JP2002255963A - NEW 1-HYDROXYYOHIMBINE OR DERIVATIVE THEREOF HAVING alpha2 RECEPTOR BLOCKING ACTIVITY, METHOD FOR PRODUCING THE SAME AND APPLICATION OF THE SAME - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a yohimbine derivative useful as an α2 receptor blocker. SOLUTION: This new compound (salt thereof) is expressed by the formula (A) (wherein, R is H, an alkyl, alkenyl, aryl or the like). The other objective method for producing the above new compound is provided. A pharmaceutical composition containing the above new compound is also provided.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a novel 1-hydroxyyohimbine or a derivative thereof having an α ₂ receptor blocking effect, a method for producing the same, and a use thereof.

[0002]

_2. Description of the Related Art The α ₂ receptor includes a neural α ₂ receptor and a non-neural α ₂ receptor. Neuronal alpha ₂ receptors are classified into presynaptic alpha ₂ receptors and postsynaptic alpha ₂ receptor, the former, in particular distributed in the peripheral and central noradrenergic nerve terminals inhibits the release of noradrenaline. In addition, it is also distributed in cholinergic and serotonergic nerve terminals and suppresses release of various neurotransmitters. The latter is distributed, for example, in the central nervous system, sympathetic ganglia, noradrenaline nerve dendrites, and the like, and is involved in physiological functions such as antihypertensive / cardiovascular, hyperpolarizing, and neuroexcitation. On the other hand, non-neuronal alpha ₂ receptors platelets distributed in adipose cells, pancreatic islet and vascular endothelial cells and the like, each platelet aggregation inhibitory activity, lipolysis inhibition, physiological functions such as insulin secretion inhibiting action and NO release effect (Ikunobu Muramatsu, Journal of the Japanese Pharmacists Association, 48 (11), 1987 (1996)). Yohimbine as known alpha ₂ receptor blockers, rauwolscine, SL84.0418, midaglizole like are known. Yohimbine is an indole-based alkaloid contained in the bark of the genus Rubiaceae tree Pausinystalia yohimbe or in the plants of the genus Rauorphia.
Rauwolscine is, H to C ₂₀ of yohimbine take place alpha, show a high selectivity for alpha ₂ receptor (Muramatsu Yunobe, Japan Pharmaceutical Association Journal, 48 (11), 1990 (1996)). Also, SL84.0
418 is a racemic mixture of deliglidol (SL86.0715) which is a (+) form and SL86.0714 which is a (-) form. As a result of in vivo and in vitro studies, α ₂
Receptor binding ability and expression of various physiological functions are derived from the (+) form of deliglidol. Midaglizole is an imidazoline derivative (E. Guillot et al,; Life Science
s, 62 (9), 840 (1998)), indicating a high selectivity for alpha ₂ receptors than yohimbine (E. Guillot et al,; Life S
ciences, 62 (9), 851 (1998)). Yohimbine is a drug used as an aphrodisiac (Akio Imagawa et al., Western Japan Urology, 49 (1), 77 (1987)). Currently, erectile dysfunction patients are rapidly increasing due to drugs, adult diseases, malignant tumor surgery and social environment, mental stress and the like. However, its treatment has not been established due to its complicated etiology (Hideki Fuse et al., Pharmaceutical Journal, 33 (7), 1752 (1997)). Recently, sildenafil, a selective inhibitor of phosphodiesterase V, has been developed and is attracting attention as a therapeutic agent for erectile dysfunction (impotence). It is. Sildenafil only improves erectile dysfunction and has no action to restore or increase libido possessed by yohimbine (Pfizer Pharmaceutical Co., Ltd., Viagra Handbook). SL84.0418, especially deliglidol, is expected as a therapeutic agent for non-insulin-dependent diabetes (E. Guillot et al,; Life Sciences, 62 (9), 839 (19
98)). Diabetes is divided into type I diabetes, insulin dependence (IDDM) and type II diabetes, non-insulin dependent (NI
DDM). IDDM is a condition that causes an absolute deficiency of insulin due to enhanced destruction of pancreatic β-cells after cell damage of the pancreatic islets of Langerhans due to an autoimmune mechanism. On the other hand, NIDDM is a condition in which genetic factors are deeply involved and develop with the addition of environmental factors such as obesity, overeating, aging and lack of exercise, and cause a relative deficiency of insulin due to insufficient insulin secretion or insulin resistance. is there. Deliglidol has an effect of promoting insulin secretion, so it is ineffective in IDDM in which insulin is absolutely deficient, but even a small amount may be a therapeutic agent for NIDDM capable of insulin secretion. Deliglidol and SL86.0714 are also ATP-dependent K ⁺
In addition to reversing the insulin secretion inhibitory effect of diazoxide, a channel opener, it has been shown to be equally effective in stimulating insulin secretion. Therefore, these compounds in addition to acting blocking alpha ₂ receptor, which may the ATP-dependent K ⁺ channel has an effect to directly or indirectly closed (E. Gui
llot et al,; Life Sciences, 62 (9), 850 (1998)).
Furthermore, midaglizole has been shown to be effective against non-insulin-dependent diabetes and asthma (Masashi Mizobe, Allergy, 39 (1), 36-41 (1990), Yasumasa Yoshie et al., Therapeutics, 22 ( 5), 551-554 (1989)). Other, α ₂
There have been many reports that receptor blockers have a platelet aggregation inhibitory effect (Haruo Takeda et al., Mochida Memorial Foundation Research Report, 6, 139-143 (1990)).

[0003] As described above, agents having alpha ₂ receptor blocking effect, aphrodisiac, diabetes drug, such as antiasthmatic agents and platelet aggregation inhibitors, which may be used in many applications.
Also, alpha ₂ receptors for expressing a number of tissues and cells, potential use to condition the tissue, cells are involved is large. However, as described above, laurusine in which the C ₂₀ H of yohimbine has the α configuration has high selectivity for the α ₂ receptor, but when the carbomethoxy group of C ₁₆ is in the β configuration, the α ₂ affinity to the body is significantly reduced, only alpha ₁ binding is known to be retained. That is, despite the very structurally similar compounds to the yohimbine is different greatly selectivity for alpha ₂ receptor to the minor differences in such arrangement alpha-configuration or beta. Furthermore, (+), but the body is a Deriguridoru (SL86.0715) expresses various physiological functions bound to alpha ₂ receptor, - which is a body SL86.0714 most alpha ₂ receptor blocking activity () It is clear that they do not. Thus, compounds having alpha ₂ receptor blocking action despite clinical application is opened, the search for compounds having alpha ₂ receptor blocking action from its structural specificity of the problem has been extremely difficult. As for the method for producing the yohimbine derivative, yohimbine (1 in FIG. 1) is reduced with sodium cyanide boron according to the reaction shown in FIG.
It is known that α, 7α-dihydroyohimbine (3 in FIG. 1) is formed respectively (JL Men, LL Oli).
ver, J. Levy, MC Levy-Appert-Colin, and J. Han
nart, Ger. Offen. 2,410,651 [Chem. Abstr., 82, 4364
0u (1975)]). A reaction of synthesizing 1-hydroxyindole with dihydroindole using sodium tungstate dihydrate and a 30% aqueous hydrogen peroxide solution is also known (M. Somei and T. Kawasaki, Heterocycles, 2).
9, 1251 (1989)). Furthermore, a method for synthesizing 1-methoxyyohimbine (8 in FIG. 1) in one step from yohimbine (1 in FIG. 1) via 2α, 7α-dihydroyohimbine (3 in FIG. 1) is also known (H. Takayama). , N. Seki, M. K
itajima, N. Aimi, H. Seki, and S. Sakai, Hetero
cycles, 33, 121 (1992)). However, there is no literature describing the pharmacological activity of compound (8).

[0004]

[0008] The present invention relates to compounds having alpha ₂ receptor blocking action, and an object thereof is to provide a particularly yohimbine derivative.

[0005]

The present inventors have SUMMARY OF THE INVENTION are synthesized various yohimbine derivatives having alpha ₂ receptors blocking action, was subjected to extensive studies, 1-hydroxy yohimbine or derivatives thereof alpha ₂ receptor blockade It has proven useful as a medicine. The present inventors have also established a novel method for synthesizing the derivative. More specifically, the present inventors have found that reduction of yohimbine hydrochloride quantitatively produces only 2α, 7α-dihydroyohimbine (3 in FIG. 1). In addition, the present inventors were able to isolate 1-hydroxyyohimbine (4 in FIG. 1) for the first time. 1-hydroxyyohimbine (4 in FIG. 1) is useful for the synthesis of novel compounds of various derivatives starting from 1-hydroxyyohimbine. Furthermore, 1-hydroxy yohimbine or a derivative thereof were found to have alpha ₂ receptor blocking action.

[0006] That is, the present invention provides (1) Formula (A):

Embedded image [Wherein, R is hydrogen, alkyl having 2 to 10 carbons which may have a substituent, cycloalkyl having 3 to 10 carbons which may have a substituent, Alkenyl having 2 to 10 carbon atoms, cycloalkenyl having 3 to 10 carbon atoms which may have a substituent, alkynyl having 2 to 10 carbon atoms which may have a substituent, An optionally substituted acyl group, an aryl group having 6 to 20 carbon atoms which may have a substituent, an aralkyl group having 7 to 20 carbon atoms which may have a substituent, or a 5 to 7-membered heterocyclic group Or a salt thereof, wherein (2) R is
Hydrogen, each of which may have a substituent, alkyl having 2 to 6 carbons, alkenyl having 2 to 6 carbons, or 7 to 6 carbons
The compound according to the above (1), which is an aralkyl of 10,
(3) The compound according to the above (1), wherein R is selected from hydrogen, allyl group, butyl group and nitrobenzyl, (4)
(5) a process for producing 2α, 7α-dihydroyohimbine, which comprises reducing yohimbine hydrochloride with a reducing agent;
The production method according to the above (4), wherein the reducing agent is sodium boron cyanide or triethylsilane, (6) 2α, 7
(7) a method for producing 1-hydroxyyohimbine, which comprises oxidizing α-dihydroyohimbine with an oxidizing agent;
The production method according to the above (6), wherein the oxidizing agent is a metal peroxide, an organic peroxide, persulfuric acid or peracid. (8) 2α, 7α
Wherein the dihydroyohimbine is obtained by reducing yohimbine hydrochloride with a reducing agent, (9) 1-hydroxyyohimbine and a compound represented by the formula R′-X wherein R ′ is X has the same meaning as in the following formula (A ′), and X represents a halogen.]: A compound represented by the following formula (A ′):

Embedded image [In the formula, R ′ has 2 to 2 carbon atoms which may have a substituent.
10 alkyl, 3 to 3 carbon atoms which may have a substituent
10 cycloalkyl, optionally substituted alkenyl having 2 to 10 carbon atoms, optionally substituted 3 to 10 cycloalkenyl having carbon atoms, optionally substituted carbon atoms Alkynyl having 2 to 10 atoms, an acyl group which may have a substituent, and 6 carbon atoms which may have a substituent
Or an aralkyl group having 7 to 20 carbon atoms which may have a substituent or a 5- to 7-membered heterocyclic group, or a salt thereof.
0) R ′ has 2 carbon atoms which may have a substituent
Wherein R′-X is allyl bromide, butyl iodide, or nitrobenzyl bromide, wherein R′-X is alkyl having 2 to 6 carbon atoms, alkenyl having 2 to 6 carbon atoms, or aralkyl having 7 to 10 carbon atoms. (12) 1-hydroxyyohimbine according to the above (9), wherein
(13) The method according to the above (9), which is obtained by oxidizing α, 7α-dihydroyohimbine with an oxidizing agent.
The above (12), wherein 2α, 7α-dihydroyohimbine is obtained by reducing yohimbine hydrochloride with a reducing agent.
(14) 1-hydroxyyohimbine is dissolved in at least the following steps: 1) methanol, 2)
Add ether solution of diazomethane, 3) Remove solvent,
4) A method for producing 1-methoxyyohimbine, which is dissolved in an elution solvent and 5) is subjected to purification, (15) Formula (A "):

Embedded image [In the formula, R ″ is hydrogen, alkyl having 1 to 10 carbons which may have a substituent, cycloalkyl having 3 to 10 carbons which may have a substituent, Alkenyl having 2 to 10 carbons which may be substituted, cycloalkenyl having 3 to 10 carbons which may have a substituent, alkynyl having 2 to 10 carbons which may have a substituent, An acyl group which may have, an aryl group having 6 to 20 carbon atoms which may have a substituent, an aralkyl group having 7 to 20 carbon atoms which may have a substituent, or a 5 to 7-membered compounds or alpha ₂ receptor blocking pharmaceutical composition characterized by containing a pharmaceutically acceptable salt represented by showing a heterocyclic group], is (16) R ", hydrogen, respectively, Alkyl having 2 to 6 carbons which may have a substituent, 2 to 6 carbons
A pharmaceutical composition according to the above (15), which is alkenyl or aralkyl having 7 to 10 carbon atoms, and (17) R ″
Is a compound selected from hydrogen, an allyl group, a butyl group and nitrobenzyl.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION The “derivative” in the present specification is a derivative of 1-hydroxyyohimbine. That is, a compound represented by the above formula (A ′) in which a hydrogen atom of a hydroxyl group bonded to the 1-position nitrogen atom of 1-hydroxyyohimbine (FIGS. 1 and 4) is substituted by another substituent (R ′) or Refers to its salt. The compound represented by the formula (A ′) is obtained by removing 1-hydroxyyohimbine from the compound represented by the formula (A), and the compounds represented by the formulas (A) and (A ′) and salts thereof are: Are also new substances.
In the compounds represented by the formulas (A) and (A ′) of the present invention, groups represented by R and R ′ other than hydrogen include:
All possible substituents are included. For example, a linear or branched alkyl having 2 to 10 carbon atoms, preferably 2 to 6 carbon atoms, which may have a substituent, or 3 to 10 carbon atoms, preferably 5 carbon atoms, which may have a substituent. ~ 7 cycloalkyl,
Straight-chain or branched-chain carbon number 2 which may have a substituent
Alkenyl having 2 to 6, preferably 2 to 6, cycloalkenyl having 3 to 10 carbon atoms which may have a substituent, and linear or branched carbon atom having 2 to 1 carbon atoms which may have a substituent.
0, preferably 2 to 6 alkynyl, an optionally substituted acyl group, and an optionally substituted 6 carbon atom (s)
To 20, preferably 6 to 10 aryl groups, optionally substituted 7 to 20 carbon atoms, preferably 7 to 10 aralkyl groups or heteroatoms selected from nitrogen, oxygen and sulfur atoms. One or more 5- to 7-membered heterocyclic groups are included.

[0008] Examples of the alkyl group include groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl and n-pentyl. As the cycloalkyl group,
For example, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane and the like can be mentioned.
Alkenyl groups include vinyl, allyl, pentenyl,
Groups such as hexenyl. Examples of the cycloalkenyl group include cyclopentenyl, cyclohexenyl and the like. Examples of the alkynyl group include groups such as ethynyl and propynyl. Examples of the acyl group include an alkylcarbonyl group having a linear or branched alkyl group such as acetyl, propionyl, butyryl, isobutyryl, valeryl, hexanoyl, octanoyl, lauroyl, palmitoyl, and stearoyl. Examples of the aryl group include phenyl and naphthyl. Examples of the aralkyl group include benzyl, phenethyl and the like. Examples of the heterocyclic group include groups such as thienyl, furyl, pyranyl, pyrrolyl, pyrazolyl, thiazolyl, isothiazolyl, isoxazolyl, imidazolyl, pyridyl, pyridinyl, pyrimidinyl, pyridazinyl, oxadiazolyl, thiadiazolyl, triazolyl, and tetrazolyl. These groups are 1
It may have one or more substituents, and these substituents include the same groups as those exemplified for R and R ′, halogen (eg, chlorine, fluorine, iodine, bromine), amino,
Groups such as nitro, hydroxy, and alkoxy having 1 to 10 carbon atoms are included. In particular, in addition to 1-hydroxyyohimbine, R and R 'each may have a substituent, and may have an alkyl having 2 to 6 carbons, an alkenyl having 2 to 6 carbons or an aryl having 6 to 10 carbons. Those which are allyl, n-butyl and nitrobenzyl are preferred.

The salts of the compounds represented by the formulas (A) and (A ') are preferably pharmaceutically acceptable salts, for example, salts with bases such as inorganic bases and organic bases, inorganic acids, Acid addition salts of organic acids, basic or acidic amino acids, and the like can be mentioned. Examples of the inorganic base include alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium, aluminum, and ammonium. As the organic base, for example, primary amines such as ethanolamine, diethylamine, diethanolamine, dicyclohexylamine, N, N'-dibenzylethylenediamine and other secondary amines, trimethylamine,
And tertiary amines such as triethylamine, pyridine, picoline, and triethanolamine. Examples of the inorganic acid include hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. As organic acids, for example, formic acid, acetic acid, lactic acid, trifluoroacetic acid, fumaric acid, oxalic acid,
Tartaric acid, maleic acid, benzoic acid, citric acid, succinic acid,
Malic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like can be mentioned. Examples of the basic amino acid include arginine, lysine, ornithine and the like. Examples of the acidic amino acid include aspartic acid and glutamic acid.

According to the production method of the present invention, 2α, 7α-dihydroyohimbine is converted from yohimbine hydrochloride (3 in FIG. 1).
Is produced by reducing yohimbine hydrochloride with a reducing agent. Generally, 1) yohimbine hydrochloride is dissolved in a solvent, 2)
A reducing agent was added to the solution, 3) solvent removal, 4) extraction with an extraction solvent under alkaline conditions, 5) washing of the extract, drying and solvent removal, 6) dissolution in an elution solvent and 7) purification. Through the steps, the desired compound (3) is obtained. The solvent that dissolves yohimbine hydrochloride is not particularly limited as long as it can dissolve yohimbine hydrochloride and does not prevent the subsequent reaction. For example, trifluoroacetic acid (TF
A), acetic acid, chloroacetic acid and dilute sulfuric acid. After dissolving in a suitable solvent, a reducing agent is added at a low temperature, preferably under ice-cooled stirring. The reducing agent can be appropriately selected by those skilled in the art, but is preferably sodium borohydride, triethylsilane, or the like. Next, it is preferable to stir at room temperature before removing the solvent. As a method for removing the solvent, the solvent can be distilled off under reduced pressure or normal pressure. The alkalinizing agent that can be used is not particularly limited as long as it does not prevent a reaction to occur next, and sodium hydroxide, sodium carbonate, potassium carbonate, and amines (for example, triethylamine and the like) can be used. In addition to chloroform, methylene chloride and ethyl acetate can be used for the extraction. Next, to wash the extract, saturated saline and water can be used, and then a known drying agent such as anhydrous sodium sulfate, anhydrous magnesium sulfate, and anhydrous calcium sulfate can be used, and known removal can be performed. The solvent can be removed by the method. As an elution solvent, chloroform-methanol-ammonia water, preferably chloroform-methanol-
A mixed solvent of (preferably 20 to 40%) aqueous ammonia (preferably 40 to 50: 1 to 5: 0.1 to 0.5, v / v) can be used. In addition, elution solvents such as chloroform-methanol, chloroform-methanol-various amines, chloroform-isopropanol, and chloroform-isopropanol-various amines can also be used. As a purification method, in addition to silica gel column chromatography, alumina column chromatography, thin-layer silica gel chromatography, thin-layer alumina chromatography, and the like can be used. Preferably, 1) dissolving yohimbine hydrochloride in trifluoroacetic acid, 2) adding sodium boron cyanide to the solution,
3) The solvent was removed under reduced pressure. 4) The solution was made alkaline with sodium hydroxide and extracted with chloroform. 5) The extract was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was removed. 6) Dissolved in an elution solvent consisting of chloroform-methanol-aqueous ammonia, and 7) Purify by silica gel column chromatography to obtain compound (3). The various specific examples described above are not limited only to the production of 2α, 7α-dihydroyohimbine (3 in FIG. 1) from yohimbine hydrochloride, and include 1-hydroxyyohimbine represented by the formula (A) from yohimbine hydrochloride and It can also be applied when producing its derivatives.

1-Hydroxyyohimbine (4 in FIG. 1) can be produced by obtaining 2α, 7α-dihydroyohimbine (3 in FIG. 1) from yohimbine hydrochloride and oxidizing it. To obtain 1-hydroxyyohimbine starting from yohimbine hydrochloride, generally, 1) dissolving yohimbine hydrochloride in a solvent, 2) adding a reducing agent to the solution, 3) removing the solvent, 4) under alkaline conditions, Extraction with an extraction solvent, 5) washing of the extract, drying and solvent removal, 6) dissolution in a solvent, 7) addition of an oxidizing agent, 8) extraction with an extraction solvent, 9) washing of the extract, drying Solvent removal, 10) dissolved in elution solvent and 1
1) The desired compound (4) is obtained through a purification step. As a solvent used for dissolving the compound (3) in the step 6), in addition to methanol, a methanol-water mixed solvent,
Ethyl acetate and ether can be used. Next, examples of the oxidizing agent include metal peroxide, organic peroxide, persulfuric acid, and peracid. Metal peroxides can be produced by the reaction of metal oxide salts with peroxides. Examples of the metal oxide salt include, for example, salts of tungstic acid, molybdic acid, and vanadic acid, and examples of the peroxide include hydrogen peroxide solution and urea hydrogen peroxide adduct. it can. In particular, urea hydrogen peroxide adducts can be used in crystals. Examples of the organic peroxide include metachlorobenzoic acid. The most preferred of these is a combination of tungstate and aqueous hydrogen peroxide. Next, for extraction, in addition to chloroform-methanol (preferably 80 to 98: 2 to 20, v / v), chloroform, methylene chloride, ethyl acetate and the like can be used for extraction by a known method. Preferably, 1) dissolving yohimbine hydrochloride in trifluoroacetic acid, 2) adding sodium boron cyanide to the solution under low-temperature stirring, 3).
After stirring at room temperature, the solvent was removed under reduced pressure. 4) The solution was made alkaline with sodium hydroxide and extracted with chloroform. 5) The extract was washed with brine and dried over anhydrous sodium sulfate. Removing the solvent, 6) dissolving in methanol, 7) adding metal peroxide and / or its salt,
8) extraction with a solvent consisting of chloroform-methanol,
9) The extract was washed with saturated saline, dried over anhydrous sodium sulfate, the solvent was removed, 10) dissolved in an elution solvent consisting of chloroform-methanol-aqueous ammonia, and 11) purified by silica gel column chromatography. To obtain the desired compound. The specific examples described above are not limited to the production of 1-hydroxyyohimbine from yohimbine hydrochloride via 2α, 7α-dihydroyohimbine (3 in FIG. 1), but also include yohimbine hydrochloride or 2α, 7
It can also be applied to the production of a 1-hydroxyyohimbine derivative represented by the formula (A) from α-dihydroyohimbine (3 in FIG. 1).

In order to produce the compound represented by the formula (A ') or a salt thereof according to the production method of the present invention, 1-hydroxyyohimbine and a compound represented by the formula R'-X wherein R' is as defined above , X represents a halogen such as fluorine, chlorine, bromine or iodine]. For example, from yohimbine hydrochloride, 2α, 7α-dihydroyohimbine (3 in FIG. 1), 1-hydroxyyohimbine (4 in FIG. 1)
Through 1-hydroxyyohimbine derivative of the present invention
In order to produce 1-allyloxyyohimbine (5 in FIG. 1), 1) dissolution in a solvent, 2) addition of anhydrous carbonate and allyl bromide, 3) extraction with an extraction solvent,
4) After washing the extract, drying, removing the solvent, 5) dissolving in the elution solvent, and 6) purifying. As a solvent for dissolving 1-hydroxyyohimbine, methanol, chloroform, methylene chloride, benzene, tetrahydrofuran, ether and the like can be used in addition to N, N-dimethylformamide. In addition to anhydrous carbonate or allyl bromide,
Those skilled in the art may suitably use metal alkoxides (eg, sodium methoxide, potassium tertiary butoxide, etc.)
, Hydroxides (such as sodium hydroxide) and amines (such as triethylamine). The above-mentioned various examples are obtained from yohimbine hydrochloride via 2α, 7α-dihydroyohimbine and 1-hydroxyyohimbine.
The present invention is not limited to the production of allyloxyyohimbine, but can be applied to the production of other 1-hydroxyyohimbine derivatives from yohimbine hydrochloride. From yohimbine hydrochloride, via 2α, 7α-dihydroyohimbine (3 in FIG. 1) and 1-hydroxyyohimbine (4 in FIG. 1),
1-n- which is one of 1-hydroxyyohimbine derivatives
To produce butyloxyyohimbine (6 in FIG. 1),
Generally, 1) dissolved in a solvent, 2) added anhydrous carbonate, 3)
A solution in which n-butyl iodide is dissolved in a solvent is added, 4) extraction with an extraction solvent, 5) washing of the extract, drying and removal of the solvent, 6) dissolution in an elution solvent, and 7) a purification step. . As the solvent for n-butyl iodide, methanol, chloroform, ethyl acetate, benzene and the like can be used in addition to N, N-dimethylformamide. Also,
Extraction can be performed using ethyl acetate, chloroform, methylene chloride, a mixed solvent of chloroform-methanol, or the like. The various specific examples described above are not limited only to the production of 1-n-butyloxyyohimbine from yohimbine hydrochloride via 2α, 7α-dihydroyohimbine and 1-hydroxyyohimbine. It can also be applied to the production of hydroxyyohimbine derivatives. Furthermore, from yohimbine hydrochloride, 2α,
Via 1α-dihydroyohimbine (3 in FIG. 1) and 1-hydroxyyohimbine (4 in FIG. 1), 1-p-nitrobenzyloxyyohimbine (7 in FIG. 1), which is one of the 1-hydroxyyohimbine derivatives, is produced. In general,
1) Dissolve in solvent, 2) Add anhydrous carbonate, 3) Add a solution of p-nitrobenzyl bromide in solvent, 4)
After extracting with an extraction solvent, 5) washing the extract, drying, removing the solvent, 6) dissolving in an elution solvent, and 7) purifying.
As the solvent for nitrobenzyl bromide, besides N, N-dimethylformamide, methanol, chloroform, ethyl acetate, benzene, ether, tetrahydrofuran, a mixed solvent thereof and the like can be used. The above-mentioned various examples are obtained from yohimbine hydrochloride by using 2α, 7α-
The production of 1-p-nitrobenzyloxyyohimbine via dihydroyohimbine and 1-hydroxyyohimbine is not limited only to production of yohimbine hydrochloride.
-It can also be applied to the production of hydroxyyohimbine derivatives. In the process of producing 2α, 7α-dihydroyohimbine, 1-hydroxyyohimbine and derivatives thereof, those skilled in the art can appropriately change the reaction time, the reaction temperature, the mixing ratio of the reagents, and the like. 2α, 7α used
The dihydroyohimbine (3 in FIG. 1) is not limited to one produced by the reduction of yohimbine hydrochloride described above, but may be one obtained by another method.

The present invention also includes a method for producing 1-methoxyyohimbine represented by 8 in FIG. This method includes:
1) dissolving 1-hydroxyyohimbine in methanol, 2) adding an ether solution of diazomethane, 3) removing the solvent, 4) dissolving in the elution solvent, and 7) purifying. 2α, 7α- from yohimbine hydrochloride
In the process of producing 1-methoxyyohimbine (8 in FIG. 1), which is one of the 1-hydroxyyohimbine derivatives, via dihydroyohimbine (3 in FIG. 1) and 1-hydroxyyohimbine (4 in FIG. 1), those skilled in the art Can be changed using known techniques as described above.

The pharmaceutical composition according to the present invention contains, as an active ingredient, the compound represented by the above formula (A ") or a pharmaceutically acceptable salt thereof. In the formula (A"), R "represents In the same group as R ′ in the formula (A ′),
Methyl has been added. That is, the compound represented by the formula (A ″) is different from the compound represented by the formula (A) in FIG.
1-hydroxyyohimbine to which the compound (8) is added, or a derivative thereof containing the compound (8), or a pharmaceutically acceptable salt thereof (hereinafter simply referred to as 1-
Hydroxyyohimbine or a derivative thereof). The pharmaceutical compositions of the present invention have alpha ₂ receptors blocking action,
In particular, it is useful as an aphrodisiac, a diabetic, an antiasthmatic, an anticoagulant, and the like. When used as a prophylactic or therapeutic agent for diabetes, asthma, etc., the 1-hydroxyyohimbine or its derivative of the present invention can be used as it is or after being subjected to various treatments such as diluting it with water. It can be used by mixing it with quasi-drugs.
The compounding amount in this case is appropriately selected according to the disease state and the product, but it can be usually 0.001 to 50% by weight, particularly 0.01 to 10% by weight in the case of a systemically administered preparation.
If the amount is less than 0.001% by weight, satisfactory preventive or therapeutic action may not be observed. If the amount is more than 5% by weight, the stability and flavor characteristics of the product itself may be impaired. Absent. As the administration method of the pharmaceutical composition of the present invention, in addition to oral administration and intravenous administration, transmucosal administration, transdermal administration, intramuscular administration, subcutaneous administration, rectal administration and the like can be appropriately selected, and depending on the administration method. Various formulations can be prepared according to known formulation techniques. Hereinafter, each preparation will be described, but the dosage form used in the present invention is not limited to these, and can be used as various preparations usually used in the field of pharmaceutical preparations.

[0015] For systemic administration the formulation, when the alpha ₂ receptors used as a prophylactic or therapeutic agent for conditions involved, the oral dose of 1-hydroxy yohimbine or a derivative thereof (as free compound), 3 mg / kg to 30
The range is preferably 0 mg / kg, more preferably 10 m / kg.
g / kg to 100 mg / kg. In the case of systemic administration, especially in the case of intravenous administration, the effective blood concentration varies from 2 μg / mL to 20
0 μg / mL, more preferably 5 μg / mL to 100 μ
g / mL. The dosage form for oral administration includes powders, granules, capsules, pills, tablets, elixirs, suspensions, emulsions, syrups and the like, and can be appropriately selected. Further, these preparations can be modified such as sustained release, stabilization, easy disintegration, hard disintegration, enteric coating, and easy absorption. In addition, as a dosage form when topical administration in the oral cavity is performed, chewing agents, sublingual agents, buccal agents,
There are troches, ointments, patches, solutions and the like, which can be appropriately selected. In addition, sustained release of those formulations,
Modifications such as stabilization, easy disintegration, hard disintegration, enteric coating, and easy absorption can be performed.

For each of the above-mentioned dosage forms, a known drug delivery system (DDS) technique can be employed. The DDS preparations referred to in the present specification include sustained release preparations, topically applied preparations (troches, buccal tablets, sublingual tablets, etc.), controlled drug release preparations, enteric preparations, gastric preparations, etc., administration route, bioavailability, etc. A formulation in which an optimal formulation is formed in consideration of side effects and the like. The components of the DDS basically consist of a drug, a drug release module, a wrap (inclusion body) and a treatment program, and each component has a half-life that causes a rapid decrease in blood concentration, especially when the release is stopped. A short drug is preferable, and a cover (inclusion body) that does not react with the living tissue at the administration site is preferable.
It is preferable to have a treatment program that maintains the best drug concentration for a set period of time. The drug release module basically has a drug reservoir, a release controller, an energy source and a release hole or release surface. It is not necessary to have all of these basic components, and the best mode can be selected by adding or deleting as appropriate. D
Materials that can be used for DS include polymers, cyclodextrin derivatives, lecithin, and the like. Polymers include insoluble polymers (silicone, ethylene-vinyl acetate copolymer, ethylene-vinyl alcohol copolymer, ethyl cellulose, cellulose acetate, etc.), water-soluble polymers and hydroxyl gel-forming polymers (polyacrylamide, polyhydroxyethyl Crosslinked methacrylates, crosslinked polyacrylics, polyvinyl alcohol, polyethylene oxide, water-soluble cellulose derivatives, crosslinked poloxamers, chitin, chitosan, etc., slowly soluble polymers (ethyl cellulose, partial esters of methyl vinyl ether / maleic anhydride copolymer, etc.) ), Gastric-soluble polymer (hydroxypropylmethylcellulose, hydroxypropylcellulose, carmellose sodium, macrogol, polyvinylpyrrolidone, dimethylaminoethyl methacrylate / methacrylic acid) Acid-copolymers), enteric polymers (hydroxypropylmethylcellulose phthalate, phthalcellulose acetate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, acrylic acid polymers, etc.), biodegradable polymers (heat-coagulated or cross-linked albumin, Cross-linked gelatin, collagen,
Fibrin, polycyanoacrylate, polyglycolic acid, polylactic acid, polyβ-hydroxyacetic acid, polycaprolactone, etc.), which can be appropriately selected depending on the dosage form. In particular, silicone, ethylene-vinyl acetate copolymer, ethylene-vinyl alcohol copolymer, methyl vinyl ether / maleic anhydride copolymer partial ester can be used for drug release control, and cellulose acetate is used as a material for osmotic pump. Can be used, ethyl cellulose,
Hydroxypropylmethylcellulose, hydroxypropylcellulose and methylcellulose can be used as a film material for sustained-release preparations, and crosslinked polyacryl can be used as an adhesive for oral mucosa or ocular mucosa.

In the preparation, the dosage form (oral administration,
Injections, suppositories and other known dosage forms), solvents, excipients, coatings, bases, binders, lubricants, disintegrants,
Manufactured by adding additives such as solubilizers, suspending agents, thickeners, emulsifiers, stabilizers, buffers, isotonic agents, soothing agents, preservatives, flavoring agents, fragrances, and coloring agents. be able to. Each of these additives will be described by way of specific examples, but is not particularly limited thereto. Examples of the solvent include purified water, water for injection, physiological saline, peanut oil, ethanol, glycerin and the like. Excipients include starches, lactose, glucose, sucrose, crystalline cellulose, calcium sulfate, calcium carbonate, talc,
Titanium oxide, trehalose, xylitol and the like can be mentioned. Examples of the coating agent include sucrose, gelatin, cellulose acetate phthalate, and the above-mentioned polymers. Examples of the base include petrolatum, vegetable oil, macrogol, an oil-in-water emulsion base, a water-in-oil emulsion base, and the like. Examples of the binder include starch and its derivatives, cellulose and its derivatives, gelatin, natural polymer compounds such as sodium alginate, tragacanth, gum arabic, synthetic polymer compounds such as polyvinylpyrrolidone, dextrin, hydroxypropyl starch and the like. it can. Lubricants include stearic acid and its salts, talc, waxes, wheat starch, macrogol, hydrogenated vegetable oils,
Sucrose fatty acid esters, polyethylene glycol and the like can be mentioned. Disintegrants include starch and its derivatives, agar, gelatin powder, sodium bicarbonate, cellulose and its derivatives, carmellose calcium,
Examples thereof include hydroxypropyl starch, carboxymethylcellulose and salts thereof and cross-linked products thereof, and low-substituted hydroxypropylcellulose. Solubilizers include cyclodextrin, ethanol,
Propylene glycol, polyethylene glycol and the like can be mentioned. As a suspending agent, gum arabic,
Examples include tragacanth, sodium alginate, aluminum monostearate, citric acid, and various surfactants. Examples of the thickener include carmellose sodium, polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, tragacanth, acacia, sodium alginate and the like. As emulsifiers, gum arabic, cholesterol, tragacanth, methylcellulose,
Various surfactants, lecithin and the like can be mentioned. Examples of the stabilizer include sodium bisulfite, ascorbic acid, tocopherol, a chelating agent, an inert gas, a reducing substance, and the like. Examples of the buffer include sodium hydrogen phosphate, sodium acetate, boric acid and the like. Examples of the tonicity agent include sodium chloride, glucose and the like. Examples of the soothing agent include procaine hydrochloride, lidocaine, benzyl alcohol and the like. Examples of the preservative include benzoic acid and salts thereof, paraoxybenzoic acid esters, chlorobutanol, inverted soap, benzyl alcohol, phenol, tylomesal, and the like. As a flavoring agent,
Sucrose, saccharin, licorice extract, sorbitol, xylitol, glycerin and the like can be mentioned. Examples of the fragrance include spruce tincture and rose oil. Examples of the coloring agent include a water-soluble food coloring agent and a lake coloring agent.

As described above, by preparing a drug into a DDS preparation such as a sustained-release preparation, an enteric preparation or a controlled-release drug preparation, the effect of maintaining the effective blood concentration of the drug and improving the bioavailability can be obtained. Can be expected. But,
The components of 1-hydroxyyohimbine or its derivatives may be inactivated or degraded in vivo, with the result that the desired effect may be reduced or eliminated. Therefore, by using a substance that inhibits a substance that inactivates or degrades the component of 1-hydroxyyohimbine or a derivative thereof in combination with the pharmaceutical composition of the present invention, the effect of the component can be further sustained. These may be incorporated into a formulation or may be administered separately. In addition, in addition to 1-hydroxyyohimbine or a derivative thereof contained in the pharmaceutical composition, those skilled in the art appropriately identify a substance that inactivates or degrades 1-hydroxyyohimbine or a derivative thereof, and selects a substance that inhibits it. However, these may be used in combination or blended to stabilize the active ingredient in the composition. Furthermore, in the preparation, as additives other than those described above, components used in ordinary compositions can be used, and the added amounts of these components may be the same as the usual amounts as long as the effects of the present invention are not impaired. can do.

The present invention will be described below with reference to Examples and Test Examples.
Will be described in more detail, but the present invention is not limited to these.
It is not something to be done. The number attached to each compound is shown in FIG.
Each compound number is shown. Example 1 From yohimbine hydrochloride (1 · HCl), 2α, 7α-dihydroyohi
Synthesis of yohimbine hydrochloride (1 · HCl, 107.6 mg, 0.28 mmol) in 2.0
 Add ice-cold solution to a solution of trifluoroacetic acid
Add sodium boro cyanide (36.4 mg, 0.55 mmol)
Was. After stirring at room temperature for 1 hour, the solvent was distilled off under reduced pressure.
did. 2N aqueous sodium hydroxide solution was added to the obtained residue.
After adding alkaline, the whole is extracted with chloroform.
did. The extract was washed with a saturated saline solution and dried over anhydrous sodium sulfate.
After drying with a solvent, the solvent was distilled off under reduced pressure. Remove the resulting oil
Loroform-methanol-28% aqueous ammonia (46: 3: 0.
(3, v / v) Silica gel column
Chromatographically, 2α, 7α-dihydroyohimbi
(3) (98.0 mg, 100%) was obtained. Compound (3): mp 190-193 ° C (colorless fine needles, ethyl acetate
Recrystallized from hexane) .UVλ_max(MeOH) nm: 206, 24
3, 293.IR (KBr): 3471, 2906, 1707, 1691,1261, 12
44, 1020, 754, 744, 735 cm^-1.¹H-NMR (CDCl_Three) δ:
1.36-1.61 (7H, m), 1.68 (1H, s, D_TwoDisappear by adding O
Dec), 1.71-1.77 (1H, m), 1.83-2.06 (4H, m), 2.18
(1H, dt, J = 11.5, 2.7 Hz), 2.30 (1H, dd, J = 11.5,
2.2 Hz), 2.77 (1H, ddd, J = 11.5, 3.4, 3.2 Hz), 2.83
 (1H, dd, J = 11.5, 2.2 Hz), 2.93 (1H, dt, J = 6.6,
2.7 Hz), 3.10 (1H, s, D_TwoDisappeared by the addition of O), 3.57
(1H, dd, J = 6.6, 2.7 Hz), 3.76 (3H, s), 4.19 (1H,
s), 6.68 (1H, dd, J = 7.8, 1.0 Hz), 6.72 (1H, ddd,
J = 7.6, 7.3, 1.0 Hz), 7.01 (1H, ddd, J = 7.8, 7.6,
1.0 Hz), 7.08 (1H, dd, J = 7.3, 1.0 Hz). High resolution
MS m / z: (EI) C_{twenty one}H₂₈N_TwoO_ThreeCalculated as: 356.2100. Actual
Observed 356.2111. Elemental analysis C_{twenty one}H₂₈N_TwoO_Three・ 1 / 8H _TwoAs O
Calculated: C, 70.31; H, 7.94; N, 7.81. Found: C, 70.
30; H, 7.93; N, 7.78. [Α]^{twenty five} _D +90.64^. (c = 0.20, C
HCl_Three).

Example 2 Synthesis of 1-hydroxyyohimbine (4) from yohimbine hydrochloride (1 · HCl) Yohimbine hydrochloride (1 · HCl, 101.0 mg, 0.26 mmol) was prepared.
Sodium cyanide (85.5 mg, 1.3 mmol) was added to a solution dissolved in 2.0 ml of trifluoroacetic acid under ice-cooling and stirring. After further stirring at room temperature for 2 hours, the solvent was distilled off under reduced pressure. After 2 N aqueous sodium hydroxide solution was added to the obtained residue to make it alkaline, the whole was extracted with chloroform. The extract was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained oil was dissolved in 9.0 ml of methanol and 1.0 ml of water. Sodium tungstate dihydrate (17.0 mg, 0.0
To the mixture was added a 30% aqueous hydrogen peroxide solution (0.59 ml, 5.2 mmol) with stirring under ice-cooling, followed by stirring at 0 ° C. for 1 hour. After adding water to the reaction solution, the whole was extracted with a mixed solvent of chloroform-methanol (95: 5, v / v). The extract was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained oil was subjected to silica gel column chromatography using a mixed solvent of chloroform-methanol-28% aqueous ammonia (46: 5: 0.5, v / v) as an eluent to give 1-hydroxyyohimbine (4) (82.1 mg , 86%). Compound (4): mp 224-226 ° C (dec.) (Colorless needles, recrystallized from methanol). UVλ _max (MeOH) nm: 227, 279, 285.
IR (KBr): 3500, 2945, 1711, 1435, 1317,1205, 118
. 9, 1150, 1019, 966 , 743 cm -1 1 H-NMR (CD 3 OD) δ:
1.19 (1H, q, J = 11.5 Hz), 1.33-1.39 (1H, m), 1.43-
1.57, (2H, m), 1.65 (1H, brt, J = 13.4 Hz), 1.91
(1H, dd, J = 13.4, 2.7 Hz), 1.99 (1H, qd, J = 11.5,
2.7 Hz), 2.31 (1H, br d, J = 11.5 Hz), 2.40 (1H, t,
J = 11.5 Hz), 2.63-2.76 (2H, m), 2.88-2.98 (3H, m),
3.10-3.15 (1H, m), 3.62 (1H, d, J = 11.5 Hz), 3.73
(3H, s), 4.22 (1H, d, J = 2.7 Hz), 6.98 (1H, t, J =
7.6 Hz), 7.09 (1H, t, J = 7.6 Hz), 7.29 (1H, d, J =
7.6 Hz), 7.37 (1H, d, J = 7.6 Hz). MS m / z: 370
^{(M +), 354 (M} + -O), 353 (M + -OH). Elemental Analysis C ₂₁ H ₂₆ N ₂ O
Calculated as ₄ : C, 68.09; H, 7.07; N, 7.56. Found:
C, 67.97; H, 7.13; N, 7.60. [Α] ³⁰ _D + 7.75 ^. (c = 0.
20, DMF).

Example 3 1-Hydroxyyohimbine (4) to 1-allyloxyyo
Synthesis of Hinbin (5) 1-hydroxyyohimbine (4, 52.8 mg, 0.14 mmol)
In 5.0 ml of N, N-dimethylformamide
Was added anhydrous potassium carbonate (59.2 mg, 0.43 mmol),
Further allyl bromide (24.7 ml, 0.29 mmol) was added.
Thereafter, the mixture was stirred at room temperature for 30 minutes. After adding water to the reaction solution,
With a chloroform-methanol (95: 5, v / v) mixed solvent.
Issued. The extract was washed with a saturated saline solution and dried over anhydrous sodium sulfate.
Then, the solvent was distilled off under reduced pressure. The resulting oil
Elute a chloroform-methanol (95: 5, v / v) mixed solvent
Silica gel column chromatography as solvent
1-allyloxyyohimbine (5) (54.6 mg, 93%)
Obtained. Compound (5): mp 126-128.5 ° C (dec.) (Colorless fine needles
Crystal, recrystallized from hexane). UVλ_max(MeOH) nm: 225, 2
78, 284.IR (KBr): 3458, 2920, 1739, 1458,1435, 1
209, 1151, 1001, 737 cm^-1.¹H-NMR (CDCl_Three) δ: 1.34
-1.43 (2H, m), 1.48-1.64 (3H, m), 1.97-2.06 (2H,
m), 2.34 (1H, dd, J = 11.5, 2.2 Hz), 2.35 (1H, t,
J = 11.5 Hz), 2.55 (1H, dt, J = 12.9, 2.9 Hz), 2.62
(1H, td, J = 10.7, 4.2 Hz), 2.66-2.72 (1H, m), 2.90-
2.98 (1H, m), 2.96 (1H, dd, J = 11.5, 2.9 Hz), 3.05
 (1H, ddd, J = 11.5, 5.6, 2.2 Hz), 3.30 (1H, s, D_TwoO
), 3.51 (1H, dd, J = 11.5, 2.2Hz),
3.75 (3H, s), 4.20 (1H, d, J = 1.2 Hz), 4.49 (1H, dd
dd, J = 11.0, 6.6, 1.2, 1.0 Hz), 4.55 (1H, dddd, J
= 11.0, 6.1, 1.2, 1.0 Hz), 5.39 (1H, ddt, J = 10.7,
1.2, 1.0 Hz), 5.44 (1H, dq, J = 17.1, 1.2 Hz), 6.05
 (1H, dddd, J = 17.1, 10.7, 6.6, 6.1 Hz), 7.08 (1H,
 ddd, J = 8.1, 7.8, 1.0Hz), 7.18 (1H, td, J = 8.1,
1.0 Hz), 7.34 (1H, ddd, J = 8.1, 1.0, 0.7 Hz), 7.43
 (1H, ddd, J = 7.8, 1.0, 0.7 Hz) .MS m / z: 410 (M⁺),
353 (M⁺-OCH_TwoCH = CH_Two). Elemental analysis C_{twenty four}H₃₀N_TwoO_FourAs a total
Calculated: C, 70.22; H, 7.37; N, 6.82. Found: C, 70.13;
 H, 7.50; N, 6.57. [Α]³⁰ _D +18.40^.(c = 0.21, CHC
l_Three).

Example 4 1-Hydroxyyohimbine (4) to 1-n-butyloxy
Synthesis of yohimbine (6) 1-hydroxyyohimbine (4, 50.5 mg, 0.14 mmol)
Dissolved in 4.0 ml of N, N-dimethylformamide
Was added anhydrous potassium carbonate (56.7 mg, 0.41 mmol),
Further, n-butyl iodide (30.8 mg, 0.17 mmol) was added to N, N-diamine.
A solution dissolved in methylformamide (1.0 ml) was added.
Thereafter, the mixture was stirred at room temperature for 2 hours. After adding water to the reaction solution,
The body was extracted with ethyl acetate. Extracts with saturated saline
After washing with water and drying over anhydrous sodium sulfate, the solvent is removed under reduced pressure.
Distilled off. Chloroform-methanol
(95: 5, v / v) Silica gel color
1-n-butyloxy
Yohimbine (6) (57.8 mg, 99%) was obtained. Compound (6): mp 150-152 ° C (dec.) (Colorless fine needles,
Recrystallized from hexane). UVλ_max(MeOH) nm: 228, 278,
285.IR (KBr): 3464, 2935, 1738, 1460, 1435, 131
9, 1207, 1151, 1003, 737 cm^-1.¹H-NMR (CDCl_Three) δ:
1.01 (3H, t, J = 7.3 Hz), 1.34-1.43 (2H, m), 1.48-1.
63 (5H, m), 1.65-1.79 (2H, m), 1.97-2.07 (2H, m),
2.34 (1H, dd, J = 11.2, 2.0 Hz), 2.36 (1H, t, J = 1
1.2 Hz), 2.53 (1H, dt, J = 12.9, 2.9 Hz), 2.63 (1H,
td, J = 11.2, 4.2 Hz), 2.66-2.72 (1H, m), 2.90-2.98
 (1H, m), 2.96 (1H, dd, J = 11.2, 2.9 Hz), 3.05 (1
H, ddd, J = 11.2, 5.6, 2.0 Hz), 3.29 (1H, s, D_TwoAdd O
3.48 (1H, d, J = 11.2 Hz), 3.76 (3H,
s), 3.98 (1H, td, J = 8.5, 6.6 Hz), 4.06 (1H, td, J
= 8.5, 6.6 Hz), 4.20 (1H, s), 7.07 (1H, ddd, J = 8.
1, 7.8, 1.0 Hz), 7.17 (1H, td, J = 8.1, 1.0 Hz), 7.3
1 (1H, dd, J = 8.1, 1.0 Hz), 7.43 (1H, dd, J = 7.8,
1.0 Hz) .MS m / z: 426 (M⁺), 353 (M⁺-n-Bu). Elemental content
Analysis C_{twenty five}H₃₄N _TwoO_FourCalculated as: C, 70.39; H, 8.03; N,
6.57. Found: C, 70.26; H, 8.12; N, 6.48. [Α]³² _D 
+21.46^.(c = 0.21, CHCl_Three).

Example 5 1-Hydroxyyohimbine (4) to 1-p-nitrobenzyl
Synthesis of loxyyohimbine (7) 1-hydroxyyohimbine (4, 50.3 mg, 0.14 mmol)
A solution in 4.0 ml of N, N-dimethylformamide
Was added anhydrous potassium carbonate (56.8 mg, 0.41 mmol),
Further, p-nitrobenzyl bromide (35.4 mg, 0.16 mm
ol) in N, N-dimethylformamide (1.0 ml)
After the addition of the liquid, the mixture was stirred at room temperature for 30 minutes. Add water to the reaction solution
After that, the whole was extracted with ethyl acetate. Extract
After washing with saturated saline and drying over anhydrous sodium sulfate,
The solvent was distilled off under reduced pressure. Chloroform-
Use a mixed solvent of methanol (95: 5, v / v) as eluent
Kagel column chromatography, 1-p-nit
Robenzyloxyyohimbine (7) (61.7 mg, 90%) was obtained.
Was. Compound (7): mp 148-149 ° C (dec.) (Yellow acicular fine crystals,
Recrystallized from ethyl acetate-hexane) .UVλ_max(MeOH) nm:
 203, 226, 269. IR (KBr): 2924, 1734, 1703, 1523,
 1460, 1437, 1348, 1155, 1109, 852, 827, 739 cm^-1.
 ¹H-NMR (CDCl _Three) δ: 1.37 (1H, q, J = 12.0 Hz), 1.38
-1.43 (1H, m), 1.50-1.61 (3H, m), 1.94-2.03 (2H,
m), 2.28 (1H, t, J = 11.0 Hz), 2.33 (1H, dd, J = 1
1.7, 2.2 Hz), 2.54 (1H, dt, J = 12.7, 2.9 Hz), 2.57
 (1H, td, J = 11.0, 4.2 Hz), 2.66-2.72 (1H, m), 2.8
9-2.98 (2H, m), 3.01-3.07 (1H, m), 3.04 (1H, s, D_Two
O), 3.23 (1H, dd, J = 11.0, 2.2 H
z), 3.59 (3H, s), 4.21 (1H, d, J = 1.2 Hz), 5.02 (1
H, d, J = 10.6 Hz), 5.07 (1H, d, J = 10.6 Hz), 7.12
(1H, ddd, J = 8.1, 7.8, 1.0 Hz), 7.21 (1H, td, J =
8.1, 1.0 Hz), 7.32 (1H, dd, J = 8.1, 1.0 Hz), 7.46
(1H, dd, J = 7.8, 1.0 Hz), 7.61 (2H, dd, J = 9.0, 2.
2 Hz), 8.31 (2H, dd, J = 9.0, 2.2 Hz). MS m / z: 354
 (M⁺-p-NO_TwoC₆H_FourCHO), 353 (M⁺-p-NO_TwoC₆H_FourCH_TwoO), 151 (p
-NO_TwoC₆H_FiveCHO). Elemental analysis C₂₈H₃₁N_ThreeO₆Calculated as: C,
 66.52; H, 6.18; N, 8.31. Found: C, 66.40; H, 6.2
2; N, 8.18. [Α]³¹ _D +48.77^. (c = 0.20, CHCl_Three).

Example 6 Synthesis of 1-methoxyyohimbine (8) from 1-hydroxyyohimbine (4) 1-hydroxyyohimbine (4, 52.6 mg, 0.14 mmol)
Was dissolved in 20.0 ml of methanol, an ether solution of diazomethane was added under ice-cooling and stirring while monitoring by thin layer chromatography until the starting materials disappeared, and the mixture was further stirred for 1 hour. The oil obtained by evaporating the solvent of the reaction solution under reduced pressure was subjected to silica gel column chromatography using a mixed solvent of chloroform-methanol-28% aqueous ammonia (46: 3: 0.3, v / v) as an eluent, 1-Methoxyyohimbine (8) (42.2 mg, 77%) was obtained. Compound (8): mp 201-203 ° C (dec.) (Colorless prism crystals,
(Recrystallized from acetone) UVλ _max (MeOH) nm: 227, 276, 28
3. IR (KBr): 3145, 2910, 1737, 1458, 1426, 1360,
1296, 1224, 1206, 1180, 1144, 1001, 955, 743 cm ^-1 .
¹ H-NMR (CDCl ₃ ) δ: 1.36-1.45 (2H, m), 1.49-1.62
(3H, m), 1.97-2.09 (2H, m), 2.32-2.39 (2H, m), 2.4
6 (1H, ddd, J = 12.7, 3.2, 2.9 Hz), 2.63 (1H, td,
J = 11.2,4.2 Hz), 2.66-2.71 (1H, m), 2.89-2.98 (2H,
m), 3.03-3.08 (1H, m), 3.36 (1H, s, disappeared by addition of D ₂ O), 3.49 (1H, dd, J = 11.2, 1.7 Hz), 3.77 (3H,
s), 3.89 (3H, s), 4.21 (1H, s), 7.09 (1H, ddd, J
= 7.8, 7.1, 1.0 Hz), 7.19 (1H, ddd, J = 8.1, 7.1, 1.0
Hz), 7.34 (1H, dd, J = 8.1, 1.0 Hz), 7.44 (1H, dd,
J = 7.8, 1.0 Hz). MS m / z: 384 (M ⁺ ), 353 (M ⁺ -OMe).
Calculated elemental analysis _{C 22 H 28 N 2 O 4} : C, 68.72; H, 7.
34; N, 7.29. Found: C, 68.65; H, 7.35; N, 7.23.
[a] ²⁹ _D ^+20.54. (c = 0.20, CHCl ₃ ). The spectral data of compound (8) was obtained from literature data (H. Takayama, N. Seki, M. Kitajima, N. Aimi, H. Se).
ki and S. Sakai, Heterocycles, 33, 121 (1992).

Test Example 1 Rats (Wistar strain, male) were used for the experiment. After ether anesthesia, or after stunning the occiput by beating, the carotid artery was cut off and killed by exsanguination, and the chest was opened to remove the thoracic aorta. Excised specimen, Kerbs-He was bubbled O ₂ (100%)
pes solution (NaCl: 126.9 mM, KCl: 5.9 mM, HEPES: 10.03 mM,
_{CaCl 2: 2.36 mM, MaCl 2} : 1.18 mM, glucose: 11.8 mM
(PH = 7.4)]. After removing the connective tissue and adipose tissue, a ring specimen having a length of about 2 mm was prepared and used for the experiment. No endothelial detachment was performed. 95 ring specimens
Normal Tyrode solution aerated with% O ₂ −5% CO ₂ (NaCl: 158.3 m
M, KCl: 4.0 mM, NaHCO 3: 10.0 mM, NaH 2 PO 4: 0.42 mM, Ca
Cl ₂ : 2.0 mM, MgCl ₂ : 1.05 mM, glucose: 5.6 mM] (5
(UC-5TD, UFER ^TM Medical Instru
ment, Kyoto). Two stainless steel hooks [one is fixed, the other is a tension transducer (T7-8-240, Orientec Co., Ltd., Tokyo: TB-61)
1T, Nihon Kohden, Tokyo)] and a load equivalent to 2.0 g was applied. The change in the tension is measured using the amplification amplifier (AP-600G, A
P-621G, Nihon Kohden, Tokyo: MSC-2, LaboSupport Corpora
, Osaka). Nutrient solution 20 ~
Exchanged at 30 minute intervals, the specimens were equilibrated for 90 minutes. At the beginning of the experiment, a high KCl solution (80 mM) [NaCl: 82.3 mM, KCl: 80.0 mM, N
aHCO ₃ : 10.0 mM, NaH ₂ PO ₄ : 0.42 mM, CaCl ₂ : 2.0 mM, MgCl
₂ : 1.05 mM, glucose: 5.6 mM]. Then, the experiment was started by washing with a normal Tyrode solution. In order to evaluate the efficacy of the yohimbine derivative of the present invention, an arterial specimen was treated with clonidine (10%) in the presence of a NO synthesis inhibitor, nitro-L-arginine methyl ester (L-NAME) (100 μM).
(0 nM or 1 μM) to induce contraction, and after the generated tension reached a constant level continuously, a sample (10 μM) was administered. After the relaxation response of the specimen reached the maximum, yohimbine (10 μM) was administered. The relaxation response obtained with yohimbine (10 μM) was defined as the maximum response (= 100%), the contraction height immediately before administration of the sample was defined as 0%, and the relaxation response of the sample was defined as yohimbine (10%).
μM). In other words, an index of relaxation response of rat aorta specimen, first, contracted with clonidine alpha ₂ agonists, to eliminate the effect of endothelial cells, the administration of L-NAME. When the contractile response becomes constant, the test compound is administered and the relaxation response is measured. Thereafter, the maximum relaxation response obtained by administering yohimbine is 100%
And Thereby, the strength of the effect of the test compound is calculated by the ratio to yohimbine. Table 1 shows the results.

[0026]

[Table 1] From the above results, it has been clarified that 1-hydroxyyohimbine or a derivative thereof of the present invention exhibits the same effect as yohimbine.

[0027]

According to the present invention, a novel yohimbine derivative represented by the formula (A), a method for producing the same, and a pharmaceutical composition of the derivative are provided. Yohimbine derivatives of the present invention,
Showed superior alpha ₂ receptors blocking action, aphrodisiac, antidiabetic agents, antiasthmatics, available as anti-platelet aggregation agents.

[Brief description of the drawings]

FIG. 1 is a reaction diagram showing a production route of a yohimbine derivative.

Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat II (reference) A61P 15/10 A61P 15/10 43/00 111 43/00 111

Claims (17)

[Claims] (1) Formula (A): [Wherein, R is hydrogen, alkyl having 2 to 10 carbons which may have a substituent, cycloalkyl having 3 to 10 carbons which may have a substituent, Alkenyl having 2 to 10 carbon atoms, cycloalkenyl having 3 to 10 carbon atoms which may have a substituent, alkynyl having 2 to 10 carbon atoms which may have a substituent, An optionally substituted acyl group, an aryl group having 6 to 20 carbon atoms which may have a substituent, an aralkyl group having 7 to 20 carbon atoms which may have a substituent, or a 5 to 7-membered heterocyclic group Or a salt thereof. 2. The compound according to claim 1, wherein R is an optionally substituted alkyl having 2 to 6 carbons, an alkenyl having 2 to 6 carbons or an aralkyl having 7 to 10 carbons. . 3. The compound according to claim 1, wherein R is selected from allyl, butyl and nitrobenzyl. 4. A method for producing 2α, 7α-dihydroyohimbine, which comprises reducing yohimbine hydrochloride with a reducing agent. 5. The method according to claim 4, wherein the reducing agent is sodium boron cyanide or triethylsilane. 6. A method for producing 1-hydroxyyohimbine, comprising oxidizing 2α, 7α-dihydroyohimbine with an oxidizing agent. 7. The method according to claim 7, wherein the oxidizing agent is a metal peroxide, an organic peroxide,
7. The method according to claim 6, wherein the method is persulfuric acid or peracid. 8. The method according to claim 6, wherein 2α, 7α-dihydroyohimbine is obtained by reducing yohimbine hydrochloride with a reducing agent. 9. 1-hydroxyyohimbine and a compound of the formula R′-X
Wherein R ′ has the same meaning as in the following formula (A ′), and X represents a halogen; and a compound represented by the formula (A ′): [In the formula, R ′ has 2 to 2 carbon atoms which may have a substituent.
10 alkyl, 3 to 3 carbon atoms which may have a substituent
10 cycloalkyl, optionally substituted alkenyl having 2 to 10 carbon atoms, optionally substituted 3 to 10 cycloalkenyl having carbon atoms, optionally substituted carbon atoms Alkynyl having 2 to 10 atoms, an acyl group which may have a substituent, and 6 carbon atoms which may have a substituent
Or an aralkyl group having 7 to 20 carbon atoms which may have a substituent or a 5- to 7-membered heterocyclic group.] Or a salt thereof. 10. The method according to claim 9, wherein R ′ is alkyl having 2 to 6 carbons, alkenyl having 2 to 6 carbons or aralkyl having 7 to 10 carbons, each of which may have a substituent. Production method. 11. The method according to claim 9, wherein R′-X is allyl bromide, butyl iodide or nitrobenzyl bromide. 12. 1-hydroxyyohimbine is 2α,
The production method according to claim 9, which is obtained by oxidizing 7α-dihydroyohimbine with an oxidizing agent. 13. The method of claim 2, wherein 2α, 7α-dihydroyohimbine is
The production method according to claim 12, which is obtained by reducing yohimbine hydrochloride with a reducing agent. 14. 1-hydroxyyohimbine is subjected to at least the following steps: 1) dissolving in methanol, 2) adding an ether solution of diazomethane, 3) removing a solvent, 4) dissolving in an elution solvent, and 5) purifying. A method for producing methoxyyohimbine. 15. A compound of the formula (A "): [In the formula, R ″ is hydrogen, alkyl having 1 to 10 carbons which may have a substituent, cycloalkyl having 3 to 10 carbons which may have a substituent, Alkenyl having 2 to 10 carbons which may be substituted, cycloalkenyl having 3 to 10 carbons which may have a substituent, alkynyl having 2 to 10 carbons which may have a substituent, An acyl group which may have, an aryl group having 6 to 20 carbon atoms which may have a substituent, an aralkyl group having 7 to 20 carbon atoms which may have a substituent, or a 5 to 7-membered compounds or alpha ₂ receptor blocking pharmaceutical composition characterized by containing a pharmaceutically acceptable salt represented by showing a heterocyclic group]. 16. The method according to claim 15, wherein R ″ is hydrogen, alkyl having 2 to 6 carbons, alkenyl having 2 to 6 carbons or aralkyl having 7 to 10 carbons, each of which may have a substituent. A pharmaceutical composition according to claim 1. 17. The pharmaceutical composition according to claim 15, wherein R ″ is selected from hydrogen, allyl group, butyl group and nitrobenzyl.