New field of compound application as antimictobial agents

FIELD: medicine.

SUBSTANCE: invention relates to application of NO-releasing non-steroid antiinflammation agent as wall as pharmaceutically acceptable salt or enantiomer thereof for production of drug useful in treating of disorders associates or mediated with Helicobacter pylory; pharmaceutical composition for treating of bacterial infections, including NO-releasing non-steroid antiinflammation agent as main ingredient; and similar composition including additionally inhibitor of acid-sensitive proton pump.

EFFECT: effective agents and pharmaceutical compositions for treating of bacterial infections.

19 cl, 4 ex

 

The scope of the invention

The present invention relates to a new nonsteroidal anti-inflammatory drugs, releasing nitric oxide (NO-releasing NSPs). More specifically, the invention relates to the use of NO-releasing NSPs to obtain medicines for treatment of bacterial infections, particularly caused or mediated by Helicobacter pylori, as well as combinations with inhibitors of the acid-susceptible proton pump for treatment of bacterial infections.

Background of the invention

NSPs are among the most commonly prescribed and used worldwide medicines. Despite therapeutic benefits NSPs, their use is limited. Application NSPs can lead to damage of the gastric mucosa caused by inhibition of production of prostaglandins, which increases the risk of gastrointestinal (gastrointestinal) side effects.

A modern approach to reduce side effects associated with NSPs, is the use of derivatives NSPs, releasing nitric oxide (NO-releasing NSPs) (del Soldato P, et al., NO-releasing NSAIDs, A novel class of safer and effective anti-inflammatory agents; Inflammopharmacology, 1996; 4; 181-188). NO-releasing NSPs reduce gastrointestinal side effects, but have a pharmacological action, Hara is characteristic for frequently used NSPs.

NO-releasing NSPs and their pharmaceutically acceptable salts, for example, described in WO 94/04484, WO 94/12463, WO 95/09831 and WO 95/30641.

Helicobacter pylori is a gram-negative spiral bacterium that forms colonies in the stomach mucosa. The relationship between gastrointestinal disorders and Helicobacter pylori infection, the presence of which in 1983 for the first time suggested Warren JR Lancet 1983; 1.1273), is currently the well-proven.

Proposed several different methods of treatment of Helicobacter pylori infections. Usually use a combination of treatments. The most commonly used include the use of proton pump inhibitor in combination with one or more antibacterial compounds, such as clarithromycin and amoxicillin. For example, WO 93/00327 describes the combination of substances with inhibitory effect on gastric secretion of acid, which raises the pH inside the stomach, and destructible acid antibacterial compounds. Some of these treatments include the use of bismuth compounds; see, for example, WO 98/03219 and WO 98/22117, the latter application describes a composition including bismuth, an antimicrobial agent and a non-steroidal anti-inflammatory agent for the treatment of gastrointestinal disorders caused or mediated by Helicobacter pylori.

In light of the fact that give the number of the population suffers from gastrointestinal disorders, caused or mediated bacterial infections such as Helicobacter pylori infection, and also in light of the fact that many bacterial strains are developing resistance to commonly used antibiotics, there is a continuing need for safe and effective drug with antibacterial effect, especially for the treatment of Helicobacter pylori infections.

Brief description of the invention

Now unexpectedly found that the NO-releasing NSPs possess an antibacterial effect, which makes them applicable for treatment of bacterial infections.

The present invention relates to the use of NO-releasing NSPs, as well as their pharmaceutically acceptable salts or enantiomers to obtain medicines for treatment of bacterial infections.

Preferably, the NO-releasing NSPs is determined by the formula I:

where M is selected from any one of

and X represents a spacer, that is, soy is inania, forming a bridge between group a donor of nitric oxide and a part corresponding to NSPs, or its pharmaceutically acceptable salt or enantiomer.

X is preferably selected from linear, branched or cyclic -(CH2)n-where n is an integer from 2 to 10; -(CH2)m-O-(CH2)p-, where m and p represent integers from 2 to 10; and -(CH2)-RS6H4-(CH2)-.

M is not limited to the above definition and can represent any other compound that forms NSPs by the hydrolysis of compounds of formula I.

In a preferred implementation of the invention M is chosen from

and X is chosen from linear -(CH2)n-where n is an integer from 2 to 6; -(CH2)2-O-(CH2)2- and-CH2-RS6H4-CH2-.

In an even more preferred variant of the invention, the NO-releasing NSPs represents the connection of any of the formulas:

and

In a particularly preferred implementation of the invention NSPs is a compound of formula Ia.

The next aspect of the invention is the use of NO-releasing NSPs, preferably, the compounds of the above formula I for the manufacture of a medicinal product for use in the treatment of Helicobacter pylori infections, especially in the treatment of gastrointestinal disorders caused or mediated by Helicobacter pylori.

As a further aspect of the invention is a method of treatment of bacterial infections, particularly infections of Helicobacter pylori, a person suffering from this bacterial infection is administered an effective quantity of a drug that contains NO-releasing NSPs, preferably, the compound of formula I as the active agent.

Also in the scope of the invention is suitable for use in the treatment of bacterial infections Pharma is efticiency composition, which includes the NO-releasing NSPs, preferably, the compound according to formula I.

In addition, the invention relates to the use of NO-releasing NSPs, preferably, compounds according to formula I, in combination with an inhibitor of an acid-susceptible proton pump, or its salt, or enantiomer, or a salt of the enantiomer in the production of pharmaceutical compositions intended for simultaneous, separate or sequential injection for the treatment of bacterial infections, especially infections of Helicobacter pylori.

The invention can be used in combination with other tools, mainly related to the treatment of bacterial infections, for example, with antibacterial agents.

The inhibitor is an acid-susceptible proton pump represents, for example, the compound of General formula II

where Het1represents a

Het2represents a

X=

where:

N in the benzimidazole group means that one of the carbon atoms with substituents R6-R9optional can be replaced by a nitrogen atom without any substituents;

R1, R2and R3are the same or different and is selected and is hydrogen, of alkyl, alkoxygroup, optionally substituted by fluorine, allylthiourea, alkoxyalkyl, dialkylamino group, piperidine group research, halogen, phenyl or fenilalanina;

R4, R5are the same or different and selected from hydrogen, alkyl or aralkyl;

R6' represents hydrogen, halogen, trifluoromethyl, alkyl or alkoxygroup;

R6-R9are the same or different and selected from hydrogen, alkyl, alkoxygroup, halogen, haloalkoxy, alkylcarboxylic, alkoxycarbonyl, oxazolyl, triptorelin, or adjacent groups R6-R9form a ring structure, which can also be substituted;

R10represents hydrogen or forms alkylenes circuit with R3and

R11and R12are the same or different and selected from hydrogen, halogen or alkyl, alkyl groups, alkoxygroup and their parts. The substituents may represent a circuit C1-C9or include cyclic alkyl groups, such as cycloalkenyl.

Examples of proton pump inhibitors of the formula II are

Omeprazole

Lansoprazole

Pantoprazole

Alprazol

Leminoprazole

Proton pump inhibitors in combination according to the formula of the invention may also be used in the form of a pharmaceutically acceptable salt or simple enantiomer.

Preferably in combination according to the formula of the invention use a proton pump inhibitor omeprazole or an alkaline salt of omeprazole, such as a magnesium salt, or (S)-omeprazole or an alkaline salt of (S)-omeprazole, such as a magnesium salt.

Suitable proton pump inhibitors are described, for example, in EP-A1-0005129, EP-A1-174726, EP-A1-166287, GB 2 163 747 or WO 90/06925, and, moreover, particularly suitable compounds are described in WO 95/01977 and WO 94/27988.

Further according to the invention described is a method of treatment of bacterial infections, especially infections of Helicobacter pylori, which comprises simultaneous, separate or sequential administration to a subject suffering from a bacterial infection, one or more pharmaceutical composition comprising NO-releasing NSPs, preferably, the compound according to formula I, and the inhibitor is an acid-susceptible proton pump. Also in the scope of the invention are used is for the treatment of bacterial infections pharmaceutical compositions for simultaneous, separate or sequential administration, which include the NO-releasing NSPs, preferably, the compound according to formula I, and the inhibitor is an acid-susceptible proton pump.

NO-releasing NSPs alone or in combination with an inhibitor of an acid-susceptible proton pump dosage form may be administered orally, rectally, epidurally, intravenously, intramuscularly, subcutaneously, infusion, nasal, or any other method suitable for injection. In the preferred case, the active compound(I) is administered orally.

The active compound(I) is administered from one to several times per day, preferably once or twice daily. A typical daily dose of the active compound(s) varies and will depend on various factors such as the individual requirements of the patient, the form of administration and the disease. In General, each dosage form includes from 0.5 to 5000 mg, preferably 5-1000 mg NO-releasing NSPs. When using the combination with a proton pump inhibitor 0.5 to 5000 mg of NO-releasing NSPs and 0.1-200 mg of proton pump inhibitor will be included in each dosage form or may be in different dosage forms. In the preferred case, the number of NO-releasing NSPs in each dosage form is 5-1000 mg, and the number of proton inhibitor n is Sosa is in the range 10-80 mg

Detailed description of the invention

The invention is described in more detail by the following non-limiting examples.

The following examples show that the NO-releasing NSPs have antibacterial activity against Helicobacter pylori and antibacterial activity depends on the concentration.

Example 1

The strain of Helicobacter pylori, a standard strain NCTC 11 637 (National Type Culture Collection, Smittskyddsinstitutet, Solna, Sweden), is sensitive to antibiotics, the standard strain.

Substance:

Helicobacter pylori was grown on plates with blood agar with 90 mm in diameter, within three days at microaerophilic conditions at 37°C. Bacteria resuspendable in PBS (phosphate saline buffer) to approximately 108CFU/ml to About 2 ml of the suspension was added to one Cup with agar and evenly distributed over the surface of the agar. The excess was collected by syringe. In the bowl of agar did holes 3 mm in diameter, like small holes, removing the agar. On each Cup was done by three wells. Made the mother solution of the substances of the formula Ia with a concentration of 100000 µg/ml 30 μl of solution was added to the wells. The cups were incubated for four days before their check for the presence around the hole zones of inhibition.

The result: around each hole there was so extensive zone of inhibition, which it was not possible to measure the diameter of the zone.

Example 2

The strain of Helicobacter pylori, a standard strain NCTC 11 637 (see example 1), is sensitive to antibiotics, the standard strain.

Substance:

A Cup with a hole prepared in example 1.

Made the mother solution of the substances of the formula Ia with a concentration of 10,000 ág/ml 30 μl of solution was added to the wells. The cups were incubated for four days before their check for the presence around the hole zones of inhibition.

The result: around each hole there was so extensive zone of inhibition that was not possible to measure the diameter of the zone.

Example 3

The strain of Helicobacter pylori, a standard strain NCTC 11 637, sensitive to antibiotics standard strain (see example 1).

Substance:

A Cup with a hole prepared in example 1. Made the mother solution of the substances of the formula Ia with a concentration of 1000 µg/ml 30 μl of solution was added to the wells. The cups were incubated for four days before their check for the presence around the hole zones of inhibition.

The result: the zone of inhibition around each well was 13 mm

Example 4

The strain of Helicobacter pylori, a standard strain NCTC 11 637, sensitive to antibiotics standard strain (see example 1).

Substance:

A Cup with a hole prepared is as in example 1.

Made the mother solution of the substances of the formula Ia with a concentration of 100 µg/ml 30 μl of solution was added to the wells. The cups were incubated for four days before their check for the presence around the hole zones of inhibition.

The result: the zone of inhibition around each well was 10.4 mm

Comparative tests

Example

The strain of Helicobacter pylori, a standard strain NCTC 11 637, sensitive to antibiotics standard strain (see example 1).

Ingredient: naproxen

A Cup with a hole prepared in example 1. Made the mother solution of naproxen concentration of 10,000 ág/ml 30 μl of solution was added to the wells. The cups were incubated for four days before their check for the presence around the hole zones of inhibition.

The result: the zone of inhibition around each well was 16.6 mm

The example In

The strain of Helicobacter pylori, a standard strain NCTC 11 637, sensitive to antibiotics standard strain (see example 1).

Ingredient: naproxen

A Cup with a hole prepared in example 1.

Made the mother solution of naproxen with a concentration of 1000 µg/ml 30 μl of solution was added to the wells. The cups were incubated for four days before their check for the presence around the hole zones of inhibition.

The result: around the holes are not formed zones of inhibition.

The example

The strain of Helicobacter plori, standard strain NCTC 11 637, sensitive to antibiotics standard strain (see example 1).

Ingredient: naproxen

A Cup with a hole prepared in example 1.

Made the mother solution of naproxen with a concentration of 100 µg/ml 30 μl of solution was added to the wells. The cups were incubated for four days before their check for the presence around the hole zones of inhibition.

The result: around the holes are not formed zones of inhibition.

Example D

The strain of Helicobacter pylori, a standard strain NCTC 11 637, sensitive to antibiotics standard strain (see example 1).

Substance: S-nitroso-N-acetylpenicillamine (SNAP)

A Cup with a hole prepared in example 1.

Made the mother liquor SNAP with a concentration of 10,000 ág/ml 30 μl of solution was added to the wells. The cups were incubated for four days before their check for the presence around the hole zones of inhibition.

The result: around the holes are not formed zones of inhibition.

Example F

The strain of Helicobacter pylori, a standard strain NCTC 11 637, sensitive to antibiotics standard strain (see example 1).

Substance: dimethyl sulfoxide (DMSO)

A Cup with a hole prepared in example 1. Made the mother liquor alone DMSO with a concentration of 20 ág/ml 30 μl of solution was added to the wells. The cups were incubated for four days before checking in PR is dmet presence around the hole zones of inhibition.

The result: around the holes are not formed zones of inhibition.

1. The use of NO-releasing NSPs (non-steroidal anti-inflammatory drugs), as well as its pharmaceutically acceptable salt or enantiomer to obtain drugs for the treatment of disorders caused or mediated by Helicobacter pylori.

2. The use of NO-releasing nonsteroidal anti-inflammatory drug or its combination with an inhibitor of an acid-susceptible proton pump in the form of a salt, or enantiomer, or a salt, enantiomer in obtaining pharmaceutical compositions intended for simultaneous, separate or sequential injection in the treatment of bacterial infections.

3. Application under item 1 or 2, where NO-releasing NSPs is a compound of formula I

where M is selected from any one of

and X is chosen from linear, branched or cyclic -(CH2)n-where n is an integer from 2 to 10; (CH2)m-O- (CH 2)p-, where m and p represent integers from 2 to 10; and-CH2-RS6H4-CH2or its pharmaceutically acceptable salt or enantiomer.

4. The use according to claim 3, where M in formula I is selected from

5. Application under item 3 or 4, where X in formula I is selected from linear -(CH2)n-where n is an integer from 2 to 6; -(CH2)2-O-(CH2)2- and-CH2-pC6H4-CH2-.

6. The use according to any one of paragraphs. 1-3, where NO-releasing NSPs is a compound of any of formulas Ia-Iq

and

7. The use according to claim 6, where NO-releasing NSPs is a compound of formula Ia

8. The use according to claim 2, where the inhibitor is an acid-susceptible proton pump is a compound of formula II

where Het1represents a

Het2represents a

X=

where

N in the benzimidazole group means that one of the carbon atoms with substituents R6-R9optional can be replaced by a nitrogen atom without any substituents;

R1, R2and R3are the same or different and selected from hydrogen, alkyl, alkoxygroup, optionally substituted by fluorine, allylthiourea, alkoxyalkyl, dialkylamino group, piperidine group research, halogen, phenyl or fenilalanina;

R4and R5are the same or different and selected from hydrogen, alkyl or aralkyl;

R6' represents hydrogen, halogen, trifluoromethyl, alkyl or alkoxygroup;

R6-R9are Odin is new or different and selected from hydrogen, of alkyl, alkoxygroup, halogen, haloalkoxy, alkylcarboxylic, alkoxycarbonyl, oxazolyl, triptorelin, or adjacent groups R6-R9form a ring structure, which can also be substituted;

R10represents hydrogen or forms alkylenes circuit with R3and

R11and R12are the same or different and selected from hydrogen, halogen or alkyl, alkyl groups, alkoxygroup and their parts and can be a branched or straight chain C1-C9or include cyclic alkyl groups, such as cycloalkyl-alkyl.

9. The use of claim 8, where the inhibitor is an acid-susceptible proton pump selected from omeprazole, its alkali metal salts, (S)-omeprazole and an alkaline salt.

10. The use of claim 8, where the inhibitor is an acid-susceptible proton pump is a lansoprazole or its pharmaceutically acceptable salt, or enantiomer, or a salt of the enantiomer.

11. The use of claim 8, where the inhibitor is an acid-susceptible proton pump is a pantoprazole, or its pharmaceutically acceptable salt, or enantiomer, or a salt of the enantiomer.

12. The use according to claim 2, where the NO-releasing NSPs is a compound of formula Ia, and the inhibitor is an acid-susceptible proton pump before the hat is omeprazole, its alkaline salt, (S)-omeprazole or an alkaline salt.

13. The use according to claim 1, where the number of NO-releasing NSPs in each dosage form is 0.5 to 5000 mg.

14. Use item 13, where the number of NO-releasing NSPs is 5-1000 mg

15. The use according to claim 2 and 12, where the number of NO-releasing NSPs is 0.5 to 5000 mg, and the amount of the proton pump inhibitor is 0.1 to 200 mg together in the same dosage form or in two separate unit dosage forms.

16. The use according to claim 2 and 12, where the number of NO-releasing NSPs is 5-1000 mg, and the amount of the proton pump inhibitor is 10-80 mg

17. Pharmaceutical composition, suitable for use in the treatment of bacterial infections comprising as an active agent NO-releasing NSPs, or its pharmaceutically acceptable salt or enantiomer.

18. Pharmaceutical composition, suitable for use in the treatment of bacterial infections comprising as an active agent NO-releasing NSPs and the inhibitor is an acid-susceptible proton pump, or salt, or enantiomer, or a salt of the enantiomer.

19. The pharmaceutical composition under item 17 or 18, where the NO-releasing NSPs is a compound of formula I

where M is selected from

and X is chosen from linear, branched or cyclic -(CH2)n-where n is an integer from 2 to 10; (CH2)m-O-(CH2)p-, where m and p represent integers from 2 to 10; and-CH2-pC6H4-CH2-; or its pharmaceutically acceptable salt or enantiomer.

Priority date 01.06.1999 established by paragraphs 1, 3 (in terms of characteristics that are dependent on claim 1), 4 (in terms of characteristics that are dependent on claim 3, through dependence on claim 1), 5 (in terms of characteristics that are dependent on claim 3, through dependence on claim 1), 5 (in terms of characteristics that are dependent on claim 4, through the dependence on the PP. 3 and 1), 7 (in terms of characteristics that are dependent on claim 6, through dependence on claim 1), 7 (in terms of characteristics that are dependent on claim 6, through dependence on PP. 3 and 1), 17.

Priority date 21.12.1999 established in paragraphs 2, 3 (in part characteristics, dependent from claim 2), 4 (in terms of characteristics that are dependent on claim 3, through dependence on p.2), 5 (in terms of characteristics that are dependent on claim 3, through dependence on p.2), 5 (in terms of characteristics that are dependent on claim 4, through the dependence on the PP. 3 and 2), 7 (in terms of characteristics that are dependent on the .6, through dependence on p.2), 7 (in terms of characteristics that are dependent on claim 6, through the dependence on the PP. 3 and 2), 8-12, 18, 19.

Priority date 25.05.2000 established by paragraphs 6, 13-16.



 

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