Quinazoline derivatives as alpha-1 adrenergic antagonists

Details Quinazoline derivatives as alpha-1 adrenergic antagonists Quinazoline derivatives as alpha-1 adrenergic antagonists

2001-08-29

2003-05-06

Rao, Deepak (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S266200, C514S266210, C544S284000, C544S291000

Reexamination Certificate

active

06559153

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to quinazoline derivatives that are alpha-1 adrenergic receptor antagonists, and in particular to certain quinazoline derivatives that are selective alpha-1B adrenergic receptor antagonists, and associated pharmaceutical compositions, methods for use as therapeutic agents, and methods of preparation thereof.
BACKGROUND OF THE INVENTION
Alpha-1 adrenergic receptors are G-protein coupled transmembrane receptors that mediate various actions of the sympathetic nervous system through the binding of the catecholamines, epinephrine and norepinephrine. Currently, several subtypes of the alpha-1 adrenergic receptors are known to exist for which the genes have been cloned: alpha-1A (previously known as alpha-1C), alpha-1B and alpha-1D. The existence of an additional subtype, the alpha-1L adrenergic receptor subtype, has been proposed; however, the gene for the alpha-1L adrenergic receptor subtype has yet to be cloned. Although these subtypes can be pharmacologically distinguished, existing subtype-selective compounds are only moderately specific and may interact with more than one alpha-1 adrenergic receptor subtype (See Giardina, D., et al.,
J. Med. Chem.,
1996, 39:4602-4607).
Non-selective alpha-1 adrenoceptor antagonists have been used to treat lower urinary tract symptoms associated with benign prostatic hyperplasia (BPH). Further, alpha-1 adrenoceptor antagonists can be effective in reducing or alleviating urinary tract disorders and/or symptoms thereof, such as pelvic hypersensitivity, overactive bladder, urinary frequency, nocturia, urinary urgency, detrusor hyperreflexia, outlet obstruction, prostatitis, incontinence, urge incontinence, urethritis, prostatodynia, idiopathic bladder hypersensitivity, and the like. Accordingly, therapeutic use of nonselective alpha-1 adrenergic receptor antagonists must be carefully monitored as such antagonists can produce significant undesirable side effects such as postural hypotension, sedation or depression, increased gastrointestinal motility and diarrhea, impaired ability to ejaculate, nasal stuffiness, akinesia and the like.
Compounds that interact more selectively with a particular alpha-1 adrenergic receptor subtype may prove clinically useful in providing more selective treatment of conditions and diseases associated with abnormal activity at the receptor subtype. For example, alpha-1 adrenergic receptor antagonists that can selectively ameliorate nociceptive and/or neurogenic pain without affecting blood pressure or causing postural hypotension, dizziness or syncope, are desirable.
Selective alpha-1B adrenergic receptor antagonists can also be useful in the treatment of CNS disorders including, but not limited to, anxiety, sleep disorders, and schizophrenia (see, e.g., Bakshi, et al. (1999)
Neuroscience
92:113-121; Carasso, et al. (1998)
Neuropharmacol.
37:401-404; and Acosta-Martinez, et al. (1999)
Neurochem. Int.
35:383-391). Recently, the non-selective alpha-1 adrenergic receptor antagonist prazosin has also been useful in the amelioration of combat trauma nightmares in veterans with posttraumatic stress disorder (see e.g., Raskind, et al. (2000)
J. Clin. Psychiatry
61(2), 129-133).
Because of their ability to selectively antagonize alpha-1B adrenergic receptors, the compounds of this invention lack the undesirable effects of non-selective alpha-1 adrenergic receptor antagonists such as prazosin, terazosin, and doxazosin.
DESCRIPTION OF THE RELATED ART
U.S. patent application Ser. No. 09/521,185 (Coffen, et al.), refers to certain oxazolone derivatives as alpha-1B adrenergic receptor antagonists.
PCT Application Publication WO97/11698 (assigned to Merck), refers to certain selective alpha-1B adrenergic receptor antagonists used in the treatment of hypertension.
PCT Application Publication WO97/23462 and U.S. Pat. No. 6,169,093 (assigned to Pfizer), refer to certain quinoline and quinazoline compounds useful in the treatment of benign prostatic hyperplasia.
Raskind, et al.,
J. Clin. Psychiatry
2000, 61(2), 129-133, refer to the use of prazosin to ameliorate combat trauma nightmares in veterans with posttraumatic stress disorder.
Brooks, et al.,
Proc. West. Pharmacol. Soc.
1999, 42, 67-69, refer to clozapine and other antipsychotic drugs for interaction with human alpha-1 adrenergic receptor subtypes.
Acosta-Martinez, et al.,
Neurochem. Int.
1999 35:383-391, refer to the localization of alpha-1B adrenergic receptor in female rat brain regions involved in stress and neuroendocrine function.
Bakshi, et al.,
Neuroscience
1999, 92:113-121, refer to alpha-1 adrenergic receptors mediating sensorimotor gating deficits which are thought to result in sensory inundation, cognitive fragmentation and attentional deficits, all of which are features common to schizophrenia and drug-induced psychotic states.
Carasso, et al.,
Neuropharmacol.
1998, 37:401-404, refer to the role of alpha-1 adrenoceptors in the psychotherapeutic actions of certain antipsychotics.
Giardina, et al.,
J. Med. Chem.
1996, 39, 4602-4607, refer to the synthesis of cyclazosin enantiomers and their activity as alpha-1B antagonists.
Patane, et al.,
J. Med. Chem,
1998, 41,1205-1208, refer to L-765314 as a potent and selective alpha-1B antagonist.
Xie, et al.,
Soc. for Neuroscience Abstract,
1998, 24, 2089, refer to certain alpha-1B adrenergic receptor mRNA expression in rat DRG after spinal nerve injury.
Lee, et al.,
J. Neurophysiol.
1999, 81, 2226-2233, refer to certain receptor subtypes mediating the adrenergic sensitivity of pain behavior.
All publications, patents, and patent applications cited herein, whether supra or infra, are each hereby incorporated by reference in its entirety.
SUMMARY OF THE INVENTION
This invention relates to compounds comprising Formula (I):
wherein:
R
1
is hydrogen, or lower alkyl;
R
2
is lower alkyl, heterocyclyl, heteroaryl, or aryl, all optionally substituted with lower alkyl, alkoxy, halogen, or cyano;
R′ and R″ are each independently lower alkyl;
A is hydrogen, —(CH
2
)
0-1
R
3
, —C(O)R
3
, —SO
2
R
3
, —C(O)OR
3
, —C(O)NR
4
R
5
, —SO
2
NR
4
R
5
, C(NR
6
)R
3
, or —C(NR
6
)NR
4
R
5
;
R
3
is independently in each occurrence lower alkyl optionally substituted with halogen, amino, alkylamino, hydroxy, alkoxy, acyloxy, aminocarbonyl, alkoxycarbonylamino, nitro, or cyano; aryl; arylalkyl; heteroaryl; heteroarylalkyl; cycloalkyl; cycloalkylalkyl; heterocyclyl; or heterocyclylalkyl;
R
4
and R
5
are each independently hydrogen or R
3
as defined above;
R
4
and R
5
taken together with the nitrogen to which they are attached form a 5- to 7-membered ring, optionally incorporating one or two additional ring heteroatoms
R
6
is hydrogen, lower alkyl or cyano; and chosen from N, S, or O;
n is an integer from 0 to 2 inclusive and m is an integer from 0 to 3 inclusive, wherein m+n is equal to or larger than 2;
or acceptable prodrug, salt or solvate thereof.
In another aspect, the invention relates to pharmaceutical compositions containing a therapeutically effective amount of at least one compound of Formula (I), or acceptable prodrug, salt or solvate thereof, in admixture with at least one suitable carrier.
In another aspect, the invention further relates to a process which comprises reacting a compound having the formula
wherein L is a leaving group,
with a compound of general formula
to provide a compound of the general Formula (I)
wherein R′, R″, R
1
, R
2
, m , n, and A are as defined herein.
In another embodiment, the invention further relates to a process which comprises reacting a compound having the formula:
with a compound of the general formula A-L, wherein L is a leaving group, to provide a compound of general Formula (I)
wherein R′, R″, R
1
, R
2
, m, n and A are as defined herein.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
Unless otherwise stated, the following terms used in this Application, including the specification and claims, have the definitions given below. It must be noted that, as used in the speci

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