JPWO2019220390A5 - - Google Patents
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- JPWO2019220390A5 JPWO2019220390A5 JP2020564243A JP2020564243A JPWO2019220390A5 JP WO2019220390 A5 JPWO2019220390 A5 JP WO2019220390A5 JP 2020564243 A JP2020564243 A JP 2020564243A JP 2020564243 A JP2020564243 A JP 2020564243A JP WO2019220390 A5 JPWO2019220390 A5 JP WO2019220390A5
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- pharmaceutical composition
- crystal form
- pyrazolo
- methyl
- pyridin
- Prior art date
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- 239000013078 crystal Substances 0.000 claims description 37
- -1 1,6-dimethyl-1H-pyrazolo [3,4-b] pyridin-4-yl Chemical group 0.000 claims description 24
- 239000008194 pharmaceutical composition Substances 0.000 claims description 19
- 238000000034 method Methods 0.000 claims description 15
- 239000000203 mixture Substances 0.000 claims description 11
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 11
- 239000000725 suspension Substances 0.000 claims description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- YPSPPJRTCRMQGD-UHFFFAOYSA-N morpholine-3-carboxamide Chemical compound NC(=O)C1COCCN1 YPSPPJRTCRMQGD-UHFFFAOYSA-N 0.000 claims description 7
- 238000002411 thermogravimetry Methods 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- 239000011877 solvent mixture Substances 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 5
- 208000023275 Autoimmune disease Diseases 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 210000003719 b-lymphocyte Anatomy 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- 239000003112 inhibitor Substances 0.000 claims description 4
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 claims description 4
- 229940124597 therapeutic agent Drugs 0.000 claims description 4
- 238000010586 diagram Methods 0.000 claims description 3
- 238000000113 differential scanning calorimetry Methods 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 238000001757 thermogravimetry curve Methods 0.000 claims description 3
- 102000004127 Cytokines Human genes 0.000 claims description 2
- 108090000695 Cytokines Proteins 0.000 claims description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 2
- 241000124008 Mammalia Species 0.000 claims description 2
- 239000012190 activator Substances 0.000 claims description 2
- 239000002260 anti-inflammatory agent Substances 0.000 claims description 2
- 229940121363 anti-inflammatory agent Drugs 0.000 claims description 2
- 230000000078 anti-malarial effect Effects 0.000 claims description 2
- 230000003356 anti-rheumatic effect Effects 0.000 claims description 2
- 239000003435 antirheumatic agent Chemical class 0.000 claims description 2
- 239000003018 immunosuppressive agent Substances 0.000 claims description 2
- 229940125721 immunosuppressive agent Drugs 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 239000003270 steroid hormone Substances 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 150000003857 carboxamides Chemical class 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 230000002519 immonomodulatory effect Effects 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 238000002844 melting Methods 0.000 claims 1
- 230000008018 melting Effects 0.000 claims 1
- 230000004580 weight loss Effects 0.000 claims 1
- 238000001228 spectrum Methods 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- 238000002441 X-ray diffraction Methods 0.000 description 2
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 230000002584 immunomodulator Effects 0.000 description 1
- 229940121354 immunomodulator Drugs 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
Description
結晶形態Ａ及びＨＡを使用して生成された実例的なＴＧＡトレースを、それぞれ図３及び６に示す。
以下の態様を包含し得る。
［１］ 遊離形態である化合物（Ｓ）－Ｎ－（４－（（５－（１，６－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－４－イル）－３－メチル－４，５，６，７－テトラヒドロ－１Ｈ－ピラゾロ［４，３－ｃ］ピリジン－１－イル）メチル）ビシクロ［２．２．２］オクタン－１－イル）モルホリン－３－カルボキサミドの結晶形態。
［２］ 形態Ａを含む、上記［１］に記載の結晶形態。
［３］ 以下の特性：
（ｉ）約２５℃の温度及び１．５４１８ÅのＸ線波長、λで測定された、２θを単位とする１８．６±０．２°２θ、４．１±０．２°２θ、及び１６．３±０．２°２θの代表的なピークを含むＸ線粉末回折パターン；
（ｉｉ）約２５℃の温度及び１．５４１８ÅのＸ線波長、λで測定された、４．１±０．２°、８．２±０．２°、１５．２±０．２°、１６．３±０．２°、１６．９±０．２°、１８．２±０．２°、１８．６±０．２°、１９．８±０．２°、及び２０．４±０．２からなる群から選択される４つ以上の２θ値を含むＸ線粉末回折パターン；並びに
（ｉｉｉ）約２５℃の温度及び１．５４１８ÅのＸ線波長、λで測定された、４．１±０．２°、８．２±０．２°、１５．２±０．２°、１６．３±０．２°、１６．９±０．２°、１８．２±０．２°、１８．６±０．２°、１９．８±０．２°、及び２０．４±０．２からなる群から選択される５つ以上の２θ値を含むＸ線粉末回折パターン
の１つを特徴とする、上記［１］又は［２］に記載の結晶形態。
［４］ 図１に示されるＸ線粉末回折スペクトルと実質的に同じＸ線回折スペクトルを有する、上記［１］、［２］、及び［３］のいずれか一項に記載の結晶形態。
［５］ 図２に示されるものと実質的に同じ示差走査熱量測定（ＤＳＣ）サーモグラムを有する、上記［１］又は［２］に記載の結晶形態。
［６］ 図３に示されるものと実質的に同じ熱重量分析（ＴＧＡ）ダイアグラムを有する、上記［１］又は［２］に記載の結晶形態。
［７］ 基本的に形態Ａからなる、上記［１］～［６］のいずれか一項に記載の結晶形態。
［８］ 前記形態が実質的に純粋な相形態の形態Ａである、上記［１］～［６］のいずれか一項に記載の結晶形態。
［９］ 前記化合物が水和物である、上記［１］に記載の結晶形態。
［１０］ 形態Ｈ
Ａ
を含む、上記［９］に記載の結晶形態。
［１１］ 以下の特性の１つを特徴とする、上記［９］又は［１０］に記載の結晶形態：
（ｉ）約２５℃の温度及び１．５４１８ÅのＸ線波長、λで測定された、２θを単位とする６．６±０．２°２θ、１６．０±０．２°２θ、及び１７．３±０．２°２θの代表的なピークを含むＸ線粉末回折パターン；
（ｉｉ）約２５℃の温度及び１．５４１８ÅのＸ線波長、λで測定された、６．６±０．２°、７．１±０．２°、１０．６±０．２°、１３．２±０．２°、１４．３±０．２°、１６．０±０．２°、１７．３±０．２°、２３．５±０．２°、２６．５±０．２、及び２７．３±０．２°２θからなる群から選択される４つ以上の２θ値を含むＸ線粉末回折パターン；並びに
（ｉｉｉ）約２５℃の温度及び１．５４１８ÅのＸ線波長、λで測定された、６．６±０．２°、７．１±０．２°、１０．６±０．２°、１３．２±０．２°、１４．３±０．２°、１６．０±０．２°、１７．３±０．２°、２３．５±０．２°、２６．５±０．２、及び２７．３±０．２°２θからなる群から選択される５つ以上の２θ値を含むＸ線粉末回折パターン。
［１２］ 図４に示されるＸ線粉末回折スペクトルと実質的に同じＸ線回折スペクトルを有する、上記［９］、［１０］、及び［１１］のいずれか一項に記載の結晶形態。
［１３］ 図５に示されるものと実質的に同じ示差走査熱量測定（ＤＳＣ）サーモグラムを有する、上記［９］又は［１０］に記載の結晶形態。
［１４］ 図６に示されるものと実質的に同じ熱重量分析（ＴＧＡ）ダイアグラムを有する、上記［９］又は［１０］に記載の結晶形態。
［１５］ 前記水和物が３．５水和物である、上記［１］、及び［９］～［１４］のいずれか一項に記載の結晶形態。
［１６］ 基本的に形態Ｈ
Ａ
からなる、上記［９］～［１５］のいずれか一項に記載の結晶形態。
［１７］ 前記形態が実質的に純粋な相形態の形態Ｈ
Ａ
である、上記［９］～［１５］のいずれか一項に記載の結晶形態。
［１８］ 上記［１］～［１７］のいずれか一項に記載の形態Ａ、Ｈ
Ａ
；及びそれらの組合せからなる群から選択される結晶形態、並びに１種以上の薬学的に許容される賦形剤を含む医薬組成物。
［１９］ 前記結晶形態が形態Ａである、上記［１８］に記載の医薬組成物。
［２０］ 前記形態Ａが実質的に純粋な相形態である、上記［１９］に記載の医薬組成物。
［２１］ 前記結晶形態が形態Ｈ
Ａ
である、上記［１８］に記載の医薬組成物。
［２２］ 前記形態Ｈ
Ａ
が実質的に純粋な相形態である、上記［２１］に記載の医薬組成物。
［２３］ 上記［１］～［１７］のいずれか一項に記載の形態Ａ、Ｈ
Ａ
；及びそれらの組合せからなる群から選択される結晶形態を、１種以上の治療剤と組み合わせて含む医薬組成物であって、前記治療剤が、抗炎症剤、免疫調節剤、免疫抑制剤、サイトカイン、非ステロイド性抗炎症薬（ＮＳＡＩＤｓ）、抗マラリア化合物、抗リウマチ化合物、Ｂ細胞活性化因子（ＢＡＦＦ）の阻害剤、Ｂリンパ球刺激因子（ＢＬｙＳ）の阻害剤、及びステロイドホルモンからなる群から独立に選択される医薬組成物。
［２４］ 前記結晶形態が形態Ａである、上記［２３］に記載の医薬組成物。
［２５］ 前記形態Ａが実質的に純粋な相形態である、上記［２４］に記載の医薬組成物。
［２６］ 前記結晶形態が形態Ｈ
Ａ
である、上記［２３］に記載の医薬組成物。
［２７］ 前記形態Ｈ
Ａ
が実質的に純粋な相形態である、上記［２６］に記載の医薬組成物。
［２８］ 自己免疫疾患の治療を必要とする対象の自己免疫疾患を治療する方法であって、前記哺乳動物に、治療上有効な量の上記［１］～［１７］のいずれか一項に記載の形態Ａ、Ｈ
Ａ
；及びそれらの組合せからなる群から選択される結晶形態を投与することを含む方法。
［２９］ 前記結晶形態が形態Ａである、上記［２８］に記載の方法。
［３０］ 前記形態Ａが実質的に純粋な相形態である、上記［２９］に記載の方法。
［３１］ 前記結晶形態が形態Ｈ
Ａ
である、上記［２８］に記載の方法。
［３２］ 前記形態Ｈ
Ａ
が実質的に純粋な相形態である、上記［３１］に記載の方法。
［３３］ 前記対象がヒトである、上記［２８］～［３２］のいずれか一項に記載の方法。
［３４］ 化合物（Ｓ）－Ｎ－（４－（（５－（１，６－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－４－イル）－３－メチル－４，５，６，７－テトラヒドロ－１Ｈ－ピラゾロ［４，３－ｃ］ピリジン－１－イル）メチル）ビシクロ［２．２．２］オクタン－１－イル）モルホリン－３－カルボキサミドの結晶形態Ｈ
Ａ
を製造する方法であって、
ｅ）非晶質の遊離形態の（Ｓ）－Ｎ－（４－（（５－（１，６－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－４－イル）－３－メチル－４，５，６，７－テトラヒドロ－１Ｈ－ピラゾロ［４，３－ｃ］ピリジン－１－イル）メチル）ビシクロ［２．２．２］オクタン－１－イル）モルホリン－３－カルボキサミドを、少なくとも約２重量％の水を含む溶媒混合物に懸濁させて、懸濁混合物を形成する工程、
ｆ）前記懸濁混合物を温度に溶解まで加熱して、溶液を形成する工程、
ｇ）前記溶液を約－１０℃に冷却して、懸濁液を形成する工程、
ｈ）前記懸濁液を濾過して、前記結晶形態Ｈ
Ａ
を回収する工程
を含む方法。
［３５］ 工程ａ）における前記溶媒混合物が、アセトン、アルコール、テトラヒドロフラン、又はアセトニトリルを含む、上記［３４］に記載の方法。
［３６］ 工程ａ）における前記溶媒混合物が、アセトン／水９８：２（重量比）及びイソプロパノール／水９５：５（重量比）から選択される、上記［３４］又は［３５］に記載の方法。
［３７］ 化合物（Ｓ）－Ｎ－（４－（（５－（１，６－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－４－イル）－３－メチル－４，５，６，７－テトラヒドロ－１Ｈ－ピラゾロ［４，３－ｃ］ピリジン－１－イル）メチル）ビシクロ［２．２．２］オクタン－１－イル）モルホリン－３－カルボキサミドの結晶形態Ａを製造する方法であって、
ｊ）非晶質の遊離形態の（Ｓ）－Ｎ－（４－（（５－（１，６－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－４－イル）－３－メチル－４，５，６，７－テトラヒドロ－１Ｈ－ピラゾロ［４，３－ｃ］ピリジン－１－イル）メチル）ビシクロ［２．２．２］オクタン－１－イル）モルホリン－３－カルボキサミドを、アセトン又はイソプロパノールに懸濁させて、懸濁混合物を形成する工程、
ｋ）前記懸濁混合物を約５０℃の温度に溶解まで加熱して、溶液を形成する工程、
ｌ）前記溶液を約４時間かけて約１５℃に冷却して、懸濁混合物を形成する工程、
ｍ）任意選択で、前記工程ｂ）及びｃ）を１回又は２回繰り返す工程、
ｎ）前記懸濁混合物を約５０℃に加熱し、ヘプタンを滴加する工程、
ｏ）前記混合物を５０℃で約１時間撹拌する工程、
ｐ）前記溶液を約４時間かけて約１５℃に冷却して、懸濁混合物を形成する工程、
ｑ）前記懸濁混合物を１５℃で１時間撹拌する工程、及び
ｒ）前記懸濁液を濾過して、前記結晶形態Ａを回収する工程
を含む方法。
Illustrative TGA traces generated using crystal forms A and HA are shown in FIGS. 3 and 6, respectively.
The following aspects may be included.
[1] Compound (S) -N- (4-((5- (1,6-dimethyl-1H-pyrazolo [3,4-b] pyridin-4-yl) -3-methyl-4) in free form , 5,6,7-Tetrahydro-1H-pyrazolo [4,3-c] Pyridine-1-yl) Methyl) Bicyclo [2.2.2] Octane-1-yl) Morpholine-3-Carboxamide crystal form.
[2] The crystal form according to the above [1], which includes the form A.
[3] The following characteristics:
(I) 18.6 ± 0.2 ° 2θ in units of 2θ measured at a temperature of about 25 ° C. and an X-ray wavelength of 1.5418 Å, λ, 4.1 ± 0.2 ° 2θ, and 16. .X-ray powder diffraction pattern containing a typical peak of 3 ± 0.2 ° 2θ;
(Ii) 4.1 ± 0.2 °, 8.2 ± 0.2 °, 15.2 ± 0.2 °, measured at a temperature of about 25 ° C. and an X-ray wavelength of 1.5418 Å, λ, 16.3 ± 0.2 °, 16.9 ± 0.2 °, 18.2 ± 0.2 °, 18.6 ± 0.2 °, 19.8 ± 0.2 °, and 20.4 ± X-ray powder diffraction pattern containing 4 or more 2θ values selected from the group consisting of 0.2;
(Iii) 4.1 ± 0.2 °, 8.2 ± 0.2 °, 15.2 ± 0.2 °, measured at a temperature of about 25 ° C. and an X-ray wavelength of 1.5418 Å, λ, 16.3 ± 0.2 °, 16.9 ± 0.2 °, 18.2 ± 0.2 °, 18.6 ± 0.2 °, 19.8 ± 0.2 °, and 20.4 ± X-ray powder diffraction pattern containing 5 or more 2θ values selected from the group consisting of 0.2
The crystal form according to the above [1] or [2], which is characterized by one of the above.
[4] The crystal form according to any one of the above [1], [2], and [3], which has substantially the same X-ray diffraction spectrum as the X-ray powder diffraction spectrum shown in FIG. 1.
[5] The crystal form according to [1] or [2] above, which has substantially the same differential scanning calorimetry (DSC) thermogram as that shown in FIG.
[6] The crystal form according to [1] or [2] above, which has substantially the same thermogravimetric analysis (TGA) diagram as that shown in FIG.
[7] The crystal form according to any one of the above [1] to [6], which basically comprises form A.
[8] The crystal form according to any one of the above [1] to [6], wherein the form is a substantially pure phase form A.
[9] The crystal form according to the above [1], wherein the compound is a hydrate.
[10] The crystal form according to the above [9], which comprises the form HA .
[11] The crystal morphology according to the above [9] or [10], which is characterized by one of the following characteristics:
(I) 6.6 ± 0.2 ° 2θ, 16.0 ± 0.2 ° 2θ, and 17 in units of 2θ measured at a temperature of about 25 ° C. and an X-ray wavelength of 1.5418 Å, λ. .X-ray powder diffraction pattern containing a typical peak of 3 ± 0.2 ° 2θ;
(Ii) 6.6 ± 0.2 °, 7.1 ± 0.2 °, 10.6 ± 0.2 °, measured at a temperature of about 25 ° C. and an X-ray wavelength of 1.5418 Å, λ, 13.2 ± 0.2 °, 14.3 ± 0.2 °, 16.0 ± 0.2 °, 17.3 ± 0.2 °, 23.5 ± 0.2 °, 26.5 ± 0 An X-ray powder diffraction pattern containing four or more 2θ values selected from the group consisting of .2 and 27.3 ± 0.2 ° 2θ; and
(Iii) 6.6 ± 0.2 °, 7.1 ± 0.2 °, 10.6 ± 0.2 °, measured at a temperature of about 25 ° C. and an X-ray wavelength of 1.5418 Å, λ, 13.2 ± 0.2 °, 14.3 ± 0.2 °, 16.0 ± 0.2 °, 17.3 ± 0.2 °, 23.5 ± 0.2 °, 26.5 ± 0 An X-ray powder diffraction pattern containing 5 or more 2θ values selected from the group consisting of .2 and 27.3 ± 0.2 ° 2θ.
[12] The crystal form according to any one of the above [9], [10], and [11], which has substantially the same X-ray diffraction spectrum as the X-ray powder diffraction spectrum shown in FIG.
[13] The crystal form according to [9] or [10] above, which has substantially the same differential scanning calorimetry (DSC) thermogram as that shown in FIG.
[14] The crystal form according to [9] or [10] above, which has substantially the same thermogravimetric analysis (TGA) diagram as that shown in FIG.
[15] The crystal form according to any one of the above [1] and [9] to [14], wherein the hydrate is 3.5 hydrate.
[16] The crystal form according to any one of the above [9] to [15], which is basically composed of the form HA .
[17] The crystal form according to any one of [9] to [15] above, wherein the form is a substantially pure phase form HA .
[18] A crystal form selected from the group consisting of the forms A, HA; and combinations thereof according to any one of the above [1] to [17], and one or more pharmaceutically acceptable forms . A pharmaceutical composition comprising an excipient.
[19] The pharmaceutical composition according to the above [18], wherein the crystal form is the form A.
[20] The pharmaceutical composition according to the above [19], wherein the form A is a substantially pure phase form.
[21] The pharmaceutical composition according to the above [18], wherein the crystal form is Form HA .
[22] The pharmaceutical composition according to the above [21], wherein the form HA is a substantially pure phase form.
[23] A crystal form selected from the group consisting of the forms A, HA; and combinations thereof according to any one of the above [1] to [17] is included in combination with one or more therapeutic agents . The therapeutic agent is a pharmaceutical composition, wherein the therapeutic agent is an anti-inflammatory agent, an immunomodulator, an immunosuppressive agent, a cytokine, a non-steroidal anti-inflammatory agent (NSAIDs), an anti-malaria compound, an anti-rheumatic compound, a B cell activator ( A pharmaceutical composition independently selected from the group consisting of an inhibitor of BAFF), an inhibitor of B lymphocyte stimulating factor (BLyS), and a steroid hormone.
[24] The pharmaceutical composition according to the above [23], wherein the crystal form is the form A.
[25] The pharmaceutical composition according to the above [24], wherein the form A is a substantially pure phase form.
[26] The pharmaceutical composition according to the above [23], wherein the crystal form is Form HA .
[27] The pharmaceutical composition according to [26] above, wherein the form HA is a substantially pure phase form.
[28] A method for treating an autoimmune disease of a subject requiring treatment of the autoimmune disease, wherein the amount is therapeutically effective for the mammal according to any one of the above [1] to [17]. A method comprising administering a crystalline form selected from the group consisting of the described forms A, HA ; and combinations thereof.
[29] The method according to [28] above, wherein the crystal form is form A.
[30] The method according to [29] above, wherein the form A is a substantially pure phase form.
[31] The method according to [28] above, wherein the crystal morphology is morphology HA .
[32] The method according to [31] above, wherein the form HA is a substantially pure phase form.
[33] The method according to any one of the above [28] to [32], wherein the subject is a human.
[34] Compound (S) -N- (4-((5- (1,6-dimethyl-1H-pyrazolo [3,4-b] pyridin-4-yl) -3-methyl-4,5,6) , 7-Tetrahydro-1H-Pyrazolo [4,3-c] Pyridine-1-yl) Methyl) Bicyclo [2.2.2] Octane-1-yl) Morpholine-3-Carboxamide Crystal Form HA is produced. It ’s a method,
e) Amorphous free form of (S) -N- (4-((5- (1,6-dimethyl-1H-pyrazolo [3,4-b] pyridin-4-yl) -3-methyl-) 4,5,6,7-tetrahydro-1H-pyrazolo [4,3-c] pyridin-1-yl) methyl) bicyclo [2.2.2] octane-1-yl) morpholin-3-carboxamide, at least The step of forming a suspended mixture by suspending it in a solvent mixture containing about 2% by weight of water.
f) The step of heating the suspension mixture to a temperature until it dissolves to form a solution.
g) A step of cooling the solution to about −10 ° C. to form a suspension,
h) A step of filtering the suspension to recover the crystalline form HA.
How to include.
[35] The method according to [34] above, wherein the solvent mixture in step a) contains acetone, alcohol, tetrahydrofuran, or acetonitrile.
[36] The method according to [34] or [35] above, wherein the solvent mixture in step a) is selected from acetone / water 98: 2 (weight ratio) and isopropanol / water 95: 5 (weight ratio). ..
[37] Compound (S) -N- (4-((5- (1,6-dimethyl-1H-pyrazolo [3,4-b] pyridin-4-yl) -3-methyl-4,5,6) , 7-Tetrahydro-1H-Pyrazolo [4,3-c] Pyridine-1-yl) Methyl) Bicyclo [2.2.2] Octane-1-yl) Morpholine-3-Carboxamide Crystal Form A And
j) Amorphous free form of (S) -N- (4-((5- (1,6-dimethyl-1H-pyrazolo [3,4-b] pyridin-4-yl) -3-methyl-) 4,5,6,7-Tetrahydro-1H-pyrazolo [4,3-c] pyridin-1-yl) methyl) bicyclo [2.2.2] octane-1-yl) morpholin-3-carboxamide, acetone. Or the step of suspending in isopropanol to form a suspended mixture,
k) A step of heating the suspension mixture to a temperature of about 50 ° C. until dissolution to form a solution.
l) A step of cooling the solution to about 15 ° C. over about 4 hours to form a suspension mixture.
m) A step of repeating the steps b) and c) once or twice, optionally.
n) A step of heating the suspension mixture to about 50 ° C. and adding heptane droplets.
o) A step of stirring the mixture at 50 ° C. for about 1 hour.
p) A step of cooling the solution to about 15 ° C. over about 4 hours to form a suspension mixture.
q) The step of stirring the suspended mixture at 15 ° C. for 1 hour, and
r) Step of filtering the suspension to recover the crystal form A
How to include.
Claims (14)
前記結晶形態が、以下の特性の１つを特徴とする、結晶形態：
（ｉ）約２５℃の温度及び１．５４１８ÅのＸ線波長、λで測定された、２θを単位とする６．６±０．２°２θ、１６．０±０．２°２θ、及び１７．３±０．２°２θの代表的なピークを含むＸ線粉末回折パターン；
（ｉｉ）約２５℃の温度及び１．５４１８ÅのＸ線波長、λで測定された、６．６±０．２°、７．１±０．２°、１０．６±０．２°、１３．２±０．２°、１４．３±０．２°、１６．０±０．２°、１７．３±０．２°、２３．５±０．２°、２６．５±０．２、及び２７．３±０．２°２θからなる群から選択される４つ以上の２θ値を含むＸ線粉末回折パターン；並びに
（ｉｉｉ）約２５℃の温度及び１．５４１８ÅのＸ線波長、λで測定された、６．６±０．２°、７．１±０．２°、１０．６±０．２°、１３．２±０．２°、１４．３±０．２°、１６．０±０．２°、１７．３±０．２°、２３．５±０．２°、２６．５±０．２、及び２７．３±０．２°２θからなる群から選択される５つ以上の２θ値を含むＸ線粉末回折パターン。 Compound (S) -N- (4-((5- (1,6-dimethyl-1H-pyrazolo [3,4-b] pyridin-4-yl) -3-methyl-4,5) in free form 6,7-Tetrahydro-1H-pyrazolo [4,3-c] pyridin-1-yl) methyl) bicyclo [2.2.2] octane-1-yl) morpholine-3-carboxamide in crystalline form .
The crystal morphology is characterized by one of the following characteristics:
(I) 6.6 ± 0.2 ° 2θ, 16.0 ± 0.2 ° 2θ, and 17 in units of 2θ measured at a temperature of about 25 ° C. and an X-ray wavelength of 1.5418 Å, λ. .X-ray powder diffraction pattern containing a typical peak of 3 ± 0.2 ° 2θ;
(Ii) 6.6 ± 0.2 °, 7.1 ± 0.2 °, 10.6 ± 0.2 °, measured at a temperature of about 25 ° C. and an X-ray wavelength of 1.5418 Å, λ, 13.2 ± 0.2 °, 14.3 ± 0.2 °, 16.0 ± 0.2 °, 17.3 ± 0.2 °, 23.5 ± 0.2 °, 26.5 ± 0 An X-ray powder diffraction pattern containing four or more 2θ values selected from the group consisting of .2 and 27.3 ± 0.2 ° 2θ; and
(Iii) 6.6 ± 0.2 °, 7.1 ± 0.2 °, 10.6 ± 0.2 °, measured at a temperature of about 25 ° C. and an X-ray wavelength of 1.5418 Å, λ, 13.2 ± 0.2 °, 14.3 ± 0.2 °, 16.0 ± 0.2 °, 17.3 ± 0.2 °, 23.5 ± 0.2 °, 26.5 ± 0 An X-ray powder diffraction pattern containing 5 or more 2θ values selected from the group consisting of .2 and 27.3 ± 0.2 ° 2θ .
ａ）非晶質の遊離形態の（Ｓ）－Ｎ－（４－（（５－（１，６－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－４－イル）－３－メチル－４，５，６，７－テトラヒドロ－１Ｈ－ピラゾロ［４，３－ｃ］ピリジン－１－イル）メチル）ビシクロ［２．２．２］オクタン－１－イル）モルホリン－３－カルボキサミドを、少なくとも約２重量％の水を含む溶媒混合物に懸濁させて、懸濁混合物を形成する工程、
ｂ）前記懸濁混合物を温度に溶解まで加熱して、溶液を形成する工程、
ｃ）前記溶液を約－１０℃に冷却して、懸濁液を形成する工程、
ｄ）前記懸濁液を濾過して、前記結晶形態を回収する工程
を含む方法。 The compound (S) -N- ((5- (1,6-dimethyl-1H-pyrazolo [3,4-b] pyridin-4-yl)) according to any one of claims 1 to 5. -3-Methyl-4,5,6,7-Tetrahydro-1H-Pyrazolo [4,3-c] Pyridine-1-yl) Methyl) Bicyclo [2.2.2] Octane-1-yl) Morpholine-3 -A method for producing the crystal form of carboxamide.
a ) Amorphous free form of (S) -N- (4-((5- (1,6-dimethyl-1H-pyrazolo [3,4-b] pyridin-4-yl) -3-methyl-) 4,5,6,7-tetrahydro-1H-pyrazolo [4,3-c] pyridin-1-yl) methyl) bicyclo [2.2.2] octane-1-yl) morpholin-3-carboxamide, at least The step of forming a suspended mixture by suspending it in a solvent mixture containing about 2% by weight of water.
b ) The step of heating the suspension mixture to a temperature until it dissolves to form a solution.
c ) The step of cooling the solution to about −10 ° C. to form a suspension,
d ) A method comprising a step of filtering the suspension to recover the crystalline form.
12. The method of claim 12 or 13 , wherein the solvent mixture in step a) is selected from acetone / water 98: 2 (weight ratio) and isopropanol / water 95: 5 (weight ratio).
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