Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-07-22
2001-11-06
Stockton, Laura L. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S115000
Reexamination Certificate
active
06313139
ABSTRACT:
The present invention relates to certain novel benzylamine derivatives, to processes for their preparation, to pharmaceutical formulations containing them and to their use in medical therapy, particularly in the treatment of depression.
European patent specification No.0 299 349 discloses certain propy!-1,2-benzisoxazole derivatives having analgesic and hypotensive activity. A number of arylethylamine derivatives which are useful in treating or in preventing a disorder of the melatoninergic system are disclosed in U.S. Pat. No. 5,276,051.
A group of benzylamine derivatives have now been found which show activity as antidepressants and are useful in treating a number of other conditions described herein. Thus, according to one aspect, the present invention provides the compounds of formula (I)
wherein R
1
and R
2
, which may be the same or different, are each selected from C
6-12
aryl, C
2-14
heteroaryl, C
6-12
arylC
1-6
alkyl, C
2-14
heteroarylC
1-6
alkyl (where the alkyl, aryl or heteroaryl moiety may be optionally substituted by one or more substituents selected from C
1-6
alkoxy, C
1-6
alkyl, C
3-6
cycloalkyl, C
4-6
cycloalkenyl, C
6-12
aryl, G
2-14
heteroaryl, halogen, amino, hydroxy, haloC
1-6
alkyl, nitro, C
1-6
alkylthio, sulphonamide, C
1-6
alkylsulphonyl, hydroxyC
1-6
alkyl, C
1-6
alkoxycarbonyl, carboxyl, carboxyC
1-6
alkyl, carboxamide and C
1-6
alkylcarboxamide), hydrogen, C
1-6
alkyl, C
3-6
cycloalkyl, C
3-6
cycloalkylC
1-6
alkyl, C
4-6
cycloalkenyl, C
2-6
alkenyl, C
2-6
alkynyl and C
1-6
alkoxyC
1-6
alkyl (where the alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, or alkoxyalkyl moieties may be optionally substituted by one or more substituents selected from amino, halogen, hydroxy, C
1-6
alkylcarboxamide, carboxamide, carboxy, C
1-6
alkoxycarbonyl, C
1-6
alkylcarboxy and carboxyC
1-6
alkyl) or one of R
1
and R
2
are as hereinbefore defined and one is hydroxy; R
3
and R
4
, which may be the same or different, are each selected from C
6-12
aryl, C
2-14
heteroaryl, C
6-12
arylC
1-6
alkyl, C
2-14
heteroarylC
1-6
alkyl (where the alkyl, aryl or heteroaryl moiety may be optionally substituted by one or more substituents selected from C
1-6
alkoxy, C
1-6
alkyl, C
3-6
cycloalkyl, C
4-6
cycloalkenyl, C
6-12
aryl, C
2-14
heteroaryl, halogen, amino, hydroxy, haloC
1-6
alkyl, nitro, C
1-6
alkylthio, sulphonamide, C
1-6
alkylsulphonyl, hydroxy C
1-6
alkyl, C
1-6
alkoxycarbonyl, carboxyl, carboxyC
1-6
alkyl, C
1-6
alkylcarboxamide and carboxamide), hydrogen, C
1-6
alkyl, C
3-6
cycloalkyl, C
3-6
cycloalkylC
1-6
alkyl, C
4-6
cycloalkenyl, C
2-6
alkenyl, C
2-6
alkynyl, C
1-6
alkoxyC
1-6
alkyl, haloC
1-6
alkyl, haloC
2-6
alkenyl, haloC
2-6
alkynyl, cyano, carboxyl, C
1-6
alkylcarboxy and carboxyC
1-6
alkyl (where the alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, or alkoxyalkyl moieties may be optionally substituted by one or more substituents selected from amino, hydroxy, C
1-6
alkylcarboxamide, carboxamide, carboxy, C
1-6
alkoxycarbonyl, C
1-6
alkylcarboxy and carboxyC
1-6
alkyl); or one of R
3
or R
4
together with one of R
1
or R
2
and the N atom to which it is attached form a 5- or 6-membered heterocyclic ring.
R
5
represents one or more ring substituents selected from halogen, hydrogen C
1-6
alkyl and C
1-6
alkoxy; and R
6
represents a single ring substituent of formula:
wherein the dotted line represents an optional bond; Y is oxygen or —NR
8
(where R
8
is hydrogen or C
1-6
alkyl) and R
7
represents one or more substituents selected from hydrogen, halogen, haloC
1-6
alkyl, C
1-6
alkyl and C
1-6
alkoxy; or
a pharmaceutically acceptable salt or solvate thereof.
The present invention further includes the compounds of formula (I) wherein:
1. One of R
1
and R
2
is hydrogen and the other is C
6-12
arylC
1-6
alkyl, C
2-14
heteroarylC
1-6
alkyl(where the alkyl, aryl or heteroaryl moiety may be optionally substituted by one or more ring substituents selected from C
1-6
alkoxy, C
2-14
heteroaryl, and carboxamide), hydrogen, C
1-6
alkyl, C
2-6
alkenyl and hydroxy; or a pharmaceutically acceptable salt or solvate thereof.
2. One of R
1
and R
2
is hydrogen and the other is C
6-12
arylC
1-6
alkyl, C
2-14
heteroarylC
1-6
alkyl(where the alkyl, aryl or heteroaryl moiety may be optionally substituted by one or more ring substituents selected from C
1-6
alkoxy, C
2-14
heteroaryl, C
1-6
alkylcarboxamide and carboxamide), hydrogen, C
1-6
alkyl, C
2-6
alkenyl and hydroxy where the alkyl or alkenyl, moieties may be optionally substituted by one or more substituents selected from hydroxy, C
1-6
alkylcarboxy and carboxyC
1-6
alkyl); or a pharmaceutically acceptable salt or solvate thereof.
3. R
1
and R
2
are both C
1-6
alkyl.
4. One of R
3
and R
4
is hydrogen and the other is C
6-12
arylC
1-6
alkyl, hydrogen, C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, cyano; or a pharmaceutically acceptable salt or solvate thereof.
5. One of R
3
and R
4
is hydrogen and the other is C
6-2
aryl, C
6-12
arylC
1-6
alkyl (where the aryl moiety may be optionally substituted by halogen), C
1-6
alkylcarboxy, haloC
1-6
alkyl, haloC
2-6
alkenyl, C
3-6
cycloalkylC
1-6
alkyl, C
4-6
cycloalkenyl, C
2-4
heteroarylC
1-6
alkyl.
6. R
6
is in the ortho position.
7. R
6
is in the meta or para positions.
8. Y is oxygen or —NCH
3
, R
7
is hydrogen and the dotted line represents a bond.
9. R
7
is halogen, haloC
1-6
alkyl.
10. R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, Y and the dotted line are as defined in points 1 to 9 supra.; or a pharmaceutically acceptable salt or solvate thereof.
The present invention further provides the compounds of formula (I) wherein R
1
, R
2
, R
5
and R
6
are as defined in relation to formula (I) supra, R
3
and R
4
, which may be the same or different, are each selected from C
6-12
aryl, C
2-14
heteroaryl, C
6-12
arylC
1-6
alkyl, C
2-14
heteroarylC
1-6
alkyl (where the alkyl, aryl or heteroaryl moiety may be optionally substituted by one or more substituents selected from C
1-6
alkoxy, C
1-6
alkyl, C
3-6
cycloalkyl, C
4-6
cycloalkenyl, C
6-12
aryl, C
2-14
heteroaryl, halogen, amino, hydroxy, haloC
1-6
alkyl, nitro, C
1-6
alkylthio, sulphonamide, C
1-6
alkylsulphonyl, C
1-6
alkylcarboxamide and carboxamide), hydrogen, C
1-6
alkyl, C
3-6
cycloalkyl, C
4-6
cycloalkenyl, C
2-6
alkenyl, C
2-6
alkynyl, C
1-6
alkoxyC
1-6
alkyl, cyano, carboxyl and carboxyC
1-6
alkyl; and R
7
is hydrogen, halogen, C
1-6
alkyl or C
1-6
alkoxy; or a pharmaceutically acceptable salt or solvate thereof.
Further examples of compounds of formula (I) above include Examples 1 to
40. As used herein the term alkyl as a group or part of a group means a straight or branched chain alkyl group. Such alkyl groups include methyl, ethyl, i-propyl, n-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, isopently, neopentyl, n-hexyl, isohexyl and neohexyl. References to alkenyl groups include groups which may be in the E- or Z-form or a mixture thereof and which when they contain at least three carbon atoms, may be branched. Examples of particular alkenyl groups include vinyl, allyl, butenyl, isobutenyl, pentenyl, isopentenyl, hexenyl, isohexenyl, neohexenyl and
1-methyl-2-propenyl. The terms alkoxy and alkynyl have meanings as understood by the person skilled in the art and include straight and branched chains. Examples of alkoxy groups include methoxy and ethoxy and examples of alkynyl groups include ethynyl, propynyl and butynyl.
As used herein the terms cycloalkyl and cycloalkenyl have meanings as understood by the person skilled in the art and include cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl and cyclohexadienyl.
The term halogen includes chloro, bromo, fluoro and iodo. The term haloC
1-6
alkyl means an alkyl group in which one or more hydrogens is replaced by halo and preferably containing one, two or three halo atoms. Examples of such groups include trifluoromethyl and fluoroisopropyl.
As used herein the term aryl as a group or part of a group means C
6-12
aryl aromatic groups and includes one or two C
6
aromatic rings. The term covers f
Carlyle Ian Craig
Dijcks Fredericus Antonius
Grove Simon James Anthony
Leysen Dirk
Linders Joannes Theodorus Maria
Akzo Nobel N. V.
Blackstone William M.
Stockton Laura L.
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