Aminomethylene substituted non-aromatic heterocycles and use...

Details Aminomethylene substituted non-aromatic heterocycles and use... Aminomethylene substituted non-aromatic heterocycles and use...

1999-10-01

2002-04-09

Shah, Mukund J. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S314000, C514S320000, C514S321000, C514S322000, C514S323000, C514S324000, C544S283000, C546S196000, C546S197000, C546S198000, C546S199000, C546S200000, C546S201000, C546S202000, C546S205000, C546S206000, C546S139000, C546S176000

Reexamination Certificate

active

06369074

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to novel aminomethylene substituted non-aromatic heterocycles, pharmaceutical compositions comprising such compounds and the use of such compounds in the treatment and prevention of inflammatory and central nervous system disorders, as well as several other disorders. The pharmaceutically active compounds of this invention are substance P receptor antagonists. This invention also relates to novel intermediates used in the synthesis of such substance P receptor antagonists.
Substance P is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, the latter being named because of their prompt stimulatory action on smooth muscle tissue. More specifically, substance P is a pharmacologically active neuropeptide that is produced in mammals and possesses a characteristic amino acid sequence that is illustrated by D. F. Veber et al. in U.S. Pat. No. 4,680,283.
The following references refer, collectively, to quinuclidine, piperidine, and azanorbornane derivatives and related compounds that exhibit activity as substance P receptor antagonists: U.S. Pat. No. 5,162,339, which issued on Nov. 11, 1992; U.S. patent application No. 724,268, filed Jul. 1, 1991; PCT Patent application PCT/US 91/02853, filed Apr. 25, 1991; PCT Patent application PCT/US 91/03369, filed May 14, 1991; PCT Patent application PCT/US 91/05776, filed Aug. 20, 1991; PCT Patent application PCT/US 92/00113, filed Jan. 17, 1992; PCT Patent application PCT/US 92/03571, filed May 5, 1992; PCT Patent application PCT/US 92/03317, filed Apr. 28, 1992; PCT Patent application PCT/US 92/04697, filed Jun. 11, 1992; U.S. patent application 766,488, filed Sep. 26, 1991; U.S. patent application 790,934, filed Nov. 12, 1991; PCT Patent application PCT/US 92/04002, filed May 19, 1992; Japanese Patent Application 065337/92, filed Mar. 23, 1992; and U.S. patent application 932,392, filed Aug. 19, 1992.
SUMMARY OF THE INVENTION
The present invention relates to compounds of the formula
wherein A is a ring system selected from phenyl, naphthyl, thienyl, quinolinyl and indolinyl, and wherein the side chain containing NR
2
R
3
is attached to a carbon atom of ring system A;
W is hydrogen, (C
1
-C
6
)alkyl optionally substituted with from one to three fluorine atoms, —S(O)
v
-(C
1
-C
6
)alkyl wherein v is zero, one or two, halo, benzyloxy or (C
1
-C
6
)alkoxy optionally substituted with from one to three fluorine atoms;
R
1
is a 4, 5 or 6 membered heterocyclic ring containing from one to three heteroatoms selected from oxygen, nitrogen and sulfur (e.g., thiazolyl, azetidinyl, pyrrolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-tirazolyl, isothiazolyl, imidazolyl, isoxazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazolyl or thiophenyl), wherein said heterocyclic ring may contain from zero to three double bonds and may optionally be substituted with one or more substituents, preferably one or two substituents, independently selected from (C
1
-C
6
) alkyl optionally substituted with from one to three fluorine atoms and (C
1
-C
6
)alkoxy optionally substituted with from one to three fluorine atoms;
the dotted lines in formula Ib indicate that one of the X′-Y′ and Y′-Z′ bonds may optionally be a double bond;
X′ is selected from ═CH—, —CH
2
—, —O—, —S—, —SO—, —SO
2
—, —N(R
4
)-, —NH—, ═N—, —CH[(C
1
-C
6
)alkyl]-, ═C[(C
1
-C
6
)alkyl]-, —CH(C
6
H
5
)- and ═C(C
6
H
5
)-;
Y′ is selected from C═O, C═NR
4
, C═S, ═CH—, —CH
2
-, ═C[(C
1
-C
6
)alkyl]-, —CH[(C
1
-C
6
)alkyl]-, ═C(C
6
H
5
)-, —CH(C
6
H
5
)-, ═N—, —NH—, —N(R
4
)-, ═C(halo)-, ═C(OR
4
)-, ═C(SR
4
)-, ═C(NR
4
)-, —O—, ═C(CF
3
)-, ═C(CH
2
C
6
H
5
)-, —S— and SO
2
, wherein the phenyl moieties of said ═C(C
6
H
5
)- and —CH(C
6
H
5
)- may optionally be substituted with from one to three substituents independently selected from trifluoromethyl and halo, and wherein the alkyl moieties of said ═[(C
1
-C
6
)alkyl]- and —CH[C
1
-C
6
)alkyl]- may optionally be substituted with from one to three fluorine atoms;
Z′ is selected from ═CH—, —CH
2
-, ═N—, —NH—, —S—, —N(R
4
)-, ═C(C
6
H
5
)-, —CH(C
6
H
5
)-, ═C[(C
1
-C
6
)alkyl]- and —CH[(C
1
-C
6
)alkyl]-;
or X′, Y′ and Z′, together with the two carbon atoms shared between the benzo ring and the X′Y′Z′ ring, form a fused pyridine or pyrimidine ring;
R
2
is hydrogen or —CO
2
(C
1
-C
10
)alkyl;
R
3
is selected from
wherein R
6
and R
10
are independently selected from furyl, thienyl, pyridyl, indolyl, biphenyl and phenyl, wherein said phenyl may optionally be substituted with one or two substituents independently selected from halo, (C
1
-C
10
) alkyl optionally substituted with from one to three fluorine atoms, (C
1
-C
10
) alkoxy optionally substituted with from one to three fluorine atoms, carboxy, benzyloxycarbonyl and (C
1
-C
3
) alkoxy-carybonyl;
R
4
is (C
1
-C
6
) alkyl or phenyl;
R
7
is selected from (C
3
-C
4
) branched alkyl, (C
5
-C
6
) branched alkenyl, (C
5
-C
7
) cycloalkyl, and the radicals named in the definition of R
6
;
R
8
is hydrogen or (C
1
-C
6
) alkyl;
R
9
and R
19
are independently selected from phenyl, biphenyl, naphthyl, pyridyl, benzhydryl, thienyl and furyl, and R
9
and R
19
may optionally be substituted with from one to three substituents independently selected from halo, (C
1
-C
10
) alkyl optionally substituted with from one to three fluorine atoms and (C
1
-C
10
) alkoxy optionally substituted with from one to three fluorine atoms;
Y is (CH
2
)
l
wherein l is an integer from one to three, or Y is a group of the formula
Z is oxygen, sulfur, amino, (C
1
-C
3
)alkylamino or (CH
2
)
n
wherein n is zero, one or two;
x is zero, one or two;
y is zero, one or two;
z is three, four or five;
o is two or three;
p is zero or one;
r is one, two or three;
the ring containing (CH
2
)
z
may contain from zero to three double bonds, and one of the carbon atoms of (CH
2
)
z
may optionally be replaced by oxygen, sulfur or nitrogen;
R
11
is thienyl, biphenyl or phenyl optionally substituted with one or two substituents independently selected from halo, (C
1
-C
10
) alkyl optionally substituted with from one to three fluorine atoms and (C
1
-C
10
) alkoxy optionally substituted with from one to three fluorine atoms;
X is (CH
2
)
q
wherein q is an integer from 1 to 6, and wherein any one of the carbon-carbon single bonds in said (CH
2
)
q
may optionally be replaced by a carbon-carbon double bond, and wherein any one of the carbon atoms of said (CH
2
)
q
may optionally be substituted with R
14
, and wherein any one of the carbon atoms of said (CH
2
)
q
may optionally be substituted with R
15
;
m is an integer from 0 to 8, and any one of the carbon-carbon single bonds of (CH
2
)
m
, wherein both carbon atoms of such bond are bonded to each other and to another carbon atom of the (CH
2
)
m
chain, may optionally be replaced by a carbon-carbon double bond or a carbon-carbon triple bond, and any one of the carbon atoms of said (CH
2
)
m
may optionally be substituted with R
17
;
R
12
is a radical selected from hydrogen, (C
1
-C
6
) straight or branched alkyl, (C
3
-C
7
) cycloalkyl wherein one of the carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; aryl selected from biphenyl, phenyl, indanyl and naphthyl; heteroaryl selected from thienyl, furyl, pyridyl, thizaolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; phenyl-(C
2
-C
6
) alkyl, benzhydryl and benzyl, wherein the point of attachment on R
12
is a carbon atom unless R
12
is hydrogen, and wherein each of said aryl and heteroaryl groups and the phenyl moieties of said benzyl, phenyl-(C
2
-C
6
) alkyl and benzhydryl may optionally be substituted with one or more substituents independently selected from halo, nitro, (C
1
-C
10
) alkyl optionally substituted with from one to three fluorine atoms

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