WO2000009530A1 - Methode d'elaboration de derives d'erythromycine - Google Patents

Methode d'elaboration de derives d'erythromycine Download PDF

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Publication number
WO2000009530A1
WO2000009530A1 PCT/JP1999/004301 JP9904301W WO0009530A1 WO 2000009530 A1 WO2000009530 A1 WO 2000009530A1 JP 9904301 W JP9904301 W JP 9904301W WO 0009530 A1 WO0009530 A1 WO 0009530A1
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Prior art keywords
group
carbon atoms
hydrogen
salt
acid
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English (en)
Japanese (ja)
Inventor
Satoshi Omura
Toru Ishida
Yoshiko Uchida
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Kitasato Institute
Takeda Pharmaceutical Co Ltd
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Kitasato Institute
Takeda Chemical Industries Ltd
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Priority to AU50673/99A priority Critical patent/AU5067399A/en
Publication of WO2000009530A1 publication Critical patent/WO2000009530A1/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins

Definitions

  • the present invention relates to digestive symptoms associated with digestive disorders in mammals, particularly postoperative ileus in humans, diabetic gastroparesis, dyspepsia, reflux esophagitis, pseudo ileus, and postgastrectomy syndrome (upper abdominal distension). Sensation, overpressure in the abdomen, nausea, vomiting, heartburn, anorexia, epigastric pain, epigastric tenderness), chronic gastritis, irritable bowel syndrome, morphine and constipation due to administration of anticancer drugs. To a method for producing an erythromycin derivative or a salt thereof, which is useful as a pharmaceutical for the purpose. Background art
  • Japanese Patent Application Laid-Open No. 10-067975 discloses an erythromycin derivative, N-demethyl-N-isopropyl_8,9-anhydroerythromycin A-6,9- Myacetal and N-demethyl-1-N-ethyl-8,9-anhydroerythromycin A-6,9-hemiacetone are described.
  • the publication discloses that N-demethylerythromycin A is reacted with an isopropylating agent in the presence of a base, and then treated with an acid to give N-demethyl-N-isopropyl poryl-1,8,9-anhydro.
  • a method for producing erythromycin A-6,91-micease is disclosed.
  • N-demethylerythromycin A is treated with an acid to form a 6,9-hemiacetyl ring, and then reacted with an ethylating agent in the presence of a base to give N-demethyl-N-ethyl.
  • a method for producing —8,9-anhydroerythromycin A—6,9-hemiacetal has been disclosed.
  • N-demethylerythromycin A is used as a starting compound and the N-alkylation reaction is carried out in the presence of an organic base in the reaction solvent described in Japanese Patent Application Laid-Open No. 10-067975. During the reaction, crystals of the raw material compound tend to precipitate, and Therefore, there is a problem that it takes a long time to complete the reaction. On the other hand, when the above-mentioned N-alkylation reaction is performed in the presence of an inorganic base, precipitation of the raw material crystals is avoided, and the reaction time is reduced, but the target product is separated from the base after the reaction. There was a problem that the operation was complicated.
  • N-demethylerythromycin derivatives for example, N-demethylerythromycin A
  • solvents having high solubility for N-demethylerythromycin derivatives such as cyclic amides (for example, N -Methyl-2-pyrrolidone, N-methyl-2-piperidone, etc.) or a mixed solvent of the cyclic amide and an alkyl nitrile (eg, acetonitrile, propionitrile, ptyronitrile, etc.) as a reaction solvent.
  • the present inventors after treating an N-demethylerythromycin derivative represented by N-demethylerythromycin A with an acid, form a cyclic amide (eg, N-methyl-12-pyrrolidone, N-methyl-2 —Piperidone, etc.) or a mixed solvent of the cyclic amide and an alkyl nitrile (eg, acetonitrile, propionitrile, ptyronitrile, etc.) as a reaction solvent, and N-alkylation, N-alkenylation or N— By subjecting it to an alkynylation reaction, the reaction selectivity is improved, and the reaction time can be shortened.
  • a cyclic amide eg, N-methyl-12-pyrrolidone, N-methyl-2 —Piperidone, etc.
  • an alkyl nitrile eg, acetonitrile, propionitrile, ptyronitrile, etc.
  • the present invention relates to erythromycin derivatives, especially N-demethyl-N-isopropyl-18,9-anhydroerythromycin A-6,9-hemiacetal and N-demethyl-N-ethyl-8,9-anhydroerythromycin A-6,9 It is intended to provide a method for producing hemiacetal in high quality (high purity), high yield, and in a short time.
  • compound (I) a salt thereof
  • R 8 -X (V) Wherein R 8 represents an alkyl group having 16 carbon atoms, an alkenyl group having 26 carbon atoms or an alkynyl group having 26 carbon atoms, and X represents a leaving group.
  • V represents an alkyl group having 16 carbon atoms, an alkenyl group having 26 carbon atoms or an alkynyl group having 26 carbon atoms, and X represents a leaving group.
  • V represents an alkyl group having 16 carbon atoms, an alkenyl group having 26 carbon atoms or an alkynyl group having 26 carbon atoms
  • X represents a leaving group.
  • each symbol is as defined above, or a salt thereof [hereinafter abbreviated as compound ( ⁇ )].
  • each symbol is as defined above, or a salt thereof (hereinafter abbreviated as compound ( ⁇ ⁇ )).
  • R 1 and R 2 is hydrogen and the other is a hydroxyl group
  • R 3 is a hydroxyl group
  • R 4 is a hydroxyl group
  • R 5 Is a methyl group
  • R 6 is a methyl group
  • R 7 is a hydroxyl group
  • R 8 is an isopropyl group.
  • each symbol is as defined above, or a salt thereof (hereinafter abbreviated as compound (IV)) in the presence of a cyclic amide or a cyclic amide and an alkyl nitrile
  • compound (IV) a salt thereof in the presence of a cyclic amide or a cyclic amide and an alkyl nitrile
  • one of R 1 and R 2 is hydrogen and the other is a hydroxyl group.
  • R 3 represents hydrogen or an optionally substituted hydroxyl group.
  • the optionally substituted hydroxyl group include the same as those described above.
  • R 3 is preferably a hydroxyl group or a hydroxyl group substituted with -4 alkyl, and more preferably a hydroxyl group.
  • R 4 represents hydrogen or a hydroxyl group. Preferably it is a hydroxyl group.
  • R 5 represents hydrogen or a lower alkyl group. Preferably, it is an alkyl group, and more preferably, a methyl group.
  • R 6 is, C physician 6 alkyl group (e.g., cyclohexyl and methyl, Echiru, propyl, isopropyl, to), C 2 - 6 alkenyl group (e.g., vinyl, 1 one Purobe sulfonyl, Ariru, the key Seniru etc.) or C Medicine 6 alkynyl group show (e.g., Echiniru, 1 one-propynyl, 2-flops Robiniru, hexynyl and the like to).
  • An alkyl group more preferably a methyl group.
  • R 7 represents hydrogen or a hydroxyl group. Preferably it is a hydroxyl group.
  • R 8 is a C ⁇ e alkyl group (eg, methyl, ethyl, propyl, isopropyl, Hexyl, etc.), C 2 - 6 alkenyl group (e.g., vinyl, 1 one Purobe sulfonyl, Ariru, the key Seniru) or C 2 - 6 alkynyl group (e.g., Echiniru, 1 one-propynyl, 2-flops Robiniru, to Kichel, etc.). It preferably represents a 4- alkyl group, more preferably an ethyl group or an isopropyl group. Most preferably, it is an isopropyl group.
  • X represents a leaving group, and examples thereof include halogen (eg, black, promoter, chloride, etc.), 3- alkylsulfonyl (eg, methanesulfonyl), paratoluenesulfonyl, and the like. Preferably it is halogen.
  • Specific examples of the compound (I) include N-demethylerythromycin A derivatives (described in JP-A-47-91229), N-demethylerythromycin B derivatives, and N-demethylerythromycin C derivatives N-demethylerythromycin D derivative (hereinafter sometimes collectively referred to as N-demethylerythromycin derivative) and the like.
  • Compound (I) can be produced using an erythromycin derivative (eg, erythromycin A) as a starting compound, for example, according to the method described in Reference Example 1 below or a method analogous thereto.
  • Erythromycin A, Erythromycin B, Erythromycin C and Erythromycin D are known compounds and can be obtained as commercial products [Erythromycin A: BIOCHEMIE (Austria), Upj ohn (US), etc .; Erythromycin C and erythromycin D: Abbott (USA) etc.).
  • Examples of the compound ( ⁇ ⁇ ) include, for example, 8,9-anhydroerythromycin A—6,91-hemiacester derivative, 8,9-anhydroerythromycin B—6,9—hemiacetal derivative, 1-Anhydroerythromycin C-16,9-hemiacetal derivative, 8,9-Anhydroerythromycin D-6,9-hemiacetal derivative (hereinafter collectively referred to as 8,9-anhydroerythromycin-6, 9 Sometimes referred to as a hemiacetal derivative).
  • one and the other is hydroxyl hydrogen of R 1 and R 2, R 3 is hydroxyl, R 4 is hydroxyl , R 5 is a methyl group, R s is a methyl group, compounds wherein R 7 is a hydroxyl group and R 8 is isopropyl group (N- demethyl one N- isopropyl _ 8, 9 one anhydroerythromycin erythromycin A- 6, the 9- Miacetal).
  • Preferred examples of the compound (V) are halogenated alkyl, halogenated C 2 - 6 alkenyl, and halogenated C 2 _ 6 alkynyl. More preferred are isopropyl halide and halogenated chill. As the halogen, chlorine, promoter, chloride, especially chloride are preferable.
  • Compound ( ⁇ ) can be produced by reacting compound (I) with compound (V) using a cyclic amide or a mixture of the cyclic amide and alkylnitrile as a reaction solvent. .
  • the amount of compound (V) to be used is about 1 to 100 molar equivalents, preferably about 1 to 25 molar equivalents, per 1 mol of compound (I) [N-demethylerythromycin derivative (or its bis form)]. Yes, especially about 2 to 15 molar equivalents.
  • the reaction is carried out using cyclic amides (eg, N-methyl-2-pyrrolidone, N-methyl-2 Solvent) or cyclic amides (eg, N-methyl-2-pyrrolidone, N-methyl-2-piperidone, etc.) and alkyl nitriles (eg, acetonitrile, propionitrile, ptyronitrile, etc.) And in a mixed solvent.
  • cyclic amides eg, N-methyl-2-pyrrolidone, N-methyl-2 Solvent
  • alkyl nitriles eg, acetonitrile, propionitrile, ptyronitrile, etc.
  • halogenated hydrocarbons eg, chloroform, dichloromethane, etc.
  • ethers eg, ethyl ether, tetrahydrofuran, etc.
  • ketones eg, acetone, methyl ethyl ketone, etc.
  • esters eg, ethyl acetate, etc.
  • One or more mixed solvents of alcohols eg, methanol, ethanol, etc.
  • alkyl nitriles amides (eg, NN-dimethylformamide, NN-dimethylamide, cyclic amides, etc.) May be used.
  • a mixed solvent of a cyclic amide and an alkyl nitrile is preferred.
  • Preferred as the cyclic amides are N_methyl-2-pyrrolidone.
  • the C 5 alkyl nitrile is Ru Asetonitoriru der.
  • the amount of the cyclic amide used is about 0.5 to 50 times (v / w), preferably about 1 to 50 times, the amount of the compound (I) 1. Quantity (V / w).
  • the amount of the mixture used is 0.5 to 50 times the amount of compound (I) (vZw), preferably about 1 to 50 times. 50 times (v / w).
  • the ratio by weight of the cyclic amides to the alkyl nitriles is usually from about 1: 0.1 to about 1:10 (V: V), preferably from about 1: 0.1 to about 1: 5 (V: v).
  • the reaction is usually performed in the presence of a base.
  • a base examples include tertiary amines (eg, triethylamine, tri-n-propylamine, etc.), metal carbonates (eg, potassium carbonate, sodium carbonate, lithium carbonate, etc.), metal bicarbonates (sodium bicarbonate) Tertiary amines and metal carbonates, and sodium carbonate and triethylamine are particularly suitable.
  • the amount of the base used in the reaction is about 110 mole equivalents, preferably about 130 moles, per 1 mole of compound (I) [N-demethylerythromycin derivative (or bis-form thereof)]. It is a molar equivalent, more preferably about 110 molar equivalents.
  • a preferred example is a mixed solvent of N-methyl-2-pyrrolidone and acetonitrile.
  • the reaction time can be greatly reduced, and the target compound can be obtained in a high yield.
  • the mixing ratio is about 1: 0.1 to about 1:10 (V: V), preferably about 1: 0.1 to about 1: 5 (V: V).
  • the reaction is carried out under ice cooling (about 0 ° C.) to the boiling point of the solvent (about 100 ° C.), preferably at room temperature (about 15 to 25 ° C.) to about 90 ° C., especially about 60 to 80 ° C. This makes it possible to shorten the reaction time.
  • the reaction time of the reaction is about 1 to 30 hours, preferably about 1 to 10 hours, more preferably about 1 to 8 hours.
  • the obtained compound ( ⁇ ) may be subjected to the next reaction without isolation.
  • Compound (III) can be produced by treating compound (II) with an acid.
  • Examples of the acid in the treatment with an acid include an organic acid (formic acid, acetic acid, propionic acid, oxalic acid, fumaric acid, maleic acid, etc.) or a mineral acid (sulfuric acid, phosphoric acid, etc.). preferable. These acids can be appropriately diluted with halogenated hydrocarbons, ethers, esters, ketones and the like.
  • the amount of the acid to be used is about 1-200 molar equivalents, preferably about 30-100 molar equivalents, particularly preferably about 40-70 molar equivalents, per 1 mol of compound (II).
  • the treatment reaction is carried out under ice cooling (about 0 ° C) to the boiling point of the solvent (about 100 ° C), preferably under ice cooling (about 0 ° C) to 80 ° C, and particularly at room temperature (about 15 to 25 ° C). ) Performed at ⁇ 50 ° C.
  • the reaction time in the treatment reaction is about 1 to 10 hours, preferably about 1 to 5 hours.
  • Compound (IV) can be produced by treating compound (I) with an acid.
  • the reaction conditions are the same as those for the reaction for obtaining compound (III) from compound (II).
  • the obtained compound (IV) may be subjected to the next reaction without isolation.
  • Compound (III) is obtained by converting compound (IV) to a cyclic amide (eg, N-methyl-2-pyrrolidone, N-methyl-2-piperidone, etc.) or a cyclic amide and an alkyl nitrile (eg, , Acetonitrile, propionitrile, ptyronitrile, etc.) as a reaction solvent and reacting with compound (V).
  • a cyclic amide eg, N-methyl-2-pyrrolidone, N-methyl-2-piperidone, etc.
  • an alkyl nitrile eg, Acetonitrile, propionitrile, ptyronitrile, etc.
  • the reaction conditions are the same as those for obtaining the compound (I) from the compound (II).
  • Compound (III) thus obtained (for example, N-demethyl-N-alkyl-8,9-anhydroerythromycin-6,9-hemiacetyl derivative, N-demethyl-N-alkenyl-8,9-anne Hydroerythromycin-6,9-hemiacetyl derivative or N-demethyl-N-alkynyl-8,9-anhydroerythromycin-16,9-hemiacetal derivative, etc.) can be obtained by any means known per se, such as condensation, It can be purified by liquid transformation, phase transfer, solvent extraction, crystallization, crystallization, isolation, recrystallization, and mouth chromatography.
  • the crude crystal of the compound is recrystallized as an isopropanol solvate from hydrated isopropanol, that is, isopropanol Z water mixed solvent, and then recrystallized from acetonitrile Z water mixed solvent to obtain a good yield.
  • the compound can be obtained as substantially pure crystals.
  • About 1 to about 20 volumes, preferably about 2 to 5 volumes, of isopropanol used for the substrate are used, and water is about 1 to 20 volumes, preferably about 2 to 20 volumes of the substrate. ⁇ 10 times capacity is used.
  • the ratio of isopropanol to water is from about 1: 0.5 to about 1: 3 (V: V), preferably from about 1: 1 to about 1: 2 (v: v).
  • the compound used in the production method of the present invention or the obtained compound may form a salt by treating with an acid.
  • the acid include organic acids (eg, glycopeptonic acid, stearic acid, propionic acid, lactobionic acid, oxalic acid, maleic acid, fumaric acid, succinic acid, lactic acid, trifluoroacetic acid, acetic acid, methanesulfonic acid, paratoluene sulfone Acid, benzenesulfonic acid, etc.), and mineral acids (eg, sulfuric acid, hydrochloric acid, hydroiodic acid, phosphoric acid, nitric acid, etc.).
  • organic acids eg, glycopeptonic acid, stearic acid, propionic acid, lactobionic acid, oxalic acid, maleic acid, fumaric acid, succinic acid, lactic acid, trifluoroacetic acid, acetic acid, methanesulfonic acid, paratoluene
  • a pharmaceutically acceptable salt is preferable, and examples thereof include a salt with an inorganic acid, a salt with an organic acid, and a salt with a basic or acidic amino acid.
  • examples of the salt with an inorganic acid include, for example, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
  • Suitable examples of salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, And salts with P-toluenesulfonic acid.
  • Preferred examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, orditin, and the like.
  • Preferred examples of the salt with an acidic amino acid include, for example, aspartic acid, glutamic acid, and the like. Salts.
  • Systemic diseases especially postoperative ileus in humans, diabetic gastroparesis, dyspepsia, reflux esophagitis, pseudo ileus, gastrointestinal symptoms associated with postgastrectomy syndrome (upper abdominal distension, upper abdominal pressure, nausea, vomiting) , Heartburn, anorexia, epigastric pain, epigastric tenderness, etc.), chronic gastritis, irritable bowel syndrome, morphine ⁇ Can be used as a drug for the prevention or treatment of constipation due to administration of anticancer drugs. Kill.
  • the present invention will be described more specifically with reference to Examples and Reference Examples, but the present invention is not limited thereto.
  • the reaction product was cooled, 0.3 L of a 1N sodium thiosulfate solution was added for decolorization, and the solvent was distilled off under reduced pressure to adjust the total liquid volume to about 110 L.
  • the pH was adjusted to pH 10.5 with 25% aqueous ammonia, and 33 L of water was added dropwise to allow crystallization to obtain N-demethylerythromycin A.
  • the compound was dissolved by heating in 20 L of methanol, cooled to room temperature, and crystallized by adding 33 L of water to obtain 7.9 kg (81% yield) of white crystals of N-demethylerythromycin A.
  • N-demethylerythromycin A obtained in Reference Example 1 28.3 g of 2-propane, 8.4 g of triethylamine and N-methyl-2-pyrromycin 60 ml of lidone was added, and the mixture was stirred at 70 ° C. for 4 hours to react. 190 ml of ethyl acetate and 120 ml of water were added to the reaction solution, the pH was adjusted to 8.5 with 5% NaOH, the layers were separated, and the aqueous layer was secondarily extracted with 100 ml of ethyl acetate. The combined ethyl acetate layers were washed twice with 60 ml of water, and the solvent was concentrated under reduced pressure to 100 ml to obtain N-demethyl-N-isopropyl-erythromycin A.
  • N-demethylerythromycin A obtained in Reference Example 1 was added 18.0 g of 2-iodopropane, 35.0 g of triethylamine and 250 ml of acetonitrile, and the mixture was added at 60 to 65 ° C for 24 hours. The mixture was stirred and reacted for an hour. 800 ml of ethyl acetate was added to the reaction solution, 500 ml of water was added, the pH was adjusted to 8.5 with 5% NaOH, and the mixture was separated. After that, the aqueous layer was secondarily extracted with 500 ml of ethyl acetate. The combined ethyl acetate layers were washed twice with 25 Om1 of water, and the solvent was concentrated under reduced pressure to 40 Oml to obtain N-demethyl_N-isopropyl-erythromycin A.
  • Capsules I having the composition shown in [Table 1] per capsule were produced as follows. First, 1) 225 g, 3) 486 g, 4) 396 g, 5) 346.5 g were mixed well to prepare a spray. 2) 2,700 g was put into a centrifugal flow type coating granulator (manufactured by Freund Corporation, CF-360 ⁇ ), and 6) 27.9 g was dissolved. The above spraying agent was coated while spraying 1,116 g of the aqueous solution. Further, 3) 144 g, 4) 157.5 g, and 5) 157.5 g were mixed well to prepare a holding powder, and the powder was coated following the above powder to obtain spherical granules. The spherical granules were dried under vacuum at 40 ° C for 16 hours and sieved with a round sieve to obtain 710 to 1000 main drug particles.
  • capsules J and capsules K having the composition shown in [Table 1] per capsule were produced.
  • an erythromycin derivative particularly N-demethyl-N-isopropyl-18,9-anhydroerythromycin A-6,9
  • -Hemiase N-demethyl-N-ethyl-8,9-anhydroerythromycin A-6,9-Hemiase can be produced, which is extremely useful as a production method for industrial mass production.
  • An advantageous method can be provided.
  • N-alkylation, N-alkenylation or N-alkynylation of an N-demethylerythromycin derivative in a solvent mixture of N-methyl-2-pyrrolidone or N-methyl-2-pyrrolidone and acetonitrile The N-alkylation, N-alkenylation or N-alkynylation of N-demethyl-8,9-anhydroerythromycin-16,9-1-hemiacetyl derivative in the same solvent
  • the reaction can be completed more efficiently in a shorter time (about 1 to 8 hours) than the conventional method.

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Abstract

Cette méthode d'élaboration de composés, représentés par la formule générale (V), ou de leurs sels: (formule dans laquelle R1 et R2 représentent chacun H, OH ou analogue, R3 représentant H, OH ou analogue, R4 représentant H ou OH, R5 représentant H ou un alkyle de faible poids moléculaire, R6 représentant un alkyle portant de 1 à 6 atomes de carbone ou analogue et R7 représentant H ou OH), consiste à faire réagir un dérivé de N-déméthylérythromycine avec un composé représenté par la formule générale: R8 - X (formule dans laquelle R8 représente un alkyle portant de 1 à 6 atomes de carbone ou analogue et dans laquelle X représente un groupe partant) en présence, soit d'un amide cyclique seul, soit d'un amide cyclique et d'un alcènenitrile, puis à traiter le produit obtenu avec un acide.
PCT/JP1999/004301 1998-08-10 1999-08-09 Methode d'elaboration de derives d'erythromycine Ceased WO2000009530A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU50673/99A AU5067399A (en) 1998-08-10 1999-08-09 Process for the preparation of erythromycin derivatives

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JP22563498 1998-08-10
JP10/225634 1998-08-10

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004037273A1 (fr) * 2002-10-25 2004-05-06 Chugai Seiyaku Kabushiki Kaisha Agent therapeutique et/ou prophylactique pour la dyschezie
CN101619085A (zh) * 2009-08-11 2010-01-06 沈阳药科大学 红霉素衍生物及其作为肿瘤细胞增殖抑制剂的用途

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6399092A (ja) * 1985-08-31 1988-04-30 Kitasato Inst:The エリスロマイシン誘導体およびその製造法
JPH1067795A (ja) * 1996-03-01 1998-03-10 Takeda Chem Ind Ltd エリスロマイシン誘導体の製造法
WO1999025722A1 (fr) * 1997-11-19 1999-05-27 Abbott Laboratories Procede de n-desmethylation d'erythromycines, et derives

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6399092A (ja) * 1985-08-31 1988-04-30 Kitasato Inst:The エリスロマイシン誘導体およびその製造法
JPH1067795A (ja) * 1996-03-01 1998-03-10 Takeda Chem Ind Ltd エリスロマイシン誘導体の製造法
WO1999025722A1 (fr) * 1997-11-19 1999-05-27 Abbott Laboratories Procede de n-desmethylation d'erythromycines, et derives

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004037273A1 (fr) * 2002-10-25 2004-05-06 Chugai Seiyaku Kabushiki Kaisha Agent therapeutique et/ou prophylactique pour la dyschezie
JPWO2004037273A1 (ja) * 2002-10-25 2006-02-23 中外製薬株式会社 排便機能障害の治療及び／又は予防剤
AU2003275652B2 (en) * 2002-10-25 2009-12-17 Chugai Seiyaku Kabushiki Kaisha Therapeutic and/or preventive agent for defecation dysfunction
US7635714B2 (en) 2002-10-25 2009-12-22 Chugai Seiyaku Kabushiki Kaisha Methods of treating dyschezia
JP4541148B2 (ja) * 2002-10-25 2010-09-08 中外製薬株式会社 排便機能障害の治療及び／又は予防剤
CN101619085A (zh) * 2009-08-11 2010-01-06 沈阳药科大学 红霉素衍生物及其作为肿瘤细胞增殖抑制剂的用途
CN101619085B (zh) * 2009-08-11 2015-04-22 沈阳药科大学 红霉素衍生物及其作为肿瘤细胞增殖抑制剂的用途

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