JP2002527406A - Compositions and methods for treating allergic diseases - Google Patents

Abstract

  (57) [Summary] The present invention relates to pharmaceutical compositions useful for treating allergic rhinitis, asthma, and related disorders. In one embodiment, the composition comprises a therapeutically effective amount of at least one neurokinin antagonist in combination with a therapeutically effective amount of at least one 5-lipoxygenase inhibitor.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001] The present invention relates generally to compositions and methods for the treatment of allergic rhinitis and other respiratory diseases. In particular, the present invention provides (i) a combination of a neurokinin receptor and a leukotriene receptor antagonist; and (ii)
Disclosed are compositions comprising a combination of an antagonist of the neurokinin receptor and an inhibitor of 5-lipoxygenase, as well as methods of treating such diseases using such compositions.

[0002] The neurokinin such as (Background of the Invention) NK ₁ receptor and NK ₂ receptor ( "NK")
Receptors are found in the central nervous and circulatory systems and peripheral tissues of mammals and are involved in various biological processes. Thus, antagonists of the neurokinin receptor are expected to be useful in treating or preventing a variety of mammalian diseases, such as pulmonary disorders (eg, asthma, cough, bronchospasm, chronic obstructive pulmonary disease, Skin disorders and pruritus (eg, atopic dermatitis, and skin wheals and redness); neuroinflammatory diseases (eg, arthritis, migraine, nociception); CNS diseases (eg, anxiety, Vomiting, Parkinson's disease, movement disorders and psychiatric disorders); convulsive disorders, kidney disorders, urinary incontinence, eye inflammation, inflammatory pain and eating disorders (eg, food intake inhibition); allergic rhinitis,
Various diseases such as neurodegenerative disorders, psoriasis, Huntington's disease, depression, and Crohn's disease. NK ₁ receptors are reported to be involved in leakage and mucus secretion microvascular and NK ₂ receptor is associated with smooth muscle contraction, particularly useful NK ₁ and NK ₂ receptor antagonists in the treatment and prevention of asthma become. N
K ₁ and NK ₂ receptor antagonists are described, for example, in US Pat.
359; 5,795,894; 5,789,422; 5,7
Nos. 83,579; 5,719,156; 5,696,267; 5,691,362; 5,688,960; 5,654,316 ( All of these are from Schering-Plough Corporation.
, Madison, New Jersey); and "Recen
t Advances in Neurokinin Receptor An
tagonists ", C.I. J. Ohmacht Jr. Et al., Annual
Reports in Medicinal Chemistry, A.J. M. D
Ohty, 33, 71-80 (1998).

[0003] The products of the 5-lipoxygenase ("5-LO") pathway of arachidonic acid metabolism, especially leukotrienes, are responsible for the chemotaxis of cells into the respiratory tract during bronchoconstriction, mucus secretion, airway mucosal edema, inflammatory processes in asthma Can mediate mobility. Therefore, 5-
Inhibition of LO should help treat, alleviate or prevent such diseases. Similarly, leukotriene ("LK") antagonists are associated with multiple airway disorders such as seasonal allergic rhinitis, perennial allergic rhinitis, cold, sinusitis, and associated symptoms associated with allergic asthma. Plays a role in the treatment of symptoms. Symptoms of such diseases include sneezing, itching and runny nose.
unyose, nasal congestion, redness of the eyes (redness of the
eye), lacrimation, itching of the ear or palate, and coughs associated with postnasal drip. A discussion of leukotriene receptors can be found in Robertson, Prost
Agrandines, 31, 395 (1986), and a discussion of leukotriene antagonists can be found in Musser et al., Agents and
Actions, 18, 332 (1986); Piwinski et al., An
natural Reports in Medicinal Chemistry,
22, 73-76 (1987); Bell et al., Annual Rep.
orts in Medicinal Chemistry, 32, 91 (19
97).

[0004] It is highly desirable to enhance the potency of neurokinin antagonists to improve their overall potency, and to reduce or prevent the above mentioned diseases by preventing the activity of 5-LO and leukotriene receptors. .

SUMMARY OF THE INVENTION The above objects and other objects and requirements are, in one embodiment, a composition for the treatment and prevention of allergic rhinitis and other respiratory diseases such as asthma, cough, wheezing. Is solved by the present invention. The compositions of the present invention comprise a therapeutically effective amount of at least one neurokinin antagonist and a therapeutically effective amount of at least one leukotriene antagonist in combination. One or more antagonists can be replaced with a pharmaceutically acceptable derivative (eg, salt, ester, etc.). Optionally, the composition comprises a pharmaceutically acceptable carrier, a decongestant (eg, pseudoephedrine, etc.), a cough remedy (eg, dextromethorphan, etc.), an expectorant (eg, Guaifenesi, etc.) ), Analgesics such as aspirin, ibuprofen and acetaminophen or mixtures thereof.

[0006] Generally, the content of neurokinin antagonist in the composition of the present invention per unit dosage is about 1 to 1,000 milligrams, and the content of leukotriene antagonist is about 2 to 500 milligrams. . Preferably, the respective amounts are about 10-500 milligrams, and about 5-500 milligrams; typically, the respective amounts are about 50-200 milligrams, and 10-50 milligrams.
Milligrams.

[0007] The present invention further provides compositions for treating and preventing allergic rhinitis and other respiratory diseases such as asthma, cough, sneezing, wherein the composition comprises at least one therapeutically effective amount. A combination comprises a neurokinin antagonist and a therapeutically effective amount of at least one 5-LO inhibitor. One or more of the compounds can be replaced with a pharmaceutically acceptable derivative (eg, salt, ester, etc.). Further, the composition can include a pharmaceutically acceptable carrier, a blood remover, a cough suppressant and expectorant, or a mixture thereof.

[0008] The present invention relates to asthma, chronic obstructive pulmonary disease ("COPD") and allergic disorders,
Further provided are methods for treating cough associated with sneezing, pruritus, runny nose congestion, redness of eyes, lacrimation, ear or palate itching, sinusitis and postnasal drip symptoms. Administering the above pharmaceutical composition to a mammal in need of such treatment.

DETAILED DESCRIPTION OF THE INVENTION In one embodiment, the present invention discloses a pharmaceutical composition useful for treating and preventing allergic rhinitis, asthma and related disorders. The composition comprises a therapeutically effective amount of at least one neurokinin antagonist and a therapeutically effective amount of at least one leukotriene antagonist in combination. One or more antagonists can be replaced with a pharmaceutically acceptable derivative (eg, salt, ester, etc.).

[0010] Several neurokinin antagonists currently known are useful in the practice of the present invention. Non-limiting examples of such useful neurokinin antagonists include, for example, oximes, hydrazones, piperidines, piperazines, arylalkylamines, hydrazones, nitroalkanes, amides, isoxazolines, quinolines, isoquinolines, azanorbornanes, naphthyridines, benzodiazepines And those belonging to a chemical class such as Many are disclosed in the U.S. patents cited earlier in this patent specification. Preferred NK antagonists are described in US Pat.
No. 5,798,359; No. 5,795,894; No. 5,789,422;
Nos. 5,783,579; 5,719,156; 5,696,26
No. 7, No. 5,691,362; No. 5,688,960; No. 5,654
, 316. Some general formulas of the compounds thus disclosed are:

[0011]

Embedded image Where Z is:

[0012]

Embedded image Where B is OR_Two; NR₆COR_Two, CONR₆R₇Or NR_TwoCONR₆R₇ M = 0 or 1, P is R_Five-Aryl; or R_Five-Heteroaryl; and Y is H, CR_TwoR_ThreeCO_TwoR₆; CR_TwoR_ThreeCONR₆R₇Or CR_TwoR_ThreeNR₆C
OR_TwoA = b = 0, 1 or 2; Q has the same definition as P above, provided that P and Q are the same or different
A is = N-OR₁; = N-NR_TwoR_ThreeOr = CR₁R_TwoX is -O-; -NR₆-; -N (R₆) CO-; or -CO-NR₆-
T is R_Four-Aryl; R_Four-Heteroaryl; R_Four-Cycloalkyl; or
R_Two-A bridged cycloalkyl; R₁Is H; C₁~ C₆Alkyl; or (CH_Two)_n-G (where n = 1 to 6
G is H; R_Four-Aryl; R_Four-Heteroaryl; COR₆; CO_TwoR₆; CO
NR₆R₇; CN; OCOR₆; SO_ThreeR_TwoC (= NOR_Two) NR₆R₇C (= NR _Two ) NR₆R₇However, when nＧ1, G is further OR₆, NR₆R₇Also
Is NR₆(CO) R₇R_TwoAnd R_ThreeIs independently H or C₁~ C₆R is alkyl;_FourAnd R_FiveIs independently OR_Two, OC (O) R_Two, OC (O) NR₆R₇, C ₁ ~ C₆Alkyl, H, halogen, CF_Three, C_TwoF_FiveOr OCF_ThreeIndependently selected from
1, 2 or 3 substituents;₆And R₇Is independently H or C₁~ C₆Selected from alkyl, with the proviso that
, R₆And R₇Is NR₆R₇This NR₆R₇Is C_Five~ C₆Part of a ring
Wherein 0 to 2 ring members are -O-, -S- and -NR_Two
Selected from the group consisting of_Five~ C₆A ring is substituted on the ring
And the substituents may be hydrogen, halogen, -OR₆And -COOR₆From
Group.

[0013] Particularly preferred neurokinin antagonists are those disclosed in the aforementioned US patents, which belong to the following general formula and stereoisomers thereof:

[0014]

Embedded image Stereoisomers having the following general formula are particularly preferred:

[0015]

Embedded image Here, R is H, CH ₂ CONH ₂ , CH ₂ CONHMe, CH ₂ CONMe ₂ or

[0016]

Embedded image It is.

[0017] Illustrative, non-limiting examples of leukotriene antagonists useful in the practice of the present invention include: montelukast (Mer)
ck & Company), pranlukast (O
no Pharmaceutical Company Limited, CA
S registration number: 103177-37-3), zafiluka (zafirluka)
st) (Zeneca Pharmaceuticals; CAS Registry Number:
107753-78-6), CP-195494 (Pfizer, Incorp.)
orated). The technical name of Montelukast is [R- (E)]-1-[[[
1- [3- [2- (7-Chloro-2-quinolinyl) ethenyl] phenyl] -3-
[2- (1-hydroxy-1-methylethyl) phenyl] propyl] thio] methyl] cyclopropaneacetic acid. The technical name of pranlukast is N- [4-oxo-2- (1H-tetrazol-5-yl) -4H-1-benzopyran-8-yl] -4- (4-phenylbutoxy) -benzamide. . The technical name of Zafirkast is [3-[[2-methoxy-4-[[[2-methylphenyl) sulfonyl] amino] carbonyl] phenyl] methyl] -1-methyl-1H-indole-
5-yl] -carbamic acid, cyclopentyl ester (EP-001995543)
Disclosed). A particularly useful leukotriene is montelukast. Montelukast is a leukotriene D4 antagonist that can antagonize the receptor for cysteinyl leukotriene. This compound is described in EP 480,717. A preferred pharmaceutically acceptable salt of montelukast is the monosodium salt, which is sodium montelukast (CAS Registry Number: 151767-0).
It is also known as 2-1).

[0018] In another embodiment, the present invention discloses other pharmaceutical compositions useful for treating and preventing allergic rhinitis, asthma and related disorders. The composition comprises a therapeutically effective amount of at least one neurokinin antagonist in combination with a therapeutically effective amount of at least one inhibitor of 5-lipoxygenase. One or more of the compounds can be replaced with a pharmaceutically acceptable derivative (eg, salt, ester, etc.).

Non-limiting examples of useful neurokinin antagonists are those disclosed in the above-cited US Patents, for example, where R is H, CH ₂ CONH ₂ ,
CH ₂ CONHMe, CH ₂ CONMe ₂ or

[0020]

Embedded image The compound which is is mentioned.

Useful 5-LO inhibitors include, for example, Zileuton (Abbott)
Laboratories, CAS registration number: 111406-87-2),
And Atreluton (Abbott Laboratories, CA
S registration number: 154355-76-7). The technical name of Zileuton is N- (1-benzo [b] thien-2-ylethyl) -N-hydroxy-urea. The technical name of Atreluton is N-[(1R) -3- [5-[(
4-fluorophenyl) methyl] -2-thienyl] -1-methyl-2-propynyl] -N-hydroxyurea.

In yet another embodiment, the invention is directed to asthma, allergic rhinitis, and other allergic disorders, sneezing, itchy snot, nasal congestion, redness of the eyes, lacrimation, ear or palate itching, wheezing. , A method of treating sinusitis, and cough associated with postnasal drip, comprising a pharmaceutical composition comprising a neurokinin antagonist and a leukotriene antagonist as described above in a mammal in need of such treatment Is administered.

In a further embodiment, the invention relates to asthma, allergic rhinitis, and other allergic disorders, sneezing, pruritus, runny nose, redness of the eyes, lacrimation, itching of the eyes or palate, Disclosed is a method for the treatment of such conditions in a mammal in need of treatment for cough associated with ringing, sinusitis, and rhinorrhea, comprising a neurokinin antagonist as described above, and 5- Administering a pharmaceutical composition comprising the LO inhibitor.

In the pharmaceutical compositions and methods of the present invention, the active ingredient will typically be in the intended mode of administration (ie, oral tablet, capsule (either solid or semi-solid or liquid). Appropriate pharmaceutical diluents, excipients, powders for construction, oral gels, elixirs, dispersible granules, syrups, suspensions, etc.) and which are consistent with conventional pharmaceutical practice. It is administered in admixture with a vehicle or carrier (collectively referred to herein as carrier materials). For example, for oral administration in the form of a tablet or capsule, the active drug component can be any oral non-toxic pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, cellulose, magnesium stearate, phosphorus It can be combined with dicalcium acid, calcium sulfate, talc, mannitol, ethyl alcohol (liquid form) and the like. In addition, if desired or needed, suitable binders, lubricants,
Disintegrants and colorants may also be incorporated into the mixture. Powders and tablets may be comprised of from about 5 to about 95% composition of the present invention. Suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethylcellulose, polyethylene glycols and waxes. Among the lubricants, mention may be made of boric acid, sodium benzoate, sodium acetate, sodium chloride and the like for use in these dosage forms. Disintegrators include starch, methyl cellulose, guar gum and the like. Sweetening and flavoring agents and preservatives may also be included where appropriate. Some of the above terms, ie, disintegrants, diluents, lubricants, binders, and the like, are discussed in more detail below.

In addition, the compositions of the present invention can be formulated in a sustained release form, and may include any one or more of those that optimize therapeutic effect (ie, neurokinin antagonism, leukotriene antagonism, 5-LO inhibition, etc.). Provides controlled release of the ingredient or active ingredient. Suitable dosage forms for sustained release include layered tablets comprising layers of varying disintegration rates,
Alternatively, a controlled release polymer matrix impregnated with the active ingredient and formed into a tablet or capsule comprising such an impregnated or encapsulated porous polymer matrix may be mentioned.

Liquid form preparations include solutions, suspensions, and emulsions. Examples include the addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions, or water or water-propylene glycol solutions for parenteral injection. 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 in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, eg nitrogen. Can be done.

For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides such as cocoa butter, is first melted and the active component is dispersed homogeneously therein, as by stirring or similar mixing. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.

[0029] Also included are solid form preparations, which are intended to be converted, shortly before use, to liquid preparations, for either oral or parenteral administration. Such liquid forms include solutions, suspensions, and emulsions.

The compounds of the present invention may also be deliverable transdermally. Transdermal compositions can take the form of creams, lotions, aerosols and / or emulsions and can be included in a reconventional matrix or reservoir type transdermal patch for this purpose.

Preferably, the compounds are administered orally.

[0032] Preferably, the pharmaceutical preparation is in a unit dosage form. In such form, the preparation contains an appropriate amount of the active component (eg, an effective amount to achieve the desired purpose).
And is subdivided into suitably sized unit doses containing,

The amount of active composition of the present invention in a unit dose preparation will generally be from about 0.01 milligram to about 1,000 milligrams, preferably about 0.01 milligram, depending on the particular application.
From about 750 milligrams, more preferably from about 0.01 to about 500 milligrams, and typically from about 0.01 to about 250 milligrams, or may be adjusted. The actual dosage employed may be varied depending upon the age, sex, weight, and severity of the condition being treated. Such techniques are well-known to those skilled in the art. Generally, human oral dosage forms containing the active ingredient can be administered one or two times per day. Dosage amount and frequency will be controlled according to the judgment of the attending physician. A generally recommended daily dosage regimen for oral administration can range from about 0.04 milligrams to about 4,000 milligrams per day, in single or divided doses.

Capsule refers to a specific container or enclosure made of methyl cellulose, polyvinyl alcohol, or modified gelatin or starch to hold or contain a composition containing the active ingredient.

Tablet refers to a compressed or molded solid dosage form containing the active ingredients with suitable diluents. Tablets may be prepared by wet granulation, dry granulation or by compression of the mixture or granules obtained by the filling method.

[0036] Oral gel refers to an active ingredient dispersed or solubilized in a hydrophilic semi-solid matrix.

Powder for make-up refers to a powder blend comprising the active ingredient which can be suspended in water or juice and a suitable diluent.

[0038] Diluent refers to the substance that normally forms the main part of the composition or dosage form. Suitable diluents include sugars such as lactose, sucrose, mannitol and sorbitol; starches derived from wheat, corn rice and potatoes; and celluloses such as microcrystalline cellulose. The amount of diluent in the composition may range from about 10 to about 90%, preferably from about 25 to about 75%, more preferably from about 30 to about 60%, even more preferably from about 12 to about 90% by weight of the total composition. About 60
% By weight.

Disintegrants refer to materials added to the composition to help it break apart (disintegrate) and release the drug. Suitable disintegrants include: starch; "cold water soluble" modified starch (eg, sodium carboxymethyl starch); natural and synthetic gums (eg, locus)
t bean)); karaya gum, gar, tragacanth and agar; cellulose derivatives such as methylcellulose and sodium carboxymethylcellulose
Microcrystalline cellulose and cross-linked microcrystalline cellulose (eg, sodium croscarmellose); alginates (eg, alginic acid and sodium alginate); clays (eg, bentonite); and effervescent mixtures. The amount of disintegrant in the composition may range from about 2 to about
It may range from about 15% by weight, more preferably from about 4 to about 10% by weight.

A binder is a substance that binds or “glues” powders together and makes them sticky by forming granules, thus serving as an “adhesive” in the formulation. Say. The binder may be a diluent or a bulking agent (b
Add the cohesive strength already available in the ulking agent. Suitable binders include: sugars such as sucrose; starches derived from wheat, corn rice and potatoes; natural gums such as acacia, gelatin and tragacanth; alginic acid, sodium alginate and calcium aluminum alginate Derivatives of seaweeds such as sodium chloride; cellulose materials such as methylcellulose and sodium carboxymethylcellulose and hydroxypropylmethylcellulose; polyvinylpyrrolidone; The amount of binder in the composition may range from about 2% to about 20% by weight of the composition.
, More preferably from about 3 to about 10% by weight, even more preferably from about 3 to about 6% by weight.

Lubricants are substances added to a dosage form such that tablets, granules, etc., can be released from the mold or mold after compression by reducing friction or wear. Say. Suitable lubricants include: metallic stearate such as magnesium stearate, calcium stearate or potassium stearate; stearic acid; high melting wax; and sodium chloride, sodium benzoate, sodium acetate, olein Water-soluble lubricants such as sodium acid, polyethylene glycol and d'l-leucine. Lubricants are usually added just before compression, as they must be present on the surface of the granules and between the granules and the parts of the tablet press. The amount of lubricant in the composition can range from about 0.2% to about 5%, preferably from about 0.5% to about 2%, more preferably from about 0% to about 2%, by weight of the composition.
. It can range from 3% to about 1.5% by weight.

Glident is a material that prevents caking and improves the flow characteristics of granules, so that the flow is smooth and uniform. Suitable glidants include silicon dioxide and talc. The amount of glidants in the composition may range from about 0.1% to about 5% by weight of the total composition, preferably from about 0.5% to
It can be in the range of about 2% by weight.

Coloring agents are excipients that provide color to the composition or the dosage form. Such excipients may include food grade dyes and food grade dyes adsorbed on a suitable adsorbent such as clay or aluminum oxide. The amount of colorant is
About 0.1% to about 5%, preferably about 0.1% to about 1%, by weight of the composition
Can vary.

Bioavailability refers to the rate and extent to which the active pharmaceutical ingredient or therapeutic moiety is absorbed from the administered dosage form into the systemic circulation, as compared to a reference or control.

Conventional methods for preparing tablets are known. Such methods include dry methods, such as direct compression and compression of the granules produced by the filling method, or wet methods or other special procedures. Conventional methods for making other forms for administration (eg, capsules, suppositories, etc.) are also well known.

It will be apparent to one skilled in the art that many modifications, variations, and alternatives to both the materials and the methods may be made to the present disclosure. Such alterations, changes, and substitutions are intended to be within the spirit and scope of the invention.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/44 A61K 31/44 31/444 31/444 31/47 31/47 31/495 31/495 31 / 551 31/551 A61P 11/00 A61P 11/00 11/02 11/02 11/06 11/06 27/14 27/14 37/08 37/08 43/00 111 43/00 111 (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), A , AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CR, CZ, DE, DK, DM, EE, ES, FI, GB, GD, GE, HR, HU, ID, IL, IN, IS, JP, KG, KR, KZ, LC, LK, LR, LT, LU, LV, MD, MG, MK, MN, MX, NO, NZ, PL, PT , RO, RU, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, US, UZ, VN, YU, ZA (71) Applicant 2000 Galloping Hill Road, Kenilworth, New Jersey 07033-0530, U.S.A. S. A F term (reference) 4C084 ZA33 ZA34 ZA59 ZB13 ZC42 4C086 AA01 BC21 BC28 BC30 BC50 BC67 CB09 MA02 MA03 MA04 NA05 ZA33 ZA34 ZA59 ZB13 ZC42 4C206 AA01 FA01 FA31 ZA33 ZA34 ZA59 ZB13 ZC42

Claims (31)

[Claims] 1. A combination comprising a therapeutically effective amount of at least one neurokinin antagonist or a pharmaceutically acceptable derivative thereof, and a therapeutically effective amount of at least one leukotriene antagonist or a pharmaceutically acceptable derivative thereof. , Pharmaceutical compositions. 2. The pharmaceutical composition according to claim 1, wherein said neurokinin antagonist or pharmaceutically acceptable derivative thereof is present in an amount of 1 to 1,000 milligrams per unit dose of said pharmaceutical composition. A pharmaceutical composition, which is present in an amount of 3. The pharmaceutical composition according to claim 1, wherein said neurokinin antagonist or pharmaceutically acceptable derivative thereof is present in an amount of 10 to 500 milligrams per unit dose of said pharmaceutical composition. A pharmaceutical composition, which is present in a pharmaceutical composition. 4. The pharmaceutical composition of claim 1, wherein said neurokinin antagonist or pharmaceutically acceptable derivative thereof is in an amount of 50 to 200 milligrams per unit dose of said pharmaceutical composition. A pharmaceutical composition, which is present in: 5. The pharmaceutical composition according to claim 1, wherein said leukotriene antagonist or a pharmaceutically acceptable derivative thereof is present in an amount of 2 to 500 milligrams per unit dose of said pharmaceutical composition. An existing pharmaceutical composition. 6. The pharmaceutical composition according to claim 1, wherein said leukotriene antagonist or a pharmaceutically acceptable derivative thereof is present in an amount of 5 to 100 milligrams per unit dose of said pharmaceutical composition. An existing pharmaceutical composition. 7. The pharmaceutical composition according to claim 1, wherein the leukotriene antagonist or a pharmaceutically acceptable derivative thereof is present in an amount of 10 to 50 milligrams per unit dose of the pharmaceutical composition. An existing pharmaceutical composition. 8. The pharmaceutical composition according to claim 1, wherein the neurokinin antagonist is piperidine, piperazine, oxime, hydrazone, olefin, quinoline, isoquinoline, nitroalkane, amide, isoxazoline, azanorbornane. ), Naphthyridine, benzodiazepine, or arylalkylamine. 9. The pharmaceutical composition according to claim 1, wherein the neurokini is used.
An antagonist has the following general formula:Wherein Z is the following:Where B is OR_Two; NR₆COR_Two, CONR₆R₇Or NR_TwoCONR ₆ R₇M = 0 or 1, P is R_Five-Aryl; or R_Five-Heteroaryl; and Y is H, CR_TwoR_ThreeCO_TwoR₆; CR_TwoR_ThreeCONR₆R₇Or CR_TwoR_ThreeNR₆COR_Two A = b = 0, 1 or 2; Q has the same definition as P above, provided that P and Q are the same but different
A = N-OR₁; = N-NR_TwoR_ThreeOr = CR₁R_TwoX is -O-; -NR₆-; -N (R₆) CO-; or -CO-NR₆-Is;
T is R_Four-Aryl; R_Four-Heteroaryl; R_Four-Cycloalkyl; or R_Two−
R is a bridged cycloalkyl;₁Is H, C₁~ C₆Alkyl; or (CH_Two)_n−G, where n = 1 to 6
G is H; R_Four-Aryl; R_Four-Heteroaryl; COR₆; CO_TwoR₆; CONR₆ R₇; CN; OCOR₆; SO_ThreeR_TwoC (= NOR_Two) NR₆R₇C (= NR_Two) N
R₆R₇Where, if n is not 1, G is also OR₆, NR₆R₇Or
NR₆(CO) R₇R_TwoAnd R_ThreeIs independently H or C₁~ C₆R is alkyl;_FourAnd R_FiveIs independently OR_Two, OC (O) R_Two, OC (O) NR₆R₇, C₁
~ C₆Alkyl, H, halogen, CF_Three, C_TwoF_FiveOr OCF_ThreeIndependently selected from
1, 2, or 3 substituents selected; and R₆And R₇Is independently H or C₁~ C₆Selected from alkyl, provided that
R₆And R₇Is NR₆R₇If it is part of the NR₆R₇Is C_Five~ C₆Part of the ring
Where 0 to 2 ring members are -O-, -S- and -NR_Two
Selected from the group consisting of_Five~ C₆The ring has a substituent on the ring.
Wherein the substituent is hydrogen, halogen, -OR₆And -COOR₆A group consisting of
A pharmaceutical composition selected from: 10. The pharmaceutical composition according to claim 1, wherein said neurokinin antagonist has the following general formula: And stereoisomers thereof, wherein R = H; CH ₂ CON
H ₂ ; CH ₂ CONHMe; CH ₂ CONMe ₂ or A pharmaceutical composition. 11. The pharmaceutical composition according to claim 1, wherein said neurokinin antagonist has the following general formula: Wherein R is H; CH ₂ CONH ₂ ; CH ₂ CONHMe
CH ₂ CONMe ₂ or A pharmaceutical composition. 12. The neurokinin antagonist wherein R is CH ₂ CON.
It is a compound which is H _2, the pharmaceutical composition according to claim 11. 13. The neurokinin antagonist wherein R is CH ₂ CON.
The pharmaceutical composition according to claim 11, which is a compound that is HMe. 14. The pharmaceutical composition of claim 1, wherein said leukotriene antagonist is selected from the group consisting of montelukast, montelukast sodium, pranlukast, zafilkast, and CP-195494. object. 15. The pharmaceutical composition according to claim 14, wherein said leukotriene antagonist is mortelkast sodium. 16. The pharmaceutical composition according to claim 1, wherein the at least one substance is selected from the group consisting of a pharmaceutically acceptable carrier, a decongestant, a cough suppressant, and an expectorant. A pharmaceutical composition further comprising: 17. Asthma, allergic rhinitis, chronic obstructive pulmonary disease, sneezing,
Pruritic runny nose, nasal congestion, redness of eyes, lacrimation, itching of eyes or palate, wheezing, cough associated with postnasal drip symptoms, and allergy-related breathing in mammalian organisms in need of such treatment A method for treating a sexual disorder, said treatment comprising a therapeutically effective amount of at least one neurokinin antagonist or a pharmaceutically acceptable derivative thereof, and a therapeutically effective amount of at least one leukotriene antagonist or a derivative thereof. Administering a pharmaceutical composition comprising a combination of pharmaceutically acceptable derivatives. 18. A therapeutically effective amount of at least one neurokinin antagonist or a pharmaceutically acceptable derivative thereof, and a therapeutically effective amount of at least one 5-lipoxygenase inhibitor or a pharmaceutically acceptable derivative thereof. A pharmaceutical composition comprising in combination. 19. The pharmaceutical composition according to claim 18, wherein said neurokinin antagonist is piperidine, piperazine, oxime, hydrazone, olefin, quinoline, isoquinoline, nitroalkane, amide, isoxazoline, azanorbornane, naphthyridine. , A benzodiazepine, or an arylalkylamine. 20. The pharmaceutical composition according to claim 18, wherein said neurokinin antagonist has the following general formula: Wherein Z is: Wherein B is OR ₂ ; NR ₆ COR ₂ , CONR ₆ R ₇ or NR ₂ CON
R ₆ R ₇ , m = 0 or 1, P is R ₅ -aryl; or R ₅ -heteroaryl; and Y is H, CR ₂ R ₃ CO ₂ R ₆ ; CR ₂ R ₃ CONR ₆ R ₇ or CR ₂ R ₃ NR ₆ COR ₂ ; a = b = 0, 1 or 2; Q has the same definition as P above, provided that P and Q are the same but different A is = N-OR ₁ ; = N-NR ₂ R ₃ ; or = CR ₁ R ₂ ; X is -O-; -NR _6- ; -N (R ₆ ) CO-; or -CO-NR ₆ - a and;
T is R ₄ - aryl; R ₄ - heteroaryl; R ₄ - cycloalkyl; or R ₂ -
R ₁ is H, C ₁ -C ₆ alkyl; or (CH ₂ ) _n -G, wherein n = 1-6.
In it, G is H; R ₄ - aryl; R ₄ - _{heteroaryl; COR 6; CO 2 R 6} ; CONR 6 R 7; CN; OCOR 6; SO 3 R 2; C (= NOR 2) NR 6 R ₇ ; C (= NR ₂ ) N
R ₆ R ₇ with the proviso that if n is not 1, G can further be OR ₆ , NR ₆ R ₇ or NR ₆ (CO) R ₇ ; R ₂ and R ₃ are independently H or be a C ₁ -C ₆ alkyl; R ₄ and R ₅ are _{independently, oR 2, OC (O)} R 2, OC (O) NR 6 R 7, C 1
-C ₆ alkyl, H, halogen, CF _3, C ₂ F _5, or independently selected from OCF _3, is 1, 2 or 3 substituents; and R ₆ and R ₇ are independently Selected from H or C ₁ -C ₆ alkyl, provided that
When R ₆ and R ₇ are part of the NR ₆ R _7, wherein NR ₆ R ₇ may form part of a C ₅ -C ₆ ring, wherein the members of 0-2 ring , -O -, - S- and -NR ₂
- is selected from the group consisting of further proviso that the C ₅ -C ₆ ring may contain a substituent on the ring, the substituent is hydrogen, halogen, from the group consisting of -OR ₆ and -COOR ₆ The pharmaceutical composition selected. 21. The pharmaceutical composition according to claim 18, wherein said neurokinin antagonist has the following general formula: And a stereoisomer thereof, wherein R is H; CH ₂ CONH ₂ ; CH ₂ CONHMe; CH ₂ CONMe ₂ ; or A pharmaceutical composition. 22. The pharmaceutical composition according to claim 18, wherein the neurokinin antagonist has the following general formula: Wherein R is H; CH ₂ CONH ₂ ; CH ₂ CONHMe
CH ₂ CONMe ₂ ; or A pharmaceutical composition. 23. The pharmaceutical composition of claim 18, wherein said neurokinin antagonist is present in an amount of about 1 to 1,000 milligrams per unit dose of said composition. . 24. The pharmaceutical composition according to claim 18, wherein said inhibitor of 5-lipoxygenase is present in an amount of about 2-500 milligrams per unit dose of said composition. . 25. The inhibitor of 5-lipoxygenase wherein Zileu
19. The pharmaceutical composition according to claim 18, which is ton or Atreluton. 26. The inhibitor of 5-lipoxygenase wherein the inhibitor of Zileu
26. The pharmaceutical composition according to claim 25, which is ton. 27. The composition of claim 18, further comprising one or more substances selected from the group consisting of pharmaceutically acceptable carriers, decongestants, cough suppressants, and expectorants. A composition comprising: 28. Asthma, allergic rhinitis, chronic obstructive pulmonary disease, sneezing,
Pruritic runny nose, nasal congestion, redness of eyes, lacrimation, itching of eyes or palate, wheezing, cough associated with postnasal drip symptoms, and allergy-related breathing in mammalian organisms in need of such treatment A method for treating a sexual disorder, comprising treating a therapeutically effective amount of at least one neurokinin antagonist or a pharmaceutically acceptable derivative thereof, and a therapeutically effective amount of at least one 5-lipoxygenase. Administering a pharmaceutical composition comprising the inhibitor or a pharmaceutically acceptable derivative thereof in combination. 29. The method according to claim 17 or 28, wherein the neurokinin antagonist has the following general formula: Wherein Z is: Wherein B is OR ₂ ; NR ₆ COR ₂ , CONR ₆ R ₇ or NR ₂ CON
R ₆ R ₇ , m = 0 or 1, P is R ₅ -aryl; or R ₅ -heteroaryl; and Y is H, CR ₂ R ₃ CO ₂ R ₆ ; CR ₂ R ₃ CONR ₆ R ₇ or CR ₂ R ₃ NR ₆ COR ₂ ; a = b = 0, 1 or 2; Q has the same definition as P above, provided that P and Q are the same but different A is = N-OR ₁ ; = N-NR ₂ R ₃ ; or = CR ₁ R ₂ ; X is -O-; -NR _6- ; -N (R ₆ ) CO-; or -CO-NR ₆ - a and;
T is R ₄ - aryl; R ₄ - heteroaryl; R ₄ - cycloalkyl; or R ₂ -
R ₁ is H, C ₁ -C ₆ alkyl; or (CH ₂ ) _n -G, wherein n = 1-6.
In it, G is H; R ₄ - aryl; R ₄ - _{heteroaryl; COR 6; CO 2 R 6} ; CONR 6 R 7; CN; OCOR 6; SO 3 R 2; C (= NOR 2) NR 6 R ₇ ; C (= NR ₂ ) N
R ₆ R ₇ with the proviso that if n is not 1, G can further be OR ₆ , NR ₆ R ₇ or NR ₆ (CO) R ₇ ; R ₂ and R ₃ are independently H or be a C ₁ -C ₆ alkyl; R ₄ and R ₅ are _{independently, oR 2, OC (O)} R 2, OC (O) NR 6 R 7, C 1
-C ₆ alkyl, H, halogen, CF _3, C ₂ F _5, or independently selected from OCF _3, is 1, 2 or 3 substituents; and R ₆ and R ₇ are independently Selected from H or C ₁ -C ₆ alkyl, provided that
When R ₆ and R ₇ are part of the NR ₆ R _7, wherein NR ₆ R ₇ may form part of a C ₅ -C ₆ ring, wherein the members of 0-2 ring , -O -, - S- and -NR ₂
- is selected from the group consisting of further proviso that the C ₅ -C ₆ ring may contain a substituent on the ring, the substituent is hydrogen, halogen, from the group consisting of -OR ₆ and -COOR ₆ The method chosen. 30. The method of claim 17 or 28, wherein the leukotriene antagonist is selected from the group consisting of montelukast, montelukast sodium, pranlukast, zafilkast, and CP-195494. 31. The inhibitor of 5-lipoxygenase wherein the inhibitor is Zileu.
29. The method according to claim 17 or 28, wherein the method is ton or Atreluton.