Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-08-28
2004-04-13
Gerstl, 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
06720342
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to therapeutically active azabicyclic compounds, a method of preparing the same and to pharmaceutical or veterinary compositions comprising the compounds. The novel compounds are useful in treating a disease in the central nervous system caused by malfunctioning of the muscarinic cholinergic system.
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 pre-frontal 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 progression of Alzheimer's disease, and in improving the cognitive functions of elderly people.
The compounds of this invention are also useful analgesic agents and therefore 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, bladder dysfunctions, anxiety, sleeping disorders, epilepsy, cerebral ischemia and gastrointestinal motility disorders.
SUMMARY OF THE INVENTION
It is an object of the invention to provide new muscarinic cholinergic compounds.
The novel compounds of the invention are heterocyclic compounds having formula I
wherein W is oxygen or sulphur; R is selected from the group consisting of 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) which is optionally substituted with C
1-6
-alkyl; R
4
is selected from the group consisting of C
1-15
-alkyl, C
2-15
-alkenyl, C
2-15
-alkynyl and C
4-15
-alkenynyl, each of which is optionally substituted with one or more independently selected from the group consisting of halogen(s), —CF
3
, —CN, Y, phenyl and phenoxy wherein phenyl or phenoxy is optionally substituted with one or more independently selected from the group consisting of —OH, halogen, —NO
2
, —CN, C
1-4
-alkyl, C
1-4
-alkylthio, C
1-4
-alkoxy, —SCF
3
, —OCF
3
, —CF
3
, —CONH
2
and —CSNH
2
; or R is phenyl or benzyloxycarbonyl, each of which is optionally substituted with one or more independently selected from the group consisting of halogen, —CN, C
1-4
-alkyl, C
1-4
-alkoxy, —OCF
3
, —CF
3
, —CONH
2
and —CSNH
2
; or R is selected from the group consisting of —OR
5
Y, —SR
5
Y, OR
5
ZY, —SR
5
ZY, —OR
5
ZR
4
and —SR
5
ZR
4
; Z is oxygen or sulphur; R
5
is C
1-15
-alkylene, C
2-15
-alkenylene, C
2-15
-alkynylene or C
4-15
-alkenynylene; Y is a 5 or 6 membered heterocyclic group optionally substituted with one or more independently selected from the group consisting of —OH, halogen, —NO
2
, —CN, C
1-14
-alkyl, C
1-4
-alkylthio, C
1-4
-alkoxy, —SCF
3
, —OCF
3
, —CF
3
, —CONH
2
and —CSNH
2
; G is
R
6
and R
7
independently are selected from the group consisting of hydrogen and C
1-6
-alkyl; or R
6
and R
7
together with the nitrogen atom optionally form a 4- to 6-membered ring; R
1
and R
2
independently are selected from the group consisting of hydrogen, —OH, ═O, C
1-15
-alkyl, C
2-15
-alkenyl, C
2-15
-alkynyl, C
1-10
-alkoxy, and C
1-5
-alkyl substituted with one or more independently selected from the group consisting of —OH, —COR
8
, —CH
2
OH, halogen, —NH
2
, carboxy and phenyl; R
8
is hydrogen, C
1-8
-alkyl; r is 0, 1 or 2;
· · ·
is a single or double bond; or a pharmaceutically acceptable salt or solvate thereof.
As used herein, the term “halogen” means Cl, Br, F, and I. Especially preferred halogens include Cl, Br, and F.
The terms “C
1-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
1-6
-alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl and the like.
The terms “C
2-n′
-alkenyl” wherein n′ can be from 3 through 15, 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, 1,3-butadienyl, 1-butenyl, hexenyl, pentenyl, and the like.
The terms “C
2-n′
-alkynyl” wherein n′ can be from 3 through 15, as used herein, represent an unsaturated branched or linear group having from 2 to the specified number of carbon atoms and at least one triple bond. Examples of such groups include, but are not limited to, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl and the like.
The terms “C
4-n′
-alkenynyl” wherein n′ can be from 5 through 15, as used herein, represent an unsaturated branched or linear hydrocarbon group having from 4 to the specified number of carbon atoms and both at least one double bond and at least one triple bond. Examples of such groups include, but are not limited to, 1-penten-4-yne, 3-penten-1-yne, 1,3-hexadiene-5-yne and the like.
The term “C
3-n
-cycloalkyl” wherein n=4-10, as used herein, represents e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl and the like.
As used herein the term C
4-12
-(cycloalkylalkyl) represents a branched or linear alkyl group substituted at a terminal carbon with a cycloalkyl group. Typical cycloalkylalkyl groups include cyclopropylethyl, cyclobutylmethyl, cyclohexylethyl, cyclohexylmethyl, 3-cyclopentylpropyl, and the like.
As used herein, the term “C
1-4
-alkoxy” represents methoxy, ethoxy, propoxy, butoxy and the like.
As used herein, the phrase “one or more selected from” shall more preferably refer to from 1-3 substituents. The term shall further preferably refer to from 1-2 substituents.
As used herein, the phrase “5 or 6 membered heterocyclic group” 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 —OH, halogen, —NO
2
, —CN, C
1-4
-alkyl, C
1-4
-alkylthio, C
1-4
-alkoxy, —SCF
3
, —OCF
3
, —CF
3
, —CONH
2
and —CSNH
2
, 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 four heteroatoms; 6-membered heterocycles with one heteroatom (e.g. pyridine, quinoline, isoquinoline, phenanthridine, cyclohepta[b]pyridine); 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-membered heterocycles with four heteroatoms.
As used herein with reference to the G substitu
Jeppesen Lone
Sauerberg Per
Gerstl Robert
Green Reza
Novo Nordisk A S
Wilk-Orescan Rosemarie R.
LandOfFree
Heterocyclic compounds and their preparation and use does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Heterocyclic compounds and their preparation and use, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Heterocyclic compounds and their preparation and use will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3273800