JP4426756B2 - Novel neurokinin antagonist, process for producing the same and pharmaceutical composition - Google Patents
Novel neurokinin antagonist, process for producing the same and pharmaceutical composition Download PDFInfo
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- JP4426756B2 JP4426756B2 JP2002536049A JP2002536049A JP4426756B2 JP 4426756 B2 JP4426756 B2 JP 4426756B2 JP 2002536049 A JP2002536049 A JP 2002536049A JP 2002536049 A JP2002536049 A JP 2002536049A JP 4426756 B2 JP4426756 B2 JP 4426756B2
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- 238000000034 method Methods 0.000 title claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 title description 4
- 239000002462 tachykinin receptor antagonist Substances 0.000 title description 2
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- -1 1,3-dihydroxyprop-2-yl Chemical group 0.000 claims description 38
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- 239000001257 hydrogen Substances 0.000 claims description 13
- 230000002265 prevention Effects 0.000 claims description 13
- 238000006243 chemical reaction Methods 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- 150000001408 amides Chemical class 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 150000002367 halogens Chemical class 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
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- 229940079593 drug Drugs 0.000 claims description 2
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
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Description
【０００１】
本発明は、下記式I
【０００２】
【化９】
（式中、Ar、R1、R2、R3及びR4は特許請求の範囲に示された意味を有する。）
を有する新規な化合物、その製法及び医薬組成物としての使用、又はその薬学的に許容しうる塩、その製法及び医薬組成物に関する。これらの化合物は有効なニューロキニン（タキキニン）拮抗剤である。
【０００４】
発明の背景
式Ｉの化合物は、国際出願第９７／３２８６５号の一般式に一部分は包含されている。しかしながら、これには、４位のピペリジル基が３−ヒドロキシプロピルアミノ基、シクロアルキルメチルアミノ基又は１，３−ジヒドロキシプロプ−２−イルアミノ基で置換されている化合物が開示されていない。その国際特許出願に記載された化合物は、広範囲の活性を有する非常に有効なニューロキニン拮抗剤である。
本発明の課題は、長時間の活性を有する新規なニューロキニン拮抗剤を提供することである。ここでは式Ｉの新規な化合物の調製による本発明に従ってこの課題を解決する。
【０００５】
発明の詳細な説明
驚くべきことに、下記式A
【０００６】
【化１０】
（式中、Ｒ1は３−ヒドロキシプロピル、１，３−ジヒドロキシプロプ−２−イル又はＣ3−Ｃ6シクロアルキルメチルであり、
Ｒ2は水素、Ｃ1−Ｃ6アルキル、ω−ヒドロキシ−Ｃ2−Ｃ4アルキル、１，３−ジヒドロキシプロプ−２−イル又はＣ3−Ｃ6シクロアルキルメチルである。）
を有するアミノ基をそれらの化合物に挿入した場合に、ＮＫ1受容体拮抗剤の活性時間が劇的に持続し得ることがわかった。
それ故、本発明は、ニューロキニン仲介疾患の治療や予防に長時間の活性を有する薬剤を調製するための下記式Ａ
【０００８】
【化１１】
（式中、Ｒ1は３−ヒドロキシプロピル、１，３−ジヒドロキシプロプ−２−イル又はＣ3−Ｃ6シクロアルキルメチルであり、
Ｒ2は水素、Ｃ1−Ｃ6アルキル、ω−ヒドロキシ−Ｃ2−Ｃ4アルキル、１，３−ジヒドロキシプロプ−２−イル又はＣ3−Ｃ6シクロアルキルメチルである。）
を有するアミノ基を含むＮＫ1受容体拮抗剤の使用に関する。
本発明は、更に、下記一般式Ｉ
【００１０】
【化１２】
（式中、Ｒ1は３−ヒドロキシプロピル、１，３−ジヒドロキシプロプ−２−イル又はＣ3−Ｃ6シクロアルキルメチルであり、
Ｒ2は水素、Ｃ1−Ｃ6アルキル、ω−ヒドロキシ−Ｃ2−Ｃ4アルキル、１，３−ジヒドロキシプロプ−２−イル又はＣ3−Ｃ6シクロアルキルメチルであり、
Ａｒは無置換フェニル又はハロゲン、ヒドロキシ、Ｃ1−Ｃ4アルキル、Ｃ1−Ｃ4アルコキシ、Ｃ1−Ｃ4フルオロアルキル、Ｃ1−Ｃ4フルオロアルコキシ又は−ＯＣＨ2Ｏ−で１〜５置換されたフェニルであり、
Ｒ3はフェニル−Ｃ1−Ｃ4アルキルであり、ここで、フェニル基は１〜３個の置換基で置換されていてもよく、その置換基は各々独立してハロゲン、ヒドロキシ、Ｃ1−Ｃ4アルキル、Ｃ1−Ｃ4アルコキシ、Ｃ1−Ｃ4フルオロアルキル又はＣ1−Ｃ4フルオロアルコキシより選ばれ、
Ｒ4は水素、Ｃ1−Ｃ4アルキル、Ｃ3−Ｃ8シクロアルキル、ＣＨ2ＣＯＯＨ、−ＣＨ2Ｃ（Ｏ）ＮＨ2、−ＯＨ又はフェニル−Ｃ1−Ｃ4アルキルである。）
を有する新規な化合物又はその薬学的に許容しうる塩に関する。
【００１２】
上記及び下記にR1、R2、R3、R4の基又はAr基の置換基に対して用いられる“アルキル”や“アルコキシ”という用語は、炭素原子6個まで、好ましくは炭素原子1〜4個を有する直鎖又は分枝鎖飽和炭化水素基、特にメチル、エチル、n-プロピル、i-プロピル、n-ブチル、tert-ブチル、メトキシ、エトキシ、n-プロポキシ又はi-プロポキシである。
上記及び下記にR1、R2、R3又はR4に対して用いられる“シクロアルキル”という用語は、炭素原子8個まで、好ましくは炭素原子3〜6個を有するシクロアルキル基、特にシクロプロピル、シクロペンチル又はシクロヘキシルである。
上記及び下記にR3の基又はArの置換基に対して用いられる“フルオロアルキル”や“フルオロアルコキシ”という用語は、炭素原子4個までとフッ素原子9個まで、好ましくは炭素原子1〜2個とフッ素原子5個までを有する直鎖又は分枝鎖フッ素置換炭化水素基、特にトリフルオロエチル、ペンタフルオロエチル、2,2,2-トリフルオロエチル、2-フルオロエチル、ジフルオロメトキシ、トリフルオロメトキシ、ペンタフルオロエトキシ、2,2,2-トリフルオロエトキシ又は2-フルオロエトキシである。
【００１３】
本発明の化合物は、サブスタンスP拮抗特性を有する有効なニューロキニン（タキキニン）拮抗剤である。本発明の化合物は、ニューロキニン仲介疾患の治療や予防に用いられ、更に持続作用を有する。
一般式Iの化合物は、酸性基、主にカルボキシル基、及び/又は塩基性、例えば、アミノ官能基を有してもよい。それ故、一般式Iの化合物は、内部塩、薬学的に使用できる無機酸、例えば、塩酸、硫酸、リン酸、スルホン酸又は有機酸 (例えば、マレイン酸、フマル酸、クエン酸、酒石酸又は酢酸) との塩又は薬学的に使用できる塩基、例えば、アルカリ又はアルカリ土類金属水酸化物又は炭酸塩、水酸化亜鉛又は水酸化アンモニウム又は有機アミン、例えば、ジエチルアミン、トリエチルアミン、トリエタノールアミンとの塩の形であってもよい。
本発明の化合物はラセミ体として存在することもでき、純粋なエナンチオマー、即ち、(R)体又は(S)体として得ることもできる。ラセミ体又は(S)体として存在する化合物が好ましい。
【００１４】
本発明の化合物は、サブスタンスP拮抗特性を有する有効なニューロキニン（タキキニン）である。本発明の化合物は下記のニューロキニン仲介疾患の治療や予防に用いられる。即ち、
気管支の炎症やアレルギーの病訴、例えば、喘息、慢性気管支炎、過敏性気管支、気腫、鼻炎、COPD、肺高血圧症、嚢胞性線維症、咳嗽の治療又は予防;
結膜炎や虹彩炎の眼の治療又は予防;
接触性湿疹の皮膚炎、神経皮膚炎、そう痒、蕁麻疹、乾癬、日焼け、火傷、虫刺症、酒さ、痒疹、敏感性又は過敏性皮膚のような皮膚の治療又は予防;
胃潰瘍や十二指腸潰瘍、潰瘍性大腸炎、クローン病、炎症性腸疾患、過敏性大腸、ヒルシュスプルング病、固有運動性の問題のような胃腸管の治療又は予防;
慢性関節リウマチ、反応性関節炎、関節制動、骨粗鬆症又はライター症候群のような関節又は骨の治療又は予防;
刺激性膀胱、失禁、尿意逼迫、尿道炎、仙痛もしくは膀胱炎、又はレストレスレッグ症候群のような膀胱の治療又は予防。
また、痴呆、アルツハイマー病、精神分裂病、精神病、不安状態、アルコール又は薬物依存症、性機能障害、摂食障害、うつ病、頭痛（例えば、偏頭痛又は緊張頭痛）、てんかん、パーキンソン病、卒中のような中枢神経系の治療又は予防;帯状疱疹や皮疹消退後の疼痛、腫瘍、膠原病、輸尿管の機能障害、痔、吐気や嘔吐、放射線治療又は細胞増殖抑制治療又は運動等による誘発、又はすべての種類の疼痛症状の治療。
【００１５】
活性が持続することから、本発明の化合物はCOPD又は不安状態が随伴するうつ病の治療及び/又は予防に特に適している。
それ故、本発明は、化合物を含む治療剤や医薬製剤としての式Iの化合物の使用に関する。ヒトに用いることが好ましい。本発明の化合物は、静脈内、皮下、筋肉内、腹腔内、鼻内、吸入、文献から既知のイオン電気導入又は増強剤によって援助されてもよい経皮、又は経口経路により投与されてもよい。
非経口投与の場合、式Iの化合物又は生理的に許容しうる塩を可溶化剤、乳化剤又は他の補助剤のようなおそらく通例用いられる物質と共に溶液、懸濁液又は乳液にすることができる。適切な溶媒としては、水、生理的食塩水又はアルコール、例えば、エタノール、プロパンジオール又はグリセロール、糖液、例えば、グルコース又はマンニトール液又は種々の溶媒の混合物が挙げられる。
更に、本化合物は、植込剤、例えば、ポリアクチド、ポリグルコリド又はポリヒドロキシ酪酸の使用又は鼻内製剤によって投与することもできる。
R4がC1-C4アルキル、特にメチルである式Iの化合物が好ましい。
Arが無置換フェニル又は2,3-メチレンジオキシフェニル、特に無置換フェニルである式Iの化合物が好ましい。
式Iの好ましい化合物は、R3が2-フェニルエチルであり、ここで、フェニル基は1〜3個の置換基で置換されていてもよく、その置換基は各々独立してハロゲン、ヒドロキシ、メチル、メトキシ、トリフルオロメチル、トリフルオロメトキシより選ばれる化合物、特にR3が2-(3,5-ビストリフルオロメチルフェニル)エチルである化合物である。
式Iの特に好ましい化合物は、-NR3R4が下記基である化合物である。
【００１６】
【化１３】
好適態様においては、本発明は
Ｒ1がシクロプロピルメチル基であり、
Ｒ2が水素原子、Ｃ1−Ｃ3アルキル基又は３−ヒドロキシプロピル基である
式Ｉの化合物に関する。
他の好適態様においては、本発明は
Ｒ1が３−ヒドロキシプロピル基又は１，３−ジヒドロキシプロプ−２−イル基であり、
Ｒ2が水素原子、Ｃ1−Ｃ3アルキル基又は２−ヒドロキシエチル基である
式Ｉの化合物に関する。
下記式Ａ−１〜式Ａ−５より選ばれたアミノ基を有するＮＫ1受容体拮抗剤が特に好ましい。
【００１８】
【化１４】
次の化合物が特に好ましい。
【００２０】
【化１５】
【化１６】
【化１７】
これらの化合物は、それ自体既知の方法で調製することができる。
有利な方法を次の図で具体的に説明する。
式Iの化合物は、下記式II
【００２４】
【化１８】
（式中、Xは適切な脱離基、好ましくはハロゲン、アルキルスルホニルオキシ、特にメチルスルホニルオキシ、又はアリールスルホニルオキシ、特にp-トリルスルホニルオキシである。）
を有するアミドと下記一般式
【００２６】
【化１９】
を有するピペリジンとを塩基の存在下に不活性溶媒中で反応させることにより調製することができる。
Arがフェニルであり、R3がビス(トリフルオロメチル)フェニルエチルであり、R4がメチルである化合物を次の図1によってこの方法について具体的に説明する。しかしながら、この方法は式Iの化合物すべてについて同じように使用し得る。
まず、1位が保護された4-オキソピペリジンとR1とR2が式Iに示された意味を有する式R1R2NHのアミンとを反応させる。次の工程では、イミン基又はエナミン基の二重結合を複合還元剤、好ましくはアルカリ金属アラナート又はアルカリ金属ボラナート、特にナトリウムボラナート又はナトリウムトリアセトキシボロヒドリドで還元する。また、化合物(c)から出発して還元条件下に対応して置換されたケトンと反応させることによる第2還元的アミノ化により化合物(d)を得ることができる。特にホルムアルデヒドとギ酸によるアルキル化を還元することによりメチル基を導入することができる。
【００２８】
【化２０】
次に保護基を切断試薬で切断することにより、好ましくはBoc基の加水分解又はベンジル基の水素添加により無置換ピペリジン-Nをもつピペリジン誘導体が得られる。
このピペラジン誘導体の反応成分は図1の右側に示されるように得られる。(R)-マンデル酸とメタンスルホン酸ハライドとを反応させて(R)-2-(メタンスルホニルオキシ)酢酸を得る。次にこれをカップリング試薬と対応して置換されたフェネチルアミンとを反応させて対応するアミドを得るか、対応する(例えば、SOCl2/SO2Cl2で)に変換してから適切に置換されたフェネチルアミンで対応するアミドに変換する。最後の工程では、このようにして得られたアミドと上記ピペリジン誘導体とを反応させ、メタンスルホン酸の置換中にキラル中心の同時逆反応によりC-N架橋が起こる。反応は不活性溶媒、好ましくは極性非プロトン性溶媒、例えば、DMF、ジメチルアセトアミド、アセトン、エチルメチルケトン又はアセトニトリ中で塩基、好ましくは第三級アミン、例えば、TEA又はN-メチルモルホリン、又はアルカリ金属炭酸塩又はアルカリ金属水素炭酸塩、例えば、炭酸カリウムの存在下に20℃〜120℃の温度で行われる。反応時間は0.5時間〜48時間である。
ここで、本発明の化合物と組成物を次の実施例によって示す。当業者は、実施例が単に例示として役立つものであり限定するものとみなされるべきでないことを承知している。
【００３０】
A 本発明の化合物の合成の実施例
実施例1
N-[2-(3,5-ビストリフルオロメチルフェニル)エチル]-2-{4-[(3-ヒドロキシプロピル)メチルアミノ]ピペリジン-1-イル}-N-メチル-2-フェニルアセトアミド
a) 33 gの1-ベンジル-4-ピペリドンと15 gの3-アミノプロパノールを300 mlのトルエン中で触媒量のp-トルエンスルホン酸と合わせ、計算量の水が分離するまで水滴分離装置を用いて還流する。次にトルエンを留去し、残留物を250 mlのアルコールに溶解し、約5℃に冷却する。6.6 gのナトリウムボロヒドリドの全部を撹拌しながらバッチ式で添加し、周囲温度で30時間撹拌する。50 mlのアセトンを添加し、混合液を約30分間撹拌し、溶媒を減圧下で除去する。残留物を100 mlの水と合わせ、150 mlの塩化メチレンで2回抽出する。合わせた有機相を乾燥する。その混合液をろ過し、溶媒を減圧下で除去し、残留物を80 mlのアルコールに溶解し、40 mlの32% 塩酸と合わせ、アセトンで希釈し、約1時間撹拌する。沈殿した結晶を吸引ろ過し、乾燥する。1-ベンジル-4-(3-ヒドロキシプロピルアミノ)ピペリジンを二塩酸塩として得る。
【００３１】
b) 47.4 gの1-ベンジル-4-(3-ヒドロキシプロピルアミノ)ピペリジン二塩酸塩から塩基を遊離し、63 mlの85% ギ酸と22 mlの37% ホルムアルデヒド溶液と合わせ、約90〜100℃で2時間撹拌する。その混合液を冷却し、37 mlのギ酸と11 mlのホルムアルデヒド溶液を添加し、約100〜110℃で1時間撹拌する。その混合液を冷却し、150 mlのメタノールと合わせ、約270 mlの32% 水酸化ナトリウム溶液で冷却しながらアルカリ性にし、40〜50℃で約30分間撹拌し、次にメタノールを留去する。残留物を100 mlの塩化メチレンで2回抽出し、合わせた塩化メチレン相を乾燥し、ろ過し、溶媒を減圧下で除去する。残留物を80 mlのエタノールに溶解し、34 mlの32% 塩酸で酸性にし、100 mlのアセトンと合わせ、撹拌する。結晶が沈殿するやいなやアセトンを添加する。沈殿を吸引ろ過し、アセトンで洗浄し、乾燥する。42.8 gの1-ベンジル-4-[-(3-ヒドロキシプロピル)メチルアミノ]ピペリジン二塩酸塩を固形物として得る。
c) 42.8 gの1-ベンジル-4-[(3-ヒドロキシプロピル)メチルアミノ]ピペリジン二塩酸塩を450 mlのメタノールに溶解し、5 gの5% パラジウム/木炭と合わせ、約50℃で4〜5 barの圧力の水素により水素添加する。触媒をろ別し、メタノールを留去し、残留物をアセトンへ入れて撹拌する。エーテルを添加し、その混合液を約2時間放置してから吸引ろ過する。28.7 gの4-[(3-ヒドロキシプロピル)メチルアミノ]ピペリジン二塩酸塩を固形物として得る。
【００３２】
d) 9 gの4-[-(3-ヒドロキシプロピル)メチルアミノ]ピペリジン二塩酸塩を125 mlのDMFに14.5 gのN-[2-(3,5-ビストリフルオロメチルフェニル)エチル]-2-メタンスルホニルオキシ-N-メチル-2-フェニルアセトアミド(国際出願第99/62893号に記載された方法と同じように調製する)と共に溶解し、20.5 gの炭酸カリウムと合わせ、80〜90℃で約4時間撹拌する。冷却後、その混合液を氷に注ぎ、150 mlの酢酸エチルで2回抽出し、合わせた有機相を水で2回洗浄し、乾燥する。乾燥剤をろ別し、溶媒を減圧下で除去し、残留物を塩化メチレン/メタノール/濃アンモニア水95:5:0.5でシリカゲルによりクロマトグラフィー処理する。TLCで均一であることがわかった画分を合わせ、溶媒を減圧下で除去する。残留物の9.5 gをメタノールに溶解し、3.4 gのフマル酸と合わせる。次にメタノールを少量の残留物だけが残るまで留去し、アセトンを添加し、その混合液を約30分間撹拌する。沈殿した結晶を吸引ろ過し、アセトンとエーテルで洗浄し、乾燥する。9 gのN-2- N-[2-(3,5-ビストリフルオロメチルフェニル)エチル]-2-{4-[(3-ヒドロキシプロピル)メチルアミノ]ピペリジン-1-イル}-N-メチル-2-フェニルアセトアミドを無色のセスキフマル酸塩として得る、m.p. 139〜144℃。
1H-NMR (250 MHz, CD3OD) δ = 7,85 - 7,26 (8H, m); 6,71 (3H, s); 4,50; 4,49 (1H, 2s); 3,67 (2H, t, J = 6,0 Hz); 3,89 - 3,09 (7H, m); 3,21; 3,00 (4H, m);2,69; 2,94 (3H,); 2,77 (3H, s); 2,49 - 1,63 (6H, m); ほとんどのシグナルがアミド回転で分裂する。
(S)-N-[2-(3,5-ビストリフルオロメチルフェニル)エチル]-2-{4-[(3-ヒドロキシプロピル)メチルアミノ]ピペリジン-1-イル}-N-メチル-2-フェニルアセトアミドを(R)-N-[2-(3,5-ビストリフルオロメチルフェニル)エチル]-2-メタンスルホニルオキシ-N-メチル-2-フェニルアセトアミド (D-(-)-マンデル酸から調製)から出発して同じように得る。
【００３３】
実施例２
Ｎ−［２−（３，５−ビストリフルオロメチルフェニル）エチル］−２−［４−（２−ヒドロキシ−１−ヒドロキシメチルエチルアミノ）ピペリジン−１−イル］−Ｎ−メチル−２−フェニルアセトアミド
ａ） ２．７５ ｇの２−アミノプロパン−１，３−ジオールと５．９ ｇの１−ベンジル−４−ピペリドンを６０ ｍｌの塩化メチレンに溶解し、９．９ ｇのナトリウムトリアセトキシボロヒドリドの全部を氷で冷却しながらバッチ式で添加する。その混合液を周囲温度で一晩放置する。６０ ｍｌの塩化メチレンと少しの水を添加してから酸性反応が得られるまで氷で冷却しながら濃塩酸を添加する。その混合液を冷却しながら約１５分間撹拌し、４ Ｎ水酸化ナトリウム溶液でかなりアルカリ性にする。水相を分離し、有機相をごく少量の水で洗浄し、硫酸ナトリウムで乾燥し、溶媒を減圧下で除去する。８ ｇの物質が得られ、これを塩化メチレン／メタノール８：２で１５０ ｇのシリカゲルによりクロマトグラフィー処理する。ＴＬＣで均一であることがわかった画分を合わせ、溶媒を減圧下で除去する。７．３ ｇの１−ベンジル−４−（１，３−ジヒドロキシプロプ−２−イルアミノ）ピペリジンを得る。
ｂ） ３４．５ ｇの１−ベンジル−４−（１，３−ジヒドロキシプロプ−２−イルアミノ）ピペリジンを４００ ｍｌのメタノールに溶解し、３．４ ｇの２０％ パラジウム／木炭と合わせ、２４〜２８℃で２．２ ｂａｒの水素により水素添加する。次に触媒をろ別し、溶媒を減圧下で除去する。２２．７ ｇの４−（１，３−ジヒドロキシプロプ−２−イルアミノ）ピペリジンを油状物として得、これを精製せずに次の反応に用いる。
【００３４】
ｃ） ９ ｇの４−（１，３−ジヒドロキシプロプ−２−イルアミノ）ピペリジンと２２．７ ｇのＮ−［２−（３，５−ビストリフルオロメチルフェニル）エチル］−２−メタンスルホニルオキシ−Ｎ−メチル−２−フェニルアセトアミドとを１１０ ｍｌのＤＭＦ中で実施例１と同じように塩基として７．２ ｍｌのトリエチルアミン、６０〜７０℃で反応時間５時間を用いて反応させる。粗生成物をシリカゲルにより塩化メチレン／メタノール９：１を用いてクロマトグラフィー処理する。ＴＬＣで均一であることがわかった画分を合わせる。油状残留物を酢酸エチルと少量の水に溶解し、水相を水酸化ナトリウム濃縮溶液でアルカリ性にする。水相を分離し、有機相を乾燥し、溶媒を減圧下で除去する。残留物をメタンスルホン酸を用いてアセトン中で結晶化する。１１ ｇのＮ−２−（３，５− Ｎ−［２−（３，５−ビストリフルオロメチルフェニル）エチル］−２−［４−（２−ヒドロキシ−１−ヒドロキシメチルエチルアミノ）ピペリジン−１−イル］−Ｎ−メチル−２−フェニルアセトアミドを無色のメタンスルホン酸塩として得る。
1Ｈ−ＮＭＲ （２５０ ＭＨｚ， ＣＤ3ＯＤ） δ ＝ ７．９５ − ７．３１ （８Ｈ， ｍ）； ４．３７； ４．３１ （1Ｈ， ２ｓ）； ３．７７ （５Ｈ， ｍ）； ３．２８ （１Ｈ， ｍ）； ３．０５； ３．０１ （４Ｈ， ｍ）； ２．７４ （３Ｈ， ｓ）； ３．４５ − ２．０８ （４Ｈ， ｍ）； ２．０７ − １．５２ （４Ｈ， ｍ）． ほとんどのシグナルはアミド回転により分裂する。
（Ｓ）−Ｎ−［２−（３，５−ビストリフルオロメチルフェニル）エチル］−２−［４−（２−ヒドロキシ−１−ヒドロキシメチルエチルアミノ）ピペリジン−１−イル］−Ｎ−メチル−２−フェニルアセトアミドを（Ｒ）−Ｎ−［２−（３，５−ビストリフルオロメチルフェニル）エチル］−２−メタンスルホニルオキシ−Ｎ−メチル−２−フェニルアセトアミド （Ｄ−（−）−マンデル酸から調製）より出発して同じように得る。
【００３５】
実施例3
N-[2-(3,5-ビストリフルオロメチルフェニル)エチル]-2-[4-(シクロプロピルメチルメチルアミノ)ピペリジン-1-イル]-N-メチル-2-フェニルアセトアミド
a) 19 gの1-ベンジル-4-ピペリドンを150 mlの水中で10 gのラネーニッケル (メタノールで湿らせ、少量のメタノールですすぐ)と40 gのメチルアミンと合わせ、周囲温度で8時間5 barの水素によって水素添加する。次に触媒をろ別し、メタノールと過剰のメチルアミンを減圧下で除去する。その混合液を酢酸エチルで抽出し、有機相を硫酸ナトリウムで乾燥し、ろ過し、減圧下で蒸発により濃縮する。19.2 gの黄色油状物を得、これを精製せずに次の反応に用いる。
b) a)で調製した油状物としての18.9 gの1-ベンジル-4メチルアミノピペリジンを250 mlのメタノールに溶解し、8.3 gのシクロプロパンカルボキシアルデヒドと11.3 gのナトリウムシアノボロヒドリドと合わせる。その混合液を40〜50℃で5時間、次に周囲温度で約16時間撹拌する。次に2 N塩酸で酸性にし、減圧下で蒸発乾固し、残留物を水に溶解する。それをエーテルで洗浄し、水酸化ナトリウム濃縮溶液でアルカリ性にし、エーテル/酢酸エチルで抽出する。有機抽出液を硫酸ナトリウムで乾燥し、溶媒を減圧下で除去する。22.7 gの 1-ベンジル-4-(シクロプロピルメチルメチルアミノ)ピペリジンを黄色がかった油状物として得る。
c) b)で調製した21.5 gの油状物を230 mlのメタノールに溶解し、2.5 gの10% パラジウム/木炭と合わせ、60℃で5 barの水素によって水素添加する。3.5時間後、触媒を取り替え、80℃で5時間5 barの水素によって水素添加を続ける。次に触媒をろ別し、溶媒を減圧下で除去する。残留物からエタノール性塩酸を用いて二塩酸塩として4-(シクロプロピルメチルメチルアミノ)ピペリジンを沈殿する。次にそれをエーテルで洗浄し、減圧下で乾燥し、12.5 gの無色の結晶を得る。
【００３６】
d) 11.9 gの4-(シクロプロピルメチルメチルアミノ)ピペリジン二塩酸塩を400 mlのアセトンに溶解し、21.7 gのN-[2-(3.5-ビストリフルオロメチルフェニル)エチル]-2-メタンスルホニルオキシ-N-メチル-2-フェニルアセトアミドと21 mlのトリエチルアミンと合わせる。その混合液を16時間還流してから溶媒を減圧下で除去し、残留物を10% 炭酸水素ナトリウム溶液に溶解する。それをエーテルで抽出し、合わせた有機相を硫酸ナトリウムで乾燥し、溶媒を減圧下で除去する。残留物を酢酸エチル/メタノール/濃アンモニア水70:30:1でシリカゲルによりろ過し、溶媒を減圧下で除去し、メタノール中フマル酸で結晶化する。沈殿を吸引ろ過し、メタノールで洗浄し、減圧下で乾燥する。9.3 gのN-[2-(3,5-ビストリフルオロメチルフェニル)エチル]-2-[4-(シクロプロピルメチルメチルアミノ)ピペリジン-1-イル]-N-メチル-2-フェニルアセトアミドをセスキフマル酸塩として得る。
1H-NMR (250 MHz, CDCl3) δ = 7.71 - 7.14 (8H, m); 4.14 (1H, s); 3.81 - 2.46 (11H, m); 2.90; 2.82 (3H, 2s); 2.36 (3H, s); 2.23 - 1.48 (4H, m); 0.82 (1H, m); 0.48; 0.07 (4H, 2m). ほとんどのシグナルがアミド回転で分裂する。
(S)-N-[2-(3,5-ビストリフルオロメチルフェニル)エチル]-2-[4-(シクロプロピルメチルメチルアミノ)ピペリジン-1-イル]-N-メチル-2-フェニルアセトアミドを(R)-N-[2-(3,5-ビストリフルオロメチルフェニル)エチル]-2-メタンスルホニルオキシ-N-メチル-2-フェニルアセトアミド (D-(-)-マンデル酸から調製)から出発して同じように得る。
【００３７】
実施例4
N-[2-(3.5-ビストリフルオロメチルフェニル)エチル]-2-{4-[(2-ヒドロキシエチル)-(3-ヒドロキシプロピル)アミノ]ピペリジン-1-イル}-N-メチル-2-フェニルアセトアミド
a) 6 gの2-ヒドロキシエチル-3-ヒドロキシプロピルアミンと18,9 gの1-ベンジル-4-ピペリドンを250 mlのエンカメチレンに溶解し、0℃で21.2 gのナトリウムトリアセトキシボロヒドリドと合わせる。その混合液を周囲温度で一晩撹拌してから2 N塩酸で酸性にし、水酸化ナトリウム濃縮溶液でアルカリ性にする。それを塩化メチレンで抽出し、その抽出液を硫酸ナトリウムで乾燥し、溶媒を減圧下で除去する。残留物を酢酸エチル/メタノール/濃アンモニア水20:80:1でシリカゲルによりクロマトグラフィー処理する。TLCで均一であることがわかった画分を合わせ、溶媒を減圧下で除去する。2.3 gの 1-ベンジル-4-[(2-ヒドロキシエチル)-(3-ヒドロキシプロピル)アミノ]ピペリジンを油状物として得る。
b) 13.3 gの 1-ベンジル-4-[(2-ヒドロキシエチル)-(3-ヒドロキシプロピル)アミノ]ピペリジンを150 mlのメタノール中の1.5 gの10% パラジウム/木炭と合わせ、周囲温度で18時間5 barの水素によって水素添加する。次に触媒をろ別し、ろ液の溶媒を減圧下で除去する。4-[(2-ヒドロキシエチル)-(3-ヒドロキシプロピル)アミノ]ピペリジンを油状物として得、これを精製せずに次の反応に用いる。
【００３８】
c) b)で調製した6.4 gの4-[(2-ヒドロキシエチル)-(3-ヒドロキシプロピル)アミノ]ピペリジンの油状物を300 mlのアセトンに溶解し、13.8 gのN-[2-(3.5-ビストリフルオロメチルフェニル)エチル]-2-メタンスルホニルオキシ-N-メチル-2-フェニルアセトアミドと33 mlのトリエチルアミンと合わせ、6時間還流する。その混合液を冷却し、溶媒を減圧下で除去し、残留物を10% 炭酸水素ナトリウム溶液に入れて撹拌し、酢酸エチルで抽出する。合わせた有機相を硫酸ナトリウムで乾燥し、溶媒を減圧下で除去し、残留物を酢酸エチル/メタノール/濃アンモニア水20:80:1でシリカゲルによりクロマトグラフィー処理する。TLCで均一であることがわかった画分を合わせ、溶媒を減圧下で除去する。8.4 gのN-[2-(3,5-ビストリフルオロメチルフェニル)エチル]-2-{4-[(2-ヒドロキシエチル)-(3-ヒドロキシプロピル)アミノ]ピペリジン-1-イル}-N-メチル-2-フェニルアセトアミドを黄褐色油状物を得る; [α]D 20 = +29.6o.
1H-NMR (250 MHz, CDCl3) δ = 7.78 - 7.24 (8H, m); 4.24 (1H, s); 3.78 (2H, m); 3.61 (2H, m); 3.64 (1H, m); 2.98; 2.87 (3H, 2s); 2.93 (4H, m); 2.74; 2.65 (4H, 2m); 2.88 - 1.77 (4H, m); 1.67 (2H, m); 1.76 - 1.45 (4H, m). ほとんどのシグナルはアミド回転で分裂する。
【００３９】
実施例5
(S)-N-[2-(3.5-ビストリフルオロメチルフェニル)エチル]-2-{4-[シクロプロピルメチル-(3-ヒドロキシプロピル)アミノ]ピペリジン-1-イル}-N-メチル-2-フェニルアセトアミド
a) 16.5 gの3-アミノプロパノールと41.7 gの1-ベンジル-4-ピペリドンを350 mlの塩化メチレンに溶解し、56 gのナトリウムトリアセトキシボロヒドリドを約10℃で徐々に添加する。その混合液を周囲温度で一晩撹拌してから冷却しながら希塩酸で酸性にし、次に水酸化ナトリウム濃縮溶液でアルカリ性にする。有機相を分離し、水相を150 mlの塩化メチレンで1回以上洗浄する。合わせた有機相を硫酸ナトリウムで乾燥し、溶媒を減圧下で除去する。32 gの1-ベンジル-4-(3-ヒドロキシプロピルアミノ)ピペリジンを黄色油状物として得、これを精製せずに次の反応工程で用いる。
b) 前の反応からの13.4 gの1-ベンジル-4-(3-ヒドロキシプロピルアミノ)ピペリジンを3.8 gのシクロプロパンカルボキシアルデヒドと共に250 mlのメタノールに溶解し、0℃において5.1 gのナトリウムシアノボロヒドリドと合わせる。その混合液を周囲温度で一晩撹拌してから冷却しながら希塩酸で酸性にし、減圧下で濃縮乾固する。次にその混合液を水酸化ナトリウム濃縮溶液でアルカリ性にし、40 mlの塩化メチレンで3回抽出する。合わせた有機相を硫酸ナトリウムで乾燥し、ろ過し、溶媒を減圧下で除去する。残留物を酢酸エチル/メタノール/濃アンモニア水20:80:1でシリカゲルによりろ過する。溶媒を除去した後、10.2 gの1-ベンジル-4-[シクロプロピルメチル-(3-ヒドロキシプロピル)アミノ]ピペリジンを黄色油状物として得る。
【００４０】
c) 10.2 gの1-ベンジル-4-[シクロプロピルメチル-(3-ヒドロキシプロピル)アミノ]ピペリジンを100 mlのメタノール中の2 gの20 % パラジウム/木炭と合わせ、60℃で4時間5 barの水素によって水素添加する。触媒を分離し、溶媒を減圧下で除去し、7.3 gの4-[シクロプロピルメチル-(3-ヒドロキシプロピル)アミノ]ピペリジンを黄色油状物として得る。
d) 4.7 gの4-[シクロプロピルメチル-(3-ヒドロキシプロピル)アミノ]ピペリジンを9.6 gの(R)-N-[2-(3,5-ビストリフルオロメチルフェニル)エチル]-2-メタンスルホニルオキシ-N-メチル-2-フェニルアセトアミド(D-(-)-マンデル酸から調製)と3.4 mlのトリエチルアミンと200 mlのアセトン中65℃で4時間一緒に撹拌する。その混合液を減圧下で蒸発濃縮し、100 mlの炭酸水素ナトリウム飽和溶液と合わせ、酢酸エチルで抽出する。合わせた有機画分を硫酸ナトリウムで乾燥し、溶媒を減圧下で除去する。合わせた有機画分を硫酸ナトリウムで乾燥し、溶媒を減圧下で除去する。残留物を塩化メチレン/メタノール1:1でシリカゲルによりクロマトグラフィー処理する。TLCで均一であることがわかった画分を集め、溶媒を減圧下で除去する。5.5 gの(S)-N-[2-(3,5-ビストリフルオロメチルフェニル)エチル]-2-{4-[シクロプロピルメチル-(3-ヒドロキシプロピル)アミノ]ピペリジン-1-イル}-N-メチル-2-フェニルアセトアミドを褐色がかった黄色油状物として得る、[α]D 20 = +35.1o1H-NMR (250 MHz, CDCl3) δ = 7.78 - 7.26 (8H, m), 4.24 (1H, s), 3.78 (2H, m); 3.63 (2H, m); 3.50 (1H, m); 2.96; 2.88 (3H, 2s); 2.93 (4H, m); 2.88 - 1.77 (5H, m); 2.37 (2H, d, J = 6,0 Hz); 1.79 - 1.45 (6H, m); 0.87 (1H, m); 0.52; 0.12 (4H, 2m). ほとんどのシグナルがアミド回転で分裂する。
実施例6〜8の化合物を国際出願第99/62893号に記載される方法と同様の方法で或いは同じように調製する。
【００４１】
【化２１】
B 本発明の化合物の検討結果: 活性持続時間の定量
麻酔したモルモットにおける血圧の NK 1 誘発低下の阻害
モルモット(300〜500 g)をペントバルビタール(50 mg/kg i.p.)で麻酔し、試験物質の十二指腸投与と動脈血圧の測定のために整えた。NK1 作用剤(30分間隔で0.2μモル/kg)の静脈内投与により血圧の一時的な降下を誘発させた。基礎血圧を求めた後、試験物質を十二指腸経路で投与した。次にNK1作用剤を30分毎に6〜8時間投与した。結果を血圧のNK1 誘発低下の阻害% として表し、ED50値を回帰分析により計算した。
本発明の化合物を国際特許出願第97/32865号から既知の下記式の化合物と比較した。
【００４４】
【化２２】
これらの化合物は3-ヒドロキシプロピル基が2-ヒドロキシエチル基で置き換えられた実施例1と実施例4の化合物に対応する。
このようにして得られた結果を下記表Iに示す。
実施例 No. 活性持続時間 [min]
1 > 360
B-1 120
2 > 360
3 > 360
4 > 360
B-4 120
5 > 360
6 > 360
7 > 360
8 > 360
【００４６】
C 本発明の化合物の処方
注射用溶液
活性物質 * 200 mg
リン酸二水素一カリウム = KH2PO4 1.2 mg
リン酸水素二ナトリウム = NaH2PO4.2H2O 0.2 mg
(バッファー)
塩化ナトリウム (等張剤) 94 mg
又は
グルコース 520 mg
アルブミン （プロテアーゼ保護） 4 mg
水酸化ナトリウム溶液 適量
塩酸 pＨ 6まで 適量
注射用水 全量10 ml
【００４７】
注射用溶液
活性物質 * 200 mg
塩化ナトリウム 94 mg
又は
グルコース 520 mg
アルブミン 4 mg
水酸化ナトリウム溶液 適量
塩酸 pＨ 9まで 適量
注射用水 全量10 ml
凍結乾燥物
活性物質 * 200 mg
マンニトール（等張剤/増量剤） 520 mg
アルブミン 4 mg
凍結乾燥物用溶媒1
注射用水 10 ml
凍結乾燥物用溶媒2
Polysorbat(登録商標)80 = Tween(登録商標)80 20 mg
（界面活性剤）
注射用水 10 ml
* 活性物質: 本発明の化合物、例えば、実施例1〜8の1種
体重67 kgのヒトに対する投与量: 1〜500 mg[0001]
The present invention relates to the following formula I
[0002]
[Chemical 9]
(In the formula, Ar, R1, R2, RThreeAnd RFourHas the meaning indicated in the claims. )
The present invention relates to a novel compound having a compound, its production method and use as a pharmaceutical composition, or a pharmaceutically acceptable salt thereof, its production method and pharmaceutical composition. These compounds are effective neurokinin (tachykinin) antagonists.
[0004]
Background of the Invention
The compounds of formula I are partly included in the general formula of WO 97/32865. However, for this, the piperidyl group at position 4 is a 3-hydroxypropylamino group, a cycloalkylmethylamino group or1,3-dihydroxyprop-2-ylCompounds that are substituted with amino groups are not disclosed. The compounds described in that international patent application are highly effective neurokinin antagonists with a wide range of activities.
An object of the present invention is to provide a novel neurokinin antagonist having long-term activity. This problem is solved according to the invention by the preparation of the novel compounds of formula I.
[0005]
Detailed Description of the Invention
Surprisingly, the following formula A
[0006]
Embedded image
(Wherein R1Is 3-hydroxypropyl,1,3-dihydroxyprop-2-ylOr CThree-C6Cycloalkylmethyl,
R2Is hydrogen, C1-C6Alkyl, ω-hydroxy-C2-CFourAlkyl,1,3-dihydroxyprop-2-ylOr CThree-C6Cycloalkylmethyl. )
When an amino group having a hydrogen atom is inserted into these compounds, NK1It has been found that the activity time of receptor antagonists can last dramatically.
Therefore, the present invention provides the following formula A for preparing a drug having long-term activity in the treatment and prevention of neurokinin-mediated diseases.
[0008]
Embedded image
(Wherein R1Is 3-hydroxypropyl,1,3-dihydroxyprop-2-ylOr CThree-C6Cycloalkylmethyl,
R2Is hydrogen, C1-C6Alkyl, ω-hydroxy-C2-CFourAlkyl,1,3-dihydroxyprop-2-ylOr CThree-C6Cycloalkylmethyl. )
NK containing amino groups having1It relates to the use of receptor antagonists.
The present invention further provides the following general formula I
[0010]
Embedded image
(Wherein R1Is 3-hydroxypropyl,1,3-dihydroxyprop-2-ylOr CThree-C6Cycloalkylmethyl,
R2Is hydrogen, C1-C6Alkyl, ω-hydroxy-C2-CFourAlkyl,1,3-dihydroxyprop-2-ylOr CThree-C6Cycloalkylmethyl,
Ar is unsubstituted phenyl or halogen, hydroxy, C1-CFourAlkyl, C1-CFourAlkoxy, C1-CFourFluoroalkyl, C1-CFourFluoroalkoxy or -OCH2Phenyl substituted with 1 to 5 by O-
RThreeIs phenyl-C1-CFourAlkyl, wherein the phenyl group may be substituted with 1 to 3 substituents, each of which is independently halogen, hydroxy, C1-CFourAlkyl, C1-CFourAlkoxy, C1-CFourFluoroalkyl or C1-CFourSelected from fluoroalkoxy,
RFourIs hydrogen, C1-CFourAlkyl, CThree-C8Cycloalkyl, CH2COOH, -CH2C (O) NH2, -OH or phenyl-C1-CFourAlkyl. )
Or a pharmaceutically acceptable salt thereof.
[0012]
R above and below1, R2, RThree, RFourThe term “alkyl” or “alkoxy” used for the substituents of Ar or the Ar group is a straight-chain or branched saturated hydrocarbon group having up to 6 carbon atoms, preferably 1 to 4 carbon atoms. In particular methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl, methoxy, ethoxy, n-propoxy or i-propoxy.
R above and below1, R2, RThreeOr RFourThe term “cycloalkyl” used for is a cycloalkyl group having up to 8 carbon atoms, preferably 3 to 6 carbon atoms, in particular cyclopropyl, cyclopentyl or cyclohexyl.
R above and belowThreeThe terms “fluoroalkyl” or “fluoroalkoxy” used for the group of or the substituent of Ar are up to 4 carbon atoms and up to 9 fluorine atoms, preferably 1-2 carbon atoms and 5 fluorine atoms. A linear or branched fluorine-substituted hydrocarbon group having, in particular, trifluoroethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2-fluoroethyl, difluoromethoxy, trifluoromethoxy, pentafluoroethoxy, 2,2,2-trifluoroethoxy or 2-fluoroethoxy.
[0013]
The compounds of the present invention are effective neurokinin (tachykinin) antagonists having substance P antagonistic properties. The compounds of the present invention are used for the treatment and prevention of neurokinin-mediated diseases and have a sustained action.
The compounds of general formula I may have acidic groups, mainly carboxyl groups, and / or basic, for example amino functional groups. Therefore, compounds of general formula I can be used as internal salts, pharmaceutically usable inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, sulfonic acids or organic acids (e.g. maleic acid, fumaric acid, citric acid, tartaric acid or acetic acid). ) Or a pharmaceutically usable base such as an alkali or alkaline earth metal hydroxide or carbonate, zinc hydroxide or ammonium hydroxide or an organic amine such as diethylamine, triethylamine, triethanolamine It may be in the form of
The compounds of the present invention can exist as racemates, and can also be obtained as pure enantiomers, ie, (R) or (S). Compounds that exist as racemates or (S) isomers are preferred.
[0014]
The compounds of the present invention are effective neurokinins (tachykinins) having substance P antagonistic properties. The compounds of the present invention are used for the treatment and prevention of the following neurokinin-mediated diseases. That is,
Treatment or prevention of bronchial inflammation and allergy complaints, such as asthma, chronic bronchitis, irritable bronchitis, emphysema, rhinitis, COPD, pulmonary hypertension, cystic fibrosis, cough;
Treatment or prevention of eyes with conjunctivitis and iritis;
Treatment or prevention of skin like contact eczema dermatitis, neurodermatitis, pruritus, urticaria, psoriasis, sunburn, burns, insect bites, rosacea, urticaria, sensitive or sensitive skin;
Treatment or prevention of gastrointestinal tract such as gastric ulcer and duodenal ulcer, ulcerative colitis, Crohn's disease, inflammatory bowel disease, irritable colon, Hirschsprung's disease, intrinsic motility problems;
Treatment or prevention of joints or bones such as rheumatoid arthritis, reactive arthritis, joint braking, osteoporosis or Reiter syndrome;
Treatment or prevention of bladder such as irritation bladder, incontinence, urgency, urethritis, colic or cystitis, or restless legs syndrome.
Also, dementia, Alzheimer's disease, schizophrenia, psychosis, anxiety, alcohol or drug addiction, sexual dysfunction, eating disorders, depression, headache (eg migraine or tension headache), epilepsy, Parkinson's disease, stroke Treatment or prevention of central nervous system such as pain after herpes zoster or rash disappearance, tumor, collagen disease, ureteral dysfunction, sputum, nausea or vomiting, induction by radiation therapy or cytostatic therapy or exercise, or Treatment of all types of pain symptoms.
[0015]
Due to their sustained activity, the compounds of the invention are particularly suitable for the treatment and / or prevention of depression associated with COPD or anxiety.
The present invention therefore relates to the use of compounds of formula I as therapeutic agents or pharmaceutical formulations containing the compounds. It is preferably used for humans. The compounds of the invention may be administered by intravenous, subcutaneous, intramuscular, intraperitoneal, intranasal, inhalation, transdermal, which may be aided by iontophoresis or enhancement agents known from the literature, or by oral route. .
For parenteral administration, the compounds of formula I or physiologically acceptable salts can be made into solutions, suspensions or emulsions, possibly with commonly used substances such as solubilizers, emulsifiers or other adjuvants. . Suitable solvents include water, saline or alcohols such as ethanol, propanediol or glycerol, sugar solutions such as glucose or mannitol solutions or mixtures of various solvents.
In addition, the compounds can be administered by use of an implant, such as polyactide, polyglucolide or polyhydroxybutyric acid or by intranasal formulation.
RFourIs C1-CFourPreference is given to compounds of the formula I which are alkyl, in particular methyl.
Preference is given to compounds of the formula I in which Ar is unsubstituted phenyl or 2,3-methylenedioxyphenyl, in particular unsubstituted phenyl.
Preferred compounds of formula I are RThreeIs 2-phenylethyl, wherein the phenyl group may be substituted with 1 to 3 substituents, each of which is independently halogen, hydroxy, methyl, methoxy, trifluoromethyl, trimethyl. Compounds selected from fluoromethoxy, especially RThreeIs a compound wherein 2- (3,5-bistrifluoromethylphenyl) ethyl.
Particularly preferred compounds of formula I are -NRThreeRFourIs a compound having the following group.
[0016]
Embedded image
In a preferred embodiment, the present invention provides
R1Is a cyclopropylmethyl group,
R2Is a hydrogen atom, C1-CThreeAn alkyl group or a 3-hydroxypropyl group
Relates to compounds of formula I.
In another preferred embodiment, the present invention provides
R1Is a 3-hydroxypropyl group or1,3-dihydroxyprop-2-ylGroup,
R2Is a hydrogen atom, C1-CThreeAn alkyl group or a 2-hydroxyethyl group
Relates to compounds of formula I.
NK having an amino group selected from the following formulas A-1 to A-51Receptor antagonists are particularly preferred.
[0018]
Embedded image
The following compounds are particularly preferred:
[0020]
Embedded image
Embedded image
Embedded image
These compounds can be prepared by methods known per se.
The advantageous method is illustrated in the following figure.
The compound of formula I is represented by formula II
[0024]
Embedded image
Wherein X is a suitable leaving group, preferably halogen, alkylsulfonyloxy, especially methylsulfonyloxy, or arylsulfonyloxy, especially p-tolylsulfonyloxy.
An amide having the following general formula
[0026]
Embedded image
It can be prepared by reacting a piperidine having a base in the presence of a base in an inert solvent.
Ar is phenyl and RThreeIs bis (trifluoromethyl) phenylethyl and RFourThis method will be described in detail with reference to the following FIG. However, this method can be used in the same way for all compounds of formula I.
First, the 4-position protected 4-oxopiperidine and R1And R2Wherein R has the meaning indicated in Formula I.1R2React with NH amine. In the next step, the imine or enamine group double bond is reduced with a complex reducing agent, preferably an alkali metal alanate or alkali metal borinate, in particular sodium boranarate or sodium triacetoxyborohydride. Alternatively, compound (d) can be obtained by second reductive amination starting from compound (c) and reacting with a correspondingly substituted ketone under reducing conditions. In particular, methyl groups can be introduced by reducing alkylation with formaldehyde and formic acid.
[0028]
Embedded image
The protecting group is then cleaved with a cleaving reagent to give a piperidine derivative having an unsubstituted piperidine-N, preferably by hydrolysis of the Boc group or hydrogenation of the benzyl group.
The reaction component of this piperazine derivative is obtained as shown on the right side of FIG. (R) -Mandelic acid and methanesulfonic acid halide are reacted to give (R) -2- (methanesulfonyloxy) acetic acid. This is then reacted with a coupling reagent and a correspondingly substituted phenethylamine to give the corresponding amide or the corresponding (e.g. SOCI2/ SO2Cl2And then converted to the corresponding amide with an appropriately substituted phenethylamine. In the last step, the amide thus obtained is reacted with the piperidine derivative, and a CN bridge occurs by simultaneous reverse reaction of the chiral center during the substitution of methanesulfonic acid. The reaction is carried out in an inert solvent, preferably a polar aprotic solvent such as DMF, dimethylacetamide, acetone, ethyl methyl ketone or acetonitrile, preferably a tertiary amine such as TEA or N-methylmorpholine, or alkaline. It is carried out at a temperature of 20 ° C. to 120 ° C. in the presence of a metal carbonate or alkali metal hydrogen carbonate, for example potassium carbonate. The reaction time is 0.5 to 48 hours.
The compounds and compositions of the present invention are now illustrated by the following examples. Those skilled in the art are aware that the examples are merely illustrative and should not be considered limiting.
[0030]
A Examples of the synthesis of compounds of the invention
Example 1
N- [2- (3,5-Bistrifluoromethylphenyl) ethyl] -2- {4-[(3-hydroxypropyl) methylamino] piperidin-1-yl} -N-methyl-2-phenylacetamide
a) 33 g of 1-benzyl-4-piperidone and 15 g of 3-aminopropanol are combined with a catalytic amount of p-toluenesulfonic acid in 300 ml of toluene and the drop separator is used until the calculated amount of water has separated. Use to reflux. The toluene is then distilled off and the residue is dissolved in 250 ml of alcohol and cooled to about 5 ° C. 6.6 g of all sodium borohydride is added batchwise with stirring and stirred at ambient temperature for 30 hours. 50 ml of acetone is added, the mixture is stirred for about 30 minutes and the solvent is removed under reduced pressure. The residue is combined with 100 ml water and extracted twice with 150 ml methylene chloride. The combined organic phases are dried. The mixture is filtered, the solvent is removed under reduced pressure, the residue is dissolved in 80 ml of alcohol, combined with 40 ml of 32% hydrochloric acid, diluted with acetone and stirred for about 1 hour. The precipitated crystals are filtered off with suction and dried. 1-Benzyl-4- (3-hydroxypropylamino) piperidine is obtained as the dihydrochloride salt.
[0031]
b) Free the base from 47.4 g 1-benzyl-4- (3-hydroxypropylamino) piperidine dihydrochloride and combine with 63 ml 85% formic acid and 22 ml 37% formaldehyde solution, approx. For 2 hours. The mixture is cooled and 37 ml formic acid and 11 ml formaldehyde solution are added and stirred at about 100-110 ° C. for 1 hour. The mixture is cooled, combined with 150 ml of methanol, made alkaline with cooling with about 270 ml of 32% sodium hydroxide solution and stirred at 40-50 ° C. for about 30 minutes, then the methanol is distilled off. The residue is extracted twice with 100 ml of methylene chloride, the combined methylene chloride phases are dried, filtered and the solvent is removed under reduced pressure. Dissolve the residue in 80 ml ethanol, acidify with 34 ml 32% hydrochloric acid, combine with 100 ml acetone and stir. As soon as the crystals precipitate, add acetone. The precipitate is filtered off with suction, washed with acetone and dried. 42.8 g of 1-benzyl-4-[-(3-hydroxypropyl) methylamino] piperidine dihydrochloride is obtained as a solid.
c) 42.8 g of 1-benzyl-4-[(3-hydroxypropyl) methylamino] piperidine dihydrochloride is dissolved in 450 ml of methanol and combined with 5 g of 5% palladium / charcoal and mixed at about 50 ° C. for 4 hours. Hydrogenate with hydrogen at a pressure of ˜5 bar. The catalyst is filtered off, methanol is distilled off and the residue is stirred into acetone. Ether is added and the mixture is allowed to stand for about 2 hours and then suction filtered. 28.7 g of 4-[(3-hydroxypropyl) methylamino] piperidine dihydrochloride is obtained as a solid.
[0032]
d) 9 g 4-[-(3-hydroxypropyl) methylamino] piperidine dihydrochloride in 125 ml DMF 14.5 g N- [2- (3,5-bistrifluoromethylphenyl) ethyl] -2 -Methanesulfonyloxy-N-methyl-2-phenylacetamide (prepared as described in International Application No. 99/62893) and combined with 20.5 g potassium carbonate at 80-90 ° C. Stir for about 4 hours. After cooling, the mixture is poured onto ice and extracted twice with 150 ml of ethyl acetate, the combined organic phases are washed twice with water and dried. The drying agent is filtered off, the solvent is removed under reduced pressure and the residue is chromatographed on silica gel with methylene chloride / methanol / conc. Aqueous ammonia 95: 5: 0.5. Fractions found to be homogeneous by TLC are combined and the solvent is removed under reduced pressure. 9.5 g of the residue is dissolved in methanol and combined with 3.4 g of fumaric acid. The methanol is then distilled off until only a small amount of residue remains, acetone is added and the mixture is stirred for about 30 minutes. The precipitated crystals are filtered off with suction, washed with acetone and ether and dried. 9 g N-2-N- [2- (3,5-bistrifluoromethylphenyl) ethyl] -2- {4-[(3-hydroxypropyl) methylamino] piperidin-1-yl} -N-methyl -2-Phenylacetamide is obtained as a colorless sesquifumarate, mp 139-144 ° C.
1H-NMR (250 MHz, CDThreeOD) δ = 7,85-7,26 (8H, m); 6,71 (3H, s); 4,50; 4,49 (1H, 2s); 3,67 (2H, t, J = 6 , 0 Hz); 3,89-3,09 (7H, m); 3,21; 3,00 (4H, m); 2,69; 2,94 (3H,); 2,77 (3H, s ); 2,49-1,63 (6H, m); Most signals are split by amide rotation.
(S) -N- [2- (3,5-Bistrifluoromethylphenyl) ethyl] -2- {4-[(3-hydroxypropyl) methylamino] piperidin-1-yl} -N-methyl-2- Phenylacetamide prepared from (R) -N- [2- (3,5-bistrifluoromethylphenyl) ethyl] -2-methanesulfonyloxy-N-methyl-2-phenylacetamide (D-(-)-mandelic acid ) To get the same.
[0033]
Example 2
N- [2- (3,5-bistrifluoromethylphenyl) ethyl] -2- [4- (2-hydroxy-1-hydroxymethylethylamino) piperidin-1-yl] -N-methyl-2-phenylacetamide
a) 2.75 g 2-aminopropane-1,3-diol and 5.9 g 1-benzyl-4-piperidone dissolved in 60 ml methylene chloride, 9.9 g sodium triacetoxyborohydride Are added batchwise while cooling with ice. The mixture is left overnight at ambient temperature. Add 60 ml of methylene chloride and a little water and then add concentrated hydrochloric acid while cooling with ice until an acidic reaction is obtained. The mixture is stirred for about 15 minutes with cooling and made fairly alkaline with 4 N sodium hydroxide solution. The aqueous phase is separated, the organic phase is washed with a very small amount of water, dried over sodium sulfate and the solvent is removed under reduced pressure. 8 g of material is obtained, which is chromatographed on 150 g of silica gel with methylene chloride / methanol 8: 2. Fractions found to be homogeneous by TLC are combined and the solvent is removed under reduced pressure. 7.3 g of 1-benzyl-4- (1,3-dihydroxyprop-2-ylAmino) piperidine is obtained.
b) 34.5 g of 1-benzyl-4- (1,3-dihydroxyprop-2-ylAmino) piperidine is dissolved in 400 ml methanol, combined with 3.4 g 20% palladium / charcoal and hydrogenated with 2.2 bar hydrogen at 24-28 ° C. The catalyst is then filtered off and the solvent is removed under reduced pressure. 22.7 g of 4- (1,3-dihydroxyprop-2-ylAmino) piperidine is obtained as an oil which is used in the next reaction without purification.
[0034]
c) 9 g of 4- (1,3-dihydroxyprop-2-ylAmino) piperidine and 22.7 g N- [2- (3,5-bistrifluoromethylphenyl) ethyl] -2-methanesulfonyloxy-N-methyl-2-phenylacetamide were carried out in 110 ml DMF. The reaction is carried out as in Example 1, using 7.2 ml of triethylamine as the base at 60-70 ° C. with a reaction time of 5 hours. The crude product is chromatographed on silica gel using methylene chloride / methanol 9: 1. Fractions found to be uniform by TLC are combined. The oily residue is dissolved in ethyl acetate and a small amount of water, and the aqueous phase is made alkaline with concentrated sodium hydroxide solution. The aqueous phase is separated, the organic phase is dried and the solvent is removed under reduced pressure. The residue is crystallized in acetone using methanesulfonic acid. 11 g of N-2- (3,5-N- [2- (3,5-bistrifluoromethylphenyl) ethyl] -2- [4- (2-hydroxy-1-hydroxymethylethylamino) piperidine-1 -Il] -N-methyl-2-phenylacetamide is obtained as colorless methanesulfonate.
1H-NMR (250 MHz, CDThreeOD) [delta] = 7.95-7.31 (8H, m); 4.37; 4.31 (13.77 (5H, m); 3.28 (1H, m); 3.05; 3.01 (4H, m); 2.74 (3H, s); 3.45-2 .08 (4H, m); 2.07-1.52 (4H, m). Most signals are split by amide rotation.
(S) -N- [2- (3,5-bistrifluoromethylphenyl) ethyl] -2- [4- (2-hydroxy-1-hydroxymethylethylamino) piperidin-1-yl] -N-methyl- 2-Phenylacetamide is converted to (R) -N- [2- (3,5-bistrifluoromethylphenyl) ethyl] -2-methanesulfonyloxy-N-methyl-2-phenylacetamide (D-(-)-mandelic acid Starting from) and obtained in the same way.
[0035]
Example 3
N- [2- (3,5-Bistrifluoromethylphenyl) ethyl] -2- [4- (cyclopropylmethylmethylamino) piperidin-1-yl] -N-methyl-2-phenylacetamide
a) 19 g 1-benzyl-4-piperidone in 150 ml water combined with 10 g Raney nickel (moistened with methanol and rinsed with a small amount of methanol) and 40 g methylamine for 8 hours at ambient temperature 5 bar Hydrogenate with hydrogen. The catalyst is then filtered off and methanol and excess methylamine are removed under reduced pressure. The mixture is extracted with ethyl acetate and the organic phase is dried over sodium sulfate, filtered and concentrated by evaporation under reduced pressure. 19.2 g of a yellow oil is obtained, which is used in the next reaction without purification.
b) 18.9 g of 1-benzyl-4methylaminopiperidine as an oil prepared in a) is dissolved in 250 ml of methanol and combined with 8.3 g of cyclopropanecarboxaldehyde and 11.3 g of sodium cyanoborohydride. The mixture is stirred at 40-50 ° C. for 5 hours and then at ambient temperature for about 16 hours. Then acidify with 2 N hydrochloric acid, evaporate to dryness under reduced pressure and dissolve the residue in water. It is washed with ether, made alkaline with concentrated sodium hydroxide solution and extracted with ether / ethyl acetate. The organic extract is dried over sodium sulfate and the solvent is removed under reduced pressure. 22.7 g of 1-benzyl-4- (cyclopropylmethylmethylamino) piperidine are obtained as a yellowish oil.
c) 21.5 g of the oil prepared in b) is dissolved in 230 ml of methanol, combined with 2.5 g of 10% palladium / charcoal and hydrogenated at 60 ° C. with 5 bar of hydrogen. After 3.5 hours, the catalyst is replaced and the hydrogenation is continued with 5 bar of hydrogen at 80 ° C. for 5 hours. The catalyst is then filtered off and the solvent is removed under reduced pressure. 4- (Cyclopropylmethylmethylamino) piperidine is precipitated as dihydrochloride from the residue using ethanolic hydrochloric acid. It is then washed with ether and dried under reduced pressure to give 12.5 g of colorless crystals.
[0036]
d) 11.9 g of 4- (cyclopropylmethylmethylamino) piperidine dihydrochloride is dissolved in 400 ml of acetone and 21.7 g of N- [2- (3.5-bistrifluoromethylphenyl) ethyl] -2-methanesulfonyl Combine with oxy-N-methyl-2-phenylacetamide and 21 ml triethylamine. The mixture is refluxed for 16 hours, then the solvent is removed under reduced pressure and the residue is dissolved in 10% sodium bicarbonate solution. It is extracted with ether, the combined organic phases are dried over sodium sulphate and the solvent is removed under reduced pressure. The residue is filtered through silica gel with 70: 30: 1 ethyl acetate / methanol / conc. Aqueous ammonia, the solvent is removed under reduced pressure and crystallized with fumaric acid in methanol. The precipitate is filtered off with suction, washed with methanol and dried under reduced pressure. 9.3 g of N- [2- (3,5-bistrifluoromethylphenyl) ethyl] -2- [4- (cyclopropylmethylmethylamino) piperidin-1-yl] -N-methyl-2-phenylacetamide Obtained as the acid salt.
1H-NMR (250 MHz, CDClThree) δ = 7.71-7.14 (8H, m); 4.14 (1H, s); 3.81-2.46 (11H, m); 2.90; 2.82 (3H, 2s); 2.36 (3H, s); 2.23-1.48 (4H, m); 0.82 (1H, m); 0.48; 0.07 (4H, 2m). Most signals are split by amide rotation.
(S) -N- [2- (3,5-bistrifluoromethylphenyl) ethyl] -2- [4- (cyclopropylmethylmethylamino) piperidin-1-yl] -N-methyl-2-phenylacetamide Starting from (R) -N- [2- (3,5-bistrifluoromethylphenyl) ethyl] -2-methanesulfonyloxy-N-methyl-2-phenylacetamide (prepared from D-(-)-mandelic acid) And get the same way.
[0037]
Example 4
N- [2- (3.5-Bistrifluoromethylphenyl) ethyl] -2- {4-[(2-hydroxyethyl)-(3-hydroxypropyl) amino] piperidin-1-yl} -N-methyl-2- Phenylacetamide
a) 6 g 2-hydroxyethyl-3-hydroxypropylamine and 18,9 g 1-benzyl-4-piperidone are dissolved in 250 ml encamethylene and at 0 ° C. with 21.2 g sodium triacetoxyborohydride Match. The mixture is stirred overnight at ambient temperature, then acidified with 2N hydrochloric acid and made alkaline with concentrated sodium hydroxide solution. It is extracted with methylene chloride, the extract is dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is chromatographed on silica gel with ethyl acetate / methanol / conc. Aqueous ammonia 20: 80: 1. Fractions found to be homogeneous by TLC are combined and the solvent is removed under reduced pressure. 2.3 g of 1-benzyl-4-[(2-hydroxyethyl)-(3-hydroxypropyl) amino] piperidine is obtained as an oil.
b) 13.3 g of 1-benzyl-4-[(2-hydroxyethyl)-(3-hydroxypropyl) amino] piperidine is combined with 1.5 g of 10% palladium / charcoal in 150 ml of methanol and 18 ° C. at ambient temperature. Hydrogenate for 5 hours with hydrogen. The catalyst is then filtered off and the solvent of the filtrate is removed under reduced pressure. 4-[(2-Hydroxyethyl)-(3-hydroxypropyl) amino] piperidine is obtained as an oil and used in the next reaction without purification.
[0038]
c) 6.4 g of 4-[(2-hydroxyethyl)-(3-hydroxypropyl) amino] piperidine oil prepared in b) was dissolved in 300 ml of acetone and 13.8 g of N- [2- ( 3.5-bistrifluoromethylphenyl) ethyl] -2-methanesulfonyloxy-N-methyl-2-phenylacetamide and 33 ml of triethylamine and reflux for 6 hours. The mixture is cooled, the solvent is removed under reduced pressure, the residue is stirred in 10% sodium bicarbonate solution and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate, the solvent is removed under reduced pressure and the residue is chromatographed on silica gel with ethyl acetate / methanol / conc. Aqueous ammonia 20: 80: 1. Fractions found to be homogeneous by TLC are combined and the solvent is removed under reduced pressure. 8.4 g N- [2- (3,5-bistrifluoromethylphenyl) ethyl] -2- {4-[(2-hydroxyethyl)-(3-hydroxypropyl) amino] piperidin-1-yl} -N -Methyl-2-phenylacetamide gives a tan oil; [α]D 20 = +29.6o.
1H-NMR (250 MHz, CDClThree) δ = 7.78-7.24 (8H, m); 4.24 (1H, s); 3.78 (2H, m); 3.61 (2H, m); 3.64 (1H, m); 2.98; 2.87 (3H, 2s); 2.93 (4H, m); 2.74; 2.65 (4H, 2m); 2.88-1.77 (4H, m); 1.67 (2H, m); 1.76-1.45 (4H, m). Most signals are disrupted by amide rotation.
[0039]
Example 5
(S) -N- [2- (3.5-Bistrifluoromethylphenyl) ethyl] -2- {4- [cyclopropylmethyl- (3-hydroxypropyl) amino] piperidin-1-yl} -N-methyl-2 -Phenylacetamide
a) 16.5 g of 3-aminopropanol and 41.7 g of 1-benzyl-4-piperidone are dissolved in 350 ml of methylene chloride and 56 g of sodium triacetoxyborohydride are slowly added at about 10 ° C. The mixture is stirred overnight at ambient temperature, then acidified with dilute hydrochloric acid while cooling and then made alkaline with concentrated sodium hydroxide solution. The organic phase is separated and the aqueous phase is washed once more with 150 ml of methylene chloride. The combined organic phases are dried over sodium sulfate and the solvent is removed under reduced pressure. 32 g of 1-benzyl-4- (3-hydroxypropylamino) piperidine is obtained as a yellow oil which is used in the next reaction step without purification.
b) 13.4 g 1-benzyl-4- (3-hydroxypropylamino) piperidine from the previous reaction was dissolved in 250 ml methanol with 3.8 g cyclopropanecarboxaldehyde and 5.1 g sodium cyanoborohydride at 0 ° C. Combine with hydride. The mixture is stirred overnight at ambient temperature, then acidified with dilute hydrochloric acid while cooling and concentrated to dryness under reduced pressure. The mixture is then made alkaline with concentrated sodium hydroxide solution and extracted three times with 40 ml of methylene chloride. The combined organic phases are dried over sodium sulfate, filtered and the solvent is removed under reduced pressure. The residue is filtered through silica gel with ethyl acetate / methanol / concentrated aqueous ammonia 20: 80: 1. After removing the solvent, 10.2 g of 1-benzyl-4- [cyclopropylmethyl- (3-hydroxypropyl) amino] piperidine is obtained as a yellow oil.
[0040]
c) 10.2 g 1-benzyl-4- [cyclopropylmethyl- (3-hydroxypropyl) amino] piperidine is combined with 2 g 20% palladium / charcoal in 100 ml methanol and 5 bar at 60 ° C. for 4 hours. Hydrogenate with hydrogen. The catalyst is separated and the solvent is removed under reduced pressure to give 7.3 g of 4- [cyclopropylmethyl- (3-hydroxypropyl) amino] piperidine as a yellow oil.
d) 4.7 g of 4- [cyclopropylmethyl- (3-hydroxypropyl) amino] piperidine with 9.6 g of (R) -N- [2- (3,5-bistrifluoromethylphenyl) ethyl] -2-methane Stir together sulfonyloxy-N-methyl-2-phenylacetamide (prepared from D-(−)-mandelic acid), 3.4 ml triethylamine and 200 ml acetone at 65 ° C. for 4 hours. The mixture is evaporated under reduced pressure, combined with 100 ml of saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic fractions are dried over sodium sulfate and the solvent is removed under reduced pressure. The combined organic fractions are dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is chromatographed on silica gel with methylene chloride / methanol 1: 1. Fractions found to be homogeneous by TLC are collected and the solvent is removed under reduced pressure. 5.5 g of (S) -N- [2- (3,5-bistrifluoromethylphenyl) ethyl] -2- {4- [cyclopropylmethyl- (3-hydroxypropyl) amino] piperidin-1-yl}- N-methyl-2-phenylacetamide is obtained as a brownish yellow oil, [α]D 20 = +35.1o1H-NMR (250 MHz, CDClThree) δ = 7.78-7.26 (8H, m), 4.24 (1H, s), 3.78 (2H, m); 3.63 (2H, m); 3.50 (1H, m); 2.96; 2.88 (3H, 2s); 2.93 (4H, m); 2.88-1.77 (5H, m); 2.37 (2H, d, J = 6,0 Hz); 1.79-1.45 (6H, m); 0.87 (1H, m); 0.52; 0.12 (4H , 2m). Most signals are split by amide rotation.
The compounds of Examples 6-8 are prepared in a manner similar to or similar to that described in International Application No. 99/62893.
[0041]
Embedded image
B Results of study of compounds of the present invention: Quantification of activity duration
Of blood pressure in anesthetized guinea pigs NK 1 Inhibition of induction reduction
Guinea pigs (300-500 g) were anesthetized with pentobarbital (50 mg / kg i.p.) and arranged for duodenal administration of the test substance and measurement of arterial blood pressure. NK1 Intravenous administration of the agent (0.2 μmol / kg at 30 minute intervals) induced a temporary drop in blood pressure. After determining the basal blood pressure, the test substance was administered by the duodenal route. Then NK1Agents were administered every 30 minutes for 6-8 hours. Results NK blood pressure1 Expressed as% inhibition of induction reduction, ED50The value was calculated by regression analysis.
The compounds of the present invention were compared with compounds of the following formula known from International Patent Application No. 97/32865.
[0044]
Embedded image
These compounds correspond to the compounds of Example 1 and Example 4 in which the 3-hydroxypropyl group is replaced with a 2-hydroxyethyl group.
The results thus obtained are shown in Table I below.
Example No. Activity duration [min]
1> 360
B-1 120
2> 360
3> 360
4> 360
B-4 120
5> 360
6> 360
7> 360
8> 360
[0046]
C Formulation of the compounds of the present invention
Injection solution
Active substance* 200 mg
Monopotassium dihydrogen phosphate = KH2POFour 1.2 mg
Disodium hydrogen phosphate = NaH2POFour.2H2O 0.2 mg
(buffer)
Sodium chloride (isotonic) 94 mg
Or
Glucose 520 mg
Albumin (protease protection) 4 mg
Sodium hydroxide solution
Hydrochloric acid up to pH 6
Water for injection, total volume 10 ml
[0047]
Injection solution
Active substance* 200 mg
Sodium chloride 94 mg
Or
Glucose 520 mg
Albumin 4 mg
Sodium hydroxide solution
Hydrochloric acid up to pH 9
Water for injection, total volume 10 ml
Freeze-dried product
Active substance* 200 mg
Mannitol (isotonic / bulking agent) 520 mg
Albumin 4 mg
Solvent for freeze-dried product 1
Water for injection 10 ml
Lyophilized solvent 2
Polysorbat® 80 = Tween® 80 20 mg
(Surfactant)
Water for injection 10 ml
* Active substance: a compound of the invention, for example one of Examples 1-8
For humans weighing 67 kg: 1-500 mg
Claims (13)
Ｒ2は水素、Ｃ1−Ｃ6アルキル、ω−ヒドロキシ−Ｃ2−Ｃ4アルキル、１，３−ジヒドロキシプロプ−２−イル又はＣ3−Ｃ6シクロアルキルメチルであり、
Ａｒは無置換フェニル又はハロゲン、ヒドロキシ、Ｃ1−Ｃ4アルキル、Ｃ1−Ｃ4アルコキシ、Ｃ1−Ｃ4フルオロアルキル、Ｃ1−Ｃ4フルオロアルコキシ又は−ＯＣＨ2Ｏ−で１〜５置換されたフェニルであり、
Ｒ3はフェニル−Ｃ1−Ｃ4アルキルであり、ここで、フェニル基は１〜３個の置換基で置換されていてもよく、その置換基は各々独立してハロゲン、ヒドロキシ、Ｃ1−Ｃ4アルキル、Ｃ1−Ｃ4アルコキシ、Ｃ1−Ｃ4フルオロアルキル又はＣ1−Ｃ4フルオロアルコキシより選ばれ、
Ｒ4は水素、Ｃ1−Ｃ4アルキル、Ｃ3−Ｃ8シクロアルキル、ＣＨ2ＣＯＯＨ、−ＣＨ2Ｃ（Ｏ）ＮＨ2、−ＯＨ又はフェニル−Ｃ1−Ｃ4アルキルである。）A compound having the following general formula I or a pharmaceutically acceptable salt thereof:
R 2 is hydrogen, C 1 -C 6 alkyl, ω-hydroxy-C 2 -C 4 alkyl, 1,3-dihydroxyprop-2-yl or C 3 -C 6 cycloalkylmethyl;
Ar is unsubstituted phenyl or halogen, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 fluoroalkyl, C 1 -C 4 fluoroalkoxy or —OCH 2 O— with 1 to 5 substitutions Phenyl,
R 3 is phenyl-C 1 -C 4 alkyl, wherein the phenyl group may be substituted with 1 to 3 substituents, each of which is independently halogen, hydroxy, C 1- C 4 alkyl, C 1 -C 4 alkoxy, selected from C 1 -C 4 fluoroalkyl or C 1 -C 4 fluoroalkoxy,
R 4 is hydrogen, C 1 -C 4 alkyl, C 3 -C 8 cycloalkyl, CH 2 COOH, —CH 2 C (O) NH 2 , —OH or phenyl-C 1 -C 4 alkyl. )
Ｒ2が水素原子、Ｃ1−Ｃ3アルキル基又は２−ヒドロキシエチル基である、請求項１〜６のいずれか１項に記載の化合物。R 1 is a 1,3-dihydroxyprop-2-yl group;
The compound according to any one of claims 1 to 6, wherein R 2 is a hydrogen atom, a C 1 -C 3 alkyl group or a 2-hydroxyethyl group.
を有するアミドと下記一般式ＩＩＩ
An amide having the general formula III
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| DE10051320A DE10051320A1 (en) | 2000-10-17 | 2000-10-17 | New 2-(4-amino-piperidin-1-yl)-2-aryl-N-(phenylalkyl)-acetamides, are neurokinin antagonists having a long duration of action, useful e.g. for treating allergic, inflammatory or central nervous system diseases |
| PCT/EP2001/011906 WO2002032865A1 (en) | 2000-10-17 | 2001-10-16 | Novel neurokinin antagonists, method for the production thereof and pharmaceutical compositions containing said compounds |
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| US20060035893A1 (en) | 2004-08-07 | 2006-02-16 | Boehringer Ingelheim International Gmbh | Pharmaceutical compositions for treatment of respiratory and gastrointestinal disorders |
| PE20060777A1 (en) | 2004-12-24 | 2006-10-06 | Boehringer Ingelheim Int | INDOLINONE DERIVATIVES FOR THE TREATMENT OR PREVENTION OF FIBROTIC DISEASES |
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| DE19608665A1 (en) * | 1996-03-06 | 1997-09-11 | Boehringer Ingelheim Kg | Novel arylglycine amide derivatives, processes for their preparation and pharmaceutical compositions containing them |
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