JP6487845B2 - 骨粗鬆症治療剤 - Google Patents
骨粗鬆症治療剤 Download PDFInfo
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- JP6487845B2 JP6487845B2 JP2015539408A JP2015539408A JP6487845B2 JP 6487845 B2 JP6487845 B2 JP 6487845B2 JP 2015539408 A JP2015539408 A JP 2015539408A JP 2015539408 A JP2015539408 A JP 2015539408A JP 6487845 B2 JP6487845 B2 JP 6487845B2
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- A—HUMAN NECESSITIES
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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Description
骨密度の低下は、骨吸収の亢進が骨形成を上回るために生じるが、骨芽細胞機能およびそれに伴う骨形成の低下も関与している(非特許文献2)。つまり骨吸収と骨形成による骨リモデリングのバランスが偏り、骨吸収が優位になることが病態に深く関与している。
現在、日本における骨粗鬆症の患者は、腰椎と大腿骨頸部を合わせると1280万人(2005年)と推定され、大腿骨頸部骨折発生数は年間14万8100人と急速に増加しており、様々な治療方法や予防剤が開発されている。
このため近年では、カテプシンK阻害剤、Srcキナーゼ阻害剤、抗スクレロスチン抗体などの新しい標的を狙った骨粗鬆症治療剤の臨床開発が行われているが(非特許文献7、8、9)、骨粗鬆症治療薬として、優れた有効性と安全性を兼ね備えた薬剤がないのが現状である。
また本発明は、下記式(I)で表されるアシルチオウレア化合物又はその塩、及び薬学的に許容される担体を含有する骨粗鬆症を治療するための医薬組成物を提供するものである。
また本発明は、下記式(I)で表されるアシルチオウレア化合物又はその塩及び薬学的に許容される担体を含有する医薬組成物を患者に投与することを特徴とする、骨粗鬆症の治療方法を提供するものである。
(1)4−(2−フルオロ−4−(3−(2−フェニルアセチル)チオウレイド)フェノキシ)−7−メトキシ−N−メチルキノリン−6−カルボキサミド
(2)4−(2−フルオロ−4−(3−(2−フェニルアセチル)チオウレイド)フェノキシ)−7−メトキシ−N−(2−モルホリノエチル)キノリン−6−カルボキサミド
(3)(S)−4−(2−フルオロ−4−(3−(2−(4−フルオロフェニル)アセチル)チオウレイド)フェノキシ)−N−(1−ヒドロキシブタン−2−イル)−7−メトキシキノリン−6−カルボキサミド
このうち有機酸との塩が好ましく、メタンスルホン酸塩がより好ましく、モノメタンスルホン酸塩が更に好ましい。
また本発明化合物には、光学異性体も含まれ、水和物、各種溶媒和物及び結晶多形も包含する。
したがって、本発明化合物又はその塩は、骨粗鬆症の患者に適用され、当該骨粗鬆症に対して優れた予防又は治療効果を発揮する医薬として有用である。更には、関節リウマチ、歯周病、骨折等の治療にも有用である。
本明細書において、「骨粗鬆症」とは、骨量の減少と骨質の劣化により骨強度が悪化して骨折のリスクが増加しやすいことが特徴的な原発性及び続発性を含めた骨疾患を指す。本発明の骨粗鬆症治療剤及び骨粗鬆症を治療するための医薬組成物により治療できる骨粗鬆症としては、例えば閉経後骨粗鬆症、男性骨粗鬆症、突発性骨粗鬆症(妊娠後骨粗鬆症など)、更には骨形成不全症などが挙げられる。
4−[2−フルオロ−4−[[[(2−フェニルアセチル)アミノ]チオキソメチル]アミノ]−フェノキシ]−7−メトキシ−N−メチル−6−キノリンカルボキサミド(化合物IA)の合成
国際公開第2009/125597号(前記特許文献1)の実施例6の記載に準じて、表記化合物IA(本発明化合物)を合成した。
ヒト前立腺がん細胞株PC-3を、2×106cells/15μLでマウス脛骨内に移植した。移植翌日に各群におけるマウスの平均体重が均等になるように群分けを行い、化合物IAを200mg/kg/dayで10日間連日経口投与を行った。移植してから11日目に移植部位のμCT撮影を行い、骨病変の評価を実施した。
以上より、本発明化合物は死亡や体重減少を示さず、ヒト前立腺がん細胞の脛骨移植系における代謝性の骨破壊亢進と異常なひ弱骨の形成抑制により、骨量を正常に維持することが示された。
ルシフェラーゼ遺伝子を導入したヒト肺がん細胞株A549をヌードマウスの左心室に移植することにより、骨選択的に転移し増殖する肺がん細胞株A549-luc-BM1を樹立した。この細胞を、2×106cells/15μLでマウス脛骨内に移植した。移植後7日目に移植部位のルシフェラーゼ活性をin vivo imaging systemにより測定し、各群の平均ルシフェラーゼ活性が等しくなるように群分けを行い、化合物IAを200 mg/kg/dayで28日間連日経口投与を行った。治療対照群は、第三世代のビスホスホネート製剤であるゾレドロン酸を用い、0.2mg/kg/dayで週2回、皮下投与を行った。骨病変の評価として、移植後36日目に移植部位のμCT撮影を行った。
以上より、本発明化合物はゾレドロン酸よりも骨代謝(骨吸収と骨形成)異常の抑制効果に優れており、骨粗鬆症治療剤として有用であることが示された。
麻酔下でマウスの卵巣を摘出し、当日にマウスの平均体重が均等になるように群分けを行った。治療陽性対照群として、エストラジオール(E2)を3μg/kg/dayで4週間連日投与した。また化合物IAは200mg/kg/dayで4週間の連日経口投与を行った。それぞれの薬剤投与後にマウスの大腿骨を摘出して、骨量を骨密度測定装置(dual-energy X-ray absorptiometry、DEXA法)およびμCTで測定し評価した。大腿骨の骨量(BMD)、大腿骨のμCT像、及び体重変化をそれぞれ図3、4及び5に示す。
図3、4に示すとおり、OVXマウスではSham群に比して大腿骨の骨量低下を呈し、エストラジオール投与群はOVXマウスに対して骨量低下抑制を示した。このことから本モデル系では適切に卵巣摘出が行われ、骨粗鬆症モデルが成立していることが確認された(CLINICAL CALCIUM, 2011,21(2), p.164)。
以上の結果から、本発明化合物は、安全性の高い骨粗鬆症治療剤として有用であることが示された。
Claims (5)
- 4−[2−フルオロ−4−[[[(2−フェニルアセチル)アミノ]チオキソメチル]アミノ]−フェノキシ]−7−メトキシ−N−メチル−6−キノリンカルボキサミド又はその薬学的に許容される塩を有効成分として含有する骨粗鬆症治療剤。
- 4−[2−フルオロ−4−[[[(2−フェニルアセチル)アミノ]チオキソメチル]アミノ]−フェノキシ]−7−メトキシ−N−メチル−6−キノリンカルボキサミド又はその薬学的に許容される塩が4−[2−フルオロ−4−[[[(2−フェニルアセチル)アミノ]チオキソメチル]アミノ]−フェノキシ]−7−メトキシ−N−メチル−6−キノリンカルボキサミド モノメタンスルホン酸塩である、請求項1記載の骨粗鬆症治療剤。
- 経口投与される、請求項1又は2記載の骨粗鬆症治療剤。
- 1日あたり0.005〜5,000mg投与される、請求項3記載の骨粗鬆症治療剤。
- 1日1回又は2〜4回に分けて投与される、請求項3又は4記載の骨粗鬆症治療剤。
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US14/041,222 US9149471B2 (en) | 2013-09-30 | 2013-09-30 | Therapeutic agent for osteoporosis |
PCT/JP2014/075804 WO2015046484A1 (ja) | 2013-09-30 | 2014-09-29 | 骨粗鬆症治療剤 |
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US20040235728A1 (en) * | 2001-11-08 | 2004-11-25 | Stoch Selwyn Aubrey | Compositions and methods for treating osteoporosis |
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