U.S. patent application number 09/781376 was filed with the patent office on 2001-07-26 for composition and method for treating allergic diseases.
Invention is credited to Shih, Neng-Yang.
Application Number | 20010009918 09/781376 |
Document ID | / |
Family ID | 26800814 |
Filed Date | 2001-07-26 |
United States Patent
Application |
20010009918 |
Kind Code |
A1 |
Shih, Neng-Yang |
July 26, 2001 |
Composition and method for treating allergic diseases
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.
Inventors: |
Shih, Neng-Yang; (North
Carldwell, NJ) |
Correspondence
Address: |
SCHERING-PLOUGH CORPORATION
PATENT DEPARTMENT (K-6-1, 1990)
2000 GALLOPING HILL ROAD
KENILWORTH
NJ
07033-0530
US
|
Family ID: |
26800814 |
Appl. No.: |
09/781376 |
Filed: |
January 12, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09781376 |
Jan 12, 2001 |
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09413025 |
Oct 6, 1999 |
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6221880 |
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60103756 |
Oct 9, 1998 |
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Current U.S.
Class: |
514/311 ;
514/220; 514/253.01; 514/300 |
Current CPC
Class: |
A61K 31/47 20130101;
A61K 31/405 20130101; A61K 31/41 20130101; A61K 31/41 20130101;
A61K 31/445 20130101; A61K 31/405 20130101; A61K 2300/00 20130101;
A61K 2300/00 20130101; A61K 2300/00 20130101; A61K 31/47 20130101;
A61K 2300/00 20130101; A61K 31/445 20130101 |
Class at
Publication: |
514/311 ;
514/253.01; 514/220; 514/300 |
International
Class: |
A61K 031/55; A01N
043/62; A61K 031/497; A61K 031/44; A01N 043/42; A61K 031/47 |
Claims
What is claimed is:
1. A pharmaceutical composition comprising, in combination, 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.
2. The pharmaceutical composition of claim 1, wherein said
neurokinin antagonist or its pharmaceutically acceptable derivative
is present in amounts of 1-1,000 milligrams per unit dosage 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 dosage 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 dosage 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
dosage 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
dosage 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
dosage of said pharmaceutical composition.
8. The pharmaceutical composition of claim 1, wherein said
neurokinin antagonist is a piperidine, piperazine, oxime,
hydrazone, olefin, quinoline, isoquinoline, nitroalkane, amide,
isoxazoline, azanorbornane, naphthyridine, benzodiazepine, or aryl
alkyl amine.
9. The pharmaceutical composition of claim 1, wherein said
neurokinin antagonist is a compound having the general formula:
7wherein Z is 8where B is OR.sub.2; NR.sub.6COR.sub.2,
CONR.sub.6R.sub.7 or NR.sub.2CONR.sub.6R.sub.7, m=0 or 1, P is
R.sub.5-aryl; or R.sub.5-heteroaryl; and Y is H,
CR.sub.2R.sub.3CO.sub.2R.sub.6; CR.sub.2R.sub.3CONR.sub.6R.sub.7 or
CR.sub.2R.sub.3NR.sub.6COR.sub.2; a=b=0, 1 or 2; Q has the same
definitions as P above, with the proviso that P and Q may be the
same or different; A is .dbd.N--OR.sub.1; .dbd.N--NR.sub.2R.sub.3;
or .dbd.CR.sub.1R.sub.2; X is --O--; --NR.sub.6--;
--N(R.sub.6)CO--; or --CO--NR.sub.6--; T is R.sub.4-aryl;
R.sub.4-heteroaryl; R.sub.4-cycloalkyl; or R.sub.2-bridged
cycloalkyl; R.sub.1 is H, C.sub.1-C.sub.6 alkyl; or
(CH.sub.2).sub.n--G where n=1-6; G is H; R.sub.4-aryl;
R.sub.4-heteroaryl; COR.sub.6; CO.sub.2R.sub.6; CONR.sub.6R.sub.7;
CN; OCOR.sub.6; SO.sub.3R.sub.2; C(.dbd.NOR.sub.2)NR.sub.6R.sub.7;
C(.dbd.NR.sub.2)NR.sub.6R.sub.7, with the proviso that when
n.noteq.1, G can additionally be OR.sub.6, NR.sub.6R.sub.7 or
NR.sub.6(CO)R.sub.7; R.sub.2 and R.sub.3 are independently H or
C.sub.1-C.sub.6 alkyl; R.sub.4 and R.sub.5 are independently 1, 2
or 3 substituents independently selected from OR.sub.2,
OC(O)R.sub.2, OC(O)NR.sub.6R.sub.7, C.sub.1-C.sub.6 alkyl, H,
halogen, CF.sub.3, C.sub.2F.sub.5, or OCF.sub.3; and R.sub.6 and
R.sub.7 are independently selected from H or C.sub.1-C.sub.6 alkyl,
with the proviso that when R.sub.6 and R.sub.7 are part of
NR.sub.6R.sub.7 then said NR.sub.6R.sub.7 may form part of a
C.sub.5-C.sub.6 ring wherein 0-2 ring members are selected from the
group consisting of --O--, --S-- and --NR.sub.2--, with the further
proviso that said C.sub.5-C.sub.6 ring may contain substituents on
said ring with said substituents being selected from the group
consisting of hydrogen, halogen, --OR.sub.6 and --COOR.sub.6.
10. The pharmaceutical composition of claim 1, wherein said
neurokinin antagonist is a compound having the general formula:
9and stereoisomers thereof, where R.dbd.H; CH.sub.2CONH.sub.2;
CH.sub.2CONHMe; CH.sub.2CONMe.sub.2 or 10
11. The pharmaceutical composition of claim 1, wherein said
neurokinin antagonist is a compound having the general formula:
11where R is H; CH.sub.2CONH.sub.2; CH.sub.2CONHMe;
CH.sub.2CONMe.sub.2 or 12
12. The pharmaceutical composition of claim 11, wherein said
neurokinin antagonist is the compound where R is
CH.sub.2CONH.sub.2.
13. The pharmaceutical composition of claim 11, wherein said
neurokinin antagonist is the compound where R is
CH.sub.2CONHMe.
14. The pharmaceutical composition of claim 1, wherein said
leukotriene antagonist is selected from the group consisting of
montelukast, montelukast sodium, pranlukast, zafirlukast and
CP-195494.
15. The pharmaceutical composition of claim 14, wherein said
leukotriene antagonist is montelukast sodium.
16. The pharmaceutical composition of claim 1, additionally
containing one or more materials selected from the group consisting
of a pharmaceutically acceptable carrier, a decongestant, a cough
suppressant and an expectorant.
17. A method for the treatment of asthma, allergic rhinitis,
chronic obstructive pulmonary disease, sneezing, itching runny
nose, nasal congestion, redness of the eye, tearing, itching of the
ears or palate, wheezing, coughs associated with postnasal drip
symptoms and respiratory disorders associated with allergy in a
mammalian organism in need of such treatment, said treatment
comprising: administering a pharmaceutical composition comprising,
in combination, 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.
18. A pharmaceutical composition comprising, in combination, 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 inhibitor of
5-lipoxygenase or a pharmaceutically acceptable derivative
thereof.
19. The pharmaceutical composition of claim 18, wherein said
neurokinin antagonist is a piperidine, piperazine, oxime,
hydrazone, olefin, quinoline, isoquinoline, nitroalkane, amide,
isoxazoline, azanorbornane, naphthyridine, benzodiazepine, or aryl
alkyl amine.
20. The pharmaceutical composition of claim 18, wherein said
neurokinin antagonist is a compound having the general formula:
13wherein Z is 14where B is OR.sub.2; NR.sub.6COR.sub.2,
CONR.sub.6R.sub.7 or NR.sub.2CONR.sub.6R.sub.7, m=0 or 1, P is
R.sub.5-aryl; or R.sub.5-heteroaryl; and Y is H,
CR.sub.2R.sub.3CO.sub.2R.sub.6; CR.sub.2R.sub.3CONR.sub.6R.sub.7 or
CR.sub.2R.sub.3NR.sub.6COR.sub.2; a=b=0, 1 or 2; Q has the same
definitions as P above, with the proviso that P and Q may be the
same or different; A is .dbd.N--OR.sub.1; .dbd.N--NR.sub.2R.sub.3;
or .dbd.CR.sub.1R.sub.2; X is --O--; --NR.sub.6--;
--N(R.sub.6)CO--; or --CO--NR.sub.6--; T is R.sub.4-aryl;
R.sub.4-heteroaryl; R.sub.4-cycloalkyl; or R.sub.2-bridged
cycloalkyl; R.sub.1 is H, C.sub.1-C.sub.6 alkyl; or
(CH.sub.2).sub.n--G where n=1-6; G is H; R.sub.4-aryl;
R.sub.4-heteroaryl; COR.sub.6; CO.sub.2R.sub.6; CONR.sub.6R.sub.7;
CN; OCOR.sub.6; SO.sub.3R.sub.2; C(.dbd.NOR.sub.2)NR.sub.6R.sub.7;
C(.dbd.NR.sub.2)NR.sub.6R.sub.7, with the proviso that when
n.noteq.1, G can additionally be OR.sub.6, NR.sub.6R.sub.7 or
NR.sub.6(CO)R.sub.7; R.sub.2 and R.sub.3 are independently H or
C.sub.1-C.sub.6 alkyl; R.sub.4 and R.sub.5 are independently 1, 2
or 3 substituents independently selected from OR.sub.2,
OC(O)R.sub.2, OC(O)NR.sub.6R.sub.7, C.sub.1-C.sub.6 alkyl, H,
halogen, CF.sub.3, C.sub.2F.sub.5, or OCF.sub.3; and R.sub.6 and
R.sub.7 are independently selected from H or C.sub.1-C.sub.6 alkyl,
with the proviso that when R.sub.6 and R.sub.7 are part of
NR.sub.6R.sub.7 then said NR.sub.6R.sub.7 may form part of a
C.sub.5-C.sub.6 ring wherein 0-2 ring members are selected from the
group consisting of --O--, --S-- and --NR.sub.2--, with the further
proviso that said C.sub.5-C.sub.6 ring may contain substituents on
said ring with said substituents being selected from the group
consisting of hydrogen, halogen, --OR.sub.6 and --COOR.sub.6.
21. The pharmaceutical composition of claim 18, wherein said
neurokinin antagonist is a compound having the general formula:
15and stereoisomers thereof, where R.dbd.H; CH.sub.2CONH.sub.2;
CH.sub.2CONHMe; CH.sub.2CONMe.sub.2 or 16
22. The pharmaceutical composition of claim 18, wherein said
neurokinin antagonist is a compound having the general formula:
17where R is H; CH.sub.2CONH.sub.2; CH.sub.2CONHMe;
CH.sub.2CONMe.sub.2 or 18
23. The pharmaceutical composition of claim 18, wherein said
neurokinin antagonist is present in amounts of about 1-1,000
milligrams per unit dosage of said composition.
24. The pharmaceutical composition of claim 18, wherein said
inhibitor of 5-lipoxygenase is present in amounts of about 2-500
milligrams per unit dosage of said composition.
25. The pharmaceutical composition of claim 18, wherein said
inhibitor of 5-lipoxygenase is Zileuton or Atreluton.
26. The pharmaceutical composition of claim 25, wherein said
inhibitor of 5-lipoxygenase is Zileuton.
27. The composition of claim 18, additionally containing one or
more materials selected from the group consisting of a
pharmaceutically acceptable carrier, a decongestant, a cough
suppressant and an expectorant.
28. A method for the treatment of asthma, allergic rhinitis,
chronic obstructive pulmonary disease, sneezing, itching runny
nose, nasal congestion, redness of the eye, tearing, itching of the
ears or palate, wheezing, coughs associated with postnasal drip
symptoms and respiratory disorders associated with allergy in a
mammalian organism in need of such treatment, said treatment
comprising: administering a pharmaceutical composition comprising,
in combination, 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
inhibitor of 5-lipoxygenase or a pharmaceutically acceptable
derivative thereof.
29. The method of claim 17 or claim 28, wherein said neurokinin
antagonist is a compound having the general formula: 19wherein Z is
20where B is OR.sub.2; NR.sub.6COR.sub.2, CONR.sub.6R.sub.7 or
NR.sub.2CONR.sub.6R.sub- .7, m=0 or 1, P is R.sub.5-aryl; or
R.sub.5-heteroaryl; and Y is H, CR.sub.2R.sub.3CO.sub.2R.sub.6;
CR.sub.2R.sub.3CONR.sub.6R.sub.7 or
CR.sub.2R.sub.3NR.sub.6COR.sub.2; a=b=0, 1 or 2; Q has the same
definitions as P above, with the proviso that P and Q may be the
same or different; A is .dbd.N--OR.sub.1; .dbd.N--NR.sub.2R.sub.3;
or .dbd.CR.sub.1R.sub.2; X is --O--; --NR.sub.6--;
--N(R.sub.6)CO--; or --CO--NR.sub.6--; T is R.sub.4-aryl;
R.sub.4-heteroaryl; R.sub.4-cycloalkyl; or R.sub.2-bridged
cycloalkyl; R.sub.1 is H, C.sub.1-C.sub.6 alkyl; or
(CH.sub.2).sub.n--G where n=1-6; G is H; R.sub.4-aryl;
R.sub.4-heteroaryl; COR.sub.6; CO.sub.2R.sub.6; CONR.sub.6R.sub.7;
CN; OCOR.sub.6; SO.sub.3R.sub.2; C(.dbd.NOR.sub.2)NR.sub.6R.sub.7;
C(.dbd.NR.sub.2)NR.sub.6R.sub.7, with the proviso that when
n.noteq.1, G can additionally be OR.sub.6, NR.sub.6R.sub.7 or
NR.sub.6(CO)R.sub.7; R.sub.2 and R.sub.3 are independently H or
C.sub.1-C.sub.6 alkyl; R.sub.4 and R.sub.5 are independently 1, 2
or 3 substituents independently selected from OR.sub.2,
OC(O)R.sub.2, OC(O)NR.sub.6R.sub.7, C.sub.1-C.sub.6 alkyl, H,
halogen, CF.sub.3, C.sub.2F.sub.5, or OCF.sub.3; and R.sub.6 and
R.sub.7 are independently selected from H or C.sub.1-C.sub.6 alkyl,
with the proviso that when R.sub.6 and R.sub.7 are part of
NR.sub.6R.sub.7 then said NR.sub.6R.sub.7 may form part of a
C.sub.5-C.sub.6 ring wherein 0-2 ring members are selected from the
group consisting of --O--, --S-- and --NR.sub.2--, with the further
proviso that said C.sub.5-C.sub.6 ring may contain substituents on
said ring with said substituents being selected from the group
consisting of hydrogen, halogen, --OR.sub.6 and --COOR.sub.6.
30. The method of claim 17 or claim 28, wherein said leukotriene
antagonist is selected from the group consisting of montelukast,
montelukast sodium, pranlukast, zafirlukast and CP-195494.
31. The method of claim 17 or claim 28, wherein said inhibitor of
5-lipoxygenase is Zileuton or Atreluton.
Description
FIELD OF THE INVENTION
[0001] The present invention generally relates to compositions and
methods for treating allergic rhinitis and other respiratory
diseases. It specifically discloses compositions which comprise (i)
combinations of antagonists of neurokinin receptors and antagonists
of leukotriene receptors, and (ii) combinations of antagonists of
neurokinin receptors and inhibitors of 5-lipoxygenase, as well as
methods for treating the above-noted diseases using such
compositions.
BACKGROUND OF THE INVENTION
[0002] Neurokinin ("NK") receptors such as the NK, and the NK.sub.2
receptors are found in the central nervous system and the
circulatory system and the peripheral tissues of mammals, and are
involved in a variety of biological processes. Antagonists of the
neurokinin receptors are, therefore, expected to be useful in the
treatment or prevention of various mammalian diseases such as, for
example, pulmonary disorders such as asthma, cough, bronchospasm,
chronic obstructive pulmonary diseases, and airway hyperactivity;
skin disorders and itch, for example, atopic dermatitis, and
cutaneous wheal and flare; neurogenic inflammatory diseases such
as, arthritis, migraine, nociception; CNS diseases such as anxiety,
emesis, Parkinson's disease, movement disorders and psychosis;
convulsive disorders, renal disorders, urinary incontinence, ocular
inflammation, inflammatory pain, and eating disorders such as food
intake inhibition; allergic rhinitis, neurodegenerative disorders,
psoriasis, Huntington's disease, depression and various disorders
such as Crohn's disease. NK.sub.1 receptors have been reported to
be involved in microvascular leakage and mucus secretion, and
NK.sub.2 receptors have been associated with smooth muscle
contraction, making NK.sub.1 and NK.sub.2 receptor antagonists
especially useful in the treatment and prevention of asthma.
NK.sub.1 and NK.sub.2 receptor antagonists have been reported such
as, for example, in U.S. Pat. Nos. 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-Plough Corporation, Madison, N.J.); and
in "Recent Advances in Neurokinin Receptor Antagonists", by C. J.
Ohnmacht Jr., et al, Annual Reports in Medicinal Chemistry, A. M.
Doherty Ed., 33, 71-80 (1998).
[0003] The products of the 5-lipoxygenase ("5-LO") pathway of
arachidonic acid metabolism, particularly the leukotrienes, can
mediate bronchoconstriction, mucous secretion, airway mucosal
edema, chemotaxis and mobilization of cells into the airway in the
inflammatory process of asthma. Therefore, inhibition of 5-LO
should help cure, reduce or prevent such diseases. Similarly,
leukotriene ("LK") antagonists play a role in treating the
multitude of symptoms associated with diseases of the respiratory
tract, such as season allergic rhinitis, perennial allergic
rhinitis, common colds, sinusitis and concomitant symptoms
associated with allergic asthma. The symptoms of such diseases may
include sneezing, itching runny nose, nasal congestion, redness of
the eye, tearing, itching of the ears or palate, and coughs
associated with postnasal drip. A discussion of leukotriene
receptors may be found in R. Robertson, Prostaglandins, 31, 395
(1986), and a discussion 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).
[0004] It would be highly desirable to enhance the efficacy of the
neurokinin antagonists to improve their overall efficacy, as well
as to reduce or prevent the above-noted ailments by interfering
with the activity of 5-LO and leukotriene receptors.
SUMMARY OF THE INVENTION
[0005] The afore-mentioned objective and other objectives and
desires are addressed by the present invention which, in one
embodiment, provides a composition for treating and preventing
allergic rhinitis and other respiratory diseases such asthma,
cough, wheezing and the like. The inventive composition 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 of the antagonists
may be substituted by a pharmaceutically acceptable derivative such
as salt, ester, and the like. Optionally, the composition may
additionally contain a pharmaceutically acceptable carrier, a
decongestant (such as, for example, pseudoephedrine), a cough
suppressant (such as, for example, dexrtomethorphan), expectorant
(such as, for example, guaifenesin), analgesics (such as, for
example, aspirin, ibuprofen and acetaminophen) or mixtures
thereof.
[0006] Generally, the amount of the neurokinin antagonist content
in the inventive composition per unit dosage form 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.
[0007] The present invention additionally provides a composition
for treating and preventing allergic rhinitis and other respiratory
diseases such asthma, cough, wheezing and the like, the composition
comprising, 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
may be substituted by a pharmaceutically acceptable derivative such
as salt, ester, and the like. Additionally, the composition may
contain a pharmaceutically acceptable carrier, a decongestant, a
cough suppressant, and expectorant, or mixtures thereof.
[0008] The invention further provides methods for treating asthma,
chronic obstructive pulmonary disease ("COPD"), and allergic
disorders, sneezing, itching runny nose, nasal congestion, redness
of the eye, tearing, itching of the ears or palate, sinusitis, and
coughs associated with postnasal drip symptoms in a mammalian
organism in need of such treatment comprising administering the
pharmaceutical compositions described above.
DETAILED DESCRIPTION OF THE INVENTION
[0009] In one embodiment, the present invention discloses
pharmaceutical compositions that are useful in 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 leukotriene antagonist. One or
more of the antagonists may be substituted by a pharmaceutically
acceptable derivative such as salt, ester, and the like.
[0010] Several neurokinin antagonists that are known currently are
useful in the practice of the present invention. Non-limiting
examples of such useful neurokinin antagonists include, for
example, those belonging to the chemical class of oximes,
hydrazones, piperidines, piperazines, aryl alkyl amines,
hydrazones, nitroalkanes, amides, isoxazolines, quinolines,
isoquinolines, azanorbornanes, naphthyridines, benzodiazepines and
the like. Many are disclosed in the U.S. patents cited earlier in
this patent application. Preferred NK antagonists are those
disclosed in the above-noted U.S. Pat. Nos. 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 of so-disclosed compounds
is: 1
[0011] wherein Z is 2
[0012] where B is OR.sub.2; NR.sub.6COR.sub.2, CONR.sub.6R.sub.7 or
NR.sub.2CONR.sub.6R.sub.7,
[0013] m=0 or 1,
[0014] P is R.sub.5-aryl; or R.sub.5-heteroaryl; and
[0015] Y is H, CR.sub.2R.sub.3CO.sub.2R.sub.6;
CR.sub.2R.sub.3CONR.sub.6R.- sub.7 or
CR.sub.2R.sub.3NR.sub.6COR.sub.2;
[0016] a=b=0, 1 or 2;
[0017] Q has the same definitions as P above, with the proviso that
P and Q may be the same or different;
[0018] A is .dbd.N--OR.sub.1; .dbd.N--NR.sub.2R.sub.3; or
.dbd.CR.sub.1R.sub.2;
[0019] X is --O--; --NR.sub.6--; --N(R.sub.6)CO--; or
--CO--NR.sub.6--;
[0020] T is R.sub.4-aryl; R.sub.4-heteroaryl; R.sub.4-cycloalkyl;
or R.sub.2-bridged cycloalkyl;
[0021] R.sub.1 is H, C.sub.1-C.sub.6 alkyl; or (CH.sub.2).sub.n--G
where n=1-6;
[0022] G is H; R.sub.4-aryl; R.sub.4-heteroaryl; COR.sub.6;
CO.sub.2R.sub.6; CONR.sub.6R.sub.7; CN; OCOR.sub.6;
SO.sub.3R.sub.2;
[0023] C(.dbd.NOR.sub.2)NR.sub.6R.sub.7;
C(.dbd.NR.sub.2)NR.sub.6R.sub.7, with the proviso that when
n.noteq.1, G can additionally be OR.sub.6, NR.sub.6R.sub.7 or
NR.sub.6(CO)R.sub.7;
[0024] R.sub.2 and R.sub.3 are independently H or C.sub.1-C.sub.6
alkyl;
[0025] R.sub.4 and R.sub.5 are independently 1, 2 or 3 substituents
independently selected from OR.sub.2, OC(O)R.sub.2,
OC(O)NR.sub.6R.sub.7, C.sub.1-C.sub.6 alkyl, H, halogen, CF.sub.3,
C.sub.2F.sub.5, or OCF.sub.3; and
[0026] R.sub.6 and R.sub.7 are independently selected from H or
C.sub.1-C.sub.6 alkyl, with the proviso that when R.sub.6 and
R.sub.7 are part of NR.sub.6R.sub.7 then said NR.sub.6R.sub.7 may
form part of a C.sub.5-C.sub.6 ring wherein 0-2 ring members are
selected from the group consisting of --O--, --S-- and
--NR.sub.2--, with the further proviso that said C.sub.5-C.sub.6
ring may contain substituents on said ring with said substituents
being selected from the group consisting of hydrogen, halogen,
--OR.sub.6 and --COOR.sub.6.
[0027] Particularly preferred neurokinin antagonists are those
disclosed in the above-mentioned U.S. patents, and belonging to the
general formula: 3
[0028] and stereoisomers thereof. More particularly preferred are
the stereoisomers with the general formula: 4
[0029] where R is H; CH.sub.2CONH.sub.2; CH.sub.2CONHMe;
CH.sub.2CONMe.sub.2 or 5
[0030] Illustrative non-limiting examples of leukotriene
antagonists useful in the practice of the present invention include
montelukast (from Merck & Company), pranlukast (from Ono
Pharmaceutical Company Limited, CAS Registry Number: 103177-37-3),
zafirlukast (from Zeneca Pharmaceuticals; CAS Registry Number:
107753-78-6), CP-195494 (from Pfizer, Incorporated), and the like.
The technical name of montelukast is
[R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydro-
xy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetic acid.
The technical name of pranlukast is
N-[4-oxo-2-(1H-tetrazol-5-yl)-4H-1-benzop-
yran-8-yl]-4-(4-phenylbutoxy)-benzamide. The technical name of
zafirlukast is
[3-[[2-methoxy-4-[[[2-methylphenyl)sulfonyl]amino]carbonyl]phenyl]meth-
yl]-1-methyl-1H-indol-5-yl]-carbamic acid, cyclopentylester,
disclosed in EP-00199543. A particularly useful leukotriene is
montelukast. Montelukast is a leukotriene D4 antagonist capable of
antagonizing the receptors for the 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 Number: 151767-02-1).
[0031] In another embodiment, this invention discloses other
pharmaceutical compositions that are useful in 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 inhibitor of 5-lipoxygenase. One
or more of the compounds may be substituted by a pharmaceutically
acceptable derivative such as salt, ester, and the like.
[0032] Non-limiting examples of useful neurokinin antagonists are
those that are disclosed in the above-cited U.S. patents,
including, for example, the compounds where R is H;
CH.sub.2CONH.sub.2; CH.sub.2CONHMe; CH.sub.2CONMe.sub.2 or 6
[0033] Useful 5-LO inhibitors include, for example, Zileuton (from
Abbott Laboratories, CAS Registry Number: 111406-87-2) and
Atreluton (from Abbott Laboratories, CAS Registry 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-th-
ienyl]-1-methyl-2-propynyl]-N-hydroxyurea.
[0034] In yet another embodiment, this invention discloses a method
for the treatment of asthma, allergic rhinitis, and other allergic
disorders, sneezing, itching runny nose, nasal congestion, redness
of the eye, tearing, itching of the ears or palate, wheezing,
sinusitis, and coughs associated with postnasal drip symptoms in a
mammalian organism in need of such treatment comprising
administering a pharmaceutical composition which comprises the
neurokinin antagonist and the leukotriene antagonist as described
above.
[0035] In a further embodiment, the present invention teaches a
method for the treatment of asthma, allergic rhinitis, and other
allergic disorders, sneezing, itching runny nose, nasal congestion,
redness of the eye, tearing, itching of the ears or palate,
wheezing, sinusitis, and coughs associated with postnasal drip
symptoms in a mammalian organism in need of such treatment
comprising administering a pharmaceutical composition which
comprises the neurokinin antagonist and the 5-LO inhibitor as
described above.
[0036] In the pharmaceutical compositions and methods of the
present invention, the active ingredients will typically be
administered in admixture with suitable pharmaceutical diluents,
excipients or carriers (collectively referred to herein as carrier
materials) suitably selected with respect to the intended form of
administration, i.e. oral tablets, capsules (either solid-filled,
semi-solid filled or liquid filled), powders for constitution, oral
gels, elixirs, dispersible granules, syrups, suspensions, and the
like, and consistent with conventional pharmaceutical practices.
For example, for oral administration in the form of tablets or
capsules, the active drug component may be combined with any oral
non-toxic pharmaceutically acceptable inert carrier, such as
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 may
also be incorporated in the mixture. Powders and tablets may be
comprised of from about 5 to about 95 percent inventive
composition. Suitable binders include starch, gelatin, natural
sugars, corn sweeteners, natural and synthetic gums such as acacia,
sodium alginate, carboxymethylcellulose, 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 may also be included where appropriate.
Some of the terms noted above, namely disintegrants, diluents,
lubricants, binders and the like, are discussed in more detail
below.
[0037] Additionally, the compositions of the present invention may
be formulated in sustained release form to provide the rate
controlled release of any one or more of the components or active
ingredients to optimize the therapeutic effects, i.e. neurokinin
antagonism, leukotriene antagonism, 5-LO inhibition and the like.
Suitable dosage forms for sustained release include layered tablets
containing layers of varying disintegration rates or controlled
release polymeric matrices impregnated with the active components
and shaped in tablet form or capsules containing such impregnated
or encapsulated porous polymeric matrices.
[0038] Liquid form preparations include solutions, suspensions and
emulsions. As an example may be mentioned water or water-propylene
glycol solutions for parenteral injections or addition of
sweeteners and opacifiers for oral solutions, suspensions and
emulsions. Liquid form preparations may also include solutions for
intranasal administration.
[0039] 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 inert compressed
gas, e.g. nitrogen.
[0040] 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 ingredient is dispersed homogeneously
therein by stirring or similar mixing. The molten homogeneous
mixture is then poured into convenient sized molds, allowed to cool
and thereby solidify.
[0041] Also included solid form preparations which are intended to
be converted, shortly before use, to liquid form preparations for
either oral or parenteral administration. Such liquid forms include
solutions, suspensions and emulsions.
[0042] The compounds of the invention may also be deliverable
transdermally. The transdermal compositions may take the form of
creams, lotions, aerosols and/or emulsions and can be included in a
transdermal patch of the matrix or reservoir type as a re
conventional in the art for this purpose.
[0043] Preferably the compound is administered orally.
[0044] Preferably, the pharmaceutical preparation is in a unit
dosage form. In such form, the preparation is subdivided into
suitably sized unit doses containing appropriate quantities of the
active components, e.g., an effective amount to achieve the desired
purpose.
[0045] The quantity of the inventive active composition in a unit
dose of preparation may be generally varied or adjusted from about
0.01 milligrams to about 1,000 milligrams, preferably from about
0.01 to about 750 milligrams, more preferably from about 0.01 to
about 500 milligrams, and typically from about 0.01 to about 250
milligrams, according to the particular application. The actual
dosage employed may be varied depending upon the patient's age,
sex, weight and severity of the condition being treated. Such
techniques are well 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 the
administration will be regulated according to the judgment of the
attending clinician. A generally recommended daily dosage regimen
for oral administration may range from about 0.04 milligrams to
about 4,000 milligrams per day, in single or divided doses.
[0046] Capsule--refers to a special container or enclosure made of
methyl cellulose, polyvinyl alcohols, or denatured gelatins or
starch for holding or containing compositions comprising the active
ingredients. Hard shell capsules are typically made of blends of
relatively high gel strength bone and pork skin gelatins. The
capsule itself may contain small amounts of dyes, opaquing agents,
plasticizers and preservatives.
[0047] Tablet--refers to a compressed or molded solid dosage form
containing the active ingredients with suitable diluents. The
tablet can be prepared by compression of mixtures or granulations
obtained by wet granulation, dry granulation or by compaction.
[0048] Oral gels--refers to the active ingredients dispersed or
solubilized in a hydrophillic semi-solid matrix.
[0049] Powders for constitution refers to powder blends containing
the active ingredients and suitable diluents which can be suspended
in water or juices.
[0050] Diluent--refers to substances that usually make up the major
portion of the composition or dosage form. Suitable diluents
include sugars such as lactose, sucrose, mannitol and sorbitol;
starches derived from wheat, corn rice and potato; and celluloses
such as microcrystalline cellulose. The amount of diluent in the
composition can range from about 10 to about 90% by weight of the
total composition, preferably from about 25 to about 75%, more
preferably from about 30 to about 60% by weight, even more
preferably from about 12 to about 60%.
[0051] Disintegrants--refers to materials added to the composition
to help it break apart (disintegrate) and release the medicaments.
Suitable disintegrants include starches; "cold water soluble"
modified starches such as sodium carboxymethyl starch; natural and
synthetic gums such as locust bean, karaya, guar, tragacanth and
agar; cellulose derivatives such as methylcellulose and sodium
carboxymethylcellulose; microcrystalline celluloses and
cross-linked microcrystalline celluloses such as sodium
croscarmellose; alginates such as alginic acid and sodium alginate;
clays such as bentonites; and effervescent mixtures. The amount of
disintegrant in the composition can range from about 2 to about 15%
by weight of the composition, more preferably from about 4 to about
10% by weight.
[0052] Binders--refers to substances that bind or "glue" powders
together and make them cohesive by forming granules, thus serving
as the "adhesive" in the formulation. Binders add cohesive strength
already available in the diluent or bulking agent. Suitable binders
include sugars such as sucrose; starches derived from wheat, corn
rice and potato; natural gums such as acacia, gelatin and
tragacanth; derivatives of seaweed such as alginic acid, sodium
alginate and ammonium calcium alginate; cellulosic materials such
as methylcellulose and sodium carboxymethylcellulose and
hydroxypropylmethylcellulose; polyvinylpyrrolidone; and inorganics
such as magnesium aluminum silicate. The amount of binder in the
composition can 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.
[0053] Lubricant--refers to a substance added to the dosage form to
enable the tablet, granules, etc. after it has been compressed, to
release from the mold or die by reducing friction or wear. Suitable
lubricants include metallic stearates such as magnesium stearate,
calcium stearate or potassium stearate; stearic acid; high melting
point waxes; and water soluble lubricants such as sodium chloride,
sodium benzoate, sodium acetate, sodium oleate, polyethylene
glycols and d'l-leucine. Lubricants are usually added at the very
last step before compression, since they must be present on the
surfaces of the granules and in between them and the parts of the
tablet press. The amount of lubricant in the composition can range
from about 0.2 to about 5% by weight of the composition, preferably
from about 0.5 to about 2%, more preferably from about 0.3 to about
1.5% by weight.
[0054] Glidents--materials that prevent caking and improve the flow
characteristics of granulations, so that flow is smooth and
uniform. Suitable glidents include silicon dioxide and talc. The
amount of glident in the composition can range from about 0.1% to
about 5% by weight of the total composition, preferably from about
0.5 to about 2% by weight.
[0055] Coloring agents--excipients that provide coloration to the
composition or the dosage form. Such excipients can include food
grade dyes and food grade dyes adsorbed onto a suitable adsorbent
such as clay or aluminum oxide. The amount of the coloring agent
can vary from about 0.1 to about 5% by weight of the composition,
preferably from about 0.1 to about 1%.
[0056] Bioavailability--refers to the rate and extent to which the
active drug ingredient or therapeutic moiety is absorbed into the
systemic circulation from an administered dosage form as compared
to a standard or control.
[0057] Conventional methods for preparing tablets are known. Such
methods include dry methods such as direct compression and
compression of granulation produced by compaction, or wet methods
or other special procedures. Conventional methods for making other
forms for administration such as, for example, capsules,
suppositories and the like are also well known.
[0058] It will be apparent to those skilled in the art that many
modifications, variations and alterations to the present
disclosure, both to materials and methods, may be practiced. Such
modifications, variations and alterations are intended to be within
the spirit and scope of the present invention.
* * * * *