WO2005000845A2 - Derives bicycliques utilises en tant qu'antagonistes des recepteurs nk-1 et nk-2 - Google Patents

Derives bicycliques utilises en tant qu'antagonistes des recepteurs nk-1 et nk-2 Download PDF

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WO2005000845A2
WO2005000845A2 PCT/EP2004/051210 EP2004051210W WO2005000845A2 WO 2005000845 A2 WO2005000845 A2 WO 2005000845A2 EP 2004051210 W EP2004051210 W EP 2004051210W WO 2005000845 A2 WO2005000845 A2 WO 2005000845A2
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formula
compound
optionally substituted
ester
linear
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WO2005000845A3 (fr
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Giuseppe Arnaldo Maria Giardina
Stefania Gagliardi
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Nikem Research S.R.L.
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic 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

  • the present invention relates to novel compounds, particularly to novel arylmethylazacyclic derivatives, to processes relating to the preparation thereof, to the pharmaceutical compositions containing them and to the therapeutic use thereof.
  • the compounds of the invention bind to specific membrane receptors, particularly to neurokinin-1 (NK-1) and neurokinin-2 (NK-2) receptors.
  • the mammalian tachykinins also known as neurokinins, are a family of small peptides which have the same carboxy-terminal region Phe-X-Gly-Leu-Met- NH 2 in common; the principal members are substance P (SP), neurokinin A (NKA) and neurokinin B (NKB) (Maggio, J.E. Ann. Rev. Neurosc. 1988, 11, 13; Maggi, C.A., Patacchini, R., Rovero, P. and Giachetti, A. J. Auton. Pharmacol. 1993, 13, 23).
  • SP substance P
  • NAA neurokinin A
  • NKB neurokinin B
  • Tachykinins are distributed differently throughout the central nervous system (CNS) and in the peripheral nervous system, where they are predominantly localised at the peripheral ends of the capsaicin-sensitive primary afferent neurons (amyelinic C fibres) which innervate numerous sites, particularly the airways, the gastrointestinal tract, the urinary tract and the skin (Holzer, P. Neurosci. 1988, 24, 739; Otsuka, M. and Yoshioka, K. Physiol. Rev. 1993, 73, 229; Maggi, C.A., Giachetti, A., Dey, R.D. and Said, S.I. Physiol. Rev. 1995, 75, 277; Maggi, CA. Pharm. Res. 1996, 33, 161).
  • tachykinins are mediated by at least three distinct G-protein coupled receptors, defined as neurokinin-1 (NK-1), neurokinin-2 (NK-2) and neurokinin-3 (NK-3) (Maggio, J.E., Mantyh, P.W. and
  • NK-1 receptors are widely distributed in the human brain area with the highest NK-1 mRNA levels localized in the locus coeruleus and ventral striatum (Caberlotto, L. Eur. J. Neurosci. 2003, 17, 1736).
  • the receptor In the perifery the receptor is localized in the paratiroid and, mucosal glands, in the lung (Mapp, C.E. Am. J. Respir. Crit Care Med. 2000; 161, 207), genitourinary and gastrointestinal tracts (Quartara, L. Neuropeptides. 1998; 32, 1) small arteries (Kummer, W. Neurosci Lett. 1999; 259, 119) and monocytes (Germonpre, P.H. Eur Respir. J. 1999; 14, 776)
  • mRNA messenger RNA for the NK-2 receptor
  • mRNA messenger RNA for the NK-2 receptor
  • testis Tsuchida, K., Shigemoto, R., Yokota, Y. and Nakanishi, S. Eur. J. Biochem. 1990, 193, 751
  • hippocampus Hagan R.M. et al., Regul. Peptides, 1993, 46, 9
  • aprepitant 5-
  • a number of peptide and non-peptide antagonists of the NK-2 receptor are known; particularly the derivatives SR 48,968 or saredutant ((S)-(-)-N-methyl- N-[4-(4-acetylamino-4-phenylpiperidin-1-yl)-2-(3,4-dichIorophenyl)butyl] ben- zamide), SR 144,190, UK 224671, UK 290795 and the cydopeptide derivative nepadutant have reached various levels of pre-clinical and clinical development.
  • WO 00/58307 describes some 2,4- disubstituted pyridines fused with an aryl nucleus as selective ligands of the
  • NK-3 receptor WO 00/02859, WO 00/20003, WO 00/20389, WO 00/69438, WO 02/051807 and WO 02/12168 describe some derivatives of naphthalene- 1-carboxamide as ligands of the NK-1 receptor.
  • R is optionally substituted C-i- ⁇ linear or branched alkyl, optionally substituted C3-8 cycloalkyl , optionally substituted aryl or cyano;
  • Ri is optionally substituted C ⁇ - 6 linear or branched alkyl, optionally substituted aryl, optionally substituted C - 8 cycloalkyl, C 3 - 8 cycloalkyl C-M linear or branched alkyl, or aryl d ⁇ linear or branched alkyl which may be substituted with an optionally substituted aryl group;
  • R 2 is hydrogen, optionally substituted C ⁇ - 6 linear or branched alkyl or R 2 together with Ri forms a saturated heterocyclic ring comprising up to 8 ring member atoms, optionally condensed with an aromatic or aliphatic ring;
  • X is carbon, nitrogen or oxygen; n is 0, 1 or 2.
  • R 3 is hydrogen, C1- 6 linear or branched alkyl, optionally substituted aryl, aryl CM alkyl where the aryl group is optionally substituted and the C ⁇ -4 alkyl group is linear or branched, hydroxy, hydroxy C ⁇ . 6 alkyl, optionally substituted C3- 8 cycloalkyl , optionally substituted saturated heterocyclic group comprising up to 8 ring member atoms and a maximum of 2 heteroatoms selected from nitrogen and oxygen;
  • Rs and Re are independently hydrogen, optionally substituted C- ⁇ - 6 linear or branched alkyl, optionally substituted aryl, aryl C- M alkyl where the aryl group is optionally substituted and the C1-4 alkyl group is linear or branched, or R 5 and R 6 together form a saturated carbocyclic or heterocyclic ring comprising up to 8 ring member atoms and a maximum of 2 heteroatoms selected from nitrogen and oxygen optionally condensed with an aromatic or aliphatic ring;
  • Z is N or CH; represents on the condition that when A is
  • the present invention also provides a process for the preparation of a compound of formula (I), or a salt and/or solvate thereof, which comprises the reaction of a compound of formula (II) or an activated derivative thereof:
  • the process comprises the reaction of a compound of formula (VII):
  • R 3 , R*, R 5 , R 6 , n and X are as defined for the compounds of formula (I) or a protected form or a group convertible into R 3 , R 4 ,Rs ⁇ -
  • the compounds of formula (I) have useful pharmaceutical properties.
  • the present invention further provides a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, for use as an active therapeutic substance.
  • the present invention further provides a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof, for the treatment or the prophylaxis of diseases dependent on the stimulation of the NK-1 and NK-2 receptors (defined herein as NK-1/NK-2 diseases): belonging to such group of diseases are lung disorders, urinary tract and gastrointestinal tract disorders, ophthalmic diseases, cutaneous diseases, adverse immunological reactions, inflammatory diseases, neurogenic inflammations and peripheral neuropathies, CNS associated diseases, particularly anxiety, depression, psychoses and schizophrenia.
  • the present invention further provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, and a pharmaceutically acceptable carrier.
  • the present invention further provides the use of a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, in the manufacture of a medicament for the prevention and/or treatment of the aforesaid NK-1 /NK-2 diseases.
  • a medicament and a composition of this invention, may be prepared by mixing a compound of the invention with an appropriate carrier.
  • This invention further provides a method for the treatment or the prophylaxis of the NK-1/NK-2 diseases in mammals, particularly in humans, which comprises the administration of a pharmaceutically acceptable, non-toxic quantity of a compound of formula (I), or a salt and/ or solvate thereof, to a mammal requiring such treatment and/or prophylaxis.
  • a pharmaceutically acceptable, non-toxic quantity of a compound of formula (I), or a salt and/ or solvate thereof to a mammal requiring such treatment and/or prophylaxis.
  • R is optionally substituted C ⁇ - 6 linear or branched alkyl, optionally substituted C 3 -8 cycloalkyl , optionally substituted aryl or cyano;
  • Ri is optionally substituted C1-6 linear or branched alkyl, optionally substituted aryl, optionally substituted C 3 . 8 cycloalkyl, C 3 - 8 cycloalkyl C ⁇ linear or branched alkyl, or aryl C1-4 linear or branched alkyl which may be substituted with an optionally substituted aryl group;
  • R 2 is hydrogen, optionally substituted C- ⁇ linear or branched alkyl or R 2 together with Ri forms a saturated heterocyclic ring comprising up to 8 ring member atoms, optionally condensed with an aromatic or aliphatic ring;
  • X is carbon, nitrogen or oxygen; n is 0, 1 or 2.
  • R 3 is hydrogen, C1-6 linear or branched alkyl, optionally substituted aryl, aryl C1-4 alkyl where the aryl group is optionally substituted and the C 1 . alkyl group is linear or branched, hydroxy, hydroxy C 1 - 6 alkyl, optionally substituted C3-8 cycloalkyl , optionally substituted saturated heterocyclic group comprising up to 8 ring member atoms and a maximum of 2 heteroatoms selected from nitrogen and oxygen;
  • Rs and Re are independently hydrogen, optionally substituted C1-6 linear or branched alkyl, optionally substituted aryl, aryl C-1-4 alkyl where the aryl group is optionally substituted and the C 1 - 4 alkyl group is linear or branched, or
  • R5 and RQ together form a saturated carbocyclic or heterocyclic ring comprising up to 8 ring member atoms and a maximum of 2 heteroatoms selected from nitrogen and oxygen optionally condensed with an aromatic or aliphatic ring;
  • Z is N or CH
  • the C - 6 linear or branched alkyl group comprises methyl, ethyl, isopropyl, 3- methyl-but-2-yl and 3,3-dimethyl-but-2-yl; aryl comprises phenyl and thienyl; the C 3 - 8 cycloalkyl group comprises cyclopropyl, cyclopentyl, cyclohexyl and cyclooctyl; the C 3 - 8 cycloalkyl C alkyl group comprises cyclohexylmethyl; substituents for optionally substituted alkyl or aryl groups are e.g. Me, Cl, F, OMe, OH, CF 3 , COOH.
  • Ri and R 2 together form a saturated heterocyclic ring comprising up to 8 ring member atoms optionally condensed with an aromatic or aliphatic ring
  • preferred rings are pyrrolidine, piperidine, isoindoline, indoline, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4- tetrahydroquinoline;
  • the optionally substituted saturated heterocyclic group comprising up to 8 ring member atoms and a maximum of 2 heteroatoms is preferably piperidine, piperazine and morpholine.
  • R is optionally substituted C3-8 cycloalkyl, phenyl or thienyl; more preferably, R is phenyl, thienyl or cyano.
  • Ri is Ci-6 linear or branched alkyl, C3.8 cycloalkyl group or C3-8 cycloalkyl C M alkyl, or benzyl; more preferably Ri is 3-methyl-but-2-yl, 3,3- dimethyl-but-2-yl, cyclohexyl, cyclohexylmethyl, or 3,5-ditrifluoromethylbenzyl; or Ri together with R 2 forms a saturated heterocyclic group, more preferably a piperidinic ring or a 1 ,2,3,4-tetrahydroisoquinolinic ring.
  • R 2 is hydrogen or C 1 - 3 alkyl.
  • X is carbon or nitrogen.
  • n is 1.
  • R 3 is hydrogen, C1-6 linear or branched alkyl, hydroxy d-C 6 alkyl, piperidin-1-yl, morpholin-4-yl; more preferably, R 3 is isopropyl, piperidin-1-yl, morpholin-4-yl.
  • R 5 and R 6 are independently hydrogen, optionally substituted C 1 - 6 linear or branched alkyl, aryl, or together form a saturated carbocyclic ring or a heterocyclic ring comprising 6 ring member atoms and 1 heteroatom selected from nitrogen and oxygen; more preferably R 5 and Re are independently hydrogen or d- ⁇ linear or branched alkyl.
  • the ring indicated by A is selected from:
  • the present invention provides a process for the preparation of a compound of formula (I), or a salt and/or solvate thereof, which comprises the reaction of a compound of formula (II) or an activated derivative thereof:
  • R, R 3 , R4, Rs, Re. A, Z, n and X are as defined for formula (I), or a group convertible into R 3 , R4, Rs and Re respectively, with a compound of formula (III):
  • a suitable activated derivative of a compound of formula (II) is a transiently activated form of the compound of formula (II) or a derivative wherein the carboxy group of the compound of formula (II) has been substituted with a different group or atom, for example by an acyl halide, preferably an acyl chloride, or an acyl azide or a carboxylic acid anhydride.
  • Suitable activated derivatives comprise: a mixed anhydride formed between the carboxylic portion of the compound of formula (II) and an alkyl chloroformate; an activated ester, such as cyanomethyl ester, thiophenyl ester, p-nitrophenyl ester, p-nitrothiophenyl ester, 2,4,6-trichlorophenyl ester, pentachlorophenyl ester, pentafluorophenyl ester, N-hydroxy-phthalimide ester, N-hydroxypiperidi ⁇ e ester, N-hydroxysuccinimide ester, N-hydroxy benzotriazole ester; alternatively, the carboxylic group of the compound of formula (II) may be activated by utilising a carbodiimide or N,N'- carbonyldiimidazole.
  • an activated ester such as cyanomethyl ester, thiophenyl ester, p-nitrophenyl ester, p-nitrothioph
  • reaction between the compound of formula (II) or the activated derivative thereof and the compound of formula (III) is carried out under conventional conditions appropriate for the particular compounds selected.
  • the reaction is carried using the same solvent and conditions used for the preparation of said activated derivative; preferably the activated derivative is prepared in situ prior to the formation of the compound of formula (I).
  • the reaction between an activated derivative of the compound of formula (II) and the compound of formula (III) may be carried out by :
  • a suitable condensing agent such as for example N,N'- carbonyldiimidazole (GDI) or a carbodiimide such as dicyclohexylcarbodiimide (DCC) or N-dimethylaminopropyl-N'-ethylcarbodiimide, preferably in the presence of N-hydroxybenzotriazole (HOBT) in order to maximise the yields and avoid racemisation processes (for reference see Synthesis, 1972, 453), or O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronio hexafluorophosphate (HBTU), in an aprotic solvent, such as a mixture of acetonitrile (MeCN) and tetrahydrofuran (THF), for example a mixture with volumetric ratio comprised of between 1:9 and 7:3 (Me
  • aprotic solvent such as a mixture of acetonitrile (MeCN) and
  • R, Ri, R 2 , R3, R4, Rs, Re, A, Z, n and X are as defined above for the compounds of formula (I).
  • hydrolysis of the compound of formula (II) is required prior to conversion to the compound of formula (I) of Diagram 1.
  • Such hydrolysis may be carried out under acidic conditions, such as in 10-
  • compound of formula (I) can be prepared directly from compound of formula (II) obtained as alkyl ester (methyl or ethyl ester).
  • alkyl ester (methyl or ethyl ester) of compound of formula (II) and compound of formula (III) are mixed and heated from 150°C to 200°C, using a microwave apparatus, for a suitable period of time, for 5 to 20 minutes.
  • the compounds of formula (III) are known and commercially available compounds or may be prepared from known compounds using known methods, or analogous methods to those used for the preparation of known compounds, for example the methods described in Liebigs Ann. der Chemie, 1936, 523, 199.
  • the compounds of formula (II) or corresponding alkyl (such as methyl or ethyl) esters thereof are prepared through the reaction of a compound of formula (IV) or the corresponding alkyl (such as methyl or ethyl) ester thereof:
  • R, A and Z are as previously defined for the compounds of formula (I) and Li represents a leaving group, such as for example a halogen atom e.g. bromine, or a mesylate group, with a compound of formula (V):
  • R3, R4, Rs, Re, n and X are as defined for the compounds of formula (I) or are a protected form or a group convertible into R 3 , R-i.Rs and Re.
  • the reaction between the compounds of formula (IV) or the corresponding alkyl (such as methyl or ethyl) ester thereof and the compounds of formula (V) is carried out under conventional amination conditions; for example, when Li is a bromine atom or a mesylate, the reaction is appropriately carried out in an aprotic solvent, such as tetrahydrofuran or dimethylformamide at any temperature which provides an adequate percentage of formation of the required product, usually at room temperature; preferably the reaction is carried out in the presence of triethylamine (TEA) or K 2 CO 3 .
  • TAA triethylamine
  • the compounds of formula (V) are known commercially available compounds or may be prepared by using analogous methods to those used for the preparation of known compounds; for example the methods described in Chemistry of the Amino Group, Patais (Ed.), Interscience, New York 1968; Advanced Organic Chemistry, March J, John Wiley & Sons, New York, 1992.
  • the compounds of formula (IV) or the corresponding alkyl (such as methyl or ethyl) esters thereof may be prepared for example through the appropriate halogenation of a compound of formula (VI) or the corresponding alkyl (such as methyl or ethyl) ester thereof:
  • R, A, Z are as defined for the compounds of formula (I).
  • Suitable halogenation reagents are conventional reagents which depend on the nature of the halogen atom required; for example, when Li is bromine, the preferred halogenation reagent is N-bromosuccinimide (NBS).
  • NBS N-bromosuccinimide
  • Halogenation of the compound of formula (VI) or the corresponding alkyl (such as methyl or ethyl) ester thereof is appropriately carried out under conventional conditions, for example, bromination is carried out through treatment with NBS in an inert solvent, such as carbon tetrachloride (CCI ), or 1 ,2-dichloroethane or CH3CN, at any temperature which provides an adequate percentage of formation of the required product, appropriately at high temperature such as a temperature comprised of between 60 °C and 100 °C, for example 80 °C; preferably the reaction is carried out in the presence of a catalytic amount of benzoyl peroxide.
  • CCI carbon tetrachloride
  • the compounds of formula (VI) are compounds known in the literature (WO 00/58307 and WO 00/20389) or may be prepared using methods analogous those used in order to prepare known compounds.
  • the present invention provides a process for the preparation of a compound of formula (I), a salt and/or solvate thereof, the process of which comprises the reaction of a compound of formula (VII):
  • the reaction between the compounds of formulas (VII) and (V) is carried out under conventional amination conditions; for example, when Li is a bromine atom, the reaction is conventionally carried out in an aprotic solvent, such as tetrahydrofuran or dimethylformamide at any temperature which provides an adequate percentage of formation of the required product, usually at room temperature; preferably the reaction is carried out in the presence of triethylamine (TEA) or K2CO 3 .
  • TAA triethylamine
  • the compound of formula (VII) is for example prepared through the appropriate halogenation of a compound of formula (VIII):
  • Suitable halogenation reagents are conventional reagents which depend on the nature of the halogen atom required; for example, when Li is bromine, the preferred halogenation reagent is N-bromosuccinimide (NBS).
  • Halogenation of the compound of formula (VIII) is carried out under conventional conditions, for example, bromination is carried out through treatment with NBS in an inert solvent, such as carbon tetrachloride (CCI4), or 1 ,2-dichloroethane or CH3CN, at any temperature which provides an adequate percentage of formation of the required product, appropriately at a high temperature such as a temperature comprised of between 60 °C and 100 °C, for example 80 °C; preferably the reaction is carried out in the presence of a catalytic amount of benzoyl peroxide.
  • an inert solvent such as carbon tetrachloride (CCI4), or 1 ,2-dichloroethane or CH3CN
  • the compound of formula (VIII) may be prepared through the reaction of a compound of formula (VI) as defined above or an activated derivative thereof, with a compound of formula (III) as defined above.
  • the compound of formula (VI) be present in the reaction mixture as an activated derivative, as previously described.
  • reaction between the compound of formula (VI) or the activated derivative thereof and the compound of formula (III) is carried out under conventional conditions appropriate for the particular compounds selected.
  • the reaction is carried using the same solvent and conditions used for the preparation of said activated derivative; preferably the activated derivative is prepared in situ prior to the formation of the compound of formula (VIII).
  • reaction between an activated derivative of the compound of formula (VI) and the compound of formula (III) may be carried out by:
  • hydrolysis is required prior to conversion to the compound of formula (VIII) of diagram 2.
  • Such hydrolysis may be carried out under acidic conditions, such as in 10-35% hydrochloric acid at a temperature comprised of between 30 and 100 °C
  • the compounds of formula (I) have useful pharmaceutical properties.
  • the present invention further provides a compound of formula (I), or a pharmaceutically salt and/or solvate thereof, to be used as an active therapeutic substance.
  • the present invention further provides a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof, for the treatment or the prophylaxis of diseases dependant on the stimulation of the NK-1 and NK-2 receptors (defined herein as NK-1/NK-2 diseases).
  • the compounds of the present invention are particularly useful in the treatment of lung disorders (especially useful in the treatment of bronchospastic and inflammatory components of asthma, in chronic obstructive lung diseases, coughs, hyper-reactivity of the airways and irritation of the lung); in urinary tract disorders (particularly urinary incontinence and the syndromes associated with diseases of the bladder), in cystitis associated inflammatory processes of the bladder and urethra, in kidney infections, in colics and spasms of the biliary tract; in disorders of the gastrointestinal tract (particularly in the disorders associated with neuronal bowel control such as intestinal spasms, ulcerative colitis, Crohn's disease, irritable bowel syndrome and the gastroesofageal reflux disorders); in ophthalmic diseases such as ocular inflammation, conjunctivitis, spring conjunctivitis and
  • the present invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, and a pharmaceutically acceptable carrier.
  • the present invention further provides the use of a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, in the manufacture of a medicament for the treatment of the aforesaid NK-1 /NK-2 diseases.
  • a medicament and a composition of this invention, may be prepared by mixing a compound of the invention with an appropriate carrier.
  • the mixture may contain a diluent, a binder, a filler, a disintegrant, a flavouring agent, a colouring agent, a lubricant or a preservative according to conventional methods.
  • Those conventional excipients may be used for example as for the preparation of the compositions of known agents for the treatment of the NK-1 /NK-2 diseases.
  • a pharmaceutical composition of the invention is in the form of a unit dose and in a form adapted for use in the medicinal or veterinary fields.
  • such preparations may be in multiple packs endowed with written or printed instructions for use as an agent in the treatment or prophylaxis of the NK-1 /NK-2 diseases.
  • the suitable dosage interval for the compounds of the invention depends on the compound which must be used and the conditions of the patient. It further depends, amongst others, on the relationship between strength and absorption and on the frequency and route of administration.
  • the compound or the composition of the invention may be formulated for administration through whichever route, and is preferably in unit dose form or in such a form whereby the patient may auto-administer a single dose.
  • the composition is indicated for oral, rectal, topical, parenteral, endovenous or intramuscular administration.
  • the preparations may be designed in order to allow the slow release of the active ingredient.
  • the compositions may, for example, be in the form of tablets, capsules, sachets, ampoules, powders, granules, lozenges, reconstitutable powders or liquid preparations, for example solutions or suspensions, or suppositories.
  • compositions for example those adapted for oral administration, may contain conventional excipients such as binding agents, for example syrup, gum arabic, gelatine, sorbitol, tragacanth gum, or polyvinylpyrrolidone; fillers, for example lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; lubricants in tablets, for example magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, sodium glycolate or microcrystalline cellulose; or pharmaceutically acceptable composition agents, for example sodium lauryl sulphate.
  • Solid compositions may be obtained through conventional mixing, filling and encapsulation methods and the like.
  • any suitable carrier may be used for the formulation of solid pharmaceutical compounds, for example magnesium stearate, glucose, sucrose, rice flour and gypsum.
  • the tablets may be coated using the methods already known in normal pharmaceutical procedures.
  • the composition may also be in the form of an ingestible capsule, for example made of gelatine containing the compound, optionally with a carrier or other excipients.
  • compositions for liquid oral administration may be in the form, for example, of emulsions, syrups or elixirs, or may be presented in the form of a dry product to be reconstituted with water or other suitable carrier prior to use.
  • Such liquid compositions may contain conventional additives such as suspension agents, for example sorbitol, syrup, methyl cellulose, gelatine, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel, edible hydrogenated fats; emulsifying agents, for example lecithin, sorbitan monooleate or gum arabic; aqueous or non-aqueous vectors, which comprise edible oils, for example peanut oil, fractionated coconut oil, oily esters, for example glycerine esters, or propylene glycol, or ethyl alcohol, glycerine, water or normal saline solution; preservatives, for example propyl or methyl p- hydroxybenzoate or sorbic acid; possibly flavouring agents or conventional
  • compositions may be formulated, for example, for rectal administration as suppositories.
  • they may be formulated into injectable formulations in aqueous or non-aqueous solution, suspension or emulsion in a pharmaceutically acceptable liquid, for example sterile pyrogen free water or an oil acceptable for parenteral administration or a mixture of liquids.
  • a pharmaceutically acceptable liquid for example sterile pyrogen free water or an oil acceptable for parenteral administration or a mixture of liquids.
  • the liquid may contain bacteriostatic agents, antioxidants or other preservatives, buffers or solutes in order to make the solution isotonic with the blood, thickening agents, suspension agents or other pharmaceutically acceptable additives.
  • Such formulations will be presented in unit dose form such as ampoules or disposable devices for injections, or in multi-dose forms such as vials from which the appropriate dose is withdrawn, or a solid form or concentrated liquid which may be used in order to prepare an injectable formulation.
  • the compounds of this invention may furthermore be administered by inhalation, through the nasal or oral passages.
  • Such administration may be carried out using a spray formulation comprising a compound of the invention and a suitable vector, optionally suspended, for example, in a hydrocarbon propellant.
  • the spray formulations comprise micronised particles of compound in association with a surfactant, solvent or dispersion agent in order to prevent the sedimentation of the suspended particles.
  • a surfactant e.g., sodium bicarbonate
  • solvent or dispersion agent e.g., sodium bicarbonate
  • the dimensions of the particles of the compound should be comprised between 2 and 10 microns.
  • a further administration method of the compounds of the invention comprises transdermal administration by means of a patch.
  • a transdermal formulation comprises a compound of the invention dispersed in a pressure sensitive adhesive which adheres to the skin, thus allowing the compound to diffuse out of the adhesive through the skin for administration to the patient.
  • pressure sensitive adhesives may be used such as natural or silicone rubber.
  • the effective dose of compound depends on the particular compound used, on the conditions of the patient and on the frequency and route of administration.
  • One dosage unit will generally contain from 20 to 1000 mg and will preferably contain from 30 to 500 mg, particularly 50, 100, 150, 200, 250, 300, 350, 400, 450, or 500 mg.
  • the composition may be administered one or more times per day, for example 2, 3 or 4 times per day, and the total daily dose for an adult weighing 70 kg will be comprised of between 100 and 3000 mg.
  • the unit dose will contain from 2 to
  • This invention further provides a method for the treatment and/or the prophylaxis of the NK-1 /NK-2 diseases in mammals, particularly in humans, which comprises the administration of a pharmaceutically acceptable, non- toxic quantity of a compound of formula (I), or a salt and/ or solvate thereof, to a mammal requiring such treatment and/or prophylaxis.
  • the strength of the compounds of the present invention as NK-1 and NK-2 receptor ligands is determined by their capacity to inhibit the binding of the radiolabeled ligands [ 125 l]-[Sar 9 ,Met(O 2 ) 11 ]-SP and [ 3 H]-SR 48968 to NK-1 expressed by the human astrocytoma U-373Mg cell line and recombinant human NK-2 receptors respectively (Emonds-Alt et al. Life Sc , 1992, 15, PL101-PL106; Heulliet et al. J-.Neurochem., 1993, 60, 868-876).
  • the receptor binding studies provide a mean Kj value on the basis of 2-5 separate experiments, carried out two or three times.
  • the compounds of the present invention display Kj values comprised of between 0.5 and 1000 nM; the most potent compounds of the present invention display Kj values comprised of between 0.5 and 100 nM.
  • NK-1 and the NK-2-antagonist activity of the compounds of the present invention is determined by their capacity to inhibit NK1 and NK-2 receptor mediated Ca 2+ mobilisation in humans (Mochizuki et. al. J. Biol. Chem., 1994, 269, 9651-9658). Functional studies on the human receptors allow the determination of the concentration of compound necessary in order to reduce
  • the compounds of the present invention behave as antagonists.
  • the therapeutic potential of the compounds of the present invention for the treatment of the NK-1 and NK-2 diseases may be determined by using appropriate disease models in rodents.
  • 2,2-Dimethyl-N-pyridin-2-yl-propionamide (5.35 g, 30 mmol) was dissolved in anhydrous THF and the solution was chilled to - 78°C n-Buthyllithium (1.6 N in hexane, 50 ml, 80 mmol) was added dropwise maintaining the internal temperature below - 60°C. The reaction was stirred at -10°C for 3 h. Then the reaction was chilled to -78°C before adding a solution of diethyl oxalate (11 ml, 80 mmol) in anhydrous THF. The reaction mixture was stirred at -78°C for 15 min and then leaved at room temperature for other 15 min.
  • Oxalyl chloride (7.5 ml, 85 mmol) was added dropwise to a suspension of 3- methyl-2-phenyl-[1 ,8]naphthyridine-4-carboxylic acid (4.5 g, 17 mmol), prepared as in Description 2, in CH 2 CI 2 (150 ml). The reaction mixture was stirred at room temperature for 1 hour. The organic solvent was evaporated under vacuum and the residue was then suspended in CH2CI2 (100 ml) containing 10% MeOH and 10% Et, 3 N. After stirring for 2 hours the organic solvent was removed under vacuum and the title compound (4.5 g) was obtained after purification by SiO 2 column chromatography; yield 94%.
  • N-Bromosuccinimide (6g, 32 mmol) and dibenzoylperoxide (0.4 g) were added to a solution of 3-methyl-2-phenyl-[1 ,8]naphthyridine-4-carboxylic acid methyl ester (4.5 g, 16 mmol), prepared as in Description 3, in CCI 4 (100 ml).
  • the reaction mixture was refluxed for 2 hours.
  • the organic solvent was removed under vacuum and the residue was suspended in CH2CI2.
  • the suspension was filtered and the organic layer was washed with 10% NaHCO3, dried over Na2SO 4 , filtered and evaporated to dryness.
  • the crude residue was used for the next step without further purification.
  • N-Bromosuccinimide (12 g, 64 mmol) and dibenzoylperoxide (0.8 g) were added to a solution of 3-methyl-2-phenyl-[1,8]naphthyridine-4-carboxylic acid methyl ester (4.5 g, 16 mmol), prepared as in Description 3, in CCI 4 (100 ml).
  • Example 3-7 were prepared using this general procedure. Final compounds were sometimes isolated as salts.
  • the compounds of the invention when subjected to receptor binding tests according to the method described by Emonds-Alt et al. Life Sci., 1992, 15, PL101-PL106, have shown high binding affinity for the human NK-1 and NK-2 receptors.

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Abstract

L'invention concerne des nouveaux dérivés de formule (1) qui présentent une activité antagoniste envers les récepteurs neurokinine 1 (NK-1) et neurokinine 2 (NK-2), ainsi que le procédé de préparation de ceux-ci. Ces composés sont utiles dans la prévention et/ou le traitement des maladies associées à la stimulation des récepteurs NK-1 et NK-2.
PCT/EP2004/051210 2003-06-25 2004-06-23 Derives bicycliques utilises en tant qu'antagonistes des recepteurs nk-1 et nk-2 WO2005000845A2 (fr)

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IT001292A ITMI20031292A1 (it) 2003-06-25 2003-06-25 Derivati biciclici nk-2 antagonisti selettivi.

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US8637505B2 (en) 2009-02-04 2014-01-28 Boehringer Ingelheim International Gmbh Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8673899B2 (en) 2008-05-01 2014-03-18 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8680093B2 (en) 2009-04-30 2014-03-25 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8748444B2 (en) 2007-12-11 2014-06-10 Vitae Pharmaceuticals, Inc. Cyclic urea inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8754076B2 (en) 2008-07-25 2014-06-17 Vitae Pharmaceuticals, Inc./Boehringer-Ingelheim Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8765744B2 (en) 2010-06-25 2014-07-01 Boehringer Ingelheim International Gmbh Azaspirohexanones
US8846668B2 (en) 2008-07-25 2014-09-30 Vitae Pharmaceuticals, Inc. Inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8846613B2 (en) 2010-11-02 2014-09-30 Boehringer Ingelheim International Gmbh Pharmaceutical combinations for the treatment of metabolic disorders
US8883778B2 (en) 2009-07-01 2014-11-11 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11 beta-hydroxysteroid dehydrogenase 1
US8927539B2 (en) 2009-06-11 2015-01-06 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11β-hydroxysteroid dehydrogenase 1 based on the 1,3-oxazinan-2-one structure
US8933072B2 (en) 2010-06-16 2015-01-13 Vitae Pharmaceuticals, Inc. Substituted 5-,6- and 7-membered heterocycles, medicaments containing such compounds, and their use
US9079861B2 (en) 2007-11-07 2015-07-14 Vitae Pharmaceuticals, Inc. Cyclic urea inhibitors of 11β-hydroxysteroid dehydrogenase 1

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WO2008106128A2 (fr) 2007-02-26 2008-09-04 Vitae Pharmaceuticals, Inc. Inhibiteurs d'urée et de carbamate de 11b-hydroxystéroïde déshydrogénase 1 cycliques

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WO2002083663A1 (fr) * 2001-04-11 2002-10-24 Glaxosmithkline S.P.A. Derives de quinoline-4-carboxamide comme antagonistes de recepteurs de nk-3 et nk-4

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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9079861B2 (en) 2007-11-07 2015-07-14 Vitae Pharmaceuticals, Inc. Cyclic urea inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8748444B2 (en) 2007-12-11 2014-06-10 Vitae Pharmaceuticals, Inc. Cyclic urea inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8673899B2 (en) 2008-05-01 2014-03-18 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8846668B2 (en) 2008-07-25 2014-09-30 Vitae Pharmaceuticals, Inc. Inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8754076B2 (en) 2008-07-25 2014-06-17 Vitae Pharmaceuticals, Inc./Boehringer-Ingelheim Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8637505B2 (en) 2009-02-04 2014-01-28 Boehringer Ingelheim International Gmbh Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8680093B2 (en) 2009-04-30 2014-03-25 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8927539B2 (en) 2009-06-11 2015-01-06 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11β-hydroxysteroid dehydrogenase 1 based on the 1,3-oxazinan-2-one structure
US8883778B2 (en) 2009-07-01 2014-11-11 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11 beta-hydroxysteroid dehydrogenase 1
US8933072B2 (en) 2010-06-16 2015-01-13 Vitae Pharmaceuticals, Inc. Substituted 5-,6- and 7-membered heterocycles, medicaments containing such compounds, and their use
US9090605B2 (en) 2010-06-16 2015-07-28 Vitae Pharmaceuticals, Inc. Substituted 5-,6- and 7-membered heterocycles, medicaments containing such compounds, and their use
US8765744B2 (en) 2010-06-25 2014-07-01 Boehringer Ingelheim International Gmbh Azaspirohexanones
US8846613B2 (en) 2010-11-02 2014-09-30 Boehringer Ingelheim International Gmbh Pharmaceutical combinations for the treatment of metabolic disorders

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