Aryl-substituted acrylamides with Leukotriene B4 (LTB-4)...

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...

Reexamination Certificate

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C514S317000, C514S428000, C514S237500, C514S381000, C549S076000, C548S496000, C548S253000, C546S194000, C546S276400, C546S268400, C546S192000, C546S124000, C544S124000, C544S168000

Reexamination Certificate

active

06291530

ABSTRACT:

SUMMARY OF THE INVENTION
The invention relates to the aryl-substituted acrylamides as defined herein which are particularly useful as selective Leukotriene B-4 (LTB-4) receptor antagonists, methods for preparation thereof, pharmaceutical compositions comprising said compounds, and a method of antagonizing LTB-4 and of treating conditions or syndromes in mammals which are responsive to LTB-4 antagonism using said compounds or pharmaceutical compositions comprising said compounds of the invention.
Leukotriene B-4 (LTB-4) is an important inflammatory mediator being a potent chemotactic agent and activator of polymorphonuclear leucocytes (PMN's) and monocytes. It modulates the production and effects of other important inflammatory mediators, e.g. interleukin-1 and gamma interferon. LTB-4 has been implicated in the pathogenesis of a number of inflammatory diseases, such as rheumatoid arthritis, inflammatory bowel disease, psorasis on-steroidal-antiinflammatory drug-induced gastropathy, adult respiratory distress syndrome (ARDS), myocardial infarction, allergic rhinitis, hemodialysis-induced neutropenia, late phase asthma, ocular conditions such as ocular allergy and inflammation, dermatitis such as atopic and contact dermatitis, and chronic obstructive pulmonary disorders, such as chronic bronchitis.
The compounds of the invention which are useful as selective LTB-4 antagonists can be used for the treatment of the above-cited LTB-4 dependent conditions.
DETAILED DESCRIPTION OF THE INVENTION
The invention relates to substituted acrylamides of formula I
wherein W is CH or N;
R is (mono- or di-carbocyclic aryl or mono- or di-heterocyclic aryl)-lower alkyl;
R
1
is hydrogen or lower alkyl;
R
2
and R
3
are hydrogen, lower akyl, lower alkoxy-lower alkyl or aryl-lower alkyl; or R
2
and R
3
joined together represent lower alkylene optionally interrupted by O, NH, N-lower alkyl or S so as to form a ring with the amide nitrogen;
X is O, S, SO, SO
2
or a direct bend;
X
1
is O, S, SO, SO
2
or a direct bond;
Y is a direct bond, lower alkylene or lower alkylidene; and
Z is carboxyl, 5-tetrazolyl, hydroxymethyl or carboxyl derivatized in form of a pharmaceutically acceptable ester;
and pharmaceutically acceptable salts thereof.
Preferred are compounds of formnula Ia
wherein R, R
1
, R
2
, R
3
, X, X
1
, Y and Z have meaning as defined above, and pharmaceutically acceptable salts thereof.
Preferred in turn are said compounds wherein, when W is CH, each of the substituents —X—Y—Z and —X
1
—R is located at either the meta (3) or para (4) positions or at either of the two meta (3 and 3′) positions of the phenyl ring; and wherein, when W is N, each of the said substituents is at either of the adjacent 5 and 6 positions of the pyridine ring; and pharmaceutically acceptable sats thereof.
The particular embodiments of the invention relate to the compounds of formula II
and of formula III
wherein in formula II the substituents —X—Y—Z and —X
1
—R are located at the meta (3) and para (4) positions or at the two meta (3 and 3′) positions and wherein in formula III the said substituents are at adjacent 5 and 6 positions of the pyridine ring;
R is (mono or di-carbocyclic aryl or mono- or di-heterocyclic aryl)-lower alkyl;
R
1
is hydrogen or lower alkyl;
R
2
and R
3
are hydrogen, lower alkyl, lower alkoxy-lower alkyl or aryl-lower alkyl; or R
2
and R
3
together with the nitrogen to which they are attached represent pyrrolidino, piperidino, or morpholino;
X is O, S or a direct bond;
X
1
is O, S or a direct bond;
Y is a direct bond, lower alkylene or lower alkylidene; and
Z is carboxyl, 5-tetrazolyl, hydroxymethyl or carboxyl derivatized in form of a pharmaceutically acceptable ester; and pharmaceutically acceptable salts thereof.
A particular embodiment of the invention relates to compounds of formula I, II or III wherein each of X and X
1
is oxygen, and R, R
1
, R
2
, R
3
, Y and Z have meaning as defined above.
Another particular embodiment of the invention relates to compounds of formula
or of formula IVa
wherein R is (mono- or di-carbocyclic aryl or mono- or di-heterocyclic aryl)-lower alkyl;
R
1
is hydrogen or lower alkyl,
R
2
and R
3
are hydrogen, lower alkyl, lowe alkoxy-lower alkyl or aryl-lower alkyl; or R
2
and R
3
together with the nitrogen which they are attached represent pyrrolidino, piperidino or morpholino;
X is O, S or a direct bond;
X
1
is O, S or a direct bond;
Y is C
1
-C
4
-alkylene or C
1
-C
4
-alkylidene;
Z is carboxyl, 5-tetrazolyl, hydroxymethyl or carboxyl derivatized in form of a pharmaceutically acceptable ester; and pharmaceutically acceptable salts thereof.
In view of the presence of a double bond as part of the structure, the substituted acrylamides of the invention exist in either two geometric isomeric forms, namely as cis or trans isomers (also denoted as Z and E isomers).
Preferred are the E-isomers (or trans isomers), illustrated by the cinnamides of
in which the substituted phenyl and the
groups are trans to each other.
Preferred compounds include the E-isomers of compounds of formulae I, II, III, IV and IVa in which R is (mono- or di-carbocyclic aryl)-lower alkyl; R
1
is lower alkyl; R
2
and R
3
represent lower alkyl; X represents oxygen (O) or a direct bond; X
1
represents oxygen (O); Y represents lower alkylene or lower alkylidene; Z represents carboxyl or 5-tetrazolyl; and pharmaceutically acceptable salts thereof.
Similarly preferred are E-pyridylacrylamides (E-isomers corresponding to compounds of formula IVa) in which X, Y, Z, X
1
, R, R
1
, R
2
and R
3
have meaning as defined for compounds of formula IVb above.
The definitions as such or in combination as used herein, unless denoted otherwise, have the following meanings within the scope of the present invention.
Aryl represents carbocyclic or heterocyclic aryl, either monocyclic or bicyclic.
Monocyclic carbocyclic aryl reprsents optionally substituted phenyl, being preferably phenyl or phenyl substituted by one to three substituents, such being advantageously lower alkyl, hydroxy, lower alkoxy, acyloxy, halogen, cyano or trifluoromethyl.
Bicyclic carbocyclic aryl represents 1- or 2-naphthyl or 1- or 2-naphthyl preferably substituted by lower alkyl, lower alkoxy or halogen.
Monocyclic heterocyclic aryl represents preferably optionally substituted thiazolyl, thienyl, furanyl or pyridyl.
Optionally substituted furanyl represents 2- or 3-furanyl or 2- or 3-furanyl preferably substituted by lower alkyl.
Optionally substituted pyridyl represents 2-, 3- or 4-pyridyl 2-, 3- or 4-pyridyl preferably substituted by lower alkyl, halogen or cyano.
Optionally substituted thienyl represents 2- or 3-thienyl 2- or 3-thienyl preferably substituted by lower alkyl.
Optionally substituted thiazolyl represents e.g. 4-thiazolyl, or 4-thiazolyl substituted by lower alkyl.
Bicyclic heterocyclic aryl represents preferably indolyl or benzothiazolyl optionally substituted by hydroxy, lower alkyl, lower alkoxy or halogen, advantageously 3-indolyl or 2-benzothiazolyl.
Aryl as in aryl-lower alkyl is preferably phenyl or phenyl substituted by one or two of lower alkyl, lower alkoxy, hydroxy, lower alkanoyloxy, halogen, trifluoromethyl or cyano; also, optionally substituted naphthyl.
Aryl-lower alkyl is advantageotsly benzyl or 1- or 2-phenethyl optionally substituted on phenyl by one or two of lower alkyl, lower alkoxy, hydroxy, lower alkanoyloxy, halogen, cyano or trifluoromethyl.
The term “lower” referred to herein in connection with organic radicals or compounds respectively defines such with up to and including 7, preferably up and including 4 and advantageously one or two carbon atoms. Such may be straight chain or branched.
A lower alkyl group preferably contains 1-4 carbon atoms and represents for example ethyl, propyl, butyl or advantaeously methyl.
A lower alkoxy group preferably contains 1-4 carbon atoms and represents for example methoxy, propoxy, isopropoxy or advantageously ethoxy.
A lower alkoxycarbonyl group preferably contains 1 to 4 carbon atoms in the alkoxy portion and represent

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