High penetration prodrug compositions and pharmaceutical composition thereof for treatment of pulmonary conditions
The invention provides compositions of novel high penetration compositions (HPC) or high penetration prodrugs (HPP) for treatment of pulmonary conditions (e.g. asthma). The HPCs/HPPs are capable of being converted to parent active drugs or drug metabolites after crossing the biological barrier and thus can render treatments for the conditions that the parent drugs or metabolites can. Additionally, the HPPs are capable of reaching areas that parent drugs may not be able to access or to render a sufficient concentration at the target areas and therefore render novel treatments. The HPCs/HPPs can be administered to a subject through various administration routes, e.g., locally delivered to an action site of a condition with a high concentration or systematically administered to a biological subject and enter the general circulation with a faster rate.
1. A topical pharmaceutical formulation comprising a pharmaceutically acceptable carrier and a compound of Structure LRA-1:
wherein
X 5 is selected from nothing, C(═O), OC(═O), CH 2 , O, and NR 5 ;
Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , and Y 8 are each independently selected from H, OH, OW, OC(═O)W, OC(═O)CH 3 , CH 2 OR 6 , CH 2 C(═O)OR 5 , OR 6 , CF 3 , OCF 3 , CH 2 (CH 2 ) n OR 6 , F, Br, I, Cl, C(═O)R 5 , (CH 3 ) 2 C(OR 6 )—, CH 3 CH(OH)—, (CH 3 ) 2 CH—, CH 3 CH 2 —, substituted and unsubstituted C 1 -C 30 alkyl, substituted and unsubstituted C 1 -C 30 alkoxyl, and substituted and unsubstituted C 1 -C 30 alkylamino, wherein n is an integer selected from 1 to 10;
R 5 is selected from H, OR 6 , CH 2 CH 2 OR 6 , CH 2 CH 2 N(CH 3 ) 2 , CH 2 CH 2 N(CH 2 CH 3 ) 2 , Cl, F, Br, I, substituted and unsubstituted C 1 -C 30 alkyl, substituted and unsubstituted C 3 -C 30 cycloalkyl, substituted and unsubstituted C 3 -C 30 heterocycloalkyl, substituted and unsubstituted C 1 -C 30 alkyloxyl, substituted and unsubstituted C 3 -C 30 cycloalkyloxyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted C 1 -C 30 alkylcarbonyl, substituted and unsubstituted C 1 -C 30 alkylamino, L 1 -L 4 -L 2 -W, and C—(═O)-W;
R 6 is selected from H, F, Cl, Br, I, C(═O)R 5 , substituted and unsubstituted C 1 -C 30 alkyl, substituted and unsubstituted C 3 -C 30 cycloalkyl, substituted and unsubstituted C 3 -C 30 heterocycloalkyl, substituted and unsubstituted C 2 -C 30 alkenyl, substituted and unsubstituted C 2 -C 30 alkynyl, substituted and unsubstituted C 1 -C 30 alkyloxyl, substituted and unsubstituted C 3 -C 30 cycloalkyloxyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, L 1 -L 4 -L 2 -W, and C—(═O)-W;
R is selected from nothing, CH 2 C(═O)OR 6 , substituted and unsubstituted C 1 -C 30 alkylene, substituted and unsubstituted C 3 -C 30 cycloalkylene, substituted and unsubstituted C 3 -C 30 heterocycloalkylene, substituted and unsubstituted C 1 -C 30 alkoxylene, substituted and unsubstituted C 2 -C 30 alkenylene, substituted and unsubstituted C 2 -C 30 alkynylene, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl, wherein any CH 2 in R may be further replaced with O, S, or NR 6 ;
R 1 and R 2 are each independently selected from H, substituted and unsubstituted C 1 -C 30 alkyl, substituted and unsubstituted C 3 -C 30 cycloalkyl, substituted and unsubstituted C 3 -C 30 heterocycloalkyl, substituted and unsubstituted C 1 -C 30 alkyloxyl, substituted and unsubstituted C 2 -C 30 alkenyl, substituted and unsubstituted C 2 -C 30 alkynyl, substituted and unsubstituted aryl and substituted and unsubstituted heteroaryl residues, wherein any CH 2 group(s) may be replaced with O, S, or NH;
R 11 and R 12 are each independently selected from nothing, H, CH 2 C(═O)OR 11 , substituted and unsubstituted C 1 -C 30 alkylene, substituted and unsubstituted C 3 -C 30 cycloalkylene, substituted and unsubstituted C 3 -C 30 heterocycloalkylene, substituted and unsubstituted C 1 -C 30 alkoxylene, substituted and unsubstituted C 2 -C 30 alkenylene, substituted and unsubstituted C 2 -C 30 alkynylene, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl, wherein any CH 2 group(s) may be replaced with O, S, or NH;
L 1 and L 2 are each independently selected from nothing, O, —O-L 3 -, —N(L 3 )-, —N(L 3 )-CH 2 —O, —N(L 3 )-CH 2 —N(L 5 )-, —O—CH 2 —O—, and —O—CH(L 3 )-O, wherein for each of L 1 and L 2 , each of L 3 and L 5 is independently selected from nothing, H, substituted and unsubstituted C 1 -C 30 alkyl, substituted and unsubstituted C 3 -C 30 cycloalkyl, substituted and unsubstituted C 3 -C 30 heterocycloalkyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted C 1 -C 30 alkoxyl, substituted and unsubstituted C 1 -C 30 alkylamino, wherein any carbon or hydrogen may be further independently replaced with O, S, or NL 3 ;
L 4 is selected from nothing and C═O;
W is selected from Structure W-1 and Structure W-2:
HA is selected from nothing, hydrochloride, hydrobromide, hydroiodide, nitric acid, sulfic acid, bisulfic acid, phosphoric acid, phosphorous acid, phosphonic acid, isonicotinic acid, acetic acid, lactic acid, salicylic acid, citric acid, tartaric acid, pantothenic acid, bitartaric acid, ascorbic acid, succinic acid, maleic acid, or any other pharmaceutically acceptable acid.
2. The topical pharmaceutical formulation of claim 1 , wherein W is Structure W-1.
3. The topical pharmaceutical formulation of claim 1 , wherein the compound of Structure LRA-1 is selected from
diethylaminoethyl [R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetate;
diethylaminoethyl 2-[1-[[(1R)-1-[3-[2-(7-chloroquinolin-2-yl)ethenyl]phenyl]-3-[2-(2-hydroxypropan-2-yl)phenyl]propyl]sulfanylmethyl]cyclopropyl]acetate;
2-pyrrolidinemethyl 2-[1-[[(1R)-1-[3-[2-(7-chloroquinolin-2-yl)ethenyl]phenyl]-3-[2-(2-hydroxypropan-2-yl)phenyl]propyl]sulfanylmethyl]cyclopropyl]acetate;
and pharmaceutically acceptable salts thereof.
4. The topical pharmaceutical formulation of claim 3 , wherein the compound of Structure LRA-1 is selected from
diethylaminoethyl [R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetate hydrochloride;
diethylaminoethyl 2-[1-[[(1R)-1-[3-[2-(7-chloroquinolin-2-yl)ethenyl]phenyl]-3-[2-(2-hydroxypropan-2-yl)phenyl]propyl]sulfanylmethyl]cyclopropyl]acetate hydrochloride; and
2-pyrrolidinemethyl 2-[1-[[(1R)-1-[3-[2-(7-chloroquinolin-2-yl)ethenyl]phenyl]-3-[2-(2-hydroxypropan-2-yl)phenyl]propyl]sulfanylmethyl]cyclopropyl]acetate hydrochloride.
5. The topical pharmaceutical formulation of claim 1 , which is a solution that can be sprayed onto skin of a patient.
6. The topical pharmaceutical formulation of claim 5 , wherein the compound of Structure LRA-1 is diethylaminoethyl [R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetate hydrochloride.
7. The topical pharmaceutical formulation of claim 5 , wherein the compound of Structure LRA-1 is 2-pyrrolidinemethyl 2-[1-[[(1R)-1-[3-[2-(7-chloroquinolin-2-yl)ethenyl]phenyl]-3-[2-(2-hydroxypropan-2-yl)phenyl]propyl]sulfanylmethyl]cyclopropyl]acetate hydrochloride.
8. The topical pharmaceutical formulation of claim 5 , which is an aqueous solution optionally comprising an alcohol.