Granted Patent B2

US 9,248,126 · App. 13/969,915 · Granted Feb 2, 2016

Abstract

Claims (18)

1. A pharmaceutical formulation comprising an LFA-1 antagonist, wherein the formulation is an inhalation formulation and wherein the LFA-1 antagonist comprises a compound of Formula I or its pharmaceutically acceptable salt or ester, having the following structure:

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(═O)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).

2. The formulation 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 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.

3. The formulation of claim 2 , wherein the LFA-1 antagonist has one of the following formulae:

4. The formulation 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 formulation of claim 1 , wherein the compound is present in an amount effective to antagonize CD11/CD18 receptors associated with leukocytes.

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

7. The formulation of claim 1 , wherein the formulation is in the form of a powder, solution, spray, or inhalant.

8. The formulation 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.

9. The formulation of claim 4 , wherein said intracellular adhesion molecules are selected from ICAM-1, -2 and -3.

Assignments (9)