MXPA01003648A - Composition and method for treating allergic diseases - Google Patents

Abstract

The present invention is directed towards a pharmaceutical composition useful for the treatment of allergic rhinitis, asthma and related disorders. In one embodiment, the composition comprises, in combination, a therapeutically effective amount of at least one neurokinin antagonist, and a therapeutically effective amount of at least one 5-lipoxygenase inhibitor.

Description

COMPOSITION AND METHOD FOR TREATING ALLERGIC DISEASES FIELD OF THE INVENTION The present invention relates generally to compositions and methods for treating allergic rhinitis and other respiratory diseases. Specifically, compositions comprising (i) combinations of neurokinin receptor antagonists and leukotriene receptor antagonists, and (ii) combinations of neurokinin receptor antagonists and 5-lipoxygenase inhibitors, as well as methods are described. to treat the aforementioned diseases with using these compositions.

BACKGROUND OF THE INVENTION Neurokinin receptors ("NK") such as, for example, NK receptors. and NK2 are found in the central nervous system, the circulatory system and the peripheral tissues of mammals, and are included in a variety of biological processes. Therefore, neurokinin receptor antagonists are expected to be useful for the treatment or prevention of various mammalian diseases such as, for example, lung disorders such as asthma, cough, bronchospasm, chronic obstructive pulmonary diseases, and hyperactivity. of the airways; skin disorders and itching, for example, atopic dermatitis and hives and skin inflammation; neurogenic inflammatory diseases such as arthritis, migraine, nociception; diseases of the central nervous system such as anxiety, emesis, Parkinson's disease, movement disorders and psychosis; seizure disorders, kidney disorders, urinary incontinence, eye inflammation, inflammatory pain, and eating disorders such as, for example, inhibition of food intake; allergic rhinitis, neurodegenerative disorders, psoriasis, Huntington's disease, depression and several disorders such as Crohn's disease. It has been reported that NK-i receptors are involved in microvascular loss and mucus secretion, and NK2 receptors have been associated with smooth muscle contraction, transforming NK receptor antagonists. and NK2 especially useful but the treatment and prevention of asthma. Antagonists of the NKi and NK2 receptor have been reported in, for example, U.S. Patents 5,798,359; 5,795,894; 5,789,422; 5,783,579; 5,719,156; 5,696,267; 5,691, 362; 5,688,960; 5,654,316 (all assigned to Schering-Plow Corporation, Madison, New Jersey) and in "Recent Advances in Neurokinin Receptor Antagonists" of C: J: Ohnmatcht Jr., et al Annual reports in Medicinal Chemistry, AM Doherty Ed. 33, 71- 80 (1998). The products of the 5-lipoxygenase pathway ("5-LO") of the metabolism of arachidonic acid, particularly leukotrienes, can mediate bronchoconstruction, mucous secretion, airway mucosal edema, chemotaxis, and cell mobilization within the pathway. In the same way, leukotriene ("LK") antagonists play a role in the treatment of multiple diseases in the inflammatory process of asthma, therefore, the inhibition of 5-LO should help to cure, reduce or prevent these diseases. symptoms associated with respiratory tract diseases, such as seasonal allergic rhinitis, permanent allergic rhinitis, common colds, sinusitis, and concomitant symptoms associated with allergic asthma.The symptoms of these diseases may include sneezing, catarrh, and itching. nose, nasal congestion, redness of the eyes, tearing, itching of the ears or palate, and cough associated with a post-nasal drip. A description of leukotriene receptors in R. Robertson, Prostaglandins, 31, 395 (1986), and a description of leukotriene antagonists can be found in J. Musser et al, Agents and Actions, 18, 332 (1986) , J. Piwinski et al, Annual Reports in Medicinal Chemistry, 22, 73-76 (1987) and R. Bell et al, Annual Reports in Medicinal Chemistry, 32, 91 (1997). It would be very convenient to increase the efficacy of the neurokinin antagonists to improve their overall efficacy, as well as to reduce or prevent the diseases listed above by interfering with the activity of 5-LO and leukotriene receptors.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to the aforementioned objective and other objects and desires which, in one embodiment, provides a composition for treating and preventing allergic rhinitis and other respiratory diseases such as, for example, asthma, cough, wheezing and the like. The composition of the invention comprises, in combination, a therapeutically effective amount of at least one neurokinin antagonist and a therapeutically effective amount of at least one leukotriene antagonist. One or more antagonists can be substituted by a pharmaceutically acceptable derivative such as, for example, a salt, ester and the like. Optionally, the composition may additionally contain a pharmaceutically acceptable carrier, a decongestant (e.g., pseudoephedrine), a cough suppressant (e.g., dextromethorphan), an expectorant (e.g., guaifenesin), analgesics (e.g. , aspirin, ibuprofen and acetaminophen) or their mixtures. Generally, the amount of the neurokinin antagonist content in the composition of the invention per unit dose is about 1-1,000 milligrams, and that of the leukotriene antagonist is about 2-500 milligrams. Preferably, the respective amounts are about 10-500 milligrams and about 5-500 milligrams, and typically the respective amounts are about 50-200 milligrams and 10-50 milligrams. t «tafe, :: * __ss_ £ ___ l___e", _.

The present invention additionally provides a composition for treating and preventing allergic rhinitis and other respiratory diseases, such as, for example, asthma, cough, wheezing and the like, and the composition comprises, in combination, a therapeutically effective amount of at least one neurokinin antagonist. and a therapeutically effective amount of at least one 5-LO inhibitor. One or more of the compounds can be replaced by means of a pharmaceutically acceptable derivative such as, for example, a salt, ester and the like. Additionally, the composition may contain a pharmaceutically acceptable carrier, a decongestant, a cough suppressant, and an expectorant, or mixtures thereof. The invention also provides a method for treating asthma, chronic obstructive pulmonary diseases ("COPD"), and allergic disorders, sneezing, runny nose and nose itching, nasal congestion, redness of the eyes, tearing, itching of the ears and palate, sinusitis , and cough associated with post-nasal drip symptoms in a mammalian organism in need of this treatment comprising the administration of a pharmaceutical composition as described above.

DETAILED DESCRIPTION OF THE INVENTION In one embodiment, the present invention describes pharmaceutical compositions that are useful for the treatment and prevention of allergic rhinitis, asthma and related disorders. The composition comprises, in combination, a therapeutically effective amount of at least one neurokinin antagonist, a therapeutically effective amount of at least one leukotriene antagonist. One or more of the antagonists can be substituted by a pharmaceutically acceptable derivative such as, for example, a salt, ester and the like. Several neurokinin antagonists useful in the practice of the present invention are known. Non-limiting examples of these useful neurokinin antagonists include, for example, those belonging to the chemical class of oximes, hydrazones, piperidines, piperazines, arylalkylamines, hydrazones, nitroalkanes, amides, isoxazolines, quinolines, isoquinolines, azanorbornanes, naphthyridines. , benzodiazepines, and the like. Many of them are described in the US patents cited above in this patent application. Preferred NK antagonists are those described in the U.S. Patents listed above 5,798,359; 5,795,894; 5,789,422; 5,783,579; 5,719,156; 5,696,267; 5,691, 362; 5,688,960; 5,654,316. The general formula of some compounds described is as follows: where Z is where B is OR2; NR6COR2; CONR6R or NR2CONR6R7 m = 0 or 1, P is R5-aryl; or Rs-heteroaryl; and Y is H, CR2R3CO2R6; CR2R3CONR6R7 or CR2R3NR6COR2; a = b = 0, 1 or 2; Q has the same definitions as previous P, with the proviso that P and Q can be the same or different; A is = N-OR; = N-NR2R3; or = CR.R2; X is -O-; -NR6-; -N (R6) CO-; or -CO-NR6-; T is R4-aryl; R4-heteroaryl; R 4 -cycloalkyl; or bridged R2-cycloalkyl; R-i is H, C Ce alkyl; or (CH2) n-G where n = 1-6, G is H; R4-aryl; R4-heteroaryl; COR6; CO2R6; CONR6R7; CN; OCOR6; S03R2; C (= NOR2) NR6R7; C (= NR2) NR6R, with the proviso that when n? 1, G can additionally be OR6, NR6R or NRe (CO) R7; R2 and R3 are independently H or C-? -C6 alkyl; R 4 and R 5 are independently 1, 2 or 3 substituents independently selected from OR 2, OC (O) R 2, OC (O) NR 6 R, C 6 alkyl H, halogen, CF3, C2F5 or OCF3; and Re and R7 are independently selected from H or C-C6 alkyl, with the proviso that when Re and R7 are part of NR6R7 then, said NR6R7 may be part of a C5-C6 ring where the members of the ring 0 -2 are selected from the group consisting of -O-, -S- and -NR2-, with the proviso that said Cs-Cβ ring may contain substituents on said ring with said substituents selected from the group consisting of hydrogen, halogen, -OR6 and -COOR6. Particularly preferred neurokinin antagonists are those described in the aforementioned US patents and pertaining to the general formula: and its stereoisomers. More preferred are stereoisomers with the following general formula: where R, is H, CH2CONH2, CH2CONHMe, CH2CONMe2 or Illustrative non-limiting examples of the leukotriene antagonists useful in the practice of the present invention include montelukast (from Merk &Company), pranlukas (from Ono Pharmaceutical Company Limited, CAS Registry No: 103177-37-3), zafiriukast (from Zeneca Pharmaceuticals; CAS Registry No.: 107753-78-6), CP-195494 (from Pfizer, Incorporated) and the like. The technical name of montelukast is acid [R- (E) -1 - [[[1- [3- [2- (7-chloro-2-quinolinyl] ethenyl] phenyl] -3- [2- (1-hydroxy-1-methylethyl) phenyl] propyl] thio] methyl] cyclopropanoacetic acid. The technical name of pranlukast is N- [4-oxo-2- (1 H-tetrazol-5-yl) -4H-1-benzopyran-8-yl] -4- (4-phenylbutoxy) -benzamide. The technical name of zafiriukast is [3 - [[2-methoxy-4 - [[[2-methylphenyl] sulfonyl] amino] carbonyl] pheny] methyl] -1-methyl-1 H-indol-5-yl. ] -Carbamic, cliclopentil, described in EP-00199543. A particularly useful leukotriene is montelukast. Montelukast is a leukotriene D4 antagonist capable of antagonizing the receptors for cysteinyl leukotrienes. This compound is described in EP 480,717. A preferred pharmaceutically acceptable salt of montelukast is the monosodium salt, also known as montelukast sodium (CAS Registry No: 151767-02-1). In another embodiment, this invention describes other pharmaceutical compositions that are useful for treating and preventing allergic rhinitis, asthma, and related disorders. The composition comprises, in combination, a therapeutically effective amount of at least one neurokinin antagonist and a therapeutically effective amount of at least one 5-lipoxygenase inhibitor. One or more compounds can be substituted by means of a pharmaceutically acceptable derivative such as, for example, salt, ester and the like. Non-limiting examples of useful neurokinin antagonists are those described in the aforementioned US patents including, for example, the compounds wherein R is H, CH2CONH2; CH2CONHMe; CH2CONMe2 or _ •. ** ,.

Useful 5-LO inhibitors include, for example, Zileuton (from Abbott Laboratories, CAS Registry No: 111406-87-2) and Atreluton (from Abbott Laboratories, CAS Registry No. 154355-76-7). The technical name for Zileuton is N- (1-benzo [b] thien-2-ylethyl) -N-hydroxy-urea. The technical name of Atreluton is N - [(1 R) -3- [5 - [(4-fluorophenyl) methyl] -2-thienyl] -1-methyl-2-propynyl] -N-hydroxyurea. Even in another embodiment, this invention describes a method for the treatment of asthma, allergic rhinitis, and other allergic disorders, sneezing, catarrh and nose itching, nasal congestion, redness of the eyes, tearing, itching of the ears or palate, wheezing, sinusitis, and cough associated with post-nasal drip symptoms in the organism of a mammal in need of this treatment, which comprises administering a pharmaceutical composition comprising a neurokinin antagonist and leukotriene antagonist as described above. In another embodiment, the present invention describes a method for the treatment of asthma, allergic rhinitis, and other allergic disorders, sneezing, catarrh and nose itching, nasal congestion, redness of the eyes, tearing, itching of the ears or palate, wheezing, sinusitis, and cough associated with post-nasal drip symptoms in the organism of a mammal in need of this treatment, which comprises administering a pharmaceutical composition comprising a neurokinin antagonist and the 5-LO inhibitor as described above.

In the pharmaceutical compositions and methods of the present invention, the active ingredients will typically be administered in admixture with suitable diluents, excipients or pharmaceutical carriers (collectively referred to as carrier materials), suitably selected with respect to the intended form of administration, i.e. oral tablets, capsules (both solid filled, semi-solid filled or liquid filled), powders for constitution, oral gels, elixirs, dispersible granules, syrups, suspensions, and the like and in accordance with conventional pharmaceutical practices. For example, for oral administration, in the form of tablets or capsules, the active drug component can be combined with any non-toxic, oral pharmaceutically acceptable inert carrier, such as, for example, lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid forms) and the like. Moreover, when desired or needed, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. The powders and tablets may be formed of about 5 and about 95 percent of the composition of the invention. Suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethyl cellulose, polyethylene glycol and waxes. Among the lubricants there may be mentioned for use in these dosage forms, boric acid, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrants include starch, methylcellulose, guar gum and the like. Sweetening and flavoring agents and preservatives can also be included when appropriate. Some of the mentioned terms, namely, disintegrants, diluents, lubricants, binders and the like, are explained in more detail below. Additionally, the compositions of the present invention can be formulated in the sustained release form to provide controlled release of one or more components or active ingredients to optimize the therapeutic effects, i.e., antagonism of the neurokinin, leukotriene antagonism, inhibition. 5-LO and the like. Suitable dosage forms for sustained release include layered tablets containing layers of varying disintegration rates or controlled release polymer matrices, impregnated with the active components and formed in the form of a tablet or capsules containing the porous polymer matrices. impregnated or encapsulated. Liquid form preparations include solutions, suspensions and emulsions. As an example, mention may be made of water, water-propylene glycol solutions for parenteral injections or the addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration. Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be combined with a pharmaceutically acceptable carrier such as, for example, an inert compressed gas, eg, nitrogen. To prepare the suppositories, a low-melting wax is first melted as for example a mixture of fatty acid glycerides, such as cocoa butter, and the active ingredient is dispersed homogeneously by stirring or by means of a similar mixing. The molten homogeneous mixture is then poured into the molds of suitable size, allowed to cool and thus solidify. Also included are solid form preparations which are intended to be converted, briefly before use, into liquid form preparations for oral or parenteral administration. These liquid forms include solutions, suspensions and emulsions. The compounds of the invention can also be distributed transdermally. The transdermal compositions can take the form of creams, lotions, aerosols and / or emulsions and can be included in a transdermal patch of the matrix or reservoir type, ie, in a conventional manner in the art. Preferably, the compound is administered orally. Preferably, the pharmaceutical preparation is a unit dose form. In this form, the preparation is subdivided into appropriately sized unit doses containing suitable amounts of the active components, for example, an effective amount to achieve the desired purpose.

The amount of the active composition of the invention *, in a unit dose of preparation, can generally be varied or adjusted between about 0.01 milligrams and about 1,000 milligrams, preferably between about 0.01 and about 750 milligrams, more preferably between about 0.01 and about 500 milligrams, and typically between about 0.01 and about 250 milligrams, according to the particular application. The actual dose used may vary depending on the age, sex, weight of the patient, and the severity of the condition to be treated. Those techniques are known to those skilled in the art. Generally, the human oral dosage form containing the active ingredients can be administered 1 or 2 times per day. The amount and frequency of administration will be regulated according to the judgment of the attending physician. A daily dose regimen generally recommended for oral administration, may be within a range between about 0.04 milligrams and about 4,000 milligrams per day, in single or divided doses. Capsule refers to a special container or container prepared from methylcellulose, polyvinyl alcohols, or denatured gelatins or starch to store or contain the compositions comprising the active ingredients. Hard shell capsules are generally prepared with relatively high gel resistance bone or pig skin gelatin combinations. The capsule itself may contain small amounts of colorants, opacifying agents, plasticizers and preservatives.

Tablet, refers to a compressed or molded solid dosage form that contains the active ingredients as suitable diluents. The tablet can be prepared by compression of mixtures or granulations obtained by means of wet or dry granulation or by compaction. Oral gels, refers to active ingredients dispersed or solubilized in a hydrophilic semi-solid matrix. Powders for construction, refers to mixtures of powder containing the active ingredients and suitable diluents that can be suspended in water or juice. "Diluent" refers to substances that usually make up the largest portion of the composition or dosage form. Suitable diluents include sugars such as, for example, lactose, sucrose, mannitol and sorbitol; starches derived from wheat, rice, corn, and potatoes; and celluloses such as, for example, microcrystalline cellulose. The amount of diluent in the composition can vary from 10% to about 90%, by weight of the total composition, preferably between about 25 and about 75%, more preferably between about 30 and about 60% by weight, including more preferably between about 12 and about 60%. Disintegrants, refers to materials added to the composition to help break up (disintegrate) and release medications. Suitable disintegrants include starches; Modified "cold water soluble" starches such as, for example, carboxymethyl sodium starch; natural and synthetic gums such as locust bean gum, karaya gum, guar, tragacanth and agar; cellulose derivatives such as, for example, methylcellulose and sodium carboxymethylcellulose; microcrystalline celluloses and cross-linked microcrystalline celluloses, such as, for example, croscarmellose sodium; alginates such as, for example, alginic acid and sodium alginate; clays such as bentonites; and effervescent mixtures. The amount of disintegrant in the composition may vary from about 2 to about 15% by weight of the composition, more preferably between about 4% and about 10% by weight. Binders, refers to substances that agglutinate or "stick" the powders and turn them "adhesives" into the formulation. The binders add cohesive resistance to that already available in the diluent or volumetric agent. Suitable binders include sugars such as, for example, sucrose; starches derived from wheat, corn and potato rice; natural gums such as acacia, gelatin and tragacanth; seaweed derivatives such as, for example, alginic acid, sodium alginate and calcium ammonium alginate; cellulosic materials such as, for example, methylcellulose and sodium carboxymethylcellulose and hydroxypropylmethylcellulose; polyvinyl pyrrolidone; and inorganic agents such as, for example, magnesium aluminum silicate. The amount of binder in the composition may vary from about 2% to about 20% by weight of the composition, more preferably between about 3% and about 10% by weight, even more preferably between about 3 and about 10% by weight. 6% by weight.

Lubricant, refers to a substance added to the dosage form to allow the tablet, granules, etc., after being compressed, to be released from the mold or die to reduce friction or wear. Suitable lubricants include metal stearates such as, for example, magnesium stearate, calcium stearate or potassium stearate; stearic acid; waxes of high melting point; and water-soluble lubricants such as, for example, sodium chloride, sodium benzoate, sodium acetate, sodium oleate, polyethylene glycols and d'l-leucine. Lubricants are usually added in the last step before compression, since they must be present on the surfaces of the granules and between them and the parts of the tablet press. The amount of lubricant in the composition may vary between about 0.2% and about 5% by weight of the composition, preferably between about 0.5 and about 2%, more preferably between about 0.3 and about 1.5% by weight. Slides, are materials that prevent the lumping and improve the flow characteristics of the granulations, so that the flow is smooth and uniform. Suitable glidants include silicon dioxide and talc. The amount of glidant in the composition may vary between about 0.1% and about 5% by weight of the total composition, preferably between about 0.5% and about 2% by weight. Coloring agents are excipients that provide coloration to the composition or dosage form. These excipients may include food grade dyes and food grade dyes adsorbed on a suitable adsorbent such as, for example, clay or aluminum oxide. The amount of the coloring agent may vary between about 0.1 and about 5% by weight of the composition, preferably between about 0.1 and about 1%. Bioavailability refers to the rate and degree at which the active drug ingredient and the therapeutic portion is absorbed into the systemic circulation from a dosage administered form compared to a standard or control. The conventional methods for preparing tablets are known. These methods include dry methods such as, for example, direct compression and compression of the granulation produced by compaction, or wet methods or other special procedures. Conventional methods are also known for preparing other forms of administration such as, for example, capsules, suppositories and the like. It will be obvious to those skilled in the art that many modifications, variations and alterations to the present description can be practiced with respect to the materials or methods. It is intended that these modifications, variations and alterations be within the spirit and scope of the present invention.

Claims (31)

NOVELTY OF THE INVENTION CLAIMS

1. - A pharmaceutical composition comprising, in combination, a therapeutically effective amount of at least one neurokinin antagonist or its pharmaceutically acceptable derivative; and a therapeutically effective amount of at least one leukotriene antagonist or its pharmaceutically acceptable derivative.

2. The pharmaceutical composition of claim 1, wherein said neurokinin antagonists or pharmaceutically acceptable derivative thereof is present in amounts of 1-1,000 milligrams per unit dose of said pharmaceutical composition.

3. The pharmaceutical composition of claim 1, wherein said neurokinin antagonist or its pharmaceutically acceptable derivative is present in amounts of 10-500 milligrams per unit dose of said pharmaceutical composition.

4. The pharmaceutical composition of claim 1, wherein said neurokinin antagonist or its pharmaceutically acceptable derivative is present in amounts of 50-200 milligrams per unit dose of said pharmaceutical composition.

5. The pharmaceutical composition of claim 1, wherein said leukotriene antagonist or its pharmaceutically acceptable derivative is present in amounts of 2-500 milligrams per unit dose of said pharmaceutical composition.

6. The pharmaceutical composition of claim 1, wherein said leukotriene antagonist or its pharmaceutically acceptable derivative is present in amounts of 5-100 milligrams per unit dose of said pharmaceutical composition.

7. The pharmaceutical composition of claim 1, wherein said leukotriene antagonist or its pharmaceutically acceptable derivative is present in amounts of 10-50 milligrams per unit dose of said pharmaceutical composition.

8. The pharmaceutical composition of claim 1, wherein said neurokinin antagonist is piperidine, piperazine, oxime, hydrazone, olefin, quinoline, isoquinoline, nitroalkane, amide, isoxazoline, azanorbornane, naphthyridine, benzodiazepine or arylalkylamine.

9. The pharmaceutical composition of claim 1, wherein said neurokinin antagonist is a compound having the general formula: where Z is # > * »_! _. where B is OR2, NR6COR2; CONR6R7 or NR2CONR6R7, m = 0 or 1, P is R5-aryl; or R5-heteroaryl; and Y is H, CR2R3CO2R6; CR2R3CONR6R7 or CR2R3NR6COR2; a = b = 0, 1 or 2; Q has the same definitions as previous P, with the proviso that P and Q can be the same or different; A is = N-OR; = N-NR2R3; or = CR.R2; X is -O-; -NR6-; -N (R6) CO-; or -CO-NR6-; T is R4-aryl; R4-heteroaryl; R 4 -cycloalkyl; or bridged R2-cycloalkyl; R. is H, alkyl of C.-C6; or (CH2) p-G where n = 1-6, G is H; R4-aryl; R4-heteroaryl; COR6; CO2R6; CONR6R7; CN; OCOR6; SO3R2; C (= NOR2) NR6R7; C (= NR2) NR6R7, with the proviso that when n? 1, G may additionally be ORß, NR6R7 or NRe (CO) R7; R2 and R3 are independently H or C6-C6 alkyl; R 4 and Rs are independently 1, 2 or 3 substituents independently selected from OR 2, OC (O) R 2, OC (O) NR 6 R 7, C 1 -C 7 alkyl, H, halogen, CF 3, C 2 F 5 or OCF 3; and R6 and R7 are independently selected from H or Ci-Cß alkyl, with the proviso that when R6 and R7 are part of NR6R7 then, said NR6R7 can be part of a Cs-Cß ring where the ring members 0-2 are selected from the group consisting of -O-, -S- and -NR2- with the proviso that said ring of Cs-Cß can contain substituents on said ring with said substituents selected from the group consisting of hydrogen, halogen, OR6 and COOR6.

10. - The pharmaceutical composition of claim 1, wherein said neurokinin antagonist is a compound having the following general formula: and its stereoisomers, where R = H; CH2CONH2; CH2CONHMe; CH2CONMe2

11. - The pharmaceutical composition of claim 1, wherein said neurokinin antagonist is a compound having the general formula where R is H; CH2CONH2; CH2CONHMe; CH2CONHMe2 or

12. - The pharmaceutical composition of claim 11, wherein said neurokinin antagonist is the compound wherein R is CH2CONH2.

13. The pharmaceutical composition of claim 11, wherein said neurokinin antagonist is the compound wherein R is CH2CONHMe.

14. The pharmaceutical composition of claim 1, wherein said leukotriene antagonist is selected from the group consisting of motelul'ast, montelukast sodium, pranlukast, zafiriukast and CP-195494.

15. The pharmaceutical composition of claim. 14, where said antagonist is montelukast sodium.

16. The pharmaceutical composition of claim 1, which additionally contains one or more materials selected from the group consisting of a pharmaceutically acceptable carrier, a decongestant, a cough suppressant, and an expectorant.

17. The use of at least one antagonist of the neurokinin or its pharmaceutically acceptable derivative in combination with at least one leukotriene antagonist or its pharmaceutically acceptable derivative, for the preparation of a medicament for treating asthma, allergic rhinitis, sneezing, cold and itchy nose, nasal congestion, redness of the eyes, tearing, itching of the ears and palate, wheezing, cough associated with post-nasal drip symptoms and respiratory disorders associated with allergy in a mammalian organism.

18. A pharmaceutical composition comprising, in combination, a therapeutically effective amount of at least one neurokinin antagonist or its pharmaceutically acceptable derivative, and a therapeutically effective amount of at least one 5-lipoxygenase inhibitor or its pharmaceutically acceptable derivative.

19. The pharmaceutical composition of claim 18, wherein said neurokinin antagonist is a piperidine, piperazine, oxime, hydrazone, olefin, quinoline, isoquinoline, nitroalkane, amide, isoxazoline, zanorbonate, naphthyridine, benzodiazepine or arylalkylamine.

20. The method of claim 18, wherein said neurokinase antagonist is a compound having the general formula: where Z is where B is OR2, NR6COR2; CONR6R7 or NR2CONR6R7, m = 0 or 1, P is R_-aryl; or R5-heteroaryl; and Y is H, CR2R3CO2R6; CR2R3CONR6R7 or CR2R3NR6COR2; a = b = 0, 1 or 2; Q has the same definitions as previous P, with the proviso that P and Q can be the same or different; A is = N-OR; = N-NR2R3; or = CR.R2; X is -O-; -NR6-; -N (R6) CO-; or -CO-NR6-; T is R4-aryl; R4-heteroaryl; R 4 -cycloalkyl; or bridged R2-cycloalkyl; R. is H, alkyl of C.-Cß; or (CH2) n-G where n = 1-6, G is H; R4-aryl; R -heteroaryl; COR6; CO2R6; CONR6R7; CN; OCOR6; SO3R2; C (= NOR2) NR6R7; C (= NR2) NR6R7, with the proviso that when n? 1, G can additionally be ORß, NR6R or NR6 (CO) R7; R2 and R3 are independently H or C6-C6 alkyl; R 4 and Rs are independently 1, 2 or 3 substituents independently selected from OR 2, OC (O) R 2, OC (O) NR 6 R 7, C 1 -C 4 alkyl, H, halogen, CF 3, C 2 F 5 or OCF 3; and R6 and R7 are independently selected from H or C-Cß alkyl, with the proviso that when Re and R are part of NR6R then, said NR6R7 can be part of a C5-C6 ring where the ring members 0- 2 are selected from the group consisting of -O-, -S- and -NR2- with the proviso that said ring of Cs-Cβ can contain substituents on said ring with said substituents selected from the group consisting of hydrogen, halogen, ORß and COORß.

21. The pharmaceutical composition of claim 18, wherein said neurokinase antagonist is a compound having the following general formula: and its stereoisomers, where R = H; CH2CONH2; CH2CONHMe; CH2CONMe2

22. - The pharmaceutical composition of claim 18, wherein said neurokinin antagonist is a compound having the formula where R is H; CH2 CONH2; CH2CONHMe; CH2CONMe2 or

23. - The pharmaceutical composition of claim 18, wherein said neurokinase antagonist is present in amounts between about 1-1, 000 milligrams per unit dose of said composition.

24. The pharmaceutical composition of claim 18, wherein said 5-lipxygenase inhibitor is present in amounts of about 2-500 milligrams per unit dose of said composition.

25. The pharmaceutical composition of claim 18, wherein said 5-lipoxygenase inhibitor is Zileuton or Atreluton.

26. The pharmaceutical composition of claim 25, wherein said 5-lipoxygenase inhibitor is Zileuton.

27. The composition of claim 18, wherein additionally contains one or more materials selected from the group consisting of a pharmaceutically acceptable carrier, a decongestant, a suppressant for cough and an expectorant.

28. The use of at least one antagonist of the neurokinin or its pharmaceutically acceptable derivative in combination with at least one inhibitor of 5-lipoxygenase or its pharmaceutically acceptable derivative, for the preparation of a medicament for the treatment of asthma, allergic rhinitis , chronic obstructive pulmonary disease sneezing, runny nose and itchy nose, nasal congestion, redness of the eyes, tearing, itching of the ears or palate, wheezing, cough associated with post-nasal drip symptoms and respiratory disorders associated with allergy in a mammal.

29. - The use of claim 17 or claim 28, wherein said neurokinin antagonist is a compound having the following general formula: where Z is where B is OR2, NR6COR2; CONR6R7 or NR2CONR6R7, m = 0 or 1, P is R5-aryl; or R5-heteroaryl; and Y is H, CR2R3CO2R6; CR2R3CONR6R7 or CR2R3NR6COR2; a = b = 0, 1 or 2; Q has the same definitions as previous P, with the proviso that P and Q can be the same or different; A is = N-OR; = N-NR2R3; or = CR.R2; X is -O-; -NR6-; -N (R6) CO-; or -CO-NR6-; T is R4-aryl; R4-heteroaryl; R 4 -cycloalkyl; or bridged R2-cycloalkyl; Ri is H, C-pCß alkyl; or (CH2) n-G where n = 1-6, G is H; R4-aryl; R4-heteroaryl; COR6; CO2R6; CONR6R7; CN; OCOR6; SO3R2; C (= NOR2) NR6R7; C (= NR2) NR6R, with the proviso that when n? 1, G can additionally be ORe, NR6R7 or NR6 (CO) R7; R 2 and R 3 are independently H or C 1 -C 2 alkyl; R4 and R5 are independently 1, 2 or 3 substituents independently selected from OR2, OC (O) R2, OC (O) NR6R7, C6-C6 alkyl, H, halogen, CF3, C2Fs or OCF3; and R6 and R7 are independently selected from H or C-Cß alkyl, with the proviso that when RT and R7 are part of NR6R7 then, said NR6R7 can be part of a C5-C6 ring where the ring members 0- 2 are selected from the group consisting of -O-, -S- and -NR2- with the proviso that said C5-C6 ring may contain substituents on said ring with said substituents selected from the group consisting of hydrogen, halogen, ORß and COORß.

30. The use of claim 17 or claim 28, wherein said leukotriene antagonist is selected from the group consisting of montelukast, montelukast sodium, pranlukast, zafiriukast and CP-195494.

31. The use of claim 17 or claim 28, wherein said 5-lipoxygenase inhibitor is Zileuton or Atreluton. - »s_ * i? ASi8! Faith _r-.í __ _ &_ _j_