JPWO2021178991A5 - - Google Patents
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- JPWO2021178991A5 JPWO2021178991A5 JP2022552324A JP2022552324A JPWO2021178991A5 JP WO2021178991 A5 JPWO2021178991 A5 JP WO2021178991A5 JP 2022552324 A JP2022552324 A JP 2022552324A JP 2022552324 A JP2022552324 A JP 2022552324A JP WO2021178991 A5 JPWO2021178991 A5 JP WO2021178991A5
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- lung
- crystalline hydrate
- pharmaceutical composition
- transplant rejection
- disease
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- 206010051604 Lung transplant rejection Diseases 0.000 claims description 36
- 239000008194 pharmaceutical composition Substances 0.000 claims description 25
- 206010035664 Pneumonia Diseases 0.000 claims description 24
- 206010035742 Pneumonitis Diseases 0.000 claims description 24
- 208000006673 asthma Diseases 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 19
- 230000001684 chronic effect Effects 0.000 claims description 18
- 208000023504 respiratory system disease Diseases 0.000 claims description 18
- 241000124008 Mammalia Species 0.000 claims description 14
- 239000003814 drug Substances 0.000 claims description 14
- 230000005980 lung dysfunction Effects 0.000 claims description 14
- 230000001154 acute effect Effects 0.000 claims description 12
- 201000009805 cryptogenic organizing pneumonia Diseases 0.000 claims description 12
- 208000013397 idiopathic acute eosinophilic pneumonia Diseases 0.000 claims description 12
- 210000004072 lung Anatomy 0.000 claims description 10
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 10
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 claims description 6
- 206010006448 Bronchiolitis Diseases 0.000 claims description 6
- 206010006474 Bronchopulmonary aspergillosis allergic Diseases 0.000 claims description 6
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 6
- 201000003883 Cystic fibrosis Diseases 0.000 claims description 6
- 206010014561 Emphysema Diseases 0.000 claims description 6
- 208000027004 Eosinophilic disease Diseases 0.000 claims description 6
- 208000018428 Eosinophilic granulomatosis with polyangiitis Diseases 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 241000233866 Fungi Species 0.000 claims description 6
- 208000034706 Graft dysfunction Diseases 0.000 claims description 6
- 208000009329 Graft vs Host Disease Diseases 0.000 claims description 6
- 208000006968 Helminthiasis Diseases 0.000 claims description 6
- 206010048643 Hypereosinophilic syndrome Diseases 0.000 claims description 6
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 claims description 6
- 208000016300 Idiopathic chronic eosinophilic pneumonia Diseases 0.000 claims description 6
- 229940076838 Immune checkpoint inhibitor Drugs 0.000 claims description 6
- 102000037984 Inhibitory immune checkpoint proteins Human genes 0.000 claims description 6
- 108091008026 Inhibitory immune checkpoint proteins Proteins 0.000 claims description 6
- 201000009324 Loeffler syndrome Diseases 0.000 claims description 6
- 208000019693 Lung disease Diseases 0.000 claims description 6
- 206010049459 Lymphangioleiomyomatosis Diseases 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 206010029888 Obliterative bronchiolitis Diseases 0.000 claims description 6
- 206010067472 Organising pneumonia Diseases 0.000 claims description 6
- 208000004530 Primary Graft Dysfunction Diseases 0.000 claims description 6
- 206010064911 Pulmonary arterial hypertension Diseases 0.000 claims description 6
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 claims description 6
- 206010069351 acute lung injury Diseases 0.000 claims description 6
- 201000000028 adult respiratory distress syndrome Diseases 0.000 claims description 6
- 208000006778 allergic bronchopulmonary aspergillosis Diseases 0.000 claims description 6
- 201000009267 bronchiectasis Diseases 0.000 claims description 6
- 201000003848 bronchiolitis obliterans Diseases 0.000 claims description 6
- 208000023367 bronchiolitis obliterans with obstructive pulmonary disease Diseases 0.000 claims description 6
- 206010006451 bronchitis Diseases 0.000 claims description 6
- 229940079593 drug Drugs 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- 230000004064 dysfunction Effects 0.000 claims description 6
- 201000001155 extrinsic allergic alveolitis Diseases 0.000 claims description 6
- 208000024908 graft versus host disease Diseases 0.000 claims description 6
- 208000022098 hypersensitivity pneumonitis Diseases 0.000 claims description 6
- 239000012274 immune-checkpoint protein inhibitor Substances 0.000 claims description 6
- 208000036971 interstitial lung disease 2 Diseases 0.000 claims description 6
- 230000000527 lymphocytic effect Effects 0.000 claims description 6
- 230000003448 neutrophilic effect Effects 0.000 claims description 6
- 208000014837 parasitic helminthiasis infectious disease Diseases 0.000 claims description 6
- 201000009732 pulmonary eosinophilia Diseases 0.000 claims description 6
- 201000000306 sarcoidosis Diseases 0.000 claims description 6
- 239000007787 solid Substances 0.000 claims description 6
- 238000000113 differential scanning calorimetry Methods 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 239000000725 suspension Substances 0.000 claims description 4
- -1 4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-6-yl Chemical group 0.000 claims description 2
- 230000001476 alcoholic effect Effects 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 239000011261 inert gas Substances 0.000 claims description 2
- CKJNUZNMWOVDFN-UHFFFAOYSA-N methanone Chemical compound O=[CH-] CKJNUZNMWOVDFN-UHFFFAOYSA-N 0.000 claims description 2
- 150000004682 monohydrates Chemical class 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims 13
- 239000013078 crystal Substances 0.000 claims 1
- 230000001568 sexual effect Effects 0.000 claims 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
Description
本開示は、その特定の態様または実施形態を参照して説明してきたが、本開示の真の趣旨および範囲から逸脱することなく、様々な変更が行われ得、等価物で置換され得ることが当業者によって理解される。さらに、適用される特許法および規則によって認められる限りにおいて、本明細書に引用されたすべての刊行物、特許および特許出願は、各文書が個別に参照により本明細書中に援用されるのと同程度に、その全体が参照により本明細書に援用される。
本発明は、例えば、以下の項目を提供する。
（項目１）
式１の化合物：
の結晶性水和物であって、前記結晶性水和物が、５．６８±０．２０、１０．４３±０．２０、１０．９４±０．２０、および１３．０８±０．２０の２θ値に回折ピークを含む粉末Ｘ線回折パターンによって特徴付けられる、結晶性水和物。
（項目２）
前記粉末Ｘ線回折パターンが、８．４９±０．２０の２θ値に１つのさらなる回折ピークを有することによってさらに特徴付けられる、項目１に記載の結晶性水和物。
（項目３）
前記粉末Ｘ線回折パターンが、１１．５５±０．２０、１２．２０±０．２０、１７．０６±０．２０、および２６．２９±０．２０から選択される２θ値に２またはそれを超えるさらなる回折ピークを有することによってさらに特徴付けられる、項目２に記載の結晶性水和物。
（項目４）
前記粉末Ｘ線回折パターンが、１１．５５±０．２０、１２．２０±０．２０、１７．０６±０．２０、および２６．２９±０．２０の２θ値にさらなる回折ピークを有することによってさらに特徴付けられる、項目２に記載の結晶性水和物。
（項目５）
前記結晶性水和物が、ピーク位置が図１に示されるパターンのピーク位置と実質的に一致する粉末Ｘ線回折パターンによって特徴付けられる、項目１～４のいずれか一項に記載の結晶性水和物。
（項目６）
前記結晶性水和物が、２１２．４±３℃の温度において吸熱熱流の最大値を示す、１０℃／分の加熱速度で記録された示差走査熱量測定トレースによって特徴付けられる、項目１～５のいずれか一項に記載の結晶性水和物。
（項目７）
前記結晶性水和物が、図２に示されるものと実質的に一致する示差走査熱量測定トレースによって特徴付けられる、項目１～６のいずれか一項に記載の結晶性水和物。
（項目８）
前記結晶性水和物が一水和物である、項目１～７のいずれか一項に記載の結晶性水和物。
（項目９）
項目１～８のいずれか一項に記載の結晶性水和物と薬学的に許容され得るキャリアとを含む薬学的組成物。
（項目１０）
（ａ）（Ｓ）－（３－（ジメチルアミノ）アゼチジン－１－イル）（２－（６－（２－エチル－４－ヒドロキシフェニル）－１Ｈ－インダゾール－３－イル）－５－イソプロピル－４，５，６，７－テトラヒドロ－３Ｈ－イミダゾ［４，５－ｃ］ピリジン－６－イル）メタノンを５５℃±１０℃の温度でアルコール溶媒中に溶解させて溶液を得ることと；
（ｂ）工程（ａ）において得られた前記溶液を１０℃±１０℃に冷却して懸濁液を生成することと；
（ｃ）不活性気体条件下で工程（ｂ）の前記懸濁液から固体を単離することと；
（ｄ）工程（ｃ）において得られた前記固体を６０℃±１５℃で乾燥させることと；
（ｅ）工程（ｄ）において得られた前記固体を周囲の湿度および温度の条件に供して結晶性水和物を得ることと；
を含む、項目１～８のいずれか一項に記載の結晶性水和物を調製する方法。
（項目１１）
前記アルコール溶媒がメタノールまたはエタノールである、項目１０に記載の方法。
（項目１２）
哺乳動物における呼吸器疾患を処置するための、項目１～８のいずれか一項に記載の結晶性水和物。
（項目１３）
前記呼吸器疾患が、喘息、慢性閉塞性肺疾患、嚢胞性線維症、肺臓炎、特発性肺線維症、急性肺傷害、急性呼吸窮迫症候群、気管支炎、気腫、サルコイドーシス、好酸球性疾患、蠕虫感染症、肺動脈性肺高血圧症、リンパ脈管平滑筋腫症、気管支拡張症、浸潤性肺疾患、薬物誘発性肺臓炎、真菌誘発性肺臓炎、アレルギー性気管支肺アスペルギルス症、過敏性肺臓炎、好酸球性多発血管炎性肉芽腫症、特発性急性好酸球性肺炎、特発性慢性好酸球性肺炎、好酸球増加症候群、レフラー症候群、閉塞性細気管支炎性器質化肺炎、肺移植片対宿主病、および免疫チェックポイント阻害剤誘発性肺臓炎からなる群から選択される、項目１２に記載の結晶性水和物。
（項目１４）
前記呼吸器疾患が喘息である、項目１２に記載の結晶性水和物。
（項目１５）
前記喘息が中等度～重度の喘息である、項目１４に記載の結晶性水和物。
（項目１６）
前記結晶性水和物が、吸入によって薬学的組成物中で投与される、項目１２に記載の結晶性水和物。
（項目１７）
哺乳動物における肺移植拒絶を防止または遅延させるための、項目１～８のいずれか一項に記載の結晶性水和物。
（項目１８）
前記肺移植拒絶が、原発性移植片機能不全、器質化肺炎、急性拒絶、リンパ球性細気管支炎、および慢性移植肺機能不全からなる群から選択される、項目１７に記載の結晶性水和物。
（項目１９）
前記肺移植拒絶が急性肺移植拒絶である、項目１７に記載の結晶性水和物。
（項目２０）
前記肺移植拒絶が慢性移植肺機能不全である、項目１７に記載の結晶性水和物。
（項目２１）
前記肺移植拒絶が、閉塞性細気管支炎、拘束性慢性移植肺機能不全、および好中球性同種移植片機能不全からなる群から選択される、項目１７に記載の結晶性水和物。
（項目２２）
前記結晶性水和物が、吸入によって薬学的組成物中で投与される、項目１７に記載の結晶性水和物。
（項目２３）
哺乳動物における呼吸器疾患を処置するための医薬の製造における、項目１～８のいずれか一項に記載の結晶性水和物の使用。
（項目２４）
前記呼吸器疾患が、喘息、慢性閉塞性肺疾患、嚢胞性線維症、肺臓炎、特発性肺線維症、急性肺傷害、急性呼吸窮迫症候群、気管支炎、気腫、サルコイドーシス、好酸球性疾患、蠕虫感染症、肺動脈性肺高血圧症、リンパ脈管平滑筋腫症、気管支拡張症、浸潤性肺疾患、薬物誘発性肺臓炎、真菌誘発性肺臓炎、アレルギー性気管支肺アスペルギルス症、過敏性肺臓炎、好酸球性多発血管炎性肉芽腫症、特発性急性好酸球性肺炎、特発性慢性好酸球性肺炎、好酸球増加症候群、レフラー症候群、閉塞性細気管支炎性器質化肺炎、肺移植片対宿主病、および免疫チェックポイント阻害剤誘発性肺臓炎からなる群から選択される、項目２３に記載の使用。
（項目２５）
前記呼吸器疾患が喘息である、項目２３に記載の使用。
（項目２６）
前記喘息が中等度～重度の喘息である、項目２５に記載の使用。
（項目２７）
前記医薬が吸入によって投与される、項目２３に記載の使用。
（項目２８）
哺乳動物における肺移植拒絶を予防または遅延させるための医薬の製造における、項目１～８のいずれか一項に記載の結晶性水和物の使用。
（項目２９）
前記肺移植拒絶が、原発性移植片機能不全、器質化肺炎、急性拒絶、リンパ球性細気管支炎、および慢性移植肺機能不全からなる群から選択される、項目２８に記載の使用。
（項目３０）
前記肺移植拒絶が急性肺移植拒絶である、項目２８に記載の使用。
（項目３１）
前記肺移植拒絶が慢性移植肺機能不全である、項目２８に記載の使用。
（項目３２）
前記肺移植拒絶が、閉塞性細気管支炎、拘束性慢性移植肺機能不全、および好中球性同種移植片機能不全からなる群から選択される、項目２８に記載の使用。
（項目３３）
前記医薬が吸入によって投与される、項目２８に記載の使用。
（項目３４）
哺乳動物における呼吸器疾患を処置する方法であって、項目１～８のいずれか一項に記載の結晶性水和物と薬学的に許容され得るキャリアとを含む薬学的組成物を前記哺乳動物に投与することを含む、方法。
（項目３５）
前記呼吸器疾患が、喘息、慢性閉塞性肺疾患、嚢胞性線維症、肺臓炎、特発性肺線維症、急性肺傷害、急性呼吸窮迫症候群、気管支炎、気腫、サルコイドーシス、好酸球性疾患、蠕虫感染症、肺動脈性肺高血圧症、リンパ脈管平滑筋腫症、気管支拡張症、浸潤性肺疾患、薬物誘発性肺臓炎、真菌誘発性肺臓炎、アレルギー性気管支肺アスペルギルス症、過敏性肺臓炎、好酸球性多発血管炎性肉芽腫症、特発性急性好酸球性肺炎、特発性慢性好酸球性肺炎、好酸球増加症候群、レフラー症候群、閉塞性細気管支炎性器質化肺炎、肺移植片対宿主病、および免疫チェックポイント阻害剤誘発性肺臓炎からなる群から選択される、項目３４に記載の方法。
（項目３６）
前記呼吸器疾患が喘息である、項目３４に記載の方法。
（項目３７）
前記喘息が中等度～重度の喘息である、項目３６に記載の方法。
（項目３８）
前記薬学的組成物が吸入によって投与される、項目３４に記載の方法。
（項目３９）
哺乳動物における肺移植拒絶を予防または遅延させる方法であって、項目１～８のいずれか一項に記載の結晶性水和物と、薬学的に許容され得るキャリアとを含む薬学的組成物を前記哺乳動物に投与することを含む、方法。
（項目４０）
前記肺移植拒絶が、原発性移植片機能不全、器質化肺炎、急性拒絶、リンパ球性細気管支炎、および慢性移植肺機能不全からなる群から選択される、項目３９に記載の方法。
（項目４１）
前記肺移植拒絶が急性肺移植拒絶である、項目３９に記載の方法。
（項目４２）
前記肺移植拒絶が慢性移植肺機能不全である、項目３９に記載の方法。
（項目４３）
前記肺移植拒絶が、閉塞性細気管支炎、拘束性慢性移植肺機能不全、および好中球性同種移植片機能不全からなる群から選択される、項目３９に記載の方法。
（項目４４）
前記薬学的組成物が吸入によって投与される、項目３９に記載の方法。
Although the present disclosure has been described with reference to particular aspects or embodiments thereof, it is understood that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the disclosure. will be understood by those skilled in the art. Additionally, to the extent permitted by applicable patent laws and regulations, all publications, patents and patent applications cited herein are incorporated by reference, as if each document were individually incorporated by reference. To the same extent, it is incorporated herein by reference in its entirety.
The present invention provides, for example, the following items.
(Item 1)
Compound of formula 1:
a crystalline hydrate of 5.68±0.20, 10.43±0.20, 10.94±0.20, and 13.08±0.20. A crystalline hydrate characterized by a powder X-ray diffraction pattern containing diffraction peaks at 2θ values of .
(Item 2)
Crystalline hydrate according to item 1, wherein the powder X-ray diffraction pattern is further characterized by having one additional diffraction peak at a 2θ value of 8.49±0.20.
(Item 3)
The powder X-ray diffraction pattern has a 2θ value of 2 or less selected from 11.55±0.20, 12.20±0.20, 17.06±0.20, and 26.29±0.20. Crystalline hydrate according to item 2, further characterized by having additional diffraction peaks exceeding .
(Item 4)
The powder X-ray diffraction pattern has additional diffraction peaks at 2θ values of 11.55±0.20, 12.20±0.20, 17.06±0.20, and 26.29±0.20. The crystalline hydrate according to item 2, further characterized by:
(Item 5)
Crystalline hydrate according to any one of items 1 to 4, wherein the crystalline hydrate is characterized by a powder X-ray diffraction pattern whose peak positions substantially correspond to the peak positions of the pattern shown in FIG. Hydrate.
(Item 6)
Items 1 to 5, wherein the crystalline hydrate is characterized by a differential scanning calorimetry trace recorded at a heating rate of 10 °C/min, showing a maximum value of endothermic heat flow at a temperature of 212.4 ± 3 °C. The crystalline hydrate according to any one of .
(Item 7)
A crystalline hydrate according to any one of items 1 to 6, wherein the crystalline hydrate is characterized by a differential scanning calorimetry trace substantially matching that shown in FIG. 2.
(Item 8)
The crystalline hydrate according to any one of items 1 to 7, wherein the crystalline hydrate is a monohydrate.
(Item 9)
A pharmaceutical composition comprising the crystalline hydrate according to any one of items 1 to 8 and a pharmaceutically acceptable carrier.
(Item 10)
(a) (S)-(3-(dimethylamino)azetidin-1-yl)(2-(6-(2-ethyl-4-hydroxyphenyl)-1H-indazol-3-yl)-5-isopropyl- dissolving 4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-6-yl)methanone in an alcoholic solvent at a temperature of 55°C ± 10°C to obtain a solution;
(b) cooling the solution obtained in step (a) to 10°C ± 10°C to form a suspension;
(c) isolating solids from said suspension of step (b) under inert gas conditions;
(d) drying the solid obtained in step (c) at 60°C ± 15°C;
(e) subjecting the solid obtained in step (d) to ambient humidity and temperature conditions to obtain a crystalline hydrate;
A method for preparing a crystalline hydrate according to any one of items 1 to 8, comprising:
(Item 11)
The method according to item 10, wherein the alcohol solvent is methanol or ethanol.
(Item 12)
Crystalline hydrate according to any one of items 1 to 8 for treating respiratory diseases in mammals.
(Item 13)
The respiratory disease is asthma, chronic obstructive pulmonary disease, cystic fibrosis, pneumonitis, idiopathic pulmonary fibrosis, acute lung injury, acute respiratory distress syndrome, bronchitis, emphysema, sarcoidosis, eosinophilic disease. , helminth infections, pulmonary arterial hypertension, lymphangioleiomyomatosis, bronchiectasis, infiltrative lung disease, drug-induced pneumonitis, fungus-induced pneumonitis, allergic bronchopulmonary aspergillosis, hypersensitivity pneumonitis , eosinophilic granulomatosis with polyangiitis, idiopathic acute eosinophilic pneumonia, idiopathic chronic eosinophilic pneumonia, hypereosinophilic syndrome, Loeffler syndrome, bronchiolitis obliterans organizing pneumonia, 13. The crystalline hydrate according to item 12, selected from the group consisting of lung graft-versus-host disease and immune checkpoint inhibitor-induced pneumonitis.
(Item 14)
13. The crystalline hydrate according to item 12, wherein the respiratory disease is asthma.
(Item 15)
The crystalline hydrate according to item 14, wherein the asthma is moderate to severe asthma.
(Item 16)
13. A crystalline hydrate according to item 12, wherein said crystalline hydrate is administered in a pharmaceutical composition by inhalation.
(Item 17)
Crystalline hydrate according to any one of items 1 to 8 for preventing or delaying lung transplant rejection in a mammal.
(Item 18)
Crystalline hydration according to item 17, wherein the lung transplant rejection is selected from the group consisting of primary graft dysfunction, organizing pneumonia, acute rejection, lymphocytic bronchiolitis, and chronic transplant lung dysfunction. thing.
(Item 19)
18. The crystalline hydrate according to item 17, wherein the lung transplant rejection is acute lung transplant rejection.
(Item 20)
18. The crystalline hydrate according to item 17, wherein the lung transplant rejection is chronic transplant lung dysfunction.
(Item 21)
18. The crystalline hydrate of item 17, wherein said lung transplant rejection is selected from the group consisting of bronchiolitis obliterans, chronic restrictive transplant lung dysfunction, and neutrophilic allograft dysfunction.
(Item 22)
18. A crystalline hydrate according to item 17, wherein said crystalline hydrate is administered in a pharmaceutical composition by inhalation.
(Item 23)
Use of a crystalline hydrate according to any one of items 1 to 8 in the manufacture of a medicament for treating respiratory diseases in mammals.
(Item 24)
The respiratory disease is asthma, chronic obstructive pulmonary disease, cystic fibrosis, pneumonitis, idiopathic pulmonary fibrosis, acute lung injury, acute respiratory distress syndrome, bronchitis, emphysema, sarcoidosis, eosinophilic disease. , helminth infections, pulmonary arterial hypertension, lymphangioleiomyomatosis, bronchiectasis, infiltrative lung disease, drug-induced pneumonitis, fungus-induced pneumonitis, allergic bronchopulmonary aspergillosis, hypersensitivity pneumonitis , eosinophilic granulomatosis with polyangiitis, idiopathic acute eosinophilic pneumonia, idiopathic chronic eosinophilic pneumonia, hypereosinophilic syndrome, Loeffler syndrome, bronchiolitis obliterans organizing pneumonia, The use according to item 23, selected from the group consisting of lung graft-versus-host disease and immune checkpoint inhibitor-induced pneumonitis.
(Item 25)
The use according to item 23, wherein the respiratory disease is asthma.
(Item 26)
The use according to item 25, wherein the asthma is moderate to severe asthma.
(Item 27)
Use according to item 23, wherein the medicament is administered by inhalation.
(Item 28)
Use of a crystalline hydrate according to any one of items 1 to 8 in the manufacture of a medicament for preventing or delaying lung transplant rejection in a mammal.
(Item 29)
The use according to item 28, wherein said lung transplant rejection is selected from the group consisting of primary graft dysfunction, organizing pneumonia, acute rejection, lymphocytic bronchiolitis, and chronic transplant lung dysfunction.
(Item 30)
The use according to item 28, wherein said lung transplant rejection is acute lung transplant rejection.
(Item 31)
29. The use according to item 28, wherein said lung transplant rejection is chronic transplant lung insufficiency.
(Item 32)
29. The use according to item 28, wherein said lung transplant rejection is selected from the group consisting of bronchiolitis obliterans, restrictive chronic transplant lung dysfunction, and neutrophilic allograft dysfunction.
(Item 33)
Use according to item 28, wherein the medicament is administered by inhalation.
(Item 34)
9. A method of treating a respiratory disease in a mammal, the method comprising administering a pharmaceutical composition comprising a crystalline hydrate according to any one of items 1 to 8 and a pharmaceutically acceptable carrier to said mammal. A method comprising administering to.
(Item 35)
The respiratory disease is asthma, chronic obstructive pulmonary disease, cystic fibrosis, pneumonitis, idiopathic pulmonary fibrosis, acute lung injury, acute respiratory distress syndrome, bronchitis, emphysema, sarcoidosis, eosinophilic disease. , helminth infections, pulmonary arterial hypertension, lymphangioleiomyomatosis, bronchiectasis, infiltrative lung disease, drug-induced pneumonitis, fungus-induced pneumonitis, allergic bronchopulmonary aspergillosis, hypersensitivity pneumonitis , eosinophilic granulomatosis with polyangiitis, idiopathic acute eosinophilic pneumonia, idiopathic chronic eosinophilic pneumonia, hypereosinophilic syndrome, Loeffler syndrome, bronchiolitis obliterans organizing pneumonia, 35. The method of item 34, wherein the method is selected from the group consisting of lung graft-versus-host disease, and immune checkpoint inhibitor-induced pneumonitis.
(Item 36)
35. The method according to item 34, wherein the respiratory disease is asthma.
(Item 37)
37. The method according to item 36, wherein the asthma is moderate to severe asthma.
(Item 38)
35. The method of item 34, wherein said pharmaceutical composition is administered by inhalation.
(Item 39)
A method of preventing or delaying lung transplant rejection in a mammal, comprising a pharmaceutical composition comprising a crystalline hydrate according to any one of items 1 to 8 and a pharmaceutically acceptable carrier. A method comprising administering to said mammal.
(Item 40)
40. The method of item 39, wherein the lung transplant rejection is selected from the group consisting of primary graft dysfunction, organizing pneumonia, acute rejection, lymphocytic bronchiolitis, and chronic transplant lung dysfunction.
(Item 41)
40. The method of item 39, wherein the lung transplant rejection is acute lung transplant rejection.
(Item 42)
40. The method of item 39, wherein the lung transplant rejection is chronic transplant lung dysfunction.
(Item 43)
40. The method of item 39, wherein said lung transplant rejection is selected from the group consisting of bronchiolitis obliterans, restrictive chronic transplant lung dysfunction, and neutrophilic allograft dysfunction.
(Item 44)
40. The method of item 39, wherein said pharmaceutical composition is administered by inhalation.
Claims (44)
（ｂ）工程（ａ）において得られた前記溶液を１０℃±１０℃に冷却して懸濁液を生成することと；
（ｃ）不活性気体条件下で工程（ｂ）の前記懸濁液から固体を単離することと；
（ｄ）工程（ｃ）において得られた前記固体を６０℃±１５℃で乾燥させることと；
（ｅ）工程（ｄ）において得られた前記固体を周囲の湿度および温度の条件に供して結晶性水和物を得ることと；
を含む、請求項１～８のいずれか一項に記載の結晶性水和物を調製する方法。 (a) (S)-(3-(dimethylamino)azetidin-1-yl)(2-(6-(2-ethyl-4-hydroxyphenyl)-1H-indazol-3-yl)-5-isopropyl- dissolving 4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-6-yl)methanone in an alcoholic solvent at a temperature of 55°C ± 10°C to obtain a solution;
(b) cooling the solution obtained in step (a) to 10°C ± 10°C to form a suspension;
(c) isolating solids from said suspension of step (b) under inert gas conditions;
(d) drying the solid obtained in step (c) at 60°C ± 15°C;
(e) subjecting the solid obtained in step (d) to ambient humidity and temperature conditions to obtain a crystalline hydrate;
A method for preparing a crystalline hydrate according to any one of claims 1 to 8, comprising:
40. The pharmaceutical composition of claim 39, wherein said pharmaceutical composition is administered by inhalation.
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| TWI262914B (en) | 1999-07-02 | 2006-10-01 | Agouron Pharma | Compounds and pharmaceutical compositions for inhibiting protein kinases |
| AU2004259012C1 (en) | 2003-07-23 | 2012-08-02 | Exelixis, Inc. | Anaplastic lymphoma kinase modulators and methods of use |
| US20050090529A1 (en) | 2003-07-31 | 2005-04-28 | Pfizer Inc | 3,5 Disubstituted indazole compounds with nitrogen-bearing 5-membered heterocycles, pharmaceutical compositions, and methods for mediating or inhibiting cell proliferation |
| US7884109B2 (en) | 2005-04-05 | 2011-02-08 | Wyeth Llc | Purine and imidazopyridine derivatives for immunosuppression |
| US8648069B2 (en) | 2007-06-08 | 2014-02-11 | Abbvie Inc. | 5-substituted indazoles as kinase inhibitors |
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| EP2414340A1 (en) | 2009-04-03 | 2012-02-08 | Dainippon Sumitomo Pharma Co., Ltd. | Compounds for treating disorders mediated by metabotropic glutamate receptor 5, and methods of use thereof |
| WO2011084486A1 (en) | 2009-12-21 | 2011-07-14 | Epitherix, Llc | 1h-pyrazolo[3,4-b]pyridines and therapeutic uses thereof |
| US8575336B2 (en) | 2011-07-27 | 2013-11-05 | Pfizer Limited | Indazoles |
| JP6192839B2 (en) | 2013-12-05 | 2017-09-06 | ファイザー・インク | Pyrrolo [2,3-d] pyrimidinyl, pyrrolo [2,3-b] pyrazinyl, and pyrrolo [2,3-d] pyridinylacrylamide |
| AU2015260905A1 (en) | 2014-05-14 | 2016-12-01 | Pfizer Inc. | Pyrazolopyridines and pyrazolopyrimidines |
| WO2016026078A1 (en) | 2014-08-19 | 2016-02-25 | Changzhou Jiekai Pharmatech Co., Ltd. | Heterocyclic compounds as erk inhibitors |
| KR101663277B1 (en) | 2015-03-30 | 2016-10-06 | 주식회사 녹십자 | Tnik ikk tbk1 pyrazole derivatives as tnik ikk and tbk1 inhibitor and pharmaceutical composition comprising same |
| CA3001542C (en) | 2015-11-03 | 2021-02-16 | Theravance Biopharma R&D Ip, Llc | Jak kinase inhibitor compounds for treatment of respiratory disease |
| WO2017077283A1 (en) | 2015-11-03 | 2017-05-11 | Topivert Pharma Limited | 4,5,6,7-tetrahydro-1h-imidazo[4,5-c]pyridine and 1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepine derivatives as janus kinase inhibitors |
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| US10947229B2 (en) | 2018-09-04 | 2021-03-16 | Theravance Biopharma R&D Ip, Llc | Dimethyl amino azetidine amides as JAK inhibitors |
| ES2955717T3 (en) | 2018-09-04 | 2023-12-05 | Theravance Biopharma R&D Ip Llc | 5- to 7-membered heterocyclic amides as JAK inhibitors |
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| TW202144343A (en) * | 2020-03-02 | 2021-12-01 | 美商施萬生物製藥研發 Ip有限責任公司 | Crystalline hydrate of a jak inhibitor compound |
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