WO1995023796A1 - Guanylhydrazone derivative - Google Patents

Abstract

A guanylhydrazone derivative represented by general formula (I) and a salt thereof, useful for treating or preventing diseases caused by various complications of diabetes and aging by virtue of its activity of inhibiting the mailard reaction and various diseases caused by lipid peroxide production by virtue of its antioxidant activity. In formulae (I) and (II) R1 represents R4-A- (A being a single bond, alkylene or phenylalkylene; and R4 being a group of general formula (II)); R2 represents hydrogen, alkyl, phenyl, phenylalkyl, nitrogenous monocyclic hetero ring or alkyl substituted by nitrogenous monocyclic hetero ring, or R?1 and R2¿ together with the carbon atom to which they are bonded represent cycloalkyl fused with R?4; and R3¿ represents hydrogen, alkyl or acyl; provided when A represents phenylalkylene, the phenyl is bonded to the carbon atom to which R2 is bonded.

Description

 Specification

 Guanylhydrazone derivative

Technical field

 The present invention relates to a guanylhydrazone derivative useful as a medicament. More specifically, the present invention

 1) General formula (I)

R ²

People No NHR ³

R ¹ N 丫 (I)

 NH

 (In the formula, all symbols have the same meanings as described below.)

Guanylhydrazone derivatives represented by the following, non-toxic salts thereof, and their acid addition salts,

 2) their manufacturing method, and

3) Drugs containing them as active ingredients. Background art

In 1912, Maillard reported that a mixture of amino acids and reducing sugars turned brown when heated [Maillard, L. C., Compt. Rend. Soc. Bio., 72, 599] (1912)]. This was due to the reaction between the amino acid and the sugar, suggesting that this reaction could then occur in vivo. By 1968, Rahbar reported that HbAIc, a minor component of hemoglobin, was increased in diabetics [Rahbar. S., Clin. Chim. Acta., 22, 296 (1968)]. Later, the chemical structure of HbAIc showed that the glucose bound to the N-terminal valine of the β-chain in an Amadori rearranged form [Koenig, RJ, Blobstein, SH, & Cerami, A., J. Biol. Chem., 252, 2992 (1977)] and that this reaction occurs nonenzymatically [Stevens, VJ, Vlassara, H., Abati, A , & Cerami, A., J. Biol. Chem., 252, 2998 (1977)], and the like, confirming that the Maillard reaction is occurring in vivo.

 In the initial stage of the Maillard reaction, the reducing sugar and the amino group of the protein undergo glycosylation, and Amadori

 CCNCC IIIII

H H = H H starts to form a dislocation product, 2 ¾ o o. As this proceeds further, the protein is referred to as cross-linked polymerisation [a glycosylated product that has progressed through this polymer (abbreviated as AGE). However, its solubility decreases and it becomes difficult to receive the action of protease, and eventually, it emits fluorescence and turns brown.

Main force two rhythm of AGE generation have been variously proposed, for example, as follows capital Brownian Li one (Brownlee) et (Brownlee, M. et al., Science, 232, 1629 (1986)) 0

 Glucose protein Schiff base

AGE

Amadori rearrangement product The Maillard reaction is a phenomenon that is also seen in healthy individuals, but is prominent in diabetic patients with elevated blood sugar levels and in protein sites with slow turnover. For example, in hemoglobin, diabetic mice are glycosylated 2.7 times more than normal mice [Monnier, VM et al., The Meillard Reaction in Foods and Nutrition, ACS Symposium Series, 215, 432, Am. Chem. So, Washington , DC (1983)], and serum albumin also has increased glycosylation in diabetic patients [Guthrow, CE et al., Pro Natl. Acad. Sci. U.S., 76, 4258 (1979)]. . In addition, repeated intravenous injections of glycosylated serum proteins into mice over a 12-week period show typical diabetic kidney damage [Monnier, VM et al., Clin. Endocrinol. Metab., U_, 431 (1982)].

Crystallin in the ocular lens is a special protein that, once biosynthesized, does not metabolize at all. When glycosylation occurred in this crystallant ¹ J, it was confirmed that a change in the steric structure occurred, and that an enzyme was involved in the intramolecular SH group to form an S—S bond and the polymer was polymerized. In rats with live cataract in rats, glucose binding is up to 10 times higher than normal, and intramolecular S—S binding is increased [Monnier, VM & Cerami, A. Clin. Endocrinol. Metab, Π_ , 431 (1982)].

 The polymerization, insolubilization, fluorescence, and yellow-brown coloration occur with the glycosylation of crystallin, and these changes are in good agreement with age-related changes in the lenses [Chiou, SH Chylack , LT, Jr., Tung, WH, & Bunn, F., J. Biol. Chem. 256, 5 176 (1981)].

Elastin, a collagen present in connective tissues, is a protein rich in lysine and hydroxy lysine, has a slow turnover, and has been found to bind to glucose in the renal glomerular basement membrane, skin tendons, etc. [Monnier, VM, Stevens, VJ, & Cerami, A., Maillard Reactions in Food, Prog. Food Nutr. Sci. 5., 315, Pergamon Press, London] [Rosenburg, H., Modrak, J.B., Hassing, JM, Al-Turk, WA, & Stohs, SJ, Biochem. Biophys. Res. Commun., 9, 498 (1979)] ₀

 In addition, non-enzymatic glycosylation of neuronal myelin protein is considered as a cause of diabetic neuropathy [Monnier, VM et al., Clin. Endocrinol. Metab. II_, 431 (1982)].

 As described above, it is thought that the Mailad reaction is involved not only in various complications of diabetes but also in various diseases associated with aging (aging).

 Recent studies have also reported that free radicals may be involved in protein glycosylation [Diabete & Metabolism (Paris), 14, 25-30 (1988)]. Conventional technology

Against this background, substances that inhibit the Maillard reaction have recently been searched. For example, Brownlee et al. Found that aminoguanidine blocks the Maillard reaction in vitro and that administration of aminoguanidine to diabetic rats produces AGEs (Advanced Glycosylation End products) in the arterial wall. Have been shown [Brownlee, M. et al., Science, 232., 1629 (1986)]. As an action mechanism, the amino group (bonded to the guanidino group) of the aminonucleoguanidine, which is a nucleophilic hydrazine compound, blocks the active carbonyl group in the Amadori rearrangement product, It is said to prevent further cross-linking of the Amadori rearrangement product. Further, Japanese Patent Application Laid-Open No. 62-142114 discloses a secondary glycosyl comprising a compound having an active nitrogen-containing group (an amino group bonded to a guanidino group) capable of reacting with an active carbonyl group in an Amadori rearrangement product. A composition that suppresses the production of an end-product of the synthesis is suggested, and specifically, aminoguanidine, α-hydrazinohistidine and lysine are disclosed.

 In addition, compounds that are structurally similar to the compound of the present invention include:

 (1) JP-A-2-765 discloses a compound represented by the general formula (C)

(C)

(Wherein R ^1C is substituted with 1 to 3 halogen atoms, C1-4 alkyl groups, or alkoxy groups, nitro groups, phenoxy groups, amino groups, hydroxyl groups, or C2-4 acylamino groups. or represents a substituted you have not carbocyclic or heterocyclic ring, X ^e represents a single bond, Cl～4 alkylene Motoma other represents a C2~4 alkenylene group, Tsuteji 1-4 such together R ^1C and X ^c Represents an alkyl group, and R ^2C is substituted or substituted with 1 to 3 hydrogen atoms, C 1-4 alkyl groups or halogen atoms, C 1-4 alkyl groups or alkoxy groups, hydroxyl groups or nitro groups. Represents an unsubstituted phenyl group.)

It is disclosed that the compound group represented by has Maillard reaction inhibitory activity.

 (2) In the specification of W092 / 19236, the general formula (D)

(式中、 R^1Dは水素またはァシル基を表わし、 R^2Dは水素または低級ァ ルキル基を表わし、 X^Dは低級アルキル基、 カルボキシ基、 カルボキシ メチル基、 またはハロゲン原子、 低級アルキル基、 ヒ ドロキシ低級ァ ルキル基、 ヒ ドロキシ基、 あるいはァセチルァミノ基で置換されてい てもよいフエニル基またはピリジル基を表わす。 ）

(Wherein, R ^1D represents hydrogen or an acyl group, R ^2D represents hydrogen or a lower alkyl group, X ^D represents a lower alkyl group, a carboxy group, a carboxymethyl group, or a halogen atom, a lower alkyl group, or a hydroxy group. Represents a phenyl group or a pyridyl group which may be substituted with a lower alkyl group, a hydroxy group, or an acetylamino group.)

It is disclosed that the compound group represented by has Maillard reaction inhibitory activity. Disclosure of the invention

 The present inventors have conducted research to find a novel compound that has an excellent inhibitory effect on the Maillard reaction and is highly safe. I found something to achieve. It has also been found that the derivative also has an antioxidant effect.

 [Comparison with conventional technology]

The guanylhydrazone derivative of the compound of the present invention is a novel compound that has never been known before. More specifically, the ^Rie group in the compound represented by the above formula (C) represents various heterocycles containing a heterocycle containing an oxygen atom, but specifically synthesized has a pyridine ring. Only things. Further, in the compound represented by the formula (C), the bond between the nitrogen atom at the 4-position and ^{Xc at} the 5-position represents a single bond. On the other hand, it is essential that the R ⁴ group in the R ¹ group in the compound (I) of the present invention has a heterocyclic ring containing an oxygen atom. Further, the compound (I) of the present invention represents a double bond in the bond between the nitrogen atom at the 4-position and the carbon atom at the 5-position to which R ¹ R ² is bonded, indicating that the compound of the formula (C) It can be said that the chemical structure is significantly different from.

Further, X ^D group in the compound represented by the formula (D) Table pyridyl group You. On the other hand, it is essential that the R ⁴ group in the R ¹ group in the compound (I) of the present invention has a heterocyclic ring containing an oxygen atom. Therefore, the chemical formula is significantly different from the formula (D). It can be said that it is a structure. Further, it can be said that the present compound is different from the compound group represented by the formula (D) also in having an antioxidant effect.

 [Detailed description of the invention]

 That is, the present invention

 1) General formula (I)

[Wherein R ¹ represents R ⁴ — A—

 A represents a single bond, a Cl-6 alkylene group, or a phenyl C2-8 alkylene group,

R ⁴

Represents

R ⁵ represents a hydrogen atom or a C 1-4 alkyl group,

R ⁶ is a hydrogen atom, an Cl～4 alkyl or C2~5 Ashiru group, R ⁷ is a hydrogen atom, Cl～4 alkyl group, one Z -. OR ⁸ group, One Y- COOR ⁹ group or a Y- CONR ^ R represents ¹¹ groups,

 Z represents a Cl-5 alkylene group,

Y represents a single bond or a C 1-4 alkylene group, R ⁸ represents a hydrogen atom or a C2-5 acyl group,

R ⁹ represents a hydrogen atom or a C 1-4 alkyl group,

R ^lfl and R ¹¹ each independently represent a hydrogen atom or a Cl-4 alkyl group;

 m represents an integer of 1 to 9,

 n represents an integer of 0 to 2,

R ² is a hydrogen atom, a Cl-4 alkyl group, a phenyl group, a phenyl Cl-47 alkyl group, a 5- to 7-membered monocyclic hetero ring containing one or two nitrogen atoms, or a nitrogen atom 1 or 2 Represents a Cl-4 alkyl group substituted with a 5- to 7-membered monocyclic ring to a tetracyclic ring,

Or R ¹ and R ² together with the carbon atom to which they are attached, represent a C5-fucycloalkyl group to which R ⁴ is fused;

R ³ represents a hydrogen atom, a Cl-4 alkyl group or a C2-5 acyl group. Provided, however, that the A represents a phenyl C2～ 8 alkylene group, phenyl group shall be bonded to the carbon atom bonded to the R ^2. ]

A guanylhydrazone derivative represented by the following, a non-toxic salt thereof or an acid addition salt thereof,

 2) their manufacturing method, and

 3) Drugs containing them as active ingredients.

In the present invention, all isomers are included unless otherwise indicated in the structural formulas in the specification. For example, the alkyl group, the alkoxy group, the alkylene group, and the alkylene group include straight-chain and branched-chain groups, and include the double bond in the alkenylene group and the compound (I) of the present invention. Double bonds in the amino groups at positions 5 and 5 include those that are E, Z and EZ mixtures. It also includes isomers resulting from the presence of asymmetric carbon atoms, such as when a branched alkyl group is present. In the general formula (I), the Cl-4 alkyl group represented by R ² , R ³ , R ⁵ , R ⁶ , R ⁷ , R ⁹ , R ¹⁰ and R ¹¹ is a methyl, ethyl, propyl, butyl group Maybe these are isomeric groups.

In the general formula (I), the C2-5 acyl group represented by R ³ , R ⁶ and R ⁸ is acetyl, propionyl, butyryl, valeryl and isomers thereof.

 In the general formula (I), the Cl-4 alkylene group represented by Y is a methylene, ethylene, trimethylene, tetramethylene group or isomers thereof.

 In the general formula (I), the Cl-5 alkylene group represented by Z is a methylene, ethylene, trimethylene, tetramethylene, pentamethylene group or an isomer thereof.

In the general formula (I), the Cl-6 alkylene group represented by A in R ¹ is a methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene or isomer group thereof. A phenyl C2-8 T alkylene group refers to an ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene group substituted with one phenylene group, and It is an isomer group. In this case, the phenylene group is bonded to the carbon atom to which R ² is bonded.

In the formula (I), a phenyl C L～4 alkyl group represented by R ^2, ethylene which is substituted by one phenyl group, trimethylene, tetramethylene and isomeric groups thereof.

In the general formula (I), the 5- to 7-membered monocyclic heterocyclic ring containing 1 or 2 nitrogen atoms represented by R ² includes pyrrole, imidazole, pyrazol, pyridine, pyridazine, and pyridyl. Midine, virazine, azepine, jia Zepin rings and the like. In addition, a Cl-4 alkyl group substituted by a 5- to 7-membered monocyclic hetero ring containing one or two nitrogen atoms refers to a methyl, ethyl, propyl, or butyl group substituted by one of the above rings. And their isomeric groups.

R ¹ The a C5~ off cycloalkyl group R ² is engaged R ⁴ is reduced to such connexion expressed together with the carbon atoms to which they are bonded, cyclopentyl fused by ^four one R, cyclohexyl, consequent b Heptyl group and isomers thereof.

In the R ⁴ group of the general formula (I), the dotted line represents a single bond or a double bond.

 [salt]

 The compound represented by the general formula (I) can be converted into a corresponding salt by a known method, if desired. Preferably, the salt is non-toxic and water-soluble. Suitable salts include, for example, salts of alkali metals (such as potassium and sodium), salts of alkaline earth metals (such as calcium and magnesium), ammonium salts, and pharmaceutically acceptable organic amines (such as tetramethylammonium). , Triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris (hydroxymethyl) methylamine, lysine, arginine, N— Methyl-D-glucamine).

The compound represented by the general formula (I) may be converted into an acid addition salt by a known method, if desired. The acid addition salts are preferably non-toxic and water-soluble. Suitable acid addition salts include, for example, inorganic salts such as hydrochloride, hydrobromide, hydrobromide, sulfate, phosphate, nitrate, or acetate, lactate, Tartrate, benzoate, citrate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfate Organic salts such as fonate, isethionate, glucuronate, and gluconate. The acid addition salt can be obtained by a known method, for example, reacting the compound represented by the general formula (I) with a desired acid in a suitable solvent in a stoichiometric amount.

 [Specific compounds of the present invention]

 Preferred compounds of the present invention include compounds represented by general formula (I-A)

(All symbols in the formula have the same meanings as described above. However, a plurality of R ⁵ may be the same or different.)

General formula (I_B)

(All symbols in the formula have the same meanings as described above. However, a plurality of may be the same or different.)

General formula (I-C) j5 Ό 'cho, NH (IC)

 f, .N, X NHR ^

(All symbols in the formula have the same meanings as described above. However, a plurality of may be the same or different.)

General formula (I-D)

(In the formula, R ^7a represents a methyl group, a hydroxymethyl group, a (CH ₂ ) ₂ —COOH group, a — (CH ₂ ) ₂ —CONH ₂ group, and other symbols have the same meanings as described above. However, two R ^{5 's} may be the same or different.), A general formula (I-E)

(All symbols in the formula have the same meanings as described above. However, two R ^{5 s} may be the same or different.)

General formula (I-F)

(All symbols in the formula have the same meanings as described above. However, two R ^{5 s} may be the same or different.)

General formula (I-G)

(IG)

(All symbols in the formula have the same meanings as described above. However, two R ^{5 s} may be the same or different.)

General formula (I-H)

(All symbols in the formula have the same meanings as described above. However, two R ^{5 s} may be the same or different.)

General formula (I-I) (II) Νγ ^ΝΗ2

 NH

(All symbols in the formula have the same meanings as described above. However, two R ^{5 s} may be the same or different.)

And the general formula (I—J)

(All symbols in the formula have the same meanings as described above.)

And the non-toxic salts thereof, and their acid addition salts.

Specific compounds of the present invention include guanylhydrazone derivatives, their non-toxic salts, their acid adduct salts, and the compounds described in Examples in Tables 1 to 10 below. table 1

 (IA-1) (IB-1) A— 1, 75

 n R R, (IB-1)

 1 0 Methyl methyl

20 ethyl methyl

3 0 Methylethyl

4 0 Isopropyl methyl

50 Methyl isopropyl

6 0 Isopropyl Isopropyl

7 0 t-butyl t-butyl

8 Ethyl methyl

9 Methylethyl

10 Isopropyl methyl

11 Methyl isopropyl

12 Isopropyl Isopropyl

13 t-butyl t-butyl

14 2 Methyl methyl

15 2 Ethyl methyl

16 2 Methylethyl

17 2 Isopropyl methyl

18 2 Methyl isopropyl

19 2 Isopropyl isopropyl

20 2 t-butyl t-butyl Table 2

NH ₂

 (IA-2) (IB-2)

(IA-2) and

 n Z

 (IB-2) 1

 1 0 1 o

2 0 1 (CH ₂ ) 1 _2-

3 0 1 (CH ₂ )

4 0 1 (CH ₂ ) ₄ —

5 1 CH ₂ —

6 1 One (CH ₂ ) ₂ —

7 1 One (CH ₂ ) ₃ —

8 1 One (CH ₂ ) ₄ —

 9 2

10 2 One (CH ₂ ) ₂ —

11 2 One (CH ₂ ) ₃ —

_{12 2 - (CH 2) 4} - Table 3

 (IA-3) (IB-3)

(IA-3) and

 n Y

 (IB-3)

1 0 1 CH ₂ —

2 0 — (CH ₂ ) ₂ —

3 0 1 (CH ₂ ) ₃ —

4 0 — (CH ₂ ) ₄ —

5 1 CH ₂ —

6 1 One (CH ₂ ) ₂ —

7 1 One (CH ₂ )

8 1 One (CH ₂ ) ₄ —

9 2 One CH ₂ —

10 2 One (CH ₂ ) ₂ —

11 2 One (CH ₂ ) ₃ —

12 2 One (CH ₂ ) ₄ — Table 4 — 1

 (IA-4)

NH ₂

 (IB-)

(Continued on next page) Table 4 — 2

— 4) and

n YR ^10a R ^lla

(丄 4)

Ό Q 丄 糸 系 丄 U 丄 H H ₂ ―

1丄丄(and H _{2) 2} - Brown Brown

 ^-.

12 1 — (CH ₂ ) ₂ — menu 7 ”J

13 1 — (CH ₂ ) ₃ — hydrogen hydrogen

 .

14 1 — (CH ₂ ) ₃ — Meny — (Le Menare “

15 1 One (CH ₂ ) ₄ — Hydrogen

 / C

1 丄 — (CH ₂ ) ₄ ―

17 2 CH CH Hydrogen Hydrogen

18 2 -CH-Methyl methyl

19 2 One (CH ₂ ) ₂ — Hydrogen Hydrogen

20 2 1 (CH ₂ ) ₂ — methyl methyl

21 2 One (CH ₂ ) ₃ — Hydrogen Hydrogen

22 2 — (CH ₂ ) ₃ — methyl methyl

23 2 One (CH ₂ ) ₄ — Hydrogen Hydrogen

24 2 ~ (CH ₂ ) ₄ -methyl methyl

Table 5

 (ic-i) (ID-1)

(IC-l) and

 n R

 (ID-1)

 1 Λ sheep

1 U

 U Zano Bu No] 1 Les

Π No, no π LJ

5 U spoon ^u Roh] may n

 4 U No Ichinore

 A D U 'No ✓ No

0 j No ✓

 7 methyl

8 butyl

9 Isopropyl

10 phenyl

1 1 2—pyridyl

12 3-pyridyl

13 2 Methyl

14 2 butyl

15 2 Isopropyl

16 2 Phenyl

17 2 2-pyridyl

18 2 3—Pyridyl Table 6

表 7 H₂

Table 7 H ₂

 (IC-3) ID-3)

(IC-1 3) and Y

 (ID-3)

1 0 1 (CH ₂ ) ₂ — Methyl

20-(CH ₂ )-methyl

30 one (CH ₂ ) ₂ — benzyl

4 0 1 (CH ₂ ) ₄ — benzyl

5 0 — (CH ₂ ) ₂ — 2-pyridyl

6 0 1 (CH ₂ ) ₄ — 2-pyridyl

7 One (CH ₂ ) ₂ — methyl

8 to (CH ₂ ) -methyl

9 — (CH ₂ ) benzyl

10 — (CH ₂ ) ₄ — benzyl

1 1 — (CH ₂ ) “2-pyridyl

12 — (CH ₂ ) ₄ — 2-pyridyl

13 2 — (CH ₂ ) “methyl

14 2 One (CH ₂ ) ₄ — Methyl

15 2 — (CH ₂ ) benzyl

16 2 — (CH ₂ ) ₄ — Benji '

17 2 One (CH ₂ ) ₂ — 2-pyridyl

18 2 One (CH ₂ ) ₄ — 2-pyridyl Table 8 H ₂

 (IC-4) (ID-)

(IC-1 4) and

 η Υ R

 1 ο ― CH) 2 ―

2 ο-, C-H2)-Methyl

3 ο one (CH 2 21 one benzyl

4 ο 1 (CH "2 4 1 1

5 0 — (CH ₂ ) “2-pyridyl

6 0 — (CH ₂ ) ₄ — 2-pyridyl

7 — (CH ₂ ) ₂ — methyl

8 One (CH ₂ ) ₄ — Methyl

9 - (CH ₂₎ - benzyl

10 One (CH ₂ ) ₄ — benzyl

1 1 1 (CH ₂ ) ₂ — 2-pyridyl

12- (CH ₂ ) -2-pyridyl

13 2 One (CH ₂ ) ₂ — Methyl

14 2 One (CH ₂ ) ₄ — Methyl

15 2 — (CH ₂ ) ₂ — benzyl

16 2 One (CH ₂ ) ₄ — benzyl

17 2 One (CH ₂ ) ₂ — 2-pyridyl

18 2 One (CH ₂ ) ₄ — 2-pyridyl t

m2-

Table 9-2

 — 1, 2, 3, 4) and

 η A R (IF— 1, 2, 3, 4)

1 U ― (CH ₂ ) ₂ ― 71 ^ tea eight

2 0 — (CH ₂ ) ₄ —

3 u — (CH ₂ ) ₂ — Menole

4 u — (CH ₂ ) ₄ — Menole

5 u — (CH ₂ ) ₂ — No Byeon

6 u — (CH ₂ ) ₄ — No, Byeon

1 — (CH ₂ ) ₂ — No

8 0 — (CH ₂ ) ₄ — No

9 0 — (CH ₂ ) ₂ — 2—

10 0 — (CH ₂ ) ₄ — 2——

1 1 — (CH ₂ ) ₂ — Water tea

¹

12 — (CH ₂ ) ₄ — hydrogen

¹

13 — (CH ₂ ) ₂ — methyl

¹

14 — (CH ₂ ) ₄ — methylile

¹

15 — (CH ₂ ) ₂ — Funyl,

¹

16 One (CH ₂ ) ₄ —,

 Funal

¹

17 — (CH ₂ ) ₂ — Fail

¹

18 — (CH ₂ ) ₄ — Noe

¹

19 — (CH ₂ ) ₂ — 2——

¹

_{2U - (CH 2) 4 -} 2-- arsenide Li down les one _{21 2 - (CH 2) 2} - Main

Water one two two L (CH ₂ ) ₄ — main

Certain one 2 — (CH ₂ ) ₂ —

1Α (H H

25 2 One (CH ₂ ) ₂ — butyl

26 2 One (CH ₂ ) ₄ — butyl

27 2 One (CH ₂ ) ₂ — phenyl

28 2 One (CH ₂ ) ₄ — phenyl

_{29 2 - (CH 2) 2} - 2- pyridyl

30 2 — (CH ₂ ) ₄ — 2-pyridyl

ο

Table 10-2

(IG-1,2,3,4) n m R

 10 0 0 Methyl

11 0 1 Methyl

12 0 2 Methyl

13 1 0 Mail

14 1 1 methyl

15 1 2 Methyl

16 20 methyl

17 2 1 Methyl

18 2 Methyl

19 00 butyl

20 0 1 butyl

21 0 2 butyl

22 1 0 Petil

23 1 1 butyl

24 1 2 butyl

25 20 butyl

26 2 1 butyl

27 2 butyl

28 0 0 Isopropyl

29 0 1 Isopropyl

30 0 2 Isopropyl

31 1 0 Isopropyl

32 1 1 Isopropyl

33 1 2 Isopropyl

34 2 0 Isopropyl

35 2 1 Isopropyl

36 2 2 Isopropyl [Method for producing the compound of the present invention]

The compound of the present invention represented by the general formula (I) has the general formula (式)

(Wherein, R "is the same meaning as R ^1, in R ¹ R ⁶ is a hydrogen atom, Cl～4 § alkyl group, a group can be removed with C2~5 Ashiru group or an acid (e.g., C2-4 alkoxy represents an alkyl group), R ⁷ is a hydrogen atom, Cl～4 alkyl group, C2-5 Ashiruokishi one Z- group, one Y- COOR ⁹ group, one Y- CONR R ¹¹ Motoma other can be removed by acid groups ( For example, C2-4 alkoxyalkyl-Z-group), and other symbols have the same meanings as described above.)

And a compound represented by the general formula (m)

 (m)

(In the formula, all symbols have the same meanings as described above.)

In the case where R ⁶ and κ or R ⁷ are groups which can be removed with an acid, the compound can be produced by subsequent acid treatment.

 Or the general formula (Π)

R ²

丄 ( ^Π )

(In the formula, all symbols have the same meanings as described above.)

And a compound represented by the general formula (m-1)

H ゥ N (ΠΙ-1)

で示される化合物と反応させた後、 引き続いてァシル化反応を行なう ことによって製造するか、 あるいは R⁶および または R⁷が酸で除去で きる基である場合は、 ァシル化反応に引き続いて酸処理を行なうこと によって製造することができる。

The compound is prepared by reacting with the compound shown in, followed by a subsequent acylation reaction, or, if R ⁶ and / or R ⁷ is a group that can be removed with an acid, followed by the acylation reaction followed by an acid treatment It can be manufactured by performing.

 The reaction between the general formula (π) and the general formula (m) or the general formula (ffl-i) occurs in the presence of a tertiary amine (pyridine, triethylamine, etc.) in an alcoholic solvent (methanol, ethanol, etc.) The reaction is carried out at a temperature of 80 to 120 ° C.

 The treatment with an acid is carried out by reacting in an alcoholic solvent (such as methanol or ethanol) in the presence of an organic acid (such as acetic acid or trifluoroacetic acid) or an inorganic acid (such as hydrochloric acid or sulfuric acid).

 The acylation reaction is carried out by reacting with an acyl halide or an acid anhydride in an organic solvent (methylene chloride, methyl ether, tetrahydrofuran, etc.) in the presence of a tertiary amine (triethylamine, pyridine, etc.). Will be

The compound represented by the general formula (II) used as a starting material can be produced by the methods shown in the reaction formulas 1 to 12, or by a known method. For example, it can be produced by the method described herein.

Reaction process formula 1-(1)

_R5

_R 5

Reaction process formula 1- (2)

Reaction process formula 2 t

Reaction scheme 3-(1)

3

Three

1) Ph ₃ PCHCOOCH ₃

2) H ゥ ZPd-C

 3) Reduction Reaction scheme 3- (2) 4

Reaction scheme 3-(2)

(IV-C)

(IV-C)

Reaction process formula 4

 Epoxidation 3

Reaction process formula 5

Reaction process formula 6

Reaction process formula 7

 (Π-2) (Π-3) (Π-5)

oo

(Π-4) (II-6)

Reaction process formula 8-(1)

 (II-7) (Π-8) II

 (II- 2, 5, 6)

1) Ph ₃ PCHCOOR ¹³

2) H ₂ ZPd-C

(3) OH- or H +)

4) reduction

 5) Span oxidation

Reaction process formula 8-(2)

 5) Swan oxidation

1) Ph ₃ PCHCOOR ¹³

2) H ₂ / Pd-C

(3) OH— or H +)

4) reduction

 5) Span oxidation

Reaction process formula 9

^ 5) Span oxidation

 (11-14) (Π-15) II

(II- 7, 8, 9, 10, 11, 12, 13)

Reaction process formula 10

Reaction process formula 11

1) PPA, heating

2) HCI, pyridine

(11-21) (VII)

Reaction process formula 12

(Π-22)

In the reaction process formula,

R ^A represents a Cl-4 alkyl group,

R ^B represents a C2-4 alkoxyalkyl group,

R ^c represents a C2-5 acyl group,

Y represents a single bond or a Cl-4 alkylene group,

ZZ represents a C2-4 alkylene group,

W represents a single bond or a methylene group,

B represents a single bond or a Cl-6 alkylene group,

BB represents a C2-8 alkylene group,

R ⁶ - ¹ represents an Cl~4 alkyl group, C2-5 Ashiru group or C2~4 Arukokishiaru Kill group,

 Represents a hydrogen atom, a Cl-47 alkenyl group or a C2-47 alkoxyalkyl group,

R ⁶ - ³ represents a C2~5 A group,

R ⁶ - ⁴ represents a hydrogen atom, Cl～4 alkyl group, C2-5 Ashiru group or C2~4 al Kokishiarukiru group,

R ⁷ - ¹ represents a hydrogen atom or a C L～4 alkyl group,

R ⁷ - ² represents a hydrogen atom, Cl～4 alkyl group or R OOC- Y- group, R ⁷ - represents a ³ HO- Z- group,

R ⁷ — ⁴ represents a hydrogen atom, Cl- ⁴ alkyl group, R OOC— Y— group or HO— Z— group,

R ⁷ - ⁵ represents a hydrogen atom, Cl～4 alkyl group, C2-5 Ashiruokishi one Z- group, C2-4 alkoxyalkyl O alkoxy one Z- group or R ⁹ OOC- Y- group,

R ⁷ - ⁶ represents an HOOC- Y- group,

R ⁷ - ⁷ represents a RU RWNOC- Y- group, R ⁷ - ⁸ is hydrogen atom, Cl～4 alkyl group, C2-5 Ashiruokishi one Z- group,

C2-4 alkoxyalkyloxy represents a Z-group, a RWOOC-Y- group or a RUR'ONOC-Y- group,

R ^7-9 is a hydrogen atom, a Cl-4 alkyl group, a C2-5 alkoxylZ- group,

C2~4 alkoxyalkyl O alkoxy one Z- group, R ⁹ OOC- Y- group or

RHR NOC— represents a Y— group,

R ⁷ - ^1Q is a hydrogen atom, Cl～4 alkyl group, C2-5 Ashiruokishi one Z- group,

To C2 4-alkoxyalkyloxy-Z-group, HOOC-Y-group or

RUR'ONOC— represents the Y— group,

R ⁷ — ¹¹ represents an RWOOC—Y— group,

R ⁹ — ¹ represents a Cl-4 alkyl group;

R ¹³ represents a Cl-4 alkyl group,

X represents a halogen atom,

Other symbols have the same meaning as above,

 9—BBN stands for 9-borabicyclo [3.3.1] nonane.

 Using the compound represented by (Π-21) and (Π-22), the general formula (Π-23) is obtained by making full use of the method described in Reaction Steps 5, 6, or 7.

(Wherein all symbols have the same meanings as described above.).

The reaction product is purified by conventional means of purification, for example, distillation under normal pressure or reduced pressure, high-performance liquid chromatography using silica gel or magnesium silicate. It can be purified by a method such as chromatography, thin-layer chromatography, column chromatography or washing, recrystallization and the like. Purification may be performed for each reaction, or may be performed after completion of several reactions.

 Other starting materials (for example, the compound represented by the general formula (II)) and each reagent in the present invention are known per se or can be produced by a known method. Industrial applicability

 The inhibitory effect of the compound of the present invention on the Maillard reaction was confirmed by a screening system using various proteins and various sugars, and specific examples are shown below.

 (1) Experimental method

 Lysozyme and fructose were dissolved in 0.2 M sodium phosphate buffer (pH 7.4) to a concentration of 10 mg / ml and 100 mM, respectively, and incubated at 37 ° C for 3 days. Electrophoresis was performed using polyacrylamide gel electrophoresis (SDS-PAGE). After electrophoresis, the cells were stained with 0.2% Coomassie Brilliant Blue R-250, and the amount of dimers produced was quantified using a densitometer.

The present compound was added before incubation, and the inhibitory effect on dimer formation at various concentrations was examined to determine the _IC5Q value.

(2) The results are shown in Table 11. table 1

本発明化合物の抗酸化作用は以下に述べる過酸化脂質生成抑制効果 を調べるスクリ一ニング系によ り確認された。

The antioxidant effect of the compound of the present invention was confirmed by a screening system for examining the lipid peroxide production inhibitory effect described below.

 (1) Experimental method

-The fasted male Sprague Dawley rat was perfused from the portal vein with an ice-cooled 0.9% sodium chloride solution under ether anesthesia, and liver tissue was removed. The isolated liver was made into a 10% homogenate using an ice-cooled 1.15% aqueous potassium chloride solution. 200 mM of FeCl ₂ was added to the obtained homogenate 1, and the mixture was incubated at 37 ° C. for 1 hour.

 According to the method of Ohkawa et al. [See Analytical Biochemistry 95., 351 (1979)], the amount of lipid peroxide produced was measured by the thiobarbituric acid (TBA) method.

The compounds of the invention were added before incubation, examine its effect, IC _5. Values were calculated.

(2) The results are shown in Table 12. Table 1 2

 Example compound

IC, _n (μ M)

 Number

 1 7.3

 1 (e) 0.5 5

 1 (f) 0.3 1

 1 (g) 0.3 7

 1 (j) 7.4 From Tables 11 and 12, it can be concluded that the compound of the present invention, its non-toxic salt and its acid addition salt have a Mailad reaction inhibitory action and an antioxidant action.

 [Toxic]

 The toxicity of the compound of the present invention was sufficiently low, and it was confirmed that the compound can be safely used as a pharmaceutical.

 [Application to pharmaceutical products]

 The compounds of the present invention represented by the general formula (I), their non-toxic salts, and their acid addition salts inhibit the Maillard reaction, so that various diabetic complications such as coronary heart disease, peripheral circulation, etc. Treatment of disorders, cerebrovascular disorders, diabetic neuropathy, nephropathy, arteriosclerosis, arthrosis, cataracts and retinopathy, and diseases caused by aging, such as atherosclerosis, senile cataracts and cancer And / or useful for prevention.

In addition, the compounds of the present invention represented by the general formula (I), their non-toxic salts, and their acid addition salts also have an antioxidant action, that is, an action of suppressing the reaction of free radicals. Treatment of various diseases caused by production, such as atherosclerosis, diabetes, myocardial infarction, peripheral circulatory disorders, cerebrovascular disorders, cancer, inflammation, digestive disorders and aging and Z or Useful for prevention.

 In order to use the compound of the present invention represented by the general formula (I), a non-toxic salt thereof, and an acid addition salt thereof for the above purpose, the compound is usually orally or parenterally administered systemically or locally. . The dosage varies depending on age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., but is usually orally administered to a single adult once to several times a day in the range of lmg to 1000mg at a time. Or parenteral administration (preferably intravenous administration) once to several times a day in the range of 0.1 mg to 100 mg per administration per adult. Of course, as described above, since the dose varies under various conditions, a dose smaller than the above dose range may be sufficient, or may be necessary beyond the range.

 When the compound of the present invention is administered, solid compositions, liquid compositions and other compositions for oral administration, injections, parenteral preparations, suppositories and the like for parenteral administration are used.

 Solid compositions for oral administration include tablets, pills, capsules, powders, granules and the like.

Capsules include hard capsules and soft capsules. In such a solid composition, the one or more active substances comprise at least one inert diluent, such as hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, magnesium aluminate metasilicate. Mixed with. The composition may, in a conventional manner, be an additive other than an inert diluent, for example, a lubricant such as magnesium stearate, a disintegrant such as calcium cellulose glycolate, a dissolving agent such as glutamic acid or aspartic acid. It may contain adjuvants. Tablets or pills as required, sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate And may be coated with a film of a gastric or enteric substance such as stomach, or may be coated with two or more layers. Also included are capsules of absorbable materials, such as gelatin.

 Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and commonly used inert diluents (for example, purified Water, ethanol). The composition may contain, in addition to the inert diluent, adjuvants such as wetting agents and suspending agents, sweetening agents, flavoring agents, fragrances, and preservatives.

 Other compositions for oral administration include sprays which contain one or more active substances and are formulated in a manner known per se. The composition may contain, in addition to the inert diluent, a buffer that provides isotonicity with stabilizers such as sodium bisulfite, for example, sodium chloride, sodium citrate, or citric acid. Good. The method for producing the spraying agent is described in detail, for example, in US Pat. Nos. 2,686,691 and 3,095,355.

Injections for parenteral administration according to the present invention include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Aqueous solutions and suspensions include, for example, distilled water for injection and physiological saline. Examples of the non-aqueous solution and suspension include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate 80. Such compositions may also contain adjuvants such as preserving, wetting, emulsifying, dispersing, stabilizing, and solubilizing agents (eg, glutamic acid, aspartic acid). These are sterilized by, for example, filtration through a bacteria-retaining filter, blending of a bactericide or irradiation. They also produce sterile solid compositions that may be dissolved in sterile water or sterile injectable solvents before use. You can also.

 Other compositions for parenteral administration include one or more active substances, topical solutions, salves such as ointments, and rectal administration for routine administration. It includes suppositories and pessaries for vaginal administration. BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail with reference examples and examples, but the present invention is not limited thereto.

 The solvent in the pressure box described in the column of separation by chromatography indicates the developing solvent used, and the ratio indicates the volume ratio. In addition, the inside of the katakana described in the NMR section indicates the measurement solvent. Reference example 1 '

 To a solution of 2,5-dimethylbenzoquinone (80 g) in methylene chloride (600 ml) was added sodium borohydride (22.3 g) at 0 ° C. Further, methanol was added to the solution until sodium borohydride was dissolved. After completion of the reaction, a 1N aqueous hydrochloric acid solution was added to the reaction mixture, and the mixture was concentrated. The residue was extracted with ethyl acetate. The extract was washed successively with water and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated to give the title compound having the following physical data.

TLC: Rf 0.11 (hexane: ethyl acetate = 5: 1). Reference example 2

 To a solution of the compound prepared in Reference Example 1 in anhydrous tetrahydrofuran (THF) (1000 ml) was added boron trifluoride 'getyl ether complex (108.5 ml). C was added dropwise. To this mixture, 3-methyl-2-buten-1-ol (71.7 ml) was added dropwise at 0 ° C, and the mixture was brought to room temperature and stirred. After completion of the reaction, the mixture was concentrated. To a solution of the obtained residue in 1,2-dichloroethane (1000 ml) was added boron trifluoride-getyl ether complex (150 ml) dropwise (TC), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, and concentrated. Chill (1000 ml), water (100 ml) and 2N aqueous sodium hydroxide solution were added, and the precipitated crystals were filtered off.The aqueous layer of the filtrate was neutralized with 2N aqueous sodium hydroxide solution, and the organic layer was separated. The organic layer was washed successively with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was washed with a mixed solution of hexane: ethyl acetate = 1: 1. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1 → 15: 1 → 10: 10), and the obtained crystals were converted to hexane. Recrystallized and have the following physical properties To give title compound (34.07g).

TLC: Rf 0.35 (hexane: ethyl acetate = 5: 1). Reference example 3

 To a solution of the compound prepared in Reference Example 2 (38.2 g) in methylene chloride (200 ml), α, α-dichloromethylmethyl ether (34.4 ml) was added dropwise at 120 ° C. Further, titanium tetrachloride (41.7 ml) was added dropwise to the solution at the same temperature. The reaction mixture was stirred at room temperature for 30 minutes. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (hexane: ethyl acetate = 15: 1) to give the title compound (37.8 g) having the following physical data.

 TLC: Rf 0.55 (hexane: ethyl acetate = 9: 1). Reference example 4

In a solution of the compound prepared in Reference Example 3 (550 _mg ) in THF (10 ml) was added sodium hydride (190 mg, containing 60%) and dimethylformamide (DMF).

(lml) were added sequentially. After stirring at room temperature for 30 minutes, methyl iodide (0.15 ml) was added to the reaction mixture at room temperature, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, and extracted with getyl ether. The extract was washed successively with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated. The title compound (540 mg) having the following physical data was obtained.

TLC: Rf 0.19 (hexane: ethyl acetate = 10: 1). Reference example 5

 The same operation as in Reference Example 1 → Reference Example 2 → Reference Example 3 was performed using 2,3-dimethylbenzoquinone to obtain the title compound having the following physical data.

TLC: Rf 0.37 (hexane: ethyl acetate = 20: 1). Reference example 6

 The same operation as in Reference Example 1-Reference Example 2 → Reference Example 3 was performed using 3,5-dimethylbenzoquinone to obtain the title compound having the following physical data.

TLC: Rf 0.20 (hexane: ethyl thiocyanate = 4: 1). Reference Example 7

 A solution of the compound prepared in Reference Example 3 (1.38 g) in tetrahydrofuran (5 ml) was added dropwise to a suspension of sodium hydride (280 mg, containing 60%) in THF (5 ml) at 0 ° C. Phosphoramide (HMPA) (3 ml) was added. After the reaction mixture was stirred at 60 ° C for 30 minutes, chloromethyl methyl ether (0.53 ml) was added dropwise at 0 ° C. After the reaction mixture was stirred at room temperature for 1 hour, water was added, and the mixture was extracted with hexane: ethyl acetate = 1: 1. The extract was washed successively with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to give the title compound (915 mg) of Honkimei having the following physical data.

TLC: Rf 0.28 (hexane: ethyl acetate = 4: 1). Reference Example 8

To a solution of the compound (280 mg) produced in Reference Example 7 in benzene (15 ml) was added methyl (triphenylphosphoranylidene) acetate (668 mg) under an argon atmosphere. The reaction mixture was stirred at 80 C overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to give the title compound (304 _mg ) having the following physical data.

 TLC: Rf 0.39 (hexane: ethyl acetate = 4: 1). Reference Example 9

 To a solution of the compound (540 mg) produced in Reference Example 8 in ethanol (5 ml) was added 5% palladium-carbon (100 mg). The reaction mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere. After the reaction mixture was filtered through Celite (trade name), the filtrate was concentrated to give the title compound (543 mg) having the following physical data.

 TLC: Rf 0.39 (hexane: ethyl acetate = 4: 1). Reference example 10

Lithium aluminum hydride (27 mg) in THF (2 ml) was added under argon atmosphere. In C, a solution of the compound (336 mg) produced in Reference Example 9 in tetrahydrofuran (1.5 ml) was added. The reaction mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added a saturated aqueous sodium sulfate solution at 0 ° C. mixture The mixture was stirred for 30 minutes, anhydrous magnesium sulfate was added, and the filtrate was concentrated to give the title compound (279 mg) having the following physical data. TLC: Rf 0.16 (hexane: ethyl acetate = 4: 1). Reference example 1 1

 To a solution of oxalyl chloride (0.20 ml) in methylene chloride (5 ml) was added dropwise a solution of dimethyl sulfoxide (0.35 ml) in methylene chloride (1 ml) at 178 ° C under an argon atmosphere. After the mixture was stirred at the same temperature for 20 minutes, a solution of the compound produced in Reference Example 10 (450 ml) in methylene chloride (2 ml) was added. After the mixture was stirred at the same temperature for 30 minutes, triethylamine (1.1 ml) was added. The reaction mixture was stirred at room temperature for 10 minutes. Water (5 ml) was added to the reaction mixture, which was extracted with ethyl acetate. The extract was washed successively with 1N aqueous hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and concentrated to give the title compound (280 mg) having the following physical data. Obtained.

TLC: Rf 0.47 (hexane: ethyl acetate = 2: 1). Reference example 1 2

参考例 4で製造した化合物を用いて、 参考例 8—参考例 9→参考例 1 0—参考例 1 1 と同様に操作して次の物性値を有する標題化合物を

Using the compound produced in Reference Example 4, Reference Example 8—Reference Example 9 → Reference Example 10—The title compound having the following physical properties was obtained in the same manner as Reference Example 11.

Ί 1 o

 TLC: Rf 0.51 (hexane: ethyl acetate = 5: 1). Reference Example 1 3

 Using the compound produced in Reference Example 5, Reference Example 7 → Reference Example 8—Reference Example 9 → Reference Example 10 → Operation as in Reference Example 11 gave the title compound having the following physical properties. .

 TLC: Rf 0.53 (hexane: ethyl acetate = 4: 1). Reference example 1 4

 Using the compound prepared in Reference Example 6, the same operation as in Reference Example 7 → Reference Example 8 → Reference Example 9 → Reference Example 10 → Reference Example 11 gave the title compound having the following physical properties. .

TLC: Rf 0.36 (hexane: ethyl acetate = 5: 1). Reference example 1 5

H₃

H ₃

(4-Methoxycarbonylbenzyl) Triphenylphosphonium bromide (3.28 g) and sodium methoxide (306 mg) in THF (7 ml) suspension at 0 ° C in methanol (4 ml) Was added. After stirring at room temperature for 30 minutes, a solution of the compound prepared in Reference Example 7 (400 mg) in THF (3 ml) was added, and the mixture was stirred at room temperature for 3 hours. After concentrating the reaction mixture, hexane: ethyl acetate: = 10: 1 was added to the residue, the mixture was filtered, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to give the title compound (590 _mg ) having the following physical data.

 TLC: Rf 0.38 (hexane: ethyl acetate = 4: 1). Reference Example 1 6

参考例 1 5で製造した化合物を用いて参考例 9→参考例 1 0—参考 例 1 1 と同様の操作をして次の物性値を有する標題化合物を得た。 TLC： Rf 0.58 (へキサン ：醉酸ェチル =3： 1) 。 参考例 1 7

Reference Example 9 → Reference Example 10—Using the compound produced in Reference Example 15, the same operation as Reference Example 11 was performed to obtain the title compound having the following physical data. TLC: Rf 0.58 (hexane: ethyl thiocyanate = 3: 1). Reference Example 1 7

参考例 1 1 で製造した化合物を用いて参考例 1 5→参考例 1 6 と同 様の操作をして次の物性値を有する標題化合物を得た。

Using the compound prepared in Reference Example 11, the same operation as in Reference Example 15 → Reference Example 16 was carried out to obtain the title compound having the following physical data.

TLC: Rf 0.60 (hexane: ethyl acetate = 3: 1).

 Reference example 17 (a) to 17 (c)

 In the same manner as in Reference Example 17 except that the compound prepared in Reference Example 11 was replaced with the compound prepared in Reference Example 12, Reference Example 13 or Reference Example 14, the following compound was obtained. Was.

 Reference example 17 (a)

TLC: Rf 0.59 (Hexane: ethyl acetate = 3: 1) Reference Example 17 (b)

TLC: Rf 0.51 (Hexane: ethyl acetate = 3 1)

 Reference example 1 7 (c)

TLC: Rf 0.59 (Hexane: ethyl acetate = 3: 1) Reference Example 18

Sodium hydride (3.9 g, containing 60%) was added to a solution of 2,5-dimethylphenol (10 g) in DMF (50 ml) at 0 ° C. The mixture was stirred at room temperature for 30 minutes. 3-Methyl-1-methylpropene (10.5 ml) was added to the reaction solution at 0 ° C, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was poured into ice water and extracted with hexane monoethyl acetate (2: 1). The organic layer was washed with water and saturated saline, dried over magnesium sulfate, and concentrated to give a target having the following physical properties. The title compound (14.5 g) was obtained.

 TLC: Rf 0.88 (Hexane: ethyl acetate = 4: 1) Reference Example 19

参考例 1 8で製造した化合物 （14.5g) の N, N—ジェチルァニリ ン (10ml) 溶液を 2 0 0 °Cで 6.5時間撹拌した。 反応混合物を室温ま で冷却した後、 酢酸ェチルで希釈した。 希釈液を 2 N塩酸、 水、 重曹 水、 水、 飽和食塩水ので順次洗净し、 硫酸マグネシウムで乾燥後濃縮 した。 残留物をカラムクロマ トグラフィー （酢酸ェチル ： へキサン = 1 : 15) で精製して下記の物性値を有する標題化合物 （12g) を得た。 TLC： Rf 0.46 (へキサン ：酢酸ェチル =9： 1) 。 参考例 2 0

A solution of the compound (14.5 g) produced in Reference Example 18 in N, N-getylaniline (10 ml) was stirred at 200 ° C. for 6.5 hours. After cooling the reaction mixture to room temperature, it was diluted with ethyl acetate. The diluted solution was washed successively with 2N hydrochloric acid, water, aqueous sodium bicarbonate, water and saturated saline, dried over magnesium sulfate and concentrated. The residue was purified by column chromatography (ethyl acetate: hexane = 1: 15) to give the title compound (12 g) having the following physical data. TLC: Rf 0.46 (hexane: ethyl acetate = 9: 1). Reference Example 20

参考例 1 9で製造した化合物 （12.3g) のエタノール溶液 （350ml) に、 サルコミ ン （2.28g) を加え、 酸素雰囲気下、 室温で 3 日間撹拌 した。 反応溶液を濃縮し、 セライ トでろ過した。 酢酸ェチルで洗浄し、 ろ液を濃縮した。 残留物をカラムクロマ トグラフィー （酢酸ェチル ： へキサン =1 ： 19) で精製して下記の物性値を有する標題化合物

Sarcomin (2.28 g) was added to an ethanol solution (350 ml) of the compound (12.3 g) produced in Reference Example 19, and the mixture was stirred at room temperature under an oxygen atmosphere for 3 days. The reaction solution was concentrated and filtered through celite. After washing with ethyl acetate, the filtrate was concentrated. The residue was subjected to column chromatography (ethyl acetate: Hexane = 1: The title compound having the following physical properties after purification by 19)

(6.94 g) was obtained.

TLC: Rf 0.58 (hexane: ethyl acetate = 4: 1). Reference Example 2 1

参考例 2 0で製造した化合物 （2g) の塩化メチレン （20ml) 溶液に、 水素化ホウ素ナト リウム （NaBHJ (477mg) を加えた。 混合物を 0 °C に冷却後、 メ タノール （6ml) をゆつく り加えた。 反応溶液に飽和塩 化アンモニゥム水溶液を加え、 撹拌した。 反応溶液を酢酸ェチルで抽 出し、 有機層を水、 飽和食塩水で洗浄し、 硫酸マグネシウムで乾燥後 濃縮して下記の物性値を有する標題化合物を得た。

Sodium borohydride (NaBHJ (477 mg) was added to a solution of the compound (2 g) prepared in Reference Example 20 in methylene chloride (20 ml). After cooling the mixture to 0 ° C, methanol (6 ml) was added. Aqueous saturated ammonium chloride solution was added to the reaction solution and stirred The reaction solution was extracted with ethyl acetate, the organic layer was washed with water and saturated saline, dried over magnesium sulfate and concentrated. The title compound having physical properties was obtained.

TLC: Rf 0.16 (hexane: ethyl acetate = 9: 1). Reference Example 2 2

To a solution of the compound produced in Reference Example 21 in methylene chloride (20 ml) was slowly added dropwise Polon trifluoride 'getyl ether complex (2.59 ml) at 0 ° C, followed by stirring for 20 minutes. Saturated aqueous sodium hydrogen carbonate was added to the reaction solution, and acetic acid was added. Extracted with ethyl. The organic layer was washed with water and saturated saline, dried over magnesium sulfate, and concentrated. The residue was purified by column chromatography (ethyl acetate: hexane = 1: 9) to give the title compound having the following physical data.

(l.72g) was obtained.

TLC: Rf 0.48 (hexane: ethyl acetate = 4: 1). Reference Example 2 3

 The title compound having the following physical properties was obtained by the same operation as in Reference Example 3 using the compound produced in Reference Example 22.

TLC: Rf 0.65 (hexane: ethyl acetate = 10: 1). Reference Example 24

参考例 2 1で製造した化合物 （9.98g) および 4—ジメチルアミノ ビ リ ジン （DMAP ； 0.76g) のピ リジン溶液 （50ml) に、 無水酢酸 (11.3ml) を水冷下で加え、 室温で 3 0分間撹拌した。 反応溶液を水 に注ぎ、 へキサン/酢酸ェチルで抽出した。 有機層を 1 N塩酸、 水お よび飽和食塩水で洗浄し、 乾燥後濃縮して下記の物性値を有する標題 化合物を得た。

Acetic anhydride (11.3 ml) was added to a solution of the compound prepared in Reference Example 1 (9.98 g) and 4-dimethylaminopyridine (DMAP; 0.76 g) in pyridine (50 ml) under water cooling. Stirred for 0 minutes. The reaction solution was poured into water and extracted with hexane / ethyl acetate. The organic layer is washed with 1 N hydrochloric acid, water and saturated saline, dried and concentrated to give the title having the following physical data. The compound was obtained.

 TLC: Rf 0.57 (Hexane: ethyl acetate = 1: 1) Reference Example 25

参考例 24で製造した化合物のエタノール溶液 （80ml) に 0 °Cで、 水酸化ナ ト リ ウ ム （2.08g) とハイ ドロスルフ ァ イ ト ナ ト リ ウ ム (2.0g) の水溶液 （20ml) を滴下した。 混合物を 0°Cで 3 0分間撹拌 し、 さらに室温で 3 0分間撹拌した。 反応溶液を氷水に注ぎ、 1 N塩 酸で中和し、 酢酸ェチルで抽出した。 有機層を水および飽和食塩水で 洗浄し、 乾燥後濃縮して下記の物性値を有する標題化合物を得た。 TLC： Rf 0.37 (へキサン ：酢酸ェチル =3： 1) 。 参考例 2 6

An aqueous solution (20 ml) of sodium hydroxide (2.08 g) and sodium hydrosulfite (2.0 g) was added to an ethanol solution (80 ml) of the compound prepared in Reference Example 24 at 0 ° C. Was added dropwise. The mixture was stirred at 0 ° C. for 30 minutes and further at room temperature for 30 minutes. The reaction solution was poured into ice water, neutralized with 1 N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried and concentrated to give the title compound having the following physical data. TLC: Rf 0.37 (hexane: ethyl acetate = 3: 1). Reference Example 2 6

参考例 2 5で製造した化合物の DMF溶液 （50ml) に、 水素化ナト リ ゥム （60%含有； 2.1_g) を 0° (：、 アルゴン雰囲気下で少しずつ加えた。 混合物を室温で 40分間撹拌した。 反応溶液にクロロメチルメチルェ一 テル （4.2ml) を 0°Cで加え、 1 0分間撹拌した。 反応溶液を氷令し た 1 N塩酸に注ぎ、 へキサン/酢酸ェチルで抽出した。 有機層を飽和 炭酸水素ナト リウム水溶液および飽和食塩水で洗浄し、 乾燥後濃縮し て下記の物性値を有する標題化合物を得た。

To a DMF solution (50 ml) of the compound prepared in Reference Example 25, sodium hydride (containing 60%; 2.1 _g ) was added little by little under an atmosphere of argon at 0 ° (40 ° _C. ). The mixture was stirred for 30 minutes. Ter (4.2 ml) was added at 0 ° C and stirred for 10 minutes. The reaction solution was poured into ice-cold 1 N hydrochloric acid and extracted with hexane / ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated saline, dried and concentrated to give the title compound having the following physical data.

TLC: Rf 0.56 (hexane: ethyl acetate = 3: 1). Reference Example 2 7

参考例 2 6で製造した化合物の塩化メチレン溶液 （100ml) に、 メ タクロロ過安息香酸 （mCPBA ; 55%， 19.4g) を 0。Cで加え、 2時間 撹拌し、 さらに室温で 3時間撹拌した。 反応懸濁溶液を飽和炭酸水素 ナトリウム水溶液に注ぎ、 クロ口ホルムで抽出した。 有機層をチォ硫 酸ナトリゥム水溶液に注いだ。 有機層を飽和炭酸水素ナトリゥム水溶 液および飽和食塩水で洗浄し、 乾燥後濃縮して下記の物性値を有する 標題化合物を得た。

In a methylene chloride solution (100 ml) of the compound prepared in Reference Example 26, metachloroperbenzoic acid (mCPBA; 55%, 19.4 g) was added. C, and the mixture was stirred for 2 hours, and further stirred at room temperature for 3 hours. The reaction suspension was poured into a saturated aqueous solution of sodium hydrogen carbonate, and extracted with a black hole form. The organic layer was poured into an aqueous solution of sodium thiosulfate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated saline, dried and concentrated to give the title compound having the following physical data.

TLC: Rf 0.32 (hexane: ethyl acetate = 3: 1). Reference Example 2 8

 0H

. To " ₃ To a methanol solution (60 ml) of the compound produced in Reference Example 27, a 5 N aqueous sodium hydroxide solution (15 ml) was added dropwise at 0 ° C. The mixture was stirred at room temperature for 1 hour. The reaction solution was neutralized with 2N hydrochloric acid in an ice bath, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, dried and concentrated. The residue was purified by column chromatography (ethyl acetate: hexane = 1: 3) to give the title compound (lO.lg) having the following physical data.

 TLC: Rf 0.28 (hexane: ethyl acetate = 3: 1). Reference Example 2 9

 To a pyridine solution (30 ml) of the compound (9.0 g) produced in Reference Example 28, pivaloyl chloride (5.3 ml) and DMAP (l.Og) were added at room temperature, and the mixture was stirred for 20 minutes. The reaction solution was poured into ice-cooled 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with 1 N hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, dried and concentrated to give the title compound having the following physical data.

TLC: Rf 0.45 (hexane: ethyl acetate = 4: 1). Reference example 30

 To a methanol solution (10 ml) of the compound (12.5 g) produced in Reference Example 29 was added a 4 N solution of hydrochloric acid-dioxane (15 ml) at room temperature, and the mixture was allowed to stand for 10 minutes. The mixed solution was concentrated, and the residue was diluted with ethyl acetate. The diluted solution was washed with brine, dried and concentrated to give the title compound having the following physical data.

 TLC: Rf 0.28 (hexane: ethyl acetate = 4: 1). Reference example 3 1

Sodium hydride (containing 60%; 1.04 g) was added to a THF solution (30 ml) of ethylphosphonoacetic acid ethyl ester (5.83 g) under a 0: argon atmosphere, followed by stirring for 30 minutes. Reference Example 28 A THF solution of 2,3,7-trimethyl-14-methoxymethyloxy-12-formylmethylbenzofuran obtained by operating the compound (5.8 g) produced in Reference Example 8 in the same manner as Reference Example 11 ( (15 ml) was added dropwise to the above reaction solution, and the mixture was stirred for 20 minutes. The reaction solution was poured into 1 N hydrochloric acid and extracted with hexane and ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated saline, dried and concentrated. The residue was purified by column chromatography (ethyl acetate: hexane = 1: 9). Thus, the title compound having the following physical properties was obtained.

 TLC: Rf 0.48 (Hexane: ethyl acetate = 3: 1) Reference Example 3 2

 10% palladium carbon (550 mg) was added to an ethanol solution (50 ml) of the compound (5.5 g) obtained in the same manner as in Reference Example 30 using the compound (6.0 g) produced in Reference Example 31. The mixture was added under an argon atmosphere, and replaced with hydrogen by an aspirator. The mixture was stirred overnight at room temperature and filtered through celite. The filtrate was concentrated to give the title compound having the following physical data.

TLC: Rf 0.33 (hexane: ethyl acetate = 3: 1). Reference example 3 3 (a) to 3 3 (c)

 Refer to Reference Example 3 → Reference Example 7 → Reference Example 28 using the compound prepared in Reference Example 30 or the compound prepared in Reference Example 32, or use the compound prepared in Reference Example 32. The compounds having the following physical properties were obtained in the same manner as in Reference Examples 3 to 7 using the obtained compounds.

 Reference Example 3 3 (a)

TLC: Rf 0.29 (Hexane: ethyl acetate = 1: 1) Reference example 3 3 (b)

 TLC Rf 0.46 (hexane ethyl acetate = 1 1)

 Reference example 3 3 (c)

 TLC Rf 0.26 (hexane ethyl acetate = 1 1) Reference example 3 4

 Reference Example 33 N-Hydroxysuccinic acid imide (0.58 g) was added to a methylene chloride solution of the compound (1.08 g) prepared in 33 (b) and dicyclocarbodiimide (1.03 g) at 0 ° C. The mixture was stirred for 1 hour. Dimethylamine (50% aqueous solution; 0.63 g) was added to the reaction solution, and the mixture was stirred at room temperature overnight. The precipitate was filtered and the filtrate was concentrated. The residue was purified by column chromatography (chloroform: methanol = 160) to give the title compound having the following physical data.

TLC Rf 0.64 (Black holm: methanol = 9 1) ₀ Reference Example 3 5

 To a solution of the compound prepared in Reference Example 7 (1.13 g) in anhydrous THF was added dropwise a THF solution of methyllithium (5.7 ml) at 178 ° C under an argon atmosphere. The mixed solution was stirred at 0 ° C for 15 minutes. Water was added dropwise to the reaction solution at 0 ° C, and THF was distilled off. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over magnesium sulfate, and concentrated to give the title compound having the following physical data.

TLC: Rf 0.18 (hexane: ethyl acetate = 5: 1). Reference Example 3 6

Dimethyl sulfoxide (1.03 ml) was added to a solution of oxalyl chloride (632 / ジ) in methylene chloride (10 ml) under an argon atmosphere. C, and the mixture was stirred for 30 minutes. A methylene chloride solution (10 ml) of the compound (1.067 g) produced in Reference Example 35 was added dropwise to the above solution, and the mixture was stirred at 178 ° C for 1 hour. Triethylamine (4.05 ml) was added dropwise to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous solution of ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over magnesium sulfate, and concentrated. The residue was subjected to column chromatography (ethyl acetate: Purification by hexane = 1: 10) gave the title compound having the following physical data.

 TLC: Rf 0.64 (hexane: ethyl acetate = 10: 1). Reference example 3 7 (a) to 3 7 (c)

 Using the corresponding compounds, the same operations as in Reference Examples 29 to 30 were carried out to obtain compounds having the following physical properties.

 Reference example 3 7 (a)

TLC： Rf 0.2 (へキサン ：酢酸ェチル =10： 1)

TLC: Rf 0.2 (Hexane: ethyl acetate = 10: 1)

 Reference example 3 7 (b)

TLC: Rf 0.35 (Hexane: ethyl acetate = 2: 1)

Reference Example 3 7 (c)

 TLC: Rf 0.57 (hexane: ethyl acetate = 5: 1) Reference Example 38

 To a suspension of 1,4-dimethoxybenzene (6.2 g) and succinic anhydride (5.0 g) in benzene at the mouth (80 ml) was added aluminum chloride (13.3 g) little by little at 0 ° C, and the ice bath was added. Removed and stirred for 30 minutes. The reaction mixture was poured into 2 N hydrochloric acid cooled with ice and shaken. The organic layer was extracted with a 2N aqueous solution of sodium hydroxide. The aqueous layer was washed with chloroform and acidified with 2N hydrochloric acid. The resulting precipitate was extracted with ethyl acetate. The organic layer is washed with water, dried over magnesium sulfate, and concentrated to give the title compound having the following physical data.

(9.9 g) was obtained.

TLC: Rf 0.39 (cloth form: methanol = 9: 1). Reference Example 3 9

 To a solution of the compound produced in Reference Example 38 in triethylene glycol (110 ml) was added an aqueous sodium hydroxide solution (10 ml) and 80% hydrazine monohydrate (6 ml), and the mixture was stirred at 190 ° C. . The mixture was stirred for 9 hours while adding an appropriate amount of water every 1 to 2 hours. The reaction solution was returned to room temperature, neutralized with 12 N hydrochloric acid, and the resulting precipitate was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, and concentrated to give the title compound having the following physical data.

 TLC: Rf 0.46 (cloth form: methanol = 9: 1). Reference example 4 0

 Reference Example 39 The compound produced in 9 and polyphosphoric acid (PPA; 100 g) were stirred at 90 ° C for 4 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, and concentrated. The residue was purified by column chromatography (ethyl acetate: hexane = 1: 3) to give the title compound (3.5 g) having the following physical data.

TLC: Rf 0.41 (hexane: ethyl acetate = 3: 1). Reference example 4 1

The compound (3.1 g) produced in Reference Example 40 and pyridine hydrochloride (15 _g ) were stirred at 200 ° C. for 30 minutes. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, and concentrated to give the title compound having the following physical data.

TLC: Rf 0.21 (hexane: ethyl acetate = 3: 1). Reference example 4 2

参考例 4 1 で製造した化合物を用いて、 参考例 1 8→参考例 1 9 参考例 2 2 と同様に操作をして下記の物性値を有する化合物を得た c TLC： Rf 0. 54 (へキサン ：酢酸ェチル = 2： 1 ) 。 実施例

Using the compound prepared in Reference Example 41, Reference Example 18 → Reference Example 19 9 A compound having the following physical properties was obtained in the same manner as in Reference Example 22. c TLC: Rf 0.54 ( Hexane: ethyl acetate = 2: 1). Example

To a solution of the compound prepared in Reference Example 3 (30.9 g) in ethanol (280 ml) and pyridine (107 ml) was added aminoguanidine · hydrochloride (16.0 g). The mixture was stirred at 100 ° C for 13 hours. The reaction mixture was concentrated, and the residue was washed with chloroform. The obtained crystals are subjected to silica gel column chromatography.

(Cloth form: methanol = 9: 1 → 4: 1). A 4N hydrochloric acid / dioxane solution was added to the ethanol solution of the obtained compound at 0 ° C. The reaction mixture was concentrated, and the obtained crystals were washed with dimethyl ether and dried to give the compound of the present invention (35.6 _g ) having the following physical data.

TLC: Rf 0.33 (cloth form: methanol = 10: 1);

NMR (CD ₃ OD): δ 8.66 (lH, s), 2.70 (2H, t, J = 7 Hz), 2.25 (3H, s), 2.13

(3H, s), 1.82 (2H, t, J = 7Hz), 1.29 (6H, s).

 Example 1 (a) to (q)

 Reference example 4, reference example 5, reference example 6, reference example 16, reference example 17, reference example 17 (a), reference example 17 (b), reference example instead of the compound produced in reference example 3. 17 (c), Reference Example 23, Reference Example 33 (a), Reference Example 33 (b), Reference Example 33 (c), Reference Example 34, Reference Example 36, Reference Example 37 ( a), Reference Example 37 (b), Reference Example 37 (c) and Reference Example 42 were carried out in the same manner as in Example 1 to obtain the following compounds.

 Example 1 (a)

HCI

TLC: Rf 0.40 (cloth form: methanol: acetic acid = 20: 2: 1); NMR (CD ₃ OD): δ 8.46 (lH, s), 3.65 (3H, s), 2.69 (2H, t, J = 7Hz), 2.33 (3H, s), 2.16 (3H, s), 1.84 (2H, t, J = 7Hz), 1.31 (6H, s).

Example 1 (b)

 TLC: Rf 0.28 (cloth form: methanol = 10: 1);

NMR (d ₆ -DMSO): δ 12.70-11.13 (lH, br), 9.55 (lH, s), 8.64 (lH, s), 7.74 (4H, br), 2.79 (2H, t, J = 7Hz), 2.12 (3H, s), 2.08 (3H, s), 1.77 (2H, t,

 Example 1 (c)

 TLC: Rf 0.25 (ethyl acetate: acetic acid: water = 20: 2: 1);

NMR (d ₆ -DMSO): δ 11.90-11.75 (lH, br), 8.44 (lH, s), 7.77 (lH, s), 7.70-7.20 (4H, br), 2.57 (2H, t, J = 7Hz ), 2.35 (3H, s), 2.11 (3H, s), 1.77 (2H, t, J = 7Hz), 1.25 (6H, s).

 Example 1 (d)

HCI

TLC: Rf 0.31 (cloth form: methanol: acetic acid = 15: 2: 1); to

 0 2

Ten

TLC: Rf 0.41 (cloth form: methanol: acetic acid = 15: 2: 1); NMR (CD ₃ OD): δ 8.07 (lH, s), 7.68 (2H, d, J = 8 Hz), 7.37 (2H) , d, J = 8Hz), 2.76-2.56 (6H, m), 2.12 (3H, s), 2.04 (3H, s), 1.82-1.62 (4H, m), 1.62-1.40 (2H, m), 1.25 (6H, s).

 Example 1 (h)

 • HCI

 TLC: Rf 0.55 (ethyl acetate: acetic acid: water = 15: 2: 1);

NMR (CD ₃ OD): δ 8.06 (lH, s), 7.68 (2H, d, J = 8 Hz), 7.25 (2H, d, J = 8 Hz), 2.76-2.52 (6H, m), 2.12 (3H, s), 2.08 (3H, s), 1.82-1.58 (4H, m), 1.56-1.33 (2H, m), 1.20 (6H, s).

 Example 1 (i)

TLC: Rf 0.32 (cloth form: methanol: acetic acid = 15: 2: 1); NMR (d ₆ -DMSO): δ 12.08 (lH, br), 9.54 (lH, s), 8.59 (lH, s) , 7.72 (4H, br), 2.97 (2H, s), 2.15 (3H, s), 2.07 (3H, s), 1.40 (6H, s). Example 1 (j)

TLC: Rf 0.32 (cloth form: methanol: acetic acid = 15: 2: 1); NMR (d ₆ -DMSO): δ 11.86 (lH, s), 9.48 (lH, s), 8.60 (lH, s) , 7.9-7.6 (4H, br), 5.1-5.0 (lH, br), 3.5-3.3 (2H, br), 3.19 (lH, d, J = 16Hz), 2.80 (lH, d, J = 16Hz), 2.17, 2.08 and 1.31 (each are 3H, s).

 Example 1 (k)

 TLC: Rf 0.16 (cloth form: methanol: acetic acid = 15: 2: 1);

NMR (d ₆ -DMSO): $ 12.05 (lH, s), 9.48 (lH, s), 8.58 (lH, s), 7.9-7.6

(4H, br), 3.08 (lH, d, J = 16Hz), 2.90 (lH, d, J = 16Hz), 2.27 (2H, t,

J = 7Hz), 2.14 (3H, s), 2.06 (3H, s), 1.90 (2H, t, J = 7Hz), 1.34 (3H, s). Example 1 (1)

HCI

TLC: Rf 0.32 (cloth form: methanol: acetic acid = 15: 2: 1); NMR (-DMSO): δ 12.04 (lH, s), 9.47 (lH, s), 8.67 (lH, s), 7.9 -7.6 (4H, br), 4.03 (2H, q, J = 7Hz), 3.08 (lH, d, J = 16Hz), 2.91 (lH, d, J = 16Hz), 2.37 (2H, t, J = 7Hz), 2.16 (3H, s), 2.08 (3H, s), 1.85 (2H, t, J =

7Hz), 1.36 (3H, s), 1.14 (3H, t, J = 7Hz).

 Example 1 (m)

TLC: Rf 0.24 (cloth form: methanol: acetic acid = 15: 2: 1); NMR (d ₆ -DMSO): δ 12.18 (lH, s), 9.6-9.4 (lH, br), 8.59 (lH, s), 7.9-7.7 (4H, br), 3.1-2.8 (2H, m), 2.91 (3H, s), 2.88 (3H, s), 2.5-2.3 (2H, m), 2.12 (3H, s) , 2.07 (3H, s), 2.0-1.8 (2H, m), 1.35 (3H, s). Example 1 (n)

 TLC: Rf 0.33 (cloth form: methanol: acetic acid = 15: 2: 1) MS: APCI (Pos.) 305 (M ++ 1), 246.

Example 1 (0)

TLC: Rf 0.35 (Form: Cloth: Methanol: Acetic acid = 15: 2: 1) NMR (CD ₃ OD): 8 7.22-7.13 (3H, m), 7.13-7.1 l (2H, m), 3.90 (2H, d, J = 2.2Hz), 2.67 (2H, t, J = 6.8Hz) , 2.14 (3H, s), 1.85-1.70 (2H, m), 1.35 (3H, s), 1.27 (3H, s), 1.20 (3H, s).

 Example 1 (p)

 less polar

TLC: Rf 0.25 (cloth form: methanol: acetic acid = 15: 2: 1); NMR (d ₆ -DMSO): δ 15.20 (lH, s), 8.83 (lH, d, J = 3.4 Hz), 8.05 (4H, br), 7.97 (lH, t, J = 7.0Hz), 7.59 (lH, t, J = 5.8Hz), 7.01 (lH, d, J = 7.8Hz), 2.64 (2H, t, J = 7.2Hz), 2.07 (3H, s), 1.85 (3H, s), 1.80 (2H, t, J = 7.2Hz), 1.27 (6H, s).

 Example 1 (q)

 more polar

TLC: Rf 0.15 (cloth form: methanol: acetic acid = 15: 2: 1); NMR (d ₆ -DMSO): 8 10.38 (lH, brs), 8.85 (lH, brs), 8.39 (lH, brs) , 7.90 (lH, brs), 7.72 (lH, brs), 9.20-7.40 (4H, br), 2.68 (2H, m), 2.11 (3H, s), 1.82 (2H, m), 1.78 (3H, s ), 1.30 (6H, d, J = 8.8Hz) ₀ Example 1)

TLC: Rf 0.52 (cloth form: methanol: acetic acid = 15: 3: 1); NMR (CD ₃ OD): δ 2.68 (2H, t, J = 7.0 Hz), 2.53 (2H, m), 2.12 ( 3H, s), 1.90 (3H, s), 1.83 (2H, t, J = 7.2Hz), 1.62 (2H, tq, J = 7.4,7.4Hz), 1.32 (3H, s), 1.28 (3H, s ), 0.97 (3H, t, J = 7.4Hz).

 Example 1 (s)

TLC: Rf 0.36 (cloth form: methanol: acetic acid = 15: 2: 1); NMR (CD ₃ OD): δ 6.62 (lH, s), 2.98 (2H, s), 2.75 (2H, t, J = 7Hz), 2.65 (2H, t, J = 7Hz), 2.0-1.8 (2H, m), 1.42 (6H, s). Formulation Example 1

 The following components were mixed in a conventional manner and then tableted to obtain 100 tablets each containing 50 mg of the active ingredient.

 • 6-Hydroxy-1,2,2,5,8-tetramethyl-1,3,4-dihydro-1H-benzo [l, 2-b] pyran-17-earl 'guanylhydrazone' hydrochloride (Example 1) Compound)… 5.0g

'Calcium cellulose glycolate (disintegrant)… 0.2g '' Magnesium stearate (lubricant)… O.lg

'Microcrystalline cellulose… 4.7g Formulation Example 2

 After mixing the following components by the usual method, the solution is sterilized by the conventional method, filled into ampoules in 5 ml portions, freeze-dried by the conventional method, and contains 20 mg of the active ingredient in one ampoule. 100 ampoules were obtained.

 • 6-Hydroxy-1,2,2,5,8-tetramethyl-3,4-dihydro2H-benzo [l, 2-b] pin-1 7-earl 'guanylhydrazone' hydrochloride (Example 1 Compound) ... 2.0 g

 'Mannitol… 200mg

• Distilled water… 500ml

Claims

The scope of the claims ) General formula (I)

[Wherein R ¹ represents R ⁴ — A—  A represents a single bond, a Cl-6 alkylene group, or a phenyl C2-8 alkylene group, R ⁴

Represents R ⁵ represents a hydrogen atom or a C 1-4 alkyl group, R ⁶ represents a hydrogen atom, a Cl-4 alkyl group or a C2-5 acyl group, R ⁷ represents a hydrogen atom, a Cl-4 alkyl group, — Z—OR ⁸ group, — Y—COOR ⁹ group, or one Y—CONI ^ R ¹¹ group,  Z represents a C1-5 alkylene group,  Y represents a single bond or a C 1-4 alkylene group, R ⁸ represents a hydrogen atom or a C2-5 acyl group, R ⁹ represents a hydrogen atom or a C 1-4 alkyl group, R ^1Q and R ¹¹ each independently represent a hydrogen atom or a Cl-4 alkyl group;  m represents an integer of 1 to 9, n represents an integer of 0 to 2, R ² is a hydrogen atom, a Cl-4 alkyl group, a phenyl group, a phenyl Cl-47 alkyl group, a 5- to 7-membered monocyclic hetero ring containing one or two nitrogen atoms, or a nitrogen atom 1 or 2 Represents a C4-4 alkyl group substituted with a 5- to 7-membered monocyclic hetero ring, Or R ¹ and R ² together with the carbon atom to which they are attached, represent a C5-fucycloalkyl group to which R ⁴ is fused; R ³ represents a hydrogen atom, a Cl-4 alkyl group or a C2-5 acyl group. Provided, however, that the A represents a phenyl C2~8 alkylene group, phenyl group shall be bonded to the carbon atom bonded to the R ^2. ] A guanylhydrazone derivative represented by the formula: or a non-toxic salt thereof or an acid addition salt thereof.