JPH0725894A - New 16-membered ring macrolide derivative - Google Patents

Abstract

PURPOSE:To provide a new compound useful as an antibacterial agent for Gram-positive bacteria. CONSTITUTION:The compound of formula I [R<1> is H or COR<6> (R<6> is 1-3C straight chain alkyl); R<2> is H or (substituted) OH; R<3> is H or (substituted) OH; where, either R<2> or R<3> is H; R<4> is H or COR<6>; R<5> is H, (substituted) 1-10C aliphatic acyl or aromatic acyl], e.g. 3''-O-methylmydecamycin A1. The compound of the formula I can be obtained by subjecting a compound of formula II [R<1> is COR<6>; R<5> is (substituted) aliphatic acyl or aromatic acyl] to biochemical transformation using microbes and, if needed, by subjecting the OH group(s) at 9-site and/or 2'-site to selective synthetic chemical reaction.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention is effective against Gram-positive bacteria.
It relates to a 6-membered ring macrolide derivative.

[0002]

BACKGROUND OF THE INVENTION Macrolide antibiotics effective against Gram-positive bacteria, mycoplasma, chlamydia, etc. are classified as clinically important antibacterial agents because they can be administered orally and have low toxicity. In particular, myocamycin has excellent pharmacokinetics and less bitterness than natural compounds (Journal of Antibiotics, 29 (5), 536 (1976), Japanese Journal of Antibiotics,
35 (6), 1462 (1982)) is actively used clinically as a semisynthetic 16-membered macrolide antibiotic mainly in the pediatric field and the like. The present inventors have shown that resistance induction is difficult,
A 16-membered macrolide antibiotic was selected as a research target because of its low interaction with other drugs and its small effect on the intestinal tract. Synthetic chemical and biochemistry of compounds effective against various Gram-positive bacteria. I have been carrying out repeated search research.

First, as an example of the newly discovered facts, as a methodology for enhancing the in vitro antibacterial activity,
We filed a patent application for an invention based on a synthetic chemical strategy of introducing a methyl group into the tertiary hydroxyl group at the 3 "position of the 16-membered macrolide (Japanese Patent Application No. 5-3545). This strategy is L-, which is a constituent sugar of erythromycin. It was described in the same patent that it was constructed based on the chemical structure of cladinose, and the present application describes the structure-activity relationship of 16-membered macrolide (Journal of Antibiotics, 21 (9), 532 (1968)). The invention obtained by further developing this strategy targeting L-cladinose is described with reference to the findings obtained above. There is another report on the 16-membered ring macrolide in which the hydroxyl group at the 3 "-position was methylated by using (Chemistry Letters, 769 (1977)). According to the present report, 3 "-O-methylcarbomycin B was described as having an enhanced antibacterial activity as compared with carbomycin B against certain specific bacteria, for example, one type of acid-fast bacterium. However, the 9-position of the methylated derivative of the 3 "-hydroxyl group prepared by these two methods has a carbonyl group, namely sp
It was ² carbons. In fact, up to the present, no 16-membered ring macrolide derivative in which the 9-position is sp ³ carbon and the tertiary hydroxyl group at the 3 "-position is methylated at the same time is not known.

Secondly, the inventors of the present invention have already filed a patent application for an invention relating to a microbial conversion method for reducing the carbonyl group at the 9-position of a 16-membered ring macrolide to a hydroxyl group having a natural configuration. Japanese Patent Application No. 4-291438). by the way,
Regarding the method of reducing the carbonyl group at the 9-position to a hydroxyl group for the purpose of elucidating the structure-activity relationship of 16-membered ring macrolides, biosynthetic research, structural analysis, etc., a synthetic chemical approach (Journal of Organic Chemistry,
39 (16), 2474 (1974), Journal of Antibiotics, 34 (12), 1577 (1981), ibid, 39 (12), 1784 (198)
6)) and a biochemical approach (JP-A-50-126880, Journal of Antibiotics, 32 (7), 777 (197).
9), JP-A-54-8793, Journal of Antibiotics, 33 (8), 911 (1980)) and the like.

Thirdly, the inventors of the present invention have already described an invention relating to a microbial conversion method in which an acyl group bonded to the 3-position hydroxyl group of the lactone ring of a 16-membered macrolide is specifically cleaved to induce a free hydroxyl group. We applied for a patent (EP 526,906, Japanese Patent Application No. 3-197694). On the other hand, a similar biochemical reaction by a kind of Bacillus subtilis (or an enzyme produced by it) has already been reported (Journal of Fermentation Technology, 57 (6), 519 (1979), JP 54-2889
2).

[0006]

It has been reported that a 16-membered ring macrolide antibacterial agent with few side effects generally has weaker in vitro antibacterial activity than that of a 14-membered ring (Anti-Microbial Agents And・ Chemotherapy, 32 (11), 1710 (1988)). Therefore, Streptococ, which is one of the main causative bacteria of upper respiratory tract infection in clinical practice
16-membered macrolide antibiotic with enhanced antibacterial activity against Enterococcus faecalis (461st Special Member Meeting of the Japanese Council for Antibiotics, 1991.2.22), which is one of the causative bacteria in multiple infections with cus and MRSA Is expected to appear.

[0007]

Means for Solving the Problems The present inventors have conducted synthetic chemical research and biochemical research to meet the above-mentioned expectations, and L-cladinose, which is a constituent sugar of erythromycin, was synthesized by the present inventors. Microorganisms with various purposeful conversion functions for 3 "-O-methylmidecamycin A ₃ (Japanese Patent Application No. 5-3545), which is a 16-membered ring macrolide derivative in which a modified sugar is an α-glycoside bond By conducting a biochemical reaction using, the 9-position is sp ³ carbon, and at the same time
We have succeeded in preparing various 16-membered macrolide derivatives in which the tertiary hydroxyl group at the 3 "position is methylated. Moreover, these derivatives are clinically important Gram-positive bacteria, especially Streptococ.
found to strongly inhibit the growth of genus cus , Enterococcus faecalis , and certain erythromycin-resistant bacteria,
The present invention has been completed.

The gist of the present invention resides in the following formula (I) as a novel compound.

[Chemical 2]

[In the formula, R ¹ is a hydrogen atom or a group of the formula COR ⁶ (provided that R ⁶ is a linear alkyl group having 1 to 3 carbon atoms), R ² is a hydrogen atom, substituted or substituted) Not a hydroxyl group, R ³ is a hydrogen atom, a substituted or unsubstituted hydroxyl group, provided that either one of R ² and R ³ is a hydrogen atom, R ⁴ is a hydrogen atom or a group of formula COR ⁶ . (Wherein R ⁶ has the same meaning as described above), R ⁵ is a hydrogen atom, a substituted or unsubstituted C 1-10 linear or branched aliphatic acyl group, or aromatic Group acyl group], or a pharmaceutically acceptable salt thereof. The compound represented by the general formula (I) according to the present invention has the following formula (II)

[0010]

[Chemical 3]

[Wherein R ¹ is a group of the formula COR ⁶ (wherein R ⁶ is a linear alkyl group having 1 to 3 carbon atoms), and R ⁵ is a substituted or unsubstituted C ¹ to C ¹ group] 10 linear or branched aliphatic acyl group or aromatic acyl group] or a salt thereof, using a single microorganism or continuously using a plurality of microorganisms Biochemical conversion,
Then, if necessary, it is produced by performing a selective synthetic chemical reaction on the hydroxyl group at 9-position and / or 2'-position.

The compound represented by the formula (II) can be synthesized by a sugar component introduction reaction, that is, a glycosylation reaction. More specifically, a protected synthetic intermediate in which D-mycaminose is β-glycosidically linked to the hydroxyl group at the 5-position of a 16-membered ring lactone is derived from L-cladinose as a sugar component acceptor. The sugar component donor (glycosyl donor) thus prepared is subjected to a glycosylation reaction, followed by a synthetic chemical reaction to produce the product. That is, the formula (I
The compound represented by I) can be produced by the method of the present inventors via a glycosylation using a thio sugar (Japanese Patent Application No.
3545) or by previously reported synthetic methods via glycosylation with glycals (Chemistry Letters, 769 (1977)). According to the former method, 3 "-O-methylmidecamycin A ₃ (formula (I
I) in which R ¹ is a propionyl group and R ⁵ is a propionyl group), and the like, according to the latter method, 3 "-O-methylcarbomycin B (in the formula (II), R ¹
Is represented by an acetyl group and R ⁵ is represented by an isovaleryl group) and the like can be synthesized. Moreover, the formula (I
When the compound represented by I) is prepared by either method, it is used in the glycosylation reaction at the 3-position of the sugar component acceptor and the 4-position of the sugar component donor (4 "after glycosylation).
By appropriately selecting the respective acyl side chains of the position), the side chain R ¹ in the 3-position in the compound represented by the formula (II) and
The 4 "position side chain R ⁵ is capable of introducing the desired acyl group (provided that with respect to the 3-position side chain R ^1, it is desirable that an acyl group of a naturally occurring).

Here, among the compounds represented by the general formula (I), four main types of compounds represented by the formulas (III) to (VI) are started from the compounds represented by the formula (II). As a substance
Process diagram for specific reaction pathways prepared by microbial conversion
Shown in.

[0014]

[Chemical 4]

First, the following formula (II
I)

[Chemical 5]

[Wherein R ¹ is a group of the formula COR ⁶ (wherein R ⁶ is a linear alkyl group having 1 to 3 carbon atoms), R ² is a hydrogen atom or a hydroxyl group, and R ³ is a hydrogen atom. Or a hydroxyl group, provided that R ²
And R ³ is a hydrogen atom, and R ⁵ is a substituted or unsubstituted C 1-10 linear or branched aliphatic acyl group, or aromatic acyl group]. As a method for producing a compound represented by the formula (II) or a salt thereof from the compound represented by the formula (II), Streptomyces mycarofaci, which is a species of actinomycetes filed by the present inventors. The microbial conversion method using the Ens SF2772 strain (Japanese Patent Application No. 4-291438) was selected. That is, the compound represented by the formula (II) is bioconverted by the SF2772 strain, and the carbonyl group at the 9-position is reduced to a hydroxyl group having a natural configuration, and the compound represented by the formula (III) is efficiently produced. Prepared. For example, 3 "-O-methylmidecamycin A ₃ (a compound represented by the formula (II) in which R ¹ is a propionyl group and R ⁵ is a propionyl group) is a biochemical conversion reaction by the SF2772 strain. Received 3 "-O-methylmidecamycin A ₁ (formula (III)
In, a compound (1) in which R ¹ is a propionyl group, R ² is a hydrogen atom, R ³ is a hydroxyl group, and R ⁵ is a propionyl group is converted. In the conversion of the 16-membered ring macrolide, a method per se for reducing the carbonyl group at the 9-position to a hydroxyl group by a biochemical reaction is known (see JP-A-54-8793 et al., "Prior Art").

Details regarding the present microbial conversion method are described in the examples described later. By the way, as a biochemical reaction having such a conversion function, it is not limited to a microbial conversion method using the SF2772 strain, as well as conversion using a microorganism other than the SF2772 strain, a conversion function other than the microorganism. The biochemical reactions used can also be exploited. In addition, Streptomyces mycarofaciens S
The F2772 strain has been deposited as FERM P-13227 at the Institute of Biotechnology, Institute of Industrial Science and Technology.

As a method for producing a compound represented by the formula (III) as a novel compound from a compound represented by the formula (II), a biochemical method such as microbial conversion or an enzyme produced by a living body is used. It is not limited to the above methods, but is also produced by synthetic chemical methods (Journal of Organic Chemistry, 39 (16), 2474 (1974)) including protection / deprotection steps for the 18th aldehyde group. It is possible to do However, when the carbonyl group at the 9-position is reduced to a hydroxyl group having a natural configuration by a synthetic chemical method, the stereoselectivity of the reaction and the yield of the above-mentioned protection / deprotection step (particularly the acetalization step at the 18-position) are reduced. Considering the rate does not always give satisfactory results. Therefore, the present inventors further proceeded with the preparation of a new derivative using reduction at the 9-position by a biochemical method.

Next, the following formula (IV) as a novel compound

[Chemical 6]

[Wherein R²Is a hydrogen atom or a hydroxyl group,
R³Is a hydrogen atom or a hydroxyl group, provided that R²And R³Which of
One is a hydrogen atom, R^FiveIs replaced or replaced
Straight or branched chain aliphatic reed having 1 to 10 carbon atoms
Group, or an aromatic acyl group], or
From a compound represented by the formula (III) or a salt thereof:
The manufacturing process is based on a fungal species found by the present inventors.
A certain Phialophora PF1083 strain (EP 526,906, Japanese Patent Application
3-197694), which is a known method for microbial conversion
It was achieved by That is, it is represented by formula (III)
Microorganism conversion of the compound with PF1083 strain, water at the 3-position of the lactone ring
Acyl group bound to acid group is specifically cleaved to release 3-position
Of the compound of formula (IV)
Well prepared. For example, 3 "-O-methyl midecamycin A₁
(In the formula (III), R¹Is represented by a propionyl group, R
²Is represented by a hydrogen atom, R³Is represented by a hydroxyl group, R^FiveIs a professional
Compound (1) represented by pionyl group depends on PF1083 strain
After undergoing the biochemical conversion reaction, 3 "-O-methyl leucomay
Shin A₇(In the formula (IV), R²Is represented by a hydrogen atom, R ³
Is represented by a hydroxyl group, R^FiveIs a compound represented by a propionyl group
(2)).

Details regarding the present microbial conversion method are described in the examples described later. By the way, as the biochemical reaction having such a conversion function, it is not limited to the microbial conversion method using the PF1083 strain, as well as the conversion using a microorganism other than the PF1083 strain, a conversion function other than the microorganism. The biochemical reactions used can also be exploited. However, a biochemical reaction for specifically cleaving the acyl group bonded to the 3-position hydroxyl group of the lactone ring of the 16-membered macrolide is not known. In addition, the PF1083 strain of the genus Fialophora has been deposited as FERM P-12281 at the Institute of Biotechnology, Institute of Biotechnology, AIST.

The method for producing the compound represented by the formula (IV) as a novel compound from the compound represented by the formula (III) is limited to the biochemical method as described above. However, regarding a method of specifically and efficiently cleaving the acyl group bonded to the 3-position hydroxyl group of the lactone ring in the 16-membered macrolide, deacylation with a compound having a tyronolide skeleton is described. Almost no reports except for

Then, the following formula (V) as a novel compound is obtained.

[Chemical 7]

[In the formula, R ¹ is a group of the formula COR ⁶ (provided that R ⁶ is a linear alkyl group having 1 to 3 carbon atoms), R ² is a hydrogen atom or a hydroxyl group, and R ³ is a hydrogen atom. Or a hydroxyl group, provided that R ²
And one of R ³ is a hydrogen atom],
Or a salt thereof, and the following formula (VI) as a novel compound:

[Chemical 8]

[In the formula, R ² is a hydrogen atom or a hydroxyl group,
R ³ is a hydrogen atom or a hydroxyl group, provided that either one of R ² and R ³ is a hydrogen atom], or a salt thereof,
The compound represented by the formula (III) or a salt thereof, and the compound represented by the formula (IV) or a salt thereof were prepared by a known biochemical reaction (Japanese Patent Publication No. Sho 48-29148). That is, the compound represented by the formula (III) and the compound represented by the formula (IV) are respectively converted into microorganisms in the genus Zygomyceae, which is a bacterium of the phylum Zygomycetes, Subphyla of the order Subphyla, and their 4 "positions A compound represented by the formula (V) and the formula (VI) by (specifically) cleaving the acyl group bonded to the hydroxyl group (the 4-position of the neutral sugar) to form a free hydroxyl group. The compound represented by was efficiently prepared. For example, 3 "-O-methylmidecamycin A ₁ (in formula (III), R ¹ is represented by a propionyl group, R ² is represented by a hydrogen atom, R ³ is represented by a hydroxyl group, and R ⁵ is represented by propionyl. Group (1)), and 3 "-O
-Methylleucomycin A ₇ (a compound ( ² ) in which R ² is a hydrogen atom, R ³ is a hydroxyl group, and R ⁵ is a propionyl group in the formula (IV)) is 3 "-O-methylmidecamycin M ₁ (in the formula (V), R ¹ is represented by a propionyl group, R ² is represented by a hydrogen atom, and R ³ is represented by a hydrogen atom. Compound (3) represented by hydroxyl group, and 3 "-O-methylleucomycin V
(In the formula (VI), R ² is represented by a hydrogen atom and R ³ is represented by a hydroxyl group (4)).
Details regarding the present microbial conversion method are described in the examples described later.

4-position of neutral sugar of 16-membered macrolide compound
Biochemically cleaves the acyl group bonded to the (4 "-position) hydroxyl group
There are many reports about the reaction (fermentation and industry,37
(8), 749 (1979)). Midecamycin A₁(Medemycin)
(Journal of Antibiotics,twenty four(7), 452
(1971)) related conversion reaction
It has been done (Japanese Patent Publication No. Sho 48-29148), and it exists naturally.
Types of microorganisms, especially molds, have the ability to deacylate
It was reported that

On the other hand, the biochemical deacylation reaction of the 4 "-position at the 16-membered macrolide derivative in which the tertiary hydroxyl group at the 3" -position was methylated was reported by the present inventors (Japanese Patent Application No. 5-354).
Although not known until now except for 5), the present inventors have further confirmed that the desired conversion reaction proceeds efficiently with a plurality of types of molds. By the way, the biochemical reaction having such a conversion function is not limited to the microbial conversion method using a genus fungus, etc., and it is not limited to the conversion using a microorganism other than a mold, and the conversion function other than the microorganism. Biochemical reactions using can also be used.

As described above, the expressions (III) to (V
The compound represented by I) or a salt thereof was prepared by using the compound represented by the formula (II) or a salt thereof as a starting material according to the reaction route shown in Process Diagram 1. By the way, when a plurality of types of microorganisms having a desired conversion function are continuously used, the conversion order is not necessarily limited to the reaction route shown in the process diagram 1, and some kind of regulation (eg substrate specific However, the order can be set relatively freely. For example, the compound represented by the formula (VI) is not only converted from the compound represented by the formula (IV), but also the compound represented by the formula (V) can be produced as a conversion substrate. .

Up to now, the compound represented by the formula (II) has been subjected to a biochemical reaction using a plurality of kinds of microorganisms alone or continuously, and the compound represented by the formula (III) to the formula (VI) The compounds shown were prepared efficiently, but the 9-position thus obtained was sp
^For a 16-membered ring macrolide derivative having ³ carbon atoms and at the same time having a methyl group introduced into the tertiary hydroxyl group at the 3 "position, a 16-membered ring macrolide derivative having 9-position sp ³ carbon can be used. Most of the possible selective / non-selective synthetic chemistries can be applied (except for the reaction to the 3 "position).

For example, for the compounds represented by the formulas (III) to (VI), or salts thereof, a known method for selectively acylating the hydroxyl group at the 9-position or the 2'-position (fermentation and industry , 37 (1
2), 1171 (1979)) or a known method of allylic rearrangement of the 9-position hydroxyl group to the 11- or 13-position in the presence of a dilute acid (Chemical and Pharmaceutical Bretan, 18 (8),
1501 (1970), Annual Report of Meiji Seika, 12 , 85 (1972), Journal of Antibiotics, 35 (11), 1521 (198)
2)) or a known method for selectively oxidizing the 9-position hydroxyl group (Journal of Antibiotics, 24 (8), 526
(1971)) and the like to produce a novel useful substance based on the present invention. As an example thereof, the 9-position hydroxyl group of the lactone ring of the compounds (1) and (2) is selectively acetylated using a known method (JP-A-48-13380) to give compounds (5) and (6). Each was synthesized.

Examples for obtaining the compound of the present invention and physicochemical properties of the compound of the present invention are shown below. According to this example, a reduction method at the 9-position of a 16-membered macrolide compound using a microorganism belonging to the genus Streptomyces, the genus Phialophora, or the genus Moldy, the deacylation method at the 3-position and the deacylation at the 4 "-position are described. Since the usefulness of the method was demonstrated, various methods for producing the substance by the same biochemical method can be devised based on this, while different biochemical methods such as direct fermentation or It is possible to devise various methods for producing the substance by utilizing biochemical conversion reactions of the kind not carried out in the invention.Furthermore, the substance, compounds (1) to (6), etc. can also be produced by synthetic chemical methods. Therefore, the present invention is not limited to the examples, and the modification means of the examples are of course represented by the general formula (I) disclosed by the present invention. Conversion Includes all methods of synthesizing, producing, extracting and purifying these by applying known means based on the properties of the products (1), (2), (3), (4), (5) and (6). To do.

[0032]

【Example】

 Example 1Compound (1) (in the general formula (I), R ¹ is propioni
Group, R ² is a hydrogen atom, and R ³ is a hydroxyl group.
R ⁴ is a hydrogen atom and R ⁵ is a propionyl group.
Compound) (3 "-O-methylmidecamycin A ₁ )
Construction method As the medium, glucose 2.0%, polypeptone 1.0%, lysate
Dipotassium hydrogenate 0.05%, magnesium sulfate heptahydrate
Of 0.05% and 0.3% sodium chloride
Before use, it was adjusted to pH 7.0 and used. The above medium
40 500 ml Erlenmeyer flasks with 100 ml dispensed at 120 ° C
Sterilize for 30 minutes and place Streptomyces in each Erlenmeyer flask.
Freezing of Mycarofaciens SF2772 strain (FERM P-13227)
Inoculate each with 2.0 ml of seeded seeds and shake at 28 ℃ for 24 hours.
Cultured. In addition, in the formula (II), R¹Is propioni
Represented by the R group, R^FiveA compound in which is represented by a propionyl group
(3 "-O-methylmidecamycin A₃) 472 mg of methanol
Add 60 ml of the solution, 1.5 ml per Erlenmeyer flask.
The mixture was added and cultured at 28 ° C. for 20 hours with shaking. After completing the culture,
 Centrifuge at 3000 rpm for 10 minutes and add 3.5 L of clear culture solution.
Then, solids such as bacterial cells were removed. Add 2.0 L of water to the solids.
After stirring, centrifuge, and wash the resulting washing solution with the transparent medium.
Matched to the nutrient solution. After adjusting this to pH 9, the conversion substance is vinegar.
Extracted twice with 5.5 L ethyl acetate and 2.8 L ethyl acetate
The layer was dried over anhydrous sodium sulfate and then filtered. Filtrate
Was concentrated under reduced pressure, and the residue obtained was subjected to preparative TLC (developing system:
Chloroform-methanol (10: 1)) and
321 mg of the product (1) was obtained. This is Sephadex LH-20
Purified by ram chromatography (1.0 L, methanol)
Thus, 223 mg of compound (1) was obtained. Physicochemical properties of compound (1) (1) Color and shape: Colorless solid (2) Molecular formula: C₄₂H₆₉NO₁₅ (3) Mass spectrum (SIMS): m / z 828 (M + H)⁺ (4) Specific rotation: [α]_D ¹⁵ -65 ° (c1.0, CH₃OH) (5) Melting point: No clear melting point at 116-120 ° C
Melting (6)¹1 H NMR spectrum (400MHz, CDCl₃) δ
(ppm): 2.24 (br d, 2-H), 2.76 (dd, 2-H), 5.14 (br
d, 3-H), 3.26 (br d, 4-H), 3.57 (s, 4-OCH₃), 3.88 (br
 d, 5-H), 0.92 (br ddd, 7-H), 1.54 (br dt, 7-H), 1.8
9 (m, 8-H), 4.07 (dd, 9-H), 5.61 (dd, 10-H), 6.67 (dd,
 11-H), 6.08 (br dd, 12-H), 5.79 (ddd, 13-H), 2.15 (d
t, 14-H), 5.03 (ddq, 15-H), 1.26 (d, 16-H₃), 2.32 (br
dd, 17-H), 2.86 (br dd, 17-H), 9.63 (br s, 18-H), 0.9
8 (d, 19-H₃), 2.51 (dq, 3-OCOCH ₂CH ₃), 2.64 (dq, 3-OCO
CH ₂CH₃), 1.22 (t, 3-OCOCH₂CH ₃ ), 4.52 (d, 1'-H), 3.22
(dd, 2'-H), 2.42 (t, 3'-H), 3.44 (t, 4'-H), 3.29 (dq,
5'-H), 1.16 (d, 6'-H₃), 2.57 (s, 3'-N (CH₃)₂), 4.92
(d, 1 "-H), 1.66 (dd, 2" -Hax), 2.29 (d, 2 "-Heq), 4.72
(d, 4 "-H), 4.54 (dq, 5" -H), 1.07 (d, 6 "-H₃), 1.10 (s,
 7 "-H₃), 3.26 (s, 3 "-OCH₃), 2.42 (apparent q, 4 "-OCO
CH ₂CH₃), 2.43 (apparent q, 4 "-OCOCH ₂CH₃), 1.17 (t,
4 "-OCOCH₂CH ₃ )

Example 2 Compound (2) (in the general formula (I), R ¹ is a hydrogen atom)
Represented, R ² is represented by hydrogen atom, R ³ is represented by a hydroxyl group,
R ⁴ is represented by a hydrogen atom and R ⁵ is represented by a propionyl group.
Compound) (3 "-O-methylleucomycin A ₇ ) production method As a medium for pre-culture, starch 2.0%, glucose 1.0%, wheat germ 0.6%, polypeptone 0.5%, powdered yeast extract 0.3%, soybean flour The conversion medium used was 0.2% and calcium carbonate 0.2%, and the conversion medium was 3.0% glucose, 1.5% starch, 1.25% soybean flour, wheat germ.
0.8%, sodium chloride 0.125% and calcium carbonate 0.1
The one having a composition of 5% was used. Before sterilization, pH 7.0
It was adjusted to and used. 20 media for each of the above precultures
Five 100 ml Erlenmeyer flasks into which 100 ml had been dispensed were sterilized at 120 ° C for 30 minutes, and the genus Phialophora PF1083 (FERM
1 platinum loop of the slant agar culture of P-12281) was inoculated and shake-cultured at 26 ° C. for 2 days to prepare a preculture liquid. Next, 500 ml Erlenmeyer flasks, each containing 100 ml of the above conversion medium, were dispensed.
The book is sterilized at 120 ° C for 30 minutes, and in this, in the formula (III), R ¹ is represented by a propionyl group, R ² is represented by a hydrogen atom, R ³ is represented by a hydroxyl group, and R ⁵ is a propionyl group. The compound (1) (3 "-O-methylmidecamycin A ₁ ) 393 represented by
After adding 22.5 ml of a methanol solution of mg to each of the Erlenmeyer flasks in an amount of 1.5 ml, each of the preculture liquids was added to each of the same 5 5
Each of them was inoculated with each of the cells and cultured at 26 ° C. for 10 days with shaking. After the completion of the culture, centrifugation was performed at 3000 rpm for 10 minutes to obtain 1.1 L of a transparent culture solution, and solid components such as bacterial cells were removed. 900 ml of water was added to the solid content, and the mixture was stirred and then centrifuged, and the obtained washing liquid was combined with the transparent culture medium. After adjusting this to pH 9,
The conversion substance was extracted twice with 1.5 L of ethyl acetate and 1.0 L, and the ethyl acetate layer was dried over anhydrous sodium sulfate and then filtered. The residue obtained by concentrating the filtrate under reduced pressure is used for preparative T
Purification by LC (developing system: chloroform-methanol-concentrated aqueous ammonia (400: 40: 1)) yielded 102 mg of compound (2). At this time, 63 mg of compound (1) was recovered. Physicochemical properties of compound (2) (1) Color and shape: colorless solid (2) Molecular formula: C ₃₉ H ₆₅ NO ₁₄ (3) Mass spectrum (EIMS): m / z 771 (M) ⁺ (4) Specific rotation Degree: [α] _D ¹⁷ -79 ° (c1.0, CH ₃ OH) (5) Melting point: Melting at 111-113 ° C without showing clear melting point (6) ¹ H NMR spectrum (400MHz, CDCl ₃ ) δ
(ppm): 2.22 (d, 2-H), 2.70 (dd, 2-H), 3.79 (br d, 3
-H), 3.09 (br d, 4-H), 3.54 (s, 4-OCH ₃ ), 4.11 (br d,
5-H), 0.95 (br ddd, 7-H), 1.60 (br dt, 7-H), 1.90 (m,
8-H), 4.10 (dd, 9-H), 5.68 (dd, 10-H), 6.26 (dd, 11-
H), 6.03 (br dd, 12-H), 5.61 (ddd, 13-H), 2.12 (dt, 1
4-H), 2.51 (br dt, 14-H), 5.29 (ddq, 15-H), 1.30 (d,
16-H ₃ ), 2.34 (br dd, 17-H), 2.87 (br dd, 17-H), 9.80
(br s, 18-H), 0.99 (d, 19-H ₃ ), 4.58 (d, 1'-H), 3.22
(dd, 2'-H), 2.42 (t, 3'-H), 3.45 (t, 4'-H), 3.28 (dq,
5'-H), 1.19 (d , 6'-H 3), 2.57 (s, 3'-N (CH 3) 2), 4.93
(d, 1 "-H), 1.66 (dd, 2" -Hax), 2.29 (d, 2 "-Heq), 4.72
(d, 4 "-H), 4.54 (dq, 5" -H), 1.07 (d, 6 "-H ₃ ), 1.10 (s,
7 "-H ₃ ), 3.26 (s, 3" -OCH ₃ ), 2.42 (apparent q, 4 "-OCOC
H ₂ CH ₃ ), 2.43 (apparentq, 4 "-OCOC H ₂ CH ₃ ), 1.17 (t, 4"-
OCOCH ₂ C H ₃ )

Example 3 Compound (3) (in the general formula (I), R ¹ is propioni
Group, R ² is a hydrogen atom, and R ³ is a hydroxyl group.
And R ⁴ is represented by a hydrogen atom and R ⁵ is represented by a hydrogen atom.
Compound) (3 "-O-methylmidecamycin M ₁ ) production method As a medium for preculture, starch 2.0%, glucose 1.0%, polypeptone 0.5%, wheat germ 0.6%, yeast extract 0.3%, soybean meal It was used by adjusting the pH to 7.0 before sterilization, using 0.2% calcium carbonate 0.2% composition, and sterilizing three 100 ml Erlenmeyer flasks into which 20 ml of this medium was dispensed, at 120 ° C for 30 minutes, Frozen seeds of Mucor Spinescence IAM 6071 strain in this Erlenmeyer flask 1.0 ml
Was inoculated and shake-cultured at 26 ° C. for 24 hours to prepare a preculture liquid. Glucose 1.8 was then used as the medium for microbial conversion.
%, Starch 0.9%, soybean meal 1.25%, wheat germ 0.8%, sodium chloride 0.125%, calcium carbonate 0.15%, and adjusted to pH 7.0 before sterilization before use. Seven 500 ml Erlenmeyer flasks into which 100 ml of each of this medium were dispensed were sterilized at 120 ° C for 30 minutes, and in this formula (III), R ¹ is represented by a propionyl group and R ² is represented by a hydrogen atom. , R ³ is a hydroxyl group and R ⁵ is a propionyl group (1) (3 "-O-methylmidecamycin A ₁ ) 88
10.5 ml of a methanol solution of mg was added to each Erlenmeyer flask at 1.5 ml. Next, 5.0 ml of each preculture liquid of the IAM 6071 strain was inoculated, and shake culture was carried out at 26 ° C. for 8 days to perform microbial conversion. After the culture was completed, the culture solution was adjusted to pH 9, and then 600 ml of ethyl acetate was added. The mixture was shaken vigorously and then centrifuged at 3500 rpm for 10 minutes to separate the ethyl acetate layer. 600 ml of ethyl acetate was added to the removed solids such as bacterial cells and the aqueous layer, and the mixture was vigorously shaken again and then centrifuged at 3500 rpm for 10 minutes, and the obtained ethyl acetate layer was combined with the above organic layer. The ethyl acetate layer was dried over anhydrous sodium sulfate and then filtered. The residue obtained by concentrating the filtrate under reduced pressure was purified by preparative TLC (developing system: chloroform-methanol-concentrated aqueous ammonia (100: 10: 1)) to obtain 32 mg of compound (3). At this time, 24 mg of compound (1) was recovered. Physicochemical properties of compound (3) (1) Color and shape: colorless solid (2) Molecular formula: C ₃₉ H ₆₅ NO ₁₄ (3) Mass spectrum (EIMS): m / z 771 (M) ⁺ (4) Specific rotation Degree: [α] _D ¹⁷ -56 ° (c1.0, CH ₃ OH) (5) Melting point: Melting at 120 to 122 ° C without showing clear melting point (6) ¹ H NMR spectrum (400MHz, CDCl ₃ ) δ
(ppm): 2.24 (br d, 2-H), 2.76 (dd, 2-H), 5.14 (br
d, 3-H), 3.26 (br d, 4-H), 3.58 (s, 4-OCH ₃ ), 3.88 (br
d, 5-H), 0.92 (br ddd, 7-H), 1.54 (br dt, 7-H), 1.8
9 (m, 8-H), 4.07 (dd, 9-H), 5.61 (dd, 10-H), 6.67 (dd,
11-H), 6.08 (br dd, 12-H), 5.79 (ddd, 13-H), 2.15 (d
t, 14-H), 2.46 (br dt, 14-H), 5.03 (ddq, 15-H), 1.26
(d, 16-H ₃ ), 2.32 (br dd, 17-H), 2.86 (br dd, 17-H),
9.63 (br s, 18-H), 0.98 (d, 19-H ₃ ), 2.51 (dq, 3-OCOC H ₂
CH ₃ ), 2.65 (dq, 3-OCOC H ₂ CH ₃ ), 1.22 (t, 3-OCOCH ₂ C H ₃ ),
4.51 (d, 1'-H), 3.21 (dd, 2'-H), 2.39 (t, 3'-H), 3.4
4 (t, 4'-H), 3.27 (dq, 5'-H), 1.16 (d, 6'-H ₃ ), 2.55
(s, 3'-N (CH ₃ ) ₂ ), 4.88 (d, 1 "-H), 1.57 (dd, 2" -Hax),
2.23 (d, 2 "-Heq), 3.01 (br t, 4" -H), 4.18 (dq, 5 "-H),
1.23 (d, 6 "-H ₃ ), 1.22 (s, 7" -H ₃ ), 3.22 (s, 3 "-OCH ₃ )

Example 4 Compound (4) (in the general formula (I), R ¹ is a hydrogen atom)
Represented, R ² is represented by hydrogen atom, R ³ is represented by a hydroxyl group,
A compound in which R ⁴ is a hydrogen atom and R ⁵ is a hydrogen atom.
(3) -O-methylleucomycin V) as a medium for pre-culturing, the medium used in Example 3 was used and adjusted to pH 7.0 before sterilization. By the method described in 1.
A preculture liquid of Spinescence IAM 6071 strain was prepared. Then, the medium used in Example 3 was used as the medium for microbial conversion, and the medium was adjusted to pH 7.0 before sterilization and used. Seven 500 ml Erlenmeyer flasks into which 100 ml each of this medium were dispensed were sterilized at 120 ° C for 30 minutes, and in this formula (IV), R ² is represented by hydrogen atom and R ³ is represented by hydroxyl group. ,
Compound (2) in which R ⁵ represents a propionyl group (2) (3 "-O-methylleucomycin A ₇ ) 82 mg in methanol solution 10.5
1.5 ml was added to each Erlenmeyer flask. Then, 5.0 ml of each preculture liquid of the IAM 6071 strain was inoculated, and shake culture was performed at 26 ° C. for 9 days to perform microbial conversion. After the culture was completed, the culture solution was adjusted to pH 9, and then 600 ml of ethyl acetate was added. After shaking the mixture vigorously, 3
The mixture was centrifuged at 500 rpm for 10 minutes, and the ethyl acetate layer was collected. Ethyl acetate 6 was added to the solid content of the removed cells and the aqueous layer.
After adding 00 ml and shaking vigorously again, the mixture was centrifuged at 3500 rpm for 10 minutes, and the obtained ethyl acetate layer was combined with the above organic layer. The ethyl acetate layer was dried over anhydrous sodium sulfate and then filtered. The residue obtained by concentrating the filtrate under reduced pressure was purified by preparative TLC (developing system: chloroform-methanol-concentrated aqueous ammonia (100: 10: 1)) to obtain 17 mg of compound (4). At this time, 14 mg of compound (2) was recovered. Physicochemical properties of compound (4) (1) Color and shape: colorless solid (2) Molecular formula: C ₃₆ H ₆₁ NO ₁₃ (3) Mass spectrum (EIMS): m / z 715 (M) ⁺ (4) Specific rotation Degree: [α] _D ¹⁷ -74 ° (c1.0, CH ₃ OH) (5) Melting point: Melting at 117 to 122 ° C without showing clear melting point (6) ¹ H NMR spectrum (400MHz, CDCl ₃ ) δ
(ppm): 2.23 (d, 2-H), 2.70 (dd, 2-H), 3.80 (br d, 3
-H), 3.10 (br d, 4-H), 3.55 (s, 4-OCH ₃ ), 4.11 (br d,
5-H), 0.95 (br ddd, 7-H), 1.60 (br dt, 7-H), 1.91 (m,
8-H), 4.11 (dd, 9-H), 5.69 (dd, 10-H), 6.27 (dd, 11-
H), 6.04 (br dd, 12-H), 5.61 (ddd, 13-H), 2.12 (dt, 1
4-H), 2.51 (br dt, 14-H), 5.29 (ddq, 15-H), 1.31 (d,
16-H ₃ ), 2.34 (br dd, 17-H), 2.88 (br dd, 17-H), 9.80
(br s, 18-H), 0.99 (d, 19-H ₃ ), 4.58 (d, 1'-H), 3.23
(dd, 2'-H), 2.40 (t, 3'-H), 3.44 (t, 4'-H), 3.26 (dq,
5'-H), 1.19 (d , 6'-H 3), 2.56 (s, 3'-N (CH 3) 2), 4.89
(d, 1 "-H), 1.57 (dd, 2" -Hax), 2.24 (d, 2 "-Heq), 3.01
(br t, 4 "-H), 4.18 (dq, 5" -H), 1.23 (d, 6 "-H ₃ ), 1.22
_{(s, 7 "-H 3)} , 3.22 (s, 3" -OCH 3)

Example 5Compound (5) (in the general formula (I), R ¹ is propioni
Group, R ² is a hydrogen atom, and R ³ is acetoxy.
A group, R ⁴ is a hydrogen atom, R ⁵ is propionyl
Compounds represented by groups) (9-O-acetyl-3 "-O-methylmide
Method for producing kamycin A ₁ ) In formula (III), R¹Is represented by a propionyl group, R²
Is represented by a hydrogen atom, R ³Is represented by a hydroxyl group, R^FiveIs propi
Compound (1) represented by onyl group (3 "-O-methylmideca
Mycin A₁) To 1.5 ml of 30 mg anhydrous toluene solution,
Add 13 μl of water pyridine and 11 μl of acetyl chloride sequentially.
Then, the mixture was stirred at room temperature for 1 hour. Triethylamine 19 μl
After adding, the mixture was extracted with 15 ml of ethyl acetate. Acetic acid
After washing the ethyl layer twice with 15 ml of water, the ethyl acetate layer was removed.
After drying over anhydrous sodium sulfate, this was filtered. Reduce filtrate
The residue obtained by pressure concentration is used for preparative TLC (development system: black).
The compound was purified with Loform-methanol (12: 1))
(5) 18 mg was obtained. Physicochemical properties of compound (5) (1) Color and shape: colorless solid (2) molecular formula: C₄₄H₇₁NO₁₆ (3) Mass spectrum (EIMS): m / z 869 (M)⁺ (4) Specific rotation: [α]_D ^{twenty four} -60 ° (c1.0, CH₃OH) (5) Melting point: No clear melting point at 118-121 ° C
Melting (6)¹1 H NMR spectrum (400MHz, CDCl₃) δ
(ppm): 2.26 (br d, 2-H), 2.74 (dd, 2-H), 5.12 (br
d, 3-H), 3.25 (br d, 4-H), 3.57 (s, 4-OCH₃), 3.93 (br
 d, 5-H), 0.93 (br ddd, 7-H), 1.57 (br dt, 7-H), 5.0
8 (dd, 9-H), 5.57 (dd, 10-H), 6.74 (dd, 11-H), 6.09 (b
r dd, 12-H), 5.88 (ddd, 13-H), 2.17 (dt, 14-H), 4.98
(ddq, 15-H), 1.26 (d, 16-H₃), 2.58 (br dd, 17-H), 2.
83 (br dd, 17-H), 9.65 (br s, 18-H), 0.96 (d, 19-H₃),
 2.51 (dq, 3-OCOCH ₂CH₃), 2.67 (dq, 3-OCOCH ₂CH₃), 1.21
(t, 3-OCOCH₂CH ₃ ), 2.02 (s, 9-OCOCH₃), 4.51 (d, 1'-
H), 3.20 (dd, 2'-H), 2.41 (t, 3'-H), 3.45 (t, 4'-H),
3.28 (dq, 5'-H), 1.16 (d, 6'-H ₃), 2.57 (s, 3'-N (C
H₃)₂), 4.93 (d, 1 "-H), 1.67 (dd, 2" -Hax), 2.30 (d, 2 "
-Heq), 4.72 (d, 4 "-H), 4.54 (dq, 5" -H), 1.08 (d, 6 "-H
₃), 1.10 (s, 7 "-H₃), 3.26 (s, 3 "-OCH₃), 2.43 (apparen
t q, 4 "-OCOCH ₂CH₃), 2.44 (apparent q, 4 "-OCOCH ₂C
H ₃), 1.18 (t, 4 "-OCOCH₂CH ₃ )

Example 6 Compound (6) (in the general formula (I), R ¹ is a hydrogen atom)
R ² is a hydrogen atom and R ³ is an acetoxy group.
R ⁴ is a hydrogen atom and R ⁵ is a propionyl group.
Compound) (9-O-Acetyl-3 "-O-methylleucomay
Compound (2) in which R ² is represented by a hydrogen atom, R ³ is represented by a hydroxyl group, and R ⁵ is represented by a propionyl group in the formula (IV ) for producing Syn A ₇ ).
To (3 "-O- methyl leucomycin A ₇₎ 28 mg of anhydrous toluene 1.4 ml, added sequentially anhydrous pyridine 12 [mu] l and acetyl chloride 9.1Myueru, was added to stirred 2 hours at room temperature. Triethylamine 17 [mu] l, The mixture was extracted with 10 ml of ethyl acetate, the ethyl acetate layer was washed twice with 10 ml of water, the ethyl acetate layer was dried over anhydrous sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. Preparative T
Purification by LC (developing system: chloroform-methanol-concentrated aqueous ammonia (240: 20: 1)) gave 15 mg of compound (6). Physicochemical properties of compound (6) (1) Color and shape: colorless solid (2) Molecular formula: C ₄₁ H ₆₇ NO ₁₅ (3) Mass spectrum (EIMS): m / z 813 (M) ⁺ (4) Specific rotation Degree: [α] _D ²⁵ -68 ° (c1.0, CH ₃ OH) (5) Melting point: Melting at 110-113 ° C without showing clear melting point (6) ¹ H NMR spectrum (400MHz, CDCl ₃ ) δ
(ppm): 2.22 (d, 2-H), 2.71 (dd, 2-H), 3.79 (br d, 3
-H), 3.09 (br d, 4-H), 3.54 (s, 4-OCH ₃ ), 4.14 (br d,
5-H), 0.98 (br ddd, 7-H), 1.62 (br dt, 7-H), 5.18 (d
d, 9-H), 5.60 (dd, 10-H), 6.40 (dd, 11-H), 6.03 (br d
d, 12-H), 5.66 (ddd, 13-H), 2.12 (dt, 14-H), 2.51 (br
dt, 14-H), 5.29 (ddq, 15-H), 1.31 (d, 16-H ₃ ), 2.46
(br dd, 17-H), 2.83 (br dd, 17-H), 9.81 (br s, 18-
H), 0.99 (d, 19-H ₃ ), 2.00 (s, 9-OCOCH ₃ ), 4.57 (d, 1'-
H), 3.21 (dd, 2'-H), 2.42 (t, 3'-H), 3.45 (t, 4'-H),
3.28 (dq, 5'-H), 1.20 (d, 6'-H ₃ ), 2.57 (s, 3'-N (C
H ₃ ) ₂ ), 4.93 (d, 1 "-H), 1.66 (dd, 2" -Hax), 2.30 (d, 2 "
-Heq), 4.72 (d, 4 "-H), 4.54 (dq, 5" -H), 1.08 (d, 6 "-H
₃ ), 1.10 (s, 7 "-H ₃ ), 3.26 (s, 3" -OCH ₃ ), 2.43 (apparen
tq, 4 "-OCOC H ₂ CH ₃ ), 2.44 (apparent q, 4" -OCOC H ₂ C
H ₃ ), 1.18 (t, 4 "-OCOCH ₂ C H ₃ )

[0038]

INDUSTRIAL APPLICABILITY The compounds (1), (2), (3) and (4) represented by the general formula (I) obtained in the present invention are themselves suitable for clinically important Gram-positive bacteria and mycoplasma. It has a strong antibacterial effect. Compounds (1) and (2)
The in vitro antibacterial activity of is shown in Table 1, and the same activities of the compounds (3) and (4) are shown in Table 3.

First, the 9th position is sp ³ carbon, and at the same time,
Compounds (1) and (2) in which the tertiary hydroxyl group at the 3 "position is methylated and the hydroxyl group at the 4" position is acylated
Is a compound in which the corresponding tertiary hydroxyl group at the 3 "position is free, that is, midecamycin A ₁ (medemycin, MDM) and leucomycin A ₇ (LM-A ₇ ) (Journal of Antibiotics, Ser. A, 20 (4), 234 (1967)), and the antibacterial activity in vitro generally doubled, and Streptococcus pneumoniae, which is one of the major causative bacteria of upper respiratory tract infections, is of clinical importance. The antibacterial activity against E. coli was significantly enhanced.

Then, in vitro of the compound obtained in the present invention
As a reference value, rokitamycin (RKM) was used to compare the antibacterial activity of the drug with other macrolide antibacterial agents with superior antibacterial activity.
(Journal of Antibiotics, 34 (8), 100
1 (1981)) and clarithromycin (CAM) are shown in Table 2 (simultaneously measured with compound (2)). The MIC of the compound (2) of the present invention shows that some of the Gram-negative bacteria ( Branhamella) are compared with rokitamycin, which belongs to the class having the strongest in vitro antibacterial activity among commercially available 16-membered macrolide antibiotics (pharmaceuticals). All were good except for catarrhalis ). Furthermore, the compound (2) has a resistance St that is higher than that of clarithromycin, which is a 14-membered new macrolide.
Clearly superior to aphylococcus , Branhame
Enterococcus, although inferior to lla catarrhalis
It was equivalent to or slightly superior to faecalis and Haemophilus influenzae . That is, it was revealed that the compound (2) of the present invention belongs to the class of the derivative having the best antibacterial activity among all macrolides with respect to Gram-positive bacteria.

Next, in addition to the compounds (3) and (4), for comparison, midecamycin M ₁ (MDM-M ₁ ) (Journal of Bacteriology, 174 (15), 5141 (1992), Japanese Patent Laid-Open Publication No. Sho. Four
8-10288) and leucomycin V (LM-V) (Journal
The antibacterial activity of Of Antibiotics, 28 (6), 401 (1975)) is shown in Table 3. 9th place is sp ³ carbon, and at the same time
Compounds (3) and (4) in which the tertiary hydroxyl group at the 3 "position is methylated and the free hydroxyl group at the 4" position have a strong antibacterial activity, and their MICs are Do
Compared to compounds in which the tertiary hydroxyl group at the 3 "-position is free, that is, midecamycin M ₁ and leucomycin V, there is an overall improvement of 2-3 tubes or more.

In general, in order for oral antibacterial agents to give excellent clinical results, it is not enough that the antibacterial activity in vitro is simply superior, and the unique ADME and actual pharmacokinetics of the drug show clinical effects. Needless to say, it has a considerable effect on By the way, even 16-membered macrolide antibacterial agents, miocamycin and rokitamycin, which have superior clinical therapeutic effects compared with natural compounds, undergo complicated metabolism after oral administration to the living body, and are metabolized due to species differences in the living body. It is reported that the acyl group of the neutral sugar moiety of the administered drug is cleaved over time, and the antibacterial activity of the drug body is gradually diminished, although the pattern of the drug is different (Pharmaceutical Journal, 102 (8), 781 (1982), 31st Annual Meeting of the Japanese Society of Chemotherapy New Drug Symposium IV TMS-19-Q, P.109).

To date, the tertiary hydroxyl group at the 3 "position has been methylated, and at the same time, the hydroxyl group at the 4" position has been acylated.
Although no report has been made on the metabolism of a membered ring macrolide derivative, it was hypothesized that the compounds represented by formulas (III) and (IV) also bound to the 4 "-position hydroxyl group reported in myocamycin and rokitamycin. If the metabolism that cleaves the acyl group acts similarly, it is assumed that the compounds represented by the formulas (V) and (VI) are produced as one of the metabolites. (2)
The neutral sugar moiety is similar to other 16-membered macrolide derivatives.
Assuming that it undergoes the metabolism of 4 "deacylation, the in vitro antibacterial activity of compound (2), which is an unmetabolized drug substance, is somewhat superior to that of rokitamycin. The antibacterial activity of compound (4), which is assumed to be the final metabolite of L., is about 4 to 8 times better than that of leucomycin V, which is the final metabolite of rokitamycin. It is nothing more than suggesting the outstanding therapeutic effect on infections of .. If compound (2) is not subject to such metabolism, the excellent antibacterial activity of (2) is maintained for a relatively long time in vivo. It is assumed that there will be no problems.

On the other hand, the in vitro antibacterial activity of the compounds (5) and (6) in which the 9-position hydroxyl group of the lactone ring of the compounds (1) and (2) is acetylated is (1) and (). Although it is slightly lower than that of 2), it has a strong antibacterial activity.

[0045] As described so far, in the midecamycins acids and leucomycin acids 16-membered macrolide derivatives, in by methylating the tertiary hydroxyl group of 3 'position
In vitro antibacterial activity was generally improved, especially Streptococcu
It was revealed for the first time that the antibacterial activity against S. pneumoniae was significantly enhanced. That is, by developing a synthetic strategy of a derivative constructed on the basis of the chemical structure of L-cladinose, which is a constituent sugar of erythromycin, based on the knowledge obtained from the structure-activity relationship of the 16-membered ring macrolide, the general formula ( Various derivatives having excellent antibacterial activity represented by I) could be created.

[Table 1]

[Table 2]

[Table 3]

─────────────────────────────────────────────────── ───

[Procedure amendment]

[Submission date] September 30, 1994

[Procedure Amendment 1]

[Document name to be amended] Statement

[Name of item to be corrected] 0045

[Correction method] Change

[Correction content]

[0045] As described so far, in the midecamycins acids and leucomycin acids 16-membered macrolide derivatives, in by methylating the tertiary hydroxyl group of 3 'position
In vitro antibacterial activity was generally improved, especially Streptococcu
It was revealed for the first time that the antibacterial activity against S. pneumoniae was significantly enhanced. That is, by developing a synthetic strategy of a derivative constructed on the basis of the chemical structure of L-cladinose, which is a constituent sugar of erythromycin, based on the knowledge obtained from the structure-activity relationship of the 16-membered ring macrolide, the general formula ( Various derivatives having excellent antibacterial activity represented by I) could be created.

[Table 1]

[Table 2]

[Table 3]

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Akira Shimizu 760 Shimooka Town, Kohoku Ward, Yokohama City, Kanagawa Prefecture Meiji Seika Co., Ltd., Pharmaceutical Research Laboratory (72) Inventor Kenichi Kurihara 760 Shimooka Town, Kohoku Ward, Yokohama City, Kanagawa Prefecture Meiji Seika Co., Ltd. Pharmaceutical Research Laboratory (72) Inventor Seiji Shibahara, 760 Shimooka-cho, Kohoku-ku, Yokohama-shi, Kanagawa Meiji Seika Chemical Research Institute

Claims (7)

[Claims] 1. The following formula (I): [In the formula, R ¹ is a hydrogen atom or a group of the formula COR ⁶ (wherein R ⁶ is a linear alkyl group having 1 to 3 carbon atoms), R ² is a hydrogen atom, a substituted or unsubstituted hydroxyl group. And R ³ is a hydrogen atom, a substituted or unsubstituted hydroxyl group,
However, one of R ² and R ³ is a hydrogen atom, R ⁴ is a hydrogen atom or a group of the formula COR ⁶ (provided that R ⁶ has the same meaning as described above), R ⁵ is a hydrogen atom, and is substituted. Or a non-substituted linear or branched aliphatic acyl group having 1 to 10 carbon atoms, or an aromatic acyl group], or a pharmaceutically acceptable salt thereof. 2. In the formula (I) of claim 1, R ¹ is a propionyl group, R ² is a hydrogen atom, R ³ is a hydroxyl group, and R ⁴ is a hydrogen atom, A compound in which R ⁵ is a propionyl group, or a pharmaceutically acceptable salt thereof. 3. In formula (I) of claim 1, R ¹ is a hydrogen atom, R ² is a hydrogen atom, R ³ is a hydroxyl group, and R ⁴ is a hydrogen atom, A compound in which R ⁵ is a propionyl group, or a pharmaceutically acceptable salt thereof. 4. In formula (I) of claim 1, R ¹ is a propionyl group, R ² is a hydrogen atom, R ³ is a hydroxyl group, and R ⁴ is a hydrogen atom, A compound in which R ⁵ is a hydrogen atom, or a pharmaceutically acceptable salt thereof. 5. In the formula (I) of claim 1, R ¹ is a hydrogen atom, R ² is a hydrogen atom, R ³ is a hydroxyl group, and R ⁴ is a hydrogen atom, A compound in which R ⁵ is a hydrogen atom, or a pharmaceutically acceptable salt thereof. 6. In the formula (I) of claim 1, R ¹ is a propionyl group, R ² is a hydrogen atom, R ³ is an acetoxy group, and R ⁴ is a hydrogen atom. , A compound in which R ⁵ is a propionyl group, or a pharmaceutically acceptable salt thereof. 7. In the formula (I) of claim 1, R ¹ is a hydrogen atom, R ² is a hydrogen atom, R ³ is an acetoxy group, and R ⁴ is a hydrogen atom. , A compound in which R ⁵ is a propionyl group, or a pharmaceutically acceptable salt thereof.