Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-05-06
2001-11-13
Berch, Mark L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S253040, C514S253110, C514S253120, C514S253130, C514S316000, C514S318000, C514S326000, C544S130000, C544S364000, C544S365000, C546S187000, C546S189000, C546S194000, C546S208000, C546S210000
Reexamination Certificate
active
06316445
ABSTRACT:
The present invention relates to novel carboxy substituted acyclic carboxamide derivatives (herein referred to as compounds or compounds of formula (1)), and stereoisomers thereof, and pharmaceutically acceptable salts thereof and their use as tachykinin receptor antagonists. Such antagonists are useful in the treatment of tachykinin-mediated diseases and conditions disclosed herein including: asthma, cough, and bronchitis.
SUMMARY OF THE INVENTION
The present invention relates to novel carboxy substituted acyclic carboxamide derivatives of formula (1):
wherein
R
1
is from 1 to 3 substituents each independently chosen from the group consisting of hydrogen, halogen, C
1
-C
6
alkyl, and C
1
-C
6
alkoxy;
R
2
is hydrogen or a radical chosen from the group consisting of
wherein
R
3
is selected from the group consisting of hydrogen, C
1
-C
4
alkyl, and —CF
3
;
Ar
1
is a radical chosen from the group consisting of
wherein
R
4
is from 1 to 3 substituents each independently chosen from the group consisting of hydrogen, halogen, hydroxy, —CF
3
, C
1
-C
6
alkyl, and C
1
-C
6
alkoxy;
R
5
is from 1 to 2 substituents each independently chosen from the group consisting of hydrogen, halogen, C
1
-C
6
alkyl, and C
1
-C
6
alkoxy;
Ar
2
is a radical chosen from the group consisting of
wherein
R
6
is from 1 to 3 substituents each independently chosen from the group consisting of hydrogen, halogen, —CF
3
, C
1
-C
6
alkyl, and C
1
-C
6
alkoxy;
R
7
is from 1 to 2 substituents each independently chosen from the group consisting of hydrogen, halogen, C
1
-C
6
alkyl, and C
1
-C
6
alkoxy;
X is a radical selected from the group consisting of
wherein
Y is —O— or —CH
2
—;
p is an integer from 1 to 4;
R
10
is selected from the group consisting of hydrogen and C
1
-C
6
alkyl;
and stereoisomers, and pharmaceutically acceptable salts thereof.
As is appreciated by one of ordinary skill in the art the compounds of the formula (1) exist as stereoisomers. Any reference in this application to one of the compounds of the formula (1) is meant to encompass either specific stereoisomers or a mixture of stereoisomers. Where indicated the compounds follow either the (+)- and (−)-designation for optical rotation or the Cahn-Ingold-Prelog designation of (R)- and (S)- for the stereochemistry of compounds represented by formula (1) and intermediates thereof. It is specifically recognized that the novel carboxy substituted acyclic carboxamide derivatives of the present invention are asymmetric at the 2-position of the butyl, that is, at the point of attachment of the Ar
1
substituent, and may exist in the (R)- or (S)-configuration or may be a mixture thereof. It is also specifically recognized that the novel substituted acyclic carboxamide derivatives of the present invention may be asymmetric at the point of attachment of the carboxy substituent on the heterocyclic carboxamide, and that, when asymmetric at that point of attachment, may be in either the (R)- or (S)-configuration or may be a mixture thereof.
The specific stereoisomers can be prepared by using enantiomerically pure or enantiomerically enriched starting materials obtained by stereospecific synthesis. The specific stereoisomers of either starting materials or products can be resolved and recovered by techniques known in the art, such as chromatography on chiral stationary phases, enzymatic resolution, or fractional recrystallization of addition salts formed by reagents used for that purpose. Useful methods of resolving and recovering specific stereoisomers are known in the art and described in
Stereochemistry of Organic Compounds
, E. L. Eliel and S. H. Wilen, Wiley (1994) and
Enantiomers, Racemates, and Resolutions
, J. Jacques, A. Collet, and S. H. Wilen, Wiley (1981).
As used in this application:
a) the term “halogen” refers to a fluorine atom, chlorine atom, bromine atom, or iodine atom;
b) the term “C
1
-C
6
alkyl” refers to a branched or straight chained alkyl radical containing from 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, cyclopentyl, cyclohexyl, etc.;
c) the term “C
1
-C
6
alkoxy” refers to a straight or branched alkoxy group containing from 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, pentoxy, hexoxy, cyclopentoxy, cyclohexoxy, etc.;
d) as used in the examples and preparations, the following terms have the meanings indicated: “kg” refers to kilograms, “g” refers to grams, “mg” refers to milligrams, “&mgr;g” refers to micrograms, “mol” refers to moles, “mmol” refers to millimoles, “nmole” refers to nanomoles, “L” refers to liters, “mL” or “ml” refers to milliliters, “&mgr;L” refers to microliters, “° C.” refers to degrees Celsius, “R
f
” refers to retention factor, “mp” refers to melting point, “dec” refers to decomposition, “bp” refers to boiling point, “mm of Hg” refers to pressure in millimeters of mercury, “cm” refers to centimeters, “nm” refers to nanometers, “[&agr;]
2
D
0
” refers to specific rotation of the D line of sodium at 20° C. obtained in a 1 decimeter cell, “c” refers to concentration in g/mL, “THF” refers to tetrahydrofuran, “DMF” refers to dimethylformamide, “brine” refers to a saturated aqueous sodium chloride solution, “M” refers to molar, “mM” refers to millimolar, “&mgr;M” refers to micromolar, “nM” refers to nanomolar, “psi” refers to pounds per square inch, “TLC” refers to thin layer chromatography, “HPLC” refers to high performance liquid chromatography, “HRMS” refers to high resolution mass spectrum, “&mgr;Ci” refers to microcuries, “i.p.” refers to intraperitoneally, “i.v.” refers to intravenously, and “DPM” refers to disintegrations per minute;
e) the designation
refers to a phenyl or a substituted phenyl and it is understood that the radical is attached at the 1-position and the substituent or substituents represented by R can be attached in any of the 2, 3, 4, 5, or 6 positions;
f) the designation
refers to a pyridine, substituted pyridine, pyridyl or substituted pyridyl and it is understood that the radical can be attached at either the 2-position, the 3-position, or the 4-position, it is further understood that when the radical is attached at the 2-position the substituent or substituents represented by R can be attached in any of the 3, 4, 5, or 6 positions, that when the radical is attached at the 3-position the substituent or substituents represented by R can be attached in any of the 2, 4, 5, or 6 positions, and that when the radical is attached at the 4-position the substituent or substituents represented by R can be attached in any of the 2, 3, 5, or 6 positions;
g) the designation
refers to a thiophene or thienyl and it is understood that the radical is attached at the 2 or 3-positions;
h) the designation
refers to a naphthalene, substituted naphthalene, naphthyl or substituted naphthyl and it is understood that the radical can be attached at either the 1-position or the 2-position, it is further understood that when the radical is attached at the 1-position the substituent or substituents represented by R can be attached in any of the 2, 3, 4, 5, 6, 7, or 8 positions and that when the radical is attached at the 2-position the substituent or substituents represented by R can be attached in any of the 1, 3, 4, 5, 6, 7, or 8 positions;
i) the term “enantiomeric excess” or “ee” refers to the percent by which one enantiomer, E1, is in excess in a mixture of the two enantiomers, E1 plus E2, such that
{(E1−E2)−(E1+E2)}×100%=ee;
j) the term “C
1
-C
4
alkyl” refers to a saturated straight or branched chain alkyl group containing from 1-4 carbon atoms and includes methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, isobutyl, and t-butyl;
k) the designation
refers to a bond for which the stereochemistry is not designated;
l) the designation
refers to a bond that protrudes forward out of the plane of the page;
m) the designation
refers to a bond that protrud
Burkholder Timothy P.
Kudlacz Elizabeth M.
Maynard George D.
Aventis Pharmaceuticals Inc.
Berch Mark L.
Ferrell Michael W.
Habte Kahsay
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