Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2003-07-03
2004-07-06
Davis, Brian (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C564S316000, C564S319000
Reexamination Certificate
active
06759435
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates generally to treatment of disease states and conditions which can be improved by administering a serotonin reuptake inhibitor (e.g., depression), and more specifically to novel amine compounds and pharmaceutical compositions thereof which are useful in the treatment of said disease states.
2. Description of Related Art
Major depression represents one of the most common mental illnesses, affecting between 5-10% of the population. The disease is characterized by extreme changes in mood which may also be associated with psychoses. It has generally been found that most antidepressant agents exert significant effects on the regulation of monoamine neurotransmitters, including serotonin.
A number of types of antidepressants have been developed in recent years. Many of these compounds regulate serotonin (5-hydroxytryptamine; 5-HT). Trazodone controls the actions of 5-HT while fluoxetine is a potent and selective inhibitor of 5-HT reuptake. 3-Chloroimipramine which inhibits both 5-HT and norepinephrine reuptake has been extensively used as an antidepressant in Europe and Canada. Other compounds which are of current interest or have been examined as antidepressants include fluvoxamine, citalopram, zimeldine, sertraline, bupropion and nomifensine.
The serotonergic neural system of the brain have been shown to influence a variety of physiologic functions, and antidepressants have the ability to treat in mammals, including humans, a variety of disorders associated with this neural system, such as eating disorders, depression, obsessive compulsive disorders, panic disorders, alcoholism, pain, memory deficits and anxiety. Other indications for antidepressants include unipolar depression, dysthymia, bipolar depression, treatment-resistant depression, depression in the medically ill, panic disorder, obsessive-compulsive disorder, eating disorders, social phobia, and premenstrual dysphoric disorder.
The adverse effects occurring most frequently during treatment with selective serotonin reuptake inhibitors (SSRI(s)) are gastrointestinal disturbances, such as, for example nausea, diarrhoea/loose stools, constipation, with an incidence of 6 to 37% (Drugs 43 (Suppl. 2), 1992). Nausea is the main adverse effect in terms of incidence. These adverse effects, although mild to moderate in severity, shy some patients away from treatment with SSRIs. The percentage of patients withdrawing because of nausea ranges from 3 to 8% of the patients. Moreover it has been frequently observed that after administration of SSRIs, patients suffer from dyspepsia. Known antidepressants also cause a variety of other adverse effects including anorexia, dry mouth, headache, nervousness, skin rash, sleep problems, somnolence, liver toxicity, mania, increased urination, seizures, sweating increase, tremors, and Tourette's syndrome. Current research is beginning to unveil that many of these drugs produce undesirable physiological side effects (Sipgset, O. Drug Saf. 1999. 20(3):277-287; Pache, P. Curr. Med Chem. 1999. 6(6): 46-480).
Often, these drugs also take about six to eight weeks to exhibit any desirable therapeutic effects. This time period can be prolonged when the correct drug or combinations of drugs has to be determined, by trial and error, before any therapeutic effects are observed.
We have thus focused our efforts on the development of novel antidepressants, which do not suffer from the side effects associated with presently known serotonin reuptake inhibitors and which take shorter to exhibit desirable therapeutic effects.
BRIEF SUMMARY OF THE INVENTION
In certain embodiments, this invention is directed to novel amine compounds, which are potent, and selective serotonin reuptake inhibitors.
In certain embodiments, this invention is directed to compounds of the formula (I) and pharmaceutically acceptable tautomers and/or salts thereof:
wherein:
R
1
is —C
1-6
alkyl;
R
2
is -phenyl, unsubstituted, mono- or polysubstituted with a substituent selected from the group consisting of -halo, —C
1-6
alkyl, —CF
3
, —O—C
1-6
alkyl, and —NO
2
;
R
3
is selected from the group consisting of —H and —C
1-6
alkyl;
R
4
is —C
1-6
alkyl;
R
5
is —C
1-6
alkyl;
R
6
is each independently selected from the group consisting of: -halo, —C
1-6
alkyl, —CF
3
, —O—C
1-6
alkyl, and —NO
2
; and
q is an integer from 0 to 4.
In certain embodiments, this invention is directed to compounds of the Formula (I) and pharmaceutically acceptable esters, ethers, and/or salts thereof, wherein R
1
is —CH
3
. In one class of these embodiments are those compounds of Formula (I) wherein R
2
is -phenyl, unsubstituted, mono- or polysubstituted with a substituent selected from the group consisting of: -halo, —C
1-6
alkyl, —CF
3
, —O—C
1-6
alkyl, and —NO
2
, and particularly selected from a group consisting of: -halo, —C
1-6
alkyl, —CF
3
, and —O—C
1-6
alkyl. In a subclass of these embodiments are those compounds of Formula (I) wherein R
2
is selected from the group consisting of: -3-chlorophenyl, -4-chlorophenyl, -4-methoxyphenyl, -3-trifluoromethyl-phenyl, -4-trifluoromethyl-phenyl, -3,4-dichlorophenyl, -3-bromophenyl, -4-bromophenyl and -3-trifluoromethyl-4-chloro-phenyl. In another class of these embodiments are those compounds of Formula (I) wherein R
3
is —H; and R
4
is —C
1-6
alkyl, and particularly is -methyl. In another class of these embodiments are those compounds of Formula (I) wherein R
5
is —CH
3
. In another class of these embodiments are those compounds of Formula (I) wherein R
6
is selected from the group consisting of —CH
3
and -halo. In another class of these embodiments are those compounds of Formula (I) wherein q is an integer from 0 to 1 and more particularly q is 0.
Particular novel compounds of structural Formula (I) which may be employed in the methods, uses and compositions of the present invention, include:
(1) Methyl-{1-[2-(1-phenyl-ethyl)-phenyl]-ethyl}-amine
(2) Methyl-{1-[2-(1-phenyl-propyl)-phenyl]-ethyl}-amine
(3) Dimethyl-{1-[2-(1-phenyl-ethyl)-phenyl]-ethyl}-amine
(4) Methyl-{1-[2-(1-phenyl-ethyl)-phenyl]-propyl}-amine
(5) (1-{2-[1-(3,4-Dichloro-phenyl)-ethyl]-phenyl}-ethyl)-methyl-amine
(6) {1-[4,5-Dimethyl-2-(1-phenyl-ethyl)-phenyl]-ethyl}-methyl-amine
(7) {1-[4,5-Dichloro-2-(1-phenyl-ethyl)-phenyl]-ethyl}-methyl-amine
(8) (1-{2-[1-(4-Chloro-phenyl)-ethyl]-phenyl}-ethyl)-methyl-amine
(9) (1-{2-[1-(3-Chloro-phenyl)-ethyl]-phenyl}-ethyl)-methyl-amine
(10) (1-{2-[1-(4-Methoxy-phenyl)-ethyl]-phenyl}-ethyl)-methyl-amine
(11) Methyl-(1-{2-[1 (4-trifluoromethyl-phenyl)-ethyl]-phenyl}-ethyl)-amine
(12) Methyl-(1-{2-[1-(3-trifluoromethyl-phenyl)-ethyl]-phenyl}-ethyl)-methyl-amine
(13) (1-{2-[-(3,4-Dichloro-phenyl)-ethyl]-phenyl}-ethyl)-methyl-amine
(14) (1-{2-[1-(4-Bromo-phenyl)-ethyl]-phenyl}-ethyl)-methyl-amine
(15) (1-{2-[1-(3-Bromo-phenyl)-ethyl]-phenyl}-ethyl)-methyl-amine
(16) (1-{2-[1-(4-Bromo-3-trifluoromethyl-phenyl)-ethyl]-phenyl}-ethyl)-methyl-amine and pharmaceutically acceptable salts and tautomers thereof.
Particular novel compounds of structural Formula (I) which may be employed in the methods, uses and compositions of the present invention, include also single enantiomers of the above compounds. For example, methyl-{1-[2-(1-phenyl-ethyl)-phenyl]-ethyl}-amine is meant to include a statistical 1:1:1:1 mixture of [R,R]-methyl-{1-[2-(1-phenyl-ethyl)-phenyl]-ethyl}-amine, [R,S]-methyl-{1-[2-(1-phenyl-ethyl)-phenyl]-ethyl}-amine, [S,R]-methyl-{1-[2-(1-phenyl-ethyl)-phenyl]-ethyl}-amine and [S,S]-methyl-{1-[2-(1-phenyl-ethyl)-phenyl]-ethyl}-amine, and also various other proportions o
A.P. Group Inc.
Davis Brian
LandOfFree
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