JPWO2008001859A1 - Opioid delta receptor agonist - Google Patents
Opioid delta receptor agonist Download PDFInfo
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- JPWO2008001859A1 JPWO2008001859A1 JP2008522628A JP2008522628A JPWO2008001859A1 JP WO2008001859 A1 JPWO2008001859 A1 JP WO2008001859A1 JP 2008522628 A JP2008522628 A JP 2008522628A JP 2008522628 A JP2008522628 A JP 2008522628A JP WO2008001859 A1 JPWO2008001859 A1 JP WO2008001859A1
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- 0 *1C=CC=C*1 Chemical compound *1C=CC=C*1 0.000 description 6
- CMCZCQGCIRIGDP-ULVUTOHESA-N CC(C)CN(CCC1(CC(CC2)OC)c3cc(OC)ccc3C3)[C@H]3[C@@]12O Chemical compound CC(C)CN(CCC1(CC(CC2)OC)c3cc(OC)ccc3C3)[C@H]3[C@@]12O CMCZCQGCIRIGDP-ULVUTOHESA-N 0.000 description 1
- WWAMNJYWAQQEMS-NQFKSEKESA-N CC(C)CN(CCC1(Cc2c(C3)c4ccccc4[nH]2)C(C2)=C(C4)C=CC2OC)C4[C@@]13O Chemical compound CC(C)CN(CCC1(Cc2c(C3)c4ccccc4[nH]2)C(C2)=C(C4)C=CC2OC)C4[C@@]13O WWAMNJYWAQQEMS-NQFKSEKESA-N 0.000 description 1
- DNUZZDORGTZULJ-IXQHIXELSA-N CC(C)CN(CCC1(Cc2c(C3)c4ccccc4[nH]2)[IH]C(CC(CC2)O)=C2C2)C2[C@@]13O Chemical compound CC(C)CN(CCC1(Cc2c(C3)c4ccccc4[nH]2)[IH]C(CC(CC2)O)=C2C2)C2[C@@]13O DNUZZDORGTZULJ-IXQHIXELSA-N 0.000 description 1
- KHKMKVIVWGJVNQ-UHFFFAOYSA-N CC1C(C)Cc2nc(cccc3)c3cc2C1 Chemical compound CC1C(C)Cc2nc(cccc3)c3cc2C1 KHKMKVIVWGJVNQ-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
- C07D217/24—Oxygen atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/14—Antitussive agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/10—Drugs for disorders of the urinary system of the bladder
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/08—Bridged systems
Abstract
本発明は、式(I)(式中、であり、R1a、R1b、R2〜R8、XおよびYは、それぞれ明細書における定義と同意義である)で示される化合物および該化合物を含有する医薬組成物を提供する。The present invention relates to a compound represented by the formula (I) (wherein R 1a, R 1b, R 2 to R 8, X and Y are as defined in the specification, respectively) and a medicament containing the compound A composition is provided.
Description
本発明は、オピオイドδ受容体アゴニスト作用を有する化合物、および該化合物を含有する医薬組成物に関する。 The present invention relates to a compound having an opioid δ receptor agonist activity and a pharmaceutical composition containing the compound.
モルヒナン骨格を有するモルヒネは、強力な鎮痛薬として古くから知られ、現在でも多用されているが、依存形成、呼吸抑制作用、便秘等、臨床上問題となる重篤な副作用があり、使用にあたっては厳重な管理を必要とする。 Morphine having a morphinan skeleton has long been known as a powerful analgesic and is still widely used, but there are serious side effects that cause clinical problems such as dependence formation, respiratory depression, and constipation. Strict management is required.
近年、中枢で鎮痛作用に関与する受容体としてμ、δ、κの3つのタイプのオピオイド受容体の存在が明らかにされている。モルヒネにみられるこれらの副作用はμ受容体アゴニスト特有のものであり、δ、κ受容体アゴニストには見られないことが分かっている。 In recent years, the existence of three types of opioid receptors, μ, δ, and κ, has been clarified as receptors involved in analgesic action in the center. These side effects seen in morphine are peculiar to μ receptor agonists and are not found in δ and κ receptor agonists.
モルヒネにみられる上記のような副作用を発現しない鎮痛薬を志向して、これまで数々のモルヒネ同族体が合成された。例えば、本発明の式(I)と構造的に関連する化合物として、特公昭45−25300号(特許文献1)には、4,5−エポキシ部位が除去されたインドロモルヒナン化合物が開示されており、鎮痛作用、鎮咳作用等の中枢神経抑制作用を示すことが示唆されている。しかしながら、オピオイドδ受容体に対する作用については記載されていない。一方、他の文献において、4,5−エポキシ部位が除去されたこのようなインドロモルヒナン化合物がオピオイドδ受容体に選択的に結合することが報告されているものの(非特許文献1および2)、これらの化合物は、オピオイドδ受容体に対するアンタゴニストであり、オピオイドδ受容体に対するアゴニスト活性は非常に弱い。
本発明の目的は、オピオイドδ受容体に対して強いアゴニスト活性を有する新規な化合物を提供することにある。本発明者らは、上記課題を解決するため鋭意検討した結果、式(I)に示されるモルヒナン誘導体が、強いアゴニスト活性を有し、特にオピオイドδ受容体に対して高い結合親和性を示すことを見出し、本発明を完成するに至った。 An object of the present invention is to provide a novel compound having a strong agonist activity for the opioid δ receptor. As a result of intensive studies to solve the above problems, the present inventors have found that the morphinan derivative represented by the formula (I) has a strong agonist activity, and particularly shows a high binding affinity for the opioid δ receptor. As a result, the present invention has been completed.
(1)式(I):
R1bは不存在または低級アルキルであり、
R2は水素、ヒドロキシ、低級アルコキシ、低級アルケニルオキシ、アリール低級アルコキシ、アリール低級アルケニルオキシ、アシルオキシまたは低級アルコキシ低級アルコキシであり、
R3およびR4は一方が水素であり、他方が水素、ヒドロキシ、低級アルコキシまたはアシルオキシであり、
R5、R6、R7およびR8は各々独立して水素、ハロゲン、ニトロ、低級アルキル、ヒドロキシ、低級アルコキシ、ハロゲノ低級アルキル、ヒドロキシ低級アルキル、ハロゲノ低級アルコキシ、ヒドロキシ低級アルコキシ、シアノ、フェニル、イソチオシアナート、SR9、SOR9、SO2R9、(CH2)rOR9、(CH2)rCOOR9、SO2NR10R11、CONR10R11、(CH2)rNR10R11または(CH2)rN(R10)COR11であり、
R5およびR6が環上の隣接する炭素原子に結合し、それらの炭素原子と一緒になって置換基を有していてもよい環を形成してもよく、
破線は結合の存在または不存在を示し、破線が結合の不存在を示す場合、R5およびR6は一緒になって=Oを形成してもよく、
rは0〜5の整数であり、
Rxは各々独立して水素、低級アルキル、低級アルケニル、アリール低級アルキル、アリール低級アルケニル、アシル、低級アルキルスルホニル、アリールスルホニル、アリール低級アルキルスルホニルまたはアシルであり、
Yは−N=または−CH=であり、
R9は水素または低級アルキルであり、
R10およびR11は各々独立して水素、低級アルキルまたはシクロアルキル低級アルキルである。ただし、
で示される化合物、その製薬上許容される塩またはそれらの溶媒和物;
(2)R1aがイソブチル、シクロプロピルメチル、フェネチルまたはベンジルであり、R1bが不存在またはメチルであり、R2が水素またはヒドロキシであり、R3およびR4の一方が水素であり、他方がヒドロキシであり、
である、上記(1)記載の化合物、その製薬上許容される塩またはそれらの溶媒和物;
(3)
(4)
(5)R3がヒドロキシであり、R4が水素である、上記(1)〜(4)のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物;
(6)上記(1)〜(5)のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を含有する医薬組成物;
(7)上記(1)〜(5)のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を含有するオピオイドδ受容体作動薬;
(8)上記(1)〜(5)のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を含有する鎮痛剤;
(9)上記(1)〜(5)のいずれかに記載の化合物を投与することを特徴とする痛みを緩和する方法;および
(10)痛みを緩和するための医薬を製造するための上記(1)〜(5)のいずれかに記載の化合物の使用
を提供するものである。(1) Formula (I):
R 1b is absent or lower alkyl,
R 2 is hydrogen, hydroxy, lower alkoxy, lower alkenyloxy, aryl lower alkoxy, aryl lower alkenyloxy, acyloxy or lower alkoxy lower alkoxy,
One of R 3 and R 4 is hydrogen and the other is hydrogen, hydroxy, lower alkoxy or acyloxy;
R 5 , R 6 , R 7 and R 8 are each independently hydrogen, halogen, nitro, lower alkyl, hydroxy, lower alkoxy, halogeno lower alkyl, hydroxy lower alkyl, halogeno lower alkoxy, hydroxy lower alkoxy, cyano, phenyl, Isothiocyanate, SR 9 , SOR 9 , SO 2 R 9 , (CH 2 ) r OR 9 , (CH 2 ) r COOR 9 , SO 2 NR 10 R 11 , CONR 10 R 11 , (CH 2 ) r NR 10 R 11 or (CH 2 ) r N (R 10 ) COR 11 ,
R 5 and R 6 may be bonded to adjacent carbon atoms on the ring, and together with those carbon atoms may form a ring that may have a substituent,
The dashed line indicates the presence or absence of a bond, and when the dashed line indicates the absence of a bond, R 5 and R 6 may together form ═O;
r is an integer from 0 to 5;
Each R x is independently hydrogen, lower alkyl, lower alkenyl, aryl lower alkyl, aryl lower alkenyl, acyl, lower alkylsulfonyl, arylsulfonyl, aryl lower alkylsulfonyl or acyl;
Y is —N═ or —CH═;
R 9 is hydrogen or lower alkyl,
R 10 and R 11 are each independently hydrogen, lower alkyl or cycloalkyl lower alkyl. However,
Or a pharmaceutically acceptable salt or solvate thereof;
(2) R 1a is isobutyl, cyclopropylmethyl, phenethyl or benzyl, R 1b is absent or methyl, R 2 is hydrogen or hydroxy, one of R 3 and R 4 is hydrogen, and the other Is hydroxy,
Or a pharmaceutically acceptable salt or solvate thereof according to (1) above;
(3)
(4)
(5) The compound according to any one of (1) to (4) above, wherein R 3 is hydroxy, and R 4 is hydrogen, a pharmaceutically acceptable salt thereof, or a solvate thereof;
(6) A pharmaceutical composition comprising the compound according to any one of (1) to (5) above, a pharmaceutically acceptable salt thereof, or a solvate thereof;
(7) An opioid δ receptor agonist containing the compound according to any one of (1) to (5) above, a pharmaceutically acceptable salt thereof, or a solvate thereof;
(8) An analgesic comprising the compound according to any one of (1) to (5) above, a pharmaceutically acceptable salt thereof, or a solvate thereof;
(9) A method for alleviating pain, comprising administering the compound according to any one of (1) to (5) above; and (10) The above (for producing a medicament for alleviating pain) The use of the compound according to any one of 1) to (5) is provided.
本発明化合物は、オピオイドδ受容体に対して強いアゴニスト活性を示し、他のオピオイド受容体と比較してオピオイドδ受容体に対して高い親和性を有する。 The compound of the present invention exhibits a strong agonist activity for the opioid δ receptor and has a higher affinity for the opioid δ receptor than other opioid receptors.
本明細書中、「ハロゲン」とはフッ素、塩素、臭素およびヨウ素を包含する。
「ハロゲノ低級アルキル」および「ハロゲノ低級アルコキシ」のハロゲン部分も上記と同様である。In the present specification, “halogen” includes fluorine, chlorine, bromine and iodine.
The halogen part of “halogeno lower alkyl” and “halogeno lower alkoxy” is the same as described above.
「低級アルキル」とは、炭素数1〜10、好ましくは炭素数1〜6、さらに好ましくは炭素数1〜3の直鎖または分枝状のアルキルを包含し、例えばメチル、エチル、n−プロピル、イソプロピル、n−ブチル、イソブチル、sec−ブチル、tert−ブチル、n−ペンチル、イソペンチル、ネオペンチル、ヘキシル、イソヘキシル、n−へプチル、イソヘプチル、n−オクチル、イソオクチル、n−ノニルおよびn−デシル等が挙げられる。 “Lower alkyl” includes linear or branched alkyl having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, more preferably 1 to 3 carbon atoms, such as methyl, ethyl, n-propyl. , Isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl, n-nonyl and n-decyl, etc. Is mentioned.
「シクロアルキル」とは炭素数3〜8、好ましくは炭素数3〜6の炭素環式基であり、例えばシクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチルおよびシクロオクチル等を包含する。「シクロアルキル低級アルキル」のシクロアルキル部分は上記「シクロアルキル」と同様である。 “Cycloalkyl” is a carbocyclic group having 3 to 8 carbon atoms, preferably 3 to 6 carbon atoms, and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. The cycloalkyl part of “cycloalkyl lower alkyl” is the same as the above “cycloalkyl”.
「低級アルケニル」とは、任意の位置に1以上の二重結合を有する炭素数2〜10、好ましくは炭素数2〜8、さらに好ましくは炭素数3〜6の直鎖または分枝状のアルケニルを包含する。具体的にはビニル、プロペニル、イソプロペニル、ブテニル、イソブテニル、プレニル、ブタジエニル、ペンテニル、イソペンテニル、ペンタジエニル、ヘキセニル、イソヘキセニル、ヘキサジエニル、ヘプテニル、オクテニル、ノネニルおよびデセニル等を包含する。「アリール低級アルケニル」、「アリール低級アルケニルオキシ」および「低級アルケニルオキシ」の低級アルケニル部分も、上記「低級アルケニル」と同様である。 “Lower alkenyl” is a straight or branched alkenyl having 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, more preferably 3 to 6 carbon atoms, having one or more double bonds at any position. Is included. Specific examples include vinyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl and decenyl. The lower alkenyl part of “aryl lower alkenyl”, “aryl lower alkenyloxy” and “lower alkenyloxy” is the same as the above “lower alkenyl”.
「シクロアルケニル低級アルキル」の「シクロアルケニル」とは、上記シクロアルキルの環中の任意の位置に1以上の二重結合を有しているものを包含し、具体的にはシクロプロペニル、シクロブテニル、シクロペンテニル、シクロヘキセニル、シクロへプチニル、シクロオクチニルおよびシクロヘキサジエニル等が挙げられる。 “Cycloalkenyl” in “cycloalkenyl lower alkyl” includes those having one or more double bonds at any position in the ring of the cycloalkyl, specifically, cyclopropenyl, cyclobutenyl, And cyclopentenyl, cyclohexenyl, cycloheptynyl, cyclooctynyl, cyclohexadienyl and the like.
「低級アルキルスルホニル」、「ヒドロキシ低級アルキル」、「ハロゲノ低級アルキル」、「シクロアルケニル低級アルキル」、「シクロアルキル低級アルキル」、「アリール低級アルキルスルホニル」、「アリール低級アルキル」および「低級アルコキシ」の低級アルキル部分は上記「低級アルキル」と同様である。 “Lower alkylsulfonyl”, “hydroxy lower alkyl”, “halogeno lower alkyl”, “cycloalkenyl lower alkyl”, “cycloalkyl lower alkyl”, “aryl lower alkylsulfonyl”, “aryl lower alkyl” and “lower alkoxy” The lower alkyl moiety is the same as the above “lower alkyl”.
「低級アルコキシ低級アルコキシ」、「ヒドロキシ低級アルコキシ」、「ハロゲノ低級アルコキシ」、「アリール低級アルコキシ」の低級アルコキシ部分は、上記「低級アルコキシ」と同様である。 The lower alkoxy part of “lower alkoxy lower alkoxy”, “hydroxy lower alkoxy”, “halogeno lower alkoxy” and “aryl lower alkoxy” is the same as the above “lower alkoxy”.
「アリール」とは、フェニル、ナフチル、アントリルおよびフェナントリル等を包含し、特にフェニルが好ましい。「アリールアルキル」、「アリールスルホニル」、「アリール低級アルキル」、「アリール低級アルコキシ」、「アリール低級アルケニル」、「アリール低級アルキルスルホニル」、「アリール低級アルケニルオキシ」のアリール部分も上記「アリール」と同様である。 “Aryl” includes phenyl, naphthyl, anthryl, phenanthryl and the like, with phenyl being particularly preferred. The aryl part of “arylalkyl”, “arylsulfonyl”, “aryl lower alkyl”, “aryl lower alkoxy”, “aryl lower alkenyl”, “aryl lower alkylsulfonyl”, “aryl lower alkenyloxy” is also referred to as “aryl” above. It is the same.
「アシル」とは炭素数1〜10、好ましくは炭素数1〜6、さらに好ましくは炭素数1〜4の直鎖または分枝の鎖状脂肪族アシル、炭素数4〜9、好ましくは炭素数4〜7の環状脂肪族アシルおよびアロイルを包含する。具体的には、ホルミル、アセチル、プロピオニル、ブチリル、イソブチリル、バレリル、ピバロイル、ヘキサノイル、アクリロイル、プロピオロイル、メタクリロイル、クロトノイル、シクロプロピルカルボニル、シクロヘキシルカルボニル、シクロオクチルカルボニルおよびベンゾイル等を包含する。
鎖状脂肪族アシルはアリールまたは低級アルキルアリール等で置換されていてもよい。また、環状脂肪族アシルおよびアロイルは低級アルキルで置換されていてもよい。
「アシルオキシ」のアシル部分も上記「アシル」と同様である。“Acyl” is a linear or branched chain aliphatic acyl having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms, 4 to 9 carbon atoms, preferably carbon atoms. Includes 4-7 cycloaliphatic acyls and aroyl. Specific examples include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl, hexanoyl, acryloyl, propioyl, methacryloyl, crotonoyl, cyclopropylcarbonyl, cyclohexylcarbonyl, cyclooctylcarbonyl and benzoyl.
The chain aliphatic acyl may be substituted with aryl or lower alkylaryl. Cycloaliphatic acyl and aroyl may be substituted with lower alkyl.
The acyl part of “acyloxy” is the same as the above “acyl”.
「R5およびR6が環上の隣接する炭素原子に結合し、それらの炭素原子と一緒になって置換基を有していてもよい環を形成してもよく」とは、例えば
等を形成することを意味する。“R 5 and R 6 may be bonded to adjacent carbon atoms on the ring, and together with those carbon atoms may form a ring that may have a substituent,” for example,
And so on.
本明細書中において「化合物(I)」という場合には、本明細書中の式(I)で示される任意の化合物を意味し、生成可能な、各々の化合物の製薬上許容される塩も包含する。「製薬上許容される塩」としては、例えば、アルカリ土類金属(マグネシウムまたはカルシウム等)との塩;有機塩基(アンモニウム、トリメチルアンモニウム、トリエチルアンモニウム等)との塩;アミノ酸との塩;無機酸(塩酸、硫酸、硝酸、リン酸、フッ化水素酸、臭化水素酸、またはヨウ化水素酸等)との塩;および有機酸(ギ酸、酢酸、クエン酸、乳酸、酒石酸、シュウ酸、マレイン酸、コハク酸、フマル酸、マンデル酸、グルタル酸、リンゴ酸、安息香酸、フタル酸、ベンゼンスルホン酸、p−トルエンスルホン酸、メタンスルホン酸またはエタンスルホン酸等)との塩が挙げられる。特に塩酸、リン酸、酒石酸またはメタンスルホン酸等が好ましい。これらの塩は、通常行われる方法によって形成させることができる。 In the present specification, the term “compound (I)” means any compound represented by the formula (I) in the present specification, and a pharmaceutically acceptable salt of each compound that can be produced. Include. “Pharmaceutically acceptable salts” include, for example, salts with alkaline earth metals (magnesium or calcium, etc.); salts with organic bases (ammonium, trimethylammonium, triethylammonium, etc.); salts with amino acids; inorganic acids Salts with (hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, etc.); and organic acids (formic acid, acetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid) Salts with acid, succinic acid, fumaric acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid or ethanesulfonic acid). In particular, hydrochloric acid, phosphoric acid, tartaric acid, methanesulfonic acid and the like are preferable. These salts can be formed by a commonly performed method.
本発明化合物はその溶媒和物(好ましくは水和物)を包含する。溶媒和物としては有機溶媒および/または水との溶媒和物が挙げられる。水和物を形成するときは、任意の数の水分子と配位していてもよい。 The compounds of the present invention include solvates (preferably hydrates) thereof. Solvates include solvates with organic solvents and / or water. When forming a hydrate, it may be coordinated with an arbitrary number of water molecules.
また、化合物(I)は特定の異性体に限定するものではなく、全ての可能な異性体(ケト−エノール異性体、ジアステレオ異性体、光学異性体、回転異性体等)を包含する。 Compound (I) is not limited to a specific isomer, and includes all possible isomers (keto-enol isomer, diastereoisomer, optical isomer, rotational isomer, etc.).
化合物(I)は、δ受容体に対して高い親和性を有し、かつδ受容体アゴニスト作用を有する。また、化合物(I)は、μ受容体やκ受容体などのオピオイド受容体と比較して、δ受容体に対して高い親和性(例えばδ受容体に対する親和性が他のオピオイド受容体に対する親和性と比較して50倍以上、好ましくは200倍以上、さらに好ましくは500倍以上)を有し、かつδ受容体アゴニスト作用を有する。 Compound (I) has a high affinity for the δ receptor and also has a δ receptor agonistic action. Compound (I) has a higher affinity for the δ receptor (for example, the affinity for the δ receptor has an affinity for other opioid receptors than the opioid receptors such as the μ receptor and the κ receptor). 50 times or more, preferably 200 times or more, more preferably 500 times or more), and has a δ receptor agonistic action.
一般式(I)で示される化合物としては、以下に示す化合物が好ましい。
(A)R1aが低級アルキルまたはシクロアルキル低級アルキルであり、R1bが不存在またはメチルであり、R2がヒドロキシであり、R3およびR4の一方が水素であり、他方がヒドロキシであり、
(B)R1aがメチル、イソブチル、またはシクロプロピルメチルであり、R1bが不存在またはメチルであり、R2がヒドロキシであり、R3およびR4の一方が水素であり、他方がヒドロキシであり、
(C)R1aがイソブチルまたはシクロプロピルメチルであり、R1bが不存在またはメチルであり、R2がヒドロキシであり、R3およびR4の一方が水素であり、他方がヒドロキシであり、
(D)R3が水素であり、R4がヒドロキシである上記の(A)〜(C)のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。
(E)R3がヒドロキシであり、R4が水素である上記の(A)〜(C)のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。As the compound represented by the general formula (I), the following compounds are preferred.
(A) R 1a is lower alkyl or cycloalkyl lower alkyl, R 1b is absent or methyl, R 2 is hydroxy, one of R 3 and R 4 is hydrogen, and the other is hydroxy ,
(B) R 1a is methyl, isobutyl, or cyclopropylmethyl, R 1b is absent or methyl, R 2 is hydroxy, one of R 3 and R 4 is hydrogen, and the other is hydroxy Yes,
(C) R 1a is isobutyl or cyclopropylmethyl, R 1b is absent or methyl, R 2 is hydroxy, one of R 3 and R 4 is hydrogen, and the other is hydroxy,
(D) The compound according to any one of (A) to (C) above, wherein R 3 is hydrogen, and R 4 is hydroxy, a pharmaceutically acceptable salt thereof, or a solvate thereof.
(E) The compound according to any one of (A) to (C) above, wherein R 3 is hydroxy, and R 4 is hydrogen, a pharmaceutically acceptable salt thereof, or a solvate thereof.
化合物(I)は、疼痛を伴う疾患(例えば慢性疼痛(骨転移、神経圧迫、頭蓋内圧亢進、軟部組織浸潤、便秘または筋の攣縮による痛み、内臓、筋・筋膜、腰または肩関節周囲の痛み、術後の慢性的な痛み)、AIDS等)を有する患者に鎮痛剤として投与することができる。また、化合物(I)は、免疫増強剤、血圧降下剤、鎮咳剤、抗うつ剤、過活動膀胱治療剤、尿失禁治療剤としても投与することができる。 Compound (I) is a painful disease (eg, chronic pain (bone metastasis, nerve compression, increased intracranial pressure, soft tissue invasion, pain due to constipation or muscle spasm, visceral, muscle / fascia, waist or shoulder joint circumference). It can be administered as an analgesic to patients with pain, chronic pain after surgery), AIDS, etc. Compound (I) can also be administered as an immunopotentiator, antihypertensive agent, antitussive, antidepressant, overactive bladder therapeutic agent, or urinary incontinence therapeutic agent.
本発明に係る化合物を、医薬組成物としてヒトに投与する場合は、散剤、顆粒剤、錠剤、カプセル剤、丸剤、液剤等として経口的に、または注射剤、坐剤、経皮吸収剤、吸入剤等として非経口的に投与することができる。また、本化合物の有効量にその剤型に適した賦形剤、結合剤、湿潤剤、崩壊剤、滑沢剤等の医薬用添加剤を必要に応じて混合し、医薬製剤とすることができる。 When the compound according to the present invention is administered to humans as a pharmaceutical composition, it can be administered orally as a powder, granule, tablet, capsule, pill, liquid, etc., or as an injection, suppository, transdermal absorption agent, It can be administered parenterally as an inhalant or the like. In addition, excipients, binders, wetting agents, disintegrants, lubricants and other pharmaceutical additives suitable for the dosage form may be mixed with an effective amount of the present compound as necessary to obtain a pharmaceutical preparation. it can.
投与量は疾患の状態、投与ルート、患者の年齢、または体重によっても異なるが、成人に経口で投与する場合、通常1μg〜10g/日であり、好ましくは0.1〜2000mg/日であり、非経口投与の場合には通常0.1μg〜1g/日であり、好ましくは0.01〜200mg/日である。 The dose varies depending on the disease state, administration route, patient age, or body weight, but when administered orally to an adult, it is usually 1 μg to 10 g / day, preferably 0.1 to 2000 mg / day, In the case of parenteral administration, it is usually 0.1 μg to 1 g / day, preferably 0.01 to 200 mg / day.
本発明の化合物(I)は、以下のスキーム1および実施例に記載のとおりに製造することができる。
本発明の化合物の合成に用いる出発物質は、当業者に公知の方法で調製することができる。本発明の化合物の合成における出発物質として使用される化合物は、周知であり、商業的に入手可能でない場合は、当業者に一般に用いられる標準的な方法によって容易に合成することができる。より詳しくは、例えば特開平4−275288号に示された方法で、ケトン体(IIa)またはジケトン体(IIb)を原料とし、酸触媒の共存下、適当な溶媒中、例えば、式(III−1)、(III−2)、(III−3)(III−4)で示されるベンゼン誘導体と縮合させることにより得ることができる。原料に光学活性体を用いれば光学活性な化合物を得ることができる。例えば、ケトン体(IIa)の光学活性体は、WO91/18901に示される方法などにより得ることができる。これらの反応は、それ自体公知の方法、またはこれに類似する方法に従って実施することができる。このような公知の方法の例としては、当分野における一般的な参照テキスト、およびその中に引用した文献などに記載されている方法が挙げられ、例えば、J. Med. Chem. 1991, 34, 1715-1720、J. Med. Chem. 1988, 31, 281-282、Chem. Pharm. Bull. 1998, 46(11), 1695-1702等を参考にしてもよい。Compound (I) of the present invention can be prepared as described in Scheme 1 below and in the Examples.
The starting materials used in the synthesis of the compounds of the present invention can be prepared by methods known to those skilled in the art. The compounds used as starting materials in the synthesis of the compounds of the present invention are well known and can be readily synthesized by standard methods commonly used by those skilled in the art if they are not commercially available. More specifically, for example, in the method disclosed in JP-A-4-275288, a ketone body (IIa) or a diketone body (IIb) is used as a raw material in the presence of an acid catalyst in an appropriate solvent, for example, the formula (III- It can be obtained by condensation with a benzene derivative represented by 1), (III-2), (III-3) or (III-4). If an optically active substance is used as a raw material, an optically active compound can be obtained. For example, an optically active substance of ketone body (IIa) can be obtained by the method shown in WO91 / 18901. These reactions can be carried out according to a method known per se or a method analogous thereto. Examples of such known methods include methods described in general reference texts in the field, and literature cited therein, for example, J. Med. Chem. 1991, 34, 1715-1720, J. Med. Chem. 1988, 31, 281-282, Chem. Pharm. Bull. 1998, 46 (11), 1695-1702, etc. may be referred to.
以下に実施例および試験例を挙げて本発明をさらに詳しく説明するが、本発明はこれらにより限定されるものではない。 Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples, but the present invention is not limited thereto.
実施例1
41および42の合成
3-OMeモルヒナン(1)1.5 g(4.39mmol)の酢酸溶液(30mL)に、塩酸フェニルヒドラジン1.27 g(8.78mmol)を加え、1時間加熱還流した。反応溶液を減圧濃縮した後、クロロホルム(300mL)を加え溶解した。有機層を10%炭酸水素ナトリウム(250mL)、水(250mL)で順次洗浄した後、乾燥(Na2SO4)した。残渣(2.37 g)をシリカゲルカラムクロマトグラフィー(クロロホルム−メタノール100:2→100:8)で分離精製し、3-OMe-モルヒナン骨格NTI(2)を淡黄色無定形として1.61 g(88%)で得た。
1H NMR (CDCl3, 300MHz) δ: 0.20 (2H, m), 0.55 (2H, m), 0.90 (1H, m), 1.15 (1H, d), 2.10 (2H, m). 2.40 (2H, m), 2.65 (1H, dd), 2.70 (2H, m), 3.00 (1H, dd), 3.20 (3H, m), 3.30 (1H, d), 3.80 (3H, s), 6.20 (1H, dd), 6.75 (1H, dd), 6.95 (1H, d), 7.00 (1H, d), 7.05 (1H, dd), 7.20 (1H, dd), 7.25 (1H, d), 7.70 (1H, broad).
MS(FAB) m/z 415 (M+H)+.
IR(KBr) νmaxcm-1: 3285. Example 1
Synthesis of 41 and 42
To an acetic acid solution (30 mL) of 3-OMe morphinan (1) 1.5 g (4.39 mmol) was added phenylhydrazine hydrochloride 1.27 g (8.78 mmol), and the mixture was heated to reflux for 1 hour. After the reaction solution was concentrated under reduced pressure, chloroform (300 mL) was added and dissolved. The organic layer was washed successively with 10% sodium hydrogen carbonate (250 mL) and water (250 mL) and then dried (Na 2 SO 4 ). The residue (2.37 g) was separated and purified by silica gel column chromatography (chloroform-methanol 100: 2 → 100: 8), and the 3-OMe-morphinan skeleton NTI (2) was obtained as 1.61 g (88%) as a pale yellow amorphous. Obtained.
1 H NMR (CDCl 3 , 300MHz) δ: 0.20 (2H, m), 0.55 (2H, m), 0.90 (1H, m), 1.15 (1H, d), 2.10 (2H, m). 2.40 (2H, m), 2.65 (1H, dd), 2.70 (2H, m), 3.00 (1H, dd), 3.20 (3H, m), 3.30 (1H, d), 3.80 (3H, s), 6.20 (1H, dd ), 6.75 (1H, dd), 6.95 (1H, d), 7.00 (1H, d), 7.05 (1H, dd), 7.20 (1H, dd), 7.25 (1H, d), 7.70 (1H, broad) .
MS (FAB) m / z 415 (M + H) + .
IR (KBr) ν max cm -1 : 3285.
41の合成
3-OMe-モルヒナン骨格NTI(2)1.2 g(2.894mmol)の無水ジクロロメタン溶液(50mL)に、アルゴン気流下0℃で1M 三臭化ホウ素ジクロロメタン溶液17.4 mL(17.4mmol)を加え、室温で暗所1.5時間攪拌した。反応溶液に0℃で6%アンモニア(50mL)を加え激しく攪拌した後、クロロホルム(200, 100, 100mL)で抽出した。有機層を飽和食塩水(200mL)で洗浄した後、乾燥(Na2SO4)し、減圧濃縮した。残渣(1.21 g)をシリカゲルカラムクロマトグラフィー(クロロホルム−メタノール100:5→100:10)で分離精製し、モルヒナン骨格NTI(41)を淡黄色油状物として1.23 gで得た。酢酸エチル−メタノール(2:1)から再結晶を行い、モルヒナン骨格NTI(41)を白色結晶として648mg(56%)で得た。
mp:259-264℃
1H NMR (CDCl3, 300MHz) δ: 0.20 (2H, m), 0.60 (2H, m), 0.90 (1H, m), 1.35 (1H, d), 2.20 (2H, m). 2.45 (2H, m), 2.70 (1H, dd), 2.80 (2H, m), 3.00 (1H, dd), 3.10 (1H, m), 3.20 (2H, m), 3.30 (1H, d), 6.50 (1H, dd), 6.70 (1H, d), 6.90 (1H, dd), 7.00 (1H, d), 7.10 (1H, dd), 7.25 (1H, dd), 7.30 (1H, d), 7.75 (1H, broad).
MS(FAB) m/z 401 (M+H)+.
IR(KBr) νmaxcm-1: 3855.41 synthesis
Add 17.4 mL (17.4 mmol) of 1M boron tribromide dichloromethane solution to an anhydrous dichloromethane solution (50 mL) of 1.2 g (2.894 mmol) of 3-OMe-morphinane skeleton NTI (2) at 0 ° C under an argon stream, and darken at room temperature. The mixture was stirred for 1.5 hours. 6% ammonia (50 mL) was added to the reaction solution at 0 ° C., and the mixture was vigorously stirred and extracted with chloroform (200, 100, 100 mL). The organic layer was washed with saturated brine (200 mL), dried (Na 2 SO 4 ), and concentrated under reduced pressure. The residue (1.21 g) was separated and purified by silica gel column chromatography (chloroform-methanol 100: 5 → 100: 10) to obtain morphinan skeleton NTI (41) as a pale yellow oil in 1.23 g. Recrystallization from ethyl acetate-methanol (2: 1) gave the morphinan skeleton NTI (41) as white crystals in 648 mg (56%).
mp: 259-264 ℃
1 H NMR (CDCl 3 , 300MHz) δ: 0.20 (2H, m), 0.60 (2H, m), 0.90 (1H, m), 1.35 (1H, d), 2.20 (2H, m). 2.45 (2H, m), 2.70 (1H, dd), 2.80 (2H, m), 3.00 (1H, dd), 3.10 (1H, m), 3.20 (2H, m), 3.30 (1H, d), 6.50 (1H, dd ), 6.70 (1H, d), 6.90 (1H, dd), 7.00 (1H, d), 7.10 (1H, dd), 7.25 (1H, dd), 7.30 (1H, d), 7.75 (1H, broad) .
MS (FAB) m / z 401 (M + H) + .
IR (KBr) ν max cm -1 : 3855.
41の塩酸塩
モルヒナン骨格NTI(41)60mg(0.15mmol)のエーテル溶液に、塩酸飽和メタノール溶液を加え、塩酸塩55 mgを得た。
mp:250-255℃(dec.).
元素分析(C26H28N2O2・HCl・0.67H2O)計算値:C, 69.54; H, 6.76; N, 6.24. 実測値:C. 69.41; H, 6.98; N, 6.22.Hydrochloric acid saturated methanol solution was added to an ether solution of 41 hydrochloride morphinan skeleton NTI (41) 60 mg (0.15 mmol) to obtain 55 mg of hydrochloride.
mp: 250-255 ° C (dec.).
Elemental analysis (C 26 H 28 N 2 O 2 · HCl · 0.67H 2 O) Calculated: C, 69.54; H, 6.76; N, 6.24. Found: C. 69.41; H, 6.98; N, 6.22.
42の合成
モルヒナン骨格NTI(41)210mg(0.525mmol)の酢酸エチル溶液(7mL)をボンベンロール(耐圧ガラス)に入れ、メタノール0.7 mL、ヨウ化メチル160 μL(2.57mmol)を加え、アルゴン気流下100℃で封管し、終夜攪拌した。反応溶液に水を加えた後、クロロホルム(6×20mL)で抽出した。水層を減圧濃縮した後、残渣をメタノールから再結晶を行い、モルヒナン骨格NTI-メチオダイド(42)を白色結晶として32mg(15%)で得た。
mp:240-243℃
1H NMR (DMSO, 300MHz) δ: 0.10 (2H, m), 0.15 (2H, m), 0.35 (1H, m), 0.85 (1H, m), 1.15 (1H, d), 2.20 (2H, m), 2.60 (2H, m), 2.75 (1H, d), 3.05 (2H, m), 3.2 (3H, s), 3.60 (2H, m), 6.15 (1H, dd), 6.35 (1H, d), 6.45 (1H, dd), 6.50 (1H, dd), 6.55 (1H, dd), 6.75 (1H, d), 6.80 (1H, d).
MS(FAB) m/z 415 (M)+.
元素分析(C27H31N2O2I・0.33H2O)
計算値:C, 59.11; H, 5.82; N, 5.11.
実測値:C. 59.20; H, 5.72; N, 5.23.42 Synthesis of morphinan skeleton NTI (41) 210 mg (0.525 mmol) in ethyl acetate (7 mL) was placed in bomben roll (pressure glass), methanol 0.7 mL, methyl iodide 160 μL (2.57 mmol) was added, The tube was sealed at 100 ° C. and stirred overnight. Water was added to the reaction solution, followed by extraction with chloroform (6 × 20 mL). The aqueous layer was concentrated under reduced pressure, and the residue was recrystallized from methanol to obtain 32 mg (15%) of morphinane skeleton NTI-methiodide (42) as white crystals.
mp: 240-243 ℃
1 H NMR (DMSO, 300MHz) δ: 0.10 (2H, m), 0.15 (2H, m), 0.35 (1H, m), 0.85 (1H, m), 1.15 (1H, d), 2.20 (2H, m ), 2.60 (2H, m), 2.75 (1H, d), 3.05 (2H, m), 3.2 (3H, s), 3.60 (2H, m), 6.15 (1H, dd), 6.35 (1H, d) , 6.45 (1H, dd), 6.50 (1H, dd), 6.55 (1H, dd), 6.75 (1H, d), 6.80 (1H, d).
MS (FAB) m / z 415 (M) + .
Elemental analysis (C 27 H 31 N 2 O 2 I · 0.33H 2 O)
Calculated values: C, 59.11; H, 5.82; N, 5.11.
Found: C. 59.20; H, 5.72; N, 5.23.
実施例2
43および44の合成
3-OMe-モルヒナン(1)1.11g(3.25mmol)の無水エタノール溶液(60mL)にメタンスルホン酸850μL(13.0mmol)、O-フェニルヒドロキシルアミン塩酸塩950mg(6.51mmol)を加え、アルゴン気流下16.5時間加熱還流した。反応溶液に10%炭酸水素ナトリウム水溶液(80mL)を加えた後(pH9)、酢酸エチル(100, 80, 70mL)で抽出した。有機層を飽和食塩水(70mL)で洗浄した後、乾燥(Na2SO4)し、減圧濃縮した。残渣(2.22 g)をシリカゲルカラムクロマトグラフィー(クロロホルム−メタノール10:1)で分離精製し、3-OMe-モルヒナン骨格NTB(3)を無色無定形として785mg(58%)で得た。
1H NMR (CDCl3,300MHz) δ : 0.10 (2H, m), 0.50 (2H, m), 0.75 (1H, m), 1.30 (1H, d), 2.10 (1H, m). 2.20 (1H, m), 2.30 (2H, d), 2.50 (1H, d), 2.60 (2H, m), 2.90 (1H, dd), 3.10 (1H, m), 3.20 (1H, d), 3.40 (1H, d), 3.55 (3H, s), 6.50 (1H, dd),6.60 (1H, d), 6.80 (1H, d), 6.90 (1H, d), 7.00 (1H, d), 7.10 (1H, dd), 7.3 (1H, dd).
MS(FAB) m/z 416 (M+H)+.
IR(KBr) νmaxcm-1: 3401. Example 2
Synthesis of 43 and 44
Add 850 μL (13.0 mmol) of methanesulfonic acid and 950 mg (6.51 mmol) of O-phenylhydroxylamine hydrochloride to 1.11 g (3.25 mmol) of 3-OMe-morphinan (1) in absolute ethanol (60 mL). Heated to reflux for hours. A 10% aqueous sodium hydrogen carbonate solution (80 mL) was added to the reaction solution (pH 9), followed by extraction with ethyl acetate (100, 80, 70 mL). The organic layer was washed with saturated brine (70 mL), dried (Na 2 SO 4 ), and concentrated under reduced pressure. The residue (2.22 g) was separated and purified by silica gel column chromatography (chloroform-methanol 10: 1) to obtain 785 mg (58%) of 3-OMe-morphinan skeleton NTB (3) as colorless amorphous.
1 H NMR (CDCl 3 , 300MHz) δ: 0.10 (2H, m), 0.50 (2H, m), 0.75 (1H, m), 1.30 (1H, d), 2.10 (1H, m) .2.20 (1H, m), 2.30 (2H, d), 2.50 (1H, d), 2.60 (2H, m), 2.90 (1H, dd), 3.10 (1H, m), 3.20 (1H, d), 3.40 (1H, d ), 3.55 (3H, s), 6.50 (1H, dd), 6.60 (1H, d), 6.80 (1H, d), 6.90 (1H, d), 7.00 (1H, d), 7.10 (1H, dd) , 7.3 (1H, dd).
MS (FAB) m / z 416 (M + H) + .
IR (KBr) ν max cm -1 : 3401.
43の合成
3-OMe-モルヒナン骨格NTB(3)792mg(1.90mmol)の無水ジクロロメタン溶液(40mL)に、アルゴン気流下0℃で1M 三臭化ホウ素ジクロロメタン溶液12 mL(12mmol)を加え、室温で暗所1時間攪拌した。反応溶液に0℃で6%アンモニア水(40mL)を加え激しく攪拌した後(pH9)、クロロホルム(150, 100, 50mL)で抽出した。有機層を飽和食塩水(100mL)で洗浄した後、乾燥(Na2SO4)し、減圧濃縮した。残渣(791mg)をシリカゲルカラムクロマトグラフィー(クロロホルム−メタノール10:0.5)で分離精製し、モルヒナン骨格NTB(43)を無色無定形として263mg(34%)で得た。
1H NMR (CDCl3, 300MHz) δ : 0.10 (2H, m), 0.50 (2H, m), 0.85 (1H, m), 1.30 (1H, d), 2.10 (1H, dd). 2.20 (1H, td), 2.40 (2H, d), 2.65 (2H, m), 2.90 (1H, dd), 3.10 (2H, m), 3.30 (2H, m), 6.50 (1H, dd), 6.70 (1H, d), 6.90 (1H, d), 7.05 (1H, d), 7.10 (1H, dd), 7.20 (1H, dd), 7.3 (1H, d).
MS(EI) m/z 401 (M)+.
IR(KBr) νmaxcm-1: 3357Synthesis of 43
To a solution of 792 mg (1.90 mmol) of 3-OMe-morphinane skeleton NTB (1.90 mmol) in anhydrous dichloromethane (40 mL) was added 12 mL (12 mmol) of 1M boron tribromide dichloromethane solution at 0 ° C. under an argon stream, and at room temperature in the dark 1 Stir for hours. To the reaction solution was added 6% aqueous ammonia (40 mL) at 0 ° C. and stirred vigorously (pH 9), followed by extraction with chloroform (150, 100, 50 mL). The organic layer was washed with saturated brine (100 mL), dried (Na 2 SO 4 ), and concentrated under reduced pressure. The residue (791 mg) was separated and purified by silica gel column chromatography (chloroform-methanol 10: 0.5) to obtain 263 mg (34%) of a morphinan skeleton NTB (43) as colorless and amorphous.
1 H NMR (CDCl 3 , 300 MHz) δ: 0.10 (2H, m), 0.50 (2H, m), 0.85 (1H, m), 1.30 (1H, d), 2.10 (1H, dd) .2.20 (1H, td), 2.40 (2H, d), 2.65 (2H, m), 2.90 (1H, dd), 3.10 (2H, m), 3.30 (2H, m), 6.50 (1H, dd), 6.70 (1H, d ), 6.90 (1H, d), 7.05 (1H, d), 7.10 (1H, dd), 7.20 (1H, dd), 7.3 (1H, d).
MS (EI) m / z 401 (M) + .
IR (KBr) ν max cm -1 : 3357
43の塩酸塩
モルヒナン骨格NTB(43)61mg(0.15mmol)の酢酸エチル溶液に、塩酸飽和メタノール溶液を加え、塩酸塩57 mgを得た。
mp: 219-220℃(dec.).
元素分析(C26H27NO3・HCl・1/3H2O)
計算値:C, 70.34; H, 6.51; N, 3.15.
実測値:C. 70.54; H, 6.36; N, 3.33.Hydrochloric acid saturated methanol solution was added to ethyl acetate solution of 43 hydrochloride morphinan skeleton NTB (43) 61 mg (0.15 mmol) to obtain 57 mg of hydrochloride.
mp: 219-220 ° C (dec.).
Elemental analysis (C 26 H 27 NO 3 · HCl · 1 / 3H 2 O)
Calculated values: C, 70.34; H, 6.51; N, 3.15.
Found: C. 70.54; H, 6.36; N, 3.33.
44の合成
モルヒナン骨格NTB(43)100mg(0.249mmol)の酢酸エチル溶液(3.5mL)をボンベンロール(耐圧ガラス)に入れ、メタノール0.35 mL、ヨウ化メチル75 μL(1.19mmol)を加え、アルゴン気流下100℃で封管し、6日間攪拌した。反応溶液にメタノール(6mL)を加えた後、減圧濃縮した。析出した固体をろ取した(68 mg、65%)後、メタノール−酢酸エチルから再結晶を行い、モルヒナン骨格NTB−メチオダイド(44)を淡褐色結晶として42mg(40%)で得た。
mp:253-254℃(dec.).
1H NMR (DMSO, 300MHz) δ : 0.50 (2H, m), 0.60 (2H, m), 0.80 (1H, m), 1.20 (1H, m), 1.60 (1H, d), 2.60 (1H, m), 2.80 (2H, m), 3.10 (3H, m), 3.50 (3H, m),3.80 (3H, s), 3.9 (2H, m), 4.1 (1H, m), 6.60 (1H, dd), 6.80 (1H, d), 7.00 (1H, dd), 7.20 (2H, m), 7.30 (1H, dd), 7.5 (1H, d).
MS(FAB) m/z 416 (M)+.
IR(KBr) νmaxcm-1: 3354.
元素分析(C27H30NO3・I)
計算値: C, 59.67; H, 5.56; N, 2.58.
実測値:C. 59.37; H, 5.59; N, 2.86.44 synthetic morphinan skeleton NTB (43) 100mg (0.249mmol) ethyl acetate solution (3.5ml) is put into bomben roll (pressure glass), methanol 0.35mL, methyl iodide 75μL (1.19mmol) is added, argon stream The tube was sealed at 100 ° C. and stirred for 6 days. Methanol (6 mL) was added to the reaction solution, followed by concentration under reduced pressure. The precipitated solid was collected by filtration (68 mg, 65%) and recrystallized from methanol-ethyl acetate to obtain 42 mg (40%) of morphinan skeleton NTB-methiodide (44) as light brown crystals.
mp: 253-254 ° C (dec.).
1 H NMR (DMSO, 300 MHz) δ: 0.50 (2H, m), 0.60 (2H, m), 0.80 (1H, m), 1.20 (1H, m), 1.60 (1H, d), 2.60 (1H, m ), 2.80 (2H, m), 3.10 (3H, m), 3.50 (3H, m), 3.80 (3H, s), 3.9 (2H, m), 4.1 (1H, m), 6.60 (1H, dd) , 6.80 (1H, d), 7.00 (1H, dd), 7.20 (2H, m), 7.30 (1H, dd), 7.5 (1H, d).
MS (FAB) m / z 416 (M) + .
IR (KBr) ν max cm -1 : 3354.
Elemental analysis (C 27 H 30 NO 3・ I)
Calculated values: C, 59.67; H, 5.56; N, 2.58.
Found: C. 59.37; H, 5.59; N, 2.86.
実施例3
45の合成
3-OMe-モルヒナン(1)250mg(0.732mmol)の無水エタノール溶液(3.75mL)にアルゴン気流下、2-アミノベンズアルデヒド271mg(2.23mmol)、メタンスルホン酸(122μL, 1.86mmol)を順次加えた後、加熱還流下18時間攪拌した。反応溶液に10%炭酸水素ナトリウム水溶液を加えた後(pH9)、クロロホルム(30, 30, 25mL)で抽出した。有機層を飽和食塩水(30mL)で洗浄した後、乾燥し(Na2SO4)、減圧濃縮した。残渣(666mg)をシリカゲルカラムクロマトグラフィー(アンモニア飽和クロロホルムーメタノール100:1)で分離精製し、3-OMe-モルヒナン骨格キノリン体(4)を無色油状物として257mg(82%)で得た。メタノールから再結晶を行い、3-OMe-モルヒナン骨格キノリン体(4)を白色結晶として189mg(61%)で得た。
mp:174-175℃
1H NMR (CDCl3,300MHz) δ : 0.20 (2H, m), 0.60 (2H, m), 0.90 (1H, m), 1.45 (1H, d), 2.20 (2H, broad), 2.45 (2H, d), 2.70 (1H, m), 3.00 (1H, m), 3.10 (1H, d), 3.30 (1H, d), 3.65 (3H, s), 3.70 (1H, d), 6.60 (1H, dd), 6.90 (1H, d), 7.00 (1H, d), 7.40 (1H, dd), 7.59 (1H, dd), 7.60 (1H, d), 7.65 (1H, d), 8.00 (1H, d).
MS(FAB) m/z 427 (M+H)+.
IR(KBr) νmaxcm-1: 3397.
元素分析(C28H30N2O2)
計算値:C. 78.84; H, 7.09; N, 6.57.
実測値:C. 78.49; H, 7.05; N, 6.63. Example 3
Synthesis of 45
After adding 271 mg (2.23 mmol) of 2-aminobenzaldehyde and methanesulfonic acid (122 μL, 1.86 mmol) sequentially to an absolute ethanol solution (3.75 mL) of 250 mg (0.732 mmol) of 3-OMe-morphinan (1) under an argon stream The mixture was stirred for 18 hours with heating under reflux. A 10% aqueous sodium hydrogen carbonate solution was added to the reaction solution (pH 9), followed by extraction with chloroform (30, 30, 25 mL). The organic layer was washed with saturated brine (30 mL), dried (Na 2 SO 4 ), and concentrated under reduced pressure. The residue (666 mg) was separated and purified by silica gel column chromatography (ammonia saturated chloroform-methanol 100: 1) to obtain 257 mg (82%) of 3-OMe-morphinan skeleton quinoline (4) as a colorless oil. Recrystallization from methanol gave 189 mg (61%) of 3-OMe-morphinan skeleton quinoline (4) as white crystals.
mp: 174-175 ℃
1 H NMR (CDCl 3 , 300MHz) δ: 0.20 (2H, m), 0.60 (2H, m), 0.90 (1H, m), 1.45 (1H, d), 2.20 (2H, broad), 2.45 (2H, d), 2.70 (1H, m), 3.00 (1H, m), 3.10 (1H, d), 3.30 (1H, d), 3.65 (3H, s), 3.70 (1H, d), 6.60 (1H, dd ), 6.90 (1H, d), 7.00 (1H, d), 7.40 (1H, dd), 7.59 (1H, dd), 7.60 (1H, d), 7.65 (1H, d), 8.00 (1H, d) .
MS (FAB) m / z 427 (M + H) + .
IR (KBr) ν max cm -1 : 3397.
Elemental analysis (C 28 H 30 N 2 O 2 )
Calculated value: C. 78.84; H, 7.09; N, 6.57.
Found: C. 78.49; H, 7.05; N, 6.63.
45の合成
3-OMe-モルヒナン骨格キノリン体(4)120mg(0.281mmol)の無水ジクロロメタン溶液(5.7mL)に、アルゴン気流下0℃で1M 三臭化ホウ素ジクロロメタン溶液1.73 mL(1.73mmol)を加え、室温で暗所1時間攪拌した。反応溶液に0℃で25%アンモニア水(1.36mL)を加えた後、クロロホルム(50, 30mL)で抽出した。有機層を飽和食塩水(15mL)で洗浄した後、乾燥(Na2SO4)し、減圧濃縮した。残渣(147mg)をクロロホルム−メタノールから再結晶を行い、モルヒナン骨格キノリン体(45)を白色結晶として75mg(64%)で得た。
mp:248℃
1H NMR (CDCl3, 300MHz) δ : 0.20 (2H, m), 0.60 (2H, m), 0.90 (1H, m), 1.40 (1H, d), 2.20 (1H, dd), 2.30 (1H, m), 2.45 (2H, m), 2.70 (1H, dd), 2.90 (1H, dd), 3.00 (1H, m), 3.10 (1H, d), 3.20 (1H, d), 3.30 (1H, d), 3.60(1H, m), 3.65 (1H, m), 6.65 (1H, dd), 6.95 (1H, dd), 7.00 (1H, d), 7.20 (2H, m), 7.50 (1H, dd), 7.55 (1H, d), 7.65 (1H, d).
MS(EI) m/z 412 (M)+.
元素分析(C27H28N2O2・0.25H2O)
計算値:C, 77.76; H, 6.89; N, 6.72.
実測値:C. 78.04; H, 6.94; N, 6.83.Synthesis of 45
Add 1.73 mL (1.73 mmol) of 1M boron tribromide dichloromethane solution at 0 ° C. to an anhydrous dichloromethane solution (5.7 mL) of 120 mg (0.281 mmol) of 3-OMe-morphinan skeleton quinoline (4) at room temperature. Stir in the dark for 1 hour. To the reaction solution was added 25% aqueous ammonia (1.36 mL) at 0 ° C., and the mixture was extracted with chloroform (50, 30 mL). The organic layer was washed with saturated brine (15 mL), dried (Na 2 SO 4 ), and concentrated under reduced pressure. The residue (147 mg) was recrystallized from chloroform-methanol to obtain 75 mg (64%) of morphinan skeleton quinoline (45) as white crystals.
mp: 248 ° C
1 H NMR (CDCl 3 , 300 MHz) δ: 0.20 (2H, m), 0.60 (2H, m), 0.90 (1H, m), 1.40 (1H, d), 2.20 (1H, dd), 2.30 (1H, m), 2.45 (2H, m), 2.70 (1H, dd), 2.90 (1H, dd), 3.00 (1H, m), 3.10 (1H, d), 3.20 (1H, d), 3.30 (1H, d ), 3.60 (1H, m), 3.65 (1H, m), 6.65 (1H, dd), 6.95 (1H, dd), 7.00 (1H, d), 7.20 (2H, m), 7.50 (1H, dd) , 7.55 (1H, d), 7.65 (1H, d).
MS (EI) m / z 412 (M) + .
Elemental analysis (C 27 H 28 N 2 O 2・ 0.25H 2 O)
Calculated values: C, 77.76; H, 6.89; N, 6.72.
Found: C. 78.04; H, 6.94; N, 6.83.
45の塩酸塩
モルヒナン骨格キノリン体(45)に塩酸飽和メタノール溶液を加えて、塩酸塩とした。
mp:250-255℃(dec.).
元素分析(C27H28N2O2・2HCl・H2O)
計算値:C, 64.41; H, 6.41; N, 5.56.
実測値:C, 64.07; H, 6.56; N, 5.58.Hydrochloric acid saturated methanol solution was added to 45 hydrochloride morphinan skeleton quinoline (45) to form hydrochloride.
mp: 250-255 ° C (dec.).
Elemental analysis (C 27 H 28 N 2 O 2 · 2HCl · H 2 O)
Calculated values: C, 64.41; H, 6.41; N, 5.56.
Found: C, 64.07; H, 6.56; N, 5.58.
実施例4
46の合成
3-OMeモルヒナン(1)200mg(0.59mmol)の1N水酸化ナトリウム水溶液(7mL)にベンズアルデヒド400μL(3.51mmol)を加え、90℃で8.5時間加熱還流した。反応溶液に1N塩酸(70mL)を加えた後、10%炭酸水素ナトリウム水溶液(70mL)を加えた(pH9)。クロロホルム(40, 40, 40mL)で抽出した後、有機層を乾燥(Na2SO4)し、減圧濃縮した。残渣(321mg)をシリカゲルカラムクロマトグラフィー(クロロホルム−酢酸エチル5:2)で分離精製し、3-OMe-モルヒナン骨格BNTX(5)を淡褐色油状物として175mg(69%)で得た。
1H NMR (CDCl3,300MHz) δ : 0.10 (2H, m), 0.50 (2H, m), 0.80 (1H, m), 1.20(1H, d), 2.10 (2H, m). 2.30 (2H, m), 2.60 (1H, dd), 2.65 (1H, dd), 2.85 (1H, dd), 2.90 (1H, d), 3.00 (1H, dd), 3.10 (2H, m), 3.15 (1H, d), 3.70 (3H, s), 6.70 (1H, dd), 6.80 (1H, d), 6.95 (1H, dd), 7.20-7.30 (5H, m), 7.35 (1H, s).
MS(EI) m/z 429 (M)+.
IR(NaCl) νmaxcm-1: 3399, 1683, 1609, 1502. Example 4
46 synthesis
To 200 mg (0.59 mmol) of 3-OMe morphinan (1) 1N aqueous sodium hydroxide solution (7 mL) was added 400 μL (3.51 mmol) of benzaldehyde, and the mixture was heated to reflux at 90 ° C. for 8.5 hours. After adding 1N hydrochloric acid (70 mL) to the reaction solution, 10% aqueous sodium hydrogen carbonate solution (70 mL) was added (pH 9). After extraction with chloroform (40, 40, 40 mL), the organic layer was dried (Na 2 SO 4 ) and concentrated under reduced pressure. The residue (321 mg) was separated and purified by silica gel column chromatography (chloroform-ethyl acetate 5: 2) to obtain 175 mg (69%) of 3-OMe-morphinane skeleton BNTX (5) as a light brown oil.
1 H NMR (CDCl 3 , 300MHz) δ: 0.10 (2H, m), 0.50 (2H, m), 0.80 (1H, m), 1.20 (1H, d), 2.10 (2H, m). 2.30 (2H, m), 2.60 (1H, dd), 2.65 (1H, dd), 2.85 (1H, dd), 2.90 (1H, d), 3.00 (1H, dd), 3.10 (2H, m), 3.15 (1H, d ), 3.70 (3H, s), 6.70 (1H, dd), 6.80 (1H, d), 6.95 (1H, dd), 7.20-7.30 (5H, m), 7.35 (1H, s).
MS (EI) m / z 429 (M) + .
IR (NaCl) ν max cm -1 : 3399, 1683, 1609, 1502.
46の合成
3-OMe-モルヒナン骨格BNTX(5)200 mg (0.469mmol)の無水ジクロロメタン溶液(10mL)に、アルゴン気流下0℃で1M 三臭化ホウ素ジクロロメタン溶液2.86 mL(2.86mmol)を加え、室温で暗所1時間攪拌した。反応溶液に6%アンモニア水(12mL)を0℃で加え激しく攪拌した後、クロロホルム(30, 30, 30mL)で抽出した。有機層を飽和食塩水(15mL)で洗浄した後、乾燥(Na2SO4)し、減圧濃縮した。残渣(196mg)をシリカゲルカラムクロマトグラフィー(クロロホルム−メタノール10:1)で分離精製し、モルヒナン骨格BNTX(46)を淡褐色油状物として172mg(89%)で得た。
1H NMR (CDCl3, 300MHz) δ : 0.15 (2H, m), 0.50 (2H, m), 0.80 (1H, m), 1.20 (2H, d), 2.10 (2H, m), 2.30 (2H, m), 2.60 (1H, d), 2.70 (1H, dd), 2.85 (1H, dd), 2.90 (1H, d), 3.05 (2H, m), 3.15 (2H, m), 6.65 (1H, dd), 6.85 (1H, d), 7.00 (1H, d), 7.20-7.25 (5H, m), 7.25 (1H, s).
MS(EI) m/z 415 (M)+.
IR(NaCl) νmaxcm-1: 3375, 1735, 1682, 1609, 1502.46 synthesis
Add 2.86 mL (2.86 mmol) of 1M boron tribromide dichloromethane solution to an anhydrous dichloromethane solution (10 mL) of 3-OMe-morphinane skeleton BNTX (5) 200 mg (0.469 mmol) at 0 ° C under an argon stream. Stir for 1 hour. To the reaction solution was added 6% aqueous ammonia (12 mL) at 0 ° C., and the mixture was vigorously stirred and extracted with chloroform (30, 30, 30 mL). The organic layer was washed with saturated brine (15 mL), dried (Na 2 SO 4 ), and concentrated under reduced pressure. The residue (196 mg) was separated and purified by silica gel column chromatography (chloroform-methanol 10: 1) to obtain 172 mg (89%) of a morphinan skeleton BNTX (46) as a light brown oil.
1 H NMR (CDCl 3 , 300 MHz) δ: 0.15 (2H, m), 0.50 (2H, m), 0.80 (1H, m), 1.20 (2H, d), 2.10 (2H, m), 2.30 (2H, m), 2.60 (1H, d), 2.70 (1H, dd), 2.85 (1H, dd), 2.90 (1H, d), 3.05 (2H, m), 3.15 (2H, m), 6.65 (1H, dd ), 6.85 (1H, d), 7.00 (1H, d), 7.20-7.25 (5H, m), 7.25 (1H, s).
MS (EI) m / z 415 (M) + .
IR (NaCl) ν max cm -1 : 3375, 1735, 1682, 1609, 1502.
46の塩酸塩
モルヒナン骨格BNTX(46)159mg(0.283mmol)の酢酸エチル溶液に塩酸飽和メタノール溶液0.5 mLを加え、塩酸塩163mgを得た。
mp:206-207℃(dec.).
元素分析(C27H29NO3・HCl・3H2O)
計算値:C, 64.08; H, 7.17; N, 2.77.
実測値:C. 63.75; H, 6.86; N, 2.77.To a solution of 46 hydrochloride morphinan skeleton BNTX (46) 159 mg (0.283 mmol) in ethyl acetate was added 0.5 mL of a hydrochloric acid saturated methanol solution to obtain 163 mg of hydrochloride.
mp: 206-207 ° C (dec.).
Elemental analysis (C 27 H 29 NO 3 · HCl · 3H 2 O)
Calculated values: C, 64.08; H, 7.17; N, 2.77.
Found: C. 63.75; H, 6.86; N, 2.77.
実施例5
47の合成
14H-3-OMeモルヒナン(8)200mg(0.615mmol)の無水エタノール溶液(3mL)にアルゴン気流下、2-アミノベンズアルデヒド227mg(1.88mmol)、メタンスルホン酸102 μL( 1.57mmol)を加えた後、加熱還流下23時間攪拌した。反応溶液に10%炭酸水素ナトリウム水溶液を加えた後(pH9)、酢酸エチル(10, 6, 4mL)で抽出した。有機層を飽和食塩水(5mL)で洗浄した後、乾燥し(Na2SO4)、減圧濃縮した。残渣(435mg)をシリカゲルカラムクロマトグラフィー(クロロホルム−メタノール10:1)で分離精製し、14H-3-OMe-モルヒナン骨格キノリン体(9)を無色油状物として247mg(98%)で得た。メタノールから再結晶を行い、14H-3-OMe-モルヒナン骨格キノリン体(9)を白色結晶として159mg(63%)で得た。
mp:200-203℃
1H NMR (CDCl3, 300MHz) δ : 0.10 (2H, m), 0.55 (2H, m), 0.90 (1H, m), 1.65 (1H, d), 2.00 (1H, td). 2.20 (1H, td), 2.50 (2H, m), 2.65 (1H, m), 2.75 (1H, m), 2.80 (1H, m), 2.85 (1H, m), 2.90 (1H, dd), 3.00 (1H, m), 3.05 (1H, d), 3.15 (1H, d), 3.45 (1H, m), 3.60 (3H, s), 3.95 (1H, d), 6.60 (1H, dd), 6.90 (1H, dd), 7.00 (1H, d), 7.30 (1H, dd), 7.50 (1H, d), 7.55 (2H, m), 7.60 (1H, d), 7.90 (1H, d).
MS(EI) m/z 410 (M)+.
IR(KBr) νmaxcm-1: 2917.
元素分析(C28H30N2O)
計算値:C, 81.90; H, 7.36; N, 6.82.
実測値:C. 81.67; H, 7.55; N, 6.89. Example 5
47 synthesis
After adding 227 mg (1.88 mmol) of 2-aminobenzaldehyde and 102 μL (1.57 mmol) of methanesulfonic acid to an absolute ethanol solution (3 mL) of 14H-3-OMe morphinan (8) 200 mg (0.615 mmol) under an argon stream, The mixture was stirred for 23 hours under heating to reflux. A 10% aqueous sodium hydrogen carbonate solution was added to the reaction solution (pH 9), followed by extraction with ethyl acetate (10, 6, 4 mL). The organic layer was washed with saturated brine (5 mL), dried (Na 2 SO 4 ), and concentrated under reduced pressure. The residue (435 mg) was separated and purified by silica gel column chromatography (chloroform-methanol 10: 1) to obtain 247 mg (98%) of 14H-3-OMe-morphinan skeleton quinoline (9) as a colorless oil. Recrystallization from methanol gave 159 mg (63%) of 14H-3-OMe-morphinan skeleton quinoline (9) as white crystals.
mp: 200-203 ℃
1 H NMR (CDCl 3 , 300 MHz) δ: 0.10 (2H, m), 0.55 (2H, m), 0.90 (1H, m), 1.65 (1H, d), 2.00 (1H, td). 2.20 (1H, td), 2.50 (2H, m), 2.65 (1H, m), 2.75 (1H, m), 2.80 (1H, m), 2.85 (1H, m), 2.90 (1H, dd), 3.00 (1H, m ), 3.05 (1H, d), 3.15 (1H, d), 3.45 (1H, m), 3.60 (3H, s), 3.95 (1H, d), 6.60 (1H, dd), 6.90 (1H, dd) , 7.00 (1H, d), 7.30 (1H, dd), 7.50 (1H, d), 7.55 (2H, m), 7.60 (1H, d), 7.90 (1H, d).
MS (EI) m / z 410 (M) + .
IR (KBr) ν max cm -1 : 2917.
Elemental analysis (C 28 H 30 N 2 O)
Calculated values: C, 81.90; H, 7.36; N, 6.82.
Found: C. 81.67; H, 7.55; N, 6.89.
47の合成
14H-3-OMeモルヒナン骨格キノリン体(9)120mg(0.292mmol)の無水ジクロロメタン溶液(6mL)に、アルゴン気流下0℃で1M 三臭化ホウ素ジクロロメタン溶液2.0 mL(2.0mmol)を加え、室温で暗所4時間攪拌した。反応溶液に0℃で6%アンモニア水(15mL)を加え激しく攪拌した後、クロロホルム(15, 10, 10mL)で抽出した。有機層を飽和食塩水(10mL)で洗浄した後、乾燥し(Na2SO4)、減圧濃縮した。残渣(137mg)をシリカゲルカラムクロマトグラフィー(クロロホルム−メタノール10:1)で分離精製し、14H-モルヒナン骨格キノリン体(47)を白色無定形として112mg(96%)で得た。メタノールから再結晶を行い、14H-モルヒナン骨格キノリン体(47)を白色結晶として82mg(71%)で得た。
mp:252℃
1H NMR (CDCl3, 300MHz) δ : 0.15 (2H, m), 0.50 (2H, m), 0.90 (1H, m), 1.60 (1H, d), 2.00 (1H, dd), 2.25 (1H, dd), 2.50 (3H, m), 2.80 (3H, m), 2.95 (1H, dd), 3.05 (1H, m), 3.10 (1H, m), 3.50 (1H, d), 3.90 (1H, d), 6.60 (1H, dd), 6.90 (1H, d), 6.95 (1H, dd), 7.30 (1H, d), 7.35 (2H, m), 7.50 (1H, dd), 7.55 (1H, d).
MS(EI) m/z 396 (M)+.
IR(KBr) νmaxcm-1: 3368.
元素分析(C27H28N2O・0.25H2O)
計算値:C, 80.86; H, 7.16; N, 6.99.
実測値:C. 81.15; H, 7.04; N, 7.06.47 synthesis
14H-3-OMe Morphinane quinoline (9) To a solution of 120 mg (0.292 mmol) in anhydrous dichloromethane (6 mL) was added 2.0 mL (2.0 mmol) of a 1M boron tribromide dichloromethane solution at 0 ° C. in an argon stream at room temperature. Stir in the dark for 4 hours. To the reaction solution was added 6% aqueous ammonia (15 mL) at 0 ° C., and the mixture was vigorously stirred and extracted with chloroform (15, 10, 10 mL). The organic layer was washed with saturated brine (10 mL), dried (Na 2 SO 4 ), and concentrated under reduced pressure. The residue (137 mg) was separated and purified by silica gel column chromatography (chloroform-methanol 10: 1) to obtain 112H (96%) of 14H-morphinan skeleton quinoline (47) as white amorphous. Recrystallization from methanol gave 14H-morphinan skeleton quinoline (47) as white crystals in 82 mg (71%).
mp: 252 ° C
1 H NMR (CDCl 3 , 300 MHz) δ: 0.15 (2H, m), 0.50 (2H, m), 0.90 (1H, m), 1.60 (1H, d), 2.00 (1H, dd), 2.25 (1H, dd), 2.50 (3H, m), 2.80 (3H, m), 2.95 (1H, dd), 3.05 (1H, m), 3.10 (1H, m), 3.50 (1H, d), 3.90 (1H, d ), 6.60 (1H, dd), 6.90 (1H, d), 6.95 (1H, dd), 7.30 (1H, d), 7.35 (2H, m), 7.50 (1H, dd), 7.55 (1H, d) .
MS (EI) m / z 396 (M) + .
IR (KBr) ν max cm -1 : 3368.
Elemental analysis (C 27 H 28 N 2 O · 0.25H 2 O)
Calculated values: C, 80.86; H, 7.16; N, 6.99.
Found: C. 81.15; H, 7.04; N, 7.06.
47の塩酸塩
14H-モルヒナン骨格キノリン体(47)50mg(0.126mmol)のクロロホルム溶液に塩酸飽和メタノール溶液を加えて、塩酸塩30mgを得た。
mp:253-254℃(dec.).
元素分析(C27H28N2O・3HCl・1.6H2O)
計算値:C, 60.64; H, 6.44; N, 5.23.
実測値:C, 60.29; H, 6.47; N, 5.32.47 hydrochloride
A hydrochloric acid saturated methanol solution was added to a chloroform solution of 14H-morphinan skeleton quinoline (47) 50 mg (0.126 mmol) to obtain 30 mg of hydrochloride.
mp: 253-254 ° C (dec.).
Elemental analysis (C 27 H 28 N 2 O · 3HCl · 1.6H 2 O)
Calculated values: C, 60.64; H, 6.44; N, 5.23.
Found: C, 60.29; H, 6.47; N, 5.32.
実施例6
48の合成
14H-3-OMe-モルヒナン(8)250mg(0.77mmol)の1N水酸化ナトリウム(6.5mL)−メタノール溶液(6.5mL)にベンズアルデヒド650μL(5.83mmol)を加え、室温で23.5時間攪拌した。反応溶液に2N塩酸を加えた後、エーテルで抽出した。水層に10%炭酸水素ナトリウム水溶液を加えた後(pH9)、酢酸エチル(50, 30, 20mL)で抽出した。有機層を飽和食塩水(50mL)で洗浄し、乾燥(Na2SO4)した後、減圧濃縮した。残渣(445mg)をシリカゲルカラムクロマトグラフィー(クロロホルム→アンモニア飽和クロロホルム)で分離精製し、14H-3-OMe-モルヒナン骨格BNTX(10)を白色無定形として319mg(定量的)で得た。
1H NMR (CDCl3,300MHz) δ : 0.10 (2H, m), 0.55 (2H, m), 0.90 (1H, m), 1.50 (1H, d), 1.80 (1H, m), 1.90 (1H, td), 2.10 (1H, td), 2.30 (2H, m). 2.40 (2H, m), 2.50 (1H, d), 2.70 (1H, dd), 2.75 (1H, dd), 2.90 (1H, m), 3.30 (1H, m), 3.50 (1H, m), 3.75 (3H, s), 6.70 (1H, dd), 6.80 (1H, d), 7.10 (1H, dd), 7.25-7.40 (5H, m), 7.35 (1H, s).
MS(EI) m/z 413 (M)+.
IR(KBr) νmaxcm-1: 1683, 1608, 1500. Example 6
48 synthesis
Benzaldehyde 650 μL (5.83 mmol) was added to 14H-3-OMe-morphinan (8) 250 mg (0.77 mmol) 1N sodium hydroxide (6.5 mL) -methanol solution (6.5 mL), and the mixture was stirred at room temperature for 23.5 hours. 2N Hydrochloric acid was added to the reaction solution, and the mixture was extracted with ether. A 10% aqueous sodium bicarbonate solution was added to the aqueous layer (pH 9), followed by extraction with ethyl acetate (50, 30, 20 mL). The organic layer was washed with saturated brine (50 mL), dried (Na 2 SO 4 ), and concentrated under reduced pressure. The residue (445 mg) was separated and purified by silica gel column chromatography (chloroform → ammonia saturated chloroform) to obtain 319 mg (quantitative) of 14H-3-OMe-morphinane skeleton BNTX (10) as white amorphous.
1 H NMR (CDCl 3 , 300MHz) δ: 0.10 (2H, m), 0.55 (2H, m), 0.90 (1H, m), 1.50 (1H, d), 1.80 (1H, m), 1.90 (1H, td), 2.10 (1H, td), 2.30 (2H, m). 2.40 (2H, m), 2.50 (1H, d), 2.70 (1H, dd), 2.75 (1H, dd), 2.90 (1H, m ), 3.30 (1H, m), 3.50 (1H, m), 3.75 (3H, s), 6.70 (1H, dd), 6.80 (1H, d), 7.10 (1H, dd), 7.25-7.40 (5H, m), 7.35 (1H, s).
MS (EI) m / z 413 (M) + .
IR (KBr) ν max cm -1 : 1683, 1608, 1500.
48の合成
14H-3-OMe-モルヒナン骨格BNTX(10)250 mg (0.6mmol)の無水ジクロロメタン溶液(12mL)に、アルゴン気流下0℃で1M 三臭化ホウ素ジクロロメタン溶液3.60 mL(3.60mmol)を加え、室温で暗所1.5時間攪拌した。反応溶液に0℃で6%アンモニア水(12mL)を加え激しく攪拌した後、クロロホルム(30, 30, 30mL)で抽出した。有機層を飽和食塩水(15mL)で洗浄した後、乾燥(Na2SO4)し、減圧濃縮した。残渣(189mg)をシリカゲルカラムクロマトグラフィー(クロロホルム→アンモニア飽和クロロホルム)で分離精製し、14H-モルヒナン骨格BNTX(48)を白色無定形として148mg(62%)で得た。
1H NMR (CDCl3, 300MHz) δ : 0.10 (2H, m), 0.50 (2H, m), 0.90 (1H, m), 1.30 (1H, m), 1.45 (1H, m), 1.80 (1H, td), 2.10 (1H, td), 2.35 (2H, m). 2.45 (2H, m), 2.70 (1H, d), 2.80 (1H, dd), 3.00 (2H, m), 3.30 (1H, d), 3.40 (1H, m), 6.65 (1H, dd), 6.75 (1H, d), 7.00 (1H, dd), 7.20-7.40 (5H, m), 7.35 (1H, s).
MS(EI) m/z 399 (M)+.
IR(KBr) νmaxcm-1: 3409, 1680, 1610.48 synthesis
14H-3-OMe-morphinane skeleton BNTX (10) 250 mg (0.6 mmol) in anhydrous dichloromethane (12 mL) was added 1.M boron tribromide dichloromethane solution 3.60 mL (3.60 mmol) at 0 ° C under an argon stream at room temperature. And stirred in the dark for 1.5 hours. To the reaction solution was added 6% aqueous ammonia (12 mL) at 0 ° C., and the mixture was vigorously stirred and extracted with chloroform (30, 30, 30 mL). The organic layer was washed with saturated brine (15 mL), dried (Na 2 SO 4 ), and concentrated under reduced pressure. The residue (189 mg) was separated and purified by silica gel column chromatography (chloroform → ammonia saturated chloroform) to obtain 14H-morphinane skeleton BNTX (48) as white amorphous in 148 mg (62%).
1 H NMR (CDCl 3 , 300 MHz) δ: 0.10 (2H, m), 0.50 (2H, m), 0.90 (1H, m), 1.30 (1H, m), 1.45 (1H, m), 1.80 (1H, td), 2.10 (1H, td), 2.35 (2H, m). 2.45 (2H, m), 2.70 (1H, d), 2.80 (1H, dd), 3.00 (2H, m), 3.30 (1H, d ), 3.40 (1H, m), 6.65 (1H, dd), 6.75 (1H, d), 7.00 (1H, dd), 7.20-7.40 (5H, m), 7.35 (1H, s).
MS (EI) m / z 399 (M) + .
IR (KBr) ν max cm -1 : 3409, 1680, 1610.
48の塩酸塩
14H-モルヒナン骨格BNTX(48)70mg(0.175mmol)の酢酸エチル溶液に塩酸飽和メタノール溶液を加え、塩酸塩34mg(45%)を得た。
mp 203-208 ℃(dec.).
元素分析(C27H29NO2・HCl・H2O)
計算値:C, 71.43; H, 7.10; N, 3.09.
実測値:C, 71.64; H, 7.04; N, 3.20.48 hydrochloride
To a solution of 14H-morphinane skeleton BNTX (48) 70 mg (0.175 mmol) in ethyl acetate was added hydrochloric acid saturated methanol solution to obtain hydrochloride 34 mg (45%).
mp 203-208 ° C (dec.).
Elemental analysis (C 27 H 29 NO 2 · HCl · H 2 O)
Calculated values: C, 71.43; H, 7.10; N, 3.09.
Found: C, 71.64; H, 7.04; N, 3.20.
実施例7
49の合成
N-イソブチル-3-OMe-モルヒナン(13)221mg(0.643mmol)の酢酸溶液(4.4mL)に、塩酸フェニルヒドラジン140mg(0.96mmol)を加え、1.5時間加熱還流した。反応溶液を減圧濃縮した後、クロロホルム(85mL)を加え溶解した。有機層を10%炭酸水素ナトリウム(85mL)、水(85mL)で順次洗浄した後、乾燥(Na2SO4)した。残渣(233mg)にメタノールを加えて、褐色固体(201 mg、75%)を沈殿させた後、クロロホルムから再結晶を行い、N-イソブチル-3-OMe-モルヒナン骨格NTI(14)を淡褐色結晶として119mg(44%)で得た。
mp:265-270℃.
1H NMR (CDCl3,300MHz) δ : 0.95 (6H, t), 1.35 (1H, d), 1.8 (1H, m), 2.30 (3H, m), 2.40 (1H, m), 2.50 (1H, m). 2.70 (2H, m), 3.05 (2H, m), 3.10 (3H, m), 3.70 (3H, s), 6.60 (1H, dd), 6.80 (1H, d), 6.90-7.05 (3H, m), 7.23 (1H, d), 7.3 (1H, d), 7.8 (1H, broad).
MS(EI) m/z 416 (M)+.
IR(KBr) νmaxcm-1: 3290. Example 7
49 synthesis
To an acetic acid solution (4.4 mL) of 221 mg (0.643 mmol) of N-isobutyl-3-OMe-morphinan (13), 140 mg (0.96 mmol) of phenylhydrazine hydrochloride was added and heated to reflux for 1.5 hours. After the reaction solution was concentrated under reduced pressure, chloroform (85 mL) was added and dissolved. The organic layer was washed successively with 10% sodium hydrogen carbonate (85 mL) and water (85 mL) and then dried (Na 2 SO 4 ). Methanol was added to the residue (233 mg) to precipitate a brown solid (201 mg, 75%), and then recrystallized from chloroform to give N-isobutyl-3-OMe-morphinane skeleton NTI (14) as light brown crystals. As 119 mg (44%).
mp: 265-270 ° C.
1 H NMR (CDCl 3 , 300MHz) δ: 0.95 (6H, t), 1.35 (1H, d), 1.8 (1H, m), 2.30 (3H, m), 2.40 (1H, m), 2.50 (1H, m). 2.70 (2H, m), 3.05 (2H, m), 3.10 (3H, m), 3.70 (3H, s), 6.60 (1H, dd), 6.80 (1H, d), 6.90-7.05 (3H m), 7.23 (1H, d), 7.3 (1H, d), 7.8 (1H, broad).
MS (EI) m / z 416 (M) + .
IR (KBr) ν max cm -1 : 3290.
49の合成
N-イソブチル-3-OMe-モルヒナン骨格NTI(14)50mg(0.12mmol)の無水ジクロロメタン溶液(2.44mL)に、アルゴン気流下0℃で1M 三臭化ホウ素ジクロロメタン溶液0.74 mL(0.74mmol)を加え、室温で暗所1時間攪拌した。反応溶液に0℃で6%アンモニア(2.4mL)を加え激しく攪拌した後、クロロホルム(40, 10, 10mL)で抽出した。有機層を飽和食塩水(80mL)で洗浄した後、乾燥(Na2SO4)し、減圧濃縮し、N-イソブチルモルヒナン骨格NTI(49)を無色油状物として50mg(定量的)で得た。
1H NMR (CDCl3, 300MHz) δ: 0.91 (6H, t), 1.26 (1H, m), 1.63 (1H, m), 1.79 (1H, m), 2.18 (2H, m), 2.43 (1H, m). 2.72 (2H, m), 3.05 (5H, m), 6.43 (1H, d), 6.66 (1H, d), 6.84 (1H, d), 6.99 (1H, d), 7.05 (1H, d), 7.20 (1H, d), 7.23 (1H, d), 7.8 (1H, broad).
MS(EI) m/z 402 (M)+.49 synthesis
N-isobutyl-3-OMe-morphinane skeleton NTI (14) 50 mg (0.12 mmol) in anhydrous dichloromethane solution (2.44 mL) was added 0.7 M (0.74 mmol) of 1M boron tribromide dichloromethane solution at 0 ° C under an argon stream. The mixture was stirred at room temperature in the dark for 1 hour. 6% ammonia (2.4 mL) was added to the reaction solution at 0 ° C., and the mixture was vigorously stirred and extracted with chloroform (40, 10, 10 mL). The organic layer was washed with saturated brine (80 mL), dried (Na 2 SO 4 ), and concentrated under reduced pressure to give N-isobutylmorphinane skeleton NTI (49) as a colorless oil in 50 mg (quantitative). .
1 H NMR (CDCl 3 , 300 MHz) δ: 0.91 (6H, t), 1.26 (1H, m), 1.63 (1H, m), 1.79 (1H, m), 2.18 (2H, m), 2.43 (1H, m). 2.72 (2H, m), 3.05 (5H, m), 6.43 (1H, d), 6.66 (1H, d), 6.84 (1H, d), 6.99 (1H, d), 7.05 (1H, d ), 7.20 (1H, d), 7.23 (1H, d), 7.8 (1H, broad).
MS (EI) m / z 402 (M) + .
49の塩酸塩
N-イソブチルモルヒナン骨格NTI(49)の酢酸エチル溶液に塩酸飽和メタノール溶液を加え、塩酸塩30 mgを得た。
mp:230-235℃(dec.).
元素分析(C26H30N2O2・HCl・1.5H2O)
計算値:C, 67.01; H, 7.35; N, 6.00.
実測値:C, 67.01; H, 6.95; N, 6.09.49 hydrochloride
Hydrochloric acid saturated methanol solution was added to an ethyl acetate solution of N-isobutylmorphinane skeleton NTI (49) to obtain 30 mg of hydrochloride.
mp: 230-235 ° C (dec.).
Elemental analysis (C 26 H 30 N 2 O 2 · HCl · 1.5H 2 O)
Calculated values: C, 67.01; H, 7.35; N, 6.00.
Found: C, 67.01; H, 6.95; N, 6.09.
実施例8
50の合成
N-イソブチル3-OMe-モルヒナン(13)280mg(0.816mmol)の無水エタノール溶液(15mL)にO-フェニルヒドロキシルアミン塩酸塩238mg(1.63mmol)、メタンスルホン酸212 μL(3.26mmol)を加え、アルゴン気流下18時間加熱還流した。反応溶液に10%炭酸水素ナトリウム水溶液(50mL)を加えた後(pH9)、クロロホルム(50, 30, 20mL)で抽出した。有機層を飽和食塩水(70mL)で洗浄した後、乾燥(Na2SO4)し、減圧濃縮した。残渣(401mg)をシリカゲルカラムクロマトグラフィー(クロロホルム−メタノール100:1→100:3)で分離精製し、N-イソブチル-3-OMe-モルヒナン骨格NTB(15)を無色無定形として132mg(39%)で得た。
1H NMR (CDCl3, 300MHz) δ : 1.00 (6H, t), 1.40 (1H, dd), 1.80 (1H, m), 2.25 (1H, m). 2.30 (3H, m),2.35 (1H, d), 2.50 (1H, m), 2.65 (2H, m), 3.10 (1H, m), 3.20 (1H, m), 3.25 (1H, m),3.39 (1H, d), 3.80 (3H, s), 6.65 (1H, dd), 6.80 (1H, d), 7.00 (1H, d), 7.10 (2H, m), 7.25 (1H, d), 7.35 (1H, d).
MS(FAB) m/z 418 (M+H)+.
IR(KBr) νmaxcm-1: 3389. Example 8
50 synthesis
238 mg (1.63 mmol) of O-phenylhydroxylamine hydrochloride and 212 μL (3.26 mmol) of methanesulfonic acid were added to an absolute ethanol solution (15 mL) of 280 mg (0.816 mmol) of N-isobutyl 3-OMe-morphinan (13), and argon was added. The mixture was heated to reflux for 18 hours under a stream of air. A 10% aqueous sodium hydrogen carbonate solution (50 mL) was added to the reaction solution (pH 9), followed by extraction with chloroform (50, 30, 20 mL). The organic layer was washed with saturated brine (70 mL), dried (Na 2 SO 4 ), and concentrated under reduced pressure. The residue (401 mg) was separated and purified by silica gel column chromatography (chloroform-methanol 100: 1 → 100: 3) to give 132 mg (39%) of N-isobutyl-3-OMe-morphinane skeleton NTB (15) as colorless and amorphous I got it.
1 H NMR (CDCl 3 , 300 MHz) δ: 1.00 (6H, t), 1.40 (1H, dd), 1.80 (1H, m), 2.25 (1H, m). 2.30 (3H, m), 2.35 (1H, d), 2.50 (1H, m), 2.65 (2H, m), 3.10 (1H, m), 3.20 (1H, m), 3.25 (1H, m), 3.39 (1H, d), 3.80 (3H, s ), 6.65 (1H, dd), 6.80 (1H, d), 7.00 (1H, d), 7.10 (2H, m), 7.25 (1H, d), 7.35 (1H, d).
MS (FAB) m / z 418 (M + H) + .
IR (KBr) ν max cm -1 : 3389.
50の合成
N-イソブチル-3-OMe-モルヒナン骨格NTB(15)130mg(0.312mmol)の無水ジクロロメタン溶液(6mL)に、アルゴン気流下0℃で1M 三臭化ホウ素ジクロロメタン溶液1.87 mL(1.87mmol)を加え、室温で暗所1.5時間攪拌した。反応溶液に0℃で6%アンモニア水(10mL)を加え激しく攪拌した後(pH9)、クロロホルム(30, 10, 10mL)で抽出した。有機層を飽和食塩水(30mL)で洗浄した後、乾燥(Na2SO4)し、減圧濃縮した。残渣(115mg)をシリカゲルカラムクロマトグラフィー(クロロホルム−メタノール100:3)で分離精製し、N-イソブチル-モルヒナン骨格 NTB(50)を淡褐色無定形として90mg(72%)で得た。エーテルから再結晶を行い、50を黄土色結晶として36mg(29%)で得た。
mp:236-241℃.
1H NMR (CDCl3, 300MHz) δ: 0.95 (6H, t), 1.35 (1H, dd), 1.80 (1H, m), 2.20 (1H, m). 2.25 (1H, m), 2.30 (1H, m), 2.35 (1H, m), 2.50 (1H, m), 2.65 (1H, m), 2.70 (1H, m), 3.00 (1H, m), 3.05 (1H, m), 3.15 (2H, m), 3.30 (1H, d), 6.65 (1H, dd), 6.75 (1H, d), 6.95 (1H, d), 7.10 (2H, m), 7.20 (1H, d), 7.35 (1H, d).
MS(EI) m/z 403 (M)+.
IR(KBr) νmaxcm-1: 337350 synthesis
1.87 mL (1.87 mmol) of 1M boron tribromide dichloromethane solution was added to an anhydrous dichloromethane solution (6 mL) of N-isobutyl-3-OMe-morphinane skeleton NTB (15) 130 mg (0.312 mmol) at 0 ° C. under an argon stream. The mixture was stirred at room temperature for 1.5 hours in the dark. To the reaction solution was added 6% aqueous ammonia (10 mL) at 0 ° C., and the mixture was vigorously stirred (pH 9) and extracted with chloroform (30, 10, 10 mL). The organic layer was washed with saturated brine (30 mL), dried (Na 2 SO 4 ), and concentrated under reduced pressure. The residue (115 mg) was separated and purified by silica gel column chromatography (chloroform-methanol 100: 3) to obtain 90 mg (72%) of N-isobutyl-morphinan skeleton NTB (50) as a light brown amorphous. Recrystallization from ether gave 50 as ocher crystals in 36 mg (29%).
mp: 236-241 ° C.
1 H NMR (CDCl 3 , 300 MHz) δ: 0.95 (6H, t), 1.35 (1H, dd), 1.80 (1H, m), 2.20 (1H, m). 2.25 (1H, m), 2.30 (1H, m), 2.35 (1H, m), 2.50 (1H, m), 2.65 (1H, m), 2.70 (1H, m), 3.00 (1H, m), 3.05 (1H, m), 3.15 (2H, m ), 3.30 (1H, d), 6.65 (1H, dd), 6.75 (1H, d), 6.95 (1H, d), 7.10 (2H, m), 7.20 (1H, d), 7.35 (1H, d) .
MS (EI) m / z 403 (M) + .
IR (KBr) ν max cm -1 : 3373
50の塩酸塩
N-イソブチルモルヒナン骨格NTB(50)25mg(0.062mmol)のエーテル溶液に塩酸飽和メタノール溶液を加え、塩酸塩23 mgを得た。
mp:225-230℃(dec.).
元素分析(C26H29NO3・HCl・1.1H2O)
計算値:C, 67.91; H, 7.06; N, 3.04.
実測値:C, 67.86; H, 6.85; N, 3.15.50 hydrochloride
A saturated methanol solution of hydrochloric acid was added to an ether solution of 25 mg (0.062 mmol) of N-isobutylmorphinane skeleton NTB (50) to obtain 23 mg of hydrochloride.
mp: 225-230 ° C (dec.).
Elemental analysis (C 26 H 29 NO 3 · HCl · 1.1H 2 O)
Calculated values: C, 67.91; H, 7.06; N, 3.04.
Found: C, 67.86; H, 6.85; N, 3.15.
実施例9
51の合成
N-イソブチル-3-OMe-モルヒナン(13)250mg(0.728mmol)の無水エタノール溶液(4mL)にアルゴン気流下、2-アミノベンズアルデヒド264mg(2.18mmol)、メタンスルホン酸120μL(1.82mmol)を加えた後、加熱還流下5時間攪拌した。反応溶液を濃縮した後、10%炭酸水素ナトリウム水溶液を加えた後(pH9)、クロロホルム(30, 20, 15mL)で抽出した。有機層を飽和食塩水(30mL)で洗浄した後、乾燥(Na2SO4)し、減圧濃縮した。残渣(580mg)をシリカゲルカラムクロマトグラフィー(クロロホルム−メタノール100:2→100:5)で分離精製し、N-イソブチル-3-OMe-モルヒナン骨格キノリン体(16)を無色油状物として219mg(70%)で得た。
1H NMR (CDCl3,300MHz) δ : 1.00 (6H, t), 1.40 (1H, m), 1.80 (1H, m). 2.25 (1H, m), 2.30 (2H, m), 2.35 (1H, m), 2.50 (1H, d), 2.95 (1H, m), 3.00 (2H, m), 3.05 (1H, m), 3.20 (1H, d), 3.60 (1H, dd), 3.65 (3H, s), 3.70 (1H, m), 6.60 (1H, dd), 6.90 (1H, dd), 7.00 (1H, d), 7.20 (1H, dd), 7.55 (1H, dd), 7.60 (1H, d), 7.65 (1H, d), 8.00 (1H, d).
MS(FAB) m/z 429 (M+H)+.
IR(NaCl) νmaxcm-1: 3406. Example 9
51 synthesis
2-aminobenzaldehyde 264 mg (2.18 mmol) and methanesulfonic acid 120 μL (1.82 mmol) were added to an absolute ethanol solution (4 mL) of N-isobutyl-3-OMe-morphinan (13) 250 mg (0.728 mmol) in an argon stream. Thereafter, the mixture was stirred for 5 hours with heating under reflux. The reaction solution was concentrated, 10% aqueous sodium hydrogen carbonate solution was added (pH 9), and the mixture was extracted with chloroform (30, 20, 15 mL). The organic layer was washed with saturated brine (30 mL), dried (Na 2 SO 4 ), and concentrated under reduced pressure. The residue (580 mg) was separated and purified by silica gel column chromatography (chloroform-methanol 100: 2 → 100: 5) to give 219 mg (70% of N-isobutyl-3-OMe-morphinan skeleton quinoline (16) as a colorless oil. ).
1 H NMR (CDCl 3 , 300MHz) δ: 1.00 (6H, t), 1.40 (1H, m), 1.80 (1H, m). 2.25 (1H, m), 2.30 (2H, m), 2.35 (1H, m), 2.50 (1H, d), 2.95 (1H, m), 3.00 (2H, m), 3.05 (1H, m), 3.20 (1H, d), 3.60 (1H, dd), 3.65 (3H, s ), 3.70 (1H, m), 6.60 (1H, dd), 6.90 (1H, dd), 7.00 (1H, d), 7.20 (1H, dd), 7.55 (1H, dd), 7.60 (1H, d) , 7.65 (1H, d), 8.00 (1H, d).
MS (FAB) m / z 429 (M + H) + .
IR (NaCl) ν max cm -1 : 3406.
51の合成
N-イソブチル-3-OMe-モルヒナン骨格キノリン体(16)210mg(0.490mmol)の無水ジクロロメタン溶液(10mL)に、アルゴン気流下0℃で1M 三臭化ホウ素ジクロロメタン溶液3.0 mL(3.0mmol)を加え、室温で暗所1.5時間攪拌した。反応溶液に0℃で6%アンモニア水(10mL)を加え激しく攪拌した後、クロロホルム(50, 30,10mL)で抽出した。有機層を飽和食塩水(15mL)で洗浄した後、乾燥(Na2SO4)し、減圧濃縮した。残渣(202mg)をエタノールから再結晶を行い、N-イソブチルモルヒナン骨格キノリン体(51)を白色結晶として118mg(58%)で得た。
mp:173-177℃
1H NMR (CDCl3, 300MHz) δ: 0.90 (6H, t), 1.30 (1H, d), 1.75 (1H, m), 2.10 (1H, td), 2.25 (1H, m), 2.45 (1H, dd), 2.90 (1H, m), 2.95 (1H, m), 3.00 (1H, m), 3.05 (1H, d), 3.15 (1H, d), 3.55 (1H, d), 3.60 (1H, m), 3.65 (1H, m), 6.55 (1H, dd), 6.90 (1H, d), 6.95 (1H, d), 7.15 (2H, m), 7.40 (1H, dd), 7.50 (1H, dd), 7.60 (1H, d).
MS(FAB) m/z 415 (M+H)+.
IR(KBr) νmaxcm-1: 3378.51 synthesis
To a solution of N-isobutyl-3-OMe-morphinan skeleton quinoline (16) 210 mg (0.490 mmol) in anhydrous dichloromethane (10 mL) was added 3.0 mL (3.0 mmol) of 1M boron tribromide dichloromethane solution at 0 ° C. under an argon stream. The mixture was stirred at room temperature for 1.5 hours in the dark. To the reaction solution was added 6% aqueous ammonia (10 mL) at 0 ° C., and the mixture was vigorously stirred and extracted with chloroform (50, 30, 10 mL). The organic layer was washed with saturated brine (15 mL), dried (Na 2 SO 4 ), and concentrated under reduced pressure. The residue (202 mg) was recrystallized from ethanol to obtain 118 mg (58%) of N-isobutylmorphinan skeleton quinoline (51) as white crystals.
mp: 173-177 ℃
1 H NMR (CDCl 3 , 300 MHz) δ: 0.90 (6H, t), 1.30 (1H, d), 1.75 (1H, m), 2.10 (1H, td), 2.25 (1H, m), 2.45 (1H, dd), 2.90 (1H, m), 2.95 (1H, m), 3.00 (1H, m), 3.05 (1H, d), 3.15 (1H, d), 3.55 (1H, d), 3.60 (1H, m ), 3.65 (1H, m), 6.55 (1H, dd), 6.90 (1H, d), 6.95 (1H, d), 7.15 (2H, m), 7.40 (1H, dd), 7.50 (1H, dd) , 7.60 (1H, d).
MS (FAB) m / z 415 (M + H) + .
IR (KBr) ν max cm -1 : 3378.
51の塩酸塩
N-イソブチルモルヒナン骨格キノリン体(51)45mg(0.109mmol)のエーテル溶液に塩酸飽和メタノール溶液を加えて、塩酸塩45mgを得た。
mp:226-231℃.
元素分析(C27H30N2O2・2HCl・2/3H2O)
計算値:C, 64.92; H, 6.72; N, 5.60.
実測値:C, 65.22; H, 6.86; N, 5.43.51 hydrochloride
A saturated methanol solution of hydrochloric acid was added to an ether solution of 45 mg (0.109 mmol) of N-isobutyl morphinan skeleton quinoline (51) to obtain 45 mg of hydrochloride.
mp: 226-231 ° C.
Elemental analysis (C 27 H 30 N 2 O 2 · 2HCl · 2 / 3H 2 O)
Calculated values: C, 64.92; H, 6.72; N, 5.60.
Found: C, 65.22; H, 6.86; N, 5.43.
実施例10
52の合成
4-OH-3-デオキシモルヒナン(17)1.08g(3.29mmol)の無水ジメチルホルムアミド溶液(12mL)に、炭酸カリウム1.15 g(8.31mmol)、ヨウ化メチル0.35 mL(5.62mmol)を加え、遮光下17時間攪拌した。反応溶液を水(100mL)に注いだ後、エーテル(150mL)で抽出した。有機層を10%炭酸水素ナトリウム水溶液(100mL)、飽和食塩水(50mL)で順次洗浄した後、乾燥(Na2SO4)した。有機層を減圧濃縮し、4-OMe-3-デオキシモルヒナン(18)を920mg(82%)で得た。得られた18の一部をメタノールから再結晶を行った。
mp:137-138℃.
1H NMR (CDCl3, 300MHz) δ : 0.10 (2H, m), 0.50 (2H, m), 0.90 (1H, m), 1.60 (1H, d), 1.80 (1H, m), 1.95 (1H, m), 2.05 (3H, m), 2.10 (1H, m), 2.40 (2H, m), 2.60 (1H, m). 2.70 (1H, m), 2.90 (1H, m), 3.00 (1H, m), 3.10 (2H, m), 3.75 (1H, dd), 3.80 (3H, s), 6.65 (1H, d), 6.70 (1H, d), 7.10 (1H, d).
MS(FAB) m/z 432 (M+H)+.
IR(KBr) νmaxcm-1: 3433,1711,
元素分析(C21H27NO3)
計算値:C, 73.87; H, 7.97; N, 4.10.
実測値:C, 73.63; H, 7.85; N, 4.09. Example 10
52 synthesis
To a solution of 4-OH-3-deoxymorphinan (17) 1.08 g (3.29 mmol) in anhydrous dimethylformamide (12 mL), add 1.15 g (8.31 mmol) of potassium carbonate and 0.35 mL (5.62 mmol) of methyl iodide. Stir for 17 hours. The reaction solution was poured into water (100 mL) and extracted with ether (150 mL). The organic layer was washed successively with 10% aqueous sodium hydrogen carbonate solution (100 mL) and saturated brine (50 mL) and then dried (Na 2 SO 4 ). The organic layer was concentrated under reduced pressure to obtain 920 mg (82%) of 4-OMe-3-deoxymorphinan (18). A part of the obtained 18 was recrystallized from methanol.
mp: 137-138 ° C.
1 H NMR (CDCl 3 , 300 MHz) δ: 0.10 (2H, m), 0.50 (2H, m), 0.90 (1H, m), 1.60 (1H, d), 1.80 (1H, m), 1.95 (1H, m), 2.05 (3H, m), 2.10 (1H, m), 2.40 (2H, m), 2.60 (1H, m). 2.70 (1H, m), 2.90 (1H, m), 3.00 (1H, m ), 3.10 (2H, m), 3.75 (1H, dd), 3.80 (3H, s), 6.65 (1H, d), 6.70 (1H, d), 7.10 (1H, d).
MS (FAB) m / z 432 (M + H) + .
IR (KBr) ν max cm -1 : 3433,1711,
Elemental analysis (C 21 H 27 NO 3 )
Calculated values: C, 73.87; H, 7.97; N, 4.10.
Found: C, 73.63; H, 7.85; N, 4.09.
19の合成
4-OMe-3-デオキシモルヒナン(18)250mg(0.73mmol)の1N水酸化ナトリウム(1mL)−メタノール(4mL)溶液にベンズアルデヒド0.45 mL(4.45mmol)を加え、室温で55.5時間攪拌した。反応溶液に2N塩酸を加えた後、酢酸エチル(50, 30, 20mL)で抽出した。有機層を10%炭酸水素ナトリウム水溶液(80mL)および飽和食塩水(50mL)で順次洗浄し、乾燥(Na2SO4)した後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(クロロホルム→アンモニア飽和クロロホルム)で分離精製し、4-OMe-3-デオキシモルヒナン骨格BNTX(19)を白色無定形として294mg(94%)で得た。
1H NMR (CDCl3, 300MHz) δ : 0.10 (2H, m), 0.50 (2H, m), 0.85 (1H, m), 1.60 (1H, d), 2.05 (2H, m), 2.40 (2H, m), 2.60 (1H, m), 2.90 (2H, m), 3.10 (2H, m). 3.20 (2H, m), 3.80 (3H, s), 3.9 (1H, d), 6.70 (2H, m), 7.10 (1H, dd), 7.30-7.39 (5H, m), 7.40 (1H, d).
MS(FAB) m/z 430 (M+H)+.
IR(NaCl) νmaxcm-1: 3407. 1684.19 synthesis
To a solution of 4-OMe-3-deoxymorphinane (18) 250 mg (0.73 mmol) in 1N sodium hydroxide (1 mL) -methanol (4 mL) was added benzaldehyde 0.45 mL (4.45 mmol), and the mixture was stirred at room temperature for 55.5 hours. 2N Hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate (50, 30, 20 mL). The organic layer was washed successively with 10% aqueous sodium hydrogen carbonate solution (80 mL) and saturated brine (50 mL), dried (Na 2 SO 4 ), and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (chloroform → ammonia saturated chloroform) to obtain 294 mg (94%) of 4-OMe-3-deoxymorphinane skeleton BNTX (19) as white amorphous.
1 H NMR (CDCl 3 , 300 MHz) δ: 0.10 (2H, m), 0.50 (2H, m), 0.85 (1H, m), 1.60 (1H, d), 2.05 (2H, m), 2.40 (2H, m), 2.60 (1H, m), 2.90 (2H, m), 3.10 (2H, m). 3.20 (2H, m), 3.80 (3H, s), 3.9 (1H, d), 6.70 (2H, m ), 7.10 (1H, dd), 7.30-7.39 (5H, m), 7.40 (1H, d).
MS (FAB) m / z 430 (M + H) + .
IR (NaCl) ν max cm -1 : 3407. 1684.
52の合成
4-OMe-3-デオキシモルヒナン骨格BNTX(19)236mg(0.55mmol)の無水ジクロロメタン溶液(11mL)に、アルゴン気流下0℃で1M 三臭化ホウ素ジクロロメタン溶液3.3 mL(3.3mmol)を加え、室温で暗所2時間攪拌した。反応溶液に0℃で6%アンモニア(11mL)を加え、激しく攪拌した後、クロロホルム(50, 20, 10mL)で抽出した。有機層を飽和食塩水(80mL)で洗浄した後、乾燥(Na2SO4)し、減圧濃縮した。残渣(245mg)をシリカゲルカラムクロマトグラフィー(アンモニア飽和クロロホルム)で分離精製し、4-OH-3-デオキシモルヒナン骨格BNTX体(52)を白色無定形として160mg(71%)で得た。得られた160mgをメタノール−エーテル(少量)から再結晶を行い、4-OH-3-デオキシモルヒナン骨格BNTX(52)を白色結晶として69mg(30%)で得た。
mp:194-196℃.
1H NMR (CDCl3, 300MHz) δ: 0.15 (2H, m), 0.55 (2H, m), 0.85 (1H, m), 1.75 (1H, d), 2.10 (2H, m), 2.40 (2H, d), 2.55 (1H, m), 2.90 (1H, m), 3.09 (3H, m), 3.20 (2H, m). 4.30 (1H, d), 6.60 (1H, d), 6.80 (1H, d), 7.00 (1H, dd), 7.21 (5H, m), 7.50 (1H, s).
MS(FAB) m/z 416 (M+H)+.
IR (NaCl)νmaxcm-1: 3279,1671,1582,
元素分析(C27H29NO3)
計算値:C, 78.04; H, 7.03; N, 3.37.
実測値:C, 77.92; H, 6.97; N, 3.49.52 synthesis
To an anhydrous dichloromethane solution (11 mL) of 236 mg (0.55 mmol) of 4-OMe-3-deoxymorphinane skeleton BNTX (19), 3.3 mL (3.3 mmol) of 1M boron tribromide dichloromethane solution was added at 0 ° C. under an argon stream, Stir at room temperature in the dark for 2 hours. 6% ammonia (11 mL) was added to the reaction solution at 0 ° C., and the mixture was vigorously stirred and extracted with chloroform (50, 20, 10 mL). The organic layer was washed with saturated brine (80 mL), dried (Na 2 SO 4 ), and concentrated under reduced pressure. The residue (245 mg) was separated and purified by silica gel column chromatography (ammonia-saturated chloroform) to obtain 160 mg (71%) of 4-OH-3-deoxymorphinane skeleton BNTX (52) as white amorphous. The obtained 160 mg was recrystallized from methanol-ether (small amount) to obtain 69 mg (30%) of 4-OH-3-deoxymorphinane skeleton BNTX (52) as white crystals.
mp: 194-196 ° C.
1 H NMR (CDCl 3 , 300MHz) δ: 0.15 (2H, m), 0.55 (2H, m), 0.85 (1H, m), 1.75 (1H, d), 2.10 (2H, m), 2.40 (2H, d), 2.55 (1H, m), 2.90 (1H, m), 3.09 (3H, m), 3.20 (2H, m). 4.30 (1H, d), 6.60 (1H, d), 6.80 (1H, d ), 7.00 (1H, dd), 7.21 (5H, m), 7.50 (1H, s).
MS (FAB) m / z 416 (M + H) + .
IR (NaCl) ν max cm -1 : 3279,1671,1582,
Elemental analysis (C 27 H 29 NO 3 )
Calculated values: C, 78.04; H, 7.03; N, 3.37.
Found: C, 77.92; H, 6.97; N, 3.49.
52の塩酸塩
4-OH-3-デオキシモルヒナン骨格BNTX(52)の酢酸エチル−メタノール溶液に塩酸飽和メタノール溶液およびエーテルを加え、塩酸塩36mgを得た。
mp:213-218℃
元素分析(C27H29NO3・HCl・H2O)
計算値:C, 69.00; H, 6.86; N, 2.98.
実測値:C, 69.15; H, 6.80; N, 2.95.52 hydrochloride
Hydrochloric acid saturated methanol solution and ether were added to ethyl acetate-methanol solution of 4-OH-3-deoxymorphinane skeleton BNTX (52) to obtain 36 mg of hydrochloride.
mp: 213-218 ℃
Elemental analysis (C 27 H 29 NO 3 · HCl · H 2 O)
Calculated values: C, 69.00; H, 6.86; N, 2.98.
Found: C, 69.15; H, 6.80; N, 2.95.
実施例11
53の合成
4-OH-3-デオキシモルヒナン(17)250mg(0.764mmol)の無水エタノール溶液(7mL)にアルゴン気流下、2-アミノベンズアルデヒド276mg(2.29mmol)、メタンスルホン酸168μL(2.29mmol)を加えた後、加熱還流下18時間攪拌した。反応溶液を濃縮した後、10%炭酸水素ナトリウム水溶液を加えた後(pH9)、酢酸エチル(40, 10, 10mL)で抽出した。有機層を飽和食塩水(30mL)で洗浄した後、乾燥(Na2SO4)し、減圧濃縮した。残渣(440mg)をシリカゲルカラムクロマトグラフィー(クロロホルム−メタノール30:1)で分離精製し、4-OH-3-デオキシモルヒナン骨格キノリン体(53)を無色油状物として260mg(83%)で得た。
1H NMR (CDCl3, 300MHz) δ: 0.18 (2H, m), 0.57 (2H, m), 0.93 (1H, m), 1.95 (1H, d), 2.27 (2H, m), 2.42 (2H, d), 2.77 (1H,dd), 3.08 (1H, m), 3.12 (1H, m), 3.25 (2H, m), 3.32 (1H, m), 3.63 (1H, d), 5.08 (1H, d), 6.38 (1H, dd), 6.51 (2H, d), 6.62 (1H, d), 6.82 (1H, dd), 6.94 (1H, dd), 7.36 (1H, d), 7.62 (1H, d).
MS(EI) m/z 412 (M)+. Example 11
Synthesis of 53
2-Aminobenzaldehyde 276 mg (2.29 mmol) and methanesulfonic acid 168 μL (2.29 mmol) were added to an absolute ethanol solution (7 mL) of 4-OH-3-deoxymorphinan (17) 250 mg (0.764 mmol) in an argon stream. Thereafter, the mixture was stirred for 18 hours with heating under reflux. The reaction solution was concentrated, 10% aqueous sodium hydrogen carbonate solution was added (pH 9), and the mixture was extracted with ethyl acetate (40, 10, 10 mL). The organic layer was washed with saturated brine (30 mL), dried (Na 2 SO 4 ), and concentrated under reduced pressure. The residue (440 mg) was separated and purified by silica gel column chromatography (chloroform-methanol 30: 1) to obtain 260 mg (83%) of 4-OH-3-deoxymorphinan skeleton quinoline (53) as a colorless oil. .
1 H NMR (CDCl 3 , 300 MHz) δ: 0.18 (2H, m), 0.57 (2H, m), 0.93 (1H, m), 1.95 (1H, d), 2.27 (2H, m), 2.42 (2H, d), 2.77 (1H, dd), 3.08 (1H, m), 3.12 (1H, m), 3.25 (2H, m), 3.32 (1H, m), 3.63 (1H, d), 5.08 (1H, d ), 6.38 (1H, dd), 6.51 (2H, d), 6.62 (1H, d), 6.82 (1H, dd), 6.94 (1H, dd), 7.36 (1H, d), 7.62 (1H, d) .
MS (EI) m / z 412 (M) + .
53の塩酸塩
4-OH-3-デオキシモルヒナン骨格キノリン体(53)を塩酸飽和メタノール溶液に加え、塩酸塩とした。
mp:261-262℃(dec.).
元素分析(C27H28N2O2・2HCl・2/3H2O)
計算値:C, 65.19; H, 6.35; N, 5.63.
実測値:C, 65.09; H, 6.44; N, 5.78.53 hydrochloride
4-OH-3-deoxymorphinan skeleton quinoline (53) was added to a hydrochloric acid saturated methanol solution to obtain a hydrochloride.
mp: 261-262 ° C (dec.).
Elemental analysis (C 27 H 28 N 2 O 2 · 2HCl · 2 / 3H 2 O)
Calculated values: C, 65.19; H, 6.35; N, 5.63.
Found: C, 65.09; H, 6.44; N, 5.78.
実施例12
54の合成
4-OMe-3-デオキシモルヒナン(18)400mg(1.1mmol)の無水エタノール溶液(5mL)にメタンスルホン酸325 μL(4.4mmol)、O-フェニルヒドロキシルアミン塩酸塩320mg(2.2mmol)を加え、アルゴン気流下17時間加熱還流した。反応溶液に10%炭酸水素ナトリウム水溶液(20mL)を加えた後(pH9)、酢酸エチル(20, 10, 10mL)で抽出した。有機層を飽和食塩水(20mL)で洗浄した後、乾燥(Na2SO4)し、減圧濃縮した。残渣(250mg)をシリカゲルカラムクロマトグラフィー(クロロホルム−酢酸エチル5:1)で分離精製し、4-OMe-3-デオキシモルヒナン骨格NTB(20)を無色無定形として195mg(43%)で得た。 Example 12
54 synthesis
To 400 mg (1.1 mmol) of 4-OMe-3-deoxymorphinan (18) in absolute ethanol solution (5 mL) was added 325 μL (4.4 mmol) of methanesulfonic acid and 320 mg (2.2 mmol) of O-phenylhydroxylamine hydrochloride, The mixture was heated to reflux for 17 hours under an argon stream. To the reaction solution was added 10% aqueous sodium hydrogen carbonate solution (20 mL) (pH 9), and the mixture was extracted with ethyl acetate (20, 10, 10 mL). The organic layer was washed with saturated brine (20 mL), dried (Na 2 SO 4 ), and concentrated under reduced pressure. The residue (250 mg) was separated and purified by silica gel column chromatography (chloroform-ethyl acetate 5: 1) to give 195 mg (43%) of 4-OMe-3-deoxymorphinane skeleton NTB (20) as colorless amorphous. .
54の合成
4-OMe-3-デオキシモルヒナン骨格NTB(20)194mg(0.45mmol)の無水ジクロロメタン溶液(5mL)に、アルゴン気流下0℃で1M 三臭化ホウ素ジクロロメタン溶液2.7 mL(2.7mmol)を加え、室温で暗所1時間攪拌した。反応溶液に0℃で6%アンモニア(11mL)を加え激しく攪拌した後、クロロホルム(30, 10, 10mL)で抽出した。有機層を飽和食塩水(20mL)で洗浄した後、乾燥(Na2SO4)し、減圧濃縮した。残渣(180mg)をシリカゲルカラムクロマトグラフィー(クロロホルム−メタノール100:1→50:1)で分離精製し、4-OH-3-デオキシモルヒナン骨格NTB(54)を白色無定形として66mg(37%)で得た。
1H NMR (CDCl3, 300MHz) δ: 0.15 (2H, m), 0.55 (2H, m), 0.90 (1H, m), 1.75 (1H, d), 2.10 (2H, m), 2.40 (2H, d), 2.70 (2H, m), 2.85 (1H, dd), 3.05 (1H, dd), 3.10 (2H, m), 3.28 (1H, d), 4.65 (1H, d), 6.28 (1H, dd), 6.63 (1H, dd), 6.83 (1H, dd), 7.09 (2H, dd), 7.24 (1H, dd), 7.33 (1H, dd).
MS(EI) m/z 401 (M)+.54 synthesis
To an anhydrous dichloromethane solution (5 mL) of 4-OMe-3-deoxymorphinane skeleton NTB (20) 194 mg (0.45 mmol) was added 2.7 mL (2.7 mmol) of 1M boron tribromide dichloromethane solution at 0 ° C. under an argon stream, Stir at room temperature in the dark for 1 hour. To the reaction solution was added 6% ammonia (11 mL) at 0 ° C., and the mixture was vigorously stirred and extracted with chloroform (30, 10, 10 mL). The organic layer was washed with saturated brine (20 mL), dried (Na 2 SO 4 ), and concentrated under reduced pressure. The residue (180 mg) was separated and purified by silica gel column chromatography (chloroform-methanol 100: 1 → 50: 1) to give 4-OH-3-deoxymorphinane skeleton NTB (54) as white amorphous 66 mg (37%) I got it.
1 H NMR (CDCl 3 , 300 MHz) δ: 0.15 (2H, m), 0.55 (2H, m), 0.90 (1H, m), 1.75 (1H, d), 2.10 (2H, m), 2.40 (2H, d), 2.70 (2H, m), 2.85 (1H, dd), 3.05 (1H, dd), 3.10 (2H, m), 3.28 (1H, d), 4.65 (1H, d), 6.28 (1H, dd ), 6.63 (1H, dd), 6.83 (1H, dd), 7.09 (2H, dd), 7.24 (1H, dd), 7.33 (1H, dd).
MS (EI) m / z 401 (M) + .
54の塩酸塩
mp:222-224℃(dec.).
元素分析(C26H27NO3・HCl・2/3H2O)
計算値:C, 69.40; H, 6.57; N, 3.11.
実測値:C, 69.27; H, 6.57; N, 3.28.54 hydrochloride
mp: 222-224 ° C (dec.).
Elemental analysis (C 26 H 27 NO 3 · HCl · 2 / 3H 2 O)
Calculated values: C, 69.40; H, 6.57; N, 3.11.
Found: C, 69.27; H, 6.57; N, 3.28.
実施例13
55の合成
4-OH-3-デオキシモルヒナン(17)250mg(0.764mmol)の酢酸溶液(5.2mL)に、塩酸フェニルヒドラジン166mg(1.15mmol)を加え、1.5時間加熱還流した。反応溶液を減圧濃縮した後、クロロホルム(120mL)を加え溶解した。有機層を10%炭酸水素ナトリウム(90mL)、水(90mL)で順次洗浄した後、乾燥(Na2SO4)した。残渣(312mg)をクロロホルムから沈殿させ、4-OH-3-デオキシモルヒナン骨格NTI(55)35mg(12 %)を得た。
1H NMR (CDCl3,300MHz) δ : 0.10 (2H, m), 0.50 (2H, m), 0.85 (2H, m), 1.85 (1H, d), 2.10 (2H, m), 2.35 (2H, m), 2.65 (1H, m), 2.85 (1H, m), 2.95 (1H, m), 3.05 (1H, m), 3.10 (1H, m), 3.25 (1H, broad), 4.35 (1H, d), 6.20 (1H, d), 6.50 (1H, d), 6.75 (1H, dd), 6.95 (2H, m), 7.15 (1H, dd), 7.20 (1H, m), 7.55 (1H, broad).
MS(EI) m/z 400 (M)+. Example 13
Synthesis of 55
To a solution of acetic acid (5.2 mL) of 250 mg (0.764 mmol) of 4-OH-3-deoxymorphinan (17), 166 mg (1.15 mmol) of phenylhydrazine hydrochloride was added and heated to reflux for 1.5 hours. After the reaction solution was concentrated under reduced pressure, chloroform (120 mL) was added and dissolved. The organic layer was washed successively with 10% sodium hydrogen carbonate (90 mL) and water (90 mL) and then dried (Na 2 SO 4 ). The residue (312 mg) was precipitated from chloroform to obtain 35 mg (12%) of 4-OH-3-deoxymorphinane skeleton NTI (55).
1 H NMR (CDCl 3 , 300MHz) δ: 0.10 (2H, m), 0.50 (2H, m), 0.85 (2H, m), 1.85 (1H, d), 2.10 (2H, m), 2.35 (2H, m), 2.65 (1H, m), 2.85 (1H, m), 2.95 (1H, m), 3.05 (1H, m), 3.10 (1H, m), 3.25 (1H, broad), 4.35 (1H, d ), 6.20 (1H, d), 6.50 (1H, d), 6.75 (1H, dd), 6.95 (2H, m), 7.15 (1H, dd), 7.20 (1H, m), 7.55 (1H, broad) .
MS (EI) m / z 400 (M) + .
55の塩酸塩
4-OH-3-デオキシモルヒナン骨格NTI(55)35mg(0.088mmol)のクロロホルム−メタノール溶液に塩酸飽和メタノール溶液を加え、塩酸塩26mgを得た。
mp:244-246℃(dec.).
元素分析(C26H28N2O2・HCl・1.5H2O)
計算値:C, 67.30; H, 6.95; N, 6.03.
実測値:C, 66.92; H, 6.80; N, 6.21.55 hydrochloride
A hydrochloric acid saturated methanol solution was added to a chloroform-methanol solution of 4-OH-3-deoxymorphinane skeleton NTI (55) 35 mg (0.088 mmol) to obtain 26 mg of hydrochloride.
mp: 244-246 ° C (dec.).
Elemental analysis (C 26 H 28 N 2 O 2 · HCl · 1.5H 2 O)
Calculated values: C, 67.30; H, 6.95; N, 6.03.
Found: C, 66.92; H, 6.80; N, 6.21.
実施例14
56の合成
N-イソブチル-4-OH-3-デオキシナルモルヒナン(21)200mg(0.607mmol)の1N水酸化ナトリウム(5mL)−メタノール(2mL)溶液にベンズアルデヒド500μL(4.92mmol)を加え、室温で8.5時間攪拌した。反応溶液に2N塩酸を加えた後、酢酸エチル(30, 20, 10mL)で抽出した。反応溶液を10%炭酸水素ナトリウム水溶液(40mL)および飽和食塩水(40mL)で順次洗浄し、乾燥(Na2SO4)した後、減圧濃縮した。残渣(445mg)をシリカゲルカラムクロマトグラフィー(クロロホルム→アンモニア飽和クロロホルム)で分離精製し、N−イソブチル−4−OH−3−デオキシモルヒナン骨格BNTX(56)を白色無定形状態として178mg(70%)で得た。白色無定形をエーテルから再結晶を行い、N-イソブチル-4-OH-3-デオキシナルモルヒナン骨格BNTX(56)を白色結晶として78mg(31%)で得た。
mp: 225-227℃
1H NMR (CDCl3,300MHz) δ : 0.90 (6H, m), 1.60 (2H, m), 1.80 (2H, m), 2.10 (1H, m), 2.20 (2H, m). 2.30 (1H, m), 2.50 (1H, dd), 2.85 (1H, dd), 2.90 (1H, m), 3.05 (1H, m), 3.10 (1H, m), 4.3 (1H, d), 6.70 (1H, d), 6.90 (1H, d), 7.10 (1H, dd), 7.25-7.40 (5H, m), 7.50 (1H, m).
MS(FAB) m/z 418 (M+H)+.
元素分析(C27H31NO3)
計算値:C, 77.67; H, 7.48; N, 3.35.
実測値:C, 77.51; H, 7.60; N, 3.50. Example 14
56 synthesis
To a solution of N-isobutyl-4-OH-3-deoxynalmorphinan (21) 200 mg (0.607 mmol) in 1N sodium hydroxide (5 mL) -methanol (2 mL) was added 500 μL (4.92 mmol) of benzaldehyde, and 8.5 hours at room temperature. Stir. 2N Hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate (30, 20, 10 mL). The reaction solution was washed successively with 10% aqueous sodium hydrogen carbonate solution (40 mL) and saturated brine (40 mL), dried (Na 2 SO 4 ), and concentrated under reduced pressure. The residue (445 mg) was separated and purified by silica gel column chromatography (chloroform → ammonia saturated chloroform) to give 178 mg (70%) of N-isobutyl-4-OH-3-deoxymorphinan skeleton BNTX (56) as a white amorphous state. I got it. The white amorphous was recrystallized from ether to obtain 78 mg (31%) of N-isobutyl-4-OH-3-deoxynal morphinan skeleton BNTX (56) as white crystals.
mp: 225-227 ° C
1 H NMR (CDCl 3 , 300MHz) δ: 0.90 (6H, m), 1.60 (2H, m), 1.80 (2H, m), 2.10 (1H, m), 2.20 (2H, m). 2.30 (1H, m), 2.50 (1H, dd), 2.85 (1H, dd), 2.90 (1H, m), 3.05 (1H, m), 3.10 (1H, m), 4.3 (1H, d), 6.70 (1H, d ), 6.90 (1H, d), 7.10 (1H, dd), 7.25-7.40 (5H, m), 7.50 (1H, m).
MS (FAB) m / z 418 (M + H) + .
Elemental analysis (C 27 H 31 NO 3 )
Calculated values: C, 77.67; H, 7.48; N, 3.35.
Found: C, 77.51; H, 7.60; N, 3.50.
56塩酸塩
N-イソブチル-4-OH-3-デオキシナルモルヒナン骨格BNTX(56)の酢酸エチル−メタノール溶液に塩酸飽和メタノール溶液を加え、塩酸塩41mgを得た。
mp:205-210℃(dec.).
元素分析(C27H31NO3・HCl・3/4H2O)
計算値:C, 69.36; H, 7.22; N, 2.99.
実測値:C, 69.28; H, 7.24; N, 3.12.56 hydrochloride
Hydrochloric acid saturated methanol solution was added to N-isobutyl-4-OH-3-deoxynal morphinane skeleton BNTX (56) in ethyl acetate-methanol solution to obtain 41 mg of hydrochloride.
mp: 205-210 ° C (dec.).
Elemental analysis (C 27 H 31 NO 3 · HCl · 3 / 4H 2 O)
Calculated values: C, 69.36; H, 7.22; N, 2.99.
Found: C, 69.28; H, 7.24; N, 3.12.
実施例15
57の合成
N-イソブチル-4-OH-3-デオキシナルモルヒナン(21)75mg(0.23mmol)の酢酸溶液(1.6mL)に、塩酸フェニルヒドラジン49mg(0.341mmol)を加え、1時間加熱還流した。反応溶液を減圧濃縮した後、クロロホルム(100mL)を加え溶解した。有機層を10%炭酸水素ナトリウム(50mL)、水(50mL)で順次洗浄した後、乾燥(Na2SO4)した。残渣(312mg)をシリカゲルカラムクロマトグラフィー(クロロホルム−メタノール100:8)で分離精製し、N-イソブチル4-OH-3-デオキシモルヒナン骨格NTI(57)を油状物として63mg(69%)で得た。
1H NMR (CDCl3, 300MHz) δ : 0.98 (6H, t), 1.70 (1H, m), 1.80 (2H, m), 2.10 (1H, m), 2.30 (2H, m), 2.50 (1H, m), 2.70 (1H, m), 2.85 (1H, m), 2.90 (1H, m), 3.05 (1H, m), 3.20 (2H, m), 4.35 (1H, d), 6.2 (1H, d), 6.58 (1H, d), 6.70 (1H, dd), 7.00 (2H, m), 7.10 (1H, dd), 7.30 (1H, d), 7.50 (1H, broad).
MS(EI) m/z 402 (M)+. Example 15
Synthesis of 57
To an acetic acid solution (1.6 mL) of N-isobutyl-4-OH-3-deoxynalmorphinan (21) 75 mg (0.23 mmol) was added phenylhydrazine hydrochloride 49 mg (0.341 mmol), and the mixture was heated to reflux for 1 hour. After the reaction solution was concentrated under reduced pressure, chloroform (100 mL) was added and dissolved. The organic layer was washed successively with 10% sodium hydrogen carbonate (50 mL) and water (50 mL) and then dried (Na 2 SO 4 ). The residue (312 mg) was separated and purified by silica gel column chromatography (chloroform-methanol 100: 8) to give N-isobutyl 4-OH-3-deoxymorphinane skeleton NTI (57) as an oil in 63 mg (69%). It was.
1 H NMR (CDCl 3 , 300 MHz) δ: 0.98 (6H, t), 1.70 (1H, m), 1.80 (2H, m), 2.10 (1H, m), 2.30 (2H, m), 2.50 (1H, m), 2.70 (1H, m), 2.85 (1H, m), 2.90 (1H, m), 3.05 (1H, m), 3.20 (2H, m), 4.35 (1H, d), 6.2 (1H, d ), 6.58 (1H, d), 6.70 (1H, dd), 7.00 (2H, m), 7.10 (1H, dd), 7.30 (1H, d), 7.50 (1H, broad).
MS (EI) m / z 402 (M) + .
57塩酸塩
N-イソブチル-4-OH-3-デオキシモルヒナン骨格NTI(57)63mg(0.156mmol)のクロロホルム−メタノール溶液に塩酸飽和メタノール溶液を加え、塩酸塩53mgを得た。
mp:225-228℃(dec.).
元素分析(C26H30N2O2・HCl・1.2H2O)
計算値:C, 67.79; H, 7.30; N, 6.08.
実測値:C, 67.57; H, 7.19; N, 6.48.57 hydrochloride
Hydrochloric acid saturated methanol solution was added to chloroform-methanol solution of N-isobutyl-4-OH-3-deoxymorphinane skeleton NTI (57) 63 mg (0.156 mmol) to obtain hydrochloride 53 mg.
mp: 225-228 ° C (dec.).
Elemental analysis (C 26 H 30 N 2 O 2 · HCl · 1.2H 2 O)
Calculated values: C, 67.79; H, 7.30; N, 6.08.
Found: C, 67.57; H, 7.19; N, 6.48.
実施例16
58の合成
3-OMe-14H-モルヒナン骨格(8) 100mg(0.308mmol)の5N塩酸水溶液(2.5mL)に、酸化白金50mgを加えた後、水素下室温で20時間攪拌した。反応溶液をセライトを用いて濾過し、 10%炭酸水素ナトリウム水溶液(35mL)を加えた後(pH9)、クロロホルム(35, 20, 15mL)で抽出した。有機層を飽和食塩水(20mL)で洗浄した後、乾燥(Na2SO4)し、減圧濃縮した。残渣(112mg)をシリカゲルカラムクロマトグラフィー(クロロホルム−メタノール95:5→10:1)で分離精製し、N-イソブチル-3-OMe-14H-モルヒナン(22)を無色油状物として73mg(73%)で得た。
1H NMR (CDCl3, 300MHz) δ : 0.95 (6H, t), 1.40 (1H, d), 1.60 (1H, dd). 1.65-1.90 (3H, m),2.05 (1H, td), 2.25 (4H, m), 2.30 (2H, m), 2.40 (1H, d), 2.60 (1H, d), 2.95 (1H, d), 3.00 (1H, m), 3.05 (1H, d), 3.75 (3H, s), 6.70 (1H, dd), 6.80 (1H, d), 7.00 (1H, d).
MS(FAB) m/z 328 (M+H)+.
IR(NaCl) νmaxcm-1: 1713. Example 16
58 synthesis
3-OMe-14H-morphinan skeleton (8) 50 mg of platinum oxide was added to 100 mg (0.308 mmol) of 5N aqueous hydrochloric acid (2.5 mL), and the mixture was stirred at room temperature for 20 hours under hydrogen. The reaction solution was filtered through celite, 10% aqueous sodium hydrogen carbonate solution (35 mL) was added (pH 9), and the mixture was extracted with chloroform (35, 20, 15 mL). The organic layer was washed with saturated brine (20 mL), dried (Na 2 SO 4 ), and concentrated under reduced pressure. The residue (112 mg) was separated and purified by silica gel column chromatography (chloroform-methanol 95: 5 → 10: 1) to give N-isobutyl-3-OMe-14H-morphinan (22) as a colorless oil, 73 mg (73%) I got it.
1 H NMR (CDCl 3 , 300 MHz) δ: 0.95 (6H, t), 1.40 (1H, d), 1.60 (1H, dd) .1.65-1.90 (3H, m), 2.05 (1H, td), 2.25 ( 4H, m), 2.30 (2H, m), 2.40 (1H, d), 2.60 (1H, d), 2.95 (1H, d), 3.00 (1H, m), 3.05 (1H, d), 3.75 (3H , s), 6.70 (1H, dd), 6.80 (1H, d), 7.00 (1H, d).
MS (FAB) m / z 328 (M + H) + .
IR (NaCl) ν max cm -1 : 1713.
23の合成
N-イソブチル-3-OMe-14H-モルヒナン(22)53mg(0.162mmol)の無水エタノール溶液(1.0mL)にアルゴン気流下、2-アミノベンズアルデヒド(60mg, 0.494mmol)、メタンスルホン酸(27μl, 0.411mmol)を順次加えた後、加熱還流下4.5時間反応させた。反応溶液に10%炭酸水素ナトリウム水溶液(10mL)を加えた後、酢酸エチル(10, 8, 5mL)で抽出した。有機層を飽和食塩水(10mL)で洗浄した後、乾燥(Na2SO4)し、減圧濃縮した。残渣(105mg)をシリカゲルカラムクロマトグラフィー(クロロホルム−メタノール98:2→10:1)で分離精製し、N-イソブチル-3-OMe-14H-モルヒナン骨格キノリン体(23)を無色油状物として51mg(76%)で得た。
1H NMR (CDCl3,300MHz) δ : 0.95 (6H, m), 1.65 (1H, d), 1.80 (1H, broad). 2.00 (1H, broad), 2.20-2.40 (3H, broad), 2.50 (2H, broad), 2.70 (1H, dd), 2.75 (1H, broad), 2.90 (1H, dd), 3.05 (1H, d), 3.15 (1H, d), 3.60 (3H, s), 3.95 (1H, d), 6.60 (1H, dd), 6.90 (1H, d), 7.00 (1H, d), 7.40 (1H, dd), 7.55 (1H, d), 7.60 (2H, m), 8.00 (1H, d).
MS(FAB) m/z 413 (M+H)+.Synthesis of 23
N-isobutyl-3-OMe-14H-morphinan (22) 53 mg (0.162 mmol) in absolute ethanol (1.0 mL) under an argon stream, 2-aminobenzaldehyde (60 mg, 0.494 mmol), methanesulfonic acid (27 μl, 0.411) mmol) were sequentially added, and the mixture was reacted for 4.5 hours with heating under reflux. To the reaction solution was added 10% aqueous sodium hydrogen carbonate solution (10 mL), and the mixture was extracted with ethyl acetate (10, 8, 5 mL). The organic layer was washed with saturated brine (10 mL), dried (Na 2 SO 4 ), and concentrated under reduced pressure. The residue (105 mg) was separated and purified by silica gel column chromatography (chloroform-methanol 98: 2 → 10: 1) to give 51 mg of N-isobutyl-3-OMe-14H-morphinan skeleton quinoline (23) as a colorless oil. 76%).
1 H NMR (CDCl 3 , 300MHz) δ: 0.95 (6H, m), 1.65 (1H, d), 1.80 (1H, broad). 2.00 (1H, broad), 2.20-2.40 (3H, broad), 2.50 ( 2H, broad), 2.70 (1H, dd), 2.75 (1H, broad), 2.90 (1H, dd), 3.05 (1H, d), 3.15 (1H, d), 3.60 (3H, s), 3.95 (1H , d), 6.60 (1H, dd), 6.90 (1H, d), 7.00 (1H, d), 7.40 (1H, dd), 7.55 (1H, d), 7.60 (2H, m), 8.00 (1H, d).
MS (FAB) m / z 413 (M + H) + .
58の合成
N-イソブチル-3-OMe-14H-モルヒナン骨格キノリン体(23)20mg(0.0485mmol)の無水ジクロロメタン溶液(1.0mL)に、アルゴン気流下0℃で1M 三臭化ホウ素ジクロロメタン溶液0.299mL(0.299mmol)を加え、室温で暗所2時間攪拌した。反応溶液に0℃で25%アンモニア水(10mL)を加えた後、クロロホルム(10, 8, 5mL)で抽出した。有機層を飽和食塩水(10mL)で洗浄した後、乾燥(Na2SO4)し、減圧濃縮した。残渣(20mg)をシリカゲルカラムクロマトグラフィー(クロロホルム−メタノール98:2→10:1)で分離精製し、N-イソブチル-14H-モルヒナン骨格キノリン体(58)を無色油状物として19mg(定量的)で得た。
1H NMR (CDCl3,300MHz) δ : 0.90 (6H, m), 1.53 (1H, d), 1.80 (2H, m). 2.21 (3H, m), 2.49 (2H, m), 2.70 (1H, m), 2.78 (1H, m), 2.93 (1H, m), 2.98 (1H, m), 3.02 (1H, m), 3.10 (1H, m), 3.91 (1H, d), 6.60 (1H, dd), 6.95 (1H, d), 6.98 (1H, dd), 7.21 (2H, m), 7.49 (2H, m), 7.61 (1H, d).
MS(EI) m/z 398 (M)+.58 synthesis
N-isobutyl-3-OMe-14H-morphinane quinoline (23) 20 mg (0.0485 mmol) in anhydrous dichloromethane (1.0 mL) was added at 0 ° C. under a stream of argon at 0 ° C. with 1M boron tribromide dichloromethane solution in 0.299 mL (0.299 mmol). ) And stirred at room temperature for 2 hours in the dark. To the reaction solution was added 25% aqueous ammonia (10 mL) at 0 ° C., followed by extraction with chloroform (10, 8, 5 mL). The organic layer was washed with saturated brine (10 mL), dried (Na 2 SO 4 ), and concentrated under reduced pressure. The residue (20 mg) was separated and purified by silica gel column chromatography (chloroform-methanol 98: 2 → 10: 1) to give N-isobutyl-14H-morphinan skeleton quinoline (58) as a colorless oil in 19 mg (quantitative). Obtained.
1 H NMR (CDCl 3 , 300MHz) δ: 0.90 (6H, m), 1.53 (1H, d), 1.80 (2H, m) .2.21 (3H, m), 2.49 (2H, m), 2.70 (1H, m), 2.78 (1H, m), 2.93 (1H, m), 2.98 (1H, m), 3.02 (1H, m), 3.10 (1H, m), 3.91 (1H, d), 6.60 (1H, dd ), 6.95 (1H, d), 6.98 (1H, dd), 7.21 (2H, m), 7.49 (2H, m), 7.61 (1H, d).
MS (EI) m / z 398 (M) + .
N-イソブチル-14H-モルヒナン骨格キノリン体(58)24mg(0.0592mmol)のクロロホルム溶液に塩酸飽和メタノール溶液を加え、塩酸塩24mgを得た。
mp:241-243℃(dec.).
元素分析(C27H30N2O・2HCl・H2O)
計算値:C, 66.25; H, 7.00; N, 5.72.
実測値:C, 66.25; H, 7.07; N, 6.07.A hydrochloric acid saturated methanol solution was added to a chloroform solution of 24 mg (0.0592 mmol) of N-isobutyl-14H-morphinane skeleton quinoline (58) to obtain 24 mg of hydrochloride.
mp: 241-243 ° C (dec.).
Elemental analysis (C 27 H 30 N 2 O · 2HCl · H 2 O)
Calculated values: C, 66.25; H, 7.00; N, 5.72.
Found: C, 66.25; H, 7.07; N, 6.07.
実施例17
59の合成
14H-3-デオキシナルトレキソン-6-ケタール体(24)20mg(0.0566mmol)の2N塩酸溶液(0.25mL)に酸化白金10mgを加えた後、水素下室温で16時間攪拌した。反応溶液をセライトを用いて濾過した後、減圧濃縮した。残渣に10%炭酸水素ナトリウム水溶液(15mL)を加えた後(pH9)、クロロホルム(15, 8, 5mL)で抽出した。有機層を飽和食塩水(12mL)で洗浄した後、乾燥(Na2SO4)し、減圧濃縮した。残渣(20mg)をシリカゲルカラムクロマトグラフィー(クロロホルム−メタノール95:5)で分離精製し、14H-3-デオキシ-N-イソブチルナルトレキソン(25)を無色油状物として10mg(54%)で得た。
1H NMR (CDCl3, 300MHz) δ: 0.95 (6H, t), 1.20 (1H, m), 1.70 (1H, m). 1.73 (1H, m), 1.80 (1H, m), 2.01 (1H, d), 2.10 (1H, d), 2.15 (1H, d), 2.23 (1H, m), 2.25 (1H, m), 2.34 (2H, m), 2.40 (1H, m), 2.58 (2H, m), 2.95 (1H, d), 3.15 (1H, m), 4.60 (1H, s), 6.67 (1H, d), 6.73 (1H, d), 7.03 (1H, dd).
MS(EI) m/z 311 (M)+.
IR(NaCl) νmaxcm-1: 1722. Example 17
59 synthesis
After adding 10 mg of platinum oxide to 2N hydrochloric acid solution (0.25 mL) of 14H-3-deoxynaltrexone-6-ketal (24) 20 mg (0.0566 mmol), the mixture was stirred at room temperature for 16 hours under hydrogen. The reaction solution was filtered using celite and concentrated under reduced pressure. To the residue was added 10% aqueous sodium hydrogen carbonate solution (15 mL) (pH 9), and the mixture was extracted with chloroform (15, 8, 5 mL). The organic layer was washed with saturated brine (12 mL), dried (Na 2 SO 4 ), and concentrated under reduced pressure. The residue (20 mg) was separated and purified by silica gel column chromatography (chloroform-methanol 95: 5) to give 14H-3-deoxy-N-isobutylnaltrexone (25) as a colorless oil in 10 mg (54%).
1 H NMR (CDCl 3 , 300 MHz) δ: 0.95 (6H, t), 1.20 (1H, m), 1.70 (1H, m). 1.73 (1H, m), 1.80 (1H, m), 2.01 (1H, d), 2.10 (1H, d), 2.15 (1H, d), 2.23 (1H, m), 2.25 (1H, m), 2.34 (2H, m), 2.40 (1H, m), 2.58 (2H, m ), 2.95 (1H, d), 3.15 (1H, m), 4.60 (1H, s), 6.67 (1H, d), 6.73 (1H, d), 7.03 (1H, dd).
MS (EI) m / z 311 (M) + .
IR (NaCl) ν max cm -1 : 1722.
26の合成
14H-3-デオキシ-N-イソブチルナルトレキソン(25)100mg(0.321mmol)の酢酸溶液(3mL)に亜鉛末420mg(6.42mmol)を加え、加熱還流下24時間攪拌した。反応溶液を濾過した後、減圧濃縮した。残渣に10%炭酸水素ナトリウム水溶液(30mL)を加えた後(pH9)、クロロホルム(30, 20, 10mL)で抽出した。有機層を飽和食塩水(30mL)で洗浄した後、乾燥(Na2SO4)し、減圧濃縮し、14H-N-イソブチル-4-OH-3-デオキシモルヒナン(26)を淡黄色無定形として100mg(定量的)で得た。
1H NMR (CDCl3, 300MHz) δ: 0.97 (6H, t), 1.72 (1H, m), 1.77 (1H, m). 1.79 (1H, m), 1.87 (1H, m), 1.90 (1H, m), 2.05 (1H, d), 2.26 (4H, m), 2.30 (1H, m), 2.45 (1H, m), 2.50 (1H, m), 2.70 (1H, dd), 2.95 (2H, m), 4.42 (1H, d), 6.60 (1H, d), 6.72 (1H, d), 6.90 (1H, dd).
MS(FAB) m/z 314 (M+H)+.
IR(KBr) νmaxcm-1: 3296, 1701.Synthesis of 26
To an acetic acid solution (3 mL) of 14H-3-deoxy-N-isobutylnaltrexone (25) 100 mg (0.321 mmol) was added zinc powder 420 mg (6.42 mmol), and the mixture was stirred for 24 hours with heating under reflux. The reaction solution was filtered and concentrated under reduced pressure. To the residue was added 10% aqueous sodium hydrogen carbonate solution (30 mL) (pH 9), and the mixture was extracted with chloroform (30, 20, 10 mL). The organic layer was washed with saturated brine (30 mL), dried (Na 2 SO 4 ), concentrated under reduced pressure, and 14H-N-isobutyl-4-OH-3-deoxymorphinan (26) was pale yellow amorphous. As 100 mg (quantitative).
1 H NMR (CDCl 3 , 300 MHz) δ: 0.97 (6H, t), 1.72 (1H, m), 1.77 (1H, m). 1.79 (1H, m), 1.87 (1H, m), 1.90 (1H, m), 2.05 (1H, d), 2.26 (4H, m), 2.30 (1H, m), 2.45 (1H, m), 2.50 (1H, m), 2.70 (1H, dd), 2.95 (2H, m ), 4.42 (1H, d), 6.60 (1H, d), 6.72 (1H, d), 6.90 (1H, dd).
MS (FAB) m / z 314 (M + H) + .
IR (KBr) ν max cm -1 : 3296, 1701.
59の合成
14H-N-イソブチル-4-OH-3-デオキシモルヒナン(26)70mg(0.223mmol)の無水エタノール溶液(2mL)にアルゴン気流下、2-アミノベンズアルデヒド83mg(0.680mmol)、メタンスルホン酸40 μL(0.566mmol)を加えた後、加熱還流下3時間攪拌した。反応溶液を濃縮した後、10%炭酸水素ナトリウム水溶液を加えた後(pH9)、酢酸エチル(15, 10, 5mL)で抽出した。有機層を飽和食塩水(10mL)で洗浄した後、乾燥(Na2SO4)し、減圧濃縮した。残渣(127mg)をシリカゲルカラムクロマトグラフィー(クロロホルム−メタノール95:5→10:1)で分離精製し、14H-N-イソブチル-4-OH-3-デオキシモルヒナン骨格キノリン体(59)を淡黄色固体として65mg(73%)で得た。
1H NMR (CDCl3, 300MHz) δ: 0.97 (6H, t), 1.82 (1H, m), 1.98 (1H, dd). 2.13 (1H, m), 2.33 (3H, m), 2.48 (1H, dd), 2.60 (1H, d), 2.82 (1H, dd), 2.92 (1H, m), 3.00 (1H, m), 3.05 (1H, m), 3.13 (3H, m), 5.27 (1H, s), 6.45 (1H, d), 6.56 (1H, d), 6.64 (2H, m), 6.80 (1H, dd), 7.00 (1H, dd), 7.38 (1H, d), 7.61 (1H, d).
MS(FAB) m/z 399 (M+H)+.
IR(KBr) νmaxcm-1: 3284.59 synthesis
14H-N-isobutyl-4-OH-3-deoxymorphinane (26) 70 mg (0.223 mmol) in absolute ethanol (2 mL) under argon stream, 2-aminobenzaldehyde 83 mg (0.680 mmol), methanesulfonic acid 40 μL (0.566 mmol) was added, and the mixture was stirred for 3 hours with heating under reflux. The reaction solution was concentrated, 10% aqueous sodium hydrogen carbonate solution was added (pH 9), and the mixture was extracted with ethyl acetate (15, 10, 5 mL). The organic layer was washed with saturated brine (10 mL), dried (Na 2 SO 4 ), and concentrated under reduced pressure. The residue (127 mg) was separated and purified by silica gel column chromatography (chloroform-methanol 95: 5 → 10: 1), and 14H-N-isobutyl-4-OH-3-deoxymorphinan skeleton quinoline (59) was pale yellow Obtained as a solid in 65 mg (73%).
1 H NMR (CDCl 3 , 300 MHz) δ: 0.97 (6H, t), 1.82 (1H, m), 1.98 (1H, dd). 2.13 (1H, m), 2.33 (3H, m), 2.48 (1H, dd), 2.60 (1H, d), 2.82 (1H, dd), 2.92 (1H, m), 3.00 (1H, m), 3.05 (1H, m), 3.13 (3H, m), 5.27 (1H, s ), 6.45 (1H, d), 6.56 (1H, d), 6.64 (2H, m), 6.80 (1H, dd), 7.00 (1H, dd), 7.38 (1H, d), 7.61 (1H, d) .
MS (FAB) m / z 399 (M + H) + .
IR (KBr) ν max cm -1 : 3284.
59の塩酸塩
14H-N-イソブチル-4-OH-3-デオキシモルヒナン骨格キノリン体(59)35mg(0.0866mmol)に塩酸飽和メタノール溶液を加え、減圧濃縮し塩酸塩31mgを得た。
mp:228-230℃.
元素分析(C27H30N2O・2HCl・H2O)
計算値:C, 66.25;H, 7.00;N, 5.72
実測値;C, 66.50;H, 7.08;N, 5.8759 hydrochloride
To 35 mg (0.0866 mmol) of 14H-N-isobutyl-4-OH-3-deoxymorphinane skeleton quinoline (59), a saturated methanol solution of hydrochloric acid was added and concentrated under reduced pressure to obtain 31 mg of hydrochloride.
mp: 228-230 ° C.
Elemental analysis (C 27 H 30 N 2 O · 2HCl · H 2 O)
Calculated values: C, 66.25; H, 7.00; N, 5.72
Found; C, 66.50; H, 7.08; N, 5.87
実施例18
60の合成
14H-4-OH-3-デオキシ-N-H-モルヒナン(27)77mg(0.299mmol)の2N酢酸(12mL)溶液に酢酸ナトリウム129mg(1.49mmol)、37%ホルムアルデヒド液(0.1mL)および10%パラジウムカーボン30mgを順次加えた後、水素下室温で9時間攪拌した。反応溶液をセライトを用いて濾過した後、アンモニア水(15mL)を加え(pH8)、クロロホルム(30, 20, 20mL)で抽出し、有機層を飽和食塩水(15mL)で洗浄した。有機層を乾燥(Na2SO4)した後、減圧濃縮し、14H-4-OH-3-デオキシ-N-メチルモルヒナン(28)を58mg(75%)で褐色固体として得た。
1H NMR (CDCl3, 300MHz) δ: 1.75 (1H, m), 1.90 (3H, m), 2.15 (1H, td), 2.30 (3H, m), 2.50 (3H, s), 2.59 (1H, m), 2.75 (1H, d), 3.05 (1H, d), 3.10 (1H, m), 4.35 (1H, d), 4.70 (1H, s), 6.65 (2H, d), 6.95 (1H, dd).
MS(FAB) m/z 272 (M+H)+.
IR(KBr) νmaxcm-1: 3504, 1692(KBr). Example 18
60 synthesis
14H-4-OH-3-deoxy-NH-morphinan (27) 77 mg (0.299 mmol) in 2N acetic acid (12 mL) solution 129 mg (1.49 mmol) sodium acetate, 37% formaldehyde solution (0.1 mL) and 10% palladium carbon After sequentially adding 30 mg, the mixture was stirred at room temperature for 9 hours under hydrogen. The reaction solution was filtered through celite, aqueous ammonia (15 mL) was added (pH 8), and the mixture was extracted with chloroform (30, 20, 20 mL). The organic layer was washed with saturated brine (15 mL). The organic layer was dried (Na 2 SO 4 ) and concentrated under reduced pressure to give 14H-4-OH-3-deoxy-N-methylmorphinan (28) as a brown solid in 58 mg (75%).
1 H NMR (CDCl 3 , 300 MHz) δ: 1.75 (1H, m), 1.90 (3H, m), 2.15 (1H, td), 2.30 (3H, m), 2.50 (3H, s), 2.59 (1H, m), 2.75 (1H, d), 3.05 (1H, d), 3.10 (1H, m), 4.35 (1H, d), 4.70 (1H, s), 6.65 (2H, d), 6.95 (1H, dd ).
MS (FAB) m / z 272 (M + H) + .
IR (KBr) ν max cm -1 : 3504, 1692 (KBr).
60の合成
14H-4-OH-3-デオキシ-N-メチルモルヒナン(28)52mg(0.193mol)の無水エタノール溶液(1.3mL)にアルゴン気流下、2-アミノベンズアルデヒド66mg(0.543mmol)、メタンスルホン酸26 μL(0.266mmol)を加えた後、加熱還流下4時間攪拌した。反応溶液に10%炭酸水素ナトリウム水溶液(5mL)を加えた後(pH9)、クロロホルム(10, 10, 7mL)で抽出した。有機層を飽和食塩水(10mL)で洗浄した後、乾燥(Na2SO4)し、減圧濃縮した。残渣(134mg)をシリカゲルカラムクロマトグラフィー(クロロホルム−メタノール10:1)で分離精製し、14H-4-OH-3-デオキシ-N-メチルモルヒナン骨格キノリン体(60)を淡黄色無定形として20mg(29%)で得た。
mp:232℃.
1H NMR (CDCl3, 300MHz) δ: 1.20 (1H, m), 1.95 (1H, dd), 2.20 (1H, d), 2.35 (1H, m), 2.50 (3H, s), 2.65 (1H, dd), 2.90 (1H, d), 2.95 (1H, d), 3.05 (2H, m), 3.10 (1H, m), 3.20 (1H, m), 3.45 (1H, s), 5.30 (1H, d), 6.45 (1H, d), 6.65 (1H, d), 6.75 (2H, m), 6.80 (1H, d), 7.10 (1H, dd), 7.45 (1H, d), 7.60 (1H, d).
MS(FAB) m/z 357 (M+H)+.
IR(KBr) νmaxcm-1: 3407.60 synthesis
14H-4-OH-3-deoxy-N-methylmorphinan (28) 52 mg (0.193 mol) in absolute ethanol (1.3 mL) under an argon stream, 2-aminobenzaldehyde 66 mg (0.543 mmol), methanesulfonic acid 26 μL ( 0.266 mmol) was added, and the mixture was stirred for 4 hours with heating under reflux. A 10% aqueous sodium bicarbonate solution (5 mL) was added to the reaction solution (pH 9), followed by extraction with chloroform (10, 10, 7 mL). The organic layer was washed with saturated brine (10 mL), dried (Na 2 SO 4 ), and concentrated under reduced pressure. The residue (134 mg) was separated and purified by silica gel column chromatography (chloroform-methanol 10: 1) to give 14H-4-OH-3-deoxy-N-methylmorphinan skeleton quinoline (60) as a pale yellow amorphous 20 mg (29 %).
mp: 232 ° C.
1 H NMR (CDCl 3 , 300 MHz) δ: 1.20 (1H, m), 1.95 (1H, dd), 2.20 (1H, d), 2.35 (1H, m), 2.50 (3H, s), 2.65 (1H, dd), 2.90 (1H, d), 2.95 (1H, d), 3.05 (2H, m), 3.10 (1H, m), 3.20 (1H, m), 3.45 (1H, s), 5.30 (1H, d ), 6.45 (1H, d), 6.65 (1H, d), 6.75 (2H, m), 6.80 (1H, d), 7.10 (1H, dd), 7.45 (1H, d), 7.60 (1H, d) .
MS (FAB) m / z 357 (M + H) + .
IR (KBr) ν max cm -1 : 3407.
60の塩酸塩
14H-4-OH-3-デオキシ-N-メチルモルヒナン骨格キノリン体(60)20mg(0.0555mmol)のクロロホルム溶液に塩酸飽和メタノール溶液を加え、塩酸塩16mgを得た。
mp:235℃(dec.).60 hydrochloride
A hydrochloric acid saturated methanol solution was added to a chloroform solution of 14H-4-OH-3-deoxy-N-methylmorphinan skeleton quinoline (60) 20 mg (0.0555 mmol) to obtain 16 mg of hydrochloride.
mp: 235 ° C (dec.).
実施例19
61の合成
14H-3-デオキシナルトレキソン(29)150mg(0.485mmol)の酢酸溶液(1.5mL)に亜鉛末300mg(4.59mmol)を加え、加熱還流下2時間攪拌した。反応溶液を濾過した後、減圧濃縮した。残渣に10%炭酸水素ナトリウム水溶液(30mL)を加えた後(pH9)、クロロホルム(10, 5, 5mL)で抽出した。有機層を水(10mL)で洗浄した後、乾燥(Na2SO4)し、減圧濃縮した。残渣(218mg)をシリカゲルカラムクロマトグラフィー(クロロホルム−メタノール10:1)で分離精製し、14H-4-OH-3-デオキシモルヒナン(30)を無色無定形として142mg(95%)で得た。
1H NMR (CDCl3, 300MHz) δ: 0.13 (2H, m), 0.75 (2H, m), 0.89 (1H, m), 1.78 (1H, dd), 1.94 (4H, m). 2.09 (1H, m), 2.32 (4H, m), 2.52 (2H, m), 2.67 (1H, m), 2.75 (1H, m), 2.92 (1H, d), 3.30 (1H, m), 4.41 (1H, d), 6.60 (1H, d), 6.68 (1H, d), 6.92 (1H, dd).
MS(FAB) m/z 312 (M+H)+.
IR(KBr) νmaxcm-1: 3274, 1701. Example 19
61 synthesis
Zinc powder 300 mg (4.59 mmol) was added to 14H-3-deoxynaltrexone (29) 150 mg (0.485 mmol) in acetic acid solution (1.5 mL), and the mixture was stirred with heating under reflux for 2 hours. The reaction solution was filtered and concentrated under reduced pressure. To the residue was added 10% aqueous sodium hydrogen carbonate solution (30 mL) (pH 9), and the mixture was extracted with chloroform (10, 5, 5 mL). The organic layer was washed with water (10 mL), dried (Na 2 SO 4 ), and concentrated under reduced pressure. The residue (218 mg) was separated and purified by silica gel column chromatography (chloroform-methanol 10: 1) to give 142H-4-OH-3-deoxymorphinan (30) as colorless amorphous in 142 mg (95%).
1 H NMR (CDCl 3 , 300 MHz) δ: 0.13 (2H, m), 0.75 (2H, m), 0.89 (1H, m), 1.78 (1H, dd), 1.94 (4H, m) .2.09 (1H, m), 2.32 (4H, m), 2.52 (2H, m), 2.67 (1H, m), 2.75 (1H, m), 2.92 (1H, d), 3.30 (1H, m), 4.41 (1H, d ), 6.60 (1H, d), 6.68 (1H, d), 6.92 (1H, dd).
MS (FAB) m / z 312 (M + H) + .
IR (KBr) ν max cm -1 : 3274, 1701.
61の合成
14H-4-OH-3-デオキシモルヒナン(30)100mg(0.321mol)の無水エタノール溶液(1.5mL)にアルゴン気流下、2-アミノベンズアルデヒド119mg(0.979mmol)、メタンスルホン酸54 μL(0.815mmol)を加えた後、加熱還流下5時間攪拌した。反応溶液に10%炭酸水素ナトリウム水溶液(10mL)を加えた後(pH9)、酢酸エチル(10, 6, 4mL)で抽出した。有機層を飽和食塩水(5mL)で洗浄した後、乾燥(Na2SO4)し、減圧濃縮した。残渣(265mg)をシリカゲルカラムクロマトグラフィー(クロロホルム−メタノール10:1)で分離精製し、14H-4-OH-3-デオキシモルヒナン骨格キノリン体(61)を無色油状物として67mg(53%)で得た。
1H NMR (CDCl3, 300MHz) δ: 0.22 (2H, m), 0.56 (2H, m), 0.99 (1H, m), 1.31 (1H, dd), 2.19 (1H, m), 2.29 (1H, m), 2.52 (3H, m), 2.88 (1H, dd), 2.91 (1H, dd), 3.00 (2H, m), 3.05 (1H, d), 3.16 (1H, d), 3.50 (1H, broad), 5.25 (1H, d), 6.43 (1H, d), 6.65 (1H, d), 6.71 (2H, d), 6.81 (1H, dd), 7.05 (1H, dd), 7.43 (1H, d), 7.63 (1H, d).
MS(FAB) m/z 397 (M+H)+.61 synthesis
14H-4-OH-3-deoxymorphinan (30) 100 mg (0.321 mol) in absolute ethanol (1.5 mL) under argon flow, 2-aminobenzaldehyde 119 mg (0.979 mmol), methanesulfonic acid 54 μL (0.815 mmol) ) Was added, followed by stirring for 5 hours under heating to reflux. To the reaction solution was added 10% aqueous sodium hydrogen carbonate solution (10 mL) (pH 9), and the mixture was extracted with ethyl acetate (10, 6, 4 mL). The organic layer was washed with saturated brine (5 mL), dried (Na 2 SO 4 ), and concentrated under reduced pressure. The residue (265 mg) was separated and purified by silica gel column chromatography (chloroform-methanol 10: 1), and 14H-4-OH-3-deoxymorphinane skeleton quinoline (61) was obtained as a colorless oil in 67 mg (53%). Obtained.
1 H NMR (CDCl 3 , 300 MHz) δ: 0.22 (2H, m), 0.56 (2H, m), 0.99 (1H, m), 1.31 (1H, dd), 2.19 (1H, m), 2.29 (1H, m), 2.52 (3H, m), 2.88 (1H, dd), 2.91 (1H, dd), 3.00 (2H, m), 3.05 (1H, d), 3.16 (1H, d), 3.50 (1H, broad ), 5.25 (1H, d), 6.43 (1H, d), 6.65 (1H, d), 6.71 (2H, d), 6.81 (1H, dd), 7.05 (1H, dd), 7.43 (1H, d) , 7.63 (1H, d).
MS (FAB) m / z 397 (M + H) + .
61の塩酸塩
14H-4-OH-3-デオキシモルヒナン骨格キノリン体(61)42mg(0.106mmol)のクロロホルム溶液に塩酸飽和メタノール溶液を加え、塩酸塩27mgを得た。
mp:240℃(dec.).
元素分析(C27H28N2O・2HCl・5/3H2O)
計算値:C, 64.93;H, 6.73;N, 5.61
実測値;C, 64.69;H, 6.68;N, 5.5861 hydrochloride
A hydrochloric acid saturated methanol solution was added to a chloroform solution of 14H-4-OH-3-deoxymorphinane skeleton quinoline (61) 42 mg (0.106 mmol) to obtain 27 mg of hydrochloride.
mp: 240 ° C (dec.).
Elemental analysis (C 27 H 28 N 2 O · 2HCl · 5 / 3H 2 O)
Calculated values: C, 64.93; H, 6.73; N, 5.61
Found; C, 64.69; H, 6.68; N, 5.58
実施例20
62の合成
14H-3-OMe-N-メチルモルヒナン(31)67mg(0.234mmol)の無水エタノール溶液(2mL)にアルゴン気流下、2-アミノベンズアルデヒド87mg(0.715mmol)、メタンスルホン酸40 μL(0.595mmol)を加えた後、加熱還流下17時間攪拌した。反応溶液を濃縮した後、10%炭酸水素ナトリウム水溶液(12mL)を加えた後(pH9)、クロロホルム(20, 10, 10mL)で抽出した。有機層を飽和食塩水(10mL)で洗浄した後、乾燥(Na2SO4)し、減圧濃縮した。残渣(152mg)をシリカゲルカラムクロマトグラフィー(クロロホルム−メタノール10:1)で分離精製し、14H- 3-OMe- N-メチルモルヒナン骨格キノリン体(32)を無色油状物として43mg(50%)で得た。
1H NMR (CDCl3, 300MHz) δ: 1.70 (1H, d), 1.97 (3H, m), 2.24 (1H, dd). 2.48 (3H, s), 2.75 (1H, dd), 2.81 (1H, dd), 2.95 (1H, dd), 3.12 (3H, m), 3.65 (3H, s), 3.98 (1H, d), 6.20 (1H, d), 6.91 (1H, d), 7.00 (1H, d), 7.38 (1H, d), 7.57 (1H, d), 7.60 (1H, dd), 7.65 (1H, d), 7.95 (1H, d).
MS(FAB) m/z 371 (M+H)+. Example 20
Synthesis of 62
14H-3-OMe-N-Methylmorphinan (31) 67 mg (0.234 mmol) in absolute ethanol (2 mL) was added with 87 mg (0.715 mmol) of 2-aminobenzaldehyde and 40 μL (0.595 mmol) of methanesulfonic acid under an argon stream. After that, the mixture was stirred for 17 hours while heating under reflux. The reaction solution was concentrated, 10% aqueous sodium hydrogen carbonate solution (12 mL) was added (pH 9), and the mixture was extracted with chloroform (20, 10, 10 mL). The organic layer was washed with saturated brine (10 mL), dried (Na 2 SO 4 ), and concentrated under reduced pressure. The residue (152 mg) was separated and purified by silica gel column chromatography (chloroform-methanol 10: 1), and 14H-3-OMe-N-methylmorphinan skeleton quinoline (32) was obtained as a colorless oil in 43 mg (50%). .
1 H NMR (CDCl 3 , 300 MHz) δ: 1.70 (1H, d), 1.97 (3H, m), 2.24 (1H, dd). 2.48 (3H, s), 2.75 (1H, dd), 2.81 (1H, dd), 2.95 (1H, dd), 3.12 (3H, m), 3.65 (3H, s), 3.98 (1H, d), 6.20 (1H, d), 6.91 (1H, d), 7.00 (1H, d ), 7.38 (1H, d), 7.57 (1H, d), 7.60 (1H, dd), 7.65 (1H, d), 7.95 (1H, d).
MS (FAB) m / z 371 (M + H) + .
62の合成
14H- 3-OMe- N-メチルモルヒナン骨格キノリン体(32)43mg(0.116mmol)の無水ジクロロメタン溶液(2.4mL)に、アルゴン気流下0℃で1M 三臭化ホウ素ジクロロメタン溶液0.716 mL(0.716mmol)を加え、室温で暗所0.5時間攪拌した。反応溶液に0℃で6%アンモニア水(4mL)を加え激しく攪拌した後、クロロホルム(20, 10, 10mL)で抽出した。有機層を飽和食塩水(15mL)で洗浄した後、乾燥(Na2SO4)し、減圧濃縮し、淡黄色結晶43mg(定量的)を得た。メタノールから再結晶を行い、14H-N-メチルモルヒナン骨格キノリン体(62)を淡黄色結晶として20mg(48%)で得た。
mp:174-177℃
1H NMR (CD3OD, 300MHz) δ: 1,28 (1H, m), 1.70 (1H, d), 2.00 (1H, td), 2.36 (1H, td), 2.52 (3H, s), 2.60 (1H, dd), 2.76 (1H, m), 2.92 (1H, dd), 3.02 (1H, m), 3.10 (1H, m), 3.20 (1H, m), 3.90 (1H, d), 4.60 (1H, m), 6.52 (1H, dd), 6.79 (1H, d), 6.99 (1H, d), 7.48 (1H, d), 7.65 (1H, dd), 7.72 (1H, dd), 7.84 (1H, dd), 7.92 (1H, d).
MS(FAB) m/z 357 (M+H)+.
IRνmaxcm-1: 3211.
元素分析(C24H24N2O・0.5H2O)
計算値:C, 78.87;H, 6.89;N, 7.67
実測値;C, 79.02;H, 6.77;N, 7.88Synthesis of 62
14H-3-OMe- N-methylmorphinane skeleton quinoline (32) 43 mg (0.116 mmol) in anhydrous dichloromethane (2.4 mL) was added 0.7M (0.716 mmol) of 1M boron tribromide dichloromethane solution at 0 ° C under an argon stream. In addition, the mixture was stirred at room temperature in the dark for 0.5 hour. To the reaction solution was added 6% aqueous ammonia (4 mL) at 0 ° C., and the mixture was vigorously stirred and extracted with chloroform (20, 10, 10 mL). The organic layer was washed with saturated brine (15 mL), dried (Na 2 SO 4 ) and concentrated under reduced pressure to obtain 43 mg (quantitative) of pale yellow crystals. Recrystallization from methanol gave 14H-N-methylmorphinan skeleton quinoline (62) as pale yellow crystals in 20 mg (48%).
mp: 174-177 ℃
1 H NMR (CD 3 OD, 300 MHz) δ: 1,28 (1H, m), 1.70 (1H, d), 2.00 (1H, td), 2.36 (1H, td), 2.52 (3H, s), 2.60 (1H, dd), 2.76 (1H, m), 2.92 (1H, dd), 3.02 (1H, m), 3.10 (1H, m), 3.20 (1H, m), 3.90 (1H, d), 4.60 ( 1H, m), 6.52 (1H, dd), 6.79 (1H, d), 6.99 (1H, d), 7.48 (1H, d), 7.65 (1H, dd), 7.72 (1H, dd), 7.84 (1H , dd), 7.92 (1H, d).
MS (FAB) m / z 357 (M + H) + .
IRν max cm -1 : 3211.
Elemental analysis (C 24 H 24 N 2 O · 0.5H 2 O)
Calculated values: C, 78.87; H, 6.89; N, 7.67
Found; C, 79.02; H, 6.77; N, 7.88
62の塩酸塩
14H-N-メチルモルヒナン骨格キノリン体(62)42mg(0.118mmol)のクロロホルム溶液に塩酸飽和メタノール溶液を加え、塩酸塩15mgを得た。
mp:235-237℃(dec.)62 hydrochloride
A hydrochloric acid saturated methanol solution was added to a chloroform solution of 14H-N-methylmorphinan skeleton quinoline (62) 42 mg (0.118 mmol) to obtain hydrochloride 15 mg.
mp: 235-237 ° C (dec.)
実施例21
63の合成
Synthesis of 63
実施例22
64の合成
64 synthesis
製剤例1
以下の成分を含有する顆粒剤を製造する。
成分 化合物(I) 10mg
乳糖 700mg
コーンスターチ 274mg
HPC-L 16mg
1000mg
化合物(I)と乳糖を60メッシュのふるいに通す。コーンスターチを120メッシュのふるいに通す。これらをV型混合機にて混合する。混合末にHPC-L(低粘度ヒドロキシプロピルセルロース)水溶液を添加し、練合、造粒(押し出し造粒 孔径0.5〜1mm)、乾燥する。得られた乾燥顆粒を振動ふるい(12/60メッシュ)で櫛過し顆粒剤を得る。Formulation Example 1
A granule containing the following ingredients is produced.
Ingredient Compound (I) 10mg
Lactose 700mg
Corn starch 274mg
HPC-L 16mg
1000mg
The compound (I) and lactose are passed through a 60 mesh sieve. Pass cornstarch through a 120 mesh sieve. These are mixed in a V-type mixer. Add HPC-L (low-viscosity hydroxypropylcellulose) aqueous solution to the mixed powder, knead, granulate (extruded granulation pore size 0.5-1mm) and dry. The obtained dried granules are combed with a vibrating sieve (12/60 mesh) to obtain granules.
製剤例2
以下の成分を含有するカプセル充填用顆粒剤を製造する。
成分 化合物(I) 15mg
乳糖 90mg
コーンスターチ 42mg
HPC-L 3mg
150mg
化合物(I)、乳糖を60メッシュのふるいに通す。コーンスターチを120メッシュのふるいに通す。これらを混合し、混合末にHPC-L溶液を添加して練合、造粒、乾燥する。得られた乾燥顆粒を整粒後、その150mgを4号硬ゼラチンカプセルに充填する。Formulation Example 2
A capsule filling granule containing the following ingredients is produced.
Ingredient Compound (I) 15mg
Lactose 90mg
Cornstarch 42mg
HPC-L 3mg
150mg
The compound (I) and lactose are passed through a 60 mesh sieve. Pass cornstarch through a 120 mesh sieve. These are mixed, and the HPC-L solution is added to the mixed powder to knead, granulate and dry. After sizing the obtained dry granules, 150 mg thereof is filled into No. 4 hard gelatin capsules.
製剤例3
以下の成分を含有する錠剤を製造する。
成分 化合物(I) 10mg
乳糖 90mg
微結晶セルロース 30mg
CMC-Na 15mg
ステアリン酸マグネシウム 5mg
150mg
化合物(I)、乳糖、微結晶セルロース、CMC-Na(カルボキシメチルセルロース ナトリウム塩)を60メッシュのふるいに通し、混合する。混合末にステアリン酸マグネシウム混合し、製錠用混合末を得る。本混合末を直打し、150mgの錠剤を得る。Formulation Example 3
A tablet containing the following ingredients is produced.
Ingredient Compound (I) 10mg
Lactose 90mg
Microcrystalline cellulose 30mg
CMC-Na 15mg
Magnesium stearate 5mg
150mg
Compound (I), lactose, microcrystalline cellulose and CMC-Na (carboxymethylcellulose sodium salt) are passed through a 60 mesh sieve and mixed. The mixed powder is mixed with magnesium stearate to obtain a mixed powder for tableting. This mixed powder is directly hit to obtain a 150 mg tablet.
製剤例4
以下の成分を加温混合後、滅菌して注射剤とした。
化合物(I) 3mg
非イオン界面活性剤 15mg
注射用精製水 1mlFormulation Example 4
The following components were heated and mixed and then sterilized to give an injection.
Compound (I) 3mg
Nonionic surfactant 15mg
Purified water for injection 1ml
試験例1:オピオイド受容体結合試験
本発明化合物のμ、δおよびκオピオイド受容体に対する結合親和性を調べた。
実験材料
μ受容体:ラット大脳膜画分
δ受容体:ラット大脳膜画分
κ受容体:モルモット大脳画分
方法:既報(J. Med. Chem. 1999, 42, 3527-3538)に準じてラット大脳およびモルモット大脳膜画分を調製した。各オピオイド受容体に対するリガンドとして[3H]DAMGO(μオピオイド受容体)、[3H]DADLE(δオピオイド受容体)、[3H]U69,593(κオピオイド受容体)を用いた。μ受容体のアッセイは、ラット大脳膜画分を用いた。δ受容体のアッセイは、ラット大脳膜画分を用いて100nM DAMGO、3mM MnCl2および100mM塩化コリンを添加した。κ受容体のアッセイは、モルモット大脳膜画分を用いて1μg/mlカプトプリルを添加した。非特異的結合は、μおよびδ受容体では20μMレバロルファン、またκ受容体では1μM U69,593を用いた。対照化合物として、次式
Ki=IC50/(1+L/Kd)
L:用いた放射性リガンドの濃度
Kd:放射性リガンドのKd値
実験結果を表1に示す。
Experimental material μ receptor: rat cerebral membrane fraction δ receptor: rat cerebral membrane fraction κ receptor: guinea pig cerebral fraction Method: Rat according to previous report (J. Med. Chem. 1999, 42, 3527-3538) Cerebral and guinea pig cerebral membrane fractions were prepared. [ 3 H] DAMGO (μ opioid receptor), [ 3 H] DADLE (δ opioid receptor), [ 3 H] U69,593 (κ opioid receptor) were used as ligands for each opioid receptor. The μ receptor assay used rat cerebral membrane fraction. For the assay of δ receptor, 100 nM DAMGO, 3 mM MnCl 2 and 100 mM choline chloride were added using rat cerebral membrane fraction. For the assay of kappa receptor, 1 μg / ml captopril was added using a guinea pig cerebral membrane fraction. Nonspecific binding used 20 μM levalorphan for μ and δ receptors and 1 μM U69,593 for kappa receptors. As a control compound:
Ki = IC 50 / (1 + L / Kd)
L: Concentration of radioligand used Kd: Kd value of radioligand Table 1 shows the experimental results.
試験例2:オピオイドδ受容体機能試験
オピオイドδ受容体に対する本発明化合物のアゴニスト活性を[35S]GTPγS結合試験により調べた。
実験材料:オピオイドδ受容体発現細胞膜画分
方法:オピオイドδ受容体発現細胞膜画分はPerkinElmer社より購入した。受容体膜画分および検体を0.5mLの緩衝液(50mM Tris、1mM EDTA、12.5mM MgCl2、100mM NaCl、0.5%BSA、3μM GDP、0.1nM[35S]GTPγS、pH7.4)中、所定の時間反応させ、B/F分離を行った。定常活性は、3μM GDP(アゴニスト非存在下)添加条件下にて、また非特異的結合は10μM GTPγS添加条件下にて測定した。対照アゴニストとして、TAN−67および[Met5]−エンケファリンを用いた。検体のアゴニスト活性は[Met5]−エンケファリンの活性を100%としたときの最大活性(Emax値;%)並びにEC50値で表した。実験結果を表2に示す。
Experimental material: Opioid δ receptor-expressing cell membrane fraction Method: Opioid δ receptor-expressing cell membrane fraction was purchased from PerkinElmer. Receptor membrane fraction and specimen were treated with 0.5 mL buffer (50 mM Tris, 1 mM EDTA, 12.5 mM MgCl 2 , 100 mM NaCl, 0.5% BSA, 3 μM GDP, 0.1 nM [ 35 S] GTPγS, pH 7. During 4), reaction was carried out for a predetermined time, and B / F separation was performed. Steady activity was measured under the condition of adding 3 μM GDP (in the absence of agonist), and non-specific binding was measured under the condition of adding 10 μM GTPγS. TAN-67 and [Met5] -enkephalin were used as control agonists. The agonist activity of the specimen was represented by the maximum activity (Emax value;%) and the EC 50 value when the activity of [Met5] -enkephalin was 100%. The experimental results are shown in Table 2.
表1および表2に示すとおり、本発明の化合物は、オピオイドδ受容体に対して強いアゴニスト活性を有することがわかる。また、本発明の化合物は、オピオイドδ受容体に対して特異的な親和性を有する。特に化合物47は、対照化合物(TAN-67)と比較して、38倍もの高いアゴニスト活性を示した。 As shown in Table 1 and Table 2, it can be seen that the compounds of the present invention have a strong agonist activity for the opioid δ receptor. The compounds of the present invention also have a specific affinity for the opioid δ receptor. In particular, Compound 47 showed 38 times higher agonist activity than the control compound (TAN-67).
本発明に係る化合物は、オピオイドδ受容体に対して強いアゴニスト活性を有し、鎮痛剤として有効な医薬となり得る。 The compound according to the present invention has a strong agonist activity with respect to the opioid δ receptor, and can be a pharmaceutical effective as an analgesic.
Claims (7)
R1bは不存在または低級アルキルであり、
R2は水素、ヒドロキシ、低級アルコキシ、低級アルケニルオキシ、アリール低級アルコキシ、アリール低級アルケニルオキシ、アシルオキシまたは低級アルコキシ低級アルコキシであり、
R3およびR4は一方が水素であり、他方が水素、ヒドロキシ、低級アルコキシまたはアシルオキシであり、
R5およびR6が環上の隣接する炭素原子に結合し、それらの炭素原子と一緒になって置換基を有していてもよい環を形成してもよく、
破線は結合の存在または不存在を示し、破線が結合の不存在を示す場合、R5およびR6は一緒になって=Oを形成してもよく、
rは0〜5の整数であり、
Rxは各々独立して水素、低級アルキル、低級アルケニル、アリール低級アルキル、アリール低級アルケニル、アシル、低級アルキルスルホニル、アリールスルホニル、アリール低級アルキルスルホニルまたはアシルであり、
Yは−N=または−CH=であり、
R9は水素または低級アルキルであり、
R10およびR11は各々独立して水素、低級アルキルまたはシクロアルキル低級アルキルである。ただし、
で示される化合物、その製薬上許容される塩またはそれらの溶媒和物。Formula (I):
R 1b is absent or lower alkyl,
R 2 is hydrogen, hydroxy, lower alkoxy, lower alkenyloxy, aryl lower alkoxy, aryl lower alkenyloxy, acyloxy or lower alkoxy lower alkoxy,
One of R 3 and R 4 is hydrogen and the other is hydrogen, hydroxy, lower alkoxy or acyloxy;
R 5 and R 6 may be bonded to adjacent carbon atoms on the ring, and together with those carbon atoms may form a ring that may have a substituent,
The dashed line indicates the presence or absence of a bond, and when the dashed line indicates the absence of a bond, R 5 and R 6 may together form ═O;
r is an integer from 0 to 5;
Each R x is independently hydrogen, lower alkyl, lower alkenyl, aryl lower alkyl, aryl lower alkenyl, acyl, lower alkylsulfonyl, arylsulfonyl, aryl lower alkylsulfonyl or acyl;
Y is —N═ or —CH═;
R 9 is hydrogen or lower alkyl,
R 10 and R 11 are each independently hydrogen, lower alkyl or cycloalkyl lower alkyl. However,
Or a pharmaceutically acceptable salt or solvate thereof.
である、請求項1記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。R 1a is isobutyl, cyclopropylmethyl, phenethyl or benzyl, R 1b is absent or methyl, R 2 is hydrogen or hydroxy, one of R 3 and R 4 is hydrogen and the other is hydroxy Yes,
The compound according to claim 1, a pharmaceutically acceptable salt thereof, or a solvate thereof.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2006181938 | 2006-06-30 | ||
JP2006181938 | 2006-06-30 | ||
PCT/JP2007/063024 WO2008001859A1 (en) | 2006-06-30 | 2007-06-28 | OPIOID δ RECEPTOR AGONIST |
Publications (1)
Publication Number | Publication Date |
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JPWO2008001859A1 true JPWO2008001859A1 (en) | 2009-11-26 |
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JP6061857B2 (en) * | 2011-09-09 | 2017-01-18 | 学校法人北里研究所 | Morphinan derivatives |
GB2502881B (en) | 2012-04-23 | 2016-03-16 | E Vision Smart Optics Inc | Systems, devices, and/or methods for managing implantable devices |
WO2014021273A1 (en) * | 2012-07-30 | 2014-02-06 | 学校法人北里研究所 | Morphinan derivatives |
US8987287B2 (en) * | 2012-12-14 | 2015-03-24 | Purdue Pharma L.P. | Spirocyclic morphinans and their use |
WO2014091295A1 (en) * | 2012-12-14 | 2014-06-19 | Purdue Pharma L.P. | Pyridonemorphinan analogs and biological activity on opioid receptors |
JP2016056097A (en) * | 2013-01-25 | 2016-04-21 | 学校法人北里研究所 | Propellane derivative |
EP2966074B1 (en) | 2013-03-08 | 2018-07-25 | The Kitasato Institute | Morphinan derivative |
JP2016106072A (en) * | 2013-03-27 | 2016-06-16 | 学校法人北里研究所 | Propellane derivative |
JP6692345B2 (en) | 2015-03-17 | 2020-05-13 | 日本ケミファ株式会社 | Morphinan derivative |
JPWO2018030382A1 (en) | 2016-08-09 | 2019-06-13 | 日本ケミファ株式会社 | Morphinan derivatives |
EP3513792B1 (en) | 2016-09-16 | 2024-03-27 | Nippon Chemiphar Co., Ltd. | Morphinan derivatives for the treatment of opioid delta receptor agonist-related diseases |
TW202302096A (en) | 2021-02-26 | 2023-01-16 | 學校法人東京理科大學 | Pharmaceutical composition for treatment or prevention of stress-related disorders |
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WO2004007503A1 (en) * | 2002-07-11 | 2004-01-22 | Toray Industries, Inc. | Therapeutic or preventive agent for nausea/vomiting |
WO2006064780A1 (en) * | 2004-12-14 | 2006-06-22 | Shionogi & Co., Ltd. | Therapeutic agent for constipation |
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JP2005231995A (en) * | 1999-12-22 | 2005-09-02 | Meiji Seika Kaisha Ltd | SPIRO COMPOUND USEFUL AS OPIOID delta RECEPTOR AGONIST/ANTAGONIST |
DE60135016D1 (en) * | 2000-11-22 | 2008-09-04 | Toray Industries | INDOIND DERIVATIVES AND THEIR USE IN MEDICAMENTS |
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WO2004007503A1 (en) * | 2002-07-11 | 2004-01-22 | Toray Industries, Inc. | Therapeutic or preventive agent for nausea/vomiting |
WO2006064780A1 (en) * | 2004-12-14 | 2006-06-22 | Shionogi & Co., Ltd. | Therapeutic agent for constipation |
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JPN6012044365; 'Coop,A.,et al' J.Med.Chem Vol.42, 1999, pp1673-1679 * |
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