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WO2004006923A1 - Aryl piperidine derivatives as inducers of ldl-receptor expression for the treatment of hypercholesterolemia - Google Patents

Aryl piperidine derivatives as inducers of ldl-receptor expression for the treatment of hypercholesterolemia Download PDF

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Publication number
WO2004006923A1
WO2004006923A1 PCT/EP2003/007613 EP0307613W WO2004006923A1 WO 2004006923 A1 WO2004006923 A1 WO 2004006923A1 EP 0307613 W EP0307613 W EP 0307613W WO 2004006923 A1 WO2004006923 A1 WO 2004006923A1
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Prior art keywords
phenyl
piperidin
naphthalen
butyl
group
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PCT/EP2003/007613
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French (fr)
Inventor
Anne Marie Jeanne Bouillot
Bernard Andre Dumaitre
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Glaxo Group Ltd
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Glaxo Group Ltd
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Priority to AU2003250058A priority Critical patent/AU2003250058A1/en
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Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to novel compounds which up-regulate LDL receptor (LDL-r) expression and to processes for their preparation, pharmaceutical compositions 5 containing them and their medical use. More particularly, this invention relates to novel aromatic piperidines and their use in therapy.
  • LDL-r LDL receptor
  • 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- 5 regulate LDL-r expression in the liver and to increase the clearance of LDL cholesterol.
  • SCAP SREBP-cleavage activating protein
  • Two 0 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)-pipehdin-1-yl]-butyl ⁇ -benzamide hydrochloride, which do not form part of the present invention.
  • R 1 may be hydrogen
  • R 2 may be hydrogen
  • R 3 may be a group
  • X may be an aryl group and n may be 1.
  • group COR 3 is formed from 2- and 4- biphenyl carboxylic acid and R 1 and R 2 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. Furthermore, the utility disclosed is different.
  • 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.
  • A may represent a substituted phenyl group
  • W represents a linear or branched alkylene group having from 2 to 6 carbon atoms
  • Y may represent a group NHCO or CONH
  • R may be a substituted phenyl group.
  • A may represent a substituted phenyl group
  • W represents a linear or branched alkylene group having from 2 to 6 carbon atoms
  • Y may represent a group NHCO or CONH
  • R may be a substituted phenyl group.
  • R 1 -R 5 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.
  • substituents including hydrogen, halogen, hydroxyl, thiol, lower alkyl, substituted lower alkyl, alkenyl, alkynyl, alkylalkenyl, alkylalkynyl, alkoxy, alkylthio, acyl, aryloxy, amino,
  • the present invention provides aryl piperidine derivatives which are particularly useful in treating cardiovascular disorders associated with elevated levels of circulating LDL-cholesterol.
  • the invention provides a compound of formula (I), physiologically acceptable prodrugs, salts or solvates thereof;
  • radicals contain a total of from 1-4 ring heteroatoms independently selected from oxygen, nitrogen and sulfur, and wherein individual rings of said radicals may be independently saturated, partially unsaturated or aromatic, provided that at least one ring is aromatic;
  • Ar is independently substituted by at least one R 1 group and independently substituted by 0-3 R 3 groups;
  • Ar 2 is a phenyl group, a 5-6 membered heteroaromatic group or a bicyclic heteroaromatic group, where each group is optionally substituted by one or two substituents independently selected from the list: C h alky!, halogen, hydroxy, C 1-4 alkoxy, C 1-6 acyl, C 1-6 acyloxy, amino, C ⁇ alkylamino, di-C ⁇ alkylamino, -(CH 2 ) n NR x R y , -O(CH 2 ) n C(O)NR x R y , -O(CH 2 ) n
  • E is -C ⁇ _ 6 alkylene-
  • X is -CONR 2 -or-NR 2 CO- (where the left hand side of the linkage is attached to E);
  • R 1 is selected from the group consisting of: -O(CR a R°) n C(O)NR x R y , -O(CH 2 ) n CN, -O(CH 2 ) n O(CH 2 ) m OR 2 , -O(CH 2 ) n CO 2 R 2 , -OSO 2 NR x R y , -OSO 2 (CH 2 ) p CH 3 ,
  • R 2 is or hydrogen
  • R 3 is selected from halogen, -O-(C ⁇ -4alkylene)-R 4 or -(C lJt alkylene)-R 4 , 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 oxygen atoms
  • R 4 is: (i) hydrogen
  • phenyl phenyl fused by a C 3 -8cycloalkyl, naphthyl or a 5- or 6-membered heteroaromatic group, each of which may be optionally substituted by one or two groups independently selected from halogen, C 1-4 alkyl, hydroxy, C 1-4 alkoxy, amino, C 1-4 alkylamino and di-C M alkylamino; (iii) C 3 .
  • R a and R b are independently hydrogen, C 1-4 alkyl or cycloalkyl, where R a and R b are not both cycloalkyl;
  • R x and R y are independently hydrogen, C 1- alkyl, hydroxy or C 1-4 alkoxy, where R x and R y are not both hydroxy or both C 1-4 alkoxy; or R x and R y together with the nitrogen to which they are attached form a 5-membered ring which ring is optionally substituted by -O(CR a R b ) n C(O)NR x R y , -O(CH 2 ) n CN, -O(CH 2 ) n O(CH 2 ) m OR 2 , -O(CH 2 ) n CO 2 R 2 , -OSO 2 NR x R y , -OSO 2 (CH 2 ) p CH 3 ,
  • alkyl, alkylene and alkoxy include both straight and branched chain saturated hydrocarbon groups.
  • alkyl groups include methyl and ethyl groups
  • examples of alkylene groups include methylene and ethylene groups
  • examples of alkoxy groups include methoxy and ethoxy groups.
  • alkenyl includes both straight and branched chain saturated hydrocarbon groups containing one double bond.
  • alkenyl groups include ethenyl or n-propenyl groups.
  • acyl refers to aliphatic or cyclic hydrocarbons attached to a carbonyl group through which the substituent bonds, such as acetyl.
  • phenyl fused by a C 3 . 8 cycloalkyl 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.
  • a halogen atom includes fluorine, chlorine, bromine or iodine.
  • C ⁇ . 3 perfluoroalkyl and C ⁇ perfluoroalkoxy includes compounds in which the hydrogens have been partially or fully replaced by fluorines, such as trifluoromethyl and trifluoromethoxy or trifluoroethyl.
  • 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.
  • a 3-7 membered heterocyclyl group means any single ring system containing at least one ring heteroatom independently selected from O, N and S, wherein said ring is saturated, unsaturated or aromatic.
  • An is phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indolyl, benzofuranyl, benzothiophenyl or indazolyl. More preferably Ar, is phenyl, 1 ,2,3,4- tetrahydronaphthyl or indolyl.
  • the link to the piperidine ring is preferably through the 2- position of he 1,2,3,4-tetrahydronaphthyl moiety and mono- substitution by R 1 is in the corresponding 1- position.
  • the link to the piperidine ring is preferably through the 3-position of the indolyl moiety and mono-substitution by R 1 is in the corresponding 1 -position.
  • E is n-butylene
  • X is -NR 2 CO-.
  • R 2 is hydrogen.
  • Ar 2 is phenyl or a 5-6-membered heteroaromatic group (more preferably phenyl, pyridyl, thiazolyl, oxazolyl or imidazolyl).
  • Ar 3 is phenyl, pyridyl or thienyl, more preferably phenyl.
  • Ar 3 is substituted by halogen (e.g. chloro), (e.g. trifluoromethyl), nitrile, C 1-4 acyl (e.g. acetyl), C 1-4 alkylsulfonyl (e.g. methylsulfonyl) or C 1-4 alkylsulfonylamino.
  • R 1 is selected from the group consisting of: -O(CR a R b ) n C(O)NR x R y , -O(CH 2 ) n CN, -O(CH 2 ) n O(CH 2 ) m OR 2 , -O(CH 2 ) n CO 2 R 2 , -OSO 2 NR x R y , -OSO 2 (CH 2 ) p CH 3 , -(CR a R b ) n C(O)NR x R y and C 2-5 alkenyl; wherein R 2 is C ⁇ alkyl or hydrogen; R a and R are independently hydrogen or C 1-4 alkyl or cycloalkyl; R x and R y are independently hydrogen or C 1-4 alkyl; or R x and R y together with the nitrogen to which they are attached form a 5-member
  • R 3 is not substituted by R 3 , however when An is substituted by R 3 preferred substituents are C ⁇ alkyl or C 1- alkoxy.
  • Ar 2 is optionally substituted by C 1-4 alkyl, halogen, hydroxy or C ⁇ alkoxy. More preferably Ar 2 is not substituted.
  • 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.
  • A is phenyl, naphthyl, 1 ,2,3,4-tetrahydronaphthyl, indolyl, benzofuranyl, benzthiophenyl or indazolyl; where An is independently substituted by at least one R 1 group and independently substituted by 0-3 R 3 groups;
  • Ar 2 is phenyl or a 5-6-membered heteroaromatic group, either of which is optionally substituted by one or two substituents independently selected from the list: C 1-4 alkyl, halogen, hydroxy and C 1-4 alkoxy;
  • Ar 3 is phenyl, pyridyl or thienyl, each of which may be substituted by 1-3 groups independently selected from the group consisting of: halogen (e.g.
  • R 1 is selected from the group consisting of: -O(CR a R b ) n C(O)NR x R y , -O(CH 2 ) n CN,
  • R a and R are independently hydrogen, C 1-4 alkyl or cycloalkyl
  • R x and R y are independently hydrogen or C 1-4 alkyl; or R x and R y together with the nitrogen to which they are attached form a 5-membered ring which ring is optionally substituted by -O(CR a R b ) n C(O)NR x R y , -O(CH 2 ) n CN, -O(CH 2 ) n O(CH 2 ) m OR 2 , -O(CH 2 ) n CO 2 R 2 , -OSO 2 NR x R y , -OSO 2 (CH 2 ) p CH 3 ,
  • n and m are independently 1-3; p is 0-2;
  • R 3 is C ⁇ alkyl or C 1-4 alkoxy.
  • Preferred compounds of formula (I) are selected from the list: 4'-Cyano-biphenyl-4-carboxylic acid ⁇ 4-[4-(1 -carbamoylmethoxy-5,6,7,8-tetrahydro- naphthalen-2-yl)-piperidin-1-yl]-butyl ⁇ -amide (Example 10); 4'-Chloro-biphenyl-4-carboxylic acid ⁇ 4-[4-(1 -carbamoylmethoxy-5,6,7,8-tetrahydro- naphthalen-2-yl)-piperidin-1-yl]-butyl ⁇ -amide (Example 13);
  • substituted means substituted by one or more defined groups.
  • groups may be selected from a number of alternative groups, the selected groups may be the same or different.
  • the term independently means that where more than one substituent is selected from a number of possible substituents, those substituents may be the same or different.
  • physiologically acceptable means a compound which is suitable for pharmaceutical use.
  • Suitable physiologically acceptable salts of the compounds of general formula (I) include acid addition salts formed with pharmaceutically acceptable inorganic acids for example, phosphates, hydrochlorides, hydrobromides or sulphates, or with pharmaceutically acceptable organic acids for example mesylates, lactates and acetates. More suitably, a physiologically acceptable salt of the compounds of general formula (I) is a phosphate salt.
  • the solvates may, for example, be hydrates.
  • prodrugs are also included within the context of this invention.
  • Prodrugs are any covalently bonded carriers that release a compound of structure (I) in vivo when such prodrug is administered to a patient.
  • Prodrugs are generally prepared by modifying functional groups in a way such that the modification is cleaved, either by routine manipulation or in vivo, yielding the parent compound.
  • Prodrugs include, for example, compounds of this invention wherein hydroxy, amine or sulfhydryl groups are bonded to any group that, when administered to a patient, cleaves to form the hydroxy, amine or sulfhydryl groups.
  • prodrugs include (but are not limited to) acetate, formate and benzoate derivatives of alcohol, sulfhydryl and amine functional groups of the compounds of formula (I).
  • esters may be employed, such as methyl esters, ethyl esters, and the like.
  • compounds, their pharmaceutically acceptable salts, their solvates and polymorphs, defined in any aspect of the invention are referred to as "compounds of the invention”.
  • Compounds of the invention may be administered as the raw chemical but the active ingredient is preferably presented as a pharmaceutical formulation.
  • Compounds of the invention 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).
  • the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically 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).
  • 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
  • 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 propyl-p- 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.
  • compositions may take the form of tablets or lozenges formulated in conventional manner.
  • compounds of 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.
  • 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.
  • 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.
  • 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.
  • 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 the invention 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.
  • the compounds of the invention may be administered in combination with an HMG CoA reductase inhibitor, an agent for inhibition of bile acid transport or fibrates.
  • 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.
  • 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.
  • NIDDM non-insulin dependent diabetes mellitus
  • 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. It will be appreciated that reference to treatment is intended to include prophylaxis as well as the alleviation of established symptoms.
  • Compounds of formula (lb), i.e. compounds of formula (I) where R 1 is -OR, may be prepared from the corresponding hydroxy compound (IV) according to reaction scheme 2.
  • Preferred reaction conditions comprise treating (IV) with a suitable base such as sodium hydride or caesium carbonate followed by addition of RL where L is a leaving group such as halogen.
  • Compounds of formula (IV) may be prepared by adapting methods described herein for the preparation of compounds of formula (I).
  • Compounds of formula (I) where An is a nitrogen containing heterocycle may be substituted on the nitrogen by nucleophilic substitution.
  • substitution may be effected by treating (I) with base such as sodium hydride followed by reaction with a suitable nucleophile.
  • Compounds of formula (I) may be prepared be coupling boronic acid compounds of formula (V) with compounds of formula (VI) according to reaction scheme 3.
  • Preferred reaction conditions comprise treatment with Pd(PPh 3 ) 4 and a suitable base such as sodium carbonate at elevated temperature.
  • Compounds of formula (II) may be prepared according to reaction scheme 4 by reacting a compound of formula (VII) with a compound of formula (VIII) where L is a leaving group such as halogen and P is a suitable protecting group.
  • Preferred conditions comprise reaction with a suitable base such as potassium carbonate. Removal of protecting group P gives compounds of formula (II).
  • a preferred nitrogen protecting group is where the nitrogen attached to E and group R 2 form phthalimide (i.e. 1 ,3-dioxo-1 ,3-dihydro-isoindol-2-yl). Removal of the phthalimide protecting group gives compounds of formula (II) where R 2 is hydrogen.
  • Preferred conditions comprise treatment with hydrazine at elevated temperature.
  • Compounds of formula (VII) may be prepared by methods described in the experimental section hereinbelow.
  • Compounds of formula (VIII) are either known or may be prepared from known compounds by methods available to the skilled person.
  • 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-butoxycarbo ⁇ yl.
  • Conventional carboxylic acid protecting groups include methyl and ethyl groups.
  • composition comprising a compound of the invention and a pharmaceutically acceptable carrier or diluent
  • a compound of the invention in the manufacture of a medicament for the treatment or prophylaxis of a disorder in which lipid imbalance is important such as atherosclerosis, pancreatitis, non-insulin dependent diabetes mellitus (NIDDM), coronary heart diseases and obesity);
  • NIDDM non-insulin dependent diabetes mellitus
  • a compound of the invention in the manufacture of a medicament for the treatment or prophylaxis of hyperlipemia, hyperlipidemia, hyperlipoproteinemia, hypercholesterolemia and/or hypertriglyceridemia;
  • vii) a method of treatment or prophylaxis of a disorder resulting from elevated circulating levels of LDL-cholesterol in a human patient comprising administering to the human an effective amount of a compound of the invention;
  • viii) a method of lowering serum lipid levels, cholesterol and/or triglycerides in a human patient comprising administering to the human an effective amount of a compound of the invention; and ix) a combination of a compound of the invention with an HMG CoA reductase inhibitor, an agent for inhibition of bile acid transport or a fibrate.
  • the invention provides a compound of formula (I)
  • radicals contain a total of from 1-4 ring heteroatoms independently selected from oxygen, nitrogen and sulfur, and wherein individual rings of said radicals may be independently saturated, partially unsaturated, or aromatic, provided that at least one ring is aromatic, where An bears at least one group independently represented by R 1 and 0-3 groups independently represented by R 3 ;
  • R 1 is selected from the group consisting of: -O(CH 2 ) n C(O)NR x R y , -O(CH 2 ) n CN, -O(CH 2 ) n O(CH 2 ) m OR 2 , CLsalkenyl, -O(CH 2 ) n C(O)OR 2 , and -OSO 2 (CH 2 ) p CH 3 ;
  • R 2 is (CH 2 ) n CH 3 or H;
  • R x and R y are independently C 1- alkyl or H; n and m are independently 1 -4; p represents 0-4;
  • R 3 is selected from halogen, - ⁇ -(Co--! alkylene)-R 4 or -(C 0 ⁇ alkylene)-R 4 , 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 4 represents
  • heterocyclyl selected from the group consisting of monocyclic radicals and fused polycyclic radicals, wherein said radicals contain a total of from 5-14 ring atoms, wherein said radicals contain a total of from 1-4 ring heteroatoms independently selected from oxygen, nitrogen and sulfur, and wherein individual rings of said radicals may be independently saturated, partially unsaturated, or aromatic, providing that at least one ring is aromatic, where Ar 3 is optionally substituted by 1 -4 groups independently selected from the group consisting of: hydroxy, alkyl, C M alkoxy, C 2 .
  • X represents -CON(H or C ⁇ alkyl )-or -N(H or C alkyl)CO-; or a physiologically acceptable prodrug, salt or solvate thereof.
  • Example 1 4'-Trifluoromethyl-biphenyl-4-carboxylic acid (4-f4-(1-carbamoylmethoxy- 5,6.7,8-tetrahvdro-naphthalen-2-yl)-piperidin-1-yll-butyl>-amide
  • Example 3 4'-Trifluoromethyl-biphenyl-4-carboxylic acid [4-(4-f1-f2-(2-methoxy- ethoxy)-ethoxyl-5,6,7,8-tetrahvdro-naphthalen-2-yl>-piperidin-1-yll-butyl ⁇ -amide
  • Example 4 4'-Trifluoromethyl-biphenyl-4-carboxylic acid f4-(4-(1-[2-(2-hydroxy- ethoxy)-ethoxy1-5,6,7,8-tetrahvdro-naphthalen-2-yl)-piperidin-1-yll-butyl)-amide
  • Example 7 4'-Cyano-biphenyl-4-carboxylic acid (4-(4-f5-methoxy-1-(2-methyl-allyl)- 1 H-indol-3-yll-piperidin-1 -yl)-butyl)-amide;
  • Example 8 f2-(H4-f(4'-Trifluoromethyl-biphenyl-4-carbonyl)-aminol-butyl)-piperidin- 4-yl)-5,6,7,8-tetrahvdro-naphthalen-1-yloxy1-acetic acid ethyl ester
  • example 8 To a solution of example 8 (0.3 g, 0.47 mmol) in EtOH was added a 1 N NaOH solution (0.5 mL, 1.1 eq) and the mixture was stirred at reflux overnight. The resulting mixture was acidified with a 1N HCI solution (2.2 eq) and evaporated. Crystallisation from H 2 O/DCM/iPr 2 O (50/2/48) gave the title compound as white crystals (0.18 g, 0.3 mmol) in a 60% yield; m.p. 100°C (become gummy solid); LC/Tof : ES + 609.2920 3.3ppm.
  • Example 10 4'-Cvano-biphenyl-4-carboxylic acid ⁇ 4-r4-(1-carbamoylmethoxy-5, 6,7,8- tetrahydro-naphthalen-2-yl)-piperidin-1-yll-butyl)-amide
  • Example 11 4'-Trifluoromethyl-biphenyl-4-carboxylic acid (4-f4-(4- carbamoylmethoxy-2,5-dimethyl-phenyl)-piperidin-1-yll-butyl)-amide
  • Example 12 Methanesulfonic acid 2,5-dimethyl-4-(1- ⁇ 4-f(4'-trifluoromethyl-biphenyl- 4-carbonyl)-aminol-butyl ⁇ -piperidin-4-yl)-phenyl ester
  • Example 13 4'-Chloro-biphenyl-4-carboxylic acid (4-r4-(1-carbamoylmethoxy- 5,6,7,8-tetrahydro-naphthalen-2-yl)-piperidin-1-vn-butyl)-amide
  • Example 14 2',4'-Dichloro-biphenyl-4-carboxylic acid H- -d-carbamoylmethoxy- 5,6.7.8-tetrahvdro-naphtalen-2-yl)-piperidin-1-vH-butyl)-amide
  • Example 15 4'-Cvano-biphenyl-4-carboxylic acid (4-r4-(1-methylcarbamoylmethoxy- 5.6,7.8-tetrahvdro-naphthalen-2-yl)-piperidin-1-vn-butyll-amide
  • Example 17 2-(4-Cvano-phenyl)-4-methyl-thiazole-5-carboxylic acid (4-f4-(1- carbamoylmetho ⁇ y-5,6,7,8-tetrahydro-naphthalen-2-yl)-piperidin-1-v ⁇ -butyl>-amide
  • Example 18 2-(4-Cvano-phenyl)-4-methyl-oxazole-5-carboxylic acid (4-f4-(1- carbamoylmethoxy-5,6,7,8-tetrahvdro-naphthalen-2-yl)-piperidin-1-yll-butyl>- amide
  • Example 19 Sulfamic acid 2-(1-(4-[(4'-cyano-biphenyl-4-carbonyl)-aminol-butyl)- piperidin-4-yl)-5,6,7,8-tetrahydro-naphthalen-1 -yl ester
  • Example 20 4'-Methanesulfonylamino-biphenyl-4-carboxylic acid (4-14-d- carbamoylmethoxy-5,6.7.8-tetrahvdro-naphthalen-2-yl)-piperidin-1-vn-butyl)-amide
  • Example 21 4'-Chloro-2-hvdroxy-biphenyl-4-carboxylic acid 4-f4-(1- carbamoylmethoxy-5,6,7,8-tetrahvdro-naphthalen-2-yl)-piperidin-1-yll-butyl)-amide
  • Example 22 4-(5-Acetyl-thiophen-2-yl)- ⁇ -(4-r4-(1-carbamoylmethoxy-5,6,7,8- tetrahydro-naphthalen-2-yl)-piperidin-1-yll-butyl)-benzamide
  • Example 23 4'-Cvano-biphenyl-4-carboxylic acid (4-14-11 -(2-methyl-allyl)-1 /-/-indazol- 3-yll-piperidin-1-yl)-butyl)-amide
  • Example 25 4'-Cvano-biphenyl-4-carboxylic acid (4- 4-f1-(1-carbamoyl-ethoxy)- 5,6,7,8-tetrahydro-naphthalen-2-yll-piperidin-1-yl ⁇ -butyl)-amide
  • Example 26 ⁇ /-(4-f4-(1 -Carbamoylmethoxy-5,6,7,8-tetrahvdro-naphthalen-2-yl)- piperidin-1-yll-butyl ⁇ -6-(4-chloro-phenyl)-nicotinamide
  • Example 28 4'-Cvano-biphenyl-4-carboxylic acid (4-(4-f1-(1-carbamoyl-1-methyl- ethoxy)-5,6,7,8-tetrahvdro-naphthalen-2-yll-piperidin-1-ylVbutyl)-amide
  • Example 29 4'-Chloro-biphenyl-4-carboxylic acid (4-(4-f1-(1-carbamoyl-1-methyl- ethoxy)-5,6,7,8-tetrahvdro-naphthalen-2-yll-piperidin-1-ylVbutyl)-amide
  • Example 31 ⁇ /-(4-f4-(1-Carbamoylmethoxy-5,6,7,8-tetrahvdro-naphthalen-2-yl)- piperidin-1-yll-butyl)-4-(5-cvano-pyridin-2-yl)-benzamide
  • Example 32 ⁇ /- ⁇ 4-r4-(1-Carbamoylmethoxy-5,6,7,8-tetrahvdro-naphthalen-2-yl)- piperidin-1-yll-butyl ⁇ -4-(5-chloro-pyridin-2-yl)-benzamide
  • Example 35 /V- 4-r4-(1-Carbamoylmethoxy-5,6,7,8-tetrahvdro-naphthalen-2-yl)- piperidin-1-yH-butylV6-(4-cvano-phenyl)-nicotinamide
  • Example 37 f2-(1-(4-r(4'-Cyano-biphenyl-4-carbonyl)-amino1-butyl)-piperidin-4-yl)- 5,6, 7, 8-tetrahydro-naphthalen-1 -yloxyl-acetic acid
  • HepG 2 cells stably transfected with a construct comprising 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 "6 M to 10 "9 M. 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. The ED 5 o ⁇ f each compounds was determined compared to the ED 50 of an internal standard.
  • the compounds of the invention are potent and specific inducers of LDL-r expression.

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Abstract

This invention relates to novel compounds which up-regulate LDL receptor (LDL-r) expression. and to processes for their preparation, pharmaceutical compositions containing them and their medical use. More particularly, this invention relates to novel aromatic piperidines of formula (I) and their use in therapy. wherein Ar1 is substituted, by at least one R1 group selected from: -O(CRaRb)nC(O)NRXRy, -O(CH2)nCN, -O(CH2)nO(CH2)mOR2, -O(CH2)nCO2R2, -OS02NRxRy, -OSO2(CH2)pCH3, -(CRaRb)nC(O)NRXRy, -(CH2)nCN, -(CH2)nO(CH2)mOR2, -(CH2)nCO2R2, -(CH2)nC(O)R2, - SO2NRxRy, -SO2(CH2)pCH3, -CH=CHC(O)NRxRy, -CH=CHCN, -CH=CHCO2R2, -CO2R2, - C(O)R2, -C(O)NRxRy and C2-5alkenyl.

Description

ARYL PIPERIDINE DERIVATIVES AS INDUCERS OF LDL-RECEPTOR EXPRESSION FOR THE TREATMENT OF HYPERCHOLESTEROLEMIA
This invention relates to novel compounds which up-regulate LDL receptor (LDL-r) expression and to processes for their preparation, pharmaceutical compositions 5 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 0 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- 5 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. Two 0 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)-pipehdin-1-yl]-butyl}-benzamide hydrochloride, which do not form part of the present invention.
5 Another publication, Bioorganic and Medicinal Chemistry Letters Vol. 5, 3, 219-222, 1995 discloses compounds having the general formula (A)
Figure imgf000002_0001
(A) where X may be COMe, SO2Me and NH2, as having high affinity for the dopamine D3 receptor and postulates their use in CNS disorders, particularly psychiatric illness. 0 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 present invention differs from the compounds 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)
Figure imgf000003_0001
where m = 0, 1 or 2; n=2 or 3; R1 and R3= H or OMe and R2 may be Ph, as selective 5-HT1A receptor ligands 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 WO99/45925 discloses compounds of formula (C)
Figure imgf000003_0002
(C) where R1 may be hydrogen, R2 may be hydrogen and R3 may be a group
Figure imgf000003_0003
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. Furthermore, the utility disclosed is different.
International Patent Application Publication Number WO98/37893 discloses compounds of formula (D)
Figure imgf000004_0001
(D) where Ar may represent an optionally substituted phenyl or naphthyl, G may be N or CH2 (sic), W may be an optionally substituted alkylene, 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 WO9402473 discloses compounds of formula (E)
Figure imgf000004_0002
(E) where A is -NHCO- or-CONH-; R^Rs may be hydrogen or phenyl, m may be 1-3 and n may be 1-3. Specifically disclosed are the following compounds:
Figure imgf000004_0003
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 WO99/45925 discloses compounds of formula (F)
< — Y-W-N N— A
(F) where A may represent a substituted phenyl group, W represents a linear or branched alkylene 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
Figure imgf000005_0001
(G)
These compounds are described as being α1A-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 WO98/35957 describes compounds of formula (H)
Figure imgf000005_0002
<H> 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)
Figure imgf000006_0001
(J) 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.
Journal Of Medicinal Chemistry, Vol. 31 , 1968-1971 , 1988 discloses certain aryl piperazines compounds, which fall outside the present invention, as 5HT-1a Serotonin Ligands as potential CNS agents. Specifically disclosed are compounds of formula (K)
Figure imgf000006_0002
<■<> where Ar=Ph and R = Ph, Ar= 2-methoxyphenyl and R =Ph and Ar=2-pyrimidyl and R=Ph.
Journal Of Medicinal Chemistry, Vol. 34, 2633-2638, 1991 discloses aryl piperazines having reduced α1 adrenergic affinity. Specifically disclosed is the compound (L)
Figure imgf000006_0003
(L) 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. According to a first aspect, the invention provides a compound of formula (I), physiologically acceptable prodrugs, salts or solvates thereof;
Figure imgf000007_0001
(I) wherein Ar, is:
(i) phenyl, naphthyl or phenyl fused by a C3.8cycloalkyl; or (ii) heterocyclyl selected from the list consisting of: monocyclic radicals and fused polycyclic radicals, wherein said radicals contain a total of from
5-14 ring atoms, wherein said radicals contain a total of from 1-4 ring heteroatoms independently selected from oxygen, nitrogen and sulfur, and wherein individual rings of said radicals may be independently saturated, partially unsaturated or aromatic, provided that at least one ring is aromatic; where Ar, is independently substituted by at least one R1 group and independently substituted by 0-3 R3 groups; Ar2 is a phenyl group, a 5-6 membered heteroaromatic group or a bicyclic heteroaromatic group, where each group is optionally substituted by one or two substituents independently selected from the list: Chalky!, halogen, hydroxy, C1-4alkoxy, C1-6acyl, C1-6acyloxy, amino, C^alkylamino, di-C^alkylamino, -(CH2)nNRxRy, -O(CH2)nC(O)NRxRy, -O(CH2)nCN, -O(CH2)nO(CH2)mOR2, C2.5alkenyl, -O(CH2)nCO2R2, -OSO2(CH2)pCH3, and -OSO2NRxRy; Ar3 is:
(i) phenyl, naphthyl or phenyl fused by a C3.8cycloalkyl; or (ii) heterocyclyl selected from the group consisting of monocyclic radicals and fused polycyclic radicals, wherein said radicals contain a total of from 5-14 ring atoms, wherein said radicals contain a total of from 1-4 ring heteroatoms independently selected from oxygen, nitrogen and sulfur, and wherein individual rings of said radicals may be independently saturated, partially unsaturated or aromatic, provided that at least one ring is aromatic; wherein Ar3 is optionally substituted by 1-4 groups independently selected from the group consisting of: hydroxy, C1-4alkyl, C1-4alkoxy, C^alkenyl, C2J,alkenyloxy, C1-4perfluoroalkoxy, C1-4alkylsulfonylamino (such as -NHSO2CH3, -NHSO2CH(CH3)2), fluoroC1-4alkylsulfonylamino (such as -NHSO2CH2CF3), C^alkylcarbonylamino, fluoroC^alkylcarbonylamino, halogen (such as chlorine), nitrile, nitro,
Figure imgf000008_0001
fluoroC1-4alkylcarbonyl, CMalkoxycarbonyl, aminocarbonyl, C alkylaminocarbonyl, di-C1-4alkylaminocarbonyl, CMalkylsulfonyl, C alkylaminosulfonyl, di-C1-4alkylaminosulfonyl, C^alkylsulfonyl and C1-4alkylsulfoxy;
E is -Cι_6alkylene-;
X is -CONR2-or-NR2CO- (where the left hand side of the linkage is attached to E); wherein
R1 is selected from the group consisting of: -O(CRaR°)nC(O)NRxRy, -O(CH2)nCN, -O(CH2)nO(CH2)mOR2, -O(CH2)nCO2R2, -OSO2NRxRy, -OSO2(CH2)pCH3,
-(CRaRb)nC(O)NRxRy, -(CH2)nCN, -(CH2)nO(CH2)mOR2, -(CH2)nCO2R2, -(CH2)nC(O)R2, -SO2NRxRy, -SO2(CH2)pCH3, -CH=CHC(O)NRxRy, -CH=CHCN, -CH=CHCO2R2, -CO2R2, -C(O)R2, -C(O)NRxRy and C2.5alkenyl; R2 is or hydrogen; R3 is selected from halogen, -O-(Cι-4alkylene)-R4 or -(ClJtalkylene)-R4, 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 oxygen atoms; R4 is: (i) hydrogen;
(ii) phenyl, phenyl fused by a C3-8cycloalkyl, naphthyl or a 5- or 6-membered heteroaromatic group, each of which may be optionally substituted by one or two groups independently selected from halogen, C1-4 alkyl, hydroxy, C1-4alkoxy, amino, C1-4alkylamino and di-CMalkylamino; (iii) C3.8cycloalkyl or a monocyclic heterocyclyl radical containing a total of 3-7 ring atoms, wherein said radical contains a total of from 1-4 ring heteroatoms independently selected from oxygen, nitrogen and sulfur, wherein said radical may be saturated, partially unsaturated or aromatic, and where the C3.8cycloalkyl or a monocyclic heterocyclyl may be substituted by one or two groups independently selected from halogen, C1-4alkyl, hydroxy, C1-4alkoxy, amino, C1-4 alkylamino and di-C^alkylamino; or (iv) amino, C1-4 alkylamino or di-Cι.4alkylamino;
Ra and Rb are independently hydrogen, C1-4alkyl or cycloalkyl, where Ra and Rb are not both cycloalkyl;
Rx and Ry are independently hydrogen, C1- alkyl, hydroxy or C1-4alkoxy, where Rx and Ry are not both hydroxy or both C1-4alkoxy; or Rx and Ry together with the nitrogen to which they are attached form a 5-membered ring which ring is optionally substituted by -O(CRaRb)nC(O)NRxRy, -O(CH2)nCN, -O(CH2)nO(CH2)mOR2, -O(CH2)nCO2R2, -OSO2NRxRy, -OSO2(CH2)pCH3,
.(CRaRb)nC(O)NRxRy, -(CH2)nCN, -(CH2)nO(CH2)mOR2, -(CH2)nCO2R2, -(CH2)nC(O)R2, -SO2NRxRy, -SO2(CH2)pCH3, -CH=CHC(O)NRxRy, -CH=CHCN, -CH=CHCO2R2, -CO2R2, -C(O)R2, -C(O)NRxRy or C2.5alkenyl; n and m are independently 1-4; and p is 0-4.
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 alkylene 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 C3.8cycloalkyl 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), Cι.3perfluoroalkyl and C^perfluoroalkoxy includes compounds in 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.
Referring to the general formula (I), a 3-7 membered heterocyclyl group means any single ring system containing at least one ring heteroatom independently selected from O, N and S, wherein said ring is saturated, unsaturated or aromatic.
Preferably An is phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indolyl, benzofuranyl, benzothiophenyl or indazolyl. More preferably Ar, is phenyl, 1 ,2,3,4- tetrahydronaphthyl or indolyl.
Where An is 1 ,2,3,4-tetrahydronaphthyl, the link to the piperidine ring is preferably through the 2- position of he 1,2,3,4-tetrahydronaphthyl moiety and mono- substitution by R1 is in the corresponding 1- position.
Where An is indolyl, the link to the piperidine ring is preferably through the 3-position of the indolyl moiety and mono-substitution by R1 is in the corresponding 1 -position.
Preferably E is n-butylene.
Preferably X is -NR2CO-. Preferably R2 is hydrogen.
Preferably Ar2 is phenyl or a 5-6-membered heteroaromatic group (more preferably phenyl, pyridyl, thiazolyl, oxazolyl or imidazolyl).
Preferably Ar3 is phenyl, pyridyl or thienyl, more preferably phenyl. Preferably Ar3 is substituted by halogen (e.g. chloro),
Figure imgf000010_0001
(e.g. trifluoromethyl), nitrile, C1-4acyl (e.g. acetyl), C1-4alkylsulfonyl (e.g. methylsulfonyl) or C1-4alkylsulfonylamino.
When Ar3 is phenyl, para- substitution is preferred. Preferably A is substituted by one R1, which R1 is selected from the group consisting of: -O(CRaRb)nC(O)NRxRy, -O(CH2)nCN, -O(CH2)nO(CH2)mOR2, -O(CH2)nCO2R2, -OSO2NRxRy, -OSO2(CH2)pCH3, -(CRaRb)nC(O)NRxRy and C2-5alkenyl; wherein R2 is C^alkyl or hydrogen; Ra and R are independently hydrogen or C1-4alkyl or cycloalkyl; Rx and Ry are independently hydrogen or C1-4alkyl; or Rx and Ry together with the nitrogen to which they are attached form a 5-membered ring which ring is optionally substituted by -O(CRaRb)nC(O)NRxRy, -O(CH2)nCN, -O(CH2)nO(CH2)mOR2, -O(CH2)nCO2R2, -OSO2NRxRy, -OSO2(CH2)pCH3, -(CRaRb)nC(O)NRxRy and C2.5alkenyl; and n and m are independently 1-3; p is 0-2.
Preferably An is not substituted by R3, however when An is substituted by R3 preferred substituents are C^alkyl or C1- alkoxy.
Preferably Ar2 is optionally substituted by C1-4alkyl, halogen, hydroxy or C^alkoxy. More preferably Ar2 is not substituted.
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.
Preferably,
A is phenyl, naphthyl, 1 ,2,3,4-tetrahydronaphthyl, indolyl, benzofuranyl, benzthiophenyl or indazolyl; where An is independently substituted by at least one R1 group and independently substituted by 0-3 R3 groups; Ar2 is phenyl or a 5-6-membered heteroaromatic group, either of which is optionally substituted by one or two substituents independently selected from the list: C1-4alkyl, halogen, hydroxy and C1-4alkoxy; Ar3 is phenyl, pyridyl or thienyl, each of which may be substituted by 1-3 groups independently selected from the group consisting of: halogen (e.g. chloro), C1-4perfluoroalkyl (e.g. trifluoromethyl), nitrite, C1- acyl (e.g. acetyl),
Figure imgf000011_0001
E is n-butylene; and X is -NR2CO-; wherein R1 is selected from the group consisting of: -O(CRaRb)nC(O)NRxRy, -O(CH2)nCN,
-O(CH2)nO(CH2)mOR2, -O(CH2)nCO2R2, -OSO2NRxRy, -OSO2(CH2)pCH3,
-(CRaRb)nC(0)NRxRy and C2.5alkenyl; wherein R2 is Cι-4alkyl or hydrogen;
Ra and R are independently hydrogen, C1-4alkyl or cycloalkyl;
Rx and Ry are independently hydrogen or C1-4alkyl; or Rx and Ry together with the nitrogen to which they are attached form a 5-membered ring which ring is optionally substituted by -O(CRaRb)nC(O)NRxRy, -O(CH2)nCN, -O(CH2)nO(CH2)mOR2, -O(CH2)nCO2R2, -OSO2NRxRy, -OSO2(CH2)pCH3,
-(CRaRb)nC(0)NRxRy, -C(O)NRxRy or C2-5alkenyl; n and m are independently 1-3; p is 0-2; and
R3 is C^alkyl or C1-4alkoxy.
Preferred compounds of formula (I) are selected from the list: 4'-Cyano-biphenyl-4-carboxylic acid {4-[4-(1 -carbamoylmethoxy-5,6,7,8-tetrahydro- naphthalen-2-yl)-piperidin-1-yl]-butyl}-amide (Example 10); 4'-Chloro-biphenyl-4-carboxylic acid {4-[4-(1 -carbamoylmethoxy-5,6,7,8-tetrahydro- naphthalen-2-yl)-piperidin-1-yl]-butyl}-amide (Example 13);
2',4'-Dichloro-biphenyl-4-carboxylic acid {4-[4-(1 -carbamoylmethoxy-5,6,7,8- tetrahydro-naphtalen-2-yl)-piperidin-1-yl]-butyl}-amide (Example 14); Λ/-{4-[4-(1-Carbamoylmethoxy-5,6,7,8-tetrahydro-naphthalen-2-yl)-piperidin-1-yl]- butyl}-4-(5-chloro-thiophen-2-yl)-benzamide (Example 24); 4'-Cyano-biphenyl-4-carboxylic acid (4-{4-[1-(1-carbamoyl-ethoxy)-5,6,7,8- tetrahydro-naphthalen-2-yl]-piperidin-1 -yl}-butyl)-amide (Example 25); Λ/-{4-[4-(1-Carbamoylmethoxy-5,6,7,8-tetrahydro-naphthalen-2-yl)-piperidin-1-yl]- butyl}-6-(4-chloro-phenyl)-nicotinamide (Example 26); 5-(4-Chloro-phenyl)-pyridine-2 -carboxylic acid {4-[4-(1-carbamoylmethoxy-5,6, 7,8- tetrahydro-naphthalen-2-yl)-piperidin-1-yl]-butyl}-amide (Example 27);
4'-Cyano-biphenyl-4-carboxylic acid (4-{4-[1-(1-carbamoyl-1-methyl-ethoxy)-5,6,7,8- tetrahydro-naphthalen-2-yl]-piperidin-1-yl}-butyl)-amide (Example 28); Λ/-{4-[4-(1-Carbamoylmethoxy-5,6,7,8-tetrahydro-naphthalen-2-yl)-piperidin-1-yl]- butyl}-4-(5-cyano-pyridin-2-yl)-benzamide (Example 31); Λ/-{4-[4-(1 -Carbamoylmethoxy-5,6,7,8-tetrahydro-naphthalen-2-yl)-piperidin-1 -yl]- butyl}-4-(5-chloro-pyridin-2-yl)-benzamide (Example 32); and Λ/-{4-[4-(1-Carbamoylmethoxy-5,6,7,8-tetrahydro-naphthalen-2-yl)-piperidin-1-yl]- butyl}-6-(4-cyano-phenyl)-nicotinamide (Example 35).
For the avoidance of doubt, unless otherwise indicated, the term substituted means substituted by one or more defined groups. In the case where groups may be selected from a number of alternative groups, the selected groups may be the same or different.
For the avoidance of doubt, the term independently means that where more than one substituent is selected from a number of possible substituents, those substituents may be the same or different.
As used herein the term "physiologically acceptable" means a compound which is suitable for pharmaceutical use.
Suitable physiologically acceptable salts of the compounds of general formula (I) include acid addition salts formed with pharmaceutically acceptable inorganic acids for example, phosphates, hydrochlorides, hydrobromides or sulphates, or with pharmaceutically acceptable organic acids for example mesylates, lactates and acetates. More suitably, a physiologically acceptable salt of the compounds of general formula (I) is a phosphate salt.
The solvates may, for example, be hydrates.
In addition, prodrugs are also included within the context of this invention. Prodrugs are any covalently bonded carriers that release a compound of structure (I) in vivo when such prodrug is administered to a patient. Prodrugs are generally prepared by modifying functional groups in a way such that the modification is cleaved, either by routine manipulation or in vivo, yielding the parent compound. Prodrugs include, for example, compounds of this invention wherein hydroxy, amine or sulfhydryl groups are bonded to any group that, when administered to a patient, cleaves to form the hydroxy, amine or sulfhydryl groups. Thus, representative examples of prodrugs include (but are not limited to) acetate, formate and benzoate derivatives of alcohol, sulfhydryl and amine functional groups of the compounds of formula (I). Further, in the case of a carboxylic acid (-COOH), esters may be employed, such as methyl esters, ethyl esters, and the like. Hereinafter, compounds, their pharmaceutically acceptable salts, their solvates and polymorphs, defined in any aspect of the invention (except intermediate compounds in chemical processes) are referred to as "compounds of the invention".
Compounds of the invention may be administered as the raw chemical but the active ingredient is preferably presented as a pharmaceutical formulation.
Compounds of the invention 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 pharmaceutically 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 propyl-p- 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 of 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 the invention 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 the invention may be administered in combination with an HMG CoA reductase inhibitor, an agent for inhibition of bile acid transport or fibrates.
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. Thus 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. In addition 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. It will be appreciated that reference to treatment is intended to include prophylaxis as well as the alleviation of established symptoms.
Compounds of the invention may be prepared in a variety of ways. In the following reaction schemes and hereafter, unless otherwise stated groups An, Ar2, Ar3, R1, R2, R3, R4, E and X are as defined in the first aspect. These processes form further aspects of the invention.
Throughout the specification, general formulae are designated by Roman numerals (I), (II), (III), (IV) etc. Subsets of these general formulae are defined as (la), (lb), (lc) etc .... (IVa), (IVb), (IVc) etc.
Compounds of formula (la), i.e. compounds of formula (I) where X is -NR2C(O)- where the nitrogen is attached to E, may be prepared according to reaction scheme 1 by reacting compounds of formula (II) with compounds of formula (III) where L is a leaving group such as halogen or hydroxy, using standard amide coupling conditions detailed in the experimental section.
Scheme 1
Figure imgf000017_0001
(ID H) (la)
Compounds of formula (lb), i.e. compounds of formula (I) where R1 is -OR, may be prepared from the corresponding hydroxy compound (IV) according to reaction scheme 2. Preferred reaction conditions comprise treating (IV) with a suitable base such as sodium hydride or caesium carbonate followed by addition of RL where L is a leaving group such as halogen. Compounds of formula (IV) may be prepared by adapting methods described herein for the preparation of compounds of formula (I).
Scheme 2
Figure imgf000018_0001
(IV) (lb)
Compounds of formula (I) where An is a nitrogen containing heterocycle may be substituted on the nitrogen by nucleophilic substitution. For instance where An is indol-3-yl, substitution may be effected by treating (I) with base such as sodium hydride followed by reaction with a suitable nucleophile.
Compounds of formula (I) may be prepared be coupling boronic acid compounds of formula (V) with compounds of formula (VI) according to reaction scheme 3. Preferred reaction conditions comprise treatment with Pd(PPh3)4 and a suitable base such as sodium carbonate at elevated temperature.
Scheme 3
Figure imgf000018_0002
(V) (
Compounds of formula (II) may be prepared according to reaction scheme 4 by reacting a compound of formula (VII) with a compound of formula (VIII) where L is a leaving group such as halogen and P is a suitable protecting group. Preferred conditions comprise reaction with a suitable base such as potassium carbonate. Removal of protecting group P gives compounds of formula (II). A preferred nitrogen protecting group is where the nitrogen attached to E and group R2 form phthalimide (i.e. 1 ,3-dioxo-1 ,3-dihydro-isoindol-2-yl). Removal of the phthalimide protecting group gives compounds of formula (II) where R2 is hydrogen. Preferred conditions comprise treatment with hydrazine at elevated temperature.
Scheme 4
Figure imgf000019_0001
(VII) (II)
Compounds of formula (VII) may be prepared by methods described in the experimental section hereinbelow. Compounds of formula (VIII) are either known or may be prepared from known compounds by methods available to the skilled person.
Compounds of formula (Ilia), i.e. compounds of formula (III) (see reaction scheme 1) where L is hydroxy, may be prepared according to reaction scheme 5 by coupling boronic acid compounds of formula (IX) with compounds of formula (X) where L is a leaving group such as halogen under analogous conditions described for reaction scheme 3.
Scheme 5
Figure imgf000019_0002
(IX) (Ilia)
Compounds of formula (IX) and (X) are either known or may be prepared from known compounds by methods available to the skilled person.
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-butoxycarboπyl. Conventional carboxylic acid protecting groups include methyl and ethyl groups.
It will be appreciated that the invention includes the following further aspects. The preferred embodiments described for the first aspect extend these further aspects:
i) a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier or diluent;
ii) the use of a compound of the invention in the manufacture of a medicament for use in the treatment of conditions resulting from elevated circulating levels of LDL-cholesterol;
iii) the use of a compound of the invention in the manufacture of a medicament for the treatment or prophylaxis of a disorder in which lipid imbalance is important such as atherosclerosis, pancreatitis, non-insulin dependent diabetes mellitus (NIDDM), coronary heart diseases and obesity);
iv) the use of a compound of the invention in the manufacture of a medicament for lowering serum lipid levels, cholesterol and/or triglycerides;
v) the use of a compound of the invention in the manufacture of a medicament for the treatment or prophylaxis of hyperlipemia, hyperlipidemia, hyperlipoproteinemia, hypercholesterolemia and/or hypertriglyceridemia;
vi) a compound of the invention for use as a medicament;
vii) a method of treatment or prophylaxis of a disorder resulting from elevated circulating levels of LDL-cholesterol in a human patient comprising administering to the human an effective amount of a compound of the invention;
viii) a method of lowering serum lipid levels, cholesterol and/or triglycerides in a human patient comprising administering to the human an effective amount of a compound of the invention; and ix) a combination of a compound of the invention with an HMG CoA reductase inhibitor, an agent for inhibition of bile acid transport or a fibrate.
In a further aspect, the invention provides a compound of formula (I)
Figure imgf000021_0001
(I) wherein
An represents
(i) phenyl, naphthyl, or phenyl fused by a C3.8cycloalkyl, or (ii) heterocyclyl selected from the group consisting of monocyclic radicals and fused polycyclic radicals, wherein said radicals contain a total of from
5-14 ring atoms, wherein said radicals contain a total of from 1-4 ring heteroatoms independently selected from oxygen, nitrogen and sulfur, and wherein individual rings of said radicals may be independently saturated, partially unsaturated, or aromatic, provided that at least one ring is aromatic, where An bears at least one group independently represented by R1 and 0-3 groups independently represented by R3;
R1 is selected from the group consisting of: -O(CH2)nC(O)NRxRy, -O(CH2)nCN, -O(CH2)nO(CH2)mOR2, CLsalkenyl, -O(CH2)nC(O)OR2, and -OSO2(CH2)pCH3; R2 is (CH2)nCH3 or H;
Rx and Ry are independently C1- alkyl or H; n and m are independently 1 -4; p represents 0-4;
R3 is selected from halogen, -©-(Co--! alkylene)-R4 or -(C0^alkylene)-R4, 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; R4 represents
(i) hydrogen, C^ perfluoroalkyl, CMperfluoroalkoxy, (ii) phenyl, phenyl fused by a C3.8cycloalkyl , naphthyl or a 5- or 6-membered heteroaromatic group, optionally substituted by one or two groups independently selected from halogen, C1-4 alkyl, hydroxy, C^ alkoxy, amino, d^ alkylamino and di-C^ alkylamino, (iii) C3.8cycloalkyl or a monocyclic heterocyclyl radical containing a total of 3- 7 ring atoms, wherein said radical contains a total of from 1-4 ring heteroatoms independently selected from oxygen, nitrogen and sulfur, wherein said radical may be independently saturated, partially unsaturated, or aromatic, and where the C3-8cycloalkyl or a monocyclic heterocyclyl may bear one or two groups independently selected from halogen, C1-4 alkyl, hydroxy, C1- alkoxy, amino, C1- alkylamino and di- C1- alkylamino, or (iv) amino, C alkylamino or di-C^alkylamino; Ar2 represents phenyl or a 5-6 membered heteroaromatic group or a bicyclic heteroaromatic group, where each group is optionally substituted by one or two groups independently selected from the group consisting of: C1-4 alkyl, halogen, hydroxy, C1-4 alkoxy, C1-6 acyl, C1-6 acyloxy, amino, CM alkylamino and di-C1-4 alkylamino groups; Ar3 represents
(i) phenyl, naphthyl, or phenyl fused by a C3.8cycloalkyl,
(ii) heterocyclyl selected from the group consisting of monocyclic radicals and fused polycyclic radicals, wherein said radicals contain a total of from 5-14 ring atoms, wherein said radicals contain a total of from 1-4 ring heteroatoms independently selected from oxygen, nitrogen and sulfur, and wherein individual rings of said radicals may be independently saturated, partially unsaturated, or aromatic, providing that at least one ring is aromatic, where Ar3 is optionally substituted by 1 -4 groups independently selected from the group consisting of: hydroxy, alkyl, CM alkoxy, C2.4 alkenyl, C2-4 alkenyloxy, C^ perfluoroalkoxy, C1-4 acylamino or an electron withdrawing group selected from the list consisting of: nitrile, nitro, C1-4, C1-4 perfluoroalkyl, C^ acyl , CM alkoxycarbonyl, aminocarbonyl, C1-4 alkylaminocarbonyl; di-C1- alkylaminocarbonyl, C1-4 alkylsulfonyl, C^ alkylaminosulfonyl and di-C1- alkylaminosulfonyl, d_4 alkylsulfonyl and Cι_4alkylsulfoxy; E represents -C^.e alkylene-;
X represents -CON(H or C^alkyl )-or -N(H or C alkyl)CO-; or a physiologically acceptable prodrug, salt or solvate thereof.
The invention is further described with reference to the following non-limiting examples. Abbreviations :
Pd(PPh3) - Tetrakis-(triphenylphosphine)-palladium(0), THF- Tetrahydrofuran, BF3- Et2O- Boron trifluoride diethyl etherate, DCM- Dichloromethane, TEA- triethylamine, CH3CN- Acetonitrile, EtOH- Ethanol, EtOAc- Ethyl acetate, iPr2O- Di-isopropyl ether, iPrOH- Isopropanol, Pd/C- Palladium on carbon, Et2O- diethyl ether, Chex- cyclohexane, MeOH- Methanol, DMF- Dimethyl formamide, DME-Ethylene glycol dimethyl ether, EDCI- 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, HOBt- 1-Hydroxybenzotriazole, rt- Room temperature, AcOH- Acetic acid, NaOH- Sodium hydroxide, KOH- potassium hydroxide, HCI- Hydrochloric acid, AcOH- Acetic acid, NaH- Sodium hydride, Na2SO4- Sodium sulfate, CCI - Carbon tetrachloride, AIBN- 2,2'-Azobis(2-methylpropionitrile), K2CO3- Potassium carbonate, Na2CO3- Sodium carbonate, NaCl- Sodium chloride, POCI3- Phosphorus oxychloride, DME- Dimethyl ether, Cs2CO3- Cesium carbonate, CrO3- Chromium(VI) oxide, BBr3- Boron tribromide, LiOH, H2O- Lithium hydroxyde, monohydrate, Mg- Magnesium, .
Intermediate 1 : 1-f4-(1-Hvdroxy-5.6,7,8-tetrahvdro-naphthalen-2-yl)-3,6-dihydro-2H- pyridin-1 -yll-ethanone
Figure imgf000023_0001
To a solution of the available 5,6,7,8-tetrahydro-naphthalen-1-ol (20.0 g, 0.135 mol) and 1-acetyl-4-piperidone (22.84 g, 1.2 eq.) in THF (400 mL) was added dropwise BF3-Et2O (68 mL, 4.0 eq). The mixture was stirred at 100°C for 2 hours, and 14 hours at room temperature. 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 Na SO4 and evaporated to dryness to give an oil which was recrystallized from acetonitrile to give the title compound (24.2 g, 89 mmol) as white crystals in a 66% yield; GC/MS: M+ C17H20NO2 271.
Intermediate 2: 1-f4-(1-Hydroxy-5.6,7,8-tetrahvdro-naphthalen-2-yl)-piperidin-1-yll- ethanone
Figure imgf000024_0001
To a solution of intermediate 1 (9 4 g, 34 7 mmol) in EtOH (300 mL) was added Pd/C,10% (0 9 g) and the reaction was stirred under hydrogen at 25°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 (9 6 g, 35 mmol) as a white foam, GC/MS M+ C17H22NO2 273
Intermediate 3 1-f4-(1-Methoxy-5.6,7,8-tetrahvdro-naphthalen-2-yl)-pιperιdιn-1-yll- ethanone
Figure imgf000024_0002
To a solution of intermediate 2 (9 6 g, 35 mmol) in DMF (300mL) was added NaH
60% (1 6 g, 1 2 eq ) and lodomethane (22 mL , 10 eq ) The mixture was stirred at
60°C for 2 hours and water (10 mL) was added After evaporation, the residue was taken up into water and extracted with DCM and dried over Na2SO4to give the title compound (10 2 g, 35 mmol) as a yellow oil in a quantitative yield, GC/MS M+
C18H2 NO2 287
Intermediate 4 4-(1 -Methoxy-5.6.7,8-tetrahvdro-naphthalen-2-yl)-pιperιdιne
Figure imgf000024_0003
To a solution of intermediate 3 (10 2 g, 35 mmol) in EtOH (200 mL) was added a
NaOH/H2O (20 mL/20 mL) solution and the mixture was stirred to reflux for 24 hours The solvent was evaporated off and water was added and the residue was extracted with DCM The organic layer was dried over Na2SO4 and evaporated to give the title compound (7 7 g, 31 mmol) as a yellow oil in a 88 5 % yield, GC/MS M+ Cι6H22NO 245 Intermediate s: 2-(4-f4-(1-Methoxy-5,6,7,8-tetrahydro-naphthalen-2-yl)-piperidin-1-ylj- butyl)-isoindole-1.3-dione
Figure imgf000025_0001
To a solution of intermediate 4 (7.7 g, 31 mmol) in acetone (200 mL) was added K2CO3 (8.55 g, 2 eq.) and 4-bromobutylphthalimide (8.86 g, 1 eq.) and the mixture was stirred at reflux for 6 hours. This mixture was filtered and the filtrate evaporated to give a residue which was diluted in DCM and filtered through a bed of silica gel. Evaporation of the solvent gave the title compound (12.2 g, 27 mmol) as yellow oil in a 87% yield; LC/MS: M+H C28H34N2O3 447.
Intermediate 6: 4-r4-(1-Methoxy-5.6,7,8-tetrahvdro-naphthalen-2-yl)-piperidin-1-vH- butylamine
Figure imgf000025_0002
A solution of intermediate 5 (12.2 g, 27 mmol) in MeOH (200 mL) was treated with hydrazine monohydrate (5.5 mL, 4 eq.). The resulting mixture was stirred to reflux for
16 hours. After cooling to rt and evaporation under reduced pressure the residue was taken up into water and a 1N HCI solution was added until the misture was at pH4.
Filtration gave yellow solution that was treated with a concentrated NaOH solution.
Extraction with DCM, drying over Na2SO , filtration and evaporation of the solvent gave the title compound (6.97 g, 22 mmol) as a yellow oil in a 81% yield; LC/MS:
M+H C20H33N2O 317.
Intermediate 7: 1-f4-(1-Benzyloxy-5,6,7,8-tetrahvdro-naphthalen-2-yl)-piperidin-1-vπ- ethanone
Figure imgf000026_0001
A solution of the intermediate 2 (11 g, 40 mmol), K2CO3 (19.0 g, 1.5 eq.) in methyl ethyl ketone (150 mL) was stirred at 80°C for 10 minutes. Benzyl bromide (7.7 g, 1.1 eq.) was added and the mixture was stirred to reflux for 2.5 hours. After filtration, the filtrate was evaporated off and the residue was washed with water, extracted with ether and evaporated. The solid was washed with iPr2O to give the title compound (9.5 g, 26.2 mmol) as beige crystals in a 66% yield; m.p. 108-110 °C.
Intermediate 8: 4-(1-Benzyloxy-5,6,7,8-tetrahvdro-naphthalen-2-yl)-piperidine
Figure imgf000026_0002
The same method was employed as in the preparation of intermediate 4 but starting from the intermediate 7 and gave the title compound as an oil in a 98% yield directly used in the next step without purification; LC/MS: M+H C22H28NO 322.
Intermediate 9: 2-(4-f4-(1 -Benzyloxy-5,6,7,8-tetrahvdro-naphthalen-2-yl)-piperidin-1- vN-butylHsoindole-1 ,3-dione
Figure imgf000026_0003
The same method was employed as in the preparation of intermediate 5 but starting from the intermediate 8 and gave the title compound as an oil in a quantitative yield directly used in the next step without purification; LC/MS: M+H C34H39N203 523. Intermediate 10: 4-f4-(1-Benzyloxy-5,6,7,8-tetrahvdro-naphthalen-2-yl)-piperidin-1- yll-butylamine
Figure imgf000027_0001
The same method was employed as in the preparation of intermediate 6 but starting from the intermediate 9 and gave the title compound as an oil which was used directly in the next step without purification; LC/MS: M+H C26H37N2O 393
Intermediate 11 : 4'-Trifluoromethyl-biphenyl-4-carboxylic acid (4-r4-(1-benzyloxy- 5,6,7.8-tetrahvdro-naphthalen-2-yl)-piperidin-1-yll-butyl>-amide
Figure imgf000027_0002
A solution of intermediate 10 (1.0 eq) in DMF was treated with the available 4'- trifluoromethyl-biphenyl-4-carboxylic acid (1.0 eq), EDCI (1.5 eq.), HOBT (1.5 eq.) and TEA (1.5 mL, 1.5 eq.). The resulting mixture was stirred for 24 hours at rt, and evaporated off. The residue was diluted with DCM and washed with water and with a 1 N NaOH solution. The organic layer was dried over Na2SO4 and evaporated off. After purification by flash chromatography using DCM/MeOH (95/5) as eluent, the title compound was obtained as white crystals after crystallisation from acetonitrile in a 45% yield; m.p. 169-170°C.
Intermediate 12: 4'-Trifluoromethyl-biphenyl-4-carboxylic acid (4-r4-(1-hydroxy- 5,6,7.8-tetrahvdro-naphthalen-2-yl)-piperidin-1-yl1-butyl)-amide
Figure imgf000028_0001
To a mixture of intermediate 11 (4.0 g, 6.2 mmol) in EtOH (150 mL) was added Pd/C, 10% (0.6 g) and the reaction was stirred under an atmospheric pressure of hydrogen at 60°C for 2 hours. The mixture was filtered through a bed of celite. The filtrate was evaporated under reduced pressure to give the title compound (3 g, 5.4 mmol) as white crystals after crystallisation from EtOH; m.p. 220-222°C.
Intermediate 13: 5-Methoxy-3-(1 ^.S.e-tetrahvdro-pyridin^-vn-l H-indole
Figure imgf000028_0002
To a solution of the available 5-methoxy-1 H-indole (50.0 g, 0.34 mol) in MeOΗ (500 mL) under N2 was added 4-piperidone hydrate hydrochloride (104.5 g, 2.6 eq.) and KOΗ (56.0 g, 3 eq). The mixture was stirred at reflux for one night. Water (11) was added slowly for one hour. The precipitate was filtered off and washed with water, ethanol and diethyl ether to give the title compound (51.58 g, 0.23 mol) as a yellow solid in a 58% yield; m.p. 184°C.
Intermediate 14: 5-Methoxy-3-pyridin-4-yl-1/-/-indole
Figure imgf000028_0003
A solution of intermediate 13 (47.0 g, 0.21 mol) in EtOH (500 mL), was treated with Pd/C 10% (4g) under hydrogen gas and stirred at rt for 24 hours. The mixture was filtered through a bed of celite and the filtrate evaporated to give the title compound (45.54 g, 0.2 mol) as an orange solid in a 96% yield; 1H NMR (CDCI3, 300 MHz) δ 7.4 (d, 1H), 7.3 (bd, 1H), 7.1 (s, 1H), 7.0 (ddp, 1H), 4.0 (s, 3H), 3.4 (dd, 2H), 2.9-3.0 (m, 3H), 2.2 (m, 2H), 1.9 (m, 2H).
Intermediate 15: 2-{4-r4-(5-Methoxy-1 H-indol-3-yl)-piperidin-1-yl -butylHsoindole-1.3- dione
Figure imgf000029_0001
The same method was employed as in the preparation of intermediate 5 but starting from intermediate 14 and gave the title compound as a yellow powder in a 70% yield; m.p. 155°C.
Intermediate 16: 4-f4-(5-Methoxy-1H-indol-3-yl)-piperidin-1-vn-butylamine
Figure imgf000029_0002
The same method was employed as in the preparation of intermediate 6 but starting from intermediate 15 and gave the title compound as a brown oil in quantitative yield; LC/MS: M+H C18H28N3O 302.
Intermediate 17: 4'-Cvano-biphenyl-4-carboxylic acid (4-[4-(5-methoxy-1H-indol-3-yl)- piperidin-1 -yll-butylV-amide
Figure imgf000029_0003
The same method was employed as in the preparation of intermediate 11 but starting from the intermediate 16 and the available 4'-cyano-biphenyl-4-carboxylic acid and gave the title compound as powder in 33% yield after recrystallisation in acetonitrile; m.p. 136°C.
Intermediate 18: 2-{4-f4-(1 H-lndol-3-yl)-piperidin-1 -yll-butyl)-isoindole-1 ,3-dione
Figure imgf000030_0001
The same method was employed as in the preparation of intermediate 5 but starting from the available 3-piperidin-4-yl-1 H-indole and gave the title compound as white crystals in a 77% yield after recrystallisation in CΗ3CN; m.p. 106-108°C.
Intermediate 19: 4-r4-(1H-lndol-3-yl)-piperidin-1-yll-butylamine
Figure imgf000030_0002
A solution of intermediate 18 (15 g, 37.5 mmol) in EtOH (250 mL) was treated with hydrazine monohydrate (2.5 mL, 1.4 eq). The resulting mixture was stirred at 55°C for 16 hours. After evaporation under reduced pressure the residue was taken up in acetone. Filtration and evaporation of filtrate gave the title compound (10.5 g, 38.7 mmol) as an oil in a quantitative yield. The crude compound was used without further purification.
Intermediate 20: 4'-Trifluoromethyl-biphenyl-4-carboxylic acid (4-[4-(1 H-indol-3-yl)- piperidin-1 -yll-butvD-amide
Figure imgf000030_0003
The same method was employed as in the preparation of intermediate 11 but starting from the intermediate 19 and the available 4'-trifluoromethyl-biphenyl-4-carboxylic acid and gave the title compound as white crystals in a 56% yield after recrystallisation in CH3CN; m.p. 208°C. Intermediate 21: 4'-Cyano-biphenyl-4-carboxylic acid (4-f4-(1-methoxy-5,6.7,8- tetrahydro-naphthalen-2-yl)-piperidin-1-yll-butyl}-amide
Figure imgf000031_0001
The same method was employed as in the preparation of intermediate 11 but starting from intermediate 6 and the available 4'-cyano-biphenyl-4-carboxylic acid and gave the title compound as a white solid after recrystallization from MeCN in a 39% yield; m.p. 154 °C; LC/MS: M+H C34H40N3O2522.
Intermediate 22: 4'-Cvano-biphenyl-4-carboxylic acid (4-f4-(1-hydroxy-5,6.7,8- tetrahydro-naphthalen-2-yl)-piperidin-1-yll-butyl}-amide
Figure imgf000031_0002
To a solution of intermediate 21 (2.1 g, 4 mmol) in DCM (150 mL) was added at 0°C a 1N BBr3 solution in DCM (30 ml, 7.5 eq). The resulting mixture was stirred for one hour and water (30 mL) was added. The product was extracted with DCM, dried over Na2SO4, filtered and evaporated. Purification by flash chromatography using DCM/MeOH 90/10 as eluent gave the title compound as a yellow foam (1.1 g, 2.2 mmol) in a 55% yield; LC/MS: M+H C33H38N3O2 508.
Intermediate 23: 2,5-Dimethyl-4-(1 ,2,3,6-tetrahvdro-pyridin-4-yl)-phenol
Figure imgf000031_0003
A solution of 2,5-dimethyl-phenol (12.2 g, 0.1 mol) and 4-piperidone hydrate hydrochloride (17.0 g, 0.10 mol) in acetic acid (50 mL) was treated with HCI gas for 15 minutes. The mixture was stirred at 95°C for 15 minutes. After cooling to rt, the mixture was treated with HCI gas for 5 min. The resulting solution was allowed to stir at rt for 4 days. The solvent was evaporated under reduced pressure to give the title compound as a colorless oil (18.0 g, 0.076 mol) in a 76% yield. White crystals were obtained from on recrystalisation from iPrOH; m.p. 210°C.
Intermediate 24 Acetic acid 4-(1-acetyl-1 ,2,3,6-tetrahvdro-pyridin-4-yl)-2,5-dimethyl-phenyl ester
Figure imgf000032_0001
To a solution of intermediate 23 (18.0 g, 0.076 mol) in pyridine (300 mL) was added acetic anhydride (140 mL) and the mixture was stirred at rt for 12 hours. The solvent was evaporated under reduced pressure and the resulting 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 yellow oil which was used without further purification; GC/MS :M+ C17H21NO3 287.
Intermediate 25: 1-r4-(4-Hvdroxy-2,5-dimethyl-phenyl)-3,6-dihvdro-2H-pyridin-1-yl1- ethanone
Figure imgf000032_0002
To a solution of intermediate 24 in MeOH (300 mL) was added a solution of K2CO3 (30.0 g) in H2O (200 mL) and the mixture was stirred to rt for 12 hours. The solvent was evaporated and the precipitate was filtered, washed with water and dried to give the title compound (17.0 g, 0.078 mol) in a 88% yield; m.p. 220°C.
Intermediate 26: 1-f4-(4-Benzyloxy-2,5-dimethyl-phenyl)-3,6-dihvdro-2H-pyridin-1-yll- ethanone
Figure imgf000033_0001
The same method was employed as in the preparation of intermediate 7 but starting from intermediate 25 (20.3 g, 83 mmol) and benzyl bromide and gave the title compound as white crystals (23.5 g, 70 mmol) in 84.5% yield; m.p. 124°C.
Intermediate 27: 4-(4-Benzyloxy-2,5-dimethyl-phenyl)-1 ,2,3,6-tetrahvdro-pyridine
Figure imgf000033_0002
The same method was employed as in the preparation of intermediate 4 but starting from intermediate 26 (23.5 g, 70 mmol) and gave the title compound as an oil (17.5 g, 59.7 mmol) in 85% yield; 1H NMR (CDCI3, 300 MHz) δ 7.47-7.32 (m, 5H), 6.91 (s, 1H), 6.72 (s, 1 H), 5.57 (1 H), 5.06 (s, 2H), 3.49 (d, 2H), 3.08 (t, 2H), 2.28 (s, 3H), 2.24 (s, 3H), 1.95 (2H).
Intermediate 28: 2-(4-f4-(4-Benzyloxy-2.5-dimethyl-phenyl)-3.6-dihvdro-2r/-pyridin-1- yll-butyll-isoindole-1 ,3-dione
Figure imgf000033_0003
The same method was employed as in the preparation of intermediate 5 but starting from intermediate 27 (17.5 g, 60 mmol) and gave the title compound as white crystals (22 g, 44.5 mmol) in 74% yield; m.p. 100°C.
Intermediate 29: 4-f4-(4-Benzyloxy-2,5-dimethyl-phenyl)-3,6-dihvdro-2H-pyridin-1-vπ- butylamine
Figure imgf000033_0004
The same method was employed as in the preparation of intermediate 6 but starting from intermediate 28 (22 g, 44 mmol) and gave the title compound as an oil (12.0 g, 33 mmol) in 75% yield. The crude compound was used in the next step without further purification.
Intermediate 30: 4'-Trifluoromethyl-biphenyl-4-carboxylic acid (4-f4-(4-benzyloxy-2,5- dimethyl-phenyl)-3,6-dihvdro-2/-/-pyridin-1-vn-butyl)-amide
Figure imgf000034_0001
The same method was employed as in the preparation of intermediate 11 but starting from intermediate 29 (7.2 g, 20 mmol) and the available 4'-trifluoromethyl-biphenyl-4- carboxylic acid (5.3 g, 20 mmol) in THF (100 mL) and gave the title compound as white crystals (11.0 g, 18 mmol) in 90% yield after precipitation in water; m.p. 205 °C; LC/MS: M+H C38H4oF3N2O2 613.
Intermediate 31: 4'-Trifluoromethyl-biphenyl-4-carboxylic acid (4-f4-(4-hvdroxy-2,5- dimethyl-phenyl)-piperidin-1-vπ-butyl)-amide
Figure imgf000034_0002
The same method was employed as in the preparation of intermediate 12 but starting from intermediate 30 (11.0 g, 18 mmol) in THF/EtOH (200 ml_ 200 mL) and gave the title compound as white crystals (6.5 g, 12.4 mmol) in 69% yield; m.p. 215 °C; LC/MS: M+H C31H36F3N2O2 525.
Intermediate 32: 4'-Chloro-biphenyl-4-carboxylic acid (4-f4-(1-methoxy-5,6,7,8- tetrahvdro-naphthalen-2-yl)-piperidin-1-vN-butyl)-amide
Figure imgf000035_0001
The same method was employed as in the preparation of intermediate 11 but starting from intermediate 6 (1.0 g, 3.16 mmol) and the available 4'-chloro-biphenyl-4- carboxylic acid (0.74 g, 1.0 eq) and gave the title compound as a white solid (1.08 g, 2.04 mmol) in a 59.3% yield after purification by flash chromatography using DCM/MeOH 95/5 as eluent; LC/MS: M+H C33H40CIN2O2 531.
Intermediate 33: 4'-Chloro-biphenyl-4-carboxylic acid 4-f4-(1-hydroxy-5,6.7.8- tetrahydro-naphthalen-2-yl)-piperidin-1-vn-butyl)-amide
Figure imgf000035_0002
To a solution of intermediate 32 (1.08 g, 2.04 mmol) in DCM (100 mL) cooled at 0°C was added BBr3 (20 L, 10.0 eq.) and the mixture was stirred at rt for 2 hours. Water (20 mL) was added at 0°C. The organic layer was dried over Na2SO4, filtered and evaporated. The title compound was obtained as a beige foam (1.2 g, 2.32 mmol, bromhydrate salt) in quantitative yield; LC/MS: M+H C32H38CIN2θ2 517.
Intermediate 34: 2',4'-Dichloro-biphenyl-4-carboxylic acid (4-f4-(1-methoxy-5,6,7,8- tetrahydro-naphthalen-2-yl)-piperidin-1-yl1-butyl}-amide
Figure imgf000035_0003
The same method was employed as in the preparation of intermediate 11 but starting from the intermediate 6 (1.0 g, 3.16 mmol) and the available 2',4'-dichloro-biphenyl- 4-carboxylic acid (0.842g, 1.0 eq.) and gave the title compound as a white solid (1.05 g, 1.86 mmol) in a 58.9% yield after purification by flash chromatography using DCM/MeOH 90/10 as eluent; LC/MS: M+H C33H39CI2N2O2 565.
Intermediate 35: 2'.4'-Dichloro-biphenyl-4-carboxylic acid (4-f4-(1-hydroxy-5,6,7,8- tetrahvdro-naphthalen-2-yl)-piperidin-1-yl1-butyl)-amide
Figure imgf000036_0001
The same method was employed as in the preparation of intermediate 33 but starting from intermediate 34 (1.05 g, 1.86 mmol) and gave the title compound (1.2 g, 2.18 mmol) in a quantitative yield; LC/MS: M+H C32H37CI2N2θ2 551.
Intermediate 36: 1-f4-(1-Benzyloxy-5,6,7,8-tetrahvdro-naphthalen-2-yl)-3.6-dihydro- 2H-pyridin-1 -yll-ethanone
Figure imgf000036_0002
A solution of intermediate 1 (15.0 g, 55.4 mmol) in anhydrous DMF (200 mL) was treated with NaH, 60% in oil dispersion, (2.65 g, 1.2 eq.) and the mixture was stirred at rt for 15 min. Then benzylbromide (6.9 mL, 1.05 eq.) was added and the reaction mixture was stirred at rt for 65 hours. After evaporation, DCM was added and the organic layer washed with water and with a 1 N NaOH solution. The organic phase was dried over Na2SO4, filtered and evaporated to give the title compound as a yellow oil (20.0 g, 55.4 mmol) in quantitative yield; 1H NMR (CDCI3, 300 MHz) δ 7.3 (m, 5H), 6.8 (dd, 2H), 5.8 (m, 1 H), 4.7 (s, 2H), 4.0 (m, 2H), 3.5 (m, 2H), 2.8 (m, 4H), 2.4 (m, 2H), 2.0 (s, 3H), 1.7 (m, 4H).
Intermediate 37: 4-(1-Ethoxy-5.6,7.8-tetrahydro-naphthalen-2-yl)-1 ,2,3.6-tetrahydror pyridine
Figure imgf000037_0001
A solution of intermediate 36 (20.0 g, 55.4 mmol) in a mixture of EtOH/water (200 mL/20 mL) was treated with an aqueous 35% NaOH solution (20 mL) and the mixture was refluxed for 24 hours. After evaporation, the product was extracted with DCM and washed with water. The organic layer was dried over Na2SO4, filtered and evaporated. The title compound was obtained as a yellow oil (17.4 g, 54.5 mmol) in a 98% yield; LC/MS: M+H C22H26NO 320.
Intermediate 38: 2-(4-[4-(1 -Benzyloxy-5,6,7,8-tetrahydro-naphthalen-2-yl)-3.6- dihvdro-2H-pyridin-1-yll-butylHsoindole-1,3-dione
Figure imgf000037_0002
The same method was employed as in the preparation of intermediate 5 but starting from the intermediate 37 and gave the title compound as a yellow oil in a 71% yield after purification by flash chromatography using DCM/MeOH 98/2 as eluent; LC/Tof : ES+ Calculated, 521.2804 ; Found, 521.2798 -1.2ppm.
Intermediate 39: 2-(4-r4-(1-Hvdroxy-5,6,7,8-tetrahvdro-naphthalen-2-yl)-piperidin-1- yll-butyl)-isoindole-1 ,3-dione
Figure imgf000037_0003
To a mixture of intermediate 38 (20.06 g, 38.6 mmol) in EtOH (400 mL) was added Pd/C, 10% (3.0 g) and the reaction was stirred under hydrogen using 6 bars as pressure, during 72h at 50°C. The reaction was then filtered through a bed of celite. The filtrate was evaporated to give the title compound as an orange oil (16.66 g, 38.6 mmol) in quantitative yield. The crude compound was used in the next step without purification.
Intermediate 40: 2-(2-d-f4-(1 ,3-Dioxo-1 ,3-dihvdro-isoindol-2-yl)-butvπ-piperidin-4-yl)- 5,6,7,8-tetrahydro-naphthalen-1-yloχy)-acetamide
Figure imgf000038_0001
A solution of intermediate 39 (10.0 g, 23.15 mmol) in anhydrous DMF (200 mL) was treated with NaH 60% in oil dispersion (1.39 g, 1.5 eq) and the mixture was stirred at rtfor 15 min. 2-Bromo-acetamide (3.83 g, 1.2 eq.) was added and the reaction mixture was stirred at rt for 7 hours. After evaporation, the product was extracted with DCM, washed with water, dried over Na2SO4, filtered and evaporated off. The title compound was obtained as a yellow solid (5.06 g, 10.34 mmol) in 45% yield after purification by flash chromatography using DCM/MeOH 95/5 as eluent; m.p. 198°C.
Intermediate 41 : 2-(2-ri-(4-Amino-butyl)-piperidin-4-yl1-5,6.7,8-tetrahvdro- naphthalen-1 -yloxyVacetamide
Figure imgf000038_0002
To a solution of intermediate 40 (3.06 g, 6.26 mmol) in MeOH (100 mL) was added hydrazine monohydrate (0.46 mL, 1.5 eq) and the mixture was heated under reflux for 20 hours. As the reaction was not completed further hydrazine was added and the mixture was heated under reflux for 6 hours. On cooling, the mixture was evaporated to dryness and the resulting solid was dissolved in water and acidified with a concentrated HCI solution (pH=4). The resulting white precipitate was filtered.
Concentrated NaOH solution was added (pH=10) and the product was extracted with DCM, dried over Na2SO4, filtered and evaporated off. The title compound was obtained as a white solid (1.18 g, 3.28 mmol) in 52% yield; m.p. 174°C.
Intermediate 42: 2-Bromo-4-methyl-thiazole-5-carboxylic acid ethyl ester To a solution of 2-methyl-1-nitrosooxy-propane (28.2 mL, 2.1 eq.) in CH3CN (700 mL) cooled to 0°C was added dropwise bromo-trimethyl-silane (32 mL, 2.1 eq.). The resulting mixture was maintained at 0°C. A solution of the available 2-amino-4- methyl-thiazole-5-carboxylic acid ethyl ester (18.6 g, 0.1 mol ) in CH3CN/AcOEt 75/25 was added dropwise and the reaction mixture was maintained at 0°C. The mixture was stirred for 24 hours at rt. The solvent was evaporated and water was added. The product was extracted with AcOEt, dried over Na2SO4, filtered and evaporated. The title compound was obtained as a yellow solid (21.74 g, 87 mmol) in 87% yield after purification by flash chromatography using DCM as eluent; GC/MS: M+ C7H8BrNO2S 250.
Intermediate 43: 2-(4-Cyano-phenyl)-4-methyl-thiazole-5-carboxylic acid ethyl ester
Figure imgf000039_0001
To a solution of intermediate 42 (10.0g, 40 mmol) in DMF (200 mL) was added Pd(PPh3)4 (2.76 g, 0.06 eq.), a 2M Na2CO3 solution (50 mL, 2.5 eq.) and 4- cyanophenyboronic acid (11.68 g, 2.0 eq) and the mixture was heated at 100°C for 24 hours. After evaporation of the solvent, water and DCM were added and the resulting solution was filtered through a bed of celite. Evaporation of the filtrate gave a residue which was purified by flash chromatography using DCM/cyclohexane 80/20 and DCM/cyclohexane 90/10 as eluents to give the title compound; GC/MS: M+ C14H12N2O2S 272.
Intermediate 44: 2-(4-Cyano-phenyl)-4-methyl-thiazole-5-carboxylic acid
Figure imgf000039_0002
A suspension of intermediate 43 (4.0 g, 14.7 mmol) in EtOH (150 mL) was treated with LiOH.H2O (1.23 g, 2 eq) and the mixture was stirred at rt for 48 hours. After evaporation of the solvent, the aqueous layer was acidified with a HCI solution. The resulting precipitate was filtered and dried. The title compound was obtained as a white solid in a quantitative yield; m.p. 265-270°C.
Intermediate 45: 2-(4-Cyano-phenyl)-4-methyl-oxazole-5-carboxylic acid
Figure imgf000040_0001
A solution of the available 2-(4-cyano-phenyl)-4-methyl-oxazole-5-carboxylic acid methyl ester (1.0 g, 4.13 mmol) in THF (50 mL) was treated with a 1 N NaOH solution (4 mL, 0.95 eq.) and the reaction mixture was stirred at rt for 3 days. Then the mixture was neutralised with a 1N HCI solution and the solvent was evaporated. The residue was washed with water to give the title compound as a white solid (0.94 g, 4.13 mmol) in a quantitative yield; LC/MS: M+H C12H9N2O3 229.
Intermediate 46: N-(4-Bromo-phenyl)-methanesulfonamide To a solution of the available 4-bromo-phenylamine (8.60 g, 50 mmol) and TEA (10.35 g, 2.05 eq.) in DCM (100 mL) cooled to -78°C was added slowly a solution of methanesulfonyl chloride (6.01 g, 1.05 eq.) in DCM. After the end of the addition, the temperature returned slowly to rt and the mixture was stirred overnight.
Then water was added and the mixture was decantated. The aqueous layer was extracted with DCM and the combined organic layer was dried over Na2S04, filtered and evaporated. The title compound was obtained as a white solid (6.75 g, 27 mmol) in a 54% yield after purification by flash chromatography using DCM as eluent; m.p. 140-142°C.
Intermediate 47:4'-Methanesulfonylamino-biphenyl-4-carboxylic acid methyl ester To a solution of intermediate 46 (6.67 g, 26.7 mmol) and the available 4- methoxycarbonylphenylboronic acid (5.76 g, 1.2 eq.) in DME (120 mL) was added Pd(PPh3)4 followed by a 2M Na2CO3 solution (35 mL, 2.6 eq.). The mixture was refluxed overnight. After the addition of water, the aqueous layer was extracted with AcOEt and the organic layer was washed with a brine solution, dried over Na2S04, filtered and evaporated off. The residue was purified by flash chromatography using DCM/cyclohexane 70/30 as eluent. The title compound was obtained as a grey solid (2.7 g, 8.85 mmol) in a 33.2% yield after recrystallisation from CH3CN; m.p. 201- 203°C.
Intermediate 48: 4'-Methanesulfonylamino-biphenyl-4-carboxylic acid
A suspension of intermediate 47 (2.6 g, 8.52 mmol) in MeOH (150 mL) was treated with a 1 N NaOH solution (21.3 mL, 2.5 eq.) and the reaction was refluxed overnight. After evaporation, a 1N solution of HCI was added. The resulting precipitate was collected by filtration and dried. The title compound was obtained as a white solid (2.5 g, 8.59 mmol) in a quantitative yield; LC-MS : M-H C14H12NO4S 290.
Intermediate 49: ethyl 3-hvdroxy-4-iodobenzoate
A solution of the available 3-hydroxy-4-iodobenzoic acid (25.0 g, 94.7 mmol) in EtOH (1000 mL) was treated with HCI gas for 30 min. The reaction mixture was heated under reflux for 48 hours. After evaporation of EtOH, the resulting precipitate was filtered through a bed of silica gel eluting with DCM/MeOH 97/3. The title compound was obtained as a white solid (25.66 g, 94.7 mmol) in a 73% yield; 1H NMR (CDCI3, 300 MHz) 57.75 (d, 1H), 7.5 (d, 1H), 7.45 (dd, 1H), 4.5 (q, 2H), 1.4 (t, 3H).
Intermediate 50: ethyl 4'-chloro-2-hvdroxy-4-biphenylcarboxylate
Figure imgf000041_0001
The same method was employed as in the preparation of intermediate 47 but starting from the intermediate 49 and the available 4-chlorocarbonylphenylboronic acid and gave the title compound as a white solid in a 74% yield after purification by flash chromatography using DCM and DCM/AcOEt 97/3 as eluent; LC-MS : M+H C15H14CIO3 277.
Intermediate 51 : 4'-chloro-2-hvdroxy-4-biphenylcarboxylic acid
Figure imgf000041_0002
The same method was employed as in the preparation of the intermediate 48 but starting from the intermediate 50 and gave the title compound as a white solid in a quantitative yield after washing in hot acetonitrile; LC-MS : M+H C13H10CIO3 249. Intermediate 52: f4-«f4-(4-(1-r(2-amino-2-oxoethyl)oxy1-5.6.7.8-tetrahvdro-2- naphthalenyl)-1-piperidinyl)butvnamino)carbonyl)phenvnboronic acid
Figure imgf000042_0001
The same method was employed as in the preparation of intermediate 11 but starting from intermediate 41 and the available 4-carboxyphenylboronic acid and gave the title compound as an orange solid in quantitative yield; LC-MS: M+H C28H39BN3O5 508.
Intermediate 53: (2-fluorophenyl)(1-methyl-4-piperidinyl)methanone
Figure imgf000042_0002
To a suspension of Mg (5.57 g, 0.23 mol) in THF (25 mL) was added a few drops of bromoethane to initiate reaction. 4-Chloro-1-methylpiperidine (24.5 g, 0.18 mol) in THF (80 mL) was then added dropwise. After addition the reaction was heated under reflux for 1 hour and then allowed to attain rt. The available 2-fluorobenzonitrile (22.2 g, 0.18 mol) in THF (44 mL) was added and the mixture was heated under reflux for 3 hours and stirred at rt overnight. The reaction was treated with a ammonium chloride solution and water. After extraction with Et2O, the organic layer was dried over Na2SO4, filtered and evaporated off. The crude oil was purified by distillation under vaccum (T=110°C) to give the title compound as a yellow oil (10.0 g, 18 mmol) in a 25% yield; LC-MS : M+H C13Hι7NFO 222.
Intermediate 54: 3-(1-methyl-4-piperidinyl)-1/-/-indazole
Figure imgf000042_0003
A suspension of intermediate 53 (8.9 g, 0.04 mol) and hydrazine hydrate (10 mL, 5 eq.) was heated at 150°C in an autoclave for 48 hours. After cooling, the reaction mixture was stirred in water and the white precipitate was filtered and dried to give the title compound (5.3 g, 0.024 mol) as a white solid with a 61% yield; m.p. 170°C.
Intermediate 55: 3-(1 -methyl-4-piperidinyl)-1 -(2-methyl-2-propen-1 -yl)-1 /-/-indazole
Figure imgf000043_0001
To a solution of intermediate 54 (5.3 g, 0.024 mol) in DMF (15 mL) was added NaH 60% in oil dispersion (1.24 g, 1.2eq.). The reaction was stirred under nitrogen for 10 min. 3-Chloro-2-methyl-1-propene (2.8 mL, 1.1 eq.) was added and the reaction was stirred at rt overnight. After evaporation, the residue was treated with water and extracted with DCM, washed with brine solution, dried over Na2SO and evaporated. After purification by flash chromatography using DCM/MeOH 85/15 as eluent, the title compound was obtained as an oil (3.48 g, 0.013 mol) in a 52% yield; 1H NMR (CDCI3, 300 MHz) δ 7.75 (d, 1 H), 7.25 (m, 2H), 7.00 (m, 1 H), 4.75 (m, 3H), 4.6 (s, 1H) 2.8 (m, 4H) 2.4 (s, 3H) 2.1 (m, 6H).
Intermediate 56: phenyl 4-f1-(2-methyl-2-propen-1-yl)-1H-indazol-3-yll-1- piperidinecarboxylate
Figure imgf000043_0002
To a solution of intermediate 55 (3.48 g, 0.013 mol) in toluene (75 mL) was added K2CO3 (3.6 g, 2eq.) and phenyl chloroformate (1.8 mL, 1.1 eq.) and the reaction was heated under reflux for 48 hours. After cooling, the reaction was filtered and the solvent evaporated to give the title compound which was used in the next step without purification.
Intermediate 57: 1-(2-methyl-2-propen-1-yl)-3-(4-piperidinyl)-1r- -indazole
Figure imgf000044_0001
To a solution of intermediate 56 (7.7 g, 0.013 mol) in a H2O/EtOH 1/1 solution (100 mL), were added KOH (15.0 g, 28 eq) and the reaction was stirred at reflux overnight. On cooling, the mixture was concentrated and extracted with DCM, washed with brine, dried over Na2SO4 and evaporated. The title compound was obtained as a yellow oil (3.23 g, 0.012 mol) in a 97% yield; LC-MS : M+H C16H22N3 256.
Intermediate 58: 2-(4-{4-f1-(2-Methyl-allyl)-1H-indazol-3-vn-piperidin-1-yl)-butyl)- isoindole-1 ,3-dione
Figure imgf000044_0002
The same method was employed as in the preparation of intermediate 5 but starting from intermediate 57 and gave the title compound as a yellow oil in 56% yield after purification by flash chromatography using DCM/MeOH 95/5 as eluent; LC/MS: M+H C28H33N4O2 457.
Intermediate 59: 4-(4-f1-(2-Methyl-allyl)-1H-indazol-3-vH-piperidin-1-yl)-butylamine
Figure imgf000044_0003
The same method was employed as in the preparation of intermediate 6 but starting from intermediate 58 and gave the title compound as a yellow oil which was used in the next step without purification; LC/MS: M+H C20H31N4 327.
Intermediate 60: methyl 6-(4-chlorophenyl)-3-pyridinecarboxylate The same method was employed as in the preparation of intermediate 47 but starting from the available methyl 6-chloro-3-pyridinecarboxylate and the 4- chlorophenyboronic acid and gave the title compound as a white solid in 90% yield after purification by flash chromatography using DCM as eluent; m.p. 124-126°C.
Intermediate 61 : 6-(4-chlorophenyl)-3-pyridinecarboxylic acid The same method was employed as in the preparation of intermediate 48 but starting from intermediate 60 and gave the title compound as a white solid in a quantitative yield; m.p. >260°C; LC-MS : M+H Cι2H9CINO2 234.
Intermediate 62: methyl 5-(4-chlorophenyl)-2-pyridinecarboxylate The same method was employed as in the preparation of intermediate 47 but starting from the available methyl 5-bromo-2-pyridinecarboxylate and 4-chlorophenyboronic acid and gave the crude title compound which was directly used in the saponification reaction.
Intermediate 63: 5-(4-chlorophenyl)-2-pyridinecarboxylic acid The same method was employed as in the preparation of intermediate 48 but starting from intermediate 62 and gave the title compound as a white solid in a 53% yield; m.p. >260°C; LC-MS : M-H Cι2H7CINO2 232.
Intermediate 64: 2-bromo-2-methylpropanamide
To a solution of the 2-bromo-2-methylpropanoyl bromide (100.0 g, 0.43 mol) in hexane (900 mL) cooled at 0°C was added an ammonium hydroxide solution (25%). A white precipitate was formed and the reaction was stirred at 0°C for 30 min.
After filtration, the precipitate was washed with water and dried. After recrystallisation from EtOH, the title compound was obtained as white needles in a 76% yield; m.p. 148°C.
Intermediate 65: methyl 4-(5-cvano-2-pyridinyl)benzoate
The same method was employed as in the preparation of the intermediate 47 but starting from the available 6-chloro-3-pyridinecarbonitrile and 4- methoxycarbonylphenylboronic acid and gave the title compound as a white solid in 77% yield after purification by flash chromatography using DCM as eluent; m.p. 166- 168°C. Intermediate 66: 4-(5-cyano-2-pyridinyl)benzoic acid
The same method was employed as in the preparation of intermediate 48 but starting from intermediate 65 and gave the title compound as a beige solid in a 80% yield; m.p >250°C; LC-MS : M-H C13H7N2O2 223.
Intermediate 67: methyl 4-(5-chloro-2-pyridinyl)benzoate
The same method was employed as in the preparation of intermediate 47 but starting from the available 2-bromo-5-chloro-pyridine and 4-methoxycarbonylphenyl-boronic acid and gave the title compound as a white powder in a quantitative yield after purification by flash chromatography using DCM as eluent; GC/MS : M+ C13H10CINO2 247.
Intermediate 68: 4-(5-chloro-2-pyridinyl)benzoic acid
The same method was employed as in the preparation of intermediate 48 but starting from intermediate 67 and gave the title compound as a solid in a quantitative yield; LC/MS : M+H C12H9CINO2 234.
Intermediate 69: 2-(2-d-f4-(1 ,3-Dioxo-1 ,3-dihydro-isoindol-2-yl)-butyll-piperidin-4-yl>- 5.6.7.8-tetrahvdro-naphthalen-1-yloxy)-2-methyl-propionamide
Figure imgf000046_0001
The same method was employed as in the preparation of intermediate 40 but starting from intermediate 39 and intermediate 64 and gave the title compound as white crystals in a 31 % yield after cristallisation from CH3CN; m.p. 170°C.
Intermediate 70: 2-(2-f1-(4-Amino-butyl)-piperidin-4-vn-5.6.7.8-tetrahvdro- naphthalen-1-yloxy)-2-methyl-propionamide
Figure imgf000046_0002
The same method was employed as in the preparation of intermediate 6 but starting from intermediate 69 and gave the title compound as a yellow oil which was directly used in the next step without purification; LC/MS: M+H C23H38N3O2 388.
Intermediate 71 : 5-(4-cvanophenyl)-2-pyridinecarboxylic acid
The same method was employed as in the preparation of intermediate 47 but starting from the available methyl 5-bromo-2-pyridinecarboxylate and the available 4- cyanocarbonylphenylboronic acid and gave title compound (as the carboxylic acid form) as a white solid in a quantitative yield; m.p.> 260°C; LC/MS : M-H C13H7N2O2 223.
Intermediate 72: methyl 6-(4-cyanophenyl)-3-pyridinecarboxylate The same method was employed as in the preparation of intermediate 47 but starting from the available methyl 6-chloro-3-pyridinecarboxylate and the available 4- cyanocarbonylphenylboronic acid and gave the title compound as a white solid in a 32% yield after purification by flash chromatography using DCM and DCM/AcOEt 98/2 as eluent; m.p. 142-144°C.
Intermediate 73: 6-(4-cyanophenyl)-3-pyridinecarboxylic acid The same method was employed as in the preparation of intermediate 48 but starting from intermediate 72 and gave the title compound as a white solid in a 91% yield; m.p. >260°C; LC/MS : M+H C12H9N2O2 225.
Intermediate 74: f2-(1-(4-f(4'-Cvano-biphenyl-4-carbonyl)-aminol-butyl)-piperidin-4- yl)-5,6,7,8-tetrahvdro-naphthalen-1-yloxy1-acetic acid fetf-butyl ester
Figure imgf000047_0001
The same method was employed as in the preparation of the example 10 but starting from intermediate 22 and bromo tert-butyl acetate and gave the title compound as white crystals in a 51% yield; m.p. 105°C.
Examples Example 1 : 4'-Trifluoromethyl-biphenyl-4-carboxylic acid (4-f4-(1-carbamoylmethoxy- 5,6.7,8-tetrahvdro-naphthalen-2-yl)-piperidin-1-yll-butyl>-amide
Figure imgf000048_0001
A solution of intermediate 12 (0.55 g, 1 mmol) and Cs2CO3 (0.7 g, 2 eq.) in methyl ethyl ketone (30 mL) was stirred at 100°C for 10 minutes. Then bromo acetamide (0.2 g, 1.5 eq.) was added and the mixture was stirred at reflux for 3 hours. The mixture was evaporated and the residue was washed with water and recrystallised from EtOH to give the title compound (0.35 g, 0.57 mmol) as white crystals in a 58% yield; m.p. 267°C; 1H NMR (CDCI3, 300 MHz) δ 8.5 (s, 1H), 7.9 (m, 4H), 7.6 (m, 4H), 7.5 (s, 1H), 7.4 (s, 1 H), 6.9 (d, 1 H), 6.7 (d, 1H), 4.0 (s, 2H) 2,9 (m, 2H), 2.5-2.7 (m, 6H), 2.3 (m, 2H), 1.9 (m, 2H), 1.4-1.6 (m, 13H).
Example 2: 4'-Trifluoromethyl-biphenyl-4-carboxylic acid (4-f4-(1-cyanomethoxy- 5,6.7.8-tetrahvdro-naphthalen-2-yl)-piperidin-1-yn-butylV-amide
Figure imgf000048_0002
The same method was employed as in the preparation of example 1 but starting from chloroacetonitrile and gave the title compound as white crystals in a 36% yield after recrystallisation in CH3CN; m.p. 167°C; LC/Tof : ES+ 590.3005 1.9 ppm.
Example 3: 4'-Trifluoromethyl-biphenyl-4-carboxylic acid [4-(4-f1-f2-(2-methoxy- ethoxy)-ethoxyl-5,6,7,8-tetrahvdro-naphthalen-2-yl>-piperidin-1-yll-butyl}-amide
Figure imgf000048_0003
The same method was employed as in the preparation of example 1 but starting from 2-(2-methoxy-ethoxy)-ethanol and gave the title compound as white crystals after recrystallisation in CH3CN; m.p. 147°C; LC/Tof : ES+ 653.3511 8.5 ppm
Example 4: 4'-Trifluoromethyl-biphenyl-4-carboxylic acid f4-(4-(1-[2-(2-hydroxy- ethoxy)-ethoxy1-5,6,7,8-tetrahvdro-naphthalen-2-yl)-piperidin-1-yll-butyl)-amide
Figure imgf000049_0001
The same method was employed as in the preparation of example 1 but starting from 2-(2-hydroxy-ethoxy)-ethanol and gave the title compound as white crystals in a 57% yield after recrystallisation in CH3CN. m.p.163°C; LC/Tof : ES+ 639.3401 1.2 ppm.
Example 5: 4'-Trifluoromethyl-biphenyl-4-carboxylic acid (4-r4-(1-carbamoxylmethyl- 1H-indol-3-yl)-piperidin-1-yll-butyl)-amide
Figure imgf000049_0002
To a solution of intermediate 20 (0.52 g, 1 mmol) in dry TΗF (20 mL) was added NaΗ 60% (0.060 g, excess) and the mixture was stirred at rt for 10 min and at 60°C for 10 min. To this solution was added 2-bromoacetamide (excess). After 2 hours at 60°C, the mixture was evaporated and the residue was taken up in water to give a beige solid. After chromatography the title compound (0.18 g, 0.3 mmol) was obtained as white crystals in a 31% yield; m.p. 265-266°C; LC/Tof: ES+ 577.2830 6.8ppm.
Example 6: 4'-Cyano-biphenyl-4-carboxylic acid (4-[4-(1-allyl-5-methoxy-1Η-indol-3- yl)-piperidin-1-yll-butyl}-amide
Figure imgf000050_0001
The same method was employed as in the preparation of example 5 but starting from intermediate 17 and allyl bromide and gave the title compound as beige crystals in a 24% yield after recrystallisation in CH3CN; m.p. 153°C; LC/MS: M+H C35H39N4O2 547.
Example 7: 4'-Cyano-biphenyl-4-carboxylic acid (4-(4-f5-methoxy-1-(2-methyl-allyl)- 1 H-indol-3-yll-piperidin-1 -yl)-butyl)-amide;
Figure imgf000050_0002
The same method was employed as in the preparation of example 5 but starting from intermediate 17 and 3-chloro-2-methylpropene and gave the title compound as beige crystals in a 27% yield after recrystallisation in CH3CN; m.p.140°C; LC/MS : M+H C36H41N4O2 561; 1H NMR (CDCI3, 300 MHz) δ 7.89 (d, 2H), 7.70 (d, 4H), 7.61 (d, 4H), 7.14 (d, 1 H), 7.01 (s, 1H), 6.84 (d, 1H), 6.71 (s, 1H), 4.83 (s, 2H) 4.63 (s, 2H), 4.45 (s, 2H), 3.84 (s, 3H), 3.51 (m, 2H), 3.10 (m, 2H), 2.78 (m, 1H), 2.49 (m, 2H), 2.16 (m, 2H), 2.04 (m, 2H), 1.73 ( , 4H),1.60 (s, 3H).
Example 8: f2-(H4-f(4'-Trifluoromethyl-biphenyl-4-carbonyl)-aminol-butyl)-piperidin- 4-yl)-5,6,7,8-tetrahvdro-naphthalen-1-yloxy1-acetic acid ethyl ester
Figure imgf000050_0003
A solution of intermediate 12 (1.0 g, 1.8 mmol) and Cs CO3 (1.8 g, 3 eq.) in methyl ethyl ketone was stirred at rt. Bromo acetic acid ethyl ester (0.6 mL, 3 eq.) was added and the mixture stirred at 110°C overnight. The mixture was evaporated and the residue was washed with water and extracted with DCM. The organic layer was dried over Na SO4 filtered, evaporated and purified by flash chromatography on silica gel. Recrystallisation from iPr2O gave the title compound (0.42 g, 0.66 mmol) as white crystals in a 37% yield; m.p. 149-150°C; LC/Tof : ES+ 637.3254 0.1 mDa.
Example 9: [2-(1-(4-f(4'-Trifluoromethyl-biphenyl-4-carbonyl)-aminol-butyl)-piperidin- 4-yl)-5,6,7,8-tetrahydro-naphthalen-1-yloxy1-acetic acid hydrochloride
Figure imgf000051_0001
To a solution of example 8 (0.3 g, 0.47 mmol) in EtOH was added a 1 N NaOH solution (0.5 mL, 1.1 eq) and the mixture was stirred at reflux overnight. The resulting mixture was acidified with a 1N HCI solution (2.2 eq) and evaporated. Crystallisation from H2O/DCM/iPr2O (50/2/48) gave the title compound as white crystals (0.18 g, 0.3 mmol) in a 60% yield; m.p. 100°C (become gummy solid); LC/Tof : ES+ 609.2920 3.3ppm.
Example 10: 4'-Cvano-biphenyl-4-carboxylic acid {4-r4-(1-carbamoylmethoxy-5, 6,7,8- tetrahydro-naphthalen-2-yl)-piperidin-1-yll-butyl)-amide
Figure imgf000051_0002
A solution of intermediate 22 (0.5 g, 1 mmol) and NaH 60% (0.08 g, 1 eq.) in DMF (10 mL) was stirred at rt for 5 minutes. Bromo acetamide (0.163 g, 1.2 eq.) was added and the mixture was stirred at rt for 2 hours. Water was added and the precipitate was filtered and recrystallised from acetonitrile to give the title compound (0.3 g, 0.53 mmol) as solid in a 53% yield; m.p. 240°C; LC/Tof: ES+ 565.3104 13.2 ppm.
Example 11 : 4'-Trifluoromethyl-biphenyl-4-carboxylic acid (4-f4-(4- carbamoylmethoxy-2,5-dimethyl-phenyl)-piperidin-1-yll-butyl)-amide
Figure imgf000052_0001
The same method was employed as in the preparation of example 1 but starting from intermediate 31 and gave the title compound as white crystals (0.17 g, 0.28 mmol) after crystallisation from methyl isopropyl ketone; m.p. 240°C; 1H NMR (CDCI3, 300 MHz) δ 7.52 (d, 2H), 7.24 (s, 4H), 7.22(d, 2H), 6.83 (s, 1 H), 6.52 (s, 1H), 6.12 (s, 2H), 5.39 (s, 1 H) 4.02 (s, 2H), 3.12 (m, 2H), 2.78 (m, 2H), 2.24 (m, 1H), 2.16 (m, 2H), 1.84 (s, 3H), 1.79 (m, 1H), 1.73 (s, 3H), 1.33 (m, 8H).
Example 12: Methanesulfonic acid 2,5-dimethyl-4-(1-{4-f(4'-trifluoromethyl-biphenyl- 4-carbonyl)-aminol-butyl}-piperidin-4-yl)-phenyl ester
Figure imgf000052_0002
The same method was employed as in the preparation of example 1 but starting from intermediate 31 (0.520 g, 1mmol) and gave the title compound as white crystals (0.4 g, 0.66 mmol) after crystallisation from acetonitrile in a 66% yield; m.p. 226°C; LC Tof : ES+ 603.2518 2.2 ppm.
Example 13: 4'-Chloro-biphenyl-4-carboxylic acid (4-r4-(1-carbamoylmethoxy- 5,6,7,8-tetrahydro-naphthalen-2-yl)-piperidin-1-vn-butyl)-amide
Figure imgf000052_0003
The same method was employed as in the preparation of example 10 but starting from the intermediate 33 (1.2 g, 2.0 mmol) and gave the title compound as a beige solid (0.46 g, 0.8 mmol) in a 40% yield after recrystallisation from CH3CN/MeOH 1/1; m.p. 262°C; LC/Tof : ES+ Calculated,574.2836; Found.574.2853 2.9ppm. Example 14: 2',4'-Dichloro-biphenyl-4-carboxylic acid H- -d-carbamoylmethoxy- 5,6.7.8-tetrahvdro-naphtalen-2-yl)-piperidin-1-vH-butyl)-amide
Figure imgf000053_0001
The same method was employed as in the preparation of example 10 but starting from intermediate 35 (1.2 g, 1.9 mmol) and gave the title compound as a beige solid (0.33 g, 0.54 mmol) in a 28.7% yield; m.p. 235°C; LC/Tof : ES+ Calculated, 608,2447; Found,608.2460 2.1 ppm.
Example 15: 4'-Cvano-biphenyl-4-carboxylic acid (4-r4-(1-methylcarbamoylmethoxy- 5.6,7.8-tetrahvdro-naphthalen-2-yl)-piperidin-1-vn-butyll-amide
Figure imgf000053_0002
A solution of the intermediate 22 (1.0 g, 1.97 mmol) in DMF was treated with NaH in 60% oil dispersion (0.160 g, 2.0 eq.) and the reaction mixture was stirred at rt for 10 min. The available 2-bromo-N-methyl-acetamide (0.33 g, 1.1 eq.) was added and the mixture was stirred at rt for 24 hours. After evaporation, water was added and the resulting precipitate was filtered off and recrystallised from lpr2O to give the title compound as a grey solid (0.45 mg, 0.78 mmol) in a 39.6% yield; m.p. 170°C; LC/MS: M+H C36H43N4O3 579.
Example 16: 2-(4-Chloro-phenyl)-4-methyl-thiazole-5-carboxylic acid (4-f4-(1- carbamoylmethoxy-5,6,7,8-tetrahvdro-naphthalen-2-yl)-piperidin-1-vπ-butyl)-amide
Figure imgf000053_0003
The same method was employed as in the preparation of intermediate 11 but starting from intermediate 41 and the available 2-(4-chloro-phenyl)-4-methyl-thiazole-5- carboxylic acid and gave the title compound as a pale yellow solid in a 60% yield after recrystallisation from CH3CN; m.p. 222°C; LC/MS: M+H C32H40CIN4O3S 595.
Example 17: 2-(4-Cvano-phenyl)-4-methyl-thiazole-5-carboxylic acid (4-f4-(1- carbamoylmethoχy-5,6,7,8-tetrahydro-naphthalen-2-yl)-piperidin-1-vπ-butyl>-amide
Figure imgf000054_0001
The same method was employed as in the preparation of intermediate 11 but starting from intermediate 41 and intermediate 44 and gave the title compound as a pale yellow solid in a 24% yield after recrystallisation from lprO2; m.p. 200-202°C; LC/Tof : ES+ Calculated, 586.2852 ; Found, 586.2826 -4.5ppm.
Example 18: 2-(4-Cvano-phenyl)-4-methyl-oxazole-5-carboxylic acid (4-f4-(1- carbamoylmethoxy-5,6,7,8-tetrahvdro-naphthalen-2-yl)-piperidin-1-yll-butyl>- amide
Figure imgf000054_0002
The same method was employed as in the preparation of intermediate 11 but starting from intermediate 41 and intermediate 45 and gave after purification by flash chromatography (eluent : DCM/MeOH 90/10 and then 85/15) and trituration from lprO2, the title compound as a white solid in a 8% yield; m.p. 203°C; LC/Tof : ES+ Calculated, 570.3080 ; Found, 570.3074 -1.1 ppm
Example 19: Sulfamic acid 2-(1-(4-[(4'-cyano-biphenyl-4-carbonyl)-aminol-butyl)- piperidin-4-yl)-5,6,7,8-tetrahydro-naphthalen-1 -yl ester
Figure imgf000055_0001
To a solution of chlorosulphonylisocyanate (4.5 mL, 50 mmol) in CH3CN (10 mL) cooled with an ice-bath was added dropwise a formic acid solution (1.7 mL, 46 mmol) in dry CH3CN (5 mL). The mixture was stirred at rt for 3 hours. Evaporation of the solvent gave a liquid which used directly without purification. To a solution of intermediate 22 (0.51 g, 1 mmol) in dry DMF (10 mL ) was added NaH 60% in oil dispersion (0.050 g, 1.25 eq.) and stirred at rt for 30 min. Sulfamoyl chloride (0.4 mL) was added and the mixture was stirred at rt for 30 min. The mixture was poured into water and the resulting precipitate was filtrated, washed with water and lprO2 to give a white solid which was purified by flash chromatography using DCM/MeOH 80/20 then DCM/IPrNH290/10 as eluents The title compound was obtained as white foam (0.095 g, 0.16 mmol) in a 16.2% yield; m.p. 150-170°C; LC-Tof : ES+ Calculated, 587.2692 ; Found, 587.2607 -14.6ppm
Example 20: 4'-Methanesulfonylamino-biphenyl-4-carboxylic acid (4-14-d- carbamoylmethoxy-5,6.7.8-tetrahvdro-naphthalen-2-yl)-piperidin-1-vn-butyl)-amide
Figure imgf000055_0002
The same method was employed as in the preparation of intermediate 11 but starting from intermediate 41 and intermediate 48 and gave the title compound as a white solid in a 20.6% yield after recrystallisation from CH3CN; m.p. 250°C; LC/MS: M+H C35H45N4O5S 633.
Example 21: 4'-Chloro-2-hvdroxy-biphenyl-4-carboxylic acid 4-f4-(1- carbamoylmethoxy-5,6,7,8-tetrahvdro-naphthalen-2-yl)-piperidin-1-yll-butyl)-amide
Figure imgf000056_0001
The same method was employed as in the preparation of intermediate 11 but starting from intermediate 41 and intermediate 51 and gave the title compound as a white solid in a 31% yield after recrystallisation from lprO2; m.p. 212°C; LC-Tof : ES+ Calculated, 590.3786 ; Found, 590.2706 -13.5ppm.
Example 22: 4-(5-Acetyl-thiophen-2-yl)-Λ -(4-r4-(1-carbamoylmethoxy-5,6,7,8- tetrahydro-naphthalen-2-yl)-piperidin-1-yll-butyl)-benzamide
Figure imgf000056_0002
The same method was employed as in the preparation of intermediate 47 but starting from intermediate 52 and the available 2-acetyl-5-bromothiophene and gave the title compound as a beige solid in a 13% yield after crystallisation from lprO2; m.p. 247°C; LC/MS: M+H C34H42N3O4S 588.
Example 23: 4'-Cvano-biphenyl-4-carboxylic acid (4-14-11 -(2-methyl-allyl)-1 /-/-indazol- 3-yll-piperidin-1-yl)-butyl)-amide
Figure imgf000056_0003
The same method was employed as in the preparation of intermediate 11 but starting from intermediate 59 and the available 4'-cyano-biphenyl-4-carboxylic acid and gave the title compound as a white crystals in a 34% yield after recrystallisation from CH3CN; m.p. 165°C; LC/MS: M+H C34H38N5O 532. Example 24: N-{4-\4-(1 -Carbamoylmethoxy-5.6.7,8-tetrahvdro-naphthalen-2-yl)- piperidin-1-yll-butyl}-4-(5-chloro-thiophen-2-yl)-benzamide
Figure imgf000057_0001
The same method was employed as in the preparation of intermediate 47 but starting from intermediate 52 and the available 2-chloro-5-bromothiophene and gave the title compound as a beige solid in a 22% yield after crystallisation from lprO2.; m.p. 260°C; LC/MS: M+H C32H39CIN3O3S 580.
Example 25: 4'-Cvano-biphenyl-4-carboxylic acid (4- 4-f1-(1-carbamoyl-ethoxy)- 5,6,7,8-tetrahydro-naphthalen-2-yll-piperidin-1-yl}-butyl)-amide
Figure imgf000057_0002
The same method was employed as in the preparation of example 10 but starting from intermediate 22 and the available 2-bromopropanamide and gave the title compound as white crystals in a 52.5% yield after crystallisation from CH3CN; m.p. 188°C; LC-Tof : ES+ Calculated, 579.3326, Found, 579.3335 1.6ppm.
Example 26: Λ/-(4-f4-(1 -Carbamoylmethoxy-5,6,7,8-tetrahvdro-naphthalen-2-yl)- piperidin-1-yll-butyl}-6-(4-chloro-phenyl)-nicotinamide
Figure imgf000057_0003
The same method was employed as in the preparation of intermediate 11 but starting from intermediate 41 and intermediate 61 and gave the title compound as a white solid in 29% yield after recrystallisation from CH3CN; m.p > 260°C; LC/MS: M+H C33H40CIN4O3 575. Example 27: 5-(4-Chloro-phenyl)-pyridine-2-carboxylic acid (4-f4-(1- carbamoylmethoxy-5,6,7,8-tetrahydro-naphthalen-2-yl)-piperidin-1-yll-butyl>-amide
Figure imgf000058_0001
The same method was employed as in the preparation of intermediate 11 but starting from intermediate 41 and intermediate 63 and gave the title compound as a white solid in a 19% yield after recrystallisation from CH3CN; m.p. 189-191°C; LC-Tof : ES+ Calculated, 575.2789 ; Found, 575.2811 3.9ppm.
Example 28: 4'-Cvano-biphenyl-4-carboxylic acid (4-(4-f1-(1-carbamoyl-1-methyl- ethoxy)-5,6,7,8-tetrahvdro-naphthalen-2-yll-piperidin-1-ylVbutyl)-amide
Figure imgf000058_0002
The same method was employed as in the preparation of example 10 but starting from intermediate 22 and intermediate 64 and gave the title compound as white crystals in a 30% yield after crystallisation from CH3CN; m.p. 214-215°C; LC-Tof : ES+ Calculated, 593.3492 ; Found, 593.3433 -9.9ppm.
Example 29: 4'-Chloro-biphenyl-4-carboxylic acid (4-(4-f1-(1-carbamoyl-1-methyl- ethoxy)-5,6,7,8-tetrahvdro-naphthalen-2-yll-piperidin-1-ylVbutyl)-amide
Figure imgf000058_0003
The same method was employed as in the preparation of example 10 but starting from intermediate 33 and intermediate 64 and gave the title compound as white crystals in a 18.6% yield after crystallisation from CH3CN; m.p. 163-164°C; LC-Tof ES+ Calculated, 602.3149 ; Found, 602.3135 -2.3ppm Example 30: 4'-Chloro-biphenyl-4-carboxylic acid (4-{4-ri-(1-carbamoyl-ethoxy)- 5.6.7.8-tetrahvdro-naphthalen-2-yl1-piperidin-1-yl)-butyl)-amide
Figure imgf000059_0001
The same method was employed as in the preparation of example 10 but starting from intermediate 33 and the available 2-bromopropanamide and gave the title compound as white crystals in a 20% yield after crystallisation from CH3CN; m.p. 179-180°C; LC-Tof : ES+ calculated, 588.2993 ; Found, 588.3091 16.6ppm.
Example 31 : Λ/-(4-f4-(1-Carbamoylmethoxy-5,6,7,8-tetrahvdro-naphthalen-2-yl)- piperidin-1-yll-butyl)-4-(5-cvano-pyridin-2-yl)-benzamide
Figure imgf000059_0002
The same method was employed as in the preparation of intermediate 11 but starting from intermediate 41 and intermediate 66 and gave the title compound as a white solid in a 19% yield after recrystallisation from CH3CN; m.p. 226-228°C; LC/MS: M+H
Figure imgf000059_0003
Example 32: Λ/-{4-r4-(1-Carbamoylmethoxy-5,6,7,8-tetrahvdro-naphthalen-2-yl)- piperidin-1-yll-butyl}-4-(5-chloro-pyridin-2-yl)-benzamide
Figure imgf000059_0004
The same method was employed as in the preparation of intermediate 11 but starting from intermediate 41 and intermediate 68 and gave the title compound as a white solid in a 23% yield after recristallisation from CH3CN; m.p > 260°C; LC-Tof : ES+ Calculated, 575.2798 ; Found, 575.2789 1.6ppm. Example 33: Λ/-(4 4-f1-(1 -Carbamoyl-1 -methyl-ethoχy)-5.6.7.8-tetrahvdro- naphthalen-2-vπ-piperidin-1-yl>-butyl)-4-(5-cvano-pyridin-2-yl)-benzamide
Figure imgf000060_0001
The same method was employed as in the preparation of intermediate 11 but starting from intermediate 70 and intermediate 66 and gave the title compound as a white solid in a 11% yield after recrystallisation from CH3CN; m.p. 181°C (gummy solid); LC-Tof : ES+ Calculated, 594.3444 ; Found 594.3416 -4.7ppm.
Example 34: 5-(4-Cvano-phenyl)-pyridine-2-carboxylic acid (4-f4-(1- carbamoylmethoxy-5,6,7,8-tetrahvdro-naphthalen-2-yl)-piperidin-1-yll-butyl)-amide
Figure imgf000060_0002
The same method was employed as in the preparation of intermediate 11 but starting from intermediate 41 and intermediate 71 and gave the title compound as a white solid in 27% yield after crystallisation from lprO2.; m.p. 186°C; LC-Tof : ES+ Calculated, 566.3131 Found, 566.3118 -2.3ppm.
Example 35: /V- 4-r4-(1-Carbamoylmethoxy-5,6,7,8-tetrahvdro-naphthalen-2-yl)- piperidin-1-yH-butylV6-(4-cvano-phenyl)-nicotinamide
Figure imgf000060_0003
The same method was employed as in the preparation of intermediate 11 but starting from intermediate 41 and intermediate 73 and gave the title compound as a white solid in 75% yield after crystallisation from lprO2.; m.p.> 259°C (decomposition); LC- Tof : ES+ Calculated, 566.3131 ; Found, 566.3113 -3.2ppm Example 36: f2-(H4-r(4'-Chloro-biphenyl-4-carbonyl)-aminol-butyl)-piperidin-4-yl)- 5.6,7,8-tetrahydro-naphthalen-1 -yloxyl-acetic acid
Figure imgf000061_0001
To a solution of example 13 (0.029 g, 0.05 mmol) in EtOH (2 mL) and MeOH (1 mL) was added a 1 N NaOH solution (0.06 mL, 1.2 eq.) and the reaction was stirred at reflux overnight. After evaporation, the white precipitate was poured into water, filtered and dried to give the title compound (sodium salt) as a white solid (0.01 g, 0.017 mmol) in a 33% yield; m.p. 260°C; LC/MS : M+H Ca^CIN^ 575.
Example 37: f2-(1-(4-r(4'-Cyano-biphenyl-4-carbonyl)-amino1-butyl)-piperidin-4-yl)- 5,6, 7, 8-tetrahydro-naphthalen-1 -yloxyl-acetic acid
Figure imgf000061_0002
To a solution of the intermediate 74 (3.0 g, 4.8 mmol) in DCM (25 mL) was added trifluoroacetic acid (25 mL) and the reaction was stirred at rt for 18 hours. After concentration, the oil was triturated in water and extracted with DCM. The organic phase was washed with a saturated NaHCO3 solution dried over Na2SO and evaporated. The title compound was obtained as a gummy oil (1.05 g, 1.8 mmol) in a 38.6% yield which was directly used in the next step without purification; LC/MS :
Figure imgf000061_0003
Example 38: (S)-1-(2-f2-(1-(4-f(4'-Cvano-biphenyl-4-carbonyl)-aminol-butyll- piperidin-4-yl)-5,6,7,8-tetrahvdro-naphthalen-1-yloxyl-acetyl>-pyrrolidine-2-carboxylic acid amide
Figure imgf000062_0001
The same method was employed as in the preparation of intermediate 11 but starting from Example 37 and L-prolinamide and gave the title compound as a gummy solid in a 51.3% yield after purification by flash chromatography using DCM/lprNH2 95/5 as eluent; m.p. 100-1 10°C (gummy); LC-Tof : ES+ Calculated, 662.3706 ; Found, 662.3689 -2.6ppm.
Biological Assays
The Examples were tested in vivo and/or in vitro according to the following assay methods.
In Vitro Assay
HepG2 cells, stably transfected with a construct comprising 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. The ED5oθf each compounds was determined compared to the ED50 of an internal standard.
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 administered once a day for 3 days, from 20 to 0.2mg/kg. Plasma lipid levels including total cholesterol, VLDIJLDL cholesterol, VLDIJLDL triglycerides and HDL- cholesterol were determined after ultracentrifugation (density 1.063g/ml to separate VLDL/LDL fraction and HDL fraction) using the Biomerieux enzymatic kit. Reductions in VLDIJLDL cholesterol and TG plasmatic levels were calculated taking solvent treated animals as control and ED5o of each compound was determined.
The compounds of the invention are potent and specific inducers of LDL-r expression.
Using the above in vitro assay all Examples of the invention induced luciferase activity having EC50 values in the range 1nM to 800nM.
4'-Chloro-biphenyl-4-carboxylic acid {4-[4-(1-carbamoylmethoxy-5,6,7,8-tetrahydro- naphthalen-2-yl)-piperidin-1-yl]-butyl}-amide (Example 13) had an EC50 value of 7 nM.
4'-Cyano-biphenyl-4-carboxylic acid (4-{4-[1-(1-carbamoyl-ethoxy)-5,6,7,8- tetrahydro-naphthalen-2-yl]-piperidin-1-yl}-butyl)-amide (Example 25) had an EC50 value of 5 nM.

Claims

Claims
1 A compound of formula (I), physiologically acceptable prodrugs, salts or solvates thereof;
Figure imgf000064_0001
(0 wherein An is:
(i) phenyl, naphthyl or phenyl fused by a C3.8cycloalkyl; or (ii) heterocyclyl selected from the list consisting of: monocyclic radicals and fused polycyclic radicals, wherein said radicals contain a total of from 5-14 ring atoms, wherein said radicals contain a total of from 1-4 ring heteroatoms independently selected from oxygen, nitrogen and sulfur, and wherein individual rings of said radicals may be independently saturated, partially unsaturated or aromatic, provided that at least one ring is aromatic; where An is independently substituted by at least one R1 group and independently substituted by 0-3 R3 groups; Ar2 is a phenyl group, a 5-6 membered heteroaromatic group or a bicyclic heteroaromatic group, where each group is optionally substituted by one or two substituents independently selected from the list:
Figure imgf000064_0002
halogen, hydroxy, C^alkoxy, C1-6acyl, d-eacyloxy, amino, C^alkylamino, di-C1-4alkylamino, -(CH2)nNRxRy, -O(CH2)nC(O)NRxRy, -O(CH2)nCN, -O(CH2)nO(CH2)mOR2, C2.5alkenyl, -O(CH2)nCO2R2, - OSO2(CH2)pCH3, and -OSO2NRxRy;
Ar3 is:
(i) phenyl, naphthyl or phenyl fused by a C3.8cycloalkyl; or (ii) heterocyclyl selected from the group consisting of monocyclic radicals and fused polycyclic radicals, wherein said radicals contain a total of from 5-14 ring atoms, wherein said radicals contain a total of from 1-4 ring heteroatoms independently selected from oxygen, nitrogen and sulfur, and wherein individual rings of said radicals may be independently saturated, partially unsaturated or aromatic, provided that at least one ring is aromatic; wherein Ar3 is optionally substituted by 1-4 groups independently selected from the group consisting of: hydroxy, Chalky!, C^ 4alkoxy, C2-4alkenyl, C2-4alkenyloxy, C^perfluoroalkoxy,
C1-4alkylsulfonylamino (such as -NHSO2CH3, - NHSO2CH(CH3)2), fluoroC^alkylsulfonylamino (such as - HNSO2CH2CF3), CMalkylcarbonyla ino, TIUOΓOCL 4alkylcarbonylamino, halogen (such as chlorine), nitrile, nitro, C^perfluoroalkyl, C^alkylcarbonyl, fluoroC1-4alkylcarbonyl,
C1- alkoxycarbonyl, aminocarbonyl, C^alkylaminocarbonyl, di- Ci^alkylaminocarbonyl, C1-4alkylsulfonyl, C^ alkylaminosulfonyl, di-C^alkylaminosulfonyl, C1-4alkylsulfonyl and C^alkylsulfoxy; E is -C1-6alkylene-;
X is -CONR2-or -NR2CO- (where the left hand side of the linkage is attached to E); wherein
R1 is selected from the group consisting of: -O(CRaRb)nC(O)NRxRy, -O(CH2)nCN, -O(CH2)nO(CH2)mOR2, -O(CH2)nCO2R2, -OSO2NRxRy, -
OSO2(CH2)pCH3, -(CRaRb)nC(O)NRxRy, -(CH2)nCN, - (CH2)nO(CH2)mOR2, -(CH2)nCO2R2, -(CH2)nC(O)R2, -SO2NRxRy, - SO2(CH2)pCH3, -CH=CHC(O)NRxRy, -CH=CHCN, -CH=CHCO2R2, - CO2R2, -C(O)R2, -C(O)NRxRy and C2.5alkenyl; R2 is C1-4alkyl or hydrogen;
R3 is selected from halogen, -O-(C1_4alkylene)-R or -(Cι.4alkylene)-R4, 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 oxygen atoms; R4 is:
(i) hydrogen;
(ii) phenyl, phenyl fused by a C3.8cycloalkyl, naphthyl or a 5- or 6- membered heteroaromatic group, each of which may be optionally substituted by one or two groups independently selected from halogen, C^ alkyl, hydroxy, C^alkoxy, amino,
C1.4alkylamino and di-C1-4alkylamino; (iii) C3.8cycloalkyl or a monocyclic heterocyclyl radical containing a total of 3-7 ring atoms, wherein said radical contains a total of from 1- 4 ring heteroatoms independently selected from oxygen, nitrogen and sulfur, wherein said radical may be saturated, partially unsaturated or aromatic, and where the C3.8cycloalkyl or a monocyclic heterocyclyl may be substituted by one or two groups independently selected from halogen, C1-4alkyl, hydroxy, C1-4alkoxy, amino, C^ alkylamino and di-C^alkylamino; or (iv) amino, C1-4 alkylamino or di-C^alkylamino;
Ra and Rb are independently hydrogen, C1- alkyl or cycloalkyl, where Ra and
Rb are not both cycloalkyl; Rx and Ry are independently hydrogen, C1-4alkyl, hydroxy or C1-4alkoxy, where Rx and Ry are not both hydroxy or both
Figure imgf000066_0001
or Rx and Ry together with the nitrogen to which they are attached form a 5- membered ring which ring is optionally substituted by - O(CRaR )nC(O)NRxRy, -O(CH2)nCN, -O(CH2)nO(CH2)mOR2, -O(CH2)nCO2R2, -OSO2NRxRy, -OSO2(CH2)pCH3, .(CRaRb)nC(O)NRxRy, -(CH2)nCN, -(CH2)nO(CH2)mOR2, -(CH2)nCO2R2, -(CH2)nC(O)R2, -SO2NRxRy, -SO2(CH2)pCH3, -CH=CHC(O)NRxRy, -CH=CHCN,
-CH=CHCO2R2, -CO2R2, -C(O)R2, -C(O)NRxRy or C2.5alkenyl; n and m are independently 1-4; and p is 0-4.
A compound according to claim 1 wherein An is phenyl, naphthyl, 1 ,2,3,4- tetrahydronaphthyl, indolyl, benzofuranyl, benzothiophenyl or indazolyl.
A compound according to any preceding claim wherein E is n-butylene.
A compound according to any preceding claim wherein X is -NR2CO-.
A compound according to any preceding claim wherein Ar2 is phenyl or a 5-6- membered heteroaromatic group. A compound according to claim 5 wherein Ar2 is optionally substituted by one or two substituents independently selected from the list: C1-4alkyl, halogen, hydroxy and C1-4alkoxy.
A compound according to any preceding claim wherein Ar3 is phenyl, pyridyl or thienyl.
A compound according to claim 7 wherein Ar3 is substituted by halogen, C1-4perfluoroalkyl, nitrile, C1- acyl,
Figure imgf000067_0001
A compound according to any preceding claim wherein An is substituted by one R1, which R1 is selected from the group consisting of: -O(CRaRb)nC(O)NRxRy, -O(CH2)nCN, -O(CH2)nO(CH2)mOR2, -O(CH2)nCO2R2, -OSO2NRxRy, -OSO2(CH2)pCH3, -(CRaRb)nC(O)NRxRy and C2.5alkenyl; wherein R2 is C1-4alkyl or hydrogen; Ra and Rb are independently hydrogen or
C1-4alkyl or cycloalkyl; Rx and Ry are independently hydrogen or C1-4alkyl; or Rx and Ry together with the nitrogen to which they are attached form a 5-membered ring which ring is optionally substituted by -O(CRaRb)nC(O)NRxRy, -O(CH2)nCN, -O(CH2)nO(CH2)mOR2, -O(CH2)nCO2R2, -OSO2NRxRy, -OSO2(CH2)pCH3, -(CRaRb)nC(O)NRxRy and C2.5alkenyl; and n and m are independently 1-3; p is 0-2.
A compound according to any preceding claim wherein An is not substituted by R3.
A compound according to any preceding claim wherein Ar2 is unsubstituted.
A compound according to claim 1 wherein:
An is phenyl, naphthyl, 1 ,2,3,4-tetrahydronaphthyl, indolyl, benzofuranyl, benzthiophenyl or indazolyl; where An is independently substituted by at least one R1 group and independently substituted by 0-3 R3 groups; Ar2 is phenyl or a 5-6-membered heteroaromatic group, either of which is optionally substituted by one or two substituents independently selected from the list: C1-4alkyl, halogen, hydroxy and C1-4alkoxy; Ar3 is phenyl, pyridyl or thienyl, each of which may be substituted by 1-3 groups independently selected from the group consisting of: halogen (e.g. chloro), C^perfluoroalkyl (e.g. trifluoromethyl), nitrite, diacyl
(e.g. acetyl), C^alkylsulfonyl (e.g. methylsulfonyl) or
C1-4alkylsulfonylamino;
E is n-butylene; and X is -NR2CO-; wherein R1 is selected from the group consisting of: -O(CRaR )nC(O)NRxRy,
-O(CH2)nCN, -O(CH2)nO(CH2)mOR2, -O(CH2)nCO2R2, -OSO2NRxRy,
-OSO2(CH2)pCH3, -(CRaRb)nC(O)NRxRy and C2.5alkenyl; wherein
R2 is C1-4alkyl or hydrogen;
Ra and Rb are independently hydrogen, C1-4alkyl or cycloalkyl; Rx and Ry are independently hydrogen, or C1- alkyl; or Rx and Ry together with the nitrogen to which they are attached form a 5-membered ring which ring is optionally substituted by -O(CRaRb)nC(O)NRxRy, -O(CH2)nCN,
-O(CH2)nO(CH2)mOR2, -O(CH2)nCO2R2, -OSO2NRxRy,
-OSO2(CH2)pCH3, -(CRaRb)nC(O)NRxRy, -C(O)NRxRy and C2.5alkenyl; n and m are independently 1-3; p is 0-2; and R3 is C1-4alkyl or C1-4alkoxy.
A compound according to claim 1 wherein the compound is selected from the list:
4'-Cyano-biphenyl-4-carboxylic acid {4-[4-(1 -carbamoylmethoxy-5,6,7,8- tetrahydro-naphthalen-2-yl)-piperidin-1-yl]-butyl}-amide (Example 10);
4'-Chloro-biphenyl-4-carboxylic acid {4-[4-(1-carbamoylmethoxy-5, 6,7,8- tetrahydro-naphthalen-2-yl)-piperidin-1 -yl]-butyl}-amide (Example 13); 2',4'-Dichloro-biphenyl-4-carboxylic acid {4-[4-(1 -carbamoylmethoxy-5, 6, 7,8- tetrahydro-naphtalen-2-yl)-piperidin-1-yl]-butyl}-amide (Example 14); Λ/-{4-[4-(1-Carbamoylmethoxy-5,6,7,8-tetrahydro-naphthalen-2-yl)-piperidin-1- yl]-butyl}-4-(5-chloro-thiophen-2-yl)-benzamide (Example 24); 4'-Cyano-biphenyl-4-carboxylic acid (4-{4-[1-(1-carbamoyl-ethoxy)-5,6,7,8- tetrahydro-naphthalen-2-yl]-piperidin-1 -yl}-butyl)-amide (Example 25); Λ/-{4-[4-(1 -Carbamoylmethoxy-5, 6,7, 8-tetrahydro-naphthalen-2-yl)-piperidin-1- yl]-butyl}-6-(4-chloro-phenyl)-nicotinamide (Example 26); 5-(4-Chloro-phenyl)-pyridine-2-carboxylic acid {4-[4-(1 -carbamoylmethoxy-
5,6,7,8-tetrahydro-naphthalen-2-yl)-piperidin-1-yl]-butyl}-amide
(Example 27); 4'-Cyano-biphenyl-4-carboxylic acid (4-{4-[1-(1-carbamoyl-1-methyl-ethoxy)- 5,6,7,8-tetrahydro-naphthalen-2-yl]-piperidin-1-yl}-butyl)-amide
(Example 28); Λ/-{4-[4-(1-Carbamoylmethoxy-5,6,7,8-tetrahydro-naphthalen-2-yl)-piperidin-1- yl]-butyl}-4-(5-cyano-pyridin-2-yl)-benzamide (Example 31); Λ -{4-[4-(1-Carbamoylmethoxy-5,6,7,8-tetrahydro-naphthalen-2-yl)-piperidin-1- yl]-butyl}-4-(5-chloro-pyridin-2-yl)-benzamide (Example 32); and
Λ/-{4-[4-(1-Carbamoylmethoxy-5,6,7,8-tetrahydro-naphthalen-2-yl)-piperidin-1- yl]-butyl}-6-(4-cyano-phenyl)-nicotinamide (Example 35).
A pharmaceutical composition comprising a compound as defined in any preceding claim and a pharmaceutically acceptable earner or diluent.
The use of a compound defined in any one of claims 1 to 13 in the manufacture of a medicament for use in the treatment of conditions resulting from elevated circulating levels of LDL-cholesterol.
A compound defined in any one of claims 1 to 13 for use as a medicament.
PCT/EP2003/007613 2002-07-12 2003-07-11 Aryl piperidine derivatives as inducers of ldl-receptor expression for the treatment of hypercholesterolemia Ceased WO2004006923A1 (en)

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