JPH05117292A - New 16-membered ring macrolide derivative and its production - Google Patents

Abstract

PURPOSE:To obtain the subject new compound useful as antibacterial agent against Gram-positive bacteria and an intermediate for various kinds of valuable compounds. CONSTITUTION:A compound of formula I [R<1> is O or (OR<4>)2 (R<4> is 1-4C straight- chain alkyl or benzyl), etc.; R<2> is H, 4-O-propionylmycarose residue, etc.; R<3> is H or COR<5> (R<5> is 1-3C straight-chain alkyl)] or a salt thereof such as a compound of formula II showing the following properties. Appearance: colorless solid. Molecular formula: C30H40NO11. Melting point: 105-111 deg.C. Solubility: soluble in chloroform, acetone, etc., insoluble in neutral and alkali water. The compound of formula II is obtained by oxidizing leucomycin A7 of formula III by a method of reacting the compound with pyridinium chlorochromate preferably in an inert organic solvent at -10 to 50 deg.C and subjecting formed 9-dehydroleucomycin A7 to acidolysis by a method of treating 9-dehydroleucomycin A7 with an acid catalyst composed of p-toluenesulfonic acid in the presence of preferably ethylene glycol.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention is effective against Gram-positive bacteria.
The present invention relates to a 6-membered ring macrolide compound and a method for producing the same.

[0002]

2. Description of the Related Art With the progress of chemotherapeutic agents mainly composed of β-lactam antibiotics, many bacterial infections have become curable. However, heavy use of antibiotics has raised the problem of incurable diseases caused by Gram-positive resistant bacteria in the medical field, and changes in social life have led to the emergence of new infections such as mycoplasma infection and chlamydia infection. Therefore, antibiotics that are more effective against pathogenic bacteria including resistant bacteria, especially against Gram-positive bacteria, are expected.

The present inventors have found that 1 is effective against various Gram-positive bacteria.
Through repeated chemical and biochemical research on 6-membered ring macrolide compounds, we have found a biochemical reaction by a fungus species that specifically cleaves the acyl group bonded to the 3-hydroxyl group of 16-membered ring macrolide. Applied for a patent (Japanese Patent Application No. 3-19
7694). On the other hand, many 16-membered macrolides have been discovered as microbial metabolites, and midecamycin in which the 3-position is an acyloxy group (acylated hydroxyl group) (JP-A-46-28834) and leucomycin A ₇ in which the 3-position is a hydroxyl group. (US Pat. No. 3,535,309) and the like are known, and some of them have been put to practical use. Midecamycin and leucomycin have a hydroxyl group at the 9-position but a carbonyl group at the 9-position (see US Pat.
60,438) is also known.

[0004]

[Problems to be Solved by the Invention] A wide range of researches have been conducted on the chemical or biochemical acylation reaction, deacylation reaction of the 3-position hydroxyl group, and conversion of the 9-position hydroxyl group into the 9-position carbonyl group by the chemical oxidation reaction. It is intended to provide a 16-membered ring macrolide compound which does not naturally exist as a microbial metabolite.

[0005]

The present invention provides the formula (1).

[0006]

[Chemical 2]

[Wherein R ¹ is an oxygen atom, a group of the formula —O (CH ₂ ) nO— (where n is an integer of 2 or 3), a group of the formula (OR ⁴ ) ₂ (where R ⁴ is the number of carbon atoms) 1 to 4 linear alkyl group or benzyl group), formula-
S (CH ₂ ) nS- group (where n is an integer of 2 or 3) or formula (SR ⁴ ).
_{2 is} a group (provided that R ⁴ has the same meaning as described above), R ² is a hydrogen atom, a 4-O-propionylmycarose residue or a group of the formula COR ⁵ (provided that R ⁵ has 1 to 3 carbon atoms). A linear alkyl group), R ³ is a hydrogen atom or a group of formula COR ⁵ (wherein R ⁵ has the same meaning as defined above)], or a pharmaceutically acceptable salt thereof. Is. The compound represented by the general formula (1) according to the present invention is produced as follows by the method shown in the process chart 1.

[0008]

[Chemical 3]

Leucomycin A, the starting material₇Is public
(US Pat. No. 3,535,309), and streptomyces
It is obtained by culturing S. kitasatoensis. Also
Recently, the present inventors have found a known substance, midecamycin (special
Kaisho 46-28834) is a fungal strain PF1083 strain
By performing deacylation with leucomycin
A ₇Has completed a method of manufacturing and patent application (Japanese Patent Application No. 3
-197694). First, the starting material, leucomai
Shin A₇Selectively oxidize the 9-position hydroxyl group of compound (2) 9-
Dehydroleucomycin A₇To manufacture. As an oxidation method
Generally, a method widely used by those skilled in the art may be used.
Compound, various chromic acid / pyridine complexes, manganese diacid,
A reagent such as nickel peroxide may be used, preferably pyridinine.
It is um-chlorochromate (PCC). The reaction solvent is
Organic solvents that are inert to oxidation reactions, such as chloroform and salts
It may be methylene chloride, acetone, ethyl acetate or the like. Reaction temperature
Is carried out at -10 ° C to 50 ° C. Compound (2) is 9
-Dehydromidecamycin (midecamycin A₃) First
Treatment with the described PF1083 strain and deacylation
Can also be obtained by Then, compound (2) is ethylene glycol
In the presence of recall, the acid-catalyzed conversion reaction
The callose residue is cleaved to produce the general formula (1) of the present invention.
, R¹Is an ethylenedioxy group, R², R³Is a hydrogen atom
To obtain compound (3). P-Toluenesulfo as an acid catalyst
Acid, benzenesulfonic acid, methanesulfonic acid, sulfuric acid,
It may be hydrochloric acid or the like, preferably p-toluenesulfonic acid.
It As a solvent, other than acetonitrile, dioxane, tet
Cyclic ethers such as lahydrofuran may be added.
The reaction temperature easily progresses between -10 ° C and 50 ° C.

By using 1,3-propanediol or a lower alcohol in place of ethylene glycol in this reaction, the corresponding cyclic acetal or dialkyl acetal can be easily produced. Furthermore, it is possible to produce the corresponding dithioacetal by using various thiols instead of the above various alcohols.

The ethylenedioxy group of the compound (3) is easily removed by acid hydrolysis in a water-containing solvent. In the general formula (1) of the present invention, R ¹ is an oxygen atom and R ² and R ³ are hydrogen. This gives compound (4) which is an atom. A preferable acid hydrolysis condition is a mixed solution of 0.5N hydrochloric acid and acetonitrile.
Reaction for obtaining compound (3) from compound (2) and compound (3)
In the reaction for obtaining compound (4), the reaction itself is known and is widely used in the structure determination and total synthesis of macrolide antibiotics. For example, Tatsuta et al.
Of the Chemical Society of Japan, 5
Vol. 1, pp. 3035-1978. It is possible to directly prepare the compound (4) from the compound (2) by properly using these acid hydrolysis conditions. For example, compound (2) is directly hydrolyzed with a mixture of 0.5 N hydrochloric acid and acetonitrile to cleave mycarose to give compound (4).

The compounds (3) and (4) have three hydroxyl groups in the molecule, and these hydroxyl groups can be selectively chemically modified. In particular, macrolide antibiotics are known to change the pharmacokinetics in animals by partially acylating hydroxyl groups, and partial acylation of hydroxyl groups is an important technique. For example, compound (4)
When the compound is reacted with acetic anhydride in an organic solvent, only the hydroxyl group of mycaminose is acylated, and in the general formula (1) of the present invention, R ¹ is an oxygen atom and R ² and R ³ are compounds represented by acetyl groups (5 )give. Similarly, when compound (3) is acylated, compound (6), that is, compound (6) in which R ¹ is an ethylenedioxy group and R ² and R ³ are acetyl groups in the general formula (1) of the present invention (6 )give. As the reaction solvent, nitriles,
Cyclic ethers and esters are used, preferably acetonitrile, and the reaction proceeds easily between -10 ° C and 50 ° C. Further, it is possible to introduce an acyl group other than an acetyl group into the two hydroxyl groups of mycaminose by the same selective acylation.

[0013]

INDUSTRIAL APPLICABILITY As shown in Table 1, the compound obtained by the present invention has antibacterial activity against Gram-positive bacteria. Furthermore, the compound obtained in the present invention is important as a synthetic intermediate for producing a useful compound. Table 1: Antibacterial action of the compounds of the present invention (MIC; μg / ml) Compound (4) Compound (5) Staphylococcus aureus 209P JC-1 3.13 6.25 Staphylococcus aureus M133 3.13 6.25 Staphylococcus epidermidis ATCC14990 3.13 6.25 Enterococcus hirae ATCC8043 1.56 3.13 Enterococcus faecalis W-73 3.13 6.25

Next, the present invention will be described in detail by way of examples.

[0015]

【Example】

Example 1 Method for producing compound (2) (in the formula (1), R ¹ is an oxygen atom, R ² is a 4-O-propionylmycarose residue, and R ³ is a hydrogen atom) Leucomycin A ₇ 782 mg was anhydrous. It was dissolved in 23 ml of methylene chloride, 667 mg of pyridinium / chlorochromate was added, and the mixture was stirred at room temperature for 16 hours under an argon atmosphere. The reaction solution was directly purified by silica gel column chromatography (100 g, chloroform-methanol (40: 1) → same (20: 1)),
350 mg of a colorless solid compound (2) was obtained.

Example 2 Compound (3) (in the formula (1), R ¹ is an ethylenedioxy group, R ² and R ³
2.169 g of compound (2) was dissolved in 65 ml of anhydrous acetonitrile, 0.30 ml of ethylene glycol and 914 mg of p-toluenesulfonic acid were added, and the mixture was reacted at room temperature for 1 hour. The reaction solution was added dropwise to 650 ml of saturated aqueous sodium hydrogen carbonate solution, and extracted with 650 ml and 160 ml of chloroform. The chloroform layer was dried over anhydrous sodium sulfate and then filtered, and the residue obtained by concentrating the filtrate under reduced pressure was subjected to silica gel column chromatography (300 g, chloroform-methanol (15: 1) →
The same (10: 1)) was used to obtain 976 mg of compound (3). Physicochemical properties of compound (3) (1) Color and shape: colorless solid (2) Molecular formula: C ₃₀ H ₄₉ NO ₁₁ (3) Mass spectrum (EIMS): m / z 599 (M) ⁺ (4) Specific rotation degrees: [α] _D ²⁴ -18 ° _{(c1.0, CH 3 OH) (} 5) ^{mp: 105~111 ℃ (6) 1 H} NMR spectrum (400 MHz, CDCl ₃₎ δ
(ppm): 2.25 (br d, 2-H), 2.75 (dd, 2-H), 3.75 (br d, 3
-H), 3.10 (br d, 4-H), 3.58 (s, 4-OCH ₃ ), 4.30 (br d, 5
-H), 1.61 (ddd, 7-H), 2.67 (m, 8-H), 6.28 (d, 10-H), 7.2
8 (dd, 11-H), 6.13 (m, 12-H), 6.13 (m, 13-H), 2.18 (m,
14-H), 5.20 (ddq, 15-H), 1.32 (d, 16-H ₃ ), 1.75 (ddd,
17-H), 2.02 (ddd, 17-H), 4.93 (t, 18-H), 1.18 (d, 19-
H ₃ ), 4.55 (d, 1'-H), 3.56 (dd, 2'-H), 2.40 (t, 3'-H),
3.07 (t, 4'-H), 3.33 (dq, 5'-H), 1.32 (d, 6'-H ₃ ), 2.
52 (s, 3'-N (CH ₃ ) ₂ ), 3.81, 3.95 (m, OCH ₂ CH ₂ O) (7) Solubility: Soluble in chloroform, acetone, ethyl acetate, methanol, acidic water, medium Insoluble in basic and alkaline water.

Example 3 Method for producing compound (4) (in formula (1), R ¹ is an oxygen atom, R ² and R ³ are hydrogen atoms) 100 mg of compound (3) was dissolved in 3.0 ml of acetonitrile,
3.0 ml of 0.5N hydrochloric acid was added and the reaction was carried out at room temperature for 16 hours. The reaction solution was added dropwise to 30 ml of a saturated sodium hydrogen carbonate aqueous solution,
It was extracted with 30 ml and 8 ml of chloroform. The chloroform layer was dried over anhydrous sodium sulfate, filtered, and the residue obtained by concentrating the filtrate under reduced pressure was used for separation TLC (development system: chloroform-methanol-concentrated aqueous ammonia (100: 10: 1)).
The compound (4) (75 mg) was obtained after purification. Physicochemical properties of compound (4) (1) Color and shape: colorless solid (2) Molecular formula: C ₂₈ H ₄₅ NO ₁₀ (3) Mass spectrum (EIMS): m / z 555 (M) ⁺ (4) Specific rotation Degree: [α] _D ²⁷ −7.9 ° (c1.0, CH ₃ OH) (5) Melting point: 114 to 118 ° C. (6) ¹ H NMR spectrum (400 MHz, CDCl ₃ ) δ
(ppm): 2.25 (br d, 2-H), 2.76 (dd, 2-H), 3.79 (b
rd, 3-H), 3.13 (br d, 4-H), 3.56 (s, 4-OCH ₃ ), 4.06
(br d, 5-H), 1.88 (m, 6-H), 1.53 (ddd, 7-H), 1.66 (dd
d, 7-H), 6.31 (d, 10-H), 7.27 (dd, 11-H), 6.14 (m, 12-
H), 6.14 (m, 13-H), 2.18 (m, 14-H), 5.22 (ddq, 15-H),
1.33 (d, 16-H ₃ ), 2.78 (ddd, 17-H), 9.69 (br d, 18-
H), 1.20 (d, 19-H ₃ ), 4.44 (d, 1'-H), 3.47 (dd, 2'-H),
2.34 (t, 3'-H), 3.05 (t, 4'-H), 3.29 (dq, 5'-H), 1.26
_{(d, 6'-H 3)} , 2.49 (s, 3'-N (CH 3) 2) (7) Solubility: chloroform, acetone, ethyl acetate, methanol, soluble in acidic water, neutral and alkaline Insoluble in water.

Example 4 Method for producing compound (4) (in formula (1), R ¹ is an oxygen atom, R ² and R ³ are hydrogen atoms) 1.468 g of compound (2) was dissolved in 44 ml of acetonitrile,
44 ml of 0.5N hydrochloric acid was added, and the mixture was reacted at room temperature for 16 hours. The reaction solution was added dropwise to 440 ml of a saturated sodium hydrogen carbonate aqueous solution, and extracted with 440 ml and 110 ml of chloroform. The chloroform layer was dried over anhydrous sodium sulfate, filtered, and the residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (100 g, chloroform-methanol-concentrated aqueous ammonia (300: 25: 2)). Then the compound
(4) 673 mg was obtained.

Example 5 Method for producing compound (5) (in formula (1), R ¹ is an oxygen atom, R ² and R ³ are acetyl groups) 100 mg of compound (4) was dissolved in 4.0 ml of anhydrous acetonitrile, 45 μl of acetic anhydride was added and reacted at room temperature for 16 hours. 0.
0.36 ml of 5N aqueous ammonia was added, and the mixture was allowed to stand at room temperature for 10 minutes, the reaction mixture was concentrated under reduced pressure, and the resulting residue was extracted with 20 ml of chloroform. The chloroform layer was washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and filtered. The residue obtained by concentrating the filtrate under reduced pressure was separated TLC (developing system: hexane-acetone (2:
1)) refine | purified and the compound (5) 109 mg was obtained. Physicochemical properties of compound (5) (1) Color and shape: colorless solid (2) Molecular formula: C ₃₂ H ₄₉ NO ₁₂ (3) Mass spectrum (EIMS): m / z 639 (M) ⁺ (4) Specific rotation Degree: [α] _D ²⁴ −8.0 ° (c1.0, CHCl ₃ ) (5) Melting point: 114 to 119 ° C. (6) ¹ H NMR spectrum (400 MHz, CDCl ₃ ) δ
(ppm): 2.22 (br d, 2-H), 2.74 (dd, 2-H), 3.79 (b
rd, 3-H), 3.05 (br d, 4-H), 3.52 (s, 4- OCH ₃ ), 4.06
(br d, 5-H), 1.84 (m, 6-H), 1.46 (dd d, 7-H), 1.58 (dd
d, 7-H), 6.31 (d, 10-H), 7.24 (dd, 11-H), 6.12 (m, 12-
H), 6.12 (m, 13-H), 5.21 (ddq, 15-H), 1.33 (d, 16-
H ₃ ), 2.40 (dd, 17-H), 2.81 (ddd, 17-H), 9.66 (br s, 1
8-H), 1.19 (d, 19-H ₃ ), 4.67 (d, 1'-H), 4.83 (dd, 2'-
H), 2.71 (t, 3'-H), 4.74 (t, 4'-H), 3.35 (dq, 5'-H), 1.
_{08 (d, 6'-H 3} ), 2.34 (s, 3'-N (CH 3) 2), 2.04 (s, COCH 3) (7) Solubility: chloroform, acetone, ethyl acetate, methanol, acidic water It is soluble in water and insoluble in neutral and alkaline water.

Example 6 Compound (6) (in the formula (1), R ¹ is an ethylenedioxy group, R ² and R ³
Is a acetyl group) Compound (3) (75 mg) was dissolved in anhydrous acetonitrile (3.0 ml), acetic anhydride (32 μl) was added, and the mixture was reacted at room temperature for 12 hours. 0.
After adding 0.25 ml of 5N ammonia water and allowing to stand at room temperature for 10 minutes, the reaction solution was concentrated under reduced pressure and the resulting residue was extracted with 15 ml of chloroform. The chloroform layer was washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and filtered. The residue obtained by concentrating the filtrate under reduced pressure was separated TLC (developing system: hexane-acetone (2:
Purification by 1)) yielded 62 mg of compound (6). Physicochemical properties of compound (6) (1) Color and shape: colorless solid (2) Molecular formula: C ₃₄ H ₅₃ NO ₁₃ (3) Mass spectrum (EIMS): m / z 683 (M) ⁺ (4) Specific rotation Degree: [α] _D ²⁷ −15 ° (c1.0, CHCl ₃ ) (5) Melting point: 187 to 192 ° C. (6) ¹ H NMR spectrum (400 MHz, CDCl ₃ ) δ
(ppm): 2.21 (br d, 2-H), 2.73 (dd, 2-H), 3.77 (br
d, 3-H), 3.02 (br d, 4-H), 3.53 (s, 4-OCH ₃ ), 4.15 (br
d, 5-H), 2.62 (m, 8-H), 6.29 (d, 10-H), 7.26 (dd, 11
-H), 6.11 (m, 12-H), 6.11 (m, 13-H), 2.49 (ddd, 14-
H), 5.19 (ddq, 15-H), 1.32 (d, 16-H ₃ ), 2.04 (ddd, 17-
H), 4.99 (dd, 18-H), 1.17 (d, 19-H ₃ ), 4.74 (d, 1'-H),
4.86 (dd, 2'-H), 2.72 (t, 3'-H), 4.78 (t, 4'-H), 3.
40 (dq, 5'-H) , 1.13 (d, 6'-H 3), 2.34 (s, 3'-N (CH 3) 2),
2.04 (s, COCH ₃ ), 3.77, 3.92 (m, OCH ₂ CH ₂ O) (7) Solubility: Soluble in chloroform, acetone, ethyl acetate, methanol, acidic water, insoluble in neutral and alkaline water Is.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Seiji Shibahara 760 Shimooka-cho, Kohoku-ku, Yokohama-shi, Kanagawa Meiji Seika Chemicals Research Institute (72) Inventor Yuzo Nagaoka 760 Shimooka-cho, Kohoku-ku, Yokohama-shi, Kanagawa Address Meiji Confectionery Co., Ltd. Chemical Research Laboratory (72) Inventor Shigeharu Inoue 760 Shimooka-cho, Kohoku-ku, Yokohama-shi, Kanagawa Meiji Confectionery Research Center

Claims (6)

[Claims] 1. The following formula (1):[In the formula, R¹Is an oxygen atom, formula -O (CH₂) nO-group (where n is 2
Or an integer of 3), formula (OR^Four) ₂Base (however, R^FourHas 1 to 4 carbon atoms
Linear alkyl group or benzyl group) of the formula -S (CH₂) nS-
Group (where n is an integer of 2 or 3) or formula (SR^Four)₂Group of (but
R^FourHas the same meaning as above), and R²Is a hydrogen atom, 4
-O-propionylmycarose residue or formula COR^FiveBase of
(However, R^FiveIs a linear alkyl group having 1 to 3 carbon atoms),
R³Is a hydrogen atom or the formula COR^FiveBase (however, R^FiveMeans the same as above
Or a pharmaceutically acceptable compound thereof.
Get salt. 2. A compound represented by the formula (1) according to claim 1, wherein R ¹ is an ethylenedioxy group and R ² and R ³ are hydrogen atoms, or a pharmaceutically acceptable salt thereof. 3. In the formula (1) of claim 1, R¹Is oxygen
Represented by an atom, R², R ³Is a compound represented by a hydrogen atom, or
Is a pharmaceutically acceptable salt thereof. 4. In the formula (1) of claim 1, R¹Is oxygen
Represented by an atom, R², R ³Is a compound represented by an acetyl group,
Or a pharmaceutically acceptable salt thereof. 5. A compound of the formula (1) according to claim 1, wherein R ¹ is an ethylenedioxy group and R ² and R ³ are acetyl groups, or a pharmaceutically acceptable salt thereof. 6. A compound represented by the formula (1) according to claim 1, wherein R ¹ is an oxygen atom, R ² is a 4-O-propionylmycarose residue, and R ³ is a hydrogen atom. , Or a pharmaceutically acceptable salt thereof, leuomycin A ₇ as a starting material.