JP5308352B2 - Opioid analgesics - Google Patents

Abstract

The object is to provide: a compound having an analgesic activity; a pharmaceutical composition and an analgesic agent, each of which comprises the compound; an analgesic treatment method using the compound; and use of the compound in an analgesic treatemnt. Disclosed is a compound represented by the formula (I) or a salt thereof. (I) wherein R1 represents a hydrogen atom or a halogen atom; R2, R3, R4 and R5 independently represent a hydrogen atom, a hydroxy group, an alkoxy group which may have a substituent or the like; and R6 represents an alkoxycarbonyl group which may have a substituent or a carboxy group.

Description

  The present invention relates to a compound having an analgesic action or a salt thereof. More specifically, it relates to a 7-hydroxymitragain derivative or a salt thereof. Furthermore, this invention relates to the pharmaceutical composition containing the said compound or its salt. Moreover, this invention relates to the analgesic containing the said compound or its salt as an active ingredient. The invention further relates to the use of said compounds or salts thereof in analgesic treatment and the manufacture of analgesics. The present invention also relates to an analgesic treatment method comprising using the compound or a salt thereof.

  Morphine is an analgesic that is indispensable for improving the quality of life (QOL) of cancer pain patients, but it has low bioavailability, and various side effects such as analgesic tolerance and physical / mental health due to continuous use. It has problems such as showing dependency formation, nausea and vomiting, constipation, drowsiness, and respiratory depression. Therefore, the appearance of an ideal analgesic to replace morphine has long been eagerly desired. In search of better analgesics, research on synthetic analgesics starting with chemical modification of the morphine molecule began in the 1920s, and many compounds were synthesized and evaluated for pharmacological activity. However, there are few examples where an effective opioid analgesic substance replacing the morphine skeleton has been developed. On the other hand, research on the development of analgesic action by morphine has also made great progress in recent years, in order to elucidate the molecular mechanism of analgesia based on the classification of opioid receptors (δ, μ, κ-receptors) and the determination of their respective amino acid sequences. An effort has been made. However, there are complex interactions between these three receptors, and no logical methodology has yet been established to separate side effects such as analgesic and narcotic properties.

  The present inventors have found that the alkaloid contained in the Rubiaceae plant Mitragyna speciosa, which has been used in Thailand and Malaysia as a morphine substitute, has a strong analgesic effect, and the active body of the alkaloid and Separation and efficient asymmetric total synthesis of a possible trace component indole alkaloid, 7-hydroxymitragynine (7-hydroxymitragynine) has been achieved (Non-patent Document 1). The inventors of the present invention have shown that 7-hydroxymitragainin suppresses contraction of the guinea pig small intestine through an opioid receptor (Non-Patent Document 1), a tail flick test using a mouse, It has been reported that in a hot plate test, it shows a significant anti-nociceptive effect by subcutaneous administration or oral administration (Non-patent Document 2). Furthermore, the present inventors have synthesized a derivative of 7-hydroxymitragain and examined its analgesic action (Non-patent Document 3).

Takayama H. et al., “Journal of Medicinal Chemistry”, 2002, Vol. 45, No. 9, p.1949-1956. Matsumoto K. et al., “Life Sciences”, 2004, Vol. 74, No. 17, p.2143-2155. Takayama H. et al., “Organic Letters”, 2006, Vol. 8, No. 25, pp. 5705-5708.

  An object of the present invention is to solve the above-described problems of the prior art. That is, an object of the present invention is to provide a compound having a powerful analgesic action instead of morphine, a pharmaceutical composition or analgesic containing the compound as an active ingredient, an analgesic treatment method using the compound, and the compound Is to provide use in analgesic treatment.

  The present inventors have intensively studied to achieve the above-mentioned object, and have found that a derivative of 7-hydroxymitragain exhibits a strong analgesic action. The present invention has been achieved based on these findings.

［式（I）中、R₁は水素原子またはハロゲン原子；R₂、R₃、R₄およびR₅は、独立して、水素原子、ヒドロキシ基（ハイドロキシ基ともいう）、置換基を有していてもよいアルコキシ基、置換基を有していてもよいアリールオキシ基、置換基を有していてもよいアルキル基、置換基を有していてもよいアリール基、置換基を有していてもよいアラルキル基、置換基を有していてもよいアルカリル基、アルキルアミド基、アミノ基、アルキルアミノ基、ハロゲン原子、フッ化アルキル基、フッ化アルコキシ基、ニトロ基、またはシアノ基；R₆は、置換基を有していてもよいアルコキシカルボニル基またはカルボキシ基である］
で表される化合物またはその塩。
（2）R₃およびR₄が水素原子である上記（1）に記載の化合物またはその塩。
（3）R₂およびR₅がメトキシ基である上記（1）または（2）に記載の化合物またはその塩。
（4）R₆がメトキシカルボニル基である上記（1）から（3）のいずれかに記載の化合物またはその塩。
（5）R₁が水素原子またはフッ素原子である上記（1）から（4）のいずれかに記載の化合物またはその塩。
（6）下式（II）：

［式（II）中、R₁は水素原子またはハロゲン原子；R₂およびR₃は、独立して、水素原子、ヒドロキシ基、置換基を有していてもよいアルコキシ基、置換基を有していてもよいアリールオキシ基、置換基を有していてもよいアルキル基、置換基を有していてもよいアリール基、置換基を有していてもよいアラルキル基、置換基を有していてもよいアルカリル基、アルキルアミド基、アミノ基、アルキルアミノ基、ハロゲン原子、フッ化アルキル基、フッ化アルコキシ基、ニトロ基、またはシアノ基；R₄は、置換基を有していてもよいアルコキシカルボニル基またはカルボキシ基である］
で表される化合物またはその塩。
（7）R₂およびR₃がメトキシ基である上記（6）に記載の化合物またはその塩。
（8）R₄がメトキシカルボニル基である上記（6）または（7）に記載の化合物またはその塩。
（9）R₁が水素原子またはフッ素原子である上記（6）から（8）のいずれかに記載の化合物またはその塩。
（10）上記いずれかの化合物またはその塩を有効成分とし、それらの有効量を含有する医薬組成物。
（11）上記いずれかの化合物またはその塩を有効成分とし、それらの有効量を含有する鎮痛剤。
（12）上記いずれかの化合物またはその塩を有効成分としてそれらの有効量を含有し、モルヒネと比較して副作用が軽減されたオピオイド鎮痛剤。
（13）上記いずれかの化合物またはその塩を使用することを特徴とする鎮痛処置方法。
（14）上記いずれかの化合物またはその塩の鎮痛処置における使用。
（15）上記いずれかの化合物またはその塩の鎮痛剤の製造における使用。That is, the present invention relates to the following.
(1) The following formula (I):

[In the formula (I), R ₁ is a hydrogen atom or a halogen atom; R ₂ , R ₃ , R ₄ and R ₅ independently have a hydrogen atom, a hydroxy group (also referred to as a hydroxy group), or a substituent. An optionally substituted alkoxy group, an optionally substituted aryloxy group, an optionally substituted alkyl group, an optionally substituted aryl group, and a substituent. An aralkyl group that may be substituted, an alkaryl group that may have a substituent, an alkylamide group, an amino group, an alkylamino group, a halogen atom, a fluorinated alkyl group, a fluorinated alkoxy group, a nitro group, or a cyano group; R ₆ is an optionally substituted alkoxycarbonyl group or carboxy group]
Or a salt thereof.
(2) The compound or salt thereof according to (1) above, wherein R ₃ and R ₄ are hydrogen atoms.
(3) The compound or salt thereof according to (1) or (2) above, wherein R ₂ and R ₅ are methoxy groups.
(4) The compound or salt thereof according to any one of (1) to (3) above, wherein R ₆ is a methoxycarbonyl group.
(5) The compound or salt thereof according to any one of (1) to (4) above, wherein R ₁ is a hydrogen atom or a fluorine atom.
(6) The following formula (II):

[In the formula (II), R ₁ is a hydrogen atom or a halogen atom; R ₂ and R ₃ independently have a hydrogen atom, a hydroxy group, an alkoxy group which may have a substituent, or a substituent. An aryloxy group which may have a substituent, an alkyl group which may have a substituent, an aryl group which may have a substituent, an aralkyl group which may have a substituent, and a substituent. An alkaryl group, an alkylamide group, an amino group, an alkylamino group, a halogen atom, a fluorinated alkyl group, a fluorinated alkoxy group, a nitro group, or a cyano group; R ₄ may have a substituent. An alkoxycarbonyl group or a carboxy group]
Or a salt thereof.
(7) The compound or salt thereof according to (6) above, wherein R ₂ and R ₃ are methoxy groups.
(8) The compound or salt thereof according to (6) or (7) above, wherein R ₄ is a methoxycarbonyl group.
(9) The compound or salt thereof according to any one of (6) to (8) above, wherein R ₁ is a hydrogen atom or a fluorine atom.
(10) A pharmaceutical composition comprising any one of the above compounds or a salt thereof as an active ingredient and containing an effective amount thereof.
(11) An analgesic containing one of the above compounds or a salt thereof as an active ingredient and containing an effective amount thereof.
(12) An opioid analgesic containing one of the above compounds or a salt thereof as an active ingredient in an effective amount thereof and having reduced side effects compared to morphine.
(13) An analgesic treatment method characterized by using any one of the above compounds or a salt thereof.
(14) Use of any of the above compounds or salts thereof in analgesic treatment.
(15) Use of any of the above compounds or a salt thereof in the manufacture of an analgesic.

  According to the present invention, in a compound having an analgesic action, a pharmaceutical composition and an analgesic agent containing the compound as an active ingredient, an analgesic treatment method using the compound, and an analgesic treatment and an analgesic agent Use of the compound can be provided.

  The compound according to the present invention exhibits a stronger analgesic action than morphine. Therefore, this compound can be effectively used in various analgesic treatments as an analgesic agent replacing morphine. Furthermore, this compound exhibits sufficient analgesic action even when administered orally. In addition, this compound has a weak gastrointestinal motility inhibitory effect at an analgesic dose, and is therefore less effective at suppressing gastrointestinal motility than an opioid compound that has a very strong gastrointestinal motility inhibitory effect at an analgesic dose such as morphine. It can be used as an opioid analgesic with reduced side effects such as constipation. Thus, since this compound has the characteristics that it can be administered orally and has few side effects, the burden on patients undergoing analgesic treatment can be reduced.

It is a figure which shows the dose effect curve of the analgesic effect by the oral administration of the compound 1, the compound 2, 7-hydroxy mitragainin, and morphine in a mouse | mouth tail flick test. The analgesic effect of the specimen was quantified using the maximum acceptable effect rate (% MPE). % MPE was calculated by the following formula:% MPE = [(latency after drug treatment−latency before drug treatment) / (maximum stimulation time−latency before drug treatment)] × 100. The maximum stimulation time (cut-off time) was 10 seconds to avoid tissue damage. Each value is expressed as the mean value ± standard error of data obtained from 7 to 9 mice. It is a figure which shows the dose effect curve of the analgesic effect by the subcutaneous administration of the compound 1, compound 2, 7-hydroxy mitragainin, and morphine in a mouse | mouth tail flick test. The analgesic effect of the specimen was quantified using the maximum acceptable effect rate (% MPE). % MPE was calculated by the following formula:% MPE = [(latency after drug treatment−latency before drug treatment) / (maximum stimulation time−latency before drug treatment)] × 100. The maximum stimulation time (cut-off time) was 10 seconds to avoid tissue damage. Each value is expressed as the mean value ± standard error of data obtained from 7 to 9 mice. FIG. 3 is a graph showing the effect of an opioid receptor antagonist on analgesic action induced by subcutaneous administration of Compound 1 to mice. The opioid receptor antagonists β-funaltrexamine (β-FNA, 40 mg / kg), naltrindole (NTI, 3 mg / kg), and nor-vinaltolfimine (norBNI, 20 mg / kg) are administered subcutaneously, respectively. Then, 30 minutes, 24 hours, and 24 hours later, Compound 1 (0.5 mg / kg) was administered, a mouse tail flick test was performed, and analgesic activity was measured. The measurement was carried out 15 minutes after the subcutaneous administration of Compound 1. Each value is expressed as the mean value ± standard error of data obtained from 8 to 9 mice. In the figure, # indicates that there was a significant difference in the Student t test compared to the solvent-treated mice (##, P <0.01). Asterisks are Bonferroni's multiple comparison method following one-way analysis of variance followed by significant differences compared to mice treated with Compound 1 alone (*, P <0.05; **, P <0.01). ). FIG. 3 is a graph showing the effect of an opioid receptor antagonist on analgesic action induced by subcutaneous administration of Compound 2 to mice. The opioid receptor antagonists β-funaltrexamine (β-FNA, 40 mg / kg), naltrindole (NTI, 3 mg / kg), and nor-vinaltolfimine (norBNI, 20 mg / kg) are administered subcutaneously, respectively. Then, 30 minutes, 24 hours, and 24 hours later, Compound 2 (0.1 mg / kg) was administered, a mouse tail flick test was performed, and analgesic activity was measured. The measurement was performed 15 minutes after subcutaneous administration of Compound 2. Each value is expressed as the mean value ± standard error of data obtained from 8 to 9 mice. In the figure, # indicates that there was a significant difference in the student t-test compared to the solvent-treated mice (##, P <0.01). The asterisk is Bonferroni's multiple comparison method following a one-way analysis of variance followed by a significant difference compared to mice treated with Compound 2 alone (*, P <0.05; **, P <0.01). ). It is a figure which shows the dose action curve of the gastrointestinal motility inhibitory effect by oral administration of the compound 1, the compound 2, 7-hydroxy mitragaginine, and morphine in the mouse | mouth charcoal powder transportation method. All specimens inhibited gastrointestinal motility in a dose-dependent manner. This suppression is an indicator of constipation of side effects. Inhibition of gastrointestinal transit was calculated by the following formula: Gastrointestinal motility inhibition rate (%) = [(control charcoal transport rate−specimen charcoal transport rate) / (control charcoal) Final transport rate)] x 100. Each value is expressed as the mean value ± standard error of data obtained from 8 to 10 mice. It is a figure which shows the dose action curve of the gastrointestinal motility inhibitory effect by the subcutaneous administration of the compound 1, the compound 2, 7-hydroxy mitragainin, and morphine in the mouse | mouth coal powder transport method. All specimens inhibited gastrointestinal motility in a dose-dependent manner. This suppression is an indicator of constipation of side effects. Inhibition of gastrointestinal transit was calculated by the following formula: Gastrointestinal motility inhibition rate (%) = [(control charcoal transport rate−specimen charcoal transport rate) / (control charcoal) Final transport rate)] x 100. Each value is expressed as the mean value ± standard error of data obtained from 8 to 10 mice. FIG. 3 is a graph showing that the pain sensation latency to thermal stimulation is prolonged by subcutaneous administration of Compound 1 in a neuropathic pain model mouse prepared by sciatic nerve ligation. In the figure, “Ligation” represents a mouse subjected to sciatic nerve ligation surgery, and “Sham” represents a mouse subjected to sham surgery. The vertical axis indicates the time until the hind limb is retracted when a thermal stimulus is applied to the hind limb sole. Each value is expressed as the mean value ± standard error of data obtained from 7 to 8 mice. “★” and “★★” indicate significant differences at P <0.05 and P <0.01, respectively, compared to sham-operated mice. FIG. 4 is a graph showing that the pain sensation latency was prolonged by subcutaneous administration of Compound 2 in a neuropathic pain model mouse prepared by sciatic nerve ligation. In the figure, “Ligation” represents a mouse subjected to sciatic nerve ligation surgery, and “Sham” represents a mouse subjected to sham surgery. The vertical axis indicates the time until the hind limb is retracted when a thermal stimulus is applied to the hind limb sole. Each value is expressed as the mean value ± standard error of data obtained from 7 to 8 mice. “★★” indicates that there is a significant difference at P <0.01 compared with mice subjected to sham surgery. FIG. 3 is a graph showing that the pain sensation latency to thermal stimulation was prolonged by oral administration of Compound 2 in a neuropathic pain model mouse prepared by sciatic nerve ligation. In the figure, “Ligation” represents a mouse subjected to sciatic nerve ligation surgery, and “Sham” represents a mouse subjected to sham surgery. The vertical axis indicates the time until the hind limb is retracted when a thermal stimulus is applied to the hind limb sole. “★★” indicates that there is a significant difference at P <0.01 compared with mice subjected to sham surgery. FIG. 3 is a graph showing changes over time in the pain sensation latency with respect to heat stimulation after oral administration of Compound 2 in a neuropathic pain model mouse prepared by sciatic nerve ligation. In the figure, “Ligation” represents a mouse subjected to sciatic nerve ligation surgery, and “Sham” represents a mouse subjected to sham surgery. The vertical axis indicates the time until the hind limb is retracted when a thermal stimulus is applied to the hind limb sole. It is a figure which shows the effect | action of morphine, a fentanyl, 7-hydroxy mitragainin, and the compound 3 to the pain sensation latency with respect to the heat stimulation in the neuropathic pain model mouse | mouth created by the sciatic nerve ligation (the upper left panel and the upper right panel, respectively). , Lower left panel, and lower right panel). The compound was administered subcutaneously. In the figure, “Ligation” represents a mouse subjected to sciatic nerve ligation surgery, and “Sham” represents a mouse subjected to sham surgery. The vertical axis indicates the time until the hind limb is retracted when a thermal stimulus is applied to the hind limb sole. Each value is expressed as the mean value ± standard error of data obtained from 7 to 8 mice. “★” and “★★” indicate significant differences at P <0.05 and P <0.01, respectively, compared to sham-operated mice. FIG. 4 is a graph showing that 50% threshold of response to mechanical stimulation was increased by subcutaneous administration of Compound 1 in a neuropathic pain model mouse prepared by sciatic nerve ligation. In the figure, “Ligation” represents a mouse subjected to sciatic nerve ligation surgery, and “Sham” represents a mouse subjected to sham surgery. It is a figure which shows the time-dependent change of the 50% threshold value of the response to a mechanical stimulus after subcutaneous administration of Compound 1 in a neuropathic pain model mouse prepared by sciatic nerve ligation. In the figure, “Ligation” represents a mouse subjected to sciatic nerve ligation surgery, and “Sham” represents a mouse subjected to sham surgery. FIG. 4 is a graph showing that the 50% threshold of response to mechanical stimulation was increased by subcutaneous administration of Compound 2 in a neuropathic pain model mouse prepared by sciatic nerve ligation. In the figure, “Ligation” represents a mouse subjected to sciatic nerve ligation surgery, and “Sham” represents a mouse subjected to sham surgery. It is a figure which shows the time-dependent change of the 50% threshold value of the response to a mechanical stimulus after subcutaneous administration of Compound 2 in a neuropathic pain model mouse prepared by sciatic nerve ligation. In the figure, “Ligation” represents a mouse subjected to sciatic nerve ligation surgery, and “Sham” represents a mouse subjected to sham surgery.

［式（I）中、R₁は水素原子またはハロゲン原子；R₂、R₃、R₄およびR₅は、独立して、水素原子、ヒドロキシ基、置換基を有していてもよいアルコキシ基、置換基を有していてもよいアリールオキシ基、置換基を有していてもよいアルキル基、置換基を有していてもよいアリール基、置換基を有していてもよいアラルキル基、置換基を有していてもよいアルカリル基、アルキルアミド基、アミノ基、アルキルアミノ基、ハロゲン原子、フッ化アルキル基、フッ化アルコキシ基、ニトロ基、またはシアノ基；R₆は、置換基を有していてもよいアルコキシカルボニル基またはカルボキシ基である］
で表される化合物またはその塩が提供される。According to the present invention, the following formula (I):

[In the formula (I), R ₁ is a hydrogen atom or a halogen atom; R ₂ , R ₃ , R ₄ and R ₅ are independently a hydrogen atom, a hydroxy group, or an optionally substituted alkoxy group. , An aryloxy group which may have a substituent, an alkyl group which may have a substituent, an aryl group which may have a substituent, an aralkyl group which may have a substituent, An alkaryl group, an alkylamide group, an amino group, an alkylamino group, a halogen atom, a fluorinated alkyl group, a fluorinated alkoxy group, a nitro group, or a cyano group which may have a substituent; R ₆ represents a substituent; It is an alkoxycarbonyl group or a carboxy group that may have]
Or a salt thereof is provided.

  “Halogen” is preferably fluorine, chlorine, bromine and iodine, more preferably fluorine.

  “Alkoxy group” means an alkyl group attached through a single terminal ether linkage. A lower alkoxy group is preferred. The lower alkoxy group means a branched or unbranched alkoxy group having 1 to 6 carbon atoms. Preferred examples include a methoxy group, an ethoxy group, an n-propoxy group, an i-propoxy group, an n- Butoxy group, s-butoxy group, t-butoxy group, n-pentyloxy group, i-pentyloxy group, neopentyloxy group, s-pentyloxy group, t-pentyloxy group, n-hexyloxy group, neohexyl Examples thereof include an oxy group, i-hexyloxy group, s-hexyloxy group, and t-hexyloxy group. More preferably, it is a branched or unbranched alkoxy group having 1 to 4 carbon atoms, and a methoxy group can be exemplified more preferably.

  The “aryloxy group” is a group formed by substituting an aromatic hydrocarbon group having a cyclic, polycyclic or condensed ring aromatic ring with an ether group. Preferred examples include a phenoxy group, naphthyl An oxy group can be mentioned.

  “Alkyl group” means a branched or unbranched saturated hydrocarbon group. Preferably it is a lower alkyl group. The lower alkyl group means a branched or unbranched saturated hydrocarbon group having 1 to 10 carbon atoms. Preferred examples include a methyl group, an ethyl group, an n-propyl group, an i-propyl group, n-butyl group, s-butyl group, t-butyl group, n-pentyl group, i-pentyl group, neopentyl group, s-pentyl group, t-pentyl group, n-hexyl group, neohexyl group, s-hexyl group , T-hexyl group, heptyl group, octyl group and the like. Preferably, it is a saturated hydrocarbon group having 1 to 4 carbon atoms.

  The “aryl group” means an aromatic hydrocarbon group having a monocyclic, polycyclic or condensed ring aromatic ring. The carbon number is preferably 6-20, more preferably 6-12. Preferable examples include a phenyl group, a naphthyl group, an anthryl group, and a phenanthryl group.

  The “aralkyl group” means an alkyl group having an aryl substituent, and preferable examples include a benzyl group, a phenethyl group, a methylbenzyl group, a naphthylmethyl group, and a naphthylethyl group.

  “Alkaryl group” means an aryl group having an alkyl substituent, and preferable examples include tolyl group, xylyl group, dimethylphenyl group, diethylphenyl group, trimethylphenyl group, triethylphenyl group, and p-alkylphenyl group. Can be mentioned.

  The “alkylamide group” is preferably a lower alkylamide group. The lower alkylamide group means a group formed by substituting an amide group with the above lower alkyl group, and preferable examples include an acetamido group, an ethylamide group, a propylamide group, and the like.

  The “alkylamino group” is preferably a lower alkylamino group. The lower alkylamino group means a group formed by substituting an amino group with the lower alkyl group, and preferred examples include a methylamino group, an ethylamino group, an n-propylamino group, and an i-propyl. An amino group, n-butylamino group, t-butylamino group, etc. can be mentioned.

  The “fluorinated alkyl group” means a group in which the above alkyl group or lower alkyl group is preferably substituted with 1 to 3, more preferably 1 fluorine atom.

  “Fluorinated alkoxy group” means a group in which the above alkoxy group or lower alkoxy group is preferably substituted with 1 to 3, more preferably 1 fluorine atom.

  The “alkoxycarbonyl group” is preferably a lower alkoxycarbonyl group. The lower alkoxycarbonyl group is a combination of the lower alkoxy group and a carbonyl group, and preferred examples include a methoxycarbonyl group, an ethoxycarbonyl group, a propylcarbonyl group, and a butoxycarbonyl group. More preferably, a methoxycarbonyl group can be illustrated.

  The substituent of the alkoxy group, aryloxy group, alkyl group, aryl group, aralkyl group and alkaryl group is not particularly limited, but is an alkyl group such as a methyl group, an ethyl group or a propyl group, such as a phenyl group or a naphthyl group. Aryl groups such as oxiranyl group, pyridyl group, furyl group and other heterocyclic groups, such as methoxy group, ethoxy group, phenoxy group, naphthyloxy group and other alkoxy groups such as methoxycarbonyl group, i-propoxycarbonyl group, t -Alkoxycarbonyl groups such as butoxycarbonyl group, phenoxycarbonyl group, sulfonic acid group, cyano group, nitro group, silyl group such as trimethylsilyl group, triphenylsilyl group, hydroxy group such as unsubstituted amide group, methylamide group, propyl Amide group, tetra Amide group such as decylamide group, acyl group such as acetyl group and benzoyl group, phosphoryl group such as dihydroxyphosphoryl group and dimethoxyphosphoryl group, sulfinyl group such as methylsulfinyl group, phenylsulfinyl group, such as methylsulfonyl group, phenyl A sulfonyl group such as a sulfonyl group, for example, a sulfonate group such as a methyl sulfonate group and a phenyl sulfonate group can be exemplified.

In the above formula (I), R ₁ is preferably a hydrogen atom or a halogen atom, more preferably a hydrogen atom or a fluorine atom, R ₃ and R ₄ are preferably a hydrogen atom, and R ₂ and R ₅ are preferably It is a methoxy group, and R ₆ is preferably a methoxycarbonyl group.

［式（II）中、R₁は水素原子またはハロゲン原子；R₂およびR₃は、独立して、水素原子、ヒドロキシ基、置換基を有していてもよいアルコキシ基、置換基を有していてもよいアリールオキシ基、置換基を有していてもよいアルキル基、置換基を有していてもよいアリール基、置換基を有していてもよいアラルキル基、置換基を有していてもよいアルカリル基、アルキルアミド基、アミノ基、アルキルアミノ基、ハロゲン原子、フッ化アルキル基、フッ化アルコキシ基、ニトロ基、またはシアノ基；R₄は、置換基を有していてもよいアルコキシカルボニル基またはカルボキシ基である］
で表される化合物またはその塩が提供される。As a more preferred embodiment of the compound according to the present invention, the following formula (II):

[In the formula (II), R ₁ is a hydrogen atom or a halogen atom; R ₂ and R ₃ independently have a hydrogen atom, a hydroxy group, an alkoxy group which may have a substituent, or a substituent. An aryloxy group which may have a substituent, an alkyl group which may have a substituent, an aryl group which may have a substituent, an aralkyl group which may have a substituent, and a substituent. An alkaryl group, an alkylamide group, an amino group, an alkylamino group, a halogen atom, a fluorinated alkyl group, a fluorinated alkoxy group, a nitro group, or a cyano group; R ₄ may have a substituent. An alkoxycarbonyl group or a carboxy group]
Or a salt thereof is provided.

In the above formula (II), R ₁ is preferably a hydrogen atom or a halogen atom, more preferably a hydrogen atom or a fluorine atom, R ₂ and R ₃ are preferably a methoxy group, and R ₄ is preferably a methoxycarbonyl group. It is.

As a further preferred embodiment of the compound according to the present invention, a compound in which R ₁ in the above formula (II) is a hydrogen atom or fluorine, R ₂ and R ₃ are methoxy groups, and R ₄ is a methoxycarbonyl group, or a compound thereof Mention may be made of salts. These compounds are represented by the following formulas (III) and (IV), respectively.

  The salt of the compound according to the present invention is preferably a pharmacologically acceptable salt. For example, a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, basic or acidic Examples include salts with amino acids. The term “pharmacologically acceptable salt” is used synonymously with the term “pharmaceutically acceptable salt” and means a salt that can be used as a pharmaceutical product. Specifically, as a suitable example of a salt with an inorganic base, a salt with an organic base, and a salt with a basic amino acid, a salt with an inorganic base such as sodium, potassium, magnesium, calcium, aluminum; methylamine, Examples thereof include salts with organic bases such as ethylamine and ethanolamine; salts with basic amino acids such as lysine and ornithine, and ammonium salts. Preferable examples of salts with inorganic acids, salts with organic acids, and salts with acidic amino acids include salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid. Salt with organic acid such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid; aspartic acid And salts with acidic amino acids such as glutamic acid. Among the above-mentioned salts, sodium salt, potassium salt, hydrochloride and the like are preferable.

  Furthermore, the compounds according to the present invention include hydrates, various pharmacologically acceptable solvates and crystal polymorphs.

  The compound according to the present invention is a derivative of 7-hydroxymitragainin represented by the following formula (V), and can be produced using 7-hydroxymitragain or a derivative thereof as a raw material.

  For example, the compound represented by the above formula (III) can be produced by adding 7-hydroxymitragain to sodium tetrahydroborate and allowing it to react (see Example 1). In addition, the compound represented by the above formula (IV) can be produced by reacting 10-fluoro-7-hydroxymitragain with sodium tetrahydroborate (see Example 1). By using 7-hydroxymitragainin having a substituent different from fluorine at the 10-position instead of 10-fluoro-7-hydroxymitragain, the same reaction is carried out, and the above formula (IV) is used. In such a compound, a compound having a substituent different from fluorine at the 10-position can be synthesized. 7-Hydroxymitragainin can be obtained by natural isolation or chemical synthesis (Ponglux D. et al., “Planta Medica”, 1994, Vol. 60, No. 6, p. 580-581; Ishikawa H. et al., “Tetrahedron Letters”, 2002, Vol. 43, No. 32, p. 5637-5639; and Non-Patent Document 1). 7-Hydroxymitragainin having a substituent at the 10-position, for example, 10-fluoro-7-hydroxymitragain, can be obtained by chemical synthesis using mitragainin as a raw material (Non-patent Document 3). Mitoragainin can be obtained by separation from nature or by chemical synthesis (Ponglux D. et al., “Planta Medica”, 1994, Vol. 60, No. 6, p. 580-581; Takayama (Takayama H.) et al., “Tetrahedron Letters”, 1995, Vol. 36, No. 51, p.9337-9340).

  The compound according to the present invention or a salt thereof can be used in the production of a pharmaceutical composition. That is, in the present invention, a pharmaceutical composition containing the present compound or a salt thereof as an active ingredient and an effective amount thereof can be provided. The pharmaceutical composition according to the present invention may contain one or a combination of two or more of the above compounds or salts thereof. In addition to the above compound or a salt thereof, it can further contain a drug necessary for treatment.

  The compound according to the present invention has a strong analgesic action. Specifically, the compound represented by the above formula (III) and the compound represented by the above formula (IV) are administered orally and subcutaneously in a mouse tail flick test well known as a method for evaluating analgesic effect. All of these showed a strong analgesic effect in a dose-dependent manner. The analgesic effects of these compounds were about 50 times and about 240 times, respectively, in oral administration compared to the efficacy of morphine (see Example 2). Based on the results of studying the effects of opioid receptor antagonists on the analgesic action of these compounds, the strong analgesic action of these compounds is considered to be the addition or cooperation of agonistic action on both the μ and δ opioid receptors. Can do. Specifically, the analgesic effects of these compounds were completely suppressed by naloxone, a non-selective opioid antagonist. In addition, the analgesic action of these compounds was remarkably suppressed by β-funaltrexamine, which is a μ opioid receptor selective antagonist, and moderately suppressed by naltrindole, a δ opioid receptor selective antagonist. . On the other hand, nor-vinaltolfimine, a selective κ opioid receptor selective antagonist, had no effect on the action of these compounds.

  Furthermore, the compound represented by the above formula (III) and the compound represented by the above formula (IV) showed a strong analgesic effect in both neuronal pain model mice by oral administration and subcutaneous administration. Neuropathic pain is pain resulting from nerve damage, and is an intractable condition that exhibits symptoms such as hyperalgesia, allodynia, and spontaneous pain. Allodynia refers to sensory abnormalities that are all accepted as pain even for stimuli that do not naturally cause pain. All of these compounds suppressed hyperalgesia and allodynia in neuropathic pain model mice and exhibited strong analgesic effects. The analgesic effect in this model mouse by subcutaneous administration of the compound represented by the above formula (III) and the compound represented by the above formula (IV) was about 50 times and about 200 times that of morphine, respectively. (See Example 4). From these results, it became clear that all of these compounds are remarkably effective for the analgesia of neuropathic pain. It is known that opioid analgesics such as morphine and nonsteroidal analgesics are ineffective for neuropathic pain. Therefore, these compounds can be considered extremely useful in the treatment of neuropathic pain.

  Therefore, the compound according to the present invention or a salt thereof can be used in the production of an analgesic. That is, in this invention, this compound or its salt can be used as an active ingredient, and the analgesic agent containing those effective amounts can be provided. The analgesic according to the present invention can contain one or a combination of two or more of the above compounds or salts thereof. In addition to the above-mentioned compound or a salt thereof, another drug having an analgesic effect can be further included.

  Since the compound according to the present invention has a stronger analgesic action than morphine, it can be effectively used in various analgesic treatments as an analgesic agent replacing morphine. Furthermore, this compound exhibits a sufficient analgesic effect upon oral administration. Therefore, the burden on the patient who receives the analgesic treatment can be reduced. Thus, according to the present invention, an analgesic treatment method characterized by using the above compound or a salt thereof can be carried out. The use of the above compound or a salt thereof can be achieved, for example, by administering an analgesic containing the above compound or a salt thereof to a subject in need of analgesic treatment, specifically, a subject having pain.

  The term “analgesic” as used herein means the reduction or elimination of pain.

  The term “pain” refers to an unpleasant sensation and emotional experience associated with or described with respect to substantial or potential damage to tissue. Pain includes cancer pain, inflammatory pain, neuropathic pain, postoperative pain, and idiopathic pain that is unexplained pain, such as phantom limb pain. More specifically, cancer diseases, herpes virus infections, human immunodeficiency virus infections, diabetes, hypothyroidism, uremia, causalgia, peripheral nerve trauma, plexus distraction, limb amputation, and pain due to vasculitis It can be illustrated.

  The term “treatment” as used herein means a reduction in the severity and / or frequency of symptoms. Thus, “analgesic treatment” means a reduction in the severity and / or frequency of pain in an individual.

  The term “subject” is used interchangeably with the term “living body” or the term “patient”.

  The compound according to the present invention also has superior characteristics compared to morphine in terms of side effects. The term “side effect” means that the drug is used separately from the main action of the drug that achieves the purpose when the drug is used at a normal use amount for the purpose of disease prevention, diagnosis, treatment or modification of physiological function. Means any adverse reaction caused to the administration subject. Opioid analgesics such as morphine have various side effects due to continuous use. For example, a powerful gastrointestinal motility suppressing action appears, and as a result, a side effect that causes great pain for patients such as constipation appears. Morphine was administered to mice and the analgesic effect and gastrointestinal motility inhibitory effect were measured. In both oral and subcutaneous administration, the analgesic dose was about 5 times the gastrointestinal motility inhibitory dose (implemented). (See Example 3). This indicates that the analgesic effect of morphine can only be obtained by taking about five times the dose that causes constipation. On the other hand, in the compound represented by the above formula (III) and the compound represented by the above formula (IV), the analgesic action dose by oral administration was about half of the gastrointestinal motility inhibitory action dose (see Example 3). ). This indicates that constipation does not appear unless these compounds are ingested at doses approximately twice the dose that causes analgesia. In addition, the analgesic dose by subcutaneous administration of these compounds was similar to that of the gastrointestinal motility inhibitory dose (see Example 3). Thus, the compound according to the present invention has a weak gastrointestinal motility inhibitory action at an analgesic dose, and therefore, compared to an opioid compound having a very strong gastrointestinal motility inhibitory action at an analgesic dose like morphine, It can be used as an opioid analgesic with reduced side effect of constipation caused by gastrointestinal motility suppression.

  The pharmaceutical composition and analgesic according to the present invention contain the above-mentioned compound or a salt thereof as an active ingredient, and may contain a pharmaceutical carrier generally used for pharmaceutical production as required. Pharmaceutical carriers include excipients, disintegrants, diluents, lubricants, flavoring agents, colorants, sweeteners, corrigents, suspending agents, wetting agents, emulsifiers, dispersants, adjuvants, preservatives Examples include agents, buffers, binders, stabilizers, coating agents, and the like.

  As the administration route, either systemic administration or local administration can be selected. In this case, an appropriate administration route is selected according to the disease, symptoms and the like. The analgesic according to the present invention can be administered by either oral route or parenteral route, but has higher bioavailability compared to morphine, and sufficient analgesic effect can be obtained by oral administration. Since the burden on the patient is small, it is preferably administered by the oral route. Examples of parenteral routes include normal intravenous administration and intraarterial administration, as well as subcutaneous, intradermal and intramuscular administration. Furthermore, transmucosal administration or transdermal administration can be performed.

  The dosage form is not particularly limited, and various dosage forms such as tablets, capsules, powders, granules, pills, solutions, emulsions, suspensions, solutions, spirits, for oral administration, Syrups, extracts, and elixirs can be used. Examples of parenteral preparations include injections such as subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections; patches, ointments or lotions for transdermal administration; Sublingual, oral patch; aerosol for nasal administration; and suppository, but is not limited to these. Further, it may be a sustained dosage form or a sustained release dosage form. These preparations can be produced by known methods usually used in the preparation process.

  When preparing an oral solid preparation, an excipient, if necessary, a binder, a disintegrant, a lubricant, a coloring agent, a corrigent, a flavoring agent and the like are added to the above-mentioned compound or a salt thereof, followed by a conventional method. Thus, tablets, coated tablets, granules, powders, capsules and the like can be produced. Such additives may be those commonly used in the art. For example, excipients include lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, silicic acid As a binder, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropyl starch, methylcellulose, ethylcellulose, shellac, calcium phosphate, polyvinylpyrrolidone, etc. Disintegrants include dry starch, sodium alginate, agar powder, sodium bicarbonate, calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride, lactose, and lubricants such as purified talc, stearin Salts, borax, polyethylene glycol and the like, as the corrigent sucrose, orange peel, citric acid, can be exemplified tartaric acid.

  When preparing an oral liquid preparation, an oral solution, a syrup, an elixir, etc. can be produced by adding a corrigent, a buffer, a stabilizer, a corrigent and the like to the above compound or a salt thereof by a conventional method. . In this case, the flavoring agents may be those listed above, examples of the buffer include sodium citrate, and examples of the stabilizer include tragacanth, gum arabic, and gelatin.

  When preparing injections, add pH adjusters, buffers, stabilizers, tonicity agents, local anesthetics, etc. to the above compounds or salts thereof, and then inject subcutaneously, intramuscularly and intravenously using conventional methods. Agent can be produced. In this case, examples of the pH adjuster and buffer include sodium citrate, sodium acetate, and sodium phosphate. Examples of the stabilizer include sodium pyrosulfite, ethylenediaminetetraacetic acid (EDTA), thioglycolic acid, and thiolactic acid. Examples of local anesthetics include procaine hydrochloride and lidocaine hydrochloride. Examples of isotonic agents include sodium chloride and glucose.

When preparing a suppository, a known pharmaceutical carrier such as polyethylene glycol, lanolin, cocoa butter, fatty acid triglyceride, etc., if necessary, a surfactant such as Tween ^{(registered trademark)} is used. After adding an agent etc., it can manufacture by a conventional method.

  When preparing an ointment, bases, stabilizers, wetting agents, preservatives and the like that are commonly used for the above-mentioned compounds or salts thereof are blended as necessary, and mixed and formulated by a conventional method. Examples of the base include liquid paraffin, white petrolatum, white beeswax, octyldodecyl alcohol, and paraffin. Examples of the preservative include methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, and the like. Creams, gels, pastes and the like can be similarly formulated.

  When producing a patch, the ointment, cream, gel, paste and the like may be applied to a normal support by a conventional method. As the support, a woven fabric, nonwoven fabric, soft vinyl chloride, polyethylene, polyurethane film or foam sheet made of cotton, suf, chemical fiber is suitable.

  The dose range is not particularly limited, and the effectiveness of the ingredients contained, dosage form, administration route, type of disease, subject nature (such as body weight, age, medical condition and use of other medicines), and the physician's It is appropriately selected depending on the judgment. In general, a suitable dose is, for example, in the range of about 0.01 μg to 100 mg, preferably about 0.1 μg to 1 mg, per kg of the subject's body weight. However, these dose modifications can be made using general routine experimentation for optimization well known in the art. The above dose can be administered once to several times a day. Alternatively, it is possible to take an administration form such as administration when pain occurs.

  EXAMPLES Hereinafter, although an Example is shown and this invention is demonstrated more concretely, this invention is not limited at all by the Example shown below.

Compound 1 and compound 2 were synthesized. This will be described below.

  The raw materials 7-hydroxymitragainin and 10-fluoro-7-hydroxymitragainin were obtained by chemical synthesis according to the method described previously (Ishikawa H. et al., “Tetrahedron Letters) ", 2002, Vol. 43, No. 32, p.5637-5639, Non-Patent Document 1, and Non-Patent Document 3).

  Compound 1 was synthesized as follows. 7-Hydroxymitragainin (37.5 mg, 0.091 mmol) was added to dry methanol (1.1 mL), and sodium tetrahydroborate (4.3 mg, 0.11 mmol) was added at 0 ° C. under an argon atmosphere. After 30 minutes, distilled water was added to the reaction mixture. The reaction mixture was concentrated under reduced pressure, poured into saturated aqueous sodium bicarbonate and the entire mixture was extracted 3 times with 5% methanol / chloroform. The extracts are combined, washed with brine, dried over magnesium sulfate and evaporated, and the residue obtained is purified by silica gel column chromatography (ethyl acetate / n-hexane = 35: 65) and then crystallized with ethyl acetate. To give 26.3 mg of compound 1 (70% yield).

The analysis data of the product is described below. Compound 1; melting point: 219-223 ° C. (ethyl acetate). UV (MeOH) λmax nm (log ε): 288 (3.13), 277 (3.06), 239 (4.16), 232 (4.14), 214 (4.50). ^{IR (KBR) νmax cm -1:} . 3341,2954,1698,1614,1467,1283 1 H-NMR (500 MHz, CDCl 3) δppm: 7.40 (1H, s, H-17), 7.00 (1H, dd , J = 8.1, 8.1 Hz, H-11), 6.35 (1H, d, J = 7.9 Hz, H-12), 6.31 (1H, d, J = 8.2 Hz, H-10), 3.87 (1H, br .s, N _a -H), 3.83 (3H, s, 9-OCH ₃ ), 3.80 (3H, s, 17-OCH ₃ ), 3.70 (3H, s, 22-OCH ₃ ), 3.47 (1H, br .s, H-2), 2.95 (2H, m, H-15 and H-21), 2.94 (1H, s, 7-OH), 2.53 (2H, m, H-5 and H-14), 2.25 (1H, ddd, J = 12.3, 12.3, 2.3 Hz, H-5), 2.16 (2H, m, H-3 and H-21), 2.03 (1H, d, J = 14.3 Hz, H-6), 1.92 (1H, ddd, J = 13.6, 13.6, 4.3 Hz, H-6), 1.79 (1H, m, H-19), 1.58 (1H, br.d, J = 11.3 Hz, H-20), 1.39 (1H, d, J = 12.8 Hz, H-14), 1.23 (1H, m, H-19), 0.85 (3H, dd, J = 7.3, 7.3 Hz) ^{_{. H 3 -18) 13 C-}} NMR (125 MHz, CDCl 3) δppm: 169.1 (C-22), 160.3 (C-17), 155.9 (C-9), 149.9 (C-13), 129.3 (C -11), 121.3 (C-8), 111.8 (C-16), 105.2 (C-12), 101.9 (C-10), 77.1 (C-7), 69.8 (C-2), 61.6 (17- OCH ₃ ), 61.6 (C-3), 58.5 (C-21), 55.1 (9-OCH ₃ ), 51.2 (22-OCH ₃ ), 50.7 (C-5), 40.7 (C-20), 40.2 ( C-15), 35.2 (C-6), 28.5 (C-14), 19.1 (C-19), 13.1 (C-18). EI-MS (%) m / z: 416 (M ⁺ , 61) , 400 (96), 399 (100), 398 (97), 397 (78), 383 (41), 256 (64), 214 (84). Anal. Calcd for C ₂₃ H ₃₂ O ₅ N ₂ : C , 66.32; H, 7.74; N, 6.73. Found: C, 66.08; H, 7.77; N, 6.71. CD (c = 0.29 mM, MeOH, 24 ° C.), Δε (λnm): 0 (318), +1.4 (293), 0 (257), -1.0 (248), 0 (233), +0.2 (231), 0 (227), -7.7 (215), +0.1 (208).

  Compound 2 was synthesized as follows. To a stirred solution of 10-fluoro-7-hydroxymitragain (23.7 mg, 0.055 mmol) in dry methanol (0.5 mL) was added sodium tetrahydroborate (2.1 mg, 0.056 mmol) at 0 ° C under an argon atmosphere. And the reaction mixture was stirred for 30 minutes. After adding distilled water, the reaction mixture was poured into saturated aqueous sodium bicarbonate solution. The whole mixture was extracted 3 times with 5% methanol / chloroform. The combined extracts were washed with brine, dried over magnesium sulfate and evaporated, and the residue obtained was purified by amino silica gel column chromatography (ethyl acetate / n-hexane = 1: 1) to yield 22.6 mg of compound 2 was obtained (95% yield).

The analysis data of the product is described below. Compound 2; UV (MeOH) λmax nm (log ε): 297 (3.13), 276 (3.10), 240 (4.22), 226 (4.11), 205 (4.60). IR (KBr) νmax cm ⁻¹ : 3364, ^{. 2947,1701,1626,1490,1284,1240 1 H-NMR (500} MHz, CDCl 3) δppm: 7.41 (1H, s, H-17), 6.76 (1H, dd, J = 12.8,8.2 Hz, H -11), 6.28 (1H, dd, J = 8.5, 3.1 Hz, H-12), 4.01 (3H, d, J = 2.7 Hz, 9-OCH ₃ ), 3.79 (3H, s, 17-OCH ₃ ) , 3.69 (3H, s, 22-OCH ₃ ), 3.46 (1H, d, J = 3.1 Hz, H-2), 2.95 (2H, m, H-15 and H-21), 2.77 (1H, br. s, 7-OH), 2.52 (2H, m, H-5 and H-14), 2.25 (1H, m, H-5), 2.15 (2H, m, H-3 and H-21), 1.95 ( 2H, m, H-6), 1.76 (1H, m, H-19), 1.58 (1H, br.d, J = 11.3 Hz, H-20), 1.37 (1H, d, J = 12.8 Hz, H -14), 1.23 (1H, m, H-19), 0.84 (3H, dd, J = 7.3, 7.3 Hz, H3-18). ¹³ C-NMR (125 MHz, CDCl ₃ ) δ ppm: 169.0 (C- 22), 160.3 (C-17), 148.4 (d, J = 237.4 Hz, C-10), 145.1 (C-13), 143.2 (d, J = 11.9 Hz) C-9), 126.8 (C-8), 116.4 (d, J = 21.5 Hz, C-11), 111.7 (C-16), 105.8 (d, J = 6.9 Hz, C-12), 77.4 (C -7), 70.0 (C-2), 61.6 (17-OCH ₃ ), 61.4 (C-3), 61.2 (d, J = 7.8 Hz, 9-OCH ₃ ), 58.4 (C-21), 51.2 ( 22-OCH ₃ ), 50.5 (C-5), 40.7 (C-20), 40.1 (C-15), 35.2 (C-6), 28.4 (C-14), 19.0 (C-19), 13.1 ( C-18). CD (c = 0.26 mM, MeOH, 24 ° C.), Δε (λ nm): 0 (337), +2.7 (297), 0 (255), -4.2 (236), -3.8 (227) , -8.4 (214), +0.1 (207). FAB-MS (NBA) m / z: 435 [M + H] ⁺ . HR-FAB-MS (NBA / PEG): calcd. For C ₂₃ H ₃₂ O ₅ N ₂ F: 435.2295, found: 435.2301.

  The analgesic action of Compound 1 and Compound 2 synthesized in Example 1 was examined. This will be described below.

(Experimental materials and methods)
1． Male ddY mice (Nippon SLC Co., Ltd.) having an animal weight of 25 to 33 g and male Hartley guinea pigs (Nippon SLC Co., Ltd.) having a weight of 320 to 550 g were used.

2． For the compound guinea pig ileal contraction test, Compound 1 and Compound 2 were each dissolved in 100% dimethyl sulfoxide to obtain a 5 mM solution, and then diluted with distilled water. For the mouse tail flick test, Compound 1 and Compound 2 were each dissolved in 25 mM phosphate buffer (pH 5.3 to 5.5). As controls, morphine and 7-hydroxymitragainin were used.

3． Guinea pig ileal contraction test The guinea pig ileum was removed and Krebs-Henseleit solution (112.08 mM NaCl; 5.90 mM KCl; 1.97 mM CaCl ₂ ; 1.18 mM MgCl ₂ ; 1.22 mM NaH ₂ PO ₄ ; 25.00 mM NaHCO ₃ ; and 11.49 mM glucose) I put it inside. 1 g tension was applied to the ileum in a 5 ml organ bath containing nutrient solution. The organ bath was kept at 37 ° C. and a mixture of 95% O ₂ and 5% CO ₂ was continuously aerated. The tissue was stimulated with a platinum needle ring electrode (the ring was placed 20 mm above the base of a 5 mm long needle). After equilibration, the ileum was transmurally stimulated with a stimulator (SEN-7203, Nippon Koden Kogyo Co., Ltd.) with a single phase pulse (0.2 Hz and duration of 0.1 ms). Shrinkage was recorded isotonically using a displacement transducer (NEC 45347, NEC Sanei Co., Ltd.). We examined the effect of drug treatment on twitching induced by transmural stimulation induced through a ring electrode. The height of twitch response to transmural stimulation was measured before and after drug treatment. The reaction was expressed as the inhibition rate (%) of the twitch response to transmural stimulation before the drug treatment.

Four. Tail Flick Test The tail flick test is a method for evaluating the analgesic effect of a compound by giving nociceptive stimuli, for example, thermal stimuli, to the tails of mice and rats and using the escape reflex by the stimuli as an index. Because the mouse swings and moves its tail from the stimulation pathway in response to thermal stimulation, the photo installed on the tail flick analgesic effect measuring device (Ugo Basile Tail-flick Unit 7360, Ugo Basile) directly under the tail The tail is exposed to the cell. The reaction time is automatically recorded. Prior to treatment with drug, solvent, or saline, nociceptive thresholds were measured three times and the average response time for each mouse was used as the pre-drug latency. In order to prevent tissue damage, the maximum stimulation time (cut-off time) was 10 seconds. Analgesia was quantified using the maximum acceptable effect rate (% MPE). % MPE was calculated by the following formula:% MPE = [(latency after drug treatment−latency before drug treatment) / (maximum stimulation time−latency before drug treatment)] × 100.

Five. Statistical analysis data were expressed as mean ± standard error. Statistical analysis was performed by Student's two-tailed t-test for comparisons between two groups, and one-way analysis of variance followed by Bonferroni's multiple comparisons for comparisons between two or more groups. When the P value was <0.05, it was determined to be statistically significant. ED ₅₀ values and 95% confidence limits were determined using the Richfield-Wilcoxon method.

(result)
1． Effect on guinea pig ileal contraction Compound 1 and Compound 2 exhibited a contraction-inhibiting action about 12 times and about 45 times that of morphine in the guinea pig ileal contraction test, respectively (Table 1). These inhibitory effects were completely suppressed by naloxone, a non-selective opioid antagonist (data not shown). From these results, it was shown that opioid receptors are involved in the analgesic action of Compound 1 and Compound 2. In addition, the maximum inhibition rate of these effects was almost the same as that of morphine (Table 1). From these results, it was found that the action of Compound 1 and Compound 2 is a full agonist. From this, it was estimated that both Compound 1 and Compound 2 have a strong analgesic action.

Table 1 shows the opioid effect of compounds on twitch contraction induced by electrical stimulation in the isolated guinea pig ileum. The effect is expressed as a pD ₂ value which is the negative logarithm of the concentration required to produce 50% of the maximum response of each compound (EC ₅₀ ). The relative effects are expressed as percentage of the pD ₂ value of morphine pD ₂ value for each compound. The maximum inhibition (%) is the inhibition when the reaction caused by the compound reaches a flat state, and the twitching is calculated as 100%. Relative maximal activity refers to intrinsic activity at the opioid receptor and is expressed as the percentage of maximum inhibition by each compound relative to the maximum inhibition of morphine. Each value is expressed as the mean value ± standard error of data obtained from 5 to 6 animals.

2． Effect in Tail Flick Test Compound 1 and Compound 2 exhibited a strong analgesic effect in a dose-dependent manner in the tail flick test when administered orally (FIG. 1). Table 2 shows the ED ₅₀ values required for analgesic action by oral administration of Compound 1, Compound 2, 7-Hydroxymitragain, and Morphine together with 95% confidence limits.

  Compound 1 and Compound 2 exhibited analgesic effects approximately 50-fold and 240-fold greater, respectively, compared to the efficacy of morphine when administered orally.

Similarly, Compound 1 and Compound 2 exhibited analgesic action about 15 times and about 70 times stronger than morphine potency, respectively, even when administered subcutaneously (FIG. 2). Table 3 shows the ED ₅₀ values required for the analgesic effect of Compound 1, Compound 2, 7-Hydroxymitragainin, and morphine by subcutaneous administration, along with 95% confidence limits.

3． The opioid receptor type selectivity of analgesic effects elicited by action site compounds 1 and 2 was examined in a mouse tail flick test using non-selective or selective opioid receptor antagonists. As a result, the analgesic effects of Compound 1 and Compound 2 administered subcutaneously were completely suppressed by naloxone, which is a non-selective opioid antagonist (data not shown). From these results, it was shown that opioid receptors are involved in the analgesic action of Compound 1 and Compound 2. In addition, the analgesic effects of Compound 1 and Compound 2 were markedly antagonized by β-funaltrexamine, which is a μ opioid receptor selective antagonist. Antagonized (Figures 3 and 4 respectively). On the other hand, nor-vinaltolfimine, a selective κ opioid receptor selective antagonist, had no effect on these effects. From these results, it was clarified that the strong analgesic action of Compound 1 and Compound 2 was the addition or cooperation of agonistic action on both μ and δ opioid receptors.

  The side effects of Compound 1 and Compound 2 synthesized in Example 1 were compared with those of morphine. Because opioid analgesics such as morphine are used continuously, a strong inhibitory effect on gastrointestinal transit (IGIT) appears, and the side effect of constipation becomes a major pain for patients. Therefore, Compound 1 and Compound 2 are expected to reduce this side effect. Thus, the gastrointestinal inhibitory action observed by oral administration of Compound 1 and Compound 2 was compared with that of morphine using the mouse charcoal powder transport method. This will be described below.

(Experimental materials and methods)
1． Compound 1 and Compound 2 were prepared by a method similar to that described in Example 2. As comparative specimens, morphine and 7-hydroxymitragainin were used.

2． Measurement of mouse small intestine charcoal transport ability The specimens were subcutaneously or orally administered to mice fasted for 18 hours under free drinking water. In the case of oral administration of morphine hydrochloride, 30 minutes later, for other specimens, 0.25 ml of 5% gum arabic and 10% activated carbon powder suspension (charcoal meal) is orally administered to mice 15 minutes after subcutaneous administration or oral administration. Administered. The mice of the control group were administered with the solvent of each sample subcutaneously or orally, and charcoal meal was orally administered after the same fixed time as the respective sample administration group. 30 minutes after oral administration of charcoal meal, dislocation of the cervical vertebrae, immediately laparotomy, excision of the entire small intestine (from the gastric pylorus to the ileocecum), the distance from the entire small intestine and the pylorus to the tip of the charcoal meal Was measured. The ratio of charcoal meal travel distance to charcoal meal relative to the entire length of the small intestine (charcoal powder transport rate%) was determined, and the gastrointestinal motility inhibition rate was calculated by the following formula. Gastrointestinal motility inhibition rate (%) = [(control charcoal transport rate-specimen charcoal transport rate) / (control charcoal transport rate)] × 100.

(result)
As shown in FIG. 5, oral administration of Compound 1 and Compound 2 showed a stronger gastrointestinal inhibitory action than morphine. This suggests that Compound 1 and Compound 2 will have constipation side effects as well as morphine. However, this gastrointestinal motility inhibitory effect must be compared and evaluated in relation to analgesic dose.

95% confidence limit (shown in parentheses) for ED ₅₀ (mg / kg) of oral dose required for analgesic and gastrointestinal motility-inhibiting effects of Compound 1, Compound 2, 7-Hydroxymitragain and Morphine The results are shown in Table 4. In Table 4, tail-flick indicates the analgesic action measured by the mouse tail flick test, and IGIT shows the gastrointestinal motility inhibitory action measured by the mouse terminal transport method.

  As shown in Table 4, the analgesic dose of morphine is about 5 times that of the gastrointestinal motility-inhibiting dose, which means that morphine's analgesic effect can only be obtained when taking about 5 times the dose that causes constipation. It is not possible.

  On the other hand, in both Compound 1 and Compound 2, the analgesic dose is about half that of the gastrointestinal motility-inhibiting dose, which means that Compound 1 and Compound 2 take about twice the dose that causes analgesic effect. If you do not, constipation will not appear.

  Similarly, the gastrointestinal inhibitory action observed by subcutaneous administration of Compound 1 and Compound 2 was compared with that of morphine using the mouse charcoal powder transport method. Similar results were obtained with subcutaneous administration of Compound 1 and Compound 2 as shown in FIG. That is, oral administration of Compound 1 and Compound 2 showed a stronger gastrointestinal inhibitory action than morphine.

95% confidence limit (shown in parentheses) for the ED ₅₀ (mg / kg) value of subcutaneous dose required for the analgesic and gastrointestinal motility-inhibiting effects of Compound 1, Compound 2, 7-Hydroxymitragainin, and Morphine The results are shown in Table 5. In Table 5, tail-flick indicates the analgesic action measured by the mouse tail flick test, and IGIT shows the gastrointestinal motility inhibitory action measured by the mouse terminal transport method.

  As shown in Table 5, the analgesic dose of morphine was about 5 times the gastrointestinal motility inhibitory dose. On the other hand, in both Compound 1 and Compound 2, the analgesic dose and the gastrointestinal motility inhibitory dose were similar.

  From these results, it became clear that Compound 1 and Compound 2 can be opioid analgesics with reduced side effects of constipation compared to morphine.

  The analgesic action of Compound 1 and Compound 2 synthesized in Example 1 was examined using neuropathic pain model mice. This will be described below.

(Experimental materials and methods)
1． Neuropathic pain model mouse The neuropathic pain model mouse is a male ddY mouse (Japan SLC Co., Ltd.), and the right sciatic nerve is surrounded by 1/3 to 1/2 of its diameter. Made by tightly ligating with 8-0 silk suture. As a control mouse, a mouse subjected to a sham operation that exposes the sciatic nerve but does not perform ligation was used. Mice were used for each test 7 days after surgery.

2． Compound 1 and compound 2 were used after being dissolved in 25 mM phosphate buffer (pH 5.3 to 5.5). Further, morphine, 7-hydroxymitragainin, and a compound represented by the following formula (VI) which is a 7-hydroxymitragaine derivative (hereinafter referred to as compound 3) were also examined in the same manner. As a control, physiological saline was used.

3. Hyperalgesia test by thermal stimulation The analgesic effect on hyperalgesia in neuropathic pain model mice is the sensitivity of the mice to thermal stimulation, that is, the time from the application of thermal stimulation to the withdrawal of the hind limbs (hereinafter referred to as the pain sensation latency). Was evaluated as an index. Specifically, heat stimulation was applied to the sole of the restrained mouse on the ipsilateral hind limb, and the time from when the heat stimulation was applied until the hind limb was retracted was measured by the thermal stimulation analgesic effect measuring device (UGO-BASILE, Biological research apparatus). The measurement was performed using The intensity of thermal stimulation was adjusted so that the average criterion for pain latency in untreated mice was 10 seconds. Leg movements and weight shifts related to walking were not counted as responses. The pain latency after thermal stimulation was measured twice or three times and the average was shown.

Four. Allodynia test by mechanical stimulation The analgesic action of neuropathic pain model mice against allodynia was evaluated using the mouse response to mechanical stimulation and the escape reflex by stimulation as indices. Specifically, a mouse is placed in an individual small chamber made of transparent Perspex ^{(registered trademark)} and having a metal mesh bottom, and a series of standardized von Frey filaments (manufactured by North Coast Medical) are used. 50% of reactions withdrawing the hind limb by Dixon's up-down method (Dixon WJ “Annual Review of Pharmacolgy and Toxicology”, 1980, Volume 20, p. 441-462) The threshold was measured. The eight selected von Frey filaments have a logarithmic increase in their bending strength (von Frey numbers: 2.36, 2.44, 2.83, 3.22, 3.61, 3.84, 4.08, and 4.17; 0.02, 0.03, 0.07, respectively) , 0.17, 0.41, 0.69, 1.20, and 1.48 g strength). Measurements were initiated with 0.17 g of filament and each filament was brought into perpendicular contact with the plantar surface of the right hind limb and sufficient force was applied for 3-4 seconds to bend the filament. Lifting the limb indicated a positive response, in which case it was tested with the next weaker or lighter filament. When no reaction to retract the hind limb was observed, the next stronger or heavier filament was used for testing. Continue these experiments until you achieve 4 measurements after the first behavior change, or until you get 4 consecutive negative scores (score 0.01 g) or 5 positive scores (score 1.5 g) did. Using the obtained score, the method described in the report of Chaplan et al. (Chaplan SR et al., “Journal of Neuroscience Methods”, 1994, Vol. 53, p. 55-63), the 50% threshold was calculated.

(result)
1． Effect in Hyperalgesia Test by Thermal Stimulation Neuropathic pain model mice are more responsive to thermal stimuli and have shorter pain latencies than control mice. Both Compound 1 and Compound 2 decreased the responsiveness to thermal stimulation of neuropathic pain model mice by subcutaneous administration (FIGS. 7 and 8 respectively). Specifically, Compound 1 and Compound 2 were administered subcutaneously at 0.2 mg / kg and 0.05 mg / kg, respectively, to extend the pain latency of neuropathic pain model mice to the same level as that of control mice. . Furthermore, Compound 1 and Compound 2 were administered subcutaneously at 0.4 mg / kg and 0.1 mg / kg, respectively, to extend the pain latency of neuropathic pain model mice from that of control mice. On the other hand, morphine and fentanyl were administered subcutaneously at 5 mg / kg and 0.04 mg / kg, respectively, to extend the pain latency of neuropathic pain model mice to the same level as that of control mice. In addition, Compound 3 prolonged the pain latency of neuropathic pain model mice to the same extent as that of control mice at 0.25 mg / kg by subcutaneous administration.

  The above effect of Compound 2 was examined by oral administration. As a result, oral pain at 0.5 mg / kg prolonged the pain latency in neuropathic pain model mice from that in control mice. (Figure 9-A). This effect was observed even 1 hour after administration of Compound 2 (FIG. 9-B).

  As described above, since both Compound 1 and Compound 2 prolong the pain sensation latency of neuropathic pain model mice, these compounds can suppress hyperalgesia in the model mice and exhibit analgesic action. found. Moreover, it became clear that the analgesic action of these compounds is stronger than that of morphine.

2． Effect in allodynia test by mechanical stimulation The neuropathic pain model mouse is more responsive to mechanical stimulation than the control mouse and has a lower 50% threshold. Both Compound 1 and Compound 2 increased the 50% threshold of responsiveness to mechanical stimulation in neuropathic pain model mice by subcutaneous administration (FIGS. 11-A and 11-B, and FIG. 12-, respectively). A and Figure 12-B). Specifically, Compound 1 and Compound 2 were subcutaneously administered at 0.8 mg / kg and 0.2 mg / kg, respectively, and the 50% threshold in neuropathic pain model mice was equal to or higher than the 50% threshold of control mice. Increased to.

  As mentioned above, both Compound 1 and Compound 2 increased the 50% threshold for mechanical stimulation of neuropathic pain model mice, so both of these compounds suppressed allodynia in the model mice and were analgesic. It turned out to show.

  The above results of examining the analgesic effect on neuropathic pain model mice suggest that both Compound 1 and Compound 2 are effective for the analgesia of neuropathic pain.

Claims (12)

Formula (I):

[Wherein, R ₁ is a hydrogen atom or a halogen atom; R ₂ , R ₃ , R ₄ and R ₅ are independently a hydrogen atom, a hydroxy group, an optionally substituted alkoxy group, or a substituent. An aryloxy group which may have a substituent, an alkyl group which may have a substituent, an aryl group which may have a substituent, an aralkyl group which may have a substituent, a substituent An alkaryl group, an alkylamide group, an amino group, an alkylamino group, a halogen atom, a fluorinated alkyl group, a fluorinated alkoxy group, a nitro group, or a cyano group that may have; R ₆ has a substituent. Which may be an alkoxycarbonyl group or a carboxy group]
Or a salt thereof. 2. The compound or a salt thereof according to claim 1, wherein R ₃ and R ₄ are hydrogen atoms. _3. The compound or a salt thereof according to claim 1, wherein R ₂ and R ₅ are methoxy groups. 4. The compound or a salt thereof according to any one of claims 1 to 3, wherein R ₆ is a methoxycarbonyl group. 5. The compound or a salt thereof according to any one of claims 1 to 4, wherein R ₁ is a hydrogen atom or a fluorine atom. The following formula (II):

[Wherein R ₁ represents a hydrogen atom or a halogen atom; R ₂ and R ₃ independently represent a hydrogen atom, a hydroxy group, an alkoxy group which may have a substituent, or a substituent. A good aryloxy group, an alkyl group which may have a substituent, an aryl group which may have a substituent, an aralkyl group which may have a substituent, and a substituent. An alkaryl group, an alkylamide group, an amino group, an alkylamino group, a halogen atom, a fluorinated alkyl group, a fluorinated alkoxy group, a nitro group, or a cyano group; R ₄ is an optionally substituted alkoxycarbonyl group Or a carboxy group]
Or a salt thereof. 7. The compound or a salt thereof according to claim 6, wherein R ₂ and R ₃ are methoxy groups. 8. The compound or a salt thereof according to claim 6 or 7, wherein R ₄ is a methoxycarbonyl group. 9. The compound or a salt thereof according to any one of claims 6 to 8, wherein R ₁ is a hydrogen atom or a fluorine atom. 10. A pharmaceutical composition comprising the compound according to any one of claims 1 to 9 or a salt thereof as an active ingredient and an effective amount thereof. An analgesic comprising the compound according to any one of claims 1 to 9 or a salt thereof as an active ingredient and containing an effective amount thereof. 10. An opioid analgesic comprising the effective amount of the compound according to any one of claims 1 to 9 or a salt thereof as an active ingredient and having reduced side effects compared to morphine.

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