JP2005232101A - Celecoxibaminoalkyl derivative - Google Patents
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- 0 Cc(cc1)ccc1-c1cc(*)n[n]1-c(cc1)ccc1S(N[*+]N)(=O)=O Chemical compound Cc(cc1)ccc1-c1cc(*)n[n]1-c(cc1)ccc1S(N[*+]N)(=O)=O 0.000 description 1
- WJAQGYRBBAFZJN-UHFFFAOYSA-N Cc(cc1)ccc1-c1cc(C(F)(F)F)n[n]1-c(cc1)ccc1S(NCCN)(=O)=O Chemical compound Cc(cc1)ccc1-c1cc(C(F)(F)F)n[n]1-c(cc1)ccc1S(NCCN)(=O)=O WJAQGYRBBAFZJN-UHFFFAOYSA-N 0.000 description 1
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Abstract
Description
本発明は、セレコキシブ（Celecoxib）の新規なアミノアルキル誘導体、並びにその製造方法およびその使用に関する。 The present invention relates to a novel aminoalkyl derivative of Celecoxib, a process for its production and its use.
下記式（III ）：
により示される化合物は、セレコキシブ（celecoxib）と称され、炎症性サイトカインの産生において重要な働きを持つ酵素であるシクロオキシゲナーゼ(COX)-2（cyclooxygenase(COX)-2）をより選択的に阻害する抗炎症化合物として（Kato M. et al, J. Pharm. Pharmacol. 2001 Dec；53(12)：1679-85）、米国食品医薬品局（FDA）の承認を受けた薬物である。この薬物は米国では既に市販され、我が国においても現在臨床試験が進行中である。また、その抗炎症作用の他に、ヒト関節リウマチ患者滑膜細胞（Kusunoki N., et al, Arthritis Rheum 2002；46(12)：3159-3167）および種々の腫瘍細胞における増殖抑制効果も報告されており（Yamazaki R., et al, FEBS Lett. 2002 531(2)：278-284）、家族性大腸ポリポーシス治療に関してもその適応がFDAにより承認されている。 The compound represented by is called celecoxib and has a more selective inhibition of cyclooxygenase (COX) -2, an enzyme that plays an important role in the production of inflammatory cytokines. As an inflammatory compound (Kato M. et al, J. Pharm. Pharmacol. 2001 Dec; 53 (12): 1679-85), it is a drug approved by the US Food and Drug Administration (FDA). This drug is already marketed in the United States, and clinical trials are ongoing in Japan. In addition to its anti-inflammatory activity, it has also been reported to inhibit growth in human rheumatoid arthritis patient synovial cells (Kusunoki N., et al, Arthritis Rheum 2002; 46 (12): 3159-3167) and various tumor cells. (Yamazaki R., et al, FEBS Lett. 2002 531 (2): 278-284), and its indications are also approved by the FDA for the treatment of familial colorectal polyposis.
本発明は、前記のセレコキシブを基にして、更に高い細胞増殖抑制作用を有する化合物、及びその用途を提供しようとするものである。 The present invention intends to provide a compound having a higher cell growth inhibitory activity and its use based on the above-described celecoxib.
本発明者は、上記のセレコキシブに比べてはるかに強力な細胞増殖抑制作用を有する化合物を提供すべく種々検討した結果、セレコキシブのスルホンアミド基にアミノアルキル基を結合させることにより、セレコキシブに比べて10倍以上の細胞増殖抑制活性を有する化合物を合成することに成功し、本発明を完成した。従って、本発明は、下記式（Ｉ）： As a result of various studies to provide a compound having a much stronger cell growth inhibitory effect than the above-described celecoxib, the present inventor has compared an aminoalkyl group to the sulfonamide group of celecoxib, thereby comparing with celecoxib. The present invention was completed by successfully synthesizing a compound having a cytostatic activity of 10 times or more. Accordingly, the present invention provides the following formula (I):
（式中、ｎは１〜３の整数である）
により表される、N-(アミノアルキル)-4-〔5-(4-トリル)-3-(トリフルオロメチル-1H-ピラソール-1-イル〕-ベンゼンスルホンアミドを提供する。上記式（Ｉ）に示される化合物の内、特に下記式（II）：
(In the formula, n is an integer of 1 to 3)
N- (aminoalkyl) -4- [5- (4-tolyl) -3- (trifluoromethyl-1H-pyrazol-1-yl] -benzenesulfonamide represented by the formula (I) Among the compounds represented by formula (II), the following formula (II):
下記式（II）：
本発明は更に、上記の化合物を含んで成る、細胞増殖阻害剤を提供する。
本発明は更に、上記の化合物を含んで成る、アポトーシス誘導剤を提供する。
本発明はまた、上記の化合物を含んで成る、プロスタグランジン産生阻害剤を提供する。
The present invention further provides a cell growth inhibitor comprising the above compound.
The present invention further provides an apoptosis inducer comprising the above compound.
The present invention also provides a prostaglandin production inhibitor comprising the above compound.
本発明の式（Ｉ）の化合物において、ｎは１〜３の整数であり、従って、H2N-(CH2)n-は、アミノプロピル基、アミノエチル基またはアミノメチル基であり、ｎが２であるアミノエチル基が特に好ましい。 In the compound of the formula (I) of the present invention, n is an integer of 1 to 3, and therefore H 2 N— (CH 2 ) n — is an aminopropyl group, an aminoethyl group or an aminomethyl group, and n An aminoethyl group in which is 2 is particularly preferred.
本発明の式（Ｉ）に属する化合物Ａは、例えば、次のようにして合成することが出来る。
本発明の化合物は、腫瘍細胞を含めて、各種の細胞に対して細胞増殖抑制作用を有する。例えば、細胞の増殖に必然的に伴うDNAの合成に際し、ブロモデオキシウリジン（bromo-deoxyuridine）(BrdU)を培地に添加して細胞にとり込ませ、各種被験物質によるBrdUの取り込み量の減少を観察することにより、当該被験物質の細胞増殖抑制作用を試験することが出来る。本発明の式（Ｉ）で示す化合物は、実施例２に示す通り、セレコキシブに比べて、腫瘍細胞に対して、約10倍の細胞増殖抑制作用を示す。従って、本発明の化合物は、腫瘍細胞増殖抑制剤として有用であり、より具体的には抗癌剤として有望である。 The compound of the present invention has a cytostatic effect on various cells including tumor cells. For example, when synthesizing DNA that is inevitably associated with cell growth, bromodeoxyuridine (BrdU) is added to the medium and incorporated into the cells, and the decrease in BrdU incorporation by various test substances is observed. Thus, the cell growth inhibitory action of the test substance can be tested. As shown in Example 2, the compound represented by the formula (I) of the present invention exhibits a cell growth inhibitory action about 10 times that of tumor cells compared to celecoxib. Therefore, the compound of the present invention is useful as a tumor cell growth inhibitor, and more specifically, is promising as an anticancer agent.
本発明の化合物はまた、アポトーシス誘導作用を有する。例えば、アポトーシスは培養細胞培養中のDNAの断片化を指標として観察することが出来る。本発明の式（Ｉ）で示される化合物は、実施例３に示す通り、腫瘍細胞、及び関節リウマチ患者由来滑膜細胞に対して、セレコキシブに比べて約10倍のアポトーシス誘導作用を有する。従って、本発明の化合物はアポトーシス誘導剤として有用であり、また抗癌剤及びリウマチ治療剤として有望である。 The compounds of the present invention also have an apoptosis-inducing action. For example, apoptosis can be observed using DNA fragmentation in cultured cell culture as an indicator. As shown in Example 3, the compound represented by formula (I) of the present invention has an apoptosis-inducing action about 10 times that of celecoxib against tumor cells and synovial cells derived from rheumatoid arthritis patients. Therefore, the compound of the present invention is useful as an apoptosis inducer and is promising as an anticancer agent and a rheumatoid therapeutic agent.
本発明の化合物は、滑膜細胞に対してプロスタグランジンE2産生抑制作用を有する。これは、例えば、被験化合物の種々の濃度での存在下で滑膜細胞を培養し、被験化合物の濃度の上昇によるプロスタグランジンE2の産生の抑制を測定することにより確認することが出来る。実施例４から明らかな通り、本発明の式（Ｉ）で示される化合物は、滑膜細胞に対して、プロスタグランジンE2産生抑制作用を有する。従って、本発明の化合物は、プロスタグランジン産生抑制剤として有用であり、具体的には、リウマチの治療剤として有望である。 The compound of the present invention has a prostaglandin E 2 production inhibitory effect on synovial cells. This can be confirmed, for example, by culturing synovial cells in the presence of various concentrations of the test compound and measuring suppression of prostaglandin E 2 production due to an increase in the concentration of the test compound. As is clear from Example 4, the compound represented by the formula (I) of the present invention has a prostaglandin E 2 production inhibitory action on synovial cells. Therefore, the compound of the present invention is useful as a prostaglandin production inhibitor, and is specifically promising as a therapeutic agent for rheumatism.
本発明の化合物を医薬として使用する場合、経口的に、又は非経口的に、たとえば注射により投与することが出来る。これらの経路での投与のためには、それらの適する常用の剤形とすることが出来る。例えば、経口投与のためには、カプセル剤、錠剤、粉剤などとして投与することができる。また、非経口投与のためには、例えば皮下注射、筋肉注射、静脈注射、関節腔内注射などにより投与することができる。これら種々の投与剤は、医薬として許容される常用の賦形剤、増量剤、安定剤などを用いて、常法に従って形成することができる。 When the compound of the present invention is used as a medicine, it can be administered orally or parenterally, for example, by injection. For administration by these routes, their suitable conventional dosage forms can be provided. For example, for oral administration, it can be administered as capsules, tablets, powders, and the like. For parenteral administration, administration can be performed by subcutaneous injection, intramuscular injection, intravenous injection, intraarticular injection, and the like. These various administration agents can be formed according to conventional methods using pharmaceutically acceptable conventional excipients, bulking agents, stabilizers and the like.
次に、実施例により本発明を更に具体的に説明する。
実施例１. 式（II）の化合物（Ａ）の合成
550mgの化合物Ａを前記の合成ルートで合成した。その理化学的性質に次の通りであった。
元素分析：C19H19F3N4O2S・0.14CHCl3・0.4H2O（F.W.448.36）.
計算値：C,51.27;H,4.48;N,12.50;Cl,3.32;F,12.71;S,7.15.
測定値：C,51.27;H,4.33;N,12.67;Cl,3.12;F,12.52;S,7.02.
化学純度： >99%（HPLCによる）
HPLC条件：カラム：Ｌ−カラムODS（4.6ｘ150mm）；溶剤：MeCN/20mMリン酸緩衝法（pH 6.5）（35：65）, １ml/min；
サンプル：１mg/ml MeOH；検出答：254nm；保持時間：21.2min.
HPLCスペクトル：図１
1H-NMRスペクトル：図２
Next, the present invention will be described more specifically with reference to examples.
Example 1 Synthesis of Compound (A) of Formula (II)
550 mg of compound A was synthesized by the above synthesis route. Its physicochemical properties were as follows.
Elemental analysis: C 19 H 19 F 3 N 4 O 2 S · 0.14
Calculated values: C, 51.27; H, 4.48; N, 12.50; Cl, 3.32; F, 12.71; S, 7.15.
Measurements: C, 51.27; H, 4.33; N, 12.67; Cl, 3.12; F, 12.52; S, 7.02.
Chemical purity:> 99% (by HPLC)
HPLC conditions: Column: L-column ODS (4.6 × 150 mm); Solvent: MeCN / 20 mM phosphate buffer method (pH 6.5) (35:65), 1 ml / min;
Sample: 1 mg / ml MeOH; detection answer: 254 nm; retention time: 21.2 min.
HPLC spectrum: Fig. 1
1 H-NMR spectrum: FIG.
実施例２. 細胞増殖抑制作用
（１）試験細胞の用意
（ａ）滑膜細胞の調製
組織の研究利用に同意した関節リウマチ患者から得た滑膜組織をコラゲナーゼ処置した。コラゲナーゼにより消化された滑膜組織をペニシリン/ストレプトマイシンおよび10％FBSを含むRPMI1640に懸濁し、細胞培養用フラスコにまいた。このフラスコを37℃、5％CO2の条件下で培養し、フラスコに付着した細胞を滑膜細胞とした。
（ｂ）腫瘍細胞
HT-29、SW480およびHCT116細胞：ペニシリン/ストレプトマイシンおよび10％FBSを含むRPMI1640で培養した。
Example 2. Cell growth inhibitory action (1) Preparation of test cells (a) Preparation of synovial cells Synovial tissue obtained from rheumatoid arthritis patients who agreed to use the tissue for research was treated with collagenase. Synovial tissue digested with collagenase was suspended in RPMI 1640 containing penicillin / streptomycin and 10% FBS, and spread in a cell culture flask. The flask was cultured under conditions of 37 ° C. and 5% CO 2 , and cells attached to the flask were used as synovial cells.
(B) Tumor cells
HT-29, SW480 and HCT116 cells: cultured in RPMI 1640 with penicillin / streptomycin and 10% FBS.
（２）BrdU取り込み試験
細胞増殖の程度は、DNA合成時に細胞に取り込まれるブロモデオキシウリジン（bromo-deoxyuridine）(BrdU)の量を指標に検討した。各種細胞を１ｘ104細胞/ウエルで96ウエルプレートにまき、セレコキシブ、本発明の式（II）の化合物A又はロフェコキシブ（rofecoxib）の存在下CO2インキュベーターにて24時間培養した。その後、BrdUを最終濃度10μMになるように培養液を加え、さらに18時間培養した。培養後、細胞内に取り込まれたBrdU量をCell Proliferation ELISA Kit (Roche Diagnostics社)を用いて測定し、薬物未処置のコントロールの取り込み量を100として、各条件での取り込み量を求め、細胞増殖の指標とした。なお、ロフェコキシブは、WO95/00501に記載の方法により合成した。
(2) BrdU incorporation test The degree of cell proliferation was examined using the amount of bromodeoxyuridine (BrdU) incorporated into cells during DNA synthesis as an index. Various cells were seeded at 1 × 10 4 cells / well in a 96-well plate and cultured for 24 hours in a CO 2 incubator in the presence of celecoxib, compound A of the formula (II) of the present invention or rofecoxib. Thereafter, BrdU was added to the culture solution to a final concentration of 10 μM, and further cultured for 18 hours. After incubation, the amount of BrdU incorporated into the cells is measured using the Cell Proliferation ELISA Kit (Roche Diagnostics), and the amount of uptake in each condition is determined with the amount of uptake of the drug-untreated control as 100. It was used as an index. Rofecoxib was synthesized by the method described in WO95 / 00501.
（３）結果
本発明の式（II）の化合物Ａは、検討した数種の腫瘍細胞（HT29、SW480、HCT116）、並びに関節リウマチ患者由来滑膜細胞の増殖を抑制した。薬物未処置条件でのBrdU取り込み量を100％としたときの、各薬物処置によるBrdU取り込み量を図３及び図４に示した。取り込み量が50％となる時の薬物濃度は、いずれの細胞においても３〜５μＭであった。セレコキシブも同様に、検討したいずれの細胞においても、その増殖を抑制したが、その50％抑制濃度は10〜20μＭであり、化合物Ａの方が強力であった。
(3) Results Compound A of the formula (II) of the present invention suppressed the growth of several types of tumor cells examined (HT29, SW480, HCT116) and synovial cells derived from rheumatoid arthritis patients. 3 and 4 show the BrdU uptake by each drug treatment when the BrdU uptake under the untreated condition is 100%. The drug concentration when the uptake amount was 50% was 3 to 5 μM in any cell. Celecoxib similarly inhibited its growth in any of the cells examined, but its 50% inhibitory concentration was 10-20 μM, and Compound A was more potent.
実施例３. アポトーシスの誘導
（1）細胞の用意
細胞は、実施例１に記載した方法により用意した。
（２）アポトーシスの誘導
アポトーシス誘導作用は、断片化したDNAを指標に検討した。各種細胞を2ｘ104cells/wellで96wellプレートにまき、セレコキシブ、化合物Aおよびロフェコキシブの存在下CO2インキュベーターにて24時間培養した。その後、断片化したDNA量をCell Death Detection ELISAPLUS (Roche Diagnostics社)を用いて測定し、薬物未処置のコントロールの断片化DNA量を１として、各条件での断片化DNA量を求め、アポトーシス誘導の指標とした。
Example 3 Induction of Apoptosis (1) Preparation of Cells Cells were prepared by the method described in Example 1.
(2) Induction of apoptosis The apoptosis-inducing action was examined using fragmented DNA as an index. Various cells were seeded in 96-well plates at 2 × 10 4 cells / well and cultured in a CO 2 incubator for 24 hours in the presence of celecoxib, compound A and rofecoxib. Subsequently, the amount of fragmented DNA was measured using Cell Death Detection ELISA PLUS (Roche Diagnostics), and the amount of fragmented DNA in each condition was determined with the amount of fragmented DNA of the drug-untreated control as 1, and apoptosis was determined. It was used as an indicator of guidance.
（３）結果
本発明の式（II）の化合物Aは、検討した数種の腫瘍細胞（HT-29、SW480およびHCT116）、並びに関節リウマチ患者由来滑膜細胞にアポトーシスを誘導し、その増殖を抑制した。その50％作用濃度（最大作用の50％を発現する薬物濃度）は、いずれの細胞においても、5μM前後であった。セレコキシブも同様に、検討したいずれの細胞においてもアポトーシスを誘導したが、その50％作用濃度は20μM前後であり、化合物Aの方が強力であった。結果を、図５及び図６に示す。
(3) Results The compound A of the formula (II) of the present invention induces apoptosis in several types of tumor cells examined (HT-29, SW480 and HCT116) and synovial cells derived from rheumatoid arthritis patients. Suppressed. The 50% action concentration (the drug concentration expressing 50% of the maximum action) was around 5 μM in all cells. Celecoxib similarly induced apoptosis in any of the cells examined, but its 50% working concentration was around 20 μM, and Compound A was more potent. The results are shown in FIGS.
実施例４. プロスタグランジンE 2 の産生抑制
（１）細胞の用意
細胞は、実施例１に記載した方法により用意した。
（２）プロスタグランジン産生抑制実験
滑膜細胞を1ｘ105細胞/ウエルで24ウエルプレートにまきCO2インキュベーターにて24時間培養した。その後、細胞をPBSで洗い、本発明の式（II）の化合物の存在下、CO2インキュベーターにて1時間培養した。培養後、3μMになるようにアラキドン酸（Cayman Chemical社）を加え、30分間培養後に上清を回収した。培養上清中のPGE2量をELISA kit（Cayman Chemical社）によって測定した。
Example 4. Production inhibition of prostaglandin E 2 (1) Preparation of cells Cells were prepared by the method described in Example 1.
(2) Prostaglandin production suppression experiment Synovial cells were plated at 1 × 10 5 cells / well in a 24-well plate and cultured in a CO 2 incubator for 24 hours. Thereafter, the cells were washed with PBS and cultured in a CO 2 incubator for 1 hour in the presence of the compound of formula (II) of the present invention. After the culture, arachidonic acid (Cayman Chemical) was added to 3 μM, and the supernatant was collected after 30 minutes of culture. The amount of PGE 2 in the culture supernatant was measured by ELISA kit (Cayman Chemical).
（３）結果
結果を図７に示す。この図から明らかな通り、本発明の式（II）の化合物は、活膜細胞によるプラスタグランジンE2の産生を抑制した。
(3) Results The results are shown in FIG. As is clear from this figure, the compound of the formula (II) of the present invention suppressed the production of plastaglandin E 2 by active membrane cells.
Claims (5)
により表される、N-(アミノアルキル)-4-〔5-(4-トリル)-3-(トリフルオロメチル-1H-ピラソール-1-イル〕-ベンゼンスルホンアミド。 The following general formula (I):
N- (aminoalkyl) -4- [5- (4-tolyl) -3- (trifluoromethyl-1H-pyrazol-1-yl] -benzenesulfonamide represented by:
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| JP2004044561A JP2005232101A (en) | 2004-02-20 | 2004-02-20 | Celecoxibaminoalkyl derivative |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US20160221976A1 (en) * | 2013-05-07 | 2016-08-04 | The Regents Of The University Of California | Radiomitigating pharmaceutical formulations |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20160221976A1 (en) * | 2013-05-07 | 2016-08-04 | The Regents Of The University Of California | Radiomitigating pharmaceutical formulations |
| US9840483B2 (en) * | 2013-05-07 | 2017-12-12 | The Regents Of The University Of California | Radiomitigating pharmaceutical formulations |
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