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US 6,686,367 B2Granted
Polyhydroxylated monocyclic N-heterocyclic derivatives as anti-coagulants
AssigneeBerlex Laboratories, Inc.
InventorGary B. Phillips
Life of this patent
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Abstract
This invention is directed to poly-hydroxylated monocyclic N-heterocyclic derivatives selected from the following formulae: wherein Z1, Z2, R1, R2, R3, R4, R5, R6, and R7 are defined herein. These compounds are useful as anti-coagulants.
Claims3
A compound selected from the group consisting of the following formulae:
- wherein:
- Z1 is —CH2—O—;
- Z2 is —O—CH2—;
- R1 and R4 are each independently hydrogen, halo, alkyl, nitro, —OR9, —C(O)OR9, —C(O)N(R9)R10, —N(R9)R10, —N(R9)C(O)R9, or —N(H)S(O)2R11;
- R2 is —C(NH)NH2, —C(NH)N(H)OR9, —C(NH)N(H)C(O)OR11, —C(NH)N(H)C(O)R9, —C(NH)N(H)S(O)2R11, or —C(NH)N(H)C(O)N(H)R9;
- R3 is hydrogen, halo, alkyl, haloalkyl, nitro, ureido, guanidino, —OR9, —C(NH)NH2, —C(NH)N(H)OR9, —C(O)N(R9)R10, —R12—C(O)N(R9)R10, —CH(OH)C(O)N(R9)R10, —N(R9)R10, —R12—N(R9)R10, —C(O)OR9, —R12—C(O)OR9, —N(R9)C(O)R9, (1,2)-tetrahydropyrimidinyl (optionally substituted by alkyl), (1,2)-imidazolyl (optionally substituted by alkyl), or (1,2)-imidazolinyl (optionally substituted by alkyl);
- R5 and R6 are independently hydrogen, halo, alkyl, haloalkyl, nitro, —N(R9)R10, —C(O)OR9, —C(O)N(R9)R10, —C(O)N(R9)CH2C(O)N(R9)R10, —N(R9)C(O)N(R9)R10, —N(R9)C(O)R10, —N(R9)S(O)2R11, or —N(R9)C(O)N(R9)—CH2C(O)N(R9)R10;
- R7 is —X—CH2—[C(R13)H]p—C(R13)H2 or —X—C([C(R13)H]p—C(R13)H2)2H where:
- p is 0 to 5;
- X is —O—, —S(O)n— (where n is 0 to 2), or —N(R9)—;
- and each R13 is independently —[C(OR9)H]mCH2—OR9 (where m is 1 to 4), —[CH2]n—OR9, —[CH2]n—SR9, —[CH2]n—N(R9)R10, —[CH2]n—OC(O)R9, —[CH2]n—SC(O)R9, —[CH2]n—N(R9)C(O)R9, —[CH2]n—OC(O)OR11, —[CH2]n—N(R9)C(O)OR11, —[CH2]n—OC(O)N(R9)R10, or —[CH2]n—N(R9)C(O)N(R9)R10 (where each n is independently 0 to 2);
- or R7 is selected from the group consisting of the following formulae:
- where
- q is 0 to 4;
- p is 0 to 5;
- each R13 is independently —[C(OR9)H]m—CH2—OR9 (where m is 1 to 4), —[CH2]n—OR9, —[CH2]n—SR9, —[CH2]n—N(R9)R10, —(CH2)n—OC(O)R9, —[CH2]n—SC(O)R9, —[CH2]n—N(R9)C(O)R9, —[CH2]n—OC(O)OR11, —[CH2]n—N(R9)C(O)OR11, —[CH2]n—OC(O)N(R9)R10, or —[CH2]n—N(R9)C(O)N(R9)R10 (where each n is independently 0 to 2);
- and
- each R14 is —X—[CH2]r— or —X—CH2—[C(R13)H]r—;
- where:
- each r is independently 0 to 5, and
- each X is —S(O)n— (where n is 0 to 2), or —N(R9)—;
- and
- each R13 is independently [CH(OR9)]m—CH2—OR9 (where m is 1 to 4), —[CH2]n—OR9, —[CH2]n—SR9, —[CH2]n—N(R9)R10, —[CH2]n—OC(O)R9, —[CH2]n—SC(O)R9, —[CH2]n—N(R9)C(O)R9, —[CH2]n—OC(O)OR11, —[CH2]n—N(R9)C(O)OR11, —[CH2]n—OC(O)N(R9)R10, or —[CH2]n—N(R9)C(O)N(R9)R10 (where each n is independently 0 to 2);
- each R9 and R10 is independently hydrogen, alkyl, aryl (optionally substituted by halo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl), or aralkyl (optionally substituted by halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl);
- each R11 is alkyl, aryl (optionally substituted by halo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl), or aralkyl (optionally substituted by halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl);
- and
- each R12 is independently an alkylene or alkylidene chain;
- as a single stereoisomer or a mixture thereof;
- or a pharmaceutically acceptable salt thereof.
26 more elements
A pharmaceutical composition useful in treating a human having a thrombotic complication associated with myocardial infarction, deep vein thrombosis following orthopedic surgery, transient ischemic attack, coronary artery bypass graft, percutaneous transluminal coronary angioplasty, acute promyelocytic leukemia, diabetes, multiple myelomas, septic shock, purpura fulminanas, adult respiratory distress syndrome, angina, or aortic valve or vascular prosthesis, which composition comprises a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound selected from the group consisting of the following formulae:
- wherein:
- Z1 is —CH2—O—;
- Z2 is —O—CH2—;
- R1 and R4 are each independently hydrogen, halo, alkyl, nitro, —OR9, —C(O)OR9, —C(O)N(R9)R10, —N(R9)R10, —N(R9)C(O)R9, or —N(H)S(O)2R11;
- R2 is —C(NH)NH2, —C(NH)N(H)OR9, —C(NH)N(H)C(O)OR11, —C(NH)N(H)C(O)R9, —C(NH)N(H)S(O)2R11, or —C(NH)N(H)C(O)N(H)R9;
- R3 is hydrogen, halo, alkyl, haloalkyl, nitro, ureido, guanidino, —OR9, —C(NH)NH2, —C(NH)N(H)OR9, —C(O)N(R9)R10, —R12—C(O)N(R9)R10, —CH(OH)C(O)N(R9)R10, —N(R9)R10, —R12—N(R9)R10, —C(O)OR9, —R12—C(O)OR9, —N(R9)C(O)R9, (1,2)-tetrahydropyrimidinyl (optionally substituted by alkyl), (1,2)-imidazolyl (optionally substituted by alkyl), or (1,2)-imidazolinyl (optionally substituted by alkyl);
- R5 and R6 are independently hydrogen, halo, alkyl, haloalkyl, nitro, —N(R9)R10, —C(O)OR9, —C(O)N(R9)R10, —C(O)N(R9)CH2C(O)N(R9)R10, —N(R9)C(O)N(R9)R10, —N(R9)C(O)R10, —N(R9)S(O)2R11, or —N(R9)C(O)N(R9)—CH2C(O)N(R9)R10;
- R7 is —X—CH2—[C(R13)H]p—C(R13)H2 or —X—C([C(R13)H]p—C(R13)H2)2H where:
- p is 0 to 5;
- X is —O—, —S(O)n— (where n is 0 to 2), or —N(R9)—;
- and each R13 is independently —[C(OR9)H]m—CH2—OR9 (where m is 1 to 4), —[CH2]n—OR9, —[CH2]n—SR9, —[CH2]n—N(R9)R10, —[CH2]n—OC(O)N(R9), —[CH2]n—SC(O)R9, —[CH2]n—N(R9)C(O)R9, —[CH2]n—OC(O)OR11, —[CH2]n—N(R9)C(O)OR11, —[CH2]n—OC(O)N(R9)R10, or —[CH2]n—N(R9)C(O)N(R9)R10 (where each n is independently 0 to 2);
- or R7 is selected from the group consisting of the following formulae:
- where
- q is 0 to 4;
- p is 0 to 5;
- each R13 is independently [C(OR9)H]mCH2—OR9 (where m is 1 to 4), —[CH2]n—OR9, —[CH2]nSR9, —[CH2]n—N(R9)R10, —[CH2]n—OC(O)R9, —[CH2]n—SC(O)R9, —[CH2]n—N(R9)C(O)R9, —[CH2]n——OC(O)N(R9)OR11, —[CH2]n—N(R9)C(O)OR11, —[CH2]n—OC(O)N(R9)R10, or —[CH2]n—N(R9)C(O)N(R9)R10 (where each n is independently 0 to 2);
- and
- each R14 is —X—[CH2]r— or —X—CH2—[C(R13)H]r—, where:
- each r is independently 0 to 5, and
- each X is —S(O)n— (where n is 0 to 2), or —N(R9)—;
- and
- each R13 is independently —[CH(OR9)]m—CH2—OR9 (where m is 1 to 4), —[CH2]n—OR9, —[CH2]n—SR9, —[CH2]n—N(R9)R10, —[CH2]n—OC(O)R9, —[CH2]n—SC(O)R9, —[CH2]n—N(R9)C(O)R9, —[CH2]n—OC(O)OR11, —[CH2]n—N(R9)C(O)OR11, —[CH2]n—OC(O)N(R9)R10, or —[CH2]n—N(R9)C(O)N(R9)R10 (where each n is independently 0 to 2);
- each R9 and R10 is independently hydrogen, alkyl, aryl (optionally substituted by halo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl), or aralkyl (optionally substituted by halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl);
- each R11 is alkyl, aryl (optionally substituted by halo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl), or aralkyl (optionally substituted by halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl);
- and
- each R12 is independently an alkylene or alkylidene chain;
- as a single stereoisomer or a mixture thereof;
- or a pharmaceutically acceptable salt thereof;
- and a pharmaceutically acceptable excipient.
26 more elements
A method of treating a human having a thrombotic complication associated with myocardial infarction, deep vein thrombosis following orthopedic surgery, transient ischemic attack, coronary artery bypass graft, percutaneous transluminal coronary angioplasty, acute promyelocytic leukemia, diabetes, multiple myelomas, septic shock, purpura fulminanas, adult respiratory distress syndrome, angina, or aortic valve or vascular prosthesis, which method comprises administering to a human in need thereof a therapeutically effective amount of a compound selected from the group consisting of the following formulae:
- wherein:
- Z1 is —CH2—O—;
- Z2 is —O—CH2—;
- R1 and R4 are each independently hydrogen, halo, alkyl, nitro, —OR9, —C(O)OR9, —C(O)N(R9)R10, —N(R9)R10, —N(R9)C(O)R9, or —N(H)S(O)R11;
- R2 is —C(NH)NH2, —C(NH)N(H)OR9, —C(NH)N(H)C(O)OR11, —C(NH)N(H)C(O)R9, —C(NH)N(H)S(O)2R11, or —C(NH)N(H)C(O)N(H)R9;
- R3 is hydrogen, halo, alkyl, haloalkyl, nitro, ureido, guanidino, —OR9, —C(NH)NH2, —C(NH)N(H)OR9, —C(O)N(R9)R10, —R12—C(O)N(R9)R10, —CH(OH)C(O)N(R9)R10, —N(R9)R10, —R12—N(R9)R10, —C(O)OR9, —R12—C(O)OR9, —N(R9)C(O)R9, (1,2)-tetrahydropyrimidinyl (optionally substituted by alkyl), (1,2)-imidazolyl (optionally substituted by alkyl), or (1,2)-imidazolinyl (optionally substituted by alkyl);
- R5 and R6 are independently hydrogen, halo, alkyl, haloalkyl, nitro, —N(R9)R10, —C(O)OR9, —C(O)N(R9)R10, —C(O)N(R9)CH2C(O)N(R9)R10, —N(R9)C(O)N(R9)R10, —N(R9)C(O)R10, —N(R9)S(O)2R11, or —N(R9)C(O)N(R9)—CH2C(O)N(R9)R10;
- R7 is —X—CH2—[C(R13)H]p—C(R13)H2 or —X—C([C(R13)H]p—C(R13)H2)2H where:
- p is 0 to 5;
- X is —O—, —S(O)n— (where n is 0 to 2), or —N(R9)—;
- and each R13 is independently —[C(OR9)H]mCH2—OR9 (where m is 1 to 4), —[CH2]n—OR9, —[CH2]n—SR9, —[CH2]n—N(R9)R10, —[CH2]n—OC(O)R9, —[CH2]n—SC(O)R9, —[CH2]n—N(R9)C(O)R9, —[CH2]n—OC(O)OR11, —[CH2]n—N(R9)C(O)OR11, —[CH2]n—OC(O)N(R9)R10, or —[CH2]n—N(R9)C(O)N(R9)R10 (where each n is independently 0 to 2);
- or R7 is selected from the group consisting of the following formulae:
- where
- q is 0 to 4;
- p is 0 to 5;
- each R13 is independently —[C(OR9)H]m—CH2—OR9 (where m is 1 to 4), —[CH2]n—OR9, —[CH2]n—SR9, —[CH2]n—N(R9)R10, —[CH2]n—OC(O)R9, —[CH2]n—SC(O)R9, —[CH2]n—N(R9)C(O)R9, —[CH2]n—OC(O)OR11, —[CH2]n—N(R9)C(O)OR11, —[CH2]n—OC(O)N(R9)R10, or —[CH2]n—N(R9)C(O)N(R9)R10 (where each n is independently 0 to 2);
- and
- each R14 is —X—[CH2]r— or —X—CH2—[C(R13)H]r—, where:
- each r is independently 0 to 5, and
- each X is —S(O)n— (where n is 0 to 2), or —N(R9)—;
- and
- each R13 is independently —[CH(OR9)]m—CH2—OR9 (where m is 1 to 4), —[CH2]n—OR9, —[CH2]n—SR9, —[CH2]n—N(R9)R10, —[CH2]n—OC(O)R9, —[CH2]n—SC(O)R9, —[CH2]n—N(R9)C(O)R9, —[CH2]n—OC(O)OR11, —[CH2]n—N(R9)C(O)OR11, —[CH2]n—OC(O)(R9)R10, or —[CH2]n—N(R9)C(O)N(R9)R10 (where each n is independently 0 to 2);
- each R9 and R10 is independently hydrogen, alkyl, aryl (optionally substituted by halo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl), or aralkyl (optionally substituted by halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl);
- each R11 is alkyl, aryl (optionally substituted by halo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl), or aralkyl (optionally substituted by halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl);
- and
- each R12 is independently an alkylene or alkylidene chain;
- as a single stereoisomer or a mixture thereof;
- or a pharmaceutically acceptable salt thereof.
25 more elements
Dependencies are inferred from the claim text.