Carboxamide compounds and their use as antagonists of a human 11cby receptor

[0001] This invention relates to a method of treatment using an antagonist of the human 11CBy receptor; a new therapeutic use of a class of carboxamide compounds which are antagonists to a human 11CBy receptor; also to novel compounds within that class, and to methods for making the compounds.

[0002] International Patent Application Publication Number WO 01/21577 (Takeda Chemical Industries Ltd.) discloses certain bisaryl compounds as melanin concentrating hormone antagonists.

[0003] WO 98/00401 (Merck & Co. Inc.) discloses benzamide derivatives as fibrinogen receptor antagonist prodrugs.

[0004] European Patent EP 0 358 118 (Boehringer Mannheim GmbH) discloses certain bisaryl compounds as inhibitors of erythrocyte aggregation and useful in the treatment of cardiac and circulatory disease.

[0005] European Patent Application EP 0 968 999 (Mitsui Chemical Inc.) discloses certain anilide derivatives useful in the treatment of arrhythmia.

[0006] WO 99/01127 (SmithKline Beecham) discloses certain N-[(amino alkoxy)phenyl] benzamides that are active as CCR5 receptor ligands, including the compounds N-[4-[2-[bis(1-methylethyl)amino]ethoxy]-2-fluorophenyl]-[1,1′-biphenyl]-4-carboxamide and N-[4-[2-[bis(1-methylethyl)amino]-ethoxy]-phenyl]-[1,1′-biphenyl]4-carboxamide. Also WO 99/06146 (SmithKline Beecham) discloses certain substituted anilides that are antagonists of the CCR5 receptor, including the compounds: biphenyl-4-carboxylic acid [4-(2-dimethylamino-ethoxy)-phenyl]-amide, biphenyl-4-carboxylic acid [4(2-diisopropylamino-ethoxy)-phenyl]-amide, N-[4-(2-diisopropylamino-ethoxy)-phenyl]-4-phenoxy-benzamide, N-[4-(2-diethylamino-ethoxy)-phenyl]-4-phenoxy-benzamide, N-[4-(2-diisopropylamino-ethoxy)-phenyl]-3-phenoxy-benzamide, N-[4-(2-diethylamino-ethoxy)-phenyl]-3-phenoxy-benzamide, 4-cyclohexyl-N-[4-(2-diisopropylamino-ethoxy)-phenyl]-benzamide, 4-cyclohexyl-N-[4-(2-diethylamino-ethoxy)-phenyl]-benzamide, 4-benzyl-N-[4-(2-diisopropylamino-ethoxy)-phenyl]-benzamide, 4-benzyl-N-[4-(2-diethylamino-ethoxy)-phenyl]-benzamide, 4′-ethyl-biphenyl-4-carboxylic acid [4-(2-diisopropylamino-ethoxy)-phenyl]-amide, and 4′-ethyl-biphenyl-4-carboxylic acid [4-(2-diethylamino-ethoxy)-phenyl]-amide.

[0007] The present invention is based on the finding that a class of carboxamides overlapping with the above-mentioned benzamides and anilides, are, surprisingly, antagonists of a human 11CBy receptor disclosed in Nature, 400, 261-265 (1999).

[0008] Accordingly these compounds are believed to have a role in preventing, ameliorating or correcting dysfunctions or diseases, including, but not limited to, infections such as bacterial, fungal, protozoan and viral infections, particularly infection caused by HIV-1 or HIV-2; pain; cancers; diabetes; obesity; feeding and drinking abnormalities, such as anorexia and bulimia; asthma; Parkinson's disease; both acute and congestive heart failure; hypotension; hypertension; urinary retention; osteoporosis; angina pectoris; myocardial infarction; ulcers; allergies; benign prostatic hypertrophy; psychotic and neurological disorders, including anxiety, schizophrenia, manic depression, delirium, dementia or severe mental retardation; and dyskinesias, such as Huntington's disease or Gilles de la Tourette's syndrome, among others, hereinafter referred to as “the Disorders”.

[0009] According to the present invention there is provided a method of treating the Disorders which comprises administering to a mammal suffering from one or more of the Disorders an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, in which:

[0010] each A is independently hydrogen, a C1-6 alkyl optionally substituted by hydroxyl, C1-6 alkoxy, C1-6 alkenyl or C1-6 acyl group or a halogen atom or hydroxyl, CN or CF3 group; R3 is hydrogen, methyl or ethyl.

[0011] Preferably R3 is methyl.

[0012] R4 is an optionally substituted aromatic carbocyclic or heterocyclic ring.

[0013] Z is an O or S atom, or an NH or CH2 group, or a single bond, at the 3 or 4 position of R4 relative to the carbonyl group.

[0014] Preferably, Z is a bond.

[0015] More preferably, Z is a bond at the 4-position of R4 relative to the carbonyl group. R5 is an optionally substituted aromatic carbocyclic or heterocyclic ring, or an optionally substituted, saturated or unsaturated, carbocyclic or heterocyclic ring.

[0016] Preferably, R5 is a phenyl ring.

[0017] and Q is

[0018] (a) where X is an O or S atom, preferably an O atom;

[0019] Y is a linear or branched C2-4 alkylene group, preferably a C3 alkylene group, optionally substituted by a hydroxyl group, or is a C5-6 cycloalkylene group,

[0020] R1 and R2 are independently a linear or branched C1-6 alkyl, preferably ethyl; phenyl C1-6 alkyl group; or

[0021] (b) where X is an O or S atom;

[0022] Y is a linear or branched C2-4 alkylene group, optionally substituted by a hydroxyl group,

[0023] R1 and R2 are linked to form a 5, 6 or 7-membered ring, preferably a 5-membered ring, optionally containing one or more further heteroatoms selected from O, S or N, where N or C ring atoms are optionally substituted by Ra, —CO-Ra, —CO—NH-Ra, or CO—O-Ra, where Ra is a linear or branched C1-6 alkyl or aryl group; and the 5, 6 or 7-membered ring is optionally fused to an optionally substituted benzene ring, or a ring atom of the 5, 6 or 7-membered ring is optionally linked by a single bond or methylene group to Y; or

[0024] (c) where X is an O or S atom,

[0025] Y is a C2-4 alkylene group, R1 is a C2-4 alkylene group linked to Y to form a 5 or 6 membered ring and R2 is a linear or branched C1-6 alkyl group; or

[0026] (d) where X is a N atom,

[0027] Y is a C24 alkylene group, R1 is a C2-4 alkylene group linked to X to form a 5 or 6 membered ring and R2 is a linear or branched C1-6 alkyl group.

[0028] Alkyl groups, including alkyl groups that are part of alkoxy, acyl, etc groups, typically contain 1 to 6 carbon atoms, and may be linear or branched, such as methyl, ethyl, i-propyl and t-butyl, and optionally substituted by hydroxyl. Aryl groups are typically phenyl, but may include bicyclic groups such as naphthyl. Cycloalkyl groups typically contain from 3 to 7 carbon atoms. Heterocyclic groups may be monocylic 5 to 7 membered rings containing up to three hetero atoms, such as pyridyl or imidazole, or bicyclic, especially heterocyclic rings fused to benzene rings, such as benzoxazole or benzimidazole. Aryl, cycloalkyl and heterocyclic groups may be optionally subsituted by up to three substituents, which may suitably be selected from aryl, alkyl, alkoxy, halogen, hydroxy and cyano, or by linked substituents such as dioxymethylene.

[0029] Suitable aromatic rings for use as R4 include phenyl, pyridyl, thienyl, furanyl and pyrazolyl. Suitable optional substituents for R4 include halogen, CF3, C1-4 alkyl, C1-4 alkoxy. R4 may have 2 or 3 substituents, but preferably has only 1 substituent in addition to Z, or more preferably is unsubstituted apart from Z. Particularly suitable substituents for R4 include chloro, fluoro, trifluoromethyl, methyl, methoxy.

[0030] R5 may be monocyclic, for example thienyl, furanyl, imidazolyl, oxadiazolyl, phenyl, pyridinyl, cyclohexyl, piperidinyl, piperazinyl, pyrazinyl, pyrimidinyl; or a fused bicyclic ring system, for example naphthyl, 3,4-dioxymethylene-phenyl, benzofuranyl, indolyl; or a bicyclic system in which a monocyclic ring has a cyclic substituent such as oxadiazolyl, benzyloxy. Suitable optional substituents for R5 include halogen, CF3, CF3O, CHF2O, CN, amino, mono- or di-C1-6 alkylamino, C1-6 alkyl, C1-6 alkoxy, C1-6 acyl, C1-6 alkyl-S—, C1-6 alkyl-SO2—, C1-6 alkenyl, phenyl-C1-6 alkyl, phenyl-C1-6 alkoxy. R5 may have 2 or 3 substituents, but preferably has only 1 substituent, especially in the para position relative to Z. Particularly suitable substituents for R5 include chloro, fluoro, trifluoromethyl, cyano, amino, methyl, ethyl, t-butyl, methoxy, acetyl, formyl, methylthio, methanesulphonyl, vinyl, benzyl, benzyloxy, hydrogen.

[0031] As for the ring substituents A, all A substituents may be hydrogen, but it is advantageous that no more than 3 are hydrogen. Suitable A substituents include halogen, C1-6 alkyl optionally substituted with hydroxy, C1-6 alkoxy, C1-6 acyl and C1-6 alkenyl. Particularly suitable A substituents include C1-2alkoxy, C1-2alkyl, C1-2 acyl. Preferable substituents for A include chloro, fluoro, methyl, ethyl, hydroxyethyl, methoxy, formyl, acetyl, vinyl and allyl. More preferable substituents for A include methoxy. Suitably, the A substituent is adjacent to the group Q.

[0032] In the system Q, in configuration (a) particularly suitable substituents for R1 and R2 include methyl, ethyl, isopropyl, benzyl, phenethyl. Y may especially be —(CH2)2—, —(CH2)3—, —(CH2)4—, —CH2—CH(CH3)—CH2—. When Y is substituted by hydroxy, it may be for example —CH2—CH(OH)—CH2—.

[0033] In configuration (b) of system Q, the ring formed by linking R1 and R2 may be pyrrolidinyl, piperidinyl, azepanyl, or imidazolyl. Fused rings include indolinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl and benzoazepinyl. When a second heteroatom is present, suitable rings include thiazinyl, oxazinyl and piperazinyl. A second N atom may be substituted, for example by phenyl, methyl, ethyl, isopropyl or acetyl. Y is typically —(CH2)2—. The ring may be linked back to Y to form a quinuclidinyl group.

[0034] In configuration (c) of system Q, the ring formed by linking R1 to Y may be a pyrrolidinyl or piperidinyl ring. The linkage to Y may be such as to create a ring linked by a single bond from a ring carbon atom directly to X or via a methylene or ethylene linking group. R2 is typically methyl so that the N atom of the ring is substituted by methyl.

[0035] In configuration (d) of system Q, the ring formed by linking R1 to N is suitably a 5 or 6-membered ring such as diazinyl or piperazinyl. Y is typically —(CH2)2—. R2 is typically methyl so that the second N atom (other than X) of the ring is substituted by methyl.

[0036] Within the scope of formula (I) is a class of compounds of general formula (II)

[0037] where A=H and OMe, R3=H, X=O, Y=CH2CH2, Z= a bond, R4=Ph, R5 is either meta or para substituted on R4, and R1, R2 and R5 are as defined for formula (I).

[0038] Also within the scope of formula (I) is a class of compounds of general formula (III)

[0039] where A=H and OMe, R3=H, X=O, Y=CH2—CH2, Z=O, CH2 or NH and is either meta or para substituted on R4, R4=Ph, R5 is Ph, and R1 and R2 are as defined for formula (I).

[0040] Also within the scope of formula (I) is a class of compounds of general formula (IV)

[0041] where A=H and OMe, R1=R2=iPr, R3=H, X=O, Y=CH2—CH2, and R4 and R5 are substituted phenyl or heterocycles as defined for formula (I)

[0042] Also within the scope of formula (I) is a class of compounds of general formula (V)

[0043] where R3=H, X=O, Y=CH2—CH2, Z=O, CH2, NH or a bond, R4=Ph, R5 is Ph or cyclohexyl (Cy), Z is either meta or para substituted on R4, and A (R6, R7) and R1, R2 are as defined in formula (I).

[0044] Also within the scope of formula (I) is a class of compounds of general formula (VI)

[0045] where X=O, Y=CH2—CH2, R4=phenyl, R5=phenyl or cyclohexyl (Cy), Z=O, CH2 or a bond, and A R8, R9), R3 and R1, R2 are as defined in formula (I).

[0046] Also within the scope of formula (I) is a class of compounds of general formula (VII)

[0047] where A=H and OMe, X=O, R3=H, R4=3-pyridyl (with respect to the carbonyl group), R5=phenyl, Z=a para bond, and R1, R2 are as defined in formula (I).

[0048] Also within the scope of formula (I) is a class of compounds of general formula (VIII)

[0049] where A=H and OMe, R3=H, X=O, R4=phenyl, Z=O, C2 or a bond, R5=Ph or cyclohexyl (Cy), Y is a chain of 3 or 4 carbon atoms optionally substituted by an hydroxyl group, and R1, R2 are as defined in formula (I).

[0050] Also within the scope of formula (I) is a class of compounds of general formula (IX)

[0051] where A=H and OMe, R3=H, X=N, R4=phenyl, Z=a para substituted bond, R5=Ph or cyclohexyl (Cy), Y and R2 form a piperazinyl ring between X and N, and R1 is as defined in formula (I).

[0052] A preferred sub-class of compounds for use in the method of treatment of this invention are compounds of formula (I) in which R3 is methyl.

[0053] Within formula (I) is a novel group of compounds in which R3 is methyl or ethyl. The novel compounds, or a salt or solvate thereof, form a further aspect of this invention.

[0054] A particular group of novel compounds is a class of compounds of general formula (VI)

[0055] where R8 and R9 are as defined for A in formula (I), R1, R2 and R5 are as defined in formula (I), and R3 is methyl or ethyl.

[0056] Suitably R5 is phenyl or cyclohexyl optionally substituted by halogen, haloalkyl, alkyl or alkoxy; Z is O, CH2 or a single bond; R8 and R9 are independently selected from hydrogen, halogen, alkyl and alkoxy; R1 and R2 are alkyl or linked together to form a ring; and R3 is ethyl or methyl.

[0057] Another aspect of this invention is a class of novel compounds, or a salt or solvate thereof, which are the compounds of formula (I) excluding the compounds:

[0058] N-[4-[2-[bis(1-methylethyl)amino]ethoxy]-2-fluorophenyl]-[1,1′-biphenyl]-4-carboxamide,

[0059] N-[4-[2-[bis(1-methylethyl)amino]ethoxy]phenyl]-[1,1′-biphenyl]-4-carboxamide, biphenyl-4-carboxylic acid [4-(2-diisopropylamino-ethoxy)-phenyl]-amide,

[0060] N-[4-(2-diisopropylamino-ethoxy)-phenyl]-4-phenoxy-benzamide,

[0061] N-[4-(2-diethylamino-ethoxy)-phenyl]-4-phenoxy-benzamide,

[0062] N-[4-(2-diisopropylamino-ethoxy)-phenyl]-3-phenoxy-benzamide,

[0063] N-[4-(2-diethylamino-ethoxy)-phenyl]-3-phenoxy-benzamide,

[0064] 4-cyclohexyl-N-[4-(2-diisopropylamino-ethoxy)-phenyl]-benzamide,

[0065] 4-cyclohexyl-N-[4-(2-diethylamino-ethoxy)-phenyl]-benzamide,

[0066] 4-benzyl-N-[4-(2-diisopropylamino-ethoxy)-phenyl]-benzamide,

[0067] 4-benzyl-N-[4-(2-diethylamino-ethoxy)-phenyl]-benzamide,

[0068] 4′-ethyl-biphenyl-4-carboxylic acid [4-(2-diisopropylamino-ethoxy)-phenyl]-amide,

[0069] and 4′-ethyl-biphenyl-4-carboxylic acid [4-(2-diethylamino-ethoxy)-phenyl]-amide.

[0070] A further aspect of this invention is those compounds of the Examples herein which are novel.

[0071] The compounds of formulae (I) to (IX), or their salts or solvates, are preferably in pharmaceutically acceptable or substantially pure form. By pharmaceutically acceptable form is meant, inter alia, of 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.

[0072] Suitable salts and solvates include pharmaceutically acceptable salts and pharmaceutically acceptable solvates.

[0073] Suitable pharmaceutically acceptable salts 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-β-phenethylamine, dehydroabietylamine, N,N′-bisdehydroabietylamine, glucamine, N-methylglucamine or bases of the pyridine type such as pyridine, collidine, quinine or quinoline.

[0074] Suitable pharmaceutically acceptable salts also includes pharmaceutically acceptable acid addition salts, such as those provided by pharmaceutically acceptable inorganic acids or organic acids.

[0075] Suitable pharmaceutically acceptable acid addition salts provided by pharmaceutically acceptable inorganic acids includes the sulphate, nitrate, phosphate, borate, hydrochloride and hydrobromide and hydroiodide.

[0076] Suitable pharmaceutically acceptable acid addition salts provided by pharmaceutically acceptable organic acids includes the acetate, tartrate, maleate, fumarate, malonate, citrate, succinate, lactate, oxalate, benzoate, ascorbate, methanesulphonate, α-keto glutarate and α-glycerophosphate.

[0077] Suitable pharmaceutically acceptable solvates include hydrates.

[0078] 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) to (IX) or its salt or solvate.

[0079] One preferred pharmaceutically acceptable form is the crystalline form, including such form in a pharmaceutical composition. In the case of salts and solvates the additional ionic and solvent moieties must also be non-toxic.

[0080] Examples of pharmaceutically acceptable salts of a compound of formula (I) to (IX) 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.

[0081] The compounds of formula (I) to (IX) may exist in more than one stereoisomeric form, and the invention extends to all such forms as well as to their mixtures thereof, including racemates.

[0082] The compounds of formula (I) to (IX), or salts or solvates thereof, may be prepared by the methods illustrated in the following general reaction schemes, or by modification thereof, using readily available starting materials, reagents and conventional synthetic procedures. If a particular enantiomer of a compound of the present invention is desired, it may be synthesised starting from the desired enantiomer of the starting material and performing reactions not involving racemization processes or it may be prepared by chiral synthesis, or by derivatisation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxy, diastereomeric salts are formed with an appropriate optically active acid or base, followed by resolution of diastereomeric salts by fractional crystallization and subsequent recovery of the pure enantiomers.

[0083] Compounds of formula (I) to (IX) may prepared by condensing suitably substituted aryl or heteroarylcarboxylic acids and suitably substituted anilines, which are commercially available or synthesized by methods known to the art from commercially available starting materials, using methods known to the art. For example, suitably substituted aryl or heteroarylcarboxylic acids are treated with an activating reagent, such as thionyl chloride, at a suitable temperature, such as at reflux, to afford aryl or heteroarylcarbonyl chlorides, and the aryl- or heteroarylcarbonyl chlorides are condensed with suitably substituted anilines in the presence of a suitable base, such as diisopropylethylamine, in a suitable solvent, such as dichloromethane, to give compounds of formula (I).

[0084] In particular, the preparation of certain carboxamides of formula (I) in which R3 is H is disclosed in WO 99/01127 and WO 99/06146 mentioned above, and analogous methods of preparation may be used in the present invention. Many additional methods for converting a carboxylic acid to an amide are known, and can be found in standard reference books such as “Compendium of Organic Synthetic Methods”, Vol. I-VI (published by Wiley-Interscience).

[0085] For example the compounds of formula (I) may be prepared by reacting a compound of formula (X)

R5-Z-R4-COL (X)

[0086] where L is a leaving group such as halogen, especially chlorine or bromine with a compound of formula (XI)

[0087] where A, Z, R3, R4, R5 and Q are as defined for formula (I).

[0088] In this process, groups convertible to R1, R2, R3, R4 and R5 may be present during the coupling, and converted to R1, R2, R3, R4 and R5 after coupling. Also it may be convenient to convert one R1, R2, R3, R4 and R5 to another R1, R2, R3, R4 and R5 group after coupling. In particular, ring formation between the groups R1, X, Y, R2 or the addition of suitable cyclic groups embodying R1, X, Y, R2, may be performed after coupling.

[0089] Accordingly, there is provided a process for the preparation of a compound of formula (I), or a salt or solvate thereof, wherein R3 is methyl or ethyl which process comprises the reaction of a compound of formula (X) as hereinbefore defined with a compound of formula (XI) wherein A and Q are as hereinbefore defined and R3 is methyl or ethyl.

[0090] There therefore also provided a process for the preparation of a compound of formula (I), or a salt or solvate thereof, with the proviso that the following compounds are excluded;

[0091] N-[4-[2-[bis(1-methylethyl)amino]ethoxy]-2-fluorophenyl]-[1,1′-biphenyl]4-carboxamide,

[0092] N-[4-[2-[bis(1-methylethyl)amino]ethoxy]phenyl]-[1,1′-biphenyl]4-carboxamide, biphenyl-4-carboxylic acid [4-(2-diisopropylamino-ethoxy)-phenyl]-amide,

[0093] N-[4-(2-diisopropylamino-ethoxy)-phenyl]A4-phenoxy-benzamide,

[0094] N-[4-(2-diethylamino-ethoxy)-phenyl]-4-phenoxy-benzamide,

[0095] N-[4-(2-diisopropylamino-ethoxy)-phenyl]-3-phenoxy-benzamide,

[0096] N-[4-(2-diethylamino-ethoxy)-phenyl]-3-phenoxy-benzamide,

[0097] 4-cyclohexyl-N-[4-(2-diisopropylamino-ethoxy)-phenyl]-benzamide,

[0098] 4-cyclohexyl-N-[4-(2-diethylamino-ethoxy)-phenyl]-benzamide,

[0099] 4-benzyl-N-[4-(2-diisopropylamino-ethoxy)-phenyl]-benzamide,

[0100] 4-benzyl-N-[4-(2-diethylamino-ethoxy)-phenyl]-benzamide,

[0101] 4′-ethyl-biphenyl-4-carboxylic acid [4-(2-diisopropylamino-ethoxy)-phenyl]-amide,

[0102] and 4′-ethyl-biphenyl-4-carboxylic acid [4-(2-diethylamino-ethoxy)-phenyl]-amide.

[0103] which process comprises the reaction of a compound of formula (X) as hereinbefore defined with a compound of formula (XI) as hereinbefore defined.

[0104] The compounds of formula (XI) may be prepared in a number of ways, for example when X is O or S coupling an appropriately substituted nitrobenzene compound with a dialkyaminoalcohol or thiol, and converting the NO2 group to NH2 by hydrogenation in the presence of palladium catalyst (or with iron/ammonium chloride) before coupling with an acid chloride, for example as illustrated below:

[0105] Acid chlorides of formula (X) may be prepared from the corresponding acids which are commercially available or described in the literature or may be prepared by methods analogous to those of the literature.

[0106] Alternatively the acids of formula (X) may be prepared by combining moieties containing respectively R5 and R4 via Z.

[0107] This may also be achieved conveniently by first coupling a compound of R4-CO-L with the compound of formula (XI) followed by reaction with a compound R5-Z-L (or L-R4-CO-L with R5-Z). For example an amine of formula (XI) may be reacted with an appropriately substituted bromobenzoyl chloride which may be then reacted with, for example, an appropriately substituted phenyl moiety with a leaving group, or a cyclic amine, as in the following scheme:

[0108] Similar reactions building up the structure of formula (I) may be carried out starting with the compound of formula (X) and adding the equivalent of formula (XI) in sections, as in the scheme below where an N-protecting group on Q, here a piperazine ring, may be removed after coupling the components of formula (I) and replacement by a desired substituent:

[0109] In an alternative strategy for building up the compounds of formula (XI) before coupling, so as to introduce a hydroxy group in Y, an appropriately substituted nitrophenol is linked to an epoxy compound which is then reacted with an amine forming a group Q which is —O—Y(OH)-NR1R2, before coupling with R5-Z-R4-CO-L, as illustrated by:

[0110] Novel compounds of formula (I) where the amide nitrogen is alkylated (R3 is methyl or ethyl) may be prepared by alkylating an anilide of formula M(I) before coupling with an acid chloride of formula (X), for example, by utilising the following reductive amination procedure:

[0111] The compounds of formula (I) may be converted into their pharmaceutically acceptable salts by reaction with the appropriate organic or mineral acids.

[0112] Solvates of the compounds of formula (I) may be formed by crystallization or recrystallization from the appropriate solvent. For example, hydrates may be formed by crystallization or recrystallization from aqueous solutions, or solutions in organic solvents containing water.

[0113] Also salts or solvates of the compounds of formula (I) which are not pharmaceutically acceptable may be useful as intermediates in the production of pharmaceutically acceptable salts or solvates. Accordingly such salts or solvates also form part of this invention.

[0114] The above-listed compounds and pharmaceutically acceptable salts thereof, especially the hydrochloride, and pharmaceutically acceptable solvates, especially hydrates, form a preferred aspect of the present invention.

[0115] By virtue of the activity of these compounds as antagonists of a human 11CBy receptor, the compounds of formula (I) are believed to have a role in preventing, ameliorating or correcting dysfunctions of diseases, including, but not limited to, “the Disorders” previously mentioned.

[0116] It is also considered that the treatment of certain of the Disorders mentioned above by an antagonist to the human 11CBy receptor are novel. Accordingly, the invention also provides a method for the treatment of diabetes, major depression, manic depression, anxiety, schizophrenia and sleep disorders, in human or non-human mammals which method comprises the administration of a therapeutically effective amount of an antagonist to the human 11CBy receptor. In particular the the invention provides a method for the treatment of diabetes in human or non-human mammals which method comprises the administration of a therapeutically effective amount of an antagonist to the human 11CBy receptor. In particular the invention provides a method for the treatment of major depression, in human or non-human mammals which method comprises the administration of a therapeutically effective amount of an antagonist to the human 11CBy receptor. In particular the invention provides a method for the treatment of manic depression, in human or non-human mammals which method comprises the administration of a therapeutically effective amount of an antagonist to the human 11CBy receptor. In particular the the invention provides a method for the treatment of anxiety in human or non-human mammals which method comprises the administration of a therapeutically effective amount of an antagonist to the human 11CBy receptor. In particular the the invention provides a method for the treatment of schizophrenia in human or non-human mammals which method comprises the administration of a therapeutically effective amount of an antagonist to the human 11CBy receptor.

[0117] In particular the the invention provides a method for the treatment of sleep disorders, in human or non-human mammals which method comprises the administration of a therapeutically effective amount of an antagonist to the human 11CBy receptor.

[0118] The administration of such compounds to a mammal may be by way of oral (including sub-lingual), parenteral, nasal, rectal or transdermal administration.

[0119] An amount effective to treat the Disorders hereinbefore described depends on the usual factors such as the nature and severity of the disorders being treated and the weight of the mammal. However, a unit dose will normally contain 1 to 1000 mg, suitably 1 to 500 mg, for example an amount in the range of from 2 to 400 mg such as 2, 5, 10, 20, 30, 40, 50, 100, 200, 300 and 400 mg of the active compound. Unit doses will normally be administered once or more than once per day, for example 1, 2, 3, 4, 5 or 6 times a day, more usually 1 to 4 times a day, such that the total daily dose is normally in the range, for a 70 kg adult of 1 to 1000 mg, for example 1 to 500 mg, that is in the range of approximately 0.01 to 15 mg/kg/day, more usually 0.1 to 6 mg/kg/day, for example 1 to 6 mg/kg/day.

[0120] It is greatly preferred that compounds of formula (I) are administered in the form of a unit-dose composition, such as a unit dose oral (including sub-lingual), nasal, rectal, topical or parenteral (especially intravenous) composition.

[0121] Such compositions are prepared by admixture and are suitably adapted for oral or parenteral administration, and as such may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable and infusable solutions or suspensions or suppositories. Orally administrable compositions are preferred, in particular shaped oral compositions, since they are more convenient for general use.

[0122] Tablets and capsules for oral administration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers, diluents, tabletting agents, lubricants, disintegrants, colourants, flavourings, and wetting agents. The tablets may be coated according to well known methods in the art.

[0123] Suitable fillers for use include cellulose, mannitol, lactose and other similar agents. Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycollate. Suitable lubricants include, for example, magnesium stearate. Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate.

[0124] These solid oral compositions may be prepared 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. Such operations are, of course, conventional in the art.

[0125] Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and if desired conventional flavouring or colouring agents.

[0126] Oral formulations also include conventional sustained release formulations, such as tablets or granules having an enteric coating.

[0127] For parenteral administration, fluid unit dose forms are prepared containing the compound and a sterile vehicle. The compound, depending on the vehicle and the concentration, can be either suspended or dissolved. Parenteral solutions are normally prepared by dissolving the compound in a vehicle and filter sterilising before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum.

[0128] Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and is sterilised by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound of the invention.

[0129] As is common practice, the compositions will usually be accompanied by written or printed directions for use in the medical treatment concerned.

[0130] Compounds of the present invention may be employed alone or in conjunction with other compounds, such as therapeutic compounds.

[0131] No adverse toxicological effects are expected for the compounds of the invention, when administered in accordance with the invention.

[0132] Accordingly, in a further aspect, the present invention provides a pharmaceutical composition for use in the treatment and/or prophylaxis of one or more of the Disorders which comprises a compound of this invention, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0133] The present invention also provides a method of treatment and/or prophylaxis of one or more of the Disorders comprising administering to the sufferer in need thereof an effective or prophylactic amount of a compound of this invention, or a pharmaceutically acceptable salt or solvate thereof.

[0134] In a further aspect the invention provides the use of a compound of this invention, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment and/or prophylaxis of one or more of the Disorders.

[0135] In a still further aspect the invention provides the use of a novel compound of this invention, or a pharmaceutically acceptable salt or solvate, thereof as a therapeutic agent, in particular for the treatment and/or prophylaxis of one or more of the Disorders.

[0136] Compounds for use in this invention and their preparation are illustrated in the following Examples and Tables.

[0137] These Examples illustrate general procedures and sources of chemicals utilised to prepare compounds whose structures are shown in the Tables of data which follow the Examples. In the case of Examples prepared as members of a coupled array, the synthetic origin of all starting componants of the array are shown in the Examples. Rather than detailing the experimental procedure for each case, the method by which individual members of the array were prepared is indicated in a Table by reference to a related Example. Mass spectral characterisation of all Examples is provided in the tables of data. Additional characterisation is provided for selected representative Examples with full experimental procedures.

EXAMPLE A1

WO-00/06146

[0138] Utilising the procedure of Example A7 with 4-biphenylcarboxylic acid [Aldrich] in place of 2′-methyl-4-biphenylcarboxylic acid.

EXAMPLE A2

[0139] Correspondingly Example A7 with 4-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzoic acid [J. Org. Chem. 50; 8; 1985; 1182].

EXAMPLE A3

[0140] Correspondingly Example A7 with 4-pyrazol-1-yl-benzoic acid [Can. J. Chem.; 41; 1963; 1540].

EXAMPLE A4

[0141] Correspondingly Example A7 with 3-biphenylcarboxylic [Med. Chem. Res.; 6; 2; 1996].

EXAMPLE A5

[0142] Correspondingly Example A7 with 4-(2-pyridyl)-benzoic acid [J. Chem. Soc.; 1940; 355, 356].

EXAMPLE A6

[0143] Correspondingly Example A7 with 3′-acetyl-biphenyl-4-carboxylic acid [Patent WO-9743262].

EXAMPLE A7

[0144] 2-methylphenyl-4-phenylcarboxylic acid [3-methoxy-4-(2-bis-(2-methylethyl)amino)-ethoxy)-phenyl amide.

[0145] To a solution of the acid (2′-methyl-biphenyl-4-carboxylic acid) [Patent WO-9901127] (55 mg, 0.26 mmol) in dimethylformamide were added (1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride [Aldrich] (50 mg, 0.26 mmol) and 1-hydroxy-7-azabenzotriazole [Aldrich] (35 mg, 0.26 mmol) followed by diisopropylethylamine (0.04 ml, 0.25 mmol) and the aniline (4-(2-diisopropylamino-ethoxy)-3-methoxy-phenylamine) (69 mg, 0.22 mmol), [prepared using the method used to form 3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine in Example A51 but with 2-diisopropylamino-ethanol in place of 1-(2-hydroxyethyl)-pyrrolidine]. The reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated, and the residue re-dissolved in dichloromethane (10 ml), filtered through an SAX [Varian] column (2 g), and the filtrate was then stirred with PS-isocyanate resin [Argonaut Technologies] (100 mg, 0.38 mmol) for 16 hours. The mixture was filtered, evaporated, and the residue purified by flash chromatography on silica gel using dichloromethane—aq. ammonia—methanol as eluent, to afford the title compound as an oil.

[0146]

1
H NMR (CDCl3): δ 1.04 (12H, d), 2.28 (3H, s), 2.90 (2H, t), 3.05 (2H, m), 3.91 (3H, s), 3.95 (2H, t), 6.88 (1H, d), 7.03 (1H, dd), 7.27-7.32 (4H, m), 7.44, (2H, d), 7.53 (1H, d), 7.94 (2H, d) and 8.01 (1H, bs); MS (AP+ve): m/z 461 [M+H]+.

EXAMPLE A8

[0147] Utilising the procedure of Example A7 with cyclohexyl-4-benzoic acid [Aldrich], in place of (2′-methyl-biphenyl-4-carboxylic acid).

EXAMPLE A9

[0148] Correspondingly Example A7 with 4-(2-thienyl)-benzoic acid [J. Chem. Soc. Perkin Trans.1; 17; 1992; 2203].

EXAMPLE A10

[0149] Correspondingly Example A7 with 4-(1-methyl-1H-pyrazol-4-yl)-benzoic acid [Patent:WO-9906409].

EXAMPLE A11

[0150] Correspondingly Example A7 with 4′-(5-methyl-[1,2,4]oxadiazol-3-yl)-biphenyl-4-carboxylic acid [Patent:WO-9743262].

EXAMPLE A12

[0151] Correspondingly Example A7 with 4-benzyl-carboxylic acid [Apin].

EXAMPLE A13

[0152] Correspondingly Example A7 with 3′-cyano-biphenyl-3-carboxylic acid [J. Chem. Soc. Perkin Trans. 2; 1; 1984; 35-38].

EXAMPLE A14

[0153] Correspondingly Example A7 with 3′-methanesulfonyl-biphenyl-4-carboxylic acid [Izv. Sib. Otd. Akad. Nauk SSSR Ser. Khim. Nauk; 11; 1966; 62].

EXAMPLE A15

[0154] Correspondingly Example A7 with 3-thiophen-2-yl-benzoic acid [Tetrahedron Lett.; 39; 24;1998;4175].

EXAMPLE A16

[0155] Correspondingly Example A7 with 3-thiophen-3-yl-benzoic acid [J. Chem. Soc. B; 1970; 1595].

EXAMPLE A17

[0156] Correspondingly Example A7 with 4-acetyl-4-biphenylcarboxylic acid [Aldrich].

EXAMPLE A18

[0157] Correspondingly Example A7 with 4′-cyano-3′-methylbiphenyl-4-carboxylic acid [WO-9850358].

EXAMPLE A19

[0158] Correspondingly Example A7 with 4′-(5-methyl-[1,3,4]oxadiazol-2-yl)-biphenyl-4-carboxylic acid [Patent:WO-9743262].

EXAMPLE A20

[0159] Correspondingly Example A7 with 4-thiophen-3-yl-benzoic acid [J. Chem. Soc. B; 1970; 1595].

EXAMPLE A21

[0160] Correspondingly Example A7 with 4-pyrazin-2-yl-benzoic acid [Patent WO-9854164].

EXAMPLE A22

[0161] Utilising the procedures of Example A93 with 2-methoxyphenylboronic acid [Aldrich] in place of 4-methylphenylboronic acid, and Example A51 with 2-(diisopropylamino)-ethanol in place of 1-(2-hydroxyethyl)-pyrrolidine.

EXAMPLE A23

[0162] Utilising the procedure of Example A22 with 4-trifluoromethylphenylboronic acid [Aldrich], in place of 2-methoxyphenylboronic acid [Aldrich]

EXAMPLE A24

[0163] Correspondingly Example A23 with 3-aminophenylboronic acid [Aldrich].

EXAMPLE A25

[0164] Correspondingly Example A23 with 4-benzyloxyphenylboronic acid Lancaster].

EXAMPLE A26

[0165] Correspondingly Example A23 with 2-naphthylboronic acid [Lancaster].

EXAMPLE A27

[0166] Correspondingly Example A23 with 3-naphthylboronic acid [Lancaster].

EXAMPLE A28

[0167] Correspondingly Example A23 with 4-methylphenylboronic acid [Lancaster].

EXAMPLE A29

[0168] Correspondingly Example A23 with 4-methylthiophenylboronic acid [Lancaster].

EXAMPLE A30

[0169] Correspondingly Example A23 with 3-trifluoromethylphenylboronic acid [Lancaster].

EXAMPLE A31

[0170] Correspondingly Example A23 with 4-carbonylphenylboronic acid [Aldrich].

EXAMPLE A32

[0171] Correspondingly Example A23 with 3,4-(methylenedioxy)phenylboronic acid [Aldrich].

EXAMPLE A33

[0172] Correspondingly Example A23 with 4-vinylphenylboronic acid [Aldrich].

EXAMPLE A34

[0173] Correspondingly Example A23 with 3-methoxyphenylboronic acid [Lancaster].

EXAMPLE A35

[0174] Utilising the procedure of Example A51 with 1-(2-hydroxyethyl)morpholine [Aldrich] in place of 1-(2-hydroxyethyl)pyrrolidine.

EXAMPLE A36

[0175] Utilising the procedure of Example A35 with 4-cyclohexylbenzoic acid [Aldrich]. in place of 4-biphenylcarboxylic acid.

EXAMPLE A37

[0176] Utilising the procedure of Example A51 with 2-dimethylaminoethanol [Aldrich], in place of 1-(2-hydroxyethyl)pyrrolidine.

EXAMPLE A39

[0177] Correspondingly Example A51 with (R)-(+)-1-methyl-2-pyrrolidinemethanol (Patent WO-9932480).

EXAMPLE A41

[0178] Correspondingly Example A51 with 3-hydroxy-1-methylpiperidine [Aldrich].

EXAMPLE A43

[0179] Correspondingly Example A51 with 2-dimethylamino-1-propanol [ICN-RF].

EXAMPLE A45

[0180] Correspondingly Example A51 with 2-(diethylamino)-ethanol [Aldrich].

EXAMPLE A47

[0181] Correspondingly Example A51 with (S)-(−)-1-methyl-2-pyrrolidinemethanol [Aldrich].

[0182] EXAMPLE A49

[0183] Correspondingly Example A51 with N-benzyl-N-methylethanolamine [Aldrich].

[0184] EXAMPLE A51

[0185] Biphenyl-4-carboxylic acid [3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl amide. To a solution of the hydroxy amine, (1-(2-hydroxyethyl)-pyrrolidine) [Aldrich], (1.87 ml, 16 mmol) in dimethylformamide was added portionwise sodium hydride [60% dispersion in oil, (544 mg, 16 mmol). After stirring at room temperature for 10 minutes a solution of the halonitrobenzene, (1-chloro-2-methoxy-4-nitro-benzene) [Avocado] (3 g, 16 mmol) in dimethylformamide (10 ml) was added dropwise. The reaction mixture was left stirring at room temperature for 16 hrs then concentrated. The residue was dissolved in ethyl acetate (2001 ml) and washed with water (3×50 ml). The organic phase was dried with magnesium sulphate, evaporated and the residue purified by flash chromatography on silica gel using dichloromethane—aq. ammonia—methanol as eluent to afford 1-[2-(2-methoxy-4-nitro-phenoxy)-ethyl]-pyrrolidine as a brown oil.

[0186]

1
H NMR (CDCl3): δ 1.82 (4H, m), 2.65 (4H, m), 3.01 (2H, t), 3.94 (3H, s), 4.24 (2H, t), 6.92 (1H, d), 7.74 (1H, d), and 7.89 (1H, dd); MS (AP+ve): m/z 267 [M+H]+.

[0187] To a solution of the amine, 1-[2-(2-methoxy-4-nitro-phenoxy)-ethyl]-pyrrolidine (2.3 g, 8.6 mmol) in ethanol (100 ml) was added 10% Pd/C (50 mg). The mixture was stirred at room temperature under an atmosphere of hydrogen at atmospheric pressure for 16 h, then filtered through celite and the filtrate concentrated to give the corresponding aniline; 3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine, as a brown solid.

[0188]

1
H NMR (CDCl3): δ 1.80 (4H, m), 2.62 (4H, m), 2.89 (2H, t), 3.80 (3H, s), 4.06 (2 h, t), 6.20 (1H, dd), 6.29 (1H, d) and 6.75 (1H, d); MS (AP+ve): m/z 237 [M+H]+.

[0189] To the carboxylic acid, (4-biphenyl carboxylic acid) [Aldrich] (47.5 mg, 0.24 mmol) suspended in dichloromethane (1 ml) was added oxalyl chloride [Aldrich] (0.06 ml, 0.72 mmol) followed by one drop of dimethylformamide. The reaction mixture was stirred at room temperature for 1 hour, concentrated, then co-evaporated three times with dichloromethane to give 4-phenylbenzoyl chloride. This was dissolved in dichloromethane (1 ml) and added to a solution containing the amine, (3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine), (47 mg, 0.2 mmol), triethylamine (0.14 ml, 1 mmol) and dichloromethane (1 ml). The reaction mixture was stirred for 16 hours at room temperature, concentrated, re-dissolved in dichloromethane (10 ml), filtered through an SAX column [Varian] (2 g) and stirred with PS-isocyanate resin [Argonaut Technologies] (100 mg, 0.38 mmol) for 16 hours. The mixture was filtered, evaporated then purified by flash chromatography on silica gel using dichloromethane—aq. ammonia—methanol as eluent to afford the title compound as an oil.

[0190]

1
H NMR (CDCl3): δ 1.88 (4H, m), 2.90 (4H, m), 3.08 (2H, t), 3.84 (3H, s), 4.21 (2H, t), 6.83 (1H, d), 7.03 (1H, dd), 7.27-7.70 (8H, m) and 8.01 (2H, d); MS (AP+ve): m/z 417 [M+H]+.

EXAMPLE A54

[0191] Utilising the procedure of Example A51 with 1-dimethylamino-2-propanol [Aldrich] in place of 1-(2-hydroxyethyl)-pyrrolidine.

EXAMPLE A56

[0192] Correspondingly Example A51 with 1-(2-hydroxyethyl)-piperidine [Aldrich].

EXAMPLE A58

[0193] Correspondingly Example A51 with 2-(hexamethyleneamino)-ethanol [Lancaster].

EXAMPLE A60

[0194] Utilising the procedures of Example A93 with 3-aminophenylboronic acid in place of 2-methoxyphenylboronic acid and Example 51 with 2-dimethylaminoethanol in place of 1-(2-hydroxyethyl)pyrrolidine.

EXAMPLE A63

[0195] Utilising the procedure of Example A60 with 4-carboxyphenylboronic acid [Aldrich] in place of 3-aminophenylboronic acid.

EXAMPLE A70

[0196] Correspondingly Example A63 with (3,4-methylenedioxyphenyl)boronic acid [Aldrich].

EXAMPLE A72

[0197] Utilising the procedure of Example 51 with N-(2-phenyl)-ethyl-N-methyl-ethanolamine [J. Org. Chem. 1985, 50(22), 4359] in place of 1-(2-hydroxyethyl)-pyrrolidine.

EXAMPLE A74

[0198] Correspondingly Example 51 with 2-dimethylaminocyclohexanol [J. Chem. Soc. C (1969), (2), 248-52].

EXAMPLE A76

[0199] Correspondingly Example 51 with 2-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-ethanol [U.S. Pat. No. 394,682]

EXAMPLE A78

[0200] Correspondingly Example 51 with 2-(3,4-dihydro-1H-isoquinolin-2-yl)-ethanol [Patent WO-9719926].

EXAMPLE A80

[0201] Correspondingly Example 51 with 2-(4-phenyl-piperazin-1-yl)-ethanol [J. Med. Chem. 1994, 37(13), 1964].

EXAMPLE A82

[0202] Correspondingly Example 51 with 1-methyl-3-pyrrolidinol [Aldrich].

EXAMPLE A84

[0203] Utilising the procedures of Example A93 with 4-methoxy-phenylboronic acid [Aldrich] in place of 2-methoxyphenylboronic acid and Example A51 with 2-diethylaminoethanol in place of 1-(2-hydroxyethyl)pyrrolidine.

EXAMPLE A88

[0204] Utilising the procedures of Example A84 with 4-methoxy-3-pyridylboronic acid [Patent WO-9924440] in place of 4-methoxy-phenylboronic acid.

EXAMPLE A89

[0205] Correspondingly Example A88 with 2-methoxy-3-pyridylboronic acid [Patent WO-9910331].

EXAMPLE A90

[0206] Correspondingly Example A88 with benzo-[b]-furan-2-boronic acid [Aldrich].

EXAMPLE A91

[0207] Correspondingly Example A88 with thiophene-3-boronic acid [Aldrich].

EXAMPLE A92

[0208] Correspondingly Example A88 with indole-5-boronic acid [Frontier].

EXAMPLE A93

[0209] 4′-Methyl-biphenyl-4-carboxylic acid [3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amide

[0210] A mixture of 3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (Example A51] (4.7 mM 1.1 g) and triethylamine (14 mmol) was treated with 4-bromobenzoyl chloride [Aldrich] in dichloromethane (20 ml) and kept at room temperature for 16 hours. The solvent was evaporated and the crude product purified by chromatography on silica gel using dichloromethane—methanol—aq. ammonia to afford 4-bromo-N-[3-methoxy-4(2-pyrrolidin-1-yl-ethoxy)-phenyl]-benzamide as a white solid in 72% yield.

[0211]

1
H NMR (DMSO-d6): δ 7.91 (2H, dd), 7.73 (2H, dd), 7.50 (1H, d), 7.30 (1H, dd), 6.94 (1H, d), 4.02 (2H, t), 3.76 (3H, s), 2.77 (2H, t), 2.51 (4H, m under DMSO-d-5 signal) and 1.67 (4H, m); MS: (ES+ve) m/z 419, 421 [M+H]+

[0212] The amide, 4-bromo-N-[3-methoxy-4(2-pyrrolidin-1-yl-ethoxy)-phenyl]-benzamide (0.1 mM 42 mg), and 4-methyl-benzene boronic acid [Aldrich] (0.1 mM 14 mg) were refluxed for 16 hours in a mixture of benzene (8 ml), ethanol (2 ml) and 2M aqueous sodium carbonate (2 ml) in the presence of tetrakis-(triphenylphosphine)-palladium[0] (5 mg) under an argon atmosphere. The mixture was cooled, the upper layer decanted, and this solution purified by chromatography on silica gel using dichloromethane: methanol (10:1) followed by acetonitrile: satd. aqueous ammonia (25:1) to afford the title compound as a white solid.

[0213]

1
H NMR (CDCl3): δ 7.92 (2H, dd), 7.68 (2H, dd), 7.50 (21H, dd), 7.26 (3H, dddd), 6.96 (1H, dd), 6.88 (1H, d), 4.13 (1H, t), 3.87 (3H, s), 2.92 (2H, t), 2.60 (4H, m), 2.41 (3H, s) and 1.80 (4H, m); MS: (AP−ve) m/z 429 [M−H]−; (AP+ve) m/z 431 [M+H]+.

EXAMPLE A100

[0214] Utilising the procedure of Example A93 with 4-(2,6-dimethoxypyrimidinyl)-boronic acid [Frontier] in place of 4-methyl-benzene boronic acid.

EXAMPLE A103

[0215] Correspondingly Example A93 with furan-3-boronic acid [Frontier].

EXAMPLE A104

[0216] Correspondingly Example A93 with mesityl-boronic acid [Frontier].

EXAMPLE A105

[0217] Utilising the procedure of Example A51 except employing chloroform in place of dichloromethane as a solvent and eluent and utilising 3-quinuclidinol [Aldrich] in place of 1-(2-hydroxyethylpyrrolidine)

EXAMPLE A107

[0218] Utilising the procedure of Example B37 except using piperidine in place of aniline.

EXAMPLE B1

[0219] Utilising the procedure of Example A7 with 3-phenoxybenzoic acid [Aldrich] in place of 2′-methyl-biphenyl-4-carboxylic acid.

EXAMPLE B2

[0220] Correspondingly Example B1 using 4-benzylbenzoic acid [Apin].

EXAMPLE B34

Correspondingly Example B1 using 3-benzylbenzoic acid [Patent WO-9828268].

EXAMPLE B35

[0221] Correspondingly Example B1 using 4-phenoxybenzoic acid [Aldrich].

EXAMPLE B37

[0222] N-[-[3-Methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]4-phenylamino-benzamide

[0223] Dry cesium carbonate (0.15 mM, 49 mg), (S)-BINAP [Aldrich] (0.015 mM, 9 mg) and palladium acetate (0.0075 mM, 2 mg) were sonicated in anhydrous ethyleneglycol dimethyl ether (15 ml) for 40 minutes under an argon atmosphere. This suspension was treated with 4-bromo-N-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-benzamide [Example A93] (0.1 mM, 42 mg) and aniline (0.11 mM, 10 mg) then refluxed for 40 hours. The suspension was filtered through a hydrophobic membrane, concentrated, then purified on C18 R.P. silica using acetonitrile:water to afford the title compound as a white solid.

[0224]

1
H NMR (MeOH-d4): δ 7.96 (2H, dd) 7.92 (1H, d), 3.1 (2H, dd), 7.20 (1H, dd), 7.04 (1H, d), 4.28 (2H, t), 3.92 (3H, s), 3.78 (2H, m), 3.60 (2H, t), 3.58-3.13 (6H, m) and 2.26-1.47 (10H, m); MS: (ES+ve) m/z 424 [M+H]+

EXAMPLE C1

[0225] Utilising the procedure of Example A7 with 2-methylbiphenyl-4-carboxylic acid [Patent WO-9606079] in place of 2′-methyl-biphenyl-4-carboxylic acid.

EXAMPLE C2

[0226] Correspondingly Example C1 using 3-methoxybiphenyl-4-carboxylic acid [Patent WO-9534540].

EXAMPLE C3

[0227] Correspondingly Example C1 using 3-methylbiphenyl-4-carboxylic acid [Patent WO-9534540].

EXAMPLE C4

[0228] Correspondingly Example C1 using 4-phenylthiophene-2-carboxylic acid [Specs].

EXAMPLE C5

[0229] Correspondingly Example C1 using 4-(3,5-dichlorophenoxy)-furan-2-carboxylic acid [Maybridge].

EXAMPLE C6

[0230] Correspondingly Example C1 using 5-methyl-1-phenylpyrazole-4-carboxylic acid Maybridge].

EXAMPLE C7

[0231] Correspondingly Example C1 using 6-phenyl-nicotinic acid [WO-0006085].

EXAMPLE C8

[0232] Correspondingly Example C1 using 3-chloro-biphenyl-4-carboxylic acid [Patent JP-09221476].

EXAMPLE C9

[0233] Correspondingly Example C1 using 5-(4-chlorophenyl)-2-trifluoromethyl-furan-3-carboxylic acid [Maybridge].

EXAMPLE C10

[0234] Correspondingly Example C1 using 2-(4-chlorophenyl)-3-(trifluoromethyl)-pyrazole-4-carboxylic acid [Maybridge].

EXAMPLE C11

[0235] Correspondingly Example C1 using 5-(2-pyridyl)-thiophene-2-carboxylic acid [Maybridge].

EXAMPLE C12

[0236] Correspondingly Example C1 using 5-(methyl-trifluoromethyl-2-H-pyrazol-3-yl)-thiophene-2-carboxylic acid [Maybridge].

Example D1

[0237] Utilising the procedure of Example D5 with 3,4-dichloronitrobenzene [Aldrich] in place of 2,4-dichloronitrobenzene.

EXAMPLE D5

[0238] Biphenyl-4-carboxylic acid [2-chloro-4-(2-diisopropylamino-ethoxy)-phenyl]-amide.

[0239] To a three-neck flask (fitted with condenser, dropping funnel and thermometer) containing iron powder (938 mg, 16.8 mmol) mixed with a solution of ammonium chloride (28 mmol) in water (28 ml), was added the amine [2-(3-chloro-4-nitro-phenoxy)-ethyl]-diisopropyl-amine [prepared by the method used to form 1-[2-(2-methoxy-4-nitro-phenoxy)-ethyl]-pyrrolidine in Example.A51 but with 2-4-dichloronitrobenzene [Aldrich] in place of 4-chloro-3-methoxynitrobenzene and 2-diisopropylaminoethanol in place of 1-(2-hydroxyethyl)-pyrrolidine], dropwise over 10 minutes. The reaction mixture was gently refluxed until t.l.c. analysis showed no starting material. The mixture was filtered while hot and the inorganic residues washed with methanol. The combined filtrates were partitioned between water (5 ml) and ethyl acetate(3×10 ml), the organic phase dried (MgSO4), filtered, and evaporated. The aqueous phase was treated with satd. aq. sodium bicarbonate (10 ml), extracted with ethyl acetate (3×10 ml), dried (MgSO4), and evaporated. Residues from both extractions were combined and purified by flash chromatography on silica gel using dichloromethane—methanol—aq. ammonia as eluent to afford 2-chloro-4-(2-diisopropylamino-ethoxy)-phenylamine as a brown oil.

[0240]

1
H NMR (CDCl3): δ 1.02 (12H, d), 2.77 (2H, t), 3.03 (2H, sept.), 3.72 (2H, bs), 3.80 (2H, t), 6.68 (2H, m) and 6.85 (1H, m); MS (AP+ve): m/z 271, 273 [M+H]+.

[0241] This material was used in place of 3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine in the procedure of Example A51 to afford the title compound as clear oil.

[0242]

1
H NMR (CDCl3): δ 1.26 (12H, d), 3.07 (2H, m), 3.35 (2H, m), 4.22 (2H, m), 6.89 (1H, dd), 7.01 (1H, m), 7.44 (3H, q), 7.62 (2H, d), 7.71 (2H, d), 7.97 (2H, d) and 8.34 (1H, d); MS (AP+ve): m/z 452, 454 [M+H]+.

EXAMPLE D9

[0243] Utilising the procedure of Example A51 with 2,4-difluoronitrobenzene [Aldrich] in place of 4-chloro-3-methoxynitrobenzene.

EXAMPLE D12

WO-00/061,461

[0244] Utilising the procedure of Example A51 with 3,4-difluoronitrobenzene [Aldrich] in place of 4-chloro-3-methoxynitrobenzene.

EXAMPLE D16

[0245] Utilising the procedure of Example A51 with 2-methyl-4-fluoronitrobenzene [Aldrich] in place of 4-chloro-3-methoxynitrobenzene

EXAMPLE D20

[0246] Utilising the procedure of Example A51 with 3-methyl-4-fluoronitrobenzene [Aldrich] in place of 4-chloro-3-methoxynitrobenzene

EXAMPLE D24

[0247] Utilising the procedure of Example A51 with 3-acetyl-4-fluoronitrobenzene [Aldrich] in place of 4-chloro-3-methoxynitrobenzene

EXAMPLE D25

[0248] Biphenyl-4-carboxylic acid [4-(2-diisopropylamino-ethoxy)-2-formyl-5-methoxy-phenyl]-amide

[0249] Biphenyl-4-carboxylic acid [4-(2-diisopropylamino-ethoxy)-3-methoxy-phenyl]-amide [Patent WO-9901127] (223 mg, 0.5 mmol) was treated with glyoxylic acid trihydrate (1 ml), dichloromethane (5 ml) and methanesulphonic acid (0.5 ml). The mixture was stirred vigorously for 24 hours then treated with satd. aq. sodium bicarbonate (30 ml) and extracted with dichloromethane (3×20 ml). The combined organic phases were dried (MgSO4), filtered and evaporated, then subjected to flash chromatography on silica gel [chloroform—methanol—aqueous acetic acid] to obtain the title compound as the acetate salt, a white solid.

[0250]

1
H NMR (CDCl3): δ 1.13 (12H, d), 2.04 (3H, s), 3.02 (2H, t), 3.20 (2H, hept.), 4.05 (3H, s), 4.10 (2H, t), 5.0 (1H, bs), 7.22 (1H, s), 7.40 (1H, t), 7.48 (2H, d), 7.65 (2H, d), 7.76 (2H, d), 8.14 (2H, d), 8.72 (1H, s) and 9.34 (1H, s); MS (AP+ve): m/z 475 [M+H+].

EXAMPLE D26

[0251] Biphenyl-4-carboxylic Acid [4-(2-diethylamino-ethoxy)-3-(1-hydroxy-ethyl)-phenyl]-amide

[0252] To biphenyl-4-carboxylic acid [3-acetyl-4-(2-diethylamino-ethoxy)-phenyl]-amide [Example D24] (20 mg, 0.05 mmol) dissolved in a 1:1 mixture of tetrahydrofuran/ethanol (3 ml), was added sodium borohydride [Aldrich] (6 mg, 0.15 mmol). The reaction mixture was stirred at ambient temperature for 16 hours. The solvent was evaporated and the residue purified by flash chromatography on silica gel using dichloromethane—aq. ammonia—methanol as eluents, to afford the title compound as a white solid.

[0253]

1
H NMR (CDCl3): δ 1.09 (6H, t), 1.49 (3H, d), 2.75 (4H, q), 2.95 (2H, t), 4.15 (2H, t), 5.01 (1H, q), 6.84 (1H, d), 7.45-7.67 (9H, m) and 7.95 (2H, d)

[0254] MS (AP+ve): m/z 433 [M+H+].

EXAMPLE D27

[0255] Biphenyl-4-carboxylic acid [4-(2-diethylamino-ethoxy)-3-ethyl-phenyl]-amide

[0256] To biphenyl-4-carboxylic acid [3-acetyl-4-(2-diethylamino-ethoxy)-phenyl]-amide [Example D24] (25 mg, 0.06 mmol) dissolved in dichloromethane (1.5 ml), was added triethylsilane (0.5 ml) and trifluoroacetic acid (0.25 ml). The resulting yellow solution was stirred at room temperature for 120 h. The solvents were evaporated and the residue purified by flash chromatography on silica gel using dichloromethane—aq. ammonia—methanol as eluents to afford the title compound as white solid.

[0257]

1
H NMR (CDCl3): δ 1.17 (6H, m), 2.64 (2H, q), 2.8 (4H, q), 3.06 (2H, t), 4.15 (2H, t), 6.82 (1H, d), 7.35-7.71 (9H, m) and 7.96 (2H, d)

[0258] MS (AP+ve): m/z 417 [M+H]+

EXAMPLE D28

WO9901127

[0259] Utilising the procedure of Example A51 with 4-fluoronitrobenzene [Aldrich] in place of 4-chloro-3-methoxynitrobenzene, and 2-diisopropylaminoethanol in place of 1-(2-hydroxyethyl)-pyrrolidine

EXAMPLE D30

WO9901127

[0260] Utilising the procedure of Example D28 with 2-dimethylaminoethanol [Aldrich] in place of 2-diisopropylaminoethanol.

EXAMPLE D32

WO9901127

[0261] Utilising the procedure of Example D28 with 2-diethylaminoethanol [Aldrich] in place of 2-diisopropylaminoethanol

EXAMPLE D38

WO9901127

[0262] Utilising the procedure of Example A22 with 4-fluoronitrobenzene [Aldrich] in place of 4-chloro-3-methoxynitrobenzene, and 4-ethylphenylboronic acid in place of 4-methoxyphenylboronic acid

EXAMPLE D39

WO99011271

[0263] Utilising the procedure of Example A84 with 4-fluoronitrobenzene [Aldrich] in place of 4-chloro-3-methoxynitrobenzene, and 4-ethylphenylboronic acid in place of 4-methoxyphenylboronic acid.

EXAMPLE E1

[0264] Biphenyl-4-carboxylic Acid [4-(2-diisopropylamino-ethoxy)-3-methoxy-phenyl]-methyl-amide.

[0265] To 4-(2-diisopropylamino-ethoxy)-3-methoxy-phenylamine (1 mmol) [Example A7] were added triethylorthoformate (8 ml) and trifluoroacetic acid (0.15 ml). The resulting solution was heated to 90° C. for 4 hr. The solution was evaporated then redissolved in ethanol and cooled to approximately −10° C. Sodium borohydride (190 mg, 5 mmol) was introduced portionwise over 10 minutes then the mixture allowed to warm to room temperature. The solution was stirred at room temperature for 16 h, then acidified to pH 1 with 2M hydrochloric acid. The mixture was concentrated to approximately 10 ml, then partitioned between ethyl acetate and water. The aqueous phase was adjusted to pH 14 using 2M aq sodium hydroxide solution, and extracted with dichloromethane (×3), dried (MgSO4), filtered and evaporated. The residue was purified by flash chromatography on silica gel using dichloromethane—aq. ammonia—methanol as eluent to afford [4-(2-diisopropylamino-ethoxy)-3-methoxy-phenyl]-methyl-amine as an oil.

[0266]

1
H NMR (CDCl3): δ 1.03 (12H, d), 2.80 (3H, s), 2.85 (2H, t), 3.02 (2H, q), 3.80 (3H, s), 3.86 (2H, t), 6.13 (1H, dd), 6.23 (1H, d) and 6.80 (1H, d); MS (AP+ve): m/z 281[M+H]+.

[0267] To 4-phenylbenzoic acid (0.2 mmol) suspended in dichloromethane was added oxalyl chloride (0.6 mmol) followed by dimethylformamide (1 drop). The reaction mixture was stirred for 1 h, evaporated, co-evaporated (×3) with dichloromethane then redissolved in dichloromethane(1 ml). A solution containing the amine [4-(2-diisopropylamino-ethoxy)-3-methoxy-phenyl]-methyl-amine (0.2 mmol) and triethylamine (140 mg, 1 mmol) dissolved in dichloromethane (1 ml) was added. This solution was stirred at ambient temperature for 14 hours, evaporated, dissolved in dichloromethane (1 ml) and treated with PS-isocyanate resin [Argonaut Technologies] (150 mg). After a further 18 h shaking at ambient temperature, the mixture was filtered, passed through an SAX column [Varian] (1 g), evaporated, and the residue purified by chromatography on silica gel using dichloromethane—aq. ammonia—methanol as eluent to afford the title compound as an oil.

[0268]

1
H NMR (CDCl3): δ 1.21 (12H, bd), 2.88-3.24 (4H, m), 3.32 (3H, s), 3.87 (3H, s), 4.11 (2H, m), 6.82-6.91 (3H, m) and 7.26-7.56 (9H, m); MS (AP+ve): m/z 476 [M+M]+.

EXAMPLE E5

[0269] Utilising the procedure of Example E1 with triethyl orthoacetate [Aldrich] in place of triethyl orthoformate.

EXAMPLE E12

[0270] Biphenyl-4-carboxylic Acid [2-chloro-4-(2-diisopropylamino-ethoxy)-5-methoxy-phenyl]-amide

[0271] Biphenyl-4-carboxylic acid [4-(2-diethylamino-ethoxy)-3-methoxy-phenyl]-methyl-amide [Example E9] (45 mg, 0.1 mmol), was dissolved in chloroform (1 ml) and treated with benzotriazole [Aldrich] (12 mg, 0.1 mmol) and N-chlorosuccinimide (13 mg, 0.11 mmol). The mixture was stirred at ambient temperature for 16 hours then evaporated and subjected to flash chromatography on silica gel (dichloromethane—methanol—aqueous ammonia) to afford the title compound as an oil.

[0272]

1
H NMR (CDCl3): δ 1.06 (6H, t), 2.63 (4H, q), 2.90 (2H, t), 3.39 (3H, s), 3.67 (3H, s), 4.03 (2H, t), 6.57 (1H, s), 6.84 (1H, s) and 7.31-7.53 (9H, m); MS (AP+ve): m/z 467, 469 [M+H]+.

EXAMPLE E13

[0273] Utilising the procedures of Example A93 with [4-(2-diethylamino-ethoxy)-3-methoxy-phenyl]-methyl-amine [Example E9] in place of 4-(2-diethylamino-ethoxy)-3-methoxy-phenylamine and 2-fluoromethylphenylboronic acid [Aldrich] in place of 4-methoxyphenylboronic acid and of Example 51 with (N-diethyl)ethanolamine in place of 1-(2-hydroxyethyl)pyrrolidine.

EXAMPLE E14

[0274] Utilising the procedure of Example E13 with 2-methylphenylboronic [Aldrich] in place of of 4-chlorophenylboronic acid.

EXAMPLE E16

[0275] Correspondingly Example E14 with 2-chloromethylphenylboronic acid [Aldrich].

EXAMPLE E17

[0276] Correspondingly Example E14 with 4-fluoromethylphenylboronic acid [Aldrich].

EXAMPLE E21

[0277] Correspondingly Example E14 with 4-chloromethylphenylboronic acid [Aldrich].

EXAMPLE E22

[0278] Correspondingly Example E14 with 4-ethylphenylboronic acid [Aldrich].

EXAMPLE E23

[0279] Correspondingly Example E14 with 4-tertbutylphenylboronic acid [Aldrich].

EXAMPLE E24

[0280] 4-Biphenylcarboxylic acid [4-(2-diethylamino-ethoxy)-3-methoxy-phenyl]-methyl-amide [Example E9] (45 mg, 0.1 mmol), was dissolved in acetonitrile (1 ml) and treated with N-fluoro-N′-chloromethyl-triethylenediamine-bis(tetrafluoroborate) (43 mg, 0.12 mmol) and heated to 80° C. for 6 hours. The solvent was evaporated and the residue subjected to flash chromatography on silica gel (dichloromethane—methanol—aqueous ammonia) to afford the title compound as an oil.

[0281] MS (AP+ve): m/z 451 [M+H]+.

EXAMPLE E25

[0282] Utilising the procedure of Example E1 with 4-(2-diisopropylamino-ethoxy)-3-methyl-phenylamine [Example D20] in place of 4-(2-diisopropylamino-ethoxy)-3-methoxy-phenylamine and triethyl orthoacetate in place of triethyl orthoformate.

EXAMPLE F1

[0283] Utilising the procedure of Example A7 with 6-phenyl-nicotinic acid (Patent WO-0006085) in place of 2′-methyl-4-biphenylcarboxylic acid and N-dimethylethanolamine in place of 2-(diisopropylamino)ethanol.

EXAMPLE G1

[0284] Biphenyl-4-carboxylic acid [4-((R)-diethylamino-hydroxy-propoxy)-3-methoxy-phenyl]-amide

[0285] 4-Nitro-2-methoxyphenol [Aldrich] (845 mg, 5 mmol) was dissolved in DMF (25 ml) and treated with sodium hydride (60% oil dispersion, 200 mg). When the effervescence ceased, the mixture was treated with (R)-p-nitrophenylsulphonyl glycidol [Aldrich] and warmed to 50° C. with stirring. After 16 hours, the mixture was cooled, evaporated, partitioned between water (20 ml) and dichloromethane (3×25 ml), dried (MgSO4), filtered and evaporated. The residue was purified by flash chromatography on silica gel (hexane—ether) to give (R)-2-(2-methoxy-4-nitro-phenoxymethyl)-oxirane as a pale brown solid in 80% yield.

[0286]

1
H NMR (CDCl3): δ 2.79 (1H, dd), 2.95 (1H, dd), 3.41 (1H, dddd), 3.96 (3H, s), 4.06 (1H, dd), 4.43 (1H, dd), 6.98 (1H, d), 7.75 (1H, d) and 7.87 (1H, dd).

[0287] (R)-2-(2-Methoxy-4-nitro-phenoxymethyl)-oxirane (0.5 mmol, 113 mg), in dichloromethane (3 ml) was treated with the amine (diethylamine) [Aldrich] (1.5 mmol, 110 mg) and titanium tetraisopropoxide [Aldrich] (50 ul). The solution was stirred at ambient temperature for 24 h, treated with water (1 ml) and shaken vigorously for 10 minutes. The resulting suspension was passed through a hydromatrix cartridge [Varian ChernElut] (5 ml) eluting with dichloromethane (10 ml) to give (R)-diethylamino-(2-methoxy-4-nitro-phenoxy)-propan-2-ol as a yellow oil

[0288]

1
H NMR (CDCl3): δ 1.07 (6H, t), 2.55-2.72 (7H, m), 3.94 (3H, s), 4.09-4.13 (3H, m), 6.97 (1H, d), 7.74 (1H, d) and 7.89 (1H, dd); MS (AP+ve): m/z 299 [M+H+].

[0289] This material was dissolved in ethanol (5 ml) and treated with hydrogen chloride (2M in diethyl ether) 0.1 ml then 10% palladium on charcoal (20 mg) and hydrogenated at atmospheric pressure for 24 hours. The solution was purged with argon then filtered through celite and evaporated to give (R)-(4-amino-2-methoxy-phenoxy)-diethylamino-propan-2-ol hydrochloride as a white crystalline solid.

[0290]

1
H NMR (CD3OD): δ 1.19 (6H, t), 3.36-3.45 (6H, m), 3.88 (s, 3H), 4.02-4.11 (2H, m), 4.03 (1H, m), 6.95-7.03 (2H, m) and 7.13 (1H, d).

[0291] A solution of this material in dichloromethane (2 ml) was treated with triethylamine (2 mmol, 280 ul) and triethylsilyl trifluoromethanesulphonate (1 mmol, 264 mg). After 30 minutes, 4-biphenylcarboxylic acid chloride [Example 1] (1 mmol, 217 mg) was introduced and the mixture stirred for 12 hours. The solvent was evaporated and the residue dissolved in methanol (100 ml) and treated with potassium carbonate (2 g). After stirring for six hours, the suspension was evaporated, formed into a slurry with dichloromethane (20 ml), filtered, the filtrate evaporated, and the residue purified by flash chromatography (dichloromethane—methanol—aq. ammonia) to give the title compound as a white solid.

[0292]

1
H NMR (CDCl3): δ 1.11 (6H, t), 2.61-2.78 (6H, m,), 3.88 (3H, s), 3.54.5 (1H, vbs), 3.99-4.13 (3H, m), 6.92 (1H, d), 6.99 (1H, dd), 7.41-7.49 (3H, m), 7.56 (1H, d), 7.63 (2H, d), 7.69 (2H, d) and 7.97 (3H, d); MS (AP+ve): m/z 449 [M+H+].

EXAMPLE G5

[0293] Utilising the procedure for the preparation of (R)-diethylamino-(2-methoxy-4-nitro-phenoxy)-propan-2-ol [Example G1] but replacing dichloromethane with 1,2-dichloroethane and diethylamine with diisopropylamine. In addition, the mixture of amine and epoxide was heated at 80° C. for 12 h rather than being kept at ambient temperature for 24 hours.

EXAMPLE G8

[0294] Utilising the procedure of Example G1 but using (S)-p-nitrophenylsulphonyl-glycidol in place of (R)-p-nitrophenylsulphonyl-glycidol, and pyrrolidine in place of diethylamine.

EXAMPLE G22

[0295] Utilising the procedure of Example A51 but using 4-dimethylamino-1-butanol [ICN-RF] in place of 1-(2-hydroxyethyl)-pyrrolidine.

EXAMPLE H1

[0296] 4-Cyclohexyl-N-[3-methoxy-4-(4-methyl-piperazin-1-yl)-phenyl]-benzamide

[0297] A solution of 1-(2-methoxy-4-nitro-phenyl)-piperazine (Patent WO-9906382) (10 mmol, 2.37 g) in dichloromethane (50 ml) was treated with ditertbutyl dicarbonate (10 mmol, 2.18 g) with stirring. Vigorous evolution of gas occurred which ceased after 1 hour. The solution was then evaporated to a yellow solid 4-(2-methoxy-4-nitro-phenyl)-piperazine-1-carboxylic acid tertbutyl ester.

[0298]

1
H NMR (CDCl3): δ 1.50 (9H, s), 3.16 (4H, t), 3.61 (4H, t), 3.96 (3H, s), 6.88 (1H, d), 7.72 (1H, d) and 7.86 (1H, dd).

[0299] This material was dissolved in ethanol (50 ml) and treated with 10% Pd on carbon (100 mg). The suspension was hydrogenated at 1 atmosphere for 2 hours, then filtered through celite and evaporated to give 4-(4-amino-2-methoxy-phenyl)-piperazine-1-carboxylic acid tertbutyl ester as a brown oil.

[0300]

1
H NMR (CDCl3): δ 1.48 (9H, s), 2.86-2.91 (4H, t), 3.52-3.60 (4H, t), 3.81 (3H, s), 6.22-6.27 (2H, m) and 6.73 (1H, d).

[0301] This aniline (0.2 mmol, 61 mg) was dissolved in dichloromethane (1 ml) and treated successively with DIEA resin [Argonaut Technologies] (0.5 g) and 4-cyclohexylbenzoyl chloride [Example A36]. The mixture was shaken gently for 12 hours then filtered, evaporated and the residue purified by flash chromatography on silica gel (dichloromethane—methanol—aq. ammonia) to afford 4-(4-{[1-(4-cyclohexyl-phenyl)-methanoyl]-amino}-2-methoxy-phenyl)-piperazine-1-carboxylic acid tertbutyl ester as a white crystalline solid

[0302]

1
H NMR (CDCl3): δ 1.25-1.47 (5H, m), 1.54 (9H, s), 1.75-1.88 (5H, m), 2.56 (1H, m), 2.98 (4H, t), 3.61 (4H, t), 3.91 (3H, s), 6.87 (1H, d), 6.93 (1H, dd), 7.32 (2H, d), 7.54 (1H, s), 7.77, (1H, s) and 7.78 (2H, d); MS (AP+ve): m/z 493 [M+H+].

[0303] This material was dissolved in dichloromethane (5 ml) and treated with anisole (1 ml) and trifluoroacetic acid (5 ml). After 2 hours the solution was evaporated, then co-evaporated twice from toluene. The residue was dissolved in dichloromethane (10 ml), washed with satd. sodium bicarbonate (2 ml), the organic phase dried (MgSO4), filtered and evaporated to a brown oil, 4-cyclohexyl-N-(3-methoxy-4-piperazin-1-yl-phenyl)-benzamide.

[0304]

1
H NMR (CDCl3): δ 1.22-1.87 (10, m), 2.57 (1, m), 3.04-3.12 (8H, m), 3.91 (3H, s), 6.95 (2H, bs), 7.32 (2H, d), 7.54 (1H, m), 7.77 (1H, s) and 7.78 (2H, d); MS (AP+ve): m/z 394 [M+H+].

[0305] This amine (0.1 mmol, 39 mg) was dissolved in ethanol (3 ml) and treated with metaformaldehyde (100 mg), Amberlyst cyanoborohydride resin [Novabiochem] (100 mg), and acetic acid (50 ul). The mixture was stirred at ambient temperature for three hours then filtered, evaporated and the residue purified by flash chromatography on silica gel (dichloromethane—methanol—aq. ammonia) to afford the title compound as a pale brown oil. This was evaporated from dilute acetic acid to give the monoacetate salt hydrate.

[0306]

1
H NMR (CDCl3): δ 1.22-1.45 (5H, m), 1.76-1.87 (5H, m), 2.02 (6H, 2×s), 2.56 (1H, m), 3.22-3.23 (4H, t), 3.29-3.30 (4H, t), 3.88 (3H, s), 6.86 (1H, d), 6.94 (1H, dd), 7.30 (1H, d), 7.59 (1H, d), 7.79 (2H, d), 7.98 (1H, s) and 8.54 (4H, bs);

[0307] MS (AP+ve): m/z 408 [M+H+].

[0308] The following tables give Examples which illustrate but do not limit the invention in any way.

1TABLE AEncompassing compounds of general formula (II), a subset of formula (I) where A = Hand OMe, R3 = H, X = O, Y = CH2CH2, Z = a bond; R4 = Ph and R5 is either meta orpara substituted on R4.(II)

Example No. R5

meta/ para [M + H]+ ProcedureA1Ph

p447A7A2

p453A7A3

p437A7A4Ph

m447A7A5

p448A7A6

p489A7A7

p461A7A8

p453A7A9

p453A7A10

p451A7A11

p529A7A12

p461A7A13

m472A7A14

p525A7A15

m453A7A16

m453A7A17

p489A7A18

p486A7A19

p529A7A20

p453A7A21

p449A7A22

p477A22A23

p515A22A24

p462A22A25

p553A22A26

p497A22A27

p497A22A28

p461A22A29

p493A22A30

p515A22A31

p475A22A32

p491A22A33

p473A22A34

p477A22A35Ph

p433A51A36

p439A51A37Ph

p397A51A38

p391A51A39

p423A51A40Ph

p417A51A41Ph

p417A51A42

p423A51A43Ph

p405A51A44

100

101

p411A51A45Ph

102

p419A51A46

103

104

p425A51A47Ph

105

p417A51A48

106

107

p423A51A49Ph

108

p467A51A50

109

110

p473A51A51Ph

111

p417A51A52

112

113

p423A51A53

114

115

p421A22A54Ph

116

p405A51A55

117

118

p411A51A56Ph

119

p431A51A57

120

121

p437A51A58Ph

122

p445A51A59

123

124

p451A51A60

125

126

p406A60A61

127

128

p497A63A62

129

130

p459A63A63

131

132

p419A63A64

133

134

p417A63A65

135

136

p421A63A66

137

138

p441A63A67

139

140

p441A63A68

141

142

p404A63A69

143

144

p437A63A70

145

146

p434A63A71

147

148

p459A63A72Ph

149

p481A51A73

150

151

p487A51A74Ph

152

p445A51A75

153

154

p451A51A76Ph

155

p493A51A77

156

157

p499A51A78Ph

158

p479A51A79

159

160

p485A51A80Ph

161

p508A51A81

162

163

p514A51A82Ph

164

p403A51A83

165

166

p409A51A84

167

168

p449A84A85

169

170

p445A88A86

171

172

p487A88A87

173

174

p425A88A88

175

176

p450A88A89

177

178

p450A88A90

179

180

p459A88A91

181

182

p425A88A92

183

184

p458A88A93

185

186

p447A93A94

187

188

p443A93A95

189

190

p485A93A96

191

192

p423A93A97

193

194

p431A93A98

195

196

p448A93A99

197

198

p431A93A100

199

200

p479A93A101

201

202

p457A93A102

203

204

p423A93A103

205

206

p407A93A104

207

208

p459A93A105Ph

209

p429A105A106

210

211

p426A107A107

212

213

p424A107A108

214

215

p454A107

[0309]

2

TABLE B

Encompassing compounds of general formula (III), a subset of formula (1)

where A = H and OMe, R1 = R2 = Me2, R3 = H,

X = O, Y = CH2—CH2, Z = O, CH2 or NH; R4 = Ph,

R5 is Ph and Z is either meta or para substituted on R4.

(III)

216

Example No.
Z
meta/ para

217

[M + H]+
Procedure

B1
O
m

218

463
B1

B2
CH2
p

219

461
B1

B3
O
m

220

229
A51

B4
CH2
p

221

4447
A51

B5
O
m

222

407
A51

B6
CH2
p

223

405
A51

B7
O
m

224

433
A51

B8
CH2
p

225

431
A51

B9
O
m

226

433
A51

B10
CH2
p

227

431
A51

B11
O
m

228

421
A51

B12
CH2
p

229

419
A51

B13
O
m

230

435
A51

B14
CH2
p

231

433
A51

B15
O
m

232

433
A51

B16
CH2
p

233

431
A51

B17
O
m

234

483
A51

B18
CH2
p

235

481
A51

B19
O
m

236

433
A51

B20
CH2
p

237

431
A51

B21
CH2
p

238

419
A51

B22
O
m

239

447
A51

B23
CH2
p

240

445
A51

B24
O
m

241

497
A51

B25
CH2
p

242

495
A51

B26
O
m

243

509
A51

B27
CH2
p

244

507
A51

B28
O
m

245

495
A51

B29
CH2
p

246

493
A51

B30
O
m

247

524
A51

B31
CH2
p

248

522
A51

B32
O
m

249

419
A51

B33
CH2
p

250

417
A51

B34
CH2
m

251

461
B1

B35
O
p

252

463
B1

B36
NH
p

253

462
B37

B37
NH
p

254

432
B37

[0310]

3

TABLE C

Encompassing compounds of general formula (IV) a subset of formula (1)

where A = H and OMe, R1 = R2 = Me2, R3 = H, X = O,

Y = CH2—CH2; R4, R5 = substituted phenyl or heterocycle,

(IV)

255

Example No.
Z
3/4 substitution w.r.t C═O

256

10 R5
[M + H]+
Method

C1
bond
4

257

Ph
461 C1

C2
bond
4

258

Ph
477
C1

C3
bond
4

259

Ph
461
C1

C4
bond
3

260

Ph
453
C1

C5
O
3

261

262

521, 523, 525
C1

C6
bond
3

263

Ph
451
C1

C7
bond
4

264

Ph
448
C1

C8
bond
4

265

Ph
481, 483
C1

C9
bond
3

266

267

539, 541
C1

C10
bond
3

268

269

539
C1

C11
bond
3

270

271

453
C1

C12
bond
3

272

273

525
C1

[0311]

4

TABLE D

Encompassing compounds of general formula (V) a subset of formula (I)

where R3 = H, X = O, Y = CH2—CH2, Z = O, CH2, NH or a bond;

R4 = Ph, R5 is Ph or cyclohexyl (Cy) and Z is either meta or para

substituted on R4.

(V)

274

Example No.
Z
R6
R7
R5
meta/ para

275

[M + H]+
Method

D1
bond
Cl
H
Ph
p

276

452, 454
D1

D2
O
Cl
H
Ph
m

277

468, 470
D1

D3
CH2
Cl
H
Ph
p

278

466, 468
D1

D4
bond
Cl
H
Cy
p

279

458, 460
D1

D5
bond
H
Cl
Ph
p

280

452, 454
D5

D6
O
H
Cl
Ph
m

281

468, 470
D5

D7
CH2
H
Cl
Ph
p

282

466, 468
D5

D8
bond
H
Cl
Cy
p

283

458, 460
D5

D9
bond
F
H
Ph
p

284

435
D9

D10
CH2
F
H
Ph
p

285

449
D9

D11
bond
F
H
Ph
p

286

441
D9

D12
bond
H
F
Ph
p

287

435
D12

D13
O
H
F
Ph
m

288

451
D12

D14
CH2
H
F
Ph
p

289

449
D12

D15
bond
H
F
Cy
p

290

441
D12

D16
bond
Me
H
Ph
p

291

431
D16

D17
O
Me
H
Ph
m

292

447
D16

D18
CH2
Me
H
Ph
p

293

445
D16

D19
bond
Me
H
Cy
p

294

437
D16

D20
bond
H
Me
Ph
p

295

431
D20

D21
O
H
Me
Ph
m

296

447
D20

D22
CH2
H
Me
Ph
p

297

445
D20

D23
bond
H
Me
Cy
p

298

437
D20

D24
bond
COCH3
H
Ph
p

299

431
D24

D25
bond
OMe
CHO
Ph
p

300

475
D25

D26
bond
CH(OH)CH3
H
Ph
p

301

433
D26

D27
bond
Et
H
Ph
p

302

417
D27

D28
bond
H
H
Ph
p

303

417
D28

D29
O
H
H
Ph
m

304

433
D28

D30
bond
H
H
Ph
p

305

361
D30

D31
O
H
H
Ph
p

306

433
D28

D32
O
H
H
Ph
p

307

405
D32

D33
O
H
H
Ph
m

308

405
D32

D34
bond
H
H
Cy
p

309

423
D28

D35
bond
H
H
Cy
p

310

395
D32

D36
CH2
H
H
Ph
p

311

431
D28

D37
CH2
H
H
Ph
p

312

403
D32

D38
bond
H
H
p-EtPh
p

313

445
D38

D39
bond
H
H
p-EtPh
p

314

417
D39

[0312]

5

TABLE E

Encompassing compounds of general formula (VI) a subset of formula (1)

where A = H, Cl, F and OMe, X = O, Y = CH2—CH2; R4 = phenyl,

R5 = phenyl or cyclohexyl (Cy), Z = O, CH2 or a bond

(VI)

315

Example No.
Z
o/p
R3
R8
R9
R5

316

[M + H]+
Method

E1
bond
p
Me
H
MeO
Ph

317

461
E1

E2
O
m
Me
H
MeO
Ph

318

477
E1

E4
CH2
p
Me
H
MeO
Ph

319

475
E1

E5
bond
p
Me
H
MeO
Cy

320

467
E1

E6
bond
p
Et
H
MeO
Ph

321

447
E1

E7
bond
p
Et
H
MeO
Ph

322

445
E1

E8
bond
p
Me
H
MeO
Ph

323

431
E1

E9
bond
p
Me
H
MeO
Ph

324

433
E1

E10
bond
p
Et
H
MeO
Cy

325

453
E1

E11
bond
p
Et
H
MeO
Cy

326

451
E1

E12
bond
p
Me
Cl
MeO
Ph

327

468, 470
E12

E13
bond
P
Me
H
MeO
2-F—Ph

328

451
E13

E14
bond
p
Me
H
MeO
2-Me—Ph

329

447
E14

E15
bond
p
Me
H
MeO
2-MeO—Ph

330

463
E14

E16
bond
p
Me
H
MeO
2-Cl—Ph

331

468, 470
E14

E17
bond
p
Me
H
MeO
4-F—Ph

332

451
E14

E18
bond
p
Me
H
MeO
4-F3C—Ph

333

501
E14

E19
bond
p
Me
H
MeO
4-Me—Ph

334

447
E14

E20
bond
p
Me
H
MeO
4-MeO—Ph

335

463
E14

E21
bond
p
Me
H
MeO
4-Cl—Ph

336

468, 470
E14

E22
bond
p
Me
H
MeO
4-Et—Ph

337

461
E14

E23
bond
p
Me
H
MeO
4tBu—Ph

338

489
E14

E24
bond
p
Me
F
MeO
Ph

339

451
E24

E25
bond
p
Et
H
Me
Ph

340

459
E25

E26
bond
p
Et
H
Me
Cy

341

465
E25

E27
CH2
P
Et
H
Me
Ph

342

473
E25

[0313]

6

TABLE F

Encompassing compounds of general formula (VII) a subset of

formula (1) where A = H and OMe, X = O, R4 = 3-pyridyl,

R5 = phenyl, Z = a para bond

(VII)

343

Example No.

344

[M + H]+
Method

F1
R1 = R2 = Me
392
F1

F2

345

418
F1

F3

346

418
F1

F4

347

448
F1

[0314]

7

TABLE G

Encompassing compounds of general formula (VIII) a subset of formula (I)

where A = H and OMe, R3 = H, X = O; R4 = phenyl, Z = O, CH2 or a bond and

R5 = Ph or cyclohexyl (Cy), Y is a chain of 3 or 4 carbon atoms optionally

substituted by an hydroxyl group.

(VIII)

Example No.
Z
m/ p
R5
XYN

348

[M + H]+
method

G1
bond
p
Ph

349

350

449
G1

G2
bond
p
Ph

351

352

461
G1

G3
bond
p
Ph

353

354

476
G1

G4
bond
p
Ph

355

356

476
G1

G5
bond
p
Ph

357

358

465
G5

G6
bond
p
Ph

359

360

475
G1

G7
bond
p
Ph

361

362

475
G1

G8
bond
p
Cy

363

364

453
G8

G9
bond
p
Ph

365

366

447
G8

G10
bond
p
Cy

367

368

455
G8

G11
bond
p
Ph

369

370

449
G8

G12
bond
p
Cy

371

372

483
G5,G8

G13
bond
p
Ph

373

374

477
G5,G8

G14
bond
p
Cy

375

376

482
G8

G15
bond
p
Ph

377

378

476
G8

G16
bond
p
Cy

379

380

481
G8

G17
bond
p
Cy

381

382

481
G8

G18
bond
p
Ph

383

384

475
G8

G19
bond
p
Ph

385

386

475
G8

G20
bond
p
Ph

387

388

444
G8,G5

G21
bond
p
Ph

389

390

461
G8

G22
bond
P
Ph

391

NMe2
419
G22

G23
O
m
Ph

392

NMe2
435
G22

G24
CH2
p
Ph

393

NMe2
433
G22

G25
bond
p
Cy

394

NMe2
425
G22

[0315]

8

TABLE H

Encompassing compounds of general formula (IX) a subset of

formula (I) where A = H and OMe, R3 = H, X = N; R4 = phenyl,

Z = a para substituted bond and R5 = Ph or cyclohexyl (Cy),

Y and R2 form a piperazinyl ring between X and N.

(IX)

395

Example

No.
R5
R1
[M + H]+
Method

H1
Cy
Me
408
H1

H2
Cy
Et
436
H1

H3
Cy
iPr
422
H1

[0316] The activity of the compounds used in this invention may be assessed by competitive binding assays to 11CBy receptors, as follows:

[0317] Radioligand Binding Studies

[0318] Radioligand binding assays were carried out on well washed membranes from HEK293 cells stably expressing 11CBy receptors. Membranes (5-15 mg protein) were incubated with [125I]-Melanin Concentrating Hormone (0.22 nM)(obtained from NEN) in the presence and absence of competing test compounds for 45 min at 37° C. in a buffer (pH 7.4), containing 50 mM Tris and 0.2% BSA. Non-specific binding was defined using 0.1 mM Melanin Concentrating Hormone (obtained from Bachem). The test compounds were added at concentrations between 10M and 10 pM in 10 concentration steps. Following incubation, the reaction was stopped by filtration through GF/B filters and washed with 4×1 ml of ice-cold 50 mM Tris buffer. Microscint 20 (Packard) was added to the filters and the radioactivity measured using a Packard TopCount.

[0319] Bound cpm in the presence of test compound was expressed as a fraction of the bound cpm in the absence of test compound and plotted against the concentration of compound. From this an IC50 was determined from which the pKi was calculated.

[0320] The most potent compounds of the present invention have pKi values in the range of 7.1 to 7.8 For example:

9ExamplepKi rangeA487.5-7.8B27.1-7.4C87.1-7.4D157.5-7.8E97.5-7.8F47.1-7.4G17.1-7.4H17.1-7.4

Carboxamide compounds and their use as antagonists of a human 11cby receptor

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CPC

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Abstract

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