ARYL PIPERIDINE DERIVATIVES AS INDUCERS OF LDL-RECEPTOR EXPRESSION

Abstract: The invention relates to a compound of formula (I), wherein Ar1 represents phenyl, naphthyl or phenyl fused by a C3-8cycloalkyl, where each group is optionally substituted by methylenedioxy or one or two groups independently represented by R<1>; Ar2 represents phenyl or a 5-6 membered heteroaromatic group, where each group is optionally substituted by one to four groups independently selected from halogen, C1-4 alkyl and C1-4 alkoxy; Ar3 represents a phenyl or a 5-6 membered heteroaromatic group, where each group is optionally substituted by one to four groups independently selected from hydroxy, alkyl, C1-4 alkoxy, C2-4 alkenyl, C2-4 alkenyloxy, C1-4 perfluoroalkoxy, C1-4 acylamino or an electron withdrawing group; A represents -C(H)-; E represents -C1-6 alkylene-; X represents -CON(H or C1-4alkyl)- or -N(H or C1-4alkyl)CO-; Y represents a direct link; R<1> represents halogen, -S(C1-4 alkyl)-, -O-(C0-4 alkylene)-R<2> or -(C0-4alkylene)-R<2>, where each alkylene group may additionally incorporate an oxygen in the chain, with the proviso that there are at least two carbon atoms between any chain heteroatoms; R<2> represents: i) hydrogen, C1-4 perfluoroalkyl, C2-3 alkenyl, ii) phenyl, naphthyl, a 5- or 6-membered heteroaromatic group or 1,2,3,4-tetrahydronaphthyl, optionally substituted by one or two halogen, hydroxy, C1-4 alkyl, C1-4 alkoxy groups, iii) C3-8cycloalkyl, a 3-7 membered heterocycloalkyl, iv) amino, C1-4 alkylamino or di-C1-4alkylamino, with the proviso that there are at least two carbon atoms between any chain heteroatoms; to salts, solvates and compositions thereof and their use in treating disorders associated with elevated levels of circulating LDL-cholesterol.

Description: ARYL PIPERIDINE DERIVATIVES AS INDUCERS OF LDL-RECEPTOR EXPRESSION This invention relates to novel compounds which up-regulate LDL receptor (LDLr) expression and to processes for their preparation, pharmaceutical compositions containing them and their medical use. More particularly, this invention relates to novel aromatic piperidines and their use in therapy. Epidemiological studies have clearly demonstrated the correlation between reduction in plasmatic LDL cholesterol and the benefit on cardiovascular events including mortality. LDL cholesterol is eliminated from plasma by specific binding to LDL-r expressed by the liver. Regulation of LDL-r expression occurs in the liver and is mainly dependent on intracellular cholesterol concentration. Increasing free cholesterol concentration leads to a reduced LDL-r expression through a mechanism involving transcriptional factors. Counteracting with this process is expected to up-regulate LDL-r expression in the liver and to increase the clearance of LDL cholesterol. International Patent Application Number PCT. EP00. 06668 concerns the novel use of the SREBP-cleavage activating protein (SCAP) in a screening method, and two compounds are disclosed, namely 4- (4-chloro-benzoylamino)-N- {4- [4- (2-ethoxy-4-ethyl-phenyl)-piperidin-1-yl]-butyl}-benzamide and 4- (4-Benzoyl)-N- {4- [4- (4-isopropyl-2-methoxy-phenyl)-piperidin-1-yl]-butyl}-benzamide hydrochloride, which do not form part of the present invention. Another publication, Bioorganic and Medicinal Chemistry Letters Vol. 5,3,219222,1995 discloses compounds having the general formula (A) EMI1.1 where X may be COMe, S02Me and NH2, as having high affinity for the dopamine D3 receptor and postulates their use in CNS disorders, particularly psychiatric illness. The compound of formula A where X is COMe is also disclosed in J. Pharmacol. Exp. Ther. 287; 1 1998 187-197 and Bioorganic and Medicinal Chemistry Letters Vol. 7,15,1995-1998,1997, again as being useful in treating CNS disorders. It will be noted that the examples of the present invention differ from those of formula (A) in use of a piperidine ring rather than a piperazine and in the utility disclosed. Journal Of Medicinal Chemistry, Vol. 40,6,952-960,1997 discloses compounds of formula (B) EMI2.1 where m=0, 1 or 2; n=2 or 3 ; Ri and R3= H or OMe and R2 may be Ph, as selective 5-HT1A receptor ligÅands having CNS activity. It will be noted that the examples of the present invention differ from those of formula (B) in use of a piperidine ring rather than a piperazine and in the utility disclosed. International Patent Application Publication Number W099/45925 discloses compounds of formula (C) EMI2.2 where R1 may be hydrogen, R2 may be hydrogen and R3 may be a group EMI3.1 where X may be an aryl group and n may be 1. Specifically disclosed are compounds where the group COR3 is formed from 2-and 4-biphenyl carboxylic acid and R1 and R2 are methyl or hydrogen respectively. The utility of the compounds is as opioid receptor binding agents which may be useful as analgesics. The substitution on the 3-and 4-positions of the piperidine ring leave the compounds of this publication outside the scope of the present invention. Furhtermore, the utility disclosed is different. International Patent Application Publication Number W098/37893 discloses compounds of formula (D) EMI3.2 where Ar may represent an optionally substituted phenyl or naphthyl, G may be N or CH2 (sic), W may be an optionally substituted alkylen, Y may be hydrogen and Z may represent a group R4CONR5, where R4 may be an optionally substituted phenyl and R5 may be hydrogen. These compounds are described as being D2 receptor antagonists useful in the treatment of CNS disorders such as Parkinson's Disease. None of the compounds specifically disclosed fall within the scope of the present invention and the disclosed utlity is different. International Patent Application Publication Number W09402473 discloses compounds of formula (E) EMI4.1 where A may be NHCO or CONH; Ri-Re may be hydrogen or a benzene ring, m may be 1-3 and n may be 1-3. Specifically disclosed are compounds EMI4.2 No. <SEP> A <SEP> n <SEP> m <SEP> Ri <SEP> R2 <SEP> R3 <SEP> R4 <SEP> R5 <tb> 5 <SEP> NHCO <SEP> 2 <SEP> 1 <SEP> H <SEP> H <SEP> Ph <SEP> H <SEP> H <tb> 12 <SEP> NHCO <SEP> 2 <SEP> 2 <SEP> H <SEP> H <SEP> Ph <SEP> H <SEP> H <tb> 19 <SEP> NHCO <SEP> 2 <SEP> 3 <SEP> H <SEP> H <SEP> Ph <SEP> H <SEP> H <tb> The compounds are described as 5HT-1A agonists having CNS activity and may be used as anti-depressants, anti-hypertensive, analgesics etc. It will be noted that the examples of the present invention differ from those of formula (E) in use of a piperidine ring rather than a piperazine and in the utility disclosed. International Patent Application Publication Number W099/45925 discloses compounds of formula (F) EMI4.3 where A may represent a substituted phenyl group, W represents a linear or branched alkylen group having from 2 to 6 carbon atoms; Y may represent a group NHCO or CONH; and R may be a substituted phenyl group. Particularly disclosed is the compound G EMI5.1 These compounds are described as being a1A-adrenergic receptors useful in the treatment of contractions of the prostate, urethra and lower urinary tract, without affecting blood pressure. It will be noted that the examples of the present invention differ from those of formula (G) in use of a piperidine ring rather than a piperazine and in the utility disclosed. International Patent Application Publication Number W098/35957 describes compounds of formula (H) EMI5.2 wherein R1-R5 are each individually selected from the group of substituents including hydrogen, halogen, hydroxyl, thiol, lower alkyl, substituted lower alkyl, alkenyl, alkynyl, alkylalkenyl, alkylalkynyl, alkoxy, alkylthio, acyl, aryloxy, amino, amido, carboxyl, aryl, substituted aryl, heterocycle, heteroaryl, substituted heterocycle, heteroalkyl, cycloalkyl, substituted cycloalkyl, alkylcycloalkyl, alkylcycloheteroalkyl, nitro and cyano. Specifically disclosed compounds are those formed by the N-alkylation of a a substituted piperidine or piperazine with a group (J) EMI5.3 where X is a leaving group. None of the compounds specifically disclosed fall within the scope of the present invention and the invention is in no way suggested by the disclosure. The compounds are said to be of use as NPY Y5 receptor antagonists in the treatment of obesity, bulemia and related disorders and NPY Y5 receptor inhibition related disorders such as memory disorders, epilepsy, dyslipidemia and depression. US Patent no. 6,048,900, published after the priority date of the present invention discloses the same information. Journal Of Medicinal Chemistry, Vol. 31,1968-1971,1988 discloses certain aryl piperazines compounds, which fall outside the present invention, as 5HT-1 a Serotonin Ligands as potential CNS agents. Specifically disclosed are compounds of formula (K) EMI6.1 where Ar=Ph and R = Ph, Ar= 2-OMePh and R =Ph and Ar=2-pyrimidyl and R=Ph. Journal Of Medicinal Chemistry, Vol. 34,2633-2638,1991 discloses aryl piperazines having reduced a1 adrenergic affinity. Specifically disclosed is the compound (L) EMI6.2 where R is 4- (BnO)-phenyl, which falls outside the scope of the present invention. The present invention provides aryl piperidine derivatives which are particularly useful in treating cardiovascular disorders associated with elevated levels of circulating LDL-cholesterol. Thus, the present invention provides, as a first aspect, a compound of formula (I) EMI7.1 wherein Ar1 represents phenyl, naphthyl or phenyl fused by a C38cycloalkyl, where each group is optionally substituted by methylenedioxy or one or two groups independently represented by R1 ; Ar2 represents phenyl or a 5-6 membered heteroaromatic group, where each group is optionally substituted by one to four groups independently selected from halogen, C14 alkyl and C14 alkoxy ; Ar3 represents a phenyl or a 5-6 membered heteroaromatic group, where each group is optionally substituted by one to four groups independently selected from hydroxy, alkyl, C14 alkoxy, C24 alkenyl, C24 alkenyloxy, C14 perfluoroalkoxy, C 4 acylamino or an electron withdrawing group; A represents-C (H)- ; E represents-C16 alkylene-; X represents-CON (H or C14alkyl)-or-N (H or C14alkyl) CO-; Y represents a direct link ; R1 represents halogen, -S(C1-4 alkyl)-, -O-(C0-4 alkylene)-R2 or -(C0-4alkylene) R2, where each alkylen group may additionally incorporate an oxygen in the chain, with the proviso that there are at least two carbon atoms between any chain heteroatoms ; R2 represents (i) hydrogen, C14 perfluoroalkyl, C2-3 alkenyl, (ii) phenyl, naphthyl, a 5-or 6-membered heteroaromatic group or 1,2,3,4 tetrahydronaphthyl, optionally substituted by one or two halogen, hydroxy, Ci-4 alkyl, C14 alkoxy groups, (iii) C38cycloalkyl, a 3-7 membered heterocycloalkyl, (iv) amino, C14 alkylamino or di-C1galkylamino, with the proviso that there are at least two carbon atoms between any chain heteroatoms; or a physiologically acceptable salt or solvate thereof. Suitable physiologically acceptable salts of the compounds of general formula (I) include acid addition salts formed with pharmaceutical acceptable inorganic acids for example, hydrochlorides, hydrobromides or sulphates, or with pharmaceutically acceptable organic acids for example mesylates, Iqctqtes and acetates. More suitably, a physiologically acceptable salt of the compounds of general formula (I) is a mesylate salt. The solvates may, for example, be hydrates. References herein after to a compound according to the invention include both compounds of formula (I) and their physiologically acceptable salts together with physiologically acceptable solvates. Referring to the general formula (I), alkyl, alkylene and alkoxy include both straight and branched chain saturated hydrocarbon groups. Examples of alkyl groups include methyl and ethyl groups, examples of alkylen groups include methylene and ethylene groups, whilst examples of alkoxy, groups include methoxy and ethoxy groups. Referring to the general formula (I), alkenyl includes both straight and branched chain saturated hydrocarbon groups containing one double bond. Examples of alkenyl groups include ethenyl or n-propenyl groups. Referring to the general formula (I), acyl refers to aliphatic or cyclic hydrocarbons attached to a carbonyl group through which the substituent bonds, such as acetyl. Referring to the general formula (I), phenyl fused by a C38cycloalkyl includes bicyclic rings such as 1,2,3,4-tetrahydronaphthyl, which, for the avoidance of doubt, is linked to the rest of the molecule through the aromatic ring. Referring to general formula (I), a halogen atom includes fluorine, chlorine, bromine or iodine. Referring to the general formula (I), C13perfluoroalkyl and Cl-3perfluoroalkoxy includes compounds which the hydrogens have been partially or fully replaced by fluorines, such as trifluoromethyl and trifluoromethoxy or trifluoroethyl. Referring to the general formula (I), a 5-6 membered heteroaromatic group includes a single aromatic ring system containing at least one ring heteroatom independently selected from O, N and S. Suitable examples include pyridyl and thiazolyl. Referring to the general formula (f), a C3-8 cycloalkyl group means any single carbocyclic ring system, wherein said ring is fully or partially saturated. Suitable examples include cyclopropyl and cyclohexyl groups. Referring to the general formula (I), a 3-7 membered heterocycloalkyl group means any single ring system containing at least one ring heteroatom independently selected from O, N and S, wherein said ring is fully or partially saturated. Suitably, Ar1 represents an optionally substituted phenyl, naphthyl or 1,2,3,4tetrahydronaphthyl group, where optional substitution is effected by R'. More suitably, Ar1 represents a substituted phenyl or naphthyl. Preferably Ar1 represents a substituted phenyl. Equally preferably, An represents a substituted naphthyl. Equally preferably, Ar1 represents a substituted 1, 2,3,4tetrahydronaphthyl group. Substitution on An is suitably represented by methylenedioxy or one or two groups independently selected from hydroxy, C14 alkyl, e. g. methyl, ethyl or isopropyl, C1-4 alkoxy, e.g. methoxy or ethoxy, -O-C0-4alkylene-R2, e.g. -O methylene-R2, where R2 represents C14 perfluoroalkyl, e. g. trifluoromethyl, a 56 membered heteroaromatic group, e. g. pyridyl, preferably 2-pyridyl, or a C38cycloalkyl, e. g. cyclopropyl. Substitution on Ar1 is equally suitably represented by one or two groups independently selected from hydroxy, C14 alkyl, e. g. methyl or ethyl, C14 alkoxy, e. g. methoxy, ethoxy, propoxy or isobutoxy, C23alkenyloxy, e. g. allyloxy or-O C.-4alkylene-R, e. g.-O-methylene-R2, where R2 represents a C38cycloalkyl, e. g. cyclopropyl. Preferably, Ar1 is a phenyl group substituted by methylenedioxy, preferably 3,4 methylenedioxy, or one or two groups independently selected from methyl, ethyl, isopropyl, hydroxy, methoxy, ethoxy, cyclopropylmethoxy and 2-pyridylmethoxy. Preferably, substitution is in one or two of the 2-, 4-or 5-positions on the phenyl ring. Equally preferably, Ar1 is a phenyl or naphthyl group substituted by one or two groups independently selected from methyl, ethyl, hydroxy, methoxy, ethoxy, propoxy, isobutoxy, allyloxy and cyclopropylmethoxy. Preferably, where Ar1 is phenyl, substitution is in one or two of the 2-or 4-positions on the phenyl ring. Where Ar1 is naphthyl, the link to group A is preferably through the 1-or 2position and mono-substitution by R'is in either the corresponding 2-or 1positions respectively. E is preferably an n-butylen group. X is suitably a-N (H or C14 alkyl) CO-group, preferably an-N (H) CO- group. Where Ar2 is a 5-6-membered heteroaromatic group, this is suitably a thiazolyl group, optionally substituted by C14 alkyl, e. g. methyl. Ar2 is preferably phenyl. Suitable electron withdrawing groups on Ar3 include halogen, nitrile, nitro, Cl-4, C1-4 perfluoroalkyl, C1-4 acyl, C1-4 alkoxycarbonyl, aminocarbonyl, C1-4 alkylaminocarbonyl, di-C1-4 alkylaminocarbonyl, C1-4 alkylsulfonyl, C1-4 alkylaminosulfonyl and di-C14 alkylaminosulfonyl, C14 alkylsulfonyl and C 4alkylsulfoxy. Ar3 is preferably phenyl or pyridyl group, suitably 2-pyridyl, substituted by halogen, e. g. chloro or C1gperfluoroalkyl, e. g. trifluoromethyl. Ar3 is equally preferably phenyl substituted by a halogen, e. g. chloro, C 4perfluoroalkyl, e. g. trifluoromethyl, C14acyl, e. g. acetyl, nitrile or C 4alkylsulfonyl, e. g. methylsulfonyl. When Ar3 is phenyl, para-substitution is preferred. More preferably, Ar3 is phenyl substituted by a halogen, e. g. chloro or nitrile. Most preferably, Ar3 is phenyl substituted by chloro in the para position. Alternatively, Ar3 is phenyl substituted by nitrile in the para position. A suitable sub-group of the present invention is represented by a compound of formula (la) EMI11.1 wherein Ar1 represents phenyl, naphthyl or phenyl fused by a C38cycloalkyl, where each group is optionally substituted by methylenedioxy or one or two groups independently represented by R1 ; Ar2 represents phenyl or a 5-6 membered heteroaromatic group, where each group is optionally substituted by one to four groups independently selected from halogen, C1-4 alkyl and C14 alkoxy ; Ar3 represents phenyl or a 5-6 membered heteroaromatic group, where each group is optionally substituted by one to four groups independently selected from halogen, hydroxy, nitrile, C14 alkyl, C14 alkoxy, C24 alkenyl, C24 alkenyloxy, C14 perfluoroalkyl,.C1-4 perfluoroalkoxy, C1-4 acyl, C1-4 alkoxycarbonyl, aminocarbonyl, C1-4 alkylaminocarbonyl di-C1-4 alkylaminocarbonyl and C14 acylamino ; A represents-C (H)- ; E represents-C16 alkylene-; X represents-CON (H or C14alkyl)-or-N (H or Cl-4alkyl) CO- ; Y represents a direct link ; R1 represents halogen, -O-(C0-4 alkylene)-R2 or -(C0-4alkylene)-R2, where each alkylen group may additionally incorporate an oxygen in the chain, with the proviso that there are at least two carbon atoms between any chain heteroatoms; R2represents (i) hydrogen, C1-4 perfluoroalkyl, (ii) phenyl, naphthyl, a 5-or 6-membered heteroaromatic group or 1,2,3,4 tetrahydronaphthyl, optionally substituted by one or two halogen, hydroxy, C14 alkyl, C14 alkoxy groups, (iii) C3-8cycloalkyl, a 3-7 membered heterocycloalkyl, (iv) amino, C1-4 alkylamino or di-C14alkylamino, with the proviso that there are at least two carbon atoms between any chain heteroatoms; or a physiologically acceptable salt or solvate thereof. A further preferred sub-group of the present invention is represented by a compound of formula (lb) EMI12.1 wherein An represents phenyl, naphthyl or 1,2,3,4-tetrahydronaphthyl, where each group is optionally substituted by one or two groups independently represented by R1 ; Ar3 represents phenyl substituted in the para position by a halogen, nitrile, Ci4acyl, C-4alkylsulfonyl or C14 perfluoroalkyl group; R1 represents C1-4 alkyl or -O-(C0-4alkylene)-R2; R2 represents hydrogen, C2-3alkenyl or C3-8cycloalkyl ; or a physiologically acceptable salt or solvate thereof. It will be understood that references to compounds of formula (I) hereinbefore and hereinafter apply equally to compounds of formula (la) and (lb). Particularly preferred, compounds of the invention include those in which each variable in Formula (I) is selected from the preferred groups for each variable. Even more preferable compounds of the invention include those where each variable in Formula (I) is selected from the more preferred or most preferred groups for each variable. Suitable compounds according to the invention include : 4'-Trifluoromethyl-biphenyl-4-carboxylic acid {4-[4-(2-ethoxy-4-methyl-phenyl) piperidin-1-yl]-butyl}-amide ; 4'-Trifluoromethyl-biphenyl-4-carboxylic acid [4- [4- (2-cyclopropylmethoxy-4- ethyl-phenyl)-piperidin-1-yl]-butyl]-amide ; 4'-Chloro-biphenyl-4-carboxylic acid {4- [4- (1-methoxy-naphtalen-2-yt)-piperidin- 1-yl]-butyl}-amide ; 4'-Chloro-biphenyl-4-carboxylic acid {4- [4- (2-methoxy-naphtalen-1-yl)-piperidin 1-yl]-butyl}-amide ; 4'-Cyano-biphenyl-4-carboxylic acid {4- [4- (2-ethoxy-4-ethyl-phenyl)-piperidin-l- yl]-butyl}-amide ; 4'-Cyano-biphenyl-4-carboxylic acid {4-[4-(1-methoxy-naphtalen-2-yl)-piperidin1-yl]-butyl}-amide; 4'Trifluoromethyl-biphenyl-4-carboxylic acid {4- [4- (1-isobutoxy-5, 6,7,8tetrahydro-naphtalen-2-yl)-piperidin-1-yl]-butyl}-amide 4'-Trifluoromethyl-biphenyl-4-carboxylic acid {4-[4-(1-allyloxy-naphtalen-2-yl) piperidin-1-yl]-butyl}-amide; 4'-Trifluoromethyl-biphenyl-4-carboxylic acid {4- [4- (1-propoxy-naphtaten-2-y))- piperidin-1-yl]-butyl}-amide ; 4'-Trifluoromethyl-biphenyl-4-carboxylic acid {4-[4-(1-Cyclopropylmethoxy5,6,7,8-tetrahydro-naphtalen-2-yl)-piperidin-1-yl]-butyl}-amide; 4'-Cyano-biphenyl-4-carboxylic acid {4-[4-(1-methoxy-5, 6,7,8-tetrahydro naphtalen-2-yl)-piperidin-1-yl]-butyl}-amide ; 4'-Methanesulfonyl-biphenyl-4-carboxylic acid {4- [4- (2-ethoxy-4-ethyl-phenyl)- piperidin-1-yl]-butyl}-amide; 4-Methyl-2- (4-trifluromethyl-phenyl)-thiazole-5-carboxylic acid {4- [4- (4-isopropyl 2-methoxy-phenyl)-piperidin-1-yl]-butyl}-amide ; 4'-Cyano-biphenyl-4-carboxylic acid {4- [4- (2-hydroxy-4-ethyl-phenyl)-piperidin-1- yl]-butyl}-amide ; 4'-Cyano-biphenyl-4-carboxylic acid {4- [4- (1-hydroxy-5, 6,7,8-tetrahydro naphtalen-2-yl)-piperidin-1-yl]-butyl}-amide ; 4'-Cyano-biphenyl-4-carboxylic acid {4- [4- (1-hydroxy-naphtalen-2-yl)-piperidin-1- yl]-butyl}-amide ; 4'-Acetyl-biphenyl-4-carboxylic acid {4- [4- (1-hydroxy-5, 6,7,8-tetrahydro naphtalen-2-yl)-piperidin-1-yl]-butyl}-amide ; 4'-Cyano-biphenyl-4-carboxylic acid {4- [4- (2-hydroxy-4-methyl-phenyl)-piperidin- 1-yl]-butyl}-amide ; or a physiologically acceptable salt or solvate thereof. The compounds of the invention are inducers of LDL-r expression and are thus of use in the treatment of conditions resulting from elevated circulating levels of LDL-cholesterol. The ability of the compounds of the invention to induce LDL-r expression by human hepatocytes in vitro is determined using a human hepatocarcinoma cell line, Hep G2, as a model system. A reporter gene assay using the LDL-r promoter in front of the reporter gene Luciferase is used as a primary screen. The in vivo profile of the compounds is evaluated by oral administration of the compounds of the invention to fat-fed hamsters. Measurements of VLDL/LDL cholesterol and triglycerides upon treatment allow the activity to be determined. The compounds of the invention are potent and specific inducers of LDL-r expression, which furthermore exhibit good oral bioavailability and duration of action. Compounds of the invention are of use in the treatment of diseases in which lipid imbalance is important, e. g. atherosclerosis, pancreatitis, non-insulin dependent diabetes mellitus (NIDDM), coronary heart diseases and obesity. Compounds of the invention are also useful in lowering serum lipid levels, cholesterol and/or triglycerides, and are of use in the treatment of hyperlipemia, hyperlipidemia, hyperlipoproteinemia, hypercholesterolemia and/or hypertriglyceridemia. The invention therefore provides a compound of formula (I) or a physiologically acceptable salt or solvate thereof for use in therapy, in particular in human medicine. There is also provided as a further aspect of the invention the use of a compound of formula (I) or a physiologically acceptable salt or solvate thereof in the preparation of a medicament for use in the treatment of conditions resulting from elevated circulating levels of LDL-cholesterol. In an alternative or further aspect there is provided a method for the treatment of a mammal, including man, in particular in the treatment of conditions resulting from elevated circulating levels of LDL-cholesterol, comprising administration of an effective amount of a compound of formula (I) or a physiologically acceptable salt or solvate thereof. It will be appreciated that reference to treatment is intended to include prophylaxis as well as the alleviation of established symptoms. Compounds of formula (I) may be administered as the raw chemical but the active ingredient is preferably presented as a pharmaceutical formulation. Accordingly, the invention also provides a pharmaceutical composition which comprises at least one compound of formula (I) or a physiologically acceptable salt or solvate thereof and formulated for administration by any convenient route. Such compositions are preferably in a form adapted for use in medicine, in particular human medicine, and can conveniently be formulated in a conventional manner using one or more pharmaceutical acceptable carriers or excipients. Thus compounds of formula (I) may be formulated for oral, buccal, parenteral, transdermal, topical (including ophthalmic and nasal), depot or-rectal administration or in a form suitable for administration by inhalation or insufflation (either through the mouth or nose). For oral administration, the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutical acceptable excipients such as binding agents (e. g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose) ; fillers (e. g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e. g. magnesium stearate, talc or silica) ; disintegrants (e. g. potato starch or sodium starch glycollate) ; or wetting agents (e. g. sodium lauryl sulphate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e. g. sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e. g. lecithin or acacia); non-aqueous vehicles (e. g. almond oil, oily esters, ethyl alcohol or fractionated vegetable oils) ; and preservatives (e. g. methyl or propylp-hydroxybenzoates or sorbic acid). The preparations may also contain buffer salts, flavouring, colouring and sweetening agents as appropriate. Preparations for oral administration may be suitably formulated to give controlled release of the active compound. For buccal administration the composition may take the form of tablets or lozenges formulated in conventional manner. For transdermal administration the compounds according to the invention may be formulated as creams, gels, ointments or lotions or as a transdermal patch. Such compositions may for example be formulated with an aqueous or oily base with the addition of suitable thickening, gelling, emulsifying, stabilising, dispersing, suspending, and/or colouring agents. The compounds of the invention may be formulated for parenteral administration by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form e. g. in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e. g. sterile pyrogen-free water, before use. The compounds of the invention may be formulated for topical administration in the form of ointments, creams, gels, lotions, pessaries, aerosols or drops (e. g. eye, ear or nose drops). Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Ointments for administration to the eye may be manufactured in a sterile manner using sterilised components. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents, thickening agents, or colouring agents. Drops may be formulated with an aqueous or non aqueous base also comprising one or more dispersing agents, stabilising agents, solubilising agents or suspending agents. They may also contain a preservative. The compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, e. g. containing conventional suppository bases such as cocoa butter or other glycerides. The compounds of the invention may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds of the invention may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt. For intranasal administration, the compounds of the invention may be formulated as solutions for administration via a suitable metered or unit dose device or alternatively as a powder mix with a suitable carrier for administration using a suitable delivery device. The compositions may contain from 0.1% upwards, e. g. 0.1-99% of the active material, depending on the method of administration. A proposed dose of the compounds of the invention is 0.25mg/kg to about 125mg/kg bodyweight per day e. g. 20mg/kg to 100mg/kg per day. It will be appreciated that it may be necessary to make routine variations to the dosage, depending on the age and condition of the patient and the precise dosage will be ultimately at the discretion of the attendant physician or veterinarian. The dosage will also depend on the route of administration and the particular compound selected. The compounds of formula (1) may, if desired, be administered with one or more therapeutic agents and formulated for administration by any convenient route in a conventional manner. Appropriate doses will be readily appreciated by those skilled in the art. For example, the compounds of formula (I) may be administered in combination with an HMG CoA reductase inhibitor, an agent for inhibition of bile acid transport or fibrates. A compound of formula (I), or a physiologically acceptable salt, solvate or derivative thereof, may be prepared by the general methods outlined hereafter. In the following description, the groups Ar1, Ar2, Ar3, R1, R2, A, E and X are as previously defined for compounds of formula (I), unless specified otherwise. According to a first general process (A), a compound of formula (I) may be prepared by reaction of a compound of formula (A) with a compound of formula (111) EMI18.1 where Xa and Xb are suitable reactants to form a group X. For example, where X is N (H or C14 alkyl) CO, Xa is NH2 or NH (C14 alkyl) and Xb is COL where L is OH or a suitable leaving group, such as halide. Such a reaction may be effected under standard amide bond-forming conditions, including those described herein. A compound of formula (li) where Xa is NH2 or NH (C14 alkyl), may be prepared by reaction of a compound of formula (IV) with a compound of formula (V) EMI19.1 where R5 represents H or CI-4alkyl, L'is a suitable group, such as halide, and P is any suitable N-protecting group, under standard alkylation conditions, including those described herein, followed by removal of the protecting group under standard conditions. A compound of formula (II) where Xa is NH2 or NH (Ci-4 alkyl), may further be prepared by reaction of a compound of formula (IV) with a compound of formula (Va) EMI19.2 where R5 represents H or C1galkyl, where E-C1 ('E minus C1') means that the chain length of group E is one carbon less than that in the resulting compound (II), and P is any suitable N-protecting group, under standard reductive amination conditions, including those described herein, followed by removal of the protecting group under standard conditions. A compound of formula (IV), where A is CH, may be prepared by reaction of a compound Ar1-sal, where sal represents the lithium or magnesium ion of Ar1, with a compound of formula (VI) EMI20.1 where P'represents a suitable N-protecting group, such as acetyl, benzyl or benzyl-4-oxo-1 carboxylate, followed by the steps of dehydration, reduction of the resulting double bond, and finally, removal of the protecting group P'. Such chemistry has been described, for example, in European Patent Application no. 0630887. Alternatively, a compound of formula (IV) where Ar1 is substituted by an activated ortho or para activating group for the reaction centre, Act, e. g. methoxy or hydroxy and A is CH, may be prepared by reaction of a compound of formula Arl-Act, with a compound of formula (VI) under suitable reaction conditions such as e. g. trifluoroborane or acetic acid and aqueous hydrochloric acid, to form a tetrahydropyridyl ring, followed by reduction, e. g. under hydrogenation conditions, of the resulting double bond and finally deprotection of the Nprotecting group, P'under standard conditions. Alternatively, a compound of formula (IV) where where Ar1 is substituted by an activated ortho or para activating group for the reaction centre, Act, e. g. methoxy or hydroxy and A is CH, may be prepared by reaction of a compound of formula Arl-Act, with a compound of formula (Vil) EMI20.2 under suitable reaction conditions such as e. g. acetic acid and aqueous hydrochloric acid to form a tetrahydropyridyl ring, followed by suitable N protection, then reduction, e. g. under hydrogenation conditions, of the resulting double bond and finally deprotection of the N-protecting group. A compound of formula (III) may be prepared by standard methods including, where Xb is C02H, deprotection of a compound of formula (X) EMI21.1 where R is a suitable carboxylic acid protecting group, such as methyl. A compound of formula (X) where R is H or a suitable protecting group and Y is a direct link, may be prepared by reaction of a compound of formula (XI), with a compound of formula (XII) EMI21.2 where bor1 represents a boronic acid group or a halide, e. g. bromide or iodide, and bor2 represents a suitable boronic acid group or a halide, e. g. bromide or iodide for coupling, under conditions suitable for boronic acid coupling, e. g. using palladium (0) and sodium carbonate. According to a second general process (B), a compound of formula (I) may be prepared by reaction of a compound of formula (IV) with a compound of formula (XIII) EMI21.3 where E-C1 ('E minus Cul') means that the chain length of group E is one carbon less than that in the resulting compound (I), under standard reductive amination conditions, e. g. sodium triacetoxyborohydride and acetic acid in a suitable solvent, such as dichloromethane. A compound of formula (XIII) may be prepared by reaction of a compound of formula (XIV) with a compound of formula (XV) EMI22.1 where R'5 is a suitable alkyl protecting group for oxygen, such as methyl, and Xa and Xb are suitable reactants to form a group X, as defined hereinbefore, followed by removal of the protecting group, under acidic conditions. According to a third general process (C), a compound of formula (I) may be prepared by reaction of a different compound of formula (t), by well known methods. For example a compound of formula (I) where Ar is substituted by Ci- 4 alkoxy may be prepared from the corresponding compound of formula (I) where the substituent is hydroxy by standard O-alkylation methods. Compounds of formula (V), (VI), (VII), (VIII), (IX), (XI), (XIV) and (XV), are known or may be prepared by standard methods, e. g. as substantially described herein. The protecting groups used in the preparation of compounds of formula (I) may be used in conventional manner. See for example'Protective Groups in Organic Chemistry'Ed. J. F. W. McOmie (Plenum Press 1973) or'Protective Groups in Organic Synthesis'by Theodora W Greene and P M G Wuts (John Wiley and Sons 1991). Conventional amino protecting groups may include for example aralkyl groups, such as benzyl, diphenylmethyl or triphenylmethyl groups; and acyl groups such as N-benzyloxycarbonyl or t-butoxycarbonyl. Conventional carboxylic acid protecting groups include methyl and ethyl groups. The invention is further described with reference to the following non-limiting examples. Abbreviations : THF-Tetrahydrofuran, BF3-Et2O- Boron trifluoride diethyl etherate, DCM Dichloromethane, TEA-triethylamine, EtOH-Ethanol, EtOAc-Ethyl acetate, IPr2O-Di-isopropyl ether, TFA-Trifluoroacetic acid, Pd/C-Palladium on carbon, Et2O-diethyl ether, IPrOH-Isopropanol, lprNH2-Isopropylamine, Chexcyclohexane, MeOH-Methanol, DMF-Dimethyl formamide, EDCl- 1-(3dimethylaminopropyl)-, ethylcarbodiimide hydrochloride, HOBt-1 Hydroxybenzotriazole, MeCN-Acetonitrile, rt-Room temperature, CDI Carbonyle diimidazole, nBuOH-nButanol, AcOH-Acetic acid CH3SO3H-Methane sulfonic acid, MgS04-Magnesium sulfate, Na2S04-Sodium sulfate, HATU-0- (7-Azabenzotriazol-1-yl)-N, N, N'N'hetramethyluroniumhexafluorophosphate Intermediate 1 4'-Trifluoromethyl-biphenyl-4-carboxylicacid To a solution of 4-Bromo-benzoic acid (28.5 g, 0.14 mol) in toluene (350 mL) were added Tetrakis (triphenylphosphine) palladium (0) (4.93 g, 0.03 eq.), a 2M solution of Na2CO3 (71 mL), Lithium chloride (18.3 g, 3 eq.). Then a solution of 4- Trifluoromethylbenzeneboronic acid (30.0 g, 0.158 mol) in EtOH (200 mL) was added and the resulting mixture was stirred at reflux for 16 hours. After evaporation under reduced pressure the residue was taken up in water and the precipitate was filtered off. The solid was treated with a 1 N HCI solution, filtered off and dried and was dissolved in a solution of EtOH (700 mL) and THF (400 mL). Filtration through a bed of silica and evaporation gave the title compound (25.0 g, 0.094 mol) as a white solid. GC/MS : M+ C14H9F302 266 Intermediate 2 4'-Chloro-biphenyl-4-carboxylic acid To a solution of 20 g (0.1 mol.) of 4-bromo benzoic acid in toluene (300 mL) was added successively 3.5 g (0.03 eq.) of tetrakis (triphenylphosphine) palladium (0), 50 ml (1 eq.) of a 2M solution of Na2CO3 and 12.9 g (3 eq.) of lithium chloride. After 15 minutes of stirring was added a solution of 10.8 g (1.2 eq.) of 4-chlorophenyl boronic acid in EtOH (120 mL). Then, the mixture was refluxed for 24 hours. After cooling, the solvents were evaporated to dryness. The residue was poured in water (300 mL) and the aqueous layer was acidified to pH=1 with a 1 N HCI solution. After filtration, the solid was washed with water and after recrystallization from 2-methoxy ethanol 15 g of the tilte compound as a white powder in a 65% yield. MP: 290-291 C. Intermediate 3 1- [4- (2-Hydroxy-4-methyl-phenyl)-3, 6-dihydro-2H-pyridin-1-yl]-ethanone To a solution of m-Cresol (50. 0 g, 0.46¯mol) and 1-Acetyl-4-piperidone (65.4 g, 1.0 eq.) was added dropwise BFs-EtzO (176 mL, 3.0 eq). The mixture was stirred at 100 C for 2 hours. After cooling to rt, the mixture was treated with a 1 N HCI solution (800 mL). The resulting solution was extracted with DCM. The organic layer was dried over Na2SO4 and evaporated to dryness to give an oil which was crytallized in MeCN to give the title compound (60.0 g, 0.26 mol) as a white powder in a 57%. GC/MS: M+ C, 4H17NO2 231 Intermediate 4 1- [4- (2-Hydroxy-4-methyl-phenyl)-piperidin-1-yl]-ethanone To a solution of intermediate 3 (60.0 g, 0.26 mol) in EtOH (600 mL) and DCM (200 mL) was added Pd/C, 10% (6 g) and the reaction was stirred under an atmospheric pressure of hydrogen at rt for 48 hours. The reaction mixture was filtered through a bed of celite. The filtrate was evaporated under reduced pressure to give the title compound (55.0 g, 0.24 mol) as a white powder. GC/MS: M+ Ca4Ha9NO2 233 Intermediate 5 1- [4- (2-Ethoxy-4-methyl-phenyl)-piperidin-1-yl]-ethanone To a solution of intermediate 4 (55.0 g, 0.24 mol) in dry acetone (800 mL) was added anhydrous Cs2CO3 (93.0 g, 1.2 eq.) and ethyl iodide (23 mL, 1.2 eq.). The reaction was stirred under reflux for 18 hours. After cooling, the reaction was filtered off and washed with acetone. The filtrate was evaporated under reduced pressure to give the title compound as an oil (53.0 g, 0.20 mol). GC/MS: M+ C16H23NO2 261 Intermediate 6 4-(2-Ethoxy-4-methyl-phenyl)-piperidine To a solution of intermediate 5 (53.0 g, 0.20 mol) in MeOH (600 mL) was added a solution of NaOH (260 mL) in H20 (260 mL). The reaction was stirred under reflux for 48 hours. After cooling, the reaction was concentrated under reduced pressure, was diluted with DCM and washed with water. The organic layer was dried over Na2SO4 and evaporated to dryness to give the title compound (40.0 g, 0.18 mol) as a yellow oil. GC/MS: M+ C14H21NO 219 Intermediate 7 2- {4- [4- (2-Ethoxy-4-methyl-phenyl)-piperidiri-1-yi]-butyl}-isoindole-1, 3-dione A solution of intermediate 6 (39.5 g, 0.18 mol) in acetone (600 mL) was treated with Cs2C03 (64.5 g, 1.1 eq.) and N- (4-Bromobutyl)-phtalimide (50.9 g, 1.0 eq.). The resulting mixture was stirred under reflux for 24 hours. After cooling to rt the reaction mixture was filtered off. The cake was washed with acetone. The filtrate was evaporated off to give the title compound (60.0 g, 0.14 mol) as a yellow oil. GC/MS: M+ C26H32N203 420 Intermediate 8 4- [4- (2-Ethoxy-4-methyl-phenyl)-piperidin-1-yl]-butylamine A solution of intermediate 7 (60.0 g, 0.14 mol) in MeOH (600 mL) was treated with hydrazine hydrate (28 mL). The resulting mixture was stirred at 60 C for 3 hours. After evaporation under reduced pressure the residue was taken up in water and treated with a concentrated HO solution until PH = 3. The white precipitate was filtered off, washed with water and the filtrate was treated with a concentrated NaOH solution until PH = 13. Extraction with DCM, drying over Na2SO4 and filtration gave. the title compound (37.0 g, 0.13 mol) as a yellow oil. GC/MS : M+ C18H30N20 290 Intermediate 9 1- [4- (4-Ethyl-2-hydroxy-phenyl)-3, 6-dihydro-2H-pyridin-1-yl]-ethanone The same method was employed as in the preparation of intermediate 3 but starting from the 3-Ethyl-phenol gave the title compound as a pink solid in a quantitative yield. GC/MS: M+ C15H19NO2 245 Intermediate 10 1- [4- (4-Ethyl-2-Hydroxy-phenyl)-piperidin-1-yl]-ethanone The same method was employed as in the preparation of intermediate 4 but starting from the intermediate 9 gave the title compound as a solid in a 89% yield. GC/MS: M+ C15H21NO2 247 Intermediate 11 1- [4- (2-Cyclopropylmethoxy-4-ethyl-phenyl)-piperidin-1-yl]-ethanone To a solution of 7.6 g of the intermediate 10 in acetone (200 mL) was added CS2CO3 (12.1 g, 37 mmol) and bromo-methylcyclopropane (5 g, 37 mmol). The mixture was then stirred at 50 C during 24 hours. After cooling, the mixture was filtrated off and the white cake was washed with DCM. The filtrate was evaporated under vacuo to give 8.6 g of the title compound as a yellow residue in a 92% yield. GC/MS :M+ C19H27NO2 301 Intermediate 12 4- (2-cyclopropylmethoxy-4-ethyl-phenyl)-piperidine To a solution of 8.5 g (28.2 mmol) of the intermediate 11 in MeOH (75 mL) was added dropwise a 1/1 solution of 35% NaOH (37 mL) and H20 (37 mL). The resulting mixture was stirred at 70 C during 6 hours. After cooling to rt and evaporation under reduced pressure, the residue was taken up in AcOEt and washed with brine. The organic phase was separated, dried over Na2SO4 and evaporated off to afford 5.65 g of the title compound as a yellow oil in a 77% yield. GC/MS: M+ C17H25NO 259 Intermediate 13 2- [4- [4- (2-Cyclopropylmethoxy-4-ethyl-phenyl)-piperidin-1-yl]-butyl]-isoindole- 1,3-dione The same method was employed as in the preparation of intermediate 7 but starting from the intermediate 12 gave the title compound as a yellow oil in a 55% yield. LC/MS (APO) : [M+H+] 461 C29H36N203 Intermediate 14 4- [4- (2-Cyclopropylmethoxy-4-ethyl-phenyl)-piperidin-1-yl]-butylamine The same method was employed as in the preparation of intermediate 8 but starting from the intermediate 13 gave the title compound as a yellow oil in a 97% yield. LC/MS (APCI) : [M+H+] 331 C21H34N2O Intermediate 15 1- [4- (1-Hydroxy-naphtalen-2-yl)-3, 6-dihydro-2H-pyridin-1-yl]-ethanone The same method was employed as in the preparation of intermediate 3 but starting from the 1-Naphtol gave the title compound as a white solid in a 54% yield. GC/MS :M+ C17H17NO2 267 lntermediate 16 1- [4- (1-Hydroxy-naphtalen-2-yl)-piperidin-1-yl]-ethanone A solution of intermediate 15 (29.0 g, 0. 112 mol) in a mixture of cyclohexene (450 mL), MeOH (100 mL), THF (350 mL) was treated with Pd (OH) 2,50% (14 g). The resulting solution was allowed to stir at reflux for 4 days. After cooling, the reaction mixture was filtered through a bed of celite. The filtrate was evaporated to dryness to give the title compound as a white solid (22.0 g, 0. 082mol) in a 73% yield after recrystallization from CH3CN. LC/MS: [M+H+] C17H1sNO2 270 Intermediate 17 1- [4- (1-Methoxy-naphtalen-2-yl)-piperidin-1-yl]-ethanone To a solution of intermediate 16 (22.0 g, 0.08 mol) in dry DMF (400 mL) was added K2CO3 (23.0 g, 2 eq.) and methyl iodide (20.4 mL, 4 eq.). The reaction was stirred at 80 C for 16 hours. After cooling, the reaction was filtered off and evaporated under reduced pressure. The oil was diluted with DCM and washed with water. The organic layer was dried over Na2SO4 and evaporated to dryness to give the title compound as a white solid in a quantitative yield. GC/MS : M+ C18H21NO2 283 Intermediate 18 4- (1-Methoxy-naphtalen-2-yl)-piperidine To a solution of the intermediate 17 (23.0 g, 82 mmol) in EtOH (400 mL) was added dropwise a 1/1 solution of a concentrated NaOH solution and H20 (100 mL). The resulting mixture was stirred at 100 C during 16 hours. After cooling to rt and evaporation under reduced pressure, the residue was taken up in DCM and washed with water. The organic phase was dried over Na2SO4 and evaporated off to give the title compound as an oil (10.6 g, 44 mmol). GC/MS: M+ C16H19NO 241 Intermediate 19 2-f4- [4- (l-Methoxy-naphtalen-2-yl)-piperidin-1-yl]-bu. tyl}-isoindole-1, 3-dione The same method was employed as in the preparation of intermediate 7 but starting from intermediate 18 gave the title compound as a oil in a 88% yield. LC/MS (APCI) : [M+H+] 443 C28H3oN203 Intermediate 20 4- [4- (1-Methoxy-naphtalen-2-yl)-piperidin-1-yl]-butylamine The same method was employed as in the preparation of intermediate 8 but starting from intermediate 19 gave the title compound as a yellow oil in a 97% yield. LC/MS (APCI) : [M+H+] 313 C2oH28N20 Intermediate 21 1-Bromo-2-methoxy-naphtalene To a solution of 1-Bromo-naphtalen-2-ol (20.0 g, 0.089 mol) in acetone (300 mL) was added K2CO3 (25.0 g, 2 eq.) and methyl iodide (16.75 mL, 3 eq.). The reaction was stirred at reflux for 3 hours. After cooling, the reaction was filtered off and evaporated under reduced pressure. The oil was diluted with DCM and washed with water. The organic layer was dried over Na2SO4 and evaporated to dryness to give the title compound as a colorless solid in a quantitative yield. GC/MS : M+ C11HgBrO 237 Intermediate 22 4-Hydroxy-4- (2-methoxy-naphtalen-1-yl)-piperidine-1-carboxylic acid ter-butyl ester A solution of intermediate 21 (10. 0 g, 0.042 mol) in THF (100 mL) was cooled to - 78 C and treated with nBuLi (2.0 M in cyclohexane, 21 mL, 1.0 eq.). The resulting mixture was stirred for 2 hours at-55 C. At-78 C a solution of the 1- Boc-4-piperidone (8.40 g, 1 eq.) in THF (30 mL) was added. The resulting mixture was allowed to stir at rt C for 3 hours. Addition of a saturated ammonium chloride solution, extraction with Et20, drying over Na2SO4 and evaporation under reduced pressure gave the title compound (6.88 g, 0.019 mol) as an oil after purification by flash chromatography (DCM as eluent) in a 46% yield. GC/MS: M+ C21H27NO4 357 Intermediate 23 . 4- (2-Methoxy-naphtalen-1-yl)-piperidine A solution of intermediate 22 (6.88 g, 0.019 mol) in DCM (100 mL) was treated with TFA (14.6 mL, 10 eq.) and triethyl silane (61 mL, 20 eq.) at rt. The resulting solution was allowed to stir at rt for 24 hours. The solvent was evaporated under reduced pressure. The residue was diluted in DCM and washed with a 1N NaOH solution, dried over Na2SO4 and evaporated off to give the title compound (3.9 g, 0. 016 mol) as an oil in a 84% yield. The crude compound was used in the next step without purification. Intermediate 24 2- {4- [4- (2-Methoxy-naphtalen-1-yl)-piperidin-1-yl]-butyl}-isoindole-1, 3-dione The same method was employed as in the preparation of intermediate 7 but starting from intermediate 23 gave the title compound as a yellow oil in a 54% yield. LC/MS (APCI) : [M+H+] 443 C28H3oN203 Intermediate 25 4- [4- (2-Methoxy-naphtalen-1-yl)-piperidin-1-yl]-butylamine The same method was employed as in the preparation of intermediate 8 but starting from intermediate 24 gave the title compound as a yellow oil in a 76% yield. GC/MS: M+ C2oH28N20 312 Intermediate 26 5-Ethyl-2- (1, 2,3,6-tetrahydro-pyridin-4-yl)-phenol A solution of 3-Ethyl-phenol (122.2 g, 1.0 mol) and 4-Piperidone hydrate hydrochloride (183.0 g, 1.2 eq.) in acetic acid (500 mL) was treated with HCI gaz for 10 min. The mixture was stirred at 95 C for 30 min. After cooling to rt, the mixture was treated again with HCI gaz for 10min. The resulting solution was allowed to stir at rt for 4 days. The solvent was evaporated under reduced pressure to give a colorless oil (200.0 g). The product was used without further purification. Intermediate 27 Acetic acid 2-(1-acetyl-1, 2,3,6-tetrahydro-pyridin-4-yl)-5-ethyl-phenyl ester To a solution of intermediate 26 (33.0 g, 0.162 mol) in pyridine (300 mL) was added acetic anhydride (100 mL). The mixture was stirred at rt for 4 hours. The solvents were evaporated under reduce pressure. The oil was diluted with DCM and washed with water. The organic layer was dried over Na2SO4 and evaporated to dryness to give the title compound (28. 0 g, 0.097 mol) as a yellow oil in a 60% yield. 1 H NMR (CDCI3, 250 MHz) 5 7 (m, 2H), 6.7 (m, 1 H), 5.65 (m, 1 H), 4.05 (m, 2H), 3.55 (dt, 2H), 2.6 (q, 2H), 2.3 (m, 2H), 2.15 (s, 3H), 2.05 (d, 3H), 1.1 (t, 3H). Intermediate 28 1- [4- (4-Ethyl-2-hydroxy-phenyl)-3, 6-dihydro-2H-pyridin-1-yi]-ethanone To a solution of intermediate 27 (28.0 g, 0.098 mol) in MeOH (700 mL) was added K2CO3 (40.0 g, 3 eq.) and the mixture was stirred under reflux for 4 hours. The solution was filtered off and the methanol was evaporated. The oil was diluted with DCM and washed with water. The organic layer was dried over Na2SO4 and evaporated to dryness to give the title compound (20.0 g, 0.082 mol) as an orange oil in a 84% yield. 1H NMR (CDCI3, 250 MHz) 5 6.7 (m, 2H), 6.6 (m, 1 H), 5. 8 (m, 1H), 4.1 (m, 2H), 3.65 (m, 2H), 2.7 (m, 5H), 2.4 (q, 2H), 1.2 (t, 3H). Intermediate 29 1- [4- (4-Ethyl-2-hydroxy-phenyl)-piperidin-1-yl]-ethanone To a solution of intermediate 28 (20.0 g, 0.082 mol) in MeOH (600 mL) was added Pd/C, 10% (1.2 g) and the reaction was stirred under an atmospheric pressure of hydrogen for 16 hours. The reaction mixture was filtered through a bed of celite. The filtrate was evaporated under reduced pressure to give the title compound (15.0 g, 0.06 mol) as an oil in a 75% yield. 1 H NMR (CDC13, 250 MHz) 6 6.85 (d, 1 H), 6.6 (m, 2H), 4.65 (m, 1 H), 3.8 (m, 1H), 3.2-2.9 (m, 2H), 2.6 (m, 1H), 2.45 (q, 2H), 2.05 (s, 3H), 1.7 (m, 2H), 1.5 (m, 2H), 1.1 (t, 3H). Intermediate 30 1- [4- (2-Ethoxy-4-ethyl-phenyl)-piperidin-1-yl]-ethanone To a solution of intermediate 29 (7.41 g, 0.03 mol) in dry acetone (150 mL) was added anhydrous Cs2C03 (14.7 g, 1.5 eq.) and ethyl iodide (4.8 mL, 2eq.). The reaction was stirred under reflux for 5 hours. After cooling, the reaction was filtered off and washed with acetone. The filtrate was evaporated under reduced pressure to give the-title compound as an oil (8.2 g, 0.03 mol) in a quantitative yield. 1 H NMR (CDC13, 250 MHz) 6 6.9 (d, 1 H), 6.6 (m, 2H), 4.7 (m, 1 H), 4.0 (q, 2H) 3.8 (m, 1H), 3.1 (m, 2H), 2.5 (m, 3H), 2.05 (s, 3H), 1.7 (m, 2H), 1.5 (m, 2H), 1.35 (t, 3H), 1.1 (t, 3H). Intermediate 31 4-(2-Ethoxy-4-ethyl-phenyl)-piperidine To a solution of intermediate 30 (8.17 g, 0.03 mol) in MeOH (150 mL) was added a solution of NaOH (37 mL) in H20 (37 mL). The reaction was stirred under reflux for 12 hours. After cooling, the reaction was concentrated under reduced pressure, was diluted with DCM and washed with water. The organic layer was dried over Na2SO4 and evaporated to dryness to give the title compound (6.6 g, 0.028 mol) as a yellow oil in a 94% yield. 1H NMR (CDC13, 250 MHz) 5 7.1 (d, 1H), 6.7 (d, 1H), 4.7 (d, 1H), 4.05 (q, 2H) 3.1 (m, 2H), 3.05 (m, 1H), 2.7 (td, 2H), 2.55 (q, 2H), 1.75 (m, 3H), 1.55 (m, 2H), 1.35 (t, 3H), 1.1 (t, 3H). Intermediate 32 2- {4- [4- (2-Ethoxy-4-ethyl-phenyl)-piperidin-1-yl]-butyl}-isoindole-1, 3-dione The same method was employed as in the preparation of intermediate 7 but starting from intermediate 31 gave the title compound as a yellow oil in a 97% yield. 1 H NMR (CD03, 250 MHz) 5 7.8 (m, 2H), 7.6 (m, 2H), 7.0 (d, 1H), 6.65 (dd, 1 H), 6.55 (sd, 1 H), 3.95 (q, 2H), 3.65 (m, 3H), 2.95 (m, 2H), 2.8 (m, 1 H), 2.5 (q, 2H), 2.4 (m, 2H), 2 (td, 2H), 1.8-1.4 m, 8H), 1.3 (t, 3H), 1.15 (t, 3H). Intermediate 33 4- [4- (2-Ethoxy-4-ethyl-phenyl)-piperidin-1-yl]-butylamine The same method was employed as in the preparation of intermediate 8 but starting from intermediate 32 gave the title compound as a yellow oil in a 81.5% yield. 1H NMR (CD03, 250 MHz) 6 7.1 (d, 1H), 6.7 (dd, 1H), 6.6, (s, 1H), 4.0 (q, 2H), 3.0 (bd, 2H), 2.9 (m, 1H), 2.7 (t, 2H), 2.55 (q, 2H), 2.3 (m, 2H), 2.0 (td, 2H), 1.7 1.2 (m, 10H), 1.4 (t, 3H), 1.1 (t, 3H). Intermediate 34 1- [4- (1-Hydroxy-5,6,7,8-tetrahydro-naphtalen-2-yl)-3, 6-dihydro-2H-pyridin-1-yl]ethanone The same method was employed as in the preparation of intermediate 3 but starting from the 5,6,7,8-tetrahydro-1-naphtol to give the title compound as a powder after crystallization in CH3CN in a 100% yield. GC/MS: M+ C17H21NO2 271 Intermediate 35 1- [4- (1-Hydroxy-5, 6,7,8-tetrahydro-naphtalen-2-yl)-piperidin-1-yl]-ethanone To a solution of intermediate 34 (55.0 g, 0.203 mol) in AcOH (500 mL) was added Pd/C, 10% (2 g) and the reaction was stirred under an atmospheric pressure of hydrogen at 50 C for 24 hours. The mixture was filtered through a bed of celite. The filtrate was evaporated under reduced pressure to give the title compound (55.0 g, 0.201 mol) as a yellow powder. GC/MS : M+ C17H22NO2 273 Intermediate 36 1-[4-(1-Isobutoxy-5, 6,7,8-tetrahydro-naphtalen-2-yl)-piperidin-1-yl]-ethanone To a solution of Intermediate 35 (10.0 g, 0.037 mol) in dry acetone (200 mL) was added K2CO3 (15.2 g, 3 eq.) and 1-Bromo-2-methylpropane (5.2 mL, 1.3 eq.). The reaction was stirred under reflux for 24 hours. After cooling, the reaction was filtered off and washed with acetone. The filtrate was evaporated under reduced pressure to give the title compound as an oil (7.0 g, 0.021 mol). GC/MS : M+ C21H31NO2 329 Intermediate 37 -(1-Isobutoxy-5, 6,7,8-tetrahydro-naphtalen-2-yl)-piperidine The same method was employed as in the preparation of intermediate 12 but starting from the intermediate 36 to give the title compound as a yellow oil in a 100% yield. GC/MS: M+ C19H29NO 287 Intermediate 38 2-{4-[4-(1-Isobutoxy-5, 6,7,8-tetrahydro-naphtalen-2-yl)-piperidin-1-yl]-butyl}isoindole-1, 3-dione The same method was employed as in the preparation of intermediate 7 but starting from the intermediate 37 to give the title compound as a colorless oil in a 73.5% yield. LC/MS (APCI) : [M+H+] CsiH4oN203 489 Intermediate 39 4-[4-(1-Isobutoxy-5,6,7,8-tetrahydro-naphtalen-2-yl)-piperidin-1-yl]-butylamine The same method was employed as in the preparation of intermediate 8 but starting from the intermediate 38 to give the title compound as a yellow oil in a 69% yield. GC/MS : M+ C23H38N20 358 Intermediate 40 1-[4-(1-Allyloxy-naphtalen-2-yl)-piperidin-1-yl]-ethanone A solution of intermediate 35 (6.0 g, 0.022 mol) in acetone (300 mL) was treated with Cs2CO3 (14.3 g, 2 eq.) and allyl bromide (2.2 mL, 1.1 eq.). The resulting mixture was stirred at reflux for 4 hours and filtrated off after cooling to rt. The filtrate was evaporated off and addition of water, extraction with DCM, drying over Na2SO4 and evaporation under reduced pressure gave the title compound (4.5 g, 0.015 mol) as beige solid, which was crystallised from iPr2O in a 67% yield. 'H NMR (CDCl3, 300 MHz) 87. 9 (d, 1 H), 7.6 (d, 1 H), 7.45 (d, 1 H), 7.3 (m, 2H), 7.1 (d, 1H), 6.0 (m, 1H), 5.4 (d, 1H), 5.2 (d, 1H), 4.65 (d, 1H), 4.35 (dd, 2H), 3.8 (d, 1H), 3.5 (m, 1H), 3.0 (t, 1H), 2.5 (t, 1H), 2.0 (s, 3H), 1.6 (m, 4H). Intermediate 41 4- (1-Allyloxy-naphtalen-2-yl)-piperidine The same method was employed as in the preparation of intermediate 12 but starting from the intermediate 40 to give the title compound as a pink oil in a quantitativeyield. 1H NMR (CDC13, 300 MHz) # 8. 0 (d, 1H), 7.8 (d, 1H), 7.5 (d, 1 H), 7.3 (m, 3H), 6.2 (m, 1H), 5.4 (d, 1H), 5.2 (d, 1H), 4.4 (d, 1H), 3.6 (m, 1H), 3.2 (m, 1H), 3.0 (m, 2H), 2.7 (m, 2H), 1.6 (m, 4H). Intermediate 42 2-{4-[4-(1-Allyloxy-naphthalen-2-yl)-piperidin-1-yl]-butyl}-isoindole-1,3-dione The same method was employed as in the preparation of intermediate 7 but starting from intermediate 41 gave the title compound as pink crystals (3.7 g, 7.9 mmol) in a 50% yield. 1H NMR (CDCl3, 300 MHz) 8 8.1 (d, 1H), 7.9 (m, 3H), 7.8 (m, 2H), 7.6 (d, 1H), 7.3 (m, 3H), 6.2 (m, 1H), 5.5 (d, 1H), 5.3 (d, 1H), 4.4 (d, 2H), 3.8 (t, 2H), 3.3 (m, 1H), 3.0 (d, 2H), 2.4 (t, 2H), 2.1 (t, 2H), 2.0 (m, 2H), 1.7 (m, 4H), 1.6 (m, 2H). Intermediate 43 4-[4-(1-Allyloxy-naphtalen-2-yl]-piperidin-1-yl]-butylamine The same method was employed as in the preparation of intermediate 8 but starting from intermediate 42 gave the title compound as yellow oil (2.1 g, 7.9 mmol) in a 79% yield. 1H NMR (CDCl3, 300 MHz) 8 8.1 (d, 1H), 7.8 (d, 1H), 7.6 (d, 1H), 7.3 (m, 3H), 6.2 (m, 1H), 5.5 (d, 1 H), 5.3 (d, 1 H), 4.4 (d, 2H), 3.8 (t, 2H), 3.3 (m, 1 H), 3.0 (d, 2H), 2.4 (t, 2H), 2.1 (t, 2H), 2.0 (m, 2H), 1.7 (m, 4H), 1.6 (m, 2H). Intermediate 44 1- [4- (1-Propoxy-naphtalen-2-yl)-piperidin-1-yl]-ethanone The same method was employed as in the preparation of intermediate 40 in using the 1-Bromo-propane to give the title compound as a colorless powder (5.8 g, 19 mmol) in a 84% yield. 1H NMR (CDC13, 300 MHz) 5 8.1 (d, 1H), 7.8 (d, 1H), 7.5 (d, 1H), 7.3 (m, 2H), 7.1 (d, 1H), 4.8 (d, 1H), 3.9 (m, 3H), 3.3 (m, 1H), 3.2 (m, 1H), 2.5 (m, 1H), 2.1 (s, 3H), 1.8 (m, 2H), 1.8 (m, 4H), 1.1 (t, 3H). Intermediate 45 4-(1-Propoxy-naphtalen-2-yl)-piperidine The same method was employed as in the preparation of intermediate 12 but starting from intermediate 44 gave the title compound as yellow oil (4.3 g, 16 mmol) in a 84% yield. 1H NMR (CDCl3, 300 MHz) 8 8.1 (d, 1H), 7.8 (d, 1H), 7.5 (d, 1H), 7.3 (m, 2H), 7.1 (d, 1H), 4.8 (d, 1H), 3.9 (m, 3H), 3.3 (m, 1H), 3.2 (m, 1H), 2.5 (m, 1H), 1.8 (m, 2H), 1.8 (m, 4H), 1.1 (t, 3H). Intermediate 46 2-{4-[4-(1-Propoxy-naphtalen-2-yl)-piperidin-1-yl]-butyl}-isoindole-1,3-dione The same method was employed as in the preparation of intermediate 7 but starting from intermediate 45 gave the title compound as yellow crystals (5.3 g, 11 mmol) in a 75% yield. 'H NMR (CDCI3, 300 MHz) 8 8.1 (d, 1H), 7.9 (m, 3H), 7.8 (m, 2H), 7.6 (d, 1H), 7.3 (m, 3H), 3.8 (t, 2H), 3.3 (m, 1H), 3.0 (d, 2H), 2.4 (t, 2H), 2.1 (t, 2H), 2.0 (m, 2H), 1.7 (m, 8H), 1.6 (m, 2H), 1.1 (t, 3H). Intermediate 47 4- [4- (1-Propoxy-naphtalen-2-yl)-piperidin-1-yl]-butylamine The same method was employed as in the preparation of intermediate 8 but starting from intermediate 46 gave the title compound as a yellow oil (3.5 g, 10 mmol). 1 H NMR (CDCI3, 300 MHz) 8 8.05 (d, 1H), 7.8 (d, 2H), 7.6 (d, 1H), 7.3 (m, 3H), 3.8 (t, 2H), 3.3 (m, 1H), 3.0 (d, 2H), 2.4 (t, 2H), 2.1 (t, 2H), 2.0 (m, 2H), 1. 7 (m, 8H), 1.6 (m, 2H), 1.1 (t, 3H). Intermediate 48 1- [4- (1-Cyclopropylmethoxy-5, 6,7,8-tetrahydro-naphtalen-2-yl)-piperidin-1-yl]ethanone To a solution of intermediate 35 (11.2 g, 0.041 mol) in dry acetone and DMF (200 mL, 1/1) was added Cs2CO3 (20.05 g, 1.5 eq.) and Bromomethylcyclopropane (6.09 g, 1.1 eq.). The reaction was stirred at 55 C for 13 hours. After cooling, the reaction was filtered off and washed with acetone. The filtrate was evaporated under reduced pressure to give the title compound as an yellow oil in a quantitative yield. The crude product was used in the next step without purification. Intermediate 49 4- (1-Cyclopropylmethoxy-5, 6,7,8-tetrahydro-naphtalen-2-yl)-piperidine The same method was employed as in the preparation of intermediate 12 but starting from the intermediate 48 to give the title compound as an oil in a 90% yield. 1H NMR (CDCl3, 300 MHz) 6 6. 95 (d, 1H), 6.8 (d, 1 H), 3.5 (m, 2H), 2.9 (m, 2H), 2.8 (m, 4H), 2.3 (m, 2H), 1.9 (m, 2H), 1.8 (m, 4H), 1.4 (m, 4H), 1.1 (m, 1H), 0.45 (m, 2H), 0.25 (m, 2H). Intermediate 50 2-{4-[4-(1-Cyclopropylmethoxy-5, 6,7,8-tetrahydro-naphtalen-2-yl)-piperidin-1-yl] butyl}-isoindole-1, 3-dione The same method was employed as in the preparation of intermediate 7 but starting from the intermediate 49 to give after flash chromatography using (DCM/MeOH, 95/5 and 90/10) as eluent, the title compound as an orange oil in a 80% yield. 'H NMR (CDCl3, 300 MHz) 6 7. 8 (m, 2H), 7.6 (m, 2H), 6.9 (d, 1 H), 6.7 (d, 1 H), 3.7 (m, 2H), 3.4 (m, 2H), 3.0 (m, 2H), 2.6 (m, 4H), 2.4 (m, 2H), 1.9 (m, 2H), 1.7 (m, 13H), 1.1 (m, 1H), 0.45 (m, 2H), 0.25 (m, 2H). Intermediate 51 4-[4-(1-Cyclopropylmethoxy-5, 6,7,8-tetrahydro-naphtalen-2-yl)-piperidin-1-yl] butylamine The same method was employed as in the preparation of intermediate 8 but starting from intermediate 50 gave the title compound as an orange oil in a 90% yield. LC/MS (APCI) : [M+H] 357 C23H36N20 Intermediate 52 1- [4- (1-methoxy-5, 6,7,8-tetrahydro-naphtalen-2-yl)-piperidin-1-yll-ethanone The same method was employed as in the preparation of intermediate. 17 but starting from intermediate 35 gave the title compound as white solid in a 57% yield. LC/MS (APCI) : [M+H+] 287 C18H25NO2 Intermediate 53 4- (1-methoxy-5, 6,7,8-tetrahydro-naphtalen-2-yl)-piperidine The same method was employed as in the preparation of intermediate 12 but starting from intermediate 52 gave the title compound as a yellow oil in a 90% yield. LC/MS (APCI) : [M+H+] 246 C16H23NO Intermediate 54 2- {4- [4- (1-methoxy-5, 6,7,8-tetrahydro-naphtalen-2-yl)-piperidin-1-yl]-butyl}isoindole-1, 3-dione The same method was employed as in the preparation of intermediate 7 but starting from intermediate 53 gave the title compound as a oil in a quantitative yield. LC/MS (APO) : [M+H+] 447 C28H34N203 Intermediate 55 4- [4- (1-methoxy-5, 6,7,8-tetrahydro-naphtalen-2-yl)-piperidin-1-yl]-butylamine The same method was employed as in the preparation of intermediate 8 but starting from intermediate 54 gave the title compound as a yellow oil in a 83% yield. LC/MS (APCI) : [M+H+] 317 C20H32N2O Intremediate 56 4'-Methanesulfonyl-biphenyl-4-carboxylicacid The same method was employed as in the preparation of intermediate 1 but starting from the 4-Bromophenylmethanesulfone gave the title compound as white powder in a 56% yield. LC/MS (ES): M+ 276 C14H12SO4 Intermediate 57 5-Isopropyl-2-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenol A solution of 3-isopropyl-phenol (68.1 g 0.5 mol) and 4-Piperidone hydrate hydrochloride (92.1 g, 1.2 eq.) in acetic acid (300 mL) was treated with HO gaz for 10 min. The mixture was stirred at 95 C for 30 min. After cooling to rt, the mixture was treated again with HCI gaz for 10 min. The resulting solution was allowed to stir at rt for 4 days. The solvent was evaporated under reduced pressure to give a colorless oil (110.0 g 0.5 mol). The product was used without further purification. Intermediate 58 Acetic acid 2- (1-acetyl-1, 2,3,6-tetrahydro-pyridin-4-yl)-5-isopropyl-phenyl ester To a solution of intermediate 57 (110.0 g, 0.5 mol) in pyridine (1000 mL) was added acetic anhydride (300 mL). The mixture was stirred at rt for 12 hours. The solvents were evaporated under reduce pressure. The oil was diluted with DCM and washed with water. The organic layer was dried over Na2SO4 and evaporated to dryness to give the title compound (150.0 g, 0.5 mol) as a yellow oil in a quantitative yield. GC/MS : M+ C18H23NO3 301 Intermediate 59 1- [4- (2-Hydroxy-4-isopropyl-phenyl)-3, 6-dihydro-2H-pyridin-1-yl]-ethanone To a solution of intermediate 58 (150.0 g, 0.5 mol) in MeOH (1500 mL) was added K2CO3 (207.0 g, 3 eq.) and the mixture was stirred under reflux for 12 hours. The solution was filtered and the methanol was evaporated. The oil was diluted with DCM and washed with water. The organic layer was dried over Na2SO4 and evaporated to dryness to give the title compound (76.0 g, 0.29 mol) as an orange oil. GC/MS zM+ C16H2, NO2 259 Intermediate 60 1- [4- (2-Hydroxy-4-isopropyl-phenyl)-piperidin-1-yl]-ethanone To a solution of intermediate 59 (56.0 g, 0.22 mol) in EtOH (1400 mL) was added Pd/C, 10% (5.6 g) and the reaction was stirred under under an atmospheric pressure of hydrogen for 48 hours. The reaction mixture was filtered through a bed of celite. The filtrate was evaporated, under reduced pressure to give the title compound (54.5 g, 0.21 mol). GC/MS : M+ C16H23NO2 261 Intermediate 61 1- [4- (4-isopropyl-2-methoxy-phenyl)-piperidin-1-yi]-ethanone To a solution of intermediate 60 (54.5 g, 0.21 mol) in dry acetone (1000 mL) was added K2CO3 (43.0 g, 1.5 eq.) and methyl iodide (130 mL, 10 eq.). The reaction was stirred at 60 C for 12 hours. After cooling, the reaction was filtered off and evaporated under reduced pressure. The oil was diluted with DCM and washed with water. The organic layer was dried over Na2SO4 and evaporated to dryness to give the title compound (55.7 g, 0.203 mol) as a yellow oil. GC/MS : M+ C17H25NO2 275 Intermediate 62 4-(4-lsopropyl-2-methoxy-phenyl)-piperidine To a solution of intermediate 61 (55.7 g, 0.200 mol) in EtOH (500 mL) was added a solution of NaOH (270 mL) in H20 (270 mL). The reaction was stirred under reflux for 12 hours. After cooling, the reaction was concentrated under reduced pressure, was diluted with DCM and washed with water. The organic layer was dried over Na2SO4 and evaporated to dryness to give the title compound (48.8 g, 0.20 mol) as a yellow oil. GC/MS: M+ C15H23NO 233 Intermediate 63 2- {4- [4- (4-Isopropyl-2-methoxy-phenyl)-piperidin-1-yl]-butyl}-isoindole-1, 3-dione The same method was employed as in the preparation of intermediate 7 but starting from intermediate 62 gave the title compound as a yellow oil in a quantitative yield. H NMR (CDC13, 250 MHz) 5 7.8 (m, 2H), 7.65 (m, 2H), 7.05 (d, 1 H), 6.7 (dd, 1H), 6.6 (s, 1H), 3.7 (s, 3H), 3.65 (m, 3H), 2.9 (m, 1H), 3.0 (bd, 2H), 2.8 (m, 2H), 2.3 (m, 2H), 2.0 (m, 2H), 1.70-1.5 (m, 6H), 1.2 (d, 6H). Intermediate 64 4- [4- (4-Isopropyl-2-methoxy-phenyl)-piperidin-1-yl]-butylamine The same method was employed as in the preparation of intermediate 8 but starting from intermediate 28 gave the title compound as an oil in a 93% yield. 1H NMR (CDC13, 250 MHz) 5 7.05 (m, 1 H), 6.7 (dd, 1 H), 6.6 (d, 1 H), 3.8 (s, 3H), 3.1 (bd, 2H), 2.8 (m, 2H), 2.7 (t, 2H), 2.3 (m, 2H), 2.0-1.3 (m, 12H), 1.15 (d, 6H). Intermediate 65 2- (1-Benzyl-1, 2,3,6-tetrahydro-pyridin-4-yl)-5-methyl-phenol To a solution of m-Cresol (20.0 g, 0.185 mol) and 1-Benzyl-4-piperidone (35.0 g, 1.0 eq.) was added dropwise BF3-Et2O (71 mL, 3.0 eq). The mixture was stirred at 100 C for 24 hours. After cooling to rt, the mixture was treated with a 1 N HCI solution (400 mL). The resulting solution was extracted with DCM. The organic layer was dried over Na2SO4 and evaporated to dryness to give an oil which was crytallized in cyclohexane to give the title compound (40.0 g, 0.14 mol) as a yellow powder. GC/MS zM+ C19H21NO 279 Intermediate 66 2- (1-Benzyl-1, 2,3,6-tetrahydro-pyridin-4-yl)-5-ethyl-phenol A solution of 3-Ethyl-phenol (6.1 g, 0.05 mol) and 1-Benzyl-4-piperidone (10.0 g 1.05 eq.) in acetic acid (100 mL) was treated with HO gaz for 10 min. The mixture was stirred at 95 C for 30 min. After cooling to rt, the mixture was treated again with HCI gaz for 5min. The resulting solution was allowed to stir at rt for 4 days. The solvent was evaporated under reduced pressure and the residue was diluted with H20 and extracted with DCM. The organic layer was washed with a 2N NaOH solution, H20 and brine, dried over Na2SO4 and evaporated to dryness. The residue was flash chromatographed using MeOH/DCM (5/95) to give the title compound (8.0 g, 0.027 mol) as a yellow oil in 54% yield. GC/MS: M+ C2oH23NO 293 Intermediate 67 1-Benzyl-4- [2- (tert-butyl-dimethyl-silanyloxy)-4-ethyl-phenyl]-1, 2,3,6-tetrahydro pyridine To a solution of intermediate 66 (3.0 g, 0.01 mol) in DMF (20 mL) was added at 50 C NaH (1.1 eq.) (60% in oil dispersion). The reaction was stirred for 15 min and the terbutyl dimethyl silyl chloride (1 ; 65 g, 0.011 mol) was added and the reaction was stirred for 18 hours at rt. The reaction was concentrated in vacuo and the residue was diluted with DCM, washed with water, dried over Na2SO4 and evaporated off. The title compound was obtained (3.1 g, 7.6 mmol) as a yellow oil in a 77% yield. GC/MS: M+ C26H37NOSi 407 Intermediate 68 4- [2- (tert-Butyl-dimethyl-silanyloxy)-4-ethyl-phenyl]-piperidine To a solution of intermediate 67 (3.1 g, 7.6 mmol) in EtOH (100 mL) was added Pd/C, 10% (0.3 g) and the reaction was stirred under an atmospheric pressure of hydrogen for 24 hours. The reaction mixture was filtered through a bed of celite. The filtrate was evaporated under reduced pressure to give the title compound (2.0 g, 6.2 mmol) as an oil in a 83% yield. GC/MS: M+ C1gH33NOSi 319 Intermediate 69 2- (4- {4- [2- (tert-Butyl-dimethyl-silanyloxy)-4-ethyl-phenyl]-piperidin-1-yl}-butyl)- isoindole-1, 3-dione A solution of intermediate 68 (2.0 g, 6.2 mmol) in acetone (800 mL) was treated with K2CO3 (1.7 g, 2.0 eq.) and N- (4-Bromobutyl)-phtalimide (2.1 g, 1.2 eq.). The resulting mixture was stirred under reflux for 6 hours. After cooling to rt the reaction mixture was filtered off. The cake was washed with acetone. The filtrate was evaporated off to give after flash chromatography using (DCM/MeOH, 95/5) as eluent the title compound (2.1 g, 4 mmol) as yellow crystals in a 66% yield. GC/MS: M+ C31H44N203Si 520 Intermediate 70 4- {4- [2- (tert-Butyl-dimethyl-silanyloxy)-4-ethyl-phenyl]-piperidin-1-yl}-butylamine A solution of intermediate 69 (2.1 g, 4 mmol) in MeOH (50 mL) was treated with hydrazine hydrate (0.23 mL, 1.2 eq..). The resulting mixture was stirred at 60 C for 5 hours. After evaporation under reduced pressure the residue was taken up in water and treated with a concentrated HCI solution until PH = 4. The white precipitate was filtered off, washed with water and the filtrate was treated with a concentrated NaOH solution until PH = 13. Extraction with DCM, drying over Na2SO4 and filtration gave the title compound (0.7 g, 1.8 mmol) as a yellow oil in a 45% yield. GC/MS: M+ C23H42N2OSi 390 Intermediate 71 4'-Cyano-biphenyl-4-carboxylic acid (4- {4- [2- (tert-butyl-dimethyl-silanyloxy)-4ethyl-phenyl-piperidin-1-yl}-butyl)-amide To a solution of intermediate 70 (0.7 g, 1.8 mmol) in dry DCM (25 mL) was added the available 4'-Cyano-biphenyl-4-carboxylic acid (0.36 g, 0.9 eq.), EDCI (0.68 g, 2.0 eq.), HOBt (0.48 g, 2.0 eq.) and TEA (0.5 mL, 2.0 eq.). The resulting mixture was stirred for 5 hours at rt. The residue was washed with water and brine. The organic layer was dried over Na2SO4 and evaporated off. Purification by flash chromatography using DCM/MeOH, 90/10 as eluent gave the title compound (0.7 g, 1.17 mmol) as white crystals in a 73% yield. MP: 140 C LC/MS : [M+H+] 596 C37H49N302Si Intermediate 72 1- [4- (1-Hydroxy-5, 6,7,8-tetrahydro-naphtalen-2-yl)-3,6-dihydro-2H-pyridin-1-yl]ethanone The same method was employed as in the preparation of intermediate 65 but starting from the 5,6,7,8-tetrahydro-1-naphtol and N-Acetyl-piperidone to give the title compound as a powder after crystallization in CH3CN in a 100% yield. GC/MS: M+ C17H21NO2 271 Intermediate 73 1- [4- (1-Hydroxy-5, 6,7,8-tetrahydro-naphtalen-2-yl)-piperidin-1-yl]-ethanone To a solution of intermediate 72 (55.0 g, 0.203 mol) in AcOH (500 mL) was added Pd/C, 10% (2 g) and the reaction was stirred under an atmospheric pressure of hydrogen at 50 C for 24 hours. The mixture was filtered through a bed of celite. The filtrate was evaporated under reduced pressure to give the title compound (55.0 g, 0.201 mol) as a yellow powder. GC/MS: M+ C17H22NO2 273 Intermediate 74 2-Piperidin-4-yl-5,6,7,8-tetrahydro-naphtalen-1-ol To a solution of intermediate 73 (27.0 g, 0.099 mol) in EtOH (750 mL) was added a solution of NaOH (250 mL) in H20 (250 mL). The reaction was stirred under reflux for 16 hours. After cooling, the reaction was concentrated under reduced pressure, was diluted with DCM and washed with water. The organic layer was dried over Na2SO4 and evaporated to dryness to give after flash chromatography using DCM/MeOH/NH40H 30,30,30 as eluent, the title compound (9.7 g, 0.042 mol) as a pink gummy oil in a 42.5% yield. 'H NMR (CDC13, 300 MHz) 8 7.9 (bs, 1H), 6.8 (d, 1H), 6.6 (d, 1H), 3.4 (m, 2H), 3.1 (m, 2H), 2.8 (m, 4H), 1.8-1.4 (m, 10H). Intermediate 75 2- (4, 4-Diethoxy-butyl)-isoindole-1, 3-dione To a solution of Isobenzofuran-1, 3-dione (10.0 g, 0.068 mol) in toluene (200 mL) were added 4-Aminobutyraldehyde diethyl acetal (14.5 g, 1.2 eq.) and TEA (14.0 mL, 1.5 eq.). The reaction was stirred to reflux for 16 hours. The toluene was removed under vacuo and the residue was dissolved in Et20 and washed with water. The organic phase was dried over Na2SO4 and concentrated under vacuo to give the title compound (21.0 g, 1.0 eq.) as an oil in a quantitative yield. GC/MS: M+ C16H21NO4 291 Intermediate 76 4- (1, 3-Dioxo-1,3-dihydro-isoindole-2-yl)-butyraldehyde To a solution of intermediate 17 (21.0 g, 0 : 068 mol) in acetone (200 mL) was added a 1 N HCI solution (100 mL) and the reaction was stirred to reflux for 2 hours. The solvent was then evaporated and a 1 N NaOH solution (200 mL) was added. The product was extracted with DCM and the organic phase was dried over Na2SO4 and concentrated under vacuo. The title compound was obtained as a yellow oil (8.4 g, 0.039 mol) in a 59% yield. 'H NMR (CDC13, 300 MHz) 8 9.6 (s, 1H), 7.8 (m, 2H), 7.4 (m, 2H), 3.6 (t, 2H), 2.4 (t, 2H), 1.8 (m, 2H). Ref: J. Med. Chem. (1992), 35,3239-46. Intermediate 77 2- {4- [4- (1-Hydroxy-5, 6,7,8-tetrahydro-naphtalen-2-yl)-piperidin-1-yl]-butyl}isoindole-1, 3-dione To a solution of intermediate 74 in dry THF and MeOH was added the intermediate 76. The reaction was stirred at rt for 30 min and AcOH (1.5 eq) was added. Then sodium triacetoxyborohydride (1.2 eq.) was added and the reaction was stirred for 24 hours at 80 C. After cooling, the solvent was evaporated and subjected to flash chromatography using (DCM/MeOH, 90/10 and 1% ammoniac solution) as eluent to give the title compound as a gummy oil in a 46% yield. 'H NMR (CDCl3, 300 MHz) 8 7.9 (m, 2H), 7.75 (m, 2H), 6.9 (d, 1 H), 6.8 (d, 1 H), 6.4 (bs, 1 H), 3.85 (m, 2H), 3.5 (m, 2H), 3.0 (m, 1 H), 2.9 (m, 2H), 2.8 (m, 2H), 2.5 (m, 4H), 2.1 (m, 2H), 1.87 (m, 10H). Intermediate 78 2- [1- (4-Amino-butyl)-piperidin-4-yl]-5, 6, 7, 8-tetrahydro-naphtalen-1-ol The same method was employed as in the preparation of intermediate 70 but starting from intermediate 77 to give the title compound as a red oil in a 90% yield. 1H NMR (CDCl3, 300 MHz) # 7. 0 (d, 1H), 6.6 (d, 1H), 3.1 (m, 2H), 2.9 (m, 1H), 2.65 (m, 4H), 2.6 (m, 2H), 2.45 (m, 2H), 2.1 (m, 2H), 1.85 (m, 8H), 1.5 (m, 6H). Intermediate 79 1- [4- ( 1-Hydroxy-naphtalen-2-yl)-3, 6-dihyd ro-2H-pyridin-1-yl]-ethanone The same method was employed as in the preparation of intermediate 65 but starting from the 1-Naphtol gave the title compound as a white solid in a 54% yield. GC/MS: M+ C17H17NO2 267 Intermediate 80 1- [4- (l-Hydroxy-naphtalen-2-yi)-piperidin-1-yl]-ethanone A solution of intermediate 73 (29.0 g, 0.112 mol) i. n a mli, xture of cyclohexene (450 mL), MeOH (100 mL), THF (350 mL) was treated with Pd (OH) 2,50% (14 g). The resulting solution was allowed to stir at reflux for 4 days. After cooling, the reaction mixture was filtered through a bed of celite. The filtrate was evaporated to dryness to give the title compound as a white solid (22.0 g, 0. 082mol) in a 73% yield after recrystallization from CH3CN. LC/MS: [M+H+] C17H19NO2 270 Intermediate 81 2-Piperidin-4-yl-naphtalen-1-ol The same method was employed as in the preparation of intermediate 74 but starting from the intermediate 80 gave the title compound as a brown solid in a quantitative yield. 'H NMR (DMSO, d6, 300 MHz) 6 9.3 (s, 1H), 8.25 (dd, 1H), 7.8 (dd, 1H), 7.5 (m, 3H), 7.25 (m, 1H), 3.45 (m, 3H), 3.1 (m, 2H), 2.9 (m, 4H). Intermediate 82 2- {4- [4- (1-Hydroxy-naphtalen-2-yl)-piperidin-1-yl]-butyl}-isoindole-1, 3-dione The same method was employed as in the preparation of intermediate 77 but starting from the intermediate 81 gave the title compound as a pink solid in a 61% yield. 1H NMR (CDCl3, 300 MHz) 8 8.3 (dd, 2H), 7.95 (m, 2H), 7.8 (m, 3H), 7.6-7.2 (m, 4H), 3.85 (m, 2H), 3.25 (m, 2H), 2.85 (m, 2H), 2.55 (m, 2H), 2.35 (m, 2H), 1.95 (m, 2H), 1.8 (m, 4H). Intermediate 83 2- [1- (4-Amino-butyl)-piperidin-4-yl]-naphtalen-1-ol The same method was employed as in the preparation of intermediate 70 but starting from intermediate 82 to give the title compound as a yellow solid in a 79% yield. LC/MS (ES): M+ C19H26N20 298 Intermediate 84 4'-Acetyl-biphenyl-4-carboxylic acid ethyl ester To a solution of 16 g (0.058 mol.) of 4-iodo-benzoic acid ethyl ester in toluene (200 mL) was added successively 3.35 g (0.05 eq.) of tetrakis (triphenylphosphine) palladium (0), 69 ml of a 2M solution of Na2CO3 and 7.5 g (3 eq.) of lithium chloride. After 15 minutes of stirring was added a solution of 10 g (1.05 eq.) of 4-acetylphenyl boronic acid in EtOH (50 mL). Then, the mixture was refluxed for 24 hours. After cooling, the solvents were evaporated to dryness. The residue was poured in water (300 mL) and the organic phase was separated ; dried over Na2SO4 and evaporated off. After purification by flash chromatography (using DCM as eluent), the tilte compound (12.0 g, 0.045 mol) was obtained as a powder in a 73% yield. GC/MS: M+ Ci7Hie03 268 Intermediate 85 4'-Acetyl-biphenyl-4-carboxylic acid To a solution of intermediate 84 (12.0 g, 0.045 mol) in EtOH (200 mL) was added a 1 N NaOH solution (85 mL, 2 eq.) and the reaction was reflux for 16 hours. After cooling, the reaction was concentrated in vacuo and a 1 N HCI solution (100 mL) was added. The precipitate obtained was filtered off, washed with water and dried to give the title compound as a colorless powder (10 g, 0.042 mol) in a 93% yield GC/MS: M+ C15H1203 240 Intermediate 86 1-Benzyl-4- [2- (tert-butyl-dimethyl-silanyloxy)-4-methyl-phenyl]-1, 2,3,6tetrahydro-pyridine The same method was employed as in the preparation of intermediate 9 but starting from the intermediate 65 gave the title compound as a yellow oil in a 30% yield. GC/MS: M+ 393 C25H35NOSi Intermediate 87 4- [2- (tert-Butyl-dimethyl-silanyloxy)-4-methyl-phenyl]-pyridine The same method was employed as in the preparation of intermediate 68 but starting from intermediate 86 to give the title compound as a white powder in a quantitativeyield. GC/MS: M+ CisH3iNOSi 305 Intermediate 88 2- (4- 4- [2- (tert-Butyl-dimethyl-silanyloxy)-4-methyl-phenyl]-pyridin-1-yl}-butyl)- isoindole-1, 3-dione The same method was employed as in the preparation of intermediate 69 but starting from intermediate 87 gave the title compound as a yellow oil in a 40% yield which crystallise in MeOH. GC/MS: M+ C3oH42N203Si 506 Intermediate 89 4- 4- [2- (tert-Butyl-dimethyl-silanyloxy)-4-methyl-phenyl]-pyridin-1-yl}-butylamine The same method was employed as in the preparation of intermediate 70 but starting from intermediate 88 gave the title compound as a yellow oil in a 96% yield. LC/MS (APCI) : [M+H+] C22H4oN20Si 377 Intermediate 90 4'-Cyano-biphenyl-4-carboxylic acid (4- {4- [2- (tert-butyl-dimethyl-silanyloxy)-4methyl-phenyl-piperidin-1-yl}-butyl)-amide The same method was employed as in the preparation of intermediate 71 but starting from intermediate 89 gave the title compound as a white oil in a 36% yield. LC/MS (APCI) : [M+H+] C36H47N302Si 582 Example 1 4'-Trifluoromethyl-biphenyl-4-carboxylic acid 4- [4- (2-ethoxy-4-methyl-phenyl)piperidin-1-yl]-butyl}-amide To a solution of intermediate 8 (0.58 g, 2 mmol) in dry DCM (20 mL) was added the intermediate 1 (0.48 g, 0.9 eq.), EDCI (0.46 g, 1.2 eq.), HOBt (0.32 g, 1.2 eq.) and TEA (0.34 mL, 1.2 eq.). The resulting mixture was stirred for 16 hours at rt. The residue was washed with a 1 N NaOH solution and brine. The organic layer was dried over Na2SO4 and evaporated off. Recrystallization from CH3CN gave the title compound as white crystals in a 65% yield. MP: 191 C. LC/MS: [M+H+] 539 C32H37F3N202 Example 2 4'-Trifluoromethyl-biphenyl-4-carboxylic acid [4- [4- (2-cyclopropylmethoxy-4ethyl-phenyl)-piperidin-1-yl]-butyl]-amide A solution of intermediate 14 (1.65 g, 5 mmol) in DMF was treated with intermediate 1 (1.27 g, 0.95 eq.), HATU (1.83 g, 0.95 eq.) and TEA (2.1 mL, 3 eq.). The resulting mixture was stirred for 18 hours at rt. The solvent was evaporated off. The residue was taken up in water, and a 1N NaOH (5 mL) solution was added and the mixture was sonicated during 5 minutes. The resulting precipitate was filtrated off and washed 3 times with water (15 mL). The white powder was dried under vacuo. Recrystallization from EtOH gave the title compound as a white powder in a 29% yield. MP: 247-249 C. LC/MS: [M+H+] 579 C35H41F3N202 Example 3 4'-Chloro-biphenyl-4-carboxylic acid {4- [4- (1-methoxy-naphtaien-2-yt)-piperidin- 1-yl]-butyl}-amide The same method was employed as in the preparation of example 1 but starting from intermediate 20 and intermediate 2 gave the title compound as white crystals after recrystallization from CH3CN in a 72% yield. MP: 197 C. LC/MS: [M+H+] 527 C33H35CIN202 Example 4 4'-Chloro-biphenyl-4-carboxylic acid {4- [4- (2-methoxy-naphtalen-1-yl)-piperidin- 1-yl]-butyl}-amide The same method was employed as in the preparation of example 1 but starting from intermediate 25 and intermediate 2 gave the title compound as a yellow powder after recrystallization in CH3CN in a 50% yield. *MP: 149 C. LC/MS: [M+H+] 527 C33H35CIN202 Example 5 4'-Cyano-biphenyl-4-carboxylic acid {4- [4- (2-ethoxy-4-ethyl-phenyl)-piperidin-1- yl]-butyl}-amide The same method was employed as in the preparation of example 1 but starting from intermediate 33 and the available 4'-Cyano-biphenyl-4-carboxylic acid to give the title compound as white needles after recrystallization from CH3CN in a 30% yield. MP: 165 C. LC/MS: [M+H+]. 510 C33H39N302 Example 6 4'-Cyano-biphenyl-4-carboxylic acid {4- [4- (1-methoxy-naphtalen-2-yl)-piperidin- 1-yl]-butyl}-amide The same method was employed as in the preparation of example 1 but starting from intermediate 20 and the available 4'-Cyano-biphenyl-4-carboxylic acid gave the title compound as white solid after recrystallization from CH3CN in a 45% yield. MP: 180 C. LC/MS: [M+H+] 518 C34H35N302 Example 7 4'Trifluoromethyl-biphenyl-4-carboxylic acid {4- [4- (1-isobutoxy-5, 6,7,8 tetrahydro-naphtalen-2-yl)-piperidin-1-yl]-butyl}-amide The same method was employed as in the preparation of example 1 but starting from intermediate 39 gave the title compound as white crystals after recrystallization from CH3CN in a 54% yield. MP: 165 C. LC/MS (APCI) : [M+H+] C37H45F3N202 607 Example 8 4'-Trifluoromethyl-biphenyl-4-carboxylic acid {4- [4- (1-allyloxy-naphtalen-2-yl)- piperidin-1-yl]-butyl}-amide The same method was employed as in the preparation of example 1 but starting from intermediate 43 to give the title compound as colorless crystals in a 45% yield after recrystallisation from CH3CN MP: 180-181 C LC/MS (APCI) : [M+H+] C36H37F3N202 587 Example 9 4'-Trifluoromethyl-biphenyl-4-carboxylic acid {4- [4- (1-propoxy-naphtalen-2-yl)- piperidin-1-yl]-butyl}-amide The same method was employed as in the preparation of example 1 but starting from intermediate 47 to give the title compound as white crystals in a 12% yield after recrystallisation from CH3CN MP: 191-192 C LC/MS (APCI) : [M+H+] C36H39F3N202 589 Example 10 4'-Trifluoromethyl-biphenyl-4-carboxylic acid {4-[4-(1-Cyclopropylmethoxy5,6,7,8-tetrahydro-naphtalen-2-yl)-piperidin-1-yll-butyl}-amide The same method was employed as in the preparation of example 1 but starting from intermediate 51 gave the title compound as white needles after recrystallization from CH3CN/MeOH in a 48% yield. MP: 181 C. LC/MS (APCI) : [M+H+] 605 C37H43F3N202 Example 11 4'-Cyano-biphenyl-4-carboxylic acid {4- [4- (1-methoxy-5, 6,7,8-tetrahydro naphtalen-2-yl)-piperidin-1-yl]-butyl}-amide The same method was employed as in the preparation of example 5 but starting from intermediate 55 gave the title compound as white solid after recrystallization from MeCN in a 39% yield. MP: 154 C. LC/MS (APCI) : [M+H+] 522 C34H39N302 Example 12 4'-Methanesulfonyl-biphenyl-4-carboxylic acid {4- [4- (2-ethoxy-4-ethyl-phenyl)piperidin-1-yl]-butyl}-amide The same method was employed as in the preparation of example 1 but starting from intermediate 33 and intermediate 60 to give the title compound as white crystals after flash chromatography using DCM/MeOH 90/10 as eluent in a 2% yield. MP: 179-180 C. LC/MS: [M+H+] 563 C33H42N204S Example 13 4-Methyl-2- (4-trifluromethyl-phenyl)-thiazole-5-carboxylic acid {4- [4- (4-isopropyl 2-methoxy-phenyl)-piperidin-1-yll-butyl}-amide The same method was employed as in the preparation of example 1 but starting from intermediate 64 and 4-Methyl-2- (4-trifluromethyl-phenyl)-thiazole-5- carboxylic acid gave the title compound as white crystals after recrystallization from MeCN in a 54% yield. MP: 170 C. Analysis for C3, H38F3N302S, (0.4H20): Calculated: C, 64.09; H, 6.73; N, 7.23. Found: C, 64.28; H, 7.07; N, 7.28 Example 14 4'-Cyano-biphenyl-4-carboxylic acid {4-[4-(2-hydroxy-4-ethyl-phenyl)-piperidin-1 yl]-butyl}-amide To a solution of intermediate 71 (0.1 g, 0.17 mmol) in THF (10 mL) was added the tetrabutylammonium fluoride (1.2 eq.). The reaction was stirred to rt during 15 min. Then H20 (10 mL) was added and the organic phase was decanted, dried over Na2SO4 and evaporated off. The title compound was obtained as white crystals (0.055 g, 0.1 mmol) after recrystallization from MeOH in a 68% yield. MP: 252 C. LC/MS (APCI) : [M+H+] 482 C31H35N3C2 Example 15 4'-Cyano-biphenyl-4-carboxylic acid {4- [4- (1-hydroxy-5, 6,7,8-tetrahydro naphtalen-2-yl)-piperidin-1-yl]-butyl}-amide The same method was employed as in the preparation of intermediate 71 but starting from intermediate 78 to give the title compound as a white powder after formation of chlorhydrate from a hot HCI 1 N/EtOH solution in a 49% yield. MP: 252 C. LC/MS (ES): M+ 507 C33H37N302 Example 16 4'-Cyano-biphenyl-4-carboxylic acid {4- [4- (1-hydroxy-naphtalen-2-yl)-piperidin-1yl]-butyl}-amide The same method was employed as in the preparation of intermediate 71 but starting from intermediate 83 to give the title compound as a colorless solid in a 55% yield. MP: 135-140 C LC/MS (APCI) : [M+H +] 504 C33H33N302 Example 17 4'-Acetyl-biphenyl-4-carboxylic acid {4- [4- (1-hydroxy-5, 6,7,8-tetrahydro naphtalen-2-yl)-piperidin-1-yl]-butyl}-amide The same method was employed as in the preparation of intermediate 71 but starting from intermediate 78 and 85 to give the title compound as a colorless powder after purification by flash chromatography (using DCM/MeOH 80/20 as eluent) and crystallisation in iPr20 in a 49% yield. MP: 180-185 C. LC/MS (APCI) : [M+H+] 525 C34H4oN203 Example 18 4'-Cyano-biphenyl-4-carboxylic acid {4- [4- (2-hydroxy-4-methyl-phenyl)-piperidin- 1-yl]-butyl}-amide The same method was employed as in the preparation of example 14 but starting from intermediate 90 to give the title compound as a white crystals in a 34% yield. MP: 184 C LC/MS (APCI) : [M+H+] 468 C30H33N3O2 Biological Assays In Vitro Assay: HepG2 cells, stably transfected with a construct comprising the the LDL-r promoter and the luciferase reporter gene, were seeded at 50.000 cells/well in 96 well plates. After 1 day, cells were incubated with compounds for 24 hours in RPMI medium containing 2% of lipoprotein-deficient serum. Compounds were tested from 10-6M to 10-9M. Cell lysates were prepared and the luciferase activity was measured by the luciferase assay system (Promega). Induction of luciferase activity was calculated taking untreated cells as control and EDso of each compounds was determinated compared to the ED50 of an internal standart. In Vivo Assay: Compounds were prepared for oral administration by milling with 0.5% hydroxypropylmethylcellulose and 5% Tween 80. Hamsters were fed for 2 weeks with a diet containing 0.2% of cholesterol and 10% of coconut oil. Then compounds were administrated once a day for 3 days, from 20 to 0.2mg/kg. Plasma lipid levels including total cholesterol, VLDL/LDL cholesterol, VLDL/LDL triglycerides and HDL-cholesterol were determinated after ultracentrifugation (density 1.063g/ml to separate VLDL/LDL fraction and HDL fraction) using the Biomerieux enzymatic kit. Reductions in VLDL/LDL cholesterol and TG plasmatic levels were calculated taking solvant treated animals as control and ED50 of each compound was determined. Biological Results EMI54.1 <tb> Ex'a'mp**,,, <SEP> viv <SEP> (ED' <tb> <SEP> 3102 <tb> <SEP> 5 <SEP> 10 <SEP> 2 <tb> <SEP> 11 <SEP> 10 <SEP> 1 <tb> Tablet compositions The following compositions A and B can be prepared by wet granulation of ingredients (a) to (c) and (a) to (d) with a solution of povidone, followed by addition of the magnesium stearate and compression. Composition A mg/tablet mg/tablet (a) Active ingredient 250 250 (b) Lactose B. P. 210 26 (c) Sodium Starch Glycollate 20 12 (d) Povidone B. P. 15 9 (e) Magnesium Stearate 5 3 500 300 Composition B mg/tablet mg/tablet (a) Active ingredient 250 250 (b) Lactose 150 150 (c) Avicel PH 101 60 26 (d) Sodium Starch Glycollate 20 12 (e) Povidone B. P. 15 9 Magnesium Stearate 5 3 500 300 Composition C mg/tablet Active ingredient 100 Lactose 200 Starch 50 Povidone 5 MagnesiumStearate 4 359 The following compositions D and E can be prepared by direct compression of the admixed ingredients. The lactose used in composition E is of the direct compression type. Composition D mg/tablet Active ingredient 250 Magnesium Stearate 4 Pregelatinised Starch NF15 146 400 Composition E mg/tablet Active ingredient 250 Magnesium Stearate 5 Lactose 145 Avicel 100 500 Composition F (Controlled release composition) mg/tablet (a) Active ingredient 500 (b) Hydroxypropylmethylcellulose 112 (Methocel K4M Premium) (c) Lactose B. P. 53 (d) Povidone B. P. C. 28 (e) Magnesium Stearate 7 700 The composition can be prepared by wet granulation of ingredients (a) to (c) with a solution of povidone, followed by addition of the magnesium stearate and compression. Composition G (Enteric-coated tablet) Enteric-coated tablets of Composition C can be prepared by coating the tablets with 25mg/tablet of an enteric polymer such as cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethyl-cellulose phthalate, or anionic polymers of methacrylic acid and methacrylic acid methyl ester (Eudragit L). Except for Eudragit L, these polymers should also include 10% (by weight of the quantity of polymer used) of a plasticizer to prevent membrane cracking during application or on storage. Suitable plasticizers include diethyl phthalate, tributyl citrate and triacetin. Composition H (Enteric-coated controlled release tablet) Enteric-coated tablets of Composition F can be prepared by coating the tablets with 50mg/tablet of an enteric polymer such as cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethyl-cellulose phthalate, or anionic polymers of methacrylic acid and methacrylic acid methyl ester (Eudragit L). Except for Eudragit L, these polymers should also include 10% (by weight of the quantity of polymer used) of a plasticizer to prevent membrane cracking during application or on storage. Suitable plasticizers include diethyl phthalate, tributyl citrate and triacetin. (ii) Capsule compositions Composition A Capsules can be prepared by admixing the ingredients of Composition D above and filling two-part hard gelatin capsules with the resulting mixture. Composition B (infra) may be prepared in a similar manner. Composition B mg/capsule (a) Active ingredient 250 (b) Lactose B. P. 143 (c) Sodium Starch Glycollate 25 (d) Magnesium Stearate 2 420 Composition C mg/capsule (a) Active ingredient 250 (b) Macrogol 4000 BP 350 600 Capsules can be prepared by melting the Macrogol 4000 BP, dispersing the active ingredient in the melt and filling-two-part hard gelatin capsules therewith. Composition D mg/capsule Active ingredient 250 Lecithin 100 Arachis Oil 100 450 Capsules can be prepared by dispersing the active ingredient in the lecithin and arachis oil and filling soft, elastic gelatin capsules with the dispersion. Composition E (Controlled release capsule) mg/capsule (a) Active ingredient 250 (b) Microcrystalline Cellulose 125 (c) Lactose BP 125 (d) Ethyl Cellulose 13 513 The controlled release capsule composition can be prepared by extruding mixed ingredients (a) to (c) using an extruder, then spheronising and drying the extrudate. The dried pellets are coated with a release controlling membrane (d) and filled into two-part, hard gelatin capsules. Composition F (Enteric capsule) mg/capsule (a) Active ingredient 250 (b) Microcrystalline Cellulose 125 (c) Lactose BP 125 (d) Cellulose Acetate Phthalate 50 (e) Diethyl Phthalate 5 555 The enteric capsule composition can be prepared by extruding mixed ingredients (a) to (c) using an extruder, then spheronising and drying the extrudate. The dried pellets are coated with an enteric membrane (d) containing a plasticizer (e) and filled into two-part, hard gelatin capsules. Composition G (Enteric-coated controlled release capsule) Enteric capsules of Composition E can be prepared by coating the controlled-release pellets with 50mg/capsule of an enteric polymer such as cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethylcellulose phthalate, or anionic polymers of methacrylic acid and methacrylic acid methyl ester (Eudragit L). Except for Eudragit L, these polymers should also include 10% (by weight of the quantity of polymer used) of a plasticizer to prevent membrane cracking during application or on storage. Suitable plasticizers include diethyl phthalate, tributyl citrate and triacetin. (iii) Intravenous injection composition Active ingredient 0.200g Sterile, pyrogen-free phosphate buffer (pH 9.0) to10 ml The active ingredient is dissolved in most of the phosphate buffer at 35-40 C, then made up to volume and filtered through a sterile micropore filter into sterile 10 ml glass vials (Type 1) which are sealed with sterile closures and overseas. (iv) Intramuscular injection composition Active ingredient 0.20 g Benzyl Alcohol 0.10 g Glycofurol 75 1.45 g Water for Injection q. s. to 3.00 mi The active ingredient is dissolved in the glycofurol. The benzyl alcohol is then added and dissolved, and water added to 3 mi. The mixture is then filtered through a sterile micropore filter and sealed in sterile 3 ml glass vials (Type 1). (v) Syrup composition Active ingredient 0.25g Sorbitol Solution 1.50g Glycerol 1.00g Sodium Benzoate 0.005g Flavour 0.0125ml Purified Water q. s. to 5. Oml The sodium benzoate is dissolved in a portion of the purified water and the sorbitol solution added. The active ingredient is added and dissolved. The resulting solution is mixed with the glycerol and then made up to the required volume with the purified water. (vi) Suppository composition mg/suppository Active ingredient 250 Hard Fat, BP (Witepsol H 15-Dynamit NoBel) 1770 2020 One-fifth of the Witepsol H15 is melted in a steam-jacketed pan at 45 C maximum. The active ingredient is sifted through a 200im sieve and added to the molten base with mixing, using a Silverson fitted with a cutting head, until a smooth dispersion is achieved. Maintaining the mixture at 45 C, the remaining Witepsol H15 is added to the suspension which is stirred to ensure a homogenous mix. The entire suspension is then passed through a 2501m stainless steel screen and, with continuous stirring, allowed to cool to 40 C. At a temperature of 38-40 C, 2.02g aliquots of the mixture are filled into suitable plastic moulds and the suppositories allowed to cool to room temperature. (vii) Pessary composition mg/pessary Active ingredient (631m) 250 Anhydrous Dextrose 380 Potato Starch 363 Magnesium Stearate 7 1000 The above ingredients are mixed directly and pessaries prepared by compression of the resulting mixture. (viii) Transdermal composition Active ingredient 200mg Alcohol USP 0. 1 ml Hydroxyethyl cellulose The active ingredient and alcohol USP are gelled with hydroxyethyl cellulose and packed in a transdermal device with a surfce area of 10 cm2.

Claims: CLAIMS 1. A compound of formula (I) EMI61.1 wherein Ar1 represents phenyl, naphthyl or phenyl fused by a C38cycloalkyl, where each group is optionally substituted by methylenedioxy or one or two groups independently represented by R1 ; Ar2 represents phenyl or a 5-6 membered heteroaromatic group, where each group is optionally substituted by one to four groups independently selected from halogen, C1-4 alkyl and C14 alkoxy ; Ar3 represents a phenyl or a 5-6 membered heteroaromatic group, where each group is optionally substituted by one to four groups independently selected from hydroxy, alkyl, C1-4 alkoxy, C2-4 alkenyl, C2-4 alkenyloxy, C1-4 perfluoroalkoxy, C14 acylamino or an electron withdrawing group; A represents-C (H)- ; E represents-C16 alkylene-; X represents-CON (H or Cl-4alkyl)-or-N (H or C14alkyl) CO-; Y represents a direct link ; R1 represents halogen, -S(C1-4 alkyl)-, -O-(C0-4 alkylene)-R2 or -(C0-4alkylene) R2, where each alkylen group may additionally incorporate an oxygen in the chain, with the proviso that there are at least two carbon atoms between any chain heteroatoms; R2 represents (i) hydrogen, C14 perfluoroalkyl, C23 alkenyl, (ii) phenyl, naphthyl, a 5-or 6-membered heteroaromatic group or 1,2,3,4 tetrahydronaphthyl, optionally substituted by one or two halogen, hydroxy, Ci-4 alkyl, C14 alkoxy groups, (iii) C38cycloalkyl, a 3-7 membered heterocycloalkyl, (iv) amino, C14 alkylamino or di-C14alkylamino, with the proviso that there are at least two carbon atoms between any chain heteroatoms; or a physiologically acceptable salt or solvate thereof. 2. A compound according to claim 1 where An represents a substituted phenyl, naphthyl or 1,2,3,4-tetrahydronaphthyl group, where optional substitution is effected by R'. 3. A compound according to claim 1 or 2 where Ar1 is substituted by methylenedioxy or one or two groups independently selected from hydroxy, C1-4 alkyl, C1-4 alkoxy, -O-C0-4alkylene-R2, where R2 represents C14 perfluoroalkyl, a 5-6 membered heteroaromatic group or a C3-8cycloalkyl. 4. A compound according to any one of claims 1-3 where Ar2 is phenyl. 5. A compound according to any one of claims 1-4 where E is an n-butylen group. 6. A compound according to any one of claims 1-5 where X is an-N (H) CO group. 7. A compound according to any one of claims 1-6 where Ar3 is phenyl substituted by a halogen, C14perfluoroalkyl, C14acyl, nitrile or C 4alkylsulfonyl. 8. A compound according to claim 7 where Ar3 is phenyl substituted by a chloro or nitrile. 9. A compound of formula (la) EMI63.1 wherein Ar1 represents phenyl, naphthyl or phenyl fused by a C38cycloalkyl, where each group is optionally substituted by methylenedioxy or one or two groups independently represented by R1 ; Ar2 represents phenyl or a 5-6 membered heteroaromatic group, where each group is optionally substituted by one to four groups independently selected from halogen, C14 alkyl and C14 alkoxy ; Ar3 represents phenyl or a 5-6 membered heteroaromatic group, where each group is optionally substituted by one to four groups independently selected from halogen, hydroxy, nitrile, C1-4 alkyl, C1-4 alkoxy, C2-4 alkenyl, C2-4 alkenyloxy, C1-4 perfluoroalkyl, C1-4 perfluoroalkoxy, C1-4 acyl, C1-4 alkoxycarbonyl, aminocarbonyl, C14 alkylaminocarbonyl ; di-C14 alkylaminocarbonyl and C14 acylamino ; A represents-C (H)- ; E represents-C16 alkylene-; X represents-CON (H or Cl-4alkyl)-. or-N (H or Cl-4alkyl) CO- ; Y represents a direct link ; R1 represents halogen, -O-(C0-4 alkylene)-R2 or -(C0-4alkylene)-R2, where each alkylen group may additionally incorporate an oxygen in the chain, with the proviso that there are at least two carbon atoms between any chain heteroatoms; R2 represents (i) hydrogen, C14 perfluoroalkyl, (ii) phenyl, naphthyl, a 5-or 6-membered heteroaromatic group or 1,2,3,4 tetrahydronaphthyl, optionally substituted by one or two halogen, hydroxy, C1-4 alkyl, C1-4 alkoxy groups, (iii) C3-8cycloalkyl, a 3-7 membered heterocycloalkyl, (iv) amino, C14 alkylamino or di-C14alkylamino, with the proviso that there are at least two carbon atoms between any chain heteroatoms; or a physiologically acceptable salt or solvate thereof. 10. A compound of formula (lb) EMI64.1 wherein Ar1 represents phenyl, naphthyl or 1,2,3,4-tetrahydronaphthyl, where each group is optionally substituted by one or two groups independently represented by R1 ; Ar3 represents phenyl substituted in the para position by a halogen, nitrile, C 4acyl, C1-4alkylsulfonyl or C1-4 perfluoroalkyl group; R1 represents C1-4 alkyl or -O-(C0-4alkylene)-R2; R2 represents hydrogen, C2-3alkenyl or C3-8cycloalkyl ; or a physiologically acceptable salt or solvate thereof. 11. A compound selected from 4'-Trifluoromethyl-biphenyl-4-carboxylic acid {4- [4- (2-ethoxy-4-methyl phenyl)-piperidin-1-yl]-butyl}-amide ; 4'-Trifluoromethyl-biphenyl-4-carboxylic acid [4- [4- (2-cyclopropylmethoxy-4- ethyl-phenyl)-piperidin-1-yl]-butyl]-amide ; 4'-Chloro-biphenyl-4-carboxylic acid {4- [4- (1-methoxy-naphtalen-2-yl) piperidin-1-yl]-butyl}-amide ; 4'-Chloro-biphenyl-4-carboxylic acid {4- [4- (2-methoxy-naphtalen-1-yl)- piperidin-1-yl]-butyl}-amide ; 4'-Cyano-biphenyl-4-carboxylic acid {4- [4- (2-ethoxy-4-ethyl-phenyl)-piperidin- 1-yl]-butyl}-amide ; 4'-Cyano-biphenyl-4-carboxylic acid {4- [4- (1-methoxy-naphtalen-2-yl)- piperidin-1-yl]-butyl}-amide; 4'Trifluoromethyl-biphenyl-4-carboxylic acid {4-[4-(1-isobutoxy-5, 6,7,8 tetrahydro-naphtalen-2-yl)-piperidin-1-yl]-butyl}-amide 4'-Trifluoromethyl-biphenyl-4-carboxylic acid {4- [4- (1-allyloxy-naphtalen-2- yl)-piperidin-1-yl]-butyl}-amide ; 4'-Trifluoromethyl-biphenyl-4-carboxylic acid {4- [4- (l-propoxy-naphtalen-2- yl)-piperidin-1-yl]-butyl}-amide ; 4'-Trifluoromethyl-biphenyl-4-carboxylic acid {4- [4- (l-Cyclopropylmethoxy- 5,6,7, 8-tetrahydro-naphtalen-2-yl)-piperidin-1-yl]-butyl}-amide ; 4'-Cyano-biphenyl-4-carboxylic acid {4- [4- (1-methoxy-5, 6,7,8-tetrahydro naphtalen-2-yl)-piperidin-1-yl]-butyl}-amide ; 4'-Methanesulfonyl-biphenyl-4-carboxylic acid {4- [4- (2-ethoxy-4-ethyl- phenyl)-piperidin-1-yl]-butyl}-amide ; 4-Methyl-2-(4-trifluromethyl-phenyl)-thiazole-5-carboxylic acid {4-{4-(4 isopropyl-2-methoxy-phenyl)-piperidin-1-yl]-butyl}-amide ; 4'-Cyano-biphenyl-4-carboxylic acid {4- [4- (2-hydroxy-4-ethyl-phenyl) piperidin-1-yl]-butyl}-amide ; 4'-Cyano-biphenyl-4-carboxylic acid {4-14-(1-hydroxy-5, 6,7,8-tetrahydro naphtalen-2-yl)-piperidin-1-yl]-butyl}-amide ; 4'-Cyano-biphenyl-4-carboxylic acid {4- [4- (l-hydroxy-naphtalen-2-yl)- piperidin-1-yl]-butyl}-amide ; 4'-Acetyl-biphenyl-4-carboxylic acid {4- [4- (1-hydroxy-5, 6,7,8-tetrahydro naphtalen-2-yl)-piperidin-1-yl]-butyl}-amide ; 4'-Cyano-biphenyl-4-carboxylic acid {4- [4- (2-hydroxy-4-methyl-phenyl)- piperidin-1-yl]-butyl}-amide ; or a physiologically acceptable salt, solvate or derivative thereof.12. Use of a compound according to any one of claims 1-11 in human medicine. 13. Use of a compound according to any one of claims 1-11 or a physiologically acceptable salt or solvate thereof in the preparation of a medicament for use in the treatment of conditions resulting from elevated circulating levels of LDL-cholesterol. 14. A method for the treatment of a mammal, including man, of conditions resulting from elevated circulating levels of LDL-cholesterol, comprising administration of an effective amount of a compound according to any one of claims 1-11 or a physiologically acceptable salt or solvate thereof. 15. A pharmaceutical composition which comprises at least one compound according to any one of claims 1-11 or a physiologically acceptable salt or solvate thereof, with one or more pharmaceutically acceptable carriers or excipients and optionally one or more further physiologically active agents. 16. A process for the preparation of compound of formula (I) comprising: (A)-reaction of a compound of formula (II) with a compound of formula (III) EMI66.1 where Xa and Xb are suitable reactants to form a group X; (B) reaction of a compound of formula (IV) with a compound of formula (XIII) EMI66.2 where E-C1 ('E minus C1') means that the chain length of group E is one carbon less than that in the resulting compound (I), under standard reductive amination conditions; or (C) reaction of a different compound of formula (I).

Inventors: BOMBRUN AGNES, BOUILLOT ANNE MARIE JEANNE, DUMAITRE BERNARD ANDRE, GOSMINI ROMAIN LUC MARIE, BOMBRUN, AGNES, BOUILLOT, ANNE, MARIE, JEANNE, DUMAITRE, BERNARD, ANDRE, GOSMINI, ROMAIN, LUC, MARIE
Applicants: BOMBRUN AGNES, BOUILLOT ANNE MARIE JEANNE, DUMAITRE BERNARD ANDRE, GLAXO GROUP LTD, GOSMINI ROMAIN LUC MARIE, BOMBRUN, AGNES, BOUILLOT, ANNE, MARIE, JEANNE, DUMAITRE, BERNARD, ANDRE, GLAXO GROUP LIMITED, GOSMINI, ROMAIN, LUC, MARIE
Application year: 2001
Main classification: C07D211
IPC codes: A61K31, A61P3, C07D211, C07D417