Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-01-05
2002-04-02
Owens, Amelia (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S269000, C514S316000, C514S326000, C544S316000, C546S205000, C546S208000, C546S188000
Reexamination Certificate
active
06365602
ABSTRACT:
This invention relates to N-substituted naphthalenecarboxamides, to pharmaceutical compositions containing such compounds, as well as to their uses and to processes for their preparation. These compounds antagonise the pharmacological actions of the endogenous neuropeptide tachykinins known as neurokinins and are useful whenever such antagonism is desired.
Tachykinins are a family of neuropeptides which share a common C-terminal amino acid sequence. Mammalian tachykinins include substance P (SP), neurokinin A (NKA) and neurokinin B (NKB). In addition there are at least two N-terminally extended forms of NKA designated as neuropeptide Y and neuropeptide K. The tachykinins are distributed widely in the peripheral and central nervous systems. At least three receptor types are known for the three principal tachykinins and based upon their relative selectivities favouring the agonists SP, NKA and NKB, the receptors are classified as NK1 (neurokinin 1), NK2 (neurokinin 2) and NK3 (neurokinin 3) receptors, respectively.
As stated above, SP, NKA and NKB are found within the central nervous system. SP is frequently co-localised with NKA. In the peripheral nervous system. NKA and SP are predominantly located in the endings of capsaicin-sensitive primary afferent neurones. A second major source of tachykinins in the periphery is in neuronal cell bodies of the myenteric and submucous plexuses of the gastrointestinal tract. Other neuronal sources include the neurones innervating the salivary glands and a small proportion of intramural neurones in the urinary bladder. Tachykinin-like immunoreactivity has been demonstrated in several other locations including the endocrine cells of the gut, parenchymal cells in the carotid body, chromaffin cells of the adrenal gland, cells of the anterior pituitary, eosinophils and vascular endothelial cells. Human lymphocytes have also been shown to produce substance P.
An important action of tachykinins is neuronal stimulation which is thought to underlie their actions in the CNS, e.g. the excitation of second-order sensory neurones in the spinal cord, the activation of spinal reflexes and induction of pain, the induction of central neurochemical responses such as stimulation of dopamine metabolism, autonomic responses and modulation of salt and water intake. In the periphery, neuronal stimulation by tachykinins leads to facilitation of transmitter release, e.g. contraction of the guinea-pig ileum is mediated partly by neurogenic mechanisms and partly by direct effects.
Tachykinins modulate neuronal activity in sympathetic ganglia. Tachykinins released from collaterals of primary afferent neurones act as mediators of slow excitatory postsynaptic potentials. Central administration of SP and NKA induce tachycardia and an increase in blood pressure in rats via activation of sympathetic nerve activity.
Tachykinins produce an endothelium-dependent vasodilatation which is measurable in vivo as a transient hypotension following i.v. infusion. The effect is mediated via NK
1
receptors located on endothelial cells and is thought to involve the release of nitric oxide. Tachykinin-mediated stimulation of endothelial cells also induces their proliferation, migration and angiogenesis, indicating a possible role in growth and repair. In certain blood vessels tachykinins induce vasoconstriction e.g. via the NK
2
and NK
3
receptors in the rabbit pulmonary artery and the rat hepatic portal vein respectively.
Smooth muscle contraction mediated by tachykinins appears to be predominantly due to a direct spasmogenic effect on the muscle. The combination of this direct effect with the tachykinin-stimulated release of tachkinins from nerve endings forms the basis for their status as excitatory neurotransmitters in the airways, intestine and urinary tract. In human bronchus, urinary bladder, urethra and colon the NK
2
receptor is the mediator of this stimulatory response. Tachykinins can also induce smooth muscle relaxation via a NK
1
receptor-mediated stimulation of prostanoid production in airway epithelial cells.
SP, NKA and/or NAB have been implicated in the pathology of numerous diseases including asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), pulmonary hypertension, airway reactivity, cough, cold, urticaria, inflammation (including neurogenic inflammation), pain, various pain states (including neuropathic pain, visceral pain, ocular pain), migraine, tension headache, angiogenesis, rheumatoid arthritis, psychoses including depression and anxiety, including major depressive disorders, major depressive disorders with anxiety, cognitive disorders, movement disorder, bipolar disorders, substance use disorders, stress disorders, sleep disorders, motion sickness, panic attacks and social phobia, mania, hypomania, aggressive behaviour, pre-menstrual tension and associated appetite disorders, memory loss, emesis, (including ondansetron-resistance emesis), hypertension, oedema, Huntingdon's disease, Alzheimer's disease, schizophrenia, neuronal injury such as stroke, epilepsy, spinal cord disorder, Parkinson's Disease, gastrointestinal-hypermotility, ‘gastric asthma’, gastroesphageal reflux disease, Crohn's disease, gastric emptying disorders. ulcerative colitis, irritable bowel syndrome, inflammatory bowel syndrome, bladder hypermotility, urinary incontinence, cystitis, obesity, bulimia nervosa, cancer, parathyroid hormone deficiency, bone loss, mammalian hair growth, sexual dysfunction, tardive dyskinesia, renal disorders, skin disorders and itch (for example atopic dermatitis and psoriasis).
Examples of reviews covering the use of tachykinin antagonists in various of these disease conditions are: Maggi, C A., Patacchini, R, Rovero, P and Giachetti, A (1993)) Tachykinin receptors and tachykinin receptor antagonists
J Auton, Pharmacol
. 13, 23-93; McLean, S. (1996), Nonpeptide antagonists of the NK
1
tachykinin receptor
Med. Res. Rev
. 16, 297-317; Raffa R B, Possible role(s) of neurokinins in CNS development and neurodegenerative or other disorders.
Neuroscience & Biobehavioral Reviews
. 22(6): 789-813, 1998 October; Holzer P, Implications of tachykinins and calcitonin gene-related peptide in inflammatory bowel disease
Digestion
. 59(4): 269-83, 1998 July-August; Maggi C A., Tachykinins as peripheral modulators of primary afferent nerves and visceral sensitivity.
Pharmacological Research
. 36(2): 153-69, 1997 August; Kudlacz E M, Expert Opinion. Invest. Drugs (1998), 7(7), 1055-62; and von Sprecher et al, Drugs (1998), 1(1), 73-91.
The N-substituted naphthalenecarboxamide compounds of the present invention are antagonists of at least one of the tachykinin receptors and are of value in treating implicated disease conditions. In particular the compounds have a high degree of NK1 and/or NK2 receptor antagonist activity. Additionally, by manipulation of the substituents on the naphthalene and piperidine rings of the formula (I) hereinbelow, the ratio of activity at the NK1 and NK2 receptors can be modified, affording compounds that are predominantly active at either NK1 or NK2 receptors, or affording compounds with a balanced activity and, as such, are particularly useful when combined antagonism of both receptors is desired. In particular preferred compounds of the present invention also possess a high degree of NK1 and/or NK2 antagonism upon oral administration.
Accordingly, the present invention provides the compounds of the formula (I):
wherein:
R is alkyl; R
1
is optionally substituted phenyl, 2-oxo-tetrahydro-1(2H)-pyrimidinyl, or 2-oxo-1-piperidinyl;
R
2
is hydrogen, alkoxy, alkanoyloxy, alkoxycarbonyl, alkanoylamino, acyl, alkyl, carbamoyl, N-alkylcarbamoyl, N,N-dialkylcarbamoyl where the alkyl groups are the same or different, hydroxy, thioacyl. thiocarbamoyl, N-alkylthiocarbamoyl, or N,N-dialkylthiocarbamoyl where the alkyl groups are the same or different;
X
1
and X
2
are independently hydrogen or halo, provided that at least one of X
1
or X
2
is halo; and
R
3
R
4
R
5
and R
6
are independently hydrogen, cyan
Bernstein Peter
Dedinas Robert
Russell Keith
Shenyl Ashokkumar
Astra Zeneca AB
Owens Amelia
Person Richard V.
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