WO2002083663A1 - Quinoline-4-carboxamide derivatives as nk-3 and nk-2 receptor antagonists - Google Patents

Quinoline-4-carboxamide derivatives as nk-3 and nk-2 receptor antagonists Download PDF

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WO2002083663A1
WO2002083663A1 PCT/EP2002/004066 EP0204066W WO02083663A1 WO 2002083663 A1 WO2002083663 A1 WO 2002083663A1 EP 0204066 W EP0204066 W EP 0204066W WO 02083663 A1 WO02083663 A1 WO 02083663A1
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compound
formula
alkyl
ethyl
phenyl
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PCT/EP2002/004066
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French (fr)
Inventor
Carlo Farina
Stefania Gagliardi
Giuseppe Arnaldo Maria Giardina
Marisa Martinelli
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Glaxosmithkline S.P.A.
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Priority claimed from GBGB0109123.0A external-priority patent/GB0109123D0/en
Priority claimed from GB0205649A external-priority patent/GB0205649D0/en
Application filed by Glaxosmithkline S.P.A. filed Critical Glaxosmithkline S.P.A.
Priority to AT02735247T priority Critical patent/ATE313539T1/en
Priority to DE60208178T priority patent/DE60208178T2/en
Priority to US10/474,542 priority patent/US20040152726A1/en
Priority to EP02735247A priority patent/EP1377567B1/en
Priority to JP2002581418A priority patent/JP2004525183A/en
Publication of WO2002083663A1 publication Critical patent/WO2002083663A1/en
Priority to US11/100,256 priority patent/US20050176762A1/en
Priority to US11/685,380 priority patent/US20070161647A1/en

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Definitions

  • the present invention relates to novel compounds, in particular to novel quinoline derivatives, to processes for the preparation of such compounds, to pharmaceutical compositions containing such compounds and to the use of such compounds in medicine.
  • the mammalian peptide Neurokinin B (NKB) belongs to the Tachykinin (TK) peptide family which also include Substance P (SP) and Neurokinin A (NKA).
  • TK Tachykinin
  • SP Substance P
  • NKB Neurokinin A
  • NK3 receptor antagonists are known (Drapeau, 1990 Regul. Pept, 31, 125-135), and findings with peptidic NK3 receptor agonists suggest that NKB, by activating the NK3 receptor, has a key role in the modulation of neural input in airways, skin, spinal cord and nigro-striatal pathways (Myers and Undem, 1993,
  • the compounds of the present invention are quinoline derivatives.
  • Other quinoline derivatives have been described previously as selective NK3 antagonists.
  • International Patent Application, Publication Numbers, WO 95/32948 and WO 96/02509 describe a series of selective and potent NK3 receptor antagonists.
  • International Patent Application, Publication Number, WO 00/58303 describes a series of 4-substituted quinoline derivatives which are stated to be NK3 and or GABA(A) receptor ligands. Such compounds are characterised by the presence of a nitrogen- containing heterocyclic moiety at the C(4) position of the quinoline ring.
  • International Patent Application, Publication Numbers, WO 97/21680, WO 98/52942, WO 00/31037 and WO 00/31038 describe compounds which have biological activity as combined NK3 and NK2 receptor antagonists.
  • PCT/EP01/13833 Copending International Patent Application Numbers, PCT/EP01/13833, PCT/EP01/14140 and PCT/EP01/13832 also describe compounds that have biological activity as combined NK3 and NK2 receptor antagonists.
  • NK3 antagonists which are far more stable from a metabolic point of view than the known peptidic NK3 receptor antagonists and are of potential therapeutic utility. These compounds also have NK2 antagonist activity and are therefore considered to be of potential use in the prevention and treatment of a wide variety of clinical conditions, which are characterised by overstimulation of the Tachykinin receptors, in particular NK3 and NK2.
  • respiratory diseases such as chronic obstructive pulmonary disease (COPD), asthma, airway hyper-reactivity, cough; inflammatory diseases such as inflammatory bowel disease, psoriasis, f ⁇ brositis, osteoarthritis, rheumatoid arthritis and inflammatory pain; neurogenic inflammation or peripheral neuropathy, allergies such as eczema and rhinitis; ophthalmic diseases such as ocular inflammation, conjunctivitis, vernal conjuctivitis and the like; cutaneous diseases, skin disorders and itch, such as cutaneous wheal and flare, contact dermatitis, atopic dermatitis, urticaria and other eczematoid dermatitis; adverse immunological reactions such as rejection of transplanted tissues and disorders related to immune enhancement or suppression such as systhemic lupus erythematosis; gastrointestinal (GI) disorders and diseases of the GI tract such as disorders associated with the neuronal control of viscera such
  • Certain of these compounds also show CNS activity and hence are considered to be of particular use in the treatment of disorders of the central nervous system such as anxiety, depression, psychosis and schizophrenia; neurodegenerative disorders such as AIDS related dementia, senile dementia of the Alzheimer type, Alzheimer's disease, Down's syndrome, Huntingdon's disease, Parkinson's disease, movement disorders and convulsive disorders (for example epilepsy); demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis and other neuropathological disorders such as diabetic neuropathy, AIDS related neuropathy, chemotherapy-induced neuropathy and neuralgia; addiction disorders such as alcoholism; stress related somatic disorders; reflex sympathetic dystrophy such as shoulder/hand syndrome; dysthymic disorders; eating disorders (such as food intake disease); fibrosing and collagen diseases such as scleroderma and eosinophilic fascioliasis; disorders of the blood flow caused by vasodilatation and vasospastic diseases such as angina, migraine and Reynau
  • the compounds of formula (I) are also considered to be useful as diagnostic tools for assessing the degree to which neurokinin-3 and neurokinin-2 receptor activity (normal, overactivity or underactivity) is implicated in a patient's symptoms.
  • Certain compounds of the present invention have also been found to exhibit surprisingly advantageous pharmacochemical properties.
  • Rl is H or alkyl
  • R2 is aryl or cycloalkyl or heteroaryl
  • R3 is H or alkyl, wherein the alkyl group may be optionally substituted by one or more fluorine atoms
  • R4 is NRgR9 ;
  • R5 is branched or linear alkyl, cycloalkyl, cycloalkylalkyl, aryl, or a single or fused ring aromatic heterocyclic group;
  • Rg represents H or up to three substituents independently selected from the list consisting of: alkyl, alkenyl, aryl, alkoxy, hydroxy, halo, nitro, cyano, carboxy, carboxamido, sulphonamido, trifluoromethyl, or amino or mono- or di-alkylamino;
  • R7 is H or halo
  • R15 is alkyl; a is 0-6; and any of R2 and R5 may optionally be substituted one or more times by halo, hydroxy, amino, cyano, nitro, carboxy, oxo, alkyl, alkenyl, aryl, alkoxy, carboxamido, sulphonamido, trifluoromethyl, or mono- or di- alkylamino; not being a compound wherein R5 is unsubstituted phenyl, and Ri , R2, R3, R4, R6, R7 and a are selected from the following:
  • R is H.
  • R2 is aryl or cycloalkyl.
  • R2 is cyclohexyl.
  • R3 is alkyl.
  • R3 is methyl.
  • R5 is aryl or an aromatic heterocyclic group.
  • R5 is phenyl or 3- thienyl.
  • R is H or fluoro.
  • R ⁇ is H or fluoro.
  • a is 1, 2 or 3.
  • a is 1.
  • Rg is H or Rj j Ri 2 where R12 is H or OH.
  • R ⁇ 1 may be C 1.3 alkyl.
  • R ⁇ ⁇ may be 3°-alkylaminoalkyl, such as R15NR16R17 where each of R15, Rjg and R17 is independently selected from methyl, ethyl and propyl.
  • R ⁇ may be propyl.
  • each of Rjg and R ⁇ may be the same one of methyl, ethyl or propyl, such as ethyl.
  • R9 is R13 R14, where R13 is a single bond and R14 is a saturated heterocyclic ring comprising one N heteroatom.
  • Said saturated heterocyclic ring may for example be a 5-7 -membered ring.
  • said saturated heterocyclic ring may be substituted once by phenylalkyl such as phenylmethyl.
  • Said saturated heterocyclic ring may additionally or alternatively be fused to a benzene ring.
  • R9 is Ri 3 R1
  • R13 is C ⁇ _3 alkyl such as methyl
  • Ri 4 is a ring moiety such as phenyl.
  • Rg and R9 together with the N atom to which they are attached form a 5-7 -membered saturated heterocyclic ring.
  • Said heterocyclic ring may for example have six ring members.
  • said heterocyclic ring may comprise one additional heteroatom which is N or S.
  • said heterocyclic ring may be fused or linked to an aryl group such as a benzene ring.
  • said heterocyclic ring comprises one additional heteroatom which is N, which one additional N atom is linked to a phenyl substituent.
  • Said heterocyclic ring may optionally be substituted once by oxo or hydroxy.
  • R] is H
  • R2 is cyclohexyl
  • R3 is methyl
  • R5 is phenyl
  • Rg is H
  • R7 is H
  • a is 1
  • R4 is selected from the following substituents:
  • Rj is H
  • R2 is unsubstituted cyclohexyl
  • R3 is unsubstituted methyl
  • R5 is unsubstituted phenyl
  • Rg is H
  • R7 is 6-F
  • a is 1 and R4 is selected from the following substituents:
  • Particularly preferred compounds of formula (I) which are of special interest as agents useful in the treatment and/or prophylaxis of conditions which are characterised by overstimulation of the Tachykinin receptors, in particular NK3 and NK2, are those listed in Table 4 below.
  • the compounds of formula (I) may have at least one asymmetric centre - for example the carbon atom labelled with an asterisk (*) in the compound of formula (I) - and therefore may exist in more than one stereoisomeric form.
  • the invention extends to all such stereoisomeric forms and to mixtures thereof, including racemates.
  • the invention includes compounds wherein the asterisked carbon atom in formula (I) has the stereochemistry shown in formula (la):
  • Ri , R2, R3, R5, Rg, and R7 are as defined in relation to formula (I), and X represents the moiety -R,
  • the compounds of formula (I) or their salts or solvates are preferably in pharmaceutically acceptable or substantially pure form.
  • pharmaceutically acceptable form is meant, inter alia, having a pharmaceutically acceptable level of purity excluding normal pharmaceutical additives such as diluents and carriers, and including no material considered toxic at normal dosage levels.
  • a substantially pure form will generally contain at least 50% (excluding normal pharmaceutical additives), preferably 75%, more preferably 90% and still more preferably 95% of the compound of formula (I) or its salt or solvate.
  • One preferred pharmaceutically acceptable form is the crystalline form, including such form in pharmaceutical composition.
  • the additional ionic and solvent moieties must also be non-toxic.
  • Suitable salts are pharmaceutically acceptable salts.
  • Suitable pharmaceutically acceptable salts include the acid addition salts with the conventional pharmaceutical acids, for example maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric, succinic, benzoic, ascorbic and methanesulphonic.
  • Suitable pharmaceutically acceptable salts include salts of acidic moieties of the compounds of formula (I) when they are present, for example salts of carboxy groups or phenolic hydroxy groups.
  • Suitable salts of acidic moieties include metal salts, such as for example aluminium, alkali metal salts such as lithium, sodium or potassium, alkaline earth metal salts such as calcium or magnesium and ammonium or substituted ammonium salts, for example those with lower alkylamines such as triethylamine, hydroxy alkylamines such as 2-hydroxyethylamine, bis-(2-hydroxyethyl)-amine or tri-(2-hydroxyethyl)-amine, cycloalkylamines such as bicyclohexylamine, or with procaine, dibenzylpiperidine, N-benzyl- D -phenethylamine, dehydroabietylamine, N,N'-bisdehydroabietylamine, glucamine, N-methylglucamine or bases of the pyridine type such as pyridine, collidine, quinine or quinoline.
  • metal salts such as for example aluminium, alkali metal salts such as lithium,
  • Suitable solvates are pharmaceutically acceptable solvates.
  • Suitable pharmaceutically acceptable solvates include hydrates.
  • the term 'alkyl' when used alone or when forming part of other groups (such as the 'alkoxy' group) includes straight- or branched-chain alkyl groups containing 1 to 12, preferably 1-6 carbon atoms, examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl group.
  • 'cycloalkyl' when used alone or when forming part of other groups (such as the 'cycloalkylalkyl' group) includes cyclic saturated or unsaturated carbon rings including 3-12, preferably 3-8 carbon ring members. Examples include cyclopropyl, cyclobutyl, cyclohexyl, cyclooctyl.
  • 'carbocyclic' refers to cycloalkyl and aryl rings.
  • 'aryl' includes phenyl and naphthyl, preferably phenyl which unless specified to the contrary optionally comprise up to five, preferably up to three substituents selected from halogen, alkyl, phenyl, alkoxy, haloalkyl, hydroxyalkyl, hydroxy, amino, nitro, cyano, carboxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyloxy, or alkylcarbonyl groups.
  • 'aromatic heterocyclic group' includes groups comprising aromatic heterocyclic rings containing from 5 to 12 ring atoms, suitably 5 or 6, and comprising up to four hetero-atoms in the or each ring selected from S, O or N.
  • Composite terms such as 'alkylcarboxy', 'cycloalkylalkyl' and so forth refer to components of a compound which include two interlinked groups, with the group named latterly in the term being the linking group, so that 'alkylcarboxy' means (alkyl)-COO- whilst 'cycloalkylalkyl' means (cycloalkyl)-(alkyl)-.
  • suitable substituents for any heterocyclic group includes up to 4 substituents selected from the group consisting of: alkyl, alkoxy, aryl and halogen or any two substituents on adjacent carbon atoms, together with the carbon atoms to which they are attached, may form an aryl group, preferably a benzene ring, and wherein the carbon atoms of the aryl group represented by the said two substituents may themselves be substituted or unsubstituted.
  • halogen refers to fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine or bromine.
  • acyl includes residues of acids, in particular a residue of a carboxylic acid such as an alkyl- or aryl- carbonyl group.
  • the invention also provides in one aspect a process for the preparation of a compound of formula (I), or a salt thereof and/or a solvate thereof, which process comprises reacting a compound of formula (II) or an active derivative thereof:
  • R'g, R'7, R'5 and X' are Rg, R7, R5 and X respectively as hereinbefore defined in relation to formula (I) or (la), or a group convertible to Rg, R7, R5 and X respectively; with a compound of formula (III):
  • R'j, R'2, and R'3 are R ⁇ , R2, and R3 as defined for formula (I) or a group or atom convertible to R ⁇ , R2, and R3 respectively; to form a compound of formula (lb): wherein R'j, R'2, R'3, X', R'5, R'g and R'7 are as defined above, and thereafter carrying out one or more of the following optional steps:
  • Suitable groups convertible into other groups include protected forms of said groups.
  • R' ⁇ , R'2, R'3, X', R'5, R'g and R'7 each represents Ri , R2, R3, X, R5, Rg and R7 respectively or a protected form thereof.
  • a suitable active derivative of a compound of formula (II) is a transient activated form of the compound of formula (II) or a derivative wherein the carboxy group of the compound of formula (II) has been replaced by a different group or atom, for example by an acyl halide, preferably a chloride, or an acylazide or a carboxylic acid anhydride.
  • Suitable active derivatives include: a mixed anhydride formed between the carboxyl moiety of the compound of formula (II) and an alkyl chloroformate; an activated ester, such as a cyanomethyl ester, thiophenyl ester, p-nitrophenyl ester, p- nitrothiophenyl ester, 2,4,6-trichlorophenyl ester, pentachlorophenyl ester, pentafluorophenyl ester, N-hydroxy-phtalimido ester, N-hydroxypiperidine ester, N- hydroxysuccinimide ester, N-hydroxy benzotriazole ester; alternatively, the carboxy group of the compound of formula (II) may be activated using a carbodiimide or N,N'- carbonyldiimidazole.
  • an activated ester such as a cyanomethyl ester, thiophenyl ester, p-nitrophenyl ester, p
  • reaction between the compound of formula (II) or the active derivative thereof and the compound of formula (III) is carried out under the appropriate conventional conditions for the particular compounds chosen.
  • the reaction is carried out using the same solvent and conditions as used to prepare the active derivative, preferably the active derivative is prepared in situ prior to forming the compound of formula (lb) and thereafter the compound of formula (I) or a salt thereof and/or a solvate thereof is prepared.
  • reaction between an active derivative of the compound of formula (II) and the compound of formula (III) may be carried out:
  • R' , R'2, R'3, X', R'5, R'g and R'7 are as defined above.
  • a compound of formula (lb) may be converted to a compound of formula (I), or one compound of formula (I) may be converted to another compound of formula (I) by interconversion of suitable substituents.
  • certain compounds of formula (I) and (lb) are useful intermediates in forming other compounds of the present invention.
  • the invention provides a process for preparing a compound of formula (I), or a salt thereof and/or a solvate thereof, which process comprises converting a compound of the above defined formula (lb) wherein at least one of R' ⁇ , R'2, R'3, X', R'5, R'g and R' 7 is not Ri , R2, R3, X, R5, Rg or R7 respectively, thereby to provide a compound of formula (I); and thereafter, as required, carrying out one or more of the following optional steps:
  • the variables R' , R'2, R'3, X', R'5, R'g and R'7 are Ri , R2, R3, X, R5, Rg and R7 respectively or they are protected forms thereof.
  • a chiral compound of formula (III) wherein R2 is a C 5 or C 7 cycloalkyl group, R3 is methyl and R is H are described in J. Org. Chem. (1996), 61 (12), 4130-4135.
  • a chiral compound of formula (III) wherein R2 is phenyl, R3 is isopropyl and R ⁇ is H is a known compound described in for example Tetrahedron Lett. ( 1994), 35(22), 3745-6.
  • the compounds of formula (III) are known commercially available compounds or they can be prepared from known compounds by known methods, or methods analogous to those used to prepare known compounds, for example the methods described in Liebigs Ann. der Chemie, (1936), 523, 199.
  • a compound of formula (II) or the corresponding alkyl (such as methyl or ethyl) ester is prepared by reacting a compound of formula (IV) or the corresponding alkyl (such as methyl or ethyl) ester:
  • R'g, R'7, R'5 and a are as defined above and L j represents a halogen atom such as a bromine atom, with a compound of formula (V):
  • R'4 is R4 as defined in relation to formula (I) or a protected form thereof.
  • R'4 is R4.
  • reaction between the compounds of formulae (IV) or the corresponding alkyl (such as methyl or ethyl) ester and (V) is carried out under conventional amination conditions, for example when L is a bromine atom then the reaction is conveniently carried out in an aprotic solvent, such as tetrahydrofuran or dimethylformamide at any temperature providing a suitable rate of formation of the required product, usually at ambient 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 they can be prepared using methods analogous to those used to prepare known compounds; for example the methods described in the Chemistry of the Amino Group, Patais (Ed.), Interscience, New York 1968; Advanced Organic Chemistry, March J, John Wiley & Sons, New York, 1992 ; J. Heterocyclic Chem. (1990), 27, 1559; Synthesis (1975), 135, Bioorg. Med. Chem. Lett. (1997), 7, 555, or Protective Groups in Organic Synthesis (second edition), Wiley Interscience, (1991) or other methods mentioned herein.
  • a compound of formula (IV) or the corresponding alkyl (such as methyl or ethyl) ester may be prepared by appropriate halogenation of a compound of formula (VI) or the corresponding alkyl (such as methyl or ethyl) ester:
  • R'g, R'7 and R'5 are as defined above in relation to formula (II).
  • Suitable halogenation reagents are conventional reagents depending upon the nature of the halogen atom required, for example when Li is bromine a preferred halogenation reagent is N-bromosuccinimide (NBS).
  • NBS N-bromosuccinimide
  • bromination is carried out by treatment with NBS in an inert solvent, such as carbon tetrachloride CCI 4 , or 1,2-dichloroethane or CH 3 CN, at any temperature providing a suitable rate of formation of the required product, suitably at an elevated temperature such as a temperature in the range of 60°C to 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 CCI 4 , or 1,2-dichloroethane or CH 3 CN
  • a compound of formula (VI) is conveniently prepared by reacting a compound of formula (VII):
  • the Pfitzinger reaction can be also carried out in presence of an acid, such as acetic acid or hydrochloric acid, at any temperature providing a suitable rate of formation of the required product, but generally at an elevated temperature, as described in J. Med. Chem. 38, 906 (1995).
  • an acid such as acetic acid or hydrochloric acid
  • the compounds of formula (VII) are known compounds or they are prepared according to methods used to prepare known compounds for example those disclosed in J. Org. Chem. 21, 171 (1955); J. Org. Chem. 21, 169 (1955).
  • R'5 is as defined in relation to formula (II) in presence of oxobutyric acid.
  • reaction between the compounds of formula (XIV) and (XV) is conveniently carried out using Doebner reaction conditions (see for example Chem. Ber. 29, 352 (1894); Chem. Revs. 35, 153, (1944); J. Chem. Soc. B, 1969, 805), for example in an alcoholic solvent such as ethanol, at any temperature providing a suitable rate of formation of the required product, but generally at an elevated temperature, such as the reflux temperature of the solvent.
  • Doebner reaction conditions see for example Chem. Ber. 29, 352 (1894); Chem. Revs. 35, 153, (1944); J. Chem. Soc. B, 1969, 805
  • an alcoholic solvent such as ethanol
  • the compounds of formula (XIV) and (XV) are known compounds or they are prepared according to methods used to prepare known compounds for example as described in Vogel's Textbook of Practical Organic Chemistry.
  • R'5 is as defined in relation to formula (II), and T5 is a group
  • Y is a protecting group such as a benzyl group, particularly a protecting group which is stable in basic conditions such as a terbutoxycarbonyl group; and a is as defined in relation to formula (II); and thereafter as required removing any protecting group, for example by dehydrogenation, and/or converting any group T5 to R4.
  • reaction between the compounds of formula (VII) and (VIII) is conveniently carried out using Pfitzinger reaction conditions (see for example J. Prakt. Chem. 33, 100 (1886), J. Prakt. Chem. 38, 582 (1888), J. Chem. Soc. 106 (1948) and Chem. Rev. 35, 152 (1944)), for example in an alkanolic solvent such as ethanol, at any temperature providing a suitable rate of formation of the required product, but generally at an elevated temperature, such as the reflux temperature of the solvent, and preferably in the presence of a base such as potassium hydroxide or potassium tert-butoxide.
  • Pfitzinger reaction conditions see for example J. Prakt. Chem. 33, 100 (1886), J. Prakt. Chem. 38, 582 (1888), J. Chem. Soc. 106 (1948) and Chem. Rev. 35, 152 (1944)
  • an alkanolic solvent such as ethanol
  • a base such as potassium hydroxide or potassium tert-butoxid
  • R4 Protected forms of R4 will vary according to the particular nature of the group being protected but will be chosen in accordance with normal chemical practice.
  • Groups convertible to R4 include groups dictated by conventional chemical practice to be required and to be appropriate, depending upon the specific nature of the R4 under consideration.
  • Suitable deprotection methods for deprotecting protected forms of R4 and conversion methods for converting T5 to R4 will be those used conventionally in the art depending upon the particular groups under consideration with reference to standard texts such as Greene, T.W. and Wuts, P.G.M. Protective Groups in Organic Synthesis, John Wiley & Sons Inc. New York, 1991 (Second Edt.) or in Kocienski, P.J. Protecting groups. George Thieme Verlag, New York, 1994 and Chemistry of the Amino Group, Patais (Ed.), Interscience, New York 1968; or Advanced Organic Chemistry, March J, John Wiley & Sons, New York, 1992.
  • a compound of formula (VIII) is prepared from a compound of formula (IX):
  • T5 is a group R4
  • a compound capable of forming a group T5 is a compound of the above defined formula (V).
  • halogenation of the compound of formula (IX) is suitably carried out using a conventional halogenation reagent.
  • Mesylation is conveniently carried out using mesyl chloride in an inert solvent such as methylene dichloride, at a temperature below room temperature, such as 0°C, preferably in the presence of triethylamine.
  • reaction conditions between the compound of formula (IX) and the compound capable of forming a group T5 will be those conventional conditions dictated by the specific nature of the reactants, for example when the T5 required is a group R4 and the required compound capable of forming a group T5 is a compound of the above defined formula (V), then the reaction between the halogenation or mesylation product of the compound of formula (IX) and the compound of formula (V) is carried out under analogous conditions to those described for the reaction between the compounds of formulae (IV) and (V).
  • T5 Other compounds capable of forming a group T5 will depend upon the particular nature of T5, but will be those appropriate compounds dictated by conventional chemical practice with reference to standard texts such as Chemistry of the Amino Group, Patais (Ed.), Interscience, New York 1968; and Advanced Organic Chemistry, March J, John Wiley & Sons, New York, 1992.
  • a compound of formula (IX) may be prepared by reacting a compound of formula (X):
  • reaction between the compounds of formulae (X) and (XI) can be carried out in an aprotic solvent, such as diethyl-ether at any temperature providing a suitable rate of formation of the required product, usually at a low temperature such as in the range of -
  • the compounds of formula (VII) are known compounds or they are prepared according to methods used to prepare known compounds for example those disclosed in
  • the compounds of formula (X) and (XI) are known compounds or they are prepared according to methods used to prepare known compounds for example those disclosed by Rrow G. R. in Organic Reactions, Vol 43, page 251 , John Wiley & Sons
  • R' ⁇ , R'2, R'3, R'5, R'g, and R'7 is respectively R ⁇ , R2, R3, R5, Rg, or R7 as defined above or a group convertible to R , R2, R3, R5, Rg, or R7 respectively as defined above providing R'2 is not aromatic in character
  • Lj represents a halogen atom such as a bromine atom, with a compound of formula (XVII):
  • Groups convertible to R4 include groups dictated by conventional chemical practice to be required and to be appropriate, depending upon the specific nature of the
  • R4 under consideration. Suitable deprotection methods for deprotecting protected forms of R4 and conversion methods for converting R'4 to R4 will be those used conventionally in the art depending upon the particular groups under consideration with reference to standard texts such as Greene, T.W. and Wuts, P.G.M. Protective Groups in Organic Synthesis, John Wiley & Sons Inc. New York, 1991 (Second Edt.) or in Kocienski, P.J. Protecting groups. George Thieme Verlag, New York, 1994 and Chemistry of the Amino Group, Patais (Ed.), Interscience, New York 1968; or Advanced Organic Chemistry, March J, John Wiley & Sons, New York, 1992.
  • Suitable groups convertible into other groups include protected forms of said groups.
  • a compound of formula (XVII) will be a compound of formula (V) as defined above.
  • R' ⁇ , R'2, R'3, R'4, R'5, R'g and R'7 each represents R , R2, R3, R4, R5,
  • Suitable deprotection methods for deprotecting protected forms of R , R2, R3, R4, R5, Rg and R7 and conversion methods for converting R'1 , R'2, R'3, R'4, R'5, R'g and R'7 to Ri , R2, R3, R4, R5, Rg and R7 respectively will be those used conventionally in the art depending upon the particular groups under consideration with reference to standard texts such as Greene, T.W. and Wuts, P.G.M. Protective Groups in Organic Synthesis, John Wiley & Sons Inc. New York, 1991 (Second Edt.) or in Kocienski, P.J. Protecting groups. George Thieme Verlag, New York, 1994 and Chemistry of the Amino Group, Patais (Ed.), Interscience, New York 1968; or Advanced Organic Chemistry, March J, John Wiley & Sons, New York, 1992.
  • reaction between the compounds of formulae (XVI) and (XVII) is carried out under conventional amination conditions, for example when Li is a bromine atom then the reaction is conveniently carried out in an aprotic solvent, such as tetrahydrofuran or dimethylformamide or acetonitrile at any temperature providing a suitable rate of formation of the required product, usually at ambient temperature; preferably the reaction is carried out in the presence of triethylamine (TEA), sodium hydride or K 2 CO 3 .
  • TAA triethylamine
  • the compounds of formula (XVII) are known, commercially available compounds or they can be prepared using methods analogous to those used to prepare known compounds; for example the methods described in the Chemistry of the Amino Group, Patais (Ed.), Interscience, New York 1968; Advanced Organic Chemistry, March J, John Wiley & Sons, New York, 1992 ; J. Heterocyclic Chem. (1990), 27, 1559; Synthesis (1975), 135, Bioorg. Med. Chem. Lett. (1997), 7, 555, or Protective Groups in Organic Synthesis (second edition), Wiley Interscience, (1991) or other methods mentioned herein.
  • a compound of formula (XVI) is prepared by appropriate halogenation of a compound of formula (XVIII) :
  • Suitable halogenation reagents are conventional reagents depending upon the nature of the halogen atom required, for example when Li is bromine a preferred halogenation reagent is N-bromosuccinimide (NBS).
  • the halogenation of the compound of formula (XVIII) is carried out under conventional conditions, for example bromination is carried out by treatment with NBS in an inert solvent, such as carbon tetrachloride CC1 4 , or 1,2-dichloroethane or CH 3 CN, at any temperature providing a suitable rate of formation of the required product, suitably at an elevated temperature such as a temperature in the range of 60°C to 100°C, for example 80°C; preferably the reaction is carried out in the presence of a catalytic amount of benzoyl peroxide.
  • the compound of formula (XVIII) may be prepared by reacting a compound of formula (VI) as defined above or an active derivative thereof with a compound of formula (III) as defined above wherein R'2 is not aromatic in character.
  • the compound of formula (VI) is present in the reaction mix as an active derivative, as hereinbefore described.
  • the reaction between the compound of formula (VI) or the active derivative thereof and the compound of formula (III) is carried out under the appropriate conventional conditions for the particular compounds chosen.
  • the reaction is carried out using the same solvent and conditions as used to prepare the active derivative, preferably the active derivative is prepared in situ prior to forming the compound of formula (XVIII).
  • reaction between an active derivative of the compound of formula (VI) and the compound of formula (III) may be carried out:
  • the compounds of formula (I) may exist in more than one stereoisomeric form - and the process of the invention may produce racemates as well as enantiomerically pure forms. Accordingly, a pure enantiomer of a compound of formula (I) can be obtained by reacting a compound of the above defined formula (II) with an appropriate enantiomerically pure primary amine of formula (Ilia) or (IIIc):
  • R ⁇ , R2, R3, X, R5, Rg, and R7 are as defined above.
  • R ⁇ represents hydrogen.
  • An alternative method for separating optical isomers is to use conventional, fractional separation methods in particular fractional crystallization methods.
  • a pure enantiomer of a compound of formula (I) is obtained by fractional crystallisation of a diastereomeric salt formed by reaction of the racemic compound of formula (I) with an optically active strong acid resolving agent, such as camphosulphonic acid, tartaric acid, O,O'-di-p-toluoyltartaric acid or mandelic acid, in an appropriate alcoholic solvent, such as ethanol or methanol, or in a ketonic solvent, such as acetone.
  • the salt formation process should be conducted at a temperature between 20°C and 80°C, preferably at 50°C.
  • a suitable conversion of one compound of formula (I) into a further compound of formula (I) involves converting one group X into another group X by for example: (i) converting a ketal into a ketone, by such as mild acidic hydrolysis, using for example dilute hydrochloric acid;
  • any reactive group in the substrate molecule may be protected and deprotected according to conventional chemical practice, for example as described by Greene, T.W. and Wuts,
  • Suitable protecting groups in any of the above mentioned reactions are those used conventionally in the art.
  • suitable hydroxy protecting groups include benzyl or trialkylsilyl groups.
  • benzyloxy group may be prepared by treatment of the appropriate compound with a benzyl halide, such as benzyl bromide, and thereafter, if required, the benzyl group may be conveniently removed using catalytic hydrogenation or a mild ether cleavage reagent such as trimethylsilyl iodide or boron tribromide.
  • a benzyl halide such as benzyl bromide
  • the compounds of formula (I) have useful pharmaceutical properties.
  • the present invention also provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use as an active therapeutic substance.
  • the present invention also provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for the treatment or prophylaxis of the Primary and Secondary Conditions.
  • the present invention further provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
  • the present invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of the Primary and Secondary Conditions.
  • the Primary conditions include respiratory diseases, such as chronic obstructive pulmonary disease (COPD), asthma, airway hyperreactivity, cough; inflammatory diseases such as inflammatory bowel disease, psoriasis, fibrositis, osteoarthritis, rheumatoid arthritis and inflammatory pain; neurogenic inflammation or peripheral neuropathy, allergies such as eczema and rhinitis; ophthalmic diseases such as ocular inflammation, conjunctivitis, vernal conjuctivitis and the like; cutaneous diseases, skin disorders and itch, such as cutaneous wheal and flare, contact dermatitis, atopic dermatitis, urticaria and other eczematoid dermatitis; adverse immunological reactions such as rejection of transplanted tissues and disorders related to immune enhancement or suppression such as systemic lupus erythematosis; gastrointestinal (GI) disorders and diseases of the GI tract such as disorders associated with the neuronal control of viscera such as ulcerative
  • the Secondary conditions include disorders of the central nervous system such as anxiety, depression, psychosis and schizophrenia; neurodegenerative disorders such as AIDS related dementia, senile dementia of the Alzheimer type, Alzheimer's disease, Down's syndrome, Huntingdon's disease, Parkinson's disease, movement disorders and convulsive disorders (for example epilepsy); demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis and other neuropathological disorders such as diabetic neuropathy, AIDS related neuropathy, chemotherapy-induced neuropathy and neuralgia; addiction disorders such as alcoholism; stress related somatic disorders; reflex sympathetic dystrophy such as shoulder hand syndrome; dysthymic disorders; eating disorders (such as food intake disease); fibrosing and collagen diseases such as scleroderma and eosinophilic fascioliasis; disorders of the blood flow caused by vasodilatation and vasospastic diseases such as angina, migraine and Reynaud's disease and pain or nociception, for example, that
  • Such a medicament, and a composition of this invention may be prepared by admixture of a compound of the invention with an appropriate carrier. It may contain a diluent, binder, filler, disintegrant, flavouring agent, colouring agent, lubricant or preservative in conventional manner.
  • compositions of known agents for treating the conditions may be employed for example as in the preparation of compositions of known agents for treating the conditions.
  • a pharmaceutical composition of the invention is in unit dosage form and in a form adapted for use in the medical or veterinarial fields.
  • preparations may be in a pack form accompanied by written or printed instructions for use as an agent in the treatment of the conditions.
  • the suitable dosage range for the compounds of the invention depends on the compound to be employed and on the condition of the patient. It will also depend, inter alia, upon the relation of potency to absorbability and the frequency and route of administration.
  • the compound or composition of the invention may be formulated for administration by any route, and is preferably in unit dosage form or in a form that a human patient may administer to himself in a single dosage.
  • the composition is suitable for oral, rectal, topical, parenteral, intravenous or intramuscular administration. Preparations may be designed to give slow release of the active ingredient.
  • Compositions may, for example, be in the form of tablets, capsules, sachets, vials, powders, granules, lozenges, reconstitutable powders, or liquid preparations, for example solutions or suspensions, or suppositories.
  • compositions may contain conventional excipients such as binding agents, for example syrup, acacia, gelatine, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinyl-pyrrolidone, sodium starch glycollate or microcrystalline cellulose; or pharmaceutically acceptable setting agents such as sodium lauryl sulphate.
  • binding agents for example syrup, acacia, gelatine, sorbitol, tragacanth, or polyvinylpyrrolidone
  • fillers for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine
  • tabletting lubricants for example magnesium stearate
  • disintegrants for example starch, polyvinyl-pyrroli
  • Solid compositions may be obtained by conventional methods of blending, filling, tabletting or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers.
  • any carrier suitable for formulating solid pharmaceutical compositions may be used, examples being magnesium stearate, starch, glucose, lactose, sucrose, rice flour and chalk. Tablets may be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating.
  • the composition may also be in the form of an ingestible capsule, for example of gelatine containing the compound, if desired with a carrier or other excipients.
  • compositions for oral administration as liquids may be in the form of, for example, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid compositions may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatine, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; aqueous or non-aqueous vehicles, which include edible oils, for example almond oil, fractionated coconut oil, oily esters, for example esters of glycerine, or propylene glycol, or ethyl alcohol, glycerine, water or normal saline; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and if desired conventional flavouring or
  • compositions may be formulated, for example for rectal administration as a suppository. They may also be formulated for presentation in an injectable form in an aqueous or non-aqueous solution, suspension or emulsion in a pharmaceutically acceptable liquid, e.g. sterile pyrogen-free water or a parenterally acceptable oil or a mixture of liquids.
  • a pharmaceutically acceptable liquid e.g. sterile pyrogen-free water or a parenterally acceptable oil or a mixture of liquids.
  • the liquid may contain bacteriostatic agents, anti-oxidants or other preservatives, buffers or solutes to render the solution isotonic with the blood, thickening agents, suspending agents or other pharmaceutically acceptable additives.
  • Such forms will be presented in unit dose form such as ampoules or disposable injection devices or in multi- dose forms such as a bottle from which the appropriate dose may be withdrawn or a solid form or concentrate which can be used to prepare an injectable formulation.
  • the compounds of this invention may also be administered by inhalation, via the nasal or oral routes.
  • administration can be carried out with a spray formulation comprising a compound of the invention and a suitable carrier, optionally suspended in, for example, a hydrocarbon propellant.
  • Preferred spray formulations comprise micronised compound particles in combination with a surfactant, solvent or a dispersing agent to prevent the sedimentation of suspended particles.
  • the compound particle size is from about 2 to 10 microns.
  • a further mode of administration of the compounds of the invention comprises transdermal delivery utilising a skin-patch formulation.
  • a preferred formulation comprises a compound of the invention dispersed in a pressure sensitive adhesive which adheres to the skin, thereby permitting the compound to diffuse from the adhesive through the skin for delivery to the patient.
  • pressure sensitive adhesives known in the art such as natural rubber or silicone can be used.
  • the effective dose of compound depends on the particular compound employed, the condition of the patient and on the frequency and route of administration.
  • a unit dose will generally contain from 20 to 1000 mg and preferably will contain from 30 to 500 mg, in particular 50, 100, 150, 200, 250, 300, 350, 400, 450, or 500 mg.
  • the composition may be administered once or more times a day for example 2, 3 or 4 times daily, and the total daily dose for a 70 kg adult will normally be in the range 100 to 3000 mg.
  • the unit dose will contain from 2 to 20 mg of active ingredient and be administered in multiples, if desired, to give the preceding daily dose. No unacceptable toxicological effects are expected with compounds of the invention when administered in accordance with the invention.
  • the present invention also provides a method for the treatment and/or prophylaxis of the Primary and Secondary Conditions in mammals, particularly humans, which comprises administering to the mammal in need of such treatment and/or prophylaxis an effective, non-toxic pharmaceutically acceptable amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
  • NK3 ligands The activity of the compounds of the present invention, as NK3 ligands, is determined by their ability to inhibit the binding of the radiolabelled NK3 ligands, [I ⁇ I]- [Me-Phe7]-NKB or [ ⁇ HJ-Senktide, to guinea-pig and human NK3 receptors (Renzetti et al, 1991, Neuropeptide, 18, 104-114; Buell et al, 1992, FEBS, 299(1), 90-95; Chung et al, 1994, Biochem. Biophys. Res. Commun., 198(3), 967-972).
  • the binding assays utilised allow the determination of the concentration of the individual compound required to reduce by 50% the [ 25 I]-[Me-Phe 7 ]-NKB and [ ⁇ H]- Senktide specific binding to NK3 receptor in equilibrium conditions (IC50).
  • Binding assays provide for each compound tested a mean IC50 value of 2-5 separate experiments performed in duplicate or triplicate.
  • the most potent compounds of the present invention show IC50 values in the range 0.1-1000 nM.
  • the NK3-antagonist activity of the compounds of the present invention is determined by their ability to inhibit senktide-induced contraction of the guinea-pig ileum (Maggi et al, 1990, Br. J. Pharmacol, 101, 996-1000) and rabbit isolated iris sphincter muscle (Hall et al., 1991, Eur. J. Pharmacol, 199, 9-14) and human NK3 receptors-mediated Ca ++ mobilisation (Mochizuki et al, 1994, J. Biol.
  • Guinea-pig and rabbit in-vitro functional assays provide for each compound tested a mean Kg value of 3-8 separate experiments, where K3 is the concentration of the individual compound required to produce a 2-fold rightward shift in the concentration-response curve of senktide.
  • Human receptor functional assay allows the determination of the concentration of the individual compound required to reduce by 50% (IC50 values) the Ca " -1" mobilisation induced by the agonist NKB. In this assay, the compounds of the present invention behave as antagonists.
  • NK-2 ligands The activity of the compounds of the present invention, as NK-2 ligands, is determined by their ability to inhibit the binding of the radiolabelled NK-2 ligands, [ 12 5l]-NKA or [3H]-NKA, to human NK-2 receptors (Aharony et al, 1992, Neuropeptide, 23, 121-130).
  • the binding assays utilised allow the determination of the concentration of the individual compound required to reduce by 50% the an( j [3H]-NKA specific binding to NK2 receptor in equilibrium conditions (IC50).
  • Binding assays provide for each compound tested a mean IC50 value of 2-5 separate experiments performed in duplicate or triplicate.
  • the most potent compounds of the present invention show IC50 values in the range 0.5-1000 nM, such as 1-1000 nM.
  • the NK-2-antagonist activity of the compounds of the present invention is determined by their ability to inhibit human NK-2 receptor-mediated Ca "1-1" mobilisation (Mochizuki et al, 1994, J. Biol. Chem., 269, 9651-9658).
  • Human receptor functional assay allows the determination of the concentration of the individual compound required to reduce by 50% (IC50 values) the Ca ++ mobilisation induced by the agonist NKA. In this assay, the compounds of the present invention behave as antagonists.
  • the therapeutic potential of the compounds of the present invention in treating the conditions can be assessed using rodent disease models.
  • the compounds of formula (I) are also considered to be useful as diagnostic tools.
  • the invention includes a compound of formula (I) for use as diagnostic tools for assessing the degree to which neurokinin-3 and neurokinin-2 receptor activity (normal, overactivity or underactivity) is implicated in a patient's symptoms.
  • Such use comprises the use of a compound of formula (I) as an antagonist of said activity, for example including but not restricted to Tachykinin agonist-induced inositol phosphate turnover or electrophysiological activation, of a cell sample obtained from a patient. Comparison of such activity in the presence or absence of a compound of formula (I), will disclose the degree of NK-3 and NK-2 receptor involvement in the mediation of agonist effects in that tissue.
  • Isatine 40 g, 0.272 mol is suspended in EtOH (1 1) and KOH (62.8 g, 1.1 mol). Suspension is stirred for 30 min. Propiophenone (36.2 cc, 0.272 mol) was added and the reaction was refluxed for 4 h. The reaction was left overnight at room temperature and then EtOH was evaporated under vacuum. The solid was dissolved in water (400 ml) and washed with Et2 ⁇ . The aqueous phase was acidified with citric acid (saturated solution) and a solid was obtained. The solid was filtered by suction, washed with water and dried in oven to obtain the title compound, mp > 280°C.
  • Method B A mixture of the piperazinone derivative (0.47g, 1 mmol, compound prepared as in Description 5), alkylating reagent (1.2 mmol) and KOH (0.23g, 4 mmol) in anhydrous DMSO (10 ml), was stirred for 36 hours at room temperature. The reaction was diluted with a saturated solution of NaCI and the product was extracted with DCM. The organic phases were dried over Na 2 SO , filtered and evaporated under vacuum; the residue was purificated by flash chromatography to afford the desired compound.
  • the compound was prepared according to Description 1, starting from 5-fluoroisatine CAS[443-69-6] and phenylethylketone, Description 2 and 3.
  • the compound was prepared according to Description 5 starting from the compound of Description 8 and piperazinone (CAS[5625-67-2]).
  • the compound was prepared according to Description 1, starting from l-thiophen-2-yl- propan-1-one CAS [13679-75-9] and isatine, Description 2 and 3.
  • the compound was prepared according to Description 5 starting from the compound of Description 10 and piperazinone (CAS [5625-67-2]).
  • the compound was prepared according to Description 1, starting from l-thiophen-3-yl- propan-1-one CAS [51179-52-3] and isatine, Description 2 and 3.
  • Example 16 6-Fluoro-3-[3-oxo-4-(2-piperidin-l-yl-ethyl)-piperazin-l-ylmethyl]-2- phenyl-quinoIine-4-carboxyl_c acid ((S)-l-cycIohexyI-ethyl)-amide.
  • the compound was prepared following the Description 6 (method A) starting from the compound of Description 9 and l-(2-chloroethyl)piperidine.
  • Example 18 3- 3-Oxo-4-(3-piperidin-l-yl-propyl)-piperazin-l-ylmethyl]-2-phenyl- quinoline-4-carboxylic acid ((S)-l-cyclohexyI-ethyl)-amide.
  • the compound was prepared following the Description 6, method A, starting from the compound of Description 5 and l-3-(chloropropyl)piperidine (CAS[5472-49-l]).
  • the compound was prepared according to Description 5 starting from the compound in Description 8 and dimethylamine.
  • Example 21 6-Fluoro-3-(l-oxo-3,4-dihydro-lH-pyrrolo[l,2-a]pyrazin-2-ylmethyl)-2- phenyl-quinoline-4-carboxylic cid ((S)-l-cyclohexyl-ethyl)-amide.
  • the compound was prepared according to Description 13 starting from the compound of Description 8 and 3,4-dihydro-2H-pyrrolo[l,2-a]pyrazin-l-one (CAS[54906-42-2]).
  • Example 23 3-[4-(3-Dimethylamino-propyl)-3-oxo-piperazin-l-ylmethyl]-2-phenyl- quinoline-4-carboxylic acid ((S)-l-cyclohexyl-et_ ⁇ yl)-amide.
  • the compound was prepared following Description 6, method B, starting from the compound prepared in Description 5 and 3-dimethylaminopropylchloride.
  • Example 24 3-(4-MethyI-3-oxo-piperazin-l-ylmethyl)-2-phenyl-quino_ine-4- carboxylic acid ((S)-l-cycIohexy_-ethyI)-amide ditrifluoroacetate.
  • the compound was prepared following Description 6, method A, starting from the compound of Description 5 and methyl iodide.
  • Example 25 3-(4-Ethyl-3-oxo-piperazin-l-ylmethyl)-2-phenyl-quinoline-4-carboxylic acid ((S)-l-cyclohexyl-ethyl)-amide.
  • the compound was prepared following the above Description 6, method A, starting from the compound in Description 5 and ethyl bromide.
  • Example 27 3-[3-Oxo-4-(2-pyrrolidin-l-yl-ethyl)-piperazin-l-ylmethyl]-2-phenyl- quinoline-4-carboxylic acid ((S)-l-cyclohexyl-ethyl)-amide.
  • the compound was prepared following Description 6 (method B) starting from the compound of Description 5 and l-(2-chloroethyl)pyrrolidine.
  • Example 28 3-[4-(2-DiethyIamino-ethyI)-3-oxo-piperazin-l-ylmethyl]-2-phenyl- quinoline-4-carboxylic acid ((S)-l-cyclohexyl-ethyl)-amide.
  • the compound was prepared following Description 6 (method B) starting from the compound of Description 5 and 2-diethylaminoethyl chloride.
  • Example 29 3-[4-(2-Dimethylamino-ethyl)-3-oxo-piperazin-l-ylmethyl]-2-phenyI- quinoline-4-carboxylic acid ((S)-l-cyclohexyl-ethyl)-amide.
  • the compound was prepared following Description 6 (method B) starting from the compound in Description 5 and dimethylamino ethyl chloride.
  • Example 30 3-[4-(2-Amino-ethyl)-3-oxo-piperazin-l-ylmethyl]-2-phenyl-quinoline-4- carboxylic acid ((S)-l-cyclohexy_-ethyl)-amide.
  • the compound was prepared following Description 6 (method B) starting from the compound in Description 5 and 4-(2-chloroethyl)morpholine.
  • Example 32 3-(4-Ethylcarbamoyl-piperazin-l-ylmethyl)-2-phenyl-quino_me-4- carboxylic acid ((S)-l-cyclohexyl-ethyl)-amide.
  • the compound was prepared following Description 16 starting from compound in Description 15 and ethylisocyanate.
  • the compound was prepared following Description 16 starting from the compound of Description 15 and isopropylisocyanate.
  • the compound was prepared according to Description 5 starting from the compound of Description 12 and piperazinone (CAS [5625-67-2]).
  • Example 35 3-[4-(3-Dimethylamino-propyl)-3-oxo-piperazin-l-ylmethyl]-6-fluoro-2- phenyl-quinoline-4-carboxy lie acid ((S)-l-cyclohexyl-ethyl)-amide.
  • the compound was prepared following Description 6, method A, starting from the compound of Description 9 and 3-dimethylaminopropylchloride.
  • TSQ 700 source 180 C; 70 V; 200 uA: 476 (M+); 378; 269; 252; 223; 99; 69; 55.

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Abstract

A compound of formula (I) as detailed in the specification or a pharmaceutically acceptable salt or solvate thereof, a process for preparing such compounds, a pharmaceutical composition comprising such compounds and the use of such compounds in medicine. Figure (I) wherein: R1 is H or alkyl; R2 is aryl or cycloalkyl or heteroaryl; R3 is H or alkyl, wherein the group may be optionally substituted by one or more fluorine atoms; R4 is NR8R9; R8 is H, lakyl or R11R12 and R9 is H, alkyl or R13R14; or R8 and R9 together with the N atom to wich they are attached form a heterocyclic ring comprising 4-8 ring members, said ring members optionally including in addition to said N atom one or more further heteroatoms selected from N, O or S; and further detailed in the specification.

Description

QUINO INE-4-CARBOXAMIDE DERIVATIVES AS NK-3 AND NK-2 RECEPTOR ANTAGONISTS
The present invention relates to novel compounds, in particular to novel quinoline derivatives, to processes for the preparation of such compounds, to pharmaceutical compositions containing such compounds and to the use of such compounds in medicine. The mammalian peptide Neurokinin B (NKB) belongs to the Tachykinin (TK) peptide family which also include Substance P (SP) and Neurokinin A (NKA). Pharmacological and molecular biological evidence has shown the existence of three subtypes of TK receptor (NKj, NK ? and NK3) and NKB binds preferentially to the NK3 receptor although it also recognises the other two receptors with lower affinity (Maggi et al, 1993, J. Auton. Pharmacol, 13, 23-93).
Selective peptidic NK3 receptor antagonists are known (Drapeau, 1990 Regul. Pept, 31, 125-135), and findings with peptidic NK3 receptor agonists suggest that NKB, by activating the NK3 receptor, has a key role in the modulation of neural input in airways, skin, spinal cord and nigro-striatal pathways (Myers and Undem, 1993,
J.Physiol, 470, 665-679; Counture et al., 1993, Regul. Peptides, 46, 426-429; Mccarson and Krause, 1994, J. Neurosci., 14 (2), 712-720; Arenas et al. 1991, J.Neuroscl, 11, 2332-8). However, the peptide-like nature of the known antagonists makes them likely to be too labile from a metabolic point of view to serve as practical therapeutic agents. International Patent Application, Publication Number WO 00/58307 describes a series of aryl fused 2,4-disubstituted pyridines, such as naphthyridine derivatives, which are stated to exhibit biological activity as NK3 receptor antagonists.
The compounds of the present invention are quinoline derivatives. Other quinoline derivatives have been described previously as selective NK3 antagonists. For example, International Patent Application, Publication Numbers, WO 95/32948 and WO 96/02509 describe a series of selective and potent NK3 receptor antagonists.
International Patent Application, Publication Number WO 00/64877 describes a series of 2-aminoquinolinecarboxamides as neurokinin receptor ligands.
International Patent Application, Publication Number, WO 00/58303 describes a series of 4-substituted quinoline derivatives which are stated to be NK3 and or GABA(A) receptor ligands. Such compounds are characterised by the presence of a nitrogen- containing heterocyclic moiety at the C(4) position of the quinoline ring. International Patent Application, Publication Numbers, WO 97/21680, WO 98/52942, WO 00/31037 and WO 00/31038 describe compounds which have biological activity as combined NK3 and NK2 receptor antagonists.
Copending International Patent Application Numbers, PCT/EP01/13833, PCT/EP01/14140 and PCT/EP01/13832 also describe compounds that have biological activity as combined NK3 and NK2 receptor antagonists.
We have now discovered a further novel class of non-peptide NK3 antagonists which are far more stable from a metabolic point of view than the known peptidic NK3 receptor antagonists and are of potential therapeutic utility. These compounds also have NK2 antagonist activity and are therefore considered to be of potential use in the prevention and treatment of a wide variety of clinical conditions, which are characterised by overstimulation of the Tachykinin receptors, in particular NK3 and NK2.
These conditions include respiratory diseases, such as chronic obstructive pulmonary disease (COPD), asthma, airway hyper-reactivity, cough; inflammatory diseases such as inflammatory bowel disease, psoriasis, fϊbrositis, osteoarthritis, rheumatoid arthritis and inflammatory pain; neurogenic inflammation or peripheral neuropathy, allergies such as eczema and rhinitis; ophthalmic diseases such as ocular inflammation, conjunctivitis, vernal conjuctivitis and the like; cutaneous diseases, skin disorders and itch, such as cutaneous wheal and flare, contact dermatitis, atopic dermatitis, urticaria and other eczematoid dermatitis; adverse immunological reactions such as rejection of transplanted tissues and disorders related to immune enhancement or suppression such as systhemic lupus erythematosis; gastrointestinal (GI) disorders and diseases of the GI tract such as disorders associated with the neuronal control of viscera such as ulcerative colitis, Crohn's disease, irritable bowel syndrome (IBS), gastro- exophageous reflex disease (GERD); urinary incontinence and disorders of the bladder function; renal disorders; increased blood pressure, proteinuria, coagulopathy and peripheral and cerebral oedema following pre-eclampsia in pregnancies (hereinafter referred to as the 'Primary Conditions').
Certain of these compounds also show CNS activity and hence are considered to be of particular use in the treatment of disorders of the central nervous system such as anxiety, depression, psychosis and schizophrenia; neurodegenerative disorders such as AIDS related dementia, senile dementia of the Alzheimer type, Alzheimer's disease, Down's syndrome, Huntingdon's disease, Parkinson's disease, movement disorders and convulsive disorders (for example epilepsy); demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis and other neuropathological disorders such as diabetic neuropathy, AIDS related neuropathy, chemotherapy-induced neuropathy and neuralgia; addiction disorders such as alcoholism; stress related somatic disorders; reflex sympathetic dystrophy such as shoulder/hand syndrome; dysthymic disorders; eating disorders (such as food intake disease); fibrosing and collagen diseases such as scleroderma and eosinophilic fascioliasis; disorders of the blood flow caused by vasodilatation and vasospastic diseases such as angina, migraine and Reynaud's disease and pain or nociception, for example, that is attributable to or associated with any of the foregoing conditions especially the transmission of pain in migraine, (hereinafter referred to as the 'Secondary Conditions').
The compounds of formula (I) are also considered to be useful as diagnostic tools for assessing the degree to which neurokinin-3 and neurokinin-2 receptor activity (normal, overactivity or underactivity) is implicated in a patient's symptoms.
Certain compounds of the present invention have also been found to exhibit surprisingly advantageous pharmacochemical properties.
According to the present invention, there is provided a compound of formula (I) below or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000005_0001
(I) wherein: Rl is H or alkyl;
R2 is aryl or cycloalkyl or heteroaryl; R3 is H or alkyl, wherein the alkyl group may be optionally substituted by one or more fluorine atoms; R4 is NRgR9;
Rg is H, alkyl or R\ 1R12 and R9 is H, alkyl or R13 R1 ; or Rg and R9 together with the N atom to which they are attached form a heterocyclic ring comprising 4-8 ring members, said ring members optionally including in addition to said N atom one or more further heteroatoms selected from N, O or S; said heterocyclic ring being saturated or unsaturated and optionally substituted one or more times by hydroxy, oxo, alkyl, aminoalkyl, di-alkylaminoalkyl and -C(= )NHRi5, and wherein said ring may be optionally fused or linked by a single bond or an alkyl chain to one or more cycloalkyl, heterocyclyl or aryl groups, which cycloalkyl, heterocyclyl or aryl groups are unsubstituted or are substituted one or more times by halo, haloalkyl, oxo and aryl; each of Rj 1 and R13 is independently either a single bond, alkyl, alkylamino or aminoalkyl or 2°- or 3°-alkylaminoalkyl, and each of R12 and R1 is independently H or a ring moiety comprising cycloalkyl, aryl or two or more fused cycloalkyl and/or aryl groups, which ring moiety optionally includes one or more heteroatoms selected from N, O and S, which ring moiety is unsubstituted or is substituted one or more times by one or more of halo, hydroxy, amino, cyano, nitro, carboxy, oxo, alkyl, arylalkyl or cycloalkylalkyl, aryl, or cycloalkyl;
R5 is branched or linear alkyl, cycloalkyl, cycloalkylalkyl, aryl, or a single or fused ring aromatic heterocyclic group;
Rg represents H or up to three substituents independently selected from the list consisting of: alkyl, alkenyl, aryl, alkoxy, hydroxy, halo, nitro, cyano, carboxy, carboxamido, sulphonamido, trifluoromethyl, or amino or mono- or di-alkylamino;
R7 is H or halo;
R15 is alkyl; a is 0-6; and any of R2 and R5 may optionally be substituted one or more times by halo, hydroxy, amino, cyano, nitro, carboxy, oxo, alkyl, alkenyl, aryl, alkoxy, carboxamido, sulphonamido, trifluoromethyl, or mono- or di- alkylamino; not being a compound wherein R5 is unsubstituted phenyl, and Ri , R2, R3, R4, R6, R7 and a are selected from the following:
Figure imgf000006_0001
Figure imgf000007_0001
Figure imgf000008_0001
Figure imgf000009_0001
Figure imgf000010_0001
Figure imgf000011_0001
with the further proviso that said compound of formula (I) is not selected from the following compounds:
2-(4-Fluoro-phenyl)-3 -(3 -oxo-piperazin- 1 -y lmethy l)-quinoline-4-carboxylic acid ((S)- cyclohexyl-ethyl)-amide;
3-(3-Oxo-piperazin-l-ylmethyl)-2-(4-trifluoromethyl-phenyl)-quinoline-4-carboxylic acid ((S)-cyclohexyl-ethyl)-amide;
2-(2-Fluoro-phenyl)-3-(3-oxo-piperazin-l-ylmethyl)-quinoline-4-carboxylic acid ((S)- cyclohexyl-ethyl)-amide;
3-[l,4']Bipiperidinyl- -ylmethyl-2-thiophen-2-yl-quinoline-4-carboxylic acid ((S)-l- cyclohexyl-ethyl)-amide;
3-[ 1 ,4']Bipiperidinyl- 1 '-ylmethyl-2-(4-fluoro-phenyl)-quinoline-4-carboxylic acid ((S)- 1 - cyclohexyl-ethyl)-amide; 3-[l,4l]Bipiperidinyl- -ylmethyl-2-(4-trifluoromethyl-phenyl)-quinoline-4-carboxylic acid ((S)-l-cyclohexyl-ethyl)-amide; and
3-[ 1 ,4']Bipiperidinyl- 1 '-ylmethyl-2-(2-fluoro-phenyl)-quinoline-4-carboxylic acid ((S)- 1 - cyclohexyl-ethyl)-amide.
Preferably, R is H.
Suitably, R2 is aryl or cycloalkyl. Preferably, R2 is cyclohexyl.
Suitably, R3 is alkyl. Preferably, R3 is methyl.
Suitably, R4 is NRgR9 wherein Rg and R9 together with the N atom to which they are attached form a heterocyclic ring comprising 4-8 ring members, said ring members optionally including in addition to said N atom one or more further heteroatoms selected from N, O or S; said heterocyclic ring being saturated or unsaturated and optionally substituted one or more times by hydroxy, oxo, alkyl, aminoalkyl, di-alkylaminoalkyl and -C(=O)NHRι 5, and wherein said ring may be optionally fused or linked by a single bond or an alkyl chain to one or more cycloalkyl, heterocyclyl or aryl groups, which cycloalkyl, heterocyclyl or aryl groups are unsubstituted or are substituted one or more times by halo, haloalkyl, oxo and aryl. Preferably R4 is NRgR9 wherein Rg and R9 together with the N atom to which they are attached form a heterocyclic ring comprising 4-8 ring members, said ring members optionally including in addition to said N atom one or more further heteroatoms selected from N, O or S; said heterocyclic ring being saturated or unsaturated and being substituted one or more times by hydroxy, oxo, alkyl, aminoalkyl, di-alkylaminoalkyl and -C(=O)NHRi5, and wherein said ring may be optionally fused or linked by a single bond or an alkyl chain to one or more cycloalkyl, heterocyclyl or aryl groups, which cycloalkyl, heterocyclyl or aryl groups are unsubstituted or are substituted one or more times by halo, haloalkyl, oxo and aryl.
Suitably, R5 is aryl or an aromatic heterocyclic group. Preferably, R5 is phenyl or 3- thienyl. Suitably, R is H or fluoro.
Suitably, Rγ is H or fluoro.
Suitably, a is 1, 2 or 3. Preferably, a is 1.
In some embodiments of the invention, Rg is H or Rj j Ri 2 where R12 is H or OH. R\ 1 may be C 1.3 alkyl. Alternatively, R\ \ may be 3°-alkylaminoalkyl, such as R15NR16R17 where each of R15, Rjg and R17 is independently selected from methyl, ethyl and propyl. For example, R\ζ may be propyl. Suitably, each of Rjg and R\η may be the same one of methyl, ethyl or propyl, such as ethyl.
In some embodiments, R9 is R13 R14, where R13 is a single bond and R14 is a saturated heterocyclic ring comprising one N heteroatom. Said saturated heterocyclic ring may for example be a 5-7 -membered ring. Optionally, said saturated heterocyclic ring may be substituted once by phenylalkyl such as phenylmethyl. Said saturated heterocyclic ring may additionally or alternatively be fused to a benzene ring.
In other embodiments, R9 is Ri 3 R1 , and R13 is Cχ_3 alkyl such as methyl, whilst Ri 4 is a ring moiety such as phenyl.
In another aspect of the invention, Rg and R9 together with the N atom to which they are attached form a 5-7 -membered saturated heterocyclic ring. Said heterocyclic ring may for example have six ring members. Optionally, said heterocyclic ring may comprise one additional heteroatom which is N or S. Advantageously, said heterocyclic ring may be fused or linked to an aryl group such as a benzene ring. In especially preferred embodiments, said heterocyclic ring comprises one additional heteroatom which is N, which one additional N atom is linked to a phenyl substituent. Said heterocyclic ring may optionally be substituted once by oxo or hydroxy. In preferred embodiments of the invention, R] is H, R2 is cyclohexyl, R3 is methyl, R5 is phenyl, Rg is H, R7 is H, a is 1 and R4 is selected from the following substituents:
R4
Figure imgf000014_0001
"-" O H — N /
Figure imgf000014_0002
~o=° N NH
H2N In further preferred embodiments of the invention, Rj is H, R2 is unsubstituted cyclohexyl, R3 is unsubstituted methyl, R5 is unsubstituted phenyl, Rg is H, R7 is 6-F, a is 1 and R4 is selected from the following substituents:
Figure imgf000015_0001
Particularly preferred compounds of formula (I) which are of special interest as agents useful in the treatment and/or prophylaxis of conditions which are characterised by overstimulation of the Tachykinin receptors, in particular NK3 and NK2, are those listed in Table 4 below.
The compounds of formula (I) may have at least one asymmetric centre - for example the carbon atom labelled with an asterisk (*) in the compound of formula (I) - and therefore may exist in more than one stereoisomeric form. The invention extends to all such stereoisomeric forms and to mixtures thereof, including racemates. In particular, the invention includes compounds wherein the asterisked carbon atom in formula (I) has the stereochemistry shown in formula (la):
Figure imgf000015_0002
wherein Ri , R2, R3, R5, Rg, and R7 are as defined in relation to formula (I), and X represents the moiety -R,
The compounds of formula (I) or their salts or solvates are preferably in pharmaceutically acceptable or substantially pure form. By pharmaceutically acceptable form is meant, inter alia, having a pharmaceutically acceptable level of purity excluding normal pharmaceutical additives such as diluents and carriers, and including no material considered toxic at normal dosage levels.
A substantially pure form will generally contain at least 50% (excluding normal pharmaceutical additives), preferably 75%, more preferably 90% and still more preferably 95% of the compound of formula (I) or its salt or solvate.
One preferred pharmaceutically acceptable form is the crystalline form, including such form in pharmaceutical composition. In the case of salts and solvates the additional ionic and solvent moieties must also be non-toxic. Suitable salts are pharmaceutically acceptable salts.
Suitable pharmaceutically acceptable salts include the acid addition salts with the conventional pharmaceutical acids, for example maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric, succinic, benzoic, ascorbic and methanesulphonic. Suitable pharmaceutically acceptable salts include salts of acidic moieties of the compounds of formula (I) when they are present, for example salts of carboxy groups or phenolic hydroxy groups.
Suitable salts of acidic moieties include metal salts, such as for example aluminium, alkali metal salts such as lithium, sodium or potassium, alkaline earth metal salts such as calcium or magnesium and ammonium or substituted ammonium salts, for example those with lower alkylamines such as triethylamine, hydroxy alkylamines such as 2-hydroxyethylamine, bis-(2-hydroxyethyl)-amine or tri-(2-hydroxyethyl)-amine, cycloalkylamines such as bicyclohexylamine, or with procaine, dibenzylpiperidine, N-benzyl- D -phenethylamine, dehydroabietylamine, N,N'-bisdehydroabietylamine, glucamine, N-methylglucamine or bases of the pyridine type such as pyridine, collidine, quinine or quinoline.
Suitable solvates are pharmaceutically acceptable solvates.
Suitable pharmaceutically acceptable solvates include hydrates. The term 'alkyl' (unless specified to the contrary) when used alone or when forming part of other groups (such as the 'alkoxy' group) includes straight- or branched-chain alkyl groups containing 1 to 12, preferably 1-6 carbon atoms, examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl group.
The term 'cycloalkyl' (unless specified to the contrary) when used alone or when forming part of other groups (such as the 'cycloalkylalkyl' group) includes cyclic saturated or unsaturated carbon rings including 3-12, preferably 3-8 carbon ring members. Examples include cyclopropyl, cyclobutyl, cyclohexyl, cyclooctyl.
The term 'alkenyl' (unless specified to the contrary) when used alone or when foπning part of other groups includes straight- or branched- unsaturated carbon chains including at least one double C=C bond and containing 2-12, preferably 2-6 carbon atoms.
The term 'carbocyclic' refers to cycloalkyl and aryl rings.
The term 'aryl' includes phenyl and naphthyl, preferably phenyl which unless specified to the contrary optionally comprise up to five, preferably up to three substituents selected from halogen, alkyl, phenyl, alkoxy, haloalkyl, hydroxyalkyl, hydroxy, amino, nitro, cyano, carboxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyloxy, or alkylcarbonyl groups.
The term 'aromatic heterocyclic group' includes groups comprising aromatic heterocyclic rings containing from 5 to 12 ring atoms, suitably 5 or 6, and comprising up to four hetero-atoms in the or each ring selected from S, O or N.
Composite terms such as 'alkylcarboxy', 'cycloalkylalkyl' and so forth refer to components of a compound which include two interlinked groups, with the group named latterly in the term being the linking group, so that 'alkylcarboxy' means (alkyl)-COO- whilst 'cycloalkylalkyl' means (cycloalkyl)-(alkyl)-. Unless specified to the contrary, suitable substituents for any heterocyclic group includes up to 4 substituents selected from the group consisting of: alkyl, alkoxy, aryl and halogen or any two substituents on adjacent carbon atoms, together with the carbon atoms to which they are attached, may form an aryl group, preferably a benzene ring, and wherein the carbon atoms of the aryl group represented by the said two substituents may themselves be substituted or unsubstituted.
It will be understood that, unless otherwise specified, groups and substituents forming part of a compound in accordance with the invention are unsubstituted.
- When used herein the term "halogen" or "halo" refers to fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine or bromine.
When used herein the term "acyl" includes residues of acids, in particular a residue of a carboxylic acid such as an alkyl- or aryl- carbonyl group.
The invention also provides in one aspect a process for the preparation of a compound of formula (I), or a salt thereof and/or a solvate thereof, which process comprises reacting a compound of formula (II) or an active derivative thereof:
Figure imgf000018_0001
(II)
wherein R'g, R'7, R'5 and X' are Rg, R7, R5 and X respectively as hereinbefore defined in relation to formula (I) or (la), or a group convertible to Rg, R7, R5 and X respectively; with a compound of formula (III):
'. (Ill)
wherein R'j, R'2, and R'3 are R\, R2, and R3 as defined for formula (I) or a group or atom convertible to R\, R2, and R3 respectively; to form a compound of formula (lb):
Figure imgf000019_0001
wherein R'j, R'2, R'3, X', R'5, R'g and R'7 are as defined above, and thereafter carrying out one or more of the following optional steps:
(i) converting any one of R'ι, R'2, R'3, X', R'5, R'g and R'7 to Rj, R2, R3, X, R5, Rg and R7 respectively as required, to obtain a compound of formula (I);
(ii) converting a compound of formula (I) into another compound of formula (I); and (iii) preparing a salt of the compound of formula (I) and/or a solvate thereof.
Suitable groups convertible into other groups include protected forms of said groups. Suitably R'ι, R'2, R'3, X', R'5, R'g and R'7 each represents Ri , R2, R3, X, R5, Rg and R7 respectively or a protected form thereof.
It is favoured if the compound of formula (II) is present as an active derivative. A suitable active derivative of a compound of formula (II) is a transient activated form of the compound of formula (II) or a derivative wherein the carboxy group of the compound of formula (II) has been replaced by a different group or atom, for example by an acyl halide, preferably a chloride, or an acylazide or a carboxylic acid anhydride.
Other suitable active derivatives include: a mixed anhydride formed between the carboxyl moiety of the compound of formula (II) and an alkyl chloroformate; an activated ester, such as a cyanomethyl ester, thiophenyl ester, p-nitrophenyl ester, p- nitrothiophenyl ester, 2,4,6-trichlorophenyl ester, pentachlorophenyl ester, pentafluorophenyl ester, N-hydroxy-phtalimido ester, N-hydroxypiperidine ester, N- hydroxysuccinimide ester, N-hydroxy benzotriazole ester; alternatively, the carboxy group of the compound of formula (II) may be activated using a carbodiimide or N,N'- carbonyldiimidazole. The reaction between the compound of formula (II) or the active derivative thereof and the compound of formula (III) is carried out under the appropriate conventional conditions for the particular compounds chosen. Generally, when the compound of formula (II) is present as an active derivative the reaction is carried out using the same solvent and conditions as used to prepare the active derivative, preferably the active derivative is prepared in situ prior to forming the compound of formula (lb) and thereafter the compound of formula (I) or a salt thereof and/or a solvate thereof is prepared.
For example, the reaction between an active derivative of the compound of formula (II) and the compound of formula (III) may be carried out:
- (a) by first preparing an acid chloride and then coupling said chloride with the compound of formula (III) in the presence of an inorganic or organic base in a suitable aprotic solvent such as dimethylformamide (DMF) at a temperature in a range from -70 to 50°C (preferably in a range from -10 to 20°C); or (b) by treating the compound of formula (II) with a compound of formula (III) in the presence of a suitable condensing agent, such as for example N,N'-carbonyl diimidazole (CDI) or a carbodiimide such as dicyclohexylcarbodiimide (DCC) or N- dimethylaminopropyl-N'-ethylcarbodiimide, preferably in the presence of N- hydroxybenzotriazole (HOBT) to maximise yields and avoid racemization processes (see Synthesis, 453, 1972), or O-benzotriazol-l-yl-N,N,N',N'- tetramethyluroniumhexafluorophosphate (HBTU), in an aprotic solvent, such as a mixture of acetonitrile (MeCN) and tetrahydrofuran (THF), for example a mixture in a volume ratio of from 1:9 to 7:3 (MeCN: THF), at any temperature providing a suitable rate of formation of the required product, such as a temperature in the range of from -70 to 50°C, preferably in a range of from -10 to 25°C, for example at 0°C. A preferred reaction is set out in Scheme 1 shown below:
Scheme 1
Figure imgf000020_0001
wherein R' , R'2, R'3, X', R'5, R'g and R'7 are as defined above.
In the case in which the corresponding alkyl (such as methyl or ethyl) ester of compound (II) is utilised, an hydrolysis to compound (II) is required before conversion to compound (lb) in Scheme 1. Such hydrolysis can be carried out under acidic conditions, such 10-36% hydrochloric acid at a temperature in the range between 30 and 100 °C.
It will be appreciated that a compound of formula (lb) may be converted to a compound of formula (I), or one compound of formula (I) may be converted to another compound of formula (I) by interconversion of suitable substituents. Thus, certain compounds of formula (I) and (lb) are useful intermediates in forming other compounds of the present invention.
Accordingly, in a further aspect the invention provides a process for preparing a compound of formula (I), or a salt thereof and/or a solvate thereof, which process comprises converting a compound of the above defined formula (lb) wherein at least one of R'ι, R'2, R'3, X', R'5, R'g and R'7 is not Ri , R2, R3, X, R5, Rg or R7 respectively, thereby to provide a compound of formula (I); and thereafter, as required, carrying out one or more of the following optional steps:
(i) converting a compound of formula (I) into another compound of formula (I); and (ii) preparing a salt of the compound of formula (I) and/or a solvate thereof.
Suitably, in the compound of formula (lb) the variables R' , R'2, R'3, X', R'5, R'g and R'7 are Ri , R2, R3, X, R5, Rg and R7 respectively or they are protected forms thereof.
The above mentioned conversions, protections and deprotections are carried out using the appropriate conventional reagents and conditions and are further discussed below.
A chiral compound of formula (III) wherein R2 is a C5 or C7 cycloalkyl group, R3 is methyl and R is H are described in J. Org. Chem. (1996), 61 (12), 4130-4135. A chiral compound of formula (III) wherein R2 is phenyl, R3 is isopropyl and R^ is H is a known compound described in for example Tetrahedron Lett. ( 1994), 35(22), 3745-6.
The compounds of formula (III) are known commercially available compounds or they can be prepared from known compounds by known methods, or methods analogous to those used to prepare known compounds, for example the methods described in Liebigs Ann. der Chemie, (1936), 523, 199. In some embodiments of the invention, a compound of formula (II) or the corresponding alkyl (such as methyl or ethyl) ester is prepared by reacting a compound of formula (IV) or the corresponding alkyl (such as methyl or ethyl) ester:
Figure imgf000022_0001
wherein R'g, R'7, R'5 and a are as defined above and Lj represents a halogen atom such as a bromine atom, with a compound of formula (V):
H-R\
(V) wherein R'4 is R4 as defined in relation to formula (I) or a protected form thereof. Suitably, R'4 is R4.
Suitably, reaction between the compounds of formulae (IV) or the corresponding alkyl (such as methyl or ethyl) ester and (V) is carried out under conventional amination conditions, for example when L is a bromine atom then the reaction is conveniently carried out in an aprotic solvent, such as tetrahydrofuran or dimethylformamide at any temperature providing a suitable rate of formation of the required product, usually at ambient temperature; preferably the reaction is carried out in the presence of triethylamine (TEA) or K2CO3.
The compounds of formula (V) are known, commercially available compounds or they can be prepared using methods analogous to those used to prepare known compounds; for example the methods described in the Chemistry of the Amino Group, Patais (Ed.), Interscience, New York 1968; Advanced Organic Chemistry, March J, John Wiley & Sons, New York, 1992 ; J. Heterocyclic Chem. (1990), 27, 1559; Synthesis (1975), 135, Bioorg. Med. Chem. Lett. (1997), 7, 555, or Protective Groups in Organic Synthesis (second edition), Wiley Interscience, (1991) or other methods mentioned herein. In cases where a is 1, a compound of formula (IV) or the corresponding alkyl (such as methyl or ethyl) ester may be prepared by appropriate halogenation of a compound of formula (VI) or the corresponding alkyl (such as methyl or ethyl) ester:
Figure imgf000023_0001
wherein R'g, R'7 and R'5 are as defined above in relation to formula (II).
Suitable halogenation reagents are conventional reagents depending upon the nature of the halogen atom required, for example when Li is bromine a preferred halogenation reagent is N-bromosuccinimide (NBS). The halogenation of the compound of formula (VI) or the corresponding alkyl
(such as methyl or ethyl) ester is suitably carried out under conventional conditions, for example bromination is carried out by treatment with NBS in an inert solvent, such as carbon tetrachloride CCI4, or 1,2-dichloroethane or CH3CN, at any temperature providing a suitable rate of formation of the required product, suitably at an elevated temperature such as a temperature in the range of 60°C to 100°C, for example 80°C; preferably the reaction is carried out in the presence of a catalytic amount of benzoyl peroxide.
A compound of formula (VI) is conveniently prepared by reacting a compound of formula (VII):
Figure imgf000023_0002
wherein R'g and R*7 are as defined in relation to formula (II), with a compound of formula (XIII):
R '-CO- CH - Me (χm) wherein R'5 is as defined in relation to formula (II).
The reaction between the compounds of formula (VII) and (XIII) is conveniently carried out using Pfitzinger reaction conditions (see for example J. Prakt. Chem. 33, 100 (1886), J. Prakt. Chem. 38, 582 (1888), J. Chem. Soc. 106 (1948) and Chem. Rev. 35, 152 (1944)). For example in an alkanolic solvent such as ethanol, at any temperature providing a suitable rate of formation of the required product, but generally at an elevated temperature, such as the reflux temperature of the solvent, and preferably in the presence of a base such as potassium hydroxide or potassium tert-butoxide. It will be appreciated that the Pfitzinger reaction can be also carried out in presence of an acid, such as acetic acid or hydrochloric acid, at any temperature providing a suitable rate of formation of the required product, but generally at an elevated temperature, as described in J. Med. Chem. 38, 906 (1995).
The compounds of formula (VII) are known compounds or they are prepared according to methods used to prepare known compounds for example those disclosed in J. Org. Chem. 21, 171 (1955); J. Org. Chem. 21, 169 (1955).
Alternatively a compound of formula (VI) may be conveniently prepared by reacting a compound of formula (XIV)
Figure imgf000024_0001
wherein R'g and R'7 are as defined in relation to formula (II), with a compound of formula (XV):
R. CHO
(XV)
wherein R'5 is as defined in relation to formula (II) in presence of oxobutyric acid.
The reaction between the compounds of formula (XIV) and (XV) is conveniently carried out using Doebner reaction conditions (see for example Chem. Ber. 29, 352 (1894); Chem. Revs. 35, 153, (1944); J. Chem. Soc. B, 1969, 805), for example in an alcoholic solvent such as ethanol, at any temperature providing a suitable rate of formation of the required product, but generally at an elevated temperature, such as the reflux temperature of the solvent.
The compounds of formula (XIV) and (XV) are known compounds or they are prepared according to methods used to prepare known compounds for example as described in Vogel's Textbook of Practical Organic Chemistry.
In some alternative embodiments of the invention, a compound of formula (II) wherein X' represents
Figure imgf000025_0001
is prepared by reacting a compound of formula (VII) as defined above with a compound of formula (VIII):
R5'— CO - CH2— (CH2)a— T5 (Vffl)
wherein R'5 is as defined in relation to formula (II), and T5 is a group
R'4-Y
where Y is a protecting group such as a benzyl group, particularly a protecting group which is stable in basic conditions such as a terbutoxycarbonyl group; and a is as defined in relation to formula (II); and thereafter as required removing any protecting group, for example by dehydrogenation, and/or converting any group T5 to R4.
The reaction between the compounds of formula (VII) and (VIII) is conveniently carried out using Pfitzinger reaction conditions (see for example J. Prakt. Chem. 33, 100 (1886), J. Prakt. Chem. 38, 582 (1888), J. Chem. Soc. 106 (1948) and Chem. Rev. 35, 152 (1944)), for example in an alkanolic solvent such as ethanol, at any temperature providing a suitable rate of formation of the required product, but generally at an elevated temperature, such as the reflux temperature of the solvent, and preferably in the presence of a base such as potassium hydroxide or potassium tert-butoxide.
Protected forms of R4 will vary according to the particular nature of the group being protected but will be chosen in accordance with normal chemical practice. Groups convertible to R4 include groups dictated by conventional chemical practice to be required and to be appropriate, depending upon the specific nature of the R4 under consideration.
Suitable deprotection methods for deprotecting protected forms of R4 and conversion methods for converting T5 to R4 will be those used conventionally in the art depending upon the particular groups under consideration with reference to standard texts such as Greene, T.W. and Wuts, P.G.M. Protective Groups in Organic Synthesis, John Wiley & Sons Inc. New York, 1991 (Second Edt.) or in Kocienski, P.J. Protecting groups. George Thieme Verlag, New York, 1994 and Chemistry of the Amino Group, Patais (Ed.), Interscience, New York 1968; or Advanced Organic Chemistry, March J, John Wiley & Sons, New York, 1992.
A compound of formula (VIII) is prepared from a compound of formula (IX):
R5'— CO - CH2— (CH2)a— OH
(IX) wherein R'5 is as defined in relation to formula (II) and a is as defined in relation to formula (VIII), by first halogenating, preferably brominating, or mesylating the compound of formula (IX) and thereafter reacting the halogenation or mesylation product so formed with a compound capable of forming a group T5 so as to provide the required compound of formula (VII).
When T5 is a group R4, a compound capable of forming a group T5 is a compound of the above defined formula (V).
The halogenation of the compound of formula (IX) is suitably carried out using a conventional halogenation reagent. Mesylation is conveniently carried out using mesyl chloride in an inert solvent such as methylene dichloride, at a temperature below room temperature, such as 0°C, preferably in the presence of triethylamine.
The reaction conditions between the compound of formula (IX) and the compound capable of forming a group T5 will be those conventional conditions dictated by the specific nature of the reactants, for example when the T5 required is a group R4 and the required compound capable of forming a group T5 is a compound of the above defined formula (V), then the reaction between the halogenation or mesylation product of the compound of formula (IX) and the compound of formula (V) is carried out under analogous conditions to those described for the reaction between the compounds of formulae (IV) and (V).
Other compounds capable of forming a group T5 will depend upon the particular nature of T5, but will be those appropriate compounds dictated by conventional chemical practice with reference to standard texts such as Chemistry of the Amino Group, Patais (Ed.), Interscience, New York 1968; and Advanced Organic Chemistry, March J, John Wiley & Sons, New York, 1992.
A compound of formula (IX) may be prepared by reacting a compound of formula (X):
Figure imgf000027_0001
wherein a is as defined in relation to formula (VIII), with a lithium salt of formula (XI):
R1 Li 5 (XI) wherein R'5 is as defined in relation to formula (II).
The reaction between the compounds of formulae (X) and (XI) can be carried out in an aprotic solvent, such as diethyl-ether at any temperature providing a suitable rate of formation of the required product, usually at a low temperature such as in the range of -
10°C to -30°C, for example -20°C. The compounds of formula (VII) are known compounds or they are prepared according to methods used to prepare known compounds for example those disclosed in
J. Org. Chem. 21, 171 (1955); J. Org. Chem. 21, 169 (1955).
The compounds of formula (X) and (XI) are known compounds or they are prepared according to methods used to prepare known compounds for example those disclosed by Rrow G. R. in Organic Reactions, Vol 43, page 251 , John Wiley & Sons
Inc.1994 (for the compounds of formula (X)) and Organometallics in Synthesis,
Schlosser M.(Ed), John Wiley & Sons Inc.1994 (for the compounds of formula (XI)).
In another aspect, the present invention provides a process for the preparation of a compound of formula (I), or a salt thereof and/or a solvate thereof, wherein a is 1, which process comprises reacting a compound of formula (XVI):
Figure imgf000028_0001
wherein each of R'ι, R'2, R'3, R'5, R'g, and R'7 is respectively R\, R2, R3, R5, Rg, or R7 as defined above or a group convertible to R , R2, R3, R5, Rg, or R7 respectively as defined above providing R'2 is not aromatic in character, and Lj represents a halogen atom such as a bromine atom, with a compound of formula (XVII):
H-R'„
(XVII) wherein R'4 is R4 as defined in relation to formula (I) or a protected form thereof or a group convertible thereto; and thereafter carrying out one or more of the following optional steps:
(i) converting any one of R'ι , R'2, R'3, R'4, R'5, R'g and R'7 to Ri , R2, R3, R4, R5,
Rg and R7 respectively as required, to obtain a compound of formula (I);
(ii) converting a compound of formula (I) into another compound of formula (I); and
(iii) preparing a salt of the compound of formula (I) and or a solvate thereof. Protected forms of R4 will vary according to the particular nature of the group being protected but will be chosen in accordance with normal chemical practice.
Groups convertible to R4 include groups dictated by conventional chemical practice to be required and to be appropriate, depending upon the specific nature of the
R4 under consideration. Suitable deprotection methods for deprotecting protected forms of R4 and conversion methods for converting R'4 to R4 will be those used conventionally in the art depending upon the particular groups under consideration with reference to standard texts such as Greene, T.W. and Wuts, P.G.M. Protective Groups in Organic Synthesis, John Wiley & Sons Inc. New York, 1991 (Second Edt.) or in Kocienski, P.J. Protecting groups. George Thieme Verlag, New York, 1994 and Chemistry of the Amino Group, Patais (Ed.), Interscience, New York 1968; or Advanced Organic Chemistry, March J, John Wiley & Sons, New York, 1992.
Suitable groups convertible into other groups include protected forms of said groups.
Advantageously, a compound of formula (XVII) will be a compound of formula (V) as defined above. Suitably R'ι , R'2, R'3, R'4, R'5, R'g and R'7 each represents R , R2, R3, R4, R5,
Rg and R7 respectively or a protected form thereof.
Suitable deprotection methods for deprotecting protected forms of R , R2, R3, R4, R5, Rg and R7 and conversion methods for converting R'1 , R'2, R'3, R'4, R'5, R'g and R'7 to Ri , R2, R3, R4, R5, Rg and R7 respectively will be those used conventionally in the art depending upon the particular groups under consideration with reference to standard texts such as Greene, T.W. and Wuts, P.G.M. Protective Groups in Organic Synthesis, John Wiley & Sons Inc. New York, 1991 (Second Edt.) or in Kocienski, P.J. Protecting groups. George Thieme Verlag, New York, 1994 and Chemistry of the Amino Group, Patais (Ed.), Interscience, New York 1968; or Advanced Organic Chemistry, March J, John Wiley & Sons, New York, 1992.
Suitably, reaction between the compounds of formulae (XVI) and (XVII) is carried out under conventional amination conditions, for example when Li is a bromine atom then the reaction is conveniently carried out in an aprotic solvent, such as tetrahydrofuran or dimethylformamide or acetonitrile at any temperature providing a suitable rate of formation of the required product, usually at ambient temperature; preferably the reaction is carried out in the presence of triethylamine (TEA), sodium hydride or K2CO3.
The compounds of formula (XVII) are known, commercially available compounds or they can be prepared using methods analogous to those used to prepare known compounds; for example the methods described in the Chemistry of the Amino Group, Patais (Ed.), Interscience, New York 1968; Advanced Organic Chemistry, March J, John Wiley & Sons, New York, 1992 ; J. Heterocyclic Chem. (1990), 27, 1559; Synthesis (1975), 135, Bioorg. Med. Chem. Lett. (1997), 7, 555, or Protective Groups in Organic Synthesis (second edition), Wiley Interscience, (1991) or other methods mentioned herein.
A compound of formula (XVI) is prepared by appropriate halogenation of a compound of formula (XVIII) :
Figure imgf000030_0001
(XVIII) wherein R'j, R'2, R'3, R'5, R'g, and R'7 are as defined above in relation to formula (XVI). Suitable halogenation reagents are conventional reagents depending upon the nature of the halogen atom required, for example when Li is bromine a preferred halogenation reagent is N-bromosuccinimide (NBS).
The halogenation of the compound of formula (XVIII) is carried out under conventional conditions, for example bromination is carried out by treatment with NBS in an inert solvent, such as carbon tetrachloride CC14, or 1,2-dichloroethane or CH3CN, at any temperature providing a suitable rate of formation of the required product, suitably at an elevated temperature such as a temperature in the range of 60°C to 100°C, for example 80°C; preferably the reaction is carried out in the presence of a catalytic amount of benzoyl peroxide. Suitably, the compound of formula (XVIII) may be prepared by reacting a compound of formula (VI) as defined above or an active derivative thereof with a compound of formula (III) as defined above wherein R'2 is not aromatic in character.
It is favoured if the compound of formula (VI) is present in the reaction mix as an active derivative, as hereinbefore described. The reaction between the compound of formula (VI) or the active derivative thereof and the compound of formula (III) is carried out under the appropriate conventional conditions for the particular compounds chosen. Generally, when the compound of formula (VI) is present as an active derivative the reaction is carried out using the same solvent and conditions as used to prepare the active derivative, preferably the active derivative is prepared in situ prior to forming the compound of formula (XVIII).
For example, the reaction between an active derivative of the compound of formula (VI) and the compound of formula (III) may be carried out:
(a) by first preparing an acid chloride and then coupling said chloride with the compound of formula (III) in the presence of an inorganic or organic base in a suitable aprotic solvent such as methylene dichloride or tetrahydrofuran at a temperature in a range from -70 to 50°C (preferably in a range from 20°C to reflux temperature); or (b) by treating the compound of formula (VI) with a compound of formula (III) in the presence of a suitable condensing agent, such as for example N,N'-carbonyl diimidazole (CDI) or a carbodiimide such as dicyclohexylcarbodiimide (DCC) or N- dimethylaminopropyl-N'-ethylcarbodiimide, preferably in the presence of N- hydroxybenzotriazole (HOBT) to maximise yields and avoid racemization processes (see Synthesis, 453, 1972), or O-benzotriazol-l-yl-N,N,N',N'- tetramethyluroniumhexafluorophosphate (HBTU), in an aprotic solvent, such as a mixture of acetonitrile (MeCN) and tetrahydrofuran (THF), for example a mixture in a volume ratio of from 1:9 to 7:3 (MeCN:THF), at any temperature providing a suitable rate of formation of the required product, such as a temperature in the range of from -70 to 50°C, preferably in a range of from -10 to 25°C, for example at 0°C. A preferred reaction is set out in Scheme 2 shown below:
Scheme 2
Figure imgf000031_0001
(VI) (Ill) (XVIII) In the case in which the corresponding alkyl (such as methyl or ethyl) ester of compounds (VI) is utilised, a hydrolysis is required before conversion to compound (XVIII) in Scheme 2. Such hydrolysis can be carried out under acidic conditions, such 10-36% hydrochloric acid at a temperature in the range between 30 and 100 °C.
As hereinbefore mentioned, the compounds of formula (I) may exist in more than one stereoisomeric form - and the process of the invention may produce racemates as well as enantiomerically pure forms. Accordingly, a pure enantiomer of a compound of formula (I) can be obtained by reacting a compound of the above defined formula (II) with an appropriate enantiomerically pure primary amine of formula (Ilia) or (IIIc):
Figure imgf000032_0001
(Ilia) (IIIc) wherein R'i , R'2 and R'3 are as defined above, to obtain a compound of formula (I'a) or (I'c):
Figure imgf000032_0002
(I'a) (I'c) wherein R'j, R'2, R'3, X', R'5, R'g, and R'7 are as defined above. Compounds of formula (I'a) or (I'c) may subsequently be converted to compounds of formula (la) or (Ic) by the methods of conversion mentioned before:
Figure imgf000032_0003
(la) (Ic)
wherein R^, R2, R3, X, R5, Rg, and R7 are as defined above. Suitably, in the above mentioned compounds of formulae (la), (Ic), (I'a), (I'c), (Ilia) and (IIIc) R\ represents hydrogen.
An alternative method for separating optical isomers is to use conventional, fractional separation methods in particular fractional crystallization methods. Thus, a pure enantiomer of a compound of formula (I) is obtained by fractional crystallisation of a diastereomeric salt formed by reaction of the racemic compound of formula (I) with an optically active strong acid resolving agent, such as camphosulphonic acid, tartaric acid, O,O'-di-p-toluoyltartaric acid or mandelic acid, in an appropriate alcoholic solvent, such as ethanol or methanol, or in a ketonic solvent, such as acetone. The salt formation process should be conducted at a temperature between 20°C and 80°C, preferably at 50°C. A suitable conversion of one compound of formula (I) into a further compound of formula (I) involves converting one group X into another group X by for example: (i) converting a ketal into a ketone, by such as mild acidic hydrolysis, using for example dilute hydrochloric acid;
(ii) reducing a ketone to a hydroxy group by use of a borohydride reducing agent; (iii) converting a carboxylic ester group into a carboxyl group using basic hydrolysis; and/or
(iv) reducing a carboxylic ester group to a hydroxymethyl group, by use of a borohydride reducing agent.
As indicated above, where necessary, the conversion of any group R'i, R'2, R'3, X', R'5, R'g, and R'7 into R , 2, R3, X, R5, Rg, and R7 which as stated above are usually protected forms of Rj, R2, R3, X, R5, Rg, or R7 may be carried out using appropriate conventional conditions such as the appropriate deprotection procedure.
It will be appreciated that in any of the above mentioned reactions any reactive group in the substrate molecule may be protected and deprotected according to conventional chemical practice, for example as described by Greene, T.W. and Wuts,
P.G.M. Protective Groups in Organic Synthesis, John Wiley & Sons Inc. New York, 1991 (Second Edt.) or in Kocienski, P.J. Protecting groups. George Thieme Verlag, New York, 1994.
Suitable protecting groups in any of the above mentioned reactions are those used conventionally in the art. Thus, for example suitable hydroxy protecting groups include benzyl or trialkylsilyl groups.
The methods of formation and removal of such protecting groups are those conventional methods appropriate to the molecule being protected. Thus for example a benzyloxy group may be prepared by treatment of the appropriate compound with a benzyl halide, such as benzyl bromide, and thereafter, if required, the benzyl group may be conveniently removed using catalytic hydrogenation or a mild ether cleavage reagent such as trimethylsilyl iodide or boron tribromide.
As indicated above, the compounds of formula (I) have useful pharmaceutical properties.
Accordingly the present invention also provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use as an active therapeutic substance.
In particular, the present invention also provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for the treatment or prophylaxis of the Primary and Secondary Conditions. The present invention further provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
The present invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of the Primary and Secondary Conditions.
As mentioned above the Primary conditions include respiratory diseases, such as chronic obstructive pulmonary disease (COPD), asthma, airway hyperreactivity, cough; inflammatory diseases such as inflammatory bowel disease, psoriasis, fibrositis, osteoarthritis, rheumatoid arthritis and inflammatory pain; neurogenic inflammation or peripheral neuropathy, allergies such as eczema and rhinitis; ophthalmic diseases such as ocular inflammation, conjunctivitis, vernal conjuctivitis and the like; cutaneous diseases, skin disorders and itch, such as cutaneous wheal and flare, contact dermatitis, atopic dermatitis, urticaria and other eczematoid dermatitis; adverse immunological reactions such as rejection of transplanted tissues and disorders related to immune enhancement or suppression such as systemic lupus erythematosis; gastrointestinal (GI) disorders and diseases of the GI tract such as disorders associated with the neuronal control of viscera such as ulcerative colitis, Crohn's disease, irritable bowel syndrome (IBS), gastro- exophageous reflex disease (GERD); urinary incontinence and disorders of the bladder function; renal disorders; increased blood pressure, proteinuria, coagulopathy and peripheral and cerebral oedema following pre-eclampsia in pregnancies.
As mentioned above, the Secondary conditions include disorders of the central nervous system such as anxiety, depression, psychosis and schizophrenia; neurodegenerative disorders such as AIDS related dementia, senile dementia of the Alzheimer type, Alzheimer's disease, Down's syndrome, Huntingdon's disease, Parkinson's disease, movement disorders and convulsive disorders (for example epilepsy); demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis and other neuropathological disorders such as diabetic neuropathy, AIDS related neuropathy, chemotherapy-induced neuropathy and neuralgia; addiction disorders such as alcoholism; stress related somatic disorders; reflex sympathetic dystrophy such as shoulder hand syndrome; dysthymic disorders; eating disorders (such as food intake disease); fibrosing and collagen diseases such as scleroderma and eosinophilic fascioliasis; disorders of the blood flow caused by vasodilatation and vasospastic diseases such as angina, migraine and Reynaud's disease and pain or nociception, for example, that is attributable to or associated with any of the foregoing conditions especially the transmission of pain in migraine.
Such a medicament, and a composition of this invention, may be prepared by admixture of a compound of the invention with an appropriate carrier. It may contain a diluent, binder, filler, disintegrant, flavouring agent, colouring agent, lubricant or preservative in conventional manner.
These conventional excipients may be employed for example as in the preparation of compositions of known agents for treating the conditions. Preferably, a pharmaceutical composition of the invention is in unit dosage form and in a form adapted for use in the medical or veterinarial fields. For example, such preparations may be in a pack form accompanied by written or printed instructions for use as an agent in the treatment of the conditions.
The suitable dosage range for the compounds of the invention depends on the compound to be employed and on the condition of the patient. It will also depend, inter alia, upon the relation of potency to absorbability and the frequency and route of administration.
The compound or composition of the invention may be formulated for administration by any route, and is preferably in unit dosage form or in a form that a human patient may administer to himself in a single dosage. Advantageously, the composition is suitable for oral, rectal, topical, parenteral, intravenous or intramuscular administration. Preparations may be designed to give slow release of the active ingredient.
Compositions may, for example, be in the form of tablets, capsules, sachets, vials, powders, granules, lozenges, reconstitutable powders, or liquid preparations, for example solutions or suspensions, or suppositories.
The compositions, for example those suitable for oral administration, may contain conventional excipients such as binding agents, for example syrup, acacia, gelatine, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinyl-pyrrolidone, sodium starch glycollate or microcrystalline cellulose; or pharmaceutically acceptable setting agents such as sodium lauryl sulphate.
Solid compositions may be obtained by conventional methods of blending, filling, tabletting or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. When the composition is in the form of a tablet, powder, or lozenge, any carrier suitable for formulating solid pharmaceutical compositions may be used, examples being magnesium stearate, starch, glucose, lactose, sucrose, rice flour and chalk. Tablets may be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating. The composition may also be in the form of an ingestible capsule, for example of gelatine containing the compound, if desired with a carrier or other excipients. Compositions for oral administration as liquids may be in the form of, for example, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid compositions may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatine, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; aqueous or non-aqueous vehicles, which include edible oils, for example almond oil, fractionated coconut oil, oily esters, for example esters of glycerine, or propylene glycol, or ethyl alcohol, glycerine, water or normal saline; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and if desired conventional flavouring or colouring agents.
The compounds of this invention may also be administered by a non-oral route. In accordance with routine pharmaceutical procedure, the compositions may be formulated, for example for rectal administration as a suppository. They may also be formulated for presentation in an injectable form in an aqueous or non-aqueous solution, suspension or emulsion in a pharmaceutically acceptable liquid, e.g. sterile pyrogen-free water or a parenterally acceptable oil or a mixture of liquids. The liquid may contain bacteriostatic agents, anti-oxidants or other preservatives, buffers or solutes to render the solution isotonic with the blood, thickening agents, suspending agents or other pharmaceutically acceptable additives. Such forms will be presented in unit dose form such as ampoules or disposable injection devices or in multi- dose forms such as a bottle from which the appropriate dose may be withdrawn or a solid form or concentrate which can be used to prepare an injectable formulation.
The compounds of this invention may also be administered by inhalation, via the nasal or oral routes. Such administration can be carried out with a spray formulation comprising a compound of the invention and a suitable carrier, optionally suspended in, for example, a hydrocarbon propellant.
Preferred spray formulations comprise micronised compound particles in combination with a surfactant, solvent or a dispersing agent to prevent the sedimentation of suspended particles. Preferably, the compound particle size is from about 2 to 10 microns. A further mode of administration of the compounds of the invention comprises transdermal delivery utilising a skin-patch formulation. A preferred formulation comprises a compound of the invention dispersed in a pressure sensitive adhesive which adheres to the skin, thereby permitting the compound to diffuse from the adhesive through the skin for delivery to the patient. For a constant rate of percutaneous absorption, pressure sensitive adhesives known in the art such as natural rubber or silicone can be used.
As mentioned above, the effective dose of compound depends on the particular compound employed, the condition of the patient and on the frequency and route of administration. A unit dose will generally contain from 20 to 1000 mg and preferably will contain from 30 to 500 mg, in particular 50, 100, 150, 200, 250, 300, 350, 400, 450, or 500 mg. The composition may be administered once or more times a day for example 2, 3 or 4 times daily, and the total daily dose for a 70 kg adult will normally be in the range 100 to 3000 mg. Alternatively the unit dose will contain from 2 to 20 mg of active ingredient and be administered in multiples, if desired, to give the preceding daily dose. No unacceptable toxicological effects are expected with compounds of the invention when administered in accordance with the invention.
The present invention also provides a method for the treatment and/or prophylaxis of the Primary and Secondary Conditions in mammals, particularly humans, which comprises administering to the mammal in need of such treatment and/or prophylaxis an effective, non-toxic pharmaceutically acceptable amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
The activity of the compounds of the present invention, as NK3 ligands, is determined by their ability to inhibit the binding of the radiolabelled NK3 ligands, [I^I]- [Me-Phe7]-NKB or [^HJ-Senktide, to guinea-pig and human NK3 receptors (Renzetti et al, 1991, Neuropeptide, 18, 104-114; Buell et al, 1992, FEBS, 299(1), 90-95; Chung et al, 1994, Biochem. Biophys. Res. Commun., 198(3), 967-972).
The binding assays utilised allow the determination of the concentration of the individual compound required to reduce by 50% the [ 25I]-[Me-Phe7]-NKB and [^H]- Senktide specific binding to NK3 receptor in equilibrium conditions (IC50).
Binding assays provide for each compound tested a mean IC50 value of 2-5 separate experiments performed in duplicate or triplicate. The most potent compounds of the present invention show IC50 values in the range 0.1-1000 nM. The NK3-antagonist activity of the compounds of the present invention is determined by their ability to inhibit senktide-induced contraction of the guinea-pig ileum (Maggi et al, 1990, Br. J. Pharmacol, 101, 996-1000) and rabbit isolated iris sphincter muscle (Hall et al., 1991, Eur. J. Pharmacol, 199, 9-14) and human NK3 receptors-mediated Ca++ mobilisation (Mochizuki et al, 1994, J. Biol. Chem., 269, 9651-9658). Guinea-pig and rabbit in-vitro functional assays provide for each compound tested a mean Kg value of 3-8 separate experiments, where K3 is the concentration of the individual compound required to produce a 2-fold rightward shift in the concentration-response curve of senktide. Human receptor functional assay allows the determination of the concentration of the individual compound required to reduce by 50% (IC50 values) the Ca" -1" mobilisation induced by the agonist NKB. In this assay, the compounds of the present invention behave as antagonists.
The activity of the compounds of the present invention, as NK-2 ligands, is determined by their ability to inhibit the binding of the radiolabelled NK-2 ligands, [125l]-NKA or [3H]-NKA, to human NK-2 receptors (Aharony et al, 1992, Neuropeptide, 23, 121-130).
The binding assays utilised allow the determination of the concentration of the individual compound required to reduce by 50% the
Figure imgf000039_0001
an(j [3H]-NKA specific binding to NK2 receptor in equilibrium conditions (IC50).
Binding assays provide for each compound tested a mean IC50 value of 2-5 separate experiments performed in duplicate or triplicate. The most potent compounds of the present invention show IC50 values in the range 0.5-1000 nM, such as 1-1000 nM. The NK-2-antagonist activity of the compounds of the present invention is determined by their ability to inhibit human NK-2 receptor-mediated Ca"1-1" mobilisation (Mochizuki et al, 1994, J. Biol. Chem., 269, 9651-9658). Human receptor functional assay allows the determination of the concentration of the individual compound required to reduce by 50% (IC50 values) the Ca++ mobilisation induced by the agonist NKA. In this assay, the compounds of the present invention behave as antagonists. The therapeutic potential of the compounds of the present invention in treating the conditions can be assessed using rodent disease models. As stated above, the compounds of formula (I) are also considered to be useful as diagnostic tools. Accordingly, the invention includes a compound of formula (I) for use as diagnostic tools for assessing the degree to which neurokinin-3 and neurokinin-2 receptor activity (normal, overactivity or underactivity) is implicated in a patient's symptoms. Such use comprises the use of a compound of formula (I) as an antagonist of said activity, for example including but not restricted to Tachykinin agonist-induced inositol phosphate turnover or electrophysiological activation, of a cell sample obtained from a patient. Comparison of such activity in the presence or absence of a compound of formula (I), will disclose the degree of NK-3 and NK-2 receptor involvement in the mediation of agonist effects in that tissue.
The following Descriptions illustrate the preparation of the intermediates, whereas the following Examples illustrate the preparation of the compounds of the invention.
Descriptions and Examples
Description 1. 3-Methyl-2-phenylqumoline 4-carboxylic acid
Isatine (40 g, 0.272 mol) is suspended in EtOH (1 1) and KOH (62.8 g, 1.1 mol). Suspension is stirred for 30 min. Propiophenone (36.2 cc, 0.272 mol) was added and the reaction was refluxed for 4 h. The reaction was left overnight at room temperature and then EtOH was evaporated under vacuum. The solid was dissolved in water (400 ml) and washed with Et2θ. The aqueous phase was acidified with citric acid (saturated solution) and a solid was obtained. The solid was filtered by suction, washed with water and dried in oven to obtain the title compound, mp > 280°C.
Description 2. ((S)-l-Cyclohexyl-ethyl)-3-methyl-2-phenylquinoline-4-carboxamide
4-Carboxy-3-methyl-2-phenylquinoline (40 g, 0.152 mol) prepared as in Description 1, was suspended in CH2C12 (600 ml) and oxalyl chloride (6.6 ml, 0.311 mol) was added drop wise at 0° C under magnetic stirring. After 15 min 2 drops of DMF were added. The reaction was vigorous with gas evolution. The mixture was stirred at room temperature until the solid was completely dissolved (about 2 h). The solution was evaporated. The crude material was re-dissolved in CH C1 (150 ml) and slowly dropped into a suspension of K2CO3 (47 g) and (S)-l-cyclohexylethyl amine (29 ml, 0.196 mol) in CH2C12 (250 ml) maintaining the temperature between 10-15°C. The dark solution was left 1 h at room temperature and 1 h refluxing. The organic phase was then washed with water, NaOH IN, brine, dried over Na2SO4 and then evaporated under vacuum. The crude residue was triturated with EtOAc. After filtration the title compound was obtained, mp = 177-180°C. MW = 372.51 [α]D = +21.77 (c = 0.4 in MeOH).
Description 3. ((S)-l-Cyclohexylethyl)-3-bromomethyl-2-phenylquinoline-4- carboxamide
3-Methyl-2-phenyl-quinoline-4-carboxylic acid ((S)-l-cyclohexyl-ethyl)-amide (9.8 g, 26 mmol; compound prepared as in Description 2) and N-bromosuccinimmide (9.8 g, 55 mmol) were suspended in CCLj (100 ml) and warmed to incipient reflux. Dibenzoyl peroxide (about 300 mg) was carefully added dropwise and the solution was then refluxed for 2 h. The solvent was removed under vacuum and the residue was re- dissolved in CH2C12 (200 ml) and filtered. DCM was then evaporated and the residue was dissolved in EtOAc and washed with a saturated solution of NaHCO3, brine, dried over Na2SO4, filtered and evaporated to give the title compound. The title compound may be used in the next step without further purification, mp: 182- 184°C. MW - 451.41 [α]D = -5.76 (c= 0.5% in CH2C12)
Description 4. 6,7-Difluoro-3-methyl-2-phenyl-quinoline-4-carboxylic acid. A solution of 5,6-difluoroisatine (4.68 g; 25.6 mmol) (prepared as in JACS 1958, 23, 1858) and phenylethylketone (3.40 ml; 25.6 mmol) in glacial acetic acid (150 ml) was stirred for 5 minutes at 105°C. HC1 37% was added (38 ml) and the reaction mixture was stirred at 105°C for 24h. The reaction was then cooled at room temperature and diluted with water (400 ml). Filtration and subsequent drying of the precipitate afforded the title compound as a solid. Description 5. 3-(3-Oxo-piperazin-l-yImethyl)-2-phenyl-quinoline-4-carboxylic acid ((S)-l-cyclohexyl-ethyl)-amide
A solution of 3-bromomethyl-2-phenyl-quinoline-4-carboxylic acid ((S)-l-cyclohexyl- ethyl)-amide (10 g, 22 mmol, prepared as in Description 3), piperazin-2-one (CAS [5625- 67-2]) (3 g, 30 mmol) and ethyldiisopropylamine (11 ml, 66 mmol) in dry THF (200 ml) was stirred for 24 h at room temperature. The solvent was evaporated to dryness in vacuum and the residue was re-dissolved in EtOAc. This mixture was washed with a dilute NaOH solution, with water and dried over Na2SO . After evaporating to dryness, the residue was triturated with Et2O to afford the desired compound, which may be used without further purification.
Description 6. General procedure for piperazinone alkylation
Method A: To a solution of the piperazinone derivative (1 mmol, compound prepared as in Description 5) in anhydrous DMF (10 ml), 60% NaH (2 mmol, 29 mg) was added at 0°C. The dark solution obtained was stirred for 10 minutes at 0°C and then for additional
20 minutes at room temperature. The solution was re-cooled at 0°C and the electrophilic species (1 mmol) were added.
The reaction was stirred overnight then poured into a saturated solution of NaCI and extracted with EtOAc. The organic phases were dried over Na2SO , filtered and evaporated under vacuum to give after purification by flash chromatography the desired compound.
Method B: A mixture of the piperazinone derivative (0.47g, 1 mmol, compound prepared as in Description 5), alkylating reagent (1.2 mmol) and KOH (0.23g, 4 mmol) in anhydrous DMSO (10 ml), was stirred for 36 hours at room temperature. The reaction was diluted with a saturated solution of NaCI and the product was extracted with DCM. The organic phases were dried over Na2SO , filtered and evaporated under vacuum; the residue was purificated by flash chromatography to afford the desired compound.
Description 7. 3-BromomethyI-6,7-difluoro-2-phenyI-quinoIine-4-carboxyIic acid ((S)-l-cyclohexyl-ethyl)-amide The compound was prepared according to Descriptions 2 and 3 starting from the compound in Description 4.
Description 8. 3-Bromomethyl-6-fluoro-2-phenyl-quinoline-4-carboxylic acid ((S)-l- cyclohexyl-ethyl)-amide
The compound was prepared according to Description 1, starting from 5-fluoroisatine CAS[443-69-6] and phenylethylketone, Description 2 and 3.
Description 9. 6-Fluoro-3-(3-oxo-piperazm-l-ylmethyl)-2-phenyl-quinoline-4- carboxylic acid ((S)-l-cyclohexyl-ethyl)-amide
The compound was prepared according to Description 5 starting from the compound of Description 8 and piperazinone (CAS[5625-67-2]).
Description 10. 3-Bromomethyl-2-thiophen-2-yl-quinoline-4-carboxylic acid ((S)-l- cycIohexyl-ethyl)-amide
The compound was prepared according to Description 1, starting from l-thiophen-2-yl- propan-1-one CAS [13679-75-9] and isatine, Description 2 and 3.
Description 11. 3-(3-Oxo-piperazin-l-ylmethyI)-2-thiophen-2-yl-quinoIine-4- carboxylic acid ((S)-l-cyclohexyI-ethyl)-amide
The compound was prepared according to Description 5 starting from the compound of Description 10 and piperazinone (CAS [5625-67-2]).
Description 12. 3-Bromomethy_-2-thiophen-3-yl-quinoline-4-carboxylic acid ((S)-l- cyc_ohexyl-ethyl)-amide
The compound was prepared according to Description 1, starting from l-thiophen-3-yl- propan-1-one CAS [51179-52-3] and isatine, Description 2 and 3.
Description 13. 4-[4-((S)-l-Cyclohexyl-ethylcarbamoyl)-6-fluoro-2-phenyl-quinolin- 3-ylmethyl]-3-oxo-piperazine-l-carboxyIic acid tert-butyl ester
To a suspension of 3 -oxo-piperazine-1 -carboxylic acid tert-butyl ester (0.3 g, 1.5 mmol, CAS [76003-29-7]) in DMF/DMSO 2/1 (10 ml), 60% NaH (60 mg, 1.5 mmol) was added at 0°C. After stirring for 30 minutes a solution of 3-bromomethyl-6-fluoro-2-phenyl- quinoline-4-carboxylic acid ((S)-l-cyclohexyl-ethyl)-amide (0.6 g, 1.3 mmol, prepared according to Description 8) in DMF (3ml) was slowly added. The reaction was stirred for 3 hours at room temperature then poured into a saturated solution of NaCI. The precipitate was filtered and purified by flash chromatography to afford the title compound.
Description 14: Piperazine-1-carboxylic acid tert-butyl ester.
To a solution of piperazine (30 g, 350 mmol) in water (370 ml) and tBuOH (420 ml), a solution of 4N NaOH (70 ml) was added. The mixture was cooled to 0°C and then
BOC2O (38 g, 170 mmol) was added portionwise. After stirring at room temperature for 45 minutes, tBuOH was evaporated under vacuum, the precipitate (diBOCpiperazine) was filtered and water was extracted with CH C12. After drying over Na2SO4 the solvent was removed under vacuum to afford the title compound. MW = 186.25
Description 15: 2-Phenyl-3-piperazin-l-ylmethyl-quinoline-4-carboxylic acid ((S)-l- cyclohexyl-ethyl)-amide.
4-[4-((S)- 1 -Cy clohexy l-ethylcarbamoyl)-2-phenyl-quinolin-3 -ylmethy 1] -piperazine- 1 - carboxylic acid tert-butyl ester (2.5 g, 4.5 mmol, prepared according to Description 5 using piperazine- 1 -carboxylic acid tert-butyl ester (Description 14) as nucleophile) was dissolved in CH2C12 (60 ml) and TFA (3 ml) was added. The red solution was stirred at room temperature overnight; then the solvent and the excess of TFA were removed under vacuum. The residue was dissolved in H2O and washed 2 times with Et2O. The water extract was made alkaline by addition of 2N NaOH solution and the product was extracted with EtOAc. The solvent was evaporated to dryness and the residue was purified by flash chromatography (eluent CH2C12: MeOH 93:7) to afford the title compound.
Description 16. General procedure for synthesis of ureas
A solution of 2-phenyl-3-piperazin-l -ylmethy l-quinoline-4-carboxylic acid ((S)-l- cyclohexyl-ethyl)-amide (0.3 g, 0.65 mmol, prepared according to Description 15), isocyanate (0.65 mmol) in CH3CN (20 ml) was stirred for 1 hour at room temperature. The solvent was evaporated under vacuum; the residue was re-dissolved in EtOAc and washed with a saturated solution of NaCI. The organic layer was dried over Na2SO4, filtered and evaporated. The residue was purified by column chromatography to afford the urea derivative.
Examples from 1 to 15, 17 and 22, in Table 1, were prepared according to the following general procedure:
A solution of 3-bromomethyl-2-phenyl-quinoline-4-carboxylic acid ((S)-l-cyclohexyl- ethyl)-amide (1 mmol, 0.45 g; compound prepared as in Description 3), 1.5 mmol of amine and ethyldiisopropylamine (3 mmol, 0.5 ml) in dry THF (15 ml) was stirred for 24 h at room temperature. The solvent was evaporated to dryness in vacuum and the residue was re-dissolved in EtOAc. This mixture was washed with a dilute NaOH solution, with water and dried over Na2SO4. After evaporating to dryness, the residue was purified by flash chromatography to afford the desired compound.
Example 16. 6-Fluoro-3-[3-oxo-4-(2-piperidin-l-yl-ethyl)-piperazin-l-ylmethyl]-2- phenyl-quinoIine-4-carboxyl_c acid ((S)-l-cycIohexyI-ethyl)-amide.
The compound was prepared following the Description 6 (method A) starting from the compound of Description 9 and l-(2-chloroethyl)piperidine.
Example 18. 3- 3-Oxo-4-(3-piperidin-l-yl-propyl)-piperazin-l-ylmethyl]-2-phenyl- quinoline-4-carboxylic acid ((S)-l-cyclohexyI-ethyl)-amide.
The compound was prepared following the Description 6, method A, starting from the compound of Description 5 and l-3-(chloropropyl)piperidine (CAS[5472-49-l]).
Example 19. 3-(l-Oxo-3,4-dihydro-lH-pyrroIo [l,2-a]pyrazin-2-yImethyl)-2-phenyI- quinoline-4-carboxylic acid (l-cyclohexyl-ethyl)-amide.
The compound was prepared according to Description 13 using 3,4-dihydro-2H- pyrrolo[l,2-a]pyrazin-l-one (CAS [54906-42-2]) and compound of Description 3. Example 20. 3-DimethyIaminomethyI-6-fluoro-2~phenyI-qumoIine-4-carboxyIic acid ((S)-l-cycIohexyl-ethyl)-amide.
The compound was prepared according to Description 5 starting from the compound in Description 8 and dimethylamine.
Example 21. 6-Fluoro-3-(l-oxo-3,4-dihydro-lH-pyrrolo[l,2-a]pyrazin-2-ylmethyl)-2- phenyl-quinoline-4-carboxylic cid ((S)-l-cyclohexyl-ethyl)-amide.
The compound was prepared according to Description 13 starting from the compound of Description 8 and 3,4-dihydro-2H-pyrrolo[l,2-a]pyrazin-l-one (CAS[54906-42-2]).
Example 23. 3-[4-(3-Dimethylamino-propyl)-3-oxo-piperazin-l-ylmethyl]-2-phenyl- quinoline-4-carboxylic acid ((S)-l-cyclohexyl-et_ιyl)-amide.
The compound was prepared following Description 6, method B, starting from the compound prepared in Description 5 and 3-dimethylaminopropylchloride.
Example 24. 3-(4-MethyI-3-oxo-piperazin-l-ylmethyl)-2-phenyl-quino_ine-4- carboxylic acid ((S)-l-cycIohexy_-ethyI)-amide ditrifluoroacetate.
The compound was prepared following Description 6, method A, starting from the compound of Description 5 and methyl iodide.
Example 25. 3-(4-Ethyl-3-oxo-piperazin-l-ylmethyl)-2-phenyl-quinoline-4-carboxylic acid ((S)-l-cyclohexyl-ethyl)-amide.
The compound was prepared following the above Description 6, method A, starting from the compound in Description 5 and ethyl bromide.
Example 26. 3-(2-Oxo-imidazoIidin-l-yImethyI)-2-phenyI-quinoIine-4-carboxyIic acid
((S)-l-cyclohexyl-ethyl)-amide.
A mixture of 3-bromomethyl-2-phenyl-quinoline-4-carboxylic acid ((S)-l-cyclohexyl- ethyl)-amide (0.5g, 1.1 mmol) (prepared as in Description 3), 2-imidazolidone (O.lg, 1.2 mmol, and K2CO3 (0.3 g, 2.2 mmol) in CH3CN (20 ml) was stirred overnight at room temperature. The carbonate was filtered and the solvent evaporated under vacuum. The solid was re-dissolved in EtOAc, washed with 0.5 N NaOH and a saturated solution of NaCI. The organic layer was dried over Na SO4, filtered and evaporated to dryness. The residue was purified on column chromatography (CH2Cl2/MeOH 95/5) to give the title compound.
Example 27. 3-[3-Oxo-4-(2-pyrrolidin-l-yl-ethyl)-piperazin-l-ylmethyl]-2-phenyl- quinoline-4-carboxylic acid ((S)-l-cyclohexyl-ethyl)-amide.
The compound was prepared following Description 6 (method B) starting from the compound of Description 5 and l-(2-chloroethyl)pyrrolidine.
Example 28. 3-[4-(2-DiethyIamino-ethyI)-3-oxo-piperazin-l-ylmethyl]-2-phenyl- quinoline-4-carboxylic acid ((S)-l-cyclohexyl-ethyl)-amide.
The compound was prepared following Description 6 (method B) starting from the compound of Description 5 and 2-diethylaminoethyl chloride.
Example 29. 3-[4-(2-Dimethylamino-ethyl)-3-oxo-piperazin-l-ylmethyl]-2-phenyI- quinoline-4-carboxylic acid ((S)-l-cyclohexyl-ethyl)-amide.
The compound was prepared following Description 6 (method B) starting from the compound in Description 5 and dimethylamino ethyl chloride.
Example 30. 3-[4-(2-Amino-ethyl)-3-oxo-piperazin-l-ylmethyl]-2-phenyl-quinoline-4- carboxylic acid ((S)-l-cyclohexy_-ethyl)-amide.
To a solution of (2-{4-[4-((S)-l-cyclohexyl-ethylcarbamoyl)-2-phenyl-quinolin-3- ylmethyl]-2-oxo-piperazin-l-yl}-ethyl)-carbamic acid tert-butyl ester (30 mg, 0.05 mmol, prepared according to Description 6 (method B) starting from the compound in
Description 5 and 2-(BOC-amino)ethylbromide) in CH2C12 (4 ml), TFA (0.2 ml) was added drop-wise at room temperature. Stirring was continued for 1 hour. The solvent was evaporated under vacuum and the residue was basified with a saturated solution of K2CO3 and extracted with ethyl acetate. The organic layer was dried over Na2SO , filtered and evaporated to give the title compound. Example 31. 3-[4-(2-Morpholin-4-yl-ethyl)-3-oxo-piperazin-l-ylmethyl]-2-phenyl- quinoline-4-carboxylic acid ((S)-l-cyclohexyl-ethyI)-amide.
The compound was prepared following Description 6 (method B) starting from the compound in Description 5 and 4-(2-chloroethyl)morpholine.
Example 32. 3-(4-Ethylcarbamoyl-piperazin-l-ylmethyl)-2-phenyl-quino_me-4- carboxylic acid ((S)-l-cyclohexyl-ethyl)-amide.
The compound was prepared following Description 16 starting from compound in Description 15 and ethylisocyanate.
Example 33. 3-(4-Isopropylcarbamoyl-piperazin-l-ylmethy_)-2-phenyl-qui_ιoline-4- carboxylic acid ((S)-l-cyclohexy_-ethyl)-amide
The compound was prepared following Description 16 starting from the compound of Description 15 and isopropylisocyanate.
Example 34.3-(3-Oxo-piperazin-l-yImethyl)-2-thiophen-3-yl-quinoline-4-carboxyIic acid ((S)-l-cyclohexyl-ethyl)-amide.
The compound was prepared according to Description 5 starting from the compound of Description 12 and piperazinone (CAS [5625-67-2]).
Example 35. 3-[4-(3-Dimethylamino-propyl)-3-oxo-piperazin-l-ylmethyl]-6-fluoro-2- phenyl-quinoline-4-carboxy lie acid ((S)-l-cyclohexyl-ethyl)-amide.
The compound was prepared following Description 6, method A, starting from the compound of Description 9 and 3-dimethylaminopropylchloride.
Table 1 rExamples)
Figure imgf000049_0001
Figure imgf000049_0002
O
Figure imgf000050_0001
Figure imgf000050_0002
Figure imgf000051_0002
Figure imgf000051_0001
Figure imgf000051_0003
Figure imgf000051_0004
Figure imgf000052_0001
Table 2 1H NMR and/or mass spectroscopy data for Examples 1-60
Ex 1H NMR (Solvent) ppm and/or MS
ESI POS; AQA ; solvent: MeOH/ spray 3 kV / skimmer: 20 V/ probe 135°C: 515 (MH+)
1H NMR (DMSO-αV 333K) δ: 8.34 (d br, IH); 8.01 (d, IH); 7.84 (d, IH); 7.75 (dd, IH); 7.62 (dd. IH); 7.57 (m, 2H); 7.50-7.38 (m, 3H); 4.04 (m, IH); 3.78 (s, 2H); 2.59 (dd, 2H); 2.43-2.29 (m, 6H); 1.89-1.60 (m, 5H); 1.51 (m, IH); 1.39-1.04 (m, 7H);l.20 (d, 3H)
ESI POS; AQA ; solvent: MeOH/ spray 3 kV / skimmer: 20 VI probe 135°C: 471 (MH+)
ESI POS; AQA ; solvent: MeOH/ spray 3 kV / skimmer: 20 VI probe 135°C: 472 (MH+)
ESI POS; AQA ; solvent: MeOH/ spray 3 kV / skimmer: 20 VI probe 135°C: 561 (MH+)
ESI POS; AQA ; solvent: MeOH/ spray 3 kV / skimmer: 20 VI probe 135°C: 504 (MH+)
ESI POS; AQA ; solvent: MeOH/ spray 3 kV / skimmer: 20 VI probe 135°C: 460 (MH+)
ESI POS; AQA ; solvent: MeOH/ spray 3 kV / skimmer: 20 VI probe 135°C: 522 (MH+)
ESI POS; AQA ; solvent: MeOH/ spray 3 kV / skimmer: 20 VI probe 135°C: 490 (MH+)
1H NMR (DMSO-d6) δ: 8.75 (d br, IH); 8.04 (d, IH); 7.89 (m,2H); 7.78 (m, 2H); 7.66 (dd, IH); 7.49 (m, 3H); 4.04 (m, IH); 3.65 (s br, 2H); 2.46 (m, 2H); 1.87-1.57 (m, 5H); 1.46 (m, IH); 1.36-0.99 (m, 9H);1.19 (d, 3H); 0.85 (t, 3H).
ESI POS; AQA ; solvent: MeOH/ spray 3 kV / skimmer: 20 VI probe 135°C: 444 (MH+)
10 ESI POS; AQA ; solvent: MeOH/ spray 3 kV / skimmer: 20 VI probe 135°C: 458 (MH+)
Ex 1H NMR (Solvent) ppm and/or MS
11 1H NMR (DMSO-d6) δ: 8.75 (d br, IH); 8.04 (d, IH); 7.89 (m,2H); 7.78 (m, 2H); 7.66 (dd, IH); 7.49 (m, 3H); 4.04 (m, IH); 3.65 (s br, 2H); 2.46 (m, 2H); 1.87-1.57 (m, 5H); 1.46 (m, IH); 1.36-0.99 (m, 9H);1.19 (d, 3H); 0.85 (t, 3H). ESI POS; AQA ; solvent: MeOH/ spray 3 kV / skimmer: 20 VI probe 135°C: 416 (MH+)
12 ESI POS; AQA ; solvent: MeOH/ spray 3 kV / skimmer: 20 VI probe 135°C: 458 (MH+)
13 ESI POS; AQA ; solvent: MeOH/ spray 3 kV / skimmer: 20 VI probe 135°C: 504 (MH+)
14 ESI POS; AQA ; solvent: MeOH/ spray 3 kV / skimmer: 20 VI probe 135°C: 541 (MH+)
15 ESI POS; AQA ; solvent: MeOH/ spray 3 kV / skimmer: 20 VI probe 135°C: 470 (MH+)
16 1H NMR (DMSO-d6) δ: 8.33 (d br, IH); 8.10 (dd, IH); 7.68 (dt,lH); 7.56-7.44 (m, 6H); 4.03 (m, IH); 3.68 (s, 2H); 3.2 7(t, 2H); 3.0 7(m, 2H);2.75 (s, 2H); 2.41-2.28 (m, 8H); 1.88-1.60 (m, 5H); 55-1.05 (m, 12H); 1.19 (d, 3H). El; TSQ 700; source 180 C; 70 V; 200 uA: 444; 219; 111; 98
17 1H NMR (DMSO-d6) δ: 8.30 (d br, IH); 8.03 (d, IH); 7.90 (d, IH); 7.77 (dd, IH); 7.64 (dd, IH); 7.56 (m, 2H); 7.45 (m, 3H); 6.45 (m, IH); 5.89 (dd, IH); 5.56 (m, IH); 4.01 (m, IH); 3.80 (s, 2H); 3.65 (dd, 2H); 3.38 (s, 2H); 2.54 (dd, 2H); 1.84-1.41(m, 6H); 1.31-1.02 (m, 5H); 1.16 (d, 3H). El; TSQ 700; source 180 C; 70 V; 200 uA: 372; 261; 217; 121
18 1H NMR (DMSO-d6) δ: 8.28 (d br, IH); 8.02 (d, IH); 7.88 (d, IH); 7.77 (dd, IH); 7.63 (dd, IH); 7.57-7.43 (m, 5H); 4.02 ( , IH); 3.69 (s, 2H); 3.20 (m, 2H); 3.00 (m, 2H); 2.75 (s, 2H); 2.50-2.30 (m, 8H); 1.87-1.37 (m, 13H); 1.33-1.06 (m, 6H); 1.20 (d, 3H). El; TSQ 700; source 180 C; 70 V; 200 uA: 441; 224; 98
19 1H NMR (DMSO-d6) δ: 8.40 (d br, IH); 8.04 (d, IH); 7.88 (d, IH); 7.80 (dd, IH); 7.66 (dd, IH); 7.52 (m, 2H); 7.45- 7.34 (m, 3H); 6.78 (dd, IH); 4.49 (dd, IH); 6.05 (dd, IH); 4.88 (d, IH); 4.79 (d, IH); 3.99 (m, IH); 3.81 (m, 2H); 3.21 (m, 2H); 1.82-1.43 (m, 6H); 1.27-1.00 (m, 5H); 1.17 (d, 3H). El; TSQ 700; source 180 C; 70 V; 200 uA: 506 (M+); 370; 352; 260; 216
20 1H NMR (CDC13) δ: 8.63 (d br, IH); 8.10 (dd, IH); 7.80 (dd, IH); 7.52-7.40 (m, 6H); 4.23 (m, IH); 3.71 and 3.63
Ex 1H NMR (Solvent) ppm and/or MS
(ABq, 2H); 1.98 (s, 6H); 1.88-1.62 (m, 5H); 1.52-1.40 (m, IH); 1.32-0.99 (m, 5H); 1.28 (d, 3H).
El; TSQ 700; source 180 C; 70 V; 200 uA: 433 (M+); 390; 306; 291; 277; 235
21 1H NMR (CDC13) δ: 8.03 (dd, IH); 8.01 (d br, IH); 7.58 (dd, IH); 5.51-7.39 (m, 6H); 6.70 (dd, IH); 6.54 (dd, IH); 6.11 (dd, IH); 4.74 (s br, 2H); 4.18 (m, IH); 3.49 (m, 2H); 3.20-2.92 (m, 2H); 1.86-1.47 (m, 6H); 1.29-1.05 (m, 5H); 1.24 (d, 3H). El; TSQ 700; source 180 C; 70 V; 200 uA: 524 (M+); 388; 370; 278; 234
22 1H NMR (DMSO-de) δ: 8.22(d br, IH); 8.18(s br, IH); 8.02(d, IH); 7.89(d, IH); 7.75(dd, IH); 7.61(m, 3H); 7.75- 7.42(m, 3H); 7.27(dd, 2H); 6.80(m, 3H); 4.51(s, 2H); 4.1 l(m, IH); 3.70(s, 2H); 2.61(m, 2H); 2.41(m, 2H); 2.29(m, 2H); 1.90-1.48(m, 6H); 1.42-1.05(m, 7H); 1.21(d, 3H). El; TSQ 700; source 180 C; 70 V;200 uA: 601 (M+.); 447; 372; 272; 230; 217; 175
23 1H NMR (DMSO-de) δ: 8.53 (s br, IH); 8.02 (d, IH); 7.84 (d, IH); 7.79 (dd, IH); 7.66 (dd, IH); 7.55-7.42 (m, 5H); 3.99 (m, IH); 3.64 (s, 2H); 3.16 (m, 2H); 2.97 (m, 2H); 2.71 (s br, 2H); 2.34 (m, 2H); 2.08 (m, 8H); 1.84-1.39 (m, 8H); 1.29-0.99 (m, 8H). El; TSQ 700; source 180 C; 70 V; 200 uA: 555 (M+); 184
24 1H NMR (DMSO-d6) δ: 8.16 (d, IH); 7.96 (d, IH); 7.75 (dd, IH); 7.60 (dd, IH); 7.42 (m, 5H); 6.90 (s br, IH); 4.15 (m, IH); 3.77 (s, 2H); 3.00 (m, 2H); 2.97 and 2.89 (ABq, 2H); 2.78 (s, 3H); 2.42 (m, 2H); 1.80-1.56 (m, 5H); 1.40 (m, IH); 1.26-0.91 (m, 5H); 1.20 (d, 3H). El; TSQ 700; source 180 C; 70 V; 200 uA: 484 (M+); 371; 263; 261; 246; 217
25 1H NMR (DMSO-d6) δ: 8.14 (d, IH); 8.01 (d, IH); 7.75 (dd, IH); 7.60 (dd, IH); 7.53-7.41 (m, 5H); 6.86 (s br, IH); 4.24 (m, IH); 3.80 and 3.75 (ABq, 2H); 3.32 (q, 2H); 3.05 (m 2H); 2.97 and 2.88 (ABq, 2H); 2.43 (m, 2H); 1.87-1.62 (m, 5H); 1.47 (m, IH); 1.32-1.01 (m, 5H). El; TSQ 700; source 180 C; 70 V; 200 uA: 498 (M+); 371; 261; 246; 217; 127
26 1H NMR (DMSO-d6-343 K) δ: 8.45 (d br, IH); 8.01 (d, IH); 7.88 (d, IH); 7.79 (dd, IH); 7.63 (dd., IH); 7.51-7.41 (m, 5H); 5.89 (s, IH); 4.41 and 4.38 (ABq, 2H); 4.01 (m, IH); 3.00-2.71 (m, 4H); 1.85-1.70 (m, 5H); 1.50 (m, IH); 1.30- 1.02 (m, 5H); 1.19 (d, 3H).
Ex 1H NMR (Solvent) ppm and/or MS
El; TSQ 700; source 180 C; 70 V; 200 uA: 456 (M+); 370; 329; 300; 246; 217
27 1H NMR (DMSO-d6) δ: 8.28 (d br, IH); 8.02 (d, IH); 7.88 (d, IH); 7.77 (dd, IH); 7.63 (dd, IH); 7.53 (m, 2H); 7.46 (m, 3H); 4.03 (m, IH); 3.67 (s, 2H); 3.31 (t, 2H); 3.05 (m, 2H); 2.75 (s, 2H); 2,50 (m, 6H); 2.39 (t, 2H); 1.86-1.62 (m, 9H); 1.50 (m, IH); 1.35-1.06 (m, 5H); 1.19 (d, 3H).
28 1H NMR (DMSO-d6) δ: 8.03 (d, IH); 7.88 (d, IH); 7.77 (dd, IH); 7.64 (dd, IH); 7.55 (m, 2H); 7.46 (m, 3H); 4.03 (m, IH); 3.68 (s, 2H); 3.28 (m, 2H); 3.08 (t, 2H); 2.76 (s, 2H); 2.65-2.50 (m, 6H); 2.40 (t, 2H); 1.87-1.60 (m, 5H); 1.51 (m, IH); 1.32-1.06 (m, 5H); 1.19 (d, 3H); 0.99 (t br, 6H). El; TSQ 700; source 180 C; 70 V; 200 uA: 569 (M+); 198; 86
29 1H NMR (DMSO-d6) δ: 8.26 (d br, IH); 8.02 (d, IH); 7.88 (d, IH); 7.77 (dd, IH); 7.63 (dd, IH); 7.53 (m, 2H); 7.46 (m, 3H); 4.03 (m, IH); 3.67 (s, 2H); 3.28 (t, 2H); 3.05 (t, 2H); 2.74 (s, 2H); 2.39 (t, 2H); 2.34 (t, 2H); 2.18 (s, 6H); 1.87-1.60 (m, 5H); 1.51 (m, IH); 1.35-1.06 (m, 5H); 1.19 (d, 3H).
30 El; TSQ 700; source 180 C; 70 V; 200 uA: 372; 370; 330; 287; 274; 216; 140; 124; 55
31 El; TSQ 700; source 180 C; 70 V; 200 uA: 583 (M+); 372; 261; 212; 100
32 1H NMR (DMSO-d6) δ: 8.23 (d br, IH); 8.01 (d, IH); 7.87 (d, IH); 7.76 (dd, IH); 7.72 (dd, IH); 7.56 (m, 2H); 7.50- 7.39 (m, 3H); 6.01 (t br, IH); 4.05 (m, IH); 3.60 (s, 2H); 3.03 (m, 6H); 2.09 (m, 4H); 1.88-1.46 (m, 6H); 1.32-1.05 (m, 5H); 1.20 (d, 3H); 0.99 (t, 3H). El; TSQ 700; source 180 C; 70 V; 200 uA: 457; 400; 372; 287; 261; 217
33 1H NMR (DMSO-d6) δ: 8.26 (d br, IH); 8.02 (d, IH); 7.86 (d, IH); 7.76 (dd, IH); 7.62 (dd, IH); 7.57 (m, 2H); 7.50- 7.39 (m, 3H); 5.73 (d br, IH); 4.04 (m, IH); 3.71 (m, IH); 3.60 (s, 2H); 3.00 (m, 4H); 2.09 (m, 4H); 1.89-1.45 (m, 6H); 1.32-1.03 (m, 5H); 1.20 (d, 3H); 1.03 (d, 6H). El; TSQ 700; source 180 C; 70 V; 200 uA: 541 (M+); 414; 387; 370; 287; 217; 172; 129
34 1H NMR (DMSO-d6) δ: 8.29 (d br, IH); 8.01 (d, IH); 7.92 (m IH); 7.84 (d, IH); 7.76 (dd, IH); 7.61 (dd, IH); 7.58 (m, IH); 7.49 (dd, IH); 7.27 (s br, IH); 4.04 (m, IH); 3.76 (s, 2H); 3.00 (m, 2H); 2.83 (s, 2H); 2.45 (t, 2H); 1.88-1.44 (m, 6H); 1.32-1.02 (m, 5H); 1.20 (d, 3H).
Ex 1H NMR (Solvent) ppm and/or MS
El; TSQ 700; source 180 C; 70 V; 200 uA: 476 (M+); 378; 269; 252; 223; 99; 69; 55.
35 1H NMR (DMSO-de) δ: 8.54 (s br, IH); 8.11 (dd, IH); 7.73 (dt, IH); 7.56-7.42 (m, 6H); 3.98 (m, IH); 3.66 (s, 2H); 3.16 (t, 2H); 2.98 (m, 2H); 2.72 (s, 2H); 2.34 (t br, 2H); 2.09 (m, 2H); 2.08 (s, 6H); 1.83-1.40 (m, 8H); 1.32-1.00 (m, 5H); 1.14 (d, 3H). El; TSQ 700; source 180 C; 70 V; 200 uA: 419; 390; 281; 264; 184; 170.
Table 3 Melting points (Mp/°C) and/or Refractory indices ([α_£)20) of certain Examples of
Table 1
Figure imgf000058_0001
Table 4 Chemical names of parent compounds of Examples 1-35 (names generated by Beilstein's Autonom
Ex Chemical name
3-{[(3-Diethylamino-propyl)-methyl-amino]-methyl}-2-phenyl-quinoline-4-carboxylic acid ((S)-l-cyclohexyl-ethyl)- amide
3 -[ 1 ,4]Diazepan- 1 -ylmethyl-2-phenyl-quinoline-4-carboxylic acid ((S)- 1 -cyclohexyl-ethyl)-amide
3 -Dipropylaminomethyl-2-phenyl-quinoline-4-carboxylic acid ((S)- 1 -cyclohexyl-ethyl)-amide
3-[(l-Ben__yl-piperidin-4-ylamino)-methyl]-2-phenyl-quinoline-4-carboxylic acid ((S)-l-cyclohexyl-ethyl-amide
3-(Indan-2-ylaminomethyl)-2-phenyl-quinoline-4-carboxylic acid ((S)- 1 -cyclohexyl-ethyl)-aπ_ide
2-Phenyl-3-thiazolidin-3-ylmethyl-quinoline-4-carboxylic acid ((S)-l-cyclohexyl-ethyl)-amide
3-{[Benzyl-(2-hydroxy-ethyl)-amino]-methyl}-2-phenyl-quinoline-4-carboxylic acid ((S)-l-cyclohexyl-ethyl)-amide
3-(2,3-Dihydro-indol-l-ylmethyl)-2-phenyl-quinoline-4-carboxylic acid ((S)-l-cyclohexyl-ethyl)-amide 3 -Butylaminomethyl-2-phenyl-quinoline-4-carboxylic acid ((S)- 1 -cyclohexyl-ethyl)-amide
10 3-((R)-3-Hy( oxy-py]τolidin-l-ylmethyl)-2-phenyl-quinoline-4-carboxylic acid ((S)-l-cyclohexyl-ethyl)-amide
11 3-Dimethylaminomethyl-2-phenyl-quinoline-4-carboxylic acid ((S)-l-cyclohexyl-ethyl)-amide
12 3-((S)-3-Hydroxy-pyrrolidm-l-ylmethyl)-2-phenyl-qumoline-4-carboxylic acid ((S)-l-cyclohexyl-ethyl)-amide
13 3 -(3 ,4-Dihy dro- 1 H-isoquinolin-2-ylmethyl)-2-phenyl-quinoline-4-carboxylic acid ((S)- 1 -cyclohexyl-ethyl)-amide
Ex Chemical name
14 3-{[Methyl-(2,2,6,6-tetramethyl-piperidin-4-yl)-amino]-methyl}-2-phenyl-quinoline-4-carboxylic acid ((S)-l- cyclohexyl-ethyl)-amide
15 3 -(4-Oxo-piperidin- 1 -ylmethyl)-2-phenyl-quinoline-4-carboxylic acid ((S)- 1 -cyclohexyl-ethyl)-amide
6-Fluoro-3-[3-oxo-4-(2-piperidin-l-yl-ethyl)-piperazin-l-ylmethyl]-2-phenyl-quinoline-4-carboxylic acid ((S)-l-
16 cyclohexyl-ethyl)-amide
3-(3,4-Dihydro-lH-pyrrolo[l,2-a]pyrazin-2-ylmethyl)-2-phenyl-quinoline-4-carboxylic acid ((S)-l-cyclohexyl-ethyl)-
17 amide
3 - [3 -Oxo-4-(3 -piperidin- 1 -yl-propyl)-piperazin- 1 -ylmethy 1] -2-phenyl-quinoline-4-carboxy lie acid ((S)- 1 -cy clohexy 1-
18 ethyl)-amide
3 -( 1 -Oxo-3 ,4-dihydro- 1 H-pyrrolo [1 ,2-a]pyrazin-2-ylmethyl)-2-phenyl-quinoline-4-carboxylic acid ((S)- 1 -cy clohexy 1-
19 ethyl)-amide
20 3 -Dimethylaminomethyl-6-fluoro-2-phenyl-quinoline-4-carboxylic acid ((S)- 1 -cyclohexyl-ethyl)-amide
6-Fluoro-3-( 1 -oxo-3 ,4-dihydro- 1 H-pyrrolo[ 1 ,2-a]pyrazin-2-ylmethyl)-2-phenyl-quinoline-4-carboxylic acid ((S)- 1 -
21 cyclohexyl-ethyl)-amide
3-(4-Oxo-l-phenyl-l,3,8-triaza-spiro[4.5]dec-8-ylmethyl)-2-phenyl-quinoline-4-carboxylic acid ((S)-l-cyclohexyl-
22 ethyl)-amide
3-[4-(3-Dimethylamino-propyl)-3-oxo-piperazin-l-ylmethyl]-2-phenyl-quinoline-4-carboxylic acid ((S)-l-cyclohexyl-
23 ethyl)-amide
3-(4-Methyl-3-oxo-piperazin-l-ylmethyl)-2-phenyl-quinoline-4-carboxylic acid ((S)-l-cyclohexyl-ethyl)-amide
24 ditrifluoroacetate
25 3-(4-Ethyl-3-oxo-piperazin-l-ylmethyl)-2-phenyl-quinoline-4-carboxy lie acid ((S)-l-cy clohexy l-ethyl)-amide
26 3-(2-Oxo-imidazolidin-l-ylmethyl)-2-phenyl-quinoline-4-carboxylic acid ((S)-l-cyclohexyl-ethyl)-amide
Ex Chemical name
3-[3-Oxo-4-(2-pyrrolidin-l-yl-ethyl)-piperazin-l-ylmethyl]-2-phenyl-quinoline-4-carboxylic acid ((S)-l-cyclohexyl-
27 ethyl)-amide
3-[4-(2-Diethylamino-ethyl)-3-oxo-piperazin-l-ylmethyl]-2-phenyl-quinoline-4-carboxylic acid ((S)-l-cyclohexyl-
28 ethyl)-amide
3-[4-(2-Dimethylamino-ethyl)-3-oxo-piperazin-l-ylmethyl]-2-phenyl-quinoline-4-carboxylic acid ((S)-l-cyclohexyl-
29 ethyl)-amide
3 -[4-(2-Amino-ethyl)-3 -oxo-piperazin- 1 -ylmethyl]-2-phenyl-quinoline-4-carboxylic acid ((S)- 1 -cyclohexyl-ethyl)-
30 amide
3-[4-(2-Morpholin-4-yl-ethyl)-3-oxo-piperazin-l-ylmethyl]-2-phenyl-quinoline-4-carboxylic acid ((S)-l-cyclohexyl-
31 ethyl)-amide
32 3 -(4-Ethylcarbamoyl-piperazin- 1 -ylmethyl)-2-phenyl-quinoline-4-carboxylic acid ((S)- 1 -cyclohexyl-ethyl)-amide
33 3 -(4-Isopropylcarbamoyl-piperazin- 1 -ylmethy l)-2-phenyl-quinoline-4-carboxylic acid ((S)- 1 -cyclohexyl-ethyl)-amide
34 3-(3-Oxo-piperazin-l-ylmethyl)-2-thiophen-3-yl-quinoline-4-carboxylic acid ((S)-l-cyclohexyl-ethyl)-amide
3-[4-(3-Dimethylamino-propyl)-3-oxo-piperazin-l-ylmethyl]-6-fluoro-2-phenyl-quinoline-4-carboxylic acid ((S)-l-
35 cyclohexyl-ethyl)-amide

Claims

Claims
1. A compound of formula (I) below or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000062_0001
(I) wherein:
R is H or alkyl; R2 is aryl or cycloalkyl or heteroaryl;
R3 is H or alkyl, wherein the alkyl group may be optionally substituted by one or more fluorine atoms;
R4 is NRgRo;
Rg is H, alkyl or Ri R 2 and R9 is H, alkyl or R 3 R 4; or Rg and R9 together with the N atom to which they are attached form a heterocyclic ring comprising 4-8 ring members, said ring members optionally including in addition to said N atom one or more further heteroatoms selected from N, O or S; said heterocyclic ring being saturated or unsaturated and optionally substituted one or more times by hydroxy, oxo, alkyl, aminoalkyl, di-alkylaminoalkyl and-C(=O)NHRi5, and wherein said ring may be optionally fused or linked by a single bond or an alkyl chain to one or more cycloalkyl, heterocyclyl or aryl groups, which cycloalkyl, heterocyclyl or aryl groups are unsubstituted or are substituted one or more times by halo, haloalkyl, oxo and aryl; each of R 1 and R13 is independently either a single bond, alkyl, alkylamino or aminoalkyl or 2°- or 3°-alkylaminoalkyl, and each of R12 and R 4 is independently H or a ring moiety comprising cycloalkyl, aryl or two or more fused cycloalkyl and/or aryl groups, which ring moiety optionally includes one or more heteroatoms selected from N, O and S, which ring moiety is unsubstituted or is substituted one or more times by one or more of halo, hydroxy, amino, cyano, nitro, carboxy, oxo, alkyl, arylalkyl or cycloalkylalkyl, aryl, or cycloalkyl;
R5 is branched or linear alkyl, cycloalkyl, cycloalkylalkyl, aryl, or a single or fused ring aromatic heterocyclic group;
Rg represents H or up to three substituents independently selected from the list consisting of: alkyl, alkenyl, aryl, alkoxy, hydroxy, halo, nitro, cyano, carboxy, carboxamido, sulphonamido, trifluoromethyl, or amino or mono- or di-alkylamino;
R7 is H or halo;
Rl5 is alkyl; a is 0-6; and any of R2 and R5 may optionally be substituted one or more times by halo, hydroxy, amino, cyano, nitro, carboxy, oxo, alkyl, alkenyl, aryl, alkoxy, carboxamido, sulphonamido, trifluoromethyl, or mono- or di- alkylamino; not being a compound wherein R5 is unsubstituted phenyl, and Ri, R2, R3, R4, Rβ, R and a are selected from the following:
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
with the further proviso that said compound of formula (I) is not selected from the following compounds:
2-(4-Fluoro-phenyl)-3-(3-oxo-piperazin-l-ylmethyl)-quinoline-4-carboxylic acid ((S)- cyclohexyl-ethyl)-amide;
3-(3-Oxo-piperazin-l-ylmethyl)-2-(4-trifluoromethyl-phenyl)-quinoline-4-carboxylic acid ((S)-cyclohexyl-ethyl)-amide;
2-(2-Fluoro-phenyl)-3-(3-oxo-piperazin-l-ylmethyl)-quinoline-4-carboxylic acid ((S)- cyclohexyl-ethyl)-amide;
3-[ 1 ,4']Bipiperidinyl- 1 '-ylmethyl-2-thiophen-2-yl-quinoline-4-carboxylic acid ((S)-l - cyclohexyl-ethyl)-amide;
3-[l ,4']Bipiperidinyl- 1 '-ylmethyl-2-(4-fluoro-phenyl)-quinoline-4-carboxylic acid ((S)- 1 - cyclohexyl-ethyl)-amide; 3-[l,4,]Bipiperidinyl- -ylmethyl-2-(4-trifluoromethyl-phenyl)-quinoline-4-carboxylic acid ((S)-l-cyclohexyl-ethyl)-amide; and
3-[ 1 ,4']Bipiperidinyl- 1 '-ylmethyl-2-(2-fluoro-phenyl)-quinoline-4-carboxylic acid ((S)- 1 - cyclohexyl-ethyl)-amide.
2. A compound of formula (I), as claimed in claim 1, wherein R is H.
3. A compound of formula (I), as claimed in claim 1 or claim 2, wherein R2 is aryl or cycloalkyl.
4. A compound of formula (I), as claimed in claim 3, wherein R2 is cyclohexyl.
5. A compound of formula (I), as claimed in any preceding claim, wherein R3 is alkyl.
6. A compound of formula (I), as claimed in claim 5, wherein R3 is methyl.
7. A compound of formula (I), according to any preceding claim wherein R4 is NRgR9 wherein Rg and R9 together with the N atom to which they are attached form a heterocyclic ring comprising 4-8 ring members, said ring members optionally including in addition to said N atom one or more further heteroatoms selected from N,
O or S; said heterocyclic ring being saturated or unsaturated and optionally substituted one or more times by hydroxy, oxo, alkyl, aminoalkyl, di-alkylaminoalkyl and -C(=O)NHRi5, and wherein said ring may be optionally fused or linked by a single bond or an alkyl chain to one or more cycloalkyl, heterocyclyl or aryl groups, which cycloalkyl, heterocyclyl or aryl groups are unsubstituted or are substituted one or more times by halo, haloalkyl, oxo and aryl.
8. A compound of formula (I), as claimed in claim 7, wherein R^ is NR R9 wherein Rg and R9 together with the N atom to which they are attached form a heterocyclic ring comprising 4-8 ring members, said ring members optionally including in addition to said N atom one or more further heteroatoms selected from N, O or S; said heterocyclic ring being saturated or unsaturated and being substituted one or more times by hydroxy, oxo, alkyl, aminoalkyl, di-alkylaminoalkyl and-C(=O)NHR 5, and wherein said ring may be optionally fused or linked by a single bond or an alkyl chain to one or more cycloalkyl, heterocyclyl or aryl groups, which cycloalkyl, heterocyclyl or aryl groups are unsubstituted or are substituted one or more times by halo, haloalkyl, oxo and aryl.
9. A compound of formula (I), according to any preceding claim, wherein R5 is an aryl or an aromatic heterocyclic group.
10. A compound of formula (I), according to claim 9, wherein R5 is phenyl or 3-thienyl.
11. A compound of formula (I), according to any preceding claim, wherein Rβ is H or fluoro.
12. A compound of formula (I), according to any preceding claim, wherein R7 is H or fluoro.
13. A compound of formula (I), according to any preceding claim, wherein a is 1, 2 or 3.
14. A compound of formula (I), according to claim 1, wherein R is H, R2 is cyclohexyl, R3 is methyl, R5 is phenyl, Rβ is H, R7 is H, a is 1 and R4 is selected from the following substituents:
R4
Figure imgf000070_0001
Figure imgf000071_0001
~~yχ H — ,
OH
Figure imgf000071_0002
• P H')0>
-"Oo - „
H2N
15. A compound of formula (I), according to claim 1, wherein Ri is H, R2 is unsubstituted cyclohexyl, R3 is unsubstituted methyl, R5 is unsubstituted phenyl, Rβ is H, R7 is 6-F, a is 1 and R4 is selected from the following substituents:
R4
Figure imgf000071_0003
16. A process for the preparation of a compound of formula (I), or a salt thereof and or a solvate thereof, according to claim 1, which process comprises reacting a compound of formula (II) or an active derivative thereof:
Figure imgf000072_0001
(II)
wherein R'g, R'7, R'5 and X' are Rg, R7, R5 and X respectively as hereinbefore defined in relation to formula (I) or (la), or a group convertible to Rg, R7, R5 and X respectively; with a compound of formula (III):
H R-,
R",
R', (Ill)
wherein R'i, R'2, and R'3 are R , R2, and R3 as defined for formula (I) or a group or atom convertible to R\, R2, and R3 respectively; to form a compound of formula (lb):
Figure imgf000072_0002
wherein R'i, R'2, R'3, X', R'5, R'g and R'7 are as defined above, and thereafter carrying out one or more of the following optional steps:
(i) converting any one of R'i, R'2, R'3, X', R*5, R'g and R'7 to Ri, R2, R3, X, R5, Rg and R7 respectively as required, to obtain a compound of formula (I); (ii) converting a compound of formula (I) into another compound of formula (I); and (iii) preparing a salt of the compound of formula (I) and or a solvate thereof.
17. A pharmaceutical composition comprising a compound of formula (I) according to any of claims 1-15, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
18. A compound of formula (I) according to any of claims 1-15, or a pharmaceutically acceptable salt or solvate thereof, for use as an active therapeutic substance.
19. A compound of formula (I) according to any of claims 1-15, or a pharmaceutically acceptable salt or solvate thereof, for the treatment or prophylaxis of the Primary and Secondary Conditions of the invention.
20. Use of a compound of formula (I) according to any of claims 1-15, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of the Primary and Secondary Conditions of the invention.
21. A method for the treatment and/or prophylaxis of the Primary and Secondary Conditions of the invention in mammals, particularly humans, which comprises administering to the mammal in need of such treatment and/or prophylaxis an effective, non-toxic pharmaceutically acceptable amount of a compound of formula
(I) according to any of claims 1-15 or a pharmaceutically acceptable salt or solvate thereof.
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US10/474,542 US20040152726A1 (en) 2001-04-11 2002-04-11 Quinoline-4-carboxamide derivatives as nk-3 and nk-2 receptor antagonists
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JP2002581418A JP2004525183A (en) 2001-04-11 2002-04-11 Quinoline-4-carboxamide derivatives as NK-3 and NK-2 receptor antagonists
US11/100,256 US20050176762A1 (en) 2001-04-11 2005-04-06 Quinoline-4-carboxamide derivatives as NK-3 and NK-2 receptor antagonists
US11/685,380 US20070161647A1 (en) 2001-04-11 2007-03-13 QUINOLINE-4-CARBOXAMIDE DERIVATIVES AS NK-3 and NK-2 RECEPTOR ANTAGONISTS

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EP2080760A1 (en) 2004-04-28 2009-07-22 Takeda Pharmaceutical Company Limited Fused quinoline derivative and use thereof
US7973163B2 (en) 2004-04-28 2011-07-05 Takeda Pharmaceutical Company Ltd. Fused quinoline derivative and use thereof
US7943770B2 (en) 2004-04-28 2011-05-17 Takeda Pharmaceutical Company Limited Fused quinoline derivative and use thereof
US7592453B2 (en) 2004-04-28 2009-09-22 Takeda Pharmaceutical Company Limited Fused quinoline derivative and use thereof
WO2006050992A1 (en) * 2004-11-12 2006-05-18 Smithkline Beecham Corporation Compounds having activity at nk3 receptor and uses thereof in medicine
WO2006130080A3 (en) * 2005-06-03 2007-01-25 Astrazeneca Ab Quinoline derivatives as nk3 anatgonists
WO2006130080A2 (en) * 2005-06-03 2006-12-07 Astrazeneca Ab Quinoline derivatives as nk3 anatgonists
WO2007012900A1 (en) 2005-07-29 2007-02-01 Merck Sharp & Dohme Limited Quinoline derivatives as neurokinin receptor antagonists
WO2007035156A1 (en) * 2005-09-21 2007-03-29 Astrazeneca Ab N-oxo-heterocycle and n-oxo-alkyl quinoline-4-carboxamides as nk-3 receptor ligands
US7964733B2 (en) 2005-09-21 2011-06-21 Astrazeneca Ab Alkyl sulfoxide quinolines as NK-3 receptor ligands
WO2008118454A3 (en) * 2007-03-23 2008-11-13 Amgen Inc Derivatives of quinoline or benzopyrazine and their uses for the treatment of (inter alia) inflammatory diseases, autoimmune diseases or various kinds of cancer
WO2008118454A2 (en) * 2007-03-23 2008-10-02 Amgen Inc. Derivatives of quinoline or benzopyrazine and their uses for the treatment of (inter alia) inflammatory diseases, autoimmune diseases or various kinds of cancer
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