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US 2003/0171404 A1Published application
Use of sulfonyl aryl or heteroaryl hydroxamic acids and derivatives thereof as aggrecanase inhibitors
AssigneePharmacia Corporation
InventorsThomas E. Barta, Elizabeth C. Arner, Daniel Becker, Terri L. Boehm, Gary A. DeCrescenzo, Joseph McDonald
Life of this patent
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Abstract
This invention is directed to a process for inhibiting aggrecanase activity. The process comprises administering a therapeutically effective amount of a sulfonyl aromatic or heteroaromatic hydroxamic acid, a derivative thereof, or a pharmaceutically acceptable salt of the hydroxamic acid or derivative to a host animal. The compound generally corresponds in structure to the following formula: 1 wherein W and the R groups are described in more detail in Applicants' specification.
Claims37
A process for preventing or treating a condition associated with aggrecanase activity in a host animal, wherein:
- the process comprises administering a compound or a pharmaceutically-acceptable salt thereof to the host animal in an amount effective to prevent or treat the condition;
- the compound corresponds in structure to Formula A:
- 2818
- the ring structure W is a 5- or 6-member aromatic or heteroaromatic ring;
- X is —CH2— or —N(R9)—;
- R9 is selected from the group consisting of hydrogen, aryl, alkyl, and arylalkyl;
- y and z are each zero or one and the sum of x and y is either zero or 1;
- R1 is a substituent that:
- contains a 5- or 6-member a cyclohydrocarbyl, heterocyclo, aryl, or heteroaryl bonded directly to the depicted SO2 group, and
- has a length greater than about that of a hexyl group and less than about that of an eicosyl group;
- where R1 contains a 6-member ring bonded directly to the depicted SO2 group, R1 has geometrical dimensions such that if R1 were to be rotated about an axis drawn through the SO2-bonded 1-position and the 4-position of the SO2-bonded R1 6-member ring, the 3-dimensional volume defined by the rotation would have a widest dimension in a direction transverse to the axis of rotation of about that of a furanyl ring to about that of 2 phenyl rings;
- where R1 contains a 5-member ring bonded directly to the depicted SO2 group, R1 has geometric dimensions such that if the R1 substituent were to be rotated about an axis drawn through the SO2-bonded 1-position and the center of the 3,4-bond of the SO2-bonded R1 5-member ring, the 3-dimensional volume defined by the rotation would have a widest dimension in a direction transverse to the axis of rotation of about that of a furanyl ring to about that of 2 phenyl rings;
- as to R2 and R3:
- R2 and R3 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, hydroxyalkyl, Ra-oxyalkyl, hydroxy, thiol, Ra-thioalkyl, haloalkyl, —N(Rb)(Rc), N(Rb)(Rc)-alkyl, N(Rd)(Re)-alkanoyl-N(Rb)-alkyl, N(Rb)(Rc)-alkoxy, N(Rb)(Rc)-alkoxyalkyl, heterocyclo, heterocycloalkyl, heterocyclooxy, heterocyclothio, heteroaryl, heteroarylalkyl, heteroaryloxy, and heteroarylthio, or
- R2 and R3, together with the carbon to which they are both bonded, form a 4- to 8-member carbocyclic or heterocyclic ring;
- as to R5 and R6:
- R5 and R6 are independently selected from the group consisting of hydrogen, halogen, nitro, hydroxy, carboxy, cyano, —N(Rb)(Rc), alkyl, haloalkyl, hydroxyalkyl, carboxyalkyl, acylalkyl, cycloalkyl, thiol, alkylthio, arylthio, cycloalkylthio, hydroxyalkylthio, alkoxy, haloalkoxy, cycloalkoxy, alkoxyalkyl, alkoxyalkoxy, heterocyclooxy, N(Rb)(Rc)-alkyl, N(Rb)(Rc)-alkoxy, N(Rb)(Rc)-carbonyl, N(Rb)(Rc)-alkylthio, and N(Rb)(Rc)-sulfonyl, or
- R5 and R6, together with the atoms to which R5 and R6 are both bonded, for an aliphatic or aromatic carbocyclic or heterocyclic ring having from 5 to 7 members;
- R20 is:
- —O—R21, wherein R21 is hydrogen, C1-C6-alkyl, aryl, aryl-C1-C6-alkyl, or a pharmaceutically acceptable cation,
- —NR13—O—R22, wherein R22 is a selectively removable protecting group, and R13 is hydrogen, C1-C6-alkyl, or benzyl,
- —NR13—O—R14, wherein R13 is hydrogen, C1-C6-alkyl, or benzyl, and R14 is hydrogen, a pharmaceutically acceptable cation, or —C(V)R15, wherein:
- V is O or S, and R15 is C1-C6-alkyl, aryl, C1-C6-alkoxy, heteroaryl-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, aryloxy, aryl-C1-C6-alkoxy, aryl-C1-C6-alkyl, heteroaryl, or amino-C1-C6-alkyl, wherein:
- the amino-C1-C6-alkyl nitrogen is unsubstituted,
- the amino-C1-C6-alkyl nitrogen is substituted with 1 or 2 substituents independently selected from the group consisting of C1-C6-alkyl, aryl, aryl-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, aryl-C1-C6-alkoxycarbonyl, C1-C6-alkoxycarbonyl, and C1-C6-alkanoyl, or
- the amino-C1-C6-alkyl nitrogen, together with the 2 substituents bonded thereto, form a 5- to 8-member heterocyclo or heteroaryl ring, or
- —NR23R24, wherein either:
- R23 and R24 are independently selected from the group consisting of hydrogen, C1-C6-alkyl, amino-C1-C6-alkyl, hydroxy-C1-C6-alkyl, aryl, and aryl-C1-C6-alkyl, or
- R23 and R24, together with the nitrogen to which they are both bonded, form a 5- to 8-member ring optionally containing an additional heteroatom that is oxygen, nitrogen, or sulfur;
- Rb and Rc are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, carboxyalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, alkoxyalkyl, bisalkoxyalkyl, perfluoroalkoxyalkyl, alkanoyl, haloalkanoyl, hydroxyalkanoyl, thiolalkanoyl, alkoxycarbonyl, alkoxycarbonylalkyl, aminocarbonyl, alkyliminocarbonyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, aryloxyalkyl, aryloxycarbonyl, arylsulfonyl, aralkanoyl, aroyl, aryliminocarbonyl, heterocyclo, heterocycloalkyl, heterocycloalkylcarbonyl, heteroaryl, heteroaryloxyalkyl, heteroarylalkoxyalkyl, heteroarylthioalkyl, alkylsulfonyl, heteroarylsulfonyl, heterocycloiminocarbonyl, arylthioalkyl, alkylthioalkyl, arylthioalkenyl, alkylthioalkenyl, heteroarylalkyl, aminoalkylcarbonyl, aminosulfonyl, and aminoalkylsulfonyl, wherein any amino nitrogen of Rb or Rc is:
- unsubstituted,
- substituted with 1 or 2 Rd substituents, or
- substituted with substituents such that the substituents, taken together with the amino nitrogen, form either:
- a saturated or partially saturated heterocyclo optionally substituted with 1, 2, or 3 Rd substituents, or
- a heteroaryl optionally substituted with 1, 2, or 3 Rf substituents;
- each Rd and Re is independently selected from the group consisting of hydrogen, alkyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkylcarbonyl, alkoxycarbonyl, and arylalkoxycarbonyl;
- each Rf is independently selected from the group consisting of halogen, cyano, nitro, hydroxy, alkyl, alkoxy, aryl, and —N(Rd)(Re).
34 more elements
A process for preventing or treating a condition associated with aggrecanase activity in a host animal, wherein:
- the process comprises administering a compound or a pharmaceutically-acceptable salt thereof to the host animal in an amount effective to prevent or treat the condition;
- the compound corresponds in structure to Formula VIIC:
- 2824
- W is a 6-member heterocyclic ring comprising the sulfonyl-bonded nitrogen;
- -A-R-E-Y is a substituent of W2 bonded at the 4-position of W2 relative to the sulfonyl-bonded nitrogen;
- A is selected from the group consisting of:
- a bond,
- —O—,
- —S—,
- —S(O)—,
- —S(O)2—,
- —N(Rk)—,
- —C(O)—N(Rk)—,
- —N(Rk)—C(O)—,
- —C(O)—O—,
- —O—C(O)—,
- —O—C(O)—O—,
- —C(H)═C(H)—,
- —C≡C—,
- —N═N—,
- —N(H)—N(H)—,
- —N(H)—C(O)—N(H)—,
- —C(S)—N(Rk)—,
- —N(Rk)—C(S)—,
- —C(H)2—,
- —O—C(H)2—,
- —C(H)2—O—,
- —S—C(H)2—, and
- —C(H)2—S—;
- R is selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and heterocycloalkylthioalkyl, wherein:
- the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl optionally is substituted with 1 or 2 substituents selected from the group consisting of halogen, nitro, hydroxy, amino, alkyl, perfluoroalkyl, trifluoromethylalkyl, hydroxyalkyl, alkoxy, perfluoroalkoxy, perfluoroalkylthio, alkoxycarbonylalkyl, C1-C2-alkylenedioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamino, alkanoylamino, and alkoxycarbonyl;
- E is absent or selected from the group consisting of:
- a bond,
- —C(O)—,
- —C(O)—Rg—,
- —Rg—C(O)—,
- —C(O)—N(Rk)—,
- —N(Rk)—C(O)—,
- —S(O)2—,
- —S(O)2—Rg—,
- —Rg—S(O)2—,
- —N(Rk)—S(O)2—, and
- —S(O)2—N(Rk)—;
- Y is absent or selected from the group consisting of hydrogen, hydroxy, nitrile, nitro, alkyl, haloalkyl, aminoalkyl, alkoxy, perfluoroalkoxy, cycloalkyl, aryl, aralkyl, heteroaryl, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, Ra-oxyalkyl, perfluoroalkylthio, alkenyl, heterocycloalkyl, and alkoxycarbonyl, wherein:
- the aryl, heteroaryl, aralkyl, or heterocycloalkyl optionally is substituted with 1 or 2 substituents independently selected from the group consisting of halogen, nitro, nitrile, alkyl, haloalkyl, alkoxy, perfluoroalkoxy, and aminoalkanoyl, aralkyl, and aryl, wherein:
- the amino nitrogen optionally is substituted with 1 or 2 substituents independently selected from alkyl and aralkyl;
- as to R5 and R6:
- R5 and R6 are independently selected from the group consisting of hydrogen, halogen, nitro, hydroxy, carboxy, cyano, —N(Rb)(Rc), alkyl, haloalkyl, hydroxyalkyl, carboxyalkyl, acylalkyl, cycloalkyl, thiol, alkylthio, arylthio, cycloalkylthio, hydroxyalkylthio, alkoxy, haloalkoxy, cycloalkoxy, alkoxyalkyl, alkoxyalkoxy, heterocyclooxy, N(Rb)(Rc)-alkyl, N(Rb)(Rc)-alkoxy, N(Rb)(Rc)-carbonyl, N(Rb)(Rc)-alkylthio, and N(Rb)(Rc)-sulfonyl, or
- R5 and R6, together with the atoms to which they are bonded, form a an aliphatic or aromatic carbocyclic or heterocyclic ring having 5 to 7 members;
- Ra is selected from the group consisting of hydrogen, alkyl, haloalkyl, N(Rb)(Rc)-alkyl, alkoxyalkyl, alkenyl, alkanoyl, haloalkanoyl, N(Rb)(Rc)-alkanoyl, aryl, arylalkyl, aroyl, arylalkylcarbonyl, and arylalkoxy;
- Rb and Rc are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, carboxyalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, alkoxyalkyl, bisalkoxyalkyl, perfluoroalkoxyalkyl, alkanoyl, haloalkanoyl, hydroxyalkanoyl, thiolalkanoyl, alkoxycarbonyl, alkoxycarbonylalkyl, aminocarbonyl, alkyliminocarbonyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, aryloxyalkyl, aryloxycarbonyl, arylsulfonyl, aralkanoyl, aroyl, aryliminocarbonyl, heterocyclo, heterocycloalkyl, heterocycloalkylcarbonyl, heteroaryl, heteroaryloxyalkyl, heteroarylalkoxyalkyl, heteroarylthioalkyl, alkylsulfonyl, heteroarylsulfonyl, heterocycloiminocarbonyl, arylthioalkyl, alkylthioalkyl, arylthioalkenyl, alkylthioalkenyl, heteroarylalkyl, aminoalkylcarbonyl, aminosulfonyl, and aminoalkylsulfonyl, wherein any amino nitrogen of Rb or Rc is:
- unsubstituted,
- substituted with 1 or 2 Rd substituents, or
- substituted with substituents such that the substituents, taken together with the amino nitrogen, form either:
- a saturated or partially saturated heterocyclo optionally substituted with 1, 2, or 3 Rd substituents, or
- a heteroaryl optionally substituted with 1, 2, or 3 Rf substituents;
- each Rd and Re is independently selected from the group consisting of hydrogen, alkyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkylcarbonyl, alkoxycarbonyl, and arylalkoxycarbonyl;
- each Rf is independently selected from the group consisting of halogen, cyano, nitro, hydroxy, alkyl, alkoxy, aryl, and —N(Rd)(Re);
- Rg is selected from the group consisting of hydrogen, halogen, hydroxy, cyano, amino, carboxy, alkyl, perfluoroalkyl, trifluoroalkyl, alkenyl, alkenyloxy, alkynyl, alkynyloxy, aldehydo, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkanoyl, alkylthio, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclo, aroyl, heteroaroyl, aryloxy, heteroaryloxy, alkoxyaryl, alkoxyheteroaryl, alkylenedioxy, aryloxyalkyl, arylthio, alkoxycarbonyloxy, aryloxycarbonyl, arylalkoxycarbonyl, arylalkoxycarbonylamino, aryloxycarbonyloxy, —N(Rh)(Ri), N(Rh)(Ri)-carbonyloxy, N(Rh)(Ri)-carbonyl, N(Rh)(Ri)-alkanoyl, hydroxyaminocarbonyl, N(Rh)(Ri)-sulfonyl, N(Rh)(Ri)-carbonyl-N(Rh)—, trifluoromethylsulfonyl-N(Rh)—, heteroarylsulfonyl-N(Rh)—. arylsulfonyl-N(Rh)-, arylsulfonyl-N(Rh)-carbonyl, alkylsulfonyl-N(Rh), arylcarbonyl-N(Rh)-sulfonyl, and alkylsulfonyl-N(Rh)-carbonyl;
- each Rh is independently selected from the group consisting of alkyl, haloalkyl, hydroxyalkyl, carboxyalkyl, unsubstituted aminoalkyl, substituted aminoalkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonyl, arylalkyl, alkanoyl, haloalkanoyl, unsubstituted aminoalkanoyl, substituted aminoalkanoyl, aryl, arylalkoxycarbonyl, aroyl, heteroaryl, and heterocyclo, wherein:
- each such group (including the substituents of any substituted amino alkyl or aminoalkanoyl) optionally is substituted by 1 or 2 Rj substituents
- Ri is selected from the group consisting of alkyl, haloalkyl, hydroxyalkyl, carboxyalkyl, unsubstituted aminoalkyl, substituted aminoalkyl, alkoxyalkyl, alkoxycarbonyl, alkenyl, alkynyl, alkanoyl, haloalkanoyl, unsubstituted aminoalkanoyl, substituted aminoalkanoyl, aryl, arylalkyl, arylalkoxycarbonyl, aroyl, heteroaryl, and heterocyclo, wherein:
- each such group optionally is substituted with 1 or 2 Rj substituents;
- each Rj is independently selected from the group consisting of alkyl, haloalkyl, hydroxyalkyl, carboxyalkyl, unsubstituted aminoalkyl, substituted aminoalkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonyl, alkanoyl, haloalkanoyl, unsubstituted aminoalkanoyl, substituted aminoalkanoyl, aryl, arylalkyl, arylalkoxycarbonyl, aroyl, heteroaryl, and heterocyclo, wherein:
- the substituents of the substituted aminoalkyl or substituted aminoalkanoyl are independently selected from the group consisting of alkyl, alkenyl, alkoxycarbonyl, aryl, arylalkyl, aryloxycarbonyl, heteroaryl, and heteroarylalkyl;
- and
- Rk is selected from the group consisting of hydrogen, alkyl, alkenyl, alkoxycarbonyl, aryl, arylalkyl, aryloxycarbonyl, heteroaryl, heteroarylalkyl, N(Rc)(Rd)-carbonyl, N(Rc)(Rd)-sulfonyl, N(Rc)(Rd)-alkanoyl, and N(Rc)(Rd)-alkylsulfonyl.
64 more elements
A process for preventing or treating a condition associated with aggrecanase activity in a host animal, wherein:
- the process comprises administering a compound or a pharmaceutically-acceptable salt thereof to the host animal in an amount effective to prevent or treat the condition;
- the compound corresponds in structure to Formula 34.1:
- 2829
- W2 is a 6-member heterocyclic ring comprising the sulfonyl-bonded nitrogen;
- R4 is a substituent of W2 bonded at the 4-position of W2 relative to the sulfonyl-bonded nitrogen;
- R4 has a chain length of from 3 to about 14 carbon atoms;
- as to R5 and R6:
- R5 and R6 are independently selected from the group consisting of hydrogen, halogen, nitro, hydroxy, carboxy, cyano, —N(Rb)(Rc), alkyl, haloalkyl, hydroxyalkyl, carboxyalkyl, acylalkyl, cycloalkyl, thiol, alkylthio, arylthio, cycloalkylthio, hydroxyalkylthio, alkoxy, haloalkoxy, cycloalkoxy, alkoxyalkyl, alkoxyalkoxy, heterocyclooxy, N(Rb)(Rc)-alkyl, N(Rb)(Rc)-alkoxy, N(Rb)(Rc)-carbonyl, N(Rb)(Rc)-alkylthio, and N(Rb)(Rc)-sulfonyl, or
- R5 and R6, together with the atoms to which they are bonded, form a an aliphatic or aromatic carbocyclic or heterocyclic ring having 5 to 7 members;
- and
- Rb and Rc are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, carboxyalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, alkoxyalkyl, bisalkoxyalkyl, perfluoroalkoxyalkyl, alkanoyl, haloalkanoyl, hydroxyalkanoyl, thiolalkanoyl, alkoxycarbonyl, alkoxycarbonylalkyl, aminocarbonyl, alkyliminocarbonyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, aryloxyalkyl, aryloxycarbonyl, arylsulfonyl, aralkanoyl, aroyl, aryliminocarbonyl, heterocyclo, heterocycloalkyl, heterocycloalkylcarbonyl, heteroaryl, heteroaryloxyalkyl, heteroarylalkoxyalkyl, heteroarylthioalkyl, alkylsulfonyl, heteroarylsulfonyl, heterocycloiminocarbonyl, arylthioalkyl, alkylthioalkyl, arylthioalkenyl, alkylthioalkenyl, heteroarylalkyl, aminoalkylcarbonyl, aminosulfonyl, and aminoalkylsulfonyl, wherein any amino nitrogen of Rb or Rc is:
- unsubstituted,
- substituted with 1 or 2 Rd substituents, or
- substituted with substituents such that the substituents, taken together with the amino nitrogen, form either:
- a saturated or partially saturated heterocyclo optionally substituted with 1, 2, or 3 Rd substituents, or
- a heteroaryl optionally substituted with 1, 2, or 3 Rf substituents;
- each Rd and Re is independently selected from the group consisting of hydrogen, alkyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkylcarbonyl, alkoxycarbonyl, and arylalkoxycarbonyl;
- and
- each Rf is independently selected from the group consisting of halogen, cyano, nitro, hydroxy, alkyl, alkoxy, aryl, and —N(Rd)(Re).
16 more elements
Dependencies are inferred from the claim text.