Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-12-16
2000-06-06
Kight, John
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546 16, A61K 31435, C07D21106
Patent
active
060719273
DESCRIPTION:
BRIEF SUMMARY
This application claims priority from PCT/GB97/01630, filed Jun. 17, 1997, now WO97/49710 published Dec. 31, 1997 which claims priority under from Great Britain Application No. 9613108.1, filed Jun. 21, 1996, Great Britain Application No. 9625051.9 filed Dec. 2, 1996, Great Britain Application No. 9626593.9, filed Dec. 20, 1996, Great Britain Application No. 9701459.1, filed Jan. 24, 1997, Great Britain Application No. 9710743.7 filed May 23, 1997, Great Britain Application No. 9710747.8, filed May 23, 1997, and Great Britian Application No. 9710748.6, filed May 23, 1997.
This invention relates to a class of azacyclic compounds which are useful as tachykinin antagonists. More particularly, the compounds of the invention are spiro-substituted azacyclic derivatives.
International (PCT) patent specification no. WO 94/20500 (published Sep. 15, 1994) discloses spiroazacyclic derivatives as substance P antagonists. In particular, WO 94/20500 relates to spirocyclic piperidine derivatives containing a 1,8-diazaspiro[5.5]undecane core.
We have now found a further class of non-peptides which are potent antagonists of tachykinins, especially of substance P. In addition, the compounds of the present invention exhibit a high level of hepatic stability as measured by, for example, conventional liver microsome analysis.
Furthermore, by virtue of their unique cyclopropyl ether moiety, a preferred sub-class of the compounds of the present invention possess a high degree of oral bioavailabilty together with high affinity for the human NK.sub.1 receptor.
The present invention provides compounds of the formula (I): ##STR1## wherein
R.sup.1 represents hydrogen hydroxy, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkylC.sub.1-4 alkyl, C.sub.1-6 alkoxy, fluoroC.sub.1-6 alkoxy, C.sub.1-6 alkoxyC.sub.1-4 alkyl, C.sub.1-6 alkoxyC.sub.1-4 alkoxy, fluoroC.sub.1-6 alkoxyC.sub.1-4 alkyl, C.sub.2-6 alkenyloxy, C.sub.3-7 cycloalkoxy, C.sub.3-7 cycloalkylC.sub.1-4 alkoxy, phenoxy, benzyloxy, cyano, halogen, NR.sup.a R.sup.a, SR.sup.a, SOR.sup.a, SO.sub.2 R.sup.a, OSO.sub.2 R.sup.a, NR.sup.a COR.sup.14, COR.sup.a, CO.sub.2 R.sup.a or CONR.sup.a R.sup.b where R.sup.a and R.sup.b each independently represent hydrogen, C.sub.1-4 alkyl or fluoroC.sub.1-4 alkyl;
R.sup.2 represents hydrogen, halogen, C.sub.1-6 alkyl or C.sub.1-6 alkoxy;
or when R.sup.2 is adjacent to R.sup.1, they may be joined together such that there is formed a 5- or 6-membered saturated or unsaturated ring containing one or two atoms selected from nitrogen, oxygen and sulfur, which ring is optionally substituted by a group selected from C.sub.1-4 alkyl, CF.sub.3, .dbd.O or .dbd.S;
R.sup.3 represents hydrogen halogen C.sub.1-6 alkyl, fluoroC.sub.1-6 alkyl, C.sub.1-6 alkoxy, fluoroC.sub.1-6 alkoxy, C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkylC.sub.1-4 alkyl, cyano, SR.sup.a, SOR.sup.a, SO.sub.2 R.sup.a, NR.sup.a R.sup.b, NR.sup.a COR.sup.14, COR.sup.a, CO.sub.2 R.sup.a, CONR.sup.a R.sup.b or C.sub.1-4 alkyl substituted by cyano, CO.sub.2 R.sup.a or CONR.sup.a R.sup.b where R.sup.a and R.sup.b are as previously defined;
R.sup.4 represents hydrogen, halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, CF.sub.3, OCF.sub.3, NO.sub.2, CN, SR.sup.a, SOR.sup.a, SO.sub.2 R.sup.a, CO.sub.2 R.sup.a, CONR.sup.a R.sup.b, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl or C.sub.1-4 alkyl substituted by C.sub.1-4 alkoxy, where R.sup.a and R.sup.b are as previously defined;
R.sup.5 represents hydrogen, halogen, C.sub.1-6 alkyl, CF.sub.3 or C.sub.1-6 alkoxy substituted by C.sub.1-4 alkoxy;
R.sup.6 represents hydrogen, COR.sup.a, CO.sub.2 R.sup.a, COCONR.sup.a R.sup.b, COCO.sub.2 R.sup.a, C.sub.1-6 alkyl optionally substituted by a group selected from (CO.sub.2 R.sup.a, CONR.sup.a R.sup.b, hydroxy, CN, COR.sup.a, NR.sup.a R.sup.b, C(NOH)NR.sup.a R.sup.b, CONHphenyl(C.sub.1-4 alkyl), COCO.sub.2 R.sup.a, CONHNR.sup.a R.sup.b, C(S)NR.sup.a R.sup.b, CONR.sup.a C.sub.1-6 alkylR.sup.12, CONR.sup.13 C.sub.2-6 alkenyl, CONR.sup.13 C.sub.2-6 alkynyl, COCONR.sup.a R.sup.b, CONR.sup.a C(NR.sup.b)N
Baker Raymond
Curtis Neil Roy
Elliott Jason Matthew
Harrison Timothy
Hollingworth Gregory John
Aulakh Charanjit S.
Kight John
Merck Sharp & Dohme Ltd.
Rose David L.
Thies J. Eric
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