Macrolide compounds and pharmaceutical composition


(57) Abstract:

Usage: as a drug for the treatment of gastrointestinal disorders. Entity: product, Macromedia compounds of General formula I: where R1- [N(CH3)2R]+Xor N(CH3)2where R is C1-C6- alkyl or C2-C6quinil, R2and R3each H or together form a simple bond; R4and R5- independently from each other H or, together with the carbonyl group to form a five-membered cyclic carbonate, R6-H, X-halogen, provided that when R1- N(CH3)2and R2and R3together form a simple bond, R4and R5cannot be hydrogen. Pharmaceutical composition based on compounds 1 when the content of the last 0.1 to 9 wt.% on the dosing unit is useful for treatment of disorders of the gastrointestinal tract. 2 S. and 3 C.p. f-crystals, 2 tab.

In the invention proposed new pharmaceutical compositions as the active ingredient contains a 12-membered macrolide compounds. These compositions are particularly useful for treating disorders of the gastro-intestinal activity in animals. Also disclosed are new compounds and methods of the OO-intestinal tract is well coordinated manner in the direction from the mouth. Transport this is due to the peristaltic contractions of the circular muscle layers. Transportation coordination is carried out jointly at the expense of the Central and peripheral nerve endings.

Disruption of normal motility can lead to the development of aperistalsis, expedited transportation, gastrointestinal Stasys (such as that observed in diabetic gastroparesis) or to the paralytic ileus. One of the common defects, when the tone of the lower esophageal sphincter low, causes the opposite movement of the contents of the stomach into esophagus. This can lead to the development of esophagitis.

The exact pathophysiology of disorders of the activity is unknown. Accordingly, no rational treatment of such diseases. Pharmacological agents used to improve the activity of the paralytic intestine, can be useful in the treatment of diseases such as dyspepsia, gastroparesis, gastroesophageal reflex and paralytic ileus caused by surgical intervention. In addition, agents that increase the activity (also called gastroprokinetic agents), can facilitate the introduction of diagnostic tools in the gastro-intestinal the awn is the only drug adopted from the USA for treatment of cardiac activity. Unfortunately, metoclopramide has serious side effects, ranging from the ability of prolactin to the development of dyskinesia and so on, Thus, the need for effective, selective and safe drug for the treatment of disorders of the gastro-intestinal activity is quite high.

After the introduction of macrolide antibiotics in hospitals has been known to cause stomach cramps and diarrhea. Are these side effects secondary to their activity as antibiotics or they are associated with effects on gastrointestinal activity and secretion is still unknown. Recently Omura with employees chemically modified erythromycin in connection with improved gastroprokinetic properties, but with slight antibacterially activity (see J. Med. Chem. 30 (11): 1941-1943, 1987; J. Antibiotics 38 (11): 1631-1632, 1987; Thor. in 21st Cent Jap. U. S. Cong. Pharm. Sci. abstract 14, 1987, Jnterscience Conf. Antimicrob. Agents and Chemotherapy, abstract N 1148 1985). Group Omori reported that some of the obtained compounds demonstrate gastroprokinetic activity, which is higher than that of erythromycin. Activity in vitro for the most effective of these compounds, however, are not inhibited LASS="ptx2">

In the invention proposed new pharmaceutical compositions which contain as the active ingredient macrolide compressed ring (ring-contracted macrolide)

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where R1is-N/CH3/2or-N/CH3/2R+x-; R is C1-C6the alkyl, C2-C6alkenyl, C2-C6-quinil, benzene or benzyl substituted from 1 to 3 substituents selected from fluorine, chlorine, C1-C4-alkyl, C1-C4alkoxy, nitro, C1-C4-alkoxycarbonyl, -N/C1-C4the alkyl/2or cyanopropyl;

R2and R3each are H or together form a bond;

R4and R5independently are H or C1-C4the acyl, or together with the carbonyl group formed five-membered cyclic carbonate;

R6is H or C1-C4the acyl;

X-the halide, hydroxide, carboxylate, sulfate, phosphate, nitrite, C1-C3alkylsulfonates or arylsulfonate (such as paratoluenesulfonyl or bansilalpet); or if R1-N/CH3/2, its pharmaceutically acceptable salt,

for the treatment of disorders of the gastro-intestinal activity.

Connection FOIA formula (l) promote gastrointestinal activity due to cholinergic mechanism, primarily and implemented for the normal stomach. This mechanism of action is shown by the fact that gastrointestinal activity, increased at the expense of the compounds of formula (l) is blocked under the action of atropine (30 µg/kg). In addition, such patent gastroprokinetic macrolides possess the desired characteristics so as to have minimal activity as antibiotics.

Thus, in the proposed invention the compounds of formula (l) for use in the treatment of disorders of the gastro-intestinal activity.

In another aspect of the invention proposed by the group of new compounds, i.e. compounds of formula (l) where R1-N/CH3/2R+X-.

In the invention proposed a method for obtaining a macrolide of formula (l) in which R1is-N/CH3/2R+X-,

which includes

/A/ /i/ interaction of the macrolide of formula (ll)

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with an alkylating agent to obtain the compounds of formula (l) in which R1is-N/CH3/2R+X-; and is optional

/ii/ reconnection from the stage /A/ /i/ to obtain the compounds of formula (l) in which R1is-N (ll) to obtain the compounds of formula (l), where R1is-N/CH3/2and R2and R3each are H; and/or non-receipt of the salt of the compound, if it is not obtained in salt form; and optionally,

(ii) coordination compounds with stage /B/ /i/ with an alkylating agent to obtain a compound of formula (l), where R1is-N/CH3/2R+X-and R2and R3each are H.

In the sense, as he used herein, the term "alkyl" includes branched, unbranched and cyclic fragments and their combinations containing a certain number of carbon atoms.

The term "alkenyl" and "quinil" refers to such alkyl groups containing 1 to 2 double and/or triple bonds. The double bond may have either "CIS" or "TRANS" configuration.

The term "C1-C4-acyl" refers to acyl fragment derived from a carboxylic acid containing from one to four carbon atoms.

The term "halide" refers to a chloride, iodide or bromide.

The term "carboxylate" refers to the anion of an organic carboxylic acid, for example acetic, succinic, citric, lactic, maleic, fumaric, palmitic, holeinone, salicylic acid, lauric, methansulfonate, benzosulfimide, sorbic, picric, benzoic, cinnamic and like acids.

Some derivatives of the invention form salts, in particular salts of joining acids. These salts accession acids are also useful as gastroprokinetic agents and form part of the invention. In another aspect of such salts are useful as intermediates, for example, for isolation and purification of derivatives. In addition, these salts have a high solubility in water.

Representatives of suitable salts include salts obtained by standard reactions with both organic and inorganic acids, such as sulfuric, hydrochloric, phosphoric and organic acids listed above.

Pharmaceutically acceptable salt accession acids are the most preferred group of salts of the invention. Pharmaceutically acceptable salts of accession are those salts which are suitable for hemoterapia warm-blooded animals.

Typical compounds of formula (l) are presented in table.1.

Pharmaceutical compositions containing as active ingredient connected to the I. These pharmaceutical compositions can be prepared for oral and parenteral injection for the treatment and prevention of disorders of the gastro-intestinal activity.

For example, the compound of formula (l) can be mixed with conventional pharmaceutical carriers and excipients and used in the form of tablets, capsules, Alexiou, suspensions, syrups, wafers, etc. of the Composition containing the compound of the invention may contain from about 0.1 to about 90 wt. active compounds, and more typically, from about 10 to about 30 wt.

The composition may contain conventional carriers and excipients, such as corn starch or gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate and alginine acid. Disintegrator commonly used in the compositions of the invention include croscarmellose sodium, microcrystalline cellulose, corn starch, nachrichtentechnische and alginine acid.

Binder for tablets include acacia, methylcellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone (Povidone, hypromellose, sucrose, starch and ethylcellulose. As lubricants you can use magnesium stearate and silicon oxide.

As a substitute you can use mint, oil gaultheria, cherry flavoring, etc.

To make the dosage form more aesthetic appearance or to facilitate identification may be desirable to use coloring agents.

Intravenous (IV) water-soluble form of the compound can be dissolved in one of the commonly used fluids for intravenous and enter the infusion. Such liquids are, for example, saline, ringer's solution or 5% dextrose.

For preparations for intramuscular injection of a sterile composition suitable soluble salts of the compounds, such as hydrochloride, it is possible to dissolve and enter into such pharmaceutical diluent such as water for injection, saline solution or 5% glucose. A suitable insoluble form of the connection, you can access and input in the form of a suspension in an aqueous solution or pharmaceutically acceptable oil base, for example in such a complex ester of long chain fatty acids as atiloleate.

For oral use such solid compositions as tablets and capsules are particularly useful. You can use t the physical rehabilitation and geriatric applications are particularly suitable suspension syrups and tablets for chewing.

In another embodiment, the unit dose form of connection can be a solution of the compound in a suitable diluent in sterile, hermetically sealed ampoules. The concentration of the compound in a unit dose can vary, for example, from about 1 to about 50% depending on the compound and its solubility, and the dose needed a doctor.

The following aspect of the invention provides a method of treating disorders of the gastro-intestinal activity in animals. The term "treatment" is used to indicate both the prevention and treatment of the disease after infection of the animal. The method includes the introduction to the animal an effective amount of compounds of the invention. Effective dose is generally from about 0.02 to about 100 mg/kg of the compound or its pharmaceutically acceptable salt. The preferred dose is from about 0.05 to about 50 mg/kg of the compound. A typical daily dose for adults is from about 50 mg to about 0.5 g

In practice, the connection can be entered in a single daily dose or in multiple doses per day. The treatment regimen may require the introduction of longer periods of time, for example within the neet depend on such factors as the nature and severity of the disease and the age and General health of the patient. The usual way in practice, the treatment is the introduction of compounds orally using tablets, capsules, suspensions, syrups, etc. Connection, you can enter in other ways, for example, in the form of suppositories or parentline by intravenous infusion.

To illustrate the invention further, we present non-limiting examples.

Chromatographic purification of products was performed on silica gel, using either chromatography with instant evaporation (silica gel that is Megs -60, mesh 230-400 mesh) or system Waters Model 500 Rger. Z. C.

Compounds were purified to a homogeneous state according to Tshand NMR.

Preparation 1. 8,9-anhydrous-erythromycin-6,9-hemiketal.

A solution of erythromycin (20,0 g, 27.3 mmole) in glacial acetic acid (100 ml) was stirred at room temperature for 1 h Portions slowly add sodium hydroxide (5 n). After each addition the resulting mixture is left to return to room temperature. After deposition, the mixture is extracted twice with dichloromethane. The combined organic layers extracted with saturated sodium bicarbonate solution, dried over sodium sulfate, filtered and evaporated. The crude product (18 to 7% methanol + 0.5% ammonium hydroxide in dichloromethane) to obtain the title compound (13,2 g, 68%) as a white solid.

Example 1. The connection is 1.

8,9-anhydrous-erythromycin-6,9-hemiketal (10.0 g, 14 mmol) in 200 ml of methanol is treated with potassium carbonate) (1.9 g, 14 mmol) and the resulting mixture is refluxed for 90 minutes the Solvent is evaporated under reduced pressure and the residue separated between dichloromethane and saturated sodium bicarbonate solution. The organic layer is evaporated to obtain 9.6 g of a white foam. This foam is cleaned by high-performance liquid chromatography (linear gradient dichloromethane to 7.5% methanol + 0.5% ammonium hydroxide in dichloromethane) to obtain compound 1 (5,4 g,54%) as a white solid. FDMS m/e 715 (M + H)

Example 2. The activity of compounds of the formula (l).

Activity in the stomach and dvenadcatiperstnoy intestine was registered by a standard method (P. Bass u J. N. Wiley, Am J. Physiol 208:908-913, 1965). Briefly, the ferrets of either sex weighing 1.0-1.5 kg analizirovali phenobarbital (30 mg/kg intravenously). Anesthesia was maintained by introducing phenobarbital in the form of pills (5 mg/kg intravenously). All the animals breathed spontaneously through a tracheal tube. In cervical artery and vein was introduced cannula for recording blood pressure and introduced test soy and proximal dvenadcatiperstnoy intestine. The strain gauges (R. B. Products, Wisconsin) sewn on the serosal surface of the stomach and dvenadcatiperstnoy guts to 2 cm proximal and 2 cm distal direction from the pyloric sphincter, respectively. Strain gauges are oriented so as to record the voltage increase only in the layer of circular muscle, as it is contractora activity of this muscle leads to polusobrannom movement of digested food. The abdominal cavity is closed by a swab and the output of the strain gauge is connected to demograficheskogo the recorder.

Drugs dissolved in 50% DMCO and prepare anew every day. Capsule injection quickly injected, and the line is washed after injection into 1/2 cm3saline solution. Between-dose interval is at least 5 minutes However, if the activity does not return to the level prior to the introduction of the drug, wait a little longer, but time should not exceed 10 minutes At the end of the experiment animals killed by intravenous introduction 1 cm3T-61.

The number and amplitude of contractions for 1 min after injection counted manually. The amplitude of all the reactions averages and expressed in, the voltage generated in 1 min Statistical analysis pravovogo connection.

In table. 2 presents the effect of illustrative compounds of formula (l) as the voltage generated in the circular muscle layers of the stomach:

Example 3. Illustrative pharmaceutical composition of tablets containing the compounds of formula (l), is prepared as follows:

Ingredient Wt. h

Connection 1 250

Polyvinylpyrrolidone 35

Microcrystalline cellulose 35

Sodium hydroxide 0,36

Potassium phosphate 1,32

The ingredients are mixed and granularit by adding 0.1 part of water. Dry granules are passed through a sieve 12-mesh and combined with the following ingredients:

Ingredients Wt. h

Connection 1, granules 320

The dihydrate sodium citrate 300

Magnesium stearate are mixed and tabletirujut 5

Example 4. An illustrative composition for intravenous administration containing the compound of formula (l) receive, dissolving the compound 6 in diluted (50%) dimethyl sulfoxide.

Example 5. Getting connection 2.

A solution of enol ether erythromycin (500 mg, 0.7 mmole) and ethylene carbonate resulting (1.0 g, 11.4 mmole) in 1,2-dimethoxyethane (25 ml) is treated with K2CO3(500 mg, 3.6 mmole). The resulting mixture is heated to boiling under reflux and with the W continue another 7 hours The resulting mixture was diluted with CH2Cl2and extracted with H2O (3100 ml). A solution of CH2Cl2dried (Na2CO4) and evaporated to dryness. The remainder chromatographic on a column of silica gel with instant evaporation using a 1 GND CH2Cl2for CH2Cl2(MeOH) NH4OH (92,5:7,5 level:0.5) and then 1 l of the last of the solvent to obtain two products. A product with a large value of Rx, 92 mg, is identical to the carbonate simple enol ether erythromycin. The second product was the compound 2; exit 215 mg): IR (CHCl3): 1976, 1727 cm-1IH NMR (CDCl3): 5,19 (d,H-11), to 4.16 (DD, H-13 is overlapped with H-3), 1,58 and 1.56 (2s, 8-and 12 IU-IU) FDMS: m/e 741 (M+) (Field mass spectrometry)

Example 6. The connection 6.

To the compound of formula ll wherein R2and R3together form a double bond and R4and R5mean hydrogen (compound 1, 1.0 g, 1.4 mmole) in chloroform (20 ml) is added and 12.6 ml of 80% propargylamine (in toluene). The resulting mixture was stirred at 25oC for 3 h, and the solvent is removed in vacuum. The residue is dissolved in chloroform (5 ml). Add diethyl ether until then, until it turns out that the deposition is completed. The hard part is removed f is for 18 h to obtain 827 mg (70,8%) of compound 6 in the form of off-white powder.

Elementary analysis (experiment/theory) C 56,79.

With 56,79 (57,55) H 8,02 (8,21) 1,72 (1,68) Br 9,39 (to 9.57)

FDMS: m/r + 754 (M-Br), 715 (M-propylbromide)IH NMR (300 MHz): N(CH3)2the shift from s of 2.26 to s 3,49 (6 protons).

Example 7. Getting connection 5.

Connection get 5 in a manner analogous to the connection 6 on the basis of compound 1 (200 mg) and under the conditions (80 μl) in chloroform (2 ml). After recrystallization obtain 85 mg (35.4%) of product as a solid product, a yellow-brown color. FDMS: m/r + 730 (M-I), 715 (M-CH3I)IH NMR (300 MHz): N(CH3)3s 3,50 (9 protons).

1. Macrolide compounds of General formula

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where R1[N(CH3)2R]+X-halogen, provided that when R1N(CH3)2and R2and R3together form a simple bond, R4and R5cannot be hydrogen.

2. Connection on p. 1, where R1N(CH3)2.

3. Connection on p. 1, where R1-[N(CH3)2R]+X.

4. Connection on p. 1, where R4and R5together with the carbonyl group to form a five-membered cyclic carbonate.

5. Pharmaceutical cononley media characterized in that the active ingredient is used as a compound of General formula under item 1 in an amount of 0.1 to 90.0 wt. on the dosing unit.


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