Piperazino derivatives as neurokinin antagonists
First Claim
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1. A compound of the formula:
- ##STR216## wherein;
u is 0 to 2;
y is 1 to 3;
with the proviso that no more than one Rc is other than H in the ##STR217## moiety;
Rc is independently selected from the group consisting of H, C1 -C6 alkyl, hydroxy(C1 -C6)alkyl, carboxy(C1 -C6)alkyl and H2 NC(O)-(C1 C6)alkyl;
R1 and R2 are independently selected from the group consisting of H, C1 -C6 alkyl, CF3, C2 F5, Cl, Br, I, F, NO2, ORa, CN, NRa Rb, ##STR218## and where Ra is not H in ##STR219## or when R1 and R2 are on adjacent carbons on a ring, they can form ##STR220## wherein n'"'"' is 1 or 2;
R3 is independently selected from the group consisting of H, C1 -C6 alkyl, CF3, C2 F5, ##STR221## Cl, Br, I, or F, ORa, OCF3 and phenyl;
Ra and Rb are independently selected from the group consisting of H, C1 -C6 alkyl, phenyl, benzyl, allyl, ##STR222## or Ra and Rb together are C2 -C6 alkylene and are attached to the same nitrogen, so that Ra and Rb, together with the nitrogen to which they are attached, join to form a 4 to 7 membered ring;
Ar1 is ##STR223## wherein n4 is 0 or 1, ##STR224## quinolyl, benzothienyl, benzothiazolyl, indolyl or 2,3-dihydrobenzofuranyl;
Ar2 is ##STR225## Z is ##STR226## p1 and p2 are independently 1 or 2, provided that p1 and p2 together are 3 or 4;
n is 0 to 2;
n3 is 0 to 4;
n5 is 1 or 2;
when n5 is 1, R5 is H, OH, C1 -C6 alkyl, hydroxy(C1 -C6)alkyl or --C(O)--Ra ; and
when n5 is 2, each R5 is independently selected from the group consisting of C1 -C6 alkyl and the two R5 groups and the nitrogen to which they are attached form a quaternary salt with a bromine atom;
Re and Rf are independently selected from the group consisting of H, C1 -C6 alkyl, allyl, ##STR227## R6 is H, C1 -C6 alkyl, C3 -C6 cycloalkyl, ##STR228## heteroaryl or substituted heteroaryl, wherein heteroaryl is selected from the group consisting of imidazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, thienyl, pyrrolyl, furyl, pyridyl, isoxazolyl, tetrazolyl, benzimidazolyl, pyrimidyl and quinolyl; and
wherein substituted heteroaryl are heteroaryl rings substituted with R1 ;
R2 and R3 ;
or a pharmaceutically acceptable salt thereof.
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Abstract
The invention relates to compounds of the formula ##STR1## These compounds are neurokinin antagonists. These compounds are useful in the treatment of chronic airway diseases such as asthma.
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Citations
7 Claims
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1. A compound of the formula:
- ##STR216## wherein;
u is 0 to 2;y is 1 to 3; with the proviso that no more than one Rc is other than H in the ##STR217## moiety;
Rc is independently selected from the group consisting of H, C1 -C6 alkyl, hydroxy(C1 -C6)alkyl, carboxy(C1 -C6)alkyl and H2 NC(O)-(C1 C6)alkyl;R1 and R2 are independently selected from the group consisting of H, C1 -C6 alkyl, CF3, C2 F5, Cl, Br, I, F, NO2, ORa, CN, NRa Rb, ##STR218## and where Ra is not H in ##STR219## or when R1 and R2 are on adjacent carbons on a ring, they can form ##STR220## wherein n'"'"' is 1 or 2;
R3 is independently selected from the group consisting of H, C1 -C6 alkyl, CF3, C2 F5, ##STR221## Cl, Br, I, or F, ORa, OCF3 and phenyl;
Ra and Rb are independently selected from the group consisting of H, C1 -C6 alkyl, phenyl, benzyl, allyl, ##STR222## or Ra and Rb together are C2 -C6 alkylene and are attached to the same nitrogen, so that Ra and Rb, together with the nitrogen to which they are attached, join to form a 4 to 7 membered ring;Ar1 is ##STR223## wherein n4 is 0 or 1, ##STR224## quinolyl, benzothienyl, benzothiazolyl, indolyl or 2,3-dihydrobenzofuranyl; Ar2 is ##STR225## Z is ##STR226## p1 and p2 are independently 1 or 2, provided that p1 and p2 together are 3 or 4; n is 0 to 2; n3 is 0 to 4; n5 is 1 or 2; when n5 is 1, R5 is H, OH, C1 -C6 alkyl, hydroxy(C1 -C6)alkyl or --C(O)--Ra ; and
when n5 is 2, each R5 is independently selected from the group consisting of C1 -C6 alkyl and the two R5 groups and the nitrogen to which they are attached form a quaternary salt with a bromine atom;Re and Rf are independently selected from the group consisting of H, C1 -C6 alkyl, allyl, ##STR227## R6 is H, C1 -C6 alkyl, C3 -C6 cycloalkyl, ##STR228## heteroaryl or substituted heteroaryl, wherein heteroaryl is selected from the group consisting of imidazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, thienyl, pyrrolyl, furyl, pyridyl, isoxazolyl, tetrazolyl, benzimidazolyl, pyrimidyl and quinolyl; and
wherein substituted heteroaryl are heteroaryl rings substituted with R1 ;
R2 and R3 ;or a pharmaceutically acceptable salt thereof. - View Dependent Claims (2, 3, 4, 6, 7)
- ##STR216## wherein;
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5. A compound selected from the group consisting of or a pharamaceutically acceptable salt thereof.
Specification
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Current AssigneeSchering Corporation (Merck & Co., Inc.)
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Original AssigneeSchering Corporation (Merck & Co., Inc.)
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InventorsShih, Neng-Yang, Chen, Xiao, Tom, Wing C., McCormick, Kevin D., Blythin, David J., Shue, Ho-Jane, Piwinski, John J.
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Primary Examiner(s)BERNHARDT, EMILY A
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Application NumberUS09/099,221Time in Patent Office510 DaysField of Search544/360, 544/364, 544/363, 544/372, 544/295, 544/366, 544/367, 544/370, 544/373, 540/598, 514/212, 514/252, 514/253US Class Current514/217.05CPC Class CodesC07D 241/04 having no double bonds betw...C07D 401/12 linked by a chain containin...C07D 401/14 containing three or more he...C07D 405/14 containing three or more he...C07D 409/14 containing three or more he...C07D 453/02 containing not further cond...C07D 487/04 Ortho-condensed systemsC07D 487/10 Spiro-condensed systems
