JP6446051B2 - 1−(3−メチル−2−オキソ−2,3−ジヒドロ−1,3−ベンゾキサゾール−6−イル)−2,4−ジオキソ−3−[(1r)−4−(トリフルオルメチル)−2,3−ジヒドロ−1h−インデン−1−イル]−1,2,3,4−テトラヒドロピリミジン−5−カルボン酸の塩 - Google Patents
1−(3−メチル−2−オキソ−2,3−ジヒドロ−1,3−ベンゾキサゾール−6−イル)−2,4−ジオキソ−3−[(1r)−4−(トリフルオルメチル)−2,3−ジヒドロ−1h−インデン−1−イル]−1,2,3,4−テトラヒドロピリミジン−5−カルボン酸の塩 Download PDFInfo
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- JP6446051B2 JP6446051B2 JP2016551038A JP2016551038A JP6446051B2 JP 6446051 B2 JP6446051 B2 JP 6446051B2 JP 2016551038 A JP2016551038 A JP 2016551038A JP 2016551038 A JP2016551038 A JP 2016551038A JP 6446051 B2 JP6446051 B2 JP 6446051B2
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- tetrahydropyrimidine
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Images
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- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A—HUMAN NECESSITIES
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- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
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- C07C229/26—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having more than one amino group bound to the carbon skeleton, e.g. lysine
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Description
X線ディフラクトグラムは、室温において、X`Pert PRO(PANalytical) XRD透過/反射回折装置(放射線:銅、Kα1、波長:1.5406Å)を用いて記録した。試料調製はしなかった。
エチル 1−(3−メチル−2−オキソ−2,3−ジヒドロ−1,3−ベンゾキサゾール−6−イル)−2,4−ジオキソ−1,2,3,4−テトラヒドロピリミジン−5−カルボキシレート
比旋光度:αD 20=+132.9°(クロロホルム、c=0.395g/100ml)。
1H−NMR(400MHz、CD2Cl2):δ[ppm]=2.40−2.52(m,1H)、2.59−2.72(m,1H)、3.12−3.25(m,1H)、3.41(s,3H)、3.44−3.56(m,1H)、6.58−6.69(m,1H)、7.04−7.11(m,1H)、7.15−7.21(m,1H)、7.24(br.s,1H)、7.29−7.38(m,2H)、7.53(s,1H)、8.54(s,1H)、12.39(br.s,1H)。
1−(3−メチル−2−オキソ−2,3−ジヒドロ−1,3−ベンゾキサゾール−6−イル)−2,4−ジオキソ−3−[(1R)−4−(トリフルオロメチル)−2,3−ジヒドロ−1H−インデン−1−イル]−1,2,3,4−テトラヒドロピリミジン−5−カルボン酸のL−リジン塩の調製
約300mgの1−(3−メチル−2−オキソ−2,3−ジヒドロ−1,3−ベンゾキサゾール−6−イル)−2,4−ジオキソ−3−[(1R)−4−(トリフルオロメチル)−2,3−ジヒドロ−1H−インデン−1−イル]−1,2,3,4−テトラヒドロピリミジン−5−カルボン酸(遊離酸)を30mlのアセトニトリル中に溶解した。回転させながら、30mlのトルエンを共溶媒として加えた。10mlの水中90mgのL−リジンの溶液を次いで加え、混合物を室温で一晩撹拌した。懸濁液を次いでろ過し、残渣を室温および環境湿度において乾燥させた。残渣をX線回折法により試験したところ、標題化合物と一致する。
1−(3−メチル−2−オキソ−2,3−ジヒドロ−1,3−ベンゾキサゾール−6−イル)−2,4−ジオキソ−3−[(1R)−4−(トリフルオロメチル)−2,3−ジヒドロ−1H−インデン−1−イル]−1,2,3,4−テトラヒドロピリミジン−5−カルボン酸のナトリウム塩の調製
約300mgの1−(3−メチル−2−オキソ−2,3−ジヒドロ−1,3−ベンゾキサゾール−6−イル)−2,4−ジオキソ−3−[(1R)−4−(トリフルオロメチル)−2,3−ジヒドロ−1H−インデン−1−イル]−1,2,3,4−テトラヒドロピリミジン−5−カルボン酸(遊離酸)を30mlのアセトニトリル中に溶解した。回転させながら、30mlの酢酸イソプロピルを共溶媒として加えた。10mlの水中65.2mgの炭酸水素ナトリウムの溶液を次いで加え、混合物を室温で60分間撹拌した。懸濁液を次いでろ過し、残渣を室温および環境湿度において乾燥させた。残渣をX線回折法により試験したところ、標題化合物と一致する。
1−(3−メチル−2−オキソ−2,3−ジヒドロ−1,3−ベンゾキサゾール−6−イル)−2,4−ジオキソ−3−[(1R)−4−(トリフルオロメチル)−2,3−ジヒドロ−1H−インデン−1−イル]−1,2,3,4−テトラヒドロピリミジン−5−カルボン酸のカリウム塩の調製
約300mgの1−(3−メチル−2−オキソ−2,3−ジヒドロ−1,3−ベンゾキサゾール−6−イル)−2,4−ジオキソ−3−[(1R)−4−(トリフルオロメチル)−2,3−ジヒドロ−1H−インデン−1−イル]−1,2,3,4−テトラヒドロピリミジン−5−カルボン酸(遊離酸)を30mlのアセトニトリル中に溶解した。回転させながら、さらに30mlのアセトニトリルを加えた。10mlの水中85.1mgの炭酸水素カリウムの溶液を次いで加え、混合物を室温で60分間撹拌した。懸濁液を次いでろ過し、残渣を室温および環境湿度において乾燥させた。残渣をX線回折法により試験したところ、標題化合物と一致する。
Claims (18)
- 1−(3−メチル−2−オキソ−2,3−ジヒドロ−1,3−ベンゾキサゾール−6−イル)−2,4−ジオキソ−3−[(1R)−4−(トリフルオロメチル)−2,3−ジヒドロ−1H−インデン−1−イル]−1,2,3,4−テトラヒドロピリミジン−5−カルボン酸のアミノ酸塩またはアルカリ金属塩であることを特徴とする、請求項1に記載の塩。
- 1−(3−メチル−2−オキソ−2,3−ジヒドロ−1,3−ベンゾキサゾール−6−イル)−2,4−ジオキソ−3−[(1R)−4−(トリフルオロメチル)−2,3−ジヒドロ−1H−インデン−1−イル]−1,2,3,4−テトラヒドロピリミジン−5−カルボン酸のリジン塩であることを特徴とする、請求項1または2に記載の塩。
- 1−(3−メチル−2−オキソ−2,3−ジヒドロ−1,3−ベンゾキサゾール−6−イル)−2,4−ジオキソ−3−[(1R)−4−(トリフルオロメチル)−2,3−ジヒドロ−1H−インデン−1−イル]−1,2,3,4−テトラヒドロピリミジン−5−カルボン酸のL−リジン塩であることを特徴とする、請求項1、2または3に記載の塩。
- 化合物のX線ディフラクトグラムが、2θ角のピーク最大を16.9において持つことを特徴とする、請求項4に記載の塩。
- 化合物のX線ディフラクトグラムが、2θ角のピーク最大を16.9、22.3および20.0において持つことを特徴とする、請求項4または5に記載の塩。
- 1−(3−メチル−2−オキソ−2,3−ジヒドロ−1,3−ベンゾキサゾール−6−イル)−2,4−ジオキソ−3−[(1R)−4−(トリフルオロメチル)−2,3−ジヒドロ−1H−インデン−1−イル]−1,2,3,4−テトラヒドロピリミジン−5−カルボン酸のナトリウム塩であることを特徴とする、請求項1または2に記載の塩。
- 化合物のX線ディフラクトグラムが、2θ角のピーク最大を17.6において持つことを特徴とする、請求項7に記載の塩。
- 化合物のX線ディフラクトグラムが、2θ角のピーク最大を17.6、17.9および19.1において持つことを特徴とする、請求項7または8に記載の塩。
- 1−(3−メチル−2−オキソ−2,3−ジヒドロ−1,3−ベンゾキサゾール−6−イル)−2,4−ジオキソ−3−[(1R)−4−(トリフルオロメチル)−2,3−ジヒドロ−1H−インデン−1−イル]−1,2,3,4−テトラヒドロピリミジン−5−カルボン酸のカリウム塩であることを特徴とする、請求項1または2に記載の塩。
- 化合物のX線ディフラクトグラムが、2θ角のピーク最大を23.7において持つことを特徴とする、請求項10に記載の塩。
- 化合物のX線ディフラクトグラムが、2θ角のピーク最大を23.7、15.3および20.5において持つことを特徴とする、請求項10または11に記載の塩。
- 障害の処置のための、請求項1から12のいずれかに記載の塩。
- 請求項1から12のいずれかに記載の塩およびこれより多くない割合の任意の他の形態の式(I)の化合物を含む薬剤。
- 請求項1から12のいずれかに記載の化合物を、式(I)の化合物の総存在量ベースで90重量パーセントより多く含む薬剤。
- 遊離酸の形態である式(I)の化合物を不活性溶媒中で溶解させること、および
塩形成性塩基の溶液と共に10℃から60℃の温度で撹拌または振とうすることを含む、請求項1から12のいずれかに記載の化合物を調製する方法。 - 心血管障害、炎症性障害、アレルギー障害および/または線維性障害の処置および/または予防のための薬剤を製造するための、請求項1から12のいずれかに記載の化合物の使用。
- 有効量の請求項1から12のいずれかに記載の化合物を含む、心血管障害の処置のための薬剤。
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Application Number | Priority Date | Filing Date | Title |
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EP13192177 | 2013-11-08 | ||
EP13192177.7 | 2013-11-08 | ||
PCT/EP2014/073801 WO2015067652A1 (de) | 2013-11-08 | 2014-11-05 | Salze von 1 -(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-3-[(1 r)-4-(trifluormethyl)-2,3-dihydro-1h-inden-1 -yl]-1,2,3,4-tetrahydropyrimidin-5-carbonsäure |
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JP2016535096A JP2016535096A (ja) | 2016-11-10 |
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JP6446051B2 true JP6446051B2 (ja) | 2018-12-26 |
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JP (1) | JP6446051B2 (ja) |
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CN (1) | CN105658647B (ja) |
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EP3615031A1 (en) * | 2017-04-27 | 2020-03-04 | Bayer Aktiengesellschaft | Selective adrenoreceptor alpha2c receptor antagonists alone, or in combination with chymase inhibitors for use in the treatment and/or prophylaxis of peripheral artery diseases (pad) |
WO2022135502A1 (zh) * | 2020-12-25 | 2022-06-30 | 广东东阳光药业有限公司 | 多取代的尿嘧啶衍生物及其用途 |
TW202404601A (zh) * | 2022-04-05 | 2024-02-01 | 加拿大商索科普拉健康與人類科學兩合公司 | 用於選擇性消退血栓性或血栓栓塞性疾病中血栓的凝乳酶抑制劑 |
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