EP1337253A1 - Composes - Google Patents

Composes

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Publication number
EP1337253A1
EP1337253A1 EP01998350A EP01998350A EP1337253A1 EP 1337253 A1 EP1337253 A1 EP 1337253A1 EP 01998350 A EP01998350 A EP 01998350A EP 01998350 A EP01998350 A EP 01998350A EP 1337253 A1 EP1337253 A1 EP 1337253A1
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EP
European Patent Office
Prior art keywords
compound
formula
alkyl
aryl
compounds
Prior art date
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EP01998350A
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German (de)
English (en)
Inventor
Carlo Farina
Giuseppe Giardina
Mario NiKem Research srl GRUGNI
Guy Marguerite Marie Gerard Nadler
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Laboratoire GlaxoSmithKline SAS
GlaxoSmithKline SpA
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Laboratoire GlaxoSmithKline SAS
GlaxoSmithKline SpA
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Priority claimed from GB0028963A external-priority patent/GB0028963D0/en
Application filed by Laboratoire GlaxoSmithKline SAS, GlaxoSmithKline SpA filed Critical Laboratoire GlaxoSmithKline SAS
Publication of EP1337253A1 publication Critical patent/EP1337253A1/fr
Withdrawn legal-status Critical Current

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    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • the present invention relates to novel compounds, in particular to novel quinoline derivatives, to processes for tlie preparation of such compounds, to pharmaceutical compositions containing such compounds and to the use of such compounds in medicine.
  • the mammalian peptide Neurokinin B 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
  • WO 00/31037 discloses certain compounds stated to be non-peptide NK-3 antagonists and also to have NK-2 antagonist activity. These compounds are disclosed 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 NK-3 and
  • NK-3 antagonists We have now discovered a further novel class of potent non-peptide NK-3 antagonists.
  • the new compounds are also far more stable from a metabolic point of view than the known peptidic NK-3 receptor antagonists and are of potential therapeutic utility.
  • the new compounds also have good NK-2 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 NK-3 and NK-2.
  • respiratory diseases such as chronic obstructive pulmonary disease (COPD), asthma, airway hyper-reactivity, 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 systhemic lupus erythematosis; gastrointestinal (GI) disorders and diseases of the GI tract such as disorders associated with the neuronal control of viscera such as ulcer
  • 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, Parlcinson'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 new compounds also show improved oral bioavailability.
  • 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
  • R2 is aryl or cycloalkyl or heteroaryl
  • R3 is H or alkyl, optionally substituted by one or more fluorines
  • R4 is -NRgRo. or R12;
  • Rg is H or methyl;
  • R9 is H, alkyl, aryl, cycloalkyl or R1 QRI 1; or Rg and R9 together form a heterocyclic ring comprising 3-8 ring members, which heterocyclic ring is optionally unsubstiruted or is substituted one or more times by R1 1 ;
  • Ri 0 is alkyl, aryl or cycloalkyl; R. ⁇ 1 is carboxy or alkylcarboxy;
  • Ri 2 is Ri3 or OR13;
  • R1 is H or alkyl or aryl, optionally substituted by one or more fluorines
  • 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, halogen, nitro, cyano, carboxy, carboxamido, sulphonamido, alkoxycarbonyl, trifluoromethyl, acyloxy, amino or mono- or di-alkylamino;
  • R7 is H or halo; a is 1-6; and any of R2, R5, R9, and Ri 0 may optionally be substituted one or more times by halo, hydroxy, amino, cyano, nitro, carboxy or oxo; not being a compound wherein Rj is H, R2 is cycloalkyl, R3 is methyl, R4 is NH2, R5 is phen
  • R3 represents methyl or ethyl or isopropyl.
  • R2 represents unsubstiruted phenyl or unsubstiruted cyclohexyl.
  • Ri is hydrogen
  • R5 is unsubstiruted phenyl.
  • each of Rg and R7 represents hydrogen.
  • a is 1, 2 or 3.
  • a is 1.
  • R4 is -NRgRo. and Rg and R9 together with the
  • N atom to which they are attached form a five- or six-membered saturated heterocyclic ring.
  • said heterocyclic ring is substituted at least once by Ri 1.
  • Said heterocyclic ring may for example be a six-membered ring which ring is substituted once at the meta- or para- position thereof by Ri ⁇ .
  • R4 is -NRgR9 and Rg is H and R9 is H, alkyl, aryl, cycloalkyl or RioRl 1 where Ri Q is phenyl.
  • R9 is -RioRl 1 and R ⁇ 1 is meta- or para- linked to said phenyl group Ri Q.
  • Said R ⁇ ⁇ may be carboxylate or carboxyalkyl, such as carboxymethyl or carboxyethyl.
  • R4 is Ri 2 and Ri 2 is OH or OMe.
  • a is 1, Rg is H, R is H, R5 is unsubstiruted phenyl, R7 is hydrogen, and R2, R3 and R4 are selected from the following combinations:
  • 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): wherein Ri , R2, R3, R5, R6- and R7 are as defined in relation to formula (I), and X represents the moiety
  • 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.
  • Suitable pharmaceutically acceptable form is the crystalline form, including such form in pharmaceutical composition.
  • 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- ⁇ -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.
  • 'alkyl' when used alone or when forming part of other groups (such as the 'alkoxy' group) denotes 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) denotes cyclic saturated or unsaturated carbon rings including 3-12, preferably 3-8 carbon ring members. Examples include cyclopropyl, cyclobutyl, cyclohexyl, cyclooctyl.
  • 'carbocyclic' denotes cycloalkyl and aryl rings.
  • 'aryl' denotes aromatic groups including 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' denotes 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 inter-linked 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 unsubstiruted.
  • 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' ⁇ , R'2, and R'3 are Ri , R2, and R3 as defined for formula (I) or a group or atom convertible to Ri , R2, and R3 respectively; to form a compound of formula (lb):
  • R'j, R'2, R3, 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,
  • 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'- carbony ldiimidazole .
  • an activated ester such as a cyanomethyl ester, thiophenyl ester, p-nitrophenyl ester,
  • 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.
  • the reaction between an active derivative of the compound of formula (II) and the compound of formula (III) may be carried out:
  • a suitable condensing agent such as for example N,N'-carbonyl diimidazole (GDI) 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),
  • a suitable condensing agent such as for example N,N'-carbonyl diimidazo
  • R' ⁇ , R ⁇ , 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 R 7 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.
  • 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, R 3 is methyl and Ri 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 Ri 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 (IN) or the corresponding alkyl (such as methyl or ethyl) ester:
  • Li represents a halogen atom such as a bromine atom, with a compound of formula (N):
  • 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 (IN) or the corresponding alkyl (such as methyl or ethyl) ester and (V) 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 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 CO 3 .
  • TAA triethylamine
  • the compounds of formula (N) 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;
  • 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:
  • 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).
  • 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 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.
  • a compound of formula (NI) is conveniently prepared by reacting a compound of formula (Nil):
  • R'5 is as defined in relation to formula (II).
  • 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
  • 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 group R'4 as defined in relation to formula (I) or a protected form thereof or a group convertible thereto, 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
  • a compound of formula (VIII) is prepared from a compound of formula (IX):
  • a compound capable of forming a group T5 is a compound of the above defined formula (N).
  • the halogenation of the compound of formula (IX) is suitably carried out using a conventional halogenation reagent.
  • Mesylation is conveniently carried out using esyl 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
  • 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):
  • 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.
  • aprotic solvent such as diethyl-ether
  • 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 Krow G. R. in Organic Reactions, Nol 43, page 251, John Wiley & Sons
  • 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 (XNI):
  • each of R' ⁇ , R'2, R'3, R'5, R'g, and R'7 is respectively Ri , R2, R3, R5, Rg, or R7 as defined above or a group convertible to Ri , R2, R3, R5, Rg, or R7 respectively as defined above providing R'2 is not aromatic in character, and represents a halogen atom such as a bromine atom, with a compound of formula (XVII):
  • 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
  • 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,
  • Suitable groups convertible into other groups include protected forms of said groups.
  • a compound of formula (XVII) will be a compound of formula
  • R' ⁇ , R * 2, R'3, R'4, R'5, R'g and R'7 each represents Ri , R2, R3, R4, R5, Rg and R7 respectively or a protected form thereof.
  • 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 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 .
  • aprotic solvent such as tetrahydrofuran or dimethylformamide
  • 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).
  • NBS N-bromosuccinimide
  • 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.
  • an inert solvent such as carbon tetrachloride CC1 4 , or 1,2-dichloroethane or CH 3 CN
  • 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.
  • 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).
  • the reaction between an active derivative of the compound of formula (VI) and the compound of formula (III) may be carried out:
  • 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-benzofriazol-l-yl-N.N.N'.N'- tetramethyluromumhexafluorophosphate (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
  • 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
  • An alternative method for separating optical isomers is to use conventional, fractional separation methods in particular fractional crystallisation 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; (ii) reducing a ketone to a hydroxy group by use of a borohydride reducing agent;
  • Ri , R2, R3, X, R5, Rg, and R7 which as stated above are usually protected forms of Ri , R2, R3, X, R5, Rg, or R7 may be carried out using appropriate conventional conditions such as the appropriate deprotection procedure.
  • 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 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 mild ether cleavage reagent such as trimethylsilyl iodide or boron tribromide.
  • 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
  • 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 hyper-reactivity, 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 systhemic lupus erythematosis; gastrointestinal (GI) disorders and diseases of the GI tract such as disorders associated with the neuronal control of viscer
  • 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,
  • 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.
  • a pharmaceutical composition of the invention is in unit dosage form and in a form adapted for use in the medical or veterinarial fields.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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, [125i]_[M e _ h e 7]_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 [125i]_py ⁇ e _ph e 7]_NKB Q ⁇ [ ⁇ 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 ileu (Maggi et al,
  • Guinea-pig and rabbit in-vitro functional assays provide for each compound tested a mean Kg value of 3-8 separate experiments, where Kg 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
  • 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,
  • [ 125 I]-NKA or [ 3 H]-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 [125j/]_N] A and [ ⁇ Hj-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 ++ mobilisation
  • 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
  • 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.
  • DESCRIPTION 1 4-Chlorocarbonyl-piperidine-l-carboxyIic acid 9H-fluoren-9- ylmethyl ester ⁇ /? (coci) 2 /— ⁇ fmoc-N ) — ⁇ - fmoc-N ) —
  • DESCRIPTION 4 4-[(l-Piperidin-4-yl-methanoyl)-amino]-benzoic acid ethyl ester.
  • DESCRIPTION 14 3-Bromomethyl-2-phenyl-quinoline-4-carboxylic acid ((S)-l- cyclohexyl-ethyl)-amide 3-Methyl-2-phenyl-quinoline-4-carboxylic acid ((S)-l-cyclohexyl-ethyl)-amide (9.8 g, 26 mmol; compound prepared as in Description 13) and N-bromosuccimmmide (9.8 g, 55 mmol) were suspended in CC1 4 (100 ml) and warmed to incipient reflux. Dibenzoyl peroxide (about 300 mg) was carefully added portionwise and the solution was then refluxed for 2 h.
  • EXAMPLE 1 4-[(l- ⁇ l-[4-((S)-l-CyclohexyI-ethylcarbamoyl)-2-phenyl-quinolin-3- ylmethyl]-piperidin-4-yl ⁇ -methanoyl)-ammo]-benzoic acid ethyl ester.
  • EXAMPLE 3 4-[(l- ⁇ l-[4-((S)-l-Cyclohexyl-ethylcarbamoyl)-2-phenyl-quinolin-3- ylmethyl] -piperidin-4-yl ⁇ -methanoyl)-amino] -benzoic acid.
  • EXAMPLES 5 and 6 were prepared following the same synthetic pathway of Example 1 starting from l-(4-piperidinylcarbonyl)-pyrrolidine (RN 35090-95-0).
  • EXAMPLES 7 and 8 were prepared following the same synthetic pathway of Examples 1 and 3, respectively, starting from 4-ethoxycarbonylpiperidine.

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Abstract

L'invention concerne certains composés de formule (I), ou des sels ou des hydrates de ces composés acceptables sur le plan pharmaceutique, dans laquelle R1 représente un atome d'H ou un groupe alkyle, R2 représente un groupe aryle ou cycloalkyle ou hétéroaryle, R3 représente un atome d'H ou un groupe alkyle, éventuellement substitué par un ou plusieurs fluor, R4 représente un groupe -NR8R9 ou R12, R8 représente un atome d'H ou un groupe méthyle, R9 représente un atome d'H, un groupe alkyle, aryle, cycloalkyle ou R10R11, ou R8 et R9 forment ensemble un hétérocycle dont le cycle comprend de 3 à 8 éléments, cet hétérocycle étant éventuellement substitué ou substitué une ou plusieurs fois par R11, R10 représente un groupe alkyle, aryle ou cycloalkyle, R11 représente un groupe carboxy ou alkylcarboxy, R12 représente un groupe R13 ou OR13, R13 représente un atome d'H ou un groupe alkyle ou aryle, éventuellement substitué par un ou plusieurs fluor, R5 représente un groupe alkyle, cycloalkyle, cycloalkylalkyle, aryle, ramifiés ou linéaires, ou un groupe hétérocyclique aromatique à cycle unique ou fusionné, R6 représente un atome d'H ou jusqu'à trois substituants, choisis de manière indépendante, parmi un groupe alkyle, alcényle, aryle, alcoxy, hydroxy, halogène, nitro, cyano, carboxy, carboxamido, sulfonamido, alkoxycarbonyle, trifluorométhyle, acyloxy, amino ou mono ou di-alkylamino, R7 représente un atome d'H ou un groupe halo, a prend la valeur de 1 à 6, et un quelconque des R2, R5, R9, et R10 peut éventuellement être substitué par un groupe halo, hydroxy, amino, cyano, nitro, carboxy ou oxo. L'invention concerne aussi un procédé de préparation de tels composés, une composition pharmaceutique comprenant de tels composés ainsi que l'utilisation de tels composés et composition en médecine.
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