# Patent

## Title
Substituted 1-piperidin-4-yl-4-pyrrolidin-3-yl-piperazine derivatives and their use as neurokinin antagonists

## Abstract

This invention concerns substituted I-piperidin-4-yl-4-pyrrolidin-3-yl-piperazine derivatives having neurokinin antagonistic activity, in particular NK1 antagonistic activity, a combined NK1/NK3 antagonistic activity and a combined NK1/NK2/NK3 antagonistic activity, their preparation, compositions comprising them and their use as a medicine, in particular for the treatment of schizophrenia, anxiety, depression, emesis and IBS. The compounds according to the invention can be represented by general Formula (I) and comprises also the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the N-oxide form thereof and prodrugs thereof, wherein all substituents are defined as in claim 1. In view of their capability to antagonize the actions of tachykinins by blocking the neurokinin receptors, and in particular antagonizing the actions of substance P and Neurokinin B by blocking the NK1, NK2 and NK3 receptors, the compounds according to the invention are useful as a medicine, in particular in the prophylactic and therapeutic treatment of tachykinin-mediated conditions, such as, for instance CNS disorders, in particular schizoaffective disorders, depression, anxiety disorders, stress-related disorders, sleep disorders, cognitive disorders, personality disorders, eating disorders, neurodegenerative diseases, addiction disorders, mood disorders, sexual dysfunction, pain and other CNS-related conditions; inflammation; allergic disorders; emesis; gastrointestinal disorders, in particular irritable bowel syndrome (IBS); skin disorders; vasospastic diseases; fibrosing and collagen diseases; disorders related to immune enhancement or suppression and rheumatic diseases and body weight control.

## Background
CROSS REFERENCE TO RELATED APPLICATIONS
This nonprovisional patent application is the National Stage of International Application No.PCT/EP2003/051041, filed 17 Dec. 2003, which claims priority from PCT/EP2002/14831, filed 23 Dec. 2002, which are hereby incorporated by reference.
FIELD OF THE INVENTION
This invention concerns substituted 1-piperidin-4-yl-4-pyrrolidin-3-yl-piperazine derivatives having neurokinin antagonistic activity, in particular NK1 antagonistic activity, a combined NK1/NK3 antagonistic activity and a combined NK1/NK2/NK3 antagonistic activity, their preparation, compositions comprising them and their use as a medicine, in particular for the treatment of schizophrenia, emesis, anxiety and depression, irritable bowel syndrome (IBS), circadian rhythm disturbances, visceral pain, neurogenic inflammation, asthma, micturition disorders such as urinary incontinence and nociception.
BACKGROUND OF THE INVENTION
Tachykinins belong to a family of short peptides that are widely distributed in the mammalian central and peripheral nervous system (Bertrand and Geppetti, Trends Pharmacol. Sci. 17:255-259 (1996); Lundberg, Can. J. Physiol. Pharmacol. 73:908-914 (1995); Maggi, Gen. Pharmacol. 26:911-944 (1995); Regoli et al., Pharmacol. Rev. 46 (1994)). They share the common C-terminal sequence Phe-Xaa-Gly-Leu-Met-NH2. Tachykinins released from peripheral sensory nerve endings are believed to be involved in neurogenic inflammation. In the spinal cord/central nervous system, tachykinins may play a role in pain transmission/perception and in some autonomic reflexes and behaviors. The three major tachykinins are Substance P (SP), Neurokinin A (NKA) and Neurokinin B (NKB) with preferential affinity for three distinct neurokinin receptor subtypes, termed NK1, NK2, and NK3, respectively. However, functional studies on cloned receptors suggest strong functional cross-interaction between the 3 tachykinins and their corresponding neurokinin receptors (Maggi and Schwartz, Trends Pharmacol Sci. 18: 351-355 (1997)).
Species differences in structure of NK1 receptors are responsible for species-related potency differences of NK1 antagonists (Maggi, Gen. Pharmacol. 26:911-944 (1995); Regoli et al., Pharmacol Rev. 46(4):551-599 (1994)). The human NK1 receptor closely resembles the NK1 receptor of guinea-pigs and gerbils but differs markedly from the NK1 receptor of rodents. The development of neurokinin antagonists has led to date to a series of peptide compounds of which might be anticipated that they are metabolically too labile to be employed as pharmaceutically active substances (Longmore J. et al., DN&P 8(1):5-23 (1995)).
The tachykinins are involved in schizophrenia, depression, (stress-related) anxiety states, emesis, inflammatory responses, smooth muscle contraction and pain perception. Neurokinin antagonists are in development 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, NK1 antagonists have a high therapeutic potential in emesis and depression and NK2 antagonists have a high therapeutic potential in asthma treatments. NK3 antagonists seem 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
The NK3 antagonist SR142801 (Sanofi) was recently shown to have antipsychotic activity in schizophrenic patients without affecting negative symptoms (Arvantis, L. ACNP Meeting, December 2001). Activation of NK1 receptors causes anxiety, stressful events evoke elevated substance P (SP) plasma levels and NK1 antagonists are reported to be anxiolytic in several animal models. The NK1 antagonist from Merck, MK-869 shows antidepressant effects in major depression, but data were not conclusive due to a high placebo response rate. Moreover, the NK1 antagonist from Glaxo-Welcome (S)-GR205,171 was shown to enhance dopamine release in the frontal cortex but not in the striatum (Lejeune et al. Soc. Neurosci., November 2001). It is therefore hypothesized that NK3 antagonism in combination with NK1 antagonism would be beneficial against both positive and negative symptoms of schizophrenia.
Anxiety and Depression
Depression is one of the most common affective disorders of modern society with a high and still increasing prevalence, particularly in the younger members of the population. The life time prevalence rates of Major depression (MDD, DSM-IV) is currently estimated to be 10-25% for women and 5-12% for men, whereby in about 25% of patients the life time MDD is recurrent, without full inter-episode recovery and superimposed on dysthymic disorder. There is a high co-morbidity of depression with other mental disorders and, particularly in younger population high association with drug and alcohol abuse. In the view of the fact that depression primarily affects the population between 18-44 years of age e.g. the most productive population, it is obvious that it imposes a high burden on individuals, families and the whole society.
Among all therapeutic possibilities, the therapy with antidepressants is incontestably the most effective. A large number of antidepressants have been developed and introduced to the market in the course of the last 40 years. Nevertheless, none of the current antidepressants fulfill all criteria of an ideal drug (high therapeutic and prophylactic efficacy, rapid onset of action, completely satisfactory short- and long-term safety, simple and favourable pharmacokinetics) or is without side effects which in one or the other way limits their use in all groups and subgroups of depressed patients.
Since no treatment of the cause of depression exists at present, nor appears imminent, and no antidepressant is effective in more than 60-70% of patients; the development of a new antidepressant which may circumvent any of the disadvantages of the available drugs is justified.
Several findings indicate involvement of SP in stress-related anxiety states. Central injection of SP induces a cardiovascular response resembling the classical “fight or flight” reaction characterised physiologically by vascular dilatation in skeletal muscles and decrease of mesenteric and renal blood flow. This cardiovascular reaction is accompanied by a behavioural response observed in rodents after noxious stimuli or stress (Culman and Unger, Can. J. Physiol. Pharmacol. 73:885-891 (1995)). In mice, centrally administered NK1 agonists and antagonists are anxiogenic and anxiolytic, respectively (Teixeira et al., Eur. J. Pharmacol. 311:7-14 (1996)). The ability of NK1 antagonists to inhibit thumping induced by SP (or by electric shock; Ballard et al., Trends Pharmacol. Sci. 17:255-259 (2001)) might correspond to this antidepressant/anxiolytic activity, since in gerbils thumping plays a role as an alerting or warning signal to conspecifics.
The NK1 receptor is widely distributed throughout the limbic system and fear-processing pathways of the brain, including the amygdala, hippocampus, septum, hypothalamus, and periaqueductal grey. Additionally, substance P is released centrally in response to traumatic or noxious stimuli and substance P-associated neurotransmission may contribute to or be involved in anxiety, fear, and the emotional disturbances that accompany affective disorders such as depression and anxiety. In support of this view, changes in substance P content in discrete brain regions can be observed in response to stressful stimuli (Brodin et al., Neuropeptides 26:253-260 (1994)).
Central injection of substance P mimetics (agonists) induces a range of defensive behavioural and cardiovascular alterations including conditioned place aversion (Elliott, Exp. Brain. Res. 73:354-356 (1988)), potentiated acoustic startle response (Krase et al., Behav. Brain. Res. 63:81-88 (1994)), distress vocalisations, escape behaviour (Kramer et al., Science 281:1640-1645 (1998)) and anxiety on the elevated plus maze (Aguiar and Brandao, Physiol. Behav. 60:1183-1186 (1996)). These compounds did not modify motor performance and co-ordination on the rotarod apparatus or ambulation in an activity cage. Down-regulation of substance P biosynthesis occurs in response to the 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, a centrally administered NK1 agonist-induced vocalisation response in guinea-pigs can be antagonised by antidepressants such as imipramine and fluoxetine as well as L-733,060, an NK1 antagonist. These studies provide evidence suggesting that blockade of central NK1 receptors may inhibit psychological stress in a manner resembling antidepressants and anxiolytics (Rupniak and Kramer, Trends Pharmacol. Sci. 20:1-12 (1999)), but without the side effects of present medications.
Emesis
Nausea and vomiting are among the most distressing side effects of cancer chemotherapy. These reduce the quality of life and may cause patients to delay or refuse, potentially curative drugs (Kris et al., J. Clin. Oncol., 3:1379-1384 (1985)). The incidence, intensity and pattern of emesis is determined by different factors, such as the chemotherapeutic agent, dosage and route of administration. Typically, early or acute emesis starts within the first 4 h after chemotherapy administration, reaching a peak between 4 h and 10 h, and decreases by 12 to 24 h. Delayed emesis (developing after 24 h and continuing until 3-5 days post chemotherapy) is observed with most ‘high-emetogenic’ chemotherapeutic drugs (level 4 and 5 according to Hesketh et al., J. Clin. Oncol. 15:103 (1997)). In humans, these ‘high-emetogenic’ anti-cancer treatments, including cis-platinum, induce acute emesis in>98% and delayed emesis in 60-90% of cancer patients.
Animal models of chemotherapy such as cisplatin-induced emesis in ferrets (Rudd and Naylor, Neuropharmacology 33:1607-1608 (1994); Naylor and Rudd, Cancer. Surv. 21:117-135 (1996)) have successfully predicted the clinical efficacy of the 5-HT3 receptor antagonists. Although this discovery led to a successful therapy for the treatment of chemotherapy- and radiation-induced sickness in cancer patients, 5-HT3 antagonists such as ondansetron and granisetron (either or not associated with dexamethasone) are effective in the control of the acute emetic phase (the first 24 h) but can only reduce the development of delayed emesis (>24 h) with poor efficacy (De Mulder et al., Annuals of Internal Medicine 113:834-840 (1990); Roila, Oncology 50:163-167 (1993)). Despite these currently most effective treatments for the prevention of both acute and delayed emesis, still 50% of patients suffer from delayed vomiting and/or nausea (Antiemetic Subcommittee, Annals Oncol. 9:811-819 (1998)).
In contrast to 5-HT3 antagonists, NK1 antagonists 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); Tattersall et al., Neuropharmacology 39:652-663 (2000)). NK1 antagonists have also been demonstrated to reduce ‘delayed’ emesis in man in the absence of concomitant therapy (Cocquyt et al., Eur. J. Cancer 37:835-842 (2001); Navari et al., N. Engl. L. Med. 340:190-195 (1999)). When administered together with dexamethasone and 5-HT3 antagonists, moreover, NK1 antagonists (such as MK-869 and CJ-11,974, also known as Ezlopitant) have been shown to produce additional effects in the prevention of acute emesis (Campos et al., J. Clin. Oncol. 19:1759-1767 (2001); Hesketh et al., Clin. Oncol. 17:338-343 (1999)).
Central neurokinin NK1 receptors play a major role in the regulation of emesis. NK1 antagonists are active against a wide 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)). The compounds are suggested to act by blocking central NK1-receptors in the nucleus tractus solitarius. Apart from NK1 antagonism, CNS penetration is thus a prerequisite for the antiemetic activity of these compounds. Loperamide-induced emesis in ferrets can be used as a fast and reliable screening model for the antiemetic activity of NK1 antagonists. Further evaluation of their therapeutic value in the treatment of both the acute and the delayed phases of cisplatin-induced emesis has been demonstrated in the established ferret model (Rudd et al., Br. J. Pharmacol. 119:931-936 (1994)). This model studies both ‘acute’ and ‘delayed’ emesis after cisplatin and has been validated in terms of its sensitivity to 5-HT3 receptor antagonists, glucocorticoids (Sam et al., Eur. J. Pharmacol. 417:231-237 (2001)) and other pharmacological challenges. It is unlikely that any future anti-emetic would find clinical acceptance unless successfully treating both the ‘acute’ and ‘delayed’ phases of emesis.
Irritable Bowel Syndrome
Patients with irritable bowel syndrome (IBS) experience impaired quality of life, and utilise health care resources extensively as they seek better “solutions” (including unnecessary repeated investigations or even surgery). Although these patients suffer from a ‘benign’ disorder (in other words, they will never die or develop significant complications), they nevertheless cause a significant economic burden by extensive health care resource utilisation, and absence from work.
A reasonable number of pre-clinical publications over the role of NK1 receptors in visceral pain has been published. Using NK1 receptor knockout mice and NK1 antagonists in animal models, different groups have demonstrated the important role played by the NK1 receptor in hyperalgesia and visceral pain. The distribution of NK1 receptors and substance P favours a major role in visceral rather than in somatic pain. Indeed more than 80% of visceral primary afferent contain substance P compared with only 25% skin afferents. NK1 receptors are also involved in gastrointestinal motility (Tonini et al., Gastioenterol. 120:938-945 (2001); Okano et al., J. Pharmacol. Exp. Ther. 298:559-564 (2001)). Because of this dual role in both gastrointestinal motility and in nociception, NK1 antagonists are considered to have potential to ameliorate symptoms in IBS patients.
BACKGROUND PRIOR ART
Compounds containing the 1-piperidin-4-yl-piperazinyl moiety were published in WO 97/16440-A1, published May 9, 1997 by Janssen Pharmaceutica N.V. for use as substance P antagonists, in WO 02/32867, published Apr. 25, 2002 by Glaxo Group Ltd. for their special advantages as neurokinin antagonists (more specifically were disclosed 4-piperazin-1-yl-piperidine-1-carboxylic acid amide derivatives), in WO 01/30348-A1, published May 03, 2001 by Janssen Pharmaceutica N.V., for use as substance P antagonists for influencing the circadian timing system, and in WO 02/062784-A1, published Aug. 15, 2002 by Hoffmann-La Roche AG for use as neurokinin-1 antagonists.
The compounds of the present invention differ from the compounds of the prior art in the substitution of the piperazinyl moiety, being a substituted pyrrolidinyl moiety as well as in their improved ability as potent, orally and centrally active neurokinin antagonists with therapeutic value, especially for the treatment of schizophrenia, emesis, anxiety and depression, irritable bowel syndrome (IBS), circadian rhythm disturbances, visceral pain, neurogenic inflammation, asthma, micturition disorders such as urinary incontinence and nociception.


DESCRIPTION OF THE INVENTION
The present invention relates to novel substituted 1-piperidin-4-yl-pyrrolidin-3-yl-piperazine derivatives according to the 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:

    
    
        n is an integer, equal to 0, 1 or 2;
        m is an integer, equal to 1 or 2, provided that if m is 2, then n is 1;
        p is an integer equal to 1 or 2;
        q is an integer equal to 0 or 1;
        Q is O or NR3;
        X is a covalent bond or a bivalent radical of formula —O—, —S— or —NR3—;
        each R3 independently from each other, is hydrogen or alkyl;
        each R1 independently from each other, is selected from the group of Ar1, Ar1-alkyl and di(Ar1)-alkyl;
        R2 is Ar2, Ar2-alkyl, di(Ar2)alkyl, Het1 or Het1-alkyl;
        Y is a covalent bond or a bivalent radical of formula —C(═O)—, —SO2−>C═CH—R or >C═N—R, wherein R is H, CN or nitro;
        each Alk represents, independently from each other, a covalent bond; a bivalent straight or branched, saturated or unsaturated hydrocarbon radical having from 1 to 6 carbon atoms; or a cyclic saturated or unsaturated hydrocarbon radical having from 3 to 6 carbon atoms; each radical optionally substituted on one or more carbon atoms with one or more, phenyl, halo, cyano, hydroxy, formyl and amino radicals;
        L is selected from the group of hydrogen, alkyl, alkyloxy, alkyloxyalkyloxy, alkylcarbonyloxy, alkyloxycarbonyl, mono- and di(alkyl)amino, mono- and di(alkyloxycarbonyl)amino, mono- and di(alkylcarbonyl)amino, mono- and di(Ar3)amino, mono- and di(Ar3alkyl)amino, mono- and di(Het2)amino, mono- and di(Het2alkyl)amino, alkylsulfanyl, adamantyl, Ar3-oxy, Ar3carbonyl, Het2, Het-oxy and Het2carbonyl;
        Ar1 is phenyl, optionally substituted with 1, 2 or 3 substituents, each independently from each other, selected from the group of halo, alkyl, cyano, aminocarbonyl and alkyloxy;
        Ar2 is naphthalenyl or phenyl, each optionally substituted with 1, 2 or 3 substituents, each independently from each other, selected from the group of halo, nitro, amino, mono- and di(alkyl)amino, cyano, alkyl hydroxy, alkyloxy, carboxyl, alkyloxycarbonyl, aminocarbonyl and mono- and di(alkyl)aminocarbonyl;
        Ar3 is naphthalenyl or phenyl, optionally substituted with 1, 2 or 3 substituents, each independently from each other, selected from the group of alkyloxy, Ar1carbonyloxyalkyl, Ar1alkyloxycarbonyl, Ar1alkyloxyalkyl, alkyl, halo, hydroxy, pyridinyl, morpholinyl, pyrrolidinyl, imidazo[1,2-a]pyridinyl, morpholinylcarbonyl, pyrrolidinylcarbonyl, amino and cyano;
        Het1 is a monocyclic heterocyclic radical selected from the group of pyrrolyl, pyrazolyl, imidazolyl, furanyl thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrmidinyl, pyrazinyl and pyridazinyl; or a bicyclic heterocyclic radical selected from the group of quinolinyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl, benzothienyl, indanyl and chromenyl; each heterocyclic radical may optionally be substituted on any atom by one or more radicals elected from the group of halo, oxo and alkyl;
        Het2 is a monocyclic heterocyclic radical selected from the group of pyrrolidinyl, dioxolyl, imidazolidinyl, 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, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl and triazinyl;
         or a bicyclic heterocyclic radical selected from the group of 2,3-dihydrobenzo[1,4]dioxine, octahydrobenzo[1,4]dioxine, benzopiperidinyl, quinolinyl, quinoxalinyl, indolyl, isoindolyl, chromanyl, benzimidazolyl, imidazo[1,2-a]pyridinyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl and benzothienyl;
         or the tricyclic heterocyclic radical 8,9-dihydro-4H-1-oxa-3,5,7a-triaza-cyclopenta[f]azulenyl; each radical may optionally be substituted with one or more radicals selected from the group of Ar1, Ar1alkyl, Ar1alkyloxyalkyl, halo, hydroxy, alkyl, piperidinyl, pyrrolyl, thienyl, oxo, alkyloxy, alkylcarbonyl, Ar1carbonyl, mono- and di(alkyl)aminoalkyl, alkyloxyalkyl and alkyloxycarbonyl; and
        alkyl is a straight or branched saturated hydrocarbon radical having from 1 to 6 carbon atoms or a cyclic saturated hydrocarbon radicals having from 3 to 6 carbon atoms; optionally substituted on one or more carbon atoms with one or more radicals selected from the group of phenyl, halo, cyano, oxo, hydroxy, formyl and amino.
    
    


More in particular, the invention relates to a compound according to the 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:

    
    
        n is an integer, equal to 1;
        m is an integer, equal to 1;
        p is an integer equal to 1 or 2;
        q is an integer equal to 0;
        Q is O
        X is a covalent bond;
        R1 is Ar1-alkyl;
        R2 is Ar2, Ar2-alkyl, di(Ar2)alkyl or Het1;
        Y is a covalent bond or a bivalent radical of formula —C(═O)—, —SO2—, >C═CH—R or >C═N—R, wherein R is CN or nitro;
        each Alk represents, independently from each other, a covalent bond; a bivalent straight or branched, saturated hydrocarbon radical having from 1 to 6 carbon atoms; or a cyclic saturated hydrocarbon radical having from 3 to 6 carbon atoms; each radical optionally substituted on one or more carbon atoms with one or more phenyl, halo and hydroxy radicals;
        L is selected from the group of hydrogen, alkyl, alkyloxy, alkyloxyalkyloxy, alkylcarbonyloxy, mono- and di(alkyl)amino, mono- and di(alkyloxycarbonyl)amino, mono- and di(alkylcarbonyl)amino, mono- and di(Ar3)amino, mono- and di(Ar3alkyl)amino, mono- and di(Het2alkyl)amino, alkylsulfanyl, adamantyl, Ar3, Het2 and Het2carbonyl;
        Ar1 is phenyl, optionally substituted with 1 or 2 halo radicals;
        Ar2 is naphthalenyl or phenyl, each optionally substituted with 1, 2 or 3 substituents, each independently from each other, selected from the group of halo, alkyl and alkyloxy;
        Ar3 is naphthalenyl or phenyl, optionally substituted with 1, 2 or 3 substituents, each independently from each other, selected from the group of alkyloxy, Ar1alkyloxycarbonyl, Ar1alkyloxyalkyl, alkyl, halo and cyano;
        Het1 is pyridinyl or a bicyclic heterocyclic radical selected from the group of quinoxalinyl, indolyl benzothienyl, indanyl and chromenyl; each heterocyclic radical may optionally be substituted on any atom by one or more radicals selected from the group of oxo and alkyl;
        Het2 is a monocyclic heterocyclic radical selected from the group of pyrrolidinyl, dioxolyl piperidinyl, morpholinyl, piperazinyl, tetrahydrofuranyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl dioxazolyl oxazolidinyl, isoxazolyl, thiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl;
         or a bicyclic heterocyclic radical selected from the group of 2,3-dihydrobenzo[1,4]dioxine, octahydrobenzo[1,4]dioxine, quinoxalinyl, indolyl, chromanyl, benzimidazolyl, imidazo[1,2-a ]pyridinyl, benzisoxazolyl, benzothiazolyl, benzofuranyl and benzothienyl;
         or the tricyclic heterocyclic radical 8,9-dihydro-4H-1-oxa-3,5,7a-triaza-cyclopenta[f]azulenyl; each radical may optionally be substituted with one or more radicals selected from the group of Ar1, Ar1alkyloxyalkyl, halo, alkyl, oxo, alkyloxy, alkylcarbonyl, Ar1carbonyl, mono- and di(alkyl)aminoalkyl, alkyloxyalkyl and alkyloxycarbonyl; and
        alkyl is a straight or branched saturated hydrocarbon radical having from 1 to 6 carbon atoms or a cyclic saturated hydrocarbon radicals having from 3 to 6 carbon atoms; optionally substituted on one or more carbon atoms with one or more radicals selected from the group of phenyl, halo and hydroxy.
    
    


More in particular, the invention relates to a compound according to the 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 R1 is Ar1methyl and attached to the 2-position or R1 is Ar1 and attached to the 3-position, as exemplified in either of the following formulas for compounds according to Formula (I) wherein m and n are equal to 1 and Ar is an unsubstituted phenyl. Preferably, Ar1methyl is a benzyl radical.




More in particular, the invention relates to a compound according to the 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 the R2—X—C(═Q)— moiety is 3,5-di-(trifluoromethyl) phenylcarbonyl.
More in particular, the invention relates to a compound according to the 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 p is 1.
More in particular, the invention relates to a compound according to the 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 Y is —C(═O)—.
More in particular, the invention relates to a compound according to the 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 Alk is a covalent bond.
More in particular, the invention relates to a compound according to the 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 L is Het2.
More in particular, the invention relates to a compound according to the 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 the compound is a compound with compound number 219, 270, 269, 281, 408, 393, 72, 164, 253, 258, 267, 286, 317, 318, 313, 308, 331, 366, 31, 32, 4, 71, 218, 259, 287, 285, 306 and 321, as mentioned in any one of Tables 1-6 further in this application.
In the framework of this application, alkyl is defined as a monovalent straight or branched saturated hydrocarbon radical having from 1 to 6 carbon atoms, for example methyl, ethyl, propyl butyl, 1-methylpropyl, 1,1-dimethylethyl, pentyl, hexyl; alkyl further defines a monovalent cyclic saturated hydrocarbon radical having from 3 to 6 carbon atoms, for example cyclopropyl methylcyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The definition of alkyl also comprises an alkyl radical that is optionally substituted on one or more carbon atoms with one or more phenyl, halo, cyano, oxo, hydroxy, formyl and amino radicals, for example hydroxyalkyl, in particular hydroxymethyl and hydroxyethyl and polyhaloalkyl, in particular difluoromethyl and trifluoromethyl.
In the framework of this application, halo is generic to fluoro, chloro, bromo and iodo.
In the framework of this application, with “compounds according to the invention” is meant a compound according to the 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.
In the framework of this application, especially in the moiety Alka-Y-Alkb in Formula (I), when two or more consecutive elements of said moiety denote a covalent bond, then a single covalent bond is denoted. For example, when Alka and Y denote both a covalent bond and Alkb is —CH2—, then the moiety Alka-Y-Alkb denotes —CH2—. Similarly, if Alka, Y and Alkb each denote a covalent bond and L denotes H, then the moiety Alka-Y-Alkb-L denotes —H.
The pharmaceutically acceptable salts are defined to comprise the therapeutically active non-toxic acid addition salts forms that the compounds according to Formula (I) are able to form. Said salts can be obtained by treating the base form of the compounds according to Formula (I) with appropriate acids, for example inorganic acids, for example hydrohalic acid, in particular hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid; organic acids, for example acetic acid, hydroxyacetic acid, propanoic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyciamic acid, salicylic acid, p-aminosalicylic acid and pamoic acid.
The compounds according to Formula (I) containing acidic protons may also be converted into their therapeutically active non-toxic metal or amine addition salts forms by treatment with appropriate organic and inorganic bases. Appropriate base salts forms comprise, for example, the ammonium salts, the alkaline and earth alkaline metal salts, in particular lithium, sodium, potassium, magnesium and calcium salts, salts with organic bases, e.g. the benzathine, N-methyl-D-glucamine, hybramine salts, and salts with amino acids, for example arginine and lysine.
Conversely, said salts forms can be converted into the free forms by treatment with an appropriate base or acid.
The term addition salt as used in the framework of this application also comprises the solvates that the compounds according to Formula (I) as well as the salts thereof, are able to form. Such solvates are, for example, hydrates and alcoholates.
The N-oxide forms of the compounds according to Formula (I) are meant to comprise those compounds of Formula (I) wherein one or several nitrogen atoms are oxidized to the so-called N-oxide, particularly those N-oxides wherein one or more tertiary nitrogens (e.g. of the piperazinyl or pyrrolidinyl radical) are N-oxidized. Such N-oxides can easily be obtained by a skilled person without any inventive skills and they are obvious alternatives for the compounds according to Formula (I) since these compounds are metabolites, which are formed by oxidation in the human body upon uptake . As is generally known, oxidation is normally the first step involved in drug metabolism (Textbook of Organic Medicinal and Pharmaceutical Chemistry, 1977, pages 70-75). As is also generally known, the metabolite form of a compound can also be administered to a human instead of the compound per se, with possibly the same effects.
The compounds according to the invention possess at least 2 oxydizable nitrogens (tertiary amines moieties). It is therefore highly likely that N-oxides will form in the human metabolism.
The compounds of Formula (I) may be converted to the corresponding N-oxide forms following art-known procedures for converting a trivalent nitrogen into its N-oxide form. Said N-oxidation reaction may generally be carried out by reacting the starting material of Formula (I) with an appropriate organic or inorganic peroxide. Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal or earth alkaline metal peroxides, e.g. sodium peroxide, potassium peroxide; appropriate organic peroxides may comprise peroxy acids such as, for example, benzenecarboperoxoic acid or halo substituted benzenecarboperoxoic acid, e.g. 3-chlorobenzenecarboperoxoic acid, peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g. tert-butyl hydroperoxide. Suitable solvents are, for example, water, lower alkanols, e.g. ethanol and the like, hydrocarbons, e.g. toluene, ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g. dichloromethane, and mixtures of such solvents.
The term “stereochemically isomeric forms” as used hereinbefore defines all the possible isomeric forms that the compounds of Formula (I) may possess. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms having that designation, said mixtures containing all diastereomers and enantiomers of the basic molecular structure. More in particular, stereogenic centers may have the R- or S-configuration; substituents on bivalent cyclic (partially) saturated radicals may have either the cis- or trans-configuration. Compounds encompassing double bonds can have an E or Z-stereochemistry at said double bond. Stereochemically isomeric forms of the compounds of Formula (I) are obviously intended to be embraced within the scope of this invention.
Following CAS nomenclature conventions, when two stereogenic centers of known absolute configuration are present in a molecule, an R or S descriptor is assigned (based on Cahn-Ingold-Prelog sequence rule) to the lowest-numbered chiral center, the reference center. R* and S* each indicate optically pure stereogenic centers with undetermined absolute configuration. If “α” and “β” are used: the position of the highest priority substituent on the asymmetric carbon atom in the ring system having the lowest ring number, is arbitrarily always in the “α” position of the mean plane determined by the ring system. The position of the highest priority substituent on the other asymmetric carbon atom in the ring system (hydrogen atom in compounds according to Formula (I)) relative to the position of the highest priority substituent on the reference atom is denominated “α”, if it is on the same side of the mean plane determined by the ring system, or “β”, if it is on the other side of the mean plane determined by the ring system.
Compounds according to Formula (I) and some of the intermediate compounds have at least two stereogenic centers in their structure.
The invention also comprises derivative compounds (usually called “pro-drugs”) of the pharmacologically-active compounds according to the invention, which are degraded in vivo to yield the compounds according to the invention. Pro-drugs are usually (but not always) of lower potency at the target receptor than the compounds to which they are degraded. Pro-drugs are particularly useful when the desired compound has chemical or physical properties that make its administration difficult or inefficient. For example, the desired compound may be only poorly soluble, it may be poorly transported across the mucosal epithelium, or it may have an undesirably short plasma half-life. Further discussion on pro-drugs may be found in Stella, V. J. et al., “Prodrugs”, Drug Delivery Systems, 1985, pp. 112-176, and Drugs, 1985, 29, pp. 455-473.
Pro-drugs forms of the pharmacologically-active compounds according to the invention will generally be compounds according to Formula (I), the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof and the N-oxide form thereof, having an acid group which is esterified or amidated. Included in such esterified acid groups are groups of the formula —COORx, where Rx is a C1-6alkyl, phenyl, benzyl or one of the following groups:




Amidated groups include groups of the formula —CONRyRz, wherein Ry is H, C1-6alkyl, phenyl or benzyl and Rz is —OH, H, C1-6alkyl, phenyl or benzyl. Compounds according to the invention having an amino group may be derivatised with a ketone or an aldehyde such as formaldehyde to form a Mannich base. This base will hydrolyze with first order kinetics in aqueous solution.

The compounds of Formula (I) as prepared in the processes described below may be synthesized in the form of racemic mixtures of enantiomers that can be separated from one another following art-known resolution procedures. The racemic compounds of Formula (I) may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali. An alternative manner of separating the enantiomeric forms of the compounds of Formula (I) involves 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 specific stereoisomer is desired, said compound would be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.
Pharmacology
Substance P and other tachykinins are involved in a variety of biological actions such as pain transmission (nociception), neurogenic inflammation, smooth muscle contraction, plasma protein extravasation, vasodilation, secretion, mast cell degranulation, and also in activation of the immune system. A number of diseases are deemed to be engendered by activation of neurokinin receptors, in particular the NK1 receptor, by excessive release of substance P and other neurokinins in particular cells such as cells in the neuronal plexi of the gastrointestinal tract, unmyelinated primary sensory afferent neurons, sympathetic and parasympathetic neurons and nonneuronal cell types (DN&P 8(1):5-23 (1995) and Longmore J. et al., “Neurokinin Receptors” Pharmacological Reviews 46(4):551-599 (1994)).
The compounds of the present invention are potent inhibitors of neurokinin-mediated effects, in particular those mediated via the NK1, NK2 and NK3 receptor, and may therefore be described as neurokinin antagonists, especially as substance P antagonists, as may be indicated in vitro by the antagonism of substance P-induced relaxation of pig coronary arteries. The binding affinity of the present compounds for the human, guinea-pig and gerbil neurokinin receptors may also be determined in vitro in a receptor binding test using 3H-substance-P as radioligand. The subject compounds also show substance-P antagonistic activity in vivo as may be evidenced by, for instance, the antagonism of substance P-induced plasma extravasation in guinea-pigs, or the antagonism of drug-induced emesis in ferrets (Watson et al., Br. J. Pharmacol. 115:84-94 (1995)).
In view of their capability to antagonize the actions of tachykinins by blocking the neurokinin receptors, and in particular by blocking the NK1, NK2 and NK3 receptor, the compounds according to the invention are useful as a medicine, in particular in the prophylactic and therapeutic treatment of tachykinin-mediated conditions. In particular are compounds according to the invention are useful as orally active, centrally penetrating medicines in the prophylactic and therapeutic treatment of tachykinin-mediated conditions.
More in particular, it has been found that some compounds exhibit a combined NK1/NK3 antagonistic activity or a combined NK1/NK2/NK3 antagonistic activity as can be seen from the Table in the experimental section.
The invention therefore relates to a compound according to the 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, for use as a medicine.
The invention also relates to the use of a compound according to any one of claims 1-3 for the manufacture of a medicament for treating, either prophylactic or therapeutic or both, tachykinin mediated conditions.
The compounds according to the invention are useful in the treatment of CNS disorders, in particular schizoaffective disorders, depression, anxiety disorders, stress-related disorders, sleep disorders, cognitive disorders, personality disorders, eating disorders, neurodegenerative diseases, addiction disorders, mood disorders, sexual dysfunction, pain and other CNS-related conditions; inflammation; allergic disorders; emesis; gastrointestinal disorders, in particular irritable bowel syndrome (IBS); skin disorders; vasospastic diseases; fibrosing and collagen diseases; disorders related to immune enhancement or suppression and rheumatic diseases and body weight control.
In particular, the compounds according to the invention are useful in the treatment or prevention of schizoaffective disorders resulting from various causes, including schizoaffective disorders of the manic type, of the depressive type, of mixed type; paranoid, disorganized, catatonic, undifferentiated and residual schizophrenia; schizophreniform disorder; delusional disorder; brief psychotic disorder; shared psychotic disorder; substance-induced psychotic disorder; and psychotic disorder not otherwise specified.
In particular, the compounds according to the invention are useful in the treatment or prevention of depression including but not limited to major depressive disorders including bipolar depression; unipolar depression; single or recurrent major depressive episodes with or without psychotic features, catatonic features, melancholic features, atypical features or postpartum onset, and, in the case of recurrent episodes, with or without seasonal pattern. Other mood disorders encompassed within the term “major depressive disorder” include dysthymic disorder with early or late onset and with or without atypical features, bipolar I disorder, bipolar II disorder, cyclothymic disorder, recurrent brief depressive disorder, mixed affective disorder, neurotic depression, post traumatic stress disorder and social phobia; dementia of the Alzheimer's type with early or late onset, with depressed mood; vascular dementia with depressed mood; substance-induced mood disorders such as mood disorders induced by alcohol, amphetamines, cocaine, hallucinogens, inhalants, opioids, phencyclidine, sedatives, hypnotics, anxiolytics and other substances; schizoaffective disorder of the depressed type; and adjustment disorder with depressed mood. Major depressive disorders may also result from a general medical condition including, but not limited to, myocardial infarction, diabetes, miscarriage or abortion, etc.
In particular, the compounds according to the invention are useful in the treatment or prevention of anxiety disorders including but not limited to panic attack; agoraphobia; panic disorder without agoraphobia; agoraphobia without history of panic disorder; specific phobia; social phobia; obsessive-compulsive disorder; post-traumatic stress disorder; acute stress disorder; generalized anxiety disorder; anxiety disorder due to a general medical condition; substance-induced anxiety disorder; and anxiety disorder not otherwise specified.
In particular, the compounds according to the invention are useful in the treatment or prevention of stress-related disorders associated with depression and/or anxiety, including but not limited to acute stress reaction; adjustment disorders, such as brief depressive reaction, prolonged depressive reaction, mixed anxiety and depressive reaction, adjustment disorder with predominant disturbance of other emotions, adjustment disorder with predominant disturbance of conduct, adjustment disorder with mixed disturbance of emotions and conduct and adjustment disorders with other specified predominant symptoms; and other reactions to severe stress.
In particular, the compounds according to the invention are useful in the treatment or prevention of sleep disorders, including but not limited to dysomnia and/or parasomnias as primary sleep disorders; insomnia; sleep apnea; narcolepsy; circadian rhythms disorders; sleep disorders related to another mental disorder; sleep disorder due to a general medical condition; and substance-induced sleep disorder.
In particular, the compounds according to the invention are useful in the treatment or prevention of cognitive disorders including but not limited to dementia; amnesic disorders and cognitive disorders not otherwise specified, especially dementia caused by degenerative disorders, lesions, trauma, infections, vascular disorders, toxins, anoxia, vitamin deficiency or endocrinic disorders; dementia of the Alzheimer's type, with early or late onset, with depressed mood; AIDS-associated dementia or amnesic disorders caused by alcohol or other causes of thiamin deficiency, bilateral temporal lobe damage due to Herpes simplex encephalitis and other limbic encephalitis, neuronal loss secondary to anoxia/hypoglycemia/severe convulsions and surgery, degenerative disorders, vascular disorders or pathology around ventricle III. Furthermore, the compounds according to the invention are also useful as memory and/or cognition enhancers in healthy humans with no cognitive and/or memory deficit.
In particular, the compounds according to the invention are useful in the treatment or prevention of personality disorders, including but not limited to paranoid personality disorder; schizoid personality disorder; schizotypical personality disorder; antisocial personality disorder; borderline personality disorder; histrionic personality disorder; narcissistic personality disorder; avoidant personality disorder; dependent personality disorder; obsessive-compulsive personality disorder and personality disorder not otherwise specified.
In particular, the compounds according to the invention are also useful in the treatment or prevention of eating disorders, including anorexia nervosa; atypical anorexia nervosa; bulimia nervosa; atypical bulimia nervosa; overeating associated with other psychological disturbances; vomiting associated with other psychological disturbances; and non-specified eating disorders.
In particular, the compounds according to the invention are also useful in 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; amyotropical lateral sclerosis; stroke and head trauma.
In particular, the compounds according to the invention are also useful in the treatment or prevention of addiction disorders including but not limited to substance dependence or abuse with or without physiological dependence, particularly where the substance is alcohol, amphetamines, amphetamine-like substances, caffeine, cocaine, hallucinogens, inhalants, nicotine, opioids (such as cannabis, heroin and morphine), phencyclidine, phencyclidine-like compounds, sedative-hypnotics, benzodiazepines and/or other substances, particularly useful for treating withdrawal from the above substances and alcohol withdrawal delirium.
In particular, the compounds according to the invention are also useful in the treatment or prevention of mood disorders induced particularly by alcohol, amphetamines, caffeine, cannabis, cocaine, hallucinogens, inhalants, nicotine, opioids, phencyclidine, sedatives, hypnotics, anxiolytics and other substances.
In particular, the compounds according to the invention are also useful in the treatment or prevention of sexual dysfunction, including but not limited to sexual desire disorders; sexual arousal disorders; orgasmic disorders; sexual pain disorders; sexual dysfunction due to a general medical condition; substance-induced sexual dysfunction and sexual dysfunction not otherwise specified.
In particular, the compounds according to the invention are also useful in the treatment or prevention of pain including but not limited to traumatic pain such as postoperative pain; traumatic avulsion pain such as brachial plexus; chronic pain such as arthritic pain such as occurring in osteo-rheumatoid or psoriatic arthritis; neuropathic pain such as post-herpetic neuralgia, trigerminal neuralgia, segmental or intercostal neuralgia, fibromyalgia, causalgia, peripheral neuropathy, diabetic neuropathy, chemotherapy-induced neuropathy, AIDS related neuropathy, occipital neuralgia, geniculate neuralgia, glossopharyngeal neuralgia, reflex sympathetic dystrophy and phantom limb pain; various forms of headache such as migraine, acute or chronic tension headache, temporomandibular pain, maxillary sinus pain and cluster headache; odontalgia; cancer pain; visceral pain; gastrointestinal pain; nerve entrapment pain; sport's injury pain; dysmennorrhoea; menstrual pain; meningitis; arachnoiditis; musculoskeletal pain; low back pain such as spinal stenosis, prolapsed disc, sciatica, angina, ankylosing spondyolitis; gout; bums; scar pain; itch; and thalamic pain such as post stroke thalamic pain.
In particular, the compounds according to the invention are also useful in the treatment or prevention of the following other CNS-related conditions: akinesia, akinetic-rigid syndromes, dyskinesia and medication-induced parionism, Gilles de la Tourette syndrome and its symptoms, tremor, chorea, myoclonus, tics and dystonia, attention-deficit /hyperactivity disorder (ADHD), Parkinson's disease, drug-induced Parkinsonism, post-encephalitic Parkinsonism, progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration, parkinsonism-ALS dementia complex and basal ganglia calcification, behavioral disturbances and conduct disorders in dementia and the mentally retarded, including restlessness and agitation, extra-pyramidal movement disorders, Down's syndrome and Akathisia.
In particular, the compounds according to the invention are also 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 damage; inflammatory conditions of the skin such as herpes and eczema; inflammatory conditions of the bladder such as cystitis and urge incontinence; eye and dental inflammation and pancreatitis, in particular chronic and acute pancreatitis.
In particular, the compounds according to the invention are also useful in the treatment or prevention of allergic disorders, including but not limited to allergic disorders of the skin such as but not limited to urticaria; and allergic disorders of the airways such as but not limited to rhinitis.
In particular, the compounds according to the invention are also 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 agents such as alkylating agents, for example cyclophosphamide, carmustine, lomustine and chlorambucil; cytotoxic antibiotics, for example dactinomycin, doxorubicin, mitomycin-C and bleomycin; anti-metabolites, for example cytarabine, methotrexate and 5-fluorouracil; vinca alkaloids, for example etoposide, vinblastine and vincristine; and other drugs such as cisplatin, dacarbazine, procarbazine and hydroxyurea; and combinations thereof; radiation sickness; radiation therapy, such as in the treatment of cancer; poisons; toxins such as toxins caused by metabolic disorders or by infection, such as gastritis, or released during bacterial or viral gastrointestinal infection; pregnancy; vestibular disorders, such as motion sickness, vertigo, dizziness and Meniere's disease; post-operative sickness; gastrointestinal obstruction; reduced gastrointestinal motility; visceral pain, such as myocardial infarction or peritonitis; migraine; increased intracranial pressure; decreased intracranial pressure (such as altitude sickness); opioid analgesics, such as morphine; gastro-oesophageal reflux disease; acid indigestion; over-indulgence of food or drink; acid stomach; sour stomach; waterbrash/regurgitation; heartburn, such as episodic heartburn, nocturnal heartburn and meal induced heartburn; and dyspepsia.
In particular, the compounds according to the invention are also useful in the treatment or prevention of gastrointestinal disorders, including but not limited to irritable bowel syndrome (IBS), skin disorders such as psoriasis, pruritis and sunburn; vasospastic diseases such as angina, vascular headache and Reynaud's disease, cerebral ischaemia such as cerebral vasospasm following subarachnoid haemorrhage; fibrosing and collagen diseases such as scleroderma and eosinophilic fascioliasis; disorders related to immune enhancement or suppression such as systemic lupus erythematosus and rheumatic diseases such as fibrositis; cough; and body weight control, including obesity.
The present invention also relates to a method for the treatment and/or prophylaxis of tachykinin-mediated diseases, in particular for the treatment and/or prophylaxis of schizophrenia, depression, anxiety disorders, emesis and irritable bowel syndrome (IBS) comprising administering to a human in need of such administration an effective amount of a compound according to the invention, in particular according to Formula (I), the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof the N-oxide form thereof, as well as the pro-drugs thereof.
The invention also relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound according to the invention, in particular a compound according to 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
The compounds according to the invention, in particular the compounds according to Formula (I), the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the N-oxide form thereof and the prodrugs thereof, or any subgroup or combination thereof may be formulated into various pharmaceutical forms for administration purposes. As appropriate compositions there may be cited all compositions usually employed for systemically administering drugs. To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, optionally in addition salt form, as the active ingredient is combined in intimate admixture 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 desirable in unitary dosage form suitable, in particular, for administration orally, rectally, percutaneously, by parenteral injection or by inhalation. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit forms in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. 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 that are intended to be converted, shortly before use, to liquid form preparations. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions. These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on, as an ointment.
It is especially advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. Unit dosage form as used herein refers to physically 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 or coated tablets), capsules, pills, powder packets, wafers, suppositories, injectable solutions or suspensions and the like, and segregated multiples thereof.
Since the compounds according to the invention are potent orally, mainly centrally active NK1, NK1/NK3 and NK1/NK2/NK3 antagonists, pharmaceutical compositions comprising said compounds for administration orally are especially advantageous.
Synthesis
The compounds according to the invention can generally be prepared by a succession of steps, each of which is known to the skilled person.
The final compounds of Formula (I) are conveniently prepared by reductively N-alkylating an intermediate compound of Formula (II) with an intermediate compound of Formula (III) . Said reductive N-alkylation may be performed in a reaction-inert solvent such as, for example, dichloromethane, ethanol or toluene or a mixture thereof, and in the presence of an appropriate reducing agent such as, for example, a borohydride, e.g. sodium borohydride, sodium cyanoborohydride or triacetoxy borohydride. In case a borohydride is used as a reducing agent, it may be convenient to use a complex-forming agent such as, for example, titanium(IV)isopropylate as described in J. Org. Chem., 1990, 55, 2552-2554. Using said complex-forming agent may also result in an improved cis/trans ratio in favour of the trans isomer. It may also be convenient to use hydrogen as a reducing agent in combination with a suitable catalyst such as, for example, palladium-on-charcoal or platinum-on-charcoal. In case hydrogen is used as reducing agent, it may be advantageous to add a dehydrating agent to the reaction mixture such as, for example, aluminium tert-butoxide. In order to prevent the undesired further hydrogenation of certain functional groups in the reactants and the reaction products, it may also be advantageous to add an appropriate catalyst-poison to the reaction mixture, e.g., thiophene or quinoline-sulphur. Stirring and optionally elevated temperatures and/or pressure may enhance the rate of the reaction.




In this and the following preparations, the reaction products may be isolated from the reaction medium and, if necessary, further purified according to methodologies generally known in the art such as, for example, extraction, crystallization, trituration and chromatography.
Especially advantageous is the preparation of a final compound according to Formula (I) according to the previously mentioned reaction scheme in which the Alk-Y-Alk-L-moiety is benzyl, thus giving rise to a compound according to Formula (I) in which the Alk-Y-Alk-L-moiety is benzyl. Said final compound is pharmacologically active and can be converted into a final compound according to the invention in which the Alk-Y-Alk-L-moiety is hydrogen by reductive hydrogenation using e.g. hydrogen as a reducing agent in combination with a suitable catalyst such as, for example, palladium-on-charcoal or platinum-on-charcoal. The resulting final compound according to the invention can then be converted into other compounds according to Formula (I) by art-known transformations, e.g. acylation and alkylation.
In particular, the final compounds of Formula (Ia) can be prepared by reacting a final compound of Formula (I′) with an intermediate compound of Formula (V) wherein W1 is an appropriate leaving group such as, for example, a halogen, e.g. chloro or bromo, or a sulfonyloxy leaving group, e.g. methanesulfonyloxy or benzenesulfonyloxy. The reaction can be performed in a reaction-inert solvent such as, for example, a chlorinated hydrocarbon, e.g. dichloromethane or a ketone, e.g. methyl isobutylketone, and in the presence of a suitable base such as, for example, sodium carbonate, sodium hydrogen carbonate or triethylamine. Stirring may enhance the rate of the reaction. The reaction may conveniently be carried out at a temperature ranging between room temperature and reflux temperature.




Alternatively, the final compounds of Formula (Ia) can also be prepared by reacting a final compound of Formula (I′) with a carboxylic acid of Formula (VI). The reaction can be performed in a reaction-inert solvent such as, for example, a chlorinated hydrocarbon, e.g. dichloromethane, in the presence of a suitable base such as, for example, sodium carbonate, sodium hydrogen carbonate or triethylamine and in the presence of an activator, such as e.g. DCC (dicyclohexylcarbodiimide), CDI (carbonyldiimidazole) and EDCI (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.HCl). Stirring may enhance the rate of the reaction. The reaction may conveniently be carried out at a temperature ranging between room temperature and reflux temperature.




In particular, the final compounds of Formula (Ib) can be prepared by reacting a final compound of Formula (I′) with a compound of Formula (VII) wherein W2 is an appropriate leaving group such as, for example, a halogen, e.g. chloro or bromo, or a sulfonyloxy leaving group, e.g. methanesulfonyloxy or benzenesulfonyloxy. The reaction can be performed in a reaction-inert solvent such as, for example, a chlorinated hydrocarbon, e.g. dichloromethane, an alcohol, e.g. ethanol, or a ketone, e.g. methyl isobutylketone, and in the presence of a suitable base such as, for example, sodium carbonate, sodium hydrogen carbonate or triethylamine. Stirring may enhance the rate of the reaction. The reaction may conveniently be carried out at a temperature ranging between room temperature and reflux temperature.




The final compounds of Formula (Ic) and Formula (Id) can be prepared either by alkylation or reductive amination of a final compound of Formula (I′) with either a compound of Formula (VIII) or (IX) wherein W3 in Formula (VIII) is an appropriate leaving group such as, for example, a halogen, e.g. chloro or bromo, or a sulfonyloxy leaving group, e.g. methanesulfonyloxy or benzenesulfonyloxy and wherein All in Formula (Id) is defined as —CH2-Alk. The reaction can be performed in a reaction-inert solvent such as, for example, a chlorinated hydrocarbon, e.g. dichloromethane, an alcohol, e.g. ethanol, or a ketone, e.g. methyl isobutylketone, and in the presence of a suitable base such as, for example, sodium carbonate, sodium hydrogen carbonate or triethylamine. Stirring may enhance the rate of the reaction. The reaction may conveniently be carried out at a temperature ranging between room temperature and reflux temperature.




The starting materials and some of the intermediates are known compounds and are commercially available or may be prepared according to conventional reaction procedures generally known in the art. For example, intermediate compounds of Formula (II) may be prepared by reductively N-alkylating an intermediate compound of Formula (XI) with an intermediate compound of Formula (XII) in which W4 is a benzyl radical, after which the resulting compound is subsequently reduced to yield an intermediate compound according to Formula (II). Said reductive N-alkylation may be performed in a reaction-inert solvent such as, for example, dichloromethane, ethanol, toluene or a mixture thereof, and in the presence of an appropriate reducing agent such as, for example, a borohydride, e.g. sodium borohydride, sodium cyanoborohydride or triacetoxy borohydride. In case a borohydride is used as a reducing agent, it may be convenient to use a complex-forming agent such as, for example, titanium(IV)isopropylate as described in J. Org. Chem., 1990, 55, 2552-2554. Using said complex-forming agent may also result in an improved cis/trans ratio in favour of the trans isomer. It may also be convenient to use hydrogen as a reducing agent in combination with a suitable catalyst such as, for example, palladium-on-charcoal or platinum-on-charcoal. In case hydrogen is used as reducing agent, it may be advantageous to add a dehydrating agent to the reaction mixture such as, for example, aluminium tert-butoxide. In order to prevent the undesired further hydrogenation of certain functional groups in the reactants and the reaction products, it may also be advantageous to add an appropriate catalyst-poison to the reaction mixture, e.g., thiophene or quinoline-sulphur. Stirring and optionally elevated temperatures and/or pressure may enhance the rate of the reaction.




The preparation of intermediate compounds (XI) and (XII) and other intermediates is described in WO 97/16440-A1, published May. 9, 1997 by Janssen Pharmaceutica N.V., which is disclosed herein by reference as well as in other publications mentioned in WO 97/16440-A1, such as, e.g. EP-0,532,456-A.
The following examples are intended to illustrate but not to limit the scope of the present invention.
EXPERIMENTAL PART
Hereinafter “RT” means room temperature, “THF ” means tetrahydrofuran, “DIPE” means diisopropylether and “DMF” means N,N-dimethylformamide.
A. Preparation of the Intermediate Compounds
Example A1
a. Preparation of Intermediate Compound 1




Et3N (0.55 mol) was added to a stirring mixture of 7-(phenylmethyl)-1,4-dioxa-8-azaspiro[4.5]decane (0.5 mol) in toluene (1500 ml). 3,5-Bis(trifluoromethyl)benzoyl chloride (0.5 mol) was added over a 1-hour period (exothermic reaction). The mixture was stirred at room temperature for 2 hours, allowed to stand for the weekend and washed three times with water (500 ml, 2×250 ml). The organic layer was separated, dried, filtered and the solvent was evaporated. Yield: 245 g (100%). Part of this fraction was crystallized from petroleum ether. The precipitate was filtered off and dried. Yield: 1.06 g of intermediate compound 1.
b1. Preparation of Intermediate Compound 2




HCl cp (300 ml) was added to a mixture of intermediate compound 1 (0.5 mol) in ethanol (300 ml) and H2O (300 ml). The reaction mixture was stirred at 60° C. for 20 hours. The precipitate was filtered off, ground, stirred in H2O, filtered off, washed with petroleum ether and dried. Yield: 192 g of intermediate compound 2 ((+−)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinone) (89.4%) (mixture of R and S enantiomers).
b2. Preparation of Intermediate Compound 10 and Intermediate Compound 11.




Intermediate compound 2 was separated into its optical isomers by chiral column chromatography over Chiralpak (CHIRALPAK AS 1000 Å 20 mm (DAICEL); eluent: hexane/2-propanol 70/30). Two product fractions were collected and each solvent was evaporated. Yield Fraction 1: 32.6 g of intermediate compound 10 (R), and Fraction 2: 30.4 g of intermediate compound 11 (S).
c. Preparation of Intermediate Compound 3




A mixture of intermediate compound 10 (0.046 mol), 1-(phenylmethyl)piperazine (0.051 mol) and Ti-isopropoxide (0.056 mol) was stirred for 2 hours at 40° C. The reaction mixture was cooled to room temperature. Ethanol, p.a. (350 ml) was added. NaBH4(0.138 mol) was added. The resulting reaction mixture was stirred for one hour at room temperature and for one hour at 50° C. More NaBH4 (5.2 g) was added and the reaction mixture was stirred for 2 hours at 50° C. Again, NaBH4 was added and the reaction mixture was stirred overnight at room temperature and for 2 hours at 50° C. Water (10 ml) was added. The mixture was stirred for 15 min. CH2Cl2 (200 ml) was added and the mixture was stirred for 15 min. The organic phase was separated, dried (MgSO4), dicalite was added, the mixture was filtered over dicalite, and the filtrate was evaporated. This fraction was separated into (CIS) and (TRANS) by column chromatography over silica gel. The desired (TRANS)-fractions were collected and the solvent was evaporated, giving 14.8 g of residue ((I), 1.06% (CIS)) and 4.9 g of residue ((II), 6% (CIS)). Resolution and purification of those (TRANS)-fractions (±20 g in total) was obtained by chromatography over stationary phase Chiralcel OD (1900 Gr) in Prochrom LC110 35 bar (eluent: hexane/ethanol 90/10). The desired fractions were collected and the solvent was evaporated. Yield: 9.5 g of intermediate compound 3 (2R-trans)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-[4-(phenyhmethyl)-1-piperazinyl]piperidine. It is without saying that the same reaction can be carried out on compound 11 for obtaining the S-isomer, as well as on any mixture of them. It is also without saying that also the cis-isomer can be used in all reactions in this application exemplified for the trans-isomer or for a mixture of cis and trans-isomers.
d. Preparation of Intermediate Compound 4




A mixture of intermediate compound 3 (0.288 mol) in methanol (700 ml) was hydrogenated at 40° C. with Pd/C, 10% (5 g) as a catalyst. After uptake of H2 (1 eq.), the catalyst was filtered off and the filtrate was evaporated. Yield: 141.2 g of intermediate compound 4 (+)-(2R-trans)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-(1-piperazinyl)piperidine.
Example A2
a. Preparation of Intermediate Compound 5




A mixture of final compound 1 (prepared according to B1a) (0.03 mol) in iPrOH (150 ml) and KOH (0.3 mol) was stirred and refluxed for 18 hours. The solvent was evaporated and the residue was taken up in CH2Cl2/H2O. The layers were separated. The organic layer was dried and filtered. The solvent was evaporated and the residue purified by column chromatography over silica gel (gradient eluent: CH2Cl2/(MeOH/NH3) 95/5 to 90/10). The product fractions were collected and the solvent evaporated. Yield: 12 g of intermediate compound 5.
b. Preparation of Intermediate Compound 6




A mixture of intermediate compound 5 (0.029 mol) in bis(1,1-dimethylethyl)-dicarbonic acid ester (0.035 mol) was stirred 18 hours at room temperature. The solvent was evaporated for 30 minutes at 50-60° C. The residue was taken up in CH2Cl2/H2O and NaOH. The organic layer was separated, washed with water, dried and the solvent evaporated. The residue was suspended in toluene and the solvent was evaporated. Yield: 15.5 g of intermediate compound 6.
c. Preparation of Intermediate Compound 7




A mixture of intermediate compound 6 (0.03 mol), Pd/C, 10% (2 g), H2 (1 eq) in methanol (250 ml) was stirred. After uptake of H2 (1 eq.), the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography over silica gel (gradient eluent: CH2Cl2/(MeOH/NH3) 90/10 to 85/15). The product fractions were collected and suspended in petroleum ether, filtered and dried Yield: 11.6 g of intermediate compound 7.
d. Preparation of Intermediate Compound 8




A mixture of 3-furancarboxylic acid (0.033 mol) in CH2Cl2 (100 ml) and 1,1′-carbonylbis-1H-imidazole (0.033 mol) was stirred for 3 hours at room temperature. Intermediate compound 7 (0.027 mol) in CH2Cl2 (100 ml) was added and stirred overnight at room temperature. The reaction mixture was washed with aqueous NaOH, with H2O, dried and the solvent was evaporated. The residue was purified by column chromatography over silica gel (gradient eluent: CH2Cl2/MeOH) 98/2 to 90/10). The product fractions were collected and the solvent was evaporated. The residue was crystallized from DIPE. The solid was dried. Yield: 7.83 g of intermediate compound 8
e. Preparation of Intermediate Compound 9




iPrOH.HCl (3 ml) was added to a mixture of intermediate compound 8 (1 g) in iPrOH (30 ml). The mixture was stirred at 65° C. for 90 minutes. The solvent was evaporated. The residue was suspended in DIPE. The precipitate was filtered and washed with DIPE. Yield: 0.93 g of intermediate compound 9 (.HCl).
Example A3
a. Preparation of Intermediate Compound 12




A mixture of 6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepine (0.02 mol) and Et3N (0.035 mol) in CH3CN (50 ml) was stirred at room temperature and under N2 flow. Chloro-oxo acetic acid ethyl ester (0.03 mol) was added dropwise at <10° C. Stirring was continued overnight. Water was added and the reaction mixture was extracted with CH2Cl2. The organic layer was separated, dried (MgSO4) , filtered and the solvent was evaporated. The residue was purified over silica gel on a glass filter (eluent: CH2Cl2/CH3OH 98/2). The pure fractions were collected and the solvent was evaporated. Yield: 2 g of intermediate compound 12 (42%).
b. Preparation of Intermediate Compound 13




A mixture of intermediate compound 12 (0.0084 mol) in 2-propanone (30 ml) was stirred, while cooling on an ice-bath. Excess Jones' reagent (prepared according to the method below) was added dropwise at room temperature. The reaction mixture was stirred for a while. Water (50 ml) was added and this mixture was alkalized with K2CO3. This mixture was evaporated. The residue was stirred in CH3OH. The salts were removed by filtration over dicalite. The filtrate was evaporated. The residue was stirred in CH2Cl2. The organic layer was decanted, dried (MgSO4), filtered and the solvent was evaporated. The residue was purified over silica gel on a glass filter (eluent: CH2Cl2/CH3OH 95/5). The pure fractions were collected and the solvent was evaporated. The residue (0.56 g) was stirred in DIPE, filtered off and dried. Yield: 0.32 g of intermediate compound 13 (25%).
Preparation of Jones' reagent: CrO3 (26.72 g) was dissolved in H2O (50 ml). H2SO4 (98%; 23 ml) was added dropwise, while cooling. Water was added until a total volume of 100 ml was obtained.
c. Preparation of Intermediate Compound 14




A mixture of intermediate compound 13 (0.0176 mol) in H2O (10 ml) and HOAc (3 ml) was stirred at 50° C. NaNO2 (1.35 g) was added portionwise over a 5 min. period and the mixture was stirred at 50° C. for 1 h. The mixture was cooled on an ice bath and filtered off. The precipitate was washed with ice water and dried in an desiccator. Yield: 1.25 g of intermediate compound 14 (35.8%).
d. Preparation of Intermediate Compound 15




A mixture of intermediate compound 14 (0.045 mol) in HOAc (90 ml) and acetic acid anhydride (9 ml) was stirred on an oil bath at 85° C. Acetylchloride (13.7 ml) was added dropwise over a 30 min. period and the mixture was stirred at 85° C. for 1 hour. The mixture was cooled, poured into ice/K2CO3 and extracted with CHCl3. The organic layer was dried and evaporated. The residue was boiled up in CH3CN and cooled. The precipitate was filtered off and dried. Yield: 14.32 g of intermediate compound 15 (47.3%).
Example A4
a. Preparation of Intermediate Compound 16




NaH (0.086 mol) was added portionwise to a solution of 3-thiophene ethanol (0.078 mol) in THF at 5° C. The mixture was stirred for 1 hour at 5° C. Bu4NI (0.001 mol) and (bromomethyl)benzene (0.080 mol) were added. The mixture was stirred at room temperature for 3 hours, taken up in H2O and extracted with AcOEt. The organic layer was separated, dried (MgSO4) and solvent was evaporated. The concentrate 1 (18 g) was purified by column chromatography over silica gel (gradient eluent: Cyclohexane/AcOEt 100/0 to 80/20). The pure fractions were collected and the solvent was evaporated. Yield: 9.9 g intermediate compound 16 (58%).
b. Preparation of Intermediate Compound 17




To a solution of intermediate compound 16 (0.023 mol) in THF (50 ml) at −50° C., BuLi[1.6M] (0.025 mol) was added portionwise under N2. The temperature was raised slowly to 0° C. The mixture was stirred at 0° C. for 1 hour and cooled to −40° C. A solution of SO2Cl2 (0.046 mol) in pentane (50 ml) was added at −40° C. The mixture was stirred at −40° C. for 1 hour. The concentrate was hydrolyzed, extracted with AcOEt, washed with a saturated solution of NaCl, dried over MgSO4 and concentrated, providing 9 g. The concentrate was purified by column chromatography over silica gel (gradient eluent: Cyclohexane/AcOEt 100/0 to 80/20). Yield 1.2 g of intermediate compound 17 (16%).
Example A5
a. Preparation of Intermediate Compound 18




NaH (60% in oil) (0.086 mol, 3.4 g) was added portionwise to a solution of 2-(2-thienyl)ethanol (0.078 mol, 10 g) in THF (150 ml) under N2 flow at 5° C. The mixture was stirred at 5° C. during 1 hour. Tetrabutylammonium iodide (0.001 mol, 0.3 g) and (bromomethyl)benzene (0.080 mol, 9.5 ml) were added consecutively to the solution. The mixture was stirred at room temperature during 3 hours poured into water, extracted with ethyl acetate, dried over MgSO4 and concentrated. The crude product (18 g) was purified by column chromatography over silica gel (gradient eluent: CH2Cl2/Cyclohexane 0/100 to 20/80) and the product fractions were concentrated. Yield: 11.4 g (66%) of intermediate compound 18.
b. Preparation of Intermediate Compound 19




n-BuLi (1.6 M) (0.015 mol, 9.45 ml) was added slowly to a solution of intermediate compound 18 (0.014 mol, 3 g) in THF (30 ml) under N2 flow at −40° C. The reaction was allowed to warm up slowly to 0° C. and cooled to −70° C. Dry ice ( ̃2 g) was added. The temperature was slowly allowed to rise to room temperature. NaOH (1 mol per liter, 30 ml) was added, the mixture was washed with diethyl ether. The aqueous layer was acidified with HCl (1N) and extracted with CH2Cl2. The organic layer was dried over MgSO4 and concentrated to yield 2.6 g (71%) of intermediate compound 19.
Example A6
a. Preparation of Intermediate Compound 20




A mixture of 2-[(3,4-dichlorophenyl)methyl]-4-oxo-1-piperidinecarboxylic acid ethyl ester (0.3 mol), 1,2-ethanediol (1.5 mol) and 4-methylbenzenesulfonic acid (2 g) in toluene (750 ml) was stirred and refluxed for 68 hours using a water separator. 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 evaporated. Yield: 113.5 g of intermediate compound 20.
b. Preparation of Intermediate Compound 21




A mixture of intermediate compound 20 (0.1 mol) and KOH (0.9 mol) in 2-propanol (500 ml) was stirred and refluxed overnight. The solvent was evaporated. The residue was dissolved in CH2Cl2 and washed with a small amount of H2O. The organic layer was dried, filtered and the solvent was evaporated. Yield: 33 g of intermediate compound 21.
c. Preparation of Intermediate Compound 22




Intermediate compound 21 (0.139 mol) was dissolved in CH2Cl2 (420 ml). 3,5-bis(trifluoromethyl)benzoylchloride (0.15 mol) was added dropwise (exothermic). Et3N (30 ml) was added. The reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was washed with a basic NaOH solution, dried, filtered and the solvent evaporated. The residue was purified over silica gel on a glass filter (gradient eluent: CH2Cl2/CH3OH from 100/0 to 95/5). The product fractions were collected and the solvent was evaporated. The residue was crystallized from DIPE, filtered off and dried. Yield: 56.3 g of fraction 1. The filtrate was evaporated. The residue was suspended in petroleum ether, filtered off and dried. Yield: 9 g of fraction 2. The total yield (65.3 g) of these fractions was separated and purified by chiral column chromatography (AD-packing, eluent: heptane/ethanol 95/5). Two product fraction groups were collected and their solvent was evaporated. Each residue was crystallized from DIPE, filtered off and dried. Yield: 23.9 g of intermediate compound 22 (optically pure).
d. Preparation of Intermediate Compound 23




A mixture of intermediate compound 22 (0.0424 mol) in HCl (6N) (230 ml) was stirred and refluxed for 4 hours. The reaction mixture was stirred overnight and extracted with CH2Cl2. The organic layer was separated, washed with water, dried and the solvent was evaporated. Yield: 20 g of intermediate compound 23 (S-isomer).
Example A7
a. Preparation of Intermediate Compound 24, 25 and 26




A mixture of 1,1-dimethylethyl-1-pyrrolidinecarboxylic acid ester (0.2 mol) and 1-(phenylmethyl)piperazine (0.2 mol) in methanol (250 ml) was stirred and hydrogenated at 50° C. with Pd/C, 10% (3 g) as a catalyst in the presence of thiophene solution (3 ml). After uptake of H2 (1 eq), the catalyst was filtered off and the filtrate was evaporated. Yield: intermediate compound 24 (racemic mixture). This fraction was separated and purified by column chromatography (DAICEL; AD-packing, 2000 g, 750 m/min; eluent: heptane/ethanol/methanol 90/5/5). Two product fraction groups were collected and their solvent was evaporated. Yield: 30 g of intermediate compound 25 (S-isomer) (ee: >99%), and 26 g of intermediate compound 26 (R-isomer) (ee: >99%).
b. Preparation of Intermediate Compound 27




A mixture of intermediate compound 26 (0.078 mol) in methanol (250 ml) was hydrogenated at room temperature with Pd/C 10% (2 g) as a catalyst. After uptake of H2 (1 eq.), the catalyst was filtered off and the filtrate was evaporated. The residue was taken up in CH2Cl2 and washed with H2O. The organic layer was separated, dried (MgSO4), filtered off and the solvent was evaporated. Yield: 16.3 g of intermediate compound 27 (82%) (R-isomer).
c. Preparation of Intermediate Compound 28




A solution of intermediate compound 27 (0.02 mol) in a small amount of CH2Cl2 was added to 3-phenyl-1-(phenylmethyl)-4-piperidinone (0.02 mol) and the mixture was stirred, toluene was added and the reaction mixture was evaporated. Titanium, tetrakis(2-propanolato) (0.025 mol) was added to the residual oil and the mixture was stirred for 3 hours at 50° C., EtOH, p.a. (30 ml) was added and the resulting mixture was stirred for 15 min. at room temperature. Finally NaBH3CN (0.04 mol) was added and the reaction mixture was stirred for 20 hours at room temperature. The mixture was washed with a basic NaOH solution and CH2Cl2 was added. The resulting mixture was stirred for 15 min. and after addition of dicalite the mixture was filtered over dicalite. The organic layer was separated, dried (MgSO4), filtered off and the solvent was evaporated. The residue was purified over silica gel on a glass filter (gradient eluent: CH2Cl2/CH3OH 100/0→90/10). The product fractions were collected and the solvent was evaporated. Yield: 6.4 g of intermediate 28.
d. Preparation of Intermediate Compound 29




A mixture of intermediate compound 28 (0.013 mol) in CH3OH (150 ml) was hydrogenated at 50° C. with Pd/C 10% (2 g) as a catalyst. After uptake of H2 (1 eq.), the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography over silica gel (gradient eluent: CH2Cl2/(CH3OH/NH3) 100/0−>80/20). The product fractions were collected and the solvent was evaporated. Yield: 2 g of intermediate compound 29.
Example A8
Preparation of Intermediate Compound 30




The intermediate compound 30 was obtained by the same method as described in A7.b, but instead of intermediate compound 26 intermediate compound 25 was used.
B. Preparation of the Final Compounds
Example B1
a) Preparation of Final Compound 1




A mixture of (2R-trans) 1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)4-(1-piperazinyl)piperidine [intermediate compound 3] (0.05 mol) and 1-(phenylmethyl)-3-pyrrolidinone (0.05 mol) in methanol (250 ml) was hydrogenated at 50° C. with Pd/C 10% (3 g) as a catalyst in the presence of a thiophene solution (2 ml). After uptake of H2 (1 eq.), the catalyst was filtered off and the solvent was evaporated. The residue was purified by column chromatography over silica gel (gradient eluent: CH2Cl2/MeOH 100/0; 99/1; 98/2; 96/4). The desired fractions were collected and the solvent was evaporated. This fraction was recrystallized from DIPE. The precipitate was filtered off, washed with DIPE and dried (vacuum; 50° C.). Yield: 16.8 g (49%) of final compound 1.
b) Preparation of Final Compound 2




Final compound 1 (0.022 mol) in methanol (250 ml) was hydrogenated with Pd/C 10% (2 g) as a catalyst. After uptake of H2 (1 eq.), the catalyst was filtered off and the solvent was evaporated. This fraction was triturated under DIPE. The precipitate was filtered off, washed with DIPE and dried (vacuum; 50° C.; 3 days). Yield: 11.58 g (92%) of final compound 2.
Example B2
Preparation of Final Compound 3




A mixture of final compound 2 (0.0016 mol), benzoylchloride (0.0018 mol) and Et3N (0.0018 mol) in CH2Cl2 (50 ml) was stirred at room temperature for 3 hours. The reaction mixture was washed with aq. diluted NaOH solution. The separated organic layer was dried (MgSO4), filtered and the solvent was evaporated. This fraction was purified by column chromatography over silica gel (gradient eluent: CH2Cl2/MeOH 100/0 to 90/10). The desired fractions were collected and the solvent was evaporated. The residue was dried (vacuum; 50° C.). Yield: 0.410 g of final compound 3.
Example B3
Preparation of Final Compound 80




A mixture of final compound 2 (0.0017 mol), methyl acrylate (0.0019 mol) in methanol (50 ml) was stirred overnight at room temperature. The solvent was evaporated and the residue was purified by column chromatography over silica gel (gradient eluent: CH2Cl2MeOH 100/0 to 90/10). The desired fractions were collected and the solvent was evaporated. The residue was dried (vacuum, 50° C.). Yield: 0.266 g of final compound 80.
Example B4
Preparation of Final Compound 5




A mixture of final compound 2 (0.003 mol), 2-chloropyrimidine (0.0033 mol) and Na2CO3 (0.004 mol) in ethanol p.a. (50 ml) was stirred and refluxed for 8 hours. The solvent was evaporated and the residue was taken up in H2O/CH2Cl2. The layers were separated, the aqueous layer was extracted with CH2Cl2 and the organic layer was washed with H2O, dried (MgSO4) and filtered. The solvent was evaporated and the residue was purified by column chromatography over silica gel (gradient eluent: CH2Cl2/CH3OH from 100/0 to 90/10). The product fractions were collected and the solvent was evaporated Yield: 1.378 g of final compound 5.
Example B5
Preparation of Final Compound 79




A mixture of final compound 2 (0.002 mol), 3,5-dimethylisoxazole-4-sulfonylchloride (0.002 mol), Na2CO3 (0.005 mol) and CH2Cl2 (50 ml) was stirred at room temperature overnight. The reaction mixture was purified by column chromatography over silica gel (eluent CH2Cl2/MeOH 95/5). The desired fractions were collected and the solvent evaporated. The residue was dried at 50° C. Yield: 0.98 g of final compound 79.
Example B6
Preparation of Final Compound 81




A mixture of intermediate compound 9 (prepared according to A2e) (0.0005 mol) in CH2Cl2 (25 ml), 3,4,5-trimethoxybenzoylchloride (0.0006 mol) and Et3N (1 ml) was stirred for 3 hours. The reaction mixture was washed with diluted NaOH during 30 minutes, washed with H2O, dried and the solvent was evaporated. The residue was purified by column chromatography over silica gel (gradient eluent: CH2Cl2/MeOH 98/2; 90/10). The desired fractions were collected and the solvent evaporated. Yield: 0.114 g of final compound 81.
Example B7
Preparation of Final Compound 104




Final compound 2 was dissolved in CH2Cl2 (100 ml). Alpha-chlorobenzeneacetyl chloride (0.01 mol) was added and the mixture was stirred for 18 hours at room temperature. The reaction mixture was washed with aqueous Na2CO3. The organic layer was separated, dried and the solvent evaporated. The residue was purified by column chromatography over silica gel (gradient eluent: CH2Cl2/MeOH 100/0 to 90/10). The desired fractions were collected and the solvent evaporated. Yield: 6 g of final compound 104.
Example B8
Preparation of Final Compound 108




A mixture of final compound 104 (prepared according to B7) (0.001 mol) and pyrrolidine (0.5 g) was stirred overnight at a bath temperature of 85° C. The excess pyrrolidine was evaporated. The residue was purified by column chromatography over silica gel (gradient eluent: CH2Cl2/MeOH 100/0 to 80/20). The desired fractions were collected and the solvent evaporated. Yield: 0.194 g of final compound 108.
Example B9
Preparation of Final Compound 109




Final compound 104 (prepared according to B7) (0.001 mol) was dissolved in methanol (5 ml). NaOCH3 (0.002 mol) was added and the mixture was stirred and refluxed for 48 hours. After 24 hours of stirring and refluxing once more NaOCH3 (0.002 mol) was added. The reaction mixture was evaporated. The residue was purified by column chromatography over silica gel (gradient eluent: CH2Cl2/MeOH 100/0 to 90/10). The desired fractions were collected and the solvent evaporated. Yield: 0.310 g of final compound 109.
Example B10
Preparation of Final Compound 110




NaH (0.002 mol) was added to 2-methylimidazole (0.002 mol) in DMF (10 ml). To the mixture final compound 104 (prepared according to B7) (0.001 mol) diluted in DMF (5 ml) was added and stirred at room temperature for 1 hour. The mixture was stirred for 18 hours at a temperature of 100° C. The solvent was evaporated. The residue was taken up in H2O/CH2Cl2. The organic layer was separated, dried and evaporated. The residue was purified by column chromatography over silica gel (gradient eluent: CH2Cl2/MeOH 100/0 to 80/20). The desired fractions were collected and the solvent evaporated. The residue was suspended in petroleum ether, filtered off and dried. Yield: 0.190 g of final compound 110.
Example B11
a. Preparation of Final Compound 230




Chloroacetyl chloride (0.01 mol) was added to a solution of final compound 2 (prepared according to B1.b) (0.01 mol) in CH2Cl2 (75 ml), Et3N (3 ml) was added and the reaction mixture was stirred for 4 hours at room temperature. The mixture was washed with a basic NaOH solution, dried and the solvent was evaporated (<35° C.). DIPE was added and the solvent was evaporated again. Yield: 5 g of final compound 230 (77.5%)
b. Preparation of Final Compound 196




Final compound 230 (prepared according to B11.a) (0.001 mol) was taken up in pyrrolidine (1 ml) and the reaction mixture was stirred for 2 hours at 60° C., the solvent was evaporated and the residue was purified by column chromatography (gradient eluent: CH2Cl2/(CH3OH/NH3) 100/0-90/10). The product fractions were collected and the solvent was evaporated. Yield: 0.257 g of final compound 196.
Example B12
Preparation of Final Compound 209




NaH (0.001 mol) was added to a solution of 2-methylimidazole (0.001 mol) in DMF (20 ml) and the resulting mixture was stirred for 1 hour and warmed to 40° C. Final compound 230 (prepared according to B11.a) (0.001 mol) was added and the reaction mixture was stirred for 18 hours at 50° C. The solvent was evaporated till dryness and the residue was taken up in CH2Cl2/H2O. The organic layer was separated, dried (MgSO4), filtered off and the solvent was evaporated. The residue was purified by column chromatography (gradient eluent: CH2Cl2/CH3OH 100/0-85/15). The product fractions were collected and the solvent was evaporated. Yield: 0.305 g of final compound 209.
Example B13
Preparation of Final Compound 207




Final compound 230 (prepared according to B11.a) (0.001 mol) and Na2CO3 (0.5 g) were added to a mixture of 2-aminobenzenemethanol (0.001 mol) in DMF (20 ml) and the reaction mixture was stirred for 18 hours at 50° C. The solvent was evaporated till dryness and the residue was taken up in CH2Cl2/H2O. The organic layer was separated, dried (MgSO4), filtered off and the solvent was evaporated. The residue was purified by column chromatography (gradient eluent: CH2Cl2/CH3OH 100/0-85/15). The desired product fractions were collected and the solvent was evaporated. Yield: 0.043 g of final compound 207.
Example B14
a. Preparation of Final Compound 206




1-Hydroxy-1H-benzotriazole (0.004 mol) and Et3N (0.004 mol) were added to a solution of 1-(1,1-dimethylethyl)-1,2-piperidinedicarboxylic acid ester (0.004 mol) in CH2Cl2, p.a. (50 ml) and the mixture was stirred at room temperature, N′-(ethylcarbonimidoyl)-N,N-dimethyl-1,3-propanediamine (0.004 mol) was added and the reaction mixture was stirred for 10 min. at room temperature. A mixture of final compound 2 (prepared according to B1.b) (0.003 mol) in CH2Cl2, p.a. (20 ml) was added and the reaction mixture was stirred overnight at room temperature. The mixture was washed with H2O/NaHCO3 and with H2O. The organic layer was separated, dried (MgSO4), filtered off and the solvent was evaporated. The residue was purified by column chromatography over silica gel (gradient eluent: CH2Cl2/CH3OH 100/0-80/20). The product fractions were collected and the solvent was evaporated. Yield: 1.3 g of final compound 206.
b. Preparation of Final Compound 294




2-propanol/HCl (3 ml) was added to a solution of final compound 206 (prepared according to B14.a) (0.0017 mol) in 2-propanol (30 ml) and the reaction mixture was stirred and refluxed for 2 hours. The solvent was evaporated and the residue was suspended in DIPE. The resulting precipitate was filtered off, taken up in H2O and washed with DIPE. The aqueous layer was alkalised and extracted with CH2Cl2. The organic layer was separated, dried (MgSO4), filtered off and the solvent was evaporated till dryness. Yield: 1.0 g of final compound 294.
c. Preparation of Final Compound 295




2-Chlorobenzoyl chloride (0.0004 mol) was added to a solution of final compound 294 (prepared according to B14.b) (0.0004 mol) in CH2Cl2, p.a. (15 ml), Na2CO3 (0.3 g) was added and the reaction mixture was stirred overnight. The crude mixture was filtered over silica gel (gradient eluent: CH2Cl2/CH3OH 100/0-90/10). The product fractions were collected and the solvent was evaporated and the residue was dried. Yield: 0.250 g of final compound 295.
Example B15
Preparation of Final Compound 167




2,2-Dimethylpropanoyl chloride (0.001 mol) and Na2CO3 (0.5 g) were added to a solution of final compound 2 (prepared according to B1.b) (0.001 mol) in CH2Cl2 (25 ml) and the reaction mixture was stirred for 2 hours. The mixture was filtered over a glass filter (gradient eluent: CH2Cl2/CH3OH 100/0-90/10). The product fractions were collected and the solvent was evaporated and the residue was dried. Yield: 0.448 g of final compound 167.
Example B16
a. Preparation of Final Compound 216




CH2Cl2 (50 ml) was added to tetrahydro-3-furancarboxylic acid (0.0012 mol) and 1,1′-carbonylbis-1H-imidazole (0.0012 mol) was added. The mixture was stirred for 45 min. at 40° C. and stirred for 3 hours at room temperature. Final compound 2 (0.001 mol) was added and the reaction mixture was stirred overnight at room temperature. The mixture was washed with a basic NaOH solution, the organic layer was separated, washed with H2O, dried (MgSO4), filtered off and the solvent was evaporated. The residue was purified by column chromatography (gradient eluent: CH2Cl2/CH3OH 100/0-80/20). The product fractions were collected and the solvent was evaporated and the residue was dried. Yield: 0.480 g of final compound 216.
b. Preparation of Final Compound 195




2-Cyanobenzoic acid (0.001 mol) was taken up in CH2Cl2 (30 ml) and 1,1′-carbonylbis-1H-imidazole (0.001 mol) was added. The resulting mixture was stirred for 2 hours at 40° C. and was cooled to room temperature. Final compound 2 (prepared according to B1.b) (0.001 mol) was added and the reaction mixture was stirred overnight at room temperature and was left to stand over the weekend. The mixture was washed with a basic NaOH solution, the organic layer was separated, dried (MgSO4), filtered off and the solvent was evaporated. The residue was filtered over silica gel (gradient eluent: CH2Cl2/CH3OH 100/0-90/10). The product fractions were collected and the solvent was evaporated and the residue was dried. Yield: 0.272 g of final compound 195.
Example B17
Preparation of Final Compound 203




Trifluoromethanecarbonic acid anhydride (0.001 mol) and Na2CO3 (0.5 g) were added to a solution of final compound 2 (prepared according to B1.b) (0.001 mol) in CH2Cl2 (15 ml) and the reaction mixture was stirred for 2 hours. The mixture was filtered on a glass filter over silica gel (gradient eluent: CH2Cl2/CH3OH 100/0-90/10.) The product fractions were collected and the solvent was evaporated and the residue was dried. Yield: 0.276 g of final compound 203.
Example B18
Preparation of Final Compound 166




A mixture of 4-[(acetyloxy)methyl]-1,2,3-thiadiazole-5-carboxylic acid methyl ester (0.002 mol) and final compound 2 (prepared according to B1.b) (0.004 mol) in CH3OH (25 ml) was stirred over the weekend at room temperature and the reaction mixture was filtered over silica gel (gradient eluent: CH2Cl2/CH3OH 100/0-90/10). The product fractions were collected and the solvent was evaporated and the residue was dried. Yield: 0.600 g of final compound 166.
Example B19
Preparation of Final Compound 375




A mixture of final compound 2 (prepared according to B1.b) (0.001 mol), intermediate compound 15 (prepared according to A3.d) (0.001 mol) and titanium, tetrakis(2-propanolato) (1 ml) in CH3OH (50 ml) was hydrogenated at 50° C. with Pd/C 10% (0.1 g) as a catalyst in the presence of thiophene soln. (0.1 ml). After uptake of H2 (1 eq.), the catalyst was filtered off and the filtrate was evaporated. The residue was taken up in H2O/CH2Cl2, dicalite was added and the resulting mixture was filtered over dicalite. The organic layer was separated, dried (MgSO4), filtered off and the solvent was evaporated. The residue was purified by column chromatography (gradient eluent: CH2Cl2/(CH3OH/NH3) 99/1-80/20). The product fractions were collected and the solvent was evaporated and the residue was dried. Yield: 0.017 g of final compound 375.
Example B20
a. Preparation of Final Compound 205




1-Hydroxy-1H-benzotriazole (0.004 mol) and Et3N (0.004 mol) were added to a solution of N-[(1,1-dimethylethoxy)carbonyl]-2-methylalanine (0.004 mol) in CH2Cl2 (50 ml) and the mixture was stirred at room temperature, N′-(ethylcarbonimidoyl)-N,N-dimethyl-1,3-propanediamine (0.004 mol) was added and the reaction mixture was stirred for 10 min. at room temperature. A mixture of final compound 2 (prepared according to B1.b) (0.003 mol) in CH2Cl2 (20 ml) was added and the reaction mixture was stirred overnight at room temperature. The mixture was washed with H2O/NaHCO3 and with H2O. The organic layer was separated, dried (MgSO4), filtered off and the solvent was evaporated. The residue was purified by column chromatography over silica gel (gradient eluent: CH2Cl2/CH3OH 100/0-80/20). The product fractions were collected and the solvent was evaporated. Yield: 0.414 g of final compound 205.
b. Preparation of Final Compound 304




50% NaH (0.0015 mol) was added to a solution of final compound 205 (prepared according to B20.a) (0.0013 mol) in DMF p.a. (25 ml) and the resulting mixture was slowly (35 min.) heated to 45° C. CH3I (0.0015 mol) was added and the reaction mixture was stirred for 4 hours at 50° C. and stirred overnight at room temperature. The solvent was evaporated and the residue was taken up in H2O and the mixture was extracted with CH2Cl2. The organic layer was separated, dried (over MgSO4), filtered off and the solvent was evaporated. The residue was purified by column chromatography (gradient eluent: CH2Cl2/CH3OH 100/0-90/10). The product fractions were collected and the solvent was evaporated and the residue was dried. Yield: 0.47 g of final compound 304.
c. Preparation of Final Compound 309




2-Propanol/HCl (2 ml) was added to a solution of final compound 304 (prepared according to B20.b) (0.00061 mol) in 2-propanol (20 ml) and the reaction mixture was stirred and refluxed for 90 min. The solvent was evaporated and the residue was taken up in H2O and washed with DIPE. The aqueous layer was alkalised and extracted with CH2Cl2. The organic layer was separated, dried (MgSO4), filtered off and the solvent was evaporated. Yield: 0.320 g of final compound 309.
d. Preparation of Final Compound 310




Cyclopropanecarbonyl chloride (0.0005 mol) was added to a solution of final compound 309 (prepared according to B20.c) (0.00048 mol) in CH2Cl2 (20 ml), Na2CO3 (0.5 g) was added and the reaction mixture was stirred for 2 hours at room temperature. The crude mixture was purified by column chromatography over silica gel (gradient eluent: CH2Cl2/CH3OH 100/0-90/10). The desired product fractions were collected and the solvent was evaporated and the residue was dried. Yield: 0.080 g of final compound 310.
Example B21
Preparation of Final Compound 147




CH2Cl2 (10 ml) was added to intermediate compound 9 (prepared according to A2.e) (0.000177 mol) and the mixture was stirred to give solution (I). Solution (I) (10 ml) was added to (RS) 2,3-dihydro-1H-indene-1-carboxylic acid (0.000266 mol),




(Novabiochem 01-64-0211) (0.000531 mol; 1.90 mmol/g) and 1-hydroxy-1H-benzotriazole (0.000407 mol) and the reaction mixture was stirred for 16 hours at room temperature.





(Novabiochem 01-64-0419) (0.001221 mol; 5.80 mmol/g) and





(PS-TsCl) (0.000266 mol; 1.97 mmol/g) were added and the mixture was stirred for 16 hours at room temperature. The scavengers were filtered off and the filtrate was evaporated. Yielding final compound 147.

Example B22
a. Preparation of Final Compound 130




A mixture of final compound 2 (prepared according to B1.b) (0.002 mol) in CH2Cl2, p.a. (50 ml) was stirred at room temperature. A solution of bis(1,1-dimethylethyl)dicarbonic acid ester (0.002 mol) in CH2Cl2 was added dropwise and the reaction mixture was stirred for 1 hour at room temperature. The solvent was evaporated and the residue was purified by column chromatography over silica gel (gradient eluent: CH2Cl2/CH3OH from 100/0 to 90/10). The product fractions were collected and the solvent was evaporated. Yield: 1.039 g of final compound 130 (78%).
b. Preparation of Final Compound 150 and 151




A mixture of intermediate compound 4 (prepared according to A1.d) (0.15 mol) and 1,1-dimethylethyl-1-pyrrolidinecarboxylic acid ester (0.165 mol) in CH3OH (500 ml) was hydrogenated overnight at 50° C. with Pd/C 10% (5 g) as a catalyst in the presence of thiophene (4 ml). After uptake of H2 (1 equiv.), the catalyst was filtered off and the filtrate was evaporated. The residue was crystallised from DIPE, the resulting precipitate was filtered off, giving solid S and the filtrate was evaporated. The residue was purified by column chromatography over silica gel (gradient eluent: CH2Cl2/CH3OH from 100/0 to 95/5) The product fractions were collected and the solvent was evaporated. This residue and solid S were combined. This fraction was separated into its enantiomers by Chiral separation (AD, eluent: Hexane/2-propanol 90/10). Two product fractions were collected and the solvent was evaporated. Yield fraction 1: 46 g of final compound 150 ([2R-[2α,4β(S*)]]) (46%) and yield fraction 2: 39 g of final compound 151 ([2R-[2α,4β(R*)]]) (39%)
Example B23
Preparation of Final Compound 349




A mixture of final compound 2 (prepared according to B1.b) (0.001 mol, 0.5 g), 1,4-dioxane-2,5-diol (0.001 mol, 0.113 g) and 3-thiophene boronic acid (0.001 mol, 0.106 g) in ethanol (5 ml) was stirred at room temperature for 18 hours . This was followed by addition of solution of K2CO3 (10%) and extracted with ethyl acetate. The combined organic layers were dried (MgSO4), filtered and concentrated under vacuum. The residue (0.6 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/MeOH/NH4OH 93/07/0.5) and the product fractions were concentrated. Yield: 0.075 g (12%) of final compound 349.
Example B24
a. Preparation of Final Compound 335




Intermediate compound 17 (prepared according to A4.b) (0.002 mol, 0.67 g) was added portionwise to a solution of final compound 2 (prepared according to B 1.b) (0.002 mol, 1.0 g) in CH2Cl2 at room temperature. The mixture was stirred at room temperature during 18 hours, washed with K2CO3 (10%), dried over MgSO4 and concentrated. The crude product (1.5 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/MeOH 98/2) and the product fractions were concentrated. Yield: 1.1 g (73%) of final compound 335.
b. Preparation of Final Compound 342




BBr3 (1M in CH2Cl2) (0.004 mol, 3.6 ml) was slowly added to a mixture of final compound 335 (prepared according to B24.a) (0.001 mol, 0.6 g) in CH2Cl2 (6 ml) at −70° C. under N2 flow. The reaction was allowed to warm up slowly to −50° C. and stirred at −50° C. during 1 hour. The mixture was hydrolyzed with K2CO3 (10%), extracted with CH2Cl2, dried over MgSO4 and concentrated. The crude product (0.65 g) was purified by column chromatography over silica gel (gradient eluent: CH2Cl2/MeOH/NH4OH 96/4/0.1 to 92/8/0.5) and the product fractions were concentrated. Yield: 0.113 g of final compound 342 (21%).
Example B25
a. Preparation of Final Compound 356




1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide.hydrochloride (0.002 mol, 0.33 g) was added portionwise to a solution of final compound 2 (prepared according to B1.b) (0.002 mol, 1 g), intermediate compound 19 (prepared according to A5.b) (0.002 mol, 0.56 g), 1-hydroxybenzotriazole (0.002 mol, 0.29 g) and triethylamine (0.003 mol, 0.37 ml) in CH2Cl2 (10 ml) at room temperature. The mixture was stirred at room temperature during 18 hours, washed with K2CO3 10%, dried over MgSO4 and concentrated. The crude product (1.65 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/MeOH/NH4OH 96/4/0.5) and the product fractions were concentrated. Yield: 0.62 g (43%) of final compound 356.
b. Preparation of Final Compound 359




The same procedure as described in Example B24.b but instead of the use of final compound 334 (prepared according to B24.a), final compound 356 (prepared according to B25.a) was used.
Example B26
Preparation of Final Compound 344




A mixture of dimethyl-N-cyanodithioiminocarbonate (1 g; 6.8 mmol) and isopropylamine (0.6 ml; 6.8 mmol) in acetonitrile (10 ml) was heated under reflux for 5 hours. After cooling the solution to −10° C., final compound 2 (prepared according to B1.b) (3.87 g; 6.8 mmol) and 3N sodium hydroxide solution (2.3 ml; 6.8 mmol) were added. The mixture was stirred for 5 minutes and a solution of silver nitrate (1.16 g; 6.8 mmol) in acetonitrile (5 ml) was added dropwise. The reaction mixture was stirred at 0° C. for 2 hours and at room temperature for 2 hours. The reaction mixture was filtered and the residue washed with acetonitrile. The solvent was evaporated and the residue was purified by column chromatography over silica gel (15-40 mm, eluent: CH2Cl2/MeOH/NH4OH 95/5/0.5). The pure fractions were collected and evaporated. Yield: 1.9 g of final compound 344 (41%).
Example B27
Preparation of Final Compound 301




Dimethyl-N-cyanodithioiminocarbonate (0.001 mol) was added to a mixture of final compound 2 (prepared according to B1.b) (0.0009 mol) in iPrOH (25 ml). The mixture was stirred and refluxed for 20 hours. H2O was added. The mixture was extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue (0.52 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 97/3/0.1). The pure fractions were collected and the solvent was evaporated. Yield: 0.27 g of final compound 301.
Example B28
Preparation of Final Compound 354




A mixture of 1,1-bis(methylthio)-2-nitroethylene (0.15 g; 0.9 mmol) and isopropylamine (0.08 ml; 0.9 mmol) in acetonitrile (5 ml) was heated under reflux overnight. After cooling the solution to −10° C., final compound 2 (prepared according to B1.b) (0.512 g; 0.9 mmol) and 3N NaOH solution (0.9 ml; 0.9 mmol) were added. The mixture was stirred for 5 minutes and a solution of silver nitrate (0.16 g; 0.9 mmol) in acetonitrile (5 ml) was added dropwise. The reaction mixture was stirred for 2 hours at 0° C., and stirred overnight at room temperature. The solution was filtered and the residue washed with acetonitrile. The solvent was evaporated and the residue was purified by column chromatography over silica gel (Kromasil 10 mm, eluent: CH2Cl2/MeOH/NH4OH 96/4/0.1). The pure fractions were collected and evaporated. Yield: 0.267 g of final compound 354 (43%).
Example B29
a. Preparation of Final Compound 383




A mixture of final compound 2 (prepared according to B1.b) (2 g; 3.5 mmol) and 2-chloromethyloxirane (0.70 ml; 8.9 mmol) in methanol (20 ml) was stirred at room temperature overnight. The solvent was evaporated and the residue was taken up in methylene chloride. The solvent was evaporated and the residue was purified by column chromatography over silica gel (15-40 mm, eluent: CH2Cl2/MeOH/NH4OH 92/8/0.5). The pure fractions were collected and evaporated. Yield: 0.23 g of final compound 383 (10%).
b. Preparation of Final Compound 384




A mixture of final compound 383 (0.230 g; 0.35 mmol), isopropylamine (0.033 ml; 0.38 mmol) and potassium carbonate (0.072 g; 0.52 mmol) in acetonitrile (5 ml) were heated under reflux overnight. The reaction mixture was filtered and the solvent was evaporated. Yield: 0.225 g of final compound 384 (95%).
c. Preparation of Final Compound 385




A mixture of final compound 384 (0.220 g; 0.29 mmol) and 1,1′-carbonyldiimidazole (0.071 g; 0.44 mmol) in CH2Cl2 (10 ml) was stirred at room temperature overnight. The solvent was evaporated and the residue was purified by column chromatography over silica gel (Kromasil 10 mm, eluent: CH2Cl2/MeOH/NH4OH 95/5/0.5). The pure fractions were collected and evaporated. Yield: 0.118 g of final compound 385 (52%).
Example B30
Preparation of Final Compound 343




A mixture of final compound 2 (prepared according to B1.b) (1.0 g; 1.76 mmol) and 3-methoxyphenyl isocyanate (0.25 ml; 1.93 mmol) in THF (10 ml) was stirred at room temperature overnight. The reaction mixture was poured onto ice-water and extracted with CH2Cl2. The organic layers were dried over MgSO4, filtered and evaporated. The residue was purified by column chromatography over silica gel (40 mm, eluent: CH2Cl2/MeOH/NH4OH 97/3/0.5). The pure fractions were collected and evaporated. Yield: 1.3 g of final compound 343 (100%).
Example B31
a) Preparation of Final Compound 243




A mixture of intermediate compound 23 (prepared according to A6.d) (0.02 mol), intermediate compound 30 (prepared according to A8) (0.02 mol) and Pt/C 5% (3 g) in thiophene solution (2 ml) and CH3OH (250 ml) was stirred at 50° C. under H2 (gas), titanium, tetrakis(2-propanolato) (15 g) was added and the reaction mixture was filtered. The filtrate was evaporated and the residue was taken up in CH2Cl2/H2O. The biphasic mixture was stirred for 15 min. and filtered through dicalite. The organic filtrate was separated, dried and the solvent was evaporated. The residue was separated by column chromatography over silica gel (gradient eluent: CH2Cl2/CH3OH 100/0→90/10). The product fractions were collected and the solvent was evaporated. The purification was repeated, two product fractions were collected and the solvent was evaporated. The desired fraction was crystallised from petroleum ether and the resulting solids were collected. Yield: 1.8 g of final compound 243.
b) Preparation of Final Compound 244




HCl/2-propanol (5 ml) was added to a solution of final compound 243 (0.0046 mol) in 2-propanol (50 ml) and the reaction mixture was stirred and refluxed for 2 hours. The resulting precipitate was filtered off and washed with DIPE/2-propanol. The solids were taken up in H2O. The mixture was alkalised and extracted with CH2Cl2. The organic layer was separated, dried and the solvent was evaporated. Yield: 2.1 g of final compound 244 (72%).
c) Preparation of Final Compound 393




A mixture of final compound 298 (prepared according to B31.a) (1.47 g) in a 5 to 6N HCl/isopropanol solution (40 ml) and THF (5 ml) was stirred at room temperature for 4 hours. The reaction mixture was concentrated, poured onto a 10% sodium carbonate solution and extracted with CH2Cl2. The organic layers were dried over MgSO4, filtered and evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/MeOH/NH4OH 85/15/1). The pure fractions were collected and evaporated. The residue was taken up with diisopropylether, filtered and dried. Yield: 0.273 g of final compound 393 (19%).
Example B32
a) Preparation of Final Compound 405




3,5-bis(trifluoromethyl)benzoylchloride (0.005 mol) was added to a solution of intermediate compound 29 (prepared according to A7.d) (0.0048 mol) in CH2Cl2 (20 ml) and the mixture was briefly stirred, Et3N (1 ml) was added and the reaction mixture was stirred for 18 hours. The mixture was washed with a diluted NaOH solution and with H2O, dried and the solvent was evaporated. Yield: 2.8 g of final compound 405.
b) Preparation of Final Compound 406




Final compound 405 (0.0043 mol) was taken up in HCl/2-propanol (5 ml) and 2-propanol (50 ml) was added (precipitation occurred), the reaction mixture was stirred and refluxed for 2 hours. The mixture was cooled and the resulting precipitate was filtered off. The precipitate was taken up in H2O, alkalised with a basic NaOH solution and extracted with CH2Cl2. The organic layer was separated, washed with H2O, dried (MgSO4), filtered off and the solvent was evaporated. The residue was purified over silica gel on a glass filter (gradient eluent: CH2Cl2/(CH3OH/NH3) 99/1−>90/10). The product fractions were collected and the solvent was evaporated. Yield: 1.5 g of final compound 406.
Example B33
Preparation of Final Compound 204




A mixture of final compound 2 (prepared according to B1.b) (0.0014 mol), 3-chloro-1,2-benzoisoxazole (0.0015 mol), Na2CO3 (0.0014 mol) and KI (0.0014 mol) in 4-methylpentanone (20 ml, p.a.) was stirred under N2 in autoclave at 160° C. over the weekend. The reaction mixture was cooled and the solvent was evaporated. The residue was partitioned between H2O/CH2Cl2 and the aqueous layer was extracted with CH2Cl2. The organic layer was dried (MgSO4), filtered off and the solvent was evaporated. The residue was purified by column chromatography over silica gel (gradient eluent: CH2Cl2/CH3OH from 100/0 to 90/10). The product fractions were collected and the solvent was evaporated. Yield: 0.783 g of final compound 204 (82%).
Example B34
Preparation of Final Compound 185




A mixture of final compound 144 (prepared according to B14.b) (0.00096 mol), 2-chloro-N,N-dimethylethanamine (0.00098 mol) and Na2CO3 (0.0029 mol) in 2-butanol (5 ml) was stirred under microwave irradiation (45 min. at 175° C.). The mixture was evaporated under vacuum and the residue was suspended in CH2Cl2, then isocyanate -resin (0.125 g, scavenger) was added and the reaction mixture was stirred for 5 hours at room temperature. The mixture was filtered off, the filter residue was washed with CH2Cl2 and the solvent was evaporated. The residue was purified by column chromatography over silica gel (gradient eluent: CH2Cl2/(CH3OH/NH3) (7N) from 100/0 to 80/20). The product fractions were collected, the solvent was evaporated and the residue was dried (vac., 50° C.) for 48 hours. Yield: 0.056 g of final compound 185 (8%).







TABLE 1













 













Co.
Exp.




Stereo


No.
No.
Alka
Y
Alkb
L
descriptors
















2
B1b
cb
cb
cb
H
2R-trans


148
B31.b
cb
cb
cb
H
[2R-[2α,4β(S)]]


149
B31.b
cb
cb
cb
H
[2R-[2α,4β(R)]]


116
B1b
cb
cb
cb
H
2S-trans


117
B1b
cb
cb
cb
H
2R-cis


118
B1b
cb
cb
cb
H
2S-cis


 


383
B29.a
cb
cb
cb




2R-trans


 


4
B4
cb
cb
cb




2R-trans


 


5
B4
cb
cb
cb




2R-trans


 


6
B4
cb
cb
cb




2R-trans


 


204
B33
cb
cb
cb




2R-trans


 


7
B4
cb
cb
cb




2R-trans


 


8
B4
cb
cb
cb




2R-trans


 


375
B19
cb
cb
cb




2R-trans


 


1
B1a
—CH2—
cb
cb




2R-trans


 


112
B1a
—CH2—
cb
cb




2R-cis


 


113
B1a
—CH2—
cb
cb




2S-trans


 


114
B1a
—CH2—
cb
cb




2S-cis


 


385
B29.c
—CH2—
cb
cb




2R-trans


 


9
B4
—CH2—
cb
cb




2R-trans


 


10
B4
—CH2—
cb
cb




2R-trans


 


11
B4
—CH2—
cb
cb




2R-trans


 


319
B23




cb
cb




2R-trans


 


349
B23




cb
cb




2R-trans


 


384
B29.b




cb
cb




2R-trans


 


103
B5
—CH2—
C═O
cb




2R-trans


 


80
B3
—CH2—CH2—
C═O
cb




2R-trans


 


198
B15
cb
C═O
cb
—CH3
2R-trans


230
B11
cb
C═O
cb
—CH2Cl
2R-trans


203
B17
cb
C═O
cb
—CF3
2R-trans


 


199
B15
cb
C═O
cb




2R-trans


 


167
B15
cb
C═O
cb




2R-trans


 


305
B15
cb
C═O
cb




[2R-[2α,4β(R)]]


 


306
B15
cb
C═O
cb




[2R-[2α,4β(S)]]


 


200
B15
cb
C═O
cb




2R-trans


 


70
B2
cb
C═O
cb




[2R-[2α,4β(R*)]]


 


71
B2
cb
C═O
cb




[2R-[2α,4β(S*)]]


 


72
B2
cb
C═O
cb




2R-trans


 


182
B2
cb
C═O
cb




2S-cis


 


126
B2
cb
C═O
cb




2S-trans


 


137
B2
cb
C═O
cb




2R-cis


 


73
B2
cb
C═O
cb




2R, trans


 


276
B14
cb
C═O
cb




2R, trans


 


179
B15
cb
C═O
cb




2R-trans


 


74
B2
cb
C═O
cb




2R-trans


 


178
B15
cb
C═O
cb




2R-trans


 


402
B15
cb
C═O
cb




[2R-[2α,4β(R*)]]


 


403
B15
cb
C═O
cb




[2R-[2α,4β(S*)]]


 


220
B15
cb
C═O
cb




2R-trans


 


130
B2
cb
C═O
cb




2R-trans


 


150
B22.b
cb
C═O
cb




[2R-[2α,4β(S*)]]


 


151
B22.b
cb
C═O
cb




[2R-[2α,4β(R*)]]


 


145
B2
cb
C═O
cb




2R-trans


 


293
B30
cb
C═O
cb




2R-trans


 


284
B30
cb
C═O
cb




2R-trans


 


343
B30
cb
C═O
cb




2R-trans


 


283
B30
cb
C═O
cb




2R-trans


 


188
B16
cb
C═O
cb




2R-trans


 


64
B2
cb
C═O
cb




2R-trans


 


190
B14
cb
C═O
cb




[2R-[2α,4β(S*)]]


 


191
B14
cb
C═O
cb




[2R [2α,4β(R*)]]


 


136
B2
cb
C═O
cb




2R-cis


 


3
B2
cb
C═O
cb




2R-trans


 


180
B2
cb
C═O
cb




2S-cis


 


127
B2
cb
C═O
cb




2S-trans


 


195
B16
cb
C═O
cb




2R-trans


 


12
B2
cb
C═O
cb




2R-trans


 


192
B2
cb
C═O
cb




[2R-[2α,4β(S*)]]


 


193
B2
cb
C═O
cb




[2R-[2α,4β(R*)]]


 


271
B14
cb
C═O
cb




2R-trans


 


13
B2
cb
C═O
cb




2R-trans


 


327
B14
cb
C═O
cb




2R-trans


 


332
B14
cb
C═O
cb




2R-trans


 


341
B14
cb
C═O
cb




2R, trans


 


14
B2
cb
C═O
cb




2R-trans


 


15
B2
cb
C═O
cb




2R-trans


 


346
B14
cb
C═O
cb




2R-trans


 


18
B2
cb
C═O
cb




2R-trans


 


16
B2
cb
C═O
cb




2R-trans


 


17
B2
cb
C═O
cb




2R-trans


 


181
B2
cb
C═O
cb




2S-cis


 


87
B2
cb
C═O
cb




2R-cis


 


159
B2
cb
C═O
cb




[2R-[2α,4β(S*)]]


 


160
B2
cb
C═O
cb




[2R-[2α,4β(R*)]]


 


22
B2
cb
C═O
cb




2R-trans


 


169
B2
cb
C═O
cb




2R-trans


 


20
B2
cb
C═O
cb




2R-trans


 


21
B2
cb
C═O
cb




2R-trans


 


19
B2
cb
C═O
cb




2R-trans


 


235
B14.b
cb
C═O
cb




2R-trans


 


144
B14.b
cb
C═O
cb




2R-trans


 


213
B14.b
cb
C═O
cb




2R-trans


 


186
B14.b
cb
C═O
cb




2R-trans


 


187
B14.a
cb
C═O
cb




2R-trans


 


115
B2
cb
C═O
cb




2R-trans


 


189
B14
cb
C═O
cb




2R-trans


 


228
B14
cb
C═O
cb




2R-trans


 


185
B34
cb
C═O
cb




2R-trans


 


23
B2
cb
C═O
cb




2R-trans


 


24
B2
cb
C═O
cb




2R-trans


 


294
B14.b
cb
C═O
cb




2R-trans


 


240
B14.b
cb
C═O
cb




2R-trans


 


241
B14.b
cb
C═O
cb




2R-trans


 


206
B14.a
cb
C═O
cb




2R-trans


 


297
B14.c
cb
C═O
cb




2R-trans


 


296
B14.c
cb
C═O
cb




2R-trans


 


295
B14.c
cb
C═O
cb




2R-trans


 


229
B14
cb
C═O
cb




2R-trans


 


210
B14
cb
C═O
cb




2R-trans


 


28
B2
cb
C═O
cb




2R-trans


 


168
B15
cb
C═O
cb




2R-trans


 


29
B2
cb
C═O
cb




2R-trans


 


97
B2
cb
C═O
cb




2R-trans


 


386
B14
cb
C═O
cb




2R-trans


 


387
B14
cb
C═O
cb




2R-trans


 


31
B16
cb
C═O
cb




2R-trans


 


184
B16
cb
C═O
cb




2S-cis


 


129
B16
cb
C═O
cb




2S-trans


 


139
B16
cb
C═O
cb




2R-cis


 


216
B16
cb
C═O
cb




[2R-[2α,4β(S(S))]]


 


217
B16
cb
C═O
cb




[2R-[2α,4β(R(S))]]


 


219
B16
cb
C═O
cb




[2R-[2α,4β(R(R))]]


 


218
B16
cb
C═O
cb




[2R-[2α,4β(S(R))]]


 


404
B20
cb
C═O
cb




2R-trans


 


32
B2
cb
C═O
cb




2R-trans, R*


 


33
B2
cb
C═O
cb




2R-trans, S*


 


34
B2
cb
C═O
cb




2R-trans


 


183
B2
cb
C═O
cb




2S-cis


 


128
B2
cb
C═O
cb




2S-trans


 


138
B2
cb
C═O
cb




2R-cis


 


35
B2
cb
C═O
cb




2R-trans


 


36
B2
cb
C═O
cb




2R-trans


 


37
B2
cb
C═O
cb




2R-trans


 


38
B2
cb
C═O
cb




2R-trans


 


39
B2
cb
C═O
cb




2R-trans, R*


 


40
B2
cb
C═O
cb




2R-trans, S*


 


41
B2
cb
C═O
cb




2R-trans


 


42
B2
cb
C═O
cb




2R-trans


 


321
B2
cb
C═O
cb




[2R-[2α,4β(R)]]


 


322
B2
cb
C═O
cb




[2R-[2α,4β(S)]]


 


360
B25
cb
C═O
cb




2R-trans


 


43
B2
cb
C═O
cb




2R-trans


 


350
B25
cb
C═O
cb




2R-trans


 


359
B25
cb
C═O
cb




2R-trans


 


369
B25
cb
C═O
cb




2R-trans


 


353
B25
cb
C═O
cb




2R-trans


 


361
B25
cb
C═O
cb




2R-trans


 


363
B25
cb
C═O
cb




2R-trans


 


352
B25
cb
C═O
cb




2R-trans


 


362
B25
cb
C═O
cb




2R-trans


 


356
B25.a
cb
C═O
cb




2R-trans


 


44
B2
cb
C═O
cb




2R-trans


 


68
B2
cb
C═O
cb




2R-trans


 


45
B2
cb
C═O
cb




2R-trans


 


48
B2
cb
C═O
cb




2R-trans


 


46
B2
cb
C═O
cb




2R-trans


 


47
B2
cb
C═O
cb




2R-trans


 


49
B2
cb
C═O
cb




2R-trans


 


25
B2
cb
C═O
cb




2R-trans


 


282
B14
cb
C═O
cb




2R-trans


 


26
B2
cb
C═O
cb




2R-trans


 


27
B2
cb
C═O
cb




2R-trans


 


50
B2
cb
C═O
cb




2R-trans


 


30
B2
cb
C═O
cb




2R-trans


 


51
B2
cb
C═O
cb




2R-trans


 


125
B2
cb
C═O
cb




2S-trans


 


380
B15
cb
C═O
cb




[2R-[2α,4β(S*)]]


 


381
B15
cb
C═O
cb




[2P-[2α,4β(R*)]]


 


166
B18
cb
C═O
cb




2R-trans


 


52
B2
cb
C═O
cb




2R-trans


 


53
B2
cb
C═O
cb




2R-trans


 


54
B2
cb
C═O
cb




2R-trans


 


55
B2
cb
C═O
cb




2R-trans


 


56
B2
cb
C═O
cb




2R-trans


 


57
B2
cb
C═O
cb




2R-trans


 


58
B2
cb
C═O
cb




2R-trans


 


59
B2
cb
C═O
cb




2R-trans


 


60
B2
cb
C═O
cb




2R-trans


 


61
B2
cb
C═O
cb




2R-trans


 


62
B2
cb
C═O
cb




2R-trans


 


63
B2
cb
C═O
cb




2R-trans


 


98
B2
cb
C═O
cb




2R-trans


 


99
B2
cb
C═O
cb




2R-trans


 


177
B15
cb
C═O
—CH2—




2R-trans


 


388
B14
cb
C═O
—CH2—




2R-trans


 


390
B14
cb
C═O
—CH2—




2R-trans


 


389
B14
cb
C═O
—CH2—




2R-trans


 


202
B11.b
cb
C═O
—CH2—




2R-trans


 


207
B13
cb
C═O
—CH2—




2R-trans


 


65
B2
cb
C═O
—CH2—




2R-trans


 


196
B11.b
cb
C═O
—CH2—




2R-trans


 


214
B14
cb
C═O
—CH2—




2R-trans


 


66
B2
cb
C═O
—CH2—




2R-trans


 


67
B2
cb
C═O
—CH2—




2R-trans


 


392
B14
cb
C═O
—CH2—




2R-trans


 


209
B12
cb
C═O
—CH2—




2R-trans


 


215
B14
cb
C═O
—CH2—




2R-trans


 


197
B11.b
cb
C═O
—CH2—




2R-trans


 


201
B11.b
cb
C═O
—CH2—




2R-trans


 


208
B12
cb
C═O
—CH2—




2R-trans


 


413
B14
cb
C═O
—CH2—CH2—




2R-trans, S


 


414
B14
cb
C═O
—CH2—CH2—




2R-trans, R


 


391
B14
cb
C═O
—CH2—CH2—




2R-trans


 


69
B2
cb
C═O








2R-trans


 


104
B7
cb
C═O








2R-trans


 


275
B14
cb
C═O








2R-trans


 


334
B14
cb
C═O








2R-trans


 


333
B14
cb
C═O








2R-trans


 


309
B20.c
cb
C═O








2R-trans


 


205
B20.a
cb
C═O








2R-trans


 


310
B20.d
cb
C═O








2R-trans


 


304
B20.b
cb
C═O








2R-trans


 


109
B9
cb
C═O








2R-trans


 


106
B8
cb
C═O








2R-trans


 


107
B8
cb
C═O








2R-trans


 


108
B8
cb
C═O








2R-trans


 


105
B8
cb
C═O








2R-trans


 


110
B10
cb
C═O








2R-trans


 


111
B10
cb
C═O








2R-trans


 


75
B5
cb




cb




2R-trans


 


307
B24.b
cb




cb




2R-trans


 


348
B24.b
cb




cb




2R-trans


 


303
B24.b
cb




cb




2R-trans


 


415
B24.b
cb




cb




2R-trans


 


416
B24.b
cb




cb




2R-trans


 


300
B24.a
cb




cb




2R-trans


 


347
B24.a
cb




cb




2R-trans


 


280
B24.a
cb




cb




2R-trans


 


378
B24.a
cb




cb




2R-trans


 


411
B24.a
cb




cb




2R-trans


 


412
B24.a
cb




cb




2R-trans


 


401
B24.a
cb




cb




2R-trans


 


394
B24.a
cb




cb




2R-trans


 


410
B24.a
cb




cb




2R-trans


 


76
B5
cb




cb




2R-trans


 


308
B24.b
cb




cb




2R-trans


 


328
B5
cb




cb




2R-trans


 


345
B24.a
cb




cb




2R-trans


 


336
B24.a
cb




cb




2R-trans


 


292
B24.a
cb




cb




2R-trans


 


351
B24.b
cb




cb




2R-trans


 


342
B24.b
cb




cb




2R-trans


 


335
B24.a
cb




cb




2R-trans


 


77
B5
cb




cb




2R-trans


 


78
B5
cb




cb




2R-trans


 


79
B5
cb




cb




2R-trans


 


301
B27
cb
C═N—CN
cb
—SCH3
2R-trans


 


344
B27
cb
C═N—CN
cb




2R-trans


 


370
B27
cb
C═N—CN
cb




2R-trans


 


355
B27
cb
C═N—CN
cb




2R-trans


 


302
B27
cb
C═N—CN
cb




2R-trans


 


371
B27
cb
C═N—CN
cb




2R-trans


 


354
B28
cb
C═C—NO2
cb




2R-trans


 


376
B28
cb
C═C—NO2
cb




2R-trans


 


377
B28
cb
C═C—NO2
cb




2R-trans





cb = covalent bond













TABLE 2













 










Co.
Exp.

Stereo


No.
No.
R2—
descriptors













81
B6




2R-trans


 


82
B6




2R-trans


 


83
B6




2R-trans


 


84
B6




2R-trans


 


85
B6




2R-trans


 


86
B6




2R-trans


 


88
B6




2R-trans


 


89
B6




2R-trans


 


90
B6




2R-trans


 


91
B6




2R-trans


 


92
B6




2R-trans


 


93
B6




2R-trans


 


94
B6




2R-trans


 


95
B6




2R-trans


 


96
B6




2R-trans


 


100
B6/B21




2R-trans


 


101
B6/B21




2R-trans


 


102
B6/B21




2R-trans


 


146
B21




2R-trans


 


147
B21




2R-trans





cb = covalent bond













TABLE 3













 













Co. No.
Exp. No.
Alka
Y
Alkb
L
Stereo descriptors





120
B1b
cb
cb
cb
H
2S-trans


123
B1b
cb
cb
cb
H
2R-cis


133
B1b
cb
cb
cb
H
2R-cis + trans


 


119
B1a
—CH2—
cb
cb




2R-trans


 


132
B1a
—CH2—
cb
cb




2R-cis + trans


 


140
B1a
—CH2—
cb
cb




2R-cis


 


154
B15
cb
C═O
cb




2R-cis


 


156
B15
cb
C═O
cb




2R-trans


 


134
B2
cb
C═O
cb




2R-cis


 


135
B2
cb
C═O
cb




2R-trans


 


157
B15
cb
C═O
cb




2R-cis


 


158
B15
cb
C═O
cb




2R-trans


 


121
B2
cb
C═O
cb




2R-trans


 


131
B2
cb
C═O
cb




2R-cis


 


152
B14
cb
C═O
cb




2R-cis


 


153
B14
cb
C═O
cb




2R-trans


 


122
B2
cb
C═O
cb




2R-cis


 


124
B2
cb
C═O
cb




2R-trans


 


155
B5
cb




cb




2R-trans


 


170
B5
cb




cb




2R-cis





cb =covalent bond













TABLE 4













 













Co.
Exp.




Stereo


No.
No.
Alka
Y
Alkb
L
descriptors





262
B31.b
cb
cb
cb
H
[(2R-trans), (R)]


244
B31.b
cb
cb
cb
H
[(2S-trans), (S)]


194
B31.b
cb
cb
cb
H
trans


311
B31.b
cb
cb
cb
H
[(2R-trans), (S)]


 


393
B31.c
cb
cb
cb




[2R-[2α,4β(S)]]


 


247
B15
cb
C═O
cb




[(2S-trans), (S)]


 


289
B15
cb
C═O
cb




[(2R-trans), (R)]


 


313
B15
cb
C═O
cb




[(2R-trans), (S)]


 


143
B2
cb
C═O
cb




cis


 


162
B15
cb
C═O
cb




trans


 


245
B15
cb
C═O
cb




[(2S-trans), (S)]


 


263
B15
cb
C═O
cb




[(2R-trans), (R)]


 


312
B15
cb
C═O
cb




[(2R-trans), (S)]


 


299
B15
cb
C═O
cb




[(2R-trans), (R)]


 


314
B15
cb
C═O
cb




[(2R-trans), (S)]


 


243
B31.a
cb
C═O
cb




[(2S-trans), (S)]


 


261
B31.a
cb
C═O
cb




[(2R-trans), (R)]


 


329
B31.a
cb
C═O
cb




[(2R-cis), (R)]


 


248
B31.a
cb
C═O
cb




[(2S-cis), (S)]


 


165
B31.a
cb
C═O
cb




trans


 


298
B31.a
cb
C═O
cb




[(2R-trans), (S)]


 


141
B2
cb
C═O
cb




cis


 


164
B15
cb
C═O
cb




trans


 


266
B15
cb
C═O
cb




[(2R-trans), (R)]


 


315
B15
cb
C═O
cb




[(2R-trans), (S)]


 


246
B15
cb
C═O
cb




[(2S-trans), (S)]


 


265
B15
cb
C═O
cb




[(2R-trans), (R)]


 


316
B15
cb
C═O
cb




[(2R-trans), (S)]


 


174
B15
cb
C═O
cb




trans


 


264
B15
cb
C═O
cb




[(2R-trans), (R)]


 


175
B15
cb
C═O
cb




trans


 


318
B15
cb
C═O
cb




[(2R-trans), (S)]


 


287
B16
cb
C═O
cb




[(2R-trans), (R)]


 


251
B16
cb
C═O
cb




[(2S-trans), (S)]


 


325
B16
cb
C═O
cb




[(2R-trans), (S)]


 


267
B15
cb
C═O
cb




[(2R-trans), (R)]


 


317
B15
cb
C═O
cb




[(2R-trans), (S)]


 


173
B16
cb
C═O
cb




trans


 


250
B16
cb
C═O
cb




[(2S-trans), (S)]


 


288
B16
cb
C═O
cb




[(2R-trans), (R)]


 


326
B16
cb
C═O
cb




[(2R-trans), (S)]


 


172
B16
cb
C═O
cb




trans


 


249
B16
cb
C═O
cb




[(2S-trans), (S)]


 


290
B16
cb
C═O
cb




[(2R-trans), (R), (R)]


 


291
B16
cb
C═O
cb




[(2R-trans), (R), (S)]


 


330
B16
cb
C═O
cb




[(2R-trans), (S), (S)]


 


331
B16
cb
C═O
cb




[(2R-trans), (S), (R)]


 


324
B16
cb
C═O
cb




[(2R-trans), (S)]


 


171
B16
cb
C═O
cb




trans


 


286
B16
cb
C═O
cb




[(2R-trans), (R)]


 


323
B16
cb
C═O
cb




[(2R-trans), (S)]


 


161
B15
ob
C═O
cb




trans


 


176
B15
cb
C═O








trans


 


142
B5
cb




cb




cis


 


163
B5
cb




cb




trans


 


268
B5
cb




cb




[(2r-trans), (R)]





cb = covalent bond













TABLE 5













 














Co.
Exp.








No.
No.
(Hal)n
Alka
Y
Alkb
L
Stereo descriptors





225
B1.b
3-F, 4-F
cb
cb
cb
H
[2R-[2α,4β(R*)]]


212
B1.b
3-F, 4-F
cb
cb
cb
H
[2R-[2α,4α(S*)]]


 


364
B15
3-F, 4-F
cb
C═O
cb




[2R-[2α,4β(R*)]]


 


365
B15
3-F, 4-F
cb
C═O
cb




[2R-[2α,4α(S*)]]


 


231
B15
3-F, 4-F
cb
C═O
cb




[2R-[2α,4β(R*)]]


 


252
B15
3-F, 4-F
cb
C═O
cb




[2R-[2α,4β(S*)]]


 


357
B15
3-F, 4-F
cb
C═O
cb




[2R-[2α,4β(R*)]]


 


358
B15
3-F, 4-F
cb
C═O
cb




[2R-[2α,4β(S*)]]


 


221
B31
3-F, 4-F
—CH2—
cb
cb




[2R-[2α,4α(R*)]]


 


222
B31
3-F, 4-F
—CH2—
cb
cb




[2R-[2α,4β(R*)]]


 


224
B31
3-F, 4-F
—CH2—
cb
cb




[2R-[2α,4α(S*)]]


 


223
B31
3-F, 4-F
—CH2—
cb
cb




[2R-[2α,4β(S*)]]


 


211
B15
3-F, 4-F
cb
C═O
cb




[2R-[2α,4β(R*)]]


 


255
B15
3-F, 4-F
cb
C═O
cb




[2R-[2α,4β(S*)]]


 


239
B15
3-F, 4-F
cb
C═O
cb




[2R-[2α,4β(R*)]]


 


256
B15
3-F, 4-F
cb
C═O
cb




[2R-[2α,4β(S*)]]


 


366
B15
3-F, 4-F
cb
C═O
cb




[2R-[2α,4β(R*)]]


 


367
B15
3-F, 4-F
cb
C═O
cb




[2R-[2α,4β(S*)]]


 


260
B15
3-F, 4-F
cb
C═O
cb




[2R-[2α,4β(S*)]]


 


368
B15
3-F, 4-F
cb
C═O
cb




[2R-[2α,4β(R*)]]


 


227
B14
3-F, 4-F
cb
C═O
cb




[2R-[2α,4β(R*)]]


 


269
B14
3-F, 4-F
cb
C═O
cb




[2R-[2α,4β(R*(S*))]]


 


281
B14
3-F, 4-F
cb
C═O
cb




[2R-[2α,4β(S*(S*))]]


 


285
B14
3-F, 4-F
cb
C═O
cb




[2R-[2α,4β(S*(R*))]]


 


270
B14
3-F, 4-F
cb
C═O
cb




[2R-[2α,4β(R*(R*))]]


 


242
B14
3-F, 4-F
cb
C═O
cb




[2R-[2α,4β(S*)]]


 


226
B14
3-F, 4-F
cb
C═O
cb




[2R-[2α,4β(R*)]]


 


258
B14
3-F, 4-F
cb
C═O
cb




[2R-[2α,4β(S*)]]


 


254
B15
3-F, 4-F
cb
C═O
cb




[2R-[2α,4β(S*)]]


 


232
B15
3-F, 4-F
cb
C═O
cb




[2R-[2α,4β(R*)]]


 


238
B15
3-F, 4-F
cb
C═O
cb




[2R-[2α,4β(R*)]]


 


257
B15
3-F, 4-F
cb
C═O
cb




[2R-[2α,4β(S*)]]


 


237
B14
3-F, 4-F
cb
C═O
cb




[2R-[2α,4β(R*)]]


 


259
B14
3-F, 4-F
cb
C═O
cb




[2R-[2α,4β(S*)]]


 


236
B15
3-F, 4-F
cb
C═O
cb




[2R-[2α,4β(R*)]]


 


253
B15
3-F, 4-F
cb
C═O
cb




[2R-[2α,4β(S*)]]


 


233
B2
3-F, 4-F
cb
C═O








[2R-[2α,4β(R*)]]


 


234
B2
3-F, 4-F
cb




cb




[2R-[2α,4β(R*)]]


 


338
B1.b
3-F, 5-F
cb
cb
cb
H
trans


 


339
B31
3-F, 5-F
—CH2—
cb
cb




trans


 


340
B2
3-F, 5-F
cb
C═O
cb




trans


 


337
B14
3-F, 5-F
cb
C═O
cb




trans


 


320
B31
3-Cl, 5-Cl
—CH2—
cb
cb




trans


 


273
B1.b
4-F
cb
cb
cb
H
trans


 


272
B31
4-F
—CH2—
cb
cb




trans


 


277
B2
4-F
cb
C═O
cb




trans


 


279
B2
4-F
cb
C═O
cb




trans


 


274
B14
4-F
cb
C═O
cb




trans


 


278
B14
4-F
cb
C═O
cb




trans





cb = covalent bond













TABLE 6













 













Co.
Exp.




Stereo


No.
No.
Alka
Y
Alkb
L
descriptors





406
B32.b
cb
cb
cb
H
cis


 


395
B15
cb
C═O
cb




cis


 


396
B15
cb
C═O
cb




cis


 


397
B15
cb
C═O
cb




cis


 


405
B32.a
cb
C═O
cb




cis


 


398
B15
cb
C═O
cb




cis


 


407
B15
cb
C═O
cb




cis


 


408
B1
cb
C═O
cb




cis


 


399
B16
cb
C═O
cb




cis


 


400
B15
cb
C═O
cb




cis





cb = covalent bond






C. Analytical Data

For a number of compounds, either melting points, LCMS data or optical rotations were recorded.
1. Melting Points
If possible, melting points (or ranges) were obtained with a Leica VMHB Koffler bank. The melting points are uncorrected.







TABLE 7







Melting points for selected compounds.










Compound no.
Result (° C.)







122
60-70



124
60-70



134
65-70



135
65-70



153
65



155
60-70



158
70



282
126



284
111



287
138



292
158



293
106



302
100



307
92



308
100



334
120



402
89.2-98.5



403
89.7-99.2










2. LCMS Conditions

Method A

The HPLC gradient was supplied by a Waters Alliance HT 2790 system (Waters, Milford, Mass.) with a column heater set at 40° C. Flow from the column was split to a Waters 996 photodiode array (PDA) detector and a Waters-Micromass ZQ mass spectrometer with an electrospray ionization source operated in positive and negative ionization mode. Reversed phase HPLC was carried out on a Xterra MS C18 column (3.5 mm, 4.6×100 mm) with a flow rate of 1.6 ml/min. Three mobile phases (mobile phase A: 95% 25 mM ammoniumacetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and re-equilibrate with 100% A for 1.5 min. An injection volume of 10 μL was used.
Mass spectra were acquired by scanning from 100 to 1000 in 1 s using a dwell time of 0.1. The capillary needle voltage was 3 kV and the source temperature was maintained at 140° C. Nitrogen was used a the nebulizer gas. Cone voltage was 10 V for positive ionization mode and 20 V for negative ionization mode. Data acquisition was performed with a Waters-Micromass MassLynx-Openlynx data system.







TABLE 8







LCMS parent peak and retention time for selected compounds.













LCMS


LCMS



Comp.
MS(MH+)
Retention
Comp.
MS(MH+)
Retention


no.
Meth. A
time
no.
Meth. A
time















2
569
5.01
34
663
5.67


1
659
6.16
13
687
5.96


28
674
5.45
35
663
5.70


3
673
5.84
42
679
5.83


20
709
5.95
14
703
5.83


12
698
6.05
26
691
5.67


29
704
5.33
44
747
6.28


32
663
5.68
78
727
5.49


33
663
6.05
79
728
5.97


31
667
5.5
30
675
5.55


69
701
6.09
67
693
5.84


41
679
6.13
52
681
5.68


80
655
5.66
36
677
5.83


51
695
5.68
43
693
6.21


70
637
5.95
59
663
5.31


71
637
5.68
56
712
5.74


72
637
5.68
64
691
5.67


66
677
5.72
103
690
6.16


45
677
5.76
104
721
6.39


23
676
5.61
105
785
5.71


85
555
5.24
106
746
5.64


86
569
5.42
107
792
6.26


68
664
6.11
108
756
5.87


37
691
6.00
109
717
5.9


74
665
6.01
110
767
5.81


47
678
5.80
111
831
6.21


24
676
6.26
112
659
6.75


81
617
4.44
113
659
6.62


82
677
5.80
114
659
6.82


83
631
4.54
115
766
6.39


11
771
6.26
116
569
5.24


84
635
5.15
119
673
6.15


16
691
5.86
121
677
4.43


17
707
5.96
130
669
6.23


19
701
6.09
131
677
5.87


54
723
6.10
140
673
6.26


49
822
6.10
141
775
6.39


22
741
6.22
142
783
6.34


7
702
6.36
143
705
6.21


8
699
6.00
144
666
5.14


5
647
5.83
145
640
5.65


6
661
5.69
152
681
5.67


10
699
5.81
154
651
5.87


9
739
6.10
156
651
5.73


21
709
5.88
157
721
6.16


73
651
5.76
159
707
5.96


61
747
6.07
161
763
5.99


15
731
6.15
162
705
6.00


65
777
5.76
163
783
6.61


90
555
5.14
164
775
6.20


88
557
4.70
165
737
6.75


91
587
5.08
166
711
5.84


92
601
4.92
167
653
6.36


93
673
5.17
168
708
5.61


94
579
4.62
169
741
6.04


89
583
5.25
170
729
6.13


95
528
4.43
171
745
5.89


96
585
5.22
172
735
5.85


97
667
5.68
173
731
5.98


98
731
6.01
174
759
6.13


99
737
6.00
175
747
6.54


176
769
6.31
223
695
6.06


177
641
5.69
224
695
6.32


178
679
6.56
225
605
5.02


179
651
6.24
226
699
5.61


180
673
6.21
227
703
5.45


181
707
6.32
228
766
6.03


182
637
6.05
229
780
6.15


183
663
5.84
210
780
6.05


184
667
5.68
211
743
5.87


185
737
5.70
212
605
5.02


186
708
5.41
231
673
5.63


187
708
5.41
232
715
5.77


188
707
5.87
233
737
6.01


189
766
6.00
234
751
5.85


190
749
5.66
235
666
5.05


191
691
5.67
236
731
5.62


192
698
5.87
237
711
5.50


193
698
5.89
238
715
5.73


194
637
5.53
239
777
5.97


195
698
6.04
240
680
5.09


196
680
5.26
241
680
5.03


197
696
5.73
242
703
5.43


198
611
5.44
243
737
6.42


199
639
5.75
244
637
5.51


200
667
6.09
245
705
5.98


201
695
5.11
246
809
6.26


202
654
5.35
247
721
6.19


203
665
6.29
248
737
7.11


204
686
6.52
249
735
5.82


205
754
6.10
250
731
5.97


206
780
6.54
251
747
6.06


207
732
5.74
252
673
5.61


208
727
5.76
253
731
5.62


209
691
5.34
254
715
5.76


213
666
5.14
255
743
5.88


214
694
5.38
256
777
5.98


215
696
5.32
257
715
5.72


216
667
5.49
258
699
5.60


217
667
5.49
259
711
5.50


218
667
5.49
260
740
5.28


219
667
5.51
261
737
6.42


220
703
5.76
262
637
5.72


221
695
6.31
263
705
5.98


222
695
6.08
264
747
6.09


265
809
6.26
336
849
6.41


266
775
6.18
337
715
5.76


267
731
5.98
340
673
5.67


268
783
6.14
341
689
5.51


269
703
5.45
342
759
5.71


270
703
5.45
343
718
5.83


281
703
5.43
344
678
5.68


283
713
5.76
345
835
6.37


285
703
5.21
346
807
6.26


286
743
5.63
347
739
6.04


287
747
5.75
348
725
5.75


288
731
5.66
349
695
5.73


289
721
5.85
350
709
5.91


290
735
5.87
351
759
5.70


291
735
5.86
352
799
6.28


294
680
5.22
353
799
6.28


295
818
6.09
354
697
5.44


296
748
5.86
355
742
5.70


297
764
6.15
356
813
6.36


298
737
6.45
357
715
6.05


299
747
6.38
358
715
6.06


302
690
4.40
359
723
5.57


304
768
6.09
360
709
5.61


305
653
5.96
361
813
6.34


306
653
5.95
362
813
6.34


310
736
5.76
363
723
5.55


311
637
5.49
364
689
5.87


312
705
6.34
365
689
5.88


313
721
6.98
366
712
5.78


314
747
7.11
367
712
5.79


315
775
6.96
368
740
5.27


316
809
7.04
369
723
5.66


317
731
6.77
370
750
5.66


318
747
6.87
371
706
5.51


321
679
5.82
374
651
5.59


322
679
5.82
375
756
5.70


323
743
6.61
376
769
5.49


324
731
6.54
377
709
5.27


325
747
6.78
378
769
5.89


326
731
6.68
379
677
5.59


329
679
5.75
380
695
5.68


330
735
5.85
381
695
5.68


331
735
5.86
382
693
5.72


332
689
5.57
385
710
5.71


386
681
5.39
396
623
6.38


387
681
5.38
397
665
6.87


388
683
5.85
398
659
6.57


389
669
5.48
399
694
6.41


390
685
5.47
400
681
6.39


391
697
5.98
401
829
6.14


392
725
5.67
404
709
5.57


393
709
5.61
407
693
6.70


394
833
6.43
408
665
6.55


395
653
6.84









Method B

The HPLC gradient was supplied by a Waters Alliance HT 2790 system (Waters, Milford, Mass.) with a column heater set at 40° C. Flow from the column was split to a Waters 996 photodiode array (PDA) detector and a Waters-Micromass ZQ mass spectrometer with an electrospray ionization source operated in positive and negative ionization mode. Reversed phase HPLC was carried out on a Xterra MS C18 column (5 mm. 3.9×150 mm) with a flow rate of 1 ml/min. Two mobile phases (mobile phase A: 85% 65 mM ammonium acetate+15% acetonitrile; mobile phase B: 20% 6.5 mM ammonium acetate+80% acetonitrile) were employed to run a gradient condition from 100% A for 3 min to 100% B in 5 min., 100% B for 6 min to 100% A in 3 min, and re-equilibrate with 100% A for 3 min). Mass spectra were acquired as in Method A.







TABLE 9







LCMS parent peak and retention time for selected compounds.










LCMS



Compound
MS(MH+)
Retention


no.
Meth. B
time





271
698
4.5


274
685
4.0


275
703
4.3


276
653
3.9


277
655
4.1


278
697
4.3


279
725
4.6


280
739
5.0


282
677
3.4


292
835
5.8


293
654
4.2


300
739
4.9


303
725
4.6


319
695
2.6


320
727
4.1


327
689
4.4


328
745
5.1


333
733
4.4


335
849
5.9









Optical Rotations

Optical rotations were recorded on a polarimeter (Perkin Elmer) at 20° C. in methanol, using a cell pathlength=1 dm, a volume=5 ml at a concentration=0.5 mg/ml.







TABLE 10







Optical rotation data for selected compounds.









Compound

Wavelength


No.
[α]
(nm)












32
+15.14
589


33
−13.19
589


39
−18.3
589


40
+20.44
589


87
−17.97°
589


124
+29.34
365


125
+29.34°
365


126
+33.54°
365


127
+31.29°
365


128
+32.32
365


129
+31.33°
365


130
−35.9°
365


136
−18.71
589


137
−19.11
589


138
−19.02°
589


139
−19.03°
589


148
−45.59
365


149
−37.29
365









D. Pharmacological Example

Example D.1
Binding Experiment for h-NK1, h-NK2, and h-NK3 Receptors
The compounds according to the invention were investigated for interaction with various neurotransmitter receptors, ion channels and transporter binding sites using the radioligand binding technique. Membranes from tissue homogenates or from cells, expressing the receptor or transporter of interests, were incubated with a radioactively labelled substance ([3H]- or [125I] ligand) to label a particular receptor. Specific receptor binding of the radioligand was distinguished from the non-specific membrane labelling by selectively inhibiting the receptor labelling with an unlabelled drug (the blank), known to compete with the radioligand for binding to the receptor sites. Following incubation, labelled membranes were harvested and rinsed with excessive cold buffer to remove non-bound radioactivity by rapid filtration under suction. Membrane bound radioactivity was counted in a scintillation counter and results were expressed in counts per minute (cpm).
The compounds were dissolved in DMSO and tested at 10 concentrations ranging from 10−10 to 10−5 M.
The ability of the compounds according to the invention to displace [3H]-Substance P from cloned human h-NK1 receptors expressed in CHO cells, to displace [3]-SR-48968 from cloned human h-NK2 receptors expressed in Sf9 cells, and to displace [3 H]-SR-142801 from cloned human h-NK3 receptors expressed in CHO cells was evaluated.
The receptor binding values (pIC50) for the h-NK1 ranges for all compounds according to the invention between 10 and 6.
Example D.2
Signal Transduction (ST)
This test evaluates in vitro functional NK1 antagonistic activity. For the measurements of intracellular Ca++ concentrations the cells were grown on 96-well (black wall/transparent bottom) plates from Costar for 2 days until they reached confluence. The cells were loaded with 2 μM Fluo3 in DMEM containing 0.1% BSA and 2.5 mM probenecid for 1 h at 37° C. They were washed 3× with a Krebs buffer (140 mM NaCl, 1 mM MgCl2×6H2O, 5 mM KCl, 10 mM glucose, 5 mM HEPES; 1.25 mM CaCl2; pH 7.4) containing 2.5 mM probenecid and 0.1% BSA (Ca++-buffer). The cells were preincubated with a concentration range of antagonists for 20 min at RT and Ca++-signals after addition of the agonists were measured in a Fluorescence Image Plate Reader (FLIPR from Molecular Devices, Crawley, England). The peak of the Ca++-transient was considered as the relevant signal and the mean values of corresponding wells were analysed as described below.
The sigmoidal dose response curves were analysed by computerised curve-fitting, using the GraphPad Program. The EC50-value of a compound is the effective dose showing 50% of maximal effect. For mean curves the response to the agonist with the highest potency was normalised to 100%. For antagonist responses the IC50-value was calculated using non-linear regression.
The pIC50 data for the signal transduction testing for a representative selection of compounds are presented in Table 11. The last columns indicates—without being limited therefore—for which the compounds might be most suitable. Of course, since for some neurokinin receptors no data was determined, it is obvious that these compounds might be attributed to another suitable use.







TABLE 11







Pharmacological data for the signal


transduction for selected compounds.


(n.d. = not determined)













Co.
pIC50
pIC50
pIC50




No
NK1
NK2
NK3
Suitable for

















227
8.5
n.d
5.8
NK1



270
8.5
5.7
5.9
NK1



305
8.5
5.8
5.8
NK1



236
8.4
n.d
5.3
NK1



269
8.4
5.6
5.2
NK1



281
8.3
5.4
5.5
NK1



332
8.3
5.8
5.5
NK1



381
8.3
5.0
5.6
NK1



393
8.3
5.0
5.0
NK1



50
8.2
n.d
5.5
NK1



166
8.2
n.d
5.8
NK1



179
8.2
n.d
5.8
NK1



231
8.2
n.d
5.5
NK1



262
8.2
6.3
5.0
NK1



271
8.2
5.3
5.7
NK1



297
8.2
5.6
5.9
NK1



303
8.2
6.2
5.5
NK1



327
8.2
5.4
5.7
NK1



328
8.2
6.2
5.2
NK1



380
8.2
5.1
5.8
NK1



404
8.2
5.3
7.1
NK1



99
8.1
n.d
5.5
NK1



219
8.1
5.4
5.5
NK1



288
8.1
5.8
6.1
NK1



299
8.1
5.6
6.1
NK1



302
8.1
5.6
6.0
NK1



310
8.1
5.7
5.4
NK1



364
8.1
5.7
6.2
NK1



403
8.1
5.6
5.6
NK1



73
8.0
n.d
5.8
NK1



97
8.0
n.d
5.6
NK1



199
8.0
n.d
5.8
NK1



216
8.0
5.3
5.8
NK1



234
8.0
n.d
5.5
NK1



237
8.0
n.d
5.4
NK1



242
8.0
n.d
5.6
NK1



274
8.0
5.0
5.4
NK1



275
8.0
5.6
5.3
NK1



276
8.0
5.5
5.3
NK1



277
8.0
5.0
5.6
NK1



300
8.0
6.1
5.7
NK1



311
8.0
5.6
5.0
NK1



341
8.0
5.7
5.5
NK1



348
8.0
6.5
5.7
NK1



367
8.0
5.9
5.8
NK1



368
8.0
5.5
5.5
NK1



65
7.9
n.d
5.5
NK1



98
7.9
n.d
5.3
NK1



109
7.9
n.d
5.1
NK1



145
7.9
n.d
5.7
NK1



161
7.9
n.d
5.5
NK1



282
7.9
5.4
5.4
NK1



284
7.9
5.3
5.4
NK1



350
7.9
5.3
5.3
NK1



358
7.9
5.5
5.8
NK1



359
7.9
5.6
5.7
NK1



363
7.9
5.4
5.8
NK1



375
7.9
5.0
5.4
NK1



378
7.9
5.8
5.7
NK1



48
7.8
n.d
5.6
NK1



187
7.8
n.d
5.3
NK1



190
7.8
n.d
5.7
NK1



191
7.8
n.d
5.6
NK1



208
7.8
n.d
5.6
NK1



225
7.8
n.d
5.0
NK1



210
7.8
n.d
5.1
NK1



260
7.8
6.4
5.4
NK1



278
7.8
5.4
5.7
NK1



279
7.8
5.4
5.7
NK1



280
7.8
5.9
5.4
NK1



293
7.8
5.2
5.3
NK1



307
7.8
5.9
5.9
NK1



355
7.8
5.3
5.2
NK1



371
7.8
5.1
5.3
NK1



377
7.8
5.0
5.2
NK1



388
7.8
5.0
6.1
NK1



389
7.8
5.0
5.2
NK1



402
7.8
5.6
6.3
NK1



25
7.7
5.3
5.3
NK1



110
7.7
n.d
5.3
NK1



196
7.7
n.d
5.0
NK1



203
7.7
n.d
6.0
NK1



207
7.7
n.d
5.4
NK1



209
7.7
n.d
5.0
NK1



213
7.7
n.d
5.8
NK1



214
7.7
n.d
5.4
NK1



294
7.7
5.1
5.0
NK1



333
7.7
5.6
5.0
NK1



344
7.7
5.4
5.0
NK1



347
7.7
6.2
5.6
NK1



370
7.7
5.2
5.1
NK1



386
7.7
5.0
5.3
NK1



387
7.7
5.0
5.3
NK1



390
7.7
5.0
5.0
NK1



391
7.7
5.0
5.5
NK1



411
7.7
5.6
6.0
NK1



18
7.6
n.d
5.6
NK1



188
7.6
n.d
5.7
NK1



197
7.6
n.d
5.0
NK1



204
7.6
n.d
5.6
NK1



228
7.6
n.d
5.2
NK1



283
7.6
5.4
5.6
NK1



376
7.6
5.0
5.4
NK1



60
7.5
n.d
5.6
NK1



46
7.5
5.4
5.9
NK1



59
7.5
n.d
5.5
NK1



85
7.5
n.d
5.0
NK1



68
7.5
n.d
5.8
NK1



16
7.5
5.3
5.6
NK1



61
7.5
n.d
5.2
NK1



15
7.5
n.d
5.7
NK1



106
7.5
n.d
5.4
NK1



108
7.5
n.d
5.6
NK1



198
7.5
n.d
5.6
NK1



215
7.5
n.d
5.3
NK1



229
7.5
n.d
5.6
NK1



240
7.5
n.d
5.0
NK1



241
7.5
n.d
5.0
NK1



247
7.5
n.d
5.0
NK1



319
7.5
5.3
5.5
NK1



334
7.5
5.3
5.1
NK1



343
7.5
5.5
5.1
NK1



349
7.5
5.6
5.2
NK1



354
7.5
5.0
5.0
NK1



385
7.5
5.0
5.4
NK1



413
7.5
5.0
5.7
NK1



53
7.4
n.d
5.5
NK1



37
7.4
n.d
5.7
NK1



47
7.4
n.d
5.4
NK1



9
7.4
n.d
5.9
NK1



130
7.4
n.d
5.5
NK1



143
7.4
n.d
5.5
NK1



149
7.4
n.d
5.0
NK1



202
7.4
n.d
5.2
NK1



220
7.4
n.d
6.0
NK1



235
7.4
n.d
5.0
NK1



298
7.4
5.5
5.5
NK1



337
7.4
5.5
5.9
NK1



414
7.4
5.0
6.2
NK1



28
7.3
5.6
n.d
NK1



22
7.3
n.d
5.6
NK1



185
7.3
n.d
5.0
NK1



201
7.3
n.d
5.0
NK1



222
7.3
n.d
5.2
NK1



212
7.3
n.d
5.0
NK1



245
7.3
n.d
5.0
NK1



249
7.3
5.3
5.3
NK1



251
7.3
5.2
5.3
NK1



340
7.3
5.2
5.2
NK1



410
7.3
5.9
5.0
NK1



2
7.2
n.d
n.d
NK1



51
7.2
n.d
5.4
NK1



62
7.2
n.d
5.4
NK1



6
7.2
5.0
5.6
NK1



105
7.2
n.d
5.0
NK1



148
7.2
n.d
5.0
NK1



177
7.2
n.d
5.6
NK1



346
7.2
5.8
5.9
NK1



352
7.2
5.2
5.5
NK1



29
7.1
5.7
n.d
NK1



111
7.1
n.d
5.2
NK1



244
7.1
n.d
5.0
NK1



412
7.1
5.6
5.3
NK1



1
7.0
n.d
n.d
NK1



80
7.0
n.d
n.d
NK1



8
7.0
5.0
5.4
NK1



10
7.0
n.d
5.2
NK1



186
7.0
n.d
5.0
NK1



250
7.0
5.2
5.3
NK1



3
6.9
n.d
5.8
NK1



20
6.9
n.d
5.3
NK1



57
6.9
n.d
5.5
NK1



63
6.9
n.d
5.5
NK1



11
6.9
n.d
5.5
NK1



118
6.9
n.d
5.0
NK1



87
6.9
n.d
5.9
NK1



138
6.9
n.d
5.2
NK1



141
6.9
n.d
5.5
NK1



144
6.9
n.d
5.0
NK1



246
6.9
n.d
5.0
NK1



356
6.9
5.0
5.4
NK1



362
6.9
5.6
5.6
NK1



137
6.8
n.d
5.2
NK1



139
6.8
n.d
5.2
NK1



223
6.8
n.d
5.8
NK1



336
6.8
6.0
5.0
NK1



38
6.7
n.d
5.1
NK1



136
6.7
n.d
5.0
NK1



243
6.7
n.d
5.0
NK1



345
6.7
6.3
5.0
NK1



129
6.6
n.d
5.0
NK1



320
6.6
5.4
5.6
NK1



392
6.6
5.0
5.1
NK1



401
6.6
5.5
5.9
NK1



55
6.5
n.d
5.1
NK1



335
6.5
6.0
5.0
NK1



331
8.5
5.7
6.6
NK1/NK2/NK3



330
8.5
6.2
6.4
NK1/NK2/NK3



313
8.4
6.2
6.6
NK1/NK2/NK3



290
8.4
5.8
6.4
NK1/NK2/NK3



291
8.4
5.9
6.4
NK1/NK2/NK3



342
8.3
6.9
6.4
NK1/NK2/NK3



253
8.3
6.4
6.3
NK1/NK2/NK3



315
8.3
6.3
6.2
NK1/NK2/NK3



232
8.2
5.5
6.9
NK1/NK2/NK3



238
8.2
5.9
6.8
NK1/NK2/NK3



211
8.2
6.0
6.7
NK1/NK2/NK3



171
8.2
6.1
6.6
NK1/NK2/NK3



263
8.2
6.1
6.5
NK1/NK2/NK3



286
8.2
6.0
6.4
NK1/NK2/NK3



324
8.2
6.7
6.4
NK1/NK2/NK3



226
8.2
5.9
6.3
NK1/NK2/NK3



267
8.1
6.2
6.7
NK1/NK2/NK3



308
8.1
6.7
6.6
NK1/NK2/NK3



266
8.1
6.0
6.5
NK1/NK2/NK3



172
8.1
6.1
6.4
NK1/NK2/NK3



312
8.1
5.8
6.3
NK1/NK2/NK3



206
8.0
6.1
6.6
NK1/NK2/NK3



239
8.0
6.0
6.6
NK1/NK2/NK3



323
8.0
5.9
6.5
NK1/NK2/NK3



162
8.0
6.0
6.3
NK1/NK2/NK3



252
8.0
6.0
6.3
NK1/NK2/NK3



254
8.0
6.6
6.3
NK1/NK2/NK3



257
8.0
6.5
6.2
NK1/NK2/NK3



317
8.0
6.4
6.2
NK1/NK2/NK3



351
8.0
6.6
6.0
NK1/NK2/NK3



264
7.9
5.8
6.7
NK1/NK2/NK3



287
7.9
5.9
6.6
NK1/NK2/NK3



258
7.9
6.3
6.4
NK1/NK2/NK3



69
7.9
6.2
6.3
NK1/NK2/NK3



259
7.9
5.7
6.3
NK1/NK2/NK3



306
7.9
5.5
6.0
NK1/NK2/NK3



27
7.8
6.2
6.5
NK1/NK2/NK3



164
7.8
7.1
6.4
NK1/NK2/NK3



255
7.8
5.9
6.4
NK1/NK2/NK3



318
7.8
6.5
6.4
NK1/NK2/NK3



79
7.8
6.0
6.3
NK1/NK2/NK3



314
7.8
5.9
6.3
NK1/NK2/NK3



326
7.8
6.3
6.3
NK1/NK2/NK3



325
7.8
6.4
6.2
NK1/NK2/NK3



265
7.7
5.8
6.8
NK1/NK2/NK3



76
7.7
5.9
6.7
NK1/NK2/NK3



173
7.7
6.1
6.6
NK1/NK2/NK3



316
7.7
6.1
6.2
NK1/NK2/NK3



268
7.7
6.6
6.0
NK1/NK2/NK3



75
7.6
6.0
6.4
NK1/NK2/NK3



175
7.6
6.0
6.4
NK1/NK2/NK3



78
7.5
6.4
6.6
NK1/NK2/NK3



261
7.5
5.9
6.3
NK1/NK2/NK3



72
7.3
7.2
6.1
NK1/NK2/NK3



361
7.1
6.0
6.2
NK1/NK2/NK3



292
7.0
6.1
6.1
NK1/NK2/NK3



366
8.2
5.7
7.0
NK1/NK3



285
8.2
5.5
6.2
NK1/NK3



296
8.2
5.8
6.1
NK1/NK3



40
8.1
5.6
6.9
NK1/NK3



189
8.1
5.0
6.6
NK1/NK3



14
8.1
5.3
6.5
NK1/NK3



200
8.1
5.0
6.4
NK1/NK3



168
8.1
5.0
6.3
NK1/NK3



193
8.1
5.0
6.3
NK1/NK3



365
8.1
5.6
6.3
NK1/NK3



167
8.1
5.7
6.2
NK1/NK3



322
8.1
5.4
6.2
NK1/NK3



217
8.1
5.5
6.1
NK1/NK3



289
8.1
5.7
6.1
NK1/NK3



26
8.0
5.8
6.8
NK1/NK3



304
8.0
5.8
6.8
NK1/NK3



178
8.0
5.7
6.6
NK1/NK3



205
8.0
5.5
6.6
NK1/NK3



31
8.0
5.6
6.4
NK1/NK3



160
8.0
5.0
6.4
NK1/NK3



192
8.0
5.0
6.2
NK1/NK3



218
8.0
5.4
6.1
NK1/NK3



357
8.0
5.5
6.1
NK1/NK3



360
8.0
5.4
6.0
NK1/NK3



32
7.9
5.3
6.7
NK1/NK3



70
7.9
5.0
6.3
NK1/NK3



21
7.9
5.3
6.4
NK1/NK3



169
7.9
5.6
6.6
NK1/NK3



195
7.9
5.0
6.4
NK1/NK3



321
7.9
5.5
6.6
NK1/NK3



369
7.9
5.4
6.2
NK1/NK3



33
7.8
5.4
6.3
NK1/NK3



39
7.8
5.5
6.4
NK1/NK3



41
7.8
5.8
6.7
NK1/NK3



17
7.8
5.1
6.6
NK1/NK3



103
7.8
5.3
6.4
NK1/NK3



295
7.8
5.7
6.5
NK1/NK3



71
7.7
5.3
6.1
NK1/NK3



34
7.7
5.5
6.5
NK1/NK3



77
7.7
5.6
6.3
NK1/NK3



45
7.7
5.2
6.8
NK1/NK3



74
7.7
5.0
6.3
NK1/NK3



115
7.7
5.1
6.5
NK1/NK3



159
7.7
5.2
6.2
NK1/NK3



174
7.7
5.7
6.0
NK1/NK3



176
7.7
5.6
6.0
NK1/NK3



13
7.6
5.4
6.7
NK1/NK3



35
7.6
5.4
6.7
NK1/NK3



42
7.6
5.0
6.6
NK1/NK3



67
7.6
5.4
6.0
NK1/NK3



36
7.6
5.0
6.7
NK1/NK3



43
7.6
5.1
6.2
NK1/NK3



66
7.6
5.3
6.4
NK1/NK3



24
7.6
5.2
6.6
NK1/NK3



49
7.6
5.5
6.6
NK1/NK3



4
7.6
5.2
6.8
NK1/NK3



163
7.6
n.d
6.8
NK1/NK3



233
7.6
n.d
6.1
NK1/NK3



256
7.6
5.8
6.4
NK1/NK3



353
7.6
5.5
6.1
NK1/NK3



30
7.5
5.4
6.0
NK1/NK3



52
7.5
5.0
6.2
NK1/NK3



23
7.5
5.5
6.3
NK1/NK3



5
7.5
5.2
6.2
NK1/NK3



56
7.4
5.5
6.9
NK1/NK3



19
7.4
5.1
6.4
NK1/NK3



54
7.4
5.0
6.1
NK1/NK3



44
7.3
5.2
6.2
NK1/NK3



64
7.3
5.6
6.8
NK1/NK3



165
7.3
5.0
6.1
NK1/NK3



12
7.1
5.0
6.9
NK1/NK3



107
7.0
5.5
6.2
NK1/NK3



142
6.9
n.d
6.1
NK1/NK3



7
6.7
5.0
6.5
NK1/NK3










E. Composition Examples

“Active ingredient” (A.I.) as used throughout these examples relates to a compound 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
500 grams of the A.I. was dissolved in 0.5 l of 2-hydroxypropanoic acid and 1.5 l of the polyethylene glycol at 60 ̃80° C. After cooling to 30 ̃40° C. there were added 35 l of polyethylene glycol and the mixture was stirred well. Then there was added a solution of 1750 grams of sodium saccharin in 2.5 l of purified water and while stirring there were added 2.5 l of cocoa flavor and polyethylene glycol q.s. to a volume of 50 l, providing an oral drop solution comprising 10 mg/ml of A.I. The resulting solution was filled into suitable containers.
Example E.2
Oral Solution
9 Grams of methyl 4-hydroxybenzoate and 1 gram of propyl 4-hydroxybenzoate were dissolved in 4 l of boiling purified water. In 3 l of this solution were dissolved first 10 grams of 2,3-dihydroxybutanedioic acid and thereafter 20 grams of the A.I. The latter solution was combined with the remaining part of the former solution and 12 l 1,2,3-propanetriol and 3 l of sorbitol 70% solution were added thereto. 40 Grams of sodium saccharin were dissolved in 0.5 l of water and 2 ml of raspberry and 2 ml of gooseberry essence were added. The latter solution was combined with the former, water was added q.s. to a volume of 20 l providing an oral solution comprising 5 mg of the active ingredient per teaspoonful (5 ml). The resulting solution was filled in suitable containers.
Example E.3
Film-Coated Tablets
Preparation of Tablet Core
A mixture of 100 grams of the A.I., 570 grams lactose and 200 grams starch was mixed well and thereafter humidified with a solution of 5 grams sodium dodecyl sulfate and 10 grams polyvinylpyrrolidone in about 200 ml of water. The wet powder mixture was sieved, dried and sieved again. Then there was added 100 grams microcrystalline cellulose and 15 grams hydrogenated vegetable oil. The whole was mixed well and compressed into tablets, giving 10,000 tablets, each containing 10 mg of the active ingredient.
Coating
To a solution of 10 grams methyl cellulose in 75 ml of denaturated ethanol there was added a solution of 5 grams of ethyl cellulose in 150 ml of dichloromethane. Then there were added 75 ml of dichloromethane and 2.5 ml 1,2,3-propanetriol. 10 Grams of polyethylene glycol was molten and dissolved in 75 ml of dichloromethane. The latter solution was added to the former and then there were added 2.5 grams of magnesium octadecanoate, 5 grams of polyvinylpyrrolidone and 30 ml of concentrated colour suspension and the whole was homogenated. The tablet cores were coated with the thus obtained mixture in a coating apparatus.
Example E.4
Injectable Solution
1.8 Grams methyl 4-hydroxybenzoate and 0.2 grams propyl 4-hydroxybenzoate were dissolved in about 0.5 l of boiling water for injection. After cooling to about 50° C. there were added while stirring 4 grams lactic acid, 0.05 grams propylene glycol and 4 grams of the A.I. The solution was cooled to room temperature and supplemented with water for injection q.s. ad 1 l, giving a solution comprising 4 mg/ml of A.I. The solution was sterilized by filtration and filled in sterile containers.

## Claims

1. A compound according to the 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:
n is an integer, equal to 1;
m is an integer, equal to 1;
p is an integer equal to 1 or 2;
q is an integer equal to 0;
Q is O;
X is a covalent bond;
each R1 independently from each other, is selected from the group of Ar1, Ar1-alkyl and di(Ar1)-alkyl;
R2 is Ar2;
Y is a covalent bond or a bivalent radical of formula —C(═O)—, —SO2—, >C═CH—R or >C═N—R, wherein R is H, CN or nitro;
each Alk represents, independently from each other, a covalent bond; a bivalent straight or branched, saturated or unsaturated hydrocarbon radical having from 1 to 6 carbon atoms; or a cyclic saturated or unsaturated hydrocarbon radical having from 3 to 6 carbon atoms; each radical optionally substituted on one or more carbon atoms with one or more, phenyl, halo, cyano, hydroxy, formyl and amino radicals;
L is selected from the group of hydrogen, alkyl, alkyloxy, alkyloxyalkyloxy, alkylcarbonyloxy, alkyloxycarbonyl, mono- and di(alkyl)amino, mono- and di(alkyloxycarbonyl)amino, mono- and di(alkylcarbonyl)amino, mono- and di(Ar3)amino, mono- and di(Ar3alkyl)amino, mono- and di(Het2)amino, mono- and di(Het2alkyl)amino, alkylsulfanyl, adamantyl, Ar3, Ar3-oxy, Ar3carbonyl, Het2, Het-oxy and Het2carbonyl;
Ar1 is phenyl, optionally substituted with 1, 2 or 3 substituents, each independently from each other, selected from the group of halo, alkyl, cyano, aminocarbonyl and alkyloxy;
Ar2 is naphthalenyl or phenyl, each optionally substituted with 1, 2 or 3 substituents, each independently from each other, selected from the group of halo, nitro, amino, mono- and di(alkyl)amino, cyano, alkyl, hydroxy, alkyloxy, carboxyl, alkyloxycarbonyl, aminocarbonyl and mono- and di(alkyl)aminocarbonyl;
Ar3 is naphthalenyl or phenyl, optionally substituted with 1, 2 or 3 substituents, each independently from each other, selected from the group of alkyloxy, Ar1carbonyloxyalkyl, Ar1alkyloxycarbonyl, Ar1alkyloxyalkyl, alkyl, halo, hydroxy, pyridinyl, morpholinyl, pyrrolidinyl, imidazo[1,2-a]pyridinyl, morpholinylcarbonyl, pyrrolidinylcarbonyl, amino and cyano;
Het2 is a monocyclic heterocyclic radical selected from the group of pyrrolidinyl, dioxolyl, imidazolidinyl, 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, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl and triazinyl;
or a bicyclic heterocyclic radical selected from the group of 2,3-dihydro-benzo [1,4]dioxine, octahydro-benzo[1,4]dioxine, benzopiperidinyl, quinolinyl, quinoxalinyl, indolyl, isoindolyl, chromanyl, benzimidazolyl, imidazo[1,2-a]pyridinyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl or benzothienyl;
or the tricyclic heterocyclic radical 8,9-dihydro-4H-1-oxa-3,5,7a-triaza-cyclopenta[f]azulenyl; each radical may optionally be substituted with one or more radicals selected from the group of Ar1, Ar1alkyl, Ar1alkyloxyalkyl, halo, hydroxy, alkyl, piperidinyl, pyrrolyl, thienyl, oxo, alkyloxy, alkylcarbonyl, Ar1carbonyl, mono- and di(alkyl)aminoalkyl, alkyloxyalkyl and alkyloxycarbonyl; and

alkyl is a straight or branched saturated hydrocarbon radical having from 1 to 6 carbon atoms or a cyclic saturated hydrocarbon radicals having from 3 to 6 carbon atoms;
optionally substituted on one or more carbon atoms with one or more radicals selected from the group of phenyl, halo, cyano, oxo, hydroxy, formyl and amino.

2. A compound according to claim 1 wherein:
R1 is Ar1-alkyl;
R2 is Ar2;
Y is a covalent bond or a bivalent radical of formula —C(═O)—, —SO2—, >C═CH—R or >C═N—R, wherein R is CN or nitro;
each Alk represents, independently from each other, a covalent bond; a bivalent straight or branched, saturated hydrocarbon radical having from 1 to 6 carbon atoms; or a cyclic saturated hydrocarbon radical having from 3 to 6 carbon atoms; each radical optionally substituted on one or more carbon atoms with one or more phenyl, halo and hydroxy radicals;
L is selected from the group of hydrogen, alkyl, alkyloxy, alkyloxyalkyloxy, alkylcarbonyloxy, mono- and di(alkyl)amino, mono- and di(alkyloxycarbonyl)amino, mono- and di(alkylcarbonyl)amino, mono- and di(Ar3)amino, mono- and di(Ar3alkyl)amino, mono- and di(Het2alkyl)amino, alkylsulfanyl, adamantyl, Ar3, Het2 and Het2carbonyl;
Ar1 is phenyl, optionally substituted with 1 or 2 halo radicals; Ar2 is naphthalenyl or phenyl, each optionally substituted with 1, 2 or 3 substituents, each independently from each other, selected from the group of halo, alkyl and alkyloxy;
Ar3 is naphthalenyl or phenyl, optionally substituted with 1, 2 or 3 substituents, each independently from each other, selected from the group of alkyloxy, Ar1alkyloxycarbonyl, Ar1alkyloxyalkyl, alkyl, halo and cyano;
Het2 is a monocyclic heterocyclic radical selected from the group of pyrrolidinyl, dioxolyl, piperidinyl, morpholinyl, piperazinyl, tetrahydrofuranyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl, dioxazolyl, oxazolidinyl, isoxazolyl, thiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl;
 or a bicyclic heterocyclic radical selected from the group of 2,3-dihydro-benzo[1,4]dioxine, octahydro-benzo[1,4]dioxine, quinoxalinyl, indolyl, chromanyl, benzimidazolyl, imidazo[1,2-a]pyridinyl, benzisoxazolyl, benzothiazolyl, benzofuranyl and benzothienyl;
or the tricyclic heterocyclic radical 8,9-dihydro-4H-1-oxa-3,5,7a-triaza-cyclopenta[f]azulenyl; each radical may optionally be substituted with one or more radicals selected from the group of Ar1, Ar1alkyloxyalkyl, halo, alkyl, oxo, alkyloxy, alkylcarbonyl, Ar1carbonyl, mono- and di(alkyl)aminoalkyl, alkyloxyalkyl and alkyloxycarbonyl; and

alkyl is a straight or branched saturated hydrocarbon radical having from 1 to 6 carbon atoms or a cyclic saturated hydrocarbon radicals having from 3 to 6 carbon atoms ; optionally substituted on one or more carbon atoms with one or more radicals selected from the group of phenyl, halo and hydroxy.

3. A compound according to claim 1, wherein R1 is Ar1methyl and attached to the 2-position or R1 is Ar1 and attached to the 3-position.

4. A compound according to claim 1, wherein R2—X—C(═Q)—moiety is 3,5-di-(trifluoromethyl) phenylcarbonyl.

5. A compound according to claim 1, wherein Y is —C(═O)—.

6. A compound according to claim 1, wherein Alk is a covalent bond.

7. A compound according to claim 1, wherein L is Het2.

8. A compound according to claim 1, selected from the group consisting of:
[2R-trans]-{2-benzyl-4-[4-(1-pyrazin-2-yl-pyrrolidin-3-yl)-piperazin-1-yl]-piperidin-1-yl}-(3,5-bis-trifluoromethyl-phenyl)-methanone,
[2R-[2α,4β(S)]]-1-(3-{4-[2-benzyl-1-(3,5-bis-trifluoromethyl-benzoyl)-piperidin-4-yl]-piperazin-1-yl}-pyrrolidin-1-yl)-2,2-dimethyl-propan-1-one,
[2R-[2α,4β(S*)]-{2-benzyl-4-[4-(1-cyclopropanecarbonyl-pyrrolidin-3-yl)-piperazin-1-yl]-piperidin-1-yl}-(3,5-bis-trifluoromethyl-phenyl)-methanone,
[2R-trans]-enantiomer of {2-benzyl-4-[4-(1-cyclopropanecarbonyl-pyrrolidin-3-yl)-piperazin-1-yl]-piperidin-1-yl}-(3,5-bis-trifluoromethyl-phenyl)-methanone,
2R-trans-(2-benzyl-4-{4-[1-(tetrahydro-furan-3-carbonyl)-pyrrolidin-3-yl]-piperazin-1-yl}-piperidin-1-yl)-(3,5-bis-trifluoromethyl-phenyl)-methanone,
[2R-[2α,4β(R(R))]]-(2-benzyl-4-{4-[1-(tetrahydro-furan-3-carbonyl)-pyrrolidin-3-yl]-piperazin-1-yl}-piperidin-1-yl)-(3,5-bis-trifluoromethyl-phenyl)-methanone,
[2R-[2α,4β(S(R))]]-(2-benzyl-4-{4-[1-(tetrahydro-furan-3-carbonyl)-pyrrolidin-3-yl]-piperazin-1-yl}-piperidin-1-yl)-(3,5-bis-trifluoromethyl-phenyl)-methanone,
[2R-trans,R*]-(2-benzyl-4-{4-[1-(furan-3-carbonyl)-pyrrolidin-3-yl]-piperazin-1-yl}-piperidin-1-yl)-(3,5-bis-trifluoromethyl-phenyl)-methanone,
[2R-[2α,4β(R)]]-(2-benzyl-4-{4-[1-(5-methyl-thiophene-2-carbonyl)-pyrrolidin-3-yl]-piperazin-1-yl}-piperidin-1-yl)-(3,5-bis-trifluoromethyl-phenyl)-methanone,
[2R-trans]-(2-benzyl-4-{4-[1-(3-hydroxymethyl-thiophene-2-sulfonyl)-pyrrolidin-3-yl]-piperazin-1-yl}-piperidin-1-yl)-(3,5-bis-trifluoromethyl-phenyl)-methanone,
[2R-[2α,4β(S)]]-(3,5-bis-trifluoromethyl-phenyl)-(2-(3,4-dichloro-benzyl)-4-{4-[1-(4-hydroxy-butyl)-pyrrolidin-3-yl]-piperazin-1-yl}-piperidin-1-yl)-methanone,
[(2R-trans),(S)]-1-(3-{4-[1-(3,5-bis-trifluoromethyl-benzoyl)-2-(3,4-dichloro-benzyl)-piperidin-4-yl]-piperazin-1-yl}-pyrrolidin-1-yl)-2,2-dimethyl-propan-1-one,
trans-(3,5-bis-trifluoromethyl-phenyl)-[4-{4-[1-(2-chloro-benzoyl)-pyrrolidin-3-yl]-piperazin-1-yl}-2-(3,4-dichloro-benzyl)-piperidin-1-yl]-methanone,
[(2R-trans),(S)]-(3,5-bis-trifluoromethyl-phenyl)-(2-(3,4-dichloro-benzyl)-4-{4-[1-(thiophene-2-carbonyl)-pyrrolidin-3-yl]-piperazin-1-yl}-piperidin-1-yl)-methanone,
[(2R-trans), (R)]-(3,5-bis-trifluoromethyl-phenyl)-(2-(3,4-dichloro-benzyl)-4-{4-[1-(thiophene-3-carbonyl)-pyrrolidin-3-yl]-piperazin-1-yl}-piperidin-1-yl)-methanone,
[(2R-trans), (R)]-(3,5-bis-trifluoromethyl-phenyl)-(2-(3,4-dichloro-benzyl)-4-{4-[1-(furan-2-carbonyl)-pyrrolidin-3-yl]-piperazin-1-yl}-piperidin-1-yl)-methanone,
[(2R-trans), (S)]-(3,5-bis-trifluoromethyl-phenyl)-(2-(3,4-dichloro-benzyl)-4-{4-[1-(furan-2-carbonyl)-pyrrolidin-3-yl]-piperazin-1-yl}-piperidin-1-yl)-methanone,
[(2R-trans), (S), (R)]-(3,5-bis-trifluoromethyl-phenyl)-(2-(3,4-dichloro-benzyl)-4-{4-[1-(tetrahydro-furan-3-carbonyl)-pyrrolidin-3-yl]-piperazin-1-yl}-piperidin-1-yl) -methanone,
[(2R-trans), (R)]-(3,5-bis-trifluoromethyl-phenyl)-(2-(3,4-dichloro-benzyl)-4-{4-[1-(pyrazine-2-carbonyl)-pyrrolidin-3-yl]-piperazin-1-yl}-piperidin-1-yl)-methanone,
[2R-[2α,4β(R*)]]-(3,5-bis-trifluoromethyl-phenyl)-(2-(3,4-difluoro-benzyl)-4-{4-[1-(1-methyl-1H-pyrrole-2-carbonyl)-pyrrolidin-3-yl]-piperazin-1-yl}-piperidin-1-yl) -methanone,
[2R-[2α,4β(R*(S*))]](3,5-bis-trifluoromethyl-phenyl)-(2-(3,4-difluoro-benzyl)-4-{4-[1-(tetrahydro-furan-3-carbonyl)-pyrrolidin-3-yl]-piperazin-1-yl}-piperidin-1-yl) -methanone,
[2R-[2α,4βS*(S*))]]-(3,5-bis-trifluoromethyl-phenyl)-(2-(3,4-difluoro-benzyl)-4-{4-[1-(tetrahydro-furan-3-carbonyl)-pyrrolidin-3-yl]-piperazin-1-yl}-piperidin-1-yl) -methanone,
[2R-[2α,4β(S*(R*))]]-(3,5-bis-trifluoromethyl-phenyl)-(2-(3,4-difluoro-benzyl)-4-{4-[1-(tetrahydro-furan-3-carbonyl)-pyrrolidin-3-yl]-piperazin-1-yl}-piperidin-1-yl) -methanone,
[2R-[2α,4β(R*(R*))]]-(3,5-bis-trifluoromethyl-phenyl)-(2-(3,4-difluoro-benzyl)-4-{4-[1-(tetrahydro-furan-3-carbonyl)-pyrrolidin-3-yl]-piperazin-1-yl}-piperidin-1-yl) -methanone,
[2R-[2α,4β(S*)]]-(3,5-Bis-trifluoromethyl-phenyl)-(2-(3,4-difluoro-benzyl)-4-{4-[1-(furan-3-carbonyl)-pyrrolidin-3-yl]-piperazin-1-yl}-piperidin-1-yl)-methanone,
[2R-[2α,4β(S*)]]-(3,5-Bis-trifluoromethyl-phenyl)-(2-(3,4-difluoro-benzyl)-4-{4-[1-(pyrazine-2-carbonyl)-pyrrolidin-3-yl]-piperazin-1-yl}-piperidin-1-yl)-methanone,
[2R-[2α,4β(S*)]]-(3,5-Bis-trifluoromethyl-phenyl)-(2-(3,4-difluoro-benzyl)-4-{4-[1-(4-methyl-[1,2,3]thiadiazole-5-carbonyl)-pyrrolidin-3-yl]-piperazin-1-yl}-piperidin-1-yl)-methanone, and
cis-(3,5-Bis-trifluoromethyl-phenyl)-(3-phenyl-4-{4-[1-(thiophene-2-carbonyl)-pyrrolidin-3-yl]-piperazin-1-yl}-piperidin-1-yl)-methanone.

9. A method for treating schizophrenia, emesis, anxiety, depression, irritable bowel syndrome (IBS), circadian rhythm disturbances, pain, neurogenic inflammation, asthma, micturition disorders and nociception in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound according to claim 1.

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

11. A process for preparing a pharmaceutical composition as claimed in claim 10, wherein a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of a compound as claimed claim 1.

12. A process for the preparation of a compound of Formula (I′′) in which an intermediate compound of Formula (II) is reacted with an intermediate compound of Formula (III), wherein the radicals R2, X, Q, R1, m, n, p and q are as defined in claim 1

13. A process for the preparation of a compound of Formula (I′) in which a final compound of Formula (IΔ) is reductively hydrogenated, wherein the radicals R2, X, Q, R1, m, n, p and q are as defined in claim 1