Claims for Patent: 7,101,882

Summary for Patent: 7,101,882

Title:	Morpholin-acetamide derivatives for the treatment of inflammatory diseases
Abstract:	The present invention relates to novel morpholin-acetamide compounds of formula (I) useful for the treatment of inflammatory diseases. Compounds of formula (I) ##STR00001## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, X, a, b and Z are as defined in the specification, processes for preparing them, formulations containing them and their use in therapy for the treatment of inflammatory diseases.
Inventor(s):	Ancliff; Rachael Anne (Stevenage, GB), Cook; Caroline Mary (Stevenage, GB), Eldred; Colin David (Stevenage, GB), Gore; Paul Martin (Stevenage, GB), Harrison; Lee Andrew (Stevenage, GB), Hodgson; Simon Teanby (Stevenage, GB), Judd; Duncan Bruce (Stevenage, GB), Keeling; Suzanne Elaine (Stevenage, GB), Lewell; Xiao Qing (Stevenage, GB), Robertson; Graeme Michael (Stevenage, GB), Swanson; Stephen (Stevenage, GB)
Assignee:	Glaxo Group Limited (Greenford, GB)
Application Number:	10/381,767
Patent Claims:	1. A compound of formula (I): ##STR00021## wherein: R.sup.1 is C.sub.1-6 alkyl, C.sub.2-6alkenyl, C.sub.2-6 alkynyl, C.sub.2-6 alkynyl-Y.sup.1--, aryl-Y.sup.1--, C.sub.2-6alkenyl-Y.sup.1--, aryl-O--Y.sup.1--, aryl-(O),-aryl-Y.sup.1, C.sub.1-6 alkyl-SO.sub.2--Y.sup.1--, M--Y.sup.1--, --CN or C.sub.3-8 cycloalkyl-Y.sup.1-- or C.sub.3-8 cycloalkenyl-Y.sup.1--, wherein cycloalkyl or cycloalkenyl may be optionally substituted by one or more hydroxyl or C.sub.1-6 alkyl groups; R.sup.2 is hydrogen or C.sub.1-6 alkyl; X is ethylene or a group of formula CR.sup.eR.sup.f wherein R.sup.e and R.sup.f independently represent hydrogen or C.sub.1-4 alkyl or R.sup.e and R.sup.f may together with the carbon atom to which they are attached form a C.sub.3-8 cycloalkyl group; R.sup.3 and R.sup.4 are each independently hydrogen or C.sub.1-4 alkyl; Z is a bond, CO, CHR.sup.6(CH.sub.2).sub.n, CHR.sup.6(CH.sub.2).sub.nO or CHR.sup.6(CH.sub.2).sub.nCO; R.sup.5 is phenyl which may be optionally substituted by one or more halogen groups or thiophenyl which may be optionally substituted by one or more halogen groups; R.sup.6 is hydrogen, C.sub.1-4alkyl, CONR.sup.7R.sup.8 or COOC.sub.1-6 alkyl; a and b are both 1; n is an integer from 0 to 4; R.sup.7 and R.sup.8 are each independently hydrogen or C.sub.1-6 alkyl; M is a C.sub.3-8 cycloalkyl or a C.sub.3-8 cycloalkenyl group fused to a monocyclic aryl; t is 0 or 1; Y.sup.1 is methylene, ethylene, or cyclopropyl; or a physiologically acceptable salt or solvate thereof. 2. A compound of formula (I) according to claim 1 wherein R.sup.1 is C.sub.1-6 alkyl C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl-Y.sup.1--, aryl-(O).sub.t-aryl-Y.sup.1, C.sub.2-6 alkenyl-Y.sup.1--, aryl-O--Y.sup.1--, C.sub.1-6 alkyl-SO.sub.2--Y.sup.1--, M--Y.sup.1--, --CN, C.sub.3-8 cycloalkyl-Y.sup.1--, or C.sub.3-8 cycloalkenyl-Y.sup.1. 3. A compound according to claim 1 wherein R.sup.1 is C.sub.1-6 alkyl C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl-Y.sup.1--, aryl-(O).sub.t-aryl-Y.sup.1, C.sub.2-6 alkenyl-Y.sup.1--, aryl-O--Y.sup.1--, C.sub.1-6 alkyl-SO.sub.2--Y.sup.1--, M--Y.sup.1--, C.sub.3-8 cycloalkyl-Y.sup.1--, or C.sub.3-8 cycloalkenyl-Y.sup.1. 4. A compound according to claim 1 wherein X is methylene. 5. A compound according to claim 1 wherein Z is CHR.sup.6(CH.sub.2).sub.n or CHR.sup.6(CH.sub.2).sub.nCO. 6. A compound according to claim 1 wherein Z is --CH.sub.2--. 7. A compound according to claim 1 wherein R.sup.5 represents phenyl optionally substituted with one or more halogen groups. 8. A compound according to claim 1 wherein R.sup.5 is 3,4-dichlorophenyl. 9. A compound selected from the group consisting of: N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-phenylacetamide; N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-[4-(methylsulfonyl)phe- nyl]acetamide salt with formic acid (1:1); N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-(3-fluorophenyl)acetam- ide; N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-(4-fluorophenyl)a- cetamide; N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-[4-(methylth- io)phenyl]acetamide; N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-(3,4-difluorophenyl)ac- etamide; N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-{[(dimethylam- ino)sulfonyl]phenyl}acetamide salt with formic acid (1:1); 2-(3-Chlorophenyl)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetam- ide; N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-(4-methylphenyl)a- cetamide; 4-[2-({[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-ox- oethyl]benzamide; 2-(4-Chlorophenyl)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetam- ide; N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-[4-(dimethylamino- )phenyl]acetamide salt with formic acid (1:1); N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-(2,5-dichlorophenyl)ac- etamide; N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-[4-(trifluoro- methyl)phenyl]acetamide; N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-(3,4-dichlorophenyl)ac- etamide; 2-(2-Chlorophenyl)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]meth- yl}acetamide; 2-[3,5-Bis(trifluoromethyl)phenyl]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-- yl]methyl}acetamide; N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-(2,4-dichlorophenyl)ac- etamide; N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}2-(4-fluoro-2-me- thylphenyl)acetamide; N-{[(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-(2,6-dichlorophenyl)acet- amide; N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-phenoxyacetamid- e; N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-(4-methoxyphenyl)ac- etamide; 2-(4-Chlorophenyl)-N-{[4-(3,4-dichlorobenzyl)-5,5-dimethylmorpho- lin-2-yl]methyl}acetamide; N-{[(cis)-4-(3,4-Dichlorobenzyl)-5-methylmorpholin-2-yl]methyl}-2-phenyla- cetamide; N-{[(trans)-4-(3,4-Dichlorobenzyl)-5-methylmorpholin-2-yl]methy- l}-2-phenylacetamide; 2-(4-Chlorophenyl)-N-{[(cis)-4-(3,4-dichlorobenzyl)-5-methylmorpholin-2-y- l]methyl}acetamide; 2-(4-Chlorophenyl)-N-{[(trans)-4-(3,4-dichlorobenzyl)-5-methylmorpholin-2- -yl]methyl}acetamide; N-({4-[3-(3,4-Dichlorophenyl)propylmorpholin-2-yl}methyl)-2-phenylacetami- de; 2-(4-Chlorophenyl))-N-{[4-(2,3-dichlorobenzyl)morpholin-2-yl]methyl}a- cetamide trifluoroacetate; 1-(4-Chlorophenyl)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}cyclop- ropanecarboxamide trifluoroacetate; N-{[(2S)-4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}2-[4-(methylsulfonyl- )phenyl]acetamide; N-{[(2R)-4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-[4-(methylsulfony- l)phenyl]acetamide; N-{[4-(3,4-Difluorobenzyl)morpholin-2-yl]methyl}-2-{4-[(methylsulfonyl)am- ino]phenyl}acetamide; N-{[(2S)-4-(4-Fluorobenzyl)morpholin-2-yl]methyl}-2-{4-[(methylsulfonyl)a- mino]phenyl}acetamide; N-{[(2R)-4-(4-Fluorobenzyl)morpholin-2-yl]methyl}-2-{4-[(methylsulfonyl)a- mino]phenyl}acetamide; N-{[4-(4-Fluorobenzyl)morpholin-2-yl]methyl}-2-{4-[(methylsulfonyl)amino]- phenyl}acetamide; N-({(2S)-4-[(5-Chlorothien-2-yl)methyl]morpholin-2-yl}methyl)-2-{3-[(meth- ylsulfonyl)amino]phenyl}acetamide; N-({(2R)-4-[(5-Chlorothien-2-yl)methyl]morpholin-2-yl}methyl)-2-{3-[(meth- ylsulfonyl)amino]phenyl}acetamide; N-({4-[(5-Chlorothien-2-yl)methyl]morpholin-2-yl}methyl)-2-{3-[(methylsul- fonyl)amino]phenyl}acetamide; N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-(2,6-difluorophenyl)ac- etamide; N-Cyclopropyl)-3-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]meth- yl}amino)-2-oxoethyl]benzamide; Methyl 3-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]ben- zoate; 3-[2-({[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoet- hyl]benzoic acid compound with N,N,N-triethylamine (1:1); 2-[3-(acetylamino)phenyl]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl- }acetamide; methyl 4-[2-({[(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]benzo- ate trifluoroacetate; methyl 4-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]ben- zoate; 2-(4-cyanophenyl)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}- acetamide trifluoroacetate; 2-(4-cyanophenyl)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetami- de; N-{[(2S,5R)-4-(3,4-dichlorobenzyl)-5-methylmorpholin-2-yl]methyl}-2-p- henylacetamide; 2-(4-chlorophenyl)-N-{[(2S,5R)-4-(3,4-dichlorobenzyl)-5-methylmorpholin-2- -yl]methyl}acetamide; N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-(3-fluoro-4-hydroxyphe- nyl)acetamide trifluoroacetate; 4-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]-N-- [2-(dimethylamino)ethyl]benzamide; 4-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]-N,- N-dimethylbenzamide; 4-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]-N-- ethylbenzamide; N-{[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-{3-[(dimethylamin- o)sulfonyl]phenyl}acetamide; N-{[(2R)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-{4-[(dimethylamin- o)sulfonyl]phenyl}acetamide; N-{[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-{4-[(dimethylamin- o)sulfonyl]phenyl}acetamide; 4-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]-N-- methylbenzamide; 4-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]-N-- isopropylbenzamide; N-cyclopropyl-4-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-- 2-oxoethyl]benzamide; 4-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]-N-- (2-methoxyethyl)benzamide; N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-(4-nitrophenyl)acetami- de; N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-(3-nitrophenyl)ace- tamide; 2-[3-(acetylamino)phenyl-N-{[4-(3-fluorobenzyl)morpholin-2-yl]met- hyl}acetamide; N-{[4-(3-fluorobenzyl)morpholin-2-yl]methyl)}-2-{4-[(methylsulfonyl)amino- ]phenyl}acetamide; 2-[3-(acetylamino)phenyl]-N-{[4-(3,4-difluorobenzyl)morpholin-2-yl]methyl- }acetamide; 2-[4-(acetylamino)phenyl]-N-{[4-(3,4-difuorobenzyl)morpholin-2-yl]methyl}- acetamide; N-{[4-(3,4-difluorobenzyl)morpholin-2-yl]methyl}-2-{3-[(methylsulfonyl)am- ino]phenyl}acetamide; N-{[4-(3,4-difluorobenzyl)morpholin-2-yl]methyl}-2-[3-(methylsulfonyl)phe- nyl]acetamide; N-{[4-(3-chlorobenzyl)morpholin-2-yl]methyl}-2-[4-(methylsulfonyl)phenyl]- acetamide; N-{[4-(3-chlorobenzyl)morpholin-2-yl]methyl}-2-[3-(methylsulfonyl)phenyl]- acetamide; 2-[3-(acetylamino)phenyl]-N-{[4-(4-fluorobenzyl)morpholin-2-yl]methyl}ace- tamide; 2-[4-(acetylamino)phenyl]-N-{[4-(4-fluorobenzyl)morpholin-2-yl]me- thyl}acetamide; N-{[4-(2,3-dichlorobenzyl)morpholin-2-yl]methyl}-2-4-(methylsulfonyl)phen- yl]acetamide; 2-[3-(acetylamino)phenyl]-N-{[4-(2,3-dichlorobenzyl)morpholin-2-yl]methyl- }acetamide; N-{[4-(2,3-dichlorobenzyl)morpholin-2-yl]methyl}-2-{4-[(methylsulfonyl)am- ino]phenyl}acetamide; N-{[4-(2,3-dichlorobenzyl)morpholin-2-yl]methyl}-2-(4-{[(methylamino)carb- onyl]amino}phenyl)acetamide; N-({4-[(5-chlorothien-2-yl)methyl]morpholin-2-yl}methyl)-2-[4-(methylsulf- onyl)phenyl]acetamide; 2-[3-(acetylamino)phenyl]-N-({4-[(5-chlorothien-2-yl)methyl]morpholin-2-y- l}methyl)acetamide; N-({4-[(5-chlorothien-2-yl)methyl]morpholin-2-yl}methyl)-2-{4-[(methylsul- fonyl)amino]phenyl}acetamide; 2-[3-(acetylamino)phenyl]-N-{[4-(3-chlorobenzyl)morpholin-2-yl]methyl}ace- tamide; N-{[4-(3-chlorobenzyl morpholin-2-yl]methyl}-2-{4-[(methylsulfonyl)amino]phenyl}acetamide; 2-[4-(acetylamino)phenyl]-N-{[4-(3-chlorobenzyl)morpholin-2-yl]methyl}ace- tamide; N-{[4-(3-chlorobenzyl)morpholin-2-yl]methyl}-2-(4-{[(methylamino)- carbonyl]amino}phenyl)acetamide; 2-[4-(acetylamino)phenyl]-N-{[4-(2,3-dichlorobenzyl)morpholin-2-yl]methyl- }acetamide; N-{[4-(2,3-dichlorobenzyl)morpholin-2-yl]methyl}-2-[3-(methylsulfonyl)phe- nyl]acetamide; 2-[4-(aminosulfonyl)phenyl]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]meth- yl}acetamide; 2-[2-(acetylamino)phenyl]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl- }acetamide; 2-(3-cyanophenyl)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetami- de; N-{[(2S,5R)-4-(2,5-dichlorobenzyl)-5-methylmorpholin-2-yl]methyl}-2-p- henylacetamide; 2-(4-chlorophenyl)-N-{[(2S,5R)-4-(2,5-dichlorobenzyl)-5-methylmorpholin-2- -yl]methyl}acetamide; N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-(2-fluorophenyl)acetam- ide; N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-(2,3-difluorophen- yl)acetamide; N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-(2,4-difluorophenyl)ac- etamide; N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-(2,5-difluoro- phenyl)acetamide; 3-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]-N-- (2-methoxyethyl)benzamide; 3-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]-N-- ethylbenzamide; 3-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]-N,- N-dimethylbenzamide; 3-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]-N-- [2-(dimethylamino)ethyl]benzamide; 2-(3-aminophenyl)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetami- de; 2-(4-aminophenyl)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}ace- tamide; 2-[4-(acetylamino)phenyl)]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-- yl]methyl}acetamide; N-{4-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]- phenyl}-2-methylpropanamide; N-{3-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]- phenyl}-2-methylpropanamide; N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-{3-[(methylsulfonyl)am- ino]phenyl}acetamide; N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-{4-[(methylsulfonyl)am- ino]phenyl}acetamide; N-{3-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]- phenyl}-2-(dimethylamino)acetamide; 2-{4-[bis(methylsulfonyl)amino]phenyl}-N-{[4-(3,4-dichlorobenzyl)morpholi- n-2-yl]methyl}acetamide; N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-[3-(methylsulfonyl)phe- nyl]acetamide; N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-[4-(methylsulfonyl)-2-- nitrophenyl]acetamide; N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-(2-hydroxyphenyl)aceta- mide; N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-{4[methyl(methyl- sulfonyl)amino]phenyl}acetamide; N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-{3-[methyl(methylsulfo- nyl)amino]phenyl}acetamide; 2-[2-amino-4-(methylsulfonyl)phenyl]-N-{[4-(3,4-dichlorobenzyl)morpholin-- 2-yl]methyl}acetamide; N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}pent-4-ynamide; N-{[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-{4-[(methylamino)- sulfonyl]phenyl}acetamide; N-{[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-{4-[(ethylamino)s- ulfonyl]phenyl}acetamide; 2-[3-(Aminosulfonyl)phenyl]-N-{[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl- ]methyl}acetamide; 2-[3-(Aminosulfonyl)phenyl]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]meth- yl}acetamide; 2-{3-[(cyclopropylamino)sulfonyl]phenyl}-N-{[(2S)-4-(3,4-dichlorobenzyl)m- orpholin-2-yl]methyl}acetamide; N-{[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-{3-[(ethylamino)s- ulfonyl]phenyl}acetamide; N-{[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-{3-[(methylamino)- sulfonyl]phenyl}acetamide; 2-[4-(aminosulfonyl)phenyl]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]meth- yl}acetamide; 2-{4-[(cyclopropylamino)sulfonyl]phenyl}-N-{[4-(3,4 dichlorobenzyl)morpholin-2-yl]methyl}acetamide; N-cyclopropyl-3-[2-({[(2S)-4-(2,3-dichlorobenzyl)morpholin-2-yl]methyl}am- ino)-2-oxoethyl]benzamide; 3-{2-[({(2S)-4-[(5-chlorothien-2-yl)methyl]morpholin-2-yl}methyl)amino]-2- -oxoethyl}-N-cyclopropylbenzamide; N-cyclopropyl-3-[2-({[(2S)-4-(4-fluorobenzyl)morpholin-2-yl]methyl}amino)- -2-oxoethyl]benzamide; 3-[2-({[(2S)-4-(3-chlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]-N- -cyclopropylbenzamide; N-cyclopropyl-3-[2-({[(2S)-4-(3,4-difluorobenzyl)morpholin-2-yl]methyl}am- ino)-2-oxoethyl]benzamide; N-cyclopropyl-3-[2-({[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}am- ino)-2-oxoethyl]benzamide; N-{[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}pentanamide; N-{[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-4-methylpentanamide- ; N-({4-[3-(3,4-dichlorophenyl)propyl]morpholin-2-yl}methyl)-2-phenoxyace- tamide; 2-cyclohexyl-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acet- amide trifluoroacetate; and 2-(4-chlorophenyl)N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}propana- mide. 10. 2-[3-(Aminosulfonyl)phenyl]-N-{[(2S)-4-(3,4-dichlorobenzyl)morpholin-- 2-yl]methyl}acetamide or a physiologically acceptable solvate thereof. 11. A pharmaceutical composition comprising a compound according to claim 1 in admixture with one or more physiologically acceptable diluents or carriers. 12. A method of manufacturing a pharmaceutical formulation comprising the step of including the compound according to claim 1 in a pharmaceutically acceptable dosage form. 13. A method of treatment of an inflammatory condition which comprises administering to a mammal an effective amount of a compound according to claim 1. 14. A process for preparing a compound according to claim 1 which comprises: (a) acylation of a compound of formula (II) ##STR00022## wherein R.sup.2, R.sup.3, R.sup.4, R.sup.5, X, Z, a and b are as defined in claim 1, with a compound of formula R.sup.1COOH or an activated derivative thereof, wherein R.sup.1 is as defined in claim 1; or (b) reacting a compound of formula (III) ##STR00023## with a compound of formula L.sup.1-Z-R.sup.5, wherein L.sup.1 is a suitable leaving group; or (c) deprotecting a compound which is protected. 15. N-{[4-(3,4-difluorobenzyl)morpholin-2-yl]methyl}2-{3-[(methylsulfonyl- )amino]phenyl}acetamide or a physiologically acceptable salt or solvate thereof. 16. A pharmaceutical composition comprising a compound according to claim 15 in admixture with one or more physiologically acceptable diluents or carriers. 17. A method of manufacturing a pharmaceutical formulation comprising the step of incorporating a compound according to claim 15 in a pharmaceutically acceptable delivery form. 18. A method of treatment of an inflammatory condition which comprises administering to a mammal an effective amount of a compound according to claim 15. 19. A compound selected from the group consisting of: 2-(4-acetylphenyl)-N-{[4-(3,4dichlorobenzyl)morpholin-2-yl]methyl}acetami- de trifluoroacetate; 2-(4acetylphenyl)-N-{[(4-(3,4dichlorobenzyl)morpholin-2-yl]methyl}acetami- de; N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-(4-isobutyrylpheny- l)acetamide trifluoroacetate; and 4-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]-N-- (2-hydroxyethyl)benzamide. 20. A compound according to claim 19 wherein the compound is 2-(4-acetylphenyl)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetam- ide trifluoroacetate. 21. A compound according to claim 19 wherein the compound is 2-(4-acetylphenyl)-N-{([4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}aceta- mide. 22. A compound according to claim 19 wherein the compound is N-{[(4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-(4-isobutyrylphenyl)a- cetamide trifluoroacetate. 23. A compound according to claim 19 wherein the compound is 4-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]-N-- (2-hydroxyethyl)benzamide. 24. A method for treating asthma or rhinitis in a mammal in need thereof, said method comprising administering an effective amount of a compound according to claim 15. 25. A composition comprising a compound according to claim 15 and an anti-histamine, wherein the anti-histamine is methapyrilene or loratadine.

Details for Patent 7,101,882

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Jubilant Hollisterstier Llc	N/A	positive skin test control-histamine	Injection	103891	March 13, 1924	7,101,882	2020-09-29