Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-02-25
2001-05-29
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S326000, C544S367000, C546S209000
Reexamination Certificate
active
06239134
ABSTRACT:
This invention relates to a series of novel diazolepiperazine, diazolepiperidine, and diazoledihydropiperidine derivatives, and to processes for their preparation, to pharmaceutical compositions containing them, and to their use in therapies concerning central nervous system disorders. These compounds are useful for treatment of conditions related to or affected by the 5-hydroxytryptamine-1-A (5-HT1A) receptor subtype in the CNS, including alcohol and drug withdrawl, sexual dysfunction, and Alzheimer's Disease. The utility of these compounds lies in their ability to bind as agonists and antagonists to 5-HT1A receptors. The compounds of the present invention are also useful in the treatment of depression and related CNS disorders (e.g., OCD, anxiety and panic) when combined with the use of serotonin reuptake inhibtors, such as Prozac® (fluoxetine hydrochloride).
BACKGROUND OF THE INVENTION
Depression is a psychiatric condition thought to be associated with decreased serotonin release. Most antidepressant agents potentiate the effects of serotonin by blocking the termination of its activity through re-uptake into nerve terminals.
U.S. Pat. No. 3,655,663 (B.K. Wasson, Apr. 11, 1972) covers 4-(3-secondary amino-2-hydroxypropoxy)-1,2,5-thiadiazoles which exhibit beta-adrenergic blocking properties useful for treatment of angina pectoris. Compounds of the present invention are structurally different from this prior art and are useful for treatment of CNS disorders.
WO 96/38431 (Eli Lilly, May 31, 1996) covers methods of making 1,2,5-thiadiazoles containing azacyclic or azabicyclic ether or thioether substituents for use as muscarinic cholinergic agonists. These compounds are useful as stimulants of the forebrain and hippocampus for treatment of Alzheimer's disease. Compounds of this invention are structurally different from these compounds and are agonists and antagonists of the 5HT1A receptor, not muscarinic agonists.
SUMMARY OF THE INVENTION
Compounds of the present invention are represented by the general formula (1):
wherein:
two atoms of X, Y, or Z are nitrogen and the third atom is sulfur or oxygen;
R is H, halogen, OH, SH, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, C
1
-C
6
thioalkyl, phenoxy, thiophenoxy, or phenyl, the phenyl ring being optionally substituted by from one to three substituents selected from C
1
-C
6
alkyl; C
1
-C
6
alkoxy; CF
3
; Cl; Br; F; CN; or CO
2
CH
3
;
A is C, CH, or N;
R
1
is aryl, heteroaryl, or cycloalkyl groups, the aryl, heteroaryl or cycloalkyl groups being optionally substituted by from 1 to 3 substituents selected from C
1
-C
6
alkyl, C
1
-C
6
alkoxy; CF
3
, Cl, Br, F, CN, or CO
2
CH
3
;
R
2
is H or C
1
-C
6
alkyl;
R
3
is C
1
-C
6
alkyl, aryl, 5- or 6-membered heteroaryl, C
3
to C
8
cycloalkyl , the cycloalkyl groups being optionally substituted by C
1
-C
6
alkyl, or a 3 to 8-membered heterocyclic ring containing one or more heteroatoms selected from O, S or N, the aryl and 5- or 6-membered heteroaryl groups being optionally substituted by from one to three substituents selected from C
1
-C
6
alkyl, C
1
-C
6
alkoxy, CF
3
, Cl, Br, F, CN, or CO
2
CH
3
;
or a pharmaceutically acceptable salt thereof.
As used herein, the term alkyl refers to C
1
-C
6
straight or branched chain, and wherein the term cycloalkyl refers to C
3
to C
8
ring, preferably a C
3
to C
6
ring, or an alkyl-substituted ring. The term “aryl” is phenyl or substituted phenyl, biphenyl, 1 or 2-naphthyl and “heteroaryl” refers to 5 or 6 membered ring heterocycles or benzofused heterocycles, specifically including, but not limited to, thiazole, thiophene, 2, 3, or 4-pyridyl, benzothiophene, or indole. The aryl or heteroaryl groups herein can be optionally substituted with one to three substituents selected from the group consisting of C
1
-C
6
alkyl; C
1
-C
6
alkoxy; CF
3
; Cl; Br; F; CN; CO
2
CH
3
.
Among the preferred compounds of this invention are those of formula (2):
wherein R, R
1
, R
2
, and R
3
, are as defined above, or a pharmaceutically acceptable salt thereof.
Further preferred are those compounds of formula (2) wherein:
R is H, halogen, OH, SH, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, C
1
-C
6
thioalkyl;
R
1
is aryl, heteroaryl, or cycloalkyl groups, optionally substituted by from 1 to 3 substituents selected from C
1
-C
6
alkyl, C
1
-C
6
alkoxy; CF
3
, Cl, Br, F, CN, or CO
2
CH
3
;
R
2
is H or C
1
-C
6
alkyl
R
3
is C
1
-C
6
alkyl, optionally substituted aryl, optionally substituted 5- or 6-membered heteroaryl, C
3
to C
8
cycloalkyl optionally substituted by C
1
-C
6
alkyl, or a 3 to 8-membered heterocyclic ring containing one or more heteroatoms selected from O, S or N;
or a pharmaceutically acceptable salt thereof.
The pharmaceutically acceptable salts are the acid addition salts which can be formed from a compound of the above general formula and a pharmaceutically acceptable acid such as phosphoric, sulfuric, hydrochloric, hydrobromic, citric, maleic, fumaric, acetic, lactic or methanesulfonic acid.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of this invention possess high affinity for the serotonin 5-HT
1
A receptor and, consequently, are useful as antidepressant and anxiolytic agents for the treatment in a mammal of a variety of central nervous system (CNS) disorders such as depression, anxiety, sleep disorders, sexual dysfunction, alcohol and/or cocaine addiction, and related problems. The compounds of this invention may also be used in the inducement of cognition enhancement in a mammal, preferably in humans. In addition, the compounds of this invention show marked selectivity for the 5-HT
1
A receptors, as opposed to the &agr;1 receptors.
In view of their receptor binding, these compounds may be characterized as anxiolytic and/or antidepressant agents useful in the treatment of depression and in alleviating anxiety. As such, the compounds may be administered neat o with a pharmaceutical carrier or excipient to a patient in need thereof. The pharmaceutical carrier may be solid or liquid.
It is understood that the therapeutically effective dosage to be used in the treatment of a specific psychosis must be subjectively determined by the attending physician. Variables involved include the specific psychosis or state of anxiety and the size, age and response pattern of the patient. The novel methods of the invention for treating, preventing or alleviating conditions as described above, or for inducing cognition enhancement, comprise administering to mammals in need thereof, including humans, an effective amount of one or more compounds of this invention or a non-toxic, pharmaceutically acceptable addition salt thereof. The compounds may be administered orally, rectally, parenterally, or topically to the skin and mucosa. The usual daily dose is depending on the specific compound, method of treatment and condition treated. An effective dose of 0.01-1000 mg/Kg may be used for oral application, preferably 0.5-500 mg/Kg, and an effective amount of 0.1-100 mg/Kg may be used for parenteral application, preferably 0.5-50 mg/Kg. It will be understood that in combination with other agonists or antagonists of the serotonin-1 receptor (5-HT
1
A), such as those listed above, the effective dose of the present compounds may be reduced relative to the effective amount of the combined active ingredient(s).
The present invention also includes pharmaceutical compositions containing a compound of this invention, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients. Applicable solid carriers or excipients can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintergrating agents or an encapsulating material. In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the s
Childers Wayne E.
Kelly Michael G.
Palmer Yvette L.
Sabb Annmarie L.
Vogel Robert L.
American Home Products Corp.
Balasubramanian Venkataraman
Mazzarese Joseph M.
Raymond Richard L.
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