JP2019506452A - テルピネオール類化合物およびその調製方法と使用 - Google Patents
テルピネオール類化合物およびその調製方法と使用 Download PDFInfo
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- JP2019506452A JP2019506452A JP2018558468A JP2018558468A JP2019506452A JP 2019506452 A JP2019506452 A JP 2019506452A JP 2018558468 A JP2018558468 A JP 2018558468A JP 2018558468 A JP2018558468 A JP 2018558468A JP 2019506452 A JP2019506452 A JP 2019506452A
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- Prior art keywords
- terpineol
- compound
- terpineols
- compounds
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- WUOACPNHFRMFPN-UHFFFAOYSA-N alpha-terpineol Chemical class CC1=CCC(C(C)(C)O)CC1 WUOACPNHFRMFPN-UHFFFAOYSA-N 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 208000006673 asthma Diseases 0.000 claims abstract description 18
- SQIFACVGCPWBQZ-UHFFFAOYSA-N delta-terpineol Natural products CC(C)(O)C1CCC(=C)CC1 SQIFACVGCPWBQZ-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229940116411 terpineol Drugs 0.000 claims abstract description 10
- -1 terpineol compound Chemical class 0.000 claims abstract description 10
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 37
- WUOACPNHFRMFPN-SECBINFHSA-N (S)-(-)-alpha-terpineol Chemical compound CC1=CC[C@@H](C(C)(C)O)CC1 WUOACPNHFRMFPN-SECBINFHSA-N 0.000 claims description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 19
- OVKDFILSBMEKLT-UHFFFAOYSA-N alpha-Terpineol Natural products CC(=C)C1(O)CCC(C)=CC1 OVKDFILSBMEKLT-UHFFFAOYSA-N 0.000 claims description 18
- 229940088601 alpha-terpineol Drugs 0.000 claims description 17
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 14
- 239000003814 drug Substances 0.000 claims description 13
- 229940079593 drug Drugs 0.000 claims description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 7
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- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 description 1
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- FVIZARNDLVOMSU-UHFFFAOYSA-N ginsenoside K Natural products C1CC(C2(CCC3C(C)(C)C(O)CCC3(C)C2CC2O)C)(C)C2C1C(C)(CCC=C(C)C)OC1OC(CO)C(O)C(O)C1O FVIZARNDLVOMSU-UHFFFAOYSA-N 0.000 description 1
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- WTBAHSZERDXKKZ-UHFFFAOYSA-N octadecanoyl chloride Chemical compound CCCCCCCCCCCCCCCCCC(Cl)=O WTBAHSZERDXKKZ-UHFFFAOYSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 1
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Classifications
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- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
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- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
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- C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
- C07C229/12—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of acyclic carbon skeletons
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/17—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrogenation of carbon-to-carbon double or triple bonds
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- C07C31/135—Monohydroxylic alcohols containing saturated rings monocyclic with a five or six-membered rings; Naphthenic alcohols
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
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- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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- C07D211/74—Oxygen atoms
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Abstract
Description
(1)ピリジンの働きで、α-テルピネオールとブロモアセチルブロミドがジクロロメタンの中でエステル化反応を発生し、エステル化中間体を得る。
(2)無機アルカリの働きで、手順(1)で得た中間体と求核剤がアセトニトリルの中で置換反応を発生し、上記のテルピネオール類化合物を得る。
(1)本発明はテルピネオール類化合物を派生化させることによって、これらの化合物の喘息抵抗効果と肺動脈高血圧抵抗の効果を効率的に向上した。
(2)本発明のテルピネオール類化合物は炎症細胞を減少することができ、良好な炎症抵抗効果を持っている。
原料α-テルピネオール(4mmol)を正確に測り、10mLのジクロロメタンに溶解させる。ピリジン(6mmol)を入れて氷浴の状態でミリスチン酸クロリド(6mmol)を添加し、室温で8時間反応した後に最終産物2a(3.74mmol,産出率93.5%)を得る。産物の構造は下記のとおりである。
原料α-テルピネオール(4mmol)を精密に測り、10mLのジクロロメタンに溶解させる。ピリジン(6mmol)を入れて氷浴の状態でステアロイル=クロリド(6mmol)を添加し、室温で8時間反応した後に最終産物2b(3.86mmol,産出率96.5%)を得る。
(1)原料α-テルピネオール1.85g(10mmol)を測り、50mLの円筒ビーカーに入れ、ジクロロメタン30mL、ピリジン1.91mL(20mmol)を入れる。氷浴状態でブロモアセチルブロミド2.09mL(20mmol)を入れて室温で7時間反応した後に中間体(5.9mmol,産出率48.2%)を得る。反応式は下記のとおりである。
α-テルピネオール(400mg)を10mLのメタノールに入れて、Pd/C(40mg)を投入し水素の環境で8h撹拌する。分離した後に無色油状の物6(38mg,93.5%)を得る。反応式は下記のとおりである。
方法:分離式気管チューブを製作して気管分離試験装置の中に設置し、張力を調整し均衡になった後にアセチルコリン塩化物100μLを投入して気管が収縮するように誘導し、気管の張力を上げ、張力が最高値に達し、且つ張力が均衡になった後に試験薬を入れて収縮した気管を対抗し、同じ長さの筋の張力変化曲線を記録し、平滑筋の拡張率を計算する。 拡張率=(モールディング後張力-薬投入後張力)/(モールディング後張力)*100%
模型組と比較し、♯→P<0.05,♯♯→P<0.01である。
方法:大鼠肺動脈高圧模型を製作し、正常照合組に同じ体積の生理的食塩水を注射する。モールディングした後の二日目に薬物で干与し、毎日各化合物に対して200mg/Kgを投入する。正常照合組および模型組に対して毎日同じ体積の生理的食塩水を投入し胃内投与を行う。30日目に麻酔状態で、右心臓カテーテル法で大鼠右心室の収縮圧を策定し、その結果は表3に示される。
Claims (9)
- テルピネオール類の化合物であって、その構造が式(I)または(II)になっており、
R1、R2、R3とR4は独立でC1〜C6アルキル基または-NO2から選択され、上記のC1〜C6アルキル基はOHに置き換えられることができ、
または、上記のR1、R2がR1、R2を繋ぐNと共同で五員環または六員環を形成し、上記の五員環または六員環の中に一つのOまたはC=Oを含むことができることを特徴とするテルピネオール類の化合物。 - 請求項1に記載のテルピネオール類の化合物であって、
上記のRがC12H25、C16H33または下記の基グループ中の一つであることを特徴とするテルピネオール類の化合物。
- 請求項1に記載のテルピネオール類の化合物の調製方法であって、
ピリジンの働きで、α-テルピネオールとアルキル塩化物をジクロロメタンの中で反応させ、反応した後に上記のテルピネオール類の化合物を得る手順を含み、
上記のアルキル塩化物はC14〜C16アルキル塩化物であり、RはC12〜C16アルキル基であることを特徴とするテルピネオール類の化合物の調製方法。 - 請求項1に記載のテルピネオール類の化合物の調製方法であって、
(1)ピリジンの働きで、α-テルピネオール類の化合物とブロモアセチルブロミドがジクロロメタンの中でエステル化反応を発生し、エステル化中間体を得る手順と、
(2)無機アルカリの働きで、手順(1)で得た中間体がアセトニトリルの中で求核剤と置換反応を発生し、上記のテルピネオール類の化合物を得る手順と、
を含み、
上記の求核剤はHNR1R2、HSR3またはHOR4であることを特徴とするテルピネオール類の化合物の調製方法。 - 請求項1に記載のテルピネオール類の化合物の調製方法であって、
Pd/Cと水素の環境で、α-テルピネオールがメタノールの中で水素添加反応を行い、上記のテルピネオール類の化合物を得る手順を含み、
上記のテルピネオール類の化合物は式(II)に示されている化合物であることを特徴とするテルピネオール類の化合物の調製方法。 - 請求項1または2に記載のテルピネオール類の化合物の製薬分野における使用。
- 請求項6に記載のテルピネオール類の化合物の製薬分野における使用であって、
上記のテルピネオール類の化合物は喘息抵抗薬物の調製に使用され、
上記の喘息抵抗薬物は気管支の拡張に使用されることを特徴とする使用。 - 請求項6に記載のテルピネオール類の化合物の製薬分野における使用であって、
上記のテルピネオール類の化合物は炎症抵抗薬物の調製に使用されることを特徴とする使用。 - 請求項6に記載のテルピネオール類の化合物の製薬分野における使用であって、
上記のテルピネオール類の化合物は肺動脈高血圧を治療、または緩和する薬物の調製に使用されることを特徴とする使用。
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