4-piperidinyl alkyl amine derivatives as muscarinic receptor...

Details 4-piperidinyl alkyl amine derivatives as muscarinic receptor... 4-piperidinyl alkyl amine derivatives as muscarinic receptor...

2002-12-02

2003-09-30

Aulakh, Charanjit S. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C546S195000, C546S189000, C546S188000, C544S129000, C544S360000, C514S316000, C514S252010, C514S235500

Reexamination Certificate

active

06627644

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to benzocycloalkylenylamine derivatives, associated pharmaceutically acceptable salts, or hydrates thereof, and associated pharmaceutical compositions and methods for use as selective muscarinic receptor antagonists.
BACKGROUND OF THE INVENTION
Acetylcholine (Ach) is the principal transmitter of the parasympathetic nervous system. The physiological actions of Ach are mediated by activation of either nicotinic or muscarinic receptors. Both of these receptor classes are heterogeneous: e.g., the muscarinic receptor family comprises five subtypes (M
1
, M
2
, M
3
, M
4
, and M
5
) each encoded by distinct genes and possessing unique pharmacology and distribution.
Almost all smooth muscle tissues express both muscarinic M2 and M3 receptors, both of which have a functional role. M2 receptors outnumber M3 receptors by a proportion of approximately 4 to 1. Generally, M3 receptors mediate the direct contractile effects of acetylcholine in the vast majority of smooth muscle tissues. M2 receptors, on the other hand, cause smooth muscle contraction indirectly by inhibiting sympathetically (&bgr;-adrenoreceptor)-mediated relaxation.
Compounds that act as antagonists of muscarinic receptors have been used to treat several disease states associated with improper smooth muscle function, as well as in the treatment of cognitive and neurodegenerative disorders such as Alzheimer's disease. Until recently, most of these compounds have been non-selective for the various muscarinic receptor subtypes, leading to unpleasant anti-cholinergic side-effects such as dry mouth, constipation, blurred vision, or tachycardia. The most common of these side-effects is dry-mouth resulting from muscarinic receptor blockade in the salivary gland. Recently developed M2 and/or M3 specific antagonists have been shown to have reduced side effects. Evidence suggests that blockade of M2 and/or M3 receptors over M5 receptor could be therapeutically effective in the treatment of disease states associated with smooth muscle disorders.
Additionally, muscarinic receptor antagonists are front-line therapy as bronchodilators in chronic obstructive pulmonary disease (COPD). It is thought that the efficacy of this class of molecules is mediated through antagonism of the natural transmitter (acetylcholine) at M3 receptors on airway smooth muscle and there may be additional benefit in COPD through inhibition of mucus secretion which may also be mediated through M3 receptors. The current standard antimuscarinic for the treatment of COPD is ipratropium (Atrovent) which is administered by aerosol 4 times per day. More recently tiotropium (Spiriva) has been developed by Boehringer-Ingelheim as a second-generation muscarinic antagonist and is expected to be launched in 2002 (in collaboration with Pfizer). Tiotropium is also given by aerosol but has a slow off-rate from the M3 receptor and, as a result, causes a prolonged bronchodilatation. Tiotropium will be given once per day. Although tiotropium has high affinity for all muscarinic receptor subtypes, it is a quaternary ammonium compound which is poorly absorbed.
Few M2 and/or M3 selective antagonists have been developed. The present invention fills this need by providing these types of antagonists useful in the treatment of disease states associated with improper smooth muscle function and respiratory disorders.
SUMMARY OF THE INVENTION
This invention relates to compounds comprising Formula I:
wherein:
A is —C(O)R
4
or —S(O)
2
R
5
;
R
1
is (C
1-6
)alkyl or allyl;
R
2
and R
3
are independently in each occurrence hydrogen, halogen, (C
1-6
)alkyl, haloalkyl, —OR′, —S(O)
0-2
R′, —NR′R″, —NR′COR″, —NR′″CONR′R″, —NR′SO
2
R″, —NR′″SO
2
NR′R″, —SO
2
NR′R″, —OSO
2
R′, nitro, cyano, heteroaryl, or aryl, wherein said heteroaryl or aryl group is optionally substituted with one or more groups selected from hydroxy, cyano, (C
1-6
)alkyl, (C
1-6
)alkoxy, haloalkoxy, alkylthio, halo, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, alkylcarbonyl, alkylaminosulfonyl, alkylsulfonylamino, alkylaminocarbonyl, and alkylcarbonylamino, with the proviso that R
2
and R
3
are not both hydrogen;
R′, R″, and R′″ are independently in each occurrence hydrogen, (C
1-6
)alkyl, (C
3
-C
6
)cycloalkyl, haloalkyl, diphenylmethyl, aryl or aryl(C
1-6
)alkyl, wherein the aryl group is optionally substituted with one or more groups selected from hydroxy, cyano, (C
1-6
)alkyl, (C
1-6
)alkoxy, haloalkoxy, alkylthio, halo, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, alkylcarbonyl, alkylaminosulfonyl, alkylsulfonylamino, alkylaminocarbonyl, alkylcarbonylamino and phenyl;
heterocycyl, wherein the heterocylcyl group is optionally substituted with one or more groups selected from hydroxy, oxo, cyano, (C
1-6
)alkyl, (C
1-6
)alkoxy, haloalkoxy, alkylthio, halo, and haloalkyl;
heteroaryl, wherein the heteroaryl is optionally substituted with one or more groups selected from (C
1-6
)alkyl, (C
1-6
)alkoxy, and halogen;
or R′ and R″ together with the nitrogen they are attached may also form a 5- to 7-membered ring, optionally incorporating one additional heteroatom chosen from O, N, or S(O)
0-2
, said ring being optionally substituted with one or two (C
1-6
)alkyl groups;
R
4
is (C
1-6
)alkyl, haloalkyl, benzyloxy, diphenylmethyl, —NR
a
R
b
, wherein R
a
and R
b
are as defined herein, —Y-heterocyclyl, —Y-heteroaryl, wherein the heterocyclyl and heteroaryl groups are independently of each other optionally substituted with one or more groups selected from (C
1-6
)alkyl, (C
1-6
)alkoxy, halo, haloalkyl, alkylsulfonyl, alkylaminosulfonyl, and alkylsulfonylamino, and wherein Y is a bond or (C
1-3
)alkylene;
R
a
is hydrogen, (C
1-6
)alkyl, haloalkyl, cycloalkyl or aryl, wherein the cycloalkyl or the aryl group are each independently of each other optionally substituted with (C
1-6
)alkyl, (C
1-6
)alkoxy, halo, haloalkyl, and alkylsulfonyl;
R
b
is hydrogen or (C
1-6
)alkyl;
or R
a
and R
b
together with the nitrogen they are attached may also form a 5- to 7-membered ring, optionally incorporating one additional heteroatom chosen from O, N, or S(O)
0-2
, said ring being optionally substituted with one or two (C
1-6
)alkyl groups;
R
5
is (C
1-6
)alkyl, haloalkyl, —NR
a
R
b
, wherein R
a
and R
b
are as defined above, aryl or heteroaryl, wherein the aryl or heteroaryl are each independently of each other optionally substituted with one or two groups selected from (C
1-6
)alkyl, (C
1-6
)alkoxy, halo, and alkylsulfonyl; and
p is an integer from 1 to 2 inclusive;
or prodrugs, individual isomers, racemic or non-racemic mixtures of isomers, and pharmaceutically acceptable salts or solvates thereof.
In another aspect, the invention relates to pharmaceutical compositions containing a therapeutically effective amount of at least one compound of Formula I, or individual isomers, racemic or non-racemic mixtures of isomers and salts or solvates thereof, in admixture with at least one suitable carrier.
In another aspect, this invention relates to a method of treatment of a disease in a mammal treatable by administration of at least one compound of Formula I, having selective activity for the muscarinic receptors, in particular a method of treatment in a subject having a disease state comprising smooth muscle disorders, preferably genitourinary tract disorders, respiratory tract disorders, gastrointestinal tract disorders; more preferably genitourinary tract disorders such as overactive bladder or detrusor hyperactivity and its symptoms, such as the changes symptomatically manifested as urgency, frequency, reduced bladder capacity, incontinence episodes, and the like; the changes urodynamically manifested as changes in bladder capacity, micturition threshold, unstable bladder contractions, sphincteric spasticity and the like; and the symptoms usually manifested in detrusor hy

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