JP5711461B2 - Il−8受容体アンタゴニスト - Google Patents
Il−8受容体アンタゴニスト Download PDFInfo
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- JP5711461B2 JP5711461B2 JP2009516744A JP2009516744A JP5711461B2 JP 5711461 B2 JP5711461 B2 JP 5711461B2 JP 2009516744 A JP2009516744 A JP 2009516744A JP 2009516744 A JP2009516744 A JP 2009516744A JP 5711461 B2 JP5711461 B2 JP 5711461B2
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- Prior art keywords
- chloro
- compound
- hydroxy
- phenyl
- toluenesulfonic acid
- Prior art date
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- YNDXUCZADRHECN-JNQJZLCISA-N triamcinolone acetonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O YNDXUCZADRHECN-JNQJZLCISA-N 0.000 description 1
- 229960003223 tripelennamine Drugs 0.000 description 1
- 229960001128 triprolidine Drugs 0.000 description 1
- CBEQULMOCCWAQT-WOJGMQOQSA-N triprolidine Chemical compound C1=CC(C)=CC=C1C(\C=1N=CC=CC=1)=C/CN1CCCC1 CBEQULMOCCWAQT-WOJGMQOQSA-N 0.000 description 1
- 229960001491 trospium Drugs 0.000 description 1
- OYYDSUSKLWTMMQ-JKHIJQBDSA-N trospium Chemical compound [N+]12([C@@H]3CC[C@H]2C[C@H](C3)OC(=O)C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CCCC1 OYYDSUSKLWTMMQ-JKHIJQBDSA-N 0.000 description 1
- 229960001530 trospium chloride Drugs 0.000 description 1
- 239000002750 tryptase inhibitor Substances 0.000 description 1
- BDIAUFOIMFAIPU-UHFFFAOYSA-N valepotriate Natural products CC(C)CC(=O)OC1C=C(C(=COC2OC(=O)CC(C)C)COC(C)=O)C2C11CO1 BDIAUFOIMFAIPU-UHFFFAOYSA-N 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
- 230000006444 vascular growth Effects 0.000 description 1
- 229940063390 vesicare Drugs 0.000 description 1
- DAFYYTQWSAWIGS-DEOSSOPVSA-N vilanterol Chemical compound C1=C(O)C(CO)=CC([C@@H](O)CNCCCCCCOCCOCC=2C(=CC=CC=2Cl)Cl)=C1 DAFYYTQWSAWIGS-DEOSSOPVSA-N 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 238000013389 whole blood assay Methods 0.000 description 1
- 210000002268 wool Anatomy 0.000 description 1
Classifications
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- A61K31/18—Sulfonamides
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- C—CHEMISTRY; METALLURGY
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- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
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- 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
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Description
3,4−ジクロロアニリン(100g)をテトラブチルメチルアミン(TBME)(660mL)に溶解させ、10〜15℃に冷却した。水酸化ナトリウム(30%水溶液94g)を加え、この溶液を機械的攪拌機で激しく攪拌した。塩化トリメチルアセチル(84mL)を、内部温度が35℃までに維持されるような速度で加えた。添加が完了したところで(10〜15分、この混合物を30〜35℃で約30分維持した後、30〜40分かけて0〜5℃に冷却した。この反応混合物を0〜5℃で1時間維持した後、濾過し、まず90:10水/メタノール(400mL)で、次に水(600mL)ですすいだ。真空下、50〜55℃で乾燥させ、生成物を灰白色結晶として得た。収量127gを得た。
化合物1の溶液(300mL)を窒素の不活性雰囲気下で−50〜−40℃に冷却した。N−ブチルリチウム(ヘキサン中2.5M、179mL)を、溶液の内部温度が−45〜−30℃の間に維持されるような速度で加えた(およそ15〜30分の添加)。HPLCが最初の反応が完了したことを示すまで、この溶液を約−35〜−25℃で保持した。次に、この溶液を再び−45〜−40℃に冷却し、この溶液に、内部温度をおよそ−14℃までに維持しつつ、溶液が酸性となるまで、二酸化硫黄(〜16.9g)の泡を通じた。反応が完了したところで、この混合物を−10〜0℃に温めた。次に、−2〜3℃で始め、塩化スルホニル(25.2mL)をテトラヒドロフラン溶液に、温度をおよそ22℃までに維持しつつ、5〜15分かけて滴下した。5分後、HPLCによって、反応が完了したことを確認し、この間、溶液は10〜15℃前後に維持した。この混合物の溶媒を減圧下でα,α,α−トリフルオロトルエンに交換し、濾過し、部分的に真空濃縮した(〜100mL)後、ジクロロメタン(350mL)を加えた。この混合物に、溶液の内部温度を15〜27℃に維持しつつ、周囲温度でジクロロメタン(625mL)中ピペラジン(61.2g)の溶液を滴下した(2時間添加)。この反応を完了するまで20〜24℃で保持した。この混合物を脱イオン水(200mL)で洗浄し、有機層を濃縮した後、ヘプタン(450mL)を加えた。生成物(70.5g)を濾過により単離し、ヘプタン(50〜100mL)で洗浄し、50〜55℃で真空乾燥させた。
化合物2(30g)を〜16%(水中w/w)の硫酸(300mL)に加えた。得られた混合物を99〜103℃で〜6時間加熱還流した。反応が完了したところで、この溶液を40〜50℃に冷却し、その後、減圧下で〜60mLまで濃縮した。アセトニトリル(225mL)を加え、得られた懸濁液を20〜25℃で〜1時間攪拌した。生成物を濾過により単離し、アセトニトリル(135mL)で洗浄し、45〜50℃で真空乾燥させた。収量33.34gを得た。
化合物3(20g)を脱イオン水(200mL)に加えた。得られた溶液のpHを、内部温度を20〜30℃の間に維持しつつ50%水酸化ナトリウム水溶液(〜6.35mL)を加えることで6.5〜7.0に調整した。次に、酢酸エチル(80mL+20mLすすぎ)中、二炭酸ジ−tert−ブチル(8.9g)の溶液を加えた。得られた混合物のpHを、内部温度を20〜30℃の間に維持しつつ50%水酸化ナトリウム水溶液(2.45mL)を加えることで6.8〜7.0に調整した。反応が完了したところで、反応溶液を濾過して少量の沈殿を除去した。濾液を二層に分け、水層を酢酸エチル(140mL)で抽出した。合わせた酢酸エチル層を水(40mL)で洗浄し、100mLまで濃縮した。ヘプタン(100mL)を加え、得られた懸濁液を60mLまで濃縮した。このプロセスをもう一度繰り返した。その後、ヘプタン(140mL)を加え、得られた懸濁液を20〜25℃で〜1時間攪拌した。生成物を濾過により単離し、ヘプタン(80mL)で洗浄し、40〜45℃で真空乾燥させた。収量15.3gを得た。
化合物4(10g)をジメチルホルムアミド(20mL)およびアセトニトリル(80mL)に加えた。内部温度を20〜30℃の間に維持しつつ、イソシアン酸2−クロロ−3−フルオロフェニル(4.77g)を加えた後、10mLのアセトニトリルですすいだ。得られた混合物を20〜25℃で〜2時間攪拌した。反応が完了したところで、メタノール(50mL)を加えた。得られた懸濁液を20〜25℃で〜10分間攪拌した。脱イオン水(150mL)を加え、得られた懸濁液を20〜25℃で〜1時間攪拌した。生成物を濾過により単離し、脱イオン水(100mL)およびメタノール(15〜20mL)で洗浄した後、40〜45℃で真空乾燥させた。収量14.15gを得た。
化合物5(50g)をテトラヒドロフラン(THF、200mL)に溶解させ、33〜37℃に加熱し、33〜37℃で保持した。別の反応で、アセトニトリル(250mL)、THF(50mL)およびp−トルエンスルホン酸一水和物(43.9g)の溶液を調製した。得られた溶液を33〜37℃に加熱し、33〜37℃で保持した。このp−トルエンスルホン酸溶液を濾過し、温度を33〜37℃に維持しつつ、化合物5とTHFの入った反応槽に移した。出発材料が消費された後、生成物の微粉シード(0.5g)を最少量のアセトニトリル(5mL)に入れた。次に、この反応混合物を〜40分にわたって53〜57℃に加熱し、この温度で少なくとも4時間保持した。反応物を0〜5℃に冷却し、生成物を濾過により単離し、アセトニトリル(250mL)で洗浄し、55〜60℃で真空乾燥させた。収量52.24gを得た。
化合物5(500g)を反応槽1に入れた後、アセトニトリル(CAN、3750mL)およびテトラヒドロフラン(THF、1250mL)を入れた。次に、この溶液を60〜65℃に加熱し、透明な溶液が得られたところで、反応槽2へ明澄化濾過を行う。反応槽1に、p−トルエンスルホン酸一水和物(TsOH・H2O、439g)、次いでACN(750mL)およびTHF(250mL)を加える。この混合物を40〜45℃で加熱し、透明な溶液が得られたところで、明澄化濾過を行い、反応槽2の温度を50〜60℃に維持しつつ、この溶液を反応槽2(出発材料溶液を含む)に加えた。この混合物を加熱還流し、反応が完了するまで70〜80℃で保持した。〜3500mLの溶媒を常圧蒸留によって除去した。次に、この反応槽に2.5Lの水、次いで4LのACNを入れ、温度を70〜80℃に調節した。溶解が見られた後、得られた溶液を64〜68℃に冷却した。5〜10分後、粉砕した生成物シード(5g)を最少量のアセトニトリルに加え、64〜68℃で1時間保持した。この混合物を2時間かけて0〜5℃に冷却し、0〜5℃で〜30分間保持した後、生成物を濾過により単離した。この固体生成物を2.5Lのアセトニトリルで洗浄し、50〜60℃で真空乾燥させた。収量480gを得た。
本化合物は、限定されるものではないが、単球および/またはマクロファージなどの哺乳類細胞による過剰な、または調節を欠いたIL−8サイトカイン、またはIL−8αもしくはβ受容体(I型もしくはII型受容体とも呼ばれる)と結合する他のケモカインの産生によって悪化または発生するヒトまたは他の哺乳類の病態の予防的または治療的治療を目的とした薬剤の製造において有用である。
本化合物および本発明の医薬処方物は、例えば、抗炎症薬、抗コリン作用薬(特にM1/M2/M3受容体アンタゴニスト)、β2−アドレナリン受容体アゴニスト、抗生物質、抗ウイルス薬などの抗感染薬、または抗ヒスタミン薬から選択される1以上の他の治療薬と組み合わせて使用すること、またはこれらを含むことができる。よって、本発明は、さらなる態様において、本化合物または生理学上機能のある本化合物の誘導体を、例えば、コルチコステロイドもしくはNSAIDなどの抗炎症薬、抗コリン作用薬、β2−アドレナリン受容体アゴニスト、抗生物質もしくは抗ウイルス薬などの抗感染薬、または抗ヒスタミン薬から選択される1以上の他の治療上有効な薬剤とともに含む組合せを提供する。本発明の一実施形態は、本化合物またはその生理学上機能のある誘導体をβ2−アドレナリン受容体アゴニスト、および/または抗コリン作動薬、および/またはPDE−4阻害剤、および/または抗ヒスタミン薬とともに含む組合せを包含する。
3−(4−{[6−({(2R)−2−ヒドロキシ−2−[4−ヒドロキシ−3−(ヒドロキシメチル)フェニル]エチル}アミノ)ヘキシル]オキシ}ブチル)ベンゼンスルホンアミド;
3−(3−{[7−({(2R)−2−ヒドロキシ−2−[4−ヒドロキシ−3−ヒドロキシメチル)フェニル]エチル}−アミノ)ヘプチル]オキシ}プロピル)ベンゼンスルホンアミド;
4−{(1R)−2−[(6−{2−[(2,6−ジクロロベンジル)オキシ]エトキシ}ヘキシル)アミノ]−1−ヒドロキシエチル}−2−(ヒドロキシメチル)フェノール;
4−{(1R)−2−[(6−{4−[3−(シクロペンチルスルホニル)フェニル]ブトキシ}ヘキシル)アミノ]−1−ヒドロキシエチル}−2−(ヒドロキシメチル)フェノール;
N−[2−ヒドロキシル−5−[(1R)−1−ヒドロキシ−2−[[2−4−[[(2R)−2−ヒドロキシ−2−フェニルエチル]アミノ]フェニル]エチル]アミノ]エチル]フェニル]ホルムアミド;
N−2{2−[4−(3−フェニル−4−メトキシフェニル)アミノフェニル]エチル}−2−ヒドロキシ−2−(8−ヒドロキシ−2(1H)−キノリノン−5−イル)エチルアミン;および 5−[(R)−2−(2−{4−[4−(2−アミノ−2−メチル−プロポキシ)−フェニルアミノ]−フェニル}−エチルアミノ)−1−ヒドロキシ−エチル]−8−ヒドロキシ−1H−キノリン−2−オン
が挙げられる。
シス−4−シアノ−4−(3−シクロペンチルオキシ−4−メトキシフェニル)シクロヘキサン−1−カルボン酸、
2−カルボメトキシ−4−シアノ−4−(3−シクロプロピルメトキシ−4−ジフルオロメトキシフェニル)シクロヘキサン−1−オンおよび
シス−[4−シアノ−4−(3−シクロプロピルメトキシ−4−ジフルオロメトキシフェニル)シクロヘキサン−1−オール]
が含まれる。また、シス−4−シアノ−4−[3−(シクロペンチルオキシ)−4−メトキシフェニル]シクロヘキサン−1−カルボン酸(シロミラスト(cilomilast)としても知られる)およびその塩、エステル、プロドラッグまたは米国特許第5,552,438号に記載されている物理形態が含まれる。
(3−エンド)−3−(2,2−ジ−2−チエニルエテニル)−8,8−ジメチル−8−アゾニアビシクロ[3.2.1]オクタンヨージド;
(3−エンド)−3−(2−シアノ−2,2−ジフェニルエチル)−8,8−ジメチル−8−アゾニアビシクロ[3.2.1]オクタンブロミド;
4−[ヒドロキシ(ジフェニル)メチル]−1−{2−[(フェニルメチル)オキシ]エチル}−1−アゾニアビシクロ[2.2.2]オクタンブロミド;および
(1R,5S)−3−(2−シアノ−2,2−ジフェニルエチル)−8−メチル−8−{2−[(フェニルメチル)オキシ]エチル}−8−アゾニアビシクロ[3.2.1]オクタンブロミド
が含まれる。
(エンド)−3−(2−メトキシ−2,2−ジ−チオフェン−2−イル−エチル)−8,8−ジメチル−8−アゾニア−ビシクロ[3.2.1]オクタンヨージド;
3−((エンド)−8−メチル−8−アザ−ビシクロ[3.2.1]オクト−3−イル)−2,2−ジフェニル−プロピオニトリル;
(エンド)−8−メチル−3−(2,2,2−トリフェニル−エチル)−8−アザ−ビシクロ[3.2.1]オクタン;
3−((エンド)−8−メチル−8−アザ−ビシクロ[3.2.1]オクト−3−イル)−2,2−ジフェニル−プロピオンアミド;
3−((エンド)−8−メチル−8−アザ−ビシクロ[3.2.1]オクト−3−イル)−2,2−ジフェニル−プロピオン酸;
(エンド)−3−(2−シアノ−2,2−ジフェニル−エチル)−8,8−ジメチル−8−アゾニア−ビシクロ[3.2.1]オクタンヨージド;
(エンド)−3−(2−シアノ−2,2−ジフェニル−エチル)−8,8−ジメチル−8−アゾニア−ビシクロ[3.2.1]オクタンブロミド;
3−((エンド)−8−メチル−8−アザ−ビシクロ[3.2.1]オクト−3−イル)−2,2−ジフェニル−プロパン−1−オール;
N−ベンジル−3−((エンド)−8−メチル−8−アザ−ビシクロ[3.2.1]オクト−3−イル)−2,2−ジフェニル−プロピオンアミド;
(エンド)−3−(2−カルバモイル−2,2−ジフェニル−エチル)−8,8−ジメチル−8−アゾニア−ビシクロ[3.2.1]オクタンヨージド;
1−ベンジル−3−[3−((エンド)−8−メチル−8−アザ−ビシクロ[3.2.1]オクト−3−イル)−2,2−ジフェニル−プロピル]−尿素;
1−エチル−3−[3−((エンド)−8−メチル−8−アザ−ビシクロ[3.2.1]オクト−3−イル)−2,2−ジフェニル−プロピル]−尿素;
N−[3−((エンド)−8−メチル−8−アザ−ビシクロ[3.2.1]オクト−3−イル)−2,2−ジフェニル−プロピル]−アセトアミド;
N−[3−((エンド)−8−メチル−8−アザ−ビシクロ[3.2.1]オクト−3−イル)−2,2−ジフェニル−プロピル]−ベンズアミド;
3−((エンド)−8−メチル−8−アザ−ビシクロ[3.2.1]オクト−3−イル)−2,2−ジ−チオフェン−2−イル−プロピオニトリル;
(エンド)−3−(2−シアノ−2,2−ジ−チオフェン−2−イル−エチル)−8,8−ジメチル−8−アゾニア−ビシクロ[3.2.1]オクタンヨージド;
N−[3−((エンド)−8−メチル−8−アザ−ビシクロ[3.2.1]オクト−3−イル)−2,2−ジフェニル−プロピル]−ベンゼンスルホンアミド;
[3−((エンド)−8−メチル−8−アザ−ビシクロ[3.2.1]オクト−3−イル)−2,2−ジフェニル−プロピル]−尿素;
N−[3−((エンド)−8−メチル−8−アザ−ビシクロ[3.2.1]オクト−3−イル)−2,2−ジフェニル−プロピル]−メタンスルホンアミド;および/または
(エンド)−3−{2,2−ジフェニル−3−[(1−フェニル−メタノイル)−アミノ]−プロピル}−8,8−ジメチル−8−アゾニア−ビシクロ[3.2.1]オクタンブロミド
が含まれる。
(エンド)−3−(2−メトキシ−2,2−ジ−チオフェン−2−イル−エチル)−8,8−ジメチル−8−アゾニア−ビシクロ[3.2.1]オクタンヨージド;
(エンド)−3−(2−シアノ−2,2−ジフェニル−エチル)−8,8−ジメチル−8−アゾニア−ビシクロ[3.2.1]オクタンヨージド;
(エンド)−3−(2−シアノ−2,2−ジフェニル−エチル)−8,8−ジメチル−8−アゾニア−ビシクロ[3.2.1]オクタンブロミド;
(エンド)−3−(2−カルバモイル−2,2−ジフェニル−エチル)−8,8−ジメチル−8−アゾニア−ビシクロ[3.2.1]オクタンヨージド;
(エンド)−3−(2−シアノ−2,2−ジ−チオフェン−2−イル−エチル)−8,8−ジメチル−8−アゾニア−ビシクロ[3.2.1]オクタンヨージド;および/または
(エンド)−3−{2,2−ジフェニル−3−[(1−フェニル−メタノイル)−アミノ]−プロピル}−8,8−ジメチル−8−アゾニア−ビシクロ[3.2.1]オクタンブロミド
が含まれる。
本発明の化合物のIL−8およびGRO−αケモカイン阻害作用は、以下のin vitroアッセイによって測定される。
比活性が2000Ci/mmolの[125I]IL−8(ヒト組換え体)は、GE Healthcareから入手する。他の化学物質は全て分析級のものである。高レベルの組換えヒトCXCR1(IL−8α型)およびCXCR2(IL−8β型)受容体を、これまでに記載されているように(Holmes, et al., Science, 1991, 253, 1278)、非接着チャイニーズハムスター卵巣(CHO)細胞で個々に発現させる。ホモジナイゼーションバッファーを40mM Tris−HCL(pH7.5)、1mM MgSO4、0.5mM EGTA(エチレン−グリコール−ビス(2−アミノエチルエーテル)−N,N,N’,N’四酢酸)、1mM PMSF(フッ化α−トルエンスルホニル)、2.5mg/Lロイペプチンおよび0.1mg/mlアプロチニンに変更すること以外は、これまでに記載されているプロトコール(Haour, et al., J. Biol. Chem., 249 pp 2195-2205 (1974)(出典明示により本膜の調製に必要な程度まで本明細書の一部とされる))に従って膜を調製する。細胞をホモジナイズし、2,000rpmで10分遠心分離する。上清を100,000xgで1時間遠心分離する。上清を廃棄し、膜を−80℃で保存する。膜タンパク質濃度は、ウシ血清アルブミン(BSA)を標品として用い、製造者のプロトコールに従ってBioRad試薬を用いて測定する。
好中球走化性アッセイを行う。ヒト一次好中球を、パーコール不連続勾配遠心分離、デキストラン沈降および低張溶解を用い、抹消全血から単離する。走化因子IL−8(CXCL8)またはGRO−α(CXCL1)を96マルチウェルチャンバー(ChemoTx System, Neuro Probe, Gaithersburg, MD)の下方のチャンバーに入れる。用いるアゴニスト濃度はEC80濃度である。この2つのチャンバーを5μMポリカーボネート膜で分離する。供試化合物を、フィルターの上部に置く前に細胞とともにプレイキュベートする。走化因子を5%CO2で加湿したインキュベーター中、37℃で45分間進行させる。このインキュベーションの終了時に、膜を取り外し、下方のチャンバーに移動した細胞を96ウェルプレートに移す。これらの細胞を、発光細胞生存アッセイ(ChemoTx System, Neuro Probe, Gaithersburg, MD)を用いて測定する。各サンプルを2回試験し、各化合物は少なくとも3回繰り返す。陽性対照細胞は化合物を添加しない細胞であり、最大走化性応答に相当する。陰性対照(無刺激)は下方のチャンバーにケモカインを添加しないものである。陽性対照と陰性対照の間の差は、細胞の走化活性を表す。
ヒト全血において、化合物の好中球に対する、GROαに誘発されるインテグリンCD11bの発現を阻害する能力を試験する。
CXCR2およびGα16を安定発現するCHO−K1細胞を、5%CO2インキュベーター内で37℃に維持しつつ、DMEM/F12(HAMの)1:1、w/10%FCS(熱不活化)、w/2mM L−グルタミン、w/0.4mg/ml G418中で集密度80%まで増殖させる。アッセイ24時間前に、細胞を採取し、96ウェル黒壁、透明底プレート(Packard View)内に40,000細胞/ウェルで平板培養し、CO2インキュベーターに戻す。アッセイ当日、化合物を所望のアッセイ濃度の300倍まで、100%DMSOで連続希釈する。培地を細胞から吸引し、100μlのロード培地(Earlの塩とともにw/L−グルタミン、0.1%BSA(Bovuminar Cohen Fraction V from Seriologicals Corp.)、4μMフロ−4−アセトキシメチルエステル蛍光指示色素(Fluo−4 AM、Molecular Probes製)および2.5mMプロベネシドを含むEMEM)に置き換え、CO2インキュベーター内にて37℃で1時間インキュベートする。ロード培地を吸引し、Earlの塩とともにw/L−グルタミン、0.1%ゼラチンおよび2.5mMプロベネシドを含む100μLのEMEMに置き換え、さらに10分インキュベートする。DMSOで300倍に連続希釈した化合物(3μl)を、297μlのKRH(120mM NaCl、4.6mM KCl、1.03mM KH2PO4、25mM NaHCO3、1.0mM CaCl2、1.1mM MgCl2、11mMグルコース、20mM HEPES(pH7.4))、w/2.5mMプロベネシドおよび0.1%ゼラチン(化合物はこの時点で3倍)の入った96ウェルプレートに移す。細胞から培地を吸引し、細胞をKRH w/2.5mMプロベネシド、w/0.1%ゼラチンで3回洗浄する。KRH(100μl) w/2.5mMプロベネシド、0.1%ゼラチンをウェルに加えた後、50μlのKRH w/2.5mMプロベネシドおよび0.1%ゼラチン中3倍の化合物をウェルに加え(化合物はこの時点で1倍)、CO2インキュベーター内にて37℃で10分インキュベートする。これまでに記載されたように分析するため(Sarau et al., 1999)、プレートをFLIPR(Fluorometric Imaging Plate Reader, Molecular Devices, Sunnyvale CA)上に置く。CXCR2に関しては、1.0nM IL−8によって誘発される最大ヒトIL−8誘発Ca2+可動化%、すなわちEC80濃度を各化合物濃度で求め、IC50を、1.0nM IL−8によって誘発される最大応答の50%を阻害する試験化合物の濃度として算出する。化合物は、本アッセイにおいて10μM未満のIC50値を示す場合に活性があるとみなされる。
Lewisラット(250〜300gm)に本化合物またはビヒクルを経口投与し、1時間後にそれらをCO2窒息により安楽死させた。ラット全血3mlを心臓穿刺により、100μlの0.25M EDTA(GIBCO, Grand Island, NY)の入ったシリンジに抜き取った。ラットCXCL2(PeproTech, Rocky Hill, NJ)保存液を、Kreb’s/0.1%BSA(KBSA)中に10μMで再構成することにより作製した。この保存液をDPBS(GIBCO)で最大使用濃度の「11倍」まで希釈し、KBSA/DPBSビヒクルで連続希釈した。適当な濃度(1.2〜100nM)の本化合物またはビヒクル10μlを12×75mmのポリプロピレン試験管に加えた後、100μlの全血を加えた。これらの試験管を37℃浴で30分、10分ごとに手で穏やかに振盪させつつインキュベートした。次に、これらのサンプルを氷上に10分置いた後、10μlの抗ラットCD11b−FITCまたはFITC標識マウスIgG2aイソ型対照(双方ともAntigenix America, Huntington Station, NY)を加え、氷上で30分インキュベートした。FACS溶解溶液(Becton Dickinson, San Jose, CA)(1ml、1倍)を加え、すぐに激しくボルテックスにかけ、その後、最後のサンプルに溶液を加えた後にさらにボルテックスにかけた。サンプルを室温で10分インキュベートし、白血球を〜300xgでペレット化し、DPBSで洗浄した。細胞を650μlの1%パラホルムアルデヒドに再懸濁させた。このFACS溶解溶液はラット赤血球を完全には溶解させない。従って、フローサイトメトリー分析に関しては、残っている赤血球をゲートアウトするために、フロー分析の1〜2分以内に各サンプルにLDS−751(Exciton, Dayton, OH)の1.67mg/mlエタノール溶液(過飽和;遠心分離により明澄化)3.5μlを加えた。サンプルデータは、CellQuestソフトウエアおよびLSRフローサイトメーター(Becton-Dickinson)を低流速設定で用い、LDS−751陰性赤血球を排除した後、前方散乱に対する側方散乱のプロットで好中球集団に対してゲーティングを行う。次に、この集団のFL1(緑色FITC蛍光、CD11b含量に直接関連)を、CellQuestソフトウエアを用いた分析により、平均チャネル蛍光として測定した。
Claims (8)
- p−トルエンスルホン酸N−[4−クロロ−2−ヒドロキシ−3−(ピペラジン−1−スルホニル)フェニル]−N’−(2−クロロ−3−フルオロフェニル)尿素である、化合物。
- p−トルエンスルホン酸N−[4−クロロ−2−ヒドロキシ−3−(ピペラジン−1−スルホニル)フェニル]−N’−(2−クロロ−3−フルオロフェニル)尿素および医薬上許容される担体または希釈剤を含む、喘息、慢性閉塞性肺疾患または成人性呼吸窮迫症候群の処置用の医薬組成物。
- ケモカイン介在疾患の治療に用いるための薬剤の製造における、p−トルエンスルホン酸N−[4−クロロ−2−ヒドロキシ−3−(ピペラジン−1−スルホニル)フェニル]−N’−(2−クロロ−3−フルオロフェニル)尿素の使用。
- 喘息、慢性閉塞性肺疾患または成人性呼吸窮迫症候群の治療に用いるための薬剤の製造における、p−トルエンスルホン酸N−[4−クロロ−2−ヒドロキシ−3−(ピペラジン−1−スルホニル)フェニル]−N’−(2−クロロ−3−フルオロフェニル)尿素の使用。
- 慢性閉塞性肺疾患の治療に用いるための薬剤の製造における、p−トルエンスルホン酸N−[4−クロロ−2−ヒドロキシ−3−(ピペラジン−1−スルホニル)フェニル]−N’−(2−クロロ−3−フルオロフェニル)尿素の使用。
- p−トルエンスルホン酸N−[4−クロロ−2−ヒドロキシ−3−(ピペラジン−1−スルホニル)フェニル]−N’−(2−クロロ−3−フルオロフェニル)尿素と1以上の付加的治療成分を含む、喘息、慢性閉塞性肺疾患または成人性呼吸窮迫症候群の処置用の医薬組成物。
- 前記付加的治療成分がCXCR3受容体アンタゴニストまたはCCR5受容体アンタゴニストである、請求項6に記載の組成物。
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EA014958B1 (ru) * | 2006-04-21 | 2011-04-29 | Смитклайн Бичам Корпорейшн | Антагонисты рецептора il-8 |
PE20080943A1 (es) * | 2006-06-23 | 2008-09-27 | Smithkline Beecham Corp | Sal toluenosulfonato de 4-{[6-cloro-3-({[(2-cloro-3-fluorofenil)amino]carbonil}amino)-2-hidroxifenil]sulfonil}-1-piperazinacarboxilato de 1,1-dimetiletilo como antagonista del receptor de il-8 |
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- 2007-06-22 EP EP07798924A patent/EP2032131A4/en not_active Withdrawn
- 2007-06-22 US US12/305,756 patent/US20090170871A1/en not_active Abandoned
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- 2008-12-18 IL IL196056A patent/IL196056A0/en unknown
- 2008-12-24 MA MA31504A patent/MA30528B1/fr unknown
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Also Published As
Publication number | Publication date |
---|---|
EA015520B1 (ru) | 2011-08-30 |
US20090170871A1 (en) | 2009-07-02 |
EP2034832A4 (en) | 2010-12-08 |
MA30528B1 (fr) | 2009-06-01 |
CR10535A (es) | 2009-03-20 |
ES2437115T3 (es) | 2014-01-09 |
IL196056A0 (en) | 2009-09-01 |
NO20090203L (no) | 2009-03-20 |
CN101505595A (zh) | 2009-08-12 |
EP2034832A2 (en) | 2009-03-18 |
CA2655468A1 (en) | 2007-12-27 |
EP2032131A2 (en) | 2009-03-11 |
EA200970051A1 (ru) | 2009-06-30 |
JP2009541353A (ja) | 2009-11-26 |
EP2034832B1 (en) | 2013-10-02 |
WO2007150016A3 (en) | 2008-12-04 |
WO2007150016A2 (en) | 2007-12-27 |
CL2007001829A1 (es) | 2008-01-25 |
TW200817006A (en) | 2008-04-16 |
JP2014055145A (ja) | 2014-03-27 |
WO2007150015A3 (en) | 2008-02-28 |
AU2007260842A1 (en) | 2007-12-27 |
EP2032131A4 (en) | 2009-09-02 |
WO2007150015A2 (en) | 2007-12-27 |
AR061571A1 (es) | 2008-09-03 |
KR20090032097A (ko) | 2009-03-31 |
JP2009541352A (ja) | 2009-11-26 |
US20090281110A1 (en) | 2009-11-12 |
NZ573733A (en) | 2011-03-31 |
AU2007260842B2 (en) | 2012-03-15 |
MX2009000162A (es) | 2009-01-23 |
BRPI0713304A2 (pt) | 2012-04-17 |
PE20080943A1 (es) | 2008-09-27 |
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