WO1994002152A2 - Phosphono derivatives as antiinflammatory and antiarthritic agents - Google Patents
Phosphono derivatives as antiinflammatory and antiarthritic agents Download PDFInfo
- Publication number
- WO1994002152A2 WO1994002152A2 PCT/US1993/004891 US9304891W WO9402152A2 WO 1994002152 A2 WO1994002152 A2 WO 1994002152A2 US 9304891 W US9304891 W US 9304891W WO 9402152 A2 WO9402152 A2 WO 9402152A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- defined above
- thru
- formula
- optionally substituted
- Prior art date
Links
- 125000001476 phosphono group Chemical group [H]OP(*)(=O)O[H] 0.000 title abstract description 16
- 230000003110 anti-inflammatory effect Effects 0.000 title abstract description 8
- 229940121363 anti-inflammatory agent Drugs 0.000 title abstract description 4
- 239000002260 anti-inflammatory agent Substances 0.000 title abstract description 4
- 229940124346 antiarthritic agent Drugs 0.000 title abstract description 4
- 239000003435 antirheumatic agent Substances 0.000 title abstract description 4
- -1 amino acid esters Chemical class 0.000 claims abstract description 97
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 33
- 150000002148 esters Chemical class 0.000 claims abstract description 32
- BWDGLLGNNPHQHY-UHFFFAOYSA-N OP(=O)P(O)(O)=O Chemical class OP(=O)P(O)(O)=O BWDGLLGNNPHQHY-UHFFFAOYSA-N 0.000 claims abstract description 17
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 66
- 125000001246 bromo group Chemical group Br* 0.000 claims description 64
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 38
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 36
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 34
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 25
- 229910052799 carbon Inorganic materials 0.000 claims description 25
- 125000000217 alkyl group Chemical group 0.000 claims description 22
- 125000004429 atom Chemical group 0.000 claims description 22
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 18
- 125000000623 heterocyclic group Chemical group 0.000 claims description 17
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 15
- 125000004432 carbon atom Chemical group C* 0.000 claims description 14
- 239000002253 acid Substances 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 10
- 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 description 10
- 125000004414 alkyl thio group Chemical group 0.000 claims description 10
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 9
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 8
- 125000004122 cyclic group Chemical group 0.000 claims description 7
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 6
- KPCZJLGGXRGYIE-UHFFFAOYSA-N [C]1=CC=CN=C1 Chemical group [C]1=CC=CN=C1 KPCZJLGGXRGYIE-UHFFFAOYSA-N 0.000 claims description 6
- 125000001544 thienyl group Chemical group 0.000 claims description 5
- WQADWIOXOXRPLN-UHFFFAOYSA-N 1,3-dithiane Chemical compound C1CSCSC1 WQADWIOXOXRPLN-UHFFFAOYSA-N 0.000 claims description 4
- 206010003246 arthritis Diseases 0.000 claims description 4
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
- MJUJXFBTEFXVKU-UHFFFAOYSA-N diethyl phosphonate Chemical compound CCOP(=O)OCC MJUJXFBTEFXVKU-UHFFFAOYSA-N 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 2
- VDFVNEFVBPFDSB-UHFFFAOYSA-N 1,3-dioxane Chemical compound C1COCOC1 VDFVNEFVBPFDSB-UHFFFAOYSA-N 0.000 claims description 2
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 claims description 2
- IMLSAISZLJGWPP-UHFFFAOYSA-N 1,3-dithiolane Chemical compound C1CSCS1 IMLSAISZLJGWPP-UHFFFAOYSA-N 0.000 claims description 2
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- OGONAKFJZXXMNQ-UHFFFAOYSA-N 3-methyl-6-phenylpyrimidin-4-one Chemical compound O=C1N(C)C=NC(C=2C=CC=CC=2)=C1 OGONAKFJZXXMNQ-UHFFFAOYSA-N 0.000 claims description 2
- ODGXHJBKHZALJP-UHFFFAOYSA-N C(C)OP(OCC)=O.C(C)OCP(=O)CCCC(=O)C1=CC(=CC=C1)F Chemical group C(C)OP(OCC)=O.C(C)OCP(=O)CCCC(=O)C1=CC(=CC=C1)F ODGXHJBKHZALJP-UHFFFAOYSA-N 0.000 claims description 2
- SZPWXAOBLNYOHY-UHFFFAOYSA-N [C]1=CC=NC2=CC=CC=C12 Chemical group [C]1=CC=NC2=CC=CC=C12 SZPWXAOBLNYOHY-UHFFFAOYSA-N 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 208000027866 inflammatory disease Diseases 0.000 claims description 2
- YNTQXTXGFTZMMR-ZDUSSCGKSA-N methyl (2s)-2-(diethylphosphorylamino)-3-(3-fluorophenyl)propanoate Chemical compound CCP(=O)(CC)N[C@H](C(=O)OC)CC1=CC=CC(F)=C1 YNTQXTXGFTZMMR-ZDUSSCGKSA-N 0.000 claims description 2
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 2
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims description 2
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 claims description 2
- UZNKRPSOIPMUBF-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinolin-2-ium-4-carboxylate Chemical compound C1=CC=C2C(C(=O)O)CNCC2=C1 UZNKRPSOIPMUBF-UHFFFAOYSA-N 0.000 claims 1
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims 1
- 125000004494 ethyl ester group Chemical group 0.000 claims 1
- KWXIJXJIKYSPNV-GFCCVEGCSA-N methyl (2R)-2-(diethylphosphorylamino)-2-phenylacetate Chemical compound COC([C@H](NP(=O)(CC)CC)C1=CC=CC=C1)=O KWXIJXJIKYSPNV-GFCCVEGCSA-N 0.000 claims 1
- NTHVDRZWJHCSPA-UHFFFAOYSA-N methyl 2-(diethylphosphorylamino)-3-(2-fluorophenyl)propanoate Chemical compound CCP(=O)(CC)NC(C(=O)OC)CC1=CC=CC=C1F NTHVDRZWJHCSPA-UHFFFAOYSA-N 0.000 claims 1
- KGGXAYWOQPZHNS-UHFFFAOYSA-N methyl 2-(diethylphosphorylamino)-3-thiophen-2-ylpropanoate Chemical compound CCP(=O)(CC)NC(C(=O)OC)CC1=CC=CS1 KGGXAYWOQPZHNS-UHFFFAOYSA-N 0.000 claims 1
- 150000004702 methyl esters Chemical class 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 31
- 230000002757 inflammatory effect Effects 0.000 abstract description 3
- 230000002917 arthritic effect Effects 0.000 abstract 2
- 201000010099 disease Diseases 0.000 abstract 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 66
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 51
- 238000006243 chemical reaction Methods 0.000 description 38
- 125000001424 substituent group Chemical group 0.000 description 33
- 150000001875 compounds Chemical class 0.000 description 31
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- 239000000203 mixture Substances 0.000 description 25
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 23
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 20
- 150000001721 carbon Chemical group 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- 229940024606 amino acid Drugs 0.000 description 16
- 235000001014 amino acid Nutrition 0.000 description 16
- 239000002904 solvent Substances 0.000 description 16
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- 239000000126 substance Substances 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
- 150000004985 diamines Chemical class 0.000 description 10
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 10
- LXAIOGNZCSLYMD-UHFFFAOYSA-N 6-[2-(dimethylamino)ethyl]-1h-pyrimidin-2-one Chemical compound CN(C)CCC1=CC=NC(=O)N1 LXAIOGNZCSLYMD-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 150000001413 amino acids Chemical class 0.000 description 9
- LGTLXDJOAJDFLR-UHFFFAOYSA-N diethyl chlorophosphate Chemical compound CCOP(Cl)(=O)OCC LGTLXDJOAJDFLR-UHFFFAOYSA-N 0.000 description 9
- 239000000284 extract Substances 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 230000008569 process Effects 0.000 description 8
- UYXQLQUXXCIFQM-UHFFFAOYSA-N 2-hydroxy-1,3,2$l^{5}-dioxaphospholane 2-oxide Chemical class OP1(=O)OCCO1 UYXQLQUXXCIFQM-UHFFFAOYSA-N 0.000 description 7
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 235000011152 sodium sulphate Nutrition 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- 238000004809 thin layer chromatography Methods 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 5
- 230000002456 anti-arthritic effect Effects 0.000 description 5
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 5
- 230000032050 esterification Effects 0.000 description 5
- 238000005886 esterification reaction Methods 0.000 description 5
- 229960005190 phenylalanine Drugs 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- AVOAXFYUTWRNEQ-UHFFFAOYSA-N 2-formamidopropanedioic acid Chemical compound OC(=O)C(C(O)=O)NC=O AVOAXFYUTWRNEQ-UHFFFAOYSA-N 0.000 description 4
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000012634 fragment Substances 0.000 description 4
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 4
- 239000012038 nucleophile Substances 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- KKMOLRJQCZVPRZ-UHFFFAOYSA-N 2,3-dimethyl-6-phenylpyrimidin-4-one Chemical compound O=C1N(C)C(C)=NC(C=2C=CC=CC=2)=C1 KKMOLRJQCZVPRZ-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 3
- 238000006957 Michael reaction Methods 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
- 125000005647 linker group Chemical group 0.000 description 3
- 125000001624 naphthyl group Chemical group 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 238000012552 review Methods 0.000 description 3
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 150000003431 steroids Chemical class 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 3
- 238000010626 work up procedure Methods 0.000 description 3
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 2
- WEGYGNROSJDEIW-UHFFFAOYSA-N 3-Acetylpyridine Chemical compound CC(=O)C1=CC=CN=C1 WEGYGNROSJDEIW-UHFFFAOYSA-N 0.000 description 2
- JPASAQMMHIRZFU-UHFFFAOYSA-N CCOCP(=O)C(=C)P(O)(O)=O Chemical compound CCOCP(=O)C(=C)P(O)(O)=O JPASAQMMHIRZFU-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical class C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 2
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 2
- 229930040373 Paraformaldehyde Natural products 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- QQIRAVWVGBTHMJ-UHFFFAOYSA-N [dimethyl-(trimethylsilylamino)silyl]methane;lithium Chemical compound [Li].C[Si](C)(C)N[Si](C)(C)C QQIRAVWVGBTHMJ-UHFFFAOYSA-N 0.000 description 2
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 229960003767 alanine Drugs 0.000 description 2
- 235000004279 alanine Nutrition 0.000 description 2
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 2
- 239000002168 alkylating agent Substances 0.000 description 2
- 229940100198 alkylating agent Drugs 0.000 description 2
- JINBYESILADKFW-UHFFFAOYSA-N aminomalonic acid Chemical compound OC(=O)C(N)C(O)=O JINBYESILADKFW-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 239000004305 biphenyl Substances 0.000 description 2
- 235000010290 biphenyl Nutrition 0.000 description 2
- 125000006267 biphenyl group Chemical group 0.000 description 2
- 230000008468 bone growth Effects 0.000 description 2
- 235000011089 carbon dioxide Nutrition 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- PFLHGSJLYNJIOF-UHFFFAOYSA-N diethyl 2-formamidopropanedioate Chemical compound CCOC(=O)C(NC=O)C(=O)OCC PFLHGSJLYNJIOF-UHFFFAOYSA-N 0.000 description 2
- KUMNEOGIHFCNQW-UHFFFAOYSA-N diphenyl phosphite Chemical compound C=1C=CC=CC=1OP([O-])OC1=CC=CC=C1 KUMNEOGIHFCNQW-UHFFFAOYSA-N 0.000 description 2
- 125000006575 electron-withdrawing group Chemical group 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000010265 fast atom bombardment Methods 0.000 description 2
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 2
- 150000008282 halocarbons Chemical class 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 150000002596 lactones Chemical class 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 235000011090 malic acid Nutrition 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- BZIPAMJMCZCLFS-UHFFFAOYSA-N methyl 2-amino-3-(3-fluorophenyl)propanoate Chemical compound COC(=O)C(N)CC1=CC=CC(F)=C1 BZIPAMJMCZCLFS-UHFFFAOYSA-N 0.000 description 2
- STZCRXQWRGQSJD-GEEYTBSJSA-M methyl orange Chemical compound [Na+].C1=CC(N(C)C)=CC=C1\N=N\C1=CC=C(S([O-])(=O)=O)C=C1 STZCRXQWRGQSJD-GEEYTBSJSA-M 0.000 description 2
- 229940012189 methyl orange Drugs 0.000 description 2
- 229920002866 paraformaldehyde Polymers 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 238000011176 pooling Methods 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 238000004611 spectroscopical analysis Methods 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 150000003512 tertiary amines Chemical class 0.000 description 2
- YONLFQNRGZXBBF-ZIAGYGMSSA-N (2r,3r)-2,3-dibenzoyloxybutanedioic acid Chemical compound O([C@@H](C(=O)O)[C@@H](OC(=O)C=1C=CC=CC=1)C(O)=O)C(=O)C1=CC=CC=C1 YONLFQNRGZXBBF-ZIAGYGMSSA-N 0.000 description 1
- NVFHUBRALOJXMJ-REOHCLBHSA-N (2s)-2-(phosphonoamino)butanedioic acid Chemical class OC(=O)C[C@@H](C(O)=O)NP(O)(O)=O NVFHUBRALOJXMJ-REOHCLBHSA-N 0.000 description 1
- HIUQIUQSEYDPNQ-YFKPBYRVSA-N (2s)-6-amino-2-(phosphonoamino)hexanoic acid Chemical class NCCCC[C@@H](C(O)=O)NP(O)(O)=O HIUQIUQSEYDPNQ-YFKPBYRVSA-N 0.000 description 1
- AOHJOMMDDJHIJH-VKHMYHEASA-N (2s)-propane-1,2-diamine Chemical compound C[C@H](N)CN AOHJOMMDDJHIJH-VKHMYHEASA-N 0.000 description 1
- LJRDOKAZOAKLDU-UDXJMMFXSA-N (2s,3s,4r,5r,6r)-5-amino-2-(aminomethyl)-6-[(2r,3s,4r,5s)-5-[(1r,2r,3s,5r,6s)-3,5-diamino-2-[(2s,3r,4r,5s,6r)-3-amino-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-6-hydroxycyclohexyl]oxy-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl]oxyoxane-3,4-diol;sulfuric ac Chemical compound OS(O)(=O)=O.N[C@@H]1[C@@H](O)[C@H](O)[C@H](CN)O[C@@H]1O[C@H]1[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](N)C[C@@H](N)[C@@H]2O)O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)N)O[C@@H]1CO LJRDOKAZOAKLDU-UDXJMMFXSA-N 0.000 description 1
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-UWTATZPHSA-N (R)-malic acid Chemical compound OC(=O)[C@H](O)CC(O)=O BJEPYKJPYRNKOW-UWTATZPHSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- GEYOCULIXLDCMW-UHFFFAOYSA-N 1,2-phenylenediamine Chemical compound NC1=CC=CC=C1N GEYOCULIXLDCMW-UHFFFAOYSA-N 0.000 description 1
- NYYLZXREFNYPKB-UHFFFAOYSA-N 1-[ethoxy(methyl)phosphoryl]oxyethane Chemical compound CCOP(C)(=O)OCC NYYLZXREFNYPKB-UHFFFAOYSA-N 0.000 description 1
- YOYAIZYFCNQIRF-UHFFFAOYSA-N 2,6-dichlorobenzonitrile Chemical compound ClC1=CC=CC(Cl)=C1C#N YOYAIZYFCNQIRF-UHFFFAOYSA-N 0.000 description 1
- VWHRYODZTDMVSS-UHFFFAOYSA-N 2-azaniumyl-3-(3-fluorophenyl)propanoate Chemical compound OC(=O)C(N)CC1=CC=CC(F)=C1 VWHRYODZTDMVSS-UHFFFAOYSA-N 0.000 description 1
- JTNCEQNHURODLX-UHFFFAOYSA-N 2-phenylethanimidamide Chemical compound NC(=N)CC1=CC=CC=C1 JTNCEQNHURODLX-UHFFFAOYSA-N 0.000 description 1
- DAOZBJCTEPJGES-UHFFFAOYSA-N 4-chloro-2-methylpyridine Chemical compound CC1=CC(Cl)=CC=N1 DAOZBJCTEPJGES-UHFFFAOYSA-N 0.000 description 1
- RREANTFLPGEWEN-MBLPBCRHSA-N 7-[4-[[(3z)-3-[4-amino-5-[(3,4,5-trimethoxyphenyl)methyl]pyrimidin-2-yl]imino-5-fluoro-2-oxoindol-1-yl]methyl]piperazin-1-yl]-1-cyclopropyl-6-fluoro-4-oxoquinoline-3-carboxylic acid Chemical compound COC1=C(OC)C(OC)=CC(CC=2C(=NC(\N=C/3C4=CC(F)=CC=C4N(CN4CCN(CC4)C=4C(=CC=5C(=O)C(C(O)=O)=CN(C=5C=4)C4CC4)F)C\3=O)=NC=2)N)=C1 RREANTFLPGEWEN-MBLPBCRHSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 229940122361 Bisphosphonate Drugs 0.000 description 1
- NJSRYSQXIIEQMQ-UQKRIMTDSA-N C(C)OC([C@@H](NP(=O)(CC)CC)CC1=CC=CC=C1)=O.[N] Chemical compound C(C)OC([C@@H](NP(=O)(CC)CC)CC1=CC=CC=C1)=O.[N] NJSRYSQXIIEQMQ-UQKRIMTDSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 238000001159 Fisher's combined probability test Methods 0.000 description 1
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical group NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 229930194542 Keto Natural products 0.000 description 1
- FFEARJCKVFRZRR-UHFFFAOYSA-N L-Methionine Natural products CSCCC(N)C(O)=O FFEARJCKVFRZRR-UHFFFAOYSA-N 0.000 description 1
- FDIKHVQUPVCJFA-YFKPBYRVSA-N L-Phosphohistidine Chemical class OP(=O)(O)N[C@H](C(=O)O)CC1=CN=CN1 FDIKHVQUPVCJFA-YFKPBYRVSA-N 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- 229930195722 L-methionine Natural products 0.000 description 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
- FEWJPZIEWOKRBE-XIXRPRMCSA-N Mesotartaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-XIXRPRMCSA-N 0.000 description 1
- 238000006845 Michael addition reaction Methods 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical group OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- 150000001241 acetals Chemical class 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 239000006286 aqueous extract Substances 0.000 description 1
- 239000012431 aqueous reaction media Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 206010003549 asthenia Diseases 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 238000005102 attenuated total reflection Methods 0.000 description 1
- XGIUDIMNNMKGDE-UHFFFAOYSA-N bis(trimethylsilyl)azanide Chemical compound C[Si](C)(C)[N-][Si](C)(C)C XGIUDIMNNMKGDE-UHFFFAOYSA-N 0.000 description 1
- 150000004663 bisphosphonates Chemical class 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000036765 blood level Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 230000000125 calcaemic effect Effects 0.000 description 1
- LSPHULWDVZXLIL-QUBYGPBYSA-N camphoric acid Chemical compound CC1(C)[C@H](C(O)=O)CC[C@]1(C)C(O)=O LSPHULWDVZXLIL-QUBYGPBYSA-N 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000000451 chemical ionisation Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 150000001923 cyclic compounds Chemical class 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000005595 deprotonation Effects 0.000 description 1
- 238000010537 deprotonation reaction Methods 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- 150000008050 dialkyl sulfates Chemical class 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000012039 electrophile Substances 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- HHFAWKCIHAUFRX-UHFFFAOYSA-N ethoxide Chemical compound CC[O-] HHFAWKCIHAUFRX-UHFFFAOYSA-N 0.000 description 1
- FEPXGMCQSOADIW-UHFFFAOYSA-N ethyl 2-(dimethylphosphorylamino)-3-phenylpropanoate Chemical compound CCOC(=O)C(NP(C)(C)=O)CC1=CC=CC=C1 FEPXGMCQSOADIW-UHFFFAOYSA-N 0.000 description 1
- COFHROICZIFWND-UHFFFAOYSA-N ethyl 2-(diphenylphosphorylamino)-3-phenylpropanoate Chemical compound C=1C=CC=CC=1P(=O)(C=1C=CC=CC=1)NC(C(=O)OCC)CC1=CC=CC=C1 COFHROICZIFWND-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- AZMMUMQYPBKXHS-UHFFFAOYSA-N gold sodium Chemical compound [Na].[Au] AZMMUMQYPBKXHS-UHFFFAOYSA-N 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 1
- 229960004452 methionine Drugs 0.000 description 1
- NBTOZLQBSIZIKS-UHFFFAOYSA-N methoxide Chemical compound [O-]C NBTOZLQBSIZIKS-UHFFFAOYSA-N 0.000 description 1
- YTNGWXICCHJHKA-JTQLQIEISA-N methyl (3s)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate Chemical compound C1=CC=C2CN[C@H](C(=O)OC)CC2=C1 YTNGWXICCHJHKA-JTQLQIEISA-N 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- SNVLJLYUUXKWOJ-UHFFFAOYSA-N methylidenecarbene Chemical compound C=[C] SNVLJLYUUXKWOJ-UHFFFAOYSA-N 0.000 description 1
- DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- DBNQIOANXZVWIP-UHFFFAOYSA-N n,n-dimethyl-1,1-bis[(2-methylpropan-2-yl)oxy]methanamine Chemical compound CC(C)(C)OC(N(C)C)OC(C)(C)C DBNQIOANXZVWIP-UHFFFAOYSA-N 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 229960001639 penicillamine Drugs 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229960002895 phenylbutazone Drugs 0.000 description 1
- VYMDGNCVAMGZFE-UHFFFAOYSA-N phenylbutazonum Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 VYMDGNCVAMGZFE-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000003236 psychic effect Effects 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 229960001153 serine Drugs 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229960004799 tryptophan Drugs 0.000 description 1
- 229960004441 tyrosine Drugs 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 238000005406 washing Methods 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 Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms
- C07F9/655345—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms the sulfur atom being part of a five-membered ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/67—Phosphorus compounds having sulfur as a ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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 Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/22—Amides of acids of phosphorus
- C07F9/24—Esteramides
- C07F9/2454—Esteramides the amide moiety containing a substituent or a structure which is considered as characteristic
- C07F9/2458—Esteramides the amide moiety containing a substituent or a structure which is considered as characteristic of aliphatic amines
-
- 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 Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/22—Amides of acids of phosphorus
- C07F9/24—Esteramides
- C07F9/2454—Esteramides the amide moiety containing a substituent or a structure which is considered as characteristic
- C07F9/247—Esteramides the amide moiety containing a substituent or a structure which is considered as characteristic of aromatic amines (N-C aromatic linkage)
-
- 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 Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/22—Amides of acids of phosphorus
- C07F9/24—Esteramides
- C07F9/2454—Esteramides the amide moiety containing a substituent or a structure which is considered as characteristic
- C07F9/2475—Esteramides the amide moiety containing a substituent or a structure which is considered as characteristic of aralkylamines
-
- 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 Table
- 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 ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
- C07F9/3808—Acyclic saturated acids which can have further substituents on alkyl
- C07F9/3821—Acyclic saturated acids which can have further substituents on alkyl substituted by B, Si, P or a metal
-
- 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 Table
- 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 ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
- C07F9/3882—Arylalkanephosphonic acids
-
- 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 Table
- 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 ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
- C07F9/4012—Esters of acyclic acids which can have further substituents on alkyl substituted by B, Si, P or a metal
-
- 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 Table
- 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 ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4015—Esters of acyclic unsaturated acids
-
- 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 Table
- 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 ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4056—Esters of arylalkanephosphonic acids
-
- 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 Table
- 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 ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4071—Esters thereof the ester moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4081—Esters with cycloaliphatic alcohols
-
- 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 Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/572—Five-membered rings
- C07F9/5728—Five-membered rings condensed with carbocyclic rings or carbocyclic ring systems
-
- 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 Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/58—Pyridine rings
-
- 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 Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/62—Isoquinoline or hydrogenated isoquinoline ring systems
-
- 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 Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
- C07F9/6509—Six-membered rings
- C07F9/6512—Six-membered rings having the nitrogen atoms in positions 1 and 3
Definitions
- the phosphono derivatives (XII) of amino acid esters are useful as antiinflammatory and antiarthritic agents.
- French Patent M 6430 (1968) discloses derivatives of N-phosphoaspartic acid and their salts for treating psychic and physic asthenia.
- Synthesis 6 444-8 (1988) discloses synthesis of N-dimethylphosphoryl DL-phenylalanine ethyl ester.
- European Patent 0085488 (1983) discloses phosphono peptide derivatives as antihypertensive agents.
- WO 9,012,017 discloses pyrazoline diphosphonates useful for aniinflammatory and/or antiarthritic use.
- diamines can be diphosphorylated with diphenylphosphite or diphenyl phosphorchloroidothionate to produce diphosphorylated diamines.
- J. Med. Chem., 27, 654 (1984) discloses how to prepare diphosphorylated diamine phenyl esters.
- the present invention does not include aromatic esters.
- phosphonophosphinate acids useful for promoting bone growth where the non-phosphate portion includes 2-pyridinyl substitution.
- the present invention includes esters but not acids, and are useful for a different purpose, namely treatment of inflammation and arthritis not bone growth.
- R 1 -CH[NR 2 -PO(OR 4 )(OR 5 )]COOR 3 (III) where R 1 is R 1-3 -(CR 1-1 R 1-2 ) n - where R 1-1 and R 1-2 are the same or different and are -H or C 1 -C 4 alkyl, where n 1 and where R 1-3 is
- R 1-4 is C 1 -C 3 alkyl or -CO-C 1 -C 4 alkyl, or combinations thereof,
- R 2 is -H or C 1 -C 4 alkyl
- R 3 is -H or C 1 -C 4 alkyl
- R 4 is -H or C 1 -C 6 alkyl
- R 5 is -H or C 1 -C 6 alkyl and where R 4 and R 5 are taken together to form a heterocyclic ring consisting of 5 thru 7 atoms and pharmaceutically acceptable salts thereof.
- R 6 -CH[NR 7 -PO(OR 4 )(OR 5 )]COOR 3 (IX) where R 3 is -H or C 1 -C 4 alkyl;
- R 4 is -H or C 1 -C 6 alkyl
- R 5 is -H or C 1 -C 6 alkyl and where R 4 and R 5 are taken together to form a heterocyclic ring consisting of 5 thru 7 atoms;
- 2- or 3-thienyI optionally substituted with 1 thru 3 -F, -Cl, -Br, -OH,
- R 6-6 is C 1 -C 3 alkyl or -CO- C 1 -C 4 alkyl or combinations thereof and where R 7 is -H or C 1 -C 4 alkyl
- 2-triazinyl optionally substituted with 1 or 2 -F, -Cl, -Br, -OH, -OR 6-4 where R 6-6 is as defined above, or combinations thereof and where R 7 is -H or C 1 -C 4 alkyl;
- R 6-5 is C 1 -C 4 alkyl
- R 4 is -H or C 1 -C 6 alkyl
- R 5 is -H or C 1 -C 6 alkyl and where R 4 and R 5 are taken together to form a heterocyclic ring consisting of 5 thru 7 atoms;
- R 8-4 is C 1 -C 3 alkyl or -CO- C 1 -C 4 alkyl, or combinations thereof,
- R 8-4 is C 1 -C 3 alkyl or -CO-C 1 -C 4 alkyl, or combinations thereof,
- R 9 is -H or C 1 -C 6 alkyl and where R 4 and R 5 are taken together to form a heterocyclic ring consisting of 5 thru 7 atoms and pharmaceutically acceptable salts thereof.
- R 10 -CH[NR 11 -PO(OR 4 )(O R5 )]COOR 3 (XI) where R 3 is -H or C 1 -C 4 alkyl;
- R 4 is -H or C 1 -C 6 alkyl
- R 5 is -H or C,-C 6 alkyl and where R 4 and R 5 are taken together to form a heterocyclic ring consisting of 5 thru 7 atoms;
- R 10-4 is C 1 -C 3 alkyl or -CO-C 1 -C 4 alkyl, or combinations thereof,
- R 11 is -H or C 1 -C 4 alkyl and pharmaceutically acceptable salts thereof.
- N,N'-diphosphonodiamine esters of formula (XV) are also disclosed.
- R 4 is -H or C 1 -C 6 alkyl
- R 5 is -H or C 1 -C 6 alkyl and where R 4 and R 5 are taken together to form a heterocyclic ring consisting of 5 thru 7 atoms;
- R 12 is
- R 13 is
- R 13-4 is C, -C 3 alkyl or -CO-C 1 -C 4 alkyl, or combinations thereof,
- M is -H, -Cl or -CH 3 ;
- R 4 is C 1 -C 6 alkyl
- R 5 is C 1 -C 6 alkyl and where R 4 and R 5 are taken together to form a heterocyclic ring consisting of 5 thru 7 atoms;
- R 14 is (1) - ⁇ optionally substituted with 1 or 2 - ⁇ or with 1 thru 5 -F, -Cl, -Br,
- - ⁇ optionally substituted with 1 thru 5 -F, -Cl, -Br, -I,
- - ⁇ optionally substituted with 1 thru 5 -F, -Cl, -Br, -I, -NO 2 ,
- - ⁇ optionally substituted with 1 thru 5 -F, -Cl, -Br, -I,
- naphthalene optionally substituted with 1-7 -F, -Cl, -Br, -I, -NO 2 , -CN, -CF 3 , C 1 -C 10 alkyl, C 3 -C 7 cycloalkyl, -OH, C 1 -C 4 alkoxy, -O- ⁇ , C 1 -C 4 alkylthio or -N(CH 3 ) 2 ,
- R 14-5 and R 14-6 are the same or different and are -H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, - ⁇ , 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, and where R 2-5 and R 2-6 are taken together with the attached nitrogen atom to form a heterocyclic ring containing 4 thru 6 carbon atoms, a 1-morpholine and 1-piperidine ring,
- R 14-7 is H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, - ⁇ , 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, and where R 14-1 is as defined above,
- R 14-8 is -H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, - ⁇ and -CH 2 - ⁇ ,
- R 14-5 , R 14-6 and R 14-7 are as defined above,
- R 14-4 is as defined above
- R 14-5 , R 14-6 and R 14-7 are as defined above,
- R 14-4 is as defined above
- R 14-5 , R 14-6 and R 14-7 are as defined above,
- R 14-4 is as defined above
- R 14-4 is as defined above
- R 14-4 is as defined above
- 2-thiazoIyl optionally substituted with 1 or 2 -F, -Cl, -Br, C 1 -C 4 alkoxy, C 1 - C 4 alkyl or - ⁇ ,
- R 15 /R 16 -II R 15 is -H and R 16 is -H, R 14-4 , -CO-O-R 14-8 , -CO-R 2 , -CN, -CO-NH-R 2 , -NH-CO-R 14-1 -S-R 14-1 and -CO-NH-thiadiazole optionally substituted with - ⁇ where R 14 , R 14-1 ,R 14-4 and R 14-8 are as defined above,
- R 15 is -H and R 16 is -F, -Cl, -Br or -I,
- R 15 and R 16 are the same or different and are C 1 -C 10 alkyl;
- W 1 is W j . j rW j . 2 where W,., and Wj. 2 are the same and are C,-C 4 alkoxy, -O- ⁇ , C 1 -C 4 alkylthio or -S- ⁇ ,
- W 1 is W 1-3 :W 1-4 where W 1-3 and W 1-4 are taken together with the attached carbon atom to form a 1,3-dioxane, 1,3-dioxolane, 1,3-dithiane, 1,3-dithiolane or 1,3-oxoathiolane ring system,
- W 1 -IV W 1 is -H:-W 1-5 where W 1-5 is
- W 1-6 is C 1 -C 4 alkyl
- R 14-4 is as defined above
- R 19 is C 1 -C 4 alkyl
- the phosphono compounds (XII) of the present invention are of four types (III, IX, X, and XI).
- the "benzyl-type” N-phosphono compounds (III) are known to those skilled in the art or can be readily prepared from known starting material by methods known to those skilled in the art.
- the novel "phenyl-type” N-phosphono compounds (X) contain a phenyl group but do not contain any linker -CR x R y -, (n would be 0).
- novel "nonphenyl-type” N-phosphono compounds (IX), "phenyl-type” N-phosphono compounds (X) and “phenylethylene-type” N-phosphono compounds (XI) are all made by methods know to those skilled in the art from known amino acids.
- novel N-phosphono compounds are prepared in a two step process. First esterification following known processes, for example those of E. Fisher, Berichte 38, 4186 (1905) or Boissonnas, et al, Helv. Chim. Acta, 41 1875 (1958) followed by phosphorylation again following known processes, for example that of J Am. Chem. Soc. 74, 5759 (1952).
- CHART A discloses a general method for the production of the phosphono compounds (Xn), of which the "benzyl-type" N-phosphono compounds (HI) is one-type.
- the amino acid esters (II) are made from available amino acids (I). This is in either racemic or optically active form and by methods known to those skilled in the art, see Fisher esterification [E. Fisher, Berichte 38, 4186 (1905)] or using thionyl chloride [Boissonnas, et al, Helv. Chim. Acta, 41 1875 (1958)].
- the amino acids have no substitution on the nitrogen atom (I-NH) or are substituted with an alkyl group (I-NR)-
- both -H and alkyl are included in the definition of the variable substituent R 2 .
- N-phosphoamino acid esters (III-NH and III-NR) are prepared from the corresponding amino acid ester (II) also by known methods, see J. Am. Chem. Soc. 74, 5759 (1952). This method uses a dialkylchlorophosphate in the presence of a base preferably triethylamine or pyridine. After extraction of the reaction mixture, the crude product is purified by known means, preferably chromatography over silica gel.
- N-phosphoamino acid ester (III-NH) can readily be converted to the corresponding N-alkylated-N-phosphoamino acid ester (III-NR) by deprotonation and alkylation with an alkyl halide or dialkyl sulfate or similar alkylating agent, see Modern Synthetic Reactions, H. O. House, 2nd Edition, p 510.
- Preferably excess base is used, more preferably a 2-3 fold excess is used.
- a strong base ⁇ Modern Synthetic Reactions, p 547) is used, most preferably sodium hydride is used.
- Suitable solvents for strong bases are known, see Modern Synthetic Reactions, p 547, more preferably dimethylformamide is used.
- CHART B discloses that the pyrimidinylhomoalanine ester (VIII) starting material is produced as follows.
- the 2,3-Dimethyl-6-phenylpyrimidin-4-one (IV) is heated with at least an equivalent of dimethylformamide dialkyl acetal, more preferably with at least 2 equivalents or most preferably in neat dimethylformamide dialkylacetal.
- the preferred dimethylformamide dialkylacetal is dimethylformamide di-t-butyl acetal.
- the reaction temperature is preferred to be 50-100° and usual reaction time is from 2-48 hr, more preferably about 95° for about 5-6 hr. Extractive workup or preferably the reaction mixture is diluted with ether and the solid dimethylaminoethylidinepyrimidone (V) is collected.
- the dimethylaminoethylidinepyrimidone (V) is reduced using sodium cyanoborohydride under typical conditions [Lane, Aldrichimica Acta, 8(1), 3 (1975)] in an acidic medium, preferably acidic to methyl orange using excess sodium cyanoborohydride, preferably an excess of 62 mole %.
- the reaction can be performed from about -10 to about 50°, preferably at about 20-25°.
- Alcoholic solvents or aqueous alcohol mixtures are suitable, preferably methanol is used.
- Acids described by Lane are suitable, preferably aqueous hydrochloric acid.
- Dimethylaminoethylpyrimidinone (VI) is used to alkylate diethylformamido malonate under conditions similar to those which have been used for other Mannich Bases [see Modern Synthetic Reactions, p 655] to produce the corresponding formamidomalonoethylpyrimidinone (VII). Following the method of House, Modern Synthetic Reactions, p 602,
- dimethylaminoethylpyrimidinone (VI) is quatemized with an alkylating agent, preferably a volatile agent so the excess can be evaporated, more preferably with methyl iodide.
- the resulting quaternary salt is treated with formamidomalonate in the presence of a base which is capable of both deprotonating the formamidomalonate and converting the quaternary Mannich Base derived from dimethylaminoethylpyrimidinone (VI), to a reactive ethylene derivative so it will react with the deprotonated formamidomalonate.
- a base such as metal alkoxides or tertiary amine bases can be used.
- the tertiary amine bases so that the reactive ethylene intermediate is formed slowly and in low concentration so that it has a chance to react with the deprotonated formamidomalonate rather than having it formed rapidly and in high concentration under which conditions it is destroyed by polymerization.
- DBU is used as the base.
- the reaction can be performed from about -20 to about 50°, with a reaction time of about 4 hr to 4 weeks; more preferably at about 20-25° for about 4 days.
- Suitable solvents for Michael reaction are described in Modern Synthetic Reactions, Chapter 10, which include alcohols and ethers, more preferably THF. After concentration of the reaction mixture it is diluted with water and aqueous hydrochloric acid to a pH of 1-3 and extracted with an organic solvent, preferably a halocarbon, more preferably chloroform. Treatment of a concentrate with ethyl acetate gives a solid form of the formamidomalonoethylpyrimidinone (VII).
- the formamidomalonoethylpyrimidinone (VII) is converted to the corresponding pyrimidinylhomoalanine ester (VIII) by complete hydrolysis of the ester and formamide groups to give a amino malonic acid.
- the amino malonic acid intermediate is not isolated but decarboxylates to an amino acid salt which also is preferably not isolated but is concentrated by removal of water and the acid used for hydrolysis. For this reason volatile acids preferably 6 N hydrochloric acid are preferred.
- the reaction temperature should be about 60 to about 100° to perform the reaction in about 10 hr to 10 days. Preferably one uses about 100° for about 24 hr. After concentration usual esterification methods for esterification of amino acids are used.
- the Fisher method or thionyl chloride method discussed above are preferred. The Fisher process is preferred over the thionyl chloride process. It should be realized that the
- pyrimidinylhomoalanine ester (VIII) is one particular amino acid ester (II) where R 1 is the 2,3-dimethyl-4-phenylpyrimidinylethyl side chain.
- N,N'-diphosphonodiamine esters are prepared according to known methods as disclosed in CHART D.
- the coupling of a diamine (XIII) and a halophosphate ester (XIV) is well known, see for example, J. Chem. Soc, 3614 (1971) which discloses that diamines can be diphosphorylated with diphenylphosphite or diphenyl phosphorochloridothionate to produce diphosphorylated diamines and J. Med. Chem., 27, 654 (1984) which discloses how to prepare diphosphorylated diamine phenyl esters.
- the diamine (Xm) be coupled with the halophosphate ester (XIV) Cl-P(O)(OR 3 )(OR 4 ).
- the preferred solvents are chloroform and methylene chloride. It is preferred to add a base to scavange the acid produced; preferred bases include DBU, pyridine and triethylamine.
- the phosphonophosphinate esters (XVIII) are prepared by known methods, the Michael Reaction.
- the phosphonophosphinate esters (XVIII) are prepared by contacting an electron deficient olefin, the ethylene phosphate esters (XVI) with a nucleophile (XVII) in the presence of a base.
- This reaction is so well known when the electron withdrawing group is a carbonyl group that it is termed the Michael Reaction, Michael Addition or 1 ,4-addition.
- Michael Reaction Michael Addition
- 1 p 595-623 For a review of this reaction see H. O. House, Modern Synthetic Reactions, Second Edition, W. A. Benjamin, Inc., Menlo Park, CA (1972), p 595-623.
- Suitable bases include methoxide, ethoxide, DBU, DBN, butyl lithium, methyl lithium, carbonate, bicarbonate, lithium hemamethyldisilazane (in THF or pyridine), hydride, lithium diisopropylamide. It is preferred that the base be DBU, lithium hexamethyldisilazane or carbonate depending on the nature of the particular starting materials.
- reaction is practiced by refluxing the ethylene phosphate ester (XVI), nucleophile (XVII) and base for about 0.5 to about 24 hours. After refluxing the mixture is diluted with water, extracted with an organic solvent such as methylene chloride, dried and concentrated under reduced pressure. The concentrate is preferably purified by (column) chromatography, distillation or crystallization as is known to those skilled in the art.
- the nucleophile (XVII) is first cooled to about 0 to about -78°, contacted slowly with a reagent such as lithium hexamethyldisilazane, and stirred a short period of about 15 minutes to about 1 hr.
- a reagent such as lithium hexamethyldisilazane
- the ethylene phosphate ester (XVI) is then added to the reaction mixture stirred cold (about 0°) for a short period (about 30 min) and then permitted to warm (about 20-25°) and stirred for another short period (about 30 min).
- M is -H. It is preferred that R 4 and R 5 is C 1 -C 4 alkyl, more preferrably ethyl. It is preferred that R 14 is 2-pyridinyl, 3pyridinyl, 2-fi ⁇ ranyl, 2-thienyl or - ⁇ optionally substituted with 1 thru 2 -F, -Cl, -N(R 14-7 )-CO-R 14-1 where R 14-7 is -H and R 14-1 is C 1 alkyl, C 2 alkyl or - ⁇ . It is even more preferred that R 14 be (substituted) - ⁇ or 2-pyridinyl.
- these compounds can be obtained by deprotonating the starting material under kinetic conditions with a strong base such as lithium hexamethyldisilzane or lithium diisopropyl amide and trapping the resulting anion with an appropriate electrophile.
- a strong base such as lithium hexamethyldisilzane or lithium diisopropyl amide
- the bisphosphonates have an asymmetric center at the carbon to which R 15 and R 16 are attached.
- the enantiomers can be separated as discussed below.
- amino acid (I), amino acid ester (II) and N-phosphono compounds (III) contain an asymmetric center and therefore produce two enantiomers one "S” and the other "R", either of which can be (+/d) and the other (-/1).
- racemic, + (racemic, +) mixture.
- they may be utilized in the racemic form without separating them.
- the optically impure mixture can be resolved by means known to those skilled in the art.
- many amino acids are available in optically pure form. It is possible to resolve the racemic mixture at the stage of the amino acid or amino ester (I or II) using methods known to those skilled in the art, see for example, Optical Resolution Procedures for Chemical Compounds, Vol 1,: Amines and Related Compounds, Paul Newman, Optical Resolution Information Center, Manhattan College, Riverdale, NY, 10471, 1978.
- N-phosphoamino acid ester includes both enantiomers as well as optically impure forms thereof, the most common of which is a racemic mixture ( ⁇ , dl).
- phosphono compounds (XII) will be used to designate and is meant to include the "benzyltype” N-phosphono compounds (III), the “nonphenyl-type” N-phosphono compounds (IX), the "phenyl-type” N-phosphono compounds (X), the "phenylethylene-type” N-phosphono compounds (XI), the N,N'diphosphonodiamine esters (XV) and the phosphonophosphinate esters (XVIII).
- R 3 is C 1 -C 4 alkyl, it is more preferred that R 3 is C 1 or C 2 alkyl. It is preferred that R 4 is C 1 -C 4 alkyl, it is more preferred that R 4 is C 2 alkyl. It is preferred that R 5 is C 1 -C 4 alkyl, it is more preferred that R 5 is C 2 alkyl. It is preferred that R 4 and R 5 are the same.
- R is ⁇ -CH 2 - optionally substituted with 1 -OH, it is more preferred that R 1 is ⁇ -CH 2 -. It is preferred that R 2 is -H or -CH 3 , it is more preferred that R 2 is -H.
- R 6 is thienyl and thienyl substituted with a -F, -Cl or -Br atom, it is more preferred that R 6 is thienyl. It is preferred that R 7 is -H or -CH 3 , it is more preferred that R 7 is -H.
- R 8 is - ⁇ optionally substituted with 1 or 2 -OH or -F, it is more preferred that R 8 is - ⁇ . It is preferred that R 9 is -H or -CH 3 , it is more preferred that R 9 is -H.
- R 10 is - CH 2 -CH 2 - ⁇ and -CH 2 -CH 2 - ⁇ -OH, it is more preferred that R 10 is -CH 2 -CH 2 - ⁇ . It is preferred that R 11 is -H or -CH 3 , it is more preferred that R 11 is -H.
- the preferred compounds are those of EXAMPLES 10, 13 and 16.
- the phosphono compounds (XII) are useful as antiinflammatory and antiarthritic agents.
- the phosphono compounds (XII) are useful in treating human inflammatory, granulomatous, calcemic artherosclerotic and hypertensive disease. Particulary preferred utilities are for the treatment of inflammation and arthritis.
- the phosphono compounds (XII) can be administered orally, rectally, buccally, parenterally (intravenous, subcataneous, intramuscularly), topically or by aerosol by suitable pharmaceutical compositions.
- the phosphono compounds (XII) are preferrably administered orally at from about 2 to about 100 mg, administered from about 1 to about 6 times a day.
- the preferred dose is from about 0.01 to about 10 ⁇ g/kg/min when administered by intravenous infusion and when given intravenously from about 0.5 to about 10 mg.
- the preferred daily dose is about 0.03 to about 85 mg/kg of body weight.
- the phosphono compounds (XII) of the present invention can also be used in combination with antiarthritic and antiinflammatory agensts such as phenylbutazone, indomethacin, gold sodium thiomulate, dexamethasone, penicillamine, sodoxicam, ibuprofen and naproxea
- the exact dosage and frequency of administration depends on the particular phosphono compounds (XII) used, the particular condition being treated, the severity of the condition being treated, the age, weight, general physical condition of the particular patient, other medication the individual may be taking as is well known to those skilled in the art and can be more accurately determined by measuring the blood level or concentration of the phosphono compounds (XII) in the patient's blood and/or the patient's response to the particular condition being treated.
- variable substituents contained in parentheses are bonded to the atom immediately to the left of the variable substituent enclosed in parenthesis.
- each of the consecutive variable substituents is bonded to the immediately preceding atom to the left which is not enclosed in parentheses.
- R i and R j are bonded to the preceding carbon atom.
- C i is the integer corresponding to the carbon atom number.
- C 6 represents the 6 position or carbon atom number in the steroid nucleus as traditionally designated by those skilled in the art of steroid chemistry.
- R 6 represents a variable substituent (either monovalent or bivalent) at the C 6 position.
- Chemical formulas of cyclic (ring) compounds or molecular fragments can be represented in a linear fashion.
- the cyclic molecular fragment, 4-(ethyl)-1-piperazinyl can be represented by -N*-(CH 2 ) 2 -N(C 2 H 5 )-CH 2 -C*H 2 .
- a rigid cyclic (ring) structure for any compounds herein defines an orientation with respect to the plane of the ring for substituents attached to each carbon atom of the rigid cyclic compound.
- the two substituents may be in either an axial or equatorial position relative to the ring and may change between axial/equatorial.
- the position of the two substituents relative to the ring and each other remains fixed. While either substituent at times may lie in the plane of the ring (equatorial) rather than above or below the plane (axial), one substituent is always above the other.
- a substituent (X 1 ) which is "below” another substituent (X 2 ) will be identified as being in the alpha ( ⁇ ) configuration and is identified by a broken, dashed or dotted line attachment to the carbon atom, i.e., by the symbol " " or "!.
- the corresponding substituent attached “above” (X 2 ) the other (X 1 ) is identified as being in the beta (ß) configuration and is indicated by an unbroken line attachment to the carbon atom.
- variable substituent when a variable substituent is bivalent, the valences may be taken together or separately or both in the definition of the variable.
- R i is defined to consist of two monovalent variable substituents
- the convention used to define the bivalent variable is of the form " ⁇ -R i-j :ß-R i-k " or some variant thereof.
- both ⁇ -R i-j and ß-R i-k are attached to the carbon atom to give -C( ⁇ -R i- j )(ß-R i-k )-.
- the two monovalent variable substituents are ⁇ -R 6-1 :ß-R 6-2 , .... ⁇ -R 6-9 :ß-R 6-10 , etc, giving -C( ⁇ -R 6-1 )(ß-R 6 . 2 )-, .... -C( ⁇ -R 6-9 )(ß-R 6 . 10 )-, etc.
- bivalent variable may be defined as two separate monovalent variable substituents
- two separate monovalent variable substituents may be defined to be taken together to form a bivalent variable.
- R i and R j may be defined to be taken together to form (1) a second bond between C 1 and C 2 or (2) a bivalent group such as oxa (-O-) and the formula thereby describes an epoxide.
- the carbon atom content of variable substituents is indicated in one of two ways.
- the first method uses a prefix to the entire name of the variable such as "C 1 -C 4 ", where both "1" and "4" are integers representing the minimum and maximum number of carbon atoms in the variable.
- the prefix is separated from the variable by a space.
- C 1 -C 4 alkyl represents alkyl of 1 through 4 carbon atoms, (including isomeric forms thereof unless an express indication to the contrary is given).
- the prefix indicates the entire carbon atom content of the variable being defined.
- alkoxycarbonyl describes a group CH 3 -(CH 2 ) n -O-CO- where n is zero, one or two.
- the carbon atom content of only each portion of the definition is indicated separately by enclosing the "C i -C j " designation in parentheses and placing it immediately (no intervening space) before the portion of the definition being defined.
- C 1 -C 3 )alkoxycarbonyl has the same meaning as C 2 -C 4 alkoxycarbonyl because the " C 1 -C 3 " refers only to the carbon atom content of the alkoxy group.
- C 2 -C 6 alkoxyalkyl and (C 1 -C 3 )alkoxy(C 1 -C 3 )alkyl define alkoxyalkyl groups containing from 2 to 6 carbon atoms
- the two definitions differ since the former definition allows either the alkoxy or alkyl portion alone to contain 4 or 5 carbon atoms while the latter definition limits either of these groups to 3 carbon atoms.
- TLC refers to thin-layer chromatography
- THF refers to tetrahydrofuran
- Saline refers to an aqueous saturated sodium chloride solution.
- IR refers to infrared spectroscopy.
- FTIR refers to Fourier transform infrared spectroscopy.
- ATR refers to attenuated total reflectance
- CMR refers to C-13 magnetic resonance spectroscopy, chemical shifts are reported in ppm ( ⁇ ) downf ⁇ eld from TMS.
- NMR nuclear (proton) magnetic resonance spectroscopy
- TMS refers to trimethylsilyl
- - ⁇ refers to phenyl (C 6 H 5 ).
- [ ⁇ ] D 25 refers to the angle of rotation of plant polarized light (specific optical rotation) at 25° with the sodium D line (5893A).
- MS refers to mass spectrometry expressed as m/e or mass/charge unit.
- [M + H] + refers to the positive ion of a parent plus a hydrogen atom.
- El refers to electron impact Cl refers to chemical ionization.
- FAB refers to fast atom bombardment.
- Ether refers to diethyl ether.
- Pharmaceutically acceptable refers to those properties and/or substances which are acceptable to the patient from a pharmacological/toxicological point of view and to the manufacturing pharmaceutical chemist from a physical/chemical point of view regarding composition, formulation, stability, patient acceptance and bioavailability.
- the ratios of solvents used are volume/volume (v/v).
- DL-3-fluorophenylalanine methyl ester (II-NH 2 , Example 1, 17.7 mmole) is dissolved in methylene chloride (40 ml) and pyridine (30 mmole) and diethylchlorophosphate (14.47 mmole) are added. After stirring at 20-25° under nitrogen for 19.5 hrs the solution is diluted with chloroform (60 ml) and washed with 10% potassium bisulfate (60 ml). The aqueous phase is washed again with chloroform (45 ml) and then the organic extracts are washed, in sequence, with dilute sodium bicarbonate (45 ml). The extracts are dried over sodium sulfate and concentrated.
- N-(diethylphosphoryl)-phenylalanine ethyl ester (III-NH 2 , Example 2, 1 mmol) and 8 mmol of methyl iodide in anhydrous tetrahydrofuran (3 ml) are combined.
- the mixture is cooled in an ice bath and treated with 3 mmol of sodium hydride as a 60% dispersion in mineral oil.
- the reaction is stirred at 0° for two hours at which time, the reaction is quenched with saturated aqueous ammonium chloride.
- the solution is concentrated and extracted with chloroform. The extracts are washed with saline and aqueous sodium iodide.
- the mixture is concentrated under reduced pressure with heat diluted with chloroform (15 ml) which is washed with water (60 ml) and 6N hydrochloric acid (20 ml).
- the aqueous phases are backwashed in sequence with chloroform (40 ml).
- the two organic extracts are finally washed, in sequence, with water (40 ml) dried over sodium sulfate and concentrated.
- the concentrate is diluted with ethyl acetate (40 ml) to give the title compound, mp 153-155°; NMR (CDCI 3 ) 8.24, 7.95, 7.45, 7.02, 6.79, 4.24, 3.56, 2.89, and 1.26 ⁇ ; CMR (CDCI 3 ) 167.2, 163.0, 159.9, 159.7, 158.9, 135.9, 130.3, 128.5, 126.7, 106.6, 64.8, 62.9, 29.9, 29.7, 29.6, 13.7 ⁇ ; IR (mull) 3361, 1740, 1722, 1677, 1662, 1485, 1467, 1454, 1377, 1296, 1291, 1251, 781, 704; MS 415 (M + ), 370, 342, 314,
- a mixture of formamidomalonoethylpyrimidinone (VII, EXAMPLE 8, 9.71 mmoles) in 6 N hydrochloric acid is heated at 100° for 24 hrs. The mixture is cooled and concentrated under reduced pressure. The residue is mixed with toluene (2 x 500 ml) and concentrated twice to azeotrope away remaining water. The solid is then taken up in absolute ethanol (400 ml) and ethanol (40 ml) which had been saturated with hydrogen chloride gas at 0° is added. After four days at reflux, the mixture is cooled and then concentrated to about 200 ml. The mixture is diluted with saturated aqueous sodium carbonate (500 ml) and chloroform (400 ml).
- 1,2-phenylenediamine (XIII, 1.08 g, 10 mmol) and pyridine (3.88 ml, 48 mmol) are combined in methylene chloride (20 ml).
- methylene chloride (20 ml) The mixture is cooled in an ice bath and diethyl chlorophosphate (XIV, 3.03 ml, 21 mmol) is added dropwize.
- the reaction is stirred for 24 hr, slowly coming to 20-25°.
- the reaction is then washed with 1N aqueous hydrochloric acid, water, then saturated aqueous sodium bicarbonate.
- ⁇ -trans-1,2-cyclohexanediamine (XIII, 1.01 g, 8.84 mmol) and DBU (2.78 ml, 18.57 mmol) are combined in methylene chloride (20 ml).
- the mixture is cooled in an ice bath and was treated with diethyl chlorophosphate (XIV, 2.68 ml), a vigorous exothe ⁇ n is observed.
- the resulting solution is stirred at 0°, slowly coming to 20-25° overnight.
- the reaction is washed with IN hydrochloric acid and then saline.
- reaction is stirred at -78° for 1.5 hr and then at 0° for 1 hr. After quenching the reaction with saturated ammonium chloride, the reaction is concentrated under reduced pressure and the residue extracted with chloroform. The extracts are washed with saline and dried over sodium sulfate. Removal of the solvent under reduced pressure affords an oil which is taken up in chloroform and chromatographed on 45g of silica, slurry-packed in chloroform. The column is eluted with methanol/chloroform (1/99, 1 1) followed by
- phosphono compounds (XII) will be used to designate and is meant to include the "benzyl-type" N-phosphono compounds of formula (III)
- N-PO(OR 4 )(OR 5 ) refers to the molecular fragment
- R 1 -CH[NR 2 -PO(OR 4 )(OR 5 )]COOR 3 (III) refers to the following structural formula
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP6504431A JPH07509241A (en) | 1992-07-16 | 1993-05-27 | Phosphono derivatives as anti-inflammatory and anti-arthritic drugs |
EP93914090A EP0650360A1 (en) | 1992-07-16 | 1993-05-27 | Phosphono derivatives as antiinflammatory and antiarthritic agents |
AU43878/93A AU4387893A (en) | 1992-07-16 | 1993-05-27 | Phosphono derivatives as antiinflammatory and antiarthritic agents |
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US91484092A | 1992-07-16 | 1992-07-16 | |
US07/914,840 | 1992-07-16 | ||
US94711492A | 1992-09-17 | 1992-09-17 | |
US07/947,114 | 1992-09-17 | ||
US96598092A | 1992-10-22 | 1992-10-22 | |
US07/965,980 | 1992-10-22 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO1994002152A2 true WO1994002152A2 (en) | 1994-02-03 |
WO1994002152A3 WO1994002152A3 (en) | 1994-04-14 |
Family
ID=27420632
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1993/004891 WO1994002152A2 (en) | 1992-07-16 | 1993-05-27 | Phosphono derivatives as antiinflammatory and antiarthritic agents |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP0650360A1 (en) |
JP (1) | JPH07509241A (en) |
AU (1) | AU4387893A (en) |
MX (1) | MX9304239A (en) |
WO (1) | WO1994002152A2 (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0521622B1 (en) * | 1991-07-03 | 1997-08-13 | PHARMACIA & UPJOHN COMPANY | Pyrazolopyrimidine and pyrimidinyl bisphosphonic esters as anti-inflammatories |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0009183A1 (en) * | 1978-09-07 | 1980-04-02 | Merck & Co. Inc. | Phosphoryl aminoacid derivatives and composition for treating hypertension containing the same |
WO1988006158A1 (en) * | 1987-02-20 | 1988-08-25 | Georges Sturtz | Gem-diphosphonic analogues of amethopterin and of deaza-n-10 amethopterin |
WO1990012017A1 (en) * | 1989-04-03 | 1990-10-18 | The Upjohn Company | Geminal bisphosphonic acids and derivatives as anti-arthritic agents |
WO1992003451A1 (en) * | 1990-08-21 | 1992-03-05 | The Upjohn Company | Bisphosphonic acid derivatives as anti-arthritic agents |
EP0473936A1 (en) * | 1990-09-04 | 1992-03-11 | American Cyanamid Company | Renin Inhibitors |
-
1993
- 1993-05-27 WO PCT/US1993/004891 patent/WO1994002152A2/en not_active Application Discontinuation
- 1993-05-27 EP EP93914090A patent/EP0650360A1/en not_active Withdrawn
- 1993-05-27 AU AU43878/93A patent/AU4387893A/en not_active Abandoned
- 1993-05-27 JP JP6504431A patent/JPH07509241A/en active Pending
- 1993-07-14 MX MX9304239A patent/MX9304239A/en unknown
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0009183A1 (en) * | 1978-09-07 | 1980-04-02 | Merck & Co. Inc. | Phosphoryl aminoacid derivatives and composition for treating hypertension containing the same |
WO1988006158A1 (en) * | 1987-02-20 | 1988-08-25 | Georges Sturtz | Gem-diphosphonic analogues of amethopterin and of deaza-n-10 amethopterin |
WO1990012017A1 (en) * | 1989-04-03 | 1990-10-18 | The Upjohn Company | Geminal bisphosphonic acids and derivatives as anti-arthritic agents |
WO1992003451A1 (en) * | 1990-08-21 | 1992-03-05 | The Upjohn Company | Bisphosphonic acid derivatives as anti-arthritic agents |
EP0473936A1 (en) * | 1990-09-04 | 1992-03-11 | American Cyanamid Company | Renin Inhibitors |
Non-Patent Citations (3)
Title |
---|
JILIN DAXUE ZIRAN KEXUE XUEBAO no. 3, 1989, pages 85 - 90 ZONGMU, W. ET AL 'STUDIES ON DIETHYL PHOSPHITE AS A PROTECTING AGENT OF THE ALPHA AMINO GROUP OF ALPHA AMINO ACIDS' * |
SYNTHESIS no. 4, 1984, pages 332 - 333 ZWIERZAK, A. 'N-ALKYLATION OF DIETHYL N-ALKYLPHOSPHORAMIDATES IN AN ANHYDROUS MEDIUM' * |
Week 7322, Derwent Publications Ltd., London, GB; AN 73-31113U * |
Also Published As
Publication number | Publication date |
---|---|
AU4387893A (en) | 1994-02-14 |
WO1994002152A3 (en) | 1994-04-14 |
EP0650360A1 (en) | 1995-05-03 |
JPH07509241A (en) | 1995-10-12 |
MX9304239A (en) | 1994-03-31 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA1310331C (en) | SUBSTITUTED .alpha.-AMINO ACIDS, THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM | |
Bennani et al. | The asymmetric synthesis of α-substituted α-methyl and α-phenyl phosphonic acids: Design, carbanion geometry, reactivity and preparative aspects of chiral alkyl bicyclic phosphonamides | |
JPH08508245A (en) | Phosphonic acid derivative | |
WO2000018775A1 (en) | Antiviral purine derivatives | |
Bortolini et al. | Efficient synthesis of isoxazolidine-substituted bisphosphonates by 1, 3-dipolar cycloaddition reactions | |
US5273989A (en) | 3,5-disubstituted 2-isoxazolines and isoxazoles, agents containing them and their use | |
JPH0480917B2 (en) | ||
US5294608A (en) | Guanidinoalkyl-1,1-bisphosphonic acid derivatives, process for their preparation and their use | |
HU204058B (en) | Process for producing phosphonic acid derivatives and pharmaceutical compositions comprising same | |
Gajda et al. | A new access to substituted tetraethyl N-Boc 2-aminoethylidene-1, 1-bisphosphonates and phosphonyl-substituted aza-Morita–Baylis–Hillman-type adducts | |
CA2095279A1 (en) | Aryl and heteroaryl (phosphinylmethyl) phosphonate squalene synthetase inhibitors and method | |
AU657554B2 (en) | Dialkyl (dialkoxyphosphinyl)methyl phosphates as anti-inflammatory agents | |
Schwender et al. | 1-Naphthylmethylphosphonic acid derivatives as osteoclastic acid phosphatase inhibitors | |
Li et al. | Asymmetric Pudovik Reaction of Chiral Fluoroalkyl α, β‐Unsaturated Ketimines and Diphenyl Phosphite | |
JPH08501794A (en) | Arylmethylphosphonates and phosphonic acids useful as anti-inflammatory agents | |
WO1994002152A2 (en) | Phosphono derivatives as antiinflammatory and antiarthritic agents | |
Jankowski et al. | Stereochemistry of 1-hydroxyphosphonate–phosphate rearrangement. Retention of configuration at the phosphorus atom | |
Teixeira et al. | Synthesis of novel pyrazolo [3, 4-b] quinolinebisphosphonic acids and an unexpected intramolecular cyclization and phosphonylation reaction | |
Kondratyuk et al. | Reaction of diethyl 1-acylamino-2, 2-dichloroethenylphosphonates with amino acids esters | |
CA2511753C (en) | Phospholipid derivatives | |
US5321153A (en) | Process for making chiral alpha-amino phosphonates selected novel chiral alpha-amino phosphonates | |
TWI499594B (en) | Synthesis of phosphoric esters | |
US5583123A (en) | Certain tetrazole derivatives | |
Prishchenko et al. | Synthesis of mono-and diphosphorus-substituted proline derivatives containing P–C–N fragments | |
US6284909B1 (en) | Preparations of thiophosphites and thiophosphonates |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A2 Designated state(s): AT AU BB BG BR BY CA CH CZ DE DK ES FI GB HU JP KP KR KZ LK LU MG MN MW NL NO NZ PL PT RO RU SD SE SK UA US VN |
|
AL | Designated countries for regional patents |
Kind code of ref document: A2 Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG |
|
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
AK | Designated states |
Kind code of ref document: A3 Designated state(s): AT AU BB BG BR BY CA CH CZ DE DK ES FI GB HU JP KP KR KZ LK LU MG MN MW NL NO NZ PL PT RO RU SD SE SK UA US VN |
|
AL | Designated countries for regional patents |
Kind code of ref document: A3 Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
ENP | Entry into the national phase in: |
Ref country code: US Ref document number: 1995 372182 Date of ref document: 19950113 Kind code of ref document: A Format of ref document f/p: F |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1993914090 Country of ref document: EP |
|
WWP | Wipo information: published in national office |
Ref document number: 1993914090 Country of ref document: EP |
|
REG | Reference to national code |
Ref country code: DE Ref legal event code: 8642 |
|
NENP | Non-entry into the national phase in: |
Ref country code: CA |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: 1993914090 Country of ref document: EP |