WO1998003531A1 - Erythromycin derivatives - Google Patents

Abstract

Compounds represented by general formula (1) or pharmaceutically acceptable salts thereof, which are useful as drugs for promoting the digestive motions, etc., wherein R1 represents hydrogen or acyl; R2 and R3 represent each hydrogen, hydroxy, acyloxy or amino, or R2 and R3 may form together =O or =NOR12 (wherein R12 represents hydrogen or lower alkyl); R4 represents hydrogen or lower alkyl; R5 and R6 represent each hydrogen or hydroxy, provided that at least one of them is hydroxy; and Y represents -NR7R8 or -N+R9R10R11X1 (wherein R¿7? to R11 represent each hydrogen, lower alkyl, lower alkenyl, cycloalkyl, etc., or R7 and R8, or R9 and R10 may, together with the adjacent nitrogen, form each azacyclo-alkyl; and X?-¿ represents an anion.

Description

 Eris mouth mycin derivative Technical field

 TECHNICAL FIELD The present invention relates to an erythromycin derivative or a salt thereof, which exhibits an action of promoting contraction of the digestive tract of a mammal and is useful as an agent for promoting contractile movement of the digestive tract. Background art

 From the viewpoint of action, gastrointestinal motility enhancers include direct acetylcholine agonists such as acratonium napadisylate, indirect acetylcholine agonists such as cisapride, dopamine blockers such as domberidon, and obiate agonists such as trimebutine maleate. It is broadly classified into four types of drugs, and is widely used as a therapeutic drug for gastrointestinal symptoms such as dysfunction of gastrointestinal motility, particularly complaints of indefinite complaints due to hypokinesia. However, these drugs are accompanied by 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 physiologic movement 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.

 On the other hand, motilin is known as a gastrointestinal hormone that stimulates the contractile movement of the gastrointestinal tract. In recent years, erythromycin and its derivatives have been found to have a motilin-like gastrointestinal contraction-promoting action. An erythromycin derivative which is acid-resistant, orally administrable, and has a strong gastrointestinal motility-promoting action has been found (JP-A-6-56873). Disclosure of the invention

Under such circumstances, the present inventors have conducted intensive studies from a new viewpoint, and as a result, have found that the acid-resistant erythromycin derivative disclosed in Japanese Patent Application Laid-Open No. 6-56873 is disclosed. When administered to animals, a novel erythromycin derivative having a hydroxyl group at position 15 was found as a metabolite in plasma and urine. Surprisingly, they have found that the compound has a gastrointestinal motility-promoting action equal to or better than that of the starting compound, The present invention has been completed on the basis of the findings described above.

 That is, the present invention provides the following general formula (1)

(In the formula, R> represents a hydrogen atom or an acyl group, and R ₂ and R ₃ are the same or different and represent a hydrogen atom, a hydroxyl group, an acyloxy group, an amino group or -0, = NO R together. R ₁₂ represents a hydrogen atom or a lower alkyl group, R ₄ represents a hydrogen atom or a lower alkyl group, R ₅ and R ₆ represent a hydrogen atom or a hydroxyl group, at least one of which represents a hydroxyl group, and Y represents —NR. ₇ R _E or —N ⁺ R ₉ R _I0 RX—, where R ₇ , R ₈ , R _E , R ₁₀ and RH may be the same or different and may have a hydrogen atom or a substituent, A lower alkyl group, a lower alkenyl group, a lower alkynyl group, a cycloalkyl group, a 3- to 7-membered heterocyclic group containing an oxygen atom, a nitrogen atom or a sulfur atom as a hetero atom, and an anion, respectively. , R ₇ and R _E, R ₉ and R ₁₀ Waso Together with the nitrogen atom adjacent respectively together may form a § The cycloalkyl group.)

And the possible stereoisomers, optical isomers and salts thereof. BRIEF DESCRIPTION OF THE FIGURES

Figure 1 shows the LC (APC I) mass spectrum of compound (3). FIG. 2 is a ¹ H—ID—NMR spectrum of compound (3).

Figure 3 is a 'H- ¹ H- DQF- COS Y spectrum of the compound (3).

 FIG. 4 is a HOHOHA spectrum of the compound (3). BEST MODE FOR CARRYING OUT THE INVENTION

 In the present invention, the acetyl group means a formyl group, an acetyl group, a propionyl group, a butyryl group, a bivaloyl group, a benzoyl group, an ethoxyquincarbonyl group, a t-butoxycarbonyl group, a benzyloxycarbonyl group or the like.

 The acyloxy group means a formyloxy group, an acetyloxy group, a propionyloxy group, a petyryloxy group, a bivaloyloxy group, a benzoyloxy group, an ethoxycarbonyloxy group, a t-butoxycarbonyloxy group, a benzyloxycarbonyloxy group, or the like.

 The lower alkyl group means a linear or branched 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, an i- Shows butyl group, sec-butyl group, t-butyl group, neopentyl group, etc. The lower alkenyl group refers to a linear or branched alkenyl group having 2 to 6 carbon atoms, preferably a vinyl group, an aryl group, an n-butenyl group, an i-butenyl group, a sec-butenyl group, or the like.

 The lower alkynyl group refers to a linear or branched alkynyl group having 2 to 6 carbon atoms, preferably an ethynyl group, a propargyl group, a petynyl group and the like.

 The cycloalkyl group refers to a cycloalkyl group having 3 to 8 carbon atoms, preferably a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, or the like.

 Examples of the 3- to 7-membered heterocyclic group containing an oxygen atom, a nitrogen atom or a sulfur atom as a hetero atom include aziridine, azetidine, pyrrolidine, piperidine, oxirane, oxetane, oxolane, tetrahydrovirane, thiirane, Thietane, thiolane, thiane and the like can be mentioned.

R ₇ and R ₈ , R ₉ and R ₁₀ may be taken together to form an azacycloalkyl group together with an adjacent nitrogen atom. A group in which one or more carbon violet atoms of the group are replaced with a nitrogen atom, such as an aziridinyl group, an azetidinyl group, a pyrrolidinyl group, a piperidinyl group, and a hexamethyleneimino group.

An oxygen atom as a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a cycloalkyl group or a hetero atom, which may have a substituent at R ₇ , R ₈ , R ₉ , R ₁₀ and R _tl ; Examples of the substituent for a 3- to 7-membered heterocyclic group containing a nitrogen atom or a sulfur atom include a hydroxyl group, an amino group, a halogen atom, a nitrile group, an alkyloxy group, a mercapto group, an acyl group, and a carbamoyl group. Can be Further, as a substituent in a 3- to 7-membered heterocyclic group containing an acid or nitrogen atom or a sulfur atom as a cycloalkyl group or a hetero atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, an aryl group And hydrocarbon groups such as aralkyl groups.

 The anion in X- indicates a chloride ion, a bromide ion, an iodide ion, a carboxylate ion, a sulfonate ion, or the like.

 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.

 General formula (1)

As the compound represented by, a compound in which R ₅ is a hydrogen atom and _Re is a hydroxyl group is preferred. Is a hydrogen atom, R ₂ and R ₃ are either a hydrogen atom, the other is a hydroxyl group, R ₄ is a methyl group, R ₅ is a hydrogen atom, _Re is a hydroxyl group, and R ₇ and R in Y Compounds in which one of _e is a methyl group and the other is an isopropyl group are more preferred. Above all, de (N-methyl) 1-11-dexoxy15-hydroxy-N-isopropyl pill-12-2-0-methyl-11-oxo-1,8,9-anhydroerythromycin A 6.91 Miquetals are particularly preferred.

 The compound of the present invention may be a possible stereoisomer or optical isomer of the compound represented by the general formula (1), or a salt thereof.

 The compound of the present invention can be obtained, for example, as follows.

 The compound of the present invention may be obtained by administering a known erythromycin derivative, for example, the compound described in the above-mentioned JP-A-6-56873 as a starting compound, for example, administering the starting compound to a mammal, It can be obtained by isolating and purifying from. That is, the raw material compound is dissolved or suspended in water or a buffer, the raw material compound is encapsulated, the raw material compound itself is orally administered to mammals such as rats, dogs and monkeys. It is administered by intravenous, intramuscular, intraperitoneal administration and the like. Biological samples collected to purify the target compound are preferably urine, bile, and feces, but may be organs such as liver, kidney, and lung, and blood. In the case of blood, plasma or serum is separated by a general technique in biochemistry, and this plasma or blood slip is used for purification. In the case of feces, liver, kidneys, etc., these are pulverized with a scissor homogenizer or the like, and then extracted with water, a buffer solution, or an organic solvent such as methanol, ethanol, ethyl acetate or the like. If necessary, solids may be removed by filtration, centrifugation or the like. Purification of the target compound from extracts of urine, bile, plasma, serum, feces or organs is performed by general methods of natural product chemistry, such as liquid-liquid extraction, solid-phase extraction, column chromatography, high-performance liquid chromatography, It is performed by a method such as recrystallization.

The erythromycin derivative or a salt thereof as a starting compound of the compound of the present invention can be obtained by known means, for example, the method described in the above-mentioned JP-A-6-56873. Example

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

 In addition, in order to show the usefulness of the compound of the present invention, the results of pharmacological tests on the gastrointestinal motility-promoting activity of typical compounds of the present invention are shown in Test Examples.

Example 1

 De (N-methyl) 1 11 1-Doxy 1 5—Hydroxy N-isopropyl 1

1 2—0—Methyl oxo 8.9—9—Anhydrohydroerythromycin A 6,

9 First Hits

 In this example, the compound (2) described in JP-A-6-56873 was disclosed.

化合物 （2 ) (原料化合物)

Compound (2) (raw material compound)

化合物 (3) (目的化合物） That is, de (N-methyl) -11-deoxy-1-N-isopropyl-12-0-methyl-11-oxo-1,8,9-hydroerythromycin A6,9-hemiketal was used as a starting compound for the rat. After administration and extraction and purification from the urine, the target compound (3)

Compound (3) (target compound)

That is, a method for obtaining a miketal from de (N-methyl) -1-11-hydroxy-15-hydroxy-N-isobutyl pill-12-0-methyl-11-oxo-1-8.9-anhydrohydroerythromycin A6.9-1 This shows the physicochemical properties of the obtained compound (3).

 For the animals, forty-five male rats of 6 to 7 weeks of age (weight of 190 to 210 g) Uc1: SD, purchased from CLEA Japan, Inc. were used. Throughout the experiment, the animals are kept in an animal room set at a temperature of 24 ± 2 ° C, a humidity of 50 to 60%, a lighting time of 5 am to 7 pm, and a ventilation rate of 10 to 15 times. They were allowed to take solid feed (CE-2, purchased from CLEA Japan) and tap water freely.

 Compound (2) was dissolved in a solution of 90% 10 OmM lactobionic acid—10% polyethylene glycol 400 to prepare 25 mg Z4 ml, which was used as an administration solution.

 The administration solution was orally administered by gavage to a rat at a ratio of lm 1 Zhead once a day for 2 days using an oral probe.

Urine from each rat excreted between the first dose and 24 hours after the last dose Was collected in its entirety.

 Urine obtained from all rats was combined and filtered using diatomaceous earth. The filtrate was adjusted to pH about 9 with sodium hydrogen carbonate, extracted three times with ethyl acetate, and the obtained ethyl acetate layers were combined and concentrated under reduced pressure.

The resulting residue was dissolved in water, which was subjected to preparative HP LC at operating conditions (I) shown below, the elution time (hereinafter, referred to as t _R.) A is the fraction of 7-10 minutes I took it out. The obtained fraction was adjusted to pH about 9 with sodium bicarbonate, extracted three times with ethyl acetate, and the obtained ethyl acetate layers were combined and concentrated under reduced pressure.

The resulting ZanKiyoshi was dissolved in solution A in the operating conditions shown below (II), which was subjected to preparative HPLC in operating conditions (II), the beak fraction t _R appear in about 11 minutes I took it out. The obtained fraction was adjusted to pH about 9 with sodium hydrogen carbonate, extracted three times with ethyl acetate, and the obtained ethyl acetate layers were combined and distilled off under reduced pressure to give compound (3), ie, de ( N-Methyl) 1 11-Doxy 15-Hydroxy N-isopropyl-1 12-0-Methyl-11-oxo 1,8,9-Anhydrodrerythromycin A 6.9-hemiketal was obtained.

HP LC operating conditions

Equipment used: Controller (SCL-10A: manufactured by Shimadzu Corporation), pump

 (LC-10 AD; Shimadzu Corporation), UV detector (SPD-10A; Shimadzu Corporation)

Operating conditions (I)

 Carrier: Octadecylsilane

 Column: Cappcelpak C18 (300 x 10 mm I.D.) Mobile phase: 45% acetonitrile 3 OmM ammonium acetate solution, pH 6 Flow rate: 5 m1 / min

 Detection: UV220 nm

Operating conditions (II)

 Carrier: Octadecylsilane

Column: TSKgel ODS 80Ts (150 4.6 mm ID) Mobile phase: Perform the following gradient by mixing solution A and solution B.

 Solution A: acetonitrile water

 (Volume ratio 3: 7, containing 1% triethylamine, pH6)

 Solution B: acetonitrile water

 (Volume ratio 6: 4, containing 1% triethylamine, pH6)

 Gradient conditions: Solution A: 100% (0 min) → 0% (30 min)

 Solution B: 0% (0min) → 100% (30min)

 Flow velocity: 1ml / in

 Detection: UV220 nm

The physicochemical properties of compound (3) are shown below.

(1) Molecular weight: mZz 773 (MH ⁺ ), 615 (MH + — C 1 adinose) [from LC (APC I) mass spectrometer]. Figure 1 shows the spectrum.

(2) Molecular formula: C _{4 () He e9} N0 ₁₃

(3) 'Η- ID- NMR scan base-vector: 500 mH z, in CDC 1 _3, 5 ppm. 5.83 (1 H. d, J = 1 1.3 Hz), 4.89 (1 H. d. J = 4.4 Hz), 4.38 (1H, d, J = 7.5 Hz) , 4.06 (1H, dq, J = 9.2Hz, 6.4Hz), 4.00 (1H.m), 3.99 (1H.q, J = 6.6Hz), 3. 99 (1 H, m), 3.70 (1H, m), 3.54 (1H.m), 3.43 (1 H.m), 3.35 (3 H, s), 3.16 ( 1 H, dd, J = 10.1Hz, 7.5Hz). 3.10 (1H.d.J = 9.2Hz), 3.

07 (3H, s), 2.93 (1 H, m), 2.68 (1H, d, J = 15.6 Hz), 2.63 (1H.m), 2.50 (1 H.dq , J = 2.0H z, 7

3Hz), 2.38 (1H.d, J = 15.3Hz), 2.21 (3H, s), 2.00 (1H.d, J = 15.6Hz), 1. 84 (1 H, m), 1.74 (1 H.m), 1.68 (3H.s), 1.66 (1 H, m), 1.61 (1H, dd, J = 4.4 Hz , 15.3Hz), 1.50 (1H, m, J = 13.0 Hz, 11.3Hz), 1.43 (3H, s), 1.40 (1H, m), 1. Three

8 (3H.d, J = 6.4 Hz), l.33 (3H, s), l.25 (3H.s) , 1.22 (3H, d.J = 6.6 Hz), 1.22 (3H.d.J = 6.OHz), 1.09 (3H.d, J = 7.3 Hz), 1.08 (3H, d. J = 7.8 Hz), 1.08 (3H, d. J = 5.9 Hz), 1.06 (3 H. d. J = 6.6 Hz)

Figure 2 shows the spectrum.

^{(4) 'Η- 1 H- DQF-} COS Y spectrum: 500 MH z, in CDC 1 _3. Figure 3 shows the spectrum.

(5) HOHAHA spectrum Bok Norre: 500MHz, during the CDC 1 _3. Figure 4 shows the spectrum. Test example 1: Motilin receptor binding test

The motilin receptor binding test was performed by the following method [V. Bormans et al., Regul, Peptides s. 15. 143 (1986)]. The upper small intestine was removed from the slaughtered egret, and the mucous membrane was detached from the muscular layer, and then homogenized in a 50 mM Tris-HCl buffer (pH 7.4) to obtain a protein solution. ¹²⁵ 1-label motilin (purchased from PEN I NSUL A) After incubating 25 pM and protein solution for 120 minutes at 25 ° C, the radioactivity in the protein was measured with a counter, and the radioactivity was measured without any addition. the difference in radioactivity upon addition of the active and a large excess of motilin (1 X 10- ⁷ M) was specific binding. The potency of the samples was expressed as the concentration of drug that reduced specific binding to 50% _IC5I) (M). The drug was dissolved in DMSO solution and added to the protein solution (final DMSO concentration was 1%). The compound (3) as the target compound and the compound (2) as the starting compound were subjected to the test as drugs. Table 1 shows the test results. Table 1 Motilin receptor binding test Compound I Cso (M) Compound (2) 19x10 " ⁹ Compound (3) ιθχΐο- 9

Test example 2: 収縮 contraction activity test on excised specimen of ギ heron duodenal longitudinal muscle

Used Usagi duodenum longitudinal muscle resected contractile activity test Chio pen tar sodium _£ Usagi made in the following method: After anesthesia with (40mgZk g iv), were bled from the thigh portion. After laparotomy, it was excised upper small intestine, nutrient solution (K rebsso 1 uti on: NaC l, 120. OmM; KC 4. 7mM; C aC l 2, 2. 4mM; KH 2 P0 4, 1. 0mM; MgSO " _{1. 2mM:. NaHC0 3, 24.} 5 mM; glucos e 5. washed well with 6 mM) in, duodenum longitudinal muscle specimens

(Length, about 10 mm; width, about 3 mm). Specimens were suspended in organbath filled with a nutrient solution for 1 0 m l was heated to 28 ° C, a mixed gas (95% 0 ₂ and 5% C0 ₂₎ was bubbled. A 1 g load was applied to the specimen, and the contraction was measured isotonicly using a force transducer (Isotonic transducer, ME-4012, manufactured by Medical Electronics Co.), and an ink recorder (Ty pe 3066) was used. , Yokogawa Electric). After suspension, acetylcholine (100; hereinafter, abbreviated as AC h) was repeatedly administered into the bath, and the experiment was started after the contraction by AC h became constant. The drug was cumulatively administered in a bath, and its contractile activity was measured. The contractile activity of the drug was expressed as the 'concentration of the drug producing 50% contraction (ED ₅₀ ), with the amount of contraction caused by 100 M ACh as 100%. The drug was dissolved in DMSO and diluted with physiological saline. Compound (3) as the target compound and compound (2) as the starting compound And subjected to the test. Table 2 shows the test results. Table 2 Usagi twelve. Contractile activity test compound with a finger intestine longitudinal muscle resected ED ₅₀ (M) Compound (2) 9. 12x 10- 9 Compound (3) 6. 61x 10-9

Industrial applicability

 The erythromycin derivative or a salt thereof in which at least one of the 14-position and the 15-position of the present invention is a hydroxyl group has a strong gastrointestinal motility-promoting activity and is useful as a gastrointestinal motility-promoting agent.

Claims

The scope of the claims 1. General formula (1)

(Wherein, is a hydrogen atom or an acyl group, and R ₂ and R ₃ are the same or different and represent a hydrogen atom, a hydroxyl group, an acyloxy group, an amino group or = 0, = N0 R ₁₂ together. R ₁₂ represents a hydrogen atom or a lower alkyl group R ₄ represents a hydrogen atom or a lower alkyl group R ₅ and _Re represent a hydrogen atom or a hydroxyl group, at least one of which represents a hydroxyl group Y represents one NR ₇ R ₈ or one N + RgR RuX-, wherein R ₇ , R ₈ , R ₉ , and the scale are the same or different and each may have a hydrogen atom or a substituent; X_ represents a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a cycloalkyl group or a 3- to 7-membered heterocyclic group containing an oxygen atom, a nitrogen atom or a sulfur atom as a hetero atom, and X_ represents an anion. Also, R ₇ and R ₈ , R ₉ and R ₁₀ Each may together form an azacycloalkyl group with the adjacent nitrogen atom.) Or a possible stereoisomer, optically active form, and salt thereof. 2. — The compound according to claim 1, wherein R ₅ is a hydrogen atom and R _e is a hydroxyl group in formula (1), or a possible stereoisomer, optically active form and salts thereof. 3. In the general formula (1), is a water atom, and one of R ₂ and R ₃ is water. Atom, according to claim 1 other is hydroxyl, R ₄ is a methyl group, R ₅ is a hydrogen atom, R _e is a hydroxyl group, one methyl group in our Keru R ₇ and R ₈ in Y, the other is Isopuropiru group Or the possible stereoisomers, optically active forms and salts thereof.  4. De (N-methyl) 1-111-Doxy15-Hydroxy-1-N-Isopropyl 12-0-Methyl-11-oxo-18.9-Anhydrodroerythromycin A 6, 9-Hemiketal and its salts.