OA12346A - Carboxamide compounds and their use as antagonistsof a human 11 CBY receptor. - Google Patents

Carboxamide compounds and their use as antagonistsof a human 11 CBY receptor. Download PDF

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Publication number
OA12346A
OA12346A OA1200300018A OA1200300018A OA12346A OA 12346 A OA12346 A OA 12346A OA 1200300018 A OA1200300018 A OA 1200300018A OA 1200300018 A OA1200300018 A OA 1200300018A OA 12346 A OA12346 A OA 12346A
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OA
OAPI
Prior art keywords
ethoxy
phenyl
benzamide
formula
compound
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OA1200300018A
Inventor
David Witty
Christopher Norbert Johnson
Martin Jones
Catherine Anne O'toole
Geoffrey Stemp
Kevin Michael Thewlis
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Smithkline Beecham Plc
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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 Smithkline Beecham Plc filed Critical Smithkline Beecham Plc
Publication of OA12346A publication Critical patent/OA12346A/en

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    • 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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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

012346
CARBOXAMIDE COMPOUNDS AND THEIR USE AS ANTAGONISTS OF A HUMAN 11CBY RECEPTOR
This invention relates to a method of treatment using an antagnnist of the human 11 CByreceptor; a new therapeutic use of a class of carboxamide compounds which are 5 antagonists to a human 1 lCBy receptor; also to novel compounds within that class, and to methods for making the compounds.
International Patent Application Publication Number WO 01/21577 (Takeda ChemicalIndustries Ltd.) discloses certain bisaryl compounds as melanin concentrating hormone 10 antagonists. WO 98/00401 (Merck & Co. Inc.) discloses benzamide dérivatives as fibrinogen receptorantagonist prodrugs. 15 Européen Patent EP 0 358 118 (Boehringer Mannheim GmbH) discloses certain bisaryl compounds as inhibitors of érythrocyte aggregation and useful in the treatment of cardiacand circulatory disease.
Européen Patent Application EP 0 968 999 (Mitsui Chemical Inc.) discloses certain 20 anilide dérivatives useful in the treatment of arrhythmia. WO 99/01127 (SmithKIine Beecham) discloses certain N-[(amino alkoxy)phenyl)benzamides that are active as CCR5 receptor ligands, including the compoundsN-[4-[2-[bis(l-methylethyl)amino]ethoxy]-2-fluorophenyl]-[l,l’-biphenyl]-4- 25 carboxamide and /V-[4-[2-[bis(l-methylethyl)amino]-ethoxy]-phenyl]-[l,r-bjphenyl]-4-carboxamide. Also WO 99/06146 (SmithKIine Beecham) discloses certain substitutedanilides that aie antagonists of the CCR5 receptor, including the compounds:biphenyl-4-carboxylic acid [4-(2-dimethylammo-ethoxy)-phenyl3-amide,biphenyl-4-carboxylic acid [4-(2-diisopropylamino-ethoxy)-phenyl]-amide, 30 A-[4-(2-diisopropylamino-ethoxy)-phenyl3-4-phenoxy-benzamide,iV-[4-(2-diethylamino-ethoxy>phenyl]-4-phenoxy-benzamide,-V-[4-(2-diisopropylamino-ethoxy)-phenyl]-3-phenoxy-benzamide,//-[4-(2-diethylamino-ethoxy)-phenyl]-3-phenoxy-benzamide, 1 012346 4-cyclohexyl-N’-[4-(2-diisopropylamino-ethoxy)-phenyl]-benzamide, 4-cyclohexyl-N -[4-(2-diethylamino-ethoxy)-phenyl]-benzamide, 4-benzyl-jV-[4-(2-diisopropylamino-ethoxy)-phenyl]-benzamide, 4-benzyl-N-[4-(2-diethylamino-ethoxy)-phenyl]-benzamide, 4'-ethyl-biphenyl-4-carboxytic acid [4-(2-düsopropyiamino-ethoxy)-phenyl]-amide,and4'-ethyl-biphenyl-4-carboxyEc acid [4-(2-diethylamino-ethoxy)-phenyl]-amide.
The présent invention is based on the fînding that a class of caiboxamides overlappingwith the above-mentioned benzamides and anilides, are, surprisingly, antagoniste of ahuman 1 lCBy receptor disclosed in Nature, 400,261-265 (1999).
Accordingly these compounds are believed to hâve a rôle in preventing, ameliorating orcorrecting dysfonctions or diseases, including, but not limited to, infections such asbacterial, fongal, protozoan and viral infections, particularly infection caused by HTV-1 orHIV-2; pain; cancers; diabètes; obesity; feeding and drinking abnormalities, such asanorexia and bulimia; asthma; Parkinson’ s disease; both acute and congestive heartfailure; hypotension; hypertension; urinary rétention; osteoporosis; anginapectoris;myocardial infarction; ulcers; allergies; benign prostatic hypertrophy; psychotic andneurological disorders, including anxiety, schizophrenia, manie dépréssion, delirium,dementia or severe mental retardation; and dyskinesias, such as Huntington’s disease orGilles de la Tourette’s syndrome, among others, hereinafter referred to as “theDisorders”.
According to the présent invention there is provided a method of treating the Disorderswhich comprises administering to a mammal sufiering from one or more of the Disordersan effective amount of a compound of formula (I), or a pharmaceutically acceptable saitor solvaté thereof, in which:
2 012346 each A is independently hydrogen, a alkyl optionally substituted by hydroxyl, Όμβ alkoxy, Ci.g alkenyl or Όμ$ acyl group or a halogen atom or hydroxyl, CN or CF3 group;R3 is hydrogen, methyl or ethyl.
Preferably R3 is methyl. 5 R4 is an optionally substituted aromatic carbocyclic or heterocyclic ring. Z is an O or S atom, or an NH or CHi group, or a single bond, at the 3 or 4 position of R4relative 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. 10 R5 is an optionally substituted aromatic carbocyclic or heterocyclic ring, or an optionallysubstituted, saturaîed or unsaturated, carbocyclic or heterocyclic ring.
Preferably, R5 is a phenyl ring. R1 15 /
andQis -X-Y-N \ R2 20 (a) where X is an O or S atom, preferably an O atom; Y is a linear or branched C2-4 alkylene group, preferably a C3 alkylene group, optionallysubstituted by a hydroxyl group, or is a C5.6 cycloalkylene group, RI and R2 are independently a linear or branched Ομ§ alkyl, preferably ethyl; phenyl Ομ6 alkyl group; or 25 (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,RI 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 Nor C ring atoms are optionally substituted by Ra, -CO-Ra, -CO-NH-Ra, or CO-O-Ra, 30 where Ra is a linear or branched Ομ^ 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, 3 012346 Y is a C2-4 alkylene group, RI is a C2-4 alkylene group linked to Y to form a 5 or 6 membered ring and R2 is a linear or brancbed Ci_g alkyl group; or (d) where X is a N atom, Y is a C2-4 alkylene group, RI is a C2-4 alkylene group linked to X to form a 5 or 6membered ring and R2 is a linear or branched Ci^ alkyl group.
Alkyl groupe, including alkyl groups that are part of alkoxy, acyl, etc groups, typicaîlycontain 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 typicaîlyphenyl, but may include bicyclic groups such as naphthyl. Cydoalkyl groups typicaîlycontain from 3 to 7 carbon atoms. Heterocyclic groups may be monocylic 5 to 7membered rings containing up to three hetero atoms, such as pyridyl or imidazole, orbicyclic, especially heterocyclic rings fused to benzene rings, such as benzoxazole orbenzimidazole. Aryl, cycloalkyl and heterocyclic groups may be optionally subsituted byup 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 andpyrazolyl. Suitable optional substituents for R4 include halogen, CF3, C{_4 alkyl, C14alkoxy. R4 may hâve 2 or 3 substituents, but preferably has only 1 substituent in additionto Z, or more preferably is unsubstrtuted apart from Z. Particularly suitable substituentsfor R4 include chloro, fluoro, trifluoromethyl, methyl, methoxy. R5 may be monocyclic, for example thienyl, furânyl, imidazolyl, oxadiazolyl, phenyl,pyridinyl, cyclohexyl, piperidinyl, piperazinyl, pyrazinyl, pyrimidinyl; or a fused bicyclicring System, for example naphthyl, 3,4-dioxymethylene-phenyl, benzofuranyl, indolyl; ora bicyclic System in which a monocyclic ring has a cyclic substituent such as oxadiazolyl,benzyloxy. Suitable optional substituents for R5 include halogen, CF3, CF3O, CHF2O,CN, amino, mono- or di-C^.g alkylamino, Ci_g alkyl, Cj.g alkoxy, C}_g acyl, C^.g alkyl-S-, Ci-6 aIkyl-SO2-, Ci_g alkenyl, phenyl-Cj^ alkyl, phenyl-Ci.g alkoxy. R5 may hâve2 or 3 substituents, but preferably has only 1 substituent, especially in the para positionrelative to Z. Particularly suitable substituents for R5 include chloro, fluoro, 4 012346 trifluoromethyl, cyano, amino, methyl, ethyl, t-butyl, methoxy, acetyl, formyl,methylthio, methanesulphonyl, vinyl, benzyl, benzyloxy, hydrogen.
As for the ring substituents A, ail A substituents may be hydrogen, but it is advantageous 5 that no more than 3 are hydrogen. Suitable A substituents include halogen, Cpg alkyloptionally substituted with hydroxy, Ci_g alkoxy, Cj.g acyl and Ci^ alkenyl.
Particularly suitable A substituents include Cl-2alkoxy, Cl-2alkyl, Cl-2 acyl. Préférablesubstituents for A include chloro, fluoro, methyl, ethyl, hydroxyethyl, methoxy, formyl,acetyl, vinyl and allyl. More préférable substituents for A include methoxy. 10 Suitably, the A substituent is adjacent to the group Q.
In the System Q, in configuration (a) particularly suitable substituents for RI and R2 include methyl, ethyl, isopropyl, benzyl, phenethyl. Y may especially be -(CH2)3-, -(082)4-, -CH2-CH(CH3)-CH2-. When Y is substituted by hydroxy, it may be 15 for example-CH2-CH(OH)-CH2-.
In configuration (b) of System Q, the ring fonned by linking RI and R2 may bepyrrolidinyl, piperidinyl, azepanyl, or imidazolyl. Fused rings include indolinyl,tetrahydroisoquinolinyl, tetrahydroquinolinyl and benzoazepinyl. When a second
20 heteroatom is présent, suitable rings include thiaziriyl, oxazinyl and piperazinyl. A second N atom may be substituted, for example by phenyl, methyl, ethyl, isopropyl oracetyl. Y is typically -(CH2)2-· The ring may be linked backto Y to form a quinuclidinylgroup. 25 In configuration (c) of System Q, the ring fonned by linking RI to Y may be a pyrrolidinyl or piperidinyl ring. The lirikage to Y may be such as to create a ring linkedby a single bond from a ring carbon atom directly to X or via a methÿlene or ethylenelinking group. R2 is typically methyl so that the N atom of the ring is substituted bymethyl. 30 5 012346 Ια configuration (d) of System Q, the ring formed by linking RI to N is suitably a 5 or 6-membered ring such as diazinyl or piperazinyl. Y is typically -(CH^-· R2 is typicallymethyl so that the second N atom (other than X) of die ring is substituted by methyl. 5 Within the scope of formula (I) is a class of compounds of general formula (Π)
where A = H and OMe, R3=H,X = O,Y = CH2CH2, Z = a bond, R4 - Ph, R5 is either10 meta or para substituted on R4, and RI, R2 and R5 are as defined for formula (I).
Also within the scope of formula (I) is a class of compounds of general formula (ΙΠ)
15 where A = H and OMe, R3 = H, X = O, Y = CH2-CH2, Z - O, 0¾ or NH and is eithermeta or para substituted on R4, R4 = Ph, R5 is Ph, and RI and R2 are as defined forformula (I).
Also within the scope of formula (I) is a class of compounds of general formula (TV)
6 012346 (IV) where A = H and OMe, RI = R2 = zPr, R3 = H, X = O, Y = CH2-CH2, and R4andR5are substituted phenyl or heterocycles as defîned for formula (I) 5 Also within the scope of formula (I) is a class of compounds of general formula (V)
(V) where R3 = H, X = O, Y=CH2-CH2, Z» O, CH2, NH or a bond, R4 - Ph, R5 is Ph orcyclohexyl (Cy), Z is either meta or para substituted on R4, and À (R6J<7) and R1,R2 are 10 as defîned in formula (I).
Also within the scope of formula (I) is a class of compounds of general formula (VI)
15 where X = O, Y = CH2-CH2, R4 = phenyl, R5 = phenyl or cyclohexyl (Cy), Z = O, CH2 or a bond, and A (R8,R9), R3 and RI JR2 are as defîned in formula (I).
Also within the scope of formula (I) is a class of compounds of general formula (VU) 7 012346
(VH) where A=Η and OMe, X = O, R3 = H, R4 = 3-pyridyl (with respect to the carbonylgroup), R5 = phenyl, Z = a para bond, and R1,R2 are as defîned in formula (I).
Also within the scope of formula (I) is a class of compounds of general formula (VIII)
where A = H and OMe, R3 = H, X = O, R4 = phenyl, Z = 0,CHç or a bond, R5 = Ph or10 cyclohexyl (Cy), Y is a chain of 3 or 4 carbon atoms optionally substituted by an hydroxyl group, and R1,R2 are as defîned in formula (I).
Also within the scope of formula (I) is a class of compounds of general formula (K)
where A = H and OMe, R3 = H, X = N, R4=phenyl, Z = a para substituted bond, R5 =Ph or cyclohexyl (Cy), Y and R2 form a piperazinyl ring between X and N, and RI is asdefîned in formula (I). 8 012346 A preferred sub-class of compounds for use in the method of treatment of this inventionare 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. Thenovel compounds, or a sait or solvaté thereof, form a further aspect of this invention. A particular group of novel compounds is a class of compounds of general formula (VI)
where R8 and R9 are as defined for A in formula (I), RI, R2 and R5 are as defined informula (I), and R3 is methyl or ethyl.
Suitably R5 is phenyl or cyclohexyl optionally substitutedby halogen, haloalkyl, alkyl oralkoxy; Z is O, 0¾ or a single bond; R8 and R9 are independently selected fiomhydrogen, halogen, alkyl and alkoxy; RI and R2 are alkyl or linked together to form aring; and R3 is ethyl or methyl.
Another aspect of this invention is a class of novel compounds, or a sait or solvatéthereof, which are the compounds of formula (I) excluding the compounds:V-[4-[2-[bis(l-methylethyl)amino3ethoxy3-2-fluorophenyl]-[l,r-biphenyl]-4-carboxaxnide, A-[4-[2-[bis(l-methylethyl)amino]ethoxy]phenyI]-[l,l’-biphenyl]-4-carboxamide,biphenyl-4-carboxylic acid [4-(2-diisopropylamino-ethoxy)-phenyl]-amide,V-[4-(2-diisopropylamino-ethoxy)-phenyl]-4-phenoxy-benzaniide,
I N-[4-(2-diethylamino-ethoxy)-phenyl]-4-phenoxy-benzamide, 7V-[4-(2-diisopropyIamino-ethoxy)-phenyl]-3-phenoxy-benzamide, jV-[4-(2-diethylamino-ethoxy)-phenyl]-3-phenoxy-benzamide, 4-cyclohexyl-N-[4-(2-diisopropylamino-ethoxy)-phenyl]-benzamide, 4-cyclohexyl-N-r4-(2-diethylamino-ethoxy)-phenyl]-benzamide, 9 012346 4-benzyl-J7-[4-(2-diisopropylamino-ethoxy)-phenyl]-benzamide, 4-benzyl-N -[4-(2-diethylammo-ethoxy)-phenylj-benzarnide, 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 arenovel.
The compounds of formulae (I) to (IX), or their salts or solvatés, are preferably inpharmaceutically acceptable or substantially pure form. By pharmaceutically acceptableform is meant, inter alia, of a pharmaceutically acceptable levei of purity excludingnormal phannaceutical additives such as diluents and carriers, and including no matérielconsidered toxic at normal dosage levels.
Suitable salts and solvatés include pharmaceutically acceptable salts and pharmaceutically acceptable solvatés.
Suitable pharmaceutically acceptable salts include métal salts, such as for examplealuminium, alkali métal salts such as lithium, sodium or potassium, alkaline earth métalsalts such as calcium or magnésium and ammonium or substituted ammonium salts, forexample those with lower alkylamines such as triethylamine, hydroxy alkylamines suchas 2-hydroxyethylamine, bis-(2-hydroxyethyl)-amine or tri-(2-hydroxyethyl)-amine,cycloalkylamines such as bicyclohexylamine, or with procaine, dibenzylpiperidine,N-benzyl-P-phenethylamine, dehydroabiétylamine, Ν,Ν'-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 acidaddition salts, such as those provided by pharmaceutically acceptable inorganic acids ororganic acids.
Suitable pharmaceutically acceptable acid addition salts provided by pharmaceuticallyacceptable inorganic acids includes the sulphate, nitrate, phosphate, borate, hydrochlorideand hydrobromide and hydroiodide.
Suitable pharmaceutically acceptable acid addition salts provided by pharmaceuticallyacceptable organic acids includes the acetate, tartrate, maleate, fumarate, malonate, 10 012346 citrate, succinate, lactate, oxalate, benzoate, ascorbate, methanesulphonate, a-ketoglutarate and a-glycerophosphate.
Suitable pharmaceutically acceptable solvatés include hydrates. A substantially pure form will generally contain at least 50% (excluding normalpharmaceutical addiüves), preferably 75%, more preferably 90% and still morepreferably 95% of the compound of formula (I) to (IX) or its sait or solvaté.
One preferred pharmaceutically acceptable form is the crystalline form, including suchform in a pharmaceutical composition. In the case of salts and solvatés the additionalionic and solvent moieties must also be non-toxic.
Examples of pharmaceutically acceptable salts of a compound of formula (I) to (K)include the acid addition salts with the conventional pharmaceutical acids, for example,maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic,mandelic, tartane, 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 ail such forms as well as to their mixtures thereof, includingracemates.
The compounds of formula (I) to (IX), or salts or solvatés thereof, may be prepared by themethods 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 présent invention is desired, it may besynthesised starting fcom the desired enantiomer of the starting material and performingreactions not involving racemization processes or it may be prepared by chiral synthesis,or by deiivatisation with a chiral auxiliary, where the resulting diastereomeric mixture isseparated and the auxiliary group cleaved to provide the pure desired enantiomers.Altematively, where the molécule contains a basic functional group, such as amino, or anacidic functional group, such as carboxy, diastereomeric salts are formed with anappropriate optically active acid or base, followed by resolution of diastereomeric salts byffactional crystallization and subséquent recovery of the pure enantiomers.
Compounds of formula (I) to (EX) may prepared by condensing suitably substituted arylor heteroarylcarboxylic acids and suitably substituted anilines, which are commercially 11 012346 available or synthesized by methods known to the art from commercially availablestartmg materiels, using methods known to the art. For example, suitably substituted arylor heteroarylcarboxylic acids are treated with an activating reagent, such as thionylchloride, at a suitable température, such as at reflux, to afford aryl or heteroarylcarbonylchlorides, and tire aryl- or heteroarylcarbonyl chlorides are condensed with suitablysubstituted anilines in the presence of a suitable base, such as diisopropylethylamine, in asuitable solvent, such as dichloromethane, to give compounds of formula (Ί).
In particular, the préparation of certain carboxamides of formula (I) in which R3 is H isdisclosed in WO 99/01127 and WO 99/06146 mentioned above, and analogous methodsof préparation may be used in the présent invention. Many additional methods forconverting a carboxylic acid to an amîde are known, and can be found in standardreference 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 offormula (X) R5-Z-R4-COL (X) where L is a leaving group such as halogen, especially chlorine or brominewith a compound of formula (XI)
where A, Z, R3, R4, R5 and Q are as defined for formula (I).
In this process, groups convertible to RI, R2, R3, R4 and R5 may be présent during thecoupling, and converted to RI, R2, R3, R4 and R5 after coupling. Also it may beconvenient to couvert one RI, R2, R3, R4 andR5 to another RI, R2, R3, R4 and R5group after coupling. In particular, ring formation between the groups RI, X,Y, R2 or 12 012346 the addition of suitable cyclic groups embodying RI, X, Y, R2, may be performed aftercoupling.
Accordingly, there is provided a process for the préparation of a compound of formula(I), or a sait or solvaté thereof, wherein R3 is methyl or ethyl which process comprises thereaction of a compound of formula (X) as hereinbefore defined with a compound offormula (XI) wherein A and Q are as hereinbefore defined and R3 is methyl or ethyl.
There therefore also provided a process for the préparation of a compound of formula (I),or a sait or solvaté thereof, with the proviso that the following compounds are excluded; 2\K4-[2-[bis(l-methylefoyl)amino]ethoxy]-2-fluorophenyl]-[l,l’-biphenyl]-4- carboxamide, A/-[4-[2-[bis(l-methylethyl)amiîio]ethoxy]phenyl]-[l,r-biphenyl]-4-carboxamide, biphenyl-4-earboxylic acid [4-(2-diisopropylamino-ethoxy)-phenyl]-amide, N-[4-(2-diisopropylamino-ethoxy)-phenyl]-4-phenoxy-benzamide, ?/-[4-(2-diethylamino-ethoxy)-phenyl]-4-phenoxy-benzamide,
Ar-[4-(2-diisopropylamino-ethoxy)-phenyl]-3-phenoxy-benzamide, N-[4-(2-diethylamino-ethoxy)-phenyl]-3-phenoxy-benzamide, 4-cyclohexyl-?Z-[4-(2-diisopropylammo-ethoxy)-phenyl)-benzamide, 4-cyclohexyl-N -[4-(2-diethylamino-e{hoxy)-phenyl]-benzanaiàe,4-benzyl-jV-[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 hereinbeforedefined with a compound of formula (XI) as hereinbefore defined.
The compounds of formula (XI) may be prepared in a number of ways, for example whenX is O or S coupling an appropriately substituted nitrobenzene compound with adialkyaminoalcohol or thiol, and converting the NO2 group to NH2 by hydrogénation in 13 012346 the presen.ee of palladium, catalyst (or with iron/ammonium chloride) before couplingwith an acid chloride, for example as illustrated below:
Acid chlorides of formula (X) may be prepared from the corresponding acids which are5 commercially available or described in the literature or may be prepared by methods analogous to those of the literature.
Altematively the acids of formula (X) may be prepared by combining moieties containingrespectively R5 and R.4 via Z. 10
This may also be achieved conveniently by fîrst coupling a compound of R4-CO-L withthe compound of formula (XI) followed by reaction with a compound R5-Z-L (or L-R4-CO-L with R5-Z). For example an amine of formula (XI) may be reacted with anappropriately substituted bromobenzoyl chloride which may be then reacted with, for 15 example, an appropriately substituted phenyl moiety with a leaving group, or a cyclic t amine, as in the following scheme: 14 012346
ΒΙΝΑΡ » (S)-(+)-2,2'-Bfs(dÎph0nylphosphino)-1,r-blnaphthyl
Similar reactions building up the structure of formula (Ί) may be carried out starting withthe coinpound of formula (X) and adding the équivalent of formula (XI) in sections, as inthe scheme below where an N-protecting group on Q, here a piperazine ring, may be 5 removed after coupling the components of formula (I) and replacement by a desired substituent:
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 10 to an epoxy compound which is then reacted with an amine forming a group Q which is - O-Y(OH)-NR1R2, before coupling with R5-Z-R4-CO-L, as illustrated by: 15 012346
Nos s p-nitrobenzenesulphonyl
Novel compounds of formula (I) where the amide nitrogen is alkylated (R3 is methyl orethyl) may be prepared by alkylating an anilide of formula (XI) before coupling with anacid chloride of formula (X), for example, by utilising the following reductive animation 5 procedure:
The compounds of formula (I) may be converted into their pharmaceutically acceptablesalts by reaction with the appropriate organic or minerai acids. 10 Solvatés of the compounds of formula (I) may be formed by crystallization orrecrystallization from the appropriate solvent. For example, hydrates may be formed bycrystallization or recrystallization from aqueous solutions, or solutions in organic solventscontaining water. 16 012346
Also salts or solvatés of the compoimds of formula (I) which are not pharmaceuticallyacceptable may be usefol as intermediates in the production of pharmaceuticallyacceptable salts or solvatés. Accordingly such salts or solvatés also form part of thisinvention. 5
The above-listed compounds and pharmaceutically acceptable salts thereof, especially thehydrochloride, and pharmaceutically acceptable solvatés, especially hydrates, form apreferred aspect of the présent invention. 10 By virtue of the activity of these compounds as antagoniste of a human 11 CBy receptor, the compounds of formula (I) are believed to hâve a rôle in preventing, ameliorating orcorrecting dysfonctions of diseases, including, but not limited to, “the Disorders”previously mentioned. 15 It is also considered that the treatment of certain of the Disorders mentioned above by an antagonist to the human 1 lCBy receptor are novel. Accordingly, the invention alsoprovides a method for the treatment of diabètes, major dépréssion, manie dépréssion,anxiety, schizophrenia and sleep disorders, in human or non-human mammals whichmethod comprises the administration of a therapeutically effective amount of an 20 antagonist to the human 1 lCBy receptor. In particular the the invention provides a method for the treatment of diabètes in human or non-human mammals which methodcomprises the administration of a therapeutically effective amount of an antagonist to thehuman 1 lCBy receptor. In particular the invention provides a method for the treatmentof major dépréssion, in human or non-human mammals which method comprises the 25 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 maniedépréssion, in human or non-human mammals which method comprises theadministration of a therapeutically effective amount of an antagonist to the human1 lCBy receptor. In particular the the invention provides a method for the treatment of 30 anxiety in human or non-human mammals which method comprises the administration ofa therapeutically effective amount of an antagonist to the human 1 lCBy receptor. Inparticular the the invention provides a method for the treatment of schizophrenia inhuman or non-human mammals which method comprises the administration of atherapeutically effective amount of an antagonist to the human 1 lCBy receptor. 17 012346
In particular the the invention provides a method for the treatment of sleep disorders, inhuman or non-human mammals which method comprises the administration of atherapeutically effective amount of an antagonist to the human 1 lCBy receptor.
The administration of such compounds to a mammal may be by way of oral (includingsub-lingual), parentéral, nasal, rectal or transdermal administration.
An amount effective to treat the Disorders hereinbefore described dépends on the usualfactors such as the nature and severity of the disorders being treated and the weight of themammal. However, a unit dose will nonnally contain 1 to 1000 mg, suitably 1 to 500mg, 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 beadministered once or more than once per day, for example 1,2,3,4,5 or 6 times a day,more usually 1 to 4 times a day, such thai the total daily dose is normally in the range, fora 70 kg adult of 1 to 1000 mg, for example 1 to 500 mg, thai is in the range ofapproximately 0.01 to 15 mg/kg/day, more usually 0.1 to 6 mg/kg/day, for example 1 to 6mg/kg/day.
It is greatly preferred that compounds of formula (I) are administered in the form of aunit-dose composition, such as a unit dose oral (including sub-lingual), nasal, rectal,topical or parentéral (especially intravenous) composition.
Such compositions are prepared by admixture and are suitably adapted for oral orparentéral administration, and as such may be in the form of tablets, capsules, oral liquidpréparations, powders, granules, lozenges, reconstitutable powders, injectable andinfusable solutions or suspensions or suppositories. Orally administrable compositionsare preferred, in particular shaped oral compositions, since they are more convenient forgeneral use.
Tablets and capsules for oral administration are usually presented in a unit dose, andcontain conventional excipients such as binding agents, fîllers, diluents, tabletting agents,lubricants, disintegrants, colourants, flavourings, and wetting agents. The tablets may becoated according to well known methods in the art. 18 012346
Suitable fillers for use include cellulose, mannitol, lactose and other similar agents.Suitable disintegrants include starch, polyvinylpyrrolidone and starch dérivatives such assodium starch glycollate. Suitable lubricants include, for exemple, magnésium stéarate.Suitable pharmaceutically acceptable wetting agents include sodium laùryl 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 theactive agent throughout those compositions employing large quantifies of fillers. Suchoperations are, of course, conventional in the art.
Oral liquid préparations may be in the form of, for example, aqueous or oily suspensions,solutions, émulsions, syrups, or élixirs, or may be presented as a dry product forreconstitution with water or other suitable vehicle before use. Such liquid préparationsmay contain conventional additives such as suspending agents, for example sorbitol,syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethyl cellulose,aluminium stéarate gel or hydrogenated edible fats; emulsifying agents, for examplelecithinj sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edibleoils), for example, almond oil, fiactionated coconut oil, oily esters such as esters ofglycérine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propylp-hydroxybenzoate or sorbic acid; and if desired conventional flavouring or colouringagents.
Oral formulations also include conventional sustained release formulations, such astablets or granules having an enteric coating.
For parentéral administration, fluid unit dose forms are prepared containing thecompound and a stérile vehicle. The compound, depending on the vehicle and theconcentration, can be either suspended or dissolved. Parentéral solutions are normallyprepared by dissolving the compound in a vehicle and filter sterilising before filling into asuitable vial or ampoule and sealing. Advantageously, adjuvants such as a localanaesthetic, preservatives and buffering agents are also dissolved in the vehicle. To 19 012346 enhance the stability, the composition can be frozen after fîlling into the vial and thewater removed under vacuum.
Parentéral suspensions are prepared in substantially the same marner except that the5 compound is suspended in the vehicle instead of being dissolved and is sterilised by exposure to ethylene oxide before suspending in the stérile vehicle. Advantageously, asurfactant or wetting agent is included in the composition to facilitate uniformdistribution of the compound of the invention. 10 As is common practice, the compositions will usually be accompanied by written orprinted directions for use in the medical treatment concemed.
Compounds of the présent invention may be employed alone or in conjuration with othercompounds, such as therapeutic compounds. 15
No adverse toxicological effects are expected for the compounds of the invention, whenadministered in accordance with the invention.
Accordingly, in a further aspect, the présent invention provides a pharmaceutical20 composition for use in the treatment and/or prophylaxie of one or more of the Disorders which comprises a compound of this invention, or a pharmaceutically acceptable sait orsolvaté thereof, and a pharmaceutically acceptable carrier.
The présent invention also provides a method of treatment and/or prophylaxie of one or25 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 pharmaceuticallyacceptable sait or solvaté thereof.
In a further aspect the invention provides the use of a compound of this invention, or a. 30 pharmaceutically acceptable sait or solvaté thereof for the manufacture of a médicament for the treatment and/or prophylaxie of one or more of the Disorders. ··»; 20 012346
In a still further aspect the invention provides the use of a novel compound of thisinvention, or a pharmaceutically acceptable sait or solvaté, thereof as a therapeutic agent,in particular for the treatment and/or prophylaxie of one or more of the Disorders. 5 Compounds for use in this invention and their préparation are illustrated in the followingExamples and Tables.
These Examples illustrate general procedures and sources of Chemicals utilised to préparécompounds whose structures are shown in the Tables of data which follow the Examples. 10 In the case of Examples prepared as members of a coupled array, tire synthetic origin of ail starting componants of the array are shown in the Examples. Rather than detailing theexperimental procedure for each case, the method by which individual members of thearray were prepared is indicated in a Table by référencé to a related Example. Massspectral characterisation of ail Examples is provided in the tables of data. Additional 15 characterisation is provided for selected représentative Examples with full experimental procedures.
Example Al [WO-00/06146]
Utilising the procedure of Example A7 with 4-biphenylcarboxylic acid [Aldrich] in place 20 of 2'-methyl-4-biphenylcarboxylic acid.
Example A2
Correspondingly Example A7 with 4-(5-methyl-[l,2,4]oxadiazol-3-yl)-benzoic acid[J.Org.Chem. 50; 8; 1985; 1182]. 25
Example A3
Correspondingly Example A7 with 4-pyrazol-l-yl-benzoic acid [CanJ.Chem.; 41; 1963;1540]. 30 Example A4
Correspondingly Example A7 with 3-biphenylcaxboxylic [Med.Chem.Res.; 6; 2; 1996].
Example A5 21 . 26) 012346
Correspondingly Example A7 with 4-(2-pyridyl)-benzoic acid [J.Chem.Soc.; 1940; 355,356].
Example À6
Correspondingly Example A7 with 3'-acetyl-biphenyl-4-carboxylic acid [Patent WO-9743262].
Example A7 2-methylphenyl-4-phenylcarboxylicacid [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](55mg, 0.26mmol) in dimethylfonnainide were added (l-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrocbloride [Aldrich] (50mg, 0.26mmol) and l-hydroxy-7-azabenzotriazole [Aldrich.] (35mg, 0.26mmol) followed by diisopropylethylamine(0.04ml, 0.25mmol) and the aniline (4-(2-diisopropylamino-ethoxy)-3-methoxy-phenylamine) (69mg, 0.22mmol), [prepared using the method used to form 3-methoxy-4-(2-pyrrolidin-l-yl-ethoxy)-phenylamine in Example A51 but with 2-diisopropylamino-éthanol in place of 1 -(2-hydxoxyethyl)-pyrrolidine]. The reaction.mixture was stirred atroom température for 16 hours. The solvent was evaporated, and the residue re-dissolvedin dichloromethane (10ml), filtered through an SAX [Varian] column (2g), and the fîltratewas then stirred with PS-isocyanate resin [Argonaut Technologies] (lOOmg, 0.38mmol)for 16 hours. The mixture was filtered, evaporated, and the residue purified by flashchromatography on silica gel using dichloromethane - aq. anamonia - methanol as eluent,to afford the title compound as an oil. *H NMR (CDC13): δ 1.04 (12H, d), 2.28 (3H, s), 2.90 (2H, t), 3.05 (2H, m), 3.91 (3H, s),3.95 (2H, t), 6.88 (1H, d), 7.03 (1H, dd), 7.27-7.32 (4H, m), 7.44, (2H, d), 7.53 (1H, d),7.94 (2H, d) and 8.01 (1H, bs); MS (AP+ve): m/z 461 [M+H]+.
Example A8
Utilising the procedure of Example A7 with cyclohexyl-4-benzoic acid [Aldrich], inplace of (2'-methyl-biphenyl-4-carboxylic acid).
Example A9 22 012346
Correspondingly Example A7 with 4-(2-thienyl)-benzoic acid [J.Chem.Soc.PerkinTrans.l; 17; 1992; 2203].
Example A10
Correspondingly Example A7 with4-(l-methyl-lH-pyrazol-4-yl)-benzoic acid[Patenf.WO-9906409].
Example Ail
Correspondingly Example A7 with 4'\5-methyl-[l ,2,4] oxadiazol-3-yl)-biphenyl-4-carboxylic acid [PatenfcWO -9743262].
Example A12
Correspondingly Example A7 with 4-benzyl-carboxylic acid [Apin].
Example A13
Correspondingly Example A7 with 3’-cyano-biphenyi-3-carboxylic acid [J.Chem.Soc.Perkin Trans.2; 1; 1984; 35-38].
Example A14
Correspondingly Example A7 with 3’-methanesulfonyl-biphenyl-4-carboxylic acidUzv.SibOtd.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]. 23 ’ .26} 012346
Example A18
Correspondingly Example A7 with 4'-cyano-3'-methylbiphenyl-4-carboxylic acid [WO-9850358].
Example A19
Coirespondingly Example A7 with4'-(5-methyl-[l,3,4]oxachazol-2-yl)-biphenyl-4-carboxylic acid [Patent: WO-9743262],
Example A20
Coirespondingly Example A7 with 4-thiophen-3-yl-benzoic acid [J.Chem.Soc.B; 1970;1595].
Example A21
Coirespondingly 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] inplace of 4-methylphenylboronic acid, and Example A51 with 2-(diisopropylamino)-ethanol in place of l-(2-hydroxyethyl)-pyirolidine.
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]. 24 012346
Example A27
Correspondingly Example A23 with 3-naphthylboronic acid [Lancaster]. 5 Example A28
Correspondingly Example A23 with 4-methylphenylboronic acid [Lancaster].
Example A29
Correspondingly Example A23 with4-methylthiophenylboronic acid [Lancaster]. 10
Example A30
Correspondingly Example A23 with 3-trifluoromethylphenylboronic acid [Lancaster].
Example A31 15 Correspondingly Example A23 with 4-carbonylphenylboronic acid [Aldrich].
Example A32
Correspondingly Example A23 with 3,4-(methylenedioxy)phenylboronic acid [Aldrich], 20 Example A33
Correspondingly Example A23 with 4-vipylphenylboronic acid [Aldrich],
Example A34
Correspondingly Example A23 with 3-methoxyphenylboronic acid [Lancaster]. 25
Example A35
Utilising the procedure of Example A51 with l-(2-hydroxyethyl)morpholine [Aldrich] inplace of l-(2-hydroxyethyl)pyrroüdine. 30 Example A36
Utilising the procedure of Example A35 with4-cyclohexylbenzoic acid [Aldrich]. inplace of 4-biphenylcarboxylic acid. 25 26) 012346
Example A37
Utilising the procedure of Example A51 with 2-dimethylaminoethanol [Aldrich], in place ·of l-(2-hydroxyethyl)pyrrolidine.
Example A39
Correspondingly Example A51 with (R)-(+)-l-methyl-2-pyxiolidinemethanol (PatentWO-9932480).
Example A41
Correspondingly Example AS1 with 3-hydroxy-l-methylpiperidine [Aldrich].
Example A43
Correspondingly Example A51 with 2-dimethylamino-l-propanol [TCN-RF].
Example A45
Correspondingly Example A51 with 2-(diethylamino)-ethanol [Aldrich].
Example A47
Correspondingly Example A51 with (S)-(-)-l-methyl-2-pyrrolidinemethanol [Aldrich].
Exemple A49
Correspondingly Example A51 with Mbenzyl-lV-methylethanolamine [Aldrich].
Example A51
BiphenyI-4-carboxyIic acid [3-methoxy-4-(2-pyrroIidm-l*yI-ethoxy)-phenyI amide.
To a solution of the hydroxy amine, (l-(2-hydroxyethyl)-pyrrolidine) [Aldrich], (1.87ml,16mmol) in dimethylformamide was added portionwise sodium hydride [60% dispersionin oil, (544mg, 16mmol). After stirring at room température for 10 minutes a solution ofthe halonitrobenzene, (l-chloro-2-methoxy-4-nitro-benzene) [Avocado] (3g, 16mmol) indimethylformamide (10ml) was added dropwise. The reaction mixture was left stirring atroom température for 16hrs then concentrated. The residue was dissolved in ethyl acetate SUBSTITUTE SHEET (RULE 26) 26 012346 (200ml) and washed with water (3 x 50ml). The organic phase was dried with magnésiumsulphate, evaporated and the residue purified by flash chromatography on silica gel usingdichloromethane - aq. ammonia - methanol as eluent to afford l-[2-(2-methoxy-4-nitro-phenoxy)-ethyl]-pyrrolidine as a brown oil. ‘HNMR (CDC13): δΐ.82 (4H, m), 2.65 (4H,m), 3.01 (2H, t), 3.94 (3H, s), 4.24 (2H, t),6.92 (1H, d), 7.74 (1H, d), and 7.89(1H, dd); MS (AP +ve): m/z 267 [M+H]+.
Toa solution of the amine, l-[2-(2-methoxy-4-nitro-phenoxy)-ethyl]-pyrrolidine(2.3g,8.6mmol) in éthanol (100ml) was added 10% Pd/C (50mg). The mixture was stirred airoom température under an atmosphère of hydrogen at atmospheric pressure for 16h, thenfiltered through celite and the filtrate concentrated to give the corresponding aniline; 3-me)hoxy-4-(2-pyrrolidin-l-yl-ethoxy)-phenylamine, as a brown solid. ‘H NMR (CDCI3): 5 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): m/z 237 [M+H]+.
To the carboxylic acid, (4-biphenyl carboxylic acid) [Aldrich] (47.5mg, 0.24mmol)suspended in dichloromethane (1ml) was added oxalyl chloride [Aldrich] (0.06ml,0.72mmol) followed by one drop of dimethylformamide. The reaction mixture was stirredat room température for 1 hour, concentrated, then co-evaporated three times withdichloromethane to give 4-phenylbenzoyl chloride. This was dissolved indichloromethane (1ml) and added to a solution containing the amine, (3-methoxy-4-(2-pyrrolidin-l-yl-ethoxy)-phenylamine), (47 mg, 0.2mmol), triethylamine (0.14ml, Immol)and dichloromethane (1ml). The reaction mixture was stirred for 16 hours at roomtempérature, concentrated, re-dissolved in dichloromethane (10ml), filtered through anSAX column [Varian] (2g) and stirred with PS-isocyanate resin [Argonant Technologies](1 OOmg, 0.38mmol) for 16 hours. The mixture was filtered, evaporated then purified byflash chromatography on silica gel using dichloromethane - aq. ammonia - methanol aseluent to afford the title compound as an oil. lH NMR (CDCI3): δ 1.88 (4H, m), 2.90 (4H, m), 3.08 (2H, t), 3.84 (3H, s), 4.21 (2H, t),6.83 (1H, d), 7.03 (1H, dd), 7.27-7.70 (8H, m) and 8.01 (2H, d); MS (AP+ve): m/z 417[M+H]+.
Example A54 ·* . e~’fRULE26) 27 012346
Utilising the procedure of Example AS1 with l-dimethylamino-2-propanol [Aldrich] inplace of l-(2-hydroxyethyl)-pyrrolidine.
Example A56 5 Correspondingly Example A51 with l-(2-hydroxyethyl)-piperidine [Aldrich].
Example A58
Correspondingly Example A51 with 2-(hexamethyleneamino)-ethanol [Lancaster]. 10 Example A60
Utilismg the procedures of Example A93 with 3-aminophenylboronic acid in place of 2-methoxyphenylboronic acid and Example SI with 2-dimethylaminoethanol in place of 1-(2-hydroxyethyl)pyirolidine. 15 Example A63
Utilismg the procedure of Example A60 with 4-carboxyphenylboronic acid [Aldrich] inplace of 3-aminophenylboronic acid.
Example A70 20 Correspondingly Example A63 with (3,4-methylenedioxyphenyl)boronic acid [Aldrich].
Example A72
Utilising the procedure of Example 51 withiV-(2-phenyl)-ethyl-iV-methyl-ethanolamine[J. Org. Chem. 1985,50(22), 4359] in place of l-(2-hydroxyethyl)-pyrrolidine. 25
Example A74
Correspondingly Example 51 with 2-dimethylaminocyclohexanol [J. Chem. Soc. C(1969), (2), 248-52]. 30
Example A76
Correspondingly Example 51 with 2-(1,2,4,5-tetrahydro-benzo[ûf]azepin-3-yl)-ethanol[Patent US-394682] xb 28 012346
Example A78
Correspondingly Example 51 with 2-(3,4-dihydro-lH-isoquinolin-2-yl)-ethanol [PatentWO-9719926]. 5
Example A80
Correspondingly Example 51 with 2-(4-phenyl-piperazin-l-yl)-ethanol[J. Med. Chem. 1994,37(13), 1964]. 10 Example A82
Correspondingly Example 51 with l-methyl-3-pyrrolidinol[Aldrich].
Example A84 15 Utilising the procedures of Example A93 with 4-methoxy-phenylboronic acid [Aldrich] in place of 2-methoxyphenylboronic acid and Example A51 with 2-dietbylaminoethanolin place of l-(2-hydroxyethyl)pyrrolidine.
Example A88 20 Utilising the procedures of Example A84 with 4-methoxy-3-pyridylboronic acid [PatentWO-9924440] in place of 4-methoxy-phenylboronic acid.
Example A89
Correspondingly Example A88 with 2-methoxy-3-pyridylboronic acid [Patent WO- 25 9910331).
Example A90
Correspondingly Example A88 with benzo-[h)-furan-2-boronic acid [Aldrich]. 30 Example A91
Correspondingly Example A88 with thiophene-3-boronic acid [Aldrich]. 29 • · 26 012346
Example A92
Correspondingly Example A88 with indole-5-boronic acid [Fronder].
Exemple A93 4'-Methyl-biphenyl-4-carboxylic acid [3-methoxy-4-(2-pyrrolidin-l-yl-ethoxy)-phenyl]-amide A mixture of 3-methoxy-4-(2-pyrrolidin-l-yl-ethoxy)-phenylamine [Example AS1](4.7mM 1.1g) and triethylamine (14mmol) was trealed with 4-bromobenzoyI chloride[Aldrich] in dichloromethane (20ml) and kept at room température for 16 hours.
The solvent was evaporated and the crude productpurified by cbromatography onsilica gel using dichloromethane - methanol - aq. ammonia to afford 4-bromo-2V-[3-methoxy-4(2-pynolidm-l-yl-ethoxy)-phenyl]-benzamide as a white solid in 72%yield.. iHNMR (DMSO-d6): δ 7.91 (2H, dd), 7.73 (2H, dd), 7.50 (1H, d), 7.30 (1H, dd), 6.94 (1H, d), 4.02 (2H, t), 3.76 (3H, s), 2.77 (2H, t), 2.51 (4H, m trader DMSO-d-Ssignal) and 1.67 (4H, m); MS: (ES+ve) m/z 419,421 [M+H]+
The amide, 4-bromo-77-[3-methoxy-4(2-pyrrolidin-l-yl-ethoxy)-phenyl]-benzamide(O.lmM 42mg), and 4-methyl-benzene boronic acid (Aldrich] (O.lmM 14mg) wererefluxed for 16 hours in a mixture of benzene (8ml), éthanol (2ml) and 2M aqueoussodium carbonate (2ml) in the presence of tetrakis-(triphenylphosphine)-palladium[0](5mg) trader an argon atmosphère. The mixture was cooled, the upper layer decanted,and this solution purified by chromatography on silica gel using dichloromethane:methanol (10:1) followedby acetonitrile: satd. aqueous ammonia (25:1) to afford thetitle compound as a white solid. iHNMR (CDC13): δ 7.92 (2H, dd), 7.68 (2H, dd), 7.50 (2H, dd), 7.26 (3H, dddd), 6.96 (1H, dd), 6.88 (1H, d), 4.13 (1H, t), 3.87 (3H, s), 2.92 (2H, t), 2.60 (4H, m), 2.41 (3H, s) and 1.80 (4H, m); MS: (AP-ve) m/z 429 [M-H]’; (AP+ve) m/z 431 [M+H]+.
Example A100
Utilising the procedure of Example A93 with 4-(2,6-dimethoxypyrimidinyl)-boronic acidCFrontier] in place of 4-methyl-benzene boronic acid. 30 “ 26) 012346
Example A103
Correspondingly Example A93 with furan-3-boronic acid [Fronder].
Example À104
Correspondingly Example A93 with mesityl-boronic acid [Frontier].
Example A105
Utilising the procedure of Example A51 except employing chloroform in place ofdichloromethane as a solvent and eluent and utilising 3-quinucIidinol (Aldrich] in placeof l-(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 of2’-methyl-biphenyl-4-carboxylicacid.
Example B2
Correspondingly Example B1 using 4-benzylbenzoic acid [Apin].
Example B34
Correspondingly Example B1 using 3-benzylbenzoic acid [Patent WO-9828268].
Example B35
Correspondingly Example B1 using 4-phenoxybenzoic acid [Aldrich].
Example B37 .V-[-(3-Methoxy-4-(2-pyrrolidin-l-yl-ethQxy)-phenyl]-4-phenylamino-benzamideDry césium carbonate (0.15mM, 49mg), (S)-BINAP [Aldrich] (0.015 mM, 9mg) andpalladium acetate (0.0075mM, 2mg) were sonicated in anhydrous ethyleneglycol 31 0123A6 dimethyl ether (15 ml) for 40 minutes under an argon atmosphère. This suspension wastreated with 4-bromo-7V-[3-methoxy-4-(2-pyrrolidin-1 -yl-ethoxy)-phenyl]-benzamide[Example A93] (O.lmM, 42mg) and aniline (0.1 ImM, lOmg) then refluxed for 40 hours.The suspension was filtered through a hydrophobie membrane, concentrated, thenpurified on Cl8 R.P. silica using acetonitrile:water to afîord the tide compound as a whitesolid. iHNMR (MeOH-d4): 5 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 Cl
Utilising the procedure of Example A7 with 2-methylbiphenyl-4-carboxylic acid [PatentWO-9606079] in place of 2’-methyl-biphenyl-4-carboxylic acid.
Example C2
Correspondingly Example Cl using 3-methoxybiphenyl-4-carboxylic acid [Patent WO-9534540].
Example C3
Correspondingly Example Cl using 3-methylbiphenyl-4-carboxylic acid [Patent WO-9534540].
Example C4
Correspondingly Example Cl using 4-phenylthiophene-2-carboxylic acid [Specs].
Example CS
Correspondingly Example Cl using 4-(3,5-dichlorophenoxy)-furan-2-carboxylic acid[Maybridge].
Example C6
Correspondingly Example Cl using 5-methyl-l-phenylpyrazole-4-carboxylic acid[Maybridge]. 32 0123A6
Example C7
Correspondingly Example Cl using 6-phenyl-nicotinic acid [WO-0006085].
Example C8
Correspondingly Example Cl using 3-chloro-biphenyl-4-carboxylic acid [Patent JP-09221476].
Example C9
Correspondingly Example Cl using 5-(4-chlorophenyl)-2-trifluoroniethyl-furan-3-carboxylic acid [Maybridge],
Example CIO
Correspondingly Example Cl using 2-(4-chlorophenyl)-3-(trifluoromethyl)-pyrazole-4-carboxylic acid [Maybridge].
Example Cil
Correspondingly Example Cl using 5-(2-pyridyl)-thiophene-2-carboxylic acid[Maybridge].
Example C12
Correspondingly Example Cl using 5-(methyl-trifluoromethyl-2-H-pyrazol-3-yl)-thiopbene-2-carboxylic acid [Maybridge].
Example DI
Utilising the procedure of Example D5 with 3,4-dichloronitrobenzene [Aldrich] in placeof 2,4-dichloronitrobenzene.
Example D5
Biphenyl-4-carboxylic acid [2-chloro-4-(2-diisopropyïamino-ethoxy)-phenyl]-amide.To a three-neck fîask (fîtted with condenser, dropping fùnnel and thermometer)containing iron powder (938mg, 16.8xnmol) mixed with a solution of ammonium chloride 33 012346 (28mmol) in water (28ml), was added the amine [2-(3-chloro-4-nitro>phenoxy)-ethyl]-diisopropyl-amine [prepared by the method used to form l-[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 inplace of l-(2-hydroxylethyl)-pyrrolidine], dropwise over 10 minutes. The reactionmixture was gently refluxed until tic. analysis showed no starting materiel. The mixturewas fîltered while hot and the inorganic residues washed with methanol. The combinedfiltrâtes were partitioned between water (5ml) and ethyl acetate(3 x 10ml), the organicphase dried (MgSC>4), fîltered, and evaporated. The aqueous phase was treated with satd.aq. sodium bicarbonate (10ml), extracted with ethyl acetate (3 x 10ml), dried (MgSO4),and evaporated. Residues fiom both extractions were combined and purifîed by flashchromàtography on silica gel using dichloromethane - methanol - aq. ammonia as eluentto afford 2-chloro-4-(2-diisopropylamino-ethoxy)-phenylamine as a brown oil. NMR (CDCI3): δ 1.02(12H, d), 2.77(2H, t), 3.03(2H, sept.), 3.72(2H, bs), 3.80(2H, t),6.68(2H, m) and 6.85(1H, m); MS (AP+ve): mfz 271,273 [M+H]+.
This material was used in place of 3-methoxy-4-(2-pyrrolidin-l-yl-ethoxy)-phenylaminein the procedure of Example A51 to afford the title compound as clear oil.iH NMR (CDCI3): δ 1.26 (12H, d), 3.07 (2H, m), 3.35 (2H, m), 4.22 (2H, m), 6.89 (1H,dd), 7.01 (1H, m), 7.44 (3H, q), 7.62 (2H, d), 7.71 (2H, d), 7.97 (2H, d) and 8.34 (1H, d);MS (AP+ve): m/z 452,454 [M+H]+.
Example D9
Utilising the procedure of Example A51 with 2,4-difluoronitrobenzene [Aldrich] in placeof 4-chloro-3-methoxynitrobenzene.
Example D12 [WO-00/06146]
Utilising the procedure of Example A51 with 3,4-difluoronitrobenzene [Aldrich] in placeof 4-chloro-3-methoxynitrobenzene.
Example D16 34 26) 012346
Utilising the procedure of Example A51 with 2-methyl-4-fluoronitrobenzene [Aldricb] inplace of 4-chloro-3-methoxynitrobenzene
Example D20 5 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 10 place of 4-chloro-3-methoxynitrobenzene
Example D25
Biphenyl-4-carboxylic acid [4-(2-diisopropylamino-ethoxy)-2-formyl-5-methoxy-phenyl]-amide 15 Biphenyl-4-carboxylic acid [4-(2-diisopropylamino-ethoxy)-3-methoxy-phenyl]-amide[Patent WO-99Q1127] (223 mg, 0.5 mmol) was treated with glyoxylic acid trihydrate(lml), dichloromethane (5 ml) and methanesulphonic acid (0.5 ml). The mixture wasstirred vigorously for 24 hours then treated with satd. aq. sodium bicarbonate (30ml) andextracted with dichloromethane (3 x 20ml). The combined organic phases were dried 20 (MgSO4), filtered and evaporated, then subjected to flash chromatography on silica gel[chloroform - methanol - aqueous acetic acid] to obtain the tittle compound as the acetatesait, a white solid. ’H NMR (CDCls): δ 1.13 (12H, d), 2.04 (3H, s), 3.02 (2H, t), 3.20 (2H, hept.), 4.05 (3H,s), 4.10 (2H, t), 5.0 (1H, bs), 7.22 (1H, s), 7.40 (1H, t), 7.48 (2H, d), 7.65 (2H, d), 7.76 25 (2H, d), 8.14 (2H, d), 8.72 (1H, s) and 9.34 (1H, s); MS (AP+ve): m/z 475 [M+H4].
Example D26
Biphenyl-4-carboxylic acid [4-(2-diethylamino-ethoxy)-3-(l-hydroxy-ethyl)-phenyl] -amide 30 To biphenyl-4-carboxylic acid [3-acetyl-4-(2-diethylamino-ethoxy)-phenyl]-amide[Example D24] (20mg, 0.05mmol) dissolved in a 1:1 mixture of tetrahydrofuran /éthanol (3ml), was added sodium borohydride [Aldrich] (6mg, 0.15mmol). The reactionmixture was stirred at ambient température for 16 hours. The solvent was evaporated and 35 .«•etsi? ;,. r- — .'JLÏ26', 0123-46 the residue purified by flash çhromaîography on silica gel using dichloromethane - aq.ammonia - methanol as eiuents, to afford the title compound as a white solid.lH NMR (CDCI3): δ 1.09 (6H, t), 1.49 (3H, d), 2.75 (4H, q), 2.95 (2H, t), 4.15(2¾t),. 5.01 (1H, q), 6.84 (1¾ d), 7.45-7.67 (9¾ m) and 7.95 (2¾ d) MS (AP+ve): m/z 433 [M+H4].
Example D27
Biphenyl-4-carboxylic acid [4-(2-diethylamino-ethoxy)-3-etliyl-phenyl]-amideTo biphenyl-4-carboxylic acid [3-acetyl-4-(2-diethylamino-ethoxy)-phenyl]-amide[Example D24] (25mg, O.Oômmol) dissolved in dichloromethane (1.5ml), was addedtriethylsilane (0.5ml) and trifluoroacetic acid (0.25ml). The resultmg yellow solution wasstiired ai room température for 120h. The solvents were evaporated and the residuepurified by flash çhromaîography on silica gel using dichloromethane - aq. ammonia -methanol as eiuents to afford the title compound as white solid. lHNMR (CDCI3): δ 1.17 (6H, m), 2.64 (2H, q), 2.8 (4¾ q), 3.06 (2H, t), 4.15 (2H, t),6.82 (1¾ d), 7.35-7.71 (9H, m) and 7.96 (2H, d) MS (AP+ve): m/z 417 [M+H]+
Example D28 [WO9901127]
Utilising the procedure of Example A51 with 4-fluoronitrobenzene [Aldrich] in place of4-chloro-3-methoxynitrobenzene, and 2-diisopropylaminoethanol in place of l-(2-hydroxyethyl)-pyrrolidine
Example D30 [WO9901127]
Utilising the procedure of Example D28 with 2-dimethylaminoethanol [Aldrich] in placeof 2-diisopropylaminoethanol.
Example D32 [WO9901127]
Utilising the procedure of Example D28 with 2-diethylaminoethanol [Aldrich] in placeof 2-diisopropylaminoethanol
Example D38 [WO99011271 36 912346
Utilising the procedure of Exemple A22 with 4-fluoronitrobenzene [Aldrich] in place of4-chloro-3-methoxynitrobenzene, and 4-ethylphenylboronic acid in place of 4-methoxyphenylboronic acid 5 Example D39 [WO9901127]
Utilising the procedure of Example A84 with 4-fluoronitrobenzene [Aldrich] in place of4-chloro-3-methoxynitrobenzene, and 4-ethylphenylboronic acid in place of 4-methoxyphenylboronic acid. 10 ËxampleEl
Biphenyl-4-carboxyIic acid [4-(2-diisopropylamino-ethoxy)-3-methoxy-pheuyl]-methyl-amide.
To 4-(2-diisQpropylamino-ethoxy)-3-methoxy-phenylamine (Immol) [Example A7]were added triethylorthofonnate (8ml) and trifluoroacetic acid (0.15ml). The resulting 15 solution was heaied to 90°C for 4hr. The solution was evaporated then redissolved inéthanol and cooled to approximately -10°C. Sodium borohydride (190mg, 5mmol) wasintroduced portionwise over 10 minutes then the mixture allowed to warm to roomtempérature. The solution was stiired at room température for 16h, then acidified to pH 1with 2M hydrochloric acid. The mixture was concentrated to approximately 10ml, then 20 partitioned between ethyl acetate and water. The aqueous phase was adjusted to pH 14using 2M aq sodium hydroxide solution, and extracted with dichloromethane (x3), dried(MgSO4), filtered and evaporated. The residue was purified by flash ehromatography onsilica gel using dichloromethane - aq. ammonia - methanol as eluent to afford [4-(2-diisopropylamino-ethoxy)-3-methoxy-phenyl]-methyl-amine as an oil. 25 lHNMR (CDCls): δ 1.03 (12H, d), 2.80 (3H, s), 2.85 (2H, t), 3.02 (2H, q), 3.80 (3H, s),3.86 (2H, t), 6.13 (1H, dd), 6.23 (1H, d) and 6.80 (1H, d); MS (AP+ve): m/z 281[M+H]+.
To 4-phenylbenzoic acid (0.2mmol) suspended in dichloromethane was added oxalylchloride (0.6mmol) followed by dimethylfonnamide (1 drop). The reaction mixture was 30 stirred for lh, evaporated, co-evaporated (x3) with dichloromethane then redissolved indichloromethane(lml). A solution containing the amine [4-(2-diisopropylamino-ethoxy)-3-methoxy-phenyI]-meth.yI-amine (0.2mmol) andtriethylamine (140mg, Immol)dissolved in dichloromethane (Iml) was added. This solution was stiired at ambient 37 012346 température for 14 hours, evaporated, dissolved in dichloromethane (1ml) and treatedwith PS-isocyanate resin [Argonaut Technologies] (150mg). After afurther 18h shakingat ambient température, the mixture was fîltered, passed through an SAX column[Varian] (lg), evaporated, and the residue purified by chromatography on silica gel usingdichloromethane - aq. ammonia - methanol as eluent to afford the title compound as anoil. lHNMR(CDC13): Ô 1.21 (12H,bd), 2.88-3.24 (4H,m), 3.32(3H, s), 3.87 (3H, s), 4.11(2H, m), 6.82-6.91 (3H, m) and 7.26-7.56 (9H, m); MS (AP+ve): m/z 476 (M+HJ*.
Example E5
Utilising the procedure of Example El with triethyl orthoacetate [Aldrich] in place oftriethyl orthoformate.
Example E12
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 (1ml) and treatedwith benzotriazole [Aldrich] (12 mg, 0.1 mmol) and Mchlorosuccinimide (13 mg, 0.1 Immol). The mixture was stirred at ambient température for 16 hours then evaporatedand subjêcted to flash chromatography on silica gel (dichloromethane - methanol -aqueous ammonia) to afford the title compound as an oil. ‘H NMR (CDCI3): δ 1.06 (6H, t), 2.63 (4H, q), 2.90 (2H, t), 3.39 (3H, s), 3.67 (3H, s), 4.03 (2H, t), 6.57 (1H, s), 6.84 (1H, s) and 7.31-7.53 (9H, m); MS (AP+ve): m/z 467,469[M+Hf.
Example E13
Utilising the procedures of Example A93 with [4-(2-diethylamino-ethoxy)-3-methoxy-phenyl]-methyl-amine [Example E9] in place of 4-(2-diethylamino-ethoxy)-3-methoxy-phenylamine and 2-fluoromethylphenylboronic acid [Aldrich] in place of 4-methoxyphenylboronic acid and of Example 51 with (W-diethyl)ethanoIamine in place ofl-(2-hydroxyethyl)pyrrolidine. 38 • .B) 012346
Example E14
Utilising the procedure of Example E13 with 2-methylphenylboronic [Aldrich] in placeof of 4-chlorophenylboronic acid^
Example E16
Correspondingly Example E14 with 2-chloromethylphenylboronic acid [Aldrich].
Example E17
Correspondingly Example E14 with 4-fluoromethylphenylboronic acid [Aldrich].
Example E2l
Correspondingly Example E14 with 4-chloromethylphenylboronic acid [Aldrich].
Example E22
Correspondingly Example E14 with 4-ethylpbenylboronic acid [Aldrich].
Example E23
Correspondingly Example E14 with 4-ierrbutylphenylboronic acid [Aldrich].
Example E24
4-Biphenylcarboxylicacid[4-(2-diethylamino-ethoxy)-3-methoxy-phenyl]-methyl-amide[Example E9J (45mg, 0. Immol), was dissolved in acetonitrile (1ml) and treated with N-fluoro-2V’-chloromethyl-triethylenediaxnine-bis(tetrafluoroborate) (43mg, 0.12mmol) andheated to 80°C for 6 hours. The solvent was evaporated and the residue subjected toflash chromatography on silica gel (dichloromethane - methanol - aqueous ammonia) toafford the title compound as an oiL MS (AP+ve): m/z 451 [M+H]+.
Example E25
Utilising 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. 39
Example Fl
Utilising the procedure of Example A7 with 6-phenyl-nicotînic acid (Patent WO-0006085) in place of 2'-methyl-4-biphen.ylcarboxylic acid and ΛΓ-dimethylethanolaminein place of 2-(diisopropylamino)ethanol.
Example G1
Biphenyl-4-carboxylic acid [4-((R)-diethyïamino-hydroxy-propoxy)-3-methoxy-phenyl]-amide 4-Nïtro-2-methoxyphenol [Aldrich] (845mg, 5mmol) was dissolved in DMF (25 ml) andtreated with sodium hydride (60% oü dispersion, 200mg). When the effervescenceceased, the mixture was treated with (Æ)-p-nitrophenylsulphonyl glycidol [Aldrich] andwanned to 50°C with stirring. After 16 hours, the mixture was cooled, evaporated,pardtioned between water (20ml) and dichloromethane (3 x 25ml), dried (MgSO4),filtered and evaporated. The residue was purified by flash chromatography on silica gel(hexane - ether) to give (/?)-2-(2-methoxy-4-nitro-phenoxymethyl)-oxirane as a palebrown solid in 80% yield. ’H NMR (CDCI3): δ 2.79 (1H, dd), 2.95 (1H, dd), 3.41 (1H, dddd), 3.96 (3H, s), 4.06(1H, dd), 4.43 (1H, dd), 6.98 (1H, d), 7.75 (1H, d) and 7.87 (1H, dd). (Zî)-2-(2-Methoxy-4-nitro-phenoxymethyl)-oxirane (0.5mmol, 113mg), indichloromethane (3 ml) was treated with the amine (diethylamine) [Aldrich] (1.5 mmol,110 mg) and titanium tetraisopropoxide [Aldrich] (50ul). The solution was stirred atambient température for 24 h, treated with water (1ml) and shaken vigorously for 10minutes. The resulting suspension was passed through a hydromatrix cartridge [VarianChemElut] (5ml) eluting with dichloromethane (10ml) to give (7?)-diethylamino-(2-methoxy-4-nitro-phenoxy)-propan-2-ol as a yellow oil lH NMR (CDCI3): δ 1.07 (6H, t), 2.55-2.72 (7H, m), 3.94 (3H, s), 4.09-4.13 (3H, m),6.97 (1H, d), 7.74 (1H, d) and 7.89 (1H, dd); MS (AP+ve): m/z 299 [M+H*].
This matériel was dissolved in éthanol (5ml) and treated with hydrogen chloride (2M indiethyl ether) 0.1 ml then 10% palladium on charcoal (20 mg) and hydrogenated atatmospheric pressure for 24 hours. The solution was purged with argon then filtered 40 S# · · ' • 26) 01î346 through celite and evaporated to give (7?)-(4-amino-2-methoxy-phenoxy)-diethylamino-propan-2-oI hydrochloride as a white crystalline solid. 'H NMR (CD3OD): δ 1.19 (6H, t), 3.36-3.45 (6H, m), 3.88 (s, 3H), 4.02-4.11 (2H, m), 4.03 (1H, m), 6.95-7.03 (2H, m) and 7.13 (1H, d). 5 A solution of this material in dichloromethane (2ml) was treated with triethylamine (2mmol, 280ul) and triethylsilyl trifluoromethanesulphonate (lmmol, 264mg). After 30minutes, 4-biphenylcarboxylic acid chloride [Example 1] (lmmol, 217mg) wasintroduced and the mixture stirred for 12 hours. The solvent was evaporated and the 10 residue dissolved in methanol (100ml) and treated with potassium carbonate (2g). Afterstirring for six hours, the suspension was evaporated, formed into a slurry withdichloromethane (20ml), filtered, the filtrat» evaporated, and the residue purified by flash,chromatography (dichloromethane - methanol - aq. ammonia) to give the tiûe compoundas a white solid. 15 ‘HNMR(CDCI3): δ 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
Example G5 20 Utilising the procedure for the préparation of (7?)-diethylamino-(2-methoxy-4-nitro- phenoxy>propan-2-ol [Example Gl] but replacing dichloromethane with 1,2-dichloroethane and diethylamine with diisopropylamine. In addition, the mixture ofamine and epoxide was heated at 80°C for 12h rather than being kept at ambienttempérature for 24 hours. 25
Example G8
Utilising the procedure of Example Gl but using (iS)-p-nitrophenyîsulphonyl-glycidol inplace of (E)-p-nitrophenylsulphonyl-glycidol, and pyrrolidine in place of diethylamine. 30 Example G22
Utilising the procedure of Example A51 but using 4-dimethylamino-l-butanol [ICN-RF3in place of l-(2-hydroxyethyl)-pyrrolidine. 41 26)
Example H1 4-Cyclohexyl-lV-[3-methoxy-4-(4-methyl-piperazin-l-yl)-phenyl]-benzamideA solution of l-(2-methoxy-4-nitro-phenyl)-piperazine (Patent WO-9906382) (lOmmol,2.37g) in dichloromethane (50ml) was treated with diiertbutyl dicarbonate (lOmmol, 2.18g) with stirring. Vigorous évolution of gas occurred wbich ceased after 1 hour. Thesolution was then evaporated to a yellow solid 4-(2-methoxy-4-nitro-phenyl)-piperazine-1-carboxylic acid tertbutyl ester. lHNMR (CDC13): δ 1.50 (9H, s), 3.16 (4H, t), 3.61 (4H, t), 3.96 (3H, s), 6.88 (1H, d), 7.72 (1H, d) and 7.86 (1H, dd).
This material was dissolved in éthanol (50ml) and treated with 10% Pd on carbon(lOOmg). The suspension was hydrogenated at 1 atmosphère for 2 hours, then filteredthrough celite and evaporated to give 4-(4-amino-2-methoxy-phenyl)-piperazine-l-carboxylic acid ieributyl ester as a brown oil. ‘H NMR (CDCI3): 5 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 (IH, d).
This aniline (0.2mmol, 61 mg) was dissolved in dichlorometbane (1ml) and treatedsuccessively with DIEA resin [Argonaut Technologies] (0.5 g) and 4-cyclohexylbenzoylcbloride [Example A36]. The mixture was shaken gently for 12 hours then filtered,evaporated and the residue purified by flash cbromatography on silica gel(dichloromethane - methanol - aq. ammonia) to afioTd 4-(4-( [l-(4-cyclohexyl-phenyl)-methanoyl]-amino}-2-methoxy-phenyl)-piperazine-l-carboxylic acid tertbutyl ester as awbite crystalline solid ‘HNMR(CDC13): δ 1.25-1.47 (5H, m), 1.54 (9H, s), 1.75-1.88 (5H, m), 2.56 (1H, m), 2.98 (4H, t), 3.61 (4H, t), 3.91 (3H, s), 6.87 (1H, d), 6.93 (1H, dd), 7.32 (2H, d), 7.54(1H, s), 7.77, (1H, s) and 7.78 (2H, d); MS (AP+ve): m/z 493 [M+H*].
This material was dissolved in dichloromethane (5ml) and treated with anisole (1ml) andtrifluoroacetic acid (5ml). After 2 hours the solution was evaporated, then co-evaporatedtwice from toluene. The residue was dissolved in dichloromethane (10ml), washed withsatd. sodium bicarbonate (2ml), the organic phase dried (MgSCfy), filtered and evaporatedto a brown oil, 4-cyclohexyl-lV-(3-methoxy-4-piperazin-l-yl-phenyl)-benzamide. 42 151 012346 JH NMR (CDCb): δ 1.22-1.87 (10, m), 2.57 (1, m), 3.04-3.12 (8H, m), 3.91 (3H, s), 6.95(2H, bs), 7.32 (2H, d), 7.54 (1H, m), 7.77 (1H, s) and 7.78 (2H, d); MS (AP+ve): m/z 394[M+H4]. 5 Thïs amine (0.Immol, 39mg) was dissolved in éthanol (3ml) and treated withmétaformaldéhyde (lOOmg), Amberlyst cyanoborohydrideresin [Novabiochem] (lOOmg), and acetic acid (50ul). The mixture was stirred at ambient température for threehours then fîltered, evaporated and the residue purified by flash chromatography on silicagel (dichloromethane - methanol - aq. ammonia) to afford the title compound as a pale 10 brown oil. This was evaporated from dilute acetic acid to give the monoacetate saithydrate. ‘H NMR (CDCI3): δ 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); 15 MS (AP+ve): m/z 408 [M+H4].
The following tables give Examples which illustrât» but do not limit the invention in anyway. >· *»-E 2S) 43
0123 A
Table A
Encompassing compounds of général formula (Π), a subset of formula (I) where A = Hand OMe, R3 = H, X = O, Y = CH2CH2 , Z = a bond; R4 = Ph and R5 is either meta or 5 para substituted on R4. ,R1 ma
LJ R5 (Π)
Example No. R5 r meta/ para [M+H]+ Procedure Al Ph V P 447 A7 A2 Λ>- V P 453 A7 A3 Ô- V P 437 A7 A4 Ph V m 447 A7 A5 0'"' P 448 A7 A6 'cm ...odç P 489 A7 A7 d- y P 461 A7 A8 0" V P 453 A7 ?.6l 44 ou346 A9 Q-- y χΟ,/ϊγ P 453 A7 A1O V P 451 A7 Ail M' P 529 A7 A12 ••-O. -.y P 461 A7 A13 Cl .y m 472 A7 A14 "•qV y P 525 A7 A15 --0 m 453 A7 A16 O- m 453 A7 A17 w-~ L O \ P 489 A7 A18 Lx y P 486 A7 A19 y ►ίγ' P 529 A7 A2O 0~- y P 453 A7 A21 O-- y P 449 A7 Z6) 45 012346 A22 Q°z y χΟ^'-Νγ' P 477 A22 A23 y>~ k O I • P 515 A22 A24 U y P 462 Â22 A25 V ...ο^ζ-ίί^ P 553 A22 A26 y ...Ο^Ζ-Ηγ- P 497 A22 A27 Q>- P 497 ' À22 A28 P 461 A22 A29 ^O~' y ...Ο^-Ν^χ P 493 A22 A30 kï y P 515 A22 46 .26) 0 A 23 4 ô A31 °o- ν ^.0^- IL/ P 475 A22 A3 2 V Ny P 491 A22 A33 rO"" V P 473 A22 A34 V P 477 A22 A35 Ph ..Οχ/-Ό° P 433 A51 A36 ο-- ,05 P 439 A51 A37 Ph Z ..-O,^-Nx P 397 A51 A38 Ο Z P 391 A51 A39 ο-- P 423 A51 A40 Ph 1 "·ο^"··Λ P 417 A51 A41 Ph « t / P 417 A51 A42 ο-- P 423 A51 47 26) 012346 A43 Ph I P 405 A51 A44 O--- 1 ·Ό^γΝχ· P 411 A51 A45 Ph < P 419 A51 A46 ο-· r P 425 A51 A47 Ph -oj? P 417 A51 A48 0- -oJV P 423 A51 A49 Ph !—Ph ...Ο^Ζ-Νχ P 467 A51 A50 o-~ /-Ph P 473 AS1 A51 Ph P 417 A51 A52 O-- ..-0-χ/~θ P 423 A51 A53 / P 421 A22 A54 Ph --θγ^τι^ P 405 A51 A55 o- P 411 A51 48 0123A6 A56 Ph ^-0 Ρ 431 Α51 A57 ο- Ρ 437 Α51 A58 Ph Ρ 445 Α51 A59 ο-- Ρ 451 Α51 A60 Ό χΟ^Ζ-^ Ρ 406 Α60 A61 0' / xo^z~\ Ρ 497 Α63 A62 CFTi' Ρ 459 Α63 A63 Û / ...Ο-Ζ—\ Ρ 419 Α63 A64 ^O" ..-Οχ/~Ν\ Ρ 417 Α63 A65 / χΟ^Ζ-Μχ Ρ 421 Α63 A66 cô / χ<Κ/~Νχ Ρ 441 Α63 A67 / ...Ο^~Νχ Ρ 441 Α63 A68 X)' / χΟ^Ζ-Μχ Ρ 404 Α63 A69 -,Ό" / Ρ 437 Α63 A70 CO" / ,--ΟχΖ~~Νχ Ρ 434 Α63 49 26) A71 ,c-Û" / x°X~Nx P 459 A63 A72 Ph xco P 481 A51 A73 σ tco P 487 A51 A74 Ph -Q )X> P 445 A51 A75 O' >£> P 451 A51 A76 Ph P 493 A51 A77 O'-' ·' P 499 A51 A78 Ph roo P 479 A51 A79 O" coo P 485 A51 A80 Ph °\ V/*m P 508 A51 A81 O-" fY> °\ ^>xN"Ph P 514 A51 A82 Ph ·°*Ό P 403 A51 A83 O'·' P 409 A51 A84 -X)'· λ~- P 449 A84 A85 =u0'" P 445 A88 A86 ΧΓ Λ- A/~\/ P 487 A88 A87 O-· Λ~ rr-χ P 425 A88 Z6) 50 0123*6 Α88 -, O / Λ" χΟχ/^V Ρ 450 Α88 Α89 00 Ρ 450 Α88 Α90 CQ- Ρ 459 Α88 Α91 Λ~ Ρ 425 Α88 Α92 ÇO' Λ- χΟ^-Ν^ Ρ 458 Α88 Α93 χΟχ/~Ό Ρ 447 Α93 Α94 χΟχΖ~Ό Ρ 443 Α93 Α95 Ρ 485 Α93 Α96 O~ ...ο^Ο Ρ 423 Α93 Α97 χΟ^ζ-Ό Ρ 431 Α93 Α98 O0' χθχ/~θ Ρ 448 Α93 Α99 oc χ0^/~Ο Ρ 431 Α93 Al 00 -.¾ Ρ 479 Α93 Α101 0> Ρ 457 Α93 Al 02 sO”" χθ^ζ-ΝΟ Ρ 423 Α93 A103 ...ο^ζ~(θ Ρ 407 Α93 Al 04 jÔC xOx/~lQ Ρ 459 Α93 Al 05 Ph --0-0 Ρ 429 Α105 51 -26) ou346 À106 Λ' P 426 A107 Al 07 ; x<K/~O P 424 A107 A108 Q \ k ,-ΟχΖ~Νγ/ P 454 A107 £b/ 52
Table B
5 R5 is Ph and Z is either meta or para substituted on R4 R1 /
jCC^2 (IH)
Example No. Z meta/ para [M+H]+ Procedure B1 0 m y χΟ-^-Νγ- 463 B1 B2 ’ch2 P y 461 B1 B3 0 m r> ..-<\Z~NX> 229 A51 B4 ch2 P y? ...ΟχΖ~Ν^Ζ 4447 1 1 "Ί1 f A51 B5 0 m / ..-O-Z'—'K 407 A51 B6 ch2 P / .-ΟχΖ^"ΝΧ 405 A51 B7 0 m 433 A51 B8 ch2 P 431 A51 26i 53 012346 B9 Ο m 433 A51 ΒΙΟ ch2 P 431 A51 Bll 0 m .-<0-Νχ 421 A51 Β12 ch2 P ..-°xZA 419 A51 Β13 0 m 435 A51 Β14 ch2 P 433 A51 Β15 0 m o ...ΟχΖ-Νχ 433 A51 Β16 ch2 P o .-°xX N\ 431 A51 Β17 O m 1— Ph ..-O^Z-N^ 483 A51 Β18 ch2 P rPh 481 A51 Β19 0 m ,.-°x/~nO 433 A51 Β20 ch2 P .-Οχ^~Ό 431 A51 Β21 ch2 P "°V< 419 A51 Β22 0 m ^•o 447 A51 54 46) Q123^6 B23 ch2 P 445 A51 B24 0 m Z 497 A51 B25 ch2 P 495 A51 B26 0 m Γ-ΌΟ 509 A51 B27 ch2 P 507 A51 B28 O m —co 495 A51 B29 ch2 P '"“-•CO 493 A51 B30 0 m 524 A51 B31 ch2 P "°^ΎΧη 522 A51 B32 0 m -°<r 419 A51 B33 ch2 P -°O" 417 A51 B34 ch2 m Z^X 461 B1 B35 0 P z^x 463 B1 B36 NH P χ®\/'Τ4ζ^ z^x 462 B37 B37 NH P z°xZ~NO 432 B37 55 ?6 > 012346
Table C
EncompMsing compounds of general formula (TV) a subset of formula (1) where A = Han e, RI - R2 - Me2, R3 = H, X = O, Y = CH2-CH2 ; R4, R5 = substituted phenyl 5 or heterocycle, (IV)
Example No. Z 3/4 substitutionw.r.t C=O J R5 [M+H]+ Method Cl bond 4 Ph 461 Cl C2 bond 4 Ph 477 ' Cl C3 bond 4 Ph 461 Cl C4 bond 3 .«y Ph 453 Cl C5 0 3 Ύ 521,523, 525 Cl C6 bond 3 PC’ Ph 451 Cl C7 bond 4 JT* Ph 448 Cl β) 56 01234b C8 bond 4 Ph 481,483 Cl C9 bond 3 .<0' 539, 541 Cl CIO bond 3 K .,-Ο" 539 Cl Cil bond 3 O' 453 Cl C12 bond 3 525 Cl 57 26) 0123A6
Table D
Encompassing compounds of general formula (V) a subset of formula (I) where R3 = H,X = O, Y = CH2-CH2, Z = O, CH2, NH or a bond; R4 - Ph, R5 is Ph or cyclohexyl (Cy) 5 and Z is either meta or para substituted on R4.
(V) 10
Example No. Z R6 R7 R5 meta ! para r [M+H] + Method DI bond Cl H Ph P y .-OsZ-Νγ- 452, 454 DI D2 O Cl H Ph m y 468, 470 DI D3 ch2 Cl H Ph P y 466, 468 DI D4 . bond Cl H Cy P y ...Ox/-Ny- 458, 460 DI D5 bond H Cl Ph P y 452, 454 D5 D6 0 H Cl Ph m y 468, 470 D5 58 012346 D7 ch2 H Cl Ph P y 466, 468 DS D8 bond H Cl Cy P V 458, 460 D5 D9 bond F H Ph P V 435 D9 D1O ch2 F H Ph P y .-ο·^~Νγ- 449 D9 Dll bond F H Ph P y 441 D9 D12 bond H F Ph P y 435 D12 D13 0 H F Ph m y 451 D12 D14 ch2 H F Ph P y 449 D12 D15 bond H F Cy P y zOy-Hy 441 D12 D16 bond Me H Ph P y 431 D16 D17 0 Me H Ph m y .--ΟχΖ'Νγ' 447 D16
Zb, 59 012346 D18 ch2 Me H Ph P 445 D16 D19 bond Me H Cy P y χθ^/-Νγ- 437 D16 D20 bond H Me Ph P V ,-0χΖ~Νγ' 431 D20 D21 O H Me Ph m V 447 D20 D22 ch2 H Me Ph P y 445 D20 D23 bond H Me Cy P y 437 D20 D24 bond COCH3 H Ph P I" 431 D24 D25 bond OMe CHO Ph P y 475 D25 D26 bond CH(OH)CH3 H Ph P r 433 D26 D27 bond Et H Ph P r ...O^y^-Ns/ 417 D27 D28 bond H H Ph P y 417 D28 D29 0 . .. H H Ph m ...O^Z-nÇ/ 433 D28 60 Z6) 012346 D30 bond H H Ph P 361 D30 D31 0 H H Ph P y- 433 D28 D32 0 H H Ph P r 405 D32 D33 0 H H Ph m ,.0s/~O 405 D32 D34 bond H H Cy P y 423 D28 D35 bond H H Cy P r 395 D32 D36 0¾ H H Ph P y 431 D28 D37 ch2 H H Ph P r xo>>/ y 403 D32 D38 bond H H P- EtPh P y ^Ο^-Μγ- 445 D38 D39 bond H H P- EtPh P r 417 D39 61 Z6)
EnGompassmg compounds of general formula (VI) a subset of formula (1) where A - H,
Cl, F and OMe, X - O, Y » CH2-CH2 ; R4 - phenyl, R5 - phenyl or cyclohexyî (Cy), Z 5 = O, CH2 or a bond 0123A6
Table E
Example No. Z o/p R3 R8 R9 R5 F [M+H] + Method El bond P Me H MeO Ph V 461 El E2 0 m Me H MeO Ph V .--Οχ/'-Νγ' 477 El E4 ch2 P Me H MeO Ph V 475 El E5 bond P Me H MeO Cy ...o^Z-nÇ. 467 El E6 bond P Et H MeO Ph r 447 El E7 bond P Et H MeO Ph /Os^-lO 445 El E8 bond P Me H MeO Ph /Οχ/~Ό 431 El E9 bond P Me H MeO Ph ,-°χΖ~ΝΟ 433 El E10 bond P Et H MeO Cy o^z-tC 453 El Eli bond P Et H MeO Cy 451 El E12 bond P Me Cl MeO Ph o^z-nC 468, 470 E12 26) 62 012346 E13 bond P Me H MeO 2-F-Ph o^-nC 451 £13 E14 bond P Me H MeO 2-Me- Ph 447 £14 E15 bond P Me H MeO 2- MeO- Ph 463 E14 E16 bond P Me H MeO 2-Cl-Ph o^-nC 468, 470 £14 E17 bond P Me H MeO 4-F-Ph 451 E14 El 8 bond P Me H MeO 4-F3C- Ph 501 £14 E19 bond P Me H MeO 4-Me- Ph 447 £14 E20 bond P Me H MeO 4- MeO- Ph 463 £14 E21 bond P Me H MeO 4-Cl-Ph. 468, 470 £14 E22 bond P Me H MeO 4-Et-Ph r 461 £14 E23 bond P Me H MeO 4tBu- Ph 489 £14 E24 bond P Me F MeO Ph 451 £24 E25 bond P Et H Me Ph V" 459 £25 E26 bond P Et H Me Cy 465 E25 E27 ch2 P Et H Me Ph "r" 473 E25 63 Z6, 01234ο
Table F
Encompassing compounds of general formula (VU) a subset of formula (1) where A = Hand OMe, X = O, R4 = 3-pyridyl, R5 » phenyl, Z = a para bond
Exemple No. F1 (M+H]+ Method Fl Rl = R2 = Me 392 Fl F2 .-Οχ/ΰχ 418 Fl F3 418 Fl F4 y 448 Fl τ 26) 64 012340
Table G
Encompassing compounds of general formula (VH) a subset of formula (!) where A = Hand OMe, R3 = H, X = O; R4 = phenyl, Z = O, CH2 or a bond and R5 = Ph or 5 cyclohexyl (Cy), Y is a chain of 3 or 4 carbon atoms optionally substituted by anhydroxyl group.
10
Example No. Z mZ P R5 XYN P ""'Ία [M+H]+ Method G1 bond P Ph o^Y^ ÔH "N ,c 449 G1 G2 bond P Ph OH “N -O 461 G1 G3 bond P Ph ÔH 'N xx 476 G1 G4 bond P Ph ÔH 'N JO .476 G1 G5 bond P Ph ÔH "N ,Q 465 G5 G6 bond P Ph ÔH "N -O 475 G1 G7 bond P Ph ÔH 475 G1 G8 bond P Cy ο'Ύ' OH "N ..-C 453 G8 G9 bond P Ph ο'^γ^ OH ''N ,O 447 G8 65 012346 G10 bond P Cy OH ,.-nO 455 GS Gll bond P Ph θ'Χχγχχ'Ν OH 449 G8 G12 bond P Cy Ο^γ^Ν OH .x< 483 G5,G8 G13 bond P Ph OH X 477 G5,G8 G14 bond P Cy Ο'^γ^Ν OH XX 482 G8 G15 bond P Ph “'Ύ'" OH XX 476 G8 G16 bond P Cy ο^Ύ^ν OH X) 481 G8 G17 bond P Cy Ογ^Ν OH X) 481 G8 G18 bond P Ph Ο^^γ^Ν OH X) 475 G8 G19 bond P Ph Ο^γ^Ν OH X) 475 G8 G20 bond P Ph 0γ^Ν OH .X 444 G8,G5 G21 bond P Ph Ο^γ^Ν OH JJ 461 G8 G22 bond P Ph NMe2 419 G22 G23 0 m Ph NMe2 435 G22 G24 ch2 P Ph NMe2 433 G22 G25 bond P Cy NMe2 425 G22 cô) 66 0 A 23
Table H
Encompassing compounds of general formula (IX) a subset of formula (I) where A = Hand OMe, R3 = H, X = N; R4 = phenyl, Z = a para substituted bond and R5 = Ph orcyclohexyl (Cy), Y and R2 form a piperazinyl ring between X and N.
Example No. R5 RI [M+HJ+ Method H1 ...... Cy Me 408 H1 H2 Cy Et 436 H1 H3 ......-Cy.. . iPr 422 H1
The activity of the compounds used in this invention may be assessed by compétitivebinding assays to 1 lCBy receptors, as fbllows:
Radioligand Binding Studies
Radioligand binding assays were carried out on well washed membranes from HEK293cells stably expressing llCBy receptors. Membranes (5-15 mg protein) were incübaiedwith [125I]-Melanin Concentrating Hormone (0.22 nM)(obtained from NEN) in theprésence and absence of competing test compounds for 45 min at 37°C in a buffer(pH7.4), containing 50mM Tris and 02% BSA. Non-specific binding was defined using0.1 mM Melanin Concentrating Hormone (obtained from Bachem). The test compoundswere added at concentrations between 10M and ΙΟρΜ in 10 concentration steps.Following incubation, the reaction was stopped by filtration through GF/B filters and 67 - 26) βΛ 23 A 6 washed with 4 x 1ml of ice-cold 50mM Tris buffer. Microscint 20 (Packard) was added tothe filters and the radioactivity measured using a Packard TopCount.
Bound cpm in the presence of test compound was expressed as a fraction of the bound5 cpm in the absence of test compound and plotted against the concentration of compound.
From this an IC50 was deteimined from which the pKi was calculated.
The most potent compounds of the présent invention hâve pKi values in the range of 7.1to7.8 For example: 10 Example pKi range A48 7.5-7.8 B2 7.1-7.4 C8 7.1-7.4 D15 7.5-7.8 15 E9 7.5-7.8 F4 7.1-7.4 G1 7.1-7.4 H1 7.1-7.4 *>) 68

Claims (11)

  1. 012346 CLAIMS
    1. Use of a compound of formula (I), or a pharmaceutically acceptable sait orsolvaté thereof, in which
    each A is independently hydrogen, a alkyl optionally substituted by hydroxyl, Ci^ alkoxy, Cj.g alkenyl or Ci.g acyl group or a halogen atom or hydroxyl, CN or CF3 group;R3 is hydrogen, methyi or ethyl; R4 is an optionally substituted aromatic carbocyclic or heterocyclic ring; Z is an O or S atom, or an NH or 0¾ group, or a single bond, at the 3 or 4 position of R4relative to the carbonyl group; R5 is an optionally substituted aromatic carbocyclic or heterocyclic ring, or an optionallysubstituted, saturated or unsaturated, carbocyclic or heterocyclic ring; R1 / andQis -X-Y-N\ R2 (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, RI and R2 are independently a linear or branched Όμβ alkyl, phenyl Ci-g 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,RI and R2 are linked to form a 5,6 or 7-membered ring optionally containing one ormore further heteroatom selected from O, S or N, where N or C ring atoms are optionally 69 0123^6 substituted by Ra, -CO-Ra, -CO-NH-Ra, or CO-O-Ra, where Ra is a linear or branchedCî_6 alkyl or aryl group; and the 5, 6 or 7-membered ring is optionally fosed to anoptionally substituted benzene ring, or a ring atom of the 5, 6 or 7-membered ring isoptionally 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 aîkylene group, RI is a C2.4 alkylene group linked to Y to form a 5 or 6membered ring and R2 is a linear or branched Cj-g alkyl group; or (d) where X is a N atom, Y is a C2-4 alkylene group, RI is a C24 alkylene group linked to X to form a 5 or 6membered ring and R2 is a linear or branched C]_6 alkyl group, in the manufacture of a médicament for treating the Disorders.
  2. 2. A compound of formula (I) as defined in claim 1, or a sait or solvaté thereof, inwhich R3 is methyl or ethyl.
  3. 3. A compound according to claim 2, which is any one of the compounds set oui inTable E herein.
  4. 4. A compound of formula (I) as defined in claim 1 or a sait or solvaté thereofiexcluding the compounds: N-[4-[2-[bis(l-methylethyl)amino]ethoxy]-2-fluorophenyl]-[l,r-biphenyl]-4- carboxamide, N-[4-[2-[bis(l-methylethyl)ammo]ethoxy]phenyl]-[l,l-biphenyl]-4-carboxamide, biphenyl-4-carboxylic acid [4-(2-diisopropylamino-ethoxy)-phenyl]-amide, N-[4-(2-diisopropylamino-ethoxy)-phenyl3-4-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-cyelohexyl-N-[4-(2-düsopropylamino-ethoxy)-phenyl3-benzamide, 4-cyclohexyl-N -[4-(2-diefoyianrino-ethoxy)-phenyl]-benzamide,4-benzyl-JV-[4-(2-diisopfopylamino-ethoxy)-phenyl3-benzamide, 4-benzyl-N -[4-(2-diethylamino-ethoxy)-phenyl]-benzamide,4'-ethyl-biphenyl-4-carboxylic acid [4-(2-diisopropylamino-ethoxy)-phenyl]-amide, 70 ο 1234b and 4'-ethyl-bipnenyl-4-carboxylic acid [4-(2-diethylamino-ethoxy)-phenyl]-amide.
  5. 5. A process for the préparation of a compound of formula (I), or a sait or solvaté thereof, as defined in claim 2, which process comprises the reaction of a compound of 5 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 group10 with a compound of formula (XI)
    15 wherein Q and A are as defined in formula (I) in claim 1 and R3 is methyl or ethyl.
  6. 6. A process for the préparation of a compound of formula (I), or a sait or solvaté thereof, as defined in claim 1, which process comprises the reaction of a compound offormula (X) wherein R5, Z, and R4 are as defined for formula (I) in claim 1 with a 20 compound of formula (XI) wherein Q, A, and R3 are as defined in claim 1, with theproviso thaï a process for the préparation of: 2V-[4-[2-[bis(l-mefoylethyl)amino]e&amp;oxy3-2-fiuorophenyl]-[l»l-biphenyl]-4- carboxamide, Ar-[4-[2-[bis(l-methylethyl)amino]ethoxy]phenyl]-[l,l-biphenyl]-4-carboxamide, 25 biphenyl-4-cafboxylic acid [4-(2-diisopropylamino-ethoxy)-phenyl]-amide, A’-[4-(2-diisopropylamino-ethoxy)-phenyl]-4-phenoxy-benzamide, 77-[4-(2-diethylamino-ethoxy)-phenyl]-4-phenoxy-benzamide, Ar-[4-(2-diisopropylamino-ethoxy)-phenyl]-3-phenoxy-benzamide, W-[4-(2-diethylamino-ethoxy)-phenyl]-3-phenoxy-benzamide, 4-cyclohexyl-7/-[4-(2-diisopropylamino-ethoxy)-phenyl]-benzamide, 71 " 26) 01234b 4-cyclohexyl-N-[4-(2-diethylamino-ethoxy)-phenyl]-benzamide, 4-benzyl-JV-[4-(2-diisopropylaimno-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-càrboxylic acid [4-(2-diethylamino-ethoxy)-phenyl]-amideis excluded.
  7. 7. A pharmaceutical composition for use in the treatment and/or prophylaxie of one or more of the Disorders winch comprises a compound of this invention, or apharmaceutically acceptable sait or solvaté thereof, and à pharmaceutically acceptablecarrier.
  8. 8. Use of a compound of this invention, or a pharmaceutically acceptable sait orsolvaté thereof, in the manufacture of a médicament for the treatment and/or prophylaxisof one or more of the Disorders.
  9. 9. Use of a compound of this invention, or a pharmaceutically acceptable sait orsolvaté thereof, for the manufacture of a médicament for the treatment and/or prophylaxisof one or more of the Disorders.
  10. 10. Use of a novel compound of this invention, or a pharmaceutically acceptable saitor solvaté, thereof as atherapeutic agent, in particular for the treatment and/orprophylaxis of one or more of the Disorders.
  11. 11. Use of an antagonist to the human llCby receptor in the manufacture of amédicament for the treatment of diabètes, major dépréssion, manie dépréssion, anxiety,schizophrenia and sleep disorders in human or non-human mammals. i 72
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