AU2150792A - Dimethylamino-hydroxy-alkan diphosphonic acids and pharmaceutical compositions containing them - Google Patents
Dimethylamino-hydroxy-alkan diphosphonic acids and pharmaceutical compositions containing themInfo
- Publication number
- AU2150792A AU2150792A AU21507/92A AU2150792A AU2150792A AU 2150792 A AU2150792 A AU 2150792A AU 21507/92 A AU21507/92 A AU 21507/92A AU 2150792 A AU2150792 A AU 2150792A AU 2150792 A AU2150792 A AU 2150792A
- Authority
- AU
- Australia
- Prior art keywords
- dimethylamino
- acid
- hydroxy
- diphosphonic
- alkan
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 239000002253 acid Substances 0.000 title claims description 25
- 150000007513 acids Chemical class 0.000 title claims description 20
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 22
- 238000000034 method Methods 0.000 claims description 17
- 238000006243 chemical reaction Methods 0.000 claims description 14
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 13
- 150000003839 salts Chemical class 0.000 claims description 13
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 10
- 239000012153 distilled water Substances 0.000 claims description 9
- 235000001014 amino acid Nutrition 0.000 claims description 8
- 150000001413 amino acids Chemical class 0.000 claims description 8
- 238000010992 reflux Methods 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 6
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 5
- 235000019253 formic acid Nutrition 0.000 claims description 5
- JJMDCOVWQOJGCB-UHFFFAOYSA-N 5-aminopentanoic acid Chemical compound [NH3+]CCCCC([O-])=O JJMDCOVWQOJGCB-UHFFFAOYSA-N 0.000 claims description 4
- 230000004097 bone metabolism Effects 0.000 claims description 4
- 201000010099 disease Diseases 0.000 claims description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 4
- SLXKOJJOQWFEFD-UHFFFAOYSA-N 6-aminohexanoic acid Chemical compound NCCCCCC(O)=O SLXKOJJOQWFEFD-UHFFFAOYSA-N 0.000 claims description 3
- 208000010191 Osteitis Deformans Diseases 0.000 claims description 3
- 208000001132 Osteoporosis Diseases 0.000 claims description 3
- 208000027868 Paget disease Diseases 0.000 claims description 3
- 229960002684 aminocaproic acid Drugs 0.000 claims description 3
- 238000002425 crystallisation Methods 0.000 claims description 3
- 230000008025 crystallization Effects 0.000 claims description 3
- 238000004821 distillation Methods 0.000 claims description 3
- 208000027202 mammary Paget disease Diseases 0.000 claims description 3
- 201000008482 osteoarthritis Diseases 0.000 claims description 3
- 206010028980 Neoplasm Diseases 0.000 claims description 2
- 208000003076 Osteolysis Diseases 0.000 claims description 2
- 206010003246 arthritis Diseases 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 208000029791 lytic metastatic bone lesion Diseases 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 239000011541 reaction mixture Substances 0.000 claims 2
- 201000002980 Hyperparathyroidism Diseases 0.000 claims 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 claims 1
- 239000012141 concentrate Substances 0.000 claims 1
- 238000007865 diluting Methods 0.000 claims 1
- 229940079593 drug Drugs 0.000 claims 1
- 239000003814 drug Substances 0.000 claims 1
- 238000001035 drying Methods 0.000 claims 1
- 235000019256 formaldehyde Nutrition 0.000 claims 1
- 229940124531 pharmaceutical excipient Drugs 0.000 claims 1
- 239000002244 precipitate Substances 0.000 claims 1
- 238000005406 washing Methods 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 description 14
- 239000000047 product Substances 0.000 description 13
- 239000000243 solution Substances 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000000203 mixture Substances 0.000 description 8
- 239000000376 reactant Substances 0.000 description 6
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- IOVCWXUNBOPUCH-UHFFFAOYSA-N Nitrous acid Chemical compound ON=O IOVCWXUNBOPUCH-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- UYZSNVLEDLCWGU-UHFFFAOYSA-N 5-(dimethylazaniumyl)pentanoate Chemical compound CN(C)CCCCC(O)=O UYZSNVLEDLCWGU-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 210000000988 bone and bone Anatomy 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
- FUZZWVXGSFPDMH-UHFFFAOYSA-N n-hexanoic acid Natural products CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 3
- -1 phosphorus halide Chemical class 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- CUIROQLTUJTNCG-UHFFFAOYSA-N (1-amino-5-phosphonopentyl)phosphonic acid Chemical compound OP(=O)(O)C(N)CCCCP(O)(O)=O CUIROQLTUJTNCG-UHFFFAOYSA-N 0.000 description 2
- RMNSYUCYOZOVDT-UHFFFAOYSA-N (1-amino-6-phosphonohexyl)phosphonic acid Chemical compound OP(=O)(O)C(N)CCCCCP(O)(O)=O RMNSYUCYOZOVDT-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- QMKBNVHEUYIAPV-UHFFFAOYSA-N [5-(dimethylamino)-1-hydroxy-1-phosphonopentyl]phosphonic acid Chemical compound CN(C)CCCCC(O)(P(O)(O)=O)P(O)(O)=O QMKBNVHEUYIAPV-UHFFFAOYSA-N 0.000 description 2
- 239000003610 charcoal Substances 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 235000013681 dietary sucrose Nutrition 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- 229940102223 injectable solution Drugs 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 230000001590 oxidative effect Effects 0.000 description 2
- 238000005954 phosphonylation reaction Methods 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 230000009103 reabsorption Effects 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 229960004793 sucrose Drugs 0.000 description 2
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- XUNJHMIOVRBSAV-UHFFFAOYSA-N 5-(dimethylamino)pentanenitrile Chemical compound CN(C)CCCCC#N XUNJHMIOVRBSAV-UHFFFAOYSA-N 0.000 description 1
- UDLYSJSZAHGMBO-UHFFFAOYSA-N 6-(dimethylamino)hexanenitrile Chemical compound CN(C)CCCCCC#N UDLYSJSZAHGMBO-UHFFFAOYSA-N 0.000 description 1
- FBEHFRAORPEGFH-UHFFFAOYSA-N Allyxycarb Chemical compound CNC(=O)OC1=CC(C)=C(N(CC=C)CC=C)C(C)=C1 FBEHFRAORPEGFH-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 229910014033 C-OH Inorganic materials 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical compound NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 229910014570 C—OH Inorganic materials 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- ISZIECUHZQGAPV-UHFFFAOYSA-N NP(O)(=O)OP(O)=O Chemical compound NP(O)(=O)OP(O)=O ISZIECUHZQGAPV-UHFFFAOYSA-N 0.000 description 1
- 229910020667 PBr3 Inorganic materials 0.000 description 1
- 229910018828 PO3H2 Inorganic materials 0.000 description 1
- 102000003982 Parathyroid hormone Human genes 0.000 description 1
- 108090000445 Parathyroid hormone Proteins 0.000 description 1
- 229920000388 Polyphosphate Polymers 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- VYDQNPISZFUMRU-UHFFFAOYSA-N [4-(dimethylamino)-1-hydroxy-1-phosphonobutyl]phosphonic acid Chemical compound CN(C)CCCC(O)(P(O)(O)=O)P(O)(O)=O VYDQNPISZFUMRU-UHFFFAOYSA-N 0.000 description 1
- BSKTVCCPQZFIPG-UHFFFAOYSA-N [6-(dimethylamino)-1-hydroxy-1-phosphonohexyl]phosphonic acid Chemical compound CN(C)CCCCCC(O)(P(O)(O)=O)P(O)(O)=O BSKTVCCPQZFIPG-UHFFFAOYSA-N 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 125000004103 aminoalkyl group Chemical group 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 1
- 239000003245 coal Substances 0.000 description 1
- 230000000536 complexating effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229940099112 cornstarch Drugs 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- XQRLCLUYWUNEEH-UHFFFAOYSA-N diphosphonic acid Chemical compound OP(=O)OP(O)=O XQRLCLUYWUNEEH-UHFFFAOYSA-N 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229960004393 lidocaine hydrochloride Drugs 0.000 description 1
- YECIFGHRMFEPJK-UHFFFAOYSA-N lidocaine hydrochloride monohydrate Chemical compound O.[Cl-].CC[NH+](CC)CC(=O)NC1=C(C)C=CC=C1C YECIFGHRMFEPJK-UHFFFAOYSA-N 0.000 description 1
- 150000001455 metallic ions Chemical class 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000000199 parathyroid hormone Substances 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 150000003009 phosphonic acids Chemical class 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- IPNPIHIZVLFAFP-UHFFFAOYSA-N phosphorus tribromide Chemical compound BrP(Br)Br IPNPIHIZVLFAFP-UHFFFAOYSA-N 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000001205 polyphosphate Substances 0.000 description 1
- 235000011176 polyphosphates Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 150000004492 retinoid derivatives Chemical class 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000041 toxicology testing Toxicity 0.000 description 1
- NWONKYPBYAMBJT-UHFFFAOYSA-L zinc sulfate Chemical compound [Zn+2].[O-]S([O-])(=O)=O NWONKYPBYAMBJT-UHFFFAOYSA-L 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se)
- C07F9/3804—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se) not used, see subgroups
- C07F9/3839—Polyphosphonic acids
- C07F9/3873—Polyphosphonic acids containing nitrogen substituent, e.g. N.....H or N-hydrocarbon group which can be substituted by halogen or nitro(so), N.....O, N.....S, N.....C(=X)- (X =O, S), N.....N, N...C(=X)...N (X =O, S)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Description
DIMETHYLAMINO-HYDROXY-ALKAN DIPHOSPHONIC ACIDS AND PHARMACEUTICAL COMPOSITION CONTAINING THEM
5 DESCRIPTION
Field of the Invention
The present invention relates to new dimethyl- amino-hydroxy-alkan diphosphonic acids and the salts 0 thereof.
Furthermore the invention relates to a method for their production, as well as the pharmaceutical compositions containing these products.
5 Description of the relevant art
It is known the high complexing activity shown with respect to divalent and polyvalent metallic ions by the diphosphonic acids and their water soluble 0 salts, in particular of the group comprising the amino- hydroxy-alkan-diphosphonic acids, even if used in substoichiometric quantities. .With respect to polyphosphates, which show like properties and can also be used in substoichiometric quantities, they have the 5 advantage, as it is well known, of being stable to the hydrolysis. Thanks to this property the above group of compounds has been used with advantage, inter alia, in the pharmaceutical field for the treatment of diseases associated with disturbances of the bone metabolism, 0 such as osteoporosis, Paget's disease, osteolysys caused by tumourand hyperparathyrodism, osteoarthrosis, arthritis and the like.
The 4-amino-l-hydroxy-butan-l,1-diphosphonic acid and its derivatives (see Italian patent No.1201087 in the name of the same applicant) has proven particularly effective in this respect. The above compound is active and effective at concentrations much lower than other similar diphosphonic compounds with correspondingly lower unwanted side effects.
Dimethylamino-hydroxy-alkan diphosphonic acids and their derivatives are also known which show similar properties and activity when alkyl group is propyl or butyl. In particular, US patent No.4054598 discloses, inter alia, the 3-dimethylamino-hydroxy-propan-l,l- diphosphonic acid, its preparation and uses, while US patent No.4624947 discloses the 4-dimethylamino- hydroxy-butan-1,1-diphosphonic acid, its preparation and uses, under the form both of the acid and of its water soluble salts. The latter compounds are also described as possbile radionuclide carriers to particular biological tissues, such as for example the bone tissue, for the execution of scintigraphic analyses (see for instance Europeant patents No.96932 and 96933) .
The known processes for the preparation of phosphonic acids and in particular of amino-hydroxy- alkan-diphosphonic acids, comprise reacting the corresponding amino-carboxylic acid with a mixture of phosphorous acid and phosphorus halide, such as phosphorus trichloride, and hydrolyzing the polyemeric products thus obtained in order to give the wanted diphosphonic acid to be recovered under purified form, for example, by crystallization.
According to US patent No.4407761, the reaction is conducted in the presence of an organic inert
substance, for example a chlorinated hydrocarbon such as chlorobenzene, while the hydrolysis is conducted with a not oxidizing strong acid. According to another process described in US patent No.4705651, the same reaction is conducted without either solvents or inert substances and with different reactants molar ratios, using water as hydrol zing agent and recovering the wanted amino diphosphonic acid by precipitation with an alcohol which is added to the hydrolized solution. According to US patents No.4054598 and No.4624947 the dimethylamino-l-hydroxy-alkan-1,1-diphosphonic acids can be prepared from the corresponding dimethylamino-l-amino-alkan-l-hydroxy-1,1-diphosphonic acids by reaction with nitrous acid, salts thereof and compounds forming nitrous acid under the reaction conditions,while the reactant acid can be obtained from the corresponding nitrile by reaction with phosphorous halide under anhydrous conditions in the presence of a solvent or an inert inorganic diluent followed by hydrolysis in water. As an alternative the reactant acid can be obtained by phosphonylation of the corresponding dimethylated aminoacid with phosphorous acid in the presence of PCI3 or by other phosphonylation reactions well known to the person skilled in the art.
It is an object of the present invention to provide new dimethylamino-l-hydroxy-alkan-1 ,1-diphosphonic acids, their derivatives and water soluble salts.
It is a further object of the present invention to provide a process for the industrial production of the above mentioned compounds.
Another object of the invention is to provide pharmaceutical compositions comprising the
dimethylamino-l-hydroxy-alkan-1,1-diphosphonic acids, their derivatives and water soluble salts according to the present invention for the administration to patients suffering from diseases associated with disturbances of bone metabolism.
Summary of the Invention
The above objects are reached with the new dimethylamino-l-hydroxy-alkan-1,1-diphosphonic acids and salts thereof which are characterized by the formula
CH3 P03H2
N - (CHo - C-OH
CH3 PO3H2 wherein n=4 or 5
More particularly, the compounds according to the present invention are the 5-dimethylamino-l-hydroxy- pentan-1,1-diphosphonic acid (DAPeDP) and the 6- dimethyla_ιino-l-hydroxy-hexan-l,1-diphosphonic acid (DAEDP) , as well as their non-toxic, pharmaceutically acceptable, water-soluble salts.
The compounds according to the present invention can be prepared in several ways. According to known methods already in use for compounds of the same class, both DAPeDP and DABDP can be obtained respectively from the 5-dimethylamino-l-amino-pentan-l,1-diphosphonic acid and from the 6-dimethyl-l-amino-esan-l,l-diphosphonic acid by reaction with nitrous acid or with reactants capable of forming nitrous acid under the reaction conditions. The dimethylated amino-alkyl diphosphonic acids used as reactants can be obtained by reaction of 5-dimethylamino-valeronitrile and, respectively, of 6-
dimethylamino-capronitrile with an amount of PBr3 slightly higher than the stoichiometric under anhydrous conditions and in the presence of an inert solvent or diluent. The product obtained in this way is then treated with hot water to hydrolize the polymers thus formed. Both DAPeDP and DAEDP can also be produced by reacting the 5-dimethylamino valeric acid and, respectively, the 6-dimethylamino caproic acid with H3PO3 and PX3 (where X = halogen) either in the presence of or in the absence of solvents or diluting agents. The molar ratios among the reactants (aminoacid: H3PC>3:PX3) are quite variable, generally comprised between 1:1:1 and 1:20:5 according to whether a solvent is used or not. Preferred molar ratio of 1:5:2 in the absence of a solvent is used.
The product obtained in this way is subjected to hydrolysis which can be performed both with a non- oxidizing strong acid in aqueous solution and for a longer time with water only. The 5-dimethylamino valeric acid and the 6-dimethylamino caproic acid can be obtained by dialkylation according to methods known in the art.
Best made of carrying out the invention
Apart from the above described known processes for producing the compounds of the present invention, according to the same invention there is provided an origianl method particularly suitable, even on industrial scale, for the production of compounds of the formula:
wherein n is equal to 4 or 5.
The method consists in reacting the 5-amino valeric acid, or respectively- the 6-amino caproic acid with formic acid and formaldehyde 40% solution with molar ratios generally comprised between 1:2:2 and 1:10:4 under reflux for a time variable from 0.5 and 3 hours. The mixture of reaction is then concentrated under vacuum and at a temperature of 100-120°C until distillation has gone to end and the residual product thus obtained is directly passed to the reaction with H3PO3 and PX3 in the previously indicated, known molar ratio without the need of isolating any intermediate product. The product resulting from the reaction can be easily recrystallized from water if necessary.
The above described method allows for the final product to be obtained from the corresponding aminoacids which are more easily available and less expensive than the corresponding dimethylamino substituted acids that are thus formed in situ and reacted with no need for their purification, this obviously resulting in a considerable overall saving of the process.
Practical examples of the method according to the invention are given herebelow. Example 1 131,2 g (1 mole) of 6-amino-caproic acid are dissolved in 190 ml (5 moles) of 99% formic acid and 170 ml (2,2 moles) of a 40% solution formic aldehyde; the solution is kept under reflux for 3 hours and then concentrated under vacuum up to about 110°C until the end of distillation. The reaction apparatus is placed under nitrogen and 246 g (3 moles) of H3PO3 are added; the temperature is raised to 90°C and 363 ml (4,14 moles) of PCI3 are gradually added. The mixture is kept
under low reflux for 3 hours and then cooled. 500 ml of distilled water are then slowly added and heat is provided at low rate until an omogeneous solution is obtained; after 6 hours reflux, the solution is filtered with decolorizing coal, concentrated and treated with methanol until a white powder is obtained which is then filtered, washed with distilled water and dried at 40°C under vacuum.
164.8 g (0,54 moles) of 6-dimethylamino-hydroxy- hexan-l,l-diphosphonic acid are obtained whose identity and high purity are confirmed with the analyses. Example 2 206 g (1,5 moles) of PCI3 are dissolved in a mixture of 5-dimethylamino-valerianic acid (145,2 g, 1 mole) and H3PO3 (246 g, 3 moles) by a dropwise addition under anhydrous conditions, under vacuum and stirring; the solution is kept under slow PCI3 reflux for 3 hours and then caused to cool.
600 ml of distilled water are cautiously added while maintaining the reaction vessel in a ice bath; once the solution is become homogeneous, it is refluxed for 6 hours and then treated with decolorizing charcoal and filtered. An equal volume of methanol is then added and the solution is left under stirring for 24 hours. The obtained product is filtered washed with distilled water and dried at 60°C.
168.9 g (0,58 moles) of 5-dimethylamino-hydroxy- pentan-1,1-diphosphonic acid are obtained, the identity is confirmed by the elementary, alkalimetric and spectroscopic analyses. The yield is equal to 58%. Example 3
206 g (1,5 moles) of PCI3 are slowly added under stirring to a suspension obtained by mixing 159.2 g (1
mole) of 6-dimethylamino caproic acid with 164 g (2 moles) of H3PO3 in 500 ml of chlorobenzene brought to 90°C under a nitrogen stream; the mixture is moderately refluxed for 3 hours and then is caused to cool. 500 ml of distilled water are then added slowly and under stirring, once any solid matter possibly present is separated and the acqueous phase is refluxed for 6 hours. After cooling and filtering with decolorizing charcoal an equal volume of methanol is added and the mixture is left under stirring for 24 hours. The product obtained is filtered, washed with distilled water and dried at 60°C. 192.3 g (0.63 moles) of 6-dimethylamino-hydroxy-hexan-l,l-diphosphonic acid are obtained the identity of which is confirmed by the elementary alkalimetric and spectroscopic analyses.
The yield is equal to 63%. The water-soluble salts of the acids according to the present invention can be obtained by complete or partial neutralization with inorganic, organic bases or quaternary ammonium, such as NaOH, KOH, NH OH, alkaline carbonates, alkanolamines, and the like, and isolating the salt by a following concentration up to crystallization or, alternately and more simply, by precipitation with a C1-C3 alcohol or acetone. The diphosphonic acids according to the present invention and their saline derivatives are suitable for the preparation of pharmaceutical compositions useful in the therapeutic or preventive treatment of diseases associated with disturbances of bone metabolism, such as osteoporosis, Paget's disease, osteolysis caused by tumours and hyperparathyroidsm, osteoarthrosis, arthrytis and the like.
The toxicological studies which have been carried out have shown a toxicity of the compounds of the invention much lower than that of the corresponding non-methylated products. The results of these studies are summarized herebelow. a) 6-dimethylamino-l-hydroxy-hexan-l ,1- diphosphonic acid (DAEDP) .
No case of death has been recorded for animals treated with doses of 60 mg/Kg of DAEDP, whereas with an equal dose of sodic aminohexandiphosphonate a death- rate of 85% has been recorded, analogous to that recorded in previous tests on the same product. Likewise, no case of death has been recorded when the animals are treated with a dose of 30 mg/Kg of DAEDP, whereas a death-rate of 25% is recorded when using an equal dose of sodic aminohexandiphosphonate. b) 5-dimethylamino-l-hydroxypentan-l ,1- diphosphonic acid (DAPeDP)
No case of death has been recorded for animals treated with doses of 90 mg/Kg of DAPeDP, whereas with an equal dose of sodic aminopentandiphosphonate a death-rate of 75% has been recorded, slightly lower than that recorded in previous tests on the same product. Likewise, no case of death has been recorded when the animals are treated with 45 mg/Kg of DAPeDP, whereas a death-rate of 25% has been recorded when an equal dose of sodic aminopentan-diphosphonate is used.
Tests of inhibition of bone reabsorption, induced by parathormone in the calve of newborn rats, show a dose-dependant inhibitory activity which has been found with all the concentrations used with a maximum of 55.9% for DAEDP and 64% for DAPeDP with the highest dose used in the relevant tests.
Re inoid Test: the results show that the dimethylated derivatives (DAEDP and DAPeDP) according to the invention are able to inhibit the bone reabsorption in vivo induced by retinoid. The compounds have been proven more effective than the corresponding non-dimethylated compounds even if used at the same doses.
The pharmaceutical compositions according to the present invention can be prepared in the form of: - tablets, capsules, granules, pills, for oral administration;
- drops for oral administration;
- solutions for intra-articular or intravenous administration; - creams for local use.
The above compositions are advantageously prepared in combination with inert excipients, such as sugars (saccharose, glucose, lactose) , starch and derivatives, cellulose and derivatives, fatty acids and salts thereof, polyalcohols, talc, aromatic esters. Typical pharmaceutical formulations containing the 5- dimethylamino-hydroxypentan-1,1,-diphosphonic acid (DAPeDP) are given below.
OPERCULATE CAPSULES - One capsule contains DAPeDP 25 mg lactose 84 mg hydrolyzed starch 5 mg talc 5 mg magnesium stearate 1 mg
DROPS - 10 ml contain
DAPeDP 1 g buffer 1 ml
stabilizing, aromatizing trace purified water balance
INJECTABLE SOLUTION - One phial contain
DAPeDP 20 mg sodium chloride 40 mg sodium bicarbonate IN soln. 0.15 mg methyl parahydroxybenzoate 5 mg purified water 5 ml
INJECTABLE SOLUTION FOR INTRA-ARTICULAR ADMINISTRATION -
One ampoule contains
DAPeDP 1 mg anhydrous sodium hydroxyde 0,325 mg lidocaine hydrochloride 1 mg glycine 20 mg water pH 6.45 1 mg
GRANULAR PRODUCT - One dose contains
DAPeDP 200 mg talc 10 mg magnesium stearate 2 mg silica gel 4 mg cornstarch 9 mg
EFFERVESCENT GRANULAR PRODUCT - One dose contains
DAPeDP 10 mg anydhrous sodium carbonate 12 mg sodium bicarbonate 63 mg anyhydrous citric acid 110 mg sodium saccharinate 5 mg saccharose 493 mg
dehydrated lemmon juice 55 mg le mon natural juice 2 mg
3% CREAM DAPeDP 3 g cetyl alcohol 18 g propylene glycol 10 g
PEG monostearate 4 g cholesterin-stearate 1 g linol-linoleic acid 1.5 g preservative, stabilizers 0.5 g distilled water 100 g
Similar formulations can be adopted when 6- dimethylamino-hydroxyhexan-1,1-diphosphonic acid (DAEDP) is used.
The dosage range of the diphosphonic acids according to the present invention and of the relevant water-soluble saline derivative, according to the therapeutic use and referred to 1 Kg of body weight can be the following:
Capsules, tablets 5 - 400 mg drops 5 - 200 mg i.v. phial 1 - 100 mg subcutaneous phial 1 - 50 mg intramuscular phial 1 - 50 mg intra-articular phial 0.1 - 5 mg
Claims (10)
1. Dimethylamino-l-hydroxyalkan-1,1-diphosphonic acids of the formula:
wheren n= 4 or 5
2. 5-dimethylamino-1-hydroxypentan-l,1-diphosphonic acid of the formula:
3. 6-dimethylamino-1-hydroxyhexan-l,1-diphosphonic acid of the formula:
4. A process for the preparation of dimethylamino- hydroxy-alkan-diphosphonic acids of the formula
wherein n= 4 or 5, characterized in that it comprises: reacting a corresponding aminoacid with formic acid and 40% solution formaldehyde according to a molar ratio comprised between 1:2:2 and 1:10:4; - concentrating under vacuum the reaction mixture at 100-120°C;
- reacting the concentrate with H3PO3 and with PX3 (X-halogen) according to a molar ratio known in the art; diluting with distilled water under reflux for about 6 hours and subjecting to crystallization;
- filtering, washing with distilled water and drying under vacuum the crystalline precipitate.
5. A process according to the claim 4, wherein said corresponding aminoacid is 5-amino valeric acid.
6. A process according to the claim 4, wherein said corresponding amino acid is 6-aminocaproic acid.
7. A process according to the claim 4, wherein the reaction between said corresponding aminoacid, formic acid and 40% solution formaldehyde is carried out under reflux for a time comprised between 0.5 and 3 hours.
8. A process according to the claim 4, wherein the concentration under vacuum of the reaction mixture between said corresponding aminoacid, formic acid and formaldehyde 40% solution is carried out until the distillation is complete.
9. A pharmaceutical composition comprising an effective amount of dimethylamino-l-hydroxy-alkan-1,1- diphosphonic acid according to the claim 1, or a pharmaceutically acceptable water-soluble salt thereof and suitable pharmaceutical excipients.
10. Use of dimethylamino-hydroxy-alkan-1,1- diphosphonic acids according to the claims 1,2 and 3 and pharmaceutically acceptable water-soluble salts thereof, for the preparation of drugs effective in the treatment of diseases associated with disturbances of bone metabolism such as osteoporosis, Paget's disease, osteolysis caused by tumours or hyperparathyroidism, osteoarthrosis, arthritis and the like.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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ITFI91A0160 | 1991-06-26 | ||
ITFI910160A IT1247034B (en) | 1991-06-26 | 1991-06-26 | DIMETHYLAMINE-HYDROXY ACIDS DIPHOSPHONICS AND THEIR SALTS, THEIR PRODUCTION PROCESS AND PHARMACEUTICAL COMPOSITIONS THAT INCLUDE THEM |
Publications (1)
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AU2150792A true AU2150792A (en) | 1993-01-25 |
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AU21507/92A Abandoned AU2150792A (en) | 1991-06-26 | 1992-05-27 | Dimethylamino-hydroxy-alkan diphosphonic acids and pharmaceutical compositions containing them |
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EP (1) | EP0592488A1 (en) |
JP (1) | JPH06508833A (en) |
AU (1) | AU2150792A (en) |
CA (1) | CA2112250A1 (en) |
IT (1) | IT1247034B (en) |
MX (1) | MX9203205A (en) |
PT (1) | PT100624B (en) |
WO (1) | WO1993000348A1 (en) |
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IT1303672B1 (en) | 1998-07-28 | 2001-02-23 | Nicox Sa | NITRATED SALTS OF DRUGS ACTIVE IN BONE DISORDERS |
DE60235085D1 (en) * | 2001-07-16 | 2010-03-04 | Univ Paris Xiii | PREPARATION OF DERIVATIVES OF BISPHOSPHONATES |
DE102014115154A1 (en) * | 2014-10-17 | 2016-04-21 | SCV-SpezialChemikalien-Vertrieb GmbH | Conjugated bisphosphonates for the diagnosis and treatment of bone diseases |
Family Cites Families (4)
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IT1194748B (en) * | 1981-02-12 | 1988-09-28 | Gentili Ist Spa | PHARMACEUTICAL COMPOSITIONS FOR THE TREATMENT OF OSTEOPATHIES |
IT1201087B (en) * | 1982-04-15 | 1989-01-27 | Gentili Ist Spa | PHARMACOLOGICALLY ACTIVE BIPPHOSPHONES, PROCEDURE FOR THEIR PREPARATION AND RELATED PHARMACEUTICAL COMPOSITIONS |
DE3434667A1 (en) * | 1984-09-21 | 1986-04-03 | Henkel KGaA, 4000 Düsseldorf | 4-DIMETHYLAMINO-1-HYDROXYBUTANE-1,1-DIPHOSPHONIC ACID, THEIR WATER-SOLUBLE SALTS, PROCESS FOR THEIR PRODUCTION AND THEIR USE |
DE3623397A1 (en) * | 1986-07-11 | 1988-01-14 | Boehringer Mannheim Gmbh | NEW DIPHOSPHONIC ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS |
-
1991
- 1991-06-26 IT ITFI910160A patent/IT1247034B/en active IP Right Grant
-
1992
- 1992-05-27 EP EP92913148A patent/EP0592488A1/en not_active Withdrawn
- 1992-05-27 JP JP5501416A patent/JPH06508833A/en active Pending
- 1992-05-27 AU AU21507/92A patent/AU2150792A/en not_active Abandoned
- 1992-05-27 WO PCT/IT1992/000058 patent/WO1993000348A1/en not_active Application Discontinuation
- 1992-05-27 CA CA002112250A patent/CA2112250A1/en not_active Abandoned
- 1992-06-24 MX MX9203205A patent/MX9203205A/en unknown
- 1992-06-25 PT PT100624A patent/PT100624B/en not_active IP Right Cessation
Also Published As
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PT100624B (en) | 1999-07-30 |
IT1247034B (en) | 1994-12-12 |
ITFI910160A1 (en) | 1992-12-26 |
MX9203205A (en) | 1994-06-30 |
CA2112250A1 (en) | 1993-01-07 |
EP0592488A1 (en) | 1994-04-20 |
ITFI910160A0 (en) | 1991-06-26 |
JPH06508833A (en) | 1994-10-06 |
PT100624A (en) | 1993-10-29 |
WO1993000348A1 (en) | 1993-01-07 |
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