KR20030059084A - Carboxamide compounds and their use as antagonists of a human 11cby receptor - Google Patents

Abstract

The compound of formula (I) is an antagonist of the dead 11 CBy receptor:

Where

Each A is independently hydrogen, hydroxyl optionally substituted by C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkenyl or C _1-6 acyl group, halogen atom, or 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 a single race at the 3 or 4 position of R 4 with respect to the O or S atom, or NH or CH ₂ group, or carbonyl group,

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

Q is Wherein X, Y, R1 and R2 are as defined in claim 1.

Description

Carboxamide compounds and their use as antagonists of the 11CV receptor {CARBOXAMIDE COMPOUNDS AND THEIR USE AS ANTAGONISTS OF A HUMAN 11CBY RECEPTOR}

The present invention provides a method of treatment with an antagonist of human 11CBy receptor; Novel therapeutic uses of the class of carboxamide compounds that are antagonists to human 11 CBy receptors; Novel compounds belonging to this class and methods for preparing such compounds.

International Patent Application Publication No. 01/21577 (Takeda Chemical Industries Ltd.) describes certain biaryl compounds as melanin enriched hormone antagonists.

WO 98/00401 (Merck & Co. Inc.) describes benzamide derivatives as fibrinogen receptor antagonist prodrugs.

European patent EP 0 358 118 (Boehringer Mannheim GmbH) describes certain biaryl compounds useful in the treatment of heart disease and blood circulation diseases and as inhibitors of erythrocyte aggregation.

European patent application EP 0 968 999 (Mitsui Chemical Inc.) describes certain aniline derivatives useful for the treatment of arrhythmias.

WO 99/01127 (Smithcline misery) contains compounds N- [4- [2- [bis (1-methylethyl) amino] ethoxy] -2-fluorophenyl]-[1,1'-biphenyl] 4-carboxamide and N- [4- [2- [bis (1-methylethyl) amino] -ethoxy] -phenyl]-[1,1'-biphenyl] -4-carboxamide Specific N-[(amino alkoxy) phenyl] benzamides that act as CCR5 receptor ligands are described. In addition, WO 99/06146 (Smithclin Misery) describes certain substituted anilides that are antagonists of the CCR5 receptor, including: biphenyl-4-carboxylic acid [4- (2-dimethylamino-) Methoxy) -phenyl] -amide, biphenyl-4-carboxylic acid [4- (2-diisopropylamino-ethoxy) -phenyl] -amide, N- [4- (2-diisopropylamino- Methoxy) -phenyl] -4-phenoxy-benzamide, N- [4- (2-diethylamino-ethoxy) -phenyl] -4-phenoxy-benzamide, N- [4- (2-di Isopropylamino-ethoxy) -phenyl] -3-phenoxy-benzamide, N- [4- (2-diethylamino-ethoxy) -phenyl] -3-phenoxy-benzamide, 4-cyclohexyl -N- [4- (2-diisopropylamino-ethoxy) -phenyl] -benzamide, 4-cyclohexyl-N- [4- (2-diethylamino-ethoxy) -phenyl] -benzamide , 4-benzyl-N- [4- (2-diisopropylamino-ethoxy) -phenyl] -benzamide, 4-benzyl-N- [4- (2-diethylamino-ethoxy) -phenyl] Benzamide, 4'-ethyl-biphenyl-4-carboxylic acid [4- (2-Diisopropylamino-ethoxy) -phenyl] -amide, and 4'-ethyl-biphenyl-4-carboxylic acid [4- (2-diethylamino-ethoxy) -phenyl] -amides.

The present invention is based on the discovery that the carboxamide class that overlaps with the above mentioned benzamide and anilide is surprisingly an antagonist of the human 11CBy receptor described in Nature, 400, 261-265 (1999).

Thus, such compounds include infections such as bacterial, fungal, protozoan and viral infections, particularly infections induced by HIV-1 or HIV-2; Pain; cancer; diabetes; obesity; Food intake and drinking abnormalities such as anorexia and bulimia; asthma; Parkinson's disease; Acute and chronic heart attacks; Hypotension; High blood pressure; Urinary tract; osteoporosis; angina pectoris; Myocardial infarction; ulcer; allergy; Benign prostatic hypertrophy; Psychosis and nervous system disorders including anxiety, schizophrenia, manic depression, delirium, dementia or severe mental retardation; And dyskinesia such as Huntington's chorea or Tourette syndrome, in particular, is believed to play a role in preventing, ameliorating or correcting dysfunctions or diseases referred to below as "diseases."

In the present invention, a method of treating a disease, comprising administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvent compound thereof, to a mammal suffering from at least one of said diseases: Provides:

Where

Each A is independently hydrogen, C _1-6 alkyl optionally substituted by hydroxyl, C _1-6 alkoxy, C _1-6 alkenyl, C _1-6 acyl group, halogen atom, hydroxyl, CN Or a CF ₃ group;

R 3 is hydrogen, methyl or ethyl, preferably methyl;

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

Z is an O or S atom, or an NH or CH ₂ group or a single bond at the 3 or 4 position of R 4 relative to the carbonyl group, preferably a bond, more preferably a bond at the 4 position of R 4 relative to the carbonyl group;

R 5 is an optionally substituted aromatic carbocyclic or heterocyclic ring, an optionally substituted, saturated or unsaturated carbocyclic or heterocyclic ring, preferably a phenyl group;

Q is Is,

here,

(a) X is O or S atom, preferably O atom,

Y is a linear or branched C _2-4 alkylene group optionally substituted by a hydroxyl group, preferably a C ₃ alkylene group, or a C _5-6 cycloalkylene group,

R 1 and R 2 are independently linear or branched C _1-6 alkyl, preferably ethyl; Phenyl C _1-6 alkyl group;

(b) X is O or S atom,

Y is a linear or branched C _2-4 alkylene group optionally substituted by a hydroxyl group,

A 5-, 6- or 7-membered ring, preferably a 5-membered ring, wherein R or R 2 is optionally containing one or more additional heteroatoms selected from O, S or N, wherein the N or C ring Ra, -CO-Ra, -CO-NH-Ra or CO-O-Ra, wherein Ra is substituted by a linear or branched C _1-6 alkyl or aryl group, and 5, 6 or The 7-membered ring is fused to an optionally substituted benzene ring, or the ring atoms of a 5, 6 or 7-membered ring are optionally bonded to Y by a single bond or a methylene bond;

(c) X is O or S atom,

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,

R 2 is a linear or branched C _1-6 alkyl group;

(d) X is an N atom,

Y is a C _2-4 alkylene group,

R 1 is a C _2-4 alkylene group bonded to X to form a five or six membered ring,

R 2 is a linear or branched C _1-6 alkyl group.

Alkyl groups, including alkyl groups that are part of alkoxy, acyl groups, and the like, typically contain 1 to 6 carbon atoms and may be linear or branched, such as methyl, ethyl, i-propyl and t-butyl, optionally in hydroxyl It may be substituted by. The aryl group is typically a phenyl group, but may include a bicyclic group such as naphthyl. Cycloalkyl groups typically contain 3 to 7 carbon atoms. Heterocyclic groups are heterocyclic fused to monocyclic 5 to 7 membered rings containing up to 3 heteroatoms such as pyridyl or imidazole, bicyclic rings, especially benzene rings such as benzoxazole or benzimidazole It may be a ring. The aryl, cycloalkyl and heterocyclic groups can be optionally substituted by up to 3 substituents that can be suitably selected from aryl, alkyl, alkoxy, halogen, hydroxy and cyano, or bonded substituents such as dioxymethylene have.

Aromatic rings suitable 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 _1-4 alkoxy. R 4 may have 2 or 3 substituents, but preferably has only one substituent in addition to Z, more preferably Z is separate and unsubstituted. Particularly suitable substituents for R 4 include chloro, fluoro, trifluoromethyl, methyl, methoxy.

R5 is monocyclic, for example thienyl, furanyl, imidazolyl, oxdiazolyl, phenyl, pyridinyl, cyclohexyl, piperidinyl, piperazinyl, pyrazinyl, pyrimidinyl; Or fused bicyclic ring systems such as naphthyl, 3,4-dioxymethylene-phenyl, benzofuranyl, indolyl, or monocyclic rings have cyclic substituents such as oxadiazolyl, benzyloxy It may be a bicyclic system. Suitable substituents for R 5 are halogen, CF ₃ , CF ₃ O, CHF ₂ O, CN, amino, mono- or di-C _1-6 alkylamino, C _1-6 alkyl, C _1-6 alkoxy, C _{1 -6} acyl, C _1-6 alkyl-S-, C _1-6 alkyl-SO _2- , C _1-6 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 in particular in the para position for Z. In particular, suitable substituents for R 5 are chloro, fluoro, trifluoromethyl, cyano, amino, methyl, ethyl, t-butyl, methoxy, acetyl, formyl, methylthio, methanesulfonyl, vinyl, benzyl, Benzyloxy and hydrogen.

For ring substituent A, all A substituents can be hydrogen, but advantageously less than 3 are hydrogen. Suitable A substituents include C _1-6 alkyl, C _1-6 alkoxy, C _1-6 acyl and C _1-6 alkenyl optionally substituted with halogen, hydroxy. Particularly suitable A substituents include C 1-2 alkoxy, C 1-2 alkyl, C 1-2 acyl. Preferred substituents for A include chloro, fluoro, methyl, ethyl, hydroxyethyl, methoxy, formyl, acetyl, vinyl and allyl. More preferably, the substituents on A include methoxy. Suitably, the A substituent is close to the group Q.

In system Q, in form (a), particularly suitable substituents for R1 and R2 include methyl, ethyl, isopropyl, benzyl, phenethyl. Y may in particular be-(CH ₂ ) ₂ -,-(CH ₂ ) ₃ -,-(CH ₂ ) _4- , -CH ₂ -CH (CH ₃ ) -CH _2- . When Y is substituted by hydroxy, it may be, for example, -CH ₂ -CH (OH) -CH _2- .

In form (b) of system Q, the ring formed by combining R1 and R2 may be pyrrolidinyl, piperidinyl, azepanyl or imidazolyl. Fused rings include indolinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl and benzoazinyl. When the second heteroatom is present, suitable rings include thiazinyl, oxazinyl and piperazinyl. The second N atom may be substituted, for example, by phenyl, methyl, ethyl, isopropyl or acetyl. Y is typically-(CH ₂ ) _2- . The ring may again be bonded to Y to form a quinuclidinyl group.

In form (c) of system Q, the ring formed by bonding R 1 to Y may be a pyrrolidinyl or piperidinyl ring. Bonding to Y may result in a bonded ring, for example, directly from a ring carbon atom to X, or by a single bond via a methylene or ethylene bond group. R 2 is typically methyl so that the N atom of the ring is substituted by methyl.

In form (d) of ring Q, the ring formed by linking R 1 to N is suitably a 5 or 6 membered ring such as diazinyl or piperazinyl. Y is typically-(CH ₂ ) _2- . R 2 is typically methyl so that the second N atom of the ring (other than X) is substituted by methyl.

The general class of compounds of formula (II) is within the scope of formula (I):

Where

A = H and OMe, R 3 = H, X = O, Y = CH ₂ CH ₂ , Z = bond, R 4 = Ph, R 5 is meta or para substituted in R 4, and R 1, R 2 and R 5 are represented by the formula (I) As defined in.

In addition, the general class of compounds of formula (III) is within the scope of formula (I):

Where

A = H and OMe, R 3 = H, X = O, Y = CH ₂ -CH ₂ , Z = O, CH ₂ or NH, meta or para substituted in R 4, R 4 = Ph, R 5 is Ph, R 1 And R 2 is as defined for Formula (I).

In addition, the general class of compounds of formula (IV) is within the scope of formula (I):

Where

A = H and OMe, R 1 = R 2 = i Pr, R 3 = H, X = O, Y = CH ₂ -CH ₂ , and R 4 and R 5 are substituted phenyl or heterocycle as defined in formula (I) .

In addition, the general class of compounds of formula (V) is within the scope of formula (I):

Where

R3 = H, X = O, Y = CH ₂ -CH ₂ , Z = O, CH ₂ , NH or a bond, R4 = Ph, R5 is Ph or cyclohexyl (Cy), Z is meta or para substituted in R4 And A (R6, R7) and R1, R2 are as defined in formula (I).

In addition, the general class of compounds of formula (VI) is within the scope of formula (I):

Where

X = O, Y = CH ₂ -CH ₂ , R 4 = phenyl, R 5 = phenyl or cyclohexyl (Cy), Z = O, CH ₂ or a bond, A (R 8, R 9), R 3 and R 1, R 2 are represented by the formula ( As defined in I).

In addition, the general class of compounds of formula (VII) is within the scope of formula (I):

Where

A = H and OMe, X = O, R3 = H, R4 = 3-pyridyl (for carbonyl groups), R5 = phenyl, Z = para bonds, and R1, R2 are as defined in formula (I).

In addition, the general class of compounds of formula (VII) is within the scope of formula (I):

Where

A = H and OMe, R 3 = H, X = N, R 4 = phenyl, Z = O, CH ₂ or a bond, R 5 = Ph or cyclohexyl (Cy), Y is 3 or optionally substituted by a hydroxyl group A chain of 4 carbon atoms, R 1 and R 2 are as defined in formula (I).

In addition, the general class of compounds of formula (VII) is within the scope of formula (I):

Where

A = H and OMe, R 3 = H, X = O, R 4 = phenyl, Z = para substituted bonds, R 5 = Ph or cyclohexyl (Cy), Y and R 2 form a piperazinyl ring between X and N And R 1 is as defined in formula (I).

Preferred subclasses of the compounds used in the treatment methods of the invention are compounds of formula (I) wherein R 3 is methyl.

A novel group of compounds wherein R 3 is methyl or ethyl is included in formula (I). The novel compounds, or salts or solvent compounds thereof, are a further aspect of the present invention.

A particular group of novel compounds is the compound class of formula (VI):

Where

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

Suitably, R 5 is phenyl or cyclohexyl optionally substituted with halogen, haloalkyl, alkyl or alkoxy; Z is O, CH ₂ or a single bond; R8 and R9 are independently selected from hydrogen, halogen, alkyl and alkoxy; R 1 and R are alkyl or are joined together to form a ring; R 3 is ethyl or methyl.

Another aspect of the invention is a class of novel compounds, or salts or solvent compounds thereof, which are compounds of formula (I) except for the following compounds:

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

N- [4- [2- [bis (1-methylethyl) amino] ethoxy] phenyl]-[1,1'-biphenyl] -4-carboxamide,

Biphenyl-4-carboxylic acid [4- (2-diisopropylamino-ethoxy) -phenyl] -amide,

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

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

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

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

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

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

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

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

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

4'-Ethyl-biphenyl-4-carboxylic acid [4- (2-diethylamino-ethoxy) -phenyl] -amide.

A further aspect of the invention is the novel compounds of the inventive examples.

The compounds of formulas (I) to (iii), their salts or solvates are preferably in pharmaceutically acceptable or substantially pure form. A pharmaceutically acceptable form means a pharmaceutically acceptable level of purity, excluding common pharmaceutical additives such as diluents and carriers, and does not include any substances that are toxic at the usual dosage level.

Suitable salts and solvent compounds include pharmaceutically acceptable salts and pharmaceutically acceptable solvent compounds.

Suitable pharmaceutically acceptable salts are 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 triethyl Amines, salts with hydroxy alkylamines such as 2-hydroxyethylamine, bis- (2-hydroxyethyl) -amine or tri- (2-hydroxyethyl) -amine, cycloalkylamine such as bicyclohexyl Amines, or salts with procaine, dibenzylpiperidine, N-benzyl-β-phenethylethylamine, dehydroabiethylamine, N, N'-bisdehydroabiethylamine, glucamine, N-methyl Bases of the glucamine or pyridine type, such as pyridine, collidine, quinine or quinoline.

Suitable pharmaceutically acceptable salts also include addition salts with pharmaceutically acceptable acids such as salts provided by pharmaceutically acceptable inorganic or organic acids.

Addition salts with suitable pharmaceutically acceptable acids provided by pharmaceutically acceptable inorganic acids include sulfates, nitrates, phosphates, borate salts, hydrochlorides and hydrobromide and hydrogen iodide salts.

Addition salts with suitable pharmaceutically acceptable acids provided by pharmaceutically acceptable organic acids include acetates, tartates, maleates, fumarates, malonates, citrate, succinates, lactates, oxalates, benzoates, asads Corbate, methanesulfonate, α-ketoglutarate and α-glycerophosphate.

Suitable pharmaceutically acceptable solvent compounds include hydrates.

The substantially pure form is generally 50% (except for general pharmaceutical additives), preferably 75%, more preferably 90%, even more preferably at least 95% of the compounds of formulas (I) to (iii), or Will contain salts or solvent compounds thereof.

One preferred pharmaceutically acceptable form is a crystalline form, which is included in the form of a pharmaceutical composition. For salt and solvent compounds, additional ionic and solvent moieties should also be nontoxic.

Examples of pharmaceutically acceptable salts of the compounds of formulas (I) to (iii) include conventional pharmaceutical acids such as maleic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, acetic acid, fumaric acid, salicylic acid, citric acid, lactic acid, mandelic acid. Acid addition salts such as tartaric acid, succinic acid, benzoic acid, ascorbic acid and methanesulfonic acid.

The compounds of formulas (I) to (iii) may exist in one or more stereoisomeric forms, and the present invention extends to all such forms and mixed forms thereof, including racemates.

Compounds of formulas (I) to (iii), or salts or solvents thereof, are prepared by the methods described in the following general reaction methods or modifications thereof using readily available starting materials, reagents, and conventional synthetic processes. Can be. When specific enantiomers of the compounds of the invention are desired, they are synthesized by carrying out a reaction which does not comprise a racemization reaction starting from the desired enantiomer of the starting material, or prepared by derivatization with chiral synthesis or chiral auxiliaries. The resulting diastereomeric mixture may be separated or the adjuvant groups may be cleaved to give the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group such as amino, or an acidic functional group such as carboxy, the diastereomeric salt is formed of a suitable photoactive acid or base and the fractional crystallization decomposes the diastereomeric salt to Pure enantiomers are recovered.

Compounds of formulas (I) to (iii) are suitably substituted aryl or heteroarylcarboxylic acids with suitably substituted anilines synthesized or commercially available by methods known in the art from commercially available starting materials. It can be prepared by condensation by a method known in the art. For example, suitably substituted aryl or heteroarylcarboxylic acids are treated with an activating agent such as thionyl chloride at a suitable temperature, for example under reflux, to provide aryl or heteroarylcarbonyl chloride, and aryl- or hetero Arylcarbonyl chloride is condensed with aniline suitably substituted in a suitable solvent such as dichloromethane in the presence of a suitable base such as diisopropylethylamine to provide the compound of formula (I).

In particular, the preparation of certain carboxamides of formula (I) in which R 3 is H is described in the aforementioned WO 99/01127 and WO 99/06146, and similar preparation methods have been used in the present invention. Many additional methods of converting carboxylic acids to amides are known and are described in standard reference books such as "Compendium of Organic Synthetic Methods", Vol. Published I-VI (published by Wiley-Interscience).

For example, a compound of formula (I) may be prepared by reacting a compound of formula (VII) with a compound of formula (XI):

R5-Z-R4-COL (Ⅹ)

Where

A, Z, R3, R4, R5 and Q are as defined for Formula (I).

In this process, groups convertible to R1, R2, R3, R4 and R5 may be present during bonding, and are converted to R1, R2, R3, R4 and R5 after bonding. Also, after bonding, the transition from one R1, R2, R3, R4 and R5 to another R1, R2, R3, R4 and R5 may be easy. In particular, ring formation of suitable additional cyclic periods containing groups R 1, X, Y, R 2, or R 1, X, Y, R 2 may be carried out after bonding.

As such, a method of preparing a compound of formula (I), or a salt or a solvent thereof, wherein R 3 is methyl or ethyl, wherein the compound of formula (VIII) is as defined above, R 3 provides a process comprising reacting with a compound of formula (XI) which is methyl or ethyl.

Thus, except for the following compounds, a method of preparing a compound of formula (I), or a salt or a solvent compound thereof, wherein the compound of formula (VIII) as defined above is a compound of formula (XI) as defined above There is also provided a method comprising reacting with:

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

N- [4- [2- [bis (1-methylethyl) amino] ethoxy] phenyl]-[1,1'-biphenyl] -4-carboxamide,

Biphenyl-4-carboxylic acid [4- (2-diisopropylamino-ethoxy) -phenyl] -amide,

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

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

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

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

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

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

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

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

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

4'-Ethyl-biphenyl-4-carboxylic acid [4- (2-diethylamino-ethoxy) -phenyl] -amide.

Compounds of formula (XI) may be used in various ways, for example, when X is O or S, as illustrated below, incorporating a suitably substituted nitrobenzene compound with a dialkylaminoalcohol or thiol and the NO ₂ group It can be prepared by conversion to NH ₂ by hydrogenation in the presence of a catalyst (or to iron / ammonium chloride) and combined with an acid chloride:

Acid chlorides of formula (iii) are either commercially available or can be prepared from the corresponding acids described in the literature, or can be prepared by methods analogous to those described in the literature.

Alternatively, the acid of formula (VII) can be prepared by bonding the moieties containing R 5 and R 4, respectively, through Z.

This can also be easily accomplished by first combining a compound of R4-CO-L with a compound of formula (XI) and reacting compound R5-ZL (or L-R4-CO-L with R5-Z). . For example, the amine of formula (XI) can be reacted with a suitably substituted bromobenzoyl chloride and then, for example, with a suitably substituted phenyl moiety having a leaving group, or a cyclic amine have:

Similar reactions to form the structure of formula (I) can be carried out starting with the compound of formula (VII) and adding an equivalent amount of the compound of formula (XI) separately, wherein the N-protecting group of Q phase in , Piperazine ring) can be removed after component combination of formula (I) and replacement by the desired substituents:

In an alternative method of preparing a compound of formula (XI) prior to bonding, in order to introduce a hydroxy group into Y, a suitably substituted nitrophenol is linked to the epoxy compound, as illustrated below, and then OY (OH)- Reacted with an amine to form group Q, which is NR 1 R 2:

The novel compounds of formula (I) in which the amide nitrogen is alkylated (R3 is methyl or ethyl) are hydrochloric acid of formula (VIII) after alkylating the anilide of formula (XI), for example by the following reduction amination process It can be prepared by combining with:

Compounds of formula (I) can be converted into pharmaceutically acceptable salts by reaction with a suitable organic or inorganic acid.

Solvents of the compounds of formula (I) The compounds may be formed by crystallization or recrystallization from a suitable solvent. For example, hydrates can be formed by crystallization or recrystallization from solutions or aqueous solutions in organic solvents containing water.

In addition, salts or solvent compounds of the compounds of formula (I) which are not pharmaceutically acceptable may be useful as intermediates in the production of pharmaceutically acceptable salts or solvent compounds. Thus, such salts or solvent compounds also form part of the present invention.

The abovementioned compounds and their pharmaceutically acceptable salts, in particular hydrochlorides, and pharmaceutically acceptable solvates, in particular hydrates, form preferred embodiments of the invention.

By the activity of these compounds as antagonists of the human 11CBy receptor, the compounds of formula (I) are believed to play a role in preventing, ameliorating or correcting the dysfunction of diseases including, but not limited to, the above mentioned "diseases". .

In addition, it is believed that the treatment of certain of the aforementioned diseases by antagonists against human 11 CBy receptors is novel. Thus, the present invention also provides a method of treating diabetes, major depression, mood swings, anxiety, schizophrenia and sleep disorders in humans or mammals other than humans, comprising administering a therapeutically effective amount of an antagonist to the human 11CBy receptor Provide a method. In particular, the present invention provides a method of treating diabetes in humans or mammals other than humans, comprising administering a antagonist to a therapeutically effective amount of the human 11CBy receptor. In particular, the present invention provides a method of treating major depression in humans or mammals other than humans, including administering a therapeutically effective amount of an antagonist to the human 11CBy receptor. In particular, the present invention provides a method of treating manic depression in humans or mammals other than humans, including administering a therapeutically effective amount of an antagonist to the human 11CBy receptor. In particular, the present invention provides methods of treating anxiety in humans or mammals other than humans, including administering a antagonist to a therapeutically effective amount of the human 11CBy receptor. In particular, the present invention provides a method of treating schizophrenia in humans or mammals other than humans, comprising administering a antagonist to a therapeutically effective amount of the human 11CBy receptor. In particular, the present invention provides methods of treating sleep disorders in humans or mammals other than humans, comprising administering a antagonist to a therapeutically effective amount of the human 11CBy receptor.

Administration of such compounds to mammals is by oral (including sublingual), parenteral, nasal, rectal or dermal administration.

The amount effective to treat a disease described above depends on general factors such as the nature and severity of the disease to be treated and the weight of the mammal. However, unit doses generally range from 1 to 1000 mg, suitably 1 to 500 mg, for example 2 to 400 mg, such as 2, 5, 10, 20, 30, 40, 50, 100, 200, 300 and 400 mg. Will contain the active compound. The unit dose is administered at least once a day, for example 1, 2, 3, 4, 5 or 6 times a day, more generally 1 to 4 times a day, and the total daily dose is generally 70 kg body weight 1 to 1000 mg, for example 1 to 500 mg, and about 0.01 to 15 mg / kg / day, more typically 0.1 to 6 mg / kg / day, for example 1 to 6 mg / kg / day, for adults. .

It is highly preferred that the compound of formula (I) is administered in the form of unit dose compositions, such as unit doses of oral (including sublingual), nasal, rectal, topical or parenteral (particularly intravenous) compositions.

Such compositions are prepared by mixing and adapted for oral or parenteral administration, they are tablets, capsules, oral liquid preparations, powders, granules, lazenges, reconstitutable powders, injectable and injectable solutions or suspensions or suppositories It may be in the form of. Orally administrable compositions, in particular, oral compositions in form, are preferred because they are more convenient for general use.

Tablets and capsules for oral administration are generally present in unit doses and contain conventional excipients such as binders, fillers, diluents, tableting agents, lubricants, disintegrants, colorants, flavoring agents and wetting agents. Tablets may be coated according to methods well known in the art.

Suitable fillers for use 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 wetting agents include sodium lauryl sulfate.

Such solid oral compositions can be prepared by conventional methods such as compounding, filling, tableting and the like. Repeated blending operations can be used to distribute active agents throughout such compositions using large amounts of fillers. Such work is of course common in the art.

Oral liquid preparations may be, for example, in the form of an aqueous or oily suspension, solution, emulsion, syrup or elix, or may be present as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations include conventional additives such as suspension preparations such as sorbitol, syrup, methyl cellulose, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel or hydrogenated edible fats; Emulsifying agents such as lecithin, sorbitan, monooleate or acacia; Non-aqueous vehicles (which may include edible oils) such as, for example, arment oil, fractionated coconut oil, oily esters such as esters of glycerin, propylene glycol or ethyl alcohol; Preservatives such as methyl or propyl p-hydroxybenzoate or sorbic acid; And conventional flavoring or coloring agents as necessary.

Oral formulations also include conventional, consistent release formulations such as tablets or granules with enteric coatings.

For parenteral administration, fluid unit dose formations containing compounds and sterile vehicles are prepared. Depending on the vehicle and concentration, the compound may be suspended or dissolved. Parenteral solutions can generally be prepared by dissolving the compound in the vehicle, filtering and sterilizing, then placing in a suitable glass bottle or ampoule and sealing. Advantageously, adjuvants such as local anesthetics, preservatives and buffers are also dissolved in the vehicle. To enhance stability, the composition can be frozen before being bottled and the water removed under vacuum.

Parenteral suspensions are prepared in substantially the same manner as above except that the compounds are suspended instead of dissolved in the vehicle and sterilized by exposure to ethylene oxide prior to suspension in the sterile vehicle. Advantageously, surfactants or humectants are included in the composition to facilitate uniform distribution of the compounds of the present invention.

In general practice, the composition will generally be attached to instructions for use in the associated medical treatment.

The compounds of the present invention can be used alone or in combination with other compounds such as therapeutic compounds.

When administered according to the present invention, no toxin side effects on the compounds of the present invention are expected.

As such, in a further aspect, the present invention includes a compound of the present invention, or a pharmaceutically acceptable salt or solvent compound thereof, and a pharmaceutically acceptable carrier for use in the treatment and / or prevention of one or more diseases. It provides a pharmaceutical composition.

The invention also provides for the treatment and / or treatment of one or more diseases, comprising administering to a patient in need thereof an effective or prophylactic amount of a compound of the invention, or a pharmaceutically acceptable salt thereof or a solvent compound thereof. Or provide a method of prevention.

In a further aspect, the invention provides a compound of the invention, or a pharmaceutically acceptable salt or solvent compound thereof, for the manufacture of a medicament for the treatment and / or prevention of one or more diseases.

In a further aspect, the present invention provides the use of the novel compounds of the present invention, or pharmaceutically acceptable salts or solvent compounds thereof, in particular as therapeutic agents for the treatment and / or prophylaxis of one or more diseases.

Compounds for use in the present invention and their preparation are described in the Examples and Tables below.

This example describes the process for preparing the compound and the source of the chemicals used, and the structure of the compound is shown in the data table following the example. In the case of embodiments prepared as elements of a linked arrangement, all starting components of the arrangement are shown in the implementation. Rather than detailing the experimental process for each case, the table shows the way in which the individual elements of the arrangement are made, with reference to the relevant examples. Mass spectral characteristics of all examples are provided in the data table. Additional features were provided for selected representative examples with complete experimental processes.

Example A1 [WO-00 / 06146]

The process of Example A7 was used using 4-biphenylcarboxylic acid [Aldrich] instead of 2'-methyl-4-biphenylcarboxylic acid.

Example A2

4- (5-Methyl- [1,2,4] oxadiazol-3-yl) -benzoic acid was carried out corresponding to Example A7 [J. Org. Chem. 50; 8; 1985; 1182.

Example A3

4-pyrazol-1-yl-benzoic acid was performed correspondingly to Example A7 [Can. J. Chem .; 41; 1963; 1540.

Example A4

3-biphenylcarboxylic acid was performed correspondingly to Example A7 [Med. Chem. Res .; 6; 2; 1996].

Example A5

4- (2-pyridyl) benzoic acid was carried out corresponding to Example A7 [J. Chem. Soc .; 1940; 355,356.

Example A6

3'-acetyl-biphenyl-4-carboxylic acid was carried out correspondingly to Example A7 (Patent WO -9743262).

Example A7

2-Methylphenyl-4-phenylcarboxylic acid [3-methoxy-4- (2-bis- (2-methylethyl) amino) -ethoxy) -phenyl amide

(1- (3-dimethylaminopropyl) -3-ethyl carbodiimide hydrochloride [al] in a solution of acid (2'-methyl-biphenyl-4-carboxylic acid) [Patent WO-9901127] in dimethylformamide. Driric] (50 mg, 0.26 mmol) and 1-hydroxy-7-azabenzotriazole [Aldrich] (35 mg, 0.26 mmol), followed by diisopropylethylamine (0.04 ml, 0.25 mmol) and Aniline (4- (2-Diisopropylamino-ethoxy) -3-methoxy-phenylamine) (69mg, 0.22mmol) [1- (2-hydroxyethyl)-2-diisopropyl instead of pyrrolidine Prepared using the method used to form 3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) -phenylamine of Example A51 using amino-ethanol]. The reaction mixture was stirred for 16 h at rt The solvent was evaporated and the residue was redissolved in dichloromethane (10 ml) and filtered through a SAX [Varian] column (2 g), then the filtrate was PS -Isocyanate resin [ Stirred with Legonut Technologies: Argonaut Technologies] (100 mg, 0.38 mmol) for 16 h The mixture was filtered, evaporated and the residue was chromatographed on silica gel using dichloromethane-aqueous ammonia-methanol as eluent. Purification by gave the title compound as an oil.

Example A8

The process of Example A7 was carried out using cyclohexyl-4-benzoic acid [Aldrich] instead of (2'-methyl-biphenyl-4-carboxylic acid).

Example A9

4- (2-thienyl) -benzoic acid [J. Chem. Soc. Perkin Trans. 1; 17; 1992; 2203, corresponding to Example A7 .

Example A10

4- (1-Methyl-1H-pyrazol-4-yl) -benzoic acid [Patent: WO-9906409] was carried out corresponding to Example A7 .

Example A11

4 '-(5-methyl- [1,2,4] oxadiazol-3-yl) -biphenyl-4-carboxylic acid [Patent: WO-9743262] was performed correspondingly to Example A7 .

Example A12

4-benzyl-carboxylic acid [affin; Apin] was performed corresponding to Example A7 .

Example A13

3'-cyano-biphenyl-3-carboxylic acid [J. Chem. Soc. Perkin Trans. 2; 1; 1984; 35-38, corresponding to Example A7 .

Example A14

3'-methanesulfonyl-biphenyl-4-carboxylic acid [Izv.Sib.Otd.Akad.Nauk SSSR Ser.Khim.Nauk; 11; 1996; 62, corresponding to Example A7 .

Example A15

3-thiophen-2-yl-benzoic acid [Tetrahedron Lett; 39; 24; 1998; 4175, corresponding to Example A7 .

Example A16

3-thiophen-3-yl-benzoic acid [J.chem.Soc.B; 1970; 1595, corresponding to Example A7 .

Example A17

4-acetyl-4-biphenylcarboxylic acid [Aldrich] was carried out corresponding to Example A7 .

Example A18

4'-Cyano-3'-methylbiphenyl-4-carboxylic acid [WO-9850358] was carried out corresponding to Example A7 .

Example A19

4 '-(5-Methyl- [1,3,4] oxadiazol-2-yl) -biphenyl-4-carboxylic acid [Patent: WO-9743262] was performed correspondingly to Example A7 .

Example A20

4-thiophen-3-yl-benzoic acid [J. Chem. Soc. B; 1970; 1595, to correspond to Example A7 .

Example A21

It was carried out corresponding to Example A7 with 4-pyrazin-2-yl-benzoic acid [Patent WO-9854164].

Example A22

4-methylphenyl boric acid instead of 2-methoxy-phenyl-boric acid in Example A93, and 1- (2-hydroxyethyl) with [Adriano Hi] -pyrrolidine instead of 2- (diisopropylamino) performed with ethanol The process of Example A51 was carried out.

Example A23

The process of Example A22 was carried out using 4-trifluoromethylphenylboric acid [Aldrich] instead of 2-methoxyphenylboric acid [Aldrich].

Example A24

3-aminophenylboric acid [Aldrich] was carried out corresponding to Example A23 .

Example A25

4-Benzyloxyphenylboric acid [Lancaster] was carried out corresponding to Example A23 .

Example A26

2-naphthylboric acid [lancaster] was carried out corresponding to Example A23 .

Example A27

3-naphthylboric acid [lancaster] was performed corresponding to Example A23 .

Example A28

4-methylphenylboric acid [lancaster] was carried out corresponding to Example A23 .

Example A29

4-Methylthiophenylboric acid [lancaster] was carried out corresponding to Example A23 .

Example A30

3-trifluoromethylphenylboric acid [lancaster] was carried out corresponding to Example A23 .

Example A31

It was carried out corresponding to Example A23 with 4-carbonylphenylboric acid [Aldrich].

Example A32

3,4- (methylenedioxy) phenylboric acid [Aldrich] was carried out in the same manner as in Example A23 .

Example A33

4-vinylphenylboric acid [Aldrich] was carried out corresponding to Example A23 .

Example A34

3-methoxyphenylboric acid [lancaster] was carried out corresponding to Example A23 .

Example A35

The process of Example A51 was carried out with 1- (2-hydroxyethyl) morpholine [Aldrich] instead of 1- (2-hydroxyethyl) pyrrolidine.

Example A36

The process of Example A35 was carried out with 4-cyclohexylbenzoic acid [Aldrich] instead of 4-biphenylcarboxylic acid.

Example A37

The process of Example A51 was carried out with 2-dimethylaminoethanol [Aldrich] instead of 1- (2-hydroxyethyl) pyrrolidine.

Example A39

(R)-(+)-1-Methyl-2-pyrrolidinemethanol (patent WO-9932480) was carried out corresponding to Example A51 .

Example A41

3-hydroxy-1-methylpiperidine [Aldrich] was carried out corresponding to Example A51 .

Example A43

2-dimethylamino-1-propanol [ICN-RF] was carried out corresponding to Example A51 .

Example A45

2- (diethylamino) -ethanol [Aldrich] was carried out corresponding to Example A51 .

Example A47

(S)-(-)-1-Methyl-2-pyrrolidinemethanol [Aldrich] was carried out corresponding to Example A51 .

Example A49

N-benzyl-N-methylethanolamine [Aldrich] was carried out corresponding to Example A51 .

Example A51

Biphenyl-4-carboxylic acid [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) -phenyl amide

Sodium hydroxide [60% dispersion in oil] (544 mg,) in a solution of hydroxy amine in dimethylformamide, i.e. (1- (2-hydroxyethyl) -pyrrolidine) [Aldrich] (1.87 ml, 16 mmol) 16 mmol) were added in equal portions. After stirring for 10 minutes at room temperature, one drop of a solution of halonitrobenzene in dimethylformamide (10 ml), i.e. (1-chloro-2-methoxy-4-nitro-benzene) [avocado] (3 g, 16 mmol) Added freshly. The reaction mixture was stirred at rt for 16 h and then concentrated. The residue was dissolved in ethyl acetate (200 ml) and washed with water (3 × 50 ml). The organic phase is dried over magnesium sulfate, evaporated and the residue is purified by flash chromatography on silica gel using dichloromethane-aqueous ammonia-methanol as eluent to give 1- [2- (2-methoxy-4) as a brown oil. -Nitro-phenoxy) -ethyl] -pyrrolidine was provided.

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

A carboxylic acid suspended in dichloromethane (1 ml), i.e. (4-biphenyl carboxylic acid) [Aldrich] (47.5 mg, 0.24 mmol), was converted to oxalyl chloride [Aldrich] (0.06 ml, 0.72 mmol). After addition, one drop of dimethylformamide was added. The reaction mixture was stirred for 1 h at rt, then concentrated and co-evaporated three times with dichloromethane to give 4-phenylbenzoyl chloride. It is dissolved in dichloromethane (1 ml), amine, i.e. (3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenylamine) (47 mg, 0.2 mmol), triethylamine (0.14 ml, 1 mmol) and dichloromethane (1 ml) were added to the solution. The reaction mixture was stirred at rt for 16 h, concentrated, redissolved in dichloromethane (10 ml), filtered through a SAX column [Varian] (2 g), and PS-isocyanate resin [Argonut Technologies] for 16 h (100 mg, 0.38 mmol) was stirred. The mixture was filtered, evaporated and purified by flash chromatography on silica gel using dichloromethane-aqueous ammonia-methanol as eluent to provide the title compound as an oil.

Example A54

The process of Example A51 was carried out with 1-dimethylamino-2-propanol [Aldrich] instead of 1- (2-hydroxyethyl) -pyrrolidine.

Example A56

1- (2-hydroxyethyl) -piperidine [Aldrich] was carried out corresponding to Example A51 .

Example A58

2- (hexamethyleneamino) -ethanol [lancaster] was carried out corresponding to Example A51 .

Example A60

The process of Example A93 was carried out with 3-aminophenylboric acid instead of 2-methoxyphenylboric acid and the process of Example 51 with 2-dimethylaminoethanol instead of 1- (2-hydroxyethyl) pyrrolidine.

Example A63

The process of Example A60 was carried out with 4-carboxyphenylboric acid [Aldrich] instead of 3-aminophenylboric acid.

Example A70

(3,4-methylenedioxyphenyl) boric acid [Aldrich] was carried out in the same manner as in Example A63 .

Example A72

N- (2-phenyl) -ethyl-N-methyl-ethanolamine instead of 1- (2-hydroxyethyl) -pyrrolidine [J. Org. Chem. 1985, 50 (22), 4359, the process of Example 51 was carried out.

Example A74

2-dimethylaminocyclohexanol [J. Chem. Soc. C (1969), (2), 248-52] was carried out corresponding to Example 51 .

Example A76

Corresponding to Example 51 with 2- (1,2,4,5-tetrahydro-benzo [d] azin-3-yl) -ethanol [Patent US-394682].

Example A78

This was carried out corresponding to Example 51 with 2- (3,4-dihydro-1H-isoquinolin-2-yl) -ethanol [patent WO-9719926].

Example A80

2- (4-phenyl-piperazin-1-yl) -ethanol [J. Med. Chem. 1994, 37 (13), 1964, corresponding to Example 51 .

Example A82

1-methyl-3-pyrrolidinol [Aldrich] was carried out corresponding to Example 51.

Example A84

In place of 2-methoxy-phenyl-boric acid 4-methoxy-phenyl-boric acid [Aldrich] in Example A93 and 1- (2-hydroxyethyl) pyrrolidine instead of Example A51 2-diethylamino-ethanol The process was carried out.

Example A88

The process of Example A84 was carried out with 4-methoxy-3-pyridineboric acid [Patent WO-992440] instead of 4-methoxy-phenylboric acid.

Example A89

It was carried out corresponding to Example A88 with 2-methoxy-3-pyridylboric acid [Patent WO-9910331].

Example A90

Benzo- [b] -furan-2-boric acid [Aldrich] was carried out corresponding to Example A88 .

Example A91

It was performed corresponding to Example A88 with thiophene-3-boric acid [Aldrich].

Example A92

Indol-5-boric acid [Aldrich] was carried out corresponding to Example A88 .

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 diluted with dichloromethane (20 ml Treated with 4-bromobenzoyl chloride [Aldrich] and maintained at room temperature for 16 hours. The solvent is evaporated and the crude product is purified by chromatography on silica gel using dichloromethane-methanol-aqueous ammonia to give 4-bromo-N- [3-methoxy-4 (as a white solid in 72% yield). 2-pyrrolidin-1-yl-ethoxy) -phenyl] -benzamide was provided.

Amides ie 4-bromo-N- [3-methoxy-4 (2-pyrrolidin-1-yl-ethoxy) -phenyl] -benzamide (0.1 mM, 42 mg) and 4-methyl-benzeneboric acid [Aldrich] (0.1 mM 14 mg) was added benzene (8 ml), ethanol (2 ml) and 2M aqueous sodium carbonate (2 ml) in the presence of tetrakis- (triphenylphosphine) -palladium [0] (5 mg) in an argon atmosphere. It was refluxed for 16 hours in a mixture of The mixture is cooled, the top layer is decanted off and the solution is purified by chromatography on silica gel with dichloromethane; methanol (10: 1) and then acetonitrile: saturated aqueous ammonia (25: 1) to give white The title compound was provided as a solid.

Example A100

Corresponding to Example A93 with 4- (2,6-dimethoxypyrimidinyl) -boric acid [frontier] instead of 4-methyl-benzene boric acid.

Example A103

It carried out correspondingly to Example A93 with furan-3-boric acid [frontier].

Example A104

Mesityl-boric acid [frontier] was carried out corresponding to Example A93 .

Example A105

The procedure of Example A51 was carried out except that chloroform was used instead of dichloromethane as a solvent and 3-quinuclidinol [Aldrich] was used instead of 1- (2-hydroxyethylpyrrolidine).

Example A107

The process of Example B37 was carried out using piperidine instead of aniline.

Example B1

The process of Example A7 was used with 3-phenoxybenzoic acid [Aldrich] instead of 2'-methyl-biphenyl-4-carboxylic acid.

Example B2

It carried out correspondingly to Example B1 using 4-benzylbenzoic acid [affin].

Example B34

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

Example B35

Corresponding to Example B1 using 4-phenoxybenzoic acid [Aldrich].

Example B37

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

Anhydrous cesium carbonate (0.15 mM, 49 mg), ( S ) -BINAP [Aldrich] (0.015 mM, 9 mg) and palladium acetate (0.0075 mM, 2 mg) were anhydrous ethylene glycol dimethyl ether (15 ml) for 40 minutes under argon atmosphere. Ultrasonic wave treatment). This suspension was collected from 4-brono-N- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) -phenyl] -benzamide [ Example A93 ] (0.1 mM, 42 mg) and Treatment with aniline (0.11 mM, 10 mg) was followed by reflux for 40 hours. The suspension was filtered through a hydrophobic membrane, concentrated and purified on C18 RP silica with acetonitrile: water to give the title compound as a white solid.

Example C1

The process of Example A7 was carried out with 2-methylbiphenyl-4-carboxylic acid [Patent WO-9606079] instead of 2'-methyl-biphenyl-4-carboxylic acid.

Example C2

It was carried out corresponding to Example C1 using 3-methoxybiphenyl-4-carboxylic acid [Patent WO-9534540].

Example C3

Corresponds to Example C1 using 3-methylbiphenyl-4-carboxylic acid [Patent WO-9534540].

Example C4

Corresponds to Example C1 using 4-phenylthiophene-2-carboxylic acid [Specs: Specs].

Example C5

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

Example C6

It was carried out corresponding to Example C1 using 5-methyl-1-phenylpyrazole-4-carboxylic acid [maveridge].

Example C7

It was carried out corresponding to Example C1 using 6-phenyl-nicotinic acid [WO-0006085].

Example C8

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

Example C9

Corresponding to Example C1 using 5- (4-chlorophenyl) -2-trifluoromethyl-furan-3-carboxylic acid [maveridge].

Example C10

Corresponding to Example C1 using 2- (4-chlorophenyl) -3- (trifluoromethyl) -pyrazole-4-carboxylic acid [maveridge].

Example C11

It was carried out corresponding to Example C1 using 5- (2-pyridyl) -thiophene-2-carboxylic acid [maveridge].

Example C12

Corresponding to Example C1 using 5- (methyl-trifluoromethyl-2- H -pyrazol-3-yl) -thiophene-2-carboxylic acid [maveridge].

Example D1

Corresponding to Example D5 using 3,4-dichloronitrobenzene [Aldrich] instead of 2,4-dichloronitrobenzene.

Example D5

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

In a three-necked flask (with condenser, dropping funnel and thermometer) containing iron powder (938 mg, 16.8 mmol) mixed with ammonium chloride solution (28 mmol) in water (28 ml), an amine, i.e. [2- (3-chloro- 4-nitro-phenoxy) -ethyl] -diisopropyl-amine [1- (2-hydroxyethyl) -pyrrolidine instead of 2-diisopropylaminoethanol, and 4-chloro-3-methoxynitrobenzene 1- [2- (2-methoxy-4-nitro-phenoxy) -ethyl] -pyrrolidine in Example A51 , except that 2,4-dichloronitrobenzene [Aldrich] is used instead. Prepared by the method used to form the solution] was added dropwise over 10 minutes. The reaction mixture was gently refluxed until tlc analysis showed no starting material. The mixture was hot filtered and the inorganic residue was washed with methanol. The combined filtrates were partitioned between water (5 ml) and ethyl acetate (3 × 10 ml) and the organic phase was dried (MgSO ₄ ), filtered and evaporated. The aqueous phase was treated with saturated aqueous sodium bicarbonate (10 ml), extracted with ethyl acetate (3 × 10 ml), dried (MgSO ₄ ) and evaporated. The residues from the two extracts were mixed and purified by flash chromatography on silica gel using dichloromethane-methanol-aqueous ammonia as eluent to afford 2-chloro-4- (2-diisopropylamino-ethoxy as brown oil. ) -Phenylamine was provided.

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

Example D9

The process of Example A51 was carried out with 2,4-difluoronitrobenzene [Aldrich] instead of 4-chloro-3-methoxynitrobenzene.

Example D12 [WO-00 / 06146]

The process of Example A51 was carried out with 3,4-difluoronitrobenzene [Aldrich] instead of 4-chloro-3-methoxynitrobenzene.

Example D16

The process of Example A51 was carried out with 2-methyl-fluoronitrobenzene [Aldrich] instead of 4-chloro-3-methoxynitrobenzene.

Example D20

The process of Example A51 was carried out with 3-methyl-4-fluoronitrobenzene [Aldrich] instead of 4-chloro-3-methoxynitrobenzene.

Example D24

The process of Example A51 was carried out with 3-acetyl-4-fluoronitrobenzene [Aldrich] instead of 4-chloro-3-methoxynitrobenzene.

Example D25

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

Glyoxylic acid trihydrate of biphenyl-4-carboxylic acid [4- (2-diisopropylamino-ethoxy) -3-methoxy-phenyl] -amide [Patent WO-9901127] (223 mg, 0.5 mmol) Treated with rate (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 × 20 ml). The combined organic phases were dried (MgSO ₄ ), filtered and evaporated and then subjected to flash chromatography on silica gel [chloroform-methanol-aqueous acetic acid] to give the title compound as an acetate salt of a white solid.

Example D26

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

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

Example D27

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

Biphenyl-4-carboxylic acid [3-acetyl-4- (2-diethylamino-ethoxy) -phenyl] -amide [ Example D24 ] (25 mg, 0.06 mmol) dissolved in dichloromethane (1.5 ml) To this was added triethylsilane (0.5 ml) and trifluoroacetic acid (0.25 ml). The resulting yellow solution was stirred for 120 hours at room temperature. The solvent was evaporated and the residue was purified by flash chromatography on silica gel using dichloromethane-aqueous ammonia-methanol as eluent to provide the title compound as a white solid.

MS (AP + ve): m / z 417 [M + H] ⁺

Example D28 [WO9901127]

The process of Example A51 with 2-diisopropylaminoethanol instead of 4-fluoronitrobenzene [Aldrich] and 1- (2-hydroxyethyl) -pyrrolidine instead of 4-chloro-3-methoxynitrobenzene Was performed.

Example D30 [WO9901127]

The process of Example D28 was carried out with 2-dimethylaminoethanol [Aldrich] instead of 2-diisopropylaminoethanol.

Example D32 [WO9901127]

The process of Example D28 was carried out with 2-diethylaminoethanol [Aldrich] instead of 2-diisopropylaminoethanol.

Example D38 [WO9901127]

The process of Example A22 was carried out with 4-fluoronitrobenzene [Aldrich] instead of 4-chloro-3-methoxynitrobenzene and 4-ethylphenylboric acid instead of 4-methoxyphenylboric acid.

Example D39 [WO9901127]

The process of Example A84 was carried out with 4-fluoronitrobenzene [Aldrich] instead of 4-chloro-3-methoxynitrobenzene and 4-ethylphenylboric acid instead of 4-methoxyphenylboric acid.

Example E1

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

To 4- (2-diisopropylamino-ethoxy) -3-methoxy-phenylamine (1 mmol) [ Example A7 ] triethylorthoformate (8 ml) and trifluoroacetic acid (0.15 ml) were added. . The resulting solution was heated at 90 ° C. for 4 hours. The solution was evaporated, redissolved in ethanol and cooled to about -10 ° C. Sodium borohydride (190 mg, 5 mmol) was introduced in equal portions over 10 minutes and the mixture was allowed to warm to room temperature. The solution was stirred at RT for 16 h and 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 with 2M aqueous sodium hydroxide solution, extracted with dichloromethane (x3), dried (MgSO ₄ ), filtered and evaporated. The residue was purified by flash chromatography on silica gel using dichloromethane-aqueous ammonia-methanol as eluent to give [4- (2-diisopropylamino-ethoxy) -3-methoxy-phenyl] -methyl as an oil. -Amine was provided.

Oxalyl chloride (0.6 mmol) was added to 4-phenylbenzoic acid (0.2 mmol) suspended in dichloromethane, followed by addition of dimethylformamide (1 drop). The reaction mixture was stirred for 1 h, evaporated, coevaporated with dichloromethane (x3) and redissolved in dichloromethane (1 ml). Amine dissolved in dichloromethane (1 ml), ie [4- (2-diisopropylamino-ethoxy) -3-methoxy-phenyl] -methyl-amine (0.2 mmol) and triethylamine (140 mg, 1 mmol) A solution containing was added. This solution was stirred for 14 hours at room temperature, evaporated, dissolved in dichloromethane (1 ml) and treated with PS-isocyanate resin [Argonnut Technologies] (150 mg). After shaking for an additional 18 hours at room temperature, the mixture is filtered, passed through a SAX column [Varian] (1 g), evaporated and the residue is chromatographed on silica gel with dichloromethane-aqueous ammonia-methanol as eluent. Purification by chromatography gave the title compound as an oil.

Example E5

The process of Example E1 was carried out with triethyl orthoacetate [Aldrich] instead of triethyl 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 ] (45 mg, 0.1 mmol) was added to chloroform (1 ml). It was dissolved and treated with benzotriazole [Aldrich] (12 mg, 0.1 mmol) and N-chlorosuccinimide (13 mg, 0.11 mmol). The mixture was stirred at rt for 16 h, then evaporated and flash chromatography on silica gel (dichloromethane-methanol-aqueous ammonia) gave the title compound as an oil.

Example E13

[4- (2-Diethylamino-ethoxy) -3-methoxy-phenyl] -methyl-amine instead of 4- (2-diethylamino-ethoxy) -3-methoxy-phenylamine [ Example E9 And the process of Example A93 with 2-fluoromethylphenylboric acid [Aldrich] instead of 4-methoxyphenylboric acid, and (N-diethyl) ethanol instead of 1- (2-hydroxyethyl) pyrrolidine. The process of Example 51 was carried out with amines.

Example E14

The process of Example E13 was carried out with 2-methylphenylboric acid [Aldrich] instead of 4-chlorophenylboric acid.

Example E16

2-chloromethylphenylboric acid [Aldrich] was carried out corresponding to Example E14 .

Example E17

4-fluoromethylphenylboric acid [Aldrich] was carried out corresponding to Example E14 .

Example E21

4-chloromethylphenylboric acid [Aldrich] was carried out corresponding to Example E14 .

Example E22

4-ethylphenylboric acid [Aldrich] was carried out corresponding to Example E14 .

Example E23

Corresponding to Example E14 with 4-tert-butylphenylboric acid [Aldrich].

Example E24

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

MS (AP + ve): m / z 451 [M + H] ⁺ .

Example E25

4- (2-Diisopropylamino-ethoxy) -3-methyl-phenylamine [ Example D20 ] and triethyl instead of 4- (2-diisopropylamino-ethoxy) -3-methoxy-phenylamine The process of Example E1 was carried out with triethyl orthoacetate instead of orthoformate.

Example F1

The process of Example A7 was carried out with N-dimethylethanolamine instead of 6-phenyl-nicotinic acid (patent WO-0006085) and 2- (diisopropylamino) ethanol instead of 2'-methyl-4-biphenylcarboxylic acid.

Example G1

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

4-nitro-2-methoxyphenol [Aldrich] (845 mg, 5 mmol) was dissolved in DMF (25 ml) and treated with sodium hydroxide (60% oil dispersion, 200 mg). When boiling stopped, the mixture was treated with ( R ) -p-nitrophenylsulfonyl glycidol [Aldrich] and warmed to 50 ° C. with stirring. After 16 h, the mixture was cooled, evaporated, partitioned between water (20 ml) and dichloromethane (3x25 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 light brown solid in 80% yield. .

( R ) -2- (2-methoxy-4-nitro-phenoxymethyl) -oxirane (0.5 mmol, 113 mg) in dichloromethane (3 ml) was added to amine (diethylamine) [Aldrich] (1.5 mmol). , 110 mg) and titanium tetraisopropoxide [Aldrich] (50 μl). The solution was stirred at rt for 24 h, treated with water (1 ml) and shaken vigorously for 10 min. The resulting suspension was passed through a hydromatrix cartridge [Varian ChemElut] (5 ml) eluted with dichloromethane (10 ml) to give ( R ) -diethylamino- (2-methoxy4-nitro-) as a yellow oil. Phenoxy) -propan-2-ol.

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

A solution of this material in dichloromethane (2 ml) was treated with triethylamine (2 mmol, 280 μl) 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 is evaporated, formed into a slurry with dichloromethane (20 ml), filtered, the filtrate is evaporated and the residue is purified by flash chromatography (dichloromethane-methanol-aqueous ammonia). To give the title compound as a white solid.

Example G5

Dichloromethane instead of 1,2-dichloroethane, and diethylamine instead of using diisopropylamine (R) - diethylamino - (2-methoxy-4-nitro-Fe-ethoxy) -propan-2-ol [Embodiment Example G1 ] was carried out. The mixture of amine and epoxide was also heated at 80 ° C. for 12 hours instead of keeping at room temperature for 24 hours.

Example G8

The process of Example G1 was carried out with (S) -p-nitrophenylsulfonyl-glycidol and pyrrolidine instead of diethylamine instead of (R) -p-nitrophenylsulfonyl-glycidol.

Example G22

The process of Example A51 was carried out with 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

Ditert-butyl dicarbonate (10 mmol, 2.18 g) with stirring the solution of 1- (2-methoxy-4-nitro-phenyl) -piperazine (Patent WO-9906382) (10 mmol, 2.37 g) in dichloromethane (50 ml) ). The gas was vigorously generated and stopped after 1 hour. The solution was then evaporated to give the yellow solid, 4- (2-methoxy-4-nitro-phenyl) -piperazine-1-carboxylic acid tert-butyl ester.

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

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

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 and then co-evaporated twice from toluene. The residue is dissolved in dichloromethane (10 ml), washed with saturated sodium bicarbonate (2 ml), the organic phase is dried (MgSO ₄ ), filtered and evaporated to 4-cyclohexyl-N- (3- Methoxy-4-piperazin-1-yl-phenyl) -benzamide was provided.

This amine (0.1 mmol, 39 mg) was dissolved in ethanol (3 ml) and treated with metaformaldehyde (100 mg), amberist cyanoborohydride resin [Novabiochem] (100 mg) and acetic acid (50 μl). The mixture was stirred at rt for 3 h, then filtered, evaporated and the residue was purified by flash chromatography on silica gel (dichloromethane-methanol-aqueous ammonia) to give the title compound as a light brown oil. It was evaporated from dilute acetic acid and provided monoacetate salt hydrate.

The following table is an illustration to illustrate the present invention and is not intended to limit the present invention.

Table A

A = H and OMe, R 3 = H, X = O, Y = CH ₂ CH ₂ , Z = a bond, R 4 = Ph, R 5 is part of formula (I), meta or para substituted in R 4 Compounds of

TABLE B

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, Z is R 4 A compound of formula (III) which is part of formula (I), meta or para substituted in:

Table C

A = H and OMe, R1 = R2 = Me ₂ , R3 = H, X = O, Y = CH ₂ CH ₂ , R4, R5 = substituted phenyl or heterocycle, as part of formula (I) IV) compound:

Table D

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 meta or para substituted at R 4 And a compound of formula (V) which is part of formula (I):

Table E

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 And some of the compounds of formula (VI):

TABLE F

A compound of formula (VII) which is part of formula (I), wherein A = H or OMe, X = O, R 4 = 3-pyridyl, R 5 = phenyl, Z = para bond

Table G

A = H and OMe, R 3 = H, X = O, R 4 = phenyl, Z = O, CH ₂ or a bond, R 5 = Ph or cyclohexyl (Cy), Y is 3 or optionally substituted by a hydroxyl group A compound of formula (VII) which is part of formula (I), which is a 4 carbon atom chain:

Table H

A = H and OMe, R 3 = H, X = N, R 4 = phenyl, Z = para substituted bonds, R 5 = Ph or cyclohexyl (Cy), Y and R 2 form a piperazinyl ring between X and N And a compound of formula (VII) which is part of formula (I):

The activity of the compounds used in the present invention was assessed by a competitive binding assay for 11CBy as follows:

Radioligand binding study

Radioligand binding assays were performed with well washed membranes from HEK293 cells stably expressing the 11CBy receptor. Membranes (5-15 mg protein) with [125I] -melanin enriched hormone (0.22 nM) (obtained from NEN) in buffer (pH7.4) containing 50 mM Tris and 0.2% BSA in the presence and absence of competing test compounds. Incubate at 37 ° C. for 45 minutes. Nonspecific binding was defined using 0.1 mM melanin enriched hormone (purchased from Bachem). Ten concentration steps add test compounds at concentrations of 10M to 10pM. After incubation, the reaction was stopped by filtration through a GF / B filter and washed with 4 × 1 ml of ice-cold 50 mM Tris buffer. Macroscint 20 (Packard) was added to the filter and radioactivity was measured using a Packard TopCount.

Binding cpm in the presence of test compound is shown as a fraction of binding cpm in the absence of test compound and plotted according to the concentration of compound. From this, IC50 was measured and pKi was calculated therefrom.

The most potent compounds of the present invention have pKi values of 7.1 to 7.8. E.g;

Example pKi range 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)

A method of treating a disease, comprising administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvent compound thereof, to a mammal suffering from one or more diseases: Where Each A is independently hydrogen, C _1-6 alkyl, unsubstituted or substituted by hydroxyl, C _1-6 alkoxy, C _1-6 alkenyl, C _1-6 acyl group, halogen atom, hydroxyl, CN Or a CF ₃ group; R 3 is hydrogen, methyl or ethyl; R 4 is a substituted or unsubstituted aromatic carbocyclic or heterocyclic ring; Z is an O atom, an S atom, an NH group or a CH ₂ group or a single bond at the 3 or 4 position of R 4 relative to a carbonyl group; R 5 is a substituted or unsubstituted aromatic carbocyclic or heterocyclic ring, or a substituted or unsubstituted, saturated or unsaturated carbocyclic or heterocyclic ring; Q is ego, Where (a) X is O or S atom, Y is a linear or branched C _2-4 alkylene group or C _5-6 cycloalkylene group unsubstituted or substituted by a hydroxyl group, R1 and R2 are independently linear or branched C _1-6 alkyl, phenyl C _1-6 alkyl groups; (b) X is O or S atom, Y is a linear or branched C _2-4 alkylene group unsubstituted or substituted by a hydroxyl group, R1 and R2 are linked to form a 5, 6 or 7-membered ring which further contains or does not contain one or more heteroatoms selected from O, S or N, wherein the N or C ring atoms are Ra, -CO-Ra,- Unsubstituted or substituted by CO-NH-Ra or CO-O-Ra, wherein Ra is a linear or branched C _1-6 alkyl or aryl group), and the 5, 6 or 7-membered ring is Fused or unfused with a substituted or unsubstituted benzene ring, or linked or linked with Y by a single bond or a methylene group; (c) X is O or S atom, Y is a C _2-4 alkylene group, R 1 is a C _2-4 alkylene group, connected to Y to form a 5 or 6 membered ring, R 2 is a linear or branched C _1-6 alkyl group; (d) X is an N atom, Y is a C _2-4 alkylene group, R 1 is a C _2-4 alkylene group, connected to X to form a five or six membered ring, R 2 is a linear or branched C _1-6 alkyl group. 2. Compounds of formula (I) or salts or solvents thereof as claimed in claim 1, wherein R < 3 > is methyl or ethyl. 3. A compound according to claim 2 which is one of the compounds listed in Table E. As a compound of formula (I) as defined in claim 1, or a salt or a solvent compound thereof, N- [4- [2- [bis (1-methylethyl) amino] ethoxy] -2-fluorophenyl]-[1,1'-biphenyl] -4-carboxamide, N- [4- [2- [bis (1-methylethyl) amino] ethoxy] phenyl]-[1,1'-biphenyl] -4-carboxamide, Biphenyl-4-carboxylic acid [4- (2-diisopropylamino-ethoxy) -phenyl] -amide, N- [4- (2-diisopropylamino-ethoxy) -phenyl] -4-phenoxy-benzamide, N- [4- (2-diethylamino-ethoxy) -phenyl] -4-phenoxy-benzamide, N- [4- (2-Diisopropylamino-ethoxy) -phenyl] -3-phenoxy-benzamide N- [4- (2-diethylamino-ethoxy) -phenyl] -3-phenoxy-benzamide, 4-cyclohexyl-N- [4- (2-diisopropylamino-ethoxy) -phenyl] -benzamide, 4-cyclohexyl-N- [4- (2-diethylamino-ethoxy) -phenyl] -benzamide, 4-benzyl-N- [4- (2-diisopropylamino-ethoxy) -phenyl] -benzamide, 4-benzyl-N- [4- (2-diethylamino-ethoxy) -phenyl] -benzamide, 4'-ethyl-biphenyl-4-carboxylic acid [4- (2-diisopropylamino-ethoxy) -phenyl] -amide, and Compound except 4'-ethyl-biphenyl-4-carboxylic acid [4- (2-diethylamino-ethoxy) -phenyl] -amide. A process for preparing a compound of formula (I), or a salt or solvent thereof, as defined in claim 2 comprising reacting a compound of formula (VII) with a compound of formula (XI): R5-Z-R4-COL (Ⅹ) Where R5, Z, R4, Q and A are the same as defined in the formula (I) of claim 1, L is a leaving group, R 3 is methyl or ethyl. Reacting a compound of formula (VII) wherein R 5, Z and R 4 as defined in formula (I) of claim 1 with a compound of formula (XI) wherein Q, A and R 3 are defined in claim 1 As a method for producing a compound of formula (I), or a salt or a solvent compound thereof, N- [4- [2- [bis (1-methylethyl) amino] ethoxy] -2-fluorophenyl]-[1,1'-biphenyl] -4-carboxamide, N- [4- [2- [bis (1-methylethyl) amino] ethoxy] phenyl]-[1,1'-biphenyl] -4-carboxamide, Biphenyl-4-carboxylic acid [4- (2-diisopropylamino-ethoxy) -phenyl] -amide, N- [4- (2-diisopropylamino-ethoxy) -phenyl] -4-phenoxy-benzamide, N- [4- (2-diethylamino-ethoxy) -phenyl] -4-phenoxy-benzamide, N- [4- (2-Diisopropylamino-ethoxy) -phenyl] -3-phenoxy-benzamide N- [4- (2-diethylamino-ethoxy) -phenyl] -3-phenoxy-benzamide, 4-cyclohexyl-N- [4- (2-diisopropylamino-ethoxy) -phenyl] -benzamide, 4-cyclohexyl-N- [4- (2-diethylamino-ethoxy) -phenyl] -benzamide, 4-benzyl-N- [4- (2-diisopropylamino-ethoxy) -phenyl] -benzamide, 4-benzyl-N- [4- (2-diethylamino-ethoxy) -phenyl] -benzamide, 4'-ethyl-biphenyl-4-carboxylic acid [4- (2-diisopropylamino-ethoxy) -phenyl] -amide, and 4'-Ethyl-biphenyl-4-carboxylic acid [4- (2-diethylamino-ethoxy) -phenyl] -amide except for preparing. A pharmaceutical composition for use in the treatment and / or prophylaxis of one or more diseases, comprising a compound of the invention, or a pharmaceutically acceptable salt or solvent compound thereof and a pharmaceutically acceptable carrier. Treating and / or preventing one or more diseases, including administering an effective amount or prophylactic amount of a compound of the invention, or a pharmaceutically acceptable salt or solvent compound thereof, to a patient suffering from one or more diseases Way. Use of a compound of the invention, or a pharmaceutically acceptable salt or solvent compound thereof, in the manufacture of a medicament for the treatment and / or prophylaxis of one or more diseases. Use of the novel compounds of the invention, or pharmaceutically acceptable salts or solvent compounds thereof, in particular as therapeutic agents for the treatment and / or prophylaxis of one or more diseases. A method of treating diabetes mellitus, major depression, mood swings, anxiety, schizophrenia and sleep disorders in humans or mammals other than humans, including administering a therapeutically effective amount of an antagonist to the human 11CBy receptor.