Compositions containing a benzamide disulfide derivative for treating allergic diseases

This application claims priority from co-pending U.S. Provisional Application, U.S. Ser. No. 60/206,083, filed May 19, 2000.

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 topical treatment of allergic diseases of the eye or nose.

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 —C(═O)—N(—R 1 )—R;

R and R 1 are independently 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 is 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).

The 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 or can be made using known techniques, such as those described in Domagala J M 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 having the X substituents in the ortho position.

Most preferred are compounds wherein R and R 1 independently=H; 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, 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 .

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-inflammatory agents include mometasone, fluticasone, dexamethasone, prednisolone, hydrocortisone, rimexolone and loteprednol. Suitable decongestants include oxymetazoline, naphazoline, tetrahydrozoline, xylometazoline, propylhexedrine, ethyinorepinephrine, pseudoephedrine, and phenylpropanolamine.

According to the present invention, the disulfide derivatives of formula (I) are useful for preventing and treating ophthalmic allergic disorders, including allergic conjunctivitis, vernal conjunctivitis, vernal keratoconjunctivitis, and giant papillary conjunctivitis; nasal allergic disorders, including allergic rhinitis and sinusitis; otic allergic disorders, including eustachian tube itching; allergic disorders of the upper and lower airways, including intrinsic and extrinsic asthma; allergic disorders of the skin, including dermatitis, eczema and urticaria; allergic disorders of the gastrointestinal tract, including systemic anaphylaxis resulting from ingestion of allergen and iatrogenic anaphylaxis caused by contrast agents used during diagnostic imaging procedures; and manifestations of systemic mastocytosis including hypotension.

The following examples are intended to be illustrative but not limiting.