Amino-tetralin derivatives as muscarinic receptor antagonists

Details Amino-tetralin derivatives as muscarinic receptor antagonists Amino-tetralin derivatives as muscarinic receptor antagonists

2002-12-02

2003-10-21

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...

C546S223000, C546S214000, C546S189000, C544S129000, C544S360000, C514S235500, C514S252010, C514S255030, C514S316000, C514S326000

Reexamination Certificate

active

06635658

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to amino-tetralin derivatives, associated acceptable salts, or hydrates thereof, and associated compositions and methods for use as M2/M3 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 or M3 specific antagonists have been shown to have reduced side effects. Evidence suggests that mechanistically, concurrent blockade of M2 and M3 receptors 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-lngelheim 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 quatemary ammonium compound which is poorly absorbed.
Few M2/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:
R
1
is (C
1-6
)alkyl;
R
2
is halogen or —OR′;
R
3
is hydrogen or —OR′;
R′ is hydrogen, (C
1-6
)alkyl, or SO
2
R″;
R″ is (C
1-6
)alkyl, haloalkyl, aryl or heteroaryl, wherein said aryl or heteroaryl groups are optionally substituted with a group selected from (C
1-6
)alkyl, halo, haloalkyl, cyano, nitro, alkylsulfonyl, and alkylsulfonylamino,
R
4
is (C
1-6
)alkyl, aryl, heterocyclyl, or heteroaryl, wherein said aryl, heterocyclyl or heteroaryl groups are optionally substituted with a group selected from (C
1-6
)alkyl, halo, haloalkyl, (C
1-6
)alkoxy, cyano, amino, mono- or di alkylamino, nitro, alkylsulfonyl, alkylcarbonyl, urea, alkylcarbonylamino, alkylsulfonylamino, alkylaminosulfonyl, alkoxycarbonyl, heterocyclyl and heteroaryl, or —NR
5
R
6
; and
R
5
and R
6
are independently of each other hydrogen, (C
1-6
)alkyl, aryl or heterocyclyl; wherein said aryl or heterocyclyl groups are optionally substituted with (C
1-6
)alkyl, halo, haloalkyl, cyano, (C
1-6
)alkoxy, and alkylsulfonyl,
or prodrugs, individual isomers, racemic or non-racemic mixtures of isomers, or salts or solvates thereof.
In preferred embodiments R
2
is (C
1-6
)alkoxy, hydroxy or —OSO
2
R″ wherein R″ is (C
1-6
)alkyl, haloalkyl, aryl or heteroaryl, and R
3
is hydrogen or (C
1-6
)alkyl; in another preferred embodiment R
2
is (C
1-6
)alkoxy and R
3
is hydrogen, and in another preferred embodiment R
2
and R
3
are (C
1-6
)alkoxy.
In another preferred embodiment R
4
is (C
1-6
)alkyl, and within this embodiment other preferred group of compounds is that wherein R
1
is ethyl or propyl.
In another preferred embodiment R
4
is an aryl group; and in another preferred embodiment R
4
is phenyl optionally substituted with a group selected from (C
1-6
)alkyl, halo, haloalkyl, (C
1-6
)alkoxy, cyano, amino, mono- or di alkylamino, nitro, alkylsulfonyl, alkylcarbonyl, urea, alkylcarbonylamino, alkylsulfonylamino, alkylaminosulfonyl, alkoxycarbonyl, heterocyclyl and heteroaryl, and within this embodiment other preferred group of compounds is that wherein R
1
is ethyl or propyl. Another preferred group of compounds is that wherein R
2
is —OR′, and R
3
is —OR′ or hydrogen.
In another preferred embodiment R
4
is a heteroaryl group; and in another preferred embodiment R
4
is selected from furanyl, thiophenyl, isooxazolyl, oxazolyl, imidazolyl, and pyrazolyl, all optionally substituted with one or two (C
1-6
) alkyl, and within this embodiment another preferred group of compounds is that wherein R
1
is ethyl or propyl, and another preferred group of compounds is that wherein R
2
is —OR′, and R
3
is —OR′ or hydrogen.
In another preferred embodiment R
4
is a heterocyclyl group; and in another preferred embodiment R
4
is piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl, diazepanyl, all optionally substituted with one or two (C
1-6
)alkyl or alkylcarbonyl groups, and within this embodiment another preferred group of compounds is that wherein R
1
is ethyl or propyl, and another preferred group of compounds is that wherein R
2
is —OR′, and R
3
is —OR′ or hydrogen.
In another preferred embodiment R
4
is —NR
5
R
6
, and R
5
is (C
1-6
)alkyl and R
6
is hydrogen or (C
1-6
)alkyl; and in another preferred embodiment R
4
is —NR
5
R
6
, R
5
is heterocyclyl and R
6
is hydrogen, and within this embodiment another preferred group of compounds is that wherein R
1
is ethyl or propyl, and another preferred group of compounds is that wherein R
2
is —OR′, and R
3
is —OR′ or hydrogen.
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 M2 and M3 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 capacit

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