JPS60214789A - 2-azaerythrinan derivative - Google Patents

Abstract

NEW MATERIAL:A compound of formula I (Y is -O-, -S-; R1, R2 are H, lower alkoxy, halogen; R3 is H, lower alkyl, nitro; R4 is H, lower alkyl, lower alkoxycarbonyl). EXAMPLE:2-Benzyl-17-methoxy-8-oxo-11a-oxa-2-aza-C-homoerythrinan. USE:Analgesic: it has central nervous system depressant action. PREPARATION:For example, the thermal condensation reaction between of 4- piperidone of formula II (R9 is benzyl, phenethyl) such as ethyl 1-benzyl-4-piperidone-3-acetate and an amine of formula III such as 2-(2-methoxyphenoxy)-ethylamine is carried out in an inert organic solvent, then the product is cyclized with heat under acidic conditions.

Description

Detailed Description of the Invention The present invention relates to 8-R4 represented by the following general formula (1), where Y is 10-1 or -S-an face screw, R1 and R
2 are the same or different and represent hydrogen, lower alkoxy, halogen, or hydroxyl group, and R3 represents hydrogen, lower alkyl, lower alkoxy, halogen, nitro group, or hydroxyl group. However, R2 and R3 may collectively represent tetramethylene. R4 is hydrogen, lower alkyl, lower alkoxycarbonyl, -CH2C)I = c', -(Rs, Re
are the same or different and represent hydrogen, lower alkyl or phenyl. ), -(CH2) n+ -@ (here m
represents l, 2 or 3. ), -(CH2) m -CobeichihiR? (here m is 1
．． 2 or 3, and R7 represents hydrogen, halogen, lower alkyl or lower alkoxy. ), -(CH2)
va-coX (here m represents 1.2 or 3)
, -CH2<β-Re (herein, R8 represents hydrogen or lower alkyl). The present inventors have synthesized a number of azaerythrinane derivatives and are actively researching their pharmacological effects. They found an analgesic effect and completed the present invention. The compound of the present invention is a novel compound that has not been described in any literature, has a central nervous system depressing effect, and is useful as a pharmaceutical.

The compound of the present invention can be produced by various methods, but R'l [II[l [■ general formula [■]] (wherein R9 = benzyl, phenethyl, methyl, or ethoxycarbonyl group, RIG" ethyl, )
The 4-piperidone compound represented by the formula [■] (wherein R1, R2, R3, and Y are the same as above) is heated and condensed in an inert organic solvent, and the condensate is converted into a monomer. It can be obtained by heating under acidic conditions to cause ring closure without separation or isolation. As the inert organic solvent used in the thermal condensation, it is preferable to use a high boiling point solvent such as benzene, toluene, xylene, DMF, dioxane, cellosolve, diglyme, etc., and heat it to reflux with a water remover attached.

Next, the ring-closing reaction under acidic conditions is carried out using mineral acids such as sulfuric acid, hydrobromic acid, hydrochloric acid, and phosphoric acid, or organic acids such as formic acid, p-toluenesulfonic acid, trichloro i[, l-+J fluoroacetic acid, etc.], or polyphosphoric acid. This is carried out by heating @(PPA), polyphosphate ester (PPE), phosphorus pentoxide, acidic ion exchange resin, etc. alone or in an aqueous solution or an organic solvent.

The reaction temperature is within the range of 30 to 250°C, preferably 80°C.
It is preferable to carry out the reaction at a temperature of 160 DEG C. to 160 DEG C., and the reaction time ranges from 30 minutes to several hours to achieve the ring-closing reaction.

When R9=CO2c2H6 of general formula (II) is used as a raw material, it may partially undergo hydrolysis during the reaction under acidic conditions, and R4=co, c2H5 of general formula [1]
Since it is produced as a mixture of and R4=H, it must be separated into a neutral substance and a basic substance and isolated. However, if either one is desired, it is possible by selecting acidic conditions.

Compound (II) used in the synthesis of general formula (1) was obtained by introducing a -CH2-CO2Rho group into the 3-position using ethyl 4-piperidone-3-carboxylate as a raw material, followed by hydrolysis and decarburization. ■
] It can be obtained by acidifying it to a ketocarboxylic acid and esterifying it. The R9-ethoxycarbonyl compound can be easily debenzylated by reacting the R9-benzyl compound of formula (II) with ethyl chloroformate.

Regarding substituents in which R4 in general formula [I] is other than R9,
Using R4-ethoxycarbonyl and R4=benzyl in general formula (1) synthesized by the ring-closing reaction, the former is hydrolyzed under acidic or alkaline conditions to form (1) R4=H form, and the latter benzyl group is Reductively eliminated by hydrolysis to form (1) R4=H form, or reacted with bromic cyanide or chloroformates such as ethyl chloroformate to form the above-mentioned (1) R4-ethoxycaponyl form,
Similarly, the (1) R4=H form may be hydrolyzed as fl, and then a desired substituent may be introduced using this (1) R4=H form. Deethoxycarbonylation is preferably carried out under acidic conditions, especially when heated to reflux in mineral acids (1) R4=H
You can get a body.

(I) Alkylation of R4=H can be easily carried out by general alkylation. For example, a method is used in which alkyl halides or reactive esters are reacted in the presence of a deoxidizing agent, or aldehydes are reductively alkylated. Aralkylation and heptalylation can also be carried out in the same manner. (1
) R4 = 2-benzoylethyl compound is obtained by Mannich reaction using acetophenone and formalin (1)
R4=3-oxy-3-phenylpropyl body is Mann
It is obtained by reducing the 2-benzoylethyl compound obtained by the ich reaction. (1) R4-butyrophenones are obtained by ketalizing 3-benzoylpropyl halides to protect the carbonyl group, reacting with (1) R4=H form, and then deketalizing by hydrolysis. (1) R+,
R2=H,R3-nitro compound is [1]R1,R2,R
3. R4=H can be obtained in good yield by nitration under general nitration conditions.

After the ring-closing reaction (1), the method for converting R4 = benzyl group into another substituent is to react the desired substituent with a halide or its active ester to form a quaternary salt, and then reductively debenzylate it. Alternatively, there is a method of debenzylation using thiophenol in an alkaline solution.

(1) A compound in which R, R2, and R3 are hydroxyl groups can be obtained by demethylating the corresponding methoxy compound. Demethylation of the methoxy group can be carried out in a good yield by a conventional method, for example, by heating with hydrobromic acid. When the substituent of R4 undergoes a change under demethylation conditions, the methoxy group of the general formula [■] shown below (in the formula, Y is the same as above) is demethylated to form (V), and then (V ) was substituted with R4 at the N position under the above alkylation conditions to obtain (Vl)[
IVI Lv]. However, in order to prevent simultaneous O-alkylation, when using a deoxidizing agent, it is preferable to use a carbonate. (Vl) can be obtained in a similar manner even in the case of substituents that do not undergo change under demethylation conditions.

The compound represented by the general formula [1] has two asymmetric carbon atoms (C-
However, in the case of an erythrinane skeleton, only those in which the ring bond erythrinane between A and B is cis-coordinated are produced during the ring-closing reaction.
Don et al. (Ber, 9B, 46. (1965)
) has been proven in its skeleton synthesis. Therefore, compound (1) produced by a similar reaction is a racemate of A/Bcis. Morphine, a typical analgesic, is levorotatory, and morphine-like synthetic analgesics are generally more active when they are levorotatory. In any case, if a racemic compound is optically resolved to obtain an optically active compound, one of the compounds will generally be more active and stronger than the racemic compound.

Optically active derivatives of the compound represented by general formula (1) can also be obtained. Optical resolution can be easily achieved by fractional crystallization using optically active t&acids and their salts in a conventional manner. Although optical resolution is possible for each of the formulas (1), it can also be obtained by a method in which a desired substituent is introduced into the R4 position after resolution of a compound in formula (13) where R4=H.

The compound represented by the general formula (1) obtained as described above can be converted into a crystalline acid addition salt with hydrochloric acid or a physiologically acceptable acid.

The analgesic effect of the compounds of the present invention will be described below.

The method of Kostar et al. (Fed, Proc, 18
．． 412 (1959)], DD strain male and female mice weighing 25 to 32 g) were used in groups of 6 mice, and 0.6
W produced when 10+wl/kg of % acetic acid was administered intraperitoneally
The number of richings was measured, and inhibition relative to the control group was used as an index. In addition, DD male and female mice weighing 23 to 30 g were used, with 4 mice in each group, 2 days after administration of each test drug (i, p,).
Based on the mortality rate in 4 hours, LD6 was determined by Wei1's method.
A value of 0 was calculated.

These results are shown in Table 1.

Table 1 These clearly demonstrate the excellent pharmacological effects of the compounds of the present invention.

Table 2 shows some of the compounds of the present invention.

In addition, the compounds in Table 2 are represented by the symbols in general formula (1). The compounds with compound numbers 171 to 173 are all optically active substances, and R, ,
Both R2 and R3 are hydrogen and Y is oxygen.

(See next page) Table 2 (See next page) Examples related to the production of the compounds of the present invention are listed below.

Example 1 2-benzyl-17-medoxy 8-oxo-11a-
Oxa-2-aza-C-homoerythritin (compound number 32) ethyl 41.3 g of 1-benzyl-4-piperidone-3-acetate and 24.4 g of 2-(2-methoxyphenoxy)-ethylamine were added to 600 ml of toluene.
and heated under reflux for 18 hours in a flask equipped with a water remover. The reaction solution was concentrated, and the residue was further reduced to 150 to 1
Heat on a 60°C oil bath for 3 hours.

After cooling, add 450 g of polyrin to the reaction mixture and add 12
Heat and stir on an oil bath at 0 to 130°C for 5 hours. After cooling, the reaction solution is poured into 2.5 liters of ice water, neutralized with potassium carbonate, and the liberated oil is extracted with chloroform, washed with water, dried, and the chloroform is distilled off.

Add 300 ml of ethyl acetate to the residue, add 30 g of silica gel, stir, and filter. The filtrate is concentrated, and a solution of hydrochloric acid in ethanol is added to the residue to crystallize the hydrochloride salt, which is collected by filtration and air-dried.

Yield: 27.2g (44%). Recrystallize from 95% ethanol. m, p, 280~281"C0IRνoutem-' i 2300 (N11) + 1690
(5-membered ring lactam) Example 2 17-medoxy-8-oxo-11a-oxa-2-other〇-homoerythrinane (compound number 124) 2-benzyl-17-medoxy-8-oxo- obtained in Example 1
24.0 g of hydrochloride of 11a-oxa-2-other C-homoerythrinane is dissolved in 200 ml of 20% ethanol and catalytically reduced at normal pressure using 3.0 g of 10% palladium-carbon as a catalyst. The catalyst is removed by filtration, the filtrate is concentrated and the residue is crystallized, 70 ml of ethanol is added thereto, heated and then allowed to cool. The precipitated crystals are collected by filtration and air-dried.

Yield: 11.0g (90%). Recrystallize from 95% ethanol. m, p, 292°C (dec,).

Example 3 17-Medoxy 2-methyl-8-oxo-11a-oxa-2-aza-C-homoerythritin (Compound No. 128) 17-Medoxy 8-oxo-11a- obtained in Example 2
Oxa-2-other〇-homoerythrinan hydrochloride 1.
Dissolve 7 g in water and neutralize with potassium carbonate.

The liberated base is extracted with chloroform, washed with water, dried, and the chloroform is distilled off. The residue contains 250mg of paraformaldehyde! Add 11ml of the mixture and heat under reflux for 3 hours. After cooling, 10 ml of ice water is added to the reaction solution, neutralized with potassium carbonate, the liberated base is extracted with chloroform, washed with water, dried, and the chloroform is distilled off. A solution of hydrochloric acid in ethanol is added to the residue to crystallize it as a hydrochloride. 95%
Recrystallize from ethanol, filter, and air dry. The amount obtained is 1.
3g (73,5%).

m, p, 271°C (dec, ).

I Rl'KRcm-'; 2600~2500
(>NH) +167B (5-membered lactam) Example 4 17-hydroxy-8-oxo-2-aza-11a-
Oxa-C-Homoerythrinane (Compound No. 158) 17-Medoxy-8-Oxo-2-Aza-11a - Oxa-C-Homoerythrinane (17.0 g) was dissolved in 48% hydrogen bromide @ 5 o m + in an oil bath at 130°C. Heat for 3 hours. After cooling, the precipitated crystals were collected by filtration, washed with water, and air-dried.Hydrobromide 11ft-19.0g, m, p, 300"c or more. Conohydrobromide was treated with aqueous ammonia to make a base and extracted with ClICl3. After washing with saturated saline and drying, ClI
Cl3 is distilled off and the residue is crystallized and recrystallized from ethanol.

Base capacity -12,8g, m, p, 233-234℃
.

IRν output cm-': 3400.3300 (-Oll
, >NH).

168B (5-membered ring lactam) Example 5 17-hydroxy-2-methyl-8-oxo-2-aza-11a-oxa-C-homoerythrinane (compound number 159) 17-medoxy-2-methyl-8-oxo-2 -Aza-
1.3 g of 11a-oxa-C-homoerythrinane in 48
% hydrobromic acid and heated on an oil bath at 130° C. for 2 hours.

After cooling, add 10 ml of ice water to the reaction solution, make alkaline with aqueous ammonia under water cooling, extract with chloroform, wash with saturated brine, dry, and evaporate chloroform. Crystallize the residue and collect by filtration (1.1 g) from L ethanol. recrystallize.

Base displacement - 0,9g Xm, p, 257-259'c
Hydrochloride (HCI ・H2O) m, p, 276-27
7°C (dec, ) (recrystallized from 95% ethanol) I Rv WCc "I: 3400 (-OH),
1673 (5-membered ring lactam) Example 6 2-furfuryl-17-hydroxy-8-oxo-2
-Aza-11a~Oxa-C-homoerythrinane (Compound No. 163) 17-Hydroxy-8-oxo-2-aza-11a-
Oxer C-homoerythrinane 2.0g in DMF30
After cooling, 3°Og of sodium bicarbonate was added and 0.85g of furfuryl chloride was added while stirring at room temperature, and stirring was continued at room temperature for the next 16 hours.

The reaction solution was concentrated under reduced pressure, the residue was made acidic by adding 10% hydrochloric acid, the liquid was separated by adding ethyl acetate, the acidic solution was converted into an ammoniacal alkali, and the liberated base was extracted with chloroform.
After washing with water and drying, chloroform was distilled off, and the residue was subjected to column chromatography (80 g of silica gel).

1.8 g of base is obtained, which is crystallized and recrystallized from ethyl acetate.

Discharge = 1.6 go all, 9.167-168°C.

Hydrochloride m, p, 248-250℃ (dec,) I R
vman-1: 3310 (-011), 1fi
72 (Five-membered ring lactam) Example 7 Optical resolution of 8-oxo-2-aza-11a-oxa-C-homoerythrinane (compound number 171) L-(+)
- Tartar rM 7.5g t equimol (7) 8-, t+'/
-2-aza-11a-oxa-C-homoerythrinane 1
2.9 g was heated and dissolved in 160 ml of 80% alcohol and allowed to cool. After about 4 hours, the precipitated crystals were collected by filtration, and then
Recrystallize twice from % aqueous athanol.

Displacement is 4.80g, m, p, 230-231'
C(dec,)(α)V=98.8° (C=0.98
9. Water) This (+)-tartrate is dissolved in water, neutralized with potassium carbonate, the free base is extracted with chloroform, washed with water, dried, and the chloroform is distilled off. 3.07 g of crude base was recrystallized from ethanol-ether hot medium.

Discharge amount is 2.21g, p, 163-164℃.

(αlV= 137.4° (C=1.161.eta/
- colorless prismatic crystal.

9.8 g of precipitated crystals were obtained from the fractionated crystallization mother liquor, neutralized with potassium carbonate to obtain 6.2 g of a crude base, a salt was made with 3.5 g of D-(-)-tartaric acid, and the salt was reconstituted from 80% aqueous ethanol. Crystallize twice. Displacement = 5.30g.

11.1), 230-231"C (dec,).

[α degree=-98.0" (C=0.851.water) Next, this (-)-tartrate was converted back to the base to obtain 3.15 g, which was recrystallized from an ethanol-ether heating medium. , 2.5
Obtain 0g.

m, p, 163~164℃ (dec,) [α Liao=-1
38,2° (C=1.003.ethanol) Example 8 (+)-2-cinnamyl-8-oxo-2-aza-11
a-Oxa-C-homoerythrinane (Compound No. 172
)(+) -8-oxo-2-aza-11a-oxa-
1.50 g of C-homoerythrinane was dissolved in 30 ml of dimethylformamide, 2.0 g of potassium carbonate was added, and 0.93 g of cinnamyl chloride was added dropwise with stirring at room temperature.
Afterwards, stir at room temperature for 16 hours. Concentrate the reaction solution under reduced pressure,
The residue is extracted with ethyl acetate, washed with water and dried, and the ethyl acetate is distilled off. The residue is purified by silica gel column chromatography. Convert 1.85 g of base into hydrochloride and concentrate to dryness to obtain an amorphous powder. The elemental analysis results match, including one molecule of water.

[α form = 71.5° (C = 0.936. ethanol)
Mass spectrum: M” 374 (100).

M-91283(43,8)l Rvjii:cn-1: 3400.2700~
2400.1690(-) body was also reacted in the same manner as above,
After post-treatment, amorphous powder hydrochloride (contains 1 molecule of water)
get.

(lW=-71,4° (C=0.966, x ta/
- Mass spectrum: M” 374 (10
0).

M-91283 (43,8) IR matches the (+) body.

Example 9 (+)-8-oxo-2-(3-phenylpropyl)-
2-aza-11a-oxa-C-homoerythrinane (compound number 173) (+) 4s-oxo-2-aza-11a-oxa-C
- Dissolve 0.70 g of homoerythrinane in 20 ml of dimethylformamide, add 1.00 g of potassium carbonate and 0.10 g of potassium iodo, and dropwise add 0.50 g of 3-phenylpropyl chloride while stirring at room temperature.
Heat and stir on a 90°C oil bath for 8 hours. The reaction solution was concentrated under reduced pressure, and the residue was extracted with ethyl acetate, washed with water, and dried, and the ethyl acetate was distilled off. The residue was treated with ethanolic hydrochloric acid, crystallized as the hydrochloride salt, collected by filtration, and ethanol-
Recrystallize from ether mixed solvent. Discharge = 552mg
, sheath, p, 229-232°C.

[α) Da=79.0° (C=0.957.ethanol) IRνW>-': 2300 to 2500.1687
The (-) body is also reacted and post-treated in the same way as above. Displacement -7
75 mg, m, p, 229-232°C.

[α = -73.8° (C = 1.001.ethanol) IR matches the (+) body.

Applicant: Nippon Shinyaku Co., Ltd. Agent: Patent Attorney Hiroshi Katama

Claims (1)

Claims: An 8-oxo-2-azaerythrinane derivative represented by the following general formula (1), an acid addition salt thereof, and an optically active substance thereof. 4 However, Y represents -0- or -3-, and R1 and R
2 are the same or different and represent hydrogen, lower alkoxy, halogen, or hydroxyl group, and R3 represents hydrogen, lower alkyl, lower alkoxy, halogen, nitro group, or hydroxyl group. However, R2 and R3 may collectively represent tetramethylene. R4 is hydrogen, lower alkyl, lower alkoxycarbonyl, /Rterc12co=CS (Rs and Rs are the same or different and represent 6 hydrogen, lower alkyl or phenyl), (CH
2) m-◎ (here m represents l, 2 or 3)
, (CH2) +1-CobeiR? (here m represents 1.2 or 3, R7 represents hydrogen, halogen, lower alkyl or lower alkoxy), 1l (CH2) m -CHbesho (here m represents 1.2 or hydrogen or lower represents alkyl),