JPH0826037B2 - Derivatives of physiologically active substance K-252 - Google Patents

Description

TECHNICAL FIELD The present invention relates to novel compounds which inhibit protein kinase C (hereinafter referred to as C-kinase) and have various pharmacological actions.

Prior Art C-kinase is a protein kinase that is activated in a phosphoride and calcium dependent manner,
It is widely distributed in tissues and organs in the body. In recent years, it has become known that this enzyme plays an extremely important role in cell membrane receptor transduction mechanism such as many hormones and neurotransmitters. Examples of physiological reactions evoked by such a signal transduction mechanism involving C-kinase are serotonin release in platelets, lysosomal enzyme release and aggregation reaction, neutrophil superoxide generation and lysosomal enzyme release, adrenal medulla. , Epinephrine release from kidney, aldosterone secretion from renal glomerulus, insulin secretion from Langerhans islets, histamine release from mast cells, acetylcholine release from ileum, and contraction of vascular smooth muscle. Further, C-kinase is considered to be involved in cell growth and carcinogenesis mechanism [Reference: Y. Nishizuka, Science, 225 , 1365 (1984); H.
Rasmussen et al., Advance in Cyclic Nucleotide and
Protein Phosphorylation Research, Vol.18, P159, edite
d by P. Greengard and GARobison, Raven Press, New Y
ork, 1984]. Thus, it has become clear that C-kinase is involved in many important physiological reactions and various pathological conditions in the living body. Therefore, if the C-kinase activity can be artificially suppressed by using its specific inhibitor, etc., it will be possible to widely prevent and treat diseases of the circulatory system, inflammation, allergies, tumors and the like. .

On the other hand, antipsychotic agents such as trifluoperazine and chloropromazine, dibenamine and tetracaine known as local anesthetics, or calmodulin inhibitor W-7 [N
-(6-aminohexyl) -5-chloro-1-naphthalenes
It has been found that drugs such as ulfonamide] have C-kinase inhibitory activity, but in each case, the C-kinase inhibitory action is not the main action of each drug and the specificity is low and the inhibitory activity is also low [Y. .Nishizuka et al., J. Biol. Chem., 255 , 83
78 (1980); RCSchatzman et al., Biochem.Biophys.Re
s.Commun., 98 , 669 (1981); BCWise et al., J. Biol.Ch
em., 257 , 8489 (1982)].

On the other hand, K-252, KT-5556 and R _A , R _B represented by the following formula
A site-modified K-252 derivative is known (K-252
JP-A-60-41489, U.S. Pat.No. 455402, KT-555
No. 6, JP-A-61-176531 and K-252 derivatives, JP-A-62-155284 and JP-A-62-155285).

K-252: R _A = CO ₂ CH ₃ , R _B = H KT-5556: R _A = CO ₂ H, R _B = H In JP- _A -60-41489, K-252 has antihistamine releasing action and antiallergy. It has a function as described in JP-A-62-1552.
84, 62-155285, it is described that the K-252 derivative has a C-kinase inhibitory activity and an antihistamine releasing action. Further, JP-A-61-176531 describes that KT-5556 has an antihistamine releasing action. In addition, compounds presumed to be the same compounds as K-252 and KT-5556 have been reported as antibacterial substances [M. Senzaki et a
L., J. Antibiotics, 38 , 1437 (1985)]. This document also discloses a compound of the above formula with R _A ═CO ₂ CH ₃ and R _B ═COCH ₃ . Compounds presumed to be the same as K-252 and halogen derivatives thereof are disclosed in JP-A-62-120388 and JP-A-62-16462.
6 and a derivative modified with R _A in JP-A-62-240689,
It is described that both have a blood pressure lowering action and a diuretic action.

Furthermore, as a compound having a structure relatively close to that of K-252, Staurosporine having the following structure and having an antibacterial action is known [S. Omura e
t al., J. Antibiotics, 30 , 275 (1977); A. Furusaki et a
l., J. Chem. Soc. Chem. Commun., 800 (1978);
185719].

Problems to be Solved by the Invention Antiallergic agents having strong C-kinase inhibitory activity,
New active ingredients such as antithrombotic agents, anti-inflammatory agents or anti-tumor agents are constantly being sought.

Means for Solving the Problems According to the present invention, there are provided novel derivatives of K-252 represented by the formula (I) and pharmaceutically acceptable salts thereof.

Formula (I); {In the formula, R ¹ and R ² are the same or different and each represents hydrogen, bromine or nitro, R ³ is hydrogen, lower alkyl, aralkyl or-(CH ₂ ) _n Z [wherein Z is hydroxy, (In the formula, R ⁴ and R ⁵ are the same or different and each represents hydrogen, lower alkyl or a group forming a heterocycle with an adjacent nitrogen atom) or And n represents 0, 1 or 2], and X
Represents carboxyl, lower alkoxycarbonyl, carbamoyl, lower alkylaminocarbonyl, hydroxymethyl or substituted or unsubstituted aminomethyl, wherein the substituent means an acyl group obtained by removing the hydroxy group from the carboxyl group of amino acid, and Y Is hydroxy, lower alkoxy or aralkyloxy,
Or -O-C (CH ₃₎ X and Y are as -Y-X- together ₂ -O-CH ₂ - or Is}.

Hereinafter, the compound represented by formula (I) is referred to as compound (I). The same applies to compounds having other formula numbers. Compound (I) has excellent C-kinase inhibitory activity, and
It also has excellent antihistamine release inhibitory activity, platelet aggregation inhibitory activity, anti-inflammatory activity or cell growth inhibitory activity.

In the definition of R ³ , R ⁴ and R ⁵ in formula (I), lower alkyl includes straight chain or branched alkyl having 1 to 3 carbon atoms, that is, methyl, ethyl, n-propyl, i-propyl. To do. In the definition of R ³ , aralkyl means that the aryl part is phenyl, naphthyl, etc., and the alkyl part is a linear or branched alkylene having 1 to 3 carbon atoms, such as methylene, ethylene, etc. One example is benzyl. The heterocycle formed by R ⁴ and R ⁵ includes
Pyrrolidine, piperidine, N-methylpiperazine, formolin, N-methylhomopiperazine and the like can be mentioned.

In the definition of X, lower alkoxycarbonyl has 2 to 2 carbon atoms.
7 straight-chain or branched alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl, n-
It includes butoxycarbonyl, n-hexyloxycarbonyl and the like. In the definition of X, the lower alkylaminocarbonyl includes a linear or branched alkylaminocarbonyl having 2 to 4 carbon atoms, that is, methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, i-propylaminocarbonyl. To do. In the definition of X, examples of the amino acid in the substituent of the substituted aminomethyl include glycine, alanine, valine, proline and the like, and the amino group of the amino acid has a protecting group (eg, benzyloxycarbonyl, t-) commonly used in peptide chemistry. Butoxycarbonyl and the like).

In the definition of Y, lower alkoxy includes linear or branched alkoxy having 1 to 3 carbon atoms, that is, methoxy, ethoxy, n-propoxy, i-propoxy. Y
In the definition of, aralkyl referred to as aralkyloxy has the same meaning as in the definition of R ³ , and preferable one is benzyloxy.

When compound (I) is a basic compound, an acid addition salt can be formed. Examples of the acid addition salt of compound (I) include hydrochloride, hydrobromide, sulfate, nitrate, formate, acetate, benzoate, maleate, fumarate, succinate, tartrate, and citrate. Acid salt, oxalate, methanesulfonate, toluenesulfonate, aspartate,
Examples thereof include glutamate. Non-toxic pharmaceutically acceptable salts, such as the acid addition salts listed above are preferred,
Other salts are also useful in the isolation and purification of biological products.

The compounds according to the invention are usually obtained from the optically active K-252 by a reaction of steric retention, but all possible stereoisomers and mixtures thereof are also included in the present invention.

Next, a method for producing the compound (I) will be described. However, the production method of compound (I) is not limited to them.

The compound (I) is represented by K-252 and the following formulas ( _IIa to _c ) derived therefrom. ^{_{(II a) (X 0 =}} COOH) (II b) is prepared by _{^{(X 0 = CH 2 OH)}} (II c) (X 0 = CH 2 NH 2) a variety of synthetic means from the compound represented by. The compound (II _a) is in JP 61-176531, the compound (II _b) and (II _c) is disclosed respectively in JP-A-62-155285.

In the production methods shown below, when the defined group is changed under the conditions of the method for implementation or is inappropriate for performing the method, a method commonly used in synthetic organic chemistry, for example, protection or deprotection of a functional group is used. It can be easily implemented by attaching it to a means such as protection [see, for example, Protective Groups in Organic Synthesis, Green, John Willie and Sons Incorporated (1981)]. See Examples 7 and 16).

Method 1: Synthesis of cyclic imide compound (I) (In the formula, R ¹ , R ² , R ³ , X and Y have the same meanings as described above).

Compound (I) is a suitable oxidant for lactam body (III),
For example, it can be obtained by reacting Collins reagent (chromic acid dipyridine complex) in a pyridine solvent at 0 ° C. to room temperature for 1 day. The oxidizing agent is used in the amount of 5 to 7 equivalents based on the compound (III).

In the reaction, when X, Y, R ³ or the like is a functional group inappropriate for the oxidation reaction, the above-mentioned means for protecting the functional group, oxidation and then deprotection are appropriately carried out (see, for example, Example 7).

Further, the compound (I) obtained here is further introduced into a novel K-252 derivative by the methods 2 to 6 described below using this as a synthetic intermediate.

Method 2: A compound having a functional group at R ¹ and / or R ² (I
-2) Synthesis 2-1: Compound (I-2- in which R ¹ and / or R ² is nitro
1) and / or (I-2-1 ') (Wherein X, Y and R ³ have the same meanings as described above) The reaction is carried out with compound (I-1a) [compound (I) wherein R ¹ and R ² are hydrogen] and a suitable nitrating agent such as The target compound (I-2-1) and / or (I-2-1 ') can be obtained by reacting nitronium tetrafluoroborate in a solvent inert to the reaction. The nitrating agent is used in an amount of 1 to 1.1 equivalents. As an inert solvent,
Sulfolane, acetonitrile and the like are used. The reaction is carried out in the range of room temperature to 80 ° C and is completed in 1 to 2 hours.

2-2: a compound in which R ¹ and / or R ² is bromine (I-2-
2) and / or (I-2-2 ') (In the formula, X, Y and R ₃ are as defined above.) The reaction is carried out by reacting the compound (Ia) with 2 to 3 equivalents of bromine in a pyridine solvent at room temperature for 1 hour to 1 day. -2-2) and / or (I-2-2 ′) can be obtained.

Method 3: Synthesis of compounds with functional groups in ^{R 3 (I-3) 3-1} : R 3 is alkyl, the compounds of the aralkyl (In the formula, X, Y, R ¹ and R ² are as defined above, and R ^3a is R ³
In the definition of, it means lower alkyl and aralkyl, and Ha
The reaction is carried out by reacting a compound (I-1b) [a compound in which R ³ is hydrogen in compound (I)] and a halide (IV) in an inert solvent such as dimethylformamide (DMF) with a base. Compound (I-3-1) can be obtained by reacting in the presence. The reaction is usually completed in 1 to 12 hours at 0 ° to room temperature.

The halide is preferably a highly reactive iodide or bromide, and is usually used in 1 to 2 equivalents relative to compound (I-1b).
The base includes sodium hydride, potassium t-butoxide and the like, and it is preferable to use 1 to 1.5 equivalents relative to compound (I-1b) in order to suppress side reactions.

3-2: a compound in which R ³ is — (CH ₂ ) _n Z, and n = 0 (I-3-
2) Compound (I-3-2a) in which 3-2a: Z (R ³ ) is OH (Wherein X, Y, R ¹ and R ² are as defined above) The reaction is carried out by reacting compound (I-1b) with ethyl chloroformate in the presence of a suitable base such as sodium hydride and a solvent inert to the reaction. Compound (V) can be obtained by reacting in, for example, tetrahydrofuran (THF). Ethyl chloroformate is used in the amount of 1 to 2 equivalents, and the base is used in the amount of 1 to 1.5 equivalents, relative to compound (I-1b). The reaction is usually 0 ° to 1 at room temperature.
It will take about 1 day to finish. Then, the compound (I-3-2a) can be obtained by reacting the compound with hydroxylamine hydrochloride in the presence of a suitable base such as triethylamine in a solvent inert to the reaction such as DMF. Hydroxylamine hydrochloride and the base are used in 5 to 10 equivalents relative to compound (V). The reaction is completed in 1 hour to 1 day at 0 ° C to room temperature.

3-2b: Z (R ³ ) is Compound (I-3-2b) (In the formula, X, Y, R ¹ , R ² , R ⁴ and R ⁵ have the same meanings as described above.) The reaction is 10 to 10% of compound (I-1b) and hydrazine (VI).
Compound (I-3-2b) is obtained by reacting 50 equivalents in an inert solvent at 70 to 110 ° C. for 4 to 10 hours. The reaction proceeds more quickly when a suitable base such as 1,8-diazabicycloundecene (DBU) is used. Inert solvents include dioxane, DMF and the like.

3-3: Compound in which R ³ is-(CH ₂ ) _n Z, wherein n = 1 (I-3-
3) Compound in which 3-3a: Z is OH (I-3-3a) (In the formula, X, Y, R ¹ and R ² are as defined above.) The reaction is carried out by reacting compound (I-1b) with 35% formaldehyde aqueous solution or paraformaldehyde in an inert solvent such as DMF. Compound (I-3-3a)
Can be obtained. Formaldehydes are compounds (I
-1b) is used in an amount of 3 to 5 equivalents. Reaction is usually 50 to 10
It is performed at 0 ° C and is completed in 1 to 12 hours.

3-3b: Z Compound (I-3-3b) of (In the formula, X, Y, R ¹ , R ² , R ⁴ and R ⁵ have the same meanings as described above.) The reaction involves reacting the compound (I-1b) with a 35% aqueous formaldehyde solution or paraformaldehyde and the like (VI
Compound (I-3-3b) can be obtained by reacting in the presence of I) in an inert solvent such as DMF. Formaldehydes and compound (VII) are compound (I-1
It is used in 3 to 5 equivalents to b). Reaction is usually 70-100 ℃
It takes place in 1 day to 1 week.

3-4: a compound in which R ³ is-(CH ₂ ) _n Z and n = 2 (I-3-
4) Compound in which 3-4a: Z is OH (I-3-4a) (Wherein X, Y, R ¹ , R ² and Hal have the same meanings as described above) Compound (I-1b) and halide (VIII) were subjected to the same alkylation conditions as in Method 3-1 described above. Compound (I-3-4a) is obtained by reacting.

3-4b: Z Compound (I-3-4b) of (In the formula, X, Y, R ¹ , R ² , R ⁴ , R ⁵ and Hal have the same meanings as described above.) First, the compound (I-1b) and halide (IX) are the same as in Method 3-1 described above. Compound (X) is obtained by reacting under the alkylation condition of.

Then, compound (X) is reacted with 10 to 15 equivalents of amine (VII) in a DMF solvent in the presence of a suitable base such as 15 to 20 equivalents of DBU to obtain compound (I-3-4b). it can. The reaction is usually completed in 1 day at room temperature.

3-5: R ³ is Compound (I-3-5) (In the formula, X, Y, R ¹ , R ² and n are as defined above) Compound (I-3b) [Compound (I-3-2b), (I-3
-3b) and (I-3-4b), wherein R ⁴ and R ⁵ are hydrogen] and N, N-dimethylformamide dimethyl acetal are reacted in an inert solvent such as DMF to give the compound (I- 3-5) can be obtained.
N, N-dimethylformamide dimethyl acetal is used in the amount of 1 to 10 equivalents based on compound (I-3b). The reaction is usually performed at 0 ° C to room temperature and is completed in 1 to 2 weeks.

Method 4: Synthesis of X-modified compound (I-4) 4-1: X is a lower alkoxycarbonyl compound (I-4)
-1) (In the formula, Y, R ¹ , R ² and R ³ have the same meanings as described above, and R ⁶ represents lower alkyl.) Here, R ⁶ represents a straight or branched alkyl group having 1 to ⁶ carbon atoms. .

The alcohol (XI) and excess thionyl chloride are added to the compound (I-1c) [a compound (I) in which X is carboxyl], and the mixture is heated to reflux to give the compound (I-1c).
4-1) can be obtained. Thionyl chloride is usually used in an amount of about 1/10 (volume ratio) of alcohol used also as a solvent. The reaction is carried out in the range of 80 to 100 ° C and is completed in 1 hour to 1 day.

4-2: a compound in which X is carbamoyl and lower alkylaminocarbonyl (I-4-2) (In the formula, Y, R ¹ , R ² and R ³ are as defined above, and R ⁷ represents hydrogen or lower alkyl.) In the definition of R ⁷ , lower alkyl is a straight chain having 1 to 3 carbon atoms. Or, it means a branched alkyl.

The compound (I-1c) is heated under reflux in thionyl chloride to give the acid chloride (XII). Then, the compound (XII) is reacted with the amine (XIII) to give the compound (I-4-
2) can be obtained. The amine component is usually used in an equivalent amount to excess amount, usually 1 to 5 equivalents, relative to the compound (XII), and anhydrous chloroform, dichloromethane or the like is used as a reaction solvent. The reaction is usually performed at room temperature and is completed in 1 to 12 hours.

Compound in which 4-3: X is a substituted aminothymer (I-4-3) (In the formula, Y, R ¹ , R ² and R ³ have the same meanings as described above, and R ⁸ represents a portion of the amino acid carboxyl group excluding a hydroxy group, and the amino group of the amino acid is free or protected. Here, the N-protecting group for amino acids is usually used in peptide chemistry, such as benzyloxycarbonyl,
Examples thereof include t-butoxycarbonyl.

Compound (I-1d) [compound (I) wherein X is aminomethyl] and M-protected amino acid (XI
Compound (I-4-3) can be obtained by condensing V) with N-oxysuccinimide and dicyclohexylcarbodiimide (DCC) in a THF solvent. Compound (XIV) is 1 to 2 relative to compound (I-1d)
Equivalent, N-oxysuccinimide 1 equivalent, DCC 1-
Used in 2 equivalents. The reaction is usually performed at 0 ° C to room temperature and is completed in 1 hour to 1 day.

A compound having a free amino group (I-4-3a)
If desired, it may be deprotected by a conventional method. For example, when the protecting group is benzyloxycarbonyl, the compound (I-4-3a) can be obtained, for example, by reducing by a catalytic reduction method.
Can be obtained. The catalyst contains 5 to 10% of palladium carbon, etc., and is usually 0.1 to 0.1% based on the weight of the compound (I-4-3).
Use 0.5 times the weight. Inert solvents include THF, DMF and the like. The reaction is usually performed at room temperature and is completed in 1 hour to 1 day (see Example 19).

Method 5: Synthesis of compound (I-5) modified with Y 5-1: Compound (I-5-1) in which Y is lower alkoxy or aroxy (In the formula, X, R ¹ , R ² , R ³ and Hal are as defined above, and R
⁹ is synonymous with the above R ^3a ) Compound (I-1e) [compound (I) wherein Y is hydroxy] and halide (XV) are reacted in a solvent inert to the reaction in the presence of a base. Thereby, the compound (I-5
-1) can be obtained.

The halide is preferably a highly reactive iodide or bromide, and is usually used in 1 to 2 equivalents relative to compound (I-1e).
The base includes sodium hydride, potassium t-butoxide and the like, and in order to suppress side reactions, it is preferably used within 1 equivalent, particularly preferably 0.9 to 1 equivalent, relative to compound (I-1e).

 DMF, THF and the like are used as the inert solvent.

The reaction is usually performed in the range of 0 ° C to room temperature for 1 hour to 1
End in days.

Method 6: Synthesis of -Y-X- compounds (I-6) 6-1: -Y -X- is _{-O-C (CH 3) 2} -O-CH 2 - of the compound (I-6-1 ) (Wherein R ¹ , R ² and R ³ are as defined above) Compound (I-1f) [Compound (I) wherein X is hydroxymethyl and Y is hydroxy] and 5 equivalents of 2, 2-dimethoxypropane and chloroform solvent,
By reacting under heating and refluxing for 1 to 12 hours in the presence of a suitable acid catalyst, for example, camphorsulfonic acid [0.1 to 0.5 equivalent based on compound (I-1f)], the compound (I-6-
1) can be obtained.

6-2: -Y-X- Compound (I-6-2) (Wherein R ¹ , R ² and R ³ have the same meanings as described above) Compound (I-1f) and thiocarbonyldiimidazole are added to DMF in the presence of a suitable base such as triethylamine at room temperature for 1 hour to 1 day. By reacting the compound (I-
6-2) can be obtained. The base is a compound (I-1f)
3 equivalents and thiocarbonyldiimidazole are used 5 equivalents.

As described above, the compound (I) having a desired functional group at a desired position can be obtained by appropriately combining the methods 1-6.

Further, the compound (I) is a clatam body (III) [compound (II
a), (IIb) and (IIc) are included]
It can also be obtained by applying ~ 6 and then applying method 1.

In each of the above methods, isolation and purification of the product after completion of the reaction can be carried out by appropriately combining methods used in ordinary organic synthesis, such as extraction, crystallization, chromatography and the like.

Compound (I) has a C-kinase inhibitory activity, an antihistamine release inhibitory activity, and a platelet aggregation inhibitory activity, and is expected to be useful as an active ingredient such as an antiallergic agent, an antihistamine agent, an antithrombotic agent. Such a pharmaceutical preparation usually comprises an effective amount of compound (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable pharmaceutical carrier. The dose of the pharmaceutical preparation varies depending on the administration method, treatment period, age, body weight, etc., but is 0.5 to 10 m per day per person orally or parenterally (eg, injection, application, inhalation).
g / kg is suitable. The dosage form includes tablets, pills, powders, granules, capsules, suppositories, injections and the like. In formulating, conventional pharmaceutical carriers such as lactose, dextrose, sucrose, sorbitol, mannitol, glucose, cyclodextrin, talc, starch, methylcellulose,
Gelatin, gum arabic, polyethylene glycol, carboxymethyl cellulose, hydroxypropyl cellulose, sodium benzoate, sodium bisulfite, aluminum stearate, magnesium stearate,
Vegetable oil, white petrolatum, distilled water for injection, etc. are appropriately selected and used in a conventional manner. This preparation contains 0.01 to 85% by weight of Compound (I) or a pharmaceutically acceptable salt thereof in the composition.

Furthermore, the compound (I) is a human cervical cancer cell spatula (He
la) cells, human breast cancer cells MCF7, human colon gland cells COLO320D
M, a human lung-differentiated squamous cell carcinoma cell PC-10, and the like, which show a remarkable cell growth inhibitory activity, and thus provide an antitumor agent containing compound (I) as an active ingredient.

When compound (I) is used as an antitumor agent, each compound is dissolved in physiological saline, glucose, lactose, or mannitol injection solution at a dose of 0.01 to 20 mg / kg, and is usually intravenously injected as an injection. Administered to. Further, it may be freeze-dried based on the Japanese Pharmacopoeia, or may be a powder injection with sodium chloride added. Further, it may contain well-known pharmaceutically acceptable diluents, adjuvants and / or carriers such as salts satisfying pharmaceutical use.
When used as an injection, it may be preferable to use an auxiliary agent for enhancing solubility together. The dose may be adjusted according to age and symptoms. The dosing schedule can be changed according to the symptoms and dose, but for example,
Once (single dose or daily dose), 1-3 times a week or 3
There is intermittent administration such as once a week. Also similar dose,
Oral administration and rectal administration are also possible. For oral administration, it can be administered in the form of tablets, powders, granules, syrups, suppositories, etc. together with a suitable adjuvant.

Example Next, Table 1 shows a representative example of the compound (I) obtained by the above production method, and Table 2 shows its intermediate. In addition, Production Examples of these compounds will be described in Examples, Production Examples of Intermediates thereof will be referred to as Reference Examples, pharmacological activity of the representative compound (I) will be referred to as Experimental Examples, and formulation examples of the representative compound (I) will be referred to as Reference Examples. Show.

In the table and in the examples Bzl, Me, Et, Pr, Bu, hex, Ac and Cbz mean benzyl, methyl, ethyl, propyl, butyl, hexyl, acetyl and benzyloxycarbonyl, respectively.

Example 1 To 50 ml of pyridine was added 3 g (30 mmol) of chromic acid under ice cooling,
After 10 minutes, K-252, 2.9 g (6.2 mmol) of pyridine solution 3
0 ml was added, and the mixture was stirred at room temperature for 1 day. The reaction mixture was filtered through Celite, THF was added to the filtrate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (chloroform) and recrystallized from chloroform to obtain 1,2.53 g (85%) of the compound, mp.288-290 ° C.
Obtained as a yellow powder.

NMR (CDCl ₃ + DMSO-d ₆ ) δ; 2.18 (s, 3H), 2.38 (dd, 1
H, J = 5,14Hz), 3.37 (dd, 1H, J = 6,14Hz), 4.00 (s.3
H), 6.05 (br.s, 1H), 6.95 (dd, 1H, J = 5,6Hz), 7.20-
8.04 (m, 6H), 9.08 (d, 1H, J = 8Hz), 9.28 (d, 1H, J = 8H
z), 10.16 (s, 1H) MS (m / e); 481 (M ⁺ ) Example 2 In the same manner as in Example 1, the compound f (K-252 ethyl ester form) 50 mg obtained in Reference Example 6 was used. From (0.1 mmol), compound 2,30 mg (60.6%) was obtained as a yellow powder with mp.> 300 ° C.

NMR (CDCl ₃ + DMSO-d ₆ ) δ; 1.51 (t, 3H, J = 8Hz), 2.2
2 (s, 3H), 2.37 (dd, 1H, J = 5,14Hz), 3.35 (dd, 1H, J =
7,14Hz), 4.53 (q, 2H, J = 8Hz), 5.61 (s, 1H), 6.93 (d
d, 1H, J = 5,7Hz), 7.28-7.70 (m, 5H), 7.98 (d, 1H, J = 8
Hz), 9.16 (d, 1H, J = 8Hz), 9.36 (d, 1H, J = 8Hz), 9.66
(Br.s, 1H) MS (m / e); 495 (M ⁺ ) Example 3 K-252n-obtained by the same method as in Example 1 and using n-propanol in the same manner as in Reference Example 6 Compound 3,50 mg (70.2%) from 70 mg (0.14 mmol) of propyl ester
It was obtained as yellow prism crystals of mp.

NMR (CDCl ₃ ) δ; 1.12 (t, 3H, J = 8Hz), 1.76-2.08
(M, 2H), 2.21 (s, 3H), 2.37 (dd, 1H, J = 5,14Hz), 3.32
(Dd, 1H, J = 8,14Hz), 3.92 (s, 1H), 4.45 (t, 2H, J = 7H
z), 6.88 (dd, 1H, J = 5,8Hz), 7.32-7.68 (m, 6H), 7.80
(D, 1H, J = 8Hz), 9.08 (d, 1H, J = 8Hz), 9.20 (d, 1H, J =
8 Hz) MS (m / e); 509 (M ⁺ ) Example 4 70 mg of K-252n-butyl ester compound obtained by the same method as in Example 1 and using n-butanol in the same manner as in Reference Example 6 0.13 mmol), compound 4,50 mg (70%) mp.2
Obtained as yellow prism crystals at 51-253 ° C.

_{NMR (CDCl 3 + DMSO-d} 6) δ; 1.04 (t, 3H, J = 7Hz), 1.3
2-2.04 (m, 4H), 2.20 (s, 3H), 2.39 (dd, 1H, J = 5,14H
z), 3.35 (dd, 1H, J = 7,14Hz), 4.46 (t, 2H, J = 7Hz), 5.
34 (s, 1H), 6.91 (dd, 1H, J = 5,7Hz), 7.30−7.70 (m, 5
H), 7.96 (d, 1H, J = 8Hz), 9.16 (d, 1H, J = 8Hz), 9.24
(S, 1H), 9.36 (d, 1H, J = 8Hz) MS (m / e); 523 (M ⁺ ) Example 5 In the same manner as in Example 1, using n-hexanol and similar to Reference Example 6. From the K-252n-hexyl ester compound 70 mg (0.14 mmol) obtained by the method of
Obtained as yellow prism crystals having a mp.228-229 ° C.

NMR (CDCl ₃ ) δ; 0.96 (m, 3H), 1.16-1.72 (m, 6H),
1.76−2.08 (m, 2H), 2.24 (s, 3H), 2.41 (dd, 1H, J = 5,1
4Hz), 3.35 (dd, 1H, J = 7,14Hz), 3.96 (s, 1H), 4.51
(T, 2H, J = 7Hz), 6.89 (dd, 1H, 5,7Hz), 7.28−7.92 (m,
7H), 9.10 (d, 1H, J = 8Hz), 9.24 (d, 1H, J = 8Hz) MS (m / e); 551 (M ⁺ ) Example 6 In the same manner as in Example 1, a reference example Compound obtained in 5
e From 50 mg (0.1 mmol), compound 6,33 mg (64%) mp.29
Obtained as a yellow powder at 5-296 ° C.

NMR (DMSO-d ₆ ) δ; 2.03-2.28 (m, 1H), 2.13 (s, 3
H), 2.86 (d, 3H, J = 3Hz), 3.35 (dd, 1H, J = 6,13Hz), 7.
00-7.20 (m, 1H), 7.32-8.52 (m, 7H), 9.04 (d, 1H, J =
8Hz), 9.23 (d, 1H, J = 8Hz) MS (m / e); 480 (M ⁺ ) Example 7 Compound (IIb) (Compound a obtained in Reference Example 1) 176 mg
Dissolve (0.4 mmol) in 5 ml of DMF, 136 mg of imidazole
(2.0 mmol) and 181 mg (1.2 mmol) of t-butyldimethylsilyl chloride were added, and the mixture was stirred at room temperature. After 1 day, 20 ml of chloroform was added, and the mixture was washed successively with a 5% aqueous citric acid solution, a saturated aqueous sodium bicarbonate solution and a saturated saline solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give a mono-t-butyldimethylsilyl compound [compound (II); X ⁰ = CH ₂ OSi (Me)]
₂ ^t = Bu] 240 mg (100%) was obtained as a pale yellow amorphous.

NMR (CDCl ₃ ) δ; 0.26 (s, 6H), 1.04 (s, 9H), 2.16
(S, 3H), 2.73 (dd, 1H, J = 5,14Hz), 3.08 (dd, 1H, J = 7,
14Hz), 4.05 (s, 2H), 4.44 (d, 1H, J = 17Hz), 4.86 (d, 1
H, J = 17Hz), 5.58 (s, 1H), 6.56 (dd, 1H, J = 5,7Hz), 7.
00-7.64 (m, 5H), 7.88 (d, 1H, J = 8Hz), 7.96 (d, 1H, J
= 8 Hz), 8.00 (s, 1H), 8.90 (d, 1H, J = 8 Hz) In the same manner as in Example 1, from the mono-t-butyldimethylsilyl compound 220 mg (0.33 mmol), the imide compound [compound (I) ^{; R 1 = R 2 = R} 3 = H, X = CH 2 OSi (Me) 2 t -Bu, Y = O
H] 140 mg (75%) was obtained as a yellow powder.

NMR (CDCl ₃ + DMSO-d ₆ ) δ; 0,24 (s, 6H), 1.06 (s, 9
H), 2.24 (s, 3H), 2.12-2.44 (m, 1H), 2.92-3.24 (m,
1H), 3.93 (d, 1H, J = 10Hz), 4.08 (d, 1H, J = 10Hz), 5.3
8 (s, 1H), 6.74 (dd, 1H, J = 5,7Hz), 7.24-7,68 (m, 5
H), 7.97 (d, 1H, J = 8Hz), 9.14 (d, 1H, J = 8Hz), 9.32
(D, 1H, J = 8Hz) MS (m / e); 567 (M ⁺ ) 80 mg (0.14 mmol) of the imide derivative was dissolved in 5 ml of THF, and a solution of tetra-n-butylammonium fluoride in THF (1M
(Concentration) 1 ml was added and the mixture was stirred at room temperature. After 1 hour, 3N hydrochloric acid aqueous solution was added to acidify the solution, which was washed with saturated saline solution and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography (2% methanol / chloroform), and the compound was 7,75 mg (100%).
Was obtained as a yellow powder having a mp. 278-280 ° C.

NMR (CDCl ₃ + DMSO-d ₆ ) δ; 2.13 (dd, 1H, J = 5,14H
z), 2.18 (s, 3H), 3.00-3.36 (m, 1H), 3.76-4.04 (m,
2H), 6.76-7.00 (m, 1H), 7.20-7.84 (m, 5H), 8.01
(D, 1H, J = 8Hz), 9.12 (d, 1H, J = 8Hz), 9.30 (d, 1H, J =
8 Hz) MS (m / e); 453 (M ⁺ ). Example 8 Compound 1,96 mg (0.2 mmol) was dissolved in DMF1 ml and cooled under ice-cooling 5
0% sodium hydride (9.6 mg, 0.2 mmol) was added and the mixture was stirred for 20 minutes. Then, 0.024 ml (0.2 mmol) of benzyl bromide was added and the mixture was stirred for 30 minutes under ice cooling. Saturated ammonium chloride solution
2 ml and 10 ml of chloroform were added, the organic layer was separated, washed with saturated brine and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (25% ethyl acetate / n-hexane) and recrystallized from methanol-chloroform to give the compound (8,35 mg, 30.6 mg).
%) As yellow prism crystals with mp.> 300 ° C. In addition, 9,18 mg (13.6%) of the compound was obtained as yellow prism crystals with a mp.

Compound 8: NMR (CDCl ₃ ) δ: 2.23 (s, 3H), 2.43 (dd, 1H,
J = 5,14Hz), 3.36 (dd, 1H, J = 7,14Hz), 3.84 (s, 1H),
4.13 (s, 3H), 4.82 (s, 2H), 6.90 (dd, 1H, J = 5,7Hz),
7.24-7.76 (m, 5H), 7.88 (d, 1H, J = 8Hz), 9.17 (d, 1H,
J = 8Hz), 9.46 (d, 1H, J = 8Hz) MS (m / e); 571 (M ⁺ ) Compound 9: NMR (CDCl ₃ ) δ: 2.48 (s, 3H), 2.49 (dd, 1H,
J = 5,14Hz), 3.47 (dd, 1H, J = 7,14Hz), 4.06 (s, 3H),
4.18 (d, 1H, J = 11Hz), 4.59 (d, 1H, J = 11Hz), 5.04 (s,
2H), 6.64-8.00 (m, 16H), 9.24 (d, 1H, J = 8Hz), 9.36
-9.50 (m, 1H) MS (m / e); 661 (M ⁺ ) Example 9 In the same manner as in Example 8, compound 1,96 mg (0.2 mmol)
As a result, 10,60 mg (60.6%) of the compound was obtained as yellow prism crystals having a mp. In addition, compound 11,25 mg (24.5%)
Was obtained as yellow prism crystals of mp.288-294 ° C.

Compound 10: NMR (CDCl ₃ ) δ: 2.41 (s, 3H), 2.52 (dd, 1
H, J = 5,14Hz), 2.98 (s, 3H), 3.40 (dd, 1H, J = 7,14H
z), 4.12 (s, 3H), 6.87 (dd, 1H, J = 5,7Hz), 7.28-7.68
(M, 5H), 7.84 (d, 1H, J = 8Hz), 9.05 (d, 1H, J = 8Hz),
9.34 (d, 1H, J = 8Hz) MS (m / e); 495 (M ⁺ ) Compound 11: NMR (CDCl ₃ ) δ: 2.40 (s, 3H), 2.49 (dd, 1
H, J = 6,14Hz), 3.16 (s, 3H), 3.24 (d, 3H), 3.42 (dd, 1)
H, J = 7,14Hz), 4.04 (s, 3H), 6.97 (dd, 1H, J = 6,7Hz),
7.32−7.68 (m, 5H), 7.90 (d, 1H, J = 8Hz), 9.18 (d, 1H,
J = 8Hz), 9.36 (d, 1H, J = 8Hz) MS (m / e); 509 (M ⁺ ) Example 10 In the same manner as in Example 8, the compound 1,96 mg (0.2 mmol)
The compound (12,84 mg, 80.3%) was obtained as yellow prism crystals with a mp.

NMR (CDCl ₃ ) δ: 1.0 (t, 3H, J = 8Hz), 1.60-1.96 (m,
2H), 2.21 (s, 3H), 2.38 (dd, 1H, J = 5,14Hz), 3.37 (d
d, 1H, J = 7,14Hz), 3.70 (t, 2H, J = 7Hz), 4,12 (s, 3H),
6.92 (dd, 1H, J = 5,7Hz), 7.36-7.72 (m, 5H), 7.84 (d,
1H, J = 8Hz), 9.21 (d, 1H, J = 8Hz), 9.44 (d, 1H, J = 8H)
z) MS (m / e); 523 (M ⁺ ) Example 11 1,96 mg (0.2 mmol) of the compound was dissolved in 1 ml of pyridine, 0.02 ml (0.4 mmol) of bromine was added, and the mixture was stirred at room temperature for 3 hours. THF
10 ml was added, and the mixture was washed successively with 10% sodium thiosulfate and saturated saline solution and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was recrystallized from pyridine-THF-chloroform to obtain the compound 13,100 mg (78.2%) as a yellow powder with mp.> 300 ° C.

_{NMR (CDCl 3 -DMSO-d 6} ) δ: 2.04-2.32 (m, 1H), 2.17
(S, 3H), 3.44 (dd, 1H, J = 7,14Hz), 3.98 (s, 3H), 6.48
(S, 1H), 7.15 (dd, 1H, J = 5,7Hz), 7.59-8.04 (m, 4
H), 9.20 (s, 1H), 9.44 (s, 1H) MS (m / e); 639 (M ⁺ ) Example 12 The compound obtained in Reference Example 3 in the same manner as in Example 1.
c From 550 mg (1.15 mmol), compound 14,424 mg (75%)
Obtained as a yellow powder, p.175-180 ° C.

NMR (CDCl ₃ ) δ; 1.26 (s, 3H), 1.47 (s, 3H), 2.36
(S, 3H), 2.34 (dd, 1H, J = 5,14Hz), 2.99 (dd, 1H, J = 7,
14Hz), 4.37 (d, 1H, J = 10Hz), 4.60 (d, 1H, J = 10Hz),
6.77 (dd, 1H, J = 5,7Hz), 7.32-7.92 (m, 6H), 9.17 (d,
1H, J = 8Hz), 9.36 (d, 1H, J = 8Hz) MS (m / e); 493 (M ⁺ ) Example 13 7,58 mg (0.12 mmol) of the compound was dissolved in 3 ml of DMF and 0.6 ml of triethylamine (0.38 mmol) and thiocarbonylimidazole 107 mg (0.6 mmol) were added, and the mixture was stirred at room temperature for 1 day. THF was added to the reaction solution, washed with saturated saline solution, and dried over anhydrous magnesium sulfate. The residue was triturated with chloroform to give 15,20 mg (33.7%) of compound mp.260.
Obtained as a yellow powder at ˜273 ° C.

NMR (CDCl ₃ + DMSO-d ₆ ) δ; 2.43 (s, 3H), 2.77 (dd, 1
H, J = 5,14Hz), 3.54 (dd, 1H, J = 7,14Hz), 5.09 (d, 1H, J
= 10Hz), 5.43 (d, 1H, J = 10Hz), 7.21 (dd, 1H, J = 5,7H
z), 7.30-7.90 (m, 6H), 9.12 (d, 1H, J = 8Hz), 9.34
(D, 1H, J = 8 Hz) MS (m / e); 495 (M ⁺ ). Example 14 The compound obtained in Reference Example 2 in the same manner as in Example 1.
b From 30 mg (0.058 mmol), compound 16,10 mg (32.5%)
Obtained as a yellow powder with mp.> 300 ° C.

NMR (CDCl ₃ + DMSO-d ₆ ) δ; 2.24 (s, 3H), 2.44 (dd, 1
H, J = 5,13Hz), 3.49 (dd, 1H, J = 7,13Hz), 4.08 (s, 3
H), 6.27 (s, 1H), 7.06 (dd, 1H, J = 5,7Hz), 7.32-7.88
(M, 3H), 8.06 (d, 1H, J = 8Hz), 8.40 (dd, 1H, J = 2,8H
z), 9.30 (d, 1H, J = 8Hz), 9.80 (d, 1H, J = 2Hz), 10.57
(S, 1H) MS (m / e); 527 (M + 1) ⁺ Example 15 The compound g obtained in Reference Example 7 was treated in the same manner as in Example 1 to obtain 1.11 g (2.18 mmol) of imide. To THF30
Sodium hydride 130 mg (3.27 mmo under ice cooling)
l), then 10 minutes later, 0.44 ml of ethyl chloroformate
(4.36 mmol) was added, and the mixture was stirred overnight at room temperature. A saturated aqueous solution of ammonium chloride was added to the reaction solution, which was then washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform), N- ethoxycarbonyl body [Compound ^{(I); R 1 = R} 2 = H, R 3 = CO 2 Et, X = CH 2 OA c, Y = OH ] 8
Obtained 85 mg (70%).

NMR (DMSO-d ₆ ) δ; 1.40 (t, 3H, J = 7Hz), 2.18 (s, 3
H), 2.21 (s, 3H), 2.00−2.36 (m, 1H), 3.00−3.44 (m,
1H), 4.24-4.60 (m, 4H), 5.90 (s, 1H), 7.10 (m, 1H),
7.28-8.16 (m, 6H), 8.98 (d, 1H, J = 8Hz), 9.19 (d, 1H,
J = 8 Hz) MS (m / e); 568 (M + 1) ⁺ above, N-ethoxycarbonyl derivative 835 mg (1.44 mmol)
Was dissolved in 50 ml of DMF and hydroxylamine hydrochloride was added under ice cooling.
1.00 g (14.4 mmol) and triethylamine 2.01 ml (144
mmol) was added and the mixture was stirred at room temperature for 3 days. After distilling off the solvent under reduced pressure, 50 ml of THF was added to the residue, washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain N-hydroxy compound [compound (I); R ¹ = R ² = H, R ³ = OH, X = CH ₂ OA _c , Y
= OH] was obtained.

The N-hydroxy compound was dissolved in a mixed solvent of 30 ml of THF and 10 ml of methanol without purification, 2.16 ml of 2N aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue is subjected to silica gel column chromatography (7% methanol-chloroform).
The compound 17 was then purified to give 112 mg (17%) of Compound 17.

NMR (DMSO-d ₆ ) δ; 1.92-2.22 (m, 1H), 2.16 (s, 3
H), 3.08-3.40 (m, 1H), 3.68-3.96 (m, 2H), 5.16 (b
rs, 1H), 5.50 (s, 1H), 7.04 (m, 1H), 7.28-8.12 (m, 6
H), 9.02 (d, 1H, J = 8Hz), 9.20 (d, 1H, J = 8Hz) MS (m / e); 470 (M + 1) ⁺ Example 16 Compound g obtained in Reference Example 7, 150 mg ( 0.3 mmol) and the imide derivative [compound (I); I got

NMR (CDCl ₃ ) δ; 1.46 and 1.58 (s, 3H), 2.20-3.20
(M, 2H), 2.32 and 2.36 (s, 3H), 3.11 and 3.38 (s,
3H), 4.04-4.72 (m, 2H), 6.60-6.84 (m, 1H), 7.20-
8.12 (m, 7H), 9.04-9.36 (m, 2H) MS (m / e); 510 (M + 1) ⁺ imide derivative 320 mg (0.63 mmol) is dissolved in chloroform 20 ml and methanol 2.5 ml, and 3N hydrochloric acid 1 ml is added. The mixture was stirred at room temperature for 1 hour. The reaction solution was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and then the chloroform layer was washed with 1.5m of 2N sodium hydroxide.
l and 10 ml of methanol were added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was washed successively with 5% aqueous citric acid and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the dialcohol compound [compound (I); R ¹ = R ² = R ³ = H , X ＝ CH ₂ OH, Y
= OH] 320 mg was obtained.

NMR (CDCl ₃ -DMSO-d ₆ ) δ; 2.08-2.12 (m, 1H), 2.20
(S, 3H), 3.08-3.36 (m, 1H), 3.80-4.00 (m, 2H), 4.8
42 (t, 1H, J = 6Hz), 6.15 (s, 1H), 6.83 (m, 1H), 7.20-
8.04 (m, 6H), 9.08 (d, 1H, J = 8Hz), 9.26 (d, 1H, J = 8H
z), 10.68 (br.s, 1H) MS (m / e); 454 (M + 1) ⁺ dialcohol 743 mg (1.64 mmol) in dioxane 20 ml
Was dissolved in water, and 3.97 ml of hydrazine hydrate was added, followed by heating at 100 ° C. for 2 hours. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (methanol / chloroform = 1.
0:90), N-amino compound [compound (I); R ¹ =
R ² = H, R ³ = NH ₂ , X = CH ₂ OH, Y = OH] 472 mg (62%) mp.24
Obtained as a yellow powder, 5-260 ° C.

NMR (DMSO-d ₆ ) δ; 2.19 (dd, 1H, J = 5, 14Hz), 2.16
(S, 3H), 3.00-3.40 (m, 3H), 3.80 (br.s, 2H), 4.96
(Br.s, 1H), 5.44 (br.s, 1H), 6.88-7.12 (m, 1H), 7,2
4-8.20 (m, 6H), 9.04 (d, 1H, J = 8Hz), 9.04 (d, 1H, J =
8 Hz) MS (m / e); 469 (M ⁺ +1) N-amino derivative (234 mg, 0.5 mmol) was dissolved in DMF (3 ml) to obtain N,
N-dimethylformamide dimethyl acetal 0.56 ml
(4.2 mmol) was added and the mixture was stirred at room temperature for 2 weeks. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (methanol / chloroform / ammonia water = 3/97/0.
Purification in 1) gave 179 mg (68%) of compound 18.

NMR (DMSO-d ₆ ) δ; 2.03 (dd, 1H, J = 5,14Hz), 2.16
(S, 3H), 3.04 (s, 6H), 3.00-3.26 (m, 1H), 3.72-4.0
0 (m, 2H), 5.16 (t, 1H, J = 6Hz), 5.48 (s, 1H), 7.04
(M, 1H), 7.28-7.72 (m, 4H), 7.90 (d, 1H, J = 8Hz), 8.
02 (d, 1H, J = 8Hz), 8.09 (s, 1H), 9.03 (d, 1H, J = 8H
z), 9.22 (d, 1H, J = 8 Hz) MS (m / e); 524 (M + 1) ⁺ Example 17 The dialcohol derivative obtained in Example 16 [compound (I);
R ¹ = R ² = R ³ = H, X = CH ₂ OH, Y = OH] 90 mg (0.2 mmol) of DMF
Dissolve in 2 ml and use 35% formaldehyde aqueous solution 0.05 ml (0.6
mmol) was added and the mixture was stirred at 70 ° C. for 2.5 hours. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (methanol / chloroform / 28% ammonia water = 2/98 /
0.2) to give compound 19 30 mg (31%).

NMR (DMSO-d ₆ ) δ; 2.07 (dd, 1H, J = 5,14Hz), 2.20
(S, 3H), 3.12-3.40 (m, 1H), 3.68-4.04 (m, 2H), 5,0
0-5.30 (m, 3H), 5.52 (s, 1H), 6.40 (t, 1H, J = 7Hz),
7.07 (dd, 1H, J = 5,7Hz), 7.30−7.80 (m, 4H), 7.92 (d,
1H, J = 8Hz), 8.07 (d, 1H, J = 8Hz), 9.08 (d, 1H, J = 8H
z), 9.28 (d, 1H, J = 8Hz) MS (m / e); 484 (M + 1) ⁺ Example 18 The dialcohol derivative obtained in Example 16 [compound (I);
R ¹ = R ² = R ³ = H, X = CH ₂ OH, Y = OH] 90 mg (0.2 mmol) of DMF
Dissolve in 2 ml and use 35% formaldehyde aqueous solution 0.05 ml (0.6
mmol) and 0.07 ml (0.6 mmol) of N-methylpiperazine
Was added and the mixture was stirred at 70 ° C. for 2 days. The solvent was evaporated under reduced pressure, 10 ml of THF was added to the residue, and the mixture was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Silica gel column chromatography of the residue (methanol / chloroform / 28% aqueous ammonia = 3/97 / 0.1)
The compound 20 was purified by the method described above to obtain 44 mg (39%) of compound 20.

NMR (DMSO-d ₆ ) δ; 1.88-2.80 (m, 9H), 2.14 (s, 3
H), 2.20 (s, 3H), 3.08-3.48 (m, 1H), 3.72-4.08 (m,
2H), 4.64 (s, 2H), 5.18 (m, 1H), 5.48 (s, 1H), 7.06
(M, 1H), 7.30-7.76 (m, 4H), 7.92 (s, 1H, J = 8Hz), 8.
05 (d, 1H, J = 8Hz), 9.05 (d, 1H, J = 8Hz), 9.24 (d, 1H, J
= 8 Hz) MS (m / e); 566 (M + 1) ⁺ Example 19 The compound obtained in Reference Example 8 in the same manner as in Example 1.
From 262 mg (0.45 mmol) of h, the imide compound [compound (I); R
¹ = R ² = R ³ = H, X = CH ₂ NHCbz, Y = OH] 170 mg (64.5%) m
Obtained as a yellow powder, p. 281-285 ° C.

NMR (CDCl ₃ -DMSO-d ₆ ) δ; 2.00-2.30 (m, 1H), 2.18
(S, 3H), 3.05 (dd, 1H, J = 7,14Hz), 3.48−3.90 (m, 2
H), 5.20 (s, 2H), 5.69 (s, 1H), 6.68-7.00 (m, 1H),
7.08−7.70 (m, 10H), 8.01 (d, 1H, J = 7Hz), 9.08 (d, 1
H, J = 8 Hz), 9.27 (d, 1H, J = 7 Hz) MS (m / e); 587 (M + 1) ⁺ imide 260 mg (0.45 mmol) was dissolved in DMF 10 ml and -20
60% sodium hydride 44 mg (1.08 mmol) was added at ℃,
After 10 minutes, 1,2-dibromoethane (4 ml, 4.5 mmol) was added,
The mixture was stirred at the same temperature for 1 hour. A saturated aqueous ammonium chloride solution and chloroform were added to the reaction solution, the organic layer was separated, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform) to give an N-bromoethyl compound [compound (I) R ¹ = R ² = H, R ³ = CH ₂ CH ₂ Br, X = CH ₂ NHCbz, Y = OH]. twenty three
0 mg (74%) was obtained.

NMR (CDCl ₃ ) δ; 2.08 (s, 3H), 2.40-2.68 (m, 1H),
3.00-4.00 (m, 7H), 5.20 (s, 2H), 5.32-5.60 (m, 1
H), 6.40-6.64 (m, 1H), 7.00-7, 64 (m, 10H), 7.84
(D, 1H, J = 8Hz), 8.66 (d, 1H, J = 8Hz), 9.20 (d, 1H, J =
8 Hz) MS (m / e); 679 (M + 1) ⁺ N-bromoethyl derivative 210 mg (0.3 mmol) was dissolved in DMF 8 ml, dimethylamine hydrochloride 243 mg (3 mmol) and DBU 0.
45 ml was added, and the mixture was stirred at room temperature for 1 day. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / chloroform / 28% aqueous ammonia = 5/95 / 0.1) to give an N-dimethylaminoethyl compound [compound (I);
R ¹ ＝ R ² ＝ H, R ³ ＝ CH ₂ CH ₂ NMe ₂ , X ＝ CH ₂ NHCbz, Y ＝ OH] 190mg
(96%) was obtained.

NMR (CDCl ₃ ) δ; 2.06 (s, 3H), 2.14 (s, 6H), 1.96−
3.96 (m, 9H), 5.19 (s, 2H), 5.80 (m, 1H), 6.51 (m, 1
H), 6.84-7, 64 (m, 10H), 7.84 (d, 1H, J = 8Hz), 8.52
(D, 1H, J = 8Hz), 9.26 (d, 1H, J = 8Hz) MS (m / e); 658 (M + 1) ⁺ N-dimethylaminoethyl derivative 190mg (0.29mmol)
It was dissolved in 5 ml, 10% palladium / carbon (200 mg) was added, and the mixture was stirred at 50-60 ° C for 2 hr under a hydrogen stream. The reaction solution was passed through Celite, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / chloroform / 28% ammonia water = 10/90 / 0.5) to obtain Compound 21 (122 mg, 81%).

NMR (DMSO-d ₆ ) δ; 1.84-3.96 (m, 11H), 2.12 (s, 3
H), 2.24 (s, 3H), 7.03 (m, 1H), 7.28-7.72 (m, 4H),
7.84 (d, 1H, J = 8Hz), 8.00 (d, 1H, J = 8Hz), 9.00 (d, 1
H, J = 8 Hz), 9.20 (d, 1H, J = 8 Hz) MS (m / e); 524 (M + 1) ⁺ Example 20 The compound obtained in Reference Example 9 in the same manner as in Example 1
From 629 mg (1 mmol) of i, the imide compound [compound (I); R ¹ =
^{R 2 = R 3 = H,} X = CH 2 NHCOCH 2 NHCbz, Y = OH ] 460 mg (73%)
I got

NMR (DMSO-d ₆ ) δ; 1.92-2.36 (m, 1H), 2.19 (s, 3
H), 2.80-3.16 (m, 1H), 3.52-4.00 (m, 4H), 5.10 (s,
2H), 5.77 (s, 1H), 6.96 (m, 1H), 7.12-8.24 (m, 12
H), 8.98 (d, 1H, J = 8Hz), 9.18 (d, 1H, J = 8Hz) MS (m / e); 645 (M + 2) ⁺ imide 400mg (0.63mmol) in the same manner as in Example 19 Reduction was performed by the method to obtain 320 mg (100%) of Compound 22.

NMR (DMSO-d ₆ ) δ; 1.92-2.28 (m, 1H), 2.16 (s, 3
H), 2.80-3.90 (m, 7H), 5.84 (br.s, 1H), 6.96 (m, 1
H), 7.24-8.40 (m, 7H), 8.97 (d, 1H, J = 8Hz), 9.16
(D, 1H, J = 8Hz) MS (m / e); 510 (M + 1) ⁺ Example 21 277 mg (0.54 mmol) of compound 22 obtained in Example 20 was dissolved in 15 ml of dioxane, and 1.3 ml of hydrazine hydrate was added. Add 3
Heated to reflux for hours. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (methanol / chloroform / 28% ammonia water = 5/95 / 0.1) to give 1.7N.
Hydrochloric acid / ethyl acetate was added to give the hydrochloride, and compound 23 140 mg (50
%) Was obtained.

NMR (DMSO-d ₆ ) δ; 2.04-2.32 (m, 1H), 2.20 (s, 3
H), 2.96-3.96 (m, 7H), 5.88 (m, 1H), 7.03 (m, 1H),
7.28-8.40 (m, 8H), 8.76 (m, 1H), 9.04 (d, 1H, J = 8H
z), 9.24 (d, 1H, J = 8Hz) MS (m / e); 525 (M + 1) ⁺ Reference Example 1 K-252, 7.01 g (15 mmol) in anhydrous THF (100 ml) was ice-cooled. Lithium aluminum hydride 1.14g (30m
mol) was added and the mixture was stirred at room temperature for 2 hours. After adding methanol to decompose excess reducing agent, the reaction mixture was filtered through Celite. The filtrate was washed with 1N hydrochloric acid and saturated saline,
It was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (chloroform-methanol) to obtain 5.34 g (81%) of a pale yellow powdery compound a.

mp.266-275 ° C (recrystallized from methanol) NMR (DMSO-d ₆ + CDCl ₃ ) δ; 9.24 (d, 1H, J = 8Hz), 8.2
−7.7 (m, 3H), 7.6−7.0 (m, 4H), 6.74. (Dd, 1H, J = 5,7
Hz), 4.90 (d, 1H, J = 18Hz), 4.69 (d, 1H, J = 18Hz), 4.1
3 (d, 1H, J = 11Hz), 3.91 (d, 1H, J = 11Hz), 3.29 (dd, 1
H, J = 7,14Hz), 2.38 (dd, 1H, J = 5,14Hz), 2.19 (s, 3H) MS (m / e); 440 (M + 1) ⁺ Reference Example 2 K-252,467 mg (1 mmol) Was dissolved in 10 ml of acetonitrile, and then 133 mg (1 mg of nitronium tetrafluoroborate)
mmol) was added and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (5%
Compound b 50 mg (10%) after purification with DMF / chloroform)
Was obtained as a yellow powder with mp.> 300 ° C.

NMR (DMSO-d ₆ ) δ; 2.12 (dd, 1H, J = 5,14Hz), 2.16
(S, 3H), 3.45 (dd, 1H, J = 7,14Hz), 3.94 (s, 3H), 4.99
(D, 1H, 18Hz), 5.06 (d, 1H, 18Hz), 6.44 (s, 1H), 7.26
(Dd, 1H, J = 5,7.4Hz), 7.39 (t, 1H, J = 8Hz), 7.53 (t, 1
H, 7Hz), 7.96 (d, 1H, 8Hz), 8.08 (t, 2H, J = 8Hz), 8.31
(Dd, 1H, J = 2.4.7Hz), 8.77 (s, 1H), 10.09 (d, 1H, J = 2
Hz) MS (m / e); 512 (M ⁺ ) Reference Example 3 87 mg (0.2 mmol) of compound a was dissolved in 5 ml of chloroform, 104 mg (1 mmol) of 2,2-dimethoxypropane and 10 mg of camphorsulfonic acid were added, and the mixture was added for 2 hours. Heated to reflux.
The reaction solution was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (1%
Purified with methanol / chloroform), compound c 68mg
(71.5%) was obtained as a tan powder with mp. 278-280 ° C.

NMR (CDCl ₃ ) δ; 1.14 (s, 3H), 1.40 (s, 3H), 2.24
(S, 3H), 2.41 (dd, 1H, J = 5,14Hz), 2.82 (dd, 1H, J = 5,
14Hz), 4.05 (d, 1H, J = 10Hz), 4.49 (d, 1H, J = 10Hz),
4.96 (s, 2H), 6.68 (dd, 1H, J = 5,7Hz), 7.24-8.20 (m,
7H), 9.40-9.60 (m, 1H) MS (m / e); 479 (M ⁺ ) Reference Example 4 To a solution of 4.53 g (10 mmol) of compound (IIa) in 50 ml of anhydrous pyridine, 1.42 ml (15 mmol) of acetic anhydride was added. In addition, the mixture was stirred at room temperature for 1 hour. The solvent in the reaction mixture was distilled off under reduced pressure, 50 ml of 1N hydrochloric acid was added to the residue, and the mixture was stirred. The insoluble material was collected by filtration, washed with 1N hydrochloric acid, and then with water. It was dried under reduced pressure to obtain 4.79 g (97%) of a pale yellow powdery compound d.

mp.267-270 ° C NMR (DMSO-d ₆ + CDCl ₃ ) δ; 9.36 (d, 1H, J = 8Hz), 8.2
−7.7 (m, 3H), 7.7−7.25 (m, 4H), 7.27 (dd, 1H, J = 5,7
Hz), 5.07 (s, 2H), 3.98 (dd, 1H, J = 7,14Hz) Reference Example 5 A solution of compound d2.5g in thionyl chloride 60ml was heated under reflux for 2 hours. Thionyl chloride in the reaction solution was distilled off under reduced pressure,
40 ml of ethyl ether was added to the solid residue and the mixture was stirred. The insoluble matter was collected by filtration, washed with ethyl ether, and dried under reduced pressure to obtain 2.29 g (8% of O-acetyl-acid chloride in the form of pale yellow powder).
8%).

To a solution of 206 mg (0.4 mmol) of the above compound in 5 ml of anhydrous chloroform (dehydrated with phosphorus pentoxide) was added 0.5 ml of 30% methylamine / methanol, and the mixture was stirred at room temperature for 3 hours, then 1 ml of 1N aqueous sodium hydroxide solution and 5 ml of methanol were added. The mixture was added and further stirred for 1 hour. To the reaction mixture was added THF (70 ml), and the resulting solution was washed with 1N hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography (chloroform-methanol), and a pale yellow powdery compound e109 mg was obtained.
(58%) was obtained.

mp.261~263 ℃ _{(methanol) NMR (DMSO-d 6)} δ; 9.22 (d, 1H, J = 7.9Hz), 8.1-7.8
(M, 3H), 7.55-7.25 (m, 4H), 7.04 (dd, 1H, J = 4.7,7.5
Hz), 5.04 (d, 1H, J = 17.5Hz), 4.97 (d, 1H, J = 17.5H
z), 3.26 (dd, 1H, J = 7.5,13.6Hz), 2.81 (d, 3H, J = 4.7H
z), 2.12 (s, 3H), 2.04 (dd, 1H, J = 4.7, 13.6Hz) MS (m / e); 466 (M ⁺ ) Reference Example 6 227 mg (0.5 mmol) of compound (IIa) in 20 ml of ethanol Thionyl chloride (1 ml) was added to the suspension, and the mixture was heated to reflux. After 2 and 4 hours, add 1 ml of thionyl chloride,
The mixture was heated under reflux for a total of 8 hours. Volatile substances in the reaction mixture were distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform-methanol) to obtain 160 mg (66%) of a pale yellow powdery compound f.

mp.193~195 ℃ (acetone - _{methanol) NMR (DMSO-d 6)} δ; 9.22 (d, 1H, J = 7.6Hz), 8.1-7.8
5 (m, 3H), 7.55-7.25 (m, 4H), 7.11 (dd, 1H, J = 4.9, 7.
3Hz), 5.04 (d, 1H, J = 17.7Hz), 4.98 (d, 1H, J = 17.7H)
z), 4.40 (m, 2H), 3.38 (dd, 1H, J = 7.3, 13.9Hz), 2.17
(S, 3H), 2.02 (dd, 1H, J = 4.9,13.9Hz), 1.43 (t, 3H, J
= 7.1 Hz) MS (m / e); 481 (M ⁺ ) Reference Example 7 439 mg (1 mmol) of compound (IIb) was suspended in 310 ml of chloroform, 0.25 ml (2 mmol) of trimethoxyethane and 23 mg of camphorsulfonic acid were added, The mixture was heated under reflux for 10 minutes.
The reaction mixture was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was triturated with chloroform-ether to give compound g380mg
(77%) was obtained.

NMR (CDCl ₃ ) δ; 1.40 and 1.52 (s, 3H), 2.12-3.52
(M, 2H), 2.29 and 2.32 (s, 3H), 3.05 and 3.36 (s,
3H), 4.04-4.68 (m, 2H), 5.02 (s, 2H), 6.44 (s, 1H),
6.73 (m, 1H), 7.20-8.12 (m, 7H), 9.34 (d, 1H, J = 8H
z) MS (m / e); 496 (M + 1) ⁺ Reference Example 8 438 mg (1 mmol) of compound (IIc) in 20 ml of THF and 10 ml of water
, Sodium bicarbonate 420mg (5mmol) was added,
Then, under ice cooling, benzyloxycarbonyl chloride 0.21
ml (1.5 mmol) was added, and the mixture was stirred at the same temperature for 1 hr. The reaction solution was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (2% methanol / chloroform), and compound h282 mg (49.3%) was mp.> 300 ° C.
Was obtained as a pale yellow powder of.

NMR (DMSO-d ₆ ) δ; 1.88-2.20 (m, 1H), 2.15 (s, 3
H), 3.00 (dd, 1H, J = 7,14Hz), 3.40-3.72 (m, 2H), 5.0
0 (br.s, 2H), 5.15 (s, 2H), 5.60 (s, 1H), 5.68-6.96
(M, 1H), 7.12-7.72 (m, 10H), 7.90-8.16 (m, 2H), 8.
56 (s, 1H), 9.20 (d, 1H, J = 8Hz) MS (m / e); 573 (M + 1) ⁺ Reference Example 9 Compound (IIc) 131 mg (0.3 mmol), N-benzyloxycarbonylglycine 94 mg ( 0.45 mmol) and DCC 93 mg
(0.45 mmol) was added, and the mixture was stirred overnight. After completion of the reaction, the precipitate was suctioned off, the solution was evaporated under reduced pressure, the residue was purified by silica gel column chromatography (2% methanol / chloroform), and compound i 156 mg (83%) was mp.
Obtained as a pale yellow powder at 157-162 ° C.

NMR (DMSO-d ₆ ) δ; 1.96-2.30 (m, 1H), 2.19 (s, 3
H), 2.58 (s, 1H), 2.72-3.08 (m, 1H), 3.60-3.88 (m,
4H), 5.00 (s, 2H), 5.11 (s, 2H), 5.72 (s, 1H), 6.86−
8.20 (m, 13H), 8.56 (s, 1H), 9.20 (dd, 1H, J = 2,8Hz) MS (m / e); 630 (M + 1) ⁺ Reference Example 10 Tablets 10% hydroxypropylcellulose solution 7,10
Add to a mixture consisting of 0 g, lactose 40 g, corn starch 18 g and carboxymethyl cellulose calcium 10 g and knead. The kneaded product is granulated by an extrusion granulator having a 1.0 mm screen and dried at 60 ° C. The dried granulation is screened through a 16-mesh screen and magnesium stearate is added to the screen to prepare tablet granules. Then 8m by the usual method
A tablet containing 100 mg of compound 7 per drug (170 mg) in m diameter is obtained.

Experimental Example 1 The C-kinase inhibitory activity of the compound obtained by the present invention was determined by the method of Y. Nishizuka et al. [J. Biol. Chem., 257 , 13341 (1
982)]. Change the concentration of the test compound,
The compound concentration that inhibits oxygen activity by 50% (IC ₅₀ ) was determined.
The results are shown in Table 3.

Experimental Example 2 The histamine release inhibitory action of the compound obtained according to the present invention was examined as follows.

Rats weighing 150 to 180 g were killed by exsanguination under dry ether anesthesia and the method of Sullivan et al. [J. Immunol., 114 , 1473 (1.
975)] and a mast cell culture solution (mast cell)
medium) (abbreviated as MCM, composition: 150 mM NaCl, 3.7 mM KCl, 3 m
M Na ₂ HPO ₄ , 3.5mM KH ₂ PO ₄ , 1mM CaCl ₂ , 5.6mM glucose,
0.1% bovine serum albumin, 10U / ml heparin), 6ml / animal
Was injected intraperitoneally. Massage the abdomen for 2 minutes,
The abdomen was opened and the peritoneal exudate was collected. The leachate collected from 6 animals was centrifuged at 4 ° C and 100 xg for 5 minutes, and the sediment was cooled with an appropriate amount of water.
MCM was added and washed 3 times, and the number of mast cells was finally about 3
Cell suspension so as × a 10 ⁴ cells / ml (peritoneal ex
udate cells, abbreviated as PEC) were prepared. The identification of mast cells was performed by staining intracellular granules with 0.05% toluidine blue. 37 ml of PEC obtained in this way
After pre-incubating at 10 ° C for 10 minutes, add 0.1 ml of various concentrations of the test drug solution and incubate for 10 minutes. Add 0.1 ml each of phosphatidyl-L-serine 100 µg / ml and concanavalin A 1000 µg / ml for another 15 minutes. Incubated. After 3 ml of ice-cooled physiological saline was added to stop the reaction, the mixture was centrifuged at 4 ° C. and 1100 × g for 10 minutes to obtain a supernatant and a precipitate. The amount of histamine in the supernatant and sediment was measured by the fluorescence method according to the method of Komatsu [Allergy 27 , 67 (1978)]. The histamine release rate was expressed as a percentage of the histamine content of the supernatant relative to the total histamine content of the cells. The histamine release inhibition rate of the test drug solution was calculated by the following equation.

The concentration of the test compound was changed and the concentration of the compound that inhibited histamine release by 50% (IC ₅₀ ) was determined. The results are shown in Table 4.

Experimental Example 3 The cell growth inhibitory activity of the compound obtained by the present invention was tested by the following method, and the results are shown in Table 5.

(1) MCF7 cell growth inhibition test: 10% fetal bovine serum 10 in a 96-well microtiter plate
RPMI containing μg / ml insulin 10 ^-8 M estradiol
0.1 ml of MCF7 cells adjusted to 4.5 × 10 ⁴ cells / ml with 1640 medium
Dispense each well into each well. After culturing at 37 ° C overnight in a carbon dioxide gas incubator, 0.05 ml of each test sample appropriately diluted with the culture medium is added. When contacting for 72 hours, incubate the cells as they are in the carbon dioxide gas incubator, remove the culture supernatant, wash once with PBS (-), add 0.1 ml of fresh medium to each well, Incubate for 72 hours at 37 ° C in a gas incubator. After removing the culture supernatant, 0.1 ml of a culture solution containing 0.02% neutral red is added to each well and cultured at 37 ° C. for 1 hour in a carbon dioxide gas incubator to stain the cells. After removing the culture supernatant, wash once with physiological saline, extract the dye with 0.001N hydrochloric acid / 30% ethanol, and then use a microplate reader at 550 nm.
The absorption of is measured. Cell growth was compared by comparing the absorption of untreated cells with cells treated with a known concentration of drug.
The concentration of the drug that causes% inhibition is calculated and used as the IC ₅₀ .

(2) HeLaS ₃ cell growth inhibition test: 2% of 10% fetal calf serum in a 96-well microtiter plate
He prepared at 3 × 10 ⁴ cells / ml in MEM medium containing M glutamine
Dispense 0.1 ml of LaS ₃ cells into each well.

 Perform the same as after the well dispensing in (1).

(3) COLO320DM cell growth inhibition test: 10% fetal bovine serum 10 in 96-well microtiter plate
COLO320DM cells were prepared at 10 ⁵ cells / ml in RPMI 1640 medium containing 0 u / ml penicillin and 100 μg / ml streptomycin.
Dispense 0.1 ml into each well. Thereafter, the same procedure as in (1) is performed, and the cells are calculated using a microcell counter. The drug concentration at which cell growth is inhibited by 50% is calculated by comparing the cell numbers of the untreated cells and the cells treated with a known concentration of drug, and this is defined as the IC ₅₀ .

Effects of the Invention Compound (I) and its pharmaceutically acceptable salts are C-
It has kinase inhibitory activity, antihistamine release inhibitory activity, platelet aggregation inhibitory activity, anti-inflammatory activity and cell growth inhibitory activity and is useful as an active ingredient of anti-allergic agents, anti-thrombotic agents, anti-inflammatory agents and anti-tumor agents. Expected to be.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Kazuyuki Iwahashi 1-2-22-16 Tamagawa Gakuen, Machida City, Tokyo (72) Inventor Akira Sato 1880-30 Ki-Socho, Machida City, Tokyo 1880-30 Inventor Kasai Masatsugu 3-12-15 Kugenuma Matsugaoka, Fujisawa City, Kanagawa Prefecture (72) Inventor Eiji Kobayashi 2-11-21-706 Kurihara, Adachi-ku, Tokyo (72) Inventor Makoto Morimoto 203-Shimochikari, Nagaizumi-cho, Sunto-gun, Shizuoka Prefecture 5 (72) Inventor Shiro Akinaga 1188 Shimochikari, Nagaizumi-cho, Sunto-gun, Shizuoka Examiner Hidenori Tsurumi

Claims (1)

[Claims] 1. A formula {In the formula, R ¹ and R ² are the same or different and each represents hydrogen, bromine or nitro, R ³ is hydrogen, lower alkyl, aralkyl or-(CH ₂ ) _n Z [wherein Z is hydroxy, (In the formula, R ⁴ and R ⁵ are the same or different and each represents hydrogen, lower alkyl or a group forming a heterocycle with an adjacent nitrogen atom) or And n represents 0, 1 or 2], and X
Represents carboxyl, lower alkoxycarbonyl, carbamoyl, lower alkylaminocarbonyl, hydroxymethyl or substituted or unsubstituted aminomethyl, wherein the substituent means an acyl group obtained by removing the hydroxy group from the carboxyl group of amino acid, and Y Is hydroxy, lower alkoxy or aralkyloxy,
Or -O-C (CH ₃₎ X and Y are as -Y-X- together ₂ -O-CH ₂ - or And a pharmacologically acceptable salt thereof.