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US 6,440,968 B1Granted
Use of maduraohtalazine derivatives as inhibitors of proinflammatory cytokines
AssigneeElbion AG
InventorsRegina Draheim, Thomas Kronbach, Lothar Heinisch, Ernst Roemer, Norbert Höfgen, Hildegard Poppe, Peter Jütten, Wolfgang Haas, Walter Werner, Udo Gräfe
Life of this patent
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Abstract
The maduraphthalazine derivatives of the formula (4) are able to inhibit the effect of the cytokines interleukin-2, interleukin-4 and interleukin-5 and are suitable for the production of pharmaceuticals.
Claims7
Compounds and salts of Formula 4
- wherein
- R1 is hydrogen, or branched-chain, or straight-chain C1-12alkyl residue optionally substituted one or more times by —OH, —SH, —NH2, —NHC1-6alkyl, —N(C1-6alkyl)2, —NHC6 -14aryl, —N(C6-14aryl)2, —N(C1-6alkyl)(C6-14aryl), —NHCOR7, —NO2, —CN, —F, —Cl, —Br, —I, —O—C1-6alkyl, —O—C6-14aryl, —O(CO)R7, —S—C1-6-alkyl, —S—C6-14aryl, —SOR8, —SO2R8, —OSO2C1-6alkyl, —OSO2C6-14aryl, —(CS)R7, —O(CO)R7, —(CO)R9, a mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycle with 3-14 ring members, mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocycle with 5-15 ring members and 1-6 heteroatoms, wherein the C6-14 aryl groups and the included carbocylic and heterocyclic substituents can be optionally substituted one or more times by R10, a mono- or polyunsaturated, straight-chain or branched-chain C2-12alkenyl residue optionally substituted one or more times by —OH, —SH, —NH2, —NHC1-6alkyl, —N(CH1-6 alkyl)2, —NHC6-14aryl, —N(C6-14aryl)2, —N(C1-6alkyl)(C6-14aryl), —NHCOR7, —NO2, —CN, —F, —Cl, —Br, —I, —O—C1-6alkyl, —O—C6-14-aryl, —O(CO)R7, —S—C1-6alkyl, —S—C6-14aryl, —SOR8, —SO2R8, —OSO2C1-6alkyl, —OSO2C6-14aryl, —(CS)R7, —O(CO)R7, —(CO)R9, mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycle with 3-14 ring members, a mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocycle with 5-15 ring members and 1-6 heteroatoms, the C6-14 aryl groups and the included carbocyclic and heterocyclic substituents can be optionally substituted one or more times by R10, mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycle with 3-14 ring members, optionally substituted one or more times by —OH, —SH, —NH2, —NH C1-6alkyl, —N(C1-6alkyl)2, —NHC6-14aryl, —N(C6-14aryl)2, —N(C1-6alkyl)(C6-14aryl), —NHCOR7, —NO2, —CN, —F, —Cl, —Br, —I, —O—C1-6-alkyl, —O—C6-14aryl, —O(CO)R7, —S—C1-6 alcyl, —S—C6-14aryl, —SOR8, —SO2R8, —OSO2C1-6alkyl, —OSO2C6-14aryl, —(CS)R7, —O(CO)R7, —(CO)R9, the C6-14 aryl groups can be optionally substituted one or more times by R10, a mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocycle with 5-15 ring members and 1-6 heteroatoms, optionally substituted one or more times by —OH, —SH, —NH2, —NHC1-6alkyl, —N(C1-6alkyl)2, —NHC6-14aryl, —N(C6-14aryl)2, —N(C1-6alkyl)(C6-14aryl), —NHCOR7, —NO2, —CN, —F, —Cl, —Br, —I, —O—C1-6alkyl, —O—C6-14aryl. —O(CO)R7, —S—C1-6alkyl, —S—C6-14aryl, —SOR8, —SO2R8, —OSO2C1-6alkyl, —OSOC2C6-14aryl, —(CS)R7, —O(CO)R7—(CO)R8, the C6-14aryl groups can be optionally substituted one or more times by R10, carbo- or a heterocyclic saturated or mono- or polyunsaturated spirocycles with 3-10 ring members, where heterocyclic systems contain 1-6 heteroatoms optionally substituted one or more times by —OH, —SH, —NH2, —NHC1-6alkyl, —N(C1-6alkyl)2, —NHC6-14aryl, —N(C6-14aryl)2, —N(C1-6alkyl)(C6-14aryl), —NHCOR7, —NO2, —CN, —F, —Cl, —Br, —I, —O—C1-6 alkyl, —O—C6-14aryl, —O(CO)R7, —S—C1-6alkyl, —S—C6-14aryl, —SOR8, —SO2R8, —OSO2C1-6 alkyl, —OSO2C6-14 aryl, —(CS)R7, —O(CO)R7, —(CO)R8, the C6-4aryl groups can be optionally substituted one or more times by R10;
- R2, R3, R4, R5, R6 can be the same or different and are hydrogen, and a straight-chaim or branched-chain C1-6alkyl residue, optionally substituted one or more times by —OH, —SH, —NH2, —NHC1-6alkyl, —N(C1-6alkyl)2, —NHC6-14aryl, —N(C6-14aryl)2, —N(C1-6 alkyl)(C6-14aryl), —NHCOR7, —NO2, —CN, —(CO)R8, —(CS)R7, —F, —Cl, —Br, —I, —O—C1-6 akyl, —O—C6-14aryl, —O(CO)R7, —S—C1-6alkyl, —S—C6-14aryl, —SOR8, —SO2R8, CO—C1-6 alkyl, optionally substituted one or more times by —OH, —SH, —NH2, —NHC1-6alkyl, —N(C1-6 alkyl)2, —NHC6-14aryl, —N(C6-14aryl)2, —N(C1-6alkyl)(C6-14aryl), —NHCOR7, —NO2, —CN, —(CO)R8, —(CS)R7, —F, —Cl, —Br, —I, —O—C1-6alkyl, —O—C6-14aryl, —O(CO)R7, —S—C1-6 alkyl, —S—C6-14aryl, —SOR8, —SO2R8 COO—C1-6alkyl residue, optionally substituted one or more times by —OH, —SH, —NH2, —NHC1-6alkyl, —N(C1-6alkyl)2, —NHC6-14aryl, —N(C6-14aryl)2, —N(C1-6alkyl)(C6-14aryl), —NHCOR7, —NO2, —CN, —(CO)R8, —(CS)R7, —F, —Cl, —Br, —I, —O—C1-6alkyl, —O—C6-14aryl, —O(CO)R7, —S—C1-6alkyl, —S—C6-14aryl, —SOR8, —SO2R8;
- R7 is a C1-6alkyl, —O—C1-6alkyl, —O—C6-14aryl, —NH2, —NHC1-6alkyl, —N(C1-6alkyl)2—NHC6-14aryl, —N(C6-14aryl)2, —N(C1-6alkyl)(C6-14aryl), —S—C1-6alkyl, residue, or a mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycle with 3-14 ring members, or mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocycle with 5-15 ring members and 1-6 heteroatoms,
- R8 is —H, a —C1-6alkyl, —NH2, —NHC1-6alkyl, —N(C1-6alkyl)2, —NHC6-14aryl, —N(C6-14aryl)2, —N(C1-6alkyl)(C6-14aryl, —NHCOR7, —OH, —O—C1-6alkyl, —O—C6-14aryl), —S—C1-6alkyl, —S—C6-14aryl residue, or a mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycle with 3-14 ring members, or mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocycle with 5-15 ring members and 1-6 hetero atoms;
- R9 is —H, a —C1-6alkyl residue, or mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycle with 3-14 ring members, or a mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocycle with 5-15 ring members and 1-6 heteroatoms,
- R10 is —OH, a —SH, —NH2, —NHC1-6alkyl, —N(C1-6akyl)2, —NHC6-14aryl, —N(C6-14aryl)2, —N(C1-6alkyl)(C6-14aryl), —NHCOR7, —NO2, —CN, —(CO)R8, —(CS)R7, —F, —Cl, —Br, —I, —O—C1-6alkyl, —O—C6-14aryl, —O(CO)R7, —S—C1-6alkyl, —S—C6-14aryl, —SOR8, or an —SO2R8 residue, and
- A, B can be a —CH2—, —CH(OH) residue or
- A+B can be a —CH═CH— residue, or
- with a pharmaceutically acceptable salt thereof, provided that R2 through R5 are not hydrogen when R6 is CH3.
7 more elements
The compounds:
- 2-phenyl-10,12,15,16-tetrahydroxy-8-methoxy-11-methyl-9,14-dioxo-6,7,9,14-tetrahydronaphthaceno[1,2-g]phthalazin-1-one;
- 10,12,15,16-tetrahydroxy-8-methoxy-11-methyl-9,14-dioxo-6,7,9,14-tetrahydronaphthaceno[1,2-g]phthalazin-1-one;
- 2-methyl-10,12,15,16-tetrahydroxy-8-methoxy-11-methyl-9,14-dioxo-6,7,9,14-tetrahydronaphthaceno[1,2-g]phthalazin-1-one;
- 2-propyl-10,12,15,16-tetrahydroxy-8-methoxy-11-methyl-9,14-dioxo-6,7,9,14-tetrahydronaphthaceno[1,2-g]phthalazin-1-one;
- 2-(2-hydroxyethyl)-10,12,15,16-tetrahydroxy-8-methoxy-11-methyl-9,14-dioxo-6,7,9,14-tetrahydronaphthaceno[1,2-g]phthalazin-1-one;
- 2-(2-acetoxyethyl)-10,12,15,16-tetrahydroxy-8-methoxy-11-methyl-9,14-dioxo-6,7,9,14-tetrahydronaphthaceno[1,2-g]phthalazin-1-one;
- 2-(2-aminoethyl)-10,12,15,16-tetrahydroxy-8-methoxy-11-methyl-9,14-dioxo-6,7,9,14-tetrahydronaphthaceno[1,2-g]phthalazin-1-one;
- 2-(2,2-diethoxyethyl)-10,12,15,16-tetrahydroxy-8-methoxy-11-methyl-9,14-dioxo-6,7,9,14-tetrahydronaphthaceno[1,2-g]phthalazin-1-one;
- 2-(2-imidazolyl)-10,12,15,16-tetrahydroxy-8-methoxy-11-methyl-9,14-dioxo-6,7,9,14-tetrahydronaphthaceno[1,2-g]phthalazin-1-one;
- 2-(2-pyridyl)-10,12,15,16-tetrahydroxy-8-methoxy-11-methyl-9,14-dioxo-6,7,9,14-tetrahydronaphthaceno[1,2-g]phthalazin-1-one;
- 2-2-pyridyl)-8,10,12,15,16-pentahydroxy-11-methyl-9,14-dioxo-6,7,9,14-tetrahydronaphthaceno[1,2-g]phthalazin-1-one;
- 2-phenyl-8,10,12,15,16-pentahydroxy-11-methyl-9,14-dioxo-6,7,9,14-tetrahydronaphthaceno[1,2-g]phthalazin-1-one;
- 2-phenyl-10,15,16-trihydroxy-8-methoxy-12-methoxycarbonyloxy-11-methyl-9,14-dioxo-6,7,9,14-tetrahydronaphthaceno[1,2-g]phthalazin-1-one;
- 2-phenyl-10,12,15,16-tetraacetoxy-8-methoxy-11-methyl-9,14-dioxo-6,7,9,14-tetrahydronaphthaceno[1,2-g]phthalazin-1-one;
- 2-phenyl-12-allyl-10,15,16-trihydroxy-8-methoxy-11-methyl-9,14-dioxo-6,7,9,14-tetrahydronaphthaceno[1,2-g]phthalazin-1-one;
- 2-phenyl-10,12,15,16-tetrahydroxy-8-methoxy-11-methyl-9,14-dioxo-9,14-dihydronaphthaceno[1,2-g]phthalazin-1-one;
- and
- 2-phenyl-6,7,10,12,15,16-hexahydroxy-8-methoxy-11-methyl-9,14-dioxo-6,7,9,14-tetrahydronaphthaceno[1,2-g]phthalazin-1-one.
15 more elements
A process for inhibiting the action of the cytokines interleukin-2, interleukin-4, and interleukin-5, which comprises administering to a patient in need therefore a compound of Formula 4
- wherein
- R1 is hydrogen, or branched-chain, or straight-chain C1-12alkyl residue optionally substituted one or more times by —OH, —SH, —NH2, —NHC1-6alkyl, —N(C1-6alkyl)2, —NHC6-14alkyl, —N(C6-14alkyl)2, —N(C1-6alkyl)(C6-14aryl), —NHCOR7, —NO2, —CN, —F, —Cl, —Br, —I, —O—C1-6alkyl, —O—C6-14aryl, —O(CO)R7, —S—C1-6-alkyl, —S—C6-14aryl, —SOR8, —SO2R8, —OSO2C1-6alkyl, —OSO2C6-14aryl, —(CS)R7, —O(CO)R7, —(CO)R9, a mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycle with 3-14 ring members, mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocycle with 5-15 ring members and 1-6 heteroatoms, wherein the C6-14 aryl groups and the included carbocylic and heterocyclic substituents can be optionally substituted one or more times by R10,
- a mono- or polyunsaturated, straight-chain or branched-chain C2-12alkenyl residue optionally substituted one or more times by —OH, —SH, —NH2, —NHC1-6akyl, —N(C1-6 alkyl)2, —NHC6-14aryl, —N(C6-14aryl)2, —N(C1-6alkyl)(C6-14aryl), —NHCOR7, —NO2, —CN, —F, —Cl, —Br, —I, —O—C1-6alkyl, —O—C6-14-aryl, —O(CO)R7, —S—C1-6alkyl, —S—C6-14-aryl, —SOR8, —SO2R8, —OSO2C1-6alkyl, —OSO2C6-4aryl, —(CS)R7, —O(CO)R7, —(CO)R9, mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycle with 3-14 ring members, a mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocycle with 5-15 ring members and 1-6 heteroatoms, the C6-14 aryl groups and the included carbocyclic and heterocyclic substituents can be optionally substituted one or more times by R10,
- mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycle with 3-14 ring members, optionally substituted one or more times by —OH, —SH, —NH2, —NH C1-6 alkyl, —N(C1-6alkyl)2, —NHC6-14aryl, —N(C6-14aryl)2, —N(C1-6alkyl)(C6-14aryl), —NHCOR7, —NO2, —CN, —F, —Cl, —Br, —I, —O—C1-6-alkyl, —O—C6-4aryl, —O(CO)R7, —S—C1-6alkyl, —S—C6-14aryl, —SOR8, —SO2R8, —OSO2C1-6alkyl, —OSO2C6-14aryl, —(CS)R7, —O(CO)R7, —(CO)R9, the C6-14 aryl groups can be optionally substituted one or more times by R10,
- a mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocycle with 5-15 ring members and 1-6 heteroatoms, optionally substituted one or more times by —OH, —SH, —NH2, —NHC1-6alkyl, —N(C1-6alkyl)2, —NHC6-14aryl, —N(C6-14aryl)2, —N(C1-6 alkyl)(C6-14aryl), —NHCOR7, —NO2, —CN, —F, —Cl, —Br, —I, —O—C1-6alkyl, —O—C6-14aryl, —O(CO)R7, —S—C1-6alkyl, —S—C6-14aryl, —SOR8, —SO2R8, —OSO2C1-6alkyl, —OSOC2C6-14 aryl, —(CS)R7, —O(CO)R7, —(CO)R8,
- the C6-14aryl groups can be optionally substituted one or more times by R10, carbo- or a heterocyclic saturated or mono- or polyunsaturated spirocycles with 3-10 ring members, where heterocyclic systems contain 1-6 heteroatoms optionally substituted one or more times by —OH, —SH, —NH2, —NHC1-6alkyl, —N(C1-6alkyl)2, —NHC6-14aryl, —N(C6-14aryl)2, —N(C1-6alkyl)(C6-14aryl), —NHCOR7, —NO2, —CN, —F, —Cl, —Br, —I, —O—C1-6alkyl, —O—C6-14aryl, —O(CO)R7, —S—C1-6alkyl, —S—C6-14aryl, —SOR8, —SO2R8, —OSO2C1-6 arkyl, —OSO2C6-14 aryl, —(CS)R7, —O(CO)R7, —(CO)R8,
- the C6-14aryl groups can be optionally substituted one or more times by R10;
- R2, R3, R4, R5, R6 can be the same or different and are hydrogen, and a straight-chain or branched-chain C1-6alkyl residue, optionally substituted one or more times by —OH, —SH, —NH2, —NHC1-6alkyl, —N(C6-14alkyl)2, —NHC6-14aryl, —N(C6-14aryl)2, —N(C1-6 alkyl)(C6-14aryl), —NHCOR7, —NO2, —CN, —(CO)R8, —(CS)R7, —F, —Cl, —Br, —I, —O—C1-6 alkyl, —O—C6 14aryl, —O(CO)R7, —S—C1-6alkyl, —S—C6-14aryl, —SOR8, —SO2R8, CO—C1-6 alkyl,
- optionally substituted one or more times by —OH, —SH, —NH2, —NHC1-6alkyl, —N(C1-6 alkyl)2, —NHC6-14aryl, —N(C6-14aryl)2, —N(C1-6alkyl)(C6-14aryl), —NHCOR7, —NO2, —CN, —(CO)R8, —(CS)R7, —F, —Cl, —Br, —I, —O—C1-6alkyl, —O—C6-14aryl, —O(CO)R7, —S—C1-6 alkyl, —S—C6-14aryl, —SOR8, —SO2R8
- COO—C1-6alkyl residue, optionally substituted one or more times by —OH, —SH, —NH2, —NHC1-6alkyl, —N(C1-6alkyl)2, —NHC6-14aryl, —N(C6-14aryl)2, —N(C1-6alkyl)(C6-14 aryl), —NHCOR7, —NO2, —CN, —(CO)R8, —(CS)R7, —F, —Cl, —Br, —I, —O—C1-6alkyl, —O—C6-14aryl, —O(CO)R7, —S—C1-6alkyl, —S—C6-14aryl, —SOR8, —SO2R8;
- R7 is a C1-6alkyl, —O—C1-6alkyl, —O—C6-14aryl, —NH2, —NHC1-6alkyl, —N(C1-6alkyl)2, —NHC6-14aryl, —N(C6-14aryl)2, —N(C1-6alkyl)(C6-14aryl), —S—C1-6alkyl, —S—C6-14aryl residue, or a mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycle with 3-14 ring members, or mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocycle with 5-15 ring members and 1-6 heteroatoms,
- R8 is —H, a —C1-6alkyl, —NH2, —NHC1-6alkyl, —N(C1-6alkyl)2, —NHC6-14aryl, —N(C6-14aryl)2, —N(C1-6alkyl)(C6-14aryl, —NHCOR7, —OH, —O—C1-6alkyl, —O—C6-14aryl), —S—C1-6alkyl, —S—C6-14aryl residue, or a mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycle with 3-14 ring members, or mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocycle with 5-15 ring members and 1-6 hetero atoms;
- R9 is —H, a —C1-6alkyl residue, or mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycle with 3-14 ring members, or a mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocycle with 5-15 ring members and 1-6 heteroatoms,
- R10 is —OH, a —SH, —NH2, —NHC1-6alkyl, —N(C1-6alkyl)2, —NHC6-14aryl, —N(C6-14aryl)2, —N(C1-6alkyl)(C6-14aryl), —NHCOR7, —NO2, —CN, —(CO)R8, —(CS)R7, —F, —Cl, —Br, —I, —O—C1-6 alkyl, —O—C6-14aryl, —O(CO)R7, —S—C1-6alkyl, —S —C6-14aryl, —SOR8, or an —SO2R8 residue, and
- A, B can be a —CH2—, —CH(OH) residue or
- A+B can be a —CH═CH— residue, or
- with a pharmaceutically acceptable salt thereof.
14 more elements
Dependencies are inferred from the claim text.