Treatment of inflammatory disorders of the epithelium with low dose 2,3-benzodiazepines

1 . A method of treating an individual afflicted with an inflammatory disorder of epithelial tissue 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 )hydrocarbyl;

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;

or a pharmaceutically-acceptable salt of such a compound, wherein said compound is administered at a dose of less than about 50 mg/day.

2 . The method according to claim 1 , wherein said compound is administered at a dose of less than about 25 mg/day.

3 . The method according to claim 1 , wherein said compound is administered at a dose of less than about 10 mg/day.

4 . The method according to claim 1 , wherein said compound is administered at a dose of less than about 1 mg/day.

5 . The method according to claim 1 , wherein said compound is administered at a dose of less than about 10 mg/ml.

6 . The method according to claim 1 , wherein said compound is administered at a dose of less than about 1 mg/ml.

7 . The method according to claim 1 , wherein said inflammatory disorder of epithelial tissue is a skin disorder.

8 . The method according to claim 1 , wherein said inflammatory disorder of epithelial tissue is a gastrointestinal disorder.

9 . The method according to claim 1 , wherein the compound is administered intracolonically or topically.

10 . The method according to claim 1 wherein the compound according to formula I comprises a racemic mixture of (R)- and (S)-enantiomers with respect to the absolute conformation at the 5-position of the benzodiazepine ring.

11 . The method according to claim 10 , 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.

12 . The method according to claim 11 , 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—C 6 )alkyl;

n is 1, 2 or 3;

or a pharmaceutically-acceptable salt of such a compound.

13 . The method according to claim 12 , 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.

14 . The method according to claim 13 , wherein the compound is selected from the group consisting of:

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

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

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

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

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

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

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

and pharmaceutically acceptable salts thereof.

15 . The method according to claim 14 , wherein the compound is 1-(3,4-dimethoxy-phenyl)-4-methyl-5-ethyl-7,8-dimethoxy-5H-2,3-benzodiazepine; or

a pharmaceutically acceptable salt thereof.

16 . The method according to claim 1 , wherein said wherein said 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.

17 . The method according to claim 16 , 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.

18 . The method according to claim 17 , 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 —H and —O(C 1 -C 6 )alkyl;

n is 1, 2 or 3;

or a pharmaceutically-acceptable salt of such a compound.

19 . The method according to claim 18 , 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.

20 . The method according to claim 19 , 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;

(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;

and pharmaceutically acceptable salts thereof.

21 . The method according to claim 20 , 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.