CA2417638A1 - Carboxamide compounds and their use as antagonists of a human 11cby receptor - Google Patents

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

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Publication number
CA2417638A1
CA2417638A1 CA002417638A CA2417638A CA2417638A1 CA 2417638 A1 CA2417638 A1 CA 2417638A1 CA 002417638 A CA002417638 A CA 002417638A CA 2417638 A CA2417638 A CA 2417638A CA 2417638 A1 CA2417638 A1 CA 2417638A1
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Prior art keywords
phenyl
ethoxy
benzamide
formula
compound
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Abandoned
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CA002417638A
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French (fr)
Inventor
Christopher Norbert Johnson
Martin Jones
Catherine Anne O'toole
Geoffrey Stemp
Kevin Michael Thewlis
David Witty
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SmithKline Beecham Ltd
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Individual
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Priority claimed from GBGB0018758.3A external-priority patent/GB0018758D0/en
Priority claimed from GB0112544A external-priority patent/GB0112544D0/en
Application filed by Individual filed Critical Individual
Publication of CA2417638A1 publication Critical patent/CA2417638A1/en
Abandoned legal-status Critical Current

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    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
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    • C07C2601/14—The ring being saturated

Abstract

Compounds of formula (I) in which: each A is independently hydrogen, C1-6alkyl optionally substituted by hydroxyl, C1-6alkoxy, C1-6alkenyl or C1-6acyl group or a halogen atom or hydroxyl, CN or CF3 group; R3 is hydrogen, methyl or ethyl; R4 is an optionally substituted aromatic carbocyclic or heterocyclic ring; 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; R5 is an optionally substituted aromatic carbocyclic or heterocyclic ring, or an optionally substituted, saturated or unsaturated, carbocyclic or heterocyclic ring; and Q
is (a) Where X, Y, R1 and R2 are as defined in claim 1; are antagonists of a human 11CBy receptor.

Description

This invention relates to a method of treatment using an antagonist of the human 11 CBy receptor; a new therapeutic use of a class of carboxamide compounds which are antagonists to a human 11 CBy receptor; also to novel compounds within that class, and to methods for malting the compounds.
International Patent Application Publication Nmnber WO 01/21577 (Takeda Chemical Industries Ltd.) discloses certain bisaryl compounds as melanin concentrating hormone antagonists.
WO 98/00401 (Merck & Co. Int.) discloses benzamide derivatives as fibrinogen receptor antagonist prodrugs.
European Patent EP 0 358 118 (Boehringer Mamiheim GmbH) discloses certain bisaryl compounds as inhibitors of erythrocyte aggregation and useful in the treatment of cardiac and circulatory disease.
European Patent Application EP 0 968 999 (Mitsui Chemical Inc.) discloses certain anilide derivatives useful in the treatment of arrhythmia.
WO 99/01127 (SmithKline Beecham) discloses certain N [(amino allcoxy)phenyl]
benzamides that are active as CCRS receptor ligands, including the compoLUZds 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 CCRS 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-diethylawino-ethoxy)-phenyl]-4-phenoxy-benzamide, N [4-(2-diisopropylamino-ethoxy)-phenyl]-3-phenoxy-benzamide, N [4-(2-diethylawino-ethoxy)-phenyl]-3-phenoxy-benzamide, SUBSTITUTE SHEET (RULE 26) 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.
The present invention is based on the fording that a class of carboxamides overlapping with the above-mentioned benzamides and anilides, are, surprisingly, antagonists of a human 11 CBy receptor disclosed in Nature, 400, 261-265 (1999).
Accordingly these compounds axe 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".
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 fomnula (I), or a pharmaceutically acceptable salt or solvate thereof, in which:
A
Q
p A
,~Z'R4 N

R5 (I) SUBSTITUTE SHEET (RULE 26) each A is independently hydrogen, a Cl_6 alkyl optionally substituted by hydroxyl, C1_6 alkoxy, C1_6 allcenyl or C1_6 acyl group or a halogen atom or hydroxyl, CN or CF3 group;
R3 is hydrogen, methyl or ethyl.
Preferably R3 is methyl.
R4 is an optionally substituted aromatic carbocyclic or heterocyclic ring.
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.
Preferably, Z is a bond.
More preferably, Z is a bond at the 4-position of R4 relative to the carbonyl group.
RS is an optionally substituted aromatic carbocyclic or heterocyclic ring, or an optionally substituted, saturated or unsaturated, carbocyclic or heterocyclic ring.
Preferably, RS is a phenyl ring.

I
and Q is -X-Y-N

' (a) where X is an O or S atom, preferably an O atom;
Y is a linear or branched C2-q. allcylene group, preferably a C3 alkylene group, optionally substituted by a hydroxyl group, or is a CS_6 cycloalkylene group, Rl and R2 are independently a linear or branched C1_6 alkyl, preferably ethyl;
phenyl C1_ 6 alkyl group; or (b) where X is an O or S atom;
Y is a linear or branched C2_q alkylene group, optionally substituted by a hydroxyl group, Rl 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 (c) where X is an O or S atom, SUBSTITUTE SHEET (RULE 26) Y is a C2_4 alkylene group, Rl is a C2_q. 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 (d) where X is a N atom, Y is a C2_q. allcylene group, Rl is a C2_q. alkylene group linked to X to form a 5 or 6 membered ring and R2 is a linear or branched C1_6 alkyl group.
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.
Suitable aromatic rings for use as R4 include phenyl, pyridyl, thienyl, furanyl and pyrazolyl. Suitable optional substituents for R4 include halogen, CF3, C1_q.
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.
R5 may be monocyclic, for example thienyl, furanyl, imidazolyl, oxadiazolyl, phenyl, pyridinyl, cyclohexyl, piperidinyl, piperazinyl, pyrazinyl, pyrimidinyl; or a fused bacyclic 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, CF30, CHF20, CN, amino, mono- or di-C 1 _6 alkylamino, C 1 _g alkyl, C 1 _6 allcoxy, C 1 _6 acyl, C 1 _6 alkyl-S-, C1_6 alkyl-S02-, Cl_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, SUBSTITUTE SHEET (RULE 26) trifluoromethyl, cyano, amino, methyl, ethyl, t-butyl, methoxy, acetyl, formyl, methylthio, methanesulphonyl, vinyl, benzyl, benzyloxy, hydrogen.
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 Cl_6 allcenyl.
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.
In the system Q, in conf guration (a) particularly suitable substituents for Rl and R2 include methyl, ethyl, isopropyl, benzyl, phenethyl. Y may especially be -(CH~)2-, -(CH2)3-, -(CH2)q-, -CHI-CH(CH3)-CH2-. When Y is substituted by hydroxy, it may be for example -CHI-CH(OH)-CHI-.
In configuration (b) of system Q, the ring formed by linking Rl and R2 inay be pyrrolidinyl, piperidinyl, azepanyl, or imidazolyl. Fused rings include indolinyl, tetrahydxoisoquinolinyl, 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 linlced back to Y to form a quinuclidinyl group.
In configuration (c) of system Q, the ring formed by linking Rl to Y may be a pyrrolidinyl or piperidinyl ring. The linkage to Y may be such as to cxeate a ring linked by a single bond from a ring carbon atom directly to X or via a methylene or ethylene linl~ing group. R2 is typically methyl so that the N atom of the ring is substituted by methyl.

SUBSTITUTE SHEET (RULE 26) In configuration (d) of system Q, the ring formed by linking Rl 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.
Within the scope of formula (I) is a class of compounds of general formula (II) ~R1 O I ~ O~N~R2 \ H / Or (II) where A = H and OMe, R3 = H, X = O, Y = CH2CH2 , Z = a bond, R4 = Ph, RS is either I O meta or para substituted on R4, and Rl, R2 and RS are as defined for formula (I).
Also within the scope of formula (I) is a class of compounds of general formula (III) Z

(III) 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, RS is Ph, and Rl and R2 are as defined for formula (I).
Also within the scope of formula (I) is a class of compounds of general formula (IV) ~ ~ ~~N~
R5'~Z~R4~N / O~
H

SUBSTITUTE SHEET (RULE 26) where A = H and OMe, Rl = R2 = iPr, R3 = H, X = O, Y = CHI-CH2 , and R4 and RS
are substituted phenyl or heterocycles as defined for formula (I) Also within the scope of formula (I) is a class of compounds of general formula (V) ~1 R7 O~'N~R2 O

R5''Z
where R3 = H, X = O, Y = CHI-CH2, Z = O, CHI, NH or a bond, R4 = Ph, RS 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).
Also within the scope of formula (I) is a class of compounds of general formula (VI) O I ~ O~N~R2 R5~Z / R3 (VI) where X = O, Y = CHI-CH2, R4 = phenyl, RS = phenyl or cyclohexyl (Cy), Z = O, CHI
or a bond, and A (R8,R9), R3 and R1,R2 are as defined in formula (I).
Also within the scope of formula (I) is a class of compounds of general formula (VII) SUBSTITUTE SHEET (RULE 26) i O~N~R2 N O
H
(VII) where A = H and OMe, X = O, R3 = H, R4 = 3-pyridyl (with respect to the carbonyl group), RS = phenyl, Z = a para bond , and Rl,R2 are as defined in formula (I).
Also within the scope of formula (I) is a class of compounds of general formula (VIII) ~1 p-.Y.-N~2 N / ~i R5~Z / H
(VIII) where A = H and OMe, R3 = H, X = O, R4 = phenyl, Z = O, CH2 or a bond, RS = 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).
Also within the scope of formula (I) is a class of compounds of general formula (IX) ~ N'~N-R1 N ~ / Oi H

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

SUBSTITUTE SHEET (RULE 26) 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.
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.
A particular group of novel compounds is a class of compounds of general formula (VI) (VI) where R8 and R9 are as defined for A in formula (I), Rl, R2 and RS are as defined in formula (I), and R3 is methyl or ethyl.
Suitably RS 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; Rl and R2 are alkyl or linlced together to form a ring; and R3 is ethyl or methyl.
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:
N-[4-[2-[bis(1-methylethyl)amino]ethoxy]-2-fluorophenyl]-[1,1'-biphenyl]-4-carboxamide, N-[4-[2-[bis(1-methylethyl)amino] ethoxy]phenyl]-[1,1'-biphenyl]-4-carboxamide, 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, SUBSTITUTE SHEET (RULE 26) 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.
A further aspect of this invention is those compounds of the Examples herein which are novel.
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.
Suitable salts and solvates include pharmaceutically acceptable salts and pharmaceutically acceptable solvates.
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-(3-phenethylamine, dehydroabietylamine, N,N'-bisdehydroabietylamine, glucamine, N-methylglucamine or bases of the pyridine type such as pyridine, collidine, quinine or quinoline.
Suitable pharmaceutically acceptable salts also includes pharmaceutically acceptable acid addition salts, such as those provided by pharmaceutically acceptable inorganic acids or organic acids.
Suitable pharmaceutically acceptable acid addition salts provided by pharmaceutically acceptable inorganic acids includes the sulphate, nitrate, phosphate, borate, hydrochloride and hydrobromide and hydroiodide.
Suitable pharmaceutically acceptable acid addition salts provided by pharmaceutically acceptable organic acids includes the acetate, tartrate, maleate, fumarate, malonate, SUBSTITUTE SHEET (RULE 26) citrate, succinate, lactate, oxalate, benzoate, ascorbate, methanesulphonate, a-keto glutarate and a,-glycerophosphate.
Suitable pharmaceutically acceptable solvates include hydrates.
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.
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.
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, malefic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric, succinic, benzoic, ascorbic and methanesulphonic.
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.
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.
Compounds of formula (I) to (IX) may prepared by condensing suitably substituted aryl or heteroarylcarboxylic acids and suitably substituted amines, which are commercially SUBSTITUTE SHEET (RULE 26) available or synthesized by methods known to the art from coxmnercially 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).
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).
For example the compounds of formula (I) may be prepared by reacting a compound of formula (X) R5-Z-R4-COL (X) where L is a leaving group such as halogen, especially chlorine or bromine with a compound of formula (XI) A
H
Q
R3 A (xI) where A, Z, R3, R4, RS and Q are as defined for formula (I).
In this process, groups convertible to Rl, R2, R3, R4 and RS may be present during the coupling, and converted to Rl, R2, R3, R4 and RS after coupling. Also it may be convenient to convert one Rl, R2, R3, R4 and RS to another Rl, R2, R3, R4 and RS
group after coupling. In particular, ring formation between the groups Rl, X,Y, R2 or SUBSTITUTE SHEET (RULE 26) the addition of suitable cyclic groups embodying Rl, X, Y, R2, may be performed after coupling.
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.
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;
N-[4-[2-[bis( 1-methylethyl)amino]ethoxy]-2-fluorophenyl]-[1,1'-biphenyl]-4-carboxamide, N-[4-[2-[bis(1-methylethyl)amino]ethoxy]phenyl]-[1,1'-biphenyl]-4-carboxamide, 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.
which process comprises the reaction of a compound of formula (X) as hereinbefore defined with a compound of formula (XI) as hereinbefore defined.
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 N02 group to NH2 by hydrogenation in SUBSTITUTE SHEET (RULE 26) the presence of palladium catalyst (or with iron/ammonium chloride) before coupling with an acid chloride, for example as illustrated below:
+
\ O~ NaH ~+ i H N O~
O',N \ O HZ I Pd on C z \
CI DMF
EtOH O
+ O
HOUN~ N
U
O
Et3N / ~ [ ~GI
CHaCl2 \ \
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.
Alternatively the acids of formula (X) may be prepared by combining moieties containing respectively RS and R4 via Z.

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 RS-Z-L (or L-CO-L with RS-Z). For example an amine of formula (XI) may be reacted with an appropriately substituted bromobenzoyl chloride which may be then reacted with, for 15 example, an appropriately substituted phenyl moiety with a leaving group, or a cyclic amine, as in the following scheme:

SUBSTITUTE SHEET (RULE 26) Pmaeuure r,a ~

H E t3N ~ O HzN O~
N I \ O/ MDC
\ CI + ~O
Br ~O
Br / N
B(oH N
Procedure A93 )z ~ BINAP Pd(OAc)z EtOH PhH \ HN~ CszC03 DME
Na CO
z a / ~ Procedure A107 Pd(PPh3)4 n.
BINAP = (S)-(+)_2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl 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:
N~ O~ HZN \ O~ O
O%N I \ O (Boc)z0 O~ I ~ H2~ I / ~ \ CI
N~ H CH C ~~ EtOH N ~O + I /
O O ~O
DIEA resin O
CH.,CL, \ N Oi TFA
I I\
-E-N~NH ~ ~ OA
EtOH ~ Formaldehyde AcOH Amberlyst BH3CN
\ N O~ Procedure Hi I / ~ .i N~N~
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 RS-Z-R4-CO-L, as illustrated by:
SUBSTITUTE SHEET (RULE 26) EtZNH
~+ ~ NaH / DMF ~N+ O~ CHI OoN+ \ O'~ NEt O.N I \ O ~ O' I \ Ti(O~Pr)4 ~ / O z O~ ~O~
~OH i Nos O O OH
EtOH
i) Et3SiOTf I Et3N HCI I EtaO
O ii) CHzCIz O Ha / Pd on C
N I ~ O NEtz ~ I CI HZN
\ ~O \ _/ , \ N Eta ~i OH O
OH
Procedure G9 iii) MeOH / Na2C03 Nos = p-nitrobenzenesulphonyl 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 (XI) before coupling with an acid chloride of formula (X), for example, by utilising the following reductive amination S procedure:
H CHs HZN ~ O~ ~) Et0- \ OEt HN ~ O~
OEt I TFA I ,i O
O
N ii) NaBH41 EtOH ~N~
'+
Et3N /
O, CHZC12 O
NiPr2 Procedure E1 The compounds of formula (I) may be converted into their pharmaceutically acceptable salts by reaction with the appropriate organic or mineral acids.
I0 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.

SUBSTITUTE SHEET (RULE 26) 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.
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.
By virtue of the activity of these compounds as antagonists of a human 11 CBy 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.
It is also considered that the treatment of certain of the Disorders mentioned above by an antagonist to the human llCBy 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 llCBy 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 llCBy 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 llCBy 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 llCBy 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 llCBy 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 llCBy receptor.

SUBSTITUTE SHEET (RULE 26) 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 llCBy receptor.
The administration of such compounds to a mammal may be by way of oral (including sub-lingual), parenteral, nasal, rectal or transderinal administration.
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 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 l, 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/lcg/day.
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.
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.
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 iii the art.

SUBSTITUTE SHEET (RULE 26) 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.
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.
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, hydraxyethylcellulose, 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.
Oral formulations also include conventional sustained release formulations, such as tablets or granules having an enteric coating.
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 SUBSTITUTE SHEET (RULE 26) enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum.
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.
As is common practice, the compositions will usually be accompanied by written or printed directions for use in the medical treatment concerned.
Compounds of the present invention may be employed alone or in conjunction with other compounds, such as therapeutic compounds.
No adverse toxicological effects are expected for the compounds of the invention, when administered in accordance with the invention.
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.
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.
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 fox the treatment and/or prophylaxis of one or more of the Disorders.
SUBSTITUTE SHEET (RULE 26) 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.
Compounds for use in this invention and their preparation are illustrated in the following Examples and Tables.
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 components 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]
Utilising the procedure of Example A7 with 4-biphenylcarboxylic acid [Aldrich]
in place of 2'-methyl-4-biphenylcarboxylic acid.
Example A2 Correspondingly Example A7 with 4-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzoic acid [J.Org.Chem. 50; 8; 1985; 1182].
Example A3 Correspondingly Example A7 with 4-pyrazol-1-yl-benzoic acid [Can.J.Chem.; 41;
1963;
1540].
Example A4 Correspondingly Example A7 with 3-biphenylcarboxylic [Med.Chem.Res.; 6; 2;
1996].
Example AS

SUBSTITUTE SHEET (RULE 26) Correspondingly Example A7 with 4-(2-pyridyl)-benzoic acid [J.Chem.Soc.; 1940;
355, 356].
Example A6 Correspondingly Example A7 with 3'-acetyl-biphenyl-4-carboxylic acid [Patent WO-9743262].
Example A7 2-methylphenyl-4-phenylcarboxylic acid [3-methoxy-4-(2-bis-(2-methylethyl)amino)-ethoxy)-phenyl amide.
To a solution of the acid (2'-methyl-biphenyl-4-carboxylic acid) [Patent WO-9901127]
(SSmg, 0.26mmo1) in dimethylformamide were added (1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride [Aldrich] (SOmg, 0.26mmo1) and 1-hydroxy-7-azabenzotriazole [Aldrich] (35mg, 0.26mmo1) followed by diisopropylethylamine (0.04rn1, 0.2Smmo1) and the aniline (4-(2-diisopropylamino-ethoxy)-3-methoxy-phenylamine) (69mg, 0.22mmo1), [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 (1 Oml), filtered through an SAX [Varian] column (2g), and the filtrate was then stirred with PS-isocyanate resin [Argonaut Technologies] (100mg, 0.38mmo1) 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.
1H NMR (CDCIg): 8 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 Utilising the procedure of Example A7 with cyclohexyl-4-benzoic acid [Aldrich], in place of (2'-methyl-biphenyl-4-carboxylic acid).
Example A9 SUBSTITUTE SHEET (RULE 26) Correspondingly Example A7 with 4-(2-thienyl)-benzoic acid [J.Chem.Soc.Perkin Trasis.l; 17; 1992; 2203].
Example A10 Correspondingly Example A7 with 4-(1-methyl-1H pyrazol-4-yl)-benzoic acid [Patent: WO-9906409].
Example AlI
Correspondingly Example A7 with 4'-(5-methyl-[1,2,4]oxadiazol-3-yl)-biphenyl-4-carboxylic acid [Patent:WO -9743262].
Example A12 Correspondingly Example A7 with 4-benzyl-carboxylic acid [Apin].
Example A13 Correspondingly Example A7 with 3'-cyano-biphenyl-3-carboxylic acid [J.Chem.Soc.Perlcin Trans.2; 1; 1984; 35-38].
Example A14 Correspondingly Example A7 with 3'-methanesulfonyl-biphenyl-4-carboxylic acid [Izv.Sib.Otd.Akad.Nauk SSSR Ser.Khim.Nauk; 11; 1966; 62].
Example A15 Correspondingly Example A7 with 3-thiophen-2-yl-benzoic acid [Tetrahedron Lett.; 39;
24; 1998; 4175].
Example A16 Correspondingly Example A7 with 3-thiophen-3-yl-benzoic acid [J.Chem.Soc.B;
1970;
1595].
Example A17 Correspondingly Example A7 with 4-acetyl-4-biphenylcarboxylic acid [Aldrich].

SUBSTITUTE SHEET (RULE 26) Example A18 Correspondingly Example A7 with 4'-cyano-3'-methylbiphenyl-4-carboxylic acid [WO-9850358].
Example A19 Correspondingly Example A7 with 4'-(5-methyl-[1,3,4]oxadiazol-2-yl)-biphenyl-4-carboxylic acid [Patent:WO-9743262].
Example A20 Correspondingly Example A7 with 4-thiophen-3-yl-benzoic acid [J.Chem.Soc.B;
1970;
1595].
Example A21 Correspondingly Example A7 with 4-pyrazin-2-yl-benzoic acid [Patent WO-9854164].
Example A22 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 Utilising the procedure of Example A22 with 4-trifluoromethylphenylboronic acid [Aldrich], in place of 2-methoxyphenylboronic acid [Aldrich]
Example A24 Correspondingly Example A23 with 3-aminophenylboronic acid [Aldrich].
Example A25 Correspondingly Example A23 with 4-benzyloxyphenylboronic acid [Lancaster].
Example A26 Correspondingly Example A23 with 2-naphthylboronic acid [Lancaster].

SUBSTITUTE SHEET (RULE 26) Example A27 Correspondingly Example A23 with 3-naphthylboronic acid [Lancaster].
Example A28 Correspondingly Example A23 with 4-methylphenylboronic acid [Lancaster].
Example A29 Correspondingly Example A23 with 4-methylthiophenylboronic acid [Lancaster].
Example A30 Correspondingly Example A23 with 3-trifluoromethylphenylboronic acid [Lancaster].
Example A31 Correspondingly Example A23 with 4-carbonylphenylboronic acid [Aldrich].
Example A32 Correspondingly Example A23 with 3,4-(methylenedioxy)phenylboronic acid [Aldrich].
Example A33 Correspondingly Example A23 with 4-vinylphenylboronic acid [Aldrich].
Example A34 Correspondingly Example A23 with 3-methoxyphenylboronic acid [Lancaster].
Example A35 Utilising the procedure of Example A51 with 1-(2-hydroxyethyl)morpholine [Aldrich] in place of 1-(2-hydroxyethyl)pyrrolidine.
Example A36 Utilising the procedure of Example A35 with 4-cyclohexylbenzoic acid [Aldrich]. in place of 4-biphenylcarboxylic acid.
SUBSTITUTE SHEET (RULE 26) Example A37 Utilising the procedure of Example A51 with 2-dimethylaminoethanol [Aldrich], in place of 1-(2-hydroxyethyl)pyrrolidine.
Example A39 Correspondingly Example A51 with (R)-(+)-1-methyl-2-pyrrolidinemethanol (Patent WO-9932480).
Example A41 Correspondingly Example A51 With 3-hydroxy-1-methylpiperidine [Aldrich].
Example A43 Correspondingly Example A51 with 2-dimethylamino-1-propanol [ICN-RF].
Example A45 Correspondingly Example A51 with 2-(diethylamino)-ethanol [Aldrich].
Example A47 Correspondingly Example A51 with (S)-(-)-1-methyl-2-pyrrolidinemethanol [Aldrich].
Example A49 Correspondingly Example A51 with N-benzyl-N methylethanolamine [Aldrich].
Example A51 Biphenyl-4-carboxylic acid (3-methoxy-4-(2-pyrrolidin-I-yl-ethoxy)-phenyl amide.
To a solution of the hydroxy amine, (1-(2-hydroxyethyl)-pyrrolidine) [Aldrich], (1.87m1, l6mmol) in dimethylforman ude was added portionwise sodium hydride [60%
dispersion in oil, (544mg, l6rmnol). After stirring at room temperature for 10 minutes a solution of the halonitrobenzene, (1-chloro-2-methoxy-4-vitro-benzene) [Avocado] (3g, l6mmol) in dimethylformamide (1 Oml) was added dropwise. The reaction mixture was left stirring at room temperature for l6hrs then concentrated. The residue was dissolved in ethyl acetate SUBSTITUTE SHEET (RULE 26) (200m1) and washed with water (3 x SOmI). 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.
1H NMR (CDC13): 81.82 (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(IH, dd); MS (AP +ve): m/z 267 [M+H]+.
To a solution of the amine, 1-[2-(2-methoxy-4-nitro-phenoxy)-ethyl]-pyrrolidine (2.3g, 8.6mtnol) in ethanol (100m1) was added 10% Pd/C (SOmg). The mixture was stirred at room temperature under an atmosphere of hydrogen at atmospheric pressure for 16h, then filtered through celite and the filtrate concentrated to give the corresponding aiuline; 3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenylasnine, as a brown solid.
1H NMR (CDC13): b 1.80 (4H, m), 2.62 (4H, m), 2.89 (2H, t), 3.80 (3H, s), 4.06 (2h, t), 6.20 (1H, dd), 6.29 (1H, d) and 6.75 (1H, d); MS (AP +ve): srrlz 237 [M+H]+.
To the caxboxylic acid, (4-biphenyl carboxylic acid) [Aldrich] (47.Smg, 0.24mmo1) suspended in dichloromethane (1m1) was added oxalyl chloride [Aldrich]
(0.06m1, 0.72nunol) 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 (1m1) and added to a solution containing the amine, (3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine), (47 mg, 0.2mmo1), triethylamine (0.14m1, Immol) and dichloromethane (1m1). The reaction mixture was stiiTed for 16 hours at room temperature, concentrated, re-dissolved in dichloromethane (lOml), filtered through an SAX column [Varian] (2g) and stirred with PS-isocyanate resin [Argonaut Technologies]
(100mg, 0.38mmo1) 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.
1H NMR (CDCl3): S I.88 (4H, m), 2.90 (4H, m), 3.08 (2H, t), 3.84 (3H, s), 4.2I
(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 SUBSTITUTE SHEET (RULE 26) Utilising the procedure of Example A51 with 1-dimethylamino-2-propanol [Aldrich] in place of 1-(2-hydroxyethyl)-pyrrolidine.
Example A56 Correspondingly Example A51 with 1-(2-hydroxyethyl)-piperidine [Aldrich].
Example A58 Correspondingly Example A51 with 2-(hexamethyleneamino)-ethanol [Lancaster].
Example A60 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 Utilising the procedure of Example A60 with 4-carboxyphenylboronic acid [Aldrich] in place of 3-aminophenylboronic acid.
Example A70 Correspondingly Example A63 with (3,4-methylenedioxyphenyl)boronic acid [Aldrich].
Example A72 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 Correspondingly Example 51 with 2-dimethylaminocyclohexanol [J. Chem. Soc. C
(1969), (2), 248-52].
Example A76 Correspondingly Example 51 with 2-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-ethanol [Patent US-394682]

SUBSTITUTE SHEET (RULE 26) Example A78 Correspondingly Example 51 with 2-(3,4-dihydro-1H-isoquinolin-2-yl)-ethanol [Patent WO-9719926].
Example A80 Correspondingly Example 51 with 2-(4-phenyl-piperazin-1-yl)-ethanol [J. Med. Chem. 1994, 37(13), 1964].
Example A82 Correspondingly Example 51 with 1-methyl-3-pyrrolidinol [Aldrich].
Example A84 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 Utilising the procedures of Example A84 with 4-methoxy-3-pyridylboronic acid [Patent WO-9924440] in place of 4-methoxy-phenylboronic acid.
Example A89 Correspondingly Example A88 with 2-methoxy-3-pyridylboronic acid [Patent WO-9910331].
Example A90 Correspondingly Example A88 with benzo-[b]-furan-2-boronic acid [Aldrich].
Example A91 Correspondingly Example A88 with thiophene-3-boronic acid [Aldrich].

SUBSTITUTE SHEET (RULE 26) Example A92 Correspondingly Example A88 with indole-5-boronic acid [Frontier].
Example A93 4'-Methyl-biphenyl-4-carboxylic acid [3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amide A mixture of 3-methoxy-4-(2-pyrrolidin-1-yI-ethoxy)-phenylamine [Example A51]
(4.7mM I.Ig) and triethylamine (I4mmol) was treated with 4-brornobenzoyl chloride [Aldrich] in dichloromethane (20m1) and kept at room temperature for I6 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.
1H NMR (DMSO-d6): 8 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]+
The amide, 4-bromo-N [3-methoxy-4(2-pyrrolidin-1-yl-ethoxy)-phenyl]-benzamide (O.lmM 42mg), and 4-methyl-benzene boronic acid [Aldrich] (O.lmM l4mg) were refluxed for 16 hours in a mixture of benzene (8m1), ethanol (2m1) and 2M
aqueous sodium carbonate (2m1) in the presence of tetrakis-(triphenylphosphine)-palladium[0]
(5mg) under an argon atmosphere. The mixture was cooled, the upper Iayer decanted, and this solution purified by chromatography on silica gel using dichloromethane:
methanol (10:1) followed by acetonitrile: satd. aqueous ammona (25:1) to afford the title compound as a white solid.
1H NMR (CDC13): 8 7.92 (2H, dd), 7.68 (2H, dd), 7.50 (2H, dd), 7.26 (3H, dddd), 6.96 ( 1 H, dd), 6. 8 8 ( 1 H, d), 4.13 ( 1 H, t), 3 .87 (3 H, s), 2.92 (2H, t), 2.60 (4H, m), 2.41 (3H, s) and 1.80 (4H, m); MS: (AP-ve) nz/z 429 [M-H]-; (AP+ve) m/z 431 [M+H]+, Example A100 Utilising the procedure of Example A93 with 4-(2,6-dimethoxypyrimidinyl)-boronic acid [Frontier] in place of 4-methyl-benzene boronic acid.
SUBSTITUTE SHEET (RULE 26) Example A103 Correspondingly Example A93 with furan-3-boronic acid [Frontier].
Example A144 Correspondingly Example A93 with mesityl-boronic acid [Frontier].
Example AlOS
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 Utilising the procedure of Example B37 except using piperidine in place of aniline.
Example B1 Utilising the procedure of Example A7 with 3-phenoxybenzoic acid [Aldrich] in place of 2'-methyl-biphenyl-4-carboxylic acid.
Example B2 Correspondingly Example B1 using 4-benzylbenzoic acid [Apin].
Example B34 Correspondingly Example Bl using 3-benzylbenzoic acid [Patent WO-9828268].
Example B35 Correspondingly Example B1 using 4-phenoxybenzoic acid [Aldrich].
Example B37 N [-[3-Methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-4-phenylamino-benzamide Dry cesium carbonate (O.lSmM, 49mg), (S)-B1NAP [Aldrich] (0.015 mM, 9mg) and palladium acetate (0.0075rnM, 2mg) were sonicated in anhydrous ethyleneglycol SUBSTITUTE SHEET (RULE 26) 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.lmM, 42mg) and aniline (0.1 lmM, lOmg) then refluxed for 40 hours.
The suspension was filtered through a hydrophobic membrane, concentrated, then purified on C 18 R.P. silica using acetonitrile:water to afford the title compound as a white solid.
1H NMR (MeOH-d4): 8 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 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 Correspondingly Example CI using 3-methoxybiphenyl-4-carboxylic acid [Patent WO-9534540].
Example C3 Correspondingly Example C1 using 3-methylbiphenyl-4-carboxylic acid [Patent WO-9534540].
Example C4 Correspondingly Example C1 using 4-phenylthiophene-2-carboxylic acid [Specs].
Example CS
Correspondingly Example C1 using 4-(3,5-dichlorophenoxy)-furan-2-carboxylic acid [Maybridge].
Example C6 Correspondingly Example C1 using 5-methyl-1-phenylpyrazole-4-carboxylic acid [Maybridge] .

SUBSTITUTE SHEET (RULE 26) Example C7 Correspondingly Example C1 using 6-phenyl-nicotinic acid [WO-0006085].
Example C8 Correspondingly Example C1 using 3-chloro-biphenyl-4-carboxylic acid [Patent JP-09221476] .
Example C9 Correspondingly Example Cl using 5-(4-chlorophenyl)-2-trifluoromethyl-furan-3-carboxylic acid [Maybridge].
Example C10 Correspondingly Example C1 using 2-(4-chlorophenyl)-3-(trifluoromethyl)-pyrazole-4-carboxylic acid [Maybridge].
Example C11 Correspondingly Example Cl using 5-(2-pyridyl)-thiophene-2-carboxylic acid [Maybridge] .
Example C12 Correspondingly Example C1 using 5-(methyl-trifluoromethyl-2-H-pyrazol-3-yl)-thiophene-2-carboxylic acid [Maybridge].
Example Dl Utilising the procedure of Example DS with 3,4-dichloronitrobenzene [Aldrich]
in place of 2,4-dichloronitrobenzene.
Example DS
Biphenyl-4-carboxylic acid [2-chloro-4-(2-diisopropylamino-ethoxy)-phenyl]-amide.
To a three-neck flask (fitted with condenser, dropping funnel and themnometer) containing iron powder (938mg, 16.8mmo1) mixed with a solution of ammonium chloride SUBSTITUTE SHEET (RULE 26) (28mmol) in water (28m1), 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-hydroxylethyl)-pyz~olidine], dropwise over 10 minutes. The reaction mixture was gently xefluxed 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 wexe partitioned between water (5m1) and ethyl acetate(3 x 1 Oml), the organic phase dried (MgS04), filtered, and evaporated. The aqueous phase was treated with satd.
aq. sodium bicarbonate (lOml), extracted with ethyl acetate (3 x 10m1), dried (MgS04), and evaporated. Residues from both extractions were combined and purified by flash chromatography on silica gel using dichloromethane - methanol - aq. ammonia as eluent to affoxd 2-chloro-4-(2-diisopropylamino-ethoxy)-phenylamine as a brown oil.
1H NMR (CDCIg): 8 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]+.
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.
1H NMR (CDC13): b 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 Utilising the procedure of Example A51 with 2,4-difluoronitrobenzene [Aldrich]
in place of 4-chloro-3-methoxynitrobenzene.
Example D12 [WO-00/06146]
Utilising the procedure of Example A51 with 3,4-difluoronutrobenzene [Aldxich]
in place of 4-chloro-3-methoxynitrobenzene.
Example D16 SUBSTITUTE SHEET (RULE 26) Utilising the procedure of Example A51 with 2-methyl-4-fluoronitrobenzene [Aldrich] in place of 4-chloro-3-methoxynitrobenzene Example D20 Utilising the procedure of Example A51 with 3-methyl-4-fluoronitrobenzene [Aldrich] in place of 4-chloro-3-methoxynitrobenzene Example D24 Utilising the procedure of Example A51 with 3-acetyl-4-fluoronitrobenzene [Aldrich] in place of 4-chloro-3-methoxynitrobenzene Example DZS
Biphenyl-4-carboxylic acid [4-(2-diisopropylamino-ethoxy)-2-formyl-5-methoxy-phenyl]-amide 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 (1m1), dichloromethane (5 ml) and methanesulphonic acid (0.5 ml). The mixture was stirred vigorously for 24 hours then treated with satd. aq. sodium bicarbonate (30m1) and extracted with dichloromethane (3 x 20m1). The combined organic phases were dried (MgS04), 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.
1H NMR (CDCl3): ~ 1.13 (12H, d), 2.04 (3H, s), 3.02 (2H, t), 3.20 (2H, kept.), 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 Biphenyl-4-carboxylic acid [4-(2-diethylamino-ethoxy)-3-(1-hydroxy-ethyl)-phenyl]-amide To biphenyl-4-carboxylic acid [3-acetyl-4-(2-diethylamino-ethoxy)-phenyl]-amide [Example D24] (20mg, O.OSmmol) dissolved in a 1:1 mixture of tetrahydrofuran l ethanol (3m1), was added sodium borohydride [Aldrich] (6mg, O.lSmmol). The reaction mixture was stirred at ambient temperature for 16 hours. The solvent was evaporated and SUBSTITUTE SHEET (RULE 26) 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.
1H NMR (CDC13): 8 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) MS (AP+ve): n~/z 433 [M+H+]
Example D27 Biphenyl-4-carboxylic acid (4-(2-diethylamino-ethoxy)-3-ethyl-phenyl]-amide To biphenyl-4-carboxylic acid [3-acetyl-4-(2-diethylamino-ethoxy)-phenyl]-amide [Example D24] (25mg, 0.06mmol) dissolved in dichloromethane (1.5m1), was added triethylsilane (O.SmI) and trifluoroacetic acid (0.25m1). The resulting yellow solution was stirred at room temperature for 120h. 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.
1H NMR (CDC13): b 1.17 (6H, m), 2.64 (2H, q), 2.8 (4H, c~, 3.06 (2H, t), 4.15 (2H, t), 6.82 (1H, d), 7.35-7.71 (9H, m) and 7.96 (2H, d) MS (AP+ve): m/z 417 (M+H]+
Example D28 [W09901127]
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 [W09901127]
Utilising the procedure of Example D28 with 2-dimethylaminoethanol [Aldrich]
in place of 2-diisopropylaminoethanol.
Example D32 (W09901127) Utilising the procedure of Example D28 with 2-diethylaminoethanol [Aldrich] in place of 2-diisopropylaminoethanol Example D38 [W09901127]

SUBSTITUTE SHEET (RULE 26) 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-methoxyphenylboroiuc acid Example D39 [W09901I27) 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 Biphenyl-4-carboxylic acid [4-(2-diisopropylamino-ethoxy)-3-methoxy-phenyl]-methyl-amide.
To 4-(2-diisopropylamino-ethoxy)-3-methoxy-phenylamine (lmmol) [Example A7]
were added triethylorthoformate (8m1) and trifluoroacetic acid (0.15m1). The resulting solution was heated to 90°C for 4hr. The solution was evaporated then redissolved in ethanol and cooled to approximately -10°C. Sodium borohydride (190mg, Smmol) was introduced portionwise over 10 minutes then the mixture allowed to warm to room temperature. The solution was stirred at room temperature for 16h, then acidified to pH 1 with 2M hydrochloric acid. The mixture was concentrated to approximately l OmI, 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 (x3), dried (MgS04), 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-rnethoxy-phenyl]-methyl-amine as an oil.
~H NMR (CDC13): 8 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): yrrlz 281[M+H]+.
To 4-phenylbenzoic acid (0.2mmo1) suspended in dichloromethane was added oxalyl chloride (0.6mmo1) followed by dimethylformamide (1 drop). The reaction mixture was stirred for 1h, evaporated, co-evaporated (x3) with dichloromethane then redissolved in dichloromethane(lml). A solution containing the amine [4-(2-diisopropylamino-ethoxy)-3-methoxy-phenyl]-methyl-amine (0.2mrno1) and triethylamine (140mg, lrnmol) dissolved in dichloromethane (1m1) was added. This solution was stirred at ambient SUBSTITUTE SHEET (RULE 26) temperature for 14 hours, evaporated, dissolved in dichloromethane (1m1) and treated with PS-isocyanate resin [Argonaut Technologies] (150mg). After a further 18h shaking at ambient temperature, the mixture was filtered, passed through an SAX column [Varian] (1g), 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.
1H NMR (CDC13): b 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): fnlz 476 [M+H]+.
Example ES
Utilising the procedure of Example EI with triethyl orthoacetate [Aldrich] in place of triethyl orthoformate.
Example E12 1 S Biphenyl-4-carboxylic acid [2-chloro-4-(2-diisopropylamino-ethoxy)-5-methoxy-phenyl]-amide Biphenyl-4-carboxylic acid [4-(2-diethylamino-ethoxy)-3-methoxy-phenyl]-methyl-amide [Example E9] (45mg, 0.1 mmol), was dissolved in chloroform (1m1) and treated with benzotriazole [Aldrich] (12 mg, 0.1 mmol) and N chlorosuccinimide (13 mg, 0.11mmo1). 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.
1H NMR (CDCl3): 8 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):
mlz 467, 469 [M+H]+.
Example E13 Utilising the procedures of Example A93 with [4-(2-diethylamino-ethoxy)-3-rnethoxy-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.

SUBSTITUTE SHEET (RULE 26) Example E14 Utilising the procedure of Example E13 with 2-methylphenylboronic [Aldrich] in place of of 4-chlorophenylboronic acid.
Example E26 Correspondingly Example E14 with 2-chloromethylphenylboronic acid [Aldrich].
Example E17 Correspondingly Example E14 with 4-fluoromethylphenylboronic acid [Aldrich].
Example E21 Correspondingly Example E14 with 4-chloromethylphenylboronic acid [Aldrich].
Example E22 Correspondingly Example E14 with 4-ethylphenylboronic acid [Aldrich].
Example E23 Correspondingly Example E14 with 4-tef°tbutylphenylboronic acid [Aldrich].
Example E24 4-Biphenylcarboxylic acid [4-(2-diethylamino-ethoxy)-3-methoxy-phenyl]-methyl-amide [Example E9] (45mg, 0.lmmol), was dissolved in acetonitrile (1m1) and treated with N
fluoro-N'-chloromethyl-triethylenediamine-bis(tetrafluoroborate) (43mg, 0.12mmo1) and heated to ~OoC 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.
MS (AP+ve): m/z 451 [M+H]+.
Example E25 TJtilising the procedure of Example El 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.

SUBSTITUTE SHEET (RULE 26) Example F1 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 Biphenyl-4-carboxylic acid [4-((R)-diethylamino-hydroxy-propoxy)-3-methoxy-phenyl]-amide 4-Nitro-2-methoxyphenol [Aldrich] (845mg, 5mmo1) was dissolved in DMF (25 ml) and treated with sodium hydride (60% oil dispersion, 200mg). 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 (20m1) and dichloromethane (3 x 25m1), dried (MgS04), filtered and evaporated. The residue was purified by flash chromatography on silica gel (hexane - ether) to give (R)-2-(2-methoxy-4-vitro-phenoxymethyl)-oxirane as a pale brown solid in 80% yield.
1H NMR (CDCl3): ~ 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).
(R)-2-(2-Methoxy-4-vitro-phenoxymethyl)-oxirane (0.5mmol, 113mg), in dichloromethane (3 mI) was treated with the amine (diethylamine) [Aldrich]
(1.5 mmol, 110 mg) and titanium tetraisopropoxide [Aldrich] (50u1). The solution was stirred at ambient temperature for 24 h, treated with water (1m1) and shaken vigorously for 10 minutes. The resulting suspension was passed through a hydromatnx cartridge [Varian ChemElut] (5m1) eluting with dichloromethane (lOml) to give (R)-diethylamino-(2-methoxy-4-vitro-phenoxy)-propan-2-of as a yellow oil 1H NMR (CDC13): 8 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~].
This material was dissolved in ethanol (5m1) and treated with hydrogen chloride (2M in diethyl ether) 0.1 nnl then 10% palladium on charcoal (20 mg) and hydrogenated at atmospheric pressure for 24 hours. The solution was purged with argon then filtered SUBSTITUTE SHEET (RULE 26) through celite and evaporated to give (R)-(4-amino-2-methoxy-phenoxy)-diethylamino-propan-2-of hydrochloride as a white crystalline solid.
1H NMR (CD30D): 8 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).
A solution of this material in dichloromethane (2m1) was treated with triethylamine (2 mmol, 280u1) and triethylsilyl trifluoromethanesulphonate (lmmol, 264mg).
After 30 minutes, 4-biphenylcarboxylic acid chloride [Example 1] (lmmol, 217mg) was introduced and the mixture stirred for 12 hours. The solvent was evaporated and the residue dissolved in methanol (100m1) and treated with potassium carbonate (2g). After stirring for six hours, the suspension was evaporated, formed into a slurry with dichloromethane (20m1), filtered, the filtrate evaporated, and the residue purified by flash chromatography (dichloromethane - methanol - aq. ammonia) to give the title compound as a white solid.
1H NMR (CDC13): 8 1.11 (6H, t), 2.61-2.78 (6H, m,), 3.88 (3H, s), 3.5-4.5 (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 GS
Utilising the procedure for the preparation of (R)-diethylamino-(2-methoxy-4-nitro-phenoxy)-propan-2-of [Example Gl] but replacing dichloromethane with 1,2-dichloroethane and diethylamine with diisopropylamine. In addition, the mixture of amine and epoxide was heated at 80oC for 12h rather than being kept at ambient temperature for 24 hours.
Example G8 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 Utilising the procedure of Example A51 but using 4-dimethylamino-1-butanol [ICN-RF]
in place of 1-(2-hydroxyethyl)-pyrrolidine.

SUBSTITUTE SHEET (RULE 26) Example Hl 4-Cyclohexyl-N-(3-methoxy-4-(4-methyl-piperazin-1-yl)-phenyl]-benzamide A solution of 1-(2-methoxy-4-vitro-phenyl)-piperazine (Patent WO-9906382) (1 Ommol, 2.37g) in dichloromethane (50m1) was treated with diter~tbutyl dicarbonate (lOmmol, 2.18g) 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-vitro-phenyl)-piperazine-1-carboxylic acid tertbutyl ester.
1H NMR (CDCl3): cS 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).
This material was dissolved in ethanol (50m1) and treated with 10% Pd on carbon (100mg). 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-I-carboxylic acid tertbutyl ester as a brown oil.
1H NMR (CDCl3): S 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).
This aniline (0.2rnmol, 6I mg) was dissolved in dichloromethane (1m1) 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 1H NMR (CDC13): ~ 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+].
This material was dissolved in dichloromethane (5m1) and treated with anisole (1m1) and trifluoroacetic acid (5m1). After 2 hours the solution was evaporated, then co-evaporated twice from toluene. The residue was dissolved in dichloromethane (lOml), washed with satd. sodium bicarbonate (2m1), the organic phase dried (MgS04), fzltered and evaporated to a brown oil, 4-cyclohexyl-N (3-methoxy-4-piperazin-1-yl-phenyl)-benzamide.

SUBSTITUTE SHEET (RULE 26) 1H NMR (CDCl3): 8 1.22-I.87 (10, m), 2.57 (l, m), 3.04-3.12 (8H, m), 3.9I (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): n~/z 394 [M+H+].
This amine (O.lmmol, 39mg) was dissolved in ethanol (3m1) and treated with metafolmaldehyde (100mg), Amberlyst cyanoborohydride resin [Novabiochem]
(100mg), and acetic acid (50u1). 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. Tlus was evaporated from dilute acetic acid to give the monoacetate salt hydrate.
1H NMR (CDC13): ~ 1.22-1.45 (5H, m), 1.76-1.87 (5H, m), 2.02 (6H, 2xs), 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);
MS (AP+ve): m/z 408 [M+H~].
The following tables give Examples which illustrate but do not limit the invention in any way.

SUBSTITUTE SHEET (RULE 26) Table A
Encompassing compounds of general formula (II), a subset of formula (I) where A = H
and OMe, R3 = H, X = O, Y = CH2CH~ , Z = a bond; R4 = Ph and RS is either meta or para substituted on R4.
eR1 O I ~ O~N~R2 \ H / Oi (II) Example RS ~1 meta / [M+H]+ Procedure No. N ara .. O~ wR2 p A1 Ph ~- p 447 A7 .O~N~
A2 ~~N p 453 A7 / \N
A3 ~,N~ ~ p 437 A7 ~N___ ;.off--N
A4 Ph ~- m 447 A7 .O~N~
AS N ~ p 448 A7 'I O~N
A6 ,, o ~ p 489 A7 / \ ; .o~-N
A7 ~ p 461 A7 __ _ ; .0~..~.N~
A8 ~ p 453 A7 . 'O~N~

SUBSTITUTE SHEET (RULE 26) A9 p 453 A7 ~ \ ___ _ --o . '~--1' A10 \N \ ____ ~ p 451 A7 N_ . .o~'N~
All ,N _ ~ p 529 A7 ~ ~ _ ..o~~--N
~N
A12 -~ ~ p 461 A7 -O~'N
A13 / I ~- m 472 A7 - .. \ vN : .O~'N~
A14 ~~ , ~- p 52S A7 ,, ~ \ so - .o~/--N
A15 - _ / ~ ~ m 453 A7 O~N
S
A16 S ~ ~ m 453 A7 \ . : .O~N~
A17 O ~ ~ ____ ~- p 489 A7 \~ - -O~N
A18 New ~- p 486 A7 / I :-O~N
A19 N-N ~ ~ _ ~ p 529 A7 /'O -:ofN
A20 S ~ p 453 A7 ____ ;-O~--N
A21 N ~ p 449 A7 i \ ____ - o~~' '=-N
SUBSTITUTE SHEET (RULE 26) A22 ~ ~ ~ ~ p 477 A22 :.O~N~
A23 F - ~ _ ~ p 515 A22 .O~_"'N~
FF
A24 H2N / ~ p 462 A22 \ ..0~"-N I
A25 ~ \ ~- p 553 A22 ,.0~_"N~
_-\ ___ A26 / \ ~. ~- p 497 A22 O~N
A27 . ~ p 497 A22 \ ~ _._ .: ~~N~
A28 -- _ ~- p 461 A22 _ : O~N
A29 --- _ ~ p 493 A22 .O~N~
A30 F ~ p 515 A22 '~ ; .o~--N~
FF I

SUBSTITUTE SHEET (RULE 26) A31 ~ -- ~ p 475 A22 _ :.O~N~

A32 JO ~ p 491 A22 .-.- "'_N

O ..,0~
~ ~

A33 -- ~- p 473 A22 __ ..O~N~
_ A34 ~ ,' ~ p 477 A22 O / ~ , o~N~

A35 Ph ~~ p 433 A51 .O~N~

A36 ~0 p 439 A51 ___ ,~~N~

A37 Ph ~ p 397 A51 ,,.0~~"'N~

A38 ~ p 391 A51 ___ A39 [ p 423 ASI

___ A40 Ph [ p 417 A51 A41 Ph p 417 A51 Nw A42 p 423 A51 ___ ''O N\

SUBSTITUTE SHEET (RULE 26) A43 Ph ~ p 405 A51 ..O~Nw A44 N p 411 A51 ___ _,0 A45 Ph ~ p 419 A51 ._O-'~N~
A46 ~ p 425 A51 _ _ _ ,_o~N~/
A47 Ph ~\~/~~ p 417 A51 ---O
A48 ~\~/~~ p 423 A51 ___ ___O
A49 Ph ~-Ph p 467 A51 .: o~N~
A50 ~-Ph p 473 A51 ___ ,,,o~N~
AS I Ph p 417 A51 ,,.0~'-"N
A52 p 423 A51 ___ ,,,o\~---N
A53 ~ 0~ ~ p 421 A22 .. . ...0~'_'N~
A54 Ph , ,O N/ p 405 A51 A55 _-_ , ,O N/ p 411 A51 SUBSTITUTE SHEET (RULE 26) A56 Ph ~ p 431 A51 ,,.0~"N
A57 ~ p 437 A51 ___ ,, O~"-N
A58 Ph P 445 A51 . .p~-N

_ _ _ , -O~--N

p ,,,o~/--N\
A61 Ph~~ ~ p 497 A63 ,,.O~N\
A62 CFs ~ 459 A63 ,,,0~~"N p A63 ~-'' N p 419 A63 Hoc ~ ''off \
A64 ~ N p 417 A63 -o A65 ~~ i ~ p 421 A63 ,,,o~/--N
\
A66 ~ p 441 A63 w v ~ , .O~N\
A67 /. /- ~ p 441 A63 ..off--N\
\ \
A68 / ~ p 404 A63 ,,.off--N~
A69 / ~ p 437 A63 ~ ~ ~! , ,o~N~
s A70 /O / I --- - ~ p 434 A63 .O~N~

SUBSTITUTE SHEET (RULE 26) A71 ~--' N p 459 A63 F3C ~ I W ~ v A72 Ph ~ 481 A51 ~~' ~N\ I / p A73 ~--' 'w ~ ~ p 487 A51 Nw I ~
A74 Ph -~-~ p 445 A51 A75 ---~ p 451 A51 N
A76 Ph o~N I ~ p 493 A51 i A77 ~-' 1,~N ~ ~ p 499 A51 Q i A78 Ph o N I ~ p 479 A51 i A79 ~--' o N I ~ p 485 A51 i A80 Ph o N~ p 508 A51 ~N~Ph A81 ~-' O ~ p 514 A51 N.Ph A82 Ph a p~,~ p 403 A51 ~~N
A83 ~--' - ,p~ p 409 A51 ~N~\
A84 i /~ p 449 A84 W I ... . .O~N~
O
A85 i /~ p 445 A88 - .O~/~'N~
A86 ~ ~ p 487 A88 I .. . 'o~N~/

A87 ~ ___- /~ p 425 A88 - .O~"N~
SUBSTITUTE SHEET (RULE 26) A88 i /~ p 450 A88 .O~N~./
O N

A89 \ I -''- / ' /O N p 450 A88 N O

A90 \ ~ ~ ___ ' .OWN p 459 A88 o ~/

A91 j ___ '- o~N p 425 A88 A92 N \ ~'' ' 'OWN p 458 A88 H

A93 ' \ I -'' ' Io N~ p 447 A93 O

A94 \ \ I -'' , 'o N~ p 443 A93 A95 \ I -' r Io N~ P 485 A93 A96 \ ~ ___- r '0 N~ p 423 A93 S

A97 \ I -'' y IO N~ p 431 A93 A98 \ \ I -' - o N~ p 448 A93 O N

A99 \ I -'' - '0 N~ p 431 A93 A100 N~ - ~ p 479 A93 ,.0~"N
~0~~0' ' A101 \ I 1 ___ ' 'o~N~ p 457 A93 A 102 ~ _ p 423 A93 S~ __ ; .O~N~

A103 ~ _ p 407 A93 O~ __ - O~N

A104 ~ -y0 N~ p 459 A93 A105 Ph /~~ p 429 A105 SUBSTITUTE SHEET (RULE 26) A106 GN'' ' /~ p 426 A107 ..O~N~

A107 GN'' ' ~ p 424 A107 ,,0~--N

A108 ~N'' ~ p 454 A107 ,: O~N

SUBSTITUTE SHEET (RULE 26) Table B
Encompassing compounds of general formula (III), a subset of formula (1 ) where A = H
and OMe, Rl = R2 = Me2, R3 = H, X = O, Y = CH2-CH2 , Z = O, CH2 or NH; R4 =
Ph, RS is Ph and Z is either meta or para substituted on R4.

O I ~ O~N~R2 \ H / Oi Z

(III) Example Z meta ~ ~ [M+H]+ Procedure /

No. para ,,O
~N~R2 Bl O m ~ 463 Bl ,,.0~'N~

B2 CH2 p ~ 461 B1 ,,.O~N~

B3 m ~O 229 A51 O ,: O

B4 CH2 p ~O 4447 A51 ,,.0~~"'N~

BS O m ~ 407 A51 ,,.0~''N~

B6 CH2 p ~ 405 A51 ,,.0~"N~

B7 O m 433 A51 .O

B8 CH2 p 431 ASI

.O

SUBSTITUTE SHEET (RULE 26) B9 O m ~ 433 A51 .O N

B 10 CH2 p ~ 431 A51 N
,,.0~,~~

B 11 O m ~ 421 A51 ,,.0 N \

B 12 CH2 p ~ 419 A51 ,,.0 N\

B13 O m /- 435 A51 ,,,0~'N~

B14 CH2 p /~ 433 A51 ,,.O~N~

B 15 O m 433 A51 ... ~,,,, '' N~

B 16 OH2 p 431 A51 .0~, ,, Nw ,, B17 O m ~Ph 483 A51 . .O~N\

B18 CH2 p ~'Ph 481 A51 . .O~N\

B19 O m 433 A51 .p~-N

.

B20 CH2 p 431 A51 ,p~--N

B21 CH2 p ~,~ ~ 419 ASI
'~N

\

B22 O m 447 A51 ' ,p~--N

SUBSTITUTE SHEET (RULE 26) B23 CH2 p 445 A51 I ,p~--N
B24 O m / 497 A51 ..off U h B25 CH2 p ' ~N Ph 495 A51 .O
B26 O m Q,~N ' ~ 509 A51 i B27 CH2 p Q,,~N I ~ 507. A51 i B28 O m , -p~N \ ~ 495 A51 B29 CH2 p ,-p ~ 493 A51 , B30 O m ,--o~N~ 524 A51 ~N~Ph B31 CH2 p - -o~N~ 522 A51 ~N~Ph B32 O m , ,p~~N~ 419 A51 B33 CH2 p , .O.~~N~ 417 A51 B34 CH2 m ~ 461 Bl B35 O p ~ 463 Bl B36 NH p ~ 462 B37 -.0~~
B37 NH p 432 B37 .: O~N
SUBSTITUTE SHEET (RULE 26) Table C
Encompassing compounds of general formula (IV) a subset of formula (I) where A
= H
and OMe, Rl = R2 = Me2, R3 = H, X = O, Y = CH2-CH2 ; R4, RS = substituted phenyl or heterocycle, O . I ~ O
R5~Z~R4~N ~ O~
H
(IV) Example Z 3l4 ~ RS [M+H]+ Method No. substitution w.r.t. C=O R4 C1 bond 4 ~ Ph 461 C1 C2 bond 4 ~ Ph 477 C1 I
C3 bond 4 ~ Ph 461 C1 i C4 bond 3 ~ Ph 453 C1 S
CS O 3 ~ c~ ~ ~'' 521, C1 523, 525 O ci C6 bond 3 N r l o Ph 451 C1 N
C7 bond 4 ~ Ph 448 C1 NJ

SUBSTITUTE SHEET (RULE 26) C8 bond 4 CI ~ Ph 481, Cl C9 bond 3 F3C I ~ '' 539, C1 ~ ~ 541 c1 C10 bond 3 ~i ~ I ~ '' 539 Cl C 11 bond 3 ~ I W = 453 Cl ~N

S

C12 bond 3 ~ ,N 525 C1 I w /
__ ~ CF~
S

SUBSTITUTE SHEET (RULE 26) 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, RS is Ph or cyclohexyl (Cy) and Z is either meta or para substituted on R4.
~1 O ~ \ O~N~R2 R5~Z
ExampleZ R6 R7 RS meta ~~ [M+H] Method No. / p N +
~ ~R2 para D1 bond Cl H Ph p ~ 452, D1 ~~N 454 D2 O Cl H Ph m ~ 468, Dl D3 CH2 C1 H Ph p ~ 466, Dl ~~,N 468 D4 bond Cl H Cy p ~ 458, Dl ~~N 460 D5 bond H Cl Ph p ~ 452, DS

~~,N 454 D6 O H CI Ph m ~ 468, D5 ~~N 470 SUBSTITUTE SHEET (RULE 26) D7 CH2 H Cl Ph p ~ 466, DS

/ ~O~N 468 D8 bond H Cl Cy p ~ 458, DS

' y~~N 460 D9 bond F H Ph p ~ 435 D9 . .O~N~

D10 CH2 F H Ph p ~ 449 D9 ..O~N~

D11 bond F H Ph p ~ 441 D9 ..O~N~

D12 bond H F Ph p ~ 435 D12 ,,.O~N~

D13 O H F Ph m ~ 451 D12 ..O~N~

D14 CH2 H F Ph p ~ 449 D12 ..O~N~

D 15 bond H F Cy p ~ 441 D 12 .0~~"'N~

D16 bond Me H Ph p ~ 431 D16 . .O~N~

D17 O Me H Ph m ~ 447 D16 . .O~N~

SUBSTITUTE SHEET (RULE 26) D18 CH2 Me H Ph p ~ 445 D16 ..O~N~

D19 bond Me H Cy p ~ 437 D16 ,.O~N~

D20 bond H Me Ph p ~ 431 D20 . .O~N~

D21 O H Me Ph m ~ 447 D20 ,O~A""N~

D22 CH2 H Me Ph p ~ 445 D20 ..O~N~

D23 bond H Me Cy p ~ 437 D20 .,O~N~

D24 bond COCH3 H Ph p ~ 431 D24 ..O~N~

D25 bond OMe CHO Ph p ~ 475 D25 ..O~N~

D26 bond CH(OI~CH3H Ph p ~ 433 D26 . .O~N~

D27 bond Et H Ph p ~ 417 D27 ,O~"'-N~

D28 bond H H Ph p ~ 417 D28 ,C?~'_'N~

D29 O H H Ph m ~ 433 D28 .O~.N~

SUBSTITUTE SHEET (RULE 26) D30 bond H H Ph p / 361 D30 ,,O~Nw , D31 O H H Ph p 433 D28 ,,.0~_"N~

D32 O H H Ph p ~' 405 D32 .,O~N~

D33 O H H Ph m ~' 405 D32 . .O~N~

D34 bond H H Cy p ~ 423 D28 . .O~N~

D35 bond H H Cy p ~ 395 D32 . .O~N~

D36 CH2 H H Ph p ~ 431 D28 . .O~N~

D37 CH2 H H Ph p ~ 403 D32 . .O~N~

D38 bond H H p- p ~ 445 D38 EtPh I ,~~N

D39 bond H H p- p ~ 417 D39 EtPh , ,p~--N~

SUBSTITUTE SHEET (RULE 26) 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, RS = phenyl or cyclohexyl (Cy), Z
= O, CH2 or a bond O I ~ O~N~R2 N ~ R9 R5~Z / R3 (VI) ExampleZ o/pR3 R8 R9 RS /~~ [M+H] Method No. . -O~N~2 +

E1 bond p Me H Me0 Ph >-- 461 El y .off--N

E2 O m Me H Me0 Ph >-- 477 El . .O~N~

E4 CH2 p Me H Me0 Ph >-- 475 El ' O~N

ES bond p Me H Me0 Cy ~ 467 El .O~N~

E6 bond p Et H Me0 Ph ~ 447 El . .O~N~

E7 bond p Et H MeO Ph ~ 445 El ' ,p~-,--N

E8 bond p Me H Me0 Ph ~ 431 El . .O~N

E9 bond p Me H Me0 Ph ~ 433 El . .O~N~

E10 bond p Et H Me0 Cy ~ 453 E1 . .O~N~

E11 bond p Et H MeO Cy ~ 451 El ,.0~'N

E12 bond p Me C1 MeO Ph ~ 468, E12 -~~'N~/ 470 SUBSTITUTE SHEET (RULE 26) E13 bond P Me H Me0 2-F-Ph~ 451 E13 :.O~N~

E14 bond p Me H Me0 2-Me- ~ 447 E14 Ph ,: ~~/-'N~/

E15 bond p Me H Me0 2- ~ 463 E14 Me0- ,:0~/-'N~/

' Ph E16 bond p Me H Me0 2-C1-Ph~ 468, E14 .: o~N~/ 470 El7 bond p Me H Me0 4-F-Ph~ 451 E14 .O~'N~

E18 bond p Me H Me0 4-F3C-~ 501 E14 Ph :O~N~

E19 bond p Me H Me0 4-Me- ~ 447 E14 Ph .= O~'N~/

E20 bond p Me H Me0 4- ~ 463 E14 Me0- ,:0~/"N~/

Ph E21 bond p Me H Me0 4-C1-Ph~' 468, E14 ,:0~/"N~/ 470 E2.2 bond p Me H Me0 4-Et-Ph/' 461 E14 .: O~'Nw/

E23 bond p Me H Me0 4tBu- j' 489 E14 Ph ,..0~'_'N~/' E24 bond p Me F Me0 Ph ~ 451 E24 :.O~N~

E25 bond p Et H Me Ph ~'' 459 E25 :.O~N~

E26 bond p Et H Me Cy ~'' 465 E25 .: O~N

E27 CH2 P Et H Me Ph ~'' 473 E25 :.O~N~

SUBSTITUTE SHEET (RULE 26) Table F
Encompassing compounds of general formula (VII) a subset of fonmula (1) where A = H
and OMe, X = O, R4 = 3-pyridyl, R5 = phenyl, Z = a para bond R'1 O~N~R2 i N O
H
(VII) Example R' [M+H]+ Method No. --''~~N'R2 F1 Rl = R2 = Me 392 F1 F2 418 Fl , \~
:O N~

', o~~

F4 ~ 448 F1 .O~N~

SUBSTITUTE SHEET (RULE 26) 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 RS = Ph or cyclohexyl (Cy), Y is a chain of 3 or 4 carbon atoms optionally substituted by an hydroxyl group.
~1 O ~ ~ O--Y~-N~R2 N ~ O'~

(VIII) Example Z rn/ RS XYN ~1 [M+H]+ Method No.
p ~~~N~R2 G1 bond p Ph o~N ~ 449 G1 off ''~N~

G2 bond p Ph O~N ~ 461 Gl -' OH N
' G3 bond p Ph O~N ~N~ 476 G1 r /
,N

OH

G4 bond p Ph O~N ~ .476 G1 - ' OH

GS bond p Ph o~N 'I,~~ 465 GS
f O ~
H

G6 bond p Ph O~/~N ~ 475 G1 /'' OH N

G7 bond p Ph o-~/~N '~ 475 Gl OH '' N

G8 bond p Cy o~N ~ 453 G8 O

OH -.- N

G9 bond p Ph o~N ~ 447 G8 off ' .. N

SUBSTITUTE SHEET (RULE 26) G10 bond p Cy o~N ~' 455 G8 ''-N~

off G11 bond p Ph o~N ~' 449 G8 off G12 bond p Cy o~N ~ 483 GS,G8 OH '--N

G13 bond p Ph o~N ~ 477 GS,G8 OH .--N

G14 bond p Cy o~N - ~-' 482 G8 N

' -OH

G15 bond p Ph o~N ' ~~ 476 G8 N

' -OH

G16 bond p Cy o~N ~ 481 G8 r-OH N
-G17 bond p Cy O~N '~ 481 G8 OH N

G18 bond p Ph o~N '~ 475 G8 N
OH ' G19 bond p Ph O~N ~ 475 G8 .y OH N
-G20 bond p Ph O~N ~ 444 G8,G5 ,.-N /
OH

G21 bond p Ph o~N ~ 461 G8 OH --' N

G22 bond P Ph o%'~/~N NMe2 419 G22 G23 O m Ph o%'~/~N NMe2 435 G22 G24 CH2 p Ph o%'~/~N NMe2 433 G22 G25 bond p Cy o%'~/~/N NMe2 425 G22 SUBSTITUTE SHEET (RULE 26) 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 RS = Ph or cyclohexyl (Cy), Y and R2 four a piperazinyl ring between X and N.
O ~ V -R1 N I / Oi / H

(IX) Io Example RS R1 [M+H]+ Method No.

H1 Cy Me 408 H1 H2 Cy Et 436 Hl H3 Cy ~ iPr 422 H1 I S The activity of the compounds used in this invention may be assessed by competitive binding assays to llCBy receptors, as follows:
RadioIigand Binding Studies 20 Radioligand binding assays were carried out on well washed membranes from cells stably expressing IlCBy receptors. Membranes (5-15 mg protein) were incubated with [125I]-Melann 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 (pH7.4), containing SOmM Tris and 0.2% BSA. Non-specific binding was defined using 25 0.1 mM Melanin Concentrating Hormone (obtained from Bachem). The test compounds were added at concentrations between l OM and lOpM in 10 concentration steps.
Following incubation, the reaction was stopped by filtration through GF/B
filters and SUBSTITUTE SHEET (RULE 26) washed with 4 x lml of ice-cold SOmM Tris buffer. Microscint 20 (Paclcard) was added to the filters and the radioactivity measured using a Paclcard TopCount.
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.
Frorn tlus an IC50 was determined from which the pKi was calculated.
The most potent compounds of the present invention have pKi values in the range of 7.1 to 7.8 For example:
Example pKi range A48 7.5-7.8 B2 7.1-7.4 C8 7.1-7.4 D 15 7.5-7.8 E9 7.5-7.8 F4 7.1-7.4 Gl 7.1-7.4 H1 7.1-7.4 SUBSTITUTE SHEET (RULE 26)

Claims (11)

1. 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:
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;
R4 is an optionally substituted aromatic carbocyclic or heterocyclic ring;
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;
R5 is an optionally substituted aromatic carbocyclic or heterocyclic ring, or an optionally substituted, saturated or unsaturated, carbocyclic or heterocyclic ring;
and Q is (a) where X is an O or S atom;
Y is a linear or branched C2-4 alkylene group, optionally substituted by a hydroxyl group, or is a C5-6 cycloalkylene group, R1 and R2 are independently a linear or branched C1-6 alkyl, phenyl C1-6 alkyl group; or (b) where X is an O or S atom;
Y is a linear or branched C2-4 alkylene group, optionally substituted by a hydroxyl group, R1 and R2 are linked to form a 5, 6 or 7-membered ring optionally containing one or more further heteroatom selected from O, S or N, where N or C ring atoms are optionally substituted by R a, -CO-R a, -CO-NH-R a, or CO-O-R a, where R a 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 liked by a single bond or methylene group to Y; or (c) where X is an O or S atom, 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 (d) where X is a N atom, Y is a C2-4 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.
2. A compound of formula (I) as defined in claim 1, or a salt or solvate thereof, in which R3 is methyl or ethyl.
3. A compound according to claim 2, which is any one of the compounds set out in Table E herein.
4. A compound of formula (I) as defined in claim 1 or a salt or solvate thereof, excluding the compounds:
N-[4-[2-[bis(1-methylethyl)amino]ethoxy]-2-fluorophenyl]-[1,1'-biphenyl]-4-carboxamide, N-[4-[2-[bis(1-methylethyl)amino]ethoxy]phenyl]-[1,1'-biphenyl]-4-carboxamide, 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.
5. A process for the preparation of a compound of formula (I), or a salt or solvate thereof, as defined in claim 2, which process comprises the reaction of a compound of formula (X) R5-Z-R4-COL (X) where R5, Z, and R4 are as defined for formula (I) in claim 1, and L is a leaving group with a compound of formula (XI) wherein Q and A are as defined in formula (I) in claim 1 and R3 is methyl or ethyl.
6. A process for the preparation of a compound of formula (I), or a salt or solvate thereof, as defined in claim 1, which process comprises the reaction of a compound of formula (X) wherein R5, Z, and R4 are as defined for formula (I) in claim 1 with a compound of formula (XI) wherein Q, A, and R3 are as defined in claim 1, with the proviso that a process for the preparation of:

N-[4-[2-[bis(1-methylethyl)amino]ethoxy]-2-fluorophenyl]-[1,1'-biphenyl]-4-carboxamide, N-[4-[2-[bis(1-methylethyl)amino]ethoxy]phenyl]-[1,1'-biphenyl]-4-carboxamide, 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 is excluded.
7. 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.
8. 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.
9. 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.
10. 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.
11. 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.
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