JP2009526831A - 新規ピロン誘導体及びそれらの合成方法 - Google Patents
新規ピロン誘導体及びそれらの合成方法 Download PDFInfo
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- JP2009526831A JP2009526831A JP2008554868A JP2008554868A JP2009526831A JP 2009526831 A JP2009526831 A JP 2009526831A JP 2008554868 A JP2008554868 A JP 2008554868A JP 2008554868 A JP2008554868 A JP 2008554868A JP 2009526831 A JP2009526831 A JP 2009526831A
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- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 229910001923 silver oxide Inorganic materials 0.000 description 1
- 229960002855 simvastatin Drugs 0.000 description 1
- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 description 1
- 229940125707 sleep disorder agent Drugs 0.000 description 1
- 230000008454 sleep-wake cycle Effects 0.000 description 1
- 208000020685 sleep-wake disease Diseases 0.000 description 1
- 230000037322 slow-wave sleep Effects 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- AEQFSUDEHCCHBT-UHFFFAOYSA-M sodium valproate Chemical compound [Na+].CCCC(C([O-])=O)CCC AEQFSUDEHCCHBT-UHFFFAOYSA-M 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- WZAIVXXKOAWTGQ-UHFFFAOYSA-N spiro[2,3-dihydronaphthalene-4,3'-piperidine]-1,2',6'-trione Chemical compound O=C1NC(=O)CCC11C2=CC=CC=C2C(=O)CC1 WZAIVXXKOAWTGQ-UHFFFAOYSA-N 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
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- 206010042772 syncope Diseases 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229960003188 temazepam Drugs 0.000 description 1
- 230000002381 testicular Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 150000001467 thiazolidinediones Chemical class 0.000 description 1
- 229960002784 thioridazine Drugs 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 108700012359 toxins Proteins 0.000 description 1
- ZFDIRQKJPRINOQ-UHFFFAOYSA-N transbutenic acid ethyl ester Natural products CCOC(=O)C=CC ZFDIRQKJPRINOQ-UHFFFAOYSA-N 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 229960001147 triclofos Drugs 0.000 description 1
- ZEWQUBUPAILYHI-UHFFFAOYSA-N trifluoperazine Chemical compound C1CN(C)CCN1CCCN1C2=CC(C(F)(F)F)=CC=C2SC2=CC=CC=C21 ZEWQUBUPAILYHI-UHFFFAOYSA-N 0.000 description 1
- 229960002324 trifluoperazine Drugs 0.000 description 1
- 229960002431 trimipramine Drugs 0.000 description 1
- ZSCDBOWYZJWBIY-UHFFFAOYSA-N trimipramine Chemical compound C1CC2=CC=CC=C2N(CC(CN(C)C)C)C2=CC=CC=C21 ZSCDBOWYZJWBIY-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 229950004526 uldazepam Drugs 0.000 description 1
- DTMPGSXFUXZBDK-UHFFFAOYSA-N uldazepam Chemical compound C12=CC(Cl)=CC=C2N=C(NOCC=C)CN=C1C1=CC=CC=C1Cl DTMPGSXFUXZBDK-UHFFFAOYSA-N 0.000 description 1
- 230000036325 urinary excretion Effects 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
- 229940102566 valproate Drugs 0.000 description 1
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- PNVNVHUZROJLTJ-UHFFFAOYSA-N venlafaxine Chemical compound C1=CC(OC)=CC=C1C(CN(C)C)C1(O)CCCCC1 PNVNVHUZROJLTJ-UHFFFAOYSA-N 0.000 description 1
- 229960004688 venlafaxine Drugs 0.000 description 1
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- 230000004580 weight loss Effects 0.000 description 1
- 239000009637 wintergreen oil Substances 0.000 description 1
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 description 1
- 229960002555 zidovudine Drugs 0.000 description 1
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Classifications
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Abstract
【選択図】なし。
Description
Ar−B−Ar’(I)
ここで、Bは、−X−Y−Z−を表し、
ここで、Xは、−(CH2)n(ここで、nは、0〜6)、Xのアルキルは、直鎖または分岐であり、
Yは、酸素、硫黄、>NH、又は、不存在;
Zは、>C=O、>O、>COO、又は、不存在;
ここで、X、YおよびZの、少なくとも1つは、存在しなければならない;
Arは、インドール核環系を表し:
ここで、前記アリールアルキル、アリールアルケニル、アラルアルキニル、又は、スチリル基は、選択的に、つぎに示す群からなる置換基から独立して選択される1〜4の置換基により環置換されることもある;それらの置換基とは、水素、ハロゲン、ハロゲン−C1〜5アルキル、アリール、1〜3のへテロ原子(窒素、酸素、および硫黄から独立して選択される)を含むC5〜7ヘテロ環基;1〜3のヘテロ原子(窒素、酸素、および硫黄から独立して選択される)を含むヘテロアリール基;C1〜5のアルキル、C2〜5のアルケニル、C2〜5のアルキニル、アリール−C1〜5アルキル、アリール−C1〜5アルケニル、アリール−C2〜5アルキニル、ヒドロキシ−C1〜5アルキル、ニトロ、アミノ、シアノ、シアナミド、グアニジノ、アミジノ、アシルアミド、ヒドロキシ、チオール、アシルオキシ、アジド、アルコキシ、カルボキシ、カルボニルアミド、S−アルキル又はアルキルチオール;及びR3又はR4は、さらに、Bヘの結合を含むか、又は、表すことができる;
ここで、Arは、R1又はR2で置換されていない、N−位も含んで、Arのどのような位置でもBに結合することができ、ここで、Ar’は、R1又はR2で置換されていない、N−位も含んで、Ar’のどのような位置でもBに結合することができ、
又は、薬学的に許容可能なそれらの塩又は立体異性体。
又は、薬学的に許容し得るそれらの塩又はそれらの立体異性体である。
Ar−B−Ar’(I)
ここで:
−B−は、:
X−Y−Z−であり、
ここで、Xは、−(CH2)n−、であり、(ここで、nは、0〜6)、アルキル部分は、直鎖または分岐である;
Yは、酸素、硫黄、>NH、又は、不存在であり;
Zは、>C=O、>O又は、>COO、又は、不存在であり;
ここで、X、YおよびZの、少なくとも1つは、存在しなければならない;
環系Arは、インドール核環、を表す。
ここで、前記アリ−ルアルキル、アリールアルケニル、アリールアルキニル、又は、スチリル基は、選択的に、次の置換基からなる群から独立して選択される1〜4の置換基により置換された環である:その置換基とは、水素、ハロゲン、ハロゲン−C1〜5アルキル、アリール、1〜3のへテロ原子(窒素、酸素、および硫黄から独立して選択される)を含むC5〜7のヘテロ環基;1〜3のヘテロ原子(窒素、酸素、および硫黄から独立して選択される)を含むヘテロアリール基;C1〜5のアルキル、C2〜5のアルケニル、C2〜5のアルキニル、アリール−C2〜5アルケニル、アリール−C2〜5アルキニル、ヒドロキシル−C1〜5アルキル、ニトロ、アミノ、シアノ、シアナミド、グアニジノ、アミジノ、アシルアミド、ヒドロキシル、チオール、アシルオキシ、アジド、アルコキシ、カルボキシ、カルボニルアミド、S−アルキル又はアルキルチオール;及びR3又はR4のいずれかは、さらに、Bヘの結合を含むか、表すことができる;
ここで、Arは、R1又はR2で置換されていない、N−位も含むAr環上のあらゆる位置においてBに結合することができ、そして、Ar’は、R1又はR2’で置換されていない、N−位も含んで、Ar’環上どのような位置でもBに結合することができる。
(i) 経口、非経口(例えば、筋肉内、腹腔内、静脈内又は皮下注射、又は、埋め込み(インプラント))、鼻腔、膣内、直腸、舌下、又は、局所投与経路に適している、また、各投与経路にとって、適切な投与用量に製剤化することができる。
(ii) 単位剤形において、約2.5μg〜25mg/kg体重の範囲内で式(I)の少なくとも1つの化合物の量を含む各単位用量である単位剤形;
(iii) 式(I)の少なくとも1の化合物が、所与の調節された速度で放出される持続放出製剤。
実施例 1
N−[2−(5−メトキシ−インドール−3−イル)−エチル]−コメンンアミド(N−[2−(5−methoxy−indol−3−yl)−ethyl]−commenamide)
N−[2−(5−メトキシ−インドール−3−イル)−エチル]−コメンアミド、の実験成績:
MS (ESI POS): 329 (M + H), 351 (M + Na), 392 (M + Na + CH3CN)
HPLCassay: 97%
1H NMR (CDC134OO MHz) δ 3.06 (t, j = 6.7 Hz, 2H, CH2CH2NH), 3.76−3.79 (m, 2H, CH25CH2NH), 3.84 (s, 3H OCH3), 6.32 (br s, IH,OH),6.76 (br s, 1Η, CH2CH2NH), 6.9 (dd, J1 = 2.3 Hz, J2= 8.8 Hz, IH aromatic H), 7.04 (d, J= 2.3 Hz, IH, aromatic H), 7.06 (d, J = 2.3 Hz, IH, aromatic H), 7.27 (s, IH, CH), 7.29(d, J = 8.8 Hz, IH, aromatic H), 7.73 (s, IH, CH),7.96 (br s, 1Η, NH).
実施例 2
O−[2−(5−メトキシ−インドール−3−イル)−エチル]−コメン酸エステル(O−[2−(5−methoxy−indole−3−yl)−ethyl]−comenic ester)
O−[2−(5−メトキシ−インドール−3−イル)−エチル]−コメン酸エステルの合成のための反応スキーム
O−[2−(5−メトキシ−インドール−3−イル)−エチル]−コメン酸エステルの実験成績:
MS (ESI POS): 330 (M + H), 352 (M + Na), 393 (M + Na +CH3CN)
HPLC assay: 97 %
1H NMR (CDCl3 400 MHz) δ 3.18−3.22 (m, 2H,CH2CH2O), 3.87 (s, 3H5 OCH3), 4.60−4.64 (m,2Η, CH2CH2O), 6.40 (br s, 1Η, OH), 6.88 (dd, J1 = 2.2 Hz, J2= 8.8 Hz, IH, aromatic H), 7.06−7.08 (m, 2H, aromatic H + CH),
7.22 (s, IH, aromatic H), 7.25−7.28 (m, IH, aromatic H), 7.96−8.0 (s + br s,2 H,NH+ CH).
実施例3
N−[2−5−メトキシ−インドール−3−イル]−エチル]−ケリドンアミド(N−[2−5 −methoxy−indol−3−yl)−ethyl]−chelidonamide):
N−[2−(5−メトキシ−インドール−3−イル)−エチル]−ケリドンアミドの合成反応スキーム
i)DMF、HOBt1.1当量、EDC1.1当量、NEt32.5当量、室温、24
N−[2−5−メトキシ−インドール−3−イル]−エチル]−ケリドンアミドの合成の一般的方法
N−[2−5−メトキシ−インドール−3−イル]−エチル]−ケリドンアミドの実験成績:
MS (ESI POS): 357 (M + H), 374 (M + Na), 398398 (M + H + CH3CN)
HPLC assay:97%
1H NMR (DMSOd6 400MHz) δ 2.91(t, J = 7.5 Hz3 2H, CH2CH2NH),3.50−3.55 (m, 2H, CH2CH2NH), 3.76 (s, 3H, OCH3), 6.64−6.71 (m, 3Η),7.07 (d, J = 2.6 Hz, IH), 7.13 (d, J = 2.1 Hz, IH), 7.20 (d, J = 8.8 Hz, IH),8.29(s, IH, NH), 8.92 (br t, J = 5.8 Hz,IH,CH2CH2NH),10.62 (br s, 1Η,COOH).
実施例 4
N−[2−(5−メトキシ−インドール−3−イル)−エチル]−クマリルアミド(N−[2−(5−methoxy−indol−3−yl)−ethyl]−coumalylamide):
N−[2−(5−メトキシ−インドール−3−イル)−エチル]−クマリルアミドの合成の一般的方法
N−[2−(5−メトキシ−インドール−3−イル)−エチル]−クマリルアミドの試験成績:
MS (ESI POS): 313 (M + H), 335 (M + Na), 376 (M + Na + CH3CN)
HPLCassay: 95%
1H NMR (CDCl3, 400MHz) δ 3.09 (t, J = 6.1Hz, 2H, CH2CH7NH), 3.70−3.74 (m, 2H, CH2CH2NH), 3.87 (s, 3H, OCH5J, 5.58 (d, J = 8.8 Hz,IH, CH;, 6.88−7.04 (m, 5Η, 4 aromatic H + 1 CH;, 7.29 (d, J = 8.8 Hz, IH, CH;, 8.03 (br s, 1Η, NH), 9.65 (br s, IH,CH2CH2NH).
実施例 5
N−[2−(2−ブロモ−5−メトキシ−インドール−3−イル)−エチル]−クマリルアミド(N−[2−(2−bromo−5−methoxy−indol−3−yl)−ethyl]−coumalylamide):
a.5−メトキシトリプタミンと無水フタール酸が、トルエン中デ16時間還流シタ。減圧下で反応濃度は、更なる精製をすることなく、次の段階で用いる粗生産物を得た。
b.粗フタロイルトリプタミンは、THF:CHCl3(1:1)に溶解し、得られた溶液は、−10℃に冷却し、次いで、ピリジウムブロマイドパーブロマイドで処理した。反応は、TLCでチェックし、室温まで暖め;CH2Cl2を加えた。溶液は、飽和Na2S2O3水で洗浄し、水相は、CH2Cl2で抽出した。合わせた有機相は、(MgSO4)で乾燥させ、濾過し、減圧下で濃縮し、そして粗生産物は、更なる精製をすることなく、次のステップで用いた。
c.フタールイミド基は、室温でエタノール中で水性メチルアミン処理により除去した。
d.N−メチルモルフィンが、ジメチルフォルムアミド中に溶かしたクマリン酸溶液に加え、続いて、窒素ガス雰囲気下で、2−(lH−ベンゾトリアゾール−l−イル)−l,1,3,3−テトラメチルウロニウムテトラフルオロボレート(TBTU)処理した。反応混液を室温で20分間攪拌後、5−メチルトリプタミンをゆっくり加え、混液は、5時間攪拌した。反応混液からのDMFは、高度の真空下で除去した。固体生産物は、CH2Cl2に溶解し、得られた有機画分は、0.2NのHCl、0.2NNaHCO3及び水で洗浄し、次いで、(MgSO4)で乾燥し、濾過し、減圧下で濃縮した。その結果得られた生産物は、クロマトグラフィで精製した。
N−[2−(2−ブロモ−5−メトキシ−インドール−3−イル)−エチル]−クマリルアミドの試験成績:
1H NMR (CDCl3, 300 MHz) δ 10.00 (s, IH, NH), 8.00 (s, IH, Aromatic COOCH), 7.06 (t,IH, J=9 Hz, CONH), 6.78−6.67 (m, 4H, Aromatic H),5.41 (d, IH, J=9.6 Hz, Aromatic COCH), 3.67 (s, 3H, OCH3), 3.52 (q, 2H,J=6.24 Hz), 2.87 (t, 2H, j=6.3 Hz)
実施例 6
N−[2−(5−エトキシ−インドール−3−イル)−エチル]−コマニルアミド(N−[2−(5−methoxy−indol−3 −yl)−ethyl]−comanilamide):
N−[2−(5−メトキシ−インドール−3−イル)−エチル]−コマニルアミドの合成の反応スキーム
iDMF,HOBt1.1当量、EDC1.1当量、NEt32.5当量、室温、6時間
N−[2−(5−メトキシ−インドール−3−イル)−エチル]−クマニルアミドの合成の通常の方法
N−[2−(5−メトキシ−インドール−3−イル)−エチル]−コマニルアミド(comanilamide)の試験成績:
MS (ESI POS): 313 (M + H), 330 (M + H2O),335 (M + Na), 376 (M + Na + CH3CN)
HPLC assay: 98%
MS (ESI POS): 313 (M + H),330 (M + H2O), 1H NMR (DMSOd6,400MHz) δ 2.88−2.92 (m, 2H, CH2CH2NH), 3.48−3.53(m, 2H, CH2CH2NH), 3.75 (s, 3H, OCH3), 6.42 (dd, J1= 2.3 Hz,J2= 5.9 Hz, IH, CH=CH), 6.71 (dd, J1= 2.1Hz, J2 = 8.8 Hz, IH, aromatic H), 6.78(d,J = 2.3 Hz, IH, aromatic H), 7.04 (d, J = 2.3 Hz, IH, CH), 7.13 (d, J =2.1 Hz, IH, aromatic H), 7.22 (d, J = 8.8 Hz, IH,aromatic H), 8.21 (d, J =5.9 Hz, IH, CH=CH−CO), 9.04 (br t, J = 5.8 Hz, IH, CH2CH2NH), 10.65 (brs,IH5 NH).
実施例7
N−[2−(5−メトキシ−インドール−3−イル)−エチル]−2−メトキシ−コメンアミド(N−[2−(5−methoxy−indol−3−yl)−ethyl]−2−methoxy−commenamide):
N−[2−(5−メトキシ−インドール−3−イル)−エチル]−2−メトキシ−コメンアミドの合成の反応スキーム
ii ) MnO2 16当量、CH3OH、還流, 1.5時間; Ag2O 1当量、 H2O、NaOH 1N、 室温、1時間、
iii) HOBt 1.1当量、EDC 1.1当量、NEt3 .5、室温、16時間、
N−[2−(5−メトキシ−インドール−3−イル)−エチル]−2−メトキシ−コメnアミドの合成の通常の方法
i. 250mlの4つ首丸底フラスコにアルゴン雰囲気下で、3.2gのコウジ酸(1当量)が80mlのメタノールに溶解された。メタノール溶液(4.6ml、1.1当量;Fluka、5.4M)中で、ナトリウムメトキシドが、磁気攪拌棒で一部を攪拌しつつ加えた。15分後、10mlのCH3OH中にヨウ化メチル2.95ml(1.1当量)の溶液が、そこに滴下により加えられ、得られた溶液は室温で反応させた。反応の後、TLC(溶出液として、ジクロロメタン/メタノール9/1)に付した。7時間後、変換率は、薬50%であった、それゆえ、別の1.1当量のCH3I(10mlのCH3OH中に2.95ml)を加えた。反応混液は、次いで室温で攪拌しつつさらに65時間反応させ、その後、水(400ml)を加えた。その溶液は、残りの容積が約25〜30mlまで濃縮し、4℃で14時間放置した。得られた沈殿物は、濾過で集め、ジエチルエーテルで洗浄し、真空下50℃で乾燥した。2−ヒドロキシメチル−5−メトキシ−4−ピランが、黄色結晶の固体として回収された(2.2g、収率63%)。
ii. 250mlの丸底フラスコに、2−ヒドロキシメチル−5−メトキシ−4−ピラン(2.2g、1当量)が85mlのメタノールンかに溶解し、19.6gの活性二酸化マンガンを加えた(16当量)。反応液は、1.5時間環流下で加熱し、次いで、室温に冷却した。不溶性部分は、濾過により除き、残っている濾液は、約当初容積の約3分の1に濃縮した。これに、30mlの水、10mlの1NNaOH及び酸化銀(1当量)が加えられた。得られた溶液は、室温で1時間反応させ、次いで、セライトパッドで濾過して、塩を除いた。濾液は、そこからメタノールを除くため減圧濃縮し、次いで、ジクロロメタンで洗浄した。つづいて、HCl2N(12ml)が水溶液相に加え、形成した沈殿物を、濾過により集め、ジエチルエーテルで洗浄し、50℃で真空下で乾燥した。5−メトキシ−4−オキソ−4H−ピラン−カルボン酸ガ白色固体として得られた(1.2g、50%収率)。
iii. アルゴン雰囲気下で、100mlの3つ首丸底フラスコに、5−メトキシ−4−オキソ−4H−ピラン−カルボン酸(340mg、1当量)と5−メトキシトリプタミン塩酸塩(500mg、1.1当量)を充填し、DMF(15ml)に溶解し、氷浴で0℃にした。HOBt(1−ヒドロキシベンゾトリアゾール モノハイドレート、300mg、1.1当量)、EDC(1−(3―ジメチルアミノプロピル)―3―エチルカルボジイミド塩酸塩、425mg、1.1当量)とトリエチルアミン(0.98ml、3.5当量)が磁気棒で攪拌しつつ加えられた。混液は、さらに15分間0℃で攪拌し、続いて、16時間室温で反応に付した。反応が経過した後、HPLC−MSに付した。水(25ml)が次いで加えられ、混液は、ジクロロメタン(2x30ml)で抽出した。しばらくすると、併せた有機層中に懸濁液が現れた。そのようにして形成された固体は、濾過により集められ、ジクロロメタンで洗浄し、50℃で乾燥した。生成物は、白色結晶として回収した(210mg)。濾液から、ロータリーエバポレータにより溶媒を除去した。得られた固体残渣は、ジクロロメタン/石油エーテルで粉末にし、室温で24時間放置した。混液は、濾過して、さらに、N−[2−(5−メトキシ−インドール−3−イル)−エチル]−2−メトキシ−コメンアミド(70mg、収率42%)を得た。
N−[2−(5−メトキシ−インドール−3−イル)−エチル]−2−メトキシ−コメンアミドの試験成績:
MS (ESI POS): 343 (M + H), 365 (M + Na), 406 (M + Na + CH3CN)
HPLC assay: 98 %
1H NMR (DMSOd6, 400MHz) δ 2.87−2.91 (m, 2H, CH2CH2NH), 3.47−3.52 (m, 2H, CH2CH2NH),3.70 (s, 3H, OCH3), 3.74 (s, 3H, OCH3), 6.70 (dd,J1= 2.2 Hz, J2= 8.8 Hz, IH, aromatic H), 6.83 (s, IH, CH), 7.03 (d, J = 2.8 Hz, IH, aromatic H), 7.12 (d, J = 2.2 Hz, IH, aromatic H), 7.21 (d, J = 8.8 Hz,IH, aromatic H), 8.12 (s, IH, CH), 9.02 (br t, J = 5.7 Hz, IH, CH7CH2NH), 10.64 (br s, IH5 NH).
実施例 8
N−[2−(5−メトキシ−インドール−3−イル)−エチル]− 2−ピロン−6−カルボキシアミド(N−[2−(5−methoxv−indol−3−yl)−ethyl]− 2−Pyrone−6−carboxamid):
ii) HCl37%、100℃、6時間
iii) DME、HOBt 1.1当量、EDC1.1当量、Py2.2当量、NEt3 1.4当量、室温、3
N−[2−(5−メトキシ−インドール−3−イル)−エチル]−2−ピロン−6−カルボキシアミド合成の一般的な方法
100mlの4つ首丸底フラスコをアルゴン雰囲気下で、5.0gのシュウ酸ジエチル(1当量)を35mlの乾燥トルエンに溶解された。カリウムエトキシド(2.9g、0.998当量)が、一部で磁気攪拌棒で攪拌しつつ加えられた。当初温度は40℃に達しており、投与懸濁液は、ゆっくりと、オレンジ色の溶液に変わった。2時間後、その溶液は、氷浴で0℃に冷やし、クロトン酸エチルエステル(4.3ml、1当量)が10秒間の滴下により加えられた。その添加収量から15分後、2,4−ヘキサジエン−5−ヒドロキシ−1,6−ジオエイトの黄色沈殿の形成がみられた。その懸濁液は、室温で一晩反応させた。つづいて、反応混液は、濾過されて、得られた黄色沈殿は、シクロヘキサンとジエチルエーテルで洗浄し、真空下、50℃で乾燥し、4.9gの黄色固体を得た。後者は、次いで、70mlの水に溶解し、5mlの37%HClで乾燥した。2〜3分後、黄色沈殿を形成した。懸濁液は、室温でさらに、30分間攪拌し、次いで、4℃で一晩保存した。中間体、ジエチル2,4−ヘキサヂエン−5−ヒドロキシ−1,6ジオエイトガ濾過により集められ、水で洗浄した。
100mlの3つ首丸底フラスコに、アルゴン雰囲気下、5−メトキシトリプタミン塩酸塩(430mg、1.1当量)が、1,2−ジメトキシエタン(DME、15ml)中に懸濁された。ピリジンが加えられ(0.34ml、1.1当量)、その懸濁液は、室温で30分間攪拌された。2−ピロン−6−カルボン酸(250mg、1当量)が加えられ、次いで、氷浴を用いて、内部温度が0℃になるまで氷浴を用いて冷やした。HOBt(1−ヒドロキシベンゾトリアゾール モノハイドレート、260mg、1.1当量)、EDC(1−(3―ジメチルアミノプロピル)−3−エチルカルボジイミド塩酸塩、370mg、1.1当量)とトリエチルアミン(0.34ml、1.4当量)が、磁気棒で攪拌しつつ加えられた。混液は、さらに15分間0℃で攪拌し、続いて、3時間室温で反応に付した。反応が経過した後、HPLC−MSに付した。得られた溶液は、真空下で濃縮し、粗残渣は、カラムクロマトグラフィで精製し、ジクロロメタン/メタノール98/2で溶出した。N−[2−(5−メトキシ−インドール−3−イル)−エチル]−2−ピロン−6−カルボキシアミドは、黄色固体として回収した(400mg、収率72%)。
N−[2−(5−メトキシ−インドール−3−イル)−エチル]−2−ピロン−6−カルボキサミドの試験成績:
MS (ESI POS): 313 (M + H), 330 (M + H2O),376 (M +Na + CH3CN)
HPLC assay: 97 %
1H NMR (DMSOd6, 400MHz) δ 2.87−2.91 (m, 2H, CH2CH7NH), 3.47−3.52
(m, 2H, CH2CH2NH), 3.75 (s, 3H, OCH3), 6.55 (d, J = 9.4 Hz, 1 H, CH), 6.70 (dd,Jf=2.9 Hz, J2 = 8.8 Hz, IH, aromatic H), 7.02 (br d, J = 6.6 Hz, IH, CH),7.06 (d, J= 2.1 Hz, IH, aromatic H), 7.13 (d, J = 2.2 Hz, IH, aromatic H),7.22 (d, J = 8.8Hz, IH, aromatic H), 7.67 (dd, J1 = 6.6 Hz, J2 = 9.4 Hz, IH,CH), 8.87(br t, J = 5.8 Hz, IH, CH2CH2TVHJ, 10.65 (br s, IH, NH).
本発明の化合物の生物学的試験
試験例 1
マウスにおけるへキソバルビタールナトリウム塩の睡眠時間の効力
表1:マウスにおけるヘキソバルビタールナトリウムで誘導された睡眠時間の被験化合物100mg/kgの効果
試験例 2
CHO−K1細胞の膜における125I−メラトニン結合:
表2: MT−1又はMT−2受容体への結合に対する被験化合物の効果
表3: MT−3受容体への結合に対する被験化合物の効果
試験例 3:
CHO−K1細胞の膜におけるセロトニン受容体サブタイプの結合:
表4: 5−HT受容体に対する被験化合物の効果
モチメータ(Motimeter)試験
ロータロッド試験
表5: メラトニンとN−[2−(5−メトキシ−インドール−3−イル)−エチル]−クマリルアミドのマウス運動活動に対する効果(水平運動)
表6: マウでのスロータロッド試験におけるN−[2−(5−メトキシ−インドール−3−イル)−エチル]−コマニルアミド、及び、N−[2−(5−メトキシ−インドール−3−イル)−エチル]−コメンアミドのジアゼパムとの相互作用の効果
試験例 5:
グルコース枯渇状態とした。FFA(遊離脂肪酸)は、所与の濃度(300μM)で、所与の時間(3時間)、FFA処理の終了10分前に細胞に添加され、その細胞は、インシュリン(20nM)/メラトニン(10nM)/被験化合物(10nM)により、を37℃で刺激された。KRP−HEPES緩衝液中で、2−[3H]−デオキシ−d−グルコース(1μCi)と標識していない2−デオキシ−グルコースが添加され、細胞が室温で10分間インキュベーションされた。非特異的なグルコースの取り込みは、10μMサイトカラシンBの存在下で平行して測定した。サイトカラシンBは、トランスポータが媒介するグルコースの取り込みを阻害する。非特異的グルコースの取り込みは、各試験において、総取り込み量から差し引いた。細胞は次いで、氷冷したリン酸緩衝液生理食塩水(PBS)で3度洗浄し、1MNaOHで20分間可溶化した。サンプルは次いでシンチレーションカウンタを用いてカウントした。2−[3H]−デオキシ−d−グルコースの取り込みは、少なくとも2回の独立した試験で各々の条件でトリプチレットで試験した。2−[3H]−デオキシ−d−グルコースの取り込み(1分当たりのカウント−cpm)は、各試験の又は3回の独立した試験結果において、平均値+SEとして表した。ANOVA検定は、P<0.005の有意差を用いた(表7)。
表7:
Claims (36)
- 下記式(I)を有する化合物:
Ar−B−Ar’(I)
ここで、−B−は、−X−Y−Z−を表し、
ここで、Xは、−(CH2)n(ここで、nは、0〜6)、Xのアルキルは、直鎖または分岐であり;
Yは、酸素原子、硫黄原子、>NH又は、不存在であり;
Zは、>C=O、>O又は、不存在であり;
ここで、X,YおよびZの、少なくとも1つは、存在しなくてはならず;
Arは、インドール核環系、を表す。
ここで、前記アリ−ルアルキル、アリールアルケニル、アラルアルキニル、又は、スチリル基は、選択的に、独立して選択されることがある次の群から選択される、1〜4の置換基により環置換されることもあり得る;すなわち、それらの置換基とは、水素、ハロゲン、ハロゲン−C1〜5アルキル、アリール、1〜3のへテロ原子(窒素、酸素、および硫黄から独立して選択される)を含むC5〜7ヘテロ環基;1〜3のヘテロ原子(窒素、酸素、および硫黄から独立して選択される)を含むヘテロアリール基;C1〜5のアルキル、C2〜5のアルケニル、C2〜5のアルキニル、アリール−C1〜5アルキル、アリール−C2〜5アルケニル、アリール−C2〜5アルキニル、ヒドロキシ−C1〜5アルキル、ニトロ、アミノ、シアノ、シアナミド、グアニジノ、アミジノ、アシルアミド、ヒドロキシ、チオール、アシルオキシ、アジド、アルコキシ、カルボキシ、カルボニルアミド、S−アルキル又はアルキルチオール;
及びR3又はR4は、さらに、Bヘの結合を含むか、又は、表すことができる;
ここで、Arは、R1又はR2で置換されていない、N−位も含んで、Ar環上のどのような位置でもBに結合することができ、また、Ar’は、R1又はR2で置換されていない、N−位も含んで、Ar’環上のどのような位置でもBに結合することができ、
又は、薬学的に許容可能なそれらの塩又はそれらの立体異性体。 - Xが、−(CH2)nであり、ここで、nが、0〜6であり、Yが>NH、又は、>O、であり、そして、Zが、>COである請求項1記載の化合物。
- Ar’が、α−ピロン環系である請求項2記載の化合物。
- Ar’が、β−ピロン環系である、請求項2記載の化合物。
- Ar’が、γ−ピロン環系である、請求項2記載の化合物。
- Xが、−(CH2)2−、Yが、>NH、又は、>Oであり、そして、Zが>COであり、
Arが、インドール環であり;R3がインドール環の3位でXへの結合であり;R1がインドール環の5位でメトキシ基であり、そして、R2とR4は、各水素であり;
Ar’は、ピロン環の2位でZに結合したγ−ピロン環であり;R1は、ピロン環の5位の水素又はヒドロキシル基であり、R2は、γ−ピロン環の6位の水素またはカルボキシ基であり;
又は、薬学的に許容可能なそれらの塩又はそれらの立体異性体、
である請求項1記載の化合物。 - Xが、−(CH2)2−、Yが>NH、又は、>Oであり、そして、Zが>COであり、
Arが、インドール環であり;R3がインドール環の3位でXへの結合であり;R1がインドール環5位のメトキシ基であり、そして、R2とR4は、各水素であり;
Ar’は、ピロン環の5位でZにより置換されたα−ピロン環であり;R1’とR2’は、各水素であり;
又は、薬学的に許容可能なそれらの塩又はそれらの立体異性体、
である請求項1記載の化合物。 - Xが、−(CH2)2−、Yが>NHであり、Zが>COであり;
Arが、インドール環であり;R3がインドール環の3位でのXへの結合であり;R1は、インドール環5位のメトキシ基であり、そして、R2とR4は、各水素であり;
Ar’は、ピロン環の2位でZにより置換されたγ−ピロン環であり;R1は、ピロン環5位のヒドロキシルであり;R2は水素であり;
又は、それらの塩又はそれらの立体異性体、
である請求項1記載の化合物。 - Xが、−(CH2)2−、Yが>Oであり、そして、Zが>COであり;
Arが、インドール環であり;R3がインドール環の3位のXへの結合であり;R1がインドール環5位のメトキシ基であり、そして、R2とR4は、各水素であり;
Ar’は、ピロン環の2位でZにより置換されたγ−ピロン環であり;R1’は、ピロン環5位のヒドロキシル基であり;R2’は水素であり;
又は、それらの塩又は立体異性体、
である請求項1記載の化合物。 - Xが、−(CH2)2−、Yが、>NH、そして、Zが、>COであり;
Arが、インドール環であり;R3がインドール環の3位でのXへの結合であり;R1がインドール環5位のメトキシ基であり、そして、R2とR4は、各水素であり;
Ar’は、ピロン環の2位でZにより置換されたγ−ピロン環であり;R1’とR2’は水素であり;
又は、それらの塩又は立体異性体、
である請求項1記載の化合物。 - Xが、−(CH2)2−、Yが、>NH、そして、Zが、>COであり;
Arが、インドール環であり;R3がインドール環の3位のXへの結合であり;R1がインドール環5位のメトキシ基であり、そして、R2とR4は、各水素であり;
Ar’は、ピロン環の5位でZにより置換されたα−ピロン環であり;R1’とR2’は水素であり;
又は、それらの塩又は立体異性体、
である請求項1記載の化合物。 - 1又はそれ以上の薬学的に許容可能な希釈剤、保存剤、溶解剤、乳化剤、アジュバント、賦形剤、又はキャリアと併用した治療上有効量を含む請求項1の化合物、それらの塩、又は立体異性体を含む薬学的製剤。
- 次の特性、すなわち:
(i) 経口、直腸、非経口、鼻腔、膣内、舌下、又は局所の各投与に適していること;
(ii) 単位剤形であって、約2.5μg〜約25mg/kgの範囲で、請求項1の化合物、塩、立体異性体の少なくとも1つを含んでいる各単位剤形であること;
(iii)請求項1の少なくとも1つの化合物が所与の調節率で放出される、持続放出製剤であること;
の少なくとも1つを有することを特徴とする、請求項12記載の薬学的製剤。 - 経口投与に適しており、単位剤形であって、各単位剤形が、0.2mg〜500mgの範囲内で、請求項1記載の化合物、塩、立体異性体の少なくとも1つを含む、請求項13記載の薬学的製剤。
- 各単位剤形が、約0.5mg〜約50mgの範囲内で、請求項1の化合物、それらの塩またはそれらの立体異性体の少なくとも1つを含む、請求項14記載の薬学的製剤。
- 各単位剤形が、約2.5mg〜約20mgの範囲内で、請求項1の化合物、それらの塩またはそれらの立体異性体の少なくとも1つを含む、請求項14記載の薬学的製剤。
- 非経口、または、局所投与に適しており、そして、単位剤形であって、各単位剤形が、約2.5μg〜約5mg/kgの範囲内で、請求項1の化合物、それらの塩、又はそれらの立体異性体の少なくとも1つを含む、請求項13記載の薬学的製剤。
- 非経口、または、局所投与に適しており、そして、単位剤形であって、各単位剤形が、約100μg〜約100mg/kgの範囲内で、請求項1の化合物、それらの塩、又はそれらの立体異性体の少なくとも1つを含む、請求項13記載の薬学的製剤。
- 前記製剤が単位剤形であって、そして、前記単位剤形が、請求項1の化合物、それらの塩又はそれらの立体異性体の少なくとも1つを、次の疾病:インシュリン抵抗性、2型糖尿病、脳梗塞を伴う神経細胞の脱落、虚血、中枢神経傷害、中枢神経障害、興奮性アミノ酸の過剰刺激による悪影響、精神障害、てんかん又その他の痙攣性疾患、不安神経症、睡眠障害、慢性疼痛、緑内障、CMV性網膜炎、尿失禁、又はアヘン耐性又は禁断症状;麻酔(感覚麻痺)を含んで; 認識増強、又は麻痺の誘導、の治療、又は、予防のために有効な用量を提供する請求項12記載の薬学的製剤。
- 前記製剤が単位剤形であって、そして、前記単位剤形が、心血管障害、血液凝固傷害、神経障害、時間生物学的障害、炎症性障害、概日睡眠障害、内分泌障害、新生物疾患、免疫系疾患、老化に伴う症状、眼科疾患、群発性頭痛、片頭痛、糖尿病性安定、体重増加障害、糖尿病性安定化、又は動物飼育の補助として、の治療又は予防のために、請求項の化合物、塩、又は、立体異性体の有効量を提供する請求項12の薬学的製剤。
- 前記製剤が、請求項1の化合物、又はそれらの塩、それらの立体異性体を、睡眠妨害、又は、睡眠の質の改善のため、又は概日リズムの改善の治療又は予防のための有効量を、その単位剤形において提供するものである、請求項12記載の薬学的製剤。
- さらに、鎮静剤、睡眠薬、抗不安薬、抗精神病薬、抗不安薬、トランキライザ、メラトニン作働剤又は拮抗剤、メラトニン、ベンゾジアゼピン、バルビツレート、または、5−HT−2拮抗剤を含む請求項21に記載の薬学的製剤。
- 前記製剤が、単位用量の中に、糖尿病の治療又は予防に有効量の請求項1の化合物、それらの塩または立体異性体を提供する、請求項12記載の薬学的製剤。
- さらに、抗糖尿病薬を含む請求項23に記載の薬学的製剤。
- 請求項1の化合物、それらの塩、又はそれらの立体異性体の有効量を含む薬学的製剤の有効量を必要とされている動物又はヒトに投与することを含む下記の疾病を治療または予防する方法であって、前記疾病が、インシュリン抵抗性、2型糖尿病、脳梗塞を伴う神経細胞の脱落、虚血、中枢神経傷害、中枢神経障害、神経変性病、興奮性アミノ酸の過剰刺激による悪影響、精神障害、てんかん又はその他の痙攣性疾患、不安神経症、睡眠障害、慢性疼痛、緑内障、CMV性網膜炎、尿失禁、又はアヘン耐性又は禁断症状;感覚麻痺の導入、又は、認識増強よりなる治療又は予防方法。
- 請求項1の化合物、それらの塩、又はそれらの立体異性体の有効量を含む薬学的製剤の有効量を必要とされている動物又はヒトに投与することを含む下記の疾病を治療または予防する方法であって、前記疾病が、心血管障害、神経障害、炎症性障害、時間生物学的障害、概日睡眠障害、内分泌障害、新生物疾患、免疫系疾患、老化に伴う症状、眼科疾患、群発性頭痛、片頭痛、体重増加障害;又は、受胎調節用の、又は、動物繁殖の補助としての毛の色、又は、皮膚の保護のため、よりなる治療又は予防する方法。
- 睡眠の質を改善するための慨日リズムを変更するための、睡眠の質を改善するための、また、睡眠障害、睡眠妨害を治療又は予防するための方法であって、それが、請求項1の化合物、それらの塩、又は、それらの立体異性体の有効量を含む製剤をそれを必要としているヒト又は動物において、ヒト又は動物への投与することを含む方法。
- 前記製剤が、睡眠の質を増強させ、又は、睡眠障害又は睡眠妨害を予防又は治療するために有用なことが知られている薬剤と併用により投与するものである、請求項27に記載の方法。
- 前記薬剤が、鎮静剤、睡眠薬、抗不安薬、トランキライザ、メラトニン作働薬又は拮抗剤、メラトニン、ベンゾジアゼピン、バルビツレート又は5HT−2拮抗剤である請求項28記載の方法。
- 光線療法と併用して投与されるものである、請求項27記載の方法。
- 請求項1の化合物、それらの塩、それらの立体異性体の有効量を含む製剤を前記ヒトに投与することを含む、それを必要とするヒトにおける糖尿病の治療又は予防する方法。
- 前記製剤が、公知の抗糖尿病薬と併用して投与される、請求項31に記載の方法。
- 前記製剤が、経口、非経口、鼻腔、膣内、直腸内、舌下又は局所の投与に適した剤形である、請求項25に記載の方法。
- 前記製剤が、経口、非経口、鼻腔、膣内、直腸内、舌下又は局所に投与に適した剤形である、請求項26に記載の方法。
- 前記製剤が、持続放出される経口剤形である請求項25の方法。
- 前記製剤が、持続放出される経口剤形である請求項26の方法。
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US5840751A (en) * | 1993-11-19 | 1998-11-24 | Warner-Lambert Company | 5,6-dihydropyrone derivatives as protease inhibitors and antiviral agents |
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US7834050B2 (en) * | 2006-03-29 | 2010-11-16 | Duke University | Small molecule insulin mimetics absent quinones |
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WO2015108039A1 (ja) * | 2014-01-14 | 2015-07-23 | アステラス製薬株式会社 | インドール化合物 |
JPWO2015108039A1 (ja) * | 2014-01-14 | 2017-03-23 | アステラス製薬株式会社 | インドール化合物 |
JP2019524797A (ja) * | 2016-08-23 | 2019-09-05 | ニューリム・ファーマシューティカルズ・リミテッドNeurim Pharmaceuticals Ltd. | 掻痒症および/または痒みの治療方法 |
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