Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...
Reexamination Certificate
2000-09-22
2001-11-06
Kifle, Bruck (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Unsubstituted hydrocarbyl chain between the ring and the -c-...
C540S522000
Reexamination Certificate
active
06313290
ABSTRACT:
The invention relates to azolobenzazepine derivatives, to pharmaceutical compositions containing the same and to the method of use thereof in the treatment of neurological disorders.
More specifically, the invention relates to compounds of the Formula I:
wherein:
X is O or S;
R
1
, R
2
, R
3
and R
4
are independently hydrogen, perfluorolower-alkyl, halogen, nitro or cyano; and
C together with the carbon atoms to which it is attached forms a 5-membered aromatic heterocycle selected from the group consisting of:
or tautomers thereof, wherein R is cyano, —C(O)OR
5
(wherein R
5
is hydrogen, lower-alkyl, lower-alkenyl, lower-alkynyl, cycloalkyl-lower-alkyl, phenyl, phenyl-lower-alkyl, phenyl-lower-alkynyl, lower-alkylthio-lower-alkyl, halo-lower-alkyl, trifluoromethyl-lower-alkyl, lower-alkoxy-lower-alkyl, hydroxy-lower-alkyl, lower-alkylamino, cycloalkylamino, or phenyl-lower-alkylamino), —C(O)NR
6
R
7
(wherein R
6
and R
7
are independently hydrogen, phenyl, phenyl-lower-alkyl, lower-alkoxy-lower-alkyl, hydroxy-lower-alkyl, lower-alkyl, lower-alkoxy, hydroxy, or cycloalkyl, or R
6
and R
7
together with the nitrogen atom to which they are attached form a 5- or 6-membered non-aromatic heterocycle selected from the group consisting of morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl and thiomorpholinyl), formyl, phenylcarbonyl, phenyl, lower-alkylcarbonyl, perfluorolower-alkyl, lower-alkoxy-carbonyl-lower-alkyl, carboxy-lower-alkyl, or phenyl-lower-alkylcarbonyl; wherein said phenyl, phenyl-lower-alkyl, phenyl-lower-alkynyl, phenyl-lower-alkyl-amino, phenylcarbonyl or phenyl-lower-alkylcarbonyl groups may optionally be substituted on the phenyl group thereof by one to three substituents, the same or different, selected from the group consisting of lower-alkyl, lower-alkoxy, halogen, hydroxy and trifluoromethyl;
or a pharmaceutically acceptable acid-addition salt of basic members thereof; or a pharmaceutically acceptable base-addition salt of acidic members thereof; with the proviso that when C together with the carbon atoms to which it is attached forms a triazole ring, at least one of R
1
, R
2
, R
3
or R
4
must be other than hydrogen.
The compounds of the Formula I have been found to function as antagonists of the effects which excitatory amino acids, such as glutamate, have upon the NMDA receptor complex and are thus useful in the treatment of neurological disorders.
Compounds within the ambit of Formula I above are those wherein:
X, R
1
, R
2
, R
3
, R
4
and C are as defined above; and
R is cyano, —C(O)OR
5
(wherein R
5
is hydrogen, lower-alkyl, lower-alkenyl, lower-alkynyl, cycloalkyl-lower-alkyl, phenyl, phenyl-lower-alkyl, phenyl-lower-alkynyl, lower-alkylthio-lower-alkyl, halo-lower-alkyl, trifluoromethyl-lower-alkyl, lower-alkylamino, cycloalkylamino, or phenyl-lower-alkyl-amino), —C(O)NR
6
R
7
(wherein R
6
and R
7
are independently hydrogen, phenyl, phenyl-lower-alkyl, lower-alkoxy-lower-alkyl, lower-alkyl, lower-alkoxy, hydroxy or cycloalkyl, or R
6
and R
7
together with the nitrogen atom to which they are attached form a morpholinyl group), formyl, phenylcarbonyl, phenyl, lower-alkylcarbonyl, perfluorolower-alkyl, lower-alkoxy-carbonyl-lower-alkyl, or carboxy-lower-alkyl; wherein said phenyl, phenyl-lower-alkyl, phenyl-lower-alkynyl, phenyl-lower-alkylamino or phenylcarbonyl groups may optionally be substituted on the phenyl group thereof by one substituent selected from the group consisting of lower-alkyl, lower-alkoxy, halogen, hydroxy and trifluoromethyl.
Other compounds within the ambit of Formula I above are those wherein:
X, R
1
, R
2
, R
3
, R
4
and C are as defined above; and
R is cyano, —C(O)OR
5
(wherein R
5
is hydrogen, lower-alkyl, lower-alkenyl, lower-alkynyl, cycloalkyl-lower-alkyl, phenyl, phenyl-lower-alkyl, phenyl-lower-alkynyl, lower-alkylthio-lower-alkyl, halo-lower-alkyl, trifluoromethyl-lower-alkyl, lower-alkylamino, cycloalkylamino, or phenyl-lower-alkyl amino), —C(O)NR
6
R
7
(wherein R
6
and R
7
are independently hydrogen, phenyl, phenyl-lower-alkyl, lower-alkoxy-lower-alkyl, lower-alkyl, lower-alkoxy, or hydroxy, or R
6
and R
7
together with the nitrogen atom to which they are attached form a morpholinyl group), formyl, phenylcarbonyl, phenyl, perfluorolower-alkyl, lower-alkoxycarbonyl-lower-alkyl, or carboxy-lower-alkyl.
Preferred compounds of the formula I above are those wherein R
1
, R
2
, R
3
and R
4
are independently hydrogen or halogen; and X, C and R are as defined directly above.
Particularly preferred compounds of the Formula I above are those wherein:
X and C are as defined directly above;
R
1
, R
2
, R
3
and R
4
are independently hydrogen or halogen; and
R is cyano, —C(O)OR
5
(wherein R
5
is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, 2-propenyl, 3-butenyl, 1-methyl-3-butenyl, 3-methyl-3-butenyl, 4-pentenyl, 3-butynyl, cyclopropylmethyl, phenyl, phenylmethyl, phenylethyl, phenylpropyl, 3-phenyl-2-propynyl, methylthioethyl, methylthiopropyl, chloroethyl, chloropropyl, 2,2,2-trifluoroethyl, isopropylamino, cyclohexylamino, tert-butyl-amino, phenylmethylamino), —C(O)NR
6
R
7
(wherein R
6
and R
7
are independently hydrogen, phenylmethyl, phenyl, methoxyethyl, ethoxyethyl, propyl, methyl, methoxy, or hydroxy, or R
6
and R
7
together with the nitrogen atom to which they are attached form a morpholinyl group), formyl, phenylcarbonyl, phenyl, trifluoromethyl, tert-butoxy-carbonylmethyl or carboxymethyl.
More particularly preferred compounds of the Formula I above are those wherein:
One of R
1
, R
2
, R
3
or R
4
is chloro and the others are hydrogen; and X, C and R are as defined directly above.
Preferred species of the invention include:
7-chloro-3-(carboxy)pyrazolo[3,4-c][1]benzazepine-4,10-(1H,9H) -dione,
7-chloro-3-cyanopyrazolo[3,4-c][1]benzazepine-4,10-(1H,9H)-dione,
7-chloro-3-trifluoromethylpyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione,
3-methoxycarbonyl-7-chloropyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione,
7-chloro-3-(ethoxycarbonyl)pyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione,
3-propoxycarbonyl-7-chloropyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione,
7-chloro-3-(2-propenyloxycarbonyl)pyrazolo[3,4-c][1]-benzazepine-4,10(1H,9H)-dione,
7-chloro-3-(isopropoxycarbonyl)pyrazolo[3,4-c][1]-benzazepine-4,10(1H,9H)-dione,
3-butoxycarbonyl-7-chloropyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione,
3-(3-butenyloxycarbonyl)7-chloropyrazolo[3,4-c][1]-benzazepine-4,10(1H,9H)-dione, and
3-(3-butynyloxycarbonyl)-7-chloropyrazolo[3,4-c][1]-benzazepine-4,10(1H,9H)-dione;
or a pharmaceutically acceptable salt thereof.
Another group of compounds within the ambit of Formula I above are those wherein:
X is O or S;
R
1
, R
2
, R
3
and R
4
are independently hydrogen, perfluorolower-alkyl, halogen, nitro or cyano; and
C together with the carbon atoms to which it is attached forms a 5-membered aromatic heterocycle of the formula:
or tautomers thereof, wherein R is cyano, —C(O)OR
5
(wherein R
5
is hydrogen, lower-alkyl, lower-alkenyl, lower-alkynyl, cycloalkyl-lower-alkyl, phenyl, phenyl-lower-alkyl, phenyl-lower-alkynyl, lower-alkylthio-lower-alkyl, halo-lower-alkyl, trifluoromethyl-lower-alkyl, lower-alkoxy-lower-alkyl, hydroxy-lower-alkyl, lower-alkylamino, cycloalkylamino, or phenyl-lower-alkylamino), —C(O)NR
6
R
7
(wherein R
6
and R
7
are independently hydrogen, phenyl, phenyl-lower-alkyl, lower-alkoxy-lower-alkyl, hydroxy-lower-alkyl, lower-alkyl, lower-alkoxy, hydroxy, or cycloalkyl, or R
6
and R
7
together with the nitrogen atom to which they are attached form a 5- or 6-membered non-aromatic heterocycle selected from the group consisting of morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl and thiomorpholinyl), formyl, phenylcarbonyl, phenyl, lower-alkylcarbonyl, perfluorolower-alkyl, lower-alkoxycarbonyl-lower-alkyl, carboxy-lower-alkyl
Brush Kelly Anne
Chapdelaine Marc Jerome
Frazee William Jackson
Garcia-Davenport Laura Enid
Lewis Joseph James
Kifle Bruck
Mitchell Kenneth F.
Zeneca Limited
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