Title of Invention	BIPIPERIDINE DERIVATIVES AND PROCESS FOR PREPARING THE SAME
Abstract	The present invention relates a piperidine derivatives of formula (I) as described in the specification have interesting pharmaceutical properties e.g. as CCR5 inhibitors and also to a process sfor preparing the piperidine derivatives.

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BIPIPER1DINYL-DER1VATIVES AND THEIR USE AS CHEMOKINE RECEPT0R5 INHIBITORS "Nevel PipcR1dino DeR1vativee- The present invention relates to pipeR1dine deR1vatives, process for their production, their uses and pharmaceutical compositions containing them. More particularly, the present invention provides a compound of formula I wherein X is a direct bond; -CHr; -CH2-CH2-; -CHRg-; -C(0)-; -0-; -NH- or NRg; R1 is optionally R10 and/or R11-substituted phenyl; optionally R10 and/or R11-substituted heteroaryl; optionally R10 and/or R11-substituted heteroaryl N-oxide; or optionally R10 and/or R11-substituted naphthyl; R2 has one of the significances given for R1 or is optionally R10 and/or R11-substituted fluorenyl; optionally R10-substituted C1-C6 alkyl; optionally R10-substituted C3-C6 alkenyl; optionally R10-substituted C2-C6 cycloalkyl; optionally R10-substituted adamantyl; or optionally R10-substituted C4-C8 cycloalkenyl; R3 has one of the significances given for R1; or is optionally R10 and/or R11-substituted fluorenyl; R10-substltuted C1-C6 alkyl; optionally R10-substituted C2-C6 alkenyl; optionally R10-substituted C3-C6 cycloalkyl; optionally R10-substituted adamantyl; or optionally R10-substituted C4-C8 cycloalkenyl; wherein A is -CH2-, -NH-, -NRg-. -S-, -SO-, SO2- or -0-, n is 0,1 or 2, and the aromatic R1ngs are each, independently optionally R10-substituted; each of R4, independently, has one of the significances of R5; or is CN; OH; OR9; F; CI; Br, or I; each of R5, independently, is H; C1-C6 alkyl; C1-C6 hydroxyalkyl; C2-C6 alkoxyalkyl; C3-C6 halogenoalkyl; phenyl; benzyl; or heteroaryl; each of R6, independently, has one of the significances given for R4; each of R7, independently, has one of the significances given for R5; Rs is H; C3-C6 alkyl; C2-C6 alkenyl; C2-C6 alkynyl; phenyl; benzyl; CN; CHzNHz; CH2NHR9; CH2NR9R9; CH2NHC(O)R9; CH2NR9C(O)R9; CH2NHC(O)NHR9; CH2NR9C(O)NHR9; CH2NR9C(O)NR9R9; CH2NHC(O)OR9; CH2NR9C(O)OR9; CH2NHSO2R9; CH2N(S02R9)2; or CH2NR9SO2R9; each Rg, independently, is Ci-Cs alkyl; C2-C6 cycloalkyl; C2-C6 alkenyl; C2-C6 alkynyl; phenyl; benzyl; heteroaryl; or CF3; R10 represents 1 to 4 substituents independently selected from C1-C6 alkyl; Ct-Ce hydroxyalkyl; C2-C6 alkoxyalkyl; C1-C6 halogenoalkyl; C2-C6 cycloalkyl; C2-C6 alkenyl; C2-C6 cycloalkenyl; C2-C6 alkynyl; phenyl; heteroaryl; heteroaryl N-oxide ; F; CI; Br; I; OH; OR9; CONH2; CONHR9; CONR9R9 ;0C(O)R9; 0C(O)0R9; 0C{0)NHR9; OCCONRgRg; OSO2R9; COOH; COOR9; CF3; CHF2; CH2F; CN; NO2; NH2; NHR9; NR9R9; NHC(O)R9; NR9C(O)R9; NHC(O)NHR9; NHC(O)NH2; NR9C(O)NHR9; NR9C{0)NR9R9; NHC(O)OR9; NR9C(O)OR9; NHSO2R9; N(S02R9)2; NR9SO2R9; SR9; S(O)R9; SO2R9; Si(CH3)3and B(OC{CH3)2)2; R11 represents two adjacent substituents which foon an annulated 4-7 membered nonaromatic R1ng optionally containing up to two heteroatoms selected independently from N, O and S; and Y is a direct bond; -C(O)-; -C(O)CH2-; -S(O)-; -S(O)2)-; -C{S)-; -CHz-; -C(-CH2-CH2-)-; •CH(R4)- or -C(R5)2-, in free form or In salt form. Any alkyl. alkenyi or alkynyl may be linear or branched. Halogeno is F, Ci, Br or I, By heteroaryl Is meant an aromatic R1ng system compR1sing mono-, bi- or tR1cyclic systems which contains up to 4 heteroatoms independently selected from N, O and S, such as for example furyl, thienyl, pyrrolyl, imklazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazotyl, tR1azolyl, tetrazolyl, pyR1dyl, pyR1dazinyl, pyR1midinyl, pyra^nyl, tR1azinyl, tetra:dnyl, indofyl, benzothiophenyl, benzofuranyl, benzimidazolyl, indazotyl, benzotR1azotyl, benzothiazotyl, benzoxazolyl, quinolinyl, isoquinolinyi, phthalazinyi, quinoxalinyl, quinazolinyl, cinnolinyl or naphthyR1dinyl. Prefenred annulated 4-7membered non-aromatic R1ng as represented by R11 is annulated 5 or 6 membered non aromatic R1ng optk>nally containing 1 or 2 oxygen and include e.g. -O-CH2-0- or -O-CH2-CH2-O-, attached to 2 adjacent carbon atoms. The compounds of formula I may exist in free form or in salt form, e.g. addition salts with e.g. organic or inorganic acids, for example, hydrochloR1c acid, acetic acid when R1, R2, and /or R3 compR1ses an optionally substituted amino group or a heterocyclic residue which can form addition salts. When the compounds of formula I have one or more asymmetR1c centers in the molecule, e.g. when a pipeR1dine R1ng is substituted, the present invention is to be understood as embracing the vaR10us optical isomers, as well as racemates, diastereoisomers and mixtures thereof. In the compounds of formula I, the following significances are preferred individually or in any sub-combination: 1. R1 Is optionally R10-substituted phenyl; optionally R10-substituted heteroaryl; or optionally R1rsubstituted phenyl, 2. R2 is optionally Rto-substituted phenyl; optionally R10-substituted heteroaryl; optionally R10-substituted heteroaryl N-oxide; or optionally R10-substituted naphthyl. 3. R3 is optionally R10-substltuted phenyl; optionally R10-substituted heteroaryl; or optionally R10-substituted naphthyl. 4. Each of R4, R5, Re or R7. independently, is H; C3-C6 alkyl; or benzyl. 5. Rs is H; C1-C6 alkyl; or Cz-Cs alkenyl. 6. Rg is C1-C6 alkyl; C3-C6 cydoalkyl; Cg-Cs alkenyl; C2-C6 alkynyl; phenyl; benzyl; heteroaryl; or CF3. 7. R10 represents 1 to 3 substltuents independently selected from C1-C6 alkyl; C1-C6 hydroxyalkyl; C2-C8 alkoxyalkyl; C1-C6 halogenoalkyl; C2-C6 cyctoalkyl; Ca-Ca alkenyl; C3-C6 cydoalkenyl; C2-C6 alkynyl; phenyl; heteroaryl; heteroaryl N-o)dde; F; CI; Br, I; OH; OR9; CONH2; CONHR9; CONR9R9; OC(O)R9; 0C(O)0R9; OC(O)NHR9; OC(O)NR9R9; OSO2R9; COOH; COOR9; CF3; CHF2; CH2F; CN; NO2; NH2; NHR9; NR9R9; NHC(O)R9; NR9C(O)R9; NHC(O)NHR9; NHC{0)NH2; NR9C(O)NHR9; NR9C(O)NR9R9; NHC(O)OR9; NR9C(O)OR9; NHSO2R9; N(S02R9)2; NR9SO2R9; SR9; S(O)R9; SO2R9 and Si(CH3)3. 8. R11 represents --O-CHz-O- attached on 2 adjacent cartoon atoms* 9. X is a direct bond or -CH2 10.Yis-C(O)-. In the preferred compounds of fonnuia I, R10 may represent 1-3 substituents selected from from C1-6alkyl; phenyl; heteroaryl; heteroaryl N-oxide; F; CI; Br, I; OH; OR9; CONHg; CONHR9; CONR9R9; COOH; COOR9; CF3; CHF2; CH2F; NH2; NHR9; NR9R9; NHC(O)R9; NR9C(O)R9; NHC(O)NHR9; NHC(O)NH2; NR9C(O)NHR9; NR9C(O)NR9R9; NHC(O)0R9 and NR9C(O)OR9. R9 is preferably C1-C6 alkyl; C3-C6 cycloalkyl; phenyl; benzyl; or heteroaryl; more preferably C3-C6 alkyl. The present invention also includes a process for the preparation of a compound of fomiula I which process compR1ses a) for the preparation of a compound of formula I wherein X Is a direct bond, -CH2-, -CH2-CH2- or -CHR9- and Y Is -CO-, -C(O)CH2-, -S(O)- or -8(O2)-, amidating a compound of formula II wherein R1 and R3 to Re are as indicated above and X' is a direct bond, *CH2-, -CHj-CHa- or -CHR9- with a compound of formula III Rz-r-A' III wherein R2 is as defined above, Y is -CO-, -C(O)CH2-, -S(O)- or -8(02)- and A' Is a leaving group, e.g. CI or Br, b) for the preparation of a compound of fonnuia I wherein X Is a direct bond and Y is -CH2-, submitting a compound of formula II as defined above wherein X* is a direct bond, to a reductive amination; or c) for ttie preparation of a compound of formula I wherein X Is CH2-, -CHz-CHr or -CHR9-and Y is -CO-, -C(O)CHr, -S(O)- or -8(02)-, reacting a compound of fomiula IV wherein R2 to R8 and Y are as defined above, with a compound of fomiula V R—X"—Hal V wherein R1 Is as defined above and X" is CH2- or -CHR9-; and, where required, converting the resulting compound of fomiula I obtained in free fonR11 into the desired salt form, or vice veR8a. The reaction steps a), b) or c) may be performed in accordance with methods known in the art or as disclosed in the Examples below. When R6 compR1ses a group which should not participate in the reaction, this group may be protected in accordance with methods known in the art. wherein X' and R1 to R8 are as defined above and Hal is CI, Br or I. In above formulae, Boc is a protecting group which means tert.-butyloxycarbonyl* This protecting group may be replaced in above reaction scheme by any amino protecting group, e.g. as disclosed in "Protective Groups in Organic Synthesis" by T. W. Greene, J.Wiley & Sons NY, 2'^ ed., Chapter 7,1991 and references therein, e.g. benzytoxycarbonyl or 9-fluorenylmethoxy carbonyl. wherein R2 to R8 and Y are as defined above and Bn is benzyl. Above reactions may be carR1ed out in accordance with methods known in the art or as disclosed hereafter. Insofar as the production of the starting mateR1als is not particulaR1y descR1bed, the compounds are known or may be prepared analogously to methods known in the art or as descR1bed hereafter. The following Examples are illustrative of the invention, without limitation. Following abbreviations are used: A mixture of (4'-Methyl-[1,4*]bipipeR1dinyl-4-yl)-diphenyl-aR11ine (0.25 g, 0.71 mmol), 2,6-dimethylbenzoic acid (0.32 g, 2.13 mmol), 2-(1H-benzotR1azole-1"yl)-1,1,3,3-tetramethyluronium tetrafiuoroborate (0.57 g, 1.5 mmol), EtN(i-Pr)2 (0.6 ml) and DMF (5 ml) is stirred for 16 h at 20*'C. The mixture is diluted with t-butyl methylether (25 ml), washed with 2N NaOH (25 ml) and bR1ne (25 ml) and dR1ed with sodium sulfate. The solvent is removed and the residue puR1fied by chromatography (SiO2, t-butyl methylether/cydohexane 1:4-1:0). The title compound is isolated as a coloR1ess solid. MS/ESI 482 (M+H)+; 'H NMR (400 MHz, DMSO) 5= 0.89 (3 H, s), 1.14-1.25 (3 H, m). 1.39 (1 H, m), 1.59 (1 H. m), 1.75 (1 H, m), 1.83-1.95 (2 H, m), 2.01 (3 H, s), 2.13 (3 H, s), 2.11-2.24 (2 H, m), 2.85 (2 H, m), 2,95 (1 H, m), 3.01 (1 H, m), 3.35 (1 H, m), 3.70-3.83 (2 H, m), 6.77 (4 H, m), 6.92-7.05 (4 H, m), 7.12 (1 H, m), 7.26 (4 H. m). (4'-Methyl-[1,4']bipipeR1dinyl-4-yl)-diphenyl-amine, used as starting mateR1al may be prepared as follows: a) A mixture of phenyl-plpeR1din-4-yl-amine (4.14 g; 15.0 mmol), iodobenzene (3.06 g; 15.0 mmol), Pd(OAc)2 (0.14 g; 0.63 mmol); BINAP (0.43 g; 0.69 mmol), t-BuOK (17.5 ml of 1M solution in THF) in toluene (20 ml) Is heated at 1 lO^'C for 5 h. The mixture is diluted with ethyl acetate, extracted with sodium hydrogencaR1t)onate and bR1ne and dR1ed with sodium sulfate. The solvent is removed and the residue subjected to chromatography (SiOa, f-butyl methylether/cydohexane 1:9-^1:1), 4-DJphenylamlno-pipeR1dine-1-carboxylicacid tert-butyl ester is isolated as a yellow solid. MS/ESI 353 (M+H)^ b) A mixture of TFA (5 ml), mettiylene chloR1de (5 ml) water (0.25 ml) and 4-diphenylamino-pipeR1dine-1-carboxylic add tert-butyl ester (1.5 g; 4.2 mmol) is stinred for 2 h at 20*^0. Sodium hydroxide (4N) is added and the mixture extracted with ethyl acetate. The oi^anic phase is dR1ed with sodium sulfate and the solvent removed. Diphenyl-pipeR1din-4-yl-amine is isolated as a coloR1ess oil. MS/ESI 253 (M+H)+ c) A suspension of diphenyl-pipeR1din-4-yl-amine (1.26 g, 5.00 mmol), 1 -(tert-butyl oxycarbonyl)-4-pipeR1done (1.00 g, 5.00 mmol), and titanium(IV) isopropoxide (1.42 g, 5.00 mmol) in 1,2-dlchloroethane (25 ml) is stirred for 1 h at 80**C and then for 16 h at 20'C. Diethylaluminum cyanide (10 ml 1M solution in toluene) is added and the mixture stirred for additional 24 h. The solvent is removed and the crude mateR1al dissolved in tetrahydrofuran (25 ml). Methylmagnesium bromide (8.7 ml 3M solution in ether) is added dropwise and the mixture stirred for 3 h at 20°C. Ammonium chloR1de (10 % solution, 50 ml) and ethyl acetate (50 ml) are added, the organic phase washed with ammonium chloR1de (10 % solution, 50 ml) and sodium hydrogencarbonate (10 % solution, 50 ml), dR1ed with sodium sulfate and the solvent removed. The residue is subjected to chromatography (Si02, ethyl acetate/cyclohexane 1:9--1:1), 4-DiphenylaminO"4'-methyl-l1,4']bipipeR1dinyl-1 '-carboxylic acid tert.-butyl ester is isolated as a coloR1ess solid MS/ESI 450 (M+H)*. d) A mixture of tR1fluoroacetic acid (2 ml) and water (0.1 ml) is added dropwise to a solution of compound a) above (0.81 g, 1.80 mmol) in methylene chloR1de (5 ml) and the mixture stirred for 3 h at 20°C. Sodium hydrogencarbonate (10% solution, 10 ml) and ethyl acetate (20ml) are added and the organic phase dR1ed with sodium sulfate. The solvent is removed and the residue sublected to chromatography (RP-18, methanol/HaO 1:3-^0:1). Tbe title compound is isolated as a coloR1ess oil. MS/ESI 350 (M+H)*; 'H NMR (400 MHz, CDCI3) n= 0.88 (3 H, s), 1.35 (4 H, m), 1.60 (4 H, m), 1.93 (2 H, m), 2.15 (2 H, m), 2.58 (2 H, m), 2.87 (2 H, m), 2.96 (2 H, m), 3.76 (1 H, m), 6.78 (4 H, m), 6.94 (2 H, m), 7.22 (4 H, m). A mixture of (4'-methyl-[1,4']bipipeR1dJnyM-yl)-diphenyl"amine (70 mg, 0.20 mmol) and 2,4,6-tR1R11ethyl-benzenesulfonyl chloR1de (65 mg, 0.30 mmol) and diisopropyl ethylamine (0.50 ml) in methylene chloR1de (3 ml) is stirred for 4h at RT. The mixture is diluted with ethyl acetate, extracted with sodium hydrogencaitonate (10 % solution) and dR1ed with sodium sulfate- The solvent is removed and the residue subjected to chromatography (Si02, t-butyl methylether/cyclohexane 1:9-^1:0). The title compound is Isolated as a coloR1ess solid. MS/ESI 532 (M+H)* methylether/methanol 1:0-10:1). The title compound is isolated as a colorless solid. MS/ESI 468 (M+H)* A mixture of TFA salt of [1,4']bipipeR1dinyl-4-yl-dlphenyl-amine (77 mg, 0.23 mmol), 2,6-dimethylbenzolc acid (100 mg, 0.67 mmol), 2-(1H-benzotR1azole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (254 mg, 0.67 mmol), EtN(i-Pr)2 (2 ml) and DMF (3 ml) is stinred for 5 h at RT. The mixture is diluted with tert-butyl methylether (10 ml), washed with 2N NaOH and bR1ne and dR1ed with sodium sulfate. The solvent Is removed and the residue puR1fied by chromatography (SiO2, f-butyl methylether/cyclohexane 1:1—»ethyl acetate-methyl acetate/HeO 98:2). The title compound is isolated as a coloR1ess solid. MS/ESI 468 (M+H)* [1,4'] BipipeR1dinyl-4-yl-dipherylamine, used as starting mateR1als, may be prepared as follows: a) A mixture of diphenyl-pipeR1din-4-yl-amine (1.06 g; 4.2 mmol), 4-oxo-pipeR1dine-1-carboxylic acid tert-butyl ester (1.0 g; 5.0 mmol), AcOH (0.62 g; 10-3 mmol) and Na(OAc)3BH (1.0 g; 4.7 mmol) In 1,2-dichloroethane (15 ml) Is stirred for 4h at 65°C. The mixture is diluted with f-butyl methylether, extracted with 1N NaOH and dR1ed with sodium sulfate. The solvent is removed and the residue subjected to chromatography (SiOa, f-butyl methylether/cyclohexane 1:9-*1:0). 4-Diphenylamino-[1,4"]bipipeR1dinyl-1'-cart50xylic acid tert-butyl ester is isolated as a coloR1ess solid. MS/ESI 436 (M+H)^ b) A mixture of 4-Diphenylamino-[1,4'lbiplpeR1dinyl-V-carboxylic acid tert-butyl ester (1.06 g; 2.4 mmol), TFA (2.5 ml), H2O (0.25 ml) and methylene chloR1de (5 ml) Is stin-ed at RT for 4 h. The mixture is added dropwise to ether and the precipitate formed is filtered off. The TFA salt of [1,4']bipipeR1dinyl-4-yl-diphenyi-amine is isolated as a coloR1ess solid. MS/ESI 336 (M+H)* By following the procedure of Example 2 above and using as starting mateR1als [1,4']bipipeR1dinyl-4-yl-dlphenyl-amine the compounds of formula X2 A mixture of [4-(4-bromo-phenylamino)-4'-methyl-[1,4']bipipeR1dinyl-1'-yl]-(2,^ phenyO-methanone (97 mg; 0.20 mmol), iodobenzene (41 mg; 0.20 mmol), Pd (OAc)2 (1.9 mg; 0.008 mmol), BINAP (5.7 mg; 0.009 mmol) and f-BuOK (0.23 ml of 1 M solution on THF=) in toluene (3 ml) is heated at 110°C for 16h. The mixture is diluted with ethyl acetate and filtered. The resulting solution is extracted with 2N NaOH and bR1ne and dR1ed with sodium sulfate. The solvent is removed and the residue subjected to chromatography (fiR8t SiO2, t-butyl methylether/cyclohexane 1:4-»1:0 and subsequently RP-18, methanol/HeO 7:3). The tiUe compound is isolated as a colodess solid. MS/ESI 560 (M+H)^. [4-(4-bromo-pherylamino)-4'-methyl-[1,4] blpipeR1dinyl-1 VI]-2,6-dimethylphenyI)-methanone, used as starting mateR1al, may be prepared as follows: a) 8-(1-Benzyl-4-methyl-pipeR1din-4-yl)-1,4-dioxa-8-a2a-splro[4.5]decane is prepared from 1,4-dioxa-8-aza-spiro[4.5]decane and 1-benzyl-pipeR1din-4-one following a procedure as descR1bed in example 1c). MS/ESI 331 (M+H)+. b) A mixture of 8-(1-ben2yl-4-methyl-pipeR1din-4-yl)-1,4-dioxa-8-aza-spiro[4.5]decane (2.0 g, 6.1 mmol) and Pd(0H)2 (20%) on charcoal (1 g) in methanol (30 ml) is hydrogenated for 16h at RT. The catalyst is filtered off and the solvent removed. Crude 8-(4-methyl-pipeR1dln-4-yl)-1,4-dioxa-8-aza-spiro[4,5]decane is isolated as a yellow oil. MS/ESi 241 (M+H)^. c) (2,6-Dimethyl-phenyl)-[4-(1,4-dioxa-8-aza-spiro(4.5]dec-8-yl)-4-methyl-plpeR1din-1 -yl]-methanone is obtained from crude 8-(4-methyl-pipeR1din-4-yl)-1,4-dioxa-8-a2a-spiro[4.5]decane and 2,6-dimethyl-benzoic acid by following a procedure as descR1bed in example 1. MS/ESI 373 (M+H)+. d) A solution of (2,6-dimethyl-phenyl)-[4-(1,4-dioxa-8-a2a-spiro[4.5]deC"8-yl)-4-mettiyl-pipeR1din-l-yl]-methanone (915 mg; 2.46 mmol) in dioxan (30 ml) and HCI (6N; 30ml) is stirred for 4h at 50C. The mixture is diluted with ethyl acetate (50 ml), extracted with 2N NaOH and bR1ne and dR1ed with sodium sulfate. Removal of the solvent affords 1'-(2,6-dimethyl-benzoyl)-4-methyl-[1,4']bipipeR1dinyi-4-one is isolated as a coloR1ess solid. MS/ESI 329 (M+H)+. e) A mixture of 1'-(2,6-dimethyl-benzoylH'-methyl-[1,4']bipipeR1dinyl-4-one (49.3 mg; 0.15 mmol), 4-bromo-phenylamine (29 mg, 0.165 mmol), acetic acid (18 mg; 0.30 mmol) and NaBH(OAc)3 (35 mg; 0.165 mmol) in (CH2CI)2 (4 ml) is stirred for 16h at RT. The mixture is diluted with ethyl acetate, extracted with 2N NaOH and bR1ne and dR1ed with sodium sulfate. The solvent is removed and the residue subjected to chromatography (RP-18, methanol/HzO 8:2-^1:0). [4-(4-bromo-pherylamino)-4'-methyl-[1,4] bipipeR1dinyl-Vyl]-2.6-dimethylphenyl)-methanone is isolated as a colorless solid. MS/ESI 484 (M+H)+. 4'-methy41,4*]bipipeR1dinyl-4-one, by following a similar procedure as descR1bed in example 51e). MS/ESI 406 (M+H)+. By following the procedure of Example 53 above and using the appropR1ate starting mateR1als the compounds of formula X3 It is prepared from 4-(4-tR1fluoromethyl-phenylamino)-pipeR1dine-1-carboxylic acid tert-butyl ester by using a procedure as descR1bed in example 1. MS/ESl 551 (M+H)+. The starting mateR1al is prepared from 4-tR1fluoromethyI-phenylamine and 4-oxo-pipeR1dine-1-carboxylic acid tert-butyl ester following a procedure as descR1bed in example 51 e). MS/ESl 345 (M+H)+. It is prepared from 4-phenylaminO'pipeR1dine-1-carboxylic acid tert-butyl ester and 4-bromo-biphenyl by using a procedure as descR1bed in example 1 - MS/ESI 558 (M+H)+. It is prepared from [1,4']bipipeR1dinyM-yl-(4-bromo-phenyl)i:>henyl-amine and 4,6-dimethyl-pyR1midine-5-carboxylic acid by following a procedure as descR1bed in example 1. MS/ESI 548 (M+H)+, [1,4']bipipeR1dinyl-4-yl-(4-bromo-phenyl)-phenyl-amine used as starting mateR1als may be prepared as follows: a) 4-(4-Bromo-phenylamino)-pipeR1dine-1-carboxylic acid tert-4)utyl ester is prepared from 4-bromo-phenylamine and 4-oxo-pipeR1dine-1 -carboxylic acid tert-butyl ester as descR1bed in example 51 e). MS/ESI 355 (K4+H)+. b) 4-[(4-Bromo-phenyl)-phenyl-amino]-pipeR1dine-1-carboxylic acid tert-butyl ester Is prepared from 4-(4-bromo-phenylamino)-pipeR1dlne-1-carboxyllc acid tert-butyl ester and iodo-benzene as descR1bed in example 51. MS/ESi 431 (M+H)+. c) (4-Bromo-phenyl)i>henyl-plpeR1din-4-yl-amine is prepared from 4-[(4-bromo-phenyl)-phenyl-amino]-pipeR1dine-1-carboxylic acid tert-butyl ester as descR1bed in example lb). MS/ESI 331 (M+H)+. d) 4-[(4-Bromo-phenyl)-phenyl-amino]-[1,4']bipipeR1dinyl-1 '-carboxylic acid tert-butyl ester is prepared from (4-bromo-phenyl)-phenyl-pipeR1din-4-yl-amine and 4-oxo-pipeR1dine-1- carboxylic acid tert-butyl ester as descR1bed in example 43a). MS/ESI 514 (M+H)+. e) [1,4']BipipeR1dinyl-4-yl-(4-bromo-phenyl)-phenyl-amine is prepared from 4-[(4-bromo- phenyl)-phenyl-amino]-[1.4']bipipeR1dinyl-1'-carboxylic acid tert-butyl ester as descR1bed in example 1b). MS/ESI 414 (M+H)+. By using a procedure as disclosed above and the con-esponding starting mateR1als, the compounds of fomR1ula X4 It is prepared from phenyl-pipeR1din-4-yl-pyR1din-3-yl-amine and 4-phenylamino-pipeR1dine-1-carboxylic acid tert-butyl ester using a procedure as descR1bed in example 1,1c) and Id). MS/ESI 485 (M+H)+. Example 78: {4-[4-Bronio-phenyl)-phenyl-amino]-4'niethyl-[1,4']bipipeR1dinyl-1 '-yl}- (2,4-dimethyi-1-oxy-pyR1din-3-yl>-inethanone It is prepared from r-(2,6-dimethyl-benzoylH'-methyl-[1.4']bipiperidinyl-4-one and ber)zo[1,3]dioxol-5-ylamine by following a procedure as described in examples 51 and 52. MS/ESI 540 (M+H)"". It is prepared from 1'-(2,6-dlmethyl-ben2oyl)-4'-methyl-[1,4']biplperidinyl-4-one and benzo[1,3]dioxol-5-ylamin6 by following a procedure as described in examples 51 and 52. MS(ESI) 561 (M+Hf Example 81: {4-[(4-Bromo-phenyl}-pyridin-3-yl-amino]-4'-methyK1,4']blplperldlnyH '- ylH2,4Kiimethyl-1 -oxy-pyridin-3-yl>-methanone It is prepared from 4-(pyridin-3-ylamino)-plperldine-1 -carboxylic add tert-butyl ester and 1,4-dibromo-benzene by following a procedure as descn*bed in example 1. MS/ESI 578 (M+IH)^ It is prepared from phenyl-pipeR1din-4-yl-amine by following a procedure as descR1bed in examples 52 and 1. MS/ESI 513 (M+H)+. 4'-Methyl-4-phenylamino-[1,4']bfpiperldJnyl-1'-carboxylic acid tert.-butyl ester is converted into (4-methyl-(1,4']bipJpeR1dinyl-4-yl)- (2-methyl-thiazol-4-yimethyl)*phenyl-amine using a procedure as descnl)ed in examples 52 and Id). from concentration-response curves obtained with the compounds In the presence of MIP-1a. In this assay, compounds of formula I have an IC50 1M. d) ExpeR1ments perfomied in muR1ne animal models show that vessel wall remodeling after expeR1mental injury (e.g. induced by allotransplantation) is significantly inhibited in the absence of functional CCR5. The compounds of fonnula I are, therefore, useful in the prevention and/or treatment of diseases or disordeR8 mediated by interactions between chemokine receptoR8, e.g. CCR5, and their ligands, e.g. in transplantation, such as acute or chronic rejection of organ, tissue or cell alio- or xenografts or delayed graft function, autoimmune diseases, e.g. rheumatoid arthR1tis, systemic lupus erythematosus, Hashimoto's thyroidls, multiple sclerosis, myasthenia gravis, diabetes type I or II and the disordeR8 associated therewith, vasculitis, pemiclous anemia, Sjoegren syndrome, uveitis, psoR1asis, alopecia areata and otheR8, allergic diseases, e.g. allergic asthma, atopic demiatitis, allergic rhinitis/conjunctivitis, allergic contact dermatitis, inflammatory diseases optionally with undeR1ying aberrant reactions, e.g. Inflammatory bowel disease, Crohn's disease or ulcerative colitis, intR1nsic asthma, inflammatory lung injury, inflammatory liver injury, inflammatory glomerular injury, atherosclerosis, osteoarthR1tis, irR1tant contact dermatitis and further eczematous dermatitises, seborrhoeic dermatitis, cutaneous manifestations of Immunologlcally-mediated disordeR8, inflammatory eye disease, keratoconjunctivitis, myocarditis or hepatitis, Ischemia/reperfusion injury, e.g. myocardial infarction, stroke, gut Ischemia, renal failure or hemorrhage shock, traumatic shock and otheR8, cancer, e.g. solid tumoR8 or lymphatic cancer such as T cell lymphomas or T cell leukemlas, metastasizing or anglogenesis, infectious diseases, e.g. toxic shock (e.g. superantigen induced), septic shock, adult respiratory distress syndrome or viral Infections, e.g. AIDS. By transplantation is meant allo-or xeno grafts of e.g. cells, tissues or solid organs, for example pancreatic islets, stem cells, bone manrow, comeal tissue, neuronal tissue, heart, lung, combined heart-lung, kidney, liver, bowel, pabcreas, trachea or oesophagus. Chronic rejection is also named graft vessel diseases. For the above uses the required dosage will of couR8e vary depending on the mode of administration, the particular condition to be treated and the effect desired. In general, satisfactory results are indteated to be obtained systemically at daily dosages of from about 0.01 tol 0 mg/kg per body weight An indicated daily dosage in the larger mammal, e.g. humans, is in the range from about 0.5 mg to about 1000 mg, conveniently administered. for example, in divided doses up to four times a day or In retard form. Suitable unit dosage fomR1s for oral administration compR1se from ca. 1 to 500 mg active ingredient. The compounds of formula I may be administered by any conventional route, in particular enterally, e.g. orally, e.g. in the form of tablets or capsules, or parenterally, e.g. in the iom of injectable solutions or suspensions, topically, e.g. in the form of lotions, gels, ointments or creams, or in a nasal or a suppository fonn. Pharmaceutical compositions compR1sing a compound of fomnula I in free form or in pharmaceutically acceptable salt fomi in association with at least one pharmaceutical acceptable carR1er or diluent may be manufactured in conventional manner by mixing with a pharmaceutically acceptable carR1er or diluent. The compounds of formula I may be administered in free form or in phamiaceutically acceptable salt form e.g. as indicated above. Such salts may be prepared in conventional manner and exhibit the same order of activity as the free compounds. In accordance with the foregoing the present invention further provides: 1.1 A method for preventing or treating disordeR8 or diseases mediated by interactions between chemokine receptoR8 and their ligands, e.g. such as indicated above, in a subject in need of such treatment, which method compR1ses administeR1ng to said subject an effective amount of a compound of formula I or a phannaceutically acceptable salt thereof; 1.2 A method for preventing or treating acute or chronic transplant rejection or inflammatory or autoimmune diseases, e.g. as indicated above, in a subject in need of such treatment, which method compR1ses administeR1ng to said subject an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof; 2. A compound of formula I or a pharmaceutically acceptable salt thereof for use as a pharmaceutical, e.g. in any of the methods as indicated under 1.1 or 1.2 above. 3. A pharmaceutical composition, e.g. for use in any of the methods as In 1.1 or 1.2 above compR1sing a compound of formula I or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable diluent or canier therefor. 4. A compound of formula I or a phanR11aceuticalty acceptable salt thereof for use in the ■ preparation of a pharmaceutical composition for use in any of the method as in 1.1 or 1J2 above. The compounds of formula I may be administered as the sole active ingredient or in conjunction with, e.g. as an adjuvant to, other drugs e.g. in immunosuppressive or immunomodulating regimens or other anti-inflammatory agents, e.g. for the treatment or prevention of alio- or xenograft acute or chronic rejection or inflammatory or autoimmune disordeR8, a chemotherapeutic agent or an anti-infective agent, e.g. an anti-viral agent such as e.g. an anti-retroviral agent or an antibiotic. For example, the compounds of fomiula I may be used in combination with a calcineuR1n inhibitor, e.g. cyclospoR1n A or FK 506; a macrocyclic lactone having immunosuppressive properties, e.g. rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, CCI779 or ABT578; an ascomycin having immunosuppressive properties, e.g. ABT-281, ASM981, etc.; corticosteroids; cyclophosphamide; azathlopR1ne; methotrexate; leflunomide; mizoR1bine; mycophenolic acid; mycophenolate mofetil; 15-deoxyspergualine or an immunosuppressive homologue, analogue or deR1vative thereof; an accelerating lymphocyte homing agent, e.g. FTY720; monoclonal antibodies to leukocyte receptoR8, e.g., MHC. CD2, CD3. CD4, CD7, CDS, CD11a/CD18, CD25. CD27, CD28, CD40. CD45, CD58, CD80, CD86, CD137, ICOS, CD150 (SU\M), OX40, 4-1BB or to their ligands, e.g. GDI 54, or antagonists thereof; other immunomodulatory compounds, e.g. a recombinant binding molecule having at least a portion of the extracellular domain of CTLA4 or a mutant thereof, e.g. an at least extracellular portion of CTLA4 or a mutant thereof joined to a non-CTLA4 protein sequence, e.g. CTLA4lg (for ex. designated ATCC 68629) or a mutant thereof, e.g. LEA29Y; adhesion molecule inhibitoR8, e.g. LFA-1 antagonists, ICAM-1 or -3 antagonists, VCAM-4 antagonists or VLA-4 antagonists; or antichemokine antibodies or antichemokine receptor antibodies or low molecular weight chemokine receptor antagonists, e.g. anti MCP-1 antibodies. Where the compounds of formula I are administered in conjunction with other immunosuppressive / Immunomodulatory, anti-inflammatory or chemotherapeutic therapy, dosages of the co-administered immunosuppressant, immunomodulatory, anti-inflammatory or chemotherapeutic compound will of couR8e vary depending on the type of co-drug employed, e.g. whether it is a steroid or a calcineuR1n inhibitor, on the specific drug employed, on the condition being treated and so forth. In accordance with the foregoing the present invention provides in a yet further aspect: 5. A method as defined above compR1sing co-administration, e.g. concomitantly or in sequence, of a therapeutically effective non-toxic amount of a compound of fomnula I and at least a second drug substance, e.g. an immunosuppressant. immunomodulatory, anti-inflammatory, anti-infective or chemotherapeutic drug, e.g. as indicated above. 6. A phannaceutical combination, e.g. a kit, compR1sing a) a fiR8t agent which is a CCR5 antagonist, e.g. a compound of fomiula I as disclosed herein, in free fomn or in pharmaceutically acceptable salt fomn, and b) at least one co-agent, e.g. an immunosuppressant, Immunomodulatory, anti-inflammatory, anti-infective or chemotherapeutic drug. The kit may compR1se instmctions for its administration. The tenms "co-administration" or "combined administration" or the like as utilized herein are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are not necessaR1ly administered by the same route of administration or at the same time. The temn "pharmaceutical combination" as used herein means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term lixed combination" means that the active ingredients, e.g. a compound of formula I and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage. The temi "non-fixed combination" means that the active ingredients, e.g. a compound of fomnula I and a co-agent, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the 2 compounds In the body of the patient. The latter also applies to cocktail therapy, e.g. the administration of 3 or more active ingredients. wherein X is a direct bond; -CH1; -CH2-CH2-; -CHR9-; -C(0)s -0-; -NH- or NR9; Ri is optionally R10 and/or Rn-substituted phenyl; optionally R10 and/or R10n-substituted heteroaryl; optionally R10 and/or Rn-substituted heteroaryl N-oxide; or optionally R10 and/or Rn-substituted naphthyl; R2 has one of the significances given for Ri; or is optionally R10 and/or Rn-substituted fluorenyl; optionally R10-substituted C1-C6 alkyl; optionally R10-substituted Ca-Ce alkenyl; optionally R10-substituted C3-C6 cycloalkyt; optionally R10-substituted adamantyl; or optionally R10-substituted C4-C8 cydoalkenyl; R3 has one of the significances given for R1; or is optionally R10 and/or Rn-substituted fluorenyl; R10-substituted C1-C16 alkyl; optionally R10-substituted C2-C6 alkenyl; optionally R10-substituted C3-C6 cycloalkyi; optionally R10-substituted adamantyl; or optionally R10-substituted C4-C8 cydoalkenyl; 3. A compound according to claim 1, wherein each of R4, R5. Re or R7 independently, Is H; C1-6 alkyl; or benzyl. 4. A compound according to claim 1, wherein Rs is H; C1-6 alkyl; or C2-6 alkenyl. 5. A compound according to claim 1 wherein X is a direct bond or -CH2- and / or Y is - C(0)-. wherein R1 is as defined above and X" is CH2- or -CHRr; and, where required, converting the resulting compound of formula I obtained in free form Into the desired salt form, or vice versa. 7. A compound according to any one of claims 1 to 5 or a pharmaceuticalty acceptable salt thereof for use as a pharmaceutical. 8. A pharmaceutical composition comprising a compound of formula I according to claim 1 or a pharmaceutlcalty acceptable salt thereof In association with a pharmaceuticalty acceptable diluent a earner therefor. 9. A phamiaceutical combination comprising a) a first agent which Is a compound of formula I according to claim 1, or a pharmaceuticalty acceptable salt thereof, and b) at least one co-agent. 10. A method for preventing or treating disorders or diseases mediated by Interactions between chemoldne receptors and their ligands, In a subject in need of such a treatment, which method comprises administering to said subject an effective amount of a compound of fonnula I according to claim 1 or a pharmaceuticalty acceptable salt thereof. 11. A compound substantially as herein described and exemplified. 12. A pharmaceutical composition substantially as herein described and exemplified.

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1582-chenp-2003 claims-duplicate.pdf

1582-chenp-2003 abstract-duplicate.pdf

1582-chenp-2003 abstract.pdf

1582-chenp-2003 claims.pdf

1582-chenp-2003 description (complete)-duplicate.pdf

1582-chenp-2003 form 2.pdf

1582-chenp-2003-abstract.pdf

1582-chenp-2003-claims.pdf

1582-chenp-2003-correspondnece-others.pdf

1582-chenp-2003-correspondnece-po.pdf

1582-chenp-2003-description(complete).pdf

1582-chenp-2003-form 1.pdf

1582-chenp-2003-form 18.pdf

1582-chenp-2003-form 3.pdf

1582-chenp-2003-form 5.pdf

1582-chenp-2003-pct.pdf