Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-02-01
2001-11-20
Seaman, D. Margaret (Department: 1612)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S300000, C514S318000, C514S326000, C514S329000, C514S330000, C514S331000, C544S129000, C546S123000, C546S194000, C546S199000, C546S207000, C546S212000, C546S214000, C546S221000, C546S223000, C546S224000, C546S225000, C546S229000, C546S232000, C546S233000
Reexamination Certificate
active
06319920
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to muscarinic receptor antagonists, especially certain 2-arylethyl-(piperidin-4-ylmethyl)amine derivatives, pharmaceutical compositions containing them, and methods for their use as therapeutic agents.
2. Background of the Invention
Muscarinic receptor antagonists prevent the effects of acetylcholine by blocking its binding to muscarinic cholinoceptors at neuroeffector sites on smooth muscle, cardiac muscle, and gland cells in peripheral ganglia and in the central nervous system, and predominantly have been employed to inhibit effects of parasympathetic nervous system activity. Thus, muscarinic receptor antagonists have far reaching physiological effects, and drugs which selectively interact with muscarinic receptors have an array of therapeutic applications. For example, muscarinic receptor antagonists have been employed in the treatment of various disorders in the gastrointestinal tract, genitourinary tract, respiratory tract, cardiovascular system, central nervous system, and have been shown to be useful in anesthesiology and ophthalmology.
Muscarinic receptor antagonists have been shown to be useful in treating various gastrointestinal disorders, including a wide variety of conditions that involve increased spasticity or motility of the gastrointestinal tract, for example diarrhea. These agents can reduce tone and motility if the conditions are due to excessive smooth muscle contractions.
Muscarinic receptor antagonists have been shown to be useful in treating various genitourinary tract disorders. These agents have been shown to lower intravesical pressure, increase bladder capacity, and reduce the frequency of urinary bladder contractions by antagonizing the parasymathetic control of this organ.
Muscarinic receptor antagonists have been shown to be useful in treating various respiratory tract disorders, particularly including those conditions that reduce secretion in both the upper and lower respiratory tracts and induce bronchial dilation. These agents can have beneficial effects when obstruction of the airway is associated with, for example, chronic bronchitis, chronic obstructive pulmonary disease, bronchial asthma or emphysema.
Muscarinic receptor antagonists have been shown to be useful in treating various cardiovascular disorders, for example, including those conditions where excessive vagal tone causes sinus or nodal bradycardia.
Muscarinic receptor antagonists have been shown to be useful in treating central nervous system disorders. These agents have been shown to be efficacious in previous dystonias or Parkinsonian symptoms, and have been highly effective in preventing motion sickness.
Muscarinic receptor antagonists have been shown to be useful in anesthesiology, particularly by inhibiting excessive salivation and secretions of the respiratory tract induced by administration of general anesthetic agents, and their concomitant bronchodilator action. They have also been shown to be useful in ophthalmology to produce mydriasis and cycloplegia when applied locally to the eye.
These and other therapeutic uses are described in
Goodman & Gillman's, The Pharmacological Basis of Therapeutics
, ninth edition, McGraw-Hill, New York, 1996; Chapter 7, pages 148-160.
DESCRIPTION OF THE RELATED ART
Certain piperidineamine compounds have been exemplified in the chemical patent literature. For example, U.S. Pat. Nos. 5,310,743; 5,541,195; and 5,646,144 (Schilling et al.) disclose 1-acyl-N-(2-chlorophenyl)ethyl-4-piperidineamine derivatives having substance P antagonistic properties. Other piperidine derivatives are described in U.S. Pat. No. 5,286,735 (Bonnaud and Bigg) useful as serotoninergic receptor ligands and for the treatment of anxiety or depression; U.S. Pat. No. 5,089,507 (Vecchietti et al.) for the treatment of pain or hyponatremic disease states; European Published Application No. EP 532 398 (assigned to Synthelabo) for treatment of psychoses, anxiety, hypertension and migraine; and PCT Published Application No. WO 97/10212 (assigned to Neurosearch A/S) for treatment of stroke, anoxia, ischemia, migraine, psychosis, epilepsy or other convulsive disorders.
The disclosures of these and other documents referred to throughout this application are incorporated herein by reference.
SUMMARY OF THE INVENTION
This invention provides compounds selected from the group of compounds represented by Formula I:
wherein
R
1
is independently in each occurrence: hydrogen, alkyl, alkyloxy, halogen, haloalkyl, or amino;
R
2
is independently in each occurrence:
(1) alkyl,
(2) alkyloxy,
(3) halogen,
(4) haloalkyl,
(5) nitro,
(6) heterocyclyl, unsubstituted or heterocyclyl optionally substituted with oxo,
(7) —O(CH
2
)
p
X wherein p is 0-6 and X is independently selected from haloalkyl or aryl,
(8) —NR
7
R
8
,
(9) —NR
6
COR
9
,
(10) —NR
6
CONR
7
R
8
,
(11) —NR
6
CSR
9
,
(12) —NR
6
CSNR
7
R
8
,
(13) —NR
6
SO
2
R
9
,
(14) —NR
6
SO
2
NR
7
R
8
,
(15) —SR
9
,
(16) —SOR
9
,
(17) —SO
2
R
9
,
(18) —SO
2
NR
7
R
8
; or
R
1
and R
2
taken together with the ring to which they are attached form a 5- or 6-membered monocyclic saturated or unsaturated ring optionally containing 0, 1 or 2 heteroatoms independently selected from nitrogen, oxygen or sulfur;
R
3
and R
4
are independently in each occurrence: lower alkyl, alkenyl, or cycloalkyl;
R
5
is independently in each occurrence:
(1) hydrogen,
(2) —COR
9
,
(3) —COOR
7
,
(4) —CONR
7
R
8
,
(5) —CO(CH
2
)
n
COR
9
,
(6) —CO(CH
2
)
n
SO
2
R
9
,
(7) —CO(CH
2
)
n
CONR
7
R
8
,
(8) —CO(CH
2
)
n
SO
2
NR
7
R
8
,
(9) —CO(CH
2
)
n
NR
6
COR
9
,
(10) —CO(CH
2
)
n
NR
6
SO
2
R
9
,
(11) —CO(CH
2
)
n
NR
6
CONR
7
R
8
,
(12) —CO(CH
2
)
n
NR
6
SO
2
NR
7
R
8
,
(13) —CSR
9
,
(14) —CSNR
7
R
8
,
(15) —SO
2
R
9
,
(16) —SO
2
NR
7
R
8
,
(17) —SO
2
(CH
2
)
n
NR
6
SO
2
R
9
, or
(18) —SO
2
NR
6
(CH
2
)
n
COOR
7
;
wherein
n is 1-6;
R
6
and R
7
are independently in each occurrence: hydrogen or lower alkyl;
R
8
is independently in each occurrence: hydrogen, lower alkyl, cycloalkyl, aryl, or heteroaryl;
R
9
is independently in each occurrence:
(1) alkyl,
(2) cycloalkyl,
(3) arylalkyl,
(4) aryl, unsubstituted or mono-, di-, or tri-substituted aryl, the substituents being independently selected from lower alkyl, alkyloxy, halogen, hydroxyalkyl, haloalkyl, cyano, nitro, —CONR
7
R
8
, —COR
7
, —COOR
7
, —NR
7
R
8
, —NCOR
9
, —SO
2
R
9
, —SO
2
NR
7
R
8
, or —O(CH
2
)
p
X wherein p is 0-6 and X is haloalkyl or aryl,
(5) heterocyclyl, unsubstituted or mono- or di-substituted heterocyclyl, the substitutents independently selected from lower alkyl, hydroxy, hydroxyalkyl, oxo, —COR
7
, or —COOR
7
, or
(6) heteroaryl, unsubstituted or mono-, di-, or tri-substituted heteroaryl, the substituents being independently selected from lower alkyl, alkyloxy, halogen, hydroxyalkyl, haloalkyl, cyano, nitro, —CONR
7
R
8
, —COR
7
, —COOR
7
, —NR
7
R
8
, —NCOR
9
, —SO
2
R
9
, —SO
2
NR
7
R
8
, or —O(CH
2
)
p
X wherein p is 0-6 and X is haloalkyl or aryl;
as an individual isomer or as a racemic or non-racemic mixture of isomers, or a pharmaceutically acceptable salt thereof.
This invention further provides a pharmaceutical composition containing a therapeutically effective amount of a compound of Formula I in admixture with one or more suitable carriers.
This invention further provides a method of treating conditions which can be ameliorated by blocking the muscarinic receptors, including diseases and disorders of the gastrointestinal tract, genitourinary tract, and respiratory tract by administering a therapeutically effective amount of a compound of Formula I to a subject afflicted with such a condition.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
Unless otherwise stated, the following terms used in the specification and claims have the meanings given below:
“Alkyl” means a monovalent branched or unbranched saturated hydrocarbon radical of one to twelve carbon atoms inclusive, such as methyl, ethyl, propyl, 1-ethylpropyl, 2-propyl, butyl, tert-butyl, n-octyl, n-nonyl, and the like.
“Lower alkyl” means an alkyl radi
Caroon Joan Marie
Clark Robin Douglas
Dillon Michael Patrick
Harris, III Ralph New
Hegde Sharathchandra Surendra
Covington Raymond
Kaku Janet
Pfister Gloria
Seaman D. Margaret
Syntex (U.S.A.) LLC
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