JPH10212295A - 13-membered ring macrolide compound, drug containing the same and method for producing the same - Google Patents

Abstract

(57) [Problem] To provide a novel 13-membered ring macrolide compound, a gastrointestinal contraction motility promoter containing the same, and a method for producing the same. SOLUTION: General formula [I] (R ₁ and R ₂ are hydrogen atoms, R ₃ is a hydrogen atom, a hydroxyl group or an amino group, or R ₂ and R ₃ together are ＯO or ＮN—OR ₁₁ , and R ₁₁ is A hydrogen atom or a lower alkyl group, R ₄ and R ₅ together are ＯO, and Y is —N (R ₆ ) (R ₇ ) or —N ⁺ (R ₈ ) (R ₉ ) ( R
₁₀₎ X ^- a A, R ₆ to R ₁₀ represents a hydrogen atom or the like, a lower alkyl group, X ^- is a compound represented by represents an anion), pharmaceutical and manufacturing method thereof containing the same.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a 13-membered macrolide compound or a salt thereof, which has the action of promoting the contraction of the digestive tract of mammals and is useful as an agent for promoting the contraction of the digestive tract.

[0002]

BACKGROUND OF THE INVENTION Gastrointestinal motility enhancers include direct acetylcholine agonists (acratonium napadisylate), indirect acetylcholine agonists (cisapride), dopamine blockers (domperidone) and opiate agonists (maleic acid). (Trimeptin), which is widely used as a therapeutic drug for gastrointestinal symptoms such as dysfunction of gastrointestinal motility, particularly complaints of indefinite complaints due to gastrointestinal dysfunction. However, these drugs have side effects such as extrapyramidal symptoms and enhanced lactation due to dopamine blocking action. In addition, the mode of gastrointestinal motility promoted by these drugs is different from the naturally occurring physiological motility that propagates from the upper gastrointestinal tract to the lower gastrointestinal tract, and may be accompanied by many side effects such as diarrhea and vomiting. Are known.

[0003] 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 is not satisfactory, and it has been difficult to supply it in large quantities. . Since motilin is a peptide consisting of 22 amino acids, it has been difficult to develop it as an oral preparation. In recent years, erythromycin and its derivatives have been found to have a strong gastrointestinal contractile motility-promoting activity similar to motilin (JP-A-60-218).
No. 321, JP-A-61-87625, JP-A-63-9
No. 9016, JP-A-63-99092, JP-A-6-5
No. 6873, and The Journal of Pharmacology
and Experimental Therapeutics, 251, 2, 707-712, 19
89). However, all of these compounds are 14-membered ring macrolide compounds, and 13-membered ring macrolide compounds have not been known.

[0004]

SUMMARY OF THE INVENTION The present inventors have conducted intensive studies to provide a substance capable of promoting gastrointestinal contraction and capable of being supplied in large quantities. As a result, the antibiotic erythromycin A was used as a raw material. Succeeded in synthesizing a novel 13-membered ring macrolide compound, and examined its pharmacological action. As a result, it was found that the novel 13-membered ring macrolide had a strong activity of promoting gastrointestinal contraction.

Accordingly, an object of the present invention is to provide a novel 13-membered ring macrolide which promotes gastrointestinal contraction and can be supplied in large quantities.

[0006]

According to the present invention, there is provided a compound represented by the general formula [I]:

[0007]

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(Wherein, R ₁ represents a hydrogen atom or an acyl group. R ₂ and R ₃ may be the same or different and represent a hydrogen atom, a hydroxyl group, an acyloxy group or an amino group, or R ₂ and R ₃ represents = O or = NOR ₁₁ together.
Here, R ₁₁ represents a hydrogen atom or a lower alkyl group. R
₄ and R ₅ are the same or different and each represents a hydrogen atom or a hydroxyl group, or R ₄ and R ₅ together represent ＯO or ＮＯNOR ₁₁ . Y is -N (R ₆ ) (R ₇ ) or -N
^{_{+ (R 8) (R 9}} ) (R 10) X - represents a. Where R ₆ , R ₇ ,
R ₈ , R ₉ and R ₁₀ are the same or different and are each a hydrogen atom,
An acyl group, a lower alkyl group which may have a substituent,
A lower alkenyl group which may have a substituent, a lower alkynyl group which may have a substituent, a cycloalkyl group which may have a substituent, or a hetero group which may have a substituent oxygen atom as atom, a 3-7 membered heterocyclic saturated monocyclic ring containing a sulfur atom or a nitrogen atom, X ^- represents an anion. R ₆ and R ₇ or R ₈ and R ₉ may be taken together to form an azacycloalkyl group together with the nitrogen atom to which they are bonded) or a salt thereof.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION In the present invention, the acyl group represented by R ₁ in a 13-membered ring macrolide compound represented by the general formula [I] (hereinafter referred to as compound [I]) is, for example, a formyl group, an acetyl group. , Propionyl group,
It means a butyryl group, a pivaloyl group, a benzoyl group, an ethoxycarbonyl group, a tert-butoxycarbonyl group, a benzyloxycarbonyl group and the like, and preferably a benzyloxycarbonyl group or an acetyl group.

The acyloxy groups represented by R ₂ and R ₃ include formyloxy, acetyloxy, propionyloxy, butyryloxy, pivaloyloxy,
Benzoyloxy group, ethoxycarbonyloxy group, t
-Butoxycarbonyloxy group, benzyloxycarbonyloxy group and the like.

The lower alkyl group of R ₁₁ in NOR ₁₁ formed by R ₂ and R ₃ or R ₄ and R ₅ together is
It means an alkyl group having 1 to 6 carbon atoms.

The acyl groups represented by R ₆ , R ₇ , R ₈ , R ₉ and R ₁₀ include formyl, acetyl, propionyl, butyryl, pivaloyl, benzoyl, ethoxycarbonyl, tert-butoxycarbonyl And a benzyloxycarbonyl group, preferably a benzyloxycarbonyl group. As the lower alkyl group, an alkyl group having 1 to 6 carbon atoms, preferably a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-
A butyl group, a sec-butyl group or a tert-butyl group.
As the lower alkenyl group, an alkenyl group having 2 to 6 carbon atoms, preferably a vinyl group, an allyl group, a 1-butenyl group,
It is a 2-butenyl group or a 3-butenyl group. The lower alkynyl group is an alkynyl group having 2 to 6 carbon atoms, preferably an ethynyl group, a propargyl group or a butynyl group. The cycloalkyl group is a cycloalkyl group having 3 to 8 carbon atoms, preferably a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group.
Examples of the 3- to 7-membered heterocyclic saturated monocyclic ring containing an oxygen atom, a sulfur atom or a nitrogen atom as a hetero atom include a tetrahydrofuranyl group, an oxetanyl group, a tetrahydrothienyl group, an azetidyl group, a pyrrolidinyl group and a piperidyl group.

An azacycloalkyl group formed by R ₆ and R ₇ or R ₈ and R ₉ together with the nitrogen atom to which they are attached, refers to one or more carbon atoms of the cycloalkyl group. A group replaced with a nitrogen atom,
For example, an aziridinyl group, an azetidinyl group, a pyrrolidinyl group, a piperidino group, a hexamethyleneimino group and the like can be mentioned.

In the present invention, in the compound [I],
The expression "optionally having a substituent (s)" for R ₆ , R ₇ , R ₈ , R ₉ and R ₁₀ means a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a cycloalkyl group,
Or 3 to 7 membered heterocyclic monocyclic ring containing an oxygen atom, a sulfur atom or a nitrogen atom as a hetero atom, 1) has no substituent, or 2) has a substituent.

Examples of the substituent include a hydroxyl group, an amino group, a halogen atom, a cyano group, an alkyloxy group, a mercapto group, an acyl group and a carbamoyl group.

In the compound [I], Y is -N ⁺ (R ₈ )
When (R ₉ ) (R ₁₀ ) X ⁻ is represented, examples of the anion represented by X ⁻ include a chloride ion, a bromide ion, an iodine ion, a trifluoroacetate ion and a trifluoromethanesulfonate ion. .

In the compound [I], R ₁ and R ₂ are hydrogen atoms, R ₃ is a hydrogen atom, a hydroxyl group or an amino group, or R ₂ and R ₃ together form ＝ O or ＮN- OR
₁₁ , R ₁₁ is a hydrogen atom or a lower alkyl group,
R ₄ and R ₅ together are ＯO, and Y is —N (R
₆₎ (R ₇₎ or _{^{-N + (R 8) (R}} 9) (R 10) X - a is, R
₆ , R ₇ , R ₈ , R ₉ and R ₁₀ are the same or different and are a hydrogen atom, a lower alkyl group optionally having a substituent, a lower alkynyl group optionally having a substituent, a substituent Or a lower alkenyl group which may have a substituent, a cycloalkyl group which may have a substituent, or an oxygen atom, a sulfur atom or a nitrogen atom which contains a hetero atom which may have a substituent. A compound having a hydroxyl group, an amino group, a halogen atom, a cyano group, an alkyloxy group, a mercapto group, an acyl group or a carbamoyl group, wherein X ^- is an anion, or a salt thereof. It has an affinity for the motilin receptor and has an excellent gastrointestinal contractile motility promoting action, as shown in the test examples described below, and is useful as a gastrointestinal contractile motility promoter for mammals.

The compound of the general formula [I] of the present invention can be prepared by reacting the compound of the general formula [II]

Embedded image (Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and Y represent the same meaning as described above) in a solvent such as water, an organic solvent or water + organic solvent, Reacts with bases such as alkali metal alcoholates, alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates, sodium hydride, sodium amides, alkyllithiums, alkylamines at -20 to 70 ° C To obtain a ring rearrangement reaction in the molecule (see Step 2 described later). The compound of the general formula [II] is disclosed in
6873, JP-A-6-212886, JP-A-8-2
No. 45,684.

Further, after the above-described ring rearrangement reaction, the substituent —N (Me) ₂ , —NHMe or —NH ₂ represented by Y in the formula (I) is converted according to the method described in Examples of the above publication. Then, another compound of the formula (I) can be produced by conversion to another Y.

The compound [I] can be produced, for example, by the following reaction formula (1-1)

[0021]

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Wherein R ₁ ′ and R ₂ ′ represent an acyl group, and CBZ represents a benzyloxycarbonyl group.
And the following reaction formula (1-2)

[0023]

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[Wherein R is a lower alkyl group which may have a substituent, a lower alkenyl group which may have a substituent, a lower alkynyl group which may have a substituent,
A cycloalkyl group which may have a substituent, or a 3- to 7-membered heterocyclic saturated monocyclic ring containing an oxygen atom, a sulfur atom or a nitrogen atom as a hetero atom which may have a substituent, and L is Halogen atom, OTs (paratoluenesulfonyloxy) group or OMs (methanesulfonyloxy)
X represents a chlorine, bromine or iodine, trifluoroacetyloxy or trifluoromethanesulfonyloxy group, etc.], and can be obtained by the steps (1) to (7). The respective steps will be described below.

Step (1): 2'-O-acyl-4 "-O-acyl-11-oxo- represented by the general formula (a) (wherein R ₁ 'and R ₂ ' represent an acyl group) By dissolving 8,9-anhydroerythromycin A (described in JP-A-6-56873) in an inert solvent and subjecting it to a deacylation reaction in the presence of a base, the compound represented by the general formula (b) is obtained. Can be manufactured.

Here, examples of the inert solvent include acetone, ether, tetrahydrofuran, dioxane, dichloromethane, chloroform, N, N-dimethylformamide, acetonitrile, dimethylsulfoxide and the like, and a mixed solvent thereof. It is tetrahydrofuran. Examples of the base include sodium hydride, sodium hydroxide, potassium hydroxide and the like. The reaction temperature is usually -20 to 50.
° C, preferably from 0 to 30 ° C.

Step (2): The compound represented by the general formula (b) (R ₁ 'represents an acyl group) obtained in the step (1) is intramolecularly dissolved in a solvent in the presence of a base. By subjecting the ring to a rearrangement reaction, the compound of the present invention represented by the general formula (c) (wherein R ₁ ′ represents an acyl group) can be produced. Although it does not specifically limit as a solvent, For example, water, an organic solvent or water + organic solvent can be mentioned, Preferably it is a mixed solvent of water + organic solvent.

Examples of the organic solvent include aromatic hydrocarbon organic solvents such as benzene, toluene and xylene; ethyl ether, butyl ether, tetrahydrofuran,
Ether organic solvents such as dioxane; methanol,
Aliphatic alcohol-based organic solvents such as ethanol, propanol and butanol; halogenated hydrocarbon-based organic solvents such as methylene chloride and 1,2-dichloroethane; nitrile-based organic solvents such as acetonitrile; N, N-dimethylformamide; Examples include aprotic polar organic solvents such as dimethyl sulfoxide, and preferred are ether-based organic solvents.

As the base, for example, sodium methylate, sodium ethylate, sodium propylate,
Alkali metal alcoholates such as sodium butyrate, potassium methylate, potassium ethylate, potassium propylate, potassium butyrate; alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; magnesium hydroxide, calcium hydroxide and the like Alkaline earth metal hydroxides; alkali metal carbonates such as sodium carbonate and potassium carbonate; sodium hydride; sodium amide; alkyllithium; and amines such as triethylamine, trimethylamine and tributylamine; Metal hydroxide or sodium hydride, more preferably sodium hydroxide, potassium hydroxide or sodium hydride. The reaction temperature is generally -20 to 70C, preferably 0 to 40C.

Step (3): The compound represented by the general formula (c) obtained in the step (2) is dissolved in a lower alcohol in the presence or absence of a base, and the acyl protecting group at the 2'-position is dissolved. By removing (R ₁ ′), the compound of the present invention represented by the general formula (d) can be produced. Examples of the lower alcohol include aliphatic lower alcohols such as methanol, ethanol, propanol and butanol, and preferably methanol. As the base, the same base as that used in step (2) can be used. The reaction temperature is usually -20 to 80C, preferably 20 to 60C.

Step (4): The compound represented by the general formula (e) is obtained by reacting the compound represented by the general formula (d) obtained in the step (3) with benzyloxycarbonyl chloride in an inert solvent in the presence of a base. (Wherein CBZ has the same meaning as described above).

Examples of the inert solvent include aromatic hydrocarbon organic solvents such as benzene, toluene and xylene; ether organic solvents such as ethyl ether, butyl ether, tetrahydrofuran and dioxane; methylene chloride;
Halogenated hydrocarbon-based organic solvents such as 1,2-dichloroethane; nitrile-based organic solvents such as acetonitrile; acetone; and the like, preferably aromatic hydrocarbon-based organic solvents, particularly preferably toluene It is.

Examples of the base include alkali metal carbonates such as sodium carbonate and potassium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; and amines such as triethylamine, trimethylamine and tributylamine. And preferably sodium bicarbonate or potassium bicarbonate. The reaction temperature is generally 0 to 80 ° C, preferably room temperature to 50 ° C.

Step (5): The benzyloxycarbonyl group at the 2'-position and the 3'-position of the compound represented by the general formula (e) obtained in the step (4) is hydrogenated in the presence of a metal catalyst such as palladium. Removal using a gas (3 to 4 atm) or a compound serving as a hydrogen source can produce the compound of the present invention represented by the formula (f). Here, examples of the compound serving as a hydrogen source include formic acid, ammonium formate, and sodium formate, and preferably ammonium formate.

Step (6): The compound of the general formula (f) obtained in the step (5) is added to the compound of the general formula [III]: RL (wherein R and L have the same meanings as described above) Is reacted in an inert solvent in the presence of a base,
The compound of the present invention represented by the general formula (g) can be produced. (JP-A-6-56873, JP-A-6-56873)
No. 211886, JP-A-63-99092)

In the compound [III], the expression "optionally having a substituent" represented by R means the above-mentioned R ₆ , R
₇ represents the same meaning as "optionally substituted" relating to R _8, R ₉ and R _10. The halogen atom represented by L is
It is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

Examples of the inert solvent include dimethyl sulfoxide, N, N-dimethylformamide, dimethoxyethane, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, acetone, acetonitrile, 1,3-
Examples thereof include dimethylimidazolidone or a mixed solvent thereof. As the base, the same base as used in step (4) can be used. The reaction temperature is usually from 0 to 150
° C, preferably 60 to 110 ° C.

Step (7): The compound represented by the formula (g) obtained in the step (6) is further converted into a compound represented by the general formula (IV): RX (wherein R and X have the same meanings as described above) And Y is -N ⁺ (R ₈ ) (R ₉ ) (R ₁₀ )
X ^- (wherein, R _8, R ₉ and R ₁₀ are as defined above R, X ^- are as defined above) to give compound a (h).

The compound represented by the general formula [I], in which R ₄ and R ₅ together form ＯO, is reacted with an appropriate reducing agent to give R ₄ or R _4.
A compound in which ₅ is a hydroxyl group can also be obtained.

The compound [I] of the present invention or a salt thereof can be obtained by applying the specific production methods described in the Examples.

The above-mentioned compound or a salt thereof can be used in a conventional pharmaceutical excipient, for example, water or gelatin, lactose, starch, magnesium stearate, talc, vegetable oil, gum, polyalkylene glycol, or other inert organic or inorganic substance. A standard pharmaceutical formulation with various carrier materials,
It is effective for oral or parenteral administration. The pharmaceutical preparations can be used in solid form, for example as tablets, suppositories, capsules, or in liquid form, for example as solutions, suspensions or emulsions. Other pharmaceutical additives may also be added and may include, for example, preservatives, stabilizers, wetting or emulsifying agents, salts that alter osmotic pressure or act as buffers. Pharmaceutical formulations can also include other therapeutically active substances.

The daily dosage of the above compounds to be administered will vary depending on the particular compound employed, the route of administration and the condition of the patient, but oral dosage forms preferably range from 0.1 mg to 200 mg per day for an adult. Is administered.
Parenteral dosage is preferably 0.01 mg / day for adults.
Doses ranging from to 20 mg are administered.

Hereinafter, the production of the compound of the present invention will be described in more detail with reference to Examples, but the present invention is not limited to these Examples.

[0044]

【Example】

 Example 1 (1)

[0045]

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2'-O-acetyl-4 "-O represented by
5.0 g of formyl-11-oxo-8,9-anhydroerythromycin A (compound 1) (see JP-A-6-56873) was dissolved in 25 ml of THF, and further dissolved in 12N.
5 ml of a -NaOH aqueous solution was added, and the mixture was reacted at room temperature for 2 hours. After completion of the reaction, the obtained reaction product is neutralized with hydrochloric acid,
The THF was distilled off and extracted with 30 ml of ethyl acetate. The organic phase was washed three times with 10 ml of a saturated saline solution, dried over magnesium sulfate, filtered, and the solvent in the filtrate was distilled off under reduced pressure.

[0047]

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4.8 g of a white powder of 2'-O-acetyl-11-oxo-8,9-anhydroerythromycin A (compound 2) represented by
%). FAB-MS m / z 756 (MH ⁺ )

(2) 3 ml of THF was placed in a flask having a capacity of 50 ml.
And 0.383 g of sodium hydride (60% in oil), 4.8 g of Compound 2 and 0.2 ml of water were further added under an argon atmosphere, and then reacted at room temperature for 1 hour. After completion of the reaction, the reaction solution was neutralized with 1N-HCl, THF was distilled off under reduced pressure, and the mixture was extracted with ethyl acetate. The organic phase was washed with brine and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography [eluent; chloroform: methanol: concentrated aqueous ammonia = 95: 5: 0.5],
The following formula:

[0050]

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3 g of a white powder of compound 3 represented by the following formula [68% yield based on compound 2] was obtained. FAB-MS m / z 698 (MH ⁺ )

Example 2 3.0 g of Compound 3 was dissolved in 20 ml of methanol and reacted at room temperature for 2 days, and further reacted under heating at 50 ° C. for 3 hours. After completion of the reaction, methanol was distilled off from the obtained reaction mixture, a saturated aqueous solution of sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated saline 3
After washing twice and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was dissolved in 3 ml of acetone, 4 ml of a 10% aqueous ammonia solution was added, and the mixture was stirred at 0 ° C. for 1 hour. The precipitated crystals were filtered, and the obtained crystals
C. for 3 hours under reduced pressure and the following formula:

[0053]

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1.3 g of compound 4 represented by the formula [Compound 3
46% based on yield).

The analytical data of compound 4 are shown below. FAB-MS m / z 656 (MH ⁺ )

¹ H-NMR (δ, CDCl ₃ ) 5.24 (q, J = 6.83 Hz, 1H, H-
12), 4.93 (d, J = 4.9Hz, 1H, H-1 "), 4.48 (d, J = 10.3Hz, 1H, H
-3), 4.36 (d, J = 7.3Hz, 1H, H-1 '), 4.05 (dq, J = 6.4Hz, J = 9.
3Hz, 1H, H-5 "), 3.78 (d, J = 9.3Hz, 1H, H-5), 3.52-3.47 (2
H, overlap, q and m, H-5 ', H-10), 3.30 (s, 3H, 3 "-OMe),
3.20 (dd, J = 7.3Hz, J = 9.8Hz, 1H, H-2 '), 3.03 (m, 1H, H-4 "),
2.88 (d, q, 1H, H-2), 2.80 (d, J = 16.1Hz, 1H, H-7), 2.50 (dd
d, 1H, H-3 '), 2.38 (d, J = 15.1Hz, 1H, H-2 "), 2.30 (s, 6H, NM
e ₂ ), 2.03 (d, J = 16.1Hz, 1H, H-7), 1.88 (ddq, J = 10.3Hz, J =
8.8Hz, J = 7.3Hz, 1H, H-4), 1.69 (dddd, 1H, H-4 '), 1.58 (d
d, J = 4.9Hz, J = 15.1Hz, 1H, H-2 "), 1.44 (s, 3H, 8-Me), 1.38
-1.31 (9H, overlap, d, d, and s, 9H, 12-Me, 6-Me, 5 "-Me),
1.27-1.14 (16H, overlapping, 2-Me, 5'-Me, 3 "-Me, 10-Me, 4-Me,
H-4 '). [Α] _D ²⁵ : −115.7 ° (c = 1.0, CHC
l ₃ )

Example 3 0.77 g (60% in oil) of sodium hydride was added to a 200 ml four-necked flask under an argon atmosphere, and 30 ml of THF containing 0.34 g of water was added dropwise under ice cooling. After the completion of the dropwise addition, the temperature was raised to room temperature.
0 g was dissolved in 10 ml of THF and added dropwise. After stirring at room temperature for 5 hours, 0.78 g of sodium hydride (60% in
oil) and water (0.33 ml) were added dropwise in three portions. After stirring at room temperature for 12 hours, 40 ml of methanol and 20 ml of a saturated aqueous solution of sodium hydrogen carbonate were added, and the mixture was reacted by heating at 60 ° C. for 3 hours. After completion of the reaction, methanol was distilled off from the obtained reaction mixture under reduced pressure, and the mixture was extracted with 100 ml of ethyl acetate. The organic phase was washed three times with 50 ml of a saturated aqueous sodium hydrogen carbonate solution, and the organic phase was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and 7 ml of acetone and 45 ml of a 10% aqueous ammonia solution were added for crystallization, followed by stirring at 0 ° C. for 1 hour. The precipitated crystals were filtered and dried under reduced pressure at 50 ° C. to obtain 1.02 g of compound 4 as white crystals.

Example 4 (1) 1.1 g of Compound 4 was placed in a 25-ml flask.
Toluene (10 ml) and sodium hydrogen carbonate (1.73 g) were added, and the mixture was stirred at room temperature. 0.5 g of benzyloxycarbonyl chloride was added dropwise thereto, and the mixture was reacted at room temperature for 2 hours.
g was added and reacted at 45 ° C. for 3 hours. After completion of the reaction, the obtained reaction mixture was cooled to 0 ° C, 0.11 g of pyridine dissolved in 2 ml of toluene was added dropwise, and the mixture was stirred at 5 to 15 ° C for 1 hour. Further, 8 ml of water was added, the mixture was stirred at room temperature for 10 minutes, and extracted with 25 ml of ethyl acetate. The organic phase was washed twice with saturated saline and dried over magnesium sulfate. The solvent is distilled off under reduced pressure to give a viscous oil, of the formula:

[0059]

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7.1 g of the compound 5 shown in the above was obtained. FAB-MS m / z 910 (MH ⁺ ), 412

(2) In a glass autoclave having a capacity of 500 ml, 7.1 g of Compound 5 and 1.3 g of sodium hydrogencarbonate were added.
g, 10% Pd / C (3.3 g) and methanol (50 ml) were added, and the mixture was reacted at a hydrogen pressure of 3 kg / cm ² at 20-30 ° C. for 6 hours. After completion of the reaction, palladium carbon was filtered off from the obtained reaction mixture, and the solvent was distilled off under reduced pressure.
Extracted with 0 ml. The organic phase was washed with 35 ml of a saturated aqueous solution of sodium hydrogen carbonate, further washed twice with a saturated saline solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 0.7 g of a white powder. The obtained powder was acetonitrile 1
Recrystallized in 00 ml, the following formula:

[0062]

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0.5 g of a white powder of the compound 6 represented by
[Yield 46% based on compound (4)] was obtained.

The analysis results of this compound 6 were as follows. FAB-MS m / z 642 (MH ⁺ )

¹ H-NMR (400 MHz, CDCl ₃ ) δ 5.23 (q, J = 6.83
Hz, 1H, H-12), 4.93 (d, J = 4.9Hz, H-1 "), 4.45 (d, J = 10.3H
z, 1H, H-3), 4.35 (d, J = 7.8Hz, 1H, H-1 '), 4.04 (dq, 1H, H-
5 "), 3.79 (d, J = 8.8Hz, 1H, H-5), 3.54 (m, 1H, H-5 '), 3.47
(q, J = 6.8Hz, 1H, H-10), 3.30 (s, 3H, 3 "-OMe), 3.13 (dd, J =
7.4Hz, J = 9.8Hz, 1H, H-2 '), 3.03 (m, 1H, H-4 "), 2.86 (dq, 1
H, H-2), 2.73 (d, J = 16.1Hz, 1H, H-7), 2.50 (ddd, J = 9.7Hz,
J = 4.4Hz, 1H, H-3 '), 2.41 (s, 3H, NMe), 2.37 (d, J = 15.1Hz,
1H, H-2 "), 2.02 (d, J = 16.1Hz, 1H, H-7), 1.95 (dddd, 1H, H-
4 '), 1.88 (J = 10.3Hz, J = 8.8Hz, J = 7.3Hz, 1H, H-4), 1.58 (d
d, J = 4.9Hz, J = 15.1Hz, 1H, H-2 "), 1.44 (s, 3H, 8-Me), 1.36
-1.34 (9H, overlap d, d, and s, 9H, 12-Me, 6-Me, 5 "-Me), 1.2
6-1.20 (9H, overlapping, 2-Me, 5'-Me, 3 "-Me), 1.20 (d, J = 6.8
3Hz, 3H, 10-Me), 1.19-1.07 (4H, overlap, q and ddd, 4-M
e, H-4 '). [Α] _D ²⁵ : -144.2 ° (c = 1.0, CHC
l ₃ )

Test Example A motilin receptor binding test was performed by the following method [V. Bormans et al., Regul, Peptides, 15, 143.
(1986)]. The duodenum was excised from the sacrificed rabbit, the mucous membrane was detached from the muscular layer, and a 50 mM Tris solution (pH
Homogenized in 7.4) to obtain a protein solution. After incubating 25 pM of ¹²⁵ I-labeled motilin (Otsuka Assay Lab.) And the protein solution for 120 minutes at 25 ° C., the radioactivity in the protein solution was measured with a γ counter, and the radioactivity was measured without any addition. The difference between the activity and the radioactivity when a large excess of motilin (1 × 10 ⁻⁷ M) was added was defined as specific binding. Specimen potency was expressed as IC ₅₀ , the concentration of drug that reduced specific binding by 50%. The drug was dissolved in a DMSO solution and added to the protein solution. (Final DMSO concentration 1%) As a result, IC ₅₀ of the compound 4 in a DMSO solution was 5.7.
× 10 ^-9 M.

 ────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Akira Takama 5 Ube Kogushi, Ube City, Ube City, Ube City

Claims (5)

[Claims] 1. A compound of the general formula [I] (Wherein, R ₁ represents a hydrogen atom or an acyl group. R ₂ and R ₃ may be the same or different and represent a hydrogen atom, a hydroxyl group, an acyloxy group or an amino group, or R ₂ and R ₃ together Represents = O or = NOR ₁₁ , where R
₁₁ represents a hydrogen atom or a lower alkyl group. R ₄ and R
₅ represents the same or different and represents a hydrogen atom or a hydroxyl group,
Alternatively, R ₄ and R ₅ together form ＝ O or ＮＯNOR ₁₁
Represents Y is -N (R ₆ ) (R ₇ ) or -N ⁺ (R ₈ ) (R ₉ )
(R ₁₀₎ X ^- represents a. Here, R ₆ , R ₇ , R ₈ , R ₉ and R ₁₀ are the same or different and each may have a hydrogen atom, an acyl group, a lower alkyl group which may have a substituent, or a substituent. A good lower alkenyl group, a lower alkynyl group which may have a substituent, a cycloalkyl group which may have a substituent, or an oxygen atom, a sulfur atom or a hetero atom which may have a substituent 3 containing nitrogen atom
May represent a 7-membered heterocyclic monocyclic ring, or R ₆ and R ₇ or R ₈ and R ₉ may together form a azacycloalkyl group with the nitrogen atom to which they are attached; X ^- is a compound or a salt thereof represented by represents an anion). 2. R ₁ and R ₂ are hydrogen atoms, R ₃ is a hydrogen atom, a hydroxyl group or an amino group, or R ₂ and R ₃ together are ＯO or ＮN—OR ₁₁ , R ₁₁ is a hydrogen atom or a lower alkyl group, R ₄ and R ₅ are ＝ O together, and Y is —N (R ₆ ) (R ₇ ) or —N ⁺ (R
_{8) (R 9) (R} 10) X - a _{and, R 6, R 7, R} 8, R 9
And R ₁₀ are the same or different and are a hydrogen atom, a lower alkyl group which may have a substituent, a lower alkynyl group which may have a substituent, a lower alkenyl group which may have a substituent A cycloalkyl group which may have a substituent, or a 3- to 7-membered saturated monocyclic ring containing an oxygen atom, a sulfur atom or a nitrogen atom as a hetero atom which may have a substituent, Group is a hydroxyl group, an amino group, a halogen atom, a cyano group, an alkyloxy group, a mercapto group,
The compound or a salt thereof according to claim 1, wherein the compound is an acyl group or a carbamoyl group, and X ^- is an anion. 3. A medicament comprising the compound according to claim 2 or a salt thereof. 4. The medicament according to claim 3, which is a gastrointestinal contraction promoter. 5. A compound of the general formula [II] Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and Y have the same meaning as in claim 1, and reacting with a base to convert the compound into a 13-membered ring macrolide compound. The method for producing the compound according to claim 1 or a salt thereof.