MXPA99000011A - Method for treating sinusitis with trifosphates deuridine and relative compounds - Google Patents

Abstract

The present invention relates to: relates to the method for treating sinusitis using phosphates of nucleosides selected from UTP, ATP, CTP or derivatives thereof, or using tetraphosphates of dinucleoside adenosine or uridi

Description

METHOD FOR TREATING SINUSITIS WITH URIDINE TRIFOSPHATES AND RELATED COMPOUNDS INTRODUCTION Technical Field This invention relates to a method for eliminating or preventing the accumulation of mucous secretions retained from the ducts. of a patient's breast by administering certain urine, adenosine or cytosine triphosphates.

BACKGROUND OF THE INVENTION Sinusitis is an inflammation of the paranasal sinuses usually associated with a respiratory infection in the upper tract. Sinusitis in this country is one of the most common problems in health care that affects approximately 31 million people. (A. Moss and V. Parsons, National Center for Health Statistics, 1986: 66-7, DHHS Publication No. (PHS) 86-1588 (1985)). Other less common causes allergies, air pollution, diving or swimming underwater, structural defects of the nose (deviated septum), and as a complication of dental work.

A common complication of sinusitis is an infection related to the middle ear (otitis media) due to the proximity of the sinuses and the eustachian tube. (M. Revonta and A. Blokmanis, Can, Fa, Physician 40, 1969-72, 1975-76 (1994)). In addition, most patients with primary ciliary dyskinesia experience episodes of chronic or recurrent sinusitis. As breast inflammation progresses, the mucus from the sinuses becomes trapped inside the sinus ducts. This blockage of mucus contributes to the headache, pain, fever and difficulty in breathing commonly reported in these disorders. The common symptoms are headache, abnormal sensitivity or discomfort on the forehead and the area of the breast of the face, nasal discharge, slight increase in temperature and general indisposition. Currently, treatment for sinusitis consists of antibiotics for infection, antihistamine / a-decongestants (usually sprays or nasal drops) or nasal saline sprays to relieve congestion, mucolytic agents, vapor inhalation, hot compresses applied on the breast area, analgesics and anti-inflammatory agent to relieve discomfort. (D. Kennedy Otolaryngol, Head Neck Surg 103, 845-46 (1990)). In addition, exposure to environmental irritants such as pollution, smoke and dust should be eliminated or reduced. If the sinusitis becomes a chronic problem, it should be considered a surgical and drained lengthening of the sinus ducts.

An additional population of patients at risk of developing sinusitis are patients who are intubated with a nasotracheal tube. (J. Reuler, West, J. Med 163 (1), 40-8 (1995).) The tube irritates the lining of the nasopharyngeal airways and due to the proximity to the breast and the large number of microorganisms present in the ducts. nasopharyngeal respiratory infections, severe sinusitis can result.In the present, treatment measures are still similar to those described above, including antibiotics, analgesics, hot compresses and surgical drainage, but also requires nasotracheal tube removal and re-intubation by tracheostomy, or, in Some cases through the oropharyngeal route The symptoms of this type of sinusitis are intense discomfort and abnormal sensitivity over the breast area, increased drainage of naso-sinus respiratory passages, fever, and potentially other infections and more severe complications. that 5'-uridinetriphosphate (UTP) and 5'-adenosine triphosphate (ATP) affect the ionic transport activity of cells epithelial of the human respiratory tract, as described in U.S. Patent No. 5,292,498. Specifically, UTP and ATP induce the secretion of water and chlorine in the lung epithelial cells of patients with cystic fibrosis, helping to liquefy and facilitate the transport of superficial mucus from the highly viscous airways that characterize this disease. has found that UTP and ATP stimulate the frequency of ciliary pulsation in the epithelial cells of the lung, also facilitating the transport of mucus from the lungs of patients with cystic fibrosis, patient with pneumonia or normal people.

(R. Boucher et al Adenosine and Adeniner Nucleotides: From Molecular Biology to Integrative Physiology, p.525-32 entitled "Mechanisms and Therapeutic Actions of Uridine Triphosphates in the Lung" (L. Berlardinelli, et al., Ed., Alumwer Academic Publishers, Boston 1995); (L. Ggheber, et al., J. Membrane Biol 147, 83-93) (1993)). A French biotechnology company, SYNTHELABO FRANCE, has developed a nasal mucosal fluid congestion treatment method under the trademark rhinATP ™ that uses adenosine triphosphate (ATP) as the active compound. This technology for rhinATP ™ was licensed under U.S. Patent No. 5,420,116 (the applicant proposes the description of these and the other references of patents and publications mentioned herein incorporated by reference). This method of treatment consists of the administration of ATP to the nasal cavity through nasal spray or nasal drops. Applicants have discovered that removal of mucus fluid retained in patients with sinusitis can be facilitated by administering UTP and its related compounds as well as other nucleoside phosphates such as P1, P4-di (uridine-5 ') tetraphosphate (U2P4); adenosine 5 'triphosphate (ATP); cytidine 5 'triphosphate (CTP); l, N6-ethenoadenosine 5 'triphosphate; adenosine-l-oxide-5 'triphosphate; 3, N4-ethenocytidine 5 'triphosphate; or P1, P ~ di (adenosin-5 ') tetraphosphate (U2P4) at the site of fluid blockade. UTP and U2P4 are the preferred embodiments of the present invention. By administering UTP or U2P4 immediately after the first symptoms appear, total breast block and the resulting symptoms can be avoided.

SUMMARY OF THE INVENTION A method of treating sinusitis is described in a person in need of this treatment. The method consists in administering to the patient a compound of the formula I, or a pharmaceutically acceptable salt thereof, in an amount effective to hydrate the mucous secretions and stimulate the frequency of the ciliary pulsation in the luminal epithelial cells of the sinus ducts: Formula I where: Xa, X2, and X3 each are 0 ~ or S ~. Preferably, X2, X3 are 0"Ri is O, imido, methylene or diha1methylene (for example, dichloromethylene, difluoromethylene) Preferably R is oxygen or difluoromethylene R2 is H or Br. Preferably, R2 is H. Particularly preferred compounds of formula I are uridine 5'-triphosphate (UTP) and uridine 5 '-O- (3-thiotriphosphate) [UTP? S]. In addition to formula I, formula II -P1,? 4- di (uridine-5 ') tetraphosphate [U2P4] is also a preferred embodiment of the invention Another compound of formula II is P1, P4-di (adenosin-5') tetraphosphate [A2P] .The method of the present invention also may include the administration of a compound of formula III (adenosine 5'-triphosphate [ATP) ol, N6-ethenoadenosine 5'-triphosphate or adenosine-1-oxide 5'-triphosphate), or of formula IV (cytidine 5 ') -triphosphate [CTP] or 3, N4-ethenocytidine 5 'triphosphate).

Formula II wherein: B is uracil or adenine, joined as shown in formula I and III.

Formula III where: Ri, Xi, X2 and X3 are defined as in formula I. R3 and R are H, while R2 is nothing and there is a double bond between Nl and C (adenine), or R3, R and 2 taken together they are -CH = CH-, forming a ring from N-6 to Nl with a double bond between N-6 and C-6 (l, N6-ethenoadenine).

Formula IV wherein: Ri, Xi, X2 and X3 are defined as in formula I. R5 and R6 are H, while R7 is nothing and there is a double bond between N-3 and C-4 (cytosine), or R5, Re and R7 taken together are -CH = CH-; forming a ring of 'N-3 to N-4 with a double bond between N-4 and C-4 (3, N4-ethenocytosine).

A second aspect of the present invention is a pharmaceutical formulation containing the compound of formula I, II, III or IV in an amount effective to hydrate mucous secretions and stimulate the frequency of ciliary pulsation in the luminal epithelial cells of the sinus ducts in a patient in need of this treatment. A third aspect of the present invention is the use of the active compounds described herein for the manufacture of a medicament for the therapeutic hydration of mucous secretions and the stimulation of the frequency of ciliary pulsation in luminal epithelial cells of the ducts of the breast in a patient in need of this treatment.

Description of the specific embodiments The method of the present invention can be used to hydrate retained mucus secretions and stimulate the frequency of ciliary pulsation in the breasts of an individual in need of this treatment. The present invention increases mucociliary clearance in three ways: (1) by increasing the frequency of ciliary pulsation of the cilia on the surface of the luminal epithelial cells, (2) by increasing the secretions of mucins by the calciform cells, and (3) increased water secretion in the liquid periciliar layer as a result of increased secretion of Cl ions by luminal epithelial cells. In addition, the data suggest that UTP increases the production and secretion of surfactant phospholipids by type II alveolar cells in vitro. (L. Gobran et al., Am. J. Physiol. 267, L625-L633 (1994)). The mucins secreted by the calciform cells form a layer on top of the cilia and capture the foreign particles, including viruses and bacteria; the mucin layer is transported by the cilia-like action; and the movement of the cilia is facilitated by the hydration of the layer of periciliar liquid that surrounds the cilia. The present invention is mainly related to the treatment of human individuals, but it can also be used for the treatment of other mammalian individuals, such as dogs and cats, for veterinary purposes. Illustrative compounds of the compounds of formula I above include: (a) uridine 5'-triphosphate (UTP); uridine 5 '-O- (3-thiotriphosphate) (UTPyS); and (c) 5-bromo-uridine 5'-triphosphate (5-BrUTP). These compounds are known or can be prepared according to known procedures or variations thereof which will be apparent to those skilled in the art. See, in general, N.Cusak and S. Hourani, Annals, N.Y. Acad. Sci. 603, 172-81) (entitled "Biological Actions of Extracellular ATP"). For example, UTP can be prepared in the manner described in Kenner et al. , J. Chem Soc. 1954, 2288; or Hall and Khorana, J. Am. Chem. Soc. 76, 5056- (1954). See Merck Index, Monograph No. 9795 (11th edition, 1989). UTP? S can be prepared in the manner described in R. S. Goody and F. Eckstein, J. Am. Chem. Soc, 93, 6252 (1971). For simplicity, the formulas I-IV herein illustrate the active compounds in the D configuration found in nature, but the present invention also comprises the compounds in the L configuration, and mixtures of the compounds in the D and L configurations , unless otherwise specified. The D configuration found in nature is preferred. Illustrative compounds of the compounds of formula II include P1, P4-di (adenosin-5") tetraphosphate (A2P4) or P1, P-di (uridin-5 ') tetraphosphate (U2P4). These compounds can be prepared according to known procedures or variations thereof which will be described by: P. Zamecnik et al., Proc. Nati Acad Sci. USA 89, 838-42 (1981); and K. Ng and L.E. Orgel, Nucleic Acids Res. 15 (8), 3572-80 (1987). U2, P4 can be prepared by means of methods similar to those described in C. Vallejo et al. Biochem. Biophys. Acta 438, 304-09 (1976). Illustrative compounds of the compounds of formula III above include: (a) adenosine 5'-triphosphate (ATP) and l, N6-ethenoadenosine 5'-triphosphate. Illustrative compounds of the compounds of formula IV above include: (a) cytidine 5'-triphosphate and (b) 3, N 4 -ethenocidithine 5'-triphosphate. These compounds can be prepared according to known procedures or variations thereof, which will be apparent to those skilled in the art. For example, phosphorylation of nucleosides by standard methods such as D. Hoard, and D. Ott, J '. Am. Chem. Soc. 87, 1785-1788 (1965); M. Yoshikawa, et al., Tetrahedron Lett. 5065-68 (1967) and idem, Bull. Chem. Soc. (Jpn) 42. 3505-08 (1969); J. Moffatt and H: Khorana, J. Am. Chem. Soc. 83, 649-59 (1961); and B. Fischer, et al., J. Med. Chem. 36, 3937-46 (1993) and references therein. The ethene derivatives of cytidine and adenosine are prepared by the methods known as: N. Kochetkov, et al., Tetrahedron Left. 1993 (1971); J. Barrio et al., Biochem. Biophys. Res. Commun. 46, 597 (1972); J. Secrist, et al., Biochemistry 11, 3499 (1972); J. Bierndt, et al., Nucleic Acids. Res. 5, 789 (1978); K. Koyasuga-Mikado, et al., Chem. Pharm. Bull. (Tokyo) 28, 932 (1980). Derivatives with alpha, beta and gamma thiophosphorus groups can be derived by or by adapting the following methods of: J. Ludwig and F. Eckstein, J. Org. Chem 54, 631-35 (1989); F. Eckstein and R. Goody, Biochemistry 15, 1685 (1976); R. Goody and F. Eckstein, J. Am. Chem. Soc. 93, 6252 (1971). The compounds of the formulas I III or IV where Rx is CC12 and CF2 can be prepared by methods similar to those described in G. Blackburn, et al., J. Chem. Soc. Perkin Trans I, 1119-25 ( 1984) . The compounds of the formula I, II, III, where Ri is CH2 can be prepared by methods similar to those described in T. Myers et al., J. Am. Chem. Soc. 85 3295-95 (1963) . In addition, UTP, ATP, CTP, A2P4, 3, N4-ethenocytidine triphosphate, l, N-ethenoadenine 5 '-triphosphate [sic], adenosine-1-oxide 5' -triphosphate, ATP? S, ATP? S, ATPctS, AMPPCH2P , AMPPNHP, N4-ethenocytidine and l, N6-ethenoadenosine are commercially available, for example, from Sigma Chemical Company, PO Box 14508. Sant. Louis, MO 63178. The active compounds of the formulas I-IV can be administered by themselves or in the form of their pharmaceutically acceptable salts, for example, an alkali metal salt such as sodium or potassium, salts of an alkaline earth metal or salts of ammonium and tetraalkylammonium, NX4 + (where X is C? -4). The pharmaceutically acceptable salts are salts which retain the desired biological activity of the parent compound and do not impart undesirable toxicological effects. The active compounds described herein may be administered to the lungs, breasts, ears or eyes by a variety of suitable means, but are preferably administered by administering a liquid / liquid suspension (a nasal spray of respirable particles inhaled by the individual). , or nasal drops of a liquid formulation, or ophthalmic drops of a liquid formulation) containing the active compound. Liquid pharmaceutical compositions of the active compound for producing a nasal spray or nasal powder, or nasal or ophthalmic drops can be prepared by combining the active compound with a suitable vehicle, such as water or sterile pyrogen-free saline by the techniques known to the art. experts in the art.

The dosage of the active compound to hydrate the mucous secretions and stimulate the frequency of ciliary pulsation in the breasts will vary depending on the condition of the individual, but in general, an effective amount is sufficient to achieve concentrations of the active compound in the sinus ducts. of the person from about 10 ~ 7 moles / liter (eg, for UTP 0.00001 mg / ml) to about 10"" 1 moles / liter (eg, for UTP 52 mg / ml), and most preferably from about 10 -6 moles / liter (for example, for UTP 0.001 mg / ml) to approximately 10_1 moles / liter (for example, for UTP, 50 mg /, L. [Sic]). Depending on the solubility of the particular formulation of the active compound that is administered, the daily dose for promoting fluid drainage can be divided into one to several administrations of the unit dose. Preferably, the daily dose schedule is no more than 4 times per day. Another means of administering the active compound in the patient's sinuses to promote drainage of fluid / secretion may include any oral form of the active compound, administered to the patient by means of a liquid suspension of the active compound which is poured into the patient's mouth, or by means of a pill form that can be swallowed by the agent.

Additional means for the administration of an effective amount of the active compound in the sinuses will include the administration of a nebulized form of the active compound in the respiratory tract, so that the active compound enters the nasopharyngeal tract and the lungs and reaches the sinuses directly or through systemic absorption and circulation. The active compound can be sprayed in different forms, such as, but not limited to, dry powder inhalants, metered inhalants or liquid / liquid suspensions. In the administration of the dry powder, the UTP can be formulated alone or in combination with the diluent or carrier, such as sugars (ie, lactose, sucrose, trehalose, mannitol) or other excipients acceptable for delivery to the lungs and ducts. respiratory The dry powder can be obtained by methods known in the art, such as spray drying, grinding, lyophilization, and the like. Another means of administering the active compound to the sinuses will include any topical form of the active compound, administered as a cream or gel in the nose, eyes or outer ear, which will subsequently permeate into the patient's sinus passages. Another means of administration of the active compound to the sinuses will include an injected form of the active compound, injected from the nose or sinus area of the face directly into the air passages of the sinus. The additional means of administration of the active compound to the sinuses includes a suppository form of the active compound, such that a therapeutically effective amount of the compound reaches the breast through systemic absorption and circulation. Another means of administering the active compound will include intra-operative instillation of a gel, cream, powder, foam, crystal or liquid suspension of the active compound such that a therapeutically effective amount reaches the sinuses. Preferred embodiments of the present invention - UTP and U2P4, as well as the other compounds for the formulas I-IV also have therapeutic benefit when used in combination with other agents used to treat sinusitis, such as, but not limited to: antibiotics; antiviral agents; antihistamine / decongestant agents; vapor inhalation; mucolytic agents; non-steroidal anti-inflammatory agents; steroids; and hot compresses applied on the area of the breast of the face. The in vivo test was performed to show the increase in the frequency of ciliary pulsation in rabbits to indicate the effectiveness of the compounds described in the present invention for the elimination or prevention of the accumulation of mucous secretions retained in the ducts of the breast. The test is a modification of the protocol described in "Ann Otol, Rhinol, Laryngol, Vol 105, pp. 140-145 (1996) Ganbo T., Hisamatsu, K., Kikushima, K., Nakajima, M. , Inoue H., Marukami, Y. Two white rabbits, adults, New Zealand, weighing 2-3 kg were anesthetized with intramuscular xylazine (5 mg / kg) and ketamine (40 mg / kg). The two maxillary sinuses on both sides of the head were surgically separated. Samples of the breast mucosa were immediately obtained from the breast tissue and placed in microscope slides with wells in RPMI 1640 solution. The slides were then placed on a microscope equipped with a photomultiplier tube. The result of the photomultiplier tube was directed through an analog-digital board to a microcomputer. The region of the tissue with the frequency of the fastest ciliary pulsation was identified and this field was placed centrally in the field of the microscope. The acquisition of the data was initiated during a period of 30 seconds (baseline) and repeated immediately after the application of the test compounds. The resulting digitized signals were conditioned and analyzed in the frequency domain using a Fast Fourier Transform program. This frequency associated with the largest power by the previous program will be defined as the best frequency and record. The product of formulation II (8.3 and 82.5 mg / ml) increased the frequency of the silane pulsation to 10.3 ± 1.3 beats / min. (Average + SD) and 18.0 ± 0.45 beats / min from a baseline value of 12.0 ± 1.1 beats / min. The present invention is explained in more detail in the following example. This example is proposed as illustrative of the invention, and should not be considered as limiting thereof.

EXPERIMENT Example 1 Treatment of acute sinusitis Uridine 5'-triphosphate (UTP) or P1, P4-di (uridin-5 ') tetraphosphate (U2P4) was administered to patients diagnosed with acute sinusitis. UTP was administered via nasal drops or nasal spray, 2-3 times a day, for a total of 3-5 days during an acute episode of sinusitis. The concentration of UTP is in the range of 10 ~ 7 to 10_1 moles / liter (for example, for UTP, 0.001 to 50 mg / ml). Treatment with UTP begins as soon as the presumptive diagnosis of sinusitis is made; not necessarily after the antibiotic therapy starts. The duration of treatment for each patient is one week (or as long as the symptoms persist). The effectiveness of UTP in the promotion of blocked sinus fluid drainage is measured by a decrease in symptomatic complaints as well as the results of physical examinations. The safety of UTP is assessed by standard safety measures of vital signs-cardiac pulsation, respiratory rate, blood pressure, electrocardiogram, and laboratory blood tests (eg, blood chemistry and complete blood count), as well as any adverse events observed or reported. The methods and compounds described herein provide a means for inducing drainage of mucous secretions from the sinus ducts in a patient afflicted with sinusitis. The method consists of administering to the individual's breasts a uridine triphosphate such as uridine 5'-triphosphate (UTP), U2P4 or any analogue of UTP, in an amount effective to hydrate mucous secretions or stimulate the frequency of ciliary pulsation in the breasts. The invention now fully described, will be evident to those who have the ordinary skills in the art that can make changes and modifications to it without departing from the spirit or scope of the appended claims.

Claims (16)

1. A method of treating sinusitis in an individual in need of this treatment, the method consists of: administering to the individual a compound of the formula I, II, III or IV, or a pharmaceutically acceptable salt thereof, in a pharmaceutical carrier that have an effective amount of this compound to promote the drainage of fluid from the breasts: Formula I. wherein: X-L, X2, and X3 are independently selected from the group consisting of OH and SH; Ri is selected from the group consisting of O, imido, methylene and dihalomethylene; and R2 is selected from the group consisting of H and Br; Formula II wherein: B is uracil or adenine, joined as shown in formulas I and III. Formula III wherein: Ri, Xi, X2 and X3 are defined as in formula I, R3 and R4 are H, while R2 is nothing and there is a double bond between Nl and C-6 (adenine), or R3 and R4 are H , whereas R is O and there is a double bond between Nl and C-6 (adenine 1-oxide), or R3A 4 and R2, taken together are -CH-CH-, forming a ring from N-6 to Nl with a double bond, between N-6 and C-6 (1, N6-ethenoadenine) Formula "IV wherein: Ri, Xi, X2 and X3 are defined as in formula I, R5 and R6 are H, while R7 is nothing and there is a double bond between N-3 and C-4 (cytosine), or R5, R6 and R7 taken together are -CH-CH-; forming a ring of N-3 to N-4 with a double bond between N-4 and C-4 (3, N4-ethenocytosine). The method according to claim 1, wherein the compound is delivered by administering a liquid / liquid suspension that includes eye drops of the compound to the eyes, or drops, powder or nasal spray of the compound to the individual's nasopharyngeal routes, so that a therapeutically effective amount of the compound makes contact with the individual's breasts directly or through systemic absorption and circulation. The method according to claim 1, wherein the compound is delivered by administering an oral form of the compound to the individual's breasts, such that a therapeutically effective amount of the compound makes contact with the individual's breasts through absorption systemic and circulation. The method according to claim 1, wherein the compound is delivered by administering a nebulized aerosol suspension or solution of the compound to the nasopharyngeal pathways of the individual, such that a therapeutically effective amount of the compound makes contact with the individual's breasts directly or by systemic absorption and circulation. The method according to claim 1, wherein the compound is administering a topical form of the compound to the sinuses through the nose, eyes, outer ear or nasopharyngeal routes of the individual, such that a therapeutically effective amount of the compound make contact with the individual's breasts directly or through systemic absorption and circulation. The method according to claim 1, wherein the compound is delivered by administering an injected form of the compound, such that a therapeutically effective amount of the compound makes contact with the individual's breasts through systemic absorption and circulation. The method according to claim 1, wherein the compound is delivered by administering a suppository form of the compound, such that a therapeutically effective amount of the compound makes contact with the individual's breasts through systemic absorption and circulation. The method according to claim 1, wherein the compound is delivered by administering an intra-operative instillation of a gel, cream, powder, foam, crystals or liquid suspension form of the active compound, such that a therapeutically effective amount of the compound makes contact with the breasts directly or through systemic absorption and circulation. The method according to claim 1, wherein the compound is administered in an amount sufficient to reach concentrations thereof on the surfaces of the individual's sinuses from about 10 ~ 7 to about 10_1 moles / liter. 10. The method according to claim 1, where X2 and 3 are OH. 11. The method according to claim 1, wherein Ri is oxygen. The method according to claim 1, wherein R2 is H. 13. The method according to claim 1, wherein the compound of the formula I is selected from the group consisting of uridine 5'-triphosphate, uridine 5'-0- (3-thiotriphosphate), 5-bromo-uridine 5'-triphosphate and the pharmaceutically acceptable salts thereof. The method according to claim 1, wherein the compound of the formula II is selected from the group consisting of P1, P-di (uridin-5 ') tetraphosphate (U2P4) and P1, P4-di (adenosine- 5 ') tetraphosphate (A2P) and the pharmaceutically acceptable salts thereof. 15. The method according to claim 1, wherein the compound of the formula III is selected from the group consisting of adenosine 5'-triphosphate, l, N6-ethenoadenosine 5'-triphosphate, adenosine 1-oxide 5'-triphosphate and the pharmaceutically acceptable salts thereof. 16. The method according to claim 1, wherein the compound of formula IV is selected from the group consisting of: cytidine 5'-triphosphate (CTP), 3, N4-ethenocytidine 5'-triphosphate and pharmaceutically acceptable salts thereof.