Heterocyclic compounds

Details Heterocyclic compounds Heterocyclic compounds

1999-06-01

2001-02-13

Cerstl, Robert (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C548S135000

Reexamination Certificate

active

06187798

ABSTRACT:

The present invention relates to therapeutically active azabicyclo[2.2.1]heptane compounds having surprising potency and favorable side effect profile. The novel compounds are useful as stimulants of the cognitive function of the forebrain and hippocampus of mammals.
Due to the generally improved health situation in the western world, elderly-related diseases are much more common now than in the past and are likely to be even more common in the future.
One of the elderly-related symptoms is a reduction of the cognitive functions. This symptom is especially pronounced in the pathophysiological disease known as Alzheimer's disease. This disease is combined with, and also most likely caused by, an up to 90% degeneration of the muscarinic cholinergic neurons in nucleus basalis, which is part of substantia innominata. These neurons project to the prefrontal cortex and hippocampus and have a general stimulatory effect on the cognitive functions of the forebrain as well as of hippocampus, namely learning, association, consolidation, and recognition.
It is a characteristic of Alzheimer's disease that although the cholinergic neurons degenerate, the postsynaptic muscarinic receptors in the forebrain and hippocampus still exist. Therefore, muscarinic cholinergic agonists are useful in the treatment of Alzheimer's disease, in halting its progression, and in improving the cognitive functions of elderly people.
Compounds active at a muscarinic cholinergic receptor are also useful analgesic agents and therefore are useful in the treatment of severely painful conditions.
Furthermore, muscarinic cholinergic receptor active compounds are useful in the treatment of glaucoma, psychosis, anxiety, mania, bipolar disorder, schizophrenia or schizophreniform conditions, depression, sleeping disorders, epilepsy, cerebral ischemia, and gastrointestinal motility disorders.
Therefore, new compounds having muscarinic cholinergic activity are desired. Some muscarinic cholinergic receptor active compounds are associated with side effects attributed to undesired modulation of the muscarinic cholinergic receptors, for example, such undesired modulation may cause excessive salivation and gastrointestinal upset. Thus, the most desired muscarinic cholinergic compounds shall have high potency and at the same time a favorable side effect profile, including a low incidence of excessive salivation.
The presently claimed compounds are surprisingly potent and provide a favorable side effect profile. Studies of the compounds claimed herein suggest that these compounds will be highly desired muscarinic receptor active compounds which can be particularly useful pharmaceutically active compounds.
This invention provides compounds of the formula I:
W is S or O;
R
8
is selected from the group consisting of hydrogen and C
1
-C
4
alkyl;
R
9
is selected from the group consisting of halogen, C
1-4
-alkyl, C
1-4
-alkoxy, —CN, —OCF
3
, —CF
3
, —CONH
2
and —CSNH
2
; and
pharmaceutically acceptable salts and solvates thereof.
Preferred compounds are those wherein R
9
is chloro and in the para position on the phenyl group.
The present invention further provides a formulation comprising a compound of Formula I and one or more carriers or diluents therefor.
Additionally, the present invention provides a method for treating a condition which is mediated by a muscarinic receptor comprising administering an effective amount of a compound of Formula I to a mammal in need of such treatment.
It is to be understood that the invention extends to each of the stereoisomeric forms of the compounds of the present invention as well as the pure diastereomeric, pure enatiomeric, and racemic forms of the compounds of this invention.
As used herein the term “treating” includes prophylaxis of a physical and/or mental condition or amelioration or elimination of the developed physical and/or mental condition once it has been established or alleviation of the characteristic symptoms of such condition.
As used herein the phrase “interacting with a muscarinic cholinergic receptor” shall include compounds which block muscarinic cholinergic receptors or modulate such receptors. The phrase shall include the effect observed when compounds act as agonists, partial agonists and/or antagonists at a muscarinic cholinergic receptor.
As used herein the phrase “a condition which is mediated by a muscarinic receptor” shall refer to a condition which can be treated by administering a compound which acts as a muscarinic receptor antagonist, agonist, or mixed agonist at a muscarinic receptor. Such conditions shall include, but are not limited to, Alzheimer's disease, severely painful conditions, glaucoma, psychosis, anxiety, mania, bipolar disorder, schizophrenia or schizophreniform conditions, depression, sleeping disorders, epilepsy, cerebral ischemia, and gastrointestinal motility disorders.
As used herein, the term “halogen” means Cl, Br, F, and I. Especially preferred halogens include Cl, Br, and I. A particularly preferred halogen is Cl.
As used herein the phrase “one or more selected from” shall more preferredly refer to from 1-3 substituents. The term shall further preferredly refer to from 1-2 substituents.
The terms “C
n
′-C
4
alkyl” wherein n′ can be 1 or 2, as used herein, represent a branched or linear alkyl group having from one to 4 carbon atoms. Typical C
1
-C
4
alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl and the like.
The term “C
1
-C
4
alkoxy” refers to a carboxy group such as, but not limited to, methoxy, ethoxy, propoxy, butoxy, and the like. The alkoxy substituent is attatched to the parent molecule through the oxygen atom of the alkoxy group.
As used herein the term “h
+
” is an alkoxide metal. As used herein, the term “alkoxide metal” means a metal suitable for alkoxide formation. Such alkoxide metals include, but are not limited to, Li
+
, K
+
, Na
+
, Cs
+
, and Ca
++
. Especially preferred alkoxide metals include Li
+
, K
+
, and Na
+
.
As used herein, the phrase “5 or 6 membered heterocyclic group” or “5 membered heterocycle” means a group containing from one to four N, O or S atom(s) or a combination thereof, which heterocyclic group is optionally substituted at carbon or nitrogen atom(s) with C
1-6
-alkyl, -CF
3
, phenyl, benzyl or thienyl, or a carbon atom in the heterocyclic group together with an oxygen atom form a carbonyl group, or which heterocyclic group is optionally fused with a phenyl group. The phrase “5 or 6 membered heterocyclic group” includes, but is not limited to, 5-membered heterocycles having one hetero atom (e.g. thiophenes, pyrroles, furans); 5-membered heterocycles having two heteroatoms in 1,2 or 1,3 positions (e.g. oxazoles, pyrazoles, imidazoles, thiazoles, purines); 5-membered heterocycles having three heteroatoms (e.g. triazoles, thiadiazoles); 5-membered heterocycles having 3-heteroatoms; 6-membered heterocycles with one heteroatom (e.g. pyridine, quinoline, isoquinoline, phenanthrine, 5,6-cycloheptenopyridine); 6-membered heterocycles with two heteroatoms (e.g. pyridazines, cinnolines, phthalazines, pyrazines, pyrimidines, quinazolines); 6-membered heterocycles with three heteroatoms (e.g. 1,3,5-triazine); and 6-member heterocycles with four heteroatoms. Particularly preferred are thiophenes, pyridines, and furans.
Examples of pharmaceutically acceptable salts include inorganic and organic acid addition salts such as hydrochloride, hydrobromide, sulphate, phosphate, acetate, fumarate, maleate, citrate, lactate, tartrate, oxalate, or similar pharmaceutically-acceptable inorganic or organic acid addition salts, and include the pharmaceutically acceptable salts listed in
Journal of Pharmaceutical Science,
66, 2 (1977) which are known to the skilled artisan. The compounds of this invention may form solvates with standard low molecular weight solvents using methods known to the skilled artisan.
As described in the following Schemes, the fol

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