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US 8,912,167 B2Granted
Heparin-based compositions and methods for the inhibition of metastasis
OwnerEugene J. Olivainventor
Life of this patent
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Abstract
The invention provides the use in combination of a heparin containing composition that has anticoagulant activity when used alone, such as an unfractionated heparin or low molecular weight heparin, in combination with an inhibitor of the anticoagulation activity/effect or effect of heparin, for the inhibition of metastasis.
Claims15
A pharmaceutical composition for the inhibition of metastasis, comprising:
- an anti-metastatic heparin preparation having anti-coagulant activity in the absence of an inhibitor thereof;
- and
- 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″ 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, aminoalkythio, 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, and
- wherein the composition is a dry composition.
38 more elements
A pharmaceutical composition for the inhibition of metastasis, comprising:
- an anti-metastatic heparin preparation having anti-coagulant activity in the absence of an inhibitor thereof;
- and
- 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′;
- wherein R3 and R3″ are each, independently, hydrogen, alkyl, or alkoxy;
- R4′ is 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;
- pNPL is 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, NH2, —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 PL group is, independently, halo, —(CH2)pPL5—V, —O—(CH2)pPL5—V, and —S—(CH2)pPL5—V wherein each pPL5 is an integer from 0 to 5;
- each NPL group is, independently, R4′ or OR4′, wherein each R4′ is, independently, alkyl, alkenyl, alkynyl, cycloalkyl, or aryl, wherein each is optionally substituted with one or more substituents, wherein each substituent is, independently, alkyl, halo, or haloalkyl;
- each R11 is, independently, H, alkyl, haloalkyl, or —(CH2)pPL4—V, wherein pPL4 is an integer from 1 to 5;
- each V is, independently, amino, amido, alkylamino, dialkylamino, —NH(CH2)pNH2 wherein p is 1 to 5, —N(CH2CH2NH2)2, guanidino, amidino, ureido, heterocycloalkyl, or heteroaryl, wherein each of the heterocycloalkyl and heteroaryl is optionally substituted with one more substituents, wherein each substituent is, independently, amino, cyano, nitro, hydroxy, —NH(CH2)pNH2 wherein p is 1 to 5, —N(CH2CH2NH2)2, amidino, guanidino, aminosulfonyl, aminoalkoxy, aminoalkylthio, lower acylamino, or benzyloxycarbonyl;
- 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, and
- wherein the composition is a dry composition.
22 more elements
A pharmaceutical composition for the inhibition of metastasis, comprising:
- an anti-metastatic heparin preparation having anti-coagulant activity in the absence of an inhibitor thereof;
- and
- a heparin-binding compound which is an inhibitor of the anti-coagulation activity of heparin, having the formula
- R1—[—X-A1-Y—X-A2-Y]m—R2 I
- or pharmaceutically acceptable salt thereof, wherein:
- each X is, independently, NR8;
- each Y is C═O;
- each R8 is, independently, hydrogen or alkyl;
- each A2 is optionally substituted arylene or optionally substituted heteroarylene, and
- each A1 is —(CH2)q-, wherein q is 1 to 7, wherein A1 and A2 are each, independently, 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;
- R1 is hydrogen, a PL group, or an NPL group, and R2 is —X-A1-Y—R11, wherein R11 is hydrogen, a PL group, or an NPL group;
- or
- R1 and R2 are each, independently, hydrogen, a PL group, or an NPL group;
- or
- R1 and R2 together are a single bond;
- or
- R1 is —Y-A2-X—R12, wherein R12 is hydrogen, a PL group, or an NPL group, and R2 is hydrogen, a PL group, or an NPL group;
- each NPL group is, independently, —B(OR4)2 or —(NR3′)q1NPL—UNPL-LKNPL—(NR3″)q2NPL—R4′, wherein:
- R3, R3′, and R3″ are each, independently, hydrogen, alkyl, or alkoxy;
- R4 and R4′ 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— and 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;
- each pNPL is, independently, an integer from zero to 8;
- q1NPL and q2NPL are each, independently, zero, 1, or 2;
- each PL group is, independently, halo, hydroxyethoxymethyl, methoxyethoxymethyl, polyoxyethylene, or —(NR5′)q1PL—UPL-LKPL—(NR5″)q2PL—V, wherein:
- R5, 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—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, —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, aminoalkythio, 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 substituents, 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, aryl alkyl, heteroaryl alkyl, cycloalkylalkyl and heterocycloalkylalkyl is optionally substituted by OH, amino, halo, C1-6 alkyl, 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)pPL or C2-8 alkenylenyl, wherein each of the —(CH2)pPL— and C2-8 alkenylenyl is optionally substituted with one or more substituents, wherein each substituent is, independently, amino, hydroxyl, aminoalkyl, hydroxylalkyl, or alkyl;
- each pPL is, independently, an integer from zero to 8;
- q1PL and q2PL are each, independently, zero, 1, or 2;
- m is an integer from 1 to 20;
- and
- at least one of A1 is a —(CH2)q— group substituted with one substituent, wherein the substituent is —(CH2)—V1, —(CH2)2—V1, —(CH2)3—V1, —(CH2)4—V1, or —(CH2)5—V1, wherein V1 is indolyl,
- wherein at least 50% of the heparin-binding compound in the composition is bound to the anti-metastatic heparin preparation in the composition, and
- wherein the composition is a dry composition.
36 more elements
A pharmaceutical composition, comprising:
- an admixture of
- (i) an anti-metastatic heparin preparation, and
- (ii) tetra-[5-(L)-lysyl-amino-O-methylsalicylamide] or a pharmaceutically acceptable salt thereof,
- wherein the composition is a dry composition.
1 more element
Dependencies are inferred from the claim text.