NO332991B1 - Kalsiumreseptormodulerende forbindelse, farmasoytisk sammensetning og anvendelse derav - Google Patents

Info

Publication number

NO332991B1

NO332991B1 NO20051328A NO20051328A NO332991B1 NO 332991 B1 NO332991 B1 NO 332991B1 NO 20051328 A NO20051328 A NO 20051328A NO 20051328 A NO20051328 A NO 20051328A NO 332991 B1 NO332991 B1 NO 332991B1

Authority

NO

Norway

Prior art keywords

salt

pyrimidine

ethyl

carboxamide

propyl

Prior art date

2002-08-26

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• 150000001875 compounds Chemical class 0.000 title claims abstract description 109
• 102000013830 Calcium-Sensing Receptors Human genes 0.000 title claims abstract description 6
• 108010050543 Calcium-Sensing Receptors Proteins 0.000 title claims abstract description 6
• 239000008194 pharmaceutical composition Substances 0.000 title claims description 6
• 150000003839 salts Chemical class 0.000 claims abstract description 76
• 239000011575 calcium Substances 0.000 claims description 49
• 239000000203 mixture Substances 0.000 claims description 24
• LPCQBTAOTIZGAE-UHFFFAOYSA-N 2h-pyrimidine-1-carboxamide Chemical compound NC(=O)N1CN=CC=C1 LPCQBTAOTIZGAE-UHFFFAOYSA-N 0.000 claims description 14
• 208000001132 Osteoporosis Diseases 0.000 claims description 9
• 238000002360 preparation method Methods 0.000 claims description 9
• 208000020084 Bone disease Diseases 0.000 claims description 8
• OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 8
• 229910052791 calcium Inorganic materials 0.000 claims description 8
• 201000010099 disease Diseases 0.000 claims description 4
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 4
• XMRIUEGHBZTNND-UHFFFAOYSA-N pyrazolo[1,5-a]pyrimidine-3-carboxamide Chemical compound C1=CC=NC2=C(C(=O)N)C=NN21 XMRIUEGHBZTNND-UHFFFAOYSA-N 0.000 claims description 3
• 230000005856 abnormality Effects 0.000 claims description 2
• CJKTUXMCNPTCQS-UHFFFAOYSA-N (2,2-diethyl-4-fluoropyrrolidin-1-yl)-(7,7-dimethyl-5-phenyl-5,6-dihydro-4H-pyrazolo[1,5-a]pyrimidin-3-yl)methanone Chemical group CCC1(CC)CC(F)CN1C(=O)C1=C(NC(CC2(C)C)C=3C=CC=CC=3)N2N=C1 CJKTUXMCNPTCQS-UHFFFAOYSA-N 0.000 claims 1
• BXHRVRKLOIWLRF-UHFFFAOYSA-N (2,2-diethyl-4-methoxypyrrolidin-1-yl)-(7,7-dimethyl-5-phenyl-5,6-dihydro-4H-pyrazolo[1,5-a]pyrimidin-3-yl)methanone Chemical group CCC1(CC)CC(OC)CN1C(=O)C1=C(NC(CC2(C)C)C=3C=CC=CC=3)N2N=C1 BXHRVRKLOIWLRF-UHFFFAOYSA-N 0.000 claims 1
• GCAJUNZLLXNQQO-UHFFFAOYSA-N 1,2,3,3a-tetrahydropyrazolo[1,5-a]pyrimidine Chemical compound N1=CC=CN2NCCC21 GCAJUNZLLXNQQO-UHFFFAOYSA-N 0.000 claims 1
• KPGWORILVIXGJV-UHFFFAOYSA-N 2-[3-(4-methylphenyl)pentan-3-yl]-5-(2,7,7-trimethyl-5-phenyl-5,6-dihydro-4H-pyrazolo[1,5-a]pyrimidin-3-yl)-1,3,4-thiadiazole Chemical group C=1C=C(C)C=CC=1C(CC)(CC)C(S1)=NN=C1C=1C(C)=NN(C(C2)(C)C)C=1NC2C1=CC=CC=C1 KPGWORILVIXGJV-UHFFFAOYSA-N 0.000 claims 1
• HJFZVTDRWQVFDN-UHFFFAOYSA-N 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine Chemical compound C1CCNC2=CC=NN21 HJFZVTDRWQVFDN-UHFFFAOYSA-N 0.000 claims 1
• RMLQZXDBDWLNLI-UHFFFAOYSA-N 5-(2-chlorophenyl)-2,7,7-trimethyl-N-[3-(4-methylphenyl)pentan-3-yl]-5,6-dihydro-4H-pyrazolo[1,5-a]pyrimidine-3-carboxamide Chemical group C=1C=C(C)C=CC=1C(CC)(CC)NC(=O)C=1C(C)=NN(C(C2)(C)C)C=1NC2C1=CC=CC=C1Cl RMLQZXDBDWLNLI-UHFFFAOYSA-N 0.000 claims 1
• HUZMHENQDRSAGB-UHFFFAOYSA-N chembl1687946 Chemical compound C=1C=C(C)C=CC=1C(CC)(CC)NC(=O)C=1C=NN(C(C2)(C)C)C=1NC2C1=CC=CC=C1 HUZMHENQDRSAGB-UHFFFAOYSA-N 0.000 claims 1
• 229910052799 carbon Inorganic materials 0.000 abstract description 5
• 125000001183 hydrocarbyl group Chemical group 0.000 abstract 3
• 125000003341 7 membered heterocyclic group Chemical group 0.000 abstract 1
• 229940002612 prodrug Drugs 0.000 abstract 1
• 239000000651 prodrug Substances 0.000 abstract 1
• 229940075993 receptor modulator Drugs 0.000 abstract 1
• 125000005750 substituted cyclic group Chemical group 0.000 abstract 1
• 235000002639 sodium chloride Nutrition 0.000 description 53
• 238000006243 chemical reaction Methods 0.000 description 30
• -1 alkali metal salt Chemical class 0.000 description 28
• 239000003814 drug Substances 0.000 description 28
• 229940079593 drug Drugs 0.000 description 27
• 102000005962 receptors Human genes 0.000 description 25
• 108020003175 receptors Proteins 0.000 description 25
• 239000000243 solution Substances 0.000 description 21
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 20
• 210000004027 cell Anatomy 0.000 description 19
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
• 239000002904 solvent Substances 0.000 description 16
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
• 238000000034 method Methods 0.000 description 14
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 13
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 11
• 230000000694 effects Effects 0.000 description 11
• 102000003982 Parathyroid hormone Human genes 0.000 description 10
• 108090000445 Parathyroid hormone Proteins 0.000 description 10
• 239000000199 parathyroid hormone Substances 0.000 description 10
• 229960001319 parathyroid hormone Drugs 0.000 description 10
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 9
• 239000002253 acid Substances 0.000 description 9
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
• QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 8
• 238000002474 experimental method Methods 0.000 description 8
• 239000003921 oil Substances 0.000 description 8
• 235000019198 oils Nutrition 0.000 description 8
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 7
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 7
• NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 7
• 235000001465 calcium Nutrition 0.000 description 7
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 7
• 239000002299 complementary DNA Substances 0.000 description 7
• 150000002148 esters Chemical class 0.000 description 7
• 230000028327 secretion Effects 0.000 description 7
• FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 6
• SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
• DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
• 229910052783 alkali metal Inorganic materials 0.000 description 6
• 239000008280 blood Substances 0.000 description 6
• 210000004369 blood Anatomy 0.000 description 6
• 238000003379 elimination reaction Methods 0.000 description 6
• 238000009472 formulation Methods 0.000 description 6
• 230000003834 intracellular effect Effects 0.000 description 6
• 229910052751 metal Inorganic materials 0.000 description 6
• 239000002184 metal Substances 0.000 description 6
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
• 125000000217 alkyl group Chemical group 0.000 description 5
• 235000001014 amino acid Nutrition 0.000 description 5
• 150000001413 amino acids Chemical class 0.000 description 5
• 230000027455 binding Effects 0.000 description 5
• 210000003169 central nervous system Anatomy 0.000 description 5
• 210000004978 chinese hamster ovary cell Anatomy 0.000 description 5
• 238000003818 flash chromatography Methods 0.000 description 5
• 210000001035 gastrointestinal tract Anatomy 0.000 description 5
• 229910052739 hydrogen Inorganic materials 0.000 description 5
• 239000001257 hydrogen Substances 0.000 description 5
• 210000003734 kidney Anatomy 0.000 description 5
• 238000000746 purification Methods 0.000 description 5
• 239000011541 reaction mixture Substances 0.000 description 5
• 238000012360 testing method Methods 0.000 description 5
• GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 5
• VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
• TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 4
• AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
• 229920002472 Starch Polymers 0.000 description 4
• 150000008065 acid anhydrides Chemical class 0.000 description 4
• 229910000147 aluminium phosphate Inorganic materials 0.000 description 4
• 239000002585 base Substances 0.000 description 4
• 239000000872 buffer Substances 0.000 description 4
• 239000003795 chemical substances by application Substances 0.000 description 4
• XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
• LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 4
• 230000008030 elimination Effects 0.000 description 4
• 238000001914 filtration Methods 0.000 description 4
• 150000002431 hydrogen Chemical group 0.000 description 4
• 238000006460 hydrolysis reaction Methods 0.000 description 4
• NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 4
• 150000007529 inorganic bases Chemical class 0.000 description 4
• BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
• 150000007524 organic acids Chemical class 0.000 description 4
• 150000007530 organic bases Chemical class 0.000 description 4
• 210000002990 parathyroid gland Anatomy 0.000 description 4
• 239000002953 phosphate buffered saline Substances 0.000 description 4
• XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
• 125000006239 protecting group Chemical group 0.000 description 4
• 230000002829 reductive effect Effects 0.000 description 4
• 239000011780 sodium chloride Substances 0.000 description 4
• 239000007787 solid Substances 0.000 description 4
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• FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
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