JPH08231580A - Erythromycin derivative - Google Patents

Abstract

PURPOSE: To obtain the subject new derivative useful as a promoter for constriction movement of digestive canal, showing promoting action on constriction movement of digestive canal of mammals, capable of being orally administered, by substituting the hydroxyl group at the 12-position of erythromycin with a lower alkyl group. CONSTITUTION: This new erythromycin derivative is shown by formula I [R1 is H or an acyl; R2 and R3 are each H, hydroxyl group, an acyloxy or R2 and R3 are bonded to form O; R4 is H or a lower alkyl; R5 is a lower alkyl; R6 is H or a lower alkyl; Y is a group of the formula R7 R8 (R7 and R8 are each H, an acyl, a lower alkyl, etc.) or the formula N<+> R9 R10 X<-> (R9 to R11 are each H or a lower alkyl; X is an anion)]. The derivative has promoting action on constriction movement of digestive canal of mammals, is useful as a promoter for constriction movement of digestive canal, and can be orally administered. This compound is obtained by treating an erythromycin of formula II with an alkylating agent in the presence of a base in an inert solvent to substitute the hydroxyl group at the 12-position of the erythromycin with a lower alkyl group and optionally deprotecting and alkylating the resultant substance.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an erythromycin derivative or a salt thereof which exhibits a contractile motility promoting action on the digestive tract of mammals and is useful as a digestive tract contractile motility promoter. More specifically, the general formula (I)

Embedded image (In the formula, R ₁ is a hydrogen atom or an acyl group, R ₂ and R ₃ are the same or different and are a hydrogen atom, a hydroxyl group, an acyloxy group or ═O together, and R ₄ is a hydrogen atom or a lower alkyl group. , R ₅ represents a lower alkyl group, R ₆ represents a hydrogen atom or a lower alkyl group, and Y represents —NR ₇ R ₈ or —N ⁺ R ₉ R ₁₀ R ₁₁ X ^— , wherein R ₇ and R ₈ are respectively. Is a hydrogen atom, an acyl group or a lower alkyl group which may have a substituent, which may be the same or different;
₉ , R ₁₀ and R ₁₁ are the same or different and each represents a hydrogen atom or a lower alkyl group which may have a substituent, and X represents an anion) or a salt thereof.

[0002]

BACKGROUND OF THE INVENTION Gastrointestinal motility promoters are classified into acetylcholine agonists (acratonium napadisylate), indirect acetylcholine agonists (cisapride), dopamine blockers (domperidone) and opiate agonists (trimebutine maleate) in terms of action. It is broadly classified into four types, and is widely used as a therapeutic drug for digestive tract dysfunction, especially digestive tract symptoms such as gastrointestinal uncertain complaints due to hypoactivity.
However, these drugs are accompanied by side effects such as extrapyramidal symptom due to dopamine blocking action and increased milk secretion. In addition, the mode of gastrointestinal motility promoted by these drugs is different from the naturally occurring physiological movement of the upper gastrointestinal tract to the lower gastrointestinal tract, and is often accompanied by side effects such as diarrhea and vomiting. Are known.

On the other hand, motilin is known as a gastrointestinal hormone that stimulates the contractile movement of the gastrointestinal tract, but the supply of motilin by extraction from nature and chemical synthesis was not satisfactory, and it was difficult to supply it in large quantities. Further, since motilin is a peptide consisting of 22 amino acids, it was difficult to develop motilin as an oral preparation. Recently, it was found that erythromycin and its derivatives have a strong activity of promoting gastrointestinal contractile motility, and one of the derivatives, EM-5.
23 is under development as a gastrointestinal motility promoter (Drug
s of the Future, 16, 110 (19
91)).

Further, International Publication WO92 / 18134 describes the general concept of the compound of the present invention, but does not describe the production examples of the compound of the present invention. That is, the compound of the present invention is a novel compound not described in the literature.

[0005]

The erythromycin derivative described in the above-mentioned documents is not satisfactory as a gastrointestinal contractile motility promoter because of its insufficient effect in vivo.

[0006]

Means for Solving the Problems As a result of intensive studies by the present inventors, the general formula (I)

Embedded image (In the formula, R ₁ is a hydrogen atom or an acyl group, R ₂ and R ₃ are the same or different and are a hydrogen atom, a hydroxyl group, an acyloxy group or ═O together, and R ₄ is a hydrogen atom or a lower alkyl group. , R ₅ represents a lower alkyl group, R ₆ represents a hydrogen atom or a lower alkyl group, and Y represents —NR ₇ R ₈ or —N ⁺ R ₉ R ₁₀ R ₁₁ X ^— , wherein R ₇ and R ₈ are respectively. Is a hydrogen atom, an acyl group or a lower alkyl group which may have a substituent, which may be the same or different;
₉ , R ₁₀ and R ₁₁ are the same or different and each is a hydrogen atom or a lower alkyl group which may have a substituent, and X is an anion), and hydrogen of the hydroxyl group at the 12-position of erythromycin The present invention was completed by finding that a compound in which an atom is substituted with a lower alkyl group or a salt thereof is useful as a gastrointestinal contractile motility promoter.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION That is, the present invention relates to general formula (I)

[Chemical 4] (In the formula, R ₁ represents a hydrogen atom or an acyl group, R ₂ and R ₃ are the same or different and each represents a hydrogen atom, a hydroxyl group, an acyloxy group or ═O together, and R _{4 represents a} hydrogen atom or a lower alkyl group. , R ₅ represents a lower alkyl group, R ₆ represents a hydrogen atom or a lower alkyl group, and Y represents —NR ₇ R ₈ or —N ⁺ R ₉ R ₁₀ R ₁₁ X ^— , wherein R ₇ and R ₈ are respectively. Is a hydrogen atom, an acyl group or a lower alkyl group which may have a substituent, which may be the same or different;
₉ , R ₁₀ and R ₁₁ are the same or different and each represents a hydrogen atom or a lower alkyl group which may have a substituent, and X represents an anion) or a salt thereof.

In the present invention, the acyl group is a hydrogen atom, a lower alkyl group which may have a substituent, an aryl group which may have a substituent, or an aralkyl which may have a substituent. Group, a lower alkyloxy group which may have a substituent, an aryloxy group which may have a substituent or a carbonyl group which is substituted with an aralkyloxy group which may have a substituent, etc. However, preferably, a formyl group, a lower alkylcarbonyl group, a phenylcarbonyl group which may have a substituent, a lower alkyloxycarbonyl group, a phenylalkyloxycarbonyl group which may have a substituent, and the like, More preferably, formyl group, acetyl group, propionyl group, butyryl group, pivaloyl group, benzoyl group, ethoxycarbonyl group, t-butoxy group. Carbonyl group, a benzyloxycarbonyl group, an acetyl group, benzyloxycarbonyl group and the like as the most preferred.

The acyloxy group refers to a monovalent group in which an oxygen atom is bonded to the above acyl group, and preferably a formyloxy group, an acetyloxy group, a propionyloxy group,
A butyryloxy group, a pivaloyloxy group, a benzoyloxy group, an ethoxycarbonyloxy group, a t-butoxycarbonyloxy group, a benzyloxycarbonyloxy group and the like are shown, and an acetyloxy group and a benzyloxycarbonyloxy group are more preferable.

The lower alkyl group refers to a linear or branched alkyl group having 1 to 6 carbon atoms, preferably methyl group, ethyl group, n-propyl group, i-propyl group, n-
A butyl group, a sec-butyl group, a t-butyl group and the like are shown.

A lower alkyl group which may have a substituent, an aryl group which may have a substituent, an aralkyl group which may have a substituent, and a lower group which may have a substituent. Alkyloxy group, a substituent in the carbonyl group substituted with an aryloxy group which may have a substituent or an aralkyloxy group which may have a substituent, a hydroxyl group, an amino group, a halogen atom, A cyano group, an alkyloxy group, a mercapto group, a formyl group and the like are shown, and preferably a hydroxyl group, an amino group and a fluorine atom are shown.

Anions are chlorine ions, bromine ions,
Iodine ion, carboxylate ion, sulfonate ion and the like are shown. Examples of the acid that forms a salt include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid and sulfuric acid, and organic acids such as acetic acid, oxalic acid, maleic acid, fumaric acid and methanesulfonic acid.

The compounds of the present invention have, for example, the general formula (I
I)

Embedded image (In the formula, R ₁ is a hydrogen atom or an acyl group, R ₂ and R ₃ are the same or different and are a hydrogen atom, a hydroxyl group, an acyloxy group or ═O together, and R ₆ is a hydrogen atom or a lower alkyl group. , Y is -NR ₇ R ₈ or -N ⁺ R
Indicating each ^- ₉ R ₁₀ R ₁₁ X. Here, R ₇ and R ₈ are the same or different and each represents a hydrogen atom, an acyl group or a lower alkyl group which may have a substituent, and R ₉ , R ₁₀ and R ₁₁ are the same or different and each represent a hydrogen atom or a substituent. A lower alkyl group which may be present, X is an anion, is reacted with an alkylating agent in an inert solvent in the presence of a base, and then deprotection or alkylation is carried out if necessary. It can be manufactured by carrying out. The compound represented by the general formula (II) is exemplified by International Publication WO9
It can be produced by the method described in 2/18134.

Examples of the alkylating agent used in the alkylation reaction include alkyl halides and alkyl sulfonates. Examples of the base include metal hydrides, metal alkoxides, metal bases such as organic metal compounds, carbonates and metal hydroxides, and organic bases such as amines, preferably sodium hydride, sodium alkoxide, Potassium alkoxide, alkyl lithium, potassium carbonate, sodium carbonate, potassium hydroxide,
Examples thereof include sodium hydroxide, triethylamine, trimethylamine and the like, and more preferable examples include sodium hydride, potassium-t-butoxide and sodium hydroxide. Examples of the inert solvent include alcohol solvents, halogenated hydrocarbon solvents, ether solvents and aprotic polar solvents, preferably methanol, ethanol, propanol, chloroform, methylene chloride, ether, tetrahydrofuran, N. , N-dimethylformamide and the like are used.

The compound (I) of the present invention can also be obtained by applying the specific production method described in Examples.

The compound of the present invention is useful as a promoter of contractile motility of the digestive tract of mammals. This was proved by the contraction test of the rabbit duodenum shown in the test example below. Further, erythromycin derivatives are generally acid-labile, and when used orally, they are susceptible to decomposition by gastric acid and their effects tend to be diminished. However, the compounds of the present invention are disclosed in International Publication WO92 / 18134. Compared with the compounds described, it is more stable under acidic conditions and exhibits a strong action to promote gastrointestinal contractile motility even after oral administration. That is, the compound of the present invention is obtained by directly administering a drug to the stomach of a dog having the stomach and intestines by using the force transducer described in International Publication WO93 / 24509 to exert its gastrointestinal contractile motility promoting effect, and the gastric motility is stopped. In an experiment for quantification using MotorIndex, which is the area between the baseline and the contraction waveform in the state, as an index, it shows a remarkable effect as compared with the compound described in International Publication WO92 / 18134.

[0017]

EXAMPLES The production of the compounds of the present invention will be described in more detail based on the following examples, but the invention is not intended to be limited by these examples.

Example 1 9-[(2,6-dideoxy-3-C-methyl-3-O
-Methyl-α-L-ribo-hexopyranosyl) oxy]
-5-ethyl-3,4-dihydroxy-2,4,6
8,10,12,14-heptamethyl-11-[[2-
O-benzyloxycarbonyl-3,4,6-trideo
Xy-3- (benzyloxycarbonylmethylamino)
-Β-D-xylo-hexopyranosyl] oxy] -6-
Aza-15-oxabicyclo [10,2,1] pentade
Synthesis of Ca-14-en-7-one (Compound 2)

[Chemical 6] 9-[(2,6-dideoxy-3-C-methyl-3-O
-Methyl-α-L-ribo-hexopyranosyl) oxy]
-5-ethyl-3,4-dihydroxy-2,4,6
8,10,12,14-heptamethyl-11-[[3
4,6-Trideoxy-3- (dimethylamino) -β-
D-xylo-hexopyranosyl] oxy] -6-aza-
15-Oxacyclo [10,2,1] pentadeca-1
4-en-7-one (Compound 1) (WO92 / 1813
4 described compound)

[Chemical 7] To a solution of 3.55 g and 6.14 g of sodium hydrogen carbonate in 40 ml of toluene was added 9.7 ml of benzyloxycarbonyl chloride under stirring at 55 to 60 ° C., and the mixture was stirred for 2.5 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel chromatography [developing solvent: ethyl acetate-n-hexane (1: 1)] to give compound 2
3.42 g (yield 71%) of white powder was obtained.

Example 2 9-[(4-O-acetyl-2,6-dideoxy-3-
C-methyl-3-O-methyl-α-L-ribo-hexopy
Lanosyl) oxy] -5-ethyl-3,4-dihydroxy
Ci-2,4,6,8,10,12,14-heptamethyl
-11-[[2-O-benzyloxycarbonyl-3,
4,6-Trideoxy-3- (benzyloxycarbonyl)
Lumethylamino) -β-D-xylo-hexopyranosi
]] Oxy] -6-aza-15-oxabicyclo [1
0,2,1] Pentadec-14-en-7-one (compound
Synthesis of thing 3)

Embedded image Compound 2 (3.42 g) was dissolved in 50 ml of dichloromethane, and 1.97 ml of pyridine and 0.99 ml of acetyl chloride were sequentially added under ice cooling, and the mixture was stirred for 1.5 hours and then warmed to room temperature over 1 hour, and then at room temperature. Stir for 2 hours. Saturated aqueous sodium hydrogencarbonate was added to the reaction solution and extracted with chloroform,
The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel chromatography [developing solvent: ethyl acetate-n-hexane (1: 1)] to give compound 3 as white powder 2.04.
g (57% yield) was obtained.

Example 3 9-[(4-O-acetyl-2,6-dideoxy-3-
C-methyl-3-O-methyl-α-L-ribo-hexopyranosyl) oxy] -5-ethyl-4-hydroxy-3
-Methoxy-2,4,6,8,10,12,14-heptamethyl-11-[[2-O-benzyloxycarbonyl-3,4,6-trideoxy-3- (benzyloxycarbonylmethylamino) -β -D-xylo-hexopyranosyl] oxy] -6-aza-15-oxabicyclo [10,2,1] pentadeca-14-en-7-one (Compound 4) and 9-[(4-O-acetyl-2). , 6-Dideoxy-3-C-methyl-3-O-methyl-α-L-
Ribo-hexopyranosyl) oxy] -5-ethyl-3-
Hydroxy-4-methoxy-2,4,6,8,10,1
2,14-Heptamethyl-11-[[2-O-benzyloxycarbonyl-3,4,6-trideoxy-3-
(Benzyloxycarbonylmethylamino) -β- D-
Xylo-hexopyranosyl] oxy] -6-aza-15
-Oxabicyclo [10,2,1] pentadeca-14-
Synthesis of en-7-one (Compound 5)

[Chemical 9] Compound 3 (1.22 g) in 6 ml of dimethylformamide
Under ice cooling, 71 mg of sodium hydride and 0.11 ml of iodomethane were sequentially added to the solution, and the mixture was stirred for 30 minutes as it was. Saturated aqueous sodium hydrogencarbonate was added to the reaction solution and the mixture was extracted with ethyl acetate, and the extract was washed successively with water and saturated brine. The ethyl acetate solution was dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography [developing solvent: ethyl acetate-n-hexane (1: 2-1: 1)] to give 594 mg of a white powder of compound 4 (yield 48%) and compound 5 White powder 6
05 mg (yield 49%) was obtained.

Example 4 9-[(2,6-dideoxy-3-C-methyl-3-O
-Methyl-α-L-ribo-hexopyranosyl) oxy]
-5-ethyl-3-hydroxy-4-methoxy-2,
4,6,8,10,12,14-heptamethyl-11-
[[3,4,6-Trideoxy-3- (methylamino)
-Β-D-xylo-hexopyranosyl] oxy] -6-
Aza-15-oxabicyclo [10,2,1] pentade
Synthesis of Ca-14-en-7-one (Compound 6)

[Chemical 10] Compound 5 (605 mg) was dissolved in 8 ml of methanol,
121 mg of potassium carbonate was added, and the mixture was stirred at 50 ° C. for 30 hours. After distilling off the solvent, the reaction solution was diluted with chloroform and washed with water and saturated saline. The chloroform solution was dried over anhydrous sodium sulfate and the solvent was distilled off. The residue obtained was then made into a solution of 8 ml of methanol, 100 mg of 10% Pd-C and 183 m of ammonium formate.
g and heated under reflux for 30 minutes. The reaction solution was filtered, diluted with chloroform, and washed successively with saturated sodium hydrogen carbonate and saturated brine. The chloroform solution was dried over anhydrous sodium sulfate and the solvent was distilled off. The obtained residue is subjected to silica gel chromatography [developing solvent: chloroform-methanol-concentrated aqueous ammonia (30: 1: 0.1)].
352 mg (yield 83
%) Was obtained.

Example 5 9-[(2,6-dideoxy-3-C-methyl-3-O
-Methyl-α-L-ribo-hexopyranosyl) oxy]
-5-ethyl-3-hydroxy-4-methoxy-2,
4,6,8,10,12,14-heptamethyl-11-
[[3,4,6-Trideoxy-3- (dimethylamido
No) -β-D-xylo-hexopyranosyl] oxy]-
6-aza-15-oxabicyclo [10,2,1] pen
Synthesis of Tadeca-14-en-7-one (Compound 7)

[Chemical 11] Compound 6 (105 mg) and a 35% aqueous solution of formaldehyde (124 mg) were added to a solution of acetonitrile (3 ml) under ice-cooling.
28 mg of sodium cyanoborohydride and acetic acid were added in catalytic amounts, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was evaporated, diluted with dichloromethane, and washed successively with saturated sodium hydrogen carbonate and saturated brine. The dichloromethane solution was dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was subjected to silica gel chromatography [developing solvent: chloroform-methanol-concentrated aqueous ammonia (40: 1:
0.1)] and white powder of Compound 7 (65 mg)
(Yield 61%) was obtained.

Example 6 9-[(2,6-dideoxy-3-C-methyl-3-O
-Methyl-α-L-ribo-hexopyranosyl) oxy]
-5-ethyl-3-hydroxy-4-methoxy-2,
4,6,8,10,12,14-heptamethyl-11-
[[3,4,6-Trideoxy-3- (ethylmethyl
Mino) -β-D-xylo-hexopyranosyl] oxy]
-6-aza-15-oxabicyclo [10,2,1] pe
Synthesis of ntadeca-14-en-7-one (compound 8)

[Chemical 12] A solution of compound 6 (155 mg), ethyl iodide 1.32 g, and diisopropylethylamine 275 mg in methanol 3 ml was stirred at room temperature for 27 hours. After distilling off the solvent, the reaction solution was diluted with chloroform and washed with water and saturated saline. The chloroform solution was dried over anhydrous sodium sulfate and the solvent was distilled off. The obtained residue is subjected to silica gel chromatography [developing solvent: chloroform-methanol-concentrated aqueous ammonia (50: 1: 0.1)].
The compound 8 was purified with a white powder of 103 mg (yield 63
%) Was obtained.

Example 7 9-[(2,6-dideoxy-3-C-methyl-3-O
-Methyl-α-L-ribo-hexopyranosyl) oxy]
-5-ethyl-3-hydroxy-4-methoxy-2,
4,6,8,10,12,14-heptamethyl-11-
[[3,4,6-Trideoxy-3- (methyl (2-propyl
Ropyl) amino) -β-D-xylo-hexopyranosi
]] Oxy] -6-aza-15-oxabicyclo [1
0,2,1] Pentadec-14-en7-one (compound
Synthesis of 9)

[Chemical 13] Compound 6 (192 mg), isopropyl iodide 1.79
g, and a solution of 340 mg of diisopropylethylamine in 3 ml of methanol were stirred at 50 ° C. for 4 days. After distilling off the solvent, the reaction solution was diluted with chloroform and washed with water and saturated saline. The chloroform solution was dried over anhydrous sodium sulfate and the solvent was distilled off. The obtained residue was subjected to silica gel chromatography [developing solvent: chloroform-methanol-concentrated aqueous ammonia (50: 1: 0.
1)] to obtain 73 mg of white powder of compound 9 (yield 36%).

Example 8 9-[(2,6-dideoxy-3-C-methyl-3-O
-Methyl-α-L-ribo-hexopyranosyl) oxy]
-5-ethyl-3-hydroxy-4-methoxy-2,
4,6,8,10,12,14-heptamethyl-11-
[[3,4,6-Trideoxy-3- (dimethyl (2-
Propynyl) ammonium) -β-D-xylo-hexo
Pyranosyl] oxy] -6-aza-15-oxabisic
[10,2,1] Pentadeca-14-en-7-one
Synthesis of bromide (compound 10)

Embedded image To a solution of compound 7 (80 mg) in 2 ml of acetonitrile,
0.015 ml of propargyl bromide was added, and the mixture was stirred at room temperature for 8 hours. The solvent of the reaction solution was evaporated, ethyl acetate was added and the mixture was stirred, and the insoluble solid was collected by filtration. The solid was once dissolved in methanol and the solvent was distilled off to give compound 1
61 mg (yield 66%) of white powder of 0 was obtained.

Example 9 9-[(2,6-dideoxy-3-C-methyl-3-O
-Methyl-4-O-imidazolylthiocarbonyl-α-
L-ribo-hexopyranosyl) oxy] -5-ethyl-
3,4-dihydroxy-2,4,6,8,10,12,
14-heptamethyl-11-[[2-O-benzyloxy
Cycarbonyl-3,4,6-trideoxy-3- (ben
Zyloxycarbonylmethylamino) -β-D-xylo
-Hexopyranosyl] oxy] -6-aza-15-oki
Sabicyclo [10,2,1] pentadeca-14-ene-
Synthesis of 7-one (Compound 11)

[Chemical 15] Compound 2 (1.29 g) was dissolved in 20 ml of dichloromethane, and 641 mg of dimethylaminopyridine and 1,1′-
520 mg of thiocarbonyldiimidazole was added, and the mixture was stirred at room temperature. 1.5 days later dimethylaminopyridine 320
mg and 1,1′-thiocarbonyldiimidazole 260
mg was added, and one day later, 260 mg of 1,1′-thiocarbonyldiimidazole was added. After stirring for 3 days, the reaction was completed. Saturated aqueous sodium hydrogencarbonate was added to the reaction solution, followed by extraction with chloroform. The extract was washed with saturated saline and then dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography [developing solvent: ethyl acetate-n-hexane (2: 3)] to obtain 1.25 g of white powder of compound 11 (yield 87%).
I got

Example 10 9-[(2,4,6-Trideoxy-3-C-methyl-
3-O-methyl-α-L-ribo-hexopyranosyl) o
Xy] -5-ethyl-3,4-dihydroxy-2,4
6,8,10,12,14-heptamethyl-11-
[[2-O-benzyloxycarbonyl-3,4,6-
Trideoxy-3- (benzyloxycarbonylmethyl)
Amino) -β-D-xylo-hexopyranosyl] oxy
Ci] -6-aza-15-oxabicyclo [10,2,
1] Pentadec-14-en-7-one (Compound 12)
Synthesis of

Embedded image A solution of compound 11 (1.25 g) in 25 ml of toluene was added with 1.0 g of tri-n-butyltin hydride and α, α′-.
Add 57 mg of azobis (isobutyronitrile),
The mixture was heated under reflux for 2.5 hours. The reaction solution was diluted with ethyl acetate and washed with water and saturated saline. The ethyl acetate solution was dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography [developing solvent: ethyl acetate-n-hexane (1: 2)] to obtain 850 mg (yield 77%) of white powder of compound 12.

Example 11 9-[(2,4,6-Trideoxy-3-C-methyl-
3-O-methyl-α-L-ribo-hexopyranosyl) oxy] -5-ethyl-4-hydroxy-3-methoxy-
2,4,6,8,10,12,14-heptamethyl-1
1-[[2-O-benzyloxycarbonyl-3,4,
6-Trideoxy-3- (benzyloxycarbonylmethylamino) -β-D-xylo-hexopyranosyl] oxy] -6-aza-15-oxabicyclo [10,2,2]
1] Pentadec-14-en-7-one (Compound 13)
And 9-[(2,4,6-trideoxy-3-C-methyl-3-O-methyl-α-L-ribo-hexopyranosyl)
Oxy] -5-ethyl-3-hydroxy-4-methoxy-2,4,6,8,10,12,14-heptamethyl-
11-[[2-O-benzyloxycarbonyl-3,
4,6-Trideoxy-3- (benzyloxycarbonylmethylamino) -β-D-xylo-hexopyranosyl] oxy] -6-aza-15-oxabicyclo [1
0,2,1] Pentade mosquito-14-en-7-one (compound
Synthesis of product 14)

[Chemical 17] Compound 12 (900 mg) in dimethylformamide 10
Under ice-cooling, 56 mg of sodium hydride and 0.087 ml of iodomethane were sequentially added to the ml solution, and the mixture was stirred for 30 minutes as it was. Saturated aqueous sodium hydrogencarbonate was added to the reaction solution and the mixture was extracted with ethyl acetate, and the extract was washed successively with water and saturated brine. The ethyl acetate solution was dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography [developing solvent: ethyl acetate-n-hexane (2: 5-1: 1)] to obtain 337 mg of a white powder of Compound 13 (yield 37%) and Compound 14. 510 mg (yield 56%) of white powder was obtained.

Example 12 9-[(2,4,6-Trideoxy-3-C-methyl-
3-O-methyl-α-L-ribo-hexopyranosyl) o
Xy] -5-ethyl-3-hydroxy-4-methoxy-
2,4,6,8,10,12,14-heptamethyl-1
1-[[3,4,6-trideoxy-3- (methylamido
No) -β-D-xylo-hexopyranosyl] oxy]-
6-aza-15-oxabicyclo [10,2,1] pen
Synthesis of Tadeca-14-en-7-one (Compound 15)

Embedded image 1 to 8 ml of a solution of compound 14 (510 mg) in methanol
100 mg of 0% Pd-C was added, and the mixture was stirred under a hydrogen atmosphere at room temperature overnight. The reaction solution was filtered, the solvent was distilled off, the residue was diluted with chloroform, and washed successively with saturated sodium hydrogen carbonate and saturated saline. The chloroform solution was dried over anhydrous sodium sulfate and the solvent was distilled off. The obtained residue is subjected to silica gel chromatography [developing solvent: chloroform-
Methanol-concentrated aqueous ammonia (40: 1: 0.1)] and white powder of compound 15 267 mg (yield 72
%) Was obtained.

Example 13 9-[(2,4,6-Trideoxy-3-C-methyl-
3-O-methyl-α-L-ribo-hexopyranosyl) o
Xy] -5-ethyl-3-hydroxy-4-methoxy-
2,4,6,8,10,12,14-heptamethyl-1
1-[[3,4,6-trideoxy-3- (dimethyla
Mino) -β-D-xylo-hexopyranosyl] oxy]
-6-aza-15-oxabicyclo [10,2,1] pe
Synthesis of ntadeca-14-en-7-one (compound 16)

[Chemical 19] Compound 15 (74 mg) and a solution of 133% of a 35% aqueous formaldehyde solution in 3 ml of methanol were mixed with 10% Pd-.
C20 mg and acetic acid 0.012 ml were added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 5 hours. The reaction solution was filtered, the solvent was distilled off, the residue was diluted with chloroform, and washed successively with saturated sodium hydrogen carbonate and saturated saline. The chloroform solution was dried over anhydrous sodium sulfate and the solvent was distilled off. The obtained residue was subjected to silica gel chromatography [developing solvent: chloroform-methanol-concentrated aqueous ammonia (50: 1: 0.
1)] to obtain 52 mg of white powder of compound 16 (yield 69%).

Example 14 9-[(2,4,6-Trideoxy-3-C-methyl-
3-O-methyl-α-L-ribo-hexopyranosyl) o
Xy] -5-ethyl-3-hydroxy-4-methoxy-
2,4,6,8,10,12,14-heptamethyl-1
1-[[3,4,6-trideoxy-3- (ethylmethy
Luamino) -β-D-xylo-hexopyranosyl] oxy
Ci] -6-aza-15-oxabicyclo [10,2,
1] Pentadec-14-en-7-one (Compound 17)
Of)

Embedded image A solution of compound 15 (228 mg), 2.0 g of ethyl iodide, and 413 mg of diisopropylethylamine in 5 ml of methanol was stirred at room temperature for 17 hours. After distilling off the solvent, the reaction solution was diluted with chloroform and washed with water and saturated saline. The chloroform solution was dried over anhydrous sodium sulfate and the solvent was distilled off. The obtained residue was subjected to silica gel chromatography [developing solvent: chloroform, methanol-concentrated aqueous ammonia (60: 1: 0.
1)] white powder of (compound 17) 122 m
g (yield 51%) was obtained.

Example 15 9-[(2,4,6-Trideoxy-3-C-methyl-
3-O-methyl-α-L-ribo-hexopyranosyl) o
Xy] -5-ethyl-3-hydroxy-4-methoxy-
2,4,6,8,10,12,14-heptamethyl-1
1-[[3,4,6-trideoxy-3- (methyl (2
-Propyl) amino) -β-D-xylo-hexopyrano
Syl] oxy] -6-aza-15-oxabicyclo [1
0,2,1] Pentadec-14-en-7-one (compound
18) Synthesis

[Chemical 21] Compound 15 (145 mg), isopropyl iodide 1.3
A solution of 8 g and 263 mg of diisopropylethylamine in 3 ml of methanol was stirred at 50 ° C. for 3 days.
After distilling off the solvent, the reaction solution was diluted with chloroform and washed with water and saturated saline. The chloroform solution was dried over anhydrous sodium sulfate and the solvent was distilled off. The obtained residue was subjected to silica gel chromatography [developing solvent: chloroform-methanol-concentrated aqueous ammonia (60: 1:
0.1)] and purified with Compound 18 as a white powder 40 mg
(Yield 26%) was obtained.

Table 1 shows the spectral data of representative compounds synthesized in the examples.

[Table 1]

Test Example A digestive tract contraction test was carried out by the following method. The duodenum specimen (5 x 15 mm) extracted from the slaughtered rabbit was
Constant temperature bath filled with Krebs solution heated to ℃ (org
an bath (10 ml) was suspended in the longitudinal muscle direction. Kre mixed gas (95% O ₂ , 5% CO ₂ )
The bs solution was continuously aerated and the contraction of the duodenal specimen was recorded isotonic (load 1 g). The potency of the compound is 10 ^{times the} contraction caused by 1 × 10 ⁻⁴ M acetylcholine.
It was expressed as the index pEC ₅₀ of the concentration EC ₅₀ (M) of the compound that caused 50% contraction when 0% was set. Table 2 shows the results.

[Table 2] As a result, the pEC _{50 of} EM-523 was 7.3, while the pEC _{50 of} compound 18 was 8.5.
It showed 10 times the activity of -523. In addition, this value is the same as the pEC ₅₀ of motilin, indicating that compound 18 has the same contractile activity in the digestive tract as that of motilin.

[0035]

EFFECTS OF THE INVENTION Since the compound of the present invention exhibits a strong digestive tract contracting action even when it is orally administered, it is useful as a contractile motility promoter for the digestive tract of mammals.

Claims (1)

[Claims] 1. A compound of the general formula (I) (In the formula, R ₁ is a hydrogen atom or an acyl group, R ₂ and R ₃ are the same or different and are a hydrogen atom, a hydroxyl group, an acyloxy group or ═O together, and R ₄ is a hydrogen atom or a lower alkyl group. , R ₅ represents a lower alkyl group, R ₆ represents a hydrogen atom or a lower alkyl group, and Y represents —NR ₇ R ₈ or —N ⁺ R ₉ R ₁₀ R ₁₁ X ^— , wherein R ₇ and R ₈ are respectively. Is a hydrogen atom, an acyl group or a lower alkyl group which may have a substituent, which may be the same or different;
₉ , R ₁₀ and R ₁₁ are the same or different and each represents a hydrogen atom or a lower alkyl group which may have a substituent, and X represents an anion) or a salt thereof.