SK1142003A3 - Carboxamide compounds and their use as antagonists of a human 11CBY receptor - Google Patents

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

Use of carboxamide compounds, carboxamide compounds, process for their preparation, pharmaceutical composition containing them and their use

Technical field

The invention relates to a novel use of carboxamide compounds for the manufacture of a medicament having antagonist activity at the human 11CBy receptor; it further relates to a new class of carboxamide compounds that are human 11CBγ receptor antagonists; processes for the preparation of these compounds and their use.

BACKGROUND OF THE INVENTION

International patent application no. WO 01/21577 (Takeda Chemical Industries Ltd.) discloses certain bis-aryl compounds as melanin-concentrating hormone antagonists.

WO 98/00401 (Merck & Co. Inc.) discloses benzamide derivatives as precursors to fibrinogen receptor antagonists.

European Patent EP 0 358 118 (Boehringer Mannheim GmbH) discloses certain bis-aryl compounds as inhibitors of erythrocyte aggregation and which are useful for the treatment of heart and circulatory diseases.

European Patent Application EP 0 968 999 (Mitsui Chemical Inc.) discloses certain anilide derivatives useful for the treatment of arrhythmias.

WO 99/01127 (SmithKline Beecham) discloses certain N - [(aminoalkoxy) phenyl] benzamides which are effective as CCR5 receptor ligands, including 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 CCR5 receptor antagonists which include the following compounds: biphenyl-4-carboxylic acid [4- (2-dimethylamino-ethoxy) -phenyl] -amide, [ N - [4- (2-diisopropylamino-ethoxy) -phenyl] -4-phenoxy-benzamide, N- [4- (2-diisopropylamino-ethoxy) -phenyl] -amide; (2-diethylamino-ethoxy) -phenyl] -4-phenoxy-benzamide,

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

4-cyclohexyl-A / - [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-] - 4'-Ethyl-biphenyl-4-carboxylic acid [4- (2-diethylamino-ethoxy) -phenyl] -benzamide, [4- (2-diisopropylamino-ethoxy) -phenyl] -amide and [4- (2- diethylamino-ethoxy) -phenyl] 4'-ethyl-biphenyl-4-carboxylic acid amide.

SUMMARY OF THE INVENTION

The present invention is based on the discovery that compounds of the carboxamide class, overlapping with the above benzamides and anilides, are surprisingly antagonists of the human 11 CBy receptor described in Nature 400, 261-265, 1999.

Accordingly, these compounds are believed to play a role in the prevention, amelioration or correction of dysfunctions or diseases, including but not limited to: infections, such as bacterial, fungal, protozoan and viral infections, particularly those caused by HIV -1 or HIV-2; pain; cancer; diabetes; obesity; eating and drinking abnormalities such as anorexia and bulimia; asthma; Parkinson's disease; acute and congestive heart failure; low blood pressure; high blood pressure; urinary retention; osteoporosis; angina pectoris; myocardial infarction; ulcers; allergies; benign prostate enlargement; psychotic and neurological disorders, including anxiety, schizophrenia, manic-depressive psychosis; delirium; dementia or severe mental retardation; and dyskinesias such as Huntington's disease or Gilles de la Tourette syndrome, which will be referred to hereinafter as disorders.

The present invention provides the use of the carboxamide compounds of formula I, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of these disorders in a mammal suffering from one or more disorders.

R 5

Q

ABOUT)

A

- where each A is independently hydrogen, C 1-6 alkyl; _{A 6-} alkyl, optionally substituted by a hydroxyl, a C 1-6 alkoxy, a C 1-6 -alkenyl or a C 1-6 -acyl group or a halogen atom or a hydroxyl, CN or CF 3 group;

R 3 is hydrogen, methyl or ethyl.

Preferably R3 is methyl.

R 4 is an optionally substituted aromatic carbocyclic or heterocyclic ring.

Z is O or S, or NH or CH ₂ , or a single bond at the 3 or 4 position on R 4 with respect to the carbonyl group.

Z is preferably a bond.

More preferably, Z is a bond at the 4-position on R 4 relative to the carbonyl group.

R 5 is an optionally substituted aromatic carbocyclic or heterocyclic ring, or an optionally substituted, saturated or unsaturated, aromatic carbocyclic or heterocyclic ring.

R 5 is preferably a phenyl ring

R1 /

and Q is -X-Y-N \

R 2

a) when X is O or S, preferably O;

Y is a straight or branched C 2-4 alkylene group, preferably a C ₃ alkylene group optionally substituted by a hydroxyl group, or is C ₅ . ₆ cycloalkylene group,

R 1 and R 2 are independently straight or branched C 1-6 -alkyl, preferably ethyl; phenylC 1-6 -alkyl; or

b) when X is O or S;

Y is a linear or branched C ₂ -4-alkylene group, optionally substituted with hydroxy,

R 1 and R 2 are attached to each other to form a 5-, 6- or 7-membered ring, preferably a 5-membered ring, optionally containing one or more additional heteroatoms selected from O, S or N, wherein the N or C atoms in the ring are optionally substituted Ra, -CO-Ra,

-4-CO-NH-Ra or CO-O-Ra, wherein Ra is a straight 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 the 5-, 6- or 7-membered ring atom is optionally bonded by a single bond or a methylene group to Y; or

c) when X is O or S,

Y is a C 2-4 alkylene group, R 1 is a C 2-4 alkylene group bonded to Y to form a 5- or 6-membered ring, and R 2 is straight or branched (C 1-4 alkyl; or

d) when X is N,

Y is a C ₂ -4-alkylene group, R 1 is a C 2-4 alkylene group linked to X to form a 5- or 6-membered ring, and R 2 is a linear or branched C ^ e alkyl.

Alkyl groups, including alkyl groups that are part of alkoxy, acyl, etc. groups, typically containing 1 to 6 carbon atoms, and may be unbranched or branched, such as methyl, ethyl, t -propyl and tert-butyl, and optionally substituted with hydroxyl. Aryl groups are typically phenyl, but may include bicyclic groups such as naphthyl. Cycloalkyl groups typically contain from 3 to 7 carbon atoms. The heterocyclic groups may be monocyclic, 5- to 7-membered rings containing up to three heteroatoms such as pyridyl or imidazole, or bicyclic, especially heterocyclic rings, fused to benzene rings such as benzoxazole or benzimidazole. The aryl, cycloalkyl and heterocyclic groups may be optionally substituted with up to three substituents, which may be suitably selected from aryl, alkyl, alkoxy, halogen, hydroxy and cyano, or attached substituents such as dioxymethylene.

Suitable aromatic rings for use as R 4 include phenyl, pyridyl, thienyl, furanyl and pyrazolyl. Suitable optional substituents for R 4 include halogen, CF ₃ , C 1-4 alkyl, C 1-6 alkyl. ₄ -alkoxy. R4 may have 2 or 3 substituents, but preferably has only 1 substituent in addition to Z, or is preferably unsubstituted in addition to Z. Particularly suitable substituents for R 4 include chloro, fluoro, trifluoromethyl, methyl, methoxy.

R 5 may be monocyclic, for example, thienyl, furanyl, imidazolyl, oxadiazolyl, phenyl, pyridinyl, cyclohexyl, piperidinyl, piperazinyl, pyrazinyl, pyrimidinyl; or

A 5-fused bicyclic ring system such as naphthyl, 3,4-dioxymethylenephenyl, benzofuranyl, indolyl; or a bicyclic system in which the monocyclic ring has a cyclic substituent such as oxadiazolyl, benzyloxy. Suitable optional substituents for R 5 include halogen, CF ₃ , CF ₃ O, CHF ₂ O, CN, amino, mono- or di-C 1. _6- alkylamino, C ₁ . C _1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -acyl, C 1-6 -alkyl; _6- alkyl-S-, C 1-6 alkyl; _6- alkyl-SO ₂ -, C 1-6 alkyl; _6- alkenyl, phenyl-C 1-6 -alkyl, phenyl-C 1-6 -alkoxy. R 5 may have 2 or 3 substituents, but preferably has only 1 substituent, especially in the para- position with respect to Z. Particularly suitable substituents for R 5 include chloro, fluoro, trifluoromethyl, cyano, amino, methyl, ethyl, tert-butyl, methoxy, acetyl, formyl, methylthio, methanesulfonyl, vinyl, benzyl, benzyloxy, hydrogen.

For substituents A, all A substituents may be hydrogen, but it is preferred that no more than 3 are hydrogen. Suitable substituents A include halogen, C 1-6 -alkyl, optionally substituted hydroxy, C 1-6 -alkoxy, C 1-6 -acyl and C 1-6 -alkenyl. Particularly suitable substituents A include C 1-6 -alkoxy, C 1-2 -alkyl, C 1-6 -alkyl. ₂ -acyl. Preferred substituents for A include chlorine, fluorine, methyl, ethyl, hydroxyethyl, methoxy, formyl, acetyl, vinyl and allyl. More preferred substituents for A include methoxy. Suitably, A is adjacent to group Q.

In system Q in configuration a), particularly suitable substituents for R 1 and R 2 include methyl, ethyl, isopropyl, benzyl, phenethyl. Y may be in particular - _(CH2) 2-, - _{(CH2) 3} -, - (CH _{2) 4} -, _-CH2 -CH _{(CH3) -CH2} -. For example, if Y is substituted with hydroxy, it may be -CH ₂ -CH (OH) -CH ₂ -.

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

In configuration c) of system Q, the ring formed by binding R 1 to Y may be a pyrrolidinyl or piperidinyl ring. The bond to Y may be such as to form a ring bonded by a single bond of the carbon atom from the ring directly to X or through a methylene or ethylene linking group. R 2 is typically methyl, so that the N atom of the ring is substituted with methyl.

In configuration d) of system Q, the ring formed by binding R 1 to N is suitably a 5 or 6-membered ring (such as diazinyl or piperazines). Y is typically - (CH ₂ ) ₂ -. R 2 is typically methyl, so that the second atom of the N (other than X) ring is substituted with methyl.

A class of compounds of formula II is within the scope of Formula I

wherein A = H, OMe, R 3 = H, X = O, Y = _{CH2 CH2,} Z = bond, R 4 = Ph, R 5 is either meta or para substituted with the R 4, and R 1, R 2 and R 5 are as defined for formula I.

Also within the scope of Formula I is a class of compounds of Formula III

(III) wherein A = H, OMe, R 3 = H, X = O, Y = _{CH2 CH2,} Z = O, CH ₂ or NH and either metaalebo the para-substituted with the R 4, R 4 = Ph, R 5 is Ph and R1 and R2 are for formula (I).

Also within the scope of Formula I is a class of compounds of Formula IV

(II) o

-7kde A = H, OMe, R 1 = R 2 = / Pr, R 3 = H, X = O, Y = CH ₂ CH ₂ and R 4 and R 5 is substituted phenyl, or heterocyclic, as defined in formula I.

Also within the scope of Formula I is a class of compounds of Formula V (V) wherein R 3 = H, X = O, Y = CH ₂ -CH _2> Z = O, CH ₂ , NH or a bond, R 4 = Ph, R 5 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 Formula VI

R5 (VI) wherein X = O, Y = CH ₂ CH ₂₎ R 4 = phenyl, R 5 = phenyl or cyclohexyl (y), Z = O, _CH2 or a bond, and A (R 8, R 9), R 3 and R 1, R2 are as defined in formula I.

Also within the scope of Formula I is a class of compounds of Formula VII

R1 (VII)

Where A = H and OMe, X = O, R 3 = H, R 4 = 3-pyridyl (relative to the carbonyl group), R 5 = phenyl, Z = para-bond, and R 1 and R 2 are as defined in formula I.

Also within the scope of Formula I is a class of compounds of Formula VIII

wherein A = H, OMe, R 3 = H, X = H, R 4 = phenyl, Z = O, _CH2 or a bond, R 5 = Ph or cyclohexyl (y), Y is a chain of 3 or 4 carbon atoms, optionally substituted by hydroxy , and R1 and R2 are as defined in formula I.

Also within the scope of Formula I is a class of compounds of Formula IX

(IX) wherein A = H and OMe, R 3 = H, X = N, R 4 = phenyl, Z = para-substituted bond, R 5 = Ph or cyclohexyl (Cy), Y and R 2 form a piperazinyl ring between X and N, and R1 is as defined in formula I.

A preferred subclass of compounds for use in the treatment of this invention are those compounds of formula I wherein R 3 is methyl.

Within the scope of Formula I, there is a new group of compounds wherein R 3 is methyl or ethyl. These novel compounds, or salts or solvates thereof, form a further aspect of the invention.

A preferred class of novel compounds is the class of compounds of formula

Where R8 and R9 are for A in formula I, R1, R2 and R5 are for formula I, and R3 is methyl or ethyl.

R 5 is suitably phenyl or cyclohexyl, optionally substituted with halo, haloalkyl, alkyl or alkoxy; Z is O, CH ₂ or a single bond; R 8 and R 9 are independently selected from hydrogen, halogen, alkyl and alkoxy; R 1 and R 2 are alkyl or linked to each other to form a ring; and R 3 is ethyl or methyl.

Further, the invention provides a class of novel compounds, or salts or solvates thereof, which are compounds of Formula I except:

N - [4- [2- [bis (V-methylethyl) amino] -ethoxy] -2-fluorophenyl] - [1,1'-biphenyl] -4-carboxamide, N - [4- [2- [bis ( Biphenyl-4-carboxylic acid 1-methylethyl) amino] -ethoxy] -phenyl] - [1,1'-biphenyl] -4-carboxamide, [4- (2-diisopropylamino-ethoxy) -phenyl] -amide; - [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- (2-diisopropylamino-ethoxy) -phenyl] -phenyl 4'-Ethyl-biphenyl-4-carboxylic acid] -amide and 4'-Ethyl-biphenyl-4-carboxylic acid [4- (2-diethylamino-ethoxy) -phenyl] -amide.

Further, the invention provides those compounds of the examples herein that are novel.

The compounds of formulas I-IX or salts or solvates thereof are preferably in a pharmaceutically acceptable or substantially pure form. By a pharmaceutically acceptable form, we mean, inter alia, a pharmaceutically acceptable level of purity, with the exception of normal pharmaceutical ingredients such as diluents and carriers, and including any material considered to be 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 aluminum, alkali metal salts such as lithium, sodium or potassium, alkaline earth metal salts such as calcium or magnesium, and ammonium or substituted ammonium salts such as lower alkylamines such as is triethylamine, hydroxyalkylamines such as 2-hydroxyethylamine, bis- (2-hydroxyethyl) -amine or tri- (2-hydroxyethyl) -amine, cycloalkylamines such as bicyclohexylamine, or with procaine, dibenzylpiperidine, Nbenzyl-p-phenethylamine, dehydro- N, N-bisdehydroabietylamine, glucamine, N-methylglucamine or pyridine-type bases such as pyridine, collidine, quinine or quinoline.

Suitable pharmaceutically acceptable salts also include pharmaceutically acceptable acid addition salts, such as those affording pharmaceutically acceptable inorganic acids or organic acids.

Suitable pharmaceutically acceptable acid addition salts that provide pharmaceutically acceptable inorganic acids include sulfates, nitrates, phosphates, borates, hydrochlorides, and hydrobromides and hydroiodides.

Suitable pharmaceutically acceptable acid addition salts that provide pharmaceutically acceptable organic acids include acetates, tartrates, maleates, fumarates, malonates, citrates, succinates, lactates, oxalates, benzoates, ascorbates, methanesulfonates, α-keto-glutarates and α-glycerophosphates.

Suitable pharmaceutically acceptable solvates include hydrates.

The substantially pure form will generally contain at least 50% (without normal pharmaceutical ingredients), preferably 75%, more preferably 90%, and even more preferably 95%, of a compound of Formulas I-IX or a salt or solvate thereof.

One preferred pharmaceutically acceptable form is a crystalline form, including such form in a pharmaceutical composition. In the case of salts and solvates, other ionic and solvent moieties must also be nontoxic.

Examples of pharmaceutically acceptable salts of compounds of formulas I-IX include acid addition salts with conventional pharmaceutical acids, such as maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, almond, tartar, succinic, benzoic, ascorbic, and methanesulfonic acid. .

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

Compounds of formulas I-IX or salts or solvates thereof may be prepared by the methods illustrated in the following general reaction schemes or modifications thereof using readily available starting materials, reagents and conventional synthetic procedures. If a particular enantiomer of a compound of the invention is desired, it may be synthesized starting from the desired enantiomer of the starting material and carrying out reactions that do not involve racemization processes, or may be prepared by chiral synthesis or derivatization with a chiral reagent, leaving the resulting mixture of diastereomers separated. cleavage to give pure desired enantiomers. Alternatively, where the molecule contains a basic functional group such as amino or an acid functional group such as carboxy, diastereomeric salts are formed with the appropriate optically active acid or base followed by resolution of the diastereomeric salts by fractional crystallization followed by removal of the pure enantiomers.

Compounds of Formulas I-IX can be prepared by condensation of appropriately substituted aryl or heteroaryl carboxylic acids and appropriately substituted anilines, which are commercially available, or synthesized by methods known in the art, from commercially available starting materials, using methods known in the art technique. For example, suitably substituted aryl or heteroarylcarboxylic acids are treated with an activating reagent such as thionyl chloride at a suitable temperature such as reflux temperature to afford aryl or heteroarylcarbonyl chlorides, and these aryl or heteroarylcarbonyl chlorides are condensed with suitably substituted anilines in the presence a suitable base such as diisopropylethylamine in a suitable solvent such as dichloromethane to provide compounds of formula I.

In particular, the preparation of certain carboxamides of formula I wherein R 3 is H is described in the above-mentioned WO 99/01127 and WO 99/06146, and analogous methods of preparation can be used in the present invention. Many other methods of converting a carboxylic acid to an amide are known and can be found in standard guides such as the Compendium of Organic Synthetic Methods, Vol. I to VI (published by Wiley-Interscience).

For example, compounds of formula I can be prepared by reacting a compound of formula X

R5-Z-R4-COL (X) wherein L is a leaving group such as halogen, especially chlorine or bromine,

with a compound of formula XI WITH A V ^Q J (XI) HN A R3 1 A

wherein A, Z, R 3, R 4, R 5 and Q are as defined for formula (I).

In this method, groups that can be converted to R 1, R 2, R 3, R 4, and R 5 can be present during the condensation, and can be converted to R 1, R 2, R 3, R 4 and R 5 after the condensation. It may also be desirable to convert one R1, R2, R3, R4 and R5 to another R1, R2, R3, R4 and R5 after condensation. In particular, ring formation between the groups R 1, X, Y, R 2 or addition of suitable cyclic groups representing R 1, X, Y, R 2 may be carried out after condensation.

Accordingly, there is provided a process for the preparation of a compound of formula I or a salt or solvate thereof, wherein R 3 is methyl or ethyl, the process comprising reacting a compound of formula X as defined above with a compound of formula XI wherein A and Q as defined above, and R 3 is methyl or ethyl.

Therefore, there is also provided a process for the preparation of a compound of formula I or a salt or solvate thereof, provided that the following compounds are excluded: N- [4- [2- [bis (1-methylethyl) amino] ethoxy] -2-fluorophenyl N- [4- [2- [bis (1-methylethyl) amino] ethoxy] phenyl] - [1,1'-biphenyl] -4- [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- (2-diisopropylamino-ethoxy) -phenyl] -amide 4'-ethyl-biphenyl-4-carboxylic acid, and 4'-ethyl-biphenyl-4-carboxylic acid [4- (2-diethylamino-ethoxy) -phenyl] -amide, which process comprises reacting a compound of formula X, such as was determined with a compound of formula XI as previously determined.

Compounds of formula XI can be prepared in a number of ways, for example when X is O or S, by coupling an appropriately substituted nitrobenzene compound with a dialkylaminoalcohol or thiol and converting the NO ₂ group to NH _{2 by} hydrogenation in the presence of a palladium catalyst (or iron / ammonium chloride) with an acid chloride, for example as shown below:

The acid chlorides of formula X can be prepared from the corresponding acids which are commercially available or described in the literature, or can be prepared by methods analogous to those in the literature.

Alternatively, the acids of formula (X) may be prepared by combining residues containing R 5 and R 5, respectively. R4, via Z.

This can also be conveniently accomplished by first combining R 4 -CO-L with a compound of Formula XI followed by reaction with R 5 -Z-L (or L-R 4 -CO-L with R 5 -Z). For example, an amine of formula XI may be reacted with a suitably substituted bromobenzoyl chloride, which may then be reacted, for example, with a suitably substituted leaving group or a cyclic amine, as shown in the following scheme:

BINAP = (S) - (+) - 2,2'-Bis (diphenylphosphino) -1,1'-binaphthyl

Similar reactions leading to the structure of formula I can be carried out starting from a compound of formula X and adding the equivalent of formula XI in portions, as in the scheme below, where the N-protecting group on Q, here piperazine ring, can be removed. of formula I and substitution with the desired substituent:

Method H1

In an alternative strategy to form compounds of Formula XI prior to coupling to introduce a hydroxy group into Y, the appropriately substituted nitrophenol is coupled to the epoxy compound, which then reacts with the amine-forming group Q, which is OY (OH) -NR 1 R 2, prior to coupling. R5-Z-R4-CO-L as illustrated in the scheme:

Nose = p-nitrobenzenesulfonyl

Novel compounds of formula I wherein the amide nitrogen is alkylated (R 3 is methyl or ethyl) can be prepared by alkylating an anilide of formula XI prior to coupling, for example with an acid chloride of formula X, using the following reductive amination procedure:

Method E1

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

Solvates of compounds of formula I may be formed by crystallization or recrystallization from a suitable solvent. For example, hydrates may be formed by crystallization or recrystallization from aqueous solutions or solutions in water-containing organic solvents.

Also, salts or solvates of compounds of Formula I that are not pharmaceutically acceptable may be useful as intermediates in the preparation of pharmaceutically acceptable salts or solvates. Accordingly, such salts or solvates also form part of the invention.

The above compounds and their pharmaceutically acceptable salts, especially hydrochlorides, and pharmaceutically acceptable solvates, especially hydrates, form a preferred aspect of the invention.

Due to the activity of these compounds as human 11CBγ receptor antagonists, the compounds of Formula I are believed to play a role in the prevention, amelioration, or correction of disease dysfunctions, including but not limited to the above disorders.

It is also believed that the treatment of certain of the above disorders with human 11CBγ receptor antagonists is novel. Accordingly, the invention also provides a method of treating diabetes, severe depression, manic depression, anxiety, schizophrenia, and sleep disorders, in human or non-human mammals, the method comprising administering a therapeutically effective amount of a human 11CBy receptor antagonist. In particular, the invention provides a method of treating diabetes in human or non-human mammals, the method comprising administering a therapeutically effective amount of a human 11CBγ receptor antagonist. In particular, the invention provides a method of treating severe depression in human or non-human mammals, the method comprising administering a therapeutically effective amount of a human 11CBγ receptor antagonist. In particular, the invention provides a method of treating manic depression in human or non-human mammals, the method comprising administering a therapeutically effective amount of a human 11CBγ receptor antagonist. In particular, the invention provides a method of treating anxiety in a human or non-human mammal, the method comprising administering a therapeutically effective amount of a human 11CBγ receptor antagonist. In particular, the invention provides a method of treating schizophrenia in a human or non-human mammal, the method comprising administering a therapeutically effective amount of a human 11CBγ receptor antagonist. In particular, the invention provides a method of treating sleep disorders in human or non-human mammals, the method comprising administering a therapeutically effective amount of a human 11CBγ receptor antagonist.

Administration of such compounds to a mammal may be by oral (including sublingual), parenteral, nasal, rectal or transdermal administration.

The amount effective to treat the above disorders will depend upon conventional factors such as the nature and intensity of the disorders to be treated and the weight of the mammal. However, a unit dose will normally contain 1 to 1000 mg, suitably 1 to 500 mg, for example an amount in the range of 2 to 400 mg, such as 2, 5, 10, 20, 30, 40, 50, 100, 200, 300 and 400 mg of active compound. Unit doses will normally be administered once or more than once a day, for example 1-, 2-, 3-, 4-, 5 or 6 times a day, more usually 1- to 4 times a day, so that the total daily dose is normally at range for a 70 kg adult from 1 to 1000 mg, for example 1 to 500 mg, i.e. in the range of about 0.01 to 15 mg / kg / day, more usually 0.1 to 6 mg / kg / day, for example 1 to 6 mg / kg / day.

It is highly preferred that the compounds of formula (I) are administered in the form of a unit dose formulation, such as an oral (including sublingual), nasal, rectal, topical or parenteral (especially intravenous) unit dose formulation.

Such compositions are prepared by mixing and 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 infusion solutions or suspensions or suppositories. Orally administrable compositions are preferred, especially shaped oral compositions, as they are more convenient for general use.

Tablets and capsules for oral administration are usually presented in a unit dose and contain conventional vehicles such as binders, fillers, diluents, tabletting

- 18 Reagents, lubricants, disintegrants, dyes, flavorings and humectants. The tablets may be coated by methods well known in the art.

Suitable fillers include cellulose, mannitol, lactose and other similar agents. Suitable disintegrants include starch, polyvinylpyrrolidone, and starch derivatives such as sodium starch glycolate. Suitable lubricants include, for example, magnesium stearate. Suitable pharmaceutically acceptable humectants include sodium lauryl sulfate.

These solid oral compositions may be prepared by conventional methods of mixing, filling, tabletting or the like. Repeated blending operations can be used to distribute the active ingredient throughout these compositions using large quantities of fillers. Such operations are, of course, conventional in the prior art.

Oral liquid compositions 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, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum 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 glycerin, propylene glycol or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and, if desired, conventional flavoring or coloring agents.

Oral formulations also include conventional sustained release formulations, such as enteric coated tablets or granules.

For parenteral administration, liquid unit dosage forms are prepared comprising a compound and a sterile vehicle. The compound may be either suspended or dissolved, depending on the vehicle and concentration. Parenteral solutions are normally prepared by dissolving the compound in a vehicle and filter sterilizing prior to filling into a suitable vial or ampoule and sealing. Preferably, in the

The vaccines will also dissolve adjuvants such as local anesthetics, preservatives and buffering agents. To enhance stability, the composition may 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 sterilized by exposure to ethylene oxide prior to suspension in the sterile vehicle. Preferably, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound of the invention.

As is common practice, written or printed instructions for use in appropriate medical treatment will be attached to the device.

The compounds of the invention may be used alone or in conjunction with other compounds, such as therapeutic compounds.

No harmful toxicological effects are expected for the compounds of this invention when administered in accordance with the present invention.

Accordingly, in another aspect, the present invention provides a pharmaceutical composition for use in the treatment and / or prophylaxis of one or more disorders comprising a compound of the invention or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier.

The present invention also provides a method of treating and / or prophylaxis of one or more disorders comprising administering to a patient in need thereof an effective or prophylactic amount of a compound of the invention or a pharmaceutically acceptable salt or solvate thereof.

Further, the present invention allows the use of a compound of the present 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 disorders.

In yet another aspect, the invention allows the use of the novel compound of the 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 disorders.

The compounds for use according to the invention and their preparation are illustrated in the following examples and tables.

These examples illustrate the general procedures and sources of chemicals used to prepare compounds whose structures are shown in the data tables following the examples. In the case of examples prepared as a set of related members, the synthetic origins of all the starting components of the set are shown in the examples. Instead of describing in detail the experimental procedure for each case, the manner in which the individual members of the population were prepared is indicated in the table by reference to the respective example. The mass spectral characteristics of all examples are shown in the data tables. Additional characteristics are given for selected representative examples with complete experimental procedures.

Example A1 [WO-00/06146]

Using the procedure of Example A7 with 4-biphenylcarboxylic acid (Aldrich) instead 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), 1182, 1985).

Example A3

Correspondingly, Example A7 with 4-pyrazol-1-yl-benzoic acid (Can. J. Chem. 41, 1540, 1963).

Example A4

Correspondingly, Example A7 with 3-biphenyl-carboxylic acid (Med. Chem. Res. 6, 2, 1996).

Example A5

Correspondingly, Example A7 with 4- (2-pyridyl) benzoic acid (J. Chem.

Soc. 1940, 355, 356).

-21 Example A6

Correspondingly, Example A7 with 3'-acetyl-biphenyl-4-carboxylic acid (WO-9743262).

Example A7 2-Methylphenyl-4-phenylcarboxylic acid [3-methoxy-4- (2-bis- (2-methylethyl) amino) ethoxy] phenylamide

To a solution of (2'-methyl-biphenyl-4-carboxylic acid) [WO9901127] (55 mg, 0.26 mmol) in dimethylformamide was added (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, hydrochloride [Aldrich] (50 mg, 0.26 mmol) and 1-hydroxy-7-azabenzotriazole [Aldrich] (35 mg, 0.26 mmol), followed by the addition of diisopropylethylamine (0.04 mL, 0.25 mmol) and aniline (4- ( 2-diisopropylamino-ethoxy) -3-methoxy-phenylamine (69 mg, 0.22 mmol) [prepared using the method used to produce 3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) -phenylamine in Example A51 but with 2-diisopropylaminoethanol instead of 1- (2-hydroxyethyl) -pyrrolidine] The reaction mixture was stirred at room temperature for 16 hours, the solvent was evaporated and the residue redissolved in dichloromethane (10 mL), filtered through a SAX [Varian] column ( 2 g) and the filtrate was then stirred with PS-isocyanate resin [Argonaut Technologies] (100 mg, 0.38 mmol) for 16 hours. The mixture was filtered, evaporated and the residue purified by flash chromatography. silica gel chromatography using dichloromethane-aqueous ammonia-methanol solution as eluent to afford the title compound as an oil.

¹ H NMR (CDCl ₃ ): 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] < ^{+ &gt};.

Example A8

Using the procedure of Example A7 with cyclohexyl-4-benzoic acid [Aldrich] instead of 2'-methyl-biphenyl-4-carboxylic acid.

Example A9

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

Example A10

Correspondingly, Example A7 with 4- (1-methyl-1H-pyrazol-4-yl) benzoic acid (WO-9906409).

Example A11

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-benzylcarboxylic acid [Apinj.

Example A13

Correspondingly Example A7 with 3'-cyano-biphenyl-3-carboxylic acid (J. Chem. Soc. Perkin Trans. 2,1, 35-38, 1984)

Example A14

Correspondingly, Example A7 with 3'-methanesulfonyl-biphenyl-4-carboxylic acid (Izv. Sib. Otd. Akad. Nauk USSR, Ser. Khim. Nauk H, 62, 1966).

Example A15

Correspondingly, Example A7 with 3-thiophen-2-yl-benzoic acid (Tetrahedron Letters 39, 24, 4175, 1998).

Example A16

Correspondingly Example A7 with 3-thiophen-3-yl-benzoic acid (J. Chem. Soc. B, 1595, 1970).

Example A17

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

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, 1595, 1970).

Example A21

Correspondingly, Example A7 with 4-pyrazin-2-yl-benzoic acid (WO-9854164).

Example A22

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

Example A23

Using the procedure of Example A22 with 4-trifluoromethylphenylboronic acid [Aldrich] instead of 2-methoxyphenylboronic acid [Aldrich].

Example A24

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

-24Example A25

Correspondingly Example A23 with 4-benzyloxyphenylboronic acid [Lancasterj.

Example A26

Correspondingly, Example A23 with 2-naphthylboronic acid [Lancasterj.

Example A27

Correspondingly, Example A23 with 3-naphthylboronic acid [Lancasterj.

Example A28

Correspondingly Example A23 with 4-methylphenylboronic acid [Lancasterj.

Example A29

Correspondingly Example A23 with 4-methylthiophenylboronic acid [Lancasterj.

Example A30

Correspondingly Example A23 with 3-trifluoromethylphenylboronic acid [Lancasterj.

Example A31

Correspondingly Example A23 with 4-carbonylphenylboronic acid [Aldrichj.

Example A32

Correspondingly Example A23 with 3,4- (methylenedioxy) phenylboronic acid [Aldrichj.

Example A33

Correspondingly Example A23 with 4-vinylphenylboronic acid [Aldrichj.

Example A34

Correspondingly Example A23 with 3-methoxyphenylboronic acid [Lancasterj.

Example A35

Using the procedure of Example A51 with 1- (2-hydroxyethyl) -morpholine [Aldrich] instead of 1- (2-hydroxyethyl) -pyrrolidine.

Example A36

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

Example A37

Using the procedure of Example A51 with 2-dimethylaminoethanol [Aldrich] instead of 1- (2-hydroxyethyl) -pyrrolidine.

Example A39

Correspondingly, Example A51 with (R) - (+) - 1-methyl-2-pyrrolidinemethanol (WO-9932480).

Example A41

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

Example A43

Correspondingly to example A51 with 2-dimethylamino-1-propanol [ICN-RF].

Example A45

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

Example A47

Correspondingly Example A51 with (S) - (-) - 1-methyl-2-pyrrolidinomethanol [Aldrich].

-26Example A49

Correspondingly, Example A51 with N-benzyl-AZ-methylethanolamine [Aldrichj.

Example A51 Biphenyl-4-carboxylic acid [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy)] - phenylamide

To a solution of hydroxyamine (1- (2-hydroxyethyl) -pyrrolidine) [Aldrich] (1.87 mL, 16 mmol) in dimethylformamide was added portionwise sodium hydride (60% dispersion in oil (544 mg, 16 mmol)). After stirring at room temperature for 10 minutes, a solution of halogenonitrobenzene (1-chloro-2-methoxy-4-nitrobenzene) [Avocado] (3 g, 16 mmol) in dimethylformamide (10 mL) was added dropwise. The reaction mixture was allowed to stir at room temperature for 16 h, then concentrated. The residue was dissolved in ethyl acetate (200 mL) and washed with water (3 x 50 mL). The organic phase was dried with magnesium sulfate, evaporated and the residue purified by flash chromatography on silica gel using dichloromethane-aqueous ammonia-ethanol solution as eluent to give 1- [2- (2-methoxy-4-nitrophenoxy) ethyl] -pyrrolidine as brown oil.

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

I

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

¹ H NMR (CDCl 3): δ 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] < ^{+ &gt};.

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

¹ H NMR (CDCl ₃ ): 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] < ^{+ &gt};.

Example A54

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

Example A56

Correspondingly to Example A51 with 1- (2-hydroxyethyl) -piperidine [Aldrich],

Example A58

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

Example A60

Using the procedures of Example A93 with 3-aminophenylboronic acid instead of 2-methoxyphenylboronic acid and Example A51 with 2-dimethylaminoethanol instead of 1- (2-hydroxyethyl) -pyrrolidine.

Example A63

Using the procedure of Example A60 with 4-carboxyphenylboronic acid [Aldrich] instead of 3-aminophenylboronic acid.

Example A70

-28 Correspondingly Example A63 with (3,4-methylenedioxyphenyl) boronic acid [Aldrich],

Example A72

Using the procedure of Example A51 with N - (2-phenyl) -ethyl- N -methyl-ethanolamine [J. Org. Chem. 50 (22), 4359, 1985] instead of 1- (2-hydroxyethyl) -pyrrolidine.

Example A74

Correspondingly Example A51 with 2-dimethylamino-cyclohexanol [J. Chem. Soc. C (2), 248-252, 1969]

Example A76

Correspondingly, Example A51 with 2- (1,2,4,5-tetrahydro-benzo [d] azepin-3-yl) ethanol [US-394682],

Example A78

Correspondingly to Example A51 with 2- (3,4-dihydro-1H-isoquinolin-2-yl) -ethanol [WO-9719926].

Example A80

Correspondingly Example A51 with 2- (4-phenyl-piperazin-1-yl) -ethanol [J. Med. Chem. 37 (13), 1964].

Example A82

Correspondingly to Example A51 with 1-methyl-3-pyrrolidinol [Aldrich],

Example A84

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

-29Example A88

Using the procedures of Example A84 with 4-methoxy-3-pyridylboronic acid [WO-9924440] instead of 4-methoxyphenylboronic acid.

Example A89

Correspondingly, Example A88 with 2-methoxy-3-pyridylboronic acid [WO-9910331],

Example A90

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

Example A91

Correspondingly to Example A88 with thiophene-3-boronic acid [Aldrich],

Example A92

Correspondingly to 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-yl-ethoxy) -phenylamine (Example A51) (4.7 mM, 1.1 g) and triethylamine (14 mmol) was treated with 4-bromobenzoyl chloride [Aldrich] in dichloromethane (20 mL) and held at room temperature for 16 hours. The solvent was evaporated and the crude product was purified by silica gel chromatography using dichloromethane-methanol-aqueous ammonia solution to give 4-bromo-N- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) -phenyl] - benzamide as a white solid in 72% yield.

¹ H NMR (DMSO-d 6): δ 7.91 (2H, dd), 7.73 (2H, dd), 7.50 (1H, d), 7.30 (1H, dd), 6.94 ( 1H, d), 4.02 (2H, t), 3.76 (3H, s), 2.77 (2H, t), 2.51 (4H, m under DMSO-d5 signal) and 1.67 ( 4H, m); MS: (ES + ve) m / z 419, 421 [M + H] +.

-30Amid, 4-bromo-N- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) -phenyl] -benzamide (0.1 mM, 42 mg) and 4-methyl-benzeneboronic acid [Aldrich] (0.1 mM, 14 mg) was refluxed for 16 hours in a mixture of benzene (8 mL), ethanol (2 mL) and 2 M aqueous sodium carbonate solution (2 mL) in the presence of tetrakis- (triphenylphosphine) palladium ( 0) (5 mg) under an argon atmosphere. The mixture was cooled, the upper layer was decanted and this solution was purified by silica gel chromatography using dichloromethane: methanol (10: 1) followed by acetonitrile saturated aqueous ammonia (25: 1) to give the title compound as a white solid.

¹ H NMR (CDCl ₃ ): 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 [MH] -; (AP + ve) m / z 431 [M + H] < ^{+ &gt};.

Example A100

Using the procedure of Example A93 with 4- (2,6-dimethoxypyrimidinyl) boronic acid [Frontier] instead of 4-methylbenzeneboronic acid.

Example A103

Correspondingly to example A93 with furan-3-boronic acid [Frontier],

Example A104

Correspondingly to example A93 with mesityl-boronic acid [Frontier],

Example A105

Correspondingly to Example A51 except for the use of chloroform instead of dichloromethane as solvent and eluent, and using 3-quinuclidinol [Aldrich] instead of 1- (2-hydroxyethylpyrrolidine) -u.

Example A107

Using the procedure of Example B37 except for the use of piperidine in place of aniline.

-31 Example Β1

Using the procedure of Example A7 with 3-phenoxybenzoic acid [Aldrich] instead of 2'-methyl-biphenyl-4-carboxylic acid.

Example B2

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

Example B34

Correspondingly, Example B1 using 3-benzylbenzoic acid [WO-9828268J.

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

¹ H NMR (MeOH-d ₄ ): δ 7.96 (2H, dd), 7.92 (1H, d), 3.1 (2H, dd), 7.20 (1H, dd), 7.04 (1H, d), 4.28 (2H, t), 3.92 (3H, s), 3.78 (2H, m), 3.60 (2H, t), 3.58 to 3.13 ( 6H, m) and 2.26-1.47 (10H, m); MS: (ES + ve) mlz 424 [M + H] ⁺ .

Example C1

Using the procedure of Example A7 with 2-methylbiphenyl-4-carboxylic acid [WO-9606079] instead of 2'-methyl-biphenyl-4-carboxylic acid.

Example 32

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

Example C3

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

Example C4

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

Example C5

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].

Example C7

Correspondingly, Example C1 using 6-phenyl-nicotinic acid [WO0006085],

Example C8

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

Example C9

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

- 33Example C10

Correspondingly Example C1 using 2- (4-chlorophenyl) -3-trifluoromethylpyrazole-4-carboxylic acid [Maybridge.

Example C11

Correspondingly Example C1 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 D1

Using the procedure of Example D5 with 3,4-dichloronitrobenzene [Aldrich] instead of 2,4-dichloronitrobenzene.

Example D5 Biphenyl-4-carboxylic acid [2-chloro-4- (2-diisopropylamino-ethoxy) -phenyl] -amide

To a three-necked flask (equipped with a condenser, separatory funnel and thermometer) containing iron powder (938 mg, 16.8 mmol), mixed with a solution of ammonium chloride (28 mmol) in water (28 mL), was added amine [2- (3-chlorine)]. -4-nitro-phenoxy) -ethyl] -diisopropylamine [prepared by the method used to prepare 1- [2- (2-methoxy-4-nitrophenoxy) -ethyl] -pyrrolidine in Example A51 but with 2,4- dichloronitrobenzene [Aldrich] instead of 4-chloro-3-methoxynitrobenzene and with 2-diisopropylaminoethanol instead of 1- (2-hydroxyethyl) pyrrolidine] dropwise over 10 minutes. The reaction mixture was gently refluxed until thin layer liquid chromatography showed no starting material. The mixture was filtered while hot and the inorganic residues were washed with methanol. The combined filtrates were partitioned between water (5 mL) and ethyl acetate (3 x 10 mL), the organic phase was dried (MgSO ₄ ), filtered and evaporated. The aqueous phase was treated with saturated aqueous sodium bicarbonate solution (10 mL), extracted with ethyl acetate (3x10

(34 ml), dried (MgSO ₄ ) and evaporated. The residues from both extractions were combined and purified by flash chromatography on silica gel using dichloromethane-methanol-aqueous ammonia solution as eluent to give 2-chloro-4- (2-diisopropylamino-ethoxy) -phenylamine as a brown oil.

¹ H NMR (CDCl ₃ ): δ 1.02 (12H, d), 2.77 (2H, t), 3.03 (2H, sept.), 3.72 (2H, bs), 3.80 ( 2H, t), 6.68 (2H, m) and 6.85 (1H, m); MS (AP + ve): m / z 271.273 [M + H] < ^{+ &gt};.

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

¹ H NMR (CDCl 3): 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 (1 H, d); MS (AP + ve): m / z 452, 454 [M + H] < ^{+ &gt};.

Example D9

Using the procedure of Example A51 with 2,4-difluoronitrobenzene [Aldrich] instead of 4-chloro-3-methoxynitrobenzene.

Example D12 [WO-00/06146]

Using the procedure of Example A51 with 3,4-difluoronitrobenzene [Aldrich] instead of 4-chloro-3-methoxynitrobenzene.

Example D16

Using the procedure of Example A51 with 2-methyl-4-fluoronitrobenzene [Aldrich] instead of 4-chloro-3-methoxynitrobenzene.

Example D20

Using the procedure of Example A51 with 3-methyl-4-fluoronitrobenzene [Aldrich] instead of 4-chloro-3-methoxynitrobenzene.

Example D24

Using the procedure of Example A51 with 3-acetyl-4-fluoronitrobenzene [Aldrich] instead of 4-chloro-3-methoxynitrobenzene.

-35 Example D25 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 [WO-9901127] (223 mg, 0.5 mmol) was treated with glyoxylic acid trihydrate (1 mL), dichloromethane (5 mL) and methanesulfonic acid (0.5 mL). The mixture was stirred vigorously for 24 hours, then treated with saturated aqueous sodium bicarbonate (30 mL) and extracted with dichloromethane (3 x 20 mL). The combined organic phases were dried (MgSO ₄ ), filtered and evaporated, then subjected to flash chromatography on silica gel [chloroform-methanol solution of acetic acid] to afford the title compound as the acetate salt, a white solid.

¹ H NMR (CDCl 3): δ 1.13 (12H, d), 2.04 (3H, s), 3.02 (2H, t), 3.20 (2H, hept.), 4.05 (3H) s, 4.10 (2H, t), 5.0 (1H, bs), 7.22 (1H, s), 7.40 (1H, t), 7.48 (2H, d), 7 .65 (2H,

d), 7.76 (2H, d), 8.14 (2H, d), 8.72 (1H, s) and 9.34 (1H, s); MS (AP + ve): m / z 475 [M + H] +.

Example D26 Biphenyl-4-carboxylic acid [4- (2-diethylaminoethoxy) -3- (1-hydroxyethyl) phenyl] amide

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

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

MS (AP + ve): m / z 433 [M + H] < ^{+ &gt};.

Example 36 Biphenyl-4-carboxylic acid [4- (2-diethylamino-ethoxy) -3-ethyl-phenyl] -amide

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

¹ H NMR (CDCl 3): δ 1.17 (6H, m), 2.64 (2H, q), 2.8 (4H, q), 3.06 (2H, t), 4.15 (2H, q); t),

6.82 (1H, d), 7.35-7.71 (9H, m) and 7.96 (2H, d);

MS (AP + ve): m / z 417 [M + H] < ^{+ &gt};.

Example D28 [WO9901127]

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

Example D30 [WO9901127]

Using the procedure of Example D28 with 2-dimethylaminoethanol [Aldrich] instead of 2-diisopropylaminoethanol.

Example D32 [WO9901127]

Using the procedure of Example D28 with 2-diethylaminoethanol [Aldrich] instead

2diisopropylaminoethanol.

Example D38 [WO9901127]

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

Example D39 [WO9901127]

Using 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-diisopropylaminoethoxy) -3-methoxyphenyl] methylamide

To 4- (2-diisopropylamino-ethoxy) -3-methoxy-phenylamine (1 mmol) (Example A7) was added triethyl orthoformate (8 mL) and trifluoroacetic acid (0.15 mL). The resulting solution was heated at 90 ° C for 4 h. The solution was evaporated, then redissolved in ethanol and cooled to about -10 ° C. Sodium borohydride (190 mg, 5 mmol) was added portionwise over 10 minutes, then allowed to warm to room temperature. The solution was stirred at room temperature for 16 h, then acidified to pH 1 with 2M hydrochloric acid. The mixture was concentrated to about 10 mL, then partitioned between ethyl acetate and water. The aqueous phase was adjusted to pH 14 using 2M aqueous sodium hydroxide solution and extracted with dichloromethane (x 3), dried (MgSO ₄ ), filtered and evaporated. The residue was purified by flash chromatography on silica gel using dichloromethane-aqueous ammonia-methanol solution as eluent to give [4- (2-diisopropylamino-ethoxy) -3-methoxyphenyl] methylamine as an oil.

¹ H NMR (CDCl 3): δ 1.03 (12H, d), 2.80 (3H, s), 2.85 (2H, t), 3.02 (2H, q), 3.80 (3H, s), 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] < ^{+ &gt};.

To 4-phenylbenzoic acid (0.2 mmol) suspended in dichloromethane was added oxalyl chloride (0.6 mmol) followed by dimethylformamide (1 drop). The reaction mixture was stirred for 1 h, evaporated, co-evaporated (x 3) with dichloromethane, then redissolved in dichloromethane (1 mL). A solution containing amine [4- (2-diisopropylaminoethoxy) -3-methoxyphenyl] methylamine (0.2 mmol) and triethylamine (140 mg, 1 mmol) dissolved in dichloromethane (1 mL) was added. This solution was stirred at ambient temperature for 14 hours, evaporated, dissolved in dichloromethane (1 mL) and treated with PS-isocyanate resin [Argonaut Technologies] (150 mg). After another 18

After shaking at ambient temperature for 38 hours, the mixture was filtered, passed through a SAX column [Varian] (1 g), evaporated and the residue purified by silica gel chromatography using dichloromethane-aqueous ammonia-methanol as eluent to give the title compound as an oil.

¹ H NMR (CDCl ₃ ): δ 1.21 (12H, d), 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 + H] < ^{+ &gt};.

Example E5

Using the procedure of Example E1 with triethyl orthoacetate [Aldrich] instead of triethyl ortho formate.

Example E12 Biphenyl-4-carboxylic acid [2-chloro-4- (2-diisopropylaminoethoxy) -5-methoxyphenyl] biphenyl-4-carboxylic acid amide [4- (2-Diethylaminoethoxy) -3-methoxyphenyl] biphenyl-4-carboxylic acid methylamide (Example E9) (45 mg, 0.1 mmol) was dissolved in chloroform (1 mL) and treated with benzotriazole [Aldrich] (12 mg, 0.1 mmol) and N-chlorosuccinimide (13 mg, 0.11 mmol). The mixture was stirred at ambient temperature for 16 hours, then evaporated and flash chromatographed on silica gel (dichloromethane-methanol-aqueous ammonia) to give the title compound as an oil.

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

Example E13

Using the procedures of Example A93 with [4- (2-diethylaminoethoxy) -3-methoxyphenyl] methyl amine (Example E9) instead of 4- (2-diethylaminoethoxy) -3-methoxy-phenylamine and 2-fluoromethylphenylboronic acid [ Aldrich] instead of 4-methoxyphenylboronic acid and from Example A51 with N-diethyl) ethanolamine instead of 1- (2-hydroxyethyl) pyrrolidine.

Example 39 E14

Using the procedure of Example E13 with 2-methylphenylboronic acid [Aldrich] instead of 4-chlorophenylboronic acid.

Example E16

correspondingly [Aldrich], Example E14 with acid 2-chlórmetylfenylborónovou Example E17 correspondingly [Aldrich], Example E14 with acid 4-Fluoromethylphenylbromone; Example E21 correspondingly [Aldrich]. Example E14 with acid 4-chlórmetylfenylborónovou Example E22

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

Example E23

Correspondingly to Example E14 with 4-tert-butylphenylboronic acid [Aldrich].

Example E24 4-Biphenylcarboxylic acid [4- (2-diethylaminoethoxy) -3-methoxyphenyl] methylamide (Example E9) (45 mg, 0.1 mmol) was dissolved in acetonitrile (1 mL) and treated with N-fluoro- N -chloromethyl-triethylenediamine-bis (tetrafluoroborane) -om (43 mg, 0.12 mmol) and heated at 80 ° C for 6 hours. The solvent was evaporated and the residue was subjected to flash chromatography on silica gel (dichloromethane-methanol-aqueous ammonia solution) to give the title compound as an oil.

MS (AP + ve): m / z 451 [M + H] < ^{+ &gt};.

-40Example E25

Using the procedure of Example E1 with 4- (2-diisopropylamino-ethoxy) -3-methylphenylamine (Example D20) instead of 4- (2-diisopropylamino-ethoxy) -3-methoxy-phenylamine and with triethyl orthoacetate instead of triethyl orthoformate.

Example F1

Using the procedure of Example A7 with 6-phenyl-nicotinic acid (WO0006085) instead of 2'-methyl-4-biphenylcarboxylic acid and N-dimethylethanolamine in place of 2- (diisopropylamino) -ethanol.

Example G1 Biphenyl-4-carboxylic acid [4 - ((R) -Diethylaminohydroxypropoxy) -3-methoxyphenyl] amide

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

¹ H NMR (CDCl ₃ ): 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).

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

-41 ¹ H NMR (CDCl ₃ ): δ 1.07 (6Η, t), 2.55 to 2.72 (7H, m), 3.94 (3H, s), 4.09 to 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] < ^{+ &gt};.

This material was dissolved in ethanol (5 mL) and treated with hydrogen chloride (2 M in diethyl ether, 0.1 mL) then 10% palladium on carbon (20 mg) and hydrogenated at atmospheric pressure for 24 hours. The solution was purged with argon, then filtered through celite and evaporated to give (R) - (4-amino-2-methoxy-phenoxy) -diethylamino-propane-

2-ol hydrochloride as a white crystalline solid.

¹ H NMR (CD 3 OD): δ 1.19 (6H, t), 3.36 to 3.45 (6H, m), 3.88 (3H, s), 4.02 to 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 (2 mL) was treated with triethylamine (2 mmol, 280 μΙ) and triethylsilyl trifluoromethanesulfonate (1 mmol, 264 mg). After 30 minutes, 4-biphenylcarboxylic acid chloride (Example 1) (1 mmol, 217 mg) was introduced and the mixture was stirred for 12 hours. The solvent was evaporated and the residue was dissolved in methanol (100 mL) and treated with potassium carbonate (2 g). After stirring for 6 hours, the suspension was evaporated, adjusted to slurry with dichloromethane (20 mL), filtered, the filtrate evaporated and the residue purified by flash chromatography (dichloromethane-methanol-aqueous ammonia) to give the title compound as a white solid.

¹ H NMR (CDCl 3): δ 1.11 (6H, t), 2.61 to 2.78 (6H, m), 3.88 (3H, s), 3.5 to 4.5 (1H, vbs), 3.99 to 4.13 (3H, m), 6.92 (1H, d), 6.99 (1H, dd), 7.41 to 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] < ^{+ &gt};.

Example G5

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

Example G8

Using the procedure of Example G1, but using (S) -p-nitrophenylsulfonylglycidol instead of (R) -p-nitrophenylsulfonylglycidol and pyrrolidine instead of diethylamine.

-42Example G22

Using the procedure of Example A51, but using 4-dimethylamino-1-butanol [ICN-RF] instead of 1- (2-hydroxyethyl) -pyrrolidine.

Example H1

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

A solution of 1- (2-methoxy-4-nitro-phenyl) -piperazine (patent WO-9906382) (10 mmol, 2.37 g) in dichloromethane (50 mL) was treated with di-tert-butyl bicarbonate (10 mmol, 2 , 18 g) with stirring. There was a rapid evolution of gas, which stopped after 1 hour. The solution was then evaporated to a yellow solid 4- (2-methoxy-4-nitro-phenyl) -piperazine-1-carboxylic acid tert-butyl ester.

¹ H NMR (CDCl ₃ ): 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 ethanol (50 mL) and treated with 10% Pd on carbon (100 mg). The suspension was hydrogenated at 1 atmosphere for 2 hours, then filtered through celite and evaporated to give 4- (4-amino-2-methoxy-phenyl) -piperazine-1-carboxylic acid tert-butyl ester as a brown oil.

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

This aniline (0.2 mmol, 61 mg) was dissolved in dichloromethane (1 mL) and treated sequentially 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-aqueous ammonia) to give 4- (4 - ((1- (4-cyclohexyl) tert -butyl ester)). (phenyl) -methanoyl] -amino} -2-methoxy-phenyl) -piperazine-1-carboxylic acid as a white crystalline solid.

¹ H NMR (CDCl 3): δ 1.25 to 1.47 (5H, m), 1.54 (9H, s), 1.75 to 1.88 (5H, m), 2.56 (1H, m) 1.98 (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] < ^{+ &gt};.

This material was dissolved in dichloromethane (5 mL) and treated with anisole (1 mL) and trifluoroacetic acid (5 mL). After 2 hours the solution was evaporated,

It was then co-evaporated twice from toluene. The residue was dissolved in dichloromethane (10 mL), washed with saturated sodium bicarbonate solution (2 mL), the organic phase was dried (MgSO 4), filtered and evaporated to a brown oil, 4cyclohexyl- N - (3-methoxy-4-piperazine) 1-yl-phenyl) -benzamide.

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

This amine (0.1 mmol, 39 mg) was dissolved in ethanol (3 mL) and treated with metaformaldehyde (100 mg), Amberlyst [Novabiochem] cyanoborohydride resin (100 mg) and acetic acid (50 μΙ). 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-aqueous ammonia solution) to give the title compound as a pale brown oil. This was evaporated from dilute acetic acid to give the monoacetate salt hydrate.

¹ H NMR (CDCl 3): δ 1.22 to 1.45 (5H, m), 1.76 to 1.87 (5H, m), 2.02 (6H, 2xs), 2.56 (1H, m) 3.22-3.23 (4H, t), 3.88 (3H, s), 6.86 (1H, d), 6.94 (1H, dd), 7.30 (1H, d) .

7.59 (1H, m), 7.79 (2H, d), 7.98 (1H, s) and 8.54 (4H, bs);

MS (AP + ve): m / z 408 [M + H] < ^{+ &gt};.

The following tables give examples that illustrate but do not limit the invention in any way.

Table A

It includes compounds of formula II, a subset of formula I, wherein A = H and OMe, R 3 = H, X = O, Y = CH ₂ CH ₂ , Z = a bond; R 4 = Ph and R 5 is either meta or para-substituted on R 4.

(H)

Example no. R 5 P '• ^O ^ - _R 2 meta / para [M + H] < ⁺ > ^. Approach A1 ph V, ο ^ γ P 447 A7 A2 L IN P 453 A7 A3 O ¹ - y _x 0 ^ ~ Hy- P 437 A7 A4 ph y ✓ «You m 447 A7 A5 .N. ABOUT' y _x 0 ^ -Ny P 448 A7 A6 m y , Ο ^ γ P 489 A7 A7 about-· y , -Ο ^ χ-ιγ P 461 A7 A8 0 y ,. · Ο.χ-γ P 453 A7 A9 you- y "Y-.οχ P 453 A7 A10 ABOUT y ... Ο ^ γ-Νγ- P 451 A7 A11 · AO- y ,, οχ-Νγ- P 529 A7 A12 ABOUT y ., 0-χ-γ P 461 A7 A13 XK y m 472 A7 A14 In χΟχΖ ~ ^Ν γ P 525 A7

Α15 , Φ ^ ο m 453 A7 Α16 Ο- y ... Ο ^ Ζ-Ηγ- m 453 A7 Α17 y , .- ° χ / ~ · Νγ- P 489 A7 Α18 Χι. y P 486 A7 Α19 χνθ- y.-θχ ^ ~ ^Ν γ P 529 A7 Α20 · 0- y Θ ^ .-- -Νγ- P 453 A7 Α21 1 1 1 1 y P 449 A7 Α22 ι y ... 0 ^ <- ^Ν γ- P 477 A22 Α23 W-- F F y P 515 A22 Α24 υ y P 462 A22 Α25 0-0 t} - y,. O ^ y ~ N y / P 553 A22 Α26 y P 497 A22

Α27 Q> - P 497 A22 Α28 -Ό " y P 461 A22 Α29 λΟ y P 493 A22 Α30 y P 515 A22 Α31 w-- y P 475 A22 Α32 y, .- Οχ / ~ ^N y P 491 A22 Α33 O- ' y,. ° x ^ ^N y P 473 A22 Α34 M , y _r P 477 A22 Α35 ph ABOUT ... ^ 0 ^ N P 433 A51 Α36 about-- o ^ ° n O-Z P 439 A51 Α37 ph /, · ° χ / ~ ^Ν \ P 397 A51 Α38 about- ..- Οχ / - ^Ν Χ P 391 A51

.ΔΠ -

Α39 ο- · I ⁰ o P 423 A51 Α40 ph I / N. ⁰ o P 417 A51 Α41 ph P 417 A51 Α42 ο-- ó b / P 423 A51 Α43 ph / —Z p P 405 A51 Α44 about-· ó z— / P 411 A51 Α45 ph r o - ”- ' P 419 A51 Α46 about-- P 425 A51 Α47 ph -oj? P 417 A51 Α48 about-- it -ΟχΑ / P 423 A51 Α49 ph / Ph P 467 A51 Α50 about-· F-Ph P 473 A51 Α51 ph , -o ^ ^N O P 417 A51 Α52 about-· ... ^ 0 -N0 P 423 A51 Α53 about / P 421 A22

Α54 ph - ° rr Ρ 405 Α51 Α55 about-- Ρ 411 Α51 Α56 ph Ρ 431 Α51 Α57 about-- ... o ^ O Ρ 437 Α51 Α58 ph - ^ H ° Ρ 445 Α51 Α59 about-- - 0 ° ^ Ρ 451 Α51 Α60 U Ο ^ χ-Ν ⁷ Ρ 406 Α60 Α61 No. / ... θ · ζΛ Ρ 497 Α63 Α62 ^CF xr / Ρ 459 Α63 Α63 / _χ 0χ / ~ Ρ 419 Α63 Α64 ^ 0 ' Ρ 417 Α63 Α65 ^ Xr / ονΛ Ρ 421 Α63 Α66 WHAT / _ .. 0 ^ ~ Ν _χ Ρ 441 Α63 Α67 WHAT / Ρ 441 Α63 Α68 ABOUT' / ,,. Ο ^ Ζ-Ν _χ Ρ 404 Α63

Α69 / P 437 A63 Α70 <xr / P 434 A63 Α71 / P 459 A63 Α72 ph P 481 A51 Α73 ABOUT WO P 487 A51 Α74 ph Λ P 445 A51 Α75 0 yb P 451 A51 Α76 ph ? O20 P 493 A51 Α77 ABOUT '^' CO P 499 A51 Α78 ph CCO P 479 A51 Α79 0'- pop P 485 A51 Α80 ph ccc P 508 A51 Α81 · 0 - P 514 A51 Α82 ph P 403 A51 Α83 ABOUT' Υ_Ν _χ P 409 A51

Α84 -.- Ο , -Oo ~ V P 449 A84 Α85 ₌ j3 ” P 445 A88 Α86 P 487 A88 Α87 0-- O ^ Z N? P 425 A88 Α88 / about o ^ y N? P 450 A88 Α89 Q / P 450 A88 Α90 about- O ^ Z N? P 459 A88 Α91 sO ' O ^ ZN ⁷ ^ P 425 A88 Α92 WHAT 'H ο ζ ^ _ / ^ P 458 A88 Α93 -"-ABOUT P 447 A93 Α94 X) χ0ν ^ ~ ^Ν 0 P 443 A93 Α95 , _f O ' - ^ο νΖ ~ ^{Ν Ν} P 485 A93 Α96 Q- 0 ° ^N 0 P 423 A93 Α97 XT , -ο.ζΌ P 431 A93 Α98 / about , ° ^ -Ό P 448 A93

A99 CK P 431 A93 A100 P 479 A93 A101 oy P 457 A93 A102 sO χθχζΌ P 423 A93 A103 O ^- ·· P 407 A93 A104 XK P 459 A93 A105 ph -o / b P 429 A105 A106 ABOUT r- P 426 A107 A107 _σ · P 424 A107 A108 ABOUT y- P 454 A107

Table B

Includes compounds of formula III, a subset of formula I, wherein A = H and OMe, R 1 = R ₂ = Me ₂ , R 3 = H, X = O, Y = CH ₂ -CH ₂ , Z = O, CH ₂ or NH; R 4 = Ph, R 5 is Ph and Z is either meta- or para-substituted on R 4.

(III)

Example no. FROM meta / para r [M + H] &lt; ⁺ &gt; ^. Approach B1 0 m in 463 B1 B2 ch ₂ P IN 461 B1 B3 0 m o Q ° 229 A51 B4 ch ₂ P o Q ° 447 A51 B5 0 m 407 A51 B6 ch ₂ P ... o ^ y-Nx 405 A51 B7 0 m OXJ ... N? 433 A51 B8 ch ₂ P ... OXJ-Νχ 431 A51 B9 0 m - ° <3 433 A51 B10 ch ₂ P , Y 3 ° 431 A51 B11 0 m 421 A51

Β12 ch ₂ P 419 A51 Β13 0 m [~ 435 A51 Β14 ch ₂ P r ~ 433 A51 Β15 0 m 0 433 A51 Β16 ch ₂ P o ... 0 ^> - N _x 431 A51 Β17 0 m / —P ^h 483 A51 Β18 ch ₂ P r-Ph 481 A51 Β19 0 m 433 A51 Β20 ch ₂ P 431 A51 Β21 ch ₂ P 419 A51 Β22 0 m -about 447 A51 Β23 ch ₂ P , ^ - ο 445 A51 Β24 0 m / __ / Ph 497 A51 Β25 ch ₂ P 495 A51

B26 0 m ? ^Z ^ OO 509 A51 B27 ch ₂ P 507 A51 B28 0 m 495 A51 B29 ch ₂ P 493 A51 B30 0 m 524 A51 B31 ch ₂ P 522 A51 B32 0 m 419 A51 B33 ch ₂ P 'O ¹ ' 417 A51 B34 ch ₂ m 461 B1 B35 0 P 463 B1 B36 NH P z ^ · 462 B37 B37 NH P 432 B37

Table C

It includes compounds of formula IV, a subset of formula I, wherein

A = H and OMe, R 1 = R ₂ = Me ₂ , R 3 = H, X = O, Y = CH ₂ -CH ₂ ; R4, R5 = substituted phenyl or heterocycle,

55 (IV)

Example no. FROM 3/4 substitution C = 0 ABOUT R 5 [M + H] &lt; ⁺ &gt; ^. process C1 bond 4 x / ph 461 C1 C2 bond 4 ph 477 C1 C3 bond 4 ph 461 C1 C4 bond 3 Λ ph 453 C1 C5 0 3 ^c In Cl 521 523 525 C1 C6 bond 3 / C ph 451 C1 C7 bond 4 F N ph 448 C1 C8 0 4 ph 481.483 C1

C9 bond 3 .A 539, 541 C1 C10 bond 3 • or ° ¾ CF, .-0 ' 539 C1 C11 bond 3 0 ' 453 C1 C12 bond 3 ... σ ' ή- 525 C1

Table D

It includes compounds of Formula V, a subset of Formula I wherein R 3 = H, X = O, Y = CH ₂ -CH ₂ , Z = O, CH ₂ NH, or a bond; R 4 = Ph, R 5 is Ph or cyclohexyl (Cy) and Z is either meta- or para-substituted at R 4.

(IN)

Example no. FROM R6 R7 R 5 hurling / steam r [M + H] &lt; ⁺ &gt; ^. process D1 bond Cl H ph P IN 452, 454 D1 D2 0 Cl H ph m IN 468, 470 D1 D3 ch ₂ Cl H ph P IN 466,468 D1

D4 bond CI H Cy P y 458, 460 D1 D5 bond H CI ph P Y 452, 454 D5 D6 0 H CI ph m Y ' 468, 470 D5 D7 ch ₂ H CI ph P in 466,468 D5 D8 bond H CI Cy P y 458, 460 D5 D9 bond F H ph P y 435 D9 D10 ch ₂ F H ph P y 449 D9 D11 bond F H ph P y 441 D9 D12 bond H F ph P y 435 D12 D13 0 H F ph P y,. · ° χΖ ~ ^Ν γ 451 D12 D14 ch ₂ H F ph P y 449 D12 D15 bond H F Cy P y ZK / -Ny 441 D12 D16 bond Me H ph P y 431 D16 D17 0 Me H ph m y 447 D16 D18 ch ₂ Me H ph P y the <V Y 445 D16

D19 bond Me H Cy P y • - ^ ° of 437 D16 D20 bond H Me ph P y 431 D20 D21 0 H Me ph m y 447 D20 D22 ch ₂ H Me ph P in 445 D20 D23 bond H Me Cy P y / θχ / ~ · ^Ν γ 437 D20 D24 bond coch ₃ H ph P _N r 431 D24 D25 bond OMe CHO ph P y 475 D25 D26 bond CH (OH) ₃ H ph P r 433 D26 D27 bond et H ph P r 417 D27 D28 bond H H ph P y 417 D28 D29 0 H H ph m y ... Ο ^ Ζ-Νγ- 433 D28 D30 bond H H ph P , · ° χΖ ^ ^Ν Χ 361 D30 D31 0 H H ph P y - ^ ° of 433 D28 D32 0 H H ph P r ... o.y ~ 'V 405 D32 D33 0 H H ph m r . ΟχΖ "^ 405 D32

D34 bond H H Cy P in 423 D28 D35 bond H H cy P o r 395 D32 D36 ch ₂ H H ph P IN 431 D28 D37 ch ₂ H H ph P o r 403 D32 D38 bond H H p- EtPh P y 445 D38 D39 bond H H P- EtPh P 417 D39

Table E

It includes compounds of formula VI, a subset of formula I, wherein A = H, Cl, F and OMe, X = O, Y = CH ₂ -CH ₂ ; R 4 = phenyl, R 5 = phenyl or cyclohexyl (Cy), Z = O, CH ₂ or a bond

(VI)

Example no. FROM m / p R3 R8 R9 R 5 [M + H] &lt; ⁺ &gt; ^. process E1 bond P Me H MeO ph IN 461 E1 E2 0 m Me H MeO ph y ..- Ο ^ ^Ν γ 477 E1 E4 ch ₂ P Me H MeO ph y.-0χΖ ~ ^Ν γ 475 E1 E5 bond P Me H MeO cy y 467 E1

Ε6 bond P et H MeO ph o ^ -nc 447 E1 Ε7 bond P et H MeO ph 445 E1 Ε8 bond P Me H MeO ph 431 E1 Ε9 bond P Me H MeO ph 433 E1 Ε10 bond P et H MeO Cy 453 E1 Ε11 bond P et H MeO Cy _x o ^ -nO 451 E1 Ε12 bond P Me Cl MeO ph 468, 470 E12 Ε13 bond P Me H MeO 2-F-Ph 0 ^ <- n C 451 E13 Ε14 bond P Me H MeO 2-Me-Ph o ^ the-nC 447 E14 Ε15 bond P Me H MeO 2-MeO-Ph 463 E14 Ε16 bond P Me H MeO 2-Cl-Ph o ^ Well 468.470 E14 Ε17 bond P Me H MeO 4-F-Ph 451 E14 Ε18 bond P Me H MeO 4-F ₃ C-Ph 501 E14 Ε19 bond P Me H MeO 4-Me-Ph 0 ^ -NC 447 E14 Ε20 bond P Me H MeO 4-MeO-Ph o ^ the-nC 463 E14 Ε21 bond P Me H MeO 4-Cl-Ph 468.470 E14 Ε22 bond P Me H MeO 4-Et-Ph 461 E14 Ε23 bond P Me H MeO 4-tBu-Ph o ^ the-nC 489 E14

E24 bond P Me F MeO ph o ^ -nc 451 E24 E25 bond P et H Me ph T 459 E25 E26 bond P et H Me Cy ..- 0χΖ ~ ^Ν χ < 465 E25 E27 ch ₂ P et H Me ph 473 E25

Table F

Includes compounds of formula VII, a subset of formula I, wherein A = H and OMe, X = O, R4 = 3-pyridyl, R5 = phenyl, Z = para-bond

(VII)

Example # F ¹ ° .- ^N ^ R2 [M + H] &lt; ⁺ &gt; ^. process F1 R 1 = R 2 = Me 392 F1 F2 418 F1 F3 418 F1 F4 in 448 F1

-62Table G

Includes compounds of formula VIII, a subset of formula I wherein A = H and OMe, R 3 = H, X = O, R 4 = phenyl, Z = O, CH ₂ or a bond and R 5 = Ph or cyclohexyl (Cy), Y is a chain of 3 or 4 carbon atoms, optionally substituted with a hydroxyl group.

(VIII)

Example no. FROM m / p R 5 Xyn r -s » [M + H] &lt; ⁺ &gt; ^. process G1 bond P ph ? H r 449 G1 G2 bond P ph ? H ...about 461 G1 G3 bond P ph ? H xy 476 G1 G4 bond P ph ? H -ABOUT 476 G1 G5 bond P ph ? H ...about 465 G5 G6 bond P ph ? H -ABOUT 475 G1 G7 bond P ph ? H .Ό 475 G1 G8 bond P cy OH ,about 453 G8 G9 bond P ph OH ...about 447 G8

G10 bond P Cy OH r .- • N ^ x 455 G8 G11 bond P ph OH r 449 G8 G12 bond P Cy Ν ^ γγ ^ Ν OH X 483 G5, G8 G13 bond P ph Ο ^ Χ OH X 477 G5, G8 G14 bond P Cy Ογ ^ Ν OH x 482 G8 G15 bond P ph OH xr 476 G8 G16 bond P Cy O ^ Y ^ N OH X 481 G8 G17 bond P cy Ο- ^ ^ γ -Ν OH X 481 G8 G18 bond P ph Ν ^ γγ ^ Ν OH x 475 G8 G19 bond P ph Ο ^ Χ OH -ABOUT 475 G8 G20 bond P ph ογ ^ Ν OH r \ X 444 G8, G5 G21 bond P ph Ο ^ ^ Ν γγ OH X 461 G8 G22 bond P ph θ '--- NMe ₂ 419 G22 G23 0 m ph NMe ₂ 435 G22 G24 ch ₂ P ph NMe ₂ 433 G22 G25 bond P Cy NMe ₂ 425 G22

-64Table H

Includes compounds of formula IX, a subset of formula I wherein A = H and OMe, R 3 = H, X = N, R 4 = phenyl, Z = para-substituted bond and R 5 = Ph or cyclohexyl (Cy), Y and R 2 form a piperazinyl ring between X and N.

(IX)

Example # R 5 R1 [M + H] &lt; ⁺ &gt; ^. process H1 Cy Me 408 H1 H2 Cy et 436 H1 F3 Cy Pr 422 H1

The activity of the compounds used in this invention can be determined by competitive binding studies on 11CBy receptors as follows:

Radioligand binding studies

Radioligand binding studies were performed on well washed membranes from HEK293 cells stably expressing 11CBy receptors. Membranes (5-15 mg protein) were incubated with [125 I] -melanine-concentrating hormone (0.22 nM) (obtained from NEN) in the presence and absence of competing test compounds for 45 minutes at 37 ° C in buffer (pH 7.4). containing 50 mM Tris and 0.2% BSA. Non-specific binding was determined using 0.1 mM melanin concentration hormone (obtained from Bachem). Test compounds were added at concentrations between 10 M and 10 µM at 10 concentration steps. After incubation, the reaction was stopped by filtration through GF / B filters and the reaction mixture was washed with 4 x 1 ml ice-cold 50 mM Tris buffer. Microscint 20 (Packard) was added to the filters and radioactivity was measured using a Packard TopCount.

-65 Bound cpm in the presence of test compound was expressed as the fraction of bound cpm in the absence of test compound and plotted against compound concentration. From this, the IC50 was determined from which pKi was calculated.

The most potent compounds of the invention have pKi values ranging from 7.1 to 7.8. For example:

Example Range pKi A48 7.5-7.8 B2 7.1-7.4 C8 7.1-7.4 D15 7.5-7.8 E9 7.5-7.8 F4 7.1-7.4 G1 7.1-7.4 H1 7.1-7.4

Claims (11)

PATENT CLAIMS 1. The use of carboxamide compounds of the formula I, or a pharmaceutically acceptable salt or solvate thereof (D wherein each A is independently hydrogen, alkyl, optionally substituted by hydroxy, alkoxy _Ο ν6, C-alkenyl or C ^ e-acyl or halogen or a hydroxyl, CN or CF ₃ group; R 3 is hydrogen, methyl or ethyl; R 4 is an optionally substituted aromatic carbocyclic or heterocyclic ring; Z is O or S, or NH or CH ₂ , or a single bond at the 3 or 4 position on R 4 with respect to the carbonyl group; R 5 is an optionally substituted aromatic carbocyclic or heterocyclic ring, or an optionally substituted, saturated or unsaturated, aromatic carbocyclic or heterocyclic ring; R1 / and Q is -X-Y-N \ R 2 a) when X is O or S; Y is a straight or branched C 2-4 alkylene group, optionally substituted by a hydroxyl group, or a C 5-6 cycloalkylene group, R 1 and R 2 are independently straight or branched C 1-6 -alkyl, phenyl-C 1-6 -alkyl; or b) when X is O or S; Y is a linear or branched _C2-.4 alkylene group, optionally substituted with hydroxy, R 1 and R 2 are attached to each other to form a 5-, 6- or 7-membered ring, optionally containing one or more additional heteroatoms selected from O, S or N, wherein the N or C atoms in the ring are optionally substituted with R a, -CO -R a, -CO-NH-R a or CO-O-R a, wherein R a is a straight or branched C 1-6 -alkyl or aryl group; and the 5-, 6- or 7-membered ring is optionally fused to an optionally substituted benzene ring, or the 5-, 6- or 7-membered ring atom is optionally bonded by a single bond or a methylene group to Y; or c) when X is O or S, Y is C _{2nd 4} -alkylene radical, R 1 is C ₂ _4-alkylene group, linked to Y to form a 5- or 6-membered ring, and R 2 is a linear or branched Ci-6 alkyl; or d) when X is N, Y is C _{2nd 4} -alkylene radical, R 1 is C ₂ .4-alkylene group linked to X to form a 5- or 6-membered ring, and R 2 is a linear or branched Ci-6 alkyl, for the manufacture of a medicament for the treatment of disorders selected from the group: infections, for example bacterial, fungal, protozoan and viral infections, especially infections caused by HIV-1 or HIV-2; pain; cancer; diabetes; obesity; eating and drinking abnormalities such as anorexia and bulimia; asthma; Parkinson's disease; acute and congestive heart failure; low blood pressure; high blood pressure; urinary retention; osteoporosis; angina pectoris; myocardial infarction; ulcers; allergies; benign prostate enlargement; psychotic and neurological disorders, including anxiety, schizophrenia, manic-depressive psychosis; delirium; dementia or severe mental retardation; and dyskinesias such as Huntington's disease or Gilles de la Tourette syndrome. The carboxamide compounds of formula I as defined in claim 1, or salts or solvates thereof, wherein R 3 is methyl or ethyl. The carboxamide compounds according to claim 2, which are selected from the compounds listed in Table E. The carboxamide compounds of formula I as defined in claim 1, or salts or solvates thereof, with the exception of 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] -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) -benzamide] -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- (2-diethylamino-ethoxy) -phenyl] -amide 4 '-ethyl-biphenyl-4-carboxylic acid. A process for the preparation of carboxamide compounds of formula I or salts or solvates thereof according to claim 2, characterized in that it comprises reacting a compound of formula X R5-Z-R4-COL (X) wherein R5, Z and R4 are as defined for formula I in claim 1, and L is a leaving with a compound of the formula XI Λ / ^Q (XI) HHT y 'A R3 A wherein Q and A are as defined for formula I in claim 1 and R 3 is methyl or ethyl. A process for the preparation of the carboxamide compounds of formula I or salts or solvates thereof as defined in claim 1, comprising reacting a compound of formula X, wherein R 5, Z and R 4 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 the preparation of the following compounds is excluded: N - [4- [2- [bis (1-methylethyl) amino] -ethoxy] -2-fluorophenyl] - [1,1'-biphenyl] -4-carboxamide, N - [4- [2- [ biphenyl-4-carboxylic acid bis (1-methyl-ethyl) -amino] -ethoxy] -phenyl] - [1,1'-biphenyl] -4-carboxamide, [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- (2-diethylamino) 4-Ethyl-biphenyl-4-carboxylic acid-ethoxy) -phenyl] -amide. A pharmaceutical composition for use in the treatment and / or prophylaxis of one or more disorders comprising a carboxamide compound of the invention or a pharmaceutically acceptable salt or solvate thereof in an effective or prophylactic amount and a pharmaceutically acceptable carrier. The carboxamide compounds of the invention or salts or solvates thereof for the treatment and / or prophylaxis of one or more disorders selected from the group consisting of: infections, for example bacterial, fungal, protozoan and viral infections, in particular infections caused by HIV-1 or HIV-2; pain; cancer; diabetes; obesity; eating and drinking abnormalities such as anorexia and bulimia; asthma; Parkinson's disease; acute and congestive heart failure; low blood pressure; high blood pressure; urinary retention; osteoporosis; angina pectoris; myocardial infarction; ulcers; allergies; benign prostate enlargement; psychotic and neurological disorders, including anxiety, schizophrenia, manic-depressive psychosis; delirium; dementia or severe mental retardation; and dyskinesias, such as Huntington's disease or Gilles de la Tourette syndrome, in a mammal in need of such treatment. Use of the carboxamide compounds of the invention or pharmaceutically acceptable salts or solvates thereof in the manufacture of a medicament for the treatment and / or prophylaxis of one or more disorders. Use of the carboxamide compounds of the invention or pharmaceutically acceptable salts or solvates thereof as a therapeutic agent, in particular for the treatment and / or prophylaxis of one or more disorders. Use of the carboxamide compounds of the invention as human 11CBγ receptor antagonists for the manufacture of a medicament for the treatment of diabetes, severe depression, manic depression, anxiety, schizophrenia and sleep disorders, in human or non-human mammals.