Method for treating gastroesophageal reflux disease cases

FIELD: medicine.

SUBSTANCE: method involves applying cannabinoid receptor agonists for treating for transitory relaxation of lower esophageal sphincter and states like gastroesophageal reflux disease, regurgitation, preventing reflux or insufficient mass increase caused by the relaxation.

EFFECT: enhanced effectiveness of treatment.

18 cl, 3 tbl

 

The scope of the invention

The present invention relates to the use of agonists of cannabinoid receptors to suppress transient relaxation of the lower esophageal sphincter. Another aspect of the present invention is directed to the use of agonists of cannabinoid receptors for the treatment of gastroesophageal reflux disease and for the treatment of regurgitation, such as regurgitation in infants, pulmonary disease, chronic laryngitis and asthma.

Prior art

The lower esophageal sphincter (LES) is subject to periodic relaxation. As a result, the liquid from the stomach enters the esophagus, because in such moments is temporarily absent a mechanical barrier, the situation referred to below as "reflux".

Gastroesophageal reflux disease (GERD) is the most common disease of the upper section of the gastrointestinal tract. Modern pharmacotherapy aimed at reducing the secretion of gastric acid or neutralization of acid in the esophagus. It is believed that the main mechanism causing reflux depends on hypotonic lower esophageal sphincter. However, for example Holloway & Dent (1990) Gastroenterol. Clin. N. Amer. 19, pp.517-535, showed that the largest number of cases of reflux occurs during transient relaxation of the lower PI is evodevo sphincter (TLESR), that is relaxation, not initiated by pateniemi. It was also shown that patients with GERD the secretion of gastric acid is usually normal.

GERD is caused by reflux of gastric contents into the esophagus, causing heartburn and other common symptoms. In many cases, in the distal esophagus develops inflammation (esophagitis). It has long been known that the suppression of the formation of stomach acid reduces the intensity of these symptoms and esophagitis. However, in some patients, symptoms persist despite adequate control of acid secretion. I believe that responsible for these symptoms is reflux other harmful factors. Most attention has been focused on the importance of bile acids, and the development of severe GERD is associated with the effect of bile acids to the esophagus.

Historically, the term cannabinoids refers to the main components of Cannabis sativa (marijuana), including approximately sixty molecules, but this term also includes endogenous cannabinoids and a wide range of chemical entities that interact with the two known cannabinoid receptors, SW and SW. Recently there was a supposition that there is an unknown subtype of cannabinoid receptors (Mol. Pharmacol. (2001), 60: pp.155-163, PNAS (1999), 96: pp.14136-14141). Cannabinoid receptors belong to the superfamily, with the strenuous G-protein, and SW receptor is expressed predominantly in the Central nervous system and to a lesser extent in peripheral tissues (Nature (1990), 346: pp.561-564), whereas SW receptor is located on the periphery and are mostly limited to cells and tissues associated with the immune functions (Nature (1993), 365: pp.61-65).

Currently, there are four major known chemical group of agonists of cannabinoid receptors:

1) eicosanoids and their analogues, which are cannabinoids animal.

Anandamide is one of the examples of this group:

2) classical cannabinoids and their analogs, which are cannabinoids vegetable origin, such as Δ9-TNS (Δ9-tetrahydrocannabinol):

3) non-classical cannabinoids, such as CF 55,940, Pfizer created:

4) aminoalkylindole cannabinoids, such as WIN 55,212-2, Sterling-Winthrop:

The only cannabinoids, received currently approved as a drug, belong to the family of classical cannabinoids. Δ9-TNS with the international generic name Dronabinol, registered in the United W is the ATA America under the brand name Marinol® for use against nausea caused by anticancer drugs and to combat weight loss in patients with AIDS (acquired immunodeficiency syndrome) by stimulating appetite. Nabilone is a synthetic derivative created by Eli Lilly (Cesamet®), registered in Canada, the UK and Ireland to suppress nausea and vomiting caused by cancer chemotherapy.

Pharmacological overview of CB1 ligands and SW receptors described Pertwee, R.G. in Curr. Med. Chem. (1999) 6: pp.635-664. For more comprehensive reviews see, for example, Barth F. Exp. Opin. Ther. Patents (1998) 8(3): pp.301-313; Pertwee, R.G. Exp. Opin. Invest. Drugs (2000) 9(7): pp.1553-1571; Goy, P.; Jagerovic, N. Exp. Opin. Ther. Patents (2000) 10(10): pp.1529-1538, and the references given there.

In WO 01/32169 Yissum Research Development is disclosed a pharmaceutical composition for treating or preventing, among other things, gastrointestinal disorders and autoimmune diseases through the introduction of specific compounds affecting SW receptor. Inflammatory bowel disease (IBD) is a disease in respect of which the tested compounds disclosed therein.

The present invention was the discovery of a new method of suppression of transient relaxation of the lower esophageal sphincter (TLESR), warning thus reflux. More specifically, the goal of this image is etenia was the discovery of a new and improved method of treating gastroesophageal reflux disease (GERD), as well as new and improved method for the treatment of regurgitation, such as regurgitation in infants, pulmonary disease, chronic laryngitis and asthma.

A brief description of the invention

Unexpectedly, it was found that agonists of cannabinoid receptors can be used to suppress transient relaxation of the lower esophageal sphincter (TLESR) and, thus, for treatment of gastroesophageal reflux disease (GERD).

Therefore, the present invention is directed to the use of cannabinoid receptor for the manufacture of drugs to suppress transient relaxation of the lower esophageal sphincter (TLESR).

Another aspect of the present invention is the use of cannabinoid receptor for the manufacture of drugs for the prevention of reflux.

Another aspect of the present invention is the use of cannabinoid receptor for the manufacture of drugs for the treatment of gastroesophageal reflux disease (GERD). Effective elimination of regurgitation is an important method of prevention and treatment of pulmonary disease caused by aspiration abandoned gastric contents. Thus, another aspect of the present invention is the use of cannabinoid receptor for manufacturing Lakers the VA for treatment or prevention of regurgitation.

Effective elimination of regurgitation in infants is an important method of prevention and treatment of pulmonary disease caused by aspiration abandoned gastric contents, and treatment of insufficient mass increase, the cause of which is, among other things, excessive loss swallow nutrients. Thus, another aspect of the present invention is the use of cannabinoid receptor for the manufacture of drugs for the treatment of regurgitation in infants.

Another aspect of the present invention is the use of cannabinoid receptor for the manufacture of drugs for the treatment of insufficient mass increase.

Another aspect of the present invention is the use of cannabinoid receptor for the manufacture of medicaments for treating or preventing lung disease. Pulmonary disease, which is treated may, among other things, to be caused by aspiration abandoned gastric contents.

Another aspect of the present invention is the use of cannabinoid receptor for the manufacture of drugs for the treatment or prevention of asthma, such as asthma, associated with reflux.

Another aspect of the present invention is the use of cannabinoid receptor DL is the manufacture of drugs for the treatment or prevention of chronic laryngitis.

Another aspect of the present invention is a method of suppressing transient relaxation of the lower esophageal sphincter (TLESR), wherein the subject in need of such suppression, enter a pharmaceutically and pharmacologically effective amount of the cannabinoid receptor.

Another aspect of the present invention is a method of preventing reflux, wherein the subject in need of such a warning, impose a pharmaceutically and pharmacologically effective amount of the cannabinoid receptor.

Another aspect of the present invention is a method of treating gastroesophageal reflux disease (GERD), wherein the subject in need of such treatment, administered pharmaceutically and pharmacologically effective amount of the cannabinoid receptor.

Another aspect of the present invention is a method of treating or preventing regurgitation, wherein the subject in need of such treatment, administered pharmaceutically and pharmacologically effective amount of the cannabinoid receptor.

Another aspect of the present invention is a method of treating or preventing regurgitation in infants, wherein the subject in need of such treatment, administered pharmaceutically and pharmacologically effective amount is honest cannabinoid receptors.

Another aspect of the present invention is a method of treatment, prevention or suppression of pulmonary disease, wherein the subject in need of such treatment, administered pharmaceutically and pharmacologically effective amount of the cannabinoid receptor. Pulmonary disease, which is treated may, among other things, to be caused by aspiration abandoned gastric contents.

Another aspect of the present invention is a method of treatment insufficient to regain weight, wherein the subject in need of such treatment, administered pharmaceutically and pharmacologically effective amount of the cannabinoid receptor.

Another aspect of the present invention is a method of treating or preventing asthma, such as asthma, associated with reflux.

Another aspect of the present invention is a method of treating or preventing chronic laryngitis.

Another aspect of the present invention is the use of cannabinoid receptor with selectivity to SW receptor, in any of the indications described above. Another aspect of the present invention is the use of cannabinoid receptor with selectivity to SW receptor, in any of the indications described above.

For the purposes of this invention, the term "agonist" should be understood as including both full agonists, and partial agonists, where "partial agonist" should be understood as a compound capable of partially, but not fully activate the cannabinoid receptors.

The expression "cannabinoid receptor" when used here, includes not only full agonists of cannabinoid receptors or partial agonists of cannabinoid receptors, but also includes indirect agonists of cannabinoid receptors. The phrase "indirect cannabinoid receptor" when used here imply inhibitors of the enzyme amidohydrolase fatty acids (FAAH), as well as inhibitors of the enzyme-carrier of anandamide (anandamide transporter, ANT). Inhibitors ANT or FAAH may be useful as indirect agonists of cannabinoid receptors by increasing the concentration of endocannabinoids on cannabinoid receptors and, thus, are useful for suppression of TLESR.

The expression "TLESR", transient relaxation of the lower esophageal sphincter, defined in this specification in accordance with Mittal, R.., Holtoway, R.H., Penagini, R., Blackshaw, L.A., Dent, J., 1995; Transient Lower esophageal sphincter relaxation. Gastroenterology 109, pp.601-610.

The expression "reflux" is defined as the liquid from the stomach capable to get into the esophagus, because in these times the mechanical barrier is temporarily absent.

The expression "GERD", gastroesophageal replaceability, determined in accordance with van Heerwarden, M.A., A.J.P.M. Smout, 2000; Diagnosis of reflux disease. Bailliere's Clin. Gastroenterol. 14, pp.759-774.

The expression "regurgitation" is defined as the ejection of undigested food and gastric juice.

The expression "pulmonary disease" is defined as any deviation from the normal function of the lung or any of its violation.

The expression "laryngitis" is defined as inflammation of the larynx, state, accompanied by dryness or soreness of throat, hoarseness, cough and difficulty swallowing. The expression "chronic" is defined as persisting for a long period of time.

Asthma is an inflammatory disorder of the Airways, characterized by periodic attacks of wheezing, shortness of breath, difficulty breathing and coughing. The expression "asthma associated with reflux" is defined in accordance with Richter; J.. 2000; Gastroesophageal Reflux Disease and Asthma: The Two Are Directly Related. Am. J. Med. 108 (4A), pp.153S-158S.

In one aspect of the present invention agonist(s) cannabinoid receptors used(e) in accordance with the present invention has(have) the exposure duration from about 4 to 24 hours. The term "duration" is defined as the period of time from the start of exposure until the exposure is not defined.

In the scope of the present invention, in particular, is the use of agonists ka is nabinoid receptors included in the four major chemical categories agonists of cannabinoid receptors. Thus, eicosanoids, and their counterparts of classical cannabinoids and their analogs, non-classical cannabinoids and their analogs and aminoalkylindole cannabinoids and their analogs are particularly useful in accordance with this invention.

Examples of specific compounds with agonistic, indirect or partial agonistic affinity to cannabinoid (CB) receptors, useful in accordance with this invention are the following compounds.

I) Eicosanoids agonists ST. receptors:

- anandamide (commercially available, for example, Tocris Cookson, Bristol, United Kingdom of great Britain and Northern Ireland), which is a compound of the formula

- (2-chloro-ethyl)-amide of eicosa-5,8,11,14-tetraenoic acid, also known as arachidonyl-2'-chloroethylamide (ACEA, commercially available, for example, Tocris Cookson, Bristol, United Kingdom of great Britain and Northern Ireland) and

- cyclopropylamino of eicosa-5,8,11,14-tetraenoic acid, also known as arachidonoylethanolamide (ASRA, commercially available, for example, Tocris Cookson, Bristol, United Kingdom of great Britain and Northern Ireland).

II) Classical agonists ST. receptors:

- Δ9-T is C (Δ 9-tetrahydrocannabinol, commercially available, e.g. from Sigma-Aldrich), compound of formula

having the chemical name 6,6,9-trimethyl-3-pentyl-6A,7,8,10A-tetrahydro-6N-benzo[C]chromen-1-ol, and the enantiomer (-)-Δ9-tetrahydrocannabinol [(-)-Δ9-THC)]

- (-)-(R,R)-6,6-dimethyl-(1,1-dimethylheptyl)-1-hydroxy-9-(hydroxymethyl)-6A,7,10,10A-tetrahydro-6N-dibenzo[b,d]Piran [11-hydroxy-Δ8-TNS-dimethylheptyl], also known as HU-210 (commercially available, for example, Tocris Cookson, Bristol, United Kingdom of great Britain and Northern Ireland).

III) non-Classical agonists ST. receptors:

- CF 55,940, a compound with the chemical name 5-(1,1-dimethyl-heptyl)-2-[5-hydroxy-2-(3-hydroxy-propyl)-cyclohexyl]-phenol (commercially available, for example, Tocris Cookson, Bristol, United Kingdom of great Britain and Northern Ireland) and the chemical structure

- 1-acetate(-)-(6S,6R,9R,10R)-5,6,6A,7,8,9,10A-octahydro-6-methyl-3-[(R)-1-methyl-4-phenylbutyl]-1,9-phenanthridinone, also known as L-nantradol (L-nantradol) (CP 50,556).

IV) Aminoalkylindole agonists ST. receptors:

- WIN 55,212-2(commercially available, for example, Tocris Cookson, Bristol, United Kingdom of great Britain and Northern Ireland), having a chemical structure

and the chemical name (2-methyl-3-morpholine-4-ylmethyl-3,4-dihydro-5-oxa-2A-Aza-acenaphthylen-1-yl)-naphthalene-1-yl-methanon, and

- L-768,242, having the chemical name (2,3-dichloro-phenyl)-[5-methoxy-2-methyl-3-(2-morpholine-4-yl-ethyl)-indol-1-yl]-methanon and chemical structure

In other aspects of the present invention is also useful agonists of cannabinoid receptors disclosed in WO 01/31169, WO 99/51560, EP 0860168, WO 97/00860, WO 01/32169, such as the connection of HU-308, WO 01/28497, such as connection AM 1703, WO 01/74763, WO 01/29007, WO 01/28557. Other agonists of cannabinoid receptors, which may be useful in accordance with the present invention, are compounds disclosed in WO 97/29079, such as arylamide formula

compounds as described in WO 98/41519, such as pyrazoles of the formula

the quinoline structure

compounds as described in WO 98/37061 and WO 00/10967, and more specifically arylsulfonate

Other compounds that may be useful in accordance with the present invention are agonists of cannabinoid receptors disclosed F.Barth in Exp. Opin. Ther. Patents (1998) 8(3): pp.301-313, and agonists of cannabinoid receptors disclosed .Goya & N.Jagerovic in Exp. Opin. Ther. Patents (2000) 10(10): pp.1529-1538. Mentioned the e above specific agonists of cannabinoid receptors, as well as agonists of cannabinoid receptors disclosed in any of the above published patent applications, are included in this description by reference. This list agonists of cannabinoid receptors in no way should be considered as an exhaustive list, limiting the scope of the invention.

Examples of indirect agonists of cannabinoid receptors, useful in accordance with the present invention, are compounds AM 374 (commercially available, for example, Calbiochem-Novabiochem Corporation) and AM 404 (commercially available from Tocris Cookson, Bristol, United Kingdom of great Britain and Northern Ireland),

The use of pharmaceutically acceptable salts agonists of cannabinoid receptors is also in the scope of the present invention. Such salts are, for example, salts formed with mineral acids such as hydrochloric acid, alkali metal salts, such as salts of sodium or potassium, or salts of alkaline earth metals such as calcium salt or magnesium.

The optical isomers of cannabinoid receptor agonists have also included in the scope of the present invention. Agonists of cannabinoid receptors, having the asymmetric carbon atom, are chiral compounds, and depending on the availability of asymm the electric atoms agonists of cannabinoid receptors may exist in the form of mixtures of isomers, in particular racemates, or in the form of pure isomers, such as single enantiomers.

Pharmaceutical

For clinical application of agonists of cannabinoid receptors in accordance with the present invention is suitably prepared in the form of pharmaceutical preparations for oral administration. Specialist in the manufacture of drugs also may include rectal, parenteral or any other path of administration. Thus, agonists of cannabinoid receptors are produced in the form of the drug with at least one pharmaceutically and pharmacologically acceptable carrier or adjuvant. The carrier may be in the form of solid, semi-solid or liquid diluent.

In the preparation of oral pharmaceutical preparations in accordance with the invention, the agonist(s) cannabinoid receptors that(e) should be prepared in the form of the drug, mixed with solid, powdered ingredients such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable ingredient, as well as with loosening agents and lubricating agents such as magnesium stearate, calcium stearate, sodium fumarate and polietilenglikolya waxes. This mixture is then processed into granules or pressed into tablets is EDI.

Soft gelatin capsules can be prepared using capsules containing a mixture of active compound or compounds according to the invention, vegetable oil, fat or other suitable filler for soft gelatin capsules. Hard gelatin capsules can contain the active compound in combination with solid powdered ingredients such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatine.

Unit dose for rectal injection can be prepared 1) in the form of suppositories which contain the active(s) substance(a), mixed(s) with a neutral fat base; 2) in the form of a gelatine rectal capsule which contains the active substance in a mixture with a vegetable oil, paraffin oil or other suitable filler for gelatin rectal capsules; (3) in the form of a ready-made micro; or 4) in the form of a dry preparation for micro, which should be dissolved in a suitable solvent just before the introduction.

Liquid preparations for oral administration can be prepared in the form of solutions, syrups or suspensions containing the active compound and the rest of the drug consisting of a sugar or sugar alcohols and a mixture of ethanol, water, glycerol, propylene glycol and poly is etilenglikola. If required, such liquid preparations may contain colouring agents, corrigentov, saccharin and carboxymethyl cellulose or other thickener. Liquid preparations for oral administration can also be prepared in the form of a dry powder that must be dissolved in a suitable solvent before use.

Solutions for parenteral administration can be prepared in the form of a solution of the compounds according to the invention in a pharmaceutically acceptable solvent. These solutions may also contain stabilizing ingredients and/or buffer ingredients, and they are trained in standard doses in the form of ampoules or vials. Solutions for parenteral administration can also be prepared in the form of a dry preparation, which should be dissolved in a suitable solvent immediately before use.

In one aspect of the present invention cannabinoid receptors can enter once or twice a day depending on the severity of the patient's condition. The usual daily dose of the cannabinoid receptor is in the range of 0.1 to 500 mg (including 0.1 and 500 mg, for example 0.1 to 100 mg, but it will depend on various factors such as route of administration, age and weight of the patient, and the severity of the patient's condition.

Biological assessment

The selection of compounds active against TLESR

Use adults with the AK dogs of both sexes, trained to stand in a band Pavlov (Pavlov sling). Perform esophagostomy mucosa and skin of dogs left to recover before performing any experiments.

Measurement of motor function

Briefly, after fasting for about 17 hours with free access to water multi-unit sleeve/sidetrack (Dentsleeve, Adelaide, South Australia) is injected through esophagostomy for measuring the pressure of the stomach, the lower esophageal sphincter (LES) and esophageal. The unit is sprayed with water, using malorastyazhimy gauge pump for perfusion (Dentsleeve, Adelaide, South Australia). In the direction of the mouth to measure swallowing push pneumatically spray tube and antimony electrode, controlling the pH at 3 cm above the LES. All signals amplify and transmit to a personal computer at 10 Hz.

When the initial measurement of motor function in the absence of fasting gastric/LES phases III, IV in the vein of the front paw injected with placebo (0.9% NaCl) or investigational compound (intravenous, 0.5 ml/kg). Ten minutes after intravenous injection in the stomach pour nutritious foods (10% peptone, 5% D-glucose, 5% Intralipid, pH 3.0) through the Central channel of the unit at 100 ml/min to a final volume of 30 ml/kg Immediately after food pump air at 40 ml/min the Time of the experiment from the beginning of the infusion of food is about the end of the discharge air is 45 minutes. This technique is established as a reliable means of initiation TLESR.

TLESR is defined as a decrease in the pressure of the lower esophageal sphincter (compared to intragastric pressure) at a rate of >1 mm Hg (133,3 PA)/s Relaxation should not precede faringealny signal ≤2 before it, in this case, the relaxation are classified as induced by swallowing. The pressure difference between the LES and stomach should be less than 2 mm Hg (266,6 PA) and the duration of complete relaxation more than 1 sec.

EXAMPLES

Example 1

Aminoalkylindoles cannabinoid WIN 55,212-2, purchased in Tocris Cookson (Bristol, United Kingdom of great Britain and Northern Ireland), was tested for adult dogs of the Labrador both sexes in accordance with the model tests described above.

The suppression of a number of TLESR was calculated in relation to the five previous control experiments with each dog, and were obtained the results presented in table 1 below.

Table 1
CONNECTIONDOSE [mg/kg]% SUPPRESSION ± SEM (N)
WIN 55,212-20,00320±18 (4)
WIN 55,212-20,0170±10 (4)
WIN 55,212-20,0382#x000B1; 1 (4)
N = number of dogs in the test; SEM = standard error

Example 2

Aminoalkylindoles cannabinoid L-768,242, synthesized at AstraZeneca R &D Molndal, Sweden, in accordance with the procedure described in Bioorg. & Med. Chem. Lett. (1996); Vol.6. No.19., pp.2263-2268, and tested as in example 1 above.

The suppression of a number of TLESR was calculated in relation to the five previous control experiments with each dog, and were obtained the results presented in table 2 below.

Table 2
CONNECTIONDOSE [Ámol/kg]% SUPPRESSION ± SEM (N)
L-768,2420,38±21 (4)
L-768,242144±6 (5)
L-768,242563±5 (4)
L-768,242776±12 (3)
N = number of dogs in the test; SEM = standard error

Example 3

The pyrazole SR141716A (antagonist CV) was synthesized at AstraZeneca R &D Molndal, Sweden, in accordance with the procedure described in J. Chem. Soc., Chem. Commun. (1995); No.15, pp.1549-1560, and tested as in example 1 above.

Stimulation of a number of TLESR was calculated in relation to the five previous control experiments with each of the dog, and were the results, presented in table 3 below.

Table 3
CONNECTIONDOSE [Ámol/kg]% STIMULATION ± SEM (N)
SR 141716 A0,2243±16(6)
N = number of dogs in the test; SEM = standard error

The results in example 3 above show a tonic effect of endocannabinoids mediating the suppression of TLESR, which in turn implies that indirect cannabinoid agonists (FAAH inhibitors and ANT) are useful for suppression of TLESR and, thus, for the treatment of GERD.

The results presented in examples 1-3 above show that agonists of cannabinoid receptors are useful for the suppression of TLESR and, thus, for the treatment of GERD.

1. The use of cannabinoid receptor, or its pharmaceutically acceptable salt or optical isomer for the manufacture of drugs to suppress transient relaxation of the lower esophageal sphincter (TLESR).

2. The use of cannabinoid receptor, or its pharmaceutically acceptable salt or optical isomer for the manufacture of drugs for the treatment of gastroesophageal reflux disease (GERD).

3. The use of cannabinoid R the receptors, or its pharmaceutically acceptable salt or optical isomer for the manufacture of drugs for the prevention of reflux.

4. The use of cannabinoid receptor, or its pharmaceutically acceptable salt or optical isomer for the manufacture of medicaments for treating or preventing regurgitation.

5. The use according to claim 4, where regurgitation, which is treated or warn, is a regurgitation in infants.

6. The use of cannabinoid receptor, or its pharmaceutically acceptable salt or optical isomer for the manufacture of drugs for the treatment of insufficient mass increase.

7. The use according to claim 6, where the lack of added weight is due to excess loss of swallow nutrients.

8. The use according to any one of claims 1 to 7, where the cannabinoid receptor is a cannabinoid receptor that is selective with respect to SV receptors.

9. The use according to any one of claims 1 to 7, where the cannabinoid receptor is a cannabinoid receptor that is selective with respect to SV receptors.

10. The use according to any one of claims 1 to 7, where the cannabinoid receptor is eicosanoid.

11. The use according to any one of claims 1 to 7, where the cannabinoid receptor depict the place a classic cannabinoid.

12. The use according to any one of claims 1 to 7, where the cannabinoid receptor is a non-classical cannabinoid.

13. The use according to any one of claims 1 to 7, where the cannabinoid receptor is aminoalkylindoles cannabinoid.

14. The use of claim 10, where the cannabinoid receptor selected from anandamide, arachidonyl-2'-chloroethylamide (ACEA) and arachidonoylethanolamide(ASRA).

15. The application of claim 11, where the cannabinoid receptor is a Δ9-tetrahydrocannabinol (Δ9-THC) or 11-hydroxy-Δ8-TNS-dimethylheptyl (HU-210).

16. The application indicated in paragraph 12, where the cannabinoid receptor is a CF 55,940:

or L-nantradol (SR 50, 556); 1-acetate (-)-(6S,6aR,9R,10aR)-5,6,6a,7,8,9,10a-octahydro-6-methyl-3-[(R)-1-methyl-4-phenylbutyl]-1,9-phenanthridinone.

17. Use item 13, where the cannabinoid receptor is a WIN 55,212-2:

or L-768,242

18. The use according to any one of claims 1 to 7, where the daily dose of the cannabinoid receptor is in the range of 0.1 to 500 mg



 

Same patents:

FIELD: pharmaceutical industry.

SUBSTANCE: rectal- and vaginal-administration suppositories contain 1,3-diethylbenzimidazolium triiodide as active principal, polyvinylpyrrolidone as solubilizer and stabilizer, and lipophilic base with specified proportions of components.

EFFECT: extended therapeutical activity and reduced occurrence of side effects.

4 cl, 2 ex

The invention relates to substituted derivatives of imidazolidine formula 1

where W denotes the R1-A-C(R13or

where the ring system may be substituted by 1, 2 or 3 identical or different substituents R13and where L denotes C(R13and ml and m2 independently of one another denote 0, 1, 2, 3 or 4, and the sum of m l + m2 is 3 or 4; Y represents a carbonyl group; A represents a direct bond or a bivalent residue of a phenylene, A denotes a divalent (C1-C6)-alkalinity balance, and (C1-C6)-alkilinity the residue is unsubstituted or substituted by one or more identical or different residues from the series (WITH1-C8)-alkyl and (C3-C10-cycloalkyl-(C1-C6)-alkyl, F denotes R10CO., HCO, or R8O-CH2; R is H or (C1-C8)-alkyl, (C3-C12-cycloalkyl-(C1-C8)-alkyl or, if necessary, substituted (C6-C14)-aryl, and all residues R are independently from each other may be the continuously or repeatedly substituted by fluorine, or the rest of the X-NH-C(=NH) -R20, X - N, R2- N or (C1-C8) -alkyl; R3- N, (C1-C10) -alkyl, which optionally can be substituted one or more times by fluorine, optionally substituted (C6-C14)-aryl, optionally substituted heteroaryl, (C6-C12-bicycloalkyl, R11NH, COOR21, CONHR4or CONHR15; R4- (C1-C10)-alkyl, which is unsubstituted or substituted once or many times, equal or different residues from the series hydroxycarbonyl, aminocarbonyl, mono - or di-((C1-C10)-alkyl)-aminocarbonyl, (C1-C8-alkoxycarbonyl, R5, R6-CO, R5denotes optionally substituted (C6-C14)-aryl, R6denotes the residue of a natural or unnatural amino acid, R8- N or (C1-C10)-alkyl, and R8independently from each other may be the same or different, R10hydroxy, (C1-C10)-alkoxy, (C1-C8-alkylsulphonyl hydroxy-(C1-C6)-alkoxy, (C1-C8)-alkoxycarbonyl-(C1-C6)-alkoxy, amino, mono - or di-((C1-C10)-alkyl)-amino, or R8R8N-CO-(C1-C means R12a-O-CO-or R12a-S(OH)2, R12ameans (C1-C10)-alkyl, optionally substituted (C6-C14)-aryl, optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C4)-alkyl, or R15, R13- N or (C1-C6)-alkyl, which may optionally be substituted one or more times by fluorine, R15means R16-(C1-C6)-alkyl, or R16; R16denotes a 6-membered to 24-membered bicyclic or tricyclic residue, R20denotes a direct bond or (C1-C6-alkylen; R21- N or (C1-C8)-alkyl, R30represents one of the residues R32(R)N-CO-N(R)-R31or R32(R)N-CS-N(R)-R31; R32-CO-N(R)-R31or R12AO-CO-N(R)-R31and R30cannot mean R32-CO-N(R)-R31,ifat the same time W denotes R1-A-C(R13), And denotes a direct bond and R1andR13- N, R31denotes the divalent residue of R33-R34-R35-R36and R36linked to the nitrogen atom in the ring of imidazolidine in formula 1, R32means (C1-C8)-alkyl, which, when neobloc substituted (C6-C14)-aryl, optionally substituted in the aryl (C6-C14)-aryl-(C1-C8)-alkyl or optionally substituted heteroaryl, R33denotes a direct bond, R34denotes a bivalent residue of a number (C1-C8-alkylene, optionally substituted (C6-C14)-Allen; R35denotes a direct bond or a bivalent residue (C1-C8)-alkylene; R36denotes a direct bond, e and h represent independently from each other 0 or 1; in all their stereoisomeric forms and their mixtures in all ratios, and their physiologically acceptable salts, process for the preparation of compounds I; pharmaceutical drug that has the ability to inhibit the adhesion and/or migration of leucocytes and/or VLA-4 receptor

The invention relates to 3-dibenzoylethylene-7-nitro-2-honokalani form (1) with analgesic activity

The invention relates to the use of derivatives tetrahydropyridine(or 4-hydroxypiperidine)butylation General formula (I) and their physiologically acceptable salts, when receiving therapeutic agents useful in therapy and veterinary medicine for the treatment of acute pain, neuropathic pain and nociceptive pain, alone or in combination with other analgesics, and in this case there is a synergy

The invention relates to medicine and can be used to treat a variety of rhinitis: allergic, polynosic, year-round
The invention relates to medicine, specifically to medicines, analgesic action

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of piperidine of the general formula (I): or their nontoxic salts wherein R1 represents hydrogen atom, cyano-group; each R2 and R3 represents (C1-C8)-alkyl, (C3-C7)-cycloalkyl and others; each R4 and R5 represents hydrogen atom, (C1-C8)-alkyl and others; R6 represents hydroxyl group, (C1-C8)-alkoxy-group and others; m represents 0 or a whole number 1-4. Compounds of the formula (I) possess inhibitory activity with respect to PDE4 and can be used in medicine in treatment of inflammatory, diabetic, allergic and other diseases.

EFFECT: valuable medicinal properties of compounds.

10 cl, 11 tbl, 111 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivative of triazaspiro[5.5]undecane of the formula (I): wherein R1 means compound of the formula (1): or (2): wherein G represents a bond, (C1-C4)-alkylene, (C2-C4)-alkenylene or -CO-; ring A represents: (1) C5-10-membered mono- or bicarbocyclic ring or (2) 5-10-membered mono- or bicyclic heterocycle comprising 1-2 nitrogen atoms and/or 1-2 oxygen atoms; substitute R6 means the following values: (1) (C1-C4)-alkyl, (2) halogen atom, (3) nitrile group, (4) trifluoromethyl group and others; R2 represents: (1) (C1-C4)-alkyl, (2) (C2-C4)alkynyl or (3) (C1-C4)-alkyl substituted with a substitute represented in claim 1 of the invention claim; each R3 and R4 represents independently: (1) hydrogen atom, (2) (C1-C4)-alkyl or (3) (C1-C4)-alkyl substituted with 1-2 substituted taken among: (a) Cyc 2 and (b) hydroxy-group (wherein Cyc 2 represents (1) C5-6-membered monocarbocyclic ring or (2) 5-6-membered monocyclic heterocycle comprising 1-2 nitrogen atoms and/or one oxygen atom), or R3 and R4 form in common group of the formula: wherein R26 represents (C1-C4)-alkyl or Cyc 2; R5 represents hydrogen atom or (C1-C4)-alkyl, its quaternary ammonium salt, its N-oxide or its nontoxic salt. Also, invention relates to pharmaceutical composition inhibiting HIV, regulator of chemokine/chemokine receptor and agent used in treatment and prophylaxis of some diseases, such as inflammatory diseases, asthma, atopic dermatitis, nettle rash, allergic diseases, nephritis, hepatitis, arthritis and other diseases that comprise as an active component above described compound of the formula (I) or its quaternary ammonium salt, its N-oxide or its nontoxic salt. Also, invention relates to (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-carboxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane or its pharmaceutically acceptable salt and pharmaceutical composition based on thereof, and to (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-carboxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane hydrochloride and pharmaceutical composition based on thereof.

EFFECT: valuable medicinal properties of derivative and composition.

16 cl, 32 ex

FIELD: organic chemistry, medicine, chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition comprising S-isomer of compound of the formula (I) or its pharmaceutically acceptable salts and solvates in common with a pharmaceutically acceptable vehicle. Also, invention relates to a method for synthesis of compound S-isomer of the formula (I), and to a method for treatment of disease relating to the group comprising respiratory diseases, allergic diseases, dermatological diseases, gastroenteric diseases and ophthalmic diseases. The composition provides avoiding adverse sedative effects in treatment of indicated diseases.

EFFECT: valuable medicinal properties of compounds.

14 cl, 6 ex

FIELD: medicine, pulmonology.

SUBSTANCE: the present innovation deals with carrying out aeroionotherapy. Moreover, beforehand one should fulfill inhalations with atrovent at the dosage of 0.25 mg once daily through nebulizer , the size of sprayed particles ranged 3-5 mcm, power of aeroionotherapy corresponds to 90 bln ions for 20 min. The innovation enables to increase peak flowmetry value up to 95% and the values of bronchial permeability by 25.3%.

EFFECT: higher efficiency of therapy.

2 ex, 1 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of triazaspiro[5,5]undecane of the formula (I):

wherein values of radicals R1-R5 are given in the invention claim, ort o their quaternary ammonium salts, N-oxides or nontoxic salts. Proposed compounds possess inhibitory and regulating activity with respect to chemokine/chemokine receptors and can be useful in prophylaxis and treatment of different inflammatory diseases, such as asthma, atopic dermatitis, nettle rash, allergic diseases, nephritis, hepatitis, arthritis or proliferative arthritis and other similar diseases. Also, invention relates to pharmaceutical compositions based on compounds of the formula (I).

EFFECT: improved control method, valuable medicinal properties of compounds.

9 cl, 5 sch, 36 tbl, 70 ex

FIELD: organic chemistry, medicine, pharmacology.

SUBSTANCE: invention relates to compounds of the formula (I):

and their pharmaceutically acceptable salts wherein R1 means hydrogen (H), chlorine or bromine atom; R2 means electron-acceptor groups -CF3, -CN, fluorine atom, -COSO3H, -CF3SO3 and -NO2; R3 means linear or branched alkyl comprising from 2 to 10 carbon atoms, linear or branched alkoxyalkyl, aliphatic alcohol comprising from 1 to 10 carbon atoms or cycloalkyl comprising from 3 to 6 carbon atoms. Also, invention relates to methods for preparing indicated compounds and to a pharmaceutical composition comprising thereof. Compounds of the present invention are agonists of β2-receptor and can be used in treatment of asthma and bronchitis.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

9 cl, 1 tbl, 48 ex

FIELD: medicine.

SUBSTANCE: method involves applying dietary treatment, balneotherapy with carbonic acid low mineral content hydrocarbonate-magnesium-sodium-calcium-chalybeate water being administered at a dose of 200 ml 3 times a day 30 min before taking meals and biologically active nutrient additive like Capilar in eating at a dose of 0.25 g 3 times a day during 21 days.

EFFECT: enhanced effectiveness in adjusting acid-base state, immune disorders, magnesium-calcium and calcium-phosphorus metabolism.

2 cl, 2 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivative of aroylpiperazine of the formula (I):

wherein Y means lower alkylene; R1 means phenyl with 1 or 2 substitutes taken among group consisting of trihalogen-(lower)-alkyl, halogen atom, lower alkylamino-, di-(lower)-alkylamino- and nitro-group; R2 means phenyl or indolyl and each comprises 1 or 2 substitutes taken among group consisting of lower alkyl, trihalogen-(lower)-alkyl, lower alkylene dioxy-, hydroxy-group, hydroxy-(lower)-alkyl, lower alkoxy- lower alkylamino- and di-(lower)-alkylamino-group; R3 means hydrogen atom; R4 means morpholinyl-(lower)-alkyl comprising 1 or 2 substitutes taken among group consisting of ethyl, hydroxy-(lower)-alkyl, halogen-(lower)-alkyl and lower alkoxy-(lower)-alkyl, or morpholinyl-(lower)-alkynyl that can comprise 1 or 2 substitutes taken among group consisting of ethyl, propyl, isopropyl, isobutyl, spirocyclo-(lower)-alkyl, lower alkoxy-(lower)-alkyl, hydroxy-(lower)-alkyl, carboxy-(lower)-alkyl, di-(lower)-alkyl-carbamoyl, lower alkoxycarbonyl and halogen-(lower)-alkyl. Also, invention relates to a method for preparing, pharmaceutical composition based on these compounds and a method for treatment of tachykinine-mediated diseases, such as respiratory diseases, ophthalmic, cutaneous, inflammatory diseases, and as analgetic agents. Describes compounds are antagonists of tachykinine.

EFFECT: improved preparing method, valuable medicinal properties of compounds and pharmaceutical composition.

8 cl, 94 ex

FIELD: medicine, gynecology, anesthesiology.

SUBSTANCE: invention concerns to a method for carrying out the anesthesiology assistance for woman in childbirth with accompanying bronchial asthma. Method involves administration of atropine, dimedrol, analgin and clophelin. Method involves additional intravenous administration of transamine for 5-7 min. Transamine is administrated in doses 12-14 and 15-17 mg/kg in woman in childbirth with body mass 75 kg and above and 74 kg and less, respectively. Method provides enhancing quality and safety of anesthesia in this class of woman in childbirth.

EFFECT: improved assistance method.

7 tbl, 4 ex

FIELD: restorative medicine, pediatrics.

SUBSTANCE: the method deals with inhalations conducted with Hanks' solution at dispersity of particles being 0.8-2 mcm, expenditure of preparation being 1 ml/3.5 min Inhalation time corresponds to 8-10 min, daily. One should perform about 10-12 procedures per a course at the background of complex therapy including the adequate mode of motor activity, curative physical culture, carbonic acid baths. The method enables to improve sputum withdrawal and, correspondingly, bronchial permeability and the values for the function of external respiration.

EFFECT: more prolonged remission.

1 ex, 2 tbl

FIELD: medicine.

SUBSTANCE: method involves endoscopically introducing Derinate into submucous layer at a dose of 3-5 ml in at least 2 points on the background of anti-ulcer therapy. The total treatment course is 2-3 sessions long with 3-4 days long pauses. Delayed Derinate absorption conditions from ulceration defect zone are to be created.

EFFECT: enhanced effectiveness of treatment; accelerated Helicobacter pylori eradication.

FIELD: medicine.

SUBSTANCE: method involves endoscopically introducing 2 ml of Derinate into periulcerous zone 2 mm far from ulcer boundary. An additional dose of 2 ml is introduced into planned stomach stump anastomosis zone into submucous layer of anterior and posterior walls along the greater stomach curvature. The total treatment course is 2-3 sessions long with 3 days long pause.

EFFECT: improved cellular immunity, blood and lymph microcirculation conditions; prevented anastomosis and duodenal stump inconsistency complications.

FIELD: medicine, gastroenterology, pharmacy.

SUBSTANCE: invention describes solid pharmaceutical compositions used in treatment of gastroenteric disorders. The composition comprises omeprazole as a proton pump inhibitor wherein at least part of drug is not covered by an enterosoluble envelope and sodium hydrocarbonate as a buffering agent. The composition is made as a chewing tablet. By the second variant the composition comprises omeprazole that is partially is not covered by an enterosoluble envelope, sodium hydrocarbonate as a buffering agent and at least one disintegrating agent and/or lubricant. In oral administration in a patient of indicated pharmaceutical compositions the effective amount of omeprazole in absorbed directly by patient stomach for immediate and effective treatment of disorders associated with gastric acid. New medicinal formulations of omeprazole are suitable for preparing and provide its rapid absorption and availability of the omeprazole preparation for a definite group of patients that are unable to swallow solid medicinal formulations.

EFFECT: improved and valuable medicinal and pharmaceutical properties of formulations.

19 cl, 4 dwg, 5 tbl, 13 ex

FIELD: medicine, gastroenterology.

SUBSTANCE: method for treatment of Helicobacter-associated stomach and duodenum intestine ulcerous disease involves using propolis in composition with starch, aromatic supplements, bilberry fruits for 15-24 days. Method promotes to enhancing effectiveness of treatment in decreasing adverse effects. Invention can be used in treatment of patients with Helicobacter-associated stomach and duodenum intestine ulcerous disease.

EFFECT: improved and enhanced effectiveness of treatment.

3 ex

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