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US 6,610,711 B2Granted
4-phenylpiperidines for the treatment of pruritic dermatoses
AssigneePfizer Inc.
InventorsRichard Edward Armer, Christopher James Dutton, David Morris Gethin, Stephen Paul Gibson, Julian Duncan Smith, Ivan Tommasini
Life of this patent
Estimating the term…
Abstract
Novel compounds having general formula (I), and pharmaceutically and veterinarily acceptable salts thereof wherein R1, R2, R3, W, Y1, Y2, X, n and y are as defined above and processes for their preparation and intermediate compounds prepared therein. The novel compounds are useful for having utility in the treatment of pruritic dermatoses including allergic dermatitis and atopy in animals and humans.
Claims41
A compound having the formula:
- or pharmaceutically and veterinarily acceptable salts thereof wherein:
- R1 and R2 are each independently H or C1-C4 alkyl;
- R3 is C1-C10 alkyl, C3-C10 alkenyl, or C3-C10 alkynyl;
- wherein said alkyl, alkenyl or alkynyl group may optionally be substituted by one or more substituents independently chosen from:
- OH;
- CN:
- one or more halo atoms;
- C1-C6 alkoxy;
- C1-C6 alkoxycarbonyl;
- C2-C6 alkanoyloxy;
- C3-C8 cycloalkyl;
- C3-C8 cycloalkoxy;
- C4-C9 cycloalkanoyl;
- aryl;
- aryloxy;
- aryl(C1-C4)alkoxy;
- heteroaryl;
- a saturated heterocyclic group;
- adamantyl or ZBNRARS wherein Z is a direct bond, CO or S(O)p wherein p=0, 1, 2 and wherein B=(CH2)m wherein m from 0 to 10 and wherein R4 and R5 are independently selected from H, C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C3-C8 cycloalkyl, aryl or heteroaryl or wherein R4 and R5 represent unbranched C2-C6 alkylene groups which when taken together with the N to which they are bonded form a 4 to 7 memebered saturated heterocyclic ring optionally containing O, S, or N—R wherein said heterocyclic ring may be substituted by one or more C1-C4 alkyl groups and wherein R6 is H, C1-C6 alkyl, C3-C6 cycloalkyl, —(C1-C6 alkylene)(C3-C8 cycloalkyl)or —(C1-C6 alkylene)aryl and wherein when Z is a direct bond and m=0, then R3 is not a terminal alkenyl or alkynyl;
- W is SO2, C═O, P(Y1)°O or P(Y1)═S;
- X is one or more substitiLents independently selected from H, halo, C1-C4 alkyl, C1-C4 alkoxy, halo (C1-C4) alkyl or halo(C1-C4)alkoxy;
- Y1 is C1-C10 alkyl which may optionally be substituted by one or more halo atoms or by OH, C1-C4 alkoxy, C2-C6 alkanoyloxy, CONH2, NH2 or aryl;
- NH2 or aryl;
- NH2, mono- or di-(C1-C4) alkylamino, C3-C8 cycloatkyl, aryl, phthalimidyl or heteroaryl;
- Y2 is H, C1-C4 alkyl, or C3-C6 alkenyl, wherein said alkyl or alkenyl groups may optionally be substituted by aryl, aryloxy or heteroaryl;
- n is 0, 1 or 2;
- y is 0 or 1, and wherein aryl is phenyl or naphthyl, and wherein aryl may optionally be substituted with 1 to 3 substituents, each independently selected from OH, C1-C4alkyl, C1-C4alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C2-C5alkanoyl, halo, CN, CH2, CN and CONH2, and when W is SO2, R1 and R2 cannot both be hydrogen.
24 more elements
A process for the formation of compounds and salts having the formula (I):
- wherein:
- R1 and R2 are each independently H or C1-C4alkyl;
- R3 is C1-C10 alkyl, C3-C10 alkenyl, or C3-C10 alkynyl;
- wherein said alkyl, alkenyl or alkynyl group may optionally be substituted by one or more substituents independently chosen from:
- OH;
- CN;
- one or more halo atoms;
- C1-C6 alkoxy;
- C1-C6 alkoxycarbonyl;
- C2-C6 alkanoyl;
- C2-C6 alkanoyloxy;
- C3-C8 cycloalkyl;
- C3-C8 cycloalkoxy;
- C4-C9 cycloalkanoyl;
- aryl;
- aryloxy;
- aryl(C1-C4)alkoxy;
- heteroaryl;
- a saturated heterocyclic group;
- adamantyl or ZBNR4R5 wherein Z is a direct bond, CO or S(O)p wherein p=0, 1, 2 and wherein B=(CH2)m, wherein m=from 0 to 10 and wherein R4 and R5 are independently selected from H, C1C10 alky, C3-C10 alkenyl, C3-C10 alkenyl, C3-C8 cycloalkyl, aryl or heteroaryl or wherein R4 and R5 represent unbranched C2-C6 alkylene groups which when taken together with the N to which they are bonded form a 4 to 7 membered saturated heterocyclic ring optionally containing O, S or N—R6 wherein said heterocyclic ring may be substituted by one or more C1-C4 alkyl groups and wherein R6 is H, C1-C6 alkyl, C3-C8 cycloalkyl, —(C1-C6 alkylene)(C3-C8 cycloalkyl) or —(C1-C6 alkylene)aryl and wherein when Z is a direct bond and m=0, then R3 is not a terminal alkenyl or alkynyl;
- W is SO2, C═O, P(Y1)═O or P(Y1)═S;
- X is one or more substitutents independently selected from H, halo, C1-C4 alkyl, C1-C4 alkoxy, halo (C1-C4) alkyl or halo(C1-C4)alkoxy;
- Y1 is C1-C10 alkyl which may optionally be substituted by one or more halo atoms or by OH, C1-C4 alkoxy, C2-C6 alkanoyloxy, CONH2, NH2 or aryl;
- NH2, mono or di-(C1-C4) alkylamino, C3-C8 cycloalkyl, aryl, phthalimidyl or heteroaryl;
- Y2 is H, C1-C4 alkyl, or C3-C6 alkenyl, wherein said alkyl or alkenyl groups may optionally be substituted by aryl, aryloxy or heteroaryl;
- n is 0, 1 or 2;
- and
- y is 0 or 1.
- said process comprising reacting a compound having the formula (IIa):
- wherein R1, R2, R3, X, Y2 and n are as defined above, by reaction with either a group of the formula Q—W—Y1, in the presence of a base, wherein W and Y1 are as defined above and Q is a leaving group;
- or with an anhydride of the formula (Y1W)2O in the presence of a base.
28 more elements
A process for the preparation of compounds and salts having the formula (I):
- wherein:
- R1 and R2 are each independently H or C1-C4 alkyl;
- R3 is C1-C10 alkyl, C3-C10 alkenyl, or C3-C10 alkynyl;
- wherein said alkyl, alkenyl or alkynyl group may optionally be substituted by one or more substituents independently chosen from:
- OH;
- CN;
- one or more halo atoms;
- C1-C6 alkoxy;
- C1-C6 alkoxycarbonyl;
- C2-C6 alkanoyl;
- C2-C6 alkanoyloxy;
- C3-C8 cycloalkyl;
- C3-C8 cycloalkoxy;
- C4-C9 cycloalkanoyl;
- aryl;
- aryloxy;
- aryl(C1-C4)alkoxy;
- heteroaryl;
- a saturated heterocyclic group;
- adamantyl or ZBNR4R5 wherein Z is a direct bond, CO or S(O)p wherein p=0, 1, 2 and wherein B=(CH2)m wherein m=from 0 to 10 and wherein R4 and R5 are independently selected from H, C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C3-C8 cycloalkyl, aryl or heteroaryl or wherein R4 and R5 represent unbranched C2-C6 alkylene groups which when taken together with the N to which they are bonded form a 4 to 7 membered saturated heterocyclic ring optionally containing O, S or N—R6 wherein said heterocyclic ring may be substituted by one or more C1-C4 alkyl groups and wherein R6 is H, C1-C6 alkyl, C3-C8 cycloalkyl, —(C1-C6 alkylene)(C3-C8 cycloalkyl) or —(C1-C6 alkylene)aryl and wherein when Z is a direct bond and m=0, then R3 is not a terminal alkenyl or alkynyl;
- W is SO2, C═O, P(Y1)═O or P(Y1)═S;
- is one or more substitutents independently selected from H, halo, C1-C4 alkyl, C1-C4 alkoxy, halo (C1-C4) alkyl or halo(C1-C4)alkoxy;
- Y1 is C1-C10 alkyl which may optionally be substituted by one or more halo atoms or by OH, C1-C4 alkoxy, C2-C6 alkanoyloxy, CONH2, NH2 or aryl;
- NH2, mono or di-(C1-C4)-alkylamino, C3-C8 cycloalkyl, aryl, phthalimidyl or heteroaryl;
- Y2 is H, C1-C4 alkyl, or C3-C6 alkenyl, wherein said alkyl or alkenyl groups may optionally be substituted by aryl, aryloxy or heteroaryl;
- n is 0, 1 or2;
- and
- y is 0 or 1;
- said process comprising reaction of a compound of formula (IIIa):
- wherein R1, R2, Y1, Y2, W, X and n are as defined above, with a compound of formula R3—X, wherein R 3 is as defined above and wherein X is chloro, bromo, iodo or a suitable leaving group.
27 more elements
Dependencies are inferred from the claim text.