Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-06-18
2002-10-29
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S467000, C548S490000, C548S494000
Reexamination Certificate
active
06472418
ABSTRACT:
BACKGROUND OF THE INVENTION
The neurokinins are a family of mammalian neuropeptides that are involved with numerous biological activities such as pain transmission, vasodilation, smooth muscle contraction, bronchoconstriction, activation of the immune system, and neurogenic inflammation. One such neuropeptide known as substance P is widely distributed throughout the peripheral and central nervous system of mammals, and is known to mediate a variety of biological actions via interaction with three neurokinin (NK or tachykinin) receptor types known as NK
1
, NK
2
, and NK
3
.
Substance P binds with higher affinity to the NK
1
receptor than it does to the other receptors. Accordingly, compounds capable of antagonizing the effects of substance P at the NK
1
receptor are useful for treating and controlling disorders mediated by such interactions, including disorders such as anxiety, pain, depression, schizophrenia, and emesis.
Since 1991, a number of high-affinity nonpeptide tachykinin antagonists have been reported; for a review see Sprecher A, et al (
IDrugs,
1:73-91, 1998).
U.S. Pat. Nos. 5,594,022 and 5,716,979 describe nonpeptides that are relatively specific NK
1
antagonists.
Since substance P mediate various biological actions, including smooth muscle contraction, pain transmission, neuronal excitation, secretion of saliva, angiogenesis, broncho-constriction, activation of the immune system and neurogenic inflammation via an interaction with NK receptors, preferably NK
1
, thus compounds capable of antagonising the effects of substance P at NK
1
receptors will be useful in treating or preventing a variety of: brain disorders including pain (inflammatory, surgical and neuropathic), anxiety, panic, depression, schizophrenia, neuralgia, stress, sexual dysfunction, bipolar disorders, movement disorders, cognitive disorders, obesity and addiction disorders; inflammatory diseases such as arthritis, asthma, bronchitis and psoriasis; gastrointestinal disorders including colitis, Crohn's disease, irritable bowel syndrome, and satiety; allergic responses such as eczema and rhinitis; vascular disorders such as angina and migraine; neuropathological disorders including scleroderma and emesis.
The compounds of the invention, NK
1
receptor antagonists, are useful as anti-angiogenic agents for the treatment of conditions associated with aberrant neovascularization such as rheumatoid arthritis, atherosclerosis and tumour cell growth. They will also be useful as agents for imaging NK
1
receptors in vivo in conditions such as ulcerative colitis and Crohn's disease.
SUMMARY OF THE INVENTION
This invention provides NK
1
receptor antagonists characterized as non-peptide acetamide derivatives. The compounds of the invention differ from those of U.S. Pat. Nos. 5,716,979 or 5,594,022 in that the compounds of Formula I below are not (N-substituted aryl-methyl) carbamates, i.e. they do not have a —O—C(O)—N— link in the backbone; certain final products being more stable than known compounds, they should show improved oral bioavailability and improved CNS penetration. The invention compounds are defined by Formula I:
and the pharmaceutically acceptable salts thereof, wherein
▪, &Circlesolid;, and ▴ indicate all stereoisomers,
R is:
pyridyl,
thienyl,
furyl,
pyrrolyl,
pyrazolyl,
quinolyl,
isoquinolyl,
naphthyl,
indolyl,
benzofuryl,
benzothiophenyl,
benzimidazolyl, and
benzoxazolyl, wherein each of the foregoing is unsubstituted, mono-, di- or trisubstituted by alkyl, hydroxy, alkoxy, halogen, —CF
3
, carboxy, sulfonamide, or nitro;
R can also be:
R
1
and R
2
are each independently H or C
1
-C
4
alkyl;
m is an integer from 0 to 3,
X is NHCONH, or NR
8
where R
8
is H or C
1
-C
4
alkyl;
R
3
is hydrogen or C
1
-C
4
alkyl;
n is an integer from 1 to 2;
R
4
is naphthyl or indolyl, wherein said groups are unsubstituted, mono-, di- or trisubstituted by
alkyl, hydroxy or formyl;
R
9
is hydrogen or C
1
-C
4
alkyl;
R
5
and R
7
are each independently hydrogen or (CH
2
)
p
R
10
where:
p is an integer of 1 to 3, and
R
10
is H, CH
3
, CN, OH, OCH
3
, CO
2
CH
3
, NH
2
, NHCH
3
, or N(CH
3
)
2
;
q is an integer of 0 to 4;
R
6
is phenyl,
pyridyl,
thienyl,
furyl,
pyrrolyl,
pyrazolyl,
imidazolyl,
quinolyl,
isoquinolyl,
naphthyl,
indolyl,
benzofuryl,
benzothiophenyl,
benzimidazolyl, or
benzoxazolyl, wherein each of the foregoing is unsubstituted, mono-, di- or trisubstituted by
alkyl,
hydroxy,
alkoxy,
halogen,
CF
3
,
NO
2
,
N(CH
3
)
2
,
OCF
3
,
SONH
2
,
NH
2
,
CONH
2
,
CO
2
CH
3
, or
CO
2
H,
or R
6
is:
straight alkyl of from 1 to 3 carbons,
branched alkyl of from 3 to 8 carbons,
cycloalkyl of from 5 to 8 carbons or
heterocycloalkyl,
each of which can be substituted with up to one or two substituents selected from
OH,
CO
2
H,
N(CH
3
)
2
,
NHCH
3
and
CH
3
; and
R
5
and R
6
, when joined by a bond, can form a ring;
R
6
is also
where X
1
represent the rest of the molecule.
Prodrugs of the above are also contemplated such as would occur to one skilled in the art; see Bundgaard, et al,
Acta Pharm Suec,
1987; 24: 233-246. For example, a suitable moiety may be attached to a nitrogen of the linker X, to the nitrogen of the NR
9
linker, or that of an indolyl radical of R
4
.
Preferred compounds of the invention are those of Formula I above wherein
R is
pyridyl,
thienyl,
furyl,
quinolyl
isoquinolyl
naphthyl,
indolyl,
benzofuryl,
benzothiophenyl,
benzimidazolyl,
benzoxazolyl, wherein each of the foregoing is unsubstituted, mono-, di- or trisubstituted by alkyl, hydroxy, alkoxy, halogen, or CF
3
,
m is an integer from 1 to 3;
R
6
is
phenyl
pyridyl,
thienyl,
furyl,
pyrrolyl,
quinolyl,
isoquinolyl,
naphthyl,
indolyl,
benzofuryl,
benzothiophenyl,
benzimidazolyl, or
benzoxazolyl,
wherein each of the foregoing is unsubstituted, mono-, di- or trisubstituted by
alkyl,
hydroxy,
alkoxy,
halogen,
CF
3
,
NO
2
N(CH
3
)
2
,
OCF
3
,
SONH
2
,
NH
2
,
CONH
2
,
CO
2
CH
3
, or
CO
2
H,
cycloalkyl of from 5 to 6 carbons or heterocycloalkyl, with up to one or two substituents selected from OH,
CO
2
H,
N(CH
3
)
2
,
NHCH
3
and
CH
3
; and
R
5
and R
6
when joined by a bond can form a ring.
More preferred compounds of the invention are those of Formula I above wherein
R is
pyridyl,
thienyl,
furyl,
quinolyl,
naphthyl,
benzofuryl,
benzothiophenyl,
benzimidazolyl, or
benzoxazolyl, where each of the foregoing is unsubstituted, mono-, di- or trisubstituted by alkyl, hydroxy, alkoxy, halogen, or —CF
3
,
R
1
and R
2
are each H;
m is an integer from 1 to 3;
X is NR
8
or NHCONH, where R
8
is H or methyl;
R
9
is hydrogen or alkyl of 1 to 3 carbon atoms;
R
6
is
phenyl,
pyridyl,
thienyl,
furyl,
pyrrolyl,
benzimidazolyl, where each of the foregoing is unsubstituted, mono-, di- or trisubstituted by
alkyl,
hydroxy,
alkoxy,
halogen,
CF
3
,
NO
2
,
N(CH
3
)
2
;
cyclohexyl or heterocycloalkyl, with up to one or two substituents selected from
OH,
CO
2
H,
N(CH
3
)
2
,
NHCH
3
and
CH
3
; and
R
5
and R
6
, when joined by a bond, can form a ring.
The most preferred compounds of the invention have Formula II:
wherein:
R is
benzofuryl,
benzoxazolyl,
3-cyanophenyl,
3-nitrophenyl, or
3-trifluoromethylphenyl;
R
3
is hydrogen or methyl;
X is NH or NHCONH;
R
5
and R
7
independently are hydrogen or CH
2
R
10
, where R
10
is H, CH
3
or OH;
R
6
is
phenyl,
substituted phenyl,
pyridyl, or,
cyclohexyl;
and the pharmaceutically acceptable salts thereof.
Most preferred compounds of the invention are:
2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-2-methyl-N-(1-phenyl-ethyl)-propionamide, [R-(R*,S*)]
2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-2-methyl-N-(1-pyridin-4-yl-ethyl)-propionamide, [R-(R*,S*)]
2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-2-methyl-N-[1-(4-nitro-phenyl)-ethyl]-propionamide, [R-(R*,R*)]
2-[(Benzofuran-2-ylmethyl)-amino]-N-(2-hydroxy-1-phenyl-ethyl)-3-(1H-indol-3-yl)-2-methyl-propionamide, [R-(R*,R*)]
[R-(R*,S*)]2-[(Benzofuran-2-ylmethyl)-amino]-N-(1-cyclohexyl-ethyl)-3-(1H-indo
Creswell Mark Wallace
Higginbottom Michael
Horwell David Christopher
Lewthwaite Russel Andrew
Pritchard Martyn Clive
Ashbrook Charles W.
Desai Rita
Kurlandsky David R.
Rotman Alan L.
Warner-Lambert & Company
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