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US 2010/0305065 A1Published application
Use of 4-(pyrrolidin-1-yl)quinoline compounds to kill clinically latent microorganisms
AssigneeHelperby Therapeutics Limited
InventorsMandy Christine Beswick, Susan Mary Cramp, Yanmin Hu, Thomas David Pallin, Hazel Joan Dyke, Anthony Coates
Life of this patent
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Abstract
There is provided the use of compounds of formula wherein R1, R2, R3 and E have meanings given in the description, for the preparation of a medicament for killing clinically latent microorganisms. There is also provided the use of compounds of formula I for treating microbial infections, as well as certain compounds of formula (I) per se.
Claims48
Use of a compound of formula I, or a pharmaceutically-acceptable derivative thereof, for the preparation of a medicament for killing clinically latent microorganisms, wherein the compound of formula I is represented by the structure
- wherein
- E represents CH or N;
- R1 represents one to four substituents on the pyrrolidinyl ring, each substituent independently representing the group —X—R4a;
- X represents
- (a) a direct bond,
- (b) —O— or
- (c) —N(R4b)—;
- R4a and R4b independently represent
- (a) H,
- (b) C1-12 alkyl, C3-12 cycloalkyl, C3-12 cycloalkenyl (which latter three groups are optionally substituted by one or more substituents selected from halo, nitro, CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl (which latter three groups are optionally substituted by one or more substituents selected from OH, ═O, halo, C1-4 alkyl and C1-4 alkoxy), OR5a, S(O)nR5b, S(O)2N(R5c)(R5d), N(R5e)S(O)2R5f, N(R5g)(R5h), B1—C(O)—B2—R5i, aryl and Het1, and which C3-12 cycloalkyl or C4-12 cycloalkenyl groups may additionally be substituted by ═O),
- (c) aryl or
- (d) Het2;
- R2 represents
- (a) H,
- (b) C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C4-12 cycloalkenyl, which latter five groups are optionally substituted by one or more substituents selected from halo, nitro, CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl (which latter three groups are optionally substituted by one or more substituents selected from OH, ═O, halo, C1-4 alkyl and C1-4 alkoxy), OR6a, S(O)pR6b, S(O)2N(R6c)(R6d), N(R6e)S(O)2R6f, N(R6g)(R6h), B3—C(O)—B4—R6i, aryl and Het3, and which C3-12 cycloalkyl or C4-12 cycloalkenyl groups may additionally be substituted by ═O,
- (c) aryl or
- (d) Het4;
- R3 represents H or one to four substituents on the fused benzene ring selected from
- (a) halo,
- (b) CN,
- (c) C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C4-12 cycloalkenyl, which latter five groups are optionally substituted by one or more substituents selected from halo, nitro, CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl (which latter three groups are optionally substituted by one or more substituents selected from OH, ═O, halo, C1-4 alkyl and C1-4 alkoxy), OR7a, S(O)qR7b, S(O)2N(R7c)(R7d), N(R7e)S(O)2R7f, N(R7g)(R7h), B5—C(O)—B6—R7i, aryl and Het5, and which C3-12 cycloalkyl or C4-12cycloalkenyl groups may additionally be substituted by ═O,
- (d) OR8a,
- (e) S(O)rR8b,
- (f) S(O)2N(R8c)(R8d),
- (g) N(R8e)S(O)2R8f,
- (h) N(R8g)(R8h),
- (i) B7—C(O)—B8—R8i,
- (j) aryl or
- (k) Het6;
- R5a to R5i, R6a to R6i, R7a to R7i and R8a to R8i independently represent, at each occurrence,
- (a) H,
- (b) C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl (which latter three groups are optionally substituted by one or more substituents selected from halo, OH, C1-6 alkoxy, aryl and Het7),
- (c) C3-10 cycloalkenyl (which latter two groups are optionally substituted by C3-10 cycloalkyl, C4-10 one or more substituents selected from halo, OH, ═O, C1-6 alkyl, C1-6 alkoxy, aryl and Het8),
- (d) aryl or
- (e) Het9,
- provided that R5b, R6b R7b or R8b does not represent H when n, p, q or r, respectively is 1 or 2;
- each aryl independently represents a C6-10 carbocyclic aromatic group, which group may comprise either one or two rings and may be substituted by one or more substituents selected from
- (a) halo,
- (b) CN,
- (c) C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C4-12 cycloalkenyl, which latter five groups are optionally substituted by one or more substituents selected from halo, nitro, CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl (which latter three groups are optionally substituted by one or more substituents selected from OH, ═O, halo, C1-4 alkyl and C1-4 alkoxy), OR9a, S(O)tR9b, S(O)2N(R9c)(R9d), N(R9e)S(O)2R9f, N(R9g)(R9h), B9—C(O)—B10—R9i, phenyl, naphthyl (which latter two groups are optionally substituted by one or more substituents selected from OH, halo, C1-4 alkyl and C1-4 alkoxy) and Het10, and which C3-12 cycloalkyl or C4-12 cycloalkenyl groups may additionally be substituted by ═O,
- (d) OR10a,
- (e) S(O)uR10b,
- (f) S(O)2N(R10c)(R10d),
- (g) N(R10e)S(O)2R10f,
- (h) N(R10g)(R10h),
- (i) B11—C(O)—B12—R10i,
- (j) phenyl (which latter group is optionally substituted by one or more substituents selected from OH, halo, C1-4 alkyl and C1-4 alkoxy) or
- (k) Het11;
- R9a to R9i and R10a to R10i independently represent, at each occurrence,
- (a) H,
- (b) alkyl, C2-12 alkenyl, C2-12 cycloalkenyl (which latter C1-12 alkynyl, C3-12 cycloalkyl, C4-12 five groups are optionally substituted by one or more substituents selected from halo, OH, C1-6 alkyl, C3-12 cycloalkyl, C4-12 cycloalkenyl (which latter two groups are optionally substituted by one or more substituents selected from OH, ═O, halo, C1-4 alkyl and C1-4 alkoxy), C1-6 alkoxy, NH2, N(H)—C1-6 alkyl, N(C1-6 alkyl)2, phenyl (which latter group is optionally substituted by one or more substituents selected from OH, halo, C1-4 alkyl and C1-4 alkoxy) and Het12, and which C3-12 cycloalkyl or C4-12cycloalkenyl groups may additionally be substituted by ═O),
- (c) phenyl (which latter group is optionally substituted by one or more substituents selected from OH, CN, halo, C1-6 alkyl and C1-6 alkoxy) or
- (e) Het13,
- provided that R9b or Rlob does not represent H when t or u, respectively is 1 or 2;
- Het1 to Het13 independently represent 4- to 14-membered heterocyclic groups containing one or more heteroatoms selected from oxygen, nitrogen and/or sulfur, which heterocyclic groups may comprise one, two or three rings and may be substituted by one or more substituents selected from
- (a) halo,
- (b) CN,
- (c) C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C4-12 cycloalkenyl, which latter five groups are optionally substituted by one or more substituents selected from halo, nitro, CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl (which latter three groups are optionally substituted by one or more substituents selected from OH, ═O, halo, C1-4 alkyl and C1-4 alkoxy), OR11a, S(O)vR11b, S(O)2N(R11c)(R11d), N(R11e)S(O)2R11f, N(R11g)(R11h), B13—C(O)—B14—R11i, phenyl, naphthyl (which latter two groups are optionally substituted by one or more substituents selected from OH, halo, C1-4 alkyl and C1-4 alkoxy) and Heta, and which C3-12 cycloalkyl or C4-12 cycloalkenyl groups may additionally be substituted by ═O,
- (d) OR12a,
- (e)═O,
- (f) S(O)wR12b,
- (g) S(O)2N(R12c)(R12d),
- (h) N(R12e)S(O)2R12f,
- (i) N(R12g)(R12h),
- (j) B15—C(O)—B16—R12i,
- (k) phenyl (which latter group is optionally substituted by one or more substituents selected from OH, halo, C1-4 alkyl and C1-4 alkoxy) or
- (l) Hetb;
- R11a to R11i and R12a to R12i independently represent, at each occurrence,
- (a) H,
- (b) C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C4-12 cycloalkenyl (which latter five groups are optionally substituted by one or more substituents selected from halo, OH, C1-6 alkyl, C3-12 cycloalkyl, C4-12 cycloalkenyl (which latter two groups are optionally substituted by one or more substituents selected from OH, ═O, halo, C1-4 alkyl and C1-4 alkoxy), C1-6 alkoxy, phenyl (which latter group is optionally substituted by one or more substituents selected from OH, halo, C1-4 alkyl and C1-4 alkoxy) and Hetc, and which C3-12 cycloalkyl or C4-12 cycloalkenyl groups may additionally be substituted by ═O),
- (c) phenyl (which latter group is optionally substituted by one or more substituents selected from OH, halo, C1-4 alkyl and C1-4 alkoxy) or
- (e) Hetd,
- provided that R11b or R12b does not represent H when v or w, respectively is 1 or 2;
- B1 to B16 independently represent a direct bond, O, S, NH or N(R13);
- n, p, q, r, s, t, u, v and w independently represent 0, 1 or 2;
- R13 represents
- (a) C1-6 alkyl,
- (b) phenyl (which latter group is optionally substituted by one or more substituents selected from OH, halo, C1-4 alkyl and C1-4 alkoxy),
- (c) C3-7 cycloalkyl (which latter group is are optionally substituted by one or more substituents selected from OH, ═O, halo, C1-4 alkyl and C1-4 alkoxy) or
- (e) Hete;
- Heta to Hete independently represent 5- or 6-membered heterocyclic groups containing one to four heteroatoms selected from oxygen, nitrogen and/or sulfur, which heterocyclic groups may be substituted by one or more substituents selected from halo, ═O and C1-6 alkyl;
- and
- unless otherwise specified
- (i) alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl groups, as well as the alkyl part of alkoxy groups, may be substituted by one or more halo atoms, and
- (ii) cycloalkyl and cycloalkenyl groups may comprise one or two rings and may additionally be ring-fused to one or two benzene rings.
82 more elements
Dependencies are inferred from the claim text.