Aralkyl and aralkylidene heterocyclic lactams and imides

Details Aralkyl and aralkylidene heterocyclic lactams and imides Aralkyl and aralkylidene heterocyclic lactams and imides

2001-11-06

2003-09-30

Solola, Taofiq (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S235800, C544S059000, C544S060000, C558S426000

Reexamination Certificate

active

06627627

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to novel aralkyl and aralkylidene heterocyclic lactams and imides, to intermediates for their preparation, to pharmaceutical compositions containing them and to their medicinal use. The compounds of the present invention include selective agonists and antagonists of serotonin 1 (5-HT
1
) receptors, specifically, of one or both of the 5-HT
1A
, and 5-HT
1D
receptors. They are useful in treating or preventing migraine, depression and other disorders for which a 5-HT
1
agonist or antagonist is indicated.
European Patent Publication 434,561, published on Jun. 26, 1991, refers to 7-alkyl, alkoxy, and hydroxysubstituted-1-(4-substituted-1-piperazinyl)-naphthalenes. The compounds are referred to as 5-HT
1
agonists and antagonists useful for the treatment of migraine, depression, anxiety, schizophrenia, stress and pain.
European Patent Publication 343,050, published on Nov. 23, 1989, refers to 7-unsubstituted, halogenated, and methoxy substituted-1-(4-substituted-1-piperazinyl)-naphthalenes as useful 5-HT
1A
ligand therapeutics.
PCT publication WO 94/21619, published Sep. 29, 1994, refers to naphthalene derivatives as 5-HT
1
agonists and antagonists.
PCT publication WO 96/00720, published Jan. 11, 1996, refers to naphthyl ethers as useful 5-HT
1
agonists and antagonists.
European Patent Publication 701,819, published Mar. 20, 1996, refers to the use of 5-HT
1
agonists and antagonists in combination with a 5-HT re-uptake inhibitor.
Glennon et al., refers to 7-methoxy-1-(1-piperazinyl)-naphthalene as a useful 5-HT
1
ligand in their article “5-HT
1D
Serotonin Receptors”,
Clinical Drug Res. Dev
., 22, 25-36 (1991).
Glennon's article “Serotonin Receptors: Clinical Implications”,
Neuroscience and Behavioral Reviews
, 14, 35-47 (1990), refers to the pharmacological effects associated with serotonin receptors including appetite suppression, thermoregulation, cardiovascular/hypotensive effects, sleep, psychosis, anxiety, depression, nausea, emesis, Alzheimer's disease, Parkinson's disease and Huntington's disease.
World Patent Application WO 95/31988, published Nov. 30, 1995, refers to the use of a 5-HT
1D
antagonist in combination with a 5-HT
1A
antagonist to treat CNS disorders such as depression, generalized anxiety, panic disorder, agoraphobia, social phobias, obsessive-compulsive disorder, post-traumatic stress disorder, memory disorders, anorexia nervosa and bulimia nervosa, Parkinson's disease, tardive dyskinesias, endocrine disorders such as hyperprolactinaemia, vasospasm (particularly in the cerebral vasculature) and hypertension, disorders of the gastrointestinal tract where changes in motility and secretion are involved, as well as sexual dysfunction.
G. Maura et al.,
J. Neurochem
, 66 (1), 203-209 (1996), have stated that administration of agonists selective for 5-HT
1A
receptors or for both 5-HT
1A
and 5-HT
1D
receptors might represent a great improvement in the treatment of human cerebellar ataxias, a multifaceted syndrome for which no established therapy is available.
European Patent Publication 666,261, published Aug. 9, 1995 refers to thiazine and thiomorpholine derivatives which are claimed to be useful for the treatment of cataracts.
SUMMARY OF THE INVENTION
The present invention relates to compounds of the formula
wherein R
1
is a group of the formula G
1
, G
2
, G
3
, G
4
, G
5
, G
6
or G
7
depicted below,
a is zero to eight,
each R
13
is, independently, (C
1
-C
4
)alkyl or a (C
1
-C
4
)methylene bridge from one of the ring carbons of the piperazine or pipendine ring of G
1
or G
2
, respectively, to the same or another ring carbon or a ring nitrogen of the piperazine or piperidine ring of G
1
or G
2
, respectively, having an available bonding site, or to a ring carbon of R
6
having an available bonding site;
E is oxygen, sulfur, SO or SO
2
;
X is hydrogen, chloro, fluoro, bromo, iodo, cyano, (C
1
-C
6
)alkyl, hydroxy, trifluoromethyl, (C
1
-C
6
)alkoxy, —SO
1
(C
1
-C
6
)alkyl wherein t is zero one or two, —CO
2
R
10
or —CONR
11
R
12
;
Y is an optionally substituted (C
1
-C
4
) heteroalkyl bridge that, together with the atoms to which it is attached, forms a five to seven membered heterocycle containing two to four heteroatoms selected from the group consisting of 1,3-oxazolidin-4-on-5-yl, 1,3-oxazolidin-2,4-dion-5-yl, 4,5-dihydro-1,2-oxazolidin-3-on-4-yl, 1,3-thiazolidin-4-on-5-yl, 1,3-thiazolidin-2,4-dion-5-yl, 1,3-pyrazolidin-4-on-5-yl, 1,3-imidazolidin-2,4-dion-5-yl, 1,2-pyrazolidin-3-on-4-yl, 1,2-thiazolidin-1,1,3-trion-4-yl, 1,2-thiazolidin-3-on-4-yl, tetrahydro-1,2-oxazin-3-on-4-yl, tetrahydro-1,3-oxazin4-on-5-yl, tetrahydro-1,3-oxazin-2,4-dion-5-yl, morpholin-3-on-2-yl, morpholin-3,5-dion-2-yl, 2,3-dihydro-1,4-oxazin-3-on-2-yl, tetrahydro-1,3-thiazin4-on-5-yl, tetrahydro-1,3-thiazin-2,4-dion-5-yl, tetrahydro-1,2-thiazin-3on-4-yl, thiomorpholin-3-on-2-yl, thiomorpholin-3,5-dion-2-yl, 2,3-dihydro-1,4-thiazin-3-on-2-yl, hexahydro-1,2-diazin-3-on-4-yl, 4,5-dihydro-2H-pyridazin-3-on-4-yl, hexahydro-1,3-diazin4-on-5-yl, hexahydro-1,3-diazin-2,4-dion-5-yl, piperazin-2-on-3-yl, piperazin-2,6-dion-3-yl, tetrahydro-1,3,4-thiadiazin-5-on-6-yl, 5,6-dihydro-1,3,4-thiadiazin-5-on-6-yl, 1,3,4-oxadiazin-5-on-6-yl, 5,6-dihydro-1,2,4-oxadiazin-5-on-6-yl, tetrahydro-1,2,4-oxadiazin-5-on-6-yl, 1,2,4-triazin-5-on-6-yl, tetrahydro-1,2,4-oxadiazin-5-on-6-yl, 5,6-dihydro-1,2,4-oxadiazin-5-on-6-yl, 1,2,4-oxadiazin-3,5-dion-6-yl, 1,2,4-trazin-6-on-5-yl, hexahydro-1,2-oxazepin-3-on-2-yl, hexahydro-1,3-oxazepin-4-on-5-yl, hexahydro-1,4-oxazepin-3-on-2-yl, hexahydro-1,4-oxazepin-3,5-dion-2-yl, hexahydro-1,4-oxazepin-3,5-dion-6-yl, 2,3,5,6-tetrahydro-1,4-oxazepin-5,7-dion-6-yl, hexahydro-1,4-oxazepin-5-on-6-yl, hexahydro-1,3-oxazepin-2,4-dion-5-yl, hexahydro-1,2-thiazepin-3-on-4-yl, hexahydro-1,4-thiazepin-3-on-2-yl, 2,3,4,5-tetrahydro-1,4-thiazepin-3-on-2-yl, hexahydro-1,4-thiazepin-3,5-dion-2-yl, hexahydro-1,4-thiazepin-3,5-dion-6-yl, 2,3,6,7-tetrahydro-1,4-thiazepin-5-on-6-yl, 6,7-dihydro-1,4-thiazepin-5-on-6-yl, hexahydro-1,3-thiazepin-2,4-dion-5-yl, hexahydro-1,2-diazepin-3-on-4-yl, hexahydro-1,3-diazepin-2,4-dion-5-yl, hexahydro-1,4-diazepin-2-on-3-yl, hexahydro-1,4-diazepin-5-on-6-yl, hexahydro-1,4-diazepin-5,7-dion-6-yl, hexahydro-1,3,5-thiadiazepin-3-on-7-yl, 4,5,6,7-tetrahydro-1-3,5-thiadiazepin-6-on-7-yl, and 2,3,5,6-tetrahydro-1,2,4-triazepin-3,5-dion-7-yl; wherein the substituents on any of the carbon atoms capable of supporting an additional bond, of said (C
1
-C
4
) heteroalkyl bridge, are chloro, fluoro, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, trifluoromethyl or cyano; wherein the substituents on any of the nitrogen atoms capable of supporting an additional bond, of said (C
1
-C
4
) heteroalkyl bridge, are (C
1
-C
4
)alkyl or trifluoromethyl;
R
2
is hydrogen, (C
1
-C
4
)alkyl, phenyl or naphthyl, wherein said phenyl or naphthyl may optionally be substituted with one or more substituents independently selected from chloro, fluoro, bromo, iodo, (C
1
-C
4
)alkyl, (C
1
-C
6
)alkoxy, trifluoromethyl, cyano and —SO
k
(C
1
-C
6
)alkyl wherein k is zero, one or two;
R
3
is —(CH
2
)
m
B, wherein m is zero, one, two or three and B is hydrogen, phenyl, naphthyl or a 5 or 6 membered heteroaryl group containing from one to four heteroatoms in the ring, and wherein each of the foregoing phenyl, naphthyl and heteroaryl groups may optionally be substituted with one or more substituents independently selected from chloro, fluoro, bromo, iodo, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, (C
1
-C
6
) alkoxy-(C
1
-C
6
)alkyl-, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, —COOH and —SO
n
(C
1
-C
6
)alkyl wherein n is zero, one or two;
R
6
is selected from the group consisting of hydrogen, (C
1
-C
6
)alkyl optionally substituted with (C
1
-C
4
)alkoxy or one to three fluorine atoms, or [(C
1
-C
4
)alkyl]aryl wherein the aryl moiety is phenyl, naphthyl, or heteroaryl-(CH
2
)
q
—, wherein the heteroaryl moiety is selected from the group consisting of pyridyl, pyrimidyl, benzoxazolyl, be

Affiliated with

Also associated with

Rating

Aralkyl and aralkylidene heterocyclic lactams and imides does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Aralkyl and aralkylidene heterocyclic lactams and imides, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Aralkyl and aralkylidene heterocyclic lactams and imides will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3007246