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US 5,635,509 AGranted
Piperidine derivatives useful as neurokinin antagonists
AssigneeZeneca Limited
InventorsRobert T. Jacobs, Scott C. Miller, Ashokkumar B. Shenvi, Cyrus J. Ohnmacht, Jr., Chris A. Veale
Life of this patent
Estimating the term…
Abstract
Compounds of formula I ##STR1## wherein Q.sup.1, Q.sup.2, Q.sup.3, and Q.sup.4 have any of the meanings given in the specification, their N-oxides, and their pharmaceutically acceptable salts are nonpeptide antagonists of neurokinin A and useful for the treatment of asthma, etc. Also disclosed are pharmaceutical compositions, processes for preparing the compounds of formula I and intermediates.
Claims11
A compound of formula I:
- wherein
- Q.sup.1 is a radical of formula Ih:
- wherein
- L.sup.h denotes a hydrocarbon radical in which the 1-position is attached to M.sup.h and the values of G.sup.h, J.sup.h, M.sup.h and L.sup.h are selected from:
- (a) G.sup.h is a single bond;
- J.sup.h is oxo or thioxo;
- M.sup.h is oxy, thio or NR.sup.ha ;
- and L.sup.h is L.sup.ha ;
- (b) G.sup.h is a single bond;
- J.sup.h is NR.sup.hb ;
- M.sup.h is NR.sup.ha ;
- and L.sup.h is L.sup.ha ;
- (c) G.sup.h is a double bond, J.sup.h is OR.sup.ha, SR.sup.ha or NR.sup.hc R.sup.hd ;
- M.sup.h is nitrogen;
- and L.sup.h is L.sup.ha ;
- (d) G.sup.h is methylene which may bear one or two methyl substituents;
- J.sup.h is oxo, thio or NR.sup.he ;
- M.sup.h is oxy, thio, sulfinyl, sulfonyl or NR.sup.ha ;
- and L.sup.h is L.sup.hb ;
- (e) G.sup.h is a single bond;
- J.sup.h is oxo, thioxo or NR.sup.he ;
- M.sup.h is nitrogen;
- and L.sup.h is L.sup.hc ;
- (f) G.sup.h is methine, which may bear a (1-3C)alkyl substituent;
- J.sup.h is oxo, thioxo or NR.sup.he ;
- M.sup.h is nitrogen;
- and L.sup.h is L.sup.hd ;
- (g) G.sup.h is cis-vinylene, which may bear one or two methyl substituents;
- J.sup.h is oxo, thioxo, or NR.sup.he ;
- M.sup.h is nitrogen;
- and L.sup.h is L.sup.he ;
- and
- (h) G.sup.h is a single bond;
- J.sup.h is oxo or thioxo:
- M.sup.h is a single bond:
- and L.sup.h is L.sup.hf ;
- wherein
- R.sup.ha is hydrogen or (1-3C)alkyl;
- R.sup.hb is hydrogen, (1-3C)alkyl, cyano, (1-3C)alkylsulfonyl or nitro;
- R.sup.hc and R.sup.hd are independently hydrogen or (1-3C)alkyl or the radical NR.sup.hc R.sup.hd is pyrrolidino, piperidino, morpholino, thiomorpholino (or its S-oxide) or piperazinyl (which piperazinyl may bear a (1-3C)alkyl substituent at the 4-position);
- R.sup.he is hydrogen or (1-3C)alkyl;
- L.sup.ha is ethylene, cis-vinylene, trimethylene or tetramethylene which radical L.sup.ha itself may bear one or two methyl substituents;
- L.sup.hb is ethylene or trimethylene which radical L.sup.hb itself may bear one or two methyl substituents;
- L.sup.hc is prop-2-en-1-yliden-3-yl, which radical L.sup.hc itself may bear one or two methyl substituents;
- L.sup.hd is cis-vinylene, which radical L.sup.hd itself may bear one or two methyl substituents;
- L.sup.he is methine, which radical L.sup.he itself may bear a (1-3C)alkyl substituent;
- and L.sup.hf is 4-oxabutan-1,4-diyl;
- Q.sup.2 is a mono valent radical selected from hydroxy, (1-3C)alkoxy, --SR.sup.5, --OC(.dbd.O)R.sup.6, and --OC(.dbd.O)NR.sup.7 R.sup.8 ;
- or divalent radical selected from thioxo and oxo;
- R.sup.5 is hydrogen, (1-3C)alkanoyl, (1-3C)alkyl, phenyl, or phenyl(1-3C)alkyl, wherein any phenyl may optionally be substituted by 1-3 substituents selected from halo, (1-3C)alkyl, and (1-3C)alkoxy;
- R.sup.6 is (1-4C)alkyl, phenyl, or phenyl(1-3C)alkyl, wherein any phenyl may optionally be substituted by 1-3 substituents selected from halo, (1-3C)alkyl, and (1-3C)alkoxy;
- R.sup.7 and R.sup.8 are independently hydrogen, (1-4C)alkyl, phenyl, or phenyl(1-3C)alkyl, wherein any phenyl may optionally be substituted by 1-3 substituents selected from halo, (1-3C)alkyl, and (1-3C)alkoxy;
- Q.sup.3 is hydrogen or (1-3C)alkyl:
- Q.sup.4 is phenyl which may bear one or two substituents independently selected from halo, trifluoromethyl, hydroxy, (1-3C)alkoxy, (1-3C)alkyl and methylenedioxy;
- or Q.sup.4 is thienyl, imidazolyl, benzo[b]thiophenyl or naphthyl any of which may bear a halo substituent;
- or Q.sup.4 is biphenylyl;
- or Q.sup.4 is carbon-linked indolyl which may bear a benzyl substituent at the 1-position;
- T is a carbon-linked five-membered aromatic ring containing 2-3 nitrogens, which is substiteted at a ring position adjacent to the carbon-link by a group Q.sup.5 ;
- and
- Q.sup.5 is (1-6C)alkyl (which may contain a double or triple bond), (3-6C)cycloalkyl (which may contain a double bond), (3-6C)oxacycloalkyl (which may contain a double bond), aryl, aryl(1-3C)alkyl, or 5- or 6-membered heteroaryl (or N-oxide thereof) consisting of carbon and one to four heteroatoms selected from oxygen, sulfur and nitrogen, in which an aryl or heteroaryl radical or portion of a radical may bear one or more substituents on carbon selected from (1-3C)alkyl, (1-3C)alkoxy, methylenedioxy, halogeno, hydroxy, (1-4C)acyloxy and NR.sup.A R.sup.B in which R.sup.A and R.sup.B are independently hydrogen or (1-3C)alkyl, or R.sup.A is hydrogen or (1-3C)alkyl and R.sup.B is (1-4C)acyl;
- or the N-oxide of a piperidino nitrogen indicated by .DELTA.;
- or a pharmaceutically acceptable salt thereof;
- or a quaternary ammonium salt thereof in which the piperidino nitrogen indicated by .DELTA. is a quadricovalent ammonium nitrogen wherein the fourth radical on the nitrogen R.sup.1 is (1-4C)alkyl or benzyl and the associated counterion A is a pharmaceutically acceptable anion.
60 more elements
Dependencies are inferred from the claim text.