US 11,479,527 B2 · High penetration prodrug compositions of mustards and mustard-related compounds

Abstract

The invention provides compositions of novel high penetration compositions (HPC) or high penetration prodrugs (HPP) of mustards and mustard-related compounds, which are capable of crossing biological barriers with high penetration efficiency. The 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 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.

A high penetration compound having the following chemical structure:

including stereoisomers and pharmaceutically acceptable salts thereof, wherein:
T is selected the group consisting of Structure Na, Structure Nb, Structure Nc, Structure Ne, Structure Ng, Structure Nh, and Structure Nm:
wherein:
R11 and R12 in Structure Na are same or different and each independently selected from H, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl;
R11, R12 and R13 in Structure Nb, Structure Nc, Structure Ng or Structure Nh are each independently substituted or unsubstituted alkylene;
R11 and R13 in Structure Ne and Structure Nm are each independently substituted or unsubstituted methine, and R12 is substituted or unsubstituted alkylene;
each R14 is selected from H, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl;
L1 is selected from the group consisting of a bond, O, S, —N(L3)-, —N(L3)-CH2—O, —N(L3)-CH2—N(L3)-, —O—CH2—O—, —O—CH(L3)-O, and —S—CH(L3)-O—;
L2 is selected from the group consisting of a bond, O, S, —N(L3)-, —N(L3)-CH2—O, —N(L3)-CH2—N(L3)-, —O—CH2—O—, —O—CH(L3)-O, —S—CH(L3)-O—, —O-L5-, —N-L5-, —S-L5-, —N(L3)-L5-;
L4 is C═O or C═S;
each L3 is independently selected from the group consisting of H, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl;
each L5 is independently selected from the group consisting of substituted and unsubstituted alkyl ene, substituted and unsubstituted cycloalkylene, substituted and unsubstituted heterocycloalkylene, substituted and unsubstituted arylene, and substituted and unsubstituted heteroarylene;
F comprises a moiety of a nitrogen mustard compound, having a structure of Structure A:
is selected from the group consisting of Structure Y-a, Structure Y-b, and Structure Y-c:
is selected from the group consisting of substituted and unsubstituted aryl, Structure Ar-a, Structure Ar-b, Structure Ar-c, Structure Ar-d, Structure Ar-e, Structure Ar-f, Structure Ar-g, Structure Ar-h and Structure Ar-i:
X1 and X2 are independently selected from the group consisting of CI, Br, F, and OSO2R4;
R4 is selected from the group consisting of unsubstituted alkyl, substituted and unsubstituted alkoxyl, substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted alkyl halide, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl groups;
X3-X7 are independently selected from the group consisting of NHCOR4, OR4, SR4, NHR4, OCOR4, R4, substituted and unsubstituted alkoxyl, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted alkyl halide, H, F, CI, Br, I, NO2, CN, CF3, NHCOCH3, OCH3, SCH3, NH2, NHCH3, OCOCH3, OCOC2H5, OC2H5, OC3H7, CH3, C2H5, and C3H7;
z is an integer;
Y1 is selected from the group consisting of CH2, O, S, and NH;
Y2 and Y3 are the same or different and each is NHCOR4, H, OH, NHCOCH3, NHCOC2H5, CI, F, Br, or I, or taken together is ═O;
Y4 is selected from the group consisting of R4, CH2, —(CH2)n—, O, S, and NH;
A is selected from the group consisting of amino acids, α-amino acids and (β-amino acids residues;
any CH2 groups may be replaced with O, S, or NH;
and
when a bond is not linked with any atom of an aryl or heteroaryl ring, the bond can be put into any position of the ring.

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High penetration prodrug compositions of mustards and mustard-related compounds

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High penetration prodrug compositions of mustards and mustard-related compounds

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Abstract

Claims10