先ずブレンドし、次に、その混合物を全体の3分の1の量のステアリン酸マグネシウムで潤滑させ、ローラー圧縮してリボンにした。その後、これらのリボンを粉砕し、その後、得られた顆粒をステアリン酸マグネシウムの残量で潤滑させて、錠剤にプレスした。その後、それらの錠剤をオパドライ・ホワイトでフィルムコーチングした。
Claims (35)
- 結晶質一水和物であることを特徴とする、請求項2に記載の塩。
- 7.42、5.48および3.96オングストロームのスペクトル格子面間隔のX線粉末回折パターンから得られた特性吸収バンドによって特徴づけられる、請求項4に記載の一水和物。
- 更に、6.30、4.75および4.48オングストロームのスペクトル格子面間隔のX線粉末回折パターンから得られた特性吸収バンドによって特徴づけられる、請求項5に記載の一水和物。
- 更に、5.85、5.21および3.52オングストロームのスペクトル格子面間隔のX線粉末回折パターンから得られた特性吸収バンドによって特徴づけられる、請求項6に記載の一水和物。
- 図1のX線粉末回折パターンによって更に特徴づけられる、請求項7に記載の一水和物。
- 169.1、120.8および46.5ppmでシグナルを示す固体炭素13CPMAS核磁気共鳴スペクトルによって特徴づけられる、請求項4に記載の一水和物。
- 更に、159.0、150.9および40.7ppmでシグナルを示す固体炭素13CPMAS核磁気共鳴スペクトルによって特徴づけられる、請求項9に記載の一水和物。
- 更に、図2の固体炭素13CPMAS核磁気共鳴スペクトルによって特徴づけられる、請求項10に記載の一水和物。
- −64.5、−114.7、−136.3および−146.2ppmでシグナルを示す固体フッ素19MAS核磁気共鳴スペクトルによって特徴づけられる、請求項4に記載の一水和物。
- 更に、−96.5、−104.4、−106.3および−154.5ppmでシグナルを示す固体フッ素19MAS核磁気共鳴スペクトルによって特徴づけられる、請求項12に記載の一水和物。
- 更に、図3の固体フッ素19MAS核磁気共鳴スペクトルによって特徴づけられる、請求項13に記載の一水和物。
- 図4の熱重量分析曲線によって特徴づけられる、請求項4に記載の一水和物。
- 図5の示差走査熱量測定曲線によって特徴づけられる、請求項4に記載の一水和物。
- 検出可能な量の前記結晶質一水和物を含む、請求項4に記載の塩。
- 約5重量%から約100重量%の前記結晶質一水和物を含む、請求項4に記載の塩。
- 約10重量%から約100重量%の前記結晶質一水和物を含む、請求項4に記載の塩。
- 約25重量%から約100重量%の前記結晶質一水和物を含む、請求項4に記載の塩。
- 約50重量%から約100重量%の前記結晶質一水和物を含む、請求項4に記載の塩。
- 約75重量%から約100重量%の前記結晶質一水和物を含む、請求項4に記載の塩。
- 前記結晶質一水和物を実質的に全重量含む、請求項4に記載の塩。
- モノプロトン化4−オキソ−4−[3−(トリフルオロメチル)−5,6−ジヒドロ[1,2,4]トリアゾロ[4,3−a]ピラジン−7(8H)−イル]−1−(2,4,5−トリフルオロフェニル)ブタン−2−アミンカチオンおよび燐酸二水素アニオンのイオンを含む塩。
- 予防または治療有効量の請求項1に記載の塩またはその医薬適合性の溶媒和物を1つ以上の医薬適合性の担体とともに含む医薬組成物。
- 予防または治療有効量の請求項4に記載の塩またはその医薬適合性の溶媒和物を1つ以上の医薬適合性の担体とともに含む医薬組成物。
- 2型糖尿病の治療方法であって、そうした治療が必要な患者に治療有効量の請求項1に記載の塩またはその医薬適合性の水和物を投与することを含む、2型糖尿病の治療方法。
- 2型糖尿病の治療方法であって、そうした治療が必要な患者に治療有効量の請求項4に記載の塩を投与することを含む、2型糖尿病の治療方法。
- 約25から100℃の範囲の温度で、有機溶媒または水性有機溶媒中の1当量の4−オキソ−4−[3−(トリフルオロメチル)−5,6−ジヒドロ[1,2,4]トリアゾロ[4,3−a]ピラジン−7(8H)−イル]−1−(2,4,5−トリフルオロフェニル)ブタン−2−アミンを約1当量の燐酸と接触させる段階を含む、請求項1に記載の塩の調製方法。
- 前記有機溶媒が、C1〜C5直鎖または分枝鎖アルカノールである、請求項29に記載の方法。
- 2型糖尿病の治療において使用するための薬物の製造における、活性成分としての、請求項1に記載の塩の使用。
- 2型糖尿病の治療において使用するための薬物の製造における、活性成分としての、請求項4に記載の塩の使用。
- 静脈内投与に適応するようにした、請求項25に記載の医薬組成物。
- 請求項29に記載の方法に従って調製された4−オキソ−4−[3−(トリフルオロメチル)−5,6−ジヒドロ[1,2,4]トリアゾロ[4,3−a]ピラジン−7(8H)−イル]−1−(2,4,5−トリフルオロフェニル)ブタン−2−アミンの燐酸塩。
- (a)水分濃度が6.8重量パーセントより高いようなイソプロパノールと水の混合物から、25℃で、請求項1に記載の前記燐酸二水素塩を結晶させる段階;
(b)得られた固相を回収する段階;および
(c)そこから溶媒を除去する段階
を含む、請求項4に記載の結晶質一水和物の調製方法。
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JP2011507890A (ja) * | 2007-12-20 | 2011-03-10 | ドクター・レディーズ・ラボラトリーズ・リミテッド | シタグリプチンおよびその薬学的に許容可能な塩の調製のためのプロセス |
JP2012528082A (ja) * | 2009-05-27 | 2012-11-12 | ジエンス ヘンルイ メデイシンカンパニー リミテッド | メチル(R)−7−[3−アミノ−4−(2,4,5−トリフルオロフェニル)−ブチリル]−3−トリフルオロメチル−5,6,7,8−テトラヒドロ−イミダゾ[1,5−α]ピラジン−1−カルボン酸塩 |
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JP2011507890A (ja) * | 2007-12-20 | 2011-03-10 | ドクター・レディーズ・ラボラトリーズ・リミテッド | シタグリプチンおよびその薬学的に許容可能な塩の調製のためのプロセス |
JP2012528082A (ja) * | 2009-05-27 | 2012-11-12 | ジエンス ヘンルイ メデイシンカンパニー リミテッド | メチル(R)−7−[3−アミノ−4−(2,4,5−トリフルオロフェニル)−ブチリル]−3−トリフルオロメチル−5,6,7,8−テトラヒドロ−イミダゾ[1,5−α]ピラジン−1−カルボン酸塩 |
JP2013542245A (ja) * | 2010-11-11 | 2013-11-21 | レッドエックス ファーマ リミテッド | 薬物誘導体 |
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