Method for the treatment of lymphangioleiomyomatosis (LAM)
View Patent ↗Treatment of lymphangioleiomyomatosis with the MEK1/2 inhibitor CI-1040 delayed the development of primary tumors and blocked the estrogen-induced lung metastases in treated animals. Such treatment also reduced the number of circulating ELT3 cells and decreased their lung colonization after intravenous injection.
1. A method for the treatment of lymphangioleiomyomatosis (LAM) comprising administering to a patient in need of said treatment a therapeutically effective amount of a compound having the formula:
wherein:
R 1 is hydrogen, hydroxy, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, halo, trifluoromethyl, or CN;
R 2 is hydrogen;
R 3 , R 4 , and R 5 independently are hydrogen, hydroxy, halo, trifluoromethyl, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, nitro, CN, or (O or NH) m —(CH 2 ) n —R 9 , where R 9 is hydrogen, hydroxy, CO 2 H or NR 10 R 11 ;
n is 0 to 4;
m is 0 or 1;
R 10 or R 11 independently are hydrogen or C 1 -C 8 alkyl, or taken together with the nitrogen to which they are attached can complete a 3- to 10-member cyclic ring optionally containing one, two, or three additional heteroatoms selected from O, S, NH, or N—C 1 -C 8 alkyl;
R 6 is hydrogen, C 1 -C 8 alkyl,
aryl, aralkyl, or C 3 -C 10 cycloalkyl;
R 7 is hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl,
C 3 -C 10 cycloalkyl (or cycloalkyl optionally containing a heteroatom selected from O, S, or NR 9 );
X is bromine or iodine;
and wherein any of the foregoing alkyl, alkenyl, and alkynyl groups can be unsubstituted or substituted by cycloalkyl (or cycloalkyl optionally containing a heteroatom selected from O, S, or NR 9 ), aryl, aryloxy, heteroaryl, or heteroaryloxy; or R 6 and R 7 taken together with the N—O to which they are attached can complete a 5- to 10-membered cyclic ring, optionally containing one, two, or three additional heteroatoms selected from O, S, or NR 10 R 11 .
2. The method of claim 1 , wherein said compound is formulated with a pharmaceutically acceptable carrier medium for administration to said patient.
3. The method of claim 1 , wherein said compound is 2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro-benzamide.
4. The method of claim 1 , wherein said patient is a mammal.
5. The method of claim 1 , wherein said patient is a human.
6. The method of claim 1 further comprising administration of at least one mTOR inhibitor.
7. The method of claim 6 , wherein said mTOR inhibitor is RAD001.
8. The method of claim 2 , wherein said compound is 2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro-benzamide.