Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-11-01
2003-05-06
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S183000, C514S299000, C548S135000
Reexamination Certificate
active
06559171
ABSTRACT:
The present invention relates to therapeutically active 7-oxo-2azabicyclo[2.2.1]heptanes, the compounds of formula I, and pharmaceutical compositions thereof. The compounds of formula I are muscarinic receptor modulators. More specifically, the compounds of the present invention are agonists of the muscarinic M-4 receptor. As such they are useful for the treatment of various diseases and conditions. The present invention relates to the use of the compounds of formula I to treat diseases and conditions treated by muscarinic receptor modulators, for example, Alzheimer's disease, glaucoma, mania, bipolar disorder, depression, sleeping disorders, epilepsy, gastrointestinal motility disorders, urinary incontinence, pain, psychosis, particularly schizophrenia or schizophreniform conditions, and cognition enhancement, such as enhancement of learning, association, consolidation, and recognition. The present invention also relates to processes for the preparation of the compounds of formula I and intermediates thereof.
Compounds which interact with muscarinic receptors are known in the art. In particular, certain oxo-2-azabicycloalkane containing compounds are described as muscarinic receptor modulators in PCT Publication No. WO 96/12711, published May 2, 1996.
The present invention relates to compounds of formula I
wherein
X is oxygen or sulfur;
R is hydrogen, phenyl, substituted phenyl, —OR
2
, —SR
2
, —SOR
2
, —SO
2
R
2
wherein R
2
is C
1
-C
10
alkyl, C
3
-C
10
alkenyl, C
3
-C
10
alkynyl, substituted with from 1 to 3 substituents selected from the group consisting of hydrogen, halogen, —CF
3
, —CN, phenyl, substituted phenyl, phenoxy, substituted phenoxy, thiophenoxy, substituted thiophenoxy, C
3
-C
8
cycloalkyl, heterocycle, and —Z-heterocycle, wherein Z is oxygen or sulfur;
R
1
is selected from the group consisting of hydrogen, C
1
-C
5
alkyl, C
2
-C
5
alkenyl and C
2
-C
5
alkynyl;
or a pharmaceutically acceptable salt thereof.
Also, the present invention provides pharmaceutical compositions comprising a compound of formula I and a pharmaceutically acceptable diluent.
The present invention further provides a method of treating diseases and conditions treated by muscarinic receptor modulators in a patient in need thereof comprising administering to the patient an effective amount of a compound of formula I or pharmaceutically-acceptable addition salt thereof. Such diseases and conditions treated by muscarinic receptor modulators include Alzheimer's disease, glaucoma, mania, bipolar disorder, depression, sleeping disorders, epilepsy, gastrointestinal motility disorders, urinary incontinence, pain, psychosis, particularly schizophrenia or schizophreniform conditions, and cognition enhancement, such as enhancement of learning, association, consolidation, and recognition. Since the present compounds are muscarinic M-4 agonists they are particularly useful for treating pain and Alzheimer's disease and providing cognitive enhancement.
As used herein, the following terms have the meanings indicated:
the term “substituted phenyl” refer to a radical of the formula
wherein Ra is from 1 to 2 substituents independently selected from the group consisting of hydrogen, halogen, C
1
-C
5
alkyl, C
1
-C
5
alkoxy, C
1
-C
5
thioalkoxy, —CF
3
, —CN, and phenyl;
the term “halogen” refers to a chlorine atom, bromine atom, or an iodide atom;
the term “C
1
-C
10
alkyl” refers to a straight or branched chain alkyl having from one to ten carbon atoms and includes, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, t-butyl, pentyl, hexl, heptyl, octyl, nonyl, decyl, and the like;
the term “C
3
-C
10
alkenyl” refers to a straight or branched chain alkenyl having from three to ten carbon atoms containing at least one double-bond and includes, allyl, but-2-enyl, but-3-enyl, 3-methylbut-3-enyl, pent-2-enyl, pent-3-enyl, pent-4-enyl, hexenyl, heptenyl, octenyl, nonenyl, docenyl, and the like;
the term “C
3
-C
10
alkynyl” refers to an unsaturated branched or linear group having from three to ten carbon atoms and at least one triple bond and includes, propargyl, but-2-ynyl, but-3-ynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl and the like;
the term “C
3
-C
8
cycloalkyl” refers to a saturated or unsaturated cyclic alkyl group having from three to eight carbon atoms and from 1 to 2 substituents independently selected from the group consisting of hydrogen, halogen, C
1
-C
5
alkyl, C
1
-C
5
alkoxy, C
1
-C
5
thioalkoxy, —CF
3
, —CN, and phenyl and includes, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl and the like, and includes cylcoalkyl groups in which one of the carbon atoms of the cycloalkyl is part of the C
1
-C
10
alkyl, C
3
-C
10
alkenyl, or C
3
-C
10
alkynyl to which it is attached and includes cyclic alkyl groups having a fused phenyl group as part of the ring;
the term “substituted phenoxy” refers to a radical of the formula
wherein Rb is from 1 to 2 substituents independently selected from the group consisting of hydrogen, halogen, C
1
-C
5
alkyl, C
1
-C
5
alkoxy, C
1
-C
5
thioalkoxy, —CF
3
, —CN, and phenyl;
the term “substituted thiophenoxy” refers to a radical of the formula
wherein Rb is from 1 to 2 substituents independently selected from the group consisting of hydrogen, halogen, C
1
-C
5
alkyl, C
1
-C
5
alkoxy, C
1
-C
5
thioalkoxy, —CF
3
, —CN, and phenyl;
the term “heterocycle” refers to a 5 or 6 membered heterocyclic group containing from one to four heteroatoms independently selected for the group consisting of N, O, and S atom(s), which heterocycle is optionally benzofused and is optionally substituted at its nitrogen atoms, if present, with C
1
-C
5
alkyl, phenyl, and benzyl and is optionally substituted at its carbon atoms with C
1
-C
5
alkyl, C
1
-C
5
alkoxy, C
1
-C
5
thioalkoxy, halogen, —CF
3
, phenyl, benzyl or thienyl; the term includes, 5-membered heterocycles having one heteroatom, for example, thiophenes, pyrroles, furans, benzothiophenes, indoles, benzofurans, and the like; 5-membered heterocycles having two heteroatoms, for example, oxazoles, isoxazoles, pyrazoles, imidazoles, thiazoles, isothiazoles, benzoxazoles, benzopyrazoles, benzimidazoles, benzothiazoles, and the like; 5-membered heterocycles having three heteroatoms, for example, triazoles, thiadiazoles, furazans, and the like; 6-membered heterocycles with one heteroatom, for example, pyridine, quinoline, isoquinoline, and the like; 6-membered heterocycles with two heteroatoms, for example, pyrazines, pyrimidines, pyridazines, quinazolines, dioxanes, quinazolines, cinnolines, benzodioxanes, and the like;
the term “C
1
-C
5
alkyl” refers to a straight or branched chain alkyl having from one to five carbon atoms and includes, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, t-butyl, pentyl, and the like;
the term “C
3
-C
5
alkenyl” refers to a straight or branched chain alkenyl having from three to five carbon atoms containing at least one double-bond and includes, allyl, 3-methyl-prop-2-enyl, but-2-enyl, but-3-enyl, pent-2-enyl, pent-3-enyl, pent-4-enyl, and the like;
the term “C
3
-C
5
alkynyl” refers to an unsaturated branched or linear group having from three to five carbon atoms and at least one triple bond and includes, propargyl, but-2-ynyl, but-3-ynyl, pentynyl and the like;
the term “C
1
-C
5
alkoxy” refers to a straight or branched chain alkoxy having from one to five carbon atoms and includes, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy, iso-butoxy, t-butoxy, pentoxy, and the like;
the term “C
1
-C
5
thioalkoxy” refers to a straight or branched chain thioalkoxy having from one to five carbon atoms and includes, thiomethoxy, thioethoxy, thiopropoxy, thiobutoxy, thiopentoxy, and the like; and the term “pharmaceutically-acceptable addition salt” refers to an acid addition salt.
The compound of formula I and the intermediates described herein form pharmaceutically acceptable acid addition salts with a wide variety of organic and
Mitch Charles Howard
Quimby Steven James
Anderson Rebecca
Eli Lilly and Company
McKane Joseph K.
Stemerick David M.
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