Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-06-09
2001-10-02
Fan, Jane (Department: 1612)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S321000, C514S322000, C514S327000
Reexamination Certificate
active
06297259
ABSTRACT:
The present invention relates to novel substituted N-methyl-N-(4-(piperidin-1-yl)-2-(aryl)butyl)benzamide derivatives (herein referred to as a compound or compounds of formula (1)) and their use as histamine receptor antagonists and tachykinin receptor antagonists. Such antagonists are useful in the treatment of asthma; bronchitis; inflammatory bowel diseases, including Crohn's disease and ulcerative colitis; allergic rhinitis, including seasonal rhinitis and sinusitis; allergies; and emesis.
The compounds of the present invention are useful in their pharmacological activities, such as histamine receptor antagonism and tachykinin receptor antagonism. Antagonism of histamine responses can be elicited through blocking of histamine receptors. Antagonism of tachykinin responses can be elicited-through blocking of tachykinin receptors. One object of the present invention is to provide new and useful antagonists of histamine. A further object of the present invention is to provide new and useful antagonists of tachykinins. A particular object of the present invention are those compounds that exhibit both H
1
and NK
1
receptor antagonism.
SUMMARY OF THE INVENTION
The present invention provides novel substituted N-methyl-N-(4-(piperidin-1-yl)-2-(aryl)butyl)benzamide derivatives of the formula:
wherein
R′ 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″ is hydrogen or a radical chosen from the group consisting of
wherein
R
20
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
1
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
2
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
1
and X
2
are as defined in one of parts A), B), or C):
A) X
1
is hydrogen;
X
2
is a radical chosen from the group consisting of
wherein
p is 1 or 2;
R
3
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
4
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
5
is hydrogen or, hydroxy;
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, C
1
-C
6
alkoxy, and —CO
2
R
9
wherein R
9
is chosen from the group consisting of hydrogen and C
1
-C
4
alkyl;
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;
R
8
is chosen from the group consisting of hydrogen, CH
3
, and —CH
2
OH;
R
10
is chosen from the group consisting of hydrogen, C
1
-C
4
alkyl, and benzyl;
Z is chosen from the group consisting of hydrogen, C
1
-C
6
alkyl, —(CH
2
)
w
—O—(CH
2
)
t
—Y, —(CH
2
)
f
A, —(CH
2
)
u
CO
2
R
11
, —(CH
2
)
u
C(O)NR
12
R
13
, —(CH
2
)
g
C(O)(CH
2
)
h
CH
3
, —(CH
2
)
w
—O—Ar
3
, —CH
2
CH
2
OCF
3
, —CH
2
CF
3
, —CH
2
CH
2
CH
2
CF
3
, —(CH
2
)
2
CH═CH
2
, —CH
2
CH═CH
2
, —CH
2
CH═CHCH
3
, —CH
2
CH═CHCH
2
CH
3
, —CH
2
CH═C(CH
3
)
2
, and —CH
2
OCH
2
CH
2
Si(CH
3
)
3
wherein
w is an integer from 2 to 5;
t is an integer from 1 to 3;
f is 2 or 3;
u is an integer from 1 to 4;
g is an integer from 1 to 3;
h is an integer from 0 to 3;
w is an integer from 2 to 4;
Y is chosen from the group consisting of hydrogen, —CF
3
, —CH═CH
2
, —CH═C(CH
3
) 2 and —CO
2
R
14
wherein R
14
is chosen from the group consisting of hydrogen and C
1
-C
4
alkyl;
A is chosen from the group consisting of —NR
15
R
16
, acetylamino, and morpholino wherein R
15
is chosen from the group consisting of hydrogen and C
1
-C
4
alkyl and R
16
is C
1
-C
4
alkyl;
R
11
is chosen from the group consisting of hydrogen and C
1
-C
4
alkyl;
R
12
is chosen from the group consisting of hydrogen, C
1
-C
4
alkyl, and benzyl;
R
13
is chosen from the group consisting of hydrogen and C
1
-C
4
alkyl;
Ar
3
is a radical chosen from the group consisting of
wherein
v is an integer from 1 to 3;
R
17
is chosen from the group consisting of hydrogen and —CO
2
R
18
wherein R
18
is chosen from the group consisting of hydrogen and C
1
-C
4
alkyl;
B) X
1
is hydroxy;
X
2
is a radical chosen from the group consisting of
wherein p, R
3
, Z, and Ar
2
are as previously defined;
C) X
2
is a radical of the formula;
wherein R
3
and R
4
are as previously defined; and
X
1
and Z
1
taken together form a second bond between the carbon atoms bearing X
1
and Z
1
;
and stereoisomers and pharmaceutically acceptable salt thereof.
As is appreciated by one of ordinary skill in the art the compounds of the formula (1) may exist as stereoisomers N-methyl-N-(4-(piperidin-1-yl)-2-(aryl)butyl)benzamide. Specifiacally, it is recognized that the the present N-methyl-N-(4-(piperidin-1-yl)-2-(aryl)butyl)benzamides exist as stereoisomers at the 2-position of the butyl, that is, at the point of attachment of the aryl substituent. 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.
The specific stereoisomers can be prepared by stereospecific synthesis using enantiomerically pure or enantiomerically enriched starting materials. 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) the designations —C(O)— or —(O)C— refer to a carbonyl group of the formula:
e) the designation “
” refers to a bond for which the stereochemistry is not designated;
f) 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, “cm of Hg” refers to pressure in millimeters of mercury, “cm” refers to centimeters, “nm” refers to nanometers, “[a]
D
20
” 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, “ps
Bratton Larry D.
Kane John M.
Kudlacz Elizabeth M.
Maynard George P.
Aventis Pharmaceuticals Inc.
Fan Jane
Kurys Barbara E.
Martin Lawrence L.
Voelk Eric K.
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