MXPA01007800A - Calcilytic compounds - Google Patents
Calcilytic compoundsInfo
- Publication number
- MXPA01007800A MXPA01007800A MXPA/A/2001/007800A MXPA01007800A MXPA01007800A MX PA01007800 A MXPA01007800 A MX PA01007800A MX PA01007800 A MXPA01007800 A MX PA01007800A MX PA01007800 A MXPA01007800 A MX PA01007800A
- Authority
- MX
- Mexico
- Prior art keywords
- hydroxy
- cyano
- dimethyl
- naphthyl
- phenoxy
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 86
- 230000001126 calcilytic Effects 0.000 title abstract description 12
- -1 N- [2R-hydroxy-3- [2-cyano-4- [3-carboxyphenyl] phenoxy] propyl] -1,1-dimethyl-2- (2-naphthyl) ethylamine hydrochloride Chemical compound 0.000 claims description 118
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 62
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 61
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 34
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 25
- 201000010099 disease Diseases 0.000 claims description 22
- 102000013830 Calcium-Sensing Receptors Human genes 0.000 claims description 14
- 108010050543 Calcium-Sensing Receptors Proteins 0.000 claims description 14
- 210000002966 Serum Anatomy 0.000 claims description 13
- 230000002159 abnormal effect Effects 0.000 claims description 12
- 125000003118 aryl group Chemical group 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 9
- 210000000988 Bone and Bones Anatomy 0.000 claims description 9
- QUSNBJAOOMFDIB-UHFFFAOYSA-N ethyl amine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims description 9
- 230000000849 parathyroid Effects 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- JCXJVPUVTGWSNB-UHFFFAOYSA-N nitrogen dioxide Inorganic materials O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 claims description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 230000013632 homeostatic process Effects 0.000 claims description 6
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 6
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 6
- 239000011707 mineral Substances 0.000 claims description 6
- 208000001132 Osteoporosis Diseases 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 230000035876 healing Effects 0.000 claims description 5
- 230000001965 increased Effects 0.000 claims description 5
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 4
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 4
- 206010017076 Fracture Diseases 0.000 claims description 4
- 206010020583 Hypercalcaemia Diseases 0.000 claims description 4
- 208000003393 Mammary Paget's Disease Diseases 0.000 claims description 4
- 208000010191 Osteitis Deformans Diseases 0.000 claims description 4
- 206010039073 Rheumatoid arthritis Diseases 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 125000001072 heteroaryl group Chemical group 0.000 claims description 4
- 230000000148 hypercalcaemia Effects 0.000 claims description 4
- 230000036210 malignancy Effects 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 201000008482 osteoarthritis Diseases 0.000 claims description 4
- 201000008968 osteosarcoma Diseases 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 201000008838 periodontal disease Diseases 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 125000000623 heterocyclic group Chemical group 0.000 claims description 3
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- HFBYLYCMISIEMM-FFHNEAJVSA-N (4R,4aR,7S,7aR,12bS)-9-methoxy-3-methyl-2,4,4a,5,6,7,7a,13-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-7-ol;phosphoric acid Chemical compound OP(O)(O)=O.C([C@H]1[C@H](N(CC[C@@]112)C)C3)C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC HFBYLYCMISIEMM-FFHNEAJVSA-N 0.000 claims description 2
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 125000000304 alkynyl group Chemical group 0.000 claims description 2
- 230000003042 antagnostic Effects 0.000 claims description 2
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000004435 hydrogen atoms Chemical class [H]* 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 2
- 150000003536 tetrazoles Chemical class 0.000 claims description 2
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims 1
- 239000005977 Ethylene Substances 0.000 claims 1
- JTXKOAAZGJOMHT-UHFFFAOYSA-N N,N-dimethyl-2-naphthalen-2-ylethanamine;hydrochloride Chemical compound Cl.C1=CC=CC2=CC(CCN(C)C)=CC=C21 JTXKOAAZGJOMHT-UHFFFAOYSA-N 0.000 claims 1
- AHEJURHRYJPYST-UHFFFAOYSA-N N-ethylnaphthalen-2-amine Chemical compound C1=CC=CC2=CC(NCC)=CC=C21 AHEJURHRYJPYST-UHFFFAOYSA-N 0.000 claims 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims 1
- 239000002253 acid Substances 0.000 description 49
- 239000000203 mixture Substances 0.000 description 43
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 29
- 239000007787 solid Substances 0.000 description 28
- 210000004027 cells Anatomy 0.000 description 23
- 238000005160 1H NMR spectroscopy Methods 0.000 description 21
- 238000000034 method Methods 0.000 description 20
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 19
- 239000011575 calcium Substances 0.000 description 17
- 239000011780 sodium chloride Substances 0.000 description 16
- 102100011140 PTRH1 Human genes 0.000 description 15
- 229910052791 calcium Inorganic materials 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- OYPRJOBELJOOCE-UHFFFAOYSA-N calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 14
- 150000003839 salts Chemical class 0.000 description 14
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 238000010992 reflux Methods 0.000 description 11
- 229910001868 water Inorganic materials 0.000 description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 10
- 230000000875 corresponding Effects 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 230000000694 effects Effects 0.000 description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
- 239000003826 tablet Substances 0.000 description 8
- 239000010410 layer Substances 0.000 description 7
- 230000028327 secretion Effects 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- KBNUZLPQQMVGPR-UHFFFAOYSA-N 4-(4-cyanophenyl)benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1C1=CC=C(C#N)C=C1 KBNUZLPQQMVGPR-UHFFFAOYSA-N 0.000 description 6
- 238000007792 addition Methods 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
- 235000019439 ethyl acetate Nutrition 0.000 description 6
- 230000003834 intracellular Effects 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N DMSO-d6 Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 5
- 235000020127 ayran Nutrition 0.000 description 5
- 238000009739 binding Methods 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 239000000284 extract Substances 0.000 description 5
- 238000003818 flash chromatography Methods 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 239000008187 granular material Substances 0.000 description 5
- 239000012528 membrane Substances 0.000 description 5
- 235000010755 mineral Nutrition 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 208000000038 Hypoparathyroidism Diseases 0.000 description 4
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L MgCl2 Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 4
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-Bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M Potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 4
- 230000027455 binding Effects 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000012267 brine Substances 0.000 description 4
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 4
- 239000006260 foam Substances 0.000 description 4
- 229920000159 gelatin Polymers 0.000 description 4
- 235000019322 gelatine Nutrition 0.000 description 4
- 235000011852 gelatine desserts Nutrition 0.000 description 4
- 210000004877 mucosa Anatomy 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 235000019198 oils Nutrition 0.000 description 4
- 239000006174 pH buffer Substances 0.000 description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- 239000002464 receptor antagonist Substances 0.000 description 4
- 102000005962 receptors Human genes 0.000 description 4
- 108020003175 receptors Proteins 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- LENZDBCJOHFCAS-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 3
- 206010001497 Agitation Diseases 0.000 description 3
- 238000001157 Fourier transform infrared spectrum Methods 0.000 description 3
- 108010010803 Gelatin Proteins 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- 238000006069 Suzuki reaction reaction Methods 0.000 description 3
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N Triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 3
- AIHIHVZYAAMDPM-MRVPVSSYSA-N [(2R)-oxiran-2-yl]methyl 3-nitrobenzenesulfonate Chemical compound [O-][N+](=O)C1=CC=CC(S(=O)(=O)OC[C@@H]2OC2)=C1 AIHIHVZYAAMDPM-MRVPVSSYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 239000000443 aerosol Substances 0.000 description 3
- 125000004432 carbon atoms Chemical group C* 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000008273 gelatin Substances 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000008188 pellet Substances 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- 239000002953 phosphate buffered saline Substances 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 235000015320 potassium carbonate Nutrition 0.000 description 3
- 235000017550 sodium carbonate Nutrition 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N (E)-but-2-enedioate;hydron Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- CHZCERSEMVWNHL-UHFFFAOYSA-N 2-hydroxybenzonitrile Chemical group OC1=CC=CC=C1C#N CHZCERSEMVWNHL-UHFFFAOYSA-N 0.000 description 2
- WOVZFJHCXJZOGT-XMMPIXPASA-N 4-[3-[(2R)-3-[[1-(1-benzothiophen-3-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]-4-cyanophenyl]benzoic acid Chemical compound C([C@H](O)CNC(C)(CC=1C2=CC=CC=C2SC=1)C)OC(C(=CC=1)C#N)=CC=1C1=CC=C(C(O)=O)C=C1 WOVZFJHCXJZOGT-XMMPIXPASA-N 0.000 description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 2
- 101710027066 ALB Proteins 0.000 description 2
- 235000003911 Arachis Nutrition 0.000 description 2
- 240000005781 Arachis hypogaea Species 0.000 description 2
- 210000004369 Blood Anatomy 0.000 description 2
- 210000003771 C cell Anatomy 0.000 description 2
- MIHZQOPRPFSPKX-HXUWFJFHSA-N CC(CC1=CC(=C(C=C1)Cl)Cl)(C)NC[C@H](COC1=C(C=CC(=C1)C(=O)O)C1=CC=CC=C1)O Chemical compound CC(CC1=CC(=C(C=C1)Cl)Cl)(C)NC[C@H](COC1=C(C=CC(=C1)C(=O)O)C1=CC=CC=C1)O MIHZQOPRPFSPKX-HXUWFJFHSA-N 0.000 description 2
- 229960004015 Calcitonin Drugs 0.000 description 2
- 102400000113 Calcitonin Human genes 0.000 description 2
- 108060001064 Calcitonin Proteins 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N D-Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- OZLGRUXZXMRXGP-UHFFFAOYSA-N Fluo-3-AM Chemical compound CC1=CC=C(N(CC(O)=O)CC(O)=O)C(OCCOC=2C(=CC=C(C=2)C2=C3C=C(Cl)C(=O)C=C3OC3=CC(O)=C(Cl)C=C32)N(CC(O)=O)CC(O)=O)=C1 OZLGRUXZXMRXGP-UHFFFAOYSA-N 0.000 description 2
- 229960001031 Glucose Drugs 0.000 description 2
- 206010053198 Inappropriate antidiuretic hormone secretion Diseases 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- NUJOXMJBOLGQSY-UHFFFAOYSA-N Manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-XIXRPRMCSA-N Mesotartaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-XIXRPRMCSA-N 0.000 description 2
- 230000035536 Oral bioavailability Effects 0.000 description 2
- 210000002997 Osteoclasts Anatomy 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N P-Toluenesulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 102000003982 Parathyroid hormone Human genes 0.000 description 2
- 108090000445 Parathyroid hormone Proteins 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 229920002873 Polyethylenimine Polymers 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N Stearic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K [O-]P([O-])([O-])=O Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-M benzoate Chemical compound [O-]C(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-M 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- BBBFJLBPOGFECG-VJVYQDLKSA-N calcitonin Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(N)=O)C(C)C)C(=O)[C@@H]1CSSC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1 BBBFJLBPOGFECG-VJVYQDLKSA-N 0.000 description 2
- 239000001110 calcium chloride Substances 0.000 description 2
- 235000011148 calcium chloride Nutrition 0.000 description 2
- 229910001628 calcium chloride Inorganic materials 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N cd3od Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N edta Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- 238000000132 electrospray ionisation Methods 0.000 description 2
- 238000005755 formation reaction Methods 0.000 description 2
- YHOMCUREJOXFPI-UHFFFAOYSA-N formylboronic acid Chemical class OB(O)C=O YHOMCUREJOXFPI-UHFFFAOYSA-N 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N fumaric acid Chemical compound OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 125000005842 heteroatoms Chemical group 0.000 description 2
- 238000000265 homogenisation Methods 0.000 description 2
- 150000002430 hydrocarbons Chemical group 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 229910001629 magnesium chloride Inorganic materials 0.000 description 2
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Chemical compound [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
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Abstract
Novel calcilytic compounds are provided.
Description
CALCILITIC COMPOUNDS
FIELD OF THE INVENTION
The present invention relates to novel calcilytic compounds, pharmaceutical compositions containing these compounds and their use as calcium receptor antagonists. In mammals, extracellular Ca2 + is under rigid homeostatic control and regulates various procedures such as blood coagulation, excitability of nerves and muscles, and proper bone formation. Extracellular Ca2 + inhibits the secretion of parathyroid hormone ("PTH") from parathyroid cells, inhibits bone resorption by osteoclasts and stimulates the secretion of calcitonin from C cells. Calcium receptor proteins allow certain specialized cells to respond to changes in extracellular Ca2 + concentration . PTH is the main endocrine factor that regulates Ca2 + homeostasis in blood and extracellular fluids. PTH, by acting on bone and kidney cells, increases the level of Ca2 + in the blood. This increase in extracellular Ca2 + then acts as a negative feedback signal, reducing the secretion of PTH. The reciprocal relationship between extracellular Ca2 + and PTH secretion forms an important mechanism that maintains the corporal Ca2 + homeostasis.
Extracellular Ca acts directly on parathyroid cells to regulate PTH secretion. The existence of a parathyroid cell surface protein which detects changes in extracellular Ca2 + has been confirmed. See Brown et al., Nature 366: 574, 1993. In parathyroid cells, this protein, the calcium receptor, acts as a receptor for extracellular Ca2 +, detects changes in the extracellular Ca2 + ion concentration, and initiates a functional cellular response, PTH secretion. Extracellular Ca2 + influences several cellular functions, reviewed in Nemeth et al., Cell Calcium 77: 319, 1990. For example, extracellular Ca2 + plays a role in parathyroid and parafollicular cells (C cells). See Nemeth, Cell Calcium 11: 323, 1990. The role of extracellular Ca2 + in bone osteoclasts has also been studied. See Zaidi, Bioscience Reports 10: 493, 1990. Several compounds are known to mimic the effects of extracellular Ca2 + on a calcium receptor molecule. Calcilytics are compounds capable of inhibiting calcium receptor activity, thus causing a decrease in one or more activities of calcium receptors evoked by extracellular Ca2 +. Calcilytics are useful as main molecules in the discovery, development, design, modification and / or construction of useful calcium modulators which are active in Ca2 + receptors. Such calcilytics are useful in the treatment of different disease states characterized by abnormal levels of one or more components, for example, polypeptides such as hormones, enzymes or growth factors, whose expression and / or secretion is regulated or affected by activity in one. or more Ca2 + receptors. The target diseases or disorders for calcilytic compounds include diseases involving abnormal mineral and bone homeostasis. Abnormal calcium homeostasis is characterized by one or more of the following activities: an abnormal increase or decrease in serum calcium; an abnormal increase or decrease in urinary calcium excretion, an abnormal increase or decrease in calcium levels in bones (for example, evaluated according to bone mineral density measurements); an abnormal absorption of calcium in the diet; an abnormal increase or decrease in the production and / or release of messengers which affect serum calcium levels such as PTH and calcitonin; and an abnormal change in the response produced by messengers that affect serum calcium levels. In this way, calcium receptor antagonists offer a unique method towards the pharmacotherapy of diseases associated with abnormal mineral or bone homeostasis, such as hypoparathyroidism, osteosarcoma, periodontal disease, fracture healing, osteoarthritis, rheumatoid arthritis, Paget's disease, hypercalcemia humoral associated with fracture healing and malignancy, and osteoporosis.
BRIEF DESCRIPTION OF THE INVENTION
The present invention comprises novel calcium receptor antagonists represented below by formula (I) and their use as calcium receptor antagonists which are useful in the treatment of a variety of diseases associated with abnormal mineral or bone homeostasis, including but not limited to they are not limited to hypoparathyroidism, osteosarcoma, periodontal disease, fracture healing, osteoarthritis, rheumatoid arthritis, Paget's disease, humoral hypercalcemia associated with fracture healing and malignancy, and osteoporosis. The present invention further provides a method for antagonizing calcium receptors in an animal, including humans, which comprises administering to an animal in need thereof an effective amount of a compound of formula (I), indicated below. The present invention further provides a method for increasing serum parathyroid levels in an animal, including humans, which comprises administering to an animal in need thereof, an effective amount of a compound of formula (I), indicated below.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of the present invention are selected from the formula (I) below:
I wherein: A represents an aryl ring that is attached in the 4 or 5 position as indicated; X is selected from the group consisting of CN, NO2, Cl, F and H; And it is selected from the group consisting of Cl, F, I and H; Q is selected from the group consisting of H, R ^ SO2R- ?, R? C (O) OR '?, tetrazole, CH2OH, COH, S02NR? R? \ C (0) NR1R?', And NR1S02R1", in where R-, and R-, 'are independently selected from the group consisting of hydrogen, C? -4 alkyl, and optionally substituted alkyl, or Ri and Ri' together form a heterocyclic ring optionally substituted with 3 to 7 elements Ar is phenyl or naphthyl, substituted or unsubstituted, heteroaryl or fused heteroaryl, so that the hetero ring can contain N, O or S and can be aromatic, dihydro or tetrahydro, substituted or unsubstituted. present, "alkyl" refers to an optionally substituted hydrocarbon group attached by single carbon-carbon bonds and having 1-20 carbon atoms attached.The alkyl hydrocarbon group can be linear, branched or cyclic, saturated or unsaturated. they are selected from F, Cl, Br, I, N, S and O. Preferably, no more than three substituents are present. preferably, the alkyl has 1-12 carbon atoms and is unsubstituted. Preferably, the alkyl group is linear. Preferably, the alkyl group is saturated. Preferably, the optionally substituted alkyl substituents are selected from the group consisting of CN, aryl, CO2R, C02NHR, OH, OR, CO, NH2, halogen, CF3, OCF3 and NO2, wherein R represents H, C1-4 alkyl, C3-6 cycloalkyl, C2-5 alkenyl, C2-5 alkynyl, heterocycloalkyl, aryl or arylalkyl of C? -4; As used herein, "lower alkyl" refers to C 1-5. As used herein, "cycloalkyl" refers to carbocyclic rings of 3 to 7 elements. As used herein "heterocycloalkyl" refers to heterocyclic rings of 4, 5, 6 or 7 elements containing from 1 to 2 heteroatoms selected from N, O and S. As used herein, "aryl" refers to to an aromatic group optionally substituted with at least one ring having a conjugated p-electron system, containing up to two conjugated or fused ring systems. Aryl includes carbocyclic aryl, heterocyclic aryl and biaryl groups, which may be optionally substituted. The aryl substituents are preferably selected from the group consisting of OH, halogen, CO 2 R ?, C 1 -4 alkyl, C 1 -4 alkoxy, C 3-6 cycloalkyl, OS 0 2 R ?, CN, N 0 2, OCF 3, CF 3, CH2CF3, (CH2) nCO2H, (CH2) nCO2R ?, 0- (CH2) n and CO2R ?, where n is an integer from 0 to 3 and Ri represents C1-4 alkyl, C3-6 cycloalkyl, or C3-6 cycloalkyl. Preferred heteroaryl substituents are selected from the group consisting of OH, OCH3, CH (CH3) 2, halogen, CO ^, d-4 alkyl, C4 alkoxy, C3-6 cycloalkyl, CN, N02, OCF3, CF3 , CH2CF3, (CH2) nC02R? and O- (CH2) nC02R ?. The compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. All of these compounds and diastereomers are contemplated within the scope of the present invention. The preferred compounds of the present invention are selected from the group consisting of: N- [2R-hydroxy-3- [2-cyano-5- [2-carbethoxyphenyl] phenoxy] propyl] -1, 1-dimethyl hydrochloride; l-2- (2-naphthyl) ethylamine; N- [2R-hydroxy-3- [2-cyano-5- [4-carbethoxyphenyl] phenoxy] propyl] -1,1-dimethyl-2- (2-naphthyl) ethylamine hydrochloride; N- [2R-hydroxy-3 - [[2-cyano-5 - [[4-carboxy] phenyl] phenoxy] propyl] -1,1-dimethyl-2- (2-naphthyl) ethylamine hydrochloride; N- [2R-Hydroxy-3 - [[2-cyano-5- [2-carboxyphenyl] phenoxy] propyl] -1, 1-d-methyl-2- (2-naphthyl) hydrochloride ethylamine; N- [2R-hydroxy-3 - [[2-cyano-4- [4-carboxyphenyl] phenoxy] propyl] -1,1-dimethyl-2- (2-naphthyl) ethylamine hydrochloride; N- [2R-Hydroxy-3 - [[2-cyano-4- [carbetoxyphenyl] phenoxy] propyl] -1, 1-dimethyl-2- (2-naphthyl) ethylamine hydrochloride, N-Hydrochloride [2R-hydroxy-3 - [[2-cyano-4- [2-formylphenyl] phenoxy] propyl] -1,1-dimethyl-2- (2-naphthyl) ethylamine; N- [2R-hydroxy-3 - [[2-cyano-4- [3-formylphenyl] phenoxy] propyl] -1,1-dimethyl-2- (2-naphthyl) ethenamine hydrochloride; N- [2R-Hydroxy-3 - [[2-cyano-4 - [[3- [hydroxymethyl] phenyl] phenoxy] propyl] -1,1-dimethyl-2- (2-naphthyl) hydrochloride ethylamine; N- [2R-hydroxy-3 - [[2-cyano-4 - [[2-hydroxymethylphenyl] phenoxy] propyl] -1,1-dimethyl-2- (2-naphthyl) ethylamine hydrochloride; N- [2R-Hydroxy-3 - [[2-cyano-4 - [[3 - [[ethyl] carboxy] phenyl] phenoxy] propyl] -1,1-dimethyl-2- (2-naphthyl) hydrochloride ethylamine; N- [2R-Hydroxy-3- [2-cyano-4- [3-carboxylphenyl] phenoxy] propyl] -1,1-dimethyl-2- (2-naphthyl) ethylamine hydrochloride; and N- [2R-hydroxy-3- [2-cyano-4- (2-carboxyphenyl) phenoxy] propyl] -1,1-dimethyl-2- (2-naphthyl) ethylamine hydrochloride. N- [2R-hydroxy-3 - [[2-cyano-5- [4-carboxyl] phenyl] phenoxy] propyl] -1,1-dimethyl-2- (4-fluorophenyl) ethenamine hydrochloride; 4'-cyano-3'- acid. { (R) -3- [1,1-Dimethyl-2- (5,6,7,8-tetrahydro-naphthalen-2-yl) -ethylamino] -2-hydroxy-propoxy} -biphenyl-4-carboxylic acid; 4'-cyano-3'- acid. { (R) -3- [2- (Decahydro-naphthalen-2-yl) -1, 1-dimethyl-ethylamino] -2-hydroxy-propoxy} -biphenyl-4-carboxylic acid; 3 '- [(R) -3- (2-Benzo [b] thiophen-2-yl-1,1-dimethyl-ethylamino) -2-hydroxy-propoxy] -4'-cyano-biphenyl-4 acid carboxylic;
4'-cyano-3'- acid. { (R) -2-hydroxy-3- [4- (2-methoxy-phenyl) -1,1-dimethyl-butylamino] -propoxy} -biphenyl-4-carboxylic acid; 4'-cyano-3'- acid. { (R) -2-hydroxy-3- [4-phenyl-1,1-dimethyl-butylamino] propoxy} -biphenyl-4-carboxylic acid; 3 '- [(R) -3- (2-Benzo [b] thiophen-3-yl-1,1-dimethyl-ethylamino) -2-hydroxy-propoxy acid} 4'-cyano-biphenyl-4-carboxylic acid; 4'-cyano-3'- acid. { (R) -3- [1,1-dimethyl-2- (4-sulfamoyl-phenyl) -ethylamino] -2-hydroxy-propoxy} -biphenyl-4-carboxylic acid; 4'-cyano-3'- acid. { (R) -2-hydroxy-3- [1- (4-trifluoromethoxy-benzyl) -cyclopropylamine] -propoxy} β-phenyl-4-carboxylic acid; 4'-cyano-3'- acid. { (R) -2-hydroxy-3- [1 - (2-methyl-benzyl) -cyclopropylamino] propoxy} -biphenyl-4-carboxylic acid; 4'-Cyano-3 '- [(R) -3- (1-cyclohexylmethyl-cyclopropylamino) -2-hydroxy-propoxy] -biphenyl-4-carboxylic acid; 4'-cyano-3'- acid. { (R) -2-hydroxy-3- [1- (4-hydroxy-benzyl) -cyclopropylamino] -propoxy} -biphenyl-4-carboxylic acid; 4'-cyano-3'- acid. { (R) -2-hydroxy-3- [1- (2-trifluoromethy1-benzyl-cyclopropylamino] propoxy] -β-phenyl-4-carboxylic acid 4'-Cyano-3'- { (R) -2-hydroxy-3- [1- (4-chloro-benzyl) -cyclopropylamino] -propoxy] -biphenyl-4-carboxylic acid 4'-Cyano-3'-. (R) ) -2-hydroxy-3- [1 - (- 3-trifluoromethyl-benzyl) cyclopropylamino] -propoxy.]. -biphenyl-4-carboxylic acid 4, -Ciano-3'- { (R) -2- hydroxy-3- [1- (4-bromo-benzyl) -cyclopropylamino] -propoxy.} - biphenyl-4-carboxylic N - [(2R) -Hydroxy-3 - [[2-cyano-5-] hydrochloride [4-carboxyl] phenyl] phenoxy] propyl]] - 1,1-dimethyl-2- (5-chlorothienyl) ethenamine Hydrochloride of (R) - [[1,1-Dimethyl-2-] acid] (5-chlorothienyl) ethylamino] -2-hydroxypropyloxy] -3- (4-cyano-phenyl-4'-carboxylic acid) 4'-Cyano-3'-. {(R) -2-hydroxy acid -3- [2- (3-methoxy-phenyl) -1, 1-dimethyl-ethylamino] -propoxy.] -biphenyl-4-carboxylic acid 3'- { (R) -3- [2- ( 4-tert-butyl-phenyl] -1,1-dimethyl-ethylamino] -2-hydroxy-propoxy.} -4'-cyano-biphenyl-4-carboxylic acid 4'-Cyano-3, -. {( R) -3- [2- (3,5-dimethyl-is oxazol-4-yl) -1, 1-dimethyl-ethylamino] -2-hydroxy-propoxy} -biphenyl-4-carboxylic acid 4, -Ciano-3'-. { (R) -3- [2- (4-Ethoxy-phenyl) -1, 1-d-methyl-ethylamino] -2-hydroxy-propoxy} -biphenyl-4-carboxylic acid 4'-Cyano-3'-. { (R) -3- [1,1-dimethyl-2- (4-pyridin-4-yl-phenyl) -eti-amino] -2-hydroxy-propoxy} -biphenyl-4-carboxylic acid (R) - [[1,1-Dimethyl-2- (4-methyltienyl) ethylammonyl] -2-hydroxypropyloxy] -3- (4-cyanob) hydrochloride Phenyl-4'-carboxylic acid) (R) - [[1,1-Dimethyl-2- (thienyl) ethylamino] -2-hydroxypropyloxy] -3- (4-cyanobiphenyl-4'-carboxylic acid) Hydrochloride (R) - [[1,1-Dimethyl-2- (5-methylthienyl) ethylamino] -2-hydroxypropyloxy] -3- (4-cyanobiphenyl-4'-carboxylic acid) acid 4'- Ciano-3, -. { (R) -2-hydroxy-3- [4- (2-methyl-phenyl) -1,1-dimethyl-butylamino] -propoxy} -biphenyl-4-carboxylic acid 4'-Cyano-3'-. { (R) -2-hydroxy-3- [4- (4-pyridyl) -1,1-dimethyl-butylamino] -propoxy} -biphenyl-4-carboxylic acid 3 '- [(R) -3- (4-benzo [1,3] dioxol-5-yl-1,1-dimethyl-butylamino) -2-hydroxy-propoxy] -4 '-cyano-b-phenyl-4-carboxylic acid 4'-Cyano-3'- acid. { (R) -3- [1,1-Dimethyl-2- (3-phenoxy-pheny] -ethylamino] -2-hydroxy-propoxy} -biphenyl-4-carboxylic acid 4'-Cyano-3'-. { (R) -3- [1,1-d.methyl-2- (4-methylsufanyl-pheny] -ethylamino] -2-hydroxy-propoxy) -biphenyl-4-carboxylic acid 4'-Cyano- 3'-. { (R) -3- [1,1-dimethyl-2- (3,4-dichloro-phenyl) -ethylamino] -2-hydroxy-propoxy} -biphenyl-4-carboxylic acid 4'-Cyano-3'-. { (R) -3- [1,1-dimethyl-2- (4-amino-phenyl) -ethylamino] -2-hydroxy-propoxy} -biphenyl-4-carboxylic acid 4, -Ciano-3'-. { (R) -3- [4- (2-Cyano-phenyl) -1, 1-d-methyl-butylamino] -2-hydroxy-propoxy} -biphenyl-4-carboxylic acid 4, -Can-3'-. { (R) -3- [4- (2-chloro-pheny] -1, 1-dimethyl-butylamino] -2-hydroxy-propoxy} -biphenyl-4-carboxylic acid 4'-Cyano-3'-. { (R) -3- [4- (3-methoxy-phenyl) -1,1-dimethyl-butylamino] -2-hydroxy-propoxy} -biphenyl-4-carboxylic acid 4'-Cyano-3'-. { (R) -3- [4- (2-trifluoromethyl-phenyl) -1, 1-dimethyl-butylamino] -2-hydroxy-propoxy} -biphenyl-4-carboxylic acid 4'-Cyano-3'-. { (R) -3- [4- (3-Trifluoromethoxy-phenyl) -1,1-dimethyl-butylamino] -2-hydroxy-propoxy} -biphenyl-4-carboxylic acid 4'-Cyano-3'-. { (R) -3- [4- (2-Fluoro-phenyl) -1, 1-dimethyl-butylamino] -2-hydroxy-propoxy} -biphenyl-4-carboxylic acid 3'-. { (R) - [2- (4-Bromo-phenyl) -1, 1-dimethyl-ethylamino] -2-hydroxy-propoxyJ ^ 'cyano-biphenyl-carboxylic acid 3'-. { (R) -3- [2- (3-Bromo-phenyl) -1,1-dimethyl-ethylamino] -2-hydroxy-propoxy} -4-cyano-biphenyl-4-carboxylic acid 3, -. { (R) -3- [2- (2-Bromo-pheny] -1-, 1-dimethyl-ethylamino] -2-hydroxy-propoxy} 4'-cyano-biphenyl-4-carboxylic acid 3 '- [(R) -3- (2-B-phenyl-4-yl-1,1-dimethylamino) -2-hydroxy -propox!] -4'-cyano-biphenyl-4-carboxylic acid 3, - [(R) -3- (2-B-phenyl-3-yl-1,1-dimethyl-ethylamino) -2- hydroxy-propoxy] -4'-cyano-biphenyl-4-carboxylic acid 3 '- [(R) -3- (2-Biphenyl-2-yl-1,1-dimethyl-ethylamino) -2 -hydroxy-propoxy] -4'-cyano-biphenyl-4-carboxylic acid 3 '- [(R) -3- (2-Benzo [1, 3] dioxol-5-yl-1,1-dimethyl-ethylamino) -2-hydroxy-propoxy] -4'-cyano-b-phenyl-4-carboxylic acid 4'-Cyan-3'- acid. { (R) -3- [1,1-Dimethyl-2- (4-phenoxy-phenyl) -ethylamino] -2-hydroxy-propoxy} -biphenyl-4-carboxylic acid (R) -1 - (4- (4-carboxyphenyl) -2-cyanophenoxy) -3- (2- (5,8-diazanaphthyl) -1,1 -dimethylethylamino) propanol Acid 4 '-ciano-3'-. { (R) -3- [1,1-Dimethyl-2- (4-etl-phenyl) -ethylamino] -2-hydroxy-propoxy} -biphenyl-4-carboxylic acid 4'-cyano-3'-. { (R) -2-hydroxy-3- [2-hydroxy-1,1-dimethyl-2- (6-methyl-pyridin-2-yl) -eti-amino] -propoxy} -biphenyl-4-carboxylic acid 3 '- [(R) -3- (2-benzyloxy-1,1-dimethyl-ethylamino) -2-hydroxy-propoxy] -4'-cyano-biphenyl-4 acid -carboxylic acid 4'-cyano-3'-. { (R) -2-hydroxy-3- [2- (3,4-dimethyl-pheny] -1, 1-dimethyl-ethylamino] -propoxy} -biphenyl-4-carboxylic acid 4'-cyano-3'-. { (R) -2-hydroxyl-3- [2- (4-methoxy-3-methyl-pheny] -1, 1-dimethyl-ethylamino] -propoxy} β-phenyl carboxylic acid 4'-cyano-3 '- [(R) -3- (1,1-dimethyl-2-quinolin-2-yl-ethylamino) -2-hydroxy-propoxy] -biphenyl-4 -carboxylic acid 4'-cyano-3'-. { (R) -3- [1,1-dimethyl-2- (3-trifluoromethyl-benzyloxy) -ethylamino) -2-hydroxy-propoxy} -biphenyl-4-carboxylic acid 4, -cyano-3 '- [(R) -2-hydroxy-3- [2- (4-trifluoromethoxy-phenol) -1, 1-dimethyl-ethylamino] -propoxy} -biphenyl-4-carboxylic acid 4'-cyano-3 '- [(R) -2-hydroxy-3- [2- (4-isopropyl-phenyl) -1,1-dimethyl-ethylamino] -propoxy acid} -biphenyl-4-carboxylic acid 4'-cyano-3 '- [(R) -3- (1,1-dimethyl-2-. {4- [1-phenyl-methanoyl-) - amino] - phenyl } -ethylamino) -2-hydroxy-propoxy] -biphenyl-4-carboxylic acid 3'-. { (R) -3- [4- (3-Chloro-4-methyl-phenyl) -1,1-dimethyl-butylamino] -2-hydroxy-propoxy} -4-cyano-biphenyl-4-carboxylic acid 3'-. { (R) -3- [4- (3,4-Dichloro-phenyl) -1,1-dimethyl-butylamino] -2-hydroxy-propoxy} 4'-cyano-biphenyl-4-carboxylic acid 3'-. { (R) -3- [4- (4-Chloro-phenyl) -1,1-dimethyl-butylamino] -2-hydroxy-propoxy} 4'-cyano-biphenyl-4-carboxylic acid 3'-. { (R) -2-hydroxy-3- [2-hydroxy-1,1-dimethyl-2- (6-methyl-pyridin-2-yl) -ethylamino] -propoxy} -biphenyl-4-carboxylic acid N- [2R-hydroxy-3- [. { 2-cyano-5- (4-carboxyphenyl). Phenoxy) propyl] -1,1-dimethyl-2- (ndan-2-yl) ethenamine 4'-cyano-3'- acid. { (R) -3- [2- (4-ethyl-3-fluoro-phenyl) -1,1-dimethyl-ethylamino] -2-hydroxy-propoxy} -biphenyl-4-carboxylic acid 4'-cyano-3'-. { (R) -3- [2- (4-Ethyl-2-fluoro-phenyl) -1, 1-dimethyl-ethylamino] -2-hydroxy-propoxy} -biphenyl-4-carboxylic acid 4'-cyano-3'-. { (R) -3- [4- (4-Fluoro-phenyl) -1, 1-dimethyl-butylamino] -2-hydroxy-propoxy} -biphenyl-4-carboxylic N- [2R-hydroxy-3- [2-cyano-5- (4-carboxyphenyl) phenoxy) propyl] -1,1-dimethyl-2- (indan-5) hydrochloride -yl) ethylamine N - [(2R) -hydroxy-3 - [[2-cyano-5 - [[4-carboxy] phenyl] phenoxy] propyl]] - 1,1-dimethyl-2- (hydroxyl) ) -2- (tetral-6-yl) ethylamine N - [(2R) -hydroxy-3 - [[2-cyano-5 - [[4-carboxyphenyl] phenoxy] propyl]] - 1, 1- dimethyl-2-thien-3-ylethylamine 4'-cyano-3'- acid. { (R) -3- [2- (4-ethyl-3,5-difluoro-phenyl) -1,1-dimethyl-ethylamino] -2-hydroxy-propoxy} -phenyl-4-carboxylic acid 4'-cyano-3'- acid. { (R) -3- [2- (4-Ethyl-2,6-difluoro-phenyl) -1,1-dimethylamino] -2-hydroxy-propoxy} -biphenyl-4-carboxylic acid 4'-cyano-3'- acid. { (R) -3- [2- (4-ethyl-2,5-difluoro-phenyl) -1, 1-d-methyl-ethylamino] -2-hydroxy-propoxy} -biphenyl-4-carboxylic acid 3- Fluoroacetate salt. { (S) -3- [2- (5-Chloro-thiophen-2-yl) -1,1-dimethyl-ethylamino] -2-hydroxy-propoxy} 4'-cyano-biphenyl-4-carboxylic acid 4'-cyano-3'-. { (R) -2-hydroxy-3- [2- (4-methoxy-pheny] -1, 1-d-methyl-ethylamino] -propoxy} -biphenyl-4-carboxylic acid The most preferred compounds useful in the present invention are selected from the group consisting of: N- [2R-hydroxy-3- [2-cyano-5- [2-carbethoxyphenyl] phenoxy] propyl] hydrochloride ]]-1, 1-dimethyl-2- (2-naphthyl) ethylamine; N- [2R-hydroxy-3- [2-cyano-5- [4-carbethoxyphenyl] phenoxy] propyl]] -1,1-d-methyl-2- (2-naphthyl) ethylamine hydrochloride; N- [2R-hydroxy-3 - [[2-cyano-5 - [[4-carboxy] phenyl] phenoxy] propyl] -1,1-dimethyl-2- [naphthyl] ethylamine hydrochloride; N- [2R-hydroxy-3 - [[2-cyano-4- [4-carboxyphenyl] phenoxy] propii] -1, 1-dimethyl-2- (2-naphthyl) ethylamine hydrochloride; N- [2R-hydroxy-3 - [[2-cyano-4- [carbethoxyphenyl] phenoxy] propyl] -1,1-dimethyl-2- (2-naphthyl) ethylamine hydrochloride; N- [2R-hydroxy-3 - [[2-cyano-4- [2-formylphenyl] phenoxy] propyl] -1,1-dimethyl-2- (naphthyl) ethylamine hydrochloride;
N- [2R-hydroxy-3 - [[2-cyano-4- [3-formylphenyl] phenoxy] propyl] -1,1-dimethyl-2- (naphthyl) ethylamine hydrochloride; N- [2R-hydroxy-3 - [[2-cyano-4- [[3 [hydroxymethyl] phenyl] phenoxy] propyl] -1,1-dimethyl-2- (naphthyl) ethenamine hydrochloride; N- [2R-Hydroxy-3 - [[2-cyano-4 - [[2-hydroxymethylene] phenoxy] propyl] -1, 1-d-methyl-2- (2-naft) hydrochloride L) ethylamine; N- [2R-hydroxy-3 - [[2-cyano-4 - [[3- [[ethyl] carboxyl]] phenyl] phenoxy] propyl] -1, -dmethyl-2- (2-naphthyl) hydrochloride ) ethylamine N- [2R-hydroxy-3- [2-cyano-4- [3-carboxyphenyl] phenoxy] propyl]] -1,1-dimethyl-2- (2-naphthyl) ethylamine hydrochloride; and N- [2R-hydroxy-3- [2-cyano-4- [2-carboxyphenyl) phenoxy] propyl] -1,1-dimethyl-2- (2-naphthyl) ethylamine hydrochloride. N- [2R-hydroxy-3 - [[2-cyano-5- [4-carboxy] phenyl] phenoxy] propyl] -1, 1-dmethyl-2- (4-fluorophenyl) ethylamine 4'-Acid -ciano-3'-. { (R) -3- [1,1-Dimethyl-2- (5,6,7,8-tetrahydro-naphthalen-2-yl) -ethylamino] -2-hydroxy-propoxy} -biphenyl-4-carboxylic acid 4'-cyano-3'-. { (R) -3- [2 (Decahydro-naphthalen-2-yl) -1, 1-dimethylamino] -hydroxy-propoxy} -biphenyl-4-carboxylic acid 3 '- [(R) -3- [2-benzo [b] thiophen-2-yl-1,1-dimethyl-ethylamino) -2-hydroxy-propoxy] -4'- cyano-biphenyl-4-carboxylic acid 4'-cyano-3'- acid. { (RH2-hydroxy-3- [4- (2-methoxy-phenyl) -1,1-dimethyl-butylamino] -propoxy.] - biphenyl-4-carboxylic acid 4'-cyano-3'- { (R) -2-hydroxy-3- [4-phenyl-1, 1-d-methyl-butylamino] -biphenyl-4-carboxylic acid 3 '- [(R) -3- (2-benzo [ b] thiophen-3-yl-1,1-dimethyl-ethylamino) -2-hydroxy-propoxy] -4'-cyano-biphenyl-4-carboxylic acid 4'-cyano-3'-. {(R ) -3- [1,1-dimethyl-2- (4-sulfamoyl-phenyl) -ethylamino] -2-hydroxy-propoxy.]. -biphenyl-4-carboxylic acid 4, -cyano-3'-. (R) -2-hydroxy-3- [1- (4- (trifluoromethoxy-benzyl) -cyclopropylamino] -propoxy] -b-phenyl-4-carboxylic acid N - [(2R) -hydroxy-3- [[2-cyano-5 - [[4-carboxyl] phenyl] phenoxy] propyl]] - 1,1-dimethyl-2- (5-chlorothienyl) ethylamine 4'-cyano-3'-. (R) -2-hydroxy-3- [2- (3-methoxy-phenyl) -1,1-dimethyl-ethylamino] -propoxy.]. -biphenyl-4-carboxylic acid 3'- { (R) -3- [2- (4-tert-butyl-phenyl) -1,1-dimethyl-ethylamino] -2-hydroxy-propoxy] -4'-cyano-biphenyl-4-carboxylic acid 4'-cyano-3'- { (R) -3- [2- (4-ethoxy-phenyl) -1,1-dimethyl-ethylamino] -2-hydroxy-propoxy} -biphenyl-4-carboxylic acid (R) - [[1,1-Dimethyl-2- (4-methylthienyl) ethylamino] -2-hydroxypropyloxy]} -3- (4-Cyanobiphenyl-4'-carboxylic acid) (R) - [[1,1-Dimethyl-2- (thienyl) ethylamino] -2-hydroxypropyloxy acid} -3- (4-Cyanobiphenyl-4'-carboxylic acid) (R) - [[1,1-Dimethyl-2- (5-methylthienyl) ethylamino] -2-hydroxypropyloxy acid} -3- (4-cyanobiphenyl-4'-carboxylic acid) 4'-cyano-3'- acid. { (R) -2-Hydroxy-3- [4- (2-methyl-pheny] -1, 1-d-methyl-butylamino] -propoxy} -biphenyl-4-carboxylic acid 4'-cyano-3'-. { (R) -2-hydroxy-3- [4- (4-pyridyl) -1,1-dimethyl-butylamino] -propoxy} -biphenyl-4-carboxylic acid 3 '- [(R) -3- (4-benzo [1,3] dioxol-5-ii-1, 1-dimethyl-butylamino) -2-hydroxy-propoxy] -4' -cyano-biphenyl-4-carboxylic acid 4'-cyano-3'-. { (R) -3- [1,1-dimethyl-2- (4-methylsulfanyl-pheny] -ethylamino] -2-hydroxy-propoxy} -biphenyl-4-carboxylic acid 4'-cyano-3'-. { (R) -3- [1,1-Dimethyl-2- (3,4-dichloro-phenyl) -ethylamino] -2-hydroxy-propoxy} -biphenyl-4-carboxylic acid 4'-cyano-3'-. { (R) -3- [4- (2-Cyano-phenyl) -1,1-dimethyl-butylamino] -2-hydroxy-propoxy} -biphenyl-4-carboxylic acid 4'-cyano-3'-. { (R) -3- [4- (2-Chloro-phenyl) -1,1-dimethyl-butylamino] -2-hydroxy-propoxy} -biphenyl-4-carboxylic acid 4'-cyano-3'-. { (R) -3- [4- (3-Methoxy-phenyl) -1,1-d-methyl-butylamino] -2-hydroxy-propoxy} -biphenyl-4-carboxylic acid 4'-cyano-3'-. { (R) -3- [4- (2-Trifluoromethyl-phenyl) -1,1-dimethyl-butylamino] -2-hydroxy-propoxy} -biphenyl-4-carboxylic acid 4'-cyano-3'-. { (R) -3- [4- (3-Trifluoromethoxy-phenyl) -1,1-dimethyl-butylamino] -2-hydroxy-propoxy} -biphenyl-4-carboxylic acid 4'-cyano-3'-. { (R) -3- [4- (2-Fluoro-phenyl) -1,1-dimethyl-butylamino] -2-hydroxy-propoxy} -biphenyl-4-carboxylic acid 3'-. { (R) -3- [2- (4-Bromo-phenyl) -1,1-dimethyl-ethylamino] -2-hydroxy-propoxy} 4'-cyano-biphenyl-4-carboxylic acid 3'-. { (R) -3- [2- (3-Bromo-phenyl) -1,1-dimethyl-ethylamino] -2-hydroxy-propoxy} 4'-cyano-biphenyl-4-carboxylic acid 3'-. { (R) -3- [2- (2-Bromo-phenyl) -1,1-dimethyl-ethylamino] -2-hydroxy-propoxy} 4'-cyano-biphenyl-4-carboxylic acid 3'-. { (R) -3- (2-benzo [1, 3] dioxol-5-yl-1,1-dimethyl-2-ylamino) -2-hydroxy-propoxy] -4'-cyano-biphenyl-4-carboxylic acid 4'-cyano-3 ' - [(R) -3- [1,1-dimethyl-2- (4-ethyl-phenyl) -ethylamino] -2-hydroxy-propoxy} -biphenyl-4-carboxylic acid 4'-cyano-3 '- [(R) -2-hydroxy-3- [2-hydroxy-1,1-dimethyl-2- (6-methyl-pyridine- 2-yl) -ethylamino] -propox! } -biphenyl-4-carboxylic acid 4'-cyano-3'-. { (R) -2-hydroxy-3- [2- (3,4-dimethyl-phenyl) -1,1-dimethyl-ethylamino] -propoxy} -biphenyl carboxylic acid 4'-cyano-3'-. { (R) -2-hydroxy-3- [2- (4-methoxy-3-methyl-phenyl) -1,1-dimethyl-ethylamino] -propoxy} -biphenyl-carboxylic acid 4'-cyano-3'- acid. { (R) -2-hydroxy-3- [2- (4-trifluoromethoxy-phenyl) -1,1-dimethyl-ethylamino] -propoxy} -biphenyl-4-carboxylic acid 4'-cyano-3'-. { (R) -2-hydroxyl-3- [2- (4-isopropyl-phenol) -1,1-dimethylamino] -propoxy} -biphenyl-4-carboxylic acid 3'-. { (R) -3- [4- (3-Chloro-methyl-phenyl) -1,1-dimethyl-butylamino] -2-hydroxy-propoxy} 4'-cyano-biphenyl-4-carboxylic acid 3'-. { (R) -3- [4- (3,4-Dichloro-phenyl) -1,1-dimethyl-butylamino] -2-hydroxy-propoxy} 4'-cyano-biphenyl-4-carboxylic acid 3'-. { (R) -3- [4- (4-Chloro-phenyl) -1,1-dimethyl-butylamino] -2-hydroxy-propoxy} 4'-cyano-biphenyl-4-carboxylic acid 4'-cyano-3'-. { (R) -2-hydroxy-3- [2-hydroxy-1,1-dimethyl-2- (6-methyl-pyridin-2-yl) -eti-amino] -propoxy} -biphenyl-4-carboxylic N- [2R-hydroxy-3- [-] hydrochloride. { 2-cyano-5- (4-carboxyphenyl) phenoxy) propyl] -1,1-dimethyl-2- (indan-2-yl) ethylamine 4'-cyano-3'- acid. { (R) -3- [2- (4-ethyl-3-fluoro-phenyl) -1,1-dimethyl-ethylamino] -2-hydroxy-propoxy} -biphenyl-4-carboxylic acid 4'-cyano-3'-. { (R) -3- [2- (4-etl-2-fluoro-phenyl) -1,1-dimethyl-ethylamino] -2-hydroxy-propoxy} -biphenyl-4-carboxylic acid 4'-cyano-3'-. { (R) -3- [4- (4-Fluoro-phenyl) -1,1-dimethyl-butylamino] -2-hydroxy-propoxy} -b-phenyl-4-carboxylic N- [2R-hydroxy-3- [2-cyano-5- (4-carboxyphenyl) phenoxy] propyl] -1,1-dimethyl-2- (indan-5-yl) hydrochloride ethylamine N - [(2R) -hydroxy-3 - [[2-cyano-5 - [[4-carboxy] phenyl] phenoxy] propyl]] - 1,1-dimethyl-2- (hydroxy) - 2- (tetral-6-yl) ethanamine N - [(2R) -hydroxy-3 - [[2-cyano-5- [4-carboxyphenyl] phenoxy] propyl]] - 1,1-dimethyl- 2-thien-3-ylethylamine 4'-cyano-3- acid. { (R) -3- [2- (4-ethyl-3,5-difluoro-phenyl) -1, 1-d-methyl-ethylamino] -2-hydroxy-propoxy} -biphenyl-4-carboxylic acid 4'-cyano-3-. { (R) -3- [2- (4-ethyl-2,6-difluoro-phenyl) -1,1-dimethyl-ethylamino] -2-hydroxy-propoxy} -biphenyl-4-carboxylic acid 4'-cyano-3-. { (R) -3- [2- (4-ethyl-2,5-difluoro-phenyl) -1,1-dimethyl-ethylamino] -2-hydroxy-propoxy} -phenyl-4-carboxylic acid salt of 3-fluoroacetate. { (S) -3- [2- (5-chloro-thiophen-2-yl) -1,1-dimethyl-ethylamino] -2-hydroxy-propoxy} 4'-cyano-biphenyl-4-carboxylic acid 4'-cyano-3'-. { (R) -2-hydroxy-3- [2- (4-methoxy-phenyl) -1,1-dimethyl-ethylamino] -propoxy} -biphenyl-4-carboxylic acid The most preferred compounds in the present invention are selected from the group consisting of: N- [2R-hydroxy-3 - [[2-cyano-5- [4-carboxyl] phenyl] hydrochloride ] phenoxy] propyl] -1,1-dimethyl-2- (4-fluorophenyl) ethylamine 4'-cyano-3'- acid. { (R) -3- [1,1-Dimethyl-2- (5,6,7,8-tetrahydro-naphthalen-2-yl) -ethylamino] -2-hydroxy-propoxy} -biphenyl-4-carboxylic acid 4'-cyano-3'-. { (R) -3- [2- (Decahydro-naphthalen-2-yl) -1, 1-dimethyl-ethylamino] -2-hydroxy-propoxy} -biphenyl-4-carboxylic acid 3 '- [(R) -3- (2-benzo [b] thiophen-2-yl-dimethyl-ethylamino) -2-hydroxy-propoxy] -4'-cyano-biphenyl-4 -carboxylic acid 4'-cyano-3'-. { (R) -2-hydroxy-3- [4- (2-methoxy-phenyl]) -1,1-d-methyl-butylamino] -propoxy} -biphenyl-4-carboxylic acid 4'-cyano-3'-. { (R) -2-hydroxy-3- [4-phenyl-1,1-d-methyl-butyl-lane] -propoxy} -biphenyl-4-carboxylic acid 3 '- [(R) -3- (2-benzo [b] thiophen-3-yl-1,1-dimethyl-ethylamino) -2-hydroxy-propoxy] -4'-cyano -biphenyl-4-carboxylic N- [2R-hydroxy-3 - [[2-cyano-5 - [[4-carboxyl] phenyl] phenoxy] propyl]] - 1, 1-d-methy hydrochloride l-2- (5-chlorothienyl) et-alamine 4'-cyano-3'- acid. { (R) -2-hydroxy-3- [2- (3-methoxy-pheny] -1, 1-dimethyl-ethylamino] -propoxy} -biphenyl-4-carboxylic acid 3'-. { (R) -3- [2- (4-tert-butyl-phenyl) -1,1-d-methy1-ethylamino] -2-hydroxy-propoxy} 4'-cyano-biphenyl-4-carboxylic acid 4'-cyano-3'-. { (R) -3- [2- (4-Ethoxy-phenyl) -1,1-dimethylamino] -2-hydroxy-propoxy} -biphenyl-4-carboxylic acid hydrochloride (R) - [[1, 1-dimethyl-2- (4-methylthienyl) ethylamino] -2-hydroxyOxypropyloxy] -3- (4-cyanobiphenyl-4'-carboxylic acid) Hydrochloride of acid (R) - [[1,1-dimethyl-2] - (t-inyl) et.lamino] -2-hydroxypropyloxy] -3- (4-cyanobiphenyl-4'-carboxylic acid) Hydrochloride of (R) - [[1,1-dimethyl-2- (5- methylthienyl) ethylamino] -2-hydroxypropyloxy] -3- (4-cyanobiphenyl-4'-carboxylic acid) 4'-cyano-3'- acid. { (R) -2-hydroxy-3- [4- (2-methyl-phenyl) -1,1-dimethyl-butylamino] -propoxy} -biphenyl-4-carboxylic acid 4'-cyano-3'-. { (R) -3- [1,1-Dimethyl-2- (4-methylsulfanyl-phenyl) -ethylamino] -2-hydroxy-propoxy} -biphenyl-4-carboxylic acid 4'-cyano-3'-. { (R) -3- [1,1-dimethyl-2- (3,4-dichloro-pheny] -ethylamino] -2-hydroxy-propoxy} -biphenyl-4-carboxylic acid 4'-cyano-3'-. { (R) -3- [4- (2-Chloro-phenyl) -1,1-d-methyl-butylamino] -2-hydroxy-propoxy} -biphenyl-4-carboxylic acid 4'-cyano-3'-. { (R) -3- [4- (3-methoxy-phenyl) -1,1-dimethyl-butylamino] -2-hydroxy-propoxy} -biphenyl-4-carboxylic acid 4'-cyano-3'-. { (R) -3- [4- (2-Trifluoromethyl-phenyl) -1,1-dimethyl-butylamino] -2-hydroxy-propoxy} -biphenyl-4-carboxylic acid 4'-cyano-3'- acid. { (R) -3- [4- (3-Trifluoromethoxy-phenyl) -1,1-dimethyl-butylamino] -2-hydroxy-propoxy} β-phenyl-4-carboxylic acid 4, -cyano-3'-. { (R) -3- [4- (2-Fluoro-phenyl) -1,1-dimethyl-butylamino] -2-hydroxy-propoxy} β-phenyl-4-carboxylic acid 3'-. { (R) -3- [2- (4-Bromo-phenyl) -1,1-dimethyl-ethylamino] -2-hydroxy-propoxy} 4'-cyano-biphenyl-4-carboxylic acid 3'-. { (R) -3- [2- (3-Bromo-phenyl) -1,1-dimethyl-ethylamino] -2-hydroxy-propoxy} 4'-cyano-b-phenyl-4-carboxylic acid 3'-. { (R) -3- [2- (2-Bromo-phenyl) -1,1-dimethyl-ethylamino] -2-hydroxy-propoxy} 4'-cyano-biphenyl-4-carboxylic acid 3 '- [(R) -3- (2-Benzo [1,3] dioxyol-5-yl-1,1-dimethyl-ethylamino) -2-hydroxy- propoxy] -4'-cyano-b-phenyl-4-carboxylic acid 4'-cyano-3'- acid. { (R) -3- [1,1-Dimethyl-2- (4-etl-phenyl) -ethylamino] -2-hydroxy-propoxy} -biphenyl-4-carboxylic acid 4'-cyano-3'-. { (R) -2-hydroxy-3- [2- (3,4-dimethyl-pheny] -1, 1-d-methyl-ethylamino] -propoxy} -biphenyl carboxylic acid 4'-cyano-3'-. { (R) -2-hydroxy-3- [2- (4-methoxy-3-methyl-phenyl) -1,1-dimethyl-ethylamino] -propoxy} -biphenyl carboxylic acid 4'-cyano-3'-. { (R) -2-hydroxy-3- [2- (4-trifluoromethoxy-phenyl) -1,1-dimethyl-ethylamino] -propoxy} -biphenyl-4-carboxylic acid 4'-cyano-3'-. { (R) -2-Hydroxy-3- [2- (4-isopropyl-phenyl) -1,1-dimethyl-ethylamino] -propoxy} -biphenyl-4-carboxylic acid 3'-. { (R) -3- [4- (3-Chloro-4-methyl-phenyl) -1,1-dimethyl-butylamino] -2-hydroxy-propoxy} 4'-cyano-biphenyl-4-carboxylic acid 3'-. { (R) -3- [4- (3,4-Dichloro-phenyl) -1,1-dimethyl-butylamino] -2-hydroxy-propoxy} 4'-cyano-biphenyl-4-carboxylic acid 3'-. { (R) -3- [4- (4-Chloro-phenyl) -1,1-dimethyl-butylamino] -2-hydroxy-propoxy} 4'-cyano-biphenyl-4-carboxylic N- [2R-Hydroxy-3- [-] hydrochloride. { 2 cyano-5- (4-carboxyphenyl) phenoxy) propyl] -1,1-dimethyl-2- (indan-2-yl) ethylamine 4'-cyano-3'- acid. { (R) -3- [2- (4-ethyl-3-fluoro-phenyl) -1, 1-dimethyl-ethylamino] -2-hydroxy-propoxy} -biphenyl-4-carboxylic acid 4'-cyano-3'-. { (R) -3- [2- (4-ethyl-2-fluoro-phenyl) -1, 1-d-methyl-ethylamino] -2-hydroxy-propoxy} -biphenyl-4-carboxylic acid 4'-cyano-3'-. { (R) -3- [4- (4-Fluoro-phenyl) -1, 1-dimethyl-butylamino] -2-hydroxy-propoxy} -biphenyl-4-carboxylic N- [2R-Hydroxy-3- [2-cyano-5- (4-carboxyphenyl) phenoxy] propyl] -1,1-dimethyl-2- (indan-5-yl) hydrochloride Ethylamine N - [(2R) -Hydroxy-3 - [[2-cyano-5 - [[4-carboxy] phenyl] phenoxy] propyl]] - 1,1-dimethyl-2- (hydroxy) -2 - (tetral-6-yl) ethylamine N - [(2R) -Hydroxy-3 - [[2-cyano-5- [4-carboxylphenyl] phenoxy] propyl]] - 1,1-dimethyl-2-thien-3 Ethylethylamine 4'-cyano-3'- acid. { (R) -3- [2- (4-ethyl-3,5-d.fluoro-phenyl) -1,1-dimethyl-ethylamino] -2-hydroxy-propoxy} -biphenyl-4-carboxylic acid 4'-cyano-3'- acid. { (R) -3- [2- (4-ethyl-2,6-difluoro-phenyl) -1,1-dimethyl-ethylamino] -2-hydroxy-propoxy} -biphenyl-4-carboxylic acid 4'-cyano-3'-. { (R) -3- [2- (4-ethyl-2,5-difluoro-phenyl) -1,1-dimethyl-ethylamino] -2-hydroxy-propoxy} -biphenyl-4-carboxylic acid 3- trifluoroacetate salt. { (S) -3- [2- (5-Chloro-thiophen-2-yl) -1,1-dimethyl-ethylamino] -2-hydroxy-propoxy} 4'-cyano-b-phenyl-4-carboxylic acid 4'-cyano-3'-. { (R) -2-hydroxy-3- [2- (4-methoxy-phenyl) -1,1-dimethylamino] -propoxy} -biphenyl-4-carboxylic N- [2R-Hydroxy-3- [2-cyano-5- [2-carbethoxyphenyl] phenoxy] propyl] -1-hydrochloride, 1-dimethyl-2- (2-naphthyl) ethylamine N- [2R-Hydroxy-3- [2-cyano-5- [4-carbethoxyphenyl] phenoxy] propyl] -1, 1-d-methyl-2 hydrochloride - (2-naphthyl) ethylamine N- [2R-Hydroxy-3 - [[2-cyano-5 - [[4-carboxy] phenyl] phenoxy] propyl] -1, 1-dimethyl- hydrochloride 2- [naphthyl] ethylamine N- [2R-Hydroxy-3 - [[2-cyano-4- [4-carboxyphenyl] phenoxy] propyl] -1, 1-dimethyl-2- (2-hydrochloride Naphthyl) Ethylamine N- [2R-Hydroxy-3 - [[2-cyano-4- [carbethoxyphenyl] phenoxy] propyl] -1, 1-dimethyl-2- (2-naphthyl) ethylamine hydrochloride N- hydrochloride [2R-Hydroxy-3 - [[2-cyano-4- [2-formylphenyl] phenoxy] propyl] -1,1-dimethyl-2- (naphthyl) ethylamine N- [2R-Hydroxy-3-] hydrochloride [[2-cyano-4- [3-formylphenyl] phenoxy] propyl] -1,1-dimethyl-2- (naphthyl) ethylamine N- [2R-Hydroxy-3 - [[2-cyano-4] hydrochloride - [[3- [hydroxymethyl] phenyl] phenoxy] propyl] -1,1-dimethyl-2- (naphthyl) ethylamine N- [2R-Hydroxy-3 - [[2-cyano-4 - [[ 2-hydroxymethylphenyl] phenoxy] propyl] -1,1-dimethyl-2- (2-naphthyl) ethylamine N- [2R-Hydroxy-3 - [[2-cyano-4 - [[3-]] hydrochloride [[etil] ca rboxyl]] phenyl] phenoxy] propyl] -1, 1 -dimethyl-2- (2-naphthyl) ethylamine N- [2R-Hydroxy-3- [2-cyano-4- [3-carboxyphenyl] phenoxy] hydrochloride ] propyl]] - 1, 1 -dimetii-2- (2-naphthyl) ethylamine and N- [2R-Hydroxy-3- [2-cyano-4- (2-carboxyphenyl) phenoxy] propyl] -1 hydrochloride, 1-dimethyl-2- (2-naphthyl) ethylamine. The pharmaceutically acceptable salts are non-toxic salts in the amounts and concentrations in which they are administered. The pharmaceutically acceptable salts include acid addition salts such as those containing sulfate, hydrochloride, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexyl sulfonate and quinate.
A preferred salt is a hydrochloride. Pharmaceutically acceptable salts can be obtained from acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, acid p-toluenesulfonic acid, cyclohexylsuiphamic acid, fumaric acid and quinic acid. Pharmaceutically acceptable salts also include basic addition salts such as those containing benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamine and zinc, when present Acidic functional groups, such as carboxylic acid or phenol. The present invention provides compounds of formula (I) above, which can be prepared using standard techniques. A comprehensive strategy for preparing preferred compounds described herein can be carried out as described in this section. The following examples illustrate the synthesis of specific compounds. By using the protocols described herein as a model, one skilled in the art can easily produce other compounds of the present invention. All reagents and solvents were obtained from commercial suppliers. The starting materials (e.g., amines and epoxides) were synthesized using standard techniques and procedures. The compound of formula I was prepared by general methods described in schemes 1, 2 and 3. A general procedure used to synthesize many of the compounds was carried out as follows. For example, the treatment of 2-Fluoro-4-bromobenzonitrile with potassium acetate in refluxing acetonitrile produces the corresponding phenol after saponification of the resulting acetate (see scheme 1). The Suzuki coupling of the bromohalide with a duly substituted boronic acid as in Scheme I leads to the formation of the corresponding biphenylcarboxy derivative which can be converted to the corresponding ester under standard conditions. Alternatively, the Suzuki coupling can be carried out with a duly substituted formylboronic acid as described in scheme 2, then the 4-formyl biphenyl analog can be oxidized under standard conditions and transformed into the corresponding ethyl ester. A solution in aryl alcohol such as 1 -scheme 1 or 5-scheme 2 in acetone is treated with K2CO3 heated for 15 minutes. R-glycidyl nosylate is added and the reaction is continued overnight to give the corresponding aryloxy epoxide such as 2-scheme 1. A solution of a glycidyl ether such as 2-scheme 1, and excess amine (usually 1.1). dimethyl-2- (2-naphthyl) ethylamine) in absolute alcohol (2 mL), acetonitrile, THF or any other similar solvent in the presence of a suitable catalyst such as LiCIO4 (1-2 mmol) is stirred overnight at reflux . The product, such as 3-scheme 1, is purified by normal phase chromatography. Hydrochloride salts were prepared by treating the corresponding free base with HCl either in gas phase or in 4M dioxane solution, or any other standard method.
SCHEME 1
SCHEME 2
Alternatively, the claimed compounds can also be synthesized by the route described in scheme 3. Selective bromination in the para-position of 2-cyanophenol can be carried out for example, through the reaction of N-bromosuccinimide in the presence of an acid such as fluoroboric acid, or any other suitable protic acid, in a solvent such as acetonitrile or any other suitable solvent, following a procedure described in the literature (Oberhauser, TJ Org. Chem., 1997, 62, 4504-4506). The formation of the corresponding aminoalcohol 6 can then be carried out by following the reaction sequence described in scheme 1. The Suzuki coupling of 6-scheme 3 with a duly substituted formylboronic acid or carboxyboronic acid would lead to the corresponding formyl biphenyl compound 7-scheme 3. In contrast, 7-scheme can be converted to the corresponding carboxy derivatives as described in scheme 2 or to the corresponding alcohol by reduction with sodium borohydride as described in scheme 3.
SCHEME 3
Nuclear magnetic resonance spectra were recorded at either 250 or 400 MHz using, respectively, a Bruker AM 250 or Bruker AC 400 spectrometer. CDCI3 is deuteriochloroform, DMSO-d6 is hexadeuteriodimethyl sulfoxide, and CD3OD is tetradeuteriomethanol. Chemical changes are reported in parts per million (?) Downstream of the internal standard tetramethylsilane. The abbreviations for 1 H-NMR data are as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = double of doublets, dt = double of triplets, app = apparent, br = broad. J indicates the coupling constant of 1 H-NMR measured in Hertz. The continuous-wave infrared (IR) spectra were recorded on a Perkin-Elmer 683 infrared spectrometer and the Fourier transform infrared spectra (FTIR) were recorded on a Nicolet Impact 400 D infrared spectrometer. The IR and FTIR spectra are recorded at transmission mode, and band positions were reported in inverse wave numbers (cm "1). Mass spectra were taken either in instruments VG 70 FE, PE Syx API lll, or VG ZAB HF, using bombing techniques Rapid Atoms (FAB) or Electrospray Ionization (ES) Elemental analyzes were obtained using a Perkin-Elmer 240C elemental analyzer.The melting points were taken on a Thomas-Hoover melting point apparatus and are not corrected. All temperatures are reported in Ceisius grades, Analtech Silica Gel GF and E. Merck Silica Gel 60 F-254 thin-film plates were used for thin-layer chromatography. a and gravity were performed on silica gel E. Merck Kieselgel 60 (230-400 mesh). The analytical and preparation HPLC was performed on Rainin or Beckman chromatographs. ODS refers to a chromatographic support of silica gel derived from octadecylsilyl. Apex-ODS of 5 μ indicates a silica gel chromatographic support derived from octadecylsilyl having a nominal particle size of 5 μ, made by Jones Chromatography, Littieton, Colorado. YMC ODS-AQ® is an ODS chromatographic support and is a registered trademark of YMC Co. Ltd., Kyoto, Japan. PRP-1® is a polymeric chromatographic support (styrene-divinylbenzene) and is a registered trademark of Hamilton Co., Reno, Nevada. Celite® is a filter aid composed of diatomaceous silica washed with acid, and is a registered trademark of Manville Corp., Denver, Colorado. With the proper handling and protection of any chemical functionality, the synthesis of the remaining compounds of formula (I) is carried out by methods analogous to the above and those described in the experimental section. In order to use a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment of humans and other mammals, it is usually formulated in accordance with standard pharmaceutical practices as a pharmaceutical composition. Calcilytic compounds can be administered by different routes including intravenous, intraperitoneal, subcutaneous, intramuscular, oral, topical (transdermal), or mucosal administration. For systemic administration, oral administration is preferred. For oral administration, for example, the compounds can be formulated in conventional oral dosage forms such as capsules, tablets and liquid preparations such as syrups, elixirs and concentrated drops. Alternatively, injection (parenteral administration) for example, intramuscular, intravenous, intraperitoneal and subcutaneous can be used. For injection, the compounds of the invention are formulated in liquid solutions, preferably in physiologically compatible solutions or pH regulators such as saline solution, Hank's solution or Ringer's solution. In addition, the compounds can be formulated in solid form and can be redissolved or suspended immediately before use. The lyophilized forms can also be produced. Systemic administration can also be by transdermal means or through the mucosa. For transdermal or mucosal administration, appropriate penetrants are used in the formulation for the barrier that will be permeated. Such penetrants are generally known in the art and include, for example, for administration through the mucosa, bile salts and fusidic acid derivatives. In addition, detergents can be used to facilitate penetration. The administration through the mucosa, for example, can be by nasal sprays, rectal suppositories or vaginal suppositories. For topical administration, the compounds of the invention can be formulated in ointments, gels or creams, as is generally known in the art.
The amounts of different calcilytic compounds that will be administered can be determined through standard procedures that consider factors such as compound IC50, EC50, the biological half-life of the compound, the age, size and weight of the patient, and the associated disease or condition. with the patient The importance of these and other factors to be considered are known to those skilled in the art. The amounts administered also depend on the routes of administration and the degree of oral bioavailability. For example, for compounds with low oral bioavailability, relatively higher doses will have to be administered. Preferably, the composition is in unit dosage form. For oral application, for example, a tablet or capsule may be administered, for nasal application, a metered dose of aerosol may be administered, for transdermal application, a topical formulation or patch may be administered; and for delivery through the mucosa, a buccal patch can be administered. In each case, the dosage is such that the patient can administer a single dose. Each dosage unit for oral administration contains suitably from 0.01 to 500 mg / kg, and preferably from 0.1 to 50 mg / kg, of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the free base . The daily dosage for parenteral, nasal, oral inhalation, transdermal or mucosal routes contains 0.01 mg to 100 mg / kg of a compound of formula (I). A topical formulation suitably contains 0.01 to 5.0% of a compound of formula (I). The active ingredient can be administered from 1 to 6 times a day, preferably once, sufficient to present the desired activity, as is readily apparent to one skilled in the art. As used herein, "treatment" of a disease includes, but is not limited to prevention, delay and prophylaxis of the disease. Diseases and disorders that can be treated or prevented, based on the affected cells, include diseases or disorders related to bones and minerals; hypoparathyroidism; those of the central nervous system such as seizures, stroke, brain trauma, damage to the spinal cord, nerve cell damage induced by hypoxia, such as in cardiac arrest or neonatal suffering, epilepsy, neurodegenerative diseases such as Alzheimer's disease, Huntington and Parkinson's disease, dementia, muscle tension, depression, anxiety, panic disorder, obsessive-compulsive disorder, post-traumatic stress disorder, schizophrenia, neuroleptic malignant syndrome and Tourette syndrome; diseases involving excessive water reabsorption by the kidney, such as syndrome of inappropriate ADH secretion (SIADH) cirrhosis, congestive heart failure and nephrosis; hypertension; prevention and / or reduction of renal toxicity from cationic antibiotics (for example, aminoglycoside antibiotics); bowel motility disorders such as diarrhea and spastic colons; ulcer diseases Gl; Gl diseases with excessive calcium absorption such as sarcoidosis; autoimmune diseases and organ transplant rejection; squamous cell carcinoma and pancreatitis. In a preferred embodiment of the present invention, the compounds are used to increase serum parathyroid hormone ("PTH") levels. The increase of serum PTH levels can be useful in the treatment of diseases such as hypoparathyroidism, osteosarcoma, periodontal disease, fracture, osteoarthritis, rheumatoid arthritis, Paget's disease, humoral hypercalcemia, malignancy and osteoporosis. Another aspect of the present invention describes a method for treating a patient comprising administering to the patient an amount of a compound of the present invention sufficient to increase the serum PTH level. Preferably, the method is performed by administering a quantity of the effective compound to cause an increase in duration and / or amount of serum PTH level sufficient to have a therapeutic effect. In different embodiments, the compound administered to a patient causes an increase in serum PTH that lasts for up to one hour, approximately one to approximately twenty-four hours, close to one to approximately twelve hours, from one to approximately six hours, of a at about five hours, from one to about four hours, from two to about five hours, from two to about four hours or from three to about six hours. In different additional modalities, the compound administered to a patient causes an increase in serum PTH of up to two times, two to five times, five to ten times, and at least ten times, greater than the maximum PTH in serum in the patient . The maximum level of serum is measured with respect to a patient not subjected to treatment. The composition of formula (I) and its pharmaceutically acceptable salts which are active when given orally can be formulated as syrups, tablets, capsules and lozenges. A syrup formulation will usually consist of a suspension or solution of the compound or salt in a liquid carrier for example, ethanol, arachis oil, olive oil, glycerin or water with a flavoring or coloring agent. When the composition is in the form of a tablet, any pharmaceutical vehicle routinely used to prepare solid formulations can be used. Examples of such carriers include magnesium stearate, magnesia, talc, gelatin, acacia, stearic acid, starch, lactose and sucrose. When the composition is in the form of a capsule, any routine encapsulation is suitable, for example using the aforementioned vehicles in a hard gelatin capsule shell. When the composition is in the form of a soft gelatin capsule shell, any pharmaceutical carrier used routinely to prepare dispersions or suspensions, for example aqueous gums, celluloses, silicates or oils, can be considered and incorporated into a capsule shell of soft gelatin Typical parenteral compositions consist of a solution or suspension of a compound or salt in a sterile aqueous or non-aqueous carrier optionally containing a parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil, or sesame oil. Typical compositions for inhalation are in the form of a solution, suspension or emulsion which can be administered as a dry powder or in the form of an aerosol using a conventional propellant such as dichlorodifluoromethane or trichlorofluoromethane. A typical suppository formulation comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is activated when administered in this manner, with a binder and / or lubricant, for example polymeric glycols, gelatins, shortening cocoa or other low-melting vegetable waxes or fats or their synthetic analogues. Typical transdermal or dermal formulations comprise a conventional aqueous or non-aqueous vehicle, for example, a cream, ointment, lotion or paste or are in the form of a medicated plaster, patch or membrane. Preferably, the composition is in unit dosage form, for example a tablet, capsule or metered dose of aerosol, so that the patient can administer a single dose. Unacceptable toxicological effects are not expected when the compounds of the present invention are administered according to the same. The biological activity of the compounds of formula (I) is demonstrated by the following tests: (I) Calcium receptor inhibitor test Calcilytic activity was measured by determining the IC5o of the test compound to block intracellular IC50 increases produced by Ca2 + extracellular in HEK 293 4.0-7 cells that stably express the human calcium receptor. HEK 293 4.0-7 cells were constructed as described in Rogers et al., J. Bone Miner. Res. 10 Suppl. 1: S483, 1995 (incorporated herein by reference). Increases in intracellular Ca2 + occurred by increasing extracellular Ca2 + from 1 to 1.75 mM. Intracellular Ca2 + was measured using fluo-3, a fluorescent calcium indicator. The procedure was as follows: 1. Cells were maintained in T-150 flasks in selection media (DMEM supplemented with 10% fetal bovine serum and 200 ug / mL hygromycin B), under 5% CO2: 95% air at 37 ° C and were grown up to 90% confluence. 2. The medium was decanted and the cell monolayer was washed twice with phosphate buffered saline (PBS) maintained at 37 ° C. After the second wash, 6 mL of 0.02% EDTA in PBS was added and incubated for 4 minutes at 37 ° C. After incubation, the cells were dispersed by uniform agitation. 3. Cells of 2 or 3 flasks were mixed and pelleted (100 x g). The cell pellet was resuspended in 10-15 mL of SPF-PCB + and pelletized again by centrifugation. This washing was done twice.
The sulfate and phosphate free parathyroid cell pH regulator (SPF-PCB) contains 20 mM Na-Hepes, pH 7.4, 126 mM NaCl! 5 mM KCl, and 1 mM MgCl2. SPF-PCB was formed and stored at 4 ° C. On the day of use, SPF-PCB was supplemented with 1 mg / mL of D-glucose and 1 mM of CaCl2 and then divided into two fractions. To a fraction, serum albumin --- of bovine (BSA, fraction V, ICN) was added at 5mg / mL (SPF-PCB +). This pH regulator was used for washing, loading and maintaining the cells. The free fraction of BSA was used to dilute the cells in the tube for fluorescence measurements. 4. The pellet was resuspended in 10 mL of SPF-PCB + containing 2.2 μM of fluo-3 (Molecular Probes) and incubated at room temperature during
minutes. 5. After the incubation period, the cells were pelleted by centrifugation. The resulting pellet was washed with SPF-PCB +. After this washing, the cells were resuspended in SPF-PCB + at a density of 1 -2 x 10 6 cells / mL. 6. To record fluorescent signals, 300 μL of cell suspension was diluted in 1.2 μL of SPF pH buffer containing 1 mM of CaCl2 and 1 mg / mL of D-glucose. Fluorescence measurements were made at 37 ° C with constant agitation using a specofluorimeter. The excitation and emission wavelengths were measured at 485 and 535 nm, respectively. To calibrate the fluorescence signals, digitonin (5 mg / mL in ethanol) was added to obtain Fmax, and the apparent Fmin was determined by adding Tris-EGTA (2.5 M Tris-Base, 0.3 M EGTA). The intracellular calcium concentration was calculated using the following equation: Intracellular Calcium = (F-Fm, n / Fma?) X Kd; where Kd = 400 nM. 7. To determine the potential calcilytic activity of the test compounds, the cells were incubated with the test compound (or vehicle as a control) for 90 seconds before increasing the extracellular Ca + concentration from 1 to 2 mM. Calcilytic compounds were detected by their ability to block, in a manner dependent on concentration, increases in the intracellular Ca2 + concentration produced by extracellular Ca2 +. In general, those compounds that have IC values or lower in the Calcium Receptor Inhibitor Test are the most preferred compounds. Compounds having an IC50 greater than 50 μM were considered inactive. Preferred compounds are those having an IC 50 of 10 μM or less, most preferred compounds have an IC 50 of 1 μM, and most preferred compounds have an IC 50 of 0.1 μM or less.
(II) Calcium receptor binding test HEK 293 4.0-7 cells stably transfected with the Human Parathyroid Calcium Receptor ("HuPCaR") progressively increased in T180 tissue culture flasks. The plasma membrane is obtained by homogenization of Dounce polytron or homogenizer in pH buffer (50mM Tris-HCl pH 7.4, 1mM EDTA, 3mM MgCl2) in the presence of a variety of protease inhibitors containing 1 μM Leupeptin, 0.04 μM Pepstatin, and 1 mM PMSF. The membrane distributed in aliquots was frozen with crepitation and stored at -80 ° C. The compound labeled with 3H was radiolabeled for a radio-specific activity of 44 Ci / mmoles and was aliquoted and stored in liquid nitrogen for radiochemical stability. A typical reaction mixture contains 2 nM of compound 3H ((R; R) -N-4'-Methoxy-t-3-3'-methy1-1-ethylphenyl-1- (1 -naphthyl) ethylamine), or compound 3H (R) -N- [2-Hydroxy-3- (3-chloro-2-cyanophenoxy) propyl] -1, 1-d, methyl-2- (4-methoxyphenyl) et Membrane sheet of 4-10 μg in homogenization pH regulator containing 0.1% gelatin and 10% EtOH in a reaction volume of 0.5 mL. Incubation is carried out in 12 x 75 polyethylene tubes in an ice water bath. To each tube is added 25 μL of the test sample in 100% EtOH, followed by 400 μL of pH buffer of cold incubation and 25 μL of 40 nM of compound 3H in 100% EtOH for a final concentration of 2nM. The binding reaction is initiated by the addition of 50 μL of 80-200 μg / mL HEK 293 in a 4.0-7 membrane diluted in pH buffer of incubation, and allowed to incubate at 4 ° C for 30 minutes. The regular wash pH is 50 mM Tris-HCl containing 0.1% PEI. Non-specific binding is determined by the addition of 100-fold excess unlabelled homologous ligand, and is generally 20% of the total binding. The binding reaction is terminated by rapid filtration on GF / C filters pretreated with 1% PEI using a Brandel Harvestor. The filters are placed in scintillation fluid and the radioactivity is evaluated by liquid scintillation counting.
The following examples are illustrative of the present invention but are not intended in any way to limit it.
EXAMPLE 1 N-r2R-hydroxy-3-IT2-cyano-5-T4-ethylcarboxyfenfenphenoxypropropin-1,1-dimethyl-2- (2-naphthyl) ethylamine hydrochloride
a) 2-Hydroxyl-4-bromobenzonitrile A mixture of 2-fluoro-5-bromovenzonitrile (30 g, 152.3 mmol), potassium acetate (222.4 g, 228.5 mmol), and 10-crown-6 ether (60.4 g, 288.5 mmole) in MeCN (400mL) was heated to reflux in 36 hours. The mixture was cooled, 2.5N NaOH (200 mL) was added, stirred at room temperature overnight. The mixture was extracted with ether (discarded). The aqueous layer was acidified with 6N HCl, extracted with EtOAc, dried over MgSO4, concentrated, purified by flash column chromatography (40% EtOAc / Hex) to give a clear yellow foam (24.45g, 81%). 1 H-NMR (300 Hz, DMSO-d 6): d 7.13 (dd, J = 1.7, 8.3 Hz, 1 H), 7.17 (d, J = 1.7 Hz, 1 H), 7.61 (d, J = 8.3 Hz, 1 H).
b) Ethyl-4-yl-3-hydroxyl-4-cyanoglienyl benzoate A mixture of example 1 to (3.0 g, 1.52 mmol), p-carboxylbenzanboronic acid (3.02 g 1.82 mmol), (Ph3P) 4Pd (0.88 g, 0.76 mmol) ), and 2M Na2CO3 (38mL, 7.6 mmol) in toluene / EtOH (60 mL, 4: 1) was heated to reflux in 24 hours. The mixture was cooled, and the layers separated. The aqueous layer was extracted with ether (discarded), acidified with 6N HCl. The tan solid (3.6 g, 99%) was filtered, dried, dissolved in EtOH, and 4M HCl in p-dioxane (20 mL) was added. The resulting mixture was heated to reflux in 24 hours. The mixture was cooled, concentrated, placed in H2O, stirred, filtered and dried off off-white solid (3.75 g, 85%). 1 H-NMR (300 MHz, DMSO-d 6): d 1.32 (t, J = 7.1 Hz, 3 H), 4.34 (q, J = 7.1 Hz, 2 H), 7.29 (s, 1 H), 7.31 (d, J = 8.3 Hz, 1 H), 7.73 (d, J = 8.3 Hz, 1 H), 7.76 (d, J = 8.3 Hz, 2 H), 8.06 (d, J = 8.3 Hz, 2 H).
c) ethyl-4-r [3-rrR-glycidinoxylmethyl] -4-cyano-phenylol benzoate A mixture of example 1b (0.71 g, 2.7 mmol), potassium carbonate (0.73 g 5.3 mmol), and R-glycidyl 3-nitrobenzenesulfonate (0.73 g, 2.8 mmol), in acetone (30 mL) was heated to reflux in 24 hours. The mixture was cooled, concentrated, placed in H2O, extracted with EtOAc. The organic extracts were washed with brine, dried over MgSO0, concentrated to give an off white solid (07 g, 82%). 1 H-NMR (300MHz, DMSO-d 6): d 1.32 (t, J = 7.1 Hz, 3H), 2.78 (dd, J = 2.6, 4.9 Hz, 1 H), 2.91 (t, J = 4.9 Hz, 1 H ), 3.44 (m, 1 H), 4.20 (dd, J = 6.5, 11.7 Hz, 1 H), 4.39 (q, J = 7.1 Hz, 2H), 4.72 (dd, J = 2.6, 11.7 Hz, 1 H ), 7.47 (dd, J = 1.4, 8 Hz, 1 H), 7.57 (d, J = 1.4 Hz, 1 H), 7.85 (d, J = 8 Hz, 1 H) 7.95 (d, J = 8.5 Hz , 1 H), 8.08 (d, J = 8.5 Hz, 1 H).
d) N-r2R-Hydroxy-3-rr2-cyano-5-rr4-ethylcarboxy1feninphenoxopropin-1,1-dimethyl-2- (2-naphthylpentamine hydrochloride A mixture of example 1c (0.5 g, 1.5 mmoles), lithium perchlorate (0.34 g, 1.7 mmol), and 1,1-dimethyl-2-naphthyl-ethylamine (0-43 g, 3.1 mmol) in dry MeCN (15 mL) was heated to reflux in 24 h. The mixture was cooled, concentrated, placed in H20, extracted with CH2Cl2, the organic extracts were washed with brine, dried over MgSO4, concentrated, purified by flash column chromatography (3% MeOH / CH2Cl2) to give a whitish foam which was dissolved in p-dioxane, and 4M HCl in p-dioxane was added, concentrated, and triturated in ether to give the desired product as an off-white solid (0.65 g, 80%). (300MHz, DMSO-d6): d 1.25 (s, 6H), 1.32 (t, J = 7.6 Hz, 3H), 3.25 (s, 3H), 3.42 (m, 2H), 4.35 (m, 3H), 6.12 (d, J = 4.6 Hz, 1 H), 7.46 (m, 5H), 7.78 (s, 1 H), 7.93 (m, 5H), 8.01 (d, J = 8.6 Hz, 1 H), 8.10 (dd) , J = 1. 3, 8.6 Hz, 1 H), 8.21 (s, 1 H), 8.82 (t, J = 8 Hz, 1 H), 9.23 (t, J = 8 Hz, 1 H). MS (m / z): 523.6 (M +).
EXAMPLE 2 N-r2R-Hydroxy-3-rr2-cyano-5-rr4-carboxH1-phenylphenoxypropyl-1,1-dimethyl-2- (2-naphthyl) ethylamine hydrochloride
N-f2R-hydroxy-3-rr2-cyano-5-r4-carboxyfenfenfenoxopropyl-1,1-dimethyl-2- (2-naphthyl) ethylamine hydrochloride To a stirred solution of Example 1d (0.3 g, 0.57 mmole) in p-dioxane (10 ml) was added 2.5N NaOH, and stirred overnight. The mixture was concentrated, placed in H20, acidified with 2N HCl to pH = 4. The whitish solid was filtered. The solid was dissolved in MeOH and 4M HCl in p-dioxane was added, concentrated to give an off-white solid (0.28 g, 100%). 1 H-NMR (300 MHz, DMSO-d 6): d 1.25 (s, 6H), 3.12 (s, 2H), 3.25 (m, 4H), 4.35 (s, 2H), 7.45 (m, 4H), 7.80 ( m, 6H), 8.05 (m, 3H), 8.21 (s, 1 H). MS (m / z): 495.4 (M +).
EXAMPLE 3 N-r 2 R -hydroxy-3-rr 2 -cyano-5-rr 2 -ethoxycarbonylfeninphenoxylpropin-1,1-dimethyl-2- (2-naphthyl) ethylamine hydrochloride
a) 2-R 3 -hydroxy-4-cyano-phenylbenzaldehyde A mixture of example 1a (1.0 g, 5.05 mmol), 2-formylbenzeneboronic acid (0.91 g, 6.06 mmol), (Ph3P) 4Pd (0.3 g, 0.26 mmol) ), and 2M Na2CO3 (10 mL, 25.3 mmol) in toluene / EtOH (20 mL, 4: 1) was heated to reflux in 24 hours. The mixture was cooled, and the layers separated. The aqueous layer was extracted with ether (discarded), acidified with 6N HCl. The tan solid (1.1 g, 99%) was filtered, dried. 1 H-NMR (300 MHz, DMSO-d 6): d 7.31 (s, 1 H), 7.34 (d, J = 8.3 Hz, 1 H), 7.73 (m, 2 H), 7.96 (m, 2 H), 10.1 ( s, 1 H), 1 1.35 (s, 1 H).
b) Ethyl-2-IT3-hydroxyl-4-cyano1phenylobenzoate] A mixture of example 3a (1.1 g, 5.02 mmol), MnO2 (2.18 g,
. 1 mmole), and KCN (0.07 g, 1.01 mmole) in EtOH (20 ml) was stirred at room temperature in 24 hours. The solid was filtered, and the filtrate was concentrated, placed in H2O, extracted with EtOAc. The organic extracts were washed with brine, dried over MgSO 4, concentrated and purified by flash column chromatography (40% EtOAc / Hex) to give an off white solid (1.3 g, 85%). 1 H NMR (300 MHz, DMSO-d 6): d 1.15 (t, J = 7 Hz, 3H), 4.12 (q, J = 7
Hz, 2H), 6.87 (m, 2H), 7.41 (dd, J = 1.3, 7.6 Hz, 1 H), 7.55 (t, J = 7.6 Hz, 1 H), 7.65
(m, 2H), 7.79 (dd, J = 1.3, 7.6 Hz, 1 H), 1.2 (s, 1 H).
c) Ethyl-2- [r3 [fR-ql-cidinoxpmethyl-4-cyano] phenyl-1-benzoate Following the procedure in Example 1c, the title compound was obtained as a pale yellow solid (0.85 g, 87%). 1 H-NMR (300 MHz, DMSO-d 6): d 1.12 (t, J = 7.1 Hz, 3 H), 2.78 (d, J = 2.6, 4.9 Hz, 1 H), 2.91 (t, J = 4.9 Hz, 1 H), 3.44 (m, 1 H), 4.05 (m, 3H), 4.65 (dd, J = 2.6, 11.7 Hz, 1 H), 6.95 (dd, J = 1.3, 7.6 Hz, 1 H), 7.25 ( s, 1 H), 7.45 (d, J = 7.6 Hz, 1H), 7.65 (t, J = 7.6 Hz, 1 H), 7.72 (t, J = 7.6 Hz, 1 H), 7.76 (d, J = 7.6 Hz, 1 H), 7.83 (d, J = 7.6 Hz, 1 H).
d) N-r 2 R -hydroxy-3-rr 2 -cyano-5-rr 2 -ethoxycarbonylpheninephenoxopropyl] -1, 1-dιmethyl-2- (2-naphthyl) ethylamine hydrochloride Following the procedure of Example 1d, the title compound was obtained as an orange solid (0.65 g, 81%). 1 H-NMR (300 MHz, DMSO-d 6): d 1.12 (t, J = 7.6 Hz, 3H), 1.23 (s, 6H), 2.89 (m, 4H), 3.42 (s, 2H), 3.98 (s, 1 H), 4.12 (q, J = 7.6 Hz, 2H), 4.23 (m, 2H), 6.98 (d, J = 8 Hz, 1 H), 7.21 (s, 1 H), 7.45 (d, J = 7.6 Hz, 1 H), 7.53 (m, 3 H), 7.62 (t, J = 8 Hz, 1 H), 7.75 (m, 2 H), 7.85 (m, 5 H). MS (m / z): 523.4 (M +).
EXAMPLE 4 N-r2R-Hydroxy-3-rr2-cyano-5- [T2-carboxypheniphenoxppropip-1A-dimethyl-2- (2-naphthyl) ethylamine hydrochloride]
Following the procedure of example 1e, compound 4d was converted to the title compound and obtained as an off-white solid (0.05 g, 69%).
1 H-NMR (300 MHz, DMSO-d 6): d 1.23 (s, 6H), 2.89 (m, 4H), 3.42 (s, 2H), 3.98 (s, 1 H), 4.23 (m, 2H), 6.98 (d, J = 8 Hz, 1 H), 7.21 (s, 1 H), 7.45 (d, J = 7.6 Hz, 1 H), 7.53 (m, 3 H), 7.62 (t, J = 8 Hz, 1 H), 7.75 (m, 2H), 7.85 (m, 5H). MS (m / z): 495.4 (M +).
EXAMPLE 5 N-r2R-hydroxy-3-rr2-cyano-4-rr4-carbethoxyphenyl-1-phenoxy-propion-1,1-dimethyl-2- (2-naphthyl) ethylamine hydrochloride
a) 2- Hydroxy-5-bromobenzonitrile To a stirred, cooled (-20 ° C) solution of 2-cyanophenol (30 g, 252 mmol) in dry MeCN (400 ml) was added HBF4.Et2O (45 g, 277.1 mmol ), and N-bromosuccinimide (53.8 g, 302.3 mmol). After the addition was completed, the mixture was warmed to room temperature and stirred in 4 hours. The mixture was cooled and quenched by 50% aqueous NaHS03. The mixture was concentrated to remove excess MeCN. The whitish solid thus obtained was filtered and dried by air (42.4 g, 85%). 1 H-NMR (300 MHz, DMSO-d 6): d 6.99 (d, J = 8.9 Hz, 1 H), 7.67 (d, J = 2.5, 8.9 Hz, 1 H), 7.88 (d, J = 2.5 Hz, 1 HOUR).
b) 2 - [[R-Glycidinoxo-1-5-bromobenzonitrile) A mixture of example 5a (5 g, 25.3 mmol), potassium carbonate (5.3 g, 37.9 mmol), and R-glycidyl-3-nitrobenzenesulfonate (6.9 g) , 26.5 mmole) in acetone (150 ml) was heated to reflux for 24 hours. The mixture was cooled, concentrated, placed in H2O, extracted with EtOAc. The organic extracts were washed with brine, dried over MgSO, concentrated to give an off-white solid (0.7 g, 82%). 1 H-NMR (300 MHz, DMSO-d 6): d 2.74 (dd, J = 2.6, 5.0 Hz, 1 H), 2.88
(t, J = 5 Hz, 1 H), 3.38 (m, 1 H), 4.02 (dd, J = 6.4, 11.6 Hz 1 H), 4.58 (dd, J = 2.6, 11.6 Hz, 1 H), 7.22 (d, J = 9.1 Hz, 1H), 7.78 (dd, J = 2.5, 9.1 Hz, 1 H), 8.05 (d, J = 2.5 Hz, 1 H).
c) N-r2R-Hydroxy-3-y2-cyano-4-r4-bromopheninphenoxypropyl-1,1-dimethyl-2- (2-naphthyl) ethylamine Following the procedure in Example 1d, the title compound was prepared as a yellow foam (9.2 g, 75%). 1 H-NMR (300 MHz, CDCl 3): d 1.14 (s, 3 H), 1.15 (s, 3 H), 2.47 (s, 2 H), 2.98 (m, 3 H), 3.02 (dd, J = 4.6, 12.1 Hz, 1 H), 3.98 (m, 1 H), 4.09 (d, J = 4.6 Hz, 2 H), 6.82 (d, J = 8.8 Hz, 1 H), 7.31 (dd, J = 2.6, 8.4 Hz, 1 H ), 7.45 (m, 2H), 7.61 (m, 3H), 7.79 (m, 3H). MS (m / z): 455.4 (M +).
d) N-r2R-Hydroxy-3-rr2-cyano-4-rr4-ethylcarboxinfenylphenoxypropyl-1, 1-dimethyl-2- (2-naphthyl) ethylamine hydrochloride A mixture of example 5c (0.4 g, 0.88 mmol), acid p-carboxylbenzanboronic acid (0.18 g, 1.06 mmol), (Ph3P) 4Pd, and 2M Na2CO3 (1.8 mL, 3.6 mmol) in toluene / EtOH (10 mL, 4: 1) was heated to reflux in 24 hours. The mixture was cooled, and the layers separated. The aqueous layer was extracted with EtOAC (discarded), acidified with 6N HCl. The tan solid was filtered, dried by air. The solid was stirred in EtOH, and 4M HCl in p-dioxane was added. The resulting mixture was heated to reflux in 24 hours. The mixture was cooled, concentrated, placed in H2O, neutralized by 2.5 N NaOH, extracted with CH2Cl2. The organic extracts were dried, concentrated and purified by flash column chromatography (3% MeOH / CH 2 Cl 2) to give a whitish foam, which was dissolved in p-dioxane and 4M HCl was added, concentrated, triturated in ether to give a whitish solid (0.34 g, 70%). 1 H-NMR (300 MHz, DMSO-d 6): d 1.25 (s, 6H), 1.32 (t, J = 7.6 Hz, 3H), 3.25 (s, 3H), 3.42 (m, 2H), 4.35 (m, 3H), 6.12 (d, J = 4.6 Hz, 1 H), 7.46 (m, 5H), 7.78 (s, 1 H), 7.92 (m, 5H), 8.01 (d, J = 8.6 Hz, 1 H) , 8.10 (dd, J = 1.3, 8.6 Hz, 1 H), 8.21 (s, 1 H), 8.82 (t, J = 8 Hz, 1 H), 9.22 (t, J = 8 Hz, 1 H). MS (m / z): 523.6 (M +).
EXAMPLE 6 N-r2R-hydroxy-3-rr2-cyano-4-r4-carboxyphenyl-phenoxy-1-propy1,1-dimethyl-2- (2-naphthyl) ethylamine hydrochloride
Following example 1e, the title compound was prepared as an off-white solid (0.06g, 55%).
1 H-NMR (300 MHz, DMSO-d 6): d 1.25 (s, 6H), 3.12 (s, 2H), 3.25 (m, 4H), 4.35 (s, 2H), 7.45 (m, 4H), 7.80 (m, 6H), 8.05 (m, 3H), 8.21 (s, 1 H). MS (m / z): 495.4 (M +).
EXAMPLE 7 N-r 2 R -hydroxy-3-rr 2 -cyano-4-r 2 -formylphennifenoxypropion-1,1-dimethyl-2- (2-naphthyl) hydrochloride
Following the procedure of Example 5d, the title compound was prepared as an off-white solid (0.06g, 70%). 1 H NMR (300 MHz, DMSO-d 6): d 1.32 (s, 6H), 3.21 (s, 2H), 3.42 (m, 3H), 4.42 (m, 3H), 6.1 1 (s, 1 H), 7.55 (m, 4H), 7.62 (t, J = 8Hz, 1 H), 7.81 (m, 3H), 7.97 (m, 6H), 8.82 (t, J = 7.6 Hz, 1 H), 9.12 (t, J = 7.6 Hz, 1 H), 9.92 (s, 1 H). MS (m / z): 479.5 (M +).
EXAMPLE 8 N-r 2 R -hydroxy-3-rr 2 -cyano-4-r 3-formylphenn-phenoxypropin-1,1-dimethyl-2- (2-naphthyl) ethylamine hydrochloride
Following the procedure of Example 5d, the title compound was prepared as a tan solid (0.06g, 72%). 1 H-NMR (300 MHz, CDCl 3): d 1.14 (s, 3 H), 1.16 (s, 3 H), 2.92 (s, 2 H), 2.98 (dd, J = 6.8, 12.1 Hz, 1 H), 3.15 (dd) , J = 4.8, 12.1 Hz, 1 H), 4.07 (m, 1 H), 4.20 (d, J = 4.8 Hz, 2H), 7.11 (d, J = 8.6 Hz, 1 H), 7.36 (dd, J = 1.7, 8.4 Hz, 1 H), 7.44 (m, 2H), 7.64 (m, 2H), 7.78 (m, 6H), 7.90 (dd, J = 1.7, 8.4 Hz, 1 H), 8.02 (s, 1 H), 10.1 (s, 1 H). MS (m / z): 479.5 (M +).
EXAMPLE 9 N-r 2 R -hydroxy-3-rr 2 -cyano-4-f 2 -hydroxymethylphennifenoxypropin-1,1-dimethyl-2- (2-naphthyl) ethylamine hydrochloride
To a stirred solution of Example 4a (0.1g, 0.21 mmol) in ethanol (5 mL) was added NaBH 4 (0.031 g, 0.84 mmol). After stirring at room temperature in 1 / 2h, the mixture was quenched with 1 N HCl, extracted with CH2Cl2. The organic layers were extracted and dried over MgSO 4, concentrated, purified by flash column chromatography (7% MeOH / CH 2 Cl 2) to give a colorless oil, which was dissolved in p-dioxane and 4M HCl in p-dioxane, concentrated and triturated in ether to give an off-white solid (0.55g, 60%). 1 H-NMR (300 MHz, CDCl 3): d 1.14 (s, 3 H), 1.16 (s, 3 H), 2.89 (d, J = 2.9 Hz, 2 H), 2.95 (dd, J = 6.8, 12.1 Hz, 1 H ), 3.05 (dd, J = 4.8, 12.1 Hz, 1 H), 4.05 (m, 1 H), 4.15 (d, J = 4.8 Hz, 2H), 4.80 (s, 2H), 7.05 (d, J = 8.6 Hz, 1 H), 7.45 (m, 6H), 7.60 (s, 1 H), 7.72 (s, 1 H), 7.81 (m, 5H). MS (m / z): 481.4 (M +).
EXAMPLE 10 N-r2R-Hydroxy-3-rr2-cyano-rr3-hydroxymethylphefenfenoxpheropin-1,1-dimethyl-2- (2-naphthyl) ethylamine hydrochloride
Following the procedure of Example 6, the title compound was prepared as a white solid (0.1g, 67%). 1 H-NMR (300 MHz, CDCl 3): d 1.14 (s, 3 H), 1.16 (s, 3 H), 2.89 (d, J = 2.9 Hz, 2 H), 2.95 (dd, J = 6.8, 12.1 Hz, 1 H ), 3.05 (dd, J = 4.8, 12.1, 1 H), 4.05 (m, 1 H), 4.15 (d, J = 4.8 Hz, 2H), 4.80 (s, 2H), 7.05 (d, J = 8.6 Hz, 1 H), 7.45 (m, 6H), 7.60 (s, 1 H), 7.72 (s, 1 H), 7.81 (m, 5H). MS (m / z): 481.4 (M +).
EXAMPLE 11 N-r 2 R -hydroxy-3-rr 2 -cyano-4-rr 3 -ethoxycarbonylphenylphenoxopropin-1,1-dimethyl-2- (2-naphthyl) ethylamine hydrochloride
Following the procedure of example 2, the title compound was prepared as off-white solid (0.050g, 79%). 1 H-NMR (300 MHz, CDCl 3): d 1.14 (s, 3 H), 1.16 (s, 3 H), 1.38 (t, J = 7.1 Hz, 3 H), 2.98 (s, 2 H), 3.02 (dd, J = 6.8, 12.1 Hz, 1 H), 3.18 (dd, J = 4.8, 12.1,
1 H), 4.05 (m, 1 H), 4.18 (d, J = 4.8 Hz, 1 H), 4.45 (q, J = 7.1 Hz, 2 H), 7.09 (d, J = 8.5
Hz, 1 H), 7.32 (d, J = 8.5 Hz, 1 H), 7.42 (m, 2H), 7.51 (t, J = 8.5 Hz, 1 H), 7.75 (m, 7H),
8. 1 (d, J = 8.5 Hz, 1 H), 8.19 (s, 1 H).
MS (m / z): 523.6 (M +).
EXAMPLE 12 N-r 2 R -hydroxy-3-rf 2 -cyano-4-r 3 -carboxypheninophenoxy] propyn-1,1-dimethyl-2- (2-naphthyl) ethylamine hydrochloride
Following the procedure of Example 1, the title compound was prepared as an off-white solid (0.1 OOg, 79%). 1 H-NMR (300 MHz, DMSO-d 6): d 1 .14 (s, 3 H), 1.16 (s, 3 H), 2.98 (s, 2 H), 3.0 (dd, J = 6.8, 12.1 Hz, 1 H) , 3.15 (dd, J = 4.8, 12.1 Hz, 1 H), 4.1 (m, 1 H), 4.31 (d, J = 4.8 Hz, 1 H), 7.4 (m, 4H), 7.6 (t, J = 8.5 Hz, 1 H), 7.72 (s, 1 H), 7.83 (m, 4 H), 7.98 (d, J = 8.5 Hz, 2 H), 8.1 (s, 1 H), 8.21 (s, 1 H). MS (m / z): 495.5 (M +).
EXAMPLE 13 N-r2R-Hydroxy-3-rr2-cyano-4-r2-carboxyphenyl-phenoxypropyl-1,1-dimethyl-2- (2-naphthyl) ethylamine hydrochloride
Following the procedure of example 1, the title compound was prepared as a tan solid (0.065g, 55%). 1 H-NMR (300 MHz, DMSO-d 6): d 1.23 (s, 6H), 2.89 (m, 4H), 3.42 (s, 2H), 3.98 (s, 1 H), 4.23 (m, 2H), 6.98 (d, J = 8 Hz, 1 H), 7.21 (s, 1 H), 7.45 (d, J = 7.6 Hz, 1 H), 7.53 (m, 3 H), 7.62 (t, J = 8 Hz, 1 H), 7.75 (m, 2H), 7.85 (m, 5H).
MS (m / z): 495.4 (M +). The formulations for pharmaceutical use that incorporate
compounds of the present invention can be prepared in different ways and
with numerous excipients. Examples of such formulations are given to
continuation.
EXAMPLE 14 Inhalant formulation
A compound of formula (I) (1 mg to 100 mg) is aerosolized from a metered dose inhaler to deliver the desired amount of drug per use.
Tablet formulation
Tablets / ingredients Per tablet 1. Active ingredient of 40 mg (Cmp of formula (I)) 2. Corn starch 20 mg 3. Alginic acid 20 mg 4. Sodium alginate 20 mg 5. Stearate of g 13 mg
Procedure for tablet formulation Ingredients 1, 2, 3 and 4 are combined in a suitable mixer. Sufficient water is added in portions to the combination with mixing carefully after each addition, until the dough has a
consistency to allow its conversion to wet granules. The wet mass is converted into granules by passing it through an oscillation granulator using a No. 8 mesh screen (2.38 mm). The wet granules are then dried in an oven at 60 ° C until dry. The dried granules are lubricated with ingredient No. 5 and the lubricated granules are compressed in a suitable tablet press.
EXAMPLE 15 Parenteral Formulation
A pharmaceutical composition for parenteral administration is prepared by dissolving a suitable amount of a compound of formula (I) in polyethylene glycol with heating. This solution is then diluted with water for injections (for 100 ml). The solution is then sterile filtered through a 0.22 micron membrane filter and sealed in sterile containers. All publications, including without limitation patents and patent applications cited in this specification, are hereby incorporated by reference as if each individual publication was specifically and individually indicated to be incorporated by reference as if it were fully disclosed.
Claims (12)
1. - A compound selected from the formula (I) below: Formula (I) wherein: A represents an aryl ring that is attached in the 4 or 5 position as indicated; X is selected from the group consisting of CN, NO, Cl, F and H; And it is selected from the group consisting of Cl, F, I and H; Q is selected from the group consisting of H, R1t S02R ?, R? C (0) OR '?, tetrazole, CH2OH, COH, SO ^ RiR ^, C (O) NR1R1', and NR? SO2R? ', In where Ri and Ri 'are independently selected from the group consisting of hydrogen, C1-4 alkyl, and optionally substituted alkyl, or R1 and Ri' together form a heterocyclic ring optionally substituted with 3 to 7 elements; Ar is phenyl or naphthyl, substituted or unsubstituted, heteroaryl or fused heteroaryl, so that the hetero-ring may contain N, O or S and may be aromatic, dihydro or tetrahydro.
2. The compound according to claim 1, further characterized in that any alkyl substituent is selected from the group consisting of CN, aryl, C02R, C02NHR, OH, OR, CO, NH2) halogen, CF3, OCF3 and N02, wherein R represents H, C1-4 alkyl, C3-6 cycloalkyl, C2-5 alkenyl, C2-5 alkynyl, heterocycloalkyl, aryl or arylalkyl of C? -.
3. The compound according to claim 1, further characterized in that any phenyl or naphthyl substituent is selected from the group consisting of OH, halogen, CO2R1, C4 alkyl, C1-4 alkoxy, C3-6 cycloalkyl, OSO2R1, CN, N02, OCF3, CF3, CH2CF3, (CH2) nC02H, (CH2) nC02R ?, 0- (CH2) n and CO2R1, wherein n is an integer from 0 to 3 and R1 represents Cr alkyl, cycloalkyl C3-6, or C3-6 cycloalkyl.
4. The compound according to claim 3, further characterized in that any heteroaryl substituent is selected from the group consisting of OH, OCH3, CH (CH3) 2, halogen, CO2R1, C? - alkyl, d-4 alkoxy , C3-6 cycloalkyl, CN, N02, OCF3, CF3, CH2CF3, (CH2) nC02R? and
5. The compound according to claim 1, selected from the group consisting of: N- [2R-hydroxy-3- [2-cyano-5- [2-carbetoxyphenol] phenoxy] hydrochloride] propii] -1, 1-dimethyl-2- (2-naphthyl) ethanol; N- [2R-hydroxy-3- [2-cyano-5- [4-carbethoxyphenyl] phenoxy] propy] -1, 1-dimethyl-2- (2-naphthyl) ethylamine hydrochloride; N- [2R-Hydroxy-3 - [[2-cyano-5 - [[4-carboxy] phenyl] phenoxy] propyl] -1, 1 -d-methyl-2- (2-naphthyl) ethe hydrochloride sheet; N- [2R-hydroxy-3 - [[2-cyano-5- [2-carboxyphene] phenoxy] propyl] -1,1-dimethyl-2- (2-naphthyl) ethylamine hydrochloride; N- [2R-hydroxy-3 - [[2-cyano-4- [4-carboxyphenyl] phenoxy] propyl] -1,1-dimethyl-2- (2-naphthyl) ethylamine hydrochloride; N- [2R-hydroxy-3 - [[2-cyano-4- [carbethoxyphenyl] phenoxy] propyl] -1,1-dimethyl-2- (2-naphthyl) ethenamine hydrochloride; N- [2R-hydroxy-3 - [[2-cyano-4- [2-formylphenyl] phenoxy] propyl] -1, 1-dimethyl-2- (2-naphthyl) ethylamine hydrochloride; N- [2R-hydroxy-3 - [[2-cyano-4- [3-formylphenyl] phenoxy] propyl] -1,1-dimethyl-2- (2-naphthyl) ethylamine hydrochloride; N- [2R-hydroxy-3 - [[2-cyano-4 - [[3- [hydroxymethyl] phenyl] phenoxy] propyl] -1, 1-dimethyl-2- (2-naphthyl) hydrochloride ethylamine; N- [2R-hydroxy-3 - [[2-cyano-4 - [[2-hydroxymethylphenyl] phenoxy] propyl] -1,1-dimethyl-2- (2-naphthyl) ethylamine hydrochloride; N- [2R-hydroxy-3 - [[2-cyano-4 - [[3 - [[ethyl] carboxyl] phenyl] phenoxy] propyl] -1,1-dimethyl-2- (2-naphthyl) hydrochloride ethylamine; N- [2R-hydroxy-3- [2-cyano-4- [3-carboxyphenyl] phenoxy] propyl] -1,1-dimethyl-2- (2-naphthyl) ethylamine hydrochloride; and N- [2R-hydroxy-3- [2-cyano-4- (2-carboxyphenyl) phenoxy] propyl] -1,1-dimethyl-2- (2-naphthyl) ethylamine hydrochloride.
6. The compound according to claim 5, selected from the group consisting of: N- [2R-hydroxy-3- [2-cyano-5- [2-carbethoxyphenyl] phenoxy] propyl]] - 1 hydrochloride 1-dimethyl-2- (2-naphthyl) ethylamine; N- [2R-hydroxy-3- [2-cyano-5- [4-carbethoxyphenyl] phenoxy] propyl]] -1,1-dimethyl-2- (2-naphthyl) ethylamine hydrochloride; N- [2R-hydroxy-3 - [[2-cyano-5 - [[4-carboxy] phenyl] phenoxy] propyl] -1,1-dimethyl-2- [naphthyl] ethylamine hydrochloride; N- [2R-hydroxy-3 - [[2-cyano-4- [4-carboxyphenyl] phenoxy] propyl] -1, 1-d, methyl-2- (2-naphthyl) ethylamine hydrochloride; N- [2R-hydroxy-3 - [[2-cyano-4- [carbethoxyphenyl] phenoxy] propyl] -1,1-dimethyl-2- (2-naphthyl) ethylamine hydrochloride; N- [2R-hydroxy-3 - [[2-cyano-4- [2-formylphenyl] phenoxy] propyl] -1,1-dimethyl-2- (naphthyl) ethylamine hydrochloride; N- [2R-hydroxy-3 - [[2-cyano-4- [3-formylphenyl] phenoxy] propyl] -1,1-dimethyl-2- (naphthyl) ethylamine hydrochloride; N- [2R-hydroxy-3 - [[2-cyano-4 - [[3 [hydroxymethyl] pheny] phenoxy] propyl] -1,1-dimethyl-2- (naphthyl) ethylamine hydrochloride; N- [2R-hydroxy-3 - [[2-cyano-4 - [[2-hydroxymethylphenyl] phenoxy] propyl] -1,1-dimethyl-2- (2-naphthyl) ethylamine hydrochloride; N- [2R-hydroxy-3 - [[2-cyano-4 - [[3 - [[ethyl] carboxyl]] phenyl] phenoxy] propii] -1, -dimethyl-2- (2-naphthyl) ethylamine hydrochloride; N- [2R-hydroxy-3- [2-cyano-4- [3-carboxyphenyl] phenoxy] propyl]] - 1,1-dimethyl-2- (2-naphthyl) ethylamine hydrochloride; and N- [2R-hydroxy-3- [2-cyano-4- [2-carboxyphenyl) phenoxy] propyl] -1,1-d-methyl-2- (2-naphthyl) ethylamine hydrochloride.
7. The compound according to claim 6, selected from the group consisting of: N- [2R-Hydroxy-3- [2-cyano-5- [2-carbethoxyphenyl] phenoxy] propyl] -1, 1 hydrochloride -dimethyl-2- (2-naphthyl) ethylamine; N- [2R-Hydroxy-3- [2-cyano-5- [4-carbethoxyphenyl] phenoxy] propyl] -1,1-dimethyl-2- (2-naphthyl) ethylamine hydrochloride; N- [2R-Hydroxy-3 - [[2-cyano-5 - [[4-carboxy] phenyl] phenoxy] propyl] -1,1-dimethyl-2- [naphthyl] ethylamine hydrochloride; N- [2R-Hydroxy-3 - [[2-cyano-4- [4-carboxyphenyl] phenoxy] propyl] -1,1-dimethyl-2- (2-naphthyl) ethylamine hydrochloride; N- [2R-Hydroxy-3 - [[2-cyano-4- [carbethoxyphenyl] phenoxy] propyl] -1,1-dimethyl-2- (2-naphthyl) ethylamine hydrochloride; N- [2R-Hydroxy-3 - [[2-cyano-4- [2-formylphenyl] phenoxy] propyl] -1,1-dimethyl-2- (naphthyl) ethylamine hydrochloride; N- [2R-Hydroxy-3 - [[2-cyano-4- [3-formylphenyl] phenoxy] propyl] -1,1-dimethyl-2- (naphthyl) ethenamine hydrochloride; N- [2R-Hydroxy-3 - [[2-cyano-4 - [[3- [hydroxymethyl] phenyl] phenoxy] propyl] -1,1-dimethyl-2- (naphthyl) ethylamine hydrochloride; N- [2R-Hydroxy-3 - [[2-cyano-4 - [[2-hydroxymethylphenyl] phenoxy] propyl] -1,1-dimethyl-2- (2-naphthyl) ethylamine hydrochloride; N- [2R-Hydroxy] -3 - [[2-cyano-4 - [[3 - [[ethyl] carboxy]] phenyl] phenoxy] propy] -1, 1-dmethyl-2-hydrochloride (2-naphthyl) ethylamine; N- [2R-Hydroxy-3- [2-cyano-4- [3-carboxyphenyl] phenoxy] propyl]] - 1, 1-d-methyl-2- (2-naphthyl) hydrochloride ) ethylene and N- [2R-Hydroxy-3- [2-cyano-4- (2-carboxylphenyl) phenoxy] propyl] -1,1-dimethyl-2- (2-hydrochloride naphthyl) ethylamine.
8. The use of a compound as claimed in claim 1 for the manufacture of a medicament for antagonizing a calcium receptor in a subject.
9. The use of a compound as claimed in claim 1 for the manufacture of a medicament for treating a disease or disorder characterized by abnormal mineral or bone homeostasis in a subject.
10. The use as claimed in claim 9 wherein the disease or disorder is selected from the group consisting of osteosarcoma, periodontal disease, fracture healing, osteoarthritis, rheumatoid arthritis, Paget's disease, humoral hypercalcemia, malignancy and osteoporosis.
11. The use as claimed in claim 10 wherein the disease or disorder is osteoporosis.
12. The use of a compound as claimed in claim 1 for the manufacture of a medicament for increasing serum parathyroid levels in a subject.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US60/118,240 | 1999-02-02 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MXPA01007800A true MXPA01007800A (en) | 2002-03-05 |
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