JPWO2019224141A5 - - Google Patents
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- JPWO2019224141A5 JPWO2019224141A5 JP2020564718A JP2020564718A JPWO2019224141A5 JP WO2019224141 A5 JPWO2019224141 A5 JP WO2019224141A5 JP 2020564718 A JP2020564718 A JP 2020564718A JP 2020564718 A JP2020564718 A JP 2020564718A JP WO2019224141 A5 JPWO2019224141 A5 JP WO2019224141A5
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- Prior art keywords
- amino
- trimethylphenyl
- benzo
- methyl
- oxazole
- Prior art date
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- 150000003839 salts Chemical class 0.000 claims description 18
- 239000011780 sodium chloride Substances 0.000 claims description 18
- OQGHGKFTKWEBSK-UHFFFAOYSA-N 5-[[5-methyl-2-(3,4,5-trimethylanilino)pyrimidin-4-yl]amino]-3H-1,3-benzoxazol-2-one Chemical compound N1=C(NC=2C=C3NC(=O)OC3=CC=2)C(C)=CN=C1NC1=CC(C)=C(C)C(C)=C1 OQGHGKFTKWEBSK-UHFFFAOYSA-N 0.000 claims description 11
- -1 5-((5-Methyl-2-((3,4,5-trimethylphenyl) amino) pyrimidin-4-yl) amino) -benzo [d] oxazole Chemical compound 0.000 claims description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- 239000012458 free base Substances 0.000 claims description 8
- 208000006673 Asthma Diseases 0.000 claims description 5
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 5
- VZCYOOQTPOCHFL-OWOJBTEDSA-N (E)-but-2-enedioate;hydron Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N fumaric acid Chemical compound OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 239000000969 carrier Substances 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims description 2
- 238000000113 differential scanning calorimetry Methods 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 239000001530 fumaric acid Substances 0.000 claims description 2
- 238000002844 melting Methods 0.000 claims description 2
- 239000000546 pharmaceutic aid Substances 0.000 claims description 2
- 238000010828 elution Methods 0.000 description 7
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 210000004072 Lung Anatomy 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
Description
ヘミフマル酸塩の溶出プロファイルは、初期溶出速度並びにこの実験条件の間の測定された溶解度に関して、微粒子化された遊離塩基とは著しく異なる。ヘミフマル酸塩は、遊離塩基と比べて増大した溶出速度並びに増大した溶解度（例えば、５０分でおよそ６倍の増加）を示す。さらに、この増大は、実験全体の継続期間にわたって観測された。比較すると、ＨＢｒ塩は、１時間で微粒子化された遊離塩基と比べて溶解度の増加を全く示さない非常に異なる溶出プロファイルを示した。図３に描写される両方の塩は、遊離塩基と比べて変化した溶出プロファイルを示す。他の塩も試験したが、しかし、ヘミフマル酸塩のみが好適な溶出プロファイルを生み出した。このプロファイルは、良好な（増加した）溶解度と、遊離塩基と比べた塩溶出の適切な速度の間の適切なバランスを表す。したがって、物質は、肺内に好適な期間の間のみとどまり（安全性を支援する）、適切な濃度の活性遊離塩基物質を送達して、効能を支援する。
本発明には、次の態様が含まれる。
１． ５－（（５－メチル－２－（（３，４，５－トリメチルフェニル）アミノ）ピリミジン－４－イル）アミノ）－ベンゾ［ｄ］オキサゾール－２（３Ｈ）－オン（化合物（Ｉ））のフマル酸塩。
３． 結晶形である５－（（５－メチル－２－（（３，４，５－トリメチルフェニル）アミノ）ピリミジン－４－イル）アミノ）－ベンゾ［ｄ］オキサゾール－２（３Ｈ）－オンのヘミフマル酸塩である、項２に記載の塩。
４． １１．３、１６．９、及び２７．２°２θ（±０．１°）の特異的ピークを有するＸ線粉末回折パターンを特徴とする、項３に記載の塩。
５． 約１１．３、１４．５、１６．９、２２．６、及び２７．２°２θ（±０．１°）の特異的ピークを有するＸ線粉末回折パターンを特徴とする、項３又は４に記載の塩。
６． ３０７℃±０．５℃のオンセット温度を有する吸熱融解を有する示差走査熱量測定トレースを特徴とする、項３～５のいずれか一項に記載の塩。
７． 項２～６のいずれか一項に記載の５－（（５－メチル－２－（（３，４，５－トリメチルフェニル）アミノ）ピリミジン－４－イル）アミノ）－ベンゾ［ｄ］オキサゾール－２（３Ｈ）－オンのヘミフマル酸塩の調製の方法であって：
（ｉ）５－（（５－メチル－２－（（３，４，５－トリメチルフェニル）アミノ）ピリミジン－４－イル）アミノ）－ベンゾ［ｄ］オキサゾール－２（３Ｈ）－オン遊離塩基を、ＤＭＳＯなどの好適な溶媒に溶解させること；
（ｉｉ）フマル酸を、ＤＭＳＯなどの好適な溶媒に溶解させること；
（ｉｉｉ）前記２種の溶液を混合すること；
（ｉｖ）任意選択で、前記５－（（５－メチル－２－（（３，４，５－トリメチルフェニル）アミノ）ピリミジン－４－イル）アミノ）－ベンゾ［ｄ］オキサゾール－２（３Ｈ）－オンのヘミフマル酸塩の種結晶を加えること；
（ｖ）前記５－（（５－メチル－２－（（３，４，５－トリメチルフェニル）アミノ）ピリミジン－４－イル）アミノ）－ベンゾ［ｄ］オキサゾール－２（３Ｈ）－オンのヘミフマル酸塩を結晶化させること；及び
（ｖｉ）前記５－（（５－メチル－２－（（３，４，５－トリメチルフェニル）アミノ）ピリミジン－４－イル）アミノ）－ベンゾ［ｄ］オキサゾール－２（３Ｈ）－オンのヘミフマル酸塩を単離すること
を含む方法。
８． 項１～６のいずれか一項に記載の５－（（５－メチル－２－（（３，４，５－トリメチルフェニル）アミノ）ピリミジン－４－イル）アミノ）－ベンゾ［ｄ］オキサゾール－２（３Ｈ）－オンのフマル酸塩を、薬学的に許容できる賦形剤、希釈剤、又は担体と共に含む医薬組成物。
９． 医薬品として使用するための、項１～６のいずれか一項に記載の５－（（５－メチル－２－（（３，４，５－トリメチルフェニル）アミノ）ピリミジン－４－イル）アミノ）－ベンゾ［ｄ］オキサゾール－２（３Ｈ）－オンのフマル酸塩。
１０． 喘息又はＣＯＰＤの治療に使用するための医薬品の製造における、項１～６のいずれか一項に記載の５－（（５－メチル－２－（（３，４，５－トリメチルフェニル）アミノ）ピリミジン－４－イル）アミノ）－ベンゾ［ｄ］オキサゾール－２（３Ｈ）－オンのフマル酸塩の使用。
１１． 喘息又はＣＯＰＤの治療に使用するための、項１～６のいずれか一項に記載の５－（（５－メチル－２－（（３，４，５－トリメチルフェニル）アミノ）ピリミジン－４－イル）アミノ）－ベンゾ［ｄ］オキサゾール－２（３Ｈ）－オンのフマル酸塩。
１２． 喘息又はＣＯＰＤの治療を必要とするヒトなどの温血動物における喘息又はＣＯＰＤを治療する方法であって、前記動物に、項１～６のいずれか一項に記載の、有効量の５－（（５－メチル－２－（（３，４，５－トリメチルフェニル）アミノ）ピリミジン－４－イル）アミノ）－ベンゾ［ｄ］オキサゾール－２（３Ｈ）－オンのフマル酸塩を投与することを含む方法。
The elution profile of hemifmalate differs significantly from the micronized free base in terms of initial elution rate as well as measured solubility during this experimental condition. Hemifumalate exhibits an increased elution rate and increased solubility (eg, approximately 6-fold increase in 50 minutes) compared to the free base. Moreover, this increase was observed over the duration of the entire experiment. By comparison, the HBr salt showed a very different elution profile showing no increase in solubility compared to the free base micronized in 1 hour. Both salts depicted in FIG. 3 show an altered elution profile compared to the free base. Other salts were also tested, but only hemifmalate produced a suitable elution profile. This profile represents the proper balance between good (increased) solubility and the appropriate rate of salt elution compared to the free base. Therefore, the substance remains in the lungs for a suitable period of time (supporting safety) and delivers the appropriate concentration of active free base substance to support efficacy.
The present invention includes the following aspects.
1. 1. 5-((5-Methyl-2-((3,4,5-trimethylphenyl) amino) pyrimidine-4-yl) amino) -benzo [d] oxazole-2 (3H) -one (compound (I)) Fumarate.
3. 3. Hemifmal of 5-((5-methyl-2-((3,4,5-trimethylphenyl) amino) pyrimidin-4-yl) amino) -benzo [d] oxazole-2 (3H) -one in crystalline form Item 2. The salt according to Item 2, which is an acid salt.
4. Item 3. The salt according to Item 3, characterized by an X-ray powder diffraction pattern having specific peaks of 11.3, 16.9, and 27.2 ° 2θ (± 0.1 °).
5. Item 3 or 4 characterized by an X-ray powder diffraction pattern with specific peaks of about 11.3, 14.5, 16.9, 22.6, and 27.2 ° 2θ (± 0.1 °). The salt described in.
6. Item 6. The salt according to any one of Items 3 to 5, characterized by a differential scanning calorimetry trace having endothermic melting with an onset temperature of 307 ° C ± 0.5 ° C.
7. 5-((5-Methyl-2-((3,4,5-trimethylphenyl) amino) pyrimidin-4-yl) amino) -benzo [d] oxazole- according to any one of Items 2 to 6. A method for preparing 2 (3H) -one hemifmalate:
(I) 5-((5-Methyl-2-((3,4,5-trimethylphenyl) amino) pyrimidine-4-yl) amino) -benzo [d] oxazole-2 (3H) -on free base , Dissolve in a suitable solvent such as DMSO;
(Ii) Dissolving fumaric acid in a suitable solvent such as DMSO;
(Iii) Mixing the above two solutions;
(Iv) Optionally, the 5-((5-methyl-2-((3,4,5-trimethylphenyl) amino) pyrimidin-4-yl) amino) -benzo [d] oxazole-2 (3H) -Add seed crystals of on-hemifmalate;
(V) Hemifmal of the 5-((5-methyl-2-((3,4,5-trimethylphenyl) amino) pyrimidin-4-yl) amino) -benzo [d] oxazole-2 (3H) -one. Crystallizing the acid salt; and
(Vi) Hemifmal of the 5-((5-methyl-2-((3,4,5-trimethylphenyl) amino) pyrimidin-4-yl) amino) -benzo [d] oxazole-2 (3H) -one Isolating the acid salt
How to include.
8. 5-((5-Methyl-2-((3,4,5-trimethylphenyl) amino) pyrimidin-4-yl) amino) -benzo [d] oxazol- A pharmaceutical composition comprising 2 (3H) -one fumarate with a pharmaceutically acceptable excipient, diluent, or carrier.
9. 5. ((5-Methyl-2-((3,4,5-trimethylphenyl) amino) pyrimidin-4-yl) amino) according to any one of Items 1 to 6 for use as a pharmaceutical product. -Benzo [d] oxazole-2 (3H) -one fumarate.
10. 5. ((5-Methyl-2-((3,4,5-trimethylphenyl) amino) according to any one of Items 1 to 6 in the manufacture of a pharmaceutical product for use in the treatment of asthma or COPD. Use of pyrimidine-4-yl) amino) -benzo [d] oxazol-2 (3H) -one phenylate.
11. 5. ((5-Methyl-2-((3,4,5-trimethylphenyl) amino) pyrimidin-4-) according to any one of Items 1 to 6 for use in the treatment of asthma or COPD. Il) Amino) -benzo [d] oxazole-2 (3H) -one fumarate.
12. A method for treating asthma or COPD in a warm-blooded animal such as a human who requires treatment for asthma or COPD, wherein an effective amount of 5- (according to any one of Items 1 to 6) is given to the animal. Administration of (5-methyl-2-((3,4,5-trimethylphenyl) amino) pyrimidin-4-yl) amino) -benzo [d] oxazole-2 (3H) -one fumarate is recommended. How to include.
Claims (9)
（ｉ）５－（（５－メチル－２－（（３，４，５－トリメチルフェニル）アミノ）ピリミジン－４－イル）アミノ）－ベンゾ［ｄ］オキサゾール－２（３Ｈ）－オン遊離塩基を、ＤＭＳＯなどの好適な溶媒に溶解させること；
（ｉｉ）フマル酸を、ＤＭＳＯなどの好適な溶媒に溶解させること；
（ｉｉｉ）前記２種の溶液を混合すること；
（ｉｖ）任意選択で、前記５－（（５－メチル－２－（（３，４，５－トリメチルフェニル）アミノ）ピリミジン－４－イル）アミノ）－ベンゾ［ｄ］オキサゾール－２（３Ｈ）－オンのヘミフマル酸塩の種結晶を加えること；
（ｖ）前記５－（（５－メチル－２－（（３，４，５－トリメチルフェニル）アミノ）ピリミジン－４－イル）アミノ）－ベンゾ［ｄ］オキサゾール－２（３Ｈ）－オンのヘミフマル酸塩を結晶化させること；及び
（ｖｉ）前記５－（（５－メチル－２－（（３，４，５－トリメチルフェニル）アミノ）ピリミジン－４－イル）アミノ）－ベンゾ［ｄ］オキサゾール－２（３Ｈ）－オンのヘミフマル酸塩を単離すること
を含む方法。 5-((5-Methyl-2-((3,4,5-trimethylphenyl) amino) pyrimidin-4-yl) amino) -benzo [d] oxazole according to any one of claims 2 to 6. A method for preparing -2 (3H) -one hemifumarate:
(I) 5-((5-Methyl-2-((3,4,5-trimethylphenyl) amino) pyrimidine-4-yl) amino) -benzo [d] oxazole-2 (3H) -on free base , Dissolve in a suitable solvent such as DMSO;
(Ii) Dissolving fumaric acid in a suitable solvent such as DMSO;
(Iii) Mixing the above two solutions;
(Iv) Optionally, the 5-((5-methyl-2-((3,4,5-trimethylphenyl) amino) pyrimidin-4-yl) amino) -benzo [d] oxazole-2 (3H) -Add seed crystals of on-hemifmalate;
(V) Hemifmal of the 5-((5-methyl-2-((3,4,5-trimethylphenyl) amino) pyrimidin-4-yl) amino) -benzo [d] oxazol-2 (3H) -one. Crystallizing the acid salt; and (vi) the 5-((5-methyl-2-((3,4,5-trimethylphenyl) amino) pyrimidin-4-yl) amino) -benzo [d] oxazole. A method comprising isolating -2 (3H) -one hemifmalate.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201862675820P | 2018-05-24 | 2018-05-24 | |
| US62/675,820 | 2018-05-24 | ||
| PCT/EP2019/062935 WO2019224141A1 (en) | 2018-05-24 | 2019-05-20 | Fumarate salt of 5-((5-methyl-2-((3,4,5-trimethylphenyl)amino)pyrimidin-4-yl)amino)-benzo[d]oxazol-2(3h)-one |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2021524458A JP2021524458A (en) | 2021-09-13 |
| JPWO2019224141A5 true JPWO2019224141A5 (en) | 2022-05-26 |
Family
ID=66770420
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2020564718A Pending JP2021524458A (en) | 2018-05-24 | 2019-05-20 | 5-((5-Methyl-2-((3,4,5-trimethylphenyl) amino) pyrimidine-4-yl) amino) -benzo [d] oxazole-2 (3H) -one fumarate |
Country Status (17)
| Country | Link |
|---|---|
| US (1) | US20210198248A1 (en) |
| EP (1) | EP3802523A1 (en) |
| JP (1) | JP2021524458A (en) |
| KR (1) | KR20210012006A (en) |
| CN (1) | CN112154148A (en) |
| AR (1) | AR115426A1 (en) |
| AU (1) | AU2019272703B8 (en) |
| BR (1) | BR112020021620A2 (en) |
| CA (1) | CA3104745A1 (en) |
| EA (1) | EA202092759A1 (en) |
| IL (1) | IL278866A (en) |
| MA (1) | MA52743A (en) |
| MX (1) | MX2020011451A (en) |
| SG (1) | SG11202011396PA (en) |
| TW (1) | TW202016104A (en) |
| WO (1) | WO2019224141A1 (en) |
| ZA (1) | ZA202007930B (en) |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2565193B1 (en) * | 2009-01-23 | 2014-03-19 | Rigel Pharmaceuticals, Inc. | Compositions and methods for inhibition of the JAK pathway |
| US8343954B2 (en) | 2010-07-28 | 2013-01-01 | Rigel Pharmaceuticals, Inc. | Compositions and methods for inhibition of the JAK pathway |
| WO2013173506A2 (en) * | 2012-05-16 | 2013-11-21 | Rigel Pharmaceuticals, Inc. | Method of treating muscular degradation |
| EP2948150A1 (en) * | 2013-01-25 | 2015-12-02 | Rigel Pharmaceuticals, Inc. | Compounds and methods for treating inflammatory bowel diseases |
| WO2017007658A1 (en) * | 2015-07-07 | 2017-01-12 | Rigel Pharmaceuticals, Inc. | A combination for immune mediated cancer treatment |
-
2019
- 2019-05-20 US US17/057,983 patent/US20210198248A1/en not_active Abandoned
- 2019-05-20 MA MA052743A patent/MA52743A/en unknown
- 2019-05-20 MX MX2020011451A patent/MX2020011451A/en unknown
- 2019-05-20 EA EA202092759A patent/EA202092759A1/en unknown
- 2019-05-20 BR BR112020021620-8A patent/BR112020021620A2/en not_active Application Discontinuation
- 2019-05-20 CN CN201980034121.9A patent/CN112154148A/en active Pending
- 2019-05-20 SG SG11202011396PA patent/SG11202011396PA/en unknown
- 2019-05-20 WO PCT/EP2019/062935 patent/WO2019224141A1/en unknown
- 2019-05-20 CA CA3104745A patent/CA3104745A1/en active Pending
- 2019-05-20 EP EP19728582.8A patent/EP3802523A1/en not_active Withdrawn
- 2019-05-20 KR KR1020207036994A patent/KR20210012006A/en unknown
- 2019-05-20 AU AU2019272703A patent/AU2019272703B8/en not_active Ceased
- 2019-05-20 JP JP2020564718A patent/JP2021524458A/en active Pending
- 2019-05-22 TW TW108117593A patent/TW202016104A/en unknown
- 2019-05-24 AR ARP190101416A patent/AR115426A1/en unknown
-
2020
- 2020-11-19 IL IL278866A patent/IL278866A/en unknown
- 2020-12-18 ZA ZA2020/07930A patent/ZA202007930B/en unknown
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