CN1091431A - leptomycin derivatives - Google Patents
leptomycin derivatives Download PDFInfo
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- CN1091431A CN1091431A CN 93114359 CN93114359A CN1091431A CN 1091431 A CN1091431 A CN 1091431A CN 93114359 CN93114359 CN 93114359 CN 93114359 A CN93114359 A CN 93114359A CN 1091431 A CN1091431 A CN 1091431A
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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
Abstract
The invention discloses the compound or its salt of a kind of general formula (1) expression, described compound and salt thereof demonstrate good gastrointestinal motor promoter action, compare with known erythromycin derivatives simultaneously, the degree of decomposing because of hydrochloric acid in gastric juice significantly reduces, thereby can be oral.
Description
The present invention relates to has promoter action to mammiferous digestive tract contractile motion, can be used as the erythromycin derivatives of digestive tract contractile motion promotor.
Gastrointestinal motor promotor, be used for seeing from it and can be divided into direct vagusstoff excitomotor (aclatonium napadisilate), indirect vagusstoff excitomotor (cisapride), Dopamine HCL by medicine (domperidone) and opiate excitomotor (Trimebutine Maleate) four big classes, their are as to because the dysfunction of gastrointestinal motor, the curative of digestion organs symptoms such as the low caused digestive tube discomfort of particularly moving and widespread use.Yet, these medicaments all be attended by because of Dopamine HCL by side effects such as the from outside symptom of hypophysis that causes of effect and lactation are hyperfunction.And, because promoted gastrointestinal motor mode of these medicaments and spontaneous physiological process are inequality from the motion that the top digestive tube is delivered to lower digestive tract, therefore usually with side effects such as diarrhoea, vomitings.
On the other hand, as the intestinal hormone of the contractile motion that stimulates digestion, the known motilin of having, yet can not be met from the supply of the motilin of natural extract and chemosynthesis, it is difficult providing in a large number.And motilin is the peptide that is made of 22 amino acid, and therefore exploitation is very difficult as oral preparations.
In recent years, find that erythromycin and derivative thereof have strong digestive tube and shrink the promotion activity, just under development (spy opens clear 60-218321 number as gastrointestinal motor promotor as the EM-523 of one of its derivative, the spy opens clear 61-87625 number, the spy opens clear 63-99016 number, the spy opens clear 63-99092 number and The Journal of Pharmacology and Experimental Therapeutics vol.251.No.2.PP 07-712, and 1989).
Yet EM-523 is unstable in acid, estimates the oral administration time spent, can weaken because of the Decomposition of hydrochloric acid in gastric juice.Therefore, present inventors have carried out the research of making great efforts in order to find resistance to acid and erythromycin derivatives that can be oral, result through studying repeatedly, the following new erythromycin derivatives that document was not put down in writing before finding just has this character and effect, and has finished the present invention based on these discoveries.
The compounds of this invention is represented with following logical formula I.
(in the formula, R1 represents hydrogen atom or acyl group; R2 and R3 can be identical or different, represent hydrogen atom, hydroxyl, acyloxy or become together=O; R4 represents hydrogen atom or low alkyl group; R5 represents low alkyl group; Y represents-NR6R7 or-N
+R8R9R10X
-Wherein R6 and R7 can be identical or different, the expression hydrogen atom, and acyl group can have substituent low alkyl group, can have substituent cycloalkyl, can have substituent low-grade alkenyl or can have substituent low-grade alkynyl; R8, R9 and R10 can be identical or different, and the expression hydrogen atom can have substituent low alkyl group, can have substituent cycloalkyl, can have substituent low-grade alkenyl or can have substituent low-grade alkynyl; X represents negatively charged ion).
In the present invention, as acyl group, can enumerate: formyl radical, ethanoyl, propionyl, butyryl radicals, pivaloyl, benzoyl group, ethoxycarbonyl, tertbutyloxycarbonyl, carbobenzoxy-(Cbz) etc.; As acyloxy, can enumerate methanoyl, acetoxyl group, propionyloxy, butyryl acyloxy, trimethyl acetoxyl, benzoyloxy group, methylamino ethoxy acyl-oxygen base, tertiary butyloxycarbonyl oxygen base, benzyloxy carbonyl oxygen base etc.; As low alkyl group, can enumerate the alkyl that carbonatoms is 1-6, be preferably methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, the tertiary butyl etc.; As cycloalkyl, can enumerate: carbonatoms is the cycloalkyl of 3-8, preferred cyclobutyl, cyclopentyl, cyclohexyl etc.; As low-grade alkenyl, can enumerate: carbonatoms is the alkenyl of 2-6, is preferably vinyl, allyl group, n-butene base, isobutenyl, secondary butenyl etc.; As low-grade alkynyl, can enumerate: carbonatoms is the alkynyl of 2-6, is preferably ethynyl, proyl, butynyl etc.; As can having substituent low alkyl group, cycloalkyl, the substituting group in low-grade alkenyl or the low-grade alkynyl can be enumerated: hydroxyl, amino, halogen atom, nitro, alkoxyl group, sulfydryl, formyl radical etc.; As negatively charged ion, can enumerate: chlorion, bromide anion, iodide ion, carboxylic acid ion, sulfonate ion.In addition, as the salifiable acid of shape, can enumerate: spirit of salt, Hydrogen bromide, hydroiodic acid HI, mineral acid and acetate such as sulfuric acid, oxalic acid, toxilic acid, fumaric acid, organic acids such as methylsulfonic acid.
The compounds of this invention (1) is the alkylating agent reaction that makes in the presence of alkali in compound (II) and the inert solvent, then as required, removes protecting group and makes with carrying out alkylation.
As the alkylating agent that is used for this alkylated reaction, can enumerate alkyl halide and alkylsulfonate etc.As alkali, for example available: sodium hydride, sodium alkylate, alkoxyl group potassium, lithium alkylide, salt of wormwood, yellow soda ash, potassium hydroxide, metal base and triethylamines such as sodium hydroxide, amines such as Trimethylamine 99.As inert solvent, can use: methyl alcohol, ethanol, propyl alcohol, chloroform, methylene dichloride, ether, tetrahydrofuran (THF), N, dinethylformamide etc.
(in the formula, R1, R2, R3, the definition of R4 and Y is same as described above.）
In addition, the concrete grammar put down in writing in can also Application Example of The compounds of this invention (1) makes.
The compounds of this invention (1), can be clear that from following test example, different with EM-523, its not only active not reduction under acidic conditions, and demonstrate strong gastrointestinal motor promoter action when oral, thereby, be extremely effective as the gastral contractile motion promotor of Mammals particularly as oral preparation.
Below, the preparation about The compounds of this invention further describes according to embodiment, but the present invention is not subjected to the restriction of these embodiment.
Embodiment 1
(1) with N, 2 '-two (carbobenzoxy)-Tuo (N-methyl) Erythromycin A (compound 1) 38.7g of 0-are dissolved in the 100ml acetate, stirred 1 hour under the room temperature.Decompression concentrates down, adds chloroform 300ml in residue, according to water 100ml twice, and saturated sodium bicarbonate aqueous solution 100ml, the order washing of water 100ml behind anhydrous magnesium sulfate drying, boils off solvent under the decompression.Obtain N, 2 '-two (the carbobenzoxy-(Cbz))-Tuo (N-methyl)-8 of 0-, the 9-Erythromycin A 6 that dewaters, the white powder 37.9g(yield 99% of 9-hemiketal (compound 2)).The method synthetic (E.H.Flynn.H, W.Murphy, R.E.McMahon, Journal of the American Chemical Society 77 3104(1955) of compound 1 usefulness document record.
(2) 37.9g compound 2 and 4-dimethylaminopyridine 38.0g are dissolved in the 200ml ethylene dichloride, ice-cooledly down the 28ml carbobenzoxy chloride were dripped in 90 minutes.Again in ice-cooled 9.0g sparrow-dimethyl aminopyridine and the 7.0ml carbobenzoxy chloride of adding down, allow it slowly get back to room temperature after 5 hours, stirred simultaneously 18 hours.In reaction solution, add the 300ml methylene dichloride, according to 1N hydrochloric acid 200ml twice, water 200ml, saturated sodium bicarbonate aqueous solution 200ml, the order washing of water 200ml behind anhydrous magnesium sulfate drying, boils off solvent under the decompression.(chloroform-methanol-strong aqua (100: 1: 0.1) is purified with silica gel column chromatography with residue, obtain N, 2 '-0,4 " 0-three (carbobenzoxy-(Cbz))-Tuo (N-methyl)-8; the 9-Erythromycin A 6 that dewaters, the white powder 36.6g(yield 83% of 9-hemiketal (compound 3)).
(3) 27.7g compound 3 is dissolved in the dimethyl formamide of 110ml, in the nitrogen gas stream, the ice-cooled 2.47g sodium hydride (60% oiliness) that adds down after stirring in 10 minutes, adds the 15ml bromotoluene and makes it to react 2 hours.Put into saturated sodium bicarbonate aqueous solution 500ml, use 500ml extracted with diethyl ether 2 times, with extraction liquid washing 2 times, behind anhydrous magnesium sulfate drying, boil off solvent under the decompression with 200ml water.Residue is purified with silica gel column chromatography (hexane-ethyl acetate (4: 1)), obtain N, 2 '-0,4 " 0-three (carbobenzoxy-(Cbz))-Tuo (N-methyl)-11-0-benzyl-8; the 9-Erythromycin A 6 that dewaters, the white powder 12.4g(yield 41% of 9-hemiketal (compound 4)).
(4) 12.4g compound 4 is dissolved in the dimethyl formamide of 50ml, in the nitrogen gas stream, the ice-cooled 2.10g(60% oiliness of adding down) sodium hydride, after stirring in 15 minutes, add the 6.5ml methyl-iodide.Make it to react 2 hours under the water cooling, reaction was put into the 300ml saturated sodium bicarbonate aqueous solution after 2 hours under the room temperature, used 200ml extracted with diethyl ether 2 times.With extraction liquid washing 2 times, behind anhydrous magnesium sulfate drying, boil off solvent under the decompression with 200ml water.Residue is purified with silica gel column chromatography (hexane-ethyl acetate (4: 1)), obtain N, 2 '-0,4 " 0-three (carbobenzoxy-(Cbz))-Tuo (N-methyl)-11-0-benzyl-12-0-methyl-8; the 9-Erythromycin A 6 that dewaters, the white powder 6.74g(yield 53% of 9-hemiketal (compound 5)).
(5) 6.74g compound 5 is dissolved in the 120ml methyl alcohol, adds 10% palladium carbon 582mg and carry out catalytic reduction.After 3 hours, the elimination catalyzer under reduced pressure boils off solvent.Residue is purified with silica gel column chromatography (chloroform-methanol-strong aqua (100: 4: 0.1)), (N-methyl)-11-0-benzyl-12-0-methyl-8 is taken off in acquisition, the 9-Erythromycin A 6 that dewaters, the white powder 4.07g(yield 90% of 9-hemiketal (compound 6)).
Embodiment 2
With 304mg take off (N-methyl)-11-0-benzyl-12-0-methyl-8, the 9-Erythromycin A 6 that dewaters, 9-hemiketal (compound 6) is dissolved in the 10ml methyl alcohol, adds 10% palladium carbon 109mg, trifluoroacetic acid 34 μ l carry out catalytic reduction.After 12 hours, filtration catalizer boils off solvent under the decompression.With residue with silica gel column chromatography (chloroform-methanol-strong aqua) (100: 4: 0.1)) purify, obtain to take off (N-methyl)-12-0-methyl-8, the 9-Erythromycin A 6 that dewaters, the white powder 212mg(yield 78% of 9-hemiketal (compound 7)).
Embodiment 3
(1) 982mg compound 6 is dissolved in the methyl alcohol of 10ml, adds 35% formalin and the 233mg sodium cyanoborohydride of 0.5ml then, in stirring at room 90 minutes.Be poured into then among the saturated sodium bicarbonate aqueous solution 50ml, the white precipitate that leaching generates also washes with water, purifies with silica gel column chromatography (chloroform-methanol-strong aqua (100: 4: 0.1)) in dry back.Obtain 11-0-benzyl-12-0-methyl-8, the 9-Erythromycin A 6 that dewaters, the white powder 764mg(yield 76% of 9-hemiketal (compound 8)).
(2) 597mg compound 8 is dissolved in the 10ml methyl alcohol, adds 10% palladium carbon 217mg, trifluoroacetic acid 60 μ l carry out catalytic reduction.After 24 hours, filtration catalizer boils off solvent under the decompression.Residue is purified with silica gel column chromatography (chloroform-methanol-strong aqua (100: 3: 0.1)), obtain 12-0-methyl-8, the 9-Erythromycin A 6 that dewaters, the white powder 292mg(yield 55% of 9-hemiketal (compound 9)).
Embodiment 4
(1) 1.04g compound 6 is dissolved in the 20ml methyl alcohol, adds the 3.4ml diisopropylethylamine, the 1.0ml iodoethane was in stirring at room 4 days.Boil off solvent under the decompression, residue is purified with silica gel column chromatography (chloroform-methanol-strong aqua (100: 2: 0.1)), obtain N-methyl-Tuo (N-methyl)-11-0-benzyl-12-0-methyl-8, the 9-Erythromycin A 6 that dewaters, the white powder 573mg(yield 53% of 9-hemiketal (compound 10)).
(2) 427mg compound 10 is dissolved in the 10ml methyl alcohol, adds 10% palladium carbon 115mg, trifluoroacetic acid 54 μ l carry out catalytic reduction.After 24 hours, filtration catalizer, boil off solvent under the decompression, purify with silica gel column chromatography (chloroform-methanol-strong aqua (100: 3: 0.1)) residue obtained, obtain N-ethyl-Tuo (N-methyl)-12-0-methyl-8, the 9-Erythromycin A 6 that dewaters, the white powder 280mg(yield 73% of 9-hemiketal (compound 11)).
Embodiment 5
(1) 1.03g compound 6 is dissolved in the 20ml methyl alcohol, adds the isopropyl iodide of 2.2ml diisopropylethylamine, 2.5ml, in 50 ℃ of stirrings.The reaction beginning is appended diisopropylethylamine 2.2ml, isopropyl iodide 2.5ml after back 1 day and 4 days.After reaction in 6 days, boil off solvent under the decompression, add chloroform 50ml, use saturated sodium bicarbonate aqueous solution 50ml in turn, water 50ml washing behind anhydrous magnesium sulfate drying, boils off solvent under the decompression.Residue is purified with silica gel column chromatography (chloroform-methanol-strong aqua (100: 2: 0.1)), obtain N-sec.-propyl-Tuo (N-methyl)-11-0-benzyl-12-0-methyl-8, the 9-Erythromycin A 6 that dewaters, the white powder 872mg(yield 80% of 9-hemiketal (compound 12)).
(2) 657mg compound 12 is dissolved in the 15ml methyl alcohol, adds 10% palladium carbon 404mg, trifluoroacetic acid 0.1ml and carry out catalytic reduction.After 24 hours, filtration catalizer, boil off solvent under the decompression, purify with silica gel column chromatography (chloroform-methanol-strong aqua (100: 3: 0.1)) residue obtained, obtain N-sec.-propyl-Tuo (N-methyl)-12-0-methyl-8, the 9-Erythromycin A 6 that dewaters, the white powder 396mg(yield 67% of 9-hemiketal (compound 13)).
Embodiment 6
(1) with 130mg take off (N-methyl)-11-0-benzyl-12-0-methyl-8, the 9-Erythromycin A 6 that dewaters, 9-hemiketal (compound 6) was dissolved in the 3ml methyl alcohol, adds cyclopentanol 0.061ml, sodium cyanoborohydride 24mg, in stirring at room 23 hours.Boil off solvent under the decompression, add water, use dichloromethane extraction then.With saturated common salt water washing extraction liquid, behind anhydrous sodium sulfate drying, boil off solvent under the decompression.Residue is purified with silica gel column chromatography (chloroform-methanol (250: 1)), obtain N-cyclopentyl-Tuo (N-methyl)-11-0-benzyl-12-0-methyl-8, the 9-Erythromycin A 6 that dewaters, the white powder 120mg(yield 85% of 9-hemiketal (compound 14)).
(2) compound 14 with 120mg is dissolved in the 5ml methyl alcohol, adds 10% palladium carbon 24mg, trifluoroacetic acid 0.026ml and carries out catalytic reduction.Filtration catalizer, decompression down boil off solvent and add chloroform in the residues of gained, with saturated sodium bicarbonate aqueous solution, saturated common salt water washing, with behind the anhydrous sodium sulfate drying, boil off solvent under the decompression.Residue is purified with silica gel column chromatography (chloroform-methanol-strong aqua (150: 1: 0.1)), obtain N-cyclopentyl-Tuo (N-methyl)-12-0-methyl-8, the 9-Erythromycin A 6 that dewaters, the white powder 53mg(yield 49% of 9-hemiketal (compound 15)).
Embodiment 7
(1) with 130mg take off (N-methyl)-11-0-benzyl-12-0-methyl-8, the 9-Erythromycin A 6 that dewaters, 9-hemiketal (compound 6) is dissolved in the 3ml methyl alcohol, stirs 22 hours in 50 ℃ after adding diisopropylethylamine 0.28ml, n-propyl iodide 0.64ml.Decompression down boils off solvent, adds chloroform in the residue of gained, uses saturated sodium bicarbonate aqueous solution, and saturated common salt water washing, with behind the anhydrous sodium sulfate drying boils off solvent under reducing pressure.With residue with silica gel column chromatography (chloroform-methanol (300: 1)) purification N-propyl group-Tuo (N-methyl)-11-0-benzyl-12-0-methyl-8, the 9-Erythromycin A 6 that dewaters, the white powder 110mg(yield 81% of 9-hemiketal (compound 16)).
(2) compound 16 with 110mg is dissolved in the 5ml methyl alcohol, adds 10% palladium carbon 22mg, trifluoroacetic acid 0.025ml and carries out catalytic reduction.Filtration catalizer boils off solvent under the decompression, adds chloroform in the residue of gained, uses saturated sodium bicarbonate aqueous solution, and the saturated common salt water washing behind anhydrous sodium sulfate drying, boils off solvent under the decompression.Residue is purified with silica gel column chromatography (chloroform-methanol-strong aqua (150: 1: 0.1)), obtain N-propyl group-Tuo (N-methyl)-12-0-methyl-8, the 9-Erythromycin A 6 that dewaters, the white powder 38mg of 9-hemiketal
Embodiment 8
(1) with 230mg take off (N-methyl)-11-0-benzyl-12-0-methyl-8, the 9-Erythromycin A 6 that dewaters, 9-hemiketal (compound 6) is dissolved in the 4ml methyl alcohol, adds diisopropylethylamine 0.50ml, ethylene bromohyrin 1.43g, stirs 14 hours in 50 ℃.Boil off solvent under the decompression, add methylene dichloride in the residue of gained, water, saturated common salt water washing behind anhydrous magnesium sulfate drying, boil off solvent under the decompression.Residue is purified with silica gel column chromatography (chloroform-methanol-dense amine water (75: 1: 0.1)), obtain the N-(2-hydroxyethyl)-Tuo (N-methyl)-11-0-benzyl-12-0-methyl-8, the 9-Erythromycin A 6 that dewaters, the white powder 189mg(yield 78% of 9-hemiketal (compound 18)).
(2) 190mg compound 18 is dissolved in the 5ml methyl alcohol, adds 10% palladium carbon 30mg, trifluoroacetic acid 0.043ml and carry out catalytic reduction.Filtration catalizer boils off solvent under the decompression, adds chloroform in the residue of gained, uses saturated sodium bicarbonate aqueous solution, and the saturated common salt solution washing behind anhydrous sodium sulfate drying, boils off solvent under the decompression.Residue is purified with silica gel column chromatography (chloroform-methanol-strong aqua (150: 1: 0.1)), obtain the N-(2-hydroxyethyl)-Tuo (N-methyl)-12-0-methyl-8, the 9-Erythromycin A 6 that dewaters, the white powder 50mg(yield 30% of 9-hemiketal (compound 19)).
Embodiment 9
With 120mg take off (N-methyl)-12-0-methyl-8, the 9-Erythromycin A 6 that dewaters, 9-hemiketal (compound 7) is dissolved in the 3ml methyl alcohol, stirs 15 hours in 40 ℃ after adding sodium bicarbonate 28mg, allyl bromide 98 0.035ml.Boil off solvent under the decompression, in the residue of gained, add chloroform,, behind anhydrous sodium sulfate drying, boil off solvent under the decompression with saturated sodium bicarbonate aqueous solution, saturated common salt water washing.Residue is purified with silica gel column chromatography (chloroform-methanol (300: 1)), obtain N-allyl group-Tuo (N-methyl)-12-0-methyl-8, the 9-Erythromycin A 6 that dewaters, the white powder 19mg(yield 15% of 9-hemiketal (compound 20)).
Embodiment 10
(1) with 100mg take off (N-methyl)-12-0-methyl-8, the 9-Erythromycin A 6 that dewaters, 9-hemiketal (compound 7) is dissolved in the 3ml acetonitrile, stirs 2 hours under room temperature after adding 35% formalin 0.18g, sodium cyanoborohydride 26mg.Boil off solvent under the decompression, use chloroform extraction after adding water.With saturated common salt water washing extraction liquid, behind anhydrous sodium sulfate drying, boil off solvent under the decompression.Residue is purified with silica gel column chromatography (chloroform-methanol-strong aqua (150: 1: 0.1)), obtain 12-0-methyl-8, the 9-Erythromycin A 6 that dewaters, the white powder 110mg of 9-hemiketal (compound 21).
(2) compound 21 with 120mg is dissolved in the 3ml chloroform, adds behind the propargyl bromide 0.095ml in stirring at room 11 hours.Boil off solvent under the decompression, the residue of gained is purified with silica gel column chromatography (chloroform-methanol-strong aqua (10: 1: 0.1)), obtain 12-0-methyl-8, the 9-Erythromycin A 6 that dewaters, the white powder 30mg(yield 23% of 9-hemiketal propargyl bromide (compound 22)).
Embodiment 11
(1) 45mg taken off (N-methyl)-12-0-methyl-8, the 9-Erythromycin A 6 that dewaters, 9-hemiketal (compound 6) is dissolved in the 2ml acetonitrile, adds diisopropylethylamine 0: 11ml, N-(2-bromotrifluoromethane)-stirred 25 hours in 50 ℃ behind the phthalic imidine 510mg.Boil off solvent under the decompression, add chloroform in the residue of gained, water, saturated common salt water washing behind anhydrous magnesium sulfate drying, boil off solvent under the decompression.Residue is purified with silica gel column chromatography (chloroform), obtains the N-(2-(N-phthalic imidine) ethyl)-Tuo (N-methyl)-12-0-methyl-8, the white powder 20mg(yield 36% of 9-dehydration Erythromycin A 6.9-hemiketal (compound 23)).
(2) with the N-(2-(N-phthalic imidine of 20mg) ethyl)-Tuo (N-methyl)-12-0-methyl-8, the 9-Erythromycin A 6 that dewaters, 9-hemiketal (compound 23) is dissolved in the 2ml methyl alcohol, adds behind the methanol solution 0.5ml of 40% methylamine stirring at room 1 hour.Boil off solvent under the decompression, add chloroform in the residue of gained, water, saturated common salt water washing behind anhydrous magnesium sulfate drying, boil off solvent under the decompression.Residue is purified with silica gel column chromatography (chloroform-methanol-strong aqua (150: 1: 0.1)), obtain the N-(2-aminoethyl)-Tuo (N-methyl)-12-0-methyl-8, the 9-Erythromycin A 6 that dewaters, the white powder 13mg(yield 80% of 9-hemiketal (compound 24)).
In the actual in the above-described embodiments compound that makes, about compound 6,7,9,11 and 13, with their NMR spectrum data, MS spectrum data and specific rotation are shown in table 1; About compound 15,17,19,20,22 and 24, with their NMR spectrum data, MS spectrum data and specific rotation are shown in table 2.
Test example 1
Motilin receptor carries out [V.Bormans etc., Regul Peptides, 15 by the following method in conjunction with test, 143(1986)], draw out duodenum from the rabbit that kills, peel off mucous membrane by muscle layer after, in Tris solution (pH7.4), homogenize and make protein liquid.Will
125I spike motilin(You Da mound ァ ッ ャ イ grinds and purchases the people) 25PM and protein liquid 25 ℃ cultivate 120 minutes after, measure radioactivity in the albumen with gamma counter.With the radioactivity when adding with add motilin(1 * 10 of big excess
-7The difference of the radioactivity in the time of M) is defined as special combination.The effectiveness of sample is to be used in the drug concentration IC50(M that special combination reduces at 50% o'clock) represent.Medicament is dissolved in the DMSO solution, adds to (final DMSO concentration is 1%) in the protein liquid.In addition, as the antacid experiment of research, be with medicine dissolution in hydrochloric acid soln (pH2.5), place under the room temperature after 120 minutes, add in the protein liquid for experiment.
Consequently, as the IC50(M of DMSO solution), with respect to EM-523 3 * 10
-9, compound 13 is 8 * 10
-9, this two samples active identical.As hydrochloric acid soln, the IC50(M of EM-523) equal 3 * 10
-7, to compare with DMSO solution, its activity reduces to 1/100th, but the IC50(M of compound 13) be 2 * 10
8, almost do not have difference with DMSO solution.Provable thus, compound 13 is decomposed than EM-523 difficulty by acid.
Table 3
IC50(M)
DMSO Solution H Cl solution
EM-523 3×10
-93×10
-7
Compound 13 8 * 10
-92 * 10
8
Test example 2
The mensuration of digestive tract contractile motion carry out by the following method [her rattan gradually, the level and smooth muscle association of Japan magazine, 13.33(1976)].PVC-グ Le dog of the about 10kg of body weight is being cut open the belly under the general anesthesia in advance, can on the serosal surface of stomach vestibular portion, duodenum and jejunum, measure the direction of circular muscle contraction separately, with slowly contact of force transducer (force transducer).In addition, for medicine directly being thrown with in stomach, pharmaceutical silicon flexible pipe is kept somewhere under one's belt, the lead of force transducer and silicon flexible pipe are drawn from the back, are fixed on the skin, and postoperative dog is raised in testing with independent cage, throws feed every day one time.
The principle of force transducer is, in case the part digestive tube that is in contact with it shrinks, and occurs flexural deformation on the force transducer, will with the proportional waveform recording of this power on pen drawing oscilloscope, because the lead that force transducer is drawn is connected on the oscilloscope, therefore can directly write down the contraction waveform.Gastral contractile motion can be divided into feed back period and empty stomach two stages of period from its oscillogram.
Experiment is after 2 weeks of performing the operation, and as the empty stomach phase, carries out when being the resting stage of shrinking the phase on an empty stomach of not producing under one's belt.Just introduce the silicon flexible pipe that is retained in the stomach, after about 10 seconds, test portion is directly injected in the stomach.After being dissolved in the ethanol in advance, medicament, total amount is defined as 3ml with the normal saline solution dilution.
In order to represent the digestive tract contractile motion facilitation effect quantitatively, baseline when motion in the stomach is stationary state and the area that shrinks between the waveform are defined as MOtOr Index(MI), be used as the momental index (Inatomi etc. of stomach, J.Pharmacol, Exp, Ther, 251,707(1989)].MI is input to the signal from the force transducer that contacts with stomach in the computer to calculate and get.The stomach amount of exercise of spontaneous propagated contraction of empty stomach phase of phase on an empty stomach, if with this method calculate MI represent MI=100～200 then.Therefore, be expression MI=150, necessary medicament is thrown with amount be decided to be MI150, as the index of the gastrointestinal motor facilitation effect of medicament.
By throw in the stomach with, EM-523 and compound 13 all show the gastrointestinal motor promoter action separately, MI150 separately is respectively 14.6 μ g/kg and 2 μ g/kg.Compound 13 in stomach, throw with the time show that its gastrointestinal motor promoter action is stronger about 6 times than EM-523.
Erythromycin derivatives of the present invention with gastrointestinal motor promoter action from the stability to acid, obviously is better than this class of EM-523 known erythromycin derivatives in the past.Erythromycin derivatives of the present invention is different with the erythromycin derivatives before unsettled in acid, and the degree of decomposing because of hydrochloric acid in gastric juice is extremely low, therefore, even orally also demonstrate very strong gastrointestinal motor promoter action.
Claims (1)
1, leads to the compound or its salt that formula I is represented
(in the formula, R1 represents hydrogen atom or acyl group; R2 and R3 can be identical or different, represent hydrogen atom, hydroxyl, acyloxy or become together=0; R4 represents hydrogen atom or low alkyl group; R5 represents low alkyl group; Y represents-NR6R7 or-N
+R8R9R10X
-Wherein R6 and R7 can be identical or different, the expression hydrogen atom, and acyl group can have substituent low alkyl group, can have substituent cycloalkyl, can have substituent low-grade alkenyl or can have substituent low-grade alkynyl; R8, R9 and R10 can be identical or different, and the expression hydrogen atom can have substituent low alkyl group, can have substituent cycloalkyl, can have substituent low-grade alkenyl or can have substituent low-grade alkynyl; X represents negatively charged ion).
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP29519692 | 1992-11-04 | ||
| JP295196/92 | 1992-11-04 |
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| CN1091431A true CN1091431A (en) | 1994-08-31 |
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| CN 93114359 Pending CN1091431A (en) | 1992-11-04 | 1993-11-04 | leptomycin derivatives |
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| AU (1) | AU5376394A (en) |
| TW (1) | TW355711B (en) |
| WO (1) | WO1994010185A1 (en) |
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| US6077943A (en) * | 1996-03-01 | 2000-06-20 | Takeda Chemical Industries, Ltd. | Method of producing erythromycin derivative |
| WO2002102818A1 (en) * | 2001-06-13 | 2002-12-27 | Ube Industries, Ltd. | Process for preparation of erythromycin compounds |
| US7091196B2 (en) | 2002-09-26 | 2006-08-15 | Rib-X Pharmaceuticals, Inc. | Bifunctional heterocyclic compounds and methods of making and using same |
| EP1723159B1 (en) | 2004-02-27 | 2019-06-12 | Melinta Therapeutics, Inc. | Macrocyclic compounds and methods of making and using the same |
| GB0611907D0 (en) | 2006-06-15 | 2006-07-26 | Glaxo Group Ltd | Compounds |
| EP1902022A1 (en) | 2005-07-12 | 2008-03-26 | Glaxo Group Limited | Piperazine heteroaryl derivates as gpr38 agonists |
| EA014061B1 (en) | 2005-07-26 | 2010-08-30 | Глаксо Груп Лимитед | Benzylpiperazine derivatives and their medical use |
| JP5028484B2 (en) | 2006-06-28 | 2012-09-19 | グラクソ グループ リミテッド | Piperazinyl derivatives useful for the treatment of GPR38 receptor mediated diseases |
| CA2750699C (en) | 2009-02-27 | 2015-12-29 | Raqualia Pharma Inc. | Oxyindole derivatives with motilin receptor agonistic activity |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0215355B1 (en) * | 1985-08-31 | 1994-04-06 | Kitasato Kenkyusho | Erythromycin derivative and process for preparing the same |
-
1993
- 1993-11-03 TW TW082109245A patent/TW355711B/en active
- 1993-11-04 AU AU53763/94A patent/AU5376394A/en not_active Abandoned
- 1993-11-04 WO PCT/JP1993/001594 patent/WO1994010185A1/en active Application Filing
- 1993-11-04 CN CN 93114359 patent/CN1091431A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| WO1994010185A1 (en) | 1994-05-11 |
| AU5376394A (en) | 1994-05-24 |
| TW355711B (en) | 1999-04-11 |
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| C01 | Deemed withdrawal of patent application (patent law 1993) | ||
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