HK1103073B - Substituted diaza-spiro-[5.5-undecane derivatives and their use as neurokinin antagonists - Google Patents

Description

Substituted diaza-spiro- [5.5] -undecane derivatives and their use as neurokinin antagonists

Technical Field

The invention relates to compounds having neurokinin antagonistic activity, in particular NK₁Antagonistic Activity, Combined NK₁/NK₂Antagonistic Activity, Combined NK₁/NK₃Antagonistic Activity and Combined NK₁/NK₂/NK₃Substituted diaza-spiro- [5.5] with antagonistic activity]Undecane compounds, their preparation, compositions containing them and their use as a medicine, in particular for the treatment and/or prevention of the following disorders: schizophrenia, emesis, anxiety and depression, Irritable Bowel Syndrome (IBS), circadian rhythm disturbances, pre-eclampsia, nociception, pain, in particular visceral and neuropathic pain, pancreatitis, neurogenic inflammation, asthma, Chronic Obstructive Pulmonary Disease (COPD) and micturition disorders such as urinary incontinence.

Background

Tachykinins belong to a family of short peptides widely distributed in the mammalian central and peripheral nervous systems (Bertrand and Geppetti, Trends Pharmacol. Sci.17: 255-. They contain the common C-terminal sequence Phe-Xaa-Gly-Leu-Met-NH 2. Tachykinins released from peripheral nerve endings are thought to be associated with neurogenic inflammation, and within the spinal cord/central nervous system, tachykinins play a role in pain transmission/sensation and some autonomic reflexes and behaviors. Three importantThe tachykinins of (A) are Substance P (SP), neurokinin A (NKA) and neurokinin B (NKB) which have preferential affinity for three direct neurokinin receptor subtypes, respectively designated NK₁、NK₂And NK₃. However, functional studies on cloned receptors have shown strong functional cross-interactions between 3 tachykinins and their corresponding neurokinin receptors (Maggi and Schwartz, Trends Pharmacol. Sci.18: 351-355 (1997)).

In NK₁Species differences in receptor structure and species-related NK₁Differences in the effects of antagonists have been implicated (Maggi, Gen. Pharmacol.26: 911-944 (1995); Regoli et al, Pharmacol. Rev.46 (4): 551-599 (1994)). Human NK₁Receptor and guinea pig and gerbil NK₁Receptors very similar to NK of rodents₁The receptors are distinctly different. The development of neurokinin antagonists has so far been a series of peptide compounds whose metabolism can be expected to be too unstable to be used as pharmaceutically active substances (Longmore j. et al, DN)&P 8(1)：5-23(1995))。

Tachykinins are associated with schizophrenia, depression, (stress-related) anxiety disorders, emesis, inflammatory responses, smooth muscle contraction and pain sensation. Neurokinin antagonists are being developed for indications such as emesis, anxiety and depression, Irritable Bowel Syndrome (IBS), circadian rhythm disturbances, visceral pain, neurogenic inflammation, asthma, micturition disorders and nociception. In particular, NK₁Antagonists have high therapeutic potential for emesis and depression, and NK₂Antagonists have a high therapeutic potential in the treatment of asthma. NK₃Antagonists appear to play a role in the treatment of pain/inflammation (Giardina, G. et al exp. Opin. Ther. patents, 10 (6): 939-960(2000)) and schizophrenia.

Schizophrenia

NK₃The antagonist SR142801(Sanofi) has recently been shown to have antipsychotic activity in schizophrenic patients without affecting negative symptoms (Arvantis, l.acnp Meeting, December 2001). NK₁Activation of receptors causes anxiety, stressful events cause increased plasma levels of Substance P (SP), and NK has been reported₁Antagonists have anxiolytic effects in several animal models. NK from Merck₁The antagonist, MK-869, showed antidepressant effects in major depression, but no conclusions were drawn due to the higher placebo response rate data. Furthermore, NK from Glaxo-Welcome₁The antagonist (S) -GR205,171 was shown to increase dopamine release in the frontal cortex rather than in the striatum (Lejeune et al soc. neurosci, November 2001). Therefore, assume NK₃Antagonists and NK₁The combination of antagonists will be beneficial against both the positive and negative symptoms of schizophrenia.

Anxiety and depression

Depression is one of the most common affective disorders in modern society, with a higher and still increasing prevalence, particularly in young people. Currently, the prevalence of major depression (MDD, DSM-IV) is estimated to be 10-25% in women and 5-12% in men, while life-span MDD will recur in about 25% of patients, with no complete internal attack recovery and overlapping dysthymic disorder. Depression has a higher co-morbidity with other psychiatric disorders, and especially in young people associated with drug and alcohol abuse. Since depression mainly affects the population between the ages of 18 and 44, i.e. the most productive population, it is clear that it constitutes a high burden on individuals, families and the whole society.

Of all the treatment possibilities, there is no discussion of the most effective treatment with antidepressants. A number of antidepressants have been developed and marketed in the last 40 years. However, none of the existing antidepressants meets all criteria for an ideal drug (high therapeutic and prophylactic efficacy, fast acting, fully meeting short-and long-term safety, simple and good pharmacokinetics) or has no side effects, which to one or other extent limits its use in all depressed patient groups or subgroups.

Since there is currently or recently no treatment of the etiology of depression, and no antidepressant is effective in more than 60-70% of patients; it is reasonable to develop new antidepressants that can prevent the disadvantages of the available drugs.

Several studies have shown that SP is associated with stress-related anxiety disorders. Central injection of SP causes a cardiovascular response resembling the classical "combat or flight" response, which is physiologically characterized by vasodilation of skeletal muscle, decreased mesenteric and renal blood flow. This cardiovascular response is seen in rodents following noxious stimuli or stress as a concomitant behavioral response (Culman and Unger, Can.J.Physiol.Pharmacol.73: 885-891 (1995)). In mice, central involvement with NK₁Agonists and antagonists increase and decrease anxiety, respectively (Teixeira et al, Eur. J. Pharmacol.311: 7-14 (1996)). NK₁The ability of the antagonist to inhibit SP (or shock; Ballard et al, Trends Pharmacol. Sci.17: 255-259(2001)) induced knockdown may correspond to this antidepressant/anxiolytic activity, since knockdown plays a role in the alteration or warning signal for the homogeneity in gerbils.

NK₁Receptors are widely distributed in the limbic system of the brain and in fear-processing pathways of the brain, including the amygdala, hippocampus, septum, hypothalamus, and periaqueductal gray. In addition, substance P is released centrally in response to traumatic or noxious stimuli, and substance P-associated neurotransmission may lead to or be involved in anxiety, fear and affective disorders accompanied by affective disorders such as depression and anxiety. In support of this view, changes in substance P content in individual brain regions may be observed in response to stress stimuli (Brodin et al, neuropeps 26: 253-260 (1994)).

Central injection of substances like P (agonists) induces defensive behavior and cardiovascular changes including conditioned space shift (Elliott, exp. brain. Res.73: 354-. These compounds do not alterThe motors of the variable rotation devices act either in coordination or movement within the activity cage. Substance P biosynthesis is down regulated in response to administration of known anxiolytic and antidepressant drugs (Brodin et al, Neuropeptides 26: 253-260 (1994); Shirayama et al, brain. Res.739: 70-78 (1996)). Similarly, NK administration was central in guinea pigs₁The agonist-induced vocalization may be induced by antidepressants such as imipramine and fluoxetine and L-733,060, an NK₁Antagonistic by an antagonist. Evidence provided by these studies suggests that central NK blockade₁The receptor can suppress psychological stress by similar antidepressants and anxiolytics (Rupniak and Kramer, trends pharmacol. sci.20: 1-12(1999)), but without the side effects of current drug therapy.

Vomiting

Nausea and vomiting are among the most distressing side effects of cancer chemotherapy. This reduces the quality of life and causes the patient to delay or reject potential therapeutic drugs (Kris et al, j. clin. oncol., 3: 1379-. The incidence, intensity and pattern of emesis is determined by various factors, such as the chemotherapeutic agent, dose and route of administration. Typically, early or acute emesis begins within the first 4 hours after chemotherapy administration, peaks in 4-10 hours, and decreases in 12-24 hours. Delayed emesis (occurring 24 hours after chemotherapy and continuing to 3-5 days) was observed in the most "hyperemetic" chemotherapeutic drugs (grades 4 and 5, according to Hesketh et al, j.clin.oncol.15: 103 (1997)). In humans, these "high-emetic" anticancer treatments, including cisplatin, cause acute emesis in > 98% of cancer patients and delayed emesis in 60-90%.

Animal models of chemotherapy, such as cisplatin-induced emesis in ferrets (Rudd and Naylor, Neuropharmacology 33: 1607-₃The in situ effect of the receptor antagonist. Although this finding led to successful treatment of chemotherapy and radiation-induced emesis in cancer patients, 5-HT₃Antagonists such as ondansetron and granisetron(both or neither in combination with dexamethasone) effectively controls the acute emetic phase (the first 24 hours) and only slows the progression of delayed emesis (> 24 hours) with very low efficiency (De Mulder et al, AnnualsofInternal Medicine 113: 834-840 (1990); Roila, Oncology 50: 163-167 (1993)). Despite the most effective treatments for preventing acute and delayed emesis, 50% of the older patients suffer from delayed emesis and/or nausea (anenetic Subcommittee, Annals Oncol.9: 811-819 (1998)).

And 5-HT₃Antagonist opposite, NK₁Antagonists such as CP-99,994(Piedimonte et al, L. Pharmacol. Exp. Ther.266: 270-273(1993)) and aprepitant (also known as MK-869 or L-754,030; Kramer et al, Science 281: 1640-1645 (1998); Rupniak and Kramer, Trends Pharmacol. Sci.20: 1-12(1999)) have now been shown to inhibit not only the acute but also the delayed phase of cisplatin-induced emesis in animals (Rudd et al, Br. J. Pharmacol.119: 931-936 (1996); Tarterall et al, Neuropharmacology 39: 652-663 (2000)). NK without concomitant treatment in humans₁Antagonists have also been shown to reduce the delay of emesis (Cocquyt et al, Eur. J. cancer 37: 835-842 (2001); Navari et al, N.Engl. L. Med.340: 190-195 (1999)). Furthermore, when combined with dexamethasone and 5-HT₃When the antagonists are administered together, NK has been demonstrated₁Antagonists such as MK-869 and CJ-11,974, also known as eplerenone (Ezlopitant), produce additive effects in the prevention of acute emesis (Campos et al, J. Clin. Oncol.19: 1759-.

In regulating emesis, central neurokinin NK₁Receptors play an important role. NK₁Antagonists have activity against a variety of emetic stimuli (Watson et al, Br. J. Pharmacol.115: 84-94 (1995); Tattersall et al, neuropharmacol.35: 1121-1129 (1996); Megens et al, J. Pharmacol. exp. Ther.302: 696-709 (2002)). Studies have shown that these compounds act by blocking central NK cells in the solitary bundle nucleus₁-a receptor. Except NK₁In addition to antagonism, CNS penetration is the antiemetic activity of these compoundsA prerequisite for sex. Loperamide-induced emesis in ferrets may be used as a rapid and reliable inspection model for NK₁Antiemetic activity of the antagonist. Further evaluation of their therapeutic value in the treatment of acute and delayed phases of cisplatin-induced emesis has been demonstrated in established ferret models (Rudd et al, br.j. pharmacol.119: 931-936 (1994)). This model investigated 'acute' and 'delayed' emesis after cisplatin use and has been confirmed for 5-HT₃Receptor antagonists, glucocorticoids (Sam et al, Eur. J. Pharmacol. 417: 231-237(2001)) and other pharmacologically evoked sensitivities. It is considered unlikely that any antiemetic agent in the future will find clinical acceptance unless the 'acute' and 'delayed' emesis of emesis is successfully treated.

Visceral pain and Irritable Bowel Syndrome (IBS)

Visceral sensation refers to all sensory mailboxes originating in the viscera (heart, lungs, gastrointestinal tract, liver biliary tract, and genitourinary tract), and is transmitted to the central nervous system resulting in conscious perception. The vagus nerve through the nodose ganglion and the major sympathetic afferents through the Dorsal Root Ganglion (DRG) and the secondary neurons of the dorsal horn all serve as the initial pathways along which visceral sensory information is transmitted to the brainstem and visceral somatic cortex. Visceral pain can be caused by the process of neoplasia (e.g. pancreatic cancer), inflammation (e.g. cholecystitis, peritonitis), ischemia and mechanical obstruction (e.g. urinary tract stones).

The main basis for the pharmacotherapy of visceral pain associated with organic functional disorders, in particular visceral cancer, is still focused on opiates.

Existing evidence suggests that non-organic visceral disorders such as Irritable Bowel Syndrome (IBS), non-cardiac chest pain (NCCP) and chronic pelvic disease may originate from a state of "visceral hyperalgesia". The latter is defined as a state in which conscious pain perception is caused by physiological non-painful visceral stimulation (e.g. intestinal distension) due to a reduced pain threshold. Visceral hyperalgesia may reflect a state of permanent post-inflammatory recovery of the membrane depolarization threshold of the neural synapses within visceral sensory channels. Initial inflammation may occur at the periphery (e.g. infectious gastroenteritis) or at the site of integration of sensory information in the gut (neurogenic in the dorsal horn). SP and calcitonin gene-related peptide (CGRP) have been demonstrated as pro-inflammatory neuropeptides in neurogenic inflammation.

Visceral hyperalgesia is currently considered as one of the main objectives in the development of drugs for the treatment of functional bowel diseases, which occur in 15-25% of the western population. They constitute a huge socio-economic problem in terms of medical care costs, punishment costs and absenteism. Existing treatments include antispasmodics (IBS and NCCP), prokinetic agents (e.g. tegasolod in constipation-IBS), laxatives (constipation-IBS) and loperamide (diarrhea-IBS). None of these methods has proven to be very effective, especially in the treatment of pain. In pain predominant IBS, low dose tricyclic antidepressants and SSRIs are used to treat visceral hyperalgesia, and both classes of compounds are considered to pass through the colon. Continued research in the field has identified a variety of molecular targets for use as drug development in visceral hyperalgesia. These include NK receptors, CGRP receptors, 5-HT₃Receptors, glutamate receptors and kappa opioid receptors. Ideally, a "visceral analgesic compound" should prevent the transmission of elevated sensations from the viscera to the CNS without affecting the normal physiological autoregulation of the gastrointestinal tract with respect to propulsive peristaltic activity, absorption and secretion and sensation. There is strong evidence linking tachykinin to visceral nociceptive signaling systems. NK in relation to visceral pain and visceral hyperalgesia₁、NK₂And NK₃Receptor action, numerous preclinical publications indicate NK₁、NK₂And NK₃The receptor is in conflict between different rodent models of inflammatory allergy. Recently, Kamp et al, j.pharmacol.exp.ther.299: 105-113(2001) suggested that the combined neurokinin receptor antagonists are more active than the selected neurokinin receptor antagonists. Substance P and NK₁、NK₁And NK₃The receptors are increased in clinical pain states, packageBrackish pain states (Lee et al, Gastroenterol.118: A846 (2000)). Due to recent NK₁Receptor antagonists have failed as analgesics in human pain tests (Goldstein et al, Clin. pharm. Ther.67: 419-426(2000)), a combination of antagonists is necessary to exert a significant clinical effect. NK₃The receptor antagonist is an anti-hyperalgesic agent (Julia et al, gastroenterol.116: 1124-1131 (1999)); pharmacol. exp. ther.299: 105-113(2001)). Recently, NK has been demonstrated to be involved in spinal cord in visceral hyperalgesia mediated by nociceptive and non-nociceptive afferent signals₁And NK₃Receptors other than NK₂Receptor (Gaudreau)&Ploudre, neurosci.lett.351: 59-62(2003). Thus, combine NK_1-2-3Antagonistic activity may represent a valuable therapeutic target for the development of novel visceral hyperalgesia treatments.

NK of visceral pain₁The effects of receptors are published in a reasonable number of preclinical publications. Use of NK in animal models₁Receptor knockout mice and NK₁Antagonists, different groups, have been shown to play important roles in hyperalgesia and in the gut, not the body. NK₁The distribution of receptors and substance P is beneficial for important functions in the gut rather than in the body. In fact, more than 80% of the viscera primarily pass into the substance containing P, while only 25% of the skin passes into it. NK₁Receptors are also involved in gastrointestinal motility (Tonini et al, Gastroenterol.120: 938-945 (2001); Okano et al, J.Phannacol.Exp.Ther.298: 559-564 (2001)). NK because of its dual role in gastrointestinal motility and pain₁Antagonists are considered to have potential symptom-ameliorating effects in IBS patients.

Urinary incontinence

Acute urinary incontinence is caused by hyperreflexia of the bladder or detrusor ("irritable bladder"). This hyperreflexia refers to hyperexcitability of the sensory afferent C-fibers of the bladder that protrude from the spinal cord. The origin of C-fiber hyperexcitability is multifactorial, but occurs, for example, after bladder infection and long-term distension of the bladder wall (e.g., benign prostatic hypertrophy, BPH). Thus, it is possible to provideTreatment should be directed to reducing neuronal hyperexcitability. Intravesical instillations of vanilloids (e.g., capsaicin) result in long-term beneficial effects in detrusor hyperreflexia refractory to conventional treatment with anticholinergic drugs. Similar to animal studies, the effects of vanilloids are mediated by neurotoxic effects of sensory nerve endings. In the human bladder, the subendothelial sensory nerves contain tachykinins that propel detrusor hyperreflexia. The latter is alleged to contribute to bladder hyperreflexia in the spine. Thus, centrally acting NH₁NK with peripheral action₂Antagonists are preferred for use in the treatment of detrusor hyperreflexia. Interestingly, NK activation₂The receptor increases the activity of aromatase in Sertoli cells. NK₂Receptor antagonists reduce mouse serum testosterone levels, and this may be of therapeutic importance in the treatment of BPH.

Background of the prior art

Compounds containing a piperidinyl moiety substituted with a piperidinyl or pyrrolidinyl moiety are disclosed in WO97/24324 (10/7/1997), WO 97/24350 (10/7/1997) and WO97/24356 (10/7/1997), all patents to Janssen pharmaceutical n.v., as substance P (neurokinin) antagonists. Compounds containing a substituted diazaspiro [4.5] decyl moiety are disclosed in WO01/94346 to F.Hoffinan-La Roche AG (12.13.2001) for use as neurokinin receptor antagonists.

The compounds of the present invention differ structurally from the compounds of the prior art in that they all comprise piperidinyl substituted by diaza-spiro- [5.5] -undecyl and in that they have an improved ability as therapeutically valuable, potent, oral and centrally active neurokinin antagonists, especially for the treatment and/or prevention of schizophrenia, emesis, anxiety and depression, Irritable Bowel Syndrome (IBS), circadian rhythm disturbances, pre-eclampsia, nociception, pain, especially visceral and neuropathic pain, pancreatitis, neurogenic inflammation, asthma, COPD and micturition disorders such as urinary incontinence.

Description of the invention

The present invention relates to novel substituted diaza-spiro- [5.5] -undecane derivatives of the general formula (I)

A pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, an N-oxide form thereof and a prodrug thereof, wherein:

R²is Ar²、Ar²Alkyl, bis (Ar)²) Alkyl, Het¹Or Het¹-an alkyl group;

x is a covalent bond or a group of formula-O-, -S-or-NR³-a divalent group of (a);

q is O or NR³；

Each R³Independently of one another, hydrogen or alkyl;

R¹selected from Ar¹、Ar¹Alkyl and bis (Ar)¹) -an alkyl group;

n is an integer equal to 0, 1 or 2;

m is an integer equal to 1 or 2, with the proviso that if m is 2, then n is 1;

z is a covalent bond or the formula-CH₂-or a divalent group > C (═ O);

j. k, p, q are integers independently of each other equal to 0, 1, 2, 3 or 4; provided that each of (j + k) and (p + q) equals 4;

t is ═ O in the alpha position with respect to the N-atom, and T is an integer equal to 0 or 1;

each Alk represents, independently of each other, a covalent bond; a divalent linear or branched saturated or unsaturated hydrocarbon group having 1 to 6 carbon atoms; or a cyclic saturated or unsaturated hydrocarbon group having 3 to 6 carbon atoms; each of said groups being optionally substituted on one or more carbon atoms with one or more of phenyl, halogen, cyano, hydroxy, formyl and amino;

y is a covalent bond or a group of the formula-C (═ O) -, -SO₂A divalent radical-CH-R or-N-R, where R is H, CN or nitro;

l is selected from the group consisting of hydrogen, alkyl, alkenyl, alkoxy, alkoxyalkoxy, alkylcarbonyloxy, alkoxycarbonyl, mono-and di (alkyl) amino, mono-and di (alkoxycarbonyl) amino, mono-and di (alkylcarbonyl) amino, mono-and di (Ar)³) Amino, mono-and di (Ar)³Alkyl) amino, mono-and di (Het)²) Amino, mono-and di (Het)²Alkyl) amino, alkylthio, norbornyl, adamantyl, tricycloundecyl, Ar³、Ar³-oxy, Ar³Carbonyl group, Het²Het-oxo, Het²Carbonyl and mono-and di (Het)²Carbonyl) amino;

Ar¹is phenyl, which is optionally substituted by 1, 2 or 3 substituents each independently of the others selected from the group consisting of: halogen, alkyl, cyano, aminocarbonyl and alkoxy;

Ar²is naphthyl or phenyl, each of said groups being optionally substituted with 1, 2 or 3 substituents independently of each other selected from the group consisting of: halogen, nitro, amino, mono-and di (alkyl) amino, cyano, alkyl, hydroxy, alkoxy, carboxy, alkoxycarbonyl, aminocarbonyl and mono-and di (alkyl) aminocarbonyl;

Ar³is naphthyl or phenyl, each of said groups being optionally substituted with 1, 2 or 3 substituents independently of each other selected from the group consisting of: alkoxy, alkylcarbonylamino, methylsulfonyl, Ar¹Carbonyloxyalkyl, Ar¹Alkoxycarbonyl, Ar¹Alkoxyalkyl, alkyl, halogen, hydroxy, pyridyl, morpholinyl, pyrrolyl, pyrrolidinyl, imidazo [1, 2-a]Pyridyl radicalMorpholinylcarbonyl, pyrrolidinylcarbonyl, amino and cyano;

Het¹is a monocyclic heterocyclic group selected from: pyrrolyl, pyrazolyl, imidazolyl, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl; or a bicyclic heterocyclic group selected from: quinolyl, quinoxalyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl, benzothienyl, indanyl, and chromenyl; wherein each monocyclic and bicyclic heterocyclic group may be optionally substituted on any atom by one or more groups each independently of the other selected from halogen, oxo and alkyl;

Het²is a monocyclic heterocyclic group selected from: pyrrolidinyl, dihydro-2H-pyranyl, dioxolyl, imidazolidinyl, tetrahydropyridinyl, tetrahydropyrimidinyl, pyrazolidinyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, imidazolidinyl, tetrahydrofuranyl, 2H-pyrrolyl, pyrrolinyl, imidazolinyl, pyrazolinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, furanyl, thienyl, oxazolyl, dioxazolyl, oxazolidinyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, pyridyl, 1H-pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, and tetrazolyl;

or a bicyclic heterocyclic group selected from: 2, 3-dihydro-benzo [1, 4 ]]Dioxins, octahydro-benzo [1, 4 ]]Dioxins, octabicycloheptyl, benzodipiperidinyl, quinolinyl, quinoxalinyl, indolyl, isoindolyl, chromanyl, benzimidazolyl, imidazo [1, 2-a ]]Pyridyl, benzoxazolyl, benzodioxolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl, dihydroisobenzofuranyl, or benzothienyl; wherein each monocyclic and bicyclic heterocyclic group may be optionally substituted on any atom by one or more groups selected from: ar (Ar)¹、Ar¹Alkyl radical, Ar¹Alkoxyalkyl, halogen, hydroxy, alkyl, piperidinyl, pyrrolyl, thienyl, oxo, alkoxy, alkylcarbonyl, Ar¹Carbonyl, mono-and di (alkyl) aminoalkyl, alkoxyalkyl and alkoxycarbonyl;

alkyl is a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms; each hydrocarbyl group is optionally substituted on one or more carbon atoms with one or more groups selected from: phenyl, halogen, trihalomethyl, aminocarbonyl, methyl, ethyl, propyl, isopropyl, tert-butyl, cyano, oxo, hydroxy, formyl and amino; and is

The alkenyl group is a straight or branched unsaturated hydrocarbon group having 1 to 6 carbon atoms and having one or more unsaturated bonds; or a cyclic unsaturated hydrocarbon group having 3 to 6 carbon atoms and having one or more unsaturated bonds; each hydrocarbyl group is optionally substituted on one or more carbon atoms with one or more groups selected from: phenyl, halogen, cyano, oxo, hydroxy, formyl and amino.

More particularly, the present invention relates to compounds of general formula (I), the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the N-oxide form thereof and prodrugs thereof, wherein:

R²is Ar²、Ar²-alkyl or Het¹；

X is a covalent bond;

q is O;

R¹is Ar¹-an alkyl group;

n is an integer equal to 1;

m is an integer equal to 1;

z is a covalent bond or the formula-CH₂-or a divalent group > C (═ O);

j. k, p, q are integers independently of one another equal to 1, 2 or 3; provided that (j + k) and (p + q) are equal to 4;

t is an integer equal to 0 or 1;

each Alk represents, independently of each other, a covalent bond; a divalent linear or branched saturated or unsaturated hydrocarbon group having 1 to 6 carbon atoms; or a cyclic saturated or unsaturated hydrocarbon group having 3 to 6 carbon atoms; each of said groups being optionally substituted with hydroxy;

y is a covalent bond or a group of formula-C (═ O) -or-SO₂-a divalent group of (a);

l is selected from the group consisting of hydrogen, alkyl, alkenyl, alkoxy, norbornyl, tricycloundecyl, Ar³、Ar³-oxy, Het²And mono-and di (Het)²Carbonyl) amino;

Ar¹is phenyl, said phenyl being optionally substituted with 2 halogens;

Ar²is naphthyl or phenyl, each of said radicals being optionally substituted by 1, 2 or 3 substituents which are independently of one another and are selected from the group consisting of halogen, cyano, alkyl and alkoxy;

Ar³is phenyl, said phenyl being optionally substituted with one substituent selected from the group consisting of: alkoxy, alkylcarbonylamino, methanesulfonyl, alkyl, halogen, pyrrolyl and cyano;

Het¹is a monocyclic heterocyclic group selected from: pyrrolyl, furyl, thienyl, pyridyl and pyrazinyl; or a bicyclic heterocyclic group selected from quinolinyl and indolyl; wherein each monocyclic and bicyclic heterocyclic group may be optionally substituted on any atom by one or more alkyl groups;

Het²is a monocyclic heterocyclic group selected from: pyrrolidinyl, dihydro-2H-pyranyl, tetrahydropyridyl, tetrahydropyrimidinyl, pyrrolyl, imidazolyl, furanyl, thienyl, oxazolidinyl, isoxazolyl, thiadiazolyl, pyridyl, 1H-pyridyl, pyrazinyl, pyridazinyl, and tetrazolyl;

or a bicyclic heterocyclic group selected from: octabicycloheptyl, quinoxalinyl, benzimidazolyl, benzodioxolyl, benzoxadiazolyl, benzofuranyl or dihydroisobenzofuranyl; wherein each monocyclic and bicyclic heterocyclic group may be optionally substituted on any atom by one or more groups selected from halo, alkyl, oxo, and alkoxycarbonyl;

alkyl is a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms; each hydrocarbyl group is optionally substituted on one or more carbon atoms with one or more groups selected from: trihalomethyl, aminocarbonyl, methyl, tert-butyl and cyano; and is

The alkenyl group is a cyclic unsaturated hydrocarbon group having 3 to 6 carbon atoms and having 1 unsaturated bond.

More particularly, the present invention relates to compounds of general formula (I), the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the N-oxide form thereof and prodrugs thereof, wherein the spiro moiety has one of the following formulae (f1) to (f9), wherein all variables are as defined in formula (I), and "a" refers to the piperidinyl moiety of formula (I) and "b" refers to the Alk-Y-Alk-L-moiety of formula (I):

more particularly, the present invention relates to compounds of general formula (I), the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the N-oxide form thereof and prodrugs thereof, wherein the spiro moiety has the formula (f1) (wherein j, k, p and q are equal to 2), f2 (wherein j and k are equal to 2; p is equal to 1 and q is equal to 3) and f12 (wherein j and q are equal to 1 and k and p are equal to 3).

More particularly, the present invention relates to compounds of general formula (I), the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the N-oxide form thereof and prodrugs thereof, wherein R¹Is Ar¹Methyl, and is attachedIn the 2-position, or R¹Is Ar¹And is attached at the 3-position, as exemplified by the following formula for compounds of formula (I) wherein m and n are equal to 1, and Ar is unsubstituted phenyl. Preferably, Ar¹Methyl is benzyl.

More particularly, the present invention relates to compounds of general formula (I), the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the N-oxide form thereof and prodrugs thereof, wherein R²-X-C (═ Q) -moiety is 3, 5-bis- (trifluoromethyl) phenylcarbonyl.

More particularly, the present invention relates to compounds of general formula (I), the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the N-oxide form thereof and prodrugs thereof, wherein m and N are both equal to 1.

More particularly, the present invention relates to compounds of general formula (I), the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the N-oxide form thereof and prodrugs thereof, wherein Y is-C (═ O) -.

More particularly, the present invention relates to compounds of general formula (I), the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the N-oxide form thereof and prodrugs thereof, wherein Alk is a covalent bond or-CH₂-。

More particularly, the present invention relates to compounds of general formula (I), the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the N-oxide form thereof and prodrugs thereof, wherein L is cyclopropyl.

More particularly, the present invention relates to compounds of general formula (I), the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the N-oxide form thereof and a prodrug thereof, wherein said compounds are the compounds having compound numbers 132, 100, 92, 93, 3, 4 and 119 as described in any one of tables 1 to 7 of the present application.

In the context of this application, alkyl is defined as a monovalent straight-chain or branched saturated hydrocarbon radical having from 1 to 6 carbon atoms, such as methyl, ethyl, propyl, butyl, 1-methylpropyl, 1-dimethylethyl, pentyl, hexyl; alkyl is also defined as a monovalent cyclic saturated hydrocarbon group having 3 to 6 carbon atoms, such as cyclopropyl, methylcyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The definition of alkyl also includes alkyl optionally substituted on one or more carbon atoms with one or more of the following groups: phenyl, halogen, cyano, oxo, hydroxy, formyl and amino, for example hydroxyalkyl, in particular hydroxymethyl and hydroxyethyl, and perhaloalkyl, in particular difluoromethyl and trifluoromethyl.

In the context of the present application, alkenyl is defined as a monovalent straight-chain or branched unsaturated hydrocarbon radical having from 1 to 6 carbon atoms and having one or more unsaturated bonds, such as, for example, methyl alkenyl, vinyl, propenyl, butenyl, 1-methylpropenyl, 1-dimethylvinyl, pentenyl and hexenyl; alkenyl is also defined as a monovalent cyclic unsaturated hydrocarbon group having 3 to 6 carbon atoms and having one or more unsaturated bonds, such as cyclopropenyl, methyl-cyclopropenyl, cyclobutenyl, cyclopentenyl and cyclohexenyl. The definition of alkenyl also includes alkenyl optionally substituted on one or more carbon atoms with one or more of the following groups: phenyl, halogen, cyano, oxo, hydroxy, formyl and amino, for example hydroxyalkenyl, in particular hydroxyvinyl and hydroxyethyl, and perhaloalkyl, in particular difluoromethyl and trifluoromethyl.

In the context of this application, halogen means fluorine, chlorine, bromine and iodine.

In the context of the present application, "compound of the invention" means a compound of general formula (I), a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, an N-oxide form thereof and a prodrug thereof.

In the context of the present application, in particular in Alk of the formula (I)^a-Y-Alk^bIn a section, when two or more of said sections are consecutive to constitute a unit tableWhen a covalent bond is indicated, it means one covalent bond. For example, when Alk^aAnd Y both represent a covalent bond, and Alk^bis-CH₂When, then Alk^a-Y-Alk^bPart represents-CH₂-. Similarly, if Alk^aY and Alk^bRespectively represent a covalent bond, and L represents H, then Alk^a-Y-Alk^bThe moiety-L represents-H.

Pharmaceutically acceptable salts are defined to include the therapeutically active non-toxic acid addition salt forms which the compounds of formula (I) are able to form. Said salts may be obtained by treatment of the base form of the compounds of formula (I) with a suitable acid, for example an inorganic acid such as hydrohalic acid, especially hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acids; organic acids such as acetic, glycolic, propionic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic and pamoic acids.

The compounds of formula (I) containing acidic protons may also be converted into their therapeutically active non-toxic metal or amine addition salt forms by treatment with suitable organic and inorganic bases. Suitable base salt forms comprise, for example, ammonium salts, alkali metal and alkaline earth metal salts, especially lithium, sodium, potassium, magnesium and calcium salts, organic base salts, such as hexadimethrine, N-methyl-D-glucosamine, hydrabamine salts, and amino acid salts, such as arginine and lysine.

Conversely, said salt forms can be converted into the free form by treatment with a suitable base or acid.

The term addition salt as used in the context of this application also includes solvates which the compounds of formula (I) and salts thereof may form. For example, these solvates are hydrates and alcoholates.

The N-oxide forms of the compounds of formula (I) are meant to comprise those compounds of formula (I) wherein one or several nitrogen atoms are oxidized to the so-called N-oxides, in particular those N-oxides wherein one or more tertiary nitrogens (e.g. piperazinyl or piperidinyl) are N-oxidized. The N-oxides are readily available to the skilled person without any inventive skill and are clearly alternatives to the compounds according to formula (I) since these compounds are metabolized and are formed by oxidation after ingestion in the human body. It is well known that oxidation is usually the first step in drug metabolism (Textbook of Organic medical and Pharmaceutical Chemistry, 1977, p.70-75). It is well known that metabolite forms of the compounds can also be administered to humans in place of the drugs themselves, with similar effects.

The compounds of the present invention have at least 2 oxidizable nitrogen atoms (tertiary amine moieties). N-oxides are therefore likely to be formed in human metabolism.

The compounds of formula (I) may be converted to the corresponding N-oxide form using methods known in the art for converting a trivalent nitrogen atom to its N-oxide form. Said N-oxidation reaction can be generally carried out by reacting the starting material of formula (I) with a suitable organic or inorganic peroxide. Suitable inorganic peroxides include, for example, hydrogen peroxide, alkali or alkaline earth metal peroxides, such as sodium peroxide, potassium peroxide; suitable organic peroxides include peroxy acids such as benzene peroxy acid or halogenated benzene peroxy acids, for example 3-chlorobenzoic acid, peroxy alkanoic acids, for example peracetic acid, alkyl hydroperoxides, for example tert-butyl hydroperoxide. Suitable solvents are, for example, water, lower alkanols, such as ethanol and the like, hydrocarbons, such as toluene, ketones, such as 2-butanone, halogenated hydrocarbons, such as methylene chloride, and mixtures of these solvents.

The term "stereochemically isomeric forms" as used hereinbefore defines all the possible isomeric forms which the compounds of formula (I) may possess. Unless otherwise indicated or indicated, the chemical name of a compound refers to the mixture of all possible stereochemically isomeric forms having that name, said mixtures containing all diastereomers and enantiomers of the basic molecular structure. More particularly, the stereocenter may have the R-or S-configuration; the substituents on the divalent cyclic (partially) saturated groups may have either the cis-or trans-configuration. Compounds containing a double bond may have E or Z-stereochemistry at said double bond. Stereochemically isomeric forms of the compounds of formula (I) are expressly included within the scope of the present invention.

According to CAS nomenclature conventions, when two stereocenters of known absolute configuration are present in a molecule, the R or S label is named (based on Cahn-Ingold-Prelog order rule) to the lowest-numbered chiral center, i.e., the reference center. R and S each represent optically pure stereocenters of undetermined absolute configuration. If "α" and "β" are used: in the ring system of the smallest number of rings, the position of the highest priority substituent on an asymmetric carbon atom is always the "α" position on the average plane determined by the ring system.

The position of the highest priority substituent on other asymmetric carbon atoms in the ring system (hydrogen atom in compounds of formula (I)) relative to the position of the highest priority substituent on the reference atom is referred to as "α" if it is on the same side of the mean plane defined by the ring system or "β" if it is on the other side of the mean plane defined by the ring system.

The compounds of formula (I) and some of the intermediate compounds have at least two stereogenic centers in their structure.

The invention also comprises derivative compounds of the pharmacologically active compounds according to the invention (often referred to as "prodrugs") which decompose in vivo to the compounds of the invention. Prodrugs are generally (but not always) less potent at targeting receptors than the compounds into which they break down. Prodrugs are particularly useful when the desired compound has chemical or physical properties that make its administration difficult or ineffective. For example, the desired compound may only be poorly soluble, it may not be readily transported across the mucosal epithelium, or it may have a short plasma half-life. Further review of Prodrugs can be found in Stella, V.J. et al, "Prodrugs", Drug Delivery Systems, 1985, pp.112-176, and Drugs, 1985, 29, pp.455-473.

The prodrug forms of the pharmacologically active compounds according to the invention are generally compounds of the formula (I) which contain esterified or amidated acid groups and which may contain esterified or amidated acid groupsPharmaceutically acceptable acid or base addition salts, stereochemically isomeric forms thereof and N-oxidized form thereof. Such esterified acidic groups are of the formula-COOR^xA group shown in the formula, wherein R^xIs C_1-6Alkyl, phenyl, benzyl or one of the following groups:

amidated groups include the formula-CONR^yR^zA group shown in the formula, wherein R^yIs H, C_1-6Alkyl, phenyl or benzyl, and R^zis-OH, H, C_1-6Alkyl, phenyl or benzyl. The compounds containing amino groups according to the invention can be derivatized with ketones or aldehydes, such as formaldehyde, to form Mannich bases. The base is hydrolyzed in aqueous solution with first order kinetics.

The compounds of formula (I) prepared in the following processes may be synthesized in the form of racemic mixtures of enantiomers which can be separated from each other according to resolution methods known in the art. Racemic compounds of formula (I) can be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. The diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization, and the enantiomers are liberated therefrom by base. An alternative method for separating the enantiomeric forms of the compounds of formula (I) is liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably, if a particular stereoisomer is desired, the compound can be synthesized by stereospecific methods of preparation. These methods suitably employ enantiomerically pure starting materials.

Pharmacology of

Substance P and other tachykinins are involved in a variety of biological activities such as pain transmission (nociception), neurogenic inflammation, smooth muscle contraction, plasma protein extravasation, vasodilation, mast cell degranulation, and immune system activation. There are a number of diseases which are thought to be caused by activation of Neurokinin Receptors, particularly the NK1 receptor, with excessive release of substance P and other neurokinins by neurons in specific cells such as the gastrointestinal tract from, unmyelinated primary sensory input neurons, sympathetic and sympathomimetic and non-neuronal cell types (DN & P8 (1): 5-23 (1995)) and Longmore J. et al, "Neurokinin Receptors" Pharmacological Reviews46 (4): 551-599 (1994)).

The compounds of the invention are potent inhibitors of neurokinin-mediated effects, especially those mediated by NK₁、NK₂And NK₃Receptor-mediated effects, and termed neurokinin antagonists, particularly substance P antagonists, are demonstrated in vitro by antagonizing substance P-induced coronary vasodilation in pigs. The affinity of the compounds for human, guinea pig and gerbil neurokinin receptors may also be used in vitro³Substance H-P is measured as a radioligand in a receptor binding assay. The test compounds also show substance P antagonistic activity in vivo and can be demonstrated, for example, by antagonising substance P-induced plasma extravasation in guinea pigs or antagonism-induced emesis in ferrets (Watson et al, Br. J. Pharmacol.115: 84-94 (1995)).

Due to their ability to antagonize the action of tachykinins by blocking neurokinin receptors, in particular by blocking NK₁、NK₂And NK₃The receptors, the compounds of the invention are useful as pharmaceuticals, particularly in the prevention and treatment of tachykinin-mediated conditions. In particular, the compounds of the present invention are useful as orally active, centrally penetrating agents in the prevention and treatment of tachykinin mediated conditions.

More particularly, it has been found that certain compounds exhibit combined NK₁/NK₂Antagonistic Activity, Combined NK₁/NK₃Antagonistic Activity or Combined NK₁/NK₂/NK₃Antagonistic activity, as can be seen in table 10 of the experimental section.

The present invention therefore relates to compounds of general formula (I), their pharmaceutically acceptable acid or base addition salts, their stereochemically isomeric forms, their N-oxide forms and prodrugs thereof, for use as a medicament.

The invention also relates to the use of a compound of general formula (I), the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the N-oxide form thereof and a prodrug thereof for the manufacture of a medicament for the prevention or treatment of tachykinin-mediated disorders.

The compounds of the invention are useful in the treatment of CNS disorders, in particular schizoaffective disorders, depression, anxiety, stress-related disorders, sleep disorders, cognitive disorders, personality disorders, affective dysfunctions, eating disorders, neurodegenerative diseases, addictive disorders, mood disorders, sexual dysfunction, pain and other CNS-related conditions; inflammation; allergic conditions; vomiting; gastrointestinal disorders, particularly Irritable Bowel Syndrome (IBS); skin disorders; vasospasm disorders; fibrotic and collagenous diseases; diseases associated with immune enhancement or suppression, as well as rheumatic diseases and weight control.

In particular, the compounds of the invention are useful in the treatment or prevention of schizoaffective disorders, including manic, depressive or mixed schizoaffective disorders; paranoid delusions, disorganized, catatonic, undifferentiated, and residual forms of schizophrenia; schizophreniform disorder; schizoaffective disorder; delusional disorder; brief psychotic disorder; shared mental disorder; substance-induced psychotic disorder and other psychotic disorders not specifically identified.

In particular, the compounds of the present invention are useful in the treatment or prevention of depression including, but not limited to, major depressive disorder including bipolar depression; unipolar depression; with or without psychotic features, stressor features, melancholic features, atypical features of postpartum onset, and single or recurrent depressive episodes with or without seasonal patterns at the time of relapse. Other mood disorders encompassed within the term "major depressive disorder" include early or late onset dysthymic character with or without atypical animals, bipolar I disorder, bipolar II disorder, cyclothymic disorder, recurrent brief depression, mixed mood disorder, functional depression, post traumatic stress disorder and social phobia; early or late onset dementia of the alzheimer's type with a low mood; vascular dementia with low emotion ; substance-induced mood disorders such as mood disorders including alcohol, amphetamine, cocaine, hallucinogens, inhalants, opioids, phencyclidine, sedatives, hypnotics, anxiolytics, and other substances; schizoaffective disorder of the depressed type; and adaptation disorders with depressed mood. Major depressive disorders may also result from general health conditions including, but not limited to, myocardial infarction, diabetes, or miscarriage.

In particular, the compounds of the present invention are useful for the treatment or prevention of anxiety disorders, including but not limited to panic attacks; agoraphobia; panic disorder without agoraphobia; history of terrorism in the field; specific fear; social fear; obsessive compulsive disorder; post-traumatic stress disorder; acute stress disorder; generalized anxiety disorder; anxiety disorders caused by general health conditions; substance-induced anxiety disorder and unspecified anxiety disorder.

In particular, the compounds of the present invention are useful for the treatment or prevention of stress-related disorders associated with depression and/or anxiety, including but not limited to acute stress; accommodation disorders such as transient depressive response, long-term depressive response, mixed anxiety and depressive response, accommodation disorders that significantly interfere with other mood, accommodation disorders that significantly interfere with other behavior, accommodation disorders that interfere with mixed mood and behavior, accommodation disorders with other specific symptoms; and other reactions to severe stress.

In particular, the compounds of the invention are useful for the treatment or prevention of sleep disorders, including but not limited to dysmnia and/or parasomnia as the major sleep disorder; insomnia; sleep apnea; narcolepsy; disorders of circadian rhythm; sleep disorders associated with other psychiatric disorders; sleep disorders caused by general health conditions; and substance-induced sleep disorders.

In particular, the compounds of the present invention are useful for the treatment or prevention of cognitive disorders, including but not limited to dementia; amnesia and non-other cognitive disorders of the herdsman, in particular dementia caused by degenerative disorders, injuries, wounds, infections, vascular disorders, toxins, hypoxia, vitamin deficiencies or endocrine disorders; early or late onset alzheimer's dementia with depressed mood; AIDS-related dementia or amnesia due to the following causes: alcohol or thiamine deficiency, bilateral temporal lobe damage caused by herpes simplex and other limbic encephalitis, hypoxia/hypoglycemia/severe convulsions and neuronal loss following surgery, degenerative disorders, vascular disease or other causes of pathology around the ventricle III. Furthermore, the compounds of the invention are also useful for memory and/or cognition enhancement in healthy people without cognitive and/or memory deficits.

In particular, the compounds of the present invention are useful for treating or preventing personality disorders, including, but not limited to, paranoid personality disorder, schizophreniform personality disorder, antisocial personality disorder, borderline personality disorder, performance-like personality disorder, self-attaching personality disorder, avoidance personality disorder, dependency personality disorder, obsessive-compulsive personality disorder, and other personality disorders not otherwise specified.

In particular, the compounds of the invention are useful in the treatment or prevention of eating disorders including anorexia nervosa, atypical anorexia nervosa, bulimia nervosa, atypical bulimia nervosa; excessive eating associated with other psychological disturbances; emesis associated with other psychological disturbances; and unspecified eating disorders.

In particular, the compounds of the present invention are useful for the treatment or prevention of neurodegenerative diseases, including but not limited to alzheimer's disease; huntington's chorea; Creutzfeld-Jacob disease; pick's disease; demyelinating disorders, such as multiple sclerosis and ALS; other neuropathies and neuralgia; multiple sclerosis; amyotrophic lateral sclerosis; stroke and head trauma.

In particular, the present invention relates toThe compounds are useful for the treatment or prevention of addictive disorders including, but not limited to, substance dependence or abuse with or without physical dependence, particularly where the trait is alcohol, amphetamine-like substances, caffeine, cocaine, hallucinogen, inhalants, nicotine, opioids (such as cannabis, heroin and morphine), phencyclidine-like substances, sedative-hypnotics, benzodiazepinesAnd/or other substances, especially for the treatment of withdrawal from the above-mentioned substances and alcohol withdrawal delirium.

In particular, the compounds of the present invention are useful for the treatment or prevention of mood disorders, particularly mood disorders caused by alcohol, amphetamines, caffeine, cocaine, hallucinogens, inhalants, nicotine, opioids, phencyclidine, sedatives, hypnotics, anxiolytics, and others.

In particular, the compounds of the present invention are useful for the treatment or prevention of sexual dysfunction, including but not limited to, sexual desire disorders, sexual arousal disorders, orgasmic disorders, dyspareunia disorders; sexual dysfunction due to general health; substance-induced sexual dysfunction and other sexual dysfunctions not specifically specified.

In particular, the compounds of the present invention are useful for the treatment or prevention of pain, including but not limited to traumatic pain such as post-operative pain; traumatic avulsion pain such as brachial plexus; chronic pain such as pancreatitis-induced chronic pain or arthritis pain such as that which occurs in bone-rheumatoid or psoriatic arthritis; neuropathic pain such as postherpetic neuralgia, trigeminal neuralgia, segmental or intercostal neuralgia, fibromyalgia, causalgia, peripheral neuropathy, diabetic neuropathy, chemotherapy-induced neuropathy, AIDS-related neuropathy, occipital neuralgia, geniculate ganglionic neuralgia, glossopharyngeal neuralgia, sympathetic reflex dystrophy, and limb pain; various forms of headache such as migraine, acute or chronic tension headache, temporomandibular pain, maxillary sinus pain and cluster headache; toothache; cancer pain; visceral pain; gastrointestinal pain; the spirit is subjected to tenderness; sports injury pain; dysmenorrhea; menstrual pain; meningitis arachnoiditis; musculoskeletal pain; lumbago such as spinal stenosis, prolapse of lumbar intervertebral disc, sciatica, angina, ankylosing spondylitis; gout; burns; scar pain; itching; thalamic pain such as post-stroke thalamic pain.

In particular, the compounds of the present invention may be used for the treatment or prevention of the following other CNS-related disorders: akinesia, akinesia-stiff syndrome, dyskinesia and pharmacotherapy-induced parkinson's disease, tourette's syndrome and its symptoms, tremor, chorea, myoclonus, tics and dystonia, Attention Deficit Hyperactivity Disorder (ADHD), parkinson's disease, drug-induced parkinsonism, postencephalitic parkinsonism, progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration, parkinsonian-ALS dementia complications and basal ganglia calcification, behavioural disorders and conduct disturbances in dementia and intellectual developmental delay, including restlessness and agitation, extrapyramidal movement disorders, down's syndrome and akathisia.

In particular, the compounds of the present invention are useful in the treatment or prevention of inflammation, including but not limited to inflammatory conditions in asthma, influenza, chronic bronchitis, and rheumatoid arthritis; inflammatory conditions in the gastrointestinal tract, such as, but not limited to, crohn's disease, ulcerative colitis, inflammatory bowel disease, and non-steroidal anti-inflammatory drug-induced injury; inflammatory states of the skin such as herpes and eczema; inflammatory conditions of the bladder such as cystitis and urinary incontinence; and inflammation of the eye and teeth and pancreatitis, especially chronic and acute pancreatitis.

In particular, the compounds of the present invention are useful for the treatment or prevention of allergic conditions, including but not limited to allergic conditions of the skin such as but not limited to urticaria; and allergic conditions such as, but not limited to, rhinitis.

In particular, the compounds of the present invention are useful in the treatment or prevention of emesis, i.e., nausea, retching and vomiting, including but not limited to acute emesis, delayed emesis and anticipatory emesis; emesis induced by drugs such as cancer chemotherapeutic drugs such as alkylating agents, e.g., cyclophosphamide, carmustine, lomustine and chlorambucil; cytotoxic antibiotics, such as actinomycin D, doxorubicin, mitomycin C and bleomycin; antimetabolites such as cytarabine, methotrexate and 5-fluorouracil; vinblastines such as etoposide, vinblastine and vincristine; and cisplatin, dacarbazine, procarbazine and hydroxyurea among others; and combinations thereof; radiation sickness; metabolic therapy, such as in the treatment of cancer; toxicants; toxins such as those released during metabolic diseases or infections such as gastritis, or bacterial or viral gastrointestinal infections; pregnancy; vestibular disorders such as motion sickness, vertigo, dizziness, and meniere's disease; post-operative disease; obstruction of the stomach and intestine; decreased gastrointestinal motility; visceral pain, such as myocardial infarction and intestinal peritonitis; migraine headache; an increase in intracranial pressure; a decrease in intracranial pressure (e.g., alpine); narcotic analgesics, such as morphine; gastro-esophageal reflux disease; acid dyspepsia; overeating or eating food; hyperacidity; acid stomach; acid regurgitation/regurgitation; heartburn, such as paroxysmal heartburn, nocturnal heartburn, and food-induced heartburn; and dyspepsia.

In particular, the compounds of the present invention are useful for treating or preventing gastrointestinal disorders, including but not limited to Irritable Bowel Syndrome (IBS), skin disorders such as psoriasis, pruritus and sunburn; vasospastic disorders such as angina, vascular headache and Reynaud's disease, cerebral vasospasm following cerebral trauma such as subarachnoid hemorrhage; fibrotic and collagenous diseases such as scleroderma and eosinophilic fascioliasis; diseases associated with immune enhancement or suppression such as systemic lupus erythematosus and rheumatic cold and heat diseases such as fibrositis; cough; and weight control, including obesity.

More particularly, the compounds of the invention are also useful for the preparation of a medicament for the treatment and/or prevention of schizophrenia, emesis, anxiety and depression, Irritable Bowel Syndrome (IBS), circadian rhythm disturbances, pre-eclampsia, nociception, pain, in particular visceral and neuropathic pain, pancreatitis, neurogenic inflammation, asthma, Chronic Obstructive Pulmonary Disease (COPD) and micturition disorders such as urinary incontinence.

The present invention also relates to methods of treating and/or preventing the following disorders: schizophrenia, emesis, anxiety and depression, Irritable Bowel Syndrome (IBS), circadian rhythm disorders, pre-eclampsia, nociception, pain, particularly visceral and neuropathic pain, pancreatitis, neurogenic inflammation, asthma, Chronic Obstructive Pulmonary Disease (COPD) and micturition disorders such as urinary incontinence, comprising administering to a human in need thereof an effective amount of a compound of the present invention, particularly a compound of formula (I), pharmaceutically acceptable acid or base addition salts thereof, stereochemically isomeric forms thereof, N-oxide forms thereof and prodrugs thereof.

The invention also relates to pharmaceutical compositions comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound of the invention, especially a compound of formula (I), pharmaceutically acceptable acid or base addition salts thereof, stereochemically isomeric forms thereof, N-oxide form thereof and prodrugs thereof.

The compounds of the present invention, especially the compounds of formula (I), their pharmaceutically acceptable acid or base addition salts, their stereochemically isomeric forms, their N-oxide forms and prodrugs thereof, or any subgroup or combination thereof may be formulated into various pharmaceutical preparations for administration purposes. Suitable compositions which may be exemplified are all compositions which are normally used for systemic administration of drugs. To prepare the pharmaceutical compositions of this invention, an effective amount of a particular compound, optionally in addition salt form, is intimately admixed with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in a suitable single dosage form, especially for oral, rectal, transdermal, injectable or inhaled administration. For example, the compositions are prepared in oral formulations, and with respect to oral liquid preparations such as suspensions, syrups, elixirs, emulsions and solutions, any of the usual pharmaceutical media may be employed such as water, glycols, oils, alcohols and the like; for powders, pills, capsules and tablets, solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents and the like. Because of their ease of administration, tablets and capsules represent the most convenient oral dosage unit form in which solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will typically comprise sterile water, at least most of which, although other ingredients may be included, for example to increase solubility. Solutions for injection, for example, carriers that can be used for preparation include saline solutions, glucose solutions, or mixed solutions of saline and glucose solutions. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. Also included are solid form preparations for conversion to liquid form preparations immediately prior to use. In compositions suitable for transdermal administration, the carrier optionally comprises a penetration enhancer and/or a suitable wetting agent, optionally in combination with a suitable minor proportion of additives that do not impart a significant deleterious effect to the skin. The additives may facilitate administration to the skin and/or may aid in the preparation of the desired composition. The compositions may be administered by various routes, for example as a transdermal patch, as a spot-on, as an ointment.

The pharmaceutical composition is particularly suitable for being prepared into unit dosage forms for convenient administration and uniform dosage. As used herein, unit dosage form refers to discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored and coated tablets), capsules, pills, powder packets, wafers, suppositories, injectable solutions and suspensions and the like, and segregated multiples thereof.

Because the compounds of the invention are orally active, predominantly centrally active NK' s₁、NK₁/NK₂、NK₁/NK₃And NK₁/NK₂/NK₃Antagonists, pharmaceutical compositions comprising said compounds are particularly advantageous for oral administration.

Synthesis of

The compounds of the invention can generally be prepared by successive steps, each of which is known to those skilled in the art.

The final compound of formula (Ia) is conveniently prepared by reductive N-alkylation of the intermediate compound of formula (II) with the intermediate compound of formula (III). The reductive N-alkylation may be carried out in a reaction inert solvent such as dichloromethane, ethanol or toluene or mixtures thereof and in the presence of a suitable reducing agent such as a borohydride, for example sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride. When a borohydride is used as the reducing agent, a complex forming agent such as titanium (IV) isopropoxide, described in J.org.chem, 1990, 55, 2552-. The use of the complex-forming agent may also lead to an improved cis/trans ratio, favouring the formation of the trans isomer. It is also convenient to use hydrogen as a reducing agent in combination with a suitable catalyst such as palladium on carbon or platinum on carbon. When hydrogen is used as reducing agent, it may be advantageous to add a dehydrating agent, for example aluminum tert-butoxide, to the reaction mixture. In order to prevent undesired further hydrogenation of some functional groups in the reactants and reaction products, it may also be advantageous to add suitable catalyst poisons, such as thiophene or quinoline-sulphur, to the reaction mixture. Stirring and optionally elevated temperature and/or pressure may increase the reaction rate.

In this and the following preparations, the reaction product may be isolated from the reaction medium and, if desired, further purified according to methods generally known in the art, such as extraction, crystallization, trituration and chromatography.

The final compound of formula (Ib) is conveniently prepared by reductive N-alkylation of the intermediate compound of formula (IV) with the intermediate compound of formula (III). The reductive N-alkylation may be carried out in a reaction inert solvent such as dichloromethane, ethanol or toluene or mixtures thereof and in the presence of a suitable reducing agent such as a borohydride, for example sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride. When a borohydride is used as the reducing agent, a complex forming agent such as titanium (IV) isopropoxide, described in J.org.chem, 1990, 55, 2552-. It is also convenient to use hydrogen as a reducing agent in combination with a suitable catalyst such as palladium on carbon or platinum on carbon. When hydrogen is used as reducing agent, it may be advantageous to add a dehydrating agent, for example aluminum tert-butoxide, to the reaction mixture. In order to prevent undesired further hydrogenation of some functional groups in the reactants and reaction products, it may also be advantageous to add suitable catalyst poisons, such as thiophene or quinoline-sulphur, to the reaction mixture. Stirring and optionally elevated temperature and/or pressure may increase the reaction rate.

The final compound of formula (Ic) is conveniently prepared by reacting the carboxylic acid compound of formula (V) with the intermediate compound of formula (III). The reaction is conveniently carried out in a reaction inert solvent such as a chlorinated hydrocarbon, for example dichloromethane, in the presence of a suitable base such as sodium carbonate, sodium bicarbonate or triethylamine, and in the presence of an activating agent such as DCC (dicyclohexylcarbodiimide), CDI (carbonyldiimidazole) and EDCI (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide. HCl). Stirring can increase the reaction rate. The reaction can be conveniently carried out at room temperature to reflux temperature.

It is particularly advantageous to prepare the final compounds of any of the formulae (Ia), (Ib) and (Ic) according to the above reaction scheme by reacting a compound of formula (II), (IV) or (V) with a compound of formula (III) wherein the Alk-Y-Alk-L-moiety is benzyl (formula (XI)), thereby producing a compound wherein the Alk-Y-Alk-L-moiety is benzyl. The final compounds are pharmacologically active and can be converted into the final compounds of the formula (I') in which the Alk-Y-Alk-L-moiety is hydrogen by reductive hydrogenation using, for example, hydrogen as reducing agent in combination with a suitable catalyst such as palladium on charcoal or platinum on charcoal. The resulting final compounds of the invention can then be converted to other compounds of formula (I) by art-known transformations such as acylation and alkylation.

In particular, the final compound of formula (Id) can be prepared by reacting a final compound of formula (I') with W wherein¹Is a suitable leaving group such as a halogen, e.g. chlorine or bromine, or a sulfonyloxy leaving group, e.g. methanesulfonyloxy or benzenesulfonyloxy. The reaction may be carried out in a reaction-inert solvent, for example a chlorinated hydrocarbon such as dichloromethane or a ketone such as methyl isobutyl ketone, and in the presence of a suitable base such as sodium carbonate, sodium bicarbonate or triethylamine. Stirring can increase the reaction rate. The reaction can be conveniently carried out at room temperature to reflux temperature.

Alternatively, the final compound of formula (Id) may be prepared by reacting the final compound of formula (I') with a carboxylic acid of formula (VII). The reaction may be carried out in a reaction inert solvent such as a chlorinated hydrocarbon, for example dichloromethane, in the presence of a suitable base such as sodium carbonate, sodium bicarbonate or triethylamine, and in the presence of an activating agent such as DCC (dicyclohexylcarbodiimide), CDI (carbonyldiimidazole) and EDCI (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide. HCl). Stirring can increase the reaction rate. The reaction can be conveniently carried out at room temperature to reflux temperature.

The final compound of formula (Ie) may be prepared by reacting a final compound of formula (I') with W in formula (VIII) wherein²Is a suitable leaving group such as a halogen, e.g. chlorine or bromine, or a sulfonyloxy leaving group, e.g. methanesulfonyloxy or benzenesulfonyloxy. The reaction may be carried out in a reaction-inert solvent such as a chlorinated hydrocarbon, e.g. dichloromethane, an alcohol, e.g. ethanol, or a ketone, e.g. methyl isobutyl ketone, and in the presence of a suitable base, e.g. sodium carbonate, sodium bicarbonate or triethylamine. Stirring can increase the reaction rate. The reaction can be conveniently carried out at room temperature to reflux temperature.

The final compound of formula (If) can be prepared by reductive N-alkylation of the intermediate compound of formula (I') with the intermediate compound of formula (IX). The reductive N-alkylation may be carried out in a reaction inert solvent such as dichloromethane, ethanol or toluene or mixtures thereof and in the presence of a suitable reducing agent such as a borohydride, for example sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride. When a borohydride is used as the reducing agent, a complex forming agent such as titanium (IV) isopropoxide, described in J.org.chem, 1990, 55, 2552-. It is also convenient to use hydrogen as a reducing agent in combination with a suitable catalyst such as palladium on carbon or platinum on carbon. When hydrogen is used as reducing agent, it may be advantageous to add a dehydrating agent, for example aluminum tert-butoxide, to the reaction mixture. In order to prevent undesired further hydrogenation of some functional groups in the reactants and reaction products, it may also be advantageous to add suitable catalyst poisons, such as thiophene or quinoline-sulphur, to the reaction mixture. Stirring and optionally elevated temperature and/or pressure may increase the reaction rate.

The final compound of formula (Ig) is obtained by Tetrahedron, 1997, 53, 16463-16470; from the Boronic Mannich reaction described in J.Am.chem.Soc.1998, 120, 11798-11799 or Tetrahedron Letters, 2002, 43, 5965-5968, conveniently using an intermediate compound of formula (I') with intermediate compounds (X) and (XI), wherein Y in formula (X) is a divalent radical of formula-CH 2-or > C (═ O), and W in formula (XI) is hydrogen or an alkyl chain. The BoronicMannich reaction can be carried out in a "one-pot" reaction regime using a saccharide of formula (X) or a dimer thereof with an arylboronic acid or arylboronic acid ester of formula (XI) in a reaction-inert solvent such as dichloromethane, ethanol or 2, 2, 2-trifluoroethanol or mixtures thereof. Stirring can increase the reaction rate. The reaction can be conveniently carried out at room temperature to reflux temperature.

The following examples are intended to illustrate but not limit the scope of the invention.

Experimental part

Hereinafter, "RT" means room temperature, "CDI" means 1, 1 '-carbonyldiimidazole, "DIPE" means diisopropyl ether, "MIK" means methyl isobutyl ketone, and "BINAP" means [1, 1' -binaphthyl]-2, 2' -diylbis [ diphenylphosphine]"NMP" means 1-methyl-2-pyrrolidone, "Pd₂(dba)₃"refers to tris (dibenzylideneacetone) dipalladium," DMF "refers to N, N-dimethylformamide," EDCI "refers to 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride," HOBT "refers to hydroxybenzotriazole.

Preparation of intermediate compounds

Example A1

a. Preparation of intermediate Compound 1

Adding Et₃N (0.55mol) to 7- (phenylmethyl) -1, 4-dioxa-8-azaspiro [ 4.5%]Decane (0.5mol) in a stirred mixture of toluene (1500 ml). 3, 5-bis (trifluoromethyl) benzoyl chloride (0.5mol) was added over 1 hour (exothermic reaction). The mixture was stirred at room temperature for 2 hours, then left to stand for the weekend and washed 3 times with water (500ml, 2X 250 ml). The organic layer was separated, dried, filtered and the solvent was evaporated. Yield: 245g (100%). 2g of this fraction was crystallized from petroleum ether to obtain 1g of intermediate compound 1 (50%).

b. Preparation of intermediate Compound 2

HClcp (300ml) was added to intermediate compound 1(0.5mol) in ethanol (300ml) and H₂In a mixture of O (300 ml). The reaction mixture was stirred at 60 ℃ for 20 hours. Filtering off the precipitate, grinding, and purifying in H₂Stirred in O, filtered, washed with petroleum ether and dried. Yield: 192g of the intermediate Compound 2 ((+ -) -1- [3, 5-bis (trifluoromethyl) benzoyl]-2- (phenylmethyl) -4-piperidone) (89.4%) (mixture of R and S enantiomers).

c. Preparation of intermediate Compound 3 and intermediate Compound 4

By chiral column chromatography using Chiralpak (CHIR ALPAK AS)20mm (DAICEL); eluent: hexane/2-propanol 70/30) to separate intermediate compound 2 into its optical isomers. Two product fractions were collected and the solvent was evaporated separately. Obtained from fraction 1: 32.6g of intermediate compound 3(R), obtained from fraction 2: 30.4g of intermediate compound 4 (S).

Example A2

a. Preparation of intermediate Compound 5

A mixture of 1- (phenylmethyl) -4, 4-piperidinediacetic acid hydrochloride (0.214mol) and urea (0.149mol) was stirred at 180 ℃ for 1 hour. EtOH and saturated sodium bicarbonate were added. The precipitate was filtered off and dried. EtOH was evaporated. Subjecting the mixture to CH reaction₂Cl₂And (4) extracting. The organic layer was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue (20g) was purified by silica gel column chromatography (eluent: CH)₂Cl₂/CH₃OH/NH₄OH 99/1/0.1; 20-45 μm). Two fractions were collected and the solvent was evaporated. Yield: 4.4g of intermediate compound 5.

a. Preparation of intermediate Compound 6

LiAlH was reacted at 5 ℃₄(0.463mol) were added portionwise to THF (400 ml). Intermediate compound 5(0.077mol) was portionwise added. Mixing the above materialsThe mixture was stirred at 5 ℃ for 15 minutes, then warmed to room temperature, stirred and refluxed for 8 hours. Slowly adding cold H₂And O. The mixture was filtered through celite. Mixing diatomaceous earth with CH₂Cl₂And (6) washing. The filtrate is treated with CH₂Cl₂And (4) extracting. The organic layer was separated and dried (MgSO)₄) Filtered and the solvent evaporated. Yield: 13.7g of intermediate compound 6 (72%).

Example A3

a. Preparation of intermediate Compound 7

Reaction under nitrogen atmosphere. A mixture of (methoxymethyl) triphenylphosphonium chloride (0.0055mol) and N- (1-methylethyl) -2-propylamine (0.0083mol) in anhydrous THF, p.a. (20ml) was stirred at-70 ℃. 2.5M BuLi in hexane (0.0055mol) was added dropwise. 2.5M BuLi in hexane (2.2ml) was added. The mixture was allowed to warm to room temperature. The reaction mixture was stirred at 20 ℃ for 30 minutes. The mixture was cooled to-25 ℃ again. A solution of intermediate compound 3 (prepared according to a1. c) (0.005mol) in some anhydrous THF, p.a. was added dropwise and the reaction mixture was allowed to warm to room temperature. The reaction mixture was stirred at room temperature overnight and then decomposed with water. Evaporating the organic solvent and subjecting the aqueous concentrate to CH₂Cl₂And (4) extracting. The separated organic layer was dried, filtered and the solvent was evaporated. The residue is purified by chromatography on silica gel (eluent: CH)₂Cl₂). The desired fractions were collected and the solvent was evaporated. Yield: 1.30g of intermediate compound 7 (57%).

b. Preparation of intermediate Compound 8

A mixture of intermediate compound 7(0.0028mol) in 1.6N HCl (6ml) and THF (6ml) was stirred at 40 ℃ for 1 hour. THF is evaporated and the aqueous concentrate is taken up with CH₂Cl₂And (4) extracting. The separated organic layer was washed with aqueous sodium carbonate solution, dried, filtered and the solvent was evaporated. Yield: 1.24g of intermediate compound 8 (100%, used directly in the next reaction step without further purification).

c. Preparation of intermediate Compound 9

Adding the intermediate compound 8(0.0081mol) into CH₃The mixture in CN (p.a.) (20ml) was stirred on an ice bath to obtain mixture (I). Dissolving in H at < 10 deg.C₂NaOCl in O (20ml)₂(0.00975mol) was added dropwise to the mixture (I). The reaction mixture was stirred at < 10 ℃ for 20 hours and at room temperature for 2 hours. NaOH (25ml, 10%) was added dropwise to the mixture at room temperature and the reaction mixture was washed with DIPE (2 times). The aqueous layer was acidified with HCl (10%) at < 10 ℃ and then with CH₂Cl₂And (4) extracting. The organic layer was dried (MgSO₄) And filtered. The solvent was evaporated and the residue was crystallized from DIPE. Yield: 3.0g of intermediate compound 9 (80%).

Example A4

a. Preparation of intermediate Compound 10

A mixture of ethyl 2- [ (3, 4-dichlorophenyl) methyl ] -4-oxo-1-piperidinecarboxylate (0.3mol), 1, 2-ethanediol (1.5mol) and 4-methylbenzenesulfonic acid (2g) in toluene (750ml) was stirred and refluxed for 68 hours using a water trap. The solvent was evaporated. The residue was partitioned between water and toluene. The organic layer was separated, washed with water, dried, filtered and the solvent was evaporated. Yield: 113.5g of intermediate compound 10.

b. Preparation of intermediate Compound 11

A mixture of intermediate compound 10 (prepared according to A4. a) (0.1mol) and KOH (0.9mol) in 2-propanol (500ml) was stirred and refluxed overnight. The solvent was evaporated. Dissolving the residue in CH₂Cl₂Then using a small amount of H₂And O washing. The organic layer was dried, filtered and the solvent was evaporated. Yield: 33g of intermediate compound 11.

c. Preparation of intermediate Compounds 12 and 13

Intermediate Compound 11 (prepared according to A4. b) (0.139mol) was dissolved in CH₂Cl₂(420 ml). 3, 5-bis (trifluoromethyl) benzoyl chloride (0.15mol) was added dropwise. Adding CH₂Cl₂(30 ml). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with 50% NaOH, water, then dried, filtered and the solvent was evaporated. The residue is purified by chromatography on silica gel (gradient eluent: CH)₂Cl₂/CH₃OH 100/0-95/5). The product fractions were collected and the solvent was evaporated. The residue was crystallized from DIPE, filtered and dried. Yield: 56.3g fraction 1. The filtrate was evaporated. The residue was suspended in petroleum ether, filtered and dried. Yield: 9g fraction 2. The fractions were separated and purified by chiral column chromatography (AD, 3-g injection; eluent: heptane/ethanol 95/5). Two product fractions were collected and their solvents were evaporated. Removing each residue from the DIPE crystallized, filtered and dried. Yield: 23.9g of intermediate compound 12 and 28.5g of intermediate compound 13.

d. Preparation of intermediate Compound 14

A mixture of intermediate compound 12 (prepared according to A4. c) (0.0424mol) in HCl (6N) (230ml) was stirred and refluxed for 4 hours, then the reaction mixture was stirred overnight and CH was used₂Cl₂And (4) extracting. The organic layer was separated, washed with water, dried and the solvent was evaporated. Yield: 20g of intermediate compound 14.

Example A5

a. Preparation of intermediate Compound 15

A solution of ethyl acetate (0.22mol) in THF (200ml) was added to a solution of nBuLi, 1.6M (0.178mol) and diisopropylamine 0.1365mol) in THF (100ml) at-78 ℃ under a stream of nitrogen. The mixture was stirred for 30 minutes. Adding at-78 deg.C

(prepared according to the teaching in Helvetica Chimica Acta, (1972), 55(7), p2432-8, which is incorporated herein)) (0.105mol) in THF (300 ml). The mixture was stirred for 2 hours. Addition of H₂And O. The mixture was extracted with EtOAc. The organic layer was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue (60g) was subjected to silica gel column chromatographyPurification (eluent: cyclohexane/EtOAc 60/40). The pure fractions were collected and the solvent was evaporated. Yield: 9.8g of intermediate compound 15 (25%).

b. Preparation of intermediate Compound 16

Intermediate compound 15(0.026mol) and LiCl (0.052mol) in DMSO (100ml) and H₂The mixture in O (10ml) was stirred at 200 ℃ for 2 hours. Addition of H₂And O. The mixture was extracted with EtOAc. The organic layer was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue (10g) was purified by column chromatography on silica gel (eluent: cyclohexane/EtOAc 60/40; 15-40 μm). The pure fractions were collected and the solvent was evaporated. Yield: 6.7g of intermediate compound 16 (86%).

c. Preparation of intermediate Compound 17

Intermediate compound 16(0.022mol) and NiRa (6.7g) were added to CH₃The mixture in OH (100ml) was hydrogenated at 3 bar pressure at room temperature overnight and then filtered through celite. The filtrate was evaporated. The residue (7.5g) was purified by silica gel column chromatography (gradient eluent: CH)₂Cl₂/CH₃OH/NH₄OH 98/2/0-85/15/1). Yield 2.7g (46%).

d. Preparation of intermediate Compound 18

Mixing the intermediate compound17(0.0104mol) and Pd/C (0.3g) in CH₃The mixture in OH (30ml) was hydrogenated at 50 ℃ under 4 bar pressure and then filtered through celite. Mixing diatomaceous earth with CH₂Cl₂And (6) washing. The filtrate was evaporated. Yield: 1.9g of intermediate compound 18 (100%). Preparation of the final Compound

Example B1

a. Preparation of Final Compound 1

Intermediate compound 3 (prepared according to A1. c) (0.02mol), 3- (phenylmethyl) -3, 9-diazaspiro- [5.5]Undecane (0.02mol) and Ti (iPrO)₄A mixture of (0.035mol) in 1, 2-dichloroethane (80ml) was stirred at 50 ℃ overnight and then warmed to room temperature under a stream of nitrogen. Add NaBH (OAc) in portions₃(0.035 mol). The mixture was stirred at room temperature for 8 hours, and poured into ice water. Adding K₂CO₃10 percent. The mixture was filtered through celite, with CH₂Cl₂And (6) washing. The filtrate is treated with CH₂Cl₂And (4) extracting. The organic layer was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue (26g) was purified by silica gel column chromatography (gradient eluent: CH)₂Cl₂/CH₃OH/NH₄OH 95/5/0.5-90/10/1; 20-45 μm). The 3 fractions were collected and the solvent was evaporated.

Yield: 1.8g of final compound 1 (15%).

b. Preparation of Final Compound 5

Intermediate compound 3 (prepared according to A1. c) (0.033mol), 3- (phenylmethyl) -3,9-diazaspiro- [5.5]Undecane (0.033mol), Ti (iPrO)₄(0.036mol) and Pd/C (1.5g) in a mixture of thiophene (1ml) and methanol (150ml) were hydrogenated at 5 bar pressure at 50 ℃ for 18 h and then filtered through celite. The filtrate is treated with CH₃And (5) OH washing. The filtrate was evaporated to dryness. Dissolving the residue in CH₂Cl₂In (1). Adding K₂CO₃10 percent. The mixture was stirred at room temperature for 30 minutes and then filtered through celite. Mixing diatomaceous earth with CH₂Cl₂And (6) washing. The filtrate is treated with CH₂Cl₂And (4) extracting. The organic layer was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue (20g) was purified by silica gel column chromatography (eluent: CH)₂Cl₂/CH₃OH/NH₄OH 94/6/0.5; 20-45 μm). Two fractions were collected and the solvent was evaporated. The residue was dissolved in iPrOH and converted to the hydrochloride salt. The precipitate was filtered off and dried. Yield: 3.5g of final compound 5 (14%) (m.p.: 183 ℃ C.).

c. Preparation of Final Compound 2

Final Compound 1 (prepared according to B1. a) (0.001mol) and Pd/C (0.1g) in CH₃The mixture in OH (6ml) was hydrogenated at 40 ℃ for 48 hours under 3 bar pressure and then filtered through celite. Mixing diatomaceous earth with CH₃OH/CH₂Cl₂And (6) washing. The filtrate was evaporated. The residue (0.6g) was purified by silica gel column chromatography (gradient eluent: CH)₂Cl₂/CH₃OH/NH₄OH 90/10/0.1-85/15/1; 35-70 μm). The pure fractions were collected and the solvent was evaporated. Yield: 0.3g of final compound 2 (58%).

Example B2

Preparation of Final Compound 3

Final Compound 2 (prepared according to B1. c) (0.0044mol), cyclopropanecarboxylic acid (0.0052mol), EDCI (0.0052mol), HOBT (0.0058mol) and Et₃N (0.0066mol) in CH₂Cl₂(25ml) the mixture was stirred at room temperature for 24 hours and poured into H₂O in combination with CH₂Cl₂And (4) extracting. The organic layer was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue (3g) was purified by silica gel column chromatography (eluent: CH)₂Cl₂/CH₃OH/NH₄OH 95/5/0.2; 15-40 μm). The pure fractions were collected and the solvent was evaporated. The residue (1.8g, 64%) was crystallized from diethyl ether. The precipitate was filtered off and dried. Yield: 1.45g of final compound 3 (51%) (m.p.: 160 ℃ C.).

Example B3

Preparation of Final Compound 4

Polystyrene-carbodiimide (1 equivalent) in CH₂Cl₂The mixture in (5ml) was stirred and cooled at 5 ℃. Is added to CH₂Cl₂(1ml) acid (for the example:. alpha. - (hydroxymethyl) phenylacetic acid) (1.5 equiv.) and the mixture was stirred at room temperature for 30 minutes. Addition of the final compound 2 (prepared according to B1. c) in CH₂Cl₂(2ml) and the mixture was stirred at 50 ℃ overnight. The reaction mixture was filtered and the solvent was evaporated. The residue was purified by chromatography on a silica gel column (Kromasil 5 μm, gradient eluent: CH)₂Cl₂ 100％-95/5CH₂Cl₂MeOH). The pure fractions were collected to yield the final compound 4 in 71% yield.

Example B4

Preparation of Final Compound 92

2-Thiophenesulfonyl chloride (0.001mol) was added portionwise to the final compound 2 (prepared according to B1. c) (0.001mol) and Et at room temperature₃N (0.001mol) in CH₂Cl₂(4ml) in solution. The mixture was stirred at room temperature for 48 hours. The organic layer is treated with K₂CO₃Washed 10% and dried (MgSO)₄) Filtered and the solvent evaporated. The residue (0.45g) was purified by silica gel column chromatography (eluent: CH)₂Cl₂/CH₃OH/NH₄OH 97/3/0.1; 15-40 μm). The pure fractions were collected and the solvent was evaporated. This fraction was dissolved in 2-propanone and converted to its oxalate salt. The precipitate was filtered off and dried. Yield: 0.28g of Compound 92 (46%) (m.p.: 132 ℃ C.).

Example B5

Preparation of Final Compound 119

Final Compound 2 (prepared according to B1. c) (0.176mmol), 4-cyanobenzenesulfonyl chloride (1.4 equiv.) and polymer-supported morpholine (1.5 equiv.) in CH₂Cl₂The mixture in (2ml) was stirred at room temperature for 24 hours. Polymer-supported tris (2-aminoethyl) amine polymer linkage (1 eq) was added and the mixture was stirred at room temperature for 24 hours and filtered. The residue was purified by column chromatography on silica gel (Kromasil 5 μm, gradient eluent: CH)₂Cl₂ 100％-95/5CH₂Cl₂MeOH). The pure fractions were collected to yield the final compound 119 in 54% yield.

Example B6

Preparation of Final Compound 6

A mixture of final compound 1 (prepared according to B1. c) (0.001mol), 2-thienylboronic acid (0.01mol) and glycolaldehyde dimer (0.001mol) in ethanol (5ml) was stirred at room temperature for 18 h. Adding K₂CO₃10 percent. The mixture was extracted with EtOAc. The organic layer was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue (0.6g) was purified by silica gel column chromatography (eluent: CH)₂Cl₂/CH₃OH/NH₄OH (95/5/0.1; 10 μm). The pure fractions were collected and the solvent was evaporated. Yield: 0.238g of final compound 6 (42%).

Example B7

a) Preparation of Final Compound 130

Intermediate Compound 14 (prepared according to A4. d) (0.0068mol), 3, 9-diazaspiro- [5.5]A mixture of 1, 1-dimethylethyl (1, 1-dimethylethyl) -undecane-3-carboxylate (0.0075mol) and titanium (IV) isopropoxide isopropyl (0.0115mol) in 1, 2-dichloroethane (50ml) was stirred at 50 ℃ overnight. Addition of NaBH (OAc)₃(0.0115 mol). The mixture was stirred at 50 ℃ for 1 hour. Adding K₂CO₃10% and CH₂Cl₂. The mixture was filtered through celite. The organic layer was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue (6.3g) was purified by silica gel column chromatography (eluent: CH)₂Cl₂/CH₃OH/NH₄OH 97/3/0.1；15-40 μm). Two fractions were collected and the solvent was evaporated. Yield: 0.8g of final compound 130 (16%) (m.p.: 80 ℃ C.).

b) Preparation of Final Compound 129

A mixture of final compound 130 (prepared according to B7. a) (0.0011mol) in HCl in iPrOH solution (8ml) and iPrOH (8ml) was stirred at room temperature for 6 hours. Addition of H₂And O. Mixing the mixture with K₂CO₃Alkalizing with CH₂Cl₂And (4) extracting. The organic layer was separated and dried (MgSO)₄) Filtered and the solvent evaporated to dryness. Yield: 0.6g of final compound 129 (86%).

Example B8

a) Preparation of Final Compound 191

Intermediate compound 3 (prepared according to A1.c) (0.012mol), intermediate compound 18 (prepared according to A5.d) (0.011mol), titanium (IV) isopropoxide (0.012mol) and thiophene (0.6g) in Pd/C (0.5ml) and CH₃The mixture in OH (100ml) was hydrogenated at 50 ℃ under 5 bar pressure and then filtered through celite. The filtrate was evaporated. Placing the residue in K₂CO₃10% and CH₂Cl₂In (1). The mixture was filtered through celite. The filtrate is treated with CH₂Cl₂And (4) extracting. The organic layer was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue (6.6g) was purified by silica gel column chromatography (eluent: CH)₂Cl₂/CH₃OH/NH₄OH 93/7/0.5; 15-40 μm). Two fractions were collected and the solvent was evaporated. Yield: 1.5g (2R-cis) (24)%) and 0.9g (2R-trans) (14%).

b) Preparation of Final Compound 195

NaH (0.0007mol) was added to a mixture of final compound 191(0.0005mol) in THF (2.5ml) at 5 ℃ under a stream of nitrogen. The mixture was stirred at 50 ℃ for 30 minutes. A solution of (bromomethyl) cyclopropane (0.0005mol) in THF (2.5ml) was added. The mixture was stirred at 60 ℃ overnight. Addition of H₂And O. The mixture was extracted with EtOAc. The organic layer was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue (0.3g) was purified by column chromatography using kromasil (gradient eluent: CH)₂Cl₂ 100-CH₂Cl₂/CH₃OH/NH₄OH 90/10/0.5; 5 μm). The pure fractions were collected and the solvent was evaporated. Yield: 0.23g of final compound 195 (70%).

Example B9

Preparation of Final Compound 204

NaH was added to a solution of final compound 191 (prepared according to b8. a) in THF at 5 ℃ under a nitrogen stream. The mixture was stirred for 30 minutes. 1-adamantyl bromomethyl ketone was added. The mixture was stirred at 60 ℃ overnight.

Yield: 8% final compound 204.

Example B10

Preparation of Final Compound 206

Intermediate Compound 3 (prepared according to A1. c) (0.028mol),

Prepared according to the teaching in CAS 180-50-7, J Med. chem.1990, 33, 2270-2275, incorporated herein by reference) (0.028mol), titanium (IV) isopropoxide (0.033mol) and Pd/C (1.5g) in CH₃The mixture in OH (150ml) was hydrogenated at 50 ℃ for 18 h under 3 bar pressure and then filtered through celite. Mixing diatomaceous earth with CH₃And (5) OH washing. The filtrate was evaporated to dryness. The residue was dissolved in cch. Adding K₂CO₃10 percent. The mixture was stirred at room temperature for 1 hour, then filtered through celite. The filtrate is treated with CH₂Cl₂And (4) extracting. The organic layer was separated and dried (MgSO)₄) Filtered and the solvent evaporated. Yield: 16g of final compound 206 (100%). The product was used directly in the next reaction step.

Example B11

Preparation of Final Compound 212

Final compound 206 (prepared according to B10), 3-furancarboxylic acid, PL-DCC (1.2 eq) and Et₃A mixture of N (1.5 equiv.) in THF was stirred in a sealed vessel in a microwave oven (150W) at 100 deg.C for 15 minutes. Yield: 11% final compound 212.

The following compounds were prepared according to one of the above examples.

TABLE 1

cb: covalent bond

TABLE 2

cb: covalent bond

TABLE 3

TABLE 4

cb: covalent bond

TABLE 5

cb: covalent bond

TABLE 6

cb: covalent bond

TABLE 7

cb: covalent bond

C. Analyzing data

For many compounds, melting point or LCMS data are recorded.

1. Melting Point

Melting points (or ranges) were obtained using Leica VMHB Koffler bank, if possible. The melting point is uncorrected.

Table 8: melting Point of selected Compound

Number of Compounds	Results (. degree.C.)
		3	143
5	183
		21	110
24	132
		36	125
42	162
		92	132
130	80
		131	90
132	110
		133	109
136	160
		137	100
140	92
		141	96
172	122
		173	128
174	130
		175	124
185	90
		178	220

LCMS conditions

HPLC gradients were provided by a Waters Alliance HT 2795 system (Waters, Milford, Mass.) at room temperature. The effluent stream from the column was split into a Waters 996 photodiode array (PDA) detector and a Waters-LCT mass spectrometer operating in positive ionization mode with an electrospray ionization source. Reverse phase HPLC was performed on a Kromasil C18 column (5 μm, 4.6X 150mm) at a flow rate of 1 ml/min. Gradient conditions were run with two mobile phases (mobile phase A: 100% 6.5mM ammonium acetate + 0.2% formic acid; mobile phase B: 100% acetonitrile) from 60% A & 40% B1 min to 100% B4 min, 100% B5 min to 60% A & 40% B3 min, and equilibrated with 60% A & 40% B for 3 min.

Mass spectra were obtained by scanning from 100-900 at 1s, using a dwell time of 0.1 s. The capillary tip voltage was 3kV and the source temperature was maintained at 100 ℃. Nitrogen was used as the nebulizer gas. For positive ionization mode, the cone voltage is 20V. Data acquisition was performed using the Waters-Micromass MassLynx-Openlynx data System.

Table 9: LCMS parent peak and retention time for selected compounds

Compound numbering	LCMSMS(MH+)	Retention time (min)
			3	636	9.0
4	679	3.8
			5	658	3.4
6	694	2.9
			7	652	4.9
8	652	5.0
			9	664	4.9
10	636	4.6
			11	650	4.51
12	704	4.73

Compound numbering	LCMSMS(MH+)	Retention time (min)
			13	661	4.47
14	679	3.97
			15	650	4.6
16	692	5.4
			17	664	5.1
18	664	5.0
			19	690	5.0
20	666	4.3
			21	666	4.2
22	679	4.0
			23	662	4.6
24	662	4.7
			25	676	4.8
26	676	4.7
			27	676	4.7
28	678	4.7
			29	692	5.1
30	692	5.3
			31	692	5.0
32	692	4.9
			33	675	4.6
34	676	3.9
			35	691	4.5
36	694	4.8
			37	692	5.4
38	692	5.3
			39	692	5.3
40	734	14.3
			41	676	4.8

Compound numbering	LCMSMS(MH+)	Retention time (min)
			42	706	4.9
43	697	4.7
			44	737	5.2
45	678	4.5
			46	690	4.3
47	718	4.4
			48	691	8.2
49	673	4.3
			50	673	4.2
51	673	4.1
			52	674	4.2
53	689	4.2
			54	689	3.9
55	689	3.8
			57	689	4.0
58	692	4.1
			59	730	5.9
60	730	5.8
			61	748	5.3
62	716	4.8
			63	716	5.1
64	712	5.5
			65	724	4.8
66	724	4.8
			67	726	3.2
68	714	5.0
			69	666	5.0
70	676	5.0
			71	692	5.2

Compound numbering	LCMSMS(MH+)	Retention time (min)
			72	744	6.0
73	719	4.4
			74	730	5.6
75	692	4.8
			76	692	4.8
77	678	4.2
			78	693	3.9
79	695	4.1
			80	734	4.1
81	730	5.1
			82	742	4.8
83	730	5.2
			84	688	5.2
85	688	4.9
			86	704	5.1
87	712	5.2
			88	716	4.6
89	712	5.0
			90	740	5.6
91	700	5.3
			92	714	5.0
93	714	5.1
			94	748	5.5
95	792	5.7
			96	782	6.0
97	782	5.8
			98	870	6.0
99	860	6.0
			100	726	4.4

Compound numbering	LCMSMS(MH+)	Retention time (min)
			101	727	5.2
102	708	5.2
			103	722	5.4
104	722	5.4
			105	722	5.4
106	742	5.4
			107	742	5.5
108	742	5.5
			109	776	5.6
110	776	5.7
			111	776	5.5
112	776	5.8
			113	776	5.8
114	776	5.8
			115	810	6.1
116	726	5.3
			117	776	5.7
118	733	5.1
			119	733	5.2
120	738	5.2
			121	738	5.3
122	768	5.0
			123	768	5.2
124	765	4.8
			125	786	＜5
126	722	5.2
			127	756	5.4
128	734	5.4
			130	736	5.7

Compound numbering	LCMSMS(MH+)	Retention time (min)
			131	704	5.0
132	734	4.8
			133	746	5.2
134	604.0	12.8
			136	672	4.6
137	702	4.4
			138	744	4.5
139	715	3.9
			140	698	4.7
141	714	4.8
			143	490	3.7
144	503	2.4
			145	506	2.2
146	528	3.7
			147	500	2.5
148	568	8.2
			149	568	3.8
150	584	4.0
			151	530	2.6
152	525	2.3
			153	528	3.7
154	568	3.8
			155	568	8.7
156	536	3.3
			157	650	4.8
158	560	4.0
			159	560	2.9
160	590	2.2
			161	604	2.4

Compound numbering	LCMSMS(MH+)	Retention time (min)
			162	501	6.7
163	516	6.7
			164	539	2.3
165	550	3.8
			166	551	2.9
167	674	4.9
			170	658	6.1
172	636	4.7
			173	636	4.8
174	666	4.4
			175	678	4.9
176	662	4.8
			178	686	4.9
178	672	3.4
			179	650	4.6
180	680	4.3
			181	779	＜5
182	692	4.8
			183	708	4.7
186	664	6.3
			187	694	5.9
188	793	6.6
			189	706	6.4
190	722	6.3
			192	582	3.94
193	638	4.76
			194	666	5.23
195	636	4.63
			196	636	4.63

Compound numbering	LCMSMS(MH+)	Retention time (min)
			197	650	4.83
198	662	4.71
			199	662	4.6
200	691	4.44
			201	691	4.54
202	690	4.9
			203	690	5.03
204	758	5.7
			205	758	5.87
207	652	5.53
			208	636	4.94
210	666	4.63
			211	666	4.74
212	662	＜5
			213	662	5.1
214	678	5.24
			215	672	5.3

D. Pharmacological examples

Example d.1: for h-NK₁、h-NK₂And NK₃Binding assays for receptors

The interaction of the compounds according to the invention with various neurotransmitter receptors, ion channels and transporter binding sites was investigated using radioligand binding techniques. A substance ([ 2 ]) labeled with a radioactive substance for expressing a receptor or a transporter of interest³H]Or (a)¹²⁵I]Ligand) from homogenates or membranes of cells to label specific receptors. The herdsman receptor bound to the radioligand is distinguished from the non-specifically labeled membrane by selective inhibition of receptor binding using an unlabeled drug (blank) known to compete with the radioligand for binding to the receptor site. After incubation, the labelled membranes were harvested and buffered with excess coolingThe solution was rinsed and rapidly filtered under suction to remove unbound reflex activity. The membranes bound to radioactivity were counted in a scintillation counter and the results (cpm) were expressed in counts per minute.

The compounds were dissolved in DMSO and maintained at 10 deg.C^-10～10^-5Tested at 10 concentrations in the M range.

Evaluation of the Compounds of the invention from cloned human h-NK expressed in CHO cells₁Receptor substitution [ alpha ]³H]Substance P, from cloned human h-NK expressed in Sf9 cells₂Receptor substitution [ alpha ]³H]SR-48968 and cloning human h-NK from expression in CHO cells₃Receptor substitution [ alpha ]³H]-the capabilities of SR 142810.

For all compounds of the invention, it is p-h-NK₁Receptor binding value (pIC)₅₀) Is in the range between 10 and 6.

Example d.2: signal conduction (ST)

This experiment assesses functional NK in vitro₁The antagonistic activity of (a). For measuring intracellular Ca⁺⁺Concentration, cells were grown in 96-well (black-coated/clear-bottom) plates from Costar for 2 days until fusion was reached. Cells were loaded with 2 μ M Fluo31 in DMEM containing 0.1% BSA and 2.5mM probenecid at 37 ℃ for 78 hours. Using a mixture containing 2.5mM probenecid and 0.1% BSA (CA)⁺⁺-buffer) of Krebs buffer (140mM NaCl, 1mM MgCl)₂×6H₂O, 5mM KCl, 10mM glucose, 5mM HEPES; 1.25mM CaCl₂(ii) a pH 7.4) Wash 3 ×. Cells were pre-incubated with a range of concentrations of antagonist for 20 minutes at room temperature and Ca was measured in a Fluorescence Image Plate Reader (FLIPR from Molecular Devices, Crawley, England) after addition of agonist⁺⁺A signal. Transient Ca⁺⁺Peaks were considered as correlation signals and the mean values of the corresponding wells were analyzed as follows.

Sigmoidal dose response curves were analyzed by computer curve fitting using the GraphPad Program. EC of the Compound₅₀The value is the effective dose showing 50% of the maximum effect. Will be paired withThe response of the agonist with the greatest effect normalized to 100% to give an average curve. For antagonistic effects, IC₅₀The values are calculated using non-linear regression.

pIC for testing signaling of representative selected compounds₅₀The data are presented in table 6. The last column indicates-without being limited thereto-the kind of action for which the compound may be most suitable. Of course, since some neurokinin receptors have no data tested, it is clear that these compounds may be attributed to another suitable use.

Table 10 pharmacological data for signaling of selected compounds (n.d. ═ untested)

Number of Compounds	NKpIC	NK2pIC50	NK3pIC50	Is suitable for
					98	6.01	＜5	＜5	NK1
40	6.01	＜5	＜5	NK1
					64	6.05	＜5	＜5	NK1
30	6.16	5.1	＜5	NK1
					203	6.18	5.47	＜5	NK1
212	6.20	5.45	5.42	NK1
					207	6.23	5.72	5.24	NK1
99	6.25	＜5	＜5	NK1
					128	6.25	5.27	＜5	NK1
112	6.26	＜5	＜5	NK1
					201	6.66	5.55	～5	NK1
115	6.31	＜5	＜5	NK1
					96	6.33	5.9	～5	NK1
117	6.35	＜5	＜5	NK1
					63	6.36	5.1	＜5	NK1
63	6.36	5.1	＜5	NK1
					178	6.36	5.31	＜5	NK1
113	6.37	＜5	＜5	NK1
					74	6.41	＜5	＜5	NK1
87	6.41	5.22	＜5	NK1
					114	6.44	＜5	＜5	NK1
90	6.45	5.27	＜5	NK1
					59	6.46	＜5	5.23	NK1
208	6.46	5.58	5.37	NK1
					198	6.47	5.32	＜5	NK1

Number of Compounds	NKpIC	NK2pIC50	NK3pIC50	Is suitable for
					72	6.49	＜5	＜5	NK1
108	6.49	5.58	5.4	NK1
					85	6.51	＜5	＜5	NK1
68	6.53	5.25	＜5	NK1
					84	6.55	5.14	＜5	NK1
211	6.55	5.34	～5	NK1
					78	6.57	＜5	＜5	NK1
95	6.57	5.72	5.63	NK1
					61	6.58	＜5	＜5	NK1
127	6.58	5.33	＜5	NK1
					202	6.61	5.34	5.14	NK1
60	6.62	5.33	5.33	NK1
					193	6.62	5.6	5.24	NK1
48	6.66	＜5	＜5	NK1
					196	6.67	5.19	～5.51	NK1
33	6.70	＜5	＜5	NK1
					16	6.72	＜5	5.07	NK1
34	6.72	5.21	＜5	NK1
					197	6.72	5.54	5.19	NK1
62	6.73	＜5	＜5	NK1
					110	6.76	n.d.	5.29	NK1
79	6.77	＜5	＜5	NK1
					44	6.79	5.35	5.34	NK1
155	6.80	5.19	n.d.	NK1
					125	6.80	5.29	5.16	NK1
55	6.80	5.4	＜5	NK1
					57	6.82	5.72	＜5	NK1
41	6.83	5.07	＜5	NK1

Number of Compounds	NKpIC	NK2pIC50	NK3pIC50	Is suitable for
					41	6.83	5.07	＜5	NK1
89	6.83	5.6	＜5	NK1
					153	6.84	＜5	n.d.	NK1
53	6.86	＜5	＜5	NK1
					86	6.89	＜5	＜5	NK1
6	6.89	5.11	＜5	NK1
					15	6.89	5.5	5.10	NK1
7	6.94	＜5	＜5	NK1
					81	6.94	5.28	＜5	NK1
107	6.94	5.38	5.50	NK1
					9	6.97	＜5	＜5	NK1
49	6.97	5.40	＜5	NK1
					46	6.98	5.20	＜5	NK1
11	6.98	5.27	n.d.	NK1
					43	6.98	5.44	＜5	NK1
37	7.02	5.09	＜5	NK1
					37	7.02	5.09	＜5	NK1
71	7.03	5.01	＜5	NK1
					71	7.03	5.01	＜5	NK1
172	7.03	5.16	5.24	NK1
					91	7.06	5.86	5.36	NK1
97	7.06	n.d.	～5	NK1
					39	7.07	5.32	5.27	NK1
25	7.08	5.40	＜5	NK1
					185	7.09	5.26	＜5	NK1
70	7.09	5.27	＜5	NK1
					45	7.10	5.27	＜5	NK1
50	7.11	5.58	＜5	NK1

Number of Compounds	NKpIC	NK2pIC50	NK3pIC50	Is suitable for
					32	7.12	5.50	5.18	NK1
176	7.14	～5.19	＜5	NK1
					123	7.15	～5.39	＜5	NK1
47	7.18	～5	＜5	NK1
					66	7.18	5.43	5.16	NK1
58	7.19	＜5	＜5	NK1
					69	7.19	5.51	5.18	NK1
42	7.21	5.05	5.03	NK1
					42	7.21	5.05	5.03	NK1
52	7.22	5.54	＜5	NK1
					179	7.23	＜5	＜5	NK1
67	7.24	5.01	＜5	NK1
					67	7.24	5.01	＜5	NK1
133	7.27	5.43	5.31	NK1
					101	7.31	5.70	5.22	NK1
82	7.33	5.70	5.05	NK1
					77	7.34	～5.09	＜5	NK1
77	7.34	～5.09	＜5	NK1
					122	7.35	5.40	＜5	NK1
8	7.36	5.55	5.35	NK1
					141	7.38	5.23	5.15	NK1
88	7.38	5.52	＜5	NK1
					174	7.39	5.16	＜5	NK1
182	7.42	＜5	5.04	NK1
					182	7.42	＜5	5.04	NK1
182	7.42	＜5	5.04	NK1
					83	7.44	5.59	5.05	NK1
22	7.44	5.75	＜5	NK1

Number of Compounds	NKpIC	NK2pIC50	NK3pIC50	Is suitable for
					181	7.47	5.15	＜5	NK1
73	7.48	＜5	＜5	NK1
					73	7.48	＜5	＜5	NK1
73	7.48	＜5	＜5	NK1
					126	7.48	5.47	5.4	NK1
14	7.50	＜5	n.d.	NK1
					14	7.50	＜5	n.d.	NK1
14	7.50	＜5	n.d.	NK1
					173	7.51	～5.79	＜5	NK1
80	7.53	＜5	＜5	NK1
					80	7.53	＜5	＜5	NK1
51	7.53	5.44	＜5	NK1
					189	7.54	5.17	＜5	NK1
36	7.55	5.37	＜5	NK1
					140	7.63	5.46	5.61	NK1
27	7.69	5.35	5.48	NK1
					187	7.7	5.15	＜5	NK1
35	7.72	＜5	＜5	NK1
					35	7.72	＜5	＜5	NK1
138	7.75	5.33	＜5	NK1
					183	7.77	5.11	5.13	NK1
186	7.77	5.30	5.27	NK1
					21	7.78	5.63	5.67	NK1
175	7.81	5.35	＜5	NK1
					188	7.82	5.26	5.43	NK1
180	7.83	5.08	＜5	NK1
					111	6.69	～6.64	5.27	NK1-2
121	6.95	5.92	5.43	NK1-2

Number of Compounds	NKpIC	NK2pIC50	NK3pIC50	Is suitable for
					76	7.59	5.94	5.40	NK1-2
200	7.63	5.84	5.16	NK1-2
					18	7.69	5.92	5.33	NK1-2
190	8.21	5.79	5.45	NK1-2
					210	6.54	5.74	5.75	NK1-3
94	6.88	＜5	6.24	NK1-3
					24	6.95	＜5	5.88	NK1-3
105	6.98	5.61	5.70	NK1-3
					104	7.19	～5.34	5.71	NK1-3
102	7.21	＜5	6.15	NK1-3
					106	7.22	5	6.28	NK1-3
167	7.25	5.69	5.71	NK1-3
					116	7.28	＜5	6.15	NK1-3
103	7.30	5.60	5.82	NK1-3
					139	7.41	5.62	6.02	NK1-3
199	7.43	5.56	6.07	NK1-3
					118	7.51	n.d.	5.82	NK1-3
137	7.56	5.46	5.77	NK1-3
					124	7.63	～5.59	5.75	NK1-3
136	7.77	5.70	6.16	NK1-3
					119	7.18	5.97	5.8	NK1-2-3
195	7.27	～5.85	5.84	NK1-2-3
					4	7.41	5.81	5.89	NK1-2-3
3	7.43	5.96	5.82	NK1-2-3
					93	7.59	5.96	6.30	NK1-2-3
131	7.76	6.11	5.85	NK1-2-3
					92	7.77	5.88	6.47	NK1-2-3

Number of Compounds	NKpIC	NK2pIC50	NK3pIC50	Is suitable for
					100	7.92	5.9	6.48	NK1-2-3
132	8.02	5.77	6.04	NK1-2-3

E. Composition examples

The "active ingredient" (a.i.) used in these examples refers to the compounds of formula (I), the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the N-oxide form thereof and prodrugs thereof.

Example e.1: oral drops

500g of A.I. are dissolved in 0.5l of 2-hydroxypropionic acid and 1.5 l of polyethylene glycol at 60-80 ℃. After cooling to 30-40 ℃, 35 liters of polyethylene glycol was added and the mixture was stirred well. A solution of 1750g of saccharin sodium in 2.5 litres of purified water was then added and 2.5 litres of cocoa flavour and polyethylene glycol were added to 50 litres whilst stirring to give an oral drop solution containing 10mg/ml a.i. The resulting solution is filled into a suitable container.

Example e.2: oral solution

9g of methyl 4-hydroxybenzoate and 1g of propyl 4-hydroxybenzoate were dissolved in 4 liters of boiled purified water. To 3 liters of this solution, 10g of 2, 3-hydroxysuccinic acid was dissolved first, and then 20g of A.I. the latter solution was mixed with the remaining part of the former solution and 12 liters of 1, 2, 3-propanetriol and 3 liters of sorbitol 70% solution were added thereto. 40g of saccharin sodium are dissolved in 0.5l of water and 2ml of raspberry and 2ml of currant essence are added. The latter solution was combined with the former and water was added to a volume of 20L to obtain an oral solution containing 5mg of the active ingredient per teaspoon (5 ml). The resulting solution is filled into a suitable container.

Example e.3: film coated tablet

Preparation of tablet cores

A mixture of 100g of a.i., 570g lactose and 200g starch was mixed thoroughly and thereafter moistened with a solution of 5g sodium lauryl sulfate and 10g polyvinylpyrrolidone handles in about 200ml water. The wet powder mixture was sieved, dried and sieved again. 100g of microcrystalline cellulose and 15g of hydrogenated vegetable oil were then added. The whole was mixed well and tableted to obtain 10000 tablets, each containing 10mg of active ingredient.

Coating film

A solution of 5g of ethylcellulose in 150ml of dichloromethane is added to a solution of 10g of methylcellulose in 75ml of denatured ethanol. Then 75ml of dichloromethane and 2.5ml of 1, 2, 3-propanetriol are added. 10g of polyethylene glycol were melted and dissolved in 75ml of dichloromethane. The latter solution was added to the former, then 2.5g magnesium stearate, 5g polyvinylpyrrolidone and 30ml of concentrated colour suspension were added and the whole was homogenized. The resulting mixture is used to coat tablet cores in a coating apparatus.

Example E.4: injectable solutions

1.8g of methyl 4-hydroxybenzoate and 0.2g of propyl 4-hydroxybenzoate were dissolved in 0.5l of boiling water for injection. After cooling to about 50 ℃, 4g of lactic acid, 0.05g of polyethylene glycol and 4g of a.i. were added with stirring. The solution was cooled to room temperature and made up to 1 litre with water for injection, giving a solution containing 4mg/ml a.i. The solution was sterilized by filtration and filled into sterile containers.

Claims (19)

1.A compound of the general formula (I)

A pharmaceutically acceptable acid or base addition salt thereof, and stereochemically isomeric forms thereof, wherein:

R²is Ar²、Ar²Alkyl, bis (Ar)²) Alkyl, Het¹Or Het¹-an alkyl group;

x is a covalent bond or a group of formula-O-, -S-or-NR³-a divalent group of (a);

q is O or NR³；

Each R³Independently of one another, hydrogen or alkyl;

R¹selected from Ar¹、Ar¹Alkyl and bis (Ar)¹) -an alkyl group;

n is an integer equal to 0, 1 or 2;

m is an integer equal to 1 or 2, with the proviso that if m is 2, then n is 1;

z is a covalent bond or the formula-CH₂-or a divalent group > C (═ O);

j. k, p, q are integers independently of each other equal to 0, 1, 2, 3 or 4; provided that each of (j + k) and (p + q) equals 4;

t is ═ O in the α -position with respect to the N-atom, and T is an integer equal to 0 or 1;

each Alk represents, independently of each other, a covalent bond; a divalent linear or branched saturated or unsaturated hydrocarbon group having 1 to 6 carbon atoms; or a cyclic saturated or unsaturated hydrocarbon group having 3 to 6 carbon atoms; each of said groups being optionally substituted on one or more carbon atoms with one or more of phenyl, halogen, cyano, hydroxy, formyl and amino;

y is a covalent bond or a group of the formula-C (═ O) -, -SO₂A divalent radical-CH-R or-N-R, where R is H, CN or nitro;

l is selected from the group consisting of hydrogen, alkyl, alkenyl, alkoxy, alkoxyalkoxy, alkylcarbonyloxy, alkoxycarbonyl, mono-and di (alkyl) amino, mono-and di (alkoxycarbonyl) amino, mono-and di (alkylcarbonyl) amino, mono-and di (Ar)³) Amino, mono-and di (Ar)³Alkyl) amino, mono-and di (Het)²) Amino, mono-and di (Het)²Alkyl) amino, alkylthio, norbornyl, adamantyl, tricycloundecyl, Ar³、Ar³-oxy, Ar³Carbonyl group, Het²Het-oxo, Het²Carbonyl and mono-and di (Het)²Carbonyl) amino;

Ar¹is phenyl, optionally substituted by 1, 2 or 3 radicals each independently of the othersSubstituted with substituents selected from: halogen, alkyl, cyano, aminocarbonyl and alkoxy;

Ar²is naphthyl or phenyl, each of said groups being optionally substituted with 1, 2 or 3 substituents independently of each other selected from the group consisting of: halogen, nitro, amino, mono-and di (alkyl) amino, cyano, alkyl, hydroxy, alkoxy, carboxy, alkoxycarbonyl, aminocarbonyl and mono-and di (alkyl) aminocarbonyl;

Ar³is naphthyl or phenyl, each of said groups being optionally substituted with 1, 2 or 3 substituents independently of each other selected from the group consisting of: alkoxy, alkylcarbonylamino, methylsulfonyl, Ar¹Carbonyloxyalkyl, Ar¹Alkoxycarbonyl, Ar¹Alkoxyalkyl, alkyl, halogen, hydroxy, pyridyl, morpholinyl, pyrrolyl, pyrrolidinyl, imidazo [1, 2-a]Pyridyl, morpholinylcarbonyl, pyrrolidinylcarbonyl, amino and cyano;

Het¹is a monocyclic heterocyclic group selected from: pyrrolyl, pyrazolyl, imidazolyl, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl; or a bicyclic heterocyclic group selected from: quinolyl, quinoxalyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl, benzothienyl, indanyl, and chromenyl; wherein each monocyclic and bicyclic heterocyclic group may be optionally substituted on any atom by one or more groups each independently of the other selected from halogen, oxo and alkyl;

Het²is a monocyclic heterocyclic group selected from: pyrrolidinyl, dihydro-2H-pyranyl, dioxolyl, imidazolidinyl, tetrahydropyridinyl, tetrahydropyrimidinyl, pyrazolidinyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, imidazolidinyl, tetrahydrofuranyl, 2H-pyrrolyl, pyrrolinyl, imidazolinyl, pyrazolinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, furyl, thienyl, oxazolyl, dioxazolyl, oxazolidinyl, isoxazolyl, thiazolyl, pyrazolidinyl, oxazolinyl, pyrazolyl, and the like,Thiadiazolyl, isothiazolyl, pyridyl, 1H-pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, and tetrazolyl; or a bicyclic heterocyclic group selected from: 2, 3-dihydro-benzo [1, 4 ]]Dioxins, octahydro-benzo [1, 4 ]]Dioxins, octabicycloheptyl, benzodipiperidinyl, quinolinyl, quinoxalinyl, indolyl, isoindolyl, chromanyl, benzimidazolyl, imidazo [1, 2-a ]]Pyridyl, benzoxazolyl, benzodioxolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl, dihydroisobenzofuranyl, or benzothienyl; wherein each monocyclic and bicyclic heterocyclic group may be optionally substituted on any atom by one or more groups selected from: ar (Ar)¹、Ar¹Alkyl radical, Ar¹Alkoxyalkyl, halogen, hydroxy, alkyl, piperidinyl, pyrrolyl, thienyl, oxo, alkoxy, alkylcarbonyl, Ar¹Carbonyl, mono-and di (alkyl) aminoalkyl, alkoxyalkyl and alkoxycarbonyl;

alkyl is a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms; each hydrocarbyl group is optionally substituted on one or more carbon atoms with one or more groups selected from: phenyl, halogen, trihalomethyl, aminocarbonyl, methyl, ethyl, propyl, isopropyl, tert-butyl, cyano, oxo, hydroxy, formyl and amino; and is

The alkenyl group is a straight or branched unsaturated hydrocarbon group having 1 to 6 carbon atoms and having one or more unsaturated bonds; or a cyclic unsaturated hydrocarbon group having 3 to 6 carbon atoms and having one or more unsaturated bonds; each hydrocarbyl group is optionally substituted on one or more carbon atoms with one or more groups selected from: phenyl, halogen, cyano, oxo, hydroxy, formyl and amino.

2. The compound of claim 1, wherein:

R²is Ar²、Ar²-alkyl or Het¹；

X is a covalent bond;

q is O;

R¹is Ar¹-an alkyl group;

n is an integer equal to 1;

m is an integer equal to 1;

z is a covalent bond or the formula-CH₂-or a divalent group > C (═ O);

j. k, p, q are integers independently of one another equal to 1, 2 or 3; provided that (j + k) and (p + q) are equal to 4;

t is an integer equal to 0 or 1;

each Alk represents, independently of each other, a covalent bond; a divalent linear or branched saturated or unsaturated hydrocarbon group having 1 to 6 carbon atoms; or a cyclic saturated or unsaturated hydrocarbon group having 3 to 6 carbon atoms; each of said groups being optionally substituted with hydroxy;

y is a covalent bond or a group of formula-C (═ O) -or-SO₂-a divalent group of (a);

l is selected from the group consisting of hydrogen, alkyl, alkenyl, alkoxy, norbornyl, tricycloundecyl, Ar³、Ar³-oxy, Het²And mono-and di (Het)²Carbonyl) amino;

Ar¹is phenyl, said phenyl being optionally substituted with 2 halogens;

Ar²is naphthyl or phenyl, each of said radicals being optionally substituted by 1, 2 or 3 substituents which are independently of one another and are selected from the group consisting of halogen, cyano, alkyl and alkoxy;

Ar³is phenyl, said phenyl being optionally substituted with one substituent selected from the group consisting of: alkoxy, alkylcarbonylamino, methanesulfonyl, alkyl, halogen, pyrrolyl and cyano;

Het¹is a monocyclic heterocyclic group selected from: pyrrolyl, furyl, thienyl, pyridyl and pyrazinyl; or a bicyclic heterocyclic group selected from quinolinyl and indolyl; wherein each monocyclic and bicyclic heterocyclic group may be optionally substituted on any atom by one or more alkyl groups;

Het²is a monocyclic heterocyclic group selected from: pyrrolidinyl, dihydro-2H-pyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, pyrrolyl, imidazolyl, furanylThienyl, oxazolidinyl, isoxazolyl, thiadiazolyl, pyridyl, 1H-pyridyl, pyrazinyl, pyridazinyl and tetrazolyl;

or a bicyclic heterocyclic group selected from: octabicycloheptyl, quinoxalinyl, benzimidazolyl, benzodioxolyl, benzoxadiazolyl, benzofuranyl or dihydroisobenzofuranyl; wherein each monocyclic and bicyclic heterocyclic group may be optionally substituted on any atom by one or more groups selected from halo, alkyl, oxo, and alkoxycarbonyl;

alkyl is a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms; each hydrocarbyl group is optionally substituted on one or more carbon atoms with one or more groups selected from: trihalomethyl, aminocarbonyl, methyl, tert-butyl and cyano; and is

The alkenyl group is a cyclic unsaturated hydrocarbon group having 3 to 6 carbon atoms and having 1 unsaturated bond.

3. A compound according to any one of claims 1-2, characterised in that R¹Is Ar¹Methyl and is attached in the 2-position, or R¹Is Ar¹And is connected at the 3-position.

4.A compound according to any one of claims 1 to 3, characterised in that the spiro moiety has formula (f1), (f2) or (f12) wherein the variables are as defined in formula (I) and "a" refers to the piperidinyl moiety of formula (I) and "b" refers to the Alk-Y-Alk-L-moiety of formula (I)

5. A compound according to any one of claims 1 to 4, characterised in that R²-X-C (═ Q) -moiety is 3, 5-bis- (trifluoromethyl) phenylcarbonyl.

6. A compound according to any one of claims 1 to 5, characterised in that m and n are both equal to 1.

7.A compound according to any one of claims 1 to 6, characterised in that Y is-C (═ O) -.

8.A compound according to any one of claims 1 to 7, characterised in that Alk is a covalent bond or-CH₂-。

9. A compound according to any one of claims 1 to 8, characterised in that L is cyclopropyl.

10. A compound selected from the group consisting of:

3- [1- [3, 5-bis (trifluoromethyl) benzoyl ] -2- [ (3, 4-dichlorophenyl) methyl ] -4-piperidinyl ] -9- [ (tetrahydro-3-furanyl) carbonyl ] -3, 9-diazaspiro [5.5] undecane;

1- [3, 5-bis (trifluoromethyl) benzoyl ] -4- [9- [ (1, 2-dimethyl-1H-imidazol-4-yl) sulfonyl ] -3, 9-diazaspiro [5.5] undecan-3-yl ] -2- (phenylmethyl) -piperidine;

1- [3, 5-bis (trifluoromethyl) benzoyl ] -2- (phenylmethyl) -4- [9- (2-thienylsulfonyl) -3, 9-diazaspiro [5.5] undecan-3-yl ] -piperidine;

1- [3, 5-bis (trifluoromethyl) benzoyl ] -2- (phenylmethyl) -4- [9- (3-thienylsulfonyl) -3, 9-diazaspiro [5.5] undecan-3-yl ] -piperidine;

3- [1- [3, 5-bis (trifluoromethyl) benzoyl ] -2- (phenylmethyl) -4-piperidinyl ] -9- (cyclopropylcarbonyl) -3, 9-diazaspiro [5.5] undecane;

3- [1- [3, 5-bis (trifluoromethyl) benzoyl ] -2- (phenylmethyl) -4-piperidinyl ] -9- [ (5-oxo-2-pyrrolidinyl) carbonyl ] -3, 9-diazaspiro [5.5] undecane; and

1- [3, 5-bis (trifluoromethyl) benzoyl ] -4- [9- [ (4-cyanophenyl) sulfonyl ] -3, 9-diazaspiro [5.5] undecan-3-yl ] -2- (phenylmethyl) -piperidine.

11. A compound according to any one of claims 1 to 10 for use as an orally active, centrally permeable medicament.

12. Use of a compound according to any one of claims 1 to 10 in the manufacture of a medicament for the treatment of tachykinin mediated conditions.

13. The use of a compound according to any one of claims 1 to 10 for the preparation of a medicament for the treatment and/or prophylaxis of: schizophrenia, emesis, anxiety and depression, irritable bowel syndrome, circadian rhythm disturbances, pre-eclampsia, nociception, pain, pancreatitis, neurogenic inflammation, asthma, COPD and micturition disorders.

14. The use of claim 13, wherein the pain is selected from visceral and neuropathic pain.

15. The use of claim 13, wherein the micturition disorder is urinary incontinence.

16. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound according to any one of claims 1 to 10.

17. A process for the preparation of a pharmaceutical composition according to claim 16, characterized in that a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of a compound according to any one of claims 1 to 10.

18. A process for the preparation of a compound of formula (I),

a) reductively N-alkylating an intermediate compound of formula (II) with an intermediate compound of formula (III) in a reaction-inert solvent and optionally in the presence of a suitable reducing agent to obtain a final compound of formula (Ia), wherein all variables are as defined in claim 1; or

b) Reductive N-alkylation of an intermediate compound of formula (IV) with an intermediate compound of formula (III) in a reaction inert solvent and optionally in the presence of a suitable reducing agent to obtain a final compound of formula (Ib), wherein all variables are as defined in claim 1; or

c) Reacting an intermediate compound of formula (III) with a carboxylic acid compound of formula (V) in a reaction-inert solvent, and optionally in the presence of a suitable base, to obtain a final compound of formula (Ic), wherein all variables are as defined in claim 1; and

(d) if desired, converting the compounds of formula (I), in particular of formulae (Ia), (Ib) and (Ic), to one another according to art-known transformations and, if desired, converting the compounds of formula (I) to therapeutically active, non-toxic acid addition salts by treatment with acids or to therapeutically active, non-toxic base addition salts by treatment with bases or to the free base form by treatment with bases or to the free acid form by treatment with acids; and, if desired, preparing stereochemically isomeric forms thereof, N-oxides thereof and quaternary ammonium salts thereof.

19. Process according to claim 18, characterized in that the Alk-Y-Alk-L-moiety in the compounds of formulae (III), (Ia), (Ib) and (Ic) is benzyl.