Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Sulfur – selenium or tellurium compound
Reexamination Certificate
2001-04-25
2002-04-16
Richter, Johann (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Sulfur, selenium or tellurium compound
C568S023000, C568S025000
Reexamination Certificate
active
06372802
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to the treatment of allergic diseases. More particularly, the present invention relates to therapeutic and prophylactic use of certain disulfide derivatives for treating or preventing allergic diseases.
2. Description of the Related Art
Antihistamines and mast cell stabilizers are two types of drugs currently used topically to treat allergic diseases. Antihistamine drugs are used to interrupt the allergic effects that histamine causes after it has been released from a mast cell. Many topical antihistamine drugs are marketed. For example, emedastine difumarate and levocabastine hydrochloride are available for ocular allergies (see
Ophthalmic Drug Facts
1999, Facts and Comparisons, St. Louis, Mo., pp. 59-80).
Mast cell stabilizers prevent mast cells from “degranulating” or releasing histamine and other components or “mediators” during an allergic reaction. Examples of ophthalmic drugs marketed as mast cell stabilizers include olopatadine (see U.S. Pat. No. 5,641,805) and cromolyn sodium.
U.S. Pat. No. 4,705,805 discloses certain disulfide derivatives that are useful as anti-thrombotic agents. The disulfide derivatives suppress blood platelet aggregation. The '705 patent does not disclose the use of disulfide derivatives in the treatment of allergic diseases.
SUMMARY OF THE INVENTION
The present invention provides methods for preventing or treating allergic diseases of the eye, nose, skin, ear, gastrointestinal tract, airways or lung. The methods may also be used to treat manifestations of systemic mastocytosis. The methods of the present invention comprise topically or systemically administering to a patient a mast cell stabilizing disulfide derivative of the formula
wherein X is —NH—C(═O)—R, or —NH—C(═O)—OR;
R=H; (un)substituted phenyl; (un)substituted benzyl; or C
1
-C
8
alkyl or alkenyl, optionally substituted with or terminated by OH, OR
2
, NR
3
R
4
; C
4
-C
7
cycloalkyl, (un)substituted aryl, or (un)substituted 5-7 membered heterocyclic ring; where optional substituents are selected from the group consisting of C
1
-C
6
alkyl or alkoxy; halogen; OH; CN; CF
3
; NO
2
; and CO
2
R
2
;
R
2
=C
1
-C
3
alkyl; and
R
3
and R
4
are independently H; benzyl; C
1
-C
8
alkyl or alkenyl; C
4
-C
7
cycloalkyl; (un)substituted aryl; or (un)substituted 5-7 membered heterocyclic ring; wherein optional substituents are selected from the group consisting of C
1
-C
6
alkyl or alkoxy; halogen; OH; CN; CF
3
; NO
2
; and CO
2
R
2
.
The present invention is also directed toward topically or systemically administrable compositions for treating or preventing allergic diseases of the eye, nose, skin, ear, gastrointestinal tract, airways or lung and treating or preventing manifestations of systemic mastocytosis, wherein the compositions comprise a disulfide derivative of formula (I).
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to novel disulfide derivatives of formula (I) wherein
X is —NH—C(═O)—R;
R is —C(—R
5
)—C═C(—R
6
)R
7
or —C(—R
5
)—C(—OH)R
6
;
R
5
is H, C
1
-C
3
alkyl;
R
6
is H, C
1
-C
3
alkyl or alkenyl; and
R
7
is H, C
1
-C
4
alkyl or alkenyl.
The remaining disulfide derivatives of formula (I) are known or are commercially available from sources such as Aldrich Chemical Company (Sigma Aldrich Library of Rare Chemicals) in Milwaukee, Wis. and Maybridge Chemical Company Ltd. in the U.K. The novel and known disulfide derivatives of formula (I) can be made using known techniques, such as those described in Domagala JM et al.
Biorganic and Medicinal Chemistry
volume 5 No. 3 pages 569-79 (1997), and U.S. Pat. No. 4,705,805 (Yamotsu K. et al., 1987). The entire contents of both of these references are incorporated by reference.
Preferred compounds of formula (I) are those wherein the X substituents are in the ortho position and wherein
X=—NH—C(═O)—R; and
R=C
1
-C
8
alkyl or alkenyl, optionally substituted with or terminated by OH, OR
2
, NR
3
R
4
; C
4
-C
7
cycloalkyl, (un)substituted aryl, or (un)substituted 5-7 membered heterocyclic ring; where optional substituents are selected from the group consisting of C
1
-C
6
alkyl or alkoxy; halogen; OH; CN; CF
3
; NO
2
; and CO
2
R
2
.
Most preferred are compounds wherein R=C
1
-C
5
alkyl or alkenyl, optionally substituted with or terminated by OH, OR
2
, NR
3
R
4
; C
4
-C
7
cycloalkyl, (un)substituted aryl, or (un)substituted 5-7 membered heterocyclic ring; where optional substituents are selected from the group consisting of C
1
-C
6
alkyl or alkoxy; halogen; OH; CN; CF
3
; NO
2
; and CO
2
R
2
.
Compounds of formula (I) may be administered topically (i.e., local, organ-specific delivery) or systemically by means of conventional topical or systemic formulations, such as solutions, suspensions or gels for the eye and ear; nasal sprays or mists for the nose; metered dose inhalers for the lung; solutions, gels, creams or lotions for the skin; oral dosage forms including tablets or syrups for the gastrointestinal tract; and parenteral dosage forms including injectable formulations. The concentration of the compound of formula (I) in the formulations of the present invention will depend on the selected route of administration and dosage form. The concentration of the compound of formula (I) in topically administrable formulations will generally be about 0.00001 to 5 wt. %. For systemically administrable dosage forms, the concentration of the compound of formula (I) will generally range from about 10 mg to 1000 mg.
The preferred formulation for topical ophthalmic administration is a solution intended to be administered as eye drops. For solutions intended for topical administration to the eye, the concentration of the compound of formula (I) is preferably 0.0001 to 0.2 wt. %, and most preferably from about 0.0001 to 0.01 wt. %. The topical compositions of the present invention are prepared according to conventional techniques and contain conventional excipients in addition to one or more compounds of formula (I). A general method of preparing eye drop compositions is described below:
One or more compounds of formula (I) and a tonicity-adjusting agent are added to sterilized purified water and if desired or required, one or more excipients. The tonicity-adjusting agent is present in an amount sufficient to cause the final composition to have an ophthalmically acceptable osmolality (generally about 150-450 mOsm, preferably 250-350 mOsm). Conventional excipients include preservatives, buffering agents, chelating agents or stabilizers, viscosity-enhancing agents and others. The chosen ingredients are mixed until homogeneous. After the solution is mixed, pH is adjusted (typically with NaOH or HCl) to be within a range suitable for topical ophthalmic use, preferably within the range of 4.5 to 8.
Many ophthalmically acceptable excipients are known, including, for example, sodium chloride, mannitol, glycerin or the like as a tonicity-adjusting agent; benzalkonium chloride, polyquaternium-1 or the like as a preservative; sodium hydrogenphosphate, sodium dihydrogenphosphate, boric acid or the like as a buffering agent; edetate disodium or the like as a chelating agent or stabilizer; polyvinyl alcohol, polyvinyl pyrrolidone, polyacrylic acid, polysaccharide or the like as a viscosity-enhancing agent; and sodium hydroxide, hydrochloric acid or the like as a pH controller.
If required or desired, other drugs can be combined with the disulfide derivatives of formula (I), including, but not limited to, antihistaminic agents, anti-inflammatory agents (steroidal and non-steroidal), and decongestants. Suitable antihistaminic agents include emedastine, mapinastine, epinastine, levocabastine, loratadine, desloratadine, ketotifen, azelastine, cetirazine, and fexofenadine. The preferred antihistaminic agent for ophthalmic use is emedastine, which is generally included in topically administrable compositions at a concentration of 0.001-0.1 wt. %, preferably 0.05 wt. %. Suitable anti-infl
Feng Zixia
Hellberg Mark R.
Miller Steven T.
Alcon Universal Ltd.
Richter Johann
Ryan Patrick M.
Witherspoon Sikarl A.
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