JPS60139646A - Naphthalene derivative - Google Patents

Abstract

NEW MATERIAL:A compound of formula I [R1 is alkoxy; R2 is carboxyl, nitro, formula II; R3, R4 are H, (substituted) alkyl, cycloalkyl, cycloalkylaminocarbonyl, (substituted) phenyl or bond between them through both N and O atoms or only O atom to form a saturated heterocyclic group of 5- or 6-membered ring; the bond of dotted line means a single or double bond]. EXAMPLE:beta-[2-(1,4,5,8-Tetramethoxy)naphthyl]acrylic acid. USE:It has actions of cerebral and coronary vasodilation, inhibition of biosynthesis of thromboxane A2, and cardiotonic, spasmolytic and antiallergic actions. PREPARATION:1mol of an aldehyde of formula III and 2mol of malonic acid are heated in the presence of piperidine at 60-100 deg.C to effect condensation reaction to give a compound of formula I where R2 is COOH. Subsequently, an amine of HNR3R4 is allowed to react to give a compound of formula II where R2 is formula II.

Description

[Detailed description of the invention] The present invention relates to naphthalene derivatives.

The naphthalene rust conductor of the present invention is a novel compound that has not been published in any literature, and is represented by the following general formula (+1).

R1R□ [In the formula, R1 represents a lower alkoxy group, R2 represents CalR3
and RLL may have the same or different hydrogen atom, a lower alkyl group, a Schiff alkyl group, a Schiff alkyl aminocarbonyl group, a lower alkoxydecacarbonyl group or a carboxyl group as a substituent. A phenyl group, a phenyl lower alkyl group that may have a lower alkoxy group as a substituent, or a lower phenyl group that may have a carboxyl group, a phenyl lower alkoxycarbonyl group, or a carboxyl group as a substituent. Indicates an alkyl group. Furthermore, R3 and Ra may be bonded together with adjacent nitrogen atoms to form a 5- or 6-membered saturated heterocyclic group with or without an oxygen atom or a nitrogen atom, and the heterocyclic group may further include phenyl group, phenyl lower alkyl group, besilyyl group, (A is a lower alkyl resin group, R5 is a hydrogen atom, a carboxyl group or a lower alkoxycarbonyl group, respectively) as a substituent. Good too.

= indicates a single bond or a double bond. ] In the above general formula (1), the lower alkoxy groups defined by R□ include, for example, meth+s, ethoxys, zu0po,
Examples include iso''JJO, 5ec-, tert-but, vesity, and he+syl.

Examples of the lower alkyl group defined by R3 and R4 include methyl, ethyl, D-pyl, iso-pyl, butyl, iso-butyl, C-butyl, tttrt-butyl, pentyl, henzyl. Examples include groups. Examples of the Schiff alkyl group include Schiff's pyl, Schiff's butyl, Schiff's pentyl, Schiff's pentyl, Schiff's hetyl, and cyclooctyl groups. Examples of the Schiff 0 pyraminocarbonyl group include Schiff 0 pyraminocarbonyl, Schiff 0 butylaminocarbonyl, Schiff 0 pyraminocarbonyl, and Schiff 0 pyraminocarbonyl.
Examples include ventyla trinocarbonyl, Schiff O bovine sylaminocarbonyl, Schiff O butylaminocarbonyl, Schiff O octylaminocarbonyl, and the like. Examples of the phenyl group which may have a lower alkodicarbonyl group or a carboxyl group as a substituent include phenyl, dicarbonylphenyl in 0-meth, dicarbonylphenyl in m-eth, and t'-1erl-dicarbonyl. Examples include bovine dicarbonylphenyl, 0-carbo bovine diphenyl, m-carbo bovine diphenyl, and p-carbo+diphenyl group.

Examples of the phenyl lower alkyl group which may have a lower alkoxy group as a substituent include besidyl, α-phenethyl, β-phenethyl,! -Phenyl 0 pills, 2
-Phenylbutyl, 3-phenylbutyl, 2-phenylbutyl, 3-phenylbutyl, 4-phenylbutyl, I-phenylpentyl, 3-phenylpentyl, 5-phenylpentyl, 1-phenyl to middle syl, 3-phenyl to middle syl, 5-phenyl to middle syl, 1. l-dimethyl-2-phenylethyl, 2-meth+sibesidil, β-(3-ethoxydiphenyl)ethyl,
β-(4--jopo+diphenyl)ethyl, 1-(2,
3-, methoxydiphenyl) 0 pills, 1-(3,4-
, ;ethoxydiphenyl)butyl, 3.4.5-trimeth+sibesidil, β-(3,4-,;methoxydiphenyl)ethyl, 4-(2,3-dimethododiphenyl), etc. can. Examples of the lower alkyl group having a carboxyl group, a phenyl lower alkoxy+dicarbonyl group, or a carboxysilyl dicarbonyl group as a substituent include carboxydimethyl, l-carbodiethyl, 2-carbodiethyl, ■-Carbo + Shi''50 pills,
2-Carbo Naka ShibuD Vir, 3-Carbo + Shizu0 Pill, 1
-(Dicarbonyl in besidyl)ethyl, 2-(penzyloxycarbonyl)ethyl, l-(α-phenethyl) radical carbonyl ethyl, 2-(β-phenethyl in radical carbonyl ethyl, 1-(2-carbonyl in carboxylic acid) Examples include 0 lysinyl carbonyl)ethyl, 1-(3-carbo+cypD lysinylcarbonyl)ethyl, and the like.

Examples include l-pyrrolidinyl, piperidino, piperazinyl, t-sulfolino groups, etc., and the above heterocyclic group is a phenyl group, a Fefutami lower alkyl group, a besilyl group, a furoyl group, a carboxyl group, or R5 is a hydrogen atom. , respectively represent a carboxyl group or a lower alkoxydecacarbonyl group. ) is substituted' Examples include 4-phenylpiperazinyl, 4-besidylpiperazinyl, Imaichi α-phenetylhiberazinyl, 4-β-phenethylhiverazinyl, 4-phenylpiperazinyl,
-(5-phenyl)goberazinyl, 4-be':
, Idylpiperidino, 4-besilyylpiperazinyl, 4
-(2-)0yl)piperazinyl, 4-(2-)0yl)piperidino, 2-carboxylicylcyhiberidino, 2-carboxylicyl[]IJdinyl%4-(l-pyridinylcarponyl) methyl)piperazinyl, 4-[+-(2-
carboxyl-hyrrolidinyl)carbonylethyl]hyperazinyl, 4-[1-(2-methodicarbonyl-1)
-di0lysinyl)carbonylethyl]perazinyl%
4-vphenylmethylpiperazinyl, 4-(2,
2-diphenylethyl)piperazinyl, 4-(4,5-
, phenylpentyl) diperazinyl group, etc. can be exemplified.

The compound of the present invention represented by the above general formula
It has cardiotonic, antispasmodic, and antiallergic effects, and is an antihypertensive agent, platelet aggregation inhibitor, cardiotonic agent, antispasmodic agent, and antiallergic agent.
- Useful as an agent.

Compounds of the invention are made by a variety of methods. Preferred specific examples thereof are shown in the following reaction scheme and will be described in detail.

According to the reaction process IK, the known aldehyde represented by the general formula (2) The compound of the present invention in which R2 represents a carboxylic group and = is a double bond (
1a) can be obtained, and the compound (1b) of the present invention can be obtained, in which compound (la)K is represented by the general formula (3), and anti= is a double bond in the amyl group.

The condensation of the aldehyde of general formula (2) with maosic acid is described, for example, in Organic Synthesis, Vol. 4, No. 327.
It is carried out according to the method described on page. That is, the reaction is carried out by heating 1'el of the aldehyde of general formula (2) and 2° C. of maleic acid in a pyridine solvent to about 60 to 100° C. in the presence of a small amount of piperi.

The reaction between compound (1a) and amyl (3) can be carried out using a conventional amide bond-forming reaction, such as acid acid method, mixed acid anhydride method, active ester method, y,7v'-disycylcarbodiimide method, etc. (DCC method), acid method, and other reaction conditions can be widely applied. Taking as an example the diethyl cyanolisinate method, which is considered to be a modification of the azide method, examples of the reaction solvent include N,N-dimethylformamide (DMF), tetrahydrofradiate (CTHF), ethyl acetate, etc. Considering the solubility of (Ia), DMF is preferred. The amount of amine (3) used is compound (1a
) is preferably 7 to 1.2 times by mole.

To a mixture of compound (Ia) and amine (3) added to the above solvent, diethyl cyanolysate is added in a molar amount of 7 to 1.2 times the amount of compound (Ia) K at 0 to 10°C,
Next, at the same temperature, an organic amine such as triethylamine or pyridyl is gradually added to the compound <1a) K in an amount usually equal to 5 times the molar amount, preferably equal to 2 times the molar amount, and then heated in the range of 0 to 25°C. It is best to stir for 1 to 24 hours. The above reaction is usually completed within 20 hours.

<Reaction Scheme-2>(1b') RiR (1/l') [In the formula, R6 is a beslyyl group, )0yl group or group. R work is the same as above. ] The compound of the present invention (1b') which shows and = is a double bond
is produced by acylating or alkylating the compound (lb') of the present invention in which R2 represents a group -CON NH and is a = or (-) double bond.

Acylation of compound (1b') is carried out by reacting compound (1b') with furoyl chloride or besilyyl chloride in an anhydrous inert organic solvent in the presence of a deoxidizing agent.

Furoyl chloride or besylyl chloride, compound (1b'l
It is preferable to use at least 1 equivalent, preferably 1.2 to 1.3 equivalents, per K. Examples of inert organic solvents include acetone, DMF, ether, THF, Bent! Examples include shi, ri00form, and tornidi. Further, examples of deoxidizing agents include triethylamine, pyridyl, potassium carbonate, etc., and these deoxidizing agents are used in an amount of at least 1 equivalent, preferably 1.2 to 1.3 equivalents, based on compound (16'). amount used. The reaction is carried out at room temperature to around the boiling point of the inert organic solvent used, preferably around room temperature.

Compound (Ib') is converted into alkyl atom in the presence of a deoxidizing agent by converting the compound (Ib') into a compound of the general formula ゛ [wherein X represents a halogen atom]. R5 and A are the same as above. It is carried out by reacting a halide represented by ]. The halide of general formula (4) is a compound (1b'
) is used in an amount of at least 1 equivalent, preferably 1.2 to 2 equivalents. The reaction is usually carried out in an anhydrous inert organic solvent. Inert organic solvents include, for example, acetoxy, DMF, ether, toluene, Besi'I! Examples include ci, riooform, and THF. Further, examples of deoxidizing agents include triethylamine, pyridyl, potassium carbonate, etc., and these deoxidizing agents include compound (1b')K
The amount used is at least 1 equivalent, preferably 1.2 to 2 equivalents. The reaction is carried out at room temperature to around the boiling point of the solvent used. KF when the solvent used is DMF
i It is preferable to carry out the reaction near room temperature, and when the solvent is other than DMF, it is preferable to carry out the reaction near one point of the solvent.

<Reaction Scheme-3> (la) (1b) (lc) (14) [In the formula, R□, R3 and R4 are the same as above. ]According to reaction step-3, reducing compound (la) from K to R
The compound (lc) of the present invention in which 2 represents a carboxyl group and = is a single bond can be obtained, and the compound (ld) of the present invention can be obtained from K by reducing compound (1b). Compound (id) can also be produced by reacting compound (1c) with amyl (3).

When reducing compound (lr) or compound (1b), catalytic reduction with hydrogen is carried out using a conventionally known catalyst such as Pd-carposi, PtO2s Raney nickel, etc. at normal pressure to I'OO atmospheric pressure, preferably normal pressure. It is better to do so.

As the reaction solvent, considering the solubility of compound (1a) and compound (1b), DMF, DMF-methanol, and DMF are used.
- Ethanol etc. are preferred.

The above reduction reaction is preferably carried out usually at room temperature to around 50°C, and is generally completed in 2 hours to 10 days.

The reaction between compound (1c) and amyl (3) can be carried out under the same reaction conditions as the reaction between compound (la) and amyl (3).

<Reaction Scheme-4>(21(1#) (1f) [In the formula, R□ is the same as above.] According to Reaction Scheme-4, nido 0 metasyl is added to the aldehyde of general formula (2). By condensation, the compound (Ie) of the present invention in which R2 represents a nido 0 group and = is type 2 packing can be obtained, and by reducing the Ibi compound (1#), R
A compound (1/) of the present invention in which 2 represents a nido 0 group and = is a single bundle bond can be obtained.

For the condensation reaction of the aldehyde of general formula (2) with 50-metallic acid, for example, a mixture of aldahyde (2) and 50-metallic acid may be heated in a solvent such as acetic acid in the presence of ammonium acetate. As for the mixing ratio of aldehyde (2) and nido-0-metallic acid, it is preferable that the latter is usually equal in mole or more, preferably 3 to 4 times the mole of the former. The amount of ammonium acetate to be used is usually at least an equimolar amount, preferably 2 to 2.2 times the molar amount of aldahyde (2). The reaction is usually carried out at a temperature of about 100 to 150°C.
The reaction proceeds preferably by heating near the boiling point of the solvent, and the reaction is generally completed in about 2 to 5 hours at IC.

Compound (1#) is reduced using, for example, sodium borohydride. This reduction is usually carried out using methanol,
The process is carried out in alcohols such as ethanol, isozylene alcohol, or a mixed solvent of these alcohols and DMF or THE. The amount of sodium borohydride to be used is usually about 1 molar to 6 times the molar amount of compound (1#) K. The reduction reaction is usually 0
The reaction is carried out at a temperature of about 30° C. and is generally completed in about 3 hours.

and is a 5- or 6-membered saturated heterocyclic group formed by bonding R3 and R4 to each other, and further, in the heterocycle, R5 of the compound is a carboxyl group, the corresponding R5 It is also produced by K when a compound in which is a dicarbonyl group in a lower alkoxy group is hydrolyzed according to a conventional method. Hydrolysis is preferably alkaline hydrolysis, usually 0.1 to
This is carried out using alkali hydroxide of about 3N, preferably 0.1-1N. The hydrolysis is usually carried out at around room temperature and is generally completed in 1 to 20 hours.

Among the compounds of the present invention, compounds having a syl group in the carboxyl group can be prepared using conventional methods such as alkali metal salts (e.g., sodium salts, potassium salts), alkaline earth metal salts (e.g., calcium salts, magnesium salts), etc. Furthermore, among the compounds of the present invention, compounds having a nitrogen atom capable of forming quaternary acinium salts may be isolated as salts of organic acids and inorganic acids, respectively. Such salts are also included within the scope of the compounds of the present invention.

The target product of the present invention obtained through each of the above reaction steps can be easily isolated and purified from the reaction mixture by conventional separation means, such as solvent extraction, recrystallization, column filtration, etc.

Further, the compounds of the present invention may include optical isomers and geometric isomers, and the present invention naturally includes such isomers.

EXAMPLES Below, in order to explain the present invention in more detail, production examples of the compounds of the present invention will be given.

Production example 1 Production of β-[2-(1,4,5,8-tetramethoxy)naphthylcoacrylic acid (Ishikinamono 1) 4.2 y (4
0mM) of malonic acid is dissolved in 1QsLl of pyridine at 55°C. To this solution was added 5.6t (20mM) of C2-carbaltyhyde in 1.4.5.8-tetramethane and piperi; do. Under the same temperature conditions, the mixture was stirred for 1 hour and then refluxed for 3 hours. When transferred to cold drained water and acidified with concentrated hydrochloric acid, crystals precipitate.

This product is taken in a furnace, washed with water, and then dried to obtain 5F compound 1 as yellow crystals. This product is made of silica talc 0 methanol (silica talc 0 methanol = 20
: l) If purified at K, a pure product with a melting point of 200-202°C can be obtained. However, the crude product can be used in the next reaction.

Production example 2 N-[β-(3,4-diphenyl)ethyl]
-/-(2-(1,4,5,8-in-tetrameth)naphthylcoacrylamide (compound 9) production Compound 1 obtained in Production Example 1 and N-β-(diphenyl in 3,4-diphth) To a solution of 1.85 P of ethyl amici in DMF20, 1.88 p of diethyl cyanolisinate was added under ice cooling, and then a solution of 1.05 p of triedyl amici in DMF2011 was added to a solution of 20
It takes a few minutes to drip. Thereafter, the mixture is stirred for 16 hours at a temperature ranging from water cooling to room temperature. The reaction mixture was transferred to water and extracted with ethyl acetate.
The organic layer was washed with water, dried (MttSO4), and concentrated, and the resulting crude product was purified by silica gel chromatography (ethyl acetate: 1:1).
Compound 9 of 4.52F is obtained as yellow crystals.

Compound 3.5.6 shown in Table 1 below in the same manner as above.
7, 10, 13.14,! 6.18 and 20 are obtained.

Production example 3 N-[β-[2-(1,4,5,8-tetrameth+shi)
Naphthyl [acryOyl] acitranilic acid (compound 4)
Production of Compound 32.2y obtained in Production Example 2 was mixed with ethanol-DMF
CI: l) 2 (1 m) was dissolved, 10% sodium hydroxide solution was added, and the mixture was stirred at room temperature for 2 hours and 30 minutes.Then, the reaction solution was made acidic with concentrated hydrochloric acid, and then extracted with ethyl acetate.Organic After drying and concentrating the layer, the obtained crystals are recrystallized from ether-chloroform to obtain compound 4 as 1.2 F yellow crystals.

Production example 4 N-[β-[2-(+, 4.5.8-tetramethodushi)
Preparation of naphthyl coacrylate] piperazine (compound type 5) Compound 1 obtained in Production Example 1 15p and piperazine 40.
55F was dissolved in 350 ml of DMF in PC, and a solution of 9.4 P of diethyl cyanolisinate in 25 ml of DMF was added under water cooling.

Then D M F 25 of triethylamine 5.25y
tu/solution was added dropwise over 30 minutes. 6. Stirred under ice-cooling to room temperature for 16 hours. Thereafter, DMF and piperazine are distilled off under reduced pressure, and the crude product is purified with silica talc (form:methanol = 30:l) to obtain compound 15 as 1Of yellow crystals.

Production Example 5 4-Besilyyl-1-[β-[2-(+, 4.5.8-
Preparation of tetrameth+naphthylcoacrylate]piperazine (compound 12) 500v of the compound +5 obtained in Production Example 4 and 200ml of penlyl chloride were dissolved in 30ml of DMF.
Add 100 μl of K2CO3 and stir at room temperature for 6 hours.

Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. After concentration, compound 12 is produced for 14 yen with silica talc 0 mudcraffie (RI00 form: methanol = 25:1), 500v
is obtained as yellow crystals.

Compound 11 shown in Table 1 below is obtained in the same manner as above.

Production example 6 1-[β-(2-(1,4,5,8-tetrameth+shi)
Preparation of naphthylcoacryloyl)-4-(1-pyridinylcarponylmethyl)piperazine (Compound 17) Compound 15 obtained in Production Example 4 A suspension of 1.4 F and 1.4 f of potassium carbonate in DMF 60111 is stirred for 20 hours at room temperature.

The precipitate is separated in a furnace, the p-liquid is concentrated, and then purified using silica talc (form:methanol=50:1 and then 30:1) to obtain 1.95f of compound 17 as yellow crystals.

Production Example 7 2-CarboC 1-[β-C2-(1,4,5,8-
Preparation of (Compound 26) Compound 1 obtained in Production Example 1 1.5p, 2-besidyl-ocycarbonyl-di-1.08r and triethylamine'JO, 53p in DMF3Qd Add 0.95 F of diethyl cyanolisinate to the solution under ice-cooling, then add 0.95 F of triethyl amici
．． Add 53F and stir at room temperature for 16 hours. Oily substance 2 obtained by processing in the same manner as in Production Example 2. IP to ethanol 5
01dK was dissolved, Pd-C200'IIg was added, and the mixture was stirred for 1 hour under a hydrogen atmosphere at normal pressure. Pd-Ct
- The mixture is separated from the furnace, the solvent is distilled off, and the mixture is purified by silica gel chromatography (reform:methanol=IO:1) to obtain 1.2 p of compound 20 as pale yellow crystals.

Compound 1 obtained in Production Example 1 in the same manner as above was condensed with an atomyl group having a besidylodicarbonyl group, and then reduced.
get.

Production example 8 (E) -2-(2-(1,4,5,8-tetrameth+
C) Preparation of naphthyl-1-nitroethylene (compound 2) 1.4; 5.8-method + 4.8f of dialdehyde, 50% of acetic acid, 2.8% of acetic acid and 3. Add to the mixture of Ip and reflux the reaction mixture for 2 hours. After cooling, the mixture is concentrated under reduced pressure, and the crude crystals are dissolved in methylene chloride and purified using silica talc 0-madographies to obtain Compound 2 (3.72%) as brown crystals.

Production Example 9 1.4.5.8-Production of 2-(2-dithoethyl)naphthalene (compound 27) (E) -2-
[2-(+, 4.5.8-〒Tramet + Shi) Nafthousand]
- Dissolve 300~ of 1-diethylene in 6 ml of DMF and 3 d of ethanol, and dissolve 80~ of sodium borohydride.
■ Add under water cooling and continue stirring for 15 minutes. Thereafter, the mixture is transferred to water, extracted with methylene chloride, and the organic layer is dried and concentrated. The resulting crystals are recrystallized from methylene chloride and 7:1:1 to obtain Compound 27.

Production example 1O to N-Schiff D to middle syl-N-Schif to 0 + cylaminocarbonyl-β-C2-(1,4,5,8-tetramethoc)
naphthylcoacrylamide (compound 8) and 1-[β-
(2-(1,4,5,8-tetramethane)naphthyl)
acryloyl]-4-phenylpiperazide (compound 14
) Compound 1 1p obtained in Production Example 1 and N-phenylpiperadiyO,51y were dissolved in 21 ml of DMF, and DC
Add Co, 7111 and stir at room temperature for 16 hours. Water was added to the reaction solution, extracted with ethyl acetate, concentrated, and subjected to silica gel chromatography (chloroform:methanol=I
When purified by O:I), compound 8 was purified with 950■ and compound 1
4 are obtained as yellow crystals of 200 Wv each.

Production example 1.1 1-[β-[2-(+,4,5.8-tetrameth+shi)
naphthylcoacryloyl]-4-L: I-(2-methodadecarbonyl)pyrrolidinylcarbonylethylcopivera,; (compound 21) and 1-[β-[2-(1,4,
5,8-tetramethoxy)naphthyl]p'cri0yl)
-4- [1-(2-carbo+shi)hyrrolidinylcarbonylethyl]Hiberazine (Compound 19) Production Compound 1522.2- obtained in Production Example 4 in the same manner as Production Example 6
Methodeca-dicarbonyl-1-(2-but0℃zu0pionyl)
11,37p and potassium carbonate 0.36p
A 25 ml suspension of DMF was added at room temperature for 2 oi.
Stir. The crude product obtained by the same treatment as in Production Example 5 was purified with silica gel chromatography (chloroform:methanol = 25:l) to yield compound 21 with a concentration of 2.42%.
is obtained as yellow crystals. Compound 21 was dissolved in 3.6 N of 1°8F methanol, 3.6 d of 1717 sodium hydroxide was added thereto, and the mixture was stirred at room temperature for 1 hour. Then, IN salt i3 and Oml were added to the reaction solution and concentrated. Add this to silica talc 0 mudcraffi (re00 form: methanol ≠ 6:
If you focus on 1), 1. Compound I9 of OF is obtained as yellow crystals.

Production Example 12 Production of 3-[2-(1,4,5,8-tetramethoxy)naphthyl]piosic acid (Compound 22) Compound 1 10F obtained in Production Example 1 was mixed with DMF-ethanol (1:1 )1
00- and catalytic reduction in the presence of Pd -C1f at normal pressure and rut temperature. 7-hole Pd-C is furnace-filtered, the filtrate is concentrated, and the resulting crystals are poured into silica.
riOO form: methanol = 20 When coffin i in two cities, 8
．． Compound 22 of 62 is obtained as white crystals.

Example 13 of wheat gluten production N-Cβ-(3,4-dimeth+sifinyl)ethyl]-
Compound 22 obtained in Production Example 12
,4-, ;diphenyl)ethylamine in met+511'
IP, diethyl cyanolisinate 153m! and triethylamine 86η are treated in the same manner as in Production Example 2, compound 2
3 is obtained.

Compounds obtained in each of the above production examples and their physical properties (melting point,
H-NMR analysis results) are shown in Tables 1 and 2.

Continuation of page 1 @Int, C1,' Identification symbol Internal office reference number 3174
95 ABK

Claims (1)

[Claims] ■ General formula [In the formula, R1 represents a lower alkoxy group, and R2 represents a lower alkoxy group. R
3 and R4 are the same or different and each has a hydrogen atom, a lower alkyl group, a cycloalkyl group, a cycloalkyl aminocarbonyl group, or a lower alkoxycarbonyl group or a carboxyl group as a substituent. a phenyl group, which may have a lower alkyl group as a substituent; a phenyl lower alkyl group, which may have a lower alkyl group as a substituent; a carbosil group, a phenyl lower alkoxydicarbonyl group, or a carbo+silyl dicarbonyl group; represents a lower alkyl group having Furthermore, R3 and R1° may be bonded together with adjacent nitrogen atoms to form a 5- or 6-membered saturated heterocyclic group with or without an oxygen atom or a nitrogen atom, and the heterocyclic group may further be R5 represents a phenyl group, a phenyl lower alkyl group, a beslyyl group, a)Dyl group, or a lower alkyl group, and R5 represents a hydrogen atom, a carboxyl group, or a lower alkoxycarbonyl group, respectively. ) may have as a substituent. = indicates a single bond or a double bond. ] A suftaredi derivative represented by the following.