Claims for Patent: 10,124,000

Summary for Patent: 10,124,000

Title:	Modulators of cellular adhesion
Abstract:	The present invention provides compounds having formula (I):
Inventor(s):	Wang Shen, Kenneth Barr, Johan D. Oslob, Min Zhong
Assignee:	Bausch and Lomb Ireland Ltd
Application Number:	US14/939,600
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 10,124,000
Patent Claims:	1. A method for treatment of an inflammatory or immune related disorder in a subject comprising topically administering to said subject in need thereof a formulation comprising an LFA-1 antagonist and a pharmaceutically acceptable excipient, wherein the LFA-1 antagonist comprises a compound of Formula I or its pharmaceutically acceptable salt or ester, wherein wherein R1 and R2 are each independently hydrogen, —(CH2)mOH, —(CH2)maryl, —(CH2)mheteroaryl, wherein m is 0-6, —CH(R1A)(OR1B), —CH(R1A)(NHR1B), U-T-Q, or an aliphatic, alicyclic, heteroaliphatic or heteroalicyclic moiety optionally substituted with U-T-Q, wherein U is absent, —O—, —S(O)0-2—, —SO2N(R1A), —N(R1A)—, —N(R1A)C(═O)—, —N(R1A)C(═O)—O—, —N(R1A)C(═O)—N(R1B)—, —N(R1A)—SO2—, —C(═O)—, —C(═O)—O—, —O—C(═O)—, aryl, heteroaryl, alkylaryl, alkylheteroaryl, —C(═O)—N(R1A)—, —O—C(═O)—N(R1A)—, —C(═N—R1E)—, —C(═N—R1E)—O—, —C(═N—R1E)—N(R1A)—, —O—C(═N—R1E)—N(R1A)—, —N(R1A)C(═N—R1E)—, —N(R1A)C(═N—R1E)—O—, N(R1A)C(═N—R1E)—N(R1B)—, —P(═O)(OR1A)—O—, or —P(═O)(R1A)—O—; T is absent, an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; and Q is hydrogen, halogen, cyano, isocyanate, —OR1B, —SR1B; —N(R1B)2, —NHC(═O)OR1B, —NHC(═O)N(R1B)2, —NHC(═O)R1B, —NHSO2R1B, —NHSO2N(R1B)2, —NHSO2NHC(═O)OR1B, —NHC(═O)NHSO2R1B, —C(═O)NHC(═O)OR1B, —C(═O)NHC(═O)R1B, —C(═O)NHC(═O)N(R1B)2, —C(═O)NHSO2R1B, —C(═O)NHSO2N(R1B)2, —C(═S)N(R1B)2, —SO2R1B, —SO2—O—R1B, —SO2—N(R1B)2, —SO2—NHC(═O)OR1B, —SO2—NHC(═O)—N(R1B)2, —SO2—NHC(═O)R1B, —O—C(═O)N(R1B)2, —O—C(═O)R1B, —O—C(═O)NHC(═O)R1B, —O—C(═O)NH—SO2R1B, —O—SO2R1B, or an aliphatic heteroaliphatic, aryl or heteroaryl moiety, or wherein R1 and R2 taken together are an alicyclic or heterocyclic moiety; wherein each occurrence of R1A and R1B is independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, —COR1C, or CONR1CR1D; wherein each occurrence of R1C and R1D is independently hydrogen, hydroxyl, or an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; and R1E is hydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, —CN, —OR1C, —NR1CR1D or —SO2R1C; R3 is C(═O)OR3A, —C(═O)H, —CH2OR3A, —CH2O—C(═O)-alkyl, —C(═O)NH(R3A), —CH2X0; wherein each occurrence of R3A is independently hydrogen, a protecting group, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl or heteroalkylheteroaryl moiety, or R3A, taken together with R1 or R2, forms a heterocyclic moiety; wherein X0 is a halogen selected from F, Cl, Br or I; R4, for each occurrence, is independently hydrogen, halogen, —CN, —NO2, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is —GRG1 wherein G is —O—, —S—, —NRG2—, —CO, —SO—, —SO2—, —C(═O)O—, —C(═O)NRG2—, —OC(═O)—, —NRG2C(═O)— or —SO2NRG2—, and RG1 and RG2 are independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; n is an integer from 0-4; AR1 is a monocyclic or polycyclic aryl, heteroaryl, alkylaryl, alkylheteroaryl, alicyclic or heterocyclic moiety; A, B, D and E are connected by single bonds; wherein D is N and each occurrence of A, B, and E is independently CHRi wherein each occurrence of Ri is independently hydrogen, halogen, —CN, —NO2, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is —GRG1 wherein G is —O—, —S—, —NRG2—, —CO—, —SO—, —SO2—, —C(═O)O—, —C(═O)NRG2—, —OC(═O)—, —NRG2C(═O)— or —SO2NRG2—, and RG1 and RG2 are independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or any two adjacent occurrences of Ri, taken together, represent an alicyclic, heteroalicyclic, aryl, or heteroaryl moiety; p is an integer from 0-4; and L is C═O or a substituted or unsubstituted C1-6alkylidene or C2-6alkenylidene chain wherein up to two non-adjacent methylene units are independently optionally replaced by —C(═O)—, the inflammatory or immune related disorder is selected from the group consisting of psoriasis; inflammatory bowel disease; adult respiratory distress syndrome; dermatitis; meningitis; uveitis; eczema; asthma; poison ivy; poison oak; Sjorgen's syndrome; pulmonary fibrosis; and rheumatoid arthritis. 2. The method of claim 1, wherein the LFA-1 antagonist comprises a compound of Formula I′ or its pharmaceutically acceptable salt or ester, having the following structure: wherein R4A and R4B are independently a halogen selected from F, Cl, Br or I; and RB1, RB2 and RE are independently hydrogen or substituted or unsubstituted lower alkyl. 3. The method of claim 2, wherein the LFA-1 antagonist has one of the following formulae: 4. The method of claim 1, wherein the compound is present in an amount effective to modulate adhesion between intracellular adhesion molecules and the leukocyte integrin family of receptors. 5. The method of claim 1, wherein the compound is present in an amount effective to antagonize CD11/CD18 receptors associated with leukocytes. 6. The method of claim 1, wherein the LFA-1 antagonist is a sodium, potassium, lithium, magnesium, or calcium salt. 7. The method of claim 1, wherein the formulation is in the form of an ointment, paste, cream, lotion, gel, powder, solution, spray, inhalant, patch, suspension, emulsion, crystalline form, oil, plaster, liposome, microemulsion, or buffered solution. 8. The method of claim 1, wherein the excipient is selected from the group consisting of alcohols, quaternary amines, organic acids, parabens, phenols, ascorbic acid, ascorbic acid esters, sodium bisulfite, butylated hydroxytoluene, butylated hydroxyanisole, tocopherols, chelating agents, glycerine, sorbitol, polyethylene glycols, urea, propylene glycol, citric buffer, hydrochloric buffer, lactic acid buffer, quaternary ammonium chlorides, cyclodextrins, benzyl benzoate, lecithin, polysorbates, vitamin E oil, allatoin, dimethicone, glycerin, petrolatum, zinc oxide, and combinations thereof. 9. The method of claim 1, further comprising a topical penetration enhancer. 10. The method of claim 9, wherein the penetration enhancer is triglycerides, aloe compositions, ethyl alcohol, isopropyl alcohol, octolyphenylpolyethylene glycol, oleic acid, polyethylene glycol 400, propylene glycol, N-decylmethylsulfoxide, fatty acid esters, N-methylpyrrolidone, or combinations thereof. 11. The method of claim 1, further comprising at least one additional therapeutic agent, wherein the additional therapeutic agent is selected from the group consisting of an anti-inflammatory agent, painkillers, antinausea medications, anti-sickness drugs, a MAC-1 modulator, and an LFA-1 modulator. 12. The method of claim 1, wherein the formulation is topically applied to skin or eyes. 13. The method of claim 1, wherein the inflammatory or immune disorder is Sjorgen's syndrome. 14. The method of claim 4, wherein said intracellular adhesion molecules are selected from ICAM-1, -2 and -3.