WO2004056772A1 - Derives de 1,4-di-piperidin-4-yl-piperazine substitues et leur utilisation comme antagonistes de la tachykinine - Google Patents

Derives de 1,4-di-piperidin-4-yl-piperazine substitues et leur utilisation comme antagonistes de la tachykinine Download PDF

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WO2004056772A1
WO2004056772A1 PCT/EP2002/014836 EP0214836W WO2004056772A1 WO 2004056772 A1 WO2004056772 A1 WO 2004056772A1 EP 0214836 W EP0214836 W EP 0214836W WO 2004056772 A1 WO2004056772 A1 WO 2004056772A1
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alkyl
disorders
group
radical
optionally substituted
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PCT/EP2002/014836
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Frans Eduard Janssens
François Maria SOMMEN
Benoît Christian Albert Ghislain DE BOECK
Joseph Elisabeth Leenaerts
Yves Emiel Maria Van Roosbroeck
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Janssen Pharmaceutica N.V.
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Priority to AU2002368487A priority Critical patent/AU2002368487A1/en
Priority to PCT/EP2002/014836 priority patent/WO2004056772A1/fr
Priority to MYPI20033797A priority patent/MY141736A/en
Priority to PL03376403A priority patent/PL376403A1/xx
Priority to PCT/EP2003/050697 priority patent/WO2004033428A1/fr
Priority to ARP030103649A priority patent/AR041545A1/es
Priority to US10/527,821 priority patent/US7410970B2/en
Priority to ES03773731T priority patent/ES2319642T3/es
Priority to EA200500616A priority patent/EA009217B1/ru
Priority to AT03773731T priority patent/ATE418543T1/de
Priority to TW092127724A priority patent/TWI324995B/zh
Priority to AU2003282115A priority patent/AU2003282115B2/en
Priority to KR1020057003472A priority patent/KR101049074B1/ko
Priority to CA2499903A priority patent/CA2499903C/fr
Priority to DE60325493T priority patent/DE60325493D1/de
Priority to MXPA05003778A priority patent/MXPA05003778A/es
Priority to EP03773731A priority patent/EP1551804B1/fr
Priority to BR0315098-4A priority patent/BR0315098A/pt
Priority to NZ539848A priority patent/NZ539848A/en
Priority to JP2004542503A priority patent/JP4674086B2/ja
Priority to PA20038584901A priority patent/PA8584901A1/es
Publication of WO2004056772A1 publication Critical patent/WO2004056772A1/fr
Priority to HR20050309A priority patent/HRP20050309A2/xx
Priority to IL167885A priority patent/IL167885A/en
Priority to NO20052192A priority patent/NO330656B1/no
Priority to HK06104676.7A priority patent/HK1084394A1/xx

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • This invention concerns l,4-di-piperidin-4-yl-piperazine derivatives having tachykinin antagonistic activity, in particular NKi antagonistic activity, their preparation, compositions comprising them and their use as a medicine, in particular for the treatment of emesis, anxiety, depression and IBS.
  • 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- NH 2 . Tachykinins released from peripheral sensory nerve endings are believed to be involved in neurogenic inflammation.
  • tachykinins may play a role in pain transmission/perception and in some autonomic reflexes and behaviours.
  • the three major tachykinins are Substance P (SP), Neurokinin A (NK A ) and Neurokinin B (NK B ) with preferential affinity for three distinct receptor subtypes, termed NK 1 ; NK 2 , and NK 3 , respectively.
  • SP Substance P
  • NK A Neurokinin A
  • NK B Neurokinin B
  • NK 1 ; NK 2 , and NK 3 three distinct receptor subtypes
  • NKi receptors Species differences in structure of NKi receptors are responsible for species- related potency differences of NB antagonists (Maggi, Gen. Pharmacol. 26:911-944 (1995) ; Regoli et al., Pharmacol. Rev. 46(4):551-599 (1994)).
  • the human NK, receptor closely resembles the NK] receptor of guinea-pigs and gerbils but differs markedly from the NKi receptor of rodents.
  • tachykinin 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(l):5-23 (1995)).
  • tachykinins are involved in emesis, (stress-related) anxiety states, inflammatory responses, smooth muscle contraction and pain perception.
  • Tachykinin 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.
  • IBS irritable bowel syndrome
  • 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.
  • 5-HT 3 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)).
  • NK t 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.
  • NKi 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)).
  • NKi antagonists such as MK-869 and CJ-11,974, also known as Ezlopitant
  • NKi antagonists 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)).
  • NKi 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. 1-14 (2002)).
  • the compounds are suggested to act by blocking central NK t -receptors in the nucleus tractus solitarius. Apart from NKi 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 NK] antagonists.
  • 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.
  • MDD Major depression
  • DSM-IV Major depression
  • depression 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.
  • NKi agonists and antagonists are anxiogenic and anxiolytic, respectively (Teixeira et al, Eur. J. Pharmacol. 311:7-14 (1996)).
  • NK] 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 NKi 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)).
  • NK! agonist-induced vocalisation response in guinea-pigs can be antagonised by antidepressants such as imipramine and fluoxetine as well as L-733,060, an NKi antagonist.
  • IBS Irritable bowel syndrome
  • IBS irritable bowel syndrome
  • NKi receptors are also involved in gastrointestinal motility (Tonini et al, Gastroenterol. 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, NKj antagonists are considered to have potential to ameliorate symptoms in IBS patients.
  • tachykinin antagonists More specifically were disclosed 4-piperazin-l-yl-piperidine-l-carboxylic acid amide derivatives, in WO 01/30348-Al, 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 August 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 piperidinyl moiety as well as in their improved ability as potent, orally and centrally active tachykinin antagonists with therapeutic value, especially for the treatment of emesis, anxiety and depression, irritable bowel syndrome (IBS), circadian rhythm disturbances, visceral pain, neurogenic inflammation, asthma, micturition disorders, and nociception.
  • IBS irritable bowel syndrome
  • the present invention relates to novel l,4-di-piperidin-4-yl-piperazine derivatives according to the general Formula (I)
  • 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 O or ⁇ R 3 ;
  • X is a covalent bond or a bivalent radical of formula -O-, -S- or - ⁇ R 3 - ; each R 3 independently from each other, is hydrogen or alkyl ; each R 1 independently from each other, is selected from the group of Ar 1 , Ar 1 - alkyl and di(Ar 1 )-alkyl ; q is an integer equal to 0 or 1 ;
  • R 2 is alkyl, Ar 2 , Ar 2 -alkyl, Het 1 or Het'-alkyl ;
  • Ar 1 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
  • Ar 2 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
  • Ar 3 is naphthalenyl or phenyl, optionally substituted with 1, 2 or 3 substituents each independently from each other selected from the group of alkyloxy, alkyl, halo, hydroxy, pyridinyl, morpholinyl, pyrrolidinyl, imidazo[l,2- ⁇ ]pyridiny
  • 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 1 m is 1 p is 1
  • R 2 is Ar 2 ;
  • L is selected from the group of hydrogen, alkyloxy, Ar 3 -oxy, alkyloxycarbonyl, mono- and di(alkyl)amino, mono-and di(Ar 3 )amino, Ar 3 and Het 2 ;
  • Ar 1 is phenyl, optionally substituted with 1, 2 or 3 alkyl radicals ;
  • Ar 2 is phenyl, optionally substituted with 1, 2 or 3 alkyl radicals ;
  • Ar 3 is phenyl, optionally substituted with 1, 2 or 3 substituents each independently from each other selected from the group of alkyloxy, alkyl, halo, hydroxy, pyridinyl, morpholinyl, pyrrolidinyl, imidazo[l,2- jpyridinyl, morpholinylcarbonyl, pyrrolidinylcarbonyl, amino and cyano ;
  • Het 2 is a monocyclic heterocyclic radical selected from the group of pyrrolidinyl, piperidinyl, morpholinyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl, isoxazolyl, thiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl ; or a bicyclic heterocyclic radical selected from the group of benzopiperidinyl, quinolinyl, quinoxalinyl, indolyl, chromenyl and benzimidazolyl ; each radical optionally substituted with one or more radicals selected from the group of Ar 1 , Ar'alkyl, halo, hydroxy, alkyl, piperidinyl, pyrrolyl, thienyl, oxo and alkyloxycarbonyl ; and alkyl is a straight hydrocarbon
  • 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 R 1 is A ⁇ methyl and attached to the 2-position or R 1 is Ar 1 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.
  • a ⁇ methyl is an unsubstituted benzyl radical.
  • 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.
  • 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.
  • halo is generic to fluoro, chloro, bromo and iodo.
  • 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, cyclamic acid, salicylic acid, p-aminosalicylic acid and pamoic acid.
  • acids for example inorganic
  • 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, /V-methyl-D-glucamine, hybramine salts, and salts with amino acids, for example arginine and lysine.
  • salts forms can be converted into the free forms by treatment with an appropriate base or acid.
  • 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.
  • 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 piperidinyl 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 .
  • oxidation is normally the first step involved in drug metabolism ( Textbook of Organic Medicinal and Pharmaceutical Chemistry, 1977, pages 70- 75).
  • the metabolite form of a compound can also be administered to a human instead of the compound per se, with much 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 are to 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.
  • 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, 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.
  • an R or S descriptor is assigned (based on Cahn-Ingold-Prelog sequence rule) to the lowest-numbered chiral center, the reference center.
  • the configuration of the second stereogenic center is indicated using relative descriptors [R* R* ] or [R* S*7, where R* is always specified as the reference center and [R* R*] indicates centers with the same chirality and [R*,S*] indicates centers of unlike chirality. For example, if the lowest-numbered chiral center in the molecule has an S configuration and the second center is R, the stereo descriptor would be specified as S-[R* S*].
  • 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 " ⁇ " 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 " ⁇ ", if it is on the same side of the mean plane determined by the ring system, or " ⁇ ", 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,
  • 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 -COOR x , where R x is a C ⁇ alkyl, phenyl, benzyl or one of the following groups :
  • Amidated groups include groups of the formula - CO ⁇ R y R z , wherein R y is H, C]. 6 alkyl, phenyl or benzyl and R z is -OH, H, C ⁇ _ 6 alkyl, 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.
  • Substance P and other neurokinins 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 NKi 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(l):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 NKi receptor, and may therefore be described as tachykinin antagonists, especially as substance P antagonists, as indicated in vitro by the antagonism of substance P-induced relaxation of pig coronary arteries which is described hereinafter.
  • the binding affinity of the present compounds for the human, guinea-pig and gerbil neurokinin receptors may be determined in vitro in a receptor binding test using 3 H-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)).
  • the compounds according to the invention are useful as a medicine, in particular in the prophylactic and therapeutic treatment of tachykinin- mediated conditions.
  • the invention therefore relates to a compound according to the general Formula
  • 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 C ⁇ S disorders,in particular depression, anxiety disorders, stress-related disorders, sleep disorders, cognitive disorders, personality disorders, schizoaffective disorders, eating disorders, neurodegenerative diseases, addiction disorders, mood disorders, sexual dysfunction, pain and other C ⁇ S-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.
  • C ⁇ S disorders in particular depression, anxiety disorders, stress-related disorders, sleep disorders, cognitive disorders, personality disorders, schizoaffective disorders, eating disorders, neurodegenerative diseases, addiction disorders, mood disorders, sexual dysfunction, pain and other C ⁇ S-related conditions ; inflammation ; allergic disorders ; emesis ; gastrointestinal disorders, in particular irritable bowel syndrome (IBS); skin disorders ; vasospastic diseases ; fibrosing and
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 He ⁇ es simplex encephalitis and other limbic encephalitis, neuronal loss secondary to anoxia / hypoglycemia / severe convulsions and surgery, degenerative disorders, vascular disorders or pathology around ventricle HI.
  • 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.
  • 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.
  • 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.
  • 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 ; schizoaffective disorder ; delusional disorder ; brief psychotic disorder ; shared psychotic disorder ; substance-induced psychotic disorder ; and psychotic disorder not otherwise specified.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 mo ⁇ hine), phencyclidine, phencyclidine-like compounds, sedative-hypnotics, benzodiazepines and/or other substances, particularly useful for treating withdrawal from the above substances and alcohol withdrawal delirium.
  • substance dependence or abuse with or without physiological dependence
  • the substance is alcohol, amphetamines, amphetamine-like substances, caffeine, cocaine, hallucinogens, inhalants, nicotine, opioids (such as cannabis, heroin and mo ⁇ hine), phencyclidine, phencyclidine-like compounds, sedative-hypnotics, benzodiazepines and/or other substances, particularly useful for treating withdrawal from the above substances and alcohol withdrawal delirium.
  • 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.
  • 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.
  • 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-he ⁇ etic neuralgia, trigeminal 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
  • 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 parkinsonism, 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.
  • ADHD attention-deficit / hyperactivity disorder
  • Parkinson's disease drug-induced Parkinsonism
  • post-encephalitic Parkinsonism progressive supranuclear palsy
  • 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 he ⁇ es and eczema ; inflammatory conditions of the bladder such as cystitis and urge incontinence ; and eye and dental inflammation and pancreatitis, in particular chronic and acute pacreatitis.
  • 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 he ⁇ es and e
  • 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.
  • 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 ;
  • 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.
  • IBS irritable bowel syndrome
  • skin disorders such as psoriasis, pruritis and sunburn
  • vasospastic diseases such as angina, vascular headache and Reynaud's disease, cerebral ischaemia such as cerebral vaso
  • 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 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.
  • 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
  • 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 pu ⁇ oses.
  • compositions there may be cited all compositions usually employed for systemically administering drugs.
  • a pharmaceutically acceptable carrier which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
  • compositions are desirable in unitary dosage form suitable, in particular, for administration orally, rectally, percutaneously, by parenteral injection or by inhalation.
  • 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.
  • tablets and capsules represent the most advantageous oral dosage unit forms in which case solid pharmaceutical carriers are obviously employed.
  • 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.
  • solid form preparations that are intended to be converted, shortly before use, to liquid form preparations.
  • 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.
  • Unit dosage form 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.
  • 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.
  • compositions comprising said compounds for administration orally are especially advantageous.
  • 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 compounds of Formula (I) are conveniently prepared by reductively N-alkylating an intermediate of Formula (II) with and intermediate of Formula (HI) .
  • 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.
  • a borohydride e.g. sodium borohydride, sodium cyanoborohydride or triacetoxy borohydride.
  • a complex -forming agent such as, for example, titanium(IV)isopropylate as described in J. Org.
  • Using said comple -forming agent may also result in an improved cisltrans 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.
  • a suitable catalyst such as, for example, palladium-on-charcoal or platinum-on-charcoal.
  • it may be advantageous to add a dehydrating agent to the reaction mixture such as, for example, aluminium tert-butoxide.
  • 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.
  • 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.
  • a compound according to the invention is pharmacological active and can be converted into a 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.
  • a suitable catalyst such as, for example, palladium-on-charcoal or platinum-on- charcoal.
  • the resulting compound according to the invention can then be converted into other compounds according to the invention by art-known transformations, e.g. acylation and alkylation.
  • the compounds of Formula (I a ) can be prepared by reacting a final compound of Formula (I 1 ) with an intermediate of Formula (V) wherein W 1 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.
  • W 1 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 at a temperature ranging between room temperature and reflux temperature.
  • the compounds of Formula (I a ) 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, 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 at a temperature ranging between room temperature and reflux temperature.
  • the compounds of Formula (I b ) can be prepared by reacting a final compound of Formula (I') with a compound of Formula (VII) wherein W 2 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 at a temperature ranging between room temperature and reflux temperature.
  • the compounds of Formula (I c ) can be prepared by reductive amination/alkylation of a final compound of Formula (I 1 ) with a compound of Formula (VHJ) wherein W 3 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 at a temperature ranging between room temperature and reflux temperature.
  • intermediates of formula (U) may be prepared by reductively N-alkylating an intermediate of formula (DC) with an intermediate of formula (X) in which W 4 is a benzyl radical, after which the compound according to Formula (X) is subsequently reduced to yield an intermediate compound according to Formula (TJ).
  • 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.
  • borohydride sodium borohydride, sodium cyanoborohydride or triacetoxy borohydride.
  • 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 cisltrans ratio in favour of the trans isomer.
  • a suitable catalyst such as, for example, palladium-on-charcoal or platinum-on-charcoal.
  • a dehydrating agent such as, for example, aluminium tert-butoxide.
  • 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.
  • RT room temperature
  • DIPE diisopropylether
  • DCM dichloromethane
  • DMF N,N- dimethylformamide
  • Example Cl Binding experiment for h-NKl, 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 ([ 3 H]- or [ 125 I] ligand) to label a particular receptor.
  • a radioactively labelled substance [ 3 H]- or [ 125 I] ligand
  • 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.
  • 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
  • All selected compounds show (sub)nanomolar affinity for the h-NKi receptor most of them with more than 100-fold selectivity towards the h-NK 2 and h-NK 3 receptors.
  • NKi 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 ⁇ M Fluo3 in DMEM containing 0.1% BSA and 2.5 mM probenecid for 1 h at 37°C. They were washed 3x with a Krebs buffer (140 mM NaCl, 1 mM MgCl 2 x6H 2 O, 5 mM KC1, 10 mM glucose, 5 mM HEPES; 1.25 mM CaCl 2 ; pH 7.4) containing 2.5 mM probenecid and 0.1 % BSA (CaAbuffer).
  • a Krebs buffer 140 mM NaCl, 1 mM MgCl 2 x6H 2 O, 5 mM KC1, 10 mM glucose, 5 mM HEPES; 1.25 mM CaCl 2 ; pH 7.4
  • the cells were preincubated with a concentration range of antagonists for 20 min at RT and Ca "1" - signals after addition of the agonists were measured in a Fluorescence Image Plate Reader (FLDPR from Molecular Devices, Crawley, England). The peak of the Ca " A 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 EC 50 -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 IC 5 o-value was calculated using non-linear regression. Table 3
  • Active ingredient 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.

Abstract

L'invention concerne des dérivés de la 1,4-di-pipéridin-4-yl-pipérazine substitués ayant une activité antagoniste à la tachykinine, notamment une activité antagoniste à NK1, leur préparation, des compositions les contenant et leur utilisation comme médicament, en particulier pour le traitement des vomissements, de l'anxiété, de la dépression et du syndrome du côlon irritable (IBS). Les composés selon l'invention peuvent être représentés par la formule générale (I) et contenir également les sels d'addition d'acide ou de base pharmaceutiquement acceptables, les formes isomériques stéréochimiques, leur forme N-oxyde et leur prodrogues, tous les substituants étant définis comme dans la revendication 1. En vue de leur capacité d'opposition aux actions de la tachykinine par le blocage des récepteurs de tachykinine et, en particulier, d'opposition des actions de substance P par le blocage du récepteur NK1, les composés selon l'invention sont utiles comme médicament, en particulier dans le traitement prophylactique et le traitement thérapeutique des états liés à la tachykinine, par exemple, les troubles du système nerveux central, notamment la dépression, les troubles d'anxiété, les troubles liés au stress, les troubles du sommeil, les troubles cognitifs, les troubles de la personnalité, les troubles schizoaffectifs, les troubles de l'alimentation, les troubles neurodégénératifs, les troubles addictifs, les troubles de l'humeur, les dysfonctionnements sexuels, la douleur et autres états liés au système nerveux central; inflammations; troubles allergiques; vomissements; troubles gastro-intestinaux, notamment le syndrome du côlon irritable (IBS); les troubles cutanés; les maladies vasospastiques; fibrose et maladie du collagène; troubles liés à l'amélioration ou à la suppression de l'immunité et aux maladies rhumatismales et au contrôle du poids.
PCT/EP2002/014836 2002-10-08 2002-12-23 Derives de 1,4-di-piperidin-4-yl-piperazine substitues et leur utilisation comme antagonistes de la tachykinine WO2004056772A1 (fr)

Priority Applications (25)

Application Number Priority Date Filing Date Title
AU2002368487A AU2002368487A1 (en) 2002-12-23 2002-12-23 Substituted 1,4-di-piperidin-4-yl-piperazine derivatives and their use as tachykinin antagonists
PCT/EP2002/014836 WO2004056772A1 (fr) 2002-12-23 2002-12-23 Derives de 1,4-di-piperidin-4-yl-piperazine substitues et leur utilisation comme antagonistes de la tachykinine
MYPI20033797A MY141736A (en) 2002-10-08 2003-10-06 Substituted 1,4-di-piperidin-4-yi-piperazine derivatives and their use as neurokinin antagonists
AU2003282115A AU2003282115B2 (en) 2002-10-08 2003-10-07 Substituted 1,4-di-piperidin-4-yl-piperazine derivatives and their use as neurokinin antagonists
DE60325493T DE60325493D1 (de) 2002-10-08 2003-10-07 Substituierte 1,4-dipiperidin-4-yl-piperazinderivate und deren verwendung als neurokininantagonisten
ARP030103649A AR041545A1 (es) 2002-10-08 2003-10-07 Derivados sustituidos de 1,4-di-piperidin-4 il-piperazina y su uso como antagonistas de neuroquininas
US10/527,821 US7410970B2 (en) 2002-10-08 2003-10-07 Substituted 1,4,-di-piperidin-4-yl-piperazine derivatives and their use as neurokinin antagonists
ES03773731T ES2319642T3 (es) 2002-10-08 2003-10-07 Derivados 1,4-di-piperidina-4-il-piperazina sustituidos y su uso como antagonistas de la neuroquinina.
EA200500616A EA009217B1 (ru) 2002-10-08 2003-10-07 Замещенные производные 1,4-дипиперидин-4-илпиперазина и их применение в качестве нейрокининовых антагонистов
AT03773731T ATE418543T1 (de) 2002-10-08 2003-10-07 Substituierte 1,4-dipiperidin-4-yl- piperazinderivate und deren verwendung als neurokininantagonisten
TW092127724A TWI324995B (en) 2002-10-08 2003-10-07 Substituted 1,4-di-piperidin-4-yl-piperazine derivatives and their use as neurokinin antagonists
PL03376403A PL376403A1 (en) 2002-10-08 2003-10-07 Substituted 1,4-di-piperidin-4-yl-piperazine derivatives and their use as neurokinin antagonists
KR1020057003472A KR101049074B1 (ko) 2002-10-08 2003-10-07 치환된 1,4-디-피페리딘-4-일-피페라진 유도체 및 뉴로키닌길항제로서의 그의 용도
CA2499903A CA2499903C (fr) 2002-10-08 2003-10-07 Derives 1,4-di-piperidin-4-yl-piperazines substitues en 1,4 et leur utilisation en tant qu'antagonistes des neurokinines
PCT/EP2003/050697 WO2004033428A1 (fr) 2002-10-08 2003-10-07 Derives 1,4-di-piperidin-4-yl-piperazines substitues en 1,4 et leur utilisation en tant qu'antagonistes des neurokinines
MXPA05003778A MXPA05003778A (es) 2002-10-08 2003-10-07 Derivados sustituidos de la 1,4-di-piperidin-4-il-piperazina y su uso como antagonistas de neurocininas.
EP03773731A EP1551804B1 (fr) 2002-10-08 2003-10-07 Derives 1,4-di-piperidin-4-yl-piperazines substitues en 1,4 et leur utilisation en tant qu'antagonistes des neurokinines
BR0315098-4A BR0315098A (pt) 2002-10-08 2003-10-07 Derivados de 1,4-dipiperidin-4-il-piperazina, uso dos mesmos, composição farmacêutica e processos para a preparação da mesma e dos referidos derivados
NZ539848A NZ539848A (en) 2002-10-08 2003-10-07 Substituted 1,4-di-piperidin-4-YL-piperazine derivatives and their use as neurokinin antagonists
JP2004542503A JP4674086B2 (ja) 2002-10-08 2003-10-07 置換された１，４−ジ−ピペリジン−４−イル−ピペラジン誘導体およびニューロキニンアンタゴニストとしてのそれらの使用
PA20038584901A PA8584901A1 (es) 2002-10-08 2003-10-08 Derivados sustituidos de 1,4-di-piperidin-4-il-piperazina y su uso como antagonistas de neuroquininas
HR20050309A HRP20050309A2 (en) 2002-10-08 2005-04-04 Substituted 1,4-di-piperidin-4-yl-piperazine derivatives and their use as neurokinin antagonists
IL167885A IL167885A (en) 2002-10-08 2005-04-06 Substituted 1,4 - di - piperidin - 4 -yl - piperazine derivatives, process for their preparation, pharmaceutical compositions comprising them and their use in the manufacture of medicaments for treating neurokinin mediated conditions
NO20052192A NO330656B1 (no) 2002-10-08 2005-05-04 Substituerte 1,4-di-piperidin-4-yl-piperazinderivater og deres anvendelse som neurokininantagonister
HK06104676.7A HK1084394A1 (en) 2002-10-08 2006-04-19 Substituted 1,4-di-piperidin-4-yl-piperazine derivatives and their use for preparing neurokinin antagonists

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WO2007020888A1 (fr) * 2005-08-12 2007-02-22 Takeda Pharmaceutical Company Limited Agent protegeant des cellules du cerveau/neuronales et agent therapeutique pour des troubles du sommeil
US7572786B2 (en) * 2002-12-23 2009-08-11 Janssen Pharmaceutica, N.V. Substituted 1-piperidin-3-yl-4-piperidin-4-yl-piperazine derivatives and their use as neurokinin antagonists
US7635698B2 (en) 2004-12-29 2009-12-22 Millennium Pharmaceuticals, Inc. Compounds useful as chemokine receptor antagonists
US7678798B2 (en) 2004-04-13 2010-03-16 Incyte Corporation Piperazinylpiperidine derivatives as chemokine receptor antagonists
US7880002B2 (en) 2004-12-29 2011-02-01 Millennium Pharmaceuticals, Inc. Substituted piperazinyl-pyrrolidine compounds useful as chemokine receptor antagonists
US8604200B2 (en) 2005-03-08 2013-12-10 Janssen Pharmaceutica N.V. Diaza-spiro-{4,4}-nonane derivatives as neurokinin (NK1) antagonists
RU2617409C1 (ru) * 2015-12-24 2017-04-25 Федеральное государственное бюджетное учреждение науки Институт элементоорганических соединений им. А.Н. Несмеянова Российской академии наук (ИНЭОС РАН) Амиды акриловой и метакриловой кислот с n-алкилпиперазино-пиперидинами и способ их получения

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7572786B2 (en) * 2002-12-23 2009-08-11 Janssen Pharmaceutica, N.V. Substituted 1-piperidin-3-yl-4-piperidin-4-yl-piperazine derivatives and their use as neurokinin antagonists
US8268826B2 (en) 2004-04-13 2012-09-18 Incyte Corporation Piperazinylpiperidine derivatives as chemokine receptor antagonists
US9067921B2 (en) 2004-04-13 2015-06-30 Incyte Corporation Piperazinylpiperidine derivatives as chemokine receptor antagonists
US7678798B2 (en) 2004-04-13 2010-03-16 Incyte Corporation Piperazinylpiperidine derivatives as chemokine receptor antagonists
US8680104B2 (en) 2004-04-13 2014-03-25 Incyte Corporation Piperazinylpiperidine derivatives as chemokine receptor antagonists
US8168788B2 (en) 2004-12-29 2012-05-01 Millennium Pharmaceuticals, Inc. Substituted piperazinyl-pyrrolidine compounds useful as chemokine receptor antagonists
US7880002B2 (en) 2004-12-29 2011-02-01 Millennium Pharmaceuticals, Inc. Substituted piperazinyl-pyrrolidine compounds useful as chemokine receptor antagonists
US8399455B2 (en) 2004-12-29 2013-03-19 Millennium Pharmaceuticals, Inc. Compounds useful as chemokine receptor antagonists
US8648197B2 (en) 2004-12-29 2014-02-11 Millennium Pharmaceuticals, Inc. Substituted piperazinyl-pyrrolidine compounds useful as chemokine receptor antagonists
US7635698B2 (en) 2004-12-29 2009-12-22 Millennium Pharmaceuticals, Inc. Compounds useful as chemokine receptor antagonists
US8604200B2 (en) 2005-03-08 2013-12-10 Janssen Pharmaceutica N.V. Diaza-spiro-{4,4}-nonane derivatives as neurokinin (NK1) antagonists
WO2007020888A1 (fr) * 2005-08-12 2007-02-22 Takeda Pharmaceutical Company Limited Agent protegeant des cellules du cerveau/neuronales et agent therapeutique pour des troubles du sommeil
US7812025B2 (en) 2005-08-12 2010-10-12 Takeda Pharmaceutical Company Limited Brain/neuronal cell-protecting agent and therapeutic agent for sleep disorder
RU2617409C1 (ru) * 2015-12-24 2017-04-25 Федеральное государственное бюджетное учреждение науки Институт элементоорганических соединений им. А.Н. Несмеянова Российской академии наук (ИНЭОС РАН) Амиды акриловой и метакриловой кислот с n-алкилпиперазино-пиперидинами и способ их получения

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