Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-10-05
2001-01-16
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S209000
Reexamination Certificate
active
06174909
ABSTRACT:
The present invention relates to novel 4-aminotetrahydrobenzisoxazoles or -isothiazoles having GABA-uptake inhibiting activity and thus being useful in the treatment of analgesia, psychosis, convulsions, anxiety or muscular and movement disorders, such as spastic disorders or symptoms in Huntington's disease or Parkinsonism. The anticonvulsant activity especially provides usefulness as broad spectrum antiepileptic agents.
BACKGROUND OF THE INVENTION
The neutral amino acid, 4-aminobutanoic acid (GABA), is an inhibitory transmitter in the central nervous system. There is considerable direct and indirect evidence that impaired operation of GABA-mediated inhibitory synapses may be an important causative factor in seizure disorders (P. Krogsgaard-Larsen et al.,
Epilepsy Res.
1987,1, 77-93) makina GABA-ergic drugs potential antiepileptic therapeutic agents.
Furthermore, enhancement of GABA-ergic activity-may be useful in the treatment of anxiety, pain, muscular and movement disorders and mental and emotional disorders (W. Loscher,
Eur. J. Pharmacol.,
1985, 110, 103-108).
While direct stimulation of GABA receptors by agonists does not seem to represent the most suitable therapeutic approach to epileptic diseases (R. G. Fariello et al., Eds.,
Neutransmitters, Seizures, and Epilepsy
11,1984, New York, Raven Press; B. Meldrum and R. Horton,
Eur. J. Pharmacol.
1980, 61, 231-237; Krogsgaard-Larsen et al.,
J. Med. Chem.
1994, 37, 2489-2505.), GABA neurotransmission may be facilitated by manipulation of the GABA uptake mechanisms. Pharmacological inhibition of the neuronal and/or glial GABA transport, assumed to be responsible for the termination of GABA neurotransmission processes, provides a mechanism for sustaining levels of synaptically released GABA in the synapses and thereby increasing GABA-mediated transmission (P. Krogsgaard-Larsen et al.,
J. Med. Chem.
1994, 37, 2489-2505).
The strategies for such pharmacological interventions may be: 1) effective blockade of both neuronal and glial GABA uptake, or 2) selective blockade of the uptake of GABA into glial cells in order to increase the amount of GABA taken up by the neuronal carrier with subsequent elevation of the GABA concentration in nerve terminals. There is evidence suggesting that glia-selective GABA uptake inhibitors may have particular interest as antiepileptic agents (E. Falch et al.,
Drug Design and Delivery,
1987, 2, 9-21; Falch et al.
Drug Dev. Res.,
1990, 21,169-188).
Classical GABA uptake inhibitors are nipecotic acid, guvacine and THPO. Oral active N-substituted derivatives of nipecotic acid and guvacine are described in F. E. Ali et al.,
J. Med. Chem.
1985, 28, 553-560; U.S. Pat. No. 4,383,999 and U.S. Pat. No. 4,514,414 to SmithKline Beckmann Corporation; EP 236342 and EP 231996 to Novo Industri A/S and H. S. White et al.,
Eur. J. Pharmacol.
1993, 236,147-149. With regard to convulsion, especially epilepsy, in spite of the fact that antiepileptic drugs are available, many patients fail to experience seizure control. Consequently, it is an object of the present invention to provide new GABA'ergic drugs effective in the treatment of diseases-associated with GABA neurotransrnission, in particular seizure control.
SUMMARY OF THE INVENTION
It has now been found that a class of novel 4-aminotetrahydrobenzisoxazoles or -isothiazoles inhibits neuronal and/or glial GABA-uptake.
Accordingly, the present invention relates to novel 4-aminotetrahydrobenzisoxazole or -isothiazole compounds having general formula Ia or Ib:
wherein R
1
and R
2
are independently selected from the group consisting of:
A) hydrogen, cycloalkyl, phenyl, or a group
where R7, R8 and R9 are independently selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy-lower alkyl, cycloalkyl, cycloalkyl-lower alkyl, phenyl, phenyl-lower alkyl, phenoxy-lower alkyl and heteroaryl selected from 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, imidazolyl, oxazolyl, pyrazolyl, pyrimidinyl, pyrrolyl, thiazolyl, 1,2,4-triazolyl, 2-pyridyl, 3-pyridyl or 4-pyridyl, any phenyl or heteroaryl group present optionally being substituted with one or two substituents selected from halogen, lower alkyl, lower alkoxy, hydroxy, nitro, lower alkylthio, lower alkylsulfonyl, lower alkyl- or di-(lower)alkylamino, cyano, trifluoromethyl, trifluoromethylthio, trifluoromethylsulfonyloxy and phenyl which again may be substituted with halogen, methyl, methoxy or trifluoromethyl; and any alkyl group present being optionally substituted with one to three hydroxy groups which again are optionally esterified with a C
2-18
carboxylic acid;
B) a group of general formula Y—(CH
2
)
r
—(CHR
11
)
s
(CH
2
)
t
— wherein Y is selected from the following groups (1)-(5):
wherein U is CHR
10b
, NR
10b
, O or S, U
1
is NR
10b
, O or S; p is 0 or 1; q is 0 or 1; V is C or N and the dotted line represents a bond when V is C and no bond when V is N;
A is O, S, CH
2
, (CH
2
)
2
, CH═CH—CH
2
, (CH
2
)
3
, CH=CH or OCH
2
;
R
a
and R
b
each represent one or more substituents selected from halogen, lower alkyl, lower alkoxy, hydroxy, nitro, lower alkylthio, lower alkylsulfonyl, lower alkyl- or di(lower alkyl)amino, cyano, trifluoromethyl, trifluoromethylsulfonyloxy and trifluoromethylthio;
r and t are independently 0, 1, 2 or 3 , s is 0 or 1, provided that when Y is a group (1) wherein U is NR
10b
, O or S or a group (4), then r+s+t is at least 2; and when Y is a group (3) or a group (5) where V is N, then r+s+t is at least 1;
R
7b
, R
8b
and R
9b
are as defined for R
7
, R
8
and R
9
in A) provided that they are not at the same time selected from hydrogen, lower alkyl, lower alkenyl and lower alkynyl;
R
10b
and R
11
are independently hydrogen, lower alkyl, lower alkenyl or lower alkynyl; and
C) a group of general formula Y
c
—(CH
2
)
n
—W—(CH
2
)
m
—O wherein n is 1, 2 or 3, m is 2 or 3; W is O or S; and Y
c
is a group (1)-(5) as defined in B) provided that n may not be 1, when Y is a group (1) or (4) wherein U or U
1
, respectively, is NR
10b
, S or O;
D) a group of general formula
wherein k is 0, 1, 2 or 3;
l is 0, 1, 2 or 3; R
11d
is as defined for R
11
in B) above; and
Y is selected from the groups (2) and (5) as defined in B) above and the following groups (6)-(10):
Wherein p, q, R
a
, R
b
, and A are as defined in B) and R
7d
-R
11d
are as defined for R
7b
-R
10b
and R
11
, respectively, under B) or
R
1
and R
2
together designate alkylene thereby forming a 4-8 membered nitrogen containing ring; or
one of R
1
and R
2
is a group R
2′
OCO wherein R
2′
is phenyl, or heteroaryl as defined in A) above or phenyl or such heteroaryl substituted with one or more substituents selected from halogen, lower alkyl, lower alkoxy, hydroxy, nitro, lower alkylthio, lower alkylsulfonyl, lower alkyl- or di(lower)alkylamino, cyano, trifluoromethyl, trifluoromethylthio, trifluoromethylsulfonyloxy, phenyl and phenyl substituted with halogen, methyl, methoxy or trifluoromethyl;
R
3
-R
6
are independently selected from hydrogen, hydroxy and lower alkyl, any alkyl group optionally being substituted with one or two hydroxy groups;
X is oxygen or sulfur;
P is hydrogen or a group ZR wherein
Z is CO, CS, SO
2
or CR
t
R
u
, R
t
and R
u
being hydrogen, hydroxy or lower alkyl, and if Z is CO or CS, then R is selected from the groups consisting of:
i) hydrogen, C
1
-C
18
alkyl, C
2
-C
18
alkenyl, C
3
-C
8
cycloalkyl, C
3
-C
8
cycloalkenyl or C
4
-C
28
cycloalk(en)yl-alk(en)yl, optionally substituted with one or two hydroxy groups, or phenyl optionally substituted with one or more substituents selected from the group consisting of halogen, trifluoromethyl, C
1
-C
4
alkyl, C
1
-C
4
alkoxy, C
1
-C
4
alkylthio, C
1
-C
5
acyloxy, or cyano; or
ii) QR
v
, wherein Q is O or S and R
v
is selected from the substituents defined for R under i) above; and
iii) NR
x
R
y
, wherein R
x
and R
y
independently are se
Falch Erik
Frolund Bente
Krogsgaard-Larsen Povl
Moltzen Lenz Sibylle
Perregaard Jens Kristian
Darby & Darby
H. Lundbeck A/S
McKane Joseph K.
Solola Taofiq A.
LandOfFree
4-aminotetrahydrobenzisoxazole or -isothiazole compounds does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with 4-aminotetrahydrobenzisoxazole or -isothiazole compounds, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and 4-aminotetrahydrobenzisoxazole or -isothiazole compounds will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2445081