JPH07309889A - New 16-membered cyclic macrolide derivative and its new production - Google Patents

Abstract

PURPOSE:To obtain the subject new derivative having highly excellent antibacterial activity on Gram-positive bacteria, etc. CONSTITUTION:The objective compound of formula I (R<1> and R<2> each is H or an OH-modifying substituent; R<2> is a l-4C alkyl), e.g. a compound (where, R<1> is H, R<2> is H, and R<3> is n-propyl group). The compound of formula I is obtained, by using, as starting material, a naturally occurring 16-membered cyclic macrolide antibiotic (salt) of formula II through a compound (salt) of formula III (R<4> and R<5> each is an OH-modifying substituent; R<6> is H or an OH-protecting substituent).

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to novel 16-membered ring macrolide derivatives effective against Gram-positive bacteria and a novel method for producing them.

[0002]

2. Description of the Related Art At present, groups in various countries are actively conducting derivative research on 16-membered macrolide antibiotics for the purpose of improving their clinical utility. Certain of these derivatives were synthesized in an attempt to improve in vitro antibacterial activity and / or pharmacokinetics by acylating a specific hydroxyl group. However, the mainstream of recent research on derivatives has been the introduction of substituted amino groups into 16-membered ring lactones (Journal of Antibiotics, 44 (4), 448 (1991)), or deoxylation of specific hydroxyl groups ( Journal of Antibiotics, 45
(1), 144 (1992)) or the alkylation of hydroxyl groups, which has a pharmacokinetic significance.

The inventors of the present invention conducted derivative research based on the idea of the chemical structure of L-cladinose, which is one of the constituent sugars of erythromycin, and found that the 9-position of the lactone ring was the sp ³ carbon and the neutral sugar moiety. The hydroxyl group at the 3 "position is methylated 1
A 6-membered ring macrolide derivative (the 4 "position may be a free hydroxyl group or an acylated hydroxyl group) is prepared by way of a glycosylation reaction, and they have excellent antibacterial activity. On the other hand, regarding the synthesis and antibacterial activity of the 16-membered ring macrolide derivative in which the 9-position is sp ² carbon and the hydroxyl group at the 3 "-position is methylated, There is already a report by Tatsuta et al. Prior to the application by the present inventors (Japanese Patent Application No. 5-3545) (Chemistry Letters, 769 (1977)).

By the way, 16-membered macrolide derivatives in which the 9-position of the lactone ring is sp ³ carbon and the hydroxyl group at the 3 "-position, which is a neutral sugar, is methylated can be roughly classified into two types, one of which is a lactone. The hydroxyl group at the 3-position of the ring is acylated, and the other is the type at which the 3-position hydroxyl group is free.Of these, the former type of derivative does not undergo glycosylation and is purely chemically synthesized. After finding a method for efficient production, the present inventors have already applied for a patent (Japanese Patent Application No. 5-
300686).

On the other hand, a 16-membered ring macrolide derivative in which the hydroxyl group at the 3-position of the lactone ring is acylated is converted by a biochemical technique such as microbial conversion, whereby the acyl bonded to the hydroxyl group at the 3-position. It is known to remove a group (Journal of Fermentation Technology, 57 (6), 519 (1979), JP-A-6-16691). As its application, the 3-position of the lactone ring is acylated,
The 9-position is a free hydroxyl group, and the 3'-position of the neutral sugar moiety is methylated.
The present inventors have already established a technique for selectively removing the acyl group bonded to the hydroxyl group at the position by a biochemical method (Japanese Patent Application No. 5-169418).

Here, a protecting group for the hydroxyl group at the 3-position of the lactone ring of the 16-membered macrolide derivative will be mentioned.
In spiramycins and tylosins, derivatives in which the 3-position hydroxyl group of the lactone ring is protected by an acetal-based substituent having an asymmetric carbon have been reported. However,
Among synthetic intermediates having a platenolide skeleton (lactone ring of leucomycin) other than spiramycins, a compound in which the hydroxyl group at the 3-position of the lactone ring is modified with an acetal-based substituent having an asymmetric carbon is not known.

[0007]

First, although it is a 16-membered ring macrolide with few side effects and drug interactions,
It is expected to find an excellent derivative having an antibacterial activity comparable to that of a 4-membered ring macrolide. On the other hand, a 16-membered macrolide derivative in which the hydroxyl group at the 3-position of the lactone ring is free and the hydroxyl group at the 3 "-position, which is a neutral sugar moiety, is methylated is chemically synthesized purely without going through a glycosylation reaction. No method of preparation has been reported so far regardless of the structure of the 9-position.
Secondly, an invention of a method for preparing the compound in which the 3-position of the lactone ring is a free hydroxyl group by pure synthetic chemistry in the shortest possible step without passing through a glycosylation reaction is expected.

[0008]

Means for Solving the Problems The inventors of the present invention have conducted synthetic chemical research to meet the above-mentioned expectations, and the 3- and 9-positions of the lactone ring are both free hydroxyl groups and neutral sugar moieties. Using natural leucomycins in which the hydroxyl group at the 4 "position is acylated (for example, leucomycin A ₅ ) as a starting material, the hydroxyl group at the 3 position of the lactone ring is protected by an acetal-based substituent having an asymmetric carbon atom. The 3 "hydroxyl group of the lactone ring is free and is a neutral sugar moiety via a synthetic intermediate in which the 3" hydroxyl group is methylthiomethylated.
We succeeded in producing a leucomycin derivative in which the tertiary hydroxyl group at the position was methylated by pure synthetic chemistry without passing through a glycosylation reaction. Moreover, it was found that certain derivatives prepared by using the production method of the present invention, like the 14-membered ring macrolide, remarkably strongly inhibit the growth of clinically important Gram-positive bacteria and the like, and completed the present invention.

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

[Chemical 5]

[In the formula, R ¹ is a substituent for modifying (or protecting) a hydrogen atom or a hydroxyl group, R ² is a substituent for modifying (or protecting) a hydrogen atom or a hydroxyl group, and R ³ is a number of carbon atoms. 1 to 4 straight chain or branched chain alkyl group] or a pharmaceutically acceptable salt thereof.

The gist of the second invention is that the following formula (II)

[Chemical 6]

A naturally-occurring 16-membered macrolide antibiotic represented by the formula: wherein R ³ is a linear or branched alkyl group having 1 to 4 carbon atoms, or a salt thereof is used as a starting material. , The following formula (III)

[Chemical 7]

[In the formula, R ³ is a linear or branched alkyl group having 1 to 4 carbon atoms, R ⁴ is a substituent for modifying (or protecting) a hydroxyl group, and R ⁵ is a modifying group for a hydroxyl group. (Or is a substituent that protects), R ⁶ is a substituent that protects a hydrogen atom or a hydroxyl group], and the compound of the following formula (3) I)

[Chemical 8]

[In the formula, R ¹ is a substituent for modifying (or protecting) a hydrogen atom or a hydroxyl group, R ² is a substituent for modifying (or protecting) a hydrogen atom or a hydroxyl group, and R ³ is a number of carbon atoms. 1 to 4 straight chain or branched chain alkyl group] or a salt thereof, can be prepared by pure synthetic chemistry. The compound represented by the general formula (I) according to the present invention is produced as follows by the method shown in Process Diagram 1.

[0015]

[Chemical 9]

[0016]

[Chemical 10]

Regarding the promising antibacterial agent, a compound in which a methyl group is selectively introduced into a hydroxyl group at the 3 "position of a neutral sugar moiety in a 16-membered ring macrolide derivative is a prior application (Japanese Patent Application No. 169418). On the other hand, for 16-membered ring macrolide compounds, especially leucomycins, it is known that direct alkylation of the hydroxyl group without going through a special synthetic intermediate causes a difficult problem. (Japanese Patent Application No. 5-206731). The present application relates to a compound in which the hydroxyl groups at the 3- and 9-positions of the lactone ring are free and the hydroxyl group at the 4 "-position, which is a neutral sugar moiety, is acylated. The synthetic method in which a methyl group is indirectly introduced to the tertiary hydroxyl group at the 3 "position is described, and the remarkably excellent antibacterial activity of the novel derivative prepared by the production method of the present invention is also described.

Prior to describing the synthetic method, the introduction of a methyl group into the hydroxyl group at the 3 "position, which is the neutral sugar moiety in the 16-membered macrolide derivative, will be described. Regarding the method of introducing a group (Japanese Patent Application No. 5-206731), the present inventors have already applied for a patent, in which a compound in which the hydroxyl group at the 4 "-position of the neutral sugar moiety has already been alkylated is reacted. The methylation was performed as a substrate. On the other hand, in the production process of the present application, it is not necessary to remove and reintroduce the acyl group bonded to the 4 "-position hydroxyl group, so that the same acyl group remains bonded in all stages of the production process. In chemistry, one of the adjacent cis hydroxyl groups is acylated (eg 4 "position) and the other is free (eg 3").
Position), various side reactions are induced when the free hydroxyl group is directly methylated. However, also in the production method of the present invention, the production method of introducing a methyl group into the tertiary hydroxyl group at the 3 "-position was selected via a methylthiomethyl ether synthetic intermediate.

Further, in the present method for introducing a methyl group into a hydroxyl group via a methylthiomethyl ether synthetic intermediate, it is not always necessary to protect the aldehyde group at the 18-position.
The protection of the 3-position hydroxyl group of the lactone ring in the production method of the present invention is achieved by an acetal-based substituent having a mild asymmetric carbon which is inexpensive as a reagent and which is a deprotection condition.
In the process diagram 1, as an example of the production method, a natural 16-membered macrolide antibiotic in which the 9-position of the lactone ring is sp ³ carbon is used as a starting material, but a compound in which the 9-position is a carbonyl group is used. Even when is used as a starting material, it is possible to indirectly introduce a methyl group into the tertiary hydroxyl group at the 3 "position efficiently by the same methodology.

First, among the free hydroxyl groups of the compound represented by the formula (II), three hydroxyl groups other than the 3 "position, that is, the 3 and 9 positions
The same or different substituents are introduced into the hydroxyl groups at the 2'-position and 2'-position to obtain the compound represented by the formula (V). Introduction formula (II)
(Wherein R ³ is a linear or branched alkyl group having 1 to 4 carbon atoms), the 2'-position hydroxyl group of the mycaminose (amino sugar) moiety of the compound is protected by an acetyl group. To obtain a compound represented by the formula (IV) (wherein R ³ is a linear or branched alkyl group having 1 to 4 carbon atoms). For example, leucomycin A ₅ (Journal of Antibiotics, 21 (4), 272 (1968)) (in formula (II),
Compound (1) (where R ³ is a normal propyl group) is reacted with acetic anhydride in anhydrous acetonitrile (Journal of Medicinal Chemistry, 20 (5), 732 (197)
7)) (a compound in which R ³ is a normal propyl group in the formula (IV)) was quantitatively obtained.

Next, a substituent is introduced into the hydroxyl groups at the 3- and 9-positions of the lactone ring of the compound represented by the formula (IV) to give a compound of the formula (V) (wherein R ³ is a straight chain having 1 to 4 carbon atoms). A chain or branched alkyl group, R ⁴ is a substituent that modifies (or protects) a hydroxyl group, and R ⁵ is a substituent that modifies (or protects) a hydroxyl group. . For example, compound (1) is reacted with ethyl vinyl ether in anhydrous methylene chloride in the presence of pyridinium p-toluenesulfonate (PPTS) to give compound (2) (in formula (V), R ³ is a normal propyl group). , R ⁴ is a 1-ethoxyethyl group, and R ⁵ is a 1-ethoxyethyl group) in good yield.

The types of substituents that can be used in the step and the reaction conditions for introducing the substituents are not limited to those described here, and the general protective groups used for hydroxyl groups can be used. Substituent (Theodora W. Gr
eene; Peter GM Wuts. Protective Groups in Organ
ic Synthesis , 2nd ed., Wiley: New York, 1991), as well as the substituents that are difficult to deprotect with respect to the substrate, and include all of their types and reaction conditions for introducing them. . Of these, acetal-based substituents having an asymmetric carbon atom, such as a 1-ethoxyethyl group, a tetrahydrofuranyl group, and a tetrahydropyranyl group, are particularly excellent from the viewpoint of mild deprotection conditions.

By the way, an acetal-based protecting group having an asymmetric carbon, such as a 1-ethoxyethyl group, is attached to the lactone ring.
When introduced at the hydroxyl groups at the 9- and 9-positions, the derivative exists as a mixture of four diastereoisomers while the substituent is introduced. However, these isomers may or may not be separated. Also, when the substituent is regarded as a modifying group for the 3-position hydroxyl group of the lactone ring, these isomers may or may not be separated.

On the other hand, the substituent relating to the hydroxyl group at the 9-position of the lactone ring, that is, R ⁵ does not necessarily have to be the same as R ⁴ .
Specifically, the same substituent, for example, an acetyl group, is introduced into the 9-position and 2'-position hydroxyl groups, and then an acetal-based substituent having an asymmetric carbon atom in the 3-position hydroxyl group of the lactone ring, such as 1-ethoxy. It is also possible to introduce an ethyl group to obtain a compound represented by the formula (V) (see Example 5).

Further, although not shown in the process drawing 1,
The 3-, 9-, and 2'-positions of the compound represented by formula (II)
The same acetal-based substituent for the two free hydroxyl groups,
For example, it is possible to introduce a 1-ethoxyethyl group and use it as a reaction substrate for methylthiomethylation.

Secondly, a key compound, a methylthiomethyl ether synthetic intermediate, is prepared and the 2'-position acetyl group is deprotected. Incidentally, various matters relating to the method for synthesizing methyl thiomethyl ether will be omitted because they have already been described in detail in the prior application (Japanese Patent Application No. 5-300686). First, our research group method (Journal of Antibiotics, 33 (1), 61
(1980)), the 3 "-position hydroxyl group of the compound represented by the formula (V) is methylthiomethylated to give a by-product, and the formula (VI) (in the formula, R ³ has 1 to 4 carbon atoms). Is a linear or branched alkyl group, R ⁴ is a substituent that modifies (or protects) a hydroxyl group, and R ⁵ is a substituent that modifies (or protects) a hydroxyl group) To synthesize.
For example, by reacting compound (2) with dimethyl sulfoxide (DMSO) and acetic anhydride, compound (3) (in formula (VI), R ³ is a normal propyl group, R ⁴ is a 1-ethoxyethyl group, R ^A compound in which ⁵ is a 1-ethoxyethyl group was synthesized. There are many known methods (Theodora W. Greene; Peter) for introducing a methylthiomethyl group into a hydroxyl group.
GM Wuts., Protective Groups in Organic Synthesi
s , 2nd ed., Wiley: New York, 1991), the production method of the present invention does not limit the method of introducing a methylthiomethyl group, and includes all known methods relating to the method of introduction.

Next, the acetyl group bonded to the 2'-position hydroxyl group of the compound represented by the formula (VI) is deprotected to give the compound represented by the formula (VI
I) (in the formula, R ³ is a linear or branched alkyl group having 1 to 4 carbon atoms, R ⁴ is a substituent for modifying (or protecting) a hydroxyl group, and R ⁵ is a modifying group for a hydroxyl group ( Alternatively, a key compound represented by (which is a protecting group), that is, a methylthiomethyl ether synthetic intermediate is quantitatively obtained. For example, by reacting compound (3) in methanol, compound (4) (in formula (VII), R ³ is a normal propyl group, R ⁴ is a 1-ethoxyethyl group, and R ⁵ is 1-ethoxy. A compound which is an ethyl group) was obtained.

Thirdly, the methylthiomethyl group introduced into the tertiary hydroxyl group at the 3 "position, which is the neutral sugar moiety of the key intermediate represented by the formula (VII), is selectively reduced to give the 3" position. The 16-membered ring macrolide derivative in which the tertiary hydroxyl group is methylated is efficiently synthesized. Regarding the methodology for leading a methoxy group by catalytically reducing a methylthiomethylated hydroxyl group and various problems in applying the method to the synthesis of a 16-membered macrolide derivative, there is already a prior application (Japanese Patent Application No. 5-300686). Since it has been described in detail in Section 3, it is omitted. Further, the control of the activity of the metal catalyst in the selective reduction reaction will be omitted as well.

The inventors of the present invention used methyl Raney nickel whose activity was appropriately controlled to methylthiomethylate the double bond and the free aldehyde group of the compound represented by the formula (VII) without undergoing reduction. By chemically converting the tertiary hydroxyl group at the 3 "position into a methoxy group, formula (VIII) (in the formula, R ³ is a linear or branched alkyl group having 1 to 4 carbon atoms, and R ⁴ is a modified hydroxyl group. We have found a substantial preparation method for selectively synthesizing a compound represented by (or protecting) a substituent and R ⁵ is a substituent that modifies (or protects) a hydroxyl group.

Then, after the compound represented by the formula (VIII) is isolated or without isolation, a substituent introduced at the 3-position and / or the 9-position hydroxyl group of the lactone ring of the compound, if necessary. A group under suitable conditions (Theodo
ra W. Greene; Peter GMWuts., Protective Groups
in Organic Synthesis , 2nd ed., Wiley: New York, 199
1) is used for deprotection, and formula (I) (in the formula, R ¹ is a substituent that modifies (or protects) a hydrogen atom or a hydroxyl group, and R ² modifies (or protects) a hydrogen atom or a hydroxyl group. A compound represented by a substituent, R ³ is a linear or branched alkyl group having 1 to 4 carbon atoms) can be obtained in good yield.

For example, the compound (4) is selectively stirred in ethanol with Raney nickel whose activity is moderately controlled at room temperature for a short period of time to selectively produce the compound (5).
(In the formula (VIII), R ³ is a normal propyl group and R ⁴ is
A compound which is a 1-ethoxyethyl group and R ⁵ is a 1-ethoxyethyl group) was obtained. By reacting this with a mixed solvent of 5% aqueous acetic acid: acetonitrile (3: 1) without isolation, compound (6) (in the formula (I), R ¹
Is a hydrogen atom, R ² is a hydrogen atom, and R ³ is a normal propyl group). Certain derivatives of the compound represented by the formula (I) produced as described above are:
By itself, like the 14-membered ring macrolide, it markedly strongly inhibits the development of clinically important Gram-positive bacteria and the like. By the way, the selective reduction reaction proceeds without problems even when R ⁵ is modified (or protected) with a substituent other than acetal, for example, an acyl group such as an acetyl group like the compound (10) (Examples) 9, 10).

In the process diagram 1, when synthesizing the compound represented by the formula (I) from the compound represented by the formula (VII), first, methylthiomethyl ether at the 3 "-position, which is a neutral sugar moiety, is added. After reduction to the methoxy group, the substituents bonded to the 3- and / or 9-position hydroxyl groups of the lactone ring were deprotected. On the other hand, the 3- and / or 9-position was previously deprotected and then the 3 "-position was reduced. The compound represented by the formula (I) can also be produced by carrying out

Further, although not shown in the process drawing 1,
The 3'-position which is a neutral sugar after introducing the same protecting group, for example, an acetal-based substituent to the three free hydroxyl groups at the 3-position, 9-position and 2'-position of the compound represented by the formula (II) It is possible to selectively convert the 3 "-position to a methoxy group after deprotecting the substituents introduced into the three hydroxyl groups when methylthiomethylating the hydroxyl groups of. You may go as.

By the way, for the compound represented by the formula (I) or a salt thereof, a known method for selectively acylating the 9-position or 2'-position hydroxyl group in the presence of a dilute acid (fermentation and Kogyo, 37 (12), 1171 (1979)) or a known method for 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 (19
72), Journal of Antibiotics, 35 (11),
1521 (1982)) or a known method for selectively oxidizing the hydroxyl group at the 9-position (Journal of Antibiotics,
24 (8), 526 (1971)), etc., and a novel useful substance based on the present invention can be produced. The present invention will now be described in detail by way of examples.

In the embodiment described in the present application,
The production method has been described by taking as an example the case where R ³ is a normal propyl group, that is, the case where the acyl side chain bonded to the hydroxyl group at the 4 ″ position which is a neutral sugar is a normal butyryl group. The scope is not limited only to the acyl side chain concerned, it can also be carried out in the case of compounds with any other naturally occurring acyl side chain.

By the way, in Example 13 of the present application, the compound (13) was produced from the compound (6) in one step. However, the production method (13) used when the compound (12) was prepared was used. Can also be easily synthesized.

[0037]

【Example】

Example 1 Compound (2) (in the formula (V), R ³ is normal propene
Represented by a R group, R ⁴ represents a 1-ethoxyethyl group, and R ⁵ represents
Compound (1) (compound represented by formula (IV) in which R ³ represents a normal propyl group) (Journal of Medicinal Chemistry, 20 (5) , 732 (1977)) 1.20 g was dissolved in a mixed solution of 36 ml of methylene chloride and 1.3 ml of ethyl vinyl ether, 488 mg of PPTS was added, and the mixture was reacted at 30 ° C. for 16 hours. The reaction solution was saturated aqueous sodium hydrogen carbonate solution 1
The mixture was gradually added to 50 ml and extracted with 150 ml of methylene chloride.
The methylene chloride layer was added with 5% potassium hydrogen sulfate aqueous solution 150 ml,
The extract was washed successively with 150 ml of saturated aqueous sodium hydrogen carbonate solution and 150 ml of saturated aqueous sodium chloride solution. The methylene chloride layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 1.70 g of the residue, which was subjected to silica gel column chromatography (120 g: hexane-ethyl acetate (1: 1) → (2:
Purification by 3)) yielded 740 mg of compound (2). Physicochemical properties of compound (2) (1) Color and shape: colorless solid (2) Molecular formula: C ₄₉ H ₈₃ NO ₁₇ (3) Mass spectrum (SIMS): m / z 958 (M + H) ⁺ (4) Specific rotation: [α] _D ¹³ -90 ° (c1.0, CHCl ₃ ) (5) Melting point: Melting at 72-75 ℃ without showing clear melting point (6) ¹ H NMR spectrum (400MHz, CDCl ₃ ) δ
(ppm): 3.87 (m, 3-H), 2.88 (br d, 4-H), 3.38 (s, 4-
OCH ₃ ), 3.43 (s, 4-OCH ₃ ), 4.15 (br d, 5-H), 3.90 (dd,
9-H), 4.01 (dd, 9-H), 6.13 (dd, 11-H), 6.17 (dd, 11-
H), 6.19 (dd, 11-H), 6.03 (br dd, 12-H), 6.04 (br dd,
12-H), 5.15 (m, 15-H), 5.23 (m, 15-H), 9.76 (s, 18-
H), 9.77 (s, 18-H), 9.87 (s, 18-H), 4.82 (q, 3-OC H (OC
H ₂ CH ₃ ) CH ₃ ), 4.87 (q, 3-OC H (OCH ₂ CH ₃ ) CH ₃ ), 4.67 (d, 1 '
-H), 4.99 (dd, 2'-H)), 2.05 (s, 2'-OCOCH ₃ ), 2.39 (s,
_{3'-N (CH 3) 2} ), 2.41 (s, 3'-N (CH 3) 2), 5.06 (br d, 1 "-
H), 1.84 (br dd, 2 "-Hax), 2.00 (d, 2" -Heq), 1.12 (s,
3 "-CH ₃ ), 4.62 (d, 4" -H), 4.37 (dq, 5 "-H), 1.69 (tq,
4 "-OCOCH ₂ C H ₂ CH ₃ ), 0.97 (t, 4" -OCOCH ₂ CH ₂ C H ₃ )

Example 2 Compound (3) (in formula (VI), R ³ is normal propene
Represented by a R group, R ⁴ represents a 1-ethoxyethyl group, and R ⁵ represents
Method for producing 1-ethoxyethyl group) Compound (2) (575 mg) was dissolved in a mixed solution of DMSO (17 ml) and acetic anhydride (1.7 ml), and the mixture was reacted at 30 ° C for 24 hours.
The reaction solution was gradually added to 500 ml of toluene and the mixture was mixed with 500 ml of water to 3
Washed twice. The toluene layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a residue of 750 m.
g was purified by silica gel column chromatography (65 g: hexane-ethyl acetate (1: 1)) to give compound (3) 325.
to obtain mg. At this time, 135 mg of compound (2) was recovered. Physicochemical properties of compound (3) (1) Color and shape: colorless solid (2) Molecular formula: C ₅₁ H ₈₇ NO ₁₇ S (3) Mass spectrum (SIMS): m / z 1018 (M + H)
⁺ (4) Specific rotation: [α] _D ¹³ -100 ° (c1.0, CHC
l ₃ ) (5) Melting point: Melting at 59 to 61 ° C. without showing clear melting point (6) ¹ H NMR spectrum (400 MHz, CDCl ₃ ) δ
(ppm): 3.86 (m, 3-H), 2.90 (br d, 4-H), 3.38 (s, 4-
OCH ₃ ), 3.44 (s, 4-OCH ₃ ), 4.18 (br d, 5-H), 3.90 (dd,
9-H), 4.01 (dd, 9-H), 6.14 (dd, 11-H), 6.19 (dd, 11-
H), 6.03 (br dd, 12-H), 6.04 (br dd, 12-H), 5.14 (m,
15-H), 5.20 (m, 15-H), 9.76 (s, 18-H), 9.78 (s, 18-
H), 9.88 (s, 18-H), 4.94 (dd, 2'-H), 3.17 (t, 4'-H),
2.03 (s, 2'-OCOCH ₃ ), 2.42 (s, 3'-N (CH ₃ ) ₂ ), 4.83 (br
d, 1 "-H), 2.26 (br d, 2" -Heq), 1.18 (s, 3 "-CH ₃ ), 1.0
5 (br d, 6 "-H), 4.51 (d, 3" -OC H ₂ SCH ₃ ), 2.20 (s, 3 "-OC
H ₂ SC H ₃ ), 1.69 (tq, 4 "-OCOCH ₂ C H ₂ CH ₃ ), 0.97 (t, 4" -OCOC
H ₂ CH ₂ C H ₃ )

Example 3 Compound (4) (in the formula (VII), R ³ is normal
Represented by a pill group, R ⁴ represents a 1-ethoxyethyl group, R ⁵
( Compound represented by 1-ethoxyethyl group ) 37 mg of compound (3) was dissolved in 1.2 ml of methanol and reacted at 30 ° C. for 16 hours. The reaction liquid was concentrated under reduced pressure, and 36 mg of the obtained residue was purified by preparative TLC (developing system: hexane-ethyl acetate (1: 1)) to obtain 27 mg of compound (4). Physicochemical properties of compound (4) (1) Color and shape: colorless solid (2) Molecular formula: C ₄₉ H ₈₅ NO ₁₆ S (3) Mass spectrum (EIMS): m / z 975 (M) ⁺ (4) ratio Optical rotation: [α] _D ¹⁷ -118 ° (c1.0, CH ₃ O
H) (5) Melting point: Melting at 63 to 66 ° C. without showing clear melting point (6) ¹ H NMR spectrum (400 MHz, CDCl ₃ ) δ
(ppm): 2.82 (dd, 2-H), 3.48 (s, 4-OCH ₃ ), 3.54 (s,
4-OCH ₃ ), 1.86 (m, 8-H), 3.95 (dd, 9-H), 4.05 (dd, 9-
H), 6.18 (dd, 11-H), 6.19 (dd, 11-H), 5.16 (m, 15-H),
5.24 (m, 15-H), 9.76 (s, 18-H), 9.77 (s, 18-H), 9.88
(s, 18-H), 0.99 (d, 19-H ₃ ), 4.80 (q, 3-OC H (OCH ₂ CH ₃ ) C
H ₃ ), 2.54 (s, 3'-N (CH ₃ ) ₂ ), 1.71 (dd, 2 "-Hax), 1.19
(s, 3 "-CH ₃ ), 4.65 (d, 4" -H), 1.07 (d, 6 "-H), 4.52 (d,
3 "-OC H ₂ SCH ₃ ), 4.65 (d, 3" -OC H ₂ SCH ₃ ), 2.18 (s, 3 "-OCH
₂ SC H ₃ ), 2.21 (s, 3 "-OCH ₂ SC H ₃ ), 2.37 (m, 4" -OCOC H ₂ CH ₂
CH ₃ ), 1.69 (tq, 4 "-OCOCH ₂ C H ₂ CH ₃ ), 0.97 (t, 4" -OCOCH ₂
CH ₂ C H ₃ )

Example 4 Compound (6) (in the formula (I), R ¹ represents a hydrogen atom)
R ² is a hydrogen atom and R ³ is a normal propyl group.
(Compound represented) The activity of Raney nickel was controlled at the beginning. That is, 1.3 ml of Raney nickel was washed twice with 2.0 ml of water each time, and then washed with 2.0 ml of acetone three times while suppressing the heat generation to appropriately adjust the activity. Then, it was washed twice with 2.0 ml of ethanol each and used for the reaction. Compound (4) 5
After dissolving 0 mg in 1.3 ml of ethanol, the Raney nickel whose activity was controlled was added to the above solution together with 1.3 ml of ethanol. This was vigorously stirred at room temperature for 20 minutes, the insoluble material was filtered off, and washed twice with 5.0 ml of ethanol each containing 1% (v / v) concentrated aqueous ammonia. The crude compound (5) obtained by combining the filtrate and the washing solution and concentrating under reduced pressure
(A compound represented by the formula (VIII) in which R ³ is a normal propyl group, R ⁴ is a 1-ethoxyethyl group, and R ⁵ is a 1-ethoxyethyl group) 57 mg of a 5% acetic acid aqueous solution 3.
After dissolving in a mixed solution of 8 ml and 1.3 ml of acetonitrile,
The reaction was carried out at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, the obtained residue was dissolved in 10 ml of chloroform, and then the mixture was washed twice with 10 ml of saturated aqueous sodium hydrogen carbonate solution and successively with 10 ml of saturated aqueous sodium chloride solution. The chloroform layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 33 mg of the residue, which was purified by preparative TLC (developing system: toluene-acetone (1: 1)) to give the compound (6 ) 8.0 mg was obtained. Physicochemical properties of compound (6) (1) Color and shape: colorless solid (2) Molecular formula: C ₄₀ H ₆₇ NO ₁₄ (3) Mass spectrum (FDMS): m / z 786 (M + H) ⁺ (4) Specific rotation: [α] _D ¹⁵ -76 ° (c0.9, CH ₃ OH) (5) Melting point: Melting at 100-104 ° C without showing clear melting point (6) ¹ H NMR spectrum (400MHz, CDCl ₃ ) δ
(ppm): 2.22 (br d, 2-H), 2.70 (dd, 2-H), 3.79 (br
d, 3-H), 3.10 (br d, 4-H), 3.54 (s, 4-OCH ₃ ), 4.11 (br
d, 5-H), 1.60 (br dt, 7-H), 1.91 (m, 8-H), 4.10 (dd,
9-H), 5.69 (dd, 10-H), 6.26 (dd, 11-H), 6.04 (br dd,
12-H), 5.61 (ddd, 13-H), 2.12 (dt, 14-H), 5.29 (ddq,
15-H), 1.31 (d, 16-H ₃ ), 2.34 (br dd, 17-H), 2.87 (br
dd, 17-H), 9.80 (s, 18-H), 0.99 (d, 19-H ₃ ), 4.59 (d,
1'-H), 3.23 (dd, 2'-H), 3.46 (t, 4'-H), 3.28 (dq, 5'-
H), 1.20 (d, 6' -H 3), 2.58 (s, 3'-N (CH 3) 2), 4.94 (d,
1 "-H), 1.67 (dd, 2" -Hax), 2.29 (d, 2 "-Heq), 1.11 (s,
3 "-CH ₃ ), 4.72 (d, 4" -H), 4.54 (dq, 5 "-H), 1.08 (d, 6"
-H ₃ ), 3.26 (s, 3 "-OCH ₃ ), 2.39 (m, 4" -OCOC H ₂ CH ₂ CH ₃ ),
1.69 (tq, 4 "-OCOCH ₂ C H ₂ CH ₃ ), 0.96 (t, 4" -OCOCH ₂ CH ₂ C
H ₃ )

Example 5 Compound (8) (in the formula (V), R ³ is normal propene
Represented by a R group, R ⁴ represents a 1-ethoxyethyl group, and R ⁵ represents
Method for producing compound represented by acetyl group) Compound (7) (in formula (V), R ³ is represented by normal propyl group, R ⁴ is represented by hydrogen atom, and R ⁵ is represented by acetyl group. Compound) (Journal of Medicinal Chemistry, 20 (5), 732 (1977)) 2.10 g methylene chloride
After dissolving in a mixed solution of 63 ml and 1.2 ml of ethyl vinyl ether, 923 mg of PPTS was added and reacted at 30 ° C. for 16 hours. 250 ml of saturated aqueous sodium hydrogen carbonate solution
The mixture was gradually added to and extracted with 250 ml of methylene chloride. The methylene chloride layer was washed successively with 250 ml of 5% aqueous potassium hydrogen sulfate solution, 250 ml of saturated aqueous sodium hydrogen carbonate solution and 250 ml of saturated aqueous sodium chloride solution. The methylene chloride layer was concentrated under reduced pressure, and 2.20 g of the residue obtained was subjected to silica gel column chromatography (200 g: hexane-ethyl acetate (2:
Purification by 3)) yielded 1.20 g of compound (8). Physicochemical properties of compound (8) (1) Color and shape: colorless solid (2) Molecular formula: C ₄₇ H ₇₇ NO ₁₇ (3) Mass spectrum (FDMS): m / z 928 (M + H) ⁺ (4) Specific rotation: [α] _D ¹⁹ -90 ° (c1.0, CHCl ₃ ) (5) Melting point: Melting at 80-85 ° C without showing clear melting point (6) ¹ H NMR spectrum (400MHz, CDCl ₃ ) δ
(ppm): 3.88 (m, 3-H), 2.87 (br d, 4-H), 3.36 (s, 4-
OCH ₃ ), 3.43 (s, 4-OCH ₃ ), 4.18 (br d, 5-H), 1.43 (br d
t, 7-H), 1.92 (m, 8-H), 5.23 (dd, 9-H), 5.55 (dd, 10-
H), 5.58 (dd, 10-H), 6.23 (dd, 11-H), 6.34 (dd, 11-
H), 6.02 (br dd, 12-H), 5.65 (ddd, 13-H), 5.69 (ddd, 1
3-H), 2.13 (br dt, 14-H), 5.15 (ddq, 15-H), 1.29 (d,
16-H ₃ ), 9.77 (br s, 18-H), 9.88 (s, 18-H), 0.99 (d, 1
9-H ₃ ), 1.01 (d, 19-H ₃ ), 4.83 (q, 3-OC H (OCH ₂ CH ₃ ) CH ₃ ),
4.89 (q, 3-OC H (OCH ₂ CH ₃ ) CH ₃ ), 3.50 (dq, 3-OCH (OC H ₂ CH
₃ ) CH ₃ ), 3.60 (dq, 3-OCH (OC H ₂ CH ₃ ) CH ₃ ), 1.16 (t, 3-OCH
(OCH ₂ C H ₃ ) CH ₃ ), 1.23 (t, 3-OCH (OCH ₂ C H ₃ ) CH ₃ ), 1.27 (d,
3-OCH (OCH ₂ CH ₃ ) C H ₃ ), 1.28 (d, 3-OCH (OCH ₂ CH ₃ ) C H ₃ ), 4.
66 (d, 1'-H), 4.99 (dd, 2'-H)), 3.28 (t, 4'-H), 1.24
(d, 6'-H ₃ ), 2.02, 2.04, 2.05, 2.07 (4 × s, 9-OCOCH ₃ ,
2'-OCOCH ₃ ), 2.39 (s, 3'-N (CH ₃ ) ₂ ), 2.41 (s, 3'-N (C
H ₃ ) ₂ ), 5.06 (d, 1 "-H), 1.84 (dd, 2" -Hax), 2.01 (dd,
2 "-Heq), 1.12 (s, 3" -CH ₃ ), 4.62 (d, 4 "-H), 1.13 (d,
6 "-H ₃ ), 1.69 (tq, 4" -OCOCH ₂ C H ₂ CH ₃ ), 0.97 (t, 4 "-OCOC
H ₂ CH ₂ C H ₃ )

Example 6Compound (9H) (in formula (VI), R ³ is normal
Represented by a pill group, R ⁴ represents a 1-ethoxyethyl group, R ⁵
Among the compounds represented by acetyl group,
Isomer with higher Rf value in TLC in
(9L) (in formula (VI), R ³ is normal propyl
Group, R ⁴ is represented by a 1-ethoxyethyl group, and R ⁵ is represented by
Of the compounds represented by the cetyl group, different compounds with the same Rf value
Sexual body) manufacturing method Compound (8) 200 mg was added to DMSO 6.0 ml and acetic anhydride 0.60 ml.
After being dissolved in the mixed solution of, the reaction was carried out at 30 ° C. for 40 hours.
The reaction solution was gradually added to 50 ml of toluene, and 50 ml of water was added 3 times.
Washed. After drying the toluene layer with anhydrous sodium sulfate,
It was filtered and the filtrate was concentrated under reduced pressure. Residue obtained 215 m
g with TLC for separation (developing system: hexane-ethyl acetate (1: 1))
32 mg of compound (9H) and compound (9L) 2 after purification
9 mg was obtained. Physicochemical properties of compound (9H) (1) Color and shape: Colorless solid (2) Molecular formula: C₄₉H₈₁NO₁₇S (3) Mass spectrum (SIMS): m / z 988 (M + H)⁺ (4) Rf value in TLC: 0.58 (hexane: acetic acid
Ethyl (1: 1)) (5) Specific rotation: [α]_D ¹⁵ -102 ° (c1.0, CHC
l₃) (6) Melting point: Melting at 68-73 ° C without showing clear melting point.
Melt (7)¹1 H NMR spectrum (400MHz, CDCl₃) δ
(ppm): 3.87 (m, 3-H), 2.88 (br d, 4-H), 3.44 (s, 4-
OCH₃), 4.20 (br d, 5-H), 1.44 (br dt, 7-H), 1.90 (m,
8-H), 5.23 (dd, 9-H), 5.58 (dd, 10-H), 6.34 (dd, 11-
H), 6.02 (br dd, 12-H), 5.65 (ddd, 13-H), 2.13 (dt, 1
4-H), 5.15 (ddq, 15-H), 1.29 (d, 16-H₃), 9.88 (br s, 1
8-H), 1.00 (d, 19-H₃), 4.84 (q, 3-OCH(OCH₂CH₃) CH₃),
3.50 (dq, 3-OCH (OCH ₂CH₃) CH₃), 3.60 (dq, 3-OCH (OCH ₂CH
₃) CH₃), 1.23 (t, 3-OCH (OCH₂CH ₃ ) CH ₃), 1.28 (d, 3-OCH
(OCH₂CH₃) CH ₃ ), 4.65 (d, 1'-H), 4.93 (dd, 2'-H)), 2.7
1 (t, 3'-H), 3.16 (t, 4'-H), 3.29 (dq, 5'-H), 1.19 (d,
6'-H₃), 2.02, 2.03 (2 × s, 9-OCOCH₃, 2'-OCOCH₃), 2.4
1 (s, 3'-N (CH₃)₂), 4.81 (d, 1 "-H), 1.68 (dd, 2" -Hax),
 2.25 (d, 2 "-Heq), 1.17 (s, 3" -CH₃), 4.55 (dq, 5 "-H),
 1.04 (d, 6 "-H₃), 4.51 (d, 3 "-OCH ₂SCH₃), 4.63, 4.64
(2 × d, 4 "-H, 3" -OCH ₂SCH₃), 2.19 (s, 3 "-OCH₂SCH ₃ ),
2.37 (m, 4 "-OCOCH ₂ CH₂CH₃), 1.69 (tq, 4 "-OCOCH₂CH ₂ C
H₃), 0.97 (t, 4 "-OCOCH₂CH₂CH ₃ ) Physicochemical properties of compound (9L) (1) Color and shape: Colorless solid (2) Molecular formula: C₄₉H₈₁NO₁₇S (3) Mass spectrum (SIMS): m / z 988 (M + H)⁺ (4) Rf value in TLC: 0.50 (hexane: acetic acid
Ethyl (1: 1)) (5) Specific rotation: [α]_D ¹⁴ -92 ° (c1.0, CHCl₃) (6) Melting point: Melting at 70-74 ℃ without showing clear melting point.
Melt (7)¹1 H NMR spectrum (400MHz, CDCl₃) δ
(ppm): 1.84 (m, 8-H), 5.56 (dd, 10-H), 6.24 (dd, 11
-H), 6.01 (br dd, 12-H), 5.69 (ddd, 13-H), 2.13 (dt,
14-H), 1.28 (d, 16-H₃), 2.89 (br dd, 17-H), 9.76 (s,
18-H), 0.99 (d, 19-H₃), 4.90 (q, 3-OCH(OCH₂CH₃) CH₃),
 3.48 (dq, 3-OCH (OCH ₂CH₃) CH₃), 3.62 (dq, 3-OCH (OCH ₂CH
₃) CH₃), 1.15 (t, 3-OCH (OCH₂CH ₃ ) CH₃), 1.27 (d, 3-OCH
(OCH₂CH₃) CH ₃ ), 4.54 (d, 1'-H), 4.95 (dd, 2'-H), 2.74
(t, 3'-H), 3.17 (t, 4'-H), 1.19 (d, 6'-H₃), 2.03, 2.
05 (2 × s, 9-OCOCH₃, 2'-OCOCH₃), 2.41 (s, 3'-N (C
H₃)₂), 4.82 (d, 1 "-H), 1.68 (dd, 2" -Hax), 2.24 (dd,
2 "-Heq), 1.17 (s, 3" -CH₃), 4.56 (dq, 5 "-H), 1.04 (d,
6 "-H₃), 4.51 (d, 3 "-OCH ₂SCH₃), 4.63, 4.64 (2 × d, 4 "-
H, 3 "-OCH ₂SCH₃), 2.20 (s, 3 "-OCH₂SCH ₃ ), 2.37 (m, 4 "-
OCOCH ₂ CH₂CH₃), 1.69 (tq, 4 "-OCOCH₂CH ₂ CH₃), 0.97 (t,
4 "-OCOCH₂CH₂CH ₃ )

Example 7 Compound (10H) (in the formula (VII), R ³ is normal
It is represented by a propyl group, and R ⁴ is represented by a 1-ethoxyethyl group.
Of the compounds represented by R ⁵ as an acetyl group (9
Method for producing isomer derived from H) 19 mg of compound (9H) was dissolved in 1.9 ml of methanol and then reacted at 30 ° C. for 16 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue (18 mg) was purified by preparative TLC (developing system: hexane-ethyl acetate (1: 2)) to give compound (10H) 14 m
got g. Physicochemical properties of compound (10H) (1) Color and shape: colorless solid (2) Molecular formula: C ₄₇ H ₇₉ NO ₁₆ S (3) Mass spectrum (SIMS): m / z 946 (M + H) ⁺ (4 ) Rf value in TLC: 0.33 (chloroform:
Methanol (30: 1)) (5) Specific rotation: [α] _D ¹⁶ -90 ° (c1.0, CH ₃ OH) (6) Melting point: Melting at 72 to 75 ° C without showing a clear melting point ( 7) ¹ H NMR spectrum (400MHz, CDCl ₃ ) δ
(ppm): 2.69 (dd, 2-H), 3.93 (m, 3-H), 2.95 (br d,
4-H), 3.55 (s, 4-OCH ₃ ), 4.07 (br d, 5-H), 1.48 (br d
t, 7-H), 1.93 (m, 8-H), 5.26 (dd, 9-H), 5.59 (dd, 10-
H), 6.33 (dd, 11-H), 6.03 (br dd, 12-H), 5.66 (ddd, 1
3-H), 2.15 (dt, 14-H), 5.16 (ddq, 15-H), 1.28 (d, 16-
H ₃ ), 2.73 (br dd 17-H), 9.89 (br s, 18-H), 1.00 (d, 1
9-H ₃ ), 4.82 (q, 3-OC H (OCH ₂ CH ₃ ) CH ₃ ), 3.50 (dq, 3-OCH
(OC H ₂ CH ₃ ) CH ₃ ), 3.60 (dq, 3-OCH (OC H ₂ CH ₃ ) CH ₃ ), 1.23
(t, 3-OCH (OCH ₂ C H ₃ ) CH ₃ ), 1.29 (d, 3-OCH (OCH ₂ CH ₃ ) C
H ₃ ), 2.03 (s, 9-OCOCH ₃ ), 4.56 (d, 1'-H), 3.36 (dd, 2'-
H)), 2.47 (t, 3'-H), 1.21 (d, 6'-H ₃ ), 2.53 (s, 3'-N (C
H ₃ ) ₂ ), 4.88 (d, 1 "-H), 1.71 (dd, 2" -Hax), 2.27 (d, 2 "
-Heq), 1.19 (s, 3 "-CH ₃ ), 4.58 (dq, 5" -H), 1.06 (d, 6 "
-H ₃ ), 4.52 (d, 3 "-OC H ₂ SCH ₃ ), 4.64, 4.65 (2 × d, 4" -H,
3 "-OC H ₂ SCH ₃ ), 2.19 (s, 3" -OCH ₂ SC H ₃ ), 2.37 (m, 4 "-OCO
C H ₂ CH ₂ CH ₃ ), 1.69 (tq, 4 "-OCOCH ₂ C H ₂ CH ₃ ), 0.97 (t, 4"-
OCOCH ₂ CH ₂ C H ₃ )

Example 8 Compound (10 L) (in the formula (VII), R ³ is normal
It is represented by a propyl group, and R ⁴ is represented by a 1-ethoxyethyl group.
Of the compounds represented by R ⁵ as an acetyl group (9
Method for producing isomer derived from L) 20 mg of the compound (9L) was dissolved in 2.0 ml of methanol, and then reacted at 30 ° C for 16 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue (19 mg) was purified by preparative TLC (developing system: hexane-ethyl acetate (1: 2)) to give compound (10 L) 15 m
got g. Physicochemical properties of compound (10 L) (1) Color and shape: Colorless solid (2) Molecular formula: C ₄₇ H ₇₉ NO ₁₆ S (3) Mass spectrum (SIMS): m / z 946 (M + H) ⁺ (4) ) Rf value in TLC: 0.24 (chloroform:
Methanol (30: 1)) (5) Specific rotation: [α] _D ¹⁶ -77 ° (c0.5, CH ₃ OH) (6) Melting point: Melting at 70-72 ° C without showing clear melting point ( 7) ¹ H NMR spectrum (400MHz, CDCl ₃ ) δ
(ppm): 2.83 (dd, 2-H), 3.47 (s, 4-OCH ₃ ), 1.86 (m,
8-H), 5.29 (dd, 9-H), 5.55 (dd, 10-H), 6.21 (dd, 11-
H), 6.02 (br dd, 12-H), 5.66 (ddd, 13-H), 2.13 (dt, 1
4-H), 5.25 (ddq, 15-H), 1.28 (d, 16-H ₃ ), 2.98 (br dd,
17-H), 9.77 (s, 18-H), 0.98 (d, 19-H ₃ ), 4.92 (q, 3-O
C H (OCH ₂ CH ₃ ) CH ₃ ), 3.49 (dq, 3-OCH (OC H ₂ CH ₃ ) CH ₃ ), 3.59
(dq, 3-OCH (OC H ₂ CH ₃ ) CH ₃ ), 1.16 (t, 3-OCH (OCH ₂ C H ₃ ) C
H ₃ ), 1.29 (d, 3-OCH (OCH ₂ CH ₃ ) C H ₃ ), 2.04 (s, 9-OCOC
H ₃ ), 4.42 (d, 1'-H), 3.25 (t, 4'-H), 1.24 (d, 6'-H ₃ ),
2.53 (s, 3'-N (CH ₃ ) ₂ ), 4.87 (d, 1 "-H), 1.70 (dd, 2" -H
ax), 2.26 (d, 2 "-Heq), 1.19 (s, 3" -CH ₃ ), 4.60 (dq, 5 "
-H), 1.06 (d, 6 "-H ₃ ), 4.52 (d, 3" -OC H ₂ SCH ₃ ), 4.65,
4.66 (2 × d, 4 "-H, 3" -OC H ₂ SCH ₃ ), 2.20 (s, 3 "-OCH ₂ SC
H ₃ ), 2.37 (m, 4 "-OCOC H ₂ CH ₂ CH ₃ ), 1.69 (tq, 4" -OCOCH ₂ C H
₂ CH ₃ ), 0.97 (t, 4 "-OCOCH ₂ CH ₂ C H ₃ )

Example 9 Compound (11H) (in the formula (VIII), R ³ is normal
It is represented by a propyl group, and R ⁴ is represented by a 1-ethoxyethyl group.
And R ⁵ is a compound (1
Method for producing isomer derived from 0H) 34 mg of compound (10H) was dissolved in 0.90 ml of ethanol, and then 0.90 ml of Raney nickel was controlled for activity in the same manner as in Example 4, and 0.90 ml of ethanol was added to control the activity. Added to the solution. This was vigorously stirred at room temperature for 40 minutes, then the insoluble matter was filtered off, and washed twice with 4.0 ml of ethanol each containing 1% (v / v) concentrated aqueous ammonia. The filtrate and washings were combined and concentrated under reduced pressure.
The product was purified with (developing system: toluene-acetone (2: 1)) to obtain 3.3 mg of compound (11H). Physicochemical properties of compound (11H) (1) Color and shape: colorless solid (2) Molecular formula: C ₄₆ H ₇₇ NO ₁₆ (3) Mass spectrum (SIMS): m / z 900 (M +
H) ⁺ (4) Rf value in TLC: 0.17 (chloroform:
Methanol (30: 1)) (5) Specific rotation: [α] _D ¹⁷ -73 ° (c0.3, CH ₃ OH) (6) Melting point: Melting at 74-77 ° C without showing clear melting point ( 7) ¹ H NMR spectrum (400MHz, CDCl ₃ ) δ
(ppm): 2.71 (dd, 2-H), 3.92 (m, 3-H), 2.97 (br d,
4-H), 3.56 (s, 4-OCH ₃ ), 4.10 (br d, 5-H), 1.50 (br d
t, 7-H), 1.93 (m, 8-H), 5.26 (dd, 9-H), 5.59 (dd, 10-
H), 6.33 (dd, 11-H), 6.03 (br dd, 12-H), 5.65 (ddd, 1
3-H), 2.15 (dt, 14-H), 5.15 (ddq, 15-H), 1.29 (d, 16-
H ₃ ), 2.72 (br dd 17-H), 9.90 (br s, 18-H), 1.00 (d, 1
9-H ₃ ), 4.83 (q, 3-OC H (OCH ₂ CH ₃ ) CH ₃ ), 3.50 (dq, 3-OCH
(OC H ₂ CH ₃ ) CH ₃ ), 3.59 (dq, 3-OCH (OC H ₂ CH ₃ ) CH ₃ ), 1.23
(t, 3-OCH (OCH ₂ C H ₃ ) CH ₃ ), 1.28 (d, 3-OCH (OCH ₂ CH ₃ ) C
H ₃ ), 2.02 (s, 9-OCOCH ₃ ), 4.57 (d, 1'-H), 2.47 (t, 3'-
H), 2.53 (s, 3'-N (CH ₃ ) ₂ ), 4.89 (d, 1 "-H), 1.64 (dd,
2 "-Hax), 2.27 (d, 2" -Heq), 1.09 (s, 3 "-CH ₃ ), 4.71 (d,
4 "-H), 1.06 (d, 6" -H ₃ ), 3.25 (s, 3 "-OCH ₃ ), 2.38 (m,
4 "-OCOC H ₂ CH ₂ CH ₃ ), 1.68 (tq, 4" -OCOCH ₂ C H ₂ CH ₃ ), 0.95
(t, 4 "-OCOCH ₂ CH ₂ C H ₃ )

Example 10 Compound (11 L) (in the formula (VIII), R ³ is normal
It is represented by a propyl group, and R ⁴ is represented by a 1-ethoxyethyl group.
And R ⁵ is a compound (1
Method for producing isomer) derived from 0 L) 18 mg of compound (10 L) was dissolved in 0.40 ml of ethanol, and then 0.50 ml of Raney nickel was controlled for activity in the same manner as in Example 4, and 0.50 ml of ethanol was added together with the above. Added to the solution. This was vigorously stirred at room temperature for 40 minutes, the insoluble matter was filtered off, and washed twice with 2.0 ml of ethanol each containing 1% (v / v) concentrated aqueous ammonia. The filtrate and washings were combined and concentrated under reduced pressure to obtain 16 mg of the residue, which was separated by TLC for separation.
The product was purified with (developing system: toluene-acetone (2: 1)) to obtain 1.7 mg of the compound (11 L). Physicochemical properties of compound (11L) (1) Color and shape: colorless solid (2) Molecular formula: C ₄₆ H ₇₇ NO ₁₆ (3) Mass spectrum (SIMS): m / z 900 (M +)
H) ⁺ (4) Rf value in TLC: 0.10 (chloroform:
Methanol (30: 1)) (5) Specific rotation: [α] _D ²⁰ -100 ° (c0.2, CH ₃ O
H) (6) Melting point: Melting at 69 to 72 ° C without showing clear melting point (7) ¹ H NMR spectrum (400MHz, CDCl ₃ ) δ
(ppm): 2.83 (dd, 2-H), 3.48 (s, 4-OCH ₃ ), 1.85 (m,
8-H), 5.28 (dd, 9-H), 5.55 (dd, 10-H), 6.22 (dd, 11-
H), 6.02 (br dd, 12-H), 5.67 (ddd, 13-H), 2.14 (dt, 1
4-H), 5.24 (ddq, 15-H), 2.98 (br dd, 17-H), 9.78 (br
s, 18-H), 0.99 (d, 19-H ₃ ), 4.92 (q, 3-OC H (OCH ₂ CH ₃ ) CH
₃ ), 3.49 (dq, 3-OCH (OC H ₂ CH ₃ ) CH ₃ ), 3.60 (dq, 3-OCH (OC
H ₂ CH ₃ ) CH ₃ ), 1.16 (t, 3-OCH (OCH ₂ C H ₃ ) CH ₃ ), 1.28 (d, 3-O
CH (OCH ₂ CH ₃ ) C H ₃ ), 2.04 (s, 9-OCOCH ₃ ), 4.44 (d, 1'-H),
2.54 (s, 3'-N (CH ₃ ) ₂ ), 4.89 (d, 1 "-H), 1.63 (dd, 2" -H
ax), 2.27 (d, 2 "-Heq), 1.09 (s, 3" -CH ₃ ), 4.70 (d, 4 "-
H), 1.06 (d, 6 "-H ₃ ), 3.26 (s, 3" -OCH ₃ ), 2.38 (m, 4 "-OC
OC H ₂ CH ₂ CH ₃ ), 1.69 (tq, 4 "-OCOCH ₂ C H ₂ CH ₃ ), 0.96 (t, 4"-
OCOCH ₂ CH ₂ C H ₃ )

Example 11 Compound (12) (in formula (I), R ¹ represents a hydrogen atom)
R ² is represented by an acetyl group and R ³ is normal propyl
It was dissolved preparation compounds of represented by group compound) to (11H) 4.0 mg in a mixed solution of 5% acetic acid aqueous solution 3.0 ml and acetonitrile 1.0 ml, was reacted at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, the obtained residue was dissolved in 10 ml of chloroform, and then the mixture was washed 3 times with 10 ml of saturated aqueous sodium hydrogen carbonate solution and successively with 10 ml of saturated aqueous sodium chloride solution. The chloroform layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 4.5 mg of the residue, which was purified by preparative TLC (developing system: chloroform-methanol (10: 1)) to give the compound (12 )
3.0 mg was obtained. Physicochemical properties of compound (12) (1) Color and shape: colorless solid (2) Molecular formula: C ₄₂ H ₆₉ NO ₁₅ (3) Mass spectrum (EIMS): m / z 828 (M + H) ⁺ (4) Specific rotation: [α] _D ¹⁷ -75 ° (c0.6, CH ₃ OH) (5) Melting point: Melting at 102-105 ° C without showing a clear melting point (6) ¹ H NMR spectrum (400MHz, CDCl ₃ ) δ
(ppm): 2.22 (br 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), 1.62 (br dt, 7-H), 1.99 (m, 8-H), 5.17 (dd,
9-H), 5.60 (dd, 10-H), 6.40 (dd, 11-H), 6.03 (br dd,
12-H), 5.65 (ddd, 13-H), 2.12 (dt, 14-H), 2.50 (br d
t, 14-H), 5.29 (ddq, 15-H), 1.30 (d, 16-H ₃ ), 2.46 (br
dd, 17-H), 2.82 (br dd, 17-H), 9.80 (s, 18-H), 0.98
(d, 19-H ₃ ), 2.00 (s, 9-OCOCH ₃ ), 4.57 (d, 1'-H), 3.20
(dd, 2'-H), 2.42 (t, 3'-H), 3.45 (t, 4'-H), 3.27 (dq,
5'-H), 1.20 (d , 6'-H 3), 2.57 (s, 3'-N (CH 3) 2), 4.93
(d, 1 "-H), 1.67 (dd, 2" -Hax), 2.30 (d, 2 "-Heq), 1.10
(s, 3 "-CH ₃ ), 4.72 (d, 4" -H), 4.54 (dq, 5 "-H), 1.08
(d, 6 "-H ₃ ), 3.26 (s, 3" -OCH ₃ ), 2.39 (m, 4 "-OCOC H ₂ CH ₂
CH ₃ ), 1.68 (tq, 4 "-OCOCH ₂ C H ₂ CH ₃ ), 0.96 (t, 4" -OCOCH ₂
CH ₂ C H ₃ )

Example 12 Compound (12) (in the formula (I), R ¹ represents a hydrogen atom.
R ² is represented by an acetyl group and R ³ is normal propyl
Method for producing compound represented by group ) 1.6 mg of the compound (11 L) was dissolved in a mixed solution of 1.2 ml of 5% acetic acid aqueous solution and 0.30 ml of acetonitrile, and then reacted at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, the residue obtained was dissolved in 5.0 ml of chloroform, and the mixture was washed 3 times with 5.0 ml of saturated aqueous sodium hydrogen carbonate solution and successively with 5.0 ml of saturated aqueous sodium chloride solution. The chloroform layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 1.2 mg of compound (12).

Example 13 Compound (13) (in the formula (I), R ¹ represents a hydrogen atom.
R ² is represented by a propionyl group and R ³ is a normal propionyl group.
Method for producing compound represented by pill group) 0.50 ml of anhydrous toluene was added to 10 mg of compound (6) and dissolved, 4.4 μl of anhydrous pyridine and propionyl chloride 4.8
After sequentially adding μl, the mixture was stirred at room temperature for 20 minutes. 10 ml of ethyl acetate and 4.1 μl of triethylamine were added to the reaction mixture.
After extraction with ethyl acetate, the ethyl acetate layer was washed twice with 10 ml of water, dried over anhydrous sodium sulfate, and filtered. 10 mg of the residue obtained by concentrating the filtrate under reduced pressure was used for separation TLC (developing system: chloroform-methanol-28% aqueous ammonia solution).
(10: 1: 0.1)) to obtain 4.0 mg of compound (13). Physicochemical properties of compound (13) (1) Color and shape: Colorless solid (2) Molecular formula: C ₄₃ H ₇₁ NO ₁₅ (3) Mass spectrum (FDMS): m / z 841 (M) ⁺ (4) Specific rotation Degree: [α] _D ¹⁹ -73 ° (c0.3, CH ₃ O
H) (5) Melting point: Melting at 99 to 103 ° C without showing clear melting point (6) ¹ H NMR spectrum (400MHz, CDCl ₃ ) δ
(ppm): 2.22 (br 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 ), 4.14 (br
d, 5-H), 1.62 (br dt, 7-H), 2.00 (m, 8-H), 5.18 (dd,
9-H), 5.61 (dd, 10-H), 6.40 (dd, 11-H), 6.03 (br dd,
12-H), 5.65 (ddd, 13-H), 2.12 (dt, 14-H), 2.51 (br d
t, 14-H), 5.29 (ddq, 15-H), 1.30 (d, 16-H ₃ ), 2.47 (br
dd, 17-H), 2.82 (br dd, 17-H), 9.80 (s, 18-H), 0.98
(d, 19-H ₃ ), 2.39 (q, 9-OCOC H ₂ CH ₃ ), 1.09 (t, 9-OCOCH ₂ C
H ₃ ), 4.57 (d, 1'-H), 3.21 (dd, 2'-H), 3.45 (t, 4'-H),
3.28 (dq, 5'-H) , 1.20 (d, 6'-H 3), 2.57 (s, 3'-N (CH 3)
₂ ), 4.93 (d, 1 "-H), 1.67 (dd, 2" -Hax), 2.28 (d, 2 "-He
q), 1.09 (s, 3 "-CH ₃ ), 4.72 (d, 4" -H), 4.54 (dq, 5 "-
H), 1.07 (d, 6 "-H ₃ ), 3.26 (s, 3" -OCH ₃ ), 2.39 (m, 4 "-O
COC H ₂ CH ₂ CH ₃ ), 1.69 (tq, 4 "-OCOCH ₂ C H ₂ CH ₃ ), 0.96 (t, 4"
-OCOCH ₂ CH ₂ C H ₃ )

[0050]

The first effect of the present invention is to create a novel 16-membered ring macrolide derivative having the strongest antibacterial activity. That is, certain derivatives of the compounds represented by the general formula (I) obtained in the present invention have extremely excellent antibacterial activity against clinically important Gram-positive bacteria and the like. Specifically, in the compound represented by the general formula (I), the 3- and 9-positions are free hydroxyl groups, and the 4 "-position hydroxyl group is compound (6) (in the formula (I)) R ¹ is a hydrogen atom, R ² is a hydrogen atom, and R ³ is a normal propyl group), rokitamycin (RK
M) (Journal of Antibiotics, 34 (8),
1001 (1981)) and antibacterial activity by simultaneous measurement of clarithromycin (CAM) are shown in Table 1. Compound (6), which is chemically derived from leucomycin A _5, has the best antibacterial activity among the commercially available 16-membered macrolide antibiotics RK.
It has remarkably excellent in vitro antibacterial activity as compared with M. Furthermore, this compound was previously filed by the present inventors as one of the compounds having the most excellent antibacterial activity among the leucomycin derivatives, and the patent application (Japanese Patent Application No. 5-169418) 3 "-O
The antibacterial activity was generally improved even when compared with -methylleucomycin A ₇ (a compound in which R ¹ is a hydrogen atom, R ² is a hydrogen atom and R ³ is an ethyl group in the formula (I)). However, its extreme antibacterial activity was completely comparable to that of CAM, which currently has the best antibacterial activity among new macrolide antibiotics. A 16-membered ring macrolide derivative having an antibacterial activity equivalent to that of CAM is hardly known in the world.

On the other hand, the antibacterial activity of the compound (12) in which the hydroxyl group at the 9-position of the lactone ring of the compound (6) is acetylated and the compound (13) in which the propionylation thereof is smaller than that of the compound (6). Although it was slightly inferior, it had excellent antibacterial activity.

[0052]

[Table 1]

The second effect of the present invention is that the compound of the present invention in which the 3-position of the lactone ring is a free hydroxyl group, that is, in the compound represented by the general formula (I), R ¹ is a hydrogen atom. Glycosylation of a compound or a compound equivalent thereto by using a naturally occurring known 16-membered macrolide antibiotic represented by the general formula (II) as a starting material and passing through a 3 "-methylthiomethyl ether synthetic intermediate It is intended to provide a novel production method which can be prepared by 6 steps or less steps without using a reaction and a 3, 18-hemiacetal-18-O-silyl synthetic intermediate. A 16-membered macrolide derivative in which the 3-position hydroxyl group of the lactone ring, which is a free hydroxyl group and the neutral sugar moiety is methylated, can be prepared for the first time by a pure synthetic chemical method. It was

The third effect of the present invention is to provide an efficient protecting group for the hydroxyl group at the 3-position of the lactone ring in the study of derivatives of leucomycins in which the 9-position of the lactone ring excluding spiramycin is sp ³ carbon. To provide. When producing an excellent derivative by a chemical reaction using a compound obtained from nature as a starting material, it is often necessary to protect a specific functional group such as an amino group or a hydroxyl group. In the study of synthetic chemical derivatives of 16-membered macrolide compounds, the examples in which an acetal substituent having an asymmetric carbon atom was applied as a protective group for the 3-position hydroxyl group of the lactone ring were limited to tylosins and spiramycins. The reason is that the protecting group is attached to the lactone ring 3 in the presence of an acid catalyst.
When a compound having a free hydroxyl group at the 9-position of the lactone ring is introduced into the hydroxyl group at the 2-position, isomerization of the molecule is induced by the presence of the hydroxyl group at the allylic position (9-position). This is because the sex was limited. The present inventors protected an acetal-based protecting group having an asymmetric carbon, especially a 1-ethoxyethyl group, against a hydroxyl group at the 3-position of the lactone ring in a 16-membered macrolide compound in which the 9-position of the lactone ring was a free hydroxyl group. It has been proved that it has sufficient characteristics as a base.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Osamu Hara 760 Shimooka-cho, Kohoku-ku, Yokohama-shi, Kanagawa Meiji Seika Co., Ltd., Pharmaceutical Research Laboratory (72) Inventor Seiji Shibahara 760, Shimooka-cho, Kohoku-ku, Yokohama-shi, Kanagawa Address Meiji Seika Co., Ltd. Pharmaceutical Research Institute

Claims (8)

[Claims] 1. The following formula (I): [In the formula, R ¹ modifies (or protects) a hydrogen atom or a hydroxyl group.
A substituent represented by R ² , R ² is a substituent that modifies (or protects) a hydrogen atom or a hydroxyl group, and R ³ is a compound represented by a linear or branched alkyl group having 1 to 4 carbon atoms, Or a pharmaceutically acceptable salt thereof. 2. A compound represented by the formula (I) according to claim 1, wherein R ¹ is a hydrogen atom, R ² is a hydrogen atom and R ³ is a normal propyl group, or a pharmaceutically acceptable compound thereof. Acceptable salt. 3. A compound represented by the formula (I) according to claim 1, wherein R ¹ is a hydrogen atom, R ² is an acetyl group, and R ³ is a normal propyl group, or a pharmaceutically acceptable compound thereof. Acceptable salt. 4. A compound represented by formula (I) according to claim 1, wherein R ¹ is a hydrogen atom, R ² is a propionyl group and R ³ is a normal propyl group, or a pharmaceutically acceptable compound thereof. Acceptable salt. 5. In the formula (I) of claim 1, R ¹ is a 1-ethoxyethyl group, R ² is an acetyl group, and R ^{3 is}
Of the compounds represented by normal propyl group, a less polar substance in TLC, or a pharmaceutically acceptable salt thereof. 6. In the formula (I) of claim 1, R ¹ is represented by a 1-ethoxyethyl group, R ² is represented by an acetyl group, and R ³
A compound having a higher polarity in TLC among compounds represented by normal propyl group, or a pharmaceutically acceptable salt thereof. 7. The following formula (II): [Wherein R ³ is a linear or branched alkyl group having 1 to 4 carbon atoms], which is a naturally-occurring 16-membered macrolide antibiotic, or a salt thereof, as a starting material. Formula (II
I) [Chemical 3] [In the formula, R ³ is a linear or branched alkyl group having 1 to 4 carbon atoms, R ⁴ is a substituent that modifies (or protects) the hydroxyl group, and R ⁵ modifies (or protects) the hydroxyl group. And a substituent represented by the formula (I), wherein R ⁶ is a substituent which protects a hydrogen atom or a hydroxyl group, or a salt thereof. [In the formula, R ¹ modifies (or protects) a hydrogen atom or a hydroxyl group.
A substituent represented by R ² , R ² is a substituent that modifies (or protects) a hydrogen atom or a hydroxyl group, and R ³ is a compound represented by a linear or branched alkyl group having 1 to 4 carbon atoms, Or a new efficient production method for obtaining a salt thereof. 8. A compound having a β-glycosidic bond of D-folosamine to the 9-position hydroxyl group of the lactone ring in the chemical synthesis of a 16-membered macrolide derivative, that is, a leucomycin derivative other than spiramycin (tylosin (Excluding) a protecting group for the 3-hydroxyl group of the lactone ring, which is an acetal-based substituent having an asymmetric carbon atom, such as a 1-ethoxyethyl group, a tetrahydrofuranyl group or a tetrahydropyranyl group.