JP2012500794A - 肥満細胞トリプターゼインヒビターとしての[4−(5−アミノメチル−2−フルオロ−フェニル)−ピペリジン−1−イル]−[7−フルオロ−1−(2−メトキシ−エチル)−4−トリフルオロメトキシ−1h−インドール−3−イル]−メタノン - Google Patents
肥満細胞トリプターゼインヒビターとしての[4−(5−アミノメチル−2−フルオロ−フェニル)−ピペリジン−1−イル]−[7−フルオロ−1−(2−メトキシ−エチル)−4−トリフルオロメトキシ−1h−インドール−3−イル]−メタノン Download PDFInfo
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- JP2012500794A JP2012500794A JP2011523975A JP2011523975A JP2012500794A JP 2012500794 A JP2012500794 A JP 2012500794A JP 2011523975 A JP2011523975 A JP 2011523975A JP 2011523975 A JP2011523975 A JP 2011523975A JP 2012500794 A JP2012500794 A JP 2012500794A
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Images
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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Abstract
さらに、本発明は治療有効量の式Iの化合物および薬学的に受容可能な担体を含む医薬組成物に関する。
【化1】
Description
上記および本発明の説明を通して用いられる場合、他に示されない限り以下の略号は以下の意味を有すると理解される:
n−BuOAc n−酢酸ブチル
n−BuLi n−ブチルリチウム
sec−BuLi sec−ブチルリチウム
t−Bu tert−ブチル
t−BuOH tert−ブタノール
CuI ヨウ化銅
DCM ジクロロメタン、CH2Cl2または塩化メチレン
DMF ジメチルホルムアミド
DMSO ジメチルスルホキシド
dppf 1,1’−ビス(ジフェニルホスフィノ)フェロセン
DSC 示差走査熱量測定
EDCI 1−エチル−3−(3−ジメチルアミノプロピル)カルボジイミド HCl
eq 当量
Et エチル
Et2O ジエチルエーテル
TEA トリエチルアミン
EtOH エタノール
EtOAc 酢酸エチル
EtOC(O)Cl クロロギ酸エチル
HPLC 高速液体クロマトグラフィー
MgSO4 硫酸マグネシウム
Me メチル
MeOH メタノール
MS 質量分析
MTBE メチル t−ブチルエーテル
NaHCO3 重炭酸ナトリウム
Na2SO3 亜硫酸ナトリウム
Na2SO4 硫酸ナトリウム
NMR 核磁気共鳴
Pd(PPh3)2Cl2 ビストリフェニルホスフィンパラジウム(II)二塩化物
PdCl2dppf 1,1’−ビス(ジフェニルホスフィノ)フェロセン パラジウム(II)二塩化物
Pd(dtbpf)Cl2 (1,1’ビス(ジ−t−ブチルホスフィノ)フェロセン
パラジウム 二塩化物
Pd2(dba)3 トリス(ジベンジリデンアセトン)ジパラジウム(0)
Pd(OAc)2 酢酸パラジウム(II)
P(Cy)3 トリシクロヘキシルホスフィン
t−Bu3P トリ−t−ブチルホスフィン
PPh3 トリフェニルホスフィン
PrOH プロパノール
iPrOH イソ−プロパノール
i−PrOAc イソ−酢酸プロピル
t−BuOK カリウム tert−ブトキシド
PPSE ポリ−リン酸トリメチルシリルエステル
K2CO3 炭酸カリウム
K2SO4 硫酸カリウム
LC 液体クロマトグラフィー
Na2SO4 硫酸ナトリウム
rt 室温
Rt 保持時間
TFA トリフルオロ酢酸
TFAA トリフルオロ酢酸無水物
TGA 熱重量分析
THF テトラヒドロフラン
TLC 薄層クロマトグラフィー
TMS−アセチレン トリメチルシリル−アセチレン
上記ならびに本明細書および添付の特許請求の範囲の全体を通して使用される場合、他に示されない限り、以下の用語は以下の意味を有することが理解されるべきである。
さらに、本発明は、治療有効量の式Iの化合物を患者に投与することによって改善され得る生理学的症状を患っている患者を治療するための式Iの化合物の使用に関する。本発明の化合物を用いて治療され得る生理学的症状の特定の実施態様としては、以下が挙げられるが、特にこれらに限定されない:炎症性疾患、例えば、関節の炎症、関節炎、関節リウマチ、リウマチ様脊椎炎、痛風性関節炎、外傷性関節炎、風疹関節炎、乾癬性関節炎および他の慢性炎症性関節疾患および全国および他の炎症性呼吸状態。本発明によって治療され得る生理学的症状の他の実施態様としては、慢性閉塞性肺疾患(COPD)、COPDの悪化、関節軟骨崩壊(joint cartilage destruction)、眼結膜炎、春季結膜炎、炎症性腸疾患、喘息、アレルギー性鼻炎、間質性肺炎、線維症、強皮症、肺線維症、肝硬変、心筋線維症、神経線維腫、肥厚性瘢痕、種々の皮膚科学的症状(例えば、アトピー性皮膚炎および乾癬)、心筋梗塞、発作、狭心症およびアテローム硬化性プラーク破壊(atherosclerotic plaque rapture)のその他の結果、ならびに歯周病、糖尿病性網膜症、腫瘍増殖、過敏症、多発性硬化症、消化性潰瘍および合胞体ウイルス感染症(syncytial viral infection)のような生理学的症状が挙げられる。
上に説明される通り、本発明の化合物は有用な薬理学的活性を示し、従って医薬組成物中に組み込まれ、そして特定の内科的疾患を患っている患者の治療に使用され得る。このように、さらなる態様に従って、本発明は、本発明の化合物およびその薬学的に受容可能な担体を含有する医薬組成物を提供する。本明細書中で使用される場合、用語「薬学的に受容可能」とは、好ましくは政府、特に連邦政府または州政府の規制当局により認可されているか、または米国薬局方もしくは動物、特にヒトにおける使用に関する別の一般的に認知されている薬局方に記載されていることを意味する。適切な薬学的担体は、E.W.Martinによる「Remington’s Pharmaceutical Sciences」に記載されている。
式Iの化合物は、文献に記載され、そして本明細書中以下に記載されている試験によると、トリプターゼ阻害活性を有し、この試験結果はヒトおよび他の哺乳動物における薬理学的活性と相関すると考えられている。従って、さらなる実施態様において、本発明は、トリプターゼインヒビターの投与によって改善され得る症状を患っているか、または罹りやすい患者を治療するための式Iまたは式Iを含有する組成物の使用に関する。例えば、式Iの化合物は、炎症性疾患、例えば関節の炎症(関節炎、関節リュウマチおよびリウマチ様脊椎炎、痛風性関節炎、外傷性関節炎、風疹関節炎、乾癬性関節炎、変形性関節症もしくは他の慢性炎症性関節疾患のような他の関節炎状態または関節軟骨崩壊の疾患を含む)、結膜炎、春季結膜炎、炎症性腸疾患、喘息、アレルギー性鼻炎、間質性肺疾患、線維症、強皮症、肺線維症、肝硬変、心筋線維症、神経腺維腫、肥大性瘢痕、種々の皮膚科的症状(例えば、アトピー性皮膚炎および乾癬)、心筋梗塞、発作、狭心症もしくはアテローム性動脈硬化性プラーク破壊のその他の結果、ならびに歯周病、糖尿病性網膜症、腫瘍増殖、過敏症、多発性硬化症、消化性潰瘍または合胞体ウイルス感染症を治療するのに有用である。
上で説明した通り、他の薬学的活性剤は、治療されるべき疾患によって、式Iの化合物と組合せて利用され得る。例えば、喘息の治療において、アルブテロール、ターブタリン、フォルモテロール、フェノテロールまたはプレナリン(prenaline)のようなβアドレナリン作用性アゴニストを包含し得、同様に、臭化イプラトロピウムのような抗コリン作用薬;ジプロピオン酸ベクロメタゾン、トリアムシノロンアセトニド、フルニソリド、プロピオン酸フルチカゾン、フロ酸モメタゾン、メチルプレドニゾン、プレドニゾロンまたはプレジノーズ(predinose)のような抗炎症性コルチコステロイド;ならびにクロモグリク酸ナトリウムおよびネドクロミルナトリウムのような抗炎症剤を包含し得る。従って、本発明は、式Iの化合物およびβアドレナリン作用性アゴニスト、抗コリン作用薬、抗炎症性コルチコステロイド、ロイコトリエン受容体アンタゴニスト、リポキシゲナーゼインヒビター、ホスホジエステラーゼ−4 インヒビターおよび抗炎症剤からなる群から選択される第二の化合物;ならびにそれらの薬学的に受容可能な担体を含有する医薬組成物にまで及ぶ。ロイコトリエンアンタゴニストとして本発明で使用することが特に意図されるのはモンテルカストである。またホスホジエステラーゼ−4 インヒビターとして本発明で用いることが特に意図されるのは、シフルモラスト(ciflumolast)である。本医薬組成物に適用される特定の薬学的担体は、本明細書中に記載される。
本発明に従って、式Iの化合物または本化合物を含有する医薬組成物は、非経口的、経粘膜的(例えば、経口、経鼻、肺内もしくは直腸内)または経皮的に患者に導入されてもよい。
一般的に、Remington’s Pharmaceutical Sciences,第18編、1990(Mack Publishing Co.Easton PA 18042)の第89章(参照により本明細書中に援用される)に記載されている経口固体投薬形態が、本明細書中で使用するために意図される。固体投薬形態としては、錠剤、カプセル、丸薬、口中錠またはトローチ剤(lozenge)、カシェ剤またはペレット剤が挙げられる。また、リポソーム被包またはプロテイノイドカプセル化を使用して、本発明の組成物を製剤し得る(例えば、米国特許第4,925,673号に記載されているプロテイノイドミクロスフィア)。リポソーム被包を使用してもよく、そしてリポソームは種々のポリマーで誘導体化されていてもよい(例えば、米国特許第5,013,556号)。治療のための可能な固体投薬形態の説明は、Marshall,K.,In:Modern Pharmaceutics,Edited by G.S.Banker and C.T.Rhodes、第10章、1979に記載されており、これは参照により本明細書中に援用される。一般的に、製剤は本発明の化合物および胃環境に対して保護を与え、そして腸内において生物学的に活性な物質(即ち、本発明の化合物)を放出する不活性成分を含有する。
単独または医薬組成物中の本発明の化合物の肺送達がまた、本明細書において意図される。吸入の間、化合物は哺乳動物の肺に送達され、そして肺上皮を通過して血流に満たされる。この他の報告はAdjei et al.,1990,Pharmaceutical Research,7:565−569;Adjei et al.,1990,International Journal of Pharmaceutics,63:135−144(酢酸ロイプロリド);Braquet et al.,1989,Journal of Cardiovascular Pharmacology,13(補遺5):143−146(エンドセリン−1);Hubbard et al.,1989,Annals of Internal Medicine,Vol.III,206−212頁(a1−アンチトリプシン);Smith et al.,1989,J.Clin.Invest.84:1145−1146(a−1−プロテイナーゼ);Oswein et al.,1990,「Aerosolization of Proteins」,Proceedings of Symposium on Respiratory Drug Delivery II,Keystone,Colorado,March(組換えヒト成長ホルモン);Debs et al.,1988,J.Immunol.140:3482−3488(インターフェロン−γおよび腫瘍壊死因子α)およびPlatz et al.,米国特許第5,284,656号(顆粒球コロニー刺激因子)が挙げられる。全身作用のための薬物の肺送達のための方法および組成物は、Wong et al.に対して1995年9月19日に発行された米国特許第5,451,569号に記載されている。
本発明の化合物の経鼻送達もまた意図される。経鼻送達により、鼻への治療薬の投与後に直接血流に化合物が移動するようになり、肺中に治療薬を付着させる必要が無い。経鼻送達のための製剤としては、デキストランまたはシクロデキストランを含有するものが挙げられる。
薬物の経皮投与の分野において種々の多数の方法(例えば、経皮パッチを介する)が公知であり本発明において適用される。経皮パッチは、例えば、米国特許第5,407,713号、第5,352,456号、第5,332,213号、第5,336,168号、第5,290,561号、第5,254,346号、第5,164,189号、第5,163,899号、第5,088,977号および第5,087,240号、第5,008,110号、および第4,921,475号に記載され、これらの開示の各々は、その全体が参照により本明細書中に援用される。
局所投与のために、本発明の化合物を含有するゲル(水またはアルコールベース)、クリームまたは軟膏が使用されてもよい。本発明の化合物はまた、パッチ適用のためのゲルまたはマトリクス基剤中に組み込まれてもよく、これにより経皮バリアを通して化合物の制御放出が可能になる。
直腸投与用の固体組成物としては、公知の方法で製剤され、そして本発明の化合物を含有する坐剤が挙げられる。
本発明の組成物中の活性成分の比率は変更されてもよく、適切な投薬量が得られるような比率を構成することが必要である。明らかに、いくつかの単位投薬形態を、ほとんど同時に投与してもよい。利用される用量は、医師により決定され、そして所望の治療効果、投与経路および治療期間、ならびに患者の症状に依存する。成人において、用量は一般的に、吸入では約0.001〜約50、好ましくは約0.001〜約5mg/kg体重/日であり、経口投与では約0.01〜約100、好ましくは0.1〜70、より特に0.5〜10mg/kg体重/日であり、そして静脈内投与では約0.001〜約10、好ましくは0.01〜1mg/kg体重/日である。いずれの場合にも、用量は治療されるべき対象に対する年齢、体重、一般的健康状態および医薬品の効果に影響し得る他の特性のような固有の要因に従って決定される。
式Iの化合物は、本明細書中でこれまでに使用されてるかまたは文献に記載される方法(例えば、R.C.LarockのComprehensive Organic Transformations,VCH publishes,1989によって記載されるもの)または本明細書中に記載されるような方法を意味する、公知の方法を適用または適合させることによって製造され得る。
1H NMR(CDCl3)δ8.11(br s,1H)、7.07(dd,J=9.1、9.3Hz,1H)、7.00−6.80(m,2H)、4.27(q,J=7.1Hz,2H)、1.33(t,J=7.1Hz,3H);19F NMR(CDCl3)δ−57.84(s,3F)、−134.01(br s,1F); MS 309(M+CH3CN+1、100%)、268(M+1).
1H NMR(CDCl3)δ7.30−17.10(m,2H)、6.16(br s,1H)、4.26(q,J=7.1Hz,2H)、1.32(t,J=7.1Hz,3H);19F NMR(CDCl3)δ−56.90(s,3F)、−114.35(d、J=8.5Hz,1F);MS 394(M+1、100%)、374、364、321、267.
1H NMR(CDCl3)δ7.15−7.00(m,2H)、6.41(br s,
1H)、4.26(q,J=7.1Hz,2H)、1.31(t,J=7.1Hz,3H)、0.27(s,9H);19F NMR(CDCl3)δ−57.59(s,3F)、−118.15(s,1F);MS 364(M+1、100%).
1H NMR(CDCl3)δ8.47(br s,1H)、7.35−7.20(m,1H)、6.95−6.80(m,2H)、6.68(d、J=2.5Hz,1H);19F NMR(CDCl3)δ−57.63(s,3F)、−136.10(d、J=8.5Hz,1F);MS 220(M+1、100%)、200.
1H NMR(CDCl3)δ7.15(d、J=2.1Hz,1H)、6.90−6.75(m,2H)、6.56(t,J=2.5Hz,1 H)、3.72(t,J=5.2Hz,2H)、3.72(t,J=5.2Hz,2H)、3.31(s,3H);19F NMR(CDCl3)δ−57.54(s,3F)、−137.00(d、J=11.3Hz,1F);MS 278(M+1、100%).
1H NMR(CDCl3)δ8.03(d、J=1.4Hz,1H)、7.20−6.95(m,2H)、4.54(t,J=4.9Hz,2H)、3.76(t,J=4.8Hz,2H)、3.33(s,3H);19F NMR(CDCl3)δ−57.74(s,3F)、−71.10(s,3F)、−134.95(d、J=11.5Hz,1F);MS 374(M+1、100%).
1H NMR(CDCl3)δ8.02(s,1H)、7.15−7.05(m,1H)、7.00−6.90(m,1H)、4.49(t,J=5.0Hz,2H)、3.75(t,J=4.9Hz,2H)、3.33(s,3H);19F NMR(CDCl3)δ−57.74(s,3F)、−135.65(d、J=11.3Hz,1F);MS 363(M+CH3CN+1)、322(M+1、100%).
1H NMR(CDCl3)δ7.37(s,1H)、7.20−7.10(m,2H)、7.10−6.85(m,4H)、4.95(br s,1H)、4.60−4.35(m,4H)、3.90(br s,1 H)、3.73(t,J=5.0Hz,2H)、3.32(s,3H)、3.25−2.70(m,3H)、2.05−1.50(m,4H);19F NMR(CDCl3)δ−57.54(s,3F)、−75.39(s,3F)、−119.31(s,1F)、−134.96(d、J=11.3Hz,1F);MS 608(M+1、100%).
1H NMR(CDCl3)δ7.42(s,1H)、7.25−7.10(m,2H)、7.05−6.85(m,3H)、4.92(br s,1H)、4.46(t,J=5.2Hz,2H)、3.86(br s,3 H)、3.74(t,J=5.1Hz,2H)、3.32(s,3H)、3.30−2.75(m,3H)、2.24(br s,2H)、2.05−1.55(m,4H);19F NMR(CDCl3)δ−57.52(s,3F)、−121.64(s,1F)、−136.03(d、J=11.3Hz,1F);MS 512(M+1、100%).
1H NMR(DMSO−d6)δ8.32(br s,2H)、7.71(s,1H)、7.43(d、1H、J=7.2Hz)、7.36(m,1H)、7.26−7.20(m,1H)、7.12−7.08(m,2H)、4.49(t,J=5.1Hz、2H)、4.00(s,2H)、3.71(t,J= 5.1Hz、2H)、3.32(s,3H)、3.21−3.07(m,3H)、2.99(br s,2H)、1.80−1.62(m,4H);19F NMR(DMSO−d6)δ−56.79(s,3F)、−119.34(s,1F)、−134.53(d、J=9.6Hz,1F);MS 512(M+1、100%). CHN:理論値:C 53.06%、H 5.16%、N 7.42%(1.0 H2Oとして算出). 実測値:C 53.03%、H 4.82%、N 7.22、Cl 6.64%.
[4−(5−アミノメチル−2−フルオロフェニル)ピペリジン−1−イル][7−フルオロ−1−(2−メトキシエチル)−4−トリフルオロメトキシ−1H−インドール−3−イル]メタノン(1320g、2.58mol)を含んでいると思われるトルエン溶液をすでに入れてある20Lのガラスジャケット反応器を攪拌し、61℃まで加熱した。安息香酸(316g、2.58mol)を加え、全ての安息香酸が溶解した後、シクロヘキサン(6.04L)を加えた。上記のバッチからの[4−(5−アミノメチル−2−フルオロフェニル)ピペリジン−1−イル][7−フルオロ−1−(2−メトキシエチル)−4−トリフルオロメトキシ−1H−インドール−3−イル]メタノン ベンゾエート(0.100g)で結晶が生じる77℃まで反応物を加熱した。結晶化を77℃で進行させ、15分後、その反応物を−10℃/hのランプで冷却した。反応が61℃まで到達したときに攪拌も冷却も停止させ、反応物を室温まで冷却した。一晩放置した後、攪拌を再開し、生成物を濾過により回収した。濾過ケークをトルエン(3L)およびシクロヘキサン(1.5L)より調製した溶媒混合物で洗浄した。サクションにより部分的に乾燥した後、生成物を40℃で乾燥させる乾燥オーブンに移し、[4−(5−アミノメチル−2−フルオロフェニル)ピペリジン−1−イル][7−フルオロ−1−(2−メトキシエチル)−4−トリフルオロメトキシ−1H−インドール−3−イル]メタノン ベンゾエートを無色の固形物として得た。:1408.8g(86%)、mp=156−159℃.元素分析:C25H26F5N3O3.C7H6O2についての算出値:C、60.66;H、5.09;N、6.63. 実測値:C、60.44;H、5.01;N、6.87。 赤外線スペクトル項目 (cm−1):1612、1526、1511、1501、1394、1362、1256、1232、1211、1158、1117、999、826.
工程A:2,2,2−トリフルオロ−N−(4−フルオロ−3−ピリジン−4−イル−ベンジル)−アセトアミド塩酸塩(13)の製造
w/w%)を加えた。その反応フラスコをパー(Parr)水素化システム内に置き、H2により50−60psiで満たした。H2を充填する間、圧力が安定状態(H2を日中は2−3時間ごとに50−60psiまで補充したが、一晩超えた後は、さらなる補充なしに10−20psiが観察された)に達するまで、その混合物を>48時間振盪した。HPLC分析が反応の完了を示すと、反応混合物をセライトのパッドを通して濾過した。そのろ液を40−50℃で蒸留する一方、n−BuOAc(1.25L)を加えた。MeOHの蒸留が完了した後、追加のn−BuOAc(1L)を加えた。得られた懸濁液を一晩室温まで冷却させた。懸濁液を10℃まで冷却し、濾過し、50℃のオーブンで乾燥させ、112g(89%)の化合物14を白色固形物として得た:mp=134℃.分析 C14H10F4N2O−HClについての算出値:C、50.24;H、3.31;N、8.37.実測値:C、50.16;H、3.08;N、8.38. MS(ESI)m/z 305.4(M+H).
1H NMR(300MHz、D2O)δ 7.16−6.98(m,3 H)、4.34(s,2H)、3.42(d、J=12.9Hz,2H)、3.14−2.99(m,3H)、1.98−1.81(m,4H).
工程A:(2−フルオロ−5−トリフルオロメトキシ−フェニル)−カルバミン酸エチルエステル(2)の製造
1H NMR(CDCl3)δ8.11(br s,1H)、7.07(dd,J=9.1、9.3Hz,1H)、7.00−6.80(m,2H)、4.27(q,J=7.1Hz,2H)、1.33(t,J=7.1Hz,3H);19F NMR(CDCl3)δ−57.84(s,3F)、−134.01(br s,1F); MS 309(M+CH3CN+1、100%)、268(M+1).
1H NMR(CDCl3)δ7.30−17.10(m,2H)、6.16(br s,1H)、4.26(q,J=7.1Hz,2H)、1.32(t,J=7.1Hz,3H);19F NMR(CDCl3)δ−56.90(s,3F)、−114.35(d、J=8.5Hz,1F);MS 394(M+1、100%)、374、364、321、267.
1H NMR(CDCl3)δ7.15−7.00(m,2H)、6.41(br s,1H)、4.26(q,J=7.1Hz,2H)、1.31(t,J=7.1Hz,3H)、0.27(s,9H);19F NMR(CDCl3)δ−57.59(s,3F)、−118.15(s,1F);MS 364(M+1、100%).
1H NMR(CDCl3)δ8.47(br s,1H)、7.35−7.20(m,1H)、6.95−6.80(m,2H)、6.68(d、J=2.5Hz,1H);19F NMR(CDCl3)δ−57.63(s,3F)、−136.10(d、J=8.5Hz,1F);MS 220(M+1、100%)、200.
1H NMR(CDCl3)δ7.15(d、J=2.1Hz,1H)、6.90−6.75(m,2H)、6.56(t,J=2.5Hz,1 H)、3.72(t,J=5.2Hz,2H)、3.72(t,J=5.2Hz,2H)、3.31(s,3H);19F NMR(CDCl3)δ−57.54(s,3F)、−137.00(d、J=11.3Hz,1F);MS 278(M+1、100%).
とEt2Oの間に分配した。2層を分離し、有機層を飽和NaHCO3(2X)、H2O およびブラインで洗浄し、MgSO4で乾燥させ、濾過して減圧下で濃縮した。粗製品を溶離液としてヘプタン/EtOAc(100/0〜50/50)を用いてシリカゲル上で精製し、23.4g(89%)の7をわずかに緑色の固形物として得た。
1H NMR(CDCl3)δ8.03(d、J=1.4Hz,1H)、7.20−6.95(m,2H)、4.54(t,J=4.9Hz,2H)、3.76(t,J=4.8Hz,2H)、3.33(s,3H);19F NMR(CDCl3)δ−57.74(s,3F)、−71.10(s,3F)、−134.95(d、J=11.5Hz,1F);MS 374(M+1、100%).
1H NMR(CDCl3)δ8.02(s,1H)、7.15−7.05(m,1H)、7.00−6.90(m,1H)、4.49(t,J=5.0Hz,2H)、3.75(t,J=4.9Hz,2H)、3.33(s,3H);19F NMR(CDCl3)δ−57.74(s,3F)、−135.65(d、J=11.3Hz,1F);MS 363(M+CH3CN+1)、322(M+1、100%).
1H NMR(CDCl3)δ7.37(s,1H)、7.20−7.10(m,2H)、7.10−6.85(m,4H)、4.95(br s,1H)、4.60−4.35(m,4H)、3.90(br s,1 H)、3.73(t,J=5.0Hz,2H)、3.32(s,3H)、3.25−2.70(m,3H)、2.05−1.50(m,4H);19F NMR(CDCl3)δ−57.54(s,3F)、−75.39(s,3F)、−119.31(s,1F)、−134.96(d、J=11.3Hz,1F);MS 608(M+1、100%).
1H NMR(CDCl3)δ7.42(s,1H)、7.25−7.10(m,2H)、7.05−6.85(m,3H)、4.92(br s,1H)、4.46(t,J=5.2Hz,2H)、3.86(br s,3 H)、3.74(t,J=5.1Hz,2H)、3.32(s,3H)、3.30−2.75(m,3H)、2.24(br s,2H)、2.05−1.55(m,4H);19F NMR(CDCl3)δ−57.52(s,3F)、−121.64(s,1F)、−136.03(d、J=11.3Hz,1F);MS 512(M+1、100%).
1H NMR(DMSO−d6)δ8.32(br s,2H)、7.71(s,1H)、7.43(d、1H、J=7.2Hz)、7.36(m,1H)、7.26−7.20(m,1H)、7.12−7.08(m,2H)、4.49(t,J=5.1Hz、2H)、4.00(s,2H)、3.71(t,J= 5.1Hz、2H)、3.32(s,3H)、3.21−3.07(m,3H)、2.99(br s,2H)、1.80−1.62(m,4H);19F NMR(DMSO−d6)δ−56.79(s,3F)、−119.34(s,1F)、−134.53(d、J=9.6Hz,1F);MS 512(M+1、100%). CHN:理論値:C 53.06%、H 5.16%、N 7.42%(calc’d as 1.0 H2O). 実測値:C 53.03%、H
4.82%、N 7.22、Cl 6.64%.
式Iの化合物の安息香酸塩
[4−(5−アミノメチル−2−フルオロフェニル)ピペリジン−1−イル][7−フルオロ−1−(2−メトキシエチル)−4−トリフルオロメトキシ−1H−インドール−3−イル]メタノン(1320g、2.58mol)を含んでいると思われるトルエン溶液をすでに入れてある20Lのガラスジャケット反応器を攪拌し、61℃まで加熱した。安息香酸(316g、2.58mol)を加え、全ての安息香酸が溶解した後、シクロヘキサン(6.04L)を加えた。上記のバッチからの[4−(5−アミノメチル−2−フルオロフェニル)ピペリジン−1−イル][7−フルオロ−1−(2−メトキシエチル)−4−トリフルオロメトキシ−1H−インドール−3−イル]メタノン ベンゾエート(0.100g)で結晶が生じる77℃まで反応物を加熱した。結晶化を77℃で進行させ、15分後、その反応物を−10℃/hのランプで冷却した。反応が61℃まで到達したときに攪拌も冷却も停止させ、反応を室温まで冷却した。一晩放置した後、攪拌を再開し、生成物を濾過により回収した。濾過ケークをトルエン(3L)およびシクロヘキサン(1.5L)より調製した溶媒混合物で洗浄した。サクションにより部分的に乾燥した後、生成物を40℃で乾燥させる乾燥オーブンに移し、[4−(5−アミノメチル−2−フルオロフェニル)ピペリジン−1−イル][7−フルオロ−1−(2−メトキシエチル)−4−トリフルオロメトキシ−1H−インドール−3−イル]メタノン ベンゾエートを無色の固形物として得た。:1408.8g(86%)、mp=156−159℃.
式Iの化合物のベシル酸塩
[4−(5−アミノメチル−2−フルオロフェニル)ピペリジン−1−イル][7−フルオロ−1−(2−メトキシエチル)−4−トリフルオロメトキシ−1H−インドール−3−イル]メタノン ベンゼンスルホン酸塩
アセトニトリル(12mL)にベンゼンスルホン酸一水和物(698mg、3.84mmol)を溶解した溶液を、攪拌したアセトニトリル(5mL)に溶解させた[4−(5−アミノメチル−2−フルオロフェニル)ピペリジン−1−イル][7−フルオロ−1−(2−メトキシエチル)−4−トリフルオロメトキシ−1H−インドール−3−イル]メタノン(2.0g、3.91mmol)の懸濁液に滴下した。溶解した遊離塩基の最期として混合物からベンゼンスルホン酸塩が結晶化し始めた。2時間後、生成物を濾過により回収し、アセトニトリルで洗浄した。フィルターケークを一晩乾燥させた。固形物を砕き、減圧オーブン中(43〜44℃、6.8−7.3Hg)で7.5時間窒素を流しながら乾燥させ、[4−(5−アミノメチル−2−フルオロフェニル)ピペリジン−1−イル][7−フルオロ−1−(2−メトキシエチル)−4−トリフルオロメトキシ−1H−インドール−3−イル]メタノンベンゼンスルホン酸塩を無色の固体として得た。:2.27g 1(86.7%)、mp=215−218℃.C25H26F5N3O3.C6H6O3Sについての分析算出値:C、55.60;H、4.82;N、6.27. 実測値:C、55.65;H、4.65;N、6.27. Karl Fischer:<0.10.赤外線スペクトルの項目(cm−1):1587、1545、1445、1210、1167、1125、1036、1018.
式Iの化合物のセスキフマル酸塩
[4−(5−アミノメチル−2−フルオロフェニル)ピペリジン−1−イル][7−フルオロ−1−(2−メトキシエチル)−4−トリフルオロメトキシ−1H−インドール−3−イル]メタノン セスキフマル酸塩 一水和物
丸底フラスコを、[4−(5−アミノメチル−2−フルオロフェニル)−ピペリジン−1−イル][7−フルオロ−1−(2−メトキシエチル)−4−トリフルオロメトキシ−1H−インドール−3−イル]メタノン(10.4g、20.4mmol)およびフマル酸(4.74g、40.7mmol)で満たした。イソプロパノール(IPA、62mL)を加え、得られた混合物をスチームバスで加熱した。塩の結晶化が起こる前に、ほとんどの物質が溶解した。スチームバスで加熱している間、さらなるIPAを30mLのポーションで加えた。合計152mLのIPAを加えた後、完全な溶液に到達した。得られた溶液を濾過し、そのろ液を室温まで冷却した。ろ液をさらに氷浴で1.5時間冷却し、その後生成物を濾過により回収した。回収した生成物を冷IPA(50mL)で洗浄し、サクションにより部分的に乾燥させ、45℃で乾燥させる乾燥オーブンに移した。一晩乾燥させた後、所望の生成物を無色の固体として得た。:11.8g(84%).IR(cm-1):3122−2700、2920、2824、1698、1584、1512、1443、1397−1368、1293−1217、822、794、639.1H NMR(300MHz、DMSO−d6):δ 10.07(br、3H)、7.71(s,1H)、7.43(dd,J=2.4、7.1、1H)、7.36(ddd、J=2.4、4.9、8.4、1H)、7.19(d、J=8.4、10.7、1H)、7.10(d、J=8.7、11.7、1H)、7.05(ddd、J=1.4、3.3、8.7、1H)、6.50(s,3H)、4.69(br、1H)、4.48(t,J=5.3、2H)、3.97(s,2H)、3.69(t,J=5.4、2H)、3.24(s,3H)、3.08(dddd、J= 3.5、3.5、12.1、12.1、1H)、2.91(br、2H)、1.75(br、2H)、1.63(br、2H).C25H26F5N3O3−1.5C4H4O4についての分析算出値:C、54.31;H、4.70;N、6.13.実測値:C、54.30;H、4.62;N、6.04. MS(ESI)m/z 512.2(M+H).
式Iの化合物のトシル化塩
[4−(5−アミノメチル−2−フルオロ−フェニル)−ピペリジン−1−イル]−[7−フルオロ−1−(2−メトキシ−エチル)−4−トリフルオロメトキシ−1H−インドール−3−イル]−メタノンp−トルエンスルホン酸
アセトニトリル(3mL)に[4−(5−アミノメチル−2−フルオロ−フェニル)−ピペリジン−1−イル]−[7−フルオロ−1−(2−メトキシ−エチル)−4−トリフルオロメトキシ−1H−インドール−3−イル]−メタノン(488mg、0.95mmol)を溶解させた混合物に、p−トルエンスルホン酸一水和物(181mg、0.95mmol)を加えた、この混合物を冷蔵庫に一晩貯蔵した。得られたベージュの結晶をサクションフィルターで回収し、トルエンで洗浄し、減圧下の50℃で一晩乾燥させた。453mg(69%)得られた。
1H NMR(DMSO−d6)δ8.08(bs、3H)、7.70(s,1H)、7.80−6.95(m,9H)、5.00−4.30(m,3H)、4.20−3.90(m,2H)、3.80−3.60(m,3H)、3.23(s,3H)、3.25−2.80(m,3H)、2.28(s,3H)、1.95−1.45(m,4H);19F NMR(DMSO−d6)δ−55.61(s,3F)、−118.98(s,1F)、−134.33(d、J=9.3Hz,1F);LC 2.627 min;MS 512(M+1、100%).Mp 219℃.赤外線スペクトルの項目(cm−1):1583、1548、1511、1501、1250、1200、1169、1123、1115.
式Iの化合物の硫酸塩
[4−(5−アミノメチル−2−フルオロ−フェニル)−ピペリジン−1−イル]−[7−フルオロ−1−(2−メトキシ−エチル)−4−トリフルオロメトキシ−1H−インドール−3−イル]−メタノン(423mg、0.827mmol)を20mLのガラスバイアル中に秤量した。この固体に硫酸(1.0N 試薬、1.5当量、1.30mmol、2.60mL)および1.7mL 水の溶液を加えた。室温で2時間攪拌した後、結晶性生成物が沈殿した。濾過および乾燥後、固体がアモルファスとして発見された。数滴の水で処理すると、そのアモルファス固体は結晶形態に戻った。Mp 62℃.赤外線スペクトルの項目(cm−1):1574、1545、1511、1483、1362、1267、1219、1212、1162、1096、1051.
式Iの化合物のクエン酸塩
[4−(5−アミノメチル−2−フルオロ−フェニル)−ピペリジン−1−イル]−[7−フルオロ−1−(2−メトキシ−エチル)−4−トリフルオロメトキシ−1H−インドール−3−イル]−メタノン(265mg、0.52mmol)を20mLのガラスバイアル中に秤量した。この溶液に2:1(v/v)アセトニトリル/水に溶解させたクエン酸溶液(0.158mmol/mlクエン酸3.30mL)を加えた。全ての固体が素早く溶解し、得られた無色の溶液を室温で1時間置いておいた。溶液を窒素ガス流の元でエバポレートし、その後室温の減圧下で乾燥させた。固体を最小限の量の水を加えた温アセトニトリル中で再結晶化させて無色の溶液を得た。冷却するとその溶液に、室温に置いておくとプレート状にに変形するような非常に長い繊維の粒子状の生成物が沈殿した。Mp 112℃.赤外線スペクトルの項目(cm−1):1721、1590、1553、1369、1245、1174、1155、1119。
式Iの化合物のメタンスルホン酸塩
[4−(5−アミノメチル−2−フルオロ−フェニル)−ピペリジン−1−イル]−[7−フルオロ−1−(2−メトキシ−エチル)−4−トリフルオロメトキシ−1H−インドール−3−イル]−メタノン(0.250g、0.489mmol)を20mLのガラスバイアル中に秤量した。水に溶解させたメタンスルホン酸(0.50mmol/ml溶液0.98mL)を加え、その混合物を攪拌しながら60℃まで加熱した。全ての固形物が溶解したわけではないが、さらに25mlのメタンスルホン酸溶液を加えて透明な溶液を得た。室温で1時間攪拌した後、溶液を、ロータリーエバポレーターにより減圧下でエバポレートして非常に粘性のオイルを得た。このオイルを、アセトニトリル中で正方形プレートに再結晶化させた。赤外線スペクトルの項目(cm−1):1596、1540、1214、1159、1112、1040、1020.
式Iの化合物の酒石酸塩
[4−(5−アミノメチル−2−フルオロ−フェニル)−ピペリジン−1−イル]−[7−フルオロ−1−(2−メトキシ−エチル)−4−トリフルオロメトキシ−1H−インドール−3−イル]−メタノン(0.250g、0.554mmol)を、20mLのガラスバイアル中に秤量した。5:1(v/v)アセトニトリル/水に溶解させたL−(+)−酒石酸溶液2.66mmol/mlを調製し、0.2084mLのこの溶液を秤量した固体に加え、攪拌しながら60℃まで加熱して透明の溶液を得た。その後この溶液を、ロータリーエバポレーターを用いて減圧下でエバポレートして温酢酸イソプロピル中で再結晶化したガラス状の固形物を分離し、そこに最小限の量のイソプロパノールを加えて透明な溶液を得た。濾過によって単離した結晶生成物を冷却し、室温にて減圧下で乾燥させた。
式Iの化合物のリン酸塩
[4−(5−アミノメチル−2−フルオロ−フェニル)−ピペリジン−1−イル]−[7−フルオロ−1−(2−メトキシ−エチル)−4−トリフルオロメトキシ−1H−インドール−3−イル]−メタノン(133.9mg、0.262mmol)に、リン酸溶液(1mmole/mL イソプロパノールに溶解、1.1当量)を加えた。この混合物を、マグネットスターラーを用いて攪拌しながら500μLのイソプロパノールに室温で溶解させた。この物質をエバポレートして室温で乾燥させ、結晶性の物質は単離されなかった。この物質を500μLのアセトン、500μLの酢酸エチル、および1mLのヘプタンに再溶解させた。この物質をオイルとして分離した。この混合物をエバポレートして窒素流下で乾燥させた。一旦乾燥させ、酢酸エチル(500μL)およびトルエン(500μL)を加え、その物質をオイルとして分離した。この混合物をエバポレートして一晩室温で乾燥させた。メチルイソブチルケトン(1mL)およびトルエン(500μL)を加え、その物質を溶解させた。混合物を室温で一晩エバポレートした。結晶が出現し、室温での減圧濾過により、回収した。物質を室温での減圧オーブン(300mbar)中で一晩乾燥させた。
式Iの化合物のグルタミン酸塩
[4−(5−アミノメチル−2−フルオロ−フェニル)−ピペリジン−1−イル]−[7−フルオロ−1−(2−メトキシ−エチル)−4−トリフルオロメトキシ−1H−インドール−3−イル]−メタノン(138.8mg、0.271mmol)、グルタミン酸溶液(162.4mg/20mL(水に溶解)、1.1当量)を加えた。メタノール(2mL)を加えて物質を溶解させた。その混合物を室温で一晩エバポレートし、白色のアモルファス物質が沈殿した。その物質にイソプロパノール(600μL)をく加えた。結晶が出現し、それを室温にて減圧濾過により回収した。物質を減圧オーブン(約300mbar)中で一晩乾燥させた。
式Iの化合物の安息香酸塩の結晶形態
サンプル準備:材料を上記の参考実施例3のように準備した。安息香酸塩の懸濁液をナノピュアウオーター中に50mg/mLの遊離塩基当量(1mLの水中に63.6mgの塩)として調製した。サンプルを500rpmで一晩攪拌し、4時間放置したのち遠心分離した(懸濁として計29時間)。13000rpmで8分間遠心分離し、回収した固体を、湿潤サンプルとしてXRPD(x−ray power diffraction)で分析し、顕微鏡で評価した。その後この湿潤固体を周囲室温で一晩空気乾燥し、乾燥サンプルとしてXRPDおよび熱分析により分析した。そのままの薬物物質を初期の物質と比較した。遊離塩基薬物物質のXRPDもまた比較として用いた。XRPDが水量の異なる複数のピークを示しており、出現した安息香酸塩は可変の水和物であると考えられる。
XRPD法
Cu対陰極を備えるジーメンスモデル D5000
プログラム:1.0 Sec.dql
範囲:2°〜40°.2−θスケール
工程サイズ:0.02°
雰囲気:周囲条件の温度および湿度
標準的なトップロード、低容量のキャビティー試験片マウントを用いた
TA Instruments Model Q−600 Simultaneous
DSC−TGA
パージガス:ヘリウム100mL/分
温度プログラム:10℃/分 線形加熱速度
サンプル準備:約3−5mgの粉末を開口アルミニウムパンに移し、TGA中にロードした。空のアルミニウムパンを参照として用いた。
XRPDおよび熱分析を湿潤および乾燥サンプルで実施した。湿潤サンプルのXRPDは、ベースラインのいくらかのシフトと上昇を示した。しかし乾燥(一晩)サンプルでは、XRPDは、初期の物質と比較してピークの向上した分解を示した。乾燥サンプルの熱分析は、初期と同じTGAプロフィールを示した。XRPDおよび熱分析に基づいて、遊離塩基または水和物形態への転換は報告されなかった。遊離塩基のXRPDより、以下を得た:
本発明の化合物の特性は、1)そのβ−トリプターゼ阻害能力(IC50およびKi値)によって証明される。
背景技術の章に記載されたように、トリプターゼの全ての作用がその触媒活性に依存しているので、その触媒活性を阻害する化合物は、トリプターゼの作用を強力に阻害する。この触媒活性の阻害は、インビトロの酵素アッセイおよび細胞アッセイにより測定される。
化合物は2連で、以下の最終濃度:0.01、0.03、0.1、0.3、1、3、10μMで添加することを除いて、プロトコルは本質的に上記と同様である(全ての希釈は手作業で行なう)。各アッセイについて、一点測定またはIC50測定のいずれにおいても、標準化合物を使用して、比較のためのIC50を導く。IC50値から、式:Ki=IC50/(1+[基質]/Km)を使用して、Kiを計算し得る。
抗原感作およびチャレンジ:雄のHartleyモルモット(225〜250g)をオボアルブミン(1%溶液0.5mL、i.p.およびs.c.)で1日目(8/25/08)に感作した。4日目(8/28/08)に、動物は1%オボアルブミン(0.5mL)のブースタ注射を受けた(i.p.)。21日目(09/16/08)に、抗原チャレンジの24時間前に、動物にビヒクル(0.5%メチルセルロース/0.2%Tween 80)または試験化合物のいずれかを経口投薬した(2mL/kg)。また、抗原チャレンジの30分前に、動物にメピラミン(10mg/kg、i.p.)を注射し、アナフィラキシー性の衰弱(anaphylactic collapse)を予防した。次いで、動物を、DeVilbiss Ultranebネブライザーを使用して、1%オボアルブミンのエアロゾルに20分間暴露させた。ネガティブコントロールの動物はチャレンジしなかった。感作溶液:鶏卵白(Sigma A55031G;lot#087K7004)由来のアルブミン1gを100mLの生理食塩水に加え、溶液中に入れた。
Claims (59)
- 薬学的に受容可能な塩としての請求項1に記載の化合物。
- 薬学的に受容可能な塩が以下:
塩酸塩、フマル酸塩、ベシル酸塩、トシラート、硫酸塩、クエン酸塩、メタンスルホン酸塩、酒石酸塩、リン酸塩、グルタミン酸塩および安息香酸塩から選択される、請求項2に記載の化合物。 - 塩が塩酸塩である、請求項3に記載の化合物。
- 塩がフマル酸塩である、請求項3に記載の化合物。
- 塩がベシル酸塩である、請求項3に記載の化合物。
- 塩がトシラートである、請求項3に記載の化合物。
- 塩が硫酸塩である、請求項3に記載の化合物。
- 塩がクエン酸塩である、請求項3に記載の化合物。
- 塩がメタンスルホン酸塩である、請求項3に記載の化合物。
- 塩が酒石酸塩である、請求項3に記載の化合物。
- 塩がリン酸塩である、請求項3に記載の化合物。
- 塩がグルタミン酸塩である、請求項3に記載の化合物。
- 塩が安息香酸塩である、請求項3に記載の化合物。
- 請求項14に記載の化合物の結晶形態A。
- 結晶形態が、以下:7.75、10.13、17.03、17.16、18.39、21.33、および21.88のθ角のうち少なくとも2つにおいてXRPDピークを有する、請求項14に記載の化合物の結晶形態。
- 結晶形態が、以下:7.75、10.13、17.03、17.16、18.39、21.33、および21.88の角度のうち少なくとも3つにおいてXRPDピークを有する、請求項16に記載の化合物の結晶形態。
- 結晶形態が、以下:7.75、10.13、17.03、17.16、18.39、21.33、および21.88の角度のうち少なくとも4つにおいてXRPDピークを有する、請求項17に記載の化合物の結晶形態。
- 結晶形態が、以下:7.75、10.13、17.03、17.16、18.39、21.33、および21.88の角度のうち少なくとも5つにおいてXRPDピークを有する、請求項18に記載の化合物の結晶形態。
- 結晶形態は162℃で溶解する、請求項14に記載の化合物の結晶形態。
- トリプターゼインヒビターの改善が必要な生理学的症状を罹患しているかまたは罹患しやすい患者を治療する方法であって、治療有効量の請求項1の化合物を該患者に投与することを包含する、方法。
- 生理学的症状が、炎症性疾患、関節軟骨崩壊疾患、結膜炎、春季結膜炎、炎症性腸疾患、喘息、アレルギー性鼻炎、間質性肺炎、線維症、慢性閉塞性肺疾患、強皮症、肺線維症、肝硬変、心筋線維症、神経線維腫、肥厚性瘢痕、皮膚科的症状、アテローム動脈硬化性プラーク破壊に関連する症状、歯周病、糖尿病性網膜症、腫瘍増殖、過敏症、多発性硬化症、消化性潰瘍および合胞体ウイルス感染からなる群から選択される、請求項21に記載の方法。
- 生理学的症状が炎症性疾患である、請求項22に記載の方法。
- 炎症性疾患が、関節の炎症、炎症性腸疾患、関節炎、関節リウマチ、リウマチ様脊椎炎、痛風性関節炎、外傷性関節炎、風疹関節炎、乾癬性関節炎、喘息または変形性関節症である、請求項23に記載の方法。
- 炎症性疾患が炎症性腸疾患である、請求項22に記載の方法。
- 生理学的症状がCOPDである、請求項22に記載の方法。
- 生理学的症状が喘息である、請求項24に記載の方法。
- 生理学的症状が皮膚科的症状である、請求項22に記載の方法。
- 皮膚科的症状が、過敏性皮膚炎、乾癬および湿疹より選択される、請求項28に記載の方法。
- 皮膚科的症状が過敏性皮膚炎である、請求項29に記載の方法。
- 皮膚科的症状が乾癬である、請求項29に記載の方法。
- 喘息を患っている患者を治療する方法であって、治療有効量の請求項1に記載の化合物ならびにβアドレナリン作用性アゴニスト、抗コリン作用薬、抗炎症性コルチコステロイド、ロイコトリエン受容体アンタゴニスト、リポキシゲナーゼインヒビター、ホスホジエステラーゼ−4 インヒビター、および抗炎症薬からなる群から選択される第二の化合物との組み合わせを患者に投与することを包含する、方法。
- 投与が、請求項1に記載の化合物が血漿と比較して肺組織に優先的に拡散するようなものである、請求項32に記載の方法。
- 治療有効量の請求項1に記載の化合物およびその薬学的に受容可能な担体を含有する医薬組成物。
- βアドレナリン作用性アゴニスト、抗コリン作用薬、抗炎症性コルチコステロイド、ロイコトリエン受容体アンタゴニスト、リポキシゲナーゼインヒビター、ホスホジエステラーゼ−4 インヒビターおよび抗炎症薬からなる群より選択される治療有効量の第二の化合物をさらに含む、請求項34に記載の医薬組成物。
- 第二の化合物がβアドレナリン作用性アゴニストである、請求項35に記載の医薬組成物。
- βアドレナリン作用性アゴニストが、アルブテロール、テルブタリン、ホルモテロール、フェノテロール、またはプレナリンより選択される、請求項36に記載の医薬組成物。
- 第二の化合物が抗コリン作用薬である、請求項35に記載の医薬組成物。
- 抗コリン作用薬が臭化イプラトロピウムまたはチオトロピウムである、請求項38に記載の医薬組成物。
- 第二の化合物が抗炎症性コルチコステロイドである、請求項35に記載の医薬組成物。
- 抗炎症性コルチコステロイドが、ベクロメタゾンジプロピオネート、トリアムシノロンアセトニド、フルニソリド、プロピオン酸フルチカゾン、フロ酸モメタゾン、メチルプレドニゾン、プレドニゾロンおよびデキサメタゾンより選択される、請求項40に記載の医薬組成物。
- 第二の化合物が抗炎症薬である、請求項35に記載の医薬組成物。
- 抗炎症薬が、クロモグリク酸ナトリウムまたはネドクロミルナトリウムである、請求項42に記載の医薬組成物。
- ロイコトリエンアンタゴニストがモンテルカストである、請求項35に記載の医薬組成物。
- ホスホジエステラーゼ−4 インヒビターがロフルミラストおよびシフルモラストより選択される、請求項35に記載の医薬組成物。
- 鈴木カップリング条件下で3−ブロモ−4−フルオロベンジルアミン塩酸塩とピリジン−4−ボロン酸をカップリングして、2,2,2−トリフルオロ−N−(4−フルオロ−3−ピリジン−4−イル−ベンジル)−アセトアミド塩酸塩を得ることを含む、請求項2に記載の2,2,2−トリフルオロ−N−(4−フルオロ−3−ピリジン−4−イル−ベンジル)−アセトアミド塩酸塩の製造方法。
- 鈴木カップリング条件は、少なくともi−プロピルアルコールの沸点を持つアルコール性溶媒、極性非プロトン生溶媒、もしくはエーテル溶媒、または前出の溶媒と水もしくはトルエンの任意の混合物から選択される鈴木カップリング溶媒を用いる、請求項4に記載の方法。
- 鈴木カップリング溶媒は、少なくともi−プロピルアルコールの沸点を持つアルコール性溶媒である、請求項5に記載の方法。
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