WO1994010185A1

WO1994010185A1 - Erythromycin derivative

Info

Publication number: WO1994010185A1
Application number: PCT/JP1993/001594
Authority: WO
Inventors: Hiroshi Koga; Kouichi Tsuzuki
Original assignee: Chugai Seiyaku Kabushiki Kaisha
Priority date: 1992-11-04
Filing date: 1993-11-04
Publication date: 1994-05-11
Also published as: AU5376394A; CN1091431A; TW355711B

Abstract

A compound represented by general formula (I) or a salt thereof, each being orally administrable because of being excellent in the effect of promoting gastrointestinal movement and extremely reduced in the extent of decomposition by the action of gastric juice as compared with the known erythromycin derivatives wherein R1 represents hydrogen or acyl; R¿2? and R3, which may be the same or different from each other, represent each hydrogen, hydroxy or acyoxy, or R2 and R3, which may be combined together to represent = O; R4 represents hydrogen or lower alkyl; R5 represents lower alkyl; Y represents -NR6R7 or -N?+R¿8R9R10X-; R6 and R7, which may be the same or different from each other, represent each hydrogen, acyl, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted lower alkenyl or optionally substituted lower alkynyl; R8, R9 and R10, which may be the same or different from one another, represent each hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted lower alkenyl or optionally substituted lower alkynyl; and X represents an anion.

Description

Specification

Erythromycin derivative

[Technical field]

The present invention relates to an erythromycin derivative or a salt thereof, which has an action of promoting the contraction of the digestive tract of mammals and is useful as an agent for promoting the contraction of the gastrointestinal tract.

[Background technology]

Gastrointestinal motility promoters are considered to be direct acetylcholine agonists (acratonium napadisylate), indirect acetylcholine agonists (cisapride), dopamine blockers (domperidone), and opiate agonists (trimeptin maleate) from the viewpoint of action. It is widely used as a therapeutic drug for gastrointestinal symptoms such as dysfunction of gastrointestinal motility, particularly indefinite complaints of gastrointestinal dysfunction due to hypokinesia. However, these drugs have side effects such as extrapyramidal symptoms and increased lactation due to dopamine blocking action. In addition, the mode of gastrointestinal motility promoted by these drugs is different from the naturally occurring physiologic movement that propagates from the upper gastrointestinal tract to the lower gastrointestinal tract, and is often accompanied by side effects such as diarrhea and vomiting. Is known o

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 has been unsatisfactory, and large-scale supply has been difficult. Since motilin is a peptide consisting of 22 amino acids, it was difficult to develop it as an oral preparation.

In recent years, erythromycin and its derivatives have strong gastrointestinal contractions EM-523, one of its derivatives, is being developed as a gastrointestinal motility promoter (Japanese Patent Publication No. 60-218321, Japanese Patent Application Laid-Open No. 61-87625, 63-99016, JP-A-63-99092, and The Journal of Pharmaceuticals and Experimental Therapeutics vol. 251, No. 2. PP 707-712, 1989).

However, EM-523 is acid-labile and is expected to be degraded by gastric acid when used orally, resulting in diminished effects. Therefore, the present inventors have conducted intensive studies to find an erythromycin derivative which is acid-resistant and orally administrable, and as a result, the following novel erythromycin derivative not described in the literature has such properties and effects. And found the present invention based on this finding.

[Disclosure of the Invention]

The compound of the present invention is represented by the following general formula (I).

[Wherein, is 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 = 0, and R ₄ is a hydrogen atom or a lower alkyl group. And R ₅ represents a lower alkyl group, and Y represents one NR ₆ R ₇ or —N + R ₈ R ₉ R 1 ₍₎ X—. Here, R ₆ and R ₇ are the same or different and each have a hydrogen atom, an acyl group, a lower alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, or a substituent. R ₈ , R _9, and R ₁₀ may be the same or different and are a hydrogen atom and a lower alkyl optionally substituted with a lower alkenyl group which may be substituted or a lower alkynyl group which may be substituted. A cycloalkyl group which may have a substituent, a lower alkenyl group which may have a substituent or a lower alkynyl group which may have a substituent, and X represents an anion, respectively. ]

In the present invention, the term "acyl group" refers to a formyl group, an acetyl group, a propionyl group, a butyryl group, a bivaloyl group, a benzoyl group, an ethoxycarbonyl group, a t-butoxycarbonyl group, a benzyloxycarbonyl group, and the like. What is meant by formyloxy, acetyloxy, propionyloxy, butyryloxy, bivaloyloxy, benzoyloxy, ethoxycarbonyloxy, t-butoxycarbonyloxy, benzyloxycarbonyloxy, etc. And a lower alkyl group refers to 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-butyl group, a sec-butyl group, a t-butyl group. And a cycloalkyl group is a cycloalkyl group having 3 to 8 carbon atoms. Preferably cyclo A butyl group, a cyclopentyl group, a cyclohexyl group or the like; a lower alkenyl group refers to an alkenyl group having 2 to 6 carbon atoms, preferably a vinyl group, an aryl group, an n-butenyl group, an i-butenyl group, a lower alkynyl group refers to an alkynyl group having 2 to 6 carbon atoms, preferably an ethynyl group, a propargyl group, a butynyl group, and the like, and a lower group which may have a substituent; Examples of the substituent in the alkyl group, cycloalkyl group, lower alkenyl group or lower alkynyl group include a hydroxyl group, an amino group, a halogen atom, a nitrile group, an alkyloxy group, a mercapto group, a formyl group, and the like. The term “chlorine ion”, “bromine ion”, “iodine ion”, “carboxylate ion”, “sulfonate ion” and the like are used. Examples of the salt-forming acid include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, and sulfuric acid, and organic acids such as acetic acid, silicic acid, maleic acid, fumaric acid, and methanesulfonic acid. .

The compound (I) of the present invention can be produced by reacting the compound (II) with an alkylating agent in an inert solvent in the presence of a base, followed by deprotection alkylation if necessary. .

[Wherein, R !, R ₂ , R ₃ , R ₄ and Y have the same meaning as described above. ]

Examples of the alkylating agent used in the alkylation reaction include alkyl halide dialkyl sulfonates. Examples of the base include metal bases such as sodium hydride, sodium alkoxide, potassium alkoxide, alkyl lithium, lithium carbonate, sodium carbonate, sodium hydroxide, sodium hydroxide, and triethylamine, trimethylamine, and the like. Amines are used. Examples of the inert solvent include methanol, ethanol, propanol, porcine form, methylene chloride, ether, tetrahydrofuran, and Ν, Ν-dimethylformamide.

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

As is clear from the following test examples, the compound (I) of the present invention did not show a decrease in activity under acidic conditions, unlike II-523. In addition, it showed a strong gastrointestinal motility-promoting effect upon oral administration, and is particularly useful as an oral agent as a constriction motility promoter for the digestive tract of mammals.

[Best Mode for Carrying Out the Invention]

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.

[Example 1]

(1) 38.7 g of N, 2'-10-bis (benzyloxycarbonyl) de (N-methyl) erythromycin A (Compound 1) was dissolved in 100 ml of acetic acid and stirred at room temperature for 1 hour. Concentrate under reduced pressure, add 300 ml of chloroform to the residue, wash twice with 100 ml of water, 100 ml of saturated aqueous sodium bicarbonate and 100 ml of water in that order, dry over anhydrous magnesium sulfate, and evaporate the solvent under reduced pressure. I left. N, 2,10-bis (benzyloxycarbonyl) -de (N-methyl) -18,9-anhydrohydroerythromycin A 6,9-hemiketal (Compound 2) white powder 37.9 g (Yield) 99%). Compound 1 was synthesized according to the method described in the literature (EH F lynn, HW Mrp hy, R. E. McMahon; Journal of American Chem. 1 Society 77 3104 (1955)).

(2) Compound 2 37.9 g and 4-dimethylaminopyridine

38. Og was dissolved in 200 ml of dichloroethane, and 28 ml of carbobenzoxy chloride was added dropwise over 90 minutes under ice cooling. Five hours later, 4-dimethylaminopyridine 9.0 and carbobenzoxy chloride 7.0 ml were added again under ice cooling, and the mixture was stirred for 18 hours while gradually returning to room temperature. 300 ml of dichloromethane was added to the reaction solution, and the mixture was washed twice with 200 ml of 1N hydrochloric acid, 200 ml of water, 200 ml of saturated sodium bicarbonate water, and 200 ml of water in that order, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. . The residue was purified by column chromatography on silica gel (chloroform-form-methanol-concentrated aqueous ammonia (100: 1: 0.1)) to give N, 2'-10,4 "-10-tris (benzyloxy). 36.6 g (83% yield) of white powder of carbonyl) de- (N-methyl) -18,91-hydroerythromycin A6.9-hemiketal (compound 3) was obtained.

(3) Dissolve 37.7 g of compound 3 in 110 ml of dimethylformamide, and add 2.47 g of sodium hydride (60% oil) in a nitrogen stream under ice-cooling for 10 minutes. After stirring, 15 ml of benzyl bromide was added and reacted for 2 hours. The mixture was poured into 500 ml of a saturated aqueous solution of sodium bicarbonate, extracted twice with 500 ml of getyl ether. The extract was washed twice with 200 ml of water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (hexane monoethyl acetate (4: 1)) to give N, 2'-0,4 "-10-tris (benzyloxycarbonyl) -de (N-methyl). There was obtained 12.4 g (yield: 41%) of 11-1-0-benzyl-18,9-anhydrohydroerythromycin A 6,9-hemiketal (compound 4) as a white powder.

(4) Compound 4 12.4 g was added to dimethylformamide 50m

Then, 2.10 g of sodium hydride (60% oil) was added in a nitrogen stream under ice-cooling, and the mixture was stirred for 15 minutes, and then 6.5 ml of methyl iodide was added. After reacting under ice-cooling for 2 hours and at room temperature for 2 hours, the reaction mixture was poured into 300 ml of saturated aqueous sodium hydrogen carbonate and extracted twice with 200 ml of getyl ether. The extract was washed twice with 20 Om1 of water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl hexane monoacetate (4: 1)) to give N, 2'-1 0,4 "— 0-tris (benzyloxycarbonyl) -de (N-methyl) -1. 11-0-benzyl-1 12-0-methyl-1,8,9-hydroerythromycin A

There was obtained 6.74 g (yield 53%) of white powder of 6,9-hemiketal (compound 5).

(5) 6.74 g of Compound 5 was dissolved in 12 Om1 of methanol, and 582 mg of 10% palladium carbon was added to perform catalytic reduction. After 3 hours, the catalyst was removed by filtration, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (formula methanol, concentrated ammonia water (100: 4: 0.1)) and de (N-methyl) 1-111-0-benzyl-1-12-O This yielded 4.07 g (yield 90%) of white powder of 1,8,9-anhydrohydroerythromycin A 6,9-hemimetal (compound 6).

[Example 2]

De (N-methyl) 1-111-O-benzyl-12-0-methyl1.8,9-anhydroerythromycin A 6,9-1-hemiketal (Compound 6) Dissolve 304 mg in 10 ml of methanol and add 10% Catalytic reduction was performed by adding 109 mg of palladium carbon and 341 trifluoroacetic acid. After 12 hours, the catalyst was removed by filtration, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform form / methanol / concentrated aqueous ammonia (100: 4: 0.1)), and de (N-methyl) -1 12-0-methyl-8,9_ Doroerythromycin A 6,9-hemiketal (Compound 7) was obtained as a white powder (212 mg, yield 78%). Satsu e

[Example 3]

(1) 982 mg of compound 6 was dissolved in 10 ml of methanol, 0.5 ml of a 35% aqueous solution of formaldehyde and 233 mg of sodium cyanoborohydride were added, and the mixture was stirred at room temperature for 90 minutes. Saturated sodium bicarbonate solution was poured into 5 Om 1, and the resulting white precipitate was collected by filtration, washed with water, dried, and then subjected to silica gel column chromatography (form: form-methanol-concentrated aqueous ammonia (100: 4: 0.1). )). There was obtained 764 mg (76% yield) of a white powder of 11-0-benzyl-1-12-0-methyl-1,8,9-anhydroerythromycin A 6,9-hemiketal (compound 8).

Compound 8

(2) 8597 mg of this compound was dissolved in 10 ml of methanol, and 217 mg of 10% palladium carbon and 601 were added for catalytic reduction. After 24 hours, the catalyst was filtered off and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol / concentrated aqueous ammonia (100: 3: 0.1)) to give 12-0-methyl-8,9-hydroerythromycin A 6,9-hemiketal (compound 292 mg (55% yield) of white powder of 9) was obtained.

[Example 4]

(1) Compound (1.04 g) was dissolved in methanol (20 ml), diisopropylethylamine (3.4 ml), and iodo chill (1.0 ml) were added thereto, followed by stirring at room temperature for 4 days. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (chloroform-form-methanol-concentrated aqueous ammonia (100: 2: 0.1)) to give N-ethyl There was obtained 573 mg (yield 53%) of (N-methyl) 1-111-0-benzyl-12-0-methyl-8,9-anhydroerythromycin A 6,9-hemiketal (compound 10) as a white powder.

(2) 10427 mg of this compound was dissolved in 10 ml of methanol, and 115 mg of 10% palladium on carbon and 541 of trifluoroacetic acid were added to perform catalytic reduction. After 24 hours, the catalyst was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to column chromatography on silica gel (form: methanol / methanol / concentrated ammonia (100: 3: 0. 1) Purify in) and purify N-ethyl-de (N-methyl) 1-12-0-methyl-8,9 280 mg (73% yield) of white powder of sulomycin A 6,9-hemiketal (compound) was obtained.

[Example 5]

(1) 1.03 g of the compound 6 was dissolved in 2 Om1 of methanol, 2.2 ml of diisopropylethylamine and 2.5 ml of isopropyl iodide were added, and the mixture was stirred at 50 ° C. One day and four days after the start of the reaction, 2.2 ml of diisopropylethylamine and 2.5 ml of isopropyl iodide were added. After reacting for 6 days, the solvent is distilled off under reduced pressure, 50 ml of chloroform is added, and 5 Om 1 of saturated sodium bicarbonate and 5 Om 1 of water are washed in this order, dried over anhydrous magnesium sulfate, and then dried under reduced pressure. The solvent was distilled off. The residue was purified by silica gel column chromatography (chloroform-form-methanol-concentrated aqueous ammonia (100: 2: 0.1)) to give N-isopropyl-1-de (N-methyl) -1-11-0-benzyl-1 872 mg (80% yield) of white powder of 0-methyl-1,8-anhydroerythromycin A6,9-hemiketal (Compound 12) was obtained.

Compound 12 (2) 12657 mg of this compound was dissolved in 15 ml of methanol, and 404 mg of 1.0% palladium on carbon and 0.1 ml of trifluoroacetic acid were added thereto for catalytic reduction. After 24 hours, the catalyst is filtered off, the solvent is distilled off under reduced pressure, and the residue obtained is subjected to silica gel column chromatography (chloroform-form-methanol-concentrated aqueous ammonia (100: 3: 0.1)). 396 mg (yield 67) of N-isopropyl-de (N-methyl) -1-12-0-methyl-18,9-anhydrodreroerythromycin A 6,9-hemiketal (compound 13) %).

Compound 13 [Example 6]

(1) De (N-methyl) -1 11-0-benzyl-1 12-0-methyl-8,9-anhydroerythromycin A 6.9- Dissolve 130 mg of miketal (compound 6) in 3 ml of methanol and add cyclopentanone. 0.01 ml and sodium cyanoborohydride 24 mg were added, and the mixture was stirred at room temperature for 23 hours. The solvent was distilled off under reduced pressure, water was added, and the mixture was extracted with dichloromethane. The extract was washed with saturated saline and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (Cross-form-methanol (250: 1)) to give N-cyclopentylide (N-methyl) -1 11-0-benzyl-1 12-0- There was obtained 12 Omg (85% yield) of white powder of methyl 1,8,9-anhydrohydroerythromycin A 6,9-hemiketal (compound 14).

(2) Dissolve 20 mg of this compound in 5 ml of methanol, 24 mg of 10% palladium on carbon, and 0.3% of trifluoroacetic acid. 026 ml was added for catalytic reduction. The catalyst was removed by filtration, the solvent was distilled off under reduced pressure, and the residue obtained was added to chloroform.The residue was washed with saturated aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. Was distilled off. The residue was purified by silica gel column chromatography (chloroform / methanol / concentrated aqueous ammonia (150: 1: 0.1)), and N-cyclopentylide (N-methyl) -12-0-methyl-8,9 — 53 mg (yield 49%) of white powder of anhydroerythromycin A 6,9-hemiketal (compound 15) was obtained.

[Example 7]

(1) De (N-methyl) -1-11-0-benzyl-1-12-0-methyl-1,8-anhydroerythromycin A 6,9- Dissolve 130 mg of miketal (compound 6) in 3 ml of methanol and diisopropylate. 0.28 ml of tilamine and 0.64 ml of 1-propane were added, and the mixture was stirred at 50 ° C for 22 hours. The solvent was distilled off under reduced pressure. After washing with an aqueous solution of sodium hydrogen oxyate and a saturated saline solution and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (formula methanol (300: 1)) to give N-propyl- (N-methyl) _1 1-0-benzyl-1 12-0-methyl-1 8,9- There was obtained 11 Omg (81% yield) of white powder of anhydrodrerithromycin A 6,9-hemiketal (compound 16).

(2) 1611 Omg of this compound was dissolved in 5 ml of methanol, and 22 mg of 10% palladium carbon and 0.025 ml of trifluoroacetic acid were added thereto for catalytic reduction. The catalyst was removed by filtration, the solvent was distilled off under reduced pressure, and chloroform was added to the obtained residue.The residue was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, dried over anhydrous sodium sulfate, and the solvent was removed. Distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-form-methanol-concentrated-aqueous ammonia (150: 1: 0.1)) to give N-propylude (N-methyl) -1 12-0-methyl-8,9-1. 38 mg (yield 38%) of a white powder of an amide erythromycin A 6,9-hemiketal (compound 17) was obtained.

[Example 8]

(1) De (N-methyl) -1 11-0-benzyl-1 12-0-methyl-8,9-Hydroerythromycin A 6,9-miketal (Compound 6) Dissolve 230 mg in methanol 4 ml and diisopropylethyl 0.55 ml of amide and 1.43 g of 2-bromoethanol were added, and the mixture was stirred at 50 ° C for 14 hours. Dichloromethane was added to the residue obtained by evaporating the solvent under reduced pressure, washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform-form-methanol-concentrated aqueous ammonia (75: 1: 0.1)) to give N- (2-hydroxyxethyl)

189 mg (78% yield) of a white powder of (N-methyl) -11-10-benzyl-1 12-0-methyl-1,8,9-hydroerythromycin A6,9-hemiketal (I-Danied compound 18) was obtained. Obtained.

(2) Dissolve 1819 Omg of this compound in 5 ml of ethanol, 3 Omg of 10% palladium on carbon, and trifluoroacetic acid. 0.043 ml was added for catalytic reduction. The catalyst was removed by filtration, the solvent was distilled off under reduced pressure, and chloroform was added to the obtained residue.The residue was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, dried over anhydrous sodium sulfate, and the solvent was removed. Distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform form-methanol-concentrated aqueous ammonia (150: 1: 0.1)) to give N- (2-hydroxyxethyl) -de (N-methyl) -1 12- 0 methyl one 8, 9 one Anhi mud erythromycin a 6, _c a white powder was obtained 5 Omg (30% yield) of the 9- Miketa Le (compound 19)

[Example 9]

De (Ν-methyl) 12-0-methyl-1,8,9-anhydrodrerithromycin Α6,9-hemiketal (compound 7) 120 mg was dissolved in methanol 3 ml, sodium hydrogencarbonate 28 mg, aryl bromide 0. 035M l were added 40 ° C for 15 hours stirred _c evaporated to a black hole Holm to the resulting residue was added under vacuum with saturated aqueous sodium bicarbonate, washed with brine, sulfuric anhydride After drying over sodium, the solvent was distilled off under reduced pressure. Residues are subjected to gel chromatography column chromatography (chloroform-methanol

(300: 1)), N-arylude (N-methyl) -1 12-0-methyl-1,8,9-anhydrohydroerythromycin A 6,9-hemiketal (compound 20) white powder 19mg

(15% yield).

[Example 10]

(1) De (N-methyl) -1 12-0-methyl-8,9-anhydrohydroerythromycin A 6,9-hemiketal (compound 7) 10 mg dissolved in 3 ml of acetonitrile, 35% aqueous solution of formaldehyde 0.18 g and sodium cyanoborohydride (26 mg) were added, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, water was added, and the mixture was extracted with chloroform. The extract was washed with saturated saline and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was chromatographed on silica gel (chloroform-metano-lu-concentrated aqueous ammonia (150: 1: Purification was carried out in 0.1)) to obtain 11 Omg of 12-O-methyl-1,8-anhydride erythromycin A6,9-hemiketal (compound 21) as a white powder.

(2) 2112 Omg of this compound was dissolved in 3 ml of chloroform in form, and 0.095 ml of propargylbutane was added, followed by stirring at room temperature for 11 hours. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (formula methanol, concentrated ammonia water (10: 1: 0.1)). 8,9-Anhydrohydroerythromycin A.6,9-Hydromic powder 3 Omg (23% yield) of the propetalgyl bromide (compound 22) was obtained.

[Example 11]

(1) De (N-methyl) -1 12-0-methyl-1,8,9-anhydrohydroerythromycin A 6,91-hemiketal (Compound 6) 45 mg is dissolved in 2 ml of acetonitrile and disopropylethylamine 0.1 lm l, N- (2-bromoethyl) monophthal 51 Omg of mid was added, and the mixture was stirred at 50 ° C for 25 hours. The solvent was distilled off under reduced pressure, and the residue obtained was added with chloroform. The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. Residues are subjected to column chromatography on silica gel.

N- (2- (N-phthalimido) ethyl) -de (N-methyl)-1-12-methyl-8,9-anhydroerythromycin A 6,9- 20 mg (yield 36%) of a white powder of the hemicetal (compound 23) was obtained.

(2) N- (2— (N-phthalimid) ethyl) -de (N-methyl) -1-12-0-methyl-8,9-anhydrohydroerythromycin A 6, 9-hemiketal (compound 23) 2 Omg was dissolved in 2 ml of methanol, 0.5 ml of a 40% methanol solution of methylamine was added, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue obtained was added with chloroform. The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform methanol / concentrated aqueous ammonia (150: 1: 0.1)), and N- (2-aminoethyl) -de (N-methyl)- — 13 mg (80% yield) of white powder of 0-methyl-1,8-anhydroerythromycin A 6,9-hemiketal (compound 24) was obtained. _Two

Of the compounds actually produced in the above examples, compounds

Table 1, the NMR spectrum data, the MS spectrum value and the optical rotation for 6, 7, 9, 11, and 13 are shown in Table 1. The NMR spectra for compounds 15, 17, 19, 20, 22, and 24 are shown in Table 1. Table 2 shows the spectrum data, MS spectrum value, and optical rotation.

! Compound HN EC I, _{solvent: CDC1 3) FABMS [a]} D number .. 8-Me 3 '-NMe 3 "-0Me and 12-OMe (m / z) (c 1.0, CHC1 ₃ )

6 1.61 2.42 3.36, 3.39 806.8 (MH ⁺ )

7 1.59 2.41 3.34, 3.38 716.9 (MH ⁺ ) -44.2 °

9 1.58 2.28 3.35, 3.38 730.2 (MH ⁺ ) -45.6.

11 1.58 2.23 3.35, 3.38 744.7 (MH ⁺ ) -46.8 °

13 1.58 2.21 3.36, 3.39 758.7 (MH ⁺ ) -43.8. ! Table 2 Compound _{H-NMRCSI, iI: CDCl 3} (iL22liCD 3 0D) FABMS [a JD

Number 8-Me 3 '-NMe 3 "-0Me 12-OMe (m / z)

15 1. 58 2.18 3.35 3.38 784 ( MH +) -38.7 ° (c0.92 CHC1 3)

17 1.58 2.23 3.35 3.39 758 (MH ⁺ ) -37.8 ° (c0.69 CHCI3)

19 1.59 2.35 3.34 3.39 760 (MH ⁺ ) -38.5 ° (c0.91 CHCI3)

20 1.59 2.23 3.34 3.39 756 (MH ⁺ ) -40.2 ° (c0.81 CHCI3)

22 1.63 2.17 3.31 3.32 769 (M ⁺ -Br) -23.3 ° (cl.30 CH3OH)

24 1.54 2.29 3.28 3.28 759 (MH ⁺ ) -23.8 ° (c0.67 CHC)

[Test Example 1]

Motilin receptor binding test was performed as follows

[V. Bormans et al., Regu l. Peptiedes,

15, 143 (1986)], the duodenum was excised from the slaughtered egret, and the mucous membrane was detached from the muscular layer, and then homogenized in a 5 OmM Tris solution (ρΗ7.4) to obtain a protein solution.

1 ²⁵ I-label motilin (purchased from Otsuka Atsushi Lab.) After incubating 25 pM and the protein solution for 120 minutes at 25 ° C, the radioactivity in the protein was measured with a 7 counter, and the radioactivity when nothing was added was added. activity and a large excess of motilin - difference (1 X 10 ⁷ M) radioactivity upon addition were the specific binding. The potency of the sample is 50

The concentration of the drug reduced to% was expressed as IC ₅ o (M). Drugs

The protein was dissolved in DMSO solution and added to the protein solution (final DMSO concentration. It was dissolved in an acid solution (pH 2.5), left at room temperature for 120 minutes, added to the protein solution, and used for the experiment.

As a result, IC _{5 in} DMSO solution. (M) is EM- 523 3x 10- ⁹ to Compound 13 8 X 10- 9 a is the activity of this second sample were comparable. In the hydrochloric acid solution, the IC ₅ Q (M) of EM-523 was 3 × 10 and the activity was reduced by a factor of 100 as compared with the DMSO solution, but the IC ₅₀ (M) of compound 13 was 2 × 10-8. There was almost no difference from the DMSO solution. This proved that Compound 13 was less easily decomposed by acid than EM-523. Table 3

[Trial example 2]

The gastrointestinal contractile movement was measured by the following method [Satoru Ito, Journal of the Japanese Society of Smooth Muscle, 13, 33 (1976)]. A beagle dog weighing about 10 kg is laparotomized under general anesthesia in advance, and a force 'transducer is chronically applied to the gastric antrum, duodenum and jejunum in a direction in which the contraction of each cricoid muscle can be measured. did. In addition, a medical silicone tube was placed in the stomach to directly administer the drug into the stomach. The lead wire of the Force 'transducer and the silicone tube were pulled out from the back and fixed to the skin. Reared in individual laboratory cages, feed once daily Was.

Force 'The principle of the transducer is that when the gasket at the abutted part shrinks and the transducer is bent, a waveform proportional to the force is recorded on a pen-written oscillograph. By connecting the lead from the transducer to the oscillograph, the contraction waveform can be recorded immediately. Gastrointestinal contractile movements can be broadly divided into two phases, the postprandial period and the fasting period, based on their contraction patterns.

The experiment was started two weeks after the operation, and was performed in the fasting period, during the rest period in which no gastric fasting contraction occurred. That is, the sample was directly injected into the stomach for about 10 seconds through a silicon tube placed in the stomach. The drug was dissolved in ethanol beforehand and diluted with saline to make a total volume of 3 ml.

To quantitatively express the effect of promoting gastrointestinal contraction, the area between the baseline and the contraction waveform when the movement in the stomach is at rest is defined as the Motor Index (MI), which is used as an index of gastric momentum. Natomi et al., J. Pharmacol. Ex p. Ther., 251, 707 (1989)]. MI entered the signal from the force transducer that hit the stomach into a computer (PC-9801, NEC) and calculated it. The gastric momentum of a fasting disseminated contraction that occurs spontaneously in the fasting period is expressed by MI calculated in this way as MI = 100 to 200. Therefore, the dose of the drug required to represent M 1 = 150 was taken as MI ₁₅ o and used as an index of the gastrointestinal motility promoting effect of the drug.

By intragastric administration, EM-523 and Compound 13 Each showed a gastrointestinal motility-promoting action, and the respective MI _{15 ()} was 14.6 t / gZkg and 2.3 / gZkg. Compound 13 showed a gastrointestinal motility-promoting effect about 6 times stronger than that of EM-523 by intragastric administration.

[Industrial applicability]

The erythromycin derivative of the present invention having a gastrointestinal motility-promoting action is remarkably superior to the conventionally known erythromycin derivative such as EM-523 in terms of acid stability. The erythromycin derivative of the present invention, unlike the conventional erythromycin derivative which is unstable to acid, has a very low degree of decomposition by stomach acid, and thus shows a strong gastrointestinal motility promoting action even when used orally.

Claims

The scope of the claims

General formula

[Wherein, is 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 = 0, and R ₄ is a hydrogen atom or a lower alkyl group. , R ₅ is a lower alkyl group, Y is —NR ₆ R ₇ or —N + R ₈ R ₉

R ₁₀ X— are shown respectively. Here, R ₆ and R ₇ are the same or different and each have a hydrogen atom, an acyl group, a lower alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, or a substituent. A lower alkenyl group which may be substituted or a lower alkynyl group which may have a substituent, R ₈ , R ₉ and R ₁₀ may be the same or different and may have a hydrogen atom or a substituent X represents an anion; a lower alkyl group, a cycloalkyl group which may have a substituent, a lower alkenyl group which may have a substituent or a lower alkynyl group which may have a substituent; Or a salt thereof.