JPS59216888A - 5-oxo-5h-(1)benzopyrano(2,3-b)pyridine derivative, its preparation and medicinal composition - Google Patents

Abstract

NEW MATERIAL:A compound of formula I (R is H, alkyl, alkoxy, nitro, hydroxy, acyl, hydroxyalkyl, halogen; m is 1-3; n is 1, 2), its salt or ester. EXAMPLE:Methyl ( 7-ethyl-3-methoxycabonyl-5-oxo-5H-[1]benzopyrano[2,3-b]pyridin-2-yl)ac etate. USE:A remedy for a variety of diseases in connective tissues such as rheumatoid arthritis and a variety of inlfammation caused by immunity. PREPARATION:The reaction between 4-oxo-4H-1-benzopyran-3-carbonitrile and an active methylene compound of formula III (R<1> is alkyl) such as dimethyl 1,3- acetonedicaboxylate, preferably at 1/1-1/5 molar ratio, is, when necessary, followed by hydrolysis to give the objective compound.

Description

Detailed Description of the Invention The present invention relates to the general formula (I) [wherein R is the same or different, hydrogen, alkyl, alkoxy, nitro, hydroxyl, acyl, hydroxyl, halogen or cyclic Tetramethylene group (-(CH2)4) which forms a 6-membered ring with two adjacent carbon atoms of
-) or butadienylene group (-CH=CH-CH=
CH-), m represents 1.2 or 3, and n represents 1 or 2, respectively] 5-oxo-5H-(1)
The present invention relates to a benzopyrano[2゜3-b]pyridine salt conductor or a salt or ester thereof, a method for producing the same, and a pharmaceutical composition.

The compound represented by the general formula (I) or its salt or ester of the present invention is a 4-oxo-4H-1 represented by the general formula (n) [wherein R and m have the same meanings as above].
-penzobion-3-carbonitrile, the general formula (N) R10oc-(CHg)n-COCH2COOR, (I
II) [In the formula, R1 represents alkyl A/, n1jl or 2, respectively] and can be produced by reacting the compound and subjecting it to a hydrolysis reaction if necessary.

The compound of the present invention represented by the general formula (I) thus produced is useful as a therapeutic agent for various connective tissue diseases such as rheumatoid arthritis and various inflammatory diseases caused by immune reactions.

The substituents R and R1 in the above formula will be explained. Examples of the alkyl group represented by R include straight chain or branched alkyl μ groups having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl) butyl, t-butyl, bench μ, and hexyl groups. Further, examples of the alkoxy group include alkoxy groups in which the alkyl moiety has 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy, and butoxy groups, and examples of the acetiμ group include acetyμ.

Those with 2 to 4 carbon atoms such as propionyl and butyryl groups, and hydroxyalkyl groups such as hydroxymethyl, 1-hydroxyethymu, 1-hydroxypropyl, 1-hydroxy-1-methyl-ethyl, 1-hydroxy Examples include those having 4-1-4 carbon atoms such as the group μ group, and examples of halogen atoms include chlorine, bromine, iodine, and fluorine. Among these substituents, alkyl, halogen and hydroxyalkyl are practically preferred. Particularly preferred are alkyl μ having 1 to 3 carbon atoms, chloro, and hydroxyalkyl having 1 to 3 carbon atoms. As the alkyl group of R1 in the general formula (I[), methi/
L/, ethyl.

Propyμ, isopropyl, butyμ, t-glutyl, etc. have a carbon number of 1. -4 can be mentioned.

Examples of the salt of the compound represented by formula (I) include pharmacologically acceptable alkali metal salts such as sodium and potassium.

More specifically, the compound represented by the general formula (I) of the present invention is produced by the following method. That is, the general formula (II
The compound of general formula (I) is produced by reacting the compound of general formula (I) with the active methylene compound represented by general formula (I[). The amount of the active methylene compound used in the reaction is usually about 1 to 5 times the mole of the starting compound of general formula (II) in practice.

In the above reaction, the presence of a base is generally desirable, and the bases used include organic amines, such as piperidine,
Secondary amines such as pyrrolidine, morpholine, diethylamine, dipropylamine, dibutylamine, tertiary amines and imidazole such as 1,8-diazabicycloC5,4,0,:]-7-undecene and triethylamine,
Examples include heterocyclic bases such as 2-methylimidazole. The amount of these organic bases used is usually based on general formula (II)
The catalytic amount to 5 times mole/l' culm degree per mole of the raw material compound.

It is generally desirable to carry out the reaction in an organic solvent, such as methanol, ethanol, propanol, etc.
/l', alcohols such as butano-p, and dimethylformamide. Although there are no particular limitations on other reaction conditions such as reaction temperature and reaction time, it is common to carry out the reaction at room temperature to around the boiling point of the solvent used for about 1 to 24 hours.

Among the diester compounds of the general formula (I) obtained as described above, in the case of a compound in which R has 1-hydroxyalkyl μ, this compound is oxidized by a conventional oxidation method, such as Jones oxidation in acetone, etc. can lead to the corresponding acyl μ group.

By hydrolyzing the diester compound of general formula (1) if necessary, it can be led to a compound of general formula (I) or a salt thereof. As conditions for hydrolysis, usual acid hydrolysis method or alkaline hydrolysis method is used. For example, in the acid hydrolysis method, sulfuric acid, hydrochloric acid, phosphoric acid, etc. are used in excess, and the acid alone or an organic acid such as formic acid is used.

With organic acids such as acetic acid, or methanol.

It is usually carried out at a temperature of room temperature to around 150 tE together with alcohols such as ethanol-μ and propano-μ, or ether/L's such as tetrahydrofuran and dioxane.

In addition, in the alkaline hydrolysis method, sodium hydroxide, potassium hydroxide, barium hydroxide, etc. are used in excess, and the above-mentioned alcohols and ethers are used as solvents, and the process is usually carried out at temperatures ranging from room temperature to around 150 tE. be exposed. The reaction time varies depending on the compound, but is usually about 1 hour to several days. Further, depending on the case, the target compound can also be produced by combining acid hydrolysis and alkaline hydrolysis.

The compound of general formula (I) thus produced can be used as a therapeutic agent for various connective tissue diseases such as rheumatoid arthritis and various inflammatory diseases caused by immune reactions.

The compound of general formula (I) can be mixed with a pharmaceutical carrier together with adjuvants in a conventional manner to form oral preparations such as tablets, granules, powders or capsules, or dissolved in distilled water for injection. It can also be used as an agent. For tablets, granules, and powders, lactose, starch, dextrin, white sugar, crystalline cellulose, kaolin, calcium carbonate, talc, etc. are preferred as pharmaceutical carriers, and for injections, sodium chloride or potassium chloride is preferred. It is preferable to strengthen it equally.

The amount of the compound of general formula (I) in the pharmaceutical composition is usually 10 to 2,000 caps per day for an adult, preferably 50 to 500 caps per day for an adult as an oral preparation, and a daily dose of 50 to 500 caps for an adult. The daily dose is 1-500 q, preferably 5-100 q.

Acute toxicity 7-ethy/l/-3-carboxy-5-oxo-5H-
(4) Add a 4% suspension of gum arabic of benzopyrano(2,3-b:)pyridine-2-acetic acid disodium salt to Jcl
: - As a result of oral administration to ICR male mice (5 weeks old), no abnormalities were observed at 2,000 Q/kLj.

Experimental examples and examples of the present invention are shown below, but the present invention is not limited thereto.

Experimental Example/ Adjuvant Arthritis Suppressing Effect The animals used were Sudewog-Daurei male rats (6 weeks old).

Adjuvant arthritis is caused by dead tuberculosis bacteria (M, butyri).
-cum strain) was suspended in liquid puffin and injected intracutaneously into the right hind leg of rats to induce the disease. Specimen (7-ethyl/L/-
A suspension obtained by suspending 70q of 3-carboxy-5-oki'/-5H-(1) benzopyrano (2,3-b) pyridine-2-acetic acid disodium salt) in 7txtVC of 4% gum arabic solution. The adjuvant was administered once a day at a rate of 0.5 ml per 100 f of body weight for 14 consecutive days. The degree of inflammation developed in the non-adjuvant-injected hindlimb, 9 forelimb tails, and ears was scored from 1 to 5 and summed for each animal.

The maximum score is 20 for the four locations. In addition, the effects on body weight gain (difference between body weight after 14 days and sensitized mortar) and thymus weight were compared with the sober and control groups. The results are shown in Table 1. The specimens improved systemic inflammation scores and associated suppression of weight gain, as well as increased thymus weight.

Table 1 *: P<0.05 The sample did not show any anti-inflammatory effect in the rat cuffgenin edema method or analgesic effect in the mouse phenylquinone rising method, and did not have any effect on the brostagfungin synthase of V. There wasn't.

Experimental Example 2 Adjuvant Arthritis Inhibition Effect Sprague-Dowley male rats (6 weeks old) were used as animals.

Adjuvant arthritis is caused by dead tuberculosis bacteria (M, butyri).
-cum strain) was suspended in liquid buffine and injected intracutaneously into the right hind limb of rats to induce the disease. Specimen [Ethi/I/(7-
ethyl/l/-3-ethoxycarbony/l/-5-oxo-5111-(1)benzopyranoC2,3-b:)pyridin-2-yl)acet-))70Wv to 491)gum arabic liquid 7g/ The suspension obtained by suspending the
The adjuvant was administered continuously for 14 days from an adjuvant injection muzzle once a day at a rate of 5 oz. The degree of inflammation developed in the hind paw on the non-adjuvant-injected side, one forelimb tail, and the ear was scored from 1 to 5 and summed for each animal. The maximum score is 20 for the four locations. In addition, the effects on body weight gain (difference between body weight after 14 days and sensitized mortar) and thymus weight were compared with the sober and control groups. The results are shown in Table 2. The specimens showed a tendency to improve systemic inflammation scores and associated suppression of weight gain, as well as increase thymus weight.

Table 2 **: P<0.01 Example/6-ethyl/I/-4-oxo-4H-1-penzopyfun-3-forceμbonitri/l/(1,99g), dimethyl
A mixture of 1,3-acetone chloride (2g), methanol/l/(20g), and piperidine (0,2g) was heated under reflux for 3 hours, concentrated, and ethanol was added to the residue to give a yellow The crystals were collected by filtration.

This was applied to a column of silicage) v (50?>) and hexane-chloroform-ethyl acetate/L' (10:
After elution with 10:1), recrystallization from methanol yields methoxyv(7-ethy)v-3-methoxyca1
2- Rubonyl-5-oxo-5H-(1) Benzopyrano C2
, 3-b) 1.04 g of pale yellow needles of pyridin-2-y/L/) acetate were obtained. Melting point 142-143t
0 Similarly, (3-alkoxycarbonyl-5-oxo-5H-CI)benzopyrano[2,3-b]
A diester derivative of acetic acid was produced.

1st A: Tri A / 4 and nitrile, 1' carbonitrile A 7 nitri, 1' carbonitrile 5 nitri, 1' Similarly, 4-oxo-4H-nut [2,1-b
) Pyran-3-carbonitrile, methi/L/(3-
Me[oxycarponi)v-5-oxo-5H-CI)-
naphtho(2',1'-2,3,:l pyrano(6,5-b
) Pyridine-2-y/l/) Acetate-F Melting point 240-2
45tE and I Q-n-propy/L/-6.718
19-tetwohydro-4-oxo-4I(-naphthoC2
,3-b) From pyran-3-carbonitrile, methyl
(3-methoxycarbony)V-11-n-propy/&
-7.8.9.10-tetrahydro-5-oxo-5H
-Natsuto [τ, 3'-2,3) Pyrano C6,5-b:)
Pyridin-2-yl)acetate Melting point 156-157
I got ti.

Example λ 6-ethyl 1v-4-oxo-4H-1-benzopyran-
3-force μ bonitri/'(1,'99g), diechi μ β
-ketoazibe) (2, (1), ethanol (151!
1/) and piperidine (0.3 liters) was heated under reflux for 1.5 hours. The precipitated crystals were collected by filtration, suspended in ethanol, and heated to reflux. After cold welding and filtering the crystals, ethyl/I/(3-ethoxycarboni/L'-7-ethylv-5-oxo-5H-CI:)benzopyrano[2
, 3-b)-pyridin-2-y/I/) propionate as colorless needle-like crystals of 1.93 tF were obtained. Melting point 168-
170t:.

Similarly, ethyl A/(3-ethoxycarbony1v-
5-oxo-5I'1-(1)benzopyrano(2,3-
b) Pyridin-2-y/L/)propionate Melting point 1
50-151tE and 6-chloro-4-oxo-4H-1-benzopyran-3
-Carbonitrile to ethyl/7 3-(7-chloro-3
-ethoxycarbony/l/-5-oxo-5)1-C
I) Benzopyrano C2,3-b) Pyridin-2-y/L
/) Propionate melting point 128-129ti was obtained.

Example 3 Ethi iL/(3-ethoxycarboni7m/-7-(1
-hydroxyethyl/l/)-5-oxo-5H-[1]
Jones reagent (chromic anhydride 6.09.97%) was added to a solution of benzopyrano[2,3-b)pyridin-2-yl)acetate (3,99 g) and acetone (50 ml) at room temperature.
Prepared from 3.6 txt sulfuric acid and 18 Mt water) 4,0
g+/ was added over 20 minutes. Add water to the reactant (150s
tt) was added, the precipitated crystals were collected by filtration, and chloroform μ.
It was dissolved in acetone/formic acid (80:1:0.1) and purified by pouring it onto a silica cake/L/(140q) column. Recrystallization from ethyl acetate yields colorless needles of ethyl (7-acetyμm3-ethoxycarbonyl-5-oxo-5H-(1)benzopyrano[2,3-b)pyridin-2-yfi/)acetate-F. Crystal 3.141F was obtained. Melting point 160
-161t30 Example Gumethi/L' (7-ethy/L/-3-methoxycarbony/l/-5-oxo-51(-CI, lbenzopyrano[2,3-b)pyridine-2- b) Acetate (7.10g), tetrahydrofuran (100g+/)
IN hydroxide solution) IJium aqueous solution (42g/)
was added and stirred at room temperature for 2 hours. After cooling, methanol-A/(200ml/) was added to the reaction solution, the precipitated crystals were collected by filtration, recrystallized from water-methanol, and dried under reduced pressure at 50°C to obtain disodium (3-carboxylate-7).
6.5q of colorless crystals of -ethyl/L/-5-oxo-51'1-1-benzopyranoC2,3-b)pyridin-2-yP)acetate were obtained. Melting point 275-28 (1 (decomposition)
.

The following compounds were obtained in the same manner.

Methyl (3-methoxycarbonyA/-7-itsupropyA/-5-oxo-5a-+: 1) Penzopyrano(2,3-b)pyridin-2-iL/) Acetate Yoridisodium (3- Carboxilado-7-isopropytV-5-oxo-5H-(1,)-benzopyrano[2
, 3-b) Pyridin-2-ylv) Colorless crystals of acetate (water-methano-)v) (did not show a clear melting point)
.

Infrared absorption spectrum) lz (KBr) cm, 16
60°580 Nuclear Magnetic Resonance Svec)/L'(D20)δ: 8.43
(IH.

s), 7.36 (IH, s 1ike), 7.28 (
IH, dd, J=2 and 3Hz), 6.89 (LH
,d,,T=8Hz),4.33(2H,s),2.6
6 (LH, quintet, 6Hz in J).

1.20 (6H, d, J=6.5Hz) Methyl (3-
Methoxycarbony/l'-11-n-propyum7.
8,9.10-Tetrahydro-5-oxo-5H-naphtho[τ,3'-2.3)pyrano(6,5-b)pyridin-2-y)v) acetate to disodium (3-carboxylad- 11-n-propy/L'-7.8,9.1
0-tetofhydro-5H-nut [τ, 3'-2.3)
Colorless needles of pyrano(6,5-b)pyridin-2-i/I/) acetate (water-methano-/I/).

Infrared absorption spectrum)v(KBr)cn+, 34
00°1670, 1650. 1630.1605.1
575 nuclear magnetic resonance spectrum (D20) δ: asx
(IH.

s), 6.95 (IH, a), 4.18 (2H, s),
ca2.37 (6H, m), 1.48 (4H, m), C
al, 1 (2H, m).

0.82 (3H, t, J=6Hz).

Examples Methyl/L/(3-methoxycarboni/L'-5-oxo-5H-C1)-benzopyranoC2,3-b]pyridin-2-y1v)acetate-) (3,27 g), A mixture of 80% sulfuric acid (20g/) and acetic acid (4ml) was heated to 70"C, water (7gl) was added, and the mixture was heated for 2.5 hours. Water was added to the reaction solution, and the precipitate was collected by filtration. After washing with chloroform, the mixture was stirred with IN aqueous sodium hydroxide solution (40 g/) at room temperature for 4 hours.

Add methanol/1/(6011/) and filter the precipitated crystals. □Collect and recrystallize from water-methanol to obtain disodifu (3-calphoxyft-5-oxo-
5H-19-[1]benzopyranoC2,3-b)-pyridin-2-i/I/) Acetate was obtained in colorless needle-like pores at 2.669 (
No clear melting point was observed. ).

Infrared absorption spectrum 1v (KBr)cn+, 3
400°1650-1600 Nuclear magnetic resonance spectrum (D20) δ: 8.33 (I
H.

a), 6.89-7.67 (4H, m), 4.09 (2
H, s) Elemental analysis value C> 5H7NO6Na2 ・2
Calculated value as H20: C47,50i H2,92
Measured value of N3.69: C47,49i, H2,71
i N 3.95 or less The following compound was obtained in the same manner.

methoxy)v(7-chloro-3-methoxycarpony/l/
-5-oxo-5H-C1) Benzopyrano[2,3-b
) Pyridine-2-y1v) Disodium from acetate
(7-chloro-3-calphoxyft-5-oxo-5H
-(1) Colorless needle crystals of benzopyrano[2,3-b)pyridin-2-yl)acetate (water-methano-)'V).

Infrared absorption spectrum/I/(KBr)cm 1: 1
665°600 20- Nuclear magnetic resonance spectrum/L/(D20)δ: 8.42
(IH.

a), 7.36 (IH, d, J=2Hz), 7.3u (
IH, dd, J = 2 and 9Hz) + 7.02 (IH
, d, J=9Hz).

4.13(2H,a) Methyl (7,9-dimethy/l/-3-methoxycarbony/L'-5-oxo-51(-CI)benzopyranoC2,3-b)pyridin-2-y /I/) Yoridisodium acetate (3-carboxylado-7,9-dimethy/l/-5-oxo-5H (1) Benzopyrano C2,3
-b) Colorless needle-like crystals of pyridin-2-i/L/) acetate C water-methano=/L/).

Infrared absorption spectrum/l/(KBr)cm 1: 34
00°1670, 1630-1580 Nuclear magnetic resonance spectrum fv (D20) δ: 8.25 (
IH.

s), 6.67(IH,br,a)+64s(tn+b
r, sL4.12 (2H, a), 1.90 (3H, s)
, 1.82 (3Ls) methi/l/ (3-methoxycarbony/L/-5-oxo-5H-(1) nuts [τ
, 1'-2.3,1 pyranoC6,5-b) pyridine-2
-a) v) Disodium (3-carboxy-5-oxo-5H-(1,:])naphthoC2' from acetate
, 1'-2.3] BifnoC6,5-b, :]] Colorless needle-like crystals of pyridine-2-I/I/acetate (water-methano-
)V).

Infrared absorption spectrum (KBr) c+n, 340
0°1650, 1615.1578.1385 nuclear magnetic resonance spectrum)/l/(D20)δ: 8.60 (IH.

m), 7.97 (IH, s), 7.38 (IT (, d,
J=9Hz).

Ca7.05 (3H, m), 6.70 (IH, d,, T
=9Hz).

4.05 (2H, s) Methi7+/ (7-medoxy-3-methoxycarboni/l/-5-oxo-5H-CI) Benzopyrano C
2,3-b) pyridin-2-yl)acetate to disodium (3-carboxylado-7-methoxy-5-
Colorless needles of oxo-5H-(1) Benzovitz C2,3-b) pyridin-2-y/L/) acetate (water-ethano-μ).

Melting point 190-200℃ (decomposition) Infrared absorption spectrum (KBr, ) cm 1: 365
0-2900, 1645. 1620. 1610.
1585. 1545 nuclear magnetic resonance spectrum/l/(D
20) δ: 8.77 (IH.

s), 7.1-7.5 (3H, m), 4.38 (2H,
a), 3.89 (3H, a) Example Z Ethyl/I/ 3-(3-ethoxycarboni/L'-
7-ethyl/l/-5-oxo-5H-(:1)benzopyrano(2,3-t+)pyridin-2-i/I/)propionate (2,6s), 80% sulfuric acid (16g/), After heating the mixture of acetic acid (4+/) to 7n to form a solution,
Water (8 g/) was added over 20 minutes, and the temperature was raised to 100°C. After heating at 10 liters for 2 hours, water was added to the reaction solution, and the precipitate was collected by filtration and washed with water. The obtained white solid was dissolved in IN aqueous sodium hydroxide solution (45 g/) and stirred at room temperature.1. After 5 hours, the reaction solution was made acidic by adding concentrated hydrochloric acid, and the precipitated solid was collected by filtration and recrystallized from dimethylformamide-water to give 3-(3-carboxy-7-ethyl/L'
-5-oxo-5H-(1) Benzopyrano(2,3-b
, lpyridin-2-y/I/) 2.019 colorless fine crystals of propionic acid were obtained. Melting point 284-287℃ (decomposition)
Similarly, from ethyl)v 3-(7-chloro-3-23-ethoxycarbonyl-5-oxo-5H-(1) benzopyrano(2,3-b]pyridin-2-y)propionate, 3 -(3-carboxy=7-chloro-5-
Colorless needle crystals of oxo-5H-[1]benzopyranoC2,3-b)pyridin-2-yl)propionic acid (dimethylformamide) were obtained. Melting point: 295-298°C (foaming decomposition) Example Z 6-ethyl/l/-4-oxo-4H-1-penzobifune-3-carbonitri/l/(8,001F), diethyl 1,3-acetone dicarboxylate) (8.8g),
Ethano-/l' (7 offr) and piperidine (0,
A mixture of 5tttl) was heated under reflux for 2 hours, then cooled, and the precipitated crystals were collected by filtration and washed with ethanol to obtain 12g of pale yellow crystals. 1.59% of the ice crystals were removed and poured onto a silica y (toog) column, and hexane-chloroform-acetone-formic acid (20:20:1:0.05) was added.
), purified, recrystallized from ethanol-μ, and ethyl)
v (7-ethyl/1/-3-ethyloxycarboniμm5
-Oxo-5H-24- [1]Benzopyrano[2,3-b)pyridin-2-y/
1.3 g of colorless needle crystals of I/) acetate were obtained.

Melting point 123-124'C.

Examples and 6-chloro-4-oxo-4H-1-penzopyfun-3
-Carbonitri/L/(5g), piperidine (0,56
1/) and diethyl 1,3-acetonedicarboxylate (4.6 g/) were added to ethanol-1v (50 pal) and heated under reflux for 1.5 hours. The precipitated crystals were collected by filtration, washed with ether until the washings were no longer colored, and recrystallized from chloroform-ethanol to give ethyl/L' (
7-chloro-3-ethoxycarbonyl A/-5-oxo-
5) (-(1)BenzopyranoC2,3-b)pyridine-
6.179 pale yellow needles of 2-I/I/) acetate were obtained. Melting point 148-149t: 0 Formulation example (tablet) Disodium (3-carpoxysift-7-ethyl/L'-
5-Oki”/-5H (1) Benzopyrano [2,3-b)
Pyridine-2-I/L/]acetate 5011v Lactose 15(1') Corn starch 351f Microcrystalline cellulose 301q270q/tablet The above ingredients were stirred and mixed to form a homogeneous mixture, and then compressed into tablets according to a conventional method. .

27-1

Claims (3)

[Claims] (1) General formula [wherein R is the same or different, hydrogen, aμkiμ, aμkoxy, nitro, hydroxyl group, aVfi/, hydroxyapkiμ, halogen, or adjacent on the ring Tetramethylene group (-(CH2
)4-) h or butadienylene group (-CH=CH-
CH=CH-), m represents 1, 2 or 3, and n represents 1 or 2, respectively], or a salt or ester thereof. (2) General formula [wherein R is the same or different, hydrogen, alkyl μ, aμ coquine, nitro, hydroxyl group, aciμ, hydroxyaμkyl, halogen, or two adjacent carbon atoms on the ring Tetramethylene group (-(CH2)4) that forms a 6-membered ring with atoms
-) or butadienylene group (-CH=CH-CH=
CH-), m represents 1, 2t or 3, respectively] to a compound represented by the general formula 8% [wherein, R1 represents alkyl and n represents 1 or 2, respectively] A method for producing a compound represented by the general formula [wherein R, m and n have the same meanings as defined above], or a salt or ester thereof, which comprises reacting and subjecting, if necessary, to a hydrolysis reaction. (3) General formula [wherein R is the same or different, hydrogen, alkyl, alkoxy, nitro, hydroxyl group, acyl, hydroxyalkyl, halogen, or a 6-membered ring together with two adjacent carbon atoms on the ring] Tetramethylene group (-(CH2)4) to form
-') or butadienylene group (-CH=CH-CH
=CH-), m is 1.2 or 3, n is 1 or 2
A pharmaceutical composition containing a compound represented by (respectively) or a salt thereof or an esthetic.