Derivatives benzoylpyridine, the method of production thereof and pharmaceutical composition based on them

 

(57) Abstract:

The invention relates to new derivatives benzoylpyridine General formula (I), where R1means alkyl with 1-8 carbon atoms, a represents a group represented by the formula of the invention, means (-CH2-)aor (-CO-)band means an integer of 0 to 8, preferably 1, 2, 3 or 4, b means of 0,1 or 2, preferably 1, R2means unsubstituted or substituted alkyl with 1-8 carbon atoms, unsubstituted phenyl, NR3R4or preferably the five-membered heterocycle represented in the claims, in which U, V, W, X and Z can mean CH, NH, O or S, R3and R4denote alkyl with 1-8 carbon atoms. The invention expands the Arsenal of derivative benzoylpyridine having high inhibitory activity against Na+/H+exchange. Also disclosed is a method of obtaining these compounds and pharmaceutical composition on the basis of new derivatives benzoylpyridine. 3 S. and 2 C.p. f-crystals.

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This invention relates to new derivatives of guanidine, possessing biological activity, and more particularly to a derivative benzoylpyridine, method for their production and pharmaceutical companies who Yu, in particular possessing inhibitory activity against Na+/H+exchange (see application DE 4337611, CL 07 D 239/95, a 61 K 31/495, 11.05.1995 year ).

The objective of the invention is the expansion of the Arsenal derivatives benzoylpyridine having high inhibitory activity against Na+/H+exchange.

The problem is solved proposed derivative benzoylpyridine General formula (I)

< / BR>
where R1means alkyl with 1-8 carbon atoms,

And means group

< / BR>
In the mean group (-CH2-)aor (-CO-)bwhere

a represents an integer from 0 to 8, preferably 1, 2, 3, or 4

b signifies 0, 1 or 2, preferably 1,

R2means unsubstituted or substituted alkyl with 1-8 carbon atoms, unsubstituted phenyl, NR3R4where R3and R4each denotes alkyl with 1-8 carbon atoms, or preferably of the five-membered heterocycle

< / BR>
in which U, V, W, X and Y denote CH, NH, O or S.

Preferred derivatives benzoylpyridine General formula (I), in which

R1means alkyl with 1 to 4 carbon atoms,

And means group

< / BR>
In the mean group (-CH2-)andor (-CO-)bwhere
< / the substituted alkyl with 1-4 carbon atoms, unsubstituted phenyl, NR3R4where R3and R4each denotes alkyl with 1-4 carbon atoms, or preferably of the five-membered heterocycle

< / BR>
in which U, V, W, X and Y denote CH, NH, O or S.

Particularly preferred derivatives benzoylpyridine General formula (I),

have

R1means methyl,

And means group

< / BR>
In means one group (-CH2-)andor (-CO-)bwhere

a represents an integer from 0 to 4,

b stands for 0 or an integer of 1

R2means of the five-membered heterocycle

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in which U, V, W, X and Y denote CH, NH, O or S.

Derivatives benzoylpyridine General formula (I) can be obtained due to the fact that the derivative of benzoic acid of General formula (II)

< / BR>
where R1has the above value, and

R means leaving nucleofuge group

subjected to interaction with the compound of General formula (III),

B2BAQ, (III)

where R2, A and b have the above meaning, and

Q means leaving, replaced by electrophile group, and formed a derivative of benzoic acid of General formula (IV)

< / BR>
suspended in a suitable, mainly anhydrous, solvent, EO mixture of a solution or suspension of the base, preferably sodium hydride, in a suitable anhydrous solvent, preferably dimethylformamide, with guanidine salt, preferably a guanidine hydrochloride.

This method is an additional object of the invention.

Activated derivatives of the acid can be obtained in itself known manner directly from derivatives of benzoic acid of General formula (IV):

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where R1, R2, A and b have the above meaning.

A number of suitable methods for obtaining activated derivatives of carboxylic acids based on the derivatives of benzoic acid of General formula (IV) listed in bibliographic data in the work of J. March, Advanced Organic Chemistry, 3rd edition (John Wiley and Sons, 1985), page 350.

The interaction of activated carboxylic acid derivative salt of guanidine is in itself known in the proton or aprotic polar but inert organic solvent.

Of the derivative of benzoic acid of formula (IV) are known and described in the literature. Hitherto unknown compounds of the formula (IV) can be obtained well-known literature methods.

Thus, the appropriate benzoic acid get, for example, usaimage replaced by a nucleophilic group in position 4. For this purpose, 10 mm 4-chloro-3-methylsulfonylbenzoyl acid and 50 mm piperazine is heated 4 hours at 120oC in an atmosphere of inert gas. Crystallization from methanol allocate appropriately substituted benzoic acid.

Suspended 10 mm of the corresponding derivative of benzoic acid in 40 ml of anhydrous dimethylformamide and mixed with 10 mm N-methylmorpholine. To the resulting solution was added 13 mm carbonyldiimidazole and stirred for 2 h at room temperature. Suspended 14 mm of sodium hydride in 30 ml of anhydrous dimethylformamide in the atmosphere of inert gas and mixed with 14 mm guanidine hydrochloride. Stirred for 1 h at 80oFrom and after cooling is filtered off from the insoluble components. Transparent guanidine solution was added to the above solution and stirred for 12 h at room temperature. After distillation of dimethylformamide under reduced pressure the residue is purified by chromatography on silica gel with a suitable solvent system. Treatment with ethereal hydrochloric acid or other pharmacologically tolerated acids makes benzoylpyridine into the corresponding salt.

On the above data, the following connections:

/BR>So pl. 175-177oC (decomp.)

Example 4

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So pl.>250oC

Example 5

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So pl. 207-210oC(decomp.)

Example 6

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So pl. 170-173oC

Example 7

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So pl. 170oC (decomp.)

Example 8

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So pl. 243oC (decomp.)

A further object of the invention is a pharmaceutical composition having inhibitory activity against Na+/H+exchange, which contains a derivative benzoylpyridine the above formula (I) or its salt, which is the product of the merger acid, and the excipient and media.

Compounds according to the invention is active against arrhythmias that occur during hypoxia. In addition, they can be used for diseases that are associated with ischemia (examples: heart, brain, gastrointestinal, pulmonary, renal ischemia, liver ischemia, ischemia of skeletal muscles). Relevant diseases are, for example, coronary heart disease, angina, pulmonary embolism in the system of the pulmonary circulation, acute or chronic renal failure, chronic renal failure, heart attack, brain reperfusion lesions restored blood supply teaching the criminal brain. The aforementioned compounds may also be used in combination with thrombolytic agents such as tissue activator of plasminogen, streptokinase and urokinase.

During reperfusion of ischemic hearts (for example, angina or heart attack) in the affected area may appear irreversible damage to cardiomyocytes. In this case, the compounds according to the invention act as cardioprotector.

When used in the ischemic area should also be given to the prevention of damage to the grafts (such as protection of the graft before, during and after implantation, as well as during storage of grafts), which may occur in connection with the transplant. In addition, compounds are drugs with a protective action when conducting angioplasticheskih surgical interventions on the heart and peripheral vessels.

When essential hypertension and diabetic nephropathy increases Na+/H+-exchange in cells. Therefore, these compounds are suitable as inhibitors of this exchange for the prophylactic therapy of these diseases.

Further, the compounds according to the invention otlichit as medicines for diseases, in which cell proliferation plays a primary or secondary role, and can be used as tools against cancer, atherosclerosis, hypertrophy and hyperplasia of bodies, fibrotic diseases and late complications caused by diabetes.

Pharmacological data:

Inhibition of Na+/H+-metabolism in cancer cells of the human colon (HT-29):

Cells HT-29 incubated at 37oC, 5% carbon dioxide in the environment for growth. After 3-5 days the growth is removed, cells are washed and add to them 7.5 μm BCECF-AM (sensitive to pH fluorescent dye) at 37oIn the absence of carbon dioxide. After 30 min, the cells washed and acidified with the following mixture: 70 mm holdingarea, 20 mm ammonium chloride, 1 mm magnesium chloride, 1.8 mm calcium chloride, 5 mm glucose and 15 mm N-2 - hydroxyethylpiperazine-N'-2-econsultancy acid, pH 7.5.

After 6 min incubation at 37oIn the absence of carbon dioxide, the cells are washed and incubated for 5 min with the environment for growth: 120 mm holdingarea, 5 mm potassium chloride, 1 mm magnesium chloride, 1.8 mm calcium chloride, 5 mm glucose and 15 mm 4-morpholinepropanesulfonic, pH 7.0.

Environment for R the th sodium, 5 mm potassium chloride, 1 mm magnesium chloride, 1.8 mm calcium chloride, 5 mm glucose and 15 mm 4-morpholinepropanesulfonic, pH 7.0.

Cells incubated for 4 min at 37oIn the absence of carbon dioxide and measure fluorimetrically (cititor 2350). Fluorescence dye BCECF measured at excitation wavelengths of 485 nm (sensitive to pH) and 440 nm (insensitive to pH) and at the wavelength of 530 nm. Calculate the pH of the cytoplasm based on the ratio of fluorescence at 485 and 440 nm. The ratio of fluorescence to calibrate nigericin by measuring the fluorescence signal after balancing the external and internal pH.

Example - IR50/10-6mol l-1< / BR>
1 - 0.500

3 - 0.029

4 - 0.031

Biologically active substances according to the General formula (I) can be used in aqueous solution for injection (e.g. intravenous, intramuscular or subcutaneous administration), in the form of tablets, suppositories, ointments, plasters for transdermal application, in the form of an aerosol for inhalation through the lungs or in the form of a nasal spray.

The content of biologically active substances in one tablet or the candle is between 5 and 200 mg, preferably between 10 and 50 mg inhalation RA is between 0.1 and 50 mg, preferably between 0.5 and 20 mg if necessary, the dose can be assigned several times a day.

The following are examples of pharmaceutical products with biologically active substance is:

Tablets

The biologically active agent according to General formula (I) - 20.0 mg

Magnesium stearate 1.0 mg

Corn starch - 62,0 mg

Lactose - 83,0 mg

Polyvinylpyrrolidone - 1.6 mg

Solution for injections

The biologically active agent according to General formula (I) - 0.3 g

Sodium chloride 0.9 g

Water for injection to 100 ml

The solution can be sterilized using standard methods.

An aqueous solution for application through the nose or inhalation

The biologically active agent according to General formula (I) - 0.3 g

Sodium chloride 0.9 g

Benzalkonium chloride - 0.01 mg

Purified water Up to 100 ml

The above solution is suitable for use through the nose in the form of a spray or in combination with apparatus, which produces an aerosol with a particle size of preferably between 2 and 6 microns, for use through the lungs.

Capsules for inhalation

Substance of General formula (I) in micronized form (particle size, on the Ute hard gelatin capsules. For inhalation use common devices for powder inhalation. Each capsule contribute, for example, between 0.2 and 20 mg of biologically active substances of General formula (I) and from 0 to 40 mg of lactose.

Aerosol for inhalation

The biologically active agent according to General formula (I) - part 1

Soy lecithin 0.2 parts

The working gas mixture To 100 parts

The composition preferably fill the capacity of the aerosol valve dosing stroke which is so designed that a given dose of 0.5 mg For the other doses in the specified range, it is advisable to apply the composition with a higher or lower content of biologically active substances.

Ointment (g/100 g ointment)

The biologically active agent according to General formula (I) to 2 grams

Fuming hydrochloric acid to 0.011 g

A mixture of equal parts of cetyl and stearyl alcohols - a 20 g

White petrolatum 5 grams

Artificial Bergamote oil - 0.075 g

Distilled water Up to 100 MT

1. Derived benzoylpyridine General formula (I)

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where R1means alkyl with 1 to 8 carbon atoms;

And means group

< / BR>
In the mean group (-CH2-)aor (-CO-)bg the means unsubstituted or substituted alkyl with 1 to 8 carbon atoms, unsubstituted phenyl, NR3R4where R3and R4each denotes alkyl of 1 to 8 carbon atoms, or preferably of the five-membered heterocycle

< / BR>
in which U, V, W, X and Y denote CH, NH, O or S.

2. Derivatives benzoylpyridine General formula (I) under item 1, in which R1means alkyl with 1 to 4 carbon atoms, a represents a group

< / BR>
In the mean group (-CH2-)aor (-CO-)bwhere a represents an integer of 0 to 4, b is 0 or an integer of 1, R2means unsubstituted or substituted alkyl with 1 to 4 carbon atoms, unsubstituted phenyl, NR3R4where R3and R4each denotes alkyl with 1 to 4 carbon atoms, or the five-membered heterocycle

< / BR>
in which U, V, W, X and Y denote CH, NH, O or S.

3. Derivatives benzoylpyridine General formula (I) under item 1, in which R1means methyl, a represents a group

< / BR>
In means one group (-CH2-)andor (-CO-)bwhere a represents an integer of 0 to 4, b is 0 or an integer of 1, R2means of the five-membered heterocycle

< / BR>
in which U, V, W, X and Y denote CH, NH, O or S.

4. The method of obtaining derivatives benzoylpyridine General formula (I)

< / BR>
where R1andor (-CO-)bwhere a represents an integer of 0 to 8, preferably 1, 2, 3 or 4, b means of 0,1 or 2, preferably 1;

R2means unsubstituted or substituted alkyl with 1 to 8 carbon atoms, unsubstituted phenyl, NR3R4where R3and R4each denotes alkyl of 1 to 8 carbon atoms, or preferably of the five-membered heterocycle

< / BR>
in which U, V, W, X and Y denote CH, NH, O or S,

characterized in that a derivative of benzoic acid of General formula (II)

< / BR>
where R1has the above meaning;

R means leaving nucleofuge group

subjected to interaction with the compound of General formula (III)

R2Q, (III)

where R2, A and b have the above meaning;

Q means leaving, replaced by the electrophile, the group,

and formed of a derivative of benzoic acid of General formula (IV)

< / BR>
suspended in a suitable, mainly anhydrous, solvent, preferably dimethylformamide, mixed with N-methylmorpholine and carbonyl diimidazol and then mixed with a solution or suspension of a base, preferably sodium hydride, in a suitable anhydrous solvent, preferably dimethylformamide, with salt guiraudie activity against Na+/H+exchange, which contains connection at one PM. 1-3 or its salt, which is the product of the merger acid and excipient and media.

 

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