Heterocyclic compounds and their use

Details Heterocyclic compounds and their use Heterocyclic compounds and their use

1997-04-10

2001-02-27

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...

C544S405000, C544S408000

Reexamination Certificate

active

06194416

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to therapeutically active azacyclic or azabicyclic compounds, a method of preparing the same and to compositions for pharmaceutical or veterinary use comprising the compounds and a carrier therefore. The novel compounds are useful as stimulants of the cognitive function of the forebrain and hippocampus of mammals and especially in the treatment of Alzheimer's disease.
BACKGROUND OF THE INVENTION
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 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 receptors in the forebrain and hippocampus still exist. Therefore, cholinergic agonists are useful in the treatment of Alzheimer's disease, in halting its progression, and in improving the cognitive functions of elderly people.
The compounds of this invention are also useful analgesic agents and therfore useful in the treatment of severe painful conditions.
Furthermore, the compounds of this invention are useful in the treatment of glaucoma, psychosis, mania, bipolar disorder, schizophrenia or schizophreniform conditions, depression, sleeping disorders, epilepsy, and gastrointestinal motility disorders.
SUMMARY OF THE INVENTION
It is an object of the invention to provide new muscarinic cholinergic compounds and nicotinic cholinergic compounds.
The novel compounds of the invention are heterocyclic compounds having the Formula I or I′
wherein
W is oxygen or sulphur;
R is hydrogen, amino, halogen, NHR
6
, NR
6
R
7
, R
4
, —OR
4
, —SR
4
, —SOR
4
, —SO
2
R
4
, C
3-10
-cycloalkyl, C
4-12
-(cycloalkylalkyl), —Z-C
3-10
-cycloalkyl and —Z-C
4-12
-(cycloalkylalkyl) wherein R
4
is C
1-15
-alkyl, C
2-15
-alkenyl, C
2-5
-alkynyl, each of which is optionally substituted with one or more halogen(s), —CF
3
, —CN, Y, phenyl or phenoxy wherein phenyl or phenoxy is optionally substituted with halogen, —CN, C
1-4
-alkyl, C
1-4
-alkoxy, —OCF
3
, —CF
3
, —CONH
2
or —CSNH
2
; or
R is phenyl or benzyloxycarbonyl, each of which is optionally substituted with halogen, —CN, C
1-4
-alkyl, C
1-4
-alkoxy, —OCF
3
, —CF
3
, —CONH
2
or —CSNH
2
; or
R is —OR
5
Y, —SR
5
Y, OR
5
—Z—Y, —SR
5
ZY, —O—R
5
—Z—R
4
or —S—R
5
—Z—R
4
wherein Z is oxygen or sulphur, R
5
is C
1-15
-alkyl, C
2-15
-alkenyl, C
2-15
-alkynyl, and Y is a 5 or 6 membered heterocyclic group; and
G is selected from one of the following azacyclic or azabicyclic ring systems:
 or G can optionally be substituted C
3
-C
8
cycloalkyl or optionally substituted C
1-6
-alkyl wherein the substitution is —NR
6
R
7
;
R
6
and R
7
independently are hydrogen, C
1-6
-alkyl; or
R
6
and R
7
together with the nitrogen atom optionally form a 4- to 6-member ring;
R
1
and R
2
independently are hydrogen, C
1-15
-alkyl, C
2-5
-alkenyl, C
2-5
-alkynyl, C
1-10
-alkoxy, C
1-5
-alkyl substituted with —OH, —COR
6
′, CH
2
—OH, halogen, —NH
2
, carboxy, or phenyl;
R
3
is hydrogen, C
1-5
-alkyl, C
2-5
-alkenyl or C
2-5
-alkynyl;
R
6
′ is hydrogen, C
1-6
-alkyl;
n is 0, 1 or 2;
m is 0, 1 or 2;
p is 0, 1 or 2;
q is 1 or 2;
r is 0, 1 or 2;
.......
is a single or double bond; or a pharmaceutically acceptable salt or solvate thereof.
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 Formula I and I′.
DETAILED DESCRIPTION
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 with reference to the G substituent, the —(CH
2
)
r
-W-oxadiazole or —(CH
2
)
r
-W-pyrazine moiety can be attached at any carbon atom of the azacyclic or azabicyclic ring. Further, R
1
and R
2
of the G substituent may be present at any position, including the point of attachment of the —(CH
2
)
r
-W-oxadiazole or —(CH
2
)
r
-W-pyrazine moiety.
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 used herein with reference to the G substituent, the numbering shall be as follows:
As used herein the term &agr; shall refer to a position on the G substituent which is one position away from the N atom of the G substituent. For example, in the following illustration (1E), both positions 2 and 6 are considered &agr;. The term &ggr; shall refer to the position on the G substituent which is opposite the N atom. For example, in the illustration (1E), position 4 is considered &ggr;. Likewise, &bgr; shall refer to the 3 and 5 position in the illustration.
As used herein with reference to the G substituent, the phrase “R
6
and R
7
together with the nitrogen atom optionally form a 4- to 6-member ring” means that R
6
and R
7
are each independently hydrogen, C
1
-C
6
alkyl; the R
6
and R
7
groups may optionally join to form a 4- to 6-member ring including the nitrogen. For example, optionally joined groups include, but not limited to:
As used herein the phrase “interacting with a muscarinic cholinergic receptor” shall include compounds which block muscarinic cholinergic receptors or modulate such receptors. Likewise, the term “interacting with a nicotinic cholinergic receptor” shall include compounds which block or modulate the receptor. The phrase shall include the effect observed when compounds act as agonists, partial agonists and/or antagonists at a cholinergic receptor.
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 term “halogen” means Cl, Br, F, and I. Especially preferred halogens include Cl, Br, and I.
The terms “C
1
-C
n
, alkyl” wherein n′ can be from 2 through 15, as used herein, represent a branched or linear alkyl group having from one to the specified number of carbon atoms. Typical C
1
-C
6
alkyl groups include methyl, ethyl, n-propyl, iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl and the like.
The terms “C
2
-C
n
, alkenyl” wherein n′ can be from 3 through 10, as used herein, represents an olefinically unsaturated branched or linear group having from 2 to the specified number of carbon atoms and at least one double bond. Examples of such groups include, but are not limited to, 1-propenyl, 2-propenyl (—CH
2
—CH═CH
2
), 1,3-butadienyl, (—CH═CHCH═CH
2
), 1-butenyl (—CH═CHCH
2
CH
3
), hexenyl, pentenyl, and the like.
The term “C
2
-C
5
alkynyl” refers to an unsaturated branched or line

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