Patent Application

App. No. 16/172,197

Abstract

Claims (24)

1 - 75 . (canceled)

76 . 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 R 1 and R 2 are each independently hydrogen, —(CH 2 ) m OH, —(CH 2 ) m aryl, —(CH 2 ) m heteroaryl, wherein m is 0-6, —CH(R 1A )(OR 1B ), —CH(R 1A )(NHR 1B ), 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 —, —SO 2 N(R 1A ), —N(R 1A )—, —N(R 1A )C(═O)—, —N(R 1A )C(═O)—O—, —N(R 1A )C(═O)—N(R 1B )—, —N(R 1A )—SO 2 —, —C(═O)—, —C(═O)—O—, —O—C(═O)—, aryl, heteroaryl, alkylaryl, alkylheteroaryl, —C(═O)—N(R 1A )—, —O—C(═O)—N(R 1A )—, —C(═N—R 1E )—, —C(═N—R 1E )—O—, —C(═N—R 1E )—N(R 1A )—, —O—C(═N—R 1E )—N(R 1A )—, —N(R 1A )C(═N—R 1E )—, —N(R 1A )C(═N—R 1E )—O—, N(R 1A )C(═N—R 1E )—N(R 1B )—, -P(═O)(OR 1A )—O—, or -P(═O)(R 1A )—O—; T is absent, an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; and Q is hydrogen, halogen, cyano, isocyanate, —OR 1B , —SR 1B ; —N(R 1B ) 2 , —NHC(═O)OR 1B , —NHC(═O)N(R 1B ) 2 , —NHC(═O)R 1B , —NHSO 2 R 1B , —NHSO 2 N(R 1B ) 2 , —NHSO 2 NHC(═O)OR 1B , —NHC(═O)NHSO 2 R 1B , —C(═O)NHC(═O)OR 1B , —C(═O)NHC(═O)R 1B , —C(═O)NHC(═O)N(R 1B ) 2 , —C(═O)NHSO 2 R 1B , —C(═O)NHSO 2 N(R 1B ) 2 , —C(═S)N(R 1B ) 2 , —SO 2 R 1B , —SO 2 —O—R 1B , —SO 2 —N(R 1B ) 2 , —SO 2 —NHC(═ 0 )OR 1B , —SO 2 —NHC(═O)—N(R 1B ) 2 , —SO 2 —NHC(═O)R 1B , —O—C(═O)N(R 1B ) 2 , —O—C(═O)R 1B , —O—C(═O)NHC(═O)R 1B , —O—C(═O)NH—SO 2 R 1B , —O—SO 2 R 1B , or an aliphatic heteroaliphatic, aryl or heteroaryl moiety, or wherein R 1 and R 2 taken together are an alicyclic or heterocyclic moiety; wherein each occurrence of R 1A and R 1B is independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, —COR 1C , or —CONR 1C R 1D ; wherein each occurrence of R 1C and R 1D is independently hydrogen, hydroxyl, or an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; and R 1E is hydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, —CN, —OR 1C , —NR 1C R 1D or —SO 2 R 1C ;

R 3 is —C(═O)OR 3A , —C(═O)H, —CH 2 OR 3A , —CH 2 O—C(═O)-alkyl, —C(═O)NH(R 3A ), —CH 2 X 0 ; wherein each occurrence of R 3A is independently hydrogen, a protecting group, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl or heteroalkylheteroaryl moiety, or R 3A , taken together with R 1 or R 2 , forms a heterocyclic moiety; wherein X 0 is a halogen selected from F, Cl, Br or I;

R 4 , for each occurrence, is independently hydrogen, halogen, —CN, —NO 2 , an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is -GR G1 wherein G is —O—, —S—, —NR G2 —, —CO—, —SO—, —SO 2 —, —C(═O)O—, —C(═O)NR G2 —, —OC(═O)—, —NR G2 C(═O)— or —SO 2 NR G2 —, and R G1 and R G2 are independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety;

n is an integer from 0-4;

AR 1 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 CHR i wherein each occurrence of R i is independently hydrogen, halogen, —CN, —NO 2 , an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is -GR G1 wherein G is —O—, —S—, —NR G2 —, —CO—, —SO—, —SO 2 —, —C(═O)O—, —C(═O)NR G2 —, —OC(═O)—, —NR G2 C(═O)— or —SO 2 NR G2 —, and R G1 and R G2 are independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or any two adjacent occurrences of R i , 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 C 1-6 alkylidene or C 2-6 alkenylidene chain wherein up to two non-adjacent methylene units are independently optionally replaced by —C(═O)—.

77 . The method of claim 76 , wherein the LFA-1 antagonist comprises a compound of Formula I′ or its pharmaceutically acceptable salt or ester, having the following structure:

wherein R 4A and R 4B are independently a halogen selected from F, Cl, Br or I; and R B1 , R B2 and R E are independently hydrogen or substituted or unsubstituted lower alkyl.

78 . The method of claim 77 , wherein the LFA-1 antagonist has one of the following formulae:

79 . The method of claim 76 , wherein the compound is present in an amount effective to modulate adhesion between intracellular adhesion molecules and the leukocyte integrin family of receptors.

80 . The method of claim 76 , wherein the compound is present in an amount effective to antagonize CD11/CD18 receptors associated with leukocytes.

81 . The method of claim 76 , wherein the LFA-1 antagonist is a sodium, potassium, lithium, magnesium, or calcium salt.

82 . The method of claim 76 , 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.

83 . The method of claim 76 , 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.

84 . The method of claim 76 , further comprising a topical penetration enhancer.

85 . The method of claim 84 , 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.

86 . The method of claim 76 , 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.

87 . The method of claim 76 , wherein the formulation is topically applied to skin or eyes.

88 . The method of claim 76 , wherein the inflammatory or immune disorder is psoriasis, responses associated with inflammatory bowel disease, Crohn's disease, ulcerative colitis, dermatitis, meningitis, encephalitis, uveitis, eczema, asthma, conditions involving infiltration of T-cells and chronic inflammatory responses, skin hypersensitivity reactions, artherosclerosis, autoimmune diseases, rheumatoid arthritis, systemic lupus erythematosus (SLE), diabetes mellitus, multiple sclerosis, Reynaud's syndrome, autoimmune thyroiditis, experimental autoimmune encephalomyelitis, Sjorgen's syndrome, juvenile onset diabetes, immune responses associated with delayed hypersensitivity mediated by cytokines and T-lymphocytes, sarcoidosis, polymyositis, granulomatosis, vasculitis, pernicious anemia, diseases involving leukocyte diapedeses, CNS inflammatory disorder, multiple organ injury syndrome secondary to septicaemia or trauma, autoimune hemolytic anemia, myasthemia gravis, antigen-antibody complex mediated diseases, transplantations, HIV, rhinovirus infection, or pulmonary fibrosis.

89 . The method of claim 79 , wherein said intracellular adhesion molecules are selected from ICAM-1, -2 and -3.

Assignments (8)