Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-09-07
2001-02-13
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...
C514S258100, C544S280000
Reexamination Certificate
active
06187778
ABSTRACT:
BACKGROUND OF INVENTION
1. Field of the Invention
This invention relates to the use of certain substituted 4-aminopyrrole(3,2-d)pyrimidine derivatives which selectively bind to mammalian Neuropeptide receptors. It further relates to the use of such compounds and compositions in treating conditions related to an excess of neuropeptide Y such as feeding disorders and certain cardiovascular diseases.
2. Description of the Related Art
Neuropeptide Y, a peptide first isolated in 1982, is widely distributed in the central and peripheral neurons and is responsible for a multitude of biological effects in the brain and the periphery. Various animal studies have shown that activation of neuropeptide Y1 receptors is related to vasoconstriction, Wahlestedt et al.
Regul. Peptides
, 13: 307-318 (1986), McCauley and Westfall,
J. Pharmacol. Exp. Ther
. 261:863-868 (1992), and Grundemar et al., Br.
J. Pharmacol
. 105:45-50 (1992); and to stimulation of consummatory behavior, Flood and Morley,
Peptides
, 10:963-966 (1989), Leibowitz and Alexander,
Peptides
, 12:1251-1260 (1991), and Stanley et al.
Peptides
, 13:581-587 (1992).
Grundemar and Hakanson.
TiPS
, May 1994 [Vol. 15], 153-159, state that, in animals, neuropeptide Y is a powerful stimulus of food intake, and an inducer of vasoconstriction leading to hypertension. They further point out that low levels of neuropeptide Y (NPY) are associated with loss of appetite. These reports clearly indicate that compounds that inhibit the activity of this protein will reduce hypertension and appetite in animals.
EP0759441 and U.S. Pat. No. 5,576,337 report that physiological disorders related to neuropeptide Y include:
disorders or diseases pertaining to the heart, blood vessels or the renal system, such as vasospasm, heart failure, shock, cardiac hypertrophy, increased blood pressure, angina, myocardial infarction, sudden cardiac death, arrythmia, peripheral vascular disease, and abnormal renal conditions such as impaired flow of fluid, abnormal mass transport, or renal failure;
conditions related to increased sympathetic nerve activity for example, during or after coronary artery surgery, and operations and surgery in the gastrointestinal tract;
cerebral diseases and diseases related to the central nervous system, such as cerebral infarction, neurodegeneration, epilepsy, stroke, and conditions related to stroke, cerebral vasospasm and hemmorrhage, depression, anxiety, schizophrenia, and dementia;
conditions related to pain or nociception;
diseases related to abnormal gastrointenstinal motility and secretion, such as different forms of ileus, urinary incontinence, and Crohn's disease;
abnormal drink and food intake disorders, such as anorexia and metabolic disorders; diseases related to sexual dysfunction and reproductive disorders;
conditions or disorders associated with inflammation;
respiratory diseases, such as asthma and conditions related to asthma and bronchoconstriction; and diseases related to abnormal hormone release, such as leutinizing hormone, growth hormone, insulin, and prolactin.
WO 96/14307 describes substituted benzylamine derivatives which selectively bind to human neuropeptide Y1 receptors.
The synthesis of certain 4-aminopyrrole (3,2-d) pyridines is described in
Pharm. Chem J
. 22, 185 (1988); 8, 14 (1974); and 7, 19 (1973). These compounds were reported to have antibacterial and antitumor activity.
SUMMARY OF THE INVENTION
This invention provides a compound of the formula:
wherein:
B, D and E are independently selected from CR
1
, CR
9
or N with the proviso that at least one of B, D and E must be CR
1
or CR
9
, and at least one of B, D and E must be N; and F and G are selected from N, NR
4
, or CR
5
with the proviso that at least one of F or G must be N or NR
4
; and one of the dotted lines represents a bond and the other represents no bond; and when B and E are both N, then one of F or G must be CR
5
; and
R
1
, R
3
, R
4
, R
5
and R
9
are independently selected from H, (C
1
-C
6
) alkyl, (C
1
-C
6
) alkoxy, (C
1
-C
6
) thioalkyl, (C
2
-C
6
) alkenyl, (C
2
-C
6
) alkynyl, (C
1
-C
6
) perfluoroalkyl, (C
1
-C
6
) perfluoroalkoxy, (CH
2
)
n
—(C
3
-C
7
) cycloalkyl, (CH
2
)
n
(C
3
-C
7
) cycloalkenyl, and (CH
2
)
n
Ar, wherein each alkyl, alkenyl, alkynyl, alicyclic and Ar group may be independently substituted with one to three substituents selected from the group consisting of Br, Cl, F, NR
6
R
7
, O(C
1
-C
6
) alkyl, NO
2
, CN, COOH, OH, SH and;
R
2
is NR
6
R
7
,
NH(CH
2
)
n
Ph, NH(CH
2
)
n
(C
3
-C
7
) cycloalkyl, NH(CH
2
)
n
, (C
3
-C
7
) cycloalkenyl, NH(CH
2
)
n
morpholinyl, NH(CH
2
)
n
piperazinyl, or NH(CH
2
)
n
pyrimidinyl wherein each ring may be independently substituted with one to three substituents selected from the group consisting of Br, Cl, F, NR
6
R
7
, O(C
1
-C
6
) alkyl, (C
1
-C
6
) alkyl, S(O)
m
(C
1
-C
6
) alkyl, NO
2
, CN, COOH, OH, and SH and;
when R
2
is
if m or n is zero the other of m or n must be at least 2; and
G is S, O, NR
8
or a bond; and R
8
is hydrogen, (C
1
-C
6
) alkyl or aryl; (C
1
-C
6
) alkyl
or
R
6
and R
7
are independently selected from hydrogen, (C
1
-C
6
)-alkyl, (C
1
-C
6
) alkyl (C
1
-C
6
) alkoxy, (CH
2
)
k
N[(C
1
-C
6
) alkyl]
2
and (CH
2
)
k
OH; and
n is and integer from zero to six;
m is an integer from zero to two;
k is an integer from two to four;
Ar is an aromatic hydrocarbon or a heterocyclic ring of three to seven atoms or a bicyclic heterocyclic ring at least atom one of which is a nitrogen, sulfur or oxygen atom;
and with the proviso that if F is NR
4
, G is CR
5
, B and E are N; D is CR
1
; R
1
is methyl, R
3
is phenyl and R
4
and R
5
are hydrogen then R
2
must not be
NEt
2
, HN(CH
2
)
2
NEt
2
, HN(CH
3
)
2
COOH, HNCH
2
CH
2
OH, HNPh, HN(CH
2
)
2
Ph,
piperidinyl, morpholinyl, NHNH
2
, HNCH(CH
3
)
2
, HN(CH
2
)
3
CH
3
, HNCH
2
CH(CH
3
)
2
, HNCH(CH
3
)CH
2
(CH
2
)
3
CH3, HNCH
2
CH═CH
2
,
and with the further proviso that if F is NR
4
, G is CR
5
, B and E are N; D is CR
1
; R1 and R
3
are both methyl and R
4
and R
5
are both hydrogen then R
2
must not be
and with the further proviso that if F is NR
4
, G is CR
5
, B and E are N; D is CR
1
; R3, R
4
and R
5
are hydrogen then R
1
and R
2
must not both be the same and be
and with the further proviso that
when B,F are N; G is NR
4
; D is CR
1
; E is CR
9
; R
1
, R
3
, and R
4
are H then R2 must not be
NH
2
, NMe
2
, NHMe, OH, OMe,
when B and G are N; F is NR
4
; E is CR
9
; D is CR
1
; R
1
, R
4
, and R
9
are H; and R
2
is OMe, then R
3
must not be
when B and G are N; F is NR
4
; E is CR
9
; D is CR
1
; R
1
, R
3
, and R
9
are H; and R
2
is NH
2
then R
4
must not be
when B and F are N; G is NR
4
; E is CR
9
; D is CR
1
; R
1
and R
9
are H; R
3
and R
4
are CH
3
then R
2
must not be
when B and F are N; G is NR
4
; E is CR
9
; D is CR
1
; R
1
and R
9
are H; R
3
is CH
3
and R4 is CH
2
CH
2
OH then R
2
must not be
when B and F are N; G is NR
4
; E is CR
9
; D is CR
1
; R
1
is CH
3
; R
3
is CH
3
; R
9
is H and
when E and F are N; G is NR
4
; B is CR
9
; D is CR
1
; R
1
; R
3
; R
4
and R
9
are H then R
2
must not be
NH
2
, OH, OCH
3
, NMe
2
, NHEt, NHMe,
when E and F are N; G is NR
4
; B is CR
9
; D is CR
1
; R
1
is CH
3
; and R
3
, R
4
; and R
9
are H then R
2
must not be NH
2
or OH; and
when E and F are N; G is NR
4
; B is CR
9
; D is CR
1
; R
1
is CH
2
CH
2
CH
3
; and R
3
, R
4
; and R
9
are H then R
2
must not be NH
2
or OH; and
when E and F are N; G is NR
4
; B is CR
9
; D is CR
1
; R
1
, R
4
; and R
9
are H and R
2
is OCH
3
then R
3
must not be
When E and G are N; F is NR
4
; B is CR
9
; D is CR
1
; R
2
is NH
2
; R
1
, R
3
; and R
9
are H then R
4
must not be CH
3
or
when E and F are N; G is NR
4
; B is CR
9
; D is CR
1
; R
2
is OH; R
1
, R
4
; and R
9
are H then R
3
must not be CH
3
, Et, or
and
when E and G are N; F is NR
4
; B is CR
9
; D is CR
1
; R
2
is
Dow Robert Lee
Hammond Marlys
Benson Gregg C.
Brokke Mervin E.
Pfizer Inc.
Richardson Peter C.
Schroeder Ben
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