Treatment of LTB4-mediated inflammatory disorders with optically-pure (R)-2,3-benzodiazepines

1. A method of treating an individual afflicted with an inflammatory disorder mediated by LTB 4 comprising administering to said individual an effective amount of at least one compound according to Formula I:

wherein:

R 1 is —(C 1 -C 7 )hydrocarbyl or —(C 2 -C 6 )heteroalkyl;

R 2 is selected from the group consisting of —H, and —(C 1 -C 7 )hydro-carbyl;

wherein R 1 and R 2 may combine to form a carbocyclic or heterocyclic 5- or 6-membered ring;

R 3 is independently selected from the group consisting of —O(C 1 -C 6 )alkyl, —OH, —O-acyl, —SH, —S(C 1 -C 3 )alkyl, —NH 2 , —NH(C 1 -C 6 )alkyl, —N((C 1 -C 6 )alkyl) 2 , —NH-acyl, —NO 2 and halogen;

n is 1, 2 or 3;

R 4 and R 5 are independently selected from the group consisting of —O(C 1 -C 6 )alkyl, —OH, O-acyl, —SH, —S(C 1 -C 3 )alkyl, —NH 2 , NH-acyl and halogen;

wherein, R 4 and R 5 may combine to form a 5, 6 or 7-membered heterocyclic ring; and

wherein, compounds according to formula I are (R)-enantiomers substantially free of the corresponding (S)-enantiomers, with respect to the absolute conformation at the 5-position of the benzodiazepine ring;

or a pharmaceutically-acceptable salt of such a compound.

2. The method of claim 1 , wherein:

R 1 is —(C 1 -C 6 )alkyl;

R 2 is selected from the group consisting of —H and —(C 1 -C 6 )alkyl;

R 3 is independently selected from the group consisting of —O(C 1 -C 6 )alkyl, —O-acyl and —OH;

n is 1, 2 or 3;

R 4 and R 5 are independently selected from the group consisting of —O(C 1 -C 6 )alkyl, —O-acyl and —OH, wherein, R 4 and R 5 may combine to form a 5, 6 or 7-membered heterocyclic ring;

or a pharmaceutically-acceptable salt of such a compound.

3. The method of claim 2 , wherein:

R 1 is —CH 2 CH 3 ;

R 2 is —CH 3

R 3 , R 4 and R 5 are independently selected from the group consisting of —OH and —O(C 1 -C 6 )alkyl;

n is 1, 2 or 3;

or a pharmaceutically-acceptable salt of such a compound.

4. The method of claim 3 , wherein:

R 1 is —CH 2 CH 3 ;

R 2 is —CH 3

R 3 , R 4 and R 5 are independently selected from the group consisting of —OH and —OCH 3 ;

n is of 1,2 or 3;

or a pharmaceutically-acceptable salt of such a compound.

5. The method of claim 4 , wherein the compound is selected from the group consisting of:

(R)-1-(3,4-dimethoxyphenyl)-4-methyl-5-ethyl-7,8-dimethoxy-5H-2,3-benzodiazepine;

(R)-1-(3,4-dimethoxyphenyl)-4-methyl-5-ethyl-7-hydroxy-8-methoxy-5H-2,3-benzodiazepine;

(R)-1-(3-hydroxy-4-methoxyphenyl)-4-methyl-5-ethyl-7,8-dimethoxy-5H-2,3-benzodiazepine;

(R)-1-(3-methoxy-4-hydroxyphenyl)-4-methyl-5-ethyl-7,8-dimethoxy-5H-2,3-benzodiazepine;

(R)-1-(3,4-dimethoxyphenyl)-4-methyl-5-ethyl-7-methoxy-8-hydroxy-5H-2,3-benzodiazepine;

(R)-1-(3-methoxy-4-hydroxyphenyl)-4-methyl-5-ethyl-7-hydroxy-8-methoxy-5H-2,3-benzodiazepine; and

(R)-1-(3-hydroxy-4-methoxyphenyl)-4-methyl-5-ethyl-7-hydroxy-8-methoxy-5H-2,3-benzodiazepine;

substantially free of the corresponding (S)-enantiomers;

or a pharmaceutically acceptable salt thereof.

6. The method of claim 5 , wherein the compound is (R)-1-(3,4-dimethoxy-phenyl)-4-methyl-5-ethyl-7,8-dimethoxy-5H-2,3-benzodiazepine substantially free of the corresponding (S)-enantiomer;

or a pharmaceutically acceptable salt thereof.

7. The method of claim 1 wherein the disorder is inflammatory bowel disease.

8. The method of claim 1 wherein the disorder is ulcerative colitis.

9. The method of claim 1 wherein the disorder is psoriasis.

10. The method of claim 1 wherein the disorder is rheumatoid arthritis.

11. The method of claim 1 wherein the disorder is Crohn's Disease.

12. The method of claim 1 wherein the disorder is radiation-induced gastrointestinal inflammation.