| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | April 2, 2002 |
| PATENT TITLE |
N-substituted naphthalene carboxamides as neurokinin-receptor antagonists |
| PATENT ABSTRACT |
A compound of formula I ##STR1## wherein: R is alkyl; R.sup.1 is optionally substituted phenyl 2-oxo-tetrahydro-1(2H)-pyrimidinyl, or 2-oxo-1-piperidinyl; R.sup.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.sub.1 and X.sub.2 are independently hydrogen or halo, provided that at least one of X.sub.1 or X.sub.2 is halo; and R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are independently hydrogen, cyano, nitro, trifluoromethoxy, trifluoromethyl, or alkylsulfonyl are antagonists of at least one tachykinin receptor and are useful in the treatment of depression, anxiety, asthma, pain, inflammation, urinary incontinence and other disease conditions. Process for their preparation are described, as are compositions containing them and their use. |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | January 5, 2001 |
| PATENT CT FILE DATE | July 7, 1999 |
| PATENT CT NUMBER | This data is not available for free |
| PATENT CT PUB NUMBER | This data is not available for free |
| PATENT CT PUB DATE | January 20, 2000 |
| PATENT FOREIGN APPLICATION PRIORITY DATA | This data is not available for free |
| PATENT REFERENCES CITED |
Monaghan, SM `Preparation of quaternary ammonium compounds for use as tachykinin antagonists` CA 128:205021 1998.* Edmonds-ALT X et al: "Pharmacological Profile and Chemical Synthesis of SR 48968, A Non-Peptide Antagonist of the Neurokinin A (NK2) Receptor" Bioorganic & Medicinal Chemistry Letters, vol. 3, No. 5, Jan. 1, 1993 pp. 925-939, XP002068450 ISSN: 0960-894X compound 13 |
| PATENT CLAIMS |
What is claimed is: 1. A compound of the formula (I): ##STR19## wherein: R is alkyl; R.sup.1 is optionally substituted phenyl, 2-oxo-tetrahydro-1(2H)-pyrimidinyl, or 2-oxo-1-piperidinyl; R.sup.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, tbioacyl, thiocarbamoyl, N-alkylthiocarbamoyl, or N,N-dialkylthiocarbamoyl where the alkyl groups are the same or different; X.sub.1 and X.sub.2 are independently hydrogen or halo, provided that at least one of X.sub.1 or X.sub.2 is halo; and R.sup.3, R.sup.4, R.sup.5, and R.sup.6 are independently hydrogen, cyano, nitro, trifluoromethoxy, trifluoromethyl, or alkylsulfonyl, provided that at least one of R.sup.3, R.sup.4, R.sup.5, and R.sup.6 is not hydrogen; or a pharmaceutically acceptable salt or an in vivo hydrolysable precursor thereof. 2. A compound according to claim 1 wherein R.sup.1 is phenyl optionally substituted by C.sub.1-6 alkyl, C.sub.1-6 alkylthio; C.sub.1-6 alkylsulfinyl; C.sub.1-6 alkylsulfonyl; C.sub.1-6 alkoxy; hydroxy; amino; halo; carboxy; C.sub.1-6 alkoxycarbonyl; nitro; C.sub.1-6 alkylamino; di-C.sub.1-6 alkylamino; trifluoromethyl; carbamoyl; C.sub.1-6 alkylcarbamoyl; di-C.sub.1-6 alkylcarbamoyl; trifluoromethylthio; trifluoromethylsulfinyl; trifluoromethylsulfonyl; C.sub.1-6 alkanesulfonamido; C.sub.1-6 alkanoyl; N--C.sub.1-6 alkoxy, N--C.sub.1-6 alkylamino; C.sub.1-6 alkanoylamino; ureido; C.sub.1-6 alkylureido; di-C.sub.1-6 alkylureido; C.sub.1-6 alkylsulfonyloxy; 2-oxopyrrolidino; N-oxo-N,N-di-C.sub.1-6 alkylamino; C.sub.1-6 alkoxycarbonylamino; C.sub.1-6 alkoxycarbonylcarbonylamino; C.sub.1-6 alkylcarbamoylC.sub.1-6 alkoxy; di-C.sub.1-6 alkylcarbamoylC.sub.1-6 alkoxy; and C.sub.1-6 alkyl substituted by any of the hereinabove substituents. 3. A compound according to claim 1 wherein R.sup.1 is a phenyl group substituted in the ortho-position by C.sub.1-6 alkylthio; C.sub.1-6 alkylsulfinyl; C.sub.1-6 alkylsulfonyl; trifluoromethylthio; trifluoromethylsulfinyl; C.sub.1-6 alkanesulfonamido; C.sub.1-6 alkanoyl; C.sub.1-6 alkoxycarbonyl; succinamido; carbamoyl; C.sub.1-6 alkylcarbamoyl; di-C.sub.1-6 alkylcarbamoyl; C.sub.1-6 alkoxy; C.sub.1-6 alkylcarbamoyl; C.sub.1-6 alkanoylamino; ureido; C.sub.1-6 alkylureido, di-C.sub.1-6 alkylureido; amino; C.sub.1-6 alkylamino or di-C.sub.1-6 alkylamino and optionally is further substituted. 4. A compound according to claim 1 wherein R.sup.1 is phenyl substituted in the ortho-position by methylsulfinyl, methylsulfonyl, methylureido, dimethylureido, amino, methylamino or dimethylamino. 5. A compound according to claim 1 wherein R.sup.1 is: ##STR20## wherein R.sup.a is hydrogen, C.sub.1-6 alkoxy, halo, C.sub.1-6 alkylsulfinyl or carboxy. 6. A compound according to claim 1 wherein R.sup.1 is phenyl and any orthoethylsulfinyl substituent has the (S)-configuration. 7. A compound according to claim 1 wherein R.sup.1 is 2-oxotetrahydro-1(2H)-pyrimidinyl. 8. A compound according to claim 1 wherein R.sup.1 is 2-oxo-1-piperidinyl. 9. A compound according to claim 1 wherein R.sup.2 is hydrogen. 10. A compound according to claim 1 which is: ##STR21## wherein R.sup.a is hydrogen, C.sub.1-6 alkoxy, halo, C.sub.1-6 alkylsulfinyl or carboxy; R.sup.3 is hydrogen; R.sup.4 is cyano or nitro; R.sup.5 is hydrogen or cyano; and R.sup.6 is hydrogen. 11. N-[(S)-2-(3,4-Dichlorophenyl)-4-[4-[(S)-2-methylsulfinylphenyl]-1-piperidi nyl]butyl]-N-methyl-3-cyano-1-naphthamide or a pharmaceutically acceptable salt thereof. 12. N-[(S)-2-(3,4-Dichlorophenyl)-4-[4-{4-methoxy-(S)-2-methylsulfinylphenyl}- 1-piperidinyl]butyl]-N-methyl-3-cyano-1-naphthamide or a pharmaceutically acceptable salt thereof. 13. A compound of the formula (IX): ##STR22## wherein R.sup.9 is hydrogen or a group R as defined in claim 1, X.sub.1, X.sub.2 and R.sup.3 -R.sup.6 are as defined in claim 1; and R.sup.8 is --CHO, --CH.sub.2 OR.sup.10 wherein R.sup.10 is hydrogen or an ester thereof or C.sub.1-6 alkyl, or a pharmaceutically acceptable salt or in vivo hydrolysable precursor thereof. 14. A compound according to claim 1 in the form of a base or pharmaceutically acceptable salt wherein R is methyl. 15. A pharmaceutical composition which comprises a compound according to claim 1 and a pharmaceutically acceptable carrier. 16. A method of treating a disease condition wherein antagonism of at least one tachykinin receptor is beneficial which comprises administering to a patient in need thereof an effective amount of a compound according to claim 1. 17. A process for preparing a compound of the formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable precursor thereof which process comprises: a) reacting a compound of the formula (III) with a compound of the formula (IV): ##STR23## wherein R, R.sup.1 -R.sup.6, X.sub.1 and X.sub.2 are as defined in claim 1; and L and L.sup.1 are groups such that reductive amination of the compounds of the formulae (III) and (IV) forms a N--C bond; or b) reacting a compound of the formula (V) with a compound of the formula (VI): ##STR24## wherein R.sup.1 -R.sup.6, R.sup.2, X.sub.1 and X.sub.2 are as defined in claim 1; and L.sup.2 is a leaving group; wherein any other functional group is protected, if necessary, and: i) removing any protecting groups; ii) optionally forming a pharmaceutically acceptable salt or in vivo hydrolysable precursor |
| PATENT DESCRIPTION |
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.sub.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.sub.2 and NK.sub.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.sub.2 receptor is the mediator of this stimulatory response. Tachykinins can also induce smooth muscle relaxation via a NK.sub.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.sub.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): ##STR2## wherein: R is alkyl; R.sup.1 is optionally substituted phenyl, 2-oxo-tetrahydro-1(2H)-pyrimidinyl, or 2-oxo-1-piperidinyl; R.sup.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.sub.1 and X.sub.2 are independently hydrogen or halo, provided that at least one of X.sub.1 or X.sub.2 is halo; and R.sup.3 R.sup.4 R.sup.5 and R.sup.6 are independently hydrogen, cyano, nitro, trifluoromethoxy, trifluoromethyl, or alkylsulfonyl, provided that at least one of R.sup.3, R.sup.4, R.sup.5, and R.sup.6 is not hydrogen; and pharmaceutically acceptable salts and in vivo hydrolysable precursors thereof. "Alkyl" means a saturated aliphatic hydrocarbon group which may be straight or branched and having about 1 to about 20 carbon atoms in the chain, Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkyl chain. Preferred alkyl groups are the lower alkyl groups which are those alkyl groups having from 1 to about 6 carbons, for example C.sub.1-6 alkyl. "Acyl" means an alkylcarbonyl group for example C.sub.1-6 alkanoyl. "Thioacyl" means an alkylthiocarbonyl group for example C.sub.1-6 alkylthiocarbonyl. R is alkyl for example C.sub.1-6 alkyl such as methyl, ethyl or n-propyl. Preferably R is methyl so that in one aspect the present invention provides the compounds of the formula (I) wherein R is methyl and the pharmaceutically acceptable salts thereof. In a further aspect the present invention provides the compounds of the formula (I) wherein R is methyl, R.sup.1, X.sub.1 and X.sub.2 are as hereinabove defined; and R.sup.2 is hydrogen, acyl, alkyl, carbamoyl, N-alkylcarbamoyl. N,N-dialkylcarbamoyl, hydroxy, thioacyl, thiocarbamoyl, N-alkylthiocarbamoyl or N,N-dialkylthiocarbamoyl, and the pharmaceutically acceptable salts thereof. In one aspect R.sup.1 is optionally substituted phenyl. Suitable substituents for the phenyl ring include: alkyl such as C.sub.1-6 alkyl for example methyl or ethyl; alkylthio such as C.sub.1-6 alkylthio for example methylthio or ethylthio; alkylsulfinyl such as C.sub.1-6 alkylsulfinyl for example methylsulfinyl, ethylsulfinyl or propylsulfinyl; alkylsulfonyl such as C.sub.1-6 alkylsulfonyl for example methylsulfonyl or ethylsulfonyl; hydroxy; alkoxy such as C.sub.1-6 alkoxy for example methoxy or ethoxy; amino; halo for example fluoro, chloro, bromo or iodo; carboxy; alkoxycarbonyl such as C.sub.1-6 alkoxycarbonyl for example methoxycarbonyl; nitro; alkylamino such as C.sub.1-6 alkylamino for example methylamino or ethylamino; di-alkylamino (wherein the alkyl groups may be the same or different) such as di-C.sub.1-6 alkylamino for example dimethylamino; trifluoromethyl; carbamoyl; alkylcarbamoyl such as C.sub.1-6 alkylcarbamoyl for example methylcarbamoyl; di-alkylcarbamoyl (wherein the alkyl groups may be the same or different) such as di-C.sub.1-6 alkylcarbamoyl for example dimethylcarbamoyl; trifluoromethylthio; trifluoromethylsulfinyl; trifluoromethylsulfonyl; alkanesulfonamido such as C.sub.1-6 alkanesulfonamido for example methanesulfonamido; alkanoyl such as C.sub.1-6 alkanoyl for example acetyl; succinamido; N-alkoxy, N-alkylamino such as N--C.sub.1-6 alkoxy, N--C.sub.1-6 alkylamino for example N-methoxy, N-methylamino; alkanoylamino such as C.sub.1-6 alkanoylamino for example acetamido or propionamido; ureido; alkylureido such as C.sub.1-6 alkylureido for example methylureido (MeNHCONH--) di-alkylureido such as di-C.sub.1-6 alkylureido for example dimethylureido; alkylsulfonyloxy such as C.sub.1-6 alkylsulfonyloxy for example methylsulfonyloxy; 2-oxopyrrolidino; N-oxo-N,N-dialkylamino such as N-oxo-N,N-di-C.sub.1-6 alkylamino for example N-oxo-N,N-dimethylamino; alkoxycarbonylamino such as C.sub.1-6 alkoxycarbonylamino for example methoxycarbonylamino; alkoxycarbonylcarbonylamino such as C.sub.1-6 alkoxycarbonylcarbonylamino for example methoxycarbonylcarbonylamino; alkylcarbamoylalkoxy such as C.sub.1-6 alkylcarbamoylC.sub.1-6 alkoxy for example methylcarbamoyl methoxy; dialkylcarbamoylC.sub.1-6 alkoxy such as di-C.sub.1-6 alkylcarbamoylalkoxy for example dimethylcarbamoylmethoxy; and C.sub.1-6 alkyl for example methyl substituted by any of the hereinabove substituents for example methylsulfinylmethyl. In one aspect R.sup.1 is a phenyl group substituted in the ortho-position and in a preferred aspect the ortho-substituent is C.sub.1-6 alkylthio for example methylthio; C.sub.1-6 alkylsulfinyl for example methylsulfinyl, ethylsulfinyl or propylsulfinyl; C.sub.1-6 alkylsulfonyl for example methylsulfonyl or ethylsulfonyl; trifluoromethylthio; trifluoromethylsulfinyl; C.sub.1-6 alkanesulfonamido for example methanesulfonamido; C.sub.1-6 alkanoyl for example acetyl or propionyl; C.sub.1-6 alkoxycarbonyl for example methoxycarbonyl; succinamido; carbamoyl; C.sub.1-6 alkylcarbamoyl for example methylcarbamoyl; di-C.sub.16 alkylcarbamoyl for example dimethylcarbamoyl; hydroxy; C.sub.1-6 alkoxy, C.sub.1-6 alkylcarbamoyl for example N-methoxy, N-methylcarbamoyl; C.sub.1-6 alkanoylamino for example acetylamino; ureido, C.sub.1-6 alkylureido for example methylureido; di-C.sub.1-6 alkylureido for example dimethylureido; amino; C.sub.1-6 alkylamino for example methylamino or ethylamino; di-C.sub.1-6 alkylamino for example dimethylamino; C.sub.1-6 alkyl-sulfonyloxy for example methylsulfonyloxy; 2-oxopyrrolidino; N-oxo-N,N-di-C.sub.1-6 alkylamino for example N-oxo-N,N-dimethylamino; C.sub.1-6 alkoxycarbonylamino for example methoxycarbonylamino; C.sub.1-6 alkoxycarbonylcarbonylamino for example methoxycarbonylcarbonylamino; C.sub.1-6 alkylcarbamoylalkoxy for example methylcarbamoylmethoxy; di-C.sub.1-6 alkylcarbamoylalkoxy for example dimethylcarbamoylmethoxy; or methylsulfinylmethyl. In addition to the ortho-substituent, the phenyl group may have further substituents. In a further aspect the ortho-substituent is C.sub.1-6 alkylthio for example methylthio; C.sub.1-6 alkylsulfinyl for example methylsulfinyl, ethylsulfinyl or propylsulfinyl; C.sub.1-6 alkylsulfonyl for example methylsulfonyl or ethylsulfonyl; trifluoromethylthio; trifluoromethylsulfinyl; C.sub.1-6 alkanesulfonamido for example methanesulfonamido; C.sub.1-6 alkanoyl for example acetyl or propionyl; C.sub.1-6 alkoxycarbonyl for example methoxycarbonyl; succinamido; carbamoyl; C.sub.1-6 alkylcarbamoyl for example methylcarbamoyl; di-C.sub.1-6 alkylcarbamoyl for example dimethylcarbamoyl; C.sub.1-6 alkoxy, C.sub.1-6 alkylcarbamoyl for example N-methoxy, N-methylcarbamoyl; C.sub.1-6 alkanoylamino for example acetylamino; ureido, C.sub.1-6 alkylureido for example methylureido; di-C.sub.1-6 alkylureido for example dimethylureido; amino; C.sub.1-6 alkylamino for example methylamino or ethylamino; or di-C.sub.1-6 alkylamino for example dimethylamino. In addition to the ortho-substituent, the phenyl group may have further substituents. Suitable further substituents, which are optional, for the ortho-substituted phenyl ring include C.sub.1-6 alkyl for example methyl or ethyl; C.sub.1-6 alkylthio for example methylthio or ethylthio; C.sub.1-6 alkylsulfinyl for example methylsulfinyl, ethylsulfinyl or propylsulfinyl; C.sub.1-6 alkylsulfonyl for example methylsulfonyl or ethylsulfonyl; C.sub.1-6 alkoxy for example methoxy, ethoxy or propoxy; halo for example bromo, fluoro, chloro or iodo; carboxy; C.sub.1-6 alkoxycarbonyl for example methoxycarbonyl; C.sub.1-6 alkanoyl for example acetyl or propionyl; nitro; amino; C.sub.1-6 alkylamino for example methylamino or ethylamino; di-C.sub.1-6 alkylamino where the alkyl groups may be the same or different, for example dimethylamino; trifluoromethyl; CF.sub.3 S(O).sub.x wherein x is 0 to 2, for example trifluoromethylthio, trifluoromethylsulfinyl or trifluoromethylsulfonyl; C.sub.1-6 alkanoylamino for example acetylamino or propionylamino; C.sub.1-6 alkylsulphonamido for example methylsulphonamido; ureido; C.sub.1-6 alkylureido for example methylureido (MeNHCONH--), di-C.sub.1-6 alkylureido for example dimethylureido (Me.sub.2 NCONH--); carbamoyl; C.sub.1-6 alkylcarbamoyl for example methylcarbamoyl; di-C.sub.1-6 alkylcarbamoyl where the alkyl groups may be the same or different, for example dimethylcarbamoyl; and C.sub.1-6 alkyl for example methyl substituted by any of the hereinabove substituents. Another suitable further substituent for the ortho-substituted ring is hydroxy. In one aspect, suitable further substituents for a phenyl group already substituted in the ortho-position are C.sub.1-6 alkyl, C.sub.1-6 alkylsulfinyl, C.sub.1-6 alkylsulfonyl, C.sub.1-6 alkoxy, amino, halo, carboxy, C.sub.1-6 alkoxycarbonyl, nitro, N--C.sub.1-6 alkylamino, N,N-di-C.sub.1-6 alkylamino (where the alkyl groups may be the same or different), trifluoromethyl, C.sub.1-6 alkylthio, carbamoyl, N--C.sub.1-6 alkylcarbamoyl and N,N-di-C.sub.1-6 alkylcarbamoyl (where the alkyl groups may be the same or different), C.sub.1-6 alkanoyl, C.sub.1-6 alkanesulfonamido, trifluoromethylthio, trifluoromethylsulfinyl, hydroxy, ureido, C.sub.1-6 alkylureido and di-C.sub.1-6 alkylureido. Preferably these further substituents are at the 4-position of the phenyl group. Preferred values for the ortho-substituent are methylsulfinyl, ethylsulfinyl, propylsulfinyl, methylsulfonyl, trifluoromethylthio, trifluoromethylsulfinyl, methanesulfonamido, acetyl, methoxycarbonyl, succinamido, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, N-methoxy, N-methylcarbamoyl, acetylamino, ureido, methylureido, dimethylureido, amino, methylamino and dimethylamino. In particular the ortho-substituent is methylsulfinyl, methylsulfonyl, methylureido, dimethylureido, amino, methylamino or dimethylamino. Of these methylsulfinyl is particularly preferred. Favourably the ortho-substituted phenyl ring is not substituted further or is substituted by up to three optional substituents. In particular the ortho-substituted phenyl ring is not substituted further or is substituted at the 4-position, that is the position para- to the bond with the piperidine ring, so forming a 2, 4-disubstituted phenyl group, preferably a 2-MeSO, 4-substituted phenyl group. Preferred substituents, if present, for the ortho-substituted phenyl ring, are methyl, methoxy, acetyl, acetylamino, methoxycarbonyl, methanesulfonylamino, methylsulfinyl, methylsulfonyl, trifluoromethyl, trifluoromethylthio, trifluoromethylsulfinyl, bromo. fluoro, chloro, hydroxy, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, methylureido and dimethylureido. In particular these preferred substituents may be at the 4-position of the phenyl ring. A preferred class of compounds is that wherein R.sup.1 is of the formula (Ia): ##STR3## wherein R.sup.a is hydrogen, C.sub.1-6 alkyl, C.sub.1-6 alkylsulfinyl, C.sub.1-6 alkylsulfonyl, C.sub.1-6 alkoxy, amino, halo, carboxy, C.sub.1-6 alkanoyloxy, nitro, N--C.sub.1-6 alkyl amino, di-C.sub.1-6 alkylamino, trifluoromethyl. C.sub.1-6 alkylthio, carbamoyl, C.sub.1-6 alkylcarbamoyl and di-C.sub.1-6 alkylcarbamoyl; and R.sup.2 is hydrogen. More preferably, R.sup.a is hydrogen, C.sub.1-6 alkoxy for example methoxy or ethoxy, halo for example bromo, chloro or fluoro, C.sub.1-6 alkylsulfinyl for example methylsulfinyl or carboxy. In one aspect R.sup.a is hydrogen or C.sub.1-6 alkoxy. In another aspect R.sup.a is hydrogen, C.sub.1-6 alkoxy or halo. More particularly R.sup.a is hydrogen, methoxy or fluoro. In a particularly preferred aspect R.sup.a is hydrogen. In another particularly preferred aspect R.sup.a is methoxy. The compounds of the invention have a number of chiral centres. It is preferred that the ortho-methylsulfinyl substituent, if present, has the stereochemistry depicted in formula (Ib): ##STR4## That is the S-stereochemistry according to the Cahn-Prelog-Ingold sequence rules. Preferred values for R.sup.1 are therefore 2(S)-methylsulfinylphenyl and 4-methoxy-2(S)-methylsulfinylphenyl. In another aspect R.sup.1 is 2-oxotetrahydro-1(2H)-pyrimidinyl. In a further aspect R.sup.1 is 2-oxo-1-piperidinyl. R.sup.2 is hydrogen; acyl such as C.sub.1-6 alkanoyl for example acetyl or propionyl; alkyl such as C.sub.1-6 alkyl for example methyl or ethyl; carbamoyl; N-alkylcarbamoyl such as C.sub.1-6 alkylcarbamoyl for example methylcarbamoyl or ethylcarbamoyl; N,N-dialkylcarbamoyl such as di-C.sub.1-6 alkylcarbamoyl for example dimethylcarbamoyl; hydroxy; thioacyl such as C.sub.1-6 alkylthiocarbonyl for example methylthiocarbonyl; thiocarbamoyl (NH.sub.2 CS--); N-alkylthiocarbamoyl such as C.sub.1-6 alkylthiocarbamoyl for example methylthiocarbamoyl (MeNHCS--); N,N-dialkylthiocarbamoyl such as di-C.sub.1-6 alkylthiocarbamoyl for example dimethylthiocarbamoyl (Me.sub.2 NCS--); alkoxy such as C.sub.1-6 alkoxy for example methoxy or ethoxy; alkanoyloxy such as C.sub.1-6 alkanoyloxy for example acetyloxy or propionoxy; alkoxycarbonyl such as C.sub.1-6 alkoxycarbonyl for example methoxycarbonyl or ethoxycarbonyl; or alkanoylamino such as C.sub.1-6 alkanoylamino for example acetylamino. In one aspect R.sup.2 is hydrogen, acyl, alkyl, carbamoyl, N-alkylcarbamoyl, N,N-dialkylcarbamoyl, hydroxy, thioacyl, thiocarbamoyl. N-alkylthiocarbamoyl or N,N-dialkylthiocarbamoyl. in a preferred aspect R.sup.2 is hydrogen, hydroxy, methoxycarbonyl, methylcarbamoyl or dimethylcarbamoyl. When R.sup.1 is optionally substituted phenyl, preferably R.sup.2 is hydrogen or hydroxy, most preferably hydrogen. When R.sup.1 is 2-oxo-tetrahydro-1-(2H)-pyrimidinyl or 2-oxo-1-piperidinyl, preferably R.sup.2 is hydrogen, methoxycarbonyl, methylcarbamoyl or dimethylcarbamoyl. In another aspect when R.sup.1 is 2-oxo-tetrahydro-1-(2H)-pyrimidinyl or 2-oxo-1-piperidinyl, R.sup.2 is hydrogen or N--C.sub.1-6 alkylcarbamoyl for example methylcarbamoyl. Ph--X.sub.1, X.sub.2 is phenyl mono-or di-substituted by halo. Preferably halo is chloro or fluoro and in particular Ph--X.sub.1, X.sub.2 is 4-chloro, 4-fluoro, 3,4-difluoro or 3,4-dichloro. Of these 3,4-dichloro is most preferred. R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are independently hydrogen, cyano, nitro, trifluoromethoxy, trifluoromethyl or alkylsulfonyl (for example C.sub.1-6 alkylsulfonyl) with the proviso that at least one of R.sup.3 -R.sup.6 is not hydrogen, Preferably R.sup.3 is hydrogen. Preferably R.sup.4 is cyano. nitro or methylsulfonyl. Preferably R.sup.5 is hydrogen or cyano. Preferably R.sup.6 is hydrogen, cyano or nitro. More preferably R.sup.3 and R.sup.6 are hydrogen, R.sup.4 is cyano or nitro, and R.sup.5 is hydrogen or cyano. Most preferably R.sup.3, R.sup.5 and R.sup.6 are hydrogen and R.sup.4 is cyano or nitro, in particular cyano so forming the 3-cyano-naphth-1-y1 group. The compounds of the present invention possess a number of chiral centres, at --CH(Ph--X.sub.1, X.sub.2)--, and possibly in the optional substituents (for example the MeSO-- substituent) on the phenyl groups if present. The present invention covers all isomers, diastereoisomers, atropisomers and mixtures thereof that antagonise tachykinins. The preferred configuration at --CH(Ph--X.sub.1, X.sub.2)-- is shown in formula (Ic) hereinbelow: ##STR5## A preferred class of compounds is that of the formula (II): ##STR6## wherein R.sup.a is hydrogen, C.sub.1-6 alkoxy, halo, C.sub.1-6 alkylsulfinyl or carboxy; R.sup.3 is hydrogen; R.sup.4 is cyano or nitro; R.sup.5 is hydrogen or cyano; and R.sup.6 is hydrogen. In particular R.sup.a is hydrogen, methoxy or fluoro; R.sup.3, R.sup.5 and R.sup.6 are all hydrogen and R.sup.4 is cyano or nitro, preferably cyano. Particular compounds of this invention include those of the Examples hereinbelow. Pharmaceutically acceptable salts of the compounds of the formula (I) include those made with inorganic or organic acids which afford a physiologically acceptable anion, such as with, for example, hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, sulfamic, para-toluenesulfonic, acetic, citric, lactic, tartaric, malonic, fumaric, maleic, maleic, ethanesulfonic, benzenesulfonic, cyclohexylsulfamic, salicyclic and quinic acids. In vivo hydrolysable precursors include in vivo hydrolysable esters, amides and carbamates which hydrolyse in the animal (e.g. human) body to produce the parent compound. Such precursors, for example esters, amides and carbamates, can be identified by administering, for example intravenously to a test animal, the compound under test and by subsequently examining the test animal's body fluids. Suitable in vivo hydrolysable precursors include esters of carboxy (RXOOC--) and of hydroxy (RYCOO--). In order to use a compound of the formula (I) or a pharmaceutically acceptable salt or an in-vivo hydrolysable precursor thereof for the therapeutic treatment (including prophylactic treatment) of mammals including humans, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition. Therefore in another aspect the present invention provides a pharmaceutical composition which comprises a compound of the formula (I) or a pharmaceutically acceptable salt or an in-vivo hydrolysable precursor and pharmaceutically acceptable carrier. The pharmaceutical compositions of this invention may be administered in standard manner for the disease condition that it is desired to treat, for example by oral, topical, parenteral, buccal, nasal, vaginal or rectal administration or by inhalation or insufflation. For these purposes the compounds of this invention may be formulated by means known in the art into the form of, for example, tablets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays, suppositories, finely divided powders or aerosols or nebulisers for inhalation, and for parenteral use (including intravenous, intramuscular or infusion) sterile aqueous or oily solutions or suspensions or sterile emulsions. In addition to the compounds of the present invention the pharmaceutical composition of this invention may also contain, or be co-administered (simultaneously or sequentially) with, one or more pharmacological agents of value in treating one or more disease conditions referred to herein. The pharmaceutical compositions of this invention will normally be administered to humans so that, for example, a daily dose of 0.01 to 25 mg/kg body weight (and preferably of 0.1 to 5 mg/kg body weight) is received. This daily dose may be given in divided doses as necessary, the precise amount of the compound received and the route of administration depending on the weight, age and sex of the patient being treated and on the particular disease condition being treated according to principles known in the art. Typically unit dosage forms will contain about 1 mg to 500 mg of a compound of this invention. For example a tablet or capsule for oral administration may conveniently contain up to 250 mg (and typically 5 to 100 mg) of a compound of the formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable precursor thereof. In another example, for administration by inhalation, a compound of the formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable precursor thereof may be administered in a daily dosage range of 5 to 100 mg, in a single dose or divided into two to four daily doses. In a further example, for administration by intravenous or intramuscular injection or infusion, a sterile solution or suspension containing up to 10% w/w (and typically 5% w/w) of a compound of the formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable precursor thereof may be used. Therefore in a further aspect, the present invention provides a compound of the formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable precursor thereof for use in a method of therapeutic treatment of the human or animal body. In yet a further aspect the present invention provides a method of treating a disease condition wherein antagonism of at least one tachykinin receptor is beneficial which comprises administering to a patient in need thereof an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable precursor thereof. The present invention also provides the use of a compound of the formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable precursor thereof in the preparation of a medicament for use in a disease condition wherein antagonism of at least one tachykinin receptor is beneficial. In particular the present invention provides a method of treating a disease condition wherein antagonism of the NK1 and/or NK2 receptors is beneficial. In particular the present invention provides a method of treating asthma which comprises administering to a patient in need thereof an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable precursor thereof. In particular the present invention provides a method of treating chronic obstructive pulmonary disease which comprises administering to a patient in need thereof an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable precursor thereof. In particular the present invention provides a method of treating pain which comprises administering to a patient in need thereof an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable precursor thereof. In particular the present invention provides a method of treating depression which comprises administering to a patient in need thereof an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable precursor thereof. In particular the present invention provides a method of treating urinary incontinence which comprises administering to a patient in need thereof an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable precursor thereof. In another aspect the present invention provides a process for preparing a compound of the formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable precursor thereof which process comprises: a) reacting a compound of the formula (III) with a compound of the formula (IV): ##STR7## wherein R, R.sup.1 -R.sup.6, X.sub.1 and X.sub.2 are as hereinbefore defined; and L and L.sup.1 are groups such that reductive amination of the compounds of the formulae (III) and (IV) forms a N--C bond; or b) reacting a compound of the formula (V) with a compound of the formula (VI): ##STR8## wherein R.sup.1 -R.sup.6, R.sup.2, X.sub.1 and X.sub.2 are as hereinbefore defined; and L.sup.2 is a leaving group; wherein any other functional group is protected, if necessary, and: i) removing any protecting groups; ii) optionally forming a pharmaceutically acceptable salt or in vivo hydrolysable precursor. Protecting groups may in general be chosen from any of the groups described in the literature or known to the skilled chemist as appropriate for the protection of the group in question, and may be introduced and removed by conventional methods; see for example: Theodora W. Greene et al., Wiley (1991), Protective Groups in Organic Chemistry; J F W McOmie, Plenum Press (1973) and Kocienski, Philip J, Georg Thieme Verlag (1994), Protecting Groups. Methods of removal are chosen so as to effect removal of the protecting group with minimum disturbance of groups elsewhere in the molecule. It will also be appreciated that certain of the various optional substituents in the compounds of the formula (I) may be introduced by standard aromatic substitution reactions or generated by conventional functional group modifications either prior to or immediately following the processes described hereinabove. The reagents and reaction conditions for such procedures are well known in the chemical art. Pharmaceutically acceptable salts may be prepared from the corresponding acid in conventional manner. Non-pharmaceutically acceptable salts may be useful as intermediates and as such are another aspect of the present invention. In vivo hydrolysable precursors may be prepared from the corresponding functional derivative in conventional manner at any convenient stage of the synthesis. It is well known in the art how to prepare optically-active forms (for example by resolution of the racemic form or by synthesis from optically-active starting materials) and how to determine the tachykinin antagonist properties by the standard tests known in the art and those described hereinafter. The compounds of the formulae (III) and (IV) are reacted under conditions of reductive amination. Typically in the compounds of the formula (III) L is hydrogen. Typically in the compounds of the formula (IV) L.sup.1 is an oxo group so forming an aldehyde moiety (i.e. L.sup.1 and the carbon atom to which is joined are OHC--). The reaction is typically performed at a non-extreme temperature, for example 0-100.degree. C., suitably ambient temperature in a substantially inert solvent for example methanol or dichloromethane. Typical reducing agents include borohydrides such as sodium cyanoborohydride. In an alternative, in the compounds of the formula (IV), L.sup.1 is a leaving group such as halo for example chloro or bromo or is a sulfonate for example methanesulfonate or p-toluenesulfonate. Such compounds are reacted with compounds of the formula (III) wherein L is hydrogen in the presence of a base. The compounds of the formula (III) are known or may be prepared in conventional manner. The compounds of the formula (IV) may be prepared in a conventional manner. For example when L.sup.1 is oxo, compounds of the formula (IV) may be prepared by oxidising a compound of the formula (VII): ##STR9## wherein X.sup.1, X.sup.2, R and R.sup.3 -R.sup.6 are as hereinbefore described. Suitable oxidation conditions include Swern conditions for example oxidation with oxalyl chloride in the presence of dimethylsulfoxide. The compounds of the formula (IV) wherein L.sup.1 is a leaving group may be prepaed in conventional manner from a compound of the formula (VII). The compounds of the formula (VII) may be prepared, for example by reacting a compound of the formula (VI) with a compound of the formula (VIII): ##STR10## wherein R, X.sub.1 and X.sub.2 are as hereinbefore defined under conventional acylation conditions The compounds of the formulae (V) and (VI) may be reacted under conventional acylation conditions wherein the compound of formula (VI) is an acid or an activated acid derivative. Typical activated acid derivatives are well known in the literature. They may be formed in situ from the acid or they may be prepared, isolated and subsequently reacted. Typically L.sup.2 is chloro thereby forming the acid chloride. Typically the acylation reaction is performed in the presence of a non-nucleophilic base, for example di-isopropylethylamine, in a substantially inert solvent at a non-extreme temperature. The compounds of the formula (V) are known or may be prepared in a conventional manner. The compounds of the formulae (IV) and (VII) are not only useful intermediates but also have good tachykinin antagonist activity, in particular at the NK1 receptor. Therefore in another aspect, the present invention provides a compound of the formula (IV) or (VII) or a pharmaceutically salt or in vivo hydrolysable precursor thereof. More particularly the present invention provides a compound of the formula (IX): ##STR11## wherein X.sup.1, X.sup.2 and R.sup.3 -R.sup.6 are as hereinbefore defined; R.sup.8 is --CHO; --CH.sub.2 OR.sup.10 wherein R.sup.10 is hydrogen or an ester thereof or C.sub.1-6 alkyl; and R.sup.9 is hydrogen or a group R as hereinbefore defined; or a pharmaceutically acceptable salt or in vivo hydrolysable precursor thereof. Suitably R.sup.9 is C.sub.1-6 alkyl for example methyl. In one aspect R.sup.8 is aldehydo (--CHO) or is a derivative thereof. A suitable derivative is an acetal, for example of the formula (R.sup.b O)CH(OR.sup.c)-- wherein R.sup.b and R.sup.c are independently selected from C.sub.1-6 alkyl or together form a C.sub.2-4 methylene chain thus forming a dioxo ring. More suitably R.sup.b and R.sup.c have the same value and are both methyl or are both ethyl. In a further aspect R.sup.8 is --CH.sub.2 OR.sup.10 wherein R.sup.10 is hydrogen or C.sub.1-6 alkyl. Preferably R.sup.10 is hydrogen, methyl or ethyl and in particular R.sup.10 is hydrogen. In yet a further aspect R.sup.10 may represent an ester forming group for example forming a group of the formula --CH.sub.2 OCOR.sup.d wherein R.sup.d is C.sub.1-6 alkyl for example methyl, aryl for example phenyl or arylC.sub.1-6 alkyl for example benzyl. Acetals of --CHO and esters of hydroxymethyl (HOCH.sub.2 --) may be prepared in standard manner. Preferred values of X.sup.1, X.sup.2, R and R.sup.3 -R.sup.6 are as described hereinabove for compounds of the formula (I). Accordingly in the compounds of the formula (IX), preferably --PhX.sub.1 X.sub.2 -- is 3,4-dichlorophenyl and R is methyl. A preferred class of compounds is that of the formula (X): ##STR12## wherein R.sup.8 is --CHO or an acetal thereof such as (CH.sub.3 O).sub.2 CH--; or an ester thereof for example acetoxymethyl, or R.sup.8 methoxymethyl or ethoxymethyl; R.sup.4 is cyano or nitro; and R.sup.5 is hydrogen or cyano. In particular R.sup.5 is hydrogen and R.sup.4 is cyano or nitro, most preferably cyano, and R.sup.8 is --CHO or --CH.sub.2 OH. These compounds antagonise the NK1 receptor in particular and therefore are particularly beneficial in treating disease conditions mediated through such receptors, for example depression, anxiety, emesis, pain and other disease conditions identified in the literature. The compounds of the formulae (IX) and (X) may be formulated and administered as described hereinbefore in relation to the compounds of the formula (I). The following biological test methods, data and Examples serve to illustrate and further describe the invention. The utility of a compound of the invention or a pharmaceutically acceptable salt or in vivo hydrolysable precursor thereof (hereinafter, collectively referred to as a "Compound") may be demonstrated by known tests and by clinical studies. SP Receptor Binding Assay (Test A) The ability of a Compound of the invention to antagonize the binding of SP at the NK1 receptor may be demonstrated with an assay using the human NK1 receptor expressed in Mouse Erythroleukemia (MEL) cells. The human NK1 receptor was isolated and characterized as described in: B. Hopkins, et al. "Isolation and characterization of the human lung NK1 receptor cDNA" Biochem. Biophys. Res. Comm., 1991, 180, 1110-1117; and the NK1 receptor was expressed in Mouse Erythroleukemia (MEL) cells using a procedure similar to that described in Test B below. In general, the Compounds of the invention having NK1 antagonist activity which were tested demonstrated statistically significant binding activity in Test A with a K.sub.i of 1 microM or much less typically being measured. Neurokinin A (NKA) Receptor Binding Assay (Test B) The ability of a Compound of the invention to antagonize the binding of NKA at the NK2 receptor may be demonstrated with an assay using the human NK2 receptor expressed in Mouse Erythroleukemia (MEL) cells, as described in: Aharony, D., et al. "Isolation and Pharmacological Characterization of a Hamster Neurokinin A Receptor cDNA" Molecular Pharmacology, 1994, 45, 9-19. The selectivity of a Compound for binding at the NK1 and the NK2 receptors may be shown by determining its binding at other receptors using standard assays, for example, one using a tritiated derivative of NKB in a tissue preparation selective for NK3 receptors. In general, the Compounds of the invention having NK2 antagonist activity which were tested demonstrated statistically significant binding activity in Test A and Test B with a K.sub.i of 1 microM or much less typically being measured. Neurokinin B (NKB) Receptor Binding Assay (Test C) The ability of a Compound of the invention to antagonise the binding of a selective NKB receptor ligand at the NK3 receptor may be demonstrated with an assay using the human NK3 receptor, cloned from human brain and expressed in Mouse Erythroleukemia (MEL) cells. Human NK3 receptor was expressed in MEL cells with a similar procedure to that described for the human NK2 receptor in: Aharony, D., et al. "Isolation and Pharmacological Characterization of a Hamster Neurokinin A Receptor cDNA" Molecular Pharmacology, 1994, 45, 9-19. The selectivity of a Compound for binding at the NK1 and the NK2 receptors may be shown by determining its binding at other receptors using standard assays, for example, one using a tritiated derivative of NKB in a clonal cells expressing the human NK3 receptors. In general, the Compounds of the invention having NK2 antagonist activity which were tested demonstrated statistically significant binding activity in Test A and Test B with a K.sub.i of 1 microM or much less typically being measured. Rabbit Pulmonary Artery: NK1 in vitro functional assay (Test D) The ability of a Compound of the invention to antagonize the action of the agonist Ac-[Arg.sup.6, Sar.sup.9, Met(O.sub.2).sup.11 ] Substance P (6-11), ASMSP, in a pulmonary tissue may be demonstrated as described in Bialecki et al. Kca channel antagonists reduce NO donor-mediated relaxation of vascular and tracheal smooth muscle. Am. J. Physiol. 268: L152-L159, 1995. Paired tissue segments of pulmonary artery excised from male New Zealand white rabbits are suspended between stainless steel stirrups for analyses of isometric relaxation under standard conditions in physiological salt solution (PSS) containing indomethacin (5 microM; to block cyclooxygenase) and propranolol (1 microM; to block .beta. adrenergic receptors). Initial tension placed on each tissue is 2 grams, which is maintained throughout the 1.0 hour equilibration period. Tissues are washed with PSS at 15 minute intervals. At the 30 and 45 minute wash the following treatments are added: Thiorphan (1 microM; to block E.C.3.4.24.11), ((3R)-3-[(1S)-1-(3,4-Dichlorophenyl)-3-(4-[(R or S)-2-methylsulfinyl-phenyl]-piperidino)propyl]-2-ethyl-2,3-dihydroisoindol -1-one) (0.03 microM; to block NK.sup.2 receptors as described in: "Aharony D., et al. Pharmacological Characterization of ZD7944: A Novel, Potent and orally-Active Non-Peptide Neurokinin-A (NK-2) Receptor Antagonist Eur. Respir. J. 12 (Suppl. 12):20S, 1998"), and the given concentration of the Compound being tested. After equilibration, phenylephrine (3 microM) is added to produce steady-state contraction of the tissue and a dose relaxation curve to ASMSP is constructed. Constructed curves are complete when each tissue fails to relax further for 2 consecutive doses. Papaverine (1 milliM) is then added to obtain a maximum reference relaxation. For antagonists behaving in a noncompetitive manner, the percent inhibition of relaxation is determined at a given concentration of the antagonist. Percent inhibition is determined when a tested Compound produces a statistically significant reduction of the magnitude of maximum relaxation and is calculated as a percentage of the papaverine reference response For antagonists behaving competitively, potencies are determined by calculating the negative log value of the apparent dissociation constant (pK.sub.B) for each concentration tested. Statistical significance is determined when the P value is <0.05 using the Student's t-test for paired comparisons. In general, the Compounds of the invention having NK1 antagonist activity which were tested demonstrated statistically significant values of the negative log apparent dissociation constant in Test D with a pK.sup.B of 6 or much greater typically being measured. NK2 in vitro functional assay (Test E) The ability of a Compound of the invention to antagonize the action of the agonist [.beta.-ala.sup.8 ] NKA (4-10), BANK, in a pulmonary tissue may be demonstrated as described in Bialecki et al. Kca channel antagonists reduce NO donor-mediated relaxation of vascular and tracheal smooth muscle. Am. J. Physiol. 268: L152-L159, 1995". Left and right pulmonary arteries are excised from male New Zealand white rabbits. The pulmonary arteries are cut into ring segments and the intimal surface rubbed gently to remove the endothelium. Paired tissue segments of pulmonary artery are suspended between stainless steel stirrups for analyses of isometric tension development under standard conditions in physiological salt solution (PSS) containing indomethacin, (5 microM; to inhibit cyclooxygenase). Initial tension placed on each tissue is 2 grams, which is maintained throughout the 45 minute equilibration period. Tissues are washed with PSS at 15 minute intervals. After the 45 minute equilibration period, 3.times.10.sup.-2 M KCl is applied for 60 minutes to test tissue viability. The tissues are then washed extensively for 30 minutes. The concentration of the Compound being tested is then added for 30 minutes before constructing a cumulative concentration-response curve with BANK. The curve is considered complete when each tissue fails to contract further for 2 consecutively increasing BANK concentrations. BaCl.sub.2 (3.times.10.sup.-2 M ) is then added to produce a maximum reference contraction. Percent inhibition is determined when a tested Compound produces a statistically significant reduction in the magnitude of maximum contraction and is calculated as a percentage of the BaCl.sub.2 reference response. For antagonists behaving competitively, potencies are determined by calculating the negative log value of the apparent dissociation constant (pK.sub.B) for each concentration tested. Statistical significance is determined when the P value is <0.05 using the Student's t-test for paired comparisons. In general, the Compounds of the invention having NK2 antagonist activity which were tested demonstrated statistically significant values of the negative log apparent dissociation constant in Test E with a pK.sup.B value of 6 or much greater typically being measured. NK.sub.1 and NK.sub.2 in vivo functional assay (Test F) The activity of a compound as an antagonist of NK1 and/or NK2 receptors also may be demonstrated in vivo in laboratory animals as described in: Buckner et al. "Differential Blockade by Tachykinin NK1 and NK2 Receptor Antagonists of Bronchoconstriction Induced by Direct-Acting Agonists and the Indirect-Acting Mimetics Capsaicin, Serotonin and 2-Methyl-Serotonin in the Anesthetized Guinea Pig." J. Pharm. Exp. Ther., 1993, Vol 267(3), pp 1168-1175. The assay is carried out as follows. Compounds are tested in anesthetized guinea pigs pretreated with i.v. indomethacin (10 mg/kg, 20 min.), propranolol (0.5 mg/kg, 15 min.), and thiorphan (10 mg/kg, 10 min). Antagonists or vehicle are administered i.v. and orally, 30 and 120 minutes prior to increasing concentrations of agonist, respectively. The agonists used in these studies are ASMSP (Ac-[Arg.sup.6, Sar.sup.9, Met(O.sub.2).sup.11 ]-SP(6-11)) and BANK (.beta.-ala-8 NKA4-10). Administered i.v., ASMSP is selective for NK.sub.1 receptors, and BANK is selective for NK.sub.2 receptors. Maximum response is defined as zero conductance (G.sub.L, 1/Rp). ED.sub.50 values are calculated (the dose of agonist resulting in a reduction of G.sub.L to 50% of baseline), and converted to the negative logarithm (-logED.sub.50). The ED.sub.50 values, obtained in the presence (P) and absence (A) of antagonist, are used to calculate a Dose Ratio (P/A), an expression of potency. Data are expressed as mean.+-.SEM and statistical differences were determined using ANOVA/Tukey-Kramer and Student's t-test, with p<0.05 considered statistically significant. Compounds of the present invention exhibit marked activity in the foregoing tests and are considered useful for the treatment of those diseases in which the NK1 and/or NK2 receptor is implicated, for example, in the treatment of asthma and related conditions. Results of testing of representative compounds of the present invention by the above methods are presented in the Table I. TABLE I Test D Test E Test F Example NK1pKb NK2pKb NK1 P/A NK2 P/A 1 8.99 8.26 32.5 (2 hr) 21.4 (2 hr) 2 8.1 8.7 25.0 (2 hr) 83.0 (2 hr) 36 8.13 7.86 45.0 (1 hr) 20.6 (1 hr) Clinical Studies Because of the range of effects attributable to the actions of SP, NKA and NKB, compounds which are capable of blocking their actions may also be useful as tools for further evaluating the biological actions of other neurotransmitters in the tachykinin family. As a result, another feature of the invention is provided by the use of a compound of Formula I or a salt or precursor thereof as a pharmacological standard for the development and standardization of new disease models or assays for use in developing new therapeutic agents for treating diseases in which SP or NKA are implicated or for assays for their diagnosis. |
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