Heparin-based compositions and methods for the inhibition of metastasis

A method for inhibiting metastasis in a mammal, comprising the step of:

• administering to a mammalian subject in need of inhibition of metastasis and not in need of treatment for pathological coagulation, an effective amount of a liquid pharmaceutical composition comprising:
• (a) an anti-metastatic heparin preparation having anti-coagulant activity in the absence of an inhibitor thereof;
• and
• (b) a heparin-binding compound which is an inhibitor of the anti-coagulation activity of heparin, having the formula
• or a pharmaceutically-acceptable salt thereof, wherein
• R1 is hydrogen, an amino acid connected by its carbonyl group, —C(═NR3)—NR3″R4′, —C(═O)—(CH2)pNPL—R4′, —C(═O)—(CH2)pPL1—V, —C(═O)-A2-NH—C(═O)—(CH2)pPL1—V, or —C(═O)-A2-NH—C(═O)—(CH2)pNPL—R4′;
• R3 and R3″ are each, independently, hydrogen, alkyl, or alkoxy;
• R4′ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with one or more substituents, wherein each substituent is, independently, alkyl, halo, or haloalkyl;
• each pNPL is, independently, an integer from 0 to 8;
• pPL1 is an integer from 1 to 5;
• and
• A2 is optionally substituted arylene or optionally substituted heteroarylene, wherein A2 is optionally substituted with one or more PL groups, one or more NPL groups, or a combination of one or more PL groups and one or more NPL groups;
• R2 is OH, OR600, NH2, NHR600, N(R600)2, an amino acid connected by its amino group, an α amino acid amide connected by its α amino group, —NH—(CH2)pPL2—V, or —NH-A1-C(═O)—NH2;
• each R600 is, independently, unsubstituted alkyl or aryl, or either alkyl or aryl substituted with OH, halo, cyan, nitro, amino, alkoxy, alkylthio, alkylamino, or dialkylamino;
• pPL2 is an integer from 1 to 5;
• and
• A1 is optionally substituted arylene or optionally substituted heteroarylene, wherein A1 is optionally substituted with one or more PL groups, one or more NPL groups, or a combination of one or more PL groups and one or more NPL groups;
• each R9 is, independently, H, a PL group, or an NPL group;
• each R10 is, independently, H, a PL group, or an NPL group;
• or R9 and R10, taken together, constitute the side chain of a D or L α amino acid;
• each R11a is, independently, a PL group or an NPL group;
• each NPL group is, independently, —B(OR40)2 or —(NR3′)q1NPL—UNPL-LKNPL—(NR3″)q2NPL—R40′;
• R3′ is hydrogen, alkyl, or alkoxy;
• R40 and R40′ are each, independently, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl is optionally substituted with one or more substituents, wherein each substituent is, independently, alkyl, halo, or haloalkyl;
• each UNPL is, independently, absent or O, S, S(═O), S(═O)2, NR3, —(C═O)—, —C(═O)—NR3—, —C(═O)—N═N—NR3—, —C(═O)—NR3—N═N—, —N═N—NR3—, —C(═N—N(R3)2)—, —C(═NR3)—, —C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)2O—, —S—C═N—, or —C(═O)—NR3—O—, wherein groups with two chemically nonequivalent termini can adopt both possible orientations;
• each LKNPL is, independently, —(CH2)pNPL— or C2-8 alkenylenyl, wherein each of the (CH2)pNPL and C2-8 alkenylenyl is optionally substituted with one or more substituents, wherein each substituent is, independently, amino, hydroxyl, aminoalkyl, hydroxylalkyl, or alkyl;
• q1NPL and q2NPL are each, independently, 0, 1, or 2;
• each PL group is, independently, halo, hydroxyethoxymethyl, methoxyethoxymethyl, polyoxyethylene, or —(NR5′)q1PL—UPL-LKPL—(NR5″)q2PL—V, wherein:
• R5′ and R5″ are each, independently, hydrogen, alkyl, or alkoxy;
• each UPL is, independently, absent or O, S, S(═O), S(═O)2, NR5, —C(═O)—, —C(═O)—NR5—, —C(═O)—N═N—NR5—, —C(═O)—NR5—N═N—, —N═N—NR5—, —C(═N—N(R5)2)—, —C(═NR5)—, —C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)2O—, —S—C═N—, or —C(═O)—NR5—O—, wherein groups with two chemically nonequivalent termini can adopt either of the two possible orientations;
• each V is, independently, nitro, cyano, amino, halo, hydroxy, alkoxy, alkylthio, alkylamino, dialkylamino, amido, alkylamido, dialkylamido, —NH(CH2)pNH2 wherein p is 1 to 5, —C(═O)NH(CH2)pNH2 wherein p is 1 to 5, —C(═O)NH(CH2)pNHC(═NH)NH2 wherein p is 1 to 5, —C(═O)NH(CH2)pNHC(═O)NH2 wherein p is 1 to 5, —NHC(═O)-alkyl, —N(CH2CH2NH2)2, diazamino, amidino, guanidino, ureido, carbamoyl, —C(═O)OH, —C(═O)ORc, —C(═O)NH—OH, —O—NH—C(═NH)NH2, —NH—S(═O)2OH, —S(═O)2OH, NRdRe, semicarbazone, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, wherein each of the aryl and cycloalkyl is substituted with one or more substituents, wherein each of the heterocycloalkyl and heteroaryl is optionally substituted with one or more substituents, and wherein each of the substituents for the aryl, cycloalkyl, heterocycloalkyl, and heteroaryl is, independently, nitro, cyano, amino, halo, hydroxy, alkoxy, alkylthio, alkylamino, dialkylamino, —NH(CH2)pNH2 wherein p is 1 to 5, —N(CH2CH2NH2)2, diazamino, amidino, guanidino, ureido, carbamoyl, —C(═O)OH, —C(═O)ORc, —C(═O)NH—OH, —O—NH—C(═NH)NH2, —NH—S(═O)2OH, S(═O)2OH, NRdRe, semicarbazone, aminosulfonyl, aminoalkoxy, aminoalkylthio, lower acylamino, or benzyloxycarbonyl;
• each Rc is, independently, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl, each optionally substituted by one or more substitutents, wherein each substituent is, independently, OH, amino, halo, C1-6 alkyl, C1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or heterocycloalkyl;
• Rd and Re are, independently, H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl, wherein each of the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl is optionally substituted by OH, amino, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or heterocycloalkyl;
• or Rd and Re together with the N atom to which they are attached form a 4-, 5-, 6-, 7-, or 8-membered heterocycloalkyl;
• each LKPL is, independently —(CH2)pPL3— or C2-8 alkenylenyl, wherein each of the —(CH2)pPL3— or C2-8 alkenylenyl is optionally substituted with one or more substituents, wherein each substituent is, independently, amino, hydroxyl, aminoalkyl, hydroxylalkyl, or alkyl;
• each pPL3 is, independently, an integer from 0 to 8;
• q1PL and q2PL are each, independently, 0, 1, or 2;
• each t1 is, independently, 0, 1, or 2;
• and
• m is an integer from 1 to 20,
• wherein at least 50% of the heparin-binding compound in the composition is bound to the anti-metastatic heparin preparation in the composition.