JPH01301657A - Novel andrimide derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (R<1> is 1-4C lower alkyl or phenyl; A is formula II or formula III; R<2> is methyl; or R<1> is CH3CH=CHCH =CHCH=CH-; A is formula II; R<2> is H). EXAMPLE:(3R, 4S)-3-[(N-benzoyl-L-phenylalanyl)-L-valyl]-4-methylpyrrolid-ine-2,5- dione. USE:A fungicide especially showing strong and special antimicrobial activity to xanthomonas campestris pv. oryzae, having low toxicity and being stable. PREPARATION:A beta-ketamide expressed by formula IV (X is blocking group of amino group) is reacted with halogenized alkyl carboxylic ester to obtain ester-amide and the ester-amide is subjected to condensed ring reaction to obtain imide derivative expressed by formula V (R<3> is H or methyl). Next, the amino group is subjected to deblocking by an acid and simultaneously made to a salt added by acid, cooled to 0 deg.C, phenylalanine is added and subjected to conventional condensation reaction to afford a compound expressed by formula I.

Description

[Detailed description of the invention] [Industrial application field]

The present invention has antibacterial activity against various bacteria, particularly against rice bacterial leaf blight (Xanthomonas campe-
The present invention relates to a novel anthrimide derivative that is expected to have a wide range of applications in the field of agricultural chemicals, especially fungicides, because it has strong and specific antibacterial activity against S. stris pv, oryzae). [Prior Art 1 (Background) Attempts to use antibiotics to control diseases in the agricultural field have been studied early in the United States. However, these studies are aimed at controlling a limited number of bacterial diseases and are not general-purpose. On the other hand, in Japan, much research has been conducted on controlling diseases mainly in rice, which is the main grain. These past studies have centered on research on rice blast, rice sheath blight (all caused by filamentous fungi), and rice leaf blight, which are the three major diseases of rice cultivation.For example, phenylacetic acid It has been found that mercury and arsenic agents are effective against rice sheath blight. However, since these drugs contain toxic mercury and arsenic, they are extremely problematic in terms of environmental pollution and public health, and are therefore not currently used. For this reason, there has been a long-awaited development of a drug that is highly specific for diseases such as rice leaf blight and has low toxicity. (Problems with the prior art) By the way, there are some attempts to use antibiotics to control rice leaf blight, one of the three major rice diseases (==t-→). Streptomycin is effective against rice bacterial leaf blight in vivo at 0.5 to 20 μg/ml, but if the concentration used is slightly higher, it may cause phytotoxicity to plants, and streptomycin is a pharmaceutical antibiotic. Therefore, it is no longer available for use due to concerns such as bioaccumulation or the appearance of resistant bacteria due to heavy use, and furthermore, that it may be constantly ingested by humans through the food chain. It was expected to be the first practical pesticide for rice leaf blight because it was effective against the above bacteria at 5 to 10 μg/ml, but its acute toxicity to mice was LD 50 C11.
mg/kg (intravenous injection) It is not used at present due to severe damage. Furthermore, although tetrazycline shows very strong activity against rice bacterial leaf blight, it is not used today for the same reason as leptomycin. In addition, Te1heracycline is not highly toxic, and in actual applications,
There is also a practical problem that the compound is not stable. Finally, as another type of antibiotic, antrimid expressed by the following formula (TI) obtained from a certain type of microbial culture has been announced (EPC Publication No. EP-), which has excellent antibacterial properties and residual It is highly safe as it is non-toxic, but there are problems with stability.

[Problem to be solved by the invention] Therefore, the problem to be solved by the present invention is to solve the above-mentioned problems with known drugs, and to provide a stable, low-toxicity drug that has strong specificity for diseases such as rice leaf blight. [Means to solve the problem]

(Summary) In order to solve the above problems, the present invention has a general formula CI) [wherein R1 is a lower alkyl group having 1 to 4 carbon atoms or a phenyl group, 2--CH- R2 represents a methyl group, or, in the formula, R1 represents a CH3CH=CHCH=CHCH=CH- group, A represents the following formula, represents a hydrogen atom]. (Synthesis) The compound (I) of the present invention can be synthesized, for example, as follows. That is, by protecting tetrahydrofuran with an amine group and An imitazole ester solution is obtained by dissolving monovaline, adding 1,1'-carbonyldiimitasole and stirring in a stream of inert gas such as argon.Next, diisopropylamine is heated at -30°C. Lithium Te1
~ After preparing the lahitorofuran solution, the temperature was lowered to -78°C.
While maintaining the temperature, N,O-bis(l-limethylsilyl)acetamide and then the previously prepared imidazole ester solution are added in this order under stirring. After the reaction is completed, extraction is performed with an organic solvent, and the extract is dried, concentrated, and recrystallized with an appropriate solvent to obtain the following formula (ITJ
) (in the formula, X represents a protecting group for the amine group).
, a halogenated alkyl carboxylic acid ester, e.g.
- pencil propionate bromide or benzyl acetate bromide;
The reaction is carried out in a suitable solvent that does not participate in the reaction, such as N,N'-dimethylpolamide (hereinafter abbreviated as (DMF)). When the reaction product is purified by subjecting it to silica gel column chroma 1 to graphite, an ester-amide represented by the following formula (■) is obtained. (Space below) (In the formula, X is as defined above, R3 represents a hydrogen atom or a methyl group, and R4 represents a Hensyl group.) The obtained ester-amide (IV) is a diastereomer, but
Isomers were determined by silica gel column chromatography.
It can be easily separated into each isomer. Next, this ester-amide (IV) was dissolved in methylene chloride, sodium hydroxide and tetrabutylammonium bisulfate were added to cause a ring condensation reaction, and the reaction solution was acidified and extracted with methylene chloride. The obtained garbage 1-derivatives represented by the formula (V) (in the formula, both X and R3 are as defined above) are purified by the method using an acid such as trifluoroacetic acid At the same time as the deprotection of the amine group, it was made into an acid addition salt, and then cooled to O'C to form the separately synthesized N-(octane-2
,4,6-)lienoyl)-β-phenylalanine or N-benzoyl-L-phenylalanine or N-acetyl-β-phenylalanine or N-benzoyl-β
The compound (I) of the present invention can be obtained by adding -phenylalanine and carrying out a conventional condensation reaction using, for example, diphenylphosphoric acid azide, triedylamine, or the like.

【Example) Hereinafter, details of the compounds of the present invention will be specifically explained using Reference Examples, Examples, and Test Examples, but it goes without saying that the spirit of the present invention is not limited thereto. (Left below) [Reaction formula]

[Synthesis method] L-alanine 5. A 2.5N sulfuric acid solution (133 mΩ) of Og (56.1 mmol) and potassium bromide 23.8 g (200.0 mmol) was kept at a temperature of -5°C to -10°C,
Lithium nitrite 6 g (84.0 mmol) under stirring
was added over about 1 hour, and the mixture was further stirred for 1.5 hours. The reaction solution was extracted three times with ethyl acetate (150 mN), and the combined extracts were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and further distilled to obtain 4.35 g of (2S)-α-bromopropionic acid. 4.35 g (28.4 mmol) of the above bromopropionic acid
, Hensyl alcohol 3.1 m (29,9 mmol) and P-)luenesulfonic acid hydrate 0.27 g (1,4
mmol) in benzene (50d), and using a Dean-Stark dehydrator to remove the produced water, 1
The mixture was heated under reflux for 7 hours. After the reaction was completed, the reaction solution was diluted with ethyl acetate, and the organic solvent layer was washed once each with an aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and further concentrated under reduced pressure to obtain 6.60 g of the title compound. (yield 48.7%). [Reaction formula] (N(-Boc-valine) (
R-2) [Synthesis method] Under an argon gas flow, N-t-butoxycarbonyl-shi-valine 3. 1. ]”-Add 2.46 g (], 55.2 mmol of carbonyldiimidazole,
Stir at room temperature for 3 hours, then convert (N-t-butoxycarbonyl-
A valyl) imitazole solution was prepared. Next, 27.67 nQ (44.2 mmol) of a 16 mol n-butyllidium solution and 4.9 g (48.4 mmol) of diisopropylamine were reacted in a hydrofuran solvent at -30°C, and diisopropylamine lithium was prepared. The reaction solution was cooled to -78°C, and while maintaining the same temperature, N,O-bis(trimethylsilyl)acetamide 9-
3 g (45.6 mmol) was gradually added dropwise over about 20 minutes to prepare an N,O-bis(trimethylsilyl)acetamide anion solution. While maintaining this anion solution at -78°C, a previously prepared (N-t-butoxycarbonyl-monovalyl) imitazole solution was added dropwise with stirring.
After further stirring for 5 hours, methanol was added to terminate the reaction. Ethyl acetate and a saturated potassium dihydrogen phosphate aqueous solution were added to this reaction solution for partition, and the organic solvent layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and mixed with ethyl acetate and hexane. The title compound 1.3 was crystallized from the liquid.
0 g (yield 36%) was obtained. (Left space below) [Reaction formula] (R-3) [Synthesis method] Octane-2,4,6-trienoic acid Qjg (2.2 mmol) and triphenylphosphine 0.57 g (2 , 2 mmol) in methylene chloride (lod
) dissolved in Add 0.4 of 2,2'-dipyridyl disulfite to this solution.
8 g (2.2 mmol) of a methylene chloride solution (10 yen) was added dropwise over about 1 hour while stirring, and after the dropwise addition, an additional 1
Stir for hours. After the reaction, the reaction mixture was concentrated under reduced pressure and quickly purified by silica gel column chromatography to obtain 0,258 g of 5-2-pyridyl octane-2,4,6-)lienthioate. Next, under an argon gas flow, β-phenylalanine 0.
], 884. g1.12 mmol) in DMF suspension (6-
), add 0.0% of N-trimethylsilylimidazole with stirring.
31. g (2.2 mmol) was added dropwise, and the mixture was further stirred for 1.5 hours. Add the above 5-2-pyridyl octane-2,4 to this reaction solution.
A methylene chloride solution (7 ml) containing 0.258 g (1.12 mmol) of ,6-dorienthioate was added dropwise to the mixture while stirring over about 40 minutes, and the mixture was further stirred for 18 hours. After stirring, the reaction solution was diluted with ethyl acetate, washed three times with dilute hydrochloric acid (pH 3), dried over magnesium sulfate, and concentrated to obtain the title compound as a crude product. The obtained crude product was dissolved in methanol, methylated by adding an excess of diazomethane ether solution, concentrated under reduced pressure, purified by silica gel column chromatography, and purified with N-(octane-2,4 ,6-1~lienoyl)-β-phenylalanine medyl ester 0.119g
I got it. 0.119 g (0,389 mmol) of the above methyl ester was dissolved in 1.5 mΩ methanol, cooled to 0°C, and then 5 ml of 0.5 M lithium hydroxide solution was added.
Stir for hours. The reaction solution was partitioned between ethyl acetate and dilute hydrochloric acid (pH = 3.0>), and the aqueous layer was extracted twice with ethyl acetate. The organic solvent layer and the extract were combined, dried over magnesium sulfate, and concentrated. 108 mg (yield 18%) of the title compound was obtained. [Reaction formula] [Synthesis method] Under an argon gas flow, β-phenylalanine 0.1.8
While stirring 4 g (], 11.2 mmol of DMF suspension (67), N-)limethylsilylimidasole (0.31d 2.21 mmol) was added dropwise, and after the addition was completed, further The mixture was stirred for 1.5 hours. To this reaction solution, methylene chloride solution (7 mQ) containing excess acetic anhydride (0.5 m9) was added.
was added while stirring over about 40 minutes, and after the addition was completed, the mixture was further stirred for 18 hours. After diluting the reaction solution with ethyl acetate, diluted with dilute hydrochloric acid (pH=3
) for three times, dried over magnesium sulfate, and concentrated to obtain 0.198 g (yield: 86%) of the title compound. [Reaction formula] [Synthesis method] Under argon gas flow, β-phenylalanine 0.184
While stirring a 112 mmol DMF suspension (6 mQ), 0.
3], g (2.21 mmol) was added dropwise, and after the dropwise addition was completed, the mixture was further stirred for 1.5 hours. To this reaction solution, a methylene chloride solution (7 ml) of 0.169 g (1.2 mmol) of benzoyl chloride was added to about 40 g. It was added dropwise over several minutes with stirring, and after the addition was completed, it was further stirred for 18 hours. Ethyl acetate was added to the reaction solution to dilute it, and diluted hydrochloric acid (pH = 3) was added to the reaction solution.
), dried over magnesium sulfate, concentrated, and further purified by silica gel column chromatography to obtain 0.23 g (yield: 83%) of the title compound. (Left below) [Reaction formula] (R-2) (R-1>(R-7a)
(R-7b) (R-6) [Synthesis method] Under argon gas flow, 35% potassium hydride oil suspension 8
4 mg (0,73111 mol) was suspended in DMF (2 mQ>), and the compound obtained in Reference Example 2 (R-2> 188 mg
(0.73 mmol) dissolved in the same DMP (2 m2) and stirred for 2 hours at room temperature. This reaction solution was then added with the compound (R-1) obtained in Reference Example 1.
0.357 mg (1,47 mmol) in DMF (2 mQ)
After the addition was completed, the mixture was stirred at room temperature for 24 hours. Dilute this reaction solution with ethyl acetate (approximately 100 mQ) and wash twice with brine and once with saturated brine. Next, it was dried over magnesium sulfate, concentrated, and purified by silica gel column chromatography.
100 mg of 2,6-dimethyl-heptane-4-onic acid benzyl ester were obtained as a mixture of stereoisomers. This mixture was separated by silica gel column chromatography to obtain compound R-7a and compound (R-7b). A solution of 51.3 mg (0.12 mmol) of compound (R-7a) in methylene chloride (4 mQ) was cooled to -20°C, and a solution of 20% sulfur hydroxide to thulium solution 4- and 53% tetrabutylammonium bisulfate was added. 9 mg < 0, 16 mmol) was added thereto, and the mixture was stirred at -20°C for 5 minutes while remaining in two layers. After stirring, the reaction solution was made acidic by adding 5 mQ of 5N hydrochloric acid, and then extracted twice with methylene chloride. The obtained extract was dried over magnesium sulfate, concentrated under reduced pressure, subjected to chroma 1 silica gel column, and eluted with ethyl acetate to obtain 36.5 mg of the title compound (yield 3).
3%). [Structural formula] [Synthesis method] Monobromoacetic acid benzyl ester 3 synthesized by a conventional method in place of compound R-1 according to the method of Reference Example 6
By using 40 mg (1,48 mmol), N'
95 mg of the title compound (
A yield of 42%) was obtained. [Structural formula] [Synthesis method] 31.2 mg (0,1
After dissolving 0 mmol) in methylene chloride (2 mQ), one portion of 1-lifluoroacetic acid was added, and the mixture was stirred at room temperature for 30 minutes to remove the Nt-butoxycarbonyl group. After concentrating the reaction solution under reduced pressure, the remaining solution was combined with separately synthesized N-benzoyl-phenylalanine (e.g. Styger).
According to the method of (Steiger) et al.; Journa 1
of Organic Chemistry vol.
9396 (1944)) 32.3 mg (0.12 mmol) was dissolved in DMF (10 mR), and after cooling to 0°C,
First 40 mg (0.14 mmol) of diphenyl phosphate azide, then 0.04 mQ (0.2 mmol) of l-ethylamine
9 mmol) was added thereto, and the mixture was stirred at O'C for 2 hours and then at room temperature for 20 hours. After the stirring was completed, the reaction solution was partitioned between ethyl acetate and 0.05M phosphate buffer (pH=5), and the aqueous layer was further extracted with ethyl acetate. The ethyl acetate layers were combined, dried over magnesium sulfate, concentrated under reduced pressure, and then purified by preparative silica gel thin layer chromatography to obtain 47 mg (yield: 85%) of the title compound. The physical property data of Compound 1 are shown below.・JR spectrum (νcm-”) 3298.1712, 1639.1536, 1195.
733-NMR spectrum δppm) (in CD30D) 0.83 3Hd J-6,9Hz0
．． 99 3l-1d J26
．． 9Hz1,. 23 3Hd, J-7
, 4Hz2.49 1Hm 4-. 91. 2Hm 7.15-7.75 108 m ・UV absorption spectrum (in methanol) (λ□ax n
m) 297 (ε-2,200> ・Mass spectrum ('8) 462 (14-H) [Structural formula] [Synthesis method] According to Example 1, compound (R-6) and N-benzoyl monophenylalanine Instead of , the compound etr (
By using 29.8 mg (0.10 mmol) of R-8> and 16 mg (0.057 mmol) of compound (R-3), the title compound 7.0+B (yield 26%) was obtained. The physical property data of Compound 2 are shown below.・JR spectrum (νcm') 3284.2927.1,715, 1652,'1
609, 1531, 12], 4, 1,003. 0O NMR spectrum (in CD30D) (δppm) 0.
80 3Hd J=6.88. . 0.88 3Hd J=6.8821.80
3Hd J=7.0H. 7.1-7.4 58 m UV absorption spectrum (in methanol) (λ□8 nm)
297 (ε-30,000> Mass spectrum ('/2) 466 (MH) 504 (M+K) 488
(M+Na) [Structural formula] ○ [Synthesis method] According to Example 1, 30.9 mg of compound (R-4) (0,
By adjusting the amount of diphenyl phosphate azide to be 50 mg (0.175 mmol) and the amount of triethylamine to be added to 0.05 m (0.36 mmol), 32.6 mg (yield 62%) of the title compound was obtained. ) was obtained. The physical property data of Compound 3 are shown below. -JR spectrum (v cm-') 3274.17], 2,1640, 1534, 1193
．． 734 (blank below) -NMR spectrum (in CD30D) (δppm>0.
80 3+(d J=6.8870.89
3Hd J=6.88□1,. 1.6
3N, dJ=7.4H22,
4018m 2.79 1. Hdd J=6.78. ．． 1
．． 4.4H. 2.86 1Hdd J=7.8H7,]
, 4.4H23,131,Hq J=7.41
-17°4,. 78 1Hd J・62H
75,421,t(br,dd J=6.711
．． ．． 7.8H2Uv absorption spectrum (in methanol) (
λmax nm) 297 (ε-2,1,00) Mass spectrum (/,) 402 (M+H) 424 (former Na) 440 (former K) (Hereafter, blank space) [:i formula] ○ [Synthesis method] Example According to 1, the compound (R-5> 38.6 mg (0,
15 mmol), the amount of diphenyl azide IJ to be added was 50 mg (0,175 n+ mol), and the amount of triethylamine to be added was 0.05 m (0,036 mmol) to obtain 28.9 mg (yield: 48 mmol) of the title compound. %) was obtained. The physical property data of Compound 4 are shown below. IR spectrum (νcm-') 3280.1712, 1642, 1535, 1195.
734, NMR spectrum (in CD30D) (δpp
m) 0.83 3Hd J=6.98
゜0.99 3Hd J=6.98゜1.20 3Hd
J=7.4H22,4518m 2.80 11(dd J=6.
78. ．． 14.5H. 2.85 1Hdd J=7.8
11. ．． 14. ．． 5H75,481Hdd J=
6.7H,,7,8+,+□7.1.0-7.75
1. OHmUV absorption spectrum (in methanol)
may nm) 297 (ε-2,200) Mass speckle (1″/2) 464 (M+H) 486 (HfNa) Test example 1 Antibacterial activity measurement Test bacteria ■ Xant, homonas oryzae SA
MO589 and ■ Xanthomonas oryz
The minimum inhibitory concentration for ae SAMO590 was determined. The measurement was carried out by adding a test bacterial solution at a concentration of OD (600 nm) -1.0 to an agar medium and culturing at 28°C for 3 days. As a result, the minimum inhibitory concentration of Compound 1 was 125 μg/mM against test bacteria ■ and 25 μg/mQ against ■, and the minimum inhibitory concentration of compound 2 was 25 μg/mM against test bacteria ■ and 50 μg/mQ against test bacteria ■.
g/7. Furthermore, all of the compounds of the present invention had good stability. Effects of the Invention As explained above, the present invention can be applied to various bacteria, especially rice leaf blight fungus (Xanthomonas campestrium).
is pv. By providing a novel antrimid derivative with strong and specific antibacterial activity against S. oryzae and low toxicity, it can contribute to agriculture and public health. , Procedural Amendment (P-632) 1. Indication of the case Patent Application No. 131043 of 1988 2. Name of the invention New Antrimide Derivative 3. Person making the amendment Relationship to the case Patent Applicant Address Kita-ku, Osaka City, Osaka Prefecture Dojimahama 2-1-40 Name
Name: Zantry Co., Ltd. (190) Representative: Keizo Kenzo 4 Agent [phase] 532 5 No date of amendment order 7, Subject of amendment (]) “Claims” column of the specification (2) “Claims” column of the specification Column 8 of ``Detailed Description of the Invention'' Contents of Amendment (1) Page 1 of the Specification - ``Claims'' shall be amended as shown in the attached sheet. (2) On page 5 of the specification, general formula (T) is revised as shown in the following formula. It was changed to "Hotan." Location: Page 6, lines 6-5 from the bottom and page 7, line 1-(4)
) Revise the formula (IV) on page 8 of the AT document as shown below. (6) On page 8 of the specification, formula (V) is revised as shown below. (7) Page 10 of the specification, lines 3-2 from the bottom - "P-toluenesulfonic acid" has been changed to "and-toluenesulfonic acid." (8) In the specification, "imidazole solution" has been changed to "imitasoli solution." Location: Page 12, line 1 and line 12. (9) Page 12 of the specification, line 2 - "16 moles" is replaced by "1.
6 molar concentration J. 00) Page 19 of the specification, end line: rR-7a” is replaced with “
Changed to Engineering R-7al. (11) Page 24 of the specification, lines 2 and 2 to 3: “Benzoyl L-phenylalanine” should be replaced with “HeZjner-”.
L: Tsuyu;”Tourakyu; Changed to /J. (12) Specification page 27: Formula (4) is revised as shown in the following formula. (13) Specification page 28, lines 12-13: rXant
homonas oryzaH is replaced with “XaJIL
It has been changed to ``JLQJIlai5-campestr;s pv Takumi Hirukan''. 9 List of attached documents (]) Attachment 1 copy = 4- [2. Claim 1 General formula (I) [In the formula, R1 represents a lower alkyl group having 1 to 4 carbon atoms or R2 represents a methyl group] or, in the formula, R1 represents CH, CH・CHCH=CHCH=CH- group, A represents the following formula, φ 1 and -CH-CH,2- R2 represents a hydrogen atom] Anthrimide derivative. ”−】−

Claims (1)

[Claims] 1 General formula (I) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (I) [In the formula, R^1 is a lower alkyl group having 1 to 4 carbon atoms or a phenyl group, and A is a lower alkyl group having 1 to 4 carbon atoms. Formula, ▲There are mathematical formulas, chemical formulas, tables, etc.▼ or ▲There are mathematical formulas, chemical formulas, tables, etc.▼, R^2 represents a methyl group, or, in the formula, R^1 is CH_3CH=CHCH=CHCH= CH
- group, A is the following formula, ▲ there are mathematical formulas, chemical formulas, tables, etc. ▼, and R^2 represents a hydrogen atom] A new andrimide derivative represented by the following formula.